CN109134604B - 1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDF, and synthesis, activity and application thereof - Google Patents
1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-GRGDF, and synthesis, activity and application thereof Download PDFInfo
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Abstract
The invention discloses (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe, a preparation method thereof, anti-arterial thrombosis activity thereof, anti-venous thrombosis activity thereof, GPIIb/IIIa expression inhibition activity thereof and in vivo P-selectin expression inhibition activity thereof. Therefore, the invention discloses the application of the derivative in preparing anti-arterial thrombosis medicaments, anti-venous thrombosis medicaments, GPIIb/IIIa antagonists and P-selectin antagonists.
Description
Technical Field
The invention relates to (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-AA, a preparation method thereof, anti-arterial thrombosis activity thereof, activity for inhibiting in vivo glycoprotein IIb/IIIa (IIb/IIIa) expression and activity for inhibiting in vivo P-selectin expression. Therefore, the invention relates to the application of the derivatives in preparing anti-arterial thrombosis medicaments, anti-venous thrombosis medicaments, GPIIb/IIIa antagonists and P-selectin antagonists. The invention belongs to the field of biological medicine.
Background
Thrombosis is a leading cause of myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis and other cardiovascular diseases, and is a leading cause of morbidity and mortality worldwide. Current antithrombotic agents, while effective in inhibiting thrombus formation, reduce their safety and limit clinical efficacy due to their effects on hemostatic function or bleeding risk. Various biological activities of beta-carboline alkaloids, including platelet aggregation inhibiting activity, have been disclosed. The inventors have also disclosed a series of beta-carboline-3-formyl oligopeptides having anti-arterial thrombotic activity which are administered intravenously at a dose of 5. mu. mol/kg. The inventors have two unsatisfactory points of their activity. The first is that intravenous injection brings them into the blood circulation and rapidly reaches high blood levels. It is due to the high concentration that they reach plasma and tissues rapidly increasing the risk of adverse reactions. This is an inherent drawback of intravenous administration and can only be solved by the invention of orally administrable compounds. The second point is that although the introduction of methyl group at the 1-position of carboline can reduce the orally effective dose to 0.01. mu. mol/kg, such compounds show only anti-arterial thrombus activity, and no anti-arterial thrombus activity. Venous thrombosis is a common complication of tumor patients and patients who undergo various operations, can cause disability or death of the patients, and needs to take anti-venous thrombosis medicines for a lifetime. Because of the existence of anti-venous thrombosis drugs, such as warfarin, can cause fatal bleeding side effects. In addition, because the mechanisms of venous thrombosis and arterial thrombosis are completely different, compounds that are effective against arterial thrombosis tend to be ineffective against venous thrombosis. Thus, the invention of compounds effective on both arterial and venous thrombosis has been the leading edge of antithrombotic drugs. Through repeated exploration, the inventor finds that (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe generated by introducing dihydroxymethyl to the 1-position of tetrahydro-beta-carboline-3-carboxylic acid and introducing Gly-Arg-Gly-Asp-Phe to the 3-position shows good anti-arterial thrombosis activity and anti-venous thrombosis activity under the condition of 0.01 mu mol/kg oral dosage, and the anti-venous thrombosis activity is 487 times stronger than that of warfarin. It can be seen that the present invention has significant technical advances. Thus, the inventors have proposed the present invention.
Disclosure of Invention
The first aspect of the present invention provides (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe of the formula.
The second content of the invention is to provide a method for synthesizing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe, which comprises the following steps:
(1) carrying out Pictet-Spengler condensation on L-tryptophan and 1, 3-dihydroxyacetone under the catalysis of dilute sulfuric acid to generate (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid;
(2) preparing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
(3) reacting (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester with tert-butyldimethylchlorosilane (TBDMSCl) in the presence of imidazole to generate (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
(4) hydrolyzing (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester in 4N NaOH aqueous solution to generate (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid;
(5) coupling (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid and Gly-OBzl into (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-OBzl by using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts and adopting a liquid phase condensation method;
(6) (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-OBzl in H2And Pd/C to (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly;
(7) uses dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts to synthesize HCl & Arg (NO) by adopting a liquid phase condensation method2)-Gly-Asp(OBzl)-Phe-OBzl；
(8) Using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts, and adopting a liquid phase condensation method to react (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly with Arg (NO)2) -Gly-Asp (OBzl) -Phe-OBzl is coupled into (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl；
(9) (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2) Removing tert-butyl dimethyl silicon base from-Gly-Asp (OBzl) -Phe-OBzl in 4N hydrogen chloride-ethyl acetate solution at 0 ℃ to prepare (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl；
(10) (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2) -Gly-Asp (OBzl) -Phe-OBzl in the presence of Pd/C to (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe.
