# US 9,750,723 B2 · Prevention and treatment of non-alcoholic fatty liver disease > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 9,750,723 B2 - Document ID: US9750723B2 - Status: Granted - Kind: B2 - Application number: 15/032,508 - Filed: 2014-10-31 - Published: 2016-09-08 - Granted: 2017-09-05 - Earliest claimed: 2014-10-31 - Assignees: Ohio University - Applicants: Ohio University - Inventors: Kelly D. McCall; Frank L. Schwartz; Douglas J. Goetz; Ramiro Malgor - Web page: https://patentgrep.com/patent/US9750723B2 ## CPC - A61K 31/4184: condensed with carbocyclic rings, e.g. benzimidazoles - A61K 31/4164: 1,3-Diazoles - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - C07D 233/84: Sulfur atoms - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) ## Abstract Methods for preventing, treating, and/or reducing the risk of developing non-alcoholic fatty liver disease in a subject in need thereof and pharmaceutical compositions for the prevention or treatment of non-alcoholic fatty liver disease. The methods include administering a therapeutically effective amount of phenylmethimazole, methimazole derivatives, and/or tautomeric cyclic thiones to the subject. The pharmaceutical composition includes phenylmethimazole, methimazole derivatives, and/or tautomeric cyclic thiones formulated for administration to a subject for the prevention or treatment of non-alcoholic fatty liver disease. ## Claims ### Claim 1 A method for treating or reducing the risk of developing non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, the method comprising administering a composition comprising a therapeutically effective amount of one or more methimazole derivatives to the subject, the methimazole derivatives having a formula selected from (I), (II), and (III): or pharmaceutically-acceptable salts or solvates thereof; wherein: (a) Y is independently selected from H, C1-C4 alkyl, C1-C4 substituted alkyl, NO2, and a phenyl moiety having Formula (IV): wherein no more than one Y of a methimazole derivative may be the phenyl moiety of Formula (IV); R1 is selected from H, OH, halogens, C1-C4 alkyl, C1-C4 substituted alkyl, C1-C4 ester, and C1-C4 substituted ester; and R4 is selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (b) R2 is independently selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (c) Z is selected from SR3, S(O)R3, OR3, and C1-C4 alkyl; wherein R3 is selected from H, C1-C4 alkyl, C1-C4 substituted alkyl, and —CH2Ph, wherein Ph is phenyl; and (d) X is selected from S and O. ### Claim 2 (depends on 1) The method according to claim 1, wherein administration of the one or more methimazole derivatives is effective to treat NAFLD. ### Claim 3 (depends on 1) The method according to claim 1, wherein administration of the one or more methimazole derivatives is effective to treat NAFLD by reducing fat content in liver tissue of the subject relative to a baseline level. ### Claim 4 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (I), and wherein R3 is selected from C1-C4 alkyl, C1-C4 substituted alkyl, and —CH2Ph. ### Claim 5 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (I), and wherein one Y has the phenyl moiety of Formula (IV). ### Claim 6 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (I), and wherein at least one Y is NO2 when Z is C1-C4 alkyl. ### Claim 7 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (I), and wherein R2 and R3 are independently selected from C1- C4 alkyl when Y is not the phenyl moiety of Formula (IV). ### Claim 8 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (I), and wherein the methimazole derivative according to Formula (I) is phenylmethimazole. ### Claim 9 (depends on 8) The method according to claim 8, wherein the phenylmethimazole is administered in a dose of from about 1 mg/kg to about 10 mg/kg once daily. ### Claim 10 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (II), and wherein X is S. ### Claim 11 (depends on 1) The method according to claim 1, wherein the composition comprises a methimazole derivative according to Formula (III), and wherein X is S. ### Claim 12 (depends on 1) The method according to claim 1, wherein the subject is a mammal, and wherein the one or more methimazole derivatives is administered systemically. ### Claim 13 (depends on 1) The method according to claim 1, further comprising co-administering at least one of metformin, a thiazolidinedione, or an HMG-Co-A inhibitor. ### Claim 14 A method for treating or reducing the risk of developing non-alcoholic fatty liver disease (NAFLD) in a subject in need thereof, the method comprising administering a composition comprising a therapeutically effective amount of one or more methimazole derivatives to the subject, wherein the one or more methimazole derivatives have a formula selected from (X) and (XI): or pharmaceutically-acceptable salts or solvates thereof; wherein: (a) Y is selected from H, C1-C4 alkyl, C1-C4 and substituted alkyl; (b) R1 is selected from H, OH, halogens, C1-C4 alkyl, C1-C4 substituted alkyl, C1-C4 ester, and C1-C4 substituted ester; (c) R2 is independently selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (d) R4 is selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (e) Z is selected from SR3 and OR3; wherein R3 is selected from H, C1-C4 alkyl, C1-C4 substituted alkyl, and —CH2Ph, wherein Ph is phenyl; (f) X is selected from S and O. ### Claim 15 (depends on 14) The method according to claim 14, wherein the composition comprises one or more methimazole derivatives according to Formula (X), and wherein the one or more methimazole derivatives have a formula selected from (XII) and (XIII): wherein R9 is selected from —OH, -M, and —OOCCH2M; and wherein M is a halogen. ### Claim 16 (depends on 14) The method according to claim 14, wherein the composition comprises one or more of the following methimazole derivatives according to Formula (XI): wherein R9 is selected from —OH, -M, and —OOCCH2M; and wherein M is a halogen. ### Claim 17 A pharmaceutical composition for treatment of or reduction of the risk of developing non-alcoholic fatty liver disease (NAFLD) comprising: (a) a therapeutically effective amount of one or more of metformin, thiazolidinediones, or HMG-Co-A inhibitors; and (b) a therapeutically effective amount of one or more methimazole derivatives having a formula selected from (I), (II), and (III): or pharmaceutically-acceptable salts or solvates thereof; wherein: (i) Y is independently selected from H, C1-C4 alkyl, C1-C4 substituted alkyl, NO2, and a phenyl moiety having Formula (IV): wherein no more than one Y of a methimazole derivative may be the phenyl moiety of Formula (IV); R1 is selected from H, OH, halogens, C1-C4 alkyl, C1-C4 substituted alkyl, C1-C4 ester, and C1-C4 substituted ester; and R4 is selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (ii) R2 is independently selected from H, C1-C4 alkyl, and C1-C4 substituted alkyl; (iii) Z is selected from SR3, S(O)R3, OR3, and C1-C4 alkyl; wherein R3 is selected from H, C1-C4 alkyl, C1-C4 substituted alkyl, and —CH2Ph, wherein Ph is phenyl; and (iv) X is selected from S and O. ### Claim 18 (depends on 17) The pharmaceutical composition according to claim 17, further comprising a pharmaceutically acceptable carrier. ### Claim 19 (depends on 17) A device comprising a reservoir of the pharmaceutical composition according to claim 17. ### Claim 20 (depends on 17) A method for treatment of or reduction of the risk of developing non-alcoholic fatty liver disease (NAFLD), the method comprising administering a therapeutically effective amount of the pharmaceutical composition according to claim 17.