WO1999043672A1 - Inhibitors of phospholipase a2 - Google Patents

Inhibitors of phospholipase a2 Download PDF

Info

Publication number
WO1999043672A1
WO1999043672A1 PCT/US1999/003388 US9903388W WO9943672A1 WO 1999043672 A1 WO1999043672 A1 WO 1999043672A1 US 9903388 W US9903388 W US 9903388W WO 9943672 A1 WO9943672 A1 WO 9943672A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
cooh
aikoxy
compound
benzyl
Prior art date
Application number
PCT/US1999/003388
Other languages
French (fr)
Other versions
WO1999043672A9 (en
Inventor
Jasbir S. Seehra
Yibin Xiang
Jean Bemis
John Mckew
Neelu Kaila
Lihren Chen
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 HU0100156A priority Critical patent/HUP0100156A3/en
Priority to AU32970/99A priority patent/AU3297099A/en
Priority to EEP200000522A priority patent/EE200000522A/en
Priority to CA002322163A priority patent/CA2322163A1/en
Application filed by Genetics Institute, Inc. filed Critical Genetics Institute, Inc.
Priority to KR1020007009459A priority patent/KR20010041346A/en
Priority to IL13754099A priority patent/IL137540A0/en
Priority to JP2000533428A priority patent/JP2002504551A/en
Priority to SK1278-2000A priority patent/SK12782000A3/en
Priority to EA200000873A priority patent/EA200000873A1/en
Priority to EP99936073A priority patent/EP1062216A1/en
Publication of WO1999043672A1 publication Critical patent/WO1999043672A1/en
Publication of WO1999043672A9 publication Critical patent/WO1999043672A9/en
Priority to HR20000513A priority patent/HRP20000513A2/en
Priority to NO20004217A priority patent/NO20004217L/en
Priority to BG104781A priority patent/BG104781A/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
    • 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
    • C07D209/32—Oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • 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
    • C07D209/22—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 with an aralkyl radical attached to the ring nitrogen atom
    • 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
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/34—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/81—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • 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
    • C07D405/12—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 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
    • C07D409/02—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
    • 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
    • C07D417/10—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 aromatic rings

Definitions

  • the present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A enzymes.
  • Leukotrienes and prostaglandins are important mediators of inflammation. 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 produciton of leukotrienes.
  • PLA 2 phospholipase A
  • the reaction catalyzed by PLA 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 prostaglandins 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 pathwasy of conversion of arachidonic acid to leukotrienes, witout affecting the production of prostaglandins. None of these widelt-used anti- inflammatory agents affects the production of PAF.
  • This non- pancreatic PLA 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. Biophys. Res. Comm.. 163:42-48 (1989)].
  • a murine PLA 2 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. Biophvs. 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,.
  • cytosolic phospholipase A (hereinafter "cPLA,") 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 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
  • the present invention provides compounds having a chemical formula selected from the group consisting of:
  • A is independent of any other group and is selected from the group consisting of -CH 2 - and -CH 2 -CH 2 -;
  • R is independent of any other R group and is selected from the group consisting of -X-R, -H. - OH, halogen, -CN, -NO,, C,-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
  • R 2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR ⁇ , -(CH 2 ) n -W-(CH 2 ) m -Z-R 5 , -(CH 2 ) n -W-R 5 , -Z-R 5 , C,-C 10 alkyl, alkenyl and substimted aryl;
  • R 3 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR 5 , -CONR 5 R «, -(CH 2 ) n -W-(CH 2 ) m -Z-R 5 , -(CH 2 ) n -W-R 5 , -Z-R 5 , C,-C 10 alkyl, alkenyl and substituted aryl;
  • R 4 is independent of any other R group and is selected from the group consisting of -H, -OH, - OR,, -SRj, -CN, -COR ⁇ , -NHR 6 , -COOH, -CONR ⁇ , -NO,, -CONHS0 2 R 8 , C,-C 5 alkyl, alkenyl and substituted aryl;
  • R 5 is independent of any other R group and is selected from the group consisting of -H, -OH, 0(CH,) n R 6 , -SR ⁇ , -CN, -COR,, -NHR,, -COOH, -NO,, -COOH, -CONR,R 7 , -CONHSO,R 8 , C,-C 5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF 3 , -CF,CF 3 and
  • R is independent of any other R group and is selected from the group consisting of -H, C-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
  • R 7 is independent of any other R group and is selected from the group consisting of -H, C-C 5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
  • R 8 is independent of any other R group and is selected from the group consisting of C-C 3 alkyl, aryl and substituted aryl;
  • Rt is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R 7 , tetrazole, -CONHSO,R 8 , -COR,, -(CH,) interceptCH(OH)R 6 and -(CH,) n CHR 6 R 5 ;
  • Rio is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R 7 , tetrazole, -CONHSO,R 8> -COR,, -(CH,) n CH(OH)R, and -(CH,) n CHR,R 5 ;
  • X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-;
  • Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N(R,)-, -CO-, -CON(R,)- and - N(R,)CO-;
  • m is, independently each time used including within the same compound, an integer from 0 to 4; and
  • n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4.
  • the compounds of the invention have phospholipase enzyme inhibiting activity.
  • Other preferrred embodiments include compounds having the following chemical formula:
  • A is -CH- and R, is -(CH 2 ) n -W-(CH,) m -ZR 5
  • R is -(CH 2 ) n -W-(CH,) m -ZR 5
  • n is 1
  • m is 1
  • W is -S- and Z is -CO-
  • Rj is -NHR
  • R is a substituted aryl group and those wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -CF 3 ,
  • R is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH,) p OH, and -0(CH 2 ) p CH 3 , and wherein p is an integer from 0 to 4.
  • R is selected from the group consisting of -H and -OCH(C 6 H 6 ) and R 3 is -COR 5 , R 5 is -OC ⁇ R, and R, is a substituted aryl group.
  • said aryl group is substimted with one or more substituents selected from the group consisting of -CF, - CF,CF 3 and -C(CH 3 ),CH,CH 3 .
  • R, and R r are independently selected from C,-C 6 alkyl, -Z-C j -C 5 alkyl, phenyl, -(CH 2 ) n - Z-(CH 2 ) n -phenyl, benzyl, -(CH 2 ) n -Z-(CH 2 ) n -benzyl, napthyl, -(CH 2 ) n -Z-(CH 2 ) n -napthyl, pyrimidinyl, -(CH 2 ) n -Z-(CH 2 ) n -pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 aikoxy, -NO 2 , -NH,, -CN, -CF 3 , or -
  • Z is O or S
  • n is an integer from 0 to 3;
  • R 2 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, C,-C 10 aikoxy, -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;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, C,-C 10 aikoxy, -CHO, - C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C r C 6 alkyl, -N(C,-C 6 alkyl),, -N-SO 2 - C,-C 6 alkyl, -SO,-C,-C 6 alkyl or a moiety of the formula:
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) ⁇ -C(O)-COOH, -CF 3 , -OH, -(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 is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 ) n -C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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 5 alkyl) 2 ;
  • L 1 is selected from -(CH 2 ) n -O-, -(CH 2 ) n -S-, -(CH 2 ) compassion-O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -C(O)-O-, -C(O)-(CH 2 ) n -O-, -C(O)-N-, or -(CH 2 ) n -S-(CH 2 ) n -C(O)-N-;
  • M' is -COOH or a moiety selected from:
  • R 10 is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, (CH 2 ) ⁇ -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl,
  • R 5 is selected from:
  • L 2 is selected from a chemical bond or a bridging group selected from -(CH 2 ) ⁇ -Z-, -(CH 2 ) n -Z-(CH 2 ) n -, -C(O)-O-, -C(O)-(CH 2 ) n -O-, -C(O)-N-, or -(CH 2 ) ⁇ -S-(CH 2 ) n -C(O)-N-;
  • M 2 is selected from -C,-C 6 alkyl, -O-C,-C 6 alkyl,
  • R 8 and R 9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or
  • L 3 is a chemical bond or a group selected from -CH 2 - , -CH 2 -Z- , -C(O)- , -O-, -S- , or -(CH 2 ) n -Z-(CH 2 ) n -;
  • M 3 is selected from -(CH 2 ) n -C 3 -C 5 cycloalkyl, furanyl, thienyl, pyrrolyl,
  • a preferred subset include those in which the core molecule is an indole.
  • R' and R 2 are hydrogen, and the moieties R 3 , R 4 , R 5 , R 8 , R 9 and R 10 , n, L 1 , L 2 , M 1 and M 2 are as defined above.
  • R 1 is in the indole 5-position.
  • R is selected from -O-C,-C 6 alkyl, -S-C r C 6 alkyl, -O-phenyl, -S-phenyl, -O-benzyl, -S- benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 aikoxy, -NO 2 , -NH 2 , -CN, -CF literal or -OH;
  • R 2 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C,-C 6 alkyl, C,-C I0 aikoxy, preferably C,-C 6 aikoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C r C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C r C 6 alkyl, -N(C,-C 6 alkyl) 2 , - N-80 2 -C j -Cg alkyl, -SO j -C ⁇ alkyl, or a moiety of the formula:
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ) n -COOH, -(CH,) n -C(O)-COOH, -CF 3 , -OH, -(CH,) 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 4 is the moiety -L'-M 1 or
  • L 1 is selected from a chemical bond or a bridging group selected from -(CH 2 ) n -O-, -(CH,) n -S-, -(CH,) n -O-(CH,) n -, -(CH 2 ) n -S-(CH 2 ) n -, -C(O)-O-, -C(O)-(CH,_) n -O-, -C(O)-N-, or -(CH 2 ) n -S-(CH,) n -C(O)-N-;
  • M is the moiety:
  • R ⁇ is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, (CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl,
  • R is a structure of the formula
  • L 2 is selected from a chemical bond or a bridging group selected from -(CH 2 ) n -O-, -(CH 2 ) ⁇ -S-, -(CH 2 ) ⁇ -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -C(O)-O-, -C(O)-(CH 2 ) n -O-, -C(O)-N-, or -(CH 2 ) n -S-(CH,) n -C(O)-N-;
  • M 2 is selected from -C,-C 6 alkyl, -O-C,-C 6 alkyl,
  • R 8 , R 9 and R 10 are as defined above; or a pharmaceutically acceptable salt thereof.
  • R is selected from -O-C,-C 6 alkyl, -S-C,-C 6 alkyl, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 6 alkyl, C,-C 6 aikoxy, -NO 2 , -NH 2 , -CN, -CF 3 , or -OH;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C ⁇ -C 10 alkyl, C,-C, 0 aikoxy, preferably C,-C I0 aikoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, -SO 2 -C,-C 6 alkyl or a moiety of the formula:
  • R , R , R , R and R are as defined above, or a pharmaceutically acceptable salt thereof.
  • R, and R r are independently selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C,-C 6 alkyl, -S-C,-C I0 alkyl, preferably -S-C,-C 6 alkyl, C,-C I0 aikoxy, preferably C,- C 6 aikoxy, -CN, -NO 2 , -NH 2 , 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 -(CH 2 ) n - bridge;
  • 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 r C 10 alkyl, preferably C r C 6 alkyl, C r C 10 aikoxy, preferably C,-C 6 aikoxy, -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 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, 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 aikoxy, preferably C,-C 6 aikoxy, -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 ⁇ alkyl, preferably C r C 6 alkyl, C,-C 10 aikoxy, preferably C r C 6 aikoxy, -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 ) conflict-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 10 alkyl, preferably C r C 6 alkyl, C r C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -NO 2 , - NH 2 , -CN, -CF 3 or -OH;
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C.-C, alkyl, -N(C,-C 6 alkyl),, -N-SO,-C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C I0 alkyl, C,-C 10 aikoxy, -CHO, - C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C.-C
  • n in each appearance is an integer independently selected from 0-3;
  • R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,- C 6 alkyl), or -N(C r C 6 alkyl) 2 ;
  • R 12 is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 ) n -C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF 3 , -OH, -COOH, -(CH 2 ) ⁇ -COOH, -(CH 2 ) ⁇ -C(O)-COOH, -C,-C 6 alkyl, -O-C,- C 6 alkyl, -NH(C,-C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • L 1 is selected from -(CH 2 ) n -, -S-, -O-, -C(O)-, -C(O)-O-,-(CH 2 ) n -O-, -(CH 2 ) n -S-, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -(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 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-N(R 6 )-, -C(O)
  • M 1 is -COOH or a moiety selected from:
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 9 in each appearance is 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 r C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R 10 is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, (CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C.-C, alkyl,
  • 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,
  • the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 5 is selected from C r C 6 lower alkyl, C,-C 6 lower aikoxy, -(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
  • 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 10 alkyl, preferably C r C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -NO,, - NH 2 , -CN, -CF 3 or -OH;
  • D is H, C,-C 6 lower alkyl, C,-C 5 lower aikoxy, -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 aikoxy, -NH, or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • Preferred compounds include those having the formula:
  • R j is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, preferably -C,-C 6 alkyl, -S-C,- C 10 alkyl, preferably -S-C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CN, -NO,, -NH 2 , 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 - (CH 2 ) n - bridge;
  • furan, pyrrole, or thiophene being optionally substituted by from 1 to 3 substituents selected from halogen, C r C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -NO 2 , -NH 2 , -CN, -CF 3 ; or
  • pyridine, pyrimidine, piperidine, or morpholine each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -NO 2 , -NH,, -CN, -CF, or -OH; or
  • Z is O or S
  • R 6 is selected from the relevant members of the group H, -CF 3 , C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, 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 r C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -NO,, -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 r C 6 alkyl, C,-C I0 aikoxy, preferably C,-C 6 aikoxy, -NH 2 , -(CH 2 ) n -NH 2 , -NH-(C r C 6 alkyl), - N-(C,-C 6 alkyl) 2 , -(CH 2 ) n -NH-(C r C 6 alkyl), -(CH 2 ) n -N-(C,-C 6 alkyl) 2 , phenyl, -O-phenyl, benzyl, or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole, or morpholine the rings of these groups being optionally substituted by from 1 to 3 substituents selected from hal
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C r C 6 aikoxy, -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;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C r C 10 alkyl, C,-C 10 aikoxy, -CHO, -C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C r C 6 alkyl, -N(C,-C 6 alkyl) 2 , -N-SO 2 - C,-C 6 alkyl, -SO 2 -C,-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH 2 -(C 3 -C 5 cycloalky), -C(O)-OH, C(O)-C r C 6 alkyl, -C(O)-O-C r C 6 alkyl
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, -(CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C r C 6 alkyl), or -N(C,-C 6 alkyl),_;
  • R 12 is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 ) n -C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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 ;
  • L 1 is selected from -(CH 2 ) n -, -S-, -O-, -C(O)-, -C(O)-O-,-(CH 2 ) n -O-, -(CH 2 ) n -S-, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -(CH 2 ) ⁇ -C(O)-(CH 2 ) n -, -(CH,) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -,-C(Z)-N(R 6 K -C(Z)-N(R 6 )-(CH 2 ) n -, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z
  • M' is -COOH or a moiety selected from:
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) n -COOH, (CH,) n -C(O)-COOH, tetrazole,
  • R 9 in each appearance is 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 H, -COOH, -(CH,) n -COOH, -(CH,) n -C(O)-COOH, -CF 3 , -OH, - (CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl,
  • the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 5 is selected from C r C 6 lower alkyl, C r C 6 lower aikoxy, -(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, -(CH 2 ) n -phenyl-O- phenyl, -(CH 2 ) n -phenyl-CH 2 -phenyl, -(CH 2 ) n -O-phenyl-CH 2 - ⁇ henyl, -(CH 2 ) n -phenyl-(O-CH 2 - phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower aikoxy, -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 r C 6 alkyl, C r C 6 aikoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • 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 5 alkyl, C,-C I0 aikoxy, preferably C,-C 6 aikoxy, -CN, -NO 2 , -NH 2 , phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -O- or -(CH 2 ) n - bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substituted by from 1 to 3 substituents selected from
  • n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
  • R 2 is selected from H, halogen, -CN, -CHO, -CF 3 , -OH, C,-C 10 alkyl, preferably C,-C 6 alkyl, C,-C 10 aikoxy, preferably C,-C 6 aikoxy, -CHO, -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C r C 6 alkyl) 2 , -N-SO 2 -C,-C 6 alkyl, or -SO 2 -C,-C 6 alkyl;
  • R 3 is selected from H, halogen, -CF 3 , -OH, -C,-C 10 alkyl, C r C 10 aikoxy, -CHO, -C(O)CH 3 , -C(O)-(CH 2 )n-CF 3 , -CN, -NO 2 , -NH 2 , -NH-C,-C 6 alkyl, -N(C,-C 6 alkyl),, -N-SO,- C,-C 6 alkyl, -SO 2 -C,-C 6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH 2 -(C 3 -C 5 cycloalky), -C(O)-OH, C(O)-C,-C 6 alkyl, -C(O)-O-C,-C 6 alkyl, -
  • n in each appearance is independently selected as an integer selected from 0-3;
  • R 8 and R 9 are independently selected in each appearance from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, -(CH 2 ) deliberately-C(O)-COOH, -C,-C 6 alkyl, -O-C r C 6 alkyl, -NH(C,- C 6 alkyl), or -N(C,-C 6 alkyl) 2 ;
  • R is selected from H, -CF 3 , C,-C 6 alkyl, -(CH 2 ) n -C 3 -C 6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen. -CF 3 , -OH. -COOH, -(CH,) n -COOH, -(CH,) 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 ;
  • L 1 is selected from -(CH,) n -, -S-, -O-, -C(O)-, -C(O)-O-,-(CH 2 ) n -O-, -(CH 2 ) n -S-, -(CH 2 ) n -O-(CH 2 ) n -, -(CH 2 ) n -S-(CH 2 ) n -, -(CH,) 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(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-N(R 6 )-, -C(O)-C(Z)-
  • M 1 is -COOH or a moiety selected from:
  • R 8 in each appearance, is independently selected from H, -COOH, -(CH 2 ) ⁇ -COOH, - (CH 2 ) n -C(O)-COOH, tetrazole,
  • R 9 in each appearance is 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),;
  • R 10 is selected from H, -COOH, -(CH 2 ) n -COOH, -(CH 2 ) n -C(O)-COOH, -CF 3 , -OH, - (CH 2 ) n -C(O)-COOH, -C,-C 6 alkyl, -O-C,-C 6 alkyl,
  • the moiety or combination of moieties comprising R 4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
  • R 5 is selected from C,-C 6 lower alkyl, C,-C 6 lower aikoxy, -(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, -(CH 2 ) n -phenyl-O- phenyl, -(CH 2 ) n -phenyl-CH 2 -phenyl, -(CH 2 ) n -O-phenyl-CH 2 -phenyl, -(CH 2 ) n - ⁇ henyl-(O-CH 2 - phenyl) 2 , -CH 2 -phenyl-C(O)-benzothiazole or a moiety of the formulae -(
  • D is H, C,-C 6 lower alkyl, C,-C 6 lower aikoxy, -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 aikoxy, -NH 2 or -NO 2 ; or a pharmaceutically acceptable salt thereof.
  • the present invention also provides for a method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention.
  • Methods of treating an inflammatory response or condition comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention are also provided.
  • Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided.
  • Figs. 1-13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are described in further detail below.
  • 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, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 aikoxy, preferably C1-C6 aikoxy, -CHO, -COOH or esters thereof, -N02, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NH(CH3), etc.
  • substituents selected from halogen, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 aikoxy, preferably C1-C6 aikoxy, -CHO, -COOH or esters thereof, -N02, -NH2, -CN, -CF3 or -OH or combinations thereof, such as -CH2CF3, -NH(CH3), etc.
  • a preferred subset of these groups include moieties formed from benzene, pyridine, napthylene or quinoline rings.
  • a further preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings.
  • a preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
  • alkyl, alkenyl and alkinyl groups referred 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.
  • Tables I- VI also report data for the listed compounds in the "LysoPC” assay and the Coumarine assay (see Example 88 below).
  • assay results are reported as an "IQ” value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay.
  • IQ is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay.
  • NA denotes that inhibitory activity was not detected from such compound in the corresponding assay and a blank box denotes that the compound was not tested in such assay as of the time of filing of the present application.
  • phospholipase enzyme activity means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 88 below).
  • a compound has "phospholipase enzyme inhibiting activity” when it inhibits the activity of a phospholipase (preferably cPLA) in any available assay (preferably an assay described below in Example 88 or Example 89) for enzyme activity.
  • a compound has (1) an I 0 value of less than about 25 ⁇ M, preferably less than about 6 ⁇ M, in the LysoPC assay; (2) an I 0 value of less than about 50 ⁇ M in the vesicle assay; (3) an I 0 value of less than about 1 ⁇ M in the PMN assay; (4) an IQ, 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 about 20-30%) in the rat carrageenan-induced footpad edema test.
  • Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA,) 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 carriers, 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 incorporated 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.
  • parenterally acceptable protein solutions having due regard to pH, isotonicity, stability, and the like, is within the skill in the art.
  • a preferred 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,
  • 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.
  • the various pharmaceutical 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 lmg 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 can be prepared according to the following methods. Temperatures are in degrees Celsius.
  • Indol-2-carboxylic acid ethyl ester I is converted to aldehyde II in two steps: reduction with lithium aluminum hydride (LAH) or other hydride in a suitable solvent such as tetrahydrofuran (THF) at 0°C, and then oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • LAH lithium aluminum hydride
  • THF tetrahydrofuran
  • an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilyl amide (KHMDS) in THF followed by reaction with a chloroformate in the presence of a base, such as triethyl amine, produces carbamate III.
  • KHMDS potassium hexamethyldisilyl amide
  • Ill is transformed into bromide IV in two steps: (1) reduction with sodium borohydride in an alcoholic solution and (2) reaction withcarbon tetrabromide in the presence of a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane.
  • a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane.
  • Displacement of the bromine in IV with potassium phenoxide, prepared by reaction of a phenol with KHMDS, in a suitable solvent such as THF or DMF affords ether V.
  • V can be converted to either trifluoromethyl ketone VII or to carboxylic acid IX in different procedures.
  • 2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give X.
  • a strong base such as sodium hydride (NaH) in THF
  • a suitable alkyl bromide to give X.
  • Hydrolysis of X with a aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropyl ethylcarbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide XL XI is hydrolyzed to corresponding acid XII in a aqueous base such as sodium hydroxide.
  • a carbodiimide such as dimethylaminopropyl ethylcarbodiimide hydrochlor
  • Indole I can be brominated on the 3-position by reaction with a bromine or N- bromosuccinimide in a suitable solvent such ascarbon tetrachloride or dichloromethane to yield bromide XIII.
  • a suitable solvent such ascarbon tetrachloride or dichloromethane
  • Reaction of XIII with a suitable alkyl bromide in the presence of a strong base such as NaH in THF or DMF affords indole XIV.
  • Palladium mediated coupling of XIV with a suitable alkene in the presence of phosphine and a base such as triethyl amine produces 3-substituted indole XV.
  • XV can be converted to amide XVII in two step reactions:
  • Indole I can be converted to XXI in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole.
  • a solvent such as THF
  • TBDMSC1 t-butyldimethylsilyl chloride
  • the silyl group on XXII is removed using tetrabutylammonium fluoride in a solvent such THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide XXIII.
  • Aldehyde II prepared by Method A, can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield XXV.
  • XXV can be converted to an unsaturated acid XXVI by two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
  • Indole I is reduced with LAH in a solvent such as THF.
  • BOC t-butoxycarbonyl
  • (BOQO) di-t-butyldicarbonate
  • the hydroxyl group in XXIX is mesylated using mesyl chloride and triethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as described in METHOD D to produce indoline XXX.
  • XXXI Deprotection of XXX using trifluoroacetic acid affords XXXI, which is either acylated (acyl chloride, triethylamine, dichloromethane) or alkylated (alkyl halide, K : C0 3 , DMF) to afford XXXII, or XXXIII respectively.
  • Carboxylic acid XXXIV is converted to aldehyde XXXV in two steps: (1) reaction with N,0- dimethylhydroxy amine in the presence of EDCI in a solvent such as dichloromethane, and
  • DIBAL diisobutyl aluminum hydride
  • METHOD H Aldehyde XXXV prepared in METHOD G, is subjected to a Wittig reaction using methyl triphenylphosphonium iodide in the presence of a strong base such as KHMDS or NaH in a solvent such as THF to afford alkene XL.
  • a strong base such as KHMDS or NaH in a solvent such as THF
  • Reduction of the nitro group of XL with iron powder in an ammonium chloride solution, followed by treatment with benzyl chloroformate in the presence of a base such as triethyl amine produces carbamate XLI.
  • XLI is treated with iodine in a basic solution such as aqueous NaHCQ in THF to yield iodide XLII.
  • Displacement of the iodine on XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH affords alcohol XLIII.
  • Indoline XXVIII prepared in METHOD F or METHOD H. can be either acylated by reaction with an acyl chloride in the presence of a base such as triethyl amine or alkylated using alkyl halide in the presence of KC0 3 in a solvent such as DMF to produce alcohol
  • XL VII can be alkylated on the amide nitrogen by treatment with alkyl halide and strong base such as NaH in DMF. Hydrolysis of the resulting amide with aqueous base such as NaOH gives acid XLIX. XLIV can also be directly hydrolyzed with NaOH to a carboxylic acid XLVIII.
