Inhibitors of IMPDH enzyme

Abstract

The present invention relates to a novel class of compounds which are IMPDH inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting IMPDH enzyme activity and consequently, may be advantageously used as therapeutic agents for IMPDH mediated processes. This invention also relates to methods for inhibiting the activity of IMPDH using the compounds of this invention and related compounds.

We claim:  
     
         1 . A method of inhibiting IMPDH activity in a mammal comprising the step of administering to said mammal a compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A is a saturated, unsaturated or partially saturated monocyclic ring optionally comprising up to 4 heteroatoms selected from N, O, and S wherein each A optionally comprises up to 4 substituents selected from R 1 , R 4  and R 5 ;  
 each R 1  is halogen, CN, NO 2 , CF 3 , OCF 3 , OH, R 3 , OR 3 , 1,2-methylenedioxy, 1,2-ethylenedioxy, SR 3 , S(O)R 3 , SO 2 R 3 , NH 2 , NHR 3 , N(R 3 ) 2 , NR 3 R 9 , COOH, or COOR 3 ;  
 each R 2  is independently R 1  or a monocyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH 2  adjacent to said N, O or S maybe substituted with C(O); and each R 2  optionally comprises up to 2 substituents, each substituent independently selected from R 1 ;  
 each R 3  is independently (C 1 -C 4 )-straight or branched alkyl, or (C 2 -C 4 )-straight or branched alkenyl or alkynyl;  
 each R 4  is independently (C 1 -C 6 )-straight or branched alkyl, or (C 2 -C 6 )-straight or branched alkenyl or alkynyl; and each R 4  optionally comprises up to 2 substituents, wherein: 
 the first of said substituents, if present, is R 1 , R 5  or R 8 , and  
 the second of said substituents, if present, is R 1 ;  
 
 each R 5  is independently selected from OR 6 , OC(O)R 7 , OC(O)R 6 , OC(O)OR 7 , OC(O)OR 6 , OC(O)N(R 7 ) 2 , OP(O)(OR 7 ) 2 , SR 7 , SR 6 , S(O)R 7 , S(O)R 6 , SO 2 R 7 , SO 2 R 6 , SO 2 N(R 7 ) 2 , SO 2 NR 6 R 7 , SO 3 R 7 , C(O)R 6 , C(O)OR 6 , C(O)R 7 , C(O)OR 7 , NC(O)C(O)R 7 , NC(O)C(O)R 6 , NC(O)C(O)OR 7 , NC(O)C(O)N(R 7 ) 2 , C(O)N(R 7 ) 2 , C(O)N(OR 7 )R 7 , C(O)N(OR 7 )R 6 , C(NOR 7 )R 7 , C(NOR 7 )R 6 , N(R 7 ) 2 , NR 7 C(O)R 6 , NR 7 C(O)R 7 , NR 6 C(O)R 6 , NR 7 C(O)OR 7 , NR 7 C(O)OR 6 , NR 7 C(O)N(R 7 ) 2 , NR 7 C(O)NR 6 R 7 , NR 7 SO 2 R 7 , NR 7 SO 2 R 6 , NR 7 SO 2 N(R 7 ) 2 , NR 7 SO 2 NR 6 R 7 , N(OR 7 )R 7 , N(OR 7 )R 6 , P(O)(OR 7 )N(R 7 ) 2 , and P(O)(OR 7 ) 2 ;  
 R 6  is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH 2  adjacent to any of said N, O, or S heteroatoms is optionally substituted with C(O); and  
 each R 6  optionally comprises up to 3 substituents, each substituent independently selected from R 1 ;  
 each R 7  is independently H, (C 1 -C 4 )-straight or branched alkyl, or (C 2 -C 4 ) straight or branched alkenyl; and each R 7  optionally comprises a substituent that is R 8 ;  
 R 8  is a monocyclic or a bicyclic ring system consisting of 5 to 6 members per ring, wherein said ring system optionally comprises up to 4 heteroatoms selected from N, O, and S, and wherein a CH 2  adjacent to said N, O or S maybe substituted with C(O); and each R 8  optionally comprises up to 2 substituents independently chosen from H, (C 1 -C 4 )-straight or branched alkyl, (C 2 -C 4 ) straight or branched alkenyl, 1,2-methylenedioxy, 1,2-ethylenedioxy and (CH 2 ) n —R 1 ;  
 wherein n is 0, 1 or 2;  
 R 9  is an amino protecting group; and  
 wherein any carbon atom in any R 3 , R 4  or R 7  is optionally replaced by O, S, SO, SO 2 , NH, or N(C 1 -C 4 )-alkyl.  
 
