Compound exhibiting pgd2 receptor antagonist

Abstract

A compound having CRTH2 receptor antagonism, represented by the following formula (I). The compound is useful for the treatment of allergic diseases having a relation to eosinophils and the like. A compound of the formula (I): wherein a group represented by the formula: is a group represented by the formula: and the like, R 1 is carboxy and the like, R 3 is —(CH 2 )n-N(—Y)—SO 2 —Ar and the like, the other symbols are as defined in claim 1.

1 . A compound of the formula (I): 
     
       
         
         
             
             
         
       
       wherein 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Z 3  is ═N— or ═C(—R 7 )—; 
       R 4 , R 5 , R 6  and R 7  are each independently hydrogen, halogen, haloalkyl, carboxy, alkyloxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted aralkyl, a group represented by the formula: —S(O)pR 8  wherein p is an integer from 0 to 2 and R 8  is alkyl or optionally substituted aryl, a group represented by the formula: —NR 9 R 10  wherein R 9  and R 10  are each independently hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl or acyl, or a group represented by the formula: —OR 11  wherein R 11  is hydrogen, alkyl, optionally substituted aryl, optionally substituted aralkyl, alkanesulfonyl, optionally substituted arylsulfonyl, optionally substituted aralkylsulfonyl, or haloalkyl; 
       R 1  is carboxy, alkyloxycarbonyl, optionally substituted aminocarbonyl or tetrazolyl; 
       Z 4  is —N═ or —C(—R 2 )═; R 2  is hydrogen, alkyl or halogen; 
       R 15  is hydrogen or alkyl; 
       R 3  is a group represented by the formula: —(CH 2 )n-N(—Y)—SO 2 —Ar wherein n is an integer from 1 to 3; Y is hydrogen, alkyl, alkenyl, alkynyl, optionally substituted aryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl or optionally substituted arylalkenyl; and Ar is optionally substituted aryl or optionally substituted heteroaryl, a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein r is an integer from 0 to 2; x is an integer from 0 to 3; m is an integer from 1 to 3; a broken line represents the presence or absence of a bond; E is optionally substituted aryl, optionally substituted heteroaryl, alkyl, optionally substituted aralkyl or optionally substituted arylalkenyl, 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein x is an integer from 0 to 3; m is an integer from 1 to 3; a broken line represents the presence or absence of a bond; E is optionally substituted aryl, optionally substituted heteroaryl, alkyl, optionally substituted aralkyl or optionally substituted arylalkenyl, 
       a group represented by the formula: —CR 23 R 24 —CR 25 R 26 —(CH 2 )y-N(—Y)—SO 2 —Ar wherein Ar and Y are as defined above; y is 0 or 1; one of R 23  or R 24  is alkyl, the other is hydrogen, alkyl, or aryl; or R 23  and R 24  are taken together to form a group represented by the formula: —(CH 2 )t- wherein t is an integer from 2 to 5; R 25  and R 26  are each independently hydrogen or alkyloxyalkyl, 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Y and Ar are as defined above, or 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Y and Ar are as defined above and u is 1 or 2; or 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein y is an integer from 1 to 3, and m, p, Y and Ar are as defined above, 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein m, y and Ar are as defined above, or 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Y and Ar are as defined above; R 20  is hydrogen or alkyl; and R 21  is hydrogen or halogen; but excluding compounds 3-(4-chlorophenylsulfonylamino)-9-(2-carboxymethyl)-1,2,3,4-tetrahydrocarbazole, its ethyl ester, 3-(4-chlorophenylsulfonylaminoethyl)indole1-acetic acid, and 3-(4-chlorophenylsulfonylaminopropyl)indole acetic acid; or 
       R 13  is hydrogen, alkyl, aralkyl, acyl or a group represented by the formula: —OR 16  wherein R 16  is hydrogen or alkyl, and R 14  is hydrogen or alkyl: or 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein q is an integer from 0 to 3; R 17  is hydrogen or alkyl; Z 1  is —CH 2 —, —C(═O)—, —C(═NOH)—, or —C(═NOMe)-; Z 2  is a group represented by the formula: —S(═O) s — wherein s is an integer from 0 to 2, a group represented by the formula: —N(—R 22 )— wherein R 22  is hydrogen, alkyl, alkyloxycarbonyl or acyl, or a group represented by the formula: —CR 18 R 19 — wherein R 18  and R 19  are each independently hydrogen, alkyl or aryl; or R 18  and R 19  are taken together to form a group represented by the formula: —(CH 2 )t- wherein t is an integer from 2 to 5; 
       R 1  and R 15  are as defined above; and 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Y, E, R 20  and R 21  are as defined above; 
       a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
     
   
   
       2 . A compound as described in  claim 1 , wherein a group represented by the formula: 
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Z 3  is ═C(—R 7 )—; R 4 , R 5 , R 6  and R 7  are as defined in  claim 1 ; 
       Z 4  is —C(—R 2 )═; R 2  is as defined in  claim 1 ; 
       R 15  is hydrogen; and 
       R 3  is a group represented by the formula: —(CH 2 )n-N(—Y)—SO 2 —Ar wherein n is an integer from 1 to 3; Y is hydrogen, alkyl, alkenyl, optionally substituted aryl, optionally substituted aralkyl, or optionally substituted heteroarylalkyl; and Ar is optionally substituted aryl or optionally substituted heteroaryl, a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein r is an integer from 0 to 2; x is an integer from 0 to 3; m is an integer from 1 to 3; a broken line represents the presence or absence of a bond; E is optionally substituted aryl or optionally substituted heteroaryl; or a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein y is an integer from 1 to 3, and m, p, Y and Ar are as defined above, a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein m, y and Ar are as defined above, or 
       a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein Y and Ar are as defined in  claim 1 , and R 20  and R 21  are hydrogen, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
     
   
   
       3 . A compound as described in  claim 1 , wherein Y is alkyl, alkenyl, optionally substituted aryl or optionally substituted aralkyl, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
   
   
       4 . (canceled) 
   
   
       5 . (canceled) 
   
   
       6 . A compound as described in  claim 2 , wherein a group represented by the formula: 
     
       
         
         
             
             
         
       
       is a group represented by the formula: 
     
     
       
         
         
             
             
         
       
       wherein m is 2; p is 0; y is 1; Y is hydrogen, alkyl, alkenyl or aralkyl; and Ar is as defined in  claim 1 , a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
     
   
   
       7 . (canceled) 
   
   
       8 . (canceled) 
   
   
       9 . A compound as described in any one of  claim 1 , wherein R 1  is carboxy, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
   
   
       10 . A compound as described in  claim 1 , wherein R 4 , R 5 , R 6  and R 7  are each independently hydrogen, halogen, alkyl, alkenyl, optionally substituted aryl or optionally substituted aralkyl, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof. 
   
   
       11 . (canceled) 
   
   
       12 . A pharmaceutical composition containing a compound, a prodrug, a pharmaceutically acceptable salt, or a solvate thereof as described in  claim 1 . 
   
   
       13 . A pharmaceutical composition as described in  claim 12 , which is used for an antagonist against the CRTH2 receptor. 
   
   
       14 . (canceled) 
   
   
       15 . (canceled)