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

Abstract

The present invention relates to the 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. This invention also relates to the use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune and inflammatory diseases associated with 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. This invention also relates to treating a subject having a disease or condition associated with abnormal Toll-like receptor 3 as well as Toll-like receptor 4 and/or TLR3/TLR4 signaling in nonimmune cells, monocytes, macrophages, and/or dendritic cells in association with related pathologies. The present invention also relates to the treatment of autoimmune-inflammatory pathologies and chemokine and cytokine-mediated diseases associated with TLR overexpression and signaling. This invention 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.

1 - 138 . (canceled)  
     
     
         139 . A method of treating a TLR-mediated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of one or more methimazole derivatives and/or cyclic thione derivatives.  
     
     
         140 . The method of  claim 139  wherein the methimazole derivatives and/or cyclic thione derivatives are selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof.  
     
     
         141 . The method according to  claim 140 , wherein the TLR-mediated disease involves cells selected from the group consisting of nonimmune cells, monocytes, macrophages, and dendritic cells.  
     
     
         142 . The method according to  claim 141 , wherein the disease is a TLR-mediated autoimmune/inflammatory disease or disorder.  
     
     
         143 . The method according to  claim 142 , TLR-mediated autoimmune/inflammatory disease or disorder involves TLR-3 or TLR-4.  
     
     
         144 . The method according to  claim 143 , wherein the disease or disorder is a TLR-mediated autoimmune/inflammatory disease or disorder associated with immune cell infiltration and destruction of the nonimmune cells.  
     
     
         145 . The method according to  claim 144 , wherein the disease or disorder is a TLR-mediated disease or disorder involving a pathologic innate immune response.  
     
     
         146 . The method according to  claim 145 , wherein the disease or disorder is a pathological condition resulting from abnormal cell proliferation; transplantation rejections, autoimmune, inflammatory, proliferative, hyperproliferative, or cardiovascular diseases.  
     
     
         147 . The method according to  claim 146 , wherein the disease or disorder is a cardiovascular disease.  
     
     
         148 . The method according to  claim 147 , wherein the cardiovascular disease or disorder is restenosis, coronary artery disease, atherosclerosis, atherogenesis, cerebrovascular diseases or events, coronary events, angina, ischemic disease, congestive heart failure, pulmonary edema associated with acute myocardial infarction, thrombosis, high or elevated blood pressure in hypertension, platelet aggregation, platelet adhesion, smooth muscle cell proliferation, a vascular or non-vascular complication associated with the use of a medical device, a wound associated with the use of a medical device, vascular or non-vascular wall damage, peripheral vascular disease or neoinitimal hyperplasia following percutaneous transluminal coronary angiograph.  
     
     
         149 . The method according to  claim 147 , wherein the disease or disorder is a cerebrovascular disease or event.  
     
     
         150 . The method according to  claim 149 , wherein the cerebrovascular disease or event is a cerebral infarction or stroke (caused by vessel blockage or hemorrhage), or transient ischemia attack (TIA), syncope, or atherosclerosis of the intracranial and/or extracranial arteries, and the like.  
     
     
         151 . The method according to  claim 147 , wherein the cardiovascular disease or disorder is a myocardial infarction, myocardial revascularization procedures, angina, cardiovascular death or acute coronary syndrome.  
     
     
         152 . The method according to  claim 139 , wherein the TLR-mediated disease or disorder is selected from the group consisting of septic shock, sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, post ischemic reperfusion injury, malaria, mycobacterial infection, meningitis, psoriasis, congestive heart failure, fibrotic disease, cachexia, graft rejection, cancer, autoimmune disease, opportunistic infections in AIDS, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, other arthritic conditions, Crohn's disease, ulcerative colitis, multiple sclerosis, systemic lupus erythrematosis, ENL in leprosy, radiation damage, asthma, and hyperoxic alveolar injury.  
     
     
         153 . A method of ameliorating one or more symptoms of atherosclerosis in a subject, comprising administering to the subject a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to ameliorate one or more symptoms of atherosclerosis.  
     
     
         154 . The method according to  claim 139 , wherein the atherosclerotic disease has inflammatory and immunological properties.  
     
     
         155 . The method according to  claim 154 , wherein the inflammatory and immunological properties are associated with expression of an innate immune response.  
     
     
         156 . A method of ameliorating one or more symptoms of myocardial disease in a subject, the method comprising administering to the subject a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to ameliorate one or more symptoms of myocardial diseases.  
     
     
         157 . The method according to  claim 156 , wherein the myocardial disease has inflammatory and immunological properties.  
     
     
         158 . The method according to  claim 157 , wherein the inflammatory and immunological properties are associated with expression of an innate immune response.  
     
     
         159 . The method according to  claim 158 , wherein the myocardial disease is coronary heart disease, reversible or irreversible myocardial ischemialreperfusion damage, acute or chronic heart failure and restenosis.  
     
     
         160 . A method of mitigating or preventing a coronary complication associated with an acute phase response to an inflammation in a subject, wherein the coronary complication is a symptom of atherosclerosis, the method comprising administering to a subject having the acute phase response, or at risk for the acute phase response, a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to mitigate or prevent the coronary complication.  
     
     
         161 . The method according to  claim 157 , wherein the method comprises mitigating or preventing an acute phase response.  
     
     
         162 . The method according to  claim 161 , wherein the acute phase response is an inflammatory response associated with a recurrent inflammatory disease.  
     
     
         163 . The method according to  claim 161 , wherein the acute phase response is an inflammatory response associated with a recurrent inflammatory disease and an innate immune response.  
     
     
         164 . The method according to  claim 161 , wherein the acute phase response is associated with a disease selected from the group consisting of leprosy, tuberculosis, systemic lupus erythematosus, polymyalgia rheumatica, polyarteritis nodosa, scleroderma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, Alzheimer's Disease AIDS, coronary calcification, calcific aortic stenosis, osteoporosis, and rheumatoid arthritis.  
     
