CN111848723B - Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formylmethionine and proline - Google Patents
Preparation, activity and application of theanyl tetrahydroimidazopyridine-6-formylmethionine and proline Download PDFInfo
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- CN111848723B CN111848723B CN201910363160.5A CN201910363160A CN111848723B CN 111848723 B CN111848723 B CN 111848723B CN 201910363160 A CN201910363160 A CN 201910363160A CN 111848723 B CN111848723 B CN 111848723B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06139—Dipeptides with the first amino acid being heterocyclic
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
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Abstract
The present invention discloses (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] of the formula]pyridine-6-formyl-AA (AA is L-methionine residue and L-proline residue), discloses a preparation method thereof, discloses antithrombotic activity thereof, discloses thrombolytic activity thereof and discloses therapeutic effect thereof on treating apoplexy for 24 hours, so that the invention discloses application thereof in preparing antithrombotic medicaments, thrombolytic medicaments and medicaments for treating ischemic stroke.
Description
Technical Field
The present invention relates to (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA, to a process for their preparation, to their antithrombotic activity, to their thrombolytic activity and to their therapeutic effect on the treatment of ischemic stroke for 24 hours, and thus to their use in the preparation of antithrombotic agents, thrombolytic agents and agents for the treatment of ischemic stroke. The invention belongs to the field of biological medicine.
Background
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 stroke over 4 h. The second problem is that continued use of rtPA can cause bleeding in the brain, thoracic cavity and abdominal cavity. The invention is a hot spot and a leading edge of research on cerebral vascular medicaments, and is a medicament which is effective on stroke for more than 4h, particularly on stroke for 24h patients and has no bleeding side effect.
The inventors have disclosed that spinacin derivatives of formula I have antithrombotic activity at an oral dose of 10nmol/kg (Pentagon, Zhaoming, Strgerstroemia. amino acid-modified spinacin derivatives, methods of preparation and use thereof, CN 102807600A [ P ]. 2011.). However, at this oral dose they show neither thrombolytic activity nor effect in treating ischemic stroke.
The inventor has disclosed that the intravenous administration of the spinacin derivative of the following formula II at a dose of 1nmol/kg can reduce the cerebral infarction volume of rats with cerebral arterial thrombosis (Peng Shi Qi, Zhao Ming, Wang Yu Ji, Wu Jian Hui, Cao Ye. cyclyl-KAK, the synthesis, the activity and the application related to thrombus, CN 106317186A [ P ] 2017.). However, it has no effect in cases with stroke above 4h at this intravenous dose.
In a further structural modification, the inventors found that a compound obtained by introducing a theanyl group to the amino group of the spinacin derivative of the above formula I and substituting the AA with an L-methionine residue and an L-proline residue was not only effective in rats with 24h stroke but also free from bleeding side effects. In light of this finding, the inventors have devised the present invention.
Disclosure of Invention
The first aspect of the present invention provides (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is an L-methionine residue and an L-proline residue) of the formula.
In a second aspect of the invention there is provided (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid
-AA (AA is L-methionine residue and L-proline residue) synthesis method comprising:
(1) preparing (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;
(2) preparing (6S) -methyl 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate;
(3) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid methyl ester;
(4) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;
(5) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA-OBzl (AA is L-methionine residue and L-proline residue);
(6) preparing (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-proline-OBzl;
(7) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-methionine;
(8) preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is L-methionine residue and L-proline residue).
The third aspect of the present invention is to evaluate the antithrombotic activity, thrombolytic activity and ischemic stroke-treating activity of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA (AA is an L-methionine residue and an L-proline residue).
