WO1994024095A1 - Immunosuppressive agents - Google Patents

Immunosuppressive agents Download PDF

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Publication number
WO1994024095A1
WO1994024095A1 PCT/US1994/004045 US9404045W WO9424095A1 WO 1994024095 A1 WO1994024095 A1 WO 1994024095A1 US 9404045 W US9404045 W US 9404045W WO 9424095 A1 WO9424095 A1 WO 9424095A1
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Prior art keywords
cyano
isoxazole
methyl
carboxylic acid
amide
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PCT/US1994/004045
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French (fr)
Inventor
Michael J. Coghlan
Jay R. Luly
Paul E. Wiedeman
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Abbott Laboratories
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Publication of WO1994024095A1 publication Critical patent/WO1994024095A1/en

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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
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    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
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    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more 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
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    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
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    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
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Definitions

  • the present invention relates to novel chemical compounds having
  • the invention also relates to means for the preparation of and pharmaceutical compositions containing such compounds, as well as methods of treatment employing the same.
  • Certain cancer chemotherapy drugs such as methotrexate and cyclophosphamide have been found to have immunosuppressive activity.
  • azathioprine Another cancer chemotherapeutic agent
  • These compounds may not be ideal long-term immunosuppressive agents: Methotrexate is non-selective in its antiproliferative effects and shows no more potency on lymphocytes than other cell types (Jolivet et al., New End. J.
  • cyclosporine cyclosporin A, Borel et al. Immunol., 32:1017-1025 (1977)
  • Cyclosporine has found widespread use since its introduction in the fields of organ transplantation and immunomodulation and has brought about a significant increase in the success rate for transplantation procedures.
  • Cyclosporine has been found to be an inhibitor of cytokine production (reviewed by Schreiber et al., Immunology Today. 13(4):136-42 (1992) and Sigal et al., Ann. Rev. Immunol., 10:519-60 (1992)).
  • Leflunomide is readily converted in vivo to its ring-opened metabolite. Although this metabolite has a wide variety of physiological effects in vitro, the definitive mode of action is presently unclear. Isoxazole immunosuppressants also appear to be safer than their macrocyclic counterparts since none of the toxic effects associated with FK-506, cyclosporine or their analogs have been noted during the study of these new therapeutic agents.
  • one object of the invention is to provide novel isoxazoles, products derived from isoxazole ring opening (and analogs thereof), and their tautomers which possess the desired immunomodulatory activity but which may be found to minimize untoward side effects.
  • Another object of the present invention is to provide synthetic processes for the preparation of such compounds.
  • a further object of the invention is to provide pharmaceutical compositions containing, as an active ingredient, one of the above compounds.
  • Yet another object of the invention is to provide a method of treating a variety of disease states including resistance by a recipient patient to transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum ***, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis,
  • glomerulonephritis and the like; and further infectious diseases caused by pathogenic microorganisms.
  • Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrheic dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis
  • renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy
  • nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy
  • endocrine diseases such as hyperthyroidism and Basedow's disease
  • hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia
  • bone diseases such as osteoporosis
  • respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy;
  • ischemic disease for example, thrombosis and cardiac infraction
  • intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation
  • renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency
  • pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C 4 release;
  • Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on.
  • the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g.
  • these ⁇ -cyano- ⁇ -hydroxy crotonyl analogs can be synthesized via an independent route.
  • the salts, esters and prodrugs of each of the above compounds are also included among the compounds of the invention.
  • the substituent E in the above formulae is -R 14 , -NR 14 R 15 , -SR 14 , -OR 14 or -CR 14 R 15 R 16 , where R 14 , R 15 and R 16 are independently selected from
  • R 6 and R 7 in the above may be hydrogen, alkyl, alkenyl, acyl, aryl, heterocyclic, biaryl, cycloalkyl, arylalkyl, hydroxyalkyl or arylsulfonyl, where each radical other than hydrogen may be substituted with between one and three substituents
  • halogen independently selected from the group consisting of halogen, haloalkyl, haloalkoxy, -CHO, -CN, -C(O)OH, -C(O)O-(C 1 -to-C 6 alkyl), -N 3 , -NO 2 , -OH and oxo.
  • aryl, aryl', heterocyclic, heterocyclic' and biaryl are each independently substituted with X, Y and Z.
  • the substituent R 10 in the above is selected at each instance from among (i) halogen, (ii) haloalkyl, (iii) haloalkoxy, (iv) -OH, (v) -(CH) m NR 6 R 7 where m is zero to six, (vi) -CHO, (vii) -(CH 2 ) m OR 6 where m is zero to six, (viii) -CH(OR 12' )(OR 12" ) where R 12' and R 12" are independently -(C 1 -to-C 3 alkyl) or, taken together, form an ethylene or propylene bridge, (ix) -(CH 2 ) m -OC(O)R 6 , (x) -CN, (xi) -C(O)OH, (xii)-C(O)O-(C 1 -to-C 6 alkyl), (xiii) -C(O)NR 6 R 7 , (xiv)
  • R 11 in turn may be -P(O)(OH)O-M+ where M+ is a positively charged inorganic or organic counterion, -S(O) 2 O-M+ or -CO(CH 2 ) m C(O)O-M+.
  • the substituents X, Y, and Z in the above are each independently selected at each instance from among (a') hydrogen, (b') halogen, (c') haloalkyl, (d') -(C 1 -to-C 7 alkyl), (e') -(C 2 -to-C 6 alkenyl), (f)-(C 2 -to-C 6 alkynyl), (g') -(CH 2 ) m NR 6 R 7 , (h') -CN, (i') -CHO, (j') -(CH 2 ) m OR 6 where m is zero to six, (k') -(CH 2 ) m C(O)OR 6 , (1') -(CH 2 ) m OC(O)R 6 , (m') -CH(OR 12' )(OR 12" ) where R 12' and R 12" are independently -(C 1 -to-C 3 alkyl) or,
  • any two adjacent of X, Y and Z, taken together with the carbon atoms to which they are attached, may form a 5- to 7-membered ring which includes zero, one or two additional heteroatoms independently selected from among -O-, -S(O) s - and -N(R 8 )-.
  • X', Y' and Z' in the above are independently selected at each instance from the same groups comprised by X, Y and Z. Additionally, X', Y' and Z' may be chosen from among -(CH 2 ) m NR 6' R 7' , -(CH 2 ) m OR 6' , -(CH 2 ) m C(O)OR 6' ,
  • the substituents R 6' and R 7' in the above are independently selected at each instance from hydrogen, aryl substituted with X, Y and Z, heterocyclic substituted with X, Y and Z, and -(C 1 -to-C 10 alkyl), where -(C 1 -to-C 10 alkyl) is optionally substituted with one to six substituents selected from among R 10 , -NR 8 R 8' , -S(O) s R 8 , -S(O) t NR 8 R 8' , biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryr, -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and -aryl-Q-heterocyclic; each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y
  • R 6' and R 7' and the nitrogen atom to which they are attached may form a 3- to 7-membered heterocyclic ring containing zero, one or two additional heteroatoms independently selected from -O-, -S(O) s - and -NR 8 -.
  • Each ring valency in the heterocyclic ring is substituted with a compatible radical which is -R 66 or -Q-R 66 , where R 66 is selected at each instance from the group consisting of hydrogen, R 10 ,-NR 8 R 8' , -S(O) s R 8 ,
  • each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
  • R 8 and R 8' in the above are independently selected at each instance from hydrogen; -R 10 other than halogen, -NO 2 or -N 3 ; -(C 1 -to-C 6 alkyl); -(C 2 -to-C 6 alkenyl) and -(C 3 -to-C 6 alkynyl).
  • Radicals -(C 1 -to-C 6 alkyl), -(C 2 -to-C 6 alkenyl) and -(C 3 -to-C 6 alkynyl) may in turn be optionally substituted with one to three substituents R 55 chosen from among amino, aryl, guanidino, heterocyclic, monoalkylamino, dialkylamino, acylamino, alkoxycarbonylamino, arylalkyloxycarbonylamino, aryloxycarbonylamino, acylguanidino, arylsulfonylguanidino, alkoxycarbonylguanidino, arylalkyloxycarbonylguanidino, aryloxycarbonylguanidino, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, N-aryl
  • R 8 and R 8' and the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring which includes zero, one or two additional heteroatoms independently chosen from -O-, -S(O) s - where s is zero, one or two, and -NR 8 -.
  • substituents (IV) and (V), -(C 2 -to-C 10 alkenyl) (which includes branched, unbranched, cyclic and bicyclic alkenyl) and -(C 3 -to-C 10 alkynyl) (which includes branched and cyclic alkynyl), are each optionally substituted with one to six substituents independently selected at each instance from R 10 , R 10' , heterocyclic, biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and
  • aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
  • each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X', Y' and Z'.
  • the substituent D in the above formulae is selected from hydrogen, loweralkyl, phenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl and -C(O)R 9 , where R 9 is (a) hydrogen, (b) -OH, (c) -O M+, (d) -(C 1 -to-C 4 alkyl) where alkyl includes branching alkyl, (e) -(C 1 -to-C 4 alkoxy) where alkoxy includes branching alkoxy,
  • R 4 and R 5 are independently selected from among -hydrogen, -(C 1 -to-C 4 hydroxyalkyl), (g) -(C 1 -to-C 4 thioalkyl), (h) -(CH 2 ) nn -(phenyl) where nn is zero to four, (i) -(CH 2 ) n -NR 4 R 5 , (j) -(CH 2 ) m -(morpholino), (k) -NR 4 R 5 , (1) -C(O)NR 4 R 5 , (m) -C(O)OR 4 , (n) phenyl substituted with X, Y and Z, (o) -O-phenyl where phenyl is substituted with X, Y and Z, (p) -O-(CH2) m -(morpholino) or (q) -S-(CH 2 ) nn -(phenyl).
  • R 4 and R 5 are independently
  • G may be -NR 24 R 25 , where R 24 and R 25 and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring including zero, one or two additional heteroatoms independently selected from -O-, -S(O) s - and -NR 8 -.
  • each ring valency is substituted with a compatible radical independently selected at each instance from -R 66 , -Q-R 66 , -R 67 and -Q-R 67 , where R 67 at each instance is independently (i) -CH(OR 12' )(OR 12" ) or
  • alkoxycarbonyl arylalkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl.
  • the substituent G must be other than R 77 where R 77 is (i) -(C 1 -to-C 6 alkyl) optionally substituted with halogen, (ii) phenyl, (iii) benzyl or (iv) -(C3-to-C6 cycloalkyl).
  • R 2 is chosen from among hydrogen, -(CH0-C4 alkyl), phenyl, and benzyl.
  • E When E is -S-phenyl or -O-phenyl where phenyl is substituted with X, Y and Z, the substituent G must be other than -(C 1 -to-C 4 alkyl).
  • the substituent G When E is phenyl substituted with X, Y and Z, the substituent G must be other than -(C 1 -to-C 6 alkyl) optionally substituted with halogen, -(C 1 -to-C 6 alkenyl) optionally substituted with halogen, -(C 5 -to-C 6 cycloalkenyl), -(C 3 -to-C 6 cycloalkyl), -(phenyl)-R 76 , -(benzyl)-R 76 or -C(O)OR 77 .
  • R 76 is selected from -C(O)R 77 , -CN, -NO 2 , halogen and -NR 78 R 79 , where R 78 and R 79 are -(C 1 -to-C 6 alkyl) radicals which may be the same or different.
  • Representative of the compounds of the present invention are those selected from the group consisting of
  • 5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(5,6-dehydro-exo-2-norbomyl)amide
  • 5-Methyl-isoxazole-4-carboxylic acid ( ⁇ -alanine t-butyl ester)amide
  • Cinnamyl 5-methylisoxazole-4-carboxylate Cinnamyl 5-methylisoxazole-4-carboxylate
  • Cinnamyl 2-cyano-3-hydroxycrotonate Cinnamyl 2-cyano-3-hydroxycrotonate
  • N-N-Dimethylaminoethyl-2-cyano-3-hydroxycrotonamide N-[2-(1-Cyclohexenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
  • 5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)amide
  • 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-1,2,3,4-tetrahydroquinolinyl)amide
  • Cinnamyl 5-methylisoxazole-4-carboxylate Cinnamyl 5-methylisoxazole-4-carboxylate
  • Cinnamyl 2-cyano-3-hydroxycrotonate Cinnamyl 2-cyano-3-hydroxycrotonate
  • compositions which comprise a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier.
  • a method of producing immunosuppression in a patient in need of such treatment which comprises administering to the patient a therapeutically effective amount of a compound of the invention.
  • Preferred compounds of the present invention include those in which D is hydrogen or -C(O)R 9 , where R 9 is as described above.
  • E is -NR 14 R 15 , -OR 14 or -SR 14 , and especially those where E is -NR 14 R 15 .
  • Particularly preferred among these compounds are those in which R 14 is X'-,Y'- and Z'-substituted aryl, heterocyclic,
  • R 15 is hydrogen, -(C 1 -to-C 6 alkyl) or -(C 1 -to-C 6 haloalkyl).
  • R 15 is hydrogen, -(C 1 -to-C 6 alkyl) or -(C 1 -to-C 6 haloalkyl).
  • Other preferred compounds of the invention include those compounds in which G is hydrogen, -(C 1 -to-C 6 alkyl), -(C 1 -to-C 6 haloalkyl) or X-, Y- and Z-substituted phenyl, and especially where G is methyl.
  • acyl refers to a carbonyl group to which is appended an alkyl, heterocyclic or aryl residue where aryl, heterocyclic and alkyl have the definitions specified below.
  • alkenyl and “loweralkenyl” as used herein refer to a branched or straight chain comprising two to ten carbon atoms which also comprises one or more carbon-carbon double bonds.
  • alkoxy and loweralkoxy refer to a loweralkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom.
  • Alkoxy and loweralkoxy groups include, for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, rm-butoxy and the like.
  • alkoxycarbonyl refers to an alkoxy group, as previously defined, attached to the parent molecular moiety through a carbonyl, -C(O)-.
  • Alkoxycarbonyl includes, but is not limited to, ethoxycarbonyl, methoxycarbonyl, isopropoxycarbonyl and the like.
  • alkyl refers to a monovalent straight chain or branched chain group of one to twelve carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, sec-butyl, isobutyl, tert-butyl and the like.
  • alkylamino and loweralkylamino refers to a group having the structure -NH-(loweralkyl), where the loweralkyl portion is as defined below.
  • Alkylamino and loweralkylamino groups include, for example, methylamino, ethylamino, isopropylamino and the like.
  • amidoalkyl refers to a group having the structure
  • R 101 C(O) R 102 appended to a loweralkyl group, as previously defined.
  • the groups R 101 and R 102 are independently selected from hydrogen, lower alkyl, aryl, arylalkyl, and halosubstituted alkyl. Additionally, R 101 and R 102 , taken together, may optionally be -(CH 2 ) aa - where aa is an integer of from two to six.
  • aminoalkyl refers to a group having the structure
  • R ⁇ 03 and R 104 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl.
  • R 103 and R 104 taken together, may optionally be -(CH 2 ) bb- where bb is an integer of from two to six.
  • aryl refers to substituted and unsubstituted carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, fluorenyl,
  • arylalkyl refers to an aryl group, as previously defined, appended to an alkyl group including, but not limited to, benzyl, 1- and 2-naphthylmethyl, halobenzyl, alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, fluorenylmethyl, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like.
  • arylalkoxy refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Arylalkoxy includes, but is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like.
  • arylalkoxycarbonyl refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-.
  • Arylalkoxycarbonyl includes, but is not limited to, benzyloxycarbonyl,
  • arylalkylamino refers to a group having the structure -NR 103 -(arylalkyl), where the arylalkyl portion is as previously defined.
  • arylalkylamino groups include benzylamino, 1-phenylethylamino and the like.
  • aryloxy refers to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom.
  • Aryloxy includes, but is not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
  • aryloxycarbonyl refers to an aryloxy group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-.
  • Aryloxycarbonyl includes, but is not limited to, phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like.
  • arylsulfonyl refers to an aryl group, as previously defined, attached to the parent molecular moiety through a sulfonyl group, -S(O)2-.
  • Arylsulfonyl includes, but is not limited to, benzenesulfonyl, 1- or 2-naphthylsulfonyl and the like.
  • biasing refers to a group where two substituted or unsubstituted aryl groups as defined above arc directly bound to each other including, but not limited to, biphenyl, 1-phenyl naphthyl, and the like.
  • bicycloalkyl refers to a ring system comprised of two fused cycloalkyl groups as defined below, including, but not limited to, norbornyl, norbornenyl and pinenyl.
  • (bicycloalkyl)alkyl refers to a bicycloalkyl group as defined above appended to a lower alkyl group including, but not limited to, norbomylmethyl and pinenylethyl .
  • carboxyalkyl refers to a carboxyl group, -CO 2 H, appended to a loweralkyl group, as previously defined.
  • cycloalkyl refers to cyclic groups of three to eight carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • (cycloalkylalkyl) as used herein refers to a cycloalkyl group appended to a lower alkyl group including, but not limited to, cyclohexylmethyl and cyclohexylethyl.
  • R 105 , R 106 and R 107 are independently selected from hydrogen, lower alkyl, heterocyclic, aminoalkyl and aryl.
  • R 106 , and R 107 , taken together, may optionally be -(CH 2 ) cc - wherein cc is an integer of from two to six.
  • haloalkyl refers to alkyl groups as defined above containing one or more halogen atoms including, but not limited to, trifluoromethyl,
  • heterocyclic refers to any aromatic or non-aromatic 5-, 6- or 7-membered ring or a bi- or tricyclic group comprising fused five, six or seven-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized by unsaturation and/or introduction of hydroxy, thiol, oxo, thiooxo, (iii) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above heterocyclic rings may be fused to a benzene ring, and (v) Any carbon or heteroatom with suitable valence may bear a substituent.
  • heterocycles include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl
  • ben-dmidazolyl benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
  • hydroxyalkyl and "hydroxyloweralkyl” as used herein refer to -OH appended to a loweralkyl group, as defined below.
  • hydroxy-protecting group refers to those groups which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, methylthiomethyl, tert-dimethylsilyl, tm-butyldiphenylsilyl, acyl substituted with an aromatic group and other groups found in Protective Groups in Organic Synthesis, 2nd Ed., Greene, T.W. John Wiley & Sons, New York, 1991.
  • loweralkyl refers to an alkyl group, as defined above, of one to eight carbon atoms.
  • thioalkoxy and thioloweralkoxy refer to a loweralkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
  • thioalkoxy and thioloweralkoxy groups include, but are not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, s-thiobutoxy, isothiobutoxy, f-thiobutoxy and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group, as defined above, appended to a loweralkyl group.
  • thioarylalkoxy refers to an arylalkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
  • thioaryloxy refers to an aryl group, as defined above, attached to the remainder of the molecule through a sulfur atom.
  • salts refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
  • salts refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention.
  • salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like.
  • alkali and alkaline earth metals such as sodium, lithium, potassium, calcium, magnesium and the like
  • nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like.
  • ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)
  • esters of the compounds of this invention include C 1 to C 6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C 5 -to-C 7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C 1 -to-C 6 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C 1 -to-C 6 alkyl amines and secondary C 1 -to-C 6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C 1 -to-C 3 alkyl primary amides and C 1 -to -C 2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
  • prodrug refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood.
  • a thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
  • prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method.
  • the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimede) method, the active ester method (p -nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like.
  • Classical methods for amino acid condensation reactions are described in "Peptide Synthesis” Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
  • the compounds of the invention possess immunomodulatory activity in animals.
  • immunosuppressants the compounds are expected to be useful in the treatment and/or prevention of rejection of transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin or cornea transplants, and also in the treatment or prevention of autoimmune, inflammatory, proliferative, and hypeiproliferative diseases, such as rheumatoid arthritis, lupus
  • erythematosus erythematosus, sytemic lupus erythematosus, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, Hashimoto's thyroiditis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis, seborrheic dermatitis, graft-versus-host diseases by medulla ossium transplantation, vernal keratocojunctivitis, eczematous dermatises, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, alopecia areata and the like.
  • the compounds of this invention are also expected to find use in the treatment of reversible obstructive airways disease. Further, the compounds of this invention may be indicated in the treatment of diseases caused by intestinal inflammations and allergies, such as Coeliac disease, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and the like; and food-related allergic diseases which have symptoms remote from the gastrointestinal tract, as for example migraine, rhinitis, and eczema.
  • diseases caused by intestinal inflammations and allergies such as Coeliac disease, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and the like
  • food-related allergic diseases which have symptoms remote from the gastrointestinal tract, as for example migraine, rhinitis, and eczema.
  • Aqueous liquid compositions of the present invention may be particularly useful for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal
  • autoimmune diseases including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy
  • a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form.
  • the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients.
  • a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat gastrointestinal disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder, activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
  • compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray.
  • pharmaceutically acceptable carrier is meant a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • parenteral refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and mtraarticular injection and infusion.
  • compositions of this invention for parenteral injection include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use.
  • suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents.
  • the absorption of the drug in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parcnterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • the active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
  • polyethylene glycols and fatty acid esters of sorbitan and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredient in finely divided form may be used in adinixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter.
  • suitable inert carriers include sugars such as lactose.
  • at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
  • the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant.
  • a compressed gas such as nitrogen or a liquified gas propellant.
  • the liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent
  • the pressurized composition may also contain a surface active agent.
  • the surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
  • a further form of topical administration is to the eye, as for the treatment of immune-mediated conditions of the eye such as automimmune diseases, allergic or inflammatory conditions, and comeal transplants.
  • the compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the comeal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera.
  • the pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used.
  • the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
  • the preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. 0976), p. 33 et seq.
  • the compounds where E is -NR 14 R 15 or -OR 14 may be prepared via condensation of the corresponding isoxazole-4-carboxylic acid or activated derivative with commercially available amines or alcohols thereby providing the respective amide or ester analogs. Many of these materials are prepared from the corresponding isoxazole acid chloride with two equivalents of amine or with an alcohol and a base used as an acid scavenger. Isoxazole-4-carboxylic acids are prepared from commercially available ⁇ -dicarbonyl compounds according to published methods involving homologation of the active methvlene followed by hydroxylamine-mediated cyclization (Schenone etal.
  • Cleavage of the isoxazoles (I) to ring opened analogues (II) may be routinely done using an excess of aqueous sodium hydroxide in a hydroxylic solvent such as methyl or ethyl alcohol at temperatures ranging from ambient to reflux.
  • a hydroxylic solvent such as methyl or ethyl alcohol
  • the resulting hydroxycyanoacrylic acid derivatives are then purified, as for example via recrystallization or flash
  • reaction Scheme I Representative of the processes of the invention is reaction Scheme I presented below.
  • a ⁇ -dicarbonyl compound 1 is reacted with a trialkylorthoformate such as triethylorthoformate in acetic anhydride to give the alkoxymethylene-dicarbonyl compound 2.
  • a trialkylorthoformate such as triethylorthoformate in acetic anhydride
  • Treatment of 2 with hydroxylamine hydrochloride in an alcoholic solution gives the isoxazole carboxylic acid ethyl ester 3.
  • the desired regioisomer is separated, and the purified ester is hydrolyzed under acidic conditions to give the carboxylic acid 4.
  • the acid is activated, for example as the acid chloride 5 using thionyl chloride.
  • Compound 5 is then reacted with the appropriate amines to give carboxamides 6 or the appropriate alcohols to give esters 7.
  • Scheme III shows the ring opening of the isoxazole with base, for example, sodium hydroxide in an alcoholic solution to give the hydroxycyanoacrylic acid derivative 12.
  • 12 can be prepared by reaction of the corresponding cyanoacetyl precursor 14 with activated acid derivatives (e.g. an acid chloride) 13.
