CN1743326A - Carboline carboxylate derivative, and its synthesizing method and use - Google Patents

Carboline carboxylate derivative, and its synthesizing method and use Download PDF

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CN1743326A
CN1743326A CN 200410074204 CN200410074204A CN1743326A CN 1743326 A CN1743326 A CN 1743326A CN 200410074204 CN200410074204 CN 200410074204 CN 200410074204 A CN200410074204 A CN 200410074204A CN 1743326 A CN1743326 A CN 1743326A
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lin
tetrahydrochysene
carboxylic acid
preparation
boc
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CN100494195C (en
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彭师奇
赵明
王超
杨哲
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Capital Medical University
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Abstract

This invention discloses a new series of derivatives of carboline carboxylic acid, their preparation method, as well as their use. The derivative is prepared by introducing amino acid to carboline carboxylic acid's lateral chain. As confirmed in experiment, these derivatives possess high solubility, high antithrombotic activity and anti-platelet aggregation. activity.

Description

Carboline carboxylate derivative, its preparation method and use
Technical field
The present invention relates to a kind of carboline carboxylate derivative, relate in particular to a kind of carboline carboxylate derivative and preparation method thereof with antithrombotic acitivity.
Background technology
Be that the sickness rate of cardiovascular disorder of representative is in rising trend with cardiovascular embolism and cerebral vessels embolism in recent years, serious harm health.The number that the U.S. in 1998 dies from cardiovascular disorder is than the lethal total number of persons of cancer, traffic accident and acquired immune deficiency syndrome (AIDS) also many (Heart and Stroke A-Z Guide:2001 Heart andStroke Statistical Update.Available at:http: //www.americanheart.org.AccessedMay 2001).Atherosclerosis, myocardial infarction, cerebral infarction and pulmonary infarction are all closely related with the formation of thrombus.Some other disease or symptom, as all relevant (Li Jiazeng, He Shilin, Wang Hongli chief editor such as diabetes, kidney disease, hepatic diseases, hemopathy, systemic lupus erythematous, malignant tumour, burn, wound, surgical operation, hemodialysis, cardiac surgery, organ transplantation, gestation, newborn infant's sudden deafness, ophthalmic diseases, thromboangiitis obliterans and disseminated inravascular coagulation with the formation of thrombus, " thrombus disease ", Science Press, 1998).
1,2,3,4-tetrahydrochysene-β-Ka Lin is the parent nucleus that extensively is present in the many important indole alkaloid in the medicinal plant.For example 1,2,3,4-tetrahydrochysene-β-Ka Lin is the N in the giantreed bThe banisterine of 6-methoxyl group-tetrahydrochysene-β-Ka Lin among-methyltetrahydroharman, the Desmodiumpulchellum Benth er Barker and 6-methoxytetraphydroharman, oleaster and the parent nucleus (Lin Qishou etc. of elaeagnine and 1-isobutyl-tetrahydrochysene-β-Ka Lin etc., the medicinal herb components chemistry, Science Press, 1997).Because 1,2,3,4-tetrahydrochysene-β-Ka Lin has tangible anti-platelet activity, so become the medicine guide structure type of extremely paying attention to, carboline carboxylate is one of them typical case's representative.
The Chinese medicine Longstamen Onion Bulb is the dry bulb of Liliaceae allium Allium macrostemon (Allium macrostemon Bunge) or Chinese onion (A.chinense G.Don).Allium macrostemon originates in ground such as northeast, North China, records in Chinese Pharmacopoeia 1990 editions.Chinese onion originates in China south.Longstamen Onion Bulb cures mainly diseases such as " obstruction of qi in the chest ", " chesting pain radiating to the back ".The obstruction of qi in the chest is equivalent to stenocardia and myocardial infarction with chesting pain radiating to the back.Longstamen Onion Bulb is contained in some sides that the Han dynasty Zhang Zhongjing proposes, and for example " melon withers, Longstamen Onion Bulb liquor soup ", " melon withers, Longstamen Onion Bulb, tuber of pinellia soup " and " dried immature fruit of citron orange, Longstamen Onion Bulb, cassia twig soup " etc. are all contained Longstamen Onion Bulb.In the anti-platelet activity screening, Bulbus Allii Macrostemonis extract shows strong active.(Yao new life etc. derive from several nitrogenous compounds in Allium macrostemon and the Chinese onion to the platelet aggregation inhibitory activity of (the S)-carboline carboxylate that is separated to from Longstamen Onion Bulb for Peng Junpeng, Qiao Yanqiu than the strong several times of acetylsalicylic acid.China's pharmaceutical chemistry magazine, May nineteen ninety-five, 134).What the traditional Chinese medical science had a doctor food homology says that promptly some medicines also are food.Chinese Government is formal announce not only can be used as medicine but also can be used as in the inventory of food and comprised the face Longstamen Onion Bulb.As seen, Longstamen Onion Bulb is foolproof simply Chinese medicine.Carboline carboxylate from Longstamen Onion Bulb is foolproof compound.Verified (S)-carboline carboxylate is as the potential significance of antithrombotic reagent elder generation guide structure (Peng Shiqi etc., Tetrahydrocarboline carboxylic acid and RGD conjugate thereof, they synthetic and at medically application, Chinese patent, application number: 01144616.6).
