CN1749257A - Platelet activation factor resisting compound - Google Patents
Platelet activation factor resisting compound Download PDFInfo
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- CN1749257A CN1749257A CN 200510085235 CN200510085235A CN1749257A CN 1749257 A CN1749257 A CN 1749257A CN 200510085235 CN200510085235 CN 200510085235 CN 200510085235 A CN200510085235 A CN 200510085235A CN 1749257 A CN1749257 A CN 1749257A
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- platelet activation
- activation factor
- ginkgolide
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Abstract
The present invention discloses a kind of platelet activation factor resisting compounds in the shown structure and their salts of organic acid or inorganic acid. Structurally, the compounds have various nitrogen-containing radicals connected to the hydroxyl radical in the tenth place of bilobalide B. The compounds of the present invention have the advantages of high water solubility, high bioavailability, full playing of the medicine effect, etc.
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 platelet activation factor resisting compound of drug effect.
The present invention adopts following technical scheme:
Platelet activation factor resisting compound is a compounds and the corresponding organic acid or the inorganic acid salt of feature with structural formula shown in figure below, and its constitutional features is to be connected with various nitrogen-containing groups on 10 hydroxyls of Ginkgolide B,
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-MR(DMSO-d6，400MHz)：1.01(s，9H，t-Bu)，1.09(d，3H，14-Me)，1.70(dd，1H，g-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 hydrochloride | 10-O-(dimethyl amido ethyl) Ginkgolide B vitriol |
| Solvability | Insoluble | Dissolving | All dissolvings | All dissolvings |
Bilobalide B derivates and the corresponding water-soluble proterties that can change former Ginkgolide B poorly water-soluble of salt thereof are 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 is the H spectrogram of Ginkgolide B.
Fig. 2 is the mass spectrum of Ginkgolide B.
Fig. 3 is the H spectrogram of 10-O-(dimethyl amido ethyl) Ginkgolide B.
Fig. 4 is the mass spectrum 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%.
Platelet activation factor resisting compound 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 3 10-O-(to the dimethylin phenmethyl) Ginkgolide B and preparation technology's flow process
Embodiment 4 10-O-(a dimethylin phenmethyl) Ginkgolide B and preparation technology's flow process
Embodiment 5 10-O-(adjacent dimethylin phenmethyl) Ginkgolide B and preparation technology's flow process
Embodiment 6 10-O-(to the dimethylin phenmethyl) Ginkgolide B and preparation technology's flow process
Embodiment 7 10-O-(1-pyrazinyl ethyl) Ginkgolide B and preparation technology's flow process
Embodiment 9,10-O-(methylamino ethyl) Ginkgolide B and preparation technology's flow process
Embodiment 11,10-O-(dimethyl amido ethyl) Ginkgolide B acetylsalicylate and preparation technology's flow process
Embodiment 12,10-O-(dimethyl amido ethyl) Ginkgolide B citrate and preparation technology's flow process
Claims (7)
1, platelet activation factor resisting compound is a compounds and the corresponding organic acid or the inorganic acid salt of feature with structural formula shown in figure below, and its constitutional features is to be connected with various nitrogen-containing groups on 10 hydroxyls of Ginkgolide B,
2, platelet activation factor resisting compound according to claim 1, the X that it is characterized in that connecting 10 Sauerstoffatoms and nitrogen-atoms is the various skeletons that are connected that contain 1-8 carbon atom, R
1And R
2For H or carbon number are the various alkyl of 1-8.
3, platelet activation factor resisting compound according to claim 1, it is characterized in that can with all kinds of organic acids or mineral acid salify.
4, platelet activation factor resisting compound according to claim 3 is characterized in that organic acid salt is citrate or acetylsalicylate.
5, platelet activation factor resisting compound according to claim 3 is characterized in that inorganic acid salt is vitriol or hydrochloride.
6, platelet activation factor resisting compound according to claim 1, its feature mainly are to have platelet activation factor (PAF) antagonistic action, can be used for disease prevention and the clinical treatments relevant with the PAF factor such as ishemic stroke, inflammation, asthma.
