WO1999043654A2 - Inhibitors of phospholipase enzymes - Google Patents

Inhibitors of phospholipase enzymes Download PDF

Info

Publication number
WO1999043654A2
WO1999043654A2 PCT/US1999/003898 US9903898W WO9943654A2 WO 1999043654 A2 WO1999043654 A2 WO 1999043654A2 US 9903898 W US9903898 W US 9903898W WO 9943654 A2 WO9943654 A2 WO 9943654A2
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cooh
indol
phenyl
alkoxy
Prior art date
Application number
PCT/US1999/003898
Other languages
French (fr)
Other versions
WO1999043654A3 (en
Inventor
Jasbir S. Seehra
John C. Mckew
Frank Lovering
Jean E. Bemis
Yibin Xiang
Lihren Chen
John L. Knopf
Original Assignee
Genetics Institute, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to JP2000533412A priority Critical patent/JP2002504541A/en
Priority to CA002322162A priority patent/CA2322162A1/en
Priority to EA200000871A priority patent/EA003876B1/en
Priority to NZ506329A priority patent/NZ506329A/en
Priority to EP99908378A priority patent/EP1062205A2/en
Priority to SK1275-2000A priority patent/SK12752000A3/en
Priority to EEP200000488A priority patent/EE200000488A/en
Priority to BR9908275-6A priority patent/BR9908275A/en
Application filed by Genetics Institute, Inc. filed Critical Genetics Institute, Inc.
Priority to KR1020007009457A priority patent/KR20010041344A/en
Priority to AU27825/99A priority patent/AU765427B2/en
Priority to IL13771999A priority patent/IL137719A0/en
Priority to HU0101146A priority patent/HUP0101146A3/en
Publication of WO1999043654A2 publication Critical patent/WO1999043654A2/en
Publication of WO1999043654A3 publication Critical patent/WO1999043654A3/en
Priority to NO20004219A priority patent/NO20004219L/en
Priority to HR20000551A priority patent/HRP20000551A2/en
Priority to BG104779A priority patent/BG104779A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/12—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems

Definitions

  • the present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A 2 enzymes.
  • Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way.
  • Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue.
  • Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science. 237:1171-76 (1987)].
  • Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites.
  • Prostaglandins also potentiate the pain response induced by stimuli.
  • Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J.. 259:315-324 (1989)] from arachidonic acid in response to stimuli.
  • Prostaglandins are produced from arachidonic acid by the action of COX- 1 and COX- 2 enzymes.
  • Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
  • PLA j phospholipase A, enzymes
  • the reaction catalyzed by PLA j is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes.
  • PAF platelet activating factor
  • anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them.
  • ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-l/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways.
  • zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
  • a family of PLA enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA 2 s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA,s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res.. 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
  • the primary structure of the first human non-pancreatic PLA 2 has been determined.
  • This non-pancreatic PLA 2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme.
  • This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem.. 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem.. 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophvs. Res. Comm.. 163:42-48 (1989)].
  • PLA 2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Nail. Acad. Sci. U.S.A.. 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA 2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
  • a murine PLA 2 has been identified in the murine macrophage cell line, designated
  • cPLA j A cytosolic phospholipase A 2 (hereinafter "cPLA j ”) has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth.
  • the enzyme of these patents is an intracellular PLA 2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
  • cPLA 2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel & Gelb, 1993); activation of cPLA 2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA 2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995).
  • mice made deficient in cPLA 2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF.
  • the cPLA 2 deficient mice have also been informative of the role of cPLA 2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997).
  • cPLA 2 is essential for prostaglandin, leukotriene, and PAF production.
  • a novel arachidonic acid-selective cytosolic PLA 2 contains a Ca 2+ -dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051. Hanel, A. M., and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A 2 enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958.
  • R, and R r are independently selected from H, halogen, -CF,, -OH, -C,-C 10 alkyl, preferably -C,-C 6 alkyl, -S-C,-C 10 alkyl, preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy, preferably
  • a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, - CF 3 or -OH; or
  • Z is O or S
  • R 6 is selected from the relevant members of the group H, -CF 3 , C,-C I0 alkyl, preferably C,-C 6 alkyl, C r C 10 alkoxy, preferably C,-C 6 alkoxy, phenyl, -O-phenyl, -S- phenyl, benzyl, -O-benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, - CF 3 , or -OH;
  • R 7 is selected from the relevant members of the group -OH, -CF 3 , C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C I0 alkoxy, preferably C,-C 6 alkoxy, -NH 2 , -(CH 2 ) n -NH 2 , -NH- (C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C,-C 6 alkyl), -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , phenyl, -O-phenyl, benzyl, or -O-benzyl; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C I0 alkyl, preferably C,-C 6 alkyl, C,-C ]0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • n is an integer from 0 to 3;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) ⁇ -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, - (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -O-(C,-C 6 alkyl)-(OH) n , -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 , -N-C(O)-N-(C,-C 6 alkyl)-(OH) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M 1 , R 8 , R 9 , R 10 , and/or R n shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) ⁇ -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -, C(O)C(O)X; where X is O or N
  • M is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C I0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C C 6 alkoxy, -CHO, -NO,, -NH,, -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH,) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 10 cycloalkyl, or the groups of:
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2,
  • Y is C 3 -C 6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, C,-C ]0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C,,, alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH, , -N(C,- C 6 ) 2 , -NH(C,-C 6 ), -N-C(O)-(C,-C 6 ), -NO 2 , or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S, such as, for example, morpholino; or a pharmaceutically acceptable salt thereof.
  • One group of compounds within this invention are those in which the indole or indoline 2-position (R 4 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
  • R 3 is -L'-M 1 , wherein L ! is as defined above, more preferably wherein L 1 is a chemical bond, and M 1 is the moiety:
  • R g is as defined in the broad genus above.
  • Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R,, R r , R 3 , and R 5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R ] is in the indole or indoline 6 position.
  • R is in the indole or indoline 5-position and is benzyloxy
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • R is selected from H, halogen, -CF 3 , -OH, -C,-C I0 alkyl, preferably -C,-C 6 alkyl, -S-
  • C,-C 10 alkyl preferably -S-C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CN, -NO 2 , -NH 2 , phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C ⁇ alkoxy, -NO 2 , -NH 2 , -CN, -CF 3 , or - OH;
  • R 7 is selected from -OH, -CF 3 , C r C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,- C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CF 3 , -OH, -C,-C ]0 alkyl, preferably -C,-C 6 alkyl, C,- C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) ⁇ -C(O)-(CH 2 ) literal-, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(Z)-NH-SO 2
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C r C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C ]0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH,) n -, -S-, -O-,
  • M 2 is selected from the group of C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -NO 2 , -NH 2 , -CN, or -CF 3 ; or
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C, 0 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH,, -CN, - CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 10 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 10 cycloalkyl, or the groups of:
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C r C 6 alkyl, C r C 6 alkoxy, -CN, -NH 2 , - NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH, or -NO,; or a pharmaceutically acceptable salt thereof.
  • One group of compounds within this invention are those in which the indole or indoline 2-position (R 4 ) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
  • R is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino
  • R ⁇ and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • a further preferred group of this invention consists of R, and R,at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C,-C 6 alkoxy, cyano, sulfonyl and halo
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • Another group of this invention comprises compounds in which R 2 and R 4 are hydrogen and the groups at R,, R 3 , and R 5 are as defined above.
  • R is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position.
  • R is in the indole or indoline 5-position and is benzyloxy
  • R 2 and R 4 are hydrogen
  • R 3 and R 5 are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , CN, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl. benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH,, -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C, 0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH,, -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH,) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 5 )-, -C(O)-C(Z)-N(R 6 )-(CH,) n -, -C(Z)-NH-SO,-, or -C(Z)-NH-SO,-(CH 2 )
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH,) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R g is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C r C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M ⁇ R 8 , g , R I0 , and/or R u shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C r C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH,) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) ⁇ -;
  • M is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -O-(CH 2 ) n -C 3 -C 5 cycloalkyl, or the groups of: a) -(CH 2 ) n -phenyl-O-phenyl, -(CH 2 ) n -phenyl-CH 2 -phenyl, -(CH,) n -O-phenyl-
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, -(CH 2 ) n -CF 3 or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C r C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • a preferred group among the compounds above are those in which the R, substitution is at the indole or indoline ring's 5-position and the other substituents are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO,, -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO,-C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • Rg is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R, 0 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R ⁇ is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • the complete moiety at the indole or indoline 3-position created by any combination of R 3 , L 1 , M 1 , R g , Rg, R 10 , and/or R ⁇ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C j -C ⁇ alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or ⁇ (CH 2 ) n -A, -(CH 2 ) n -S-A, or -(CH 2 ) n -O-A wherein A is selected from :
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3
  • R ]2 is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3' or a pharmaceutically acceptable salt thereof.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C r C 6 alkyl), -N-(C r C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C, 0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • L is a bridging or linking moiety selected from a chemical bond -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(Z)-NH-SO 2 -, or -C(Z)-
  • M is the moiety
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • Rg is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R ⁇ is selected from H, C,-C 6 lower alkyl, C,-C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n -
  • R 3 shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 3 -M 3 :
  • L 3 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 3 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicychc ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C ⁇ alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C r C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl,
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , - NO 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -CF 3 or -(CH 2 ) n -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • Another preferred group of this invention are those of the formulae:
  • R j is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO,, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C r C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C ]0 alkyl, preferably C,- C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C r C 6 alkyl, or -SO 2 -C r C 6 alkyl;
  • R 8 is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH;
  • R 9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ;
  • R ]0 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ) n -COOH,
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C 10 cycloalkyl, -C r C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -, or -(CH 2 ) n -S-(CH 2 ) n -;
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C ⁇ C,,, alkoxy, preferably C,-C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or ⁇ (CH 2 ) n -A, -(CH 2 ) n -S-A, or -(CH 2 ) n -O-A wherein A is selected from:
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF 3 ;
  • R ]2 is H, C r C 6 lower alkyl, C,-C 6 lower alkoxy, or -CF. 3'
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C,-C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C ⁇ C g alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , -CF 3 , or -OH;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C I0 alkyl, preferably C,-
  • L 1 is a bridging or linking moiety selected from a chemical bond, -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) n -,-(CH 2 ) n -S-(CH 2 ) n -, -C(Z)-N(R 6 )-, -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-(CH 2 ) n -,
  • M 1 is selected from the group of -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, tetrazole,
  • R g in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 9 is selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH,
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) ⁇ -COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C r C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R u is selected from H, C,-C 6 lower alkyl, C r C 6 cycloalkyl, -CF 3 , -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH,
  • R 3 , L 1 , M 1 , R 8 , R g , R 10 , and/or R ⁇ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, C 3 -C ]0 cycloalkyl, -C,-C 6 alkyl-C 3 -C 10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L 2 -M 2 :
  • L 2 indicates a linking or bridging group of the formulae -(CH 2 ) n -, -S-, -O-, -C(O)-, -(CH 2 ) n -C(O)-, -(CH 2 ) n -C(O)-(CH 2 ) n -, -(CH 2 ) n -O-(CH 2 ) ⁇ -, or -(CH 2 ) n -S-(CH 2 ) n -, - C(O)C(O)X; where X is O or N,
  • M 2 is selected from:
  • a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C ]0 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C r C 6 alkoxy, -CHO, -NO 2 , -NH 2 , -CN, -CF 3 or -OH; R 5 is selected from -(CH 2 ) n -S-(CH 2 ) n -C 3 -C 5 cycloalkyl, -(CH 2 ) n -O-(CH 2 )
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2
  • Y is C 3 -C 5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , - NH 2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
  • n is an integer from 0 to 3 , preferably 1 to 3, more preferably 1 to 2
  • Y is napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C r C 6 alkoxy,
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -CF 3 or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • R is benzyloxy and R 4 , R 3 and R 5 are as defined above.
  • R is selected form H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NO 2 , -NH 2 , phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
  • R 6 is selected from H, C,-C 6 alkyl, C C 6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 6 alkyl, C r C 6 alkoxy, -NH 2 , -NO 2 , -CF 3 , or -OH;
  • R 7 is selected from -CF 3 , C,-C 6 alkyl, C,-C 6 alkoxy, -NH-(C,-C 6 alkyl), -N-(C,-C 6 alkyl) 2 , pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally
  • R 3 is selected from -COOH, -C(O)-COOH, -(CH 2 ) n -C(O)-COOH, -(CH 2 ) ⁇ -COOH,
  • -CH CH-COOH, -(CH 2 ) n C(O)NS(O)(O)(C r C 6 lower alkyl), -(CH 2 ) N C(O)NS(O)(O)(C,-C 6 lower haloalkyl),
  • R 8 and Rg are independently selected from H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n - COOH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from the group of H, halogen, -CF 3 , -OH, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -C r C 6 alkyl, -O-C r C 6 alkyl, -NH(C,-C 6 alkyl), -N(C,-C 6 alkyl) 2 ,
  • R Thallium is selected from H, C,-C 6 lower alkyl, -CF 3 , -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, or
  • n is an integer from 0 to 3;
  • R 4 is selected from H, -CF 3 , C,-C 6 lower alkyl, C,-C 6 lower alkoxy, or halogen;
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower alkoxy, -(CH 2 ) n -C 3 -C 5 cycloalkyl or the groups of:
  • D is H, C,-C 6 lower alkyl, C r C 6 lower alkoxy, or -CF 3 ;
  • B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF 3 , -OH, -C,-C 6 alkyl, C,-C 6 alkoxy, -NH 2 , or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • aryl and substituted aryl are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms.
  • aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties.
  • the aryl and heteroaryl groups of this invention also include the following:
  • a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine.
  • substituted aryl groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, -NO 2 , -NH 2 , -CN, -CF 3 or -OH or combinations thereof, such as -CH 2 CF 3 , -NH(CH 3 ), etc.
  • substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 alkoxy, preferably C,-C 6 alkoxy, -CHO, -COOH or esters thereof, -NO 2 , -NH 2 , -CN, -CF 3 or -OH or combinations thereof, such as -CH 2 CF 3 , -NH(CH 3 ), etc.
  • a preferred subset of these groups include moieties formed from benzene, pyridine, napthylene or quinoline rings.
  • a further prefe ⁇ ed group includes those of furan, pyrrole, thiophene, pyrimidine, and mo ⁇ holine rings.
  • a prefe ⁇ ed group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
  • alkyl, alkenyl and alkinyl groups refe ⁇ ed to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched.
  • Halogens herein are understood to include F, Cl, Br and I.
  • phospholipase enzyme activity means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 116 below).
  • a compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA 2 ) in any available assay (preferably an assay described below in Example 116 or Example 117) for enzyme activity.
  • a compound has (1) an IC 50 value of less than about 25 ⁇ M, preferably less than about 6 ⁇ M, in the LysoPC assay; (2) an IC 50 value of less than about 50 ⁇ M in the vesicle assay; (3) an IC 50 value of less than about 1 ⁇ M in the PMN assay; (4) an IC 50 value of less than about 15 ⁇ M in the Coumarine assay; and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat ca ⁇ ageenan-induced footpad edema test.
  • Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA 2 ) activity and, therefore, are useful in "treating” (i.e., treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
  • inflammatory or inflammation-related responses or conditions e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF
  • the present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention.
  • Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art.
  • pharmaceutically acceptable means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s).
  • the characteristics of the carrier will depend on the route of administration.
  • the pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention.
  • the pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution.
  • Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are inco ⁇ orated herein by reference.
  • the term "therapeutically effective amount” means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • a meaningful patient benefit i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions.
  • the term refers to that ingredient alone.
  • the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
  • a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated.
  • Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors.
  • compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
  • compositions of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection.
  • compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir.
  • the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant.
  • the tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention.
  • a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils
  • the liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol.
  • the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention.
  • compounds of the present invention When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution.
  • a prefe ⁇ ed pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art.
  • the pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
  • the amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further.
  • compositions used to practice the method of the present invention should contain about 0.1 ⁇ g to about 100 mg (preferably about .1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of compound of the present invention per kg body weight.
  • the duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
  • the indole may be alkylated at the c-3 position with the appropriate alkyl bromide and treatment with a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C - 100 °C.
  • a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C - 100 °C.
  • it may be alkylated in a two step procedure by treatment of the indole with n-BuLi in a solvent such as THF or ether followed by ZnC12 and then concentrated and treated with the appropriate alkylating agent in a variety of solvents such as THF, ether, toluene or benzene.
  • the indole nitrogen may then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide.
  • a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide.
  • the ester can be hydrolyzed under basic conditions with sodium hydroxide in water and methanol and THF.
  • it may be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperatures (50 °C - 100 °C).
  • the product acid by be coupled to a sulfonamide by the agency of a variety of coupling reagents such as DCC, EDCI or carbonyl diimidazole in a solvent such as THF, methylene chloride, dichloroethane or DMF in the presence of a base such as triethyl amine and/or N, N-dimethyl pyridine.
  • a solvent such as THF, methylene chloride, dichloroethane or DMF
  • a base such as triethyl amine and/or N, N-dimethyl pyridine.
  • Rl nitro the nitro group can be reduced by exposure to Pt/C in the presence of hydrogen in a solvent such as methanol, ethyl acetate or THF.
  • the resulting amine can be acylated or sulfonylated by exposure to the appropriate agent in the presence of a base such as triethyl amine, sodium bicarbonate or pyridine in a biphasic solvent system such as methylene chloride:water ( 1 : 1 ) or THF: water ( 1 : 1 ) or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine.
  • a base such as triethyl amine, sodium bicarbonate or pyridine
  • a biphasic solvent system such as methylene chloride:water ( 1 : 1 ) or THF: water ( 1 : 1 ) or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine.
  • Rl Br
  • it may be replaced with the copper salt of the desired nucleophile such as thiomethoxide, methoxide or sulphinic acid.
  • the indoleglyoxalyl chloride may be reacted with the desired amino ester in a biphasic system with methylene chloride and saturated sodium bicarbonate or in a monophasic system with a solvent such as methylene chloride, ethyl acetate or THF and a base such as triethylamine, Hunigs base or pyridine.
  • the indole nitrogen may then be alkylated with a variety of alkylatmg reagents in a solvent such as DMF, DMSO or THF and a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide.
  • the ester may then be hydrolyzed with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
  • the 3-carboxyindole is elaborated via reductive amination by allowing the aldehyde to condense with an amino ester in a solvent such as methylene chloride or dichloromethane with or without acetic acid.
  • a solvent such as methylene chloride or dichloromethane with or without acetic acid.
  • the resulting imine is reduced in-situ with a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride.
  • the acid is then prepared by hydrolysis of the resulting ester with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
  • Rl alkyl
  • 5-benzyloxyindole may be treated with a base such at methyl or ethyl grignard and acylated at the 3-position with ethyloxychloride in a suitable solvent such at ether or THF.
  • the indole nitrogen may then be alkylated with a benzylbromide by the action of a base such as sodium hydride or n-butyllithium in a solvent such a THF or DMF.
  • the ester is then hydrolysed under basic conditions with sodium hydroxide or tetrabutylammonium hydroxide in a suitable solvent system such at wate ⁇ MeOHTHF.
  • Coupling of the appropriate aminoester may then be effected by the use of a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF.
  • a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF.
  • the target acid may the be revealed by hydrolysis of the ester under the same conditions discussed above.
  • Indole-3-acetic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh3)4 as a catalyst in a mixed solvent (ethanol- benzene- water) at elevated temperature to give the l-alkyl-5-substituted indole.
  • aldehyde ⁇ Alkylation of the nitrogen atom of I with a suitable base such a sodium hydride or potassium carbonate and an alkyl halide gave the aldehyde ⁇ .
  • the aldehyde could be transformed to the thiazolidinedione in using a base such as piperdine and isolated with an acid such as acetic acid.
  • Deprotonation with a suitable base such as sodium hydride and alkylation on the nitrogen atom of the thiazolidinedione with selected electrophiles such as alkyl or benzyl halides provided compounds such as IV.
  • nitro-indole I was converted to the unsaturated ester via a Homer- Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran. Reduction of the nitro group of II can be accomplished via hydrogenation with palladium on carbon in the presence of hydrogen and acylation of the resulting amine under Schotten-Bowmann conditions to give amides such as HI. Saponification of the ester function gave the acid-indole
  • 5-Chloro-2-methylindole could be reductively alkylated at the 3-position with a suitable aldehyde in the presence of an acid such as trifluoroacetic acid and a reducing agent such as triethylsilane in a suitable solvent such as methylene chloride to give the ester ⁇ .
  • the nitrogen atom could be alkylated by treatment with a suitable base such as sodium hydride and diphenyl bromo methane and the resulting compound in could be saponified to give IV.
  • the starting indole is C3 functionalized by either reaction of DMF/POC13 or by reacting the magnesium salt of the indole with methyl oxalyl chloride.
