CN110577573A - YIGS pentapeptide modified S, R-heptacyclic aldehyde, and synthesis, activity and application thereof - Google Patents
YIGS pentapeptide modified S, R-heptacyclic aldehyde, and synthesis, activity and application thereof Download PDFInfo
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- CN110577573A CN110577573A CN201810589787.8A CN201810589787A CN110577573A CN 110577573 A CN110577573 A CN 110577573A CN 201810589787 A CN201810589787 A CN 201810589787A CN 110577573 A CN110577573 A CN 110577573A
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention discloses S, R-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is Lys residue or Arg residue), discloses a preparation method thereof, discloses anti-arterial thrombosis activity thereof, discloses activity thereof for inhibiting in vivo GPIIb/IIIa expression, and discloses activity thereof for inhibiting in vivo P-selectin expression. Therefore, the invention discloses the application of the compounds in the preparation of the anti-venous thrombosis drugs, the application in the preparation of the anti-arterial thrombosis drugs, the application in the preparation of GPIIb/IIIa antagonists and the application in the preparation of P-selectin antagonists。
Description
Technical Field
The invention relates to S, R-heptacyclic aldehyde-Tyr-Ile-Gly-Ser-AA, a preparation method thereof, anti-arterial thrombosis activity thereof, activity thereof for inhibiting the expression of glycoprotein IIb/IIIa (IIb/IIIa) in vivo and activity thereof for inhibiting the expression of P-selectin in vivo. 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 linkage of this novel heptacyclic aldehyde is Tyr-Ile-Gly-Ser-AA (wherein AA is a Lys residue or an Arg residue) should have greater antithrombotic activity. 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-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is a Lys residue or an Arg residue) of the following formula.
The second content of the invention is to provide a synthesis method of S, R-heptacyclic aldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is Lys residue or Arg residue), 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] and bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -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] and bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione, namely S, R-heptacyclal (4);
(5) Uses dicyclohexylcarbodiimide and N-hydroxybenzotriazole as catalysts to synthesize HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl and HCl, Tyr-Ile-Gly-Ser (Bzl) -Arg (NO) by adopting a liquid phase condensation method2)-OBzl
(6) In the presence of sodium cyanoborohydride, HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl and (2S,5S) -tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyridoindole } -1, 4-dione are subjected to ammoniation reduction to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyridoindole } -1, 4-dione (5 a);
(7) (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione in the presence of trifluoroacetic acid and trifluoromethanesulfonic acid to give (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione, i.e.S, r-heptacyclic aldehyde-Tyr-Ile-Gly-Ser-Lys (6 a);
(8) In the presence of sodium cyanoborohydride, HCl, Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2) OBzl and (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ 1-Carbonylmethyl group]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And then the indole } -1, 4-diketone is subjected to ammoniation reduction to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione (5 b);
(9) (2S,5S) -tetrahydropyrazines [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione in the presence of trifluoroacetic acid and trifluoromethanesulfonic acid to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Arg]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-diones, i.e. S, R-heptacyclal-Tyr-Ile-Gly-Ser-Arg(6b)；
The third aspect of the present invention is to evaluate the antithrombotic activity of S, R-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is Lys residue or Arg residue).
The fourth aspect of the present invention is to evaluate the antithrombotic activity of S, R-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is a Lys residue or an Arg residue).
The fifth aspect of the present invention is to evaluate the activity of S, R-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is a Lys residue or an Arg residue) for inhibiting the expression of GPIIb/IIIa in vivo.
The sixth aspect of the present invention is to evaluate the activity of S, R-heptacyclaldehyde-Tyr-Ile-Gly-Ser-AA (wherein AA is a Lys residue or an Arg residue) 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-Tyr-Ile-Gly-Ser-Lys ] -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, pH 8; viii) trifluoroacetic acid, trifluoromethanesulfonic acid, ice bath
5a (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione;
6a (2S,5S) -Tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indolino } -1, 4-dione.
FIG. 2 is a synthetic route for (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Arg ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione
ii) 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, pH 8; viii) trifluoroacetic acid, trifluoromethanesulfonic acid, ice bath
5b (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione;
6b (2S,5S) -Tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Arg ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indolino } -1, 4-dione.
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.
