Carboxylic acid derivatives, processes for the preparation thereof and pharmaceutical aggents comprising the same as active ingredient

Abstract

A carboxylic acid derivative of formula (I) wherein R 1 is COOH, COOR 6 etc.; A is alkylene etc.; R 2 is alkyl, alkenyl, alkynyl etc.; B is carbocyclic ring or heterocyclic ring; R 4 is alkyl, cycloalkyl etc.; R 6 is carbocyclic ring or heterocyclic ring; or non-toxic salts thereof, a process for the preparation thereof and a pharmaceutical agent comprising the same as active ingredient. The compound of the formula (I) can bind to Prostaglandin E 2 receptors, especially, EP 3 receptor and/or EP 4 receptor and show the antagonizing activity, and useful for the prevention and/or treatment of disease, for example, pain, allergy, Alzheimer's disease, cancer.

1 . A carboxylic acid compound of formula (I)  
       
         
           
           
               
               
           
         
         wherein R 1  is COOH, COOR 6 , CH 2 OH, CONHSO 2 R 7  or CONR 8 R 9 ,  
         R 6  is C1-6 alkyl, (C1-4 alkylene)-R 16 ,  
         R 7  is (1) C1-4 alkyl, or (2) substituted by 1-2 of substitutes substituents selected from C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1) C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- or bi-heterocyclic ring containing at least one of hetero atom selected from nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by the above substituents or unsubstituted carbocyclic ring or heterocyclic ring,  
         R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8 R 9 ,  
         R 8  and R 9  each independently, is hydrogen or C1-4 alkyl,  
         A is C2-6 alkylene or —(C1-3 alklylene) w -G-(C1-3 alkylene)-,  
         w is 0 or 1,  
         G is oxygen, sulfur or NR 10 ,  
         R 10  is hydrogen or C1-4 alkyl,  
         R 2  is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF 3 , cyano, nitro, hydroxy, NR 11 R 12 , CONR 11 R 12 , SO 2 NR 11 R 12 , or —S(O) x —(C1-6)alkyl,  
         m is 0, 1 or 2, when m is 2, then two R 2  may be same or different,  
         R 11  and R 12  each independently is hydrogen or C1-4 alkyl,  
         x is 0, 1 or 2,  
         B ring is C5-7 mono-carbocyclic ring or 5-7 membered mono-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur,  
         R 3  is hydrogen or C1-4 alkyl,  
         R 4  is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) C3-6 cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4 alkoxy(C1-4)alkoxy, or (8) C1-8 alkyl substituted by 1-2 of substituents selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,  
         R 5  is C5-10 mono- or bi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ring containing at least one of nitrogen, oxygen and sulfur, which ring is unsubstituted or substituted by 1-2 of R 13 ,  
         R 13  is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF 3 , cyano, C1-4 alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4 alkylene) y -J-(C1-8 alkylene) z , —R 14 , benzoyl or thiophenecarbonyl and two R 13  may be same or different,  
         y is 0 or 1,  
         z is 0 or 1,  
         R 14  is phenyl or pyridyl,  
         J is oxygen, S(O) t  or NR 15 ,  
         t is 0, 1 or 2,  
         R 15  is hydrogen, C1-4 alkyl or acetyl;  
         excluding a carboxylic acid compound of formula (I),  
         wherein R 1  is COOH or COOR 6 ,  
         R 6  is C1-6 alkyl, (C1-4 alkylene)-R 16 .  
         R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8 R 9 ,  
         R 8  and R 9  each independently, is hydrogen or C1-4 alkyl,  
         A is C2-6 alkylene,  
         R 2  is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF 3 , cyano, nitro, hydroxy, NR 11 R 12 , CONR 11 R 12 , SO 2 NR 11 R 12 , or —S(O) x -(C1-6)alkyl,  
         m is 0, 1 or 2, when m is 2, then two R 2  may be same or different,  
         R 11  and R 12  each independently is hydrogen or C1-4 alkyl,  
         x is 0, 1 or 2,  
         B ring is phenyl,  
         R 3  is hydrogen or C1-4 alkyl,  
         R 4  is (1) C1-8 alkyl, (2) C2-8 alkenyl, (3) C2-8 alkynyl, (4) C3-6 cycloalkyl, (5) hydroxy, (6) C1-4 alkoxy, (7) C1-4 alkoxy(C1-4)alkoxy, or (8) C1-8 alkyl substituted by 1-2 of substituents selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,  
         R 5  is unsubstituted phenyl or naphthyl or phenyl or naphthyl substituted by 1-2 or R 13 ,  
         R 13  is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF 3 , cyano, C1-4 alkoxy(C1-4)alkyl, phenyl, phenyl(C1-6)alkyl, —(C1-4 alkylene) y -J-(C1-8 alkylene) z —R 14 , benzoyl or thiophenecarbonyl and two R 13  may be the same or different,  
         y is 0 or 1,  
         z is 0 or 1,  
         R 14  is phenyl or pyridyl,  
         J is oxygen, S(O) t  or NR 15 ,  
         t is 0, 1 or 2,  
         R 15  is hydrogen, C1-4 alkyl or acetyl;  
         or non-toxic salts.  
       