  • Ester L can be deprotonated with a strong base such as lithium diisobutylamide (LDA) in a solvent such as THF, and subsequently alkylated with an alkyl halide such as methyl iodide to give LI.
  • LDA lithium diisobutylamide
  • Reduction of LI to amine LIII can be accomplished using hydrogenation catalyzed by palladium in a solvent such as ethanol.
  • L can be oxidized to alcohol LH using LDA and oxaziridine in a solvent such as THF.
  • Alkylation of LII with a alkylating reagent such as methyl iodide in the presence of a strong base such as NaH in DMF, followed by catalytic hydrogenation in the presence of palladium produces amine LIV.
  • METHOD K illustrates the synthesis of substituted aminobenzoic acid esters.
  • Mono-acid LV can be converted to amide LVI by the following steps: (1) reaction with oxalyl chloride in dichloromethane to form acid chloride and (2) treatment with a suitable amine such as dimethyl amine. Reduction of the nitro group to the amine is accomplished with hydrogenation catalyzed by palladium as described in METHOD J. LV can be reduced to alcohol LVIII with hydroborane-THF complex in THF. Protection of the hydroxy group as a silyl ether using TBDMSC1 in the presence of imidazole and subsequently, reduction of the nitro group (H 2 / Pd-C) to the amine affords LIX.
  • LVIII can be convened to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent such as manganese dioxide (Mn0 2 ) in ethyl acetate and (2) addition of a desired Grignard reagent such as methyl magnesium bromide in THF. Oxidation of LX with MnQ in THF and reduction of the nitro group (H 2 / Pd-C) produces ketone LXIII. Reduction of LVII (H / Pd-C) yields LXI.
  • a suitable reagent such as manganese dioxide (Mn0 2 ) in ethyl acetate
  • Grignard reagent such as methyl magnesium bromide
  • Alcohol LXIV prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon in a solvent such as ethanol. The resulting alcohol is treated with p- methoxybenzyl chloride in the presence of KC0 3 in a solvent such as THF to afford LXV. Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures described in METHOD D.
  • Step 1 2-C5-Phenylmethoxy)indolyl aldehyde
  • Step 2 Benzyl (l-(2-fo ⁇ nyl-5-phenylmethoxy)indolyl)formate
  • Step 3 Benzyl ⁇ -(2-hydroxymethyl-5-phenylmethoxy1indolyl)formate
  • Step 4 Benzyl ⁇ -f2-bromomethyl-5-phenylmethoxy)indolyl)formate
  • Step 5 Benzyl Cl-(2-('2-formylphenoxy)methyl-5-phenylmethoxy indolyl)formate
  • Step 6 120 mg (0.24 mmol) of the aldehyde of step 5 was dissolved in 11 mL of 5: 1 :5 THF- acetonitrile-2,2-dimethylethanol. To this solution was added a solution of 56 mg (0.5 mmol) of sodium chlorite in 0.5 mL water and 1 drop of aqueoues hydrogen peroxide solution. After 4 hours, another 56 mg (0.5 mmol) of sodium chlorite was added. The mixture was stirred at room temperature for three days. Aqueous work up and flash chromatography using 2.5: 1:0.05 hexane:ethyl acetate-acteic acid afforded 110 mg of the title compound.
  • Step 1 Benzyl (l-f2-(2-(l-hydroxy-2.2.2-trifluoroethyl phenoxy)methyl-5- phenylmethoxy ndolyP-formate
  • Step 1 Ethyl 2-Cl-benzyl-5-benzyloxy)indolecarboxylate
  • Step 3 Ethyl 3-(2-( l-benzyl-5-benzyloxy)indolecarboxamido)benzoate
  • step 2 l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0.018 g, 0.15 mmol) and ethyl 3-aminobenzoate (0.27 g, 1.66 mmol) were stirred in tetrahydrofuran (9 mL) at room temperature overnight. The next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated.
  • EDCI l-(3-dimethylaminopropyl)-3- ethylcarbodiimide
  • DMAP 4-dimethylaminopyridine
  • ethyl 3-aminobenzoate 0.27 g, 1.66 mmol
  • Ethyl 5-methoxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to P C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgS0 and concentrated to yield 24.8 g of alcohol, which was used for the next reaction directly.
  • LAH Lithium Aluminum Hydride
  • Step 2 2-(5-methoxy)indolylmethoxy-tert-buthyldimethylsilane
  • DMF dimethyl methoxy-buthyldimethylsilane
  • imidazole 5.5g, 81.5 mmol
  • t- butyldimethylsilyl chloride 5.4g, 35.8 mmol
  • the reaction was poured into water and extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated.
  • Step 3 3-(2-tert-butydimethylsilyloxymethyl-5-methoxy ndolyl C2.4-bisd . l- dimethypropyl)phenoxy)methyl ketone
  • Step 4 S- ⁇ -tert-butydimethylsilyloxymethyl-S-methoxy-l-methyOindolyl (2.4-bisd . l- dimethypropyl ' )phenoxy)methyl ketone
  • Step 5 3-C2-Hydroxymethyl-5-methoxy-l-methyl)indolyl (bis-2,4- .1. dimethy lpropyPphenoxylmethyl ketone
  • Step 6 Methyl 3-f2-(3-f2.4-bisd . l-dimethypropyl)phenoxy)acetyl-5-methoxy-l- methylindolyl)methylthioacetamido)-4-methoxybenzoate
  • EXAMPLES 13. 14. 15 and .16 in Table I were prepared by the procedures of Example 12 using Ethyl 2-(5-benzyloxy)indolecarboxylate, acetyl chlorides and suitable alkyl halides.
  • Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0° C, to which Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) was added via addition funnel over 40 minutes. The reaction was stirred a for 2 hours at 0 °C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3X400 mL), the filtrates were combined, dried over MgS0 and concentrated to yield 24.8 g.
  • LAH Lithium Aluminum Hydride
  • Step 2 tert-Butyl l-(5-benzyloxy-2-hydroxymethy)lindolinylformate 25 g (85 mmol) of crude alcohol, prepared in step 1, and 4-dimethylamino pyridine (DMAP) (1.19 g, 9.78 mmol) were dissolved in dichloromethane (180 mL). The solution was cooled to CP C and then triethylamine (13.6 mL, 98 mmol) was added to it. After 10 minutes of stirring a solution of di-tert-butyl dicarbonate (21.3 mL, 98mmol) dissolved in dichloromethane (20 mL) was added via syringe pump over 2 hours.
  • DMAP 4-dimethylamino pyridine
  • the carbamate, prepared in step 2 (15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with triethylamine (9.0 mL, 64.4 mmol). The solution was cooled to -10 p C at which time mesyl chloride (4.3 mL. 56 mmol) was added over 5 minutes. The reaction was stirred for a further 2 hour at -10°C, it was then concentrated and used directly for the next displacement reaction.
  • Step 5 Ethyl 3-f2-f5-henzyloxy-l-tert- butoxycarbonvPindolinyPmethylthioacetamidobenzoate
  • Step 7 Ethyl 3-(2-(5-benzyloxy- 1 -(2 ,4-bisf 1.1 -dimethy PpropyDphenoxyacetyPindolinvD methylthioacetamidobenzoate
  • step 7 The ester (0.231 g, 0.31 mmol) of step 7 was dissolved in THF (4.3 mL), methanol
  • Step 3 2-(5-Benzyloxy-l-f2.4-bisd . l- dimethy propyPphenoxyacetyPindolinylmethylthioacetic acid
  • Step 4 Methyl 3-(2-(5-benzyloxy- 1 -(2.4-bisf 1.1 -dimethy)propyPphenoxyacetyPindolinyl) methylthioacetamido-4-methylbenzoate
  • the titled compound was prepared from ester, prepared in step 4, according to the procedure described in step 3.
  • Step 1 2-(5-Benzyloxy-l- .5-bisCtrifluoromethyPphenoxyacetyl)indolinyPmethanol
  • Step 2 Ethyl 2-(5-benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyPindolinyl) methylthioacetate
  • Step 1 5-(2-(-5-Benzyloxy-l-G.5-bisCtrifluoromethyl)phenoxyacetyPindolinyl) methy lthioacetamido)benzene- 1.3-dicarboxylate
  • Step 1 Methyl 5-('2-C-5-benzyloxy-l-(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl) methylthioacetamido)-3-tert-butyldimethylsilyloxymethylbenzoate
  • This compound was prepared according to the procedure described in step 1 of Example 38.
  • Step 2 Methyl 5-(2-C-5-benzyloxy-l-C3.5-bis(trifluoromethyPphenoxyacetyPindolinyl) methylthioacetamido)-3-hydroxymethylbenzoate
  • the titled compound was prepared according to the procedure described in step 2 of Example 38.
  • EXAMPLE 42 in table 3 was prepared according to the procedures described in Example 41.
  • Step 1 2-('5-Hydroxy-l-C3.5-bis(trifluoromethvPphenoxyacetyPindolinyPmethanol
  • Step 2 2-(5-C4-Methoxy)henzyloxy-l-f3.5- bisftrifluoromethyPphenoxyacetyPindolinvPmethanol
  • Step 3 Methyl 5-(2- ⁇ '-5-(4-methoxy)benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyP indolinvPmethylthioacetamido)benzene-1.3-dicarboxylate
  • Step 4 Methyl 5-(2- ⁇ 5-Hydro ⁇ y-l-(3.5-bisftrifluoromethyPphenoxyacetyP indolinyPmethylthioacetamido)benzene- 1.3-dicarboxylate
  • Stepl Methyl 5-(2-C5-(3.5-Dibromo)benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyP indolinyPmethylthioacetamidolbenzene- 1.3-dicarboxylate
  • the titled compound was prepared from the ester, prepared in step 1 , according to the procedure described in step 5 of Example 44.
  • Example 44 but using corresponding alkylating reagent.
  • This compound was prepared according to the procedures described in step 6 of Example 17. but with methyl 4-methoxybenzoate.
  • Step 2 Methyl 3-(2-(5-benzyloxy-l-C2-naphthoxyacetvPindolinyPmethylthioacetamido)-4- methoxybenzoate
  • Step 1 Ethyl 3-C2-( " 5-benzyloxy-l-tert-butoxycarbonyl)indolinyl)methylsulfonyl acetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 5-Benzyloxy-l-(2.4-bisd . l-dimethy)propyPphenoxyacetyl)-2-hydroxymethylindoline
  • Step 2 2-(5-Benzyloxy- 1 -C2 ,4-bisf 1.1 -dimethy)propyl)phenoxyacetyPindolinylmethyl _ methylsulfonate
  • Step 3 Methyl 2-(2-(-5-benzyloxy-l-C2.4-bisd . l-dimethy ' )propyPphenoxyacetyP indolinyPmethylthiobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • EXAMPLE 68 was prepared according to the procedures described in Example 67.
  • EXAMPLE 71 was prepared according to the procedures described in Example 70. but using allyl bromide.
  • Step 1 Ethyl 3-(2-(5-benzyloxy-1 -C2-C4- pyridinyPethyPindolinyPmethylthioacetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 Ethyl 3-( ' 2-(5-benzyloxy-l-('2-naphthyPmethy)indolinyPmethylthioacetamidobenzoate
  • the titled compound was prepared according to the procedure described in step 3 of Example 59.
  • Step 1 2-C2-( " -5-Benzyloxy- 1 -d .1 -dimethyPethoxycarbonyPindoliny Pmethyl methylsulfonate
  • tert-Butyl l-(5-benzyloxy-2-hydroxymethy)lindolinylformate (6.72 g, 19 mmol), prepared in step 2 of Example 17. was dissolved in CHC1 2 (80 mL, dried over MgS0 4 before use). The clear yellow solution was cooled in a dry-ice bath. EjN (4.0 mL) was then added followed by methanesulfonyl chloride (2.0 mL). The reaction mixmre was stirred for
  • Step 2 Methyl 2-(2-(5-Benzyloxy-l-d . l-dimethyl)ethoxycarbonyl)indolinyPmethylthio benzoate
  • Mesylate (7.2 g, 1.8 mmol), prepared in step 1, was dissolved in DMF (50 mL). The clear light brown solution was degassed by vigorously bubbling with Ar for 30 min. Cesium carbonate (13.8 g) was added followed by methyl thiosalicylate (2.4 mL). The solution changed to a bright yellow and the suspension was stirred overnight. Methyl thiosalicylate (0.15 mL) was added to complete the reaction and the mixmre was stirred overnight.
  • ester (1 g), prepared in step 3 was dissolved in DMF (6 mL).
  • p-Benzylbenzyl bromide was added (1 eq) followed by KC0 3 (1 eq).
  • the reaction mixture was stirred overnight at room temperature.
  • additional p-benzylbenzyl bromide (0.5 eq) was added and the reaction was stirred for another 2 hours.
  • the reaction was diluted with HO and extracted with EtOAc (2 x). The organic layers were combined and dried over MgSQ.
  • the MgS0 4 was filtered and the solvent was evaporated to give an oily material which was dried overnight on high vacuum to give the product (1.59 g, 109 % yield).
  • Step 1 Methyl l-(5-Benzyloxy-2-(hydroxymethyPindolinyPmethylbenzoate
  • Step 2 Methyl 4-d-(5-Benzyloxy-2-0 is-2.4-trifluoromethyPbenzyloxymethyPindolinyl) methylbenzoate
  • the titled compound was prepared according to the prodedure described in step 5 of
  • Step 1 2-d-(2.4-Bis(trifluoromethyPbenzyl)indolinyPcarboxylic acid
  • 2-Indolinylcarboxylic acid (0.43 g, 2.6 mmol) was dissolved in DMF (5 mL), placed under N 2 , and cooled to Of C, the sodium hydride (0.26 g of a 60 % dispersion, 6.5 mmol) was added and stirring was continued for 1 hour at this temperamre.
  • 2,4- Bis(trifluoromethyl)benzyl bromide (1.22 mL, 6.5 mmol) was next added and the reaction was warmed to room temperamre overnight.
  • the reaction was then diluted with 1/2 samrated ammonium chloride/ethyl acetate, the aqueous layer was extracted with ethyl acetate (3X), the organic layers were dried over magnesium sulfate and concentrated.
  • the crude product was purified via chromatography (hexane:ethyl acetate 9: 1) to yield 0.96 g of the ester.
  • the resulting ester (0.87 g, 0.1.41 mmol) was dissolved in THF/ methanol and then
  • the titled compound was prepared according to the prodedure described in Example 84, but using phenylsulfonylamide.
  • Step 1 2-TrimethyIsilylethyl l-(5-benzyloxy-2-hydroxymethyPindolinylformate
  • Step 3 2-Trimethylsilylethyl l-C5-f4-methoxy)benzyloxy-2-hydroxymethyl)indolinylformate
  • Step 4 2-Trimethylsilylethyl l-CS- ⁇ -methoxy ⁇ enzyloxy ⁇ -bromomethyPindolinylformate
  • Step 5 2-Trimethylsilylethyl l-(5-(4-methoxy)benzyloxy-2-azidomethyPindolinylformate
  • Step 6 2-Trimethylsilylethyl l-(5-(4-methoxy)benzyloxy-2-aminomethyPindolinylformate
  • Step 7 Methyl 5-(2-(5-Methoxybenzyloxy-l-(2-trimethylsilyloxy)ethoxycarbony)lindolinyP methylaminocarboxamido- 1.3-benzenedicarboxylate
  • the product was extracted with ethyl acetate, and the combined organic layers were washed with water, samrated aqueous NaHCQ, brine and dried over MgS0 4 .
  • the crude product was purified by flash chromatography using 10% MeOH/CHCl 2 to afford 0.78 g of the product.
  • Step 8 Methyl 5-(2-(5-Methoxybenzyloxy)indolinyl)methylaminocarboxamido-1.3- benzenedicarboxylate
  • Step 9 Methyl 5-(2-(5-Methoxybenzyloxy-l-(bis-2.4-trifluoromethyPbenzyPindolinyP methylaminocarboxarnido- 1.3-benzenedicarboxylate
  • EXAMPLE 87 was prepared according to the prodedure described in Example 86. but using 4-(3,5-bis(trifluoromethyl)phenoxymethyl)benzyl bromide.
  • Step 1 Bisfmethyl 4-methoxy-3-dithioacetamidobenzoate
  • reaction mixmre was allowed to warm to -30°C over 20 min. and then cooled to -50 °C again.
  • the reaction mixture was quenched with HO (500 mL) at -50 °C and warmed up to room temperamre and stirred for 0.5 h.
  • the reaction mixture was partitioned between CH 2 C1 2 (500 mL) and H 2 0.
  • the aqueous layer was extracted with CHC1 2 (3 x 500 mL).
  • the combined CH,C1 2 extracts were concentrated in vacuo to give a yellow oil. This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0°C and stirred at room temperature overnight.
  • the titled compound was prepared from nitro compound of step 1 according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure described in step 4 of Intermediate 3.
  • Step 1 Methyl 2-(3-nitro-4-methoxyphenyl)-2-methylacetate
  • the titled compound was prepared from nitro compound, prepared in step 1 , according tothe procedure described in step 4 of Intermediate 3.
  • Step 1 Methyl 2-(3-nitro-4-methoxyphenyl)-2-allylacetate
  • This compound was synthesized form ester, prepared in step 1 of Intermediate 3, according to the procedure described in step 1 of Intermediate 6, but using allyl bromide.
  • the titled compound was prepared from 2-naphthol according to the procedure described in of Intermediate 8.
  • the titled compound was prepared from 3,5-bis(trifluoromethyl)phenol according to the procedure described in of Intermediate 8.
  • the titled compound was prepared from nitro compound, prepared in step 1, according to the procedure described in step 4 of Intermediate 3.
  • the titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure described in step 4 of Intermediate 3.
  • Step l Methyl 5-nitro-3-d -hydro xy)ethylbenzoate
  • the titled compound was prepared from nitro compound, prepared in step 2, according to the procedure described in step 4 of Intermediate 3.
  • Step 1 Bis 2-bromoethyPdisulfide
  • Step 2 Bis-Onethyl 4-methoxy-3-(2-dithioethyPaminobenzoate Bromide (0.39 mg, 1.387 mmol), prepared in step 1, and methyl 3-amino-4-methoxy benzoate (1.00 g, 5.51 mmol) were added into a flask, flush with nitrogen and take up in DMF (5 mL) and then heat to 60° C for 24 hours at which time the reaction was diluted with ethyl acetate and quenched into water, extracted with ethyl acetate (3X), the combined organic layers were washed with water (3X), dried and concentrated to yield 1.27 g of a product that was purified by chromatography (hexane:ethyl acetate 5: 1 to 3: 1) to yield 0.15 g of the desired product.
  • the aldehyde is reacted with the alpha-carbon of a heterocycle such at 2,4-thiazolidinedione or rhodanine or 2-thiohydantoin in the presence of a base such a potassium carbonate or potassium hydroxide in a solvent system such a wate ⁇ efhanol or ethanol.
  • a base such as potassium carbonate or potassium hydroxide
  • a solvent system such as a wate ⁇ efhanol or ethanol.
  • the final acid may then be realized by cleavage of the ester with hydrogen fluoride in a solvent such as acetonitrile.
  • Indole-2-carboxylic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh 3 ) as a catalyst in a mixed solvent (ethanol-benzene- water) at elevated temperature to give the l-alkyl-5-substiruted indole.
  • the starting material for the inhibitors in this class 2-Ethoxycarbonyl-5-benzyloxyindole I, was deprotonated with a suitable base such as sodium hydride and alkylated on the nitrogen atom with selected electrophiles such as alkyl or benzyl halides to provide compounds II. Saponification of the ester functionality with a base such as aqueous sodium hydroxide in miscible solvents such as tetrahydrofuran and methanol gave inhibitors III.
  • a suitable base such as sodium hydride and alkylated on the nitrogen atom with selected electrophiles such as alkyl or benzyl halides
  • Acid isosteres such as tetrazole were prepared from the carboxylic acids I via the nitriles III . Conversion to the nitriles was accomplished through primary amide formation of the acid functionality via the acid chloride with a suitable reagent such as oxalyl chloride and reaction with ammonia followed by a dehydration sequence using a suitable reagent such as oxalyl chloride and a base such as pyridine.
  • the nitriles such as UI could be converted to the tetrazoles by reaction with an azide source such as sodium azide in an appropriate high boiling point solvent such as N-methyl pyrrolidinone to give compounds such as IV.
  • 2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give VI.
  • a strong base such as sodium hydride (NaH) in THF
  • a suitable alkyl bromide to give VI.
  • Hydrolysis of VI witha aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethyl carbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide VII.
  • Amide VII is hydrolyzed to corresponding acid VIII in a aqueous base such as sodium hydroxide.
  • Aldehyde K is prepared from Indol-2-carboxylic acid ethyl ester I in two steps: (1) Reduction with lithium aluminium hydride or other hydride in a suitable solvent such as THF at 0°C and (2) oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF.
  • Aldehyde LX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield indole X .
  • Indole X can be converted to an unsaturated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
  • Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole.
  • TBDMSC1 t-butyldimethylsilyl chloride
  • a base such as imidazole.
  • Grignard reagent such as ethyl magnesium bromide
  • a suitable acyl chloride such as acetyl chloride in ether
  • alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF affords ketone III.
  • the silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide IV.
  • R" halogen, CN, alkyl, aikoxy, alkoxycarbonyl, amido, acyl, H, OH
  • R aikoxy, benzyloxy, phenoxy, halogen, CN, N0 2 , alkyl or aryl
  • R' alkyl, aryl
  • Step 1 The aldehyde from Example 124, (5.2 g) was suspended in ethanol (150 mL). To the thick slurry was added 2,4-thiazolidinedione (1.28g) and potassium carbonate (6.1g). The mixture was heated in a bath at 60 °C (later dropped to 45 °C). After 1 h TLC showed no reaction. Sodium hydroxide (2.1 g) was added and the mixture was heated at 58 °C. After 45 minutes the TLC showed reaction progress. Additional 2,4-thiazolidinedione (0.1 g) was added. The mixture was stirred overnight at room temperature.
  • Step 2 To the material prepared in step 1 (1.1 g) in DMF (15 mL) at 0 °C was added sodium hydride (0.08 g. 60% dispersion in mineral oil). The suspension was stirred for 30 minutes. To the reaction mixture was added the benzyl bromide (0.54 g) and the reaction was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated. Column chromatography (1:6 ethyl acetate: hexane to 1:4 ethyl acetate:hexane) afforded the desired product (1.18 g, 75%) as a yellow solid.
  • Step 3 To the material prepared in step 2 (0.34 g) in acetonitrile (15 mL) was added HF (48% aqueous, 3.7 mL) via syringe. The reaction was stirred overnight. The reaction was not complete by TLC therefore THF was added to dissolve the starting material and additional HF (0.6 mL) was added. The reaction was stirred for 2 h after which the TLC showed reaction completion. Water was added which resulted in the formation of a yellow solid. The yellow solid was dissolved in ethyl acetate, washed with brine, dried over MgSO 4 and concentrated. The resulting crude solid was suspended in ethanol and stirred for 30 min, filtered and dried to afford the title compound (140 mg, 48%) as a yellow solid.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • the compounds of the following Examples 101-106 were prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
  • Step 1 The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
  • Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
  • Step 3 The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
  • Example 117A To a suspension of the acid prepared in Example 117A (1.5g, 3.0mmol) in CH 2 C1 2 (20ml) was added oxalyl chloride (0.8ml, 9.1mmol) and three drops of DMF. The mixture became homogeneous and was stirred for lh at rt. The reaction was concentrated and redissolved in CH 2 C1 2 (5ml) and NH 4 OH (2.0ml) was added. The biphasic mixture was stirred for 24h and concentrated. The remaining aqueous residue was extracted with CH 2 C1, and the combined organic layers washed with brine, dried and concentrated to give 1.4g (95%) of the desired intermediate as a yellow powder.
  • EXAMPLE 1 19 benzyl 1 -(4- ⁇ [3 ,5-bis(trifluoromethyl)phenoxy]methyl ⁇ benzyl)-2-( 1 H- 1 ,2,3 ,4-tetraazol-5-yl)- 1 H- indol-5-yl ether acid was prepared in an analogous manner to Example 118 according to steps 1-3 starting from the acid prepared in EXAMPLE 117C.
  • Example 101 The thiasolidinedione prepared in Example 101 (O.lg, 0.2mmol), was alkylated by treatment with sodium hydride (0.006g, 0.22mmol), and the bromomethyl SEM ester (0.058g, 0.2mmol) in
  • Step 1 To ethyl 5-benzyloxy-2-indolcarboxylate (1 g, 3.4 mmol) in 12 ml of DMF, sodium hydride (0.163g, 60% oil dispersion, 4.07 mmol) is added at room temperature. The reaction is stirred for 30 minutes. a-Bromo-a'-[3,5-bis(trifluoromethyl)phenoxyl]-p-xylene (1.54 g, 3.73 mmol) is added at this time and the reaction stirred overnight. On completion of the reaction (monitored by TLC) it is quenched with water, extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate, concentrated and used for the next step.
  • sodium hydride 0.163g, 60% oil dispersion, 4.07 mmol
  • a-Bromo-a'-[3,5-bis(trifluoromethyl)phenoxyl]-p-xylene (1.54 g, 3.73 m
  • Step 2 The ester ( 2.1 g, 3.39 mmol) is dissolved in 40 mL of 1/1 THF/ methanol and then IN sodium hydroxide (15 mL) is added and the resulting mixture is stirred for 16 hours at RT, workup gave crude product that is purified via chromatography (1:1 Hexane:Ethyl acetate with 1% acetic acid) to yield (1.73 g, 85%) of solid.
  • EXAMPLE 123 5-((ri-benzyl-5-(benzyloxy)-lH-indol-2-yllcarbonyI ⁇ amino)isophthalic acid
  • Step 1 This intermediate was prepared according to the procedure described in Example 122, but using benzyl bromide.
  • Step 2 The acid (0.27 g, 0.75 mmol) prepared in step 1, EDCI (0.18 g, 0.97 mmol), DMAP (3 mg, 0.02 mmol) and dimethyl-5 aminoisophthalate (0.18g, 0.75 mmol) were dissolved in THF
  • Step 3 The title compound was prepared from ester, prepared in step 2 above, according to the procedure described in step 2, Example 122.
  • Step 1 Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0° C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO 4 and concentrated to yield 24.8 g (96%).
  • LAH Lithium Aluminum Hydride
  • Step 2 Indole alcohol (26.1 g, 103 mmol) from step 1 is dissolved in THF (900 ml). Manganese dioxide (106.6 g) is added and the mixture is stirred for 2h at room temperature. After the reaction is complete the mixture is filtered through celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, dried to give the desired aldehyde (22.9 g, 89%).
  • Step 3 This intermediate was prepared from indole, prepared in step 2 above and 2- (bromomethyl)naphthalene, according to the procedure described in step 1, Example 122.
  • Step 4 To sodium hydride (0.025 g, 60% oil dispersion, 0.63 mmol) in 7.5 mL of THF is added trimethyl phosphonoacetate (0.1 mL, 0.62 mmol) in 2.5 mL of THF at room temperature. The reaction is stirred for 10 minutes. Next the aldehyde (0.24 g, 0.62 mmol) prepared in step 3 above in 2.5 mL THF is added dropwise at room temperature. Reaction is stirred for another 30 minutes NOT FURNISHED UPON FILING
  • Step 1 p-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCl (1.1 eq) dissolved in methylene chloride at 0°C over 20 min. The reaction was allowed to warm to 25°C. After stirring at 25°C for 1 day, workup with methylene chloride and water afforded crude product in ca. 100% yield.
  • Step 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0.19M), and
  • Step 4 The intermediate from step 3, Example 131 was dissolved in dry DMF (0.1 M), followed by NaH (1.2 eq). After 1.5 h at 25 °C, added the bromobenzyl ketone from step 3 and stirred for 1 d at 25°C. Workup (ethyl acetate/hexanes) and trituration (ethyl acetate/hexanes) afforded the product in 46% yield.
  • Step 5 The product from step 4 was dissolved in methylene chloride and 1 N HCl (ca. 0.04 M) and stirred at 25°C for 1 h. Workup (sodium bicarbonate), and trituration with ether afforded the product alcohol (89%).
  • Step 6 The alcohol from step 5 was dissolved in dry methylene chloride (0.014 M), treated with thionyl chloride (1.2 eq) and stirred at 25°C for 1 d. Concentration and trituration with ethyl acetate/hexanes afforded the product chloride (100%). NOT FURNISHED UPON FILING
  • a typical assay consisted of the lipid mixture (85 ⁇ l) to which was added consecutively, the inhibitor (5 ⁇ l in DMSO) and cPLA, 10 ng for an automated system or 1 ng for a manual assay, in 10 ⁇ l of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below.
  • Soluble Substrate Assay (LysoPO l-[ l4 C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 ⁇ M) was dried under a stream of nitrogen. The lipid was resuspended by vortexing 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consisted of lipid suspension (85 ⁇ l) to which was added consecutively the inhibitor (5 ⁇ l in DMSO) and cPLA, 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA. This assay was conducted by either the manual assay or automated assay protocol described below.
  • RBL-2H3 cells were routinely cultured as 37C in a 5 % C0 2 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded into spinner flasks at 3 x 10 cells/ml and 100 ng/ml DNP specific-IgE was added. After 20 hrs, the cells were harvested by centrifugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 cells/ml in serum free media.
  • the cells were then preincubated with either inhibitor in DMSO (1 % v/v) or DMSO (1 % v/v) for 15 min at 37C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGD ⁇ content in accordance with known methods.
  • 7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). Inhibitors were mixed with 200 ⁇ L assay buffer (80mM Hepes, pH 7.5, 1 mM EDTA) containing 60 ⁇ M 7-hydroxycoumarinyl 6- heptenoate. The reaction was initiated by adding 4 ⁇ g cPLA2 in 50 ⁇ L assay buffer. Hydrolysis of the 7-hydroxycoumarinyl 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 increasein emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.