Drawings
FIG. 1(6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ]]A synthetic route to the pyridine-6-formyl-L-proline residue (7a) and the L-proline residue (7 b). i) HCHO, H2O, concentrated H2SO4;ii)CH3OH,SOCl2(ii) a iii) anhydrous DMF, Boc-The, HATU, NMM; iv)2N NaOH; v) HCl Pro-OBzl, DCC, HOBt, NMM; vi) ethyl acetate solution of hydrogen chloride (4M); vii) H2/Pd。
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 (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid (1)
A mixture of 10.0g (64.5mmol) L-His with 80mL distilled water was sonicated to a suspension. To this suspension was slowly added dropwise 2mL of concentrated sulfuric acid at 0 ℃ with stirring. After that, 20mL of an aqueous formaldehyde solution (40%) was added. The reaction mixture was reacted at 60 ℃ for 7h and then cooled to room temperature. Adjusting the pH value of the reaction mixture to 6 by using stronger ammonia water at 0 ℃ under stirring, and standing to ensure that the product is fully separated out. The precipitated product was filtered off and dried to yield 7.4g (69%) of the title compound as a colorless solid.
EXAMPLE 2 preparation of (6S) -methyl 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate (2)
After 7.8mL of thionyl chloride was slowly dropped into 120mL of methanol at 0 ℃ with stirring, activation was carried out for 30 minutes, 5.09g (30.4 mmol) of (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid was added thereto, and the mixture was stirred at room temperature for 72 hours, the reaction mixture was concentrated under reduced pressure, and the residue was diluted with methanol and concentrated under reduced pressure. This operation was repeated three times. 7.4g (96%) of the title compound are obtained as a colorless solid.
EXAMPLE 3 preparation of t-Butoxycarbonylphenyltheanine
3.6g (20.7mmol) theanine was dissolved in 30mL distilled water, the resulting aqueous solution diluted with 30mL dioxane and 5.5g (25.2mmol) (Boc)2O, the reaction mixture was adjusted to pH 9 with 2N NaOH at 0 ℃ with stirring, and the pH of the reaction solution was maintained at 9 with 2N NaOH. Stirring at room temperature for 96 hours, and slowly dropwise adding saturated KHSO at 0 deg.C under stirring4Adjusting pH of the aqueous solution to neutral, and concentrating under reduced pressure to remove dioxane. The residue was adjusted to pH 2 with saturated aqueous potassium hydrogensulfate solution, followed by extraction with ethyl acetate (40 mL. times.3), and the combined ethyl acetate layers were washed 3 times with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated to dryness under reduced pressure to give 4.8g (85%) of the title compound.
EXAMPLE 4 preparation of methyl (6S) -5-tert-Butoxycarbonylphosphinyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate (3)
3.1g (11.3mmol) of t-butoxycarbonyltheanine and 2.87g (11.3mmol) of (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4, 5-c)]Methyl bipyridine-6-carboxylate was dissolved in anhydrous N, N-Dimethylformamide (DMF), 4.7g (12.4mmol) of 2- (7-azobenzotriazol) -N, N, N ', N' -tetramethyluronium Hexafluorophosphate (HATU) was added with stirring at 0 deg.C, and then pH was adjusted to 9 with N-methylmorpholine (NMM). Stir at room temperature for 8h, then concentrate under reduced pressure to remove DMF. The residue was dissolved in ethyl acetate, and the resulting solution was washed with saturated aqueous sodium bicarbonate solution 2 times, then with saturated aqueous sodium chloride solution 2 times, and the ethyl acetate layer solution was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure to dryness to give a yellow oil which was subjected to silica gel column chromatography to give 3.6g (73%) of the title compound as a colorless solid. ESI-MS (M/z):438[ M + H]+。1H NMR(DMSO-d6,300MHz) δ/ppm=11.94(s,1H),7.79(t,J=6.0Hz,1H),7.53(d,J=6.0Hz,1H),7.07(m,1H),5.71 (m,1H),4.81(m,1H),4.41(m,1H),3.58(d,J=6.0Hz,3H),3.40-2.84(m,4H),2.22-1.64 (m,4H),1.35(d,J=6.0Hz,9H),1.01(m,3H)。
