CN112239448A - Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, antithrombotic activity and use - Google Patents
Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, antithrombotic activity and use Download PDFInfo
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Abstract
The invention discloses 4 (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is L-Phe, L-His, L-Trp and L-Tyr residue), discloses a preparation method thereof and discloses an antithrombotic effect thereof, thereby disclosing the application of the same in preparing antithrombotic medicaments.
Description
Technical Field
The present invention relates to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA, to a process 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
Arterial embolization has become one of the diseases with high morbidity and mortality at present. Arterial thrombosis is responsible for transient ischemic attacks, acute coronary syndromes, myocardial infarction and atrial fibrillation. Between 18% and 47% of patients with atrial fibrillation have coronary artery disease, and about 20% of patients with atrial fibrillation with coronary artery disease receive percutaneous coronary intervention. Arterial thrombosis is also responsible for artificial heart valves, arteriovenous fistulas and other post-operative arterial thrombi and unstable angina. For example, following liver transplantation surgery, patients are at risk for liver arterial thrombosis. In addition, patients with antiphospholipid syndrome are also at risk for arterial thrombosis. Although tumors are more widely associated with venous thrombi than with arterial thrombi, there is an increasing awareness of the incidence of arterial thrombi, including peripheral arterial thrombi, in the treatment of specific malignancies and tumors. Arterial cannulation and ischemic stroke have led to an increasing number of arterial thrombosis cases in children. More than a decade ago, there was an initial alert to the risk of arterial thrombosis due to cocaine abuse. Venous and arterial thrombi are considered as two distinct diseases in the traditional sense because of the different etiologies. Recent epidemiological studies have shown that the association between venous and arterial thrombi is difficult to sever. This condition can be attributed to their risk factors overlapping each other. As a result, prevention and treatment of arterial thrombosis have been increasingly emphasized.
Direct oral anticoagulation is the only strategy for clinical treatment of arterial thrombosis. Although the curative effect of the oral anticoagulant on the arterial thrombosis is exact, the oral anticoagulant has bleeding side effects. For example, aspirin can induce gastrointestinal or intracranial bleeding at effective oral doses. This risk greatly limits the benefit of the patient. Clinically, there is a need for a medicament with a therapeutic effect comparable to that of aspirin, without the risk of aspirin-like gastrointestinal or intracranial hemorrhage. In response to this clinical need, researchers at home and abroad have paid a large amount of heart blood. However, no substantial progress has been made.
The search for safe and effective anti-thrombotic agents is an important interest for the research of new drugs by the inventor. The inventors discovered over the last 3 years that (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid coupled with an aromatic amino acid (L-Phe, L-His, L-Trp, L-Tyr) resulted in (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA of the formula (AA being the residue of L-Phe, L-His, L-Trp and L-Tyr) which is a safe and effective antithrombotic agent. Based on this finding, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention is to provide (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is a L-Phe, L-His, L-Trp or L-Tyr residue).
The second aspect of the present invention is to provide a method for synthesizing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA (AA is L-Phe, L-His, L-Trp and L-Tyr residue), which comprises:
1) preparing D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate by a standard method under the catalysis of thionyl chloride;
2) converting D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate into (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid benzyl ester under the catalytic action of boron trifluoride ethoxy ether;
3) preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid by Pd/C catalytic hydrogenation of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate by a standard method;
4) preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl by a standard method under the catalytic action of diphenyl phosphorazide and N-methylmorpholine;
5) (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl is catalytically hydrogenated to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA.
The third aspect of the present invention is to evaluate the antithrombotic activity of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA.
