CN107033215A - Imidazopyridine acyl-KAGDV, it is synthesized, antithrombotic acitivity and application - Google Patents
Imidazopyridine acyl-KAGDV, it is synthesized, antithrombotic acitivity and application Download PDFInfo
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Abstract
The invention discloses the 4 of following formula, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys-Ala-Gly-Asp-Val.Its preparation method is disclosed, its antithrombotic acitivity is disclosed, thus the invention discloses its application in antithrombotic reagent.
Description
Invention field
The present invention relates to 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyl-Lys-Ala-Gly-Asp-Val, it is related to
Its preparation method, the antithrombotic acitivity for being related to it, thus the present invention relates to its application as antithrombotic reagent.This
Invention belongs to biomedicine field.
Background technology
Coronary heart disease, cerebral apoplexy and vasculitis etc. are very common cardiovascular and cerebrovascular diseases.With people's living standard
Improve constantly, the number of the infected cumulative year after year of cardiovascular and cerebrovascular disease.Risk factors of cardiovascular and cerebrovascular disease is popular, China's heart
The illness rate of cranial vascular disease persistently rises.According to statistics, just there is 1 cardiovascular patient in every 5 adults.
Thrombosis is the Important cause of disease of cardiovascular and cerebrovascular disease.Antithrombotic still relies on drug therapy.What clinic was commonly used
Thrombus class medicine has aspirin, clopidogrel and warfarin etc..All there are some side effects, such as bleeding and stomach in them
Enteron aisle stimulation etc..Therefore, it is highly significant to find good effect, the antithrombotic reagent of Small side effects.
In recent years, it has been found that the compound containing imidazo tetrahydropyridine heterocycle is the excellent configuration of antithrombotic acitivity.
Inventor once disclosed the 4 of following formula, and (AA is amino to 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-AA in formula
Sour residue) there is definite antithrombotic acitivity under 10nmol/kgd oral dose.
But, inventor is dissatisfied to the antithrombotic acitivity of the series compound.In order to further improve activity, invention
People expands series of experiment research, finally found that the AA replaced with thrombus target peptide in disclosed structure, can
Improve antithrombotic acitivity.According to these researchs, the present invention is inventors herein proposed.
The content of the invention
First content of the present invention is to provide 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls
-Lys-Ala-Gly-Asp-Val。
The present invention second content be to provide 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls -
Lys-Ala-Gly-Asp-Val synthetic method, this method includes：
(1) L-Histidine carries out 4,5,6,7- tetrahydrochysene -3H- of Pictet-Spengler condensation generations under dilute sulfuric acid catalysis with formaldehyde
Imidazo [4,5-c] pyridine -6- carboxylic acids；
(2) 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids are converted into the-Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- miaows
Azoles simultaneously [4,5-c] pyridine -6- carboxylic acids；
- the Boc-4 of (3) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids are coupled with Lys (Boc)-OBzl
To-the Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl；
- the Boc-4 of (4) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl are in 2N
- the Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) are saponified into NaOH solution；
(5) Boc-Ala obtains Boc-Ala-Gly-OBzl with glycine benzyl ester coupling；
(6) Boc-Ala-Gly-OBzl is saponified into Boc-Ala-Gly in 2N NaOH solutions；
(7) Boc-Asp (OBzl) obtains Boc-Asp (OBzl)-Val-OBzl with the coupling of valine benzyl ester；
(8) Boc-Asp (OBzl)-Val-OBzl are obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Asp(OBzl)-Val-OBzl；
(9) Boc-Ala-Gly and L-Asp (OBzl)-Val-OBzl couplings are obtained
Boc-Ala-Gly-Asp(OBzl)-Val-OBzl；
(10) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl are obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Ala-Gly-Asp(OBzl)-Val-OBzl；
(11) 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) and L-Ala-Gly-As
P (OBzl)-Val-OBzl couplings obtain the-Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys
(Boc)-Ala-Gly-Asp(OBzl)-Val-OBzl；
(12) 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-Ala-Gly-Asp (O
Bzl)-Val-OBzl obtains 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys-Ala in TFA/TFMSA
-Gly-Asp-Val.
The 3rd content of the present invention is evaluation 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls
Anti thrombotic actions of-the Lys-Ala-Gly-Asp-Val to SD rats.
