CN1297448A - Paroxetine ascorbate - Google Patents
Paroxetine ascorbate Download PDFInfo
- Publication number
- CN1297448A CN1297448A CN99805160A CN99805160A CN1297448A CN 1297448 A CN1297448 A CN 1297448A CN 99805160 A CN99805160 A CN 99805160A CN 99805160 A CN99805160 A CN 99805160A CN 1297448 A CN1297448 A CN 1297448A
- Authority
- CN
- China
- Prior art keywords
- paroxetine
- compound
- ascorbate
- solution
- paroxetine ascorbate
- 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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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Psychology (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Paroxetine ascorbate is useful in the treatment of certain CNS disorders.
Description
The present invention relates to a kind of new compound, prepare the method and the application in the treatment internal disease thereof of this compound.
The medicine of the character with antidepressant and Kang Pajinsenshi disease has been described among U.S. Pat-A-3912743 and the US-A-4007196.Wherein the compound of a kind of particularly important of Pi Luing is a paroxetine, promptly 4-(4 '-fluorophenyl)-3-(3 ', 4 '-methylenedioxy benzene oxygen methyl)-trans-isomer(ide) of piperidines.This compound uses in treatment with the form of hydrochloride, is used for the treatment of and particularly prevention depression obsessive-compulsive disorder (OCD) and Phobias.
We have been surprised to find a kind of new salt of paroxetine now, can be used for the surrogate as the hydrochloride that uses in the market, or are used for the intermediate as the preparation hydrochloride.
According to the present invention, the paroxetine ascorbate that provides.
New salts of the present invention provides with noncrystalline form on the one hand, can be solid or oily matter.Oily matter preferably absorbs with a kind of solid carrier, can use a kind of carrier that can be used as a kind of component of pharmaceutical composition especially.
On the other hand, new salts of the present invention provides with crystallized form.When crystallized form existed to surpass a kind of polymorphic form, each polymorphic form constituted another aspect of the present invention.
Paroxetine ascorbate can contact with the paroxetine free alkali by the xitix with metering and prepare.One of preferred acid or alkali are in solution, and more preferably the two is all in solution.For solution is made in acid, temperature can be improved, but the good yield of salt will be sought out, can pass through evaporation section or whole solvent, or controlled chilling, preferably stage refrigerative method obtains.The solvent of normal use is to be suitable for paroxetine free alkali mobile solvent, toluene for example, alcohols is methyl alcohol for example, ethanol, Virahol, ester class such as ethyl acetate, ketone such as acetone and butanone, halogenated alkane such as methylene dichloride and ethers such as tetrahydrofuran (THF) and ether, but preferably avoid using the extremely undissolved therein solvent of xitix.The suitable solvent of xitix is comprised water and lower alcohol.
This salt can come out with isolated in solid form from the above-mentioned solution that obtains by the method for routine.For example, noncrystalline attitude salt can pass through precipitation, spraying drying, reach the lyophilize of solution, or the vacuum-drying of oily matter, or the melt curing that free alkali and acid-respons obtained is obtained.Crystal salt can obtain with appropriate solvent crystallization or recrystallization.
When this salt obtained with solvate with the solvent that it was dissolved in, this solvate constituted another aspect of the present invention.Solvate can change the salt of non-solvent compound by heating into, for example, by the stove drying, or handles with a kind of solvent exchange that can not form solvate.
Before isolating paroxetine salt, can earlier water be removed with the azeotrope distillating method, avoiding the formation of hydrate, or obtain the product that exists with anhydrate form.In this case, the suitable solvent of salts solution can form solvent such as the toluene and the Virahol of azeotrope with water for those.The mixture that also should be appreciated that solvent also can be used to help azeotropic water removing.
More generally, crystallization can be carried out in any solvent that forms needed crystalline structure, and the crystal seed that needs or can use desired structure when requirement is arranged is arranged.When polymorphic form exists, every kind of polymorphic form preferably from the solution of salt direct crystallization come out, although use the crystal seed of another kind of polymorphic form to come out a kind of polymorphic form recrystallization from solution also passable.
The paroxetine free alkali can be according to United States Patent (USP) 4,007, and 196 and the method preparation summarized of EP-B-0223403.Xitix can obtain on market.
