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

• US 9,326,972 B2
• Filed: 02/09/2012
• Issued: 05/03/2016
• Est. Priority Date: 03/16/2004
• Status: Active Grant

• Current Assignee: Ohio University
• Original Assignee: Ohio University
• Inventors: Kohn, Leonard D., Harii, Norikazu, Benavides-Peralta, Uruguaysito, Gonzalez-Murguiondo, Mariana, Lewis, Christopher J., Goetz, Douglas J., Malgor, Ramiro, Schwartz, Frank, Napolitano, Giorgio, Giuliani, Cesidio, McCall, Kelly D.
• Primary Examiner(s): Badio, Barbara P
• Assistant Examiner(s): TOWNSLEY, SARA ELIZABETH
• Application Number:
  US13/370,079
• Publication Number:
  US 20120238610A1
• Time in Patent Office: 1,545 Days
• Field of Search: 514/392
• US Class Current: 1/1
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/4166 having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
• CPC Class Codes: A61K 31/56 Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/04 for non-specific disorders of the connective tissue
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/28 : for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• CPC Class Codes: A61P 27/16 : Otologicals
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/06 : for tuberculosis
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/12 : Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 35/02 : specific for leukemia
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• CPC Class Codes: A61P 9/14 : Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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.

Claims

1. A method of treatment or prevention of septic shock, sepsis or toxic shock syndrome in horses, comprising the step of administering an effective amount of

2. The method of claim 1, wherein said method is a method of treating septic shock, sepsis or toxic shock syndrome in horses.

3. The method of claim 1, wherein said method is a method of preventing septic shock, sepsis or toxic shock syndrome in horses.

4. The method of claim 1, wherein said treatment comprises amelioration of septic shock, sepsis or toxic shock syndrome in horses.

5. The method of claim 1, wherein said treatment comprises amelioration of toxic shock syndrome in horses.

6. The method of claim 1, wherein said treatment comprises amelioration of septic shock in horses.

7. The method of claim 1, wherein said treatment comprises amelioration of sepsis in horses.

8. The method of claim 1, wherein said method is a method of preventing toxic shock syndrome in horses.

9. The method of claim 1, wherein said method is a method of preventing septic shock in horses.

10. The method of claim 1, wherein said method is a method of preventing sepsis in horses.

11. The method of claim 1, wherein the effective amount of

12. The method of claim 1, wherein the effective amount of

13. The method of claim 1, wherein the effective amount of

14. The method of claim 1, wherein the effective amount of

15. The method of claim 1, wherein the effective amount of

16. The method of claim 1, wherein the effective amount of

17. The method of claim 1, wherein the effective amount of

18. The method of claim 1, wherein the effective amount of

19. The method of claim 18, wherein the statin is selected from lovastatin, simvastatin, dihydroxy open-acid simvastatin, pravastatin, fluvastatin, atorvastatin, cerivastatin, and pitavastatin.

20. The method of claim 1, wherein the effective amount of

21. The method of claim 1, wherein the effective amount of

22. The method of claim 1, wherein the effective amount of