CN106317187B - Five methoxytryptamine base carbonyl propionyl-PAK peptides, preparation, activity and application - Google Patents
Five methoxytryptamine base carbonyl propionyl-PAK peptides, preparation, activity and application Download PDFInfo
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Abstract
The invention discloses five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of following formula, disclose its preparation method, disclose its antithrombotic acitivity, it discloses its thrombus dissolving activity and discloses the effect that it treats rats with stroke, thus the invention discloses it to prepare antithrombotic reagent, the application in thrombolytic agent and treatment ishemic stroke drug.
Description
Technical field
The present invention relates to five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val, are related to it
Preparation method, be related to its antithrombotic acitivity, be related to its thrombus dissolving activity and be related to it treat ishemic stroke work
With, thus the present invention relates to it preparing antithrombotic reagent, the application in thrombolytic agent and treatment ishemic stroke drug.
The invention belongs to biomedicine fields.
Background technique
Ishemic stroke be it is a kind of more typically and the serious cranial vascular disease of harm, feature be disease incidence is high, case fatality rate is high,
Disability rate height and high recurrence rate.Clinical treatment ishemic stroke faces the reality of not active drug, especially apoplexy face 4h at present
Above patient is non-extremely i.e. residual.Invention is clinical important need to the effective drug of patient of apoplexy face 4h or more.Inventor
The imidazolinium compounds of Formulas I was once disclosed on the ischemia/reperfusion in rats apoplexy model for 24 hours of apoplexy face, shows outstanding curative effect.Connect
The imidazolinium compounds of 6 days Formula II of continuous intravenous injection, 1 time a day, initial dose are 5 μm of ol/kg, and rear 5 dosage is 2 μ
Mol/kg has outstanding curative effect.Aa in formula1And aa2It can be to exist simultaneously, aa1In the presence of but aa2It is not present, or is not present simultaneously；When
aa1And aa2When existing simultaneously, aa1For R (Arg), and aa2For G (Gly), A (Ala) or Q (Gln)；Work as aa1In the presence of but aa2It does not deposit
When, aa1For R (Arg)；aa3It can be S (Ser), V (Val) or F (Phe).Since the position 2- of the imidazolinium compounds of Formula II is
4- oxygen acetyl-Lys.And the side-chain amino group and main-chain carboxylic group of the Lys is connected with RGD antithrombotic tetrapeptide and ARPAK thrombolysis peptide respectively
It connects, needs to simplify so structure is more complicated.
Inventor passes through 3 years experimental studies, and discovery replaces 2- (the 4- oxygen acetyl of Formulas I with five methoxytryptamine base carbonyl propionos
Base) phenyl -4,4,5,5- tetramethyl -1,3-, bis- Sinerol imidazolinyl substitution can obtain structure simply and eutherapeutic meaning
Unimaginable technical effect.According to this discovery, the present invention is inventors herein proposed.
Summary of the invention
One of contents of the present invention are to provide five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg- of following formula
Gly -Asp-Val
The two of the contents of the present invention are to provide five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-
The preparation method of Asp-Val, method includes the following steps:
1) five methoxytryptamine base carbonyl propionic acid are prepared；
2) Boc-Arg (NO is prepared2)-Gly-OBzl；
3) Boc-Arg (NO is prepared2)-Gly；
4) Boc-Asp (OBzl)-Val-OBzl is prepared；
5) HCl-Asp (OBzl)-Val-OBzl is prepared；
6) Boc-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
7) HCl-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
8) Fmoc-Lys (Boc)-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
9) Fmoc-Lys-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
10) Boc-Pro-Ala-OBzl is prepared；
11) Boc-Pro-Ala is prepared；
12) Boc-Pro-Ala-Lys (Z)-OBzl is prepared；
13) Boc-Pro-Ala-Lys (Z) is prepared；
14) Fmoc-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
15) Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
16) by Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl and five methoxies
Tryptamines base carbonyl propionic acid reacts to obtain five methoxytryptamine base carbonyl propionyl-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly -
Asp(OBzl)-Val-OBzl；
17) by five methoxytryptamine base carbonyl propionyl-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp
(OBzl)-Val-OBzl is deprotected to obtain five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-
Val。
The contents of the present invention third is that evaluation five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp
The antithrombotic acitivity of-Val, thrombus dissolving activity and the effect for treating ishemic stroke.
Detailed description of the invention
Fig. 1 five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val (1) synthetic route:
(a) DCC, HOBt, NMM, THF；(b) 2N NaOH, THF；(c) 4N hydrogen chloride-ethyl acetate solution；(d) piperidines/DMF (e)
Succinic anhydride；(f)TFA/TFMSA.
