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Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application

A technology for BCL-2 and inhibitors, which is applied in the field of drugs for synthesizing Bcl-2/BCL-XL anti-apoptotic protein inhibitors, and can solve the problems of increasing drug doses, etc.

Active Publication Date: 2020-10-30
长沙创新药物工业技术研究院有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

It is precisely because cancer cells can use the pro-survival protein BCL-2 / BCL-XL to inhibit the therapeutic effect of traditional chemotherapy, which makes clinical doctors have to increase the dose of drugs again and again, which leads to nausea, hair loss, etc. chemotherapy side effects

Method used

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  • Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application
  • Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application
  • Novel BCL-2/BCL-XL inhibitor, pharmaceutical composition and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Synthesis of compound (I)

[0047] The synthetic process is shown in reaction scheme 1

[0048]

[0049] Refer to the relevant intermediate 5a of the reference in the prior art ("BCL-2 Selective Inhibitor--Synthetic Process Improvement of ABT-199" Xu Yunlei et al., "Synthetic Chemistry", Volume 23, Issue 11, 1063-1067) and the synthesis of intermediate 9a. Intermediates 1a, 3a, 4a, 5a, 7a, 8a, and 9a can refer to prior art references ("BCL-2 Selective Inhibitor--Synthetic Process Improvement of ABT-199" Xu Yunlei et al., "Synthetic Chemistry", Volume 23 Issue 11, 1063-1067) Synthesis.

[0050] Synthesis of Intermediate Compound 1a

[0051] Add 333g (832mmol) of sodium hydride, 186g (2.06mol) of dimethyl carbonate and 880mL of tetrahydrofuran into a round-bottomed flask equipped with a magnetic stirrer, a condenser and an inert gas source, and stir to dissolve; add the raw materials dropwise at (60°C) Compound 0a39g (396mmol) was dissolved in 440mL of tetrahydrofu...

Embodiment 2

[0073] The synthesis of embodiment 2 compound II

[0074] The synthetic process is shown in reaction scheme 2

[0075]

[0076] The synthesis of intermediate compound 11a is shown in Example 1.

[0077] Synthesis of Compound II

[0078] Add 50 mL of an aqueous solution containing 0.8 g (20 mmol) of sodium hydroxide in a round bottom flask equipped with a magnetic stirrer, then add 3.72 g (10 mmol) of compound 11a and compound 5b 2.55g (10mmol), stirred overnight at room temperature, and monitored the reaction by TLC. Extract with dichloromethane (2×100mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography [eluent: petroleum ether / ethyl acetate=5 / 1] to obtain (compound II) 4.72g, yield 80%. Its NMR see attached Figure 9 . LCMS [M+H]: 591.2. 1 H NMR (400MHz, Chloroform) δ8.28(d,1H), 7.79(s,1H),7.59(m,1H),7.41-7.45(...

Embodiment 3

[0079] The synthesis of embodiment 3 compound III

[0080] The synthetic process is shown in reaction scheme 3

[0081]

[0082] The synthesis of intermediate compound 11a is shown in Example 1.

[0083] Synthesis of Compound III

[0084] Add 50 mL of an aqueous solution containing 0.8 g (20 mmol) of sodium hydroxide in a round bottom flask equipped with a magnetic stirrer, then add 3.72 g (10 mmol) of compound 11a and compound 5c 2.15 g (10 mmol), stirred overnight at room temperature, and monitored the reaction by TLC. Extract with dichloromethane (2×100mL), combine the organic phases, wash with saturated brine successively, dry over anhydrous sodium sulfate, concentrate under reduced pressure, and the residue is subjected to silica gel column chromatography [eluent: petroleum ether / ethyl acetate=5 / 1] to obtain (compound III) 4.40g, yield 80%. Its NMR see attached Figure 10 . LCMS [M+H]: 551.2. 1 H NMR (400MHz, Chloroform) δ8.29(d,1H), 7.81(s,1H),7.58(m,1H),7.41...

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Abstract

The invention relates to a compound for inhibiting the activity of Bcl-2 / BCL-XL anti-apoptotic protein, a composition containing the compound and application of the compound serving as a synthetic drug, in particular to application of the compound serving as a drug for synthesizing a Bcl-2 / BCL-XL anti-apoptotic protein inhibitor and application of the compound to cancer.

Description

technical field [0001] The present invention relates to antitumor compounds, in particular to a compound for inhibiting the activity of Bcl-2 / BCL-XL anti-apoptotic protein, a composition containing the compound and its use as a synthetic drug, especially as a compound for synthesizing Bcl-XL 2 / Use of BCL-XL anti-apoptotic protein inhibitors and use for cancer. Background technique [0002] BCL-2 anti-apoptotic protein is the encoded product of bcl-2 proto-oncogene, a cell survival promoting factor, a membrane integration protein, with a molecular weight of 26kDa, located in mitochondria, endoplasmic reticulum and continuous perinuclear membrane, and in embryonic tissue widely expressed. The BCL-2 anti-apoptotic protein is associated with many diseases. There is also a need in the therapeutic field for compounds that inhibit the activity of the BCL-2 anti-apoptotic protein. [0003] BCL-XL is also a member of the BCL-2 family. As an anti-apoptotic protein, it is overexpre...

Claims

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Application Information

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IPC IPC(8): C07D471/04A61K31/496A61P35/00A61P35/02
CPCC07D471/04A61P35/00A61P35/02
Inventor 陈永恒周文强邓泽平成佳蒋江平
Owner 长沙创新药物工业技术研究院有限公司
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