CN110092902A - A kind of tanshinone IIA high-molecular compound and its preparation and application - Google Patents
A kind of tanshinone IIA high-molecular compound and its preparation and application Download PDFInfo
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Abstract
Present invention relates particularly to a kind of Tanshinone I I A high-molecular compound and its applications in pharmacy, belong to pharmaceutical technology field;A kind of tanshinone IIA high-molecular compound and intermediate, it is characterized in that shown in the structure such as formula (II) of the tanshinone IIA high-molecular compound and intermediate: tanshinone IIA high-molecular compound of the invention has good water-soluble, significant pharmacological activity, can be used for preparing prevention or the therapeutic agent of following disease: the cardiovascular and cerebrovascular diseases such as atherosclerosis, hyperlipidemia, cerebral ischemia, apoplexy, myocardial infarction, arrhythmia cordis, angina pectoris, cardiomyopathy, myocardial hypertrophy;The nervous system diseases such as Alzheimer's disease, early senile dementia;The liver diseases such as virus hepatitis, cirrhosis;The cancers such as breast cancer, leukaemia, liver cancer, colon cancer, melanoma;
Description
The present invention is 201610479054.X, the divisional application of a kind of tanshinone IIA high-molecular compound and its preparation and application
Technical field
Present invention relates particularly to a kind of tanshinone IIA high-molecular compound and its applications in pharmacy, belong to medical skill
Art field.
Background technique
Salviamiltiorrhizabung is clinically widely used in the treatment of coronary heart diseases and angina pectoris.As Radix Salviae Miltiorrhizae it is most be extracted into point it
One, tanshinone IIA has anti-inflammatory, anti-oxidant and cytotoxic activity and neuroprotective.However, the cause of tanshinone IIA
Ordering defect is that oral administration biaavailability is low, to find out its cause, first is that this is close with its design feature since poorly water-soluble leads to absorption difference
It is inseparable.Tanshinone IIA is the very strong planar molecule of hydrophobicity, polarity very little, in water as a diterpene-kind compound
In it is almost insoluble, solubility is also little in methanol, ethyl alcohol, only in some weakly polar organic solvents such as chloroform, ethyl acetate, second
Ether is medium preferable solubility, this feature significantly limits its clinical application.The second is by oral administration due to tanshinone IIA
There are serious first pass effect after administration, cause extremely low into haemoconcentration.
The most drugs clinically used are small-molecule drugs, this makes it quickly be distributed to the tissue of health, finally
It is distributed to whole body.As a result relatively small number of drug reaches target spot, and over the course for the treatment of along with serious secondary anti-
It answers.These side reactions, which are often dose dependent, cannot reach effective treatment.Polymer drug have it is long-acting, efficient, less toxic,
The advantages that sustained release, selectivity good, Small side effects.In general high-molecular compound is synthesized by covalent bond for parent drug
Molecule is connected on suitable macromolecule.This high-molecular compound in human body can be by hydrolyzing or digesting as parent medicine
Object molecule and macromolecule.On the one hand high-molecular compound can efficiently reduce side effects of pharmaceutical drugs, on the other hand can extend drug
Release time, increase dissolubility.
Polyethylene glycol (PEG) is linear structure, has good water-soluble and biocompatibility, nontoxic, disimmune, nothing
Teratogenesis and no antigen are one of the medicinal synthetic polymers for obtaining FDA approval.The present invention is carrier with polyethylene glycol, is led to
It crosses different spacer group and tanshinone IIA and carries out covalent bond, obtain covalent conjunct agent and increase the water-soluble of tanshinone IIA
Property, improve its bioavilability.
Summary of the invention
The purpose of the present invention is to provide a kind of tanshinone IIA high-molecular compound and its intermediate that medical value is high,
The high-molecular compound and intermediate structure such as formula (I), (II), shown in (III):
X is various amino acid (glycine, alanine, lysine, threonine, proline, cysteine, cystine, color ammonia
Acid, phenylalanine, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid, glutamic acid), and
The dipeptides of two kinds of amino acid composition;(C=O)-R1(C=O)-, wherein R1For C1-C4Linear saturation alkyl, C1-C4Straight chain insatiable hunger
With alkyl, C1-C4Branch saturated alkyl, C1-C4Branch unsaturated alkyl.
