CN105669696B - A kind of prasugrel hydrochloride compound - Google Patents
A kind of prasugrel hydrochloride compound Download PDFInfo
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- CN105669696B CN105669696B CN201410670472.8A CN201410670472A CN105669696B CN 105669696 B CN105669696 B CN 105669696B CN 201410670472 A CN201410670472 A CN 201410670472A CN 105669696 B CN105669696 B CN 105669696B
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- prasugrel
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- prasugrel hydrochloride
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- hydrochloride compound
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Abstract
The invention belongs to pharmaceutical technology fields, and in particular to a kind of prasugrel hydrochloride compound.Prasugrel is the potent thianthrene of a new generation and pyridines antiplatelet drug.It is applied by the observation to healthy volunteer and in stable angina pectoris and acute coronary syndrome intervention operation, it was found that it has faster stronger more longlasting antiplatelet effects than clopidogrel, the incidence of ischemic event can be substantially reduced, but the risk of bleeding increased.It should be noted that identification thrombus high-risk patient and bleeding risk people at highest risk in clinical use.
Description
Technical field
The invention belongs to medical research fields, and in particular to a kind of prasugrel hydrochloride compound.
Background technique
2 months 2009, EU Committee had approved by a mouth of two company's joint development of the first-three republicanism EliLilly
Antiplatelet new drug prasugrel (prasugrel) is taken, receive emergency treatment for pre- tetrandra root and delay percutaneous coronary intervention will be carried out
Atherothrombosis (atherothrombosis) event of the Acute Coronary Syndrome Patients of art.This is pula
Gray gets the Green Light for the first time in the world.
Prasugrel is a new oral effective Thienopyridines drug.As clopidogrel, prasugrel is also
One inactive pro-drug could need to irreversibly press down after cytochrome P 450 Enzyme metabolic conversion to active metabolite
P2Y12 adenosine diphosphate (ADP) receptor on blood platelet processed.The curative effect of prasugrel is better than clopidogrel, this can be with its pharmacokinetics
Improvement is explained: prasugrel has higher pro-drug to active metabolite conversion ratio and higher biological utilisation
Degree reduces main ischemic cardiovascular event hair so working faster and can reduce the Different therapeutical effect between individual to a greater degree
Raw rate.
Prasugrel is the potent thianthrene of a new generation and pyridines antiplatelet drug.By observation to healthy volunteer and
It is applied in stable angina pectoris and acute coronary syndrome intervention operation, it is found that it has than clopidogrel and faster stronger more hold
Long antiplatelet effects can substantially reduce the incidence of ischemic event, but the risk of bleeding increased.In clinical use
In it should be noted that identification thrombus high-risk patient and bleeding risk people at highest risk.
On July 10th, 2009, Food and Drug Adminstration of the US (FDA) publication statement allow antiplatelet drug prasugrel
(prasugrel) for reducing the thrombotic risk in percutaneous coronary intervention (pci).
The DA angiocarpy benefit for thinking the medicine consistent with renal drug Advisory Board has exceeded its risk, and supports to ratify
Prasugrel.Prasugrel hydrochloride is the Thienopyridines that Li Lai company and the first pharmacy Sankyo Co., Ltd research and develop jointly
Medicine.It has passed through the license of European commission.In Europe, the medicine is with trade name Efient sale.
The document of prasugrel related to the present invention discloses: WO2014092589, CN103772408,
CN103012427、WO2013010502、CN102838618、WO2012175031、JP2012180280、WO2012023145、
EP2409689、CZ302833、WO2011124124、WO2011127300、WO2011092720、WO2011057593、
WO2011057592、WO2011052500、WO2011052499、WO2011004392、WO2010137613、
WO2010070677, CN101177430, WO2008000418, WO2007114526 and WO2004098713.But these documents are equal
It is different from substantial contribution and content of the invention.
Summary of the invention
It is an object of the present invention to provide a kind of prasugrel hydrochloride compound, structural formula is as follows:
Above compound is to have X-ray diffraction peak at 7.3,14.7,16.6,18.3,26.0 in 2 θ.
There is above compound the X-ray similar with attached drawing 1 to spread out map.
Above compound has the differential thermal analysis map similar with attached drawing 2.
Above compound can be used for preparing tablet, capsule, granule, injection and freeze-dried powder.
It is another object of the present invention to be to provide a kind of pharmaceutical composition, it includes above compound and pharmaceutically may be used
The auxiliary material of receiving.
Another object of the present invention is to provide above compounds to prepare the application in cardiovascular and cerebrovascular diseases medicament.
Another object of the present invention is to provide aforementioned pharmaceutical compositions to prepare the application in cardiovascular and cerebrovascular diseases medicament.
