Novel Substituted Imidazole Compounds

Abstract

Novel 1,4,5-substituted imidazole compounds and compositions for use in therapy as CSBP/p38 kinase inhibitors.

1 . A pharmaceutical composition comprising 1-(1,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof in a sterile aqueous solution or oily suspension. 
     
     
         2 . The pharmaceutical composition according to  claim 1  which further comprises a solvent selected from the group consisting of glycerol, diluted alcohol, and propylene glycol. 
     
     
         3 . The pharmaceutical composition according to  claim 1  which further comprises at least one of a bactericidal agent, a fungicidal agent, or a surface active agent. 
     
     
         4 . A method of inhibiting at least one proinflammatory cytokine selected from IL-1, IL-6, IL-8, TNF-α and TNF-β in a mammalian cell comprising administering to said cell a cytokine interfering amount of 1-(1,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof. 
     
     
         5 . A method of decreasing the in vivo levels of a cytokine to normal or sub-normal levels in a mammalian cell comprising administering to said cell a cytokine interfering amount of 1-(1,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole, or a pharmaceutically acceptable salt thereof. 
     
     
         6 . The method according to  claim 5  wherein the cell is a natural killer cell, fibroblast, basophile, neutrophile, endothelial cell, brain astrocyte, bone marrow stromal cell, epidural keratinocyte or a B-lymphocyte. 
     
     
         7 . A process for preparing a compound of Formula (I) 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  is a pyrimidinyl ring, which ring is substituted with Y—R a  and optionally with an additional independent substituent selected from C 1-4  alkyl, halogen, hydroxyl, C 1-4  alkoxy, C 1-4  alkylthio, C 1-4  alkylsulfinyl, CH 2 OR 12 , amino, mono and di-C 1-6  alkyl substituted amino, an N-heterocyclyl ring which ring has from 5 to 7 members and optionally contains an additional heteroatom selected from oxygen, sulfur or NR 15 , N(R 10 )C(O)R b  or NHR a ; 
 Y is oxygen or sulfur; 
 R 4  is phenyl, naphth-1-yl or naphth-2-yl 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)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) v COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m′ COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 ) m′ NR 10 C(Z)R 3 , NR 10 S(O) m′ R 8 , NR 10 S(O) m′ NR 7 R 17 , ZC(Z)R 3  or (CR 10 R 20 ) m′ NR 13 R 14 ; 
 Z is oxygen or sulfur; 
 n is an integer having a value of 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; 
 R 2  is —C(H) (A) (R 22 ); 
 A is an optionally substituted aryl, heterocyclyl, or heteroaryl ring, or A is a substituted C 1-10  alkyl; 
 R 22  is a substituted C 1-10  alkyl; 
 R a  is aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, heteroarylC 1-6 alkyl, wherein each of these moieties may be optionally substituted; 
 R b  is hydrogen, C 1-6  alkyl, C 3-7  cycloalkyl, aryl, arylC 1-4  alkyl, heteroaryl, heteroarylC 1-4 alkyl, heterocyclyl, or heterocyclylC 1-4  alkyl, wherein each of these moieties may be optionally substituted; 
 R 3  is heterocyclyl, heterocyclylC 1-10  alkyl or R 8 ; 
 R 5  is hydrogen, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl or NR 7 R 17 , excluding the moieties SR 5  being SNR 7 R 17  and SOR 5  being SOH; 
 R 7  and R 17  is each independently selected from hydrogen or C 1-4  alkyl or R 7  and R 17  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 NR 15 ; 
 R 8  is C 1-10  alkyl, halo-substituted C 1-10  alkyl, C 2-10  alkenyl, C 2-10  alkynyl, C 3-7  cycloalkyl, C 5-7  cycloalkenyl, aryl, arylC 1-10  alkyl, heteroaryl, heteroarylC 1-10  alkyl, (CR 10 R 20 ) n OR 11 , (CR 10 R 20 ) n S(O) m R 18 , (CR 10 R 20 ) n NHS(O) 2 R 18  (CR 10 R 20 ) n NR 13 R 14 ; wherein the aryl, arylalkyl, heteroaryl, heteroaryl alkyl may be optionally substituted; 
 R 9  is hydrogen, C(Z)R 11  or optionally substituted C 1-10  alkyl, S(O) 2 R 18 , optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl; 
 R 10  and R 20  is each independently selected from hydrogen or C 1-4  alkyl; 
 R 11  is hydrogen, C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, heterocyclyl C 1-10  alkyl, aryl, arylC 1-10  alkyl, heteroaryl or heteroarylC 1-10  alkyl, wherein these moieties may be optionally substituted; 
 R 12  is hydrogen or R 16 ; 
 R 13  and R 14  is each independently selected from hydrogen or optionally substituted C 1-4  alkyl, optionally substituted aryl or optionally substituted aryl-C 1-4  alkyl, or together with the nitrogen 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 NR 9 ; 
 R 15  is R 10  or C(Z)-C 1-4  alkyl; 
 R 16  is C 1-4  alkyl, halo-substituted-C 1-4  alkyl, or C 3-7  cycloalkyl; 
 R 18  is C 1-10  alkyl, C 3-7  cycloalkyl, heterocyclyl, aryl, aryl 1-10 alkyl, heterocyclyl, heterocyclyl-C 1-10 alkyl, heteroaryl or heteroaryl 1-10 alkyl; 
 
       or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of Formula (X): 
       
         
           
           
               
               
           
         
       
       wherein R 1 , R 2  and R 4  are as defined for Formula (I) above or are precursors of the groups R 1 , R 2  and R 4 , with phosphorus oxychloride or phosphorus pentachloride to yield a compound of Formula (I) and thereafter if necessary, converting a precursor of R 1 , R 2  and R 4  to the group R 1 , R 2  and R 4 . 
     