Compound of the present invention can be used for treatment and prevents following disease:
Alcoholism; Anxiety; Dysthymia disorders; Obsessive-compulsive disorder; Phobias; Chronic pain; Obesity; Senile dementia; Migraine; Hungry disease; Apositia; Social phobia; The moon is syndromes (PMS) in earlier stage; Pubescence dysthymia disorders; Trichotillomania; Depression; Substance abuse disease.
These diseases are called " these diseases " hereinafter.
The present invention further provides the method for one or more diseases in a kind of the treating and/or preventing " these diseases ", this method can by need the treatment patient's significant quantity and/or the salt of the present invention of preventive dose carry out.
The present invention further provides a kind of pharmaceutical composition that is used for the treatment of and/or prevents " these diseases ", said composition comprises the blend of a kind of salt of the present invention and a kind of pharmaceutically useful carrier.
The present invention also provides a kind of salt of the present invention to be used for the treatment of and/or to prevent the purposes of " these diseases ".
The present invention also provides salt of the present invention to be used to make the purposes of the medicine of a kind for the treatment of and/or preventing " these diseases ".
The present invention is more suitable in treatment dysthymia disorders, the application on OCD and the Phobias.
Composition of the present invention is fit to oral administration usually, but the method that is used for parenteral admin after the composition dissolves is also in protection scope of the present invention.
Composition is used for patient with the form of a units dosage composition usually, this units dosage composition comprises 1 to 200mg with free alkali number activity calculated component, be more typically 5 to 100mg, for example 10 to 50mg such as 10,12.5,15,20,25,30 or 40mg.Preferred units dosage composition comprises 20mg with free alkali number activity calculated component.This composition normal circumstances following every day of administration 1 to 6 time, for example every day 2,3 or 4 times so that the total amount of the promoting agent of being given active ingredient with free alkali number calculate 5 in the scope of 400mg.Most preferred unitary dose is to be administered once every day.
Preferred unit dosage form comprises tablet or capsule.
Composition of the present invention can for example mix filler and compressing tablet by general blending means preparation.
Be used for appropriate carrier of the present invention and comprise a kind of thinner, a kind of tackiness agent, a kind of disintegrating agent, a kind of tinting material, a kind of flavouring agent and/or sanitas.These reagent can use by universal method, for example according to market on the similar method of the antidepressive sold use.
The special case of pharmaceutical composition comprises EP-B-0223403 and US4, described in 007,196, product of the present invention can be used as active ingredient wherein.
Illustrate the present invention: embodiment 1 below: the preparation of paroxetine ascorbate
(1.12g adds toluene (5ml, 6.38mmol) solution that contains the 1.28mol paroxetine base in methyl alcohol 6.38mmol) (15ml) solution to xitix.Remove with the method for vacuum and to desolvate, remaining oily matter is with toluene (15ml) dilution, and the solvent vacuum is removed.Grind with ether (about 15ml), and filter under nitrogen protection, obtain faint yellow solid, (2 * 10ml) washings, drying is 3 hours in vacuum drier with ether.Yield 2.99g.
IR (whiteruss grinding): 1716,1603,1510,1465,1377,1224,1186,1136,1037,930,831,722,540cm
-1Embodiment 2: the preparation of tablet
| Component | The 20mg sheet | The 30mg sheet |
| Paroxetine ascorbate Lin Suanergai (DCP) Microcrystalline Cellulose primojel Magnesium Stearate | (20.00mg calculating) 83.34mg 50.67mg 8.34mg 1.67mg with free alkali | (30.00mg calculating) 125.0mg 76.0mg 12.5mg 2.5mg with free alkali |
The commercial source of component: dicalcium phosphate dihydrate-Emcompress or Ditab
*Microcrystalline Cellulose-Avicel PH102
*Primojel-Explotab
** trade(brand)name method 1. is weighed after DCP is sieved, and adds in the rail mounted mixing machine.2. in mixing machine, add 30 purpose paroxetine ascorbates.3. add 20 purpose Avieel and Explotab, and all powder was mixed 10 minutes.4. add Magnesium Stearate and mixed 10 minutes.
