CN106317190A - Cyclohistidyl-KRPAK, and synthesis, thrombus related activity and applications thereof - Google Patents

Cyclohistidyl-KRPAK, and synthesis, thrombus related activity and applications thereof Download PDF

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CN106317190A
CN106317190A CN201510344803.3A CN201510344803A CN106317190A CN 106317190 A CN106317190 A CN 106317190A CN 201510344803 A CN201510344803 A CN 201510344803A CN 106317190 A CN106317190 A CN 106317190A
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boc
lys
pro
ala
obzl
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彭师奇
赵明
王玉记
吴建辉
曹晔
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Capital Medical University
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Abstract

The invention discloses a cyclohistidyl-KRPAK, and synthesis, thrombus related activity and applications thereof. The invention concretely discloses the cyclohistidyl-KRPAK with the formula of (6s)-4,5,6,7-tetrahydro-3H-imidazo[4,5-c]pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys), a preparation thereof, an application of the cyclohistidyl-KRPAK in treatment of stroke rats, and an application of the cyclohistidyl-KRPAK in the preparation of ischemic stroke treatment medicines.

Description

Ring histidyl- -KRPAK, Its synthesis , Thrombosis related activity and application
Technical field
The present invention relates to (6s)-4,5,6,7-tetrahydrochysene-3H-imidazoles [4,5-c] pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys, relate to its preparation method, relate to the effect of its treatment cerebral infarction, thus the present invention relates to its application in preparing cerebral infarction medicine.The invention belongs to biomedicine field.
Background technology
Cerebral infarction is that a class more typically and endangers serious cerebrovascular disease, and feature is that sickness rate is high, case fatality rate is high, disability rate is high and relapse rate is high.It is non-the most residual that current clinical treatment cerebral infarction faces the reality not having active drug, the especially patient of apoplexy face more than 4h.Inventing the effective medicine of patient to apoplexy face more than 4h is clinical important need.Inventor once disclosed the imidazolinium compounds of Formula II on the ischemia/reperfusion in rats apoplexy model of apoplexy face 24h, showed outstanding curative effect.The i.e. imidazolinium compounds of 6 days Formula II of continuous intravenous injection, every day 1 time, initial dose is 5 μm ol/kg, and the dosage of latter 5 times is that 2 μm ol/kg have outstanding curative effect.Aa in formula1And aa2Can be to exist simultaneously, aa1Exist but aa2Do not exist, or do not exist simultaneously；Work as aa1And aa2In the presence of Tong Shi, aa1For R (Arg), and aa2For G (Gly), A (Ala) or Q (Gln)；Work as aa1Exist but aa2In the presence of not, aa1For R (Arg)；aa3Can be S (Ser), V (Val) or F (Phe).Need owing to the substituted imidazoline construction unit of Formula II is more complicated to simplify.
Inventor, through 3 years experimentatioies, finds with 4, and 5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-formoxyl replace the substituted imidazoline construction unit of Formula II can obtain simple in construction and good effect beyond thought double technique effect.Find according to this, inventors herein propose the present invention.
Summary of the invention
First content of the present invention is to provide (6s)-4 of above formula, 5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys.