     
         165 . The method according to  claim 161 , wherein the acute phase response is an inflammatory response associated with a condition selected from the group consisting of a bacterial infection, a viral infection, a fimgal infection, an organ transplant, a wound, an implanted prosthesis, parasitic infection, sepsis, endotoxic shock syndrome, and biofilm formation.  
     
     
         166 . A method of ameliorating one or more symptoms of a TLR3 or TLR4-mediated autoimmune/inflammatory disease or disorder associated with immune cell infiltration and destruction of the nonimmune cells in a subject in need thereof, the method comprising administering to the subject a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to ameliorate one or more symptoms of TLR-mediated autoimmune/inflammatory disease or disorder associated with immune cell infiltration and destruction of the nonimmune cells.  
     
     
         167 . The method according to  claim 166 , wherein the TLR-mediated autoimmune/inflammatory disease or disorder is an acute inflammatory disease selected from the group consisting of: (a) endotoxemia; (b) septicemia; (c) toxic shock syndrome; and (d) infectious disease.  
     
     
         168 . The method according to  claim 167 , wherein the TLR-mediated autoimmune/inflammatory disease or disorder is TLR-4 mediated.  
     
     
         169 . The method according to  claim 167 , wherein the TLR-mediated autoimmune/inflammatory disease or disorder is selected from septic shock of whatever type, etiology, or pathogenesis; or septic shock that is a member selected from the group consisting of renal failure; acute renal failure; cachexia; malarial cachexia; hypophysial cachexia; uremic cachexia; cardiac cachexia; cachexia suprarenalis or Addison's disease; cancerous cachexia; and cachexia as a consequence of infection by the human immunodeficiency virus (HIV).  
     
     
         170 . The method according to  claim 167 , wherein the TLR-mediated autoimmune/inflammatory disease or disorder is endotoxic shock.  
     
     
         171 . The method according to  claim 170 , wherein endotoxic shock is induced by gram-negative bacteria.  
     
     
         172 . The method according to  claim 170 , wherein the endotoxic shock is induced by gram-positive bacteria.  
     
     
         173 . The method according to  claim 170 , wherein the septic shock is LPS-induced shock.  
     
     
         174 . The method according to  claim 170 , the method further comprises administering an antibiotic to the subject.  
     
     
         175 . A method of treating a TLR3 or TLR4-mediated pathological condition resulting from or in abnormal cell proliferation, a transplant rejection, an autoimmune, inflammatory, proliferative, hyperproliferative or vascular disease, for reducing scar tissue or for inhibiting wound contraction in a subject in need thereof, the method comprising administering a therapeutically effective amount of a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, to a subject in need of such therapy.  
     
     
         176 . The method according to  claim 175 , wherein the pathological condition resulting from abnormal cell proliferation is a cancer, a Karposi's sarcoma, a cholangiocarcinoma, a choriocarcinoma, a neoblastoma, a Wilm's tumor, Hodgkin's disease, a melanoma, multiple myelomas, a chronic lymphocytic leukemia or an acute or chronic granulocytic lymphoma.  
     
     
         177 . The method according to  claim 175 , wherein the autoimmune, inflammatory, proliferative, hyperproliferative or vascular disease is selected from the group consisting of rheumatoid arthritis, restenosis, lupus erythematosus, systemic lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, diabetes mellitus, uveitis, nephritic syndrome, multiple sclerosis, an inflammatory skin disease, an inflammatory lung disease, an inflammatory bowel disease, an inflammatory disease that affects or causes obstruction of a body passageway, an inflammation of the eye, nose or throat, a fungal infection and a food related allergy.  
     
     
         178 . A method of ameliorating one or more symptoms of a TLR3-mediated pathological condition resulting from an allergen in a subject in need thereof, the method comprising administering to the subject a methimazole derivative and/or tautomeric cyclic thione in an amount sufficient to ameliorate one or more symptoms resulting from an allergen.  
     
     
         179 . A method of ameliorating one or more symptoms of a TLR3-mediated pathological condition resulting from an allergy in a subject in need thereof, the method comprising administering to the subject a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to ameliorate one or more symptoms resulting from an allergy.  
     
     
         180 . The method according to  claim 140 , wherein the TLR-mediated disease is a TLR3 or TLR4-mediated disease, disorder or condition caused by one or more conditions selected from the group consisting of asthma, chronic bronchoconstriction, acute bronchoconstriction, bronchitis, small airways obstruction, emphysema, obstructive airways disease, inflammatory airways disease, acute lung injury or bronchiectasis.  
     
     
         181 . The method according to  claim 180 , wherein the asthma is atopic asthma; 
 non-atopic asthma; allergic asthma; atopic bronchial IgE-mediated asthma; bronchial asthma; essential asthma; true asthma; intrinsic asthma caused by pathophysiologic disturbances; extrinsic asthma caused by environmental factors; essential asthma of unknown or unapparent cause; bronchitic asthma; emphysematous asthma; exercise-induced asthma; allergen induced asthma; cold air induced asthma; occupational asthma; infective asthma caused by bacterial, fingal, protozoal or viral infection; non-allergic asthma; incipient asthma; wheezy infant syndrome; and bronchiolytis.    
     
     
         182 . The method according to  claim 140 , wherein the TLR-mediated disease is a TLR3-mediated pathological condition results from an obstructive airways disease or inflammatory airways disease.  
     