  • the resulting esters and aldehydes were then Nalkylated by treating the salt of the indole, generated by treating the indole with a strong base, with a variety of alkyl halides.
  • aldehydes when r' is a nitro group, the nitro is reduced to the amine using Pt/C and H2 or copper acetate/sodium borohydride and then acylated usind various acid chlorides, isocyanates, chloroformates or reductively alkylated using aldehydes and sodium triacetoxyborohydride.
  • These aldehydes could then be oxidised to the desired acid which could be coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester.
  • esters generated above could be treated in a similar fashion.
  • the ester could hydrolyzed and then coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product.
  • Method 1(a)
  • the starting amine was treated with various sulfonyl chlorides in the presence of pyridiine and then the excess sulfonylchloride was scavenged by adding a polymer bound amine.
  • the desired products where then hydrolyzed using sodium hydroxide in THF MeOH and the reaction was aidified using IR-120 resin to yield the desired products.
  • the starting indole was bis alkylated by the addition of a strong base such as sodium hydride and then an alkylating agent such as an alkyl or aryl halide followed by the hydrolysis of the resulting ester with sodium hydroxide in THF MeOH.
  • the acid was then coupled with an alkyl or aryl amino ester and then hydrolyzed to yield the desired acid.
  • Step 1 To a solution of 5-nitro indole (21.24 g, 131 mmol) in dioxane (128 mL) in a reaction vessel wrapped in aluminum foil is added silver(I)oxide (30.34 g, 131 mmoL, 1.5 eq) and methyl 4-(bromomethyl)-3-methoxy-benzoate (34 g, 131 mmol) and the mixture is brought to 60 °C and stirred 20 h. The reaction is cooled, filtered through celite, taken up in ethyl acetate (500 mL), washed with brine (2 X 50 mL), dried (MgSO 4 ) and filtered.
  • Step 2 The C3-alkylated indole (1.5 g, 4.4 mmol) was dissolved with 15 mL THF. In a separate flask, NaH (185 g, 4.61 mmol) was suspended with 25 mL THF at 0 °C. The solution of starting material was cannulated into the NaH suspension, giving a deep red solution. This was then allowed to stir at room temperature for 10 minutes.
  • Step 3 The N-alkylated nitroindole (0.95 g) was dissolved with 40 mL anhydrous THF. The system was purged with argon. To the clear, yellow solution, Pt C (0.462 g) was added. The argon was then removed by evacuation and hydrogen was introduced to the system. The reaction was sti ⁇ ed 6.5 h. The hydrogen was evacuated and argon was then purged through the system. The reaction mixture was filtered through celite with THF. The solvent was removed by rotary evaporation to give the crude amine as a dark oil.
  • Step 4 The amine from above (0.7 g) was dissolved in 40 mL CH 2 C1 2 . 4- methylmo ⁇ holine (0.3 mL, 3.0 mmol) and cyclopentyl chloroformate (383 mg, 2.57 mmol) were then added to give a yellow/orange solution. The reaction was allowed to proceed at room temperature for 3 h. The reaction mixture was acidified with 1 N HCl and the mixture was extracted with 50 mL CH 2 C1 2 . The combined organic phases were washed with brine, dried over MgSO 4 , filtered and concentrated to give the crude carbamate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1 , step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 547
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 461
  • Step 1 The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • Step 2 The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • Step 3 The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
  • the intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
  • the intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the intermediate 5-amino indole is prepared as in Example 1, step 3, using the 5-nitro indole intermediate.
  • the intermediate urea is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • the title compound is prepared as in Example 1, step 5, using the urea intermediate.
  • the intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent followed by preparation of the intermediate 5-amino indole as in Example 1, step 3, using the 5-nitro indole.
  • the intermediate sulfonamide is next prepared as in Example 1, step 4, using the appropriate acylating agent.
  • the title compound is then prepared as in Example 1, step 5, using the sulfonamide intermediate.
  • Example 14 4-r(l-benzhydryl-5-fluoro-lH-indoI-3-yl)methyIl-3-methoxybenzoic acid
  • the intermediate 5-fluoro indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent.
  • the title compound is prepared as in Example 1, step 5, using the above intermediate.
  • Example 16 The intermediate 5-methyl indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1) 460 Example 16
  • step 2 To the intermediate from Example 13, step 2 (0.25 g, 0.46 mmol), in DMF (1 mL) is added CuCN (0.05g, 1.2 eq) and the reaction mixture is stirred at 145 °C overnight and then cooled. To the cooled reaction mixture is added FeCl 3 (0.09 g, 1.2 eq). The reaction mixture is stirred 5 min, taken up in ethyl acetate (30 mL), washed with brine (3 X 10 mL), dried (MgSO 4 ), filtered and concentrated. The product was purified by silica chromatography (20% ethyl acetate/hexanes) to afford the intermediate ester (0.2 g, 89%) as a colorless oil. Step 2
  • step 3 (1 g, 1.9 mmol), in a solution of THF (2 mL) and methanol (2 mL) is added sodium hydroxide (0.41 mL, 4.63 M, 1 eq). The mixture is stirred for 20 min and then concentrated. The residual water is chased off by the addition of toluene and it's removal (3 X) a white powder (1 g, 100%).
  • step 4 (0.5 g, 0.87 mmol), in CH 2 C1 2 (4 mL) is added EDCI (0.2 g, 1.0 mmol, 1.2 eq), DMAP (0.011 g, 0.087 mmol, 0.1 eq) and ortho-toluene sulfonamide.
  • the reaction is stirred overnight at room temperature, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO 4 ), filtered and concentrated.
  • Silica chromatography 1% acetic acid, 25% ethyl acetate/hexanes afforded the title compound (0.4 g, 63%) as a colorless solid.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 1, step 5, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 28 cvclopentyl N-(l-benzhvdryl-3-F4-((F(2- chlorophenyl)sulfonyl1aminolcarbonyl)-2-methoxybenzvn-lH-indol-5- yllcarbamate
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 3 step 4, and the appropriate sulfonamide.
  • Example 32 cvclopentyl N-f l-benzhydryl-3-F4-( ⁇ r(2.4-dimethvI-1.3-thiazol-5- yl)sulfonvIlamino)carbonyl)-2-methoxybenzyH-lH-indol-5-vI)carbamate
  • the title compound is prepared as illustrated in Example 19 starting with the product of
  • Example 3 step 4, and the appropriate sulfonamide.
  • Example 33 cvclopentyl N-ll-benzhvdryl-3-F4-( ⁇ F(3.5-dimethyl-4- isoxazolyl)sulfonyllaminolcarbonyl)-2-methoxybenzyll-lH-indoI-5- yllcarbamate
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
  • the intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • the intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
  • the intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate amide is prepared as in Example 1 , step 4, using the appropriate acylating agent.
  • Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
  • Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
  • the intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
  • Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
  • Example 19 The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
  • the intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 3, step 1.
  • the intermediate 3-alkylated 5-bromoindole is prepared as illustrated in Example 13, step 1, using the appropriate alkylating agent.
  • the intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 13, step 2.
  • step 2 the desired intermediate is prepared as illustrated in Example 3, step 2.
  • the intermediate carbamate is prepared from the above intermediate as illustrated in Example 3, step 3.
  • Step 1 To a solution of methyl 3-aminobenzoate (2.4 g, 16.0 mmol) in CH 2 C1 2 (50 mL) and saturated sodium bicarbonate (50 mL) at 5 °C is added 3-indolylglyoxalyl chloride (3.0 g, 14.4 mmol). The reaction is stirred to room temperature over 2 h, taken up in ethyl acetate (200 mL), washed with brine (3 X 50 mL), dried (MgSO 4 ), filtered and concentrated. Crystallization of the crude material afforded the desired intermediate (2.7 g, 58%) as a colorless solid.
  • Step 2 To a solution of the above intermediate (0.3 g, 0.93 mmol) in DMF (1.5 mL) at 0 °C is added potassium bis(trimethylsilyl)amide (0.41 g, 2.06 mmol). After the reaction is stirred at room temperature 30 min 4-benzylbenzyl bromide (0.27 g, 1.03 mmol) is added. The reaction is sti ⁇ ed 3 h, taken up in ethyl acetate (10 mL), washed with brine (3 X 2 mL), dried (MgSO 4 ), filtered and concentrated. Radial silica chromatography (2 mm, 10% - 35% ethyl acetate/hexanes) afforded the desired intermediate (0.19 g, 41%) as a colorless oil.
  • Step 3 The ester obtained in step 2 was treated with sodium hydroxide (2 mL, 5 M) in THF (5 mL) and MeOH (2 mL). The reaction was stirred overnight, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO 4 ), filtered and concentrated. Trituration of the material in ethyl acetate with hexanes afforded the title compound (0.105 g, 60%) as a colorless solid. MS: m/z (M-1) 487
  • Example 61 3- ⁇ F2-(l-benzhydryl-lH-indol-3-yl)-2-oxoacetyl1amino)benzoic acid
  • the intermediate prepared in Example 59, step 1 was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
  • step 3 0.3 g, 0.7 mmol
  • dichloroethane (2 mL) and DMF (1 mL) is added methyl 3-amino benzoate (0.113 g, 0.735 mmol, 1.05 eq) and acetic acid (0.13 mL, 2.1 mmol, 3 eq).
  • Step 2 To the above indole in DMF at 0 °C was added sodium hydride (0.4 g, 60% dispersion in oil). After warming to room temperature, 4-benzylbenzylbromide (2.2 g) was added and the mixture was sti ⁇ ed overnight. As the reaction was not yet done (TLC) additional 4-benzylbenzylbromide (1.0 g) was added and the reaction stined for 2.5 h. The reaction was taken up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) afforded the desired compound (3.1 g 90%).
  • Step 3 The above ester was placed in a solution of NaOH (2N):THF:MeOH (1:2:1) and sti ⁇ ed overnight at room temperature. The reaction was acidified with 6 N HCl and the product extracted with ethyl acetate. The organic layers were dried (MgSO 4 ), filtered and concentrated. The solid was triturated with ethanol and sti ⁇ ed for 1 h. The solid was filtered and dried affording the title compound (1.85 g) as a yellow solid. MS: m/z (M-1) 474
  • Example 69 The indole prepared in Example 69, step 1, was alkylated with the appropriate alkyl bromide and hydrolyzed as described in Example 69, steps 2 and 3.
  • Step 1 To a solution of the acid from Example 69, step 3, (0.810 g) in THF (28 mL) was added CDI. The reaction was stined 30 min and then ethyl 3-aminobenzoate (0.330 g) was added and the reaction was sti ⁇ ed overnight. The reaction mixture was taken up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. The crude material was triturated with ethanol and stined for 1 h, filtered and dried. The desired product (0.76 g, 75%) was isolated as a yellow solid. Step 2 - The above ester was dissolved in NaOH (2N):THF:MeOH (1:2: 1) and sti ⁇ ed
  • Example 69 The alkylated indole from Example 69 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
  • Example 70 The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
  • Example 77 To the acid obtained in Example 71 (0.1 g) in CH 2 C1 2 (10 mL) is added THF ( 5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixmre was stined a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stined overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO 4 ), filtered and concentrated. Chromatography (7% MeOH/CH 2 Cl 2 ) afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z (M-1) 746 Example 77
  • Example 82 The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and phenylboronic acid were used.
  • Example 82 A 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and phenylboronic acid were used.
  • Example 22 The procedure in Example 22 was followed using 3-formyl indole (0.4g, 2.8mmol), sodium hydride (0.102g, 3.0mmol) and the iodide (0.97g, 2.8mmol) in DMF (10ml). Flash chromatography (Hex/EtOAc, 1/1) gave 0.86g (84%) of the desired intermediate.
  • step 1 The intermediate from step 1 (0.8 g, 2.2 mmol) and 2.4-thiazolidinedione (0.25, g, 2.2 mmol) was dissolved in toluene (5 mL). Piperidine (0.064 mL, 0.6 mmol) and acetic acid (0.012 mL) were added and the mixture was heated to reflux for 2h. The reaction was allowed to cool to rt, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine , dried (MgSO4), filtered and concentrated. Flash chromatography (hexane/ ethyl acetate , 3/2) afforded the title compound (0.345 g (33%) as an orange solid.
  • Example 83 3- ⁇ l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl ⁇ propanoic acid The procedure in Example 22 step 1 was followed except 2 eq. of sodium hydride was used and 0.142g (65%) of the title compound was isolated as a white oily solid.
  • Example 84
  • stepl (l.Og, 2.8mmol) in toluene (20ml) was added carbomethoxyethyhdene triphenylphosphorane (0.98g, 2.9mmol). The mixture was heated overnight at reflux and then concentrated. The residue was dissolved in CH 2 C1 2 and silica gel was added. The mixture was concentrated and the resulting solid was purified by flash chromatography (Hex/EtOAc. 3/1). Compound 30 l.Olg (88%) was isolated as a yellow solid. Step 2
  • Stepl The same procedure as Example 84 step 2 was used to prepare the desired intermediate from the nitroindole (Example 114 step 1). Step 2 The procedures in Example 84, step 1 and 3 were used to prepare the title compound from the above intermediate.
  • Example 86A The acid from Example 86A was used to prepare the title compound according to the procedure in example 85.
  • Example 84 step 1 The ester from Example 84 step 1 was saponified according to the procedure in Example 84 step 3 and recrystallization from hot EtOAc afforded 0.155g (90%) of the title compound as a white solid.
  • Example 85 The procedure in Example 85 was used to prepare the title compound from the product of Example 87A.
  • Stepl - The intermediate from Example 3 step 2 (leq) (see scheme #) was weighed in to a flask along with the 4-trilflouromethylbenzene sulfonyl chloride (1.2 eq) and then they were flushed with nitrogen, taken up in dichloroethane (0.15 M) and then pyridine was added (1.2 eq) at which time the reaction was left to stir overnight and then worked up by the addition of the polymer bound amine ( Parlow, J.J, Mischke, D. A., Woodard, S.S.J Org. Chem.
  • Step 2 The crude material from stepl was dissolved THF/MeOH (2.5/1) and then 4N NaOH was added ( 3 eq) and the reaction was stined until complete hydrolysis was observed by TLC. At this point the reaction quenched with enough amberlite ir 120 to make the solution acidic and then the resin was filtered off and rinsed and the desired product was obtained in 94% yield by drying and concentrating the solution. MS: m/z (M-1) 669
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 76% of the title compound after chromatographic purification.
  • Step 2 An analogous proceedure to step 2 for Example 89 above yielded 83% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 54% of the desired product after chromatographic purification. MS: m/z (M-1) 681
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 56% of the title compound after chromatographic purification.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 82% of the desired product.
  • Example 95
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 96% of the desired product.
  • Step 1 Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
  • Step 2 An analogous proceedure to step 2 for Example 89 yielded 89% of the desired product.
  • Example 3 The compound of Example 3 (1.0 eq) was dissolved in THF (0.15M) and then carbonyl diimidizole (1.2 eq) was added and the reaction was stirred under N 2 for three hours at which time ammonium hydroxide was added (3ml g) and the reaction was stined overnight when TIC analysis showed it was complete. To the reaction was added water and ethyl acetate, the layers were separated and the aqueous layer was extracted three times, the combined organic extracts were dried concentrated and chromatographed to yield 64% of the desired primary amide.
  • Example 98 cvclopentyl N-(l-benzhvdryl-3-F2-methoxy-4-(lH-1.2.3.4-tetraazol-5- yl)benzyll-lH-indol-5-yllcarbamate Step 1 - To the compound of Example 97 (1.0 eq) under N 2 was added CH 2 C1 2
  • Step 2 To the nitrile (1.0 eq) isolated in step 1 was add sodium azide (3 eq) and triethyl amine hydrochloride (1.5 eq) and n-methyl-2-prynolidinone (0.05m) and then the reaction was heated to reflux under an inert atmosphere for 2.5 hours when it was poured into ice and water that was then acidified to pH 2 and the product was filtered off and then further purified by preparative chromatography to yield the desired compound in 22% yield. MS: m/z (M-1 ) 597
  • Step 2 The ester from the previous step was dissolved in THF/MeOH (3:1) and then IN NaOH (3.0eq) was added and the reaction was stined for until TLC analysis showed that the reaction was complete. The reaction was then concentrated, diluted with water, acidified to pH 2 with cone HCL, extracted with ethyl acetate 3X, the combined organics were dried over magnesium sulfate concentrated and purified via chromatography to yield the desired acid in 64% yield.
  • Step 1 The acid (see scheme #) was coupled with the appropriate amino ester following the procedure in Example 99, step one, except the reaction was run at room temperature and that the procedure yielded 80% of the desired product isolated by recrystalization.
  • Step 2 The nitro ester from step one (1.0 eq) was weighed into a flask along with 5% Platinum on Carbon (40 wt%) and the vessel was sealed with a septum and evacuated and flushed with argon 3X, then freshly distilled THF is added and the reaction is evacuated 2X and after the second evacuation a balloon of hydrogen inserted into the septum.
  • step 3 The amine (1.0 eq) was dissolved in dichloromethane (0.3M) and then an equivalent amount of saturated sodium bicarbonate was added and finally the acid chloride introduced.
  • the biphasic reaction mixture was vigorously sti ⁇ ed until TLC analysis indicated that the reaction was complete (generally a few hours) and then the reaction was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed to yield the desired amide in 41% yield.
  • Step 4 According to step 2, Example 99, the ester was hydrolyzed to the acid and yielded 71% of the final product. MS: m/z (M-1) 556
  • Step 2 To the acid chloride generated in step 1 was added dichloromethane (0.1M) and then a solution of alanine methyl ester (1.05eq, free base) in dichloromethane (1.0M) and then triethylamine (1.5eq)was added and the resulting mixture was stined overnight and worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired amide.
  • dichloromethane 0.1M
  • a solution of alanine methyl ester (1.05eq, free base)
  • triethylamine 1.5eq
  • Step 3 The ester from step 2 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • Step 1 The acid chloride (1.0 eq) synthesized in step 1, Example 101, was weighed into a flask along with o-tolylsulfonamide (1.5eq), DMAP (0.1 eq) and taken up in dichloromethane
  • Step 1 According to the general procedure in step 1, Example 101, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • Step 1 According to the general procedure in step 1, Example 99, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield.
  • Step 2 The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
  • step 2 To the acid from step 2 (1 eq) (see scheme- 1) was added methyl 3-aminobenzoate (1.05 eq), EDCI (1.37 eq) and DMAP (0.2 eq) followed by anhydrous DMF (0.086M), stined at 25°C, overnight. Workup with ethyl acetate/ IN HCl followed by chromatographic purification afforded the desired product in 80% yield. Step 4
  • Step 1 The 5-Hydroxy-2-Methylindole-3-Carboxylate (1 eq) was combined with benzyl bromide (1.3 eq) and K 2 CO 3 (325 mesh, 1.3 eq) in CH 3 CN (0.1 M). The resulting mixture was heated to reflux for 2 h. An additional amount of benzyl bromide (0.2 eq) and the heating was continued for 2 h. The reaction was worked up by addition of water and extraction with CH 2 C1 2 . The organic extracts were washed with water, dried and concentrated. Flash chromatography provided the desired benzyl ether (63 % yield), as well as the conesponding
  • Step 2 An ice cooled solution of the benzyl ether from step 1 (1 eq) in dry DMF (0.25 M) was treated with NaH (60 % in mineral oil, 1.1 eq). 2,4-Bis trifluoromethyl benzyl bromide (1.1 eq) was added after 1 h and the resulting mixture was sti ⁇ ed at 25°C for 2 h. Solvent was evaporated under vacuo, the residue was dissolved in EtOAc, washed with water, dried and concentrated. The desired product was obtained in 77 % yield after recrystallization from hexane/CHCl j .
  • Step 3 The product from step 2 (1 eq) in THF/MeOH (3/1) was heated to reflux with IN
  • Step 1 The acid prepared in step 3 (1 eq) of example 108 was reacted with EDCI (2 eq) and dimethyl 5-aminophthalate (5 eq) in THF (0.02 M) in the presence of DMAP (2 eq). The reaction was heated to reflux for 48 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 32 % yield.
  • Step 2 The material from step 1 (1 eq) was hydrolyzed by the action of LiOHH 2 O (2.2 eq) in THF/MeOH/water (3/1/1, 0.07 M). After stirring at 25°C overnight, the reaction mixture was quenched with AcOH and solvent was evaporated. EtOAc/water work up and trituration in hexane/CH,Cl 2 afforded the title compound in 82 % yield. MS: m/z (M-1) 669
  • Step 1 An analogous procedure to step 2 example 108 using the main product of step 1 above and the appropriate bromide yielded the desired N-substituted indole in 71 % yield after recrystallization.
  • Step 2 The ester from step 2 above (1 eq) in THF/MeOH (3/1) was heated to reflux with 4N KOH (2 eq). After 5 days solvent was evaporated and the residue partitioned between IN HCl and CHC1 3 . The organic extract was washed, dried and concentrated. The title compound was obtained in 92 % yield after chromatographic purification and crystallization. MS: m/z ( M - 1 ) 420 Example 110
  • Step 1 The acid in Example 109 was converted in the conesponding amide following an analogous procedure to step 1 of Example 108.
  • the product was contaminated with the aniline starting material which could only be partially removed by chromatography.
  • Step 2 Hydrolysis of the crude material following step 2
  • Example 108 provided the title compound after chromatographic purification (4 % yield in Example 109).
  • Step 1 The minor product of step 1 (1 eq) Example 107 was dissolved in THF (0.1 M). KOH (2 eq) and 18-crown-6 (2 eq) were added and the resulting mixture was heated to reflux for 1.5 days. Work up as on step 2 Example 108 above provided the title compound in 32 % yield. MS: m/z (M-1) 370
  • Step 1 The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 °C under nitrogen for 1 h. Workup with NaOH and water followed by concentration afforded crude product (100%).
  • Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 M), and treated with t- butyldimethylsilyl chloride (1.16 eq) and imidazole (1.26 eq) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (93%).
  • Step 3 The silyl ether from step 2 was dissolved in methylene chloride (0.26 M), and treated with BOC anhydride (1.24 eq), triethylamine (1.53 eq) and DMAP (0.21 eq) at 25 °C for 3 d. Workup and chromatographic purification afforded the pure product (99%).
  • Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid/ water/ THF (3:1:1) (0.04 M) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (100%).
  • Steps 5 The alcohol from step 4 was dissolved in methylene chloride (0.2 M), and under nitrogen at -40°C treated with triethylamine (1.33 eq), and mesyl chloride (1.23 eq) for 1 h.
  • naphthalene-2-thiol (1.31 eq)
  • THF (1 M)
  • hthium hexamethyldisilazide 1 eq
  • Step 6 The purified BOC thioether from step 5 was heated under nitrogen at 160- 170°C for 1.25 h, and recrystalhzed from ethyl acetate and hexanes to afford the free indole thioether in 64% yield.
  • Step 7 The indole thioether from step 6 was dissolved in DMF (0.2 M), and treated with sodium hydride (1.1 eq) at 25°C for 45 min. 4-Chlorobenzyl chloride (1.3 eq) and KI (cat.) were added, and the mixture was sti ⁇ ed at 25°C for 3 d. Workup (ethyl acetate/water) and trituration (ethyl acetate/hexanes) afforded the pure product (52%).
  • Step 8 A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to - 70 °C.
  • methyl oxalyl chloride (3 eq) in ether 1.5 M
  • the reaction was sti ⁇ ed at - 40 °C for 2 h, allowed to warm to 25 °C. Quenched with sodium bicarbonate EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone.
  • Step 9 The ester from step 8 was hydrolyzed using the general method in step 2 example 108 to yield the desired alpha keto acid.
  • Step 10 The indole thioether from step 9 was dissolved in dry methylene chloride (0.05 M), and treated with oxalyl chloride (2.05 eq) at 0°C for 1 h. In a separate dry flask were weighed 3-aminobenzoic acid (10 eq) and triethylamine (15 eq) in methylene chloride (0.5 M). The resulting solution was then added dropwise, at 0°C, and the mixture was allowed to warm to 25°C overnight. Workup (methylene chloride/aqueous HCl) and repeated purification by chromatography afforded the pure title compound product.
  • Step 11 The product from step 9 was hydrolyzed using the procedure from step 2 Example 108 to yield the desired compound in 28%. MS: m/z (M-1) 709
  • Step 1 Following step 4 of the above procedure using methyl iodide followed by trituration (ethyl acetate/hexanes) afforded the pure product (72%).
  • Step 2 An analogous procedure to step 5 through step 11 above yielded 58% of the title compound. MS: m/z (M-1) 599
  • Example 114 l-benzhvdryl-5-F(cvclopentylcarbonyl)aminol-lH-indole-3-carboxylic acid Step 1 5-nitroindole was alkylated as in Example 3 stepl with the appropriate bromide to yield the desired N-alkylated product.
  • Step 2 The indole from step 1 (l.Oeq) was dissolved in DMF (0.4M) and treated with phosporous oxychloride (6.9 eq) at room temperature and then the mixture was sti ⁇ ed for 1 day at 80 C at which time the reaction was poured onto ice and triturated with ethyl acetate/hexanes, followed by workup with sodium bicarbonate/chloroform yielded the C3 formylated product.
  • Step 3 The nitro indole from step 2 was reduced according to the procedure in
  • Example 100 step 2 to yield the amino aldehyde.
  • Step 4 The indole from step 3 was acylated according to the procedure from
  • Step 5 The indole from step 4 (1.0 eq), 2 methyl-2butene (45 eq), sodium dihydrogen phosphate (11.6 eq). were dissolved in t-BuOH (0.2M), water (0.2M) and then sodium chlorite (11.6q) was added and the reaction was heated to 65 C for 24 hours. The reaction was diluted with water, extracted 3 times with ethyl acetate, dried and concentrated and then purified by chromatography to yield the title compound.
  • Step 1 Following the procedure of Example 69, 5-niroindole was acylated in the 3-position with ethylmagnesiumbromide and ethyloxalylchloride. Step 2 The above intermediate was elaborated to the final product following steps 2-5 of Example 114 to afford the title compound.
  • Example 116
  • Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of Tables I and ⁇ , assay results are reported as a percent inhibition at the concentration specified.
  • Each compound was suspended in 0.3ml absolute ethanol, 0.1 ml Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0.1ml IN NaOH was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All compounds remained in solution.
  • Compounds were administered i.v. in a volume of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1% Type TV canageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan.
  • Step 1 To l-benzhydryl-6-chloro-lH-indole (1.0 eq) and methyl 2-(4-formy 1-2,6- dimethylphenoxy) acetate (0.6 eq) in CH 2 C1 2 (0.1M) at 0°C was added neat triethysilane (3eq) followed by triflouroacetic acid (3eq). After 10 minutes at 0°C the reaction was warmed to room temperature and stined until the initially formed spot by TLC yields a new spot.