Second content of the present invention is to provide (6s)-4 of above formula, 5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] the synthetic method of pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys, and the method includes:
(1) in the presence of dicyclohexylcarbodiimide (DCC) Boc-Pro in anhydrous THF with and N-hydroxy-succinamide (HOSu) condensation be Boc-Pro-OSu, at NaHCO3In the presence of Boc-Pro-OSu with Ala react generation Boc-Pro-Ala；
(2) in the presence of DCC and HOBt, Boc-Pro-Ala is condensed as Boc-Pro-Ala-Lys (Z)-OBzl with Lys (Z)-OBzl in anhydrous THF；
(3) in hydrogen chloride-ethyl acetate solution, Boc-Pro-Ala-Lys (Z)-OBzl sloughs Boc protection group and generates Pro-Ala-Lys (Z)-OBzl；
(4) Boc-Arg (NO in the presence of DCC and HOBt2) be condensed as Boc-Arg (NO with Pro-Ala-Lys (Z)-OBzl in anhydrous THF2)-Pro-Ala-Lys(Z)-OBzl；
(5) Boc-Arg (NO in hydrogen chloride-ethyl acetate solution2)-Pro-Ala-Lys (Z)-OBzl slough Boc protection group generate Arg (NO2)-Pro-Ala-Lys(Z)-OBzl；
(6) in the presence of dilute sulfuric acid, formaldehyde and L-Histidine react at 60 DEG C, generate (6s)-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-carboxylic acid；
(7) (6s)-3 in the presence of DCC and HOBt, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazos [4,5-c] pyridine-6-carboxylic acid in anhydrous tetrahydro furan with Lys (Boc)-OBzl condensation for (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-Lys (Boc)-OBzl.
(8) (6s)-3 in the presence of Pd/C, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazos [4,5-c] pyridine-6-formyl-L-Lys (Boc)-OBzl slough in methanol solution OBzl generate (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-Lys (Boc)；
(9) (6s)-3 in the presence of DCC and HOBt, 5-bis--Boc-4,5,6,7-tetrahydrochysenes-3H-imidazo [4,5-c] pyridine-6-formyl-L-Lys (Boc) in anhydrous tetrahydro furan with HCl Arg (NO2)-Pro-Ala-Lys (Z)-OBzl condensation for (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-formyl-L-Lys (Boc)-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl。
(10) compound prepared by step (9) is sloughed protection group, obtain the compound shown in above formula.
Wherein said HOBt is the breviary term of N-hydroxy benzo triazole, and DCC is the breviary term of dicyclohexyl carbonyl diimine, and Boc is the breviary term of tertbutyloxycarbonyl, and Pd/C is palladium/carbon.
3rd content of the present invention is to evaluate above formula (6s)-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] the activity of pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys treatment cerebral infarction.
Accompanying drawing explanation
Figure 1(6s)-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] the synthetic route of pyridine-6-formyl-Lys-Arg-Pro-Ala-Lys. (i) H2SO4, HCHO, 60 DEG C；(ii) 1N NaOH, (Boc)2O；(iii) DCC, HOBt, NMM；(iv)H2, Pd/C；(v) 4N hydrogen chloride-ethyl acetate solution；(vi)TFA/TFSA；(vi) HOSu, DCC.
Detailed description of the invention
In order to the present invention is expanded on further, it is given below a series ofEmbodiment.TheseEmbodimentBeing entirely illustrative, they are only used for being specifically described the present invention, are not construed as limitation of the present invention.
Embodiment1 preparation (6s)-4,5,6,7-tetrahydrochysenes-3H-imidazo [4,5-c] pyridine-6-carboxylic acid (1)
10g (64.5mmol) L-His 80mL distilled water and 20mL formaldehyde mixed solution are dissolved, the dropping dense H of 1mL the most inward2SO4, 60 DEG C of microwave reactions 5 hours, it is cooled to room temperature, in compound of reaction, under ice bath, drips strong aqua ammonia adjust pH to 7, have a large amount of Precipitation.Filter, obtain 10.5g (97%) title compound, for colorless solid.ESI-MS(m/z)167[M+H]+。
Embodiment2 preparation (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysenes-3H-imidazo [4,5-c] pyridine-6-carboxylic acid (2)
