CN102796166B - Glucose-modified 4H-beta-carboline carboxylic acid derivative and preparation method and application thereof - Google Patents

Glucose-modified 4H-beta-carboline carboxylic acid derivative and preparation method and application thereof Download PDF

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CN102796166B
CN102796166B CN201110139384.1A CN201110139384A CN102796166B CN 102796166 B CN102796166 B CN 102796166B CN 201110139384 A CN201110139384 A CN 201110139384A CN 102796166 B CN102796166 B CN 102796166B
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beta
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CN102796166A (en
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赵明
彭师奇
朱祺尧
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Capital Medical University
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Abstract

The invention discloses a glucose-modified 4H-beta-carboline carboxylic acid derivative and a preparation method thereof, and application of the derivative to preparation of an anti-thrombotic medicine. The invention also discloses a composition for preparing the anti-thrombotic medicine. The composition consists of an effective dose of compound shown as a general formula I and a pharmaceutically acceptable carrier or auxiliary material, wherein the compound accounts for 0.1 to 99 percent, preferably 10 to 60 percent of the total weight of the medicinal composition. The anti-platelet aggregation activity of the compound is evaluated by a common carotid artery-jugular vein extracorporeal circulation bypass thread model. Test results show that the compound has high anti-thrombotic activity and can be prepared into the anti-thrombotic medicinal composition and can be used for preparing the anti-thrombotic medicine.

Description

4H-β-carboline carboxylic acid derivative of glucose modified and its preparation method and application
Technical field
The present invention relates to compound of a kind of synthetic and its preparation method and application, particularly relate to a kind of 4H-β-carboline carboxylic acid derivative to glucose modified, the invention still further relates to its preparation method and the application in preparing antithrombotic reagent thereof.
Background technology
Vessel embolism is the important diseases of harm people life and health.Thrombosis is the most important cause of disease of vessel embolism morbidity.Finding antithrombotic reagent is one of focus of new drug research.As everyone knows, 1,2,3,4-tetrahydro-beta-carboline-3-S-carboxylic acid is the important indole alkaloid of a class being extensively present among herbal medicine, has platelet aggregation inhibitory activity.Introduce the bioavailability that amino acid can improve 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid for 1 and/or 3 at 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid.In addition glucose has good water-solublely, and glucose can greatly improve the water-soluble of compound after being introduced into compound, makes more easily absorption and distribution in vivo of compound.Glucose is as the necessary material participating in the many physiological processs of human body, and its introducing is safe.Therefore at the carboxyl terminal of 1,2,3,4-tetrahydro-beta-carboline-3-S-carboxylic acid, introduce amino acid, and can strengthen the water-soluble of compound at N end introducing glucose, can improve biological activity.
Summary of the invention
First technical problem that the present invention will solve is that it is the compound (6a-n) of I that general formula is provided:
Figure BDA0000064092490000011
In formula, AA is glycine residue, alanine residue, Isoleucine residue, leucine residue, α-amino-isovaleric acid residue, methionine residue, phenylalanine, tyrosine residues, threonine residues, serine residue, tryptophan residue, asparagicacid residue, glutaminic acid residue or hydroxyl.
The compound that is I to synthetic general formula (6a-n) is numbered:
In 6a, AA represents alanine residue; In 6b, AA represents glycine residue; In 6c, AA represents phenylalanine residue; In 6d, AA represents tryptophan residue; In 6e, AA represents leucine residue; In 6f, AA represents α-amino-isovaleric acid residue; In 6g, AA represents asparagicacid residue; In 6h, AA represents tyrosine residues; In 6i, AA represents Isoleucine residue; In 6j, AA represents methionine residue; In 6k, AA represents threonine residues; In 6l, AA represents glutaminic acid residue; In 6m, AA represents serine residue; AA representation hydroxy in 6n.
More than numbering just for convenience of description, there is no any limited significance to invention.
The Second Problem that the present invention will solve is to provide the preparation method of general formula compound (6a-n), and the method comprises the following steps:
(1) L-Trp is carried out to Pictet-Spengler condensation with formaldehyde under dilute sulphuric acid catalysis, obtain 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
(2), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid carries out Boc protection and obtains N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid under the existence of triethylamine;
(3), by N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and the coupling of methyl esters protected amino acid, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester;
(4) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester is sloughed to methyl esters protecting group under the NaOH aqueous solution exists, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(5) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid is sloughed to Boc protecting group under HCl and EtOAc existence, obtain N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(6) by N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(7), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid,
Wherein described in step (3), (4), (5) and (6), amino acid is selected from glycine, ALANINE, ILE, L-Leu, Valine, L-Methionine, L-Phe, TYR, L-threonine, Serine, L-Trp, L-Aspartic acid or Pidolidone.
This preparation method can summarize by the synthetic route of Fig. 1.
The 3rd technical problem that the present invention will solve has been to provide the application of described compound in preparing antithrombotic reagent.A composition of preparing antithrombotic reagent, is comprised of the described compound 6a-n of significant quantity and pharmaceutically acceptable carrier or auxiliary material, and the content of wherein said the compounds of this invention is the 0.1%-99% of described pharmaceutical composition gross weight, preferably 10-60%.For a preparation method for antithrombotic pharmaceutical composition, after the compound 6a-n of significant quantity is coordinated with pharmaceutically acceptable carrier or thinner, by the formulation method of this area routine, be prepared into any one suitable pharmaceutical composition.Aforementioned pharmaceutical compositions can be used for preparing antithrombotic reagent.For an antithrombotic pharmaceutical preparation, by the mixture of compound 6a-n and pharmaceutically acceptable excipient or additional dose, make tablet, capsule, pulvis, granule, lozenge or oral liquid.
The 4th technical problem to be solved by this invention is to adopt arteria carotis communis-vein extracorporeal circulation bypass thread model to evaluate the platelet aggregation inhibitory activity of compound of the present invention.
Accompanying drawing explanation
Fig. 1 is the synthetic route chart of the compounds of this invention 6a-n.
I) formaldehyde, sulfuric acid; Ii) Boc 2o, DMF; Iii) L-amino acid methyl ester, DCC; Iv) NaOH, THF; V) 4N hydrochloric ethyl acetate; Vi) D-Glucose, NaBH 3cN, in 6a, AA represents alanine residue; In 6b, AA represents glycine residue; In 6c, AA represents phenylalanine residue; In 6d, AA represents tryptophan residue; In 6e, AA represents leucine residue; In 6f, AA represents α-amino-isovaleric acid residue; In 6g, AA represents asparagicacid residue; In 6h, AA represents tyrosine residues; In 6i, AA represents Isoleucine residue; In 6j, AA represents methionine residue; In 6k, AA represents threonine residues; In 6l, AA represents glutaminic acid residue; In 6m, AA represents serine residue; AA representation hydroxy in 6n.
Embodiment
Following examples and testing data, be described in more detail with other technical characterictic and advantage the present invention is above-mentioned.
Embodiment 13S-1, the preparation of 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (1)
200mL water is placed in to the round-bottomed flask of 250mL, slowly adds 0.2mL 98% vitriol oil.In the dilute sulfuric acid aqueous solution obtaining, add 5.0g (24.5mmol) L-Trp sonic oscillation to L-Trp to dissolve completely.Toward adding 8mL concentration in the solution obtaining, be 38% formaldehyde solution.Reaction solution stirring at room 6h, TLC (methylene dichloride: methyl alcohol=5: 1) show that L-Trp disappears, termination reaction.In reaction soln, slowly drip strong aqua, adjust reacting liquid pH value to 6-7, have a large amount of colorless solid Precipitations, standing 2h.Decompression leaches the precipitation of generation and with a small amount of washing, by the solid drying leaching, obtains 4.8g (90.7%) title compound, is colorless solid.Mp?280-282℃；ESI-MS(m/z)217[M+H] +；Anal.Calcd?forC 12H 12N 2O 2：C，66.65；H，5.59；N，12.96。
Embodiment 2N-Boc-3S-1, the preparation of 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (2)
Be suspended in 15mL DMF 1 of 1.1g (5.0mmol), under stirring at room, add 1.4mL triethylamine.After 30min, ice bath adds the Boc-N of 1.1g (7.7mmol) under stirring 3, stirring reaction 72h under room temperature.Reaction finishes with watch-glass, reaction solution to be dried to obtain to yellow solid naturally afterwards.After being dissolved by appropriate ethyl acetate, by (20ml*3) saturated NaCl solution extraction, wash.Then use anhydrous Na SO 4dry 1h, filters, and is evaporated to dry.Residue CHCl 3after crystallization, obtaining title compound 1.2g (76%), is faint yellow solid.Mp?165-170℃；ESI-MS(m/z)317[M+H] +；Anal.Calcd?for?C 17H 20N 2O 4：C，64.54；H，6.37；N，8.86.
