Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

PDE[delta] protein degradation targeting chimera, and preparation method and application thereof

A compound and pharmaceutical technology, applied in the field of medicine, to achieve good enzyme inhibitory activity, good anti-tumor drug development value, and the effect of inhibiting the growth of tumors

Active Publication Date: 2020-03-17
SECOND MILITARY MEDICAL UNIV OF THE PEOPLES LIBERATION ARMY
View PDF5 Cites 1 Cited by
  • 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • PDE[delta] protein degradation targeting chimera, and preparation method and application thereof
  • PDE[delta] protein degradation targeting chimera, and preparation method and application thereof
  • PDE[delta] protein degradation targeting chimera, and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0065] Embodiment 1: the synthesis of compound 1

[0066] A. tert-butyl (3-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-4-yl)amino)propyl)carbamate preparation of

[0067] 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%.

[0068] 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

[0070] Embodiment 2-7: the synthesis of compound 2-7

[0071] Operation is identical with embodiment 1 with feeding intake.

Embodiment 8

[0072] Embodiment 8: the synthesis of compound 8

[0073] A. tert-butyl (8-((2-(2,6-dioxopiperidin-3-yl)-1,3-dioxoisoindol-5-yl)amino)octyl)carbamate preparation of

[0074] 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%.

[0075] 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...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

No PUM Login to View More

Abstract

The invention relates to the technical field of medicine, in particular to a PDE[delta] protein degradation targeting chimera, and a preparation method and application thereof. The PDE[delta] proteindegradation targeting chimera is derivatives having a general chemical formula (I) and pharmaceutically acceptable salts thereof. Pharmacological experiments show that the derivatives or salts have astrong inhibitory activity on KRAS-PDE[dela] protein interactions, and have strong in-vitro antitumor activity. The invention also provides a method for preparing the above-mentioned derivatives and the pharmaceutically acceptable salts thereof. In-vivo experiments show that compounds (I) can effectively down-regulate the expression of PDE[delta] in vivo, can significantly delay tumor growth, andcan be applied to tumor diseases caused by Kras mutation. The compounds, as the PDE[delta] protein degradation targeting chimera, have 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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
Patent Type & Authority Applications(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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com