  • activated acid derivatives e.g. an acid chloride
  • Step B 5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide:
  • Cinnamyl 5-methylisoxazole-4- oil 69.12 5.39 5.76 69.15 5.48 5.53 carboxylate
  • Step A 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid
  • Step B 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid chloride
  • Step C N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide
  • HMLR human mixed lymphocyte reaction
  • the in vitro immunosuppressant activity of the compounds of the present invention was also determined in a one way allogeneic mixed leukocyte response (MLR) assay using rat lymph node and spleen cells, conducted as follows: Responder cells were obtained from the lymph nodes of Brown Norway rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and the stimulator cells were isolated from the spleens of Lewis rats (Harlan Sprague Dawley, Inc., Indianapolis, IN). 200-250 gram rats were sacrificed by asphyxiation with CO 2 and the popliteal and mesenteric lymph nodes or spleen were removed by sterile dissection.
  • MLR mixed leukocyte response
  • the tissue was placed in RPMI 1640 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 ⁇ M 2-mercaptoethanol, 50 units/mL penicillin G, and 50 ⁇ g/mL streptomycin (complete RPMI medium). After mechanically disrupting the tissue and allowing debris to settle at 1 ⁇ g, the suspended cells were aspirated. The cell suspensions were centrifuged 10 min at 400 ⁇ g and the responder cells resuspended in complete RPMI medium at 2 X 10 6 cells/mL.
  • the spleen cells were suspended in 0.14 M NH4CI/0.017 M Tris-HCl lysing buffer, pH 7.4, for 2 minutes, mixed with RPMI 1640, and centrifuged as before. The spleen cells were subsequendy washed three times by centrifugation in RPMI 1640. To inhibit their ability to proliferate, spleen cells were suspended at 1 ⁇ 10 7 cells/mL in complete RPMI medium and incubated in the presence of 25 ⁇ g/mL of mitomycin C for 30 minutes at 37 °C. The mitomycin C-treated spleen cells were washed three times by centrifugation in RPMI 1640 before being suspended in complete RPMI medium at 4 ⁇ 10 6 cells/mL.
  • the cells were labeled with 0.5 ⁇ Ci per well of tritiated thymidine ( 3 H-TdR; DuPont NEN Research Products, Boston, MA). The cells were harvested by vacuum filtration onto glass fiber filters and the filter radioactivity measured with a MATRIX 9600 direct beta counter (Packard Instrument Company, Meriden, CT).

Abstract

Compounds having a formula selected from the group consisting of (I), (a) and (III) and the respective pharmaceutically acceptable salts, esters and prodrugs thereof, wherein E is selected from the group consisting of -R?14, -NR14R15, -SR14, -OR14¿ and -CR?14R15R16 and R14, R15 and R16¿ are independently selected from (I) hydrogen, (II) -NR6R7, (III) substitued -(C¿1?-to-C10alkyl), (IV) substituted -(C2-to-C10 alkenyl), (V) substituted -(C3-to-C10 alkynyl), (VI) substituted aryl, (VII) substituted heterocyclic, (VIII) substituted biaryl, (IX) substituted -aryl-heterocyclic, (X) substituted -heterocyclic-aryl, (X) substituted -Q-aryl, (XI) substituted -Q-heterocyclic, (XII) substituted -Q-biaryl, (XIII) substituted -aryl-Q-aryl', (XIV) substituted -heterocyclic-Q-heterocyclic', (XV) substituded -heterocyclic-Q-aryl, and (XVI) substituted -aryl-Q-heterocyclic. As well as pharmaceutical composition comprising such compounds and methods for the therapeutic use thereof.

Description

IMMUNOSUPPRESSIVE AGENTS
This is a continuation-in-part of U.S. patent application Serial No. 08/056,500, filed May 1, 1993 and pending, which is a continuation-in-part of U.S. patent application Serial No. 08/048,499 filed on April 16, 1993 and abandoned.
Field of the Invention
The present invention relates to novel chemical compounds having
immunomodulatory activity, and in particular to isoxazole and ring-opened isoxazole immunosuppressive and/or antiinflammatory agents. The invention also relates to means for the preparation of and pharmaceutical compositions containing such compounds, as well as methods of treatment employing the same.
Background of the Invention
Certain cancer chemotherapy drugs, such as methotrexate and cyclophosphamide, have been found to have immunosuppressive activity. The proposed immunosuppressive modes of action of cyclophosphamide and another cancer chemotherapeutic agent, azathioprine, have been described (Elion, G.B., Science. 244:41-47 (1989), and Clarke, L. and Waxman, D.J., Cancer Research. 49:2344-2450 (1989)). These compounds, however, may not be ideal long-term immunosuppressive agents: Methotrexate is non-selective in its antiproliferative effects and shows no more potency on lymphocytes than other cell types (Jolivet et al., New End. J. Med., 309:1094-1104 (1983)); long-term use of methotrexate therapy, for example in rheumatoid arthritis, is therefore limited due to its toxic effects (Alarcon et al., Arthritis and Rheumatism. 32:671-676 (1989)). Problems associated with cyclophosphamide include mutagenicity, carcinogenicity and the fact that its effects on lymphocytes are not rapidly reversible.
Another class of compounds having immunomodulatory activity have been identified from fermentation isolates. One such compound, cyclosporine (cyclosporin A, Borel et al. Immunol., 32:1017-1025 (1977)), has found widespread use since its introduction in the fields of organ transplantation and immunomodulation and has brought about a significant increase in the success rate for transplantation procedures. Cyclosporine has been found to be an inhibitor of cytokine production (reviewed by Schreiber et al., Immunology Today. 13(4):136-42 (1992) and Sigal et al., Ann. Rev. Immunol., 10:519-60 (1992)). However, unsatisfactory side-effects associated with cyclosporine such as nephrotoxicity (Bennett, W.M. and Pulliam, J. P. Ann. Internal Med., 99:851-854 (1983)) have led to a continued search for immunosuppressant compounds having improved efficacy and safety. This effort has resulted in the identification of a number of macrocyclic compounds isolated from the genus Streptomyces, such as the 23-membered macrocyclic lactone FK-506 and its analog FR-900520 (ascomycin), which have immunosuppressive activity. Unfortunately, these compounds, too, have demonstrated some toxicity in mammals.
Recently a class of isoxazoles has been indentified having immunosuppressant activity. These heterocycles are rapidly converted in vivo to ring-opened metabolites which are believed to be the active therapeutic agents. Antiinflammatory metabolites as well as the parent isoxazoles were first disclosed by Ertel et al. in German patent number 2555789. The first of these analogs to show promise is leflunomide (HWA-486) which has demonstrated efficacy in models of autoimmune disease, rheumatoid arthritis and allograft transplantation (Bartlett et al. in "Therapeutic Approaches to Inflammatory Disease", ed. Lewis, A.J. et al., Elsevier, New York (1989), pp. 215-228). Leflunomide is readily converted in vivo to its ring-opened metabolite. Although this metabolite has a wide variety of physiological effects in vitro, the definitive mode of action is presently unclear. Isoxazole immunosuppressants also appear to be safer than their macrocyclic counterparts since none of the toxic effects associated with FK-506, cyclosporine or their analogs have been noted during the study of these new therapeutic agents.
Although the immunosuppressive activity of leflunomide is under study in clinical trials, its usefulness could be improved upon. The metabolite of this compound has a considerable half-life which may hamper treatment of opportunistic infections in
immunosuppressed patients. Research efforts are therefore underway to discover novel isoxazoles which possess superior properties. These efforts include the preparation of ester and thioester analogs, the synthesis of prodrugs, the chemical modification of the parent isoxazole, and the synthesis of hybrid species derived from mimics of the active metabolite.
Despite these efforts, the need remains for compounds having immunosuppressive activity which do not have the serious side effects frequently associated with
immunosuppressant therapy such as increased risk of malignancy or prolonged susceptibility to viral or other infections. Chronic conditions such as rheumatoid arthritis and organ transplantation where immunomodulatory drugs are taken for a number of years can lead to the already-cited complications. Optimally one would also want a drug in which the suppression of immune function was rapidly reversible. Accordingly, one object of the invention is to provide novel isoxazoles, products derived from isoxazole ring opening (and analogs thereof), and their tautomers which possess the desired immunomodulatory activity but which may be found to minimize untoward side effects.
Another object of the present invention is to provide synthetic processes for the preparation of such compounds.
A further object of the invention is to provide pharmaceutical compositions containing, as an active ingredient, one of the above compounds. Yet another object of the invention is to provide a method of treating a variety of disease states including resistance by a recipient patient to transplantation of organs or tissue such as heart, kidney, liver, medulla ossium, skin, cornea, lung, pancreas, intestinum tenue, limb, muscle, nervus, duodenum, small-bowel, pancreatic-islet-cell, etc.; graft-versus-host diseases brought about by medulla ossium transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis,
glomerulonephritis, and the like; and further infectious diseases caused by pathogenic microorganisms. Further uses may include the treatment and prophylaxis of inflammatory and hyperproliferative skin diseases and cutaneous manifestations of immunologically-mediated illnesses, such as psoriasis, atopical dermatitis, contact dermatitis and further eczematous dermatitises, seborrheic dermatitis, Lichen planus, Pemphigus, bullous pemphigoid, Epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, Lupus erythematosus, acne and Alopecia areata; various eye diseases (autoimmune and otherwise) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, dystrophia epithelialis corneae, corneal leukoma, ocular pemphigus, Mooren's ulcer, Scleritis, Graves' opthalmopathy, Vogt-Koyanagi-Harada syndrome, sarcoidosis, etc.; reversible obstructive airway disease, which includes condition such as asthma (for example, bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma and dust asthma), particularly chronic or inveterate asthma (for example, late asthma and airway hyper-responsiveness), bronchitis and the like; inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis, ischemic bowel diseases, inflammatory bowel diseases, necrotizing enterocolitis, intestinal lesions associated with thermal bums and leukotriene B4-mediated diseases; intestinal inflammations/allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; food-related allergic diseases which have symptomatic manifestation remote from the gastro-intestinal tract (e.g. migraine, rhinitis and eczema); renal diseases such as interstitial nephritis, Goodpasture's syndrome, hemolytic-uremic syndrome and diabetic nephropathy; nervous diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism and Basedow's disease; hematic diseases such as pure red cell aplasia, aplastic anemia, hypoplastic anemia, idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia and anerythroplasia; bone diseases such as osteoporosis;
respiratory diseases such as sarcoidosis, fibroid lung and idiopathic interstitial pneumonia; skin disease such as dermatomyositis, leukoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gingiva, periodontium, alveolar bone and substantia ossea dentis; nephrotic syndrome such as glomerulonephritis; male pattern aleopecia or alopecia senilis by preventing epilation or providing hair germination and/or promoting hair generation and hair growth; muscular dystrophy;
Pyoderma and Sezary's syndrome; Addison's disease; active oxygen-mediated diseases, as for example organ injury such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) which occurs upon preservation, transplantation or ischemic disease (for example, thrombosis and cardiac infraction): intestinal diseases such as endotoxin-shock, pseudomembranous colitis and colitis caused by drug or radiation; renal diseases such as ischemic acute renal insufficiency and chronic renal insufficiency;
pulmonary diseases such as toxinosis caused by lung-oxygen or drug (for example, paracort and bleomycins), lung cancer and pulmonary emphysema; ocular diseases such as cataracta, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreal scarring and corneal alkali burn; dermatitis such as erythema multiforme, linear IgA ballous dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental pollution (for example, air pollution), aging, carcinogenis, metastasis of carcinoma and hypobaropathy; disease caused by histamine or leukotriene-C4 release;
Behcet's disease such as intestinal-, vasculo- or neuro-Behcet's disease, and also Behcet's which affects the oral cavity, skin, eye, vulva, articulation, epididymis, lung, kidney and so on. Furthermore, the compounds of the invention are useful for the treatment and prevention of hepatic disease such as immunogenic diseases (for example, chronic autoimmune liver diseases such as the group consisting of autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute liver necrosis (e.g. necrosis caused by toxin, viral hepatitis, shock or anoxia), B-virus hepatitis, non-A/non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and hepatic failure such as fulminant hepatic failure, late-onset hepatic failure and "acute-on-chronic" liver failure (acute liver failure on chronic liver diseases), and moreover are useful for various diseases because of their useful activity such as augmention of chemotherapeutic effect, preventing or treating activity of cytomegalovirus infection, particularly HCMV infection, anti-inflammatory activity, and so on.
Summary of the Invention
In one aspect of the present invention are disclosed compounds having the formula (I), as well as the related products of ring opening (II) and their tautomers (III),
Figure imgf000007_0001
Figure imgf000007_0002
Figure imgf000007_0003
where B in formula (II) represents -OH, lower alkoxy or -O-(hydroxy-protecting group). The ring-opened products (II) where B is -OH and their tautomers (III) may arise from the parent isoxazole via the following mechanism, in the course of which functional group D is eliminated:
Figure imgf000007_0004
Alternatively, these α-cyano-β-hydroxy crotonyl analogs can be synthesized via an independent route. Also included among the compounds of the invention are the salts, esters and prodrugs of each of the above compounds.
The substituent E in the above formulae is -R14, -NR14R15, -SR14, -OR14 or -CR14R15R16, where R14, R15 and R16 are independently selected from
(I) hydrogen,
(II) -NR6R7,
(III) -(C1-to-C10 alkyl),
(IV) -(C2-to-C10 alkenyl),
(V) -(C3-to-C10 alkynyl),
(VI) aryl,
(VII) heterocyclic,
(VIII) biaryl,
(IX) -aryl-heterocyclic,
(X) -heterocyclic-aryl,
(X) -Q-aryl, (XI) -Q-heterocyclic,
(XII) -Q-biaryl,
(XIII) -aryl-Q-aryl",
(XIV) -heterocyclic-Q-heterocyclic',
(XV) -heterocyclic-Q-aryl, and
(XVI) -aryl-Q-heterocyclic.
The substituents R6 and R7 in the above may be hydrogen, alkyl, alkenyl, acyl, aryl, heterocyclic, biaryl, cycloalkyl, arylalkyl, hydroxyalkyl or arylsulfonyl, where each radical other than hydrogen may be substituted with between one and three substituents
independently selected from the group consisting of halogen, haloalkyl, haloalkoxy, -CHO, -CN, -C(O)OH, -C(O)O-(C1-to-C6 alkyl), -N3, -NO2, -OH and oxo.
The substituent (III) in the above, -(C1-to-C10 alkyl), which includes straight and branched alkyl, cycloalkyl, (cycloalkyl)alkyl, bicycloalkyl and (bicycloalkyl)alkyl, is optionally substituted with between one and six substituents independently selected at each instance from (a) R10, (b) R10', and (c) heterocyclic, biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl or
-aryl-Q-heterocyclic, where aryl, aryl', heterocyclic, heterocyclic' and biaryl are each independently substituted with X, Y and Z.
The substituent R10 in the above is selected at each instance from among (i) halogen, (ii) haloalkyl, (iii) haloalkoxy, (iv) -OH, (v) -(CH)mNR6R7 where m is zero to six, (vi) -CHO, (vii) -(CH2)mOR6 where m is zero to six, (viii) -CH(OR12')(OR12") where R12' and R12" are independently -(C1-to-C3 alkyl) or, taken together, form an ethylene or propylene bridge, (ix) -(CH2)m-OC(O)R6, (x) -CN, (xi) -C(O)OH, (xii)-C(O)O-(C1-to-C6 alkyl), (xiii) -C(O)NR6R7, (xiv) -(C3-to-C6 cycloalkyl), (xv) aryl substituted with X, Y and Z, (xvi) -NO2, (xvii) -N3, (xviii) guanidino optionally substituted with a substituent which may be loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl, (xix) -OR11, (xx) oxo, (xxi) epoxy, (xxii) thiooxo, (xxiii) -SH, (xxiv) -S(O)sR6 where s is zero, one or two, and (xxv) -S(O)tNR6R7 where t is one or two. R11 in turn may be -P(O)(OH)O-M+ where M+ is a positively charged inorganic or organic counterion, -S(O)2O-M+ or -CO(CH2)mC(O)O-M+.
The substituent R10' in the above is selected at each instance from (i)
-(CH2)mNR6'R7', (ii) -(CH2)mOR6', (iii) -(CH2)mOC(O)R6', (iv) -C(O)NR6'R7',
(v) -S(O)tNR6'R7', (vi) -S(O)sR6', (vii) aryl substituted with X', Y' and Z', and (viii) heterocyclic substituted with X', Y' and Z'.
The substituents X, Y, and Z in the above are each independently selected at each instance from among (a') hydrogen, (b') halogen, (c') haloalkyl, (d') -(C1-to-C7 alkyl), (e') -(C2-to-C6 alkenyl), (f)-(C2-to-C6 alkynyl), (g') -(CH2)mNR6R7, (h') -CN, (i') -CHO, (j') -(CH2)mOR6 where m is zero to six, (k') -(CH2)mC(O)OR6, (1') -(CH2)mOC(O)R6, (m') -CH(OR12')(OR12") where R12' and R12" are independently -(C1-to-C3 alkyl) or, taken together, form an ethylene or propylene bridge, (n') -C(O)NR6R7, (o') -NO2, (p') -N3, (q') guanidino optionally substituted with a substituent chosen from lower alkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl, (r') -OR11, (s') -S(O)sR6 where s is zero, one or two, and (t') -S(O)tNR6R7 where t is one or two. Altematively, any two adjacent of X, Y and Z, taken together with the carbon atoms to which they are attached, may form a 5- to 7-membered ring which includes zero, one or two additional heteroatoms independently selected from among -O-, -S(O)s- and -N(R8)-.
The substituents X', Y' and Z' in the above are independently selected at each instance from the same groups comprised by X, Y and Z. Additionally, X', Y' and Z' may be chosen from among -(CH2)mNR6'R7', -(CH2)mOR6', -(CH2)mC(O)OR6',
-(CH2)mOC(O)R6', -C(O)NR6'R7', -S(O)tNR6'R7' and -S(O)sR6'.
The divalent substituent Q in the above is independently selected at each instance from -(C1-to-C6 alkylene)-, -(C2-to-C6 alkenylene)-, -(C2-to-C6 alkynylene)-, -(CH2)mO- where m is zero to six, -O(CH2)m- where m is zero to six, -N(R8)C(O)-, -C(O)N(R8)-, -S(O)s- where s is zero, one or two, -N(R8)-, -N(R8)S(O)r, -S(O)tN(R8)-, -C(O)-, -N=N- and -C(S)-.
The substituents R6' and R7' in the above are independently selected at each instance from hydrogen, aryl substituted with X, Y and Z, heterocyclic substituted with X, Y and Z, and -(C1-to-C10 alkyl), where -(C1-to-C10 alkyl) is optionally substituted with one to six substituents selected from among R10, -NR8R8', -S(O)sR8, -S(O)tNR8R8', biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryr, -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and -aryl-Q-heterocyclic; each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
Alternatively, R6' and R7' and the nitrogen atom to which they are attached may form a 3- to 7-membered heterocyclic ring containing zero, one or two additional heteroatoms independently selected from -O-, -S(O)s- and -NR8-. Each ring valency in the heterocyclic ring is substituted with a compatible radical which is -R66 or -Q-R66, where R66 is selected at each instance from the group consisting of hydrogen, R10,-NR8R8', -S(O)sR8,
-S(O)tNR8R8', aryl, heterocyclic, biaryl, -aryl-Q-aryr, -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl, -aryl-Q-heterocyclic. Again, each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
The substituents R8 and R8' in the above are independently selected at each instance from hydrogen; -R10 other than halogen, -NO2 or -N3; -(C1-to-C6 alkyl); -(C2-to-C6 alkenyl) and -(C3-to-C6 alkynyl). Radicals -(C1-to-C6 alkyl), -(C2-to-C6 alkenyl) and -(C3-to-C6 alkynyl) may in turn be optionally substituted with one to three substituents R55 chosen from among amino, aryl, guanidino, heterocyclic, monoalkylamino, dialkylamino, acylamino, alkoxycarbonylamino, arylalkyloxycarbonylamino, aryloxycarbonylamino, acylguanidino, arylsulfonylguanidino, alkoxycarbonylguanidino, arylalkyloxycarbonylguanidino, aryloxycarbonylguanidino, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, N-arylcarboxamido and N,N-diarylcarboxamido.
Altematively, R8 and R8' and the nitrogen atom to which they are attached may form an optionally substituted 3- to 7-membered heterocyclic ring which includes zero, one or two additional heteroatoms independently chosen from -O-, -S(O)s- where s is zero, one or two, and -NR8-.
The above substituents (IV) and (V), -(C2-to-C10 alkenyl) (which includes branched, unbranched, cyclic and bicyclic alkenyl) and -(C3-to-C10 alkynyl) (which includes branched and cyclic alkynyl), are each optionally substituted with one to six substituents independently selected at each instance from R10, R10', heterocyclic, biaryl, -Q-aryl, -Q-heterocyclic, -Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and
-aryl-Q-heterocyclic. Each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X, Y and Z.
Similarly, in the above substituents (VI) through (XVI) which comprise aryl, heterocyclic, biaryl, -aryl-heterocyclic, -heterocyclic-aryl, -Q-aryl, -Q-heterocyclic,
-Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl
and-aryl-Q-heterocyclic, each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X', Y' and Z'.
The substituent D in the above formulae is selected from hydrogen, loweralkyl, phenyl, 2-chlorophenyl, 2,4-dichlorophenyl, 2-chloro-4-fluorophenyl and -C(O)R9, where R9 is (a) hydrogen, (b) -OH, (c) -O M+, (d) -(C1-to-C4 alkyl) where alkyl includes branching alkyl, (e) -(C1-to-C4alkoxy) where alkoxy includes branching alkoxy,
(0 -(C1-to-C4 hydroxyalkyl), (g) -(C1-to-C4 thioalkyl), (h) -(CH2)nn-(phenyl) where nn is zero to four, (i) -(CH2)n-NR4R5, (j) -(CH2)m-(morpholino), (k) -NR4R5, (1) -C(O)NR4R5, (m) -C(O)OR4, (n) phenyl substituted with X, Y and Z, (o) -O-phenyl where phenyl is substituted with X, Y and Z, (p) -O-(CH2)m-(morpholino) or (q) -S-(CH2)nn-(phenyl). In the above, R4 and R5 are independently selected from among -hydrogen, -(C1-C6 alkyl) optionally substituted with halogen, and phenyl substituted with X, Y and Z.
The substituent G in the above formulae is chosen from among -R14, -OR14, -S(O)sR14, -CR14R15R16, -OCR14R15, -OCR14, -C=NR14, -NR14R15 and Z (a radical selected from the same groups comprised by X, Y and Z), or G may be selected from aryl, heterocyclic, biaryl, -heterocyclic-aryl, -aryl-heterocyclic, -Q-aryl, -Q-heterocyclic,
-Q-biaryl, -aryl-Q-aryl', -heterocyclic-Q-heterocyclic', -heterocyclic-Q-aryl and
-aryl-Q-heterocyclic, where each such aryl, aryl', heterocyclic, heterocyclic' or biaryl radical is independently substituted with X', Y' and Z'. Alternatively, G may be -NR24R25, where R24 and R25 and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring including zero, one or two additional heteroatoms independently selected from -O-, -S(O)s- and -NR8-. In such a heterocyclic ring, each ring valency is substituted with a compatible radical independently selected at each instance from -R66, -Q-R66, -R67 and -Q-R67, where R67 at each instance is independently (i) -CH(OR12')(OR12") or
(ii) guanidino optionally substituted with loweralkyl, aryl, acyl, arylsulfonyl,
alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl or alkylsulfonyl.
The compounds encompassed by the above formulae are subject to the following provisos:
When E is -NHCH2-(heterocyclic), the substituent G must be other than pyrrolyl.
When E is -N(R2)-[(Cι-to-Cιo alkylene)-C(O)O-(C1-to-C4 alkyl)],
-N(R2)-(aryl),-N(R2)-(heterocyclic), -N(R2)-(heterocyclic)-(aryl), -N(R2)-(biaryl),
-N(R2)-(phenyl)-O-(aryl), -N(R2)-(phenyl)-C(O)-(aryl), -N(R2)-C(CH3)2-CH2-(aryl), -OH, -NH2, -SH, methyl, hydrogen, N-morpholino, N-thiomorpholino, or N-piperidinyl optionally substituted with -(C1-to-C2 alkyl), the substituent G must be other than R77 where R77 is (i) -(C1-to-C6 alkyl) optionally substituted with halogen, (ii) phenyl, (iii) benzyl or (iv) -(C3-to-C6 cycloalkyl). In the above, the substituent R2 is chosen from among hydrogen, -(CH0-C4 alkyl), phenyl, and benzyl.