Abstract

Inhibitors of cPLA2 activity are disclosed, having a chemical formula selected from the group consisting of (I), (II), and (III), (IV), (V) or (VI).

Description

INHIBITORS OF PHOSPHOLIPASE A2
This application is a continuation-in-part of application Ser. No. 08/918,400, filed August 26, 1997, which was a continuation of application Ser. No. 08/703,115, August 26, 1996.
Background of the Invention
The present invention relates to chemical inhibitors of the activity of various phospholipase enzymes, particularly phospholipase A enzymes.
Leukotrienes and prostaglandins are important mediators of inflammation. 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 produciton 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 (hereinafter PLA2). The reaction catalyzed by PLA 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 PLA, 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 prostaglandins 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 pathwasy of conversion of arachidonic acid to leukotrienes, witout affecting the production of prostaglandins. None of these widelt-used anti- inflammatory agents affects the production of PAF.
Consequently the direct inhibition of the activity of PLA 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 PLA2 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 have an approximately 14 kD molecular weight and contain seven disulfide bonds which are necessary for activity. These PLAr,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 has been determined. This non- pancreatic PLA: 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. Biophys. 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 PLAis 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 PLAis regulated by protein kinase C and G proteins [R. Burch and J. Axelrod. Proc. Natl. 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 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 μmols/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. Biophvs. 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 A (hereinafter "cPLA,") 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 enzyme, purified from its natural source or otherwise produced in purified form, which functions intracellularly to produce arachidonic acid in response to inflammatory stimuli.
Now that several phospholipase enzymes have been identified, it would be desirable to identify chemical inhibitors of the action of enzymes, which inhibitors could be used to treat inflammatory conditions, particularly where inhibition of production of prostaglandins, leukotrienes and PAF are al desired. There remains a need in the art for an identification of such anti-inflammatory agents for therapeutic use in a variety of disease states.
Summary of the Invention
The present invention provides compounds having a chemical formula selected from the group consisting of:
Figure imgf000006_0001
Figure imgf000006_0002
or a pharmaceutically acceptable salt thereof, wherein:
A is independent of any other group and is selected from the group consisting of -CH2- and -CH2-CH2-;
B is independent of any other group and is selected from the group consisting of -(CH2)n-, -(CH20)n-, -(CH2S)n-, -(OCH2)n-, -(SCH2)n-, -(CH =CH)n-, -(C = C)n-, -CON(R6)-, -N(R6)CO-, -0-, -S- and -N(R6)-;
R, is independent of any other R group and is selected from the group consisting of -X-R, -H. - OH, halogen, -CN, -NO,, C,-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR5, -CONR^, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C,-C10 alkyl, alkenyl and substimted aryl;
R3 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR5, -CONR5R«, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C,-C10 alkyl, alkenyl and substituted aryl;
R4 is independent of any other R group and is selected from the group consisting of -H, -OH, - OR,, -SRj, -CN, -CORβ, -NHR6, -COOH, -CONR^, -NO,, -CONHS02R8, C,-C5 alkyl, alkenyl and substituted aryl; R5 is independent of any other R group and is selected from the group consisting of -H, -OH, 0(CH,)nR6, -SRβ, -CN, -COR,, -NHR,, -COOH, -NO,, -COOH, -CONR,R7, -CONHSO,R8, C,-C5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CF3, -CF,CF3 and
Figure imgf000007_0001
R, is independent of any other R group and is selected from the group consisting of -H, C-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R7 is independent of any other R group and is selected from the group consisting of -H, C-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R8 is independent of any other R group and is selected from the group consisting of C-C3 alkyl, aryl and substituted aryl;
Rt, is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R7, tetrazole, -CONHSO,R8, -COR,, -(CH,)„CH(OH)R6 and -(CH,)nCHR6R5;
Rio is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R7, tetrazole, -CONHSO,R8> -COR,, -(CH,)nCH(OH)R, and -(CH,)nCHR,R5;
W is, independently each time used including within the same compound, selected from the group consisting of -O-, -S-, -CH-, -CH =CH-, -C ≡ C- and -N(R,)-;
X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-;
Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N(R,)-, -CO-, -CON(R,)- and - N(R,)CO-; m is, independently each time used including within the same compound, an integer from 0 to 4; and n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4. Preferably, the compounds of the invention have phospholipase enzyme inhibiting activity. Other preferrred embodiments include compounds having the following chemical formula:
Figure imgf000008_0001
compounds having the following chemical formula:
Figure imgf000008_0002
compounds having the following chemical formula:
Figure imgf000008_0003
In particularly preferred embodiments, A is -CH- and R, is -(CH2)n-W-(CH,)m-ZR5 These preferred compounds includes those wherein n is 1 , m is 1 , W is -S- and Z is -CO-; those wherein Rj is -NHR,; those wherein R, is a substituted aryl group and those wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -CF3,
-CF2CF3, -(CH,)pCOOH, -(CH2)pCH3, -0(CH,)pCH3, -(CH2)pOH, -(CH2)pS(C,H,), -(CH2)pCONH, and -CHRπCOOH, wherein R,, is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH,)pOH, and -0(CH2)pCH3, and wherein p is an integer from 0 to 4. Other preferred comounds include those wherein R; is selected from the group consisting of -H and -OCH(C6H6) and R3 is -COR5, R5 is -OC^R, and R, is a substituted aryl group. In particularly preferred compounds, said aryl group is substimted with one or more substituents selected from the group consisting of -CF, - CF,CF3 and -C(CH3),CH,CH3.
Among the compounds of this invention are those of the formula:
Figure imgf000010_0001
wherein
R, and Rr are independently selected from C,-C6 alkyl, -Z-Cj-C5 alkyl, phenyl, -(CH2)n- Z-(CH2)n-phenyl, benzyl, -(CH2)n-Z-(CH2)n-benzyl, napthyl, -(CH2)n-Z-(CH2)n-napthyl, pyrimidinyl, -(CH2)n-Z-(CH2)n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -NH,, -CN, -CF3, or -OH;
Z is O or S;
n is an integer from 0 to 3;
R2 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, C,-C10 aikoxy, -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 H, halogen, -CF3, -OH, -C,-C10 alkyl, C,-C10 aikoxy, -CHO, - C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-CrC6 alkyl, -N(C,-C6 alkyl),, -N-SO2- C,-C6 alkyl, -SO,-C,-C6 alkyl or a moiety of the formula:
Figure imgf000010_0002
n in each appearance is independently selected as an integer selected from 0-3; R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)π-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(Cr C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000011_0001
R is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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,-C5 alkyl)2;
L1 is selected from -(CH2)n-O-, -(CH2)n-S-, -(CH2)„-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M' is -COOH or a moiety selected from:
Figure imgf000012_0001
R10 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000012_0002
with a proviso that the moiety or combination of moieties comprising R3 include an acidic group selected from carboxylic acid or a moiety of the formulae:
Figure imgf000012_0003
R5 is selected from:
a) a moiety of the formula -L -M ;
L2 is selected from a chemical bond or a bridging group selected from -(CH2)π-Z-, -(CH2)n-Z-(CH2)n-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)π-S-(CH2)n-C(O)-N-;
M2 is selected from -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000013_0001
wherein R8 and R9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or
b) a moiety of the formulae:
Figure imgf000013_0002
wherein L3 is a chemical bond or a group selected from -CH2- , -CH2-Z- , -C(O)- , -O-, -S- , or -(CH2)n-Z-(CH2)n-;
M3 is selected from -(CH2)n-C3-C5 cycloalkyl, furanyl, thienyl, pyrrolyl,
Figure imgf000014_0001
or a pharmaceutically acceptable salt thereof.
Of the compounds in the group just defined, a preferred subset include those in which the core molecule is an indole. Within the indole group is another subset wherein R' and R2 are hydrogen, and the moieties R3, R4, R5, R8, R9 and R10, n, L1, L2, M1 and M2 are as defined above. Within this subset is another preferred group wherein R1 is in the indole 5-position.
Also among the compounds of this invention are those of the formula:
Figure imgf000014_0002
wherein :
R, is selected from -O-C,-C6 alkyl, -S-CrC6 alkyl, -O-phenyl, -S-phenyl, -O-benzyl, -S- benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -NH2, -CN, -CF„ or -OH; R2 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, C,-CI0 aikoxy, preferably C,-C6 aikoxy, -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 H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -CrC6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-CrC6 alkyl, -N(C,-C6 alkyl)2, - N-802-Cj-Cg alkyl, -SOj-C^ alkyl, or a moiety of the formula:
Figure imgf000015_0001
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH,)n-C(O)-COOH, -CF3, -OH, -(CH,)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,- C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is the moiety -L'-M1 or
Figure imgf000015_0002
L1 is selected from a chemical bond or a bridging group selected from -(CH2)n-O-, -(CH,)n-S-, -(CH,)n-O-(CH,)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH,_)n-O-, -C(O)-N-, or -(CH2)n-S-(CH,)n-C(O)-N-; M is the moiety:
Figure imgf000016_0001
Rιυ is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000016_0002
Figure imgf000016_0003
with a proviso that the combination of moieties comprising R4 include a carboxylic acid or a moiety of the formulae:
Figure imgf000017_0001
R, is a structure of the formula
Figure imgf000017_0002
L2 is selected from a chemical bond or a bridging group selected from -(CH2)n-O-, -(CH2)π-S-, -(CH2)π-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)n-S-(CH,)n-C(O)-N-;
M2 is selected from -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000017_0003
wherein R8, R9 and R10 are as defined above; or a pharmaceutically acceptable salt thereof.
Also preferred are compounds of the group above with the structure:
Figure imgf000018_0001
wherein
R, is selected from -O-C,-C6 alkyl, -S-C,-C6 alkyl, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3, or -OH;
R3 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -Cι-C10 alkyl, C,-C,0 aikoxy, preferably C,-CI0 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, -SO2-C,-C6 alkyl or a moiety of the formula:
Figure imgf000018_0002
wherein R , R , R , R and R are as defined above, or a pharmaceutically acceptable salt thereof.
Also among the compounds of the present invention are those of the formulae:
Figure imgf000019_0001
wherein
R, and Rr are independently selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, -S-C,-CI0 alkyl, preferably -S-C,-C6 alkyl, C,-CI0 aikoxy, preferably C,- C6 aikoxy, -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, Cj-C.o aikoxy, preferably C,-C6 aikoxy, -NO2, -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,-C10 alkyl, preferably C,-C6 alkyl, CrC10 aikoxy, preferably C,-C6 aikoxy, -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, CrC10 alkyl, preferably CrC6 alkyl, CrC10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a moiety of the formulae:
Figure imgf000020_0001
Z is O or S;
R6 is selected from the relevant members of the group H, -CF3, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, 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 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3, or -OH;
R7 is selected from the relevant members of the group -OH, -CF3, C^C^ alkyl, preferably CrC6 alkyl, C,-C10 aikoxy, preferably CrC6 aikoxy, -NH2, -(CH2)n-NH2, -NH-(C,-C6 alkyl), - N-(C,-C6 alkyl)2, -(CH2)n-NH-(C,-C6 alkyl), -(CH2)„-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 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,-C10 aikoxy, preferably C,-C6 aikoxy, -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 aikoxy, preferably CrC6 aikoxy, -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,-C10 alkyl, preferably CrC6 alkyl, CrC10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, - NH2, -CN, -CF3 or -OH;
n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-C.-C, alkyl, -N(C,-C6 alkyl),, -N-SO,-C,-C6 alkyl, or -SO2-C,-C6 alkyl; R3 is selected from H, halogen, -CF3, -OH, -C,-CI0 alkyl, C,-C10 aikoxy, -CHO, - C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C.-C, alkyl, -N(C,-C6 alkyl)2, -N-SO2- CrC6 alkyl, -SO2-C,-C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C6 cycloalkyl), -C(O)-OH, C(O)-C,-Cfi alkyl, -C(O)-O-C,-C6 alkyl, -C(O)- CF3, -(CH2)n-S-CH2-(C3-C5 cycloalkyl), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000022_0001
n in each appearance is an integer independently selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,- C6 alkyl), or -N(CrC6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000022_0002
R12 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH2)π-COOH, -(CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,- C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(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-, -C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)n-O-, -C(O)- N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000023_0001
(C-|-C6 lower haloalkyl;
Figure imgf000023_0002
Figure imgf000024_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000024_0002
R9 in each appearance is independently 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 H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C.-C, alkyl,
Figure imgf000025_0001
R„ is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000025_0002
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000025_0003
Figure imgf000026_0001
R5 is selected from CrC6 lower alkyl, C,-C6 lower aikoxy, -(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)n-phenyl-CH2-phenyl, -(CH2)π-O-phenyl-CH2- phenyl, -(CH2)n-phenyl-(O-CH2-phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae:
Figure imgf000026_0002
wherein n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2,
Y is C3-C5 cycloalkyl 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, 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 aikoxy, preferably C,-C6 aikoxy, -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,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably CrC6 aikoxy, -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,-C10 alkyl, preferably CrC6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO,, - NH2, -CN, -CF3 or -OH;
d) a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH,)n-O-A, wherein A is the moiety:
Figure imgf000027_0001
wherein
D is H, C,-C6 lower alkyl, C,-C5 lower aikoxy, -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 aikoxy, -NH, or -NO2; or a pharmaceutically acceptable salt thereof.
Preferred compounds include those having the formula:
Figure imgf000028_0001
wherein
Rj is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, -S-C,- C10 alkyl, preferably -S-C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CN, -NO,, -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) furan, pyrrole, or thiophene, being optionally substituted by from 1 to 3 substituents selected from halogen, CrC10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3; or
b) pyridine, pyrimidine, piperidine, or morpholine, each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH,, -CN, -CF, or -OH; or
c) benzofuran, indole, napthalene, purine, or quinoline, each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably CrC6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a moiety of the formulae:
Figure imgf000029_0001
Z is O or S;
R6 is selected from the relevant members of the group H, -CF3, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, 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, CrC10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO,, -NH2, -CN, -CF3, or -OH;
R7 is selected from the relevant members of the group -OH, -CF3, C,-C10 alkyl, preferably CrC6 alkyl, C,-CI0 aikoxy, preferably C,-C6 aikoxy, -NH2, -(CH2)n-NH2, -NH-(CrC6 alkyl), - N-(C,-C6 alkyl)2, -(CH2)n-NH-(CrC6 alkyl), -(CH2)n-N-(C,-C6 alkyl)2, phenyl, -O-phenyl, benzyl, or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole, or morpholine the 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 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably CrC6 aikoxy, -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 H, halogen, -CF3, -OH, -CrC10 alkyl, C,-C10 aikoxy, -CHO, -C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-CrC6 alkyl, -N(C,-C6 alkyl)2, -N-SO2- C,-C6 alkyl, -SO2-C,-C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C5 cycloalky), -C(O)-OH, C(O)-CrC6 alkyl, -C(O)-O-CrC6 alkyl, -C(O)-CF3, or -(CH2)n-S-CH2-(C3-C5 cycloalky), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, CrC6 alkyl, C,-C6 aikoxy, -NO2, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000030_0001
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(Cr C6 alkyl), or -N(C,-C6 alkyl),_;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000030_0002
Figure imgf000031_0001
R12 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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;
L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)π-C(O)-(CH2)n-, -(CH,)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-,-C(Z)-N(R6K -C(Z)-N(R6)-(CH2)n-, -C(O)-C(Z)-N(R6)-, -C(O)-C(Z)-N(R6)-(CH2)n-, -C(Z)-NH-SO2-, -C(Z)-NH-SO2-(CH2)π-, -C(O)-(CH2)n-O-, -C(O)- N-, or -(CH,)n-S-(CH,)n-C(O)-N-;
M' is -COOH or a moiety selected from:
Figure imgf000031_0002
lower haloalkyl]
Figure imgf000032_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH,)n-C(O)-COOH, tetrazole,
Figure imgf000032_0002
R9 in each appearance is 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 H, -COOH, -(CH,)n-COOH, -(CH,)n-C(O)-COOH, -CF3, -OH, - (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl,
Figure imgf000033_0001
Figure imgf000033_0002
lower haloalkyi;.
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000033_0003
R5 is selected from CrC6 lower alkyl, CrC6 lower aikoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-phenyl-O- phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-ρhenyl, -(CH2)n-phenyl-(O-CH2- phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000034_0001
D is H, C,-C6 lower alkyl, C,-C6 lower aikoxy, -CF3or -(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, -CrC6 alkyl, CrC6 aikoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
Yet other preferred compounds include those having the formula:
Figure imgf000034_0002
wherein
R, is selected from H, halogen, -CF3, -OH, -C,-CI0 alkyl, preferably -C,-C6 alkyl, -S-C,- C10 alkyl, preferably -S-C,-C5 alkyl, C,-CI0 aikoxy, preferably C,-C6 aikoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -O- or -(CH2)n- bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substituted by from 1 to 3 substituents selected from halogen, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, - NO2, -NH2, -CN, -CF3; or
n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(CrC6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, CrC10 aikoxy, -CHO, -C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl),, -N-SO,- C,-C6 alkyl, -SO2-C,-C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C5 cycloalky), -C(O)-OH, C(O)-C,-C6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)-CF3, or -(CH2)n-S-CH2-(C3-C5 cycloalky), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO,, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000035_0001
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)„-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl, -NH(C,- C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000036_0001
R is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen. -CF3, -OH. -COOH, -(CH,)n-COOH, -(CH,)n-C(O)-COOH, -C,-C6 alkyl, -O-C,- C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
L1 is selected from -(CH,)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH,)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-, -C(Z)-NH-SO,-(CH2)n-, -C(O)-(CH2)π-O-, -C(O)- N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000036_0002
Figure imgf000037_0001
lower haloalkyi;
Figure imgf000037_0002
Figure imgf000037_0003
R8, in each appearance, is independently selected from H, -COOH, -(CH2)π-COOH, - (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000037_0004
R9 in each appearance is 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),;
R10 is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, - (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000038_0001
lower alkyl
Figure imgf000038_0002
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000038_0003
R5 is selected from C,-C6 lower alkyl, C,-C6 lower aikoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-phenyl-O- phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)n-ρhenyl-(O-CH2- phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000039_0001
D is H, C,-C6 lower alkyl, C,-C6 lower aikoxy, -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 aikoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
The present invention also provides for a method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention. Methods of treating an inflammatory response or condition, comprising administering to a mammalian subject a therapeutically effective amount of a compound of the present invention are also provided. Pharmaceutical compositions comprising compounds of the present invention and a pharmaceutically acceptable carrier are also provided.
Pharmaceutically acceptable salts of the compounds of the compounds described herein are also part of the present invention and may be used in practicing the compounds and methods disclosed herein.
Brief Description of the Figures
Figs. 1-13 depict schemes for synthesis of compounds of the present invention. The depicted schemes are described in further detail below.
Detailed Description of Preferred Embodiments
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, pyrroline, 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 morpholine; 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, C1-C10 alkyl, preferably C1-C6 alkyl, C1-C10 aikoxy, preferably C1-C6 aikoxy, -CHO, -COOH or esters thereof, -N02, -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 preferred group includes those of furan, pyrrole, thiophene, pyrimidine, and morpholine rings. A preferred group of bicyclic aromatic groups includes benzofuran, indole, napthalene, and quinoline rings.
The alkyl, alkenyl and alkinyl groups referred 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.
Preferred compounds of the present invention are disclosed in Tables I- VI below. Methods for synthesis of the compounds listed in Tables I- VI are described below. Compound Nos. in the tables correspond to example numbers below describing synthesis of that particular compound.
Tables I- VI also report data for the listed compounds in the "LysoPC" assay and the Coumarine assay (see Example 88 below). In the data columns of the tables, assay results are reported as an "IQ" value, which is the concentration of a compound which inhibits 50% of the activity of the phospholipase enzyme in such assay. Where no numerical IQ0 value appears, "NA" denotes that inhibitory activity was not detected from such compound in the corresponding assay and a blank box denotes that the compound was not tested in such assay as of the time of filing of the present application.
Figure imgf000042_0001
Figure imgf000043_0002
Figure imgf000043_0001
Figure imgf000043_0003
Figure imgf000044_0002
Figure imgf000044_0001
Figure imgf000044_0003
Figure imgf000045_0001
Figure imgf000046_0001
44
Figure imgf000047_0001
0
oo 00
CN CN CN CN d
Figure imgf000048_0001
Figure imgf000048_0002
Figure imgf000049_0001
Figure imgf000049_0002
oo m
(N
CN
Figure imgf000050_0001
Figure imgf000050_0002
oo
CN
Figure imgf000051_0001
Figure imgf000051_0002
Figure imgf000052_0001
Figure imgf000052_0002
Figure imgf000053_0001
Figure imgf000054_0001
Figure imgf000055_0001
Figure imgf000056_0001
Figure imgf000057_0001
o «n
Λ
→
Figure imgf000058_0001
O
Figure imgf000059_0001
Figure imgf000060_0002
Figure imgf000060_0001
Figure imgf000061_0002
Figure imgf000061_0001
Figure imgf000062_0002
Figure imgf000062_0001
CN en
MD MD MD
Figure imgf000063_0001
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000066_0002
Figure imgf000067_0001
Figure imgf000067_0002
Figure imgf000068_0001
Figure imgf000069_0001
Compounds of the present invention were also tested for in vivo activity in a rat paw edema test according to the procedure described in Example 89. The results are reported in Table VII.
Table VII
Figure imgf000070_0001
As used herein, "phospholipase enzyme activity" means positive activity in an assay for metabolism of phospholipids (preferably one of the assays described in Example 88 below). A compound has "phospholipase enzyme inhibiting activity" when it inhibits the activity of a phospholipase (preferably cPLA) in any available assay (preferably an assay described below in Example 88 or Example 89) for enzyme activity. In preferred embodiments, a compound has (1) an I 0 value of less than about 25 μM, preferably less than about 6 μM, in the LysoPC assay; (2) an I 0 value of less than about 50 μM in the vesicle assay; (3) an I 0 value of less than about 1 μM in the PMN assay; (4) an IQ, 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 about 20-30%) in the rat carrageenan-induced footpad edema test.
Compounds of the present invention are useful for inhibiting phospholipase enzyme (preferably cPLA,) 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 carriers, 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 incorporated 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 preferred 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 lmg 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.
Methods of Synthesis for Examples 1-87
Compounds of the present invention can be prepared according to the following methods. Temperatures are in degrees Celsius.
METHOD A
Indol-2-carboxylic acid ethyl ester I is converted to aldehyde II in two steps: reduction with lithium aluminum hydride (LAH) or other hydride in a suitable solvent such as tetrahydrofuran (THF) at 0°C, and then oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Deprotonation of aldehyde II with a strong base such as potassium hexamethyldisilyl amide (KHMDS) in THF, followed by reaction with a chloroformate in the presence of a base, such as triethyl amine, produces carbamate III. Ill is transformed into bromide IV in two steps: (1) reduction with sodium borohydride in an alcoholic solution and (2) reaction withcarbon tetrabromide in the presence of a phosphine reagent such as bis(diphenylphosphino)propane in dichloromethane. Displacement of the bromine in IV with potassium phenoxide, prepared by reaction of a phenol with KHMDS, in a suitable solvent such as THF or DMF affords ether V. V can be converted to either trifluoromethyl ketone VII or to carboxylic acid IX in different procedures. Reaction of V with trifluoromethyl trimethylsilane (TMSCξ) in the presence oftetrabutylammonium fluoride gives trifluoromethyl alcohol, which is then oxidized with periodinane (Dess-Martin reagent) in dichloromethane to afford ketone VI. In this stage the carbamate can be removed with either trifluoroacetic acid (TFA) or with a base such as sodium hydroxide. The indole nitrogen is then alkylated with a suitable alkyl bromide in the presence of a base such as sodium hydride to produce VII. Alternatively, V can be deprotected with TFA or aqueous base, and then reacted with alkyl bromide to give VIII, which is oxidized with sodium chlorite in an aqueous THF to yield acid IX.
METHOD B
2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give X. Hydrolysis of X with a aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropyl ethylcarbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide XL XI is hydrolyzed to corresponding acid XII in a aqueous base such as sodium hydroxide.
METHOD C
Indole I can be brominated on the 3-position by reaction with a bromine or N- bromosuccinimide in a suitable solvent such ascarbon tetrachloride or dichloromethane to yield bromide XIII. Reaction of XIII with a suitable alkyl bromide in the presence of a strong base such as NaH in THF or DMF affords indole XIV. Palladium mediated coupling of XIV with a suitable alkene in the presence of phosphine and a base such as triethyl amine produces 3-substituted indole XV. XV can be converted to amide XVII in two step reactions:
(1) hydrolysis with aqueous base such as NaOH and (2) coupling with an amine in the presence of carbodiimide such as EDCI. Ester XIV can be transformed to lithium salt XVIII by hydrolysis with aqueous base and then reaction with lithium hydroxide in a suitable solvent such as ether. Lithiation with n-butyl lithium in a suitable solvent such as THF, and then acylation with an acyl chloride in THF affords ketone XIX. Carbodiimide (EDCI) catalyzed coupling of XIX and a suitable amine gives amide XX.
METHOD D
Indole I can be converted to XXI in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of XXI with Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -6θC, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF affords ketone XXII. The silyl group on XXII is removed using tetrabutylammonium fluoride in a solvent such THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide XXIII. Displacement of the bromine of XXIII with a thiol compound in the presence of a base such as CS2CO3, or with an alcohol in the presence of a strong base such as NaH in DMF affords XXIV (sulfide, or ether respectively).
METHOD F.
Aldehyde II, prepared by Method A, can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield XXV. XXV can be converted to an unsaturated acid XXVI by two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide. Coupling reaction of XXVI with an amine catalyzed by a diimide such as EDCI (dimethylaminopropyl ethylcarbodiimide hydrochloride), followed by hydrolysis with aqueous base such as sodium hydroxide affords XXVII.
METHOD F
Indole I is reduced with LAH in a solvent such as THF. A second reduction with sodium cyanoborohydride in a solvent such as acetic acid to yield alcohol XXVIII. Protection of the nitrogen of XXVIII with t-butoxycarbonyl (BOC) using di-t-butyldicarbonate ((BOQO) in the presence of a base such as triethylamine affords carbamate XXIX. The hydroxyl group in XXIX is mesylated using mesyl chloride and triethylamine in a solvent such as dichloromethane, and then displaced by either a thiol or an alcohol as described in METHOD D to produce indoline XXX. Deprotection of XXX using trifluoroacetic acid affords XXXI, which is either acylated (acyl chloride, triethylamine, dichloromethane) or alkylated (alkyl halide, K:C03, DMF) to afford XXXII, or XXXIII respectively.
METHOD G
Carboxylic acid XXXIV is converted to aldehyde XXXV in two steps: (1) reaction with N,0- dimethylhydroxy amine in the presence of EDCI in a solvent such as dichloromethane, and
(2) reduction with diisobutyl aluminum hydride (DIBAL) in a solvent such as THF. Treatment of XXXV with trimethyl phosphonoacetate in the presence of a strong base such as KHMDS in a solvent such as THF results in the formation of ester XXXVI. Reduction of XXXVI with tin in hydrogen chloride, followed by cyclization in a heated inert solvent such as toluene gives XXXVII. Alkylation on nitrogen of XXXVII under conditions described in
METHOD F, and then hydrolysis of the ester with aqueous base such as NaOH affords acid XXXVIII. XXXVIII can be converted to an amide XXXIX by coupling with a suitable amine such as benzylamine in the presence of EDCI.
METHOD H Aldehyde XXXV, prepared in METHOD G, is subjected to a Wittig reaction using methyl triphenylphosphonium iodide in the presence of a strong base such as KHMDS or NaH in a solvent such as THF to afford alkene XL. Reduction of the nitro group of XL with iron powder in an ammonium chloride solution, followed by treatment with benzyl chloroformate in the presence of a base such as triethyl amine produces carbamate XLI. XLI is treated with iodine in a basic solution such as aqueous NaHCQ in THF to yield iodide XLII. Displacement of the iodine on XLII with lithium benzoate in a solvent such as DMF, followed by hydrolysis with NaOH affords alcohol XLIII.
METHOD I
Indoline XXVIII, prepared in METHOD F or METHOD H. can be either acylated by reaction with an acyl chloride in the presence of a base such as triethyl amine or alkylated using alkyl halide in the presence of KC03 in a solvent such as DMF to produce alcohol
XLIV. Treatment of XLI V with mesyl chloride and triethyl amine in a solvent such as dichloromethane, followed by displacement with a thiol such as methyl mercaptoacetate in the presence of a base such as Cs,C03 in a solvent such as acetonitrile yields ester XLV. Hydrolysis of XLV with an aqueous base such as NaOH gives acid XL VI, which can be coupled with an amine catalyzed by a diimide such as EDCI in a solvent such as dichloromethane to afford amide XLVII. XL VII can be alkylated on the amide nitrogen by treatment with alkyl halide and strong base such as NaH in DMF. Hydrolysis of the resulting amide with aqueous base such as NaOH gives acid XLIX. XLIV can also be directly hydrolyzed with NaOH to a carboxylic acid XLVIII.
METHOD J
METHOD J illustrates the synthesis of alpha-substituted aminophenylacetic acid esters. Ester L can be deprotonated with a strong base such as lithium diisobutylamide (LDA) in a solvent such as THF, and subsequently alkylated with an alkyl halide such as methyl iodide to give LI. Reduction of LI to amine LIII can be accomplished using hydrogenation catalyzed by palladium in a solvent such as ethanol. L can be oxidized to alcohol LH using LDA and oxaziridine in a solvent such as THF. Alkylation of LII with a alkylating reagent such as methyl iodide in the presence of a strong base such as NaH in DMF, followed by catalytic hydrogenation in the presence of palladium produces amine LIV.
METHOD K
METHOD K illustrates the synthesis of substituted aminobenzoic acid esters. Mono-acid LV can be converted to amide LVI by the following steps: (1) reaction with oxalyl chloride in dichloromethane to form acid chloride and (2) treatment with a suitable amine such as dimethyl amine. Reduction of the nitro group to the amine is accomplished with hydrogenation catalyzed by palladium as described in METHOD J. LV can be reduced to alcohol LVIII with hydroborane-THF complex in THF. Protection of the hydroxy group as a silyl ether using TBDMSC1 in the presence of imidazole and subsequently, reduction of the nitro group (H2 / Pd-C) to the amine affords LIX. LVIII can be convened to the secondary alcohol LX in two steps: (1) oxidation with a suitable reagent such as manganese dioxide (Mn02) in ethyl acetate and (2) addition of a desired Grignard reagent such as methyl magnesium bromide in THF. Oxidation of LX with MnQ in THF and reduction of the nitro group (H2 / Pd-C) produces ketone LXIII. Reduction of LVII (H / Pd-C) yields LXI.
METHOD ! .
Alcohol LXIV, prepared in METHOD I, can be debenzylated by hydrogenolysis catalyzed by palladium on carbon in a solvent such as ethanol. The resulting alcohol is treated with p- methoxybenzyl chloride in the presence of KC03 in a solvent such as THF to afford LXV. Alcohol LXV can be transformed into ether or sulfide LXVI by the procedures described in METHOD D. Deprotection of the p-methoxybenzyl group with TFA in a solvent such as dichloromethane, and subsequent alkylation on oxygen with a suitable reagent such as 4- benzylbenzyl bromide in the presence of KC03 in a solvent such as THF affords LXVII. EXPERIMENTAL SECTION
