CN1827116A - First-class new medicine cyclovirobuxine D series for treating cardiovascular and cerebrovascular disease and method for preparing the same - Google Patents
First-class new medicine cyclovirobuxine D series for treating cardiovascular and cerebrovascular disease and method for preparing the same Download PDFInfo
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- CN1827116A CN1827116A CN 200610020713 CN200610020713A CN1827116A CN 1827116 A CN1827116 A CN 1827116A CN 200610020713 CN200610020713 CN 200610020713 CN 200610020713 A CN200610020713 A CN 200610020713A CN 1827116 A CN1827116 A CN 1827116A
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Abstract
By organic synthesis and high molecular polymerization and other measures in this invention, graft hydrophilic polietilenglicol on the sideline of cyclovirobuxine D, and obtain a series of modified cyclovirobuxine D new drugs for cerebrovascular disease therapy. Characterize product structure with IR, 1H-NMR, GPC, MS, and so on; at the same time do its water-solubility, hemolysis test and hypoxia-resistant test on rat. The results above show: activated polietilenglicol has been successfully grafted on cyclovirobuxine D, and this turns water-insoluble cyclovirobuxine D into water-soluble polyaethylenglycolization cyclovirobuxine D; also it has good blood compatibility and physiologic activity. So the new drugs of polyaethylenglycolization cyclovirobuxine D system can be made into ampules, oral liquid, capsule, troche, and any other form feasible to clinic. The average molecular weight of the polietilenglicol is 200-60000.
Description
Technical field
The present invention relates to medical technical field, hydrophilic Polyethylene Glycol be directly grafted on the amino side chain of cyclovirobuxinum D, obtain the Pegylation cyclovirobuxinum D new drug of a series of modifications, use IR by methods such as organic synthesis and high molecular polymerizations,
1H-NMR, GPC, MS etc. have carried out structural characterization to product, the Multitests such as anoxia enduring of water solublity and hemolytic test and mice simultaneously it have been carried out, the result shows, activated polyglycol successfully is grafted on the cyclovirobuxinum D, makes water-fast cyclovirobuxinum D become water miscible Pegylation cyclovirobuxinum D.And have good blood compatibility and physiologically active.Therefore the cyclovirobuxinum D of Pegylation series new drug can be made into and comprises injection, oral liquid, capsule, all clinical other suitable dosage forms such as tablet.
Technical background
Cyclovirobuxinum D (cyclovirobuxine D, CVB-D) the 1st, from Buxaceae plant little leaf boxwood (BuxusmicrophyllaSieb.et Zucc.Var.Sinica Rehd.et Wils.) and belong to the effective ingredient of extraction separation the thing together, have another name called cyclovirobuxine D.Cyclovirobuxinum D has good arrhythmia, resists myocardial ischemia and cardiotonic, and acute cerebral ischemia is had protective effect, is widely used in treatment of diseases such as clinical crown cardiopathia, arrhythmia.Cyclovirobuxinum D is taken in version in 2000 and version " Chinese pharmacopoeia in 2005 with nomenclature of drug " Buxine " at present.Yet, pharmacological evaluation and clinical application research show that cyclovirobuxinum D scope safe in utilization is narrower, and owing to be fat-soluble biological alkali, water solublity is very poor, therefore improve the bioavailability of cyclovirobuxinum D, improve biodynamic mathematic(al) parameter in its body, enlarge its safe handling scope, it is carried out structure of modification and pharmacology activity research is very necessary.But at present less to the research of its structural modification aspect, yet its water solublity is not well improved.
The present invention carries out chemical modification to it, is intended to introduce hydrophilic radical, and its water solublity is further improved.And the effect quality of chemical modification depends on the quality of chemical modifier performance to a great extent.Wherein Polyethylene Glycol and derivant thereof are used at most in chemical modification owing to have following premium properties.
The polyethylene glycols dressing agent is PH neutrality, nontoxic, water miscible polymer, because the avirulence and the good biocompatibility of Polyethylene Glycol, it is one of the synthetic polymer that can use as injection drug in the body of the only a few of drugs approved by FDA.Polyethylene Glycol has the hydrophilic of height, bigger hydrodynamics volume is arranged in aqueous solution, and do not have immunogenicity.When being coupled to drug molecule or medical surfaces, its advantageous property can be given the drug molecule after the modification, change their biologies in aqueous solution and distribute behavior and dissolubility, around the medicine of its modification, produce the space barrier, reduce the enzymolysis of medicine, avoid very fast elimination in the metabolism of kidney, and make the medicine can be by immune cell recognition.
