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Heteroaryl amide derivative and use thereof as TGR5 agonist

A heteroaryl and heterocyclic group technology, applied in the direction of medical preparations containing active ingredients, drug combinations, digestive system, etc., can solve the problems of weakening GLP-1 secretion and increasing blood sugar levels

Inactive Publication Date: 2017-01-11
BEIJING SIHUAN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Studies have shown that type 2 diabetes will weaken the secretion of GLP-1, thereby increasing the blood sugar level in the body, and GLP-1 is a peptide compound that cannot be taken orally, thus greatly inhibiting its clinical application

Method used

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  • Heteroaryl amide derivative and use thereof as TGR5 agonist
  • Heteroaryl amide derivative and use thereof as TGR5 agonist
  • Heteroaryl amide derivative and use thereof as TGR5 agonist

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0115] The present invention also provides the preparation method of above-mentioned compound:

[0116] 1. Preparation of intermediate 1:

[0117] (1) When Y is an oxygen atom,

[0118]

[0119] Dissolve raw material 1, raw material 2, basic catalyst, and Cu(I) in an aprotic solvent, heat until the reaction is complete, cool to room temperature, filter, add water and an organic solvent (such as ethyl acetate, dichloromethane), Separate the liquid, wash the organic phase with a saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, concentrate, and purify by column chromatography to obtain an intermediate product, which is then subjected to a conventional deesterification reaction to obtain intermediate 1.

[0120] In this reaction, R' is selected from C 1-6 Alkyl, preferably C 1-4 alkyl, X is halogen; the Cu(I) source refers to copper(I) salts such as copper(I) bromide and copper(I) iodide or copper(I) which are typically more soluble in o...

experiment example 1

[0173] Experimental example 1 In vitro cell activity test of the compound of the present invention

[0174] Test product: Compounds 1, 2, 3, 4 and 5 of the present invention, see the preparation examples of each compound for their chemical names and preparation methods.

[0175] The meanings represented by the abbreviations of the following experiments are as follows:

[0176] DMSO: dimethyl sulfoxide

[0177] GPBA: G protein-coupled bile acid receptor

[0178] CHO-K1: Chinese hamster ovary cell substrain

[0179] cAMP: cyclic adenosine monophosphate

[0180] homogeneous time-resolved fluorescence technique

[0181] Kit detection principle: Cyclic AMP assay kit is based on homogeneous time-resolved fluorescence technology ( ), intended to directly quantify the content of cyclic AMP in suspension or adherent cells. The detection method is based on the existence of competitive immunobinding between cAMP produced by cells and d2 (energy acceptor) dye-labeled cAMP and...

Embodiment 1

[0206] Example 1 Preparation of (5-(2,5-dichlorophenoxy)pyrimidin-4-yl)(4-methyl-3,4-dihydroquinoxalin-1(2H)-yl)methanone

[0207]

[0208] 1) Preparation of 5-bromopyrimidine-4-formyl chloride

[0209]

[0210] Dissolve 5-bromopyrimidine-4-carboxylic acid (0.6g, 2.96mmol) in thionyl chloride (10mL), add N,N-dimethylformamide (0.05mL), heat to 90°C and stir for 3 hours . The reaction solution was concentrated to dryness, added toluene (10 mL), and concentrated to dryness again, and the obtained crude product was directly used in the next reaction.

[0211] 2) Preparation of methyl 5-bromopyrimidine-4-carboxylate

[0212]

[0213] 5-Bromopyrimidine-4-carbonyl chloride (0.65 g, 2.94 mmol) obtained in the previous step was dissolved in anhydrous methanol (10 mL), and stirred at 25°C for 16 hours. The reaction solution was concentrated to dryness, and the obtained crude product was washed with petroleum ether to obtain the title compound (0.58g, yield 90.6%)

[0214] ...

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Abstract

The invention belongs to the technical field of medicines, and in particular relates to a heteroaryl amide TGR5 agonist compound represented by formula (I) and pharmaceutically acceptable salts, esters, stereoisomers or prodrugs thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X1, X2, X3 and Y are as defined in the specification; the invention also relates to preparing methods, pharmaceutical formulations, pharmaceutical compositions and use in preparation of medicines for treatment and / or prevention of diseases related to TGR5 activity regulation of the heteroaryl amide TGR5 agonist compound and the pharmaceutically acceptable salts, esters, stereoisomers or prodrugs thereof.

Description

[0001] 1. Technical field [0002] The present invention belongs to the technical field of medicine, and in particular relates to a TGR5 agonist compound, its pharmaceutically acceptable salt, its ester, its stereoisomer or prodrug; The composition and its use in preparation for treating and / or preventing diseases related to TGR5 activity regulation. [0003] 2. Background technology [0004] At present, diabetes is in a period of rapid growth in the world. The number of people directly affected by diabetes in the world exceeds 250 million, accounting for 6% of the world's population, and another 318 million people suffer from insufficient glucose metabolism. my country has become one of the countries with the fastest growing prevalence of diabetes in the world. At present, there are about 40 million diabetic patients and those with impaired glucose tolerance. The number of patients is second only to India, ranking second in the world. Diabetes requires lifelong monitoring and ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D401/06A61K31/506A61K31/498A61P3/10A61P3/08A61P5/50A61P3/04A61P3/00A61P9/10A61P27/02A61P3/06A61P9/12A61P9/00A61P19/02A61P11/06A61P11/00A61P17/06A61P1/04A61P1/00A61P1/16A61P13/12A61P25/28A61P25/00A61P25/18
CPCC07D403/06C07D401/06
Inventor 吴永谦
Owner BEIJING SIHUAN PHARMA
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