CN115466304A - Dioxane-tetrahydrocarboline-3-formylamino acid with glycoprotein IIAlbeta as target and preparation and application thereof - Google Patents
Dioxane-tetrahydrocarboline-3-formylamino acid with glycoprotein IIAlbeta as target and preparation and application thereof Download PDFInfo
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Abstract
The invention discloses 3S-1- (1,1-dimethyl-1,3-dioxane spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA (AA is glycine residue, L-asparagine residue, L-glutamine residue, L-serine residue, L-threonine residue and L-tyrosine residue), discloses the characteristic that the AA selectively enters a glycoprotein IIalpha III beta active pocket, and discloses the anti-arterial thrombosis activity and the anti-inflammatory activity of the AA. Therefore, the invention discloses the application of the compounds in preparing anti-arterial thrombosis medicaments and anti-inflammatory medicaments.
Description
Technical Field
The invention relates to 3S-1- (1,1-dimethyl-1,3-dioxane spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA (AA is glycine residue, L-asparagine residue, L-glutamine residue, L-serine residue, L-threonine residue and L-tyrosine residue), relates to the characteristic that the AA selectively enters an IIalpha III beta active pocket, and relates to the anti-arterial thrombosis activity and the anti-inflammatory activity of the AA. Therefore, the invention relates to the application of the compound in preparing anti-arterial thrombosis medicaments and anti-inflammatory medicaments. The invention belongs to the field of biological medicine.
Background
Cardiovascular diseases belong to frequently encountered diseases and common diseases, and have the advantages of long disease course, rapid disease progression, high fatality rate and disability rate. Arterial thrombosis is a major link to the onset of cardiovascular disease. After thrombosis, the lumen of the blood vessel becomes stenotic, resulting in blockage of the blood vessel, which in turn leads to myocardial necrosis, hypoxia and ischemia, and atherosclerosis. Inflammation can cause damage to the body and lead to various systemic diseases. In cardiovascular diseases, inflammation is an important cause of atherosclerosis. As such, arterial thrombosis and inflammation are commonly involved in the pathogenesis of cardiovascular disease. That is, the invention of the drug with double functions of anti-arterial thrombosis and anti-inflammation is of great importance for treating cardiovascular diseases.
P-selectin, tumor necrosis factor-alpha, glycoprotein IIAlaIII beta and interleukin-6 are important receptors of double-action medicines for resisting arterial thrombosis and inflammation. Only those compounds that are able to enter their active pocket have the potential to reduce the plasma concentration of these receptors or to down-regulate their expression. After analyzing the forms of active pockets of P-selectin, tumor necrosis factor-alpha, glycoprotein IIAlIIIbeta and interleukin-6, the inventor designs 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA, wherein AA represents an amino acid residue commonly found in human body. The inventor uses molecular docking technology to dock 3S-1- (1,1-dimethyl-1,3-dioxane spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA with P-selectin, tumor necrosis factor-alpha, glycoprotein IIalpha III beta and interleukin-6 respectively. The results show that 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA (AA is glycine residue, L-asparagine residue, L-glutamine residue, L-serine residue, L-threonine residue and L-tyrosine residue) selectively enters the active pocket of glycoprotein IIaIIIbeta. The attached figure 2 of the specification is a docking condition and a docking scoring chart of the six compounds and the glycoprotein IIAlIIIbeta active pocket. From this figure, it can be seen that the active pocket of glycoprotein IIaIIIbeta is well suited for these six compounds. Unlike glycoprotein IIAlIIbeta, these six compounds do not readily enter the active pocket of P-selectin, tumor necrosis factor-alpha and interleukin-6. Based on these theoretical studies, the present inventors completed the following experimental studies.
Disclosure of Invention
The first aspect of the present invention is to confirm that 3S-1- (1,1-dimethyl-1,3-dioxane spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA having the following structure is a novel compound, and AA is a glycine residue, an L-asparagine residue, an L-glutamine residue, an L-serine residue, an L-threonine residue, and an L-tyrosine residue.
The second aspect of the present invention provides a method for synthesizing 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA (AA is as defined above), comprising:
1) Preparing 3S-1,1-dihydroxymethyl-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate;
2) Preparing benzyl 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-carboxylate;
3) Preparing 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
4) Using dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to prepare 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA-benzyl ester;
5) Preparing 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA.
