CN109134605A - 1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GYIGSK, synthesis, activity and application - Google Patents
1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-GYIGSK, synthesis, activity and application Download PDFInfo
- Publication number
- CN109134605A CN109134605A CN201710458265.XA CN201710458265A CN109134605A CN 109134605 A CN109134605 A CN 109134605A CN 201710458265 A CN201710458265 A CN 201710458265A CN 109134605 A CN109134605 A CN 109134605A
- Authority
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- China
- Prior art keywords
- gly
- carboline
- tetrahydro
- formyl
- ile
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000694 effects Effects 0.000 title abstract description 37
- 230000015572 biosynthetic process Effects 0.000 title description 4
- GMKZMEPZXHFKPZ-UHFFFAOYSA-N C1CNC(C2=NC3=CC=CC=C3C21)(CO)CO Chemical compound C1CNC(C2=NC3=CC=CC=C3C21)(CO)CO GMKZMEPZXHFKPZ-UHFFFAOYSA-N 0.000 title description 2
- 238000003786 synthesis reaction Methods 0.000 title description 2
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- 238000002360 preparation method Methods 0.000 claims abstract description 4
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- 239000005557 antagonist Substances 0.000 claims abstract description 3
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- 238000000034 method Methods 0.000 claims description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 16
- LPIJOZBIVDCQTE-UHFFFAOYSA-N tetrahydroharman Chemical compound N1C2=CC=CC=C2C2=C1C(C)NCC2 LPIJOZBIVDCQTE-UHFFFAOYSA-N 0.000 claims description 14
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 10
- -1 tert-butyldimethylsilyl chloride silicon Alkane Chemical class 0.000 claims description 10
- ZUPHXNBLQCSEIA-UHFFFAOYSA-N (1xi,3xi)-1,2,3,4-Tetrahydro-1-methyl-beta-carboline-3-carboxylic acid Chemical compound N1C2=CC=CC=C2C2=C1C(C)NC(C(O)=O)C2 ZUPHXNBLQCSEIA-UHFFFAOYSA-N 0.000 claims description 8
- 238000009833 condensation Methods 0.000 claims description 8
- 230000005494 condensation Effects 0.000 claims description 8
- ZRUBCNOEBUECNG-KFJBMODSSA-N methyl (3S)-1,1-bis(hydroxymethyl)-2,3,4,4a-tetrahydropyrido[3,4-b]indole-3-carboxylate Chemical compound COC(=O)[C@H]1NC(C2=NC3=CC=CC=C3C2C1)(CO)CO ZRUBCNOEBUECNG-KFJBMODSSA-N 0.000 claims description 8
- 238000006243 chemical reaction Methods 0.000 claims description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000007791 liquid phase Substances 0.000 claims description 6
- WZHYQHKXXRMALW-UHFFFAOYSA-N methyl 1-methyl-2,3,4,9-tetrahydro-1h-pyrido[3,4-b]indole-3-carboxylate Chemical compound C1=CC=C2C(CC(NC3C)C(=O)OC)=C3NC2=C1 WZHYQHKXXRMALW-UHFFFAOYSA-N 0.000 claims description 6
- ULBGQMDUNSJLSE-UMJHXOGRSA-N (3S)-1,1-bis(hydroxymethyl)-2,3,4,4a-tetrahydropyrido[3,4-b]indole-3-carboxylic acid Chemical compound C(O)C1(N[C@@H](CC2C3=CC=CC=C3N=C12)C(=O)O)CO ULBGQMDUNSJLSE-UMJHXOGRSA-N 0.000 claims description 5
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 claims description 4
- 230000008878 coupling Effects 0.000 claims description 4
- 238000010168 coupling process Methods 0.000 claims description 4
- 238000005859 coupling reaction Methods 0.000 claims description 4
- 150000002460 imidazoles Chemical class 0.000 claims description 3
- JXYACYYPACQCDM-UHFFFAOYSA-N Benzyl glycinate Chemical compound NCC(=O)OCC1=CC=CC=C1 JXYACYYPACQCDM-UHFFFAOYSA-N 0.000 claims description 2
- 238000006929 Pictet-Spengler synthesis reaction Methods 0.000 claims description 2
- 238000007171 acid catalysis Methods 0.000 claims description 2
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 claims description 2
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- 125000002059 L-arginyl group Chemical group O=C([*])[C@](N([H])[H])([H])C([H])([H])C([H])([H])C([H])([H])N([H])C(=N[H])N([H])[H] 0.000 claims 1
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- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 claims 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 54
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 7
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
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- KYITYFHKDODNCQ-UHFFFAOYSA-M sodium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [Na+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 KYITYFHKDODNCQ-UHFFFAOYSA-M 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
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- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
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- DMBKPDOAQVGTST-GFCCVEGCSA-N (2r)-2-[(2-methylpropan-2-yl)oxycarbonylamino]-3-phenylmethoxypropanoic acid Chemical compound CC(C)(C)OC(=O)N[C@@H](C(O)=O)COCC1=CC=CC=C1 DMBKPDOAQVGTST-GFCCVEGCSA-N 0.000 description 1
- CNBUSIJNWNXLQQ-NSHDSACASA-N (2s)-3-(4-hydroxyphenyl)-2-[(2-methylpropan-2-yl)oxycarbonylamino]propanoic acid Chemical compound CC(C)(C)OC(=O)N[C@H](C(O)=O)CC1=CC=C(O)C=C1 CNBUSIJNWNXLQQ-NSHDSACASA-N 0.000 description 1
- QJCNLJWUIOIMMF-YUMQZZPRSA-N (2s,3s)-3-methyl-2-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)OC(C)(C)C QJCNLJWUIOIMMF-YUMQZZPRSA-N 0.000 description 1
- FSNCEEGOMTYXKY-UHFFFAOYSA-N 1,2,3,4-tetrahydro-beta-carboline-3-carboxylic acid Chemical group N1C2=CC=CC=C2C2=C1CNC(C(=O)O)C2 FSNCEEGOMTYXKY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
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- 239000005046 Chlorosilane Substances 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 102000015636 Oligopeptides Human genes 0.000 description 1
- 108010038807 Oligopeptides Proteins 0.000 description 1
- 108010035030 Platelet Membrane Glycoprotein IIb Proteins 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 229910006124 SOCl2 Inorganic materials 0.000 description 1
