Prostamide receptor antagonists

Abstract

The present invention provides prostamide receptor antagonist compounds that may be represented by the general formula I. wherein A, R 1 , R 2 , R 3 , R 4 and R 6 are as defined in the specification.

1 . A compound having prostamide receptor antagonist activity represented by formula III  
     
       
         
         
             
             
         
       
       wherein m is an integer of from 1 to 3;  
       n is 0 or an integer of from 1 to 4;  
       R is CONR 3 R 4 ;  
       R 1  and R 2  are independently selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 4 -C 12  alkylcycloalkyl, C 6 -C 10  aryl, C 7 -C 12  alkyl aryl radicals and heteroatom-substituted derivatives thereof, wherein one or more of the hydrogen or carbon atoms in said radicals is replaced with a halogen, oxygen, nitrogen or sulfur-containing radical;  
       R 3  and R 4  are selected from the group consisting of H, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, C 2 -C 6  alkynyl, C 3 -C 7  cycloalkyl, C 4 -C 12  alkylcycloalkyl, C 6 -C 10  aryl, C 7 -C 12  alkyl aryl radicals and heteroatom-substituted derivatives thereof, wherein one or more of the hydrogen or carbon atoms in said radicals is replaced with a halogen, oxygen, nitrogen or sulfur-containing radical and pharmaceutically acceptable salts thereof;  
       Y is O or S, Z is N or CH and wherein X is selected from the group consisting of H, C 1 -C 6  alkyl, hydroxyl, halogen, COOR 6 , NO 2 , N(R 6 ) 2 , CON(R 6 ) 2 , SR 6 , sulfoxy, sulfone, CN and OR 6 , wherein R 6  is C 1 -C 6  alkyl.  
     
   
   
       2 . The compound of  claim 1  wherein m is 1 or 2.  
   
   
       3 . The compound of  claim 1  wherein n is 2 to 4.  
   
   
       4 . The compound of  claim 1  wherein R 1  and R 2  are selected from the group consisting of H, C 1 -C 6  alkyl, C 3 -C 7  cycloalkyl and C 4 -C 12  alkylcycloalkyl.  
   
   
       5 . The compound of  claim 1  wherein X is hydrogen or halogen.  
   
   
       6 . The compound of  claim 6  wherein X is fluoro.  
   
   
       7 . A prostamide receptor antagonist.  
   
   
       8 . A prostamide F 2α  receptor antagonist.  
   
   
       9 . A prostamide D 2  antagonist.  
   
   
       10 . A prostamide E 2  antagonist.  
   
   
       11 . A method of testing for compounds having prostamide receptor agonist activity and not activity at the corresponding prostaglandin receptor which comprises; 
 contacting a tissue or cell responsive to a prostaglandin and a prostamide with various concentrations of said prostaglandin and measuring a first response in a concentration dependent manner contacting said tissue or cell with said various concentrations of said prostaglandin in the presence of a prostamide antagonist and measuring a second response in a concentrated dependent manner,    contacting said tissue or cell with various concentrations of a compound which is to be evaluated for prostamide agonist activity and measuring a third response in a concentration dependent manner,    contacting said tissue or cell with said various concentrations of said compound which is to be evaluated for prostamide agonist activity in the presence of said prostamide antagonist and measuring a fourth response in a concentration dependent manner, and determining compounds having prostamide agonist activity as compounds wherein the difference between said third and fourth response is greater than the difference between said first and second response.    
   
   
       12 . The method of  claim 11  wherein said tissue is cat iris sphincter tissue.  
   
   
       13 . The method of  claim 11  wherein said tissue is cat lung tissue.  
   
   
       14 . The method of  claim 11  wherein said tissue is rabbit uterine tissue.  
   
   
       15 . A method of measuring the relative activity of a prostamide agonist by contacting two or more prostamide agonists with a tissue that is responsive to a prostamide agonist in the presence of a specified concentration of a prostamide antagonist of this invention and measuring the relative activity of each of said prostamide agonists by comparing the relative response of said tissue.