     
         183 . The method according to  claim 182 , wherein the obstructive airways disease or inflammatory airways disease is selected from the group consisting of chronic eosinophilic pneumonia, chronic obstructive pulmonary disease (COPD), COPD that includes chronic bronchitis, pulmonary emphysema or dyspnea associated or not associated with COPD, COPD that is characterized by irreversible, progressive airways obstruction, adult respiratory distress syndrome (ARDS), exacerbation of airways hyper-reactivity consequent to other drug therapy or airways disease that is associated with pulmonary hypertension.  
     
     
         184 . The method according to  claim 183 , wherein the obstructive airways disease or inflammatory airways disease is bronchitis.  
     
     
         185 . The method according to  claim 184 , wherein the bronchitis is chronic bronchitis, acute bronchitis, acute laryngotracheal bronchitis, arachidic bronchitis, catarrhal bronchitis, croupus bronchitis, dry bronchitis, infectious asthmatic bronchitis, productive bronchitis, staphylococcus bronchitis, streptococcal bronchitis or vesicular bronchitis.  
     
     
         186 . The method according to  claim 180 , wherein the bronchiectasis is cylindric bronchiectasis, sacculated bronchiectasis, fusiform bronchiectasis, capillary bronchiectasis, cystic bronchiectasis, dry bronchiectasis or follicular bronchiectasis.  
     
     
         187 . The method according to  claim 175 , wherein the autoimmune or inflammatory disease associated with Toll-like receptor 3 or 4 overexpression results from other inflammation inducing conditions that may be treated to ameliorate symptoms associated with inflammation or to diminish the existing inflammation.  
     
     
         188 . The method according to  claim 187 , wherein the other inflammation or irritation associated therewith is selected from the group consisting of insect bites or stings, contact with a particular type plant, radiation, non-infectious conjunctivitis, hemorrhoids, abrasions, ingrown finger or toenail (granulation), skin graft donor sites, vaginitis, psoriasis, herpes simplex, pruritis ani/cruri, chemical inflammation.  
     
     
         189 . The method according to  claim 175 , wherein the autoimmune or inflammatory disease associated with Toll-like receptor 3 or 4 overexpression results from other inflammation inducing conditions that may be treated to ameliorate symptoms associated with inflammation or to diminish the existing inflammation wherein the inflammation is the result of extraneously induced damage to cells or tissue.  
     
     
         190 . The method according to  claim 189 , wherein the other inflammation or irritation is a chemical and/or physical influence upon the skin or mucus membranes of the subject.  
     
     
         191 . The method according to  claim 189 , wherein the other inflammation or irritation associated therewith is induced by microorganisms acting on the skin or body.  
     
     
         192 . The method according to  claim 191 , wherein the inflammatory responses that may be ameliorated is on the skin or a mucus membrane of a subject and is selected from the group consisting of inflammation around erupting wisdom teeth, following extraction of teeth, periodontal abscesses, prosthesis induced pressure sores on the mucosa, fimgal infections, for treating exposed bone surface in alveolitis sicca dolorosa, which is a painful condition which may arise following extraction of teeth, chronic and acute inflammatory diseases, pancreatitis, rheumatoid arthritis, osteoarthritis, asthma, inflammatory bowel disease, psoriasis and in certain neurological disorders such as Alzheimer's disease.  
     
     
         193 . The method according to  claim 191 , wherein the other inflammation or irritation associated therewith is induced by environmental factors selected from the group consisting of sun or wind exposure, trauma or wounds, cuts, bums or abrasions, exposure to chemicals such as alkaline soaps, detergents, liquid solvents, oils, preservatives, and disease.  
     
     
         194 . A method of ameliorating one or more symptoms of a TLR3- or TLR4-linked disease resulting from pathogen or pathogen molecular signals in a subject in need thereof, the method comprising administering to the subject a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount sufficient to ameliorate one or more symptoms resulting from pathogen or pathogen molecular signals by inhibiting the increased IMF-3 signal pathway, but not the NF-kappa B signal pathway.  
     
     
         195 . The method according to  claim 194 , wherein the pathogen related agent or product is a virus, bacteria, dsRNA, Type 1 IFN, or environmental induction event.  
     
     
         196 . The method according to  claim 195 , wherein the bacteria is exemplified by, but not limited to, Chlamidia or enterobacteria.  
     
     
         197 . The method according to  claim 195 , wherein the bacteria are gram negative bacteria.  
     
     
         198 . The method according to  claim 195  , wherein the virus is an RNA virus, enterovirus, Chlamydia, or coxacki virus.  
     
     
         199 . The method according to  claim 195  wherein the virus is a single strand RNA virus.  
     
     
         200 . The method according to  claim 195 , wherein the virus is Influenza A.  
     
     
         201 . The method according to  claim 194 , wherein the TLR3- or TLR4-linked disease involves a pathogen or pathogen molecular signal which increases Type 1 interferon gene expression.  
     
     
         202 . The method according to  claim 201 , wherein the pathogen related agent or product is a virus, bacteria, dsRNA, Type 1 IFN, or environmental induction event.  
     
     
         203 . The method according to  claim 201 , wherein the bacteria are gram-negative bacteria.  
     
     
         204 . The method according to  claim 201 , wherein the virus is an RNA virus, enterovirus, or coxacki virus.  
     
     
         205 . The method according to  claim 201 , wherein the virus is a single strand RNA virus.  
     
     
         206 . The method according to  claim 201 , wherein the virus is Influenza A.  
     
     
         207 . The method according to  claim 194 , wherein the TLR3- or TLR4-linked disease involves a pathogen or pathogen molecular signal which increases STAT-1 activation.  
     
     
         208 . The method according to  claim 207 , wherein the pathogen related agent or product is a virus, bacteria, dsRNA, Type 1 IFN, or environmental induction event.  
     
     
         209 . The method according to  claim 208 , wherein the bacteria re a gram negative bacteria.  
     