Summary of the invention
Based on above-mentioned principle, the present invention designs and has synthesized a series of polyglycol supported cyclovirobuxinum D class noval chemical compound 2 series and 3 series.
3(3a：PEG?400，3b：1000，3c：2000，
3d：4000，3e：6000，3f：10000，3g：20000)
And finish the structure test and characterize.Comprise Fourier transform infrared spectroscopy (FT-IR), BioradFT 40 type infrared spectrophotometers are filmed the sample preparation except that PEG-400 and PEG-400-DA adopt KBr, and other sample all adopts with KBr and grinds back tabletting sample preparation altogether.
1The H-NMR collection of illustrative plates,
1The H-NMR collection of illustrative plates adopts Varian INOVA-400 magnetic resonance device to measure, mark in TMS does, CDCl
3Make solvent.Molecular weight determination (GPC) adopts Agilent 1100 gel permeation chrommatographs (GPC), and polystyrene (PSt) is made standard specimen, oxolane dimension eluant, elution rate 1.00mL/min.KRUSS DSA 100 contact angle optical measuring instruments are used in the test of surface contact angle.Grind the pressed disc method sample preparation, choose smooth face.Measure with deionized water; Get the meansigma methods of continuous 3 measurement error in 0.5 ° of scope.Soluble test, with reference to solubility test method in the Pharmacopoeia of the People's Republic of China (2005 editions two ones): precision takes by weighing the Pegylation cyclovirobuxinum D 2～100mg that is ground into fine powder and places volumetric flask, adds entry and normal saline respectively by drug quality (g) and 1: 1,1: 10,1: 30,1: 100,1: 1000,1: 10000 ratio of liquor capacity (mL) respectively.Each sample bottle places 25 ℃ of water-baths, every the powerful concussion of 5min 30s, observes the dissolving situation in the 30min.And multinomial experiments such as hemolytic experiment and mice anoxia enduring.
Comprise injection, oral liquid, capsule, the research of other dosage form that various clinical such as tablet are suitable but also carried out preparation.Promptly in said medicine, can add pharmaceutically acceptable various adjuvant, make corresponding preparation.Raw materials used and reagent is Polyethylene Glycol (PEG) (200,400,1000,2000,4000,6000,10000,20000,40000,60000 etc.), adds the methylbenzene azeotropic distillation before using and dewaters; Succinic anhydride, dicyclohexylcarbodiimide (DCC); N-maloyl imines (NHS), (DMAP), chloroform, dichloromethane, ether, pyridine: be commercially available analytical pure, purify according to a conventional method before the use; Oxolane, acetic acid, toluene, NaHCO
3Anhydrous Na
2SO
4: be commercially available, directly use.
The synthetic route of Pegylation cyclovirobuxinum D
Fig.1synthetic?route(2)of?pegylated?cyclovirobuxine?D
The selection of polymer
In multiple water-soluble polymer, the Polyethylene Glycol good water solubility, toxicity is low, good biocompatibility, nonantigenic has been used for a year a lot of types of drug.The difference of molecular weight polyethylene glycol, the difference that can cause modifying the back pharmaceutical properties, along with the difference of mean molecule quantity, shape is shaped on very big difference.The size of molecular weight polyethylene glycol mainly exerts an influence to the pharmacokinetics of pegylated medicament, general molecular weight is big more, degree of modification is high more, the antigenicity of conjugate is more little, and the interior eliminating time of the body of conjugate is long more, the biological activity of conjugate is also reduced thereupon, and molecular weight is excessive then can to cause excessive grooming.Molecular weight polyethylene glycol is big more, and system goes out slow more clearly, and circulation time is long more in vivo.
Come a year cyclovirobuxinum D so the present invention has chosen the Polyethylene Glycol of 22 kinds of different mean molecule quantities,, comprise the various dosage forms that can be used for making novel intravenous formulations class medicine in order to further filtering out new drug with good hemolytic and physiologically active.
The specific embodiment
Embodiment 1
Polyethylene Glycol-list acid 5 (PEG-DA's) is synthetic
60g (10mmol) PEG-6000 is dissolved in 150mL anhydrous chloroform (CaH
2Steam under existing) in, adding 5g (50mmol) succinic anhydride, the exsiccant pyridine of 4mL stirs back flow reaction 48h down, and the reactant mixture reduction vaporization is to doing the saturated NaHCO of residue
3The aqueous solution dissolving is filtered, and filtrate is chilled to 0～5 ℃, and hcl acidifying, chloroform extraction three times, the chloroform solution water of merging are given a baby a bath on the third day after its birth inferior, anhydrous Na
2SO
4Drying is removed behind the desiccant filtrate is concentrated, and adds a large amount of exsiccant ether sedimentations and goes out product.Product ether recrystallization three times are weighed after the drying, the heavy 57g of product, productive rate 90%.
