CN106699844A - The-RGDVGRPAK decapeptide, and preparation, activities and application thereof - Google Patents
The-RGDVGRPAK decapeptide, and preparation, activities and application thereof Download PDFInfo
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- CN106699844A CN106699844A CN201510409685.XA CN201510409685A CN106699844A CN 106699844 A CN106699844 A CN 106699844A CN 201510409685 A CN201510409685 A CN 201510409685A CN 106699844 A CN106699844 A CN 106699844A
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- gly
- arg
- obzl
- val
- lys
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- 238000002360 preparation method Methods 0.000 title abstract description 6
- 239000003146 anticoagulant agent Substances 0.000 claims abstract description 8
- 230000002785 anti-thrombosis Effects 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 51
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 20
- 238000010168 coupling process Methods 0.000 claims description 18
- 238000005859 coupling reaction Methods 0.000 claims description 18
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 17
- 230000008878 coupling Effects 0.000 claims description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 17
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 13
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- 239000003527 fibrinolytic agent Substances 0.000 claims description 3
- YIRBOOICRQFSOK-NSHDSACASA-N benzyl (2s)-2-amino-3-methylbutanoate Chemical compound CC(C)[C@H](N)C(=O)OCC1=CC=CC=C1 YIRBOOICRQFSOK-NSHDSACASA-N 0.000 claims description 2
- 125000001967 indiganyl group Chemical group [H][In]([H])[*] 0.000 claims description 2
- 229960000103 thrombolytic agent Drugs 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims 1
- 208000007536 Thrombosis Diseases 0.000 abstract description 30
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- 208000032382 Ischaemic stroke Diseases 0.000 abstract 2
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 5
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- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 description 5
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- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 2
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- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
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Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptide, discloses a preparation method of the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptide,and discloses an activity, an antithrombotic activity and a thrombus dissolving activity of the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptide in treating ischemic stroke. Therefore, the invention discloses application of the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptide to the preparation of antithrombotic and thrombolytic medicines for treating ischemic stroke.
Description
Technical field
The present invention relates to The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptides, it is related to its preparation method,
It is related to it to treat the activity of ishemic stroke, antithrombotic acitivity and thrombus dissolving activity.Thus prepared the present invention relates to it
Treatment ishemic stroke, the application in antithrombotic and thrombolytic agent.Biomedicine field of the present invention.
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.Cerebral arterial thrombosis, with fatal rate and disability rate very high.
Thromboembolism treatment is one of common important means.There is bleeding, again embolism, reperfusion injury etc. in existing thrombolytic drug
Problem, therefore the new anti-cerebral arterial thrombosis new drug of searching has important application value.In the experimental study of 3 years