The Examples which follow further illustrate the invention. All temperatures set forth in the Examples are in degrees Celsius. All the compounds were characterized by proton magnetic resonance spectra taken on a Varian Gemini 300 spectrometer or equivalent instruments.
EXAMPLE 1
2-C2-C 1 -Phenylmethoxycarbonyl-5-phenylmethoxy)indolyl)methoxybenzoic acid
Step 1 : 2-C5-Phenylmethoxy)indolyl aldehyde
12.3 g (42 mmol) of ethyl 2-(5-phenylmethoxy)indolyl) carboxylate was dissolved in 100 mL of THF, to which was added 130 mL (130 mmol) of 1 M solution of lithium aluminum hydride in THF at 0°C. The reacton was stirred at this temperature for 2 hours and quenched by adding 65 mL of 6 N NaOH solution slowly. The product was extracted with ethyl acetate, and the organic phase was washed with aqueous ammonium chloride. Evaporation of the solvent afforded crude alcohol, which without further purification was dissolved in 400 mL of THF, 52 g of manganese(IV) oxide was added, and the mixture was stirred at room temperature overnight. Removal of manganese oxide by filtration and flash chromatographic purification using 3: 1 hexane:ethyl acetate yielded 8.15 g of the title compound.
Step 2: Benzyl (l-(2-foπnyl-5-phenylmethoxy)indolyl)formate
To a solution of 6.9 g (27.5 mmol) of the aldehyde of step lin 140 mL of THF was slowly added 61 mL (30.5 mmol) of 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene at -35 °C. After stirring at this temperature for 10 min, 4.4 mL (29.5 mmol) of benzyl chloro formate was added at -35 °C, and the mixture was then warmed from -35°C to 0 °C for 3.5 hours. The reaction was quenched by pouring into aqueous ammonium chloride. Aqueous work up and flash chromatography using 12: 1 toluene: ethyl acetate afforded 4.8 g of the title compound.
Step 3: Benzyl π-(2-hydroxymethyl-5-phenylmethoxy1indolyl)formate
To a solution of 2.9 g (7.5 mmol) of the aldehyde of step 2 in 40 mL of THF and 20 mL of trifluoroethanol was added 760 mg (20 mmol) of sodium borohydride at OC. The mixture was stirred at 0 °C for 30 min and then quenched by adding aqueous ammonium chloride. Flash chromatography using 2: 1 hexane-ethyl acetate afforded 2.2 g of the title compound.
Step 4: Benzyl π-f2-bromomethyl-5-phenylmethoxy)indolyl)formate
To a solution of 2.2 g (5.7 mmol) of the alcohol of step 3 and 2.05 g (5.0 mmol) of l ,3-bis(diphenylphosphino)propane in 60 mL of dichloromethane was added a solution of 2.0 g (6 mmol) of carbon tetrabromide in 4 mL of dichloromethane at 15°C. The mixture was stirred at room temperature for 2 hours and 1 g (3 mmol) of 1 ,3- bis(diphenylphosphino)propane was added at room temperature. After 1 hour stirring, the reaction was quenched by adding aqueous ammonium chloride. Aqueous work up and flash chromatography using 4: 1 hexane: ethyl acetate afforded 1.7 g of the title compound.
Step 5: Benzyl Cl-(2-('2-formylphenoxy)methyl-5-phenylmethoxy indolyl)formate
To a solution of 439 mg (3.6 mmol) of methyl 2-hydroxybenzoate in 18 mL of THF was added 6 mL (3 mmol) of 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene at 0 °C. The solution was stirred at 0°C for 10 min, to which was added a solution of 1.25 g (2.8 mmol) of the bromide, prepared in step 4, in THF at 0°C. The reaction was warmed to room temperature and stirred at this temperature for 2 hours. After aqueous work up (NHC1 / ethyl acetate), the organic solvent was collected, dried over sodium sulfate and evaporated. The product was solidified and washed with ethyl acetate: hexane 1 : 1. Yield 690 mg (51 %).
Step 6: 120 mg (0.24 mmol) of the aldehyde of step 5 was dissolved in 11 mL of 5: 1 :5 THF- acetonitrile-2,2-dimethylethanol. To this solution was added a solution of 56 mg (0.5 mmol) of sodium chlorite in 0.5 mL water and 1 drop of aqueoues hydrogen peroxide solution. After 4 hours, another 56 mg (0.5 mmol) of sodium chlorite was added. The mixture was stirred at room temperature for three days. Aqueous work up and flash chromatography using 2.5: 1:0.05 hexane:ethyl acetate-acteic acid afforded 110 mg of the title compound.
EXAMPLE 2
4-C2-C 1 -Phenylmethoxycarbonyl-5-phenylmethoxy indoly0methoxybenzoic acid
The title compound was prepared according to the procedure described in Example 1 , but using 4-hydroxybenzaldehyde.
EXAMPLE 3
3-(2-(l-Phenylmethoxycarbonyl-5-phenylmethoxy)indolyl1methoxybenzoic acid
The title compound was prepared according to the procedure described in Example 1 , but using 3-hydroxybenzaldehyde.
EXAMPLE 4
Benzyl ( 1 -C2-(2- -oxo-2.2.2-trifluoroethyl)phenoxy methyl-5- phenylmethoxy ndolyPformate
Step 1 : Benzyl (l-f2-(2-(l-hydroxy-2.2.2-trifluoroethyl phenoxy)methyl-5- phenylmethoxy ndolyP-formate
A solution of 0.4 g (0.8 mmol) of the aldehyde, prepared in step 1 of Example 1. in 4 mL of THF was cooled to 0°C. To this were added 0.24 mL (1.6 mmol) of trifluoromethyl trimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate. The reaction was stirred for 2.5 hpurs at 0°C, and additional 0.2 mL (1.3 mmol) of trifluoromethyl trimethylsilane and 5 mg of tetrabutylammonium fluoride trihydrate were added. After stireed at 0°C for 2 hours, the reaction was worked up with aqueous ammonium chloride and ethyl acetate. Silica gel chromatographic purification using 4:1 hexane-ethyl acetate afforded corresponding TMS ether. Treatment of TMS ether with 1.3 mL of IN Hcl solution at room temperature, aqueous woukup using brine and ethyl acetate and chromatographic purification using 3: 1 hexane-ethyl acetate gave 230 mg of the titled compound.
Step 2:
To a solution of 150 mg (0.27 mmol) of trifluoroethanol, prepared in step 1, in 5.5 mL of dichloromethane was added 255 mg (0.6 mmol) of the Dess-Martin's periodinate. The mixture was stirred at room temperature for 1 hour, and then partitioned between aqueous
NaHC03 and ethyl acetate. The organic phase was washed once with aqueous NaHCQand purified with chromatography using 3: 1 hexane-ethyl acetate to yield 150 mg of the titled compound. EXAMPLE 5
3-C2-C 1 -Benzyl-5-benzyloxy)indolecarboxamido')benzoic acid
Step 1 : Ethyl 2-Cl-benzyl-5-benzyloxy)indolecarboxylate
To a solution of 1 g (3.4 mmol) of ethyl 5-benzyloxyindole-2-carboxylate in 12 ml of DMF, sodium hydride (0.163g, 60% oil dispersion, 4.07 mmol) was added at room temperature. The reaction was stirred for 30 minutes. Benzyl bromide (0.44 mL, 3.73 mmol) was added at this time and the reaction stirred for another hour. On completion of the reaction (monitored by TLC = 0.5 Rf in 3: 1 Hexane: Ethyl acetate) it was quenched with water, extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate, concentrated and used for the next step.
Step 2: 2-d-Benzyl-5-benzyloxy')indolecarboxyic acid
The ester (3.4 mmol), prepared in step 2, was dissolved in THF (20 mL), methanol (20 mL) and then IN NaOH (15 mL) was added. The reaction mixture was stirred at room temperature over night at which time it was concenterated, diluted with water, acidified to pH 5 with 10% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the indole acid ( 1.14 g, 94.2 % , TLC = 0.5 Rf in 1 : 1 Hexane: Ethyl acetate with 1 % acetic acid).
Step 3: Ethyl 3-(2-( l-benzyl-5-benzyloxy)indolecarboxamido)benzoate
The acid (0.54 g, 1.5 mmol) of step 2, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (EDCI) (0.32 g, 1.66 mmol), 4-dimethylaminopyridine (DMAP) (0.018 g, 0.15 mmol) and ethyl 3-aminobenzoate (0.27 g, 1.66 mmol) were stirred in tetrahydrofuran (9 mL) at room temperature overnight. The next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 3: 1 hexane :ethyl acetate to give pure amide (0.578 g, 76% , TLC = 0.4 Rf in 3: 1 Hexane: Ethyl acetate). Step 4:
The ester (0.578 g, 1.15 mmol), prepared in step 3, was dissolved in THF (13.6 mL), methanol (13.6 mL) and then IN NaOH (9.6 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 with 10% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the titled compound (0.437 g, 80 % , TLC = 0.5 Rf in 3:1 hexane:ethyl acetate with 1 % acetic acid).
The Examples 6. 7. 8. 9. 10 and ii in Table I were prepared by the procedures of Example 5 using suitable amines and alkyl halides.
EXAMPLE 12
3-(2-(3-(2.4-bisf 1.1 -dimethypropyl)phenoxyacetyl)-5-methoxy- 1 -methyl ndolyl) methylthioacetamido-4-methoxybenzoic acid
Step 1 : 2-f5-Methoxy)indolylmethanol
Ethyl 5-methoxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to P C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgS0 and concentrated to yield 24.8 g of alcohol, which was used for the next reaction directly.
Step 2: 2-(5-methoxy)indolylmethoxy-tert-buthyldimethylsilane The crude indole alcohol prepared in step 1(6.2 g, 32.6 mmol) was dissolved in DMF (10.5 mL). To this solution was added imidazole (5.5g, 81.5 mmol) and t- butyldimethylsilyl chloride (5.4g, 35.8 mmol). The mixture was stirred at room temperature overnight. The reaction was poured into water and extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19: 1 hexane:ethyl acetate to give pure product (9.5g, 31 mmol, 94 % yield, TLC: 0.8 Rf in toluene: ethyl acetate 2: 1)
Step 3: 3-(2-tert-butydimethylsilyloxymethyl-5-methoxy ndolyl C2.4-bisd . l- dimethypropyl)phenoxy)methyl ketone
2.32 g (7.95 mmol) of 2.4-Bis-tert-amylphenoxyacetic acid was dissolved in dichloromethane (21 mL), oxalyl chloride (1.4 mL 16.1 mmol) was added, followed by dimethyl formamide (0.5 mL) at room temperature. After one hour the reaction is concentrated and azeotroped with toluene and left on the high vacuum for two hours.
In another reaction vessel, a solution of the silyl protected indole, prepared in step 2, (2 g, 6.56 mmol) in ether (20 mL) was added dropwise to ethyl magnesium bromide (2.4 mL of a 3M solution in ether, 7.2 mmol) in ether (10 ml), the latter maintained at -78°C. The reaction was stirred at -60C for 2 hr. To this reaction solution, the above prepared acid chloride in ether (4 mL) was added slowly. The reaction was maintained between -59C and
-60°C for another 2 hrs. The reaction was then quenched with saturated sodium bicarbonate. Extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate and concentrated. The crude material was purified on a silica gel column using 19: 1 Hexane:Ethyl acetate to give pure product (2.36 g, 50% , TLC: 0.15 Rf in hexane:ethyl acetate 19: 1.
Step 4: S-^-tert-butydimethylsilyloxymethyl-S-methoxy-l-methyOindolyl (2.4-bisd . l- dimethypropyl')phenoxy)methyl ketone
To the ketone (1.97g, 3.4 mmol) of in step 3 in 12 ml of DMF, sodium hydride
(0.163g, 60% oil dispersion, 4.07 mmol) was added at room temperature. The reaction was stirred for 30 minutes. Methyl iodide (0.23 mL, 3.73 mmol) was added at this time and the reaction stirred for another hour. On completion of the reaction (monitored by TLC) it was quenched with water, extracted with ethyl acetate (3X). Organic layers were dried over magnesium sulfate, concentrated and the crude product was used for the next step.
Step 5: 3-C2-Hydroxymethyl-5-methoxy-l-methyl)indolyl (bis-2,4- .1. dimethy lpropyPphenoxylmethyl ketone
A mixture of N-methyl indole, prepared in step 4, (2.01 g, 3.4 mmol) and tetra-butyl ammoniumfluoride (TBAF) (8.5 mL of a 1M solution in THF, 8.5 mmol) in THF (17.9 mL) were stirred at room temperature for one hour. At this time the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using hexane:ethyl acetate 2: 1 to yield pure alcohol (0.82 g, 60 % , TLC: 0.3 Rf in 2: 1 hexane: ethyl acetate).
Step 6: Methyl 3-f2-(3-f2.4-bisd . l-dimethypropyl)phenoxy)acetyl-5-methoxy-l- methylindolyl)methylthioacetamido)-4-methoxybenzoate
The indole alcohol, prepared in step 5, (0.20 g, 0.43 mmol) was dissolved in dichloromethane (0.7 mL) and treated with triethylamine (0.1 mL, 0.64 mmol) and cooled to
0° C at which time mesyl chloride (0.04 mL 0.52 mmol) was added over 5 minutes, followed by addition of two drops of DMF. The reaction was stirred for a further 2 hour at 0C, it was then concentrated and used directly for the next reaction.
The above prepared mesylate was dissolved in DMF (0.8 mL). The solution was degassed by bubbling nitrogen through for ten min. Cesium carbonate (0.25 g, 1.29 mmol) was added and then thiol (0.11 g, 0.43 mmol), prepared in Intermediate 1 , was added. The mixture was stirred overnight, then poured into saturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated. The crude material was purified on a silica gel column using hexane:ethyl = 2: 1 acetate to give pure product (0.12 g, 40% , TLC: 0.3 Rf in hexane:ethyl acetate 1 : 1).
Step 7: The ester, prepared in step 6, (0.12 g, 0.17 mmol) was dissolved in THF (1.0 mL), methanol (1.0 mL) and then IN NaOH (0.4 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 withl0% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the titled compound (85 mg, 72 % , TLC = 0.3 Rf in 1 : 1 Hexane: Ethyl acetate with 1 % acetic acid).
EXAMPLES 13. 14. 15 and .16 in Table I were prepared by the procedures of Example 12 using Ethyl 2-(5-benzyloxy)indolecarboxylate, acetyl chlorides and suitable alkyl halides.
EXAMPLE 17
3-(2-(-5-benzyloxy- 1 -(2.4-bis( 1.1 -dimethy)propyl)phenoxyacetyl)indolinyl) methylthioacetamidobenzoic acid
Step 1 : 2-(5-Benzyloxy)indolinylmethanol
Ethyl 5-benzyloxy-2-indolecarboxylate (30 g, 102 mmol) was dissolved in 250 mL of THF and cooled to 0° C, to which Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) was added via addition funnel over 40 minutes. The reaction was stirred a for 2 hours at 0 °C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts were filtered and washed with ethyl acetate (3X400 mL), the filtrates were combined, dried over MgS0 and concentrated to yield 24.8 g. This crude material was then dissolved in glacial acetic acid (260 mL) and the resulting yellow solution was cooled to 15 C, sodium cyanoborohydride (18.5 g, 294 mmol) was added portionwise over 10 minutes, and the resulting mixture was stirred for 3 hours. The reaction was quenched by pouring slowly into 1.5 liters of nearly saturated NaHCQ, extracted with ethyl acetate (3X), dried over MgSQ and concentrated to yield a orange solid (29.6 g).
Step 2: tert-Butyl l-(5-benzyloxy-2-hydroxymethy)lindolinylformate 25 g (85 mmol) of crude alcohol, prepared in step 1, and 4-dimethylamino pyridine (DMAP) (1.19 g, 9.78 mmol) were dissolved in dichloromethane (180 mL). The solution was cooled to CP C and then triethylamine (13.6 mL, 98 mmol) was added to it. After 10 minutes of stirring a solution of di-tert-butyl dicarbonate (21.3 mL, 98mmol) dissolved in dichloromethane (20 mL) was added via syringe pump over 2 hours. After 1 hour of stirring the reaction was quenched by the addition of 1/2 saturated NHC1 solution and extracted with CH2C12 (3X), dried over MgSQ, and concentrated to yield 36.3 g of a yellow oil, which was purified by column chromatography using a hexane: ethyl acetate gradient of 9: 1 to 4: 1 to 1 : 1 to deliver the product (15.25 g, 44%).
Step 3: Ethyl 2-(5-benzyloxy-l-tert-butoxycarbonyl)indolinylmethylthioacetate
The carbamate, prepared in step 2, (15.25 g, 43 mmol) was dissolved in dichloromethane (180 mL) and treated with triethylamine (9.0 mL, 64.4 mmol). The solution was cooled to -10p C at which time mesyl chloride (4.3 mL. 56 mmol) was added over 5 minutes. The reaction was stirred for a further 2 hour at -10°C, it was then concentrated and used directly for the next displacement reaction.
The above prepared mesylate was dissolved in DMF (85 mL, degassing the solvent is strongly reccomended) cesium carbonate (35 g, 107.3 mmol) was added and then ethyl thioacetate (4.70 mL, 42.9 mmol) was added. The mixture was stirred for 1 day, then poured into 1/2 sturated ammonium chloride and extracted with ethyl acetate (3X), dried, concentrated and chromatographed (hexane:ethyl acetate gradient 10: 1 to 4: 1) to yield 8.55 g of a yellow oily product.
Step 4: 2-(5-Benzyloxy-l-tert-butoxycarbonyl)indolinylmethylthioacetic acid
To a solution of the indoline ester, prepared in step 3, (5g, 11 mmol) in 1M potassium hydroxide in methanol (100 mL), water (10 mL) was added. The reaction was stirred at room temperature for two hours at which time it was diluted with water, acidified to pH 5 with 10% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the indoline acid ( 4.5g, 95.5%, TLC = 0.5 Rf in 2: 1 hexane: ethyl acetate with 1 % acetic acid). The crude material was used for the next step directly.
Step 5: Ethyl 3-f2-f5-henzyloxy-l-tert- butoxycarbonvPindolinyPmethylthioacetamidobenzoate
The acid (3g, 7 mmol), prepared in step 4, l-(3-dimethylaminopropyl)-3- ethylcarbodiimide (1.6g, 8.4 mmol), 4-dimethylaminopyridine (0.85g, 7 mmol) and ethyl 3- aminobenzoate (1.27 g, 7.7 mmol) were stirred in tetrahydro furan (43 mL) at room temperature overnight. On next day the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 3: 1 hexane:ethyl acetate to give the product (3.4g, 85 % , TLC = 0.3 Rf in 3: 1 hexane: ethyl acetate).
Step 6: Ethyl 3-(2-(5-benzyloxy ndolinyPmethylthioacetarnidobenzoate
To the indoline (3.4g, 5.9 mmol) of step 5, trifluoroacetic acid (24 mL) was added and the reaction stirred for 1 hour at OC. The reaction was quenched by the addition of water and the TFA neutralized by the addition of sodium bicarbonate, the aqueous layer was extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2: 1 hexane:ethyl acetate to yield product (2.7 g, 96 % , TLC = 0.3 Rf in 2: 1 hexane: ethyl acetate).
Step 7 : Ethyl 3-(2-(5-benzyloxy- 1 -(2 ,4-bisf 1.1 -dimethy PpropyDphenoxyacetyPindolinvD methylthioacetamidobenzoate
The 2, 4-bis( 1 ,1 -dimethy lpropyl)phenoxyacetic acid (0.228 g, 0.78 mmol) was dissolved in dichloromethane (2 mL), to which oxalyl chloride (0.14 mL 1.6 mmol) was added followed by dimethyl formamide (0.1 mL) at room temperature. After one hour the reaction is concentrated and azeotroped with toluene and left on the high vacuum for two hours. The indoline ester (0.308 g, 0.65 mmol), prepared in step 6, and 4- dimethylaminopyridine (0.008 g, 0.066 mmol) were dissolved in dichloromethane (1.2 mL) and then the above prepared acid chloride in dichloromethane (0.5mL) was added followed by the addition of triethylamine (0.28mL, 1.95 mmol). The reaction was stirred at room temperature overnight, and then diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2: 1 hexane:ethyl acetate to yield product (0.291 g, 60 % , TLC = 0.4 Rf in 2: 1 hexane:ethyl acetate).
Step 8:
The ester (0.231 g, 0.31 mmol) of step 7 was dissolved in THF (4.3 mL), methanol
(4.3 mL) and than IN NaOH (3.2 mL) was added. The reaction mixture was stirred at room temperature overnight at which time it was concenterated, diluted with water, acidified to pH 5 with 10% HC1 and extracted with ethyl acetate (3X), the organic extracts were dried over magnesium sulfate and concentrated to give the titled product ( 0.207 g, 93.2 % , TLC = 0.3 Rf in 2: 1 hexane:ethyl acetate with 1.5 % acetic acid).
EXAMPLE 18
3-(2-(-5-Benzyloxy- 1 -(2.4-bisC 1.1 -dimethy)propyl)phenoxyacetyPindolinvP methylthioacetamido-4-methylbenzoic acid
Step 1 : Ethyl 2-('5-benzyloxy)indolinylmethylthioacetate
The N-tert-butoxy carbonyl indoline (3.0 g, 6.6 mmol), prepared in step 3 of Example
17, was added to a flask and cooled to 0°C. To this reaction mixture trifiuoroacetic acid was added (35 mL) and the reaction was stired for 1 hour at 0°C and then 1 hour at rt. The reaction was quenched by the addition of water, and the TFA was neutralized by the addition of solid sodium bicarbonate, the aqueous layer was extracted with ethyl acetate (4X) and dried over magnesium sulfate and concentrated to an orange oil (1.85 g, 79%) that was used directly for the next step. Step 2: Ethyl 2-C5-benzyloxy-l-(2.4-bisd . l-dimethy)propyl)phenoxyacetvP- indolinylmethylthioacetate
2,4-Bis(l , l-dimethy)propyl)phenoxyacetic acid (2.0g, 6.8 mmol), dichloromethane (15 mL), oxalyl chloride (1.2 mL, 13.6 mmol), dimethylformamide (0.1 mL) were stirred at 0° C for 45 minutes at which time the reaction is concentrated and azeotroped with toluene (IX) and concentrated on the high vac for 2 hours before use. The indoline ester (1.85g, 5.2 mmol), prepared in stepl, and 4-dimethylaminopyridine (0.08 g) were dissolved in dichloromethane (15 mL) and then the above generated acid chloride in dichloromethane (5 mL) was added followed by the addition of triethylamine (0.95 mL, 6.8 mmol). The reaction was stirred 16 hours at rt, worked up and concentrated (4.0 g, orange oil), chromatographed using a 9: 1 to 6: 1 gradient of hexane: ethyl acetate to yield the product (2.5g, 75 %) that was used for the next step without further purification.
Step 3: 2-(5-Benzyloxy-l-f2.4-bisd . l- dimethy propyPphenoxyacetyPindolinylmethylthioacetic acid
The ester (2.5 g, 3.9 mmol), prepared in step 2, was dissolved in THF (20 mL), methanol (6 mL) and then IN sodium hydroxide (12 mL) was added. The resulting mixture was stirred 24 hours at which time it was concentrated, diluted with water, acidified to pH 4 with concentrated HC1 and extracted with ethyl acetate (4X), the organic extracts were dried over magnesium sulfate, concentrated, and purified via chromatography (3: 1 hexane:ethyl acetate with 1 % acetic acid) to yield 1.17 g ( 50%) of the product as white solid.
Step 4 : Methyl 3-(2-(5-benzyloxy- 1 -(2.4-bisf 1.1 -dimethy)propyPphenoxyacetyPindolinyl) methylthioacetamido-4-methylbenzoate
The acid (0.20 g, 0.33 mmol), prepared in step 3, EDCI (0.08 g, 0.43 mmol), DMAP (4 mg, 0.03 mmol) and methyl 3-amino-4-hydroxy benzoate (0.06 g, 0.33 mmol) were dissolved in THF (3 mL) and refluxedlδ hours. Aqueous workup with ammonium chloride and ethyl acetate and purification via silica gel chromatography (hexane:ethyl acetate 3: 1) yielded 0.13 g (52%) of the product as a white solid. Step 5:
The titled compound was prepared from ester, prepared in step 4, according to the procedure described in step 3.
EXAMPLES 17 to 36 in Table 2 were prepared according to the procedurs described in either Example 17 or Example 18.
EXAMPLE 37
2-f 5-Benzyloxy- 1 -(3.S-bisCtrifluoromethyPphenoxyacetyPindolinyPmethylthioacetic acid
Step 1 : 2-(5-Benzyloxy-l- .5-bisCtrifluoromethyPphenoxyacetyl)indolinyPmethanol
A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and equalizing dropping funnel was charged with 17.0 g ( 59 mmol) of 3,5- bis(trifluoromethyl)phenoxyacetic aci, DMF (5 drops) and anhydrous CHC12 (300 mL). Oxalyl chloride (23 mL, 263 mmol) was added dropwise over 10 min. After stirring for 2.5 h at room temperature solvent, excess oxalyl chloride were removed in vacuo to afford acid chloride as a white solid. This was used immediately in the next reaction.
A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and equalizing dropping funnel was charged with 15.3 g (60 mmol) of 2-(5- Benzyloxy)indolinylmethanol, prepared in stepl of Example 17, DMAP (0.73 g, 6 mmol) and anhydrous CH,C12 (300 mL). After cooling to 0°C, a solution of above prepared acid chloride (59 mmol) in anhydrous CHC12 (100 mL) was added dropwise, followed by NE$ (9 mL, 64.7 mmol). After stirring for 1 h at 0°C the reaction mixture was washed with saturated NaHCO, solution (100 mL), 1 N HC1 solution (100 mL) and HO (100 mL), dried over Na2S04 and filtered. The solvent was removed in vacuo. Purification by column chromatography in silica gel using 25-40% AcOEt in hexane afforded product as a light yellow solid. Yield 22.0 g (71 %).
Step 2: Ethyl 2-(5-benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyPindolinyl) methylthioacetate
A 500-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (19.0 g, 36.15 mmol), prepared in step 1 , anhydrous CHC12 (300 mL), and NEt3 (7.5 mL, 54.23 mmol). MsCl was added dropwise over 2 min and the reaction mixture was stirred at room temperature for 10 min. The solution was diluted with CHC12
(500 mL) and washed with IN HC1 solution (100 mL) and saturated NaHCQ solution (100 mL). The CH2C12 solution was dried over Na,S04 and filtered. The solvent was removed and the mesylate was used in the next step without further purification.
A 500-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ethyl thioacetate (4.2 mL, 38.5 mmol), and anhydrous THF (75 mL). After cooling in a dry ice/acetone bath NaN(SiMξ)2 (1 M solution in THF, 50 mL, 50 mmol) was added. After 15 min a solution of above prepared mesylate (21 g, 35 mmol) in anhydrous THF (60 mL) was added. After 15 min the reaction mixture was allowed to warm to room temperature. After stirring at room temperature for 100 min the reaction was heated at reflux for 4 h. The solution was allowed to cool to room temperature. It was diluted with CHC13 (500 mL), washed with saturated NaC03 solution (200 mL) and IN HC1 solution (200 mL). The organic solution was dried over NaS04 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel using 15% AcOEt in hexane to afford 13.8 g (63%) of product.
Step 3:
A 250-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (12.45 g, 19.8 mmol), prepared in step 2, THF (100 mL), MeOH (33 mL) and HO (33 mL). LiOH H20 (1.08 g, 25.7 mmol) was added and the reaction mixmre was stirred at room temperature for 3 h. The solvents were removed in vacuo. The residue was taken into
IN HC1 solution (200 mL) and extracted with AcOEt (2 x 400 mL). The combined extracts were washed with 1 N HC1 solution (100 mL), dried over NaS04 and filtered. The solvent was removed in vacuo to afford the titled compound. Yield 11.9 g (100%).
EXAMPLE 38
5-(2-(-5-Benzyloxy- 1 -(3.5-bisOrifluoromethyPphenoxyacetyPindoliny Pmethylfhioacetamidol benzene- 1.3-dicarboxylic acid
Step 1 : 5-(2-(-5-Benzyloxy-l-G.5-bisCtrifluoromethyl)phenoxyacetyPindolinyl) methy lthioacetamido)benzene- 1.3-dicarboxylate
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with acid (1.2 g, 2 mmol), prepared in step 3 of Example 37, anhydrous THF (40 mL), EDCI (0.544 g, 2.8 mmol), DMAP (0.024 g, 0.2 mmol), and 5-amino-l ,3- benzenedicarboxylic acid (0.46 g, 2.2 mml). The reaction mixmre was heated at reflux until no change was detected by TLC. The solvent was removed in vacuo. The residue was dissolved in CH2C12 (200 mL), washed with 1 N HC1 solution (25 mL), dried over NaS04 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel using 1-2% MeOH in CHC12 to afford 1.2 g (77%) of product.
Step 2:
A 25-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (0.6 g, 0.76 mmol), prepared in stepl, THF (7.5 mL), MeOH (2.5 mL) and H20 (2.5 mL). LiOH H20 (0.084 g, 2 mmol) was added, and the reaction mixture was stirred at room temperature for 6 h. The solvents were removed in vacuo. The residue was taken into IN HC1 solution (10 mL) and extracted with AcOEt (2 x 50 mL). The combined extracts were dried over Na2S04 and filtered and removed in vacuo. The crude material was purified by column chromatography on silica gel (eluant: 5 % MeOH in CHC13 + 0.5-0.7% AcOH) to yield 0.28 g (46%) of the titled compound.
EXAMPLES 39. 40. 43 in Table 3 were prepared according to the procedurs described in either Example 38. EXAMPLE 41
S-^-C-S-Benzyloxy-l-CS.S-bisCtrifluoromethyPphenoxyacetyPindolinyPmethylthioacetamido)- 3-hydroxymefhylbenzoic acid
Step 1 : Methyl 5-('2-C-5-benzyloxy-l-(3.5-bis(trifluoromethyl)phenoxyacetyl)indolinyl) methylthioacetamido)-3-tert-butyldimethylsilyloxymethylbenzoate
This compound was prepared according to the procedure described in step 1 of Example 38.
Step 2: Methyl 5-(2-C-5-benzyloxy-l-C3.5-bis(trifluoromethyPphenoxyacetyPindolinyl) methylthioacetamido)-3-hydroxymethylbenzoate
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with silyl propected ester (1.32 g, 1.5 mmol), prepared in step 1, anhydrous THF (10 mL), and TBAF (1 M solution in THF, 2.5 mol equiv.). The reaction mixmre was stirred at room temperature for 3 hours. The solvent was removed in vacuo. The oily residue was purified by column chromatography on silica gel using 0-30% Acθ£t in C HCL to afford 0.94 g (92%) of desired product.
Step 3:
The titled compound was prepared according to the procedure described in step 2 of Example 38.
EXAMPLE 42 in table 3 was prepared according to the procedures described in Example 41. EXAMPLE 44
5-C2-(-5-Hydroxy- 1 -(3.5-bisCtrifluoromethvPphenoxyacetyPindolinyPmethylthioacetamido benzene-1.3-dicarboxylic acid
Step 1 : 2-('5-Hydroxy-l-C3.5-bis(trifluoromethvPphenoxyacetyPindolinyPmethanol
A 500-mL Parr Hydrogenation bottle was charged with 2-(5-Benzyloxy-l-(3,5- bis(trifluoromethyl)phenoxyacetyl)indolinyl)methanol (10 g, 19.1 mmol), prepared in step 1 of Example 37, 5% Pd on carbon (1.0 g), AcOEt (150 mL) and MeOH (100 mL) and subsequently hydrogenated at 50 psi for 18 h. The reaction mixture was filtered through Celite and concentrated in vacuo to afford crude product. This was used in the next step reaction without further purification.
Step 2: 2-(5-C4-Methoxy)henzyloxy-l-f3.5- bisftrifluoromethyPphenoxyacetyPindolinvPmethanol
A 1-L oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with alcohol (8.56 g, 19.7 mmol), prepared in stepl , 200 mesh K2C03 (6.53 g, 47.2 mmol), KI (3.91 g, 23.6 mmol) and finally the p-methoxy benzyl chloride (3.2 mL, 23.6 mmol) in 450 mL of anhydrous acetonitrile. The reaction mixture was heated at reflux for 4 h. The reaction mixture was partitioned between AcOEt (500 mL) and H20 (200 mL). The aqueous layer was extracted with AcOE<3 x 500 mL). The combined AcOEt extracts were washed with brine (500 mL), dried over NaS0 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 40% AcOEt in hexane) afforded desired product. Yield 8.7 g (83 %).
Step 3: Methyl 5-(2-<'-5-(4-methoxy)benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyP indolinvPmethylthioacetamido)benzene-1.3-dicarboxylate
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (3.2 g, 5.77 mmol), prepared in step 2, and anhydrous CH 12 (44 mL). The reaction mixture was cooled to 0°C and added anhydrous E N (1.2 mL, 8.61 mmol) followed by MsCl (0.53 mL, 6.84 mmol). The reaction mixture was stirred at 0°C for 5 min. The reaction mixture was partitioned between CHC12 (100 mL) and H20 (50 mL). The aqueous layer was extracted with CBC12 (3 x 100 mL). The combined CHC12 extracts were washed with 1 N HC1 solution (100 mL), samrated NaHCQ solution (100 mL), H,0 (100 mL), brine (100 mL), dried over NaS04and filtered. The solvents were removed in vacuo to afford mesylate. This was used in the next step reaction without further purification.
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with above prepared mesylate (3.60 g, 5.70 mmol), anhydrous Cs O;, (5.19 g, 15.9 mmol) and anhydrous DMF (20 mL). The reaction solution was passed through N, for 15 min. Methyl 5-thioacetamido-l ,3-benzenedicarboxylate, prepared in Intermediate 2, was added in one portion and the reaction mixture was heated at 50 °C for 18 h. The reaction mixmre was partitioned between AcOEt (500 mL) and HO (200 mL). The aqueous layer was extracted with AcOEt(3 x 100 mL). The combined
AcOEt extracts were washed with samrated NaC03 solution (100 mL), H20 (100 mL), brine (500 mL), dried over Na,S04 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 5 % AcOEt in CHC12 ) afforded product. Yield 2.5 g (53%).
Step 4: Methyl 5-(2-^5-Hydroχy-l-(3.5-bisftrifluoromethyPphenoxyacetyP indolinyPmethylthioacetamido)benzene- 1.3-dicarboxylate
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ester (2.60 g, 3.17 mmol), prepared in step 3, and anhydrous CHCL (30 mL).
To the reaction mixture was added TFA (25 mL) in several portions over 1 min. The reaction mixmre was poured onto 500 mL samrated NaHCQ solution and extracted with CH2C12 (3 x 100 mL). The combined CHC12 extracts were washed with saturated NaC03 solution (200 mL), H20 (200 mL), brine (500 mL), dried over Na_S04 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel (eluant: 12.5 % - 20% AcOEt in CHC12 ) afforded the product. Yield 1.5 g (68%).
98 Step 5:
A 25-mL round bottom flask fitted with a magnetic stirring bar was charged with ester (270 mg, 0.40 mmol), prepared in step 4, LiOH hydrate (3.3 equiv.), THF (3.6 mL), MeOH (1.2 mL) and H,0 (1.2 mL). The reaction mixture was heterogeneous with white solid suspended in the solution. After stirring for 4 h, more solvents were added in 3 : 1 : 1 = THF : MeOH : H20 to make a clear solution. The reaction mixture was stirred at room temperature for 18 h and monitored by TLC. The reaction mixmre was acidified with 1 N HC1 solution to pH = 2 or with acetic acid to pH = 4 and then partitioned between AcOEt (20 mL) and H,0 (20 mL). The aqueous layer was extracted with AcOE<3 x 20 mL). The combined AcOEt extracts were washed with HO (20 mL), brine (20 mL), dried over NaS04 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel followed by recrystallization from acetone / hexane afforded 130 mg of the titled compound (50%).
EXAMPLE 45
S^-^-G.S-Dibromo^enzyloxy-l^.S-bisCtrifluoromethyPphenoxyacetyPindolinyP methylthioacetamido)benzene-l .3-dicarboxylic acid
Stepl : Methyl 5-(2-C5-(3.5-Dibromo)benzyloxy-l-(3.5-bis(trifluoromethyPphenoxyacetyP indolinyPmethylthioacetamidolbenzene- 1.3-dicarboxylate
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar and reflux condenser was charged with methyl 5-(2-(-5-Hydroxy-l-(3,5- bis(trifluoromethyl)phenoxyacetyl) indolinyl)methylthioacetamido)benzene- 1 ,3-dicarboxylate (0.19 g, 0.27 mmol), prepared in step 4 of Example 4, 200 mesh KC03 (2.4 equiv.) and 3,5- dibromobenzyl bromide (1.2 equiv.) in 7.5 mL of anhydrous acetonitrile. The reaction mixture was heated at 70 °C for 2 h. The reaction mixmre was partitioned between AcOEt
(30 mL) and H20 (20 mL). The aqueous layer was extracted with AcOEt(3 x 30 mL). The combined AcOEt extracts were washed with brine (50 mL), dried over NaS04 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel using 15 % EtOAc in dichloromethane afforded 0.20 g of the product (77%).
Step 2:
The titled compound was prepared from the ester, prepared in step 1 , according to the procedure described in step 5 of Example 44.
EXAMPLES 46 to 50 in table 4 were prepared according to the procedures described in
Example 44, but using corresponding alkylating reagent.
EXAMPLE 51
Methyl 3-(2-(5-benzyloxy- 1 -(4-benzylbenzoyl)indolinyPmethylthioacetamido)benzoate
4-Benzylbenzoic acid (0.19g, 0.91 mmol) was dissolved in dichloromethane (2.3 ml), next oxalyl chloride (0.16 mL, 1.82 mmol) was added followed by dimethylformamide (0.5 mL) at room temperamre. After one hour the reaction was concentrated and azeotroped with toluene and left on high vaccum for two hours.
Ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.308 g, 0.65 mmol), prepared in step 6 of Examle 17, and 4-dimethylaminopyridine (8 mg, 0.066 mmol) were dissolved in dichloromethane (1.2 mL) and then the above prepared acid chloride in dichloromethane (0.5 mL) was added followed by the addition of triethylamine (0.28 mL,
1.95 mmol). The reaction was stirred at room temperamre overnight. The reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2: 1 hexane:ethyl acetate to yield 0.354 g of the titled product (81.7%, TLC = 0.4 Rf in 2: 1 hexane : ethyl acetate) .
101 EXAMPLE 52
3-(2-(5-Benzyloxy- 1 -C4-benzylbenzoyl)indolinyl)methylthioacetamido)benzoic acid
The ester (0.354 g, 0.53 mmol), prepared in Example 51, was dissolved in THF (5.6 mL), methanol (5.6 mL) and than IN NaOH (4.2 mL) was added. The reaction mixmre was stirred at room temperamre overnight at which time it was concentrated, diluted with water, acidified to pH 5 withl0% HCl and extracted with ethyl acetate (3X). The organic extracts were dried over magnesium sulfate and concentrated to give the titled product (0.32 g, 94.4 %, TLC = 0.3 Rf in 2: lhexane:ethyl acetate with 1.5 % acetic acid).
EXAMPLES 53 to 58 in Table 5 were prepared according to the procedures described in Example 51 and 52.
EXAMPLE 59
3-(2-(5-Benzyloxy-l-('2-naphthoxyacetyl)indolinyPmethylthioacetamido')-4-methoxybenzoic acid
Step 1 • Methyl 3-(2-(5-benzyloxyindolinyPmethylthioacetamidoV4-methoxybenzoate
This compound was prepared according to the procedures described in step 6 of Example 17. but with methyl 4-methoxybenzoate.
Step 2: Methyl 3-(2-(5-benzyloxy-l-C2-naphthoxyacetvPindolinyPmethylthioacetamido)-4- methoxybenzoate
The indole ester (0.22 g, 0.45 mmol), prepared in step 1 , 2-naphthoxyacetic acid
