Isosteviol derivant and application thereof

A technology of isosteviol and its derivatives, which is applied in the direction of drug combination, active ingredients of heterocyclic compounds, medical preparations containing active ingredients, etc., and can solve the problem of low bioavailability

Inactive Publication Date: 2009-06-03
SOUTHEAST UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the half-life of isosteviol is only 30 minutes, and it is easily cleared by the body; isosteviol is relatively fat-soluble, and its bioavailability is not high

Method used

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  • Isosteviol derivant and application thereof
  • Isosteviol derivant and application thereof
  • Isosteviol derivant and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] Example 1: (4α, 8β, 13β)-13-methyl-16-oxo-17-norkaurane-18-acid n-butyl ester (I 1 )

[0067] Dissolve 3g (0.0094mol) of isosteviol in 80mL of DMSO, add 6g of potassium hydroxide, 1.4mL (0.013mol) of 1-bromobutane, heat to reflux for 3h, pour into ice water, solids precipitate out, filter, filter The cake was recrystallized with ethanol to obtain 3.2 g of light yellow crystals, with a yield of 91%.

[0068] 1 H NMR (300MHz, CDCl 3 ),δ H , ppm: 0.71(s, 3H, 20-H 3 ), 0.98(s, 3H, 17-H 3 ), 1.19(s, 3H, 19-H 3 ), 0.91-1.88 (m, 25H, 1-H 2 ,2-H 2 , 3-H ax , 5-H, 6-H 2 ,7-H 2 , 9-H, 11-H 2 , 12-H 2 , 14-H 2 , 15-H β , COOCH 2 C 3 H 7 ), 2.16-2.21(d, 1H, 3-H eq , J=14.91Hz), 2.60-2.67 (dd, 1H, 15-H α , J=18.6, 3.69Hz), 3.98-4.10 (m, 2H, COOC H 2 C 3 h 7 )

Embodiment 2

[0069] Example 2: (4α, 8β, 13β)-13-methyl-16-oxo-17-norkaurane-18-acid isopropyl ester (I 2 )

[0070] In a 250mL three-necked flask, dissolve 5g (0.016mol) of isosteviol in 100mL of DMSO, add 10g of potassium hydroxide, 2mL (0.021mol) of 2-bromopropane, stir mechanically, heat to reflux for 3h, pour into ice water, A white solid was precipitated, filtered and recrystallized to obtain 5.4 g of white crystals with a yield of 95%.

[0071] 1 H NMR (500MHz, CDCl 3 ),δ H , ppm: 0.73(s, 3H, 20-H 3 ), 0.96(s, 3H, 17-H 3 ), 1.16(s, 3H, 19-H 3 ), 1.20-1.22 (dd, 6H, CH (C H 3 ) 2 , J=6.27, 3.13Hz), 0.86-2.65 (m, 18H, 1-H 2 ,2-H 2 , 3-H ax , 5-H, 6-H 2 ,7-H 2 , 9-H, 11-H 2 , 12-H 2 , 14-H 2 , 15-H β ), 2.15-2.18 (d, 1H, 3-H eq , J=15.00Hz), 2.60-2.65 (dd, 1H, 15-H α , J=18.59, 3.86Hz), 4.93-4.98 (m, 1H, C H (CH 3 ) 2 )

Embodiment 3

[0072] Example 3: Bis((4α, 8β, 13β)-13-methyl-16-oxo-17-norkaurane-18-oic acid) methylene ester (I 3 )

[0073] Dissolve 0.64g (0.002mol) of isosteviol and 0.68g (0.002mol) of tetrabutylammonium hydrogensulfate in 5mL of 2M sodium hydroxide solution, extract the organic layer with dichloromethane, dry over anhydrous magnesium sulfate, filter, and keep the filtrate at room temperature After reacting for 24 hours, it was washed, dried over anhydrous magnesium sulfate, filtered, concentrated, and column chromatography gave 0.5 g of white solid with a yield of 77%.

[0074] 1 H NMR (300MHz, CDCl 3 ),δ H , ppm: 0.73 (s, 6H, 20, 20'-H 3 ), 0.98(s, 6H, 17, 17'-H 3 ), 1.20 (s, 6H, 19, 19'-H 3 ), 0.90-1.90 (m, 36H, 1, 1'-H 2 , 2,2′-H 2 , 3,3′-H ax , 5,5'-H, 6,6'-H 2 ,7,7′-H 2 ,9,9′-H,——11,11′-H 2 ,12,12′-H 2 , 14, 14′-H 2 ,15,15′-H β ), 2.15-2.19 (d, 2H, 3, 3'-H eq , J=13.47Hz), 2.58-2.66 (dd, 2H, 15, 15'-H α , J=18.59, 3.68Hz), 5.71(s, 2H, OC H 2 O)

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Abstract

The invention discloses isosteviol derivant and the application thereof, wherein, as shown in formula (I) or formula (II), A is cyclopentane, cyclopentanone, valerolactam, substituted cyclopentane, substituted cyclopentanone or substituted valerolactam; R is alkyl, substituted alkyl, -COOR2 or -COO(CH2)n-O-R4; R2 is alkyl or substituted alkyl; R4 is alkyl acyl, nitryl, heterocyclic acyl, substituted heterocyclic acyl, aromatic acyl or substituted aromatic acyl; and n or m is respectively integral numbers from 1 to 6. The compound has the effects of regulating blood sugar and treating cardiovascular diseases.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a class of isosteviol derivatives. Background technique [0002] Isosteviol ((4α, 8β, 13β)-13-methyl-16-oxo-17-norkaurane-18-oic acid, 3) belongs to tetracyclic diterpenoids and is a natural sweetener stevia Acid hydrolysis products of glycosides. [0003] [0004] Pharmacological studies have shown that isosteviol can reduce the ATP level of cardiomyocytes and exert an anti-myocardial ischemia effect; it can reduce the concentration of intracellular calcium ions, relax blood vessels, and lower blood pressure; it can inhibit monosaccharide transport and reduce glucose production; it can inhibit polα activity, preventing tumor cell growth. In addition, isosteviol is derived from stevioside. As a natural sweetener, stevioside has the characteristics of easy availability of raw materials, low cost, and low toxicity and side effects. However, the half-life of isosteviol is on...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C69/757C07C69/78C07C205/57C07C203/02C07D213/80C07D221/22A61K31/215A61K31/445A61K31/439A61P3/10A61P9/00
Inventor 吉民陈峻青余佳周文
Owner SOUTHEAST UNIV
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