When E is -S-phenyl or -O-phenyl where phenyl is substituted with X, Y and Z, the substituent G must be other than -(C1-to-C4 alkyl). When E is phenyl substituted with X, Y and Z, the substituent G must be other than -(C1-to-C6 alkyl) optionally substituted with halogen, -(C1-to-C6 alkenyl) optionally substituted with halogen, -(C5-to-C6 cycloalkenyl), -(C3-to-C6 cycloalkyl), -(phenyl)-R76, -(benzyl)-R76 or -C(O)OR77. In the above, R76 is selected from -C(O)R77, -CN, -NO2, halogen and -NR78R79, where R78 and R79 are -(C1-to-C6 alkyl) radicals which may be the same or different.
It is intended that when, in the above formulae, a symbol representing a variable radical such as Q, X, Y, Z, X', Y', Z' or Rx (where x is any integer) appears more than once in a single molecular formula, the radicals so represented may be the same or different at each instance. Also, where a bond to a chiral carbon atom in the above formulae is represented by a wavy line, both orientations are intended.
Representative of the compounds of the present invention are those selected from the group consisting of
5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-fluorophenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-phenylpropylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-nitrophenyl)ethylamide;
5-Methyl-isoxazole-4-hydroxamic acid benzylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-fluorophenylhydrazide;
5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl- 1 ,2,3,4-tetrahydroquinolinyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-1,2,3,4-tetrahydroquinolinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid isobutylamide;
5-Methyl-isoxazole-4-carboxylic acid (n-pentyl)amide;
5-Methyl-isoxazole-4-carboxylic acid pyrrolidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid morpholinohydrazide;
5-Methyl-isoxazole-4-carboxylic acid 4-trifluoromethylbenzimide;
5-Methyl-isoxazole-4-carboxylic acid 2-fluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid trαns-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cis-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid diethylamide;
5-Methyl-isoxazole-4-carboxylic acid ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2,2,2-trifluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid allylamide;
5-Methyl-isoxazole-4-carboxylic acid propargylamide; 5-Methyl-isoxazole-4-carboxylic acid (acetonitrile)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methoxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-methoxypropyl)amide;
5-Methyl-isox-izole-4-carboxylic acid (2-diethoxyacetal)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-thioethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxybutyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-piperidinoethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylpiperazino)amide;
5-Methyl-isoxazole-4-carboxylic acid (ethylglycinate)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-propionic acid)amide;
5-Methylisoxazole-4-carboxylic acid (1-piperidino)amide;
5-Methylisoxazole-4-carboxylic acid (4-chlorophenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-norbomyl)amide;
5-Methyl-4-{4-(3-trifluoromethylphenyl)piperaziιιe-1-ylcarbonyl}-isoxazole;
5-Methyl-isoxazole-4-carboxylic acid (cyclobutylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (norephedrine)amide;
5-Methyl-isoxazole-4-carboxylic add (4-methoxycarbonyl-cyclohexylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-{(4-phenyl)-benzyl} amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(4-phenoxy)-benzylamide;
5-Methyl-isoxazole-4-carboxylic acid {2-[(2-chloro-4-t-butyl-phenoxy)methyl]benzyl}amide; 5-Methyl-isoxazole-4-carboxylic acid (furfuryl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-trifluoromethoxy-phenyl)hydrazide ;
5-Methyl-isoxazole-4-carboxylic acid {(-)-cis-myrtanyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (3-aminopropyl)amide;
5-Methylisoxazole-4-carboxylic acid (4-methoxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(4S)-benzyloxazolidinone}imide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(+)-norephedrine} amide;
5-Methyl-isoxazole-4-carboxylic acid (4-ethylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {2-hydroxy-5-(7-chloro-6-
(ethoxycarbonylmethoxy)benzisoxazol-3-yl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid {4-(2,3-dichloro-4- (ethoxycarbonylmethoxy)benzoyl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (aziridinyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (4-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-phenylethyl )amide;
5-Methyl-isoxazole-4-carboxylic acid cinnamimide;
5-Methyl-isoxazole-4-carboxylic acid 4-chlorocinnamimide;
5-Methyl-isoxazole-4-carboxylic acid {L-(S)-amphetamine}amide;
5-(3-Butenyl) isoxazole-4-carboxylic acid (4-trifluoromethylphenyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cycloleucinolamide;
5-Methyl-isoxazole-4-carboxylic acid (tyrosine methyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid 1-aminohomopiperidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid (2-amino-2-norbomanecarboxylic acid)amide;
5-Methyl-isoxazole-4-carboxylic acid 2-thienylmethylamide;
5-Methyl-isoxazole-4-carboxylic acid (2,6-dimethylmorpholin-4-yl)amide;
5-Methyl-isoxazole-4-carboxylic acid 2-(N,N-dimethyl)aminoethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-cyclohex-1-enylethylamide;
5-Methyl-isoxazole-4-carboxylic acid 3-methoxypropylamide;
Ethyl 4-[3,5-di(5-methyl-isoxazole-4-carbonylamino)]-1H-1,2,4-triazolin- 1-yl)benzoate]amide;
5-Methyl-isoxazole-4-carboxylic acid N-benzyl-N-norbornylamide;
5-Methyl-isoxazole-4-carboxylic acid (convolvinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid 4-propylpiperidineamide;
5-Methyl-isoxazole-4-carboxylic acid {4-[(4-hydroxy-3-tert-butyl)- phenoxyethoxy]phenyl}amide;
5-Methyl-isoxazole-4-carboxylic acid 4-[2-(phenylaminocarbonyl)-propionyl]anilide;
5-Trifluoromethyl-isoxazole-4-carboxylic acid 3-methyl-1-butylamide;
5-Methyl-isoxazole-4-carboxylic acid 5-(N-morpholino)pentylamide;
5-Methyl-isoxazole-4-carboxylic acid (5-diisopropylamino-1,3,4-thiadiazol-2-yl)amide; 5-Methyl-isoxazole-4-carboxylic acid (L-proline t-butyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid (L-leucine-t -butyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(1-cyano)cyclopentylamide;
5-Methyl-isoxazole-4-carboxylic acid N-ethyl-N-(1-carboxyl)cycloheptylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-[2-(2-methoxyethoxy)ethoxy]anilide;
5-Methyl-isoxazole-4-carboxylic acid (glycine trityl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid (ketamine hydrochloride)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(5,6-dehydro-exo-2-norbomyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (β-alanine t-butyl ester)amide;
4-Trifluoromethyl benzoyl 5-methyltrifluoro-isoxazole-4-carboximide;
3-(3-Methoxy)phenoxycarbonyl-5-methyl-isoxazole-4-carboxylic acid 3-methylbutylamide; 3-(N,N-Dimethylaminocarbonyl)-5-methyl-isoxazole-4-carboxylic acid
3-(4-methoxyphenyl)propylamide;
3-(2-Chloro-4-fluorophenacyl)-5-methyl-isoxazole-4-carboxylic acid cyclohexylamide;
N (5-Phenyl-4-isoxazoyl)-N'-(4-toluenesulfonyl) 1,4-phenylenediamide;
5-Phenyl-isoxazole-4-carboxylic acid butylamide;
5-Trifluoromethyl-isoxazole-4-carboxylic acid (3-methylbutyl)amide;
5-(2-Methoxyphenyl)-isoxazole-4-carboxylic acid 4-(3-nitrophenyl)thiazol-2-ylamide;
2-(4-Trifluoromethylphenyl)ethyl 5-methyl isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
2-(4-Fluorophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
4-Chlorophenethyl 5-methylisoxazole-4-carboxylate;
4-Trifluoromethylphenyl 5-methylisoxazole-4-carboxylate;
Cinnamyl 5-methylisoxazole-4-carboxylate;
2-(3-Trifluoromethylphenyl)ethyl 5-methylisoxazole-4-carboxylate;
3-Phenylbutyl 5-methylisoxazole-4-carboxylate;
(3-Furanyl)methyl 5-methyl-isoxazole-4-carboxylate;
2-(1-Piperidyl)ethyl 5-methyl-isoxazole-4-carboxylate;
3-Pyridyl 5-methyl-isoxazole-4-carboxylate;
4-[2-Methyl-5-(4-nitrophenyl)oxazolyl]methyl 5-methyl-isoxazole-4-carboxylate;
7-Chloro-4-quinolyl 5-methyl-isoxazole-4-carboxylate;
2-Methoxyethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-trifluoromethylisoxazole-4-carboxylate;
3-Hydroxypropyl (5-phenyl-4-isoxazolyl) ketone;
2-Methylypropyl (5-trifluoromethyl-4-isoxazolyl) ketone;
1,1,2,2,3,3,3-Heptafluoropropyl (5-trifluoromethyl-4-isoxazolyl) ketone;
3-Furanyl (5-trifluoromethyl-4-isoxazolyl) ketone;
N[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Phenylpropyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-methoxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-ethoxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-[2-(4-Trifluoromethylphenyl)ethyl-2-cyano-3-hydroxycrotonate;
N-[n-Pentyl]-2-cyano-3-hydroxycrotonamide;
N-(Isobu-yl)-2-cyano-3-hydroxycrotonamide;
N-(ttαns-4-tert-butylcyclohexyl)-2-cyano-3-hydroxycrotonamide; N-(cis-4-tert-butyl cyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(2-Fluoroethyl)-2-cyano-3-hydroxycrotonamide;
N,N-Diethyl-2-cyano-3-hydroxycrotonamide;
N-Ethyl-2-cyano-3-hydroxycrotonamide;
N-(2,2,2-Trifluoroethyl)-2-cyano-3-hydroxycrotonamide;
N-[2(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonamide;
N-Allyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methoxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(3-Methoxypropyl)-2-cyano-3-hydroxycrotonamide;
N-Acetonitrile-2-cyano-3-hydroxycrotonamide;
N-Propargyl-2-cyano-3-hydroxycrotonamide;
N-(2-Hydroxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(4-Hydroxybutyl)-2-cyano-3-hydroxycrotonamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxycrotonimide;
3-Phenyl-1-butyl-2-cyano-3-hydroxycrotonate;
N-(Acetic acid)-2-cyano-3-hydroxycrotonamide;
N-(2-Norbomyl)-2-cyano-3-hydroxycrotoamide;
N-(3-Propionic acid)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Piperidin-1-ylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Cyclobutylmethyl-2-cyano-3-hydroxy crotonamide;
N-(Ethylglycinate)-2-cyano-3-hydroxycrotonamide;
Cinnamyl 2-cyano-3-hydroxycrotonate;
N-(Epi-4-Carboxycyclohexylmethyl)-2-Cyano-3-hydroxycrotonamide;
N-(2-Methylcyclohexyl)-2-cyano-3-hydroxy crotonamide;
N-(2-Hydroxy-2-phenylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(3-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-(Furfuryl)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Methoxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Methylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-((-)-cis-Myrtanyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Ethylphenyl)ethy]-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxy-crotonic acid aziridinyl amide;
N-[2-(4-Hydroxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
2-Phenylethyl-2-cyano-3-hydroxycrotonamide; 2-Cyano-3-hydroxycrotonic 4-chlorocinnamimide;
2-Cyano-3-hydroxycrotonic cinnamimide;
(4(S)-Benzyl-2-oxazolidinone)-2-cyano-3-hydroxycrotonimide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2',4'-dichlorophenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4'-methoxyphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyanc-3-hydroxy-3-(4'-t-butylphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(trαns-phenylcyclopropyl)-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-biphenyl-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3',4',5'-tri-methoxy-phenyl)- acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-trifluoromethylphenyl)acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(furan-2-yl)acrylamide;
N-(4-Trifluoτomethylphenyl)-2-cyano-3-hydroxy-5-phenyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-methyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carboxyethylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-ethyl-oct-2-enoic acid amide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hycdroxy-3-(2-thienylmethyl)crotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-heptadieneamide;
(3-Furanyl)methyl 2-cyano-3-hydroxycrotonate;
2-(1-Piperidyl)ethyl 2-cyano-3-hydroxycrotonate;
3-Pyridyl 2-cyano-3-hydroxycrotonate;
4-(2-methyl-5-(p-nitrophenyl)oxazolyl)methyl 2-cyano-3-hydroxycrotonate;
7-Chloro-4-quinolyl 2-cyano-3-hydroxycrotonate;
2-(4-Nitrophenyl)ethyl 2-cyano-3-hydroxycrotonate;
2-(4-Nitrophenyl)ethyl 4,4,4-trifluoro-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonyl hydroxamide;
N-Benzyl-2-cyano-3-hydroxycrotonyl hydroxamide;
N-(7-Trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)-2-cyano-3-hydroxycrotonamide; N-Cycloleucyl-2-cyano-3-hydroxycrotonamide;
N-(L-Tyrosinyl methyl ester)-2-cyano-3-hydroxycrotonamide;
N-(1-Homopiperidinyl)-2-cyano-3-hydroxycrotonylhydrazide;
N-[2-(2-Carboxy)norbornyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Thienylmethyl)-2-cyano-3-hydroxycrotonamide;
N-(2,6-Dimethylmorpholinyl)-2-cyano-3-hydroxycrotonamide;
N-N-Dimethylaminoethyl-2-cyano-3-hydroxycrotonamide; N-[2-(1-Cyclohexenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-Benzyl-N-(2-norbornyl)-2-cyano-3-hydroxycrotonamide;
N-Convolvinyl-2-cyano-3-hydroxycrotonamide;
N-(4-Propylpiperidinyl)-2-cyano-3-hydroxycrotonamide;
N-{4-[(4-Hydroxy-3-t-butyl)-phenoxyethoxy]phenyl}-2-cyano-3-hydroxycrotonamide;
N-4-[2-(Phenylaminocarbonyl)propionyl]phenyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methyl-1- amyl)-2-cyano-3-hydroxy-4,4,4-trifluorocrotonamide;
N-(5-Morpholinylamyl)-2-cyano-3-hydroxycrotonamide;
N-(5-Diisopropylamino-1,3,4-thiadiazole-2-yl)-2-cyano-3-hydroxycrotonamide;
N-(L-Prolyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-(L-Leucyl-t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-( 1 -Cyanocyclopentylmethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(1-Carboxycycloheptyl)ethyl]-2-cyano -3-hydroxycrotonamide;
N-{4-[2-(2-Methoxyethoxy)ethoxy]phenyl}-2-cyano-3-hydroxycrotonamide;
N-(Glycine trityl ester)-2-cyano-3-hydroxycrotonamide;
N-{[2-(2-Chlorophenyl)]-1-oxocyclohexan-2-yl hydrochloride}-2-cyano- 3-hydroxycrotonamide;
N-(5-exo-Norbomen-2-yl)-N-methyl-2-cyano-3-hydroxycrotonamide;
N-(β-Alanyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-Pyrrolidinyl-2-cyano-3-hydroxy-4,4,4-triluforocrotonic acid hydrazide;
N-Moipholinyl-2-cyano-3-hydroxy-4,4,4-trifluorocrotonic acid hydrazide;
N-(3-Methylbutyl)-4,4,4-trifluoro-2-cyano-3-hydroxycrotonamide;
1-(3-Phenyl-2-cyano-3-hydroxyacryloylamido)-4-(4-toluenesulfonylamino)benzene; N-Butyl-3-phenyl-2-cyano-3-hydroxyacrylamide;
3-Hydroxypropyl 1-(3-phenyl-2-cyano-3-hydroxyacryloyl) ketone;
2-Methylypropyl 1 -(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
2-Methoxyethyl 3-(4-nitrophenyl)-2-cyano-3-hydroxyacrylate;
1,1,2,2,3,3,3-Heptafluoropropyl 1-(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone; 3-Furanylmethyl 1-(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
N-4-(3-Nitrophenyl)thiazol-2-yl 3-(2-methoxyphenyl)-3-hydroxy-2-cyanoacrylamide; N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-fluorophenyl)isoxazole-4-carboxamide;
N-(4-Fluorophenyl)-5-(4-fluorophenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(carbomethoxymethyl)isoxazole-4-carboxan-ide;
N-(4-Trifluoromethylphenyl)-5-(2-carbomethoxyethyl)isoxazole-4-carboxamide;
N-(2-Pyridyl)-5-(2-benzylphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-carboethoxypropyl)isoxazole-4-carboxamide; N-(4-t-Butylphenyl)-5-(methoxymethyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-furanyl)isoxazole-4-carboxamide;
N-(2-Bromophenyl)-5-(4-hexadecyloxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2,4-bis(1,1,2-trifluoro-2-chloroethoxy)phenyl) isoxazole- 4-carboxamide;
N-(2-Bromophenyl)-5-(5,6,7,8-tetrahyydro-2-naphthyl)isoxazole-4-carboxamide;
N-(2,5-Dimethoxyphenyl)-5-(2-thienyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-N,N dimethylsulfonamidophenyl)isoxazole-
4-carboxamide;
N-(4-Fluorophenyl)-5-(E -2-phenylethylenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-methylsulfonylphenyl)isoxazole-4-carboxamide;
N-Morpholino-5-(4-phenoxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-((2-phenoxyethoxy)phenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(4-t-butylphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-nitro-4-(2-(4-(2-(2,4,4,trimethylpentyl) phenoxy) ethoxy)phenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-carbomethoxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide;
N-(2-(5-(4-t-Butylphenyl)thienyl))-5-(3-butenyl)isoxazole-4-carboxamide;
N-(4-(4-Trifluoromethylphenyl)phenyl)-5-(4-cyanophenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(6-undecyl)isoxazole-4-carboxamide
N-(4-Trifluoromethylphenyl)-5-(3,5-bis(trifluoromethyl)phenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(1-adamantyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(E -3-pentenyl)isoxazole-4-carboxamide;
4-Trifluoromethylphenyl 5-((phenylsulfonyl)methyl)isoxazole-4-carboxylate;
α-Naphthyl 5-((thiophenyl)methyl)isoxazole-4-carboxylate;
2-Methylypropyl (5-(2-pyridyl)-4-isoxazolyl) ketone;
3-Furanyl (5-(2-propenyl)-4-isoxazolyl) ketone;
1,1,2,2,3,3,3-Heptafluoropropyl (5-cyclohexyl-4-isoxazolyl) ketone;
N-[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-fluorophenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-fluorophenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carbomethoxy crotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-carbomethoxy-2-pentenamide;
N-(2-Pyridyl)-2-cyano-3-hydroxy-3-(2-benzylphenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-6-carboethoxy-2-hexenarnide;
N-(4-t-Butylphenyl)-2-cyano-3-hydroxy-4-methoxy crotonamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-hexadecyloxyphenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2,4-bis(1,1,2-trifluoro-2-chloroethoxy)phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(5,6,7,8-tetrahydro-2-naphthyl)
acrylamide;
N-(4-Trifluoromemylphenyl)-2-cyano-3-hydroxy-3-(2-thienyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-N,N dimethylsulfonamido phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-methylsulfonylphenyl) acrylamide;
N-Morpholino-2-cyano-3-hydroxy-3-(4-phenoxyphenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-((2-phenoxyethoxy)phenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-nitro-4-(2-(4-(2-(2,4,4,Trimethylpentyl) phenoxy) ethoxy)phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-carbomethoxyphenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-methoxy-2-pentenamide;
N-(2-(5-(4-t-Butylphenyl)thienyl))-2-cyano-3-hydroxy-2,6-heptadienamide;
N-(4-(4-Trifluoromethylphenyl)phenyl)-2-cyano-3-hydroxy-3-(4-cyanophenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-(n-pentyl)non-2-enamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3,5-bis(trifluoromethyl) phenyl)
acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(1-adamantyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-octadienamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxy-4-phenylsulfonyl crotonate;
α-Naphthyl 2-cyano-3-hydroxy-4-thiophenyl crotonate;
2-(4-Trifluoromethylphenyl)ethyl 2-cyano-3-hydroxy-5-methoxy-2-pentenoate;
3-Furanyl (1-cyano-2-hydroxy-2,4 pentadienyl) ketone;
2-Methylypropyl (1-cyano-2-hydroxy-2-(2-pyridyl)ethylenyl) ketone; and
1,1,2,2,3,3,3-Heptafluoropropyl (1-cyano-2-hydroxy-2-cyclohexylethylenyl) ketone; and the respective pharmaceutically acceptable salts, esters and prodrugs thereof.
Of these, preferred examples include those selected from the group consisting of
5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-fluorophenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-phenylpropylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-nitrophenyl)ethylamide;
5-Methyl-isoxazole-4-hydroxamic acid benzylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-fluorophenylhydrazide;
5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-1,2,3,4-tetrahydroquinolinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid isobutylamide;
5-Methyl-isoxazole-4-carboxylic acid (n-pentyl)amide;
5-Methyl-isoxazole-4-carboxylic acid pyrrolidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid morpholinohydrazide;
5-Methyl-isoxazole-4-carboxylic acid 4-trifluoromethylbenzamide;
5-Methyl-isoxazole-4-carboxylic acid 2-fluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid trαns-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cis-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid diethylamide;
5-Methyl-isoxazole-4-carboxylic acid ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2,2,2-trifluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid allylamide;
5-Methyl-isoxazole-4-carboxylic acid propargylamide;
5-Methyl-isoxazole-4-carboxylic acid (acetonitrile)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methoxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-methoxypropyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-diethoxyacetal)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-thioethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxybutyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-piperidinoethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylpiperazino)amide;
5-Methyl-isoxazole-4-carboxylic acid (ethylglycinate)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-propionic acid)amide;
5-Methylisoxazole-4-carboxylic acid (1-piperidino)amide;
5-Methylisoxazole-4-carboxylic acid (4-chlorophenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methylcyclohexyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (2-norbornyl)amide;
5-Methyl-4-{4-(3-trifluoromethylphenyl)piperazine-1-ylcarbonyl}-isoxazole;
5-Methyl-isoxazole-4-carboxylic acid (cyclobutylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (norephedrine)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methoxycarbonylcyclohexylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N- { (4-phenyl)-benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(4-phenoxy)-benzylamide;
5-Methyl-isoxazole-4-carboxylic acid {2-[(2-chloro-4-t-butyl-phenoxy)methyl]benzyl}amide; 5-Methyl-isoxazole-4-carboxylic acid (furfuryl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-trifluoromethoxyphenyl)hydrazide ;
5-Methyl-isoxazole-4-carboxylic acid {(-)-cis-myrtanyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (3-aminopropyl)amide;
5-Methylisoxazole-4-carboxylic acid (4-methoxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(4S)-benzyloxazolidinone}imide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(+)-norephedrine}amide;
5-Methyl-isoxazole-4-carboxylic acid (4-ethylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {2-hydroxy-5-(7-chloro-6- (ethoxycarbonylmethoxy)benzisoxazol-3-yl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid {4-(2,3-dichloro-4- (ethoxycarbonylmethoxy)benzoyl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (aziridinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-phenylethyl )amide;
5-Methyl-isoxazole-4-carboxylic acid cinnamimide;
5-Methyl-isoxazole-4-carboxylic acid 4-chlorocinnamimide;
5-Methyl-isoxazole-4-carboxylic acid {L-(S)-amphetamine}amide;
5-(3-Butenyl) isoxazole-4-carboxylic acid (4-trifluoromethylphenyl)amide;
2-(4-Trifluoromethylphenyl)ethyl 5-methyl isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
2-(4-Fluorophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
4-Chlorophenethyl 5-methylisoxazole-4-carboxylate;
4-Trifluoromethylphenyl 5-methylisoxazole-4-carboxylate;
Cinnamyl 5-methylisoxazole-4-carboxylate;
2-(3-Trifluoromethylphenyl)ethyl 5-methylisoxazole-4-carboxylate;
3-Phenylbutyl 5-methylisoxazole-4-carboxylate; N[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Phenylpropyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-methoxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-ethoxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-[2-(4-Trifluoromethylphenyl)ethyl-2-cyano-3-hydroxycrotonate;
N-[n-Pentyl]-2-cyano-3-hydroxycrotonamide;
N-(Isobutyl)-2-cyano-3-hydroxycrotonamide;
N-(trαns-4-tert-Butylcyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(cis-4-tert-Butyl cyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(2-Fluoroethyl)-2-cyano-3-hydroxycrotonamide;
N,N-Diethyl-2-cyano-3-hydroxycrotonamide;
N-Ethyl-2-cyano-3-hydroxycrotonamide;
N-(2,2,2-Trifluoroethyl)-2-cyano-3-hydroxycrotonamide;
N-[2(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonamide;
N-Allyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methoxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(3-Methoxypropyl)-2-cyano-3-hydroxycrotonamide;
N-Acetonitrile-2-cyano-3-hydroxycrotonamide;
N-Propargyl-2-cyano-3-hydroxycrotonamide;
N-(2-Hydroxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(4-Hydroxybutyl)-2-cyano-3-hydroxycrotonamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxycrotonimide;
3-Phenyl-1-butyl-2-cyano-3-hydroxycrotonate;
N-(Acetic acid)-2-cyano-3-hydroxycrotonamide;
N-(2-Norbomyl)-2-cyano-3-hydroxycrotoamide;
N-(3-Propionic acid)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Piperidin-1-ylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Cyclobutylmethyl-2-cyano-3-hydroxy crotonamide;
N-(Ethylglycinate)-2-cyano-3-hydroxycrotonamide;
Cinnamyl 2-cyano-3-hydroxycrotonate;
N-(Epi-4-Carboxycyclohexylmethyl)-2-Cyano-3-hydroxycrotonamide; N-(2-Methylcyclohexyl)-2-cyano-3-hydroxy crotonamide;
N-(2-Hydroxy-2-phenylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(3-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-(Furfuryl)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Methoxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Methylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-((-)-cis-Myrtanyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Ethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxy-crotonic acid aziridinyl amide;
N-[2-(4-Hydroxyphenyl)ethy]-2-cyano-3-hydroxycrotonamide;
2-Phenylethyl-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxycrotonic 4-chlorocinnamimide;
2-Cyano-3-hydroxycrotonic cinnamimide;
(4(S)-Benzyl-2-oxazolidinone)-2-cyano-3-hydroxy-crotonimide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2',4'-dichlorophenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyanc-3-hydroxy-3-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4,-methoxyphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4'-t-butylphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(trαns-phenylcyclopropyl)-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-biphenyl-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3',4,,5'-tri-methoxy-phenyl)- aciylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-trifluoromethylphenyl)acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(furan-2-yl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-phenyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-methyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carboxyethylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-ethyl-oct-2-enoic acid amide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-thienylmethyl)crotonamide; and N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-heptadieneamide and the respective pharmaceutically acceptable salts, esters and prodrugs thereof.
