Bcl-2 protein apoptosis inducer and application

A general formula, stereoisomer technology, applied in the field of immunity and autoimmune diseases, can solve the problem of reducing the efficacy of BCL-2 inhibitors

Pending Publication Date: 2022-05-13
HANGZHOU HERTZ PHARMA +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The G101V and D103Y mutations in the BCL-2 gene reduce the efficacy of BCL-2 inhibitors (Cancer Discov.2019, 9, 342-353)

Method used

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  • Bcl-2 protein apoptosis inducer and application
  • Bcl-2 protein apoptosis inducer and application
  • Bcl-2 protein apoptosis inducer and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0403] Example 1: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-4-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4] Oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (001)

[0404]

[0405] Step 1, Dissolve (S)-2-(2-bromophenyl)pyrrolidine-1-carboxylate tert-butyl ester (4.5 g) and isopropylboronic acid (3.1 g) in 15 mL of 1,4-epoxyhexa In the mixed solvent of ring and 3mL water, under nitrogen protection, add potassium carbonate (6g) and Pd(dffp) 2 Cl 2 (0.9g), heated to reflux overnight. TLC monitoring, after the reaction was completed, it was lowered to room temperature, ethyl acetate was added, washed with water and saturated brine respectively, the organic phase was separated and dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography to obtain the product (S)-tert-butyl 2-(2-isopropylph...

Embodiment 2

[0416] Example 2: (S)-3-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl) Pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4] Oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)pyridinamide (002)

[0417]

[0418] The synthetic method of parameter embodiment 1, replace methyl 2,4-difluorobenzoate with methyl 3,5-difluoropyridine-2-carboxylate, can synthesize target compound (S)-3-((1H- Pyrrolo[2,3-b]pyridin-5-yl)oxy)-5-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-azaspiro[ 3.5] Nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]-7- yl)sulfonyl)pyridinamide (90mg), LC-MS (ESI-MS): 833[M+H] + .

Embodiment 3

[0419] Example 3: (S)-2-((1H-pyrrolo[2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropyl ylphenyl)pyrrolidin-1-yl)-7-azaspiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][ 1,4]oxazine-3,1'-cyclopropane]-7-yl)sulfonyl)benzamide (003)

[0420]

[0421] The synthetic method of parameter embodiment 1, replace methyl 2,4-difluorobenzoate with methyl 2,3,4 trifluorobenzoate, can synthesize target compound (S)-2-((1H-pyrrolo [2,3-b]pyridin-5-yl)oxy)-3-fluoro-4-(2-(2-(2-isopropylphenyl)pyrrolidin-1-yl)-7-aza Spiro[3.5]nonan-7-yl)-N-((5-nitro-2H,4H-spiro[benzo[b][1,4]oxazine-3,1'-cyclopropane]- 7-yl)sulfonyl)benzamide (66mg), LC-MS (ESI-MS): 850[M+H] + .

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PUM

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Abstract

The invention discloses a Bcl-2 protein apoptosis inducer, and further discloses application of a compound and a pharmaceutical composition containing the compound in preparation of drugs for treating anti-apoptosis protein BCL-2 related diseases such as infectious diseases, immune diseases, inflammatory diseases and cell proliferation abnormality diseases. The compound provided by the invention has strong BCL2/BAK blocking activity, has strong inhibitory activity on BCL-2 (G101V) and BCL-2 (D103Y), and has strong proliferation inhibitory activity on mutant cell strains. The compound can be applied to treatment of infectious diseases, immune diseases, inflammatory diseases or abnormal cell proliferation and the like which benefit from inhibition of the anti-apoptotic protein BCL-2 alone or in combination with other medicines.

Description

technical field [0001] The present invention relates to a class of compounds or pharmaceutically acceptable salts capable of inhibiting anti-apoptotic B-cell lymphoma-2 (Bcl-2) family proteins, and as medicines for treating hyperproliferative diseases, such as cancer and inflammation, as well as immune and autoimmune diseases immune disease. Background technique [0002] Apoptosis is regulated through two distinct pathways, the extrinsic pathway and the intrinsic pathway. The outer pathway, mediated by cell surface death receptors, and the inner pathway involve B-cell lymphoma-2 (Bcl-2) family proteins. Bcl-2 family proteins include anti-apoptotic proteins such as BCL-2, BCL-XL and MCL-1, and pro-apoptotic proteins such as Bid, Bim, Bad, Bak and Bax. [0003] Antiapoptotic Bcl-2 family members were found to be upregulated in tumor cells and correlated with disease stage and prognosis. Therefore, Bcl-2 proteins are being studied as potential drug therapeutic targets, inclu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D471/04C07D519/00A61K31/5386A61K31/538A61K31/444A61K31/438A61K31/4545A61P35/00A61P13/08A61P11/06A61P9/10A61P19/02A61P37/06A61P25/28A61P1/18A61P29/00A61P1/00A61P17/06A61P17/00A61P11/00A61P9/00A61P9/14
CPCC07D471/04C07D519/00A61P35/00A61P13/08A61P11/06A61P9/10A61P19/02A61P37/06A61P25/28A61P1/18A61P29/00A61P1/00A61P17/06A61P17/00A61P11/00A61P9/00A61P9/14A61K31/444A61K31/438A61K31/4545A61K31/538A61K31/5386A61K31/496
Inventor 刘兴国苏明波吴一哲高安慧周星露钟利胡苗黄景来景杭辉金欣欣朱建荣
Owner HANGZHOU HERTZ PHARMA
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