CN112239442A - Dihydroxydimethylisochroman-3-formyl-Phe, preparation thereof, and anti-ischemic stroke effect and application thereof - Google Patents
Dihydroxydimethylisochroman-3-formyl-Phe, preparation thereof, and anti-ischemic stroke effect and application thereof Download PDFInfo
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Abstract
The invention discloses a formula (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe, a preparation method thereof and a therapeutic effect thereof on rats suffering from 24 hours of ischemic stroke. Therefore, the invention discloses the application of the compound in preparing the medicine which is still effective for ischemic stroke after 24 hours.
Description
Technical Field
The present invention relates to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe of formula, to a process for their preparation, and to their therapeutic effect against ischemic stroke attacks for 24 hours. The invention thus relates to their use in the manufacture of a medicament which is effective against ischemic stroke attacks for 24 hours. The invention belongs to the field of biological medicine.
Technical Field
Ischemic stroke is a common, severely damaging cerebrovascular disease. Ischemic stroke is characterized by high morbidity, high disability rate, high recurrence rate and high mortality rate, and is one of the most serious fatal diseases for human beings. Currently, rtPA is the only clinically accepted effective drug for the treatment of ischemic stroke. However, rtPA has two difficult problems to overcome in treating ischemic stroke. The first problem is that rtPA is not effective in patients with ischemic stroke that has occurred for more than 4 hours. The second problem is that continued use of rtPA can cause bleeding in the brain, thorax and abdominal cavities. The invention is a hot spot and a leading edge of research on cerebrovascular drugs, and the drugs are effective on patients with ischemic stroke of more than 4 hours, especially patients with ischemic stroke of 24 hours, and have no bleeding side effect. The inventors have focused on the development of a drug that is effective in ischemic stroke for more than 4 hours, especially in patients with ischemic stroke for 24 hours, without bleeding side effects. After 3 years of exploration, the inventors found that (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe of the formula was not only effective in rats with 24 hours of ischemic stroke but also had no bleeding side effects. 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-Phe.
The second aspect of the present invention provides a method for synthesizing (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe, 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 diethyl 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-Phe-OBzl by a standard method under the catalysis of diphenyl phosphorazide and N-methylmorpholine;
5) (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe-OBzl is catalytically hydrogenated to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe.
The third aspect of the present invention is to evaluate the therapeutic effect of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe on rats with 24 hours ischemic stroke onset.
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FIG. 1 Synthesis of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe route (i) benzyl alcohol, SOCl2(ii) a (ii) Acetone, BF3-Et2O；(iii)H2Pd/C, MeOH; (iv) Phe-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(300MHz,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 1.14g Pd/C is added, the mixture is stirred evenly, hydrogen is introduced, the mixture reacts for 24 hours at room temperature, and the compound 2 completely disappears. 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 (4)
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 Na2SO4Drying for 12h, filtering, and collecting filtrateConcentrated under reduced pressure, and 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-Phe (5)
From 427mg (0.89mmol) of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe-OBzl (4) 304mg (88%) of the title compound are obtained as a colorless solid according to the method of example 3. Mp is 119.1-121.7 ℃;
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 6 evaluation of Compound 5 Activity for treating rats with ischemic stroke attacks for 24 hours
Male SD rats (280. + -.20 g) were anesthetized with a 10% chloral hydrate (4mL/kg) by intraperitoneal injection. A2 cm long incision was made vertically in the middle of the neck of the rat, and the right common carotid artery, external carotid artery and internal carotid artery were isolated along the intramuscular side of the sternocleidomastoid. Respectively clamping an opening of an internal carotid artery and a proximal end of a common carotid artery by using a noninvasive artery clamp, ligating a distal end of an external carotid artery, cutting a small opening on the external carotid artery, loosening the artery clamp at the proximal end of the common carotid artery, and taking 10 mu L of blood to enter a 1mL centrifuge tube. Thereafter, the proximal end of the common carotid artery is clamped with a non-invasive artery clamp. The blood in the tube was allowed to clot at ambient temperature for 30 minutes and then allowed to clot at-20 ℃ overnight to convert to a firm clot. The clot is removed, 1mL of normal saline is added, and the clot is smashed into a uniform suspension of fine thrombus mass and normal saline by a steel shovel. The thrombus mass suspension was transferred to a 1mL syringe. The artery clamp at the proximal end of the common carotid artery of the rat is loosened, and 1mL of thrombus mass suspension is slowly injected into the brain of the rat from the external carotid artery of the rat to the proximal end through the internal carotid artery. Then the external carotid artery is ligated to the proximal end, and the artery clamp at the internal carotid artery and common carotid artery is opened to restore blood flow. The degree of neurological deficit was assessed by the Zealonga method 24 hours after the rats were awakened. 0 point indicates no sign of neurological deficit, 1 point indicates that the front limb on the uninjured side cannot stretch, 2 points indicates walking to the uninjured side, 3 points indicates turning to the uninjured side to form rear-end walking, 4 points indicates that the disorder is identified without autonomous walking, and 5 points indicates death. Rats were evenly grouped according to score. Each group of rats was orally administered 1 time saline (3mL/kg/d) or a physiological saline solution of Compound 5a (dose of 100 nmol/kg/day) per day. Oral administration was continued for 3 days, and scored daily. Calculating the death rate of each group of rats to be 5 points/total number multiplied by 100 percent according to the scores; number of cases/total cases with a score on the last day lower than the score before dosing but not 0 x 100%; the cure rate is 0 counts/total counts on the last day x 100%. The data are shown in Table 1. The results show that the mortality rate of the rats treated by the compound 5 is zero and is far lower than that of the rats treated by the normal saline, and the curative rate of the rats treated by the compound 5 is zero, but the significant efficiency is 70 percent and is higher than that of the rats treated by the normal saline. Therefore, the invention has outstanding technical effects.
TABLE 1 neurobiological score of Compound 5 a-treated stroke 24-hour rats
Claims (3)
1. (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe of the formula,
2. a process for the preparation of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe according to 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-dimethylisochroman-3-formyl-Phe-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-Phe-OBzl to (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe.
3. Use of (R) -6, 7-dihydroxy-1, 1-dimethylisochroman-3-formyl-Phe according to claim 1 for the preparation of a medicament for the treatment of ischemic stroke.
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| CN115403653A (en) * | 2022-05-19 | 2022-11-29 | 首都医科大学 | D (+) -beta- (3, 4-dihydroxyphenyl) -lactyl-Pro-Ala-Lys, synthesis and application thereof |
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| CN115403653A (en) * | 2022-05-19 | 2022-11-29 | 首都医科大学 | D (+) -beta- (3, 4-dihydroxyphenyl) -lactyl-Pro-Ala-Lys, synthesis and application thereof |
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