Thiazolidinone compounds and use thereof

Patent metadata

Field	Value
Publication number	US-10544113-B2
Application number	US-201715449406-A
Country	US
Kind code	B2
Filing date	Mar 3, 2017
Priority date	Mar 7, 2016
Publication date	Jan 28, 2020
Grant date	Jan 28, 2020

Abstract

A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium.

First claim

What is claimed is:

1. A pharmaceutical composition for treating an opioid receptor-associated condition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound of Formula (I) below, and a therapeutic agent:

in which
U is

V is

 in which R 1 is C 1-6 alkyl; each of R 2 , R 4 , and R 5 , independently, is H; and R 3 is —C(O)OR, R being H, acetyl, C 1-6 alkyl, C 1-6 multihaloalkyl, C 3-8 cycloalkyl, C 2-8 heterocycloalkyl, C 6-14 aryl, or C 1-13 heteroaryl;
X is S;
Y is CH 2 ; and
W is —C(O)—.

2. The pharmaceutical composition of claim 1 , wherein the therapeutic agent is a mu-opioid receptor antagonist.

3. The pharmaceutical composition of claim 2 , wherein the mu-opioid receptor antagonist is naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, β-FNA, naloxonazine, or nalmefene.

4. A method of treating an opioid receptor-associated condition, the method comprising administering to a subject in need thereof a pharmaceutical composition of claim 1 wherein the therapeutic agent is a mu-opioid receptor antagonist.

5. The method of claim 4 , wherein the mu-opioid receptor antagonist is naloxone, naltrexone, samidorphan, cyprodime, clocinnamox, β-FNA, naloxonazine, or nalmefene.

6. The method of claim 4 , wherein the opioid receptor-associated condition is pain, immune disease, esophageal reflux, diarrhea, anxiety, or heroin addiction.

7. The method of claim 6 , wherein the opioid receptor-associated condition is pain.

8. The method of claim 7 , wherein the pain is cancer pain, post operative pain, low back pain, rheumatoid arthritis pain, osteoarthritis pain, neuropathic pain, or fibromyalgia pain.

9. The pharmaceutical composition of claim 1 , wherein the compound is selected from the group consisting of the following compounds:
Compound 58: 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid,
Compound 152: 4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid ethyl ester,
Compound 489: Oxetan-3-yl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate, and
Compound 660: (-)-Ethyl 4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoate.

10. The pharmaceutical composition of claim 9 , wherein the compound is Compound 58: 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid.

11. The pharmaceutical composition of claim 9 , wherein the compound is Compound 152: 4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid ethyl ester.

12. A pharmaceutical composition for treating an opioid receptor-associated condition, the pharmaceutical composition comprising a pharmaceutically acceptable carrier, a compound, and a therapeutic agent, wherein the compound is selected from the group consisting of the following compounds:
Compound 58: 4-(2-(4-Fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoic acid,
Compound 59: Methyl 4-(2-(4-fluorophenyl)-4-oxothiazolidin-3-yl)-3-methylbenzoate,
Compound 152: 4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid ethyl ester,
Compound 159: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(methylsulfonyl)-benzamide,
Compound 160: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(propylsulfonyl)-benzamide,
Compound 162: N-(Ethylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 163: N-(Butylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 167: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2-methylpropyl)sulfonyl]benzamide,
Compound 169: N-(Cyclopropylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 171: N-(Cyclohexylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 173: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-sulfamoylbenzamide,
Compound 174: N-(Dimethylsulfamoyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 175: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(trifluoromethyl)sulfonyl]benzamide,
Compound 176: N-(Benzylsulfonyl)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 177: N-[(3-Fluorobenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 179: N-[(3,5-Dimethylbenzyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 183: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(phenylsulfonyl)-benzamide,
Compound 185: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(4-methylphenyl)sulfonyl]benzamide,
Compound 186: N-[(4-Ethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 187: N-[(4-Cyanophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 188: 4-[2(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-methoxyphenyl)sulfonyl]-3-methylbenzamide,
Compound 189: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-{[4-(trifluoromethoxy)phenyl]sulfonyl}benzamide,
Compound 190: Ethyl 4-({4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzoyl}sulfamoyl) benzoate,
Compound 192: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-[(2,4,6-trimethylphenyl)-sulfonyl]benzamide,
Compound 194: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(3-fluorophenyl)sulfonyl]-3-methylbenzamide,
Compound 196: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-[(4-fluorophenyl)sulfonyl]-3-methylbenzamide,
Compound 198: N-[(4-Chlorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 200: N-[(4-Bromophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 202: N-{[4-(Acetylamino)phenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 204: N-[4-Chloro-2-fluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 206: N-[(2,4-Difluorophenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3- methylbenzamide,
Compound 208: N-[(4-Chloro-2,5-dimethylphenyl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 210: N-{[5-(Dimethylamino)-1-naphthalenyl]sulfonyl}-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 211: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-(3-pyridinylsulfonyl)- benzamide,
Compound 213: N-[(3,5-Dimethyl-1,2-oxazol-4-yl)sulfonyl]-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 215: N-Ethoxy-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 216: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-methoxy-3-methylbenzamide,
Compound 217: N-(Benzyloxy)-4-[2-(4-fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzamide,
Compound 218: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methyl-N-phenoxybenzamide,
Compound 219: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-N-hydroxy-3-methylbenzamide,
Compound 220: 4-[2-(4-Fluorophenyl)-4-oxo-1,3-thiazolidin-3-yl]-3-methylbenzohydrazide,
Compound 229: 4-[2-(4-Fluoro-phenyl)-4-oxo-thiazolidin-3-yl]-3-methyl-benzoic acid propyl ester,
Compound 231: 4-[2-

Assignees

• National Health Res Inst
• National Health Res Institute
• Univ Minnesota

Inventors

• Ueng Shau-Hua
• Yeh Shiu-Hwa
• Lin Shu-Yu
• Shih Chuan
• Loh Horace

Classifications

• A61K31/454

  containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone · CPC title

• A61K31/427

  not condensed and containing further heterocyclic rings · CPC title

• A61K31/497

  containing further heterocyclic rings · CPC title

• A61K31/402

  1-aryl substituted, e.g. piretanide · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title