EXAMPLE 5 preparation of (6S) -5-tert-Butoxycarbonylphosphinyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid (4)
1.2g (2.7mmol) of (6S) -5-tert-butoxycarbonyltheanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c)]Dissolving pyridine-6-methyl formate in methanol, adding 10mL NaOH methanol solution (2M) at 0 deg.C under stirring, reacting for 2 hr, and slowly adding saturated KHSO dropwise4The aqueous solution was adjusted to neutral pH, the precipitated salts were removed by filtration, the filtrate was concentrated under reduced pressure, the residue was dissolved in 20mL of anhydrous ethanol, the insoluble salts were removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to give 1.12g (93%) of the title compound as a colorless solid. ESI-MS (M/z):422[ M-H]-。
EXAMPLE 6 preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid (4')
0.48g (1.13mmol) of (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] is stirred at 0 deg.C]Pyridine-6-carboxylic acid with 6mL hydrogen chlorideDissolving the ethyl acetate solution (4M), reacting at room temperature for 4h, concentrating the reaction solution under reduced pressure, adding a proper amount of anhydrous ethyl acetate into the residue, dissolving, and pumping to dry. This operation was repeated three times to give 0.15g (33%) of the title compound as a colorless powder. ESI-MS (M/e):324[ M + H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=8.46(s, 2H),7.84(m,1H),7.55(d,1H),5.10(d,J=15Hz,1H),4.21(m,1H),3.94(m,2H), 3.06-2.69(m,4H),2.19-1.91(m,4H),0.97(m,3H)。
EXAMPLE 7 preparation of (6S) -5-tert-Butoxycarbonylphosphinyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-proline benzyl ester (5a)
1.12g (2.65mmol) of (6S) -5-tert-butoxycarbonyltheanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4, 5-c)]Dissolving pyridine-6-carboxylic acid with 20mL of anhydrous tetrahydrofuran, sequentially adding 0.43g (3.18mmol) of N-hydroxy benzotriazole (HOBt) and 0.66g (3.18mmol) of N, N-dicyclohexyl carbodiimide (DCC) solution dissolved with dry tetrahydrofuran at 0 ℃ under stirring, and fully stirring for 30 minutes to obtain a solution A; 0.65g (2.69mmol) of HCl Pro-OBzl dissolved in 20mL of anhydrous tetrahydrofuran was added to the reaction solution A, and the pH was adjusted to 9 with N-methylmorpholine. After stirring at room temperature for 8 hours, the mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate, and insoluble matter was filtered off. The ethyl acetate layer was washed successively with saturated aqueous sodium bicarbonate solution 3 times, saturated aqueous sodium chloride solution 3 times, dried over anhydrous sodium sulfate for 12 hours, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give 0.23g (14%) of the title compound as a colorless powder. ESI-MS (M/e):628[ M + H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=11.83(s,1H),8.21(m,1H),7.83(m,1H),7.46(m,2 H),7.33(m,5H),6.97(m,2H),5.50(m,1H),5.04(m,2H),4.79(m,1H),4.63(m,1H),4.49 (m,2H),3.21-2.55(m,6H),2.16(m,2H),1.77(m,2H),1.34(m,9H),1.00(m,3H)。
EXAMPLE 8 preparation of (6S) -5-tert-Butoxycarbonylphosphinyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-methylsulfamic acid benzyl ester (5b)
From 1.06g (2.51mmol) of (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] e]Pyridine-6-carboxylic acid and 1.02g (2.48mmol) of Tos. Met-OBzl gave 0.37g (23%) of the title compoundThe compound is a non-toner powder. ESI-MS (M/e):645[ M + H]+。1H NMR(DMSO-d6,300MHz)δ/ppm=11.88(s,1H), 8.33(m,1H),7.88(m,1H),7.49(m,1H),7.31(m,5H),7.10(m,1H),5.50(m,1H),5.05(m, 2H),4.79(m,1H),4.46(m,2H),3.79(m,1H),3.23-2.74(m,4H),2.44-2.13(m,4H), 1.97-1.56(m,7H),1.35(m,9H),0.98(m,3H)。