The third aspect of the present invention is to evaluate the anti-arterial thrombosis activity of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA.
A fourth aspect of the invention is to evaluate the anti-inflammatory activity of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA.
Drawings
FIG. 1, 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA: i) Trifluoroacetic acid, 1,3-dihydroxyacetone; ii) N, N-dimethylformamide, p-toluenesulfonic acid, 2,2-dimethylpropane; iii) Pd/C, H 2 (ii) a iv) dicyclohexylcarbodiimide, 1-hydroxybenzotriazole, N-methylmorpholine.
FIG. 2 and FIG. 2 show the docking of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-AA in the active pocket of glycoprotein IIaIIIβ; AA is glycine residues, L-asparagine residues, L-glutamine residues, L-serine residues, L-threonine residues and L-tyrosine residues, and the docking scores are 41.77,35.92,47.69,47.15, 45.93 and 35.83, respectively.
Detailed Description
To further illustrate the invention, a series of examples are given below. These examples are purely illustrative and are intended to be a detailed description of the invention only and should not be taken as limiting the invention.
EXAMPLE 1 preparation of benzyl 3S-1,1-dimethylol-1,2,3,4-tetrahydro- β -carboline-3-carboxylate (1)
3.0g (10.2 mmol) of L-tryptophan benzyl ester are dissolved in 30mL of dichloromethane, and 3mL of trifluoroacetic acid are slowly added dropwise to the resulting clear and transparent solution in ice bath, followed by 1.08g (12 mmol) of 1,3-dihydroxyacetone and reaction at room temperature for 14 hours. TLC showed disappearance of L-tryptophan benzyl ester (dichloromethane/methanol, 10/1). 100mL of a saturated aqueous sodium bicarbonate solution was added to the reaction solution and stirred, followed by standing for separation, a methylene chloride phase was separated, concentrated under reduced pressure, the residue was dissolved in 30mL of ethyl acetate, and the resulting solution was sequentially dissolved in saturated NaHCO 3 Aqueous (10 mL. Times.3) and saturated aqueous NaCl (10 mL. Times.3). The obtained ethyl acetate layer was dried over anhydrous sodium sulfate for 12 hours, filtered, and the filtrate was concentrated under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane/methanol, 70/1) to give 2.82g (76%) of the title compound as a pale yellow powder. ESI-MS (m/e): 367[ M ] +H] + 。
EXAMPLE 2 preparation of benzyl 3S-1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-carboxylate (2)
1.5g (4 mmol) of 3S-1,1-dimethylol-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid benzyl ester (1) is dissolved with 30mL of ethyl acetate and 23mL of dichloromethane, 4mL of ethyl acetate solution of hydrogen chloride is added under ice bath, and after stirring for 10 minutes, solid particles are precipitated. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 10mLN, N-dimethylformamide to give a light brown clear solution. Then, 1.35mL (10 mmol) of 2,2-dimethylpropane and 90mg of p-toluenesulfonic acid were added thereto, and the mixture was stirred at room temperature for 17 hours. TLC monitoring showed disappearance of compound 1 (ethyl acetate/petroleum ether = 1/1). 80mL of ethyl acetate was added, followed by 80mL of saturated NaHCO 3 An aqueous solution. The resulting solution was successively saturated with NaHCO 3 Aqueous solution (30 mL. Times.3) and saturated aqueous NaCl solution (30 mL. Times.3). The ethyl acetate layer obtained was washed with anhydrous Na 2 SO 4 Drying for 12 hours, filtering, and concentrating the filtrate under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1) to give 1.05g (63%) of the title compound as a pale yellow powder. ESI-MS (m/e): 407[ m ] +H] + 。
