Method for treating inflammatory conditions

Abstract

A method for treating an autoimmune disease in a subject includes administering to the subject a therapeutically effective amount of an agent comprising an imidazole, an estrogen receptor agonist, or pharmaceutically acceptable salts thereof.

1 .- 30 . (canceled) 
     
     
         31 . A method for treating an inflammatory condition in a subject, the method comprising:
 systemically administering to the subject a therapeutically effective amount of an agent comprising at least one imidazole or estrogen receptor agonist having a formula selected from the group consisting of:   
       
         
           
           
               
               
           
         
         wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8  each independently represent substituents selected from the group consisting of hydrogen, C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halogen, silyl, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, C 2 -C 24  alkylcarbonyl (—CO-alkyl), C 6 -C 20  arylcarbonyl (—CO-aryl), acyloxy (—O-acyl), C 2 -C 24  alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20  aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24  alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20  arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), mono-(C 1 -C 24  alkyl)-substituted carbamoyl (—(CO)—NH(C 1 -C 24  alkyl)), di-(C 1 -C 24  alkyl)-substituted carbamoyl (—(CO)—N(C 1 -C 24  alkyl) 2 ), mono-substituted arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH 2 ), carbamido (—NH—(CO)—NH 2 ), cyano(—CN), isocyano (—N + C − ), cyanato (—O—CN), isocyanato (—O—N + ═C − ), isothiocyanato (—S—CN), azido (—N═N+═N − ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH 2 ), mono- and di-(C 1 -C 24  alkyl)-substituted amino, mono- and di-(C 5 -C 20  aryl)-substituted amino, C 2 -C 24  alkylamido (—NH—(CO)-alkyl), C 6 -C 20  arylamido (—NH—(CO)-aryl), imino, alkylimino, arylimino, nitro (—NO 2 ), nitroso (—NO), sulfo (—SO 2 —OH), sulfonato (—SO 2 —O − ), C 1 -C 24  alkylsulfanyl (—S-alkyl), arylsulfanyl, C 1 -C 24  alkylsulfinyl (—(SO)-alkyl), C 6 -C 20  arylsulfinyl (—(SO)-aryl), C 1 -C 24  alkylsulfonyl (—SO 2 -alkyl), C 5 -C 20  arylsulfonyl (—SO 2 -aryl), phosphono (—P(O)(OH) 2 ), phosphonato (—P(O)(O − ) 2 ), phosphinato (—P(O)(O − )), phospho (—PO 2 ), phosphino (—PH 2 ), and combinations thereof or a pharmaceutically acceptable salt thereof, and 
         wherein at least one of R 2 , R 3 , R 6 , or R 8  is a hydrogen, a halogen, an imidazole, a substituted imidazole, an aryl, or a substituted aryl. 
       
     
     
         32 . The method of claim  1 , wherein the agent is an estrogen receptor agonist having the formula of: 
       
         
           
           
               
               
           
