Substituted pyridines as p2x3 and p2x2/3 antagonists

Abstract

Methods of treating diseases associated with P2X 3 and/or a P2X 2/ with compounds formula I: or a pharmaceutically acceptable salt thereof, wherein, X, Y, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and R 7 are as defined herein.

We claim: 
     
         1 . A method for modulating P2X 3  and R2X 2/3  receptor activity in a subject comprising administering to a subject in need thereof an therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein: 
       
         
           
           
               
               
           
         
         R 1  is C 1-6 alkyl or halo; 
         R 2  is C 3-6 cycloalkyl, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, or heteroaryl-C 1-6 alkyl; 
         R 3  is hydrogen, halo, C 1-6 alkyl, or C 1-6 alkoxy-carbonyl; 
         R 4  is hydrogen, halo, C 1-6 alkyl; or,
 R 3  and R 4  together with the atoms to which they are attached may form a fused 6-membered aromatic ring that optionally includes one or two nitrogens; or, R 3  and R 4  together with the atom to which they are attached may form C 3-6 cycloalkyl; 
 
         R 5 , R 6  and R 7  each independently is fluoro or hydrogen. 
         X is CR a−  wherein R a  is C 1-6 alkyl or halo; and, 
         Y is —O—, —CHR b —, or —NR c —, wherein R b  and R c  each independently is hydrogen or C 1-6 alkyl; 
       
       with the proviso that when Y is CH 2 , R 2  is C 3-6 cycloalkyl, C 1-6 alkoxy-C 1-6 alkyl, or hydroxy-C 1-6 alkyl. 
     
     
         2 . The method of  claim 1 , said method comprising administering a compound of formula I wherein R 5 , R 6  and R 7 . 
     
     
         3 . The method according to  claim 2 , said method comprising administering a compound of formula I wherein R 1  is methyl. 
     
     
         4 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 2  is selected from the group consisting of cyclopropyl, 2-methoxy-1-methyl-ethyl, 2-hydroxy-1-methyl-ethyl, 5-methylpyrazin-2-yl-methyl, 1-pyrazin-2-yl-ethyl, pyrimidin-5-yl-methyl, 6-methyl-pyridazin-3-yl-methyl, pyridazin-3-yl-methyl, 5-methyl-pyrimidin-2-yl-methyl, and 2-methyl-pyrimidin-5-yl-methyl. 
     
     
         5 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 2  is 2-hydroxy-1-methyl-ethyl; 5-methylpyrazin-2-yl-methyl; or 1-pyrazin-2-yl-ethyl. 
     
     
         6 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 3  is C 1-6 alkyl. 
     
     
         7 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 3  is ethyl or isopropyl. 
     
     
         8 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 4  is hydrogen. 
     
     
         9 . The method of  claim 2 , said method comprising administering a compound of formula I wherein R 3  and R 4  together with the atoms to which they are attached form a fused phenyl ring. 
     
     
         10 . The method of  claim 2 , said method comprising administering a compound of formula I wherein Y is —O—. 
     
     
         11 . The method of  claim 2 , said method comprising administering a compound of formula I wherein Y is —CHR b —. 
     
     
         12 . The method of  claim 2 , said method comprising administering a compound of formula I wherein Y is —NR c —. 
     
     
         13 . The method of  claim 9 , said method comprising administering a compound of formula III wherein: 
       
         
           
           
               
               
           
         
       
       n is from 0 to 2;
 Y is: —O—; —CH 2 — or —NH— 
 R 8  is:
 C 1-6 alkyl; 
 C 1-6 alkoxy; 
 C 1-6 alkyl-sulfonyl; 
 halo-C 1-6 alkyl; or 
 halo; 
 
 X is CR a−  wherein R a  is C 1-6 alkyl or halo; and, 
 R 1  and R 2  are as recited in  claim 9 . 
 
     
     
         14 . The method of  claim 13 , said method comprising administering a compound of formula III wherein R 1  is methyl and Y is O. 
     
     
         15 . The method of  claim 1 , said method comprising administering a compound a compound selected from the group consisting of:
 4′-Methyl-5-(2-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;   4′-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;   4′-Methyl-5-(2-methyl-5-oxo-pyrrolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;   (S)-1-[5-(2-Methoxy-1-methyl-ethylcarbamoyl)-4′-methyl-biphenyl-3-yl]-5-oxo-pyrrolidine-2-carboxylic acid methyl ester;   5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;   5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;   5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;   5-((R)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid cyclopropyl amide;   5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carb oxylic acid cyclopropyl amide;   5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carb oxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;   5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;   5-((S)-4-Isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;   2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carb oxylic acid ((S)-2-hydroxy-1-methyl-ethyl)-amide;   2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;   2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;   2′-Fluoro-5-((R)-4-isopropyl-2-oxo-oxazolidin-3-yl)-4′-methyl-biphenyl-3-carboxylic acid cyclopropylamide;   4′-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide;   4′-Methyl-5-(2-oxo-benzooxazol-3-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;   4′-Methyl-5-(2-oxo-imidazolidin-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide;   4′-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (5-methyl-pyrazin-2-ylmethyl)-amide;   4′-Methyl-5-(2-oxo-2,3-dihydro-indol-1-yl)-biphenyl-3-carboxylic acid (1-pyrazin-2-yl-ethyl)-amide; and,   4′-Methyl-5-(8-oxo-7,8-dihydro-purin-9-yl)-biphenyl-3-carboxylic acid ((S)-1-pyrazin-2-yl-ethyl)-amide.   
     
     
         16 . The method of  claim 1  wherein aberrant P2X 3  and R2X 2/3  receptor activity causes inflammatory pain, surgical pain, visceral pain, dental pain, premenstrual pain, central pain, pain due to burns, migraine or cluster headaches, nerve injury, neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer pain, viral, parasitic or bacterial infection, post-traumatic injury, or pain associated with irritable bowel syndrome, said method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 .