CN110577530B - Heptacyclic aldehyde, its synthesis, antithrombotic activity and use - Google Patents
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- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C07D471/00—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
- 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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- C07B2200/07—Optical isomers
Abstract
The invention discloses heptacyclic aldehydes of the formula (2 'S, 5' S) -tetrahydropyrazines [1 ', 2': 1,6]And bis { (1R) - [ 1-Carbonylmethyl group]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]And indole } -1 ', 4' -dione. Discloses a preparation method thereof and further discloses the venous thrombosis resisting activity thereof, so that the invention discloses the application of the medicine in preparing the venous thrombosis resisting medicine.
。
Description
Technical Field
The present invention relates to (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione. Relates to a preparation method thereof, and further relates to the venous thrombosis resisting activity thereof, so that the invention relates to the application thereof in preparing the venous thrombosis resisting medicine. The invention belongs to the field of biological medicine.
Background
Both arterial and venous thrombosis have become diseases with high morbidity and mortality, and the worldwide number of deaths from ischemic heart disease and ischemic stroke is 1/4 of all deaths due to disease. Venous thrombosis is a major disease burden in less-developed, moderately-developed and highly-developed countries. Venous thrombosis includes primarily deep vein thrombosis and pulmonary embolism. The number of patients with deep vein thrombosis and pulmonary embolism exceeds the total number of patients with myocardial infarction and apoplexy, and is higher than the total number of deaths caused by breast cancer and AIDS. Since the incidence of venous thrombosis increases exponentially with age, the threat of this condition to the health of people in the aging countries of our country is particularly severe. If the population cardinality is considered, the absolute negative influence on the national civilization of China is particularly serious. Therefore, the prevention and treatment of venous thrombosis have been the focus of attention in the field of medicine, and the invention of novel anti-venous thrombosis medicines has clinical importance.
The beta-carboline is an important pharmacophore for inhibiting thrombus. The inventors hypothesize that the intermolecular condensation of two beta-carboline pharmacophores, e.g., two (R) -1-carbonylmethyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole-3-carboxylic acids, results in (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione. The novel heptacyclic aldehyde has strong anti-vein thrombosis activity. Based on this assumption, the inventors have proposed the present invention.
Disclosure of Invention
In a first aspect of the invention there is provided (2 'S, 5' S) -tetrahydropyrazinyl [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione of the formula.
In a second aspect of the present invention, there is provided a process for the preparation of (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1 ', 4' -dione, 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 (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate (1);
2) carrying out hydrogenolysis debenzylation on (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester in methanol under the catalysis of Pd/C to obtain (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid (2);
3) intermolecular condensation of (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid in anhydrous DMF (N, N-dimethylformamide) in the presence of benzotriazole-N, N ' -tetramethyluronium hexafluorophosphate (HBTu) to (2 ' S,5 ' S) -tetrahydropyrazino [1 ', 2 ': 1,6] and bis { (1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyridin [3,4-b ] oxindole } -1 ', 4 ' -dione (3);
4) glacial acetic acid is used as a solvent, concentrated hydrochloric acid and water are used as catalysts, and (2 'S, 5' S) -tetrahydropyrazine [1 ', 2': 1,6] bis { (1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole } -1 ', 4' -dione (3) is converted into (2 'S, 5' S) -tetrahydropyrazine [1 ', 2': 1,6] bis [ (1R) -1-carbonylmethyl-2, 3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole ] -1 ', 4' -dione (4).
The third aspect of the present invention is to evaluate the antithrombotic effect of (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis [ (1R) -1-carbonylmethyl-2, 3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole ] -1 ', 4' -dione.
Drawings
FIG. 1 (2 'S, 5' S) -tetrahydropyrazines [1 ', 2': 1,6]And bis { (1R) - [ 1-Carbonylmethyl group]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]Synthetic routes to indolino } -1 ', 4' -dione (i) dichloromethane, trifluoroacetic acid; (ii) CH (CH)3OH，Pd/C，H2(ii) a (iii) HBTu, NMM, anhydrous DMF; (iv) h2O, glacial acetic acid and concentrated hydrochloric acid.
