CN104649962A - Perampanel sesquihydrate compound - Google Patents
Perampanel sesquihydrate compound Download PDFInfo
- Publication number
- CN104649962A CN104649962A CN201310600780.9A CN201310600780A CN104649962A CN 104649962 A CN104649962 A CN 104649962A CN 201310600780 A CN201310600780 A CN 201310600780A CN 104649962 A CN104649962 A CN 104649962A
- Authority
- CN
- China
- Prior art keywords
- lun panai
- pyrrole lun
- semihydrate
- panai
- pyrrole
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- HQKXIQCDDQAAMJ-UHFFFAOYSA-N Nc1ccccc1C1=CC(c2ncccc2)=CN(C2C=CC=CC2)C1=O Chemical compound Nc1ccccc1C1=CC(c2ncccc2)=CN(C2C=CC=CC2)C1=O HQKXIQCDDQAAMJ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/63—One oxygen atom
- C07D213/64—One oxygen atom attached in position 2 or 6
Abstract
The invention belongs to the technical field of medicines and particularly relates to a perampanel sesquihydrate and a preparation method thereof. The perampanel sesquihydrate contains one and a half crystal water. The perampanel sesquihydrate has the advantages that the purity is high; the stability is good, and the moisture absorption and the weight increment are not obvious even at a high humidity condition; by virtue of the perampanel sesquihydrate, the inhibiting effect to the activity of AMPA receptor glutamic acid is increased by about 20%. The invention further relates to application of a composition of the perampanel sesquihydrate in the treatment of neuropsychiatric diseases.
Description
Technical field
The invention belongs to medical art, be specifically related to pyrrole Lun Panai times semihydrate and preparation method thereof, the invention still further relates to the application of the composition treatment psychoneural field disease using this hydrate.
Background technology
Epilepsy is a kind of chronic syndrome of the recurrent exerbation caused by neurone paradoxical discharge, and be common disease, global morbidity is about 5 ‰ ~ 10 ‰, about has 20 ~ 70 new cases every year in every ten thousand people.Except some patients to be treated for the cause of disease by modes such as operations, most of needs of patients long-term taking antiepileptic drug (Antiepileptic Drugs, AEDs).Although the AEDs ratifying in the world at present to go on the market is more than 20 kinds, after the mono-medicine of existing AEDs or combination therapy, still have an appointment 1/3 patient present drug resistance, be intractable epilepsy, therefore drug research and development personnel are being devoted to the new antiepileptic drug of exploitation always.In October, 2012, U.S. FDA have approved a kind of new oral antiepileptic drug pyrrole Lun Panai (perampanel).
Pyrrole Lun Panai defends material (Eisai) company by Japan and researches and develops listing, English perampanel by name, and commodity are called Fycompa, and the indication of FDA this time approval is the assisting therapy of >=12 years old patient's epilepsy partial seizures.Pyrrole Lun Panai is the different azoles propionic acid of a kind of alpha-amino group-3-hydroxyl-5 methyl-4-(α-amino-3-hydroxy-5-methyl-4-isoxa-zolep-propionate acid, AMPA) receptor antagonist, it reduces neurone be overexcited by suppressing postsynaptic AMPA receptors glutamate activity.This is the first antiepileptic drug with this mechanism of action of FDA approval.The formulation of listing is tablet, has 2mg, 4mg, 6mg, 8mg, 10mg, and the plurality of specifications such as 12mg.
L-glutamic acid is the main excitatory transmitter of central nervous system, and " glutamate receptor is divided into two classes: a class is ionotropic receptor, comprising: N-methyl-D-aspartate to relate to a series of overwrought nervous system disorders
Acceptor (NMDAR), kainate receptor (KAR) and alpha-amino group-3 hydroxyl-5 methyl-4 isoxzzole acceptor (AMPAR), they and ionic channel coupling, form receptor channel complex, mediate fast signal transmission; Another kind ofly belong to metabotropic receptor (mGluRs), G-albumen coupling in it and film, the signal transduction system consisted of second messenger in G-albumen effect enzyme, brain etc. after these acceptors are activated works, and produces physiological response more slowly.
Pyrrole Lun Panai is noncompetitive AMPA type glutamate receptor antagonistic.By suppressing glutamate activity, reducing neuronic being overexcited and working.For assisting therapy epilepsy partial seizure, accompany or do not accompany the generalized seizures of secondary.
Pyrrole Lun Panai is a kind of novel antiepileptic drug, and share the seizure frequency that significantly can reduce the insane carbuncle patient of partial seizure with other antiepileptic drugs, untoward reaction patient can tolerate, and can be used as the adjuvant drug for the treatment of insane carbuncle.My company researchist is through experiment repeatedly, filter out optimum pharmaceutical adjunct, the basis that cost reduces also assures that quality, not only there is the curative effect suitable with import drugs, reasonable price simultaneously, especially be applicable to the patient needing long-term prescription, while meeting the need of market, also benefit extensive patients.
Pyrrole Lun Panai has great advantage in validity and security, but in actual production process, applicant finds, there is purification difficult, foreign matter content is higher, crystal formation is by patent protection and have the problems such as certain moisture absorption weightening finish in pyrrole Lun Panai preparation technology.