But the solubleness extreme difference of carboline carboxylate is dissolved in any solvent hardly, causes its bioavailability extreme difference thus.This shortcoming has seriously limited its application on food and medicine.
Summary of the invention
Technical problem to be solved by this invention provides a class solubleness height, carboline carboxylate derivative that antithrombotic acitivity is high.
Another technical problem to be solved by this invention provides the preparation method of this carboline carboxylate derivative.
Technical problem to be solved by this invention realizes by following approach:
The invention provides a kind of carboline carboxylate derivative, have the structure of general formula I.
Figure A20041007420400051
General formula I
Wherein R is selected from-CH 3, CH 2C 6H 5,-CH (CH 3) 2,-CH 2OH ,-CH (OH) CH 3,-CH 2C 6H 4-OH-p, Pyrrolidine-2-base ,-CH 2SH ,-CH 2CH 2SCH 3,-CH 2CH 2COOH ,-CH 2COOH, 1,3-imidazoles methyl or indoles-3-methyl.
Another technical problem to be solved by this invention provides the preparation method of above-mentioned compound of Formula I, and the synthetic method of this compound of Formula I may further comprise the steps:
1, L-tryptophane and formaldehyde condensation are made (3S)-β-Ka Lin carboxylic acid,
2,2 N to (3S)-β-Ka Lin carboxylic acid protect, and prepare N-protected base-β-Ka Lin carboxylic acid,
3, with N-protected base-β-Ka Lin carboxylic acid and amino acid ester condensation prepared N-protected base-β-Ka Lin amido-carboxylic acid esters,
4, N-protected base-β-Ka Lin amido-carboxylic acid esters is taken off protecting group and ester is hydrolyzed to acid promptly gets general formula compound of the present invention.
In the above-mentioned synthetic method, wherein the condensation reaction in the step 1 is to carry out under mineral acid catalysis, is preferably the vitriol oil; Wherein the protecting group of 2 N of (3S)-β-Ka Lin carboxylic acid both can be that tertbutyloxycarbonyl can be a benzyl also in the step 2, was preferably tertbutyloxycarbonyl; Condensing agent in the step 3 is preferably DCC (dicyclohexyl carbodiimide); Wherein deprotection and ester hydrolysing step can be first saponification hydrogenolysis or first saponification acidolysis more again in the step 4, are preferably first saponification acidolysis again;
Amino acid is proteinic basic structural unit, extensively is present in the organism, and normal physiological function has and important effect to keeping.Because amino acid has acid, alkali amphoteric unique texture, so can be used for the structural modification of drug molecule, can improve the interaction of drug molecule and acceptor by amino acid.
The present invention introduces amino acid at the side chain of carboline carboxylate, can obviously improve the pharmacokinetic property of carboline carboxylate, can improve the solubility property of carboline carboxylate on the one hand, also can improve the absorption and the transhipment of carboline carboxylate on the other hand, thereby can significantly improve the antithrombotic acitivity of carboline carboxylate.
Description of drawings
The synthetic route of the carboline carboxylate that Fig. 1 is amino acid modified
Embodiment
Specify the present invention below with reference to embodiment, embodiments of the invention only are used to technical scheme of the present invention is described, and non-limiting scope of the present invention.
The preparation of The compounds of this invention intermediate
One, 1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid
0.18ml diluting concentrated sulfuric acid in 400ml water, adds 5g (22.4mmol) Trp (tryptophane) then.Treat that Trp dissolves the back fully and adds 10ml formaldehyde, room temperature reaction is after 6 hours, and the TLC plate shows that raw material disappears, and adds the pH to 8-9 of 10ml ammoniacal liquor (2.5%) conditioned reaction thing.Reaction mixes leaves standstill suction filtration after 30 minutes, and the white solid that obtains gets 4.6g (95.1%) title compound with ethanol, water, ammoniacal liquor recrystallization, is white solid.
Two, N-Boc-1,2,3, the preparation of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid
The following 1g of ice bath (4.17mmol) 1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is suspended in 1.1g (Boc) 2In the solution that O (tertiary butyloxycarbonyl acid anhydride) and 10ml DMF (dimethyl formamide) make.The solution that obtains adds 1.5ml triethylamine adjust pH 8-9.The reaction mixture ice bath stirs 4h down.In the reaction process 2,3,4,9-tetrahydrochysene-β-Ka Lin-3-carboxylic acid dissolves gradually, and TLC (chloroform/methanol/Glacial acetic acid: 5: 3: 0.4) shows raw material point disappearance.Concentrating under reduced pressure removes and to desolvate, residue with acetic acid ethyl dissolution after, use 5%KHSO successively 4, saturated NaCl washes, and the organic layer anhydrous sodium sulfate drying filters, concentrating under reduced pressure, residue washs with chloroform, obtains 1g (68%) title compound.