- SBMNPABNWKXNBJ-BQBZGAKWSA-N Ser-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@@H](N)CO SBMNPABNWKXNBJ-BQBZGAKWSA-N 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
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- 230000006838 adverse reaction Effects 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 150000003797 alkaloid derivatives Chemical class 0.000 description 1
- 230000002785 anti-thrombosis Effects 0.000 description 1
- 210000000702 aorta abdominal Anatomy 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
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- 229920002678 cellulose Polymers 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000012230 colorless oil Substances 0.000 description 1
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- 229920001971 elastomer Polymers 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
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- 239000003292 glue Substances 0.000 description 1
- 230000002439 hemostatic effect Effects 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- CWRATHCADZOYAT-UHFFFAOYSA-N methyl quinoline-3-carboxylate Chemical compound C1=CC=CC2=CC(C(=O)OC)=CN=C21 CWRATHCADZOYAT-UHFFFAOYSA-N 0.000 description 1
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- DJXNJVFEFSWHLY-UHFFFAOYSA-N quinoline-3-carboxylic acid Chemical compound C1=CC=CC2=CC(C(=O)O)=CN=C21 DJXNJVFEFSWHLY-UHFFFAOYSA-N 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention discloses (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys, disclose its preparation method, disclose its anti-arterial thrombus activity, disclose its anti-phlebothrombosis activity, the activity that it inhibits GPIIb/IIIa expression is disclosed, the activity that it inhibits palatelet-selectin expression is disclosed.Thus the invention discloses it prepare the application in anti-arterial thrombus drug, prepare in anti-phlebothrombosis drug using, in the application prepared in GPIIb/IIIa antagonist and preparing the application in palatelet-selectin antagonist.
Description
Technical field
The present invention relates to (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
Lys is related to its preparation method, is related to its anti-arterial thrombus activity, is related to its anti-phlebothrombosis activity, is related to it and inhibits
The activity of GPIIb/IIIa expression is related to the activity that it inhibits internal palatelet-selectin expression.Thus the present invention relates to it to prepare
Application in anti-arterial thrombus drug, prepare the application in anti-phlebothrombosis drug, in preparation GPIIb/IIIa antagonist
Application and preparing the application in solidifying palatelet-selectin antagonist.The invention belongs to biomedicine fields.
Background technique
The formation of thrombus is the master for leading to myocardial infarction, cerebral apoplexy, pulmonary embolism, deep vein thrombosis and other cardiovascular diseases
The main reason for wanting reason, being global incidence and the death rate.Current medicine for treating thrombus object, although thrombus can be inhibited with effective
Formation reduce its safety and limit clinical efficacy but since it influences hemostatic function or bleeding risk.B-carboline class
The multiple biological activities of alkaloid include that the activity of platelet aggregation is inhibited to be disclosed.Inventor also once disclosed a series of
With the active B-carboline -3- formyl oligopeptides of anti-arterial thrombus, their intravenously administrable dosage is 5 μm of ol/kg.Inventor is to it
Activity have two o'clock dissatisfied.First point is, intravenous injection makes that they enter blood circulation and to be rapidly reached high blood medicine dense
Degree.Just because of high concentration, they reach rapidly blood plasma and tissue and increase the risk that adverse reaction occurs.This is intravenously administrable
The inherent shortcoming of itself can only just can solve by inventing orally available compound.Second point is, although the position 1- in carboline is drawn
Enter methyl, effective oral dose can be made to be reduced to 0.01 μm of ol/kg, but such compound only shows anti-arterial thrombus
Activity, not anti-phlebothrombosis activity.Phlebothrombosis is tumor patient and the universal complication of patient for receiving various operations, can be made
Patient is disabled or lethal, needs to take anti-phlebothrombosis drug throughout one's life.Due to existing anti-phlebothrombosis drug, such as warfarin
It can cause fatal bleeding side reaction.In addition, because the mechanism of venous thronbosis and Arterial thrombosis is entirely different,
It is often invalid to phlebothrombosis to arterial thrombus compounds effective.Then, invention is all effective to arterial thrombus and phlebothrombosis
Compound become antithrombotic reagent forward position.By exploring repeatedly, inventor has found the 1- in tetrahydro-beta-carboline -3- carboxylic acid
Position introduces double methylols, introduces (3S) -1,1- dihydroxymethyl-tetrahydro-that Gly-Tyr-Ile-Gly-Ser-Lys is generated at 3-
B-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys shows good anti-dynamic under 0.01 μm of ol/kg oral dose
Arteries and veins thrombus activity and anti-phlebothrombosis activity, anti-phlebothrombosis activity are 487 times stronger than warfarin.Because the toxic side effect of drug is all
It can reduce and disappear with dosage, so 487 times of effective dose reduction shows this structural modification and has technical effect outstanding.
Then, inventor proposes the present invention.