EXAMPLE 1 preparation of benzyl 1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylate (1)
5mL of 1,1,3, 3-tetramethoxypropane and 5mL of trifluoroacetic acid were sequentially added to 150mL of dichloromethane under ice bath conditions, and activated in an ice water bath for 40 min. 5.00g (17.00mmol) L-tryptophan benzyl ester were then added. The solution was reddish brown. The reaction mixture was stirred first for 1h on ice and then for 12h at room temperature. The reaction solution was washed with saturated aqueous sodium bicarbonate solution 6 times, and a large amount of bubbles were generated. Then, a saturated aqueous solution of sodium chloride was added thereto and the mixture was washed with water for 3 times. The dichloromethane layer was collected, dried for 2 hours by adding anhydrous sodium sulfate. Filtration was performed under normal pressure, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (v: v; petroleum ether: ethyl acetate 1:1) to give 5.39g (13.68mmol) of the title compound as a yellow oil. The yield was 81%. ESI-MS (M/e)393[ M + H]-。
EXAMPLE 2 preparation of 1- (2, 2-Dimethoxyethyl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid (2)
To 5.39g (13.68mmol) of Compound 1 and 100mL of methanol solution was added 540mg Pd/C, introducing H2The reaction was stirred at room temperature for 4 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 3.34g (11.00mmol) of the title compound as a yellow oil in 80% yield. ESI-MS (m/e): 303[ M-H]-。
EXAMPLE 3 preparation of (2S,5S) -Tetrahydropyrazine [1,2:1,6] and bis { (1S,1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione (3)
3.34g (11.00mmol) of Compound 2 was suspended in 60mL of N-dimethylformamide, and 1.49g (11.00mmol) of N-hydroxybenzotriazole and 2.72g (13.20mmol) of dicyclohexylcarbodiimide were sequentially added to the suspension under ice bath, followed by adjusting the pH of the reaction solution to 8-9 with N-methylmorpholine. The reaction was carried out at room temperature for 8 hours. The reaction solution was filtered under reduced pressure, and the filtrate was concentrated under reduced pressure. Then dissolved in 100mL of ethyl acetate, and a white solid was precipitated or not dissolved. Then, the mixture was filtered under reduced pressure, and the filtrate was collected. Washing the obtained ethyl acetate solution with saturated sodium bicarbonate water solution for 3 times, saturated sodium chloride water solution for 3 times, 5% potassium bisulfate water solution for 3 times, saturated sodium chloride water solution for 3 times, saturated sodium bicarbonate water solution for 3 times and saturated sodium chloride water solution for 3 times in sequence; the ethyl acetate layer was collected, dried over anhydrous sodium sulfate for 2 hours, and then filtered under reduced pressure, and the filtrate was collected. The solvent was removed under reduced pressure and the resulting yellow syrup was isolated by silica gel column chromatography (v: v; petroleum ether: ethyl acetate ═ 1:1) to give 670mg (1.17mmol) of the title compound as a yellow solid in 21% yield.
1H-NMR(300MHz,DMSO-d6)δ/ppm：11.00(d,J＝6.9Hz,2H),7.47(m,4H),7.11(m,4H),6.99(s,1H),5.23(s,1H),4.45(m,3H),4.19(s,1H),3.53(m,3H),4.19(s,1H),3.29(s,4H),3.21(s,3H),3.15(s,3H),3.10(s,3H),2.84(m,3H),2.19(s,2H)。
EXAMPLE 4 preparation of (2S,5S) -Tetrahydropyrazine [1,2:1,6] and bis { (1S,1R) - [ 1-Carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1, 4-dione (4)