The preparation of embodiment 3N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ALANINE methyl esters (3a)
2 of 2.0g under ice bath (6.33mmol) is dissolved in the anhydrous THF of 30mL, adds 1.2g (8.9mmol) HOBt.Stir after 10min, in reaction solution, add 1.75g (8.5mmol) dicyclohexylcarbodiimide (DCC).0.97g (6.96mmol) HCl-L-AlaOMe is added in reaction solution.With N methylmorpholine, adjust reaction solution pH 8-9.Room temperature reaction 3h after continuation reaction 2h under ice bath.Remove by filter and remove dicyclohexylurea (DCU) (DCU), be evaporated to after dry and use acetic acid ethyl dissolution.Gained solution is used respectively 5%NaHCO 3solution, saturated NaCl solution, 5%KHSO 4solution, saturated NaCl solution, saturated NaHCO 3solution, each extraction of saturated NaCl solution are washed three times.Ethyl acetate layer anhydrous Na 2sO 4dry, filter, be evaporated to dry.Making 2.44g (96%) target compound, is colorless solid.Mp?144?146℃；ESI/MS?402[M+H] +；IR(KBr)：3451，3011，2949，2847，1730，1604，1450，1392，1370，1066，897cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝9.89(s，1H)，7.98(s，1H)，7.32(t，J＝7.5Hz，1H)，7.23(t，J＝7.8Hz，1H)，6.97(d，J＝7.8Hz，1H)，6.81(d，J＝7.5Hz，1H)，4.88(d，J＝5.2Hz，1H)，4.59(m，J＝5.5Hz，1H)，4.25(dd，J＝10.0Hz，J＝4.7Hz，1H)，4.17(dd，J＝10.1Hz，J＝3.5Hz，1H)，3.64(s，3H)，2.94(d，J＝10.1Hz，2H)，1.55(d，J＝5.2Hz，3H)，1.43(s，9H).
Embodiment 4N-[(3S)-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-glycine methyl ester (3b)
According to the operation of embodiment 3, make 2.50g (97%) title compound, be colorless solid; Mp 133-135 ℃; ESI/MS 388[M+H] +.IR (KBr): 3448,3010,2945,2843,1732,1600,1453,1390,1371,1062,899cm -1; 1h-NMR (BHSC-500, DMSO-d 6): δ/ppm=9.93 (s, 1H), 8.02 (s, 1H), 7.30 (t, J=7.5Hz, 1H), 7.20 (t, J=7.6Hz, 1H), 6.95 (d, J=7.6Hz, 1H), 6.83 (d, J=7.6Hz, 1H), 4.89 (d, J=5.4Hz, 1H), 4.22 (dd, J=10.2Hz, J=4.5Hz, 1H), 4.18 (s, 2H), 4.19 (dd, J=10.2Hz, J=3.7Hz, 1H), 3.66 (s, 3H), 2.95 (d, J=10.1Hz, 2H), 1.45 (s, 9H).
Embodiment 5N-[(3S)-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-Phe methyl esters (3c) is according to the operation of embodiment 3, makes 2.71g (98%) title compound, is colorless solid, Mp 150-152 ℃, ESI/MS 478[M+H] +, IR (KBr): 3446,3205,3006,2948,2847,1731,1645,1603,1451,1392,1370,1069,904cm -1, 1H-NMR (BHSC-500, DMSO-d 6): δ/ppm=9.92 (s, 1H), 7.97 (s, 1H), 7.31 (t, J=7.5Hz, 1H), 7.28 (t, J=7.9Hz, 2H), 7.19 (t, J=7.6Hz, 1H), 7.14 (d, J=7.6Hz, 2H), 7.02 (t, J=7.6Hz, 1H), 6.96 (d, J=7.8Hz, 1H), 6.80 (d, J=7.6Hz, 1H), 4.93 (d, J=5.4Hz, 1H), 4.82 (t, J=5.4Hz, 1H), 4.27 (dd, J=10.2Hz, J=4.5Hz, 1H), 4.18 (dd, J=10.2Hz, J=3.4Hz, 1H), 3.62 (s, 3H), 3.17 (d, J=5.4Hz, 2H), 2.93 (d, J=10.2Hz, 2H), 1.48 (s, 9H).
The preparation of embodiment 6N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Trp methyl esters (3d)
According to the operation of embodiment 3, make 2.45g (93%) title compound, be faint yellow solid, Mp161-163 ℃, ESI/MS 517[M+H] +, IR (KBr): 3442,3204,3000,2948,2839,1729,1642,1604,1448,1391,1372,1062,900cm -1, 1h-NMR (BHSC-500, DMSO-d 6): δ/ppm=9.87 (s, 1H), 9.86 (s, 1H), 8.09 (s, 1H), 7.32 (t, J=7.5Hz, 1H), 7.30 (t, J=7.4Hz, 1H), 7.12 (d, J=7.8Hz, 1H), 7.11 (t, J=7.8Hz, 1H), 7.10 (d, J=7.6Hz, 1H), 7.09 (t, J=7.8Hz, 1H), 7.04 (d, J=7.6Hz, 1H), 6.98 (d, J=7.5Hz, 1H), 6.83 (s, 1H), 4.94 (d, J=5.4Hz, 1H), 4.76 (t, J=5.3Hz, 1H), 4.29 (d, J=5.2Hz, 2H), 3.64 (s, 3H), 3.19 (d, J=5.4Hz, 2H), 2.95 (d, J=6.4Hz, 2H), 1.49 (s, 9H).
The preparation of embodiment 7N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Leu methyl esters (3e)
According to the operation of embodiment 3, make 2.35g (93%) title compound, be colorless solid; Mp 173-175 ℃; ESI/MS 444[M+H] +; Anal.Calcd for C 24h 33n 3o 5: C, 64.99; H, 7.50; N, 9.47.
The preparation of embodiment 8N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Valine methyl esters (3f)
According to the operation of embodiment 3, make 2.46g (95%) title compound, be colorless solid; Mp 138-140 ℃; ESI/MS 430[M+H] +.IR (KBr): 3443,3202,3001,2951,2845,1729,1648,1602,1450,1392,1370,1067,902cm -1; 1h-NMR (BHSC-500, DMSO-d 6): δ/ppm=10.04 (s, 1H), 7.96 (s, 1H), 7.29 (t, J=7.4Hz, 1H), 7.21 (t, J=7.7Hz, 1H), 7.00 (d, J=7.7Hz, 1H), 6.89 (d, J=7.4Hz, 1H), 4.84 (t, J=5.4Hz, 1H), 4.42 (d, J=5.4Hz, 1H), 4.22 (dd, J=10.2Hz, J=4.5Hz, 1H), 4.03 (dd, J=10.2Hz, J=3.7Hz, 1H), 3.62 (s, 3H), 3.10 (m, J=5.4Hz, 1H), 2.95 (d, J=6.7Hz, 2H), 1.47 (s, 9H), 1.05 (d, J=5.4Hz, 6H).
The preparation of embodiment 9N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Aspartic acid methyl esters (3g)
According to the operation of embodiment 3, make 2.23g (90%) title compound, be colorless solid; Mp 158-160 ℃; ESI/MS 460[M+H] +; IR (KBr): 3441,3210,3004,2955,2841,1732,1643,1604,1453,1390,1371,1061,903cm -1; 1h-NMR (BHSC-500, DMSO-d 6): δ/ppm=10.05 (s, 1H), 8.05 (s, 1H), 7.37 (t, J=7.4Hz, 1H), 7.25 (t, J=7.4Hz, 1H), 7.00 (d, J=7. δ Hz, 1H), 6.95 (d, J=7.4Hz, 1H), 4.92 (d, J=5.5Hz, 1H), 4.77 (t, J=5.5Hz, 1H), 4.24 (d, J=5.6Hz, 2H), 3.62 (s, 3H), 3.58 (s, 3H), 2.91 (d, J=5.2Hz, 2H), 2.85 (d, J=5.4Hz, 2H), 1.49 (s, 9H).
The preparation of embodiment 10N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-TYR methyl esters (3h)
According to the operation of embodiment 3, make 2.31g (93%) title compound, be faint yellow solid; Mp 143-145 ℃; ESI/MS 494[M+H] +; IR (KBr): 3439,3203,3001,2955,2847,1732,1644,1601,1453,1391,1372,1062,903cm -1; 1h-NMR (BHSC-500, DMSO-d 6): δ/ppm=9.99 (s, 1H), 8.02 (s, 1H), 7.37 (t, J=7.6Hz, 1H), 7.22 (t, J=7.7Hz, 1H), 7.15 (d, J=7.5Hz, 2H), 7.02 (d, J=7.5Hz, 1H), 6.96 (d, J=7.7Hz, 1H), 6.91 (d, J=7.5Hz, 2H), 4.98 (s, 1H), 4.93 (d, J=5.4Hz, 1H), 4.80 (t, J=5.6Hz, 1H), 4.29 (m, J=5.2Hz, 2H), 3.64 (s, 3H), 3.15 (d, J=5.2Hz, 2H), 2.97 (d, J=5.0Hz, 2H), 1.49 (s, 9H).
