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Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases

A cerebrovascular disease and leonurine technology, applied in the field of medicine, can solve the problems of poor fat solubility and low bioavailability of stachydrine, and achieve the effects of good treatment effect, repair of nerve cell damage and novel structure

Active Publication Date: 2021-03-26
青岛海合生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Among these active compounds, the pharmacological effects of leonurine and stachydrine are the most extensive, but stachydrine has the defects of poor fat solubility and low bioavailability; while leonurine is prone to glucuronidation in vivo and has low bioavailability

Method used

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  • Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases
  • Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases
  • Leonurine derivative and application thereof in preparing medicine for preventing or treating ischemic cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] Example 1: Synthesis of 1,3-bis(tert-butoxycarbonyl)-2-methyl-2-isothiourea (1):

[0030]

[0031] At room temperature, S-methylisothiouronium sulfate (14g, 50.29mmol, 1eq) was dissolved in water / dichloromethane (75mL / 75mL) mixture, di-tert-butyl dicarbonate (14.2g, 63.37mmol , 1.3eq) was injected into the system, and then 75mL of sodium hydroxide solution with a concentration of 1mol / mL was added, and the reaction was stirred for 12h. Filter, beat with water at 50°C for 1.5h, filter, and dry the filter cake to obtain a white solid, namely compound 1 (13.4g, yield 92%); mp=115.4-116.2°C; 1 H NMR (500MHz, DMSO-d 6 ): δ 11.05 (s, 1H), 2.27 (s, 3H), 1.43 (d, J=7.7Hz, 18H). ESI-MS: m / zcalcd for C 12 h 22 N 2 o 4 S[M+H] + 291.14.Found: 291.13.

Embodiment 2

[0032] Embodiment 2: the synthesis of N, N'-Boc-N "-(4-hydroxyl-butyl)-guanidine (2):

[0033]

[0034] The obtained compound 1 (1.45g, 5mmoL, 1eq) was dissolved in DMF (10mL), and 4-amino-1-butanol (450mg, 5mmoL, 1eq) was added at 25°C, reacted for 9h, washed with water, and extracted with DCM , collected the lower layer solution, evaporated to dryness, column chromatography (petroleum ether: ethyl acetate = 2: 1), to obtain an amorphous white solid, namely compound 2 (1.48g, yield rate 90%); mp = 119.8-121.4 ° C ; 1 H NMR (500MHz, DMSO-d 6 ): δ 11.49(s, 1H), 8.28(t, J=5.0Hz, 1H), 4.41(s, 1H), 3.40(d, J=5.8Hz, 2H), 3.28(d, J=6.3Hz, 2H), 1.52(dd, J=14.4, 7.2Hz, 2H), 1.47(s, 9H), 1.45-1.4l(m, 2H), 1.39(s, 9H).ESI-MS: m / z calcd for C 15 h 29 N 3 o 5 [M+Na] + 354.20.Found: 354.01.

Embodiment 3

[0035] Embodiment 3: the synthesis of acetosyringic acid (3):

[0036]

[0037] Dissolve syringic acid (1g, 5.04mmol) in 7mL of acetic anhydride, heat to reflux for 2h, the temperature of the system drops to 50°C, add the reaction solution to 20mL of ice water, stir at 0°C for 1h, a white precipitate is observed Formed, filtered to obtain a filter cake, rinsed with an appropriate amount of ice water, and dried to obtain a white powder, that is, compound 3 (1 g, yield 83%); mp = 182.0-186.7 ° C; 1 H NMR (500MHz, DMSO-d 6 ): δ 7.28(s, 2H), 3.81(s, 6H), 2.27(s, 3H). 13 C NMR (126MHz, DMSO-d 6 ): δ167.76, 166.67, 151.64 (2C), 131.50, 129.25, 105.87 (2C), 56.11 (2C), 20.14. ESI-MS: m / zcalcd for C 11 h 12 o 6 [M+Na] + 263.05. Found: 262.79.

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PUM

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Abstract

The invention provides a leonurine derivative and application of the leonurine derivative in preparation of a medicine for preventing or treating ischemic cerebrovascular diseases. The leonurine derivative has a structure as shown in a general formula (I), wherein X is selected from O or NH; Y is selected from any one of natural amino acid, substituted amino acid or amino alcohol; Z is selected from H, proline and any substituted proline. Pharmacological experiments prove that the leonurine derivative provided by the invention has the effects of neuroprotection, cerebral infarction area reduction and animal neurobehavioral scoring, and is good in safety, so that the leonurine derivative has important significance for developing novel medicines for preventing or treating ischemic cerebrovascular diseases.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a leonurine derivative and its application in the preparation of medicines for preventing or treating ischemic cerebrovascular diseases. Background technique [0002] Stroke refers to cerebrovascular disease caused by insufficient blood flow and oxygen content in blood vessels. From the perspective of pathological properties, it can be divided into two types, namely, ischemic stroke and hemorrhagic stroke. Hemorrhagic stroke is a brain injury caused by cerebral parenchymal or cerebrovascular hemorrhage, and ischemic stroke is a disease of brain infarction caused by cerebrovascular blockage and reduced or absent cerebral blood flow. Clinical stroke cases show that ischemic stroke accounts for 80%, hemorrhagic stroke accounts for 15%, and the etiology of the remaining 5% is unknown. It can be seen that ischemic stroke is a very destructive disease. From the analysis o...

Claims

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Application Information

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IPC IPC(8): C07C279/08C07D207/16C07C323/58C07K5/078C07K5/097A61K31/245A61K31/401A61K31/235A61K38/05A61P9/10A61P25/00
CPCC07C279/08C07D207/16C07C323/58C07K5/06139C07K5/0821A61P9/10A61P25/00A61K38/00
Inventor 李峰侯英伟
Owner 青岛海合生物科技有限公司
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