Above-mentioned compound can often use auxiliary material, injection with pharmaceutically acceptable auxiliary material or carrier, such as oral preparation
Common auxiliary material etc. together, is prepared into oral preparation such as tablet, capsule, granule, the preparations such as injection such as injection, freeze-dried powder
Form.
Detailed description of the invention
Fig. 1 is the x-ray diffractogram of powder of the Prasugrel Hydrochloride form of the embodiment of the present invention 1；
Fig. 2 is the DSC figure of the Prasugrel Hydrochloride form of the embodiment of the present invention 1；
Specific embodiment
The invention will be further described with reference to embodiments, and professional and technical personnel in the field may be better understood
The present invention, but the embodiment range that simultaneously the invention is not limited in any way.
The preparation of embodiment 1- prasugrel hydrochloride
2.2 kilograms of prasugrel free alkalis are added into reaction kettle, 7.7 liters of ethyl acetate is heated with stirring to about 50 DEG C,
Dissolution clarification.Stop heating, be slowly stirred and be cooled to 25 ± 5 DEG C, insulated and stirred 1h, filters.Filter cake ether/ethanol (0.5
Rise/1 liter) mashing, then 2L × 2 time are rinsed with ethyl alcohol, it drains, about 1.6 kilograms of weight in wet base.45 ± 5 DEG C of vacuum drying 12 hours or more,
Obtain about 1.3 kilograms of prasugrel free alkali fine work.
Reaction kettle is separately taken, 1.20 kilograms of above-mentioned gained prasugrel free alkali fine work are added and 12 liters contain 10% nopinene
Acetone (weight ratio) is warming up to about 30 DEG C of stirring and dissolvings.It filters, acetone (weight ratio) of the filter paper with 2L containing 10% nopinene floats
It washes, merging filtrate, pours into clean reaction kettle.40 DEG C are continuously heating to, starts that 200g concentrated hydrochloric acid (about 10 minutes) are added dropwise.It protects
40 DEG C of temperature are stirred 1 hour.Kept for 40 DEG C continue that 150 grams of concentrated hydrochloric acids (about 1 hour) are added dropwise.Drop keeps the temperature crystallization 2 hours after finishing.It takes out
Filter, filter cake Acetone rinse 0.5L × 2 time drain, 35 DEG C vacuum drying 12 hours or more, yield is about 1.2 kilograms.
Powder x-ray diffraction: being radiated using Cu-K, X-ray ray powder diffraction (XRPD) map of prasugrel hydrochloride
See attached drawing 1.
Differential scanning calorimetric analysis: the differential scanning calorimetric thermogram spectrum of prasugrel hydrochloride is shown in attached drawing 2.
The metabolism of experimental example 1- raw material and drug effect
Experimental animal: male Wistar rat 32,200~230g of weight is purchased from Sichuan University.
Experimental method: rat is randomly divided into 4 groups, and every group 8, normal condition is raised, free water, after fasting 12h, every group
It is given prasugrel hydrochloride (embodiment 1) with solid irrigation stomach device respectively, 25,50,100 and 150mgkg of dosage-1.When taking blood
Between point: in administration before and administration after 5,15,30 minutes and 1,2,3,4,6,8,10,12,24,36,48 hour by eyeball after vein
Clump takes 300-500 microlitres of blood, sets in test tube of hepari Ep pipe.
Handle sample method: anticoagulant heparin venous blood is centrifuged 10 minutes in 5000 revs/min of room temperature, takes 100 microlitres of blood plasma,
1300 microlitres of ethyl acetate are added, vortex oscillation 3 minutes, 14000 revs/min were centrifuged 10 minutes, took upper organic phase 1200 micro-
It rises, nitrogen volatilizes.With aqueous 40 microlitres, 40 microlitres of methanol and 20 microlitres of acetonitrile 100 microlitres of dissolution residual substances of mixed liquor, whirlpool
After oscillation 1 minute, 13400 revs/min are centrifuged 1 minute.Take 20 microlitres of progress HPLC detections of supernatant.
After rat oral gavage gives embodiment 1, metabolite (prasugrel active metabolite R, CAS:204204-73- in blood
9) reached peak value at 6-7 hours.Rat platelet aggregation rate ED50 is 0.35mgkg-1。
The study on the stability of experimental example 2- raw material
The present invention is carried out 6 months accelerated tests (40 DEG C ± 2 DEG C, 75% ± 5%RH) of example 1,6 months long-term
It tests (30 DEG C ± 2 DEG C, 65% ± 5%RH).Long term test study on the stability will be continued for embodiment 1, inspection target
It include character, specific rotation, acid value, moisture, related substance, chlorinty and content.