Y1For-NH2,-OH;Y2For mono methoxy PEG, average molecular weight 550,750,1000,2000,5000,
8000;Y3For PEG, carboxyl PEG, wherein the average molecular weight of PEG be 600,800,1000,1500,2000,4000,6000,
8000,10000,20000;The average molecular weight of carboxyl PEG be 600,800,1000,1500,2000,4000,6000,8000,
10000、20000。
Dipeptides is glycine, alanine, lysine, threonine, proline, cysteine, cystine, tryptophan, phenylpropyl alcohol
Propylhomoserin, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid, any two kinds of ammonia in glutamic acid
The dipeptides of base acid composition.
When X is amino acid, Y1For-NH2;When X is-(C=O)-R1When (C=O)-, Y1For-OH.
When X is amino acid, Y3For carboxyl PEG;When X is-(C=O)-R1When (C=O)-, Y3For PEG.
Another object of the present invention is to provide the preparation methods of tanshinone IIA high-molecular compound and its intermediate, close
It is as follows at route:
Route one: X is-(C=O)-R1(C=O)-
Route two: X is amino acid
Tanshinone IIA high-molecular compound of the invention has good water-soluble, significant pharmacological activity, can be used for making
The prevention of standby following disease or therapeutic agent: atherosclerosis, hyperlipidemia, cerebral ischemia, apoplexy, myocardial infarction, the rhythm of the heart lose
Often, the cardiovascular and cerebrovascular diseases such as angina pectoris, cardiomyopathy, myocardial hypertrophy;The nervous systems diseases such as Alzheimer's disease, early senile dementia
Disease;The liver diseases such as virus hepatitis, cirrhosis;The cancers such as breast cancer, leukaemia, liver cancer, colon cancer, melanoma.
The present invention is further illustrated by following embodiment, but should be noted that the scope of the present invention not by these embodiments
Any restrictions.
Detailed description of the invention
Fig. 1 is the external cerebral ischemia active testing result of tanshinone IIA high-molecular compound
Specific embodiment
The preparation of embodiment 1:4- carboxyl-butyl ester tanshinone IIA (WGZB-24)
Weigh 5g (17mmol) tanshinone IIA, 5.6g (51mmol) SeO2In the mono- neck bottle of 1L, 700~800 ml are added
Acetonitrile as solvents, 5~6h of back flow reaction stop heating and being cooled to room temperature, are evaporated under reduced pressure to solid, methylene chloride is molten by solid
It filters after solution, is washed filtrate 2~3 times with saturated ammonium chloride solution, anhydrous sodium sulfate is dry, and it is red to obtain 1.32g for column chromatographic purifying
Color solid chemical compound 2, yield 25%.
Weigh 620mg (2mmol) compound 2,300mg (3mmol) succinic anhydride in the mono- neck bottle of 100ml, with 30ml without
After the dissolution of water methylene chloride, 0.83ml (6mmol) triethylamine is added, simultaneously nitrogen protection is vacuumized, after reacting at room temperature 30~40min
Stop reaction, with saturated ammonium chloride solution washing reaction liquid 2~3 times, 800mg red is evaporated under reduced pressure to after anhydrous sodium sulfate is dry
Solid chemical compound 4- carboxyl-butyl ester tanshinone IIA, yield 97.56%.
Obtaining spacer group with legal system is C1-C4Straight chain unsaturated alkyl;C1-C4Branch saturated alkyl;C1-C4Branch is unsaturated
The formula (I) of alkyl.
