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Chenodeoxycholic acid derivative or its pharmaceutically acceptable salt, its preparation method and use

A technology of chenodeoxycholic acid and derivatives, applied in the field of medicinal chemistry

Active Publication Date: 2021-06-11
CHINA PHARM UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

FXR agonists are mainly divided into steroidal and non-steroidal structures. Currently, there are few drugs on the market, and they are mainly used for the treatment of NASH, biliary cirrhosis, and cholangitis. There are few reports on the research and development of lipid-regulating drugs.

Method used

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  • Chenodeoxycholic acid derivative or its pharmaceutically acceptable salt, its preparation method and use
  • Chenodeoxycholic acid derivative or its pharmaceutically acceptable salt, its preparation method and use
  • Chenodeoxycholic acid derivative or its pharmaceutically acceptable salt, its preparation method and use

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Experimental program
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preparation example Construction

[0032] The synthetic method of partial compound 7 (7a, 7b, 7c, 7d, 7e, 7f, 7g, 7h) of the present invention comprises the following steps:

[0033]

[0034] Reagents and conditions: (a) CH 3 OH; (b)Ac 2 O, DCM; (c) NaOCl, CH 3 COOH, EA; (d) NaOH, HCl; (e) CH 3 OH; (f)NH 2 OH HCl, NaOH, EtOH; (g) LiOH, CH 3 COOH; (h)R-OH, H 2 SO 4 or R-NH, EDCI, HOBt, Et 3 N.

[0035] Some compounds were prepared as follows:

[0036] Melting point was measured by XRC-1 micro melting point apparatus (the thermometer was not calibrated), IR was measured by Nicolet iS10 Fourier transform infrared spectrometer (KBr tablet), 1H-NMR nuclear magnetic resonance was measured by BrukerAV300 (300MHz) nuclear magnetic resonance instrument (TMS is the internal standard), and the mass spectra were determined by Agilem Q-TOF 6520 (HR-MS) and Agilent 1100LC-MSD-Trap / SL mass spectrometer (ESI-MS), respectively.

[0037] The column chromatography silica gel is 100-200 mesh or 200-300 mesh silica gel...

Embodiment 1

[0039] Synthesis of intermediate 3α, 7α, 12α-trihydroxy-5β-cholanoic acid methyl ester (2)

[0040] Cholic acid (5g, 12.2mmol) was dissolved in methanol, and a few drops of H 2 SO 4 , heated to 60°C, and refluxed for 5h. Methanol was removed under reduced pressure to obtain 5 g of crude product, which was directly dropped. Yield: 96.7%. MS m / z[M+H] + = 423.3.

Embodiment 2

[0042] Synthesis of intermediate 3α, 7α-acetoxy-12α-hydroxy-5β-cholanoic acid methyl ester (3)

[0043] Intermediate 2 (crude product 5g, 11.8mmol) was dissolved in DCM, triethylamine (2.6ml), DMAP (75mg, 0.61mmol) were added, acetic anhydride (3.6g, 35.4mmol) was added dropwise, and reacted at room temperature for 3h. Add H 2 O quenched the reaction and stirred for 2h. with DCM and H 2 O extraction, saturated brine dehydration, anhydrous Na 2 SO 4 Dry and spin dry under reduced pressure. Purified by column chromatography, compound 3.3g. Yield: 58.9%. MS m / z[M+H] + = 507.3.

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Abstract

The invention discloses a chenodeoxycholic acid derivative with the structure of general formula I or a pharmaceutically acceptable salt thereof, a preparation method and application thereof, the compound can upregulate the transcription level of FXR mRNA and SHP mRNA, can obviously activate FXR, and can be used It can be used to prepare medicines for treating or preventing hyperlipidemia, atherosclerosis, non-alcoholic steatohepatitis, type II diabetes and other diseases related to blood lipids.

Description

technical field [0001] The invention relates to the technical field of medicinal chemistry, in particular to a chenodeoxycholic acid derivative or a pharmaceutically acceptable salt thereof, a preparation method and application thereof. Background technique [0002] Dyslipidemia is a systemic disease in which one or more lipids in plasma are higher than normal due to abnormal lipid metabolism or operation, which is manifested as high total cholesterol (TC) and / or triglyceride (TG) in blood Or high-density lipoprotein cholesterol (HDL-C) is too low. Dyslipidemia can lead to metabolic diseases such as atherosclerosis, non-alcoholic fatty liver, and type II diabetes. The incidence of cardiovascular disease is closely related to the level of lipoprotein in the body, and the increase of TG, the increase of LDL-C and the decrease of HDL-C are the main risk factors of cardiovascular disease. [0003] Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, is a l...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00C07J43/00A61P3/06A61P9/10A61P1/16A61P3/10A61K31/575A61K31/58A61K31/56
CPCA61P1/16A61P3/06A61P3/10A61P9/10C07J41/0055C07J41/0061C07J43/003
Inventor 向华肖茂旭任胜楠陶睿骆国顺
Owner CHINA PHARM UNIV