Biaryl substituted nitrogen containing heterocycle inhibitors of lta4h for treating inflammation

Abstract

The present invention relates to a chemical genus of biaryl substituted nitrogen-attached heterocycles that are inhibitors of LTA4H (leukotriene A4 hydrolase). The compounds have the general formula: They are useful for the treatment and prevention and prophylaxis of inflammatory diseases and disorders.

1 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is selected from the group consisting of aryl, aryl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl, substituted phenyl, heteroaryl, heterocyclylalkyl and nitro; and heteroaryl, heteroaryl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, sulphonamide, amido, phenyl, heteroaryl, heterocyclylalkyl and nitro; 
 X is selected from the group consisting of direct bond, SO, S(O 2 ), NR 10 , CH 2 CH 2 , CH 2 NH, NHCH 2 , CH═CH, CH 2 C═O, OCR 1a R 1b  and CR 1a R 1b O; 
 R 10  is selected separately in each occurrence from the group consisting of H and lower alkyl; 
 R 1a  and R 1b  are selected from the group consisting of H and lower alkyl, or R 1a  and R 1b  taken together may form a 3-6 membered ring, which may optionally contain a heteroatom chosen from O, S, SO, SO 2 , and NR 10 ; 
 m is zero, 1 or 2; 
 n is an integer chosen from 1, 2 and 3; 
 p is an integer from 0-3; 
 Y is selected from H, H; O; and H, R 3 ; 
 R 3  is lower alkyl; 
 taken together ZW is H or 
 Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a C 3 -C 6  carbocycle, a C 3 -C 6  heterocycle, —O—, —NR 10 —, —SO—, —S(O) 2 —, —C(═O)— or —C═O(NH)—, provided that said —O—, —NR 10 —, —SO—, —S(O) 2 —, —C(═O)— or —C═O(NH)— are not at the point of attachment to nitrogen and are separated by at least one —(CH 2 ) 2 —; 
 W is selected from acyl, hydroxyl, carboxyl, amino, carboxamido, sulphonamide, aminoacyl, —COOalkyl, —CHO, —C(O)fluororalkyl, —C(O)CH 2 C(O)Oalkyl, —C(O)CH 2 C(O)Ofluoroalkyl, —SH, —C(O)NH(OH), —C(O)N(OH)R, —N(OH)C(O)OH, —N(OH)C(O)R 4 , heterocyclyl, substituted aryl, and substituted heterocyclyl; and 
 R 4  is selected from the group consisting of H and lower alkyl. 
 
     
     
         2 . A compound according to  claim 1 , wherein Ar is phenyl or substituted phenyl and m is zero of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 R 1  or R 2  are independently chosen from hydrogen, halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, sulphonamide, amido, phenyl, substituted phenyl, heteroaryl, heterocyclylalkyl and nitro; or R 1  and R 2  taken together may form a 5-6 membered ring, which may optionally contain an oxygen. 
 
     
     
         3 . A compound according to  claim 2 , wherein
 n is 1 or 2;   p is 1 or 2; and   ZW is H or   Z is (CH 2 ) 1-10  and   W is selected from acyl, hydroxyl, carboxyl, amino, carboxamido, aminoacyl, and —COOalkyl.   
     
     
         4 . (canceled) 
     
     
         5 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to  claim 1 . 
     
     
         6 . A method for inhibiting leukotriene A4 hydrolase comprising contacting the LTA4H enzyme with a therapeutically effective amount of a compound according to  claim 1 . 
     
     
         7 . A method for treating a disorder associated with leukotriene A4 hydrolase comprising administering to a mammal a therapeutically effective amount of a compound or a salt, hydrate or ester thereof according to  claim 1 . 
     
     
         8 . A method according to  claim 7  wherein said disorder is associated with inflammation. 
     
     
         9 . A method according to  claim 8  wherein said disorder is selected from allergic inflammation, acute inflammation and chronic inflammation. 
     
     
         10 . A method according to  claim 7 , wherein said disorder is chosen from asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (IBD), ulcerative colitis, and psoriasis. 
     
