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RU-2861717-C2 - METHODS FOR TREATING INFLAMMATION

RU2861717C2RU 2861717 C2RU2861717 C2RU 2861717C2RU-2861717-C2

Abstract

FIELD: pharmaceutics; medicine. SUBSTANCE: proposed is a method for treating inflammation in a subject in need thereof, comprising administering a therapeutically effective amount of said compound selected from a compound of formula VII, formula VII(c) or compound 17ya to a subject in need thereof. EFFECT: effective treatment of inflammation. 17 cl, 3 dwg, 12 tbl, 4 ex

Inventors

  • STEINER, MITCHELL S.
  • BARNETTE, KESTER GARY

Dates

Publication Date
20260508
Application Date
20210804
Priority Date
20210405

Claims (20)

  1. 1. A method of treating inflammation in a subject in need thereof by administering to the subject a composition containing a therapeutically effective amount of a compound of formula VII:
  2. Where
  3. X represents a bond;
  4. Q is NH and
  5. A is a phenyl, indolyl or indazolyl ring optionally substituted with at least one of the following: (C 1 -C 4 ) alkyl, halo(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkylamino, amino(C 1 -C 4 ) alkyl, F, Cl, Br, I, CN, -CH 2 CN, NH 2 , hydroxyl, OC(O)CF 3 , -OCH 2 Ph, -NHCO-(C 1 -C 4 ) alkyl, COOH, -C(O)Ph, C(O)O-(C 1 -C 4 ) alkyl, C(O)H, -C(O)NH 2 or NO 2 ;
  6. or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof.
  7. 2. The method for treating inflammation according to claim 1, wherein X is a bond.
  8. 3. The method for treating inflammation according to claim 1, wherein X is a bond; Q is NH; and A is an indolyl ring optionally substituted with at least one of the following: (C 1 -C 4 ) alkyl, halo(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkylamino, amino(C 1 -C 4 ) alkyl, F, Cl, Br, I, CN, -CH 2 CN, NH 2 , hydroxyl, OC(O)CF 3 , -OCH 2 Ph, -NHCO-(C 1 -C 4 ) alkyl, COOH, -C(O)Ph, C(O)O-(C 1 -C 4 ) alkyl, C(O)H, -C(O)NH 2 or NO 2 ;
  9. or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof.
  10. 4. A method of treating inflammation in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of a compound of formula VII(c):
  11. ,
  12. Where
  13. R 4 and R 5 are independently hydrogen, (C 1 -C 4 ) alkyl, halo(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) alkyl, O-(C 1 -C 4 ) haloalkyl, (C 1 -C 4 ) alkylamino, amino(C 1 -C 4 ) alkyl, F, Cl, Br, I, CN, –CH 2 CN, NH 2 , hydroxyl, OC(O)CF 3 , –OCH 2 Ph, –NHCO–(C 1 -C 4 ) alkyl, COOH, –C(O)Ph, C(O)O–(C 1 -C 4 ) alkyl, C(O)H, –C(O)NH 2 or NO 2 ; and
  14. n is 1–4;
  15. or a pharmaceutically acceptable salt, hydrate, polymorph or isomer thereof.
  16. 5. A method of treating inflammation in a subject in need thereof by administering to the subject a composition comprising a therapeutically effective amount of compound 17ya, represented as:
  17. 6. The method of treating inflammation according to any one of claims 1-5, wherein the inflammation is caused by or associated with viral-induced inflammation, arthritis, gout, acute respiratory distress syndrome (ARDS), systemic acute respiratory syndrome (SARS), allergies, Alzheimer's disease, asthma, autoimmune diseases, atherosclerosis, cardiovascular diseases, cancer, chronic obstructive pulmonary disease, celiac disease, Crohn's disease, type I diabetes, type II diabetes, endometriosis, fatty liver disease, glomerulonephritis, hepatitis, inflammatory bowel disease, multiple sclerosis, muscular dystrophies such as Duchenne muscular dystrophy, obesity, Parkinson's disease, periodontitis, psoriasis, rheumatoid arthritis, sinusitis, tuberculosis, ulcerative colitis.
  18. 7. A method for treating inflammation according to any one of claims 1-5, wherein the inflammation responds to suppression of IL-1β production.
  19. 8. A method for treating inflammation according to any one of claims 1-5, wherein the inflammation responds to suppression of TNF-α production.
  20. 9. The method for treating inflammation according to claim 6, wherein the virus-induced inflammation is caused by the SARS-CoV, MERS-CoV or SARS-CoV-2 viruses.