In, inventor has found that The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptides have such activity.According to
This discovery, inventors herein proposes the present invention.
The content of the invention
First content of the invention is to provide The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptides.
Second content of the invention is to provide the preparation side of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys
Method, the method is comprised the following steps：
(1) Boc-Asp (OMe) and Val-OBzl couplings obtain Boc-Asp (OMe)-Val-OBzl；
(2) Boc-Asp (OMe)-Val-OBzl obtained in the ethyl acetate solution of 4N hydrogen chloride L-Asp (OMe)-
Val-OBzl；
(3) Boc-Gly and L-Asp (OMe)-Val-OBzl couplings obtain Boc-Gly-Asp (OMe)-Val-OBzl；
(4) Boc-Gly-Asp (OMe)-Val-OBzl obtain L-Gly- in the ethyl acetate solution of 4N hydrogen chloride
Asp(OMe)-Val-OBzl；
(5) Boc-Arg (Tosh) and L-Gly-Asp (OMe)-Val-OBzl couplings obtain Boc-Arg (Tosh)-Gly-
Asp(OMe)-Val-OBzl；
(6) Boc-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl are obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Arg(Tosh)-Gly-Asp(OMe)-Val-OBzl；
(7) Boc-The and L-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl couplings obtain Boc-The-Arg (Tosh)
-Gly-Asp(OMe)-Val-OBzl；
(8) Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl are in Pd/C and H2In the presence of obtain Boc-
The-Arg(Tosh)-Gly-Asp(OMe)-Val；
(9) Boc-Ala and Lys (Z)-OBzl couplings obtain Boc-Ala-Lys (Z)-OBzl；
(10) Boc-Ala-Lys (Z)-OBzl obtained in the ethyl acetate solution of 4N hydrogen chloride L-Ala-Lys (Z)-
OBzl；
(11) Boc-Pro and L-Ala-Lys (Z)-OBzl couplings obtain Boc-Pro-Ala-Lys (Z)-OBzl；
(12) Boc-Pro-Ala-Lys (Z)-OBzl obtain L-Pro-Ala- in the ethyl acetate solution of 4N hydrogen chloride
Lys(Z)-OBzl；
(13)Boc-Arg(NO2) obtain L-Arg (NO with L-Pro-Ala-Lys (Z)-OBzl couplings2)-Pro-Ala-
Lys(Z)-OBzl；
(14) Boc-Gly and L-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl coupling obtain Boc-Gly-Arg (NO2)-
Pro-Ala-Lys(Z)-OBzl；
(15)Boc-Gly-Arg(NO2)-Pro-Ala-Lys (Z)-OBzl obtain in the ethyl acetate solution of 4N hydrogen chloride
L-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-OBzl；
(16) Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val and L-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-
OBzl couplings obtain Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-Gly-Arg (NO2)-Pro-Ala-
Lys(Z)-OBzl；
(17)Boc-The-Arg(Tosh)-Gly-Asp(OMe)-Val-Gly-Arg(NO2)-Pro-Ala-Lys (Z)-OBzl is in 2N
Boc-The-Arg (Tosh)-Gly-Asp-Val-Gly-Arg (NO are obtained in the methanol solution of NaOH2)-
Pro-Ala-Lys(Z)；
(18)Boc-The-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys (Z) is in trifluoroacetic acid/fluoroform
The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys. is obtained in sulfonic acid (4: 1) solution
Liquid phase process wherein used above is the conventional and disclosed technology of this area, and Pd/C is palladium/carbon.TFA
It is trifluoroacetic acid, TFMSA is TFMS, and HCl/EtOAc is the ethyl acetate solution of hydrogen chloride.
3rd content of the invention is to evaluate The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys treatment ischemics
The activity of apoplexy.
4th content of the invention is to evaluate the antithrombotic of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys
Activity.
5th content of the invention is to evaluate the thrombus dissolving of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys
Activity.
Brief description of the drawings
The synthetic route .i of Fig. 1 The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys) HOBt, DCC, NMM,
THF；ii)4N HCl/EtOAc；Iii) Pd/C, H2；Iv) 2N NaOH, methyl alcohol；V) TFA, TFMSA.
Specific embodiment
In order to 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 being specifically described the present invention, are not construed as limitation of the present invention.