The third content of the invention is to evaluate the antithrombotic activity of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe.
The fourth content of the invention is to evaluate the antithrombotic activity of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe.
The fifth aspect of the present invention is to evaluate the activity of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe in inhibiting the expression of GPIIb/IIIa.
The sixth aspect of the present invention is to evaluate the activity of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe in inhibiting P-selectin expression.
Drawings
FIG. 1 is a synthetic route of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe i)1, 3-dihydroxyacetone, concentrated H2SO4，H2O; ii) methanol, SOCl2(ii) a iii) tert-butyldimethylsilyl chloride (TBDMSCl), imidazole, anhydrous N, N-Dimethylformamide (DMF); iv)4N NaOH, methanol, iceBathing; v) N, N' -Dicyclohexylcarbodiimide (DCC), 1-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran; vi) Pd/C, H2(ii) a vii)4N hydrogen chloride in ethyl acetate; TBS in 3-7 is tert-butyldimethylsilyl.
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) -1, 1-dimethylol-tetrahydro-beta-carboline-3-carboxylic acid (1)
6.12g (30mmol) of L-tryptophan was suspended in 100mL of distilled water. And slowly dropwise adding concentrated sulfuric acid in the ice bath until the L-tryptophan is completely dissolved. To the solution was added 3.24g (36mmol) of 1, 3-dihydroxyacetone, and the reaction was carried out at room temperature for 72 hours. TLC (ethyl acetate/water/glacial acetic acid, 10/1/2) showed the reaction was complete. Filtration and washing of the filter cake with ice water gave 6.13g (74%) of the title compound as a yellow powder.
EXAMPLE 2 preparation of (3S) -1, 1-dimethylol-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (2)
5.2mL of thionyl chloride was slowly added dropwise to 55mL of methanol in a ice salt bath, and stirred for 30 minutes. 5.52g (20mmol) of (3S) -1, 1-dimethylol-tetrahydro-beta-carboline-3-carboxylic acid (1) was added to the solution and stirred until completely dissolved. Stirred at room temperature for 12 hours. TLC (dichloromethane/methanol, 20:1) showed the reaction was complete. Concentrated under reduced pressure and the residue triturated with ethyl acetate to give a tan solid. The solid was dissolved in 200mL ethyl acetate and the resulting solution was sequentially saturated NaHCO3Washed with an aqueous solution (30 mL. times.3) and with a saturated aqueous NaCl solution (30 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 5.34g (92%) of the title compound as a yellow solid. ESI-MS (M/e):291[ M + H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm＝10.55(s,1H),7.39(d,J＝7.5Hz,1H),7.34(d,J＝7.5Hz,1H),7.02(td,J1＝7.5Hz,J2＝1.2Hz,1H),6.99(td,J1＝7.5Hz,J2＝0.9Hz,1H),4.79(m,2H),3.96(m,1H),3.77(m,1H),3.75(s,3H),3.647～3.499(m,3H),2.96(dd,J1＝14.7Hz,J2＝4.2Hz,1H),2.59(dd,J 1＝14.7Hz,J2＝11.1Hz,1H)。
Example 3 preparation of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (3)
A mixture of 5.22g (18mmol) of (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-carboxylic acid methyl ester (2) and 50mL of anhydrous N, N-Dimethylformamide (DMF) was stirred until complete dissolution. Under ice-bath, 4.4g (64.8mmol) of imidazole was added to the solution and stirred until completely dissolved. To the solution was added 8.15g of t-butyldimethylsilyl chloride (TBDMSCl), and the mixture was stirred at room temperature for 12 hours. TLC (petroleum ether/ethyl acetate, 20/1) showed the reaction was complete. 350mL of saturated aqueous NaCl solution was added to the solution in ice bath, followed by extraction with ethyl acetate 3 times. The ethyl acetate layer was successively treated with saturated NaHCO3Washed with an aqueous solution (40 mL. times.3) and with a saturated aqueous NaCl solution (40 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow oil which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1). 8.19g (88%) of the title compound are obtained as a colorless oil. ESI-MS (M/e):519[ M + H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm＝10.31(s,1H),7.41(d,J＝7.5Hz,1H),7.33(d,J＝7.5Hz,1H),7.04(t,J＝7.5Hz,1H),6.95(t,J＝7.5Hz,1H),4.00(m,1H),3.79(m,4H),3.72(s,3H),2.99(dd,J1＝14.7Hz,J2＝3.9Hz,1H),2.59(dd,J1＝15.0Hz,J2＝11.1Hz,1H),0.83(s,9H),0.82(s,9H),0.04(s,3H),0.00(s,3H),-0.05(s,6H)。