Embodiment 2:4- carboxyl-butyl ester tanshinone IIA-mPEG preparation
100mg (0.24mmol) 4- carboxyl-butyl ester tanshinone IIA is weighed, 220mg (0.29mmol) molecular weight is 750
MPEG, 74mg (0.36mmol) DCC, 44mg (0.36mmol) DMAP are in the mono- neck bottle of 100ml, with 40 ml anhydrous methylene chlorides
After dissolution, simultaneously nitrogen protection is vacuumized, is reacted for 24 hours at 25~45 DEG C, suction filtration removes DCU, washs filter with saturated ammonium chloride solution
Liquid 2~3 times, anhydrous sodium sulfate is dry, and red oil is obtained after vacuum distillation, is dissolved grease with fraction of methylene chloride
Afterwards, a large amount of ether are added under condition of ice bath, generates precipitating, filters and obtain red powder solid chemical compound 4- carboxylic after drying
Base-butyl ester tanshinone IIA-mPEG.
Obtaining spacer group with legal system is C1-C4Straight chain unsaturated alkyl;C1-C4Branch saturated alkyl;C1-C4Branch is unsaturated
Alkyl, 4- carboxyl-butyl ester tanshinone IIA-mPEG that mPEG average molecular weight is 550,1000,2000,5000,8000.
Embodiment 3:4- carboxyl-butyl ester tanshinone IIA-PEG preparation
100mg (0.24mmol) 4- carboxyl-butyl ester tanshinone IIA is weighed, 720mg (0.36mmol) molecular weight is 2000
PEG, 74mg (0.36mmol) DCC, 44mg (0.36mmol) DMAP are in the mono- neck bottle of 100ml, with 45ml anhydrous methylene chloride
After dissolution, simultaneously nitrogen protection is vacuumized, is reacted for 24 hours at 25~45 DEG C, suction filtration removes DCU, washs filter with saturated ammonium chloride solution
Liquid 2~3 times, anhydrous sodium sulfate is dry, and red oil is obtained after vacuum distillation, is dissolved grease with fraction of methylene chloride
Afterwards, a large amount of ether are added under condition of ice bath, generates precipitating, filters and obtain red powder solid chemical compound 4- carboxylic after drying
Base-butyl ester tanshinone IIA-PEG.
Obtaining spacer group with legal system is C1-C4Straight chain unsaturated alkyl;C1-C4Branch saturated alkyl;C1-C4Branch is unsaturated
Alkyl, PEG average molecular weight are 600,800,1000,1500,4000,6000,8000 (WGZB-01), 10000,20000
4- carboxyl-butyl ester tanshinone IIA-PEG.
Embodiment 4: the preparation of glycine-tanshinone IIA (WGZB-02-1)
Weigh 310mg (1mmol) compound 2,210mg (1.2mmol) Boc- glycine, 248mg (1.2mmol) DCC,
122mg (1mmol) DMAP after the dissolution of 45ml anhydrous methylene chloride, is vacuumized and nitrogen protection, 25 in the mono- neck bottle of 100ml
Stop reaction after reacting 30~40min at~45 DEG C, suction filtration removes DCU, washs filtrate 2~3 times with saturated ammonium chloride solution, nothing
Aqueous sodium persulfate is dry, and column chromatographic purifying obtains 305mg red solid compound Boc- glycine-tanshinone IIA, yield
65.3%.
1H NMR (300MHz, CDCl3): δ 1.25 (9H, s ,-CH3× 3), 1.38 (6H, s ,-CH of δ3× 2), δ 1.74 (2H,
M, CH2), δ 1.83 (2H, m, CH2), δ 3.19 (2H, t, J=6.45Hz, CH2), δ 3.90 (2H, d, J=5.73Hz, CH2), δ
5.24 (2H, s, CH2), δ 7.44 (1H, s, Ar), δ 7.52 (1H, d, J=8.16Hz, Ar), δ 7.60 (1H, d, J=8.16Hz,
Ar);ESI-MS (m/z): 490 [M+Na]+.
292mg (0.62mmol) compound 9 is weighed in the mono- neck bottle of 50ml, with 8ml methylene chloride by Boc- glycine-pellet
Join ketone IIA dissolution, 4ml trifluoroacetic acid (V is addedMethylene chloride∶VTrifluoroacetic acid=2: 1), stopping reaction after reacting at room temperature 30min, decompression is steamed
Methylene chloride and trifluoroacetic acid are removed in distillation, obtain red oil, and chloroform is added and makes it dissolve, is washed with saturated sodium bicarbonate solution
Organic phase 2 times, the dry organic phase of anhydrous sodium sulfate, column chromatographic purifying obtains 140mg red solid compound glycine-tanshinone
IIA, yield 61.1%.
