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Proline borneol derivative as well as preparation method and application thereof in preparation of medicines for treating cardiovascular and cerebrovascular diseases

A technology for cardiovascular and cerebrovascular diseases and proline cinnol, which is applied in the field of medicine, can solve the problems of low bioavailability of stachydrine hydrochloride, high toxicity, restricting research and development, etc., so as to reduce the size of cerebral infarction and inhibit cytotoxicity. Effect

Active Publication Date: 2021-02-26
WEIFANG UNIV OF SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, more and more evidence shows that stachydrine hydrochloride has low in vivo bioavailability and high toxicity, which limits its further research and development.

Method used

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  • Proline borneol derivative as well as preparation method and application thereof in preparation of medicines for treating cardiovascular and cerebrovascular diseases
  • Proline borneol derivative as well as preparation method and application thereof in preparation of medicines for treating cardiovascular and cerebrovascular diseases
  • Proline borneol derivative as well as preparation method and application thereof in preparation of medicines for treating cardiovascular and cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0031] Example 1: N -methyl- L -The synthetic route of proline a is as follows:

[0032] ;

[0033] Will L - Dissolve proline (4.0 g, 34.8 mmol) in methanol (40 mL), add 40% formaldehyde aqueous solution (2.8 mL, 38.2 mmol) and 10% palladium carbon (1 g) in sequence, add hydrogen, and add hydrogen at room temperature Reacted for 24 hours, after the reaction was complete, filtered, and the mother liquor was concentrated and dried to obtain 4 g of white solids, with a yield of 89%, namely N -methyl- L - Proline (compound a). ESI-MS: (m / z, %) = 130 [M+H] + .

Embodiment 2

[0034] Example 2: The synthetic route of 1,7,7-trimethylbicyclo[2.2.1]hept-2-ylmethyl-L-prolylglycine (compound WK-1) is as follows:

[0035] ;

[0036] The described that embodiment 1 is made N -methyl- L - Proline (1.29 g, 10 mmol) was added to dichloromethane (20 mL), followed by addition of dicyclohexylcarbodiimide DCC (2.47 g, 12 mmol) and bartinol glycinate (2.1 g, 10 mmol), After reacting at room temperature (25°C) for 24 hours, the white solid was removed by filtration, and the mother liquor was concentrated to dryness to obtain 1.6 g of white solid with a yield of 50%, which was compound WK-1.

[0037] 1 H NMR (500 MHz, CD 3 OD) δ = 4.43 (t, J = 8.4 Hz, 1H), 4.13 (s, 2H),3.82-3.71 (m, 1H), 3.37-3.25 (m, 1H), 3.02 (s, 3H), 2.73-2.67 (m, 1H), 2.25- 2.18 (m, 2H), 2.17-2.06 (m, 1H), 1.96-1.65 (m, 7H), 1.02 (s, 3H), 0.98 (s,6H).

Embodiment 3

[0038] Example 3: The synthetic route of 1,7,7-trimethylbicyclo[2.2.1]hept-2-ylmethyl-L-propylcarbamate (compound WK-2) is as follows:

[0039] ;

[0040] The described that embodiment 1 is made N -methyl- L -Proline (1.29 g, 10 mmol) was added to dichloromethane (20 mL), followed by dicyclohexylcarbodiimide DCC (2.47 g, 12 mmol) and bartinol alanine (2.2 g, 10 mmol ), reacted at room temperature for 24 hours, filtered off the white solid, and concentrated the mother liquor to dryness to obtain 2.0 g of white solid with a yield of 60%, which was compound WK-2.

[0041] 1 H NMR (500 MHz, CD 3 OD) δ = 4.45 (t, J = 8.4 Hz, 1H), 4.12 (s, 1H),3.81-3.73 (m, 1H), 3.35-3.25 (m, 1H), 3.05 (s, 3H), 2.75-2.68 (m, 1H), 2.26- 2.18 (m, 2H), 2.19-2.07 (m, 1H), 1.97-1.64 (m, 7H), 1.42 (s, 3H), 1.05 (s,3H), 0.99 (s, 6H).

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Abstract

The invention provides a proline borneol derivative as well as a preparation method and application thereof in preparation of a medicine for treating cardiovascular and cerebrovascular diseases. The proline borneol derivative is a compound shown in a formula (I) or a stereoisomer or a pharmaceutically acceptable salt form thereof, and has a structure shown in the formula (I). Pharmacological experiments prove that the proline borneol derivative provided by the invention has a remarkable nerve protection effect, can be used for preparing medicines for treating cardiovascular and cerebrovasculardiseases, and particularly can be used for preparing medicines for resisting cerebral arterial thrombosis.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a proline ketamine derivative, a preparation method thereof and an application in preparation of medicines for treating cardiovascular and cerebrovascular diseases. Background technique [0002] Stroke is a major disease that seriously endangers human life and safety, and is characterized by high morbidity, disability and mortality. According to its nature, it is divided into ischemic stroke and hemorrhagic stroke, among which ischemic stroke accounts for 75% to 85% of the total number of stroke patients. In the ranking of the causes of death published by the Ministry of Health of my country in 2008, stroke is the third leading cause of death in urban areas and the second leading cause of death in rural areas. Epidemiological surveys show that the incidence of stroke in young people has been increasing in recent years. Among them, the proportion of stroke in adults ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/078A61K38/05A61P9/10
CPCA61K38/00A61P9/10C07K5/06139
Inventor 李峰李文保
Owner WEIFANG UNIV OF SCI & TECH
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