CA2330055A1 - Paroxetine ascorbate - Google Patents
Paroxetine ascorbate Download PDFInfo
- Publication number
- CA2330055A1 CA2330055A1 CA002330055A CA2330055A CA2330055A1 CA 2330055 A1 CA2330055 A1 CA 2330055A1 CA 002330055 A CA002330055 A CA 002330055A CA 2330055 A CA2330055 A CA 2330055A CA 2330055 A1 CA2330055 A1 CA 2330055A1
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- CA
- Canada
- Prior art keywords
- paroxetine
- ascorbate
- salt
- 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.)
- Abandoned
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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
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- 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)
- Psychology (AREA)
- Hospice & Palliative Care (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
PAROXETINE ASCORBATE
The present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-)traps isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorder (OCD) and panic.
We have now surprisingly discovered a novel salt of paroxetine which may be used as an alternative to the currently marketed hydrochloride, or as an intermediate in the preparation of the hydrochloride.
According to the present invention there is provided paroxetine ascorbate.
In one aspect the novel salt of this invention is provided in non-crystalline form, which may a solid or an oil. The oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition In another aspect the novel salt of this invention is provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention.
Paroxetine ascorbate may be prepared by contacting stoichiometric amounts of ascorbic acid and paroxetine free base. Preferably either the acid or base is in solution, more preferably both are in solution. filevated temperature may be used to bring the acid into solution, but good yields of the salt are obtained by evaporation of some or all of the solvent or by controlled cooling, preferably in stages. Most commonly used solvents are suitable for mobilizing paroxetine free base, for example toluene, alcohols such as WO 99/55698 PC'T/G899/01244 methanol, ethanol, propan-2-ol, esters such as ethyl acetate. ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which ascorbic acid is very insoluble are preferably avoided. Suitable solvents for ascorbic acid include water and lower alcohols.
The salt may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid. The crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
When the salt is obtained as a solvate, by association with the solvent in which it is dissolved, such solvate forms a further aspect of this invention. Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
Prior to the isolation of the paroxedne salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form.
In that case, suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
More generally, crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable. When polymorphs exist, individual polymorphs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymorph using seeds of another polymorph may also be carned out.
Paroxetine free base may be prepared according to the procedures generally outlined in US
Patent No 4,007,196 and EP-B-0 223403. Ascorbic acid is commercially available.
The compounds of this invention may be used to treat and prevent the following disorders:
The present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
Pharmaceutical products with antidepressant and anti-Parkinson properties are described in US-A-3912743 and US-A-4007196. An especially important compound among those disclosed is paroxetine, the (-)traps isomer of 4-(4'-fluorophenyl)-3-(3',4'-methylenedioxy-phenoxymethyl)-piperidine. This compound is used in therapy as the hydrochloride salt for the treatment and prophylaxis of inter alia depression, obsessive compulsive disorder (OCD) and panic.
We have now surprisingly discovered a novel salt of paroxetine which may be used as an alternative to the currently marketed hydrochloride, or as an intermediate in the preparation of the hydrochloride.
According to the present invention there is provided paroxetine ascorbate.
In one aspect the novel salt of this invention is provided in non-crystalline form, which may a solid or an oil. The oil is preferably absorbed on a solid carrier, especially a carrier that is usable as a component of a pharmaceutical composition In another aspect the novel salt of this invention is provided in crystalline form. When the crystalline form exists as more than one polymorph, each polymorph forms another aspect of this invention.
Paroxetine ascorbate may be prepared by contacting stoichiometric amounts of ascorbic acid and paroxetine free base. Preferably either the acid or base is in solution, more preferably both are in solution. filevated temperature may be used to bring the acid into solution, but good yields of the salt are obtained by evaporation of some or all of the solvent or by controlled cooling, preferably in stages. Most commonly used solvents are suitable for mobilizing paroxetine free base, for example toluene, alcohols such as WO 99/55698 PC'T/G899/01244 methanol, ethanol, propan-2-ol, esters such as ethyl acetate. ketones such as acetone and butanone, halogenated hydrocarbons such as dichloromethane, and ethers such as tetrahydrofuran and diethyl ether, but solvents in which ascorbic acid is very insoluble are preferably avoided. Suitable solvents for ascorbic acid include water and lower alcohols.