139mg (24.30mmol) of compound 3 was dispersed in 9ml of glacial acetic acid under ice-bath conditions, and 2ml of water and 1ml of concentrated hydrochloric acid were added in this order. The reaction was carried out for 1 hour under ice-bath conditions. Under the ice-water bath condition, the pH value of the reaction solution was adjusted to 7 with a 2N aqueous solution of sodium hydroxide. Reaction solutionA large amount of yellow solid precipitated. Extraction was carried out with 30ml of ethyl acetate three times, insoluble matter was present in the ethyl acetate layer, and the ethyl acetate phases were combined. Then carrying out extraction washing by using a saturated sodium bicarbonate solution, combining ethyl acetate phases after 8 times of extraction washing. A large amount of bubbles are generated in the process of extraction and washing. The ethyl acetate phase was then dried over anhydrous sodium sulfate for 2 hours, filtered under reduced pressure, and the filtrate was collected and spin-dried under reduced pressure to give 105mg (21.87mmol) of the title compound as a yellow solid in 90% yield. ESI-MS (M/e):479[ M-H]-。
EXAMPLE 5 preparation of Boc-Ile-Gly-OBzl
5.50g (23.81mmol) of Boc-Ile-OH was suspended in 80mL of anhydrous tetrahydrofuran, and 3.21g (23.81mmol) of N-hydroxybenzotriazole and 4.91g (23.81mmol) of dicyclohexylcarbodiimide were added to the suspension in this order under ice-bath conditions, followed by stirring in ice-bath for 30 minutes. 5.35g (21.64mmol) of tos.Gly-OBzl was added thereto, and the pH was adjusted to 8 to 9 with N-methylmorpholine. The reaction was carried out at room temperature for 8 hours, filtered and the insoluble matter was removed by filtration. The solvent was concentrated under reduced pressure. The resulting solution was further dissolved in 80mL of ethyl acetate to precipitate a white solid or to dissolve it. And filtering again, and collecting the filtrate. Washing the obtained ethyl acetate solution with saturated sodium bicarbonate water solution for 3 times, saturated sodium chloride water solution for 3 times, 5% potassium bisulfate water solution for 3 times, saturated sodium chloride water solution for 3 times, saturated sodium bicarbonate water solution for 3 times and saturated sodium chloride water solution for 3 times in sequence; the ethyl acetate layer was collected, dried over anhydrous sodium sulfate for 2 hours, and then filtered under reduced pressure, and the filtrate was collected. The filtrate was concentrated under reduced pressure to give a yellow oily compound, which was separated by silica gel column chromatography (v: v; dichloromethane: methanol: 70:1) to give 7.87g (21.86mmol) of the title compound as a colorless solid in 92% yield. ESI-MS (M/e):379[ M + H]+。
EXAMPLE 6 preparation of HCl. Ile-Gly-OBzl
7.87g (21.86mmol) of Boc-Ile-Gly-OBzl were slowly mixed with 80mL of hydrogen chloride in ethyl acetate (4N) with stirring in an ice bath. The resulting solution was stirred in an ice bath for 3 h. After that, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in 80mL of anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated three times. The residue was thoroughly washed with dehydrated ether to obtain 5.82g (19.67 m) of the title compoundmol) as a colorless solid in 91% yield. ESI-MS (M/e):314[ M + H]+。
EXAMPLE 7 preparation of Boc-Tyr-Ile-Gly-OBzl
Using example 5 from 6.95g (24.72mmol) of Boc-Tyr-OH and 8.78g (29.67mmol) of tos.Gly-OBzl, silica gel column chromatography separation (v: v; dichloromethane: methanol ═ 25:1) gave 10.77g (18.67mmol) of the title compound as a colorless solid in 76% yield. ESI-MS (M/e) 542[ M + H]+。
EXAMPLE 8 preparation of Boc-Tyr-Ile-Gly-OH