Abstract

This invention concerns compounds and pharmaceutical compositions useful for treating or preventing inflammatory conditions in a mammal, the methods comprising administration of novel pharmaceutically useful compounds of general formulae (I) or (II) or pharmaceutically acceptable salts thereof, wherein R1-R5 are as defined in the specification.

Description

INHIBITORS OF PHOSPHOLIPASE ENZYMES
Background of the Invention
The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A2 enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation, each of which classes contributes to the development of an inflammatory response in a different way. Leukotrienes recruit inflammatory cells such as neutrophils to an inflamed site, promote the extravasation of these cells and stimulate release of superoxide and proteases which damage the tissue. Leukotrienes also play a pathophysiological role in the hypersensitivity experienced by asthmatics [See, e.g. B. Samuelson et al., Science. 237:1171-76 (1987)]. Prostaglandins enhance inflammation by increasing blood flow and therefore infiltration of leukocytes to inflamed sites. Prostaglandins also potentiate the pain response induced by stimuli.
Prostaglandins and leukotrienes are unstable and are not stored in cells, but are instead synthesized [W. L. Smith, Biochem. J.. 259:315-324 (1989)] from arachidonic acid in response to stimuli. Prostaglandins are produced from arachidonic acid by the action of COX- 1 and COX- 2 enzymes. Arachidonic acid is also the substrate for the distinct enzyme pathway leading to the production of leukotrienes.
Arachidonic acid which is fed into these two distinct inflammatory pathways is released from the sn-2 position of membrane phospholipids by phospholipase A, enzymes (hereinafter PLAj). The reaction catalyzed by PLAj is believed to represent the rate-limiting step in the process of lipid mediated biosynthesis and the production of inflammatory prostaglandins and leukotrienes. When the phospholipid substrate of PLAj is of the phosphotidyl choline class with an ether linkage in the sn-1 position, the lysophospholipid produced is the immediate precursor of platelet activating factor (hereafter called PAF), another potent mediator of inflammation [S.I. Wasserman, Hospital Practice, 15:49-58 (1988)].
Most anti-inflammatory therapies have focussed on preventing production of either prostglandins or leukotrienes from these distinct pathways, but not on all of them. For example, ibuprofen, aspirin, and indomethacin are all NSAIDs which inhibit the production of prostaglandins by COX-l/COX-2, but have no effect on the inflammatory production of leukotrienes from arachidonic acid in the other pathways. Conversely, zileuton inhibits only the pathway of conversion of arachidonic acid to leukotriense, without affecting the production of prostaglandins. None of these widely-used anti-inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA2 has been suggested as a useful mechanism for a therapeutic agent, i.e., to interfere with the inflammatory response. [See, e.g., J. Chang et al, Biochem. Pharmacol.. 36:2429-2436 (1987)].
A family of PLA, enzymes characterized by the presence of a secretion signal sequenced and ultimately secreted from the cell have been sequenced and structurally defined. These secreted PLA2s have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLA,s are found in large quantities in mammalian pancreas, bee venom, and various snake venom. [See, e.g., references 13-15 in Chang et al, cited above; and E. A. Dennis, Drug Devel. Res.. 10:205-220 (1987).] However, the pancreatic enzyme is believed to serve a digestive function and, as such, should not be important in the production of the inflammatory mediators whose production must be tightly regulated.
The primary structure of the first human non-pancreatic PLA2 has been determined. This non-pancreatic PLA2 is found in platelets, synovial fluid, and spleen and is also a secreted enzyme. This enzyme is a member of the aforementioned family. [See, J. J. Seilhamer et al, J. Biol. Chem.. 264:5335-5338 (1989); R. M. Kramer et al, J. Biol. Chem.. 264:5768-5775 (1989); and A. Kando et al, Biochem. Biophvs. Res. Comm.. 163:42-48 (1989)]. However, it is doubtful that this enzyme is important in the synthesis of prostaglandins, leukotrienes and PAF, since the non-pancreatic PLA2 is an extracellular protein which would be difficult to regulate, and the next enzymes in the biosynthetic pathways for these compounds are intracellular proteins. Moreover, there is evidence that PLA2 is regulated by protein kinase C and G proteins [R. Burch and J. Axelrod, Proc. Nail. Acad. Sci. U.S.A.. 84:6374-6378 (1989)] which are cytosolic proteins which must act on intracellular proteins. It would be impossible for the non-pancreatic PLA2 to function in the cytosol, since the high reduction potential would reduce the disulfide bonds and inactivate the enzyme.
A murine PLA2 has been identified in the murine macrophage cell line, designated
RAW 264.7. A specific activity of 2 mols/min/mg, resistant to reducing conditions, was reported to be associated with the approximately 60 kD molecule. However, this protein was not purified to homogeneity. [See, C. C. Leslie et al, Biochem. Biophys. Acta.. 963:476-492 (1988)]. The references cited above are incorporated by reference herein for information pertaining to the function of the phospholipase enzymes, particularly PLA^.
A cytosolic phospholipase A2 (hereinafter "cPLAj") has also been identified and cloned. See, U.S. Patent Nos. 5,322,776 and 5,354,677, which are incorporated herein by reference as if fully set forth. The enzyme of these patents is an intracellular PLA2 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
It is now desirable to identify pharmaceutically useful compounds which inhibit the actions of these phospholipase enzymes for use in treating or preventing inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are all desired results. There remains a need in the art for an identification of such anti- inflammatory agents for therapeutic use in a variety of disease states.
Numerous pieces of evidence have supported the central role of cPLA2 in lipid mediator biosynthesis: cPLA2 is the only enzyme which is highly selective for phospholipids containing arachidonic acid in the sn-2 position (Clark et al., 1991, 1995; Hanel & Gelb, 1993); activation of cPLA2 or its increased expression have been linked with increased leukotriene and prostaglandin synthesis (Lin et al., 1992a, 1992b, 1993); and following activation, cPLA2 translocates to the nuclear membrane, where it is co-localized with the cyclooxygenase and lipoxygenase that metabolize arachidonate to prostaglandins and leukotrienes (Schievella et al., 1995; Glover et al., 1995). Although these data are compelling, the most definitive evidence for the central role of cPLA2 in eicosanoid and PAF production came from mice made deficient in cPLA2 through homologous recombination (Uozumi et al., 1997; Bonventre et al., 1997). Peritoneal macrophages derived from these animals failed to make leukotrienes, prostaglandins, or PAF. The cPLA2 deficient mice have also been informative of the role of cPLA2 in disease, since these mice are resistant to bronchial hyperreactivity in an anaphylaxis model used to mimic asthma (Uozumi et al., 1997). Thus, despite the size of the phospholipase A2 superfamily, cPLA2 is essential for prostaglandin, leukotriene, and PAF production.
Clark, J. D., Lin, L.-L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin. A. Y., Milona, N., and Knopf, J. L. (1991). A novel arachidonic acid-selective cytosolic PLA2 contains a Ca2+-dependent translocation domain with homology to PKC and GAP. Cell 65, 1043-1051. Hanel, A. M., and Gelb, M. H. (1993). Processive interfacial catalysis by mammalian 85-kilodalton phospholipase A2 enzymes on product-containing vesicles: application to the determination of substrate preferences. Biochemistry 32, 5949-5958.
Lin, L.-L., Lin, A. Y., and DeWitt, D. L. (1992a) IL-1 _ induces the accumulation of cPLA2 and the release of PGE2 in human fibroblasts. J. Biol. Chem. 267, 23451-23454. Lin, L.-L., Lin, A. Y., and Knopf, J. L. (1992b) Cytosolic phospholipase A2 is coupled to hormonally regulated release of arachidonic acid. Proc. Natl. Acad. Sci. USA 89, 6147-6151. Lin, L.-L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269-278.
Glover, S., de Carvalho, M., Bayburt, T., Jonas, M., Chi, E., Leslie, E., and Gelb, M. (1995) Translocation of the 85-kDa phospholipase A^ from cytosol to the nuclear envelope in rat basophilic leukemia cells stimulated with calcium ionophore or IgE/antigen. J. Biol. Chem. 270, 15359-15367. Schievella, A. R., Regier, M. K., Smith, W. L., and Lin, L.-L. ( 1995). Calcium-mediated translocation of cytosolic phospholipase A2 to the nuclear envelope and endoplasmic reticulum. J. Biol. Chem. 270, 30749-30754.
Uozumi, N., Kume, K., Nagase, T., Nakatani, N., Ishii, S., Tashiro, F., Komagata, Y., Maki, K., Ikuta, K., Ouchi, Y., Miyazaki, J-i., & Shimizu, T. (1997). Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390, 618-622. Bonventre, J. V., Huang, Z., Reza Taheri, M., O'Leary, E., Li, E., Moskowitz, M. A., and Sapirstein, A. (1997) Reduced fertility and postischaemic brain injury in mice deficient in cytosolic phospholipase A2. Nature 390, 622-625.
Summary of the Invention
Compounds of this invention have the following formulae:
Figure imgf000006_0001
wherein:
R, and Rr are independently selected from H, halogen, -CF,, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, -S-C,-C10 alkyl, preferably -S-C,-C6 alkyl, C,-C10 alkoxy, preferably
C,-C6 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S- benzyl; or a ring moiety of the groups a), b) or c), below, directly bonded to the indole ring or bonded to the indole ring by a -S-, -O- or -(CH2)n- bridge;
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C,0 alkoxy, preferably C,-C6 alkoxy, -NO,, -NH2, -CN, -CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a moiety of the formulae:
l?6 f?6
RT^ -N. .N. -N. y"
P-T ^ R7"
Figure imgf000008_0001
Figure imgf000008_0002
Z is O or S;
R6 is selected from the relevant members of the group H, -CF3, C,-CI0 alkyl, preferably C,-C6 alkyl, CrC10 alkoxy, preferably C,-C6 alkoxy, phenyl, -O-phenyl, -S- phenyl, benzyl, -O-benzyl, or -S-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3, or -OH;
R7 is selected from the relevant members of the group -OH, -CF3, C,-C10 alkyl, preferably C,-C6 alkyl, C,-CI0 alkoxy, preferably C,-C6 alkoxy, -NH2, -(CH2)n-NH2, -NH- (C,-C6 alkyl), -N-(C,-C6 alkyl)2, -(CH2)n-NH-(C,-C6 alkyl), -(CH2)n-N-(C,-C6 alkyl)2, phenyl, -O-phenyl, benzyl, or -O-benzyl; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine. piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-C]0 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
n is an integer from 0 to 3;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,-
C6 alkyl, C,-C]0 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000009_0001
lower alkyl) or
Figure imgf000009_0002
or a moiety selected from the formulae -L'-M1 ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)π-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000010_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, - (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000011_0001
Rg is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -O-(CH2)n-COOH, -O-CH2-C=C-COOH, -O-C=C-CH2-COOH, -NH(C,-C5 alkyl), -N(C,-C6 alkyl)2, -N-C(O)-(CH2)n-COOH. -N-SO2- (CH2)n-COOH, -C(O)-N-(CH2)n-COOH;
R10 is selected from the group of H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -O-(C,-C6 alkyl)-(OH)n, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -N-C(O)-N-(C,-C6 alkyl)-(OH)2,
Figure imgf000011_0002
lower haloalkyl;
Figure imgf000011_0003
Figure imgf000012_0001
lower alkyl)
Figure imgf000012_0002
Figure imgf000012_0003
Figure imgf000012_0004
R„ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000012_0005
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, R9, R10, and/or Rn shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000012_0006
n is an integer from 0 to 3; R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C 10 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)π-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-, C(O)C(O)X; where X is O or N
M is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably CrC6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C C6 alkoxy, -CHO, -NO,, -NH,, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH,)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C10 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000014_0001
(CH,), " (CH2),
"\ (CH2W (CH2
Y O^ Y
Figure imgf000014_0002
wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2,
Y is C3-C6 cycloalkyl, phenyl, biphenyl, each optionally substituted by from 1 to 3 groups selected from halogen, C,-C]0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyrroline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, oxathiazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO,, -NH,, -CN, -CF3, or by one phenyl ring, the phenyl ring being optionally substituted by by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO,, -NH2, -CN, -CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C,0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C^C,,, alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
d) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000015_0001
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -CF3 or -(CH2)n-CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH, , -N(C,- C6)2, -NH(C,-C6), -N-C(O)-(C,-C6), -NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S, such as, for example, morpholino; or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position (R4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
Another R3 is -L'-M1, wherein L! is as defined above, more preferably wherein L1 is a chemical bond, and M1 is the moiety:
Figure imgf000016_0001
and Rg is as defined in the broad genus above.
Another group of this invention comprises compounds in which R2 and R4 are hydrogen and the groups at R,, Rr , R3, and R5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R] is in the indole or indoline 6 position.
In a further preferred group herein, R, is in the indole or indoline 5-position and is benzyloxy, R2 and R4 are hydrogen and R3 and R5 are as defined above.
Among the more preferred compounds of this invention are those of the following formulae:
Figure imgf000016_0002
wherein: R, is selected from H, halogen, -CF3, -OH, -C,-CI0 alkyl, preferably -C,-C6 alkyl, -S-
C,-C10 alkyl, preferably -S-C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000017_0001
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C^ alkoxy, -NO2, -NH2, -CN, -CF3, or - OH;
R7 is selected from -OH, -CF3, CrC6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,- C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH;
R, is selected from H, halogen, -CF3, -OH, -C,-C]0 alkyl, preferably -C,-C6 alkyl, C,- C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-CrC6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000018_0001
lower alkyl) or
Figure imgf000018_0002
lower alkyl) or
o
O S II OH £>— P — OH
/ II
O o II
or a moiety selected from the formulae -L -M ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)π-C(O)-(CH2)„-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000018_0003
Figure imgf000019_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000019_0002
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(CrC6 alkyl), or -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000019_0003
Figure imgf000019_0004
Figure imgf000020_0001
Figure imgf000020_0002
R„ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000020_0003
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, Rg, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000020_0004
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C]0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2: L2 indicates a linking or bridging group of the formulae -(CH,)n-, -S-, -O-,
-C(O)-, -(CH2)π-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, CrC!0 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to pyridine, pyrimidine, piperidine, piperazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-CI0 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C,0 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH,, -CN, - CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C10 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)π-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000021_0001
Figure imgf000022_0001
(CH^ (CH2
XT Y > wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -CrC6 alkyl, CrC6 alkoxy, -CN, -NH2, - NO2or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000022_0002
wherein
D is H, C,-C6 lower alkyl, CrC6 lower alkoxy, -CF3 or -(CH2)n-CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH, or -NO,; or a pharmaceutically acceptable salt thereof.
One group of compounds within this invention are those in which the indole or indoline 2-position (R4) is substituted only by hydrogen and the substituents at the other indole or indoline positions are as described above.
In an another preferred group of this invention R, is in the indole or indoline 5 or 6 position and is cyclopentylcarboxamide or cyclopentyloxycarbonylamino, R^ and R4 are hydrogen, and R3 and R5 are as defined above. A further preferred group of this invention consists of R, and R,at the indole or indoline 5 and or 6 position and are each selected from the group consisting of C,-C6alkoxy, cyano, sulfonyl and halo, R2 and R4 are hydrogen, and R3 and R5 are as defined above.
Another group of this invention comprises compounds in which R2 and R4 are hydrogen and the groups at R,, R3, and R5 are as defined above. Within this group are two further preferred groups. In the first, R, is in the indole or indoline 5 position and in the second R, is in the indole or indoline 6 position.
In a further preferred group herein, R, is in the indole or indoline 5-position and is benzyloxy, R2 and R4 are hydrogen and R3 and R5 are as defined above.
A preferred group of compounds of this invention have the following formulae:
Figure imgf000023_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, CN, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000023_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl. benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH,, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R, is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C,0 alkyl, preferably C,- C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH,, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-CrC6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)„-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000024_0001
' *(CrC6 lower alkyl) or
Figure imgf000024_0002
lower alkyl)
Figure imgf000024_0003
or a moiety selected from the formulae -L 1 -M Λ fl . ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH,)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R5)-, -C(O)-C(Z)-N(R6)-(CH,)n-, -C(Z)-NH-SO,-, or -C(Z)-NH-SO,-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000025_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH,)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000025_0002
Rg is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CrC6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000026_0001
Figure imgf000026_0002
lower alkyl)
lower haloalkyl; .
Figure imgf000026_0003
R„ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000026_0004
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M\ R8, g, RI0, and/or Ru shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000026_0005
n is an integer from 0 to 3; R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -CrC6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH,)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)π-;
M is selected from:
a) the group of CrC6 lower alkyl, C,-C6 lower alkoxy, C3-CI0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-CI0 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of: a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH,)n-O-phenyl-
CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl),, -CH,-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000028_0001
^(CH,)^ (CH2
/ O"^ Y wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000028_0002
wherein
D is H, C,-C6 lower alkyl, CrC6 lower alkoxy, -(CH2)n-CF3 or -CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, CrC6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
A preferred group among the compounds above are those in which the R, substitution is at the indole or indoline ring's 5-position and the other substituents are as defined above.
Another preferred group of this invention are those of the formulae: I6
R7^ or 0
Figure imgf000029_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO,, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000029_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R, is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,- C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO,-C,-C6 alkyl, or -SO2-C,-C6 alkyl; R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH,)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000030_0001
lower alkyl) or
Figure imgf000030_0002
(C-ι-C-6 lower alkyl) or
Figure imgf000030_0003
or a moiety selected from the formulae -L -M
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000030_0004
Figure imgf000031_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000031_0002
Rg is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R,0 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000031_0003
Figure imgf000032_0001
(CrC6 lower alkyl)
Figure imgf000032_0002
lower alkyl or
Figure imgf000032_0003
lower haloalkyl; .
Rπ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000032_0004
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, Rg, Rg, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000032_0005
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from:
a) the group of CrC6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-CI0 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C C alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocychc ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, Cj-C^ alkoxy, preferably CrC6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl or ~(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A wherein A is selected from :
Figure imgf000033_0001
Figure imgf000034_0001
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3
R]2 is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF 3' or a pharmaceutically acceptable salt thereof.
Other compounds of this invention have the following formulae:
Figure imgf000035_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000035_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(CrC6 alkyl), -N-(CrC6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C,0 alkyl, preferably C,- C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2-C,-C6 alkyl; R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)π-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000036_0001
Figure imgf000036_0002
lower alkyl) , or
Figure imgf000036_0003
or a moiety selected from the formulae -L -M or L M
L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000036_0004
Figure imgf000037_0001
L is a bridging or linking moiety selected from a chemical bond -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M is the moiety
Figure imgf000037_0002
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000037_0003
Rg is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000038_0001
Figure imgf000038_0002
lower alkyl)
lower haloalkyl;
Figure imgf000038_0003
Rπ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n-
COOH, -(CH2)n-C(O)-COOH,
Figure imgf000038_0004
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, L2, M2, R8, R9, R]0, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000038_0005
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L3-M3:
L3 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M3 is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicychc ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C^C^ alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, CrC6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl,
-(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of:
a) -(CH2)n-ρhenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000040_0001
(CH,)^ (CH2
O^ ^Y wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2, - NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000040_0002
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -CF3 or -(CH2)n-CF3; B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
Another preferred group of this invention are those of the formulae:
Figure imgf000041_0001
wherein:
Rj is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO,, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000041_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, CrC6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C]0 alkyl, preferably C,- C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-CrC6 alkyl, or -SO2-CrC6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)π-COOH, -CH=CH-COOH, -(CH2)nC(O)NS(O)(O)(C,-C6 lower alkyl), -(CH2)NC(O)NS(O)(O)(C,-C6 lower haloalkyl),
Figure imgf000042_0001
R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH;
R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R]0 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000043_0001
Figure imgf000043_0002
lower alkyl)
lower haloalkyl;
Figure imgf000043_0003
R„ is selected from H, C,-C6 lower alkyl, -CF3, -COOH, -(CH2)n-COOH,
-(CH2)π-C(O)-COOH, or
Figure imgf000043_0004
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -CrC6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C,0 alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C^C,,, alkoxy, preferably C,-C6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl or ~(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A wherein A is selected from:
Figure imgf000044_0001
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0003
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3;
R]2 is H, CrC6 lower alkyl, C,-C6 lower alkoxy, or -CF. 3'
or a pharmaceutically acceptable salt thereof.
The compounds of this invention have the following formulae:
Figure imgf000046_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000046_0002
Figure imgf000046_0003
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C^Cg alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-CI0 alkyl, preferably C,-
C6 alkyl, CrC10 alkoxy, preferably C,-C6 alkoxy, -CHO, -CN, -NO2, -NH,, -NH-C,-C6 alkyl, -N(C,-C6 alkyl),, -N-SO2-CrC6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH,)π-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000047_0001
lower alkyl) or
lower alkyl) or
Figure imgf000047_0002
or a moiety selected from the formulae -L -M ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000048_0001
Figure imgf000048_0002
Rg, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000048_0003
R9 is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH,
-(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)π-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(CrC6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000049_0001
Figure imgf000049_0002
(C-)-C6 lower alkyl)
(Cι-C6 lower haloalkyl;
Figure imgf000049_0003
Ru is selected from H, C,-C6 lower alkyl, CrC6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000049_0004
with a proviso that the complete moiety at the indole or indohne 3-position created by any combination of R3, L1, M1, R8, Rg, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000049_0005
n is an integer from 0 to 3; R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C]0 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)π-, or -(CH2)n-S-(CH2)n-, - C(O)C(O)X; where X is O or N,
M2 is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, CrC10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pyrrole, thiophene, imidazole, pyrazole, pyrrolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or morpholine, the six-membered heterocychc ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably CrC6 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; R5 is selected from -(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of:
a) -(CH2)π-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-
CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000051_0001
" O^ ^Υ , wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, - NH2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O, preferably S or O; or
/(CH2)V b) a moiety of the formula γ wherein n is an integer from 0 to 3 , preferably 1 to 3, more preferably 1 to 2, Y is napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, CrC6 alkoxy,
-NH2, -NO2 or a five membered heterocyclic ring containing one heteroatom selected from N ,
S, or O, preferably S or O; or
c) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000051_0002
wherein D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-CF3 or -CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
In a further preferred group within the subgenus above, R, is benzyloxy and R4, R3 and R5 are as defined above.
Yet another preferred group herein are the compounds of the formulae:
Figure imgf000052_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000052_0002
R6 is selected from H, C,-C6 alkyl, C C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, CrC6 alkoxy, -NH2, -NO2, -CF3, or -OH; R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)π-COOH,
-CH=CH-COOH, -(CH2)nC(O)NS(O)(O)(CrC6 lower alkyl), -(CH2)NC(O)NS(O)(O)(C,-C6 lower haloalkyl),
Figure imgf000053_0001
Figure imgf000053_0002
Figure imgf000054_0001
R8 and Rg are independently selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CrC6 alkyl, -O-CrC6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000054_0002
Figure imgf000054_0003
lower alkyl)
lower haloalkyl; .
Figure imgf000054_0004
R„ is selected from H, C,-C6 lower alkyl, -CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or
Figure imgf000055_0001
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, or halogen;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl or the groups of:
a) -C(O)-O-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-ρhenyl, -(CH2)n-S-phenyl, - (CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)π-O-phenyl-CH2-phenyl, - (CH2)n-phenyl-(O-CH2-phenyl)2, -C(O)-O-phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, - C(O)-O-napthyl, -(CH2)n-S-napthyl, -(CH2)n-S-ρyridinyl, -(CH2)n-pyridinyl or -(CH2)n- napthyl, the phenyl, pyridinyl and napthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, - NH2, or -NO2; or
b) a moiety of the formula -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000055_0002
wherein
D is H, C,-C6 lower alkyl, CrC6 lower alkoxy, or -CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pyrrolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2, or -NO2; or a pharmaceutically acceptable salt thereof.
