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

Abstract

A carboxylic acid derivative of formula (I) wherein R 1 , 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 5 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 .- 5  (canceled)  
     
     
         6 . A method for the prevention, treatment or both the prevention and treatment of pain, allodynia, hyperalgesia, pruritus, urticaria, atopic dermatitis, contact dermatitis, allergic conjunctivitis, various symptoms by treating with dialysis, asthma, rhinitis, sneeze, urinary frequency, neurogenic bladder, urinary disturbance, ejaculatory failure, defervescence, systemic inflammatory response syndrome, learning disturbance, Alzheimer's disease, cancer, retinopathy, patch of red, scald, burn, burn by steroid, renal failure, nephropathy, acute nephritis, chronic nephritis, abnormal blood levels of electrolytes, threatened premature delivery, threatened abortion, hypermenorrhea, dysmenorrhea, uterine fibroids, premenstrual syndrome, reproductive disorder, stress, anxiety disorders, depression, psychosomatic disorder, mental disorder, thrombosis, embolism, transient ischemia attack, cerebral infarction, atheroma, organ transplant, myocardial infarction, cardiac failure, hypertension, arteriosclerosis, circulatory failure and circulatory failure induced ulcer, neuropathies, vascular dementia, edema, various arthritis, rheumatism, diarrhea, constipation, disorder of bilious excretion, ulcerative colitis, or Crohn's disease, said method comprising administering to a subject an effective amount of the carboxylic acid compound of formula (I) or non-toxic salts thereof.  
       
         
           
           
               
               
           
         
         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 selected form C1-4 alkyl, C 1- 4 alkoxy and halogen atom or unsubstituted (2-1) C6-12 mono- or bi-carbocyclic ring or (2-25-15 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 8  and R 9  each independently, is hydrogen or C1-4 alkyl,  
         R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8 R 9 ,  
         A is C1-6 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 by1-2 of substitutes selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,  
         R 5  is substituted by 1-2 of R 13  or unsubstituted 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,  
         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) x -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.  
       
     
     
         7 . A method for the prevention, treatment or both the prevention and treatment of bone diseases, cancer, systemic granuloma, immunological diseases, allergy atopic dermatitis, asthma, pyorrhea, gingivitis, periodontitis, neuronal cell death, Alzheimer's disease's disease, pulmonary injury, hepatopathy, acute hepatopathy, nephritis, renal failure, myocardial ischemia, Kawasaki disease, scald, ulcerative colitis, Crohn's disease, multiple organ failure, sleeping disorder, or platelet aggregation, said method comprising administering to subject an effective amount of the carboxylic acid compound of formula (I) or non-toxic salts thereof:  
       
         
           
           
               
               
           
         
         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 selected form 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 8  and R 9  each independently, is hydrogen or C1-4 alkyl,  
         R 16  is hydroxy, C1-4 alkoxy, COOH, C1-4 alkoxycarbonyl, CONR 8  R 9 ,  
         A is C1-6 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 substitutes selected from halogen atom, hydroxy, C1-6 alkoxy, C1-4 alkoxy(C1-4)alkoxy, phenyl and C3-6 cycloalkyl,  
         R 5  is substituted by 1-2 of R 13  or unsubstituted 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,  
         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-(C1-8alkylene) x -R 14 , benzoyl or thiophenecarbonyl and two R 13  may be same or different,  
         y is 0 or 1,  
         z is 0or 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.