The preparation of [embodiment 1] N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-Ala (5a)
The preparation of step 1, N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-alanine methyl ester (3a)
2g (6.33mmol) N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid is dissolved among the anhydrous THF of 30ml, adds 1.2g (8.9mmol) N-hydroxy benzo triazole (HOBt) under the ice bath inward, adds 1.75g (8.5mmol) DCC after 10 minutes inward.1.07g (6.96mmol) HClAlaOMe (alanine methyl ester hydrochloride) is suspended among the anhydrous THF of 3ml, adds the 1ml N-methylmorpholine then and regulates pH to 8-9, reacts 20 minutes.After 10 minutes this solution is added in the top solution that contains the N-hydroxy benzo triazole.The reaction mixture stirred overnight at room temperature, TLC (chloroform/methanol, 15: 1) shows that raw material point disappears, and leaches DCU (dicyclohexylurea (DCU)), filtrate decompression is concentrated into dried, the residue acetic acid ethyl dissolution.The solution that obtains is used saturated NaHCO successively 3, saturated NaCl, 5%KHSO 4, saturated NaCl, saturated NaHCO 3, saturated NaCl is washed till neutrality, anhydrous Na 2SO 4Dry.Filter, be evaporated to dried, 2.6g (%) title compound, be faint yellow solid.Rf=0.383 (chloroform/methanol, 15: 1)
Step 2, N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) preparation of L-Ala (4a)
1.0g (2.5mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-carbamino alanine methyl esters is dissolved in the mixed solvent of 4ml methyl alcohol and 2ml chloroform, ice bath adds 0.45g (11.34mmol) NaOH down, it is yellow that reaction solution graduates into, TLC after 70 minutes (chloroform/methanol, 30/1) demonstration reacts completely, and concentrating under reduced pressure boils off solvent, residue adds the 30ml water dissolution, use ethyl acetate extraction, water layer is transferred pH value with 4NHCl under ice bath be 1-2, separates out yellow oil, ethyl acetate extraction, anhydrous Na 2SO 4Drying, filtration, concentrating under reduced pressure get title compound 750mg (79%), are faint yellow solid.
The preparation of step 3, N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-Ala (5a)
Ice bath is down toward 700mg (1.85mmol) N-[(2-N-Boc-1; 2; 3; 4-tetrahydrochysene-β-Ka Lin-3-formyl radical) adds 8ml HCl-ethyl acetate (4N) in the solution of L-Ala and 8ml anhydrous ethyl acetate; Stir mixes TLC (chloroform/methanol after 60 minutes; 5/1) show that raw material point disappears, reaction solution is evaporated to dried, adds the 10ml ethyl acetate in the residue that obtains; be evaporated to dried again; this operation three times repeatedly, the residue that obtains adds the 20ml ethyl acetate, grinds; filter; solid gets title compound 500mg (86%) with propyl carbinol-ether recrystallization, is the reddish-brown powder.ESI/MS：288[M+H] +， [ α ] D 25 = - 80.0 (C＝1.0，DMF) 1HNMR(300MHZ，DMSO-d6)：δ/ppm＝1.378(d，J＝6.6Hz，3H，)，2.887(s，1H)，2.930(s，1H)，3.371(s，1H)，4.275(m，1H)，4.356(m，2H)，4.481(m，1H)，7.031(s，1H)，7.120(s，1H)，7.382(d，J＝7.8Hz，1H)，7.469(d，J＝6.6Hz，1H)，9.022(s，1H)，9.861(s，1H)，11.186(s，1H).
The preparation of embodiment 2 N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) phenylalanine (5b)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-phenylalanine methyl ester (3b)
Adopt the operation of step 1 among the embodiment 1, from 1g (3.16mmol) N-Boc-1,2,3, suspension and the 0.6ml N-methylmorpholine of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid, the anhydrous THF of 15ml, 0.6g (4.45mmol) HOBt, 0.87g (4.3mmol) DCC, 0.75g HClPheOMe (3.48mmol) and the anhydrous THF of 3ml get 1.5g (%) title compound, are faint yellow solid.ESI/MS：478[M+H] +，378[M+H-Boc] +。Rf=0.4 (chloroform/methanol, 15: 1)
2, the preparation of phenylalanine (4b) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)
Adopt the operation of step 2 among the embodiment 1, by 900mg (1.89mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl phenylalanine methyl ester obtains 650mg (74.5%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) phenylalanine (5b)
Adopting the operation of step 3 among the embodiment 1, by 600mg (1.3mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) phenylalanine obtains 490mg (95%) title compound, is the reddish-brown solid.ESI/MS：364[M+H] +， [ α ] D 25 = - 30 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=1.277-1.412 (m, 2H), 2.988 (m, 2H), 3.216 (m, 1H), 4.188 (m, 2H), 4.656 (m, 1H), 7.012 (s, 1H), 7.122 (s, 1H), 7.204 (t, J=6.8Hz, 1H), 7.380 (d, J=7.8Hz1H), 7.384 (d, J=7.6Hz, 2H), 7.464 (d, J=6.4Hz, 1H), 7.467 (t, J=6.8Hz, 2H), 9.012 (d, J=7.8Hz, 1H), 9.813 (s, 1H), 11.133 (s, 1H).