EXAMPLE 9 preparation of benzyl (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-proline (6a)
0.05g (0.08mmol) of (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] is stirred at 0 deg.C]Dissolving pyridine-6-formyl-L-proline benzyl ester in 2mL of hydrogen chloride ethyl acetate solution (4M), reacting at room temperature for 4h, concentrating the reaction solution under reduced pressure, adding a proper amount of anhydrous ethyl acetate into the residue, dissolving, and draining. This operation was repeated three times. 0.05g (98%) of the title compound are obtained as a colorless powder. ESI-MS (M/e) 511[ M + H]+。
EXAMPLE 10 preparation of (6S) -5-tert-Butoxycarbonylphosphinyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-methionine (6b)
From 0.10g (0.16mmol) of (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] using the method of example 9]And pyridine-6-formyl-L-methionine benzyl ester gave 0.08g (93%) of the title compound as a colorless powder. ESI-MS (M/e) 555[ M + H ]]+。
EXAMPLE 11 preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-proline (7a)
0.12g (0.21mmol) of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c]pyridine-6-formyl-L-proline benzyl ester was mixed with 20mg Pd/C, hydrogen was added and stirred at room temperature, after 4h Pd/C was filtered off, the filtrate was concentrated to dryness under reduced pressure to give 0.09g (93%) of the title compound as a colorless solid. ESI-MS (M/e) 421[ M + H]+;mp:200-202℃; (c=0.1,CH3OH);IR(cm-1):2973,2919,2876,1722,1633,1557,1440,1376,1302,1187, 1152,989,949,806;1H NMR(DMSO-d6,300MHz)δ/ppm=14.71(s,1H),8.98(s,1H),8.47 (s,2H),8.12(m,1H),5.52(m,1H),5.09(m,1H),4.55(m,2H),4.22(m,1H),3.65(m,2H), 3.24-2.88(m,4H),2.43-1.80(m,8H),1.01(m,3H)。
EXAMPLE 12 preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-methionine (7b)
From 0.08g (0.14mmol) of (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] e by the method of example 11]And pyridine-6-formyl-L-methionine benzyl ester to give 0.07g (92%) of the title compound as a colorless solid. ESI-MS (M/e):455[ M + H]+;mp:183-184℃;(c=0.1,CH3OH);IR(cm-1):2976,2916, 2871,1724,1649,1537,1441,1379,1348,1204,1151,1108,986,943,875,803;1H NMR (DMSO-d6,300MHz)δ/ppm=8.82(m,1H),8.45(m,2H),8.10(m,1H),8.12(m,1H),8.09 (m,1H),5.51(m,1H),5.01(m,1H),4.57(m,1H),4.23(m,2H),3.25(m,2H),3.11-2.84(m, 4H),2.46-1.95(m,9H),2.02(m,2H),0.99(m,3H)。
Experimental example 1 evaluation of antithrombotic Activity of 7a and 7b
Male SD rats (200. + -.20 g) were randomly divided into groups of 10 animals each, kept for 1 day and stopped overnight. Compound 4' (dose 1. mu. mol/kg) or compound 7a, b in saline (dose 10nmol/kg) or aspirin in saline (dose 167. mu. mol/kg) or saline (dose 3mL/kg) was gavaged. After 30min, rats were anesthetized with a 20% solution of uligose in physiological saline (7mL/kg) and operated. The right carotid artery and the left jugular vein of the rat were isolated, accurately weighed silk was placed in the bypass cannula, one end of the tube was inserted into the left vein, the other end was inserted into the right artery and 0.2mL heparin sodium anticoagulated was injected. Allowing blood flow to flow from the right artery through the bypass cannula into the left vein, taking out the thread with thrombus after 15min, weighing, calculating the weight of the thread before and after blood circulation, and performing t-test to obtain the weight of the thrombus represented by the mean value + -SD mg and representing the antithrombotic activity. The data are shown in Table 1. The results show that the oral administration of 10nmol/kg compounds 7a and b can not only effectively inhibit thrombosis, but also the activity is not obviously different from that of 1 mu mol/kg compound 4' and 167 mu mol/kg aspirin, thereby the technical effect of the invention is obvious.
