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Tetrahydroisoquinolinyl-3-carboxylic acid modified LARGD heptapeptides, and synthesis, antithrombotic activity and application thereof

A tetrahydroisoquinoline and antithrombotic technology, applied in the field of biomedicine, can solve problems such as unsatisfactory clinical efficacy

Inactive Publication Date: 2013-12-18
CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Because the existing antithrombotic drugs are designed either purely against P-selectin or purely against glycoprotein IIb / IIIa, and because they only inhibit the cross-linking of platelets and leukocytes mediated by soluble P-selectin through fibrinogen Thrombus formation or thrombus formed solely by inhibiting glycoprotein IIb / IIIa-mediated cross-linking of platelets through fibrinogen and platelets cannot achieve satisfactory clinical efficacy

Method used

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  • Tetrahydroisoquinolinyl-3-carboxylic acid modified LARGD heptapeptides, and synthesis, antithrombotic activity and application thereof
  • Tetrahydroisoquinolinyl-3-carboxylic acid modified LARGD heptapeptides, and synthesis, antithrombotic activity and application thereof
  • Tetrahydroisoquinolinyl-3-carboxylic acid modified LARGD heptapeptides, and synthesis, antithrombotic activity and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Example 1 Preparation of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0026] To 4.0g (24.2mmol) L-phenylalanine, first add 21.6ml formaldehyde dropwise, then add 36ml 35% concentrated hydrochloric acid dropwise. Heat the obtained suspension in an oil bath to 95°C and stir for 2 hours to completely dissolve the phenylalanine. After 2.5 hours of reaction, a colorless precipitate begins to form. After 7 hours of reaction, TLC (chloroform / methanol=5 / 1) shows that L-phenylalanine Amino acid disappeared, and 4.2 g of light yellow solid was obtained by suction filtration. Add the obtained pale yellow solid to 86ml of ethanol (80%) and heat in an oil bath at 80°C until the colorless solid dissolves, cool to room temperature, slowly add 2N NaOH solution dropwise, a colorless precipitate precipitates, and when the precipitate reaches the maximum, filter to obtain 4.17 g (97.5%) of the title compound as a colorless solid. ESI-MS(m / e)176[M+H] + .

Embodiment 2

[0027] Example 2 Preparation of (3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid

[0028]Dissolve 2.5g (62.2mmol) of sodium hydroxide in 62ml of water under ice bath, then add 10g (56.5mmol) of (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid to prepare a mixture Suspension. 14.8g (67.8mmol) (Boc) dissolved in 40ml tetrahydrofuran 2 O was added to the suspension. The reaction mixture was stirred for 24 h, and the CO produced by the reaction was continuously removed during the reaction. 2 , when the solution became clear, TLC (methanol / chloroform: 1:10) showed that (3S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid disappeared, and the reaction was stopped. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the resulting oil was dissolved in ethyl acetate. The resulting solution was sequentially washed with 5% KHSO 4 Wash with saturated NaCl aqueous solution. The organic layer was dried over anhydrous sodium sulf...

Embodiment 3

[0029] Example 3 Preparation of N-[(3S)-N-Boc-1,2,3,4-tetrahydroisoquinoline-3-formyl]-Leu-OBzl

[0030] Add 149mg (1.1mmol) N -Hydroxybenzotriazole (HOBt), after stirring for 10 min, 221 mg (1.1 mmol) of dicyclohexylcarbodiimide (DCC) was added to obtain the reaction solution (I). Suspend 393 mg (1 mmol) of Tos·Leu-OBzl in 4 ml of anhydrous THF, add 1 ml of N-methylmorpholine (NMM) to adjust the pH to 9, and stir to obtain the reaction solution (II). Add the reaction solution (I) to the reaction solution (II), stir at room temperature for 12h, TLC (ethyl acetate / petroleum ether, 1:3) shows that (3S)-N-Boc-1,2,3,4-tetrahydro The isoquinoline-3-carboxylic acid disappeared. Dicyclohexylurea (DCU) was filtered off, the filtrate was concentrated to dryness under reduced pressure, and the residue was dissolved in 50 ml of ethyl acetate. The resulting solution was sequentially washed with 5% NaHCO 3 Wash 3 times with aqueous solution, 3 times with saturated NaCl aqueous solution...

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Abstract

The invention provides 3 novel antithrombotic quasi-peptides disclosed as general formula I, a molecular simulation method of the 3 novel antithrombotic quasi-peptides, a preparation method of the 3 novel antithrombotic quasi-peptides, inhibiting action of the 3 novel antithrombotic quasi-peptides on expression of glycoprotein IIb / IIIa and P-lectin, anti-thrombocyte aggregation action of the 3 novel antithrombotic quasi-peptides, and antithrombotic action of the 3 novel antithrombotic quasi-peptides on a rat thrombosis model. Therefore, the invention provides clinical application prospects of the 3 novel antithrombotic quasi-peptides disclosed as general formula I as an antithrombotic agent. In the general formula I, AA represents Ser or Val or Phe residue.

Description

technical field [0001] The present invention relates to three novel antithrombotic peptidomimetics, to their molecular imitation methods, to their preparation methods, to their inhibitory effects on the expression of glycoprotein IIb / IIIa and P-selectin, to their anti-platelet aggregation effects, It is further related to their antithrombotic effect on the rat model of thrombosis. Therefore, the present invention relates to the clinical application prospects of three novel antithrombotic peptidomimetics as antithrombotic agents. The invention belongs to the field of biomedicine. Background technique [0002] Globally, thrombotic disease is the leading cause of morbidity and mortality. There are two types of thrombi in patients with thrombosis, one is a thrombus formed by cross-linking platelets with white blood cells through fibrinogen, and the other is a thrombus formed by cross-linking platelets through fibrinogen and platelets. [0003] P-selectin exists in two forms: ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/06C07K1/02A61K38/08A61P7/02
Inventor 赵明彭师奇吴建辉王玉记杨国栋
Owner CAPITAL UNIVERSITY OF MEDICAL SCIENCES
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