Patent EA-001430-B1 (EA)
Title: Novel substituted imadozole compounds
Inventor: ADAMS JERRY L
IPC: A61K31/506
Filed: 1997-01-10
Abstract: 1. A compound represented by the formula   R1 is a 4-pyrimidinyl ring which is substituted with a C1-4 alkoxy group, and is additionally optionally substituted independently by C1-4 alkyl, halogen, hydroxyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono- or di-C1-6 alkylsubstituted amino, N(R10)C(O)Rc or an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, SOR5, OR12. halosubstituted C1-4 alkyl, C1-4 alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)m``COR3, S(O)mR3, OR3, halosubstituted C1-4 alkyl, C1-4 alkyl, (CR10R20)m``NR10C(Z)R3, NR10S(O)m`R8, NR10S(O)m`NR7R17, ZC(Z)R3 or (CR10R20)m``NR13R14; n is an integer from 1 to 10; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2; m" is 0, or an integer having a value of 1 to 5; v is 0, or an integer having a value of 1 or 2; R2 is an optionally substituted heterocyclyl, or an optionally substituted heterocyclylC1-10 alkyl moiety; Z is oxygen or sulfur; Rc is hydrogen, C1-6 alkyl, C3-7 cycloalkyl, aryl, aryl-C1-4 alkyl, heteroaryl, heteroaryl-C1-4alkyl, heterocyclyl, or heterocyclyl-C1-4alkyl; R3 is heterocyclyl, heterocyclyl-C1-10 alkyl or R8; R5 is hydrogen, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl or NR7R17, excluding the moieties SR5 being SNR7R17 and SOR5 being SOH; R7 and R17 is each independently selected from hydrogen or C1-4 alkyl or R7 and R17 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R8 is C1-10 alkyl, halosubstituted C1-10 alkyl, C2-10 alkenyl, C2-10 alkynyl, C3-7 cycloalkyl, C5-7 cycloalkenyl, aryl, aryl-C1-10 alkyl, heteroaryl, heteroaryl-C1-10 alkyl, (CR10R20)nOR11, (CR10R20)nS(O)mR18, (CR10R20)nNHS(O)2R18, (CR10R20)nNR13R14; wherein the aryl, arylalkyl, heteroaryl, heteroarylalkyl may be optionally substituted; R9 is hydrogen, C(Z)R11 or optionally substituted C1-10 alkyl, S(O)2R18, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl; R10 and R20 is each independently selected from hydrogen or C1-4alkyl; R11 is hydrogen, C1-10 alkyl, C3-7 cycloalkyl, heterocyclyl, heterocyclyl-C1-10 alkyl, aryl, aryl-C1-10 alkyl, heteroaryl or heteroaryl-C1-10 alkyl; R12 is hydrogen or R16; R13 and R14 is each independently selected from hydrogen or optionally substituted C1-4 alkyl, optionally substituted aryl or optionally substituted aryl-C1-4 alkyl, or R13 and R14 together with the nitrogen to which they are attached form a heterocyclic ring of 5 to 7 members which ring optionally contains an additional heteroatom selected from oxygen, sulfur or NR9; R15 is R10 or C(Z)-C1-4 alkyl; R16 is C1-4 alkyl, halosubstituted-C1-4 alkyl, or C3-7 cycloalkyl; R18 is C1-10 alkyl, C3-7 cycloalkyl, aryl, arylalkyl, heterocyclyl, heterocyclyl-C1-10alkyl, heteroaryl or heteroaryl C1-10alkyl; or a pharmaceutically acceptable salt thereof. 2. The compound according to claim 1, wherein R1 is substituted with an isopropoxy, ethoxy, or methoxy group. 3. The compound according to claim 1, wherein R4 is an optionally substituted phenyl. 4. The compound according to claim 3, wherein the phenyl is substituted one or more substituents, independently selected from halogen, SR5, S(O)R5, OR12, halosubstituted C1-4 alkyl , or C1-4 alkyl. 5. The compound according to claim 4, wherein the phenyl is substituted with fluoro. 6. The compound according to claim 1, wherein R2 is morpholinopropyl, piperidine, N-methylpiperidine, N-benzylpiperidine, or 2,2,6,6-tetramethylpiperidine. 7. The compound according to claim 1 which is: 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl)imidazole or a pharmaceutically acceptable salt thereof. 8. The compound according to claim 1 which is: 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl) imidazole or a pharmaceutically acceptable salt thereof. 9. The compound according to claim 1 which is: 5-(2-ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole or a pharmaceutically acceptable salt thereof. 10. A pharmaceutical composition comprising a compound according to any of claims 1 to 9 and a pharmaceutically acceptable carrier or diluent. 11. A method of treating an inflammation in a mammal in need thereof , which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of claims 1 to 9. 12. A method of treating a CSBP/RK/p38 kinase mediated disease in a mammal in need thereof, which comprises administering to said mammal an effective amount of a compound of Formula (I) according to any of claims 1-9. 