(0.11 g, 0.53 mmol), EDCI (0.10 g, 0.53 mmol) and DMAP (5 mg, 0.04 mmol) were weighed into a flask that was equipped with a condenser, flushed with nitrogen, and then tetrahydrofuran (5 mL) was added and the reaction was brought to reflux for 18 hours; the reaction was diluted with 1/2 samrated ammonium chloride and ethyl acetate, extracted 3X with ethyl acetate, dried over magnesium sulfate, concentrated to yield (0.30 g, 100% crude) a white solid that was used without purification.
Step 3:
The ester ( 0.12 g, 0.20 mmol), prepared in step 2, was dissolved in THF/ methanol and then IN sodium hydroxide (0.8 mL) was added and the resulting mixture was stirred 16 hours at RT and a further 5 hours at 45°C, workup yielded 0.12 g of a yellow solid that was purified via preparative TLC (1 : 1 hexane: ethyl acetate with 1 % acetic acid) to yield 0.12 g of the titled product (95 %).
EXAMPLES 60 to 63 in Table 5 were prepared according to the procedures described either in Example 59 or in Examples 51 and _5_2.
EXAMPLE 64
3-(2-(5-benzyloxy- 1 -tert-butoxycarbonyPindolinyPmethylsulfonylacetamidobenzoic acid
Step 1 : Ethyl 3-C2-("5-benzyloxy-l-tert-butoxycarbonyl)indolinyl)methylsulfonyl acetamidobenzoate
To a solution of Ethyl 3-(2-(5-benzyloxy-l-tert-butoxycarbonyl)indolinyl)methy lthioacetamidobenzoate (0.05g, 0.09 mmol), prepared in step 5 of Example 17, in dichloromethane (0.1 mL) at room temperature, m-chloroperbenzoic acid (0.06g of 60% m- cPBA, 0.21 mmol) was added and the reaction stirred overnight. Next day the reaction was quenched with an aqueous solution of sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude sulfone (0.52g, 98 %, TLC = 0.3 Rf in 1 : 1 hexane: ethyl acetate) was used for the next reaction directly.
104 Step 2:
The titled compound was prepared according to the procedure described in step 3 of Example 59.
EXAMPLES 66 and 65 were prepared according to the procedures described in Example 18.
EXAMPLE 67
2-(2-(-5-Benzyloxy- 1 -(2.4-bisf 1.1 -dimethy )propyl)phenoxyacetyPindolinyPmethylthiobenzoic acid
Step 1 : 5-Benzyloxy-l-(2.4-bisd . l-dimethy)propyPphenoxyacetyl)-2-hydroxymethylindoline
The diisopropylethylamine (3.5 mL, 20.5 mmol), DMAP(0.25 g, 2.05 mmol) and the indoline alcohol (4.53 g, 17.7 mmol), prepared in step 1 of Example 17, were v/eighed into a flask which was flushed with nitrogen and cooled to θ C at which time a 0° C solution of di- tert-amylphenoxyacetyl chloride (20.5 mmol) in CHC12 (50 mL) was added via cannula.
The resulting solution was left to warm to room temperamre overnight and then quenched by the addition of 1/2 samrated ammonium chloride and CHC12, the solution was extracted with CH2C12 (3X), the combined layers were dried over magnesium sulfate and concentrated to yield (10.4 g) of a yellow foam that was purified via chromatography using a gradient (hexane:ethyl acetate 7: 1 to 3: 1 to 1 : 1) to yield 3.62 g of the product.
Step 2 : 2-(5-Benzyloxy- 1 -C2 ,4-bisf 1.1 -dimethy)propyl)phenoxyacetyPindolinylmethyl _ methylsulfonate
To a solution of alcohol (1.2 g, 2.26 mmol) in CHC12 (15 mL), prepared in step 1, is added triethylamine (0.44 mL, 3.16 mmol). The solution is brought to -50PC and then mesyl chloride (0.23 mL, 2.93 mmol) is added. The mixmre is stirred 2 h at -50fC, quenched with saturated ammonium chloride and allowed to come to rt. The mixmre is taken up in CHC13 (50 mL), washed with samrated sodium bicarbonate (1 X 10 mL), brine (1 X 10 mL), dried (MgS04), filtered and concentrated to afford the product (1.19 g, 86%).
Step 3: Methyl 2-(2-(-5-benzyloxy-l-C2.4-bisd . l-dimethy')propyPphenoxyacetyP indolinyPmethylthiobenzoate
To a solution of mesylate (0.54 g, 0.89 mmol), prepared in step 2, in degassed DMF (2 mL) is added CsCO, (0.724 g, 2.22 mmol) and methyl thiosalicylate (0.134 mL, 0.98 mmol). The mixmre is stirred 4 h, taken up in ethyl acetate (20 mL), washed with brine (3 X 3 mL), dried (MgS04), filtered and concentrated. Chromatography (gradient, hexane:ethyl acetate 15: 1 to 4: 1) afforded 0.53 (86%) of the title compound as a yellow oil.
Step 4:
The titled compound was prepared according to the procedure described in step 3 of Example 59.
EXAMPLE 68 was prepared according to the procedures described in Example 67.
EXAMPLE 69
3-(N-(2-(-5-Benzyloxy-l-(2.4-bisd . l-dimethy propyPphenoxyacetyPindolinyP methylthioethyPaminobenzoic acid
The titled product was prepared according to the procedures described in step 3 of Example 59, but using Intermediate 15. EXAMPLE 70
3-N-Methyl-(2-("-5-Benzyloxy- 1 -(2 ,4-bisC 1.1 -dimethy)propyl)phenoxyacetyPindolinyP methylthioacetamido-4-methoxybenzoic acid
An oven-dried 100 mL, 3-neck round bottom flask, equipped with a stir bar and nitrogen inlet, was charged with methyl 3-(2-(-5-Benzyloxy-l-(2,4-bis(l ,l-dimethy)propyP- phenoxyacetyl)indolinyPmethylthioacetamido-4-methoxybenzate (581 mg, 0.757 mmol), prepared in the synthesis of Example 20 using the procedures described in Example 18, and 10 mL of THF was added via syringe. To the resulting yelllow solution was added NaH
(60% suspension in mineral oil, 39 mg, 0.975 mmol). The reaction mixmre was stirred at 25 °C for 1.5 h to afford a pale suspension. Methyl iodide (161 mg, 1.14 mmol) was added, and the reaction mixture was stirred at 25 °C for 2 days. After chilling to 0 °C, water was added (10 mL), followed by 50 mL of half saturated ammonium chloride, and 100 mL of EtOAc. The layers were separated, and the aqueous phase was extracted once with EtOAc (50 mL).
The combined organic phases were dried (sodium sulfate), filtered, and concentrated to afford 0.6 g of crude product as an orange oil. This material was dissolved in 15 mL of THF and 10 mL of methanol, and 7 mL of IN NaOH solution was added, under nitrogen. After being stirred for 2 h at 25 °C, the reaction mixture was concentrated to dryness on the rotary, and 100 mL of IN HCl, and 100 mL of EtOAc were added. The layers were separated, and the organic phase was dried (magnesium sulfate), filtered, and concentrated. The crude material obtained (0.565 g) was purified by column chromatography on silica gel (eluant: chloroform to 3 % MeOH in chloroform) to afford the titled compound (0.415 g, 70% yield).
EXAMPLE 71 was prepared according to the procedures described in Example 70. but using allyl bromide.
EXAMPLE 72
3-(2-C5-benzyloxy- 1 -C2-(4-pyridinyP)ethyPindoliny Pmethylthioacetamidobenzoic acid
Step 1: Ethyl 3-(2-(5-benzyloxy-1 -C2-C4- pyridinyPethyPindolinyPmethylthioacetamidobenzoate
To a solution of ethyl 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.30 g, 0.63 mmol), prepared in step 6 of Example 17, in dichloromethane (3.0 mL) and acetic acid (2.0 mL), 4-vinylpyridine (0.08 mL, 0.75 mmol) was added. The reaction was stirred at room temperamre overnight. The reaction was quenched with half samrated sodium bicarbonate, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using a gradient of 2: 1 hexane: ethyl acetate to 100% ethyl acetate to yield 0.023 g of product (25 % , TLC = 0.7 Rf in ethyl acetate).
Step 2:
The titled compound was prepared according to the procedure described in step 3 of Example 59.
EXAMPLE 73
3-f 2-(5-benzy loxy- 1 -(2-naphthvPmethy)indolinyl)methylthioacetamidobenzoic acid
Step 1 : Ethyl 3-('2-(5-benzyloxy-l-('2-naphthyPmethy)indolinyPmethylthioacetamidobenzoate
A mixmre of 3-(2-(5-benzyloxy)indolinyl)methylthioacetamidobenzoate (0.2g, 0.42 mmol), prepared in step 6 of Example 17, 2-(bromomethyl)naphthalene (0.1 g, 0.42 mmol) and potassium carbonate (0.17 g, 1.26 mmol) in N,N-dimethylformamide (2 mL) was stirred at room temperature overnight. Next the reaction was diluted with ethyl acetate and water, extracted with ethyl acetate (3X), dried over magnesium sulfate and concentrated. The crude material was purified on silica gel using 2: 1 hexane:ethyl acetate to yield 0.22 g of product (85 % , TLC = 0.5 Rf in 2: 1 hexane:ethyl acetate).
Step 2:
The titled compound was prepared according to the procedure described in step 3 of Example 59.
EXAMPLES 74 and 75 in Table 6 were prepared according to the procedures described in Example 73.
EXAMPLE 76
2-('2-(-5-Benzyloxy-l-(2-naphthyPmethyl)indolinyPmethylthiobenzoic acid
Step 1 : 2-C2-("-5-Benzyloxy- 1 -d .1 -dimethyPethoxycarbonyPindoliny Pmethyl methylsulfonate
tert-Butyl l-(5-benzyloxy-2-hydroxymethy)lindolinylformate (6.72 g, 19 mmol), prepared in step 2 of Example 17. was dissolved in CHC12 (80 mL, dried over MgS04 before use). The clear yellow solution was cooled in a dry-ice bath. EjN (4.0 mL) was then added followed by methanesulfonyl chloride (2.0 mL). The reaction mixmre was stirred for
2 h at -40 °C then quenched with H,0. It was washed with satuarated NaHCQ (300 mL) and the aqueous layer extracted twice with CHC12. The combined CH,C12 layers were dried over MgS04, filtered and evaporated to dryness to give the product (7.30 g, 89.1 % yield), which was used for the next reaction directly.
Step 2: Methyl 2-(2-(5-Benzyloxy-l-d . l-dimethyl)ethoxycarbonyl)indolinyPmethylthio benzoate Mesylate (7.2 g, 1.8 mmol), prepared in step 1, was dissolved in DMF (50 mL). The clear light brown solution was degassed by vigorously bubbling with Ar for 30 min. Cesium carbonate (13.8 g) was added followed by methyl thiosalicylate (2.4 mL). The solution changed to a bright yellow and the suspension was stirred overnight. Methyl thiosalicylate (0.15 mL) was added to complete the reaction and the mixmre was stirred overnight. The reaction was then quenched by the addition of saturated NaHC (400 mL). The mixture was extracted with CHC12 (3 x) and the combined CHC12 solution was back- washed with H20 (200 mL). The organic layer was dried over MgSQ, filtered and evaporated to dryness to give the product (9.71 g, 99%).
Step 3: Methyl 2-(2-(5-Benzyloxy)indolinyPmethylthiobenzoate
Ethyl acetate (75 mL, dried over MgS04 before use) was charged in a 500 mL round bottom flask. HCl gas was bubbled through and the EtOAc/HCl solution was cooled in an ice bath. Methyl ester (8.4 g), prepared in step 2, was dissolved in EtOAc (25 mL, dried over MgS04 before use). This solution was transferred to the HCl/EtOAc solution by syringe. The solution turned to red and was stirred in an ice bath. A white precipitate appeared in 1 h and the solution was stirred overnight to complete the reaction. The solid was collected by filtration, washed with dry EtOAc, suspended in saturated NaHCQ (175 mL) and stirred with EtOAc (400 mL). The milky emulsion gradually dissolved and the mixmre changed to a clear solution. The layers were separated and the aqueous layer was extracted (2 x) with EtOAC, while the combined EtOAC layers were dried over MgS04, filtered and evaporated to dryness to give the product (6.06 g, 90 % yield).
Step 4: Methyl 2-(2-(5-Benzyloxy-l-(4-benzyPbenzyPindolinyPmethylthiobenzoate
In a 50 mL round bottom flask, ester (1 g), prepared in step 3, was dissolved in DMF (6 mL). p-Benzylbenzyl bromide was added (1 eq) followed by KC03 (1 eq). The reaction mixture was stirred overnight at room temperature. To complete the reaction additional p-benzylbenzyl bromide (0.5 eq) was added and the reaction was stirred for another 2 hours. After its completion, the reaction was diluted with HO and extracted with EtOAc (2 x). The organic layers were combined and dried over MgSQ. The MgS04 was filtered and the solvent was evaporated to give an oily material which was dried overnight on high vacuum to give the product (1.59 g, 109 % yield).
I l l Step 5:
The ester (1.52 g), prepared in step 4, was dissolved in THF (10 mL) in a 50 mL round bottom flask. To it was added NaOH (1 eq, 2N) followed by MeOH (3 mL) and the reaction mixmre was stirred overnight. Additional NaOH (0.3 eq) was added to complete the reaction and the mixture was stirred throughout the weekend. Then it was acidified and diluted with H20 and extracted with EtOAc (2 x). The organic layers were combined and dried over MgS04. The MgS04 was filtered and the solvent was evaporated and dried on high vacuum to give a crude reddish solid. This solid was dissolved in EtOAc and hexane was added to precipitated the product. The resulting solid was filtered and the impure filter cake was combined with the filtrate and evaporated to dryness. This material was treated with EtOAc and EtOH. The resulting solid was filtered then suspended in EtOH, with stirring and heating at a low temperamre. Then it was allowed to cool to room temperamre. The suspension was filtered and washed with EtOH to give the titled product (280 mg, 19 % yield).
EXAMPLES 77. 78 and 79 in Table 6 were prepared according to the procedures described in Example 76.
EXAMPLE 80
4-( 1 -(5-Benzyloxy-2-(bis-2.4-trifluoromethyPbenzyloxymethyPindolinyPmethylbenzoic acid
Step 1 : Methyl l-(5-Benzyloxy-2-(hydroxymethyPindolinyPmethylbenzoate
2-(5-Benzyloxy)indolinylmethanol (3.21 g, 12.6 mmol), prepared in DMF (20 mL), methyl 4-(bromomethyl)benzoate (2.88 g, 14.5 mmol) and potassium carbonate (1.77 g, heated to 125 °C before use) were mixed and stirred at room temperamre for 2 h. The reaction was diluted with 100 mL of HO and extracted three times with EtOAc. The combined EtOAc layers were evaporated to dryness to give the crude product (5.66 g). The crude material was purified on a silica gel column using hexane:ethyl acetate 3: 1 to 2: 1. The appropriate fractions were combined, evaporated to dryness and further dried on high vacuum to the product (3.00 g, 64%).
Step 2: Methyl 4-d-(5-Benzyloxy-2-0 is-2.4-trifluoromethyPbenzyloxymethyPindolinyl) methylbenzoate
Ester (700 mg), prepared in step 1, and bis-(2,4-trifluoromethyl)benzyl bromide (0.35 mL) were dissolved in DMF (5 mL). The resulting clear yellow solution was cooled in an ice bath and then NaH (85 mg) was added in small portions over a period of 5 minutes.
The suspension was stirred at 0°C for 4 h. To complete the reaction, another 0.35 mL of 2,4-bis(trifluoromethyl)-benzyl bromide was added and the stirring was continued for another 3 h 40 min. The reaction was then diluted with HO and extracted three times with EtOAc. The combined EtOAc layers were evaporated to give a crude product which was then purifed on a silica gel columnusing hexane:ethyl acetate 8: 1. The appropriate fractions were combined and evaporated to dryness to give the product (0.417 g, 38.2 % yield).
Step 3:
The titled compound was prepared according to the prodedure described in step 5 of
Example 76.
EXAMPLES 81 and 82 in Table 6 were prepared according to the procedures described in Example 80.
EXAMPLE 83
5-(2-d-("2.4-Bis(trifluoromethyPbenzyPindolinyPcarboxamido-1.3-benzenedicarboxylic acid
Step 1 : 2-d-(2.4-Bis(trifluoromethyPbenzyl)indolinyPcarboxylic acid
2-Indolinylcarboxylic acid (0.43 g, 2.6 mmol) was dissolved in DMF (5 mL), placed under N2, and cooled to Of C, the sodium hydride (0.26 g of a 60 % dispersion, 6.5 mmol) was added and stirring was continued for 1 hour at this temperamre. 2,4- Bis(trifluoromethyl)benzyl bromide (1.22 mL, 6.5 mmol) was next added and the reaction was warmed to room temperamre overnight. The reaction was then diluted with 1/2 samrated ammonium chloride/ethyl acetate, the aqueous layer was extracted with ethyl acetate (3X), the organic layers were dried over magnesium sulfate and concentrated. The crude product was purified via chromatography (hexane:ethyl acetate 9: 1) to yield 0.96 g of the ester. The resulting ester (0.87 g, 0.1.41 mmol) was dissolved in THF/ methanol and then
IN sodium hydroxide (4.21 mL) was added and the resulting mixmre was stirred 2 hours at RT, workup and purification via Chromatography (7: 1 hexane:ethyl acetate with 1 % acetic acid) yielded 0.58 g of the product.
Step 2:
The acid (0.25 g, 0.64 mmol), prepared in step 1 , EDCI (0.16 g, 0.83 mmol), DMAP (7 mg, 0.06 mmol) and dimethyl 5-aminoisophthalate (0.16 g. 0.77 mmol) were dissolved in THF (2 mL) and refluxed 16 hours which yielded after aqueous workup 0.33 g of a crude product. The ester (0.29 g, 0.50 mmol) was dissolved in THF/ methanol and then
IN sodium hydroxide (1.5 mL) was added and the resulting mixture was stirred 16 hours at RT, workup and purification via Chromatography (1 : 1 hexane:ethyl acetate with 1 % acetic acid) yielded 0.22 g of the titled compound.
EXAMPLE 84 N-Methylsulfonyl-2-C 1 -(2 ^-bisCtrifluoromethvPbenzyPindolinyPcarboxamide
The acid (0.13g, 0.32 mmol), prepared in step 1 of Example 83, EDCI (0.07 g, 0.39 mmol), DMAP (4 mg, 0.03 mmol) and methylsulfonanilide (0.04 g, 0.39 mmol) were dissolved in THF (5 mL) and refluxed 16 hours which yielded after workup (0.16 g), purification via Chromatography (98:2 dichloromethane: methanol) yielded 0.04 g of the titled compound (29%).
EXAMPLE 85
N-Phenylsulfonyl-2-( 1 -(bis-2.4-trifluoromethyl)benzyPindolinyPcarboxamide
The titled compound was prepared according to the prodedure described in Example 84, but using phenylsulfonylamide.
EXAMPLE 86
5-(2-f 5-Methoxybenzyloxy- 1 -(2.4- bisOrifluoromethyPbenzyPindolinyPmethylaminocarboxamido- 1 ,3-benzenedicarboxylic acid
Step 1 : 2-TrimethyIsilylethyl l-(5-benzyloxy-2-hydroxymethyPindolinylformate
An oven-dried 1 L round bottom flask, equipped with a stir bar was charged with 2-
(5-benzyloxy)indolinylmethanol (33.2 g, 130 mmol), prepared in stepl of Example 17. 2- (trimethylsilyl)ethyl p-nitrophenyl carbonate 36.8 g, 130 mmol), NEt (38 ml, 273 mmol), and 300 mL of anhydrous DMF. The reaction mixture was stirred at 60°C for 28 hours and at room temperature overnight. The resulting solution was concentrated to dryness in vacuo, and 1 L of CHCk and 200 mL of samrated NaHCQ solution were added. The layers were separated, and the organic phase was dried (NaS04), filtered, and concentrated. The crude material obtained (55.7 g) was purified by column chromatography on silica gel (eluant: 0-5 % MeOH in dichloromethane) to afford product (33.5 g, 60% yield).
Step 2: 2-Trimethylsilylethyl l-C5-hydroxy-2-hydroxymethyl)indolinylformate
An oven-dried 500 mL Parr pressure flask was charged with the alcohol (30 g, 75 mmol), prepared in step 1 , Pd/C (10 % , 2.2 g), 100 mL of MeOH, and 300 mL of EtOAc. After being shaken overnight in a Parr apparatus under H atmosphere (50 psi), the reaction mixmre was filtered through Florisil. The filtrate was concentrated to dryness on the rotary. The crude material obtained (24 g) was purified by column chromatography on silica gel
(eluant: 0-3 % MeOH in dichloromethane) to afford product (20.9 g, 90% yield).
Step 3: 2-Trimethylsilylethyl l-C5-f4-methoxy)benzyloxy-2-hydroxymethyl)indolinylformate
An oven-dried 1 L round bottom flask, equipped with a stir bar was charged with the diol (27.1 g, 87.7 mmol), prepared in step 2, 4-methoxybenzyl chloride (Aldrich, 15 mL, 110 mmol), K2C03 (200 mesh, 30.4 g, 220 mmol), KI (Aldrich, 18.3 g, 110 mmol), and 800 mL of anhydrous acetonitrile. The reaction mixture was heated at reflux for 4 h. The solution was allowed to cool to room temperature and water (800 mL) and CHQ1(1.5 L) were added. The layers were separated, and the aqueous phase was extracted with CHQ1
(800 mL). The combined extracts were washed with water (200 mL), dried (NaS04), filtered, and concentrated. The crude material obtained (45 g) was purified by column chromatography on silica gel (eluant: 20-25 % EtOAc in hexane), and recrystallization from EtOAc/Hexane to afford product (22.2 g, 59% yield).
Step 4: 2-Trimethylsilylethyl l-CS-^-methoxy^enzyloxy^-bromomethyPindolinylformate
To a solution of 3.0 g (6.4 mmol) of the alcohol, prepared in step 3, in 30 mL of dichloromethane was added 2.53 g (7.6 mmol) of carbon tetrabromide and 3.15 g (7.6 mmol) of l ,3-bis(diphenylphosphino)propane. The reaction was stirred at room temperamre for 18 h. The reaction was quenched with saturated aqueous NHC1, and the product was extracted with dichloromethane. The combined organic extracts were washed with brine and dried over MgS04. The crude product was purified by flash chromatography using hexane:ethyl acetate 3:2 to afford 1.51 g of the product.
Step 5: 2-Trimethylsilylethyl l-(5-(4-methoxy)benzyloxy-2-azidomethyPindolinylformate
To a solution of 1.4 g (2.6 mmol) of the bromide, prepared in step 4, in 15 mL of dimethylformamide was added 0.51 g (7.9 mmol) of sodium azide. The reaction was heated to 75 °C, and was stirred for 18 h. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over MgSQ,. The crude product was purified by flash chromatography using hexane:ethyl acetate 4: 1 to afford 1.08 g of the product.
Step 6: 2-Trimethylsilylethyl l-(5-(4-methoxy)benzyloxy-2-aminomethyPindolinylformate
To a solution of 0.88 g (1.9 mmol) of the azide, prepared in step 5, in 20 mL of ethanol was added 90 mg (10%/wt) of Pd/CaCQ. The mixmre was placed under atmospheric hydrogen, and was stirred for 18 h. The reaction was then filtered through a pad of celite and the organic phase was concentrated. The crude product was purified by flash chromatography using 10% MeOH/CHCl2 to afford 0.717 g of the product.
Step 7: Methyl 5-(2-(5-Methoxybenzyloxy-l-(2-trimethylsilyloxy)ethoxycarbony)lindolinyP methylaminocarboxamido- 1.3-benzenedicarboxylate
To a solution of 0.164 g (0.6 mmol) of triphosgene in 5 mL of dichloromethane was added a solution of 0.31 g (1.5 mmol) of dimethyl-5-aminoisophthalate and 0.39 g (3.0 mmol) of diisopropylethylamine in 20 mL of dichloromethane over a 30 minute period via a syringe pump. The reaction was stirred for 1 h at room temperamre following the addition, and then a solution of 0.64 g (1.5 mmol) of the amino, prepared in step 6, in 5 mL of dichloromethane was added in one portion. The reaction was stirred for 2 h, and then quenched with water. The product was extracted with ethyl acetate, and the combined organic layers were washed with water, samrated aqueous NaHCQ, brine and dried over MgS04. The crude product was purified by flash chromatography using 10% MeOH/CHCl2 to afford 0.78 g of the product.
Step 8: Methyl 5-(2-(5-Methoxybenzyloxy)indolinyl)methylaminocarboxamido-1.3- benzenedicarboxylate
To a solution of 0.485 g (0.7 mmol) of the ester, prepared in step 7, in 20 mL of acetonitrile was added 2.2 mL (2.2 mmol) of a 1.0 M tetrabutylammonium fluoride solution in THF. The reaction was stirred at room temperamre for 18 h. The reaction was quenched with brine, and the product was extracted with ethyl acetate. The combined organic extracts were washed with samrated aqueous NH,C1, brine and dried over MgSQ,. The crude product was purified by flash chromatography using 5 % MeOH/CHCl2 to afford 0.342 g of the product.
Step 9: Methyl 5-(2-(5-Methoxybenzyloxy-l-(bis-2.4-trifluoromethyPbenzyPindolinyP methylaminocarboxarnido- 1.3-benzenedicarboxylate
To a solution of 0.15 g (0.3 mmol) of the indoline diester, prepared in step 8, in 5 mL of dimethylformamide was added 0.097 g (0.3 mmol) of 2,4-bis(trifluoromethyl)benzyl bromide and 0.12 g (0.9 mmol) of potassium carbonate. The reaction was stirred at room temperamre for 18 h. The reaction was quenched with water, and the product was extracted with ethyl acetate. The combined organic extracts were washed with water, brine and dried over MgS04. The crude product was purified by flash chromatography using hexane:ethyl acetate 1 : 1 to afford 0.066 g of the product.
Step 10:
To a solution of 0.063 g (0.1 mmol) of the diester, prepared in step 9, in 5 mL of tetrahydrofuran was added 0.8 mL (0.8 mmol) of a 1.0 N NaOH solution and 0.5 mL of methanol. The reaction was stirred at room temperature for 18 h. The organic solvents were evaporated, and the resulting solid was suspended in water and acidified to pH 3 with 10% HCl. The product was extracted with ethyl acetate, and the combined organic extracts were washed with water, brine and dried over MgSQ. The crude product was purified by flash chromatography using 5% MeOH/CHCl2 to afford 0.049 g of the titled compound.
EXAMPLE 87 was prepared according to the prodedure described in Example 86. but using 4-(3,5-bis(trifluoromethyl)phenoxymethyl)benzyl bromide.
INTERMEDIATE 1
Methyl 4-methoxy-3-thioacetamidobenzoate
Step 1 : Bisfmethyl 4-methoxy-3-dithioacetamidobenzoate)
A 2-L oven-dried round bottom flask fitted with a magnetic stirring bar was charged with Dithioacetic acid (10.2-15.5 g, 56-85 mmol) and anhydrous CHC12 (50 mL). Oxalyl chloride (2.1 mol equiv.) was added dropwise over 10 min. The reaction mixmre was stirred at room temperature for 4-5 h. Methyl 4-methoxy-3-amidobenzoate (2.1 mol equiv.) in anhydrous CH2C12 (300-500 mL) and DMAP (0.1 mol equiv.) were added at room temperamre. NEt3 (4.2 mol equiv.) was added dropwise over 30 min. After stirring overnight at room temperamre the reaction mixmre was washed with 1 N HCl solution (2 x 300 mL), dried over Na,S04 and filtered. The solvent was removed in vacuo. Purification of the residue by column chromatography on silica gel using hexane:ethyl acetate = 5: 1 afford desired product in 56% yield.
Step ->•
A 1-L round bottom flask fitted with a magnetic stirring bar was charged with disulfide, prepared in step 1, (15.7-26.3 g, 36.6-57.5 mmol) and PPh (l . l mol equiv.). The reactants were suspended in dioxane/HO (4/1 , 375-500 mL) and concentrated HCl solution (5 drops) was added. The reaction mixture was heated at 40°C until all disulfide was consumed. Solvents were removed in vacuo. The residue was purified immediately by column chromatography on silica gel using hexane : ethyl acetate 2: 1 to afford the titled product in 89% yield.
INTERMEDIATE 2
Methyl 5-thioacetamido- 1.3-benzenedicarboxylate
The titled compound was synthesized according to the procedures described in Intermediate 1 using 5-amino-l , 3-benzenedicarboxylate.
UINTERMEDIATE 3
Methyl 2-(3-amino-4-methoxyphenyP-2-methoxyacetate
Step 1 : Methyl 2-(3-nitro-4-methoxyphenyPacetate
An oven-dried 2-L, 3-neck round bottom flask, equipped with a mechanical stir motor, a low-temperature thermometer and an equalizing dropping funnel, was charged with acetic anhydride (631 mL) and subsequently cooled to -78°C. Fuming nitric acid (Baker, 90% , 27 mL) was added dropwise via the dropping funnel protected with a drying tube filled with CaCl2. After addition was completed, the reaction temperamre was allowed to warm to 20 °C over 1 h. The reaction mixture was cooled to -78C again and added 4- methoxyphenylacetic acid (50 g, 0.28 mol) dropwise via the dropping funnel. After stirring at -50 °C for 1 h. , the reaction mixmre was allowed to warm to -30°C over 20 min. and then cooled to -50 °C again. The reaction mixture was quenched with HO (500 mL) at -50 °C and warmed up to room temperamre and stirred for 0.5 h. The reaction mixture was partitioned between CH2C12 (500 mL) and H20. The aqueous layer was extracted with CHC12 (3 x 500 mL). The combined CH,C12 extracts were concentrated in vacuo to give a yellow oil. This was added slowly to a 2 M solution of NaOH (2 L) cooled at 0°C and stirred at room temperature overnight. The reaction mixmre was partitioned between CHC12 (500 mL) and H20. The aqueous layer was extracted with CHC12 (3 x 500 mL). The combined CH>C12 extracts were stirred with 2 M NaOH solution (1 L) for 1 h. The layers were separated and the organic layer was washed with HO (500 mL), brine (500 mL), dried over NaS04 and filtered. The solvents were removed in vacuo to afford crude product as a light yellow solid (56 g). Purification by recrystallization from MeOH (600 mL) gave product. Yield 48 g (77%).
Step 2: Methyl 2-f3-nitro-4-methoxyphenyP-2-hydroxyacetate
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ester (2.3 g, 10 mmol), prepared in step 1, and anhydrous THF (1C0 mL). The reaction mixture was cooled to -78°C and a solution of NaN(SiMe3)2 (1.0 M in THF, 12 mL,
12 mmol) was added dropwise over 10 min. After stirring at -78°C for 30 min. , the deep purple solution was added dropwise a solution of racemic camphor sulfonyloxazindine (3.4 g, 15 mmol), prepared by mixing the commercially available (lS)-( + )-(10- camphorsulfonyPoxaziridine (1.7 g) and (lR)-(-)-(10-camphorsulfonyl)oxaziridine (1.7 g) in 50 L THF. After stirring at -78 °C for 30 min. , the reaction mixmre was quenched with sat. NH4C1 solution (45 mL) at -78 °C and then allowed to warm to room temperamre. The reaction mixture was partitioned between ether (250 mL) and HO (50 mL). The aqueous layer was extracted with ether(3 x 250 mL). The combined ether extracts were washed with brine (250 mL), dried over N S04 and filtered. The solvents were removed in vacuo. Purification by column chromatography on silica gel (eluant: 50% AcOEt in hexane) afforded desired product. Yield 2.2 g (88%).
Step 3: Methyl 2-(3-nitro-4-methoxyphenyP-2-methoxyacetate
A 10-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2, AgO (0.68 g, 3.0 mmol) and toluene (3 mL). To this was added CH,I (0.36 g, 5.75 mmol) dropwise. The reaction flask was capped tightly and placed into a sonication chamber. The reaction mixmre was sonicated for 18 h while stirring at room temperamre. The reaction mixture was filtered through Celite and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel (eluant: 30% AcOEt in hexane) to afford desired product. Yield 0.26 g (82%).
Step 4:
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar and a three way adapter, connecting to a hydrogen balloon and a water aspirator was charged with nitro compound (0.7 g, 2.6 mmol), 5% Pd on Carbon (10% by weight) and MeOH (20 mL). The reaction flask was placed under vacuum via the water aspirator and subsequently filled with H2. This was repeated three times. The reaction mixture was stirred for 18 hours under positive H2 pressure until all starting material was reacted. The reaction mixmre was filtered through Celite and concentrated in vacuo to dryness. The residue was purified by column chromatography on silica gel using 10% ethyl acetate in dichloromethane to afford the titled compound (0.57 g, 97%)
INTEMEDTATF. 4
Methyl 2-(3-amino-4-methoxyphenyl)-2-tert-butyldimethylsilyloxyacetate
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.30 g, 1.24 mmol), prepared in step 2 of Intermediate 3 and anhydrous CH2C12 (10 mL). The reaction mixmre was cooled to 0CC and added 2,6-lutidine
(dried over NaOH pellet, 0.36 mL, 3.11 mmol) followed by addition ofBuMe^SiOTf (0.43 mL, 1.87 mmol) dropwise. After stirring at 0°C for 30 min., the reaction mixmre was partitioned between CH,C12 (20 mL) and H20 (15 mL). The aqueous layer was extracted with CH2C12 (3 x 20 mL). The combined CHC12 extracts were washed with brine (20 mL), dried over Na2S04 and filtered. The solvents were removed in vacuo. Purification by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded desired product. Yield 0.42 g (95%). Step 2:
The titled compound was prepared from nitro compound of step 1 according to the procedure described in step 4 of Intermediate 3.
INTERMEDIATE 5
Methyl 2-G-amino-4-methoxyphenyPacetate
The titled compound was prepared from nitro compound, prepared in step 1 of Intermediate 3, according to the procedure described in step 4 of Intermediate 3.
INTERMEDIATE 6
Methyl 2-(3-amino-4-methoxyphenyP-2-methylacetate
Step 1 : Methyl 2-(3-nitro-4-methoxyphenyl)-2-methylacetate
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with redistilled diisopropylamine (0.84 mL, 6.0 mmol) and anhydrous THF (10 mL) and cooled to 0 °C. A solution of n-BuLi (2.5 M in hexane, 2.4 mL, 6.0 mmol) was added dropwise over 5 min. After stirring at 0°C for 15 min. , the reaction temperamre was allowed to cool to -78 °C and added a solution of easter (1.13 g, 5.0 mmol), prepared in step
1 of Intermediate 3, in 10 mL THF dropwise. After stirring at -78°C for 45 min., dimethy Isulfate (1.60 g, 12.5 mmol) was added dropwise and the reaction mixmre was allowed to warm to room temperature and stirred overnight. The reaction mixmre was partitioned between CH,C12 (50 mL) and H20 (50 mL). The aqueous layer was extracted with CH2C12 (3 x 50 mL). The combined CHC1, extracts were washed with brine (50 mL), dried over Na2S04and filtered. The solvents were removed in vacuo. Purification by column chromatography on silica gel (eluant: 30% AcOEt in hexane) afforded 0.7 g of product (58%).
Step 2:
The titled compound was prepared from nitro compound, prepared in step 1 , according tothe procedure described in step 4 of Intermediate 3.
INTERMEDIATE 7
Methyl 2-G-amino-4-methoxyphenyP-2-allylacetate
Step 1 : Methyl 2-(3-nitro-4-methoxyphenyl)-2-allylacetate
This compound was synthesized form ester, prepared in step 1 of Intermediate 3, according to the procedure described in step 1 of Intermediate 6, but using allyl bromide.
Step 2:
A 25-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with ester (0.30 g, 1.13 mmol), prepared in step 1 , SnCl 2H20 (1.28 g, 5.66 mmol) and EtOH (5 mL). The reaction mixture was heated at 70°C for 30 min. The reaction mixmre was cooled to room temperature and poured onto ice/water (20 mL) and basified with samrated Na C03 solution to pH = 8. AcOEt (50 mL) was added. The resulting emulsion was filtered through Celite. The filtrate was partitioned between AcOEt (20 mL) and HO (15 mL). The aqueous layer was extracted with AcOEt(3 x 50 mL). The combined AcOEt extracts were washed with brine (50 mL), dried over NaS04 and filtered. The solvents were removed in vacuo. Purification of the residue by column chromatography on silica gel
(eluant: 10% AcOEt in CH,C12) afforded the titled compound. Yield 0.16 g (60%).
INTERMEDIATE 8
! ,4-Bisf 1.1 -dimethypropyPphenoxyacetic acid
The 2, 4-bis( 1 , 1 -dimethy )propylphenol (12 g, 51.2 mmol) in dimethylformamide (100 mL) was cooled to -30 C, treated with solid potassium bis(trimethylsilyl)amide (12.3g, 61.5 mmol), stirred for 30 minutes and then methyl bromoacetate (5.7 mL, 61.5 mmol) was added, the reaction was stirred 1 hour at this temperamre and five hours after removal of the cooling bath, workup yielded (16.6g, = 100%) a yellow oil. The oil was dissolved in THF/methanol and treated with IN sodium hydroxide (155 mL) and stirred for 48 hours. The reaction was concentrated, diluted with water, acidified to pH 4 with concentrated HCl, extracted with ethyl acetate (4X), dried over magnesium sulfate and concentrated. Crystalization from ethyl acetate and hexane yielded 12.85 g of the titled compound. (86%).
INTERMEDIATE 9
4-Benzylphenoxyacetic acid
The titled compound was prepared from 4-benzylphenol according to the procedure described in of Intermediate 8.
INTERMEDIATE 10
2-Naphthoxyacetic acid
The titled compound was prepared from 2-naphthol according to the procedure described in of Intermediate 8.
INTERMEDIATE 1 1
3.5-Bis(trifluoromethyPphenoxyacetic acid
The titled compound was prepared from 3,5-bis(trifluoromethyl)phenol according to the procedure described in of Intermediate 8.
INTERMEDIATE 12
Methyl 5-amino-3-(N.N-dimethyPcarbamoylbenzoate Step 1 : Methyl 5-nitro-3-(N.N-dimethyPcarbamoylbenzoate
A 100-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with 5-nitro-3-methoxycarbonylbenzoic acid (3.15 g, 10 mmol), DMF (1 drop), anhydrous CH2C12 (70 mL), and oxalyl chloride (3.7 mL, 42.3 mmol). The reaction mixmre was stirred at room temperature for 2 h. The solvent was removed in vacuo to afford acid chloride as a white solid. This was used immediately in the next step without further purification.
An oven-dried round bottom flask fitted with a magnetic stirring bar was charged with above prepared acid chloride (14 mmol), anhydrous CHC12 (50 mL), and dimethylamine hydrochloride (70 mmol). NEt, (2 mL, 144 mmol) was added dropwise. After stirring at room temperamre for 30-60 min excess NEξ (1 mL, 72 mmol) was added and stirring was continued. After 30-60 min the solution was washed with samrated NaC03 solution (2 x 20 mL), dried over Na,S04 and filtered. The solvent was removed in vacuo to afford 3.3 g of product. This was used in the next step without further purification.
Step 2:
The titled compound was prepared from nitro compound, prepared in step 1, according to the procedure described in step 4 of Intermediate 3.
INTERMEDIATE 13
Methyl 5-amino-3-acetylbenzoate
Step 1 : Methyl 5-nitro-3-acetylbenzoate
A 250-mL oven-dried round bottom flask fitted with a magnetic stirring bar was charged with di-tert-butyl malonate (2.16 g, 10 mmol), anhydrous toluene (50 mL), and NaH
