US2007004758A1PendingUtilityA1

Compositions and treatments for inhibiting kinase and/or hmg-coa reductase

55
Assignee: GRIFFIN JOHNPriority: Apr 29, 2004Filed: Aug 31, 2006Published: Jan 4, 2007
Est. expiryApr 29, 2024(expired)· nominal 20-yr term from priority
C07D 405/14C07D 401/04A61K 31/4439C07D 403/04Y02A50/30A61K 31/4178A61K 31/506A61K 31/4172
55
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Claims

Abstract

The present invention provides compositions of matter, kits and methods for their use in the treatment of MAP kinase-related conditions and/or HMG-CoA reductase-related conditions. In particular, the invention provides compositions for treating inflammatory and/or cardiovascular conditions in an animal subject by inhibiting p38α MAP kinase and/or HMG-CoA reductase, as well as providing formulations and modes of administering such compositions. The invention further provides methods for the rational design of inhibitors of MAP kinase, HMG-CoA reductase, or both for use in the practice of the present invention.

Claims

exact text as granted — not AI-modified
1 . A method of inhibiting a MAP kinase comprising administering an effective amount of at least one compound comprising formula V:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 R 4  is optionally substituted  
                     
 and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
 
     
     
         2 . The method as recited in  claim 1  wherein said R 1  has the following stereochemistry:  
       
         
           
           
               
               
           
         
       
     
     
         3 . The method as recited in  claim 1  wherein said inhibited MAP kinase is p38 MAP kinase.  
     
     
         4 . The method as recited in  claim 1 , further comprising inhibiting an HMG CoA reductase.  
     
     
         5 . The method as recited in  claim 1  wherein said administering treats a MAP kinase-related condition.  
     
     
         6 . The method as recited in  claim 1  wherein said administering treats a MAP kinase-related condition and an HMG CoA reductase-related condition.  
     
     
         7 . The method as recited in  claim 1  wherein said administering treats an inflammatory condition.  
     
     
         8 . A compound comprising formula V:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       being 0 or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 R 4  is optionally substituted  
                     
 and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof,  
 with the proviso that when R 4  is the pyridinyl ring optionally substituted with one or more substituents selected from halogen atoms and hydroxyl, C 1-3  alkyl, C 1-3  alkoxy and trifluoromethyl groups, then the bridging group of R 1  is —CH 2 —CH 2 —.  
 
     
     
         9 . The compound as recited in  claim 8  wherein R 2  is a C 3-4  branched alkyl group.  
     
     
         10 . The compound as recited in  claim 8  wherein R 2  is isopropyl.  
     
     
         11 . The compound as recited in  claim 8  wherein R 2  is t-butyl.  
     
     
         12 . The compound as recited in  claim 8  wherein R 2  is —CF 3 .  
     
     
         13 . The compound as recited in  claim 8  wherein R 2  is phenyl.  
     
     
         14 . The compound as recited in  claim 8  wherein R 2  is  
       
         
           
           
               
               
           
         
       
     
     
         15 . The compound as recited in  claim 8  wherein R 2  is  
     
     
         16 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         18 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         20 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         21 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         23 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         24 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         25 . The compound as recited in  claim 8  wherein R 4  is  
       
         
           
           
               
               
           
         
       
     
     
         26 . The compound as recited in  claim 8  wherein R 5  is an optionally substituted phenyl group.  
     
     
         27 . The compound as recited in  claim 8  wherein R 5  is 4-fluorophenyl.  
     
     
         28 . The compound as recited in  claim 8  wherein R 5  is 3-trifluoromethylphenyl.  
     
     
         29 - 32 . (canceled)  
     
     
         33 . A compound comprising formula V:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 R 4  is optionally substituted  
                     
 and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof,  
 with the proviso that when R 4  is the pyridinyl ring, said pyridinyl ring is substituted with one or more optionally substituted amino groups.  
 
     
     
         34 . A compound comprising formula Va:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       being 0 or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 the pyrimidinyl ring is optionally substituted;  
 and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
 
     
     
         35 . A compound comprising formula Vb:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       being 0 or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 the pyridinyl ring is optionally substituted, with the proviso that when the pyridinyl ring is unsubstituted or substituted with one or more substituents selected from halogen atoms and hydroxyl, C 1-3  alkyl, C 1-3  alkoxy and trifluoromethyl groups, then the bridging group of R 1  is —CH 2 —CH 2 —; and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof.  
 
     
     
         36 . A pharmaceutical composition comprising an effective amount of at least one compound as recited in  claim 8  with a pharmaceutically acceptable carrier.  
     
     
         37 . A method of treating a condition in a subject in need thereof comprising administering to said subject an effective amount of at least one compound comprising formula V:  
       
         
           
           
               
               
           
         
       
       wherein R 1  is  
       
         
           
           
               
               
           
         
       
       n being 0 or any integer; 
 R 2  is optionally substituted alkyl, aryl, or heteroaryl;  
 R 4  is optionally substituted  
                     
 and R 5  is optionally substituted aryl or heteroaryl, or a salt thereof,  
 with the proviso that when R 4  is the pyridinyl ring optionally substituted with one or more substituents selected from halogen atoms and hydroxyl, C 1-3  alkyl, C 1-3  alkoxy and trifluoromethyl groups, then the bridging group of R 1  is —CH 2 —CH 2 —.  
 
     
     
         38 . The method as recited in  claim 37  wherein said condition is a MAP kinase and/or an HMG-CoA reductase related condition.

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