阅读说明：本技术 Ldv修饰的s,r-七环醛，其合成,活性和应用 (LDV modified S, R-heptacyclic aldehyde, and synthesis, activity and application thereof ) 是由 赵明 蒋雪云 桂琳 彭师奇 薛双悦 于 2018-06-04 设计创作，主要内容包括：本发明公开了下式S,R-七环醛-Leu-Asp-Val,公开了它的制备方法,公开了它的抗静脉血栓活性,公开了它的抗动脉血栓活性,公开了它抑制体内GPIIb/IIIa表达的活性,公开了它抑制体内P-选择素表达的活性。因而本发明公开了它在制备抗动脉血栓药物中的应用、在制备抗静脉血栓药物中的应用、在制备GPIIb/IIIa拮抗剂中的应用和在制备P-选择素拮抗剂中的应用。<Image he="356" wi="700" file="DDA0001683425280000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention discloses the following formula S, R-heptacyclic aldehyde-Leu-Asp-Val, discloses its preparation method, discloses its anti-arterial thrombosis activity, discloses its activity for inhibiting in vivo GPIIb/IIIa expression and discloses its activity for inhibiting in vivo P-selectin expression, so that the invention discloses its application in preparing anti-arterial thrombosis medicine, in preparing anti-venous thrombosis medicine, in preparing GPIIb/IIIa antagonist and in preparing P-selectin antagonist)

1.(2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione of formula,

2. a process for the preparation of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione of claim 1 comprising:

(1) Carrying out Pictet-Spengler condensation on L-tryptophan benzyl ester and 1,1,3, 3-tetramethoxypropane under the catalysis of trifluoroacetic acid to obtain 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate;

(2) In methanol solution, 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate reacts with H under the catalysis of Pd/C₂removing benzyl ester by reaction to obtain 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid;

(3) Performing intermolecular condensation of 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid in anhydrous N, N-dimethylformamide in the presence of dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole } -1, 4-dione;

(4) adding (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione in the presence of glacial acetic acid, water and concentrated hydrochloric acid, and carrying out acidolysis reaction to obtain (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione;

(5) Using dicyclohexylcarbodiimide and N-hydroxybenzotriazole as catalysts, and synthesizing HCl & Leu-Asp (OBzl) -Val-OBzl by adopting a liquid phase condensation method;

(6) Subjecting HCl & Leu-Asp (OBzl) -Val-OBzl and (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione to ammoniation reduction in the presence of sodium cyanoborohydride to give (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp (OBzl) -Val-OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione;

(7) In methanol solution, (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp (OBzl) -Val-OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione is produced under the condition that pH is 13 (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione is produced.

3. use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione according to claim 1 for the preparation of an anti-venous thrombosis medicament.

4. use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione according to claim 1 for the preparation of an anti-arteriothrombotic medicament.

5. Use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione according to claim 1 for the preparation of a GPIIb/IIIa antagonist.

6. Use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione according to claim 1 for the preparation of a P-selectin antagonist.

Technical Field

The present invention relates to S, R-heptacyclic aldehyde-Leu-Asp-Val, its preparation process, its anti-arterial thrombus activity, its anti-venous thrombus activity, the activity of inhibiting the expression of glycoprotein IIb/IIIa and the activity of inhibiting the expression of P-selectin. Therefore, the invention relates to the application of the derivatives in preparing anti-arterial thrombosis medicaments, anti-venous thrombosis medicaments, GPIIb/IIIa antagonists and P-selectin antagonists. The invention belongs to the field of biological medicine.

background

Thrombosis is a common pathology of ischemic heart disease, ischemic stroke and venous thrombosis. The number of deaths from ischemic heart disease and ischemic stroke is 1/4 out of all deaths from disease worldwide. Venous thrombosis is a major disease burden in less-developed, moderately-developed and highly-developed countries. Thrombosis can exacerbate a range of related diseases, for example, rarely occurring blocked thrombosis of a biomaterial tube can have unpredictable consequences for patients who undergo repeated tube changes, or undergo thrombolytic therapy or prolonged anticoagulant therapy, can cause re-embolization of patients who undergo percutaneous intracoronary intervention, can be associated with heparin-induced thrombocytopenia, and tortuous coronary thrombosis can cause acute coronary syndrome. In addition, thrombosis is a complication of related diseases, for example massive cerebral venous thrombosis is a complication in early pregnant women with epilepsy, and stent thrombosis is a serious complication in patients undergoing percutaneous intracoronary intervention. Therefore, the novel antithrombotic drug has clinical importance.