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 connects peptide and leads to method
1mmol c-terminus compound is dissolved in dry THF, 1.2mmol N- hydroxy benzenes a pair of horses going side by side three is sequentially added under ice bath stirring
1.2mmol N, the N- dicyclohexylcarbodiimide (DCC) of nitrogen azoles (HOBt) and dry THF dissolution, stirs 0.5h, will
1.05mmol aminoterminal compound is dissolved in dry THF, is added in above-mentioned reaction solution, and N-methylmorpholine (NMM) is adjusted to pH9, room temperature
Stir 6h, TLC (CHCl3/CH3OH, 10/1) show that c-terminus raw material completely disappears, reaction terminates.It is filtered to remove DCU, filtrate subtracts
It is dissolved after pressure concentration with ethyl acetate, obtained solution is successively with saturation NaHCO3Aqueous solution is washed 3 times, and NaCl aqueous solution is saturated
3 times are washed, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3Aqueous solution is washed 3 times and saturation NaCl
Aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate decompression is concentrated to dryness, column layer (CHCl3/
CH3OH, 10/1) analysis obtains target compound after purification.
Embodiment 2 removes N- tertbutyloxycarbonyl protecting group and leads to method
1mmol is contained to compound a small amount of dry ethyl acetate dissolution, the ice bath stirring of N- tertbutyloxycarbonyl protecting group
Lower addition 10mL 4N hydrogen chloride/ethyl acetate solution, ice bath stirring 1-2h, TLC (CHCl3/CH3OH, 10/1) show that raw material is complete
It totally disappeared mistake, reaction terminates.Reaction solution is concentrated under reduced pressure.Residue adds 5ml anhydrous ethyl acetate, and solution is concentrated to dryness.The behaviour
It is repeated 3 times.Residue adds 5ml anhydrous ether, solution is concentrated to dryness.The operation is repeated 3 times.Obtained target chemical combination
Object is directly used in the next step.
The hydrolysis removing benzyl ester protecting group of embodiment 3 leads to method
Compound containing benzyl ester protecting group is dissolved in methanol, 2M NaOH aqueous solution is slowly added dropwise under ice bath and stirring, adjusts
To pH12,5h, TLC (CHCl are reacted3/CH3OH, 10/1) show that raw material completely disappears, reaction terminates.It is slowly dripped under ice bath stirring
Add saturation KHSO4Aqueous solution is adjusted to pH7, is concentrated under reduced pressure and removes methanol, remaining aqueous solution is slowly added dropwise full under ice bath stirring
And KHSO4Aqueous solution is adjusted to pH3, and ethyl acetate extracts 3 times, and combined ethyl acetate layer is washed 3 times with saturation NaCl aqueous solution, uses
Anhydrous Na2SO4It dries, filters, filtrate decompression concentration obtains target compound.
4 hydrogenolysis of embodiment removes benzyl ester protecting group and leads to method
Compound containing benzyl ester protecting group is dissolved in methanol, is added Pd/C (the 20% of reaction volume), decompression extraction is anti-
The air in system is answered, hydrogen is passed through, 10h, TLC (CHCl is stirred at room temperature3/CH3OH, 10/1) show that raw material completely disappears, it reacts
Terminate.It is filtered to remove Pd/C, filtrate decompression concentration obtains target compound.
