Pharmaceutical uses and synthesis of nicotinanilide-n-oxides

Abstract

Disclosed are nicotinanilide-N-oxide compounds, methods for their production, pharmaceutical compositions which include these compounds, and methods for their use in various therapies.

1 . A compound having the structure (I): 
     
       
         
         
             
             
         
       
       and optical isomers, diastereomers, enantiomers and pharmaceutically acceptable salts thereof, wherein 
       R 1  is halide or (C 1 -C 6 alkyl)S; 
       R 2  is hydrogen; 
       R 3  is phenyl; and 
       each occurrence of R 4  is independently selected from halogen, and alkyl; and 
       n is 0, 1, or 2. 
     
   
   
       2 . A compound of  claim 1  wherein n is 0. 
   
   
       3 . A compound of  claim 1  wherein n is 1. 
   
   
       4 - 10 . (canceled) 
   
   
       11 . A compound of  claim 1  wherein R 1  is chloride. 
   
   
       12 - 29 . (canceled) 
   
   
       30 . A composition comprising a compound of  claim 1  and a pharmaceutically acceptable carrier, adjuvant or incipient. 
   
   
       31 . A method for antagonizing chemokine receptors comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
   
   
       32 . A method for inhibiting a chemokine-mediated cellular event comprising administering to a patient in need thereof an effective amount of a compound of  claim 1 . 
   
   
       33 . A method of  claim 32  wherein the compound has a biological activity selected from inhibition of IL-8; GRO-α driven neutrophil chemotaxis; a CXCR1 receptor; and a CXCR2 receptor. 
   
   
       34 - 35 . (canceled) 
   
   
       36 . The method of  claim 32  for the treatment of a disorder selected from Inflammatory Bowel Disease (IBD), psoriasis, rheumatoid arthritis, Acute Respiratory Distress Syndrome (ARDS), cancer, atherosclerosis, reperfusion injury, and graft vs. host disease. 
   
   
       37 . A method for inhibiting a G-protein-coupled, seven-transmembrane domain (7TM) receptor in a patient comprising administering to the patient a compound of  claim 1  in an amount effective to inhibit the receptor. 
   
   
       38 . The method of  claim 37  wherein the compound has an activity selected from modulating the binding of Peptide YY (PYY) to a NPY cell receptor; modulating the binding of somatostatin to a somatostatin cell receptor; and modulating the binding of MIP-1β to a CCR5 cell receptor. 
   
   
       39 - 40 . (canceled) 
   
   
       41 . A method for treating an inflammation event, comprising administering to a patient in need thereof, through a therapeutically or prophylactically acceptable manner, a therapeutically or pharmaceutically effective amount of the compound of  claim 1 . 
   
   
       42 . The method of  claim 41  wherein administration is selected from transdermal, oral, intravenous, intramuscular, vaginal, rectal, pulmonary, subcutaneous, sublingual and transmucosal administration. 
   
   
       43 . (canceled) 
   
   
       44 . A method for identifying a binding partner to a compound of  claim 1  comprising providing said compound(s) bound to a solid support to provide solid phase compounds;
 contacting a cell or cell components with said solid phase compounds in isolation or mixture;   removing uncomplexed cellular material, for example by gentle washing with aqueous buffer; and recovering said binding partner from the solid phase compounds.   
   
   
       45 . A compound having the formula 2-chloro-5-(2,4-difluorobenzylcarbamoyl)pyridine 1-oxide.