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 (3S) -1- (2, 2-Dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylate (1)
A mixed solution of 180mL of methylene chloride, 10mL of 1,1,3, 3-tetramethoxypropane and 10mL of trifluoroacetic acid was stirred for 40min under ice-bath. Then, 10.25g (34.86mmol) of L-Trp-OBzl was added. The reaction mixture was stirred at rt for 14h and TLC (petroleum ether/ethyl acetate ═ 1:1) showed disappearance of L-Trp-OBzl. The reaction solution is respectively saturated NaHCO3Aqueous solution (40mL × 3), saturated aqueous NaCl solution (40mL × 3), separated dichloromethane dried over anhydrous sodium sulfate for 12h, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate ═ 3:1) to give 5.12g (37%) of the title compound as a brownish red oil. ESI-MS (M/e) 393[ M + H ]]-。
EXAMPLE 2 preparation of (3S) -1- (2, 2-Dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid (2)
To a solution of 5.12g (13.00mmol) of benzyl (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylate in 100mL of methanol was added 500mg of Pd/C, charged with hydrogen and stirred at room temperature for 18h, and TLC (petroleum ether/ethyl acetate 1:1) showed 1 disappearance, and the reaction was terminated. Pd/C was filtered off, and the filtrate was concentrated to dryness under reduced pressure to give 3.63g (92%) of the title compound as a bright yellow oil. ESI-MS (M/e):303[ M-H]-。
EXAMPLE 3 preparation of (2 'S, 5' S) -Tetrahydropyrazine [1 ', 2': 1,6] and bis { (1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione (3)
To a solution of 6.12g (20.13mmol) of (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid (2) in 100mL of anhydrous DMF was added 3.00g (22.22mmol) of HBTU with stirring in ice bath. The reaction solution was then adjusted to pH 8-9 with N-methylmorpholine, and after 24h the reaction was terminated by point TLC (petroleum ether/ethyl acetate 1:1) indicating 2 had disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 150mL of ethyl acetate. Then, saturated NaHCO was used separately3Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), 5% KHSO4Aqueous solution (30 mL. times.3), saturated aqueous NaCl solution (30 mL. times.3), saturated aqueous NaHCO solution3The resulting mixture was washed with an aqueous solution (30 mL. times.3) and with a saturated aqueous NaCl solution (30 mL. times.3). The ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The resulting dark yellow solid was separated by silica gel column chromatography (petroleum ether/ethyl acetate ═ 2:1) to give 1.14g (10%) of the title compound as a yellow solid. ESI-MS (M/e):573[ M + H]+；1H NMR(300MHz,DMSO-d6)δ/ppm＝11.08(s,2H),7.39(d,J＝7.5Hz,2H),7.34(d,J＝8.1Hz,2H),7.08(t,J＝7.2Hz,2H),6.97(t,J＝7.2Hz,2H),5.93(dd,J1＝3.6Hz,J2＝9.0Hz,2H),4.62(dd,J1＝3.3Hz,J2＝11.4Hz,2H),4.53(t,J＝4.8Hz,2H),3.34(s,6H),3.26(s,6H),3.20(m,2H),2.79(m,2H),2.24(m,4H)。
EXAMPLE 4 preparation of (2 'S, 5' S) -Tetrahydropyrazine [1 ', 2': 1,6] and bis { (1R) - [ 1-Carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indoline } -1 ', 4' -dione (4)
380mg (0.66mmol) of (2 'S, 5' S) -tetrahydropyrazine [1 ', 2': 1,6] are stirred in an ice bath]And bis { (1R) - [ 1-dimethoxyethyl-2-yl]-2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ]]To a solution of indole } -1 ', 4' -dione (3) and 9mL of glacial acetic acid were added 6mL of water and 3mL of concentrated hydrochloric acid, and stirred for 2 hours, and TLC showed (petroleum ether/ethyl acetate ═ 1:1)3 to disappear, and the reaction was terminated. The reaction was adjusted to pH 7 with aqueous NaOH (2M) in an ice bath. The resulting solution was extracted with ethyl acetate (50 mL. times.3), and the combined ethyl acetate layers were each extracted with saturated NaHCO3Washed with aqueous solution (30 mL. times.3), washed with saturated aqueous NaCl solution (30 mL. times.3), the ethyl acetate phase was dried over anhydrous sodium sulfate for 12h, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 288mg (90%) of the title compound as a yellow solid. ESI-MS (M/e):481[ M + H]+；1H-NMR(300MHz,DMSO-d6)δ/ppm＝10.95(s,2H),9.79(m,2H),7.42(d,J＝8.1Hz,2H),7.38(d,J＝7.5Hz,2H),7.10(t,J＝6.9Hz,2H),6.99(t,J＝6.9Hz,2H),6.22(dd,J1＝3.6Hz,J2＝9.0Hz,2H),4.67(dd,J1＝3.3Hz,J2＝11.4Hz,2H),3.26(m,2H),3.11(m,4H),2.84(m,2H)。
EXAMPLE 5 evaluation of anti-thrombotic Effect of (2 'S, 5' S) -Tetrahydropyrazine [1 ', 2': 1,6] bis { (1R) - [ 1-Carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione (4)
Experimental materials include warfarin sodium (CAS: 129-06-6, Bailingwei science and technology Co., Ltd.), urethane (CAS:51-79-6, Cat No. 30191228, national drug group chemical reagents Co., Ltd.), physiological saline (Shijiazhuang Siyao Co., Ltd.), trisodium citrate dihydrate (CMCNa, Cat No. 20170713, Beijing chemical plant).