(60% suspension in mineral oil, 0.88 g, 22 mmol). The reaction mixmre was heated at 80C for 1 h. A solution of methyl 5-nitro-3-chloroformylbenzoate (10 mmol), prepared in step 1 of Intermediate 12, in anhydrous toluene (20 mL) was added and heating was continued for 2 h. The reaction mixmre was cooled to room temperamre and p-toluenesulfonic acid (0.21 g, 1.2 mmol) was added. The resulting mixmre was filtered and the oily residue was washed with toluene until a white solid was left. The filtrates were combined and the solvent was removed in vacuo. The resulting oil was dissolved in anhydrous toluene (50 mL) and p- toluenesulfonic acid (0.3 g, 1.74 mmol) was added. After heating to reflux for 18 h the reaction mixmre was allowed to cool to room temperamre, washed with samrated Nd O3 solution (2 x 25 mL), dried over NaS04 and filtered. The solvent was removed in vacuo. The crude material was purified by column chromatography on silica gel (eluant: CHGL) to afford product. Yield 1.06 g (50%).
Step 2:
The titled compound was prepared from nitro compound, prepared in step 1 , according to the procedure described in step 4 of Intermediate 3.
INTERMEDIATE 14
Methyl 5-amino-3-( 1 -tert-butyldimethylsilyloxy)ethylbenzoate
Step l : Methyl 5-nitro-3-d -hydro xy)ethylbenzoate
An oven-dried round bottom flask fitted with a magnetic stirring bar was charged with compound methyl 5-nitro-3-acetylbenzoate (0,5 g), prepared in step 1 of Intermediate
13, BH3 THF (1 M solution in THF, 5 mol equiv.), and anhydrous THF. After stirring at room temperature for 24 h, HO (20 mL) was added and the solution was concentrated in vacuo. The residue was taken in HO (20 mL) and extracted with CH (3 x 100 mL). The combined CH extracts were washed with samrated NaC03 solution (20 mL), dried over Na,S04 and filtered. The solvent was removed in vacuo to afford product. This was used in the next step without further purification. Step 2: Methyl 5nitro-3-d-tert-butyldimethylsilyloxy')ethylbenzoate
An oven-dried round bottom flask fitted with a magnetic stirring bar was charged with alcohol (0.5g, 5 mmol), prepared in step 1, tert-BuMeSiCl (1.3 mol equiv.), imidazole (2.15 mol equiv.), and anhydrous THF. After stirring at room temperamre for 28 hours the solvent was removed in vacuo. The residue was taken in HO (50 mL) and extracted with CHC13 (2 x 100 mL). The combined CHQ extracts were washed with HO (50 mL), dried over Na2S04 and filtered. The solvent was removed in vacuo. The crude material was purified on silica gel using 25 %-50% dicloromethane in hexane to afford the product (0.69 g, 91 %).
Step 3:
The titled compound was prepared from nitro compound, prepared in step 2, according to the procedure described in step 4 of Intermediate 3.
INTERMEDIATE 15
Methyl 4-methoxy-3-(2-thioethyPaminobenzoate
Step 1 : Bis 2-bromoethyPdisulfide
The dithioethanol (0.79 mL, 6.48 mmol), carbon tetrabromide (4.3 g, 13.0 mmol) and 1 ,3 bis(diphenylphosphino)propane (5.34 g, 13.0 mmol) were weighed into a flask and flushed with nitrogen and then taken up in CHC12 (15 L) and stirred for 16 hours, workup consisted of pouring into 1/2 samrated ammonium chloride and extracted with CHC12 (3X) dry magnesium sulfate and concentrated to yield (9.0 g) of a crude product that was chromatographed (Hexane:Ethyl acetate9: l) to yield 1.49 g of product.
Step 2: Bis-Onethyl 4-methoxy-3-(2-dithioethyPaminobenzoate Bromide (0.39 mg, 1.387 mmol), prepared in step 1, and methyl 3-amino-4-methoxy benzoate (1.00 g, 5.51 mmol) were added into a flask, flush with nitrogen and take up in DMF (5 mL) and then heat to 60° C for 24 hours at which time the reaction was diluted with ethyl acetate and quenched into water, extracted with ethyl acetate (3X), the combined organic layers were washed with water (3X), dried and concentrated to yield 1.27 g of a product that was purified by chromatography (hexane:ethyl acetate 5: 1 to 3: 1) to yield 0.15 g of the desired product.
Step 3:
The disulfide (0.15 g, 0.24 mmol), prepared in step 2, and the triphenylphoshpine
(0.14 g, 0.53 mmol) were taken up in THF (3 mL). HO (0.3 mL) and two drops of cone.
HCl were added and the resulting mixmre was stirred at 40° C for 2 hours, the reaction was diluted with water and ethyl acetate, extracted with ethyl acetate (3 X) and dried over magnesium sulfate to yield 0.27 g of a crude product that was purified by chromatography
(hexane:ethyl acetate 9: 1 to 6: 1) to yield 0.11 g of the titled compound.
Methods of Synthesis for Examples 88-135
Additional compounds of the invention can be made according to the following methods. Specific examples of synthesis of compounds pursuant to these methods are also disclosed below.
Method A
The aldehyde is reacted with the alpha-carbon of a heterocycle such at 2,4-thiazolidinedione or rhodanine or 2-thiohydantoin in the presence of a base such a potassium carbonate or potassium hydroxide in a solvent system such a wateπefhanol or ethanol. The resulting product may then be
N-alkylated with a base such a sodium hydride in a solvent such a DMF or DMSO. The final acid may then be realized by cleavage of the ester with hydrogen fluoride in a solvent such as acetonitrile.
Method B
Indole-2-carboxylic acid was alkylated with an appropriate alkyl bromide which was then subjected to Suzuki coupling conditions using Pd(PPh3) as a catalyst in a mixed solvent (ethanol-benzene- water) at elevated temperature to give the l-alkyl-5-substiruted indole.
Method C
The starting material for the inhibitors in this class, 2-Ethoxycarbonyl-5-benzyloxyindole I, was deprotonated with a suitable base such as sodium hydride and alkylated on the nitrogen atom with selected electrophiles such as alkyl or benzyl halides to provide compounds II. Saponification of the ester functionality with a base such as aqueous sodium hydroxide in miscible solvents such as tetrahydrofuran and methanol gave inhibitors III. Further extensions at the 2-position were carried out through amide formation of the acid functionality via acid chloride formation with a suitable reagent such as oxalyl chloride and reaction with an amino-ester in the presence of a base such as pyridine in a suitable solvent such as methylene chloride. Saponification provided the chain extended acid moiety V. Method D
Acid isosteres such as tetrazole were prepared from the carboxylic acids I via the nitriles III . Conversion to the nitriles was accomplished through primary amide formation of the acid functionality via the acid chloride with a suitable reagent such as oxalyl chloride and reaction with ammonia followed by a dehydration sequence using a suitable reagent such as oxalyl chloride and a base such as pyridine. The nitriles such as UI could be converted to the tetrazoles by reaction with an azide source such as sodium azide in an appropriate high boiling point solvent such as N-methyl pyrrolidinone to give compounds such as IV.
Method E
Other acid isosteres such as the thiazolidinedione group with longer carbon atom bridges were prepared through a sequence involving the unsaturated aldehyde moiety at the 2-position such as compound IV. Partial reduction of the ester group in I with a suitable reagent such as diisobutyl aluminum hydride or reduction to a hydroxy group with a suitable reagent such as lithium aluminum hydride followed by oxidation to the aldehyde with a suitable oxidizing agent gave the aldehyde II. A Horner-Wittig reaction with trimethoxyphosphonoacetate in a suitable solvent such as tetrahydrofuran gave the unsaturated ester III, which was converted to the aldehyde IV under the conditions described for II. The aldehyde could then be transformed to the thiazolidinedione V using a base such as piperdine and isolated with an acid such as acetic acid.
Method F
2-Indolyl carboxylic acid ethyl ester I is deprotonated with a strong base such as sodium hydride (NaH) in THF, and then reacted with a suitable alkyl bromide to give VI. Hydrolysis of VI witha aqueous base such as sodium hydroxide and reaction with aniline or a substituted aniline in the presence of a carbodiimide such as dimethylaminopropylethyl carbodiimide hydrochloride (EDCI) in a suitable solvent such as dichloromethane affords amide VII. Amide VII is hydrolyzed to corresponding acid VIII in a aqueous base such as sodium hydroxide.
Method G Aldehyde K is prepared from Indol-2-carboxylic acid ethyl ester I in two steps: (1) Reduction with lithium aluminium hydride or other hydride in a suitable solvent such as THF at 0°C and (2) oxidation with an oxidizing reagent such as manganese dioxide in a solvent such as THF. Aldehyde LX can be alkylated by a suitable alkyl bromide (or iodide), such as benzyl bromide or ethyl iodide in the presence of a strong base such as sodium hydride or KHMDS in a solvent such as DMF to yield indole X . Indole X can be converted to an unsaturated acid XI in two steps: (1) Wittig reaction with a suitable reagent such as trimethyl phosphonoacetate in the presence of a base such as sodium hydride in a solvent such as THF and (2) Hydrolysis by aqueous sodium hydroxide.
Method H
Indole I can be converted to II in two steps: (1) reduction with LAH in a solvent such as THF and (2) silylation with t-butyldimethylsilyl chloride (TBDMSC1) in a solvent such as dichloromethane or DMF in the presence of a base such as imidazole. Treatment of II with Grignard reagent such as ethyl magnesium bromide in a solvent such as THF at -60°C, acylation of the resulting magnesium salt with a suitable acyl chloride such as acetyl chloride in ether and finally, alkylation on the nitrogen with an alkyl halide such as ethyl bromide in the presence of a strong base such as NaH in DMF affords ketone III. The silyl group on III is removed using tetrabutylammonium fluoride in a solvent such as THF, the resulting alcohol is then converted to bromide using carbon tetrabromide and bis(diphenylphosphino)ethane in a solvent such as dichloromethane to yield bromide IV. Displacement of the bromine of IV with a thiol compound in the presence of a base such as cesium carbonate, or with an alcohol in the presence of a strong base such as NaH in DMF affords V (sulfide or ether respectively).
Method A
Figure imgf000136_0001
Method B
Figure imgf000137_0001
R5 R1
Figure imgf000137_0002
Method C
Figure imgf000138_0001
Method D
Figure imgf000139_0001
l)(COCl)2, DMF, CH3CN 2) Pyπdine
Figure imgf000139_0002
IV III
Figure imgf000139_0003
Method E
Figure imgf000140_0001
trimethoxyphosphonoacetate
Figure imgf000140_0002
III pipeπdine
Figure imgf000140_0003
METHOD F
Figure imgf000141_0001
R = aikoxy, benzyloxy, phenoxy, halogen, CN, N02,
Figure imgf000141_0002
R' = alkyl, benzyl, alkenyl, alkynyl
R"= halogen, CN, alkyl, aikoxy, alkoxycarbonyl, amido, acyl, H, OH
9/43672
Method G
Figure imgf000142_0001
IX
R'X (Br, I), NaH
Figure imgf000142_0002
R = aikoxy, benzyloxy, phenoxy, halogen, CN, N02, alkyl or aryl R' = alkyl, aryl
Method H
ether
Figure imgf000143_0001
R'"SH, CsC03 \ R'OH, NaH or K2C03
CN, N02, alkyl or aryl
Figure imgf000143_0002
Y = halogen, mesylate
EXAMPLE 88
4-r(5-l(E -r5-(benzyloxy -l -(4-(r3.5- bis(trifluoromethyl)phenoxylmethyUbenzyl)-lH-indol-2-vI1methylidene)-2.4- dioxo-1.3-thiazoIan-3-yl)methyπbenzoic acid
Step 1 - The aldehyde from Example 124, (5.2 g) was suspended in ethanol (150 mL). To the thick slurry was added 2,4-thiazolidinedione (1.28g) and potassium carbonate (6.1g). The mixture was heated in a bath at 60 °C (later dropped to 45 °C). After 1 h TLC showed no reaction. Sodium hydroxide (2.1 g) was added and the mixture was heated at 58 °C. After 45 minutes the TLC showed reaction progress. Additional 2,4-thiazolidinedione (0.1 g) was added. The mixture was stirred overnight at room temperature. The mixture was poured into water (500 mL) and acidified to pH 2 with 6 N HCl, extracted with ethyl acetate, dried (MgSO4) and filtered. Trituration from ethanol afforded an orange solid which was filtered and washed with ethanol to give the desired product (5.74 g, 94%) as an orange solid.
Step 2 - To the material prepared in step 1 (1.1 g) in DMF (15 mL) at 0 °C was added sodium hydride (0.08 g. 60% dispersion in mineral oil). The suspension was stirred for 30 minutes. To the reaction mixture was added the benzyl bromide (0.54 g) and the reaction was stirred overnight. Water was added and the mixture was extracted with ethyl acetate. The combined organic layers were concentrated. Column chromatography (1:6 ethyl acetate: hexane to 1:4 ethyl acetate:hexane) afforded the desired product (1.18 g, 75%) as a yellow solid.
Step 3 - To the material prepared in step 2 (0.34 g) in acetonitrile (15 mL) was added HF (48% aqueous, 3.7 mL) via syringe. The reaction was stirred overnight. The reaction was not complete by TLC therefore THF was added to dissolve the starting material and additional HF (0.6 mL) was added. The reaction was stirred for 2 h after which the TLC showed reaction completion. Water was added which resulted in the formation of a yellow solid. The yellow solid was dissolved in ethyl acetate, washed with brine, dried over MgSO4 and concentrated. The resulting crude solid was suspended in ethanol and stirred for 30 min, filtered and dried to afford the title compound (140 mg, 48%) as a yellow solid.
EXAMPLE 89
5-r(E -(5-(benzyloxy)-l-l3-r3,5-bis(trifluoromethyl)phenoxylpropyll-lH-indol-
2-vI methvIidene1-1.3-thiazolane-2,4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 90 5-((E -(5-(benzyloxy -l-r2.4-bis(trifIuoromethyl benzyll-lH-indol-2- yl}methylidene')-1.3-thiazolane-2,.4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 91
5-((E -r5-(benzyloxy)-l-(4-chlorobenzvn-lH-indol-2-yllmethylidenel-1.3- thiazolane-2.4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 92
5-{(E -r5-(benzyloxy -l-(2-naphthylmethyl)-lH-indol-2-vnmethvIidene}-1.3- thiazolane-2.4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 93
5-l(E -ri-(4-benzyIbenzyl)-5-(benzyloxy -lH-indol-2-yllmethvIidene)-1.3- thiazoIane-2.4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 94
5-1 (E -r5-(benzyloxy)-l-(4-chlorobenzyl)-lH-indol-2-yIlmethylidene 1-1.3- thiazolane-2.4-dione
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 95
5-((E -{5-(benzvIoxy -l-r2.4-bis(trifluoromethyl)benzvn-lH-indol-2- yl)methylidene)-1.3-thiazolane-2.4-dione The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
EXAMPLE 96
2-(5-(fE)-r5-fbenzyloxy)-l-(4-(r3.5- bis(trifIuoromethyl)phenoxy1methyllbenzyl)-lH-indol-2-yllmethylidene}-2.4- dioxo-1.3-thiazolan-3-yl)acetic acid
Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
EXAMPLE 97
4-r(5-((E -r5-(benzyloxy -l-(4-chlorobenzyl)-lH-indol-2-yllmethylidene)-2.4- dioxo-1.3-thiazolan-3-yl)methyllbenzoic acid
Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
EXAMPLE 98
2-(5- EVr5-(benzyloxy)-l-(2-naphthylmethyl)-lH-indol-2yl1methylidene}-2.4- dioxo-lt3-thiazolan-3-yl)acetic acid Step 1- The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
EXAMPLE 99
4-r(5-irE -r5-(benzyloxy)-l-(2-naphthylmethvn-lH-indol-2-yl1methvIidene)-2.4- dioxo-1.3-thiazolan-3-yl)methynbenzoic acid
Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
EXAMPLE 100
2-(5-((E)-r5-(benzyloxy -l-(4-chlorobenzvn-lH-indol-2-yllmethylidene)-2.4- dioxo-1.3-thiazolan-3-yl)acetic acid
Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3. The compounds of the following Examples 101-106 were prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
EXAMPLE 101
5-((E -(5-(benzyloxy -l-r2.4-bis(trifluoromethvI)benzvπ-lH-indoI-2- vIlmethylidene -2-thioxo-1.3-thiazolan-4-one
EXAMPLE 102
5- E -r5-(benzvIoxy -l-(2-naphthylmethvn-lH-indol-2-yllmethylidene}-2- thioxo-1.3-thiazoIan-4-one
EXAMPLE 103
5-r(E)-(5-(benzyloxy)-l-{3-r3.5-bis(trifluoromethyl phenoxylpropyl}-lH-indol- 2-yl)methyIidene1-2-thioxo-1.3-thiazolan-4-one
EXAMPLE 104
5-((E)-r5-(benzyloxy)-l-(4-chIorobenzyl)-lH-indol-2-yllmethylidene}-2-thioxo- 1.3-thiazolan-4-one
Gl 1418 EXAMPLE 105
5-{(E -ri-(4-benzylbenzyl)-5-(benzyloxy)-lH-indoI-2-vIlmethylidene)-2-thioxo- 1.3-thiazolan-4-one
EXAMPLE 106
5-{(E -r5-(benzyloxy)-l-(4-{r3.5-bis(trifluoromethyl)phenoxylmethyl)benzyl)- lH-indol-2-yllmethylidenel-2-thioxo-1.3-thiazolan-4-one
EXAMPLE 107
4-{[5-((E -(5-(benzyloxy)-l-r2.4-bis(trifluoromethvnbenzvIl-lH-indol-2- yl)methvIidene -4-oxo-2-thioxo-1.3-thiazolan-3-yllmethyllbenzoic acid Step 1 - The desired intermediate was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and rhodanine.
Step 2 - The desired intermediate was prepared from the above intermediate as illustrated in Example 88, step 2, using the appropriate alkylating agent.
Step 3 - The title compound was prepared from the above intermediate as illustrated in Example 88, step 3.
EXAMPLE 108
5-((E -{5-(benzyloxy -l-r2.4-bis(trifluoromethvnbenzyll-lH-indol-2- yl}methylidene)-2-thioxotetrahvdro-4H-imidazoI-4-one
The title compound was prepared as illustrated in Example 88, step 1, starting with the appropriate indole and 2-thiohydantoin
EXAMPLE 109 l-benzyl-5-(2-thienyl -lH-indole-2-carboxylic acid
To a sealed tube containing 2-[5-bromo-l -benzyl- lH-indole-2carboxylic acid (100 mg, 0.303 mmol) and 2-thiopheneboronic acid (116 mg, 0.909 mmol), (C6H5)4Pd (42 mg, 0.036 mmol), Na^Oj (2.42 mmol) in a mixture of benzene-ethanol-H2O (5/l/2=v/v, 4.5 mL) was heated at 100 °C for 23 h. The mixture was poured onto diethyl ether and adjusted to pH 3 before extracting with diethyl ether. The organic layer was washed with NaH2PO4, dried over MgSO4 and evaporated to give the crude product which was purified on silica gel column ( 15% EtOAc in hexane with 1% HCOOH) to give 65 mg of the product.
EXAMPLE 110 5-(l-benzofuran-2-yl)-l-benzyl-lH-indole-2-carboxylic acid
The title compound was prepared according to the procedure described in Example 109 except that benzo[b]fran-2-boronic acid was used.
EXAMPLE 111 l-benzyl-5-(4-fluorophenyl)-lH-indole-2-carboxylic acid The title compound was prepared according to the procedure described in Example 109 except that 4-fluorophenylboronic acid was used.
EXAMPLE 112 l-benzyl-5-(3-methoxyphenyl)-lH-indole-2-carboxyIic acid
The title compound was prepared according to the procedure described in Example 109 except that 3-methoxyphenylboronic acid was used.
EXAMPLE 113 l-benzyI-5-phenyl-lH-indoIe-2-carboxylic acid
The title compound was prepared according to the procedure described in Example 109 except that phenylboronic acid was used.
EXAMPLE 114 l-benzhvdryl-5-bromo-lH-indole-2-carboxylic acid
To 5-bromoindole-2-carboxylic acid (1.024 g, 4.26 mmol) in l-methyl-2-pyrrolidinone (13 mL) at 0 °C were added 'Pr2NEt (25.6 mmol), tetrabutylammonium iodide (157 mg, 0.426 mmol) and bromodiphenylmethane (1.20 g, 4.86 mmol). The reaction mixture was heated at 50 °C for 21 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 ( 15% EtOAc in hexane) yielded 1.51 g (87 % yield) of the product.
EXAMPLE 115
5-r3-(acetylamino phenyl1-l-benzhydryl-lH-indole-2-carboxylic acid
The title compound was prepared according to the procedure described in Example 109 except that 3-acetamidobenzeneboronic acid and l-benzhydryl-5-bromo-lH-indole-2-carboxylic acid were used.
EXAMPLE 116 l-benzhvdryl-5-(2-thienyl)-lH-indole-2-carboxylic acid The title compound was prepared according to the procedure described in Example 109 except that l-benzhydryl-5-bromo-lH-indole-2-carboxylic acid and 2-thiopheneboronic acid were used.
EXAMPLE 117A 5-(benzyloxy)-l-[2,4-bis(trifIuoromethyl)benzyl]-lH-indoIe-2-carboxylic acid
Step 1
To an ice-cold (0°C) solution of 2-ethoxycarbonyl-5-benzyloxyindole (5.0g, 16.9mmol) in dimethylformamide (50ml) was added sodium hydride (0.62g, 18.6mmol). The ice bath was removed after lOmin and the reaction was stirred at rt for an addition 30min at which time bis(trifluoromethyl)benzyl bromide (3.8ml, 20.3mmol) was added dropwise. The green mixture was stirred at rt for 4h, water was added and the mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4 and concentrated. The product was recrystallized from EtO Ac/Hex to afford 6.87g (81%) of the desired intermediate as an off-white powder.
Step 2
To a solution of the above intermediate (1.3g, 2.5mmol) in THF (50ml) was added IN NaOH
(5ml) and MeOH (6ml). The mixture was stirred overnight at rt and then concentrated. The residue was suspended in water and acidified with HOAc. The product was extracted with EtOAc, the combined organic layers were washed with brine, dried over MgSO4 and concentrated to afford a quantitative yield of the title compound as an off-white solid.
EXAMPLE 117B
5-[({5-(benzyloxy)-l-[2,4-bis(trifluoromethyl)benzyl]-lH-indol-2- yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyI)oxy]benzoic acid
Step 1
To a solution of the title compound above (0.4g, O.δmmol) in CH2C12 (5ml) and a few drops of DMF was added oxalyl chloride (0.2ml, 2.4mmol). The reaction was stirred for 1.5h and concentrated. The resulting yellow residue was dissolved in CH2C12 (2ml) and added to a solution of the pyridyl aminobenzoate ether (0.24g, 0.8mmol) and pyridine (0.1ml, 0.9mmol) in CH2C12 (8ml). The reaction was stirred overnight at rt, water was added and the product was extracted with CH2C12. The combined organic layers were washed with saturated aqueous NH4C1, water, brine and dried over MgSO4. Concentration and flash chromatography (Hex/EtOAc, 3/2) afforded 0.182g (51%) of the desired intermediate as a tan solid. Step 2
To a solution of the above intermediate (0.136g, 0.2mmol) in THF (3ml), was added LiOH (0.022g, 0.5mmol) and water (0.5ml). The mixture was stirred overnight at rt, concentrated and the resulting residue was suspended in water and acidified with HO Ac. The product was extracted with EtOAc, the combined organic layers were washed with water, brine and dried over MgSO4. Concentration gave 0.122g of the title compound (94%) as a white crystalline solid.
EXAMPLE 117C
5-(benzyloxy)-l-(4-{[3,5-bis(trifluoromethyl)phenoxy]methyl}benzyI)-lH- indoIe-2-carboxylic acid
The procedure in EXAMPLE 117A steps I and 2 were followed using 2-ethoxycarbonyl-5- benzyloxyindole (2.0g, 3.2mmol) and the appropriate alkylating reagent to afford 1.7g (41% for 2 steps) of the title compound as a yellow solid.
EXAMPLE 117D
5-(benzyloxy)-l-(4-{[3,5-bis(trifIuoromethyI)phenoxy]methyI}benzyl)-lH- indoIe-2-carboxyIic acid
The procedure in EXAMPLE 117A steps I and 2 were followed using 2-ethoxycarbonyl-5- benzyloxyindole (2.0g, 3.2mmol) and the appropriate alkylating reagent to afford 1.7g (41% for 2 steps) of the title compound as a yellow solid.
EXAMPLE 118
5-(benzyloxy)-l-[2,4-bis(trifluoromethyI)benzyl]-2-(lH-l,2,3,4-tetraazol-5-yl)- lH-indole.
Step 1
To a suspension of the acid prepared in Example 117A (1.5g, 3.0mmol) in CH2C12 (20ml) was added oxalyl chloride (0.8ml, 9.1mmol) and three drops of DMF. The mixture became homogeneous and was stirred for lh at rt. The reaction was concentrated and redissolved in CH2C12 (5ml) and NH4OH (2.0ml) was added. The biphasic mixture was stirred for 24h and concentrated. The remaining aqueous residue was extracted with CH2C1, and the combined organic layers washed with brine, dried and concentrated to give 1.4g (95%) of the desired intermediate as a yellow powder.
Step 2
To an ice-cold solution of DMF (0.23 ml, 3.0mmol) in CH3CN (10ml) was added oxalyl chloride (0.24ml, 0.28mmol). A white precipitate formed immediately and the solution was stirred for an additional 5 min. A solution of the above intermediate (1.2g, 2.5mmol) in CH3CN (5ml) was added. The resulting yellow-orange solution was stirred for 10 min and pyridine (0.44ml, 5.5mmol) was added. After 5 min the red mixture was partitioned between 10% aqueous HCl and EtOAc. The organic layer was dried and concentrated to give l.Og (84%) of the desired intermediate as a yellow powder.
Step 3
Gl 1563
5-(benzyloxy)- 1 -(4- { [3 ,5-bis(trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indole-2-carboxylic acid
To a solution of the above intermediate (0.94g,2.0mmol) in N-methyl-2-pyrrolidinone (10ml) was added sodium azide (0.39g, 5.9mmol). The mixture was heated at reflux for 2h. The reaction was allowed to cool to rt and poured into 50ml of ice water. The resulting solution was adjusted to pH=2 with 10% aqueous HCl and a tan precipitate formed. The mixture was filtered and washed with EtOAc. Flash chromatography (CH2Cl2/MeOH, 10: 1) gave 0.78g (78%) of the tide compound as a white powder.
EXAMPLE 1 19 benzyl 1 -(4- { [3 ,5-bis(trifluoromethyl)phenoxy]methyl } benzyl)-2-( 1 H- 1 ,2,3 ,4-tetraazol-5-yl)- 1 H- indol-5-yl ether acid was prepared in an analogous manner to Example 118 according to steps 1-3 starting from the acid prepared in EXAMPLE 117C.
EXAMPLE 120
4-(r5-(rE -{5-(benzyloxy)-l-r2.4-bis(trifIuoromethvnhenzyl1-lH-indoI-2- vI}methylidene -4-oxo-2-thioxo-1.3-thiazolan-3-yIlmethvI>benzoic acid Step 1
The thiasolidinedione prepared in Example 101 (O.lg, 0.2mmol), was alkylated by treatment with sodium hydride (0.006g, 0.22mmol), and the bromomethyl SEM ester (0.058g, 0.2mmol) in
DMF (2ml). Flash chromatography (Hex/EtOAc, 4/1) gave 0.073g (50%) of the desired intermediate as a thick oil.
Step 2
To a solution of the above intermediate (0.07g, O.lmmol) in CH3CN (5ml) was added aqueous
48% HF (2ml). After 2h water was added and the product was extracted with EtOAc, the combined organic layers were washed with water, brine and dried over MgSO4. Concentration gave 0.025g of the title compound (42%) as an orange powder.
Example 121
5-((Z,2E)-3-{5-(benzyIoxy)-l-[2,4-bis(trifluoromethyI)benzyl]-lH-indol-2-yl}-2- propenylidene)-l,3-thiazoIane-2,4-dione
Step 1
A solution of the intermediate prepared in EXAMPLE 117A, step 1 (4.4g, 8.4mmol) in THF (30ml) was cooled to 0°C and a solution of lithium aluminum hydride in THF (1.0M, 8.4ml) was added dropwise with vigorous stirring. After lh at 0°C the reaction was carefully quenched with a saturated solution of NH4C1. The salts were filtered and washed with EtOAc. Concentration of the solvents afforded 3.9g (96%) of the alcohol as a yellow foam. The alcohol (1.6g, 3.3mmol) was dissolved in THF (50ml) and MnO2 (2.9 lg, 33.4mmol) was added. The reaction was stirred for 12h and filtered through a pad of Celite. Concentration of the filtrate gave 1.47g (92%) of the desired intermediate as a thick clear oil.
Step 2
To an ice-cold solution of tπmethylphosphonoacetate (0.5ml, 3.1mmol) in DMF (10ml) was added sodium hydπde (0.14g, 3.4mmol) and the reaction was stirred for 20mιn. A solution of the above intermediate (1.47g, 3.1mmol) in DMF (3ml) was added, the ice bath was removed and the reaction was allowed to stir overnight at rt Water was added and the aqueous phase was extracted with EtOAc The organic layer was washed with water, brine, dried over magnesium sulfate and concentrated. Flash chromatography (Hex/EtOAc, 3/2) provided 1 5g (93%) of the desired intermediate as a yellow solid. Step 3
The above intermediate (0.5g, 0.9mmol) was dissolved in CH2C12 (10ml) and the solution was cooled to -20°C. A solution of diisobutylaluminium hydride (1.0M in toluene, 1.9ml) was added dropwise, and the reaction was allowed to stir at rt overnight. Water was added, and the mixture was filtered through a pad of celite. The filtrate was diluted with EtOAc, washed with water and the combined organic layers washed with brine, dried and concentrated. Flash chromatography (Hex EtOAc, 3/2) gave 0.49g (75%) of an orange solid. This material was dissolved in THF (12ml) and MnO2 (l.lg, 12.3mmol) was added. The mixture was stirred overnight and filtered through a pad of Celite. Concentration of the solvent afforded 0.4g (65%) of the desired intermediate as a thick tan oil. Step 4
The above intermediate (O.lg, 0.2mmol) was dissolved in toluene (1ml), followed by piperidine (6μl, 0.1 mmol) acetic acid (1.2μl) and 2,4-thiazolidinedione (0.023g, 0.2mmol). 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 EtOAc. The combined organic layers were washed with water and brine, dried and concentrated. Flash chromatography (Hex/EtOAc, 3/2) gave 0.056g (47%) of the title compound as a red powder.
EXAMPLE 122
5-(benzyloxy -l-(4-ir3.5-bis(trifluoromethyl)phenoxylmethv benzyl)-lH- indole-2-carboxylic acid
Step 1: To ethyl 5-benzyloxy-2-indolcarboxylate (1 g, 3.4 mmol) in 12 ml of DMF, sodium hydride (0.163g, 60% oil dispersion, 4.07 mmol) is added at room temperature. The reaction is stirred for 30 minutes. a-Bromo-a'-[3,5-bis(trifluoromethyl)phenoxyl]-p-xylene (1.54 g, 3.73 mmol) is added at this time and the reaction stirred overnight. On completion of the reaction (monitored by TLC) it is quenched with water, extracted with ethyl acetate (3X). Organic layers are dried over magnesium sulfate, concentrated and used for the next step.
Step 2: The ester ( 2.1 g, 3.39 mmol) is dissolved in 40 mL of 1/1 THF/ methanol and then IN sodium hydroxide (15 mL) is added and the resulting mixture is stirred for 16 hours at RT, workup gave crude product that is purified via chromatography (1:1 Hexane:Ethyl acetate with 1% acetic acid) to yield (1.73 g, 85%) of solid. EXAMPLE 123 5-((ri-benzyl-5-(benzyloxy)-lH-indol-2-yllcarbonyI}amino)isophthalic acid
Step 1: This intermediate was prepared according to the procedure described in Example 122, but using benzyl bromide.
Step 2: The acid (0.27 g, 0.75 mmol) prepared in step 1, EDCI (0.18 g, 0.97 mmol), DMAP (3 mg, 0.02 mmol) and dimethyl-5 aminoisophthalate (0.18g, 0.75 mmol) were dissolved in THF
(8.8 mL) and refluxed for 16 hours, after workup and purification (Hexane:Ethyl Acetate 3: 1) yielded (0.25 g, 60%) of pure product.
Step 3: The title compound was prepared from ester, prepared in step 2 above, according to the procedure described in step 2, Example 122.
EXAMPLE 124
(E -3-r5-(benzyloxy)-l-(2-naphthylmethyl)-lH-indol-2-vIl-2-propenoic acid
Step 1: Ethyl 5-benzyloxy-2-indolcarboxylate (30 g, 102 mmol) is dissolved in 250 mL of THF and cooled to 0° C and Lithium Aluminum Hydride (LAH) (255 mL of a 1.0 M solution in THF) is added via addition funnel over 40 minutes. The reaction was stirred a further 2 hours at 0° C and then worked up by the addition of 4N NaOH (190 mL). The resulting salts are filtered and washed with ethyl acetate (3X400 mL), the filtrates are combined and dried over MgSO4 and concentrated to yield 24.8 g (96%).
Step 2: Indole alcohol (26.1 g, 103 mmol) from step 1 is dissolved in THF (900 ml). Manganese dioxide (106.6 g) is added and the mixture is stirred for 2h at room temperature. After the reaction is complete the mixture is filtered through celite and washed with ethyl acetate. The filtrate is concentrated under reduced pressure, dried to give the desired aldehyde (22.9 g, 89%).
Step 3: This intermediate was prepared from indole, prepared in step 2 above and 2- (bromomethyl)naphthalene, according to the procedure described in step 1, Example 122.
Step 4: To sodium hydride (0.025 g, 60% oil dispersion, 0.63 mmol) in 7.5 mL of THF is added trimethyl phosphonoacetate (0.1 mL, 0.62 mmol) in 2.5 mL of THF at room temperature. The reaction is stirred for 10 minutes. Next the aldehyde (0.24 g, 0.62 mmol) prepared in step 3 above in 2.5 mL THF is added dropwise at room temperature. Reaction is stirred for another 30 minutes NOT FURNISHED UPON FILING
NOT FURNISHED UPON FILING
NOT FURNISHED UPON FILING
NOT FURNISHED UPON FILING
EXAMPLE 133
2-((r3-acetyI-l-r4-(1.3-benzothiazol-2-ylcarbonyI)benzvIl-5-(benzyloxy)-lH- indol-2-yI1methyUsulfanyl)acetic acid
Step 1 p-Toluoyl chloride (0.8 M) was added to triethylamine (2.44 eq) and methoxymethyl amine HCl (1.1 eq) dissolved in methylene chloride at 0°C over 20 min. The reaction was allowed to warm to 25°C. After stirring at 25°C for 1 day, workup with methylene chloride and water afforded crude product in ca. 100% yield.
Step 2 Under anhydrous conditions benzothiazole was dissolved in THF (0.35 M). At -78
°C added BuLi (1.1 eq). After 1 h at -78°C, added the amide from step 1 in THF, over 15 min. The reaction was allowed to warm to 25°C. After stirring at 25°C for 1 day, workup with ethyl acetate and water and chromatography afforded pure tolyl ketone product (52%).
Step 3 The tolyl ketone from step 2 was dissolved in carbon tetrachloride (0.19M), and
NBS (1.2 eq) and AIBN (0.11 eq) were added. After 1 d at 60°C, about 1:1 of starting material and product were present. Resubmission under the same conditions, followed by filtration and recrystallization from ethyl acetate afforded pure bromobenzyl ketone product (28%).
Step 4 The intermediate from step 3, Example 131 was dissolved in dry DMF (0.1 M), followed by NaH (1.2 eq). After 1.5 h at 25 °C, added the bromobenzyl ketone from step 3 and stirred for 1 d at 25°C. Workup (ethyl acetate/hexanes) and trituration (ethyl acetate/hexanes) afforded the product in 46% yield.
Step 5: The product from step 4 was dissolved in methylene chloride and 1 N HCl (ca. 0.04 M) and stirred at 25°C for 1 h. Workup (sodium bicarbonate), and trituration with ether afforded the product alcohol (89%).
Step 6: The alcohol from step 5 was dissolved in dry methylene chloride (0.014 M), treated with thionyl chloride (1.2 eq) and stirred at 25°C for 1 d. Concentration and trituration with ethyl acetate/hexanes afforded the product chloride (100%). NOT FURNISHED UPON FILING
Activity data for the compounds of Examples 88-135 are reported in Table VIII (assay described in Example 136) and Table IX (assay of Example 137).
Example 136 Activity Assays
(a) Vesicle Assay l-palmitoyl-2-[l C] arachidonyl phosphotidylcholine (58 mCi/mmol) (final concentration 6 μM) and 1 ,2-dioleyolglycerol (final concentration 3 μM) were mixed and dried under a stream of nitrogen. To the lipids was added 50 mM Hepes pH 7.5 (2x final concentration of lipids) and the suspension was sonicated for 3 min. at 4°C. To the suspension was added 50 mM Hepes pH 7.5, 300 mM NaCl, 2 mM DTT, 2 mM CaCk and 2 mg/ml bovine serum albumin (BSA) (Sigma A7511) (1.2x final concentration of lipids). A typical assay consisted of the lipid mixture (85 μl) to which was added consecutively, the inhibitor (5 μl in DMSO) and cPLA,, 10 ng for an automated system or 1 ng for a manual assay, in 10μl of the BSA buffer. This assay was conducted by either the manual assay or automated assay protocol described below.
(b) Soluble Substrate Assay (LysoPO l-[l4C]-palmitoyl-2-hydroxyphosphotidyl-choline (57 mCi/mmol) (final concentration 4.4 μM) was dried under a stream of nitrogen. The lipid was resuspended by vortexing 80 mM Hepes pH 7.5, 1 mM EDTA (1.2 x final concentration). A typical assay consisted of lipid suspension (85 μl) to which was added consecutively the inhibitor (5μl in DMSO) and cPLA, 200 ng in 80 mM Hepes pH 7.5, 2 mM DTT and 1 M EDTA. This assay was conducted by either the manual assay or automated assay protocol described below.
NOT FURNISHED UPON FILING
(f) RBL Assay
RBL-2H3 cells were routinely cultured as 37C in a 5 % C02 atmosphere in minimal essential medium containing nonessential amino acids and 12% fetal calf serum. The day before the experiment, cells were seeded into spinner flasks at 3 x 10 cells/ml and 100 ng/ml DNP specific-IgE was added. After 20 hrs, the cells were harvested by centrifugation and washed once in serum-free minimal essential media, and resuspended to 2 x 10 cells/ml in serum free media. The cells were then preincubated with either inhibitor in DMSO (1 % v/v) or DMSO (1 % v/v) for 15 min at 37C followed by stimulation with DNP-BSA (300 ng/ml). After 6 min, the cells were removed by centrifugation, and the supernatant was assayed for PGD^ content in accordance with known methods.
(g) Coumarine Assay
7-hydroxycoumarinyl 6-heptenoate was used as a monomeric substrate for cPLA2 as reported previously (Huang, Z. et al., 1994, Analytical Biochemistry 222, 110-115). Inhibitors were mixed with 200μL assay buffer (80mM Hepes, pH 7.5, 1 mM EDTA) containing 60 μM 7-hydroxycoumarinyl 6- heptenoate. The reaction was initiated by adding 4 μg cPLA2 in 50μL assay buffer. Hydrolysis of the 7-hydroxycoumarinyl 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 increasein emission at 460 nm per minute. In the presence of a cPLA2 inhibitor, the rate of increase is less.
Example 137
Rat Carrageenan-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 comounds remained in solution. Compounds were administered i.v. in a volumne 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 IV carrageenan into the hind footpad. Footpad volume was measured before dosing with compound and 3 hours after dosing with carageenan. 43672
Table VIII
Figure imgf000166_0001
Table VIII
Table VI 11
Figure imgf000168_0001
Table VIII
Figure imgf000169_0001
Table VIII
Figure imgf000170_0001
Table VIII
Figure imgf000171_0001
Table VIII
Figure imgf000172_0001
Table VIII
Figure imgf000173_0001
Table VIII
Figure imgf000174_0001
2
Table VIII
Figure imgf000175_0001
Table VIII
Figure imgf000176_0001
Table VIII
Figure imgf000177_0001
/43672
Table VIII
Figure imgf000178_0001
2
Table VIII
Figure imgf000179_0001
All patent and literature references cited herein are incorporated as if fully set forht herein.