In a further aspect of the present invention, pharmaceutical compositions are disclosed which comprise a therapeutically effective amount of a compound of the invention in combination with a pharmaceutically acceptable carrier. In yet another aspect of the present invention is disclosed a method of producing immunosuppression in a patient in need of such treatment, which comprises administering to the patient a therapeutically effective amount of a compound of the invention.
Detailed Description of the Invention
Preferred compounds of the present invention include those in which D is hydrogen or -C(O)R9, where R9 is as described above.
Also preferred are the compounds of the invention in which E is -NR14R15, -OR14 or -SR14, and especially those where E is -NR14R15. Particularly preferred among these compounds are those in which R14 is X'-,Y'- and Z'-substituted aryl, heterocyclic,
-heterocyclic-aryl or -aryl-heterocyclic, and those in which R15 is hydrogen, -(C1-to-C6 alkyl) or -(C1-to-C6 haloalkyl). Other preferred compounds of the invention include those compounds in which G is hydrogen, -(C1-to-C6 alkyl), -(C1-to-C6 haloalkyl) or X-, Y- and Z-substituted phenyl, and especially where G is methyl.
As used above and throughout this specification and in the appended claims, the following terms have the meanings specified:
The term "acyl" as used herein refers to a carbonyl group to which is appended an alkyl, heterocyclic or aryl residue where aryl, heterocyclic and alkyl have the definitions specified below.
The terms "alkenyl" and "loweralkenyl" as used herein refer to a branched or straight chain comprising two to ten carbon atoms which also comprises one or more carbon-carbon double bonds.
The terms "alkoxy" and "loweralkoxy" as used herein refer to a loweralkyl group, as defined below, attached to the remainder of the molecule through an oxygen atom. Alkoxy and loweralkoxy groups include, for example, methoxy, ethoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy, rm-butoxy and the like.
The term "alkoxycarbonyl" as used herein refers to an alkoxy group, as previously defined, attached to the parent molecular moiety through a carbonyl, -C(O)-.
Alkoxycarbonyl includes, but is not limited to, ethoxycarbonyl, methoxycarbonyl, isopropoxycarbonyl and the like.
The term "alkyl" as used herein refers to a monovalent straight chain or branched chain group of one to twelve carbon atoms including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n -butyl, sec-butyl, isobutyl, tert-butyl and the like.
The terms "alkylamino" and "loweralkylamino" as used herein refers to a group having the structure -NH-(loweralkyl), where the loweralkyl portion is as defined below. Alkylamino and loweralkylamino groups include, for example, methylamino, ethylamino, isopropylamino and the like. The term "amidoalkyl" as used herein refers to a group having the structure
-N R101C(O) R102 appended to a loweralkyl group, as previously defined. The groups R101 and R102 are independently selected from hydrogen, lower alkyl, aryl, arylalkyl, and halosubstituted alkyl. Additionally, R101 and R102, taken together, may optionally be -(CH2)aa- where aa is an integer of from two to six.
The term "aminoalkyl" as used herein refers to a group having the structure
-NR103 R104 appended to a loweralkyl group, as previously defined. The groups Rϊ03 and R104 are independently selected from hydrogen, lower alkyl, aryl and arylalkyl.
Additionally, R103 and R104, taken together, may optionally be -(CH2)bb- where bb is an integer of from two to six.
The term "aryl" as used herein refers to substituted and unsubstituted carbocyclic aromatic groups including, but not limited to, phenyl, 1- or 2-naphthyl, fluorenyl,
(1,2)-dihydronaphthyl, (1,2,3,4)-tetrahydronaphthyl, indenyl, indanyl and the like, optionally substituted with 1, 2 or 3 substituents independently selected from halo, nitro, cyano, C1 to C12 alkyl, alkoxy and halosubstituted alkyl.
The term "arylalkyl" as used herein refers to an aryl group, as previously defined, appended to an alkyl group including, but not limited to, benzyl, 1- and 2-naphthylmethyl, halobenzyl, alkoxybenzyl, hydroxybenzyl, aminobenzyl, nitrobenzyl, guanidinobenzyl, fluorenylmethyl, phenylmethyl(benzyl), 1-phenylethyl, 2-phenylethyl, 1-naphthylethyl and the like.
The term "arylalkoxy" as used herein refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Arylalkoxy includes, but is not limited to, benzyloxy, 2-phenethyloxy, 1-naphthylmethyloxy and the like.
The term "arylalkoxycarbonyl" as used herein refers to an arylalkyl group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-. Arylalkoxycarbonyl includes, but is not limited to, benzyloxycarbonyl,
2-phenethyloxycarbonyl, 1-naphthylmethyloxycarbonyl and the like.
The term "arylalkylamino" as used herein refers to a group having the structure -NR103-(arylalkyl), where the arylalkyl portion is as previously defined. Examples of arylalkylamino groups include benzylamino, 1-phenylethylamino and the like.
The term "aryloxy" as used herein refers to an aryl group, as previously defined, attached to the parent molecular moiety through an oxygen atom. Aryloxy includes, but is not limited to, phenoxy, 1-naphthoxy, 2-naphthoxy and the like.
The term "aryloxycarbonyl" as used herein refers to an aryloxy group, as previously defined, attached to the parent molecular moiety through a carbonyl group, -C(O)-. Aryloxycarbonyl includes, but is not limited to, phenoxycarbonyl, 1-naphthoxycarbonyl, 2-naphthoxycarbonyl and the like.
The term "arylsulfonyl" as used herein refers to an aryl group, as previously defined, attached to the parent molecular moiety through a sulfonyl group, -S(O)2-. Arylsulfonyl includes, but is not limited to, benzenesulfonyl, 1- or 2-naphthylsulfonyl and the like.
The term "biaryl" as used herein refers to a group where two substituted or unsubstituted aryl groups as defined above arc directly bound to each other including, but not limited to, biphenyl, 1-phenyl naphthyl, and the like.
The term "bicycloalkyl" as used herein refers to a ring system comprised of two fused cycloalkyl groups as defined below, including, but not limited to, norbornyl, norbornenyl and pinenyl.
The term "(bicycloalkyl)alkyl" as used herein refers to a bicycloalkyl group as defined above appended to a lower alkyl group including, but not limited to, norbomylmethyl and pinenylethyl .
The term "carboxyalkyl" as used herein refers to a carboxyl group, -CO2H, appended to a loweralkyl group, as previously defined.
The term "cycloalkyl" as used herein refers to cyclic groups of three to eight carbons including, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term "(cycloalkylalkyl" as used herein refers to a cycloalkyl group appended to a lower alkyl group including, but not limited to, cyclohexylmethyl and cyclohexylethyl.
The term "guanidinoalkyl" as used herein refers to a group of the structure
-NR105C(=NR106)NHR107 appended to a loweralkyl group, as previously defined. The substituents R105, R106 and R107 are independently selected from hydrogen, lower alkyl, heterocyclic, aminoalkyl and aryl. Alternatively, R106, and R107, taken together, may optionally be -(CH2)cc- wherein cc is an integer of from two to six.
The terms "halo" and "halogen" as used herein refer to an atom selected from fluorine, chlorine, bromine and iodine.
The term "haloalkyl" as used herein refers to alkyl groups as defined above containing one or more halogen atoms including, but not limited to, trifluoromethyl,
1,1-dichloroethyl, 1,1-difluoro-2,2-dichloroethyl, and the like.
The term "heterocyclic" as used herein, except where otherwise specified, refers to any aromatic or non-aromatic 5-, 6- or 7-membered ring or a bi- or tricyclic group comprising fused five, six or seven-membered rings having between one and three heteroatoms independently selected from oxygen, sulfur and nitrogen, wherein (i) each 5-membered ring has 0 to 2 double bonds and each 6-membered ring has 0 to 3 double bonds, (ii) the nitrogen and sulfur heteroatoms as well as the carbon atoms may optionally be oxidized by unsaturation and/or introduction of hydroxy, thiol, oxo, thiooxo, (iii) the nitrogen heteroatom may optionally be quaternized, (iv) any of the above heterocyclic rings may be fused to a benzene ring, and (v) Any carbon or heteroatom with suitable valence may bear a substituent. Representative heterocycles include, but are not limited to, pyrrolyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, cytosinyl, thiocytosinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, xanthenyl, xanthonyl, xanthopterinyl, oxazoyl, oxazolidinyl, thiouracilyl, isoxazolyl, isoxazolidinyl, morpholinyl, indolyl, quinolinyl, uracilyl, urazolyl, uricyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, isoquinolinyl, thyminyl,
ben-dmidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
The terms "hydroxyalkyl" and "hydroxyloweralkyl" as used herein refer to -OH appended to a loweralkyl group, as defined below.
The term "hydroxy-protecting group" as used herein refers to those groups which are known in the art to protect a hydroxyl group against undesirable reaction during synthetic procedures and to be selectively removable including, but not limited to, methylthiomethyl, tert-dimethylsilyl, tm-butyldiphenylsilyl, acyl substituted with an aromatic group and other groups found in Protective Groups in Organic Synthesis, 2nd Ed., Greene, T.W. John Wiley & Sons, New York, 1991.
The term "loweralkyl" as used herein refers to an alkyl group, as defined above, of one to eight carbon atoms.
The terms "thioalkoxy" and "thioloweralkoxy" as used herein refer to a loweralkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom. Examples of thioalkoxy and thioloweralkoxy groups include, but are not limited to, thiomethoxy, thioethoxy, thioisopropoxy, n-thiobutoxy, s-thiobutoxy, isothiobutoxy, f-thiobutoxy and the like.
The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy group, as defined above, appended to a loweralkyl group.
The term "thioarylalkoxy" as used herein refers to an arylalkyl group, as previously defined, attached to the remainder of the molecule through a sulfur atom.
The term "thioaryloxy" as used herein refers to an aryl group, as defined above, attached to the remainder of the molecule through a sulfur atom.
The term "pharmaceutically acceptable salts, esters, amides and prodrugs" as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention. The term "salts" refers to the relatively non-toxic, inorganic and organic acid addition salts of compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds or by separately reacting the purified compound in its free base form with a suitable organic or inorganic acid and isolating the salt thus formed. Representative salts include the hydrobromide, hydrochloride, sulfate, bisulfate, phosphate, nitrate, acetate, oxalate, valerate, oleate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactiobionate and laurylsulphonate salts and the like. These may include cations based on the alkali and alkaline earth metals, such as sodium, lithium, potassium, calcium, magnesium and the like, as well as nontoxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine and the like. (See, for example S. M. Berge, et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) which is incorporated herein by reference.)
Examples of pharmaceutically acceptable, non- toxic esters of the compounds of this invention include C1 to C6 alkyl esters wherein the alkyl group is a straight or branched chain. Acceptable esters also include C5-to-C7 cycloalkyl esters as well as arylalkyl esters such as, but not limited to benzyl. C1-to-C6 alkyl esters are preferred. Esters of the compounds of the present invention may be prepared according to conventional methods.
Examples of pharmaceutically acceptable, non-toxic amides of the compounds of this invention include amides derived from ammonia, primary C1-to-C6 alkyl amines and secondary C1-to-C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary amines the amine may also be in the form of a 5 or 6 membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1-to-C3 alkyl primary amides and C1-to -C2 dialkyl secondary amides are preferred. Amides of the compounds of the invention may be prepared according to conventional methods.
The term "prodrug" refers to compounds that are rapidly transformed in vivo to yield the parent compound of the above formula, for example by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference.
Where appropriate, prodrugs of derivatives of compounds of the present invention may be prepared by any suitable method. For those compounds in which the prodrug moiety is an amino acid or peptide functionality, the condensation of the amino group with amino acids and peptides may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC (dicyclohexylcarbodiimede) method, the active ester method (p -nitrophenyl ester method, N-hydroxysuccinic acid imide ester method, cyanomethyl ester method and the like), the Woodward reagent K method, the DCC-HOBT (1-hydroxy-benzotriazole) method and the like. Classical methods for amino acid condensation reactions are described in "Peptide Synthesis" Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
Numerous asymmetric centers may exist in the compounds of the present invention. Except where otherwise noted, the present invention contemplates the various stereoisomers and mixtures thereof. Accordingly, whenever a bond is represented by a wavy line, it is intended that both steric orientations are intended.
The compounds of the invention, including but not limited to those specified in the examples, possess immunomodulatory activity in animals. As immunosuppressants, the compounds are expected to be useful in the treatment and/or prevention of rejection of transplanted organs or tissues, such as kidney, heart, lung, bone marrow, skin or cornea transplants, and also in the treatment or prevention of autoimmune, inflammatory, proliferative, and hypeiproliferative diseases, such as rheumatoid arthritis, lupus
erythematosus, sytemic lupus erythematosus, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, Hashimoto's thyroiditis, nephrotic syndrome, psoriasis, atopical dermatitis, contact dermatitis, seborrheic dermatitis, graft-versus-host diseases by medulla ossium transplantation, vernal keratocojunctivitis, eczematous dermatises, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedemas, vasculitides, erythemas, cutaneous eosinophilias, alopecia areata and the like.
The compounds of this invention are also expected to find use in the treatment of reversible obstructive airways disease. Further, the compounds of this invention may be indicated in the treatment of diseases caused by intestinal inflammations and allergies, such as Coeliac disease, gastroenteritis, mastocytosis, Crohn's disease, ulcerative colitis, and the like; and food-related allergic diseases which have symptoms remote from the gastrointestinal tract, as for example migraine, rhinitis, and eczema.
Aqueous liquid compositions of the present invention may be particularly useful for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, dysophia epithelialis comeae, leukoma, Mooren's ulcer, sclevitis and Graves' ophthalmopathy) and rejection of corneal
transplantation.
When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound may be administered as pharmaceutical compositions containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. By a "therapeutically effective amount" of the compound of the invention is meant a sufficient amount of the compound to treat gastrointestinal disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgement. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder, activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
The pharmaceutical compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which may be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. By "pharmaceutically acceptable carrier" is meant a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. The term "parenteral" as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and mtraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection include pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), carboxymethylcellulose and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parcnterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, com, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol,
polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, may be prepared as a dry powder which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form may be used in adinixture with a larger-sized pharmaceutically acceptable inert carrier comprising particles having a size, for example, of up to 100 micrometers in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 micrometers.
Altematively, the composition may be pressurized and contain a compressed gas, such as nitrogen or a liquified gas propellant. The liquified propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve therein to any substantial extent The pressurized composition may also contain a surface active agent. The surface active agent may be a liquid or solid non-ionic surface active agent or may be a solid anionic surface active agent It is preferred to use the solid anionic surface active agent in the form of a sodium salt.
A further form of topical administration is to the eye, as for the treatment of immune-mediated conditions of the eye such as automimmune diseases, allergic or inflammatory conditions, and comeal transplants. The compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is maintained in contact with the ocular surface for a sufficient time period to allow the compound to penetrate the comeal and internal regions of the eye, as for example the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris/cilary, lens, choroid/retina and sclera. The pharmaceutically acceptable ophthalmic vehicle may, for example, be an ointment, vegetable oil or an encapsulating material.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic. Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology. Volume XIV, Academic Press, New York, N.Y. 0976), p. 33 et seq.
One or more of the processes discussed below may be then employed to produce the desired compound of the invention. The compounds where E is -NR14R15 or -OR14 may be prepared via condensation of the corresponding isoxazole-4-carboxylic acid or activated derivative with commercially available amines or alcohols thereby providing the respective amide or ester analogs. Many of these materials are prepared from the corresponding isoxazole acid chloride with two equivalents of amine or with an alcohol and a base used as an acid scavenger. Isoxazole-4-carboxylic acids are prepared from commercially available β-dicarbonyl compounds according to published methods involving homologation of the active methvlene followed by hydroxylamine-mediated cyclization (Schenone etal. J. Het Chem. 28 453-457 (1991) and Doleschall et al. J. Chem. Soc, Perkin Trans. 1 1875-1879 (1988), incorporated herein by reference). Those analogs where E is -CR14R15R16 are made using the previously detailed isoxazole synthesis using a β-diketone as the starting material.
Cleavage of the isoxazoles (I) to ring opened analogues (II) may be routinely done using an excess of aqueous sodium hydroxide in a hydroxylic solvent such as methyl or ethyl alcohol at temperatures ranging from ambient to reflux. The resulting hydroxycyanoacrylic acid derivatives are then purified, as for example via recrystallization or flash
chromatography.
Representative of the processes of the invention is reaction Scheme I presented below. In Scheme I, a β-dicarbonyl compound 1 is reacted with a trialkylorthoformate such as triethylorthoformate in acetic anhydride to give the alkoxymethylene-dicarbonyl compound 2. Treatment of 2 with hydroxylamine hydrochloride in an alcoholic solution gives the isoxazole carboxylic acid ethyl ester 3. If necessary, the desired regioisomer is separated, and the purified ester is hydrolyzed under acidic conditions to give the carboxylic acid 4. The acid is activated, for example as the acid chloride 5 using thionyl chloride. Compound 5 is then reacted with the appropriate amines to give carboxamides 6 or the appropriate alcohols to give esters 7.
Analogously when the starting material is a β-diketone 8, rather than a β-ketoester, homologation of the α-methylene group gives the alkoxymethylenediketone 9, as shown in Scheme II. Cyclization with hydroxylamine hydrochloride gives the acyl isoxazole compound 10.
Scheme III shows the ring opening of the isoxazole with base, for example, sodium hydroxide in an alcoholic solution to give the hydroxycyanoacrylic acid derivative 12.
Alternatively, 12 can be prepared by reaction of the corresponding cyanoacetyl precursor 14 with activated acid derivatives (e.g. an acid chloride) 13.
Figure imgf000036_0001
The compounds, processes and uses of the present invention will be better understood in connection with the following examples, which are intended as an illustration of and not a limitation upon the scope of the invention. Both below and throughout the specification, it is intended that citations to the literature are expressly incorporated by reference.
Example 1
5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide
Step A: 5-Methylisoxazole-4-carboxylic acid chloride
5-Methylisoxazole-4-carboxylic acid (prepared following the procedure of Schenone et al) (2.65 g, 20.8 mmol) and 10 mL of SOCl2 were combined and stirred at reflux for 3 hours. The excess SOCl2 was removed by distillation at atmospheric pressure. The residual acid chloride was purified via bulb-to-bulb distillation at high vacuum and ambient temperature thereby affording 2.7 lg of pure tide compound.
Step B: 5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide:
To a solution of the compound resulting from Step A (310 mg, 2.14 mmol) in 5 mL of dry acetonitrile stirred at ambient temperature was added 4-trifluoromethylphenethyl amine (800 mg, 4.23 mmol) in 2 mL of acetonitrile dropwise. After stirring for 75 minutes, the reaction was filtered and the collected precipitate was washed with acetonitrile (2×50 mL). The combined filtrates were concentrated in vacuo and the residual crude amide was purified by recrystallization from toluene and overnight vacuum drying, m.p. 93°C. Anal calcd for C14H13N2O2F3: C, 56.38; H, 4.39; N, 9.39. Found: C, 56.41; H, 4.37; N, 9.18.
Examples 2-64
Following the procedures described in Example 1 but substituting in each case the appropriate amine reagent for the 4-trifluoromethylphenethyl amine of Step B, the following amide derivatives were prepared:
Ex. # Name MP (ºC) % C % H % N % C % H % N
Calcd Calcd Calcd Found Found Found
2 3,5-D-methylisoxazole-4-carboxylic 181 - - - - - - acid 2-(trifluoromethylphenyl)ethyl- amide
3 3,5-Dimethylisoxazole-4-carboxylic 156-7 - - - - - - acid (4-fluorophenyl)amide
4 5-Methyl-isoxazole-4-carboxylic acid 78-80 62.90 5.28 11.28 62.82 5.26 11.26 2-(4-fluorophenyl)ethylamide
5 5-Methyl-isoxazole-4-carboxylic acid 88-92 68.83 6.60 11.47 68.77 6.57 11.51 2-phenylpropylamide
6 5-Methyl-isoxazole-4-carboxylic acid 139-141 56.73 4.76 15.27 56.77 4.85 15.05
2-(4-nitrophenyl)ethylamide
7 5-Methyl-isoxazole-4-hydroxamic acid 116-118 62.06 5.21 12.06 61.86 5.26 11.87 benzylamide
8 5-Methyl-isoxazole-4-carboxylic acid 146-148 56.17 4.29 17.86 55.93 4.32 17.53 4-fluorophenylhydrazide
9 5-Methyl-isoxazole-4-carboxylic acid oil 58.07 4.22 9.03 58.01 4.39 8.68 (7-trifluoromethyl-1,2,3,4- tetrahydroquinolinyl)amide
Example 9: 1H NMR (CDCl3, 300 MHz) δ 1.89-2.0 (m, 2H), 2.34 (s,3H), 2.87 (t, J = 7.5Hz, 2H), 3.70 (t, J = 7.5Hz, 2H),
7.39-7.55 (m, 3H), 8.34 (s, 1H). 13C NMR (CDCI3) δ 11.46, 22.9, 26.2, 44.5, 112.1, 120.8*, 129.6, 138.4, 149.8, 161.7,
170.3 (* indicates resonances with observed C-F couplings).
