Kaurene diterpene derivative, medicinal composition thereof and application of kaurene diterpene derivative to medicament

A technology of kaurane-type and derivatives, which is applied in the field of kaurene-type diterpene derivatives, and can solve problems such as the limitation of clinical application value

Active Publication Date: 2012-07-25
KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

CBX is a non-selective 11β-HSD1 inhibitor, which can simultaneously inhibit 11β-HSD1 and 11β-HSD2, and its clinical application value is greatly limited

Method used

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  • Kaurene diterpene derivative, medicinal composition thereof and application of kaurene diterpene derivative to medicament
  • Kaurene diterpene derivative, medicinal composition thereof and application of kaurene diterpene derivative to medicament
  • Kaurene diterpene derivative, medicinal composition thereof and application of kaurene diterpene derivative to medicament

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Preparation of compound K1:

[0051]Dried plant chrysanthemum (Nonelia insignis Franech) branches and leaves 22kg, after crushing, use 95% ethanol to extract three times (20L / time, 2 days / time), extract with ethyl acetate after concentrating, obtain crude product ( 750g), the crude product (200g) was segmented with silica gel (1000g) mixing column chromatography (sequentially with petroleum ether / acetone (9.5:0.5), acetone, methanol elution), wherein the crude product (113g) of the large polar section was repeatedly used Compound K1 (65 g) was obtained by normal and reverse phase column chromatography.

Embodiment 2

[0053] Preparation of compounds A, B, C, K2:

[0054] Dried plant Dalibai (Diplopterygium gigantean (wall.) Nakai) aerial part 5.4kg, crushed and extracted three times (15L / time) with 95% ethanol, the extract was suspended in water, then extracted four times with ethyl acetate, the organic phase After concentrating, it was dissolved with methanol, decolorized by MCI column, and then the extract was mixed with silica gel and column chromatography was segmented, and the small polar segment was repeatedly used for positive and negative phase column chromatography to obtain compounds A (450mg), B (18mg), and C (14mg) , K2 (3g).

Embodiment 3

[0056] Preparation of Compound K3

[0057]

[0058] Under ice-water bath condition, in the DCM (1.5mL) solution of compound K1 (33mg), add PDC (58mg), make it rise to room temperature naturally after reacting for 2 hours, TLC finds that the reaction is complete, and the reaction solution is directly column chromatographed ( Petroleum ether:ethyl acetate=3:1) to obtain compound K3 (31 mg, 95%).

[0059] Compound K3: white solid, 1 H NMR (500MHz, MeOD) δ6.03(s, 1H), 5.42(s, 1H), 3.28(s, 1H), 2.82(d, J=12Hz, 1H), 2.65(dd, J=12Hz, 4Hz , 1H), 2.57(d, J=12Hz, 1H), 2.20(d, J=8Hz, 1H), 2.02(m, 1H), 1.97(d, J=12Hz, 1H), 1.92(s, 1H) , 1.89(d, J=4Hz, 1H), 1.88(s, 1H), 1.80(d, J=8Hz, 1H), 1.70-1.76(m, 2H), 1.59(s, 1H), 1.57(d, J=4Hz, 1H), 1.48(d, J=8Hz, 1H), 1.29(s, 3H), 1.25(d, J=4Hz, 4H), 1.23(dd, J=12Hz, 4Hz, 2H), 1.09 (dd, J=12Hz, 4Hz, 1H), 1.02(s, 3H), 0.88(t, J=8Hz, 4Hz, 1H).

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Abstract

The invention provides a kaurene diterpene derivative shown as a general formula (I) and replaced by different groups at loci C-11, C-15, C-16 and C-19, a medicinal composition taking the kaurene diterpene derivative as an active ingredient, preparation methods thereof, and an application of the kaurene diterpene derivative to preparation of a type 1 11beta-hydroxysteroid dehydrogenase (11beta-HSD1) inhibitor. The invention further provides an application of a compound shown as a general formula (I) to preparation of a medicament for treating diabetes and relevant metabolic diseases (hypertension, obesity, senile dementia and the like).

Description

Technical field: [0001] The invention belongs to the technical field of pharmaceutical compounds and medicines, and in particular relates to a class of kaurane-type diterpene derivatives, the pharmaceutical composition of which is the active ingredient, its preparation method and the preparation of type 1 11-beta-hydroxysteroid dehydrogenase (11beta-HSD1) selective inhibitor neutralizing the application of anti-diabetic and related metabolic (hypertension, obesity, senile dementia, etc.) drugs. Background technique: [0002] Diabetes and glucocorticoid-related metabolic diseases (including obesity, dyslipidemia, hypertension and cardiovascular complications, etc.) have become major health problems that plague modern people (Rosenstock, J.et.DiabetesCare 2010, 33, 1516) . According to incomplete statistics of the World Health Organization (WHO), there are approximately 1.6 billion overweight people in the world, of which 400 million people show clinical symptoms of diabetes ...

Claims

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Application Information

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IPC IPC(8): C07C61/35C07C329/16C07C69/16C07C275/28C07C275/30C07C62/38C07C62/32C07C235/40C07C247/14C07C323/30C07F9/12A61K31/19A61K31/265A61K31/22A61K31/17A61K31/26A61K31/661A61P3/10A61P9/12A61P3/04A61P25/28
Inventor 赵勤实冷颖邓旭李明明赵昱沈瑜何隽
Owner KUNMING INST OF BOTANY - CHINESE ACAD OF SCI
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