Embodiment 1 prepares Boc-Ala-Lys (Z)-OBzl (1)
2.08g (11mmol) Boc-Ala is dissolved in 20mL anhydrous tetrahydro furans (THF), 1.35g (10 is added under ice bath
Mmol) I-hydroxybenzotriazole (HOBt) and the Asia of 2.47g (12mmol) dicyclohexyls carbonyl two dissolved with anhydrous THF
Amine (DCC), stirs 0.5 hour, obtains reaction solution A.After 30 minutes, by 4.07g (10mmol) HClLys (Z)-OBzl
Dissolved with 15mL THF, and pH to 9 is first adjusted with N-methylmorpholine, be added in reaction solution A, 12 are stirred at room temperature
Hour, TLC (solvent CHCl3: MeOH=30: 1) shows that HClLys (Z)-OBzl disappears.It is filtered to remove reaction
Dicyclohexylurea (DCU) (DCU) in liquid, reaction solution is concentrated under reduced pressure into dry, residue 100mL ethyl acetate dissolving, filter
Except insoluble matter.Filtrate is washed 3 times with saturated sodium bicarbonate aqueous solution successively, and 5% aqueous potassium hydrogen sulfate is washed 3 times, saturation chlorination
Sodium water solution is washed 3 times, the ethyl acetate layer for separating anhydrous sodium sulfate drying 12h, filtering, what filtrate decompression was concentrated to give
Faint yellow color solid passes through silicagel column column chromatography (CH2Cl2∶CH3OH=90: 1) purifies, obtains 4.0g (74%) title
Compound, is colorless solid.ESI-MS(m/z)：542[M+H]+。
Embodiment 2 prepares HClAla-Lys (Z)-OBzl (2)
2.0g (3.7mmol) Boc-Ala-Lys (Z)-OBzl is dissolved in and dry on a small quantity in ethyl acetate, added under ice salt bath
20mL 4N hydrogen chloride-ethyl acetate solution, reacts 4 hours, TLC (CHCl under ice bath3: MeOH, 30: 1) show
Raw material point disappears, and reaction is complete.Reaction solution is concentrated under reduced pressure, and residue with Ethyl acetate dissolves and is concentrated under reduced pressure.The behaviour
It is repeated 3 times, cleared free hydrogen chloride, residue is worn away 3 times with absolute ether again, obtains 1.6g (90%) title
Compound, is colourless powder.ESI-MS(m/z)：442[M+H]+。
Embodiment 3 prepares Boc-Pro-Ala-Lys (Z)-OBzl (3)
Using the method for embodiment 1 from 731mg (3.4mmol) Boc-Pro and 1.8g (3.3mmol) HClAla-Lys (Z)
- OBzl obtains 1.7g (78%) title compound, is slightly yellow grease.ESI-MS(m/z)：639[M+H]+。
Embodiment 4 prepares HClPro-Ala-Lys (Z)-OBzl (4)
1.4g (92%) is obtained from 1.7g (2.5mmol) Boc-Pro-Ala-Lys (Z)-OBzl using the method for embodiment 2
Title compound, is slightly yellow grease.ESI-MS(m/z)：539[M+H]+。
Embodiment 5 prepares Boc-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl(5)
Using the method for embodiment 1 from 798mg (2.5mmol) Boc-Arg (NO2) and 1.6g (2.4mmol)
HClPro-Ala-Lys (Z)-OBzl obtains 1.5g (71%) title compound, is white solid.ESI-MS(m/z)：840
[M+H]+。
Embodiment 6 prepares HClArg (NO2)-Pro-Ala-Lys(Z)-OBzl(6)
Using the method for embodiment 2 from 1.5g (1.8mmol) Boc-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl obtains
1.2g (86%) title compound, is white powder.ESI-MS(m/z)：740[M+H]+
Embodiment 7 prepares Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl(7)
Using the method for embodiment 1 from 403mg (2.3mmol) Boc-Gly and 1.4g (2.2mmol)
HCl·Arg(NO2)-Pro-Ala-Lys (Z)-OBzl obtains 1.4g (68%) title compound, is white solid.ESI-MS
(m/z)：897[M+H]+。
Embodiment 8 prepares Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)(8)
Using the method for embodiment 2 from 1.4g (1.5mmol) Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-
OBzl obtains 1.2g (93%) title compound, is white solid.ESI-MS(m/z)：797[M+H]+。