16) five methoxytryptamine base carbonyl propionic acid are prepared；
Embodiment 5 prepares five methoxytryptamine base carbonyl propionic acid
Dry THF is dissolved in by five methoxytryptamine of 1.9g (10.0mmol), 1.20g (12.0mmol) is added under ice bath stirring
Succinic anhydride is adjusted to pH9 with NMM, and 6h, TLC (CHCl is stirred at room temperature3/CH3OH, 10/1) show that c-terminus raw material completely disappears,
Reaction terminates.It is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution successively uses 5%KHSO4Aqueous solution is washed 3 times, is satisfied
It is washed 3 times with NaCl aqueous solution.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate decompression obtains after being concentrated to dryness
2.81g (96.9%) title compound is faint yellow solid.ESI-MS (m/e): 289 [M-H]-。
Embodiment 6 prepares Boc-Pro-Ala-OBzl
Peptide logical method is connect according to embodiment 1, and dry THF is dissolved in by 0.84g (3.90mmol) Boc-Pro c-terminus compound,
0.96g (4.68 mmol) DCC of 0.63g (4.68mmol) HOBt and dry THF dissolution, stirring are sequentially added under ice bath stirring
1.30g (3.7mmol) HClAla-OBzl aminoterminal compound is dissolved in dry THF, is added in above-mentioned reaction solution by 0.5h,
NMM is adjusted to pH9, and 6h is stirred at room temperature, and TLC (petroleum ether/acetone, 3/2) shows that c-terminus raw material completely disappears, and reaction terminates.It crosses
DCU is filtered out, is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution is successively with saturation NaHCO3Aqueous solution is washed 3 times,
Saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3Aqueous solution washes 3
Secondary and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate decompression is concentrated into
It is dry, column layer (CHCl3/CH3OH, 100/1) analysis obtains 1g (72%) title compound after purification, and it is colorless solid.ESI-MS(m/
E): 377 [M+H]+。
Embodiment 7 prepares Boc-Pro-Ala
Removing benzyl ester protecting group logical method is hydrolyzed according to embodiment 3, and 1g (2.66mmol) Boc-Pro-Ala-OBzl is dissolved in first
2M NaOH aqueous solution is slowly added dropwise under alcohol, ice bath and stirring, is adjusted to pH12, reacts 5h, TLC (CHCl3/CH3OH, 10/1) it is aobvious
Show that raw material completely disappears, reaction terminates.Saturation KHSO is slowly added dropwise under ice bath stirring4Aqueous solution is adjusted to pH7, and reduced pressure removes
Methanol is removed, saturation KHSO is slowly added dropwise in remaining aqueous solution under ice bath stirring4Aqueous solution is adjusted to pH3, ethyl acetate extraction 3
Secondary, combined ethyl acetate layer is washed 3 times with saturation NaCl aqueous solution, uses anhydrous Na2SO4It dries, filters, filtrate decompression concentration obtains
0.7g (92%) title compound is colorless solid.ESI-MS (m/e): 285 [M-H]-。
Embodiment 8 prepares Boc-Pro-Ala-Lys (Z)-OBzl
Peptide logical method is connect according to embodiment 1, and drying is dissolved in by 1.0g (3.7mmol) Boc-Pro-Ala c-terminus compound
THF sequentially adds 0.91g (4.44mmol) DCC of 0.60g (4.44mmol) HOBt and dry THF dissolution under ice bath stirring,
0.5h is stirred, 1.25g (3.10mmol) HClLys (Z)-OBzl aminoterminal compound is dissolved in dry THF, is added above-mentioned anti-
It answers in liquid, NMM is adjusted to pH9, and 6h is stirred at room temperature, and TLC (petroleum ether/acetone, 1/1) shows that c-terminus raw material completely disappears, reacts
Terminate.It is filtered to remove DCU, is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution is successively with saturation NaHCO3It is water-soluble
Liquid is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3
Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate subtracts
Pressure is concentrated to dryness, column layer (CHCl3/CH3OH, 100/1) analysis obtains 1.5g (76%) title compound after purification, and it is colourless solid
Body.ESI-MS (m/e): 639 [M+H]+。
The preparation preparation of embodiment 9 Boc-Pro-Ala-Lys (Z)
Removing benzyl ester protecting group, which is hydrolyzed, according to embodiment 3 leads to method for 1g (1.56mmol) Boc-Pro-Ala- Lys (Z)-
OBzl is dissolved in methanol, and 2M NaOH aqueous solution is slowly added dropwise under ice bath and stirring, is adjusted to pH12, reacts 5h, TLC (CHCl3/
CH3OH, 10/1) show that raw material completely disappears, reaction terminates.Saturation KHSO is slowly added dropwise under ice bath stirring4Aqueous solution is adjusted to
PH7 is concentrated under reduced pressure and removes methanol, and saturation KHSO is slowly added dropwise in remaining aqueous solution under ice bath stirring4Aqueous solution is adjusted to pH3,
Ethyl acetate extracts 3 times, and combined ethyl acetate layer is washed 3 times with saturation NaCl aqueous solution, uses anhydrous Na2SO4It dries, filters,
Filtrate decompression concentration, obtains 0.8g (93.5%) title compound.ESI-MS (m/e): 547 [M-H]-。
Embodiment 10 prepares Boc-Arg (NO2)-Gly-OBzl
Peptide, which is connect, according to embodiment 1 leads to method by 4.98g (15.5mmol) Boc-Arg (NO2) c-terminus compound is dissolved in drying
THF sequentially adds 3.81g (18.6 mmol) DCC of 2.51g (18.6mmol) HOBt and dry THF dissolution under ice bath stirring,
0.5h is stirred, 6.49g (15.0mmol) HClGly-OBzl aminoterminal compound is dissolved in dry THF, above-mentioned reaction is added