10 5-Methyl-isoxazole-4-carboxylic acid 100-102 70.29 6.29 10.93 70.56 6.30 10.93 (6-methy 1-1,2,3,4- tetrahydroquinolinyl)amide
11 5-Methyl-isoxazole-4-carboxylic acid 80-81 59.32 7.74 15.37 59.37 7.79 15.33 isobutylamide
12 5-Methyl-isoxazole-4-carboxylic acid 61 61.20 8.21 14.27 61.32 8.12 14.62 (n-pentyl)amide
13 5-Methyl-isoxazole-4-carboxylic acid 175-6 - - - - - pyrrolidinehydrazide
14 5-Methyl-isoxazole-4-carboxylic acid 164 51.18 6.20 19.90 51.15 6.15 19.89 morpholinohydrazide
15 5-Methyl-isoxazole-4-carboxylic acid 148-150 52.36 3.04 9.39 52.10 2.98 9.23 4-trifluoromethylbenzimide
16 5-Methyl-isoxazole-4-carboxylic acid 93-94 48.83 5.26 16.27 48.54 5.21 16.15 2-fluoroethylamide
17 5-Methyl-isoxazole-4-carboxylic acid 98 68.15 9.15 10.60 68.17 9.16 10.51 trαns-4-(t-butylcyclohexyl)amide
18 5-Methyl-isoxazole-4-carboxylic acid 194-5 68.15 9.15 10.60 67.95 8.86 10.51 cis-4-(t-butylcyclohexyl)amide
19 5-Methyl-isoxazole-4-carboxylic acid oil 59.32 7.74 15.37 58.38 7.87 14.66 diethylamide
20 5-Methyl-isoxazole-4-carboxylic acid 99-100 54.53 6.53 18.17 54.50 6.52 18.01 ethylamide
21 5-Methyl-isoxazole-4-carboxylic acid 133-134 40.39 3.38 13.45 40.40 3.30 13.24
2,2,2-trifluoroethylamide
22 5-Methyl-isoxazole-4-carboxylic acid 56-57 57.82 6.60 16.85 57.85 6.11 16.85 allylamide
23 5-Methyl-isoxazole-4-carboxylic acid 131-132 58.53 4.91 17.60 58.31 4.93 16.72 propargylamide
24 5-Methyl-isoxazole-4-carboxylic acid 95-96 50.90 4.27 25.44 50.87 4.33 25.26 (acetonitrile)amide
25 5-Methyl-isoxazole-4-carboxylic acid 68-69 52.16 6.56 15.20 52.16 6.64 15.31 (2-methoxyethyl)amide
26 5-Methyl-isoxazole-4-carboxylic acid 50-51 54.53 7.11 14.13 54.40 7.16 14.06 (3-methoxypropyl)amide
27 5-Methyl-isoxazole-4-carboxylic acid 46-47 54.53 7.48 11.56 54.67 7.39 11.49 (2-diethoxyacetal)amide
28 5-Methyl-isoxazole-4-carboxylic acid 87-89 45.14 5.41 15.04 45.48 5.14 14.86 (2-thioethyl)amide
29 5-Methyl-isoxazole-4-carboxylic acid 112-114 49.40 5.92 16.46 49.33 5.99 16.41 (2-hydroxyethyl)amide
30 5-Methyl-isoxazole-4-carboxylic acid 83 54.53 7.11 14.13 54.46 7.12 13.80 (4-hydroxybutyl)amide
31 5-Methyl-isoxazole-4-carboxylic acid 183-185 52.65 7.36 15.35 52.59 7.33 15.24
(2-piperidinoethyl)amide HCl
32 5-Methyl-isoxazole-4-carboxylic acid 185-187 46.07 6.57 21.49 45.99 6.46 21.56
(4-methylpiperazino)amide HCl
33 5-Methyl-isoxazole-4-carboxylic acid 68-70 50.94 5.69 13.20 51.11 5.53 13.21
(ethylglycinate)amide
34 5-Methyl-isoxazole-4-carboxylic acid 123-126 48.48 5.08 14.13 48.17 5.13 13.70 (3-propionic acid)amide
35 5-Methylisoxazole-4-carboxylic acid 154-156 48.88 6.56 17.10 48.55 6.46 17.33 (1-piperidino)amide hydrochloride
36 5-Methylisoxazole-4-carboxylic acid 110-113 58.99 4.95 10.58 58.85 4.94 10.53 (4-chlorophenethyl)amide
37 5-Methyl-isoxazole-4-carboxylic acid 95-98 64.86 8.11 12.61 64.37 8.09 12.35 (2-methylcyclohexyl)amide
38 5-Methyl-isoxazole-4-carboxylic acid 131-4 65.45 7.27 12.73 65.04 7.34 12.45 (2-norbomyl)amide
39 5-Methyl-4-{4-(3- 165-170 51.14 4.56 11.18 51.05 4.52 11.22 trifluoromethylphenyl)piperazine-1- ylcarbonyl}-isoxazole HCl
40 5-Methyl-isoxazole-4-carboxylic acid 110-112 61.85 7.22 14.43 61.72 7.35 14.70 (cyclobutylmethyl)amide
41 5-Methyl-isoxazole-4-carboxylic acid 118-122 64.6 6.19 10.76 64.53 5.96 10.77 (norephedrine)amide
42 5-Methyl-isoxazole-4-carboxylic acid 95-97.0 60.00 7.14 10.00 60.33 7.09 9.95 (4-methoxycarbonyl- cyclohexylmethyl)amide
43 5-Methyl-isoxazole-4-carboxylic acid 132-135 63.40 5.72 11.37 62.85 5.65 11.17
(2-hydroxyphenethyl)amide
44 5-Methyl-isoxazole-4-carboxylic acid - - - - - - N-methyl-N-{(4-phenyl)- benzyl}amide
45 5-Methyl-isoxazole-4-carboxylic acid - - - - - - N-methyl-N-(4-phenoxy)- benzylamide
46 5-Methyl-isoxazole-4-carboxylic acid oil - - - - - - {2-[(2-chloro-4-t-butyl- phenoxy)methyl]benzyl} amide
47 5-Methyl-isoxazole-4-carboxylic acid 92-93 58.24 4.88 13.58 58.41 4.84 13.52 (furfuryl)amide
48 5-Methyl-isoxazole-4-carboxylic acid 126-128 47.85 3.35 13.95 47.92 3.23 13.90 (4-trifluoromethoxy-phenyl)hydrazide
49 5-Methyl-isoxazole-4-carboxylic acid 107-109 68.67 8.45 10.67 68.63 8.20 10.69 { (-)-cis-myrtanyl}amide
50 5-Methyl-isoxazole-4-carboxylic acid 151-157 43.74 6.42 19.12 40.66 5.95 17.78 (3-aminopropyl)amide hydrochloride
51 5-Methylisoxazole-4-carboxylic acid 80-81 64.60 6.20 10.76 64.64 6.14 10.74 (4-methoxyphenethyl)amide
52 5-Methyl-isoxazole-4-carboxylic acid 116-118 62.93 4.92 9.78 62.89 4.99 9.77 {(4S)-benzyl-oxazolidinone}imide
53 5-Methyl-isoxazole-4-carboxylic acid 86-87 68.83 6.60 11.47 68.80 6.71 11.41 (4-methylphenethyl)amide
54 5-Methyl-isoxazole-4-carboxylic acid 124-125 64.60 6.19 10.76 64.61 6.05 10.77 {(+)-norephedrine} amide
55 5-Methyl-isoxazole-4-carboxylic acid 91-93 69.74 7.02 10.84 69.80 6.91 10.80
(4-ethylphenethyl)amide
56 5-Methyl-isoxazole-4-carboxylic acid 138-40 - - - - - - { 2-hydroxy-5-(7-chloro-6- (ethoxycarbonylmethoxy)benzisoxazo
l-3-yl)benzyl}amide
57 5-Methyl-isoxazole-4-carboxylic acid 98-101 - - - - - - {4-(2,3-dichloro-4- (ethoxycarbonylmethoxy)- benzoyl)benzyl} amide
58 5-Methyl-isoxazole-4-carboxylic acid 97-98 - - - - - - (aziridinyl)amide
59 5-Methyl-isoxazole-4-carboxylic acid 133-135 63.40 5.73 11.38 63.38 5.87 11.31 (4-hydroxyphenethyl)amide
60 5-Methyl-isoxazole-4-carboxylic acid 79-81 67.81 6.13 12.17 67.75 6.07 12.21 (2-phenylethyl)amide
61 5-Methyl-isoxazole-4-carboxylic acid 184-186 65.62 4.72 10.93 66.02 4.95 10.90 cinnamimide
62 5-Methyl-isoxazole-4-carboxylic acid 185-187 57.84 3.81 9.64 58.25 3.75 9.60 4-chlorocinnamimide
63 5-Methyl-isoxazole-4-carboxylic acid 89-91 68.83 6.60 11.46 68.98 6.66 11.47
{L-(S)-amphetamine} amide
64 5-(3-Butenyl) isoxazole-4-carboxylic 103 58.07 4.22 9.03 57.93 4.27 8.89 acid (4-trifluoromethylphenyl)amide
Example 65
2-(4-Trifluoromethylphenyl) ethyl 5-methyl-isoxazole-4-carboxylate
To a solution of the compound resulting from Example 1 Step A (1.20 g, 8.24 mmol), in 12 mL of dry acetonitrile stirred at ambient temperature, was added
4-trifluoromethylphenethyl alcohol (3.04 g, 16 mmol) and pyridine (1.62 g, 20.5 mmol) in 10 mL of acetonitrile portionwise. The reaction was stirred for 8 hours and then 2N HCl was added. The resulting mixture was extracted with EtOAc and the combined organic extracts were washed with water and brine, dried over MgSO4, and filtered. The solvent was removed in vacua to afford crude product which was purified by flash chromatography on silica gel eluting with 40% EtOAc-heptane to afford the desired ester. 1H NMR (CDCI3, 300 MHz) δ 2.57 (s, 3H), 3.11 (t, J = 6.5Hz, 2H), 4.48 (t, J = 6.5Hz, 2H), 7.5-7.7 (AA'BB', 4H), 8.81(s, 1H). 13C NMR d 12.1, 33.9, 64.5, 108.9, 125.0*, 126.5*, 129.7, 130.1, 143.0, 150.3*, 160.1, 174.1 (* indicates resonances with observed C-F couplings).
Examples 66-72
Following the procedures described in Example 65 but substituting in each case the appropriate alcohol reagent for 4-trifluoromethylphenethyl alcohol, the following ester derivatives were similarly prepared:
Ex. # Name MP (ºC) % C % H % N % C % H % N
Calcd Calcd Calcd Found Found Found
66 2-(4-Nitrophenyl)ethyl 5-methyl74-76 56.52 4.38 10.14 56.29 4.24 10.07 isoxazole-4-carboxylate
67 2-(4-Fluoroρhenyl)ethyl 5-methyl40-42 62.65 4.85 5.62 62.81 4.84 5.59 isoxazole-4-carboxylate
68 4-Chlorophenethyl 5-methylisoxazol 73-74 58.77 4.55 5.27 58.81 4.51 5.28 4-carboxylate
69 4-Trifluoromethylphenyl 5- 38-40 53.15 2.97 5.16 53.32 2.88 5.25 methylisoxazole-4-carboxylate
70 Cinnamyl 5-methylisoxazole-4- oil 69.12 5.39 5.76 69.15 5.48 5.53 carboxylate
71 2-(3-Trifluoromethylphenyl)ethyl 5- 26-28 56.19 4.04 4.68 56.21 3.94 4.71 methylisoxazole-4-carboxylate
72 3-Phenylbutyl 5-methylisoxazole-4- oil 69.48 6.61 5.40 69.50 6.76 5.42 carboxylate
Example 73
N-[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide
To the compound resulting from Example 1 (110 mg) in 10 mL of MeOH stirred at 25 °C was slowly added 10 mL of a 2 N NaOH solution . The reaction was then stirred at reflux for 3 hours followed by cooling to ambient temperature. Dilution with 50 mL of water foll wed by acidification with concentrated HCl afforded a precipitate. The collected solid was washed with water and recrystalized twice from EtOH to give the title compound, m.p. 177-178 °C. Anal calcd for C14H13N2O2F3: C, 56.38; H, 4.39; N, 9.39. Found: C, 56.48; H, 4.47; N, 9.02.
Examples 74-123
Following the procedures described in Example 73 but substituting in each case as starting material the product of the Example indicated below for the product of Example 1, the following metabolite derivatives were similarly prepared.
Ex. # Name Starring MP (°C) % C % H % N % C % H % N material Calcd Calcd Calcd Found Found Found
Ex. #
74 N-(2-Phenylproρyl)-2-cyano-3- 5 73-74 68.83 6.60 11.47 68.70 6.56 11.38 hydroxycrotonamide
75 N-[2-(4-Fluorophenyl)ethyl]-2- 4 151-153 62.90 5.28 11.28 62.98 5.28 11.29 cyano-3-hydroxycrotonamide
76 N-[2-(4-Nitrophenyl)ethyl]-2- 6 171-173 56.73 4.76 15.27 51.04 4.28 13.71 cyano-3-hydroxycrotonamide
77 N-(4-Trifluoromethylphenyl)-2- NA 174 54.93 3.90 9.86 55.05 3.86 9.80 cyano-3-methoxycrotonamide
78 N-(4-Trifluoromethylphenyl)-2- NA 138 56.38 4.39 9.39 56.23 4.30 9.40 cyano-3-ethoxycrotonamide
79 N-[2-(4-Fluorophenyl)ethyl]-2- 67 82-84 62.65 4.85 5.62 62.81 4.92 5.61 cyano-3-hydroxycrotonate
80 N-[2-(4- 65 110-112 56.19 4.04 4.68 55.94 4.05 4.56 Trifluoromethylphenyl)-ethyl-2- cyano-3-hydroxycrotonate
81 N-[n-Pentyl]-2-cyano-3- 12 57 61.20 8.21 14.27 61.24 8.32 14.22 hydroxycrotonamide
82 N-(Isobutyl)-2-cyano-3- 11 105-106 59.32 7.74 15.37 59.31 7.79 15.22 hydroxycrotonamide
83 N-(trans-4-tert- 17 155-6 68.14 9.15 10.60 68.17 9.08 10.58 butylcyclohexyl)-2-cyano-3- hydroxycrotonamide
84 N-(cis-4-tert-butyl cyclohexyl)- 18 139 68.14 9.15 10.60 68.13 9.15 10.52 2-cyano-3-hydroxycrotonamide
85 N-(2-Fluoroethyl)-2-cyano-3- 16 92-93 48.83 5.26 16.27 48.73 5.24 16.13 hydroxycrotonamide
86 N,N-Diethyl-2-cyano-3- 19 oil 59.32 7.74 15.37 59.17 7.72 15.17 hydroxycrotonamide
87 N-Ethyl-2-cyano-3- 20 88 54.53 6.53 18.17 54.21 6.53 18.06 hydroxycrotonamide
88 N-(2,2,2-Trifluoroethyl)-2- 21 170-171 40.39 3.38 13.45 39.97 3.29 13.35 cyano-3-hydroxycrotonamide
89 N-[2-(4-Nitrophenyl)ethyl]-2- 66 120-121 56.52 4.38 10.14 56.88 4.50 10.17 cyano-3-hydroxycrotonate
90 N-Benzyl-2-cyano-3- NA 66.65 5.59 12.95 66.41 5.60 12.82 hydroxycrotonamide
91 N-Allyl-2-cyano-3- 22 99-100 57.82 6.06 16.85 57.60 6.00 16.75 hydroxycrotonamide
92 N-(2-Methoxyethyl)-2-cyano-3- 25 62-64 52.16 6.56 15.20 52.35 6.51 15.11 hydroxycrotonamide
93 N-(3-Methoxypropyl)-2-cyano- 26 38-39 54.53 7.11 14.13 54.58 7.04 14.01 3-hydroxycrotonamide
94 N-Acetonitrile-2-cyano-3- 24 167-168 50.90 4.27 25.44 50.94 4.11 25.16 hydroxycrotonamide (dec)
95 N-Propargyl-2-cyano-3- 23 126 58.53 4.91 17.06 58.55 4.83 17.10 hydroxycrotonamide
96 N-(2-Hydroxyethyl)-2-cyano-3- 29 96-97 49.4 5.92 16.46 49.46 5.82 16.45 hydroxycrotonamide
97 N-(4-Hydroxybutyl)-2-cyano-3- 30 84-85 54.53 7.11 14.13 54.64 7.08 13.99 hydroxycrotonamide
98 4-Trifluoromethylphenyl-2- 15 101-103 57.14 6.06 10.52 57.12 5.96 10.50 cyano-3-hydroxycrotonimide
Triethylamine salt
99 3-Phenyl-1-butyl-2-cyano-3- 72 119-125 69.48 6.61 5.40 66.25 6.13 5.07 hydroxycrotonate
100 N-(Acetic acid)-2-cyano-3- NA 148-149 45.65 4.37 15.21 45.75 4.32 15.06 hydroxycrotonamide
101 N-(2-Norbornyl)-2-cyano-3- 38 93-6 65.45 7.27 12.73 65.69 7.25 12.78 hydroxycrotoamide
102 N-(3-Propionic acid)-2-cyano- 34 142-144 48.48 5.08 14.13 48.53 4.94 13.85 3-hydroxy-crotonamide
103 N-[2-(4-Chlorophenyl)ethyl]-2- 36 171-173 58.99 4.95 10.58 58.87 4.80 10.51 cyano-3-hydroxycrotonamide
104 N-(2-Piperidin-1-ylethyl)-2- 31 79-85 47.86 5.74 11.96 46.03 5.27 11.40 cyano-3-hydroxycrotonamide
Trifluoroacetate salt
105 N-[2-(4-Chlorophenyl)ethyl]-2- 68 75-77 58.77 4.55 5.27 58.87 4.40 5.27 cyano-3-hydroxycrotonate
106 N-Cyclobutylmethyl-2-cyano-3- 40 105-107 61.85 7.22 14.43 61.95 7.13 14.44 hydroxy crotonamide
107 N-(Ethylglycinate)-2-cyano-3- 33 122-123 50.94 5.96 13.20 50.78 5.61 13.20 hydroxycrotonamide
108 Cinnamyl 2-cyano-3- 70 101-103 69.12 5.39 5.76 68.91 5.38 5.76 hydroxycrotonate
109 N-(Epi-4- 42 192-195 58.65 6.77 10.53 59.00 6.83 10.55 Carboxycyclohexylmethyl)-2- cyano-3-hydroxycrotonamide
110 N-(2-Methylcyclohexyl)-2- 37 117-120 64.86 8.11 12.61 64.87 8.08 12.61 cyano-3-hydroxy crotonamide
111 N-(2-Hydroxy-2-phenylethyl)- 43 117-118 63.40 5.72 11.37 63.28 5.81 11.28 2-cyano-3-hydroxycrotonamide
112 N-[2-(3- 71 73-83 56.19 4.04 4.68 52.06 3.60 4.37 Trifluoromethylphenyl)ethyl]-2- cyano-3-hydroxycrotonate
113 N-(Furfuryl)-2-cyano-3- 47 108-109 58.24 4.88 13.58 58.03 4.99 13.45 hydroxy-crotonamide
114 N- [2-(4-Methoxyphenyl)ethyl]- 51 131-133 64.60 6.20 10.76 64.51 6.10 10.72 2-cyano-3-hydroxycrotonamide
115 N-[2-(4-Methylphenyl)ethyl]-2- 53 139-141 68.83 6.60 11.47 69.17 6.63 11.53 cyano-3-hydroxycrotonamide
116 N-((-)-cis-Myrtanyl)-2-cyano-3- 49 81-83 68.67 8.45 10.67 68.67 8.25 10.71 hydroxycrotonamide
117 N-[2-(4-Ethylphenyl)ethy]-2- 55 126-127 69.74 7.02 10.84 69.71 7.10 10.83 cyano-3-hydroxycrotonamide
118 2-Cyano-3-hydroxy-crotonic 58 115-116 55.25 5.29 18.41 39.34 4.02 12.99 acid aziridinyl amide
119 N-[2-(4-Hydroxyphenyl)ethy]- 59 151-153 63.40 5.73 11.38 63.18 5.74 11.38 2-cyano-3-hydroxycrotonamide
120 2-Phenylethyl-2-cyano-3- 60 133-135 67.81 6.13 12.17 67.81 5.99 12.12 hydroxycrotonamide
121 2-Cyano-3-hydroxycrotonic 4- 62 143-145 61.30 6.69 10.72 61.28 6.65 10.61 chlorocinnamimide triethylamine
salt
122 2-Cyano-3-hydroxycrotonic 61 116-118 67.20 7.61 11.76 66.98 7.34 11.64 cinnamimide triethylamine salt
123 (4(S)-Benzyl-2-oxazolidinone)- 52 128-130 62.93 4.92 9.78 62.70 4.83 9.72 2-cyano-3-hydroxy-crotonimide
Example 124-139
The following compounds were prepared by the reaction of the corresponding cyanoacetyl precursor with an activated acid derivative, such as an acid chloride, as depicted in scheme III.
