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Isoxazole ring derivatives as well as preparation method and application thereof

A derivative and isoxazole technology, which is applied in the field of isoxazole cyclized camptothecin derivatives and their preparation, can solve problems to be optimized and the like, and achieve a combination of maintaining binding capacity, improving biological activity, and reducing the possibility of ring opening. Effect

Active Publication Date: 2016-12-07
深圳瀜新生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, many structural modifications of camptothecin are mainly on the 7, 9, and 10 positions, or on the A ring, or opening, expanding and derivatizing the E ring, in order to obtain compounds with better effects, but now Some structural transformations still need to be optimized

Method used

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  • Isoxazole ring derivatives as well as preparation method and application thereof
  • Isoxazole ring derivatives as well as preparation method and application thereof
  • Isoxazole ring derivatives as well as preparation method and application thereof

Examples

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preparation example Construction

[0057] The preparation method of camptothecin derivative, comprises the steps:

[0058] 3) 10-hydroxy-camptothecin is reacted with hexamethylenetetramine to obtain 9-formylated 10-hydroxy-camptothecin, and then the aldehyde group is reacted with hydroxylamine hydrochloride to generate 9-aldoxime-10-hydroxy-camptothecin Base, under the action of diisopropyl azodicarboxylate and triphenylphosphine, the 9-position aldoxime reacts with the 10-position hydroxyl group to form isoxazole, and generates 9 and 10-position isoxazole camptothecin;

[0059] 4) Esterify the 20-hydroxyl group of 9 and 10-position isoxazole camptothecin with BOC-glycine, remove the BOC protecting group, and acylate the amino terminal of glycine with succinic anhydride to obtain a hydrophilic group at the 20-position The 9,10-position isoxazole camptothecin derivatives, that is, isoxazole cyclized camptothecin derivatives

[0060]

[0061] The reaction steps are as follows:

[0062]

[0063] Applicatio...

Embodiment 1

[0080] The isoxazole derivative of camptothecin (quinoline isoxazole compound), the chemical structure formula without hydrophilic group at the 20th position is as follows, the chemical name is: (S)-8-ethyl-8-hydroxy-8H- isoxazolo[4,5-f]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-9,12(11H,14H)-dione

[0081]

[0082] The chemical name of the isoxazole cyclized camptothecin derivative with a hydrophilic group at the 20th position is: (S)-4-((2-((8-ethyl-9,12-dioxo-9,11, 12,14-tetrahydro-8H-isoxazolo[4,5-f]pyrano[3',4':6,7]indolizino[1,2-b]quinolin-8-yl)oxy)-2-oxoethyl)amino )-4-oxobutanoic acid, its chemical structure is as follows:

[0083]

[0084] The preparation method of above-mentioned camptothecin derivatives comprises the following steps, and its synthetic route is as follows:

[0085]

[0086]

[0087] Concrete synthetic steps are as follows:

[0088] 1) A solution of 10-hydroxycamptothecin (compound 1, 100 mg, 0.27 mmol) and hexamethylenetetramine (HMTA...

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Abstract

The invention discloses a CPT (camptothecin) derivative, a preparation method thereof and an application of the CPT derivative in preparation of a drug for treating tumor. The CPT derivative has the general structural formula as shown in the specification, in the formula, R1 is H, alkyls of C1-C4 or (CH3)2-N-CH2-; R2 is H or a pharmaceutically acceptable hydrophilic group with the total carbon number not exceeding 8. Structural modification is performed in positions 9, 10 and 20 of CPT, so that on the premise that the stability of the new CPT derivative is maintained, the bioactivity of the derivative is improved, the water solubility of the derivative is increased, the toxicity is reduced, and improvement of high efficiency of in-vivo tumor resistance of the derivative and application of the derivative as a drug are realized.

Description

technical field [0001] The invention belongs to the field of chemical synthesis, and relates to isoxazole cyclized camptothecin derivatives and a preparation method and application thereof. Background technique [0002] Cancer is currently the number one killer of human health. According to statistics released by the Ministry of Health in 2010, malignant tumors have become the leading cause of death in China, and more than 1 million patients die of tumors every year. According to the statistics of the World Health Organization (WHO), the average annual death rate of malignant tumors in the world is nearly 7 million, and the number of new cases is about 8.7 million, and it is still increasing every year. The death rate ranks second, second only to heart disease Cerebrovascular disease. Therefore, the treatment of cancer is urgent. [0003] Camptothecin (CPT) is a cytotoxic alkaloid extracted from Camptotheca involucrata in 1966, and its structural formula is as follows: ...

Claims

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Application Information

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IPC IPC(8): C07D498/22A61K31/4745A61P35/00
CPCC07D498/22
Inventor 余慧东李希建黄湧侯廷军潘培辰沈明云岑国亮
Owner 深圳瀜新生物科技有限公司
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