     
         210 . The method according to  claim 208 , wherein the virus is an RNA virus, enterovirus, or coxacki virus.  
     
     
         211 . The method according to  claim 208 , wherein the virus is a single strand RNA virus.  
     
     
         212 . The method according to  claim 208 , wherein the virus is Influenza A.  
     
     
         213 . The method according to  claim 194 , wherein the TLR3- or TLR4-linked disease involves a pathogen or pathogen molecular signal which increases interferon sensitive response element (ISRE) activation.  
     
     
         214 . The method according to  claim 213 , wherein the pathogen related agent or product is a virus, bacteria, dsRNA, Type 1 IFN, or environmental induction event.  
     
     
         215 . The method according to  claim 214 , wherein the bacteria are gram negative bacteria.  
     
     
         216 . The method according to  claim 214 , wherein the virus is an RNA virus, enterovirus, or coxacki virus.  
     
     
         217 . The method according to  claim 214 , wherein the virus is a single strand RNA virus.  
     
     
         218 . The method according to  claim 214 , wherein the virus is Influenza A.  
     
     
         219 . The method according to  claim 194 , wherein the TLR3- or TLR4-linked diseases involves increased activation of interferon sensitive response element.  
     
     
         220 . The method according to  claim 219 , wherein the pathogen related agent or product is lypopolysaccharide, Type 1 IFN, or environmental induction event, hyperlipidemia.  
     
     
         221 . The method according to  claim 220 , wherein the pathogen is bacteria.  
     
     
         222 . The method according to  claim 221 , wherein the bacteria are gram-negative bacteria.  
     
     
         223 . The method according to  claim 220 , wherein the pathogen is a virus.  
     
     
         224 . The method according to  claim 223 , wherein the virus is an enterovirus.  
     
     
         225 . method for treating a TLR-mediated disease or disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of one or more methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, that decreases that decreases the endogenous amount of intracellular or extracellular cytokine in the subject suffering from the disease.  
     
     
         226 . The method according to  claim 225 , wherein the cytokine is TNFα.  
     
     
         227 . The method according to  claim 225 , wherein the disease selected from the group consisting of graft versus host disease, acute respiratory distress syndrome, granulomatous disease, transplant rejection, cachexia, parasitic infections, fungal infections, trauma, and bacterial infections.  
     
     
         228 . The method according to  claim 225 , wherein the disorder is an autoimmune or inflammatory disease associated with toll-like receptor 3 or 4 overexpression.  
     
     
         229 . The method according to  claim 225 , wherein the disorder is an autoimmune or inflammatory disease associated with toll-like receptor 3 overexpression in a cell selected from nonimmune cells, monocytes, macrophages, and dendritic cells.  
     
     
         230 . The method according to  claim 225 , wherein the disorder is a TLR3-mediated inflammatory disease involving activation of, or pathologic signaling of, IRF-3.  
     
     
         231 . The method according to  claim 225 , wherein the disorder is a TLR3-mediated inflammatory disease involving overexpression or pathologic signaling by Type 1 interferons.  
     
     
         232 . The method according to  claim 225 , wherein the disorder is a TLR3-mediated inflammatory disease involving overexpression or pathologic signaling of ISRE containing genes.  
     
     
         233 . The method according to  claim 225 , wherein the disorder is a TLR3-mediated inflammatory disease involving activation of, or pathologic signaling by, STAT1.  
     
     
         234 . The method according to  claim 225 , wherein the disorder is a TLR3-mediated inflammatory disease involving a pathological condition resulting from abnormal cell proliferation; transplantation rejection, autoimmune, inflammatory, proliferative, hyperproliferative, or cardiovascular disease.  
     
     
         235 . The method according to  claim 225 , wherein the disorder is Hashimoto's hyroiditis.  
     
     
         236 . The method according to  claim 225 , wherein the disorder is inflammatory lung disease.  
     
     
         237 . The method according to  claim 225  wherein the disorder is Type 1 diabetes.  
     
     
         238 . The method according to  claim 225 , wherein the disorder is Insulin-dependent Diabetes.  
     
     
         239 . The method according to  claim 225 , wherein the disorder is a TLR-mediated autoimmune disease.  
     
     
         240 . The method according to  claim 225 , wherein the TLR-mediated autoimmune disease is Alopecia, Areata, Ankylosing Spondylitis, Antiphospholipid Syndrome, Autoimmune Addison's Disease, Autoimmune Hemolytic Anemia, Autoimmune Hepatitis, Behcet's Disease, Bullous Pemphigoid, Cardiomyopathy, Celiac Sprue-Dermatitis, Chronic Fatigue Immune Dysfimction Syndrome (CFIDS), Chronic Inflammatory Demyelinating Polyneuropathy, Churg-Strauss Syndrome, Cicatricial Pemphigoid, CREST Syndrome, Cold Agglutinin Disease, Crohn's Disease, Discoid Lupus, Essential Mixed Cryoglobulinemia, Fibromyalgia-Fibromyositis, Graves' Disease, Guillain-Barre, Hashimoto's Thyroiditis, Post partum thyroiditis, Hypothyroidism, Idiopathic Puhnonary Fibrosis, Idiopathic Thrombocytopenia Purpura (ITP), IgA Nephropathy, Insulin dependent Diabetes, Type 2 Diabetes, Complications of Type 1 or 2 diabetes, Juvenile Arthritis, Lichen Planus, Systemic Lupus, Meniere's Disease, Mixed Connective Tissue Disease, Multiple Sclerosis, Myasthenia Gravis, Pemphigus Vulgaris, Pernicious Anemia, Polyarteritis Nodosa, Polychondritis, Polyglandular Syndromes, Polymyalgia Rheumatica, Polymyositis and Dermatomyositis, Primary Agammaglobulinemia, Primary Biliary Cirrhosis, Psoriasis, Raynaud's Phenomenon, Reiter's Syndrome, Rheumatic Fever, Rheumatoid Arthritis, Sarcoidosis, Scleroderma, Sjogren's Syndrome, Stiffinan Syndrome, Iakayasu Arteritis, Temporal Arteritis/Giant Cell Arteritis, Ulcerative Colitis, Uveitis, Vasculitis, Vitiligo, Wegener's Granulomatosis, or myasthenia gravis.  
     
