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Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof

A protein inhibitor, bcl-2 technology, applied in the field of medicine, can solve the problems of tumor cell apoptosis, affect the effect of tumor treatment, and produce drug resistance

Active Publication Date: 2015-12-30
SHANDONG UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0005] At present, there are about five types of Bcl-2 inhibitors, most of which have been in clinical research, such as Gossypol is in Phase I / II clinical trials, etc., but after clinical research, it has been found that due to the diversity of apoptosis pathways, some inhibitors still cannot be used. Tumor cells undergo apoptosis, which affects the therapeutic effect of tumors and produces drug resistance, which greatly limits the clinical application of such drugs

Method used

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  • Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof
  • Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof
  • Substituted3-indole Bcl-2 protein inhibitor and preparation method and application thereof

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preparation example Construction

[0084] The preparation method of the substituted 3-indole Bcl-2 inhibitor is one of the following four synthetic routes:

[0085] Synthetic route 1: 3-indole carboxylate methyl ester reacts with p-bromobromobian to obtain intermediate 2A, 2A reacts with various substituted phenylboronic acids to obtain intermediate 3B-3E, and then 3B-3E is desorbed under alkaline conditions. Methyl esters to obtain intermediates 4B-4E, various substituted amino acids 5A-5G, and various substituted benzenesulfonamides through amide condensation reactions to obtain intermediates 7A-7K, then de-Boc to obtain 8A-8K, and finally the important intermediate 4B The target products 10-27, 29-30, 32, 34, 36-37 were obtained by amide condensation reaction between -4E and 8A-8K.

[0086] Synthetic route one:

[0087]

[0088] Synthetic route 2: various substituted amino acids 5A-5G, and various substituted benzenesulfonamides 6A-6D through amide condensation reaction to obtain intermediates 7A-7K, the...

Embodiment 1

[0117] Synthesis of Example 1.1-(4-bromobenzyl)-1H-indole-3-methyl carboxylate (2A)

[0118] Compound 0.7g 1H-indole-3-carboxylic acid methyl ester 1A was dissolved in 20mL DMSO, and 1.1g K 2 CO 3 Stir at 30°C, slowly drop 1.88g of p-bromobromide in DMSO solution, and react overnight. After the reaction, 5 times the volume of water was added, followed by extraction with ethyl acetate, drying over magnesium sulfate, concentration, and column chromatography (P / E=30:1) to obtain a white product (1.1 g, 80%). m.p.117-119°C; 1 H-NMR (400MHz, DMSO-d 6 ),δ8.58(s,1H),8.03-8.01(m,1H),7.72-7.41(m,3H),7.24-7.20(m,4H),5.50(s,2H),3.81(s,3H ).

[0119] Synthesis of 1–((4'-chloro–[1,1'-biphenyl]-4-yl)methyl)-1H-indole-3-carboxylic acid methyl ester (3B)

[0120] Put compound 0.69g2A, 0.004g palladium acetate, 0.016g triphenylphosphine, 0.25g sodium carbonate, 0.33g p-chlorophenylboronic acid into a two-necked flask, add 25mLDMSO, and use N 2 Stir at 80°C after protecting the vacuum. A...

Embodiment 2

[0128] Example 2. (S)-N-((4-chloro-3-nitrophenyl)sulfonyl)-2-(2-(1-(4-chlorophenylcarbonyl)-5-methoxy- Synthesis of 2-methyl-2-methyl-1H-indol-3-yl)acetyl)-3-(4-(4-nitrobenzyloxy)phenyl)propanamide (33)

[0129] Dissolve the compound 0.36g4H in 30mL of dichloromethane, add 0.39gDIEA under ice-cooling, add 0.46gHATU after 10 minutes, turn to room temperature and stir, add 0.46g8F after half an hour, stir overnight, after the reaction is complete, spin off the dichloromethane, Extracted with ethyl acetate, washed with citric acid, dried over anhydrous magnesium sulfate, concentrated and column chromatography (P / E=1:1) gave a light yellow solid (0.25g, 23%), m.p.122-124°C; 1 H-NMR (400MHz, DMSO-d 6 ), δ12.83(s, 1H), 8.53(d, J=2.0Hz, 1H), 8.34(d, J=6.8Hz, 1H), 8.26(d, J=6.8Hz, 1H), 8.13(dd ,J 1 =8.8Hz,J 2=2.0Hz,2H),7.80(d,J=8.4Hz),7.72-7.59(m,5H),7.05(d,J=8.4Hz,1H),6.92(d,J=8.4Hz,1H), 6.76-6.67(m,3H),5.33-5.13(m,2H),4.46-4.41(m,1H),3.90(s,3H),3.53-3.45(m,3H),2.91(dd,J 1 =13....

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Abstract

The invention discloses a substituted3-indole Bcl-2 protein inhibitor and a preparation method and an application thereof. The compound has a structure as shown in the general formula I or II. The compound of the invention has a strong inhibitory activity to Bcl-2 protein and can prevent or treat related mammalian diseases caused by abnormal expression of Bcl-2 protein. The invention also relates to a pharmaceutical application of a compound of the compound having the structure as shown in the general formula I or II.

Description

technical field [0001] The invention relates to a substituted 3-indole Bcl-2 protein inhibitor and its preparation, pharmaceutical composition and medical application, belonging to the technical field of medicine. Background technique [0002] B-cell lymphoma / leukemia-2 (B-cellleukemia / lymphoma-2, Bcl-2) protein family is an important regulatory factor in the endogenous pathway of apoptosis and plays an important regulatory role in the pathway of apoptosis. According to the difference in structure and function, the Bcl-2 protein family can be divided into anti-apoptotic family proteins and pro-apoptotic family proteins. In normal cells, the heterodimerization of pro-apoptotic family proteins and anti-apoptotic family proteins keeps the cells in a normal growth state, avoiding premature apoptosis of cells and preventing cells from transforming into tumor cells due to non-apoptosis . However, in some malignant tumors, anti-apoptotic protein members of the Bcl-2 protein famil...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/42C07D209/18A61K31/404A61P35/00A61P25/00A61P31/12A61P29/00A61P3/10A61P33/06
CPCC07D209/18C07D209/42Y02A50/30
Inventor 方浩刘婷婷万义超杨新颖徐文方
Owner SHANDONG UNIV
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