The preparation of embodiment 11N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ILE methyl esters (3i)
According to the operation of embodiment 3, make 2.21g (92%) title compound, be colorless solid.Mp?168?170℃；ESI/MS?444[M+H] +.
The preparation of embodiment 12N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Methionine methyl esters (3j)
According to the operation of embodiment 3, making 2.63g (97%) title compound, is colorless solid.Mp?159-161℃；ESI/MS?462[M+H] +；IR(KBr)：3441，3203，3004，2953，2847，1732，1641，1603，1454，1390，1372，1061，900cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝10.04(s，1H)，7.97(s，1H)，7.32(t，J＝7.5Hz，1H)，7.22(t，J＝7.8Hz，1H)，6.99(d，J＝7.8Hz，1H)，6.81(d，J＝7.5Hz，1H)，4.86(t，J＝5.3Hz，1H)，4.45(t，J＝5.5Hz，1H)，4.28(d，J＝5.1Hz，2H)，3.68(s，3H)，2.93(d，J＝5.3Hz，2H)，2.42(t，J＝5.4Hz，2H)，2.28(d，J＝5.6Hz，2H)，2.10(s，3H)，1.44(s，9H).
The preparation of embodiment 13N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-threonine methyl esters (3k)
According to the operation of embodiment 3, making 2.23g (92%) title compound, is colorless solid.Mp?140-142℃；ESI/MS?432[M+H] +；IR(KBr)：3437，3200，3002，2951，2844，1735，1649，1600，1450，1392，1370，1065，901cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝9.98(s，1H)，7.87(s，1H)，7.34(t，J＝7.4Hz，1H)，7.25(t，J＝7.6Hz，1H)，6.95(d，J＝7.6Hz，1H)，6.72(d，J＝7.4Hz，1H)，4.87(t，J＝5.4Hz，1H)，4.67(m，J＝5.6Hz，1H)，4.48(t，J＝5.6Hz，1H)，3.99(m，J＝5.2Hz，2H)，3.65(s，3H)，2.97(d，J＝5.7Hz，2H)，2.19(d，J＝3.7Hz，1H)，1.47(s，9H)，1.19(d，J＝5.6Hz，3H).
The preparation of embodiment 14N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Pidolidone methyl esters (3l)
According to the operation of embodiment 3, making 2.37g (93%) title compound, is faint yellow solid.Mp?154-156℃；ESI/MS?474[M+H] +；IR(KBr)：3441，3203，3000，2944，2831，1731，1645，1604，1455，1390，1372，1067，903cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝9.89(s，1H)，8.04(s，1H)，7.39(t，J＝7.6Hz，1H)，7.28(t，J＝7.6Hz，1H)，7.01(d，J＝7.7Hz，1H)，6.84(d，J＝7.6Hz，1H)，4.90(d，J＝5.4Hz，1H)，4.43(t，J＝5.6Hz，1H)，4.22(d，J＝5.5Hz，2H)，3.66(s，3H)，3.64(s，3H)，2.96(d，J＝5.4Hz，2H)，2.28(t，J＝5.6Hz，2H)，2.24(t，J＝5.7Hz，2H)，1.43(s，9H).
The preparation of embodiment 15N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Serine methyl esters (3m)
According to the operation of embodiment 3, making 2.35g (92%) title compound, is colorless solid.Mp?139-141℃；ESI/MS?418[M+H] +.IR(KBr)：3442，3200，3001，2952，2845，1730，1644，1606，1455，1392，1370，1067，900cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝9.95(s，1H)，7.97(s，1H)，7.29(t，J＝7.6Hz，1H)，7.22(t，J＝7.9Hz，1H)，6.99(d，J＝7.9Hz，1H)，6.83(t，J＝7.6Hz，1H)，4.87(d，J＝5.4Hz，1H)，4.52(t，J＝5.6Hz，1H)，4.19(d，J＝5.2Hz，2H)，4.13(d，J＝5.6Hz，2H)，3.63(s，3H)，2.95(d，J＝5.6Hz，1H)，2.92(d，J＝5.6Hz，1H)，2.28(s，1H)，1.45(s，9H).
The preparation of embodiment 16N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-the third amino acid (4a)
The N-of 1.0g (2.5mmol) under 0 ℃ of condition of ice bath (N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ALANINE methyl esters is dissolved in the tetrahydrofuran (THF) of 6ml, and the NaOH of 0.45g (11.34mmol) adds in reaction solution.Reaction solution reacts 70min under ice bath.Reaction finishes rear concentrating under reduced pressure except desolventizing, and reaction residues is dissolved in 30ml water, by ether extraction, washes 3 times. the saturated KHSO of water 4adjusting pH is 2, by ethyl acetate (20ml*3) extraction, gained ethyl acetate layer anhydrous Na 2sO 4dry, filter, be evaporated to dry, obtain 0.76g (79%) target compound, be faint yellow solid.Mp?169-171℃；ESI/MS?388[M+H] +.IR(KBr)：3439，3234，3215，3000，2952，2847，1732，1645，1602，1453，1390，1373，1061，904cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝11.02(s，1H)，9.95(s，1H)，7.98(s，1H)，7.29(t，J＝7.6Hz，1H)，7.17(t，J＝7.9Hz，1H)，7.03(d，J＝7.9Hz，1H)，6.94(d，J＝7.6Hz，1H)，4.93(d，J＝5.4Hz，1H)，4.66(m，J＝5.4Hz，1H)，4.27(d，J＝6.3Hz，2H)，2.97(d，J＝9.5Hz，2H)，1.48(d，J＝5.4Hz，3H)，1.45(s，9H).
Embodiment 17N-[(3S)-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-glycine (4b)
According to the operation of embodiment 16, make 0.89g (95%) title compound, be faint yellow solid.Mp148-150℃；ESI/MS：374[M+H] +.IR(KBr)：3444，3230，3008，2942，2841，1730，1602，1455，1391，1370，1064，898cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝11.03(s，1H)，9.98(s，1H)，8.01(s，1H)，7.29(t，J＝7.5Hz，1H)，7.18(t，J＝7.6Hz，1H)，6.97(d，J＝7.6Hz，1H)，6.85(d，J＝7.6Hz，1H)，4.90(d，J＝5.4Hz，1H)，4.24(dd，J＝10.2Hz，J＝4.5Hz，1H)，4.17(s，2H)，4.16(dd，J＝10.2Hz，J＝3.7Hz，1H)，2.93(d，J＝10.0Hz，2H)，1.46(s，9H).
Embodiment 18N-[(3S)-N-Boc-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-Phe (4c)
According to the operation of embodiment 16, make 1.09g (94%) title compound, be faint yellow solid.Mp129-131 ℃, ESI/MS:464[M+H] +.IR (KBr): 3446,3205,3006,2948,2847,1731,1645,1603,1451,1392,1370,1069,904cm -1, 1h-NMR (DMSO-d 6): δ/ppm=10.94 (s, 1H), 9.93 (s, 1H), 7.97 (s, 1H), 7.30 (t, J=7.3Hz, 1H), 7.26 (t, J=7.4Hz, 2H), 7.17 (t, J=7.6Hz, 1H), 7.15 (d, J=7.4Hz, 2H), 7.10 (t, J=7.4Hz, 1H), 7.02 (t, J=7.4Hz, 1H), 6.97 (d, J=7.4Hz, 1H), 4.93 (d, J=5.2Hz, 1H), 4.78 (t, J=5.2Hz, 1H), 4.27 (d, J=5.2Hz, 2H), 3.07 (d, J=4.5Hz, 2H), 2.98 (d, J=5.2Hz, 2H), 1.49 (s, 9H). embodiment 19N-(N-Boc-3S-1, 2, 3, 4-tetrahydro-beta-carboline-3-carboxylic acid) preparation of-L-Trp (4d) is according to the operation of embodiment 16, make 0.88g (70%) title compound, for faint yellow solid.Mp?158-160℃；ESI/MS：503[M+H] +；IR(KBr)：3445，3238，3217，3008，2951，2842，1728，1641，1600，1450，1393，1370，1058，897cm -1； 1H-NMR(DMSO-d 6)：δ/ppm＝10.98(s，1H)，9.87(s，1H)，9.84(s，1H)，8.01(s，1H)，7.30(t，J＝7.1Hz，1H)，7.16(t，J＝7.1Hz，1H)，7.14(t，J＝7.4Hz，1H)，7.12(t，J＝7.2Hz，1H)，7.06(d，J＝7.4Hz，1H)，7.05(d，J＝7.2Hz，1H)，6.99(d，J＝7.1Hz，1H)，6.96(d，J＝7.1Hz，1H)，6.82(s，1H)，4.89(t，J＝5.2Hz，1H)，4.84(t，J＝5.1Hz，1H)，4.25(m，J＝5.0Hz，2H)，2.91(d，J＝5.0Hz，2H)，2.88(d，J＝5.1Hz，2H)，1.53(s，9H).