Ex. # Name MP (°C) % C % H % N % C % H % N
Calcd Calcd Calcd Found Found Found
124 N-(4-Trifluoromethylphenyl)-2- 187-188 50.90 2.26 6.98 50.85 2.30 6.97 cyano-3-hydroxy-3-(2',4'- dichlorophenyl)acrylamide
125 N-(4-Trifluoromethylphenyl)-2- 244-246 61.45 3.33 8.43 61.26 3.33 8.40 cyano-3-hydroxy-3- phenylcrotonamide
126 N-(4-Trifluoromethylphenyl)-2- 260-262 59.67 3.61 7.73 59.75 3.51 7.69 cyano-3-hydroxy-3-(4'- methoxyphenyl)acrylamide
127 N-(4-Trifluoromethylphenyl)-2- 251-252 64.94 4.93 7.21 65.25 4.99 7.22 cyano-3-hydroxy-3-(4'-t- butylphenyl)acrylamide
128 N-(4-Trifluoromethylphenyl)-2- 200-202 64.51 4.06 7.52 64.88 3.93 7.57 cyano-3-hydroxy-3-(trans- phenylcyclopropyl)-acrylamide
129 N-(4-Trifluoromethylphenyl)-2- 272-274 67.64 3.70 6.85 67.78 3.59 6.89 cyano-3-hydroxy-3-biphenyl- acrylamide
130 N-(4-Trifluoromethylphenyl)-2- 185-186 56.87 4.05 6.63 56.80 4.09 6.63 cyano-3-hydroxy-3-(3',4',5'-trimethoxy-phenyl)-acrylamide
131 N-(4-Trifluoromethylphenyl)-2- 163-165 62.42 3.78 8.08 62.27 3.85 8.18 cyano-3-hydroxy-4- phenylcrotonamide
132 N-(4-Trifluoromethylphenyl)-2- 231-232 54.01 2.51 6.99 53.69 2.50 - cyano-3-hydroxy-3-(4- trifluoromethylphenyl)acrylamide
133 N-(4-Trifluoromethylphenyl)-2- 255-257 55.90 2.81 8.69 56.08 2.77 8.78 cyano-3-hydroxy-3-(furan-2- yl)acrylamide
134 N-(4-Trifluoromethylphenyl)-2- 259-261 63.68 3.65 7.81 63.67 3.53 7.78 cyano-3-hydroxy-5-phenyl-penta- 2,4-dienoic acid amide
135 N-(4-Trifluoromethylphenyl)-2- 192-194 56.76 3.74 9.45 56.73 3.65 9.45 cyano-3-hydroxy-4-methyl-penta- 2,4-dienoic acid amide
136 N-(4-Trifluoromethylphenyl)-2- 190-191 52.63 3.82 8.18 52.67 3.85 8.18 cyano-3-hydroxy-4- carboxyethylcrotonamide
137 N-(4-Trifluoromethylphenyl)-2- 107-108 61.01 5.97 7.91 60.96 5.87 7.87 cyano-3-hydroxy-4-ethyl-oct-2- enoic acid amide
138 N-(4-Trifluoromethylphenyl)-2- 155 54.54 3.15 7.95 54.64 3.12 7.94 cyano-3-hydroxy-3-(2- thienylmethyl)crotonamide
Figure imgf000055_0001
Examples 140-172
Following the procedures described in Example 1 but substituting in each case the appropriate amine reagent for the 4-trifluoromethylphenethyl amine of Step B, the following amide derivatives may be prepared:
Ex. # Name
140 5-Methyl-isoxazole-4-carboxylic acid cycloleucinolamide;
141 5-Methyl-isoxazole-4-carboxylic acid (tyrosine methyl ester)amide;
142 5-Methyl-isoxazole-4-carboxylic acid 1-aminohomopiperidinehydrazide;
143 5-Methyl-isoxazole-4-carboxylic acid (2-amino-2-norbornanecarboxylic acid)amide;
144 5-Methyl-isoxazole-4-carboxylic acid 2-thienylmethylamide;
145 5-Methyl-isoxazole-4-carboxylic acid (2,6-dimethylmorpholine)amide;
146 5-Methyl-isoxazole-4-carboxylic acid 2-(N,N-dimethylamino)ethylamide;
147 5-Methyl-isoxazole-4-carboxylic acid 2-cyclohex-1-enylethy lamide;
148 5-Methyl-isoxazole-4-carboxylic acid N-benzyl-N-norbornylamide;
149 5-Methyl-isoxazole-4-carboxylic acid (convolvinyl)amide;
150 5-Methyl-isoxazole-4-carboxylic acid 4-propylpiperidineamide;
151 5-Methyl-isoxazole-4-carboxylic acid {4-[(4-hydroxy-3-t-butyl)- phenoxyethoxy]phenyl} amide;
152 5-Methyl-isoxazole-4-carboxylic acid 4-[2-(phenylaminocarbonyl)- propionyl]anilide;
153 5-Trifluoromethyl-isoxazole-4-carboxylic acid 3-methyl-1-butylamide;
154 5-Methyl-isoxazole-4-carboxylic acid 5-(l-morpholino)amylamide;
155 5-Methyl-isoxazole-4-carboxylic acid (5-diisopropylamino- 1,3,4- thiadiazol-2-yl)amide;
156 5-Methyl-isoxazole-4-carboxylic acid (L-proline tert-butyl ester)amide;
157 5-Methyl-isoxazole-4-carboxylic acid (L-leucine tert-butyl ester)amide;
158 5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(1- cyano)cyclopentanylamide;
159 5-Methyl-isoxazole-4-carboxylic acid N-ethyl-N-(1- carboxyl)cyclohepty lamide;
160 5-Methyl-isoxazole-4-carboxylic acid 4-[2-(2- methoxyethoxy)ethoxy]anilide;
161 5-Methyl-isoxazole-4-carboxylic acid (glycine trityl ester)amide; 162 5-Methyl-isoxazole-4-carboxylic acid (ketamine hydrochloride)amide;
163 5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(5,6-dehydro-exo-2- norbornyl)amide;
164 5-Methyl-isoxazole-4-carboxylic acid (β-alanine t-butyl ester)amide;
165 4-Trifluoromethylbenzoyl 5-trifluoromemyl-isoxazole-4-carboximide
166 3-(3-Methoxy)phenoxycarbonyl-5-methyl-isoxazole-4-carboxylic acid 3- methylbutylamide;
167 3-(N,N-Dimethylaminocarbonyl)-5-methyl-isoxazole-4-carboxylic acid
3-(4-methoxyphenyl)propylamide;
168 3-(2-Chloro-4-fluorophenacyl)-5-methyl-isoxazole-4-carboxylic acid
cyclohexylamide;
169 N-(5-Phenyl-4-isoxazoyl)-N'-(4-toluenesulfonyl) 1,4 phenylenediamide;
170 5-Phenyl-isoxazole-4-carboxylic acid butylamide;
171 5-Trifluoromethyl-isoxazole-4-carboxylic acid (3-methylbutyl)amide; and
172 5-(2-Methoxyphenyl)-isoxazole-4-carboxylic acid 4-(3-nitrophenyl)thiazol- 2-ylamide.
Examples 173-179
Following the procedures described in Example 65 but substituting in each case the appropriate alcohol reagent for 4-trifluoromethylphenethyl alcohol, the following ester derivatives may be prepared:
Ex. # Name
173 (3-Furanyl)methyl 5-methyl-isoxazole-4-carboxylate;
174 2-(1-Piperidyl)ethyl 5-methyl-isoxazole-4-carboxylate;
175 3-Pyridyl 5-methyl-isoxazole-4-carboxylate;
176 4-[2-Methyl-5-(4-nitrophenyl)oxazolyl]methyl 5-methyl-isoxazole-4- carboxylate;
177 7-Chloro-4-quinolyl 5-methyl-isoxazole-4-carboxylate;
178 2-Methoxyethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate; and
179 2-(4-N-trophenyl)ethyl 5-trifluoromethylisoxazole-4-carboxylate. Example 180
3-Hydroxypropyl (5-phenyl-4-isoxazolyl) ketone
Homologation of the α-methylene group of 1-hydroxy-6-phenylhexane-4,6-dione with triethylorthoformate followed by cyclization with hydroxylamine hydrochloride as depicted in scheme II and described in Schenone et al and Doleschall et al gives the desired tide compound.
Examples 181-183
Following the procedure described in Example 180 but substituting in each case the appropriate β-diketone reagent for the 1-hydroxy-6-phenylhexane4,6-dione above, the following compounds may be prepared:
Ex. # Name
181 2-Methylypropyl (5-trifluoromethyl-4-isoxazolyl) ketone;
182 1,1,2,2,3,3,3-Heptafluoropropyl (5-trifluoromethyl-4-isoxazolyl) ketone; and
183 3-Furanyl (5-trifluoromethyl-4-isoxazolyl) ketone.
Examples 184-229
Following the procedures described in Example 73 but substituting in each case the appropriate isoxazole precursor for the resultant compound of Example 1, the following compounds may be prepared:
Ex. # Name
184 (3-Furanyl)methyl 2-cyano-3-hydroxycrotonate;
185 2-(1-Piperidyl)ethyl 2-cyano-3-hydroxycrotonate;
186 3-Pyridyl 2-cyano-3-hydroxycrotonate;
187 4-(2-methyl-5-(p -nitrophenyl)oxazolyl)methyl 2-cyano-3-hydroxycrotonate;
188 7-Chloro-4-quinolyl 2-cyano-3-hydroxycrotonate;
189 2-(4-Nitrophenyl)ethyl 2-cyano-3-hydroxycrotonate;
190 2-(4-Nitrophenyl)ethyl 4,4,4-trifluoro-2-cyano-3-hydroxycrotonate;
191 N-Benzyl-2-cyano-3-hydroxycrotonyl hydroxamide
192 N-(7-Trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)-2-cyano-3- hydroxycrotonamide;
193 N-Cycloleucyl-2-cyano-3-hydroxycrotonamide; 194 N-(L-Tyrosinyl methyl ester)-2-cyano-3-hydroxycrotonamide;
195 N-(l-Homopiperidinyl)-2-cyano-3-hydroxycrotonylhydrazide;
196 N-[2-(2-Carboxy)norbornyl]-2-cyano-3-hydroxycrotonamide;
197 N-(2-Thienylmethyl)-2-cyano-3-hydroxycrotonamide;
198 N-(2,6-Dimethylmorpholinyl)-2-cyano-3-hydroxycrotonamide;
199 N,N-Dimethylaminoethyl-2-cyano-3-hydroxycrotonamide;
200 N-[2-(1-Cyclohexenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
201 N-Benzyl-N-(2-norbomyl)-2-cyano-3-hydroxycrotonamide;
202 N-Convolvinyl-2-cyano-3-hydroxycrotonamide;
203 N-(4-Propylpiperidinyl)-2-cyano-3-hydroxycrotonamide;
204 N-{4-[(4-hydroxy-3-t-butyl)-phenoxyethoxy]phenyl}-2-cyano-3- hydroxycrotonamide;
205 N-4-[2-(Phenylaminocarbonyl)propionyl]phenyl-2-cyano-3- hydroxycrotonamide;
206 N-(2-Methyl-1-amyl)-2-cyano-3-hydroxy-4,4,4-trifluorocrotonamide;
207 N-(5-Morpholinylamyl)-2-cyano-3-hydroxycrotonamide;
208 N-(5-Diisopropylamino-1,3,4-thiadiazole-2-yl)-2-cyano-3- hydroxycrotonamide;
209 N-(L-Prolyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
210 N-(L-Leucyl-t-butyl ester)-2-cyano-3-hydroxycrotonamide;
211 N-(1-Cyanocyclopentylmethyl)-2-cyano-3-hydroxycrotonamide;
212 N-[(1-Carboxy)cycloheptyl]-N-ethyl-2-cyano-3-hydroxycrotonamide;
213 N-{4-[2-(2-Methoxyethoxy)ethoxy]phenyl}-2-cyano-3-hydroxycrotonamide;
214 N-(Glycine trityl ester)-2-cyano-3-hydroxycrotonamide;
215 N-{[2-(2-Chlorophenyl)]-1-oxocyclohexan-2-yl hydrochloride}-2-cyano-3- hydroxycrotonamide;
216 N-(5-exo-Norbomen-2-yl)-N-methyl-2-cyano-3-hydroxycrotonamide;
217 N-(β-Alanyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
218 N-Pyrrolidinyl-2-cyano-3-hydroxy-4,4,4-trifluorocrotonic acid hydrazide;
219 N-Morpholinyl-2-cyano-3-hydroxy-4,4,4-trifluorocrotonic acid hydrazide;
220 N-4-(3-Nitrophenyl)thiazol-2-yl 3-(2-methoxyphenyl)-3-hydroxy-2- cyanoacrylamide.
221 N-(3-Methylbutyl)-4,4,4-trifluoro-2-cyano-3-hydroxycrotonamide;
222 1 -(3-Phenyl-2-cyano-3-hydroxyacryloylamino)-4-(4- toluenesulfonylamino)benzene;
223 N-Butyl-3-phenyl-2-cyano-3-hydroxyacrylamide; 224 3-Hydroxypropyl (3-phenyl-2-cyano-3-hydroxyacryloyl) ketone;
225 2-Methylypropyl (4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
226 2-Methoxyethyl-3-(4-nitrophenyl)-2-cyano-3-hydroxyacrylate;
227 1,1,2,2,3,3,3-Heptafluoropropyl (4,4,4-trifluoro-2-cyano-3- hydroxycrotonyl)ketone;
228 3-Furanylmethyl (4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone; and
229 2-Furanylmethyl (4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone.
Example 230
N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide
Step A: 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid
Homologation of the α-methylene group of ethyl 5-methoxy-3-oxo-pentanoate with triethylorthoformate followed by cyclization with hydroxylamine hydrochloride as depicted in scheme I and described in Schenone et al and Doleschall et al gives the desired ethyl ester. Hydrolysis under the acidic conditions detailed in the cited references delivers the
corresponding carboxylic acid.
Step B: 4-(2-Methoxyethyl) isoxazole-4-carboxylic acid chloride
The compound resulting from Step A and SOCl2 are combined and stirred at reflux for 3 hours. The excess SOCl2 is removed by distillation at atmospheric pressure. The residual acid chloride is purified via bulb-to-bulb distillation at high vacuum thereby affording the title compound.
Step C: N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide
To a solution of the compound resulting from Step B dry acetonitrile stirred at ambient temperature is added 2 equivalents of 4-trifluoromethylphenethyl amine in acetonitrile dropwise. After stirring for 75 minutes, the reaction is filtered and the collected precipitate is washed with acetonitrile (2×50 mL). The combined filtrates are concentrated in vacua and the residual crude amide is purified by recrystallization from toluene and overnight vacuum drying. Example 231
2-f4-Trifluoromethylphenyl)ethyl 5-(2-methoxyethyl) isoxazole-4-carboxylate
To a solution of the compound resulting from Example 232 Step B in 12 mL of dry acetonitrile stirred at ambient temperature, is added 2 equivalents of
4-trifluoromethylphenethyl alcohol and 1.1 equivalents of pyridine in acetonitrile portionwise. The reaction is stirred for 8 hours and then 2 N HCl is added. The resulting mixture is extracted with EtOAc and the combined organic extracts are washed with water and brine, dried over MgSO4 and filtered. The solvent is removed in vacua to afford crude product which is purified by flash chromatography on silica gel eluting with an
EtOAc-heptane gradient to afford the desired ester.
Examples 232-258
Following the procedures described in Example 230 but substituting in each case the appropriate amine reagent for the 4-trifluoromethylphenethyl amine of Step C, the following amide derivatives may be prepared:
Ex. # Name
232 N-(4-Trifluoromethylphenyl)-5-(2-fluorophenyl)isoxazole-4-carboxamide;
233 N-(4-Fluorophenyl)-5-(4-fluorophenyl)isoxazole-4-carboxamide;
234 N-(4-Trifluoromethylphenyl)-5-(carbomethoxymethyl)isoxazole-4- carboxamide;
235 N-(4-Trifluoromethylphenyl)-5-(2-carbomethoxyethyl)isoxazole-4- carboxamide;
236 N-(2-Pyridyl)-5-(2-benzylphenyl)isoxazole-4-carboxamide;
237 N-(4-Trifluoromethylphenyl)-5-(3-carboethoxypropyl)isoxazole-4- carboxamide;
238 N-(4-t-Butylphenyl)-5-(methoxymethyl)isoxazole-4-carboxamide;
239 N-(4-Trifluoromethylphenyl)-5-(2-furanyl)isoxazole-4-carboxamide;
240 N-(2-Bromophenyl)-5-(4-hexadecyloxyphenyl)isoxazole-4-carboxamide;
241 N-(4-Trifluoromethylphenyl)-5-(2,4-bis(1,1,2-trifluoro-2- chloroethoxy)phenyl) isoxazole-4-carboxamide;
242 N-(2-Bromophenyl)-5-(5,6,7,8-tetrahydro-2-naphthyl)isoxazole-4- carboxamide;
243 N-(2,5-Dimethoxyphenyl)-5-(2-thienyl)isoxazole-4-carboxamide; 244 N-(4-Trifluoromethylphenyl)-5-(3-N,N
dimethylsulfonamidophenyl)isoxazole-4-carboxamide;
245 N-(4-Fluorophenyl)-5-(E -2-phenylethylenyl)isoxazole-4-carboxamide;
246 N-(4-Trifluoromethylphenyl)-5-(2-methylsulfonylphenyl)isoxazole-4- carboxamide;
247 N-Morpholino-5-(4-phenoxyphenyl)isoxazole-4-carboxamide;
248 N-(4-Trifluoromethylphenyl)-5-((2-phenoxyethoxy)phenyl)isoxazole-4- caiboxamide;
249 N-(4-Trifluoromethylphenyl)-5-(4-t-butylphenyl)isoxazole-4-carboxamide;
250 N-(4-Trifluoromethylphenyl)-5-(3-nitro-4-(2-(4-(2-(2,4,4,Trimethylpentyl) phenoxy) ethoxy)phenyl)isoxazole-4-carboxamide;
251 N-(4-Trifluoromethylphenyl)-5-(2-carbomethoxyphenyl)isoxazole-4- carboxamide;
252 N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide;
253 N-(2-(5-(4-t-Butylphenyl)thienyl))-5-(3-butenyl)isoxazole-4-carboxamide;
254 N-(4-(4-Trifluoromethylphenyl)phenyl)-5-(4-cyanophenyl)isoxazole-4- carboxamide;
255 N-(4-Trifluoromethylphenyl)-5-(6-undecyl)isoxazole-4-carboxamide
256 N-(4-Trifluoromethylphenyl)-5-(3,5-bis(trifluoromethyl)phenyl)isoxazole-4- carboxamide;
257 N-(4-Trifluoromethylphenyl)-5-(1-adammtyl)isoxazole-4-carboxamide; and
258 N-(4-Trifluoromethylphenyl)-5-(E -3-pentenyl)isoxazole-4-carboxamide.
Examples 259-260
Following the procedures described in Example 232 but substituting in each case the appropriate alcohol reagent for 4-trifluoromethylphenethyl alcohol, the following ester derivatives may be prepared:
Ex. # Name
259 4-Trifluoromethylphenyl 5-((phenylsulfonyl)methyl)isoxazole-4- carboxylate; and
260 α-Naphthyl 5-((thiophenyl)methyl)isoxazole-4-carboxylate. Example 261
2-Methylypropyl (5-(2-pyridyl )-4-isoxazoIyl) ketone
Homologation of the α-methylene group of 1-(2-pyridyl)-5-methyl-1,3-hexanedione with triethylorthoformate followed by cyclization with hydroxylamine hydrochloride as depicted in scheme 13 and described in Schenone et al and Doleschall et al gives the desired tide compound.
Examples 262-263
Following the procedure described in Example 261 but substituting in each case the appropriate β-diketone reagent for the 1-(2-pyridyl)-5-methyl-1,3-hexanedione above, the following compounds may be prepared:
Ex. # Name
262 3-Furanyl (5-(2-propenyl)-4-isoxazolyl) ketone; and
263 1,1,2,2,3,3,3-Heptafluoropropyl (5-cyclohexyl-4-isoxazolyl) ketone.
Example 264
N-[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hvdroxycrotonamide
To the compound resulting from Example 230 in MeOH stirred at 25 °C is slowly added 2 N NaOH solution . The reaction is then stirred at reflux for 3 hours followed by cooling to ambient temperature. Dilution with 50 mL of water followed by acidification with concentrated HCl affords a precipitate. The collected solid is washed with water and recrystalized twice from EtOH to give the tide compound.
Examples 265-294
Following the procedures described in Example 266 but substituting in each case the appropriate isoxazole precursor for the resultant compound of Example 232, the following compounds may be prepared: Ex. # Name
265 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-fluorophenyl)
acrylamide;
266 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-fluorophenyl)
acrylamide;
267 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carbomethoxy
crotonamide;
268 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-carbomethoxy-2- pentenamide;
269 N-(2-Pyridyl)-2-cyano-3-hydroxy-3-(2-benzylphenyl) acrylamide;
270 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-6-carboethoxy-2- hexenamide;
271 N-(4-t-Butylphenyl)-2-cyano-3-hydroxy-4-methoxy crotonamide;
272 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-hexadecyloxyphenyl) acrylamide;
273 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2,4-bis(1,1,2-trifluoro- 2-chloroethoxy)phenyl) acrylamide;
274 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(5,6,7,8-tetrahydro-2- naphthyl) acrylamide;
275 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-thienyl) acrylamide;
276 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-N,N
dimethylsulfonamido phenyl) acrylamide;
277 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2- methylsulfonylphenyl) acrylamide;
278 N-Morpholino-2-cyano-3-hydroxy-3-(4-phenoxyphenyl) acrylamide;
279 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-((2- phenoxyethoxy)phenyl) acrylamide;
280 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-nitro-4-(2-(4-(2- (2,4,4,Trimethylpentyl) phenoxy) ethoxy)phenyl) acrylamide;
281 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-carbomethoxyphenyl) acrylamide;
282 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-methoxy-2-pentenamide;
283 N-(2-(5-(4-t-Butylphenyl)thienyl))-2-cyano-3-hydroxy-2,6-heptadienamide;
284 N-(4-(4-Trifluoromethylphenyl)phenyl)-2-cyano-3-hydroxy-3-(4- cyanophenyl) acrylamide; 285 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-(n-pentyl)non-2- enamide;
286 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3,5-bis(trifluoromethyl) phenyl) acrylamide;
287 N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(1-adamantyl)
acrylamide;
288 N-(4-Trifluoromethylρhenyl)-2-cyano-3-hydroxy-2,6-octadienamide;
289 4-Trifluoromethylphenyl-2-cyano-3-hydroxy-4-phenylsulfonyl crotonate;
290 α-Naphthyl 2-cyano-3-hydroxy-4-thiophenyl crotonate;
291 2-(4-Trifluoromethylphenyl)ethyl 2-cyano-3-hydroxy-5-methoxy-2- pentenoate;
292 3-Furanyl (1-cyano-2-hydroxy-2,4 pentadienyl) ketone;
293 2-Methylypropyl (1-cyano-2-hydroxy-2-(2-pyridyl)ethylenyl) ketone;
294 1,1,2,2,3,3,3-Heptafluoropropyl (1-cyano-2-hydroxy-2- cyclohexylethylenyl) ketone.
Example 295
In vitro Assay of Biological Activity
The in vivo immunosuppressant activity of the compounds of the present invention was determined using the human mixed lymphocyte reaction (HMLR) assay described by Kino, T. et al. in Transplantation Proceedings, XIX(5):36-39, Suppl. 6 (1987).
The in vitro immunosuppressant activity of the compounds of the present invention was also determined in a one way allogeneic mixed leukocyte response (MLR) assay using rat lymph node and spleen cells, conducted as follows: Responder cells were obtained from the lymph nodes of Brown Norway rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) and the stimulator cells were isolated from the spleens of Lewis rats (Harlan Sprague Dawley, Inc., Indianapolis, IN). 200-250 gram rats were sacrificed by asphyxiation with CO2 and the popliteal and mesenteric lymph nodes or spleen were removed by sterile dissection. The tissue was placed in RPMI 1640 supplemented with 10 % heat-inactivated fetal bovine serum, 2 mM L-glutamine, 50 μM 2-mercaptoethanol, 50 units/mL penicillin G, and 50 μg/mL streptomycin (complete RPMI medium). After mechanically disrupting the tissue and allowing debris to settle at 1 × g, the suspended cells were aspirated. The cell suspensions were centrifuged 10 min at 400 × g and the responder cells resuspended in complete RPMI medium at 2 X 106 cells/mL. To remove red cells, the spleen cells were suspended in 0.14 M NH4CI/0.017 M Tris-HCl lysing buffer, pH 7.4, for 2 minutes, mixed with RPMI 1640, and centrifuged as before. The spleen cells were subsequendy washed three times by centrifugation in RPMI 1640. To inhibit their ability to proliferate, spleen cells were suspended at 1 × 107 cells/mL in complete RPMI medium and incubated in the presence of 25 μg/mL of mitomycin C for 30 minutes at 37 °C. The mitomycin C-treated spleen cells were washed three times by centrifugation in RPMI 1640 before being suspended in complete RPMI medium at 4 × 106 cells/mL.
For the MLR, 1 × 105 lymph node cells were mixed with 5 × 105 mitomycin
C-treated spleen cells in 0.2 mL of complete RPMI 1640 and cultured in 95% air / 5% CO2 atmosphere for 120 hours at 37 °C. Test compounds were dissolved at 10 mM in
dimethylsulfoxide, diluted in complete RPMI medium, and 25 μL of the test compound was added to the lymph node cells before addition of the spleen cells. During the final 6 hours, the cells were labeled with 0.5 μCi per well of tritiated thymidine (3H-TdR; DuPont NEN Research Products, Boston, MA). The cells were harvested by vacuum filtration onto glass fiber filters and the filter radioactivity measured with a MATRIX 9600 direct beta counter (Packard Instrument Company, Meriden, CT).
The results of the in vitro and in vivo assays, shown below in Table 1, demonstrate that the compounds tested are effective immunomodulators at micromolar concentrations.
