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 selected from R 5  and R 5 -(C 1 -C 6 heteroalkylene)- where R 5  is selected from hydrogen, halogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring, amino or hydroxy;  
         R 2  and R 3  are independently hydrogen, alkyl, heteroalkyl, aryl, aryl(akylene), heteroaryl, heteroaryl(alkylene), carbocycle, carbocycle(alkylene), heterocycle, and heterocycle(alkylene);  
         each occurrence of R 4  is independently selected from halogen, alkyl, heteroalkyl, aryl, heteroaryl, carbocycle aliphatic ring and heterocycle aliphatic ring, amino or hydroxy; and  
         n is 0, 1, 2 or 3.  
       
     
     
         2 . A compound of  claim 1  wherein n is 0.  
     
     
         3 . A compound of  claim 1  wherein n is 1.  
     
     
         4 . A compound of  claim 1  wherein n is 0 or 1 and R 2  is H.  
     
     
         5 . A compound of  claim 4  wherein R 1  is R 5 —SO 2 — and R 5  is selected from alkyl, heteroalkyl, aryl, carbocycle, aryl(alkylene), and carbocycle(alkylene).  
     
     
         6 . A compound of  claim 5  wherein, for R 5 , alkyl is C 1 -C 10 alkyl; heteroalkyl is C 1 -C 10 alkyl with 1, 2 or 3 heteroatoms selected from N, O and S; aryl is phenyl, substituted phenyl, naphthyl or substituted naphthyl; carbocycle is C 3 -C 8 carbocycle; and alkylene is C 1 -C 10 alkylene.  
     
     
         7 . A compound of  claim 5  wherein R 1  is selected from (C 1 -C 6 alkyl)SO 2 —, PhSO 2 —, fluorinatedphenylSO 2 —, PhCH 2 SO 2 —, cyclopentylSO 2 —, m-carboxyphenylSO 2 —, m-methylphenylSO 2 —, and HOOC—(C 1 -C 4 alkylene)SO 2 —.  
     
     
         8 . A compound of  claim 1  wherein R 1  is selected from halogen, amino, hydrocarbylamino, dihydrocarbylamino, hydrocarbyloxy, hydrocarbylthio, heterocyclyl, (heteroalkyl)amino, and (heteroaryl)amino.  
     
     
         9 . A compound of  claim 7  wherein R 1  is selected from amino, (C 1 -C 6 alkyl)(C 1 -C 6 alkyl)amino, PhNH—, PhCH 2 NH—,  
       
         
           
           
               
               
           
         
       
       and HOCH 2 CH 2 NH—.  
     
     
         10 . A compound of  claim 8  wherein R 1  is selected from halide and (C 1 -C 6 alkyl)S—.  
     
     
         11 . A compound of  claim 10  wherein R 1  is chloride.  
     
     
         12 . A compound of  claim 4  wherein R 3  is selected from aryl, aryl(alkylene), heteroaryl, and heteroaryl(alkylene).  
     
     
         13 . A compound of  claim 12  wherein R 3  is aryl.  
     
     
         14 . A compound of  claim 1  having structure (II)  
       
         
           
           
               
               
           
         
       
     
     
         15 . A compound of  claim 14  wherein R 1  is selected from (C 1-6 alkyl)SO 2 —, PhSO 2 —, fluorinatedphenylSO 2 —, PhCH 2 SO 2 —, cyclopentylSO 2 —, m-carboxyphenylSO 2 —, m-methylphenylSO 2 —, and HOOC—(C 1 -C 4 alkylene)SO 2 —.  
     
     
         16 . A compound of  claim 4  wherein R 3  is benzyl or phenyl, the benzyl or phenyl having 0, 1, 2, 3 or 4 substituents selected from alkoxy, alkoxycarbonyl, alkyl, alkylamido, alkylcarbonyl, amido, benzyl optionally substituted with halogen, benzyloxy, carboxy, cyano, dialkylamido, haloalkyl, haloalkyloxy, halogen, hydroxy, nitro, oxoalkyl, phenyl optionally substituted with halogen, thioalkyl, thiocyanate, and thiohaloalkyl.  
     
     
         17 . A compound of  claim 1  wherein R 3  is selected from cycloalkyl, cycloalkyl(alkylene), cycloalkyl(heteroalkylene), heterocycloalkyl, heterocycloalkyl(alkylene), heterocycloalkyl(heteroalkylene), heteroaryl, heteroaryl(alkylene), and heteroaryl(heteroalkylene).  
     
     
         18 . A compound of  claim 1  wherein said compound is 6-Chloro-N-(4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         19 . A compound of  claim 1  wherein said compound is N-(4-Fluoro-phenyl)-6-(2-hydroxy-ethylamino)-1-oxy-nicotinamide.  
     
     
         20 . A compound of  claim 1  wherein said compound is 6-Bromo-N-(4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         21 . A compound of  claim 1  wherein said compound is 5,6-Dichloro-N-(4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         22 . A compound of  claim 1  wherein said compound is 6-Ethanesulfonyl-N-(4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         23 . A compound of  claim 1  wherein said compound is N-(4-Fluoro-phenyl)-1-oxy-6-(propane-2-sulfonyl)-nicotinamide.  
     
     
         24 . A compound of  claim 1  wherein said compound is N-(4-Fluoro-phenyl)-6-methanesulfonyl-1-oxy-nicotinamide.  
     
     
         25 . A compound of  claim 1  wherein said compound is 6-Benzenesulfonyl-N-(4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         26 . A compound of  claim 1  wherein said compound is N-(4-Fluoro-phenyl)-1-oxy-6-phenylmethanesulfonyl-nicotinamide.  
     
     
         27 . A compound of  claim 1  wherein said compound is 6-Chloro-N-(3-chloro-4-fluoro-phenyl)-1-oxy-nicotinamide.  
     
     
         28 . A compound of  claim 1  wherein said compound is 6-Chloro-N-(4-iodo-phenyl)-1-oxy-nicotinamide.  
     
     
         29 . A compound of  claim 1  wherein R 1  is selected from halogen, heteroalkyl or amino, R 2  is H, R 3  is aryl and R 4  is H.  
     
     
         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 inhibits IL-8 and or GRO-α driven neutrophil chemotaxis.  
     
     
         34 . The method of  claim 32  wherein the compound inhibits a CXCR1 receptor.  
     
     
         35 . The method of  claim 32  wherein the compound inhibits a CXCR2 receptor.  
     
     
         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 . A method of  claim 37  wherein the compound modulates the binding of Peptide YY (PYY) to a NPY cell receptor.  
     
     
         39 . A method of  claim 37  wherein the compound modulates the binding of somatostatin to a somatostatin cell receptor.  
     
     
         40 . A method of  claim 37  wherein the compound modulates the binding of MIP-1β to a CCR5 cell receptor.  
     
     
         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 . A method for identifying a binding partner to a compound of  claim 1  comprising: 
 immoblizing proteins known to be involved in the TNF-α signaling pathway onto a suitable carrier; and    passing a solution of said compounds in isolation or mixture over said proteins and analyzing for compound:protein complex formation using surface plasmon resonance (SPR).    
     
     
         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.