Accelerated test
Packaging: medicinal low density polyethylene (LDPE) bag inner packing adds housing aluminum-plastic composite membrane bag after desiccant
Investigation condition: 40 DEG C ± 2 DEG C, 75% ± 5%RH
- 3 prasugrel hydrochloride accelerated test result of table (40 DEG C ± 2 DEG C, 75% ± 5%RH)
Long term test
- 4 prasugrel hydrochloride long-term test results of table (30 DEG C ± 2 DEG C, 60% ± 5%RH)
Claims (3)
1. a kind of prasugrel hydrochloride crystal, it is characterised in that its structural formula is as follows:
The crystal is to have X-ray diffraction peak, the differential thermal of the crystal at 7.3 °, 14.7 °, 16.6 °, 18.3 °, 26.0 ° in 2 θ
Analysis chart has map as shown in Fig. 2, and the x-ray diffraction pattern of the crystal has map as shown in Fig. 1.
2. a kind of pharmaceutical composition, it is characterised in that containing prasugrel hydrochloride crystal described in claim 1 and pharmaceutically may be used
The auxiliary material of receiving.
3. prasugrel hydrochloride crystal described in claim 1 or claim 2 described pharmaceutical composition are preparing cardiovascular and cerebrovascular
Application in disease medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410670472.8A CN105669696B (en) | 2014-11-21 | 2014-11-21 | A kind of prasugrel hydrochloride compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410670472.8A CN105669696B (en) | 2014-11-21 | 2014-11-21 | A kind of prasugrel hydrochloride compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105669696A CN105669696A (en) | 2016-06-15 |
| CN105669696B true CN105669696B (en) | 2019-03-26 |
Family
ID=56957429
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
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| CN201410670472.8A Active CN105669696B (en) | 2014-11-21 | 2014-11-21 | A kind of prasugrel hydrochloride compound |
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011069473A1 (en) * | 2009-12-09 | 2011-06-16 | Zentiva, K.S. | A method for the preparation of prasugrel hydrochloride in polymorphous form b |
| WO2012023145A2 (en) * | 2010-08-18 | 2012-02-23 | Hetero Research Foundation | Prasugrel hydrochloride crystalline particles |
| CN102838618A (en) * | 2011-06-22 | 2012-12-26 | 广东东阳光药业有限公司 | Method for preparing prasugrel, and prasugrel hydrochloride novel crystal forms |
| CN103694251A (en) * | 2014-01-06 | 2014-04-02 | 南京简成医药科技有限公司 | Novel preparation process of prasugrel hydrochloride |
| WO2014092589A1 (en) * | 2012-12-12 | 2014-06-19 | Instytut Farmaceutyczny | Process for preparation of prasugrel hydrochloride polymorphic form b of pharmaceutical purity |
-
2014
- 2014-11-21 CN CN201410670472.8A patent/CN105669696B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011069473A1 (en) * | 2009-12-09 | 2011-06-16 | Zentiva, K.S. | A method for the preparation of prasugrel hydrochloride in polymorphous form b |
| WO2012023145A2 (en) * | 2010-08-18 | 2012-02-23 | Hetero Research Foundation | Prasugrel hydrochloride crystalline particles |
| CN102838618A (en) * | 2011-06-22 | 2012-12-26 | 广东东阳光药业有限公司 | Method for preparing prasugrel, and prasugrel hydrochloride novel crystal forms |
| WO2014092589A1 (en) * | 2012-12-12 | 2014-06-19 | Instytut Farmaceutyczny | Process for preparation of prasugrel hydrochloride polymorphic form b of pharmaceutical purity |
| CN103694251A (en) * | 2014-01-06 | 2014-04-02 | 南京简成医药科技有限公司 | Novel preparation process of prasugrel hydrochloride |
Non-Patent Citations (4)
| Title |
|---|
| Effects of Solvent on Polymorph Formation and Nucleation of Prasugrel Hydrochloride;Wei Du等;《Cryst. Growth Des.》;20140730;第4519-4525页，Figure 2. Figure 4. |
| 合成盐酸普拉格雷的工艺改进;段妍琴，等;《合成化学》;20121231;第2卷(第1期);第125-127页，1.2节 |
| 盐酸普拉格雷合成工艺的改进;代黎，等;《药学实践杂志》;20130525;第31卷(第3期);第195-197页，1.5节 |
| 盐酸普拉格雷的合成工艺改进;张雅然，等;《中国新药杂志》;20140228;第23卷(第3期);第275-277页，2.3节 |
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|---|---|
| CN105669696A (en) | 2016-06-15 |
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