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Substitutive five membered heterocyclic compound, preparation and medical use thereof

A kind of technology of five-membered heterocycle and compound, applied in the field of substituted five-membered heterocycle compound

Inactive Publication Date: 2008-10-01
SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Except for GLP-1 and its peptide analogues, there is no report about the successful clinical application of non-peptide small molecule GLP-1R agonists

Method used

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  • Substitutive five membered heterocyclic compound, preparation and medical use thereof
  • Substitutive five membered heterocyclic compound, preparation and medical use thereof
  • Substitutive five membered heterocyclic compound, preparation and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0193] The preparation of embodiment 1,2-(p-tolyl imino)-thiazol-4-ketone

[0194] NMR calibration: δH / C 7.26 / 77.0ppm (CDCl 3 ); δH / C 2.50 / 39.51ppm (DMSO-d 6 ).

[0195]

[0196] Add 17g (0.22mol) NH 4 Dissolve SCN in 100ml of acetone, stir at room temperature, slowly add 28.2g (0.2mol) of benzoyl chloride dropwise, a white solid appears, and the solution gradually turns yellow and thickens. After the dropwise addition, reflux for half an hour. Slowly add a solution of 21.43g (0.2mol) p-toluidine in acetone (50ml) dropwise, the rate of addition should make the solution slightly boil. After the dropwise addition, continue to reflux for half an hour and cool down.

[0197] The reaction solution was poured into 1.5L of water, stirred, and a yellow solid was precipitated. Suction filtration, the solid was dissolved in 30g NaOH aqueous solution (270ml), boiled for 5 minutes, cooled, and suction filtration to obtain 26.6g of solid (yield 80%).

[0198] Add 9.021g (0.054mol...

Embodiment 2

[0207] Embodiment 2, the preparation of N-methyl-2-(p-tolyl imino)-thiazol-4-one

[0208] NMR calibration: δH / C 7.26 / 77.0ppm (CDCl 3 ); δH / C 2.50 / 39.51ppm (DMSO-d 6 ).

[0209]

[0210] Add 1.4g (0.0191mol) CH 3 NCS, 2g (0.0187mol) of p-toluidine, 8ml of absolute ethanol, heated to reflux for 4 hours, cooled, crystallized, and suction filtered to obtain 2.92g of solid (yield 87%).

[0211] Add 2.92g (0.0162mol) N to a 100ml three-neck flask 1 -(p-tolyl)-N 2 - Methylthiourea, 4.60 g (0.0486 mol) of chloroacetic acid, 4 g (0.0486 mol) of sodium acetate, a small amount of TEBA, 100 ml of absolute ethanol. Heat to reflux overnight and filter while hot. The filter cake was washed twice with a small amount of absolute ethanol. The combined filtrates were concentrated to a small volume under reduced pressure. Cooling, crystallization, suction filtration, and drying to obtain 1.088 g of white-yellow solid (yield 30.5%).

[0212] 1 HNMR (300MHz, CDCl 3 ) δ 2.35 (s, 3H), 3...

Embodiment 3

[0229] Preparation of Example 3, 2-(p-tolylimino)-5-(2,4-dimethoxyphenylmethylene)-thiazol-4-one

[0230]

[0231]Add 1g (4.85mmol) 2-(p-tolylimino)-thiazol-4-one, 2.4g (14.55mmol) 2,4-dimethoxybenzaldehyde, 1.2g (14.55mmol) in 100ml one-port bottle Sodium acetate, 40ml glacial acetic acid, heated to reflux. The color of the reaction solution gradually deepened, and after reflux for 4 hours, cooling and crystallization occurred. After suction filtration, the filter cake was washed once with ethyl acetate and dried to obtain 0.8 g of orange solid (yield 46.6%).

[0232] 1 HNMR (300MHz, DMSO-d 6 )δ2.30(s, 3H), 3.34(s, NH), 3.80(s, 3H), 3.87(s, 3H), 6.65-6.73(m, 2H), 6.93-6.96(d, J=8.1Hz , 1H), 7.19-7.24 (t, J = 8.1 Hz, 3H), 7.39 (d, 1H), 7.65 (d, J = 8.1 Hz, 1H).

[0233] The following compounds were also synthesized by the above method:

[0234] 2-(p-tolylimino)-5-(p-N,N-dimethylaminophenylmethylene)-thiazol-4-one

[0235]

[0236] 1 HNMR (300MHz, DMSO-d 6 ) δ 2....

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Abstract

The invention provides a substituted five-member heterocyclic compound the formula of which is as follows and salt, ester, a solvate, a metal complex, or a prodrug with the same pharmacological effect thereof and an application as a glucagon-like peptide-1 receptor regulation agent being used for preventing and / or treating the diseases such as metabolic disorders (including but not limited to sugar diabetes, insulin resistance and adiposis), cardiovascular diseases, neurodegenerative diseases ( such as: Alzheimer's Disease, AD, also named: Alzheimer's dementia), etc.

Description

technical field [0001] The present invention relates to a class of substituted five-membered heterocyclic compounds and their use as glucagon-like peptide-1 receptor (GLP-1R) regulators to prevent and / or treat metabolic diseases (including but not limited to diabetes, insulin resistance and obesity), cardiovascular diseases and neurodegenerative diseases (such as "Alzheimer's Disease" (Alzheimer's Disease, AD), also known as Alzheimer's dementia (Alzheimer's dementia)], etc. medical use. Background technique [0002] Glucose metabolism disorder, especially diabetes, has become a major disease that seriously threatens human health and life in modern society. It is predicted that diabetes patients in the world are increasing at an annual rate of 6%, and by the end of 2006 there were 320 million patients (60 million people in my country, ranking second). Diabetes mellitus is a group of clinical syndromes caused by the interaction of genetic and environmental factors. It is ma...

Claims

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Application Information

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IPC IPC(8): C07D277/54C07D401/12C07D409/12A61K31/426A61K31/427A61P3/00A61P9/00A61P25/28C07D277/00C07D211/00C07D333/00
CPCC07D263/46C07D277/36C07D277/34C07D263/48C07D277/54C07D263/40C07D233/96C07D277/42C07D277/38A61P3/00A61P3/04A61P3/10A61P9/00A61P25/00A61P25/28
Inventor 王明伟刘青林黎琳张月云周玲孙美玲苏昊然滑玉林
Owner SHANGHAI INST OF MATERIA MEDICA CHINESE ACAD OF SCI
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