Detailed Description of the Invention As used herein, the terms "aryl" and "substituted aryl" are understood to include monocyclic, particularly including five- and six-membered monocyclic, aromatic and heteroaromatic ring moieties and bicyclic aromatic and heteroaromatic ring moieties, particularly including those having from 9 to 10 ring atoms. Among these aryl groups are understood to be phenyl rings, including those found in phenoxy, benzyl, benzyloxy, biphenyl and other such moieties. The aryl and heteroaryl groups of this invention also include the following:
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pyrrole, thiophene, imidazole, pyrazole, isothiazole, isoxazole, pyrrolidine, pyπoline, imidazolidine, pyrazolidine, pyrazole, pyrazoline, imidazole, tetrazole, or oxathiazole; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not limited to, pyran, pyridine, pyrazine, pyrimidine, pyridazine, piperidine, piperazine, tetrazine, thiazine, thiadizine, oxazine, or moφholine; or
c) a bicyclic ring moiety optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, indolizine, indazole, quinoline, isoquinoline, quinolizine, quinazoline, cinnoline, phthalazine, or napthyridine.
The "substituted aryl" groups of this invention include such moieties being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 alkoxy, preferably C,-C6 alkoxy, -CHO, -COOH or esters thereof, -NO2, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NH(CH3), etc.
A preferred subset of these groups, optionally substituted as just described, include moieties formed from benzene, pyridine, napthylene or quinoline rings. A further prefeπed group includes those of furan, pyrrole, thiophene, pyrimidine, and moφholine rings. A prefeπed group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
The alkyl, alkenyl and alkinyl groups refeπed to herein indicate such groups having from 1 to 10, preferably 1 to 6 carbon atoms, and may be straight, branched or cyclic. Unless indicated otherwise, it is preferred that these groups be straight or branched. Halogens herein are understood to include F, Cl, Br and I. As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 116 below). A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA2) in any available assay (preferably an assay described below in Example 116 or Example 117) for enzyme activity. In prefeπed embodiments, a compound has (1) an IC50 value of less than about 25 μM, preferably less than about 6 μM, in the LysoPC assay; (2) an IC50 value of less than about 50 μM in the vesicle assay; (3) an IC50 value of less than about 1 μM in the PMN assay; (4) an IC50 value of less than about 15 μM in the Coumarine assay; and/or (5) measurable activity (preferably at least about 5% reduction in edema, more preferably at least about 10% reduction, more preferably at least about 15%, most preferably 20-30%) in the rat caπageenan-induced footpad edema test.
Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA2) activity and, therefore, are useful in "treating" (i.e., treating, preventing or ameliorating) inflammatory or inflammation-related responses or conditions (e.g., rheumatoid arthritis, psoriasis, asthma, inflammatory bowel disease, and other diseases mediated by prostaglandins, leukotrienes or PAF) and other conditions, such as osteoporosis, colitis, myelogenous leukemia, diabetes, wasting and atherosclerosis.
The present invention encompasses both pharmaceutical compositions and therapeutic methods of treatment or use which employ compounds of the present invention.
Compounds of the present invention may be used in a pharmaceutical composition when combined with a pharmaceutically acceptable carrier. Such a composition may also contain (in addition to a compound or compounds of the present invention and a carrier) diluents, fillers, salts, buffers, stabilizers, solubilizers, and other materials well known in the art. The term "pharmaceutically acceptable" means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredient(s). The characteristics of the carrier will depend on the route of administration. The pharmaceutical composition may further contain other anti-inflammatory agents. Such additional factors and/or agents may be included in the pharmaceutical composition to produce a synergistic effect with compounds of the present invention, or to minimize side effects caused by the compound of the present invention.
The pharmaceutical composition of the invention may be in the form of a liposome in which compounds of the present invention are combined, in addition to other pharmaceutically acceptable earners, with amphipathic agents such as lipids which exist in aggregated form as micelles, insoluble monolayers, liquid crystals, or lamellar layers in aqueous solution. Suitable lipids for liposomal formulation include, without limitation, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, and the like. Preparation of such liposomal formulations is within the level of skill in the art, as disclosed, for example, in U.S. Patent No. 4,235,871; U.S. Patent No. 4,501,728; U.S. Patent No. 4,837,028; and U.S. Patent No. 4,737,323, all of which are incoφorated herein by reference.
As used herein, the term "therapeutically effective amount" means the total amount of each active component of the pharmaceutical composition or method that is sufficient to show a meaningful patient benefit, i.e., treatment, healing, prevention or amelioration of an inflammatory response or condition, or an increase in rate of treatment, healing, prevention or amelioration of such conditions. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone. When applied to a combination, the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially or simultaneously.
In practicing the method of treatment or use of the present invention, a therapeutically effective amount of a compound of the present invention is administered to a mammal having a condition to be treated. Compounds of the present invention may be administered in accordance with the method of the invention either alone or in combination with other therapies such as treatments employing other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors. When co-administered with one or more other anti-inflammatory agents, cytokines, lymphokines or other hematopoietic factors, compounds of the present invention may be administered either simultaneously with the other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors, or sequentially. If administered sequentially, the attending physician will decide on the appropriate sequence of administering compounds of the present invention in combination with other anti-inflammatory agent(s), cytokine(s), lymphokine(s), other hematopoietic factor(s), thrombolytic or anti-thrombotic factors.
Administration of compounds of the present invention used in the pharmaceutical composition or to practice the method of the present invention can be carried out in a variety of conventional ways, such as oral ingestion, inhalation, or cutaneous, subcutaneous, or intravenous injection. When a therapeutically effective amount of compounds of the present invention is administered orally, compounds of the present invention will be in the form of a tablet, capsule, powder, solution or elixir. When administered in tablet form, the pharmaceutical composition of the invention may additionally contain a solid carrier such as a gelatin or an adjuvant. The tablet, capsule, and powder contain from about 5 to 95% compound of the present invention, and preferably from about 25 to 90% compound of the present invention. When administered in liquid form, a liquid carrier such as water, petroleum, oils of animal or plant origin such as peanut oil, mineral oil, soybean oil, or sesame oil, or synthetic oils may be added. The liquid form of the pharmaceutical composition may further contain physiological saline solution, dextrose or other saccharide solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol. When administered in liquid form, the pharmaceutical composition contains from about 0.5 to 90% by weight of compound of the present invention, and preferably from about 1 to 50% compound of the present invention.
When a therapeutically effective amount of compounds of the present invention is administered by intravenous, cutaneous or subcutaneous injection, compounds of the present invention will be in the form of a pyrogen-free, parenterally acceptable aqueous solution. The preparation of such parenterally acceptable protein solutions, having due regard to pH, isotonicity, stability, and the like, is within the skill in the art. A prefeπed pharmaceutical composition for intravenous, cutaneous, or subcutaneous injection should contain, in addition to compounds of the present invention, an isotonic vehicle such as Sodium Chloride Injection, Ringer's Injection, Dextrose Injection, Dextrose and Sodium Chloride Injection, Lactated Ringer's Injection, or other vehicle as known in the art. The pharmaceutical composition of the present invention may also contain stabilizers, preservatives, buffers, antioxidants, or other additives known to those of skill in the art.
The amount of compound(s) of the present invention in the pharmaceutical composition of the present invention will depend upon the nature and severity of the condition being treated, and on the nature of prior treatments which the patient has undergone. Ultimately, the attending physician will decide the amount of compound of the present invention with which to treat each individual patient. Initially, the attending physician will administer low doses of compound of the present invention and observe the patient's response. Larger doses of compounds of the present invention may be administered until the optimal therapeutic effect is obtained for the patient, and at that point the dosage is not increased further. It is contemplated that the various pharmaceutical compositions used to practice the method of the present invention should contain about 0.1 μg to about 100 mg (preferably about .1 mg to about 50 mg, more preferably about 1 mg to about 2 mg) of compound of the present invention per kg body weight.
The duration of intravenous therapy using the pharmaceutical composition of the present invention will vary, depending on the severity of the disease being treated and the condition and potential idiosyncratic response of each individual patient. It is contemplated that the duration of each application of the compounds of the present invention will be in the range of 12 to 24 hours of continuous intravenous administration. Ultimately the attending physician will decide on the appropriate duration of intravenous therapy using the pharmaceutical composition of the present invention.
Compounds of the present invention invention can be made according to the methods and examples described below. Synthesis of preferred compounds of the present invention are described in the examples below.
Method A
The indole may be alkylated at the c-3 position with the appropriate alkyl bromide and treatment with a lewis acid such as silver(I)oxide or silver tetrafluoroborate in a solvent such as dioxane or THF at elevated temperatures of 50 °C - 100 °C. Alternatively it may be alkylated in a two step procedure by treatment of the indole with n-BuLi in a solvent such as THF or ether followed by ZnC12 and then concentrated and treated with the appropriate alkylating agent in a variety of solvents such as THF, ether, toluene or benzene. The indole nitrogen may then be alkylated by treatment with a strong base such as sodium bis(trimethylsilyl)amide, n-BuLi, sodium hydride or potassium hydride in a solvent such as DMF, DMSO or THF followed by exposure to the appropriate alkyl halide. The ester can be hydrolyzed under basic conditions with sodium hydroxide in water and methanol and THF. Alternatively it may be cleaved by treatment with sodium thiomethoxide in a solvent such as THF or DMF at elevated temperatures (50 °C - 100 °C). The product acid by be coupled to a sulfonamide by the agency of a variety of coupling reagents such as DCC, EDCI or carbonyl diimidazole in a solvent such as THF, methylene chloride, dichloroethane or DMF in the presence of a base such as triethyl amine and/or N, N-dimethyl pyridine. In the case of Rl = nitro the nitro group can be reduced by exposure to Pt/C in the presence of hydrogen in a solvent such as methanol, ethyl acetate or THF. The resulting amine can be acylated or sulfonylated by exposure to the appropriate agent in the presence of a base such as triethyl amine, sodium bicarbonate or pyridine in a biphasic solvent system such as methylene chloride:water ( 1 : 1 ) or THF: water ( 1 : 1 ) or a monophasic organic solvent such as methylene chloride, THF or DMF with triethylamine. The resulting acid may then be hydrolyzed and modified as described above. Also in the case Rl = Br, it may be replaced with the copper salt of the desired nucleophile such as thiomethoxide, methoxide or sulphinic acid.
Method A
Figure imgf000061_0001
Pt/C CH2C12
H2 EDCI THF DMAP R4SQ 2NH2
Figure imgf000061_0002
Figure imgf000062_0001
R1 R2 R3 R4 R5 R«
NH2, nitro, halogen H, MeO alky!. alkenyl, aryl carbamate alkyl, aryl H, halogen, alkyl aryl alkyl urea heterocyc c methoxy
5,6-methylenedιoxy alkyl amide methoxy aryl amide sulfonamide
Method B
The indoleglyoxalyl chloride may be reacted with the desired amino ester in a biphasic system with methylene chloride and saturated sodium bicarbonate or in a monophasic system with a solvent such as methylene chloride, ethyl acetate or THF and a base such as triethylamine, Hunigs base or pyridine. The indole nitrogen may then be alkylated with a variety of alkylatmg reagents in a solvent such as DMF, DMSO or THF and a base such as sodium hydride, n-BuLi or potassium bis(trimethylsilyl)amide. The ester may then be hydrolyzed with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
Method B
Figure imgf000063_0001
Method C
The 3-carboxyindole is elaborated via reductive amination by allowing the aldehyde to condense with an amino ester in a solvent such as methylene chloride or dichloromethane with or without acetic acid. The resulting imine is reduced in-situ with a reducing agent such as sodium borohydride, sodium cyanoborohydride or sodium triacetoxyborohydride. The acid is then prepared by hydrolysis of the resulting ester with sodium hydroxide or lithium hydroxide in a solvent system such as water:methanol:THF.
Method C
Figure imgf000064_0001
Figure imgf000064_0002
Rl = alkyl
Figure imgf000064_0003
Method D
5-benzyloxyindole may be treated with a base such at methyl or ethyl grignard and acylated at the 3-position with ethyloxychloride in a suitable solvent such at ether or THF. The indole nitrogen may then be alkylated with a benzylbromide by the action of a base such as sodium hydride or n-butyllithium in a solvent such a THF or DMF. The ester is then hydrolysed under basic conditions with sodium hydroxide or tetrabutylammonium hydroxide in a suitable solvent system such at wateπMeOHTHF. Coupling of the appropriate aminoester may then be effected by the use of a coupling agent such as DCC or EDCI in a solvent such as methylenechloride, THF or DMF. The target acid may the be revealed by hydrolysis of the ester under the same conditions discussed above. Method D
Figure imgf000065_0001
Method E
Indole-3-acetic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh3)4 as a catalyst in a mixed solvent (ethanol- benzene- water) at elevated temperature to give the l-alkyl-5-substituted indole.
Method E
Figure imgf000066_0002
0^ (X
Method F
Alkylation of the nitrogen atom of I with a suitable base such a sodium hydride or potassium carbonate and an alkyl halide gave the aldehyde π. The aldehyde could be transformed to the thiazolidinedione in using a base such as piperdine and isolated with an acid such as acetic acid. Deprotonation with a suitable base such as sodium hydride and alkylation on the nitrogen atom of the thiazolidinedione with selected electrophiles such as alkyl or benzyl halides provided compounds such as IV.
Method F
Figure imgf000067_0001
piperidine
Figure imgf000067_0002
III
Figure imgf000067_0003
Method G
The nitro-indole I was converted to the unsaturated ester via a Homer- Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran. Reduction of the nitro group of II can be accomplished via hydrogenation with palladium on carbon in the presence of hydrogen and acylation of the resulting amine under Schotten-Bowmann conditions to give amides such as HI. Saponification of the ester function gave the acid-indole
IV.
Method G
Figure imgf000068_0001
Method H
5-Chloro-2-methylindole could be reductively alkylated at the 3-position with a suitable aldehyde in the presence of an acid such as trifluoroacetic acid and a reducing agent such as triethylsilane in a suitable solvent such as methylene chloride to give the ester π. The nitrogen atom could be alkylated by treatment with a suitable base such as sodium hydride and diphenyl bromo methane and the resulting compound in could be saponified to give IV.
Method H
Figure imgf000069_0001
NaH R-Br
Figure imgf000069_0002
Method I
The starting indole is C3 functionalized by either reaction of DMF/POC13 or by reacting the magnesium salt of the indole with methyl oxalyl chloride. The resulting esters and aldehydes were then Nalkylated by treating the salt of the indole, generated by treating the indole with a strong base, with a variety of alkyl halides. In th case of the aldehydes, when r' is a nitro group, the nitro is reduced to the amine using Pt/C and H2 or copper acetate/sodium borohydride and then acylated usind various acid chlorides, isocyanates, chloroformates or reductively alkylated using aldehydes and sodium triacetoxyborohydride. These aldehydes could then be oxidised to the desired acid which could be coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product. The esters generated above could be treated in a similar fashion. The ester could hydrolyzed and then coupled to an amino alkyl or aryl esters by an EDCI coupling method or by first transforming the acid into the acid chloride under the action of oxalyl chloride and the reacting this with an amino alkyl or aryl ester. These were then hydrolyzed to yield the final product. Method 1(a)
Figure imgf000070_0001
Method 1(b)
1) R MgX CH3OCCOCl
Figure imgf000070_0003
Figure imgf000070_0002
Figure imgf000070_0004
Method J
The starting amine was treated with various sulfonyl chlorides in the presence of pyridiine and then the excess sulfonylchloride was scavenged by adding a polymer bound amine. The desired products where then hydrolyzed using sodium hydroxide in THF MeOH and the reaction was aidified using IR-120 resin to yield the desired products.
Method J
Figure imgf000071_0001
Method K
The starting indole was bis alkylated by the addition of a strong base such as sodium hydride and then an alkylating agent such as an alkyl or aryl halide followed by the hydrolysis of the resulting ester with sodium hydroxide in THF MeOH. The acid was then coupled with an alkyl or aryl amino ester and then hydrolyzed to yield the desired acid.
Method K
Figure imgf000071_0002
Example 1
4-r(5-|[(cvclopentyloxy)carbonyllamino}-l-propyl-lH-indol-3-yl)methyll-3- methoxybenzoic acid
Step 1 - To a solution of 5-nitro indole (21.24 g, 131 mmol) in dioxane (128 mL) in a reaction vessel wrapped in aluminum foil is added silver(I)oxide (30.34 g, 131 mmoL, 1.5 eq) and methyl 4-(bromomethyl)-3-methoxy-benzoate (34 g, 131 mmol) and the mixture is brought to 60 °C and stirred 20 h. The reaction is cooled, filtered through celite, taken up in ethyl acetate (500 mL), washed with brine (2 X 50 mL), dried (MgSO4) and filtered. The crude material was purified by silica chromatography (15% ethyl acetate / hexanes) to afford the desired product (5.8 g, 55%). Step 2 - The C3-alkylated indole (1.5 g, 4.4 mmol) was dissolved with 15 mL THF. In a separate flask, NaH (185 g, 4.61 mmol) was suspended with 25 mL THF at 0 °C. The solution of starting material was cannulated into the NaH suspension, giving a deep red solution. This was then allowed to stir at room temperature for 10 minutes. 1-iodopropane was added (0.47 mL, 1.1 mmol) and the reaction was allowed to pr°ceed overnight at room temperature. As the reaction was not complete (TLC) and additional 0.5 mL of 1-iodopropane was added and the reaction continued for another 3 h. There was no change in the TLC and the reaction was poured into cold 1 N HCl and extracted with CH2C12 (3 X 75 mL). The combined organic layers were dried over MgSO4, filtered and evaporated to yield the crude N-alkylated nitroindole. The crude material was absorbed onto silica and loaded onto a silica gel column. The column was eluted with 100% CH2C12 to give the pure yellow N-alkylated nitroindole (0.96 g, 57%).
Step 3 - The N-alkylated nitroindole (0.95 g) was dissolved with 40 mL anhydrous THF. The system was purged with argon. To the clear, yellow solution, Pt C (0.462 g) was added. The argon was then removed by evacuation and hydrogen was introduced to the system. The reaction was stiπed 6.5 h. The hydrogen was evacuated and argon was then purged through the system. The reaction mixture was filtered through celite with THF. The solvent was removed by rotary evaporation to give the crude amine as a dark oil. Chromatography (5% ethyl acetate/CH2Cl2) afforded the desired product (0.7 g, 80%) Step 4 - The amine from above (0.7 g) was dissolved in 40 mL CH2C12. 4- methylmoφholine (0.3 mL, 3.0 mmol) and cyclopentyl chloroformate (383 mg, 2.57 mmol) were then added to give a yellow/orange solution. The reaction was allowed to proceed at room temperature for 3 h. The reaction mixture was acidified with 1 N HCl and the mixture was extracted with 50 mL CH2C12. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated to give the crude carbamate. The crude product was absorbed onto silica gel and loaded onto a silica gel column. The column was eluted with 100% CH2C12 to afford the desired product (0.87 g, 39%) as a yellow foam. Step 5 - The carbamate (0.831 g) was dissolved with hydrolysis solution (2: 1: 1
THF:MeOH:2N NaOH) and the reaction was allowed to proceed for 5.25 h. The reaction was acidified to pH 2 with 2N HCl and extracted with CH2C12. The organic layer was washed with water and brine. The combined organic layers were then dried over MgSO4, filtered and evaporated to yield the crude acid, which was recrystallized from CH2C12 to afford the title compound (0.575 g, 71%) as pink crystals. MS: mz (M- 1) 449
Example 2
Cvclopentyl N-l3-r2-methoxy-4-({f(2-methyIphenyl)suIfonyllamino}carbonyl) benzyll-l-propyl-lH-indol-5-yl)carbamate
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate. Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 3 4-F(l-benzhvdryl-5-jr(cvclopentyloxy)carbonyllamino}-lH-indol-3- yl)methvπ-3-methoxybenzoic acid
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 4
4-ir5-{r(cyclopentyloxy)carbonvnamino>-l-(2-naphthylmethyl)-lH-indol-3- yllmethyll-3-methoxybenzoic acid
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent. Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate. Step 3 - The intermediate carbamate is prepared as in Example 1 , step 4, using the appropriate acylating agent.
Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 547
Example 5
4-(r5-{r(cvclopentyloxy)carbonyl1amino}-l-(cyclopropylmethyl)-lH-indol-3- vπmethyl)-3-methoxybenzoic acid
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent. Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-l) 461
Example 6
4-{r5-lf(cyclopentyloxy)carbonvI1aminol-l-(4-pyridinylmethyI)-lH-indol-3- vπmethyll-3-methoxybenzoic acid Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate.
Example 7
4-r(5-ir(cyclopentyloxy)carbonvIlamino}-l-isopropyl-lH-indol-3yl)methyI]- 3-methoxybenzoic acid
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2 - The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate. Step 3 - The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 4 - The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-1) 449
Example 8
4-r(l-cyclopentyl-5-{[(cvclopentyloxy)carbonyl1amino}-lH-indol-3- yl)methyπ-3-methoxybenzoic acid
Step 1 - The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent.
Step 2
The intermediate 5-amino indole is prepared as in Example 1, step 3, using the above intermediate.
Step 3
The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 4 The title compound is prepared as in Example 1, step 5, using the above intermediate.
MS: m/z (M-1) 475
Example 9
4-r(l-benzhydryl-5-{r(butylamino)carbonvnaminol-lH-indol-3-yl)methyll-3- methoxybenzoic acid
The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the intermediate 5-amino indole is prepared as in Example 1, step 3, using the 5-nitro indole intermediate. The intermediate urea is prepared as in Example 1, step 4, using the appropriate acylating agent. The title compound is prepared as in Example 1, step 5, using the urea intermediate. MS: m/z (M-1) 560
Example 10
4-({l-benzhvdryl-5-r(methylsulfonyl)amino1-lH-indoI-3-yllmethyl)-3- methoxybenzoic acid
The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent followed by preparation of the intermediate 5-amino indole as in Example 1, step 3, using the 5-nitro indole. The intermediate sulfonamide is next prepared as in Example 1, step 4, using the appropriate acylating agent. The title compound is then prepared as in Example 1, step 5, using the sulfonamide intermediate. MS: m/z (M-1) 539 Example 11
4-({l-benzhydryI-5-r(cyclopentvIcarbonyl)amino1-lH-indol-3-yl)methyl)-3- methoxybenzoic acid
The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and intermediate 5-amino indole is prepared as in Example 1, step 3, using this 5-nitro indole intermediate. The corresponding intermediate amide is then prepared as in Example 1, step 4, using the appropriate acylating agent. The final title compound is prepared as in Example 1, step 5, using this amide intermediate. MS: m/z (M-1) 557
Example 12
4-F(l-benzhvdryl-5-nitro-lH-indol-3-yl)methyπ-3-methoxybenzoic acid
The intermediate 5-nitro indole is prepared as in Example 1, step 2, using the appropriate alkylating agent and the title compound is prepared as in Example 1, step 5, using this intermediate. MS: m z (M-1) 657
Exmaple 13
4-F(l-benzhydryl-5-bromo-lH-indol-3-yl)methyπ-3-methoxybenzoic acid The intermediate 5-bromo indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z
(M-1) 526
Example 14 4-r(l-benzhydryl-5-fluoro-lH-indoI-3-yl)methyIl-3-methoxybenzoic acid The intermediate 5-fluoro indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1) 464
Example 15
4-r(l-benzhydryl-5-methyl-lH-indol-3-yl)methyn-3-methoxybenzoic acid
The intermediate 5-methyl indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M- 1) 460 Example 16
4-r(5-benzhvdryl-5H-ri.31dioxolor4.5-flindol-7-yl)methyll-3-methoxybenzoic acid
The intermediate 5,6-methylenedioxy indole is prepared as in Example 1, step 1, using the appropriate indole and as in Example 1, step 2, using the appropriate alkylating agent. The title compound is then prepared as in Example 1, step 5, using the above intermediate. MS: m/z (M-1) 490
Example 17 4-r(l-benzhydryI-5-cvano-lH-indol-3-yl)methvπ-3-rnethoxybenzoic acid Step 1
To the intermediate from Example 13, step 2 (0.25 g, 0.46 mmol), in DMF (1 mL) is added CuCN (0.05g, 1.2 eq) and the reaction mixture is stirred at 145 °C overnight and then cooled. To the cooled reaction mixture is added FeCl3 (0.09 g, 1.2 eq). The reaction mixture is stirred 5 min, taken up in ethyl acetate (30 mL), washed with brine (3 X 10 mL), dried (MgSO4), filtered and concentrated. The product was purified by silica chromatography (20% ethyl acetate/hexanes) to afford the intermediate ester (0.2 g, 89%) as a colorless oil. Step 2
To the intermediate ester (0.20.41 mmol) in DMF (2 mL) is added sodium thiomethoxide (0.1 g, 3.4 eq) and the reaction mixture is stirred at 90 °C for 10 min. The reaction is cooled, poured into ethyl acetate (5 mL), washed with sodium biphosphate (1 X 2 mL), brine (2 X 2 mL), dried (MgSO4), filtered and concentrated. Purification by silica chromatography (1% acetic acid, 25% ethyl acetate/hexanes) afforded the title compound (0.114 g, 59%) as a colorless amoφhous powder. MS: m/z (M-1) 471
Example 18
4-iri-benzhvdryl-5-ιmethylsulfonyl)-lH-indoI-3-yllmethyl}-3- methoxybenzoic acid
Step 1
To the intermediate from Example 13, step 3 (1 g, 1.9 mmol), in a solution of THF (2 mL) and methanol (2 mL) is added sodium hydroxide (0.41 mL, 4.63 M, 1 eq). The mixture is stirred for 20 min and then concentrated. The residual water is chased off by the addition of toluene and it's removal (3 X) a white powder (1 g, 100%).
Step 2
To the sodium salt prepared above (0.88 g, 1.6 mmol) in DMF (3 mL) is added methanesulfinic acid, sodium salt (0.72 g, 4.4 eq) and Cul (0.74 g, 2.4 eq). The reaction mixture is stiπed at 130 °C overnight, cooled, taken up in ethyl acetate (50 mL) and acetic acid (10 mL), filtered (celite), washed with brine (4 X 10 mL), dried (MgSO4), filtered and concentrated. Silica chromatography (1% acetic acid, 25% ethyl acetate/hexanes - 1% acetic acid, 50% ethyl acetate/hexanes) afforded the title compound (0.2 g, 24%) as a colorless amoφhous solid. MS: m/z (M-1) 524
Example 19
Cvclopentyl N-{l-benzhydryl-3-r2-methoxy-4-((r(2- methylphenyl)sulfonyllamino}carbonyl)benzyll-lH-indol-5-yl)carbamate
To the product of Example 3, step 4 (0.5 g, 0.87 mmol), in CH2C12 (4 mL) is added EDCI (0.2 g, 1.0 mmol, 1.2 eq), DMAP (0.011 g, 0.087 mmol, 0.1 eq) and ortho-toluene sulfonamide. The reaction is stirred overnight at room temperature, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO4), filtered and concentrated. Silica chromatography (1% acetic acid, 25% ethyl acetate/hexanes) afforded the title compound (0.4 g, 63%) as a colorless solid.
Example 20
Cvclopentyl N-{3-r2-methoxy-4-(U(2-methylphenyl)suIfonyllaminol carbonyl)benzyll-l-propyI-lH-indol-5-yl)carbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 1, step 5, and the appropriate sulfonamide.
Example 21
Cvclopentyl N-{l-(cvclopropylmethyI)-3-r2-methoxy-4-({r(2- methylphenyl)sulfonvI1amino)carbonyl)benzyl1-lH-indol-5-yl)carbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 5, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 614
Example 22
Cvclopentyl N-r3-r2-methoxy-4-({r(2-methylphenyl)sulfonyl1aminolcarbonyl) benzyl1-l-(4-pyridinylmethyl)-lH-indol-5-yncarbamate The title compound is prepared as illustrated in Example 19 starting with the product of
Example 6, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 651 Example 23
Cvclopentyl N-F3-r2-methoxy-4-αFf2- methylphenyl)sulfonyπamino}carbonyl)benzyl1-l-(2-naphthylmethyl)-lH- indol-5-yllcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 4, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 700
Example 24
Cvclopentyl N-(l-isopropyl-3-F2-methoxy-4-(ir(2- methylphenyl)sulfonyllaminolcarbonyl)benzyl1-lH-indol-5-yl}carbamate The title compound is prepared as illustrated in Example 19 starting with the product of
Example 7, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 602
Example 25
Cvclopentyl N-Jl-cyclopentyl-3-r2-methoxy-4-((F(2-methylphenyl) sulfonyllaminolcarbonyl)benzyll-lH-indol-5-yl}carbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 8, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 628
Example 26 Cvclopentyl N-{l-benzhydryI-3-F2-methoxy-4-
({F(trifluoromethyl)suIfonyllamino}carbonyl)benzyll-lH-indol-5-yllcarbanιate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 704