Brief description of the drawings
Fig. 14,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys-Ala-Gly-Asp-Val synthetic route
I) HCHO, H2SO4, 65 DEG C；ii)(Boc)2O, 4N NaOH；Iii) HOBt, DCC, THF；iv)2N
NaOH, CH3OH；v)HCl/EA；vi)TFA/TFMSA.
Embodiment
In order to which the present invention is expanded on further, a series of embodiments are given below.These embodiments be entirely it is illustrative,
They are only used for that the present invention is specifically described, and are not construed as limitation of the present invention.
Embodiment 1 prepares 4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids (1)
0.8mL H are slowly added dropwise into the solution of 5g (32.3mmol) L-His and 18mL water under ice bath and stirring2SO4,
Make to be completely dissolved.Add the formalins of 6mL 40% into the solution.Remove ice bath, 60 DEG C of reaction 8h, TLC (second
Acetoacetic ester: water: glacial acetic acid=4: 1: 1) monitor raw material point and disappear.Reaction solution is cooled under room temperature, ice bath and uses concentrated ammonia liquor
PH is adjusted to 6, there are a large amount of colorless solids to separate out.Filtering.Filter residue is washed with water and acetone, obtains 4.52g (84%) title
Compound.ESI-MS(m/e)：168[M+H]+。
Embodiment 2 prepares the-Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- carboxylic acids (2)
To tetrahydrochysene -3H- imidazos [4, the 5-c] pyridine -6- carboxylic acids of 5g (29.9mmol) 4,5,6,7- and 40mL under ice bath and stirring
Add the 14.3g (65.7mmol) (Boc) of 40mL Isosorbide-5-Nitraes-dioxane dissolving in the solution of water2O, is adjusted with 4N NaOH solutions
PH to 8-9 is saved, 24h is reacted at room temperature, TLC (dichloromethane: methanol=15: 1) monitors raw material point and disappeared.Reaction solution is used full
And KHSO4Solution adjusts pH to 7, and decompression is steamed after Isosorbide-5-Nitrae-dioxane, uses saturation KHSO4Solution adjusts pH to 2.
It is extracted with ethyl acetate three times, ester layer is washed three times with saturation NaCl.Anhydrous sodium sulfate drying 30min is used, is filtered.Will
Filtrate decompression is evaporated.Plus a small amount of ethyl acetate just dissolves it, stands.There is solid precipitation, filter.Obtain 1.2g (11%)
Title compound, is colorless solid.ESI-MS(m/e)：368[M+H]+。
Embodiment 3 prepares 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc)-OBzl (3)
Under ice bath, the tetrahydrofuran (THF) dried with 20mL is by-the Boc-4 of 367mg (1mmol) 3,5- bis-, 5,6,7- tetrahydrochysenes
- 3H- imidazos [4,5-c] pyridine -6- carboxylic acids.Plus 142mg (1.05mmol) HOBt and 258mg (1.25
Mmol) DCC, stir-activating 30min.The THF dried with 10mL is by 558mg (1.1mmol)
TosLys (Boc)-OBzl dissolves, and adjusts pH to 8 with NMM, the solution is added dropwise in reaction solution, NMM is finally used
Adjust reaction solution pH to 8.5h is reacted at room temperature, TLC (petroleum ether: acetone=3: 1) shows that raw material disappears.It is filtered to remove two
Cyclohexyl urea (DCU), evaporated under reduced pressure reaction solution after residue ethyl acetate dissolves, uses saturation NaHCO successively3
Solution, saturation NaCl solution, 5%KHSO4Solution, saturation NaCl solution, saturation NaHCO3Solution, saturation NaCl
Solution is respectively washed three times.Ethyl acetate layer anhydrous Na2SO430min is dried, filtering, filtrate decompression is evaporated.Gained is yellow
Color grease purifies (petroleum ether/acetone is eluant, eluent) through silica gel column chromatography, obtains 248mg (36%) title compound, is nothing
Color solid.ESI-MS(m/e)：686[M+H]+。
Embodiment 4 prepares 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys (Boc) (4)
Under ice bath, with 20mL methanol by the-Boc-4 of 685mg (1mmol) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c]
Pyridine -6- formyls-Lys (Boc)-OBzl is dissolved, and pH to 12, ice bath reaction 5h, TLC (stones are adjusted with 2N NaOH solutions
Oily ether: acetone=3: 1) show that raw material point disappears.Use saturation KHSO4Solution adjusts pH to 7.Decompression steams methanol, uses
Saturation KHSO4Solution adjusts pH to 2, is extracted with ethyl acetate 3 times, ethyl acetate layer is washed three times with saturation NaCl solution,
Use anhydrous Na2SO430min is dried, filtering is spin-dried for filtrate.584mg (98%) title compound is obtained, is colorless solid.