Table 1
Example Human MLR Rat MLR
% Inhibition % Inhibition
at 10 μM* at 10 μM*
1 < 10 50
2 < 10 < 10
3 < 10 < 10
4 13 25
5 18(0.1) < 10
6 25(0.1) < 10
7 17 < 10
8 < 10 80
9 < 10 26
10 68 <10
11 42 -
12 43 -
13 < 10 < 10
14 < 10 < 10
15 38 13 (0.1) 16 42 29
17 55 50
18 32 <10
19 19 12
20 20 15
21 24 34
22 48 46(0.1)
23 45 29
24 44 <10
25 25 <10
26 44 38(0.1)
27 26 23
28 36 24
29 36 21
30 36 44
31 50 25
32 17 12
33 27 23
34 27 <10
35 <10 <10
36 31 25
37 <10 39
38 <10 20
39 36 27
40 37 <10
41 50 15
42 39 <10
43 27 16
44 46 38
45 34 <10
46 94 99
47 22 42(0.1)
48 30 25
49 75 13
50 54 16
51 40 98 52 <10 35
53 45 52(0.1)
54 <10 32
55 40 <10
56 39 48
57 55 26
58 35 <10
59 38 <10
60 34 <10
61 49 19
62 48 <10
63 46 100
64 33 <10
65 28(0.01) <10
66 46 13 (0.1)
67 29 43
68 40 <10
69 19 <10
70 25 43(0.1)
71 25 19
72 43 73
73 21 79
74 <10 <10
75 <10 75
76 22 <10
77 34 <10
78 25(1.0) 38
79 <10 <10
80 21 <10
81 64 <10
82 33 -
83 <10 <10
84 <10 <10
85 44 27
86 35 27
87 46 49(0.1) 88 <10 <10
89 34 -
90 26 <10
91 53 <10
92 34 32
93 55 20
94 32 33(1.0)
95 29 <10
96 30 24
97 31 <10
98 40 61(0.1)
99 18 <10
100 36 <10
101 36 <10
102 19 <10
103 <10 38
104 52 <10
105 <10 <10
106 44 <10
107 26 27(1.0)
108 25 <10
109 25 38(1.0)
110 32 <10
111 63 <10
112 53 35
113 30 <10
114 36 <10
115 74 100
116 53 39(1.0)
117 48 32
118 <10 <10
119 31 <10
120 35 65
121 31 18
122 <10 <10
123 39 <10 124 < 10 < 10
125 < 10 22
126 18 < 10
127 30 64
128 31 35(1.0)
129 45 45
130 38 33(0.1)
131 42 < 10
132 50 < 10
133 45 < 10
134 32 36(1.0)
135 46 97
136 < 10 75
137 29 23(1.0)
138 57 17
139 30 21(1.0)
* Concentration at 10 μM unless otherwise indicated in parentheses
It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the disclosed embodiments will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to the chemical structures, substituents, derivatives, intermediates, syntheses, formulations and/or methods of use of the invention, may be made without departing from the spirit and scope thereof.

Claims

What is claimed is:
1. A compound having a formula selected from the group consisting of
Figure imgf000071_0001
Figure imgf000071_0002
and
Figure imgf000071_0003
and the respective pharmaceutically acceptable salts, esters and prodrugs thereof, wherein
E is selected from the group consisting of -R14, -NR14R15, -SR14, -OR14, and
-CR14R15R16, where R14, R15 and R16 are independently selected from the group consisting of
(I) hydrogen;
(II) -NR6R7, where R6 and R7 are independently selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) alkenyl,
(d) acyl,
(e) aryl,
(f) heterocyclic,
(g) biaryl,
(h) cycloalkyl,
(i) arylalkyl,
(j) hydroxyalkyl, and
(k) arylsulfonyl,
and each radical R6 and R7, when other than hydrogen, is optionally substituted with between one and three substituents independently selected from the group consisting of
(i) halogen,
(ii) haloalkyl,
(iii) haloalkoxy,
(iv) -CHO, (v) -CN,
(vi) -C(O)OH,
(vii) -C(O)O-(C1-to-C6 alkyl),
(viii) -N3,
(ix) -NO2,
(x) -OH, and
(xi) oxo;
(III) -(C1-to-C10 alkyl), where alkyl comprises straight and branched alkyl, cycloalkyl, (cycloalkyl)alkyl, bicycloalkyl and (bicycloalkyl)alkyl, optionally substituted with between one and six substituents independently selected at each instance from the group consisting of
(a) R10, where R10 is selected at each instance from the group consisting of
(i) halogen,
(ii) haloalkyl,
(iii) haloalkoxy,
(iv) -OH,
(v) -(CH)mNR6R7, where m is zero to six,
(vi) -CHO,
(vii) -(CH2)mOR6,
(viii) -CH(OR12')(OR12"), where R12' and R12" are independently
-(C1-to-C3 alkyl) or, taken together, form an ethylene or propylene bridge,
(ix) -(CH2)m-OC(O)R6,
(x) -CN,
(xi) -C(O)OH,
(xii) -C(O)O-(C1-to-C6 alkyl),
(xiii) -C(O)NR6R7,
(xiv) -(C3-to-C7 cycloalkyl),
(xv) aryl substituted with X, Y and Z,
(xvi) -NO2,
(xvii) -N3,
(xviii) guanidino, optionally substituted with a substituent selected from the group consisting of loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl, (xix) -OR11, where R11 is selected at each instance from the group consisting of
(a') -P(O)(OH)O-M+, where M+ is a positively charged inorganic or organic counterion,
(b') -S(O)2O-M+, and
(c') -CO(CH2)mC(O)O-M+,
(xx) oxo,
(xxi) epoxy,
(xxii) thiooxo,
(xxiii) -SH,
(xxiv) -S(O)sR6, where s is zero, one or two, and
(xxv) -S(O)tNR6R7, where t is one or two, where X, Y, and Z are each independently selected at each instance from the group consisting of
(a') hydrogen,
(b') halogen,
(c') haloalkyl,
(d') -(C1-to-C7 alkyl),
(e') -(C2-to-C6 alkenyl),
(f') -(C2-to-C6 alkynyl),
(g') -(CH2)mNR6R7,
(h') -CN,
(i') -CHO,
(j') -(CH2)mOR6,
(k') -(CH2)mC(O)OR6,
(I') -(CH2)mOC(O)R6,
(m') -CH(OR12')(OR12"),
(n') -C(O)NR6R7,
(o') -NO2,
(p') -N3,
(q') guanidino optionally substituted with a substituent selected from the group consisting of lower alkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl and alkylsulfonyl,
(r') -OR11
(s') -S(O)sR6, and (t') -S(O)tNR6R7,
or any two adjacent of X, Y and Z, taken together with the carbon atoms to which they are attached, form a 5- to 7-membered ring which includes between zero and two additional heteroatoms independently selected from the group consisting of -O-, -S(O)s- and -N(R8)-,
(b) R10', where R10' is selected at each instance from the group consisting of
(i) -(CH2)mNR6'R7',
(ii) -(CH2)mOR6',
(iii) -(CH2)mOC(O)R6',
(iv) -C(O)NR6'R7',
(v) -S(O)tNR6'R7',
(vi) -S(O)sR6',
(vii) aryl substituted with X', Y' and Z', where X', Y' and Z' are independently selected at each instance from the group consisting of
(a') X, Y and Z,
(b') -(CH2)mNR6'R7',
(c') -(CH2)mOR6',
(d') -(CH2)mC(O)OR6',
(e') -(CH2)mOC(O)R6',
(f') -C(O)NR6'R7',
(g') -S(O)tNR6'R7', and
(h') -S(O)sR6', and
(viii) heterocyclic substituted with X', Y' and Z' where R6' and R7' are independently selected at each instance from the group consisting of
(i) hydrogen,
(ii) -(C1-to-C10 alkyl) optionally substituted with between one and six substituents selected from the group consisting of
(a') R10,
(b') biaryl substituted with X, Y and Z,
(c') -Q-aryl where aryl is substituted with X, Y and Z, (d') -Q-heterocyclic where heterocyclic is subsiituted with X, Y and Z, (e') -Q-biaryl, where biaryl is substituted with X, Y and Z,
(f') -aryl-Q-aryl', where aryl and aryl' are each
independently substituted with X, Y and Z,
(g') -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X, Y and Z,
(h') -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X, Y and Z,
(i') -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X, Y and Z, and
(j') -NR8R8', where R8 and R8'are independently selected at each instance from the group consisting of
(i') hydrogen,
(ii') -R10 other than halogen, -NO2 and -N3, (iii') -(C1-to-C6 alkyl) optionally substituted with between one and three substituents R55 where each R55 is independently selected from the group consisting of amino, aryl, guanidino, heterocyclic, monoalkylamino, dialkylamino, acylamino, alkoxycarbonylamino, arylalkyloxycarbonylamino, aryloxycarbonylamino, acylguanidino, arylsulfonylguanidino, alkoxycarbonylguanidino,
arylalkyloxycarbonylguanidino, aryloxycarbonylguanidino, alkoxycarbonyl, alkylsulfonyl, arylsulfonyl, N-alkylcarboxamido, N,N-dialkylcarboxamido, N-arylcarboxamido and N,N-diarylcarboxamido,
(iv') -(C2-to-C6 alkenyl) optionally substituted with between one and three substituents R55, and
(v') -(C3-to-C6 alkynyl) optionally substituted with between one and three substituents R55,
or where R8and R8' and the nitrogen atom to which they are attached form an optionally substituted 3- to 7-membered heterocyclic ring which includes between zero and two additional heteroatoms independently selected from the group consisting of -O-, -S(O)s- where s is zero, one or two, and -NR8-,
(k') -S(O)sR8, and
(l') -S(O)tNR8R8',
(iii) aryl substituted with X, Y and Z, and
(iv) heterocyclic substituted with X, Y and Z, or where R6' and R7' and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring comprising between zero and two additional heteroatoms independently selected from the group consisting of -O-, -S(O)s- and -NR8-, in which each ring valency is substituted with a compatible radical selected from the group consisting of
(i) -R66, and
(ii) -QR66, where R66 is selected at each instance from the group consisting of
(a') hydrogen,
(b') R10,
(c') aryl substituted with X, Y and Z
(d') heterocyclic substituted with X, Y and Z,
(e') biaryl substituted with X, Y and Z,
(f') -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X, Y and Z,
(g') -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X, Y and Z,
(h') -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X, Y and Z,
(i') -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X, Y and Z,
(j') -NR8R8',
(k') -S(O)sR8, and
(1') -S(O)tNR8R8', and where Q is selected at each instance from the group consisting of
(i) -(C1-to-C6 alkylene)-,
(ii) -(C2-to-C6 alkenylene)-,
(iii) -(C2-to-C6 alkynylene)-,
(iv) -(CH2)mO-, where m is zero to six,
(v) -O(CH2)m-, where m is zero to six,
(vi) -N(R8)C(O)-,
(vii) -C(O)N(R8)-,
(viii) -S(O)s-, where s is zero, one or two,
(ix) -N(R8)-,
(x) -N(R8)S(O)t-,
(xi) -S(O)tN(R8)-,
(xii) -C(O)-,
(xiii) -N=N- and (xiv) -C(S)-,
(c) heterocyclic substituted with X, Y and Z,
(d) biaryl substituted with X, Y and Z,
(e) -Q-aryl,
(f) -Q-heterocyclic where heterocyclic is substituted with X, Y and Z,
(g) -Q-biaryl, where biaryl is substituted with X, Y and Z,
(h) -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X, Y and Z,
(i) -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X, Y and Z,
(j) -heterocyclic-Q-aryl, where heterocyclic and aryl are each
independently substituted with X, Y and Z, and
(k) -aryl-Q-heterocyclic, where heterocyclic and aryl are each
independently substituted with X, Y and Z;
(IV) -(C2-to-Cιo alkenyl), where alkenyl comprises branched, unbranched, cyclic and bicyclic alkenyl, optionally substituted with between one and six substituents independently selected at each instance from the group consisting of
(a) R10,
(b) R10',
(c) heterocyclic substituted with X, Y and Z,
(d) biaryl substituted with X, Y and Z,
(e) -Q-aryl, where aryl is substituted with X, Y and Z,
(f) -Q-heterocyclic, where heterocyclic is substituted with X, Y and Z,
(g) -Q-biaryl, where biaryl is substituted with X, Y and Z,
(h) -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X, Y and Z,
(i) -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X, Y and Z,
(j) -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X, Y and Z, and
(k) -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X, Y and Z; (V) -(C3-to-C10alkynyl), where alkynyl comprises branched and cyclic alkynyl, optionally substituted with between one and six substituents independently selected at each instance from the group consisting of
(a) R10,
(b) R10',
(c) heterocyclic substituted with X, Y and Z,
(d) biaryl substituted with X, Y and Z,
(e) -Q-aryl, where aryl is substituted with X, Y and Z,
(f) -Q-heterocyclic, where heterocyclic is substituted with X, Y and Z,
(g) -Q-biaryl, where biaryl is substituted with X, Y and Z,
(h) -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X, Y and Z,
(i) -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X, Y and Z,
(j) -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X, Y and Z, and
(k) -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X, Y and Z;
(VI) aryl substituted with X', Y' and Z'.
(VII) heterocyclic substituted with X', Y' and Z';
(VIII) biaryl substituted with X', Y' and Z';
(IX) -aryl-heterocyclic, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(X) -heterocyclic-aryl, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(X) -Q-aryl where aryl is substituted with X', Y' and Z';
(XI) -Q-heterocyclic where heterocyclic is substituted with X', Y' and Z';
(XII) -Q-biaryl, where biaryl is substituted with X', Y' and Z';
(XIII) -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X', Y' and Z';
(XIV) -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X', Y' and Z';
(XV) -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X', Y' and Z'; and
(XVI) -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X', Y' and Z'; D is selected from the group consisting of
(I) hydrogen;
(II) loweralkyl;
(III) -C(O)R9 where R9 is selected from the group consisting of
(a) hydrogen,
(b) -OH,
(c) -O-M+,
(d) -(C1-to-C4 alkyl), where alkyl comprises branching alkyl,
(e) -(C1-to-C4 alkoxy), where alkoxy comprises branching alkoxy,
(f) -(C1-to-C4 hydroxyalkyl),
(g) -(C1-to-C4 thioalkyl),
(h) -(CH2)nn-(phenyl), where nn is between zero and four,
(i) -(CH2)n-NR4R5,
(j) -(CH2)m-(morpholino),
(k) -NR4R5,
(l) -C(O)NR4R5, where R4 and R5 are independently selected from the group consisting of
(i) -hydrogen,
(ii) -(C1-C6 alkyl) optionally substituted with halogen, and
(iii) phenyl substituted with X, Y and Z,
(m) -C(O)OR4,
(n) phenyl substituted with X, Y and Z,
(o) -O-phenyl, where phenyl is substituted with X, Y and Z,
(p) -O-(CH2)m -(morpholino), and
(q) -S-(CH2)nn-(phenyl);
(IV) phenyl;
(V) 2-chlorophenyl;
(VI) 2,4-dichlorophenyl; and
(VII) 2-chloro-4-fluorophenyl; and
G is selected from the group consisting of
(I) -NR24R25, where R24 and R25 and the nitrogen atom to which they are attached form a 3- to 7-membered heterocyclic ring comprising between zero and two additional heteroatoms independently selected from the group consisting of -O-, -S(O)s- and -NR8-, in which each ring valency is substituted with a compatible radical selected at each instance from the group consisting of
(a) -R66,
(b) -Q-R66,
(c) -R67, and
(d) -Q-R67,
where R67 is selected at each instance from the group consisting of
(i) -CH(OR12')(OR12"), and
(ii) guanidino optionally substituted with a substituent selected from the group consisting of loweralkyl, aryl, acyl, arylsulfonyl, alkoxycarbonyl, arylalkoxycarbonyl, aryloxycarbonyl, alkylsulfonyl;
(II) aryl substituted with X', Y' and Z';
(III) heterocyclic substituted with X', Y' and Z';
(IV) biaryl substituted with X', Y' and Z';
(V) -heterocyclic-aryl, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(VI) -aryl-heterocyclic, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(VII) -Q-aryl , where aryl is substituted with X', Y' and Z';
(VIII) -Q-heterocyclic, where heterocyclic is substituted with X', Y' and Z';
(IX) -Q-biaryl, where biaryl is substituted with X', Y' and Z';
(X) -aryl-Q-aryl', where aryl and aryl' are each independently substituted with X', Y' and Z';
(XI) -heterocyclic-Q-heterocyclic', where heterocyclic and heterocyclic' are each independently substituted with X', Y' and Z';
(XII) -heterocyclic-Q-aryl, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(XIII) -aryl-Q-heterocyclic, where heterocyclic and aryl are each independently substituted with X', Y' and Z';
(XIV) -R14;
(XV) -OR14;
(XVI) -S(O)sR14;
(XVII) -CR14R15R16;
(XVIII) -C=CR14R15;
(XIX) -C≡CC14; (XX) -ONR14;
(XXI) -NR14R15; and
(XXII) Z, subject to the provisos that
(I) when E is -NHCH2-(heterocyclic), then G is other than pyrrolyl;
(II) when E is selected from the group consisting of
(a) -N(R2)-[(C1-to-C10 alkylene)-C(O)O-(C1-to-C4 alkyl)], where R2 is selected from the group consisting of
(i) hydrogen
(ii) -(C1-to-C4 alkyl),
(iii) phenyl, and
(iv) benzyl,
(b) -N(R2)-(aryl),
(c) -N(R2)-(heterocyclic),
(d) -N(R2)-(heterocyclic)-(aryl),
(e) -N(R2)-(biaryl),
(f) -N(R2)-(phenyl)-O-(aryl),
(g) -N(R2)-(phenyl)-C(O)-(aryl),
(h) -N(R2)-C(CH3)2-CH2-(aryl),
(i) -OH,
(j) -NH2,
(k) -SH,
(l) methyl,
(m) hydrogen,
(n) N-morpholino,
(o) N-thiomorpholino, and
(p) N-piperidinyl optionally substituted with -(C1-to-C2 alkyl), then G is other than R77 where R77 is a substituent selected from the group consisting of
(a) -(C1-to-C6 alkyl) optionally substituted with halogen,
(b) phenyl,
(c) benzyl, and
(d) -(C3-to-C6 cycloalkyl); (III) when E is selected from the group consisting of -S-phenyl and -O-phenyl where phenyl is substituted with X, Y and Z, then G is other than -(C1-to-C4 alkyl); and
(IV) when E is phenyl substituted with X, Y and Z, then G is other than a substituent selected from the group consisting of
(a) -(C1-to-C4 alkyl) optionally substituted with halogen,
(b) -(C1-to-C4 alkenyl) optionally substituted with halogen,
(c) -(C5-to-C6 cycloalkenyl),
(d) -(C3-to-C6 cycloalkyl),
(e) -(phenyl)-R76, where R76 is a substituent selected from the group consisting of
(i) -C(O)R77,
(ii) -CN,
(ui) -NO2,
(iv) -NR78R79, where R78 and R79 are independently selected from the group consisting of -(C1-to-C6 alkyl) radicals, and
(v) halogen,
(f) -(benzyl)-R76, and
(g) -C(O)OR77.
2. A compound according to Claim 1 wherein D is selected from the group consisting of hydrogen and -C(O)R9.
3. A compound according to Claim 1 wherein G is selected from the group consisting of
(a) hydrogen,
(b) -(C1-to-C6 alkyl), including branching alkyl, optionally substituted with between one and six halogen substituents, and
(c) phenyl substituted with X, Y and Z.
4. A compound according to Claim 3 wherein G is methyl.
5. A compound according to Claim 1 wherein E is selected from the group consisting of -NR14R15, -OR14 and -CR14R15R16.
6. A compound according to Claim 5 wherein E is -NR14R15.
7. A compound according to Claim 6 wherein R14 is selected from the group consisting of
(a) aryl substituted with X', Y' and Z',
(b) heterocyclic substituted with X', Y' and Z',
(c) -aryl-heterocyclic, where aryl and heterocyclic are each independently substituted with X', Y' and Z', and
(d) -heterocyclic-aryl, where aryl and heterocyclic are each independently substituted with X', Y' and Z'.
8. A compound according to Claim 6 wherein R15 is selected from the group consisting of
(a) hydrogen,
(b) -(C1-to-C6 alkyl), where alkyl comprises branched alkyl, and
(c) -(C1-to-C6 alkyl) substituted with between one and six halogen substituents.
9. A compound according to Claim 2 wherein
E is selected from the group consisting of -NR14R15, -OR14 and -CR14R15R16;
D is hydrogen; and
G is selected from the group consisting of
(a) hydrogen,
(b) -(C1-to-C6 alkyl), including branching alkyl, optionally substituted with between one and six halogen substituents, and
(c) phenyl substituted with X, Y and Z.