Example 27 cvclopentyl N-Fl-benzhvdryl-3-(2-methoxy-4- IF(methylsulfonyl)amino1carbonyllbenzyl)-lH-indol-5-yncarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 650 Example 28 cvclopentyl N-(l-benzhvdryl-3-F4-((F(2- chlorophenyl)sulfonyl1aminolcarbonyl)-2-methoxybenzvn-lH-indol-5- yllcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 29 cvclopentyl N-(3-f4-F(IF5-(acetylimino)-4-methyl-4.5-dihvdro-1.3.4- thiadiazol-2-yllsulfonyl)amino carbonyll-2-methoxybenzyll-l-benzhvdryl- lH-indol-5-yl)carbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 30 cvclopentyl N-(l-benzhydryl-3-{4-F(IF5-(dimethylamino)-l- naphthyllsulfonvI}amino)carbonyll-2-methoxybenzyl)-lH-indol-5- yPcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of
Example 3, step 4, and the appropriate sulfonamide.
Example 31 cvclopentyl N-Fl-benzhydryl-3-(4-{F(benzylsulfonyDamino1carbonvU-2- methoxybenzyl)-lH-indol-5-yllcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 726
Example 32 cvclopentyl N-f l-benzhydryl-3-F4-({r(2.4-dimethvI-1.3-thiazol-5- yl)sulfonvIlamino)carbonyl)-2-methoxybenzyH-lH-indol-5-vI)carbamate The title compound is prepared as illustrated in Example 19 starting with the product of
Example 3, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 747 Example 33 cvclopentyl N-ll-benzhvdryl-3-F4-({F(3.5-dimethyl-4- isoxazolyl)sulfonyllaminolcarbonyl)-2-methoxybenzyll-lH-indoI-5- yllcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 731
Example 34 cvclopentyl N-(3-{4-F(IF5-(acetylamino)-1.3.4-thiadiazoI-2- yl1sulfonyI}amino)carbonvn-2-methoxybenzyl}-l-benzhydryl-lH-indol-5- yPcarbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 35 cvclopentyl N-(l-benzhvdryl-3-(2-methoxy-4-F((F4-(3-methyl-5-oxo-4.5- dihydro-lH-pyrazol-l-yl)phenyl1sulfonyI}amino)carbonyI1benzvII-lH-indol- 5-yl)carbamate
The title compound is prepared as illustrated in Example 19 starting with the product of Example 3, step 4, and the appropriate sulfonamide.
Example 36
N-{4-F(l-benzhydryl-5-nitro-lH-indol-3-yl)methvn-3-methoxybenzoyl}-2- methylbenzenesulfonamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 12, step 2, and the appropriate sulfonamide. MS: m/z (M-1) 644
Example 37
N-{4-F(l-benzhvdryl-5-nitro-lH-indol-3-vnmethvn-3- methoxybenzoylHtrifluoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of
Example 12, step 2, and the appropriate sulfonamide. MS: m/z (M-1) 622 Example 38
N-{4-F(l-benzhydryl-5-bromo-lH-indol-3-yl)methyl1-3-methoxybenzoyl}-2- methylbenzenesulfonamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 13, step 2, and the appropriate sulfonamide. MS: m/z (M-1) 679
Example 39
N-{4-F(l-benzhydryI-5-bromo-lH-indol-3-yl)methyIl-3- methoxybenzoyl}(trifluoro)methanesulfonamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 13, step 2, and the appropriate sulfonamide. MS: m/z (M-1) 657
Example 40
N-ll-benzhydryl-3-F2-methoxy-4-((F(trifluoromethyl)sulfonyllamino} carbonyl)benzyπ-lH-indoI-5-yl}cyclopentanecarboxamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 11, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 688
Example 41
N-F4-({l-benzhydryl-5-F(methylsulfonyl)amino1-lH-indol-3-yllmethyl)-3- methoxybenzoyll(trifluoro)methanesulfonamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 10, step 4, and the appropriate sulfonamide. MS: m/z (M-1) 670
Example 42
N-{4-F(l-benzhydryl-5-{F(butylamino)carbonyllamino}-lH-indol-3- yl)methyn-3-methoxybenzoyl}(trifluoro)methanesulfonamide The title compound is prepared as illustrated in Example 19 starting with the product of
Example 9, step 4, and the appropriate sulfonamide. MS: m/z (M-1 ) 691 Example 43
N-{l-benzhydryl-3-F2-methoxy-4-(IF(2-methylphenyl)sulfonyllaminol carbonyl)benzyll-lH-indol-5-yllcyclopentanecarboxamide
The title compound is prepared as illustrated in Example 19 starting with the product of Example 11 , step 4, and the appropriate sulfonamide. MS: m/z (M-1 ) 710
Example 44
4-(l5-F(cvclopentylcarbonyl)amino1-l-FphenyI(2-pyridinyl)methyn-lH-indol- 3-yllmethyl)-3-methoxybenzoic acid Step 1
The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2
The intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4
The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide. MS: m/z (M-1) 738
Example 45
N-F4-(ll-benzhvdryl-5-F(benzylsulfonyl)amino1-lH-indol-3-yl}methyl)-3- methoxybenzoyll(trifluoro)methanesulfonamide Step 1
The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2
The intermediate sulfonamide is prepared as in Example 1, step 4, using the appropriate acylating agent. Step 3
The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4
The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide. MS: m/z (M-1 ) 746 Example 46
N-{ l-benzhydryl-3-F2-methoxy-4-(IF(trifluoromethyl)sulfonyllamino} carbonyl)benzyll-lH-indol-5-yl}-3-thiophenecarboxamide
Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2
The intermediate amide is prepared as in Example 1 , step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4
The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z (M-1 ) 702
Example 49 benzyl N-ll-benzhydryl-3-F2-methoxy-4-
({F(trifluoromethyl)sulfonvnamino}carbonyl)benzyl1-lH-indol-5-yl}carbamate
Step l The intermediate 5-amino indole is prepared as in Example 1, step 3.
Step 2
The intermediate carbamate is prepared as in Example 1, step 4, using the appropriate acylating agent.
Step 3 The intermediate acid is prepared as in Example 1, step 5, using the above intermediate.
Step 4
The title compound is prepared as illustrated in Example 19 starting with the intermediate above and the appropriate sulfonamide.
MS: m/z (M-1 ) 726
Example 50
4-F(l-benzhydryl-5-nitro-lH-indol-3-yl)methyllbenzoic acid
Step l
The intermediate 3-alkylated 5-nitroindole is prepared as illustrated in Example 1, step 1, using the appropriate alkylating agent. Step 2
The intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 3, step 1.
Step 3
The title compound is prepared as illustrated in Example 1, step 5.
MS: m/z (M-1 ) 461
Example 51
4-F(l-benzhydryl-5-bromo-lH-indol-3-yl)methyllbenzoic acid
Step l
The intermediate 3-alkylated 5-bromoindole is prepared as illustrated in Example 13, step 1, using the appropriate alkylating agent.
Step 2
The intermediate 3-alkylated 5-nitroindole is N-alkylated as illustrated in Example 13, step 2.
Step 3
The title compound is prepared as illustrated in Example 13, step 3. MS: m/z (M-1 ) 494
Example 52
4-F(l-benzhydryl-5-{F(cyclopentyloxy)carbonyllaminol-lH-indol-3- yl)methyl]benzoic acid Step 1
Starting with the material prepared in Example 50, step 2, the desired intermediate is prepared as illustrated in Example 3, step 2.
Step 2
The intermediate carbamate is prepared from the above intermediate as illustrated in Example 3, step 3.
Step 3
The title compound is prepared from the above intermediate as illustrated in Example 3, step 4.
MS: m/z (M-1 ) 543
Example 53 cvclopentyl N-{l-benzhydryl-3-F4-({F(2-methylphenyl)sulfonyllaminol carbonyl)benzyl1-lH-indol-5-yllcarbamate
The title compound is prepared from the product of Example 52, step 3, as illustrated in Example 19. MS: m/z (M-1) 697 Example 54 cvclopentyl N-{l-benzhydryl-3-r4-({f(trifluoromethyl)sulfonvI1amino} carbonyl)benzyll-lH-indol-5-yllcarbamate
The title compound is prepared from the product of Example 52, step 3, as illustrated in Example 26. MS: m/z (M-1) 674
Example 55
N-{4-F(l-benzhydryl-5-nitro-lH-indol-3-yl)methyl1benzoyll
(trifluoro)methanesulfonamide
The title compound is prepared from the product of Example 55, step 3, as illustrated in Example 26. MS: m/z (M-1) 592
Example 56
N-{4-F(l-benzhydryl-5-nitro-lH-indol-3-yl)methvπbenzov -2- methylbenzenesulfonamide The title compound is prepared from the product of Example 55, step 3, as illustrated in
Example 19. MS: m/z (M-1) 614
Example 57
N-{4-F(l-benzhydryl-5-bromo-lH-indoI-3-yl)methyl1benzoyl}-2- methylbenzenesulfonamide
The title compound is prepared from the product of Example 51, step 3, as illustrated in Example 38. MS: m/z (M-1) 649
Example 58 N-{4-F(l-benzhvdryl-5-bromo-lH-indol-3-yl)methyl1benzoyll (trifluoro)methanesulfonamide
The title compound is prepared from the product of Example 51 step 3 as illustrated in Example 39. MS: m/z (M-1) 627
Example 59
3-({2-Fl-(4-benzylbenzyl)-lH-indol-3-yll-2-oxoacetyl}amino)benzoic acid
Step 1 - To a solution of methyl 3-aminobenzoate (2.4 g, 16.0 mmol) in CH2C12 (50 mL) and saturated sodium bicarbonate (50 mL) at 5 °C is added 3-indolylglyoxalyl chloride (3.0 g, 14.4 mmol). The reaction is stirred to room temperature over 2 h, taken up in ethyl acetate (200 mL), washed with brine (3 X 50 mL), dried (MgSO4), filtered and concentrated. Crystallization of the crude material afforded the desired intermediate (2.7 g, 58%) as a colorless solid.
Step 2 - To a solution of the above intermediate (0.3 g, 0.93 mmol) in DMF (1.5 mL) at 0 °C is added potassium bis(trimethylsilyl)amide (0.41 g, 2.06 mmol). After the reaction is stirred at room temperature 30 min 4-benzylbenzyl bromide (0.27 g, 1.03 mmol) is added. The reaction is stiπed 3 h, taken up in ethyl acetate (10 mL), washed with brine (3 X 2 mL), dried (MgSO4), filtered and concentrated. Radial silica chromatography (2 mm, 10% - 35% ethyl acetate/hexanes) afforded the desired intermediate (0.19 g, 41%) as a colorless oil.
Step 3 - The ester obtained in step 2 was treated with sodium hydroxide (2 mL, 5 M) in THF (5 mL) and MeOH (2 mL). The reaction was stirred overnight, taken up in ethyl acetate (50 mL), washed with sodium biphosphate (1 X 10 mL), brine (2 X 10 mL), dried (MgSO4), filtered and concentrated. Trituration of the material in ethyl acetate with hexanes afforded the title compound (0.105 g, 60%) as a colorless solid. MS: m/z (M-1) 487
Example 60 3-f(2-ri-r4-iF3.5-bis(trifluoromethyl)phenoxy1methyl)benzvn-lH-indol-3- yll-2-oxoacetyl}amino)benzoic acid
The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2. Step 2 The product ester was hydrolyzed as described in Example 59, step 3. MS: m/z (M-1 ) 639
Example 61 3-{F2-(l-benzhydryl-lH-indol-3-yl)-2-oxoacetyl1amino)benzoic acid The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2.
Step 2
The product ester was hydrolyzed as described in Example 59, step 3.
MS: m/z (M-1 ) 473 Example 62
3-F(2-( l-F3-(4-benzylphenoxy)propyll-lH-indol-3-yl}-2- oxoacetyPaminolbenzoic acid
Step l
The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2. Step 2
The product ester was hydrolyzed as described in Example 59, step 3. MS: m/z (M-1 ) 531
Example 63
3-r(2-ll-F3.4-bis(benzyloxy benzvn-lH-indol-3-yll-2- oxoacetvDaminolbenzoic acid
Step l
The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2. Step 2
The product ester was hydrolyzed as described in Example 59, step 3. MS: m/z (M-1 ) 609
Example 64
3-F(2-(l-F2-(benzylsulfonyl)benzvn-lH-indol-3-yl)-2- oxoacetvDaminolbenzoic acid
Step l
The intermediate prepared in Example 59, step 1, was N-l alkylated with the appropriate reagent using the procedure described in Example 59, step 2. Step 2
The product ester was hydrolyzed as described in Example 59, step 3. MS: m/z (M-1 ) 551
Example 65
3-F(ll-benzhydryl-5-F(cvclopentylcarbonyl)amino~l-lH-indol-3- yllmethvPaminolbenzoic acid
Step l
To a solution of the aldehyde prepared in Example 114, step 3 (0.3 g, 0.7 mmol) in dichloroethane (2 mL) and DMF (1 mL) is added methyl 3-amino benzoate (0.113 g, 0.735 mmol, 1.05 eq) and acetic acid (0.13 mL, 2.1 mmol, 3 eq). After stirring 30 min sodium triacetoxyborohydride (0.18 g, 0.84 mmol, 1.2 eq) is added and the reaction is allowed to stir an additional 4 h after which it is taken up in ethyl acetate (20 mL), washed with saturated sodium bicarbonate (1 X 10 mL), brine (2 X 5 mL), dried (MgSO4), filtered and concentrated. Silica chromatography (30% ethyl acetate/hexanes) afforded the desired intermediate (0.24 g, 60%) as a colorless oil. Step 2
The product ester was hydrolyzed as described in Example 59 step 3 to give the title compound (0.11 g, 55%). MS: m/z (M-1 ) 542
Example 66
2-F4-((l-benzhydryl-5-F(cvclopentylcarbonyl)aminol-lH-indol-3- yllmethvDpiperazinolacetic acid
The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z (M-1) 549
Example 67
2-Fl-({l-benzhydryI-5-F(cvclopentylcarbonyl)aminol-lH-indoI-3-yIlmethyl)- 3-oxo-2-piperazinynacetic acid
The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z (M-1) 563
Example 68
2-F({l-benzhydryl-5-F(cvclopentylcarbonyl)aminol-lH-indol-3- yl}methyl)amino1-3-hydroxypropanoic acid The title compound was prepared as described in Example 65 using the appropriate amine. MS: m/z (M-1) 510
Example 69 2-Fl-(4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yπ-2-oxoacetic acid Step 1 - Ethylmagnesium bromide (3M in ether, 57 mL) was diluted in ether (50 mL).
5-Benzyloxyindole (12.7 g) dissolved in ether (150 mL) was added to the Grignard solution at - 78 °C. After 1.25 h, ethyloxalyl chloride (17.12 g) was added. The reaction was stirred 15 min, quenched with saturated sodium bicarbonate, taken up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. The resulting solid was triturated with ethanol and stiπed for 1 h. The desired product (5.75 g, 31%) was isolated as a yellow solid and used without further purification.
Step 2 - To the above indole in DMF at 0 °C was added sodium hydride (0.4 g, 60% dispersion in oil). After warming to room temperature, 4-benzylbenzylbromide (2.2 g) was added and the mixture was stiπed overnight. As the reaction was not yet done (TLC) additional 4-benzylbenzylbromide (1.0 g) was added and the reaction stined for 2.5 h. The reaction was taken up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. Chromatography (20% ethyl acetate/hexanes) afforded the desired compound (3.1 g 90%).
Step 3 - The above ester was placed in a solution of NaOH (2N):THF:MeOH (1:2:1) and stiπed overnight at room temperature. The reaction was acidified with 6 N HCl and the product extracted with ethyl acetate. The organic layers were dried (MgSO4), filtered and concentrated. The solid was triturated with ethanol and stiπed for 1 h. The solid was filtered and dried affording the title compound (1.85 g) as a yellow solid. MS: m/z (M-1) 474
Example 70 2-{5-(benzyloxy)-l-F2.4-bis(trifluoromethyl)benzyl1-lH-indol-3-yll-2- oxoacetic acid
The indole prepared in Example 69, step 1, was alkylated with the appropriate alkyl bromide and hydrolyzed as described in Example 69, steps 2 and 3. MS: m/z (M-1 ) 520
Example 71
3-(l2-Fl-f4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yll-2- oxoacetyl}amino)benzoic acid
Step 1 - To a solution of the acid from Example 69, step 3, (0.810 g) in THF (28 mL) was added CDI. The reaction was stined 30 min and then ethyl 3-aminobenzoate (0.330 g) was added and the reaction was stiπed overnight. The reaction mixture was taken up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. The crude material was triturated with ethanol and stined for 1 h, filtered and dried. The desired product (0.76 g, 75%) was isolated as a yellow solid. Step 2 - The above ester was dissolved in NaOH (2N):THF:MeOH (1:2: 1) and stiπed
4h. The mixture was acidified with 6 N HCl and extracted with ethyl acetate. The combined organic layers were dried (MgSO4), filtered and concentrated. The crude solid was triturated with ethanol/hexane to afford the title compound (0.48 g, 69%) as a yellow solid. Example 72
5-F(2-I5-(benzyloxy)-l-F2.4-bisftrifluoromethvnbenzvn-lH-indol-3-yl)-2- oxoacetyPaminolisophthalic acid
The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2. MS: m/z (M-1 ) 683
Example 73
3-rf2-(5-(benzyloxy)-l-F2.4-bis rifluoromethyl benzyll-lH-indol-3-yll-2- oxoacetyPaminolbenzoic acid The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2. MS: m/z (M-1) 639
Example 74 5-({2-Fl-(4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yπ-2-oxoacetyl}amino)- 2-F(5-chloro-3-pyridinyl)oxy1benzoic acid
The alkylated indole from Example 69 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
Example 75
5-Fr2-I5-(benzyloxy)-l-F2.4-bis(trifluoromethvnbenzvn-lH-indol-3-yll-2- oxoacetyl)aminol-2-F(5-chloro-3-pyridinyl)oxylbenzoic acid
The alkylated indole from Example 70 was coupled to the appropriate amino acid and hydrolyzed as illustrated in Example 71, steps 1 and 2.
Example 76
2-Fl-(4-benzylbenzyl)-5-fbenzyloxy -lH-indol-3-vn-N-r3-f(F(4- methylphenyl sulfonynamino}carbonyl)phenyl1-2-oxoacetamide
To the acid obtained in Example 71 (0.1 g) in CH2C12 (10 mL) is added THF ( 5 mL) to help dissolve the compound. EDCI (0.045 g) and DMAP (0.02 g) was added and the mixmre was stined a room temperature of 1 h. p-Toluenesulfonamide (0.04 g) was added and the reaction was stined overnight. The reaction mixture was take up in ethyl acetate and washed with water, dried (MgSO4), filtered and concentrated. Chromatography (7% MeOH/CH2Cl2) afforded the title compound (0.045 g, 40%) as a yellow solid. MS: m/z (M-1) 746 Example 77
2-F5-bromo-l-(cyclopropylmethyl)-lH-indol-3-vπacetic acid
To 5-bromoindole-3-acetic acid (890 mg, 3.5 mmol) in l-methyl-2-pynolidinone (12 mL) at 0 °C were added 'Pr2NEt (21 mmol) and bromomethylcyclopropane (10.5 mmol). The reaction mixture was heated at 50 °C for 19 h before partitioning between diethyl ether and ice water. After adjusting the pH to 3, the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with NaH2PO4, dried over MgSO4 and evaporated to dryness. Purification on silica gel column ( 30% EtOAc in hexane) yielded 927 mg (86 % yield) of the product.
Example 78
2-Fl-(cyclopropylmethyl)-5-(2-thienyl)-lH-indol-3-yllacetic acid
To a sealed tube containing 2-[5-bromo-l-(cyclopropylmethyl)-lH-indol-3-yl]acetic acid (100 mg, 0.32 mmol), 2-thiopheneboronic acid (124 mg, 0.97 mmol), (C6H5)4Pd (37 mg, 0.032 mmol), Na^Oj (2.6 mmol) in a mixture of benzene/EtOH/H2O (5/1/3, 4.5 mL) was heated at 85 °C for 19 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The mixture was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column ( 33% EtOAc in hexane with 1 % HCOOH) to give 79 mg (78% yield) of the product.
Example 79
2-π-(cyclopropylmethyl)-5-F3-(trifluoromethyl)phenyll-lH-indoI-3-vUacetic acid
The title compound was prepared according to the procedure described in Example 78 except that 3-(trifluoromethyl)phenylboronic acid was used.
Example 80 2-F5-(l-benzofuran-2-yl)-l-benzyl-lH-indol-3-yl1acetic acid
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and benzo[b]furan-2-boronic acid were used.
Example 81 2-(l-benzyI-5-phenyl-lH-indo!-3-yl)acetic acid
The title compound was prepared according to the procedure described in Example 78 except that 2-[5-bromo-l-benzyl-lH-indol-3-yl]acetic acid and phenylboronic acid were used. Example 82 A
5-((E)-{l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methyIidene)-l,3- thiazolane-2,4-dione
Step 1
The procedure in Example 22 was followed using 3-formyl indole (0.4g, 2.8mmol), sodium hydride (0.102g, 3.0mmol) and the iodide (0.97g, 2.8mmol) in DMF (10ml). Flash chromatography (Hex/EtOAc, 1/1) gave 0.86g (84%) of the desired intermediate.
Step 2
The intermediate from step 1 (0.8 g, 2.2 mmol) and 2.4-thiazolidinedione (0.25, g, 2.2 mmol) was dissolved in toluene (5 mL). Piperidine (0.064 mL, 0.6 mmol) and acetic acid (0.012 mL) were added and the mixture was heated to reflux for 2h. The reaction was allowed to cool to rt, water was added and the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water, brine , dried (MgSO4), filtered and concentrated. Flash chromatography (hexane/ ethyl acetate , 3/2) afforded the title compound (0.345 g (33%) as an orange solid.
Example 82 B
4-{[5-((E)-{l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methylidene)-2,4- dioxo-l,3-thiazolan-3-yl]methyl}benzoic acid
The procedure in Example 22 steps 1 and 2 were followed to give 0.14g (47% for 2 steps) of the title compound as a yellow powder.
Example 82 C
2-[5-((E)-{l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methylidene)-2,4- dioxo-l,3-thiazolan-3-yl]acetic acid The procedure in Example 22 steps 1 and 2 were followed to give 0.107g (42% for 2 steps) of the title compound as a yellow powder.
Example 83 3-{l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}propanoic acid The procedure in Example 22 step 1 was followed except 2 eq. of sodium hydride was used and 0.142g (65%) of the title compound was isolated as a white oily solid. Example 84
3-{l-benzhydryl-5-F(cvclopentylcarbonyl)amino1-lH-indol-3-yllpropanoic acid
Step 1
To a solution of the aldehyde from Example 114, stepl (l.Og, 2.8mmol) in toluene (20ml) was added carbomethoxyethyhdene triphenylphosphorane (0.98g, 2.9mmol). The mixture was heated overnight at reflux and then concentrated. The residue was dissolved in CH2C12 and silica gel was added. The mixture was concentrated and the resulting solid was purified by flash chromatography (Hex/EtOAc. 3/1). Compound 30 l.Olg (88%) was isolated as a yellow solid. Step 2
To a solution of the above intermediate (O.lg, 0.24mmol) in THF (10ml), was added platinum on activated carbon (5% Pt, 0.05g, 50 wt%). Hydrogen gas was bubbled into the suspension for 2min, the vessel was sealed tightly and the reaction was stined overnight at rt. Argon gas was then bubbled through the reaction for 15min before the mixture was filtered through a pad of Celite. The pad was washed with EtOAc and the filtrate was concentrated. The residue was dissolved in CH2C12 (5ml). Aqueous saturated NaHCO3 (3ml) was added, followed by cyclopentanecarbonyl chloride (0.036ml). The biphasic mixture was stiπed for 2h at rt and diluted with CH2C12. The organic layer was washed with water and brine, dried and concentrated to a white solid. Recrystallization from EtOAc/Hex gave 0.1 lg (95%) of the desired intermediate as a white solid. Step 3
Hydrolysis of the above ester with NaOH (IN, 2 mL) in THF (2mL) and MeoOH (2 mL) followed by recrystallization from hot EtOAc afforded 0.054g (50%) of the title compound as a white solid.
Example 85
N-(l-benzhydryl-3-{3-[(methylsulfonyl)amino]-3-oxopropyl}-lH-indoI-5- yl)cyclopentanecarboxamide
To a solution of the acid from Example 84 step 3 (O.lg, 0.22mmol) in THF (5ml) was added methanesulfonamide (0.027g, 0.28mmol), EDCI (0.54g, 0.28mmol) and DMAP (0.012g, 0.1 mmol). The mixture was heated at 50°C overnight then diluted with EtOAc, washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 1/1) gave O.lg (87%) of the title compound as a white solid. Example 86 A
(E)-3-{l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indoI-3-yl}-2- propenoic acid
Stepl The same procedure as Example 84 step 2 was used to prepare the desired intermediate from the nitroindole (Example 114 step 1). Step 2 The procedures in Example 84, step 1 and 3 were used to prepare the title compound from the above intermediate.
Example 86 B
N-(l-benzhydryl-3-{(E)-3-[(methylsulfonyl)amino]-3-oxo-l-propenyl}-lH- indol-5-yl)cyclopentanecarboxamide
The acid from Example 86A was used to prepare the title compound according to the procedure in example 85.
Example 87 A (E)-3-{l-benzhydryl-5-nitro-lH-indol-3-yl}-2-propenoic acid
The ester from Example 84 step 1 was saponified according to the procedure in Example 84 step 3 and recrystallization from hot EtOAc afforded 0.155g (90%) of the title compound as a white solid.
Example 87B
N-((E)-3-{l-benzhydryl-5-nitro-lH-indol-3-yl}-2- propenoyl)methanesulfonamide
The procedure in Example 85 was used to prepare the title compound from the product of Example 87A.
Example 88
4-F(l-benzhydryl-5-chloro-2-methyl-lH-indol-3-yl)methyllbenzoic acid Step 1 To an ice-cold (0°C) solution of trifluoroacetic acid (1.7ml, 15mmol) and triethylsilane (4.8ml, 30mmol) in CH2C12 (20mL) was added a solution of 5-chloro-2-methylindole (1.66g, lOmmol) and methyl 4-formylbenzoate (1.8g, 1 lmmol) in CH2C12 (50mL) over a period of 5 min. The resulting homogeneous solution was stined at 0°C for lh and rt for 2h, at which time EtOAc (150mL) and aqueous sodium bicarbonate (to pH=8) was added. The organic layer was washed with water and brine, dried over MgSO4 and concentrated. Flash chromatography (Hex/EtOAc, 4/1) gave 1.98g (63%) of desired intermediate as a light-tan solid. Step 2 Sodium hydride (0.2g, 5mmol) was washed with dry hexanes (3x10ml) and then suspended in DMF (6mL) and cooled to 0°C. A solution of the above intermediate ( 1.57g, 5mmol) in DMF (4mL) was dropwise at 0°C and the resulting mixture was stined for 30min at which time the diphenylbromomefhane (1.24g, 5mmol) was added. The mixture was allowed to reach it and stiπed for an additional 48h. EtOAc (30mL) was added followed by aqueous NaH2PO4 solution (10ml). The organic layer was washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 7/1) provided 0.98g (41%) of the desired intermediate as a ivory foam. Step 3 The above intermediate was saponified according to the procedure in Example 84 step 3. Flash chromatography (EtOAc) provided 0.3g (89%) of the title compound as a tan crystalline solid. MS: m/z (M-1 ) 464
Example 89
4-{Fl-benzhydryl-5-({ F4-ftrifluoromethyl)phenyllsulfonvI}amino)-lH-indol-3- yllmethyU-3-methoxybenzoic acid
Stepl - The intermediate from Example 3 step 2 (leq) (see scheme #) was weighed in to a flask along with the 4-trilflouromethylbenzene sulfonyl chloride (1.2 eq) and then they were flushed with nitrogen, taken up in dichloroethane (0.15 M) and then pyridine was added (1.2 eq) at which time the reaction was left to stir overnight and then worked up by the addition of the polymer bound amine ( Parlow, J.J, Mischke, D. A., Woodard, S.S.J Org. Chem. 1997, 62, 55908-5919) (1.6g/lmmol) and the resulting slurry was stined a minimum of 15 minutes and then it was filtered and washed with dichloroethane and the dichloroethane solution was dried and concentrated to yield 98% of the desired product with high purity.
Step 2 - The crude material from stepl was dissolved THF/MeOH (2.5/1) and then 4N NaOH was added ( 3 eq) and the reaction was stined until complete hydrolysis was observed by TLC. At this point the reaction quenched with enough amberlite ir 120 to make the solution acidic and then the resin was filtered off and rinsed and the desired product was obtained in 94% yield by drying and concentrating the solution. MS: m/z (M-1) 669
Example 90
4-{F5-({F2-(acetylamino)-4-methyl-1.3-thiazol-5-yl]sulfonyl}amino)-l- benzhydrvI-lH-indol-3-yllmethyll-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 76% of the title compound after chromatographic purification. Step 2: An analogous proceedure to step 2 for Example 89 above yielded 83% of the desired product. MS: m/z (M-1 ) 679
Example 91
4-F(l-benzhvdryl-5-(F(4-chloro-3-nitrophenyl)sulfonyl1amino)-lH-indol-3- yl methyn-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 54% of the desired product after chromatographic purification. MS: m/z (M-1) 681
Example 92
4-F(l-benzhvdryl-5-IF(dimethylamino)sulfonyl1aminol-lH-indol-3-yl)methyl1-
3 - Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded
49% of the title compound after chromatographic purification. Step 2: An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product. MS: m/z (M-1) 568
Example 93
4-{Fl-benzhydryl-5-(IF4-(trifluoromethoxy)phenyl1suIfonyl)amino)-lH-indol- 3-yIlmethyll-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 100% of the desired product. MS: m/z (M-1) 685
Example 94
4-F(l-benzhydryl-5-{F(2-methylphenyI)sulfonyl]amino}-lH-indol-3- yl)methvπ-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 56% of the title compound after chromatographic purification.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 82% of the desired product. MS: m/z (M-1 ) 615 Example 95
4-F(l-benzhvdryl-5-{F(5-chloro-1.3-dimethyl-lH-pyrazol-4- yl)sulfonyllamino}-lH-indol-3-yl)methyll-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound. Step 2: An analogous proceedure to step 2 for Example 89 yielded 96% of the desired product. MS: m/z (M-1 ) 655
Example 96
4-F(l-benzhydryl-5-IF(3.5-dimethyl-4-isoxazolyl)sulfonyllamino}-lH-indol-3- yl)methvn-3-methoxybenzoic acid
Step 1: Following step 1 for Example 89 using the appropriate sulfonyl chloride yielded 100% of the title compound.
Step 2: An analogous proceedure to step 2 for Example 89 yielded 89% of the desired product.
MS: m/z (M-1 ) 621
Example 97
Cvclopentyl-N-l3-F4-faminocarbonyl)-2-methoxybenzyll-l-benzhydryl-lH- indol-5-yl)carbamate
The compound of Example 3 (1.0 eq) was dissolved in THF (0.15M) and then carbonyl diimidizole (1.2 eq) was added and the reaction was stirred under N2 for three hours at which time ammonium hydroxide was added (3ml g) and the reaction was stined overnight when TIC analysis showed it was complete. To the reaction was added water and ethyl acetate, the layers were separated and the aqueous layer was extracted three times, the combined organic extracts were dried concentrated and chromatographed to yield 64% of the desired primary amide.
Example 98 cvclopentyl N-(l-benzhvdryl-3-F2-methoxy-4-(lH-1.2.3.4-tetraazol-5- yl)benzyll-lH-indol-5-yllcarbamate Step 1 - To the compound of Example 97 (1.0 eq) under N2 was added CH2C12
(0.06M) and then (methoxycarbonylsulfamoyl)triethylammonium hydroxide inner salt (5.0 eq) portion wise over 5 hours and then the slurry was stined overnight at which time TLC analysis indicated the reaction was complete so it was concentrated and chromatographed to yield 78% of the desired product. Step 2 - To the nitrile (1.0 eq) isolated in step 1 was add sodium azide (3 eq) and triethyl amine hydrochloride (1.5 eq) and n-methyl-2-prynolidinone (0.05m) and then the reaction was heated to reflux under an inert atmosphere for 2.5 hours when it was poured into ice and water that was then acidified to pH 2 and the product was filtered off and then further purified by preparative chromatography to yield the desired compound in 22% yield. MS: m/z (M-1 ) 597
Example 99
4-F((l-benzhvdryl-5-F(cyclopentylcarbonyl)amino1-lH-indol-3- yl}carbonyl)aminol-3-thiophenecarboxylic acid step 1 To the indole acid (1.0 eq) was added the amine (1.2 eq) the dimethylaminopyridine (10 mol %), l-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.5 eq) and then DMF(0.3M) and the reaction was stined under nitrogen for 24 hours at 40°C for 24 hours at which time it was poured into 1/2 saturated ammonium chloride solution and ethyl acetate and then the layers were separated and the aqueous layer was extracted 3 times, the combined organic layers were washed with water 2X, dried, concentrated and chromatographed to yield 38% of the amide.
Step 2 The ester from the previous step was dissolved in THF/MeOH (3:1) and then IN NaOH (3.0eq) was added and the reaction was stined for until TLC analysis showed that the reaction was complete. The reaction was then concentrated, diluted with water, acidified to pH 2 with cone HCL, extracted with ethyl acetate 3X, the combined organics were dried over magnesium sulfate concentrated and purified via chromatography to yield the desired acid in 64% yield.
Example 100
3-F({l-benzhvdryl-5-F(cyclopentylcarbonyl)aminol-lH-indol-3- yllcarbonvDaminolbenzoic acid
Step 1 : The acid (see scheme #) was coupled with the appropriate amino ester following the procedure in Example 99, step one, except the reaction was run at room temperature and that the procedure yielded 80% of the desired product isolated by recrystalization. Step 2: The nitro ester from step one (1.0 eq) was weighed into a flask along with 5% Platinum on Carbon (40 wt%) and the vessel was sealed with a septum and evacuated and flushed with argon 3X, then freshly distilled THF is added and the reaction is evacuated 2X and after the second evacuation a balloon of hydrogen inserted into the septum. The reaction is left under atmospheric hydrogen for 16 hours at which time tic analysis indicates complete reduction and the reaction is flushed with argon and then filtered through a bed of celite and the catalyst is washed exhaustively with ethyl acetate, the filtrate was dried and concentrated and purified via chromatography to deliver 71% of the desired amine. step 3: The amine (1.0 eq) was dissolved in dichloromethane (0.3M) and then an equivalent amount of saturated sodium bicarbonate was added and finally the acid chloride introduced.