     
     
         2 . The method according to  claim 1 , wherein in said compound, A is a six-member monocyclic ring.  
     
     
         3 . The method according to  claim 2 , wherein in said compound, A is a heterocyclic ring comprising one heteroatom selected from N, O, and S.  
     
     
         4 . The method according to  claim 2 , wherein in said compound, A is phenyl.  
     
     
         5 . A compound of the formula:  
       
         
           
           
               
               
           
         
       
       wherein: 
 A and R 1  are as defined in  claim 1;  and  
 Z is O, S, NH or NR 3 , wherein R 3  is as defined in  claim 1 .  
 
     
     
         6 . The compound according to  claim 5 , wherein in said compound, A is a six-member monocyclic ring.  
     
     
         7 . The compound according to  claim 6 , wherein in said compound, A is a heterocyclic ring comprising one heteroatom selected from N, O, and S.  
     
     
         8 . The compound according to  claim 6 , wherein in said compound, A is phenyl.  
     
     
         9 . A pharmaceutical composition comprising: 
 a. a compound of formula                          in an amount effective to inhibit IMPDH activity, wherein A, R 1  and R 2  are as defined in  claim 1;     b. an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation agent; and    c. a pharmaceutically acceptable adjuvant.    
     
     
         10 . The composition according to  claim 9 , wherein in said compound, A is a six-member monocyclic ring.  
     
     
         11 . The composition according to  claim 10 , wherein in said compound, A is a heterocyclic ring comprising one heteroatom selected from N, O, and S,.  
     
     
         12 . The composition according to  claim 10 , wherein in said compound, A is phenyl.  
     
     
         13 . A pharmaceutical composition comprising: 
 a. a compound of formula                          wherein: 
 A and R 1  are as defined in  claim 1;  and  
 Z is O, S, NH or NR 3 , wherein R 3  is as defined in  claim 1;   
   b. an additional agent selected from an immunosuppressant, an anti-cancer agent, an anti-viral agent, antiinflammatory agent, antifungal agent, antibiotic, or an anti-vascular hyperproliferation agent; and    c. a pharmaceutically acceptable adjuvant.    
     
     
         14 . The composition according to  claim 13 , wherein in said compound, A is a six-member monocyclic ring.  
     
     
         15 . The composition according to  claim 14 , wherein in said compound, A is a heterocyclic ring comprising one heteroatom selected from N, O, and S.  
     
     
         16 . The composition according to  claim 14 , wherein in said compound, A is phenyl.  
     
     
         17 . A method for treating or preventing an IMPDH mediated disease in a mammal comprising the step of administering to said mammal a composition according to  claim 9 .  
     
     
         18 . A method for treating or preventing an IMPDH mediated disease in a mammal comprising the step of administering to said mammal a composition according to  claim 13 .  
     
     
         19 . The method according to either of claims  17  or  18 , wherein said method is used to suppress an immune response and wherein said additional agent is an immunosuppressant.  
     
     
         20 . The method according to  claim 19 , wherein said IMPDH mediated disease is an autoimmune disease.  
     
     
         21 . The method according to either of claims  17  or  18 , wherein the IMPDH mediated disease is a viral disease and wherein said additional agent is an anti-viral agent.  
     
     
         22 . The method according to either of claims  17  or  18 , wherein the IMPDH mediated disease is a vascular disease and wherein said additional agent is an anti-vascular hyperproliferation agent.  
     
     
         23 . The method according to either of claims  17  or  18 , wherein the IMPDH mediated disease is cancer and wherein said additional agent is an anti-cancer agent.  
     
     
         24 . The method according to either of claims  17  or  18 , wherein the IMPDH mediated disease is an inflammatory disease and wherein said additional agent is an antiinflammatory agent.