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An anti-tumor diazobicyclic apoptosis protein inhibitor

A technology of cycloalkylamine and compound, applied in the field of medicinal chemistry, can solve the problems of weak effect on solid tumors, and achieve the effects of good binding affinity, good IAP inhibitory activity, and broad market prospects

Active Publication Date: 2021-05-28
NANJING HUAWE MEDICINE TECH DEV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] At present, clinically, immune checkpoint inhibitors alone have a weak effect on solid tumors, and combined treatment of solid tumors with IAP inhibitors and immune checkpoint inhibitors can achieve better therapeutic effects. IAP inhibitors have synergistic effects on immune checkpoint inhibitors. The role of cancer has very good application prospects, but there are still many major challenges in the development of this variety

Method used

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  • An anti-tumor diazobicyclic apoptosis protein inhibitor
  • An anti-tumor diazobicyclic apoptosis protein inhibitor
  • An anti-tumor diazobicyclic apoptosis protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Example 1: Preparation of methyl pyrrolidine-2-carboxylate

[0094]

[0095] Take 40 g (0.35 mol) of proline and 250 mL of methanol in a 500 mL single-neck reaction flask, cool to 0°C, and take another 45 g (0.38 mol) of thionyl chloride in a 250 mL constant pressure dropping funnel, slowly add dropwise to the above In the solution system, heat was released with the dropwise addition system, and the internal temperature was controlled to be less than 5°C, and the dropwise addition was completed in about 20 minutes. The temperature was raised to 70°C to obtain a clear solution, which was refluxed for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure to obtain 43 g of a light yellow oily liquid, and the crude product was directly used in the next reaction.

Embodiment 2

[0096] Example 2: Preparation of methyl N-Boc pyrrolidine-2-carboxylate

[0097]

[0098] Take 43g (0.33mol) methyl pyrrolidine-2-carboxylate and 400mL dichloromethane in a 2L single-neck reaction flask, add 88g (0.87mol) triethylamine to obtain a white emulsion, stir at room temperature for 15 minutes, and cool to 0°C.

[0099] Another 152 g (0.69 mol) of Boc acid anhydride was dissolved in 600 mL of dichloromethane in a constant pressure funnel, and added dropwise to the above system, a large number of bubbles were released with the dropwise addition, exothermic, and the drop rate was controlled to maintain the system temperature <10 ° C. After the dropwise addition, a white suspension was obtained, which was stirred at room temperature for 12 hours. Filtration to remove the white precipitate, the filtrate was evaporated under reduced pressure to obtain a white suspension, which was washed with 300 mL of citric acid solution (0.5M), extracted with ether (3*500 mL), the o...

Embodiment 3

[0100] Example 3: Preparation of N-Boc-2-propenyl-pyrrolidine-2-carboxylic acid methyl ester

[0101]

[0102] Take 20 g (87.3 mmol) of methyl N-Boc pyrrolidine-2-carboxylate and 200 mL of tetrahydrofuran in a 500 mL three-neck flask, under nitrogen protection, and cool to -78°C.

[0103] Another 105mL (105mmol, 1M) of lithium bistrimethylsilylamide was taken in a constant pressure dropping funnel, added dropwise to the above system, the drop rate was controlled, and the temperature in the system was maintained <-78°C to obtain a yellowish brown solution. After the dropwise addition was completed, the mixture was stirred at -78°C for 1.5 hours.

[0104] Separately, 15.9 g (131 mmol) of allyl bromide was dissolved in 100 mL of tetrahydrofuran, and added dropwise to the above system. Return to room temperature and stir for 1 hour to obtain a reddish-brown solution. TLC detected that the reaction was complete, and 50 mL of water was added to quench the reaction. Extraction ...

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Abstract

The present invention provides a new apoptosis protein inhibitor or its pharmaceutically acceptable salt, isomer and its preparation method, pharmaceutical composition, wherein the definition of each group is as shown in the description; the present invention also provides the The application of the compound and its pharmaceutically acceptable salt and isomer in the preparation of medicines for diseases related to IAP protein, the compound of the present invention has better binding affinity with XIAP, cIAP1, cIAP2 protein, and MDA-MB- 231 breast cancer and PC‑3 pancreatic cancer cell lines have good inhibitory effect on cell growth, have great medicinal value and broad market prospect.

Description

technical field [0001] The art belongs to the field of medicinal chemistry, and in particular relates to a cell apoptosis protein inhibitor and a preparation method and use thereof. Background technique [0002] Apoptosis, or programmed cell death, is a genetically and biochemically regulated mechanism that plays an important role in the development and homeostasis of invertebrates and vertebrates. Abnormal apoptosis leading to premature cell death has been linked to a variety of developmental disorders. Apoptotic defects leading to a lack of cell death have been linked to cancer and chronic viral infections. [0003] Current cancer therapies, including chemotherapeutic agents, radiation and immunotherapy, indirectly induce apoptosis in cancer cells. Thus, the inability of cancer cells to execute apoptotic programs due to defects in normal apoptotic machinery is often associated with increased resistance to chemotherapy, radiation, or immunotherapy-induced apoptosis. Such...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61K31/407A61K31/4178A61K31/4162A61K31/496A61K31/4725A61P35/00A61P35/02
CPCA61P35/00A61P35/02C07D487/04
Inventor 宋志春张崇光何东伟包金远张孝清
Owner NANJING HUAWE MEDICINE TECH DEV
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