By 1.67g (10mmol) (6s)-4 under ice bath, 5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acids are dissolved in 5ml2N sodium hydrate aqueous solution.5.23g (24mmol) (Boc) is added in this reactant liquor2The solution of O Yu 10mL dioxane.It is stirred at room temperature, TLC (CH2Cl2: MeOH=15: 1) monitoring reaction raw materials point disappearance.After having reacted, filtering, filtrate reduced in volume removes dioxane.The saturated KHSO of water layer of residual4Aqueous solution is acidified to pH value to 2, is extracted with ethyl acetate three times, combined ethyl acetate layer, and by a small amount of water backwash, ethyl acetate layer anhydrous Na2SO4Being dried, filter, the faint yellow solid ethyl acetate being concentrated under reduced pressure to give is soaked and is worn away, and filters, obtains 1.55g (42%) title compound, for colorless solid.ESI-MS(m/z)367[M+H]+。
Embodiment3 preparation (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-formyl-Lys (Boc)-OBzl (3)
Ice bath and the lower 3.67g (10.0mmol) (6s)-3 of stirring, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo [4,5-c] pyridine-6-carboxylic acid, 1.48g (11.0mmol) HOBt and 2.47g (12.0mmol) DCC adds the anhydrous THF of 50ml and dissolves, and reactant liquor activates 30 minutes.Then the hanging drop by 3.91g (10.5mmol) Tos Lys (Boc)-OBzl and the anhydrous THF of 50mL and with 1.0mL NMM regulation pH to 9 is added in the reactant liquor of activation.Remove ice bath, be stirred at room temperature 12 hours, filter 1,3-Dicyclohexylurea (DCU).Filtrate reduced in volume is to dry, and residue with Ethyl acetate dissolves, then filters DCU.Filtrate layers uses saturated NaHCO successively3Solution is washed 3 times, and saturated NaCl solution is washed 3 times, saturated KHSO4Solution is washed 3 times, and saturated NaCl solution is washed 3 times, saturated NaHCO3Solution is washed 3 times, and saturated NaCl solution is washed 3 times, ethyl acetate layer anhydrous Na2SO4Being dried, filtration, filtrate reduced in volume, residue obtains 3.97g (58%) title compound through column chromatography (petroleum ether/acetone system 8: 1-2: 1) purification, for colorless solid, ESI-MS (m/z) 686 [M+H]+。
Embodiment4 preparation (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-formyl-L-Lys (Boc) (4)
Weigh 200mg (0.29mmol) (6s)-3, 5-bis--Boc-4, 5, 6, 7-tetrahydrochysene-3H-imidazoles [4, 5-c] and pyridine-6-formyl-L-Lys (Boc)-OBzl in 50mL eggplant-shape bottle, after dissolving with 10mL methanol, add 20mg Pd/C, the air in reaction bulb is first taken away with vacuum pump, then pass to hydrogen, the most repeatedly for three times, finally keep logical hydrogen state response 12 hours, after utilizing TLC (petroleum ether: acetone=3: 1) monitoring to disappear to raw material speckle, filtration under diminished pressure, concentrate filtrate to do to obtain 160mg (92%) title compound, for colorless solid, ESI/MS (m/e): 596 [M+H]+。
Embodiment5 preparation HCl Pro-Ala-Lys (Z)-OBzl
5-1) prepare Boc-Pro-Ala
In the solution of the anhydrous THF of 1.075g (5.0mmol) Boc-Pro and 20mL, add 0.637g (5mmol) N-hydroxy-succinamide (HOSu) under ice bath, and make to be completely dissolved.The solution of a small amount of anhydrous THF Yu 1.236g (6.0mmol) dicyclohexyl carbonyl diimine (DCC) is added in this solution.Being stirred at room temperature 7 hours, TLC (dichloromethane: methanol=10: 1) monitoring Boc-Pro disappears.Filtering DCU, filtrate reduced in volume removes THF.Residue first with acetic acid ethyl dissolution, uses saturated NaHCO the most successively3Water-soluble and saturated NaCl aqueous solution is washed.Ethyl acetate layer is evaporated to do, and residue adds appropriate THF and dissolves.In this solution, add oneself be dissolved in 0.489g (5.5mmol) the Ala solution of a small amount of water.The reactant liquor NaHCO obtained3Solid adjusts pH to 9, room temperature reaction 12 hours, and concentrating under reduced pressure removes THF, and residue adds 5mL water dissolution, uses saturated KHSO4Aqueous solution adjusts pH to 2, the most repeatedly extracts by ethyl acetate, and the ethyl acetate layer of merging is washed till neutrality with saturated NaCl aqueous solution, is dried with anhydrous sodium sulfate.Filtering, filtrate reduced in volume obtains 1.41g (98%) title compound, for colorless solid.ESI-MS (m/e): 285 [M-H]-。
5-2) prepare Boc-Pro-Ala-Lys (Z)-OBzl
UseEmbodimentThe method of 3 obtains 3.09g (97%) title compound from 1.43g (5.0mmol) Boc-Pro-Ala and 2.71g (5.0mmol) Lys (Z)-OBzl, for buff white solid.ESI-MS (m/e): 639 [M+H]+。.