The pyrrole Lun Panai times hemi-hydrate crystalline that the present inventor obtains on the basis of great many of experiments, the advantage had: purity is high, maximum contaminant is less than 1 ‰; Good stability, even if moisture absorption weightening finish is also not obvious under high humidity conditions.
Allow people surprisingly, identical prescription and technique, wait pyrrole Lun Panai times of semihydrate tablet and the pyrrole Lun Panai tablet of dosage (pyrrole Lun Panai times semihydrate is converted into pyrrole Lun Panai), better to effect display effect in experimentation on animals for the treatment of relative disease.
Summary of the invention
One object of the present invention, discloses a kind of pyrrole Lun Panai times semihydrate.
Another object of the present invention, discloses the preparation method of pyrrole Lun Panai times semihydrate.
Another object of the present invention, discloses the pharmaceutical composition comprising pyrrole Lun Panai times semihydrate.
The invention also discloses pyrrole Lun Panai times semihydrate and prepare treatment use.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The invention provides a kind of pyrrole Lun Panai times semihydrate (shown in formula I),
(formula I)
Thermogravimetry a kind ofly measures in the chemical process of moisture in material, and, method the most accurately the most single-minded to water, has been listed in the standard method of moisture determination in many materials, especially organic compound, reliable results.Through multiple batches of mensuration, the moisture that described invention compound contains is between 7.90%-8.10% (weight percent).In pyrrole Lun Panai times semihydrate, the theoretical content of water is 8.00%, can assert that invention compound contains a hypocrystalline water.
Wherein the measurement result of 6 batches is as follows:
This pyrrole Lun Panai times of hemi-hydrate crystalline, adopts D/Max-2500.9161 type x-ray diffractometer to measure, condition determination: Cu Ka target, tube voltage 40KV, tube current 100mA.X-ray powder diffraction charateristic avsorption band (2 θ), D value and relative intensity are as follows,
In the present invention, the mensuration of 2 θ values uses light source, and precision is ± 0.2 °, and therefore represent above-mentioned got value and allowed certain reasonably limit of error, its limit of error is ± 0.2 °.
Fusing point test: measure fusing point according to Pharmacopoeia of People's Republic of China (2010 editions, two) annex VI C first method, the fusing point recorded is 176 DEG C-182 DEG C.
Another object of the present invention, discloses the preparation method of pyrrole Lun Panai times hemi-hydrate crystalline, by being dissolved at n-hexyl alcohol-furans-heated in water solution by pyrrole Lun Panai, naturally cools to room temperature, then is incubated for some time and obtains.
Specifically comprise the following steps: that pyrrole Lun Panai semihydrate adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.1-4.8:0.4-0.8:4-9, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
A large amount of experiments proves: the adding of furans, the proportioning of mixed solution, standing temperature and time are most important to obtaining pyrrole Lun Panai times hemi-hydrate crystalline of the present invention.
Another object of the present invention, provides the composition comprising the pyrrole Lun Panai times semihydrate that pyrrole Lun Panai times hemi-hydrate crystalline and one or more pharmaceutically acceptable carriers form.
Pharmaceutical composition of the present invention is prepared as follows: use standard and conventional technology; the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics are combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations.
Allow people surprisingly, identical prescription and technique, in pyrrole Lun Panai times of semihydrate tablet and the pyrrole Lun Panai tablet of dosage (pyrrole Lun Panai times semihydrate is converted into pyrrole Lun Panai), to the restraining effect of postsynaptic AMPA receptor glutamate activity, the former exceeds the latter about 20%.
The amount of the active ingredient (the compounds of this invention) contained in pharmaceutical composition and unit dosage form specifically can be applied according to the situation of the state of an illness of patient, diagnosis, the amount of compound used or concentration regulate in a wider scope, and the weight range of active compound is 1% ~ 30%(weight of composition).
stability test
At 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), the mensuration of moisture in hydrate crystal of the present invention:
Result: at 40 DEG C, under different relative humidity (RH) condition (75%, 92.5%), water tariff collection is constant, and explanation has good stability, and is applicable to manufacture and the standing storage of pharmaceutical preparation.
embodiment:
Below in conjunction with embodiment, the present invention is described further, makes professional and technical personnel in the field better understand the present invention.Embodiment is only indicative, never means that it limits the scope of the invention by any way.
embodiment 1
In the 10L reactor that stirring, thermometer, condenser are housed, add 500 grams of pyrrole Lun Panai and 1070.0ml n-hexyl alcohol, 20.5ml furans, 1080.0ml water, starts stirring, is heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, then leaves standstill insulation 4 hours, crystallization, filter, through indoor seasoning, obtain pyrrole Lun Panai times of semihydrate white crystals 254.6 grams, fusing point is the fusing point recorded is 176-182 DEG C, content 99.76%, single contaminant is less than 0.06%.Measure through thermogravimetry, the moisture containing 8.00% (weight percent).