     
         11 . A method according to  claim 7 , wherein said disorder is chosen from hypercholesterolemia, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm and myocardial infarction. 
     
     
         12 . A compound of formula: 
       
         
           
           
               
               
           
         
       
       wherein
 Ar is selected from the group consisting of aryl other than phenyl, aryl other than phenyl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, benzyl, benzyloxy, phenyl, substituted phenyl, heteroaryl, heterocyclylalkyl and nitro; and heteroaryl, heteroaryl substituted with from one to three substituents independently selected from the group consisting of halogen, loweralkyl, loweracyl, loweralkoxy, fluoroloweralkyl, fluoroloweralkoxy, formyl, cyano, sulphonamide, amido, phenyl, heteroaryl, heterocyclylalkyl and nitro; 
 X is selected from the group consisting of direct bond, O, SO, S(O 2 ), NR 10 , CH 2 , CF 2 , CH 2 CH 2 , CH 2 NH, NHCH 2 , CH═CH, C═O, CH 2 C═O, CR 1a R 1b , OCR 1a R 1b  and CR 1a R 1b O; 
 R 10  is selected separately in each occurrence from the group consisting of H and lower alkyl; 
 R 1a  and R 1b  are selected from the group consisting of H and lower alkyl, or R 1a  and R 1b  taken together may form a 3-6 membered ring, which may optionally contain a heteroatom chosen from O, S, SO, SO 2 , and NR 10 ; 
 m is zero, 1 or 2; 
 n is an integer chosen from 1, 2 and 3; 
 p is an integer from 0-3; 
 Y is selected from H, H; O; and H, R 3 ; 
 R 3  is lower alkyl; 
 taken together ZW is H or 
 Z is (CH 2 ) 1-10 ; in which one or two (CH 2 ) may optionally be replaced by a C 3 -C 6  carbocycle, a C 3 -C 6  heterocycle, —O—, —NR 10 —, —SO—, —S(O) 2 —, —C(═O)— or —C═O(NH)—, provided that said —O—, —NR 10 —, —SO—, —S(O) 2 —, —C(═O)— or —C═O(NH)— are not at the point of attachment to nitrogen and are separated by at least one —(CH 2 ) 2 —; 
 W is selected from acyl, hydroxyl, carboxyl, amino, carboxamido, sulphonamide, aminoacyl, —COOalkyl, —CHO, —C(O)fluororalkyl, —C(O)CH 2 C(O)Oalkyl, —C(O)CH 2 C(O)Ofluoroalkyl, —SH, —C(O)NH(OH), —C(O)N(OH)R, —N(OH)C(O)OH, —N(OH)C(O)R 4 , heterocyclyl, substituted aryl, and substituted heterocyclyl; and 
 R 4  is selected from the group consisting of H and lower alkyl. 
 
     
     
         13 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one compound according to  claim 12 . 
     
     
         14 . A method for inhibiting leukotriene A4 hydrolase comprising contacting the LTA4H enzyme with a therapeutically effective amount of a compound according to  claim 12 . 
     
     
         15 . A method for treating a disorder associated with leukotriene A4 hydrolase comprising administering to a mammal a therapeutically effective amount of a compound or a salt, hydrate or ester thereof according to  claim 12 . 
     
     
         16 . A method according to  claim 15  wherein said disorder is associated with inflammation. 
     
     
         17 . A method according to  claim 16  wherein said disorder is selected from allergic inflammation, acute inflammation and chronic inflammation. 
     
     
         18 . A method according to  claim 15 , wherein said disorder is chosen from asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis, multiple sclerosis, inflammatory bowel diseases (IBD), ulcerative colitis, and psoriasis. 
     
     
         19 . A method according to  claim 15 , wherein said disorder is chosen from hypercholesterolemia, atherosclerosis, thrombosis, stroke, acute coronary syndrome, stable angina, peripheral vascular disease, critical leg ischemia, intermittent claudication, abdominal aortic aneurysm and myocardial infarction.