Example 3 preparation of 3S-1- (1,1-dimethyl-1,3-dioxaspiro-spiro-yl) -1,2,3,4-tetrahydro- β -carboline-3-carboxylic acid (3)
1.0g (2.4 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate (2) is dissolved in 15mL of methanol, 150mg of Pd/C is added under stirring, air is pumped out by using a water pump, and hydrogen is introduced to react for 5 hours at normal temperature. TLC monitoring showed disappearance of compound 2 (dichloromethane/methanol, 10/1). Filtering, and concentrating the filtrate under reduced pressure. The residue was triturated with dry ether to give 760mg (98%) of the title compound as a colorless powder. ESI-MS (m/e): 315[ M-H ]] - ； 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝11.05(s,1H),7.44(d,J＝7.7Hz,1H),7.36(d,J＝8.0Hz,1H),7.08 (m,1H),6.98(m,1H),4.47(m,1H),3.94(m,2H),3.66(m,2H),2.82(m,2H),2.50(s,1H), 1.63(s,3H),1.40(s,3H)。
EXAMPLE 4 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-glycine benzyl ester (4 a)
770mg (2.40 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (3) was dissolved in 10mL of anhydrous tetrahydrofuran, 552mg (2.67 mmol) of dicyclohexylcarbodiimide and 362mg (2.67 mmol) of 1-hydroxybenzotriazole were added to the resulting solution under ice bath, after stirring for 30 minutes 540mg (2.67 mmol) of benzyl glycinate and 20. Mu. L N-methylmorpholine were added to adjust the pH of the reaction solution to 8, and reacted for 9 hours at room temperature, and TLC showed disappearance of compound 3 (petroleum ether/ethyl acetate = 1/1). Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 20mL ethyl acetate. The resulting solution was sequentially saturated NaHCO 3 Aqueous solution washing (10 mL. Times.3), saturated aqueous NaCl washing (10 mL. Times.3), 5% 4 Aqueous solution (10 mL. Times.3), saturated aqueous NaCl solution (10 mL. Times.3), saturated aqueous NaHCO solution 3 Aqueous (10 mL. Times.3) and saturated aqueous NaCl (10 mL. Times.3). The obtained ethyl acetate layer liquid was treated with anhydrous Na 2 SO 4 Drying for 12 hours, filtering, and concentrating the filtrate under reduced pressure. The residue was isolated by silica gel column chromatography (dichloromethane/methanol, 110/1) to give 800mg (71%) of the title compound as a colorless powder. ESI-MS (m/e): 464[ M ] +H] + ； 1 H NMR(300MHz,CDCl 3 )δ/ppm＝8.63(s,1H),7.51 (s,1H),7.4-7.1(m,9H),5.20(s,2H),4.18(m,2H),4.01(m,2H),3.96(m,1H),3.84(m,1H), 3.73(m,1H),3.48(s,1H),3.26(m,1H),2.75(m,1H),1.62(s,3H),1.58(s,3H)。
EXAMPLE 5 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-asparagine benzyl ester (4 b)
From 540mg (1.70 mmol) of compound 3 and 500mg (1.93 mmol) of L-asparagine benzyl ester hydrochloride by the experimental method of example 4, 780mg (89%) of the title compound are obtained as colorless powder. ESI-MS (m/e): 521[ M ] +H] + ； 1 H NMR (300MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.32(d,J＝7.9Hz,1H),7.59-7.24(m,8H),7.04 (m,3H),5.18(m,2H),4.76(m,1H),4.41(m,1H),3.99(m,1H),3.78(m,1H),3.70-3.49(m,2H), 3.33(s,2H),2.94(m,2H),2.70(m,2H),1.62(s,3H),1.39(s,3H)。
EXAMPLE 6 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-glutamine benzyl ester (4 c)
Using the experimental method of example 4, from 600mg (1.90 mmol) of compound 3 and 763mg (2.30 mmol) of L-glutamine benzyl ester hydrochloride, 380mg (38%) of the title compound are obtained as a colorless powder. ESI-MS (m/e): 535[ M ] +H] + ； 1 H NMR (300MHz,CDCl 3 ):δ/ppm＝8.77(s,1H),7.61(d,J＝8.1Hz,1H),7.46(m,1H),7.40-7.28(m, 6H),7.10(m,2H),5.92(m,2H),5.19(m,2H),4.65(m,1H),3.96(m,3H),3.84(m,1H),3.66 (m,1H),3.15(m,1H),2.68(m,1H),2.19(m,3H),1.90(m,2H),1.60(s,3H),1.55(s,3H)。
