Therapeutic methods using prostaglandin ep4 agonist components

Abstract

Methods are provided directed to adminstering a therapeutically effective amount of a prostaglandin EP 4 agonist component to a mammal afflicted with or prone to affliction with a disease or condition selected from an esophageal ulcer, alcohol gastrophathy, a duodenal ulcer, non-steroidal anti-inflammatory drug-induced gastropathy, non-steroidal anti-inflammatory drug-induced enteropathy and intestinal ischemia. Such administration results in treating or preventing the disease or condition.

1 . A method comprising administering a therapeutically effective amount of a prostaglandin EP 4  agonist component to a mammal afflicted with or prone to affliction with a disease or condition selected from the group consisting of an esophageal ulcer, alcohol gastropathy, a duodenal ulcer, non-steroidal anti-inflammatory drug-induced gastropathy, non-steroidal anti-inflammatory drug induced enteropathy and intestinal ischemia, thereby treating or preventing the disease or condition.  
   
   
       2 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component is administered to a gastrointestinal tract of the mammal.  
   
   
       3 . The method of  claim 1 , wherein the disease or condition is an esophageal ulcer  
   
   
       4 . The method of  claim 1 , wherein the disease or condition is alcohol gastropathy.  
   
   
       5 . The method of  claim 1 , wherein the disease or condition is a duodenal ulcer.  
   
   
       6 . The method of  claim 1 , wherein the disease or condition is non-steroidal anti-inflammatory drug-induced gastropathy.  
   
   
       7 . The method of  claim 1 , wherein the disease or condition is non-steroidal anti-inflammatory drug induced enteropathy.  
   
   
       8 . The method of  claim 1 , wherein the disease or condition is intestinal ischemia.  
   
   
       9 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component is selected from the group consisting of prostaglandin EP 4  agonists, pharmaceutically acceptable salts of prostaglandin EP 4  agonists, pro-drugs of prostaglandin EP 4  agonists and mixtures thereof.  
   
   
       10 . The method of  claim 9 , wherein the prostaglandin EP 4  agonists are selected from the group consisting of  
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     and mixtures thereof: 
 wherein a dashed line indicates the presence or absence of a bond;  
 A is —(CH 2 ) 6 —, cis —CH 2 CH═CH—(CH 2 ) 3 —, or —CH 2 C≡C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be substituted with S or O; or A is —(CH 2 ) m —Ar—(CH 2 ) o — wherein Ar is interarylene or heterointerarylene, the sum of m and o is from 1 to 4, and wherein one CH 2  may be substituted with S or O;  
 X is S or O;  
 J is C═O, CHOH, or CH 2 CHOH; and  
 E is C 1-12  alkyl, R 2 , or —Y—R 2  wherein Y is CH 2 , S, or O, and R 2  is aryl or heteroaryl.  
 
   
   
       11 . The method of  claim 10 , wherein A is —(CH 2 ) 6 —, cis —CH 2 CH═CH—(CH 2 ) 3 —, or —CH 2 C≡C—(CH 2 ) 3 —, wherein 1 or 2 carbon atoms may be substituted with S or O; and E is C 1-6  alkyl R 2 , or —Y—R 2  wherein Y is CH 2 , S, or O, and R 2  is aryl or heteroaryl.  
   
   
       12 . The method of  claim 11 , wherein R 2  is phenyl, naphthyl, biphenyl, thienyl, or benzothienyl having from 0 to 2 substituents selected from the group consisting of F, Cl, Br, methyl, methoxy, and CF 3 .  
   
   
       13 . The method of  claim 12 , wherein R 2  is CH 2 -naphthyl, CH 2 -biphenyl, CH 2 —(2-thienyl), CH 2 —(3-thienyl), naphthyl, biphenyl, 2-thienyl, 3-thienyl, CH 2 —(2-(3-chlorobenzothienyl)), CH 2 —(3-benzothienyl), 2-(3-chlorobenzothienyl), or 3-benzothienyl.  
   
   
       14 . The method of  claim 9 , wherein the prostaglandin EP 4  agonists are selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     and mixtures thereof, 
 wherein x is 0 or 1, and R 1  is H, chloro, fluoro, bromo, methyl, methoxy, or CF 3 .  
 
   
   
       15 . The method of  claim 9 , wherein the prostaglandin EP 4  agonists are selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     and mixtures thereof.  
   
   
       16 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component coprises at least one of  
     
       
         
         
             
             
         
       
     
     a pharmaceutically acceptable salt thereof, and a prodrug thereof.  
   
   
       17 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component comprises at least one of  
     
       
         
         
             
             
         
       
     
     a pharmaceutically acceptable salt thereof, and a prodrug thereof.  
   
   
       18 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component comprises a prodrug of  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       19 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component comprises a prodrug of  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt thereof.  
   
   
       20 . A method of  claim 1 , wherein the prostaglandin EP 4  agonist component comprises a prod rug of a prostaglandin EP 4  agonist.  
   
   
       21 . The method of  claim 20 , wherein the prodrug is an ester, ether, or amide of a carbohydrate; or the prodrug is an ester, ether, or amide of an amino acid.  
   
   
       22 . The method of  claim 20 , wherein the prodrug is an amide, ester, or ether of an amino acid.  
   
   
       23 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component comprises a glucoside ester, ether, or amide; a glucuronide ester, ether, or amide; a cyclodextrin ester, ether, or amide; or a dextran ester, ether, or amide.  
   
   
       24 . The method of  claim 1 , wherein the prostaglandin EP 4  agonist component is selected from the group consisting of  
     
       
         
         
             
             
         
       
     
     , pharmaceutically acceptable salts thereof, prodrugs thereof and mixtures thereof.  
   
   
       25 . The method of  claim 24 , wherein the disease or condition is an esophageal ulcer  
   
   
       26 . The method of  claim 24 , wherein the disease or condition is alcohol gastropathy.  
   
   
       27 . The method of  claim 24 , wherein the disease or condition is a duodenal ulcer.  
   
   
       28 . The method of  claim 24 , wherein the disease or condition is non-steroidal anti-inflammatory drug-induced gastropathy.  
   
   
       29 . The method of  claim 24 , wherein the disease or condition is non-steroidal anti-inflammatory drug-induced enteropathy.  
   
   
       30 . The method of  claim 24 , wherein the disease or condition is intestinal ischemia.