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Preparation method and application of a class of continuon-type macrocyclic diterpenoids

A technology of sacron-type and compound, which is applied in the field of preparation of continu-type macrocyclic diterpene compounds, can solve problems such as toxicity, and achieve the effect of improving the degree of liver damage and good PXR agonistic activity

Active Publication Date: 2022-07-19
GUANGZHOU ZHONGDA NANSHA TECH INNOVATION IND PARK
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Also has a certain toxicity

Method used

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  • Preparation method and application of a class of continuon-type macrocyclic diterpenoids
  • Preparation method and application of a class of continuon-type macrocyclic diterpenoids
  • Preparation method and application of a class of continuon-type macrocyclic diterpenoids

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Example 1: Preparation of Compounds 1 to 5

[0049]

[0050] The seeds (8kg) of S. japonica were soaked with 95% ethanol (75L×3) to obtain 817.2g crude extract. The extract was dispersed in water (3 L) and extracted with petroleum ether, ethyl acetate and n-butanol in sequence. The ethyl acetate fractional extract (352.8 g) was subjected to gradient elution (MeOH / H) with D101 macroporous adsorption resin 2 O, 6:4→10:0) separated into three parts (Fr.I-III). The Fr.II part (215.6 g) was separated into four parts (Fr.IIA-IID) by normal phase silica gel column chromatography (PE / EtOAc, 50:1→1:1). Fr.IIC segment (2.9g) by reversed phase C 18 Silica gel column chromatography (MeOH / H 2 O,6:4→10:0) separated into five parts (Fr.IIC 1 -IIC 5 ), where Fr.IIC 1 A fraction (132.2 mg) was subjected to normal phase silica gel column chromatography (CH 2 Cl 2 / MeOH, 100:1→0:1) gradient elution separation and semi-preparative chiral separation HPLC (MeCN / H 2 O, 75 / 25, 3mL...

Embodiment 2

[0062] Example 2: Preparation of Compound 8

[0063]

[0064] Fr.IIC in Example 1 2 Fragment (1.435g) was separated by Sephadex LH-20 gel column (MeOH) and then by normal phase silica gel column chromatography (PE / EtOAc, 10:1→0:1) to obtain three segments (Fr.IIC). 2a -IIC 2c ). Fr.IIC 2a (207.2 mg) by normal phase silica gel column chromatography (PE / EtOAc, 15:1→0:1) followed by semi-preparative chiral separation by HPLC (MeCN / H 2 O, 70 / 30, 3 mL / min) to obtain compound 8 (67.3 mg, t R 8.9min).

[0065] figure 1 and figure 2 They are the H NMR, C and DEPT135 spectra of compound 8, respectively. Its spectral data is consistent with the known compound Euphorbia Factor L 9 Consistent.

Embodiment 3

[0066] Example 3: Preparation of Compound 17

[0067]

[0068]Compound 15 (30 mg, 0.047 mmol) was dissolved in 2 mL of methanol, 1% sodium hydroxide was added, and the reaction was carried out at room temperature for 1 hour. The reaction solution was quenched with 5 mL of water, and extracted with ethyl acetate (5 mL×3). The organic layer was concentrated and spun dry, and purified by silica gel column chromatography CC (PE / EtOAc, 10:1) to give compound 17 (15.3 mg).

[0069] Its spectral data are consistent with literature reports, so its structure is determined.

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PUM

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Abstract

The invention discloses a preparation method and application of a class of continuation alkane-type macrocyclic diterpene compounds. For the first time, the present invention uses the continuation alkane-type macrocyclic diterpenoids in the preparation of anti-cholestasis medicines. The results of cell experiments show that the sacronane-type macrocyclic diterpene compounds in the present invention have good pregnane X receptor agonist activity and anti-cholestasis activity, and are expected to be developed into novel pregnane X receptor agonists and anti-cholestatic agents. Cholestatic drugs.

Description

technical field [0001] The invention relates to the field of medicine, and in particular relates to a preparation method and application of a class of sequelae-type macrocyclic diterpenoids. Background technique [0002] Cholestasis is an important pathological process in which the continuous progress of bile secretion and excretion disorders eventually leads to a series of hepatobiliary diseases. Long-term cholestasis usually causes a series of hepatobiliary diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, etc., and eventually develops into liver fibrosis and even liver cirrhosis, which seriously threatens human life and health. According to statistics, about 60% of the above-mentioned hepatobiliary diseases are accompanied by cholestasis. At present, there are only 2 anti-cholestasis drugs approved by the FDA, which can improve the symptoms of patients to a certain extent, but there are also serious adverse reactions such as abnormal thyroid fu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K31/122A61K31/336A61K31/341A61K31/381A61K31/4406A61K31/235A61K31/216A61K31/22A61K31/4427A61P1/16C07C67/48C07C67/56C07C69/78C07C69/618C07C69/21C07D213/80C07D213/803C07D405/12C07D303/32C07D301/32C07C45/64C07C49/743C07D307/68C07D333/38C07D493/10C07C67/29C07C67/283C07C67/293
CPCA61K31/122A61K31/336A61K31/341A61K31/381A61K31/4406A61K31/235A61K31/216A61K31/22A61K31/4427A61P1/16C07C67/48C07C67/56C07C69/78C07C69/618C07C69/21C07D213/80C07D213/803C07D405/12C07D303/32C07D301/32C07C45/64C07C49/743C07D307/68C07D333/38C07D493/10C07C67/29C07C67/283C07C67/293C07B2200/07C07C2603/38
Inventor 毕惠嫦尹胜刘培庆黄冬
Owner GUANGZHOU ZHONGDA NANSHA TECH INNOVATION IND PARK
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