Example 4 preparation of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid (4)
Adding a 4N NaOH aqueous solution dropwise into a solution of 7.77g (15mmol) of (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester (3) and 40mL of tetrahydrofuran in an ice salt bath, and adjusting the pH value of the solution to be 13-14. The reaction mixture was stirred for 30 minutes. TLC (petroleum ether/ethyl acetate, 20/1) showed the reaction was complete. And (3) dropwise adding a 2N hydrochloric acid solution into the ice salt bath, and adjusting the pH value of the solution to 7. Concentrating under reduced pressure to remove tetrahydrofuran and methanol. Saturated KHSO is dripped into the ice salt bath4Aqueous solution, adjusting the pH of the solutionIs 2 to 3. The solution was extracted 3 times with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous NaCl solution 3 times, and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave 6.96g (90%) of the title compound as a colorless powder. ESI-MS (M/e) 505[ M + H ]]+。
EXAMPLE 5 preparation of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro- β -carboline-3-formyl-Gly-OBzl (5)
A solution of 6.90g (13.4mmol) of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro- β -carboline-3-carboxylic acid (4), 2.76g (13.4mmol) of DCC, 1.81g (13.4mmol) of HOBt and 150mL of anhydrous tetrahydrofuran was stirred under ice-bath for 30 minutes. To the solution was added 3.24g (16.08mmol) of HCl.Gly-OBzl, and N-methylmorpholine was added dropwise to adjust the pH of the reaction mixture to 9, followed by stirring at room temperature for 8 hours. TLC (petroleum ether/ethyl acetate, 5/1) showed the reaction was complete. The reaction mixture is filtered, the filtrate is concentrated under reduced pressure, the residue is dissolved in 150mL of ethyl acetate, filtered and the filtrate is successively taken up with 5% NaHCO3Aqueous 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% NaHCO3Washed with an aqueous solution (30 mL. times.3), washed with a saturated aqueous NaCl solution (30 mL. times.3), and dried over anhydrous sodium sulfate for 12 hours. Filtration and concentration of the filtrate under reduced pressure gave a yellow syrup which was purified by silica gel column chromatography (petroleum ether/ethyl acetate, 6/1) to give 4.86g (82%) of the title compound as yellow syrup. ESI-MS (M/e):652[ M + H]+。
EXAMPLE 6 preparation of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro- β -carboline-3-formyl-Gly (6)
4.86g (7.46mmol) of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro- β -carboline-3-formyl-Gly-OBzl (5) were dissolved in 100mL of methanol. Adding 486mg of Pd/C into the solution, pumping out the air in the bottle, introducing hydrogen, repeating the operation for three times, and introducing the hydrogen for 6 hours at room temperature. TLC (petroleum ether/ethyl acetate, 5/1) showed the reaction was complete. Pd/C was filtered off under reduced pressure and the filtrate was concentrated under reduced pressure to give 4.05g (97%) of the title compound as a yellow powder. ESI-MS (M/e):562[ M + H]+。
EXAMPLE 7 preparation of Boc-Arg (NO)2)-Gly-OBzl
From 3.19g (10mmol) of Boc-Arg (NO) using the method of example 52) And 3.50g (12mmol) HCl Gly-OBzl to give 4.20g (90%) of the title compound as a colorless powder. ESI-MS (M/e) 467[ M + H]+。