Summary of the invention
First content of the invention is to provide (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl of following formula
Gly-Tyr-Ile-Gly-Ser-Lys。
Second content of the invention is to provide (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-
The synthetic method of Ile-Gly-Ser-Lys, this method comprises:
(1) L-Trp carries out Pictet-Spengler condensation generation under dilute sulfuric acid catalysis with C3H6O3
(3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylic acid；
(2) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester is prepared；
(3) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester in the presence of imidazoles with fert-butyidimethylsilyl
Chlorosilane (TBDMSCl) reaction generates (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid
Methyl esters；
(4) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylate methyl ester is 4N's
Hydrolysis generates (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid in NaOH aqueous solution；
(5) using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, (3S)-is made using liquid phase condensations method
1,1- bis- (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid and Gly-OBzl coupling are (3S) -1,1- two
(tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-OBzl；
(6) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-OBzl exists
H2With (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-is converted in the presence of Pd/C
Gly；
(7) it using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, is synthesized using liquid phase condensations method
HCl·Tyr-Ile-Gly-Ser-Lys(Z)-OBzl；
(8) using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, (3S)-is made using liquid phase condensations method
1,1- bis- (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly and HClTyr-Ile-Gly-Ser-
Lys (Z)-OBzl coupling is (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-
Tyr-Ile-Gly-Ser-Lys(Z)-OBzl；
(9) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-Tyr-
Ile-Gly-Ser-Lys (Z)-OBzl is in hydrogen chloride-ethyl acetate solution that concentration is 4N, 0 DEG C of removing fert-butyidimethylsilyl
Silicon substrate prepares (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys (Z) -
OBzl；
(10) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl -- Gly-Tyr-Ile-Gly-Ser-Lys (Z) -
OBzl hydrogenolysis in the presence of Pd/C generates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-
Ser-Lys。
(11) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl -- Gly-Tyr-Ile-Gly-Ser-Lys (Z) -
OBzl is in H2With generation (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly- in the presence of Pd/C
Ser-Lys。
Third content of the invention is evaluation (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-
The anti-dynamic thrombus activity of Ile-Gly-Ser-Lys.
4th content of the invention is evaluation (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-
Ile-Gly-Ser-Lys's resists quiet thrombus activity.
5th content of the invention is evaluation (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-
Ile-Gly-Ser-Lys inhibits the activity of GPIIb/IIIa expression.
6th content of the invention is evaluation (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-
Ile-Gly-Ser-Lys inhibits the activity of palatelet-selectin expression.
Detailed description of the invention
Fig. 1 (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys conjunction
At route .i) 1,3-Dihydroxyacetone, dense H2SO4, H2O；Ii) methanol, SOCl2；Iii) tert-butyl chloro-silicane
(TBDMSCl), imidazoles, anhydrous n,N-Dimethylformamide (DMF)；Iv) 4N NaOH, methanol, ice bath；V) N, N'- dicyclohexyl
Carbodiimide (DCC), I-hydroxybenzotriazole (HOBt), N-methylmorpholine (NMM), tetrahydrofuran；Vi) Pd/C, H2；vii)4N
The ethyl acetate solution of hydrogen chloride；TBS is tert-butyldimethyl silyl in 3-7.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylic acid (1)
6.12g (30mmol) L-Trp is suspended in 100mL distilled water.Under ice bath, the concentrated sulfuric acid is slowly added dropwise inward
Until L-Trp is completely dissolved.3.24g (36mmol) 1,3-Dihydroxyacetone is added into solution, reacts at room temperature 72 hours.
TLC (ethyl acetate/water ice acetic acid, 10/1/2) display has been reacted.Filtering, filter cake are rinsed with ice water, obtain 6.13g (74%)
Title compound is yellow powder.
Embodiment 2 prepares (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester (2)
5.2mL thionyl chloride is slowly added dropwise to 55mL methanol under ice salt bath, stirs 30 minutes.5.52g is added to solution
(20mmol) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylic acid (1), stirring is to being completely dissolved.It is small to be stirred at room temperature 12
When.TLC (methylene chloride/methanol, 20:1) shows fully reacting.It is concentrated under reduced pressure, residue is worn away with ethyl acetate is entered, and obtains palm fibre
Yellow solid.Solid 200mL ethyl acetate dissolves, and obtained solution is successively with saturation NaHCO3Aqueous solution washes (30mL × 3)
And saturation NaCl aqueous solution is washed (30mL × 3), anhydrous sodium sulfate is 12 hours dry.Filtering, filtrate decompression concentration, obtains 5.34g
(92%) title compound is yellow solid.ESI-MS(m/e):291[M+H]+；1H-NMR(300MHz,DMSO-d6):δ/ppm
=10.55 (s, 1H), 7.39 (d, J=7.5Hz, 1H), 7.34 (d, J=7.5Hz, 1H), 7.02 (td, J1=7.5Hz, J2=
1.2Hz,1H),6.99(td,J1=7.5Hz, J2=0.9Hz, 1H), 4.79 (m, 2H), 3.96 (m, 1H), 3.77 (m, 1H),
3.75 (s, 3H), 3.647~3.499 (m, 3H), 2.96 (dd, J1=14.7Hz, J2=4.2Hz, 1H), 2.59 (dd, J1=
14.7Hz,J2=11.1Hz, 1H).
Embodiment 3 prepares (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylate methyl ester
(3)
5.22g (18mmol) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester (2) and 50mL is anhydrous
The mixture of N,N-dimethylformamide (DMF) is stirred to being completely dissolved.Under ice bath, 4.4g (64.8mmol) miaow is added into solution
Azoles is simultaneously stirred to being completely dissolved.8.15g tert-butyl chloro-silicane (TBDMSCl) is added into solution, is stirred at room temperature 12
Hour.TLC (petrol ether/ethyl acetate, 20/1) shows fully reacting.350mL is first added into solution under ice bath and is saturated NaCl
Aqueous solution, then be extracted with ethyl acetate 3 times.Ethyl acetate layer is successively with saturation NaHCO3Aqueous solution is washed (40mL × 3) and is saturated
NaCl aqueous solution is washed (40mL × 3), and anhydrous sodium sulfate is 12 hours dry.Filtering, filtrate decompression concentration, obtained yellow oil
Purify (petrol ether/ethyl acetate, 10/1) with silica gel column chromatography.8.19g (88%) title compound is obtained, is colorless oil
Object.ESI-MS(m/e):519[M+H]+；1H-NMR(300MHz,DMSO-d6): δ/ppm=10.31 (s, 1H), 7.41 (d, J=
7.5Hz, 1H), 7.33 (d, J=7.5Hz, 1H), 7.04 (t, J=7.5Hz, 1H), 6.95 (t, J=7.5Hz, 1H), 4.00 (m,
1H),3.79(m,4H),3.72(s,3H),2.99(dd,J1=14.7Hz, J2=3.9Hz, 1H), 2.59 (dd, J1=15.0Hz,
J2=11.1Hz, 1H), 0.83 (s, 9H), 0.82 (s, 9H), 0.04 (s, 3H), 0.00 (s, 3H), -0.05 (s, 6H).
