CN100542613C - It with the poly-aspartate derivant scutellarin prodrug of carrier and preparation method thereof - Google Patents
It with the poly-aspartate derivant scutellarin prodrug of carrier and preparation method thereof Download PDFInfo
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- CN100542613C CN100542613C CNB2007100248878A CN200710024887A CN100542613C CN 100542613 C CN100542613 C CN 100542613C CN B2007100248878 A CNB2007100248878 A CN B2007100248878A CN 200710024887 A CN200710024887 A CN 200710024887A CN 100542613 C CN100542613 C CN 100542613C
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- DJSISFGPUUYILV-ZFORQUDYSA-N scutellarin Chemical compound O1[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1OC(C(=C1O)O)=CC2=C1C(=O)C=C(C=1C=CC(O)=CC=1)O2 DJSISFGPUUYILV-ZFORQUDYSA-N 0.000 title claims abstract description 43
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- 239000002904 solvent Substances 0.000 claims description 5
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- DXRFZHILMCWCNG-UHFFFAOYSA-N N,N-dimethyl-1,8-naphthyridin-2-amine Chemical compound C1=CC=NC2=NC(N(C)C)=CC=C21 DXRFZHILMCWCNG-UHFFFAOYSA-N 0.000 claims description 2
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- CKLJMWTZIZZHCS-UHFFFAOYSA-N Aspartic acid Chemical compound OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 claims 1
- 150000007984 tetrahydrofuranes Chemical group 0.000 claims 1
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003795 chemical substances by application Substances 0.000 abstract description 2
- XOZZVTZRMJPFBR-UHFFFAOYSA-N 2-amino-N-(2,2-dihydroxyethyl)butanediamide Chemical compound OC(CNC(C(N)CC(=O)N)=O)O XOZZVTZRMJPFBR-UHFFFAOYSA-N 0.000 abstract 1
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- Medicinal Preparation (AREA)
Abstract
The invention provides a kind of is the prodrug and the method for making thereof of the scutellarin of carrier with the poly-aspartate derivant, with the poly-(α of poly-aspartate derivant, β-N, N-dihydroxy ethyl-DL-agedoite) [Poly (α, β-N, N-dihydroxyethyl-DL-aspartamide), PDHEA] be carrier, with N, N-dicyclohexylcarbodiimide (DCC) is a condensing agent, by the esterification between poly-aspartate derivant and the scutellarin, obtained novel water solublity scutellarin prodrug.On the scutellarin prodrug main chain of the present invention's preparation more active group-ethoxy is arranged, help improving the water solublity of prodrug, improve the bioavailability of scutellarin.And its preparation method is simple, is easy to realize.
Description
Technical field
The present invention relates to a kind of macromolecule precursor medicament and preparation method thereof, relate in particular to a kind of scutellarin prodrug and preparation method thereof.
Technical background
Scutellarin (scutellarin) claim scutellarin again, is the main component of feverfew Erigeron breviscapus (Vant.) Hand.-Mazz. (Erigeron breviscapus) extract breviscapine, belongs to flavone compound.Verified have blood vessel dilating, increase heart coronary flow, cerebral blood flow increasing amount, reduction cerebral vascular resistance, raising blood-brain barrier permeability and antagonism by the platelet aggregation effect that adenosine diphosphate (ADP) causes, has been used for for many years clinical.Be mainly used in diseases such as paralysis after treatment cerebral thrombosis, cerebral infarction, the apoplexy, coronary heart disease, angina pectoris clinically, determined curative effect.Its existing preparation has conventional tablet, injection and injection powder pin.The conventional tablet oral administration biaavailability is extremely low, has only 0.4 ± 0.19%.
The design of prodrug can solve the water solublity and the stability problem of some drugs effectively, increases the blood retention time of medicine, changes in the medicine body to distribute, and improves bioavailability and reduces toxic and side effects.In recent years, the macromolecule prodrug has caused that researcher pays close attention to greatly, improves drug effect by the prolong drug half-life in vivo; Avoid degraded, increase stability of drug; Improve cell by the picked-up of endocytosis to medicine; Make medicine locus specificity identification be arranged by part to targeted cells.Polyamino acid and derivant thereof are class novel high polymer materials, it has good biocompatibility, can be by complete degraded and absorbed, have no side effect, advantages such as non-immunogenicity for the focus of people's research, are used as slow releasing carrier of medication in the recent period, research focuses mostly in the research of poly-asparagine and derivant thereof, occupies critical role in the synthetic and preparation of prodrug.