The preparation of embodiment 3.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Xie Ansuan (5c)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-valine methyl ester (3c)
Adopt the operation of step 1 among the embodiment 1, from 1g (3.16mmol) N-Boc-1,2,3, suspension and the 0.6ml N-methylmorpholine of 4-tetrahydrochysene-β-Ka Lin-3-carboxylic acid, the anhydrous THF of 15ml, 0.6g (4.45mmol) N-hydroxy benzo triazole, 0.87g (4.3mmol) DCC, 0.58g HClVal-Ome (3.48mmol) and the anhydrous THF of 3ml get 1.3g (%) title compound, are faint yellow solid.ESI/MS：452[M+Na] +，430[M+H] +。IR (cm -1): 3412,1691,1455,1511,1622,1383,741.Rf=0.417 (chloroform/methanol, 15: 1)
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Xie Ansuan (4c)
Adopt the operation of step 2 among the embodiment 1, by 0.75g (1.75mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl valine methyl ester obtains 0.515g (71%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Xie Ansuan (5c)
Adopting the operation of step 3 among the embodiment 1, by 600mg (1.3mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Xie Ansuan obtains 380mg (95%) title compound, is faint yellow solid.Mp169℃-171℃，ESI/MS：316[M+H] +， [ α ] D 25 = - 70 (C＝1，DMF)， 1HNMR(300MHZ，DMSO-d6)：δ/ppm＝0.938(d，J＝6.9Hz，3H)，0.971(s，3H)，2.166(dd，J＝6.9Hz，J＝5.7Hz，1H)，2.849(d，J＝5.4Hz，1H)，3.153-3.381(m，J＝4.9Hz，1H，)，4.230(s，2H)，4.337(s，1H)，4.479(m，2H)，7.013(t，J＝7.2Hz，1H)，7.104(t，J＝7.4Hz，1H)；7.366(d，J＝7.8Hz，1H)，7.462(d，J＝7.5Hz，1H)，8.787(s，1H)，9.824(s，1H)，11.190(s，1H)，12.680(s，1H)。
The preparation of embodiment 4.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Serine (5d)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-serine methylester (3d)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get 2.6g (%) title compound, be faint yellow solid with 1.08g (6.96mmol) HClSerOMe.ESI/MS:419.1[M+H] +, Rf=0.267 (chloroform/methanol, 15: 1)
2, the preparation of Serine (4d) N-[(2-N-Boc-1,2,3,4--tetrahydrochysene-β-Ka Lin-3-formyl radical)
Adopt the operation of step 2 among the embodiment 1, by 1.3g (3.12mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl serine methylester obtains 1.05g (84%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Serine (5d)
Adopting the operation of step 3 among the embodiment 1, by 1.05g (2.6mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Serine obtains 700mg (85%) title compound, is the reddish-brown solid.ESI/MS：304[M+H] +， [ α ] D 25 = - 70 (C＝1，DMF)， 1HNMR(300MHZ，DMSO-d6)：δ/ppm＝2.896(d，J＝6.9Hz，1H)，3.407(m，J＝5.4Hz，1H)，3.779(d，J＝4.5Hz，2H)，4.305(t，J＝4.9Hz，1H)，4.455(m，J＝5.1Hz，2H)，4.489(s，1H)，7.122(t，J＝7.8Hz，1H)，7.384(d，J＝7.8Hz，1H)，7.468(d，J＝7.5Hz，1H)，9.104(d，J＝7.2Hz，1H)，9.861(s，1H)，11.190(s，1H)，12.9(s，1H)。
The preparation of embodiment 5.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Threonine (5e)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-Threonine methyl esters (3e)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 2.7g title compound, be faint yellow solid with 1.08g (6.96mmol) HClThrOMe oily matter.Rf=0.267 (chloroform/methanol, 15: 1)
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-Threonine (4e)
Adopt the operation of step 2 among the embodiment 1, by 1g (2.32mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl Threonine methyl esters obtains 750mg (78%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Threonine (5e)
Adopting the operation of step 3 among the embodiment 1, by 750mg (1.8mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Threonine obtains 580mg (91%) title compound, is the reddish-brown solid.Mp180℃-182℃，ESI/MS：318[M+H] +， [ α ] D 25 = - 28 (C=1, ethanol), IR (cm -1): 3378,2976,1677,747, 1HNMR (300MHZ, DMSO-d6): δ/ppm=2.873 (t, J=5.5Hz 1H), 3.451 (m, J=5.4Hz, 1H), 4.230 (m, J=5.4Hz, 1H), 4.355 (m, J=6.4Hz, 2H) 4.448 (s, 1H), 5.316 (s, 1H), 7.028 (t, J=7.8Hz, 1H), 7.121 (t, J=8.4Hz, 1H), 7.384 (dJ=8.1Hz, 1H), 7.463 (d, J=7.5Hz, 1H), 8.951 (d, J=8.4Hz, 1H), 9.861 (m, 1H) 11.223 (d, J=4.2Hz, 1H), 12.9 (s, 1H).
The preparation of embodiment 6.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tyrosine (5f)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-L-Tyrosine methyl ester (3f)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 3.2g title compound, be faint yellow solid with 1.62g g (6.96mmol) HClTyrOMe.ESI/MS:516[M+Na] +, 491[M+H] +, Rf=0.350 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tyrosine (4f)
Adopt the operation of step 2 among the embodiment 1, by 1g (2.17mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyltyrosine methyl esters obtains 650mg (67%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tyrosine (5f)
Adopting the operation of step 3 among the embodiment 1, by 620mg (1.39mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tyrosine obtains 450mg (84%) title compound, is faint yellow solid.ESI/MS：380[M+H] +， [ α ] D 25 = - 88 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=2.848 (m, J=9.9Hz, 1H), 3.160 (s, 1H), 3.055 (dd, J=9.6Hz, J=4.8Hz, 2H), 4.235 (m, J=5.6Hz, 1H), 4.353 (m, J=6.2Hz, 2H), 4.448 (s, 1H), 6.702 (d, J=8.4Hz, 2H), 7.009 (t, J=7.2Hz, 1H), 7.023 (t, J=7.8Hz, 1H), 7.145 (d, J=8.1Hz, 2H), 7.377 (d, J=8.1Hz, 1H), 7.444 (d, J=7.5Hz, 1H), 8.979 (d, J=7.5Hz, 1H), 9.354 (s, 1H), 9.861 (s, 1H), 11.192 (s, 1H), 12.9 (s, 1H).
The preparation of embodiment 7.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) proline(Pro) (5g)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-proline methyl ester (3g)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 2.8g title compound, be faint yellow solid with 1.15g (6.96mmol) HClProOMe.Rf=0.276 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) proline(Pro) (4g)
Adopt the operation of step 2 among the embodiment 1, by 0.5g (1.17mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl proline methyl ester obtains 400mg (83%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) proline(Pro) (5g)
Adopting the operation of step 3 among the embodiment 1, by 400mg (0.97mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) proline(Pro) obtains 300mg (89%) title compound, is faint yellow solid.ESI/MS：314[M+H] +， [ α ] D 25 = - 36 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=1.965 (m, J=8.7Hz, 2H) 1.973 (m, J=8.7Hz, 2H), 2.834 (t, J=5.6Hz, 1H), 3.160 (s, 1H), 3.682 (s, 1H), 3.763 (d, J=6.3Hz, 1H), 4.261 (m, J=5.4Hz, 1H), 4.358 (m, J=6.3Hz, 2H), 4.721 (s, 1H), 7.031 (t, J=7.5Hz, 1H), 7.122 (t, J=7.8Hz, 1H), 7.384 (d, J=7.5Hz, 1H), 7.513 (t, J=8.4Hz, 1H), 9.861 (s, 1H), 11.134 (S, 1H).
The preparation of embodiment 8.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) halfcystine (5h)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-acthiol-J (3h)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 2.7g title compound, be faint yellow solid with 1.2g (6.96mmol) HClCysOMe.Rf=0.259 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-β-Ka Lin-3-formyl radical) halfcystine (4h)
Adopt the operation of step 2 among the embodiment 1, by 1.0g (2.31mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl acthiol-J obtains 450mg (48%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) halfcystine (5h)
Adopting the operation of step 3 among the embodiment 1, by 700mg (1.67mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) halfcystine obtains 580mg (98%) title compound, is faint yellow solid.Mp.200-201℃，ESI/MS：286[M+H] +， [ α ] D 25 = - 86 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=2.875 (d, J=6.5Hz, 2H), 3.368 (d, J=6.7Hz, 2H), 4.063 (m, J=6.7Hz, 1H), 4.463 (d, J=5.8Hz, 2H), 4.688 (d, J=5.6Hz, 1H), 7.028 (t, J=7.2Hz, 1H), 7.119 (t, J=7.8Hz, 1H), 7.369 (d, J=7.8Hz, 1H), 7.507 (d, J=7.6Hz, 1H) 9.317 (d, J=7.5Hz, 1H); 9.861 (s, 1H), 11.2185 (d, J=6.3Hz, 1H).