In liquid, NMM is adjusted to pH9, and 6h, TLC (CH is stirred at room temperature2Cl2∶CH3OH, 15/1) show that c-terminus raw material completely disappears, it reacts
Terminate.It is filtered to remove DCU, is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution is successively with saturation NaHCO3It is water-soluble
Liquid is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3
Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate subtracts
Pressure is concentrated to dryness, column layer (CHCl3/CH3OH, 60/1) analysis obtains 6g (87%) title compound after purification, and it is colorless solid.ESI-
MS (m/e): 467 [M+H]+。
Embodiment 11 prepares Boc-Arg (NO2)-Gly
Removing benzyl ester protecting group, which is hydrolyzed, according to embodiment 3 leads to method for 1g (2.14mmol) Boc-Arg (NO2)-Gly-OBzl
It is dissolved in methanol, 2M NaOH aqueous solution is slowly added dropwise under ice bath and stirring, is adjusted to pH12, reacts 5h, TLC (CHCl3/CH3OH,
10/1) display raw material completely disappears, and reaction terminates.Saturation KHSO is slowly added dropwise under ice bath stirring4Aqueous solution is adjusted to pH7, decompression
Concentration removes methanol, and saturation KHSO is slowly added dropwise in remaining aqueous solution under ice bath stirring4Aqueous solution is adjusted to pH3, ethyl acetate
Extraction 3 times, combined ethyl acetate layer are washed 3 times with saturation NaCl aqueous solution, use anhydrous Na2SO4It dries, filters, filtrate decompression is dense
Contracting, obtains 0.797g (99%) title compound, is colorless solid.ESI-MS (m/e): 376 [M-H]-。
Embodiment 12 prepares Boc-Asp (OBzl)-Val-OBzl
Peptide logical method is connect according to embodiment 1, and drying is dissolved in by 4.5g (13.85mmol) Boc-Asp (OBzl) c-terminus compound
THF sequentially adds the 3.42g (16.62 mmol) of 2.24g (16.62mmol) HOBt and dry THF dissolution under ice bath stirring
DCC stirs 0.5h, and 5.0g (13.2mmol) HClVal-OBzl aminoterminal compound is dissolved in dry THF, is added above-mentioned anti-
It answers in liquid, NMM is adjusted to pH9, and 6h, TLC (CH is stirred at room temperature2Cl2∶CH3OH, 30/1) show that c-terminus raw material completely disappears, instead
It should terminate.It is filtered to remove DCU, is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution is successively with saturation NaHCO3Water
Solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, and 5%
NaHCO3Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters,
Filtrate decompression is concentrated to dryness, column layer (CHCl3/CH3OH, 60/1) analysis obtains 6g (91%) title compound after purification, and it is colourless solid
Body.ESI-MS (m/e): 512 [M+H]+。
Embodiment 13 prepares HClAsp (OBzl)-Val-OBzl
N- tertbutyloxycarbonyl protecting group, which is removed, according to embodiment 2 leads to method for 1g (1.95mmol) Boc-Asp (OBzl)-
Val-OBzl is dissolved with a small amount of dry ethyl acetate, and 10mL 4N hydrogen chloride/ethyl acetate solution, ice bath are added under ice bath stirring
Stir 1-2h, TLC (CHCl3/CH3OH, 10/1) show that raw material completely disappears, reaction terminates.Reaction solution is concentrated under reduced pressure.Residue
Add 5ml anhydrous ethyl acetate, solution is concentrated to dryness.The operation is repeated 3 times.Residue adds 5ml anhydrous ether, solution subtracts
Pressure is concentrated to dryness.The operation is repeated 3 times.Obtained target compound is directly used in the next step.
Embodiment 14 prepares Boc-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl
Peptide, which is connect, according to embodiment 1 leads to method by 5.03g (15.5mmol) Boc-Arg (NO2)-Gly c-terminus compound is dissolved in
Dry THF sequentially adds 3.81 g (18.6mmol) of 2.51g (18.6mmol) HOBt and dry THF dissolution under ice bath stirring
DCC stirs 0.5h, 6g (13.37mmol) HClAsp (OBzl)-Val-OBzl aminoterminal compound is dissolved in dry THF, is added
Enter in above-mentioned reaction solution, NMM is adjusted to pH9, and 6h, TLC (CH is stirred at room temperature2Cl2∶CH3OH, 20/1) show that c-terminus raw material is complete
It disappears, reaction terminates.It is filtered to remove DCU, is dissolved after filtrate decompression concentration with ethyl acetate, obtained solution is successively with saturation
NaHCO3Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3
It is secondary, 5%NaHCO3Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It is dry,
Filtering, filtrate decompression are concentrated to dryness, column layer (CHCl3/CH3OH, 20/1) analysis after purification 7.02g (68.%) title compound,
For colorless solid.ESI-MS (m/e): 771 [M+H]+。
Embodiment 15 prepares HClArg (NO2)-Gly-Asp(OBzl)-Val-OBzl
N- tertbutyloxycarbonyl protecting group, which is removed, according to embodiment 2 leads to method for 1g (1.30mmol) Boc-Arg (NO2)-Gly-
Asp (OBzl)-Val-OBzl is dissolved with a small amount of dry ethyl acetate, and 10mL 4N hydrogen chloride/acetic acid second is added under ice bath stirring
Ester solution, ice bath stirring 1-2h, TLC (CHCl3/CH3OH, 10/1) show that raw material completely disappears, reaction terminates.Reaction solution decompression
Concentration.Residue adds 5ml anhydrous ethyl acetate, and solution is concentrated to dryness.The operation is repeated 3 times.Residue adds the anhydrous second of 5ml
Ether, solution are concentrated to dryness.The operation is repeated 3 times.Obtained target compound is directly used in the next step.