Make the required following drift of sheet of five jiaos of matrix agent:
30mg sheet 9.5mm circumscribed circle
20mg sheet 8.25mm circumscribed circle
This tablet just can create on single-punch press or roller press satisfactorily.Embodiment 3: the preparation of tablet
Method 1. is sieved paroxetine ascorbate, primojel and dicalcium phosphate dihydrate, and mixes in a suitable mixing machine.(rail mounted, Cuble formula or high energy shear mixed machine) 2. adds Magnesium Stearate, and with it with single-punch press or roller press tablet forming.
| Component | The 10mg sheet | The 20mg sheet | The 30mg sheet |
| Paroxetine ascorbate primojel particle Lin Suanergai (DITAB) or Dicafos Magnesium Stearate | 10mg (calculating) 2.98mg 158.88mg 1.75mg with free alkali | 20mg (calculating) 5.95mg 317.75mg 3.50mg with free alkali | 30mg (calculating) 8.93mg 476.63mg 5.25mg with free alkali |
Claims (7)
1. paroxetine ascorbate.
2. according to the compound of claim 1, this compound exists with non-crystalline state.
3. according to the compound of claim 1, this compound exists with crystalline state.
4. method for preparing the compound of claim 1 or 2, this method is by the precipitation of paroxetine ascorbate solution, spraying drying or lyophilize, or the vacuum-drying by paroxetine ascorbate oily matter, or the curing of paroxetine ascorbate melt prepares.
5. prepare the method for the compound of claim 1 or 3, this method carries out crystallization by the solution from paroxetine ascorbate or recrystallization prepares.
6. according to the preparation method of claim 4 or 5, the solution of paroxetine ascorbate wherein, oily matter or melt prepare by handling the paroxetine free alkali with xitix.
7. method that treats and/or prevents any or multiple " these diseases ", this method is undertaken by the paroxetine ascorbate that gives patient's significant quantity and/or preventive dose.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9808896.6 | 1998-04-25 | ||
| GBGB9808896.6A GB9808896D0 (en) | 1998-04-25 | 1998-04-25 | Novel compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1297448A true CN1297448A (en) | 2001-05-30 |
Family
ID=10831008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN99805160A Pending CN1297448A (en) | 1998-04-25 | 1999-04-23 | Paroxetine ascorbate |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1089995A1 (en) |
| JP (1) | JP2002513019A (en) |
| KR (1) | KR20010042977A (en) |
| CN (1) | CN1297448A (en) |
| AP (1) | AP2000001963A0 (en) |
| AU (1) | AU3618499A (en) |
| BG (1) | BG104940A (en) |
| BR (1) | BR9909868A (en) |
| CA (1) | CA2330055A1 (en) |
| EA (1) | EA200001104A1 (en) |
| GB (1) | GB9808896D0 (en) |
| HU (1) | HUP0102116A3 (en) |
| ID (2) | ID26654A (en) |
| IL (1) | IL139081A0 (en) |
| NO (1) | NO20005352L (en) |
| PL (1) | PL343677A1 (en) |
| SK (1) | SK15912000A3 (en) |
| TR (1) | TR200003084T2 (en) |
| WO (1) | WO1999055698A1 (en) |
| ZA (1) | ZA200005912B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110607553A (en) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | Method for preparing medicine or medicine intermediate monocrystal or amorphous substance with adjustable particle size |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0003232D0 (en) * | 2000-02-11 | 2000-04-05 | Smithkline Beecham Plc | Novel composition |
| IL159280A0 (en) * | 2001-06-14 | 2004-06-01 | Teva Pharma | A process for preparing paroxetine hcl which limits formation of pink colored compounds |
| JP4508646B2 (en) * | 2002-01-09 | 2010-07-21 | エミスフェアー・テクノロジーズ・インク | Polymorph of sodium 4-[(4-chloro-2-hydroxybenzoyl) amino] butanoate |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1422263A (en) * | 1973-01-30 | 1976-01-21 | Ferrosan As | 4-phenyl-piperidine compounds |