Obtaining spacer group with legal system is alanine (WGZB-06-1), lysine, threonine, proline, cysteine, Guang
Propylhomoserin, tryptophan, phenylalanine (WGZB-10-1), leucine, isoleucine, arginine, histidine, serine, tyrosine,
The formula (I) of aspartic acid, glutamic acid.
1H NMR (300MHz, CDCl3): δ 1.37 (6H, s ,-CH3× 2), 1.63 (2H, m, CH of δ2), δ 1.75 (2H, m,
CH2), δ 3.10 (2H, t, J=6.45Hz, CH2), δ 3.57 (2H, s, CH2), δ 5.24 (2H, s, CH2), δ 7.44 (1H, s, Ar),
δ 7.52 (1H, d, J=8.16Hz, Ar), δ 7.60 (1H, d, J=8.16Hz, Ar);ESI-MS (m/z): 368 [M+H]+.
Embodiment 5: glycine-tanshinone IIA-carboxyl PEG preparation
Weigh 50mg (0.14mmol) glycine-tanshinone IIA, the carboxyl that 340mg (0.17mmol) molecular weight is 2000
PEG, 35mg (0.17mmol) DCC, 20mg (0.14mmol) DMAP are molten with 40ml anhydrous methylene chloride in the mono- neck bottle of 100ml
Xie Hou vacuumizes simultaneously nitrogen protection, reacts for 24 hours at 25~45 DEG C, and suction filtration removes DCU, washs filtrate 2 with saturated ammonium chloride solution
~3 times, anhydrous sodium sulfate is dry, and red oil, after being dissolved grease with fraction of methylene chloride, ice are obtained after vacuum distillation
A large amount of ether are added under the conditions of bath, generates precipitating, filters and obtain powdered red solid compound glycine-Radix Salviae Miltiorrhizae after drying
Ketone IIA- carboxyl PEG (WGZB-02).
Obtaining carboxyl PEG average molecular weight with legal system is 600,800,1000,1500,4000 (WGZB-03), 6000,8000
(WGZB-04), glycine-tanshinone IIA-carboxyl PEG of 10000,20000 (WGZB-05).
With legal system obtain spacer group be alanine, lysine, threonine, proline, cysteine, cystine, tryptophan,
Phenylalanine, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid, glutamic acid, carboxyl PEG
Tanshinone IIA-carboxylic that average molecular weight is 600,800,1000,1500,2000,4000,6000,8000,10000,20000
Base PEG.Wherein alanine-tanshinone IIA-carboxyl PEG product is WGZB-06, WGZB-07, WGZB-08, WGZB-09;Phenylpropyl alcohol
Propylhomoserin-tanshinone IIA-carboxyl PEG product is WGZB-10, WGZB-11, WGZB-12, WGZB-13;Glutamic acid-tanshinone
IIA- carboxyl PEG product is WGZB-14, WGZB-15, WGZB-16, WGZB-17;Aspartic acid-tanshinone IIA-carboxyl PEG
Product is WGZB-18, WGZB-19, WGZB-20, WGZB-21;
Embodiment 6: tanshinone IIA high-molecular compound plasma stability experiment
Chromatographic condition: C18Chromatographic column: 150L × 4.6 Shimadzu VP-ODS;Mobile phase: A:0.03% phosphate aqueous solution
B: acetonitrile;Flow velocity: 1mL/min;Detection wavelength: 270nm;Column temperature: 25 DEG C;Sample introduction: 20 μ L.
The preparation of solution: weighing 25mg sample in 10mL volumetric flask respectively, is made into the molten of 2.5mg/mL with ethyl alcohol dissolution
Liquid (needs ultrasonic dissolution assisting).The preparation of contrast solution: precision weighs tanshinone IIA 10mg, is dissolved with ethyl alcohol, is made into 40 μ g/mL
Contrast solution.