TABLE 1 antithrombotic Activity of Compounds 7a, b
n-10, a) P <0.01 compared to saline, P >0.05 compared to compound 4' and aspirin; b) p <0.05 compared to saline, P >0.05 compared to compound 4' and aspirin.
Experimental example 2 evaluation of thrombolytic Activity of Compounds 7a, b
SD rats (male, 200. + -.20 g) were anesthetized with an intraperitoneal injection of 20% gulose in physiological saline (7 mL/kg). The rat is anesthetized and then fixed in a supine position, the right common carotid artery of the rat is separated, the artery clamp is clamped at the proximal end, the proximal end and the distal end respectively penetrate into an operation line, the operation line at the distal end is ligated, the cannula at the distal end is inserted, the artery clamp is loosened, 1mL of arterial blood is taken out, and the arterial blood is placed in a 1mL centrifuge tube. A vertically fixed rubber tube (5 mm long, 2.5mm inner diameter, 5.0mm outer diameter, sealing the tube bottom with rubber plug, sealing para membrane) is injected with 0.1mL rat arterial blood, and then a fixing bolt of a stainless steel thrombus is rapidly inserted into the tube (the thrombus fixing spiral is wound by a stainless steel wire with the diameter of 0.2mm, the spiral part is 10mm long and contains 15 spiral rings, the diameter of the spiral rings is 1.0mm, the support handle is connected with the spiral, the length is about 7.0mm, and the fixing bolt is in a question mark shape).
The bypass cannula consists of three parts, wherein the middle section is a polyethylene rubber tube with the length of 60.0mm and the inner diameter of 3.5 mm; both ends are 100.0mm long, and internal diameter 1.0mm, the same polyethylene pipe of external diameter 2.0mm, and this pipe one end is drawn into the sharp pipe, and is about 10.0 mm long (being used for inserting rat carotid artery and vein), and the external diameter is 1.0mm, and the outside cover section of its other end is long for 7.0mm, and the external diameter is 3.5 mm's polyethylene pipe (in being used for inserting the polyethylene rubber tube in middle section), and the inner wall of 3 sections pipes all needs silanization (1% silicon oil ether solution). The thrombus-wrapped thrombus fixing spiral is placed in the middle-section polyethylene rubber tube, and the other two ends of the rubber tube are respectively sleeved with the thickened ends of the two pieces of polyethylene, so that blood leakage can be avoided in the circulating process. The tube was filled with heparin normal saline solution (50IU/kg) through the tip end with a syringe to remove air bubbles for use.
The left external jugular vein of separation rat, proximal end and distal end penetrate the operation line respectively, and the blood vessel of ligature distal end cuts a osculum on the left external jugular vein that exposes, inserts the bypass pipeline taper pipe that has been prepared above-mentioned into left external jugular vein opening part by the osculum, keeps away from bypass pipe middle section (contains the thrombus fixed spiral of accurate weighing) internal thrombus fixed spiral simultaneously. An accurate amount of a physiological saline solution (50IU/kg) of heparin sodium was injected through the tip tube at the other end with a syringe, at which time the syringe was not removed from the polyethylene tube, and the flexible tube between the syringe and the polyethylene tube was clamped with an artery clamp. Stopping bleeding by an artery clamp at the proximal end of the right common carotid artery, ligating the distal end, cutting a small opening of the right common carotid artery at a position short of the artery clamp, pulling out the injector from the tip of the polyethylene tube, and inserting the tip of the polyethylene tube into the proximal end of the oblique opening of the artery. Both ends of the bypass pipeline are used for fixing the artery and the vein by using a No. 4 surgical suture.
