Bile acid derivative and pharmaceutical use thereof

A bile acid and bile acid technology, applied in the preparation of bile acid nitrate derivatives and their pharmaceutically acceptable salts, in the field of medicine for diseases, can solve the problem of drug loss of targeting effect

Inactive Publication Date: 2007-02-07
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

[0015] The present invention solves the problem in the prior art that the ester bond between the carrier bile acid and the drug is easily hydrolyzed and causes the loss of the drug by providing the nitrate derivatives of cholic acid or ursodeoxycholic acid shown in the following formulas Ia and Ib Disadvantages of targeting

Method used

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  • Bile acid derivative and pharmaceutical use thereof
  • Bile acid derivative and pharmaceutical use thereof
  • Bile acid derivative and pharmaceutical use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0059] Example 1.N α - Preparation of ursodeoxycholoyl-(3-O-nitro-L-serine) (Ia-1)

[0060] 1.1 Synthesis of 3-O-nitro-L-serine nitrate

[0061] Take 25 ml of fuming nitric acid and put it into a three-necked flask, and cool it to -10°C in an ice-salt bath; add 5 grams of serine to the reaction solution in batches, control the temperature of the reaction solution below 0°C, and react for 30 minutes under stirring. After the reaction was completed, the reaction liquid was dropped into 100 ml of diethyl ether to precipitate a precipitate, which was collected by filtration, thoroughly washed with diethyl ether, and dried to obtain 7.9 g of a white solid with a melting point of 85-88°C and a yield of 78%. IR (film, cm -1 ): 3398, 3005, 1648, 1570, 1384, 1285, 985, 845, 757, 643. 1 H-NMR (DMSO-d 6 ): 8.53 (br s, 3H); 4.98 (q, 1H); 4.85 (q, 1H); 4.50 (br s, 1H). MS (FAB m / e): 211.9 (M+HNO 3 -1), 299.1(2M-1).

[0062] 1.2N α -Synthesis of ursodeoxycholoyl-(3-O-nitro-L-serine)...

Embodiment 2

[0064] Example 2.N α - Preparation of ursodeoxycholoyl-(3-O-nitro-D-serine) (Ia-2)

[0065] Using D-serine instead of L-serine, referring to the method of Example 1.1, 3-O-nitro-D-serine nitrate was obtained, yield: 72%, melting point: 87-91°C. 1 H-NMR (DMSO-d 6 ): 8.49 (brs, 3H) 5.01 (br m, 2H) 4.68 (br m, 1H). MS (FAB m / e): 151.1 (M+1) 301.0.1 (2M+1).

[0066] Using 3-O-nitro-D-serine nitrate instead of 3-O-nitro-L-serine nitrate, refer to the method of Example 1.2 to obtain the target compound Ia-2. Yield: 74%, melting point: 133-136°C. 1 H-NMR (DMSO-d 6 ): 13.16(br m, 1H); 8.38(d, 1H, J=7.0Hz); 4.84(m, 1H); 4.68(m, 2H); 2.16(br m, 2H); 1.99(s, 3H) ; 1.95-0.84 (brm, steroidal CH 2 and CH); 0.89 (d, 3H, J = 8.1 Hz); 0.61 (s, 3H).

Embodiment 3

[0067] Example 3.N α - Preparation of Choyl-(3-O-nitro-L-serine) (Ia-3)

[0068] Using cholic acid instead of ursodeoxycholic acid, referring to the method of Example 1.2, the target compound Ia-3 was obtained. Yield: 71%, melting point: 133-136°C. 1 H-NMR (DMSO-d 6 ): 13.11(br m, 1H); 8.38(d, 1H, J=7.2Hz); 4.81(brd, 1H); 4.69(m, 2H); 3.78(s, 1H); 3.61(s, 1H); 3.39 (q, 2H); 3.18 (br m, 1H); 2.23-1.07 (br m, steroidal CH 2 and CH); 0.93 (d, 3H, J = 5.9 Hz); 0.81 (s, 3H); 0.58 (s, 3H).

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Abstract

The invention discloses bile nitrate derivant in the Ia and Ib as drug composition of activated ingredient, which treats hepatitis virus, wherein R1 is trans- or cis-OH; R2 is H or OH; A is L- or D-serine, threonine or cysteine residue, cis- or trans-3-hydroxyproline or 4-hydroxyproline residue; X is oxygen or sulphur.

Description

technical field [0001] The invention relates to bile acid nitrate derivatives, pharmaceutically acceptable salts thereof, pharmaceutical compositions containing these compounds as active ingredients, and the use of the compounds for preparing medicines for treating diseases such as hepatitis. The invention also relates to a preparation method of bile acid nitrate derivatives and pharmaceutically acceptable salts thereof. Background technique [0002] Viral hepatitis, liver fibrosis, liver cirrhosis and other liver diseases have a high incidence rate and are difficult to treat. 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. Portal hypertension is one of the main complications of liver cirrhosis. Patients will experience symptoms such as rupture of esophageal and gastric varices, ascites...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07J9/00A61K31/575A61K9/08A61K9/20A61K9/48A61P1/16
Inventor 仲伯华李宏武刘河陈兰福吴波
Owner INST OF PHARMACOLOGY & TOXICOLOGY ACAD OF MILITARY MEDICAL SCI P L A
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