Embodiment 9 prepares Boc-Asp (OMe)-Val-OBzl (9)
Using the method for embodiment 1 from 2.7g (11mmol) Boc-Asp (OMe) and 3.79g (10mmol)
ToshVal-OBzl obtains 4.0g (92%) title compound, is white solid.ESI-MS(m/z)：437[M+H]+。
Embodiment 10 prepares HClAsp (OMe)-Val-OBzl (10)
3.0g (88%) is obtained from 4.0g (9.2mmol) Boc-Asp (OMe)-Val-OBzl using the method for embodiment 2
Title compound, is slightly yellow grease.ESI-MS(m/z)：337[M+H]+。
Embodiment 11 prepares Boc-Gly-Asp (OMe)-Val-OBzl (11)
Using the method for embodiment 1 from 1.42g (8.1mmol) Boc-Gly and 3.0g (8.0mmol) HClAsp (OBzl)
- Val-OBzl obtains 2.9g (73%) title compound, is white solid.ESI-MS(m/z)：494[M+H]+。
Embodiment 12 prepares HClGly-Asp (OMe)-Val-OBzl (12)
2.4g is obtained from 2.9g (5.8mmol) Boc-Gly-Asp (OMe)-Val-OBzl using the method for embodiment 2
(95%) title compound, is white solid.ESI-MS(m/z)：394[M+H]+。
Embodiment 13 prepares Boc-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl (13)
Using the method for embodiment 1 from 2.8g (6.4mmol) Boc-Arg (Tosh) and 2.7g (6.3mmol) HClGly
- Asp (OBzl)-Val-OBzl obtains 3.5g (70%) title compound, is white solid.ESI-MS(m/z)：803[M
+H]+。
Embodiment 14 prepares HClArg (Tosh)-Gly-Asp (OMe)-Val-OBzl (14)
Obtained from 2.0g (2.5mmol) Boc-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl using the method for embodiment 2
It is white solid to 1.7g (92%) title compound.ESI-MS(m/z)：703[M+H]+。
Embodiment 15 prepares Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl (15)
Using the method for embodiment 1 from 2.4g (8.7mmol) Boc-The and 5.9g (8.0mmol) HClArg (Tosh)
- Gly-Asp (OMe)-Val-OBzl obtains 5.0g (65%) title compound, is white solid.ESI-MS(m/z)：957
[M+H]+。
Embodiment 16 prepares Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val (16)
2.0g (2.1mmol) Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-OBzl is dissolved in 10mL methyl alcohol,
100mg Pd/C (5%) are added, the air in decompression discharge reaction bulb is passed through hydrogen displacement, after replacing 5 times repeatedly,
Logical hydrogen is stirred at room temperature 12 hours, and (solvent dichloromethane: methyl alcohol=20: 1) shows that raw material point disappears, reaction to TLC
Completely, reaction is stopped.Pd/C is filtered, filtrate decompression concentration removes solvent, obtains 1.6g (88%) title compound,
It is white solid.ESI-MS(m/z)：865[M-H]-。
Embodiment 17 prepares Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-Gly-Arg (NO2)-Pro-Ala-
Lys(Z)-OBzl(17)
Using embodiment 1 method from 900mg (1.0mmol) Boc-The-Arg (Tosh)-Gly-Asp (OMe)-
Val and 800mg (0.96mmol) HClGly-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl obtains 600mg (40%)
Title compound, is white solid.ESI-MS(m/z)：1647[M+H]+。
Embodiment 18 prepares Boc-The-Arg (Tosh)-Gly-Asp-Val-Gly-Arg (NO2)-Pro-Ala-Lys(Z)
(18)
By 200mg (0.12mmol) Boc-The-Arg (Tosh)-Gly-Asp (OMe)-Val-Gly-Arg (NO2)-
Pro-Ala-Lys (Z)-OBzl is dissolved in 15mL methyl alcohol, adds the 2N NaOH aqueous solution to be maintained at pH under ice bath
12, react 6 hours, (solvent dichloromethane: methyl alcohol=10: 1) shows that raw material point disappears to TLC.Use saturation sulfuric acid
Hydrogen potassium withers pH to 7, and methyl alcohol is removed under reduced pressure, and obtains 170mg (91%) title compound, is white solid,
ESI-MS(m/z)：1543[M+H]+。
Embodiment 19 prepares The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (19)
By 170mg previous step products
Boc-The-Arg(Tosh)-Gly-Asp-Val-Gly-Arg(NO2)-Pro-Ala-Lys (Z) add eggplant bottle in, under ice salt bath plus
