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Ethyl RPAK modified biscarbolopiperazinedione as well as preparation, activity and application thereof

A diketone and ethyl technology, which can be used in medical preparations containing active ingredients, chemical instruments and methods, and bulk chemical production, etc., can solve the problems of thoracic and abdominal bleeding, no curative effect

Active Publication Date: 2020-12-18
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, there are two insurmountable problems in the treatment of ischemic stroke with rtPA
The first complication is that rtPA is not effective in patients with ischemic stroke >4 hours
The second problem is that continuous use of rtPA can cause cerebral, thoracic and abdominal hemorrhage

Method used

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  • Ethyl RPAK modified biscarbolopiperazinedione as well as preparation, activity and application thereof
  • Ethyl RPAK modified biscarbolopiperazinedione as well as preparation, activity and application thereof
  • Ethyl RPAK modified biscarbolopiperazinedione as well as preparation, activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] Example 1 Preparation of (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl ester (1)

[0021] Add 5 mL of 1,1,3,3-tetramethoxypropane and 3.5 mL of trifluoroacetic acid to 150 mL of dichloromethane under stirring at 0°C, react for 40 minutes, then add 5 g (17.00 mmol) of Trp-OBzl, The reaction was carried out at 40°C. After reacting for 4 hours, the pH value of the reaction solution was adjusted to 7 with concentrated ammonia water at 0°C with stirring, concentrated under reduced pressure, and the residue was dissolved in 100 mL of dichloromethane, washed three times with saturated aqueous sodium bicarbonate solution, saturated chlorinated The sodium solution was washed 3 times, the dichloromethane phase was dried with anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a yellow oil, which was purified by silica gel column chromatography to obtain 5.50 g (82%)...

Embodiment 2

[0022] Example 2 Preparation of (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (2)

[0023] 5.50g (13.96mmol) (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid benzyl The ester (1) was dissolved in 50 mL of acetone, and NaOH aqueous solution (2M) was added thereto under stirring at 0° C. to adjust the pH value of the solution to 12, and reacted for 3 hours to keep the pH value of the reaction solution at 12. Thereafter, the pH was adjusted to neutral with saturated potassium hydrogensulfate aqueous solution, and concentrated under reduced pressure. 50 mL of acetone was added to the residue, the insoluble solid was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain 3.63 g (86%) of the title compound as a yellow sticky substance. ESI-MS(m / e):303[M-H] - .

Embodiment 3

[0024] Example 3 Preparation of (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis[1S,1R-(1-dimethoxyeth-1-yl)-2,3,4 ,9-Tetrahydro-1H-pyridino[3,4-b]indole]-1',4'-dione (3)

[0025] 3.63g (11.94mmol) (3S)-1-(2,2-dimethoxyeth-1-yl)-2,3,4,9-tetrahydro-β-carboline-3-carboxylic acid (2 ) was dissolved in 20 mL of anhydrous N,N-dimethylformamide, and then 5.44 g (14.32 mmol) of 2-(7-azobenzotriazole)-N,N,N',N'-tetra Methylurea hexafluorophosphate, the solution was adjusted to pH 8 with N-methylmorpholine under stirring at 0°C, and after stirring at room temperature for 16 hours, 150 mL of distilled water was added to the reaction solution, followed by extraction with dichloromethane ( 50mL×3), combined the dichloromethane phase, and then washed with saturated aqueous sodium chloride solution (50mL×3), the dichloromethane phase was dried with anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain The yellow oil was pu...

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Abstract

The invention discloses (2 'S, 5' S) tetrahydropyrazine [1 ', 2': 1, 6] bis [1S, 1R (1-ethyl-Arg-Pro-Ala-Lys)-2, 3, 4, 9-tetrahydro-1H-pyridine [3, 4-b]oindole] 1 ', 4'-diketone of the following formula, a preparation method thereof, thrombolytic activity thereof and antithrombotic activity thereof, and a characteristic that the compound is still effective 24 hours after onset of ischemic stroke.Therefore, the invention discloses an application of the compound in preparation of thrombolytic drugs, an application of the compound in preparation of antithrombotic drugs, an application of the compound in preparation of drugs which are still effective 24 hours after onset of ischemic stroke, and an application of the compound in preparation of drugs with triple effects of thrombolysis, antithrombosis and being still effective 24 hours after onset of ischemic stroke.

Description

technical field [0001] The present invention relates to (2'S,5'S)-tetrahydropyrazine[1',2':1,6]bis[1S,1R-(1-ethyl-Arg-Pro-Ala-Lys)-2,3, 4,9-tetrahydro-1H-pyridino[3,4-b]indole]-1',4'-dione, its preparation method, its thrombolytic activity, its antithrombotic activity and features related to its effectiveness for 24 hours after the onset of ischemic stroke. Therefore the present invention relates to its application in the preparation of thrombolytic drugs, to its application in the preparation of antithrombotic drugs, to its application in the preparation of drugs that are still effective for 24 hours after the onset of ischemic stroke, and to its use in the preparation of drugs with lytic properties. Thrombotic, antithrombotic, and triple-action drugs that are effective for 24 hours after the onset of ischemic stroke. The invention belongs to the field of biomedicine. [0002] technical background [0003] Ischemic stroke is a common and serious cerebrovascular disease. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/11A61K38/07A61P7/02A61P9/10
CPCC07K5/1019C07K19/00A61P7/02A61P9/10A61K38/00Y02P20/55
Inventor 赵明彭师奇冯琦琦张娟凤
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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