The processing of sample solution: taking above-mentioned each solution 1mL in the EP pipe of 2mL respectively, after volatilizing solvent, respectively plus 1.5ml
Blank plasma, be vortexed mix, be placed under 37 DEG C of water-baths and cultivate 0,0.5,2,4,6,8,12h, take respectively at every point of time
Acetonitrile-methanol (1: 1) protein precipitation of 2 times of volumes (400 μ l), vortex mixed 2min, 12000rpm is added in the blood plasma of 200 μ L
It is centrifuged 5min, takes 100 μ L of supernatant, taking 20 μ L, sample introduction is analyzed.The contrast solution 0.5mL for taking TS after volatilizing solvent, is added
The blank plasma of 0.5mL is vortexed and mixes, and acetonitrile-methanol (1: 1) protein precipitation of 2 times of volumes (400 μ l) is added, and is vortexed and mixes
2min, 12000rpm are centrifuged 5min, take 100 μ L of supernatant, taking 20 μ L, sample introduction is analyzed.
Blank plasma: taking 200 μ L blank plasmas, and after ibid handling protein precipitation, 12000rpm is centrifuged 5min, takes supernatant
100 μ L, taking 20 μ L, sample introduction is analyzed.
Experimental result: under the same conditions, PEG molecular weight releases more greatly the amount of parent drug molecule more to spacer group
It is few, extend the half-life period of drug.
The tanshinone IIA high-molecular compound of 1 different molecular weight different interval group of table releases parent medicine in blood plasma
Object molecular percentage ratio
Embodiment 7: tanshinone IIA high-molecular compound anti tumor activity in vitro experiment
Material: human breast cancer cell line Bcap-37
Test method: the tumour cell to test in cell log growth period is inoculated with by certain cell concentration
In in 96 well culture plates, sieved sample (can directly add after suspension cell fishplate bar) is added in culture afterwards for 24 hours, and cell is at 37 DEG C 5%
CO2Under the conditions of continue cultivate 48h after, be added MTT continue culture 4h hours, be dissolved under microplate reader and detected with DMSO.
Experimental result: under the same conditions, molecular weight is bigger, and anti-tumor activity is stronger for spacer group, wherein WGZB-01,
The activity of WGZB-04, WGZB-05, WGZB-07, WGZB-09, WGZB-15 are better than tanshinone IIA, and tanshinone IIA system
It is standby at still retaining anti-tumor activity after Macromolecule Prodrug
2 tanshinone IIA high-molecular compound extracorporeal anti-tumor the selection result of table
MCF-7 | IC50(μM) |
WGZB-01 | 0.2198 |
WGZB-02 | 45.62 |
WGZB-03 | 42.21 |
WGZB-04 | 12.41 |
WGZB-05 | 6.706 |
WGZB-06 | 48.53 |
WGZB-07 | 19.41 |
WGZB-08 | 92.37 |
WGZB-09 | 6.887 |
WGZB-11 | 932.8 |
WGZB-13 | 329 |
WGZB-15 | 10.98 |
WGZB-17 | 121.9 |
WGZB-19 | 486.7 |
WGZB-21 | 280.5 |
WGZB-24 | 28.46 |
WGZB-02-1 | 29.86 |
WGZB-06-1 | 8.69 |
WGZB-10-1 | 13.43 |
Tanshinone IIA | 41.79 |
Embodiment 8: the external cerebral ischemia activity experiment of tanshinone IIA high-molecular compound
Experimental method: the sodium dithionite (Na being added in low sugar DMEM culture medium2S2O4) dry powder sufficiently dissolves, make
Final concentration 20mM, uses NaHCO3Adjusting pH is 7.2, as anoxic liquid.Primary cortical neurons cell is in 24 orifice plate tissue culture plates