Enter 1mL TFA and 0.25mL TFMSA, (n-butanol: water: glacial acetic acid=1: 1: 1) shows former to TLC after 1 hour
Shots disappear, and stop reaction, use absolute ether cyclic washing, and decompressing and extracting, then with water dissolves, uses 25% ammoniacal liquor
Adjust pH to 7, use Sephadex G10Desalination, C18Post is purified, and is freezed, and obtains 30mg (22%) title compound,
It is white powder.Mp 180-183℃；[α]20 D=-100.00 (c=0.10, H2O).IR(KBr)：vR-CH3=2962,
2873,1450,1381；vR-CH2-R=2930,1257；vCO-NH=1680,3387；vNH2=3400,600.ESI-MS
(m/e)：1111[M+H]+.1HNMR (800MHz, D2O) δ/ppm=0.8912 (d, J=2.40Hz, 3H),
0.8827 (d, J=2.40Hz, 3H), 1.0337 (t, J=7.36Hz, 3H), 1.3480 (d, J=7.28Hz, 3H),
1.3898 (m, 2H), 1.5968 (m, 2H), 1.6270 (m, 2H), 1.6380 (m, 2H), 1.6885 (m, 2H), 1.7550
(m, 2H), 1.8448 (m, 2H), 1.8673 (dq, J1=6.24Hz, J2=6.40Hz, 1H), 1.9625 (ddd, J=6.40
Hz, J=6.56Hz, J=7.20Hz, 2H), 2.1020 (ddd, J=14.08Hz, J=6.88Hz, J=7.20Hz,
2H), 2.0513 (ddt, J=6.72Hz, J=6.8Hz, J=6.08Hz, 1H), 2.2386 (ddt, J=6.72Hz, J=
6.80Hz, J=6.08Hz, 1H), 2.7833 (dd, J=7.36Hz, J=15.20Hz, 1H), 2.8317 (dd, J=7.36
Hz, J=15.20Hz, 1H), 2.9356 (t, J=7.36Hz, 2H), 3.1241 (dd, J1=7.36Hz, J2=14.56Hz,
2H), 3.1555 (m, 2H), 3.1640 (m, 2H), 3.5643 (dt, J1=4.56Hz, J2=9.92Hz, 1H), 3.7552
(dt, J1=4.56Hz, J2=9.92Hz, 1H), 3.8620 (s, 2H), 3.9306 (s, 2H), 4.0342 (t, J=6.56Hz,
1H), 4.0611 (d, J=6.80Hz, 1H), 4.2380 (dd, J1=7.12Hz, J2=14.32Hz, 1H), 4.2752 (dd,
J1=5.44Hz, J2=8.56,1H), 4.3341 (t, J=7.04Hz, 1H), 4.3659 (d, J=7.76Hz, 1H),
4.5925 (dd, J1=5.2Hz, J2=8.24Hz, 1H).
Experimental example 1 evaluates the antithrombotic acitivity of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide)
By SD male rats (180-220g), random packet is every group 15, quiet to know raising one day, stops feeding
Support overnight.The physiology salt for giving The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide) through gavage is water-soluble
The normal saline solution (dosage is 167 μm of ol/kg) or physiological saline of liquid (dosage is 100nmol/kg) or aspirin
After (dosage is 10ml/kg) 30min, rat is anaesthetized with the normal saline solution of 20% Ethylurethanm, is performed the operation afterwards.
The right carotid and left neck vein of rat are separated, the silk thread of correct amount is placed in bypass intubation, one end insertion of pipe is left
Vein, another end pipe insertion right artrial simultaneously injects 0.2mL liquaemin anti-freezings.So that blood flow flows through side from right artrial
Road intubation enters left side vein, the silk thread with thrombus is taken out after 15min and is weighed, and calculates silk thread before and after blood circulation
Weight, obtain thrombus weight withAntithrombotic acitivity is represented and represented, makees t inspections.Data list table 1 in.
Result shows oral 100nmol/kg compounds The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide)
Can effectively inhibition thrombosis.
The anti-thrombus activity of the 100nmol/kg The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide) of table 1
N=10,167 μm of ol/kg of aspirin dose, are administered orally, and decapeptide dosage is 100nmol/kg；a)
Represent compared with NS, p ＜ 0.01.
Test result indicate that：It is 100nmol/kg to concentration, the wet weight of thrombus of decapeptide is 18.13 ± 3.76mg, with life
Compared to there is significant difference (28.56 ± 4.12mg, p ＜ 0.01), decapeptide has certain anti-thrombus activity to reason salt solution.Sun
Property control wet weight of thrombus be 12.97 ± 2.48mg.