The Zhang Can of China Medicine University etc. has synthesized the water solublity that the scutellarin polyethyleneglycol prodrug is used for improving scutellarin, and gained prodrug dissolubility in the water in the time of 25 ℃ is 14.4mgml
-1The Zhou Qingsong of Sichuan University etc. has also synthesized the scutellarin PEG fat of different molecular weight, and has carried out pharmacokinetic, and gained prodrug dissolubility in the water in the time of 25 ℃ is 18.7mgml
1But adopt Polyethylene Glycol significant disadvantages also to be arranged, have certain bio-toxicity exactly as preceding drug carrier.
Crinis Carbonisatus such as Shen Jian, Chen Qiang is understood a kind of polyasparamide derivative (PDHEA) that contains rich activity hydroxy (ZL01134166.1), is easier to and the medicine bonding than Polyethylene Glycol etc.
Summary of the invention
Goal of the invention: the object of the present invention is to provide more hydrophilic active group is arranged on a kind of main chain, good biocompatibility, the scutellarin prodrug that has better water-solubility than scutellarin.
Another object of the present invention provides the preparation method of above-mentioned scutellarin prodrug.
Technical scheme: with the poly-aspartate derivant is the prodrug of the scutellarin of carrier, and its structural formula is:
X=10～1000 wherein, y=10～1000, x+y=10～1010.
Above-mentioned is that the preparation method of the scutellarin prodrug of carrier may further comprise the steps with the poly-aspartate derivant:
1, aspartic acid and strong phosphoric acid are mixed by weight 30:1～10:1,, make butanimide (PSI) in 100～250 ℃ of decompression reactions 10 hours;
2, with the PSI that makes and diethanolamine by weight 1:2～1:5 0～5 ℃ of low temperature ring-opening reaction 2～4 hours in solvent;
3, step 2 gained reactant is added in the precipitant butanols, filters, washing, drying makes white powder poly-aspartate derivant (PDHEA);
4, PDHEA is dissolved in N, dinethylformamide (DMF) by weight 1:20～1:50;
5, scutellarin is dissolved among the DMF by weight 1:20～1:50;
6, step 5 gained drips of solution is added in the step 4 gained solution, stir fully after, add 0.2～2 times of catalyst to scutellarin weight to dimethylamino naphthyridine (DMAP);
7, with 0.35～2 times of condensing agent N to scutellarin weight, N '-dicyclohexylcarbodiimide (DCC) is dissolved among the DMF by weight 1:10～1:50;
8, step 7 gained drips of solution is added in the step 6 gained solution, 20～50 ℃ of following stirring reactions 12～120 hours;
9, after filtration or centrifugal, get clear liquid and partly place bottle, evaporate to dryness after reaction finishes;
10, with the light green solid on the normal propyl alcohol wash bottle wall, filter, colourless with normal propyl alcohol washing solid to filtrate, will be deposited in 40～60 ℃ of following vacuum dryings, get poly-aspartate derivant-scutellarin prodrug (PDHEAS).
Wherein the described solvent of step 2 is oxolane, dioxane or N, dinethylformamide.
Step 3 and 4 described poly-aspartate derivant molecular weight are 2000～20000, preferred molecular weight 5000.
Among the present invention, characterize the synthetic of prodrug with IR and NMR.
Above-mentioned is that the reaction equation of preparation method of scutellarin prodrug of carrier is as follows with the poly-aspartate derivant:
x＝10～500，y＝10～500，x+y＝10～500
Beneficial effect: provided by the present invention is on the scutellarin prodrug main chain of carrier more hydrophilic active group, good biocompatibility, inanimate object toxicity to be arranged with the poly-aspartate derivant, have better water-solubility than scutellarin, scutellarin prodrug dissolubility in the water in the time of 25 ℃ is 63～85mgml
-1, and the dissolubility of scutellarin is less, has only 0.05mgml
-1Therefore can more effectively enter in patient's body, improve bioavailability of medicament, enlarge its application clinically.And its preparation method is simple, is easy to realize.