The salt may be isolated in solid form by conventional means from a solution thereof obtained as above. For example, the non-crystalline salt may be prepared by precipitation, spray drying, and freeze drying of solutions, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid. The crystalline salt may be prepared by crystallization or recrystallization from appropriate solvents.
When the salt is obtained as a solvate, by association with the solvent in which it is dissolved, such solvate forms a further aspect of this invention. Solvates may be returned to the unsolvated salt by heating, for example by oven-drying, or by treatment with a displacement solvent which does not form a solvate.
Prior to the isolation of the paroxedne salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form.
In that case, suitable solvents for the solution of the salt are those which form an azeotrope with water such as toluene and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
More generally, crystallization may be carried out from any solvent which allows formation of the desired crystal structure, using seeds of the desired structure where necessary or desirable. When polymorphs exist, individual polymorphs are preferably crystallized directly from a solution of the salt, although recrystallizing a solution of one polymorph using seeds of another polymorph may also be carned out.
Paroxetine free base may be prepared according to the procedures generally outlined in US
Patent No 4,007,196 and EP-B-0 223403. Ascorbic acid is commercially available.
The compounds of this invention may be used to treat and prevent the following disorders:
Alcoholism Anxiety Depression Obsessive Compulsive Disorder Panic Disorder Chronic Pain Obesity Senile Dementia Migraine Bulimia Anorexia Social Phobia Pre-Menstrual Syndrome (PMS) Adolescent Depression Trichotillomania Dysthymia Substance Abuse These disorders are herein after referred to as "the Disorders".
The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable Garner.
The present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
The present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
Most suitably the present invention is applied to the treatment of depression, OCD and panic.
The compositions of this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
The present invention further provides a method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of a salt of the invention to a sufferer in need thereof.
The present invention further provides a pharmaceutical composition for use in the treatment and/or prevention of the Disorders which comprises an admixture of a salt of the invention with a pharmaceutically acceptable Garner.
The present invention also provides the use of a salt of the invention for treating and/or preventing the Disorders.
The present invention also provides the use of a salt of the invention in the manufacture of a medicament for treating and/or preventing the Disorders.
Most suitably the present invention is applied to the treatment of depression, OCD and panic.
The compositions of this invention are usually adapted for oral administration, but formulations for dissolution for parental administration are also within the scope of this invention.
WO 99/55698 PCTlGB99/01144 The composition is usually presented as a unit dose composition containing from 1 to 200mg of active ingredient calculated on a free base basis, more usually from 5 to 100mg, for example 10 to SOmg such as 10, 12.5, 15, 20, 25, 30 or 40mg by a human patient. Most preferably unit doses contain 20mg of active ingredient calculated on a free base basis.
Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400rng of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B-223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
The following Examples illustrate the present invention:
Example 1: Preparation of paroxetine ascorbate A 1.28 mol solution of paroxetine base in toluene (5 mI, 6.38 mmol) was added to a solution of ascorbic acid (1.128, 6.38 mmol) in methanol (15 ml). The solvent was removed in vacuo, the residual oil was diluted with toluene (15 ml) and the solvent removed in vacuo. Trituration with diethyl ether (c. 15 ml) and filtration under nitrogen gave a pale yellow solid which was washed with diethyl ether (2 x 10 ml), dried in a vacuum desiccator for 3 hours.
Yield 2.998.
IR nujol mull:
Bands at 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722, 540 cm-I
Example 2: preparation of tablets INGREDIENTS 20 mg Tablet 30mg Tablet Paroxetine ascorbate 20.00 mg 30.0 mg (based on free base)(based on free base) Dicalcium Phosphate 83.34 mg 125.0 mg (DCP) Microcrystalline Cellulose50.67 mg 76.0 mg Sodium Starch Glycollate8.34 mg 12.5 mg Magnesium Stearate 1.67 mg 2.5 mg Commercial source of the ingredients i 5 Dicalcium Phosphate Dihydrate - Emcompress or Ditab*
Microcrystalline Cellulose - Avicel PH 102*
Sodium Starch Glycollate - Explotab.*
* Tradenames Method 1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine Ascorbate to the bowl.
3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes.
4. Add magnesium stearate and mix for 5 minutes.
Tablet into Pentagonal Tablets using the following punches:
30 mg Tablet 9.5 mm Circumcircle 20 mg Tablet 8.25 mm Circumcircle The tablets are made satisfactorily on a single punch or a Rotary press.
