CN1296409C - Ligustrazine polyethleneglycol ester and preparation method thereof - Google Patents
Ligustrazine polyethleneglycol ester and preparation method thereof Download PDFInfo
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- CN1296409C CN1296409C CNB200310100267XA CN200310100267A CN1296409C CN 1296409 C CN1296409 C CN 1296409C CN B200310100267X A CNB200310100267X A CN B200310100267XA CN 200310100267 A CN200310100267 A CN 200310100267A CN 1296409 C CN1296409 C CN 1296409C
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- ligustrazine
- ester
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Abstract
The present invention provides ligustrazine polyethyleneglycol ester [PEG(OCH2OCH2COOC8N2H12)2] as a compound of the effective ingredient of rhizome ligustici wallichii as a polymer, which has the structural formula of PEG(OCH2OCH2COOC8N2H12)2. The present invention has the infrared absorption characteristics of 1720cm<-1> to 1750cm<-1>(C=O) and 1185cm<-1> to 1275cm<-1>(C-O-C), and thus, ester groups can be determined. The present invention has the physical characteristics of white or yellowish solid and the melting point temperature of 46 DEG C to 55 DEG C. The present invention also provides a preparation method for the ligustrazine polyethyleneglycol ester, ligustrazine derivatives converted from a lateral chain is combined with polyethylene glycol diacid under the action of the condensing agents of (3-dimethylaminopropyl)-3-ethide carbodiimide (EDCI), dicyclohexylcarbodiimide (DCCI), carbonyldiimidazole (CDI), etc. so as to combine the lateral chain of ligustrazine with functional polymers through ester bonds and obtain the ligustrazine polyethyleneglycol ester, and the ligustrazine polyethyleneglycol ester can degrade at different speeds in different water systems and can release the ligustrazine derivatives having bioactivity so as to improve the conditions of fast metabolism, frequent medicine supply and obvious peak valley phenomenon in ligustrazine preparations utilized for clinical treatment at present.
Description
The research of compound that affiliated technical field the present invention is 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.
The 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 speed that all 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.
Polyglycol supported medicine 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.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 and Discovery1992,9,93[4]).But polymkeric substance is only seen in the research that this technology is used for natural drug at present propped up carried anticancer medicine taxol one example (referring to the polyglycol supported taxol of CN1283643A or the prodrug [5] of Docetaxel).
The present invention is a kind of derivative of new Ligustrazine with the compound-Ligustrazine macrogol ester of polyglycol supported Ligusticum wallichii effective constituent preparation, its effect mainly is the release rate of control Ligusticum wallichii effective constituent, reaches property of medicine longer duration, improves purposes such as bioavailability and convenient drug administration.
Summary of the invention the present invention is directed to the Ligustrazine of present clinical use and drains soon, and the problem that bioavailability is low provides Ligustrazine macrogol ester [PEG (OCH
2OCH
2COOC
8N
2H
12)
2] and preparation method thereof.
Technical scheme provided by the invention is: test shows that the biological activity of Ligustrazine depends on its mother nucleus structure, so, the methyl of selecting the Ligustrazine side chain as with the binding site of polymkeric substance.Specific embodiments is as follows:
At first Ligustrazine is oxidized to 2-methylol-3,5, the 6-trimethylpyrazine is oxidized to polyglycol diacid with polyoxyethylene glycol again, and then, the mol ratio of above-mentioned two kinds of materials being pressed (2: 1) is dissolved in exsiccant methylene dichloride (1.1 * 10
-4Mol/ml) in, add condensing agent-carbonyl dimidazoles (CDI) again (with 2-methylol-3,5, the mol ratio of 6-trimethylpyrazine is 1: 1), its purpose is above-mentioned two kinds of materials are condensed into ester bond, reflux is not when having gas and produce, be considered as reaction and finish, the reaction times is 2h-4h, and is last, temperature less than 30 ℃ situation under, drip with the refrigerative anhydrous diethyl ether, produce, filter until the adularescent precipitation, after the vacuum-drying, can obtain the end capped polymkeric substance-macrogol ester of Ligustrazine [PEG (OCH
2OCH
2COOC
8N
2H
12)
2], productive rate is 2%-99%.
Synthetic route is:
The physical property of Ligustrazine macrogol ester is: white or faint yellow solid shape, 46 ℃-55 ℃ of fusing points.Infrared signature is: the absorption peak of ester bond is at 1720cm
-1～1750cm
-1(C=O) and 1185cm
-1～1275cm
-1(C-O-C) between, structural formula is as follows:
At the used condensing agent of the present invention, except carbonyl dimidazoles (CDI), (3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI) (reaction times is in 24 hours) and dicyclohexylcarbodiimide (DCCI) (reaction times is in 7 days) also can be finished this preparation process.
Intermediate among the present invention can also comprise that more than two s' of Ligustrazine (comprising two) methyl changes into the derivative of the Ligustrazine of active group, and polypeptide, aliphatic diacid or acid anhydrides.
Compound-Ligustrazine the macrogol ester of polyglycol supported Ligusticum wallichii effective constituent preparation is a kind of derivative of new Ligustrazine, its advantage is: the transformation period that will prolong Ligustrazine is with its accretion rate that slows down, and reach the purpose of medicine sustained release by controlling polymers ester linkage breaking condition in aqueous systems, need frequent drug administration to solve present Ligustrazine preparation, problems such as peak valley is obvious realize property of medicine longer duration, improve benefits such as bioavailability and convenient drug administration.
The invention will be further described with preparation example for embodiment.
Preparation example 1
With EDCI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 2000) ester of condensing agent
1. intermediate is synthetic
(1) 2-methylol-3,5,6-trimethylpyrazine synthetic
The 14.0g phosphoric acid Ligustrazine is dissolved in the 18ml Glacial acetic acid, under the condition of 70 ℃ of water-baths, adds the 13.5ml hydrogen peroxide solution, behind the back flow reaction 7h,,, add anhydrous Na with chloroform extraction with 20% sodium hydroxide solution adjust pH to 9～10
2SO
4Dry, filter, the Ligustrazine that filtrate gets final product whitely through rotary evaporation-1-oxynitride, take by weighing 3.0g Ligustrazine-1-oxynitride and be dissolved in the 10.4ml diacetyl oxide, behind backflow 2h under the condition of 150 ℃ of oil baths,, leave standstill with 20% sodium hydroxide solution adjust pH to 9～10, use ethyl acetate extraction, add anhydrous Na
2SO
4Drying is filtered, filtrate behind rotary evaporation, get final product flaxen 2-methylol-3,5,6-trimethylpyrazine, fusing point are 72-77 ℃.
(2) polyglycol diacid is synthetic
20.0gPEG-2000 be dissolved in the 50ml distilled water, agitation condition slowly drips potassium permanganate solution (3.8gKMnO down
4Be dissolved in the 100ml water), room temperature reaction 3 hours.H with 1mol/l
2SO
4Solution is transferred pH value to 3.0, adds an amount of anhydrous Na
2SO
3Continue H with 1mol/l
2SO
4Solution is transferred pH value to 3.0, and solution becomes gets clear.With the above-mentioned solution of chloroform extraction, add anhydrous Na
2SO
4Drying is filtered, the filtrate rotary evaporation, and vacuum-drying promptly gets polyoxyethylene glycol-2000-diacid, the heavy 20.7g of product, productive rate is 94%, and fusing point is 45 ℃-46 ℃, and the characteristic absorbance of its infrared spectrum is 1112cm
-1(C-O-C), 1746cm
-1(C=O), 3451cm
-1(O-H).
2.2-methylol-3,5, the esterification of 6-trimethylpyrazine and polyoxyethylene glycol-2000-diacid
Take by weighing 2.0g polyoxyethylene glycol-2000-diacid and be dissolved in the citrate buffer solution 100ml of pH=3.8, add 0.2g1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (EDCI), room temperature is placed 2h.Add 0.16g2-methylol-3,5 then, the 6-trimethylpyrazine at room temperature stirs 24h.With the above-mentioned solution of dichloromethane extraction, use anhydrous Na
2SO
4Drying is filtered, and concentrated filtrate drips anhydrous diethyl ether under cold condition, and the adularescent precipitation produces, filter, get final product 2-methylol-3,5,6-trimethylpyrazine grafting PEG-2000 ester, the heavy 0.05g of product, productive rate is 2%, and fusing point is 46 ℃～48 ℃, and the characteristic absorbance of its infrared spectrum is 1254cm
-1(C-O-C), 1747cm
-1(C=O).
Preparation example 2
With DCCI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 2000) ester of condensing agent.
Intermediate 2-methylol-3,5 wherein, 6-trimethylpyrazine and polyoxyethylene glycol-2000-diacid is synthetic with preparation example 1.
2.0g polyoxyethylene glycol-2000-diacid is dissolved in the 40ml exsiccant methylene dichloride, adds 0.65g2-methylol-3,5,6 trimethylpyrazines.Add 3.06g dicyclohexylcarbodiimide (DCCI) then, stirring at room 7 days has precipitation to produce in the solution.Remove by filter precipitation, concentrate, under cold condition, drip anhydrous diethyl ether, the adularescent precipitation produces.Cold condition filters down, get final product flaxen 2-methylol-3,5,6-trimethylpyrazine grafting PEG-2000 ester, the heavy 1.82g of product, productive rate is 69%, fusing point is 47 ℃～48 ℃, the characteristic absorbance of its infrared spectrum is with preparation example 1.
Preparation example 3
With CDI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 2000) ester of condensing agent
Intermediate 2-methylol-3,5,6-trimethylpyrazine and polyoxyethylene glycol-2000-diacid is synthetic with preparation example 1.