To a solution of 10.77g (18.67mmol) Boc-Tyr-Ile-Gly-OBzl and 150mL methanol was added 1.10g Pd/C and H was bubbled2The reaction was stirred at room temperature for 8 h. Pd/C was filtered off, and the filtrate was concentrated under reduced pressure to give 8.03g (16.82mmol) of the title compound as a colorless solid in a yield of 90%. ESI-MS (m/e): 452[ M + H]+。
EXAMPLE 9 preparation of Boc-Ser-Lys (Z) -OBzl
From 2.00g (9.76mmol) of Boc-Ser-OH and 4.37g (10.73mmol) of HCl.Lys (Z) -OBzl, silica gel column chromatography was performed using the method of example 5 (v: v; dichloromethane: methanol ═ 40:1) to give 5.12g (9.21mmol) of the title compound as a colorless solid in 94% yield. ESI-MS (m/e): 558[ M + H]+。
EXAMPLE 10 preparation of HCl Ser-Lys (Z) -OBzl
5.12g (9.21mmol) of Boc-Ser-Lys (Z) -OBzl was prepared using the method of example 6. 4.25g (8.61mmol) of the title compound are obtained as a colorless solid in 94% yield. ESI-MS (m/e): 493[ M + H ]]+。
EXAMPLE 11 preparation of Boc-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl
from 2.11g (4.43mmol) of Boc-Tyr-Ile-Gly-OH and 2.62g (5.31mmol) of HCl.Ser-Lys (Z) -OBzl, silica gel column chromatography (v: v; dichloromethane: methanol: 10:1) was used as described in example 5 to give 1.19g (1.34mmol) of the title compound as a colorless solid in 30% yield. ESI-MS (m/e): 891[ M + H]+。
EXAMPLE 12 preparation of HCl Tyr-Ile-Gly-Ser-Lys (Z) -OBzl
From 1.19g (1.34mmol) of Boc-Tyr-Ile-Gly-S using the method of example 6er-Lys (Z) -OBzl. 1.00g (1.21mmol) of the title compound are obtained as a colorless solid in a yield of 90%. ESI-MS (m/e): 826[ M + H]+。
EXAMPLE 13 preparation of Boc-Ser (Bzl) -Arg (NO)2)-OBzl
Using the method of example 5, from 2.88g (9.76mmol) of Boc-Ser (Bzl) -OH and 4.37g (10.73mmol) of tos.Arg (NO)2) OBzl, silica gel column chromatography (v: v; dichloromethane: methanol-20: 1) to yield 4.33g (7.37mmol) of the title compound as a colorless solid in 76% yield. ESI-MS (m/e): 587[ M + H]+。
EXAMPLE 14 preparation of HCl.Ser (Bzl) -Arg (NO)2)-OBzl
From 4.33g (7.37mmol) of Boc-Ser (Bzl) -Arg (NO) using the method of example 62) OBzl, 3.64g (6.96mmol) of the title compound are obtained as a colorless solid in a yield of 95%. ESI-MS (m/e): 522[ M + H]+。
EXAMPLE 15 preparation of Boc-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl
Using the method of example 5, 2.11g (4.43mmol) of Boc-Tyr-Ile-Gly-OH and 2.78g (5.31mmol) of HCl.Ser (Bzl) -Arg (NO)2) -OBzl. Separation by silica gel column chromatography (v: v; dichloromethane: methanol ═ 10:1) gave 2.04g (2.23mmol) of the title compound as a colorless solid in 50% yield. ESI-MS (m/e): 920[ M + H ]]+。
EXAMPLE 16 preparation of HCl Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl
Using the method of example 6, 2.04g (2.23mmol) of Boc-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2) OBzl, 1.81g (2.11mmol) of the title compound are obtained as a colorless solid in a yield of 95%. ESI-MS (m/e): 855[ M + H]+。
EXAMPLE 17 preparation of (2S,5S) -Tetrahydropyrazine [1,2:1,6] and bis { (1S,1R) - [ N-Ethyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] oxindole } -1, 4-dione (5a)
100mg (0.21mmol) of Compound 4 was dispersed in 3mL of dichloromethane. Adding 2 drops of triethylamine to adjust the pH value to 8 under ice bath to obtain a solution A; 521mg (0.63mmol) of HCl Tyr-Ile-Gly-Ser-Lys (Z) -OBzl were dispersedAdding 2 drops of triethylamine into 5mL of dichloromethane in ice bath to adjust the pH value to be 8 to obtain a solution B; combine solutions a and B. And a drying agent magnesium sulfate is added to activate for 1 hour at normal temperature. Every 1 hour, 13mg (0.21mmol) of sodium cyanoborohydride as a reducing agent was added, 4 times in total, and 53mg (0.84mmol) of sodium cyanoborohydride in total was added. The reaction was terminated after 8 hours at room temperature, and the solvent was concentrated under reduced pressure. The residue was dissolved by adding 10mL of ethyl acetate. The obtained ethyl acetate solution is extracted and washed for 3 times by using a saturated sodium bicarbonate aqueous solution, a saturated sodium chloride aqueous solution is washed to be neutral, an ethyl acetate layer is collected, dried for 2 hours by using anhydrous sodium sulfate, filtered, and the filtrate is concentrated to be dry under reduced pressure. The resulting yellow solid was separated by silica gel column chromatography (v: v; dichloromethane: methanol ═ 15:1) to give 44mg (0.02mmol) of the title compound as a yellow solid in a yield of 10%1H-NMR(300MHz,DMSO-d6)δ/ppm：10.99(s,1H),10.93(s,1H),9.12(d,J＝7.2Hz,2H),8.05(m,6H),7.44(m,26H),7.07(m,10H),6.70(m,6H),5.77(s,1H),5.29(s,1H),5.10(s,4H),5.00(s,4H),4.85(s,1H),4.36(m,8H),3.78(m,3H),3.55(m,4H),3.45(m,6H),2.77(m,8H),2.36(s,4H),2.20(s,4H),1.98(s,4H),1.66(s,6H),1.30(m,8H),0.83(m,12H)。
EXAMPLE 18 preparation of (2S,5S) -Tetrahydropyrazine [1,2:1,6] and bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione (6a)
30mg (0.02mmol) of 5a was dissolved in 1mL of trifluoroacetic acid while cooling on ice, and 333. mu.L of trifluoromethanesulfonic acid was added thereto, whereby the solution turned from yellow to dark brown. The reaction was carried out in ice bath for 0.5 hour, 15mL of precooled ether was added, a yellow solid precipitated, and the mixture was stirred well. Standing and discarding the supernatant. Additional pre-chilled ether was added and the procedure was repeated three times. 2mL of water was added, and the pH was adjusted to 7 with a 10-fold dilution of aqueous ammonia (the solution gradually changed from cloudy to clear as the pH was adjusted). Filtering under reduced pressure, and collecting filtrate. Through a Sephadex-G25 column, 15mg (0.01mmol) of the title compound were obtained as a yellow solid. The yield was 64%.
Melting range: 223.2 to 224.1 ℃; ESI-MS (m/e): 1582[ M + H]+IR(cm-1):3114.31,3021.04,2804.77,1999.00,1749.25,1650.92,1442.12,1391.42,1167.80,1028.70,679.27,638.69；1H-NMR(300MHz,DMSO-d6)δ/ppm：11.10(m,2H),8.16(m,3H),7.95(m,2H),7.56(m,2H),7.46(m,8H),7.08(m,9H),6.79(m,2H),6.55(m,4H),5.81(s,1H),5.30(s,1H),4.45(m,1H),3.85(m,4H),3.73(m,7H),3.55(m,10H),3.13(m,4H),2.83(m,4H),2.18(m,8H),1.99(m,4H),1.88(s,2H),1.69(s,4H),1.50(s,4H),1.08(m,4H),0.82(m,6H),0.67(m,6H)。
EXAMPLE 19 preparation of (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione (5b)
From 100mg (0.21mmol) of 4 and 40mg (0.63mmol) of HCl Tyr-Ile-Gly-Ser (Bzl) -Arg (NO) using the method of example 172) -OBzl. Separation by silica gel column chromatography (v: v; dichloromethane: methanol ═ 10:1) gave 35mg (0.02mmol) of the title compound as a yellow solid in 8% yield.1H-NMR(300MHz,DMSO-d6)δ/ppm：11.03(s,1H),10.94(s,1H),9.12(d,J＝7.2Hz,2H),8.51(m,3H),8.07(m,9H),7.47(m,2H),7.32(s,10H),7.27(s,10H),7.04(m,10H),6.79(d,J＝7.8Hz,3H),6.61(d,J＝7.4Hz,3H),6.52(d,J＝8.1Hz,2H),5.77(s,1H),5.28(s,1H),5.08(s,4H),4.60(s,2H),4.41(m,6H),4.26(m,5H),3.80(m,6H),3.54(m,7H),3.45(m,4H),3.14(m,4H),2.28(s,4H),2.15(m,4H),2.00(s,4H),1.64(m,10H),0.84(m,12H)。
EXAMPLE 20 preparation of (2S,5S) -Tetrahydropyrazine [1,2:1,6] and bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Arg ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione (6b)
Desalting was performed by the method of example 18 from 50mg (0.02mmol) of compound 5b on a Sephadex-G25 column. 16mg (0.01mmol) of the title compound are obtained as a yellow solid in 32% yield.