Description

Cross-reference to related applications This application claims the benefit of priority to U.S. Provisional Patent Application No. 63/171,013, filed April 5, 2021, which is incorporated herein by reference. Field of technology The present invention relates to methods for treating inflammation using compounds having cytoskeleton disrupting activity and compositions comprising said compounds with pharmaceutically acceptable excipients and/or additional cytoskeleton disrupting compounds. State of the art Inflammation is the immune system's response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or radiation. This response acts by removing damaging stimuli and initiating the healing process. Thus, inflammation is a protective mechanism vital to maintaining health. Typically, during acute inflammatory responses, events and interactions at the cellular and molecular levels effectively minimize damage or infection. This process of mitigating harmful consequences promotes the restoration of tissue homeostasis and the resolution of acute inflammation. However, uncontrolled acute inflammation can contribute to the development of various serious inflammatory diseases in humans, such as, but not limited to, gout, arthritis, Alzheimer's disease, reaction to viral infections, allergies, asthma, autoimmune diseases, neurodegenerative diseases, Parkinson's disease, celiac disease, glomerulonephritis, cardiovascular diseases, hepatitis, inflammatory bowel disease, fatty liver disease, atherosclerosis, type 2 diabetes, cancer, obesity, endometriosis and many others. At the tissue level, inflammation is characterized by redness, swelling, heat, pain, and loss of tissue function, resulting from the local immune, vascular, and inflammatory cell response to infection or injury. Important microcirculatory events that occur during the inflammatory process include changes in vascular permeability, leukocyte recruitment and accumulation, and the release of inflammatory mediators. Various pathogenic factors, such as infection, tissue trauma, or myocardial infarction, can induce inflammation through tissue damage. The cause of inflammation can be infectious or non-infectious. In response to tissue damage, the body triggers a cascade of chemical signals that stimulate reactions aimed at healing the damaged tissue. These signals activate the chemotaxis of leukocytes from the general bloodstream to the site of injury. These activated leukocytes produce cytokines, which trigger inflammatory responses. Central to the host's innate response is the inflammasome, a multiprotein intracellular complex that responds to environmental stimuli, monosodium urate crystals, cholesterol crystals, islet amyloid polypeptides, pathogenic microbes, and viruses (e.g., coronaviruses), leading to the activation of highly proinflammatory cytokines: interleukin-1 beta (IL-1β) and IL-18. Inflammasomes also induce a type of cell death called pyroptosis. Inflammasome complexes include Nod-like receptors (NLRs) and AIM2, adaptor apoptosis-associated speck-like protein (ASC), and caspase-1. An example is NLRP3 (also known as NALP3 or cryopyrin), which is a member of the NLR family. The assembly and activation of NLRP3 inflammasomes are mediated by microtubules. Microtubules actively transport ASCs through mitochondria into the perinuclear space to colocalize with NLRP3 in the endoplasmic reticulum. After inflammasome assembly is complete, caspase-1 converts pro-IL1-β into activated IL1-β and IL-18, which initiate an excessive immune response leading to an inflammatory cascade, tissue damage, and inflammatory disease. Microtubules are cytoskeletal filaments composed of heterodimers of α- and β-tubulin and are involved in a wide range of cellular functions, including cell shape maintenance, vesicle transport, cell motility, and cell division. Tubulin is the main structural component of microtubules and a confirmed target for various anticancer drugs. Compounds that disrupt the balance between assembled microtubules and tubulin subunits in cells may be effective in reducing inflammation. Other compounds that disrupt the microtubule-tubulin balance in cells, such as paclitaxel and vinblastine, have limited use due to their toxicity. Drugs that target the cytoskeleton, particularly microtubule components, are important therapeutic agents for cancer and inflammation. The clinical activity of these compounds is determined by the location at which they bind to the α- and β-tubulin heterodimers that make up microtubule filaments. Three major binding sites on the α- and β-tubulin subunits have been identified as those for taxanes, vinca alkaloids, and colchicine. Such drugs are generally divided into two main categories: microtubule-stabilizing agents (e.g., taxanes) and microtubule-destabilizing or depolymerizing agents (e.g., vinca alkaloids and colchicine). Colchicine has a narrow therapeutic index, with no clear distinction between nontoxic, toxic,