CN1900082A - Medicinal compound for resisting platelet activating factor - Google Patents
Medicinal compound for resisting platelet activating factor Download PDFInfo
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- CN1900082A CN1900082A CN 200510041060 CN200510041060A CN1900082A CN 1900082 A CN1900082 A CN 1900082A CN 200510041060 CN200510041060 CN 200510041060 CN 200510041060 A CN200510041060 A CN 200510041060A CN 1900082 A CN1900082 A CN 1900082A
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- ginkgolide
- activating factor
- platelet activating
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Abstract
The present invention discloses a kind of medicine compound antaonizing platelet activating factor. The medicine compound is bilobalide B with nitrogen-containing radical connected to the hydroxyl radial in the site 10 and has the structure as shown. The medicine compound of the present invention has high water solubility, high bioavailability and high curative effect, and its salt has greatly raised water solubility, bioavailability and curative effect.
Description
Technical field
The present invention relates to the medicine that a class has platelet activation factor (PAF) antagonistic action, relate in particular to a kind of medical compounds of anti-platelet activating factor.
Background technology
Ginkgo is of long duration as medicinal plant, about 1000 Christian eras, and China's Ginkgo Leaf treatment asthma and bronchitis just used among the people.Along with going deep into of extract drugs process standardization and pharmacological action activity research, countries in the world, particularly European countries such as Germany, France have been widely used in Semen Ginkgo extrac (GBE) diseases such as treatment respiratory system, cardio-cerebrovascular.Bilobalide is a series of diterpene-kind compounds that are present in Ginkgo Leaf and the rhizome, the chemical property quite stable.Bilobalide is platelet activation factor (platelet-activating factor, PAF) strong antagonist, platelet activation factor is a very strong physiological regulation device, on a lot of physiological phenomenons, playing the part of important role, as irritated, inflammation and asthma or the like, therefore seeking the use that suitable substance P AF antagonist is used as in the medical treatment is very important problem of medical circle.
Ginkgolide B (Ginkgolide B, GB) be from Ginkgo Leaf, extract a kind of six the ring cage structures diterpene compound, it is the strongest platelet activation factor (PAF) antagonist of finding so far, it participates in thrombosis directly, can stimulate coronary artery and cerebral arteries, cause their contraction, spasm, cause cardiac muscle and cerebral tissue ischemic.In recent years research finds that also stronger anti-inflammatory action is arranged.In inflammatory reaction, the LPA effect of the activated Phospholipase A2 of neutrophilic leukocyte membrane phospholipid is hydrolyzed into arachidonic acid (AA).AA further metabolism under the effect of 5-lipoxygenase (5-LO) is leukotriene (LTs) and hydroxyeicosatetraenoic acid products such as (HETEs), and wherein, some product is important inflammatory mediator, and the activation of Phospholipase A2 needs intracellular Ca2+ to participate in.Ginkgolide B has the effect that influences rat neutrophilic leukocyte arachidonic acid metabolism enzyme and intracellular free calcium.Its anti-inflammatory action may be relevant with the rising of the generation of the release of its inhibition neutrophilic leukocyte lysosomal enzyme, superoxide anion and intracellular Ca2+ level.
But Ginkgolide B is a kind of diterpene compound of six ring cage structures, rigid structure, and water insoluble, bioavailability is poor, causes giving full play to of drug effect to be restricted, and influences clinical application effect.
Summary of the invention
The invention provides a kind of can improve water-soluble, bioavailability good and help giving full play to the medical compounds of the anti-platelet activating factor of drug effect.
The present invention adopts following technical scheme:
A kind of medical compounds of anti-platelet activating factor, this medical compounds are to be connected with nitrogen-containing group on 10 hydroxyls of Ginkgolide B, and its structural formula is as follows:
Wherein, X is the connection skeleton that contains 1-8 carbon atom, and R1 and R2 are that H or carbon number are the alkyl of 1-8.
Compared with prior art, the present invention has following advantage:
The present invention is to be parent with the Ginkgolide B, through structural modification, becomes the nitrogen containing derivative of Ginkgolide B, has improved water-solublely, improves bioavailability, heightens the effect of a treatment; Especially behind its salify, it is water-soluble, bioavailability and curative effect all are improved largely and strengthen.
Have platelet activation factor (PAF) antagonistic action, can be used for disease prevention and the clinical treatments relevant such as ishemic stroke, inflammation, asthma with the PAF factor.
