EP1102764A1 - Sels de paroxetine - Google Patents

Sels de paroxetine

Info

Publication number
EP1102764A1
EP1102764A1 EP99938439A EP99938439A EP1102764A1 EP 1102764 A1 EP1102764 A1 EP 1102764A1 EP 99938439 A EP99938439 A EP 99938439A EP 99938439 A EP99938439 A EP 99938439A EP 1102764 A1 EP1102764 A1 EP 1102764A1
Authority
EP
European Patent Office
Prior art keywords
paroxetine
salt
acid
solution
toluene
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.)
Withdrawn
Application number
EP99938439A
Other languages
German (de)
English (en)
Inventor
David SmithKline Beecham Pharmaceuticals CROWE
Stephen SmithKline Beecham Pharmaceuticals MOORE
Deirdre SmithKline Beecham Pharmaceu. O'KEEFFE
Michael SmithKline Beecham Pharmaceu. URQUHART
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from GBGB9817312.3A external-priority patent/GB9817312D0/en
Priority claimed from GBGB9817324.8A external-priority patent/GB9817324D0/en
Priority claimed from GBGB9817308.1A external-priority patent/GB9817308D0/en
Priority claimed from GBGB9817311.5A external-priority patent/GB9817311D0/en
Priority claimed from GBGB9817310.7A external-priority patent/GB9817310D0/en
Priority claimed from GBGB9817323.0A external-priority patent/GB9817323D0/en
Priority claimed from GBGB9817367.7A external-priority patent/GB9817367D0/en
Priority claimed from GBGB9817338.8A external-priority patent/GB9817338D0/en
Priority claimed from GBGB9817337.0A external-priority patent/GB9817337D0/en
Priority claimed from GBGB9817315.6A external-priority patent/GB9817315D0/en
Priority claimed from GBGB9817314.9A external-priority patent/GB9817314D0/en
Priority claimed from GBGB9817313.1A external-priority patent/GB9817313D0/en
Priority claimed from GBGB9817335.4A external-priority patent/GB9817335D0/en
Priority claimed from GBGB9817319.8A external-priority patent/GB9817319D0/en
Priority claimed from GBGB9817318.0A external-priority patent/GB9817318D0/en
Priority claimed from GBGB9823834.8A external-priority patent/GB9823834D0/en
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Publication of EP1102764A1 publication Critical patent/EP1102764A1/fr
Withdrawn legal-status Critical Current

