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A pdeδ protein degradation targeting chimera and its preparation method and application

A protein and compound technology, applied in the field of medicine, to achieve the effects of good anti-tumor activity, good anti-tumor drug development value, and good enzyme inhibitory activity

Active Publication Date: 2022-03-18
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There is no report about a PDEδ protein degradation targeting chimera of the present invention and its preparation method and application

Method used

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  • A pdeδ protein degradation targeting chimera and its preparation method and application
  • A pdeδ protein degradation targeting chimera and its preparation method and application
  • A pdeδ protein degradation targeting chimera and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] Embodiment 1: the synthesis of compound 1

[0050] A. tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)carbamate preparation of

[0051] Compound 2-(2,6-dioxopiperidin-3-yl)-4-fluoroisoindole-1,3-dione (0.20g, 0.7mmol) and tert-butyl(3-aminopropyl)amino Formate (0.14g, 0.8mmol) was dissolved in DMF, DIPEA (0.18g, 1.4mmol) was added, stirred at 90°C for 12h, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, Dry over anhydrous sodium sulfate, concentrate to obtain the crude product, and purify by silica gel column chromatography (eluent: dichloromethane / methanol=100:1) to obtain yellow solid tert-butyl (3-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)carbamate 0.12 g, yield 40%.

[0052] B. 4-(3,4-Dimethyl-7-oxo-2-(p-tolyl)-2,7-dihydro-6H-pyrazoline[3,4-d]pyridazine-6- Preparation of -N-(3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisopropanol-4-...

Embodiment 2-7

[0054] Embodiment 2-7: the synthesis of compound 2-7

[0055] Operation is identical with embodiment 1 with feeding intake.

Embodiment 8

[0056] Embodiment 8: the synthesis of compound 8

[0057] A. tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)amino)octyl)carbamate preparation of

[0058] Compound 2-(2,6-dioxopiperidin-3-yl)-5-fluoroisoindole-1,3-dione (0.20g, 0.7mmol) and tert-butyl(8-aminooctyl)amino Formate (0.19g, 0.8mmol) was dissolved in DMF, DIPEA (0.18g, 1.4mmol) was added, stirred at 90°C for 12h, the reaction solution was poured into ice water, extracted with ethyl acetate, washed with saturated aqueous sodium chloride, Dry over anhydrous sodium sulfate and concentrate to obtain a crude product, which is purified by silica gel column chromatography (eluent: dichloromethane / methanol = 100:1) to obtain a yellow solid tert-butyl (8-((2-(2,6- Dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)amino)octyl)carbamate 0.12 g, yield 34%.

[0059] B. 4-(3,4-Dimethyl-7-oxo-2-(p-tolyl)-2,7-dihydro-6H-pyrazoline[3,4-d]pyridazine-6- Preparation of base)-N-(8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxo...

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Abstract

The present invention relates to the technical field of medicine, in particular to a PDEδ protein degradation targeting chimera and its preparation method and application. The PDEδ protein degradation targeting chimera is a derivative with a general chemical structure (I) and its pharmaceutical Acceptable salts. Pharmacological experiments show that the derivative or salt of the present invention has strong inhibitory activity on KRAS-PDEδ protein interaction, and has strong anti-tumor activity in vitro. The present invention also provides a preparation method of the above-mentioned derivatives and pharmaceutically acceptable salts thereof. In vivo experiments show that compound (I) can effectively down-regulate the expression of PDEδ in vivo, and can significantly delay tumor growth, and can be applied to tumor diseases caused by Kras mutations. As the first reported PDEδ protein degradation targeting chimera, this kind of compound has further development and research value.

Description

technical field [0001] The invention relates to the technical field of medicine, in particular to a PDEδ protein degradation targeting chimera and its preparation method and application. Background technique [0002] RAS proteins can regulate many cellular activities in the human body, including cell proliferation, cell differentiation, etc. About 30% of tumors are caused by mutations in the RAS gene, among which KRAS is the most common mutation subtype in the RAS family, about 30% of lung cancers, 45% of colon cancers, and 90% of pancreatic cancers are caused by KRAS mutations caused. KRAS is therefore recognized as an attractive target for the treatment of cancer. However, due to the lack of good small molecule binding cavities on the surface of KRAS protein, the development of small molecule inhibitors based on KRAS has always been one of the difficulties in the field of medicinal chemistry. [0003] PDEδ, also named PDE6D, can affect the dynamic distribution of KRAS i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D487/04A61P35/00
CPCC07D487/04A61K31/5025A61P35/00Y02P20/55
Inventor 盛春泉董国强程俊飞陈龙王旭
Owner SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
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