A kind of cholic acid derivative and its preparation method and application

A technology of derivatives and cholic acids, applied in the field of cholic acid derivatives and their preparation, to achieve the effects of inhibiting liver cell damage, broad application prospects and inhibiting liver cell apoptosis

Active Publication Date: 2020-11-17
MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still few types of organic substances that can inhibit the apoptosis of hepatocytes

Method used

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  • A kind of cholic acid derivative and its preparation method and application
  • A kind of cholic acid derivative and its preparation method and application
  • A kind of cholic acid derivative and its preparation method and application

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preparation example Construction

[0064] The present invention provides the preparation method of cholic acid derivative described in above-mentioned scheme, comprises the following steps:

[0065] When R 1 with R 1 ’ Same, R 2 with R 2 ’ Same, R 3 with R 3 ’ same, when Y is the following group,

[0066]

[0067]

[0068] The preparation method of described cholic acid derivatives comprises the following steps:

[0069] (1) under the action of a condensing agent, the compound of the structure shown in formula A is reacted with N-hydroxysuccinimide to obtain an intermediate having the structure shown in formula 1-1;

[0070]

[0071] (2) The intermediate having the structure shown in formula 1-1, the compound Y1 and the solvent are mixed and reacted to obtain cholic acid derivatives; the compound Y1 has one of the following structures:

[0072]

[0073] Concrete synthetic route is as shown in formula one:

[0074]

[0075] In the present invention, under the action of a condensing agent, ...

Embodiment 1

[0126](4R,4'R)-N,N'-(ethane-1,2-diyl)bis(4-((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3 , 7-dihydroxyl-10,13-dimethylhexadecahydro-1H-cyclopenta[a]phenanthrene-17-yl) pentamide) synthesis; denoted as compound 1a, the steps are as follows:

[0127] Add ursodeoxycholic acid (10g, 25.47mmol), EDCI (4.40g, 38mmol), N-hydroxysuccinimide (3.5g, 30.5mmol) and anhydrous DMF (50mL) to the flask successively, at 35°C , Stir the reaction under the protection of argon for 12h. Water (120 mL) was added to the reaction and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated NaHCO 3 solution (3×50mL) and washed with Na 2 SO 4 dry. The extract was concentrated under reduced pressure to obtain the product (1-1) (8.08 g, 64%) as a white powder. 1 HNMR (600MHz, CD 3 OD-d 4 )δ3.55-3.46(m,2H),2.84(s,4H),2.72-2.64(m,1H),2.62-2.52(m,1H),2.07(dt,J=12.8,3.4Hz,1H) ,1.98-1.79(m,4H),1.68-1.18(m,16H),1.13(q,J=9.5Hz,1H),1.09-1.04(m,1H),1.03-0.98(m,6H),0.76 –0.7...

Embodiment 2

[0131] Ethane-1,2-diyl(4R,4'R)-bis(4-(((3R,5S,7S,8R,9S,10S,13R,14S,17R)-3,7-dihydroxy- 10,13-hexadecyldimethyl-1H-cyclopenta[a]phenanthrenyl-17-yl) pentanoate) synthesis, denoted as compound 2a; The steps are as follows:

[0132] Add ursodeoxycholic acid (3g, 7.64mmol), 1,4-dioxane (15mL), 3,4-dihydro-2H-pyran (1.93g, 22.9mmol) and p-toluenesulfonate to the flask successively Acid hydrate (0.29g, 1.53mmol), stirred at room temperature for 3h. Water (50 mL) was added to the reaction and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with anhydrous Na 2 SO 4 Dry, concentrate under reduced pressure, and purify by silica gel column chromatography. Elution with 1:10 to 1:5 ethyl acetate-n-hexane gave (2-1) (2.8 g, 65%) as a white powder. 1 ( m,22H),0.95–0.91(m,6H),0.69–0.63(m,3H).

[0133] Put (2-1) (0.5g, 0.9mmol), HOBT (0.15g, 1.08mmol), EDCI (0.35g, 1.8mmol), DBU (0.27g, 1.8mmol), and anhydrous DMF into the reaction bottle in turn , stirred a...

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Abstract

The invention relates to the technical field of medicine synthesis, and provides a cholic acid derivative as well as a preparation method and application thereof. The cholic acid derivative provided by the invention has a remarkable effect of inhibiting hepatocyte apoptosis, can effectively inhibit hepatocyte damage induced by glycochenodeoxycholic acid, and the inhibition rate of part of the derivative is superior to that of a positive control tauroursodeoxycholic acid; the cholic acid derivative provided by the invention provides a reference for research and development of liver protection drugs, and has a wide application prospect in preparation of the liver protection drugs.

Description

technical field [0001] The invention relates to the technical field of pharmaceutical synthesis, in particular to a bile acid derivative and its preparation method and application. Background technique [0002] Liver injury is a common pathological state in clinical practice. The causes of liver injury include hepatitis virus, alcohol, drug abuse, free fatty acid metabolism syndrome, immune-mediated inflammatory processes affecting the liver, and genetic diseases. Apoptosis of hepatocytes is a characteristic of liver injury, and at the same time, hepatocytes have a strong regenerative function through cell proliferation. For example, 70% of livers after hepatectomy regenerate to their original mass within about 1 week. However, when cell loss exceeds a certain threshold, liver regeneration is insufficient to counteract hepatocyte apoptosis, and functional hepatocytes are replaced by fibrotic scars, compromising liver function and ultimately leading to chronic liver disease....

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J9/00A61P1/16
CPCA61P1/16C07J9/00C07J9/005
Inventor 王玉成王菊仙何红伟牛伟萍牛伟晓张国宁朱梅王明华
Owner MEDICINE & BIOENG INST OF CHINESE ACAD OF MEDICAL SCI
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