Description of drawings
Fig. 1 is the infrared absorption spectra of PSI (a), PDHEA (b) and PDHEAS (c).PDHEA is at 3300cm
-1υ is arranged
-OHAbsorb, at 1715cm
-1There is υ at the place
C=OAbsorb, at 1650～1550cm
-1There is υ in the amide groups at the place
C=OAnd υ
C-NStack absorb.Above-mentioned absworption peak all exists in the spectrogram of PDHEAS, at 735～839cm
-1The place two of phenyl ring occurs and replaces absworption peak, and this shows that scutellarin is bonded on the PDHEA.
Fig. 2 is PSI (a), PDHEA (b) and PDHEAS (c)
1HNMR spectrogram (solvent DMSO-d
6).Comparison PSI and PDHEA's
1HNMR finds that obvious difference: PDHEA is group N (CH at δ=3.62ppm place
2CH
2OH)
2In methylene-CH
2-proton peak.Compare with PDHEA, PDHEAS's
1Chemical shift 7.2ppm and 7.6ppm place are the characteristic peak of phenyl ring among the H NMR.
By above IR,
1HNMR has proved conclusively the structure of the prepared product of the present invention, scutellarin by O=C-OH and PDHEA-the OH condensation, be connected on the PDHEA.
The specific embodiment
Below by embodiment the present invention is specifically described, be necessary to be pointed out that at this, following examples only are used for the present invention is further specified, and can not be interpreted as limiting the scope of the invention.
Embodiment 1:
Take by weighing 200 gram aspartic acids, add strong phosphoric acid 10 gram catalyst, carry out polycondensation reaction under 180 ℃, progressively reduce pressure 1 * 10
4Pa reacted 10 hours, can make butanimide PSI, productive rate 95%.
PSI5.0g is dissolved among the 25mlDMF, is cooled to 0 ℃, under this temperature, drip 13.0 gram diethanolamine, room temperature reaction 2h.Be added drop-wise to mixture in the 150ml n-butyl alcohol and constantly stirring, leave standstill the 1h after-filtration and show neutral until the filtrate pH value with a large amount of washing with acetones.Vacuum drying 24h must gather (α, β-N-dihydroxy ethyl-DL-agedoite) PDHEA white powder 8.7g under the room temperature, and productive rate 85%, molecular weight are 2000.
Scutellarin 0.70 gram is dissolved among the 20ml DMF, then drips of solution is added in the 10mlDMF solution of 0.30 gram PDHEA.Above-mentioned mixed liquor is stirred fully, add 0.15 gram DMAP, stirring reaction.0.35 gram DCC is dissolved among the 5ml DMF, forms colourless solution, be added drop-wise in the above-mentioned mixed liquid.30 ℃ of following stirring reactions were used filter paper filtering at a slow speed after 120 hours, or filtrate is centrifugal with centrifuge, got clear liquid and partly placed pyriform bottle, evaporate to dryness.Wash light green solid on the pyriform bottle wall with normal propyl alcohol, filter, colourless with normal propyl alcohol washing solid to filtrate, to be deposited in 60 ℃ of following vacuum dryings, get light green solid scutellarin prodrug PDHEAS 0.39 gram, productive rate 39%, percent grafting 28.2%, the dissolubility of PDHEAS are 63.3mgml
-1, the oral LD of mice
50Be 4280mg/Kg.
Embodiment 2:
With the preparation method of PDHEA among the embodiment 1, the response time of different is PSI and diethanolamine is 2.5 hours, obtains molecular weight and be 5000 PDHEA.