Use standard and conventional technology, make the compounds of this invention acceptable solid or liquid vehicle on technology of pharmaceutics be combined, and make it at random on technology of pharmaceutics acceptable auxiliary and vehicle be combined and be prepared into particulate or microballoon.Said composition is for the preparation of oral preparations, injection.Only citing is illustrated, and never means that it limits the scope of the invention by any way.
embodiment 2
Tablet containing pyrrole Lun Panai times semihydrate
Prescription: pyrrole Lun Panai times semihydrate 10.7 grams, Microcrystalline Cellulose 12 g, pregelatinized Starch 16g, carboxymethylstach sodium 5 g, lactose 210 grams, 25 grams of PEG-4000, Magnesium Stearate 6 grams, 30 grams of PVP K30s, croscarmellose sodium 33 grams, distilled water is appropriate, makes 10000.
Technique:
The preparation of label: mixed with auxiliary material by main ingredient by determined prescription, granulate, particle air seasoning below 40 DEG C, with the whole grain of l6 mesh sieve, adds Magnesium Stearate and remaining starch, compressing tablet, to obtain final product.
Sealing coat dressing: added by talcum powder in 5% polyvinylpyrrolidone (PVP) anhydrous alcohol solution, stir, is mixed with the suspension of 20% as sealing coat coating liquid.In fluidized-bed, carry out dressing, its processing condition are as follows: spray pressure 0.3 MPa, feed liquor speed 5mL/min, inlet temperature 37 DEG C, temperature out 31 DEG C, dry air flow 200 m
3/ h, sealing coat weightening finish for essence blade heavy 9%.
Claims (6)
1. times semihydrate of pyrrole Lun Panai shown in formula I,
（Ⅰ）
Measure with thermogravimetry, described hydrate contains the moisture of weight percent 7.90%-8.10%;
The crystal of described pyrrole Lun Panai times semihydrate, in measuring as characteristic X-ray powder with CuKa ray, its collection of illustrative plates has following 2 θ diffraction angle, spacing (d value) and relative intensity (I/I
0),
The error of 2 θ diffraction angle is ± 0.2.
2. the preparation method of pyrrole Lun Panai times hemi-hydrate crystalline described in claim 1, by being dissolved at n-hexyl alcohol-furans-heated in water solution by pyrrole Lun Panai, naturally cools to room temperature, then is incubated for some time and obtains.
3. according to the method for claim 2, it is characterized in that comprising the following steps: that pyrrole Lun Panai semihydrate adds in the mixed solution of 7-9 times of (weight or measurement (WM) ratio) n-hexyl alcohol-furans-water=3.1-4.8:0.4-0.8:4-9, be heated to dissolve, filtrate naturally cools to 25 DEG C-30 DEG C, leave standstill insulation 3-5 hour again, crystallization, filter, drying obtains.
4. one kind forms the composition of pyrrole Lun Panai times semihydrate containing pyrrole Lun Panai times hemi-hydrate crystalline according to claim 1 and one or more pharmaceutically acceptable carriers.
5. the composition of pyrrole Lun Panai times semihydrate according to claim 4, is characterized in that said composition is for the preparation of oral preparations.
6. the application of pyrrole Lun Panai times semihydrate described in claim 1 in the medicine manufacturing treatment Neuropsychic diseases.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310600780.9A CN104649962A (en) | 2013-11-25 | 2013-11-25 | Perampanel sesquihydrate compound |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310600780.9A CN104649962A (en) | 2013-11-25 | 2013-11-25 | Perampanel sesquihydrate compound |
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| CN104649962A true CN104649962A (en) | 2015-05-27 |
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| CN201310600780.9A Pending CN104649962A (en) | 2013-11-25 | 2013-11-25 | Perampanel sesquihydrate compound |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110799185A (en) * | 2017-06-29 | 2020-02-14 | 维塔弗洛国际有限公司 | Combinations comprising capric acid for the treatment of epilepsy |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008111590A2 (en) * | 2007-03-05 | 2008-09-18 | Eisai R & D Management Co., Ltd. | Ampa and nmda receptor antagonists for neurodegenerative diseases |
| CN101511186A (en) * | 2005-04-04 | 2009-08-19 | 卫材R&D管理有限公司 | Dihydropyridine compounds and compositions for headaches |
| CN101914057B (en) * | 2004-07-06 | 2012-07-04 | 卫材R&D管理有限公司 | Crystal of 1,2-dihydropyridine compound and method for producing same |
-
2013
- 2013-11-25 CN CN201310600780.9A patent/CN104649962A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101914057B (en) * | 2004-07-06 | 2012-07-04 | 卫材R&D管理有限公司 | Crystal of 1,2-dihydropyridine compound and method for producing same |
| CN101511186A (en) * | 2005-04-04 | 2009-08-19 | 卫材R&D管理有限公司 | Dihydropyridine compounds and compositions for headaches |
| WO2008111590A2 (en) * | 2007-03-05 | 2008-09-18 | Eisai R & D Management Co., Ltd. | Ampa and nmda receptor antagonists for neurodegenerative diseases |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110799185A (en) * | 2017-06-29 | 2020-02-14 | 维塔弗洛国际有限公司 | Combinations comprising capric acid for the treatment of epilepsy |
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Application publication date: 20150527 |