Compound used as ACC (Acetyl CoA Carboxylase) inhibitor and application thereof

A technology of compounds and solvates, applied to compounds as ACC inhibitors and their application fields, can solve the problems of lack of therapeutic strategies and limited therapeutic effects, etc.

Active Publication Date: 2019-02-05
NANJING SANHOME PHARMACEUTICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, there is no effective treatment strategy for this type of disease. The existing treatment drugs are still insulin sensitizers and antioxidants (such as vitamin E) represented by thiazolidinediones, in addition to lipid-lowering drugs, angiotensin receptor antagonists, etc. Drugs, polyunsaturated fatty acids, etc., the therapeutic effect is very limited

Method used

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  • Compound used as ACC (Acetyl CoA Carboxylase) inhibitor and application thereof
  • Compound used as ACC (Acetyl CoA Carboxylase) inhibitor and application thereof
  • Compound used as ACC (Acetyl CoA Carboxylase) inhibitor and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0112] Example 1: 3-(1-(2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy)ethyl)-5-methyl- 6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidin-3(2H)-yl)cyclobutane-1-carboxylic acid

[0113]

[0114] Step 1: Preparation of ethyl 3-oxocyclobutanecarboxylate

[0115]

[0116] In a 1000mL single-necked bottle, dissolve 3-oxocyclobutanecarboxylic acid (25.0g, 219.1mmol) in toluene (500mL), add triethyl orthoacetate (106.6g, 657.3mmol), and heat at 110°C Stir for 5h. After the reaction was completed, it was cooled to room temperature, and dilute hydrochloric acid (1.0M, 20 mL) was added to quench the reaction. The organic layer was separated, washed once with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain 24.9 g of the title compound, which was directly used in the next reaction without purification.

[0117] Step 2: Preparati...

Embodiment 2

[0141] Example 2: 3-(3,3-difluorocyclobutyl)-1-(2-(2-methoxyphenyl)-2–((tetrahydro-2H-pyran-4-yl)oxy Base) ethyl)-5-methyl-6-(oxazol-2-yl)thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione

[0142]

[0143] Step 1: Preparation of ethyl 2-(3-(3,3-difluorocyclobutylamino)ureido)-4-methyl-thiophene-3-carboxylate

[0144]

[0145] In a low-temperature bath at -5°C, dissolve ethyl 2-amino-4-methylthiophene-3-carboxylate (5.786g, 19.5mmol) and triethylamine (11.84g, 117mmol) in anhydrous dichloromethane (110mL) The solution was added dropwise to a solution of triphosgene (5.786 g, 19.5 mmol) in dry dichloromethane (50 mL). After dripping, stir at 0°C for 1.5h and move to room temperature. Add 3,3-difluorocyclobutylamine (2.8 g, 19.5 mmol) and react overnight. Concentration, silica gel column chromatography, and then beating with ethyl acetate, the product was dissolved in ethyl acetate. The mother liquor was concentrated to obtain 4.5 g of the title compound, with a yield of 80%. M...

Embodiment 3

[0158] Example 3: (1R,3r)-3-(1-((R)-2-(2-methoxyphenyl)-2-((tetrahydro-2H-pyran-4-yl)oxy )ethyl)-5-methyl-6-(oxazol-2-yl)-2,4-dioxo-1,4-dihydrothieno[2,3-d]pyrimidine-3(2H) Preparation of -yl)-1-methylcyclobutanecarboxylic acid

[0159]

[0160] Step 1: Preparation of methyl 3-(dibenzylamino)-1-methylcyclobutanecarboxylate

[0161]

[0162] In a 1000mL single-necked bottle, dissolve methyl 1-methyl-3-oxo-cyclobutanecarboxylate (4.95g, 34.8mmol) in anhydrous tetrahydrofuran (200mL), add glacial acetic acid (22mL), dibenzylamine (7.56g, 38.3mmol), sodium triacetoxyborohydride (14.8g, 69.7mmol), and stirred overnight at room temperature. After the reaction, filter, concentrate the filtrate, add dichloromethane (300mL) to dissolve, wash with water, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride in turn, dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate, and place on a silica gel column Chromatography (petrol...

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Abstract

The invention belongs to the field of medical chemistry and relates to a compound used as an ACC (Acetyl CoA Carboxylase) inhibitor and application thereof. Specifically, the invention provides a compound shown as a formula I or isomers, pharmaceutically acceptable salts, solvates, crystals or prodrugs thereof, a preparation method of the compounds, a pharmaceutical composition containing the compounds and application of the compounds or the pharmaceutical composition to treatment and/or prevention ACC expression related diseases, such as fibrotic diseases, metabolic diseases, cancers or tissue proliferation diseases. The compound provided by the invention has very good inhibition activity on ACC and is very hopefully prepared into a treatment medicine for the fibrotic diseases, the metabolic diseases, the cancers or the tissue proliferation diseases. The formula I is shown in the description.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a class of compounds as acetyl-CoA carboxylase (ACC) inhibitors or their pharmaceutically acceptable salts, isomers, solvates, crystals or prodrugs, and their preparation methods As well as pharmaceutical compositions containing these compounds and the use of these compounds or compositions for treating and / or preventing diseases related to ACC expression, such as fibrotic diseases, metabolic diseases, cancer or tissue proliferation diseases. Background technique [0002] Acetyl-CoA carboxylase (ACC) is a biotinidase that catalyzes the reaction of acetyl-CoA to malonyl-CoA, which is the rate-limiting step in the first stage of fatty acid synthesis. In mammals, ACC exists as two tissue-specific isoenzymes, in which ACC1 is mainly present in lipogenic tissues such as liver and adipose tissue, while ACC2 is mainly present in oxidative tissues such as liver, heart and skeletal musc...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D495/04C07D519/00A61K31/519A61P3/00A61P35/00A61P1/16A61P3/04A61P3/10
CPCA61P1/16A61P3/00A61P3/04A61P3/10A61P35/00C07D495/04C07D519/00A61K31/519A61P1/00A61K31/5377
Inventor 王勇赵立文王亚洲全旭姜春环陈宏雁陈孟华李超廖业欣刘奇王琛王海杨圣伟郑国闯
Owner NANJING SANHOME PHARMACEUTICAL CO LTD
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