CN107686483B - Heptacyclic acetals, their preparation, antithrombotic activity and use - Google Patents
Heptacyclic acetals, their preparation, antithrombotic activity and use Download PDFInfo
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- C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings
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Abstract
The invention discloses three heptacyclic acetals, pyrazinedionebis-R, R-carbolines, pyrazinedionebis-S, S-carbolines and pyrazinedionebis-S, R-carbolines. The invention discloses a preparation method thereof, further discloses the antithrombotic activity thereof, and therefore discloses the application thereof in preparing antithrombotic medicaments.
Description
Technical Field
The invention relates to three heptacyclic acetals, pyrazinedionebis-R, R-carbolines, pyrazinedionebis-S, S-carbolines and pyrazinedionebis-S, R-carbolines, to processes for their preparation, and to their antithrombotic activity. The invention thus relates to their use in the preparation of antithrombotic agents. The invention belongs to the field of biological medicine.
Technical Field
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 fuse, e.g., two (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acids condense intermolecularly to pyrazinedione and bis-S, S-carboline; two (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid molecules are condensed into pyrazinedione bi-R, R-carboline; intermolecular condensation of (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid with (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid produces pyrazinedione bis-S, R-carboline. The three novel heptacyclic compounds should have strong antithrombotic activity. Based on this assumption, the inventors have proposed the present invention.
Disclosure of the invention
The first aspect of the present invention is to provide three heptacyclic acetals, pyrazinedionebis-R, R-carboline, pyrazinedionebis-S, S-carboline and pyrazinedionebis-S, R-carboline of the formula.
The second aspect of the present invention provides a process for preparing three heptacyclic acetals, pyrazinedionebis-R, R-carbolines, pyrazinedionebis-S, S-carbolines and pyrazinedionebis-S, R-carbolines, which comprises:
(1) carrying out Pictet-Spe-gler condensation on L-tryptophan benzyl ester and 1,1,3, 3-tetramethoxypropane under the catalysis of trifluoroacetic acid to obtain (S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (1);
(2) hydrogenating and removing benzyl ester of (S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid in a methanol solution under the catalysis of Pd/C to obtain (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (2);
(3) intermolecular condensation of (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid in anhydrous DMF (N, N-dimethylformamide) in the presence of 2- (7-benzotriazole oxide) -N, N' -tetramethyluronium hexafluorophosphate (HATu) and N-hydroxybenzotriazole (HOBt) to pyrazinedione bis-S, S-carboline; (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid is condensed into pyrazinedionebis-R, R-carboline in anhydrous DMF (N, N-dimethylformamide) molecules; condensation of (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid with (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid intermolecular in anhydrous DMF (N, N-dimethylformamide) to pyrazinedionebis-S, R-carboline.
The third aspect of the present invention is to evaluate the antithrombotic effect of pyrazinedionebis-S, S-carboline, pyrazinedionebis-R, R-carboline and pyrazinedionebis-S, R-carboline.
The fourth content of the invention is to illustrate the application of the pyrazinedionebis-S, S-carboline, pyrazinedionebis-R, R-carboline and pyrazinedionebis-S, R-carboline in the preparation of antithrombotic drugs.
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FIG. 1 Synthesis routes for pyrazinedionebis-S, S-carbolines, pyrazinedionebis-R, R-carbolines and pyrazinedionebis-S, R-carbolines i) CH2Cl2,TFA；ⅱ)Pd/C,H2,CH3OH; iii) HATu, HOBt, triethylamine, anhydrous DMF.