Experimental example 2 evaluates the thrombus dissolving activity of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide)
SD rats (male, 200 ± 20g) press the dosage intraperitoneal injection urethane normal saline solution of 1200mg/kg
Anaesthetized.Its dorsal position is fixed after anesthetized rat, separates its RCCA, artery clamp is clamped at proximal part,
Proximal part and distal end are respectively penetrated into surgical thread, the surgical thread ligation of distal end, distal end intubation, by artery clamp pine
Open, take out about 1mL arterial bloods, be placed in 1mL centrifuge tubes.Toward vertical fixed rubber tube (15mm long,
Internal diameter 2.5mm, external diameter 5.0mm, ttom of pipe are sealed with plug, and para films are tamping) in injection 0.1ml rats move
Arteries and veins blood, a fixing bolt for the thrombus of stainless steel is then rapidly inserted into pipe, and (thrombus fixes spiral diameter
For the stainless steel wire of 0.2mm is coiled into, spiral part 10mm long includes 15 bung flanges, a diameter of the 1.0 of bung flange
Mm, support handle is connected with spiral, 7.0mm is about, in question mark type).After blood clotting 45min, from glass tube
In the careful thrombus wrapped up by thrombus that takes out fix spiral, accurately claim its weight.
Bypass intubation is made up of three parts, and interlude is 60.0mm long, the polyethylene rubber tube of internal diameter 3.5mm；Two ends are equal
It is 100.0mm long, the identical polyethylene pipe of internal diameter 1.0mm, external diameter 2.0mm, the pipe one end pulls into spike tube,
10.0mm (for inserting rat carotid artery and vein) is about, external diameter is 1.0mm, one section of the outer cover of its other end
A length of 7.0mm, external diameter is the polyethylene pipe (for insert in the polyethylene rubber tube in stage casing) of 3.5mm, 3 sections of pipes it is interior
Wall is required to silanization (1% silicone oil diethyl ether solution).The thrombus that thrombus is wrapped up fixes spiral and is placed in stage casing polyethylene
In sebific duct, the overstriking end of the other two ends of sebific duct respectively with two polyethylene is nested, it is ensured that will not during circulation
Leakage blood.With syringe heparin-saline solution (50IU/kg) will be filled by spike tube end in pipe, exclude bubble, it is standby.
The left vena jugularis externa of rat is separated, proximal part and distal end respectively penetrate surgical thread, ligature the blood vessel of distal end,
An osculum is cut on exposed left vena jugularis externa, the above-mentioned bypass duct spike tube for preparing is inserted quiet outside left neck by osculum
At arteries and veins opening, while fixing spiral away from shunt valve stage casing (thrombus containing accurate weighing fixes spiral) interior thrombus.With note
Emitter injects the normal saline solution (50IU/kg) of the liquaemin of correct amount by the spike tube of the other end, now syringe
Polyethylene pipe should not be withdrawn, the flexible pipe between syringe and polyethylene pipe is clamped with artery clamp.In the near of RCCA
Heart end is stopped blooding with artery clamp, ligatures distal end, RCCA nearby is being cut into an osculum from artery clamp, from poly- second
Syringe is extracted in the tip of alkene pipe, and the tip of polyethylene pipe is inserted the proximal part of artery angle.The two ends of bypass duct
Arteriovenous are fixed with No. 4 sutures.
With scalp acupuncture by physiological saline (3mL/kg), the normal saline solution (20000IU/kg) of urokinase or
The normal saline solution (dosage is 100nmol/kg) of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide)
By the stage casing (fixing spiral containing the thrombus being precisely weighed) of shunt valve, the nearly vein that spiral is fixed away from thrombus is pierced into
Place, opens artery clamp, blood flow is flowed to vein from artery by bypass duct.Solution in syringe is slowly injected into
Blood, by blood circulation, by the sequential action of vein-heart-artery on the thrombus of spiral.Blood circulation 1h it
Afterwards, the spiral of fixed thrombus, accurate weighing are taken out from bypass duct.Calculate fix blood in every rat bypass duct
The weight difference of thrombus before and after the spiral blood circulation of bolt, with averageThrombus dissolving activity is represented and represented, makees t
Inspection.Data list table 2 in.Result shows 100nmol/kg The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys
(decapeptide) can effectively lysigenous thrombus.