Embodiment 16 prepares Fmoc-Lys (Boc)-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl
According to embodiment 1 connect peptide lead to method be dissolved in by 7.82g (16.68mmol) Fmoc-Lys (Boc) c-terminus compound it is dry
Dry THF sequentially adds the 4.12g (20.0 mmol) of 2.71g (20.0mmol) HOBt and dry THF dissolution under ice bath stirring
DCC stirs 0.5h, by 11.796g (16.68mmol) HClArg (NO2)-Gly-Asp (OBzl)-Val-OBzl aminoterminal
Compound is dissolved in dry THF, is added in above-mentioned reaction solution, and NMM is adjusted to pH9, and 6 h, TLC (CH are stirred at room temperature2Cl2∶CH3OH, 20/
1) display c-terminus raw material completely disappears, and reaction terminates.It is filtered to remove DCU, is dissolved, is obtained with ethyl acetate after filtrate decompression concentration
The solution arrived is successively with saturation NaHCO3Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4Aqueous solution is washed 3 times,
Saturation NaCl aqueous solution washes 3 times, 5%NaHCO3Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Combined ethyl acetate
Layer uses anhydrous Na2SO4It dries, filters, filtrate decompression is concentrated to dryness, column layer (CHCl3/CH3OH, 15/1) analysis after purification 12.7g
(68%) title compound is colorless solid.ESI-MS (m/e): 1121 [M+H]+。
Embodiment 17 prepares Fmoc-Lys-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl
N- tertbutyloxycarbonyl protecting group, which is removed, according to embodiment 2 leads to method for 1g (0.89mmol) Fmoc-Lys (Boc)-Arg
(NO2) a small amount of dry ethyl acetate dissolution of-Gly-Asp- (OBzl)-Val-OBzl, 10mL 4N chlorine is added under ice bath stirring
Change hydrogen/ethyl acetate solution, ice bath stirring 1-2h, TLC (CHCl3/CH3OH, 10/1) show that raw material completely disappears, reaction terminates.
Reaction solution is concentrated under reduced pressure.Residue adds 5ml anhydrous ethyl acetate, and solution is concentrated to dryness.The operation is repeated 3 times.Residue
Add 5ml anhydrous ether, solution is concentrated to dryness.The operation repeats 3 times.It is anti-that obtained target compound is directly used in lower step
It answers.
Embodiment 18 prepares Fmoc-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp (OBzl)-Val-
OBzl
It is molten by 2.45g (4.46mmol) Boc-Pro-Ala-Lys (Z) c-terminus compound that the logical method of peptide is connect according to embodiment 1
The 1.10g (5.35 of 0.72g (5.35mmol) HOBt and dry THF dissolution are sequentially added under dry THF, ice bath stirring
Mmol) DCC stirs 0.5h, by 4.7g (4.46mmol) Fmoc-Lys (HCl)-Arg (NO2)-Gly-Asp(OBzl) -Val-
OBzl aminoterminal compound is dissolved in dry THF, is added in above-mentioned reaction solution, and NMM is adjusted to pH9, and 6h, TLC (CHCl is stirred at room temperature3/
CH3OH, 10/1) show that c-terminus raw material completely disappears, reaction terminates.It is filtered to remove DCU, uses acetic acid second after filtrate decompression concentration
Ester dissolution, obtained solution is successively with saturation NaHCO3Aqueous solution is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%KHSO4It is water-soluble
Liquid is washed 3 times, and saturation NaCl aqueous solution washes 3 times, 5%NaHCO3Aqueous solution is washed 3 times and saturation NaCl aqueous solution is washed 3 times.Merge
Ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate decompression is concentrated to dryness, and column chromatographs (CHCl3/CH3OH, 10/1) purifying
3.5g (50.9%) title compound is obtained afterwards, is colorless solid.ESI-MS (m/e): 1552 [M+H]+。
Embodiment 19 prepares Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl
By 0.5g Fmoc-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl use
20% piperidines of 1mL/DMF dissolution, reacts 30 minutes, TLC (CHCl3/CH3OH, 5: 1).Ether is added to be precipitated, centrifugation obtains title
Compound is colorless solid, is directly used in and reacts in next step.