The biphasic reaction mixture was vigorously stiπed until TLC analysis indicated that the reaction was complete (generally a few hours) and then the reaction was diluted with dichloromethane and water, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried, concentrated and chromatographed to yield the desired amide in 41% yield.
Step 4: According to step 2, Example 99, the ester was hydrolyzed to the acid and yielded 71% of the final product. MS: m/z (M-1) 556
Example 101
3-F((l-benzhydryl-5-F(cvclopentylcarbonyl)aminol-lH-indol-3- yllcarbonyPaminolpropanoic acid step 1 To the final product in Example 114 (l.Oeq) in dichloromethane (0.1M) at 0°C was added oxallyl chloride (2.0 eq) and then a few drops of DMF. The reaction was stined a few hours at room temperature and concentrated and azeotroped 2X with toluene and placed on the high vacuum for 2 hours before being used crude for the next step. Step 2: To the acid chloride generated in step 1 was added dichloromethane (0.1M) and then a solution of alanine methyl ester (1.05eq, free base) in dichloromethane (1.0M) and then triethylamine (1.5eq)was added and the resulting mixture was stined overnight and worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired amide.
Step 3: The ester from step 2 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid.
Example 102 N-Fl-benzhvdryl-3-({F(2-methylphenyl)sulfonvnaminolcarbonyI)-lH-indol-5- yllcvclopentanecarboxamide
Step 1: The acid chloride (1.0 eq) synthesized in step 1, Example 101, was weighed into a flask along with o-tolylsulfonamide (1.5eq), DMAP (0.1 eq) and taken up in dichloromethane
(0.1M) under nitrogen and then triethylamine (1.5eq) was added and the resulting mixture was stiπed for 12 hours and then worked up by the addition of 1/2 saturated ammonium chloride, the layers were separated, the aqueous layer was extracted three times with dichloromethane, the combined organic layers were dried and concentrated and purified via chromatography to yield the desired acylsulfonamide in 52% yield.
Example 103 3-F(2-ll-benzhvdryl-5-F(cvclopentylcarbonyl)amino1-lH-indol-3-yl}-2- oxoacetvPaminolpropanoic acid
Step 1: According to the general procedure in step 1, Example 101, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid. MS: m/z (M-1) 536
Example 104
3-1(2-11 -benzhvdryl-5-F(cvclopentylcarbonyI)amino1-lH-indol-3-yll-2- oxoacetvDaminolbenzoic acid Step 1: According to the general procedure in step 1, Example 99, using the product from Example 115 and the appropriate amino ester yielded the desired product in 100% yield. Step 2: The ester from step 1 was hydrolyzed under the conditions outlined for step 2, Example 99, to yield the desired acid. MS: m/z (M-1) 584
Example 105
3-((2-Fl-(4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yllacetyl}amino)benzoic acid
Step 1
An oven dried flask was charged with 5-benzyloxy indole-3-acetic acid (1 eq) (see scheme- 1) and anhydrous DMF (0.18 M) under nitrogen. Reaction mixture was then cooled to 0°C and to this was added NaH (2.2eq, 60% dispersion in mineral oil), stined at 25°C for lh followed by addition of a solution of the appropriate benzyl bromide (2.2eq, 40% purity) (see scheme- 1, steps 5,6) in anhydrous DMF, stined overnight. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 66% yield. Step 2
Dissolved the indole derivative from step 1(1 eq) (see scheme- 1) in THF/MeOH/H2O (3:1:1 0.094 M) and to this was added LiOHΗ-O (1.2 eq), stined at 25°C, overnight. Workup with ethyl acetate/water followed by chromatographic purification afforded the desired product in 74% yield. Step 3
To the acid from step 2 (1 eq) (see scheme- 1) was added methyl 3-aminobenzoate (1.05 eq), EDCI (1.37 eq) and DMAP (0.2 eq) followed by anhydrous DMF (0.086M), stined at 25°C, overnight. Workup with ethyl acetate/ IN HCl followed by chromatographic purification afforded the desired product in 80% yield. Step 4
Dissolved the ester (1 eq) from step 3 (see scheme- 1) in THF/MeOH/H2O (3:1:1 0.04 M) and to this was added LiOHH2O (1.2 eq), stiπed at 25°C, overnight. Workup with ethyl acetate/lN HCl followed by trituration with CH^l^exane (1:1) for 0.5h and then recrystallization from CH2C12 afforded the titled product in 97% yield. MS: m/z (M-1 ) 579
Example 106
3-Ff2-I5-(benzyloxy -l-r2.4-bisftrifluoromethyl)benzyll-lH-indol-3- vUacetvDaminol benzoic acid Step 1 Following procedure in step 1 of example 105, scheme- 1 and using the appropriate benzyl bromide afforded the desired product in 50% yield after chromatographic purification. Step 2
Following procedure in step 2 example 105, scheme- 1 and using the appropriate indole derivative afforded the desired product in 67% yield after chromatographic purification. Step 3
Following procedure in step 3 example 105, scheme- 1 and using the appropriate indole derivative afforded the desired product in 75% yield after chromatographic purification. Step 4 Following procedure in step 4 example 105, scheme- 1 and using the appropriate indole afforded the desired product in 63% yield after chromatographic purification. MS: m/z (M-1 ) 625
Example 107
5-(benzyloxy)-l-F2.4-bisftrifluoromethyl)benzvn-2-methyl-lH-indole-3- carboxylic acid
Step 1: The 5-Hydroxy-2-Methylindole-3-Carboxylate (1 eq) was combined with benzyl bromide (1.3 eq) and K2CO3 (325 mesh, 1.3 eq) in CH3CN (0.1 M). The resulting mixture was heated to reflux for 2 h. An additional amount of benzyl bromide (0.2 eq) and the heating was continued for 2 h. The reaction was worked up by addition of water and extraction with CH2C12. The organic extracts were washed with water, dried and concentrated. Flash chromatography provided the desired benzyl ether (63 % yield), as well as the conesponding
N,O-bisbenzyl derivative (22 % yield).
Step 2: An ice cooled solution of the benzyl ether from step 1 (1 eq) in dry DMF (0.25 M) was treated with NaH (60 % in mineral oil, 1.1 eq). 2,4-Bis trifluoromethyl benzyl bromide (1.1 eq) was added after 1 h and the resulting mixture was stiπed at 25°C for 2 h. Solvent was evaporated under vacuo, the residue was dissolved in EtOAc, washed with water, dried and concentrated. The desired product was obtained in 77 % yield after recrystallization from hexane/CHClj.
Step 3: The product from step 2 (1 eq) in THF/MeOH (3/1) was heated to reflux with IN
NaOH (12 eq). After 48 h the reaction was quenched with AcOH and solvent was evaporated. The resulting product was recrystalhzed to afford crude material in 72 % yield. Further purification by flash chromatography followed by recrystallization provided pure title compound. MS: m/z (M-1 ) 506
Example 108 5-F((5-fbenzyloxy)-l-F2.4-bis(trifluoromethyl)benzvn-2-methyl-lH-indol-3- yl arbonvDaminolisophthalic acid
Step 1: The acid prepared in step 3 (1 eq) of example 108 was reacted with EDCI (2 eq) and dimethyl 5-aminophthalate (5 eq) in THF (0.02 M) in the presence of DMAP (2 eq). The reaction was heated to reflux for 48 h. EtOAc/water work up, followed by flash chromatography produced the desired amide in 32 % yield.
Step 2: The material from step 1 (1 eq) was hydrolyzed by the action of LiOHH2O (2.2 eq) in THF/MeOH/water (3/1/1, 0.07 M). After stirring at 25°C overnight, the reaction mixture was quenched with AcOH and solvent was evaporated. EtOAc/water work up and trituration in hexane/CH,Cl2 afforded the title compound in 82 % yield. MS: m/z (M-1) 669
Example 109
5-(benzyloxy)-2-methyl-l-(2-naphthylmethyl)-lH-indole-3-carboxylic acid Step 1: An analogous procedure to step 2 example 108 using the main product of step 1 above and the appropriate bromide yielded the desired N-substituted indole in 71 % yield after recrystallization.
Step 2: The ester from step 2 above (1 eq) in THF/MeOH (3/1) was heated to reflux with 4N KOH (2 eq). After 5 days solvent was evaporated and the residue partitioned between IN HCl and CHC13. The organic extract was washed, dried and concentrated. The title compound was obtained in 92 % yield after chromatographic purification and crystallization. MS: m/z ( M - 1 ) 420 Example 110
5-flF5-fbenzyloxy)-2-methyl-l-(2-naphthylmethvn-lH-indol-3- yl1carbonyllamino)isophthalic acid
Step 1: The acid in Example 109 was converted in the conesponding amide following an analogous procedure to step 1 of Example 108. The product was contaminated with the aniline starting material which could only be partially removed by chromatography. Step 2: Hydrolysis of the crude material following step 2 Example 108 provided the title compound after chromatographic purification (4 % yield in Example 109).
Example 111 l-benzyl-5-(benzyloxy)-2-methyl-lH-indole-3-carboxylic acid
Step 1: The minor product of step 1 (1 eq) Example 107 was dissolved in THF (0.1 M). KOH (2 eq) and 18-crown-6 (2 eq) were added and the resulting mixture was heated to reflux for 1.5 days. Work up as on step 2 Example 108 above provided the title compound in 32 % yield. MS: m/z (M-1) 370
Example 112
3-[(2-{5-(benzyloxy)-l-(4-chlorobenzyl)-2-[(2-naphthylsulfanyl)methyl]-lH- indol-3-yl}-2-oxoacetyl)amino]benzoic acid Step 1 The starting ethyl 5-benzyloxyindole-2-carboxylate (Scheme 21, step 1) was treated with LAH (1.3 eq) in THF (0.27 M) at 0 °C under nitrogen for 1 h. Workup with NaOH and water followed by concentration afforded crude product (100%).
Step 2 The crude alcohol from step 1 was dissolved in DMF (0.38 M), and treated with t- butyldimethylsilyl chloride (1.16 eq) and imidazole (1.26 eq) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (93%).
Step 3 The silyl ether from step 2 was dissolved in methylene chloride (0.26 M), and treated with BOC anhydride (1.24 eq), triethylamine (1.53 eq) and DMAP (0.21 eq) at 25 °C for 3 d. Workup and chromatographic purification afforded the pure product (99%). Step 4 The N-BOC silyl ether from step 3 was treated with acetic acid/ water/ THF (3:1:1) (0.04 M) at 25 °C for 1 d. Workup and chromatographic purification afforded the pure product (100%).
Steps 5 The alcohol from step 4 was dissolved in methylene chloride (0.2 M), and under nitrogen at -40°C treated with triethylamine (1.33 eq), and mesyl chloride (1.23 eq) for 1 h. In a separate dry flask was weighed naphthalene-2-thiol (1.31 eq), and THF (1 M) was added, followed by hthium hexamethyldisilazide (IN in THF, 1 eq) and this mixture was stined at 25°C for 30 min. The resulting solution was then added dropwise, over 30 minutes, to the above mesylate solution, at -40°C. The reaction mixture was allowed to warm to 25°C, and stined there for 4.5 h. Workup and chromatographic purification afforded the BOC thioether. Step 6 The purified BOC thioether from step 5 was heated under nitrogen at 160- 170°C for 1.25 h, and recrystalhzed from ethyl acetate and hexanes to afford the free indole thioether in 64% yield.
Step 7 The indole thioether from step 6 was dissolved in DMF (0.2 M), and treated with sodium hydride (1.1 eq) at 25°C for 45 min. 4-Chlorobenzyl chloride (1.3 eq) and KI (cat.) were added, and the mixture was stiπed at 25°C for 3 d. Workup (ethyl acetate/water) and trituration (ethyl acetate/hexanes) afforded the pure product (52%).
Step 8: A solution of EtMgBr in ether (3 N, 2.17 eq) was cooled to - 70 °C. The product of step 7 in scheme 21 (1 eq) in ether (0.55 M) was added and the reaction mixture was stined at - 70 °C for 2 h. After the addition of methyl oxalyl chloride (3 eq) in ether (1.5 M) the reaction was stiπed at - 40 °C for 2 h, allowed to warm to 25 °C. Quenched with sodium bicarbonate EtOAc/water work up and crystallization from hexane/EtOAc the desired ketone.
Step 9 The ester from step 8 was hydrolyzed using the general method in step 2 example 108 to yield the desired alpha keto acid.
Step 10 The indole thioether from step 9 was dissolved in dry methylene chloride (0.05 M), and treated with oxalyl chloride (2.05 eq) at 0°C for 1 h. In a separate dry flask were weighed 3-aminobenzoic acid (10 eq) and triethylamine (15 eq) in methylene chloride (0.5 M). The resulting solution was then added dropwise, at 0°C, and the mixture was allowed to warm to 25°C overnight. Workup (methylene chloride/aqueous HCl) and repeated purification by chromatography afforded the pure title compound product.
Step 11 The product from step 9 was hydrolyzed using the procedure from step 2 Example 108 to yield the desired compound in 28%. MS: m/z (M-1) 709
Example 113
3-F(2-l5-(benzyloxy)-l-methyl-2-F(2-naphthylsulfanyl)methyll-lH-indol-3- yl)-2-oxoacetyl)amino1benzoic acid
Step 1 Following step 4 of the above procedure using methyl iodide followed by trituration (ethyl acetate/hexanes) afforded the pure product (72%). Step 2 An analogous procedure to step 5 through step 11 above yielded 58% of the title compound. MS: m/z (M-1) 599
Example 114 l-benzhvdryl-5-F(cvclopentylcarbonyl)aminol-lH-indole-3-carboxylic acid Step 1 5-nitroindole was alkylated as in Example 3 stepl with the appropriate bromide to yield the desired N-alkylated product.
Step 2 The indole from step 1 (l.Oeq) was dissolved in DMF (0.4M) and treated with phosporous oxychloride (6.9 eq) at room temperature and then the mixture was stiπed for 1 day at 80 C at which time the reaction was poured onto ice and triturated with ethyl acetate/hexanes, followed by workup with sodium bicarbonate/chloroform yielded the C3 formylated product.
Step 3 The nitro indole from step 2 was reduced according to the procedure in
Example 100, step 2 to yield the amino aldehyde.
Step 4 The indole from step 3 was acylated according to the procedure from
Example 100, step 3.
Step 5 The indole from step 4 (1.0 eq), 2 methyl-2butene (45 eq), sodium dihydrogen phosphate (11.6 eq). were dissolved in t-BuOH (0.2M), water (0.2M) and then sodium chlorite (11.6q) was added and the reaction was heated to 65 C for 24 hours.The reaction was diluted with water, extracted 3 times with ethyl acetate, dried and concentrated and then purified by chromatography to yield the title compound.
Example 115
2-{l-benzhydryl-5-F(cvclopentylcarbonyl)amino1-lH-indol-3-yll-2-oxoacetic acid
Step 1 Following the procedure of Example 69, 5-niroindole was acylated in the 3-position with ethylmagnesiumbromide and ethyloxalylchloride. Step 2 The above intermediate was elaborated to the final product following steps 2-5 of Example 114 to afford the title compound. Example 116
Table I reports data for the compounds described in the examples above in cPLA2 inhibition assays (described below). In the data columns of Tables I and π, assay results are reported as a percent inhibition at the concentration specified.
Coumarin Assay 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Nalytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 μL assay buffer (80 mM Heped, pH 7.5, 1 mM EDTA) containing 60 μM 7-hydroxycoumarinyl 6-heptenoate. The reaction was initiated by adding 4 μg cPLA2 in 50 μL assay buffer. Hydrolysis of the 7-hydroxycounarimyl 6-heptenoate ester was monitored in a fluorometer by exciting at 360 nm and monitoring emission at 460 nm. Enzyme activity is proportional to the increase in emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.
Table I
Figure imgf000107_0001
10
Figure imgf000108_0001
10
Figure imgf000109_0001
10
15
Figure imgf000110_0001
10
Figure imgf000111_0001
10
Figure imgf000112_0001
81 2.5
Figure imgf000113_0001
Figure imgf000113_0002
Figure imgf000113_0003
Figure imgf000113_0004
Figure imgf000113_0005
10
Figure imgf000113_0006
Figure imgf000113_0007
Figure imgf000113_0008
Figure imgf000113_0009
60 50 12.5
15
Figure imgf000113_0010
Figure imgf000113_0011
Figure imgf000113_0012
Figure imgf000113_0013
Figure imgf000113_0014
20
Figure imgf000114_0001
Figure imgf000114_0002
Figure imgf000114_0003
9 50 12.5
Figure imgf000114_0004
Figure imgf000114_0005
2 50 12.5 6 50
Figure imgf000114_0006
Figure imgf000114_0007
Figure imgf000114_0008
Figure imgf000114_0009
Figure imgf000114_0010
Figure imgf000114_0011
Figure imgf000114_0012
Figure imgf000114_0013
Figure imgf000114_0014
Figure imgf000115_0001
Figure imgf000115_0004
Figure imgf000115_0005
6B
Figure imgf000115_0006
Figure imgf000115_0002
Figure imgf000115_0007
Figure imgf000115_0008
Figure imgf000115_0009
Figure imgf000115_0003
Figure imgf000115_0010
Figure imgf000115_0011
Figure imgf000115_0012
Figure imgf000115_0013
10
15
Figure imgf000116_0001
25 50
Figure imgf000117_0001
Figure imgf000117_0002
112 53 2.5
Figure imgf000117_0003
Figure imgf000117_0004
10
Figure imgf000117_0005
117 50 1.6
118 50 0.6
119 50 2.5
120 50
15
121 20 1.6
122 64 1.25
123 50 1.2
124 50 1.3
125 50 0.8
20
126 50 5.5
127 50 1.1
128 50 0.9
129 50 1.1
130 50 2
25
131 50 0.6 132 50 0.4
133 50 0.3
134 50 0.8
135 50 0.7
136 50 0.4
137 50 0.8
138 50 0.4
Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure described below. The results are reported in Table π.
Rat Canageenan-Induced Footpad Edema Test
Each compound was suspended in 0.3ml absolute ethanol, 0.1 ml Tween-80 and 2.0 ml Dulbecco's PBS (without calcium or magnesium). To this mixture, 0.1ml IN NaOH was added. After solution was complete, additional amounts of PBS were added to adjust the concentration to 1 mg/ml. All compounds remained in solution. Compounds were administered i.v. in a volume of 5 ml/kg to male Sprague Dawley rats at the same time that edema was induced by injection of 0.05ml of 1% Type TV canageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan.
Table II
Figure imgf000119_0001
Figure imgf000119_0002
rv 15.87
Figure imgf000119_0003
Figure imgf000119_0004
Figure imgf000119_0005
rv -0.65 rv -5.7 rv 4.46
10 IV 25.32
11 rv 13.98
Figure imgf000119_0006
Figure imgf000119_0007
Figure imgf000119_0008
Figure imgf000119_0009
Figure imgf000119_0010
Figure imgf000120_0001
Figure imgf000120_0002
Figure imgf000120_0003
Figure imgf000120_0004
Figure imgf000120_0005
Figure imgf000120_0006
10
Figure imgf000120_0007
26 rv 25.31
27 rv 6.48
28 rv 0.29
Figure imgf000120_0008
15
Figure imgf000120_0009
Figure imgf000120_0010
Figure imgf000120_0011
40 IV 5 8.21
41 IV 5 10.1
20
42 IV 5 7.72 10
15
20
Figure imgf000121_0001
25 76 rv 14.84
80 rv 10.18
82B rv 4.94
84 rv 6.15
85 rv 7.13
86A rv 7.4
10
Figure imgf000122_0001
Figure imgf000122_0002
Figure imgf000122_0003
Figure imgf000122_0004
Figure imgf000122_0005
15
Figure imgf000122_0006
Figure imgf000122_0007
Figure imgf000122_0008
Figure imgf000122_0009
Figure imgf000122_0010
20
97 rv 5 21.31
98 IV 5 18.39
Figure imgf000122_0011
Figure imgf000123_0001
Example 117 2-(4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methvH-2.6- dimethylphenoxylacetic acid
Step 1: To l-benzhydryl-6-chloro-lH-indole (1.0 eq) and methyl 2-(4-formy 1-2,6- dimethylphenoxy) acetate (0.6 eq) in CH2C12 (0.1M) at 0°C was added neat triethysilane (3eq) followed by triflouroacetic acid (3eq). After 10 minutes at 0°C the reaction was warmed to room temperature and stined until the initially formed spot by TLC yields a new spot. The reaction was then quenched by the addition of saturated sodium bicarbonate, diluted with CH2C12 and washed with saturated sodium bicarbonate, water and brine, dried over magnesium sulfate and purified by column chromatography to yield 89% of the desired product. Step 2 The resulting ester was hydrolyzed as in example 1 step 5 to yield the title compound after trituration and/or column chromatography. m/z (M-l)508.3 Example 118
2-(4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methvn-3- methoxyphenoxylacetic acid
Step l:This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and methyl 2- (4-formyl-3-methoxyphenoxy)acetate according to the procedure in Example 117 Step 1. Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the titie acid.
Example 119 2-{4-F(l-benzhydryl-6-chloro-lH-indol-3-yl)methyllphenoχy}acetic acid
Step l:This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and methyl 2- (4-formylphenoxy)acetate according to the procedure in Example 117 Step 1.
Step The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid.
Example 120
2-l4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methyl~l-3-chlorophenoxy}acetic acid
Step l:This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and methyl 2- (3-chloro-4-formylphenoxy)acetate according to the procedure in Example 117 Step 1 in 70% yield.
Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the titie acid.
Example 121
2-l4-Fri-benzhvdryl-6-chloro-lH-indol-3-yl)methyll-2- methoxyphenoxylacetic acid
Step l:This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and methyl 2- (4-formyl-2-methoxyphenoxy)acetate according to the procedure in Example 117 Step 1 in 71% yield.
Step 2: The ester intermediate was hydrolyzed according to step 2 Example 117 yield the title acid, m/z (M- 1)510.2 Example 122
(E)-4-{4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methvπphenoxy}-2-butenoic acid
Step 1: This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and (E)-4-(4- formylphenoxy)-2-butenoate according to the procedure in Example 117 Step 1 in 91% yield. Step 2:The ester intermediate was hydrolyzed according to step 2 Example 117 to yield the title acid, m/z (M- 1)506.3
Example 123
4-l4-F(l-benzhydryl-6-chloro-lH-indoI-3-yl)methyllanilino)-4-oxobutanooic acid Step 1 This intermediate compound was prepared from the l-benzhydryl-6-chloro-lH-indole and 4-nitrobenzaldehyde according to the procedure in Example 117 Step 1 in 42% yield. Step 2 -benzhydryl-6-chloro-3-(4-nitrobenzyl)-lH-indole was reduced by dissolving in THF (0.1 M), subjecting it to 1 atmosphere of hydrogen gas in the presence of 10%platinum on carbon catalyst (25%w/w). When the starting material had all been converted to a new spot by TLC analysis the reaction was filtered and concentrated to yield the desired intermediate in nearly quantitative yield.
Step 3:To the intermediate above (1.0 eq) in CH2C12 (0.1M) at 0°C was added triethylamine (1.5 eq) followed by 3-carbomefhoxyproprionyl chloride(1.5 eq). The reaction was warmed to room temperature, stined until complete disappearance of starting material as monitored by TLC, and then worked by the addition of saturated sodium bicarbonate, dilution with CH2C12, and washing the organic layer with water, saturated sodium bicarbonate and brine, dried, concentration and purified by column chromatography to yield the desired compound in 81% yield. Step4: The ester from step 3 was then hydrolyzed according to step 2 Example 117 to yield the title acid, m/z (M- 1)521.3
Example 124 sodium 3-l4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methvnanilinol-3- oxopropanoic acid
Step 1 The intermediate from example 117, step 1 was acylated with methyl malonyl chloride according to the procedure for step 1 of Example 117 in 82 % yield. Step 2 The ester was hydrolyzed according to step 2 for Example 123 to yield the title compound, m/z (M- 1)507.2 Example 125
2-{4-F(l-benzhydryl-6-chloro-lH-indol-3-yl)methvnanilino}-2-oxoacetic acid
Step 1 The intermediate from example 117, step 1 was acylated with methyl oxalyl chloride according to the procedure for step 1 of Example 117 in 67 % yield. Step 2 The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound, m/z (M- 1)493.2
Example 126
2-F(l-benzhydryl-6-chloro-lH-indol-3-yl)methvncvclopropanecarboxylic acid
Step 1: This intermediate compound was prepared from the l-benzhydryl-6-chloro-lH-indole and ethyl 2-formyl-l -cyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 53% yield.
Step 2: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 93 % yield, m/z (M-1) 1414.2
Example 127 2-F(l-benzhvdryl-6-chloro-5-fluoro-lH-indol-3- vDmethyllcyclopropanecarboxylic acid
Step 1 : 6-chloro-5-flouroindole was N-alkylated with benzhydryl bromide according to the procedure in Example 69 step 2 to yield the target intermediate. Step 2: The product from step 1 was C3 acylated with ethyl 2-formyl-l- cyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 53% yield. Step 3: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 73 % yield, m/z (M- 1)432.2
Examplel28
2-F(l-benzhydryl-5.6-dichloro-lH-indol-3-yl)methyl1cvclopropanecarboxylic acid
Step 1: 5,6-dichloroindole was n alkylated with benzhydryl bromide according to the procedure in Example 69 step 2 to yield the target intermediate in 70% yield. Step 2: The intermediate from step 1 was C3 acylated with ethyl 2-formyl-l- cyclopropanecarboxylate according to the procedure in Example 117 Step 1 in 62% yield. Step 3: The ester was hydrolyzed according to step 2 for Example 117 to yield the title compound in 73 % yield, m/z (M- 1)448.2 Example 129
2-(ll-Fbis(4-hvdroxyphenyl)methyl1-6-chIoro-lH-indol-3- yllmethyPcvclopropanecarboxylic acid
Step 1: 6-chloroindole was C3 alkylated with ethyl 2-formyl-l -cyclopropanecarboxylate according to the procedure in Example 117 Step 1. Step 2: The intermediate ffrom step 1 (2.0 eq.) was dissolved in THF (0.5 M) and cooled to -40°C and then triethylamine (2.0 eq) was added followed by methanesulfonyl chloride (2.0 eq). The reaction was stiπed at this temperature until TLC analysis indicated no more starting alcohol, and then it was cannulated directly into a mixture of the c3 alkylated indole from step 1 (1.0 eq) in DMF (1.0 M) at -20°C that had been stined for 30 minutes at room temperature with sodium hydride (4.0 eq of a 60% dispersion). The resulting mixture was warmed to room temperature overnight and quenched when the reaction was deemed complete by the addition of saturated ammonium chloride, diluted with ethyl acetate and washed with saturated ammonium chloride, saturated sodium bicarbonate and water (2X), dried, concentrated and purified by column chromatography. Step 3: The intermediate from step 2 was dissolved in THF (l.OM) and treated with a solution of tetrabutylammonium flouride (2.5 eq) and stiπed at room temperature until TLC analysis indicates that both silyl ethers had been cleaved. The reaction was then poured into saturated ammonium chloride and extracted with ethyl acetate (3X), the combined organic washed were washed with water, brine, dried and concentrated and purified by column chromatography to yield the intermediate in 73 % yield.
Step 4: The ester from step 3 was hydrolyzed according to step 2 for Example 123 to yield the title compound in 92% yield, m/z (M- 1)447.12
Example 130 '4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methyl1-3-hvdroxybenzoic acid Step This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and 4- hydroxy-2-methoxybenzaldehyde according to the procedure in Example 117 Step 1. Step 2: The ester was hydrolyzed according to step 2 for Example 117 to yield the titie compound
Example 131 '4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methyll-3-(3- hvdroxypropoxy)benzoic acid
Step 1: The intermediate from Example 130, step 1, was dissolved in DMF (l.OM), solid potassium carbonate (3 eq) followed by 2-(3-bromopropoxy)tetrahydro-2H-pyran (1.5 eq) was added and the reaction was left to stir for 24 hours at room temperature. The workup consisted of diluting with half saturated ammonium chloride and ethyl acetate, extracting aqueous layer with ethyl acetate (2X), washing the organic layer with water (2X), drying, concentration followed by purification via column chromatography.
Step 2: The intermediate from step 1 was dissolved in THF (l.OM), treated with glacial acetic acid (2.0 eq) and heated at 45°C for 24 hours, at which time the reaction was partitioned between saturated sodium bicarbonate and ethyl acetate, the combined organic layers where washed with water (2X), dried, concentrated and purified by column chromatography to yield 88% of the desired compound.
Step 3: The ester was hydrolyzed according to step 2 for Example 123 to yield the title compound, m/z (M- 1)524.3
Example 132
'4-({l-F(4-aminophenyl)(phenyl)methvn-6-chloro-lH-indol-3-yllmethyl)-3- methoxybenzoic acid
Step 1 :This compound was prepared from 6 chloroindole and methyl 2-(4-formyl-2- methoxyphenoxy)acetate according to the procedure in Example 117 Step 1 in 61% yield. Step 2: The intermediate from step 1 was N-alkylated according to the procedure for Example 129, step 2, with tert-butyl N-{4-[hydroxy(phenyl)methyl]phenyl}carbamate.
Step 3: The nitrogen protection was removed by heating the compound to 180°C to yield 45% of the desired amino ester.
Step 4: The intermediate from step 3 was hydrolyzed following step 2 for Example 117 to yield the title compound in 78% yield, m/z (M- 1)495.2
Example 133
'4-(l6-chloro-l-F(4-methoxyphenyl)(phenyl)methyll-lH-indol-3-yl}methyl)-3- methoxybenzoic acid
Step 1: The intermediate from Example 132, step 1, (1.0 eq) was dissolved in DMF (l.OM), cooled to 0°C, and treated with sodium hydride (1.5 eq) and stined for 30 minutes to affect deprotonation. The l-[bromo(phenyl)methyl]-4-methoxybenzene (1.5 eq), as a solution in DMF (2.0M), was added to the anion and the reaction was warmed to room temperature, when the reaction was deemed complete by TLC analysis it was partitioned between ethyl acetate and half saturated ammonium chloride, extracting the aqueous layer with ethyl acetate (2X), washing the organic layer with water (2X), drying, concentration followed by purification via column chromatography yielded the desired intermediate.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound, m/z (M- 1)510.2 Example 134
'4-((l-Fbis(4-methoxyphenyl)methyll-6-chloro-lH-indol-3-yl}methyl)-3- methoxybenzoic acid
Step 1: The intermediate from Example 132 was N-alkylated with l-[bromo(4- methoxyphenyl)methyl]-4-methoxybenzene according to the procedure described in Example 133, step 1, to yield the desired intermediate.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the titie compound, m/z (M- 1)540.3
Example 135
'4-({6-chloro-l-F(2-morpholinophenyl)(phenyl)methyl1-lH-indol-3- yl}methyl)-3-methoxybenzoic acid
Step 1: The intermediate from Example 132 was N-alkylated according to the procedure for Example 129, step 2, with the appropriate electrophile.
Step 2: The intermediate form step 1 was hydrolyzed foUowing step 2 for Example 117 to yield the title compound.
Example 136
4-(l6-chloro-l-F(2.4-dimethoxy-5-pyrimidinyl)(phenyl)methyll-lH-indol-3- yl}methyl)-3-methoxybenzoic acid
Step 1: The intermediate from Example 132 was N-alkylated according to the procedure for Example 129, step 2, with the appropriate electrophile to yield the desired intermediate in 16% yield.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound, m/z (M- 1)542.3
Example 137 '4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methvn-3-methoxybenzoic acid
Step l:This compound was prepared from the l-benzhydryl-6-chloro-lH-indole and the appropriate aldehyde according to the procedure in Example 117 Step 1.
Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound, m/z (M- 1)481.14 Example 138
2- 4-F(l-benzhvdryl-6-chloro-lH-indol-3-yl)methyll-3- methoxybenzoyllamino)acetic acid
Step 1: The intermediate from Example 137, step 2, treated with glycine ethyl ester according to the procedure in Example 76 to yield the desired ester. Step 2: The intermediate from step 1 was hydrolyzed following step 2 for Example 117 to yield the title compound, m/z (M- 1)537.2
All patents and literature references cited herein are incoφorated as if fully set forth herein.

