Carboxylic acid derivatives and pharmaceutical compositions comprising the same as an active ingredient

Abstract

Compounds represented by formula (I), prodrugs thereof and salts thereof, and pharmaceutical compositions comprising the same as an active ingredient (wherein each symbol has the meaning as defined in the specification.). Because of having an EDG-1 agonism, the compounds represented by formula (I) are useful in preventing and/or treating peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy, sepsis, angiitis, nephritis, pneumonia, stroke, myocardial infarction, edematous state, atherosclerosis, varicosity such as hemorrhoid, anal fissure or fistula ani, dissecting aneurysm of the aorta, angina, DIC, pleuritis, congestive heart failure, multiple organ failure, bedsore, burn, chronic ulcerative colitis, Crohn's disease, heart transplantation, renal transplantation, dermal graft, liver transplantation, osteoporosis, pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure, or glomerular sclerosis.

1 . A method of treating a disease that is also treatable by an EDG-1 agonist, comprising administering to a subject in need of treatment a therapeutically effective amount of a carboxylic acid compound represented by formula (I), prodrug or non-toxic salt thereof thereby treating a disease that is also treatable by an EDG-1 agonist  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl,  
 ring A is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom,  
 E is —CH 2 —, —O—, —S— or —NR 6 — (wherein R 6  is hydrogen or C1-8 alkyl),  
 R 2  is C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl,  
 R 3  is hydrogen or C1-8 alkyl,  
 R 4  is hydrogen or C1-8 alkyl, or  
 R 2  and R 4  taken together form —CH 2 —CH 2 — or —CH═CH—,  
 G is —CONR 7 —, —NR 7 CO—, —SO 2 NR 7 —, —NR 7 SO 2 —, —CH 2 NR 7 — or —NR 7 CH 2 — (wherein R 7  is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1, Cyc1 is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom),  
 Q is C1-4 alkylene or  
                     
 J 1 , J 2 , J 3  and J 4  are each independently carbon atom or nitrogen atom (with the proviso that the number of nitrogen is less than two),  
 R 5  is  
 (1) C1-8 alkyl,  
 (2) halogen atom,  
 (3) nitro,  
 (4) cyano,  
 (5) trifluoromethyl,  
 (6) trifluoromethoxy,  
 (7) phenyl,  
 (8) tetrazolyl,  
 (9) —OR 9 ,  
 (10) —SR 10 ,  
 (11) —COOR 11 ,  
 (12) —NR 12 R 13 ,  
 (13) —CONR 14 R 15 ,  
 (14) —SO 2 NR 16 R 17 ,  
 (15) —NR 18 COR 19 ,  
 (16) —NR 20 SO 2 R 21 ,  
 (17) —SO 2 R 22  or  
 (18) —OP(O)(OR 23 ) 2 ,  
 (wherein R 9 -R 18 , R 20  and R 23  are each independently hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 R 12  and R 13 , R 14  and R 15 , R 16  and R 17  together with nitrogen atom to which they are attached, form 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom (the hetero ring may be optionally substituted by C1-8 alkyl, hydroxy or amino)  
 R 19  and R 21  are each independently C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 R 22  is hydroxy, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 Cyc2 is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom), wherein, when Q is  
                     
  and J 2  is carbon atom substituted by R 5 , G may be  
                     
 (wherein U is oxygen atom, nitrogen atom or sulfur atom, W is carbon atom or nitrogen atom,  
 R 8  and R 5 , which bonds J 2 , taken together form bond, carbon atom or nitrogen atom), 
 p is 0 or an integer of 1-5,  
 q is an integer of 4-6,  
 r is 0 or an integer of 1-4,  
 s is 0 or an integer of 1-4, and  
   is single bond or double bond,  
 a prodrug thereof or a non-toxic salt thereof, wherein said prodrug has a carboxylate ester, a carboxylic amide or an alcohol in place of —COOH in formula (I).  
 