5-3) prepare HCl Pro-Ala-Lys (Z)-OBzl
0.638g (1mmol) Boc-Pro-Ala-Lys (Z)-OBzl is dissolved in 10mL ethyl acetate.Adding hydrogen chloride-ethyl acetate solution that 15mL concentration is 4N under ice bath in the solution obtained, TLC (dichloromethane: methanol=1: 1) display Boc-Pro-Ala-Lys (Z)-OBzl disappears.Reaction mixture at room temperature concentrating under reduced pressure, residue concentrates with acetic acid ethyl dissolution reduced pressure at room temperature again, 3 times the most repeatedly, and Ex-all dissociates hydrogen chloride.Residue absolute ether crystallize, obtains 0.516g (90%) title compound, is directly used in the next step.ESI-MS (m/e): 539 [M+H]+。
Embodiment6 preparation HCl Arg (NO2)-Pro-Ala-Lys(Z)-OBzl
UseEmbodimentThe method of 3 is from 798mg (2.5mmol) Boc-Arg (NO2) and 1.322g (2.3mmol) HCl Pro-Ala-Lys (Z)-OBzl obtain 1.642g (78%) Boc-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl, for colorless solid.ESI-MS(m/z)864[M+Na]+。
UseEmbodimentThe method of 5-3 is from 2.099g (2.5mmol) Boc-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl obtains 1.9g (98%) title compound, for colorless solid.It is directly used in the next step.ESI-MS(m/z)742[M+H]+。
Embodiment7 preparation 3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazoles [4,5-c] pyridine-6-acyl group-Lys (Boc)-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl (5)
UseEmbodimentThe method of 3 is from 819mg (1.38mmol) (6s)-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazoles [4,5 c] pyridine-6-formyl-L-Lys (Boc) and 1.120g (1.44mmol) HCl Arg (NO2)-Pro-Ala-Lys (Z)-OBzl, purification obtains 526mg (29%) title compound, for colorless solid.ESI-MS (m/e): 1318 [M+H]+；1H-NMR (300MHz, DMSO-d6): δ/ppm=8.25-7.96 (m, 6H), 7.35-7.20 (m, 8H), 5.10 (s, 2H), 5.00 (s, 2H), 4.81 (m, 1H), 4.61-4.07 (m, 5H), 3.59-3.41 (m, 2H), 3.23-2.94 (m, 3H), 2.89-2.85 (m, 6H), 2.73 (s, 3H), 1.99-1.65 (m, 5H), 1.57 (s, 9H), 1.44 (s, 9H), 1.37 (s, 9H), 1.32-1.12 (m, 8H).
