Remedy for chronic disease

Abstract

A remedy and/or a preventive for a chronic disease which contains an EDG-2 antagonist. Because of binding to a subtype EDG-2 of LPA receptor, an EDG-2 antagonist is useful in treating and/or preventing chronic diseases (for example, diseases caused by the progress of chronic asthma, glomerular nephritis, obesity, arteriosclerosis, rheumatoid and atopic diseases) induced and made chronic by tissue cells whose proliferation is accelerated by LPA mediated by EDG-2.

1 . A method for the treatment of a chronic disease selected from the group consisting of chronic asthma, glomerular nephritis, obesity, prostate hyperplasia, a disease induced by the progress of arteriosclerosis, and rheumatoid or atopic dermatitis, wherein said method comprises administering to a mammal having said chronic disease an effective amount of an EDG-2 antagonist, 
 wherein the EDG-2 antagonist is a compound of formula (II)                          wherein R 1b  is C1-20 alkyl optionally having substituent(s), aryl, heteroring, alkyloxy, aryloxy, alkylthio, arylthio, or halogen,    R 2b  is alkyl optionally having substituent(s), aryl, heteroring, alkyloxy, aryloxy or halogen,    R 3b  is hydrogen, lower alkyl or halogenated alkyl,    R 4b  is a group selected from (a) phenyl, aryl or heteroring optionally having substituent(s), (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted alkenyl, and    X b  is oxygen or sulfur, and    wherein R 3b  and R 4b  may be taken together with the carbon to which they are attached to form a 5-10 membered ring, and    when R 3b  is hydrogen, R 4b  is not methyl, or    a salt thereof; or    the EDG-2 antagonist is a compound of formula (III)                          wherein R c  is optionally substituted aliphatic hydrocarbon or a ring group optionally having substituent(s),    G c  is a bond or a spacer having a main chain of 1 to 8 atoms,    T c  is —CH 2 — or a spacer having a main chain of 1 atom having a hydrogen bond-accepting group optionally having substituent(s),    J c  is nitrogen or carbon,    B c  is optionally substituted aliphatic hydrocarbon or a ring group optionally having substituent(s),    K c  is (1) a bond or (2) a spacer having a main chain of 1 to 8 atoms which may form a ring together with the substituent of the ring group represented by R c , ring D c  or the substituent of the ring D c ,    Q c  is (1) a bond or (2) a spacer having a main chain of 1 to 8 atoms which may form a ring together with the ring group represented by R c , a substituent of the ring group represented by R c , or K c ,    ring D c  is a ring optionally having more substituent(s),    L c  is a bond or a spacer having a main chain of 1 to 3 atoms,    ring E c  is, a ring group optionally having substituent(s),    M c  is a bond or a spacer having a main chain of 1 to 8 atoms,    Z c  is an acidic group, and    t is 0 or 1, or    a salt thereof.    
     
     
         2 . A pharmaceutical composition comprising an EDG-2 antagonist in combination with one or more selected from LPA receptor antagonist, anti-androgenergic agent, α1 receptor blocker or 5α-reductase inhibitor, 
 wherein the EDG-2 antagonist is a compound of formula (II)                          wherein R 1b  is C1-20 alkyl optionally having substituent(s), aryl, heteroring, alkyloxy, aryloxy, alkylthio, arylthio, or halogen,    R 2b  is alkyl optionally having substituent(s), aryl, heteroring, alkyloxy, aryloxy or halogen,    R 3b  is hydrogen, lower alkyl or halogenated alkyl,    R 4b  is a group selected from (a) phenyl, aryl or heteroring optionally having substituent(s), (b) substituted or unsubstituted alkyl, and (c) substituted or unsubstituted alkenyl, and    X b  is oxygen or sulfur, and    wherein R 3b  and R 4b  may be taken together with the carbon to which they are attached to form a 5-10 membered ring, and    when R 3b  is hydrogen, R 4b  is not methyl, or    a salt thereof, or    the EDG-2 antagonist is a compound of formula (III)                          wherein R c  is optionally substituted aliphatic hydrocarbon or a ring group optionally having substituent(s),    G c  is a bond,    T c  is —CH 2 — or a spacer having a main chain of 1 atom having a hydrogen bond-accepting group optionally having substituent(s),    J c  is nitrogen or carbon,    B c  is optionally substituted aliphatic hydrocarbon or a ring group optionally having substituent(s),    K c  is (1) a bond or (2) a spacer having a main chain of 1 to 8 atoms which may form a ring together with the substituent of the ring group represented by R c , ring D c  or the substituent of the ring D c ,    Q c  is (1) a bond or (2) a spacer having a main chain of 1 to 8 atoms which may form a ring together with the ring group represented by R c , a substituent of the ring group represented by R c , or K c ,    ring D c  is a ring optionally having more substituent(s),    L c  is a bond or a spacer having a main chain of 1 to 3 atoms,    ring E c  is selected from the group consisting of benzene optionally having substituent(s), piperidine optionally having substituent(s), isoxazole optionally having substituent(s), pyrazole optionally having substituent(s), pyridine optionally having substituent(s), thiazole optionally having substituent(s), imidazole optionally having substituent(s), pyrrole optionally having substituent(s), and pyrrolidine optionally having substituent(s),    M c  is a bond or a spacer having a main chain of 1 to 8 atoms,    Z c  is an acidic group, and    t is 0 or 1, or    a salt thereof.    
     
     
         3 . The method according to  claim 1 , wherein the chronic disease is prostate hyperplasia.  
     
     
         4 . The method according to  claim 1 , wherein the EDG-2 antagonist is said compound of formula (II) or a salt thereof.  
     
     
         5 . The method according to  claim 1 , wherein the EDG-2 antagonist is said compound of formula (III) or a salt thereof.  
     
     
         6 . The method according to  claim 1 , wherein the method comprises administering to said mammal one or more members selected from the group consisting of an LPA receptor antagonist, an anti-androgenergic agent, an α1 receptor blocker, and an 5α-reductase inhibitor, in combination with the EDG-2 antagonist.  
     
     
         7 . The pharmaceutical composition according to  claim 2 , wherein the pharmaceutical composition is effective for treatment of a chronic disease selected from the group consisting of chronic asthma, glomerular nephritis, obesity, prostate hyperplasia, a disease induced by the progress of arteriosclerosis, and rheumatoid or atopic dermatitis.  
     
     
         8 . The pharmaceutical composition according to  claim 7 , wherein the composition is effective for the treatment of prostate hyperplasia.  
     
     
         9 . The pharmaceutical composition according to  claim 2 , wherein the EDG-2 antagonist is said compound of formula (II) or a salt thereof.  
     
     
         10 . The pharmaceutical composition according to  claim 2 , wherein the EDG-2 antagonist is the compound of formula (III) or a salt thereof.