     
         241 . A method for the treatment of diseases, disorders, conditions or symptoms mediated by TLR3 in a subject, which comprises administering to the subject a pharmaceutical composition comprising a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in an amount effective for prevention, inhibition or suppression of diseases, disorders, conditions or symptoms mediated by TLR3, wherein the disease or condition is one or more of the following: graft versus host disease, acute respiratory distress syndrome, granulomatous disease, transplant rejection, cachexia, parasitic infections, fingal infections, trauma, and bacterial infections.  
     
     
         242 . The method according to  claim 140 , wherein the compounds of the present invention are administered in conjunction with one or more drugs, agents or therapeutics selected from the group consisting of: glucocorticoids, 5-lipoxygenase inhibitors, β-2 adrenoceptor agonists, muscarinic M1 and M3 antagonists, muscarinic M2 agonists, NK3 antagonists, LTB4 antagonists, cysteinyl leukotriene antagonists, bronchodilators, PDE4 inhibitors, PDE inhibitors, elastase inhibitors, MMP inhibitors, phospholipase A2 inhibitors, phospholipase D inhibitors, histamine HI antagonists, histamine H3 antagonists, dopamine agonists, adenosine A2 agonists, NK1 and NK2 antagonists, GABA-b agonists, nociceptin agonists, expectorants, mucolytic agents, decongestants, antioxidants, anti-IL-8 anti-bodies, anti-IL-5 antibodies, anti-IgE antibodies, anti-TNF antibodies, IL-10, adhesion molecule inhibitors, and growth hormones.  
     
     
         243 . The method according to  claim 141 , wherein the compounds of the present invention are administered in conjunction with one or more therapeutic steroids.  
     
     
         244 . The method according to  claim 243 , wherein the one or more therapeutic teroids are selected from the group consisting of corticoids, glucocorticoids, dexamethasone, prednisone, prednisolone, and betamethasone.  
     
     
         245 . The method according to  claim 141 , wherein the Toll-like receptor 3 induced disease is one or more diseases or pathologies selected from the group consisting of a metabolic related disorder and a weight related disorder.  
     
     
         246 . The method according to  claim 245 , wherein the TLR-mediated disease is a Toll-like receptor 3 induced inflammatory disease and related pathologies.  
     
     
         247 . The method according to  claim 245 , wherein the Toll-like receptor 3 induced inflammatory disease is selected from the group consisting of type I diabetes, type II diabetes, inadequate glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia and syndrome X.  
     
     
         248 . The method according to  claim 245 , wherein the Toll-like receptor 3 induced disease is one or more vascular diseases.  
     
     
         249 . The method according to  claim 248 , wherein the Toll-like receptor 3 induced disease is one or more diseases or pathologies selected from the group consisting of atherosclerosis, transplant atherosclerosis, vein-graft atherosclerosis, stent restenosis, and angioplasty restenosis.  
     
     
         250 . The method according to  claim 249 , wherein the compounds of the present invention are administered in conjunction with one or more compounds selected from the group consisting of steroids, cyclooxygenase-2 inhibitors, NSAIDs, DMARDS, antibiotics, immunosuppressive agents, 5-lipoxygenase inhibitors, LTB 4  antagonists and LTA 4  hydrolase inhibitors and anti-cell adhesion molecules.  
     
     
         251 . The method according to  claim 140 , wherein the methods are used prophylactically to treat a subject at risk of developing an inflammatory condition.  
     
     
         252 . The method according to  claim 140 , wherein the pharmaceutical composition is in prodrug form.  
     
     
         253 . The method according to  claim 140 , wherein the pharmaceutical composition comprises from about 0.01% to about 25% of the active compound and from about 75% to about 99.99% of the pharmaceutically-acceptable carrier.  
     
     
         254 . A method of prophylaxis or treatment of a disease, disorder, condition or complication thereof as described herein, comprising administering to an individual in need of such prophylaxis or treatment a therapeutically effective amount or dose of one or more methimazole derivatives and/or cyclic thione derivatives selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof, in combination with at least one additional active agent.  
     
     
         255 . The method according to  claim 254 , wherein the additional active agent comprises one or more agent selected from the group consisting of: 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 and adiponectin.  
     
     
         256 . The method according to  claim 254 , wherein the additional active agent or agents is a lipid modifying compound or agent.  
     
     
         257 . The method according to  claim 254 , wherein the additional active agent comprises one or more HMG-CoA synthase inhibitors; squalene epoxidase inhibitors; squalene synthetase inhibitors (also known as squalene synthase inhibitors), acyl-coenzyme cholesterol acyltransferase (ACAT) inhibitors; microsomal triglyceride transfer protein (MTP) inhibitors; probucol; niacin; bile acid sequestrants; LDL (low density lipoprotein) receptor inducers; platelet aggregation inhibitors, for example glycoprotein Ilb/IIla fibrinogen receptor antagonists and aspirin; human peroxisome proliferator activated receptor gamma (PPARO) agonists, PPAR agonists; PPAR alpha/gamma dual agonists, vitamin B6 (also known as pyridoxine) and the pharmaceutically acceptable salts thereof such as the HCl salt; vitamin B12 (also known as cyanocobalamin); folic acid or a pharmaceutically acceptable salt or ester thereof such as the sodium salt and the methylglucamine salt; anti-oxidant vitamins such as vitamin C and E and beta carotene; beta-blockers; angiotensin II antagonists such as losartan; angiotensin converting enzyme inhibitors such as enalapril and captopril; calcium channel blockers such as nifedipine and diltiazam; endothelian antagonists; agents that enhance ABCA1 gene expression; FXR ligands including both inhibitors and agonists; bisphosphonate compounds such as alendronate sodium; and cyclooxygenase-2 inhibitors such as rofecoxib and celecoxib.  
     
