CN106543072A - Mo Fanselin compounds - Google Patents
Mo Fanselin compounds Download PDFInfo
- Publication number
- CN106543072A CN106543072A CN201510601260.9A CN201510601260A CN106543072A CN 106543072 A CN106543072 A CN 106543072A CN 201510601260 A CN201510601260 A CN 201510601260A CN 106543072 A CN106543072 A CN 106543072A
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- CN
- China
- Prior art keywords
- fanselin
- crystal
- filtered
- incubated
- preparation
- 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.)
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4468—Non condensed piperidines, e.g. piperocaine having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members 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
- C07D211/56—Nitrogen atoms
- C07D211/58—Nitrogen atoms attached in position 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention belongs to pharmaceutical technology field, and in particular to the crystal of a kind of Mo Fanselin, the crystal purity of the Mo Fanselin that the present invention is obtained is high, and maximum contaminant is less than 1 ‰, and its preparation method adds 6-7 times for a Mo Fanselin（Weight or measurement (WM) ratio）Alcohol-water=6：0.01-0.05 times of acetone in 4 mixed liquor, is added, 65 DEG C-68 DEG C are heated to, insulation 40 minutes, filtered while hot naturally cools to room temperature, 3-4 hours are incubated again, crystallization is separated out, is filtered, drying obtains above-mentioned Mo Fanselin crystal of high-purity, this preparation method is reproducible, pilot-scale is amplified to, content and crystal formation can reappear very well, beneficial to industrialized production.
Description
Technical field
The invention belongs to pharmaceutical technology field, and in particular to crystal of a Mo Fanselin and preparation method thereof.
Background technology
Mo Fanselin（Common name：Pimavanserin, trade name：Nuplazid）Be the patent drugss of drugmaker of Acadia independent research, for treating parkinson mental symptom, be the similar thing of non-dopamine neurotransmitter, the effect of dopamine can not be affected so that selectivity blocks five hydroxytryptamine 2A receptors.Mo Fanselin（Pimavanserin, Nuplazid）Breakthrough Sex therapy certification is authorized in 3 food and medicine Surveillance Authority of the Huo U.S. (FDA) of September in 2014.Breaking through Sex therapy certification is created by FDA, it is intended to is accelerated exploitation and is examined the new drug of the disease for treating serious or life-threatening.
The structural formula of Mo Fanselin is as follows：
Mo Fanselin structural formulas
Mo Fanselin has various preparation methoies, and because its process for purification is different, purity is also different.In research process, the method for repeating document, the Mo Fanselin that the present invention is obtained have the advantage that：Purity is high, and maximum contaminant is less than 1 ‰；Good stability to light.
The content of the invention
One object of the present invention, discloses the crystal of a kind of Mo Fanselin.
Another object of the present invention, discloses a preparation method for Mo Fanselin crystal.
A further object of the present invention, discloses comprising a pharmaceutical composition for Mo Fanselin crystal.
Present invention is specifically described in conjunction with the purpose of the present invention.
The invention provides one kind Mo Fanselin（Shown in formula I）Crystal,
The Mo Fanselin crystal, is determined using D/Max-2500.9161 types x-ray diffractometer, condition determination：Cu Ka targets, tube voltage 40KV, tube current 100mA.X-ray powder diffraction characteristic absorption peak（2θ）It is as follows with D values,
In the present invention, the measure of 2 θ values uses light source, and precision is ± 0.2 °, therefore represents above-mentioned taken value and allowed certain rational range of error, and its range of error is ± 0.2 °.
Another object of the present invention, discloses a preparation method for Mo Fanselin crystal.
Document report, a Mo Fanselin have various preparation methoies, and because its process for purification is different, purity is also different.In research process, repeat the Mo Fanselin crystallization that the method for document is obtained, to light less stable.The present inventor is by substantial amounts of experiment, explore the relation of refining solvent and the Mo Fanselin crystal for obtaining, by by a Mo Fanselin in the ethanol-water solution containing acetone heating for dissolving, naturally cool to room temperature, then be incubated the Mo Fanselin crystal that a period of time obtains the present invention.
The preparation method of a Mo Fanselin crystal of the present invention, it is characterised in that comprise the following steps：Mo Fanselin adds 6-7 times（Weight or measurement (WM) ratio）Alcohol-water=6：0.01-0.05 times of acetone in 4 mixed liquor, is added, 65 DEG C-68 DEG C are heated to, 40 minutes are incubated, filtered while hot naturally cools to room temperature, then is incubated 3-4 hours, separate out crystallization, filtered, drying obtains above-mentioned Mo Fanselin crystal of high-purity.
The method is reproducible, is amplified to pilot-scale, and content and crystal formation can reappear very well.
Used Mo Fanselin, according to the method synthesis that document is provided, the chemical constitution Jing nuclear magnetic resoance spectrum of a Mo Fanselin of synthesis, elementary analysiss prove that chemical constitution is correct.
A further object of the present invention, there is provided the compositionss comprising a Mo Fanselin crystal and a Mo Fanselin of one or more pharmaceutically acceptable carrier composition.
The pharmaceutical composition of the present invention prepares as follows：Using standard and conventional technique, crystal of the present invention is combined with acceptable liquid-carrier on galenic pharmacy, and be allowed to arbitrarily be combined with acceptable adjuvant and excipient on galenic pharmacy and be prepared into microgranule or microsphere.Said composition is used to prepare oral agents.
The active ingredient contained in pharmaceutical composition and unit dosage form（Crystal of the present invention）Amount can be specifically applied according to the situation of the state of an illness of patient, diagnosis, the amount or concentration of compound used are adjusted in a wider scope, and the amount scope of reactive compound is the 1%～30% of compositionss（Weight）.
