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Spiro piperidone derivative

A technology of spirocyclic piperidone and derivatives, which is applied in the field of medicine and achieves the effect of good antitumor activity

Pending Publication Date: 2021-10-08
THE NAVAL MEDICAL UNIV OF PLA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the existing KRAS-PDEδ small molecule inhibitors have problems such as metabolism and selectivity, so it is necessary to further screen to find small molecule inhibitors with new structural types, enrich the structural types of inhibitors, and find good in vivo activity and druggability New small molecule inhibitors of

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0057] Example 1: 1-Benzyl-4-(anilino)piperidine-4-carbonitrile (14)

[0058] Compounds 11 (3.0 g, 15.8 mmol) and 12 (1.48 g, 15.8 mmol) were weighed and dissolved in 20 mL of glacial acetic acid, then transferred to an ice bath, and compound 13 (4.7 g, 47.4 mmol) was slowly added dropwise after cooling. After the addition, transfer to room temperature for reaction. After 4 hours, the reaction was completed, and 2N NaOH solution was added to quench the reaction, and the pH was adjusted to 10. Then DCM was extracted (30 mL×3), the organic phases were combined, washed with saturated brine, spin-dried and slurried with ether to obtain the product. White solid, 2.8g, yield 60.9%.

Embodiment 2

[0059] Example 2: 1-Benzyl-4-(anilino)piperidine-4-carboxamide (15)

[0060] Compound 14 (2.8 g, 9.6 mmol) was weighed and dissolved in 14 mL of concentrated sulfuric acid, and reacted at room temperature. After 18 hours, the reaction was completed, and the reaction solution was added dropwise to 80 mL of 25% ammonia solution in an ice bath, and the pH was adjusted to above 10 after the addition was completed. Filter, retain the solid and dry it, and then beat with methanol to obtain the product. White solid, 2.2g, yield 94.2%.

Embodiment 3

[0061] Example 3: 1-Benzyl-4-(anilino)piperidine-4-carboxamide (16)

[0062] Weighed compound 15 (2.16g, 7mmol) and dissolved it in 15mL methanol, sonicated and transferred to 55°C for stirring, slowly added DMA (2.5g, 21mmol) dropwise, and then continued to react at 55°C. After 16 hours, the reaction was stopped and the reaction solution was spin-dried, and the crude product was slurried with ether to obtain the product. White solid, 1.53g, yield 68.6%.

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Abstract

The invention relates to the technical field of medicines, in particular to a spiro piperidone derivative defined in the specification, wherein the pharmacological experiments show that the derivative or salt has very strong inhibitory activity on KRAS-PDE delta protein-protein interaction and has relatively strong in-vitro anti-tumor activity. The invention also provides a preparation method of the derivative and the pharmaceutically acceptable salt thereof, and an application of the derivative and the pharmaceutically acceptable salt thereof in preparation of a KRAS-PDE delta inhibitor and an antitumor drug.

Description

technical field [0001] The invention relates to the field of medical technology, in particular to a class of KRAS-PDEδ protein-protein interaction (PPIs) inhibitors with anti-tumor activity and pharmaceutically acceptable salts thereof, as well as a preparation method and the anti-tumor activity of the compound, which can be used for Treatment of KRAS-dependent related cancers. Background technique [0002] Pancreatic cancer is extremely malignant and difficult to detect in the early stages of the disease. It is one of the solid tumors with the highest mortality rate in the world. Mutations in the KRAS gene have an important impact on the occurrence and development of pancreatic cancer. However, the development of drugs targeting KRAS protein is progressing slowly, and many drugs targeting KRAS have failed in clinical trials. Recently, KRAS G12C Covalently bound inhibitors have shown excellent therapeutic effects, but the predominantly mutated form of the KRAS gene in pan...

Claims

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Application Information

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IPC IPC(8): C07D471/10A61P35/00
CPCC07D471/10A61P35/00Y02A50/30
Inventor 盛春泉陈龙董国强武善超陈树强黄亚辉何世鹏
Owner THE NAVAL MEDICAL UNIV OF PLA
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