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Colchicine derivative-bile acid coupling compounds and medical use thereof

A technology of colchicine and derivatives, which is applied in the field of preparation of drugs for the treatment of liver cirrhosis and liver fibrosis, and can solve the problems of small drug loading and complex chemical composition

Inactive Publication Date: 2009-05-27
INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, liver-targeted drugs with macromolecules such as lactosylated albumin or lactosylated polylysine as carriers are easily cleared by the reticuloendothelial system, have small drug loads, and complex chemical compositions, so they need to be administered by injection.

Method used

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  • Colchicine derivative-bile acid coupling compounds and medical use thereof
  • Colchicine derivative-bile acid coupling compounds and medical use thereof
  • Colchicine derivative-bile acid coupling compounds and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of N-cholylglutamic acid-trimethylcolchicinic acid conjugate (Ia-1)

[0029] 1.1 Synthesis of N-choylglutamic acid-α-methyl ester

[0030] 16.1 g (0.1 mol) of glutamic acid-α-methyl ester was dissolved in 160 ml of 1N sodium hydroxide solution, and the mixture was cooled to 0°C. Take 36.7 grams (90 mmol) of cholic acid and dissolve it in 110 milliliters of tetrahydrofuran, and cool it to -15°C in an ice salt bath; add 5.20 milliliters of N-methylmorpholine and 6.02 milliliters of isobutyl chloroformate in turn, React in the bath for 8-10 minutes. The glutamic acid-α-methyl ester solution was added to the reaction solution, stirred under ice bath for 1.5 hours, removed from the ice bath, and stirred at room temperature for 2 hours. After the reaction, the pH was acidified to 3 with 5% citric acid, extracted three times with ethyl acetate, the ethyl acetate layers were combined, washed with 5% citric acid and saturated brine, and dried over anhydro...

Embodiment 2

[0035] Example 2 Preparation of N-ursodeoxycholoylglutamic acid-trimethylcolchicinic acid conjugate (Ia-2)

[0036] With ursodeoxycholic acid instead of cholic acid, refer to the method of Example 1 to obtain compound Ia-2, yield: 72%, TLC: chloroform: methanol = 20: 1, R f = 0.5. MS (m / e): 847.0 (M+1); elemental analysis (C 48 h 66N 2 o 11 ): theoretical value C 68.06%, H 7.85%, N3.31%; experimental value C 68.12%, H 7.74%, N3.40%.

Embodiment 3

[0037] Example 3 Preparation of N-cholylglutamic acid-deacetylcolchicine conjugate (Ia-3)

[0038] With deacetylcolchicine instead of trimethylcolchic acid, referring to the method of Example 1, compound Ia-3 was obtained, yield: 58%, TLC: chloroform: methanol = 25: 1, R f = 0.3. MS (m / e): 877.3 (M+1); elemental analysis (C 49 h 68 N 2 o 12 ): theoretical value C 67.10%, H 7.81%, N3.19%; experimental value C 67.25%, H 7.70%, N3.24%.

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PUM

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Abstract

The invention provides a coupling compound of cholic acid or bear deoxycholic acid and colchicine derivative which are as shown in formulas (Ia and Ib), salt thereof which is acceptable in non-toxicity pharmacy, a method for preparing the coupling compound and the salt and compositions and application of drugs containing the compounds. In a structural formula, R represents OH (cholic acid) or H (bear deoxycholic acid), A represents amino acid, n is an integer between 1 and 3, m is an integer between 0 and 2, the structural type of the amino acid is D type or L type, and D represents acetyl colchicine or colchicine and other active metabolites of the colchicine.

Description

technical field [0001] The present invention relates to new colchicine derivative-bile acid conjugates and their non-toxic pharmaceutically acceptable salts, pharmaceutical compositions containing these compounds as active ingredients and their use in the preparation of drugs for treating liver cirrhosis and liver fibrosis The application; the present invention also relates to the preparation method of colchicine derivative-bile acid conjugate and non-toxic pharmaceutically acceptable salt thereof. Background technique [0002] Liver cirrhosis is a major disease that threatens human health. Among the more than 500 million hepatitis B and C patients in the world, 25% will develop into liver cirrhosis; the development of fatty liver caused by various reasons (alcohol, obesity, diabetes, etc.) will also lead to liver cirrhosis. [0003] The results of clinical trials have shown that colchicine has a definite curative effect in the treatment of liver cirrhosis and liver fibrosi...

Claims

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Application Information

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IPC IPC(8): C07J9/00A61K47/48A61K31/165A61P1/16A61K47/54
Inventor 仲伯华马庆靳雪源陈兰福李美英牛俊奇
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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