The preparation of embodiment 20N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Leu (4e)
According to the operation of embodiment 16, make 0.82g (76%) title compound, be faint yellow solid.Mp?161-163℃；ESI/MS：430[M+H] +；Anal.Calcd?for?C 23H 31N 3O 5：C，64.32；H，7.27；N，9.78.
The preparation of embodiment 21N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Valine (4f)
According to the operation of embodiment 16, make 0.74g (71%) title compound, be faint yellow solid.Mp?148-150℃；ESI/MS：416[M+H] +；IR(KBr)：3441，3236，3212，3002，2951，2845，1731，1643，1600，1450，1392，1374，1060，900cm -1； 1H-NMR(DMSO-d 6)：δ/ppm＝10.94(s，1H)，9.23(s，1H)，7.96(s，1H)，7.29(t，J＝7.5Hz，1H)，7.18(t，J＝7.6Hz，1H)，7.06(d，J＝7.4Hz，1H)，6.97(d，J＝7.5Hz，1H)，4.95(d，J＝5.2Hz，1H)，4.48(d，J＝5.2Hz，1H)，4.27(d，J＝5.1Hz，2H)，2.92(d，J＝5.5Hz，2H)，2.78(m，J＝4.5Hz，1H)，1.49(s，9H)，1.25(d，J＝5.6Hz，6H).
The preparation of embodiment 22N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Aspartic acid (4g)
According to the operation of embodiment 16, make 0.78g (72%) title compound, be faint yellow solid.Mp?141-143℃；ESI/MS：432[M+H] +；IR(KBr)：3442，3236，3217，3005，2950，2843，1728，1642，1600，1450，1392，1370，1058，896cm -1； 1H-NMR(DMSO-d 6)：δ/ppm＝10.99(s，2H)，9.94(s，1H)，7.98(s，1H)，7.26(t，J＝7.1Hz，1H)，7.11(t，J＝7.1Hz，1H)，7.05(d，J＝7.2Hz，1H)，6.94(d，J＝7.2Hz，1H)，4.87(t，J＝5.2Hz，1H)，4.76(t，J＝5.3Hz，1H)，4.20(m，J＝4.8Hz，2H)，2.89(d，J＝5.2Hz，2H)，2.66(d，J＝5.2Hz，2H)，1.47(s，9H).
The preparation of embodiment 23N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-TYR (4h)
According to the operation of embodiment 16, make 0.80g (67%) title compound, be faint yellow solid.Mp?147-149℃；ESI/MS：480[M+H] +；IR(KBr)：3441，3236，3217，3004，2955，2846，1731，1647，1600，1450，1392，1371，1058，899cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝10.97(s，1H)，9.60(s，1H)，8.15(s，1H)，7.32(t，J＝7.2Hz，1H)，7.14(t，J＝7.4Hz，1H)，7.01(d，J＝7.2Hz，1H)，6.96(d，J＝7.2Hz，1H)，6.94(d，J＝7.5Hz，2H)，6.88(d，J＝7.2Hz，2H)，5.03(s，1H)，4.94(d，J＝5.2Hz，1H)，4.84(d，J＝5.3Hz，1H)，4.27(d，J＝5.2Hz，2H)，3.07(m，J＝3.4Hz，2H)，2.92(d，J＝4.5Hz，2H)，1.48(s，9H).
The preparation of embodiment 24N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ILE (4i)
According to the operation of embodiment 16, make 0.82g (76%) title compound, be faint yellow solid.Mp?139-141℃；ESI/MS：430[M+H] +.
The preparation of embodiment 25N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Methionine (4j)
According to the operation of embodiment 16, make 0.80g (72%) title compound, be faint yellow solid.Mp?148-150℃；ESI/MS：448[M+H] +；IR(KBr)：3436，3232，3213，3007，2953，2849，1735，1648，1600，1450，1393，1375，1055，897cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝11.01(s，1H)，9.97(s，1H)，8.01(s，1H)，7.33(t，J＝7.0Hz，1H)，7.18(t，J＝7.5Hz，1H)，7.05(d，J＝7.5Hz，1H)，6.95(t，J＝7.0Hz，1H)，4.44(t，J＝5.5Hz，1H)，4.25(m，J＝5.2Hz，1H)，4.23(m，J＝5.0Hz，2H)，2.89(d，J＝4.4Hz，2H)，2.46(t，J＝5.4Hz，2H)，2.16(m，J＝5.6Hz，2H)，2.09(s，3H)，1.50(s，9H).
The preparation of embodiment 26N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-threonine (4k)
According to the operation of embodiment 16, make 0.79g (78%) title compound, be faint yellow solid.Mp?143-145℃；ESI/MS：405[M+H] +；IR(KBr)：3444，3235，3217，3005，2950，2843，1730，1641，1600，1450，1389，1370，1055，896cm -1； 1H?NMR(DMSO-d 6)：δ/ppm＝10.97(s，1H)，8.92(s，1H)，7.95(s，1H)，7.29(t，J＝7.2Hz，1H)，7.15(t，J＝7.4Hz，1H)，7.05(d，J＝7.4Hz，1H)，6.98(d，J＝7.2Hz，1H)，4.89(d，J＝5.3Hz，1H)，4.46(d，J＝5.4Hz，1H)，4.37(m，J＝5.1Hz，1H)，4.27(d，J＝4.8Hz，2H)，2.95(d，J＝5.5Hz，2H)，2.16(s，1H)，1.48(s，9H)，1.26(d，J＝5.2Hz，3H).
The preparation of embodiment 27N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Pidolidone (4l)
According to the operation of embodiment 16, make 0.85g (76%) title compound, be faint yellow solid.Mp?160-162℃；ESI/MS：446[M+H] +；IR(KBr)：3444，3231，3212，3008，2954，2843，1730，1642，1600，1450，1391，1371，1058，900cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝11.02(s，2H)，9.87(s，1H)，8.11(s，1H)，7.28(t，J＝7.2Hz，1H)，7.14(t，J＝7.2Hz，1H)，7.06(d，J＝7.4Hz，1H)，6.97(t，J＝7.2Hz，1H)，4.90(t，J＝5.1Hz，1H)，4.42(t，J＝5.4Hz，1H)，4.21(d，J＝5.1Hz，2H)，2.87(d，J＝5.3Hz，2H)，2.22(t，J＝5.2Hz，2H)，2.08(t，J＝5.2Hz，2H)，1.47(s，9H).
The preparation of embodiment 28N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Serine (4m)
According to the operation of embodiment 16, make 0.82g (84%) title compound, be faint yellow solid.Mp?136-138℃；ESI/MS：390[M+H] +；IR(KBr)：3437，3236，3213，3005，2950，2846，1730，1641，1600，1451，1392，1370，1058，897cm -1； 1H-NMR(DMSO-d 6)：δ/ppm＝10.92(s，1H)，9.93(s，1H)，7.97(s，1H)，7.30(t，J＝7.3Hz，1H)，7.19(t，J＝7.6Hz，1H)，7.06(d，J＝7.6Hz，1H)，6.98(d，J＝7.3Hz，1H)，4.92(d，J＝5.5Hz，1H)，4.46(t，J＝5.2Hz，1H)，4.27(d，J＝5.0Hz，2H)，4.06(d，J＝5.1Hz，2H)，2.93(d，J＝5.4Hz，2H)，2.07(s，1H)，1.51(s，9H).
