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Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof

A technology of ubenimestinol ester and ubenimex, which is applied in the direction of drug combination, carboxylic acid ester preparation, carboxylic acid amide preparation, etc., can solve the problems of poor solubility in various organic solvents, poor metabolic stability, and bioavailability. To improve the dynamic properties of the belt, increase water solubility, and significantly inhibit enzyme activity

Inactive Publication Date: 2009-09-16
SHANDONG UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] (5) APN participates in the degradation of endogenous analgesic substances endorphins and enkephalins, thereby causing excessive release of substance P, leading to pain
[0015] The structure of ubenimex contains a primary amino group and a carboxyl group, both of which can form internal salts, so it is difficult to dissolve in various organic solvents, and the water solubility is also poor, resulting in low bioavailability and poor metabolic stability, which limits the its use

Method used

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  • Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof
  • Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof
  • Aminopeptidase N inhibitor bestatin dino ester, synthesis and application thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0124] An antineoplastic agent, ubenmesedinol, having the following structure:

[0125]

[0126] Synthetic route of uben mestinol ester:

[0127]

[0128] Uben mestinol synthetic method, the steps are as follows:

[0129] (1) With optically pure ubenimex as the starting material, under the alkaline condition of pH=9-10, ubenimex and di-tert-butyl dicarbonate are reacted (the molar amount of di-tert-butyl dicarbonate 1.1 times that of Ubenimex), the primary amino group of Ubenimex is Boc-protected,

[0130] (2) Using anhydrous tetrahydrofuran as a solvent, under the catalysis of 0°C temperature and dicyclohexylcarbodiimide (DCC) (the molar weight of DCC is 1.1 times that of Ubenimex), the product of step (1) Boc-protected ubenimex condenses with HOBt (1.08 times the molar weight of ubenimex) to form an active ester,

[0131] (3) The product active ester reflected in the previous step reacts with N'N dimethylethanolamine at room temperature under the catalysis of p-dime...

Embodiment 2

[0134] Accurately weigh sodium chloride according to the prescription amount, add 70% of the prescription amount to dissolve in water for injection, add 1% active carbon by volume, stir, filter, HCl to adjust pH5, add the ubene medinolate of the prescription amount embodiment 1 , stir to dissolve, add water for injection to 1000ml, filter, fill in 2ml ampoules, and sterilize for 30 minutes.

Embodiment 3

[0136] Accurately weigh glucose according to the prescription amount, add 70% of the prescription amount in water for injection to dissolve, add 1% activated carbon by volume, stir, filter, adjust pH5 with HCl, add the ubene mesidinol ester of the prescription amount embodiment 1, and stir Dissolve, add water for injection to 1000ml, filter, fill in 2ml ampoules, and sterilize for 30 minutes.

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Abstract

The invention provides an intensive antitumor medicament, namely bestatin deanol ester, a preparation method and application thereof. The bestatin deanol ester not only can effectively inhibit ectopic expression of aminopeptidase N activity, but also greatly improve the water solubility of the parent drug bestatin of the bestatin deanol ester, has slow release effect, is more excellent than the parent drug bestatin either from healing effect or preparation, and has wide application. Particularly, the invention mainly relates to the following three aspects: (1) design and synthesis of the bestatin deanol ester; (2) N'N deanol which is a micromolecule fragment, can be connected with other medicaments containing carboxyl, improves the pharmacokinetic property of the medicaments, and improves water solubility; and (3) a method for synthesizing an ester substance to which the invention relates with wide application and mild condition.

Description

technical field [0001] The present invention relates to the prodrug of aminopeptidase N inhibitor Bestatin (ubenimex), the design, synthesis and possible medical application of ubenimestinol ester. It belongs to the field of pharmaceutical technology. Background technique [0002] 1. Aminopeptidase N (APN) [0003] Aminopeptidase N (APN / CD13) is a zinc ion-dependent type II metallo-exopeptidase belonging to the M1 aminopeptidase family. Its physiological function is to participate in the degradation of the N-terminal amino acid of the substrate. Under normal conditions, APN is widely expressed at low levels in tissues such as the kidney, small intestine, and central nervous system of mammals, and participates in the physiological regulation of the body. Studies have shown that aminopeptidase N is a multifunctional enzyme with a wide range of substrates, and it plays an important role in tumorigenesis, immune function regulation, viral infection and analgesia. [0004] (1...

Claims

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Application Information

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IPC IPC(8): C07C237/20C07C231/12C07C67/08A61K31/223A61P35/00
Inventor 徐文方栾业鹏张娜曲显俊尚鲁庆马鸿飞
Owner SHANDONG UNIV
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