Experimental animals SD strain rat, male, 250 + -20 g, purchased from Beijing Wittiulihua laboratory animals technology GmbH.
Experimental method the rat inferior vena cava ligation model is adopted in the experiment.
The grouping and dosage of (2 'S, 5' S) -tetrahydropyrazino [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indole } -1 ', 4' -dione (compound 4 for short) were 1. mu. mol/kg, the dosage of the positive control warfarin sodium was 4.87. mu. mol/kg, and the negative control was 0.5% CMCNa.
The preparation of the agent comprises the anesthetic which is a physiological saline solution (20%) of urethane, the compound 4 which is a suspension of 0.5% CMCNa, and the warfarin sodium which is a suspension of 0.5% CMCNa.
Experimental procedures rats were acclimatized and fasted for one day prior to surgery and were gavaged with a dose of 0.3mL/100g body weight. The administration is carried out 30min later and 2min before operation, and 20% urethane solution is used for abdominal cavity administration anesthesia. Fixing the rat on a rat fixing plate, preparing skin on the abdomen, sterilizing, opening the abdominal cavity along the leucorrhea line, and opening to expose one corner of the liver until the opening is about 4cm long. The organs such as small intestine in the abdominal cavity were removed and 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 left renal vein, ligating inferior vena cava with suture soaked with physiological saline at junction of inferior vena cava and left renal vein, moving intestine and other organs back to 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 2cm 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. The thrombus was weighed and the results were counted using the t-test. The operation was performed alternately with four of each group. The experimental data are shown in table 1.
The data in Table 1 show that compound 4 not only significantly inhibited venous thrombosis in rats at an oral dose of 0.1. mu. mol/kg, but also was significantly more active than 4.87. mu. mol/kg warfarin sodium. The present invention has an unexpected technical effect.
TABLE 1 anti-thrombotic Activity of Compound 4
| Compound (I) | Dosage form | Thrombus weight (mean. + -. SD mg) |
| 0.5％CMCNa | 3mL/kg | 21.74±4.51 |
| Warfarin sodium | 4.87μmol/kg | 14.52±5.17 |
| Compound 4 | 1μmol/kg | 7.86±3.80a |
a) P <0.01 to 0.5% CMCNa and P <0.05 to 4.87. mu. mol/kg warfarin sodium; n is 8.
Claims (2)
1. Use of (2 'S, 5' S) -tetrahydropyrazinyl [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1 ', 4' -dione of formula in the preparation of an anti-venous thrombosis medicament.
2. The use of (2 'S, 5' S) -tetrahydropyrazinyl [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indoline } -1 ', 4' -dione as claimed in claim 1 for the preparation of an anti-venous thrombosis medicament, characterized in that the compound is prepared by the following process:
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 (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-benzyl carboxylate;
2) carrying out hydrogenolysis debenzylation on (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester in methanol under the catalysis of Pd/C to obtain (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro-beta-carboline-3-carboxylic acid;
3) intermolecular condensation of (3S) -1- (2, 2-dimethoxyethyl-2-yl) -2,3,4, 9-tetrahydro- β -carboline-3-carboxylic acid in anhydrous DMF (N, N-dimethylformamide) in the presence of benzotriazole-N, N ' -tetramethyluronium hexafluorophosphate to (2 ' S,5 ' S) -tetrahydropyrazino [1 ', 2 ': 1,6] bis { (1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyrido [3,4-b ] indolino } -1 ', 4 ' -dione;
4) glacial acetic acid is used as a solvent, concentrated hydrochloric acid and water are used as catalysts, and (2 'S, 5' S) -tetrahydropyrazine [1 ', 2': 1,6] bis { (1R) - [ 1-dimethoxyethyl-2-yl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole } -1 ', 4' -dione is converted into (2 'S, 5' S) -tetrahydropyrazine [1 ', 2': 1,6] bis { (1R) - [ 1-carbonylmethyl ] -2,3,4, 9-tetrahydro-1H-pyridine [3,4-b ] indole } -1 ', 4' -dione.
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| CN107686483A (en) * | 2016-08-05 | 2018-02-13 | 首都医科大学 | Seven cyclic ketals, it is prepared, anti-thrombus activity and application |
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