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3,5-disubstituted rhodanine anti-apoptotic protein bcl-2 inhibitor and its preparation method and application

An anti-apoptotic protein, rhodanine technology, applied in the field of medicine, can solve the problems of drug resistance, poor selectivity, and limited clinical application of drugs

Active Publication Date: 2017-06-16
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, clinical studies have found that the existing Bcl-2 inhibitors have many shortcomings, especially poor selectivity and drug resistance, which have greatly limited the clinical application of such drugs

Method used

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  • 3,5-disubstituted rhodanine anti-apoptotic protein bcl-2 inhibitor and its preparation method and application
  • 3,5-disubstituted rhodanine anti-apoptotic protein bcl-2 inhibitor and its preparation method and application
  • 3,5-disubstituted rhodanine anti-apoptotic protein bcl-2 inhibitor and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0105] Example 1. (Z)-4-[[4-[(3-phenyl-2-thio-4-thiazolidinedione-5-ylidene)methyl]phenoxy]methyl]benzoic acid Synthesis of (4AA)

[0106] Synthesis of 3-phenyl-2-thioxo-4-thiazolidinedione (2A)

[0107] Under ice-bath conditions, add 2mL of ethanol to aniline (1A, 0.93g, 10mmol) and triethylamine (5.05g, 50mmol), stir for 10 minutes, add carbon disulfide (1.52g, 20mmol) dropwise, and a light yellow solid precipitates out of the system. Filter and wash with ether. The obtained solid was added to 5 mL aqueous solution of sodium chloroacetate (1.28 g, 11 mmol), stirred until the solid was dissolved, added hydrochloric acid (6 mol / L, 14 mL), stirred at 85° C. for 0.5 hour, cooled, and filtered to obtain a pale yellow solid, which was washed with Chloroform recrystallization gave a pale yellow solid (1.60 g, 80%). M.p.: 195-197°C. 1 H NMR (600MHz, CDCl 3 )δ7.54 (td, J = 7.2Hz, 1.8Hz, 2H), 7.50 (tt, J = 7.2Hz, 1.8Hz, 1H), 7.20 (dt, J = 7.2Hz, 1.8Hz, 2H), 4.20 ( s,2H).

[010...

Embodiment 2

[0111] Example 2. (E)-3-[4-[[4-[(Z)-(3-phenyl-2-thio-4-thiazolidinedione-5-ylidene)methyl]phenoxy Synthesis of yl]methyl]phenyl]acrylic acid (4AB)

[0112] The preparation methods of intermediates and target compounds are as in Example 1. Yield 62%; m.p.>250°C; 1 H NMR (300MHz, DMSO-d 6 )δ12.42(s,1H),7.82(s,1H),7.73(d,J=8.1Hz,2H),7.68(d,J=9.0Hz,2H),7.55(m,6H),7.41( m,2H),7.23(d,J=9.0Hz,2H),6.55(d,J=16.2Hz,1H),5.27(s,2H).HRMS(AP-ESI)m / z calcd for C 26 h 19 NO 4 S 2 [M-H] - 472.0683,found 472.0663.

Embodiment 3

[0113] Example 3. (Z)-4-nitro-3-[[4-[(3-phenyl-2-thio-4-thiazolidinedione-5-ylidene)methyl]phenoxy] Synthesis of methyl]benzoic acid (4AC)

[0114] The preparation methods of intermediates and target compounds are as in Example 1. Yield 84%; m.p.229-230°C; 1 H NMR (400MHz, DMSO-d 6 )δ13.68(s,1H),8.31(d,J=1.6Hz,1H),8.25(d,J=8.4Hz,1H),8.14(dd,J=8.4Hz,1.6Hz,1H),7.83 (s,1H),7.70(d,J=8.8Hz,2H),7.58-7.52(m,3H),7.43-7.41(m,2H),7.26(d,J=8.8Hz,2H),5.62( s,2H).HRMS(AP-ESI)m / z calcd for C 24 h 16 N 2 o 6 S2 [M+H] + 493.0523,found 493.0531.

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PUM

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Abstract

The invention discloses a 3,5-disubstituted rhodanine anti-apoptosis protein Bc1-2 inhibitor as well as preparation method and an application thereof. The compound has a structure of a general formula I. The compound disclosed by the invention has high inhibitory activity on Bc1-2 and can be used for preparation of medicines for preventing or treating related mammal diseases caused by abnormal expression of anti-apoptosis protein Bc1-2. The invention also relates to a pharmaceutical application of a composition of the compound with the structure of the general formula I. The structural formula is as shown in the specification.

Description

technical field [0001] The invention relates to a 3,5-disubstituted rhodanine anti-apoptotic protein Bcl-2 inhibitor, a preparation method and application thereof, belonging to the technical field of medicine. 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. It can orderly eliminate unnecessary or damaged cells in the body, and plays an important role in embryonic development and maintaining cell homeostasis. Apoptosis is closely related to the occurrence of many human diseases. Excessive apoptosis will lead to stroke, heart failure, neurodegenerative diseases, etc., while inhibition of apoptosis is related to the occurrence of tumors and other diseases. Studies have found that the ability to escape apoptosis is one of the hallmarks of cancer cells. [0003] B-cell lymphoma / lymphoma-2 (Bcl-2) p...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D277/36C07D417/06A61K31/426A61K31/427A61P35/00A61P9/10A61P15/06A61P25/28A61P37/00A61P35/02
CPCC07D277/36C07D417/06
Inventor 方浩付焕生杨新颖徐文方易凡
Owner SHANDONG UNIV
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