Physiological saline (3mL/kg) or a physiological saline solution of urokinase (dosage of 20000IU/kg) or a physiological saline solution of compound 4' (dosage of 1000nmol/kg) or a physiological saline solution of compounds 7a, b (dosage of 10nmol/kg) is passed through the middle section of the bypass tube (containing the thrombus fixing helix accurately weighed) and inserted into the proximal venous end away from the thrombus fixing helix by using a scalp needle, and the arterial clamp is released to allow blood flow from the artery to the vein through the bypass tube. The solution in the syringe is slowly injected into the blood, and acts on the spiral thrombus through the blood circulation in the order of vein-heart-artery. After 1h of blood circulation, the helix holding the thrombus was removed from the bypass tube and accurately weighed. Calculating the weight difference of the thrombus before and after spiral blood circulation of the immobilized thrombus in the bypass duct of each rat, namely the weight loss of the thrombus. Data (mean. + -. SD mg) were subjected to a t-test. Loss of thrombus represents thrombolytic activity. The results in Table 2 show that the 10nmol/kg compounds 7a and b can not only effectively dissolve thrombus, but also have no significant difference in activity from 1000nmol/kg compounds 4' and 20000IU/kg urokinase, thereby showing that the technical effect of the invention is obvious.
TABLE 2 thrombolytic Activity of Compounds 7a, b
n-10, a) to physiological saline ratio P <0.05 to compound 4' and urokinase ratio P >0.05.
Experimental example 3 evaluation of therapeutic Effect of Compounds 7a, b on ischemic Stroke 24h rats
A2 cm long incision was made vertically in the middle of the neck of male SD rats (body weight 300. + -.20 g), and the right common carotid artery, external carotid artery and internal carotid artery were isolated along the intramuscular side edge of the sternocleidomastoid muscle. Respectively clamping an opening of an internal carotid artery and a proximal carotid end of a common carotid artery by using a noninvasive artery clamp, ligating a distal end of the external carotid artery, cutting a small opening on the external carotid artery, loosening the artery clamp at the proximal carotid end of the common carotid artery, taking 10 mu L of blood, and then clamping the proximal carotid end of the common carotid artery by using the noninvasive artery clamp. The obtained 10. mu.L of blood was placed in a 1 mLEP tube at normal temperature for 15 minutes to coagulate the blood, and then transferred to a-20 ℃ refrigerator and left overnight to make the blood clot firm. Rats were anesthetized with a 10% chloral hydrate (4mL/kg) by intraperitoneal injection. The blood clot was removed, 1mL of physiological saline was added, the blood clot was pounded with a steel spatula into small thrombus blocks of uniform size, a suspension of the small thrombus was prepared and transferred to a 1mL syringe. Loosening the artery clamp at the proximal end of the common carotid artery, slowly injecting 1mL of thrombus suspension into the brain of a rat from the external carotid artery of the rat to the proximal end through the internal carotid artery, then ligating the proximal end of the external carotid artery, opening the internal carotid artery and the common carotid artery to obtain the artery clamp, and recovering blood flow. 3 drops of a physiological saline solution of penicillin (40mg/10mL) are dropped on the wound, and the wound is sutured and waits for recovery. The degree of neurological deficit was assessed by the Zealonga method 24 hours after the rats were awakened. Score 0 indicates no sign of loss of nerve function, score 1 indicates that the intact forelimb cannot stretch, score 2 indicates walking to the intact side, score 3 indicates turning to the intact side to form rear-end walking, score 4 indicates no autonomous walking for disorder, and score 5 indicates death. And randomly grouped according to the scores. Rats were given compound 7a, b in saline solution (dose 10nmol/kg) or saline (dose 3mL/kg) via tail vein injection 1 time per day at a dose of 3 mL/kg; injections were continued for 3 days, and scored daily. Mortality, effectual and cure rates were calculated from the scores for each group (mortality ═ death/total) × 100%, (effectual ═ last day score lower than number/total scored before dosing) × 100%, (heald ═ last day score 0/total) × 100%). The results are shown in Table 3. The data in table 3 show that the mortality rate and the cure rate of the stroke rats treated by the compounds 7a and b are lower than those of normal saline, which shows that the technical effect of the invention is obvious.
