Pyridine Compounds For The Treatment Of Prostaglandin Mediated Diseases

Abstract

Compounds of formula (I) or a pharmaceutically acceptable derivative thereof: wherein X, Y, Z, R 2a , R 2b , R 3a , R 3b , R 8 , R 9 , and R x are as defined in the specification, a process for the preparation of such compounds, pharmaceutical compositions comprising such compounds and the use of such compounds in medicine (EP, —receptor antagonists).

1 . A compound of formula (I): 
     
       
         
         
             
             
         
       
     
     wherein:
 X is N and Y is CH, or X is CH and Y is N; 
 Z is O, S, SO or SO 2 ; 
 R 1  is CO 2 H, CONHSO 2 R 6 , CH 2 CO 2 H, NR 4 COR 7 , tetrazole or CH 2 tetrazole; 
 R 2a  and R 2b  are each independently selected from hydrogen, halo, CN, SO 2 alkyl, SR 5 , NO 2 , optionally substituted alkyl, optionally substituted alkoxy, optionally substituted aryl, and optionally substituted heteroaryl; 
 R 3a  and R 3b  are each independently selected from hydrogen, halo, optionally substituted alkyl, optionally substituted alkoxy, or NR 10 R 11 ; 
 R x  is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted CQ a Q b -heterocyclyl, optionally substituted CQ a Q b -bicyclic heterocyclyl, or optionally substituted CQ a Q b -aryl; 
 R 4  is hydrogen or an optionally substituted alkyl; 
 R 5  is hydrogen or an optionally substituted alkyl; 
 R 6  is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; 
 R 7  is optionally substituted alkyl, optionally substituted heterocyclyl, optionally substituted aryl, optionally substituted alkoxy, optionally substituted heterocyclyloxy or optionally substituted aryloxy; 
 R 8  is hydrogen, fluorine or alkyl; 
 R 9  is hydrogen, hydroxy, fluorine or alkyl; 
 or R 8  and R 9  together with the carbon to which they are attached form a cycloalkyl ring, optionally containing up to one heteroatom selected from O, S, NH and N-alkyl; or R 8  and 
 R 9  together with the carbon to which they are attached form a carbonyl group; 
 Q a  and Q b  are each independently selected from hydrogen, CH 3  and fluorine; 
 R 10  and R 11  are each independently selected from hydrogen or alkyl; or R 10  and R 11  together with the nitrogen to which they are attached form an aliphatic heterocyclic ring, optionally containing an additional heteroatom selected from O, S, NH and N-alkyl; 
 and derivatives thereof. 
 
   
   
       2 . A compound according to  claim 1  wherein Z is O. 
   
   
       3 . A compound according to  claim 1  or  claim 2  wherein R 8  and R 9  are each hydrogen. 
   
   
       4 . A compound according to any one of  claims 1  to  3  wherein R 1  is CO 2 H, CONHSO 2 R 6 , or tetrazole. 
   
   
       5 . A compound according to any one of  claims 1  to  4  wherein R 2a  is hydrogen, R 2b  is halogen and is positioned 1,4-relative to the Z substituent and 1,3-relative to the methylene pyridyl moiety. 
   
   
       6 . A compound according to  claim 1  which is a compound of formula (IA): 
     
       
         
         
             
             
         
       
     
     wherein:
 X is N and Y is CH, or X is CH and Y is N; 
 R 1  is CO 2 H, CONHSO 2 R 6 , or tetrazole; 
 R 2  is halogen; 
 R 3  is hydrogen, halogen, or optionally substituted alkyl; 
 R x  is optionally substituted alkyl, optionally substituted alkenyl , optionally substituted alkynyl, optionally substituted CQ a Q b -heterocyclyl, optionally substituted CQ a Q b -bicyclic heterocyclyl, or optionally substituted CQ a Q b -aryl; 
 R 6  is optionally substituted alkyl, optionally substituted aryl, or optionally substituted heterocyclyl; and 
 Q a  and Q b  are each independently selected from hydrogen, CH 3  and fluorine; 
 and derivatives thereof. 
 
   
   
       7 . A compound according to  claim 1  selected from the compounds of Examples 1 to 41 or a pharmaceutically acceptable derivative thereof. 
   
   
       8 . The compound of formula (I) which is 6-[(5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)methyl]-2-pyridinecarboxylic acid or a pharmaceutically acceptable derivative thereof. 
   
   
       9 . A pharmaceutical composition comprising a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof together with a pharmaceutical carrier and/or excipient. 
   
   
       10 . A compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof for use as an active therapeutic substance. 
   
   
       11 . A compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof for use in the treatment of a condition which is mediated by the action of PGE 2  at EP 1  receptors. 
   
   
       12 . A method of treating a human or animal subject suffering from a condition which is mediated by the action of PGE 2  at EP 1  receptors which comprises administering to said subject an effective amount of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof. 
   
   
       13 . A method of treating a human or animal subject suffering from a pain, or an inflammatory, immunological, bone, neurodegenerative or renal disorder, which method comprises administering to said subject an effective amount of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof. 
   
   
       14 . A method of treating a human or animal subject suffering from inflammatory pain, neuropathic pain or visceral pain which method comprises administering to said subject an effective amount of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof. 
   
   
       15 . Use of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment of a condition which is mediated by the action of PGE 2  at EP 1  receptors. 
   
   
       16 . Use of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as a pain, or an inflammatory, immunological, bone, neurodegenerative or renal disorder. 
   
   
       17 . Use of a compound according to any one of  claims 1  to  8  or a pharmaceutically acceptable derivative thereof for the manufacture of a medicament for the treatment or prevention of a condition such as inflammatory pain, neuropathic pain or visceral pain. 
   
   
       18 . A process for preparing a compound of formula (I) according to  claim 1  comprising:
 reacting a compound of formula (II):   
     
       
         
         
             
             
         
       
       wherein P is a protecting group and Z, R 8 , R 9 , R 2a , R 2b , R 3a  and R 3b  are as defined for a compound of formula (I); 
       with a compound R x -L; 
       wherein R x  is as defined for a compound of formula (I), and L is Cl, Br or OH; 
       and if required, and in any order; 
       converting one group R 1  to another group R 1 ; and/or 
       effecting deprotection; and/or 
       forming a derivative thereof.