Scutellarin 0.47 gram is dissolved among the 15ml DMF, drips of solution is added in the 8mlDMF solution of 0.21 gram PDHEA then.Above-mentioned mixed liquor is stirred fully, add 0.47 gram DMAP, stirring reaction.0.8 gram DCC is dissolved among an amount of 20ml DMF, forms colourless solution, be added drop-wise in the above-mentioned mixed liquid.50 ℃ of following stirring reactions.With filter paper filtering at a slow speed, get the stillness of night partly to place pyriform bottle, evaporate to dryness after 72 hours.Wash light green solid on the pyriform bottle wall with normal propyl alcohol, filter, it is colourless to filtrate to wash solid with normal propyl alcohol, to be deposited in 40 ℃ of following vacuum dryings, get light green solid scutellarin prodrug PDHEAS 0.35 gram, productive rate 52%, percent grafting 32.9%, the dissolubility of PDHEAS are 73.7mgml
-1, the oral LD of mice
50Be 4600mg/Kg.
Embodiment 3:
With the preparation method of PDHEA among the embodiment 1, the response time of different is PSI and diethanolamine is 4 hours, obtains molecular weight and be 20000 PDHEA.
1.41 gram scutellarins are dissolved among the 60ml DMF, then drips of solution are added in the 30mlDMF solution of 0.92 gram PDHEA.Above-mentioned mixed liquor is stirred fully, add 2.8 gram DMAP, stirring reaction.0.50 gram DCC is dissolved among the 25ml DMF, forms colourless solution, be added drop-wise in the above-mentioned mixed liquid.20 ℃ of following stirring reactions were used filter paper filtering at a slow speed after 12 hours, got clear liquid and partly placed pyriform bottle, evaporate to dryness.Wash light green solid on the pyriform bottle wall with normal propyl alcohol, filter, it is colourless to filtrate to wash solid with normal propyl alcohol, to be deposited in 60 ℃ of following vacuum dryings, get light green solid scutellarin prodrug PDHEAS 1.39 grams, productive rate 43%, percent grafting 18.7%, the dissolubility of PDHEAS are 85.6mgml
-1, the oral LD of mice
50Be 4060mg/Kg.
Embodiment 4:
With embodiment 1 described method, different is takes by weighing 300 gram aspartic acids, adds strong phosphoric acid 10 gram catalyst, carries out polycondensation reaction under 100 ℃, progressively reduces pressure 1 * 10
4Pa reacted 10 hours, can make butanimide PSI, productive rate 85%.PSI 5.0g is dissolved in the 25ml oxolane, is cooled to 5 ℃, under this temperature, drip 25.0 gram diethanolamine, room temperature reaction 2h.Be added drop-wise to mixture in the 150ml n-butyl alcohol and constantly stirring, leave standstill the 1h after-filtration and show neutral until the filtrate pH value with a large amount of washing with acetones.Vacuum drying 24h gets the PDHEA white powder under the room temperature.
Embodiment 5:
With embodiment 1 described method, different is takes by weighing 200 gram aspartic acids, adds strong phosphoric acid 20 gram catalyst, carries out polycondensation reaction under 250 ℃, progressively reduces pressure 1 * 10
4Pa reacted 10 hours, can make butanimide PSI, productive rate 95%.PSI 5.0g is dissolved in the 25ml dioxane, is cooled to 3 ℃, under this temperature, drip 25.0 gram diethanolamine, room temperature reaction 2h.Be added drop-wise to mixture in the 150ml n-butyl alcohol and constantly stirring, leave standstill the 1h after-filtration and show neutral until the filtrate pH value with a large amount of washing with acetones.Vacuum drying 24h gets the PDHEA white powder under the room temperature.
Embodiment 6:
With embodiment 1 described method, different is that scutellarin 0.70 gram is dissolved among the 14ml DMF, then drips of solution is added in the 6ml DMF solution of 0.30 gram PDHEA.
Embodiment 7:
With embodiment 1 described method, different is that scutellarin 0.70 gram is dissolved among the 14ml DMF, then drips of solution is added in the 15ml DMF solution of 0.30 gram PDHEA.
Claims (3)
1, a kind of is the scutellarin prodrug of carrier with the poly-aspartate derivant, and its structural formula is:
X=10～1000 wherein, y=10～1000, x+y=10～1010.