The preparation of embodiment 9.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) methionine(Met) (5i)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-methionine(Met) methyl esters (3i)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 2.85g title compound, be faint yellow solid with 1.39g (6.96mmol) HClTyrOMe.Rf=0.328 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) methionine(Met) (4i)
Adopt the operation of step 2 among the embodiment 1, by 1g (2.17mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formylmethionine methyl esters obtains 700mg (72%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) methionine(Met) (5i)
Adopting the operation of step 3 among the embodiment 1, by 600mg (1.34mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) methionine(Met) obtains 370mg (80%) title compound, is faint yellow solid.Mp.186-189℃，ESI/MS：348[M+H] +， [ α ] D 25 = - 86 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=1.435 (m, J=5.5Hz, 2H), 2.509 (m, J=5.7Hz, 2H), 3.388 (d, J=6.4Hz, 2H), 3.462 (m, J=6.5Hz, 1H), 4.393 (d, J=5.4Hz, 2H), 4.08 (d, J=5.5Hz, 1H), 7.033 (t, J=7.8Hz, 1H), 7.116 (t, J=7.5Hz), 7.374 (d, J=7.8Hz, 1H), 7.494 (d, J=7.8Hz, 1H), 9.136 (d, J=5.5Hz, 1H), 9.861 (s, 1H), 11.207 (s, 1H).
The preparation of embodiment 10.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-glutamic acid (5j)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-glutamic acid methyl ester (3j)
Adopt the operation of step 1 among the embodiment 1, with 1.47g (6.96mmol) HClGlu (oMe) 2Replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 3.00g title compound, be faint yellow solid.Rf=0.500 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-glutamic acid (4j)
Adopt the operation of step 2 among the embodiment 1, by 2.8g (5.9mmol) 2-N-Boc-1,2,3, the two methyl esters of 4-tetrahydrochysene-β-Ka Lin-3-carbamylglutamic obtain 2.0g (76%) title compound, are faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-glutamic acid (5j)
Adopting the operation of step 3 among the embodiment 1, by 2.0g (4.49mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) L-glutamic acid obtains 1.6g (94%) title compound, is the light green solid.Mp.186-189℃，ESI/MS：346[M+H] +， [ α ] D 25 = - 66 (C=1, ethanol), 1HNMR (300MHZ, DMSO-d6): δ/ppm=2.114 (m, J=5.5Hz, 2H), 2.4025 (t, J=8.1Hz, 2H), 3.313 (d, J=5.1Hz, 2H), 4.222 (m, J=6.5Hz, 1H), 4.503 (d, J=5.4Hz, 2H), 4.481 (d, J=5.5Hz, and 1H) 7.028 (t, J=7.5Hz, 1H), 7.118 (t, J=7.5Hz, 1H), 7.380 (d, J=7.8Hz, 1H), 7.477 (t, J=7.8Hz, 1H), 9.066 (d, J=5.5Hz, 1H), 9.893 (s, 1H), 11.271 (s, 1H), 11.7 (s, 1H), 12.500 (s, 1H).
The preparation of embodiment 11.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) aspartic acid (5k)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-aspartic acid methyl esters (3k)
Adopt the operation of step 1 among the embodiment 1, with 1.37g (6.96mmol) HClAsp (oMe) 2Replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 2.80g title compound, be faint yellow solid.ESI/MS:460[M+H] +, Rf=0.317 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) aspartic acid (4k)
Adopt the operation of step 2 among the embodiment 1, by 700mg (1.53mmol) 2-N-Boc-1,2,3, the two methyl esters of 4-tetrahydrochysene-β-Ka Lin-3-carbamyl aspartic acid obtain 470mg (72%) title compound, are faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) aspartic acid (5k)
Adopting the operation of step 3 among the embodiment 1, by 460mg (1.07mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) aspartic acid obtains 356mg (91%) title compound, is the reddish-brown solid.ESI/MS：332[M+H] +， [ α ] D 25 = - 12 (C＝1，DMF)，IR(cm -1)：2936，1729，750。 1HNMR(300MHZ，DMSO-d6)：/ppm＝2.889(d，J＝5.3Hz，2H)，3.362(d，J＝5.2Hz，2H)，4.322(m，J＝6.5Hz，1H)，4.511(d，J＝5.4Hz，2H)，4.671(d，J＝5.5Hz，1H)7.045(d，J＝8.1Hz，1H)，7.108(d，J＝7.8Hz，1H)，7.383(d，J＝8.4Hz，1H)，7.437(d，J＝7.3Hz，1H)；9.05(d，J＝5.5Hz，1H)，9.893(s，1H)，11.231(s，1H)，11.701(s，1H)，12.423(s，1H)。
The preparation of embodiment 12.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Histidine (5l)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-Histidine methyl esters (3l)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 3.00g title compound, be faint yellow solid with 1.43g (6.96mmol) HClHisOMe.ESI/MS:460[M+H] +, Rf=0.338 (chloroform/methanol, 15: 1).