Embodiment8 preparation 4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridines-6-acyl group-Lys-Arg-Pro-Ala-Lys (6)
To 60mg (0.045mmol) 3 under ice bath, 5-bis--Boc-4,5,6,7-tetrahydrochysenes-3H-imidazoles [4,5-c] pyridine-6-acyl group-Lys (Boc)-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl adds 3mL TFA and l mL TFMSA, TLC (CH after stirring 30min2Cl2: MeOH=1: 1) display raw material point disappearance, stopped reaction.Reactant absolute ether cyclic washing, is evaporated to do, residue water dissolution, adjusts pH value to 8 with ammonia.The solution obtained is first with Sephadex G10 desalination, then with preparing postT3Prep OBDTM5 μm 30 × 150mm purification.Corresponding fraction lyophilizing obtains 9mg (26%) title compound, for colorless solid.ESI-MS (m/e): 820 [M+H]+；1H-NMR (500MHz, DMSO-d6null): δ/ppm=8.654 (s，1H)，8.576(s，1H)，8.153(m，1H)，8.042(m，1H)，8.007(m，1H)，7.962(m，1H)，7.771(m，3H)，7.703(m，2H)，7.644(m，1H)，4.430(m，1H)，4.348-4.331(m，2H)，4.325-4.235(m，5H)，4.128(m，1H)，3.602(m，1H)，3.504(m，1H)，3.313(m，1H)，3.090-3.052(m，2H)，2.800-2.720(m，5H)，1.999(m，1H)，1.865-1.821(m，3H)，1.720-1.683(m，3H)，1.583-1.484(m，9H)，1.374-1.301(m，4H)，1.204-1.176(m，6H).
Experimental example 1 evaluates the compound 6 therapeutical effect to cerebral infarction rat
Evaluation methodology
SD male rat (280-300g) 10% chloral hydrate (400mg/kg) intraperitoneal injection of anesthesia, hit exactly slightly biased right part from cervical region and vertically open the long otch of about 2em, isolate right common carotid artery, external carotid artery and internal carotid artery along sternocleidomastoid medial border.Press from both sides respectively with noinvasive bulldog clamp and close internal carotid artery opening part and common carotid artery proximal part, cut an osculum at external carotid artery, ligature external carotid artery distal end, unclamp the bulldog clamp of common carotid artery proximal part, take 10 μ L blood, after taking blood, close common carotid artery proximal part with noinvasive bulldog clamp folder again.The 10 μ L blood obtained are loaded in 1mLEP pipe, places the most at normal temperatures and make blood coagulation in 30 minutes, be then transferred in-20 DEG C of refrigerators place 1 hour, make blood clotting solid.Take out blood clotting after 1 hour, add 1mL normal saline steel shovel and blood clotting is pounded size than more uniform tiny thrombosis, standby in then tiny thrombosis suspension being transferred to 1mL syringe.While unclamping rat ICA folder, by the thrombosis suspension in above-mentioned 1mL syringe slowly from rat external carotid artery to proximal part through the brain of internal carotid injection rat, then ligation external carotid artery proximal part, opens and obtains bulldog clamp at internal carotid artery and common carotid artery, recovers blood flow.It is then peeled off the total vein of rat neck, injects medicine, ligature vein, 3 penicillins (40mg/10mL) of wound dropping, sew up a wound, wait that animal revives.The dosage of test compound is 1nmol/kg (being dissolved in normal saline).Rat revive 24 hours after by Zealonga method (Wen Wang, Jingdong Xu, Lei Li, Peichang Wang, Xunming Ji, Houxi Ai, Li Zhang, Lin Li, Neuroprotective effect of morroniside on focal cerebral ischemia in rats.Brain Research Bu lletin, 2010,83,196-201) evaluation neurological functional deficit.0 point indicates without any neurological deficit sign, and 1 point represents and do not damages side forelimb not tensible, and 2 points represent to walk to not damaging skidding, and 3 points represent and turn-take into shape walking of knocking into the back to not damaging side, 4 points represent disturbance of consciousnesss without autonomous, 5 points represent death.Above each group appraisal result is carried out statistics compare, and make t inspection.
Rat revives after 24 hours Zealonga method evaluation neurological functional deficit, after anaesthetizing with urethane, broken end takes brain rapidly, after cerebral tissue being placed in-20 DEG C of refrigerators 2 hours, in the past antinion starts the row crown serial section of about 2mm, totally 6, it is subsequently placed in 37 DEG C of lucifuges in 2%TTC solution and hatches 30min, and observe the color change of brain section, normal structure is dyed redness by TTC, and ischemic tissue is white.Then with digital photo camera, process through SPSS statistical software, calculate Infarction volume and the area of normal structure in coronal section, add up the Infarction volume percent value of each group, and do t inspection.
