Diphenyl substituted cycloalkanes, compositions containing such compounds and methods of use

Abstract

The instant invention provides compounds of formula I which are 5-lipoxygenase activating protein inhibitors. Compounds of formula I are useful as anti-atherosclerotic, anti-asthmatic, anti-allergic, anti-inflammatory and cytoprotective agents.

1 . A compound represented by formula I-1: 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts, esters and solvates thereof wherein:
 “a” is an integer selected from 1, 2 and 3; and b and c are each integers independently selected from 0, 1 and 2; 
 “A” represents a methylene or ethylene group; 
 each R 1a  is independently selected from the group consisting of: —H, —F, —Cl, —Br, —C 1-6 alkyl, —CN, —OH, —OC 1-6  alkyl, -fluoroC 1-6  alkyl, -fluoroC 1-6  alkoxy, —N(R a ) 2 , —C 1-6  alkylN(R a ) 2 , —NHC(O)C 1-4 alkyl, —C(O)NHC 1-4 alkyl and —C(O)N(C 1-4 alkyl) 2 ; 
 each R 1b  is independently selected from the group consisting of: —H, —F, —C 1-6  alkyl, —OH, —OC 1-6  alkyl, -fluoroC 1-6  alkyl, -fluoroC 1-6 alkoxy, —N(R a ) 2  and —C 1-6 alkylN(R a ), 
 or one R 1b  group can represent oxo and the other is as previously defined; 
 R 1  is selected from the group consisting of: 
 —C(O)—Hetcy 1 , 
 b) —C 1-10 alkyl, —C 2-10 alkenyl, —C 2-10 alkynyl, —OC 1-10 alkyl, —OC 3-10 alkenyl and —OC 3-10 alkynyl, said groups being optionally substituted with: —C(O)-Hetcy 1 , HAR, and -Hetcy 1 , wherein Hetcy 1  is selected from azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl and γ-lactam; 
 c) HAR optionally substituted with 1-2 members selected from the group consisting of: —F, —Cl, —Br, —C 1-6  alkyl, —CN, —OH, —OC 1-6  alkyl, -fluoroC 1-6  alkyl, -fluoroC 1-6 alkoxy, —NH 2 , —NHC 1-4  alkyl, —N(C 1-4 alkyl) 2 , —C 1-6 alkylNH 2 , —C 1-6  alkyl-NHC 1-4 alkyl, —C 1-6  alkylN(C 1-4 alkyl) 2 , —C 1-6  alkyl-CN, —NHC(O)C 1-4  alkyl, —C(O)NHC 1-4  alkyl and —C(O)N(C 1-4 alkyl) 2 ; 
 R 4  and R 5  are each independently selected from the group consisting of —H, —C 1-6  alkyl, —OC 1-6  alkyl, —OH, -fluoro, -fluoroC 1-6 alkyl, -fluoroC 1-6 alkoxy, —N(R a ) 2 , and 
 Y is quinolinyl; 
 each R a  is independently selected from the group consisting of —H and: 
 (a) —C 1-10 alkyl, —C 3-10 alkenyl, or —C 3-10 alkynyl, optionally substituted with 1-3 fluoro groups or 1-2 members selected from the group consisting of: —OH, —OC 1-6 alkyl, —CN, —NH 2 , —NHC 1-4  alkyl, and —N(C 1-4 alkyl) 2 ; 
 (b) Aryl or Ar—C 1-6 alkyl-, the aryl portions being optionally substituted with 1-2 of —C 1-6  alkyl, —CN, —OH, —OC 1-6  alkyl, -fluoroC 1-6  alkyl, -fluoroC 1-6 alkoxy, —C 1-6 alkylNH 2 , —C 1-6 alkylNHC 1-4 alkyl, —C 1-6 alkylN(C 1-4 alkyl) 2 , —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , —NHC(O)C 1-4 alkyl, —C(O)NHC 1-4 alkyl, —C(O)N(C 1-4 alkyl) 2 , —CO 2 H and —CO 2 C 1-6 alkyl groups, and 1-3 —F, —Cl or —Br groups; and the alkyl portion of Ar—C 1-6 alkyl- being optionally substituted with —OH, —OC 1-6 alkyl, —NH 2 , —NHC 1-4 alkyl, —N(C 1-4 alkyl) 2 , and 1-3 fluoro groups. 
 