     
     
         2 . A carboxylic acid derivative compound of formula (I) according to the  claim 1 , wherein R 1  is COOH, COOR 6 , CH 2 OH, CONHSO 2 R 7  or CONR 8 R 9 , 
 R 6  is C1-6 alkyl, (C1-4 alkylene)-R 16 ,    R 7  is (1) C1-4 alkyl, or (2) substituted by 1-2 of substituents selected from C1-4 alkyl, C1-4 alkoxy and halogen atom or unsubstituted (2-1) C6-12 mono- or bi-carbocyclic ring or (2-2) 5-15 membered mono- or bi-heterocyclic ring containing at least one of hetero atom selected from nitrogen, oxygen and sulfur, or (3) C1-4 alkyl substituted by the above substituted or unsubstituted carbocyclic ring or heterocyclic ring,    R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8 R 9 ,    R 8  and R 9  each independently, is hydrogen or C1-4 alkyl,    A is C2-4 alkylene or —(C1-2 alkylene) w -G-(C1-2 alkylene)-,    w is 0 or 1,    G is oxygen, sulfur or NR 10 ,    R 10  is hydrogen or C1-4 alkyl,    R 2  is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF 3  or cyano,    B ring is C5-6 mono-carbocyclic ring or 5-6 membered mono-heterocyclic ring containing 1-2 of nitrogen(s), 1 of oxygen and/or 1 of sulfur,    m is 0 or 1,    R 3  is hydrogen or C1-4 alkyl,    R 4  is C1-8 alkyl, C3-6 cycloalkyl or C1-8 alkyl substituted by 1-2 of C3-6 cycloalkyl,    R 5  is C5-10 mono- or bi-carbocyclic ring or 5-10 membered mono- or bi-heterocyclic ring containing 1-2 of nitrogen(s), 1-2 of oxygen(s) and/or 1 of sulfur, which ring is unsubstituted or substituted by 1-2 of R 13 ,    R 13  is C1-6 alkyl, C1-6 alkoxy, halogen atom, CF 3 , cyano or —(C1-4 alkylene) y -J-(C1-8 alkylene) z —R 14 ,    y is 0,    J is oxygen,    z is 1,    R 14  is phenyl;    excluding a carboxylic acid compound of formula (I),    wherein R 1  is COOH or COOR 6 ,    R 6  is C1-6 alkyl, (C1-4 alkylene)-R 16      R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8 R 9 ,    R 8  and R 9  each independently, is hydrogen or C1-4 alkyl    A is C2-4 alkylene,    R 2  is C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, halogen atom, CF 3 , cyano,    B ring is phenyl,    m is 0 or 1,    R 3  is hydrogen or C1-4 alkyl,    R 4  is C1-8 alkyl, C3-6 cycloalkyl, or C1-8 alkyl substituted by 1-2 of C3-6 cycloalkyl, and    R 5  is unsubstituted phenyl or naphthyl or phenyl or naphthyl substituted by 1-2 of R 13 ,    R 13  is C1-6 alkyl, C1-6 alkoxy, holgen atom, CF 3 , cyano or —(C1-4 alkylene) y -J-(C1-8 alkylene) z -R 14 ,    y is 0    J is oxyegen,    z is 1,    R 14  is phenyl;    or non-toxic salts thereof.    
     
     
         3 . A carboxylic acid compound of formula (I) according to the  claim 1  selected from 
 (1)4-[4-cyano-2-[2-(1,2,3,4-tetrahydro-5-naphthyl)propanoylamino]phenyl]butanoic acid,    (2)4-[4-cyano-2-[2-(benzothiophen-3-yl)propanoylamino]phenyl]butanoic acid,    (3) 4-[4-cyano-2-[2-(1,4-benzodioxan-5-yl)propanoylamino]phenyl]butanoic acid,    (4) 4-[4-cyano-2-[2-(1,4-benzodioxan-5-yl)propanoylamino]phenyl]butanoic acid,    (5) N-[4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]benzenesulfonamide,    (6) N-[4-[4-cyano-2-[2-(1-naphthyl)propanoylamino]phenyl]butanoyl]methanesulfonamide,    (7) 4-cyano-2-[2-(1-naphthyl)propanoylamino]benzylthioacetic acid,    (8)4-cyano-2-[2-(1-naphthyl)propanoylamino]benzyloxyacetic acid,    (9) N-methyl-2-[2-(1-naphthyl)propanoylamino]benzylaminoacetic acid,    (10) 2-[2-(1-naphthyl)propanoylamino]benzylaminoacetic acid,    or non-toxic salts thereof.    
     
     
         4 . A pharmaceutical composition having an activity of Prostaglandin E 2  receptor antagonist, which comprises a carboxylic acid compound of formula (I) according to the  claim 1  or non-toxic salts thereof as active ingredients.  
     
     
         5 . A pharmaceutical composition according to  claim 4 , wherein Prostaglandin E 2  receptors are EP 3,  and/of EP 4,  or EP 3  and EP 4 .  
     
     
         6 . (canceled):  
     
     
         7 . (canceled):