Gemcitabine/FTA/furazan conjugate in NO-donor type, preparation method and application

A technology of gemcitabine and conjugates, applied in the field of application in the preparation of antitumor drugs

Active Publication Date: 2015-08-12
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

[0008] Therefore, according to the latest research progress in life science and information science, we use advanced concepts and methods of new drug design to modify and transform the structure of dFdC, and introduce fat-soluble benzenesulfonylfurazan and FTA, in order

Method used

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  • Gemcitabine/FTA/furazan conjugate in NO-donor type, preparation method and application
  • Gemcitabine/FTA/furazan conjugate in NO-donor type, preparation method and application
  • Gemcitabine/FTA/furazan conjugate in NO-donor type, preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: 4-((4-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5-(((2-(((2E, 6E)-3,7,11-trimethyl-2,6,10-trien-1-yl)thio)benzoyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo -1,2-dihydropyrimidin-4-yl)amino)-4-oxobutanoyl)oxy)propoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole- 2-Oxide (I 1 ) preparation

[0067] 4-amino-1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsilyl)oxy )methyl)-3,3-difluoro-tetrahydrofuran-2-yl)pyrimidin-2(1H)-one (3)

[0068] Gemcitabine 2 (2.63g, 10.00mmol) was dissolved in 200mL dry DMF solution, TBDMS-Cl (6.00g, 40.00mmol) and imidazole (2.72g, 40.00mmol) were added, stirred at room temperature for 18h, and the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (mobile phase methanol:ethyl acetate=1:20) to obtain 4.28 g of white solid with a yield of 87.3%. ESI-MS(m / z):491[M+H] + .

[0069] 4-(2-((4-((1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldimethylsily...

Embodiment 2

[0075] Example 2: 4-((4-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxyl-5-(((2-(((2E, 6E)-3,7,11-trimethyl-2,6,10-trien-1-yl)thio)benzoyl)oxy)methyl)tetrahydrofuran-2-yl)-2-oxo -1,2-Dihydropyrimidin-4-yl)amino)-4-oxobutanoyl)oxy)but-2-yn-1-yl)oxy)-3-(phenylsulfonyl)-1 , 2,5-oxadiazole-2-oxide (I 2 ) preparation

[0076] 4-((4-((4-((1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldi Methylsilyl)oxy)methyl)-3,3-difluorotetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxo Butyryl)oxy)but-2-yn-1-yl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (4b)

[0077] Referring to the synthetic method of (4a), 4-((4-((3-carboxypropionyl)oxy)but-2-yn-1-yl)oxy)-3-(phenylsulfonyl)-1, 2,5-Oxadiazole-2-oxide (1b) was reacted with NHS, DMAP, EDCI and compound 3 instead of (1a) to finally obtain light yellow solid (4b) with a yield of 49.3%.

[0078] 4-((4-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- Oxo-1,2-dihydropyrimidin-...

Embodiment 3

[0083]Example 3: 4-((4-((4-((1-((2R,4R,5R)-3,3-fluoro-4-hydroxyl-5-((2-((2-(2- (((2E,6E)-3,7,11-trimethyl-2,6,10-trienebutan-1-yl)thio)benzamido)ethyl)dithio)acetoxy Base)methyl)tetrahydrofuran-pyridin-2-yl)-2-oxo-1,2-dihydro-4-yl)amino)-4-oxobutanoyl)oxy)butoxy)-3- (Phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (I 3 ) preparation

[0084] 4-((4-((4-((1-((2R,4R,5R)-4-((tert-butyldimethylsilyl)oxy)-5-(((tert-butyldi Methylsilyl)oxy)methyl)-3,3-difluorotetrahydrofuran-2-yl)-2-oxo-1,2-dihydropyrimidin-4-yl)amino)-4-oxo Butyryl)oxy)but-2-yl)oxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2-oxide (4c)

[0085] Referring to the synthesis method of (4a), 4-(2-((3-carboxypropyl)oxy)butoxy)-3-(phenylsulfonyl)-1,2,5-oxadiazole-2- The oxide (1c) was reacted with NHS, DMAP, EDCI and compound 3 instead of (1a) to finally obtain a pale yellow solid (4c) with a yield of 51.0%.

[0086] 4-((4-((4-((1-((2R,4R,5R)-3,3-difluoro-4-hydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-2- Oxo-1,2-dihydropyrimi...

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Abstract

The invention discloses a gemcitabine/FTA/furazan conjugate in a NO-donor type, a preparation method and an application. A product in the invention is the novel gemcitabine/FTA/furazan conjugate in the NO-donor type or a pharmaceutically-acceptable salt thereof represented as the general formula I and the general formula II. The product has excellent functions of treating common tumor and drug-resistant tumor proliferation, can achieve a synergistic treatment effect of a plurality of drug fragments and is easy to prepare.

Description

technical field [0001] The present invention relates to the field of biomedicine, in particular to a class of NO donor-type gemcitabine / FTA / furazan conjugates and pharmaceutically acceptable salts thereof, their preparation methods, pharmaceutical compositions containing these derivatives and their Medical use, especially the application in the preparation of antitumor drugs. Background technique [0002] Malignant tumors are a type of disease that seriously endangers human life and health. The current treatment methods not only produce drug resistance to a certain extent, but also cannot inhibit the metastasis of tumor cells, resulting in a high mortality rate. Gemcitabine (gemcitabine, dFdC) is a new anti-metabolite anticancer drug approved by the US FDA in 1996. It is mainly used clinically for the treatment of non-small cell lung cancer, pancreatic cancer, bladder cancer, breast cancer and other solid tumors. However, there are poor fat solubility and poor transmembrane...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00A61K31/7068A61P35/00
CPCC07H1/00C07H19/073
Inventor 凌勇陈忠平鞠曹云许伯慧吴园园杨韬徐启兵黄海英
Owner 苏州康纯医药科技有限公司
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