Embodiment 4 prepares (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid (4)
Toward 7.77g (15mmol) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-β-click under ice salt bath
4N NaOH aqueous solution is added dropwise in the solution of quinoline -3- carboxylate methyl ester (3) and 40mL tetrahydrofuran, the pH value for adjusting solution is 13~
14.Reaction mixture stirs 30 minutes.TLC (petrol ether/ethyl acetate, 20/1) shows fully reacting.It is dripped inward under ice salt bath
Add 2N hydrochloric acid solution, the pH value for adjusting solution is 7.It is concentrated under reduced pressure and removes tetrahydrofuran and methanol.Saturation is added dropwise under ice salt bath inward
KHSO4Aqueous solution, the pH value for adjusting solution is 2~3.Solution is extracted with ethyl acetate 3 times.Ethyl acetate layer saturation NaCl water
Solution is washed 3 times, and anhydrous sodium sulfate is 12 hours dry.Filtering, filtrate decompression concentration, obtains 6.96g (90%) title compound, is
Colourless powder.ESI-MS(m/e):505[M+H]+。
Embodiment 5 prepares (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl -
Gly-OBzl(5)
By two (tertiary butyl dimethyl Si base) methyl-tetrahydro-β-click of 6.90g (13.4mmol) (3S) -1,1- under ice bath
Quinoline -3- carboxylic acid (4), the solution of 2.76g (13.4mmol) DCC, 1.81g (13.4mmol) HOBt and 150mL anhydrous tetrahydro furan
Stirring 30 minutes.3.24g (16.08mmol) HClGly-OBzl is added into solution, N-methylmorpholine is added dropwise and adjusts reaction solution
PH be 9, be stirred at room temperature 8 hours.TLC (petrol ether/ethyl acetate, 5/1) shows fully reacting.Reaction mixture filtering, filter
Liquid is concentrated under reduced pressure, and residue 150mL ethyl acetate dissolves, and filtering, filtrate successively uses 5%NaHCO3Aqueous solution wash (30mL ×
3), saturation NaCl aqueous solution washes (30mL × 3), 5%KHSO4Aqueous solution is washed (30mL × 3), and saturation NaCl aqueous solution washes (30mL
× 3), 5%NaHCO3Aqueous solution is washed (30mL × 3), and saturation NaCl aqueous solution is washed (30mL × 3), and anhydrous sodium sulfate dry 12 is small
When.Filtering, filtrate decompression concentration, obtained yellow syrup silica gel column chromatography are purified (petrol ether/ethyl acetate, 6/1), are obtained
4.86g (82%) title compound is yellow syrup.ESI-MS(m/e):652[M+H]+。
Embodiment 6 prepares (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly
(6)
By two (tertiary butyl dimethyl Si base) methyl-tetrahydro of 4.86g (7.46mmol) (3S) -1,1--B-carboline -3- first
Acyl-Gly-OBzl (5) is dissolved in 100mL methanol.Add 486mg Pd/C into solution, extract air in bottle out, be passed through hydrogen, repeats three
After secondary, room temperature is led to hydrogen 6 hours.TLC (petrol ether/ethyl acetate, 5/1) shows fully reacting.Decompression filters out Pd/C, and filtrate subtracts
Pressure concentration, obtains 4.05g (97%) title compound, is yellow powder.ESI-MS(m/e):562[M+H]+。
Embodiment 7 prepares Boc-Ile-Gly-OBzl
Using the method for embodiment 5 from 4.62g (20mmol) Boc-Ile and 4.84g (24mmol) HClGly-OBzl
7.24g (96%) title compound is obtained, is yellow syrup.ESI-MS(m/e):379[M+H]+。
Embodiment 8 prepares HClIle-Gly-OBzl
By ethyl acetate (4M) solution of 7.24g (19.2mmol) Boc-Ile-Gly-OBzl 80mL hydrogen chloride under ice bath
It dissolves and reacts 4 hours.TLC (petrol ether/ethyl acetate, 2/1) shows fully reacting.Reaction mixture is concentrated under reduced pressure, residual
Object is dissolved with anhydrous ethyl acetate, and obtained solution is concentrated under reduced pressure again.The operation is repeated 3 times.Obtained yellow syrup sample object is used
Anhydrous ether is sufficiently worn away, and 5.85g (91%) title compound is obtained, and is yellow solid.ESI-MS(m/e):279[M+H]+。
Embodiment 9 prepares Boc-Tyr-Ile-Gly-OBzl
Using the method for embodiment 5 from 4.40g (15.3mmol) Boc-Tyr and 5.80g (18.4mmol) HClIle-
Gly-OBzl obtains 7.30g (88%) title compound, is yellow solid.ESI-MS(m/e):542[M+H]+。
Embodiment 10 prepares Boc-Tyr-Ile-Gly
5.70g (98%) is obtained from 7.00g (12.9mmol) Boc-Tyr-Ile-Gly-OBzl using the method for embodiment 6
Title compound is yellow solid.ESI-MS(m/e):452[M+H]+。
Embodiment 11 prepares Boc-Ser (Bzl)-Arg (NO2)-OBzl
Using the method for embodiment 5 from 2.95g (10mmol) Boc-Ser (Bzl) and 5.78g (12mmol) HClArg
(NO2)-OBzl obtains 5.30g (90%) title compound, it is yellow solid.ESI-MS(m/e):587[M+H]+。
Embodiment 12 prepares HClSer (Bzl)-Arg (NO2)-OBzl
Using the method for embodiment 8 from 5.2g (8.87mmol) Boc-Ser (Bzl)-Arg (NO2)-OBzl obtains 4.78g
(97%) title compound is yellow solid.ESI-MS(m/e):487[M+H]+。
Embodiment 13 prepares Boc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO2)-OBzl
Using the method for embodiment 5 from 2.9g (6.46mmol) Boc-Tyr-Ile-Gly and 4.05g (7.75mmol)
HCl·Ser(Bzl)-Arg(NO2)-OBzl obtains 4.90g (75%) title compound, it is yellow solid.ESI-MS(m/e):