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 (3S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (1)
150mL of CH was added under ice bath2Cl25mL of a mixture of 1,1,3, 3-tetramethoxypropane and 5mL of trifluoroacetic acid was stirred for 40min, and then 5g (17.0mmol) of L-Trp-OBzl was added thereto. Reaction mixture stirred for 14h before point TLC (CH)2Cl2:CH3OH,30:1) shows the disappearance of the starting point. Saturated NaHCO is used for reaction liquid3Washing with water solution for 3 times, washing with saturated NaC water solution for 3 times, and mixing CH2Cl2Layer, anhydrous NaSO4Drying, filtering under reduced pressure, concentrating the filtrate under reduced pressure, and purifying the residue by silica gel column Chromatography (CH)2Cl2:CH3OH,100:1) to yield 5.9g (87%) of the title compound as a red-brown oil. ESI-MS (M/e)393[ M + H]-。
EXAMPLE 2 preparation of (3S) -1- (2, 2-Dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid (2)
3.96g (10.0mmol) of (3S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b]Indole-3-carboxylic acid (1) with 150mL CH3OH is dissolved, 400mg Pd/C is added, the mixture is stirred evenly, hydrogen is filled, the mixture reacts for 18h, and a TLC plate (CH)2Cl2:CH3OH,30:1) shows the disappearance of the starting point. The reaction mixture was filtered under reduced pressure and the filtrate was concentrated under reduced pressure to give 2.73g (89%) of the title compound as a yellow solid. ESI-MS (M/e)303[ M-H]-。
Example 3 preparation of (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] and bis { (1S, S) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1 ', 4' -dione (pyrazinedione-bis-S, S-carboline), (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] and bis { (1R, R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] and indole } -1 ', 4' -dione (pyrazinedione-bis-R, r-carboline) and (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis { (1S, R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione (pyrazinedionebis-S, R-carboline)
886mg (2.91mmol) of (3S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3, 4-b)]Indole-3-carboxylic acid was dissolved in 50mL anhydrous DMF in a 100mL reaction flask, 1.29g (3.4mmol) HATU was added under stirring in ice bath, the pH of the reaction solution was adjusted to 8-9 with collidine, and reacted for 24 hours on a TLC plate (CH)2Cl2:CH3OH,60:1) shows the disappearance of the starting point. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100mL ethyl acetate and then saturated NaHCO was added3Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO4Aqueous wash (30 mL. times.3), saturated aqueous NaCl wash (30 mL. times.3), 5% NaHCO3Aqueous washes (30m L × 3), aqueous saturated NaCl washes (30mL × 3) extraction washes 3 times, combined ethyl acetate layers, dried over anhydrous sodium sulfate, filtered under reduced pressure, and the filtrate concentrated under reduced pressure to give the title compound as a dark yellow solid. 111 mg of pyrazinedionebis-S, S-carboline, 128mg of pyrazinedionebis-R, R-carboline and 278mg of pyrazinedionebis-S, R-carboline were isolated from the dark yellow solid. The total yield is 62%.
Experimental example 1 evaluation of anti-venous thrombosis Activity of Pyrazinedionatobis-S, S-carboline, Pyrazinedionatobis-R, R-carboline and Pyrazinedionatobis-S, R-carboline
1. Rat model male SD rats (200 ± 20g) were acclimatized and fasted for one day, and were intraperitoneally injected with 20% urethane solution 30min after gavage and 2min before surgery. The anesthetized rats were prepared by preparing their abdomens, sterilizing, and opening the abdominal cavity (down to the coagulated gland and up to the corner of the liver) along the leucorrhea line. The small intestine and other organs are pulled out of the abdominal cavity and wrapped with gauze soaked with normal saline. The perivascular connective tissue was isolated blunt, exposing the inferior vena cava and its branches. The abdominal aorta and inferior vena cava were peeled off below the renal veins, and the inferior vena cava was ligated with saline-soaked sutures at the junction of the inferior vena cava and left renal vein. The organ pulled out of the abdominal cavity is placed back into the abdominal cavity according to the anatomical position, and the abdominal cavity is sutured layer by the suture line. After operation, the rat is placed in an environment at 25 ℃ and circulated for 4 hours, the abdominal cavity is opened, the branches are ligated one by one, the 2cm inferior vena cava is taken out from the ligation position at the junction of the inferior vena cava and the left renal vein, and the thrombus is taken out and weighed.
2. Administration methods and dosages for intragastric administration. The blank control is physiological saline, and the administration dosage is 0.3mL/100 g; the positive control is warfarin, and the administration dose is 4.9 mu mol/kg; the administration dose of the pyrazinedionebis-S, S-carboline, pyrazinedionebis-R, R-carboline and pyrazinedionebis-S, R-carboline is 1 mu mol/kg.
3. Statistical methods data statistics were performed using t-test and anova, and suppository weights were expressed as x ± SD mg.
4. Results the results are shown in Table 1. It can be seen that the suppository weight of the rat treated by the pyrazinedione bis-S, S-carboline, pyrazinedione bis-R, R-carboline and pyrazinedione bis-S, R-carboline is obviously smaller than that of the rat treated by the normal saline under the dosage of 1 mu mol/kg after gastric lavage, and has no obvious difference with that of the rat treated by 4.9 mu mol/kg warfarin, indicating that the rat treated by the pyrazine dixoline and the rat treated by the warfarin have good anti-venous thrombosis activity.
TABLE 1 Compound anti-thrombotic Activity
n is 12; a) p <0.01 to saline; b) the ratio p to normal saline is less than 0.01, and the ratio p to warfarin is more than 0.05; c) the ratio of p to normal saline is more than 0.05.