The preparation of embodiment 29N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-the third amino acid (5a)
Under condition of ice bath, N-(the N-Boc-3S-1 of 0.7g (1.85mmol), 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-the third amino acid is dissolved in 10mL hydrochloric ethyl acetate (4mol/L), react ice bath and stir lower reaction 1h, after reaction finishes rear decompressing and extracting, residue is dissolved in ethyl acetate, and decompressing and extracting is removed de-chlorine hydride 3 times repeatedly.The residue obtaining obtains 0.50g (94%) target product with methanol/ether recrystallization, is faint yellow solid.Mp?167-169℃；ESI/MS：288[M+H] +；[α] D 25＝-80(c＝0.39，CHCl 3/CH3OH，1∶1，v/v)；IR(KBr)：3439，3234，3215，3000，2952，2847，1732，1645，1602，1453，1061，904cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.86(s，1H)，10.00(s，1H)，9.96(s，1H)，8.02(s，1H)，7.31(t，J＝6.6Hz，1H)，7.18(t，J＝7.8Hz，1H)，6.87(d，J＝7.9Hz，1H)，6.81(d，J＝7.6Hz，1H)，4.65(m，J＝5.4Hz，1H)，3.95(m，J＝5.4Hz，1H)，3.91(d，J＝5.3Hz，2H)，2.81(d，J＝5.6Hz，2H)，1.48(d，J＝5.6Hz，3H).
Embodiment 30N-[(3S)-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-glycine (5b)
According to the operation of embodiment 29, make 0.47g (94%) title compound, be faint yellow solid.Mp?181-183℃；ESI/MS：274[M+H] +；[α] D 25＝-104(c＝0.38，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3434，3230，3213，3004，2950，2844，1730，1646，1601，1455，1062，900cm -1； 1H-NMR(BHSC-500，DMSO-d 6)：δ/ppm＝11.05(s，1H)，9.94(s，1H)，8.00(s，1H)，7.27(t，J＝7.6Hz，1H)，7.19(t，J＝7.6Hz，1H)，6.95(d，J＝7.6Hz，1H)，6.87(d，J＝7.6Hz，1H)，4.16(s，2H)，4.08(dd，J＝5.4Hz，J＝4.5Hz，1H)，3.89(d，J＝5.3Hz，2H)，2.83(d，J＝5.4Hz，2H)，2.05(s，1H).
The preparation of embodiment 31N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Phe (5c)
According to the operation of embodiment 29, make 0.64g (95%) title compound, be faint yellow solid.Mp?177-179℃；ESI/MS：364[M+H] +；[α] D 25＝-30(c＝0.41，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3435，3231，3213，3003，2950，2844，1730，1642，1600，1450，1060，901cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.33(s，1H)，10.05(s，1H)，9.93(s，1H)，8.01(s，1H)，7.33(t，J＝6.8Hz，1H)，7.30(t，J＝6.4Hz，2H)，7.20(t，J＝7.6Hz，1H)，7.17(d，J＝7.8Hz，2H)，7.10(t，J＝6.8Hz，1H)，7.02(d，J＝7.6Hz，1H)，6.89(d，J＝7.4Hz，1H)，4.86(t，J＝5.4Hz，1H)，4.00(m，J＝5.4Hz，1H)，3.88(d，J＝6.2Hz，2H)，3.07(d，J＝6.5Hz，2H)，2.81(d，J＝6.2Hz，2H).
The preparation of embodiment 32N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Trp (5d)
According to the operation of embodiment 29, make 0.64g (86%) title compound, be faint yellow solid.Mp?170-172℃；ESI/MS：403[M+H] +；[α] D 25＝-64(c＝0.39，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3445，3238，3217，3008，2951，2842，1728，1641，1600，1450，1058，897cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.52(s，1H)，11.15(s，1H)，10.97(s，1H)，10.21(s，1H)，8.02(s，1H)，7.31(t，J＝7.2Hz，1H)，7.18(t，J＝7.3Hz，1H)，7.14(t，J＝7.5Hz，1H)，7.12(t，J＝7.5Hz，1H)，7.12(d，J＝7.5Hz，1H)，7.10(d，J＝7.5Hz，1H)，7.04(d，J＝7.5Hz，1H)，6.98(d，J＝7.2Hz，1H)，6.85(s，1H)，4.87(t，J＝5.5Hz，1H)，3.95(t，J＝5.5Hz，1H)，3.86(d，J＝5.4Hz，2H)，2.94(d，J＝5.4Hz，2H)，2.79(d，J＝5.5Hz，2H).
The preparation of embodiment 33N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Leu (5e)
According to the operation of embodiment 29, make 0.48g (79%) title compound, be yellow solid.Mp?185-187℃；ESI/MS：330[M+H] +.
The preparation of embodiment 34N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Valine (5f)
According to the operation of embodiment 29, make 0.55g (95%) title compound, be yellow solid.Mp?169-171℃；ESI/MS：316[M+H] +；[α] D 25＝-70(c＝0.38，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3441，3236，3212，3002，2951，2845，1731，1643，1600，1450，1060，900cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.68(s，1H)，10.19(s，1H)，9.88(s，1H)，8.03(s，1H)，7.32(t，J＝7.5Hz，1H)，7.17(t，J＝7.8Hz，1H)，7.05(d，J＝7.4Hz，1H)，6.98(d，J＝7.4Hz，1H)，4.48(t，J＝5.2Hz，1H)，3.94(t，J＝5.2Hz，1H)，3.90(d，J＝5.2Hz，2H)，2.82(d，J＝5.4Hz，2H)，2.80(m，J＝6.9Hz，1H)，1.06(d，J＝6.9Hz，6H).
The preparation of embodiment 35N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Aspartic acid (5g)
According to the operation of embodiment 29, make 0.56g (91%) title compound, be faint yellow solid.Mp?179-181℃；ESI/MS：332[M+H] +；[α] D 25＝-12(c＝0.39，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3442，3236，3217，3005，2950，2843，1728，1642，1600，1450，1058，896cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.42(s，1H)，11.40(s，1H)，10.32(s，1H)，9.99(s，1H)，8.05(d，J＝5.5Hz，1H)，7.31(d，J＝7.3Hz，1H)，7.16(d，J＝7.4Hz，1H)，7.11(t，J＝7.4Hz，1H)，6.95(t，J＝7.3Hz，1H)，4.77(t，J＝5.5Hz，1H)，3.96(t，J＝5.4Hz，1H)，3.87(d，J＝5.5Hz，2H)，2.81(d，J＝5.2Hz，2H)，2.73(d，J＝5.3Hz，2H).
The preparation of embodiment 36N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-TYR (5h)
According to the operation of embodiment 29, make 0.59g (84%) title compound, be faint yellow solid.Mp?171-173℃；ESI/MS：380[M+H] +；[α] D 25＝-88(c＝0.36，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3441，3236，3217，3004，2955，2846，1731，1647，1600，1450，1058，899cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.44(s，1H)，10.19(s，1H)，9.96(s，1H)，8.05(s，1H)，7.29(t，J＝7.5Hz，1H)，7.18(t，J＝8.1Hz，1H)，7.01(d，J＝8.1Hz，2H)，7.00(d，J＝7.2Hz，2H)，6.97(d，J＝7.8Hz，1H)，6.70(d，J＝8.4Hz，2H)，5.02(s，1H)，4.85(t，J＝5.3Hz，1H)，3.97(t，J＝6.2Hz，1H)，3.87(d，J＝5.6Hz，2H)，3.06(d，J＝5.6Hz，2H)，2.78(d，J＝5.9Hz，2H).
The preparation of embodiment 37N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ILE (5i)
According to the operation of embodiment 29, make 0.51g (83%) title compound, be faint yellow solid.Mp?157-159℃；ESI/MS：330[M+H]+ .
The preparation of embodiment 38N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Methionine (5j)
According to the operation of embodiment 29, make 0.53g (83%) title compound, be faint yellow solid.Mp?186-189℃；ESI/MS：348[M+H] +；[α] D 25＝-86(c＝0.39，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3436，3232，3213，3007，2953，2849，1735，1648，1600，1450，1055，897cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.21(s，1H)，10.11(s，1H)，9.96(s，1H)，8.14(s，1H)，7.29(t，J＝7.8Hz，1H)，7.16(t，J＝7.8Hz，1H)，7.02(d，J＝7.5Hz，1H)，6.93(d，J＝7.8Hz，1H)，4.48(t，J＝5.5Hz，1H)，3.99(t，J＝5.4Hz，1H)，3.89(d，J＝6.5Hz，2H)，2.79(d，J＝6.4Hz，2H)，2.51(t，J＝5.7Hz，2H)，2.24(m，J＝5.5Hz，2H)，2.09(s，3H).
The preparation of embodiment 39N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-threonine (5k)
According to the operation of embodiment 29, make 0.54g (91%) title compound, be faint yellow solid.Mp?180-182℃；ESI/MS：318[M+H] +；[α] D 25＝-28(c＝0.36，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3444，3235，3217，3005，2950，2843，1730，1641，1600，1450，1055，896cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.42(s，1H)，10.23(s，1H)，9.89(s，1H)，8.05(s，1H)，7.30(t，J＝7.5Hz，1H)，7.18(t，J＝8.1Hz，1H)，7.10(d，J＝8.4Hz，1H)，7.00(d，J＝7.8Hz，1H)，4.52(d，J＝5.3Hz，1H)，4.37(m，J＝5.4Hz，1H)，3.96(d，J＝6.4Hz，1H)，3.86(d，J＝5.4Hz，2H)，2.80(d，J＝5.4Hz，2H)，2.17(s，1H)，1.26(d，J＝5.2Hz，3H).