TABLE 3 neurobiological score of stroke 24 hours rats injected intravenously 7a, b 1 time daily for 3 days
From the above data, it can be seen that the compound of the present invention has both antithrombotic activity, thrombolytic activity and 24h ischemic stroke treatment activity, i.e., 10nmol/kg of compound 7a can be orally administered once, b can effectively inhibit thrombosis, 10nmol/kg of compound 7a can be injected once, b can effectively dissolve thrombus, 10nmol/kg of compound 7a can be intravenously administered once a day for 3 consecutive days, b can effectively restore neurobiological behavior of rats with 24h ischemic stroke, and no bleeding side effect exists. Compared with the compounds disclosed once, the compounds of the invention have outstanding technical effects.
Claims (5)
2. a process for the preparation of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid a according to claim 1, comprising the eight steps of:
(1) preparing (6S) -4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;
(2) preparing (6S) -methyl 4,5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylate;
(3) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid methyl ester;
(4) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-carboxylic acid;
(5) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA-OBzl;
(6) preparing (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-proline-OBzl;
(7) preparing (6S) -5-tert-butoxycarbonyl-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-L-methionine;
(8) preparation of (6S) -5-theanyl-4, 5,6, 7-tetrahydro-3H-imidazo [4,5-c ] pyridine-6-formyl-AA.
3. Use of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid as defined in claim 1 for the preparation of an antithrombotic medicament.
4. Use of theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid amide according to claim 1 for the preparation of a thrombolytic drug.
5. Use of the theacyltetrahydro-3H-imidazopyridine-6-carboxylic acid amide of claim 1 in the manufacture of a medicament for the treatment of ischemic stroke.
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102807600A (en) * | 2011-06-03 | 2012-12-05 | 首都医科大学 | Amino acid modified spinacin derivative and preparation method and application thereof |
CN103450199A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Theanine-modified carboline acyl amino acid benzyl ester, as well as preparation, anti-tumor activity and application thereof |
CN105198960A (en) * | 2014-06-13 | 2015-12-30 | 首都医科大学 | Imidazopyridine-6-formyl-Met-AA-OBzl and synthesis, activity and application thereof |
CN108976226A (en) * | 2017-05-31 | 2018-12-11 | 首都医科大学 | The spinacin of nonpolar amino acid benzyl ester modification, its synthesis, activity rating and application |
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Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102807600A (en) * | 2011-06-03 | 2012-12-05 | 首都医科大学 | Amino acid modified spinacin derivative and preparation method and application thereof |
CN103450199A (en) * | 2012-06-01 | 2013-12-18 | 首都医科大学 | Theanine-modified carboline acyl amino acid benzyl ester, as well as preparation, anti-tumor activity and application thereof |
CN105198960A (en) * | 2014-06-13 | 2015-12-30 | 首都医科大学 | Imidazopyridine-6-formyl-Met-AA-OBzl and synthesis, activity and application thereof |
CN108976226A (en) * | 2017-05-31 | 2018-12-11 | 首都医科大学 | The spinacin of nonpolar amino acid benzyl ester modification, its synthesis, activity rating and application |
Non-Patent Citations (1)
Title |
---|
5,6,7,8-四氢咪唑并[1,2-a]吡啶-3-硼酸盐酸盐的合成;潘琪等;《精细化工中间体》;20160630;第46卷(第3期);第20-23页 * |
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