(1) spectrum analysis before and after the structural modification of Ginkgolide B is as follows:
The mass spectrum (MS) of Ginkgolide B (before being structural modification) and hydrogen spectrum (1H-NMR) spectrum analysis: MS:424 (molecular ion peak)
1H-NMR(DMSO-d6，400MHz)：1.01(s，9H，t-Bu)，1.09(d，3H，14-Me)，1.70(dd，1H，8-H)，1.91(ddd，1H，7α-H)，2.12(dd，1H，7β-H)，2.83(q，1H，14-H)，4.02(dd，1H，1-H)，4.63(d，1H，2-H)，4.90(d，1H，1-OH)，5.00(d，1H，10-H)，5.29(d，1H，6-H)，6.06(s，1H，12-H)，6.47(s，1H，3-OH)，7.46(d，1H，10-OH)
The mass spectrum (MS) of 10-O-(dimethyl amido ethyl) Ginkgolide B (after being structural modification) and hydrogen spectrum (1H-NMR) atlas analysis
MS:495 (molecular ion peak, 2.49)
1H-NMR(DMSO-d6，400MHz)：1.03(s，9H，t-Bu)，1.08(d，3H，14-Me)，1.74(dd，1H，8-H)，1.85(ddd，1H，7α-H)，2.14(dd，1H，7β-H)，2.18(s，6H，N(CH3)2)，2.29，2.62，3.56，4.38(d×2，t×2，1H×4，NCH2CH2O)，2.82(q，1H，14-H)，4.08(d，1H，1-H)，4.55(d，1H，2-H)，5.14(s，1H，10-H)，5.31(d，1H，6-H)，6.14(s，1H，12-H)，6.40(s，1H，3-OH)，7.22(s，1H，1-OH)
Analyze explanation:
A. mass spectral molecular ion peak and total hydrogen number as seen in the original molecule structure, introduced a part dimethyl amido ethyl group, replaced a hydrogen atom in the original molecule structure.
B.1H-NMR in the spectrum, the peak type of 10-H is by the doublet of substrate, becomes unimodally in product, illustrates that above group becomes ether with 10-position hydroxyl.
C.1-the hydrogen of position on the hydroxyl with introduce the possibility that can there be hydrogen bond in nitrogen-atoms on the group, so chemical shift is that 7.22 unimodal home to return to is a 1-position hydroxyl hydrogen.
(2) compound water soluble before and after the structural modification relatively
Compound water soluble before and after the structural modification is simply contrasted, and the sample of getting 15mg equally adds water 1ml, observes the dissolving situation.
| Compound | Ginkgolide B | 10-O-(dimethyl amido ethyl) Ginkgolide B | 10-O-(dimethyl amido ethyl) Ginkgolide B phosphoric acid salt | 10-O-(dimethyl amido ethyl) Ginkgolide B aspartate |
| Solvability | Insoluble | Not molten entirely | All dissolvings | All dissolvings |
Bilobalide B derivates and corresponding salt is water-soluble can change the water-fast proterties of former Ginkgolide B is described by behind the structural modification.
(3) platelet aggregation inhibitory activity compares before and after the structural modification
The platelet aggregation reaction is closely related with pathogenesis such as thrombus in vivo formation, atherosclerosiss.This class disease is current harm humans health, causes one of the highest chief culprit of mortality ratio.And control thrombotic disease medicine, comprise 1. antithrombotics 2. antiplatelet drug 3. the pharmacological action of thrombolytic agent etc. all react relevant with anticoagulant.
Platelet aggregation test system adopts turbidimetry, observes the effect of medicine to ADP (or zymoplasm, arachidonic acid, collagen) inductive rat platelet aggregation reaction, is index to suppress assembling percentage, estimates the antiplatelet aggregative activity of medicine.Model name: platelet aggregation assay method; Laboratory animal: SD rat; Test system: external.
| Compound | Ginkgolide A | Ginkgolide B | 10-O-(dimethyl amido ethyl) Ginkgolide B | 10-O-(dimethyl amido ethyl) Ginkgolide B hydrochloride |
| Inhibiting rate % | 46 | 71 | 80 | 84 |
Pass judgment on:＜30% is invalid
30-55% is weak imitates
The 55-70% produce effects
＞70% is potent
Ginkgolide B is described by the product behind the structural modification, changes water-soluble after, pharmaceutical activity is increase greatly thereupon also.
Description of drawings
Fig. 1 a, Fig. 1 b are the H spectrograms of Ginkgolide B.
Fig. 2 a, Fig. 2 b are the mass spectrums of Ginkgolide B.
Fig. 3 a, Fig. 3 b are the H spectrograms of 10-O-(dimethyl amido ethyl) Ginkgolide B.
Fig. 4 a, Fig. 4 b are the mass spectrums of 10-O-(dimethyl amido ethyl) Ginkgolide B.
Embodiment
The present invention is by the structural modification to Ginkgolide B, obtains the constant nitrogen containing derivative of the new precursor structure of a class, is made into corresponding organic acid or inorganic acid salt, can improve water-solublely, overcomes defectives such as the water-fast unfavorable factor of Ginkgolide B.The present invention can be dissolved in the 600mg Ginkgolide B 40mL N in the preparation, in the dinethylformamide, and moles of halogenated nitrogenous compound and 10 times of molar weight salt of wormwood such as adding successively, reflux 2 hours is reacted complete substantially.Stop heating, cooling is filtered, filter cake washing with acetone several, and merging filtrate, concentrating under reduced pressure gets faint yellow solid, this solid column chromatography, ethyl acetate/petroleum ether (1: 1) wash-out gets target compound, yield 30-40%.