Middle culture 7-10 days is chosen the good cell of growth conditions and is tested.The culture medium in 24 orifice plates is gently sucked before administration, is used
After PBS buffer solution is washed 2 times, continue to cultivate with pastille culture medium.Experiment includes blank control group, model control group, WGZB- altogether
02、WGZB-03、WGZB-04、WGZB-05、WGZB-06、WGZB-07、WGZB-08、 WGZB-09、WGZB-02-1、WGZB-
06-1, Lead compound sample sets.After for 24 hours.The culture medium for removing drug containing, is replaced as anoxic liquid, is added in blank control group
Isometric maintenance culture medium (Neurobasal Media49 ml+B27-Supplement 1ml).By culture medium in incubator
Supernatant is completely removed after middle incubation 2h, is added after being washed twice with PBS buffer solution and maintains culture medium.It is placed again into 37 DEG C, 5%
CO2Continue after cultivating 2h in incubator, modeling is completed, and neuronal cell can be used for testing.Tissue culture plate is placed in down after modeling
Set the growth and cellular damage situation of microscopically observation cortical neuronal cells.The culture medium in 24 orifice plates is removed, dimension is added
Every hole adds 50 μ L of MTT solution (5 mg/ml) after holding 450 μ L of culture medium, is put into 37 DEG C of incubation 4h.Abandon the culture medium containing MTT
Later, 200 μ L of DMSO liquid is added in every hole, is placed on shaking table and shakes 10min.It is moved in 96 orifice plates from 150 μ L are taken out in every hole,
The OD value in each hole is measured at microplate reader 490nm, with the survival condition of OD value reflection cell.Experiment is repeated 3 times.
Experimental result: as shown in Figure 1, after neuronal cell anoxia/reoxygenation injury, model group neuronal cell survival rate and
Blank group reduces (P < 0.01) compared to extremely significant property.Compared with model group, compound WGZB-02, WGZB-03, WGZB-04,
WGZB-05, WGZB-06, WGZB-07, WGZB-08, WGZB-09, WGZB-02-1 and Lead compound can extremely significant property liters
The survival rate of neuronal cell after high modeling and WGZB-06-1 grams be significant to increase the survival rate of neuronal cell after modeling.
The above is only optimization experiment mode of the invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.
Claims (4)
1. a kind of tanshinone IIA high-molecular compound and intermediate, it is characterised in that the tanshinone IIA high-molecular compound and in
Shown in the structure of mesosome such as formula (II):
Wherein X be following amino acid any one: glycine, alanine, lysine, threonine, proline, cysteine, Guang
Propylhomoserin, tryptophan, phenylalanine, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid and paddy
Propylhomoserin;X is dipeptides, the dipeptides be glycine, alanine, lysine, threonine, proline, cysteine, cystine,
Tryptophan, phenylalanine, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid, in glutamic acid
The dipeptides of any two kinds of amino acid composition;
Y2 is mono methoxy PEG, average molecular weight 550,750,1000,2000,5000,8000;Y3 is PEG, carboxyl
PEG, wherein the average molecular weight of PEG is 600,800,1000,1500,2000,4000,6000,8000,10000,20000;Carboxylic
The average molecular weight of base PEG is 600,800,1000,1500,2000,4000,6000,8000,10000,20000.