7, platelet activation factor resisting compound according to claim 1 and 2 is characterized in that can be made into the oral preparations or the injection of clinical needs.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNB2005100852356A CN100358899C (en) | 2005-04-29 | 2005-07-22 | Platelet activation factor resisting compound |
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| CN200510039158 | 2005-04-29 | ||
| CN200510039158.0 | 2005-04-29 | ||
| CNB2005100852356A CN100358899C (en) | 2005-04-29 | 2005-07-22 | Platelet activation factor resisting compound |
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| CN1749257A true CN1749257A (en) | 2006-03-22 |
| CN100358899C CN100358899C (en) | 2008-01-02 |
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Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100445288C (en) * | 2006-04-26 | 2008-12-24 | 秦引林 | Bilobalide B derivatives and pharmaceutical application thereof |
| CN101323621B (en) * | 2007-06-11 | 2012-04-25 | 秦引林 | Synthetic technological process of bilobalide B derivates |
| CN101675925B (en) * | 2008-09-17 | 2012-05-23 | 秦引林 | Dimethylaminoethyl ginkgolide B mesylate injection and preparation method thereof |
| CN102068426B (en) * | 2009-11-24 | 2013-01-02 | 秦引林 | New application of Ginkgolide B derivative in medicament preparation |
| 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 |
| CN108117561A (en) * | 2016-11-30 | 2018-06-05 | 江苏柯菲平医药股份有限公司 | A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process |
| CN108175767A (en) * | 2017-11-24 | 2018-06-19 | 江苏康缘药业股份有限公司 | A kind of Chinese medicine composition is in the purposes of soft tissue injury |
| CN108379257A (en) * | 2017-02-03 | 2018-08-10 | 江苏柯菲平医药股份有限公司 | Dimethylaminoethyl ginkgolide B mesylate is preparing the application in preventing or treating asthmatic medicament |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR0136986B1 (en) * | 1993-12-31 | 1998-04-25 | 김준웅 | New ginkoride derivatives and a process preparing them |
-
2005
- 2005-07-22 CN CNB2005100852356A patent/CN100358899C/en active Active
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100445288C (en) * | 2006-04-26 | 2008-12-24 | 秦引林 | Bilobalide B derivatives and pharmaceutical application thereof |
| CN101323621B (en) * | 2007-06-11 | 2012-04-25 | 秦引林 | Synthetic technological process of bilobalide B derivates |
| CN101675925B (en) * | 2008-09-17 | 2012-05-23 | 秦引林 | Dimethylaminoethyl ginkgolide B mesylate injection and preparation method thereof |
| CN102068426B (en) * | 2009-11-24 | 2013-01-02 | 秦引林 | New application of Ginkgolide B derivative in medicament preparation |
| CN108117561A (en) * | 2016-11-30 | 2018-06-05 | 江苏柯菲平医药股份有限公司 | A kind of dimethylaminoethyl ginkgolide B mesylate metabolite and synthesis and purification process |
| CN108379257A (en) * | 2017-02-03 | 2018-08-10 | 江苏柯菲平医药股份有限公司 | Dimethylaminoethyl ginkgolide B mesylate is preparing the application in preventing or treating asthmatic medicament |
| 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 |
| CN108175767A (en) * | 2017-11-24 | 2018-06-19 | 江苏康缘药业股份有限公司 | A kind of Chinese medicine composition is in the purposes of soft tissue injury |
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| Publication number | Publication date |
|---|---|
| CN100358899C (en) | 2008-01-02 |
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Assignee: JIANGSU CAREFREE PHARMACEUTICAL CO., LTD. Assignor: Qin Yinlin Contract fulfillment period: 2008.10.10 to 2018.11.6 contract change Contract record no.: 2008320000982 Denomination of invention: Platelet activation factor resisting compound Granted publication date: 20080102 License type: Exclusive license Record date: 20081015 |
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Address after: 210016 Jiangsu Province, Nanjing city Zhongshan Road No. 323, 2 (former banshanyuan No. 12 Building 1 layer 1) Patentee after: JIANGSU CAREPHAR PHARMACEUTICAL CO., LTD. Address before: 210016 Jiangsu Province, Nanjing city Zhongshan Road No. 323, 2 (former banshanyuan No. 12 Building 1 layer 1) Patentee before: JIANGSU CAREFREE PHARMACEUTICAL CO., LTD. |
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