| EP0223403B1 (en) * | 1985-10-25 | 1993-08-04 | Beecham Group Plc | Piperidine derivative, its preparation, and its use as medicament |
| US5276042A (en) * | 1993-04-16 | 1994-01-04 | Crenshaw Roger T | Treatment of premature ejaculation |
| ES2117557B1 (en) * | 1996-02-29 | 1999-07-01 | Ferrer Int | NEW PROCEDURE FOR OBTAINING (-) - TRANS -N-P-FLUOROBENZOILMETIL-4- (P-FLUOROFENIL) -3- ((3,4- (METHYLENDIOXI) PHENOXI) METHYL) -PIPERIDINE. |
-
1998
- 1998-04-25 GB GBGB9808896.6A patent/GB9808896D0/en not_active Ceased
-
1999
- 1999-04-23 HU HU0102116A patent/HUP0102116A3/en unknown
- 1999-04-23 WO PCT/GB1999/001244 patent/WO1999055698A1/en not_active Application Discontinuation
- 1999-04-23 CN CN99805160A patent/CN1297448A/en active Pending
- 1999-04-23 TR TR2000/03084T patent/TR200003084T2/en unknown
- 1999-04-23 EP EP99918151A patent/EP1089995A1/en not_active Withdrawn
- 1999-04-23 ID IDW20002169A patent/ID26654A/en unknown
- 1999-04-23 BR BR9909868-7A patent/BR9909868A/en not_active Application Discontinuation
- 1999-04-23 PL PL99343677A patent/PL343677A1/en not_active Application Discontinuation
- 1999-04-23 IL IL13908199A patent/IL139081A0/en unknown
- 1999-04-23 AU AU36184/99A patent/AU3618499A/en not_active Abandoned
- 1999-04-23 ID IDW20002168A patent/ID26083A/en unknown
- 1999-04-23 AP APAP/P/2000/001963A patent/AP2000001963A0/en unknown
- 1999-04-23 JP JP2000545858A patent/JP2002513019A/en active Pending
- 1999-04-23 KR KR1020007011809A patent/KR20010042977A/en not_active Application Discontinuation
- 1999-04-23 EA EA200001104A patent/EA200001104A1/en unknown
- 1999-04-23 CA CA002330055A patent/CA2330055A1/en not_active Abandoned
- 1999-04-23 SK SK1591-2000A patent/SK15912000A3/en unknown
-
2000
- 2000-10-23 ZA ZA200005912A patent/ZA200005912B/en unknown
- 2000-10-24 NO NO20005352A patent/NO20005352L/en not_active Application Discontinuation
- 2000-11-13 BG BG104940A patent/BG104940A/en unknown
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110607553A (en) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | Method for preparing medicine or medicine intermediate monocrystal or amorphous substance with adjustable particle size |
| CN110607554A (en) * | 2018-10-30 | 2019-12-24 | 中国科学院化学研究所 | Method for preparing medicine or medicine intermediate monocrystal or amorphous substance |
| CN110607554B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | Method for preparing medicine or medicine intermediate monocrystal or amorphous substance |
| CN110607553B (en) * | 2018-10-30 | 2024-03-22 | 中国科学院化学研究所 | Method for preparing medicine or medicine intermediate monocrystal or amorphous substance with adjustable particle size |
Also Published As
| Publication number | Publication date |
|---|---|
| PL343677A1 (en) | 2001-08-27 |
| BR9909868A (en) | 2000-12-19 |
| NO20005352D0 (en) | 2000-10-24 |
| JP2002513019A (en) | 2002-05-08 |
| SK15912000A3 (en) | 2001-04-09 |
| TR200003084T2 (en) | 2001-02-21 |
| AP2000001963A0 (en) | 2000-12-31 |
| ZA200005912B (en) | 2001-12-19 |
| NO20005352L (en) | 2000-10-24 |
| WO1999055698A1 (en) | 1999-11-04 |
| ID26654A (en) | 2001-01-25 |
| HUP0102116A2 (en) | 2002-05-29 |
| KR20010042977A (en) | 2001-05-25 |
| EP1089995A1 (en) | 2001-04-11 |
| AU3618499A (en) | 1999-11-16 |
| HUP0102116A3 (en) | 2002-12-28 |
| IL139081A0 (en) | 2001-11-25 |
| BG104940A (en) | 2001-09-28 |
| GB9808896D0 (en) | 1998-06-24 |
| EA200001104A1 (en) | 2001-04-23 |
| ID26083A (en) | 2000-11-23 |
| CA2330055A1 (en) | 1999-11-04 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |