CN100410279C - Aldehydic acids tetramethylpyrazine ester and method for preparing same - Google Patents
Aldehydic acids tetramethylpyrazine ester and method for preparing same Download PDFInfo
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- CN100410279C CN100410279C CNB2004100428769A CN200410042876A CN100410279C CN 100410279 C CN100410279 C CN 100410279C CN B2004100428769 A CNB2004100428769 A CN B2004100428769A CN 200410042876 A CN200410042876 A CN 200410042876A CN 100410279 C CN100410279 C CN 100410279C
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Abstract
The present invention provides polyacid ligustrazine ester as a compound for a polymer to carry the effective ingredient of ligusticus wallichii franchet. The present invention also provides a preparation method for the polyacid ligustrazine ester, a ligustrazine derivative converting a lateral chain into an active group is combined with polyacid under the action of a condensing agent of dicyclohexylcarbodiimide (DCCI), the lateral chain of ligustrazine can be combined with a functional polymer through ester bonds to obtain the polyacid ligustrazine ester which can enhance the water solubility of the ligustrazine, slow up the metabolism velocity of the ligustrazine and improve the conditions of the frequent medicine supply and the obvious peak valley phenomenon of ligustrazine preparations utilized for clinical treatment at present.
Description
Technical field
The present invention is the research of compound of a kind of polymkeric substance Zhi Zaizhong pharmaceutically active ingredient and preparation method thereof, relates to bio-medical material and field of medicaments, belongs to the derivative compound of Ligustrazine.
Background technology
Ligustrazine is to separate the alkaloid monomer of purifying by this platymiscium of umbelliferae algae Ligusticum wallichii, is one of effective constituent of activating blood herbs Ligusticum wallichii.Ligustrazine has abundant pharmacological action.Promptly become the common drug of domestic clinical treatment ischemic cerebrovascular disease since the mid-1970s.Problems such as metabolism is fast in vivo but find Ligustrazine in using, and needs frequent drug administration, and peak valley is obvious.
In order to address the above problem, the investigator of China once made some good tries, for example, with various small molecules Ligustrazine was carried out chemically modified (referring to " structural modification of Ligustrazine and biological activity [J] " chemistry circular, 2003,7,454; Author: Yang Jie, Duan Yufeng, Han Guoping, Huang Xinwei [1]), can not well solve the Ligustrazine fast problem of metabolism in vivo but Ligustrazine is modified with small molecules.The somebody attempts Ligustrazine and the good polymkeric substance of biocompatibility, as gelatin, polyoxyethylene glycol, blend such as Mierocrystalline cellulose are with preparation medicament sustained-release tablets (referring to CN1430963A ligustrazine phosphoric acid sustained-release sheet and preparation method thereof [2]), and use osmotic pump principle and be prepared into controlled release preparation etc. (referring to the osmotic pump controlled-releasing agent of CN1421207A phosphoric acid Ligustrazine and preparation method thereof [3]), though above-mentioned several method can both delay the release rate of Ligustrazine, can reach the purpose of slowly-releasing, but the speed that portion can not its release of better controlled.Therefore clinical a large amount of uses at present still is the hydrochloride and the phosphoric acid salt injection liquid of Ligustrazine, though it has promoting blood circulation and removing blood stasis, rapid-action advantage, but action time is short, need long-term successive administration just can reach the effect of treatment, the administration cycle is long, for patient, cumbersome, and also cost is higher.
It is a kind of new technology that development in recent years is got up by DeR with the technology that reaches its effective constituent release purpose of control that polymkeric substance props up the medicine carrying thing.For example, Western medicine such as polyglycol supported anticarcinogen obtained good efficacy (referring to Ouchi, T:Hagihara, Y; Takahashi, K; Takano, Y; Lgarashi, I.Drug Design andDiscovery 1992,9,93[4]).But polyglycol supported blood-activating and stasis-removing Ligusticum wallichii effective constituent Ligustrazine two examples (referring to Chinese patent, application number 200310100267X) that polymkeric substance props up carried anticancer medicine taxol (referring to the polyglycol supported taxol of CN1283643A or the prodrug [5] of Docetaxel) and this research group report are only seen in the research that this technology is used for natural drug at present.
The compound of the present invention preparation-poly-acids Ligustrazine ester is a kind of novel derivative, its effect mainly is to improve the water-soluble of Ligusticum wallichii effective constituent and slow down its accretion rate, reaches property of medicine longer duration, improves purposes such as bioavailability and convenient drug administration.
Summary of the invention
The Ligustrazine that the present invention is directed to present clinical use is drained soon, the problem that bioavailability is low, and the preparation superpolymer props up the medicine carrying thing.Ligustrazine derivant that the poly-acids (referring to Chinese patent, 97194360.5) that is usually used in pharmaceutical carrier and Ligustrazine generate by the ester bond Chemical bond and preparation method thereof is provided.
The biological activity according to Ligustrazine determined of technical scheme provided by the present invention depends on the characteristics of its mother nucleus structure, the methyl of selecting the Ligustrazine side chain as and the binding site of polymkeric substance.Specific embodiments is as follows:
At first Ligustrazine is oxidized to 2,5-dihydroxymethyl-3,6-dimethylpyrazine or 2-methylol-3,5, the 6-trimethylpyrazine, then, above-mentioned substance and poly-sour mol ratio by 1: 19 are dissolved in exsiccant N, in the dinethylformamide (150ml), add again condensing agent-dicyclohexylcarbodiimide (DCCI) [2,4-dihydroxymethyl-3,6-dimethylpyrazine or 2-methylol-3,5, the mol ratio of 6-trimethylpyrazine and dicyclohexylcarbodiimide (DCCI) is 1: 1], at room temperature reacted 10 hours, thin-layer chromatography shows 2,5-dihydroxymethyl-3,6-dimethylpyrazine or 2-methylol-3,5, the grafting of 6-trimethylpyrazine is complete, then, chloroform is added in the reaction mixture, collect gained throw out and vacuum-drying.
The physical property of polyacrylic acid Ligustrazine ester is: faint yellow solid.υ(C＝O)1732.0cm
-1；υ(-N＝C-)1474cm
-1。
Synthetic route and product molecular structure are seen accompanying drawing 1.
Intermediate among the present invention can also comprise that one or more methyl of Ligustrazine change into the derivative of the Ligustrazine of other active group, and polypeptide, polyamino acid, aliphatic diacid or acid anhydrides.
It is the derivative of the novel Ligustrazine of a class that poly-acids props up the compound one that carries the preparation of Ligusticum wallichii effective constituent, their advantage is: will improve the water-soluble of Ligustrazine, its accretion rate slows down, need frequent drug administration to solve present Ligustrazine preparation, problems such as peak valley is obvious reach property of medicine longer duration, improve purposes such as bioavailability and convenient drug administration.
Embodiment
The invention will be further described with preparation example below.
Preparation example 1
Take the molecular weight as the synthetic polyacrylic acid Ligustrazine ester of 800-1000 polyacrylic acid
(1) 2,5-dihydroxymethyl-3, synthetic (intermediate) of 6-dimethylpyrazine
50.4g phosphoric acid Ligustrazine is dissolved in the 90ml Glacial acetic acid, under the condition of 98 ℃ of oil baths, adds the 90ml hydrogen peroxide solution, behind the back flow reaction 24h, with 20% sodium hydroxide solution adjust pH to 9～10, with chloroform extraction, adds anhydrous Na
2SO
4Drying is filtered, and through the Ligustrazine-1 that rotary evaporation gets final product whitely, 4-dinitrogen oxide compound, fusing point are 212-224 ℃.Take by weighing 16.8g Ligustrazine-1,4-dinitrogen oxide compound is dissolved in the 150ml diacetyl oxide, behind backflow 4h under the condition of 150 ℃ of oil baths, with 20% sodium hydroxide solution adjust pH to 9～10, leaves standstill 24 hours, uses ethyl acetate extraction, adds anhydrous Na
2SO
4Drying is filtered, and gets final product flaxenly 2 behind rotary evaporation, 5-dihydroxymethyl-3,6-dimethylpyrazine.
(2) 2,5-dihydroxymethyls-3,6-dimethylpyrazine and polyacrylic esterification
Take by weighing the 3.168g polyacrylic acid and be dissolved in exsiccant N, the N--dimethyl formamide adds 386.4mg, 2,5-dihydroxymethyl-3,6-dimethylpyrazine, add 1.504g dicyclohexylcarbodiimide (DCCI) again, add a small amount of dimethylamino pyridine then, reaction added trichloromethane after 10 hours under the room temperature in product, thin-layer chromatography shows 2,5-dihydroxymethyl-3, the grafting of 6-dimethylpyrazine is complete, filtering-depositing, drying, the heavy 0.88g of product.
In PU-1901 type ultraviolet device, obtain UV spectrum (UV).Suppose that polymkeric substance in the water props up the medicine carrying thing and has identical molar extinction coefficient with the free medicine, and the both observes langbobier law (LambertBeer ' s law), and (typical curve of λ=294nm) produce can be measured and polyacrylic acid grafted Ligustrazine content with UV according to the Ligustrazine of concentration known.Ligustrazine has distinctive uv-absorbing at λ=294nm and λ=210nm place.Polymer conjugate has identical molar extinction coefficient with Ligustrazine when supposing 294nm, and the both observes langbobier law, and the content of measuring Ligustrazine in the polyacrylic acid Ligustrazine ester according to the standard working curve of the Ligustrazine of concentration known is 29.49%.
IR: the infrared absorption of product: υ (C=O) 1732.0cm
-1υ (N=C-) 1474cm
-1
Preparation example 2
Repeating the step of preparation example 1, is that 100,000 polyacrylic acid substituted molecule amount is the 800-1000 polyacrylic acid with molecular weight, makes 2,4-dihydroxymethyl-3,6-dimethylpyrazine graft polypropylene acid esters.
Preparation example 3
Take by weighing 699.2mg2-methylol-3,5, the 6-trimethylpyrazine substitutes 2,5-dihydroxymethyl-3,6-dimethylpyrazine, the step of repetition preparation example 1.2-methylol-3,5 wherein, 6-trimethylpyrazine synthetic referring to Chinese patent (application number 200310100267X).
Preparation example 4
Intermediate synthetic with preparation example 1 is that 15,000～50,000 polyglutamic acid substitutes the polyacrylic acid in the preparation example 1 with molecular weight, synthesizes polyglutamic acid Ligustrazine ester.
Claims (1)
1. a poly-acids Ligustrazine ester is characterized in that it is the derivative of Ligustrazine, and structural formula is as follows:
R in the structural formula
1Be H or OH; R
2Be polyacrylic acid.
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| Application Number | Priority Date | Filing Date | Title |
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| CN100410279C true CN100410279C (en) | 2008-08-13 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102204913B (en) * | 2011-04-02 | 2012-09-19 | 南京中医药大学 | Application of ligustrazine derivative in preparation of medicament for treating melanoma |
| CN103242247B (en) * | 2013-05-10 | 2016-03-30 | 南京中医药大学 | The synthesis of H168 and process for purification |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1415296A (en) * | 2002-10-31 | 2003-05-07 | 上海医药工业研究院 | Compsn. containing ligustrazine, penetrating skin paste agent of igustrazine and its preparation method |
| CN1421207A (en) * | 2002-12-20 | 2003-06-04 | 北京中惠药业有限公司 | Control released osmotic pump prepn containing ligustrazine phosphate and its prepn process |
| CN1430963A (en) * | 2003-01-09 | 2003-07-23 | 武汉大学 | Slowly releasing tablet of ligustrazine of phosphoric acid and its preparing method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1415296A (en) * | 2002-10-31 | 2003-05-07 | 上海医药工业研究院 | Compsn. containing ligustrazine, penetrating skin paste agent of igustrazine and its preparation method |
| CN1421207A (en) * | 2002-12-20 | 2003-06-04 | 北京中惠药业有限公司 | Control released osmotic pump prepn containing ligustrazine phosphate and its prepn process |
| CN1430963A (en) * | 2003-01-09 | 2003-07-23 | 武汉大学 | Slowly releasing tablet of ligustrazine of phosphoric acid and its preparing method |
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