     
         258 . The method according to  claim 254 , wherein the additional active agent comprises one or more antidiabetics, hypoglycemic active ingredients, HMG-CoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, alpha-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, cannabinoid 1 receptor antagonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, beta-3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed sertoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, cannabinoid 1 receptor antagonists, RXR modulators or TR-beta agonists or amphetamines.  
     
     
         259 . The method according to  claim 254 , wherein the additional active agent or agents is a statin.  
     
     
         260 . The method according to  claim 254 , wherein the statin is selected from the group consisting of lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, and pitavastatin.  
     
     
         261 . A method for the diagnosis, early diagnosis, differential diagnosis, assessment of the severity and therapy-accompanying monitoring and prognosis of an inflammatory or autoimmune disease comprising testing a biological fluid or cell sample of a subject in whom disease is present or suspected for the activation or expression of TLR 3 and/or TLR4, wherein the activation or expression of TLR 3 and/or TLR4 is indicative of the presence, the expected cause, the severity and/or the success of initiated measures for the therapy of the disease.  
     
     
         262 . The method according to  claim 261 , wherein the inflammatory or autoimmune disease is is selected from septic shock of whatever type, etiology, or pathogenesis; or septic shock that is a associated with renal failure; acute renal failure; cachexia; malarial cachexia; hypophysial cachexia; uremic cachexia; cardiac cachexia; cachexia suprarenalis or Addison's disease; cancerous cachexia; and cachexia as a consequence of infection by the human immunodeficiency virus (HIV).  
     
     
         263 . The method according to  claim 261 , wherein the inflammatory or autoimmune disease is selected from the group consisting of Type 1 diabetes, colitis, autoimmune thyroiditis, atherosclerosis, and vascular complications of diabetes.  
     
     
         264 . The method according to  claim 261 , wherein the levels of expression of TLR3 in thyrocytes is measured as a method for diagnosis for Hashimoto's thyroiditis.  
     
     
         265 . The method according to  claim 261 , wherein the level of expression of TLR3 in pancreatic islet cells is measured as a method for diagnosis of insulinitis or Type 1 diabetes.  
     
     
         266 . The method according to  claim 261 , wherein the levels of expression of TLR4 in monocytes, vascular endothelial cells, or intestinal epithelial cells, is measured as a method for diagnosis of a an autoimmune or inflammatory disease.  
     
     
         267 . The method according to  claim 261 , wherein the disease is vascular disease or colitis.  
     
     
         268 . A method of diagnosing a TLR3 or TLR4 mediated related disease in a subject, the method comprising detecting the level of expression of TLR3 (a) in a test sample of nonimmune tissue cells obtained from the subject, and (b) in a control sample of known normal nonimmune tissue cells of the same cell type, wherein a higher or lower level of expression of TLR3 or TLR4 in the test sample as compared to the control sample is indicative of the presence of an TLR3 related disease in the subject from which the test tissue cells were obtained.  
     
     
         269 . A method of diagnosing, in a subject, an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression in nonimmune cells, the method comprising detecting the level of expression of TLR3 or TLR4 (a) in a test sample of nonimmune cells obtained from the subject, and (b) in a control sample of known normal nonimmune cells of the same cell type, wherein a higher or lower level of expression of TLR3 or TLR4 in the test sample as compared to the control sample is indicative of the presence of an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression in the subject from which the test tissue cells were obtained.  
     
     
         270 . A method of identifying a compound that inhibits the expression of TLR3 or TLR4, the method comprising contacting cells which normally exhibit TLR3 or TLR4 expression or activity with an enhancer of this expression or activity, e. g. LPS, Type I IFN, dsRNA transfection, a virus, IL-1β, TNF-α, together with, preceded, or followed by a candidate compound, and determining the responsiveness or lack responsiveness by the cell to the test compound.  
     
     
         271 . A method of identifying a compound that inhibits toll-like receptor 3 or TLR4 overexpression in a nonimmune cell, the method comprising contacting nonimmune cells which overexpress TLR3 or TLR4 with a candidate compound, and determining the activity or expression of TLR3 or TLR4.  
     
     
         272 . A method for screening a test compound for the potential to prevent, ameliorate, stabilize, or treat an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression in the subject comprising the steps of first contacting a nonimmune cell sample from a subject that has, or is at risk for developing, an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression in the subject with the test compound; b) contacting a second nonimmune cell sample from the subject with a known standard compound, wherein the first and second nonimmune cell samples are contacted with the test compound in the same manner; and c) measuring TLR3 or TLR4 expression or activity in the first and second samples, wherein the compound is determined to have the potential if the TLR3 or TLR4 expression or activity in the first sample is decreased relative to the second sample.  
     
     
         273 . A method for screening a test compound for the potential to prevent, ameliorate, stabilize, or treat an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression in the subject comprising the steps of: a) first contacting a nonimmune cell sample from a first subject that has, or is at risk for developing, an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression or signaling in the subject with the test compound; b) contacting a second nonimmune cell sample from a second subject that does not have, or is not predisposed to developing, an autoimmune or inflammatory disease associated with toll-like receptor 3 or TLR4 overexpression or signaling with the test compound, wherein the first and second nonimmune cell samples are contacted with the test compound in the same manner; and c) measuring TLR3 or TLR4 expression or activity in the first and second samples, wherein the compound is determined to have the potential if the TLR3 or TLR4 expression or activity in the first sample is decreased relative to the second sample.  
     