920[M+H]+。
Embodiment 14 prepares HClTyr-Ile-Gly-Ser (Bzl)-Arg (NO2)-OBzl
Using the method for embodiment 8 from 3.7g (3.67mmol) Boc-Tyr-Ile-Gly-Ser (Bzl)-Arg (NO2)-
OBzl obtains 3.30g (95%) title compound, is yellow solid.ESI-MS(m/e):487[M+H]+。
Embodiment 15 prepares Boc-Ser-Lys (Z)-OBzl
Using the method for embodiment 5 from 2.04g (10mmol) Boc-Ser and 5.78g (12mmol) 4.88g (12mmol)
HClLys (Z)-OBzl obtains 4.89g (90%) title compound, is yellow solid.ESI-MS(m/e):557[M+H]+。
Embodiment 16 prepares HClSer-Lys (Z)-OBzl
3.1g (94%) title is obtained from 3.7g (6.6mmol) Boc-Ser-Lys (Z)-OBzl using the method for embodiment 8
Compound is colorless solid.ESI-MS(m/e):457[M+H]+。
Embodiment 17 prepares Boc-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl
Using the method for embodiment 5 from 2.26g (5mmol) Boc-Tyr-Ile-Gly and 3.0g (6mmol) HClSer-
Lys (Z)-OBzl obtains 2.68g (60%) title compound, is colorless solid.ESI-MS(m/e):890[M+H]+。
Embodiment 18 prepares HClTyr-Ile-Gly-Ser-Lys (Z)-OBzl
It is obtained using the method for embodiment 8 from 2.6g (2.92mmol) Boc-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl
2.34g (97%) title compound is colorless solid.ESI-MS(m/e):790[M+H]+。
Embodiment 19 prepares (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl -
Gly-Tyr-Ile-Gly-Ser-Lys(Z)-OBzl(7)
Using the method for embodiment 5 from two (tertiary butyl dimethyl Si base) first of 1.32g (2.36mmol) (3S) -1,1-
Base-tetrahydro-beta-carboline -3- formyl-Gly (6) and 2.34g (2.83mmol) HClTyr-Ile-Gly-Ser-Lys (Z)-OBzl
0.48g (15%) title compound is obtained, is colorless solid.ESI-MS(m/e):1334[M+H]+；1H-NMR(300MHz,
DMSO-d6): δ/ppm=10.26 (s, 1H), 9.14 (s, 1H), 8.26 (d, J=7.2Hz, 1H), 8.04 (m, 4H), 7.89 (d,
J=7.8Hz, 1H), 7.71 (m, 1H), 7.35 (m, 11H), 7.22 (m, 1H), 7.04 (m, 3H), 6.94 (m, 1H), 6.15 (d, J
=8.1Hz, 1H), 5.11 (s, 1H), 5.01 (s, 2H), 4.84 (m, 1H), 4.56 (m, 1H), 4.40 (m, 1H), 4.23 (m,
2H), 3.93 (d, J=9.6Hz, 1H), 3.76 (m, 8H), 3.57 (m, 2H), 2.92 (m, 4H), 2.68 (m, 1H), 2.54 (m,
1H),2.29(m,1H),1.73(m,3H),1.30(m,6H),1.11(m,1H),0.77(m,24H),0.01(s,3H),-0.01
(s,3H),-0.05(s,3H),-0.11(s,3H)；13C-NMR(75MHz,DMSO-d6): δ/ppm=173.43,172.14,
171.61,171.56,170.53,169.07,168.87,156.53,156.22,137.74,136.39,136.33,135.11,
132.09,131.96,130.62,129.16,128.85,128.78,128.45,128.22,128.17,126.81,121.10,
118.62,117.90,115.31,111.45,109.08,66.73,66.34,65.72,65.59,65.48,62.25,59.10,
57.63,55.34,54.46,53.40,53.04,52.58,42.50,42.18,40.88,39.21,37.06,30.98,
30.48,29.43,26.31,26.17,24.83,23.00,19.11,18.53,18.37,15.79,14.00,11.59,-
4.96,-5.00,-5.03。
Embodiment 20 prepares (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
Lys(Z)-OBzl(8)
Using the method for embodiment 8 from two (tertiary butyl dimethyl Si base) first of 0.24mg (0.18mmol) (3S) -1,1-
Base-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl obtains 0.18g (90%) title compound
Object is colorless solid.ESI-MS(m/e):1106[M+H]+。
Embodiment 21 prepares (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
Lys(9)
Using the method for embodiment 6 from 0.18g (0.16mmol) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- first
Acyl-Gly-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl (8) obtains 42mg (21%) title compound, is colorless solid.ESI-
MS(m/e):880[M-H]-；Mp:202℃(dec.)；(c=0.1, water)；IR(cm-1):3269.48,
3060.77,2928.36,2876.72,1644.87,1514.23,1454.75,1387.57,1231.02,1051.92,
1022.59,1002.06,822.77,744.64；1H-NMR(300MHz,DMSO-d6): δ/ppm=10.58 (s, 1H), 8.34
(m, 1H), 8.14 (m, 2H), 8.04 (m, 2H), 7.64 (d, J=7.5Hz, 1H), 7.38 (d, J=7.5Hz, 1H), 7.32 (d, J
=7.5Hz, 1H), 6.99 (m, 4H), 6.64 (d, J=8.1Hz, 1H), 4.79 (s, 1H), 4.50 (m, 1H), 4.22 (m, 2H),
3.87~3.47 (m, 12H), 2.90 (m, 2H), 2.73 (m, 3H), 2.51 (m, 2H), 1.74 (m, 2H), 1.52 (m, 4H), 1.13
(m,2H),1.10(m,1H),0.83(m,6H)；13C-NMR(75MHz,DMSO-d6): δ/ppm=174.86,173.86,
171.59,171.43,169.75,169.15,169.02,156.52,136.45,136.20,130.63,127.84,127.01,
120.84,118.53,117.80,115.40,111.58,108.56,65.13,64.07,62.58,59.53,57.49,
55.84,54.74,53.44,42.67,42.37,37.20,36.96,31.79,27.36,26.09,24.84,22.73,
15.80,11.58。
Embodiment 22 evaluates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
The anti-arterial thrombus activity of Lys
The present embodiment selects rat carotid artery-vena jugularis externa extracorporeal bypass to recycle thread model, using aspirin
Normal saline solution is positive control, and physiological saline is blank control, (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- first
Acyl-Gly-Tyr-Ile-Gly-Ser-Lys (compound 9) is therapeutic agent.Bypass circuit is made of three sections of polyethylene rubber tubes.In
Segment length 80.0mm, internal diameter 3.5mm.Both ends pipe range 100.0mm, internal diameter 1.0mm, outer diameter 2.0mm.It is dynamic for insertion rat neck
One end of arteries and veins or the vein pipe pulls into spike tube.Choosing weight is the uniform silk of a length of crude degree in the surface 60.0mm of 4.0 ± 0.1mg