Embodiment 20 prepares five methoxytryptamine base carbonyl propionyl-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-
Asp(OBzl)-Val-OBzl
It is molten by five methoxytryptamine base carbonyl propionic acid c-terminus compound of 0.418g (1.44mmol) that the logical method of peptide is connect according to embodiment 1
0.36 g of 0.23g (1.73mmol) HOBt and dry THF dissolution are sequentially added under dry THF, ice bath stirring
(1.73mmol) DCC stirs 0.5h, by 2.11g (1.59mmol) Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2) -
Gly-Asp (OBzl)-Val-OBzl aminoterminal compound is dissolved in dry THF, is added in above-mentioned reaction solution, NMM is adjusted to pH9, room
Temperature stirring 6h, TLC (CHCl3∶CH3OH, 8/1) show that c-terminus raw material completely disappears, reaction terminates.It is filtered to remove DCU, filtrate
It is dissolved after reduced pressure with ethyl acetate, obtained solution is successively with saturation NaHCO3Aqueous solution is washed 3 times, and NaCl aqueous solution is saturated
3 times are washed, 5%KHSO4Aqueous solution is washed 3 times, and saturation NaCl aqueous solution is washed 3 times, 5% NaHCO3Aqueous solution is washed 3 times and saturation NaCl
Aqueous solution is washed 3 times.Combined ethyl acetate layer anhydrous Na2SO4It dries, filters, filtrate decompression is concentrated to dryness, column layer (CHCl3/
CH3OH, 8/1) analysis obtains 1.34g (50.18%) title compound after purification, and it is colorless solid.ESI-MS (m/e): 1602 [M+H]+。
Embodiment 21 prepares five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val (1)
Under ice bath, by five methoxytryptamine base carbonyl propionyl acyl-Lys (Boc-Pro-Ala-Lys of 100mg (0.062mmol)
(Z))-Arg(NO2)-Gly-Asp (OBzl)-Val-OBzl mixes with 1mL trifluoroacetic acid and 0.33 mL trifluoromethanesulfonic acid, it stirs
40min pours into 50mL anhydrous ether, and Precipitation is toppled over ether and washed repeatedly, is concentrated under reduced pressure to give faint yellow solid powder.
It is dissolved with water, ammonium hydroxide tune pH=8, through Sephadex G10 desalination, is lyophilized with the fraction of C18 column purification, collection.After freeze-drying
42mg (61.3%) title compound is colorless solid.
Mp:172.5-174.1 DEG C；(c=0.11, H2O)；ESI-MS (m/e): 1143 [M+H]+；1H-
NMR (300MHz, MeOD): δ/ppm=7.242 (d, J=8.7Hz, 1H), 7.060 (d, J=2.1Hz, 2H), 6.776 (dd,
J1=2.4Hz, J2=6.6Hz 1H), 4.651 (m, 2H), 4.500-4.000 (m, 8H), 3.836 (s, 3H), 3.500-3.000
(m, 17H), 3.000-2.800 (m, 4H), 2.733 (d, J=5.7Hz, 2H), 2.600-2.300 (m, 5 H), 2.300-1.900
(m, 6H), 1.900-1.600 (m, 10H), 1.600-1.300 (m, 9H), 0.940 (m, 6H)；
Test example 1 evaluates the anti-thrombus activity test of compound 1
It is random to be grouped by male SD rat (200 ± 20g), it every group 10, raises 1 day, stops feeding and stay overnight.Stomach-filling is given
Give compound 1 normal saline solution (dosage 100nmol/kg) or aspirin normal saline solution (dosage be 167 μ
Mol/kg) or after physiological saline (dosage 10ml/kg) 30min, the normal saline solution of 20% Ethylurethanm of rat is anaesthetized,
It performs the operation later.The silk thread of correct amount is placed in bypass intubation by the right carotid and left neck vein for separating rat, and one end of pipe is inserted
Enter left vein, another end pipe is inserted into right artrial and to inject 0.2mL heparin sodium anticoagulant.So that blood flow flows through bypass from right artrial
Intubation enters left side vein, and the silk thread with thrombus is taken out after 15min and is weighed, the weight of silk thread before and after blood circulation is calculated,
Obtained thrombus weight indicates and represents antithrombotic acitivity with mean value ± SD mg, makees t inspection.Data are included in table 1.The result shows that mouth
Thrombosis can be effectively inhibited by taking 100nmol/kg compound 1.After illustrating that structure simplifies, technical effect is obvious.
