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Anti-apoptotic protein Bcl-2 inhibitor and preparation method and application thereof

A technology for selecting and compounding compounds, which is applied in the direction of antineoplastic drugs, pharmaceutical formulations, medical preparations containing active ingredients, etc., and can solve the problems of drug clinical application limitations, drug resistance, poor selectivity, etc.

Active Publication Date: 2021-09-28
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical studies have found that there are still many shortcomings in the existing Bcl-2 inhibitors, especially the poor selectivity and the generation of drug resistance, which cause the clinical application of this class of drugs to be greatly limited

Method used

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  • Anti-apoptotic protein Bcl-2 inhibitor and preparation method and application thereof
  • Anti-apoptotic protein Bcl-2 inhibitor and preparation method and application thereof
  • Anti-apoptotic protein Bcl-2 inhibitor and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0101] The preparation of embodiment 1 compound Bcl-003

[0102]

[0103] Under argon protection, add raw materials benzo[d]thiazol-6-ol X-3 (10g, 66.14mmol), 2,4-difluorobenzoic acid methyl ester II-3 (13.7g, 79.37mmol) and potassium phosphate (21.1g, 99.21mmol), dissolved in 70mL diethylene glycol dimethyl ether, heated to 115°C with stirring, and reacted at this temperature for 24 hours. After naturally cooling to room temperature, the reaction solution was diluted with 300 mL of ethyl acetate, washed with water (200 mL×2), saturated aqueous sodium chloride solution (200 mL×2), dried over anhydrous sodium sulfate, and removed by rotary evaporation. Chromatography gave Intermediate III-3: 6g, yield: 30%. 1 H NMR (400MHz, CDCl 3 )δ8.93 (s, 1H), 8.11 (d, J = 8.9Hz, 1H), 8.00 (dd, J = 8.8, 6.6Hz, 1H), 7.51 (d, J = 2.4Hz, 1H), 7.23 ( dd, J=8.9, 2.4Hz, 1H), 6.91(ddd, J=8.8, 7.6, 2.5Hz, 1H), 6.67(dd, J=9.8, 2.5Hz, 1H), 3.82(s, 3H); ESI -MS m / z 304.0(M+H) + .

[0104] Usin...

Embodiment 2

[0160] The preparation of embodiment 2 compound Bcl-006

[0161]

[0162] Compound Bcl-003 (30mg, 0.034mmol) was dissolved in 2mL of anhydrous 1,4-dioxane solvent, Lawsson's reagent (27mg, 0.068mmol) was added at room temperature, and the reaction temperature was raised to 85°C, react under stirring for 6 hours, stop heating and cool to room temperature, dilute the reaction solution with 20mL ethyl acetate, wash with water (15mL×2), saturated aqueous sodium chloride solution (15mL×2), and anhydrous sulfuric acid Dry over sodium, remove the solvent by rotary evaporation, and flash column chromatography to obtain the final product Bcl-006: 12 mg, yield: 40%, yellow solid. 1 H NMR (400MHz, CDCl 3)δ9.00(s,1H),8.75(d,J=2.2Hz,1H),8.46(t,J=5.3Hz,1H),8.29 (d,J=9.3Hz,1H),8.16(d, J=8.9Hz, 1H), 7.74(dd, J=9.2, 2.0Hz, 1H), 7.52(d, J=2.3Hz, 1H), 7.29(dd, J=8.9, 2.4Hz, 1H), 7.24( d,J=8.3Hz,2H),6.92(d,J=8.3Hz,2H), 6.60(dd,J=13.8,5.7Hz,2H),6.12(d,J=2.3Hz,1H),4.02( dd,J=11.5,3.6Hz,2H), ...

Embodiment 3

[0166] Preparation of Example 3 Compound Bcl-051

[0167]

[0168] Take II-51 (5.0g, 24.88mmol) and IV-3 (8.3g, 26.12mmol) as raw materials, mix them with dipotassium hydrogen phosphate (5.2g, 29.87mmol) in a 250mL reaction flask, and protect them under argon Add 60 mL of anhydrous dimethyl sulfoxide. The reaction solution was placed in an oil bath preheated to 80°C for 6 hours, then the heating was stopped and the reaction was cooled to room temperature. The reaction solution was diluted with 200 mL of ethyl acetate, and water (150 mL×2) and saturated aqueous sodium chloride ( 150mL×2) washed, then dried over anhydrous sodium sulfate, the solvent was removed by rotary evaporation, and the product VII-51 was obtained by flash column chromatography: 11.8g, yield: 95%. ESI-MS m / z 501.0(M+H) + .

[0169] VII-51 (5.0g, 10mmol) obtained in the above step was used as raw material, and X-51 (2.78g, 10.5mmol), Cs 2 CO 3 (3.51g, 10.76mmol) mixed and dissolved in 40mL NMP solven...

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Abstract

The invention provides an anti-apoptotic protein Bcl-2 inhibitor and a preparation method and application thereof, and particularly provides a compound as shown in a formula (I), or an optical isomer, a tautomer or a pharmaceutically acceptable salt thereof. The compound has excellent Bcl-2 inhibitory activity, so that the compound can be used for treating or preventing related mammalian diseases or symptoms caused by abnormal expression of anti-apoptotic protein Bcl-2.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and medicine, and relates to a novel active compound capable of inhibiting anti-apoptotic (anti-apoptotic) Bcl-2 protein and its preparation method and application. Background technique [0002] Apoptosis, also known as programmed cell death, is a programmed suicide death process triggered by internal or external stimuli. Apoptosis is a precisely controlled cell death mechanism in organisms, which can orderly eliminate unnecessary or damaged cells in the body, and plays an important role in embryonic development and maintenance of cell homeostasis. Apoptosis is closely related to the occurrence of many human diseases, and inhibition of apoptosis is related to the occurrence of diseases such as tumors. Studies have found that the ability to escape apoptosis is one of the important signs of cancer cells. [0003] Bcl-2 family proteins are the most important molecular targets for antago...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07D471/04C07D417/12C07D417/14C07D405/14A61K31/63A61P35/00A61P35/02
CPCC07D405/12C07D471/04C07D417/12C07D417/14C07D405/14A61P35/00A61P35/02
Inventor 马大为李征王开亮夏尚华甘露邓乾亚俞强
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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