Line is as thrombus carrier.The silicon ethereal solution of three sections of polyethylene glues effective 1% is subjected to silanization, after drying completely, by silk thread
It is placed in middle section polyethylene pipe one end, three sections of polyethylene pipes are assembled, and its junction is sealed and fixed with sealed membrane.It is male
Property SD rat (200 ± 20g) oral aspirin normal saline solution (dosage be 167 μm of ol/kg) or oral normal saline
Or 20% urethane solution (0.7mL/100g body is injected intraperitoneally after 30 minutes in oral administration of compound 9 (dosage is 0.01 μm of ol/kg)
Weight) it is anaesthetized.Anesthetized rat is lain on the back on fixed mouse plate, skin of neck is cut off, separates right common carotid artery and left vena jugularis externa,
And the distal end of right common carotid artery and left vena jugularis externa is ligatured with surgical thread.An angle is cut in left vena jugularis externa, will be filled
The spike tube of the bypass duct of full heparin sodium aqua is inserted into left vena jugularis externa by angle and is open, with surgical thread by polyethylene pipe and vein
Blood vessel is fixed, and it is anticoagulant that quantitative (0.1mL/100g weight) heparin sodium is added in other end syringe.It is dynamic that right neck is clamped with artery clamp
Arteries and veins proximal part cuts an angle in right carotid, removes one section of shunt valve of syringe, is inserted into the proximal part of right carotid, uses hand
Art line fixes polyethylene pipe and arteries, unclamps artery clamp, and blood flow flows through quiet on the left of polyethylene pipe inflow from right artrial
Arteries and veins establishes extracorporal circulatory system.It maintains blood flow unobstructed, the silk thread for having thrombus is taken out after body circulation 15 minutes, sucks silk thread with filter paper
On blood after weigh and record wet weight of thrombus.Data are counted using t inspection.Data are shown in Table 1.The rat that compound 9 is treated
Arterial thrombus be significantly lighter than the arterial thrombus of saline therapy rat, illustrate that compound 9 can effectively inhibit arterial thrombus
It is formed.In addition, rafter acid sodium aqueous solution anticoagulant measurement for embodiment 23 and embodiment 24 of the rat carotid artery blood with 3.8%.
The anti-arterial thrombus activity of 1 compound 9 of table
And physiological saline ratio p < 0.05 a)；N=9.
Embodiment 23 evaluates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
The anti-phlebothrombosis activity of Lys
The present embodiment selects rat Ligation of inferior vena cava model, uses the normal saline solution of warfarin sodium right for the positive
According to physiological saline is blank control, (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-
Ser-Lys (compound 9) is therapeutic agent.SD male rat (250 ± 20g) adapts to environment and fasting one day before surgery.Change
The oral dose for closing object 9 is 0.01 μm of ol/kg.The oral dose of positive control warfarin sodium is 4.87 μm of ol/kg.Blank control
For physiological saline.After 30min is administered, 20% urethane solution of rats by intraperitoneal injection.Anaesthetize 2min.Rat is fixed on rat and fixes
On plate, the disinfection of abdomen preserved skin opens abdominal cavity along hunter's line, down toward solidification gland, up to one jiao of liver of exposing.Remove intraperitoneal small intestine
Equal organs are simultaneously wrapped up with the gauze for infiltrating physiological saline.Blunt separation blood vessel surrounding connective tissue, exposure inferior caval vein and its
Abdominal aorta and inferior caval vein are peeled away below renal vein by branch, and the suture then soaked with physiological saline is in cavity of resorption
The organs such as intestines are moved back to abdominal cavity by anatomical position by Ligation of inferior vena cava by vein and left renal vein intersection, layer-by-layer with suture
Suture abdominal cavity.Rat after enviromental cycle 4 hours, opens celiac branch ligation, hands over from inferior caval vein and left renal vein in 25 DEG C
Start to take out 2cm inferior caval vein at ligation at remittance, is taken out thrombus weighing.Thrombus weight is counted, t inspection is as a result carried out.It is real
It tests data and is shown in Table 2.The phlebothrombosis for the rat that compound 9 is treated significantly is lighter than the phlebothrombosis of saline therapy rat, says
It is bright to effectively inhibit venous thronbosis in 0.01 μm of ol/kg dosages for Compound 9.In addition, the rat that compound 9 is treated
The phlebothrombosis of the rat of its high 487 times of warfarin sodium treatment of phlebothrombosis weight and dose ratio is not significantly different again, explanation
The anti-phlebothrombosis activity of compound 9 is at least 487 times stronger than warfarin sodium.This is unexpected technical effect.