EXAMPLE 8 preparation of Boc-Arg (NO)2)-Gly
From 4.10g (8.8mmol) of Boc-Arg (NO) by the method of example 42) -Gly-OBzl gave 3.21g (90%) of the title compound as a colorless powder. ESI-MS (M/e):357[ M + H]+。
EXAMPLE 9 preparation of Boc-Asp (OBzl) -Phe-OBzl
Using the method of example 5, from 3.23g (10mmol) Boc-Asp (OBzl) and 3.50g (12mmol) HCl Phe-OBzl 5.08g (91%) of the title compound are obtained as yellow syrup. ESI-MS (M/e):561[ M + H]+。
EXAMPLE 10 preparation of HCl. Asp (OBzl) -Phe-OBzl
5.08g (9.07mmol) of Boc-Asp (OBzl) -Phe-OBzl were dissolved in 50mL of a solution of hydrogen chloride in ethyl acetate (4M) under ice-bath and reacted for 4 hours. TLC (dichloromethane/methanol, 20/1) showed the reaction was complete. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in anhydrous ethyl acetate, and the resulting solution was concentrated under reduced pressure. This operation was repeated 3 times. The resulting yellow syrup sample was thoroughly triturated with anhydrous ether to give 4.25g (95%) of the title compound as a yellow solid. ESI-MS (M/e) 461[ M + H ]]+。
EXAMPLE 11 preparation of Boc-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl
Starting from 2.55g (6.72mmol) Boc-Arg (NO) using the method of example 52) -Gly and 4.00g (8.06mmol) HCl. Asp (OBzl) -Phe-OBzl gave 3.38g (62%) of the title compound as a colorless solid. ESI-MS (M/e) 819[ M + H]+。
EXAMPLE 12 preparation of HCl.Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl
From 3.30g (4.03mmol) of Arg (NO) by the method of example 102) -Gly-Asp (OBzl) -Phe-OBzl gives 2.29g (96%) of the title compound as a colorless solid. ESI-MS (M/e) 719[ M + H]+。
EXAMPLE 13 preparation of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl group-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl(7)
From 1.80g (3.20mmol) of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly (6) and 2.87g (3.80mmol) of HCl. Arg (NO) by the method of example 52) -Gly-Asp (OBzl) -Phe-OBzl gives 2.76g (68%) of the title compound as a yellow solid. ESI-MS (M/e):1261[ M + H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm＝10.26(s,1H),8.40(d,J＝7.5Hz,2H),8.24(m,2H),8.15(d,J＝7.8Hz,1H),7.29(m,17H),7.03(t,J＝7.5Hz,1H),6.94(t,J＝7.5Hz,1H),5.07(m,4H),4.74(dd,J1＝13.5Hz,J2＝8.4Hz,1H),4.51(dd,J1＝14.7Hz,J2＝7.5Hz,1H),4.37(m,1H),3.79(m,9H),3.16(m,2H),3.00(m,3H),2.73(dd,J1＝16.5Hz,J2＝5.4Hz,1H),2.54(m,1H),2.41(m,1H),1.73(m,1H),1.55(m,3H),0.83(s,9H),0.77(s,9H),0.01(s,3H),0.00(s,3H),-0.04(s,3H),-0.11(s,3H)；13C-NMR(75MHz,DMSO-d6):δ/ppm＝173.55,172.16,171.41,170.80,170.21,169.26,169.01,159.79,137.32,136.45,136.34,136.10,135.12,129.56,128.83,128.80,128.74,128.47,128.41,128.31,127.04,126.82,121.11,118.63,117.90,111.45,109.06,66.74,66.51,66.18,65.73,59.10,54.36,53.42,52.65,49.49,42.31,40.88,40.75,40.60,40.32,40.04,39.77,39.49,39.21,37.00,36.79,29.82,26.46,26.31,26.17,18.52,18.36,-4.96,-5.00,-5.04。
EXAMPLE 14 preparation of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl(8)
From 0.43g (0.34mmol) of (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO) using the method of example 102) -Gly-Asp (OBzl) -Phe-OBzl (8) gives 0.33g (97%) of the title compound as a colorless solid. ESI-MS (M/e):1034[ M + H]+。
EXAMPLE 15 preparation of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe (9)
From 0.33g (0.32mmol) of (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO) using the method of example 62)-Gly-Asp(OBzl) -Phe-OBzl (8) gave 0.02g (8%) of the title compound as a colorless powder. ESI-MS (M/e):807[ M-H]-；Mp 172℃(dec.)；