ESI-MS(m/e)：596[M+H]+。
Embodiment 5 prepares Boc-Ala-Gly-OBzl
The THF dried under ice bath and stirring with 30mL dissolves 945mg (5mmol) Boc-Ala.Sequentially add 708
Mg (5.25mmol) HOBt and 1.291g (6.25mmol) DCC, activates 30min.With dry THF by 2.022
After g (6mmol) TosGly-OBzl dissolvings, pH to 8 is adjusted with NMM, then the solution is added dropwise in reaction solution, most
Afterwards reaction solution pH to 8 is adjusted with NMM.Room temperature reaction 12 hours, TLC (dichloromethane: methanol=25: 1) display reaction
After finishing, by reaction solution evaporated under reduced pressure, remaining grease ethyl acetate dissolves, and is filtered to remove DCU, filtrate is successively
Use saturation NaHCO3Solution, saturation NaCl solution, saturation KHSO4Solution, saturation NaCl solution, saturation NaHCO3
Solution, saturation NaCl solution are respectively washed three times, ethyl acetate layer anhydrous Na2SO4Dry 30min, filtering.Filtrate subtracts
Pressure is concentrated to dryness, and obtained yellow oil is worn away through absolute ether, obtains 1.471g (88%) title compound,
For colorless solid.ESI-MS(m/e)：337[M+H]+。
Embodiment 6 prepares Boc-Ala-Gly
Under ice bath, 1.680g (5mmol) Boc-Ala-Gly-OBzl is dissolved with 40mL methanol, 2N NaOH are used
Solution adjusts pH to 12, and ice bath reaction 5h, TLC (dichloromethane: methanol=25: 1) show that raw material point disappears.With full
And KHSO4Solution adjusts pH to 7.Decompression steams methanol, uses saturation KHSO4Solution adjusts pH to 2, uses second
Acetoacetic ester is extracted three times, and ethyl acetate layer is washed three times with saturation NaCl solution, uses anhydrous Na2SO4Dry 30min,
Filtering.Filtrate decompression is concentrated to dryness.1.11g (90%) title compound is obtained, is colorless solid.ESI-MS(m/e)：245
[M+H]-。
Embodiment 7 prepares Boc-Asp (OBzl)-Val-OBzl
According to the method for embodiment 5 from 1.615g (5mmol) Boc-Asp (OBzl) and 2.369g (6mmol) TosVal
- OBzl obtains 2.081g (81%) title compound, is colorless solid.ESI-MS(m/e)：513[M+H]+。
Embodiment 8 prepares HClAsp (OBzl)-Val-OBzl
Under ice bath and stirring, with ethyl acetate dry on a small quantity by 1.024g (2mmol) Boc-Asp (OBzl)-Val
- OBzl dissolves.Add into the solution and reacted 6 hours under the ethyl acetate solution of 20ml 4N hydrogen chloride, ice bath, TLC (stones
Oily ether: acetone=3: 1) display after completion of the reaction, reaction solution is concentrated under reduced pressure into dry.Add dry acetic acid into residue
Ethyl ester, is concentrated under reduced pressure into dry, is repeated twice.Add absolute ether into residue again, be concentrated under reduced pressure into dry, repetition three
It is secondary.0.751g (91%) title compound is obtained, is faint yellow solid.ESI-MS(m/e)：413[M+H]+。
Embodiment 9 prepares Boc-Ala-Gly-Asp (OBzl)-Val-OBzl
According to the method for embodiment 5 from 1.230g (5mmol) Boc-Ala-Gly and 2.700g (6
Mmol) HClAsp (OBzl)-Val-OBzl obtains 2.650g (83%) title compound, is colorless solid.ESI-MS
(m/e)：641[M+H]+。
Embodiment 10 prepares HClAla-Gly-Asp (OBzl)-Val-OBzl
Obtained according to the method for embodiment 8 from 1.280g (2mmol) Boc-Ala-Gly-Asp (OBzl)-Val-OBzl
0.969g (90%) title compound, is faint yellow solid.ESI-MS(m/e)：541[M+H]+。
