EP2 Receptor Agonists

Abstract

The disclosure provides EP2 receptor agonist compounds and methods for using the compounds for treating conditions which can be alleviated by agonism of an EP2 receptor.

1 . A compound of formula (I): 
       
         
           
           
               
               
           
         
         or a salt, solvate and chemically protected form thereof, wherein: 
         R 5  is an optionally substituted C 5-20  aryl or C 4-20  alkyl group; 
         A is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         wherein X and Y are independently selected from the group consisting of: O and CR 3 ; S and CR 3 ; NH and CR 3 ; NH and N; O and N; S and N; N and S; and N and O, and where the dotted lines indicate a double bond in the appropriate location, and where Q is either N or CH; 
         R 3  is selected from H, F, Cl and optionally substituted C 1-4  alkyl, C 1-4  alkoxy, C 5-7  aryl and C 5-7  aryl-C 1-4  alkyl groups; 
         R 4  is selected from H, F, Cl and optionally substituted C 1-4  alkyl, C 1-4  alkoxy, C 5-7  aryl and C 5-7  aryl-C 1-4  alkyl groups; 
         R 6  is selected from H, F, Cl and optionally substituted C 1-4  alkyl, C 1-4  alkoxy, C 5-7  aryl and C 5-7  aryl-C 1-4  alkyl groups; 
         D is selected from: 
       
       
         
           
           
               
               
           
         
         B is selected from the group consisting of: 
       
       
         
           
           
               
               
           
         
         where R N′  is selected from H and C 1-4  alkyl; 
         where one of R P3  and R P4  is —C m  alkylene-R 2  and the other of R P3  and R P4  is H, m and n can be 0 or 1, and m+n=1 or 2; and additionally when R P3  is —C m  alkylene-R 2 , m can also be 2 or 3, and m+n=1, 2, 3 or 4, and when R 2  is tetrazol-5-yl, m+n may be 0; or 
         where one of R P3  and R P4  is —O—CH 2 —R 2 , and the other of R P3  and R P4  is H, n is 0; 
         R N  is H or optionally substituted C 1-4  alkyl; 
         R 2  is either: 
         (i) —CO 2 H (carboxy); 
         (ii) —CONH 2 ; 
         (iii) —CH 2 —OH (methoxy); or 
         (iv) tetrazol-5-yl. 
       
     
     
         2 . A compound according to  claim 1 , wherein R 5  is phenyl optionally substituted with one or more substituents independently selected from: C 1-4  alkyl, C 1-4  alkoxy, C 5-6  aryl, halo, acyl, amino, alkoxylene. 
     
     
         3 . A compound according to  claim 1 , wherein R 5  is a C 4-10  alkyl group. 
     
     
         4 . A compound according to  claim 1 , wherein A is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound according to  claim 1 , wherein A is a five membered ring, and R 3  (if present) and R 4  are independently selected from H and optionally substituted C 1-4  alkyl. 
     
     
         6 . A compound according to  claim 1 , wherein A is a six-membered ring, and either:
 (i) R 3 , R 4  and R 6  (if present) are H; or   (ii) one of R 3 , R 4  and R 6  (if present) are Cl or F.   
     
     
         7 . A compound according to  claim 1 , wherein D is: 
       
         
           
           
               
               
           
         
       
     
     
         8 . A compound according to  claim 7 , wherein R N  is H. 
     
     
         9 . A compound according to  claim 1 , wherein B is: 
       
         
           
           
               
               
           
         
       
     
     
         10 . A compound according to  claim 1 , wherein R 2  is carboxy or tetrazoly-5-yl. 
     
     
         11 . A compound according to  claim 10 , wherein R 2  is carboxy. 
     
     
         12 . A compound according to  claim 1 , wherein R P4  is H, and R P3  is —CH═CH—R 2 . 
     
     
         13 . A compound according to  claim 1 , wherein R P3  is —O—CH 2 —R 2 . 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent. 
     
     
         15 . A method of treating a condition which can be alleviated by agonism of an EP 2  receptor, which method comprises administering to a patient in need of treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         16 . A method of treating a condition comprising administering to a patient in need of treatment an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, wherein the condition is selected from dysmenorrhoea, pre-term labour, glaucoma, ocular hypertension, immune disorders, inflammatory disorders, osteoporosis, asthma, chronic obstructive pulmonary disease, allergy, bone disease, fracture repair, male sexual dysfunction, female sexual dysfunction, infertility, periodontal disease, gastric ulcer, renal disease and psoriasis, psoriatic arthritis, dermatitis, rheumatoid arthritis, transplant rejection, inflammatory bowel disease, systemic lupus erythematosus, vasculitis, acute respiratory distress syndrome, pulmonary fibrosis, cystic fibrosis, Graves' disease, scleroderma, multiple sclerosis, and type I diabetes. 
     
     
         17 . The method of treating a condition according to  claim 16  wherein the condition is selected from dysmenorrhoea, pre-term labour, glaucoma, ocular hypertension, immune disorders, inflammatory disorders, osteoporosis, asthma, chronic obstructive pulmonary disease, allergy, bone disease, fracture repair, male sexual dysfunction, female sexual dysfunction, infertility, periodontal disease, gastric ulcer, renal disease and psoriasis. 
     
     
         18 . The method according to  claim 16 , wherein the condition is glaucoma or ocular hypertension.