 
   
   
       2 . The method according to  claim 1 , wherein the disease is selected from the group consisting of arteriosclerosis obliterans, thromboangitis obliterans, Buerger's disease, diabetic neuropathy, sepsis, angitis, nephritis, pneumonia, stroke, myocardial infarction, edematous state, atherosclerosis, varicosity, hemorrhoid, anal fissure, fistula ani, dissecting aneurysm of the aorta, angina, DIC, pleuritis, congestive heart failure, multiple organ failure, bedsore, burn, chronic ulcerative colitis, Crohn's disease, heart transplantation, renal transplantation, dermal graft, liver transplantation, osteoporosis, pulmonary fibrosis, interstitial pneumonia, chronic hepatitis, liver cirrhosis, chronic renal failure, and glomerular sclerosis.  
   
   
       3 . The method according to  claim 1 , wherein the disease is heart transplantation, renal transplantation, dermal graft, or liver transplantation.  
   
   
       4 . A method of treating rejection in heart transplantation, renal transplantation, dermal graft, or liver transplantation, comprising administering to a subject in need of treatment a therapeutically effective amount of a carboxylic acid compound represented by formula (I), prodrug or non-toxic salt thereof thereby treating rejection in heart transplantation, renal transplantation, dermal graft, or liver transplantation  
     
       
         
         
             
             
         
       
     
     wherein 
 R 1  is C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl,  
 ring A is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom,  
 E is —CH 2 —, —O—, —S— or —NR 6 — (wherein R 6  is hydrogen or C1-8 alkyl),  
 R 2  is C1-8 alkyl, C1-8 alkoxy, halogen atom, nitro or trifluoromethyl,  
 R 3  is hydrogen or C1-8 alkyl,  
 R 4  is hydrogen or C1-8 alkyl, or  
 R 2  and R 4  taken together form —CH 2 —CH 2 — or —CH═CH—,  
 G is —CONR 7 —, —NR 7 CO—, —SO 2 NR 7 —, —NR 7 SO 2 —, —CH 2 NR 7 — or —NR 7 CH 2 — (wherein R 7  is hydrogen, C1-8 alkyl, Cyc1 or C1-8 alkyl substituted by Cyc1, Cyc1 is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom),  
 Q is C1-4 alkylene or  
                     
 J 1 , J 2 , J 3  and J 4  are each independently carbon atom or nitrogen atom (with the proviso that the number of nitrogen is less than two),  
 R 5  is  
 (1) C1-8 alkyl,  
 (2) halogen atom,  
 (3) nitro,  
 (4) cyano,  
 (5) trifluoromethyl,  
 (6) trifluoromethoxy,  
 (7) phenyl,  
 (8) tetrazolyl,  
 (9) —OR 9 ,  
 (10) —SR 10 ,  
 (11) —COOR 11 ,  
 (12) —NR 12 R 13 ,  
 (13) —CONR 14 R 15 ,  
 (14) —SO 2 NR 16 R 17 ,  
 (15) —NR 18 COR 19 ,  
 (16) —NR 20 SO 2 R 21 ,  
 (17) —SO 2 R 22  or  
 (18) —OP(O)(OR 23 ) 2 ,  
 (wherein R 9 -R 18 , R 20  and R 23  are each independently hydrogen, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 R 12  and R 13 , R 14  and R 15 , R 16  and R 17  together with nitrogen atom to which they are attached, form 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom (the hetero ring may be optionally substituted by C1-8 alkyl, hydroxy or amino)  
 R 19  and R 21  are each independently C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 R 22  is hydroxy, C1-8 alkyl, Cyc2 or C1-8 alkyl substituted by Cyc2,  
 Cyc2 is C5-7 mono-carbocyclic ring or 5-7 membered mono-cyclic hetero ring containing 1-2 nitrogen atoms, one oxygen atom and/or one sulfur atom), wherein, when Q is  
                     
  and J 2  is carbon atom substituted by R 5 , G may be  
                     
 (wherein U is oxygen atom, nitrogen atom or sulfur atom, W is carbon atom or nitrogen atom,  
 R 8  and R 5 , which bonds J 2 , taken together form bond, carbon atom or nitrogen atom), 
 p is 0 or an integer of 1-5,  
 q is an integer of 4-6,  
 r is 0 or an integer of 1-4,  
 s is 0 or an integer of 1-4, and  
   is single bond or double bond,  
 a prodrug thereof or a non-toxic salt thereof, wherein said prodrug has a carboxylate ester, a carboxylic amide or an alcohol in place of —COOH in formula (I).