Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression

Abstract

Treatment of autoimmune and/or inflammatory diseases associated with overexpression of Toll-like receptor 3 (TLR3) as well as Toll-like receptor 4 (TLR4) and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. The use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune and inflammatory diseases associated with TLR3 as well as TLR4 and/or TLR3/TLR4 cellular signaling in association with related pathologies is disclosed. Methods of treating a subject having a disease or condition associated with abnormal TLR-3 as well as TLR-4 and/or TLR3/TLR4 cellular signaling in association with related pathologies are also disclosed. The present disclosure also relates to the treatment of autoimmune-inflammatory pathologies and chemokine and cytokine-mediated diseases associated with TLR overexpression and signaling. The disclosure also relates to pharmaceutical formulations capable of inhibiting the IRF-3/Type 1 IFN/STAT/ISRE/IRF-1 pathway associated with Toll-like receptor overexpression or signaling.

What is claimed is: 
     
         1 . A method for treatment or prevention of septic shock, sepsis, or toxic shock syndrome, the method comprising administering to a mammal in need thereof a therapeutically effective amount of: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. 
     
     
         2 . The method of  claim 1 , wherein the mammal is chosen from human, cow, sheep, pig, horse, goat, dog, cat, mouse, rat, rabbit, guinea pig, and hamster. 
     
     
         3 . The method of  claim 1 , wherein the mammal is human. 
     
     
         4 . The method of  claim 1 , wherein the mammal is a rodent. 
     
     
         5 . The method of  claim 1 , wherein the method is for the treatment of septic shock, sepsis, or toxic shock syndrome. 
     
     
         6 . The method of  claim 1 , wherein the method is for the prevention of septic shock, sepsis, or toxic shock syndrome. 
     
     
         7 . The method of  claim 1 , wherein the treatment of septic shock, sepsis, or toxic shock syndrome comprises amelioration of septic shock, sepsis or toxic shock syndrome in the mammal in need thereof. 
     
     
         8 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered systemically. 
     
     
         9 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more drugs, agents or therapeutics chosen from 5-lipoxygenase inhibitors, PDE4 inhibitors, PDE inhibitors, dopamine agonists, anti-IL-8 antibodies, and anti-IL-5 antibodies. 
     
     
         10 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more drugs, agents or therapeutics chosen from beta-2 adrenoceptor agonists, muscarinic M1 and M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine Hl antagonists, histamine H3 antagonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-B agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones. 
     
     
         11 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more therapeutic steroids. 
     
     
         12 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more therapeutic steroids chosen from corticoids, glucocorticoids, dexamethasone, prednisone, prednisolone, and betamethasone. 
     
     
         13 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is provided as a pharmaceutical composition comprising from about 0.01% to about 25% of the 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, and from about 75% to about 99.99% of a pharmaceutically-acceptable carrier. 
     
     
         14 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with at least one additional active agent for the prophylaxis or treatment of septic shock, sepsis or toxic shock syndrome. 
     
     
         15 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more additional agents chosen from sulfonylureas, meglitinides, biguanides, alpha-glucosidase inhibitors, peroxisome proliferators-activated receptor-gamma agonists, insulin, insulin analogues, HMG-CoA reductase inhibitors, cholesterol-lowering drugs, anti-platelet agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor antagonists, adiponectin, a lipid modifying compound or agent, and a statin. 
     
     
         16 . The method of  claim 15 , wherein the statin is chosen from lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, and pitavastatin. 
     
     
         17 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more additional agents chosen from HMG-CoA synthase inhibitors, squalene epoxidase inhibitors, squalene synthetase inhibitors, acyl-coenzyme A:cholesterol acyltransferase inhibitors, microsomal triglyceride transfer protein inhibitors, probucol, niacin, bile acid sequestrants, LDL receptor inducers, platelet aggregation inhibitors, human peroxisome proliferator activated receptor gamma agonists, PPAR agonists, PPAR alpha/gamma dual agonists, vitamin B6 and the pharmaceutically acceptable salts thereof, vitamin B12, folic acid or a pharmaceutically acceptable salt or ester thereof, anti-oxidant vitamins, beta-blockers, angiotensin II antagonists, angiotensin converting enzyme inhibitors, calcium channel blockers, endothelian antagonists, agents that enhance ABCA1 gene expression, FXR ligands, bisphosphonate compounds, and cyclooxygenase-2 inhibitors. 
     
     
         18 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more additional agents chosen from hypoglycemic active ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, CETP inhibitors, LDL receptor inducers, ACAT inhibitors, antioxidants, squalene synthetase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, cannabinoid 1 receptor antagonists, CCK agonists, serotonin reuptake inhibitors, bombesin agonists, galanin antagonists, leptin agonists, and lipase inhibitors. 
     
     
         19 . The method of  claim 1 , wherein the therapeutically effective amount of 
       
         
           
           
               
               
           
         
       
       or pharmaceutical salt thereof, is administered in conjunction with one or more additional agents chosen from bile acid absorption inhibitors, polymeric bile acid adsorbents, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, lipoprotein(a) antagonists, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta-3 agonists, MSH agonists, mixed sertoninergic and noradrenergic compounds, 5HT agonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, amylase inhibitors, PPAR modulators, RXR modulators, TR-beta agonists, and amphetamines.