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Cholic acid derivative and preparation method and application thereof

A kind of derivative, cholic acid technology, applied in the field of medicine and its preparation and application, can solve the problems of gastrointestinal discomfort, peripheral neuropathy and the like

Active Publication Date: 2019-12-10
EAST CHINA NORMAL UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] However, it cannot be ignored that statins have some serious side effects, the most common of which are liver damage and myopathy (myalgia, myositis, rhabdomyolysis, etc.), and other manifestations include gastrointestinal discomfort, headache, sleeplessness, etc. disorder, peripheral neuropathy

Method used

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  • Cholic acid derivative and preparation method and application thereof
  • Cholic acid derivative and preparation method and application thereof
  • Cholic acid derivative and preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0262] Example 1 Preparation of Compounds 13 and 36

[0263] The compound Lithocholic acid (3.76g, 10mmol) was dissolved in anhydrous methanol (150mL), and SOCl was added dropwise at 0°C 2 (4.76g, 2.9mL, 40mmol), after the dropwise addition was completed, it was naturally warmed to room temperature and stirred for 5h. After the complete reaction was detected by TLC, the reaction solution was concentrated, then ethyl acetate (250 mL) was added to dissolve the residue, and the organic phase was successively washed with saturated NaHCO 3 solution (3×50mL), washed with saturated NaCl solution (3×50mL), anhydrous NaCl 2 SO 4 It was dried, concentrated, and purified by silica gel column chromatography (PE:EA=3:1) to obtain compound 1 (3.88 g, 99%) as a white solid. 1 H NMR (500MHz, CDCl 3 )δ3.67(s,3H),3.59-3.65(m,1H),2.30-2.40(m,1H),2.20-2.26(m,1H),1.93-1.99(m,1H),1.74-1.90( m,5H),1.63-1.73(m,2H),1.57-1.60(m,1H),1.48-1.54(m,1H),1.23-1.44(m,11H),1.02-1.17(m,5H), 0.92(s,3H),0.91...

Embodiment 2

[0281] Example 2 Preparation of Compounds 14, 37, 15, 38, 19 and 42

[0282] Compound 13 (56mg, 0.13mmol) was dissolved in anhydrous methanol (10mL). After complete dissolution, 4M NaOH solution (2mL) was added to the reaction system, and the system immediately became cloudy. After the addition was complete, it was stirred at room temperature for 24h. After the complete reaction was detected by TLC, the reaction solution was concentrated, and then H was added to the residue. 2 O (10mL), and then use 1M hydrochloric acid to adjust the pH of the solution to be about 3, a large amount of white solid is precipitated, the white solid is filtered out, and then the white solid is dissolved with anhydrous methanol, and anhydrous Na 2 SO 4 It was dried, concentrated, and purified by silica gel column chromatography (DCM:MeOH=20:1) to obtain compound 14 (52 mg, 95%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ11.94(brs,1H),5.36(d,J=2.7Hz,1H),4.50-4.56(m,1H),4.15-4.20(m,1H),3.58-3.6...

Embodiment 3

[0294] Example 3 Preparation of Compounds 20-22 and 43-45

[0295] Dissolve compound 13 (87mg, 0.2mmol) in anhydrous THF (12mL), slowly add CH 3 The THF solution of MgCl (1.0M, 2mL) was added dropwise, and reacted for about 0.5h after naturally rising to room temperature. After the complete reaction was detected by TLC, slowly add saturated NH 4 Cl solution until no bubbles were generated, the solid was filtered out with suction, the filtrate was extracted with ethyl acetate (3×50mL), the combined organic phases were washed with saturated NaCl solution (3×30mL), anhydrous NaCl 2 SO 4 It was dried, concentrated, and purified by silica gel column chromatography (PE:EA=1:1) to obtain compound 20 (69 mg, 80%) as a white solid. 1 H NMR (500MHz, DMSO-d 6 )δ5.35(d,J=2.3Hz,1H),4.51-4.54(m,1H),4.15-4.19(m,1H),4.02(s,1H),3.57-3.64(m,1H),2.96 -3.05(m,1H),1.89-1.95(m,1H),1.72-1.82(m,2H),1.57-1.66(m,2H),1.49-1.57(m,1H),1.36-1.46(m, 4H),1.27-1.36(m,4H),1.14-1.25(m,3H),1.02-1.07(m,4H),...

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Abstract

The invention discloses a cholic acid derivative represented by the formula (I) and a preparation method thereof. The target product cholic acid derivative is prepared by esterification, oxidation, bromination, debromination, 4,4-dimethylation, C-7 oxidation, reduction, TBSCl protection, iodation, cyano substitution, Wittig, Grignard, TBS-removing protection and other reactions. The invention alsoprovides an application of the cholic acid derivative in inhibiting cholesterol synthesis and reducing cholesterol and triglyceride levels in a body; the cholic acid derivative can be used for preparing drugs for preventing and treating hypercholesterolemia, hypertriglyceride, atherosclerosis and other diseases, and has good application prospects.

Description

technical field [0001] The invention belongs to the technical field of medicine and its preparation and application, and in particular relates to a cholic acid derivative and its preparation method and application. Background technique [0002] Hypercholesterolemia is one of the serious diseases that endanger people's health, and it is an independent and important risk factor for stroke, coronary heart disease, myocardial infarction, and sudden cardiac death. The damage of hypercholesterolemia to the body is hidden, gradual, progressive and systemic, and its direct damage is to accelerate systemic atherosclerosis. Because vital organs of the whole body rely on arteries for blood and oxygen supply, once the arteries are blocked by atheromatous plaques, serious consequences will result. Renal failure caused by arteriosclerosis is also closely related to hypercholesterolemia. In addition, hypercholesterolemia is also an important risk factor for hypertension, impaired glucose...

Claims

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Application Information

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IPC IPC(8): C07J9/00A61P9/10A61P3/06A61K31/575
CPCC07J9/00C07J9/005A61P3/06A61P9/10
Inventor 汤杰宋保亮杨帆仇文卫江世友李慧
Owner EAST CHINA NORMAL UNIV
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