13. The method according to claim 12 wherein a CSBP/RK/p38 kinase medicated disease is psoriatic arthritis, Reiter's syndrome, gout, gouty arthritis, traumatic arthritis, rubella arthritis and acute synovitis, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic condition, sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, stroke, neurotrauma, asthma, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcososis, bone resorption disease, osteoporosis, restenosis, cardiac and renal reperfusion injury, thrombosis, glomerularonephritis, diabetes, homology disease, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative colitis, eczema, contact dermatitis, psoriasis, sunburn erythema and conjunctivitis. 14. A process for preparing a compound of Formula (I) as defined in claim 1 which comprises reacting a compound of the Formula (II)   with a compound of the Formula (III)   wherein p is 0 or 2; and a base strong enough to deprotonate the isonitrile moiety of Formula (II); and R1, R2 and R4 are as defined in claim 1 or are precursors of the groups R1, R2 and R4 and Ar is an optionally substituted phenyl group, and thereafter if necessary, converting a precursor of R1, R2 and R4 to a group R1, R2 and R4. 15. The process according to claim 14 wherein p=0. 16. The process according to claim 14 wherein p=2. 17. The process according to claim 16 wherein the base is an amine, a carbonate, a hydride, or an alkyl or aryl-lithium reagent. 18. The process according to claim 16 wherein the imine of Formula (III), is isolated prior to reaction with compound of Formula (II). 19. The process according to claim 16 wherein the imine of Formula (III), is formed in situ prior to reaction with compound of Formula (II). 20. The process according to claim 19 wherein the imine is formed in situ by reacting an aldehyde of the formula R1CHO, wherein R1 is as defined for Formula (I), with a primary amine of the formula R2NH2, wherein R2 is as defined for Formula (I). 21. The process according to claim 20 wherein formation of the imine in situ is carried out in dehydrating conditions. 22. The process according to claims 16, 20 or 21 is carried out in presence of solvent wherein the solvent is N,N-dimethylformamide (DMF), halogenated solvent,. tetrahydrofuran (THF), dimethylsulfoxide (DMSO), alcohol, benzene, toluene, MeCNor dimethoxyethane (DME). 23. The process according to claim 20 wherein the aldehyde R1CHO is a pyrimidinealdehyde of the formula   wherein X is C1-4 alkoxy and X1 is defined as the optional substituent of the R1 moiety in Formula (I) according to claim 1, to yield a compound of Formula (I) or a pharmaceutically acceptable salt thereof. 24. The process according to claim 20 wherein R2 moiety in the primary amine R2NH2 is piperidine, 1-formyl-4-piperidine, 1-benzyl-4-piperidine, 1-methyl-4-piperidine, 1-ethoxycarbonyl-4-piperidine, 1-tert-butyloxycarbonyl-4-piperidine, 2,2,6,6-tetramethyl-4-piperidine, morpholinoethyl, morpholinopropyl, pyrrolidinylpropyl or piperidinylpropyl. 25. The compound according any of claims 14-23 wherein a compound of Formul (I) is: 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-isopropoxy-4-pyrimidinyl)imidazole, 1-(4-piperidinyl)-4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)imidazole or 5-(2-ethoxy-4-pyrimidinyl)-4-(4-fluorophenyl)-1-(4-piperidinyl)imidazole or a pharmaceutically acceptable salt thereof. 26. The compound according to the formula   R1 is a 4-pyridyl ring which is substituted with a C1-4 alkoxy, and is additionally optionally substituted independently by C1-4 alkyl, halogen, hydroxyl, C1-4 alkoxy, C1-4 alkylthio, C1-4 alkylsulfinyl, CH2OR12, amino, mono- or di-C1-6alkylsubstituted amino, N(R10)C(O)Rc or N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR15; R4 is phenyl, naphth-1-yl or naphth-2-yl, or a heteroaryl, which is optionally substituted by one or two substituents, each of which is independently selected, and which, for a 4-phenyl, 4-naphth-1-yl, 5-naphth-2-yl or 6-naphth-2-yl substituent, is halogen, cyano, nitro, C(Z)NR7R17, C(Z)OR16, (CR10R20)vCOR12, SR5, SOR5, OR12. halosubstituted C1-4 alkyl, C1-4 alkyl, ZC(Z)R12, NR10C(Z)R16, or (CR10R20)vNR10R20 and which, for other positions of substitution, is halogen, cyano, C(Z)NR13R14, C(Z)OR3, (CR10R20)m``COR3, S(O)mR3, OR3, halosubstituted C1-4 alkyl, C1-4 alkyl, (CR10R20)m``NR10C(Z)R3, NR10S(O)m`R8, NR10S(O)m`NR7R17, ZC(Z)R3 or (CR10R20)m``NR13R14; v is 0, or an integer having a value of 1 or 2; n is an integer from 1 to 10; m is 0, or the integer 1 or 2; m' is an integer having a value of 1 or 2; m" is 0, or an integer having a value of 1 to 5