Example 3: preparation of tablets INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet Paroxetine ascorbate10 mg 20 mg 30 mg (as on free (as on free (as on free base) base) base) Sodium Starch Glycollate2.98 mg 5.95 mg 8.93 mg Granular Dicalcium Phosphate 158.88 mg 317.75 mg 476.63 mg (DITAB) or Dicafos Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg Method 1. Paroxetine ascorbate, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer.
Such a composition is normally taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400rng of active ingredient calculated on a free base basis. Most preferably the unit dose is taken once a day.
Preferred unit dosage forms include tablets or capsules.
The compositions of this invention may be formulated by conventional methods of admixture such as blending, filling and compressing.
Suitable carriers for use in this invention include a diluent, a binder, a disintegrant, a colouring agent, a flavouring agent and/or preservative. These agents may be utilized in conventional manner, for example in a manner similar to that already used for marketed anti-depressant agents.
Specific examples of pharmaceutical compositions include those described EP-B-223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
The following Examples illustrate the present invention:
Example 1: Preparation of paroxetine ascorbate A 1.28 mol solution of paroxetine base in toluene (5 mI, 6.38 mmol) was added to a solution of ascorbic acid (1.128, 6.38 mmol) in methanol (15 ml). The solvent was removed in vacuo, the residual oil was diluted with toluene (15 ml) and the solvent removed in vacuo. Trituration with diethyl ether (c. 15 ml) and filtration under nitrogen gave a pale yellow solid which was washed with diethyl ether (2 x 10 ml), dried in a vacuum desiccator for 3 hours.
Yield 2.998.
IR nujol mull:
Bands at 1716, 1603, 1510, 1465, 1377, 1224, 1186, 1136, 1037, 930, 831, 722, 540 cm-I
Example 2: preparation of tablets INGREDIENTS 20 mg Tablet 30mg Tablet Paroxetine ascorbate 20.00 mg 30.0 mg (based on free base)(based on free base) Dicalcium Phosphate 83.34 mg 125.0 mg (DCP) Microcrystalline Cellulose50.67 mg 76.0 mg Sodium Starch Glycollate8.34 mg 12.5 mg Magnesium Stearate 1.67 mg 2.5 mg Commercial source of the ingredients i 5 Dicalcium Phosphate Dihydrate - Emcompress or Ditab*
Microcrystalline Cellulose - Avicel PH 102*
Sodium Starch Glycollate - Explotab.*
* Tradenames Method 1. Pass DCP through a screen and weigh it into a Planetary mixer.
2. Add 30 mesh Paroxetine Ascorbate to the bowl.
3. Add 20 mesh Avicel and Explotab and mix all the powders for 10 minutes.
4. Add magnesium stearate and mix for 5 minutes.
Tablet into Pentagonal Tablets using the following punches:
30 mg Tablet 9.5 mm Circumcircle 20 mg Tablet 8.25 mm Circumcircle The tablets are made satisfactorily on a single punch or a Rotary press.
Example 3: preparation of tablets INGREDIENTS 10 mg Tablet 20 mg Tablet 30mg Tablet Paroxetine ascorbate10 mg 20 mg 30 mg (as on free (as on free (as on free base) base) base) Sodium Starch Glycollate2.98 mg 5.95 mg 8.93 mg Granular Dicalcium Phosphate 158.88 mg 317.75 mg 476.63 mg (DITAB) or Dicafos Magnesium Stearate 1.75 mg 3.50 mg 5.25 mg Method 1. Paroxetine ascorbate, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer.
(Planetary, Cuble or High Energy Shear mixer.) 2. Add Magnesium Stearate and compress it into a tablet using a single punch or Rotary Tablet machine.
Claims (7)
1. Paroxetine ascorbate.
2. A compound according to claim 1 in non-crystalline form.
3. A compound according to claim I in crystalline form.
4. A process for the preparation of a compound as claimed in claim 1 or 2 by precipitation, spray drying or freeze drying a solution of paroxetine ascorbate, or by vacuum drying of oils of paroxetine ascorbate, or solidification of melts of paroxetine ascorbate.
5. A process for the preparation of a compound as claimed in claim 1 or 3 by crystallization or re-crystallization from a solution of paroxetine ascorbate.
