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Benzo oxygen-containing heterocyclic compound and medical application thereof

A technology of compounds and hydrates, applied in the field of novel benzoxygen-containing heterocyclic compounds, can solve problems such as liver toxicity and unsafe molecular structure design, and achieve lower blood sugar levels, lower risk of hypoglycemia, good selectivity and safety effect

Pending Publication Date: 2022-03-11
SHANGHAI AB PHARMATECH LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although TAK-875 showed good curative effect, due to the hepatotoxicity caused by its drug, Takeda Corporation of Japan terminated its clinical research in 2013
It is worth mentioning that the study of TAK-875 hepatotoxicity has nothing to do with the mechanism of action of the drug, but is mainly caused by the unsafe design of its molecular structure

Method used

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  • Benzo oxygen-containing heterocyclic compound and medical application thereof
  • Benzo oxygen-containing heterocyclic compound and medical application thereof
  • Benzo oxygen-containing heterocyclic compound and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0249] Synthesis of Compound IIa-1

[0250] The first step: raw materials RM-Ia-1 (0.052g, 0.24mmol.), SM1-1 (0.050g, 0.24mmol, 1.0eq.) and PPh3 (0.126g, 0.48mmol, 2eq.) were dissolved in 2L In THF, under nitrogen protection, under cooling in an ice-water bath, add DIAD (0.097g, 0.48mmol, 2eq.) while stirring. After the addition, stir in an ice-water bath for 1h at 20-30°C, react overnight, and the reaction is complete. After HPLC showed that the reaction was finished, the reaction solution was cooled to room temperature, water was added, DCM was added to extract, and the organic phases were combined, washed with brine, dried, and concentrated to obtain a crude product; the crude product was separated by a TLC scraper to obtain an intermediate product RM-IIa-1 (0.029g);

[0251] Confirmed by mass spectrometry, the ESI-MS [(M+H) of RM-IIa-1 + ]: m / z theoretical value 405.0, measured value 405.0.

[0252] The second step: add MeOH (2mL) to the intermediate product RM-IIa-1 (0...

Embodiment 2

[0255] Synthesis of Compound IIa-2

[0256] The synthetic method for preparing compound IIa-2 is the same as in Example 1, and the product IIa-2 is obtained through two steps of etherification and hydrolysis, wherein compound RM-Ia-2 (0.23 mmol) is used in the reaction instead of compound RM-Ia-4 The intermediate RM-IIa-2 was obtained, and the light yellow solid product IIa-2 (0.016g) was obtained by hydrolysis of the intermediate, the two-step yield: 17.8%.

[0257]Confirmed by mass spectrometry, ESI-MS of IIa-2 [(M-H) + ]: m / z theoretical value 389.0, measured value 389.0.

Embodiment 3

[0259] Synthesis of Compound IIa-3

[0260] The synthetic method for preparing compound IIa-3 is the same as in Example 1, and the product IIa-3 is obtained through two-step reaction of etherification and hydrolysis, wherein compound RM-Ia-3 (0.24mmol) is used to replace compound RM-Ia-4 in the reaction The intermediate RM-IIa-3 was obtained, and the product IIa-3 (0.030g) was obtained as a light yellow solid by hydrolysis of the intermediate, and the two-step yield: 32%.

[0261] Confirmed by mass spectrometry, ESI-MS of IIa-3 [(M-H) + ]: m / z theoretical value 389.0, measured value 389.0.

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PUM

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Abstract

The invention discloses a compound as shown in a formula Ia or IIa, cis-trans isomers, enantiomers, diastereoisomers, racemes, tautomers, solvates, hydrates or pharmaceutically acceptable salts of the compound or a mixture of the cis-trans isomers, the enantiomers, the diastereoisomers, the racemes, the tautomers, the solvates, the hydrates and the pharmaceutically acceptable salts, a pharmaceutical composition containing the compound and application of the compound as a GPR40 agonist. Wherein n, E, E1, R1, R2, R3, R4, R5, R5b, R6, R7, Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, X1, X2, X3, X4, Y, Y1 and possible isotope substitution markers of all elements in the compound are defined in the specification.

Description

technical field [0001] The present invention relates to a novel benzo-oxygen-containing heterocyclic compound, especially a benzo-penta-membered oxygen-containing heterocyclic compound. The compound can be used as an agonist of the GPR40 target, and can lower blood sugar by stimulating pancreatic beta cells to release insulin Level, safe and effective treatment of diseases such as type II diabetes. Background technique [0002] Diabetes mellitus is a chronic endocrine and metabolic disease characterized by hyperglycemia caused by defects in insulin secretion, insulin resistance, or both. Diabetes can severely damage every major organ system in the body, causing heart disease, stroke, nerve damage, kidney failure, blindness, and infections that can lead to amputation. The disease has many complications and high rates of disability and death. [0003] Type 2 diabetes, which accounts for about 90 percent of all diabetes cases, usually produces its own insulin, but does not pro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D307/83C07D407/12A61P3/10A61P3/00A61K31/343A61K31/353A61K31/5377
CPCC07D307/83C07D407/12A61P3/10A61P3/00A61K31/343A61K31/353A61K31/5377C07D491/048A61K31/216A61K31/428A61K31/192C07D491/052
Inventor 詹正云
Owner SHANGHAI AB PHARMATECH LTD
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