Hetero-Substituted Acetanilide Derivatives As Analgesic Agents

Abstract

Hetero-substituted acetanilide derivatives are disclosed as analgesic agents. The compounds of the invention are useful in methods for treating a disease or condition in a mammal characterized by pain and/or fever.

1 . A method of controlling pain or fever in a subject in need thereof comprising administering to the subject a compound of Formula (I): 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  and R 2  taken together with the atoms to which they are attached form a radical selected from the group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl, wherein, in addition to the heteroatom N, said radical may optionally contain 1 to 3 additional heteroatoms, independently selected from the group consisting of O, N and S; additionally, said radical may be further optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and oxo; 
         R 3  is hydrogen or C 1-6 alkanyl; 
         R 4  is a substituent selected from the group consisting of hydrogen, C 1-6 alkanyl, C 1-6 alkanyloxy, fluorinated alkanyl, fluorinated alkanyloxy, halogen, hydroxyl, nitro, amino, C 1-6 alkanylamino; C 1-6 dialkanylamino and cyano; 
         n is an integer from 1 to 3; 
         and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof. 
       
     
     
         2 . The method of  claim 1  wherein R 1  and R 2  taken together with the atoms to which they are attached form a 5 to 10 membered cycloheteroalkanyl radical, wherein, in addition to the heteroatom N, said radical may optionally contain 1 to 3 additional heteroatoms, independently selected from the group consisting of O, N and S; additionally, said radical may be further optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and oxo; 
     
     
         3 . The method of  claim 1  wherein R 1  and R 2  taken together with the atoms to which they are attached form a 5 to 10 membered cycloheteroalkenyl radical, wherein, in addition to the heteroatom N, said radical may optionally contain 1 to 3 additional heteroatoms, independently selected from the group consisting of O, N and S; additionally, said radical may be further optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and oxo; 
     
     
         4 . The method of  claim 1  wherein R 1  and R 2  taken together with the atoms to which they are attached form a 5 to 10 membered heteroaryl radical, wherein, in addition to the heteroatom N, said radical may optionally contain 1 to 3 additional heteroatoms, independently selected from the group consisting of O, N and S; additionally, said radical may be further optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and oxo; 
     
     
         5 . The method of  claim 1  wherein R 1  and R 2  taken together with the atoms to which they are attached form a radical selected from the group consisting of a 5 to 10 membered cycloheteroalkanyl, 5 to 10 membered cycloheteroalkenyl and a 5 to 10 membered heteroaryl; additionally, said radical may be further optionally substituted with one to three substituents independently selected from the group consisting of C 1-6 alkanyl and oxo; 
     
     
         6 . The method of  claim 1  wherein R 3  is hydrogen. 
     
     
         7 . The method of  claim 1  wherein R 4  is hydrogen. 
     
     
         8 . The method of  claim 1  wherein n is 1. 
     
     
         9 . The method of  claim 1  wherein the pain is caused by headache, earache, dysmenorrhea, arthralgia, myalgia, musculoskeletal pain, arthritis, immunizations, teething, tonsillectomy. 
     
     
         10 . The method of  claim 1  wherein the fever is caused by bacterial or viral infections and as a substitute for aspirin in upper GI disease, aspirin allergy, bleeding disorders, clients on anticoagulant therapy, and gouty arthritis. 
     
     
         11 - 20 . (canceled) 
     
     
         21 . A method of controlling pain or fever in a subject in need thereof comprising administering to the subject a compound of Formula (I) wherein the compound of formula (I) is selected from the group consisting of:
 Pyridine-2-carboxylic acid (4-hydroxy-phenyl)-amide;   (S)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;   (R)-Pyrrolidine-2-carboxylic acid (4-hydroxy-phenyl)-amide;   1H-Pyrrole-2-carboxylic acid (4-hydroxy-phenyl)-amide;   1H-Indazole-3-carboxylic acid (4-hydroxy-phenyl)-amide;   5-Methyl-1H-pyrazole-3-carboxylic acid (4-hydroxy-phenyl)-amide; and   3H-Imidazole-4-carboxylic acid (4-hydroxy-phenyl)-amide   
       and enantiomers, diastereomers, tautomers, solvates, or pharmaceutically acceptable salts thereof 
     
     
         22 . (canceled) 
     
     
         23 . (canceled)