Experimental example 2 evaluation of anti-arterial thrombosis Activity of Pyrazinedionato-bis-S, S-carboline, Pyrazinedionato-bis-R, R-carboline and Pyrazinedionato-bis-S, R-carboline
1. Rat model male SD rats (200 ± 20g) were acclimatized and fasted for one day, and were intraperitoneally injected with 20% urethane solution 30min after gavage and 2min before surgery. Before operation, an anticoagulant heparin sodium 2.4mg/mL physiological saline solution is prepared. Randomly grouping SD male rats of experimental animals, separating right carotid artery and left jugular vein, ligating distal ends, 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 proximal ends. 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. The administration method and dosage administration mode is intragastric administration. The blank control is physiological saline, and the administration dosage is 0.3mL/100 g; the positive control is aspirin, and the administration dosage is 167 mu mol/kg; the administration dose of the pyrazinedionebis-S, S-carboline, pyrazinedionebis-R, R-carboline and pyrazinedionebis-S, R-carboline is 1 mu mol/kg.
3. Statistical methods data statistics were performed using t-test and anova, and the suppository weights were expressed as x ± SDmg.
4. Results the results are shown in Table 2. It can be seen that the thrombus weight of the rat treated by the pyrazinedione bis-S, S-carboline, pyrazinedione bis-R, R-carboline and pyrazinedione bis-S, R-carboline is obviously less than that of the rat treated by the normal saline under the dosage of 1 mu mol/kg by intragastric administration, and has no obvious difference with that of the rat treated by 167 mu mol/kg aspirin, which indicates that the compounds have good anti-arterial thrombosis activity.
TABLE 2 anti-arterial thrombotic Activity of the Compounds
n is 12; a) p <0.01 to saline; b) p <0.05 to saline.
Claims (3)
1. Three heptacyclic acetals of the formula pyrazinedionebis-R, R-carboline, pyrazinedionebis-S, S-carboline and pyrazinedionebis-S, R-carboline,
2. a process for preparing three heptacyclic acetals, pyrazinedionebis-R, R-carbolines, pyrazinedionebis-S, S-carbolines and pyrazinedionebis-S, R-carbolines of claim 1, comprising:
(1) carrying out Pictet-Spe-gler condensation on L-tryptophan benzyl ester and 1,1,3, 3-tetramethoxypropane under the catalysis of trifluoroacetic acid to obtain (S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid;
(2) hydrogenating and removing benzyl ester of (S) -benzyl-1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid in a methanol solution under the catalysis of Pd/C to obtain (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid;
(3) condensation of (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid intermolecularly in anhydrous DMF (N, N-dimethylformamide) in the presence of 2- (7-oxide benzotriazole) -N, N' -tetramethyluronium hexafluorophosphate (HATu) and N-hydroxybenzotriazole to pyrazinedione and bis-S, S-carboline; (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid is condensed into pyrazinedionebis-R, R-carboline in anhydrous DMF (N, N-dimethylformamide) molecules; condensation of (R) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid with (S) -1- (2, 2-dimethoxyethyl) -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acid intermolecular in anhydrous DMF (N, N-dimethylformamide) to pyrazinedionebis-S, R-carboline.
3. Use of the three heptacyclic acetals, pyrazinedionebis-R, R-carbolines, pyrazinedionebis-S, S-carbolines and pyrazinedionebis-S, R-carbolines of claim 1 for the preparation of an anti-thrombotic medicament.
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| CN110551128B (en) * | 2018-06-04 | 2020-10-16 | 首都医科大学 | Amino acid modified S, R-heptacyclic aldehyde, synthesis, activity and application thereof |
| CN110551126B (en) * | 2018-06-04 | 2021-01-29 | 首都医科大学 | Amino acid modified S, R-heptacyclic aldehyde, and synthesis, activity and application thereof |
| CN110577531B (en) * | 2018-06-08 | 2021-03-30 | 首都医科大学 | Amino acid modified S, S-heptacyclic aldehyde, preparation, activity and application thereof |
| CN110577530B (en) * | 2018-06-08 | 2021-03-30 | 首都医科大学 | Heptacyclic aldehyde, its synthesis, antithrombotic activity and use |
| CN110577570B (en) * | 2018-06-11 | 2021-06-08 | 首都医科大学 | RGD tetrapeptide modified S, R-heptacyclic aldehyde, and synthesis, activity and application thereof |
| CN111995661B (en) * | 2019-05-27 | 2022-04-22 | 首都医科大学 | Ethyl ARPAK modified bis-carbolino-piperazinediones, preparation, activity and application thereof |
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| CN112010855B (en) * | 2019-05-28 | 2021-06-08 | 首都医科大学 | Hexacyclic piperazinedione compounds, preparation, biological activity and application thereof |
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| CN114763355B (en) * | 2021-01-12 | 2023-07-28 | 首都医科大学 | Heptacycloindole diketopiperazine compound, preparation, antithrombotic activity and application thereof |
| CN114763354B (en) * | 2021-01-12 | 2023-05-05 | 首都医科大学 | Heptacycloindole diketopiperazine non-covalent bond trimer, preparation, thrombolytic activity and application thereof |
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