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Benzo oxygen-containing heterocyclic compound and medical application thereof

A compound and hydrate technology, applied in the directions of heterocyclic compound active ingredients, anhydride/acid/halide active ingredients, drug combinations, etc., can solve the problems of insufficient molecular structure design, liver toxicity, etc., and reduce the risk of hypoglycemia , lowering blood sugar levels, good selectivity and safety

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 research on 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

[0253] Synthesis of Compound IIb-1

[0254] The synthetic reaction is as following general formula one:

[0255]

[0256] first step:

[0257] The raw materials RM-Ib-1 (0.051g, 0.24mmol) and SM1-1 (0.050g, 0.24mmol, 1.0eq.) were dissolved in 2mL of DMF, and potassium carbonate (0.050g, 0.36mmol, 1.5eq .), under the protection of nitrogen, heated to 90 degrees, reacted overnight, and the reaction was completed. After HPLC showed that the reaction was completed, the reaction solution was cooled to room temperature, water was added, ethyl acetate was added to extract, and the organic phases were combined, washed with brine, dried, and concentrated to give intermediate RM-IIb-1 (0.1g).

[0258] Confirmed by mass spectrometry, the ESI-MS [(M+H) of RM-IIb-1 + ]: The theoretical value of m / z is 343.1, and the measured value is 343.0.

[0259] Step two:

[0260] Add MeOH (2mL), THF (1mL) and LiOH aqueous solution (1N, 1mL) successively to the intermediate RM-IIb-1, stir at room...

Embodiment 2

[0264] Synthesis of Compound IIb-2

[0265] The synthetic reaction is as following general formula two:

[0266]

[0267] first step:

[0268] Starting materials RM-Ib-2 (0.043g, 0.19mmol), SM1-1 (0.039g, 0.19mmol, 1.0eq.) and PPh 3 (0.146g, 0.56mmol, 3eq.) was dissolved in 4mL of THF, under nitrogen protection, under cooling in an ice-water bath, DIAD (0.113g, 0.56mmol, 3eq.) was added during stirring, and after the addition was completed, stirred in an ice-water bath for 1h, 20- 30 degrees, react overnight, the reaction is complete. After HPLC showed that the reaction was finished, the reaction liquid 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 with a TLC scraper to obtain intermediate RM-IIb-2.

[0269] Confirmed by mass spectrometry, the ESI-MS [(M+H) of RM-IIb-2 + ]: m / z theoretical value 421.0, m...

Embodiment 3

[0275] Synthesis of compound IIb-3

[0276] The synthetic method for preparing compound IIb-3 is the same as in Example 1, and the product IIb-3 is obtained through etherification and hydrolysis, wherein compound RM-Ib-3 (0.48mmol) is used in the reaction instead of compound RM-Ib-1 to obtain intermediate Body RM-IIb-3, the white solid product IIb-3 (0.039g) was obtained by hydrolysis of the intermediate, two-step yield: 20%.

[0277] Confirmed by mass spectrometry, ESI-MS of IIb-3 [(M-H) + ]: m / z theoretical value 405.0, measured value 404.8.

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Abstract

The invention discloses a compound as shown in a formula Ib or IIb, cis-trans isomers, enantiomers, diastereoisomers, racemes, tautomers, solvates, hydrates or pharmaceutically acceptable salts 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, L1, R1, R2, R3, R4, R5, R5b, Ra, Rb, Rc, Rd, Re, Rf, Rg, Ri, Rj, X5, X6, Y, Y1, Z 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 seriously 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 accounts for about 90% of all diabetes cases, and patients are usually able to produce their own insulin, but...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D407/12C07D317/62C07D317/66C07D317/50A61K31/36A61P3/10
CPCC07D407/12C07D317/62C07D317/66C07D317/50A61P3/10A61P3/08C07D317/54A61K31/36
Inventor 詹正云
Owner SHANGHAI AB PHARMATECH LTD
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