4-((substituted phenyl) difluoromethyl) phenoxy carboxylic acid derivative, and preparation method and uses thereof

Patent metadata

Field	Value
Publication number	US-9487470-B2
Application number	US-201314396455-A
Country	US
Kind code	B2
Filing date	Apr 25, 2013
Priority date	Apr 26, 2012
Publication date	Nov 8, 2016
Grant date	Nov 8, 2016

Abstract

The present invention discloses a 4-((substituted phenyl)difluoromethyl)phenoxycarboxylic acid derivative and preparation process and use thereof. More specifically, the present invention relates to a compound of the following formula I, which is defined in the specification. The compounds according to the present invention can be used as PPAR agonists, and demonstrates a strong effect on reducing the levels of total cholesterol (TC), triglyceride (TG), and low density lipoprotein cholesterol (LDL-C) in blood plasma, and thus the compound according to the present invention can be used in the preparation of a medicament for treating or preventing hyperlipoidemia or cardio-cerebrovascular diseases caused by hyperlipoidemia, such as diabetes, atherosclerosis, stroke, coronary heart disease, etc. The present invention also relates to a novel intermediate compound for the preparation of the compound of formula I and preparation method thereof.

First claim

The invention claimed is:

1. A compound of formula I, or pharmaceutically acceptable salts thereof or solvates thereof

wherein,
R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, substituted or unsubstituted linear or branched C1-C6 alkoxyacyl, substituted or unsubstituted C6-C10 aryloxyacyl, substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted linear or branched C1-C6 alkyl ester;
R 2 is hydrogen, substituted or unsubstituted linear or branched C1-C6 alkyl, or substituted or unsubstituted C6-C10 aryl;
R 3 is hydrogen, fluoro, chloro, bromo, or substituted or unsubstituted linear or branched C1-C6 alkyl;
The position of R 1 on the benzene ring can be ortho-position, para-position or meta-position to difluoromethylene group;
The position of R 3 on the benzene ring can be ortho-position or meta-position to difluoromethylene group;
R 4 is substituted or unsubstituted C1-C6 alkyl;
R 2 and R 4 can also be cyclized together, in order to form a 5-7 membered ring, together with carbon atoms and oxygen atoms between them;
wherein, said “substituted” means being substituted with the following substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 epoxy group, hydroxyl, nitro, amino, mercapto, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C1-C5 alkylmercapto, difluoromethyl, trifluoromethyl, difluoromethoxy, and carboxyl.

2. The compound according to claim 1 , wherein R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, linear or branched C1-C6 alkyl, C6-C10 aryl, linear or branched C1-C6 alkoxy, C6-C10 aryloxy, linear or branched C1-C6 alkoxyacyl, C6-C10 aryloxyacyl, or linear or branched C1-C6 alkyl ester.

3. The compound according to claim 1 , characterized in that R 1 can be selected from hydrogen, fluoro, chloro, bromo, trifluoromethyl, methyl, methoxy, methoxyacyl, or isopropyl 2-O-2-methylpropioate.

4. The compound according to claim 1 , characterized in that R 2 can be selected from hydrogen, methyl, ethyl, propyl, isopropyl, and benzyl.

5. The compound according to claim 1 , characterized in that R 3 can be selected from hydrogen, fluoro, chloro, bromo, methyl, and ethyl.