Melting range: 217.3 to 218.9 ℃; ESI-MS (m/e): 1638[ M + H]+IR(cm-1):3278.77,2960.33,2931.97,2875.65,1643.82,1514.58,1452.32,1403.25,1330.49,1317.54,1230.77,1146.53,1106.27,1070.77,931.97,823.98,744,43,666.76,631.49,603.33；1H-NMR(300MHz,DMSO-d6)δ/ppm：10.98(d,J＝10.2Hz,2H),9.45(s,1H),8.58(m,1H),8.06(m,6H),7.63(m,2H),7.45(m,4H),7.33(m,10H),6.99(m,8H),7.08(d,J＝7.5Hz,2H),6.61(d,J＝7.2Hz,2H),6.50(d,J＝7.2Hz,2H),5.76(s,1H),5.27(s,1H),4.38(s,2H),4.24(m,7H),3.92(m,3H),3.60(m,10H),3.04(m,6H),2.77(m,2H),2.39(m,4H),1.93(m,4H),1.69(s,2H),1.45(m,8H),1.15(m,2H),0.84(m,2H),0.69(m,6H),0.54(m,3H),0.35(m,3H)。
Experimental example 1 evaluation of anti-venous thrombosis Activity of Compounds 6a and 6b
1) Experimental methods
SD rats (200 + -20 g) were acclimatized and fasted for one day before surgery, and the rats were gavaged with a dose of 0.3mL/100g body weight and anesthetized with a intraperitoneal administration of 20% urethane solution 2min before surgery 30min after administration. Preparing skin of abdomen of rat, sterilizing, opening abdominal cavity along the leucorrhea line, descending to coagulated gland, and ascending to expose one corner of liver. The organs such as small intestine in abdominal cavity are pulled out to expose inferior vena cava, and the pulled-out organs are wrapped with gauze soaked with normal saline. Blunt-separating connective tissue around blood vessel, exposing inferior vena cava and its branch, peeling off abdominal aorta and inferior vena cava below renal vein, ligating inferior vena cava at junction of inferior vena cava and left renal vein with suture soaked with physiological saline, placing organs such as intestine back into abdominal cavity according to anatomical position, and suturing abdominal cavity layer by layer with suture.
After operation, the rat is placed in an environment with the temperature of 25-28 ℃ for circulation for 4 hours, the abdominal cavity is opened, the branches of the rat are tied one by one, the 2 cm inferior vena cava is taken out from the tying position of the junction of the inferior vena cava and the left renal vein, and the thrombus is taken out from the inferior vena cava.
2) Methods of administration and dosages
The administration mode is intragastric administration. Blank control: physiological saline with the administration dosage of 0.3mL/100 g; positive control: warfarin (dose 4.87. mu. mol/kg); 4 (administration dose is 1. mu. mol/kg); inventions 6a and 6b (administered at a dose of 0.1. mu. mol/kg).
3) Statistical method
The statistics of the experimental data are all performed by adopting a t test, and the suppository weight is expressed by (mean value +/-SD mg).
4) results of the experiment
As can be seen from the results of table 1, the ratio P of 6a and 6b to physiological saline was <0.01, indicating that 6a and 6b have good anti-venous thrombosis activity; 0.1. mu. mol/kg6a and 6b are comparable to 4.87. mu. mol/kg warfarin in anti-thrombotic activity (and also comparable to 1. mu. mol/kg4 anti-thrombotic activity). Under the same activity conditions, the compounds 6a and 6b of the invention are reduced by 48.7 times compared with warfarin dose and 10 times compared with 4 doses. The present invention has an unexpected technical effect.
TABLE 1 anti-thrombotic Activity of Compounds 6a and 6b
a) P <0.01 to normal saline, P >0.05 to 4.87 μmol/kg warfarin and 1 μmol/kg 4; n-12
Experimental example 2 evaluation of anti-arterial Thrombus Activity of Compounds 6a and 6b
1) Experimental methods
Healthy SD male rats weighing 180-220g, preoperatively fasting for 24 hours, and preoperatively preparing anticoagulant heparin sodium (2.4mg/mL), physiological saline solution and urethane (20g/100mL, anesthetic dose 7 mL/kg). Randomly grouping SD male rats of experimental animals, wherein n is 9, the volume of the administration of rats by intragastric administration is 3mL/kg, anesthetizing with urethane after intragastric administration for 30 minutes, separating the right carotid artery and the left jugular vein, ligating the far end, filling a polyethylene tube containing 6cm of silk threads precisely weighed in advance with heparin sodium physiological saline solution, inserting one end of the polyethylene tube into the left jugular vein, inserting one end of the polyethylene tube into the right carotid artery, and ligating the near end. Blood flow from the right artery into the left vein through a polyethylene tube, the silk was removed after 15 minutes and the wet weight of the thrombus was recorded.