Claims

What is claimed is:
1 ) A compound of the formulae:
Figure imgf000131_0001
wherein:
R, is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, -S-C,-C10 alkyl, CrC10 alkoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000131_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O-benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CN, -CF3, or -OH;
R7 is selected from -OH, -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,- C6 alkyl)2, pyridinyl, thienyl, furyl, pyrrolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, -CN, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH; R2 is selected from H, halogen, -CF3, -OH, -C,-C,0 alkyl, C,-C10 alkoxy-CHO. -CN, NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000132_0001
lower alkyl) or
Figure imgf000132_0002
or a moiety selected from the formulae -L -M
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000132_0003
Figure imgf000133_0001
Rg, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH,
(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000133_0002
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -O-(CH2)n-COOH, -O-CH2-C=C-COOH, -O-C=C-CH2-COOH, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -N-C(O)-(CH2)n-COOH, -N-SO2- (CH2)n-COOH, -C(O)-N-(CH2)n-COOH;
R10 is selected from the group of H, halogen, -CF3, -OH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -O-(C,-C6 alkyl)-(OH)n, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2, -N-C(O)-N-(C,-C6 alkyl)-(OH)2,
Figure imgf000134_0001
Figure imgf000134_0002
Figure imgf000134_0003
Figure imgf000134_0004
RΓÇ₧ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000135_0001
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, Rg, R10, and/or Ru shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000135_0002
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C!0 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from the group of CrC6 lower alkyl, C C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, - NO2, -NH2, -CN, or -CF3; or
a) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pynole, thiophene, imidazole, pyrazole, pynolidine, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C]0 alkoxy, - NO2, -NH2, -CN, or -CF3; or
b) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to pyridine, pyrimidine, piperidine, piperazine, or moφholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, - NH2, -CN, -CF3 or -OH; or c) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, indole, indoline, napthalene, purine, or quinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-O-(CH2)n-C3-CI0 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000136_0001
(CH2) " (CHz) "\ (CH2)
Y " (CH2) o- "\.
Figure imgf000136_0002
wherein n is an integer from 0 to 3, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pyrrolyl, benzothiazole and pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -CN, -NH2, -NO2or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O; or b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A. wherein A is the moiety:
Figure imgf000137_0001
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -CF3 or -(CH2)n-CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pynolyl groups, each optionally substituted by from 1 to 3, preferably 1 to 2, substituents selected from H, halogen, -CN, -CHO, -CF3, -OH, -C,-C6 alkyl, C,-C5 alkoxy, - NH2 , -N(C,-C6)2, -NH(CrC6), -N-C(O)-(C,-C6), -NO2, or by a 5- or 6-membered heterocyclic or heteroaromatic ring containing 1 or 2 heteroatoms selected from O, N or S; or a pharmaceutically acceptable salt thereof.
2. A compound of Claim 1 wherein R,., R4, and R2 are hydrogen, or a pharmaceutically acceptable salt thereof.
3. A compound of Claim 2 further wherein R, is in the indole or indoline 5- position, or a pharmaceutically acceptable salt thereof.
4. A compound of Claim 3 further wherein R, is a benzyloxy group, or a pharmaceutically acceptable salt thereof.
5. A compound of Claim 1 wherein R3 is -L'-M1, M1 is the moiety:
Figure imgf000137_0002
and L1 and R, are as defined in Claim 1
6. A compound having the formulae:
Figure imgf000138_0001
wherein:
R, is selected form H, halogen, -CF3, -OH, -CrC6 alkyl, C,-C6 alkoxy, -NO2, -NH2, CN, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000138_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, CrC6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl and thiazolyl, the rings of these groups being optionally substimted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, CrC6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C,0 alkyl, C,-C,0 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2- C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000139_0001
lower alkyl) or
Figure imgf000139_0002
lower alkyl)
Figure imgf000139_0003
or a moiety selected from the formulae -L -M ,
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000139_0004
Figure imgf000140_0001
Rg, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000140_0002
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C5 alkyl, -O-C,-C5 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000140_0003
Figure imgf000140_0004
lower alkyl)
lower haloalkyl] .
Figure imgf000140_0005
RΓÇ₧ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH. -(CH2)n
COOH, -(CH2)n-C(O)-COOH,
Figure imgf000141_0001
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, R9, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000141_0002
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C]0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from:
a) the group of C,-C6 lower alkyl, C C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -NO2, -NH2, -CN, or - CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pynole, thiophene, imidazole, pyrazole, pyπolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-CI0 alkoxy, -NO2, -NH2, -CN, or -CF3; or c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or moφholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C,0 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C]0 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000142_0001
(CH≥)^ (CH2 o^ ^Y wherein n is an integer from 0 to 3, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pynolyl benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O; or
b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000143_0001
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-CF3 or -CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pynolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
7. A compound of Claim 5 wherein the R, substitution is at the indole or indoline ring's 5-position, or a pharmaceutically acceptable salt thereof.
8. A compound having the formulae:
Figure imgf000143_0002
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000143_0003
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-CI0 alkyl, C,-C10 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2- C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000144_0001
' *(CrC6 lower alkyl) or
lower alkyl) or
Figure imgf000144_0002
or a moiety selected from the formulae -L -M ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)π-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-; M' is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000145_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)π-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000145_0002
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CrC6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000146_0001
Figure imgf000146_0002
lower alkyl)
lower haloalkyl]
Figure imgf000146_0003
RΓÇ₧ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000146_0004
with a proviso that the complete moiety at the indole or indohne 3-position created by any combination of R3, L1, M1, R8, R,,, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000146_0005
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-CI0 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2: L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)π-, or -(CH2)n-S-(CH2)n-;
M2 is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C C10 alkyl, C,-C10 alkoxy, -NO2, -NH2, -CN, or - CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pynole, thiophene, imidazole, pyrazole, pyπolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, C,-C10 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocychc ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or moφholine, the six-membered heterocychc ring being optionally substituted by from 1 to 3 substituents selected from halogen, C C]0 alkyl, C,-CI0 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-CI0 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl or ~(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A wherein A is selected from :
Figure imgf000148_0001
Figure imgf000148_0002
Figure imgf000148_0003
Figure imgf000149_0001
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3;
R12 is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3;
or a pharmaceuticaUy acceptable salt thereof.
9. A compound of the formulae:
Figure imgf000149_0002
wherein:
R, is selected form H, halogen, -CF3, -OH, -CrC6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000149_0003
Figure imgf000150_0001
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substimted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl, or -O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2- CrC6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH,
-CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000150_0002
lower alkyl) or
lower alkyl) or
Figure imgf000150_0003
or a moiety selected from the formulae -L -M or L M ; L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)n-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000151_0001
Figure imgf000151_0002
L2 is a bridging or linking moiety selected from a chemical bond -S-, -O-,
-C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)π-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M is the moiety
Figure imgf000152_0001
Rg, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000152_0002
Rg is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(CrC6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000152_0003
Figure imgf000152_0004
(CrC6 lower alkyl)
Figure imgf000152_0005
lower haloalkyl;
Rn is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000153_0001
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, L2, M2, Rg, R9, R]0, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000153_0002
n is an integer from 0 to 3;
R4 is selected from H, -CF3,
Figure imgf000153_0003
lower alkyl, Cj-C6 lower alkoxy, C3-C]0 cycloalkyl, -C,-C6 alkyl-C3-CI0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L3-M3:
L3 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -NO2, -NH2, -CN, or - CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pynole, thiophene, imidazole, pyrazole, pyπolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C]0 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or moφholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C,0 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000154_0001
(CH≥)^ (CH2
TΓ ^Y wherein n is an integer from 0 to 3, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pynolyl, benzothiazole, or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C5 alkyl, C,-C6 alkoxy, -NH2, -NO2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O; or
b) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000155_0001
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, -CF3 or -(CH2)n-CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pynolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
10. A compound of the formulae:
Figure imgf000155_0002
wherein:
R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C5 alkoxy, -NO2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000155_0003
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, CrC5 alkoxy, -NO2, -NH2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2- C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)ΓÇ₧-COOH, -CH=CH-COOH, -(CH2)nC(O)NS(O)(O)(C,-C6 lower alkyl), -(CH2)NC(O)NS(O)(O)(C,-C6 lower haloalkyl),
Figure imgf000156_0001
Figure imgf000157_0001
R8 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH;
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000157_0002
Figure imgf000157_0003
lower alkyl)
Figure imgf000157_0004
lower haloalkyl;
RΓÇ₧ is selected from H, C,-C6 lower alkyl, -CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or
Figure imgf000158_0001
n is an integer from 0 to 3;
R4 is selected from H, -CF3, CrC6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C]0 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-;
M2 is selected from:
a) the group of C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substimted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, C,-CI0 alkoxy, -NO2, -NH2, -CN, or - CF3; or
b) a five-membered heterocychc ring containing one or two ring heteroatoms selected from N, S or O including, but not hmited to, furan, pynole, thiophene, imidazole, pyrazole, pynolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, C,-C10 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or moφholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C1-C10 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicyclic ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine. quinoline or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, CF3 or -OH;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)π-C3-C5 cycloalkyl or -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A wherein A is selected from :
Figure imgf000159_0001
Figure imgf000159_0002
Figure imgf000160_0001
Figure imgf000160_0002
D is H, C,-C6 lower alkyl, CrC6 lower alkoxy, or -CF3;
R12 is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3;
or a pharmaceutically acceptable salt thereof.
11. A compound of the formulae:
Figure imgf000160_0003
wherein: R, is selected form H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000161_0001
Re
,0 N.
R7-
O
Figure imgf000161_0002
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, pyrazolyl, thiazolyl, -O-phenyl, benzyl or - O-benzyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 alkoxy, -NO2, -NH2, -CF3, or -OH;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, C,-C,0 alkoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2- C,-C6 alkyl;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)n-tetrazole,
Figure imgf000162_0001
lower alkyl) or
Figure imgf000162_0002
lower alkyl) or
o
O -s II- -OH Ω—P — OH O
or a moiety selected from the formulae -L -M ;
wherein L1 is a bridging or linking moiety selected from a chemical bond, -(CH2)n-, -S-, -O-, -C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-,-(CH2)n-S-(CH2)π-, -C(Z)-N(R6)-, -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, or -C(Z)-NH-SO2-(CH2)n-;
M1 is selected from the group of -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, tetrazole,
Figure imgf000162_0003
Figure imgf000163_0001
Rg, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000163_0002
R, is selected from H, halogen, -CF3, -OH, -COOH, -(CH2)ΓÇ₧-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH,
-(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000163_0003
Figure imgf000163_0004
lower alkyl)
lower haloalkyl;
Figure imgf000163_0005
RΓÇ₧ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000164_0001
with a proviso that the complete moiety at the indole or indoline 3-position created by any combination of R3, L1, M1, R8, R9, R10, and/or Rπ shall contain at least one acidic moiety selected from or containing a carboxylic acid, a tetrazole, or a moiety of the formulae:
Figure imgf000164_0002
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, C3-C10 cycloalkyl, -C,-C6 alkyl-C3-C10 cycloalkyl, -CHO, halogen, or a moiety of the formula -L2-M2:
L2 indicates a linking or bridging group of the formulae -(CH2)n-, -S-, -O-,
-C(O)-, -(CH2)n-C(O)-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)n-, or -(CH2)n-S-(CH2)n-, -
C(O)C(O)X; where X is O or N,
M2 is selected from:
a) the group of C C6 lower alkyl, C,-C6 lower alkoxy, C3-CI0 cycloalkyl, phenyl or benzyl, the cycloalkyl, phenyl or benzyl rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, C,-C10 alkoxy, -NO2, -NH,, -CN, or - CF3; or
b) a five-membered heterocyclic ring containing one or two ring heteroatoms selected from N, S or O including, but not limited to, furan, pynole, thiophene, imidazole, pyrazole, pynolidine, pyrazole, or tetrazole, the five-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-CI0 alkoxy, -NO2, -NH2, -CN, or -CF3; or
c) a six-membered heterocyclic ring containing one, two or three ring heteroatoms selected from N, S or O including, but not hmited to, pyridine, pyrazine, pyrimidine, piperidine, piperazine, thiazine, or moφholine, the six-membered heterocyclic ring being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a bicychc ring moiety containing from 8 to 10 ring atoms and optionally containing from 1 to 3 ring heteroatoms selected from N, S or O including, but not limited to benzofuran, chromene, indole, isoindole, indoline, isoindoline, napthalene, purine, quinohne or isoquinoline, the bicyclic ring moiety being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, C,-C10 alkoxy, -CHO, -NO2, -NH2, -CN, - CF3 or -OH;
R5 is selected from -(CH2)n-S-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C5 cycloalkyl, or the groups of:
a) -(CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl- CH2-phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000165_0001
(CH^ (CH2
O"^ ^Y wherein n is an integer from 0 to 3, Y is C3-C5 cycloalkyl, phenyl, benzyl, napthyl, pyridinyl, quinolyl, furyl, thienyl, pynolyl, benzothiazole or pyrimidinyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NO2, -NH2 or a five membered heterocyclic ring containing one heteroatom selected from N, S, or O; or (CHzJπs^ b) a moiety of the formula ' Y wherein n is an integer from 0 to 3, Y is napthyl, pyridinyl, quinolyl, furyl, thienyl, pynolyl benzothiazole, or pyrimidinyl, the rings of these groups being optionaUy substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2, -NO2or a five membered heterocychc ring containing one heteroatom selected from N, S, or O; or
c) a moiety of the formulae -(CH2)π-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000166_0001
wherein
D is H, C,-C '66 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-CF3 or -CF3;
B and C are independently selected from phenyl, pyridinyl, pyrimidinyl, furyl, thienyl or pynolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
12. A compound of the formulae:
Figure imgf000166_0002
wherein:
R, is selected form H, halogen, -CF3, -OH, -CrC6 alkyl, C,-C6 alkoxy, -NO2, -NH2, phenyl, -O-phenyl, benzyl, -O-benzyl, -S-benzyl or a moiety of the formulae:
Figure imgf000167_0001
R6 is selected from H, C,-C6 alkyl, C,-C6 alkoxy, phenyl, -O-phenyl, benzyl, -O- benzyl, the phenyl and benzyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R7 is selected from -CF3, C,-C6 alkyl, C,-C6 alkoxy, -NH-(C,-C6 alkyl), -N-(C,-C6 alkyl)2, pyridinyl, thienyl, furyl, pynolyl, phenyl, -O-phenyl, benzyl, -O-benzyl, pyrazolyl or thiazolyl, the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, CrC6 alkoxy, -NH2, -NO2, -CF3, or -OH;
R3 is selected from -COOH, -C(O)-COOH, -(CH2)n-C(O)-COOH, -(CH2)n-COOH, -CH=CH-COOH, -(CH2)nC(O)NS(O)(O)(C,-C6 lower alkyl), -(CH2)NC(O)NS(O)(O)(CrC6 lower haloalkyl),
Figure imgf000167_0002
Figure imgf000168_0001
Figure imgf000168_0002
R8 and R> are independently selected from H, halogen, -CF3, -OH, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
R10 is selected from the group of H, halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,-C6 alkyl), -N(C,-C6 alkyl)2,
Figure imgf000168_0003
Figure imgf000169_0001
lower alkyl)
lower haloalkyl;
Figure imgf000169_0002
Rn is selected from H, C,-C6 lower alkyl, -CF3, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, or
Figure imgf000169_0003
n is an integer from 0 to 3;
R4 is selected from H, -CF3, C,-C6 lower alkyl, C,-C6 lower alkoxy, or halogen;
R5 is selected from C,-C6 lower alkyl, C,-C6 lower alkoxy, -(CH2)n-C3-C5 cycloalkyl or the groups of:
a) -C(O)-O-(CH2)n-C3-C5 cycloalkyl, -(CH2)n-phenyl, -(CH2)n-S-phenyl, - (CH2)n-phenyl-O-phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -
(CH2)n-phenyl-(O-CH2-phenyl)2, -C(O)-O-phenyl, -C(O)-O-benzyl, -C(O)-O-pyridinyl, - C(O)-O-napthyl, -(CH2)n-S-napthyl, -(CH2)n-S -pyridinyl, -(CH2)n-pyridinyl or -(CH2)n- napthyl, the phenyl, pyridinyl and napthyl rings of these groups being optionally substituted by from 1 to 3 substituents selected from H, halogen, -CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, - NH2, or -NO2; or
b) a moiety of the formula -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000169_0004
wherein
D is H, C,-C6 lower alkyl, C,-C6 lower alkoxy, or -CF3;
B and C are independently selected from phenyl, pyridinyl, furyl, thienyl or pynolyl groups, each optionally substituted by from 1 to 3, substituents selected from H, halogen, - CF3, -OH, -C,-C6 alkyl, C,-C6 alkoxy, -NH2, or -NO2; or a pharmaceutically acceptable salt thereof.
13. A compound of Claim 1 which is selected from:
a) 4-[(5-{ [(cyclopentyloxy)carbonyl]amino}-l-propyl-lH-indol-3-yl)methyl]-3- methoxybenzoic acid;
b) Cyclopentyl-N- { 3-[2-methoxy-4-( { [(2-methylphenyl)sulfonyl]amino } carbonyl) benzyl]- 1 -propyl- 1 H-indol-5-yl } carbamate;
c) 4-[( 1 -benzhydryl-5- { [(cyclopentyloxy)carbonyl] amino } - 1 H-indol-3- yl)methyl]-3-methoxybenzoic acid;
d) 4- { [5- { [(cyclopentyloxy)carbonyl]amino } - 1 -(2-naphthylmethyl)- 1 H-indol-3- yl]methyl}-3-methoxybenzoic acid;
e) 4-{ [5-{ [(cyclopentyloxy)carbonyl]amino}-l-(cyclopropylmethyl)-lH-indol-3- yl]methyl}-3-methoxybenzoic acid;
f) 4-{ [5-{ [(cyclopentyloxy)carbonyl]amino}-l-(cyclopropylmethyl)-lH-indol-3- yl]methyl}-3-methoxybenzoic acid;
g) 4-{ [5-{ [(cyclopentyloxy)carbonyl]amino}-l-(4-pyridinylmethyl)-lH-indol-3- yl]methyl } -3-methoxybenzoic acid;
h) 4-[(5-{ [(cyclopentyloxy)carbonyl]amino}-l-isopropyl-lH-indol-3yl)methyl]-3- methoxybenzoic acid;
i) 4- [( 1 -cy clopentyl-5- { [(cyclopentyloxy)carbonyl] amino } - 1 H-indol-3 - yl)methyl]-3-methoxybenzoic acid; or j) 4- [(1 -benzhydryl-5- { [(butylamino)carbonyl]amino}-lH-indol-3-yl)methyl]-3- methoxybenzoic acid; or a pharmaceutically acceptable salt thereof.
14. A compound of Claim 1 which is selected from:
a) 4-({ l-benzhydryl-5-[(methylsulfonyl)amino]-lH-indol-3-yl}methyl)-3- methoxybenzoic acid;
b) 4-({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3-yl}methyl)-3- methoxybenzoic acid;
c) 4- [( 1 -benzhydryl-5-nitro- 1 H-indol-3-yl)methyl]-3-methoxybenzoic acid;
d) 4-[( 1 -benzhydryl-5-fluoro- 1 H-indol-3-yl)methyl]-3-methoxybenzoic acid;
e) 4-[( l-benzhydryl-5-methyl- lH-indol-3-yl)methyl]-3-methoxybenzoic acid;
f) 4-[(5-benzhydryl-5H-[l,3]dioxolo[4,5-f]indol-7-yl)methyl]-3-methoxybenzoic acid;
g) 4-[(l-benzhydryl-5-cyano-lH-indol-3-yl)methyl]-3-methoxybenzoic acid;
h) 4- { [ 1 -benzhydryl-5-(methylsulfonyl)- 1 H-indol-3-yl]methyl } -3- methoxybenzoic acid; or
j) cyclopentyl-N-{ l-benzhydryl-3-[2-methoxy-4-({ [(2-methylphenyl)sulfonyl] amino } carbonyl)benzy 1]- 1 H-indol-5-yl } carbamate;
or a pharmaceutically acceptable salt thereof.
15. A comound of Claim 1 which is selected from:
a) Cyclopentyl-N- { 3-[2-methoxy-4-( { [(2-methylphenyl)sulfonyl]amino } carbonyl)benzyl]- 1 -propyl- lH-indol-5-yl } carbamate; b) N- { 1 -(cyclopropylmethyl)-3- [2-methoxy-4-( { [(2-methylphenyl)sulfonyl] amino } carbonyl)benzyl]- 1 H-indol-5-yl } carbamate;
c) cyclopentyl-N-[3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino} carbonyl)benzyl]-l-(4-pyridinylmethyl)-lH-indol-5-yl]carbamate;
d) cyclopentyl-N-[3-[2-methoxy-4-({[(2-methylphenyl)sulfonyl]amino}carbonyl) benzyl]- 1 -(2-naphthylmethyl)- 1 H-indol-5-yl]carbamate;
e) cyclopentyl-N-{ l-isopropyl-3-[2-methoxy-4-({ [(2-methylphenyl)sulfonyl] amino } carbonyl)benzyl]- lH-indol-5-yl } carbamate;
f) cyclopentyl-N- { 1 -cyclopentyl-3-[2-methoxy-4-( { [(2-methylphenyl)sulfonyl] amino } carbonyl)benzyl]- lH-indol-5-yl } carbamate;
g) cyclopentyl N-{ l-benzhydryl-3-[2-methoxy-4-({[(trifluoromethyl) sulfonyl] amino } carbonyl)benzyl] - 1 H-indol-5-yl } carbamate ;
h) cyclopentyl N-[l-benzhydryl-3-(2-methoxy-4-{[(methylsulfonyl)amino] carbonyl}benzyl)-lH-indol-5-yl]carbamate;
i) N-{ l-benzhydryl-3-[4-({ [(2-chlorophenyl)sulfonyl]amino}carbonyl)-2- methoxybenzyl]- lH-indol-5-yl } ; or
j) cyclopentyl N-(3-{4-[({ [5-(acetylimino)-4-methyl-4,5-dihydro- 1,3,4- thiadiazol-2-yl]sulfonyl } amino)carbonyl]-2-methoxybenzyl } - 1 -benzhydryl- 1 H-indol-5- yl)carbamate; or a pharmaceutically acceptable salt thereof.
16. A compound of Claim 1 which is selected from:
a) cyclopentyl N-(l-benzhydryl-3-{4-[({[5-(dimethylamino)-l- naphthyl]sulfonyl}amino)carbonyl]-2-methoxybenzyl}-lH-indol-5-yl)carbamate;
b) cyclopentyl N- [ 1 -benzhydryl-3-(4- { [(benzylsulfonyl)amino]carbonyl } -2- methoxybenzyl)- 1 H-indol-5-yl]carbamate; c) cyclopentyl N-{ l-benzhydryl-3-[4-({ [(2,4-dimethyl-l,3-thiazol-5- yl)sulfonyl] amino } carbonyl)-2-methoxybenzyl] - 1 H-indol-5-yl } carbamate ;
d) cyclopentyl N-{ l-benzhydryl-3-[4-({ [(3,5-dimethyl-4- isoxazolyl)sulfonyl] amino } carbonyl)-2-methoxybenzyl]- 1 H-indol-5-yl } carbamate;
e) cyclopentyl N-(3-{4-[({[5-(acetylamino)-l,3,4-thiadiazol-2- yl]sulfonyl } amino)carbonyl]-2-methoxybenzyl } - 1 -benzhydryl- 1 H-indol-5-yl)carbamate;
f) cyclopentyl N-( 1 -benzhydryl-3- { 2-methoxy-4-[( { [4-(3-methyl-5-oxo-4,5- dihydro- IH-pyrazol- 1 -yl)phenyl]sulfonyl } amino)carbonyl]benzyl } - 1 H-indol-5-yl)carbamate;
g) N- { 4-[( 1 -benzhydryl-5-nitro- 1 H-indol-3-yl)methyl]-3-methoxybenzoyl } -2- methylbenzenesulfonamide;
h) N-{4-[(l-benzhydryl-5-nitro-lH-indol-3-yl)methyl]-3-methoxybenzoyl}
(trifluoro)methanesulfonamide ;
i) N- { 4-[( 1 -benzhydryl-5-bromo- 1 H-indol-3-yl)methyl]-3-methoxybenzoyl } -2- methylbenzenesulfonamide; or
j) N-{4-[(l-benzhydryl-5-bromo-lH-indol-3-yl)methyl]-3-methoxybenzoyl}
(trifluoro)methanesulfonamide; or a pharmaceutically acceptable salt thereof.
17. A compound of Claim 1 which is selected from:
a) N-{ l-benzhydryl-3-[2-methoxy-4-({ [(trifluoromethyl)sulfonyl]amino} carbonyl)benzyl]-lH-indol-5-yl}cyclopentanecarboxamide;
b) N-[4-({ l-benzhydryl-5-[(methylsulfonyl)amino]-lH-indol-3-yl}methyl)-3- mefhoxybenzoyl](trifluoro)methanesulfonamide;
c) N-{4-[(l -benzhydryl-5- { [(butylamino)carbonyl]amino}-lH-indol-3- yl)methyl]-3-methoxybenzoyl}(trifluoro) methane sulfonamide; d) N-{ l-benzhydryl-3-[2-methoxy-4-({ [(2-methylphenyl)sulfonyl]amino} carbonyl)benzyl]-lH-indol-5-yl}cyclopentanecarboxamide;
e) 4-( { 5-[(cyclopentylcarbonyl)amino]- 1 -[phenyl(2-pyridinyl)methyl]- lH-indol- 3-yl}methyl)-3-methoxybenzoic acid;
f) N-[4-( { 1 -benzhydryl-5-[(benzylsulfonyl)amino]- 1 H-indol-3-yl } methyl)-3- methoxybenzoyl] (trifluoro)methanesulfonamide ;
g) N- { 1 -benzhydryl-3-[2-methoxy-4-( { [(trifluoromethyl)sulfonyl]amino } carbonyl)benzyl]- 1 H-indol-5-yl } -3-thiophenecarboxamide;
h) Benzyl N-{ l-benzhydryl-3-[2-methoxy-4-({ [(trifluoromethyl)sulfonyl]amino} carbonyl)benzyl]-lH-indol-5-yl}carbamate;
g) 4-[(l-benzhydryl-5-nitro-lH-indol-3-yl)methyl]benzoic acid;
h) 4-[(l-benzhydryl-5-bromo-lH-indol-3-yl)methyl]benzoic acid;
i) 4-[( 1 -benzhydryl-5- { [(cyclopentyloxy)carbonyl] amino } - lH-indol-3- yl)methyl]benzoic acid; or
j) cyclopentyl N- { 1 -benzhydryl-3-[4-( { [(2-methylphenyl)sulfonyl]amino } carbonyl)benzyl]-lH-indol-5-yl}carbamate; or a pharmaceutically acceptable salt thereof.
18. A compound of Claim 1 which is selected from:
a) cyclopentyl N- { 1 -benzhydryl-3-[4-( { [(trifluoromethyl)sulfonyl] amino } carbony l)benzyl] - 1 H-indol-5-yl } carbamate ;
b) N- { 4- [( 1 -benzhydryl-5-nitro- 1 H-indol-3-yl)methyl]benzoyl } (trifluoro)methanesulf onamide ;
c) N- { 4- [( 1 -benzhydryl-5-nitro- 1 H-indol-3 -yl)methy l]benzoyl } -2- methylbenzenesulfonamide; d) N- { 4-[( 1 -benzhydryl-5-bromo- 1 H-indol-3-yl)methyl]benzoyl }-2- methy lbenzenesulf onamide ;
e) N- { 4-[( 1 -benzhydryl-5-bromo- 1 H-indol-3-yl)methyl]benzoyl } (trifluoro)methanesulfonamide ;
f) 3-( { 2-[ 1 -(4-benzylbenzyl)- 1 H-indol-3-yl]-2-oxoacetyl } amino)benzoic acid;
g) 3-( { 2-[ 1 -(4- { [3,5-bis(trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indol-3- yl]-2-oxoacetyl}amino)benzoic acid;
h) 3-{ [2-(l-benzhydryl-lH-indol-3-yl)-2-oxoacetyl]amino}benzoic acid;
i) 3-[(2- { 1 - [3-(4-benzylphenoxy)propyl]- 1 H-indol-3-yl } -2-oxoacetyl) amino]benzoic acid; or
j) 3-[(2-{ l-[3,4-bis(benzyloxy)benzyl]-lH-indol-3-yl}-2-oxoacetyl) amino]benzoic acid; or a pharmaceutically acceptable salt thereof.
19. A compound of Claim 1 which is selected from:
a) 3-[(2- { 1 -[2-(benzylsulfonyl)benzyl]- lH-indol-3-yl } -2-oxoacetyl) amino]benzoic acid;
b) 3-[({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3- yl}methyl)amino]benzoic acid;
c) 2-[4-( { l-benzhydryl-5-[(cyclopentylcarbonyl)amino]- lH-indol-3- yl}methyl)piperazino] acetic acid;
d) 2-[l-({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3-yl}methyl)- 3-oxo-2-piperazinyl]acetic acid;
e) 2-[({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3- yl}methyl)amino]-3-hydroxypropanoic acid; f) 2-[l-(4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yl]-2-oxoacetic acid:
g) 2- { 5-(benzyloxy )- 1 - [2,4-bis(trifluoromethyl)benzyl]- 1 H-indol-3-yl } -2- oxoacetic acid;
h) 3-( { 2- [ 1 -(4-benzylbenzyl)-5-(benzyloxy)- 1 H-indol-3-yl]-2-oxoacetyl } amino)benzoic;
i) 5-[(2- { 5-(benzyloxy)- 1 -[2,4-bis(trifluoromethyl)benzyl]- lH-indol-3-yl } -2- oxoacetyl)amino]isophthalic acid; or
j) 3-[(2-{5-(benzyloxy)-l-[2,4-bis(trifluoromethyl)benzyl]-lH-indol-3-yl}-2- oxoacetyl)amino]benzoic acid; or a pharmaceutically acceptable salt thereof.
20. A compound of Claim 1 which is selected from:
a) 5-( { 2- [ 1 -(4-benzylbenzyl)-5-(benzyloxy)- 1 H-indol-3-yl]-2-oxoacetyl } amino)- 2-[(5-chloro-3-pyridinyl)oxy]benzoic acid;
b) 5-[(2-{5-(benzyloxy)-l-[2,4-bis(trifluoromethyl)benzyl]-lH-indol-3-yl}-2- oxoacetyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid;
c) 2-[l-(4-benzylbenzyl)-5-(benzyloxy)-lH-indol-3-yl]-N-[3-({ [(4- methylphenyl)sulfonyl]amino}carbonyl)phenyl]-2-oxoacetamide;
d) 2-[5-bromo-l-(cyclopropylmethyl)-lH-indol-3-yl]acetic acid;
e) 2-[ l-(cyclopropylmethyl)-5-(2-thienyl)- lH-indol-3-yl]acetic acid;
f) 2- { 1 -(cyclopropylmethyl)-5-[3-(trifluoromethyl)phenyl]- 1 H-indol-3-yl } acetic acid;
g) 2-[5-(l-benzofuran-2-yl)-l-benzyl-lH-indol-3-yl]acetic acid;
h) 2-(l-benzyl-5-phenyl-lH-indol-3-yl)acetic acid; i) 4-{[5-((E)-{ l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methylidene)-2,4- dioxo-l,3-thiazolan-3-yl]methyl} benzoic acid; or
j) 2-[5-((E)-{ l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}methylidene)-2,4- dioxo-l,3-thiazolan-3-yl]acetic acid; or a pharmaceutically acceptable salt thereof.
21. A compound of Claim 1 which is selected from:
a) 3-{ l-[3-(3-benzylphenoxy)propyl]-lH-indol-3-yl}propanoic acid;
b) 3-{ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3-yl}propanoic acid;
c) N-(l-benzhydryl-3-{3-[(methylsulfonyl)amino]-3-oxopropyl}-lH-indol-5- yl)cyclopentanecarboxamide;
d) (E)-3- { 1 -benzhydryl-5-[(cyclopentylcarbonyl)amino]- 1 H-indol-3-yl } -2- propenoic acid;
e) N-( 1 -benzhydryl-3- { (E)-3- [(methylsulfonyl)amino]-3-oxo- 1 -propenyl } - 1 H- indol-5-yl)cyclopentanecarboxamide;
f) (E)-3- { 1 -benzhydryl-5-nitro- 1 H-indol-3-yl } -2-propenoic acid ester;
g) N-((E)-3-{ l-benzhydryl-5-nitro-lH-indol-3-yl}-2- propenoyl)methanesulfonamide;
h) 4-{ [l-benzhydryl-5-({ [4-(trifluoromethyl)phenyl]sulfonyl}amino)-lH-indol-3- yl]methyl}-3-methoxybenzoic acid;
i) 4- { [5-( { [2-(acetylamino)-4-methyl- 1 ,3-thiazol-5-yl] sulfonyl } amino)- 1 - benzhydryl-lH-indol-3-yl]methyl}-3-methoxybenzoic acid; or
j) 4-[(l -benzhydryl-5- { [(4-chloro-3-nitrophenyl)sulfonyl]amino}-lH-indol-3- yl)methyl]-3-methoxybenzoic acid; or a pharmaceutically acceptable salt thereof.
22. A compound of Claim 1 which is selected from:
a) 4- [(1 -benzhydryl-5- { [(dimethylamino)sulfonyl]amino}-lH-indol-3-yl)methyl]-
3-methoxybenzoic acid;
b) 4-{ [l-benzhydryl-5-({ [4-(trifluoromethoxy)phenyl]sulfonyl} amino)- lH-indol- 3-yl]methyl } -3-methoxybenzoic acid;
c) 4-[( 1 -benzhydryl-5- { [(2-methylphenyl)sulfonyl] amino } - 1 H-indol-3- yl)methyl]-3-methoxybenzoic acid;
d) 4-[(l -benzhydryl-5- { [(5-chloro-l,3-dimethyl-lH-pyrazol-4- yl)sulfonyl]amino}-lH-indol-3-yl)methyl]-3-methoxybenzoic acid;
e) 4-[( 1 -benzhydryl-5- { [(3,5-dimethyl-4-isoxazolyl)sulfonyl]amino }- lH-indol-3- yl)methyl]-3-methoxybenzoic acid;
f) cyclopentyl N-{3-[4-(aminocarbonyl)-2-methoxybenzyl]-l-benzhydryl-lH- indol-5-yl } carbamate;
g) cyclopentyl N-{ l-benzhydryl-3-[2-methoxy-4-(lH-l,2,3,4-tetraazol-5- yl)benzyl]-lH-indol-5-yl}carbamate;
h) 4-[({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3- yl } carbonyl)amino]-3-thiophenecarboxylic acid;
i) 3-[({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3- yl } carbonyl)amino]benzoic acid; or
j) 3-[({ l-benzhydryl-5-[(cyclopentylcarbonyl)amino]-lH-indol-3- yl}carbonyl)amino]propanoic acid; or a pharmaceutically acceptable salt thereof.
23. A compound of Claim 1 which is selected from:
a) N-[ 1 -benzhydryl-3-( { [(2-methylphenyl)sulfonyl]amino } carbonyl)- 1 H-indol-5- yl]cyclopentanecarboxamide;
b) 3-[(2-{ 1 -benzhydryl-5- [(cyclopentylcarbonyl)amino]-lH-indol-3-yl} -2- oxoacetyl)amino]propanoic acid;
c) 3-[(2- { 1 -benzhydryl-5- [(cyclopentylcarbonyl)amino]- 1 H-indol-3-yl } -2- oxoacetyl)amino]benzoic acid;
d) 3-( { 2-[ 1 -(4-benzylbenzyl)-5-(benzyloxy)- lH-indol-3-yl]acetyl } amino)benzoic acid;
e) 3-[(2-{5-(benzyloxy)-l-[2,4-bis(trifluoromethyl)benzyl]-lH-indol-3- yl } acetyl)amino] benzoic acid;
f) 5-(benzyloxy)-l-[2,4-bis(trifluoromethyl)benzyl]-2-methyl-lH-indole-3- carboxyhc acid;
g) 5-[( { 5-(benzyloxy)- l-[2,4-bis(trifluoromethyl)benzyl]-2-methyl- lH-indol-3- yl}carbonyl)amino]isophthahc acid;
h) 5-(benzyloxy)-2-methyl- 1 -(2-naphthylmethyl)- 1 H-indole-3-carboxylic acid;
i) 5-({ [5-(benzyloxy)-2-methyl-l-(2-naphthylmethyl)-lH-indol-3-yl]carbonyl} amino)isophthalic acid; or
j) l-benzyl-5-(benzyloxy)-2-methyl-lH-indole-3 -carboxylic acid; or a pharmaceutically acceptable salt thereof.
24. A compound of Claim 1 which is selected from:
a) 3- [(2- { 5-(benzyloxy)- 1 -(4-chlorobenzyl)-2- [(2-naphthylsulfanyl)methyl]- 1 H- indol-3-yl}-2-oxoacetyl)amino]benzoic acid; b) 3- [(2- { 5-(benzyloxy)- 1 -methyl-2- [(2-naphthylsulfanyl)methyl]- 1 H-indol-3-yl } -
2-oxoacetyl)amino]benzoic acid;
c) 2-{4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]-2,6- dimethylphenoxy} acetic acid;
d) 2- { 4-[( 1 -benzhydryl-6-chloro- 1 H-indol-3-yl)methyl]-3-methoxyphenoxy } acetic acid;
e) 2- { 4- [( 1 -benzhydryl-6-chloro- 1 H-indol-3 -yl)methyl]phenoxy } acetic acid;
f) 2-{4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]-3- chlorophenoxy} acetic acid;
g) 2-{4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]-2- methoxyphenoxy} acetic acid;
h) (E)-4- { 4- [( 1 -benzhydryl-6-chloro- 1 H-indol-3 -yl)methyl]phenoxy } -2-butenoic acid;
i) 4- { 4- [( 1 -benzhydryl-6-chloro- 1 H-indol-3-yl)methyl] anilino } -4-oxobutanooic acid; or
j ) Sodium 3-{4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]anilino}-3- oxopropanoic acid; or a pharmaceutically acceptable salt thereof.
25. A compound of Claim 1 which is selected from:
a) 2- { 4-[( 1 -benzhydryl-6-chloro- 1 H-indol-3-yl)methyl]anilino } -2-oxoacetic acid;
b) 2-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]cyclopropanecarboxylic acid; c) 2-[( 1 -benzhydryl-6-chloro-5-fluoro- 1 H-indol-3-yl)methyl]cyclopropane carboxylic acid;
d) 2-[(l-benzhydryl-5,6-dichloro-lH-indol-3-yl)methyl]cyclopropanecarboxylic acid;
e ) 2-({ l-[bis(4-hydroxyphenyl)methyl]-6-chloro-lH-indol-3-yl}methyl) cyclopropanecarboxylic acid;
f) '4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]-3-hydroxybenzoic acid;
g) '4-[( 1 -benzhydryl-6-chloro- 1 H-indol-3-yl)methyl]-3-(3-hydroxypropoxy) benzoic acid;
h) '4-({ l-[(4-aminophenyl)(phenyl)methyl]-6-chloro-lH-indol-3-yl}methyl)-3- methoxybenzoic acid;
i) '4-( { 6-chloro- 1 - [(4-methoxyphenyl)(phenyl)methyl]- 1 H-indol-3-yl } methyl)-3- methoxybenzoic acid;
j) '4-({ l-[bis(4-methoxyphenyl)methyl]-6-chloro-lH-indol-3-yl}methyl)-3- methoxybenzoic acid;
k) '4-( { 6-chloro- 1 - [(2-moφholinophenyl)(phenyl)methyl]- 1 H-indol-3- yl}methyl)-3-methoxybenzoic acid;
I ) 4-( { 6-chloro- l-[(2,4-dimethoxy-5-pyrimidinyl)(phenyl)methyl]- lH-indol-3- yl } methyl)-3-methoxybenzoic acid;
m) '4-[(l-benzhydryl-6-chloro-lH-indol-3-yl)methyl]-3-methoxybenzoic acid; or
n) 2-( { 4-[( 1 -benzhydryl-6-chloro- lH-indol-3-yl)methyl]-3-methoxybenzoyl } amino)acetic acid; or a pharmaceutically acceptable salt thereof.
26. A pharmaceutical composition comprising a compound of Claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
27. A pharmaceutical composition comprising a compound of Claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
28. A pharmaceutical composition comprising a compound of Claim 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
29. A pharmaceutical composition comprising a compound of Claim 8, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
30. A pharmaceutical composition comprising a compound of Claim 9, or a pharmaceutically acceptable salt thereof, and a pharmaceuticaUy acceptable carrier or excipient.
31. A pharmaceutical composition comprising a compound of Claim 10, or a pharmaceutically acceptable salt thereof, and a pharmaceuticaUy acceptable carrier or excipient.
32. A pharmaceutical composition comprising a compound of Claim 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
33. A method for treating inflammation in a mammal, the method comprising administering to a mammal in need thereof a pharmaceuticaUy effective amount of a compound of Claim 1 , or a pharmaceutically acceptable salt thereof.
PCT/US1999/003898 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes WO1999043654A2 (en)

Priority Applications (15)

Application Number Priority Date Filing Date Title
KR1020007009457A KR20010041344A (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
CA002322162A CA2322162A1 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
AU27825/99A AU765427B2 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
EP99908378A EP1062205A2 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
SK1275-2000A SK12752000A3 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
EEP200000488A EE200000488A (en) 1998-02-25 1999-02-24 Phospholipase enzyme inhibitors and pharmaceutical compositions
BR9908275-6A BR9908275A (en) 1998-02-25 1999-02-24 Phospholipase enzyme inhibitors
JP2000533412A JP2002504541A (en) 1998-02-25 1999-02-24 Phospholipase enzyme inhibitor
EA200000871A EA003876B1 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
NZ506329A NZ506329A (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
IL13771999A IL137719A0 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes
HU0101146A HUP0101146A3 (en) 1998-02-25 1999-02-24 Indole derivatives as inhibitors of phospholipase enzymes and pharmaceutical compositions containing them
NO20004219A NO20004219L (en) 1998-02-25 2000-08-23 Inhibitors of phospholipase enzymes
HR20000551A HRP20000551A2 (en) 1998-02-25 2000-08-24 Inhibitors of phospholipase enzymes
BG104779A BG104779A (en) 1998-02-25 2000-09-19 Inhibitors of phospholipase enzymes

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3059298A 1998-02-25 1998-02-25
US09/030,592 1998-02-25

Publications (2)

Publication Number Publication Date
WO1999043654A2 true WO1999043654A2 (en) 1999-09-02
WO1999043654A3 WO1999043654A3 (en) 1999-10-28

Family

ID=21854952

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/003898 WO1999043654A2 (en) 1998-02-25 1999-02-24 Inhibitors of phospholipase enzymes

Country Status (21)