     
         8 . The process according to  claim 7  wherein the compound of Formula (I) is: 
       1-(1,3-Dihydroxyprop-2-yl)-4-(4-fluorophenyl)-5-(2-phenoxypyrimidin-4-yl)imidazole; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         9 . The process according to  claim 7  wherein R 1  is a 4-pyrimidinyl ring substituted in the 2-position. 
     
     
         10 . The process according to  claim 7  wherein Y is oxygen, and the R a  moiety is an optionally substituted aryl or arylalkyl. 
     
     
         11 . The process according to  claim 9  wherein Y is oxygen, and the R a  moiety is an optionally substituted aryl or arylalkyl. 
     
     
         12 . The process according to  claim 11  wherein the R a  is phenyl. 
     
     
         13 . The process according to  claim 7  wherein R 4  is an optionally substituted phenyl. 
     
     
         14 . The process according to  claim 13  wherein the phenyl is substituted one or more times independently by halogen, SR 5 , S(O)R 5 , OR 12 , halo-substituted-C 1-4  alkyl, or C 1-4  alkyl. 
     
     
         15 . The process according to  claim 14  wherein the phenyl is substituted in the 4-position. 
     
     
         16 . The process according to  claim 15  wherein the 4-position is substituted by halogen. 
     
     
         17 . The process according to  claim 16  wherein the halogen is fluoro. 
     
     
         18 . The process according to  claim 7  wherein A is an optionally substituted C 1-10  alkyl. 
     
     
         19 . The process according to  claim 18  wherein A is a hydroxy substituted C 1-10  alkyl. 
     
     
         20 . The process according to  claim 7  wherein R 22  is a hydroxy substituted C 1-10  alkyl. 
     
     
         21 . The process according to  claim 19  wherein R 22  is a hydroxy substituted C 1-10  alkyl. 
     
     
         22 . The process according to  claim 7  wherein R 2  is a 1,3-propanediol. 
     
     
         23 . A compound of Formula (X) 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is a 1,3-propanediol; 
 R 1  is a pyrimidinyl substituted by Y—R a ; 
 Y is oxygen or sulfur; 
 R a  is an aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, heteroarylC 1-6 alkyl moiety and wherein each of these moieties may be optionally substituted; 
 R 4  is phenyl, naphth-1-yl or naphth-2-yl 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)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) v COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m′ COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 ) m′ NR 10 C(Z)R 3 , NR 10 S(O) m′ R 8 , NR 10 S(O) m′ NR 7 R 7 , ZC(Z)R 3  or (CR 10 R 20 ) m′ NR 13 R 14 . 
 
     
     
         24 . The compound according to  claim 23  wherein R 1  is a 4-pyrimidinyl ring substituted in the 2-position, and Y is oxygen. 
     
     
         25 . The compound according to  claim 24  wherein R a  moiety is an optionally substituted aryl or arylalkyl. 
     
     
         26 . The compound according to  claim 25  wherein R a  is phenyl. 
     
     
         27 . The compound according to  claim 23  wherein R 4  is an optionally substituted phenyl. 
     
     
         28 . The compound according to  claim 27  wherein R 4  is a phenyl substituted in the 4-position by halogen. 
     
     
         29 . The compound according to  claim 27  wherein R 4  is 4-fluorophenyl. 
     
     
         30 . A compound of the formula 
       
         
           
           
               
               
           
         
       
       wherein
 R 2  is a 1,3-propanediol; 
 R 1  is a pyrimidinyl substituted by Y—R a ; 
 Y is oxygen or sulfur; 
 R a  is an aryl, arylC 1-6 alkyl, heterocyclic, heterocyclylC 1-6  alkyl, heteroaryl, heteroarylC 1-6 alkyl moiety and wherein each of these moieties may be optionally substituted; 
 R 4  is phenyl, naphth-1-yl or naphth-2-yl 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)NR 7 R 17 , C(Z)OR 16 , (CR 10 R 20 ) v COR 12 , SR 5 , SOR 5 , OR 12 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, ZC(Z)R 12 , NR 10 C(Z)R 16 , or (CR 10 R 20 ) v NR 10 R 20  and which, for other positions of substitution, is halogen, cyano, C(Z)NR 13 R 14 , C(Z)OR 3 , (CR 10 R 20 ) m′ COR 3 , S(O) m R 3 , OR 3 , halo-substituted-C 1-4  alkyl, C 1-4  alkyl, (CR 10 R 20 ) m′ NR 10 C(Z)R 3 , NR 10 S(O) m′ R 8 , NR 10 S(O) m′ NR 7 R 7 , ZC(Z)R 3  or (CR 10 R 20 ) m′ NR 13 R 14 . 
 
     
     
         31 . The compound according to  claim 30  wherein R 1  is a 4-pyrimidinyl ring substituted in the 2-position, and Y is oxygen. 
     
     
         32 . The compound according to  claim 31  wherein R a  moiety is an optionally substituted aryl or arylalkyl. 
     
     
         33 . The compound according to  claim 25  wherein R a  is phenyl. 
     
     
         34 . The compound according to  claim 30  wherein R 4  is an optionally substituted phenyl. 
     
     
         35 . The compound according to  claim 34  wherein R 4  is a phenyl substituted in the 4-position by halogen. 
     
     
         36 . The compound according to  claim 35  wherein R 4  is 4-fluorophenyl.