2) Methods of administration and dosages
The administration mode is intragastric administration. Blank control: physiological saline with the administration dosage of 0.3mL/100 g; positive control: aspirin (administered at a dose of 167 μmol/kg); 4 (administration dose is 1. mu. mol/kg); inventions 6a and 6b (administered at a dose of 0.1. mu. mol/kg).
3) Statistical method
the statistics of the experimental data are all performed by adopting a t test, and the suppository weight is expressed by (mean value +/-SD mg).
4) Results of the experiment
As can be seen from the results of table 2, the ratio P of 6a and 6b to physiological saline was <0.05, indicating that 6a and 6b have good anti-arterial thrombotic activity; 0.1. mu. mol/kg6a and 6b are comparable to 1. mu. mol/kg4 in anti-arterial thrombotic activity. Compounds 6a and 6b of the invention decreased by 10-fold compared to the 4 dose under the same activity conditions. The present invention has an unexpected technical effect.
TABLE 2 anti-arterial Thrombus Activity of Compounds 6a and 6b
a) P <0.05 to saline, P <0.05 to aspirin, and P >0.05 to 1 μmol/kg 4; n is 9.
Experimental example 3 evaluation of the Activity of Compounds 6a and 6b to inhibit GPIIb/IIIa expression in vivo
1) The experimental method comprises the following steps:
Serum: in vivo evaluation of arterial thrombosis SD rats were sacrificed, carotid artery blood was collected and centrifuged at 3000rpm/min at 4 ℃ for 15 minutes.
Enzyme linked immunoassay kit: rat platelet membrane glycoprotein IIb/IIIa kit (origin: enzyme linked biology; cat # m1003231)
enzyme-linked immunosorbent assay (manufacturer: Molecular Devices; model: SpectraMax M3)
Oven (manufacturer: lester; model: 101-1AB)
Sample adding: and setting a standard hole, a sample hole to be detected and a blank hole. Standard wells, each well is added with 50 μ L of standard substance with different concentrations; mu.L of sample diluent was added to the sample well, followed by 10. mu.L of sample. Blank wells were not added.
Adding an enzyme: mu.L per well, plated, shaken and incubated in an oven at 37 ℃ for 1 hour. Blank wells were not added.
Washing the plate: diluting the concentrated washing liquid by 20 times with distilled water, removing the sealing plate membrane, spin-drying, filling the washing liquid in each hole, and standing for 30 seconds for spin-drying. This was repeated five times.
Adding a color developing agent: each well was first filled with 50. mu.L of developer A and then 50. mu.L of developer B. Shaking, incubating in oven at 37 deg.C in dark for 15min
Adding a termination solution: mu.L per well, optical density was measured using a microplate reader at a wavelength of 450nm over 15 minutes. The experimental data were set to blank wells with 0 standard concentration and zeroed.
2) Administration methods and dosages: same as example 22
3) Statistical method
Data statistics were performed using the t-test and expressed as (mean ± SD).
4) results of the experiment
As can be seen from the results in Table 3, the ratio P of 0.1. mu. mol/kg of 6a and 6b to the physiological saline is less than 0.01, which shows that 6a and 6b have good activity of inhibiting the expression of GPIIb/IIIa in vivo; the ratio of 0.1. mu. mol/kg6a and 6b to 1. mu. mol/kg 4P < 0.01. Thus, 0.1. mu. mol/kg6a and 6b showed better activity for inhibiting GPIIb/IIIa expression in vivo than 1. mu. mol/kg 4. The present invention has an unexpected technical effect.
TABLE 3 Effect of Compounds 6a and 6b on GPIIb/IIIa expression
a) P <0.01 to normal saline, P <0.01 to 1 μmol/kg 4; n is 6.
Experimental example 4 evaluation of the Effect of Compounds 6a and 6b on P-selectin expression
1) The experimental method comprises the following steps:
Serum: in vivo evaluation of arterial thrombosis SD rats were sacrificed, carotid artery blood was collected and centrifuged at 3000rpm/min at 4 ℃ for 15 minutes.
Enzyme linked immunoassay kit P-selectin: rat P-selectin enzyme linked immunoassay kit (source: CUSABIO company; product number: CSB-E07399r)
Enzyme-linked immunosorbent assay (manufacturer: Molecular Devices; model: SpectraMax M3)
Oven (manufacturer: lester; model: 101-1AB)
Preparing a reagent: according to the specification, a series of concentration gradient standards, a washing liquid working solution, a biotin-labeled antibody working solution and a horseradish peroxidase-labeled avidin working solution are prepared. Then allowed to equilibrate at room temperature for at least thirty minutes.
