CN102796166A - 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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CN102796166A
CN102796166A CN2011101393841A CN201110139384A CN102796166A CN 102796166 A CN102796166 A CN 102796166A CN 2011101393841 A CN2011101393841 A CN 2011101393841A CN 201110139384 A CN201110139384 A CN 201110139384A CN 102796166 A CN102796166 A CN 102796166A
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carboxylic acid
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tetrahydrochysene
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CN102796166B (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

The 4H-β-Ka Lin carboxylic acid derivative of glucose modified
Technical field
The present invention relates to a kind of compound of synthetic, particularly relate to a kind of 4H-β-Ka Lin carboxylic acid derivative, the invention still further relates to its preparation method and the application in the preparation antithrombotic reagent thereof glucose modified.
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.Seeking antithrombotic reagent is one of focus of new drug research.As everyone knows, 1,2,3,4-tetrahydrochysene-β-Ka Lin-3-S-carboxylic acid is the one type of important VALLESIACOTAMIN that extensively is present among the herbal medicine, has platelet aggregation inhibitory activity.1,2,3, introduce amino acid and can improve 1,2,3, the bioavailability of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid for 1 and/or 3 of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid.Glucose has good water-solubility in addition, and glucose can greatly improve the water-soluble of compound after being introduced into compound, compound is more absorbed easily in vivo and distributes.Glucose is as the necessary material of participating in the many physiological processs of human body, and its introducing is safe.Therefore 1,2,3, the carboxyl terminal of 4-tetrahydrochysene-β-Ka Lin-3-S-carboxylic acid is introduced 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 the formula, AA is glycine residue, alanine residue, Isoleucine residue, leucine residue, Xie Ansuan residue, methionine residue, phenylalanine(Phe), tyrosine residues, threonine residues, serine residue, tryptophan residue, asparagicacid residue, glutaminic acid residue or hydroxyl.
To the synthetic general formula is that the compound (6a-n) of I is numbered:
AA represents alanine residue among the 6a; AA represents glycine residue among the 6b; AA represents phenylalanine residue among the 6c; AA represents tryptophan residue among the 6d; AA represents leucine residue among the 6e; AA represents the Xie Ansuan residue among the 6f; AA represents asparagicacid residue among the 6g; AA represents tyrosine residues among the 6h; AA represents the Isoleucine residue among the 6i; AA represents methionine residue among the 6j; AA represents threonine residues among the 6k; AA represents glutaminic acid residue among the 6l; AA represents serine residue among the 6m; AA representation hydroxy among the 6n.
More than numbering is just described for ease, does not have any limited significance to invention.
Second problem that the present invention will solve provides the preparation method of general formula compound (6a-n), and this method may further comprise the steps:
(1) the L-tryptophane is carried out the Pictet-Spengler condensation with formaldehyde under dilute sulphuric acid catalysis, obtain 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
(2) with 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid carries out the Boc protection and obtains N-Boc-3S-1 in the presence of triethylamine, and 2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
(3) with N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid and the coupling of methyl esters protection amino acid obtain N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid methyl ester;
(4) N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid methyl ester is sloughed methyl esters protection base in the presence of the NaOH aqueous solution, obtain N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(5) N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid is sloughed Boc protection base in the presence of HCl and EtOAc, obtain N-(3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(6) with N-(3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid at NaBH 3Under the reductive action of CN, with glucose the western Buddhist alkali reaction of reduction taking place, obtains N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(7) with 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is at NaBH 3Under the reductive action of CN, with glucose the western Buddhist alkali reaction of reduction taking place, obtains N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid,
Wherein amino acid is selected from glycocoll, L-L-Ala, L-Isoleucine, L-leucine, L-Xie Ansuan, L-methionine(Met), L-phenylalanine(Phe), L-tyrosine, L-Threonine, L-Serine, L-tryptophane, L-aspartic acid or L-L-glutamic acid described in step (3), (4), (5) and (6).
This preparation method can use the synthetic route of Fig. 1 to summarize.