     
         274 . A pharmaceutical combination, comprising: a methimazole derivative and/or cyclic thione derivative selected from the group consisting of tautomeric methimazole derivatives, non-tautomeric methimazole derivatives, and non-tautomeric cyclic thione derivatives, and combinations thereof; at least one additional therapeutic agent selected from the group consisting of anti-obesity agents; appetite suppressants; anti-diabetic agents; anti-hyperlipidemia agents; hypolipidemic agents; hypocholesterolemic agents; lipid-modulating agents; cholesterol-lowering agents; lipid-lowering agents; anti-hypertensive agents; agents used to treat sleep disorders; agents used to treat substance abuse and addictive disorders; anti-anxiety agents; anti-depressants; anti-psychotic agents; cognition enhancing agents; agents used to treat cognitive disorders; agents used to treat Alzheimer's disease; agents used to treat Parkinson's disease; anti-inflammatory agents; agents used to treat neurodegeneration; agents used to treat arteriosclerosis; agents used to treat respiratory conditions; agents used to treat bowel disorders; cardiac glycosides; and anti-tumor agents; and at least one pharmaceutically acceptable carrier or diluent.  
     
     
         275 . The pharmaceutical combination according to  claim 274 , wherein the anti-obesity agent is selected from melanocortin receptor (MC4R) agonists; melanin-concentrating hormone receptor (MCHR) antagonists; growth hormone secretagogue receptor (GHSR) antagonists; orexin antagonists; CCK agonists; GLP-1 agonists and other Pre-proglucagon-derived peptides; NPY1 or NPY5 antagonists; NPY2 and NPY4 modulators; corticotropin releasing factor agonists; histamine receptor-3 (H3) modulators; aP2 inhibitors; PPAR gamma modulators; PPAR delta modulators; acetyl-CoA carboxylase (ACC) inhibitors, adiponectin receptor modulators, beta 3 adrenergic agonists, including AJ9677, L750355 and CP331648 or other known beta 3 agonists; thyroid receptor beta modulator; lipase inhibitors, including orlistat and ATL-962; serotonin receptor agonists, including BVT-933; monoamine reuptake inhibitors or releasing agents, including fenfluramine, dexfenfluramine, fluvoxamine, fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex, clortermine, picilorex, sibutramine, dexamphetamine, phentermine, phenylpropanolamine and mazindol; anorectic agents, including topiramate; ciliary neurotrophic factor, including Axokine; brain-derived neurotrophic factor; leptin and other cannabinoid-1 receptor antagonists, including SR-141716 and SLV-319.  
     
     
         276 . The pharmaceutical combination according to  claim 274 , wherein the anti-diabetic agent is selected from insulin secretagogues; insulin sensitizers; anti-hyperglycemic agents; biguanides; sulfonyl ureas; glucosidase inhibitors; aldose reductase inhibitors; PPAR gamma agonists including thiazolidinediones; PPAR-alpha agonists, including fibric acid derivatives; PPAR-delta antagonists or agonists; PPAR alpha/gamma dual agonists; dipeptidyl peptidase IV inhibitors; SGLT2 inhibitors; glycogen phosphorylase inhibitors; meglitinides; insulin; glucagon-like peptide-1; glucagon-like peptide 1 agonists; and protein tyrosine phosphatase-1B inhibitor.  
     
     
         277 . The pharmaceutical combination according to  claim 274 , wherein the anti-inflammatory agent is selected from prednisone; dexamethasone; cyclooxygenase inhibitors including COX-1 and COX-2 inhibitors selected from NSAID's, aspirin, indomethacin, ibuprofen, piroxicam, Naproxen, Celebrex and Vioxx; CTLA4-Ig agonists and antagonists; CD40 ligand antagonists; IMPDH inhibitors including mycophenolate; integrin antagonists; alpha-4 beta-7 integrin antagonists; cell adhesion inhibitors; interferon gamma antagonists; ICAM-1; tumor necrosis factor antagonists selected from infliximab, OR1384, TNF-alpha inhibitors including tenidap, anti-TNF antibodies or soluble TNF receptors including etanercept; rapamycin selected from sirolimus and Rapamune; eflunomide; prostaglandin synthesis inhibitors; budesonide; clofazimine; CNI-1493; CD4 antagonists including priliximab; p38 mitogen-activated protein kinase inhibitors; protein tyrosine kinase inhibitors; IKK inhibitors; agents for treatment of irritable bowel syndrome selected from Zelnorm and Maxi-K openers.  
     
     
         278 . The method according to  claim 140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , wherein the pharmaceutical composition comprises a safe and effective amount of the tautomeric methimazole derivative,  
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, —NO 2 , and the phenyl moiety:  
       
         
           
           
               
               
           
         
       
       and wherein no more than one Y group in said active compound may be the phenyl moiety; R 1  is selected from the group consisting of H, —OH, halogens, C 1 -C 4  alkyl, and C 1 -C 4  substituted alkyl; R 2  is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C4 substituted alkyl, and a phenyl moiety; R 3 is H ; R 4  is selected from the group consisting of H, C 1 -C 4  alkyl, and Cl-C 4  substituted alkyl; and Z is selected from —SR 3  and —OR 3  ; and wherein said compound is C 1 -C 4  alkyl when Y is not a phenyl moiety, and a pharmaceutically-acceptable carrier.  
     