-64.0 (c-0.1, water); IR (cm)-1):3298.54,3082.02,2939.45,1656.57,1531.80,1416.51,1185.21,1134.78,721.17,698.36；1H-NMR(300MHz,DMSO-d6):δ/ppm＝12.86(s,1H),12.40(s,1H),11.08(s,1H),9.61(s,1H),9.24(s,1H),8.83(m,1H),8.28(m,2H),8.21(d,J＝7.8Hz,1H),8.10(d,J＝7.8Hz,1H),7.56(m,1H),7.46(d,J＝7.8Hz,1H),7.38(d,J＝8.1Hz,1H),7.26(m,6H),7.13(t,J＝7.2Hz,1H),7.03(t,J＝7.2Hz,1H),5.70(s,1H),5.41(m,2H),4.76(m,1H),4.61(m,1H),4.38(m,1H),4.07(m,2H),3.95(m,3H),3.85(m,1H),3.74(m,2H),3.31(dd,J1＝15.9Hz,J2＝4.8Hz,1H),3.07(m,3H),2.91(m,2H),2.66(dd,J1＝16.8Hz,J2＝4.8Hz,1H),2.42(m,1H),1.70(m,1H),1.53(m,3H)；13C-NMR(75MHz,DMSO-d6):δ/ppm＝173.03,171.99,171.93,171.02,169.28,168.90,168.59,158.72,158.29,157.17,137.83,136.99,129.61,128.67,125.90,119.46,119.16,115.22,106.89,63.69,62.63,54.11,52.61,49.66,42.06,37.03,36.71,29.89,25.42,23.83。
Example 16 evaluation of the anti-arterial Thrombus Activity of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe
In this example, a rat common carotid artery-external jugular vein in vitro bypass circulation silk thread model was selected, using aspirin in normal saline as a positive control, and normal saline as a blank control, and (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe (compound 9) as a therapeutic drug. The bypass circulation is formed by three sections of polyethylene rubber pipes. The middle section is 80.0mm long and the inner diameter is 3.5 mm. The length of the two end pipes is 100.0mm, the inner diameter is 1.0mm, and the outer diameter is 2.0 mm. One end of the tube was pulled into a sharp tube for insertion into the rat carotid artery or vein. The thread with a weight of 4.0 +/-0.1 mg and a length of 60.0mm and uniform surface roughness is selected as a thrombus carrier. Silanizing the three sections of polyethylene rubber tubes with 1% of silicon ether solution, placing the silk threads at one end of the middle section of polyethylene tube after completely airing, assembling the three sections of polyethylene tubes, and sealing and fixing the joints of the three sections of polyethylene tubes by using a sealing film. Male SD rats (200 + -20 g) were anesthetized by intraperitoneal injection of 20% urethane solution (0.7mL/100g body weight) 30 minutes after oral administration of aspirin in physiological saline (dose of 167. mu. mol/kg) or compound 9 (dose of 0.01. mu. mol/kg). The anesthetized rat was supine fixed on the rat plate, the neck skin was cut open, the right common carotid artery and the left external jugular vein were separated, and the distal ends of the right common carotid artery and the left external jugular vein were ligated with an operation wire. A bevel opening is cut on the left external jugular vein, a sharp tube of a bypass pipeline filled with the heparin sodium solution is inserted into the opening of the left external jugular vein through the bevel opening, a polyethylene tube and a vein are fixed by an operation line, and a certain amount (0.1mL/100g body weight) of heparin sodium is added into the other end of the polyethylene tube for anticoagulation. Clamping the proximal end of the right carotid artery by an artery clamp, cutting an oblique opening in the right carotid artery, taking down a section of the syringe of the bypass tube, inserting the syringe into the proximal end of the right carotid artery, fixing the polyethylene tube with the artery blood vessel by an operation line, loosening the artery clamp, and enabling blood flow to flow from the right artery to the polyethylene tube and flow into the left vein to establish extracorporeal circulation. The blood flow is maintained smooth, the silk thread with thrombus is taken out after the systemic circulation is carried out for 15 minutes, the blood on the silk thread is sucked by filter paper, and then the wet weight of the thrombus is weighed and recorded. Data were counted using t-test. The results are shown in Table 1. The arterial thrombosis of the rats treated with compound 9 was significantly less than that of the rats treated with normal saline, indicating that compound 9 can effectively inhibit arterial thrombosis. In addition, rat carotid blood was anticoagulated with 3.8% aqueous sodium citrate solution for the assays of examples 18 and 19.