Drawings
FIG. 1 is a synthetic route for (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA. (i) Benzyl alcohol, SOCl2(ii) a (ii) Acetone, BF3-Et2O；(iii)H2Pd/C, MeOH; (iv) AA-OBzl, diphenyl phosphorazide, N-methylmorpholine and anhydrous tetrahydrofuran; (v) h2,Pd/C,MeOH。
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 D (+) -beta- (3, 4-dihydroxyphenyl) lactate (1)
91.0mL of thionyl chloride was slowly added dropwise to 150mL of benzyl alcohol stirred at 0 ℃. After dropping, stirring for 1h at room temperature, adding 55.0g (250mmol) of salvianic acid A sodium, stirring for 48h at room temperature, and completely reacting. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate, washed with saturated aqueous NaCl solution (30 mL. times.3), and washed with anhydrous Na2SO4Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 20.1g (35%) of the title compound as a yellow oil.1H NMR(300M Hz,DMSO-d6):δ/ppm＝8.75(s,1H),8.67(s,1H),7.31(m,5H),6.61(s,1H),6.58(s,1H),6.42(dd,J1＝1.8Hz,J2＝2.1Hz,1H),5.55(d,J＝6.0Hz,1H),5.12(s,2H),4.19(q,J1＝6.9Hz,J2＝6.0Hz,1H),2.73(qd,J1＝8.1Hz,J2＝5.4Hz,2H)；ESI-MS(m/e):287[M-H]-。
EXAMPLE 2 preparation of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate (2)
10.0g (30.6mmol) of benzyl D (+) -beta- (3, 4-dihydroxyphenyl) lactate (1) was dissolved in 104mL of acetone. 4.4mL of boron trifluoride diethyl ether were slowly added dropwise with stirring at 0 ℃. After dropping, the mixture was stirred at room temperature for 4 hours, and the compound 1 completely disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate. The resulting solution was washed with saturated aqueous NaCl (30 mL. times.3), and then with anhydrous Na2SO4Drying for 12h, filtration, concentration of the filtrate under reduced pressure and purification of the residue by column chromatography on silica gel gave 11.4g (80%) of the title compound as a yellow oil.1H NMR(300MHz,DMSO-d6):δ/ppm＝1.58(s,1H),1.54(s,1H),7.39(m,5H),6.52(s,1H),6.47(s,1H),1.93(s,1H),4.47(m,1H),2.71(m,2H),1.40(m,6H)；ESI-MS(m/e):327[M-H]-。
EXAMPLE 3 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3)
11.4g (34.8mmol) of benzyl (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate (2) were dissolved in 60mL of methanol. Then adding 1.14g Pd/C, stirring uniformly, introducing hydrogen, reacting at room temperature for 24h to obtain the compound2 completely disappeared. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 10.5g (95%) of the title compound as a colorless solid.1H NMR(300MHz,DMSO-d6):δ/ppm＝12.60(s,1H),8.82(d,J＝6.9Hz,2H),8.66(d,J＝5.4Hz,2H),6.52(s,1H),6.46(s,1H),4.34(m,1H),2.68(d,J＝7.2Hz,2H),1.37(d,J＝3.8Hz,6H)；ESI-MS(m/e):237[M-H]-。
EXAMPLE 4 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe-OBzl (4a)
595mg (2.50mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) were dissolved in 12mL of anhydrous tetrahydrofuran, and 1mL of diphenylphosphoryl azide (DPPA) was added thereto and stirred for 30 min. 802mg (2.75mmol) of Phe-OBzl are added at 0 ℃ with stirring. The pH of the reaction solution is adjusted to 8-9 by N-methylmorpholine. After stirring at room temperature for 24h, compound 3 completely disappeared. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 100mL of ethyl acetate and successively treated with 1N CH3COONa aqueous solution (30 mL. times.3), saturated NaCl aqueous solution (30 mL. times.3), and saturated KHSO4Washing with an aqueous solution (30 mL. times.3), washing with a saturated aqueous NaCl solution (30 mL. times.3), and washing with anhydrous Na2SO4After drying for 12h, filtration and concentration of the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give 427mg (36%) of the title compound as a colorless solid.1H-NMR(300MHz,DMSO-d6):δ/ppm＝8.82(s,1H),8.66(s,1H),7.77(d,J＝7.8Hz,1H),7.25(m,10H),6.52(s,1H),6.44(s,1H),5.14(s,2H),4.64(q,J1＝6.6Hz,J2＝7.2Hz,1H),4.13(m,1H),3.12(d,J＝5.1Hz,2H),2.58(m,2H),1.40(d,J＝10.2Hz,6H)；ESI-MS(m/e):474[M-H]-。
EXAMPLE 5 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His-OBzl (4b)