A kind of medical compounds of anti-platelet activating factor is characterized in that this medical compounds is to be connected with nitrogen-containing group on 10 hydroxyls of Ginkgolide B, and its structural formula is as follows:
Wherein, X is the connection skeleton that contains 1-8 carbon atom, R1 and R2 are that H or carbon number are the alkyl of 1-8, water-soluble for further having improved, improve bioavailability, heighten the effect of a treatment, present embodiment can be with the above-mentioned Ginkgolide B salify that is modified with nitrogen-containing group, that is: medical compounds is the organic acid salt that is connected with the Ginkgolide B of nitrogen-containing group on 10 hydroxyls, and this organic acid salt is citrate or acetylsalicylate; The said medicine compound also can be the inorganic acid salt that is connected with the Ginkgolide B of nitrogen-containing group on 10 hydroxyls, and this inorganic acid salt is vitriol or hydrochloride.The present invention can make various pharmaceutical preparations according to clinical needs, oral preparations such as tablet, capsule, particle, soft capsule, oral liquid etc., injection such as injection liquid, powder pin, transfusion etc.
Preparation technology's flow process of embodiment 2,10-O-(dimethyl amido ethyl) Ginkgolide B and hydrochloride thereof
Look into newly through Science and Technology of Shanghai Cha Xin referral centre of the Chinese Academy of Sciences, report claims: in the document scope of being retrieved with in the time limit, do not see with this compound 10-O-(dimethyl amido ethyl) Ginkgolide B identical in structure material and report, prove that this compound has novelty, the topology discovery of this compound.
Embodiment 12,10-O-(dimethyl amido ethyl) Ginkgolide B citrate and preparation technology's flow process
Claims (5)
1, a kind of medical compounds of anti-platelet activating factor is characterized in that this medical compounds is to be connected with nitrogen-containing group on 10 hydroxyls of Ginkgolide B, and its structural formula is as follows:
Wherein, X is the connection skeleton that contains 1-8 carbon atom, and R1 and R2 are that H or carbon number are the alkyl of 1-8.
2, the medical compounds of anti-platelet activating factor according to claim 1 is characterized in that medical compounds is the organic acid salt that is connected with the Ginkgolide B of nitrogen-containing group on 10 hydroxyls.
3, the medical compounds of anti-platelet activating factor according to claim 2 is characterized in that this organic acid salt is citrate or acetylsalicylate.
4, the medical compounds of anti-platelet activating factor according to claim 1 is characterized in that medical compounds is the inorganic acid salt that is connected with the Ginkgolide B of nitrogen-containing group on 10 hydroxyls.
5, the medical compounds of anti-platelet activating factor according to claim 4 is characterized in that this inorganic acid salt is vitriol or hydrochloride.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510041060 CN1900082A (en) | 2005-07-18 | 2005-07-18 | Medicinal compound for resisting platelet activating factor |
| PCT/CN2005/002390 WO2006116905A1 (en) | 2005-04-29 | 2005-12-30 | Medicinal compounds as antagonists of the platelet- activating factor receptor |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200510041060 CN1900082A (en) | 2005-07-18 | 2005-07-18 | Medicinal compound for resisting platelet activating factor |
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| CN1900082A true CN1900082A (en) | 2007-01-24 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200510041060 Pending CN1900082A (en) | 2005-04-29 | 2005-07-18 | Medicinal compound for resisting platelet activating factor |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101880286A (en) * | 2009-05-08 | 2010-11-10 | 北京美倍他药物研究有限公司 | Water-soluble amino-acid ester derivative of ginkgolide B |
| CN101675925B (en) * | 2008-09-17 | 2012-05-23 | 秦引林 | Dimethylaminoethyl ginkgolide B mesylate injection and preparation method thereof |
| CN108084204A (en) * | 2017-11-24 | 2018-05-29 | 江苏康缘药业股份有限公司 | Ginkgolide derivatives and its application |
-
2005
- 2005-07-18 CN CN 200510041060 patent/CN1900082A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101675925B (en) * | 2008-09-17 | 2012-05-23 | 秦引林 | Dimethylaminoethyl ginkgolide B mesylate injection and preparation method thereof |
| CN101880286A (en) * | 2009-05-08 | 2010-11-10 | 北京美倍他药物研究有限公司 | Water-soluble amino-acid ester derivative of ginkgolide B |
| CN108084204A (en) * | 2017-11-24 | 2018-05-29 | 江苏康缘药业股份有限公司 | Ginkgolide derivatives and its application |
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