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

Benzenesulfonyl furazan modified gemcitabine derivative and preparation method and use thereof

A technology of benzenesulfonylfurazan and gemcitabine, applied in the field of gemcitabine derivatives modified by benzenesulfonylfurazan and its preparation and application

Active Publication Date: 2015-06-10
苏州康纯医药科技有限公司
View PDF4 Cites 11 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the present invention discloses a class of benzenesulfonylfurazan-modified gemcitabine derivatives and pharmaceutically acceptable salts thereof with medicinal value, and there is no report on such compounds

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
  • Benzenesulfonyl furazan modified gemcitabine derivative and preparation method and use thereof
  • Benzenesulfonyl furazan modified gemcitabine derivative and preparation method and use thereof
  • Benzenesulfonyl furazan modified gemcitabine derivative and preparation method and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Example 1 4-(2-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-2-yl)- 2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxobutyryl)oxy)ethoxy)-3-(phenylsulfonyl)-1,2,5- Oxadiazole-2-oxide (I 1 ) preparation

[0051] 2-Phenylthioglycolic acid (2)

[0052] Dissolve compound 1 (12.10g, 0.11mol) and sodium hydroxide in 50mL of 95% ethanol, add 100mL of aqueous solution made of chloroacetic acid (11.40g, 0.12mol) and sodium carbonate (6.35g, 0.06mol), at room temperature Stir for 3h, reflux for 1h. After cooling to room temperature, 6 mol / L hydrochloric acid was added to adjust the pH to 2, a white precipitate was formed, and filtered to obtain 16.40 g of white rod-shaped crystals, yield 89.0%, mp: 60-62°C.

[0053] 3,4-Diphenylsulfonyl-1,2,5-oxadiazole-2-oxide (4)

[0054] Dissolve compound 2 (16.00g, 0.10mol) in 65mL glacial acetic acid, add 30% hydrogen peroxide (20mL, 0.20mol), stir at room temperature for 2.5h to obtain intermediate compound ben...

Embodiment 2

[0066] Example 2 4-(2-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-pyridin-2-yl )-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoyl)oxy)propoxy)-3-(phenylsulfonyl)-1,2, 5-oxadiazole-2-oxide (I 2 ) preparation

[0067] 4-(3-Hydroxypropoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (5b)

[0068] Referring to the synthesis method of (5a), 1,3-propanediol was reacted with compound (4) instead of ethylene glycol, and a white solid (5b) was finally obtained with a yield of 57.2%.

[0069] 4-(2-((3-carboxypropyl)oxy)propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (6b)

[0070] Referring to the synthesis method of (6a), (5b) instead of (5a) was reacted with 1,4-succinic anhydride and DMAP to finally obtain light yellow solid (6b) with a yield of 92.0%.

[0071] 4-(2-((4-((1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl) ylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino...

Embodiment 3

[0076] Example 3 4-(2-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5-(hydroxymethyl)tetrahydrofuran-pyridin-2-yl )-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoyl)oxy)butoxy)-3-(phenylsulfonyl)-1,2, 5-oxadiazole-2-oxide (I 3 ) preparation

[0077] 4-(3-Hydroxybutoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (5c)

[0078] Referring to the synthesis method of (5a), 1,4-butanediol was reacted with compound (4) instead of ethylene glycol, and a white solid (5c) was finally obtained with a yield of 52.6%.

[0079] 4-(2-((3-carboxypropyl)oxy)butoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (6c)

[0080] Referring to the synthesis method of (6a), (5c) instead of (5a) was reacted with 1,4-succinic anhydride and DMAP to finally obtain light yellow solid (6b) with a yield of 88.0%.

[0081] 4-(2-((4-((1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl) ylsilyl)oxy)methyl)-3,3-difluoro-tetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-...

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 discloses a benzenesulfonyl furazan modified gemcitabine derivative and a preparation method and use thereof. The benzenesulfonyl furazan modified gemcitabine derivative comprises a compound as shown in a universal formula I and pharmaceutically acceptable salts thereof. According to the rational drug design principle and the combination principle, the clinical pharmacology activity of gemcitabine is retained; meanwhile, with gemcitabine as a lead compound, a benzenesulfonyl furazan NO donor is respectively coupled to N4 amino of gemcitabine through different linking groups to synthesize a benzenesulfonyl furazan modified NO donor type gemcitabine derivative, in order to obtain a compound with stronger anti-tumor activity and better bioavailability than gemcitabine.

Description

technical field [0001] The invention relates to a gemcitabine derivative modified by benzenesulfonyl furazan, a preparation method and application thereof. Background technique [0002] Gemcitabine (dFdC) is a new antimetabolite anticancer drug approved by the US FDA in 1996. dFdC is a cell cycle-specific antitumor drug that mainly acts on cells in S phase and can also prevent G 1 The progression of cells in S phase to S phase affects cell cycle redistribution and increases cycle-sensitive cell components. After a series of phosphorylation in cells, dFdC acts as a competitive deoxycytidine triphosphate substrate. It competes to insert DNA double strands, causing DNA double strands to be misrecognized, thereby exerting its unique cytotoxic effect and inhibiting tumor cell growth. , promote cell apoptosis (Jordheim LP, Durantel D, Zoulim F, et al. at Rev Drug Discov, 2013, 12:447-464). Although dFdC has been used clinically, its polarity is large and its transmembrane abili...

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
IPC IPC(8): C07H19/073A61K31/7068A61P35/00
CPCC07H1/00C07H19/06
Inventor 凌勇杨宇民李祥华王成牛张海健吴园园徐启宾冯娇
Owner 苏州康纯医药科技有限公司
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