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Bile acid-drug conjugate with amino acid as connexon, and medical application thereof

A technology of bile acid and conjugates, which is applied in the field of bile acid-drug conjugates with amino acids as linkers and their medical applications, which can solve the problems of difficult cross-linking, great influence on physical and chemical properties and biological properties, etc.

Inactive Publication Date: 2015-01-21
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

[0003] However, as a small molecule carrier, bile acid is difficult to cross-link, and the cross-linking with drugs has a great influence on its physical, chemical and biological properties.

Method used

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  • Bile acid-drug conjugate with amino acid as connexon, and medical application thereof
  • Bile acid-drug conjugate with amino acid as connexon, and medical application thereof
  • Bile acid-drug conjugate with amino acid as connexon, and medical application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0042] Embodiment 1 cholic acid-L-alanine-ribavirin conjugate (I 1 ) preparation

[0043]

[0044] 1.1 Synthesis of benzyloxycholate (II 1 )Synthesis

[0045] Dissolve 41g of cholic acid in 200ml of dimethylformamide, then add 20ml of dicyclohexylamine, stir at room temperature, and add 12ml of benzyl bromide dropwise. The reaction was stirred overnight, and the solvent was evaporated under reduced pressure. Add 800ml of ethyl acetate to the residue, stir, and filter; the filtrate is washed with saturated NaHCO 3 Washed with aqueous solution (2X300ml), the organic layer was separated and dried overnight with anhydrous sodium sulfate. The desiccant was filtered off, the filtrate was evaporated to dryness under reduced pressure, separated by silica gel column chromatography, and eluted with a mixed solvent of petroleum ether: ethyl acetate: methanol (10:10:1), the desired components were collected, and evaporated to dryness under reduced pressure , get II 1 36.5 g of wh...

Embodiment 2

[0054] Embodiment 2 cholic acid-L-valine-ribavirin conjugate (I 2 ) preparation

[0055]

[0056] With reference to the method of Example 1.3, replace L-alanine hydrochloride and III with L-valine hydrochloride 1 Reaction, the reaction product is separated and purified to obtain 3-O-((S)-1-carboxy-2-methylpropylaminocarbonyl)-benzyloxycholate IV 2 , yield 32%.

[0057] With reference to the method of embodiment 1.4, use IV 2 instead of IV 1 React with ribavirin, and the reaction product obtains benzyl cholate-L-valine-ribavirin conjugate (V 2 ), yield 58%.

[0058] Referring to the method of Example 1.5, V 2 Catalytic hydrogenation, the reaction product is separated and purified to obtain the target compound I 2 , yield 91%. Elemental analysis (C 38 h 59 N 5 o 12 ) Theoretical value (%): C58.67, H7.64, N9.00; Experimental value (%): C58.92, H7.69 N9.17.

Embodiment 3

[0059] Embodiment 3 cholic acid-L-leucine-ribavirin conjugate (I 3 ) preparation

[0060]

[0061] With reference to the method of Example 1.3, replace L-alanine hydrochloride and III with L-leucine hydrochloride 1 Reaction, the reaction product is separated and purified to obtain 3-O-((S)-1-carboxy-3-methylbutylaminocarbonyl)-benzyloxycholate IV 3 , yield 39%.

[0062] With reference to the method of embodiment 1.4, use IV 3 instead of IV 1 React with ribavirin, and the reaction product is separated and purified to obtain benzyl cholate-L-leucine-ribavirin conjugate (V 3 ), yield 36%.

[0063] Referring to the method of Example 1.5, V 3 Catalytic hydrogenation, the reaction product is separated and purified to obtain the target compound I 3 , yield 93%. Elemental analysis (C 39 h 61 N 5 o 12 ) Theoretical value (%): C59.15, H7.76, N8.84; Experimental value (%): C58.95, H7.90 N9.11.

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Abstract

The invention relates to a bile acid-drug conjugate with amino acid as a connexon, and non-toxic pharmaceutically acceptable salts, hydrates, or solvates thereof. The bile acid-drug conjugate has an anti-hepatitis-virus or anti-tumor effect. The bile acid-drug conjugate is represented by a formula I. In the structural formula I, R1 represents H, methyl, isopropyl, isobutyl or benzyl. When R1 is not H, the configuration of carbon atom connected with R1 is D- or L-. R2 represents H or OH. R3 represents -OR4, -NHCH2COOR4 or -NHCH2CH2SO3H. R4 represents H or C1-C5 alkyl. N is an integer of 0 or 1-6. D- is a residue with active hydroxyl drug. That is to say, D-OH is a drug molecule with active hydroxyl.

Description

technical field [0001] The present invention relates to conjugates of bile acids and hydroxyl-containing drugs through amino acid linkers and non-toxic pharmaceutically acceptable salts thereof, as well as pharmaceutical compositions containing these conjugates as active ingredients, these conjugates and their non-toxic Toxic pharmaceutically acceptable salts and pharmaceutical compositions containing these compounds as active ingredients are used in the preparation of medicines for treating viral hepatitis, liver cancer and other diseases. Background technique [0002] Bile acids are endogenous hepatocyte-specific natural ligands. After oral administration, bile acids are quickly absorbed from the intestines into the liver, combined with glycine or taurine in the liver, discharged into the small intestine with bile, and then absorbed into the liver; during the enterohepatic circulation, only a small amount of drugs enter the blood, so they have High degree of organ specifi...

Claims

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Application Information

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IPC IPC(8): C07J43/00C07J17/00A61K47/48A61K31/7056A61K31/7068A61P1/16A61P31/12A61P35/00
CPCC07J43/003C07J41/0055C07J43/00
Inventor 仲伯华靳雪源祝传宝姚宜山樊士勇史卫国贾红新
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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