Table 2 100nmol/kg The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide) thrombolysis activity
N=10, urokinase dosage is 20000IU/kg；Decapeptide dosage is 1nmol/kg, a) compared with physiological saline, p ＜ 0.01,
B) with urokinase ratio, p ＞ 0.05.
Test result indicate that：To concentration for the thrombus loss of weight of the decapeptide of 100nmol/kg is 36.47 ± 4.69mg, with life
Reason brine ratio relatively has significant difference (27.40 ± 3.20mg, p ＜ 0.01), compares with positive control urokinase, p ＞ 0.05
Indifference, quite, the thrombus loss of weight of positive control urokinase is 40.14 ± 5.43mg to activity.
Experimental example 3 evaluates The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys and ishemic stroke rat is controlled
Treatment is acted on
About 2cm otch long is opened vertically at the positive middle part of the neck of male SD rat (300 ± 20g of body weight), breast is locked along chest
Isolate RCCA, external carotid artery and internal carotid in prominent intramuscular lateral margin.Pressed from both sides to close in neck respectively with noninvasive artery clamp and moved
At arteries and veins opening and arteria carotis communis proximal part, the distal end of external carotid artery is ligatured, an osculum is cut in external carotid artery, unclamp neck
The artery clamp of total artery proximal part, takes 10 μ L blood, closes the proximal part of arteria carotis communis with noninvasive artery clamp folder again afterwards.
Room temperature makes blood clotting in 30 minutes during the 10 μ L blood for obtaining are placed on into 1mL EP pipes, is then transferred to -20 DEG C
Placed 1 hour in refrigerator, make blood clotting solid.Rat is 400 with 10% chloraldurate intraperitoneal injection of anesthesia, dosage
mg/kg.Blood clotting is taken out, 1mL physiological saline is added, blood clotting is pounded with steel shovel uniform thin
Microthrombus block, prepares the suspension of tiny thrombus and is transferred in 1mL syringes.Unclamp the dynamic of arteria carotis communis proximal part
Arteries and veins is pressed from both sides, by 1mL thrombus suspension slowly from rat external carotid artery to proximal part by the big of internal carotid injection rat
Brain, then ligatures external carotid artery proximal part, opens and artery clamp is obtained at internal carotid and arteria carotis communis, recovers blood flow.Deng
Wait to revive.Rat presses Zealonga methods evaluation neurological functional deficit after reviving 24 hours.0 point indicates without any
Neurological deficit sign, 1 point represent do not damage the not tensible of side forelimb, 2 points represent to do not damage skidding walk, 3 points
Represent to do not damage side turn-take into shape walking of knocking into the back, 4 points represent that the disturbances of consciousness represent dead without autonomous, 5 points.Greatly
Mouse injects 1 The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide) through tail vein daily, and dosage is 100
nmol/kg.Continuous injection 6 days, daily scoring.Result lists table 3 in.As shown by data
The-Arg-Gly-Asp-Val-Gly-Arg-Pro-
Continuously treatment is 0 point except 7 cerebral ischemias rat biology of 24 hours can be made to score in 6 days to Ala-Lys (decapeptide),
Also the rat that the Neurobiology scoring in 24 hours of 7 cerebral ischemias is 2 points, 3 points and 4 points can be improved as 1 point, because unlike
Disclosed compound initial dose needs 5 μm of ol/kg, and 5 maintenance doses need 2 μm of ol/kg afterwards,
6 dosage of The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys (decapeptide) are 100nmol/kg.Such one
Come, initial dose and maintenance dose reduce 50 times and 20 times respectively.
The The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys of table 3 (decapeptide) continuously treatment 6 days it is small to cerebral ischemia 24
When the scoring of rat biology influence
N=14.
