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Amide compound and application thereof as TGR5 agonist

A compound and solvent compound technology, applied in the field of medicine, can solve problems such as 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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  • Amide compound and application thereof as TGR5 agonist
  • Amide compound and application thereof as TGR5 agonist
  • Amide compound and application thereof as TGR5 agonist

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0125] The present invention also provides the preparation method of above-mentioned compound:

[0126] Preparation method 1:

[0127]

[0128] Dissolve raw material 1 in an organic solvent, add an acid halide reagent and N,N-dimethylformamide at low temperature, continue the reaction after the addition is complete, dissolve the crude product in an organic solvent, add raw material 2 and a basic catalyst at low temperature, React at room temperature or under heating for several hours, concentrate, and separate by column chromatography to obtain the compound of formula (I).

[0129] Preparation method 2:

[0130]

[0131] Dissolve raw material 3 in an organic solvent, add raw material 2 and a basic catalyst at low temperature, react at room temperature or under heating for several hours, concentrate, and separate and purify by column chromatography to obtain the compound of formula (I).

[0132] Preparation method 3:

[0133]

[0134] Dissolve raw material 5 in an o...

experiment example 1

[0170] Experimental Example 1 The in vitro cell activity test of the compound of the present invention

[0171] Test product: compound 1, 2, 3, 4, 5 or 6 of the present invention, its chemical name and preparation method are shown in the preparation examples of each compound. The meanings represented by the abbreviations of the following experiments are as follows:

[0172] DMSO: dimethyl sulfoxide

[0173] GPBA: G protein-coupled bile acid receptor

[0174] CHO-K1: Chinese hamster ovary cell substrain

[0175] cAMP: cyclic adenosine monophosphate

[0176] homogeneous time-resolved fluorescence technique

[0177] experimental method:

[0178] 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) d...

Embodiment 1

[0194] Example 1 Preparation of 5-(2-chlorophenyl)-N-(4-chlorophenyl)-N,3-dimethylisothiazole-4-carboxamide

[0195]

[0196] 1) Preparation of 2-chlorobenzoyl chloride

[0197]

[0198] 2-Chlorobenzoic acid (5.0g, 31.9mmol) was dissolved in toluene (100mL), thionyl chloride (3.99g, 33.5mmol) was added under stirring condition, the temperature was raised to 75°C for 16 hours, and the title compound ( 5.58g, yield 100%).

[0199] 2) Preparation of ethyl 2-(2-chlorobenzoyl)-3-oxobutyrate

[0200]

[0201] Add ethyl acetoacetate (1.95mL, 15.4mmol) dropwise into petroleum ether (3.4mL), add 33% sodium hydroxide aqueous solution (0.7mL) under ice-cooling, and react at this temperature for 30 minutes. 2-Chlorobenzoyl chloride (3.36g, 19.2mmol) and 33% NaOH aqueous solution (3.6mL) were added dropwise to the system at the same time, stirred at 0°C for 1 hour, raised to 35°C to continue the reaction for 1 hour, and filtered , the filter cake was washed with petroleum ether...

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Abstract

Belonging to the technical field of medicine, the invention in particular relates to an amide TGR5 agonist compound shown as formula (I), its pharmaceutically acceptable salts, esters, stereoisomers, solvent compounds or prodrugs, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, X, Y, Z, and ring A are defined as the specification. The invention also relates to a preparation method of the compounds, pharmaceutical preparations, pharmaceutical compositions, and application of the compounds in preparation of drugs for treatment and / or prevention of TGR5 activity regulation related diseases. (formula (I)).

Description

[0001] 1. Technical field [0002] The present invention belongs to the technical field of medicine, and specifically relates to a TGR5 agonist compound, its pharmaceutically acceptable salt, its ester, its stereoisomer, its solvate or its prodrug; the present invention also relates to the preparation method of these compounds, The pharmaceutical preparation, the pharmaceutical composition and the application in preparation for treating and / or preventing diseases related to the regulation of TGR5 activity. [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...

Claims

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Application Information

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IPC IPC(8): C07D261/18C07D263/34C07D261/14C07D275/03C07D207/34A61K31/42A61K31/421A61K31/425A61K31/402A61K45/06A61P3/10A61P3/08A61P5/50A61P3/04A61P3/00A61P9/10A61P27/02A61P3/06A61P9/12A61P9/00A61P19/02A61P11/06A61P11/00A61P17/06A61P1/00A61P1/16A61P13/12A61P25/00A61P25/28A61P25/18
CPCC07D261/18C07D207/34C07D261/14C07D263/34C07D275/03
Inventor 吴永谦
Owner BEIJING SIHUAN PHARMA
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