Preparation 3, the 5- bis- of embodiment 11-Boc-4,5,6,7- tetrahydrochysene-3H- imidazos [4,5-c] pyridine-6- formyls-Lys (Boc)-
Ala-Gly-Asp(OBzl)-Val-OBzl(5)
According to the method for embodiment 5 from the-Boc-4 of 893mg (1.5mmol) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos
[4,5-c] pyridine -6- formyls-Lys (Boc) and 862mg (1.65mmol) HClAla-Gly-Asp (OBzl)-Val-OBzl are obtained
1.22g (73%) title compound, is colorless solid.ESI-MS(m/e)：1118[M+H]+。
Embodiment 12 prepares 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazos [4,5-c] pyridine -6- formyls-Lys-
Ala-Gly-Asp-Val(6)
Under ice bath and stirring, to-the Boc-4 of 57mg (0.05mmol) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos [4,5-c]
1.71mL trifluoroacetic acids are added dropwise in pyridine -6- formyls-Lys (Boc)-Ala-Gly-Asp (OBzl)-Val-OBzl, make
It is completely dissolved.Careful that 0.57mL trifluoromethanesulfonic acids are added dropwise, solution is changed into blackish green.Plus the reaction of drying tube ice bath
25min, adds a large amount of ether, there is colorless solid precipitation.Abandoning supernatant after centrifugation, solid adds diethyl ether again, such as
This wears away three times repeatedly.With a small amount of water by gained solid dissolving, pH is adjusted to 8 with the ammoniacal liquor of dilution, then with dilute
The glacial acetic acid regulation pH to 6-7 released.Through Sephadex G10 pillar desalinations, freeze-drying obtains 16.9mg (52%)
Title compound, is colorless solid.Mp：167.1-168.2℃.ESI-MS(m/e)：638
[M+H]+.1H-NMR (300Hz, DMSO-d6)：δ/ppm=8.46 (d, J=6.0Hz, 1H), 8.21 (d, J=
6.0Hz, 2H), 8.11 (t, J=3.0Hz, 1H), 7.56 (d, J=6.0Hz, 1H), 7.47 (s, 1H), 4.56 (dd,
J=12.0Hz, 6.0Hz, 1H), 4.36 (dd, J=12.0Hz, 6.0Hz, 1H), 4.27 (t, J=6.0Hz, 1H),
3.90 (m, 1H), 3.80 (m, 2H), 3.63 (dd, J=15.0Hz, 3.0Hz, 1H), 3.53 (dd, J=9.0
Hz, 3.0Hz, 1H), 2.74 (m, 4H), 2.60 (m, 1H), 2.03 (m, 1H), 1.60 (m, 3H), 1.24 (m,
5H), 0.82 (d, J=6.0Hz, 1H).
Experimental example 1 evaluates the antithrombotic acitivity of compound 6：
By male SD rat (200 ± 20g), random packet, is raised 1 day by every group 12, is stopped feeding and is stayed overnight.
Gavage gives normal saline solution (dosage is 10nmol/kg) or the normal saline solution (agent of aspirin of compound 6
Measure as 167 μm of ol/kg) or physiological saline (dosage is 10mL/kg) 30min after, the life of 20% Ethylurethanm of rat
Saline solution anesthesia is managed, is performed the operation afterwards.The right carotid and left neck vein of rat are separated, the silk thread of correct amount is put
In bypass intubation, left vein is inserted in one end of pipe, and another end pipe insertion right artrial simultaneously injects 0.2mL liquaemin anti-freezings.
Claim so that blood flow flows through silk thread of the taking-up with thrombus after bypass intubation enters left side vein, 15min from right artrial
Amount, calculates the weight of silk thread before and after blood circulation, and obtained thrombus weight is represented with mean value ± SD mg and represents antithrombotic work
Property, make t inspections.Data are included in table 1.As a result oral 10nmol/kg compounds 6 and oral 167 μm of ol/kg are shown
Aspirin is the same can effectively inhibition thrombosis.Illustrate that the activity of compound 6 is stronger than aspirin 16700 times,
Obtain unexpected technique effect.