TABLE 1 anti-arterial thrombotic Activity of Compound 9
a) P <0.01 to saline; n is 9.
Example 17 evaluation of anti-venous thrombosis Activity of (3S) -1, 1-Dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe
In this example, the rat inferior vena cava ligation model was selected, and warfarin sodium in saline was used as a positive control, saline was used as a blank control, and compound 9 in saline was used as a therapeutic agent. SD male rats (250 + -20 g) were acclimatized and fasted for one day prior to surgery. The oral dose of Compound 9 was 0.01. mu. mol/kg. The oral dose of the positive control warfarin sodium was 4.87. mu. mol/kg. The blank was physiological saline. After 30min of administration, rats were injected intraperitoneally with a 20% urethane solution. Anaesthesia for 2 min. The rat is fixed on a rat fixing plate, the abdomen is preserved and disinfected, the abdominal cavity is opened along the leucorrhea line, and the abdominal cavity is descended to the coagulated gland and is ascended to expose one corner of the liver. 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 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 the rats were circulated for 4 hours at 25 ℃ in the environment, the abdominal branches were opened and ligated, and 2cm of the inferior vena cava was taken out from the junction of the inferior vena cava and the left renal vein, from which the thrombus was taken out and weighed. Counting the thrombus weight, and carrying out t test on the result. The experimental data are shown in table 2. The venous thrombosis in rats treated with compound 9 was significantly less than that in rats treated with saline, indicating that compound 9 was effective in inhibiting venous thrombosis at a dose of 0.01 μmol/kg. In addition, there was no significant difference in venous thrombus weight in rats treated with compound 9 compared to rats treated with warfarin sodium at a dose 487 times higher than that, indicating that compound 9 had an anti-venous thrombus activity equivalent to that of warfarin 487 times. This is an unexpected technical effect.
TABLE 2 anti-thrombotic Activity of Compounds 9a-c
a) P <0.01 to saline and p >0.05 to warfarin; n is 8.
Example 18 evaluation of the Activity of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe for inhibiting GPIIb/IIIa expression
This example selects enzyme-linked immunoassay to determine GPIIb/IIIa concentration of rat carotid artery blood of example 14. Rat carotid blood from example 16 was anticoagulated with 3.8% aqueous sodium citrate, centrifuged at 1000rpm for 15 minutes, and the supernatant was equilibrated at room temperature for 30 minutes and assayed. The kit for determination is a rat platelet membrane GP-IIb/IIIa enzyme linked immunosorbent assay kit. The kit was equilibrated at room temperature for 30 minutes to be assayed.
According to the requirements of the kit, preparing a standard substance. The standard substance in the kit is taken and centrifuged at 10000rpm for 30 seconds. 1mL of the sample diluent solution was added, and the mixture was repeatedly blown and beaten 5 times by a pipette gun to mix the solutions uniformly to obtain a standard S7. 7 1.5mL centrifuge tubes (S0-S6) were removed in sequence and 250. mu.L of each sample dilution was added. Aspirate 250. mu.L of standard S7 into the first centrifuge tube (S6) and gently pipette. Aspirate 250. mu.L from S6 into a second centrifuge tube (S5) and gently pipette. And performing dilution of the standard product by times by analogy. S0 is a sample dilution. The concentration of the obtained standard S7 is 400ng/mL, the concentration of S6 is 200ng/mL, the concentration of S5 is 100ng/mL, the concentration of S4 is 50ng/mL, the concentration of S3 is 25ng/mL, the concentration of S2 is 12.5ng/mL, the concentration of S1 is 6.25ng/mL, and the concentration of S0 is 0 ng/mL.
And (4) preparing a washing working solution according to the requirements of the kit. I.e., 1 volume of concentrated wash solution was diluted with 25 volumes of triple distilled water. And preparing a biotin labeled antibody working solution according to the requirements of the kit. I.e., 1 volume of biotin labeled antibody was diluted with 100 volumes of diluent. And (3) preparing a horse radish peroxidase labeled avidin working solution according to the requirements of the kit. That is, 1 volume of horseradish peroxidase-labeled avidin was diluted with 100 volumes of diluent. The determination steps are as follows:
1) the ELISA plate is respectively provided with a standard hole and a sample hole to be detected. Adding 100 μ L of standard substance or serum into each well, shaking gently, mixing, coating with plate, incubating at 37 deg.C for 2 hr, discarding liquid, and drying by spin-drying without washing.