Sample adding: and setting a standard hole and a sample hole to be detected. Add 100 μ L of standard or test sample to each well, cover the plate, shake well, and incubate in 37 ℃ oven for 2 hours. And (5) spin-drying.
Adding biotin labeled antibody working solution: mu.L per well, plated, shaken and incubated in an oven at 37 ℃ for 1 hour. Spin-drying, soaking the plate in 200 μ L of plate washing liquid for 2min every time, and washing the plate three times.
Adding horseradish peroxidase labeled avidin working solution: mu.L per well, plated, shaken and incubated in an oven at 37 ℃ for 1 hour. Spin-drying, soaking the plate for 2 minutes in 200 mu L of plate washing liquid per hole, and washing the plate for five times.
Adding a substrate solution: each well is 90 mu L, and the mixture is incubated and developed for 15-30 min in an oven at 37 ℃ in the dark
adding a termination solution: 50 μ L per well, and after 5 minutes, the optical density was measured using a microplate reader at a wavelength of 450nm over 15 minutes. The experimental data were set to blank wells with 0 standard concentration and zeroed.
2) administration methods and dosages: same as Experimental example 22
3) Statistical method data statistics are measured by t test and expressed as (mean + -SD).
4) Results of the experiment
As can be seen from the results in Table 4, the ratio P of 0.1. mu. mol/kg of 6a and 6b to physiological saline was less than 0.01, indicating that 6a and 6b have good activity of inhibiting the expression of P-selectin in vivo; 0.1. mu. mol/kg6a and 6b are comparable to 1. mu. mol/kg4 in inhibiting P-selectin expression activity in vivo. Compounds 6a and 6b of the invention decreased by 10-fold compared to the 4 dose under the same activity conditions.
TABLE 4 Effect of Compounds 6a and 6b on P-selectin expression
a) P <0.01 to normal saline, P <0.05 to 1 μmol/kg 4; n is 6.
Claims (6)
1.(2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-AA ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione of the formula,
wherein AA is a Lys residue or an Arg residue.
2. A process for the preparation of (2S,5S) -tetrahydropyrazinyl [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-AA ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione of claim 1, which comprises:
(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) Uses dicyclohexylcarbodiimide and N-hydroxybenzotriazole as catalysts to synthesize HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl and HCl, Tyr-Ile-Gly-Ser (Bzl) -Arg (NO) by adopting a liquid phase condensation method2)-OBzl；
(6) In the presence of sodium cyanoborohydride, HCl, Tyr-Ile-Gly-Ser-Lys (Z) -OBzl and (2S,5S) -tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyridoindole } -1, 4-dione are subjected to ammoniation reduction to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys (Z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyridoindole } -1, 4-diketones;
(7) (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys (z) -OBzl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione in the presence of trifluoroacetic acid and trifluoromethanesulfonic acid to give (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Lys ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1, 4-dione;
(8) In the presence of sodium cyanoborohydride, HCl, Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2) OBzl and (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ 1-Carbonylmethyl group]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And then the indole } -1, 4-diketone is subjected to ammoniation reduction to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione;
(9) (2S,5S) -tetrahydropyrazines [1,2:1,6]And bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser (Bzl) -Arg (NO)2)-OBzl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione in the presence of trifluoroacetic acid and trifluoromethanesulfonic acid to obtain (2S,5S) -tetrahydropyrazine [1,2:1,6]and bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-Arg]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1, 4-dione.
3. Use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-AA ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -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-Tyr-Ile-Gly-Ser-AA ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1, 4-dione according to claim 1 for the preparation of an anti-arterial thrombosis medicament.
5. Use of (2S,5S) -tetrahydropyrazino [1,2:1,6] bis { (1S,1R) - [ N-ethyl-Tyr-Ile-Gly-Ser-AA ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -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-Tyr-Ile-Gly-Ser-AA ] -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.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN113754663A (en) * | 2020-06-04 | 2021-12-07 | 首都医科大学 | RR-heptacyclic aldehyde, its synthesis, antithrombotic activity and application |
| CN113754662A (en) * | 2020-06-04 | 2021-12-07 | 首都医科大学 | RS-heptacyclic aldehyde, its synthesis, activity and application |
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