10. A compound selected from the group consisting of
5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-fluorophenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-phenylpropylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-nitrophenyl)ethylamide;
5-Methyl-isoxazole-4-hydroxamic acid benzylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-fluorophenylhydrazide;
5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-1,2,3,4-tetrahydroquinolinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid isobutylamide; 5-Methyl-isoxazole-4-carboxylic acid (n-pentyl)amide;
5-Methyl-isoxazole-4-carboxylic acid pyrrolidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid morpholinohydrazide;
5-Methyl-isoxazole-4-carboxylic acid 4-trifluoromethylbenzimide;
5-Methyl-isoxazole-4-carboxylic acid 2-fluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid trαns-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cis-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid diethylamide;
5-Methyl-isoxazole-4-carboxylic acid ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2,2,2-trifluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid allylamide;
5-Methyl-isoxazole-4-carboxylic acid propargylamide;
5-Methyl-isoxazole-4-carboxylic acid (acetonitrile)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methoxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-methoxypropyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-diethoxyacetal)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-thioethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxybutyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-piperidinoethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylpiperazino)amide;
5-Methyl-isoxazole-4-carboxylic acid (ethylglycinate)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-propionic acid)amide;
5-Methylisoxazole-4-carboxylic acid (1-piperidino)amide;
5-Methylisoxazole-4-carboxylic acid (4-chlorophenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-norbomyl)amide;
5-Methyl-4-{4-(3-trifluoromethylphenyl)piperazine-1-ylcarbonyl}-isoxazole;
5-Methyl-isoxazole-4-carboxylic acid (cyclobutylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (norephedrine)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methoxycarbonyl-cyclohexylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-{(4-phenyl)-benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(4-phenoxy)-benzylamide;
5-Methyl-isoxazole-4-carboxylic acid {2-[(2-chloro-4-t-butyl-phenoxy)methyl]benzyl}amide; 5-Methyl-isoxazole-4-carboxylic acid (furfuryl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-trifluoromethoxy-phenyl)hydrazide ; 5-Methyl-isoxazole-4-carboxylic acid {(-)-cis-myrtanyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (3-aminopropyl)amide;
5-Methylisoxazole-4-carboxylic acid (4-methoxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(4S)-benzyl-oxazolidinone}imide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(+)-norephedrine}amide;
5-Methyl-isoxazole-4-carboxylic acid (4-ethylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {2-hydroxy-5-(7-chloro-6- (ethoxycarbonylmethoxy)benzisoxazol-3-yl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid {4-(2,3-dichloro-4- (ethoxycarbonylmethoxy)benzoyl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (aziridinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-phenylethyl )amide;
5-Methyl-isoxazole-4-carboxylic acid cinnamimide;
5-Methyl-isoxazole-4-carboxylic acid 4-chlorocinnamimide;
5-Methyl-isoxazole-4-carboxylic acid {L-(S)-amphetamine}amide;
5-(3-Butenyl) isoxazole-4-carboxylic acid (4-trifluoromethylphenyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cycloleucinolamide;
5-Methyl-isoxazole-4-carboxylic acid (tyrosine methyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid 1-aminohomopiperidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid (2-amino-2-norbomanecarboxylic acid)amide; 5-Methyl-isoxazole-4-carboxylic acid 2-thienylmethylamide;
5-Methyl-isoxazole-4-carboxylic acid (2,6-dimethylmorpholin-4-yl)amide;
5-Methyl-isoxazole-4-carboxylic acid 2-(N,N-dimethyl)aminoethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-cyclohex-1-enylethylamide;
5-Methyl-isoxazole-4-carboxylic acid 3-methoxypropylamide;
Ethyl 4-[3,5-di(5-methyl-isoxazole-4-carbonylamino)]-1H-1,2,4-triazolin- 1-yl)benzoate]amide;
5-Methyl-isoxazole-4-carboxylic acid N-benzyl-N-norbomylamide;
5-Methyl-isoxazole-4-carboxylic acid (convolvinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid 4-propylpiperidineamide;
5-Methyl-isoxazole-4-carboxylic acid {4-[(4-hydroxy-3-tert-butyl)- phenoxyethoxy]phenyl}amide;
5-Methyl-isoxazole-4-carboxylic acid 4-[2-(phenylaminocarbonyl)-propionyl]anilide; 5-Trifluoromethyl-isoxazole-4-carboxylic acid 3-methyl-1-butylamide;
5-Methyl-isoxazole-4-carboxylic acid 5-(N-morpholino)pentylamide; 5-Methyl-isox-izole-4-carboxylic acid (5-diisopropylamino-1,3,4-thiadiazol-2-yl)amide; 5-Methyl-isoxazole-4-carboxylic acid (L-proline t -butyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid (L-leucine-t -butyl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(1-cyano)cyclopentylamide;
5-Methyl-isoxazole-4-carboxylic acid N-ethyl-N-(1-carboxyl)cycloheptylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-[2-(2-methoxyethoxy)ethoxy]anilide;
5-Methyl-isoxazole-4-carboxylic acid (glycine trityl ester)amide;
5-Methyl-isoxazole-4-carboxylic acid (ketamine hydrochloride)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(5,6-dehydro-exo-2-norbomyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (β-alanine t -butyl ester)amide;
4-Trifluoromethyl benzoyl 5-trifluoromethyl-isoxazole-4-carboximide;
3-(3-Methoxy)phenoxycarbonyl-5-methyl-isoxazole-4-carboxylic acid 3-methylbutylamide; 3-(N,N-Dimethylaminocarbonyl)-5-methyl-isoxazole-4-carboxylic acid
3-(4-methoxyphenyl)propylamide;
3-(2-Chloro-4-fluorophenacyl)-5-methyl-isoxazole-4-carboxylic acid cyclohexylamide; N (5-Phenyl-4-isoxazoyl)-N'-(4-toluenesulfonyl) 1,4-phenylenediamide;
5-Phenyl-isoxazole-4-carboxylic acid butylamide;
5-Trifluoromethyl-isoxazole-4-carboxylic acid (3-methylbutyl)amide;
5-(2-Methoxyphenyl)-isoxazole-4-carboxylic acid 4-(3-nitrophenyl)thiazol-2-ylamide; 2-(4-Trifluoromethylphenyl)ethyl 5-methyl isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
2-(4-Fluorophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
4-Chlorophenethyl 5-methylisoxazole-4-carboxylate;
4-Trifluoromethylphenyl 5-methylisoxazole-4-carboxylate;
Cinnamyl 5-methylisoxazole-4-carboxylate;
2-(3-Trifluoromethylphenyl)ethyl 5-methylisoxazole-4-carboxylate;
3-Phenylbutyl 5-methylisoxazole-4-carboxylate;
(3-Furanyl)methyl 5-methyl-isoxazole-4-carboxylate;
2-(1-Piperidyl)ethyl 5-methyl-isoxazole-4-carboxylate;
3-Pyridyl 5-methyl-isoxazole-4-carboxylate;
4-[2-Methyl-5-(4-nitrophenyl)oxazolyl]methyl 5-methyl-isoxazole-4-carboxylate;
7-Chloro-4-quinolyl 5-methyl-isoxazole-4-carboxylate;
2-Methoxyethyl 5-(4-nitrophenyl)isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-trifluoromethylisoxazole-4-carboxylate;
3-Hydroxypropyl (5-phenyl-4-isoxazolyl) ketone;
2-Methylypropyl (5-trifluoromethyl-4-isoxazolyl) ketone;
1,1,2,2,3,3,3-Heptafluoropropyl (5-trifluoromethyl-4-isoxazolyl) ketone; 3-Furanyl (5-trifluoromethyl-4-isoxazolyl) ketone;
N[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Phenylpropyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-methoxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-ethoxycτotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-[2-(4-Trifluoromethylphenyl)ethyl-2-cyano-3-hydroxycrotonate;
N-[n-Pentyl]-2-cyano-3-hydroxycrotonamide;
N-(Isobutyl)-2-cyano-3-hydroxycrotonamide;
N-(trαns-4-tert-butylcyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(cis-4-tert-butyl cyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(2-Fluoroethyl)-2-cyano-3-hydroxycrotonamide;
N,N-Diethyl-2-cyano-3-hydroxycrotonamide;
N-Ethyl-2-cyano-3-hydroxycrotonamide;
N-(2,2,2-Trifluoroethyl)-2-cyano-3-hydroxycrotonamide;
N-[2(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonamide;
N-Allyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methoxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(3-Methoxypropyl)-2-cyano-3-hydroxycrotonamide;
N-Acetonitrile-2-cyano-3-hydroxycrotonamide;
N-Propargyl-2-cyano-3-hydroxycrotonamide;
N-(2-Hydroxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(4-Hydroxybutyl)-2-cyano-3-hydroxycrotonamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxycrotonimide;
3-Phenyl-1-butyl-2-cyano-3-hydroxycrotonate;
N-(Acetic acid)-2-cyano-3-hydroxycrotonamide;
N-(2-Norbomyl)-2-cyano-3-hydroxycrotoamide;
N-(3-Propionic acid)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Piperidin-1-ylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Cyclobutylmethyl-2-cyano-3-hydroxy crotonamide;
N-(Ethylglycinate)-2-cyano-3-hydroxycrotonamide;
Cinnamyl 2-cyano-3-hydroxycrotonate; N-(Epi-4-Carboxycyclohexylmethyl)-2-Cyano-3-hydroxycrotonamide;
N-(2-Methylcyclohexyl)-2-cyano-3-hydroxy crotonamide;
N-(2-Hydroxy-2-phenylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(3-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-(Furfuryl)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Methoxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Methylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-((-)-cis-Myrtanyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Ethylphenyl)ethy]-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxy-crotonic acid aziridinyl amide;
N-[2-(4-Hydroxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
2-Phenylethyl-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxycrotonic 4-chlorocinnamimide;
2-Cyano-3-hydroxycrotonic cinnamimide;
(4(S)-Benzyl-2-oxazolidinone)-2-cyano-3-hydroxycrotonimide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2',4'-dichlorophenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4,-methoxyphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4'-t-butylphenyl)acrylamide;
N-(4-Trifluoromemylphenyl)-2-cyano-3-hydroxy-3-(trαns-phenylcyclopropyl)-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-biphenyl-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3',4',5,-tri-methoxy-phenyl)- acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-trifluoromethylphenyl)acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(furan-2-yl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-phenyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-methyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carboxyethylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-ethyl-oct-2-enoic acid amide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-thienylmethyl)crotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-heptadieneamide;
(3-Furanyl)methyl 2-cyano-3-hydroxycrotonate;
2-(1-Piperidyl)ethyl 2-cyano-3-hydroxycrotonate;
3-Pyridyl 2-cyano-3-hydroxycrotonate;
4-(2-methyl-5-(p-nitrophenyl)oxazolyl)methyl 2-cyano-3-hydroxycrotonate;
7-Chloro-4-quinolyl 2-cyano-3-hydroxycrotonate; 2-(4-Nitrophenyl)ethyl 2-cyano-3-hydroxycrotonate;
2-(4-Nitrophenyl)ethyl 4,4,4-trifluoro-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonyl hydroxamide;
N-Benzyl-2-cyano-3-hydroxycrotonyl hydroxamide;
N-(7-Trifluoromethyl-1,2,3,4-tetrahydroquinolinyl)-2-cyano-3-hydroxycrotonamide;
N-Cycloleucyl-2-cyano-3-hydroxycrotonamide;
N-(L-Tyrosinyl methyl ester)-2-cyano-3-hydroxycrotonamide;
N-(1-Homopiperidinyl)-2-cyano-3-hydroxycrotonylhydrazide;
N-[2-(2-Carboxy)norbomyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Thienylmethyl)-2-cyano-3-hydroxycrotonamide;
N-(2,6-Dimethylmorpholinyl)-2-cyano-3-hydroxycrotonamide;
N,N-Dimethylaminoethyl-2-cyano-3-hydroxycrotonamide;
N-[2-(l-Cyclohexenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-Benzyl-N-(2-norbomyl)-2-cyano-3-hydroxycrotonamide;
N-Convolvinyl-2-cyano-3-hydroxycrotonamide;
N-(4-Propylpiperidinyl)-2-cyano-3-hydroxycrotonamide;
N-{4-[(4-Hydroxy-3-t-butyl)-phenoxyethoxy]phenyl}-2-cyano-3-hydroxycrotonamide;
N-4-[2-(Phenylaminocarbonyl)propionyl]phenyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methyl-1-amyl)-2-cyano-3-hydroxy-4,4,4-trifluorocrotonamide;
N-(5-Morpholinylamyl)-2-cyano-3-hydroxycrotonamide;
N-(5-Diisopropylamino-1,3,4-thiadiazole-2-yl)-2-cyano-3-hydroxycrotonamide;
N-(L-Prolyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-(L-Leucyl-t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-(1-Cyanocyclopentylmethyl)-2-cyano-3-hydroxycrotonamide;
N-[(l-Carboxy)cycloheptyl]-N-ethyl-2-cyano-3-hydroxycrotonamide;
N-{4-[2-(2-Methoxyethoxy)ethoxy]phenyl}-2-cyano-3-hydroxycrotonamide;
N-(Glycine trityl ester)-2-cyano-3-hydroxycrotonamide;
N-{[2-(2-Chlorophenyl)]-1-oxocyclohexan-2-yl hydrochloride}-2-cyano- 3-hydroxycrotonamide;
N-(5-exo-Norbomen-2-yl)-N-methyl-2-cyano-3-hydroxycrotonamide;
N-(β-Alanyl t-butyl ester)-2-cyano-3-hydroxycrotonamide;
N-Pyrrolidinyl-2-cyano-3-hydroxy-4,4,4-trifluorocrotonic acid hydrazide;
N-Morpholinyl-2-cyano-3-hydroxy-4,4,4-trifluorocrotonic acid hydrazide;
N-(3-Methylbutyl)-4,4,4-trifluoro-2-cyano-3-hydroxycrotonamide;
1-(3-Phenyl-2-cyano-3-hydroxyacryloylamido)-4-(4-toluenesulfonylamino)benzene; N-Butyl-3-phenyl-2-cyano-3-hydroxyacrylamide;
3-Hydroxypropyl 1-(3-phenyl-2-cyano-3-hydroxyacryloyl) ketone; 2-Methylypropyl 1-(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
2-Methoxyethyl 3-(4-nitrophenyl)-2-cyano-3-hydroxyacrylate;
1,1,2,2,3,3,3-Heptafluoropropyl 1-(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
3-Furanylmethyl 1-(4,4,4-trifluoro-2-cyano-3-hydroxycrotonyl) ketone;
N-4-(3-Nitrophenyl)thiazol-2-yl 3-(2-methoxyphenyl)-3-hychoxy-2-cyanoacrylamide;
N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-fluorophenyl)isoxazole-4-carboxamide;
N-(4-Ruorophenyl)-5-(4-fluorophenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(carbomemoxymethyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-carbomemoxyethyl)isoxazole-4-carboxamide;
N-(2-Pyridyl)-5-(2-benzylphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-carboethoxypropyl)isoxazole-4-carboxamide;
N-(4-t-Butylphenyl)-5-(methoxymethyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-furanyl)isoxazole-4-carboxamide;
N-(2-Bromophenyl)-5-(4-hexadecyloxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2,4-bis(1,1,2-trifluoro-2-chloroethoxy)phenyl) isoxazole- 4-carboxamide;
N-(2-Bromophenyl)-5-(5,6,7,8-tetrahydro-2-naphthyl)isoxazole-4-carboxamide;
N-(2,5-Dimethoxyphenyl)-5-(2-thienyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-N,N dimethylsulfonamidophenyl)isoxazole- 4-carboxamide;
N-(4-Fluorophenyl)-5-(E -2-phenylethylenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-methylsulfonylphenyl)isoxazole-4-carboxamide;
N-Morpholino-5-(4-phenoxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-((2-phenoxyethoxy)phenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(4-t-butylphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(3-nitro-4-(2-(4-(2-(2,4,4,trimethylpentyl) phenoxy)
ethoxy)phenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-carbomethoxyphenyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(2-methoxyethyl)isoxazole-4-carboxamide;
N-(2-(5-(4-t-Butylphenyl)thienyl))-5-(3-butenyl)isoxazole-4-carboxamide;
N-(4-(4-Trifluoromethylphenyl)phenyl)-5-(4-cyanophenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(6-undecyl)isoxazole-4-carboxamide
N-(4-Trifluoromethylphenyl)-5-(3,5-bis(trifluoromethyl)phenyl)isoxazole-4-carboxamide; N-(4-Trifluoromethylphenyl)-5-(1-adamantyl)isoxazole-4-carboxamide;
N-(4-Trifluoromethylphenyl)-5-(E -3-pentenyl)isoxazole-4-carboxamide;
4-Trifluoromethylphenyl 5-((phenylsulfonyl)methyl)isoxazole-4-carboxylate; α-Naphthyl 5-((thiophenyl)methyl)isoxazole-4-carboxylate;
2-Methylypropyl (5-(2-pyridyl)-4-isoxazolyl) ketone;
3-Furanyl (5-(2-propenyl)-4-isoxazolyl) ketone;
1,1,2,2,3,3,3-Heptafluoropropyl (5-cyclohexyl-4-isoxazolyl) ketone;
N-[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-fluorophenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-fluorophenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carbomethoxy crotonamide;
N-(4-Trifluoromemylphenyl)-2-cyano-3-hydroxy-5-carbomethoxy-2-pentenamide;
N-(2-Pyridyl)-2-cyano-3-hydroxy-3-(2-benzylphenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-6-carboethoxy-2-hexenamide;
N-(4-t-Butylphenyl)-2-cyano-3-hydroxy-4-methoxy crotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-hexadecyloxyphenyl) acrylamide; N-(4-Trifluoromethylρhenyl)-2-cyano-3-hydroxy-3-(2,4-bis(1,1,2-trifluoro-2-chloroethoxy)phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(5,6,7,8-tetrahydro-2-naphthyl)
acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-thienyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-N,N dimethylsulfonamido phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-methylsulfonylphenyl) acrylamide; N-Morpholino-2-cyano-3-hydroxy-3-(4-phenoxyphenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-((2-phenoxyethoxy)phenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3-nitro-4-(2-(4-(2-(2,4,4,Trimethylpentyl) phenoxy) ethoxy)phenyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-carbomethoxyphenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-methoxy-2-pentenamide;
N-(2-(5-(4-t-Butylphenyl)thienyl))-2-cyano-3-hydroxy-2,6-heptadienamide;
N-(4-(4-Trifluoromethylphenyl)phenyl)-2-cyano-3-hydroxy-3-(4-cyanophenyl) acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-(n-pentyl)non-2-enamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3,5-bis(trifluoromethyl) phenyl)
acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(1-adamantyl) acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-octadienamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxy-4-phenylsulfonyl crotonate;
α-Naphthyl 2-cyano-3-hydroxy-4-thiophenyl crotonate;
2-(4-Trifluoromethylphenyl)ethyl 2-cyano-3-hydroxy-5-methoxy-2-pentenoate; 3-Furanyl (1-cyano-2-hydroxy-2,4 pentadienyl) ketone;
2-Methylypropyl (1-cyano-2-hydroxy-2-(2-pyridyl)ethylenyl) ketone; and
1,1,2,2,3,3,3-Heptafluoropropyl (1-cyano-2-hydroxy-2-cyclohexylethylenyl) ketone; and the respective pharmaceutically acceptable salts, esters and prodrugs thereof.
11. A compound according to Claim 10 selected from the group consisting of
5-Methyl-isoxazole-4-carboxylic acid 2-(4-trifluoromethylphenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-fluorophenyl)ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-phenylpropylamide;
5-Methyl-isoxazole-4-carboxylic acid 2-(4-nitrophenyl)ethylamide;
5-Methyl-isoxazole-4-hydroxamic acid benzylamide;
5-Methyl-isoxazole-4-carboxylic acid 4-fluorophenylhydrazide;
5-Methyl-isoxazole-4-carboxylic acid (7-trifluoromethyl- 1,2,3,4-tetrahydroquinolinyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (6-methyl-l,2,3,4-tetrahydroquinolinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid isobutylamide;
5-Methyl-isoxazole-4-carboxylic acid (n-pentyl)amide;
5-Methyl-isoxazole-4-carboxylic acid pyrrolidinehydrazide;
5-Methyl-isoxazole-4-carboxylic acid morpholinohydrazide;
5-Methyl-isoxazole-4-carboxylic acid 4-trifluoromethylbenzimide;
5-Methyl-isoxazole-4-carboxylic acid 2-fluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid trans-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid cis-4-(tert-butylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid diethylamide;
5-Methyl-isoxazole-4-carboxylic acid ethylamide;
5-Methyl-isoxazole-4-carboxylic acid 2,2,2-trifluoroethylamide;
5-Methyl-isoxazole-4-carboxylic acid allylamide;
5-Methyl-isoxazole-4-carboxylic acid propargylamide;
5-Methyl-isoxazole-4-carboxylic acid (acetonitrile)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methoxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-methoxypropyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-diethoxyacetal)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-thioethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxybutyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-piperidinoethyl)amide; 5-Methyl-isoxazole-4-carboxylic acid (4-methylpiperazino)amide;
5-Methyl-isoxazole-4-carboxylic acid (ethylglycinate)amide;
5-Methyl-isoxazole-4-carboxylic acid (3-propionic acid)amide;
5-Methylisoxazole-4-carboxylic acid (l-piperidino)amide;
5-Methylisoxazole-4-carboxylic acid (4-chlorophenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-methylcyclohexyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-norbomyl)amide;
5-Methyl-4-{4-(3-trifluoromethylphenyl)piperazine-1-ylcarbonyl}-isoxazole;
5-Methyl-isoxazole-4-carboxylic acid (cyclobutylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (norephedrine)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-methoxycarbonylcyclohexylmethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (2-hydroxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N- { (4-phenyl)-benzyl} amide;
5-Methyl-isoxazole-4-carboxylic acid N-methyl-N-(4-phenoxy)-benzylamide;
5-Methyl-isoxazole-4-carboxylic acid {2-[(2-chloro-4-t-butyl-phenoxy)methyl]benzyl}amide; 5-Methyl-isoxazole-4-carboxylic acid (furfuryl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-trifluoromethoxyphenyl)hydrazide ;
5-Methyl-isoxazole-4-carboxylic acid {(-)-rij-myrt-inyl} amide;
5-Methyl-isoxazole-4-carboxylic acid (3-aminopropyl)amide;
5-Methylisoxazole-4-carboxylic acid (4-methoxyphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(4S)-benzyloxazolidinone}imide;
5-Methyl-isoxazole-4-carboxylic acid (4-methylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {(+)-norephedrine} amide;
5-Methyl-isoxazole-4-carboxylic acid (4-ethylphenethyl)amide;
5-Methyl-isoxazole-4-carboxylic acid {2-hydroxy-5-(7-chloro-6- (ethoxycarbonylmethoxy)benzisoxazol-3-yl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid {4-(2,3-dichloro-4- (ethoxycarbonylmethoxy)benzoyl)benzyl}amide;
5-Methyl-isoxazole-4-carboxylic acid (aziridinyl)amide;
5-Methyl-isoxazole-4-carboxylic acid (4-hydroxyphenethyl)amide;
5-Methyl-isoxazo.e-4-carboxylic acid (2-phenylethyl )amide;
5-Methyl-isoxazole-4-carboxylic acid cinnamimide;
5-Methyl-isoxazole-4-carboxylic acid 4-chlorocinnamimide;
5-Methyl-isoxazole-4-carboxylic acid {L-(S)-amphetamine) amide;
5-(3-Butenyl) isoxazole-4-carboxylic acid (4-trifluoromethylphenyl)amide;
2-(4-Trifluoromethylphenyl)ethyl 5-methyl isoxazole-4-carboxylate;
2-(4-Nitrophenyl)ethyl 5-methyl-isoxazole-4-carboxylate; 2-(4-Fluorophenyl)ethyl 5-methyl-isoxazole-4-carboxylate;
4-Chlorophenethyl 5-methylisoxazole-4-carboxylate;
4-Trifluoromethylphenyl 5-methylisoxazole-4-carboxylate;
Cinnamyl 5-methylisoxazole-4-carboxylate;
2-(3-Trifluoromethylphenyl)ethyl 5-methylisoxazole-4-carboxylate;
3-Phenylbutyl 5-methylisoxazole-4-carboxylate;
N[2-(4-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(2-Phenylpropyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-methoxycrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-ethoxycrotonamide;
N-[2-(4-Fluorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-[2-(4-Trifluoromethylphenyl)ethyl-2-cyano-3-hydroxycrotonate;
N-[n-Pentyl]-2-cyano-3-hydroxycrotonamide;
N-(Isobutyl)-2-cyano-3-hydroxycrotonamide;
N-(trans-4-tert-Butylcyclohexyl)-2-cyano-3-hydroxycrotonamide;
N-(cis-4-tert-Butyl cyclohexyl)-2-cyano-3-hydroxycrotonaniide;
N-(2-Fluoroethyl)-2-cyano-3-hydroxycrotonamide;
N,N-Diethyl-2-cyano-3-hydroxycrotonamide;
N-Ethyl-2-cyano-3-hydroxycrotonamide;
N-(2,2,2-Trifluoroethyl)-2-cyano-3-hydroxycrotonamide;
N-[2(4-Nitrophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Benzyl-2-cyano-3-hydroxycrotonamide;
N-Allyl-2-cyano-3-hydroxycrotonamide;
N-(2-Methoxyediyl)-2-cyano-3-hydroxycrotonamide;
N-(3-Methoxypropyl)-2-cyano-3-hydroxycrotonaιnide;
N-Acetonitrile-2-cyano-3-hydroxycrotonamide;
N-Propargyl-2-cyano-3-hydroxycrotonamide;
N-(2-Hydroxyethyl)-2-cyano-3-hydroxycrotonamide;
N-(4-Hydroxybutyl)-2-cyano-3-hydroxycrotonamide;
4-Trifluoromethylphenyl-2-cyano-3-hydroxycrotonimide;
3-Phenyl-1-butyl-2-cyano-3-hydroxycrotonate;
N-(Acetic acid)-2-cyano-3-hydroxycrotonamide;
N-(2-Norbomyl)-2-cyano-3-hydroxycrotoamide;
N-(3-Propionic acid)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonamide; N-(2-Piperidin-1-ylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Chlorophenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-Cyclobutylmethyl-2-cyano-3-hydroxy crotonamide;
N-(Ethylglycinate)-2-cyano-3-hydroxycrotonamide;
αnnamyl 2-cyano-3-hydroxycrotonate;
N-(Epi-4-Carboxycyclohexylmethyl)-2-Cyano-3-hydroxycrotonamide;
N-(2-Methylcyclohexyl)-2-cyano-3-hydroxy crotonamide;
N-(2-Hydroxy-2-phenylethyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(3-Trifluoromethylphenyl)ethyl]-2-cyano-3-hydroxycrotonate;
N-(Furfuryl)-2-cyano-3-hydroxy-crotonamide;
N-[2-(4-Methoxyphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Methylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
N-((-)-cis-Myrtanyl)-2-cyano-3-hydroxycrotonamide;
N-[2-(4-Ethylphenyl)ethyl]-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxy-crotonic acid aziridinyl amide;
N-[2-(4-Hydroxyphenyl)ethy]-2-cyano-3-hydroxycrotonamide;
2-Phenylethyl-2-cyano-3-hydroxycrotonamide;
2-Cyano-3-hydroxycrotonic 4-chlorocinnamimide;
2-Cyano-3-hydroxycrotonic cinnamimide;
(4(S)-Benzyl-2-oxazolidinone)-2-cyano-3-hydroxy-crotonimide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2',4'-dichlorophenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hychoxy-3-(4'-methoxyphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4'-t-butylphenyl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(trans-phenylcyclopropyl)-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-biphenyl-acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(3',4,,5'-tri-methoxy-phenyl)- acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-phenylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(4-trifluoromethylphenyl)acrylamide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(furan-2-yl)acrylamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-5-phenyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-methyl-penta-2,4-dienoic acid amide; N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-carboxyethylcrotonamide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-4-ethyl-oct-2-enoic acid amide;
N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-3-(2-thienylmethyl)crotonaimide; and N-(4-Trifluoromethylphenyl)-2-cyano-3-hydroxy-2,6-heptadieneamide; and the respective pharmaceutically acceptable salts, esters and prodrugs thereof.
12. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 1 in combination with a pharmaceutically acceptable carrier.
13. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to Claim 10 in combination with a pharmaceutically acceptable carrier.
14. A method of producing immunosuppression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 1.
15. A method of producing immunosuppression in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound according to Claim 10.
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