The preparation of embodiment 40N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Pidolidone (5l)
According to the operation of embodiment 29, make 0.60g (94%) title compound, be faint yellow solid.Mp?186-189℃；ESI/MS：346[M+H] +；[α] D 25＝-66(c＝0.39，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3444，3231，3212，3008，2954，2843，1730，1642，1600，1450，1058，900cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.59(s，1H)，11.48(s，1H)，10.27(s，1H)，9.95(s，1H)，8.12(s，1H)，7.33(t，J＝7.8Hz，1H)，7.18(t，J＝7.8Hz，1H)，7.02(d，J＝7.5Hz，1H)，6.95(d，J＝7.5Hz，1H)，4.52(t，J＝5.4Hz，1H)，3.98(t，J＝5.5Hz，1H)，3.85(d，J＝6.5Hz，2H)，2.81(d，J＝5.1Hz，2H)，2.24(t，J＝5.1Hz，2H)，2.11(m，J＝5.5Hz，2H).
The preparation of embodiment 41N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Serine (5m)
According to the operation of embodiment 29, make 0.50g (89%) title compound, be faint yellow solid.Mp?162-164℃；ESI/MS：304[M+H] +；[α] D 25＝-70(c＝0.36，CHCl 3/CH 3OH，1∶1，v/v)；IR(KBr)：3437，3236，3213，3005，2950，2846，1730，1641，1600，1451，1058，897cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝11.50(s，1H)，10.19(s，1H)，9.96(s，1H)，8.10(s，1H)，7.31(t，J＝7.5Hz，1H)，7.18(t，J＝7.8Hz，1H)，7.09(d，J＝7.8Hz，1H)，6.89(d，J＝7.5Hz，1H)，4.59(t，J＝5.1Hz，1H)，4.04(d，J＝5.1Hz，2H)，3.96(t，J＝5.1Hz，1H)，3.81(d，J＝5.9Hz，2H)，2.78(d，J＝5.5Hz，2H)，2.30(s，1H).
The preparation of embodiment 42N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-the third amino acid (6a)
1.62g (5mmol) N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-the third amino acid is dissolved in 10ml methyl alcohol.5.00g (25mmol) Glucose-H 2o is dissolved in 10ml deionized water.Under stirring under room temperature, D/W is added in reaction solution.Add again sodium cyanoborohydride 1.53g (25mmol) in batches.Under stirring at room, react after 1h, reaction solution is placed in microwave reactor (400W, 70 ℃) and reacts 2h, reaction finishes rear standing to room temperature.Under condition of ice bath, drip concentrated hydrochloric acid regulator solution pH=2.5, adularescent solid is separated out, and suction filtration is removed white solid, after the concentrated remove portion water of filtrate decompression, adds dehydrated alcohol, and standing rear suction filtration is removed the white solid of separating out, and filtrate decompression is concentrated.By the upper strong acid cation exchange resin column of this filtrate, first with distilled water wash-out, remove unreacted sugar component, use again 3% N-methylmorpholine aqueous solution wash-out, collect product component, the water of removing in product component obtains yellow solid, recrystallization (alcohol-water), obtains 0.29g (13%) target compound, is faint yellow solid.Mp?159-161℃；ESI/MS?450[M-H] -.[α] D 25＝-16(c＝0.5，CH 3OH)；IR(KBr)：3293，2929，1568，1417，1336，1234，1082，874cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.75(s，1H)，7.98(s，1H)，7.40(d，J＝7.2Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.01(t，J＝7.9Hz，1H)，6.94(t，J＝7.6Hz，1H)，4.14(d，J＝15.9Hz，1H)，3.92-3.28(m，9H)，2.89(d，J＝4.5Hz，2H)，2.71(m，2H)，1.24(d，J＝5.4Hz，3H).
Embodiment 43N-[(3S)-N-pentahydroxy-hexyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-glycine (6b)
According to the operation of embodiment 42, make 0.76g (35%) title compound, be faint yellow solid.Mp?152-154℃；ESI/MS：436[M-H] -.[α] D 25＝-11(c＝0.5，CH 3OH)；IR(KBr)：3320，2930，1667，1602，1446，1397，1228，1077，882cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.68(s，1H)，8.16(s，1H)，7.40(d，J＝7.5Hz，1H)，7.27(d，J＝7.2Hz，1H)，7.01(t，J＝8.4Hz，1H)，6.95(t，J＝7.5Hz，1H)，4.23(d，J＝16.5Hz，1H)，3.89(m，8H)，3.04(t，J＝15.62H)，2.83(d，J＝11.7Hz，1H)，2.66(s，1H).
Embodiment 44N-[(3S)-N-pentahydroxy-hexyl-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid] preparation of-L-Phe (6c)
According to the operation of embodiment 42, make 0.36g (23%) title compound, be faint yellow solid.Mp?174-176℃；ESI/MS：526[M-H] -；[α] D 25＝-20(c＝0.5，CH 3OH)；IR(KBr)：3350，2932，1680，1558，1401，1337，1225，1080，901cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.67(s，1H)，8.38(s，1H)，7.38-7.14(m，7H)，7.03(t，J＝6.9Hz，1H)，6.95(t，J＝7.2Hz，1H)，4.44(s，1H)，3.87-2.88(m，14H).
The preparation of embodiment 45N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Trp (6d)
According to the operation of embodiment 42, make 0.32g (19%) title compound, be faint yellow solid.Mp?151-153℃；ESI/MS：565[M-H] -；[α] D 25＝-24(c＝0.5，CH 3OH)；IR(KBr)：3379，2929，1671，1604，1451，1398，1334，1229，1078，746cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.70(s，1H)，7.78(s，1H)，7.41-7.25(m，3H)，7.11-6.91(m，5H)，4.32(s，1H)，4.05-3.45(m，9H)，3.24-2.74(m，6H).
The preparation of embodiment 46N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Leu (6e)
According to the operation of embodiment 42, make 0.35g (28%) title compound, be faint yellow solid.Mp?183-185℃；ESI/MS：492[M-H] -；[α] D 25＝-9(c＝0.5，CH 3OH)；IR(KBr)：3367，2953，2843，1642，1593，1403，1232，1078，878cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.73(s，1H)，7.65(d，J＝8.1Hz，1H)，7.38(d，J＝7.5Hz，1H)，7.27(t，J＝7.8Hz，1H)，7.01(t，J＝6.9Hz，1H)，6.94(t，J＝7.5Hz，1H)，4.14-4.08(m，2H)，3.90-3.70(m，3H)，3.60(d，J＝9.6，1H)，3.54-3.45(m，4H)，2.91(d，J＝5.4Hz，2H)，1.64-1.41(m，3H)，0.848(s，6H).
The preparation of embodiment 47N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Valine (6f)
According to the operation of embodiment 42, make 0.36g (25%) title compound, be faint yellow solid.Mp?175-177℃；ESI/MS：478[M-H] -；[α] D 25＝-16(c＝0.5，CH 3OH)；IR(KBr)：3347，2963，2845，1657，1589，1402，1335，1225，1081，882cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.68(s，1H)，7.86(d，J＝8.7Hz，1H)，7.38(d，J＝7.8Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.02(d，J＝7.2Hz，1H)，6.94(d，J＝7.2Hz，1H)，4.24-3.43(m，10H)，3.02-2.66(m，3H)，2.10(m，1H)，0.86(d，J＝6.6Hz，6H).
The preparation of embodiment 48N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Aspartic acid (6g)
According to the operation of embodiment 42, make 0.32g (31%) title compound, be faint yellow solid.Mp?162-164℃；ESI/MS：494[M-H] -；[α] D 25＝-11(c＝0.5，CH 3OH)；IR(KBr)：3356，2930，1680，1615，1399，1227，1080，880cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.65(s，1H)，8.31(d，J＝8.4Hz，1H)，7.39(d，J＝7.5Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.02(t，J＝7.2Hz，1H)，6.95(t，J＝7.2Hz，1H)，4.50(dd，J＝12.0Hz，J＝6.9Hz，1H)，4.21-3.35(m，9H)，3.03(d，J＝10.8Hz，2H)，2.81(m，2H)，2.67(m，2H).
