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Anti-tumor diazo dicyclic apoptosis protein inhibitor

A technology of cycloalkylamine group and compound, applied in the field of medicinal chemistry, can solve the problems of weak effect on solid tumors and the like

Active Publication Date: 2019-07-19
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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  • Anti-tumor diazo dicyclic apoptosis protein inhibitor
  • Anti-tumor diazo dicyclic apoptosis protein inhibitor
  • Anti-tumor diazo dicyclic apoptosis protein inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0093] Embodiment 1: the preparation of pyrrolidine-2-methyl carboxylate

[0094]

[0095] Take 40g (0.35mol) of proline and 250mL of methanol in a 500mL single-port reaction flask, cool to 0°C, take another 45g (0.38mol) of thionyl chloride in a 250mL constant pressure dropping funnel, and slowly add it dropwise to the above In the solution system, the system releases heat with the dropwise addition, and the internal temperature is controlled to be <5°C, and the dropwise addition is 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 down to room temperature, the solvent was distilled off under reduced pressure to obtain 43 g of light yellow oily liquid, which was directly used in the next reaction.

Embodiment 2

[0096] Embodiment 2: the preparation of N-Boc pyrrolidine-2-methyl carboxylate

[0097]

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

[0099] Another 152g (0.69mol) of Boc anhydride was dissolved in 600mL of dichloromethane in a constant pressure funnel, and added dropwise to the above system. A large number of bubbles were released along with the dropwise addition, exothermic, and the addition rate was controlled to maintain the internal temperature of the system <10°C. After the dropwise addition, a white suspension was obtained, which was stirred at room temperature for 12 hours. Filter to remove the white precipitate, evaporate the solvent from the filtrate under reduced pressure to obtain a white suspension, add 300mL citric acid solution (0.5M) to wash, extract with...

Embodiment 3

[0100] Embodiment 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, protect with nitrogen, and cool to -78°C.

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

[0104] Another 15.9 g (131 mmol) of allyl bromide was dissolved in 100 mL of tetrahydrofuran, added dropwise to the above system, and the rate of addition was controlled to maintain the internal temperature of the system < -78°C. After the addition was complete, stir at -78°C for 1 hour. Return to room temperature and stir ...

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Abstract

The invention provides a novel apoptosis protein inhibitor or pharmaceutically acceptable salts and isomers as well as preparation methods thereof and a pharmaceutical composition. The definition of each group is shown in the description. The invention further provides application of the compound and pharmaceutically acceptable salts and isomers thereof to preparation of medicines for treating IAP(Immimmunosuppressive Acidic Protein) related diseases. The compound disclosed by the invention has high binding affinity to XIAP, cIAP1 and cIAP2 proteins, has an excellent inhibiting effect on cellgrowth in MDA-MB-231 breast cancer and PC-3 pancreatic cancer cell lines, and also has high medicinal value and wide market prospects.

Description

technical field [0001] This field belongs to the field of medicinal chemistry, and specifically relates to a cell apoptosis protein inhibitor and its preparation method and application. Background technique [0002] Apoptosis, or programmed cell death, is a genetically and biochemically regulated mechanism that plays an important role in development and homeostasis in both invertebrates and vertebrates. Abnormalities in apoptosis leading to premature cell death have been linked to a variety of developmental disorders. Defects in apoptosis leading to a lack of cell death have been linked to cancer and chronic viral infection. [0003] Current cancer therapies, including chemotherapeutics, radiation and immunotherapy, indirectly induce apoptosis in cancer cells. Thus, the inability of cancer cells to execute the apoptotic program due to defects in the normal apoptotic machinery is often associated with increased resistance to chemotherapy-, radiation- or immunotherapy-induce...

Claims

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Application Information

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Patent Type & Authority Applications(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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