From 476mg (2.0mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 700mg (2.2mmol) of His-OBzl, 335mg (36%) of the title compound are obtained as a colorless solid according to the method of example 4.1HNMR(300MHz,DMSO-d6):δ/ppm＝11.89(s,1H),8.83(s,1H),8.67(s,1H),8.33(s,1H),7.57(s,1H),7.34(s,1H),6.79(s,1H),6.78(s,1H),6.53(s,1H),5.10(q,J1＝12.6Hz,J2＝14.1Hz,2H),4.57(m,1H),4.17(d,J＝8.40Hz,1H),2.90(s,2H),2.68(m,1H),1.43(d,J＝16.2Hz,2H)；ESI-MS(m/e):464[M-H]-。
EXAMPLE 6 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp-OBzl (4c)
From 1.2g (5.0mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 2.8g (6mmol) of Trp-OBzl, 437mg (17%) of the title compound are obtained as colorless solid according to the method of example 4.1H NMR(300MHz,DMSO-d6):δ/ppm＝11.0(s,1H),8.83(s,1H),8.67(s,1H),7.64(d,J＝7.80Hz,1H),7.52(d,J＝7.50Hz,1H),7.34(m,6H),7.11(m,2H),6.97(m,1H),6.49(s,1H),6.42(s,1H),5.11(s,2H),4.66(d,J＝7.50Hz,1H),4.15(d,J＝2.40Hz,1H),3.17(d,J＝5.10Hz,2H),2.64(m,1H),2.47(m,1H),1.24(s,6H)；ESI-MS(m/e):513[M-H]-。
EXAMPLE 7 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Tyr-OBzl (4d)
From 1.19g (5.00mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid (3) and 2.4g (5.50mmol) of Tyr-OBzl 514mg (21%) of the title compound are obtained as colorless solid according to the method of example 4.1H NMR(300MHz,DMSO-d6):δ/ppm＝9.27(s,1H),8.83(s,1H),8.67(s,1H),7.67(d,J＝7.80Hz,1H),7.35(d,J＝4.20Hz,5H),6.95(d,J＝8.40Hz,2H),6.64(d,J＝8.40Hz,2H),6.51(s,1H),6.44(s,1H),5.13(d,J＝2.10Hz,2H),4.54(q,J1＝7.20Hz,J2＝6.10Hz,1H),4.13(d,J＝8.10Hz,1H),2.99(d,J＝6.30Hz,2H),2.64(m,2H),1.40(d,J＝7.80Hz,6H)；ESI-MS(m/e):490[M-H]-。
EXAMPLE 8 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe (5a)
From 427mg (0.89mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe-OBzl (4a), 304mg (88%) of the title compound are obtained as a colorless solid according to the method of example 3. Mp:119-122 deg.C;
IR(cm-1):3408,3387,2970,1660,1517,1449,1291,1187,1148,1096,833,699,645；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.93(s,1H),8.73(d,J＝42.0Hz,2H),7.59(d,J＝19.5Hz,1H),7.27(m,5H),6.52(s,1H),6.45(s,1H),4.53(q,J1＝7.5Hz,J2＝5.7Hz,1H),4.11(dd,J1＝8.4Hz,J2＝2.4Hz,1H),3.18(s,1H),3.09(m,2H),2.62(m,1H),1.22(d,J＝11.7Hz,6H)；FT-MS(m/e):384.14845[M-H]-(theoretical value: 384.14471).
EXAMPLE 9 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His (5b)
From 335mg (0.72mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-His-OBzl (4b) 246mg (91%) of the title compound are obtained as a colorless solid according to the method of example 3. And Mp: 172-175 ℃;
IR(cm-1):3130,2850,1580,1516,1384,1260,1189,1149,1092,835；1HNMR(300MHz,DMSO-d6):δ/ppm＝8.06(d,J＝7.50Hz,1H),7.64(s,1H),6.87(s,1H),4.50(d,J＝19.5Hz,2H),4.42(q,J1＝6.90Hz,J2＝6.00Hz,1H),4.16(m,1H),3.39(dd,J1＝6.90Hz,J2＝7.20Hz,1H),2.98(m,2H),2.67(m,2H),1.43(d,J＝16.2Hz,6H)；FT-MS(m/e):374.13678[M-H]-(theoretical value: 374.13521).
EXAMPLE 10 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp (5c)
235mg (65%) of the title compound are obtained as a colorless solid by the method of example 3 from 437mg (0.85mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Trp-OBzl (4 c). Mp:186-187 deg.C;
IR(cm-1):3383,2975,1724,1659,1520,1456,1362,1280,1186,1147,1096,740；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.9(s,1H),11.0(s,1H),8.83(s,1H),8.67(s,1H),7.55(d,J＝7.80Hz,1H),7.44(d,J＝8.10Hz,1H),7.34(d,J＝7.80Hz,1H),7.14(s,1H),7.05(t,J＝7.50Hz,1H),6.99(t,J＝12.3Hz,1H),6.50(s,1H),6.44(s,1H),4.57(dd,J1＝17.7Hz,J2＝7.20Hz,1H),4.14(d,J＝9.00Hz,1H),3.23(d,J＝5.10Hz,2H),2.66(d,J＝13.8Hz,1H),2.42(m,1H),1.35(s,1H)；FT-MS(m/e):423.15973[M-H]-(theoretical value: 423.15561).
EXAMPLE 11 preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Tyr (5d)
281mg (67%) of the title compound are obtained as a colorless solid from 514mg (1.05mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Tyr-OBzl (4d) according to the method of example 3. Mp:134-135 deg.C;
IR(cm-1):3359,2975,1714,1613,1510,1444,1364,1220,1186,1147,1104,831；1H NMR(300MHz,DMSO-d6):δ/ppm＝12.9(s,1H),9.25(s,1H),8.84(s,1H),8.68(s,1H),7.46(d,J＝8.10Hz,1H),6.99(d,J＝8.10Hz,2H),6.67(d,J＝8.10Hz,2H),6.52(s,1H),6.45(s,1H),4.44(q,J1＝7.20Hz,J2＝5.70Hz,1H),4.13(dd,J1＝2.40Hz,J2＝4.50Hz,1H),2.96(m,3H),2.64(m,1H),1.40(d,J＝10.8Hz,6H)；FT-MS(m/e):400.13291[M-H]-(theoretical value: 400.13963).