The anti-thrombus activity of 1 compound 1 of table
N=10；And physiological saline ratio p < 0.01. a)
The thrombus dissolving activity of the evaluation compound 1 of experimental example 2
SD rat (male, 200 ± 20g) presses 1200mg/kg-1Dosage intraperitoneal injection urethane normal saline solution carry out
Anesthesia.Its dorsal position is fixed after anesthetized rat, its right common carotid artery is separated, clamps artery clamp at proximal part, by proximal part and
Distal end respectively penetrates surgical thread, the surgical thread ligation of distal end, and artery clamp is unclamped, takes out about 1mL artery by distal end intubation
Blood is placed in 1mL centrifuge tube.Toward vertically fixed rubber tube (long 15mm, internal diameter 2. 5mm, outer diameter 5.0mm, tube bottom rubber plug
Sealing, para film is tamping) in inject 0.1ml rat artery blood, the thrombus of a stainless steel material is then rapidly inserted into pipe
Fixing bolt (the fixed spiral of thrombus is coiled into the stainless steel wire that diameter is 0.2 mm, and the long 10mm of spiral part includes 15 spiral shells
Circle, the diameter of bung flange are 1.0mm, and support handle is connected with spiral, are about 7.0mm, are in question mark type).After blood clotting 45min, from glass
The fixed spiral of the thrombus wrapped up by thrombus is carefully taken out in glass pipe, accurately claims its weight.
Bypass intubation is made of three parts, and interlude is long 60.0mm, the polyethylene rubber tube of internal diameter 3.5mm；Both ends are
The identical polyethylene pipe of long 100.0mm, internal diameter 1.0mm, outer diameter 2.0mm, the pipe one end pull into spike tube, are about 10.0mm and (use
In insertion rat carotid artery and vein), outer diameter 1.0mm, the outer cover one Duan Changwei 7.0mm, outer diameter 3.5mm of the other end
Polyethylene pipe (for being inserted into the polyethylene rubber tube in middle section), the inner wall of 3 sections of pipes is required to silanization (1% silicone oil ether
Solution).The fixed spiral of the thrombus of thrombus package is placed in the polyethylene rubber tube of middle section, the other both ends of sebific duct are poly- with two respectively
The overstriking end of ethylene is nested, and guarantees that blood will not be leaked during circulation.With syringe heparin will be filled by spike tube end in pipe
Normal saline solution (50IU/kg) excludes bubble, spare.
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 prepared is inserted into left vena jugularis externa by osculum and is open
Place, while far from shunt valve middle section (the fixed spiral of the thrombus containing accurate weighing) the interior fixed spiral of thrombus.Passed through with syringe another
The normal saline solution (50IU/kg) of the heparin sodium of the spike tube injection correct amount of one end, syringe not withdraw polyethylene at this time
Pipe, the hose between syringe and polyethylene pipe is clamped with artery clamp.Stop blooding in the proximal part artery clamp of right common carotid artery, ties
Distal end is pricked, right common carotid artery is nearby being cut into an osculum from artery clamp, syringe is extracted from the tip of polyethylene pipe, will gather
The proximal part of the tip insertion artery angle of ethylene tube.Arteriovenous is fixed with No. 4 sutures in the both ends of bypass duct.
With scalp acupuncture by the normal saline solution (dosage 20000IU/kg) of physiological saline (3ml/kg) or urokinase or
The normal saline solution (dosage 100nmol/kg) of compound 1 by the middle section of shunt valve, (fix by the thrombus containing accurate weighing
Spiral), the nearly vein end far from the fixed spiral of thrombus is penetrated, artery clamp is unclamped, flows to blood flow from artery by bypass duct
Vein.Solution in syringe is slowly injected into blood, by blood circulation, by vein-heart-artery sequential action in spiral shell
On the thrombus of rotation.After blood circulation 1h, the spiral of fixed thrombus, accurate weighing are taken out from bypass duct.It calculates every big
The weight difference that the spiral blood circulation front and back thrombus of thrombus is fixed in mouse bypass duct, is indicated and is represented molten with mean value ± SD mg
Thrombus activity, makees t inspection.Data are included in table 3.The result shows that 100nmol/kg compound 1 can effectively lysigenous blood
Bolt.After illustrating that structure simplifies, technical effect is obvious.