The 3rd technical problem that the present invention will solve provided the application of described compound in the preparation antithrombotic reagent.A kind of compsn for preparing antithrombotic reagent is made up 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 said pharmaceutical composition gross weight, preferred 10-60%.A kind ofly be used for antithrombotic preparation of drug combination method, be with the compound 6a-n of significant quantity with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it.Aforementioned pharmaceutical compositions can be used for preparing antithrombotic reagent.A kind ofly be used for antithrombotic pharmaceutical prepn, process tablet, capsule, pulvis, granule, lozenge or oral liquid by compound 6a-n and pharmaceutically acceptable excipient or the auxilliary mixture that adds agent.
The 4th technical problem to be solved by this invention is to adopt carotid atery-vein extracorporeal circulation bypass thread model to estimate the platelet aggregation inhibitory activity of compound of the present invention.
Description of drawings
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, AA represents alanine residue among the 6a; AA represents glycine residue among the 6b; AA represents phenylalanine residue among the 6c; AA represents tryptophan residue among the 6d; AA represents leucine residue among the 6e; AA represents the Xie Ansuan residue among the 6f; AA represents asparagicacid residue among the 6g; AA represents tyrosine residues among the 6h; AA represents the Isoleucine residue among the 6i; AA represents methionine residue among the 6j; AA represents threonine residues among the 6k; AA represents glutaminic acid residue among the 6l; AA represents serine residue among the 6m; AA representation hydroxy among the 6n.
Embodiment
Following examples and testing data are done more detailed explanation to the present invention is above-mentioned with other technical characterictic and advantage.
Embodiment 13S-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (1)
200mL water is placed the round-bottomed flask of 250mL, slowly add 0.2mL 98% vitriol oil.Add 5.0g (24.5mmol) L-tryptophane in the dilute sulfuric acid aqueous solution that obtains and sonic oscillation to L-tryptophane dissolves fully.Add 8mL concentration in the solution that obtains and be 38% formaldehyde solution.Reaction solution stirring at room 6h, TLC (methylene dichloride: methyl alcohol=5: 1) show that the L-tryptophane disappears termination reaction.In reaction soln, slowly drip strong aqua, transfer reacting liquid pH value, have a large amount of colorless solid depositions to separate out, leave standstill 2h to 6-7.Decompression leaches the deposition of generation and with a small amount of washing, with the solid drying that leaches, gets 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-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (2)
1 of 1.1g (5.0mmol) is suspended among the 15mL DMF, adds the 1.4mL triethylamine under the stirring at room.Ice bath stirs the Boc-N that adds 1.1g (7.7mmol) down behind the 30min 3, stirring reaction 72h under the room temperature.Reaction finish the back with watch-glass with reaction solution dry naturally yellow solid.With an amount of ETHYLE ACETATE with its dissolving after, come together with (20ml*3) saturated NaCl solution and to wash.Use anhydrous Na SO then 4Dry 1h filters, and is evaporated to dried.Residue is used CHCl 3Obtain title compound 1.2g (76%) after the crystallization, be 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-alanine methyl ester (3a)
2 of 2.0g under the ice bath (6.33mmol) is dissolved in the anhydrous THF of 30mL, adds 1.2g (8.9mmol) HOBt.After stirring 10min, in reaction solution, add 1.75g (8.5mmol) NSC 57182 (DCC).0.97g (6.96mmol) HCl-L-AlaOMe is added in the reaction solution.Transfer reaction solution pH 8-9 with the N methylmorpholine.Room temperature reaction 3h behind the continuation reaction 2h under the ice bath.Remove by filter and remove NSC 30023 (DCU), be evaporated to and use acetic acid ethyl dissolution after doing.Gained solution is used 5%NaHCO respectively 3Solution, saturated NaCl solution, 5%KHSO 4Solution, saturated NaCl solution, saturated NaHCO 3Each collection of solution, saturated NaCl solution is given a baby a bath on the third day after its birth time.Ethyl acetate layer is used anhydrous Na 2SO 4Drying is filtered, is evaporated to dried.Make 2.44g (96%) target compound, be 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).
The preparation of embodiment 4N-[(3S)-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-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).