2) Adding 100 μ L biotin labeled antibody working solution into each well, coating with new plate, incubating at 37 deg.C for 1 hr, discarding the liquid in the well, spin-drying, and washing the plate for 3 times. Soaking for 2min each time, 200 μ L/hole, and drying.
3) Adding 100 μ L of horse radish peroxidase avidin working solution into each well, coating with new plate patch, incubating at 37 deg.C for 1 hr, discarding the liquid in the well, spin-drying, and washing the plate for 3 times. Soaking for 2min each time, 200 μ L/hole, and drying.
4) Add 90. mu.L of substrate solution to each well in sequence, and develop color in the dark at 37 ℃ for 15-30 minutes.
5) The reaction was stopped by adding 50. mu.L of stop solution to each well in sequence.
6) The OD value of each well was measured sequentially at a wavelength of 450nm with a microplate reader within 5 minutes of terminating the reaction.
7) A standard curve is drawn according to the OD value of the standard substance, and the GPIIb/IIIa concentration of the serum sample is calculated, and the data is shown in a table 3. The GPIIb/IIIa content of the serum of the rat treated with the compound 9 at the dose of 0.01 mu mol/kg is significantly lower than the GPIIb/IIIa content of the serum of the rat treated with the normal saline. That is, compound 9 can effectively inhibit GPIIb/IIIa expression in rats. Furthermore, the GPIIb/IIIa content of 0.01. mu. mol/kg compound 9 treated rat serum was not significantly different from the GPIIb/IIIa content of 167. mu. mol/kg aspirin treated rat serum. As can be seen, the activity of compound 9 in inhibiting GPIIb/IIIa expression in rats is 1670 times that of aspirin. This is an unexpected technical effect.
TABLE 3 Activity of Compound 9 to inhibit GPIIb/IIIa expression
a) P <0.01 to saline, p >0.05 to aspirin; n is 6
Example 19 evaluation of the Activity of (3S) -1, 1-Dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe for inhibiting P-selectin expression
Enzyme-linked immunoassay was selected for the present example to determine the P-selectin concentration in the carotid artery blood of the rat of example 14. Rat carotid blood from example 16 was anticoagulated with 3.8% aqueous sodium citrate, centrifuged at 1000rpm for 15 minutes, and the supernatant was equilibrated at room temperature for 30 minutes and assayed. The kit for determination is a rat P-selectin enzyme linked immunosorbent assay kit. The kit was equilibrated at room temperature for 30 minutes to be assayed.
According to the requirements of the kit, preparing a standard substance. The standard substance in the kit is taken and centrifuged at 10000rpm for 30 seconds. 1mL of the sample diluent solution was added, and the mixture was repeatedly blown and beaten 5 times by a pipette gun to mix the solutions uniformly to obtain a standard S7. 7 1.5mL centrifuge tubes (S0-S6) were removed in sequence and 250. mu.L of each sample dilution was added. Aspirate 250. mu.L of standard S7 into the first centrifuge tube (S6) and gently pipette. Aspirate 250. mu.L from S6 into a second centrifuge tube (S5) and gently pipette. And performing dilution of the standard product by times by analogy. S0 is a sample dilution. The concentration of the obtained standard S7 is 400ng/mL, the concentration of S6 is 200ng/mL, the concentration of S5 is 100ng/mL, the concentration of S4 is 50ng/mL, the concentration of S3 is 25ng/mL, the concentration of S2 is 12.5ng/mL, the concentration of S1 is 6.25ng/mL, and the concentration of S0 is 0 ng/mL.
And (4) preparing a washing working solution according to the requirements of the kit. I.e., 1 volume of concentrated wash solution was diluted with 25 volumes of triple distilled water. And preparing a biotin labeled antibody working solution according to the requirements of the kit. I.e., 1 volume of biotin labeled antibody was diluted with 100 volumes of diluent. And (3) preparing a horse radish peroxidase labeled avidin working solution according to the requirements of the kit. That is, 1 volume of horseradish peroxidase-labeled avidin was diluted with 100 volumes of diluent. The determination steps are as follows:
1) the ELISA plate is respectively provided with a standard hole and a sample hole to be detected. Adding 100 μ L of standard substance or serum into each well, shaking gently, mixing, coating with plate, incubating at 37 deg.C for 2 hr, discarding liquid, and drying by spin-drying without washing.
