Use of phenylmethimazoles, methimazole derivatives, and tautomeric cyclic thiones for the treatment of autoimmune/inflammatory diseases associated with toll-like receptor overexpression
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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.
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Citations
304 Claims
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1-138. -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.
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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.
- 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.
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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.
- 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.
- 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.
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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.
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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.
- 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.
- 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.
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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.
- 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.
- 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.
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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.
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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.
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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.
- , TNF-α
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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.
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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.
- 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
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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.
- 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;
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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. - View Dependent Claims (275, 276, 277)
- 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;
Specification