Claims

What is claimed is:
1. A compound having a chemical formula selected from the group consisting of:
Figure imgf000181_0001
Figure imgf000181_0002
or a pharmaceutically acceptable salt thereof, wherein:
A is independent of any other group and is selected from the group consisting of -CH2- and -CH2-CH2-;
B is independent of any other group and is selected from the group consisting of -(CH2)n-, -(CH:0)π-, -(CH2S)n-, -(OCH2)n-, -(SCH2)n-, -(CH=CH)π-, -(C = C)n-, -CON(R,)-, -N(R,)CO-, -0-, -S- and -N(R,)-;
R, is independent of any other R group and is selected from the group consisting of -X-R -H. - OH, halogen, -CN, -NO, C,-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R2 is independent of any other R group and is selected from the group consisting of -H, -COOH, -CORj, -CONRjR,, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C,-Cl0 alkyl, alkenyl and substituted aryl;
R3 is independent of any other R group and is selected from the group consisting of -H, -COOH, -COR5, -CONRjR,, -(CH2)n-W-(CH2)m-Z-R5, -(CH2)n-W-R5, -Z-R5, C,-C10 alkyl, alkenyl and substituted aryl;
R is independent of any other R group and is selected from the group consisting of -H, -OH, - OR,, -SR,, -CN, -COR,, -NHR,, -COOH, -CONR,R7, -NO2, -CONHS02R8, C,-C5 alkyl, alkenyl and substituted aryl;
R5 is independent of any other R group and is selected from the group consisting of -H, -OH, - 0(CH2)nR,, -SR,, -CN, -COR,, -NHR,, -COOH, -N02, -COOH, -CONR,R7, -CONHS02R8, C,-C5 alkyl, alkenyl, alkinyl, aryl, substituted aryl, -CFj, -CF2CF3 and
Figure imgf000182_0001
R, is independent of any other R group and is selected from the group consisting of -H, C-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R7 is independent of any other R group and is selected from the group consisting of -H, C-C5 alkyl, alkenyl, alkinyl, aryl and substituted aryl;
R8 is independent of any other R group and is selected from the group consisting of C-C3 alkyl, aryl and substituted aryl;
R, is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R7, tetrazole, -CONHSQ,R8, -COR,, -(CH2)nCH(OH)R, and - (CH2)πCHR,R5;
R10 is independent of any other R group and is selected from the group consisting of -H, -OH, a halogen, -CN, -OR,, -COOH, -CONR,R7, tetrazole, -CONHSC^Rs, -COR,, -(CH2)nCH(OH)R, and -(CH2)nCHR,R5;
W is, independently each time used including within the same compound, selected from the group consisting of -0-, -S-, -CR-, -CH =CH-, -C Γëí C- and -N(R,)-;
X is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -0-, -S- and -N(R6)-;
Z is independent of any other group and is, independently each time used including within the same compound, selected from the group consisting of -CH-, -0-, -S-, -N(R,)-, -CO-, -CON(R,)- and -N(R,)CO-; m is, independently each time used including within the same compound, an integer from 0 to 4; and n is independent of m and is, independently each time used including within the same compound, an integer from 0 to 4.
2. The compound of claim 1 having phospholipase enzyme inhibiting activity.
The compound of claim 1 wherein said compound has the following chemical formula:
Figure imgf000183_0001
The compound of claim 1 wherein said compound has the following chemical formula:
Figure imgf000183_0002
5. The compound of claim 1 wherein compound has the following chemical formula:
Figure imgf000183_0003
6. The compound of claim 1 wherein A is -CH- and R2 is -(CH2)n-W-(CH2)m-ZR5
7. The compound of claim 6 wherein n is 1 , m is 1 , W is -S- and Z is -CO-.
8. The compound of claim 7 wherein R; is -NHR,.
9. The compound of claim 8 wherein R is a substituted aryl group.
10. The compound of claim 9 wherein said aryl group is substituted with one or more substituents independently selected from the group consisting of a halogen, -CF,
-CF2CF3, -(CH2)pCOOH, -(CH2)pCH3, -0(CH2)pCH3, -(CH2)pOH, -(CH2)pS(C,H6),
-(CH2)pCONH2 and -CHR,,COOH, wherein R,, is selected froup the group consisting of alkyl, alkenyl, alkynyl, -(CH2)pOH, and -0(CH2)pCH3, and wherein p is an integer from 0 to 4.
11. The compound of claim 6 wherein R; is selected from the group consisting of -H and - OCH2(QH,).
12. The compound of claim 6 wherein Rj is -COR5, R5 is -OCH2R, and R, is a substituted aryl group.
13. The compound of claim 12 wherein said aryl group is substituted with one or more substituents selected from the group consisting of -CF5, -CF2CF3 and
-C(CH3)2CH2CH3.
14. A method of inhibiting the phospholipase enzyme activity of an enzyme, comprising administering to a mammalian subject a therapeutically effective amount of a compound of claim 1.
15. A method of treating an inflammatory condition, comprising administering to a mammalian subject a therapeutically effective amount of a compound of claim 1.
16. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
17. A compound of the formula:
Figure imgf000185_0001
wherein
R, and Rr are independently selected from C,-C6 alkyl, -Z-C,-C6 alkyl, phenyl, -(CH2)n- Z-(CH2)n-phenyl, benzyl, -(CH2)n-Z-(CH2)n-benzyl, napthyl, -(CH2)n-Z-(CH2)π-napthyl, pyrimidinyl, -(CH2)n-Z-(CH2)n-pyrimidinyl, the alkyl, phenyl, benzyl, napthyl and pyrimidinyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, CrC6 alkyl, C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3, or -OH;
Z is O or S;
n is an integer from 0 to 3;
R2 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, C,-CI0 aikoxy, -CHO, -CN, - NO2, -NH,, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-C,-C6 alkyl, or -SO2-C,-C6 alkyl;
R3 is selected from H, halogen, -CF3, -OH, -C,-C!0 alkyl, C,-C]0 aikoxy, -CHO, - C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO-- C,-C6 alkyl, -SO2-C,-C6 alkyl or a moiety of the formula:
Figure imgf000185_0002
n in each appearance is independently selected as an integer selected from 0-3; R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(Cr C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000186_0001
R12 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CrC6 alkyl, -O-C,- C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
L1 is selected from -(CH2)n-O-, -(CH2)ΓÇ₧-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH2)ΓÇ₧-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000187_0001
R1U is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-CrC6 alkyl,
Figure imgf000187_0002
with a proviso that the moiety or combination of moieties comprising R3 include an acidic *roup selected from carboxylic acid or a moiety of the formulae:
Figure imgf000187_0003
R5 is selected from:
a) a moiety of the formula -L 2 -M Λ f2.
L2 is selected from a chemical bond or a bridging group selected from -(CH2)n-Z-, -(CH2)π-Z-(CH2)n-, -C(O)-O-, -C(O)-(CH2)„-O-, -C(O)-N-, or -(CH2)π-S-(CH2)n-C(O)-N-;
M2 is selected from -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000188_0001
wherein R8 and R9 are as defined above and can be substituted anywhere on the cyclic or bicyclic ring; or
b) a moiety of the formulae:
Figure imgf000188_0002
wherein IJ is a chemical bond or a group selected from -CH2- , -CH2-Z- , -C(O)- , -O-, -S- , or -(CH2)n-Z-(CH2)n-;
M3 is selected from -(CH2)n-C3-C5 cycloalkyl, furanyl, thienyl, pyrrolyl,
Figure imgf000189_0001
or a pharmaceutically acceptable salt thereof.
18. A compound of Claim 17 of the formula:
Figure imgf000189_0002
wherein R' and R2 are hydrogen, and the moieties R3, R4, R5, R8, R9 and R , n, L\ L~, M1 and M2 are as defined in Claim 17, or a pharmaceutically acceptable salt thereof.
19. A compound of the formula:
Figure imgf000190_0001
wherein
R, is selected from -O-Cj-C6 alkyl, -S-Cj-C6 alkyl, -O-phenyl, -S-phenyl, -O-benzyl, -S- benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3, or -OH;
R2 is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -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 H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)., - N-SO2-C,-C6 alkyl, -SO2-C,-C6 alkyl, or a moiety of the formula:
Figure imgf000190_0002
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,- C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is the moiety -L'-M1 or
Figure imgf000191_0001
L1 is selected from a chemical bond or a bridging group selected from -(CH2)n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)π-, -(CH2)n-S-(CH2)π-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is the moiety:
Figure imgf000191_0002
R'° is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000191_0003
Figure imgf000192_0001
with a proviso that the combination of moieties comprising R4 include a carboxylic acid or a moiety of the formulae:
Figure imgf000192_0002
R, is a structure of the formula -L 2 -MA~l;.
L2 is selected from a chemical bond or a bridging group selected from -(CH2)n-O-, -(CH2)π-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -C(O)-O-, -C(O)-(CH2)n-O-, -C(O)-N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M2 is selected from -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000192_0003
wherein R , R9 and R are as defined above; or a pharmaceutically acceptable salt thereof.
20. A compound of Claim 19 of the formula:
Figure imgf000193_0001
wherein
R, is selected from -O-Cj-C8 alkyl, -S-C,-C6 alkyl, -O-phenyl, -O-benzyl, -S-benzyl, the alkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3, or -OH;
R3 is selected from H, halogen, -CF3, -OH, -CrC10 alkyl, preferably -C,-C10 alkyl, CrC,0 aikoxy, preferably C,-CI0 aikoxy, -CHO, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2-CrC6 alkyl, -SO2-C,-C6 alkyl or a moiety of the formula:
Figure imgf000193_0002
wherein R4, R5, R8, R9 and R10 are as defined in Claim 19, or a pharmaceutically acceptable salt thereof.
21. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
22. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of Claim 19, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
23. A compound of the formula:
Figure imgf000194_0001
wherein
R, and R,, are independently selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, -S-C,-Cl0 alkyl, preferably -S-C,-C6 alkyl, C,-C10 aikoxy, preferably C,- C6 aikoxy, -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,-C10 aikoxy, preferably C,-C6 aikoxy, -NO2, -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 aikoxy, preferably C,-C6 aikoxy, -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,-CI0 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a moiety of the formulae:
Figure imgf000195_0001
Figure imgf000195_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, C,-C10 aikoxy, preferably C,-C6 aikoxy, 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,-CI0 aikoxy, preferably CrC6 aikoxy, -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,-C10 aikoxy, preferably C,-C6 aikoxy, -NH2, -(CH2)π-NH2, -NH-(C,-C6 alkyl), - N-(C,-C6 alkyl)2, -(CH2)n-NH-(CrC6 alkyl), -(CH2)π-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 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 Cm alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -NO,, -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,-CI0 alkyl, preferably CrC6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -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,-C10 alkyl, preferably C,-C6 alkyl, C,-CI0 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, - NH2, -CN, -CF3 or -OH;
n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2; R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C,0 alkyl, preferably C,-C6 alkyl, C,-C,0 aikoxy, preferably C,-C6 aikoxy, -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 H, halogen, -CF3, -OH, -C1-C10 alkyl, C,-C10 aikoxy, -CHO, - C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2- Cj-Cg alkyl, -SO2-C,-C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C6 cycloalkyl), -C(O)-OH, C(O)-C,-C6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)- CF3, -(CH2)n-S-CH2-(C3-C5 cycloalkyl), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000197_0001
n in each appearance is an integer independently selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,- C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000197_0002
Figure imgf000198_0001
R12 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from halogen, -CF3, -OH, -COOH, -(CH2)ΓÇ₧-COOH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,- C6 alkyl, -NH(C,-C6 alkyl), or -N(C,-C6 alkyl)2;
L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)n-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(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-, -C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)n-O-, -C(O)- N-, or -(CH2)_-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000198_0002
' *(C╬╣-C6 lower haloalkyl;
Figure imgf000199_0001
Figure imgf000199_0002
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000199_0003
R9 in each appearance is 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 H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -CrC6 alkyl, -O-C,-C6 alkyl,
Figure imgf000200_0001
lower alkyl
Figure imgf000200_0002
Figure imgf000200_0004
lower haloalkyl;
Figure imgf000200_0003
Rn is selected from H, C,-C6 lower alkyl, C,-C6 cycloalkyl, -CF3, -COOH, -(CH2)n- COOH, -(CH2)n-C(O)-COOH,
Figure imgf000200_0005
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000200_0006
Figure imgf000201_0001
R5 is selected from C,-C6 lower alkyl, C,-C6 lower aikoxy, -(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)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 imgf000201_0002
(CH2)^ (CHϋJrt
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 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, 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, Cj-C^ aikoxy, preferably C,-C6 aikoxy, -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,-C10 alkyl, preferably Cj-C6 alkyl, CrC10 aikoxy, preferably C,-C6 aikoxy, -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,-C10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -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 imgf000202_0001
wherein
D is H, CrC6 lower alkyl, C,-C6 lower aikoxy, -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 aikoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
24. A compound of Claim 23 having the formula:
Figure imgf000203_0001
wherein
R, is selected from H, halogen, -CF3, -OH, -C,-C10 alkyl, preferably -C,-C6 alkyl, -S-C,- C10 alkyl, preferably -S-C,-C6 alkyl, C,-C10 aikoxy, preferably CrC6 aikoxy, -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) furan, pyrrole, or thiophene, being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C]0 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -NO2, -NH2, -CN, -CF3; or
b) pyridine, pyrimidine, piperidine, or morpholine, each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl. C,-C10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
c) benzofuran, indole, napthalene, purine, or quinoline, each being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, C,-CI0 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; or
d) a moiety of the formulae:
Figure imgf000204_0001
Z is O or S;
R6 is selected from the relevant members of the group H, -CF3, C,-C10 alkyl, preferably CΓC6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, 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 aikoxy, preferably C,-C6 aikoxy, -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,-C10 aikoxy, preferably C,-C6 aikoxy, -NH2, -(CH2)n-NH2, -NH-(C,-C6 alkyl), - N-(CrC6 alkyl)2, -(CH2)n-NH-(C,-C6 alkyl), -(CH2)n-N-(C,-C6 alkyl)2, phenyl, -O-phenyl, benzyl, or -O-benzyl, furan, pyrrole, thiophene, pyridine, pyrimidine, thiazole, pyrazole, or morpholine the rings of these groups being optionally substituted by from 1 to 3 substituents selected from halogen, C,-C10 alkyl, preferably C,-C6 alkyl, CrC10 aikoxy, preferably C,-C6 aikoxy, -CHO, -NO2, -NH2, -CN, -CF3 or -OH; n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-C10 alkyl, preferably C,-C6 alkyl, C,-C,0 aikoxy, preferably C,-C6 aikoxy, -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 H, halogen, -CF3, -OH, -C,-CI0 alkyl, C,-C10 aikoxy, -CHO, -C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2- C,-C6 alkyl, -SOj-Cj- alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C5 cycloalky), -C(O)-OH, C(O)-C,-C6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)-CF3, or -(CH2)n-S-CH2-(C3-C5 cycloalky), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, C,-C6 alkyl, C,-C6 aikoxy, -NO2, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000205_0001
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)π-C(O)-COOH, -CF3, -OH, -(CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(Cr C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000205_0002
Figure imgf000206_0001
R12 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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;
L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)π-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)-(CH2)π-, -(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)„-, -C(Z)-NH-SO2-, -C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)n-O-, -C(O)- N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000206_0002
(C-╬╣-06 lower haloalkyl;
Figure imgf000207_0001
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000207_0002
R9 in each appearance is 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;
R'┬░ is selected from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000208_0001
Figure imgf000208_0002
lower alkyl
Figure imgf000208_0003
lower haloalkyl;.
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000208_0004
R5 is selected from C,-C6 lower alkyl, C,-C6 lower aikoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-CI0 cycloalkyl, -(CH2)n-O-(CH2)n-C3-C10 cycloalkyl, -(CH2)n-phenyl-O- phenyl, -(CH2)n-phenyl-CH2-phenyl, -(CH2)n-O-phenyl-CH2-phenyl, -(CH2)π-phenyl-(O-CH2- phenyl)2, -CH2-phenyl-C(O)-benzothiazole or a moiety of the formulae -(CH2)π-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000209_0001
D is H, C,-C6 lower alkyl, C,-C6 lower aikoxy, -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 aikoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
25. A compound of Claim 24 having the formula:
Figure imgf000209_0002
wherein
R, is selected from H, halogen, -CF3, -OH, -C C10 alkyl, preferably -CrC6 alkyl, -S-C,- C10 alkyl, preferably -S-C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, -CN, -NO2, -NH2, phenyl, -O-phenyl, -S-phenyl, benzyl, -O-benzyl, -S-benzyl; or furan, pyrrole, or thiophene, bonded to the indole ring by a chemical bond or a -S-, -O- or -(CH2)n- bridge, the phenyl, benzyl, furan, pyrrole, or thiophene rings being optionally substituted by from 1 to 3 substituents selected from halogen, CrC10 alkyl, preferably C,-C6 alkyl, C,-C10 aikoxy, preferably C,-C6 aikoxy, - NO2, -NH2, -CN, -CF3; or
n is an integer from 0 to 3, preferably 1 to 3, more preferably 1 to 2;
R2 is selected from H, halogen, -CN, -CHO, -CF3, -OH, C,-CI0 alkyl, preferably C,-C6 alkyl, C,-CI0 aikoxy, preferably CrC6 aikoxy, -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 H, halogen, -CF3, -OH, -C,-C10 alkyl, C,-C10 aikoxy, -CHO, -C(O)CH3, -C(O)-(CH2)n-CF3, -CN, -NO2, -NH2, -NH-C,-C6 alkyl, -N(C,-C6 alkyl)2, -N-SO2- CrC6 alkyl, -SO2-C,-C6 alkyl, phenyl, phenyloxy, benzyl, benzyloxy-C(O)-phenyl, -C(O)- benzyl, -CH2-(C3-C5 cycloalky), -C(O)-OH, C(O)-C,-C6 alkyl, -C(O)-O-C,-C6 alkyl, -C(O)-CF3, or -(CH2)n-S-CH2-(C3-C5 cycloalky), the rings of the relevant R3 groups being optionally substituted by from 1 to 3 groups selected from halogen, CrC6 alkyl, C,-C5 aikoxy, -NO2, -CF3, - C(O)-OH, or -OH; or a moiety of the formula:
Figure imgf000210_0001
n in each appearance is independently selected as an integer selected from 0-3;
R8 and R9 are independently selected in each appearance from H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, -(CH2)π-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl, -NH(C,- C6 alkyl), or -N(C,-C6 alkyl)2;
R4 is selected from -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CH=CH-COOH, tetrazole, -(CH2)n-tetrazole, the moiety -L'-M1 or a moiety of the formulae:
Figure imgf000211_0001
R'2 is selected from H, -CF3, C,-C6 alkyl, -(CH2)n-C3-C6 cycloalkyl, phenyl, or benzyl, the cycloalkyl, phenyl or benzyl groups being optionally substituted by from 1 to 3 groups selected from 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;
L1 is selected from -(CH2)n-, -S-, -O-, -C(O)-, -C(O)-O-,-(CH2)π-O-, -(CH2)n-S-, -(CH2)n-O-(CH2)n-, -(CH2)n-S-(CH2)n-, -(CH2)n-C(O)-(CH2)n-, -(CH2)n-O-(CH2)π-, -(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-, -C(Z)-NH-SO2-(CH2)n-, -C(O)-(CH2)π-O-, -C(O)- N-, or -(CH2)n-S-(CH2)n-C(O)-N-;
M1 is -COOH or a moiety selected from:
Figure imgf000211_0002
Figure imgf000212_0001
lower haloalkyl;
Figure imgf000212_0002
Figure imgf000212_0003
R8, in each appearance, is independently selected from H, -COOH, -(CH2)n-COOH, (CH2)n-C(O)-COOH, tetrazole,
Figure imgf000212_0004
R9 in each appearance is 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 H, -COOH, -(CH2)n-COOH, -(CH2)n-C(O)-COOH, -CF3, -OH, (CH2)n-C(O)-COOH, -C,-C6 alkyl, -O-C,-C6 alkyl,
Figure imgf000213_0001
lower alkyl
Figure imgf000213_0002
with a proviso that the moiety or combination of moieties comprising R4 include an acidic group selected from carboxylic acid, a tetrazole or a moiety of the formulae:
Figure imgf000213_0003
R5 is selected from C,-C6 lower alkyl, C,-C6 lower aikoxy, -(CH2)n-C3-C10 cycloalkyl, -(CH2)n-S-(CH2)n-C3-C10 cycloalkyl, -(CH2)π-O-(CH2)n-C3-C10 cycloalkyl, -(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 -(CH2)n-A, -(CH2)n-S-A, or -(CH2)n-O-A, wherein A is the moiety:
Figure imgf000214_0001
D is H, C,-C6 lower alkyl, C,-C6 lower aikoxy, -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 aikoxy, -NH2 or -NO2; or a pharmaceutically acceptable salt thereof.
26. A compound of Claim 1 which is 4-[(5-{(E)-[5-(benzyloxy)-l-(4-{ [3,5-bis (trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indol-2-yl]methylidene } -2,4-dioxo- 1 ,3-thiazolan-3- yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
27. A compound of Claim 1 which is 5-[(E)-(5-(benzyloxy)-l-{3-[3,5-bis (trifluoromethyl)phenoxy]propyl } - 1 H-indol-2-yl)methylidene]- 1 ,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
28. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-l-[2,4-bis (trifluoromethyl)benzyl]- 1 H-indol-2-yl } methylidene)- 1 ,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
29. A compound of Claim 1 which is 5- { (E)-[5-(benzyloxy)- 1 -(4-chlorobenzyl)- 1 H- indol-2-yl]methylidene}-l,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
30. A compound of Claim 1 which is 5-{ (E)-[5-(benzyloxy)-l-(2-naphthylmethyl)-lH- indol-2-yl]methylidene}-l,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
31. A compound of Claim 1 which is 5-{(E)-[l-(4-benzylbenzyl)-5-(benzyloxy)-lH- indol-2-yl]methylidene}-l,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
32. A compound of Claim 1 which is 5- { (E)- [5-(benzyloxy)- 1 -(4-chlorobenzyl)- 1 H- indol-2-yl]methylidene}-l,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
33. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]- 1 H-indol-2-yl } methy lidene)- 1 ,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
34. A compound of Claim 1 which is 2-(5-{(E)-[5-(benzyloxy)-l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl } benzyl)- 1 H-indol-2-yl]methylidene } -2,4-dioxo- 1 ,3- thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
35. A compound of Claim 1 which is 4-[(5-{ (E)-[5-(benzyloxy)-l-(4-chlorobenzyl)- lH-indol-2-yl]methylidene} -2,4-dioxo- l,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
36. A compound of Claim 1 which is 2-(5-{(E)-[5-(benzyloxy)-l-(2-naphthylmethyl)- lH-indol-2yl]methylidene}-2,4-dioxo-l,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
37. A compound of Claim 1 which is 4-[(5-{(E)-[5-(benzyloxy)-l-(2-naphthylmethyl)- lH-indol-2-yl]methylidene}-2,4-dioxo-l,3-thiazolan-3-yl)methyl]benzoic acid or a pharmaceutically acceptable salt thereof.
38. A compound of Claim 1 which is 2-(5- { (E)-[5-(benzyloxy)- 1 -(4-chlorobenzyl)- 1 H- indol-2-yl]methylidene } -2,4-dioxo- l,3-thiazolan-3-yl)acetic acid or a pharmaceutically acceptable salt thereof.
39. A compound of Claim 1 which is 5-((E)- { 5-(benzyloxy)- 1 -[2,4- bis(trifluoromethyl)benzyl]-lH-indol-2-yl}methylidene)-2-thioxo-l,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
40. A compound of Claim 1 which is 5-{(E)-[5-(benzyloxy)-l-(2-naphthylmethyl)-lH- indol-2-yl]methylidene}-2-thioxo-l,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
41. A compound of Claim 1 which is 5-[(E)-(5-(benzyloxy)-l-{3-[3,5- bis(trifluoromethyl)phenoxy]propyl } - 1 H-indol-2-yl)methylidene]-2-thioxo- 1 ,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
42. A compound of Claim 1 which is 5- {(E)-[5-(benzyloxy)-l -(4-chlorobenzyl)- 1H- indol-2-yl]methylidene}-2-thioxo-l,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
43. A compound of Claim 1 which is 5-{(E)-[l-(4-benzylbenzyl)-5-(benzyloxy)-lH- indol-2-yl]methylidene}-2-thioxo-l,3-thiazolan-4-one or a pharmaceutically acceptable salt thereof.
44. A compound of Claim 1 which is 5-{(E)-[5-(benzyloxy)-l-(4-{[3,5- bis(trifluoromethyl)phenoxy]methyl }benzyl)- 1 H-indol-2-yl]methylidene } -2-thioxo- 1 ,3-thiazolan- 4-one or a pharmaceutically acceptable salt thereof.
45. A compound of Claim 1 which is 4-{ [5-((E)-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-lH-indol-2-yl}methylidene)-4-oxo-2-thioxo-l,3-thiazolan-3- yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof.
46. A compound of Claim 1 which is 5-((E)-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]- 1 H-indol-2-yl } methylidene)-2-thioxotetrahydro-4H-imidazol-4-one or a pharmaceutically acceptable salt thereof.
47. A compound of Claim 1 which is l-benzyl-5-(2-thienyl)-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
48. A compound of Claim 1 which is 5-( 1 -benzofuran-2-yl)- 1 -benzyl- 1 H-indole-2- carboxylic acid or a pharmaceutically acceptable salt thereof.
49. A compound of Claim 1 which is 1 -benzyl-5-(4- fluorophenyl)- lH-indole-2- carboxylic acid or a pharmaceutically acceptable salt thereof.
50. A compound of Claim 1 which is l-benzyl-5-(3-methoxyphenyl)-lH-indole-2- carboxylic acid or a pharmaceutically acceptable salt thereof.
51. A compound of Claim 1 which is l-benzyl-5-phenyl-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
52. A compound of Claim 1 which is l-benzhydryl-5-bromo-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
53. A compound of Claim 1 which is 5-[3-(acetylamino)phenyl]-l-benzhydryl-lH- indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
54. A compound of Claim 1 which is l-benzhydryl-5-(2-thienyl)-lH-indole-2- carboxylic acid or a pharmaceutically acceptable salt thereof.
55. A compound of Claim 1 which is 5-[({5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-lH-indol-2-yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof.
56. A compound of Claim 1 which is 5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
57. A compound of Claim 1 which is 5-(benzyloxy)-l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
58. A compound of Claim 1 which is 5-[({5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-lH-indol-2-yl}carbonyl)amino]-2-[(5-chloro-3-pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof.
59. A compound of Claim 1 which is 5-(benzyloxy)-l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indole-2 -carboxylic acid or a pharmaceutically acceptable salt thereof.
60. A compound of Claim 1 which is 4-{ [5-((E)-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]- 1 H-indol-2-yl } methylidene)-4-oxo-2-thioxo- 1 ,3-thiazolan-3- yl]methyl}benzoic acid or a pharmaceutically acceptable salt thereof.
61. A compound of Claim 1 which is 5-((Z,2E)-3-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]- lH-indol-2-yl }-2-propenylidene)- 1 ,3-thiazolane-2,4-dione or a pharmaceutically acceptable salt thereof.
62. A compound of Claim 1 which is 5-(benzyloxy)-l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
63. A compound of Claim 1 which is 5-({ [l-benzyl-5-(benzyloxy)-lH-indol-2- yl]carbonyl}amino)isophthalic acid or a pharmaceutically acceptable salt thereof.
64. A compound of Claim 1 which is (E)-3-[5-(benzyloxy)-l-(2-naphthylmethyl)-lH- indol-2-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof.
65. A compound of Claim 1 which is (E)-3-{5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-lH-indol-2-yl}-2-propenoic acid or a pharmaceutically acceptable salt thereof.
66. A compound of Claim 1 which is (E)-3-[5-(benzyloxy)-l -(4-chlorobenzyl)- 1H- indol-2-yl]-2-propenoic acid or a pharmaceutically acceptable salt thereof.
67. A compound of Claim 1 which is l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl} benzyl)- lH-indole-2-carboxylic acid or a pharmaceutically acceptable salt thereof.
68. A compound of Claim 1 which is 5-({ [5-(benzyloxy)-l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indol-2-yl]carbonyl}amino)-2-[(5-chloro-3- pyridinyl)oxy]benzoic acid or a pharmaceutically acceptable salt thereof.
69. A compound of Claim 1 which is 3-({ [l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indol-2-yl]carbonyl}amino)benzoic acid or a pharmaceutically acceptable salt thereof.
70. A compound of Claim 1 which is 2-[4-({ [l-(4-{ [3,5- bis(trifluoromethyl)phenoxy]methyl}benzyl)-lH-indol-2-yl]carbonyl}amino)phenyl]acetic acid or a pharmaceutically acceptable salt thereof.
71. A compound of Claim 1 which is 3-{ [3-acetyl-5-(benzyloxy)-l-(2- naphthylmethyl)-lH-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof.
72. A compound of Claim 1 which is 4-{[5-(benzyloxy)-l-(2-naphthylmethyl)-3- (2,2,2-trifluoroacetyl)-lH-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof.
73. A compound of Claim 1 which is 3-{[5-(benzyloxy)-l-[2,4- bis(trifluoromethyl)benzyl]-3-(2,2,2-trifluoroacetyl)-lH-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof.
74. A compound of Claim 1 which is 2-({[3-acetyl-l-[4-(l,3-benzothiazol-2- ylcarbonyl)benzyl]-5-(benzyloxy)-lH-indol-2-yl]methyl}sulfanyl)acetic acid or a pharmaceutically acceptable salt thereof.
75. A compound of Claim 1 which is 2-({ [3-acetyl-l-[4-(l,3-benzothiazol-2- ylcarbonyl)benzyl]-5-(benzyloxy)-lH-indol-2-yl]methyl}sulfanyl)benzoic acid or a pharmaceutically acceptable salt thereof.
76. A compound of Claim 1 which is 4-{[3-acetyl-l-[4-(l,3-benzothiazol-2- ylcarbonyl)benzyl]-5-(benzyloxy)-lH-indol-2-yl]methoxy}benzoic acid or a pharmaceutically acceptable salt thereof.
PCT/US1999/003388 1998-02-25 1999-02-17 Inhibitors of phospholipase a2 WO1999043672A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
IL13754099A IL137540A0 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
EEP200000522A EE200000522A (en) 1998-02-25 1999-02-17 Phospholipase A2 Enzyme Inhibitor, a Pharmaceutical Composition Containing It and a Method for Inhibiting the Phospholipase Enzyme Activity
CA002322163A CA2322163A1 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
SK1278-2000A SK12782000A3 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
KR1020007009459A KR20010041346A (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase A2
AU32970/99A AU3297099A (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
JP2000533428A JP2002504551A (en) 1998-02-25 1999-02-17 Phospholipase A2 inhibitor
HU0100156A HUP0100156A3 (en) 1998-02-25 1999-02-17 Indole derivatives as inhibitors of phospholipase a2 and use of them for producing pharmaceutical compositions
EA200000873A EA200000873A1 (en) 1998-02-25 1999-02-17 Phospholipase A Inhibitors
EP99936073A EP1062216A1 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2
HR20000513A HRP20000513A2 (en) 1998-02-25 2000-07-31 Inhibitors of phospholipase a2
NO20004217A NO20004217L (en) 1998-02-25 2000-08-23 Inhibitors of phospholipase A2
BG104781A BG104781A (en) 1998-02-25 2000-09-19 Inhibitors of phospholipase a2