The anti-phlebothrombosis activity of 2 compound 9 of table
And physiological saline ratio p<0.01, a) with warfarin ratio p>0.05；N=8
Embodiment 24 evaluates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
Lys inhibits the activity of GPIIb/IIIa expression
The present embodiment selects the GPIIb/IIIa concentration of the rat carotid artery blood of enzyme-linked immunization measurement embodiment 14.Implement
The rat carotid artery blood of example 24 is anticoagulant with 3.8% rafter acid sodium aqueous solution, and 1000rpm is centrifuged 15 minutes, takes supernatant room temperature flat
Weighing apparatus 30 minutes, it is to be determined.The kit of measurement is rat platelet film GP-IIb/IIIa enzyme linked immunological kit.Kit
It is equilibrium at room temperature 30 minutes, to be determined.
It is required according to kit, first prepares standard items.The standard items in kit are taken to be centrifuged 30 seconds in 10000rpm.Add
1mL sample diluting liquid solution, being blown and beaten repeatedly with liquid-transfering gun 5 times makes to mix, and obtains standard items S7.Take 7 1.5mL centrifuge tube (S0-
S6 it) successively arranges, it is each that 250 μ L sample dilutions are added.It draws in 250 μ L standard items S7 to first centrifuge tubes (S6), gently
Piping and druming mixes.From being drawn in 250 μ L to second centrifuge tubes (S5) in S6, gently piping and druming is mixed.And so on carry out standard items
Doubling dilution.S0 is Sample dilution.The concentration of gained standard items S7 is 400ng/mL, and the concentration of S6 is 200ng/mL, S5
Concentration be 100ng/mL, the concentration of S4 is 50ng/mL, and the concentration of S3 is 25ng/mL, and the concentration of S2 is 12.5ng/mL, S1's
Concentration is 6.25ng/mL, and the concentration of S0 is 0ng/mL.
It is required according to kit, prepares wash operating solution.The dense cleaning solution of i.e. 1 times volume is dilute with 25 times of volume tri-distilled waters
It releases.It is required according to kit, prepares biotin labelled antibodies working solution.100 times of bodies of the biotin labelled antibodies of i.e. 1 times volume
Product diluted.It is required according to kit, prepares Horseradish peroxidase-conjugated avidin working solution.That is 1 times of volume it is peppery
Root peroxidase labelling Avidin is diluted with 100 times of volume dilution liquid.Determination step is as follows:
1) ELISA Plate sets gauge orifice and sample to be tested hole respectively.Every hole adds 100 μ L standard items or serum respectively, shakes gently
It mixes, is covered with plate patch, 37 DEG C incubate 2 hours, discard liquid, dry, and do not have to washing.
2) every hole adds 100 μ L biotin labelled antibodies working solutions, is covered with new plate patch, and 37 DEG C incubate 1 hour, discard in hole
Liquid, drying, board-washing 3 times.It impregnates 2 minutes every time, 200 holes μ L/, drying.
3) every hole adds 100 μ L horseradish peroxidase Avidin working solutions, is covered with new plate patch, and 37 DEG C incubate 1 hour, abandon
Liquid in hole is removed, is dried, board-washing 3 times.It impregnates 2 minutes every time, 200 holes μ L/, drying.
4) sequentially every hole adds 90 μ L substrate solutions, and 37 DEG C are protected from light colour developing 15-30 minutes.
5) sequentially every hole adds 50 μ L stop baths to terminate reaction.
6) the OD value for sequentially measuring each hole in reaction 5 minutes in 450nm wavelength with microplate reader is being terminated.
7) standard curve is drawn according to the OD value of standard items, calculates the GPIIb/IIIa concentration of serum sample, data are shown in Table
3.Physiological saline is substantially less than in the GPIIb/IIIa content of the rat blood serum of 0.01 μm of ol/kg dosages for Compound 9 treatment to control
Treat the GPIIb/IIIa content of rat blood serum.I.e. compound 9 can effectively inhibit GPIIb/IIIa in rat body and express.In addition,
The GPIIb/IIIa content of the rat blood serum of 0.01 μm of ol/kg compound 9 treatment and 167 μm of ol/kg aspirin for treatment rats
The GPIIb/IIIa content of serum is not significantly different.As it can be seen that compound 9 inhibit rat GPIIb/IIIa expression activity compare Ah
It is 1670 times strong to take charge of a woods.This is unexpected technical effect.
3 compound 9 of table inhibits GPIIb/IIIa expression activity
And physiological saline ratio p<0.01, a) with aspirin ratio p>0.05；N=6
Embodiment 25 evaluates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-
Lys inhibits the activity of palatelet-selectin expression
The present embodiment selects the palatelet-selectin concentration of the rat carotid artery blood of enzyme-linked immunization measurement embodiment 24.Embodiment
24 rat carotid artery blood is anticoagulant with 3.8% rafter acid sodium aqueous solution, and 1000rpm is centrifuged 15 minutes, takes supernatant equilibrium at room temperature
It is 30 minutes, to be determined.The kit of measurement is P of Rats-selectin enzyme linked immunological kit.Kit equilibrium at room temperature 30 divides
Clock, it is to be determined.
It is required according to kit, first prepares standard items.The standard items in kit are taken to be centrifuged 30 seconds in 10000rpm.Add
1mL sample diluting liquid solution, being blown and beaten repeatedly with liquid-transfering gun 5 times makes to mix, and obtains standard items S7.Take 7 1.5mL centrifuge tube (S0-
S6 it) successively arranges, it is each that 250 μ L sample dilutions are added.It draws in 250 μ L standard items S7 to first centrifuge tubes (S6), gently
Piping and druming mixes.From being drawn in 250 μ L to second centrifuge tubes (S5) in S6, gently piping and druming is mixed.And so on carry out standard items
Doubling dilution.S0 is Sample dilution.The concentration of gained standard items S7 is 400ng/mL, and the concentration of S6 is 200ng/mL, S5
Concentration be 100ng/mL, the concentration of S4 is 50ng/mL, and the concentration of S3 is 25ng/mL, and the concentration of S2 is 12.5ng/mL, S1's
Concentration is 6.25ng/mL, and the concentration of S0 is 0ng/mL.