Links

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

Definitions

  • the present invention relates to novel compounds, to processes for preparing them and to their use in treating medical disorders.
  • an acid selected from the group consisting of hydrobromic, hydroiodic, hexanoic, malic, aspartic, adipic, palmitic, stearic, ethylenediaminetetraacetic (EDTA), naphthoic, naphthalenesulphonic, pamoic, gluconic, salicylic, hydroxynaphthoic and hydroxybutyric acids.
  • Malic, aspartic and gluconic acids exist in enantiomeric forms and this invention includes salts with both the D and L-acids and racemic mixtures thereof.
  • Malic, aspartic, adipic, EDTA and pamoic acids are dibasic and the invention therefore includes both salts in which the ratio of paroxetine to acid (by mole) is 1: 1 and salts in which the ratio of paroxetine to acid (by mole) is 2: 1, as well as mixed salts with, for example, an alkali metal or ammonium cation.
  • novel salts of this invention are provided in non-crystalline form, which may take the form of 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.
  • novel salts of this invention are provided in crystalline form.
  • each polymorph forms another aspect of this invention.
  • Paroxetine salts may be prepared by contacting stoichiometric amounts of the acid (enantiomer or racemic mixture) and paroxetine free base.
  • the acid may be used in excess, usually no more than 1.5 equivalents.
  • the base and/or the acid is in solution, more preferably both are in solution.
  • Mixed salts can be prepared by forming the precursor 1 : 1 or hydrogen salt (of paroxetine with the acid, or the metal or ammonium ion with the acid) in situ, or using it preformed in solution, and contacting it in solution with a solution containing the metal or ammonium ion, or treating a metal or ammonium hydrogen malate with paroxetine.
  • paroxetine free base for example toluene, alcohols such as 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.
  • concentration of paroxetine base is preferably in the range 5 to 50% weight/volume, more preferably in the range 10 to 30%.
  • Suitable solvents for the acids used in accordance with the present invention include water, lower alcohols such as methanol, ethanol and isopropanol, ethers such as diethyl ether and tetrahydrofuran, hydrocarbons such as toluene and benzene, esters such as ethyl acetate, ketones such as acetone, butanone and isobutyl methyl ketone, and halogenated hydrocarbons such as chloroform.
  • Hydrogen bromide is preferably used in the form of an aqueous solution, for example the commercially available 48% aqueous solution, but may also be used in more dilute solutions, optionally further diluted with a miscible organic solvents. Hydrogen bromide may be also be added in the form of a gas; this method is particularly appropriate when it is desired to prepare the paroxetine salt in an anhydrous solvent system.
  • concentration of hydrogen bromide in non-aqueous solutions is preferably in the range 0.1 to 9 molar, preferably between 1 and 3 molar.
  • Hydrogen iodide is preferably used in the form of an aqueous solution, for example the commercially available 47% or 55% aqueous solutions, but may also be used in more dilute solutions, optionally further diluted with a miscible organic solvents.
  • concentration of hydrogen iodide in non-aqueous solutions is preferably in the range 0.1 to 7.6 molar, preferably between 1 and 3 molar.
  • Hexanoic acid is miscible with most solvents.
  • Malic acid is preferably added as a solid or in solution, for example in water, ethers such as diethyl ether or tetrahydrofuran, a ketone such as acetone, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of malic acid solutions are preferably in the range 0.1 to 4 molar, preferably between 1 and 2 molar.
  • the most suitable solvent for aspartic acid is water.
  • Aspartic acid may be used either as a solid or in solution, suitable concentrations being in the range 0.01 to 1 molar, preferably between 0.1 and 0.5 molar.
  • Adipic acid is preferably added as a solid or in solution, for example in water (at elevated temperatures), acetone, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of adipic acid solutions are preferably in the range 0.1 to 4 molar, preferably between 1 and 2 molar.
  • Palmitic acid is preferably added as a solid or in solution, for example in toluene, ether, acetone, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of palmitic acid solutions are preferably in the range 0.1 to 2 molar, preferably between 0.5 and 1 molar.
  • Stearic acid is preferably added as a solid or in solution, for example in toluene, acetone, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of stearic acid solutions are preferably in the range 0.1 to 2 molar, preferably between 0.5 and 1 molar.
  • EDTA is preferably added as a solid or in solution, for example in hot water, or lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of ethylenediaminetetraacetic acid solutions are preferably in the range 0.1 to 2 molar, preferably between 0.5 and 1 molar.
  • Naphthoic acid is preferably added as a solid or in solution, for example in an ether such as diethyl ether or tetrahydrofuran, or a lower alcohol such as methanol, ethanol, or propan-2- ol, or a mixture of solvents.
  • concentration of naphthoic acid solutions are preferably in the range 0.1 to 2 molar, preferably between 0.3 and 1 molar.
  • the 1- or 2-naphthalene sulphonic acid is preferably added as a solid or an aqueous or lower alcoholic or toluene solution optionally further diluted with a miscible organic solvent.
  • concentration of 1- or 2-naphthalene sulphonic acid solutions are preferably in the range 0.1 to 3 molar, preferably 0.5 to 1.5 molar.