6. The compound according to claim 1 , wherein said compound is selected from:
isopropyl 2-(4-((4-chlorophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-bromophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl-(4-((4-fluorophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-trifluoromethylphenyl)difluoromethyl) phenoxy)-2-methylpropionate;
isopropyl 2-(4-(phenyldifluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-methylphenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-methoxyphenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((3-chlorophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((3-methylphenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((3-trifluoromethylphenyl)difluoromethyl) phenoxy)-2-methylpropionate;
isopropyl 2-(4-((2-chlorophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((2-methylphenyl)difluoromethyl)phenoxy)-2-methylpropionate;
isopropyl 2-(4-((2-trifluoromethylphenyl)difluoromethyl) phenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-methoxyacylphenyl)difluoromethyl) phenoxy)-2-methylpropionate;
bis-(isopropyl 2-methylpropionate-2-oxyphenyl-4-)-difluoromethane;
isopropyl 2-(4-((4-chlorophenyl)difluoromethyl)-3-methylphenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-chlorophenyl)difluoromethyl)-2-chlorophenoxy)-2-methylpropionate;
benzyl 2-(4-(4-chlorophenyl)difluoromethyl)phenoxy)-acetate;
ethyl 2-(4-((4-chlorophenyl)difluoromethyl)phenoxy) butyrate;
methyl 2-(4-((4-chlorophenyl)difluoromethyl)phenoxy) propionate;
ethyl 4-(4-((4-chlorophenyl)difluoromethyl)phenoxy) butyrate;
sodium 2-(4-((4-chlorophenyl)difluoromethyl)phenoxy)-2-methylpropionate;
2-(4-((4-chlorophenyl)difluoromethyl)phenoxy)-2-methylpropionic acid;
methyl 2-(4-((4-chlorophenyl)difluoromethyl)phenoxy)-4-hydroxy-butyrate;
3-(4-((4-chlorophenyl)difluoromethyl)phenoxy)-dihydrofuran-2(3H)-one;
isopropyl 2-(4-((4-chlorophenyl)difluoromethyl)-2-bromophenoxy)-2-methylpropionate;
isopropyl 2-(4-((4-trifluoromethylphenyl)difluoromethyl)-2-bromophenoxy)-2-methylpropionate; and
isopropyl 2-(4-((4-methoxyacylphenyl)difluoromethyl)-2-bromophenoxy)-2-methylpropionate.

7. A pharmaceutical composition, comprising an effective dosage of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

8. A method of treating hyperlipoidemia comprising administering a pharmaceutical composition comprising an effective dosage of a compound of formula I according to claim 1 , or a pharmaceutically acceptable salt or solvate thereof to a patient in need thereof.

9. A process for the preparation of a compound of formula I according to claim 1 , comprising reacting the compound according to the following formula II with an oxidant and a fluorination reagent to obtain the compound of formula I,

wherein,
R 1 is hydrogen, fluoro, chloro, bromo, trifluoromethyl, substituted or unsubstituted linear or branched C1-C6 alkoxyacyl, substituted or unsubstituted C6-C10 aryloxyacyl, substituted or unsubstituted linear or branched C1-C6 alkyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted linear or branched C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryloxy, substituted or unsubstituted linear or branched C1-C6 alkyl ester;
R 2 is hydrogen, substituted or unsubstituted linear or branched C1-C6 alkyl, or substituted or unsubstituted C6-C10 aryl;
R 3 is hydrogen, fluoro, chloro, bromo, or substituted or unsubstituted linear or branched C1-C6 alkyl;
the position of R 1 on the benzene ring can be ortho-position, para-position or meta-position to difluoromethylene group;
the position of R 3 on the benzene ring can be ortho-position or meta-position to difluoromethylene group;
R 4 is substituted or unsubstituted C1-C6 alkyl;
R 2 and R 4 can also be cyclized together, in order to form a 5-7 membered ring, together with carbon atoms and oxygen atoms between them;
wherein, said “substituted” means being substituted with the following substituents selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 alkenyl, C1-C6 alkynyl, C3-C6 epoxy group, hydroxyl, nitro, amino, mercapto, C1-C5 alkylamino, di(C1-C5 alkyl)amino, C1-C5 alkylmercapto, difluoromethyl, trifluoromethyl, difluoromethoxy, and carboxyl; and
R 5 can be absent, which forms thiocarbonyl with the carbon atom between the two benzene rings, or is a substituted or unsubstituted linear or branched C1-C6 alkyl, or substituted or unsubstituted aryl, alternatively, two R 5 groups bond with each other and form a 5-7 member ring, together with two sulfur atoms and a carbon atom linking the two sulfur atoms.

10. The process according to claim 9 , characterized in that said fluorination reagent is a nucleophilic fluorination reagent.

11. A process according to claim 10 , characterized in that said nucleophilic fluorination reagent ca

Assignees

• Zhejiang Hisun Pharm Co Ltd

Inventors

• Bai Hua
• Hong Jian
• Cai Lifeng
• Wei Hegeng
• Liu Xiaoyu
• Zheng Xiaohe

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title