It is required according to kit, prepares wash operating solution.The dense cleaning solution of i.e. 1 times volume is dilute with 25 times of volume tri-distilled waters
It releases.It is required according to kit, prepares biotin labelled antibodies working solution.100 times of bodies of the biotin labelled antibodies of i.e. 1 times volume
Product diluted.It is required according to kit, prepares Horseradish peroxidase-conjugated avidin working solution.That is 1 times of volume it is peppery
Root peroxidase labelling Avidin is diluted with 100 times of volume dilution liquid.Determination step is as follows:
1) ELISA Plate sets gauge orifice and sample to be tested hole respectively.Every hole adds 100 μ L standard items or serum respectively, shakes gently
It mixes, is covered with plate patch, 37 DEG C incubate 2 hours, discard liquid, dry, and do not have to washing.
2) every hole adds 100 μ L biotin labelled antibodies working solutions, is covered with new plate patch, and 37 DEG C incubate 1 hour, discard in hole
Liquid, drying, board-washing 3 times.It impregnates 2 minutes every time, 200 holes μ L/, drying.
3) every hole adds 100 μ L horseradish peroxidase Avidin working solutions, is covered with new plate patch, and 37 DEG C incubate 1 hour, abandon
Liquid in hole is removed, is dried, board-washing 3 times.It impregnates 2 minutes every time, 200 holes μ L/, drying.
4) sequentially every hole adds 90 μ L substrate solutions, and 37 DEG C are protected from light colour developing 15-30 minutes.
5) sequentially every hole adds 50 μ L stop baths to terminate reaction.
6) the OD value for sequentially measuring each hole in reaction 5 minutes in 450nm wavelength with microplate reader is being terminated.
7) standard curve is drawn according to the OD value of standard items, calculates the palatelet-selectin concentration of serum sample, data are shown in Table 4.
It is big that saline therapy is substantially less than in the palatelet-selectin content of the rat blood serum of 0.01 μm of ol/kg dosages for Compound 9 treatment
The palatelet-selectin content of mouse serum.I.e. compound 9 can effectively inhibit palatelet-selectin in rat body and express.In addition, 0.01 μm of ol/
The palatelet-selectin content for the rat blood serum that kg compound 9 is treated and the P- of 167 μm of ol/kg aspirin for treatment rat blood serums are selected
Cellulose content does not have significant difference.As it can be seen that compound 9 inhibits the activity of palatelet-selectin expression in rat body stronger than aspirin
1670 times.This is unexpected technical effect.
4 compound 9 of table inhibits palatelet-selectin expression activity
And physiological saline ratio p<0.01, a) with aspirin ratio p>0.05；N=6.
Claims (6)
1. (3S) -1,1- dihydroxymethyl of following formula-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Arg/Lys,
2. (3S)-1,1- dihydroxymethyl of claim 1-tetrahydro-beta-carboline-3- formyl-Gly-Tyr-Ile-Gly-Ser-
The preparation method of Arg/Lys, this method comprises:
(1) L-Trp carries out Pictet-Spengler condensation with C3H6O3 under dilute sulfuric acid catalysis and generates (3S)-
1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylic acid；
(2) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester is prepared；
(3) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- carboxylate methyl ester in the presence of imidazoles with tert-butyldimethylsilyl chloride silicon
Alkane (TBDMSCl) reaction generates (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid first
Ester；
(4) NaOH water of (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylate methyl ester in 4N
Hydrolysis generates (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acid in solution；
(5) using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, (3S) -1,1- is made using liquid phase condensations method
Two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- carboxylic acids and Gly-OBzl coupling are two (tertiary fourth of (3S) -1,1-
Base dimethylsilyl bis) methyl-tetrahydro-B-carboline -3- formyl-Gly-OBzl；
(6) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-OBzl is in H2With
(3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly is converted in the presence of Pd/C；
(7) using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, HCl is synthesized using liquid phase condensations method
Tyr-Ile-Gly-Ser-Lys(Z)-OBzl；
(8) using dicyclohexylcarbodiimide and 1- hydroxy benzo triazole as catalyst, (3S) -1,1- is made using liquid phase condensations method
Two (tertiary butyl dimethyl Si base) methyl-tetrahydros-B-carboline -3- formyl-Gly and HClTyr-Ile-Gly-Ser-Lys
(Z)-OBzl coupling is (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-Tyr-
Ile-Gly-Ser-Lys(Z)-OBzl；
(9) (3S) -1,1- two (tertiary butyl dimethyl Si base) methyl-tetrahydro-B-carboline -3- formyl-Gly-Tyr-Ile-
Gly-Ser-Lys (Z)-OBzl is in hydrogen chloride-ethyl acetate solution that concentration is 4N, 0 DEG C of removing t-Butyldimethylsilyl,
Prepare (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl；
(10) (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl -- Gly-Tyr-Ile-Gly-Ser-Lys (Z)-OBzl
Hydrogenolysis generates (3S) -1,1- dihydroxymethyl-tetrahydro-beta-carboline -3- formyl-Gly-Tyr-Ile-Gly-Ser- in the presence of Pd/C
Lys。
3. (3S)-1,1- dihydroxymethyl of claim 1-tetrahydro-beta-carboline-3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys
Preparing the application in anti-arterial thrombus drug.
4. (3S)-1,1- dihydroxymethyl of claim 1-tetrahydro-beta-carboline-3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys
Preparing the application in anti-phlebothrombosis drug.
5. (3S)-1,1- dihydroxymethyl of claim 1-tetrahydro-beta-carboline-3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys
Preparing the application in GPIIb/IIIa antagonist.
6. (3S)-1,1- dihydroxymethyl of claim 1-tetrahydro-beta-carboline-3- formyl-Gly-Tyr-Ile-Gly-Ser-Lys
Preparing the application in palatelet-selectin antagonist.
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