Bcl-2 protein inhibitor and preparation method and application thereof

A technology represented by C3-C8, applied in the field of medicine, can solve the problems of failing to meet the needs of clinical application and prone to drug resistance

Active Publication Date: 2019-05-21
SHANDONG UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] So far, a variety of anti-apoptotic Bcl-2 protein inhibitors have been reported, but only Venetoclax (ABT-199) has been approved by the FDA, and most of them are still in preclinical and clinical research
Due to the complexity and diversity of apoptosis pathways, the existing Bcl-2 protein inhibitors cannot meet the needs of clinical application and are prone to drug resistance

Method used

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

Examples

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preparation example Construction

[0057] Two, the preparation method of Bcl-2 protein inhibitor

[0058] A method for preparing a Bcl-2 protein inhibitor, the steps comprising: the starting material L-tyrosine 1 undergoes dibromination to obtain an intermediate 2, and the intermediate 2 obtains a key intermediate 3 through a Pictet-Spengler reaction; the intermediate 3 Methylation, N-Boc protection gives intermediate 4; intermediate 4 hydrodebromination, O-alkylation and de-Boc protection give intermediates 5a and 5b, or only O-alkylation and de-Boc protection Intermediates 5c-5k are obtained; intermediates 5a-5k are N-alkylated to obtain 6a-6w; intermediates 6a-6w are hydrolyzed with methyl esters, and reacted with different benzenesulfonamides by mixed anhydride method to obtain compounds shown in B1-B30 .

[0059] The synthetic route is as follows:

[0060]

[0061] Among them, R 1 , R 2 , R 3 is as defined above;

[0062] Reagents and conditions: a) bromine, glacial acetic acid, room temperature; ...

Embodiment 1

[0102] Example 1. (S)-7-(benzyloxy)-N-((4-chloro-3-nitrophenyl)sulfonyl)-2-propyl-1,2,3,4-tetrahydro Synthesis of Isoquinoline-3-carboxamide (B1)

[0103] Synthesis of (S)-2-amino-3-(3,5-diiodo-4-hydroxyphenyl)propionic acid hydrobromide (2)

[0104] Dissolve 10.00 g of L-tyrosine in 100 mL of glacial acetic acid, slowly add 20 mL of glacial acetic acid solution containing 26.46 g of bromine dropwise, and react at room temperature for 4 hours; spin off the glacial acetic acid, and wash the crude product with ether to obtain 21.21 g of a white solid. Yield 96%. 1 H NMR (400MHz, DMSO-d 6 )δ13.94(s,1H),9.90(s,1H),8.25(s,3H),7.45(s,2H),4.23(t,J=6.0Hz,1H),3.06(dd,J=14.5 ,5.8Hz,1H),2.99(dd,J=14.5,6.9Hz,1H).

[0105] Synthesis of (S)-6,8-diiodo-7-hydroxyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate hydrochloride (3)

[0106] Dissolve 21.21g of compound 2 in 190mL of concentrated hydrochloric acid, add 15.5mL of ethylene glycol dimethyl ether and 5.90g of paraformaldehyde in seq...

Embodiment 2

[0118]Example 2. (S)-2-Benzyl-7-(benzyloxy)-N-((4-chloro-3-nitrophenyl)sulfonyl)-1,2,3,4-tetrahydro Synthesis of Isoquinoline-3-carboxamide (B2)

[0119] The preparation methods of intermediates and target compounds are as in Example 1. Yield 54%, mp: 176-178°C. 1 H NMR (400MHz, DMSO-d 6 )δ9.99(s,1H),8.34(d,J=1.7Hz,1H),8.04–7.88(m,1H),7.83(d,J=8.4Hz,1H),7.52–7.24(m,10H ),7.17(d,J=8.1Hz,1H),6.99–6.80(m,2H),5.07(s,2H),4.34(d,J=12.7Hz,1H),4.20(s,2H),4.18 –4.07(m,1H),4.07–3.90(m,1H),3.23(dd,J=17.0,5.5Hz,1H),3.11(dd,J=17.0,8.8Hz,1H).HRMS(AP-ESI )m / z Calcd for C 30 h 26 ClN 3 o 6 S[M-H] - 590.1153,found:590.1160.

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Abstract

The invention relates to a Bcl-2 protein inhibitor and a preparation method and application thereof, in particular to a compound as shown in a formula (I), a stereisomer or pharmaceutically acceptablesalt thereof, a preparation method of the compounds, a pharmaceutical preparation containing the compounds and application of the compounds, the stereisomer or the pharmaceutically acceptable salt thereof in preparing drugs for preventing / or treating related mammal diseases induced by abnormal expression of a Bcl-2 protein. The formula is as shown in the description.

Description

technical field [0001] The invention relates to a Bcl-2 protein inhibitor, a preparation method thereof, a pharmaceutical composition and a medical application, belonging to the technical field of medicine. Background technique [0002] B-cell lymphoma / leukemia-2 (B-cell leukemina / lymphoma-2, Bcl-2) family proteins are key regulators of the endogenous mitochondrial-mediated apoptosis pathway in mammals. The members of this family that have been discovered so far can be divided into anti-apoptotic proteins (Bcl-2, Bcl-X) according to the differences in function and structure. L and Mcl-1, etc.), multi-domain pro-apoptotic proteins (BAX and BAK), and pro-apoptotic BH3-only proteins (Bad, Bid, Bim, Puma, and NOXA, etc.). [0003] The mitochondrial-mediated endogenous apoptotic pathway is triggered by endogenous stimuli such as genetic damage, hypoxia, and high cytoplasmic calcium ion concentration. When the cells receive the above-mentioned apoptotic stimulation, the pro-apop...

Claims

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Application Information

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IPC IPC(8): C07D217/26A61P35/00A61P35/02A61P25/00A61P25/28A61P31/12A61P29/00A61P33/06A61P3/10A61K31/472A61K31/635
CPCY02A50/30
Inventor 方浩刘仁帅刘璐璐杨新颖
Owner SHANDONG UNIV
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