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N-(PAK)-2,3-dioxide-isoquinoline-7-formyl-RGDV/F, synthesis, activity and application thereof

A technology of dioxyisoquinoline and dihydroxyisoquinoline, which is applied in the field of biomedicine and can solve problems such as no effective drugs

Active Publication Date: 2017-04-26
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

At present, the clinical treatment of ischemic stroke faces the reality that there are no effective drugs, especially for patients with strokes lasting more than 4 hours, either dying or being disabled

Method used

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  • N-(PAK)-2,3-dioxide-isoquinoline-7-formyl-RGDV/F, synthesis, activity and application thereof
  • N-(PAK)-2,3-dioxide-isoquinoline-7-formyl-RGDV/F, synthesis, activity and application thereof
  • N-(PAK)-2,3-dioxide-isoquinoline-7-formyl-RGDV/F, synthesis, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1 Preparation of (7S)-5,6,7,8-tetrahydro-2,3-dihydroxyisoquinoline-7-carboxylic acid

[0029] To 988 mg (0.005 mmol) of (S)-3,4-dihydroxy-Phe was sequentially added 5.9 mL of H 2 O, 0.7mL 32% hydrochloric acid, stir evenly, after complete dissolution, add 1.2mL 40% formaldehyde solution, react at room temperature for 6 hours. TLC (dichloromethane:methanol, 10:1) showed that (S)-3,4-dihydroxy-Phe disappeared, and saturated sodium bicarbonate was added dropwise in ice bath to make the pH to 5, and a large amount of colorless precipitates were precipitated. Filtration yielded 1.01 g (95%). Mp 281-286℃, ESI-MS(m / z): 210[M+H] + .

Embodiment 2

[0030] Example 2 Preparation of (7S)-5,6,7,8-tetrahydro-2,3-dihydroxyisoquinoline-7-carboxylic acid benzyl ester

[0031] 1 g (4.08 mmol) of (7S)-5,6,7,8-tetrahydro-2,3-dihydroxyisoquinoline-7-carboxylic acid, 1.02 g of p-toluenesulfonic acid, 8 mL of benzyl alcohol and 8 mL of n-hexane The mixture was heated and stirred at 90-95°C for 36h to make it clear. After the reaction mixture was cooled to room temperature, a large amount of diethyl ether was added to precipitate a large amount of colorless solid, which was filtered, washed with diethyl ether, and dried to obtain 1.08 g (77%) of the title compound as a colorless powder. ESI-MS(m / z):300[M+H] + .

Embodiment 3

[0032] Example 3 Preparation of (7S)-N-tert-butoxycarbonyl-5,6,7,8-tetrahydro-2,3-dihydroxyisoquinoline-7-carboxylic acid benzyl ester

[0033] 1g (3.32mmol) (7S)-benzyl 5,6,7,8-tetrahydro-2,3-dihydroxyisoquinoline-7-carboxylate was dissolved in 50ml THF under ice bath, and then 0.93g Boc 2 O, adjust the pH to 8 with NMM, react at room temperature for 48h, and monitor the completion of the reaction by TLC. The reaction compound was concentrated to dryness under reduced pressure, and the yellow oil was purified by column chromatography (petroleum ether / acetone: 6 / 1-1 / 1) to obtain 243 mg (35%) of the title compound as a yellow powder. ESI-MS(m / z): 400[M+H] + .

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Abstract

The invention discloses (7S)-N[(Pro-Ala-Lys)-5-6-7-8-tetralin-2,3-dioxide-isoquinoline-7-formyl]-Arg-Gly-Asp-AA in the formula shown in the description, a preparation method thereof, antithrombotic activity and an effect of (7S)-N[(Pro-Ala-Lys)-5-6-7-8-tetralin-2,3-dioxide-isoquinoline-7-formyl]-Arg-Gly-Asp-AA on treatment of cerebral ischemia rats, so that the invention discloses application of (7S)-N[(Pro-Ala-Lys)-5-6-7-8-tetralin-2,3-dioxide-isoquinoline-7-formyl]-Arg-Gly-Asp-AA in preparation of antithrombotic drugs and ischemic stroke treatment drugs.

Description

technical field [0001] The present invention relates to (7S)-N-[(Pro-Ala-Lys)-5,6,7,8-tetrahydro-2,3-dioxoisoquinoline-7-formyl]-Arg-Gly of formula -Asp-AA (Arg-Gly-Asp-AA is Arg-Gly-Asp-Val when AA=Val; Arg-Gly-Asp-AA is Arg-Gly-Asp-Phe when AA=Phe), involving them The preparation method relates to their antithrombotic activity and their effect on treating cerebral ischemia rats, so the present invention relates to their application in the preparation of antithrombotic drugs and drugs for treating ischemic stroke. The invention belongs to the field of biomedicine. [0002] Background technique [0003] Ischemic stroke is a relatively common and serious cerebrovascular disease, characterized by high incidence, high mortality, high disability rate and high recurrence rate. At present, the clinical treatment of ischemic stroke faces the reality that there is no effective drug, especially for patients with stroke lasting more than 4 hours, either dying or being disabled. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06A61K38/08A61P7/02A61P9/10
Inventor 彭师奇赵明王夏
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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