EXAMPLE 7 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiroyl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-serine benzyl ester (4 d)
Using the experimental method of example 4, 328mg (1.04 mmol) of compound 3 and 288mg (1.24 mmol) of L-serine benzyl ester hydrochloride gave 440mg (86%) of the title compound as colorless powder. ESI-MS (m/e) 494[ M ] +H] + ； 1 H NMR (300MHz,DMSO-d 6 ):δ/ppm＝10.91(s,1H),8.15(d,J＝7.7Hz,1H),7.56-7.20(m,7H),7.02 (m,2H),5.17(s,2H),4.50(dd,J 1 ＝7.7Hz,J 2 ＝4.6Hz,1H),4.39(m,1H),3.99(m,1H), 3.91-3.63(m,4H),3.57(m,1H),2.96(m,2H),2.56(m,1H),1.61(s,3H),1.38(s,3H)。
EXAMPLE 8 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-threonine benzyl ester (4 e)
From 700mg (2.22 mmol) of compound 3 and 652mg (2.65 mmol) of L-threonine benzyl ester hydrochloride by the experimental method of example 4, 1.03g (92%) of the title compound are obtained as colorless powder. ESI-MS (m/e): 508[ M ] +H] + ； 1 H NMR (300MHz,CDCl 3 ):δ/ppm＝8.63(s,1H),7.49(d,J＝7.7Hz,1H),7.43-7.31(m,7H),7.19(m, 1H),7.10(m,1H),5.22(m,2H),4.70(dd,J 1 ＝9.0Hz,J 2 ＝2.6Hz,1H),4.43(m,1H),3.99(m, 3H),3.78(m,2H),3.24(m,1H),2.74(dd,J 1 ＝15.5Hz,J 2 ＝11.9Hz,1H),2.17(s,1H),1.62(s, 3H),1.57(s,3H),1.24(m,3H)。
EXAMPLE 9 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-tyrosine benzyl ester (4 f)
Experimental method 7 of example 410mg (2.24 mmol) of Compound 3 and 829mg (2.70 mmol) of L-tyrosine benzyl ester hydrochloride give 655mg (52%) of the title compound as a colourless powder. ESI-MS (m/e): 570[ 2 ], [ M ] +H] + ； 1 H NMR (300MHz,DMSO-d 6 ):δ/ppm＝10.93(s,1H),9.23(s,1H),8.25(d,J＝7.6Hz,1H),7.34(m, 7H),7.15-6.93(m,4H),6.67(d,J＝8.5Hz,2H),5.12(m,2H),4.54(d,J＝7.3Hz,1H),4.38(m, 1H),4.09(t,J＝5.3Hz,1H),3.98(m,1H),3.78(s,1H),3.58(s,2H),3.17(d,J＝5.3Hz,2H), 3.07-2.82(m,4H),2.50(m,1H),1.61(s,3H),1.38(s,3H)。
EXAMPLE 10 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-glycine (5 a)
76mg (92%) of the title compound as a colorless powder was obtained from 100mg (0.18 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formylglycine benzyl ester (4 a) by the experimental procedure of example 3; mp is 148-1450 ℃;
FT-MS(m/e):374.1744[M+H] + (theoretical value: 374.1638); 1 H NMR(300 MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),8.21(m,1H),7.42-7.00(m,4H),4.45(d,J＝8.7Hz, 1H),4.00(m,1H),3.85-3.75(m,3H),3.60(m,2H),3.0(m,2H),2.58(m,1H),1.62(s,3H), 1.40(s,3H)。
EXAMPLE 11 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-asparagine (5 b)
Using the experimental method of example 3, 160mg (0.31 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-asparagine benzyl ester (4 b) gave 128mg (97%) of the title compound as a colorless powder; mp is 164-165 ℃;
FT-MS(m/e):431.1946[M+H] + (theoretical value: 431.1852); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.96(s,1H),8.12(d,J＝8.0Hz,1H),7.53-7.28(m, 3H),7.18-6.84(m,3H),4.61(m,1H),4.41(m,1H),4.05(m,2H),3.80(m,1H),3.61(m,2H), 3.17(s,2H),2.99(m,1H),2.59(m,3H),1.62(s,3H),1.40(s,3H)。
EXAMPLE 12 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-glutamine (5 c)
Using the experimental procedure of example 3, from 120mg (0.22 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-glutamine benzyl ester (4 c) 50mg (51%) of the title compound was obtained as a colorless powder; mp is 158-159 ℃;
FT-MS(m/e):445.2112[M+H] + (theoretical value: 445.2009); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.96(s,1H),8.12(d,J＝7.5Hz,1H),7.53-7.21(m, 3H),7.05(m,2H),6.80(s,1H),4.41(m,1H),4.26(m,1H),4.00(m,1H),3.79(m,1H), 3.70-3.52(m,3H),3.05(m,1H),2.59(m,1H),2.18(m,2H),2.03(m,1H),1.88(m,1H),1.62(s, 3H),1.40(s,3H)。
EXAMPLE 13 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-serine (5 d)