The preparation of embodiment 49N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-TYR (6h)
According to the operation of embodiment 42, make 0.33g (22%) title compound, be faint yellow solid.Mp?173-175℃；ESI/MS：542[M-H] -；[α] D 25＝-28(c＝0.5，CH 3OH)；IR(KBr)：3357，2930，1612，1515，1450，1398，1241，1080，886cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.68(s，1H)，7.84(d，J＝7.51H)，7.36(d，J＝7.8Hz，1H)，7.26(d，J＝7.8Hz，1H)，7.01(m，3H)，6.93(d，J＝8.4Hz，1H)，6.67(d，J＝8.4Hz，1H)，6.61(d，J＝8.4Hz，1H)，5.02(s，1H)，4.17(t，J＝7.5Hz，1H)，3.99-3.20(m，9H)，3.05-2.74(m，6H).
The preparation of embodiment 50N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-ILE (6i)
According to the operation of embodiment 42, make 0.33g (22%) title compound, be faint yellow solid.Mp?151-153℃；ESI/MS：492[M-H] -；[α] D 25＝-4(c＝0.5，CH 3OH)；IR(KBr)：3346，2963，1585，1514，1462，1397，1354，1270，1082，882cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.71(s，1H)，7.76(s，1H)，7.39(d，J＝4.2Hz，1H)，7.28(d，J＝4.5Hz，1H)，7.02(t，J＝7.2Hz，1H)，6.98(t，J＝7.6Hz，1H)，4.19(t，J＝5.5Hz，1H)，4.08-3.44(m，9H)，2.96(d，J＝9.6Hz，2H)，2.80(t，J＝5.7Hz，3H)，2.66(s，1H)，1.44(m，2H)，1.11(s，3H)，0.83(m，3H).
The preparation of embodiment 51N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-Methionine (6j)
According to the operation of embodiment 42, make 0.41g (33%) title compound, be faint yellow solid.Mp?163-165℃；ESI/MS：510[M-H] -；[α] D 25＝-2(c＝0.5，CH 3OH)；IR(KBr)：3301，2918，1650，1599，1516，1404，1333，1229，1025，822cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.72(s，1H)，7.89(s，1H)，7.39(d，J＝7.5Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.02(t，J＝6.9Hz，1H)，6.94(d，J＝6.6Hz，1H)，4.20(t，J＝9.2Hz，1H)，4.10(t，J＝10.2Hz，1H)，3.87(s，2H)，3.78(s，2H)，3.61-3.43(m，4H)，2.92(d，J＝4.5Hz，2H)，2.41(t，J＝7.5Hz，2H)，2.04(m，2H)，2.09(s，3H).
The preparation of embodiment 52N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-threonine (6k)
According to the operation of embodiment 42, make 0.32g (19%) title compound, be faint yellow solid.Mp?179-181℃；ESI/MS：480[M-H] -；[α] D 25＝-16(c＝0.5，CH 3OH)；IR(KBr)：3364，2930，1675，1603，1398，1080，882cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.69(s，1H)，7.89(d，J＝8.4Hz，1H)，7.40(d，J＝7.5Hz，1H)，7.27(d，J＝8.1Hz，1H)，7.02(t，J＝6.9，1H)，6.95(t，J＝6.9Hz，1H)，4.29(s，1H)，4.19(s，1H)，4.16(m，1H)，3.90(m，3H)，3.78(t，J＝5.4Hz，1H)，3.66(d，J＝2.7Hz，1H)，3.56(d，J＝8.4Hz，1H)，3.48-3.31(m，3H)，2.96(m，2H)，2.71(s，2H)，1.06(d，J＝6Hz，3H).
The preparation of embodiment 53N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Pidolidone (6l)
According to the operation of embodiment 42, make 0.43g (24%) title compound, be faint yellow solid.Mp?191-193℃；ESI/MS：508[M-H] -；[α] D 25＝-4(c＝0.5，CH 3OH)；IR(KBr)：3331，2931，1678，1593，1402，1328，1230，1081，874cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.69(s，1H)，8.27(d，J＝7.8Hz?1H)，7.39(d，J＝7.5Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.02(t，J＝6.9Hz，1H)，6.95(t，J＝6.9Hz，1H)，4.18(t，J＝4.8Hz?1H)，3.93(t，J＝5.5Hz，1H)，3.85(d，J＝6.5Hz，2H)，3.68(t，J＝4.5Hz，2H)，3.57(d，J＝10.5Hz，1H)，3.50-3.30(m，3H)，3.02(d，J＝12Hz，1H)，2.85(d，J＝11.1Hz，1H)，2.70(d，J＝5.1Hz，2H)，2.29(t，J＝7.5Hz，2H)，1.89(m，2H).
The preparation of embodiment 54N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-Serine (6m)
According to the operation of embodiment 42, make 0.31g (26%) title compound, be faint yellow solid.Mp?176-178℃；ESI/MS：466[M-H] -；[α] D 25＝-3(c＝0.5，CH 3OH)；IR(KBr)：3330，2932，1605，1404，1328，1266，1079，870cm -1； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.70(s，1H)，8.05(d，J＝7.51H)，7.40(d，J＝7.5Hz，1H)，7.27(d，J＝8.1Hz，1H)，7.02(t，J＝6.6Hz，1H)，6.95(t，J＝7.2Hz，1H)，4.23(d，J＝6.6Hz，1H)，4.20(d，J＝5.1Hz，1H)，3.93(d，J＝5.1Hz，1H)，3.87(t，J＝6.6Hz，1H)，3.70(d，J＝5.9Hz，3H)，3.57(d，J＝10.8Hz，1H)，3.52-3.36(m，4H)，2.92(m，2H)，2.66(d，J＝4.8Hz，2H)，2.23(s，1H).
Embodiment 55N-pentahydroxy-hexyl-3S-1, the preparation of 2,3,4-tetrahydro-beta-carboline-3-carboxylic acid (6n)
By 0.24g (1mmol) 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is dissolved in 5ml methyl alcohol.2.00g (10mmol) Glucose-H 2o is dissolved in 10ml deionized water.Under stirring under room temperature, D/W is added in reaction solution.Add again sodium cyanoborohydride 0.32g (5mmol) in batches.Under stirring at room, react after 1h, reaction solution is placed in microwave reactor (400W, 70 ℃) and reacts 3h, reaction finishes rear standing to room temperature.Under condition of ice bath, drip concentrated hydrochloric acid regulator solution pH=2.5, adularescent solid is separated out, and suction filtration is removed white solid, after the concentrated remove portion water of filtrate decompression, adds dehydrated alcohol, and standing rear suction filtration is removed the white solid of separating out, and filtrate decompression is concentrated.By the upper strong acid cation exchange resin column of this filtrate, first with distilled water wash-out, remove unreacted sugar component, then use 3% N-methylmorpholine aqueous solution wash-out, collect product component, the water of removing in product component obtains yellow solid.Recrystallization (alcohol-water), makes 0.17g (45%) target compound, is faint yellow solid.Mp?182-184℃；ESI/MS：379[M-H] -；[α] D 25＝-30(c＝0.5，CH 3OH)；IR(KBr)：3349，2925，1586，1454，1286，1213，1078，862； 1H-NMR(300MHz，DMSO-d 6)：δ/ppm＝10.72(s，1H)，7.38(d，J＝7.5Hz，1H)，7.27(d，J＝7.8Hz，1H)，7.01(t，J＝6.9Hz，1H)，6.95(t，J＝6.9Hz，1H)，4.15(m，1H)，3.93(dd，J＝5.7Hz，J＝3.0Hz，1H)，3.85(d，J＝4.2Hz，1H)，3.72(d，J＝3.3Hz，1H)，3.58(d，J＝10.8Hz，1H)，3.51-3.36(m，4H)，3.03(d，J＝7.5Hz?2H)，2.86(m，2H).
The In Vitro Anti platelet aggregation activity of experimental example 16a-n is measured
1) experiment material
Health pig blood, by Beijing, resource group provides.
2) medicine and reagent and instrument
Adenosine diphosphate (ADP) (ADP, sigma), platelet activation factor (PAF, sigma), arachidonic acid (AA, sigma), zymoplasm (TH, sigma), 3.8% Sodium Citrate, Satorus photoelectric analytical balance, electric centrifuge (Jiangsu, model 800), platelet aggregation instrument (CHRONO-LOG, USA, 490-2D).
3) measuring method and result
Pig carotid artery is got blood, with 3.8% Sodium Citrate (V sodium Citrate: V pig blood=1: 9) anti-freezing.Centrifugal 10 minutes of 1000 turn/min platelet rich plasma (PRP), then with 3000 turn/min centrifugal 10 minutes, obtain platelet poor plasma (PPP).With adenosine diphosphate (ADP), (ADP, final concentration is 10 -5m), (zymoplasm, final concentration is 10 to TH -5m), arachidonic acid (AA, final concentration 10 -6m) and platelet activation factor (PAF, final concentration is 10 -7m) for inductor induced platelet is assembled.All compound physiological saline solutions, the final concentration of 6a-n is 2000 μ M, 1500 μ M, 1000 μ M, 100 μ M, 10 μ M and 1 μ M.The result of measuring is listed table 1 in.