Rat revives latter 24 hours, evaluates neurological functional deficit by Zealonga method, and appraisal result is listed inTable 1, rat cerebral infarction volume basis is such asFollowing table 2.Result shows that 1nmol/kg compound 6 can protect the cranial nerve of rats with stroke effectively.Because compound unlike disclosed in needs 5 μm ol/kg dosage, the dosage of compound 6 is 1nmol/kg.So, 1 decrease in dose 5000 times.Obtain beyond thought technique effect.
Table 11 nmol/kg compound 6 is treated rat and is revived and mark after 24h
N=10；A) p ＜ 0.01 is compared with normal saline group.
Table 21 nmol/kg compound 6 treats rat brain Infarction volume percentage ratio
N=10；A) with normal saline than p ＜ 0.01, with t-PA than p ＞ 0.05.

Claims (3)

1. the 4 of following formula, 5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-Lys-Arg-Pro-Ala-Lys
2. the 4 of claim 1, the preparation side of 5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-Lys-Arg-Pro-Ala-Lys Method, the method includes:
(1) in the presence of dilute sulfuric acid, formaldehyde and L-Histidine react at 60 DEG C, generate 6s-4,5,6,7-tetrahydrochysene-3H-miaows Azoles pyridine-6-carboxylic acid；
(2) 6s-3 in the presence of DCC and HOBt, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazopyridine-6-carboxylic acids are in nothing With N in water oxolaneω-Boc-Lys-OBzl condensation is 6s-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo pyrroles Pyridine-6-formyl-L-Nω-Boc-Lys-OBzl；
(3) 6s-3 in the presence of Pd/C, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-L-Nω-Boc -Lys-OBzl sloughs OBzl in methanol solution and generates 6s-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazo pyrroles Pyridine-6-formyl-L-Nω-Boc-Lys；
(4) in the presence of dicyclohexylcarbodiimide Boc-Pro in anhydrous THF with and N-hydroxy-succinamide contract It is combined into Boc-Pro-OSu, at NaHCO3In the presence of Boc-Pro-OSu with Ala react generation Boc-Pro-Ala；
(5) in the presence of DCC and HOBt Boc-Pro-Ala in anhydrous THF with Nω-Z-Lys-OBzl condensation is Boc-Pro-Ala-Nω-Z-Lys-OBzl；
(6) Boc-Pro-Ala-N in hydrogen chloride-ethyl acetate solutionω-Z-Lys-OBzl sloughs Boc protection group and generates Pro -Ala-Nω-Z-Lys-OBzl；
(7) Boc-N in the presence of DCC and HOBtG-NO2-Arg in anhydrous THF with Pro-Ala-Nω-Z- Lys-OBzl condensation is Boc-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(8) Boc-N in hydrogen chloride-ethyl acetate solutionG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl sloughs Boc Protection group generates NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(9) 6s-3 in the presence of DCC and HOBt, 5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-L-Nω -Boc-Lys in anhydrous tetrahydro furan with HCl NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl condensation is 6s-3,5-bis--Boc-4,5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-L-Nω-Boc-Lys-NG-NO2-Arg-Pro -Ala-Nω-Z-Lys-OBzl；
(10) compound prepared by step (9) is sloughed protection group, obtain the compound shown in Formulas I.
3. the 4 of claim above formula, 5,6,7-tetrahydrochysene-3H-imidazopyridine-6-formyl-Lys-Arg-Pro-Ala-Lys are in system Application in standby treatment cerebral infarction medicine.
CN201510344803.3A 2015-06-23 2015-06-23 Cyclohistidyl-KRPAK, and synthesis, thrombus related activity and applications thereof Pending CN106317190A (en)

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