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Histidine (4l)
Adopt the operation of step 2 among the embodiment 1, by 450mg (0.96mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl Histidine methyl esters obtains 330mg (76%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Histidine (5l)
Adopting the operation of step 3 among the embodiment 1, by 320mg (0.77mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) Histidine obtains 258mg (94%) title compound, is yellow solid.ESI/MS：354[M+H] +， [ α ] D 25 = - 6 (C＝1，H 2O)， 1HNMR(300MHZ，DMSO-d6)：δ/ppm＝3.188(m，2H)，3.353(d，J＝5.3Hz，2H)，3.501(d，J＝5.4Hz，2H)，4.371(d，J＝5.5Hz，1H)4.727(d，J＝5.5Hz，1H)，7.036(t，J＝7.2Hz，1H)，7.133(t，J＝7.2Hz，1H)，7.369(d，J＝7.8Hz，1H)，7.509(d，J＝7.8Hz，1H)，7.596(s，1H)，9.116(s，1H)，9.395(d，J＝7.8Hz，1H)，9.893(s，1H)，11.250(s，1H)。
The preparation of embodiment 13.N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tryptophane (5m)
1, the preparation of N-(N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical)-tryptophan methyl ester (3m)
Adopt the operation of step 1 among the embodiment 1, replace 1.07g (6.96mmol) HClAlaOMe 2g (6.33mmol) to get the 3.20g title compound, be faint yellow solid with 1.78g (6.96mmol) HClTrpOMe.FAB/MS:517[M+H] +, Rf=0.133 (chloroform/methanol, 15: 1)
2, the preparation of N-(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tryptophane (4m)
Adopt the operation of step 2 among the embodiment 1, by 1.0g (1.83mmol) 2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl tryptophan methyl ester obtains 680mg (70%) title compound, is faint yellow solid.
3, the preparation of N-(1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tryptophane (5m)
Adopting the operation of step 3 among the embodiment 1, by 660mg (1.19mmol) N-[(2-N-Boc-1,2,3,4-tetrahydrochysene-β-Ka Lin-3-formyl radical) tryptophane obtains 480mg (91%) title compound, is the light green solid.ESI/MS：403[M+H] +， [ α ] D 25 = - 64 (C＝1，DMF)， 1HNMR(300MHZ，DMSO-d6)：δ/ppm＝3.186(d，J＝5.4Hz，2H)，3.521(d，J＝5.4Hz，2H)，4.347(d，J＝5.5Hz，1H)4.667(d，J＝5.5Hz，1H)，6.986(t，J＝7.2Hz，2H)，7.442(d，J＝7.5Hz，4H)，7.521(d，J＝7.3Hz，2H)，7.599(s，1H)，9.015(d，J＝7.2Hz，1H)，9.813(s，1H)，10.965(s，1H)，11.149(s，1H)，12.901(s，1H)。
The antithrombotic of test example 1 The compounds of this invention is measured
One, test materials
Supply test agent: the sample that the embodiment of the invention is prepared
Control sample: NS (physiological saline), carboline carboxylate (synthetic), acetylsalicylic acid (available from Shandong Xinhua pharmaceutical factory) by laboratory oneself, inventor place
Laboratory animal: male Wistra rat (available from about Department Of Medicine, Peking University laboratory animal portion, body weight 250 grams)
Two, test method and result
Be dissolved in physiological saline before will measuring for test agent.(5.0mg/ml 3ml/kg) after the anesthesia, separates right carotid and left jugular vein to the Wistra rat with vetanarcol.The silk thread that the long prior precision of a 6cm is weighed is placed in the polyethylene tube, after intubate being full of the normal saline solution (50IU/ml) of heparin sodium, an end inserts the left side vein, adds quantitative heparin sodium anti-freezing from an end, and the adding testing compound, insert the right side artery then.Blood flow flows into the left side vein from the right side artery polyethylene tube of flowing through, and takes out with the silk thread of thrombus after 15 minutes and writes down weight in wet base, in moisture eliminator, placed for two weeks with the silk thread of thrombus after, weighing dry weight (seeing Table 1).
Table 1 compound of the present invention is to thrombotic influence
Compound Wet weight of thrombus (x ± SDmg) The thrombus dry weight (x ± SDmg)
NS carboline carboxylate aspirin 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 38.67±8.66 31.69±5.72 a 25.95±3.92 a，b 28.97±9.56 a 24.35±7.78 a，b 23.67±6.88 a，b 25.52±9.65 a 32.24±3.18 33.22±5.67 34.34±7.50 21.47±2.92 a，b，c 20.69±5.44 a，b，c 29.03±6.93 a 28.78±7.46 a 26.15±7.23 a 14.40±2.30 11.62±2.56 4.11±0.99 5.13±1.34 11.67±1.88 4.14±1.77 12.28±3.54 12.14±4.31 4.13±1.53 10.83±5.91 2.55±0.64 2.59±1.55 6.21±2.72 12.34±1.26 7.20±4.91
N=12 a) compares p＜0.05 with the NS group; B) compare p＜0.05 with carboline carboxylate; C) compare p＜0.05 with acetylsalicylic acid
As can be seen from the test results, the antithrombotic acitivity of The compounds of this invention obviously is better than control sample, illustrates that The compounds of this invention has very high antithrombotic acitivity.