10.0g polyoxyethylene glycol-2000-diacid is dissolved in the 50ml exsiccant methylene dichloride, adds 1.69g2-methylol-3,5, the 6-trimethylpyrazine.Add 1.87g1,1 '-carbonyl dimidazoles (CDI), reflux, inside has bubble to produce, and can make clarifying liming become muddy, is defined as CO
2, getting final product stopped reaction up to no gas generation, the reaction times is 2h-4h, the cooling back concentrates, and drips anhydrous diethyl ether under cold condition, the generation of adularescent precipitation.Continuation is filtered under cold condition, drying get final product flaxen 2-methylol-3,5,6-trimethylpyrazine grafting PEG-2000 ester, the heavy 1.51g of product, productive rate is 13%, fusing point is 46 ℃～47 ℃, and the characteristic absorbance of its infrared spectrum of characteristic absorbance of its infrared spectrum is with preparation example 1.
Preparation example 4
With DCCI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 400) ester of condensing agent
Repeat the step of preparation example 2, different is to replace PEG-2000 with polyoxyethylene glycol PEG-400, make polyoxyethylene glycol-400-diacid, and then make 2-methylol-3,5,6-trimethylpyrazine grafting PEG-400 ester, productive rate is 35%, orange-yellow heavy-gravity liquid, the characteristic absorbance of its infrared spectrum are 1270cm
-1(C-O-C), 1751cm
-1(C=O).
Preparation example 5
With CDI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 400) ester of condensing agent
Repeat the step of preparation example 3,, make 2-methylol-3 with polyoxyethylene glycol-400-two acid substitutions polyoxyethylene glycol-2000-diacid, 5,6-trimethylpyrazine grafting PEG-400 ester, productive rate is 46%, orange-yellow heavy-gravity liquid, the characteristic absorbance of its infrared spectrum is with preparation example 4.
Preparation example 6
With DCCI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 10000) ester of condensing agent
Repeat the step of preparation example 2, different is to replace PEG-2000 with polyoxyethylene glycol PEG-10000, make polyoxyethylene glycol-10000-diacid, and then make 2-methylol-3,5,6-trimethylpyrazine grafting PEG-10000 ester, productive rate is 93%, faint yellow solid, fusing point are 53 ℃～55 ℃, and the characteristic absorbance of infrared spectrum is 1258cm
-1(C-O-C), 1749cm
-1(C=O).
Preparation example 7
With CDI is synthetic Ligustrazine polyoxyethylene glycol (molecular weight 20000) ester of condensing agent
Repeat the step of preparation example 3,, make 2-methylol-3 with polyoxyethylene glycol-20000-two acid substitutions polyoxyethylene glycol-2000-diacid, 5,6-trimethylpyrazine grafting PEG-20000 ester, productive rate is 98.5%, faint yellow solid, fusing point are 54 ℃～56 ℃, and the characteristic absorbance of infrared spectrum is with preparation example 6.
Claims (4)
1. the structural formula of Ligustrazine macrogol ester is as follows:
PEG is a polyoxyethylene glycol in the structural formula.
2. described Ligustrazine macrogol ester of claim 1, it is characterized in that: its physics is characterized by white or faint yellow solid shape, 46 ℃-55 ℃ of fusing points.
3. the described Ligustrazine macrogol ester of claim 1 is characterized in that: be positioned at 1720～1750cm
-1With 1185～1275cm
-1Infrared signature absorbs and belongs to C=O key and C-O-C key respectively, can be defined as ester group.
4. the preparation method of the described Ligustrazine macrogol ester of claim 1, it is characterized in that: the Ligustrazine side chain combines with polyoxyethylene glycol by ester bond; At first one or more methyl on the Ligustrazine is changed into other active group, and the terminal hydroxy group of polyoxyethylene glycol is oxidized to carboxyl, the molecular weight of used polyoxyethylene glycol carries out esterification then between 1000～10000; The used condensing agent of esterification comprises: (3-dimethylamino-propyl)-3-ethyl carbodiimide, dicyclohexylcarbodiimide, carbonyl dimidazoles; 2-methylol-3,5 in the esterification, the 6-trimethylpyrazine, polyglycol diacid, the mol ratio of condensing agent is 2: 1: 2; Esterification is at room temperature carried out, and the reaction times was less than 7 days; Aftertreatment partly is to drip with the refrigerative anhydrous diethyl ether during less than 30 ℃ in temperature, produces until the adularescent precipitation to form.
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|---|---|---|---|
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150150A (en) * | 1995-08-04 | 1997-05-21 | 广荣化学工业株式会社 | Process for producing pyrazine compounds |
| CN1253134A (en) * | 1998-11-11 | 2000-05-17 | 浙江省应用化学重点研究实验室 | Process for preparing tetramethyl pyrazine |
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
-
2003
- 2003-10-15 CN CNB200310100267XA patent/CN1296409C/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1150150A (en) * | 1995-08-04 | 1997-05-21 | 广荣化学工业株式会社 | Process for producing pyrazine compounds |
| CN1253134A (en) * | 1998-11-11 | 2000-05-17 | 浙江省应用化学重点研究实验室 | Process for preparing tetramethyl pyrazine |
| CN1424313A (en) * | 2002-12-20 | 2003-06-18 | 山东大学 | Chuanxiong alkoxide derivative and its preparation and medicinal composition containing it and use thereof |
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Granted publication date: 20070124 Termination date: 20101015 |