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,

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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PUM

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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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