Using the experimental procedure of example 3, 150mg (0.30 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-serine benzyl ester (4 d) gave 110mg (90%) of the title compound as a colorless powder; mp is 154-155 ℃;
FT-MS(m/e):404.1852[M+H] + (theoretical value: 404.1743); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.95(s,1H),7.96(d,J＝7.8Hz,1H), 7.40(dd,J 1 ＝15.4Hz,J 2 ＝7.8Hz,2H),7.11(m,1H),7.97(m,1H),4.39(m,2H),4.00(d, J＝11.7Hz,1H),3.80(m,2H),3.70(m,2H),3.60(m,1H),3.01(m,1H),2.60(m,1H),1.62(s, 3H),1.40(s,3H)。
example 14 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-threonine (5 e)
The experimental procedure used in example 3 was repeated to synthesize 170mg (0.34 mmol) of 3S-1- (1,1-dimethyl-13-Dioxacyclohexospiral) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-threonine benzyl ester (4 e) to give 120mg (86%) of the title compound as a colorless powder; mp at 159-160 deg.C;
ESI-MS(m/e):418.2005[M+H] + (theoretical value: 418.1900); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.96(s,1H),7.68(d,J＝8.8Hz,1H), 7.44(d,J＝7.7Hz,1H),7.38(d,J＝8.0Hz,1H),7.08(m,1H),6,96(m,1H),4.43(m,1H),4.31 (dd,J 1 ＝8.8Hz,J 2 ＝3.0Hz,1H),4.22(m,1H),4.01(m,1H),3.83(m,1H),3.66(m,2H),3.17 (s,2H),3.02(m,1H),2.63(dd,J 1 ＝14.8Hz,J 2 ＝10.7Hz,1H),1.62(s,3H),1.40(s,3H),1.12 (d,J＝6.3Hz,3H)。
example 15 preparation of (3S) -1- (1,1-dimethyl-1,3-dioxanone spiro-yl) -1,2,3,4-tetrahydro-beta-carboline-3-formyl-L-tyrosine (5 f)
From 120mg (0.21 mmol) of 3S-1- (1,1-dimethyl-1,3-dioxane spiroyl) -1,2,3,4-tetrahydro- β -carboline-3-formyl-L-tyrosine benzyl ester (4 f) using the experimental procedure of example 3, 95mg (94%) of the title compound are obtained as colorless powder; mp is 109-110 ℃;
FT-MS(m/e):480.2167[M+H] + (theoretical value: 480.2056); 1 H NMR(300MHz,DMSO-d 6 ):δ/ppm＝10.94(s,1H),8.14(s,1H),8.01(d,J＝7.9Hz,1H), 7.39(m,2H),7.14-6.92(m,4H),6.67(m,2H),4.48(m,1H),4.31(m,1H),3.98(d,J＝11.8,1H), 3.78(m,1H),3.59(m,7.1,2H),3.09-2.81(m,3H),2.50(m,1H),1.61(s,3H),1.39(s,3H)。
EXAMPLE 16 evaluation of the anti-arterial Thrombus Activity of Compounds 5a-f
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 group was randomly divided into a saline group (0.3 mL/100g,11 rats), an aspirin group (167. Mu. Mol/kg,11 rats), and a compound 5a-f group (0.1. Mu. Mol/kg,11 rats). The drug was administered orally to rats in the prescribed dose. 30 minutes after administration, rats were anesthetized by intraperitoneal injection of 20% urethane solution (7 mL/kg), and surgery was started 2 minutes 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 15 minutes of circulation, the venous end is cut off, whether the blood circulation is normal or not is observed, if the blood circulation is normal, a thrombus thread is taken out from the arterial end, dry and floating blood is stained on paper, then weighing is carried out, the activity is expressed by the thrombus weight, and the data are listed in table 1 through one-factor variance analysis. The thrombus weights in Table 1 show that aspirin effectively inhibits arterial thrombosis in rats at an oral dose of 167 μmol/kg. The thrombus weight of rats treated with compounds 5a,5d,5e and 5f at an oral dose of 0.1. Mu. Mol/kg did not differ significantly from the thrombus weight of rats treated with physiological saline. This result demonstrates that the molecular docking and docking scores at 5a,5d,5e and 5f for the glycoprotein ilaiiibeta activity pocket deviate in predicting their anti-arterial thrombotic activity. Nonetheless, compounds 5b and 5c showed excellent arterial thrombotic activity at an oral dose of 0.1 μmol/kg. Therefore, the invention has outstanding technical effects.
