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
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  • 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

Method used

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  • 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-...

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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

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Application Information

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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
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