2) Adding 100 μ L biotin labeled antibody working solution into each well, coating with new plate, incubating at 37 deg.C for 1 hr, discarding the liquid in the well, spin-drying, and washing the plate for 3 times. Soaking for 2min each time, 200 μ L/hole, and drying.
3) Adding 100 μ L of horse radish peroxidase avidin working solution into each well, coating with new plate patch, incubating at 37 deg.C for 1 hr, discarding the liquid in the well, spin-drying, and washing the plate for 3 times. Soaking for 2min each time, 200 μ L/hole, and drying.
4) Add 90. mu.L of substrate solution to each well in sequence, and develop color in the dark at 37 ℃ for 15-30 minutes.
5) The reaction was stopped by adding 50. mu.L of stop solution to each well in sequence.
6) The OD value of each well was measured sequentially at a wavelength of 450nm with a microplate reader within 5 minutes of terminating the reaction.
7) A standard curve was drawn according to the OD value of the standard, and the P-selectin concentration of the serum sample was calculated, and the data are shown in Table 4. The P-selectin content of the serum of compound 9-treated rats at the 0.01 μmol/kg dose was significantly lower than that of the serum of saline-treated rats. That is, compound 9 can effectively inhibit P-selectin expression in rats. Furthermore, the P-selectin content of 0.01. mu. mol/kg compound 9 treated rat serum was not significantly different from that of 167. mu. mol/kg aspirin treated rat serum. It can be seen that the activity of compound 9 in inhibiting P-selectin expression in rats is equivalent to 1670 times that of aspirin. This is an unexpected technical effect.
TABLE 4 Activity of Compound 9 to inhibit P-selectin expression
a) P <0.01 to saline, p >0.05 to aspirin; n is 6.
Claims (6)
1.(3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg-Gly-Asp-Phe with the following formula,
2. a process for the preparation of (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe according to claim 1, comprising:
(1) carrying out Pictet-Spengler condensation on L-tryptophan and 1, 3-dihydroxyacetone under the catalysis of dilute sulfuric acid to generate (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid;
(2) preparing (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
(3) reacting (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester with tert-butyldimethylchlorosilane (TBDMSCl) in the presence of imidazole to generate (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester;
(4) hydrolyzing (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid methyl ester in 4N NaOH aqueous solution to generate (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid;
(5) coupling (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-carboxylic acid and Gly-OBzl into (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-OBzl by using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts and adopting a liquid phase condensation method;
(6) (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-OBzl is converted into (3S) -1, 1-bis (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly by hydrogenolysis in the presence of Pd/C;
(7) uses dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts to synthesize HCl & Arg (NO) by adopting a liquid phase condensation method2)-Gly-Asp(OBzl)-Phe-OBzl；
(8) Using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole as catalysts, and adopting a liquid phase condensation method to react (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly with HCl & Arg (NO)2) -Gly-Asp (OBzl) -Phe-OBzl is coupled into (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl；
(9) (3S) -1, 1-di (tert-butyldimethylsilyloxy) methyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2) Removing tert-butyl dimethyl silicon base from-Gly-Asp (OBzl) -Phe-OBzl in 4N hydrogen chloride-ethyl acetate solution at 0 ℃ to prepare (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2)-Gly-Asp(OBzl)-Phe-OBzl；
(10) (3S) -1, 1-dihydroxymethyl-tetrahydro-beta-carboline-3-formyl-Gly-Arg (NO)2) -Gly-Asp (OBzl) -Phe-OBzl is hydrogenolysed in the presence of Pd/C to yield (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe.
3. Use of (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe according to claim 1 for the preparation of an anti-arterial thrombosis medicament.
4. Use of (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe according to claim 1 for the preparation of a medicament for the treatment of venous thrombosis.
5. Use of (3S) -1, 1-dimethylol-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe according to claim 1 for the preparation of a GPIIb/IIIa antagonist.
6. Use of (3S) -1, 1-dihydroxymethyl-tetrahydro- β -carboline-3-formyl-Gly-Arg-Gly-Asp-Phe according to claim 1 for the preparation of a P-selectin antagonist.
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