Claims (5)
1.The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys decapeptides.
2. the prepared method of the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys of claim 1, the method bag
Include：
(1) Boc- β-carboxyl-OMe-Asp and Val-OBzl couplings obtain Boc- β-carboxyl-OMe-Asp-Val-OBzl；
(2) Boc- β-carboxyl-OMe-Asp-Val-OBzl obtains L- β-carboxyl in the ethyl acetate solution of 4N hydrogen chloride
-OMe-Asp-Val-OBzl；
(3) Boc-Gly and L- β-carboxyl-OMe-Asp-Val-OBzl couplings obtain Boc-Gly- β-carboxyl
-OMe-Asp-Val-OBzl；
(4) Boc-Gly- β-carboxyl-OMe-Asp-Val-OBzl is obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Gly- β-carboxyl-OMe-Asp-Val-OBzl；
(5)Boc-NG- Tosh-Arg and L-Gly- β-carboxyl-OMe-Asp-Val-OBzl couplings obtain Boc-NG-Tosh-Arg
- Gly- β-carboxyl-OMe-Asp-Val-OBzl；
(6)Boc-NGEthyl acetate solutions of-Tosh-Arg-Gly- β-carboxyl-the OMe-Asp-Val-OBzl in 4N hydrogen chloride
In obtain L-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Asp-Val-OBzl；
(7) Boc-The and L-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Val-OBzl couplings are obtained
Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Val-OBzl；
(8)Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Val-OBzl is in Pd/C profits H2In the presence of obtain
Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Val；
(9) Boc-Ala and Nω- Z-Lys-OBzl couplings obtain Boc-Ala-Nω-Z-Lys-OBzl；
(10)Boc-Ala-Nω- Z-Lys-OBzl is obtained in the acetic acid acetyl solution of 4N hydrogen chloride
L-Ala-Nω-Z-Lys-OBzl；
(11) Boc-Pro and L-Ala-Nω- Z-Lys-OBzl couplings obtain Boc-Pro-Ala-Nω-Z-Lys-OBzl；
(12)Boc-Pro-Ala-Nω- Z-Lys-OBzl is obtained in the ethyl acetate solution of 4N hydrogen chloride
L-Pro-Ala-Nω-Z-Lys-OBzl；
(13)Boc-NG-NO2- Arg and L-Pro-Ala-Nω- Z-Lys-OBzl couplings obtain L-NG-
NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(14) Boc-Gly and L-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-OBzl couplings obtain Boc-Gly-
NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(15)Boc-Gly-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-OBzl is in the ethyl acetate solution of 4N hydrogen chloride
Obtain L-Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(16)Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Asp-Val and L-Gly-NG-NO2-Arg-Pro
-Ala-Nω- Z-Lys-OBzl couplings obtain Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Asp-Val
-Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-OBzl；
(17)Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Asp-Val-Gly-NG-NO2-Arg-Pro-Ala
-Nω- Z-Lys-OBzl obtains Boc-The-N in the methanol solution of 2N NaOHG- Tosh-Arg-Gly- β-carboxyl
-OMe-Asp-Val-Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys；
(18)Boc-The-NG- Tosh-Arg-Gly- β-carboxyl-OMe-Asp-Val-Gly-NG-NO2-Arg-Pro-Ala
-Nω- Z-Lys is in trifluoroacetic acid/TFMS=4: obtains The-Arg-Gly-Asp-Val-Gly in 1 solution
-Arg-Pro-Ala-Lys。
3. the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys of claim 1 prepares answering for antithrombotic reagent
With.
4. the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys of claim 1 prepares answering for thrombolytic agent
With.
5. the The-Arg-Gly-Asp-Val-Gly-Arg-Pro-Ala-Lys of claim 1 prepares ishemic stroke medicine
Using.
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| CN102875644A (en) * | 2012-09-05 | 2013-01-16 | 永光制药有限公司 | GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof |
| US8633158B1 (en) * | 2012-10-02 | 2014-01-21 | Tarix Pharmaceuticals Ltd. | Angiotensin in treating brain conditions |
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