Country Link
EP (1) EP1062205A2 (en)
JP (1) JP2002504541A (en)
KR (1) KR20010041344A (en)
CN (1) CN1310706A (en)
AU (1) AU765427B2 (en)
BG (1) BG104779A (en)
BR (1) BR9908275A (en)
CA (1) CA2322162A1 (en)
EA (1) EA003876B1 (en)
EE (1) EE200000488A (en)
GE (1) GEP20032920B (en)
HR (1) HRP20000551A2 (en)
HU (1) HUP0101146A3 (en)
ID (1) ID26250A (en)
IL (1) IL137719A0 (en)
NO (1) NO20004219L (en)
NZ (1) NZ506329A (en)
PL (1) PL343007A1 (en)
SK (1) SK12752000A3 (en)
TR (1) TR200002447T2 (en)
WO (1) WO1999043654A2 (en)

Cited By (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19917504A1 (en) * 1999-04-17 2000-10-19 Dresden Arzneimittel New hydroxy-indole derivatives, useful in treatment of degenerative joint disease, viral and parasitic infections, bronchial, dermatological, neurodegenerative and prostate disorders, etc.
EP1084108A1 (en) * 1998-05-01 2001-03-21 Eli Lilly And Company Spla 2? inhibitor compounds for treatment of disease
WO2001030774A1 (en) * 1999-10-26 2001-05-03 Aventis Pharma Deutschland Gmbh Substituted indoles for modulating nfkb activity
DE19962300A1 (en) * 1999-12-23 2001-06-28 Asta Medica Ag New N-benzylindolyl glyoxylic acid derivatives are useful as antitumor agents
WO2001047885A1 (en) * 1999-12-27 2001-07-05 Grünenthal GmbH Substituted indole mannich bases
WO2002005808A1 (en) * 2000-07-14 2002-01-24 The University Of Queensland Novel methods and compositions for the treatment or prevention of dysmenorrhoea and menstrual side effects: the use of phospholipase inhibitors
WO2002010152A2 (en) * 2000-07-28 2002-02-07 Zentaris Ag Novel indole derivatives and their use as medicaments
WO2003000253A1 (en) * 2001-06-20 2003-01-03 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US6525083B2 (en) 2000-07-25 2003-02-25 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
JP2003510274A (en) * 1999-09-28 2003-03-18 バクスター ヘルスケア ソシエテ アノニム Indolyl-3-glyoxylic acid derivatives having therapeutically important properties
US6565829B2 (en) 2001-08-03 2003-05-20 Pharmacia & Upjohn Company 5-arylsulfonyl indoles useful for treating disease
JP2003530319A (en) * 2000-02-11 2003-10-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Indol-3-yl derivatives
US6635771B2 (en) 2001-12-03 2003-10-21 Wyeth N-benzhydryl indole compounds
WO2003087087A2 (en) * 2002-04-09 2003-10-23 Astex Technology Limited Heterocyclic compounds and their use as modulators of p38 map kinase
WO2004052854A2 (en) * 2002-12-10 2004-06-24 Wyeth Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US6797708B2 (en) 2001-12-03 2004-09-28 Wyeth Inhibitors of cytosolic phospholipase A2
JP2005515997A (en) * 2001-12-03 2005-06-02 ワイス Inhibitor of cytoplasmic phospholipase A2
US6958348B2 (en) 2001-09-13 2005-10-25 Synta Pharmaceuticals Corp. 3-glyoxylamideindoles for treating cancer
US6984735B2 (en) 2001-12-03 2006-01-10 Wyeth Process for making an aldehyde
EP1633716A2 (en) * 2003-04-16 2006-03-15 Bristol-Myers Squibb Company Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
US7101875B2 (en) 2001-12-03 2006-09-05 Wyeth Methods for treating arthritic disorders
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7153882B2 (en) 2000-11-02 2006-12-26 The United States Of America As Represented By The Department Of Health And Human Services Agents useful for reducing amyloid precursor protein and treating demantia and methods of use thereof
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7186746B2 (en) 2002-08-29 2007-03-06 Merck & Co., Inc. Indoles having anti-diabetic activity
WO2007065684A2 (en) * 2005-12-09 2007-06-14 Novartis Ag Bicyclic heteroyclic compounds as antiinflammatory or antiallergic agents
US7253286B2 (en) 2000-10-20 2007-08-07 Eisai Co., Ltd Nitrogen-containing aromatic derivatives
WO2007092207A1 (en) * 2006-02-03 2007-08-16 Wyeth Compositions for the delivery of substituted naphthyl indole derivatives and methods of their use
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
EP1844771A3 (en) * 2001-06-20 2007-11-07 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7393960B2 (en) 2002-08-29 2008-07-01 Merck & Co., Inc. Indoles having anti-diabetic activity
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US7645752B2 (en) 2006-01-13 2010-01-12 Wyeth Llc Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7705023B2 (en) 2004-06-18 2010-04-27 Biolipox Ab Indoles useful in the treatment of inflammation
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US7932284B2 (en) 2006-01-24 2011-04-26 Eli Lilly And Company Indole sulfonamide modulators of progesterone receptors
US7960399B2 (en) 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8097623B2 (en) 2005-01-19 2012-01-17 Biolipox Ab Indoles useful in the treatment of inflammation
EP2431029A2 (en) 2002-06-07 2012-03-21 Kieran Francis Scott Method of inhibiting prostate cancer cell proliferation
US8211885B2 (en) 2008-01-31 2012-07-03 Sanofi-Aventis Cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
AU2007281747B2 (en) * 2006-08-07 2013-11-07 Ironwood Pharmaceuticals, Inc. Indole compounds
TWI460176B (en) * 2006-10-19 2014-11-11 Takeda Pharmaceutical Indole compound
TWI465431B (en) * 2012-04-10 2014-12-21 Pfizer Indole and indazole compounds that activate ampk
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9006240B2 (en) 2005-08-02 2015-04-14 Eisai R&D Management Co., Ltd. Method for assay on the effect of vascularization inhibitor
RU2448708C3 (en) 2006-05-18 2017-09-28 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. ANTI-TUMOR MEANS AGAINST THYROID CANCER CANCER
JP5368096B2 (en) 2006-08-28 2013-12-18 エーザイ・アール・アンド・ディー・マネジメント株式会社 Anti-tumor agent for undifferentiated gastric cancer
KR101445892B1 (en) 2007-01-29 2014-09-29 에자이 알앤드디 매니지먼트 가부시키가이샤 Composition for treatment of undifferentiated-type of gastric cancer
KR101513326B1 (en) 2007-11-09 2015-04-17 에자이 알앤드디 매니지먼트 가부시키가이샤 Combination of anti-angiogenic substance and anti-tumor platinum complex
MX2012014776A (en) 2010-06-25 2013-01-29 Eisai R&D Man Co Ltd Antitumor agent using compounds having kinase inhibitory effect in combination.
KR101762999B1 (en) 2011-04-18 2017-07-28 에자이 알앤드디 매니지먼트 가부시키가이샤 Therapeutic agent for tumor
CN104755463A (en) 2012-12-21 2015-07-01 卫材R&D管理有限公司 Amorphous form of quinoline derivative, and method for producing same
JP6872195B2 (en) * 2015-10-29 2021-05-19 国立大学法人東北大学 Collagen production inhibitor
CN106810488B (en) * 2015-11-27 2021-02-19 中国科学院上海药物研究所 One class is used as GPR17 and CysLT1Compound of dual antagonist, preparation method and application thereof
CN108530354B (en) * 2018-05-07 2019-12-10 青岛农业大学 Synthesis method of benzenesulfonyl quinoline compound

Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3271416A (en) * 1961-10-24 1966-09-06 Merck & Co Inc Indolyl aliphatic acids
FR1583552A (en) * 1967-04-11 1969-11-14
CH484111A (en) * 1966-04-12 1970-01-15 Sumitomo Chemical Co Process for preparing new derivatives of N-benzoyl-3-indolylic aliphatic acid
US3629284A (en) * 1965-04-19 1971-12-21 Sumitomo Chemical Co Process for the preparation of 3-indolyl aliphatic acid derivatives
FR2152377A1 (en) * 1971-09-09 1973-04-27 Sumitomo Chemical Co 1-phenyl-2-methyl-5-alkyl or alkoxy-3-indolylacetic acid - derivs - antiinflammatory, analgesic, antipyretic
FR2158464A1 (en) * 1971-11-03 1973-06-15 Ici Ltd
EP0337766A1 (en) * 1988-04-14 1989-10-18 Ici Americas Inc. Hetera-aliphatic carboxamides
EP0337767A1 (en) * 1988-04-13 1989-10-18 Ici Americas Inc. Cyclic amides
US4894386A (en) * 1987-04-15 1990-01-16 Ici Americas Inc. Aliphatic carboxamides
WO1992003132A1 (en) * 1990-08-20 1992-03-05 Abbott Laboratories Indole derivatives which inhibit leukotriene biosynthesis
EP0620215A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetamide derivatives as sPLA2 inhibitors
EP0620214A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetic acid hydrazide sPLA2 inhibitors
WO1995013266A1 (en) * 1993-11-12 1995-05-18 Merckle Gmbh Chem.-Pharm. Fabrik Acylpyrrole-alkanoic acids and indole-2-alkanoic acids plus their derivatives for use as inhibitors of phospholipase a¿2?
US5420289A (en) * 1989-10-27 1995-05-30 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
EP0675110A1 (en) * 1994-04-01 1995-10-04 Eli Lilly And Company 1H-Indole-3-glyoxylamide sPLA2 inhibitors
WO1996037467A1 (en) * 1995-05-22 1996-11-28 Merck Frosst Canada Inc. N-benzylindol-3-yl butanoic acid derivatives as cyclooxygenase-2 inhibitors
WO1996037469A1 (en) * 1995-05-22 1996-11-28 Merck Frosst Canada Inc. N-benzylindol-3-yl propanic acid derivatives as cyclooxygenase-2 inhibitors
WO1997013751A1 (en) * 1995-10-10 1997-04-17 Pfizer Inc. Indole carbamates as leukotriene antagonists
WO1998005637A1 (en) * 1996-08-01 1998-02-12 Merckle Gmbh Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a¿2?
WO1998008818A1 (en) * 1996-08-26 1998-03-05 Genetics Institute, Inc. Inhibitors of phospholipase enzymes

Patent Citations (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3271416A (en) * 1961-10-24 1966-09-06 Merck & Co Inc Indolyl aliphatic acids
US3629284A (en) * 1965-04-19 1971-12-21 Sumitomo Chemical Co Process for the preparation of 3-indolyl aliphatic acid derivatives
CH484111A (en) * 1966-04-12 1970-01-15 Sumitomo Chemical Co Process for preparing new derivatives of N-benzoyl-3-indolylic aliphatic acid
FR1583552A (en) * 1967-04-11 1969-11-14
FR2152377A1 (en) * 1971-09-09 1973-04-27 Sumitomo Chemical Co 1-phenyl-2-methyl-5-alkyl or alkoxy-3-indolylacetic acid - derivs - antiinflammatory, analgesic, antipyretic
FR2158464A1 (en) * 1971-11-03 1973-06-15 Ici Ltd
US4894386A (en) * 1987-04-15 1990-01-16 Ici Americas Inc. Aliphatic carboxamides
EP0337767A1 (en) * 1988-04-13 1989-10-18 Ici Americas Inc. Cyclic amides
EP0337766A1 (en) * 1988-04-14 1989-10-18 Ici Americas Inc. Hetera-aliphatic carboxamides
US5420289A (en) * 1989-10-27 1995-05-30 American Home Products Corporation Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole-alkanoic acid derivatives as inhibitors of PLA2 and lipoxygenase
WO1992003132A1 (en) * 1990-08-20 1992-03-05 Abbott Laboratories Indole derivatives which inhibit leukotriene biosynthesis
EP0620215A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetamide derivatives as sPLA2 inhibitors
EP0620214A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetic acid hydrazide sPLA2 inhibitors
WO1995013266A1 (en) * 1993-11-12 1995-05-18 Merckle Gmbh Chem.-Pharm. Fabrik Acylpyrrole-alkanoic acids and indole-2-alkanoic acids plus their derivatives for use as inhibitors of phospholipase a¿2?
EP0675110A1 (en) * 1994-04-01 1995-10-04 Eli Lilly And Company 1H-Indole-3-glyoxylamide sPLA2 inhibitors
WO1996037467A1 (en) * 1995-05-22 1996-11-28 Merck Frosst Canada Inc. N-benzylindol-3-yl butanoic acid derivatives as cyclooxygenase-2 inhibitors
WO1996037469A1 (en) * 1995-05-22 1996-11-28 Merck Frosst Canada Inc. N-benzylindol-3-yl propanic acid derivatives as cyclooxygenase-2 inhibitors
WO1997013751A1 (en) * 1995-10-10 1997-04-17 Pfizer Inc. Indole carbamates as leukotriene antagonists
WO1998005637A1 (en) * 1996-08-01 1998-02-12 Merckle Gmbh Acylpyrroldicarboxylic acids and acylindoldicarboxylic acids and their derivatives and inhibitors of the cytosolic phospholipase a¿2?
WO1998008818A1 (en) * 1996-08-26 1998-03-05 Genetics Institute, Inc. Inhibitors of phospholipase enzymes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 121, no. 11, 12 September 1994 (1994-09-12) Columbus, Ohio, US; abstract no. 124872, XP002114445 & CHEN, SI-FENG ET AL: ZHONGGUO YAOLI XUEBAO, vol. 15, no. 4, 1994, pages 299-302, *
R.D. DILLARD ET AL.: JOURNAL OF MEDICINAL CHEMISTRY, vol. 39, 1996, pages 5137-5158, XP002046055 WASHINGTON US *

Cited By (120)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1084108A4 (en) * 1998-05-01 2005-01-12 Lilly Co Eli Spla 2? inhibitor compounds for treatment of disease
EP1084108A1 (en) * 1998-05-01 2001-03-21 Eli Lilly And Company Spla 2? inhibitor compounds for treatment of disease
DE19917504A1 (en) * 1999-04-17 2000-10-19 Dresden Arzneimittel New hydroxy-indole derivatives, useful in treatment of degenerative joint disease, viral and parasitic infections, bronchial, dermatological, neurodegenerative and prostate disorders, etc.
JP2003510274A (en) * 1999-09-28 2003-03-18 バクスター ヘルスケア ソシエテ アノニム Indolyl-3-glyoxylic acid derivatives having therapeutically important properties
WO2001030774A1 (en) * 1999-10-26 2001-05-03 Aventis Pharma Deutschland Gmbh Substituted indoles for modulating nfkb activity
HRP20020357B1 (en) * 1999-10-26 2010-10-31 Sanofi-Aventis Deutschland Gmbh SUBSTITUTED INDOLES FOR MODULATING NFkB ACTIVITY
US7342029B2 (en) 1999-10-26 2008-03-11 Sanofi-Aventis Deutschland Gmbh Substituted indoles
KR100795709B1 (en) 1999-10-26 2008-01-21 사노피-아벤티스 도이칠란트 게엠베하 Substituted indoles
CZ304885B6 (en) * 1999-10-26 2015-01-07 Sanofi - Aventis Deutschland GmbH Substituted indole, process for its preparation pharmaceutical composition in which the indole is comprised, the use of the indole for the preparation of a medicament and process for preparing the medicament
DE19962300A1 (en) * 1999-12-23 2001-06-28 Asta Medica Ag New N-benzylindolyl glyoxylic acid derivatives are useful as antitumor agents
WO2001047913A3 (en) * 1999-12-23 2002-04-25 Zentaris Ag Substituted n-benzyl-indol-3-yl glyoxylic acid derivatives having an anti-tumoral effect
AU772745B2 (en) * 1999-12-23 2004-05-06 Zentaris Gmbh Substituted N-Benzyl-indol-3-YL glyoxylic acid derivatives having an anti-tumoral effect
WO2001047913A2 (en) * 1999-12-23 2001-07-05 Zentaris Ag Substituted n-benzyl-indol-3-yl glyoxylic acid derivatives having an anti-tumoral effect
US7091220B2 (en) 1999-12-27 2006-08-15 Gruenenthal Gmbh Substituted indole Mannich bases
WO2001047885A1 (en) * 1999-12-27 2001-07-05 Grünenthal GmbH Substituted indole mannich bases
JP2003530319A (en) * 2000-02-11 2003-10-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング Indol-3-yl derivatives
JP4938194B2 (en) * 2000-02-11 2012-05-23 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング Indol-3-yl derivatives
WO2002005808A1 (en) * 2000-07-14 2002-01-24 The University Of Queensland Novel methods and compositions for the treatment or prevention of dysmenorrhoea and menstrual side effects: the use of phospholipase inhibitors
EP1305285A1 (en) * 2000-07-25 2003-05-02 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
US6525083B2 (en) 2000-07-25 2003-02-25 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
EP1305285A4 (en) * 2000-07-25 2005-08-03 Merck & Co Inc N-substituted indoles useful in the treatment of diabetes
WO2002010152A2 (en) * 2000-07-28 2002-02-07 Zentaris Ag Novel indole derivatives and their use as medicaments
EP1939195A1 (en) * 2000-07-28 2008-07-02 AEterna Zentaris GmbH New indole derivatives and their use as medicine
US7989453B2 (en) 2000-07-28 2011-08-02 Aeterna Zentaris Gmbh Indole derivatives and their use as medicament
US7365081B2 (en) 2000-07-28 2008-04-29 Aeterna Zentaris Gmbh Indole derivatives and their use as medicaments
US8008324B2 (en) 2000-07-28 2011-08-30 Aeterna Zentaris Gmbh Indole derivatives and their use as medicament
WO2002010152A3 (en) * 2000-07-28 2002-08-01 Zentaris Ag Novel indole derivatives and their use as medicaments
US7253286B2 (en) 2000-10-20 2007-08-07 Eisai Co., Ltd Nitrogen-containing aromatic derivatives
US8372981B2 (en) 2000-10-20 2013-02-12 Eisai R&D Management Co., Ltd. Nitrogen-containing aromatic derivatives
US7786162B2 (en) 2000-11-02 2010-08-31 Raptor Pharmaceutical Corp. Agents useful for reducing amyloid precursor protein and treating dementia and methods of use thereof
US8258172B2 (en) 2000-11-02 2012-09-04 Raptor Pharmaceutical Corp Agents useful for reducing amyloid precursor protein and treating dementia and methods of use thereof
US7153882B2 (en) 2000-11-02 2006-12-26 The United States Of America As Represented By The Department Of Health And Human Services Agents useful for reducing amyloid precursor protein and treating demantia and methods of use thereof
US8691864B2 (en) 2000-11-02 2014-04-08 Nigel H. Greig Agents useful for reducing amyloid precursor protein and treating dementia and methods of use thereof
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
WO2003000253A1 (en) * 2001-06-20 2003-01-03 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US7368471B2 (en) 2001-06-20 2008-05-06 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
EP1844771A3 (en) * 2001-06-20 2007-11-07 Wyeth Substituted indole acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7629377B2 (en) 2001-06-20 2009-12-08 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US6565829B2 (en) 2001-08-03 2003-05-20 Pharmacia & Upjohn Company 5-arylsulfonyl indoles useful for treating disease
US6958348B2 (en) 2001-09-13 2005-10-25 Synta Pharmaceuticals Corp. 3-glyoxylamideindoles for treating cancer
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions
US6797708B2 (en) 2001-12-03 2004-09-28 Wyeth Inhibitors of cytosolic phospholipase A2
US7906548B2 (en) 2001-12-03 2011-03-15 Wyeth Llc Methods for the use of inhibitors of cytosolic phospholipase A2
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
JP2005515997A (en) * 2001-12-03 2005-06-02 ワイス Inhibitor of cytoplasmic phospholipase A2
US6635771B2 (en) 2001-12-03 2003-10-21 Wyeth N-benzhydryl indole compounds
US7101875B2 (en) 2001-12-03 2006-09-05 Wyeth Methods for treating arthritic disorders
US6984735B2 (en) 2001-12-03 2006-01-10 Wyeth Process for making an aldehyde
WO2003087087A3 (en) * 2002-04-09 2003-12-18 Astex Technology Ltd Heterocyclic compounds and their use as modulators of p38 map kinase
WO2003087087A2 (en) * 2002-04-09 2003-10-23 Astex Technology Limited Heterocyclic compounds and their use as modulators of p38 map kinase
EP2431029A2 (en) 2002-06-07 2012-03-21 Kieran Francis Scott Method of inhibiting prostate cancer cell proliferation
US7393960B2 (en) 2002-08-29 2008-07-01 Merck & Co., Inc. Indoles having anti-diabetic activity
US7345085B2 (en) 2002-08-29 2008-03-18 Merck & Co., Inc. Indoles having anti-diabetic activity
US7186746B2 (en) 2002-08-29 2007-03-06 Merck & Co., Inc. Indoles having anti-diabetic activity
US7056943B2 (en) 2002-12-10 2006-06-06 Wyeth Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2004052854A2 (en) * 2002-12-10 2004-06-24 Wyeth Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US7566791B2 (en) 2002-12-10 2009-07-28 Wyeth Substituted 3-carbonyl-1h-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7348351B2 (en) 2002-12-10 2008-03-25 Wyeth Substituted 3-alkyl and 3-arylalkyl 1H-indol-1yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7160918B2 (en) 2002-12-10 2007-01-09 Hassan Mahmoud Elokdah Substituted indole oxo-acetyl amino acetic acid derivatives as inhibitors of plasminogen activator inhibitor (PAI-1)
US7078429B2 (en) 2002-12-10 2006-07-18 Wyeth Substituted 3-carbonyl-1H-indol-1-yl acetic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7674818B2 (en) 2002-12-10 2010-03-09 Wyeth Llc Aryl, aryloxy, alkyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2004052854A3 (en) * 2002-12-10 2004-08-05 Wyeth Corp Aryl, aryloxy, and alkyloxy substituted 1h-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (pai-1)
US7259182B2 (en) 2002-12-10 2007-08-21 Wyeth Aryl, aryloxy, and aklyloxy substituted 1H-indol-3-yl glyoxylic acid derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7459478B2 (en) 2002-12-10 2008-12-02 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
US7101903B2 (en) 2002-12-10 2006-09-05 Wyeth Substituted dihydropyrano indole-3,4-dione derivatives as inhibitiors of plasminogen activator inhibitor-1 (PAI-1)
EP1633716A4 (en) * 2003-04-16 2008-03-26 Bristol Myers Squibb Co Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
EP1633716A2 (en) * 2003-04-16 2006-03-15 Bristol-Myers Squibb Company Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
US7411083B2 (en) 2003-09-25 2008-08-12 Wyeth Substituted acetic acid derivatives
US7446201B2 (en) 2003-09-25 2008-11-04 Wyeth Substituted heteroaryl benzofuran acids
US7442805B2 (en) 2003-09-25 2008-10-28 Wyeth Substituted sulfonamide-indoles
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7417063B2 (en) 2004-04-13 2008-08-26 Bristol-Myers Squibb Company Bicyclic heterocycles useful as serine protease inhibitors
US7960399B2 (en) 2004-06-08 2011-06-14 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US8809528B2 (en) 2004-06-08 2014-08-19 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US9102653B2 (en) 2004-06-08 2015-08-11 Novartis Ag Substituted quinazolinones as vanilloid antagonists
US8211902B2 (en) 2004-06-08 2012-07-03 Novartis Ag Quinazolinone derivatives useful as vanilloid antagonists
US7705023B2 (en) 2004-06-18 2010-04-27 Biolipox Ab Indoles useful in the treatment of inflammation
US7754747B2 (en) 2004-08-23 2010-07-13 Wyeth Llc Oxazolo-naphthyl acids
US8969379B2 (en) 2004-09-17 2015-03-03 Eisai R&D Management Co., Ltd. Pharmaceutical compositions of 4-(3-chloro-4-(cyclopropylaminocarbonyl)aminophenoxy)-7=methoxy-6-quinolinecarboxide
US8097623B2 (en) 2005-01-19 2012-01-17 Biolipox Ab Indoles useful in the treatment of inflammation
US7777040B2 (en) 2005-05-03 2010-08-17 Cgi Pharmaceuticals, Inc. Certain substituted ureas, as modulators of kinase activity
US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US8283373B2 (en) 2005-05-27 2012-10-09 Pfizer Inc. Inhibitors of cytosolic phospholipase A2
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7888383B2 (en) 2005-12-09 2011-02-15 Novartis Ag Organic compounds
WO2007065684A3 (en) * 2005-12-09 2007-08-02 Novartis Ag Bicyclic heteroyclic compounds as antiinflammatory or antiallergic agents
WO2007065684A2 (en) * 2005-12-09 2007-06-14 Novartis Ag Bicyclic heteroyclic compounds as antiinflammatory or antiallergic agents
US7645752B2 (en) 2006-01-13 2010-01-12 Wyeth Llc Sulfonyl substituted 1H-indoles as ligands for the 5-hydroxytryptamine receptors
US7932284B2 (en) 2006-01-24 2011-04-26 Eli Lilly And Company Indole sulfonamide modulators of progesterone receptors
WO2007092207A1 (en) * 2006-02-03 2007-08-16 Wyeth Compositions for the delivery of substituted naphthyl indole derivatives and methods of their use
AU2007281747B2 (en) * 2006-08-07 2013-11-07 Ironwood Pharmaceuticals, Inc. Indole compounds
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
TWI460176B (en) * 2006-10-19 2014-11-11 Takeda Pharmaceutical Indole compound
US8211885B2 (en) 2008-01-31 2012-07-03 Sanofi-Aventis Cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals
US8772327B2 (en) 2008-04-28 2014-07-08 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
US8334314B2 (en) 2008-04-28 2012-12-18 Asahi Kasei Pharma Corporation Phenylpropionic acid derivative and use thereof
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US9945862B2 (en) 2011-06-03 2018-04-17 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
TWI465431B (en) * 2012-04-10 2014-12-21 Pfizer Indole and indazole compounds that activate ampk
US10517861B2 (en) 2013-05-14 2019-12-31 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of endometrial cancer subjects to lenvatinib compounds
US10822307B2 (en) 2014-08-28 2020-11-03 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10407393B2 (en) 2014-08-28 2019-09-10 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11186547B2 (en) 2014-08-28 2021-11-30 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
US11547705B2 (en) 2015-03-04 2023-01-10 Merck Sharp & Dohme Llc Combination of a PD-1 antagonist and a VEGF-R/FGFR/RET tyrosine kinase inhibitor for treating cancer
US11369623B2 (en) 2015-06-16 2022-06-28 Prism Pharma Co., Ltd. Anticancer combination of a CBP/catenin inhibitor and an immune checkpoint inhibitor
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity
US11944622B2 (en) 2018-10-05 2024-04-02 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

Also Published As

Publication number Publication date
BG104779A (en) 2001-10-31
TR200002447T2 (en) 2000-11-21
JP2002504541A (en) 2002-02-12
SK12752000A3 (en) 2001-03-12
IL137719A0 (en) 2001-10-31
HRP20000551A2 (en) 2001-04-30
AU765427B2 (en) 2003-09-18
HUP0101146A2 (en) 2001-08-28
ID26250A (en) 2000-12-07
GEP20032920B (en) 2003-03-25
EA200000871A1 (en) 2001-04-23
CN1310706A (en) 2001-08-29
NO20004219D0 (en) 2000-08-23
PL343007A1 (en) 2001-07-30
KR20010041344A (en) 2001-05-15
EA003876B1 (en) 2003-10-30
CA2322162A1 (en) 1999-09-02
HUP0101146A3 (en) 2001-11-28
EE200000488A (en) 2002-02-15
EP1062205A2 (en) 2000-12-27
AU2782599A (en) 1999-09-15
WO1999043654A3 (en) 1999-10-28
BR9908275A (en) 2000-10-24
NZ506329A (en) 2004-01-30
NO20004219L (en) 2000-10-23

Similar Documents

Publication Publication Date Title
EP1062205A2 (en) Inhibitors of phospholipase enzymes
US6500853B1 (en) Inhibitors of phospholipase enzymes
US6828344B1 (en) Inhibitors of phospholipase enzymes
SK12782000A3 (en) Inhibitors of phospholipase a2
SK12742000A3 (en) Inhibitors of phospholipase enzymes
US6630496B1 (en) Inhibitors of phospholipase enzymes
DE60221391T2 (en) SUBSTITUTED INDOLESE DERIVATIVES AS INHIBITORS OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
EP1569901B1 (en) ARYL, ARYLOXY, AND ALKYLOXY SUBSTITUTED i 1H /i -INDOL-3-YL GLYOXYLIC ACID DERIVATIVES AS INHIBITORS OF PLASMINOGEN ACTIVATOR INHIBITOR-1 (PAI-1)
US7268159B2 (en) Substituted indoles
US20030153751A1 (en) Inhibitors of phospholipase enzymes
CZ89394A3 (en) Derivative of +h-indole-3-acetamide, process of its preparation, and pharmaceutical preparation in which it is comprised
JP2006514641A (en) Substituted dihydropyranoindole-3,4-dione derivatives as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
AU2010294018A1 (en) Use of indole derivatives as NURR-1 activators for the application thereof as a medicament for the treatment of Parkinson's disease
MXPA00008292A (en) Inhibitors of phospholipase enzymes
EP2001847A2 (en) Soluble adenylate cyclase inhibitors
CZ20003115A3 (en) Phospholipase inhibitors
CZ20003117A3 (en) Phospholipase inhibitors
MXPA00008295A (en) Inhibitors of phospholipase enzymes

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 99805157.8

Country of ref document: CN

AK Designated states

Kind code of ref document: A2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 137719

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 1999908378

Country of ref document: EP

Ref document number: 1200000703

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 506329

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 27825/99

Country of ref document: AU

Ref document number: 2000/02447

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 12752000

Country of ref document: SK

ENP Entry into the national phase

Ref document number: 2322162

Country of ref document: CA

Ref document number: 2322162

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: P20000551A

Country of ref document: HR

Ref document number: PA/a/2000/008292

Country of ref document: MX

Ref document number: IN/PCT/2000/254/KOL

Country of ref document: IN

ENP Entry into the national phase

Ref document number: 2000 533412

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV2000-3115

Country of ref document: CZ

Ref document number: 1020007009457

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: 200000871

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 1999908378

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV2000-3115

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020007009457

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: 27825/99

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1020007009457

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV2000-3115

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1999908378

Country of ref document: EP