6. A process according to claim 4 or 5 in which the solution, oil or melt of paroxetine ascorbate is prepared by treating paroxetine free base with ascorbic acid.
7. A method for treating and/or preventing any one or more of the Disorders by administering an effective and/or prophylactic amount of paroxetine ascorbate to a sufferer in need thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB9808896.6 | 1998-04-25 | ||
| GBGB9808896.6A GB9808896D0 (en) | 1998-04-25 | 1998-04-25 | Novel compound |
| PCT/GB1999/001244 WO1999055698A1 (en) | 1998-04-25 | 1999-04-23 | Paroxetine ascorbate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2330055A1 true CA2330055A1 (en) | 1999-11-04 |
Family
ID=10831008
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002330055A Abandoned CA2330055A1 (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) | ID26083A (en) |
| IL (1) | IL139081A0 (en) |
| NO (1) | NO20005352D0 (en) |
| PL (1) | PL343677A1 (en) |
| SK (1) | SK15912000A3 (en) |
| TR (1) | TR200003084T2 (en) |
| WO (1) | WO1999055698A1 (en) |
| ZA (1) | ZA200005912B (en) |
Families Citing this family (4)
| 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 |
| EP1469827B1 (en) | 2002-01-09 | 2017-12-27 | Emisphere Technologies, Inc. | Polymorphs of sodium 4- (4-chloro-2-hydroxybenzoyl)amino butanoate |
| CN110607555B (en) * | 2018-10-30 | 2024-02-20 | 中国科学院化学研究所 | Method for preparing taxol monocrystal or amorphous substance |
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 |
| DE3688827T2 (en) * | 1985-10-25 | 1994-03-31 | Beecham Group Plc | Piperidine derivative, its manufacture and its use as a medicine. |
| 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 JP JP2000545858A patent/JP2002513019A/en active Pending
- 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 PL PL99343677A patent/PL343677A1/en not_active Application Discontinuation
- 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 IDW20002168A patent/ID26083A/en unknown
- 1999-04-23 BR BR9909868-7A patent/BR9909868A/en not_active Application Discontinuation
- 1999-04-23 KR KR1020007011809A patent/KR20010042977A/en not_active Application Discontinuation
- 1999-04-23 EA EA200001104A patent/EA200001104A1/en unknown
- 1999-04-23 AU AU36184/99A patent/AU3618499A/en not_active Abandoned
- 1999-04-23 SK SK1591-2000A patent/SK15912000A3/en unknown
- 1999-04-23 AP APAP/P/2000/001963A patent/AP2000001963A0/en unknown
- 1999-04-23 ID IDW20002169A patent/ID26654A/en unknown
- 1999-04-23 CA CA002330055A patent/CA2330055A1/en not_active Abandoned
- 1999-04-23 HU HU0102116A patent/HUP0102116A3/en unknown
- 1999-04-23 IL IL13908199A patent/IL139081A0/en unknown
-
2000
- 2000-10-23 ZA ZA200005912A patent/ZA200005912B/en unknown
- 2000-10-24 NO NO20005352A patent/NO20005352D0/en not_active Application Discontinuation
- 2000-11-13 BG BG104940A patent/BG104940A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HUP0102116A3 (en) | 2002-12-28 |
| BG104940A (en) | 2001-09-28 |
| NO20005352L (en) | 2000-10-24 |
| EA200001104A1 (en) | 2001-04-23 |
| ZA200005912B (en) | 2001-12-19 |
| BR9909868A (en) | 2000-12-19 |
| SK15912000A3 (en) | 2001-04-09 |
| GB9808896D0 (en) | 1998-06-24 |
| CN1297448A (en) | 2001-05-30 |
| HUP0102116A2 (en) | 2002-05-29 |
| JP2002513019A (en) | 2002-05-08 |
| IL139081A0 (en) | 2001-11-25 |
| AU3618499A (en) | 1999-11-16 |
| ID26654A (en) | 2001-01-25 |
| KR20010042977A (en) | 2001-05-25 |
| TR200003084T2 (en) | 2001-02-21 |
| PL343677A1 (en) | 2001-08-27 |
| WO1999055698A1 (en) | 1999-11-04 |
| EP1089995A1 (en) | 2001-04-11 |
| NO20005352D0 (en) | 2000-10-24 |
| AP2000001963A0 (en) | 2000-12-31 |
| ID26083A (en) | 2000-11-23 |
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| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |
