Phenylacetic Acid Compound

Abstract

A compound represented by formula (I), wherein R 1 represents a hydrogen atom, etc., R 2 and R 3 each independently represents a hydrogen atom, optionally oxidized C1-4 alkyl group or optionally protected hydroxyl group, or R 2 and R 3 taken together represent optionally oxidized C2-5 alkylene group, R 4 represents an optionally oxidized C1-6 alkyl group, etc., R 5 represents an optionally oxidized C1-6 alkyl group, etc., R 6 represents an optionally oxidized C1-6 alkyl group, etc., m represents 0 or an integer from 1 to 3, n represents 0 or an integer from 1 to 4, and i represents 0 or an integer from 1 to 7.

1 - 10 . (canceled) 
     
     
         11 . A compound represented by formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom or C1-4 alkyl group, 
         R 2  and R 3  each independently represent a hydrogen atom, optionally oxidized C1-4 alkyl group or optionally protected hydroxyl group, with the proviso that R 2  and R 3  do not represent an optionally protected hydroxyl group at the same time, or R 2  and R 3  taken together represent optionally oxidized C2-5 alkylene group, 
         R 4 , R 5  and R 6  each independently represent a halogen atom, optionally oxidized C1-6 alkyl group, optionally protected hydroxyl group, trihalomethyl group, —SO 2 R 7  group, —SOR 7  group, or —SR 7  group, 
         R 7  represents C1-6 alkyl group or optionally substituted phenyl group, 
         indicates that the substituent is attached in front of the sheet, 
         m represents 0 or an integer from 1 to 3, 
         n represents 0 or an integer from 1 to 4, and 
         i represents 0 or an integer from 1 to 7, with the proviso that when m is 2 or more, R 4  may be the same or different, when n is 2 or more, R 5  may be the same or different, and when i is 2 or more, R 6  may be the same or different, 
         a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof. 
       
     
     
         12 . A compound represented by formula (I) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom or C1-4 alkyl group, 
         R 2  and R 3  in the formula (I) taken together represent optionally oxidized C2-5 alkylene group, 
         R 4 , R 5  and R 6  each independently represent a halogen atom, optionally oxidized C1-6 alkyl group, optionally protected hydroxyl group, trihalomethyl group, —SO 2 R 7  group, —SOR 7  group, or —SR 7  group, 
         R 7  represents C1-6 alkyl group or optionally substituted phenyl group, 
       
       
         
           
           
               
               
           
         
         indicates that the substituent is attached in front of the sheet, 
         m represents 0 or an integer from 1 to 3, 
         n represents 0 or an integer from 1 to 4, and 
         i represents 0 or an integer from 1 to 7, with the proviso that when m is 2 or more, R 4  may be the same or different, when n is 2 or more, R 5  may be the same or different, and when i is 2 or more, R 6  may be the same or different, 
         a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof,
 with the proviso that a compound represented by formula (I-a) 
 
       
       
         
           
           
               
               
           
         
         
            wherein all symbols in the formula have the same meanings as defined above, a salt thereof, an N-oxide thereof or a hydrate thereof, is excluded. 
         
       
     
     
         13 . A compound represented by formula (I-b) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom or C1-4 alkyl group, 
         R 3  represents a hydrogen atom or optionally oxidized C1-4 alkyl group, 
         R 4 , R 5  and R 6  each independently represent a halogen atom, optionally oxidized C1-6 alkyl group, optionally protected hydroxyl group, trihalomethyl group, —SO 2 R 7  group, —SOR 7  group, or —SR 7  group, 
         R 7  represents C1-6 alkyl group or optionally substituted phenyl group, 
       
       
         
           
           
               
               
           
         
         indicates that the substituent is attached in front of the sheet, 
         m represents 0 or an integer from 1 to 3, 
         n represents 0 or an integer from 1 to 4, and 
         i represents 0 or an integer from 1 to 7, with the proviso that when m is 2 or more, R 4  may be the same or different, when n is 2 or more, R 5  may be the same or different, and when i is 2 or more, R 6  may be the same or different, 
         a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, 
         with the proviso that a compound selected from the group consisting of 
         (1) hydroxy(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(trifluoromethyl)phenyl)acetic acid, and 
         (2) 2 -hydroxy-2-(3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(trifluoromethyl)phenyl)propionic acid, 
         or a salt thereof, an N-oxide thereof or a hydrate thereof, is excluded. 
       
     
     
         14 . A compound represented by formula (I-c) 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents a hydrogen atom or C1-4 alkyl group, 
         R 4 , R 5  and R 6  each independently represent a halogen atom, optionally oxidized C1-6 alkyl group, optionally protected hydroxyl group, trihalomethyl group, —SO 2 R 7  group, —SOR 7  group, or —SR 7  group, 
         R 7  represents C1-6 alkyl group or optionally substituted phenyl group, 
       
       
         
           
           
               
               
           
         
         indicates that the substituent is attached in front of the sheet, 
         m represents 0 or an integer from 1 to 3, 
         n represents 0 or an integer from 1 to 4, and 
         i represents 0 or an integer from 1 to 7, with the proviso that when m is 2 or more, R 4  may be the same or different, when n is 2 or more, R 5  may be the same or different, and when i is 2 or more, R 6  may be the same or different, 
         a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, 
         with the proviso that a compound selected from the group consisting of 
         (1) (3-((2,6-dimethyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(trifluoromethyl)phenyl)acetic acid, and 
         (2) (3-((2-ethyl-6-methyl-4-(((2S)-4-methyl-3,4-dihydro-2H-1,4-benzoxazin-2-yl)methoxy)benzoyl)amino)-4-(trifluoromethyl)phenyl)acetic acid, 
         or a salt thereof, an N-oxide thereof or a hydrate thereof, is excluded. 
       
     
     
         15 . A pharmaceutical composition comprising
 the compound represented by formula (I) according to  claim 11 ,   or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, as an active ingredient.   
     
     
         16 . The pharmaceutical composition according to  claim 15 , which is a DP receptor antagonist. 
     
     
         17 . The pharmaceutical composition according to  claim 15 , further comprising one or more other compounds selected from the group consisting of an antihistamine agent, suppressor for mediator liberation, thromboxane synthetase inhibitor, antagonist for thromboxane A2 receptor, antagonist for leukotriene receptor, leukotriene synthase inhibitor, cytokine inhibitor, steroid agent, sympathomimetic agent, phosphodiesterase IV inhibitor, xanthine derivative, anticholinergic agent, anti-IgE antibody formulation, immunosuppressive agent, chemokine receptor antagonist, adhesion molecule inhibitor, other prostanoid receptor antagonist, nonsteroidal anti-inflammatory agent and nitric oxide synthase inhibitor. 
     
     
         18 . A method for prevention and/or treatment of a disease mediated by a DP receptor, comprising administering an effective dose of the compound represented by formula (I) according to  claim 11 ,
 or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal.   
     
     
         19 . A method for prevention and/or treatment of a disease wherein the disease is an allergy disease, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases generated secondarily as a result of behavior accompanied by itch, diseases accompanied by flushing, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, cancer, leukemia, viral infection, multiple sclerosis, sleeping disorders, or diseases associated to platelet aggregation,
 comprising administering an effective dose of the compound represented by formula (I) according to  claim 11 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal.   
     
     
         20 . The method according to  claim 19 , wherein the disease is an allergic disease which is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, or a food allergy. 
     
     
         21 . A pharmaceutical composition comprising a compound according to  claim 12 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, as an active ingredient. 
     
     
         22 . The pharmaceutical composition according to  claim 21 , which is a DP receptor antagonist. 
     
     
         23 . The pharmaceutical composition according to  claim 21 , further comprising one or more other compounds selected from the group consisting of an antihistamine agent, suppressor for mediator liberation, thromboxane synthetase inhibitor, antagonist for thromboxane A2 receptor, antagonist for leukotriene receptor, leukotriene synthase inhibitor, cytokine inhibitor, steroid agent, sympathomimetic agent, phosphodiesterase IV inhibitor, xanthine derivative, anticholinergic agent, anti-IgE antibody formulation, immunosuppressive agent, chemokine receptor antagonist, adhesion molecule inhibitor, other prostanoid receptor antagonist, nonsteroidal anti-inflammatory agent and nitric oxide synthase inhibitor. 
     
     
         24 . A method for prevention and/or treatment of a disease mediated by a DP receptor, comprising administering an effective dose of a compound according to  claim 12 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal. 
     
     
         25 . A method for prevention and/or treatment of a disease wherein the disease is an allergy disease, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases generated secondarily as a result of behavior accompanied by itch, diseases accompanied by flushing, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, cancer, leukemia, viral infection, multiple sclerosis, sleeping disorders, or diseases associated to platelet aggregation,
 comprising administering an effective dose of a compound according to  claim 12 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal.   
     
     
         26 . The method according to  claim 25 , wherein the disease is an allergic disease which is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, or a food allergy. 
     
     
         27 . A pharmaceutical composition comprising the compound represented by formula (I-b) according to  claim 13 , or a salt thereof,
 an N-oxide thereof or a solvate thereof, or a prodrug thereof, as an active ingredient.   
     
     
         28 . The pharmaceutical composition according to  claim 27 , which is a DP receptor antagonist. 
     
     
         29 . The pharmaceutical composition according to  claim 27 , further comprising one or more other compounds selected from the group consisting of an antihistamine agent, suppressor for mediator liberation, thromboxane synthetase inhibitor, antagonist for thromboxane A2 receptor, antagonist for leukotriene receptor, leukotriene synthase inhibitor, cytokine inhibitor, steroid agent, sympathomimetic agent, phosphodiesterase IV inhibitor, xanthine derivative, anticholinergic agent, anti-IgE antibody formulation, immunosuppressive agent, chemokine receptor antagonist, adhesion molecule inhibitor, other prostanoid receptor antagonist, nonsteroidal anti-inflammatory agent and nitric oxide synthase inhibitor. 
     
     
         30 . A method for prevention and/or treatment of a disease mediated by a DP receptor, comprising administering an effective dose of the compound represented by formula (I-b) according to  claim 13 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal. 
     
     
         31 . A method for prevention and/or treatment of a disease wherein the disease is an allergy disease, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases generated secondarily as a result of behavior accompanied by itch, diseases accompanied by flushing, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, cancer, leukemia, viral infection, multiple sclerosis, sleeping disorders, or diseases associated to platelet aggregation,
 comprising administering an effective dose of the compound represented by formula (I-b) according to  claim 13 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal.   
     
     
         32 . The method according to  claim 31 , wherein the disease is an allergic disease which is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, or a food allergy. 
     
     
         33 . A pharmaceutical composition comprising
 the compound represented by formula (I-c) according to  claim 14 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, as an active ingredient.   
     
     
         34 . The pharmaceutical composition according to  claim 33 , which is a DP receptor antagonist. 
     
     
         35 . The pharmaceutical composition according to  claim 33 , further comprising one or more other compounds selected from the group consisting of an antihistamine agent, suppressor for mediator liberation, thromboxane synthetase inhibitor, antagonist for thromboxane A2 receptor, antagonist for leukotriene receptor, leukotriene synthase inhibitor, cytokine inhibitor, steroid agent, sympathomimetic agent, phosphodiesterase IV inhibitor, xanthine derivative, anticholinergic agent, anti-IgE antibody formulation, immunosuppressive agent, chemokine receptor antagonist, adhesion molecule inhibitor, other prostanoid receptor antagonist, nonsteroidal anti-inflammatory agent and nitric oxide synthase inhibitor. 
     
     
         36 . A method for prevention and/or treatment of a disease mediated by a DP receptor, comprising administering an effective dose of the compound represented by formula (I-c) according to  claim 14 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal. 
     
     
         37 . A method for prevention and/or treatment of a disease wherein the disease is an allergy disease, systemic mastocytosis, disorders accompanied by systemic mast cell activation, anaphylaxis shock, bronchoconstriction, urticaria, eczema, acne, allergic bronchial pulmonary aspergillosis, sinusitis, migraine, nasal polypus, anaphylactic vasculitis, eosinophilic syndrome, contact dermatitis, diseases accompanied by itch, diseases generated secondarily as a result of behavior accompanied by itch, diseases accompanied by flushing, inflammation, chronic obstructive pulmonary diseases, ischemic reperfusion injury, cerebrovascular accident, autoimmune disease, traumatic brain disorder, hepatopathy, graft rejection, chronic rheumatoid arthritis, pleurisy, osteoarthritis, Crohn's disease, ulcerative colitis, irritable bowel syndrome, interstitial cystitis, muscular dystrophy, polymyositis, cancer, leukemia, viral infection, multiple sclerosis, sleeping disorders, or diseases associated to platelet aggregation,
 comprising administering an effective dose of the compound represented by formula (I-c) according to  claim 14 , or a salt thereof, an N-oxide thereof or a solvate thereof, or a prodrug thereof, to a mammal.   
     
     
         38 . The method according to  claim 37 , wherein the disease is an allergic disease which is allergic rhinitis, allergic conjunctivitis, atopic dermatitis, bronchial asthma, or a food allergy.