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Novel coupling compound of bile acid and anti-hepatitis virus medicament and medical use thereof

An anti-hepatitis virus and bile acid technology, applied in the preparation of viral hepatitis therapeutic drugs, in the field of salt preparation, can solve the problems of complex chemical composition, small drug loading and the like

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

[0005] 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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  • Novel coupling compound of bile acid and anti-hepatitis virus medicament and medical use thereof
  • Novel coupling compound of bile acid and anti-hepatitis virus medicament and medical use thereof
  • Novel coupling compound of bile acid and anti-hepatitis virus medicament and medical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Example 1 Synthesis of α-cholyl-benzyloxycarbonyl-lysine methyl ester (I)

[0028] Weigh 1.08g (5.25mM) DCC and dissolve it in 5ml tetrahydrofuran, and put it in the refrigerator to cool. Weigh 2.04g (5mM) cholic acid and dissolve it in 10ml tetrahydrofuran, stir to dissolve it, cool in an ice-salt bath, add 0.766g (5mM) HOBt below 0°C, 2.4g ε-benzyloxycarbonyl-lysine methyl ester ( 5mM), 0.55ml N-methylmorpholine, stirred, kept below 0°C and poured into cold DCC solution in tetrahydrofuran, kept below 0°C and stirred for 2 hours, removed the ice bath, and stirred overnight at room temperature. The white insoluble solid was filtered off, and tetrahydrofuran was distilled off under reduced pressure to obtain a yellow viscous liquid, which was dissolved in ethyl acetate, washed successively with saturated NaHCO3 aqueous solution, 10% citric acid solution, saturated NaHCO3 aqueous solution and saturated NaCl aqueous solution, and the organic layer was collected and washed ...

Embodiment 2

[0030] Example 2 Synthesis of α-choyl-lysine methyl ester (II)

[0031] Weigh an appropriate amount of 10% palladium carbon in a round bottom bottle, add a small amount of anhydrous methanol to make it suspended under an ice bath (to prevent burning), dissolve 2 g of I with a small amount of methanol, and slowly pour it into the methanol solution of palladium carbon. Catalyzed hydrogenation until the reaction was complete, filtered off palladium carbon, washed with anhydrous methanol, combined the filtrates, evaporated the solvent under reduced pressure to obtain a light yellow viscous liquid, added anhydrous diethyl ether to grind it to solidify, and filtered to obtain 1.45 g of a near-white solid. Yield 90%.

[0032] TLC: developing solvent: ethyl acetate: methanol: ammonia water (6:4:1 drops), Rf=0.4

Embodiment 3

[0033] Example 3 Synthesis of choyl-lysine methyl ester-adenosine monophosphate (III)

[0034]Dissolve 0.5g II in 10ml Na2CO3 / NaHCO3 buffer solution of pH 9.50, add 1g adenosine adenosine monophosphate phosphoryl imidazole (ara-AMPIm), react at 40°C for 48 hours, remove the solvent under reduced pressure to obtain a viscous liquid , adding anhydrous ether, ground and solidified, and filtered to obtain a light yellow solid mixture. This mixture was separated with a 27×33cm thin-layer silica gel preparation plate, and 200 mg of the sample was loaded each time, dissolved in methanol, and evenly coated on the bottom of the thin plate, and washed with isopropyl Alcohol:methanol:ammonia water (6:3:1) was developed as a developer, and the product band at Rf0.52 was scraped off and eluted with methanol to obtain 0.3g of light yellow solid (III), with a yield of 40%.

[0035] TLC: developing solvent: isopropanol: methanol: ammoniacal liquor (6:3:1), Rf=0.45

[0036] MS(m / e):894.9(M+1)...

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Abstract

The invention relates to a bile acid-anti-hepatitis virus drug conjugate which is shown in the following formula, non-toxic pharmaceutically acceptable salts thereof, a preparation method, a pharmaceutical composition containing the compounds and a use. In the structural formula of figure (I), R represents OH (bile acid) or H (ursodeoxycholic acid), A represents amino acid, n is an integer from 1 to 3, and the structure of the amino acid is D type or L type. D represents the above structure (II).

Description

technical field [0001] The present invention relates to new bile acid-anti-hepatitis virus drug conjugates and non-toxic pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing these compounds as active ingredients, and these conjugates and non-toxic pharmaceutically acceptable salts thereof Accepted salts and pharmaceutical compositions containing these compounds as active ingredients are used in the preparation of drugs for the treatment of viral hepatitis; the present invention also relates to the preparation of nucleoside derivatives of bile acids and their non-toxic pharmaceutically acceptable salts method. Background technique [0002] Viral hepatitis is a major disease that threatens human health. The number of people infected with hepatitis B virus and hepatitis C virus in the world is as high as 360 million and 170 million respectively, while in my country, 120 million and 40 million people are infected with hepatitis B virus or...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K47/28A61K31/675A61K31/7056A61K31/7076A61K9/08A61K9/20A61K9/48A61P1/16A61P31/14A61P31/20A61K47/54
Inventor 仲伯华王文靳雪源陈兰福刘河牛俊奇
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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