The preparation of embodiment 5N-[(3S)-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-phenylalanine methyl ester (3c) makes 2.71g (98%) title compound according to the operation of embodiment 3, 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 -11H-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tryptophan methyl ester (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-leucine 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-valine methyl ester (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-L-Tyrosine methyl ester (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Isoleucine 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-methyl methionine (3j)
Operation according to embodiment 3 makes 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Threonine methyl esters (3k)
Operation according to embodiment 3 makes 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-glutamic acid methyl ester (3l)
Operation according to embodiment 3 makes 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-serine methylester (3m)
Operation according to embodiment 3 makes 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-third amino acid (4a)
N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-alanine methyl ester of 1.0g (2.5mmol) is dissolved in the THF of 6ml under 0 ℃ of condition of ice bath, and the NaOH of 0.45g (11.34mmol) adds in the reaction solution.Reaction solution reacts 70min under ice bath.Reaction finishes the back concentrating under reduced pressure except that desolvating, and reaction residues is dissolved in the 30ml water, washes 3 times with the ether collection. and water is used saturated KHSO 4Transferring pH is 2, and with ETHYLE ACETATE (20ml*3) extraction, the gained ethyl acetate layer is used anhydrous Na 2SO 4Drying is filtered, is evaporated to dried, obtains 0.76g (79%) target compound, is 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).
The preparation of embodiment 17N-[(3S)-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-glycocoll (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).
The preparation of embodiment 18N-[(3S)-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-phenylalanine(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). the preparation of embodiment 19N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tryptophane (4d) makes 0.88g (70%) title compound according to the operation of embodiment 16, is 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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-leucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Xie Ansuan (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tyrosine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Isoleucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-methionine(Met) (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-L-glutamic acid (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-third amino acid (5a)
Under the condition of ice bath; 0.7g N-(1.85mmol) (N-Boc-3S-1,2,3; 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-third amino acid is dissolved in the 10mL hydrochloric ethyl acetate (4mol/L); The reaction ice bath stirs reaction 1h down, and residue was dissolved in the ETHYLE ACETATE after reaction finished the back decompressing and extracting, and decompressing and extracting is removed de-chlorine hydride 3 times repeatedly.The residue that obtains obtains 0.50g (94%) title product with the methanol 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).
The preparation of embodiment 30N-[(3S)-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-glycocoll (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-phenylalanine(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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tryptophane (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-leucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Xie Ansuan (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tyrosine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Isoleucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-methionine(Met) (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-L-glutamic acid (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-third amino acid (6a)
1.62g (5mmol) N-(3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-third amino acid is dissolved in the 10ml methyl alcohol.5.00g (25mmol) Glucose-H 2O is dissolved in the 10ml deionized water.Stir under the room temperature down, D/W is added in the reaction solution.Add sodium cyanoborohydride 1.53g (25mmol) more in batches.Behind the reaction 1h, reaction solution placed in the microwave reactor (400W, 70 ℃) react 2h under the stirring at room, reaction is left standstill to room temperature after finishing.Under the condition of ice bath, drip concentrated hydrochloric acid regulator solution pH=2.5, the adularescent solid is separated out, and suction filtration is removed white solid, and filtrate decompression concentrates and removes after the portion water, adds absolute ethyl alcohol, leaves standstill the back suction filtration and removes the white solid of separating out, and filtrate decompression concentrates.This filtrating is gone up strong acid cation exchange resin column; Earlier remove unreacted sugar component, use 3% N-methylmorpholine aqueous solution wash-out again, collect the product component with the zero(ppm) water wash-out; The water of removing in the 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).
The preparation of embodiment 43N-[(3S)-N-pentahydroxy-hexyl-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-glycocoll (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).