2, a kind of is the preparation method of the scutellarin prodrug of carrier with the poly-aspartate derivant, it is characterized in that this method may further comprise the steps:
(1) aspartic acid and strong phosphoric acid are mixed by weight 30:1～10:1,, make butanimide in 100～250 ℃ of decompression reactions 10 hours;
(2) with the butanimide that makes and diethanolamine by weight 1:2～1:5 in solvent, under 0～5 ℃, reacted 2～4 hours; Described solvent is oxolane, dioxane or N, dinethylformamide
(3) step (2) gained reactant is added in the butanols, filters, washing, drying makes poly-aspartate derivant;
(4) poly-aspartate derivant is dissolved in N, dinethylformamide by weight 1:20～1:50;
(5) scutellarin is dissolved in N by weight 1:20～1:50, in the dinethylformamide;
(6) step (5) gained drips of solution is added in step (4) the gained solution, stir fully after, add 0.2～2 times to scutellarin weight to dimethylamino naphthyridine;
(7) with 0.35～2 times of N to scutellarin weight, N '-dicyclohexylcarbodiimide is dissolved in N by weight 1:10～1:50, in the dinethylformamide solution;
(8) step (7) gained drips of solution is added in step (6) the gained solution, 20～50 ℃ of following stirring reactions 12～120 hours;
(9) after filtration or centrifugal, get clear liquid and partly place bottle, evaporate to dryness after reaction finishes;
(10) with the light green solid on the normal propyl alcohol wash bottle wall, filter, colourless with normal propyl alcohol washing solid to filtrate, will be deposited in 40～60 ℃ of following vacuum dryings, get poly-aspartate derivant-scutellarin prodrug.
3, according to claim 2 a kind of be the preparation method of the scutellarin prodrug of carrier with the poly-aspartate derivant, it is characterized in that the described poly-aspartate derivant molecular weight in step (3) and (4) is 2000～20000.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2007100248878A CN100542613C (en) | 2007-07-06 | 2007-07-06 | It with the poly-aspartate derivant scutellarin prodrug of carrier and preparation method thereof |
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| CN101220065A (en) * | 2008-01-24 | 2008-07-16 | 沈阳药科大学 | Novel scutellarin compounds and uses thereof |
| CN102671213B (en) * | 2011-03-16 | 2013-09-11 | 昆明制药集团股份有限公司 | Scutellarin prodrug and preparation method thereof |
| CN102861342B (en) * | 2011-07-07 | 2014-07-30 | 昆明制药集团股份有限公司 | Scutellarin prodrug using cyclodextrin as carrier and preparation method for scutellarin prodrug |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1369514A (en) * | 2001-11-12 | 2002-09-18 | 南京南大表面和界面化学工程技术研究中心有限责任公司 | Polyasparagine derivative containing high-activity hydroxy radical |
| CN1566125A (en) * | 2003-06-14 | 2005-01-19 | 白永成 | Preparation method of scutellarin complex salt and preparation thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1369514A (en) * | 2001-11-12 | 2002-09-18 | 南京南大表面和界面化学工程技术研究中心有限责任公司 | Polyasparagine derivative containing high-activity hydroxy radical |
| CN1566125A (en) * | 2003-06-14 | 2005-01-19 | 白永成 | Preparation method of scutellarin complex salt and preparation thereof |
Non-Patent Citations (6)
| Title |
|---|
| 不同分子量灯盏乙素-PEG酯的合成、性质及小肠吸收研究. 周庆颂，蒋学华，李珂佳，樊新星.生物医学工程学杂志，第23卷第2期. 2006 |
| 不同分子量灯盏乙素-PEG酯的合成、性质及小肠吸收研究. 周庆颂，蒋学华，李珂佳，樊新星.生物医学工程学杂志，第23卷第2期. 2006 * |
| 灯盏乙素聚乙二醇前药的合成与表征. 叶海，张灿，沈文斌，盛龙生.中国天然药物，第4卷第4期. 2006 |
| 灯盏乙素聚乙二醇前药的合成与表征. 叶海，张灿，沈文斌，盛龙生.中国天然药物，第4卷第4期. 2006 * |
| 灯盏乙素酯类前药的合成、理化性质及降解研究. 操锋，郭健新，平其能，邵云，梁静.药学学报，第41卷第7期. 2006 |
| 灯盏乙素酯类前药的合成、理化性质及降解研究. 操锋，郭健新，平其能，邵云，梁静.药学学报，第41卷第7期. 2006 * |
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