   
   
       2 . The compound of  claim 1  having structural formula Ia-1: 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts, esters and solvates thereof, wherein “a” is an integer selected from 1, 2 and 3; and b and c are each integers independently selected from 0, 1 and 2; provided that the sum of “a”+b+c is from 1 to 5. 
   
   
       3 . The compound of  claim 2  wherein “a” is an integer selected from 1 and 2; and one of b and c is 0 (zero) and the other is 1. 
   
   
       4 . The compound of  claim 1  having structural formula Ib-1: 
     
       
         
         
             
             
         
       
     
     and the pharmaceutically acceptable salts, esters and solvates thereof wherein: “a” is an integer selected from 2 and 3; and b and c are integers independently selected from 0 and 1; provided that the sum of “a”+b+c is from 2 to 4. 
   
   
       5 . The compound of  claim 4  wherein “a” is 2, and b and c are integers selected from 0 and 1. 
   
   
       6 . The compound of  claim 5  wherein “a” is 2, b is 1 and c is 0 or 1. 
   
   
       7 . The compound of  claim 1  wherein three R 1a  groups shown in the generic structural drawing of formula I, represent —H and one R 1a  group is selected from the group consisting of: —F, —Cl, —C 1-6  alkyl, —CN, —OC 1-6  alkyl, -fluoroC 1-6  alkyl, -fluoroC 1-6 alkoxy, —N(R a ) 2 , —C 1-6 alkylN(R a ) 2 , —NHC(O)C 1-4 alkyl, —C(O)NHC 1-4 alkyl and —C(O)N(C 1-4 alkyl) 2 . 
   
   
       8 . The compound of  claim 1  wherein one R 1b  represents —H and the other R 1b  is selected from the group consisting of: —H, —F, —C 1-6 alkyl, —OH, —OC 1-6  alkyl, -fluoroC 1-6 alkyl, -fluoroC 1-6 alkoxy, —N(R a ) 2  and —C 1-6 alkylN(R a ) 2  and oxo. 
   
   
       9 . The compound of  claim 8  wherein both R 1b  groups represent —H. 
   
   
       10 - 21 . (canceled) 
   
   
       22 . The compound of  claim 1  wherein: Y is 
     
       
         
         
             
             
         
       
     
     HAR is selected from: 
     
       
         
         
             
             
         
       
     
     wherein R 6  is selected from —H, —C 1-3 alkyl, —C 3-6 cycloalkyl, —F and —Cl; R a  is selected from —C 1-4 -alkyl and C 3-6 cycloalkyl, each optionally substituted with 1-3 fluoro groups or a member selected from the group consisting of: —OC 1-6 alkyl, —CN, —NH 2 , —NHC 1-4 alkyl and —N(C 1-4 alkyl) 2 ;
 Z 1  is O or S. 
 
   
   
       23 . The compound of  claim 1  selected from the group consisting of: 
     
       
         
               
             
                   
               
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
               
               
               
             
                   
                 Y 
                 R 1   
               
                   
               
                 a) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 b) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 c) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 d) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 e) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
                 g) 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 
                   
                     
                     
                         
                         
                     
                   
                 
               
                   
               
           
              
              
              
             
          
           
              
              
              
              
              
              
              
              
              
              
              
              
              
              
             
          
         
       
     
     and the pharmaceutically acceptable salts and solvates thereof. 
   
   
       24 . A pharmaceutical composition comprised of a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       25 . A method for preventing the synthesis, the action, or the release of leukotrienes in a patient which comprises administering to the patient an effective amount of a compound of  claim 1 . 
   
   
       26 . A method for treating a leukotriene-mediated medical condition comprising administering a therapeutically effective amount of a compound of  claim 1  to a patient in need of such treatment. 
   
   
       27 - 35 . (canceled)