Vorinostat derivative based on lithium hydroxide, and preparation method and application thereof

A technology of vorinostat and lithium hydroxide, which is applied in the preparation of sugar derivatives, sugar derivatives, sugar derivatives, etc., can solve the problems of inability to achieve oral administration, achieve side effects and inability to inject drug administration, steps Simple and effective cost control

Active Publication Date: 2018-02-16
ZHEJIANG MEDICAL COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In particular, when we are facing patients who cannot swallow, such as infants, critically ill patients, paralyzed or comatose patients, oral administration cannot be achieved, and the problem of inability to inject drugs becomes particularly prominent at this time (US20100240601)

Method used

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  • Vorinostat derivative based on lithium hydroxide, and preparation method and application thereof
  • Vorinostat derivative based on lithium hydroxide, and preparation method and application thereof
  • Vorinostat derivative based on lithium hydroxide, and preparation method and application thereof

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preparation example Construction

[0046] And the preparation method of vorinostat derivative of the present invention can refer to as follows:

[0047] Will Condensation reaction with vorinostat, then removal of the protecting group, and purification to obtain the vorinostat derivative;

[0048] In formula (i), R 9 -R 12 are independently hydrogen, protected hydroxyl, or protected carboxyl, wherein, R 9 -R 12 There is at least one protected hydroxyl group or protected carboxyl group; preferably, in formula (i), R 9 -R 12 are independently protected hydroxyl or protected carboxyl; more preferably, in formula (i), R 9 -R 12 There is at least one protected hydroxyl group and one protected carboxyl group in, for example, R 9 is a protected carboxyl group, R 10 -R 12 is a protected hydroxyl group; alternatively, R 12 is a protected carboxyl group, R 9 -R 11 is a protected hydroxyl group; or, it can be R 9 is a protected hydroxyl group, R 10 -R 12 is a protected carboxyl group; or, R 12 is a protec...

Embodiment 1

[0072] Example 1 O-[N N-dimethyl-N-4-(2,3,4-tri-O-tert-butyldimethylsilyl-6-benzyl-β-D-glucopyranose Preparation of acid-1-yl)-3-nitrobenzyloxycarbonylethylenediamine]-formyl-vorinostat (iii)

[0073] Dissolve 913 mg (3.46 mmol) of vorinostat in 20 mL of pyridine, and cool at 0° C. for 5 minutes. At 0°C, 3 g (3.14 mmol) of compound (ii) was added to the above solution to form a red suspension. The suspension was warmed up to 25 °C, kept stirring for 5 hours, and then 100 mL of water was added to quench the reaction. The reaction solution was extracted with ethyl acetate (50mL×3 times), the combined organic layers were sequentially extracted with 0.5M HCl (30mL×4 times), saturated brine (30mL×2 times), dried over anhydrous sodium sulfate, and evaporated by rotary evaporation The mixture was concentrated and separated by preparative chromatography (dichloromethane:methanol=50:1) to obtain 3.4g of intermediate compound (iii) with a yield of 92%.

[0074] Characterization of th...

Embodiment 2

[0075] Example 2 O-[N N-dimethyl-N-4-(6-benzyl-β-D-pyranoglucuron-1-yl)-3-nitrobenzyloxycarbonylethylenediamine] - Preparation of formyl-vorinostat (iv)

[0076] Dissolve 3.4g (2.87mmol) of intermediate (iii) in 18mL of tetrahydrofuran, add 4.63g (28.7mmol) of triethylamine trihydrofluoride at 25°C, heat to 50°C, and keep the reaction for 16 hours. After the reaction is complete, the reaction solution is concentrated with a rotary evaporator, 50 mL of water is added to the concentrated solution, extracted with ethyl acetate / acetonitrile (3 / 1) (20 mL×4 times), the organic layers are combined, washed twice with saturated saline, and anhydrous sulfuric acid Sodium-dried, filtered, the filtrate was concentrated with a rotary evaporator, and separated by preparative chromatography (dichloromethane:methanol=50:1) to obtain 35.0 g of a crude product, namely the intermediate compound (iv). The yield was 74%. directly into the next reaction.

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Abstract

The invention provides a vorinostat derivative based on lithium hydroxide, and a preparation method and application thereof. The vorinostat derivative based on lithium hydroxide uses vorinostat as a parent drug, and a water-soluble group is connected to the hydroxamic acid position of the mother nucleus of vorinostat to realize modification; thus, the water-solubility of the vorinostat parent drugis effectively improved, and the occurrence of adverse reactions can be effectively prevented. Meanwhile, the vorinostat derivative of the invention has good tumor inhibition effect and can be further used for preparing tumor-treating drugs. Furthermore, the invention also provides the preparation method for the lithium hydroxide-based vorinostat derivative. The preparation method has the advantages of few preparation procedures, simple operation, etc.

Description

technical field [0001] The invention relates to the field of preparation of antineoplastic drugs, in particular to a lithium hydroxide-based vorinostat derivative and a preparation method and application thereof. Background technique [0002] Vorinostat, whose chemical name is "N-hydroxy-N'-phenylsuberamide" or "suberoylanilide hydroxamic acid (SAHA)", is the first histone protein developed by Merck in the United States. Deacetylase (HDAC) inhibitor class antineoplastic drugs. Because vorinostat can selectively induce the late differentiation of tumor cells, thereby inhibiting the proliferation of such cells under suitable conditions, vorinostat is used to treat tumor patients with continuous proliferation of cancer cells. It is also clinically indicated for the treatment of cutaneous T-cell lymphoma (CTCL: a type of non-Hodgkin's lymphoma, which is a type of T-cell cancer that affects white blood cells of the skin) ). [0003] Vorinostat It was approved for marketing i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07H15/203C07H1/00A61K31/7034A61P35/00
CPCC07H1/00C07H15/203Y02P20/55
Inventor 杜文婷王旭李军陈海永
Owner ZHEJIANG MEDICAL COLLEGE
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