2. tanshinone IIA high-molecular compound according to claim 1 and intermediate, synthetic route are as follows:
(1) route one: X is-(C=O)-R1- (C=O)-
Specific step is as follows:
I. compound 1 is aoxidized through oxidant SeO2, back flow reaction 5~6 hours, obtains compound 2, solvent for use is acetonitrile, two
Six ring of oxygen, acetic acid, DMF or DMSO, compound 1 therein and molar ratio=1 SeO2: 3~5;
Ii. compound 2 is alkali in Et3N, and anhydrous methylene chloride, anhydrous chloroform make solvent, is reacted under room temperature with compound 3
Compound I is obtained, wherein molar ratio=1 of compound 2 and Et3N: 3~5, molar ratio=1 of compound 2 and compound 3: 1.5
~3;
Iii. under the action of catalyst and condensing agent, compound I and PEG or mPEG react at 25~45 DEG C and obtain chemical combination
Object II, compound III;Wherein molar ratio=1 of compound I and PEG: 1.5~2, molar ratio=1 of compound I and mPEG:
1.2~2;Solvent is anhydrous methylene chloride, anhydrous chloroform and anhydrous DMF;Used catalyst and condensing agent: 2- (7- azo benzo
Triazole)-N, N, N ' N '-tetramethylurea hexafluorophosphoric acid ester, O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, O- benzo three
Nitrogen azoles-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, n,N-diisopropylethylamine, N, N '-dicyclohexylcarbodiimide, 4- diformazan
Aminopyridine, N- dimethylamino-propyl-N- ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazole, N- hydroxysuccinimidyl acyl are sub-
Amine;Its R1 be C1-C4 linear saturation alkyl, C1-C4 straight chain unsaturated alkyl, C1-C4 branch saturated alkyl, C1-C4 branch not
Saturated alkyl;
(2) route two: X is amino acid
Specific step is as follows:
I. the method prepare compound 2 according to route one;
Under the conditions of ii.25~45 DEG C, under the action of catalyst and condensing agent compound 2 and compound 4 in anhydrous methylene chloride,
Compound 5 is obtained in anhydrous chloroform;Used catalyst and condensing agent: 2- (7- azo benzotriazole)-N, N, N ' N '-tetramethyl
Urea hexafluorophosphoric acid ester, O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester, O- benzotriazole-N, N, N ', N '-tetramethylurea
Tetrafluoro boric acid, n,N-diisopropylethylamine, N, N '-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, N- dimethylamino third
Base-N- ethyl-carbodiimide hydrochloride, 1- hydroxy benzo triazole, n-hydroxysuccinimide;Compound 2 and compound 4
Molar ratio=1: 1.2~2;The compound 4 be glycine, alanine, lysine, threonine, proline, cysteine,
Cystine, tryptophan, phenylalanine, leucine, isoleucine, arginine, histidine, serine, tyrosine, aspartic acid or
Glutamic acid, R2 are the substituent group on above-mentioned amino acid α carbon, and R3 is amino-substituent;
Iii. compound 5 obtains compound I under the conditions of deamination protecting group;Deamination protecting group: tertbutyloxycarbonyl removes item
Part: trifluoroacetic acid, HCl/EA or HCl/CH3OH, benzyloxycarbonyl group remove condition: hydrogen bromide, hydrogen reducing or Na/NH3 liquid, 2- connection
Phenyl -2- propylene carbonyl oxygen removes condition: trifluoroacetic acid or hydrogen bromide, and p-toluenesulfonyl removes condition: sodium or ammonia;
Under the conditions of iv.25~45 DEG C, in the action compound I and carboxyl PEG of catalyst and condensing agent in anhydrous methylene chloride, nothing
Compound III is obtained in water chloroform and anhydrous DMF;Wherein molar ratio=1 of compound I and carboxyl PEG: 1.2~2;It is used to urge
Agent and condensing agent: 2- (7- azo benzotriazole)-N, N, N ' N '-tetramethylurea hexafluorophosphoric acid ester, O- benzotriazole-four
Methylurea hexafluorophosphoric acid ester, O- benzotriazole-N, N, N ', N '-tetramethylurea tetrafluoro boric acid, n,N-diisopropylethylamine, N,
N '-dicyclohexylcarbodiimide, 4-dimethylaminopyridine, N- dimethylamino-propyl-N- ethyl-carbodiimide hydrochloride, 1- hydroxyl
Benzotriazole, n-hydroxysuccinimide.
A kind of exist by the tanshinone IIA high-molecular compound and intermediate of carrier of macromolecule 3. according to claim 1
Preparation protects it to the application in the prevention or treatment in following disease medicament: cardiovascular and cerebrovascular disease, the nervous system disease, liver
Disease and cancer.
4. application according to claim 3, it is characterised in that the cardiovascular and cerebrovascular disease includes atherosclerosis, height
Pionemia, cerebral ischemia, apoplexy, myocardial infarction, arrhythmia cordis, angina pectoris, cardiomyopathy, myocardial hypertrophy;The nervous system disease includes
Alzheimer's disease, early senile dementia;Liver disease includes virus hepatitis, cirrhosis;Cancer include breast cancer, leukaemia,
Liver cancer, colon cancer, melanoma.
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