Example 12 Compounds 5a-d were evaluated for antithrombotic activity.
1) Drawing a polyethylene tube into a thin tube with one end being an oblique opening, wherein the fixed length is 10.0cm, and the thin tube is respectively used for inserting a right jugular vein (with a thicker tube diameter) and a left carotid artery (with a thinner tube diameter); the length of the middle section polyethylene tube is 8.0cm, the thrombus line is pressed in the carotid intubation direction, and the tube needs to be filled with heparin before intubation.
2) Male rats weighing 200 ± 20g were acclimatized and fasted for one day prior to surgery. The groups were randomly divided into an oral physiological saline (0.3mL/100g,10 rats), an oral aspirin (167. mu. mol/kg,10 rats), and oral Compound 5a-d (30nmol/kg,10 rats). After 30min of administration, rats were anesthetized by intraperitoneal injection of 20% urethane solution (7mL/kg), and surgery was started 2min later. The rat lies on the back on the fixed plate in the operation, cuts open neck skin, separates right common carotid artery and left jugular vein, line ball under the blood vessel, ligature telecentric end, near telecentric end department at the vein and cut a osculum, insert the intubate vein end, inject heparin, then take off the syringe of injection heparin, the tie line is fixed, reuse artery presss from both sides and presss from both sides the artery and nears the heart end, cuts a osculum near telecentric end direction, ligates the artery end, loosens the artery after the tie line is fixed and presss from both sides, establishes the extracorporeal circulation bypass. After circulating for 15 minutes, the venous end is firstly cut off to observe whether the blood circulation is normal, if the blood circulation is normal, a thrombus line is taken out from the arterial end, dry floating blood is stained on paper, then weighing is carried out, the activity is expressed by the weight of the thrombus, and the data are listed in table 1. The thrombus weights in the table show that compounds 5a-d are effective in inhibiting arterial thrombosis in rats at an oral dose of 30 nmol/kg. This is an unexpected technical effect of the present invention.
TABLE 1 anti-arterial Thrombus Activity of Compounds 5a-d
a) P <0.01 to saline, P <0.05 to compound 3; b) p <0.05 to saline, P <0.05 to compound 3; n is 10.
Claims (3)
1. (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA of the formula,
in the formula, AA is L-Phe, L-His, L-Trp and L-Tyr residues.
2. A process for preparing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA of claim 1, comprising:
2.1 preparing D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate by a standard method under the catalysis of thionyl chloride;
2.2D (+) -beta- (3, 4-dihydroxyphenyl) benzyl lactate is converted into (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid benzyl ester under the catalytic action of boron trifluoride diethyl ether;
preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylic acid by Pd/C catalytic hydrogenation of benzyl 3(R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-carboxylate by standard methods;
2.4 preparing (R) -6, 7-dihydroxy-1, 1-dimethyl isochroman-3-formyl-AA-OBzl by a standard method under the catalysis of diphenyl phosphorazide and N-methylmorpholine;
catalytic hydrogenation of 5(R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA-OBzl to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA.
3. Use of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-AA according to claim 1 for the preparation of an antithrombotic agent.
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| CN102477066A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | N-(S-1,2,3,4-tetrahydro-6,7-dihydroxyisoquinolyl-3-formyl)amino acid, synthetic method thereof, and application thereof |
| CN102477068A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | Amino acid derivative for preparing thrombus dissolving medicament, and preparation method and application thereof |
| CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
| CN112010830A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, thrombolytic activity and use |
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2019
- 2019-07-16 CN CN201910642596.8A patent/CN112239448A/en not_active Withdrawn
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102477066A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | N-(S-1,2,3,4-tetrahydro-6,7-dihydroxyisoquinolyl-3-formyl)amino acid, synthetic method thereof, and application thereof |
| CN102477068A (en) * | 2010-11-30 | 2012-05-30 | 首都医科大学 | Amino acid derivative for preparing thrombus dissolving medicament, and preparation method and application thereof |
| CN103450330A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Dihydroxyltetrahydroisoquinoline-3-formyl amino acids as well as synthesis, antithrombotic effect and application thereof |
| CN112010830A (en) * | 2019-05-28 | 2020-12-01 | 首都医科大学 | Dihydroxydimethylisochroman-3-carboxylic aromatic amino acids, their preparation, thrombolytic activity and use |
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