     
         279 . The method according to  claim 140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , wherein the pharmaceutical composition comprises a safe and effective mount of the non-tautomeric methimazole derivative  
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, —NO 2 , and the phenyl moiety:  
       
         
           
           
               
               
           
         
       
       and wherein no more than one Y group in said active compound may be the phenyl moiety; R 1  is selected from the group consisting of H, —OH, halogens, C 1 -C 4  alkyl, and C 1 -C 4  substituted alkyl; R 2  is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, and a phenyl moiety; R 3  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, and —CH 2 Ph; R 4  is selected from the group consisting of H, C 1 -C 4  alkyl, and C 1 -C 4  substituted alkyl; and Z is selected from —SR 3 , S(O)R 3 , —OR 3  and C 1 -C 4  alkyl; and wherein at least two of the R 2  and R 3  groups in said compound are C 1 -C 4  alkyl when Y is not a phenyl moiety, and at least one Y is —NO 2  when Z is alkyl; and a pharmaceutically-acceptable carrier.  
     
     
         280 . The method according to  claim 140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , wherein the pharmaceutical composition comprises a safe and effective amount of the non-tautomeric cyclic thione derivative  
       
         
           
           
               
               
           
         
       
       wherein Y is selected from the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, —NO 2 , and the phenyl moiety:  
       
         
           
           
               
               
           
         
       
       and wherein no more than one Y group in said active compound may be the phenyl moiety; R 1  is selected from the group consisting of H, —OH, halogens, C 1 -C 4  alkyl, and C 1 -C 4  substituted alkyl; R 2  is selected from the group consisting of C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, and a phenyl moiety; R 4  is selected from the group consisting of H, C 1 -C 4  alkyl, and C 1 -C 4  substituted alkyl; X is S; and a pharmaceutically-acceptable carrier.  
     
     
         281 . The method according to claims  278  or  279 , wherein Z is SR 3  and Y is H.  
     
     
         282 . The method according to  claim 281 , wherein R 3  is C 1 -C 4  alkyl.  
     
     
         283 . The method according to  claim 282 , wherein R 3  is methyl.  
     
     
         284 . The method according to  claim 283 , wherein at least one R 2  group is methyl.  
     
     
         285 . The method according to  claim 280 , wherein both R 2  groups are methyl.  
     
     
         286 . The method according to  claim 279 , wherein the active compound has the formula N.  
     
     
         287 . The method according to  claim 279 , wherein the active compound has the formula  
       
         
           
           
               
               
           
         
       
     
     
         288 . The method according to  claim 280 , wherein the active compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         289 . The method according to  claim 280 , wherein the active compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         290 . The method according to  claim 279 , wherein the active compound has the formula:  
       
         
           
           
               
               
           
         
       
     
     
         291 . The method according to claims  278  or  279 , wherein Z is SR 3  and one of the Y groups is the phenyl moiety.  
     
     
         292 . The method according to  claim 291 , wherein R 1  and R 4  are H.  
     
     
         293 . The method according to  claim 279 , wherein Z is SR 3  and R 3  is a methyl, and one of the Y groups is the phenyl moiety wherein R 1  and R 4  are H, and the R 2  group is methyl.  
     
     
         294 . The method according to  claim 278 , wherein Z is SR 3  and R 3  is H, and one of the Y groups is the phenyl moiety wherein R 1  and R 4  are H, and the R 2  group is methyl.  
     
     
         295 . The method according to  claim 280 , wherein one of the Y groups is the phenyl moiety, wherein R 1  and R 4  are H, and both R 2  groups are methyl.  
     
     
         296 . The method according to  claim 278 , wherein the active compound is:  
       
         
           
           
               
               
           
         
       
     
     
         297 . The method according to  claim 279 , wherein the active compound is  
       
         
           
           
               
               
           
         
       
     
     
         298 . The method according to  claim 280 , wherein the active compound is  
       
         
           
           
               
               
           
         
       
     
     
         299 . The method according to claims  278 ,  279  or  280 , wherein the pharmaceutical composition is in prodrug form.  
     
     
         300 . The method according to claims  278 ,  279  or  280 , wherein the pharmaceutical composition comprises from about 0.01% to about 25% of the active compound and from about 75% to about 99.99% of the pharmaceutically-acceptable carrier.  
     
     
         301 . The method according to  claim 280 , wherein the pharmaceutical composition comprises a safe and effective amount of an active compound having the formula:  
       
         
           
           
               
               
           
         
       
     
     
         302 . The method according to  claim 140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , wherein the pharmaceutical composition comprises a safe and effective amount of  
       
         
           
           
               
               
           
         
       
       wherein Y is selected form the group consisting of H, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, —NO 2 , and the phenyl moiety:  
       
         
           
           
               
               
           
         
       
       R 1  is selected from the group consisting H, —OH, halogens, C 1 -C 4  alkyl, C 1 -C 4  substituted alkyl, C 1 -C 4  ester and C 1 -C 4  substituted ester; R 2  is selected from the group consisting of H, C 1 -C 4  alkyl and C 1 -C 4  substituted alkyl; R 4  is selected from the group consisting of H, C 1 -C 4  alkyl and C 1 -C 4  substituted alkyl; X is S; and wherein the R 2  groups in said compound are C 1 -C 4  alkyl when Y is not a phenyl moiety, and a harmaceutically acceptable carrier.  
     
     
         303 . The method according to claims  140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , wherein the active compound is selected from the group consisting of  
       
         
           
           
               
               
           
         
       
       wherein R9 is selected from the group consisting of —OH, -M and —OOCCH 2 M; wherein M is selected from F, Cl, Br and I.  
     
     
         304 . The method according to claims  140 ,  153 ,  156 ,  160 ,  166 ,  175 ,  194 ,  225 ,  241 ,  254  or  274 , 
 wherein the active compound is selected from the group consisting of                          wherein R 10  is selected from the group consisting of H, —NO 2 , Ph, 4-HOPh and 4-MPh, wherein M is selected from F, Cl, Br and I.