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A stachydrine derivative, its preparation method and its application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases

A technology for cardiovascular and cerebrovascular diseases and derivatives, applied in the field of medicine, can solve problems such as limited research and development, undiscovered cardiovascular and cerebrovascular drugs, and high toxicity of stachydrine hydrochloride, and achieve the effect of inhibiting cytotoxicity

Active Publication Date: 2020-09-08
MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] However, more and more evidence shows that the toxicity of stachydrine hydrochloride is relatively high, which limits its further research and development. Therefore, new compounds are designed on the basis of the structure of stachydrine to reduce its toxicity, and then a new type of heart with high efficiency and low toxicity can be developed. Cerebrovascular drugs are of great significance
[0009] So far, no patents or other literature reports on cardiovascular and cerebrovascular drugs based on stachydrine structure have been found

Method used

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  • A stachydrine derivative, its preparation method and its application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases
  • A stachydrine derivative, its preparation method and its application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases
  • A stachydrine derivative, its preparation method and its application in the preparation of medicines for treating cardiovascular and cerebrovascular diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: The synthetic route of N-methyl-L-proline b is as follows:

[0047]

[0048] Dissolve L-proline (4.0g, 34.8mmol) in methanol (40mL), add 40% aqueous formaldehyde solution (2.8mL, 38.2mmol) and 10% palladium on carbon (1g) in turn, add hydrogen, and at room temperature After the reaction was completed for 24 hours, it was filtered, and the mother liquor was concentrated and dried to obtain 4 g of white solid with a yield of 89%, which is N-methyl-L-proline (compound b). ESI-MS: (m / z, %)=130[M+H] + .

Embodiment 2

[0049] Example 2: The synthetic route of (S)-2-(1-methylpyrrole-2-carboxamide)-benzoic acid (compound B-1) is as follows:

[0050]

[0051] The N-methyl-L-proline b (1.29g, 10mmol) prepared in Example 1 was added to dichloromethane (20mL), and dicyclohexylcarbodiimide DCC (2.47g, 12mmol) was added in sequence It was reacted with anthranilic acid (1.37g, 10mmol) at room temperature for 24 hours, and the white solid was filtered off. The mother liquor was concentrated and dried to obtain 1.6g of white solid with a yield of 61%, which is compound B-1.

[0052] 1 H NMR (500MHz, CD 3 OD)δ=8.45(d,J=8.3Hz,1H), 8.10(dd,J=7.9,1.3Hz,1H), 7.61-7.53(m,1H), 7.22(t,J=7.6Hz,1H) ,4.43(t,J=8.4Hz,1H),3.82-3.72(m,1H),3.36-3.22(m,1H),3.02(s,3H),2.77-2.67(m,1H),2.25(ddd , J = 18.2, 9.2, 3.9 Hz, 2H), 2.17-2.06 (m, 1H).

Embodiment 3

[0053] Example 3: The synthetic route of (S)-N-(4-amino-4-oxobutyl)-1-methylpyrrole-2-carboxamide (compound B-2) is as follows:

[0054]

[0055] The N-methyl-L-proline b (1.29g, 10mmol) was added to dichloromethane (20mL), and DCC (2.47g, 12mmol) and γ-aminobutanamide (1.02g, 10mmol) were added successively, Reacted at room temperature for 24 hours, filtered, and the mother liquor was concentrated to dryness to obtain 1.6 g of white solid with a yield of 75.1%, which was compound B-2.

[0056] 1 H NMR (500MHz, CD 3 OD)δ=3.94(t,J=7.9Hz,1H),3.71-3.59(m,1H), 3.28(d,J=7.1Hz,2H), 3.13(dt,J=20.8,10.5Hz,1H) , 2.88(s, 3H), 2.59-2.46(m, 1H), 2.29-2.22(m, 2H), 2.22-2.10(m, 1H), 2.08-1.97(m, 2H), 1.88-1.77(m, 2H).

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Abstract

The present invention provides a stachydrine derivative, a preparation method therefor, and applications thereof in the preparation of drugs for treating cardiovascular and cerebrovascular diseases. The stachydrine derivative is a component represented by formula (I), or a stereoisomer thereof or a pharmaceutically-acceptable salt form thereof. The synthesis method for the stachydrine derivative comprises: enabling Lproline and formaldehyde to have a hydrogenation reaction under the action of a catalyst to prepare N-methyl-L-proline; and enabling the N-methyl-L-proline and H-X-R1 to have a condensation reaction under the action of dicyclohexylcarbodiimide to prepare the component represented by formula (I). Proved by pharmacological experiments in the present invention, the stachydrine derivative provided in the present invention has the effect for protecting nerves, and has the effect for treating cardiovascular and cerebrovascular diseases. The present invention also provides applications of the stachydrine derivative in the preparation of drugs for treating cardiovascular and cerebrovascular diseases.

Description

Technical field [0001] The invention belongs to the technical field of medicine, and specifically relates to a stachyine derivative, a preparation method thereof, and application in preparing 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 in 2008, stroke was the third leading cause of death in urban areas and the second leading cause of death in rural areas. Epidemiological investigations have shown that the incidence of stroke among young people has increased in recent years. Among them, strokes in adults under 45 years old have been reported in Western countries and China at 5% and 13.44%, respectively. Stroke is divided into ischemic stroke and hemorrhagic stroke according to its nature, and ischemic stroke a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16C07K5/078A61K38/05A61K31/401A61P9/00A61P9/10A61P25/00
CPCA61K38/00C07D207/16C07K5/06165A61K31/401A61K38/05A61P9/00A61P9/10A61P25/00
Inventor 李文保李峰张良张鹏代龙管华诗
Owner MARINE BIOMEDICAL RES INST OF QINGDAO CO LTD
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