The preparation of embodiment 44N-[(3S)-N-pentahydroxy-hexyl-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid]-L-phenylalanine(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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tryptophane (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-leucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Xie Ansuan (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-tyrosine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-Isoleucine (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-methionine(Met) (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-tetrahydrochysene-β-Ka Lin-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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-L-glutamic acid (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-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-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-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid (6n)
With 0.24g (1mmol) 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is dissolved in the 5ml methyl alcohol.2.00g (10mmol) Glucose-H 2O is dissolved in the 10ml deionized water.Stir under the room temperature down, D/W is added in the reaction solution.Add sodium cyanoborohydride 0.32g (5mmol) more in batches.Behind the reaction 1h, reaction solution placed in the microwave reactor (400W, 70 ℃) react 3h under the stirring at room, reaction is left standstill to room temperature after finishing.Under the condition of ice bath, drip concentrated hydrochloric acid regulator solution pH=2.5, the adularescent solid is separated out, and suction filtration is removed white solid, and filtrate decompression concentrates and removes after the portion water, adds absolute ethyl alcohol, leaves standstill the back suction filtration and removes the white solid of separating out, and filtrate decompression concentrates.This filtrating is gone up strong acid cation exchange resin column, remove unreacted sugar component with the zero(ppm) water wash-out earlier, use 3% N-methylmorpholine aqueous solution wash-out again, collect the product component, the water of removing in the 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 external platelet aggregation inhibitory activity of experimental example 16a-n is measured
1) experiment material
Health pig blood, group provides by Beijing resource.
2) medicine and reagent and instrument
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 commentaries on classics/min platelet rich plasma (PRP), centrifugal 10 minutes again with 3000 commentariess on classics/min, must platelet poor plasma (PPP).(ADP, final concentration are 10 with ADP -5M), (zymoplasm, final concentration are 10 to TH -5M), arachidonic acid (AA, final concentration 10 -6M) and platelet activation factor (PAF, final concentration are 10 -7M) assemble for the inductor induced platelet.All compounds are used physiological saline solution, and 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 who measures lists table 1 in.
Table 16a-n is to the IC of ADP, PAF, TH and AA inductive platelet aggregation 50(μ M) value
Figure BDA0000064092490000211
Can find out that by table 1 6a-n suppresses the IC of ADP, PAF, AA and TH inductive platelet aggregation 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 far is better than other three kinds of inductor inductive platelet aggregation inhibitory activities TH inductive platelet aggregation inhibitory activity.6a-n has the certain selectivity restraining effect to TH.
Antithrombotic acitivity is measured (carotid atery-vein extracorporeal circulation bypass thread model, activity is represented with wet weight of thrombus) in the body of experimental example 26a-n
1) laboratory animal
The 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%), saline water.
3) measuring method and result
(NS 3mL/kg) is blank, and (30mg/kg) makes positive control with Frosst) with saline water.Frosst), 6a-n (0.1nmol/kg) are facing with before being made into the medicine physiological salt soln.Other joins the mixture of being made up of moles such as Klss, L-Met, Gluccose (10nmol/kg) and is the physiological salt soln 1 of solute.Male SD rat (body weight 200-220g) is irritated stomach give 6a-n, after 30 minutes, abdominal injection 20% urethane solution is anaesthetized, the right carotid of isolated from rat and left jugular vein.Put into the long silk thread of 6cm of weighing in advance in the stage casing of polyethylene tube; (50IU/kg) is full of polyethylene tube with heparin-saline, and an end is inserted left jugular vein, adds quantitative heparin sodium anti-freezing (50IU/mL with syringe from the other end; 1mL/kg), insert right carotid then.Blood flow flows into left jugular vein from the right carotid polyethylene tube of flowing through, behind the 15min in Herba Clinopodii, take out silk thread and weigh, gross weight deducts silk thread weight and is wet weight of thrombus.The average and the standard deviation (
Figure BDA0000064092490000221
Figure BDA0000064092490000222
) of the wet weight of thrombus of each group of statistics; And doing the t check, the result lists table 2 in.
Table 26a-n antithrombotic acitivity
N=10; Glu=glucose; The dosage of 6a-n is 0.1nmol/kg; 1, the dosage of L-Met and glucose is 10nmol/kg.a) compare P＜0.01 with the saline water group; B) organize than p＜0.01 with saline water group and 1+L-Met+Glu; C) compare P＜0.01 with the saline water group, organize than p＜0.05 with 1+L-Met+Glu.Wet weight of thrombus is expression with
Figure BDA0000064092490000224
.