The external platelet aggregation inhibitory activity of test example 2 The compounds of this invention is measured
One, test materials
1, for test agent: the sample that the embodiment of the invention is prepared
2, control sample: carboline carboxylate (oneself is synthetic), acetylsalicylic acid (available from Shandong Xinhua pharmaceutical factory)
3, laboratory animal: male White Rabbit (available from about Department Of Medicine, Peking University laboratory animal portion, body weight 3000 grams)
Two, test method and result
Rabbit ear edge vein is got blood, with 3.8% Sodium Citrate (V Sodium Citrate: V Rabbit blood=1: 9) anti-freezing.Centrifugal 10 minutes of 800-1200g/min platelet rich plasma (PRP), centrifugal 10 minutes again with 3500g/min, platelet poor plasma (PPP).With ADP (adenosine diphosphate (ADP)) is that (final concentration is 10 to the gathering of inductor induced platelet -5Mmol/l).Test-results sees Table 2.
Table 2 compound of the present invention is to the influence of AD inductive platelet aggregation
Compound Maximum platelet aggregation-against rate (%)
Concentration (10 -4mol/l) Concentration (10 -5mol/l)
Aspirin carboline carboxylate 5a 5b 5c 5d 5e 5f 5g 5h 5i 5j 5k 5l 18.75 53.12 20.8 26.4 25.3 27.8 25 28 15.8 34.7 46.1 15.6 28.4 10.94 40.62 6.25 4.17 18.9 9.38 27.3 95.8 16 24.2 25.3 38.3 4.17 15.8
Though carboline carboxylate and amino acid modified thing all do not have a strong platelet aggregation inhibitory activity external as can be seen from the test results, all apparently higher than acetylsalicylic acid, are 10 in concentration -5The external platelet aggregation inhibitory activity of mol/l The compounds of this invention 5f has reached 95.8%, apparently higher than carboline carboxylate, illustrates that the amino acid modified strategy that the present invention adopts has clear and definite application value.

Claims (10)

1, a kind of carboline carboxylate derivative has the structure of general formula I,
General formula I
Wherein R is selected from :-CH 3,-CH 2C 6H 5,-CH (CH 3) 2,-CH 2OH ,-CH (OH) CH 3,-CH 2C 6H 4-OH-p, Pyrrolidine-2-base ,-CH 2SH ,-CH 2CH 2SCH 3,-CH 2CH 2COOH ,-CH 2COOH, 1,3-imidazoles methyl or indoles-3-methyl.
2, the synthetic method of compound of Formula I may further comprise the steps:
1), L-tryptophane and formaldehyde condensation are made (3S)-β-Ka Lin carboxylic acid,
2), 2 N of (3S)-β-Ka Lin carboxylic acid are protected preparation N-protected base-β-Ka Lin carboxylic acid,
3), with N-protected base-β-Ka Lin carboxylic acid and amino acid ester condensation prepared N-protected base-β-Ka Lin amido-carboxylic acid esters,
4), N-protected base-β-Ka Lin amido-carboxylic acid esters is taken off protecting group and ester is hydrolyzed to acid promptly gets general formula compound of the present invention.
3, according to the synthetic method of claim 2, wherein the condensation reaction in the step 1 is to carry out under mineral acid catalysis.
4, according to the synthetic method of claim 3, wherein said mineral acid is the vitriol oil.
5, according to the synthetic method of claim 2, wherein the protecting group of 2 N of (3S)-β-Ka Lin carboxylic acid is tertbutyloxycarbonyl or benzyl in the step 2.
6, want 5 synthetic method according to right, wherein the protecting group of 2 N of (3S)-β-Ka Lin carboxylic acid is a tertbutyloxycarbonyl in the step 2.
7, want 2 synthetic method according to right, used condensing agent is DCC in the step 3;
8, according to the synthetic method of claim 2, wherein deprotection and ester hydrolysing step are first saponification hydrogenolysis or first saponification acidolysis more again in the step 4.
9, according to the synthetic method of claim 8, wherein deprotection steps is first saponification acidolysis again in the step 4.
10, the purposes of compound of Formula I in the preparation antithrombotic reagent.
Figure A2004100742040003C1
General formula I
Wherein R is selected from-CH 3, CH 2C 6H 5,-CH (CH 3) 2,-CH 2OH ,-CH (OH) CH 3,-CH 2C 6H 4-OH-p, Pyrrolidine-2-base ,-CH 2SH ,-CH 2CH 2SCH 3,-CH 2CH 2COOH ,-CH 2COOH, 1,3-imidazoles methyl, indoles-3-methyl.
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