The antithrombotic acitivity of table 1.10nmol/kg compounds 6
N=12；A) with physiological saline than p ＜ 0.01, with aspirin than p ＞ 0.05.
Claims (4)
1. the 4 of following formula, 5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyl-Lys-Ala-Gly-Asp-Val,
2. the 4 of claim 1,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-Lys-Ala-Gly-Asp-Val preparation side
Method, this method includes：
(1) L-Histidine carries out 4,5,6,7- tetrahydrochysene -3H- of Pictet-Spengler condensation generations under dilute sulfuric acid catalysis with formaldehyde
Imidazopyridine -6- carboxylic acids；
(2) 4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- carboxylic acids are converted into the-Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazos
Pyridine -6- carboxylic acids；
- the Boc-4 of (3) 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazopyridine -6- carboxylic acids and Nω- Boc-Lys-OBzl couplings are obtained
3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-Nω-Boc-Lys-OBzl；
(4) 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-Nω- Boc-Lys-OBzl is molten in 2N NaOH
- the Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-N are saponified into liquidω-Boc-Lys；
(5) Boc-Ala obtains Boc-Ala-Gly-OBzl with glycine benzyl ester coupling；
(6) Boc-Ala-Gly-OBzl is saponified into Boc-Ala-Gly in 2N NaOH solutions；
(7) Boc- β-carboxyl-OBzl-Asp obtains Boc- β-carboxyl-OBzl-Asp-Val-OBzl with the coupling of valine benzyl ester；
(8) Boc- β-carboxyl-OBzl-Asp-Val-OBzl obtains L- β-carboxyl in the ethyl acetate solution of 4N hydrogen chloride
-OBzl-Asp-Val-OBzl；
(9) Boc-Ala-Gly and L- β-carboxyl-OBzl-Asp-Val-OBzl couplings obtain Boc-Ala-Gly- β-carboxyl
-OBzl-Asp-Val-OBzl；
(10) Boc-Ala-Gly- β-carboxyl-OBzl-Asp-Val-OBzl is obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Ala-Gly- β-carboxyl-OBzl-Asp-Val-OBzl；
(11) 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-Nω- Boc-Lys and L-Ala-Gly- β-carboxyl
- OBzl-Asp-Val-OBzl couplings obtain the-Boc-4 of 3,5- bis-, 5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls
-Nω- Boc-Lys-Ala-Gly-B- carboxyls-OBzl-Asp-Val-OBzl；
(12) 3,5- bis--Boc-4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls-Nω- Boc-Lys-Ala-Gly- β-carboxyl
- OBzl-Asp-Val-OBzl obtains 4,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyls in TFA/TFMSA
-Lys-Ala-Gly-Asp-Val。
3. the 4 of claim 1,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyl-Lys-Ala-Gly-Asp-Val are to SD rats
Anti thrombotic action.
4. the 4 of claim 1,5,6,7- tetrahydrochysene -3H- imidazopyridine -6- formyl-Lys-Ala-Gly-Asp-Val are used as anti-blood
The clinical practice of bolt medicine.
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| CN102796167A (en) * | 2011-05-26 | 2012-11-28 | 首都医科大学 | (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof |
| CN102807600A (en) * | 2011-06-03 | 2012-12-05 | 首都医科大学 | Amino acid modified spinacin derivative and preparation method and application thereof |
| CN103450196A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | AGDV peptide modified carboline-hexahydropyrazine-1,4-dione, preparation method, antithrombotic effect, and applications thereof |
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2015
- 2015-07-13 CN CN201510409681.1A patent/CN107033215A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102796167A (en) * | 2011-05-26 | 2012-11-28 | 首都医科大学 | (S)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-L-prolyl-L-alanyl-L-amino acid, and preparation method and application thereof |
| CN102807600A (en) * | 2011-06-03 | 2012-12-05 | 首都医科大学 | Amino acid modified spinacin derivative and preparation method and application thereof |
| CN103450196A (en) * | 2012-05-29 | 2013-12-18 | 首都医科大学 | AGDV peptide modified carboline-hexahydropyrazine-1,4-dione, preparation method, antithrombotic effect, and applications thereof |
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Application publication date: 20170811 |