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Bcl-2 selective inhibitor, and preparation method and usage thereof

A technology selected from, CH2, applied in the direction of organic active ingredients, medical preparations containing active ingredients, organic chemistry, etc.

Inactive Publication Date: 2019-02-01
CENTAURUS BIOPHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Inhibitors with high activity to the target protein have been publicly reported in this field, but the lack of selectivity often brings serious side effects, such as inhibiting Bcl-XL (Andrew J Souers, Joel D Leverson, Erwin R Boghaert et al. Nature Medicine, 2013, 19, 202-210)

Method used

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  • Bcl-2 selective inhibitor, and preparation method and usage thereof
  • Bcl-2 selective inhibitor, and preparation method and usage thereof
  • Bcl-2 selective inhibitor, and preparation method and usage thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0120] Step A: 5-Bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine

[0121]

[0122] 5-Bromo-1H-pyrrolo[2,3-b]pyridine (3.94g) was dissolved in anhydrous THF (60mL), cooled to 0°C, and 1N LiHMDS solution in THF (2.2mL) was added, after 10 minutes, Triisopropylchlorosilane (4.24 g) was added, slowly raised to room temperature, and stirred for 40 hours. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the product (7.0 g).

[0123] 1 H NMR (400MHz, CDCl 3)δ8.27(d, J=2.4Hz, 1H), 7.98(d, J=2.4Hz, 1H), 7.31(d, J=3.6Hz, 1H), 6.49(d, J=3.6Hz, 1H) , 1.78~1.89 (m, 3H), 1.12 (d, J=7.6Hz, 18H).

[0124] Step B: Dimethyl (1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridin-5-yl)boronate

[0125]

[0126] Under nitrogen protection, 5-bromo-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (5.37g) was dissolved in an...

Embodiment 2

[0190] Step A: 1-Morpholinyl-2-(2-nitrophenyl)ethyl-1-one

[0191]

[0192] 2-(2-Nitrophenyl)acetic acid (9 g) was suspended in dichloromethane (100 mL), cooled to 0°C. N,N-Dimethylformamide (0.5 mL) was added, and oxalyl chloride (6.35 mL) was slowly added dropwise. After the dropwise addition was completed, return to room temperature and stir for 2 hours. It was then concentrated in vacuo to obtain an oil, which was dissolved in dichloromethane (20 mL) and dropped into a 0° C. dichloromethane solution (100 mL) containing morpholine (5.2 mL) and triethylamine (17 mL). After the dropwise addition, return to room temperature and react overnight. The reaction solution was poured into water, extracted with ethyl acetate, the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed to obtain a crude product. The product (10.7g) was obtained after washing with petroleum ether / dichloromethane.

[0193] ...

Embodiment 3

[0209] Step A: 6-Chloropyridyl-3-methanesulfonyl chloride

[0210]

[0211] 6-Chloropyridinyl-3-amine (1.77 g) was dissolved in concentrated hydrochloric acid (14 mL), and cooled to -5°C. Slowly add an aqueous solution (12 mL) of sodium nitrite (1.04 g) dropwise. During the dropwise addition, keep the temperature between -5°C and 0°C. After the dropwise addition, keep it below 0°C for later use.

[0212] Slowly add thionyl chloride (4.5mL) dropwise to water cooled to -3°C, keep the temperature below 7°C, return to room temperature after dropwise addition, add cuprous chloride (70mg), cool to -5°C ℃, add the previously prepared diazonium salt solution, stir for 30 minutes and then filter. The filter cake was dissolved in ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was removed to obtain the product (1.1g).

[0213] 1 H NMR (400MHz, CDCl 3 ) δ9.04 (d, J = 2.4 Hz, 1H), 8.25 ~ 8.28 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H).

[0214] Step B: 6-Chloropyridyl-3...

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Abstract

The invention relates to a compound as shown in the Formula (I), as well as pharmaceutically acceptable salts, solvates, polymorphs or pro-drugs thereof. The invention further relates to pharmaceutical compositions containing the compound as shown in the Formula (I), as well as usage of the pharmaceutical compositions in preparation of drugs used for treating diseases associated with expression ofanti-apoptotic Bcl-2 proteins.

Description

technical field [0001] The present invention relates to compounds that selectively inhibit the activity of Bcl-2 anti-apoptosis protein, and also relates to the preparation method, pharmaceutical composition and application of these compounds. Background technique [0002] Apoptosis plays an important role in ensuring the balance between cell proliferation and death in organisms. Disruption of this pathway leads to a variety of diseases. Anti-apoptotic Bcl-2 protein plays an important role in the regulation of apoptosis and is associated with many diseases. In various cancers and disorders of the immune system, overexpression of Bcl-2 protein is associated with resistance to chemotherapy, disease development Correlation with overall prognosis, there is therefore a need in the therapeutic field for active compounds that inhibit the anti-apoptotic protein Bcl-2. Patents WO2005049593 and WO2005024636 describe the relationship between Bcl-2 protein and the following cancers: b...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04A61K31/4545A61K31/5377A61K31/444A61P35/00A61P35/02
CPCC07D471/04
Inventor 王虎庭商现星何伟男张久庆胡远东朱岩张慧张淑远侯登刘琦超
Owner CENTAURUS BIOPHARMA
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