The IC of table 16a-n to the platelet aggregation of ADP, PAF, TH and AA induction 50(μ M) value
Figure BDA0000064092490000211
6a-n suppresses the IC of the platelet aggregation of ADP, PAF, AA and TH induction as can be seen from Table 1 50respectively at 6.18-339.54 μ M, 0.17-131.74 μ M, 2.57-664.69 μ M and 0.48-91.81 μ M.6a-n is far better than the platelet aggregation inhibitory activity to other three kinds of inductors induction to the platelet aggregation inhibitory activity of TH induction.6a-n has certain selective inhibitory to TH.
In the body of experimental example 26a-n, antithrombotic acitivity is measured (arteria carotis communis-vein extracorporeal circulation bypass thread model, activity represents with wet weight of thrombus)
1) laboratory animal
SD male rat, body weight 200-220g, is provided by Beijing Vital River Experimental Animals Technology Co., Ltd..
2) experiment material
Polyethylene tube (two kinds of external diameter 1.6mm and 1.3mm), heparin (50IU/mL), urethane (20%), physiological saline.
3) measuring method and result
Take physiological saline (NS, 3mL/kg) as blank, with acetylsalicylic acid (30mg/kg), make positive control.Acetylsalicylic acid, 6a-n (0.1nmol/kg) are being made into medicine normal saline solution before use.Separately joining by mole mixtures forming (10nmol/kg) such as Klss, L-Met, Gluccose is the normal saline solution 1 of solute.By male SD rat (body weight 200-220g) gavage, give 6a-n, after 30 minutes, abdominal injection 20% urethane solution is anaesthetized, the right carotid of separated rat and left jugular vein.In the stage casing of polyethylene tube, put into the long silk thread of 6cm of weighing in advance, with heparin-saline (50IU/kg), be full of polyethylene tube, left jugular vein is inserted in one end, with syringe, from the other end, add quantitative heparin sodium anti-freezing (50IU/mL, 1mL/kg), then insert right carotid.Blood flow flows into left jugular vein from the right carotid polyethylene tube of flowing through, after 15min in Herba Clinopodii, take out silk thread and weigh, gross weight deducts silk thread weight and is wet weight of thrombus.The average of the wet weight of thrombus of each group of statistics and standard deviation (
Figure BDA0000064092490000221
Figure BDA0000064092490000222
), and do t check, result is listed table 2 in.
Table 26a-n antithrombotic acitivity
Figure BDA0000064092490000223
N=10; Glu=glucose; The dosage of 6a-n is 0.1nmol/kg; The dosage of 1, L-Met and glucose is 10nmol/kg.a) compare P < 0.01 with physiological saline group; B) with physiological saline group and 1+L-Met+Glu group than p < 0.01; C) compare P < 0.01 with physiological saline group, with 1+L-Met+Glu group than p < 0.05.Wet weight of thrombus is used
Figure BDA0000064092490000224
represent.
Data from table 2 can see, under 0.1nmol/kg dosage, each group of 6a-n has significant difference with physiological saline group than all, has all demonstrated good antithrombotic acitivity.Wherein the antithrombotic acitivity of 6a, 6b, 6c, 6d, 6f, 6g, 6h, 6i, 6j, 6k and the 6m under 0.1nmol/kg dosage is stronger than the activity of 1 group under 10nmol/kg dosage.
The dosage of experimental example 36e relies on experiment
According to the method for experimental example 2, select active stronger 6j to measure the activity under 0.1nmol/kg, 0.01nmol/kg and 0.001nmol/kg Three doses, the results are shown in Table 3.
Table 36j dose-effect relationship
N=10, a) with physiological saline group ratio, p < 0.01; B) with physiological saline group, 6j, 0.01nmol/kg and 6j, 0.001nmol/kg group is than p < 0.01; C) with physiological saline group ratio, p < 0.01,6j, 0.001nmol/kg group is used than p < 0.05. wet weight of thrombus
Figure BDA0000064092490000232
represent.
The data of table 3 show, 6j dose-dependently ground demonstration antithrombotic acitivity.
Above-described embodiment is described the preferred embodiment of the present invention; not scope of the present invention is limited; design under the prerequisite of spirit not departing from the present invention; various distortion and improvement that those of ordinary skills make technical scheme of the present invention, all should fall in the definite protection domain of the claims in the present invention book.

Claims (9)

1. the compound that general formula is I:
Figure FDA0000401295310000011
In formula, AA is glycine residue, alanine residue, Isoleucine residue, leucine residue, α-amino-isovaleric acid residue, methionine residue, phenylalanine, tyrosine residues, threonine residues, serine residue, tryptophan residue, asparagicacid residue, glutaminic acid residue or hydroxyl;
The method of preparing above-claimed cpd, is characterized in that comprising the following steps:
(1) L-Trp is carried out to Pictet-Spengler condensation with formaldehyde under dilute sulphuric acid catalysis, obtain 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
(2), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid carries out Boc protection and obtains N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid under the existence of triethylamine;
(3), by N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and the coupling of methyl esters protected amino acid, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester;
(4) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester is sloughed to methyl esters protecting group under the NaOH aqueous solution exists, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(5) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid is sloughed to Boc protecting group under HCl and EtOAc existence, obtain N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(6) by N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(7), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid,
Wherein said amino acid is selected from glycine, ALANINE, ILE, L-Leu, Valine, L-Methionine, L-Phe, TYR, L-threonine, Serine, L-Trp, L-Aspartic acid or Pidolidone.
2. a method of preparing compound described in claim 1, is characterized in that comprising the following steps:
(1) L-Trp is carried out to Pictet-Spengler condensation with formaldehyde under dilute sulphuric acid catalysis, obtain 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid;
(2), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid carries out Boc protection and obtains N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid under the existence of triethylamine;
(3), by N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid and the coupling of methyl esters protected amino acid, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester;
(4) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid methyl ester is sloughed to methyl esters protecting group under the NaOH aqueous solution exists, obtain N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(5) N-(N-Boc-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid is sloughed to Boc protecting group under HCl and EtOAc existence, obtain N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(6) by N-(3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid)-L-amino acid;
(7), by 3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid is at NaBH 3under the reductive action of CN, there is the western Buddhist alkali reaction of reduction with glucose, obtain N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid,
Wherein said amino acid is selected from glycine, ALANINE, ILE, L-Leu, Valine, L-Methionine, L-Phe, TYR, L-threonine, Serine, L-Trp, L-Aspartic acid or Pidolidone.
3. for the preparation of the composition of antithrombotic reagent, by the compound claimed in claim 1 of significant quantity and pharmaceutically acceptable carrier or auxiliary material, formed.
4. composition according to claim 3, is characterized in that: the weight content of described compound of Formula I in described pharmaceutical composition is 0.1%-99%.
5. composition according to claim 3, is characterized in that: the weight content of described compound of Formula I in described pharmaceutical composition is 10-60%.
6. a method of preparing the antithrombotic pharmaceutical composition described in claim 3,4 or 5, it is characterized in that: after the compound of Formula I claimed in claim 1 of significant quantity is coordinated with pharmaceutically acceptable carrier or thinner, by the formulation method of this area routine, be prepared into any one suitable pharmaceutical composition.
7. for an antithrombotic pharmaceutical preparation, it is characterized in that: the mixture by compound of Formula I claimed in claim 1 and pharmaceutically acceptable excipient or additional dose is made tablet, capsule, pulvis, granule, lozenge or oral liquid.
8. the application of compound claimed in claim 1 in preparing antithrombotic reagent.
9. described in claim 3,4 or 5, for antithrombotic pharmaceutical composition, preparing the application of antithrombotic reagent.
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Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
三唑类化合物研究与应用;白雪 等;《化学研究与应用》;20070731;第19卷(第7期);721－722 *
光动力疗法用糖基光敏剂的研究进展;张沛 等;《有机化学》;20101231;第30卷(第6期);775－782 *
张沛 等.光动力疗法用糖基光敏剂的研究进展.《有机化学》.2010,第30卷(第6期),775－782.
白雪 等.三唑类化合物研究与应用.《化学研究与应用》.2007,第19卷(第7期),721－722.
邹慧.黄酮木脂素水飞蓟宾类似物的合成及抗氧化活性.《海峡药学》.2008,第20卷(第3期),124－125.
黄酮木脂素水飞蓟宾类似物的合成及抗氧化活性;邹慧;《海峡药学》;20081231;第20卷(第3期);124－125 *

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