Make the PEG-400-diacid respectively by this method, PEG-1000-diacid, PEG-2000-diacid, PEG-4000-diacid, PEG-10000-diacid, PEG-20000-diacid.
Synthesizing of intermediate 6
Getting the above-mentioned polyglycol diacid of 5g is dissolved in the refining dichloromethane of 30mL, the dicyclohexylcarbodiimide (DCC) and the N-maloyl imines (NHS) that add 2 times of moles, the cyclohexylamine that adds 1.2 times of moles again, room temperature ultrasonic promotes reaction after 3.5 hours, be settled out product with exsiccant absolute ether, product is through vacuum drying, and is standby.
Make single-ended activated PEG-400-diacid-active ester of monocycle hexylamine, the PEG-6000-diacid-active ester of monocycle hexylamine respectively by this method with the cyclohexylamine sealing.
Synthesizing of chemical compound 2
The activated PEG of getting the above-mentioned single-ended sealing of 1mmol is dissolved in the refining dichloromethane of 30mL, the dicyclohexylcarbodiimide (DCC) and the N that add 1.2 moles, N-dimethylamino naphthyridine (DMAP), room temperature ultrasonic promotes reaction after 5 hours, the DCC of the HAc/THF decomposing excessive of adding 10%, behind the 10min, reactant liquor washs three times with 0.1NHCl, anhydrous Na
2SO
4Drying, filtrate evaporate to dryness (slight fever,＜40 ℃), residue isopropyl alcohol recrystallization gets product.
Make the PEG-400-diacid-CVB-D and the PEG-6000-diacid-CVB-D of single-ended sealing respectively by this method.
Synthesizing of chemical compound 3
Getting 2.0g (0.5mmoL) PEG-4000-diacid is dissolved in the refining dichloromethane of 30mL, add 0.2g (1mmol) dicyclohexylcarbodiimide (DCC) and 0.116g (1mmoL) N-maloyl imines (NHS), add 0.4g (1mmol) cyclovirobuxinum D (CVB-D) again, room temperature ultrasonic promotes reaction after 4 hours, the DCC that adds the 8mL10%HAc/THF decomposing excessive, behind the 10min, reactant liquor washs three times with 0.1NHCl, anhydrous Na
2SO
4Drying, filtrate evaporate to dryness (slight fever,＜40 ℃), residue isopropyl alcohol recrystallization gets product.
Make PEG-400-diacid-CVB-D respectively by this method, PEG-1000-diacid-CVB-D, PEG-2000-diacid-CVB-D, PEG-6000-diacid-CVB-D, PEG-10000-diacid-CVB-D, PEG-20000-diacid-CVB-D.
Embodiment 2
Get PEG-6000-diacid-CVB-D150g, add and make with extra care water for injection 20000ml, dissolving is filtered, and preparation 2ml/ props up, and sterilization gets 10000 of aqueous injection.Every contains PEG-6000-diacid-CVB-D15mg.
Claims (4)
1 is used for the treatment of the Pegylation cyclovirobuxinum D new drug of cardiovascular and cerebrovascular disease, it is characterized in that hydrophilic Polyethylene Glycol being grafted on the amino side chain of cyclovirobuxinum D by methods such as organic synthesis and high molecular polymerizations, can be the unimolecule cyclovirobuxinum D, also can be the bimolecular cyclovirobuxinum D; The side chain amino of cyclovirobuxinum D can be an amino, also can be that two amino react simultaneously.And use IR,
1H-NMR, GPC, MS etc. have carried out structural characterization to product.
2 according to the described Pegylation cyclovirobuxinum D of claim 1 new drug, it is characterized in that used Polyethylene Glycol mean molecule quantity is between 200～60000.
3 according to the described Pegylation cyclovirobuxinum D of claim 1 new drug, it is characterized in that this medicine can be applicable to treat all clinical practice indications of cyclovirobuxinum D (Buxine) that comprise cardiovascular and cerebrovascular disease.
4 according to the described Pegylation cyclovirobuxinum D of claim 1 new drug, it is characterized in that in this medicine constituent adding pharmaceutically acceptable various adjuvants, make and comprise injection, oral liquid, capsule, all clinical other suitable dosage forms such as tablet.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101462692B1 (en) | 2008-11-10 | 2014-11-21 | 주식회사 알엔에스 | Skin whitening cosmetics |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| KR101462692B1 (en) | 2008-11-10 | 2014-11-21 | 주식회사 알엔에스 | Skin whitening cosmetics |
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