The beta-carboline is an important pharmacophore for inhibiting thrombus. However, the effective dose of beta-carboline, such as 3S-1,2,3, 4-tetrahydro-beta-carboline-3-carboxylic acid, is as high as 5. mu. mol/kg, and still remains to be reduced. The inventors hypothesized that two β -carboline pharmacophores fused, for example, 1 (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid and 1 (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid are intermolecularly condensed to (2S,5S) -tetrahydropyrazino [1,2:1,6] and bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] oxindole } -1, 4-dione, which is then acidolyzed to (2S,5S) -Tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione (S, R-heptacyclal for short). The S, R-heptacyclic aldehyde should have strong antithrombotic activity. The inventors further hypothesized that the aldehyde group of this novel heptacyclic aldehyde should have greater antithrombotic activity in conjunction with Leu-Asp-Val. Based on this assumption, the inventors have proposed the present invention.

Disclosure of Invention

the first aspect of the present invention is to provide S, R-heptacyclic aldehyde-Leu-Asp-Val of the formula.

the second content of the invention is to provide a method for synthesizing S, R-heptacyclic aldehyde-Leu-Asp-Val, which comprises the following steps:

(1) Carrying out Pictet-Spengler condensation on L-tryptophan benzyl ester and 1,1,3, 3-tetramethoxypropane under the catalysis of trifluoroacetic acid to obtain 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate (1);

(2) In methanol solution, 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate reacts with H under the catalysis of Pd/C₂The benzyl ester is removed by reaction to obtain 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid (2);

(3) Performing intermolecular condensation of 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid in anhydrous N, N-dimethylformamide in the presence of dicyclohexylcarbodiimide and N-hydroxybenzotriazole to obtain (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole } -1, 4-dione (3);

(4) Adding (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione in the presence of glacial acetic acid, water and concentrated hydrochloric acid, and carrying out acidolysis reaction to obtain (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione (4);

(5) Using dicyclohexylcarbodiimide and N-hydroxybenzotriazole as catalysts, and synthesizing HCl & Leu-Asp (OBzl) -Val-OBzl by adopting a liquid phase condensation method;

(6) Ammoniation reduction of HCl & Leu-Asp (OBzl) -Val-OBzl and (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione in the presence of sodium cyanoborohydride, to obtain (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp (OBzl) -Val-OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione (5);

(7) In methanol solution, (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp (OBzl) -Val-OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione is produced under the condition that pH is 13, (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione is produced, namely S, R-heptacyclic aldehyde-Leu-Asp-Val (6).

The third content of the invention is to evaluate the antithrombotic activity of S, R-heptacyclic aldehyde-Leu-Asp-Val.

the fourth aspect of the present invention is to evaluate the antithrombotic activity of S, R-heptacyclic aldehyde-Leu-Asp-Val.

The fifth aspect of the present invention is to evaluate the activity of S, R-heptacyclic aldehyde-Leu-Asp-Val in inhibiting GPIIb/IIIa expression in vivo.

the sixth aspect of the present invention is to evaluate the activity of S, R-heptacyclic aldehyde-Leu-Asp-Val in inhibiting P-selectin expression in vivo.

Drawings

FIG. 1 is a synthetic route for (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Leu-Asp-Val ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione.

i) Dichloromethane, trifluoroacetic acid, 1,1,3, 3-tetramethoxypropane; ii) palladium on carbon, hydrogen, methanol; iii) N-hydroxybenzotriazole, dicyclohexylcarbodiimide, N-methylmorpholine, N, N-dimethylformamide; iv) glacial acetic acid, concentrated hydrochloric acid, water and ice bath; v) dicyclohexylcarbodiimide, N-hydroxybenzotriazole, N-methylmorpholine, tetrahydrofuran; vi) ethyl hydrogen chloride acetate, ice bath; vii) sodium cyanoborohydride vii)4N NaOH, methanol, ice bath.

Detailed Description

To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.