TABLE 1 Effect of Compounds 5a-f on arterial thrombosis
a) P <0.01 to saline, P >0.05 to compound 3; n =11
Example 17 evaluation of anti-inflammatory Activity of Compounds 5b and 5c
Laboratory animal
ICR mice, male, 20 + -2 g, purchased from Experimental animals technology, inc., viton, beijing.
Dosage and mode of administration
The oral dose of compounds 5b and 5c was 0.1 μmol/kg, the oral dose of positive control aspirin was 1.1mmol/kg, and the negative control was normal saline.
Experimental methods
The experiment adopts ICR induced mouse ear swelling model.
Experimental procedures
The newly arrived mice were allowed to rest for one day and then randomly grouped, 12 mice per group. And (3) performing intragastric administration on the mice by adopting a sequential method, wherein 6 mice are administered in each group at intervals of 5 minutes according to a specified dose, grabbing the mice according to the intragastric order after half an hour, exposing the right ear of the mice, uniformly smearing 30 mu L of dimethylbenzene on the edge of the auricle of the right ear by using a pipette, and finishing the establishment of the model after the dimethylbenzene is naturally volatilized. After application of xylene, the mice had restlessness and red and swollen right ears. Two hours after the model building, anaesthetizing the mouse by ether, removing the neck to kill the mouse, cutting the ears at the two sides of the mouse along the root, overlapping the edges of the ears, using an electric ear swelling ear-sticking device (model: YLS 025A) with the diameter of 7mm to stick down two round ears with the same area and size of the same part of the ears, and weighing the two round ears respectively, wherein the ear swelling degree is the difference value of the weights of the two ears.
Results of the experiment
Ear swelling = right ear weight-left ear weight; swelling degree of ear
mg, statistical comparisons between groups by one-way variance test; ear swelling is shown in Table 2; the results show that the swelling degree of ears of mice treated with compounds 5b and 5c at an oral dose of 0.1 μmol/kg is significantly different from that of normal saline, and not significantly different from that of compound 3. It can be seen that when the oral dosage of the compound 3 is as low as 1/10 after being modified by L-asparagine and L-glutamineStill has excellent anti-inflammatory activity. That is, the present invention has a remarkable technical effect.
TABLE 2 Activity of Compounds 5b and 5c to inhibit inflammation
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 =12.
Claims (4)
1. 3S-1-dioxane spiro-1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA with the structure as shown,
wherein AA is glycine residue, L-asparagine residue, L-glutamine residue, L-serine residue, L-threonine residue or L-tyrosine residue.
2. A method of preparing 3S-1-dioxane spiroyl-1,2,3,4-tetrahydro- β -carboline-3-formyl-AA of the structure of claim 1, comprising the steps of:
2.1. preparing 3S-1,1-dimethylol-tetrahydro-beta-carboline-3-benzyl carboxylate;
2.2. preparing 3S-1-dioxane spiro-1,2,3,4-tetrahydro-beta-carboline-3-benzyl carboxylate;
2.3. preparing 3S-1-dioxane spiro-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
2.4. adopting dicyclohexylcarbodiimide as a condensing agent and 1-hydroxybenzotriazole as a catalyst to synthesize 3S-1-dioxane spiroyl-1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA-benzyl ester in a liquid phase manner;
2.5. preparing 3S-1-dioxane spiro-1,2,3,4-tetrahydro-beta-carboline-3-formyl-AA.
3. The use of 3S-1-dioxane spiroyl-1,2,3,4-tetrahydro- β -carboline-3-formyl-AA of the structure of claim 1 in the preparation of an anti-arterial thrombosis medicament.
4. The use of 3S-1-dioxane spiroyl-1,2,3,4-tetrahydro- β -carboline-3-formyl-AA of the structure of claim 1 in the preparation of an anti-inflammatory medicament.
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