Data from table 2 can see that each group of 6a-n has significant difference with the saline water group than all under 0.1nmol/kg dosage, 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 the 0.1nmol/kg dosage is than 1 group active strong under the 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 three kinds of dosage of 0.001nmol/kg, the result sees table 3.
Table 36j dose-effect relationship
Figure BDA0000064092490000231
N=10 is a) with saline water group ratio, p＜0.01; B) with saline water group, 6j, 0.01nmol/kg and 6j, 0.001nmol/kg organize than p＜0.01; C) with saline water group ratio; P＜0.01; 6j, the 0.001nmol/kg group is than the expression with
Figure BDA0000064092490000232
of p＜0.05. wet weight of thrombus.
The data of table 3 show that 6j dose-dependently ground shows antithrombotic acitivity.
Above-described embodiment describes preferred implementation of the present invention; Be not that scope of the present invention is limited; Design under the prerequisite of spirit not breaking away 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 claims of the present invention.

Claims (9)

1. compound that general formula is I:
In the formula, AA is glycine residue, alanine residue, Isoleucine residue, leucine residue, Xie Ansuan residue, methionine residue, phenylalanine(Phe), tyrosine residues, threonine residues, serine residue, tryptophan residue, asparagicacid residue, glutaminic acid residue or hydroxyl.
2. method for preparing the said compound of claim 1 is characterized in that may further comprise the steps:
(1) the L-tryptophane is carried out the Pictet-Spengler condensation with formaldehyde under dilute sulphuric acid catalysis, obtain 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
(2) with 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid carries out the Boc protection and obtains N-Boc-3S-1 in the presence of triethylamine, and 2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid;
(3) with N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid and the coupling of methyl esters protection amino acid obtain N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid methyl ester;
(4) N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid methyl ester is sloughed methyl esters protection base in the presence of the NaOH aqueous solution, obtain N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(5) N-(N-Boc-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid is sloughed Boc protection base in the presence of HCl and EtOAc, obtain N-(3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(6) with N-(3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid at NaBH 3Under the reductive action of CN, with glucose the western Buddhist alkali reaction of reduction taking place, obtains N-(N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid)-L-amino acid;
(7) with 3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is at NaBH 3Under the reductive action of CN, with glucose the western Buddhist alkali reaction of reduction taking place, obtains N-pentahydroxy-hexyl-3S-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid,
Wherein said amino acid is selected from glycocoll, L-L-Ala, L-Isoleucine, L-leucine, L-Xie Ansuan, L-methionine(Met), L-phenylalanine(Phe), L-tyrosine, L-Threonine, L-Serine, L-tryptophane, L-aspartic acid or L-L-glutamic acid.
3. compsn that is used to prepare antithrombotic reagent is made up of the described compound of the claim 1 of significant quantity and pharmaceutically acceptable carrier or auxiliary material.
4. compsn according to claim 3 is characterized in that: the weight content of said compound of Formula I in said pharmaceutical composition is 0.1%-99%.
5. compsn according to claim 3 is characterized in that: the weight content of said compound of Formula I in said pharmaceutical composition is 10-60%.
6. method for preparing claim 3,4 or 5 described antithrombotic pharmaceutical compositions; It is characterized in that: with after pharmaceutically acceptable carrier or thinner cooperate, the formulation method conventional by this area is prepared into any one appropriate drug compsn with it with the described compound of Formula I of the claim 1 of significant quantity.
7. one kind is used for antithrombotic pharmaceutical prepn, it is characterized in that: process tablet, capsule, pulvis, granule, lozenge or oral liquid by described compound of Formula I of claim 1 and the perhaps auxilliary mixture that adds agent of pharmaceutically acceptable excipient.
8. the application of the described compound of claim 1 in the preparation antithrombotic reagent.
9. claim 3, the 4 or 5 described application that are used for antithrombotic pharmaceutical composition at the preparation antithrombotic reagent.
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