Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof

A technology of pentacyclic triterpenoids and conjugates, which is applied in the field of prodrugs of amino acid conjugates of pentacyclic triterpenoids and their medical applications, and can solve the problems that oral preparations are difficult to exert curative effect.

Inactive Publication Date: 2009-11-18
BEIJING MEIBEITA DRUG RES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, its oral preparations are di

Method used

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  • Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof
  • Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof
  • Amino acid conjugate prodrug of pentacyclic triterpenoid and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 3-O-(glycyl)-oleanolic acid (I 1 ) preparation

[0021] Dissolve 2.3g (5.0mmol) oleanolic acid, 1.1g (5.0mmol) N-benzyloxycarbonylglycine with 25ml dimethylformamide, then add 0.1ml dimethylaminopyridine, 1.3g (6mmol) dicyclohexyl Carbodiimide, stirred overnight at room temperature, filtered, and evaporated the filtrate to dryness under reduced pressure. The residue was separated by silica gel column chromatography, eluted with a mixed solvent of dichloromethane / methanol / acetic acid (9:1:0.01), and the desired components were collected and evaporated to dryness under reduced pressure to obtain 3-O-(N-benzyl Oxycarbonylglycyl)-oleanolic acid 2.4 g.

[0022] Dissolve 2.4 g of 3-O-(N-benzyloxycarbonylglycyl)-oleanolic acid in 25 ml of dioxane, add 0.2 g of 5% palladium carbon, and stir for 4 hours under 1 atmosphere of hydrogen Afterwards, the catalyst was filtered off. The filtrate was concentrated under reduced pressure, then separated by silica gel column ...

Embodiment 2

[0024] Example 2 3-O-(L-alanyl)-oleanolic acid (I 2 ) preparation

[0025] According to the method of Example 1, replace N-benzyloxycarbonylglycine with N-benzyloxycarbonyl-L-alanine, and condense with oleanolic acid under the action of dicyclohexylcarbodiimide to obtain 3-O-( N-Benzyloxycarbonyl-L-alanyl)-oleanolic acid.

[0026] According to the method of Example 1, replace 3-O-(N-benzyloxycarbonylglycyl)-oleanolic acid with 3-O-(N-benzyloxycarbonyl-L-alanyl)-oleanolic acid, Catalytic hydrogenation deprotection affords I 2 . Proton NMR spectrum: δ(ppm, DMSO-d 6 ):0.72(S,3H);0.82(S,3H);0.87(S,3H);0.90(S,3H);0.91(S,3H);0.95(S,3H);1.11(S,3H) ;1.26(d,3H);2.76(br d,1H);3.54(q,1H);4.78(dd,1H);5.16(br s,1H);8.27(br s,2H); , 1H).

Embodiment 3

[0027] Example 3 3-O-(L-valyl)-oleanolic acid (I 3 ) preparation

[0028] According to the method of Example 1, replace N-benzyloxycarbonylglycine with N-benzyloxycarbonyl-L-valine, and condense with oleanolic acid under the action of dicyclohexylcarbodiimide to obtain 3-O- (N-Benzyloxycarbonyl-L-valyl)-oleanolic acid.

[0029] Using 3-O-(N-benzyloxycarbonyl-L-valyl)-oleanolic acid instead of 3-O-(N-benzyloxycarbonylglycyl)-oleanolic acid, catalytic hydrogenation deprotection, to obtain I 3 . Proton NMR spectrum: δ(ppm, DMSO-d 6 ):0.73(S,3H);0.82(S,3H);0.87(S,3H);0.90(S,3H);0.91(S,3H);0.92(m,6H);0.96(S,3H) ; 1.11(S, 3H); 2.25(m, 1H); 2.75(br d, 1H); 3.69(m, 1H); 4.76(dd, 1H); 2H); 12.20 (br S, 1H).

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Abstract

The invention provides a conjugate formed by pentacyclic triterpenoid and amino acid through an ester bond or an urethane bond of the formula I and the formula II, wherein R1 is hydrogen, a methyl, an isopropyl, an isobutyl, a 2-methylpropyl or a benzyl; X is H2 or O; R2 is H, CH3 or COOH; R3 is CH3 or COOH; and R4 is H or CH3.

Description

Technical field: [0001] The present invention relates to prodrugs formed by coupling pentacyclic triterpenes such as oleanolic acid, glycyrrhetinic acid and ursolic acid with amino acids through ester bonds or carbamate bonds and their non-toxic pharmaceutically acceptable salts ; and pharmaceutical compositions containing these compounds as active ingredients and their use in the preparation of drugs for treating hepatitis. technical background: [0002] Pentacyclic triterpenoids such as oleanolic acid, glycyrrhetinic acid, and ursolic acid have various biological activities such as liver protection and detoxification, anti-inflammatory, anti-ulcer, anti-virus, and anti-tumor, and are used clinically to treat various acute and chronic hepatitis. Its chemical structure is as follows: [0003] [0004] Glycyrrhetinic acid Oleanolic acid Ursolic acid [0005] However, these compounds have poor water solubility and low oral bioavailability, for example, the absolute bi...

Claims

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Application Information

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IPC IPC(8): C07J63/00A61K31/56A61P1/16
Inventor 杨美英李小明
Owner BEIJING MEIBEITA DRUG RES
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