The thrombolysis activity of 2 compound 1 of table
N=10；And physiological saline ratio p < 0.01. a)
Experimental example 3 evaluates therapeutic effect of the compound 1 to ishemic stroke rat
About 2cm long notch is opened vertically at the positive middle part of the neck of male SD rat (300 ± 20g of weight), along nutator
Inside fate separates out right common carotid artery, external carotid artery and internal carotid.It is pressed from both sides respectively with noninvasive artery clamp and closes internal carotid opening
With arteria carotis communis proximal part, the distal end of external carotid artery is ligatured, an osculum is cut in external carotid artery, unclamps arteria carotis communis proximal part
Artery clamp takes 10 μ l blood, closes the proximal part of arteria carotis communis with noninvasive artery clamp folder again later.10 μ l blood of acquirement are placed on
Make blood clotting within room temperature 30 minutes in 1ml EP pipe, is then transferred in -20 DEG C of refrigerators and places 1 hour, make blood clotting
It is solid.10% chloraldurate intraperitoneal injection of anesthesia of rat, dosage are 400 mg/kg.Blood clotting is taken out, 1ml physiology is added
Blood clotting is pounded uniform tiny thrombi with steel shovel by salt water, is prepared the suspension of tiny thrombus and is transferred to 1ml note
In emitter.The artery clamp for unclamping arteria carotis communis proximal part slowly passes through 1ml thrombus suspension from rat external carotid artery to proximal part
The brain of internal carotid injection rat is crossed, external carotid artery proximal part is then ligatured, opening must move at internal carotid and arteria carotis communis
Arteries and veins folder, restores blood flow.Wait revival.Rat presses Zealonga method after reviving 24 hours and evaluates neurological functional deficit.0 point
Indicate without any neurological deficit sign, 1 point indicate do not damage side forelimb not tensible, 2 points indicate to do not damage skidding walk,
3 points indicate to turn-take into shape walking of knocking into the back, 4 points of expressions disturbances of consciousness without autonomous, 5 points of expressions death to not damaging side.According to
Score average packet.Each group rat injects 1 compound 1, dosage 100nmol/kg through tail vein daily.Continuous injection 6
It, scores daily.As a result it is included in table 3.Statistics indicate that continuously treatment can make 11 cerebral ischemias, 24 hours rats in 6 days to compound 1
It is 0 point that Neurobiology, which scores 6, and 3 are 1 point, and 2 are 1 point.Because unlike the compound initial dose needs having disclosed
5 μm of ol/kg, rear 5 maintenance doses need 2 μm of ol/kg, and 6 dosage of compound 1 are 100nmol/kg.So, first
Secondary dosage and maintenance dose reduce 50 times and 20 times respectively.In addition the benefit that structure simplifies, present invention obtains unexpected
Technical effect.
The continuously influence to the scoring of 24 hours rat nerve biology of cerebral ischemia in treatment 6 days of 3 compound 1 of table
N=11.
Claims (5)
1. five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of following formula
2. the preparation side of five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of claim 1
Method, method includes the following steps:
1) five methoxytryptamine base carbonyl propionic acid are prepared；
2) Boc-Arg (NO is prepared2)-Gly-OBzl；
3) Boc-Arg (NO is prepared2)-Gly；
4) Boc-Asp (OBzl)-Val-OBzl is prepared；
5) HClAsp (OBzl)-Val-OBzl is prepared；
6) Boc-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
7) HClArg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
8) Fmoc-Lys (Boc)-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
9) Fmoc-Lys-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
10) Boc-Pro-Ala-OBzl is prepared；
11) Boc-Pro-Ala is prepared；
12) Boc-Pro-Ala-Lys (Z)-OBzl is prepared；
13) Boc-Pro-Ala-Lys (Z) is prepared；
14) Fmoc-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
15) Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO is prepared2)-Gly-Asp(OBzl)-Val-OBzl；
16) by Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl and five methoxytryptamine bases
Carbonyl propionic acid reacts to obtain five methoxytryptamine base carbonyl propionyl-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp
(OBzl)-Val-OBzl；
17) by five methoxytryptamine base carbonyl propionyl-Lys (Boc-Pro-Ala-Lys (Z))-Arg (NO2)-Gly-Asp(OBzl)-
Val-OBzl is deprotected to obtain five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val.
3. five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of claim 1 are anti-in preparation
Application in thrombus drug.
4. five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of claim 1 prepare it is molten
Application in thrombus drug.
5. five methoxytryptamine base carbonyl propionyl-Lys (Pro-Ala-Lys)-Arg-Gly-Asp-Val of claim 1 are controlled in preparation
Treat the application in ishemic stroke drug.
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