         
         and wherein R 1 , R 2 , R 3 , and R 4  each independently represent substituents selected from the group consisting of hydrogen, C 1 -C 24  alkyl, C 2 -C 24  alkenyl, C 2 -C 24  alkynyl, C 3 -C 20  aryl, C 6 -C 24  alkaryl, C 6 -C 24  aralkyl, halogen, silyl, hydroxyl, sulfhydryl, C 1 -C 24  alkoxy, C 2 -C 24  alkenyloxy, C 2 -C 24  alkynyloxy, C 5 -C 20  aryloxy, acyl, C 2 -C 24  alkylcarbonyl (—CO-alkyl), C 6 -C 20  arylcarbonyl (—CO-aryl), acyloxy (—O-acyl), C 2 -C 24  alkoxycarbonyl (—(CO)—O-alkyl), C 6 -C 20  aryloxycarbonyl (—(CO)—O-aryl), C 2 -C 24  alkylcarbonato (—O—(CO)—O-alkyl), C 6 -C 20  arylcarbonato (—O—(CO)—O-aryl), carboxy (—COOH), carboxylato (—COO − ), carbamoyl (—(CO)—NH 2 ), mono-(C 1 -C 24  alkyl)-substituted carbamoyl (—(CO)—NH(C 1 -C 24  alkyl)), di-(C 1 -C 24  alkyl)-substituted carbamoyl (—(CO)—N(C 1 -C 24  alkyl) 2 ), mono-substituted arylcarbamoyl (—(CO)—NH-aryl), thiocarbamoyl (—(CS)—NH 2 ), carbamido (—NH—(CO)—NH 2 ), cyano(—CN), isocyano (—N + C − ), cyanato (—O—CN), isocyanato (—O—N + ═C − ), isothiocyanato (—S—CN), azido (—N═N+═N − ), formyl (—(CO)—H), thioformyl (—(CS)—H), amino (—NH 2 ), mono- and di-(C 1 -C 24  alkyl)-substituted amino, mono- and di-(C 5 -C 20  aryl)-substituted amino, C 2 -C 24  alkylamido (—NH—(CO)-alkyl), C 6 -C 20  arylamido (—NH—(CO)-aryl), imino, alkylimino, arylimino, nitro (—NO 2 ), nitroso (—NO), sulfo (—SO 2 —OH), sulfonato (—SO 2 —O − ), C 1 -C 24  alkylsulfanyl (—S-alkyl), arylsulfanyl, C 1 -C 24  alkylsulfinyl (—(SO)-alkyl), C 5 -C 20  arylsulfinyl (—(SO)-aryl), C 1 -C 24  alkylsulfonyl (—SO 2 -alkyl), C 5 -C 20  arylsulfonyl (—SO 2 -aryl), phosphono (—P(O)(OH) 2 ), phosphonato (—P(O)(O − ) 2 ), phosphinato (—P(O)(O − )), phospho (—PO 2 ), phosphino (—PH 2 ), and combinations thereof or a pharmaceutically acceptable salt thereof. 
       
     
     
         33 . The method of  claim 32 , wherein at least one of R 2  or R 3  is a hydrogen, a halogen, an aryl, or a substituted aryl. 
     
     
         34 . The method of  claim 33 , wherein the estrogen receptor agonist has the formula: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and pharmaceutically acceptable salts thereof. 
     
     
         35 . The method of  claim 31 , wherein the agent is an imidazole. 
     
     
         36 . The method of  claim 35 , wherein the agent is 1-[phenyl(4-phenylphenyl)methyl]-1H-imidazole or a pharmaceutically acceptable salt thereof. 
     
     
         37 . The method of  claim 31 , wherein the inflammatory condition is selected from the group consisting of osteoarthritis, rheumatoid arthritis, septic arthritis, gout, pseudogout, juvenile idiopathic arthritis, Still's disease, Ankylosing spondylitis, lupus erythematosus, sarcoidosis, Henoch-Schönlein purpura, psoriatic arthritis, reactive arthritis, haemochromatosis, hepatitis, Wegener's granulomatosis, Lyme disease, familial mediterranean fever, hyperimmunoglobulinemia D with recurrent fever, TNF receptor associated periodic syndrome, inflammatory bowel disease, and diseases that can mimic arthritis. 
     
     
         38 . The method of  claim 31 , wherein the estrogen receptor agonist binds to the estrogen receptor and cause an increase in therapeutic estrogen levels in a mammal. 
     
     
         39 . The method of  claim 31 , wherein the agent prevents activation and infiltration of neutrophils and monocytes. 
     
     
         40 . The method of claim  1 , wherein the agent prevents cartilage degradation & bone damage. 
     
     
         41 . The method of  claim 31 , wherein the agent prevents inflammation and infiltration of activated neutrophils and monocytes in the joint. 
     
     
         42 . The method of  claim 31 , wherein the agent does not prevent TNF alpha production in whole blood cultures. 
     
     
         43 . The method of  claim 31 , wherein the agent prevents NF kappa B pathway to cellular damage. 
     
     
         44 . The method of  claim 31 , further comprising:
 administering to the subject a therapeutically effective amount of an anti-TNF or an anti-IL-1 compound   
     
     
         45 . The method of  claim 44 , wherein the anti-TNF or anti-IL-1 compound is administered in a single dose prophylactic dose and the agent is administered following administration of the anti-TNF or anti-IL-1 compound. 
     
     
         46 . The method of  claim 41 , wherein the agent is administered through an intravenous or oral route. 
     
     
         47 . The method of  claim 31 , wherein the agent is administered in a dose of about 1 mg to about 1000 mg.