Stability test
Inventor is studied to the chemical stability of crystal formation of the present invention, strong illumination（4500Lx±500lx）, inspection target is outward appearance, content and relevant material.
As a result：From 0-10 days under intense light conditions, outward appearance, relevant material, content do not change, and illustrate that chemical stability is good, are adapted to the manufacture and long term storage of pharmaceutical preparation.
Under the conditions of same light is shone, the stability of the Mo Fanselin crystal that document is obtained：
Specific embodiment：
With reference to embodiment, the present invention is described further, makes professional and technical personnel in the field be better understood from the present invention.Embodiment is only explanatory, is in no way intended to it and limits the scope of the present invention by any way.
Embodiment
1
Equipped with stirring, thermometer, in the 1000ml reaction bulbs of condenser, the alcohol-water of addition 100 grams of Mo Fanselin and 650ml -=6：4 mixed liquor, adds 3ml acetone, starts stirring, is heated to 65 DEG C -68 DEG C, treats all molten clear, is incubated 40 minutes, filtered while hot.Filtrate naturally cools to room temperature, then is incubated 3-4 hours, separates out crystallization, filters, and drying obtains final product above-mentioned Mo Fanselin crystal of high-purity, and content 100.4%, dissolvent residual detection meet the requirements.
The X-ray diffraction instrument model of the crystallization and condition determination：2500 type diffractometers of Rigaku D/max； CuKa
40Kv 100mA;2 θ sweep limitss：0-50°。
Embodiment 2Capsule prescription containing a Mo Fanselin novel crystal forms：10 grams of Mo Fanselin novel crystal forms, 650 grams of Lactose, 80 grams of polyvinylpolypyrrolidone, 50 grams of PEG-4000,88 grams of hydroxypropyl methyl cellulose distill appropriate amount of water, make 1000.Technique：PEG-4000 is crushed jointly with a Mo Fanselin, crosses 80 mesh sieves, and with distilled water soft material, granulation, cold drying after mixing with other materials, granulate fills capsule.
Claims (5)
1. formula（Ⅰ）A Mo Fanselin compound,
（Ⅰ）
It is characterized in that：In being determined as characteristic X-ray powder with CuKa rays, its collection of illustrative plates has the following 2 θ angles of diffraction and relative intensity, wherein relative intensity (I/I0) as follows not less than 10,
The error of the 2 θ angles of diffraction is 0.2.
2. the preparation method of a Mo Fanselin crystal described in claim 1, by by a Mo Fanselin in the ethanol-water solution containing acetone heating for dissolving, naturally cool to room temperature, then be incubated a period of time and obtain.
3. according to the method for claim 2, it is characterised in that comprise the following steps：Mo Fanselin add 6-7 times of alcohol-water -=6：0.01-0.05 times of acetone in 4 mixed liquor, is added, 65 DEG C-68 DEG C are heated to, 40 minutes are incubated, filtered while hot naturally cools to room temperature, then is incubated 3-4 hours, separate out crystallization, filtered, drying is obtained.
4. a kind of compositionss containing described in claim 1 Mo Fanselin crystal and one or more pharmaceutically acceptable carrier composition.
5. 4 required by right described in compositionss, it is characterised in that said composition be used for prepare oral solid formulation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510601260.9A CN106543072A (en) | 2015-09-21 | 2015-09-21 | Mo Fanselin compounds |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510601260.9A CN106543072A (en) | 2015-09-21 | 2015-09-21 | Mo Fanselin compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN106543072A true CN106543072A (en) | 2017-03-29 |
Family
ID=58362388
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510601260.9A Pending CN106543072A (en) | 2015-09-21 | 2015-09-21 | Mo Fanselin compounds |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106543072A (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10449185B2 (en) | 2017-08-30 | 2019-10-22 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10517860B2 (en) | 2016-03-25 | 2019-12-31 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US10981870B2 (en) | 2015-07-20 | 2021-04-20 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form |
| US11135211B2 (en) | 2017-04-28 | 2021-10-05 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| US11464768B2 (en) | 2016-12-20 | 2022-10-11 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis |
-
2015
- 2015-09-21 CN CN201510601260.9A patent/CN106543072A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10981870B2 (en) | 2015-07-20 | 2021-04-20 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form |
| US10981871B2 (en) | 2015-07-20 | 2021-04-20 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C |
| US11840515B2 (en) | 2015-07-20 | 2023-12-12 | Acadia Pharmaceuticals Inc. | Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c |
| US10517860B2 (en) | 2016-03-25 | 2019-12-31 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US10953000B2 (en) | 2016-03-25 | 2021-03-23 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11191757B2 (en) | 2016-03-25 | 2021-12-07 | Acadia Pharmaceuticals Inc. | Combination of pimavanserin and cytochrome P450 modulators |
| US11464768B2 (en) | 2016-12-20 | 2022-10-11 | Acadia Pharmaceuticals Inc. | Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis |
| US11135211B2 (en) | 2017-04-28 | 2021-10-05 | Acadia Pharmaceuticals Inc. | Pimavanserin for treating impulse control disorder |
| US10449185B2 (en) | 2017-08-30 | 2019-10-22 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10646480B2 (en) | 2017-08-30 | 2020-05-12 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US10849891B2 (en) | 2017-08-30 | 2020-12-01 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
| US11452721B2 (en) | 2017-08-30 | 2022-09-27 | Acadia Pharmaceuticals Inc. | Formulations of pimavanserin |
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| PB01 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20170329 |
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| WD01 | Invention patent application deemed withdrawn after publication |