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US3010298A 1998-02-25 1998-02-25
US09/030,102 1998-02-25

Publications (2)

Publication Number Publication Date
WO1999043672A1 true WO1999043672A1 (en) 1999-09-02
WO1999043672A9 WO1999043672A9 (en) 2000-05-04

Family

ID=21852517

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/003388 WO1999043672A1 (en) 1998-02-25 1999-02-17 Inhibitors of phospholipase a2

Country Status (19)

Country Link
EP (1) EP1062216A1 (en)
JP (1) JP2002504551A (en)
KR (1) KR20010041346A (en)
CN (1) CN1298404A (en)
AU (1) AU3297099A (en)
BG (1) BG104781A (en)
BR (1) BR9909242A (en)
CA (1) CA2322163A1 (en)
EA (1) EA200000873A1 (en)
EE (1) EE200000522A (en)
HR (1) HRP20000513A2 (en)
HU (1) HUP0100156A3 (en)
ID (1) ID26123A (en)
IL (1) IL137540A0 (en)
NO (1) NO20004217L (en)
PL (1) PL342516A1 (en)
SK (1) SK12782000A3 (en)
TR (1) TR200002445T2 (en)
WO (1) WO1999043672A1 (en)

Cited By (114)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001053275A2 (en) * 2000-01-17 2001-07-26 Bayer Aktiengesellschaft Substituted aryl ketones
WO2002000620A1 (en) * 2000-06-27 2002-01-03 Smithkline Beecham Corporation Fatty acid synthase inhibitors
WO2002005796A2 (en) * 2000-07-14 2002-01-24 Eli Lilly And Company Use of a spla2 inhibitor for the treatment of sepsis
WO2002053534A1 (en) * 2000-12-28 2002-07-11 Daiichi Pharmaceutical Co., Ltd. Vla-4 inhibitors
WO2002094830A2 (en) * 2001-05-23 2002-11-28 Merck Frosst Canada & Co. DIHYDROPYRROLO[1,2-A]INDOLE AND TETRAHYDROPYRIDO[1,2-a]-INDOLE DERIVATIVES AS PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS
US6525083B2 (en) 2000-07-25 2003-02-25 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
US6635771B2 (en) 2001-12-03 2003-10-21 Wyeth N-benzhydryl indole compounds
US6797708B2 (en) 2001-12-03 2004-09-28 Wyeth Inhibitors of cytosolic phospholipase A2
US6872744B2 (en) 2001-09-27 2005-03-29 Syntex (U.S.A.) Llc Indole derivatives as anti-inflammatory agents
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
US7022714B2 (en) 2002-07-31 2006-04-04 Euro-Celtique S.A. Aryl substituted benzimidazoles and their use as sodium channel blockers
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)
US7074817B2 (en) 2001-06-20 2006-07-11 Wyeth Substituted indole 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)
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
WO2006077364A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
WO2006077366A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
WO2006077367A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflamation
WO2006077365A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
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
US7163954B2 (en) 2003-09-25 2007-01-16 Wyeth Substituted naphthyl benzothiophene acids
EP1747003A1 (en) * 2004-05-03 2007-01-31 Ilypsa, Inc. Phospholipase inhibitors localized in the gastrointestinal lumen
US7183309B2 (en) 2004-10-27 2007-02-27 Janssen Pharmaceutica N.V. Indole derivatives useful as progesterone receptor modulators
US7186746B2 (en) 2002-08-29 2007-03-06 Merck & Co., Inc. Indoles having anti-diabetic activity
WO2007048847A2 (en) * 2005-10-28 2007-05-03 Nikem Research S.R.L. Indole and azaindole derivatives for the treatment of inflammatory and autoimmune diseases
EP1814865A2 (en) * 2004-09-21 2007-08-08 Athersys, Inc. Benzimidazole acetic acids exhibiting crth2 receptor antagonism and uses thereof
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)
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
US7291639B2 (en) 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful as inhibitors of plasminogen activator inhibitor-1 (PAI-1)
WO2008009924A2 (en) * 2006-07-18 2008-01-24 Biolipox Ab Indoles useful in the treatment of inflammation
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)
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-1 (PAI-1)
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
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
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
US7528262B2 (en) 2005-10-14 2009-05-05 Athersys, Inc. Indole derivatives as histamine 3 receptor inhibitors for the treatment of cognitive and sleep disorders, obesity and other CNS disorders
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
US7666898B2 (en) 2005-11-03 2010-02-23 Ilypsa, Inc. Multivalent indole compounds and use thereof as phospholipase-A2 inhibitors
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US7691894B2 (en) 2003-07-24 2010-04-06 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
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
US7763656B2 (en) * 2002-07-24 2010-07-27 Ptc Therapeutics, Inc. Use of Acetylamino benzoic acid compounds for nonsense suppression and the treatment of disease
US7795280B2 (en) 2002-11-07 2010-09-14 N.V. Organon Indoles useful in the treatment of androgen-receptor related diseases
US7812036B2 (en) 2004-04-23 2010-10-12 N.V. Organon Androgens
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
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
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8394969B2 (en) 2008-09-26 2013-03-12 Merck Sharp & Dohme Corp. Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8598156B2 (en) 2010-03-25 2013-12-03 Glaxosmithkline Llc Chemical compounds
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9000025B2 (en) 2010-08-20 2015-04-07 Amira Pharmaceuticals, Inc. Autotaxin inhibitors and uses thereof
US9012450B2 (en) 2011-12-28 2015-04-21 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US9018210B2 (en) 2011-12-28 2015-04-28 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9260416B2 (en) 2011-05-27 2016-02-16 Amira Pharmaceuticals, Inc. Heterocyclic autotaxin inhibitors and uses thereof
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9556166B2 (en) 2011-05-12 2017-01-31 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9573958B2 (en) 2012-08-31 2017-02-21 Principia Biopharma, Inc. Benzimidazole derivatives as ITK inhibitors
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US9707233B2 (en) 2011-09-02 2017-07-18 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US9815839B2 (en) 2010-12-20 2017-11-14 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds
US9850262B2 (en) 2013-11-12 2017-12-26 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US9944646B2 (en) 2012-04-02 2018-04-17 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9975907B2 (en) 2009-06-29 2018-05-22 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10351568B2 (en) 2010-01-28 2019-07-16 President And Fellows Of Harvard College Compositions and methods for enhancing proteasome activity
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11471455B2 (en) 2018-10-05 2022-10-18 Annapurna Bio, Inc. Compounds and compositions for treating conditions associated with APJ receptor activity

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP5001650B2 (en) * 2003-07-11 2012-08-15 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 Benzimidazole carboxamide
NZ544970A (en) * 2003-07-28 2009-02-28 Janssen Pharmaceutica Nv Benzimidazole, benzthiazole and benzoxazole derivatives and their use as LTA4H modulators
US7119214B2 (en) * 2004-04-13 2006-10-10 Cephalon France Thio-substituted tricyclic and bicyclic aromatic methanesulfinyl derivatives
CN101048382B (en) * 2004-10-27 2010-05-05 霍夫曼-拉罗奇有限公司 New indole or benzimidazole derivatives
WO2006109633A1 (en) * 2005-04-07 2006-10-19 Daiichi Sankyo Company, Limited Substituted indole compound
WO2011075643A1 (en) 2009-12-18 2011-06-23 Incyte Corporation Substituted heteroaryl fused derivatives as pi3k inhibitors
WO2011130342A1 (en) 2010-04-14 2011-10-20 Incyte Corporation FUSED DERIVATIVES AS ΡI3Κδ INHIBITORS
WO2012018980A2 (en) * 2010-08-04 2012-02-09 Yun Michael Shim Compositions and methods for treating inflammatory diseases
US9108984B2 (en) 2011-03-14 2015-08-18 Incyte Corporation Substituted diamino-pyrimidine and diamino-pyridine derivatives as PI3K inhibitors
US9126948B2 (en) 2011-03-25 2015-09-08 Incyte Holdings Corporation Pyrimidine-4,6-diamine derivatives as PI3K inhibitors

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0620215A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetamide derivatives as 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?
WO1997005135A1 (en) * 1995-07-31 1997-02-13 Shionogi & Co., Ltd. Pyrrolidine derivatives having phospholipase a2 inhibitory activity
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 (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0620215A1 (en) * 1993-04-16 1994-10-19 Eli Lilly And Company 1H-indole-3-acetamide derivatives as 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?
WO1997005135A1 (en) * 1995-07-31 1997-02-13 Shionogi & Co., Ltd. Pyrrolidine derivatives having phospholipase a2 inhibitory activity
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

Cited By (194)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6864219B2 (en) 2000-01-17 2005-03-08 Bayer Aktiengesellschaft Substituted aryl ketones
WO2001053275A2 (en) * 2000-01-17 2001-07-26 Bayer Aktiengesellschaft Substituted aryl ketones
WO2001053275A3 (en) * 2000-01-17 2003-04-17 Bayer Ag Substituted aryl ketones
WO2002000620A1 (en) * 2000-06-27 2002-01-03 Smithkline Beecham Corporation Fatty acid synthase inhibitors
US6670388B1 (en) 2000-06-27 2003-12-30 Smithkline Beecham Corporation Fatty acid synthase inhibitors
WO2002005796A2 (en) * 2000-07-14 2002-01-24 Eli Lilly And Company Use of a spla2 inhibitor for the treatment of sepsis
WO2002005796A3 (en) * 2000-07-14 2002-09-06 Lilly Co Eli Use of a spla2 inhibitor for the treatment of sepsis
US6525083B2 (en) 2000-07-25 2003-02-25 Merck & Co., Inc. N-substituted indoles useful in the treatment of diabetes
US7157487B2 (en) 2000-12-28 2007-01-02 Daiichi Pharmaceutical Co., Ltd. Vla-4 inhibitors
CN100471838C (en) * 2000-12-28 2009-03-25 第一制药株式会社 VLA-4 inhibitors
WO2002053534A1 (en) * 2000-12-28 2002-07-11 Daiichi Pharmaceutical Co., Ltd. Vla-4 inhibitors
WO2002094830A3 (en) * 2001-05-23 2003-03-06 Merck Frosst Canada Inc DIHYDROPYRROLO[1,2-A]INDOLE AND TETRAHYDROPYRIDO[1,2-a]-INDOLE DERIVATIVES AS PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS
WO2002094830A2 (en) * 2001-05-23 2002-11-28 Merck Frosst Canada & Co. DIHYDROPYRROLO[1,2-A]INDOLE AND TETRAHYDROPYRIDO[1,2-a]-INDOLE DERIVATIVES AS PROSTAGLANDIN D2 RECEPTOR ANTAGONISTS
US7291639B2 (en) 2001-06-20 2007-11-06 Wyeth Aryloxy-acetic acid compounds useful 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)
US7351730B2 (en) 2001-06-20 2008-04-01 Wyeth Substituted naphthyl indole derivatives as inhibitors of plasminogen activator inhibitor type-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)
US7410994B2 (en) 2001-09-27 2008-08-12 Roche Palo Alto Llc Indole derivatives as anti-inflammatory agents
US6872744B2 (en) 2001-09-27 2005-03-29 Syntex (U.S.A.) Llc Indole derivatives as anti-inflammatory agents
US7074939B2 (en) 2001-09-27 2006-07-11 Roche Palo Alto Llc Indole derivatives as anti-inflammatory agents
US6984735B2 (en) 2001-12-03 2006-01-10 Wyeth Process for making an aldehyde
US7101875B2 (en) 2001-12-03 2006-09-05 Wyeth Methods for treating arthritic disorders
US7713964B2 (en) 2001-12-03 2010-05-11 Wyeth Llc Methods for treating asthmatic conditions
US7605156B2 (en) 2001-12-03 2009-10-20 Wyeth Methods for the use of inhibitors of cytosolic phospholipase A2
US6635771B2 (en) 2001-12-03 2003-10-21 Wyeth N-benzhydryl indole compounds
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
EP2431029A2 (en) 2002-06-07 2012-03-21 Kieran Francis Scott Method of inhibiting prostate cancer cell proliferation
US7763656B2 (en) * 2002-07-24 2010-07-27 Ptc Therapeutics, Inc. Use of Acetylamino benzoic acid compounds for nonsense suppression and the treatment of disease
US7022714B2 (en) 2002-07-31 2006-04-04 Euro-Celtique S.A. Aryl substituted benzimidazoles and their use as sodium channel blockers
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
US7795280B2 (en) 2002-11-07 2010-09-14 N.V. Organon Indoles useful in the treatment of androgen-receptor related diseases
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)
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)
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)
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)
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)
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)
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)
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)
US7078419B2 (en) 2003-03-10 2006-07-18 Boehringer Ingelheim Pharmaceuticals, Inc. Cytokine inhibitors
EP1633716A2 (en) * 2003-04-16 2006-03-15 Bristol-Myers Squibb Company Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
EP1633716A4 (en) * 2003-04-16 2008-03-26 Bristol Myers Squibb Co Biarylmethyl indolines, indoles and tetrahydroquinolines, useful as serine protease inhibitors
US7094790B2 (en) 2003-05-07 2006-08-22 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US8106088B2 (en) 2003-05-07 2012-01-31 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7358263B2 (en) 2003-05-07 2008-04-15 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7807697B2 (en) 2003-05-07 2010-10-05 Abbott Laboratories Fused bicyclic-substituted amines as histamine-3 receptor ligands
US7893279B2 (en) 2003-07-24 2011-02-22 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
US7691894B2 (en) 2003-07-24 2010-04-06 Daiichi Pharmaceutical Co., Ltd. Cyclohexanecarboxylic acid compound
US7265148B2 (en) 2003-09-25 2007-09-04 Wyeth Substituted pyrrole-indoles
US7420083B2 (en) 2003-09-25 2008-09-02 Wyeth Substituted aryloximes
US7803835B2 (en) 2003-09-25 2010-09-28 Wyeth Llc Substituted acetic acid derivatives
US7342039B2 (en) 2003-09-25 2008-03-11 Wyeth Substituted indole oximes
US7351726B2 (en) 2003-09-25 2008-04-01 Wyeth Substituted oxadiazolidinediones
US7332521B2 (en) 2003-09-25 2008-02-19 Wyeth Substituted indoles
US7141592B2 (en) 2003-09-25 2006-11-28 Wyeth Substituted oxadiazolidinediones
US7268159B2 (en) 2003-09-25 2007-09-11 Wyeth Substituted indoles
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
US7582773B2 (en) 2003-09-25 2009-09-01 Wyeth Substituted phenyl indoles
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
US7812036B2 (en) 2004-04-23 2010-10-12 N.V. Organon Androgens
EP1750730A4 (en) * 2004-05-03 2008-01-09 Ilypsa Inc Treatment of hypercholesterolemia, hypertriglyceridemia and cardiovascular-related conditions using phosphalipase-a2 inhibitors
EP1750699A4 (en) * 2004-05-03 2008-01-09 Ilypsa Inc Treatment of diet-related conditions using phospholipase-a2 inhibitors comprising indoles and related compounds
EP1750699A2 (en) * 2004-05-03 2007-02-14 Ilypsa, Inc. Treatment of diet-related conditions using phospholipase-a2 inhibitors comprising indoles and related compounds
EP1750730A2 (en) * 2004-05-03 2007-02-14 Ilypsa, Inc. Treatment of hypercholesterolemia, hypertriglyceridemia and cardiovascular-related conditions using phosphalipase-a2 inhibitors
EP1747003A1 (en) * 2004-05-03 2007-01-31 Ilypsa, Inc. Phospholipase inhibitors localized in the gastrointestinal lumen
EP1747003A4 (en) * 2004-05-03 2008-01-09 Ilypsa Inc Phospholipase inhibitors localized in the gastrointestinal lumen
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
EP1814865A4 (en) * 2004-09-21 2009-09-02 Wyeth Corp Benzimidazole acetic acids exhibiting crth2 receptor antagonism and uses thereof
EP1814865A2 (en) * 2004-09-21 2007-08-08 Athersys, Inc. Benzimidazole acetic acids exhibiting crth2 receptor antagonism and uses thereof
US7345084B2 (en) 2004-10-27 2008-03-18 Janssen Pharmaceutica N.V. Indole derivatives useful as progesterone receptor modulators
US7183309B2 (en) 2004-10-27 2007-02-27 Janssen Pharmaceutica N.V. Indole derivatives useful as progesterone receptor modulators
WO2006077365A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
WO2006077367A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflamation
WO2006077366A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
WO2006077364A1 (en) * 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
US8097623B2 (en) 2005-01-19 2012-01-17 Biolipox Ab Indoles useful in the treatment of inflammation
US8283373B2 (en) 2005-05-27 2012-10-09 Pfizer Inc. Inhibitors of cytosolic phospholipase A2
US7557135B2 (en) 2005-05-27 2009-07-07 Wyeth Inhibitors of cytosolic phospholipase A2
US7683091B2 (en) 2005-08-17 2010-03-23 Wyeth Substituted indoles and methods of their use
US8129424B2 (en) 2005-10-14 2012-03-06 Athersys, Inc. Indole derivatives as histamine 3 receptor inhibitors for the treatment of cognitive and sleep disorders, obesity and other CNS disorders
US7855224B2 (en) 2005-10-14 2010-12-21 Athersys, Inc. Indole derivatives as histamine 3 receptor inhibitors for the treatment of cognitive and sleep disorders, obesity and other CNS disorders
US7528262B2 (en) 2005-10-14 2009-05-05 Athersys, Inc. Indole derivatives as histamine 3 receptor inhibitors for the treatment of cognitive and sleep disorders, obesity and other CNS disorders
WO2007048847A3 (en) * 2005-10-28 2007-06-14 Nikem Research Srl Indole and azaindole derivatives for the treatment of inflammatory and autoimmune diseases
WO2007048847A2 (en) * 2005-10-28 2007-05-03 Nikem Research S.R.L. Indole and azaindole derivatives for the treatment of inflammatory and autoimmune diseases
US7666898B2 (en) 2005-11-03 2010-02-23 Ilypsa, Inc. Multivalent indole compounds and use thereof as phospholipase-A2 inhibitors
US7834037B2 (en) 2005-11-04 2010-11-16 Amira Pharmaceuticals, Inc. 5-lipoxygenase-activating protein (FLAP) inhibitors
US7977359B2 (en) 2005-11-04 2011-07-12 Amira Pharmaceuticals, Inc. 5-lipdxygenase-activating protein (FLAP) inhibitors
US8841295B2 (en) 2005-11-04 2014-09-23 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8710081B2 (en) 2005-11-04 2014-04-29 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
US8399666B2 (en) 2005-11-04 2013-03-19 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein (FLAP) inhibitors
WO2008009924A3 (en) * 2006-07-18 2008-03-27 Biolipox Ab Indoles useful in the treatment of inflammation
WO2008009924A2 (en) * 2006-07-18 2008-01-24 Biolipox Ab Indoles useful in the treatment of inflammation
US8884020B2 (en) 2006-08-07 2014-11-11 Ironwood Pharmaceuticals, Inc. Indole compounds
US8211885B2 (en) 2008-01-31 2012-07-03 Sanofi-Aventis Cyclic indole-3-carboxamides, their preparation and their use as pharmaceuticals
US8772495B2 (en) 2008-05-23 2014-07-08 Panmira Pharmaceuticals, Llc 5-lipoxygenase-activating protein inhibitor
US8394969B2 (en) 2008-09-26 2013-03-12 Merck Sharp & Dohme Corp. Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8410284B2 (en) 2008-10-22 2013-04-02 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8563746B2 (en) 2008-10-29 2013-10-22 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8329914B2 (en) 2008-10-31 2012-12-11 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US10428087B2 (en) 2009-06-29 2019-10-01 Incyte Corporation Pyrimidinones as PI3K inhibitors
US10829502B2 (en) 2009-06-29 2020-11-10 Incyte Corporation Pyrimidinones as PI3K inhibitors
US9975907B2 (en) 2009-06-29 2018-05-22 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US11401280B2 (en) 2009-06-29 2022-08-02 Incyte Holdings Corporation Pyrimidinones as PI3K inhibitors
US10351568B2 (en) 2010-01-28 2019-07-16 President And Fellows Of Harvard College Compositions and methods for enhancing proteasome activity
US8895596B2 (en) 2010-02-25 2014-11-25 Merck Sharp & Dohme Corp Cyclic benzimidazole derivatives useful as anti-diabetic agents
US8598156B2 (en) 2010-03-25 2013-12-03 Glaxosmithkline Llc Chemical compounds
US9062055B2 (en) 2010-06-21 2015-06-23 Incyte Corporation Fused pyrrole derivatives as PI3K inhibitors
US9849109B2 (en) 2010-08-20 2017-12-26 Amira Pharmaceuticals, Inc. Autotaxin inhibitors and uses thereof
US9000025B2 (en) 2010-08-20 2015-04-07 Amira Pharmaceuticals, Inc. Autotaxin inhibitors and uses thereof
US9815839B2 (en) 2010-12-20 2017-11-14 Incyte Corporation N-(1-(substituted-phenyl)ethyl)-9H-purin-6-amines as PI3K inhibitors
US9657012B2 (en) 2010-12-22 2017-05-23 Ironwood Pharmaceuticals, Inc. FAAH inhibitors
US9556166B2 (en) 2011-05-12 2017-01-31 Proteostasis Therapeutics, Inc. Proteostasis regulators
US10532996B2 (en) 2011-05-12 2020-01-14 Proteostasis Therapeutics, Inc. Proteostasis regulators
US9260416B2 (en) 2011-05-27 2016-02-16 Amira Pharmaceuticals, Inc. Heterocyclic autotaxin inhibitors and uses thereof
US10646492B2 (en) 2011-09-02 2020-05-12 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US11819505B2 (en) 2011-09-02 2023-11-21 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US10092570B2 (en) 2011-09-02 2018-10-09 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9707233B2 (en) 2011-09-02 2017-07-18 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US9730939B2 (en) 2011-09-02 2017-08-15 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US10376513B2 (en) 2011-09-02 2019-08-13 Incyte Holdings Corporation Heterocyclylamines as PI3K inhibitors
US11433071B2 (en) 2011-09-02 2022-09-06 Incyte Corporation Heterocyclylamines as PI3K inhibitors
US9018210B2 (en) 2011-12-28 2015-04-28 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10377741B2 (en) 2011-12-28 2019-08-13 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US9012450B2 (en) 2011-12-28 2015-04-21 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10822326B2 (en) 2011-12-28 2020-11-03 Global Blood Therapeutics, Inc. Substituted heteroaryl aldehyde compounds and methods for their use in increasing tissue oxygenation
US10806733B2 (en) 2011-12-28 2020-10-20 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US10034879B2 (en) 2011-12-28 2018-07-31 Global Blood Therapeutics, Inc. Substituted benzaldehyde compounds and methods for their use in increasing tissue oxygenation
US9944646B2 (en) 2012-04-02 2018-04-17 Incyte Holdings Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US10259818B2 (en) 2012-04-02 2019-04-16 Incyte Corporation Bicyclic azaheterocyclobenzylamines as PI3K inhibitors
US9573958B2 (en) 2012-08-31 2017-02-21 Principia Biopharma, Inc. Benzimidazole derivatives as ITK inhibitors
US9849135B2 (en) 2013-01-25 2017-12-26 President And Fellows Of Harvard College USP14 inhibitors for treating or preventing viral infections
US10017491B2 (en) 2013-03-15 2018-07-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10315991B2 (en) 2013-03-15 2019-06-11 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US8952171B2 (en) 2013-03-15 2015-02-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11530191B2 (en) 2013-03-15 2022-12-20 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9422279B2 (en) 2013-03-15 2016-08-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10100043B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Substituted aldehyde compounds and methods for their use in increasing tissue oxygenation
US10100040B2 (en) 2013-03-15 2018-10-16 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9776960B2 (en) 2013-03-15 2017-10-03 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11236109B2 (en) 2013-03-15 2022-02-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11053195B2 (en) 2013-03-15 2021-07-06 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10266551B2 (en) 2013-03-15 2019-04-23 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9802900B2 (en) 2013-03-15 2017-10-31 Global Blood Therapeutics, Inc. Bicyclic heteroaryl compounds and uses thereof for the modulation of hemoglobin
US10858317B2 (en) 2013-03-15 2020-12-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10829470B2 (en) 2013-03-15 2020-11-10 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9981939B2 (en) 2013-03-15 2018-05-29 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9957250B2 (en) 2013-03-15 2018-05-01 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9458139B2 (en) 2013-03-15 2016-10-04 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9604999B2 (en) 2013-03-15 2017-03-28 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US10435393B2 (en) 2013-03-15 2019-10-08 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US9850203B2 (en) 2013-09-26 2017-12-26 Pharmakea, Inc. Autotaxin inhibitor compounds
US9850262B2 (en) 2013-11-12 2017-12-26 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US11242361B2 (en) 2013-11-12 2022-02-08 Proteostasis Therapeutics, Inc. Proteasome activity enhancing compounds
US10611750B2 (en) 2013-11-18 2020-04-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as bet bromodomain inhibitors
US10703764B2 (en) 2013-11-18 2020-07-07 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US10336722B2 (en) 2013-11-18 2019-07-02 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10377769B2 (en) 2013-11-18 2019-08-13 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US9388161B2 (en) 2013-11-18 2016-07-12 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10450269B1 (en) 2013-11-18 2019-10-22 Global Blood Therapeutics, Inc. Compounds and uses thereof for the modulation of hemoglobin
US11084831B1 (en) 2013-11-18 2021-08-10 Forma Therapeutics, Inc. Benzopiperazine compositions as BET bromodomain inhibitors
US11111229B2 (en) 2013-11-18 2021-09-07 Forma Therapeutics, Inc. Tetrahydroquinoline compositions as BET bromodomain inhibitors
US10722502B2 (en) 2014-02-07 2020-07-28 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10137118B2 (en) 2014-02-07 2018-11-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11452720B2 (en) 2014-02-07 2022-09-27 Global Blood Therapeutics, Inc. Crystalline polymorphs of the free base of 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10479803B2 (en) 2014-06-11 2019-11-19 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10077277B2 (en) 2014-06-11 2018-09-18 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US11130767B2 (en) 2014-06-11 2021-09-28 Incyte Corporation Bicyclic heteroarylaminoalkyl phenyl derivatives as PI3K inhibitors
US10336759B2 (en) 2015-02-27 2019-07-02 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US11084822B2 (en) 2015-02-27 2021-08-10 Incyte Corporation Salts and processes of preparing a PI3K inhibitor
US10004725B2 (en) 2015-03-30 2018-06-26 Global Blood Therapeutics, Inc. Methods of treatment
US10695330B2 (en) 2015-03-30 2020-06-30 Global Blood Therapeutics, Inc. Methods of treatment
US9732097B2 (en) 2015-05-11 2017-08-15 Incyte Corporation Process for the synthesis of a phosphoinositide 3-kinase inhibitor
US9988401B2 (en) 2015-05-11 2018-06-05 Incyte Corporation Crystalline forms of a PI3K inhibitor
US10125150B2 (en) 2015-05-11 2018-11-13 Incyte Corporation Crystalline forms of a PI3K inhibitor
US11020382B2 (en) 2015-12-04 2021-06-01 Global Blood Therapeutics, Inc. Dosing regimens for 2-hydroxy-6-((2-(1-isopropyl-1h-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US10011566B2 (en) 2015-12-15 2018-07-03 Astrazeneca Ab Compounds
US11453644B1 (en) 2015-12-15 2022-09-27 Astrazeneca, Ab Compounds
US10988445B2 (en) 2015-12-15 2021-04-27 Astrazeneca Ab Compounds
US10526286B2 (en) 2015-12-15 2020-01-07 Astrazeneca Ab Compounds
US10577345B2 (en) 2016-05-12 2020-03-03 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10077249B2 (en) 2016-05-12 2018-09-18 Global Blood Therapeutics, Inc. Process for synthesizing 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)-pyridin-3-yl)methoxy)benzaldehyde
US10493035B2 (en) 2016-10-12 2019-12-03 Global Blood Therapeutics, Inc. Tablets comprising 2-hydroxy-6-((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde
US11034654B2 (en) 2017-06-14 2021-06-15 Astrazeneca Ab 2,3-dihydroisoindole-1-carboxamides useful as ROR-gamma modulators
US11014884B2 (en) 2018-10-01 2021-05-25 Global Blood Therapeutics, Inc. Modulators of hemoglobin
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
TR200002445T2 (en) 2000-12-21
KR20010041346A (en) 2001-05-15
CN1298404A (en) 2001-06-06
EP1062216A1 (en) 2000-12-27
JP2002504551A (en) 2002-02-12
EE200000522A (en) 2002-02-15
BR9909242A (en) 2000-11-14
HUP0100156A2 (en) 2001-07-30
IL137540A0 (en) 2001-07-24
ID26123A (en) 2000-11-23
SK12782000A3 (en) 2001-04-09
NO20004217L (en) 2000-10-23
HUP0100156A3 (en) 2002-12-28
WO1999043672A9 (en) 2000-05-04
EA200000873A1 (en) 2001-04-23
NO20004217D0 (en) 2000-08-23
CA2322163A1 (en) 1999-09-02
BG104781A (en) 2001-10-31
PL342516A1 (en) 2001-06-18
AU3297099A (en) 1999-09-15
HRP20000513A2 (en) 2001-12-31

Similar Documents

Publication Publication Date Title
WO1999043672A1 (en) Inhibitors of phospholipase a2
US6630496B1 (en) Inhibitors of phospholipase enzymes
AU717430B2 (en) Inhibitors of phospholipase enzymes
AU765427B2 (en) Inhibitors of phospholipase enzymes
US6828344B1 (en) Inhibitors of phospholipase enzymes
AU2782699A (en) Inhibitors of phospholipase enzymes
EP0275667B1 (en) 3-hetero-substituted-n-benzyl-indoles
US6916841B2 (en) Inhibitors of phospholipase enzymes
EP1255751B1 (en) 1,3-dihydro-2h-indol-2-one derivatives and their use as ligands for v1b or v1b and v1a arginine-vasopressin receptors
JPH0680666A (en) Angiotensin ii antagonist
CZ89394A3 (en) Derivative of +h-indole-3-acetamide, process of its preparation, and pharmaceutical preparation in which it is comprised
CZ20003117A3 (en) Phospholipase inhibitors
WO2002006272A1 (en) Polyfluoroalkyltriazole derivatives, preparation and therapeutic use thereof
MXPA00008294A (en) Inhibitors of phospholipase a2
MXPA99001864A (en) Inhibitors of phospholipase enzymes
EP2640724A1 (en) Novel indolizine derivatives, and preparation and therapeutic use thereof
MXPA00008295A (en) Inhibitors of phospholipase enzymes
CZ20003113A3 (en) Phospholipase inhibitors
MXPA00008292A (en) Inhibitors of phospholipase enzymes

Legal Events

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

Ref document number: 99805379.1

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL 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: A1

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
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: C2

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM HR HU ID IL 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: C2

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

COP Corrected version of pamphlet

Free format text: PAGES 1-178, DESCRIPTION, REPLACED BY NEW PAGES 1-169; PAGES 179-218, CLAIMS, REPLACED BY NEW PAGES 170-208; DUE TO LATE TRANSMITTAL BY THE RECEIVING OFFICE

WWE Wipo information: entry into national phase

Ref document number: 137540

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: P20000513A

Country of ref document: HR

WWE Wipo information: entry into national phase

Ref document number: 1200000704

Country of ref document: VN

WWE Wipo information: entry into national phase

Ref document number: 1999936073

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2000/02445

Country of ref document: TR

WWE Wipo information: entry into national phase

Ref document number: 506512

Country of ref document: NZ

Ref document number: 12782000

Country of ref document: SK

ENP Entry into the national phase

Ref document number: 2322163

Country of ref document: CA

Ref document number: 2322163

Country of ref document: CA

Kind code of ref document: A

Ref document number: 2000 533428

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 32970/99

Country of ref document: AU

Ref document number: PA/a/2000/008294

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1020007009459

Country of ref document: KR

Ref document number: PV2000-3117

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: 200000873

Country of ref document: EA

WWP Wipo information: published in national office

Ref document number: 1999936073

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: PV2000-3117

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1020007009459

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1999936073

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1020007009459

Country of ref document: KR