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Proline derivatives and their application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases

A technology for cardiovascular and cerebrovascular diseases and derivatives, applied in the field of medicine, can solve the problems of low bioavailability, short half-life of stachydrine, poor anti-ischemic stroke activity, etc., and achieve the effect of inhibiting cytotoxicity

Active Publication Date: 2022-07-26
青岛海生洋润生物科技有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Animal studies have shown that stachydrine and motherwort both exhibit anti-ischemic stroke activity in animal model groups, but stachydrine has a short half-life and poor anti-ischemic stroke activity in vivo
Leonurine is prone to glucuronidation in vivo, and its bioavailability is low.

Method used

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  • Proline derivatives and their application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases
  • Proline derivatives and their application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases
  • Proline derivatives and their application in the preparation of drugs for treating cardiovascular and cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0048] Embodiment 1: the synthetic route of N-methyl-L-proline b is as follows:

[0049]

[0050] Dissolve L-proline (4.0 g, 34.8 mmol) in methanol (40 mL), add 40% aqueous formaldehyde solution (2.8 mL, 38.2 mmol) and 10% palladium on carbon (1 g) in turn, add hydrogenation, at room temperature The reaction was carried out for 24 hours. After the reaction was completed, it was filtered, and the mother liquor was concentrated to dryness to obtain 4 g of white solid with a yield of 89%, which was N-methyl-L-proline (compound b). ESI-MS: (m / z, %)=130 [M+H] + .

Embodiment 2

[0051] Embodiment 2: The synthetic route of compound B-4 is as follows:

[0052]

[0053] The N-methyl-L-proline b (1.29 g, 10 mmol) was added to dichloromethane (20 mL), followed by DCC (2.47 g, 12 mmol) and glycine (0.75 g, 10 mmol), and reacted at room temperature for 24 hours, filtered, and concentrated the mother liquor to obtain 1 g of white solid with a yield of 54%, which was compound B-4. 1 H NMR (500MHz, CD 3 OD)δ=4.14(t,J=8.3,1H),4.00(s,2H),3.71(ddd,J=11.4,7.7,4.1,1H),3.22(d,J=11.1,1H),2.95( d, J=10.5, 3H), 2.58 (dd, J=12.2, 7.5, 1H), 2.24-2.02 (m, 3H).

Embodiment 3

[0054] Embodiment 3: the synthetic route of compound B-5 is as follows:

[0055]

[0056] The B-4 (1.86 g, 10 mmol) was added to dichloromethane (20 mL), followed by DCC (2.47 g, 12 mmol) and Y5 (3.1 g, 10 mmol), reacted at room temperature for 24 hours, filtered, and the mother liquor was concentrated to obtain no residue. The color oily substance was 1.4 g, the yield was 30%, which was compound B-5. ESI-MS: (m / z, %)=480 [M+H] + . 1 H NMR (500MHz, D 2 O)δ=7.43(s, 2H), 4.49(d, J=7.8Hz, 2H), 4.42(t, J=6.5Hz, 2H), 4.31(t, J=8.5Hz, 1H), 3.92(s) ,6H),3.85-3.80(m,1H),3.31-3.25(m,3H),2.99(s,3H),2.68-2.61(m,1H),2.32-2.04(m,3H),1.94-1.84 (m, 2H), 1.80–1.73 (m, 2H).

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Abstract

The invention provides a proline derivative, its preparation method and its application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases. The proline derivative has the structure of the general formula (I); pharmacological experiments prove that the proline derivative provided by the present invention has a significant neuroprotective effect, and can be used for preparing medicines for the treatment of cardiovascular and cerebrovascular diseases, especially It is used for the preparation of anti-ischemic stroke drugs.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a proline derivative, a preparation method thereof, and an application in the preparation of a medicine for treating cardiovascular and cerebrovascular diseases. Background technique [0002] Stroke is a refractory disease that seriously endangers human life and has the characteristics of high morbidity, high disability and high mortality. In the ranking of causes of death announced by the Ministry of Health of my country in 2008, stroke was 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 among young people has been increasing in recent years. Among them, the proportion of stroke in adults under the age of 45 is 5% and 13.44% reported in Western countries and China, respectively. Stroke is divided into ischemic stroke and hemorrhagic stroke according to it...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16A61P9/10A61P25/00A61P9/00
CPCC07D207/16A61P9/10A61P25/00A61P9/00A61K31/401
Inventor 李文保李峰张良侯晨辉管华诗
Owner 青岛海生洋润生物科技有限公司
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