  • Pamoic acid is preferably added as a solid or in solution, for example in chloroform or pyridine, or a mixture of solvents.
  • concentration of pamoic acid solutions are preferably in the range 0.05 to 1 molar, preferably between 0.1 and 0.3 molar.
  • Gluconic acid is preferably added as an aqueous solution optionally further diluted with a miscible organic solvent.
  • concentration of gluconic acid is preferably in the range 0.1 to 4 molar, preferably 1 to 3 molar.
  • the hydroxynaphthoic acids are preferably added as a solid or in solution, for example in an ether such as diethyl ether or tetrahydrofuran, or a lower alcohol such as methanol,
  • B ethanol, or propan-2-ol, or benzene, or toluene, or a mixture of solvents.
  • concentration of hydroxynaphthoic acid solutions are preferably in the range 0.1 to 2 molar, preferably between 0.3 and 1 molar.
  • Salicylic acid is preferably added as a solid or in solution, for example in water or an ether such as diethyl ether or tetrahydrofuran, a ketone such as acetone, butanone, or isobutyl methyl ketone, chloroform, toluene, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • concentration of salicylic acid solutions are preferably in the range 0.1 to 4 molar, preferably between 0.5 and 2 molar.
  • a double decomposition approach may be employed in which a salt of 4-hydroxybutyric acid, for example the sodium salt, is contacted in solution with a salt of paroxetine, for example the hydrochloride salt.
  • the salts are preferably chosen so that the by-product salt (sodium chloride, in the example) is readily removed from solution. This approach is particularly convenient as a result of the tendency of 4-hydroxybutyric acid to form a lactone.
  • Acid salts of paroxetine may be dissolved in a wide range of solvents, including water, alcohols, ketones, hydrocarbons, chlorinated hydrocarbons, esters and ethers.
  • Particularly suitable solvents for paroxetine hydrochloride are methanol, propan-2-ol, dichloromethane, toluene and acetone.
  • the 4- hydroxybutyric acid or salt thereof is preferably added to a solution of paroxetine free base or its salt as a solid or in solution, for example in water or an ether such as diethyl ether or tetrahydrofuran, a ketone such as acetone, butanone, or isobutyl methyl ketone, or a lower alcohol such as methanol, ethanol, or propan-2-ol, or a mixture of solvents.
  • the concentration of 4-hydroxybutyric acid solutions are preferably in the range 0.1 to 5 molar, preferably between 0.5 and 2 molar.
  • the acids may also be used in the form of a soluble salt such as the ammonium salt or a salt of an amine, for example ethylamine or diethylamine.
  • paroxetine salts may be isolated in solid form by conventional means from a solution thereof obtained as above.
  • the non-crystalline salts may be prepared by
  • SUBSTTTU SHEET RULE 26 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 salts may be prepared by directly crystallising from a solvent in which the product has limited solubility, or by triturating or otherwise crystallising a non-crystalline salt.
  • An improved yield of the salt is obtained by evaporation of some or all of the solvent or by crystallisation at elevated temperature followed by controlled cooling, preferably in stages. Careful control of precipitation temperature and seeding may be used to improve the reproducibity of the production process and the particle size distribution and form of the product.
  • An alternative method of preparing paroxetine salts is to start with a salt of paroxetine with an organic acid, such as acetic acid or maleic acid.
  • an organic acid such as acetic acid or maleic acid.
  • Use of another salt of paroxetine as a starting material is suitable for preparation of the crystalline salt or, if a volatile acid such as acetic acid is used, non-crystalline salts by methods that involve evaporation (such as freeze-drying and spray-drying).
  • water Prior to the isolation of the paroxetine salt, water may be removed by azeotropic distillation to avoid the formation of hydrates or to obtain the product in anhydrous form.
  • suitable solvents for the solution of the salt are those which form an azeotrope with water, such as toluene, pyridine, isopropanol, isobutyl methyl ketone and xylene. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
  • 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. Clearly it is convenient where possible to crystallise from the solvent used for salt formation.
  • 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 carried out.
  • paroxetine hydrobromide may be recrystallised from a variety of organic solvents, such as propan-2-ol, acetone, or tetrahydrofuran; paroxetine hydriodide may be recrystallised from a variety of organic solvents, for example toluene or ethyl acetate; paroxetine hexanoates can be recrystallised from solvent systems which are suitable for its preparation, for example toluene and acetonitrile; paroxetine malates can be recrystallised from solvent systems which are suitable for its preparation, for example acetone, ethyl acetate, and acetonitrile; paroxetine adipates can be recrystallised from solvent systems which are suitable for its preparation, for example toluene, acetone, or lower alcohols followed by precipitation with ethyl acetate, ether, or hexane;
  • organic solvents such as propan-2-
  • the salt may obtained as a solvate or hydrate, when during isolation from solution it becomes associated with the solvent in which it is dissolved. Any such solvate or hydrate 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.
  • Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0223403. The acids are commercially available.
  • the compounds of this invention may be used to treat and prevent the following disorders:
  • the 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 carrier.
  • 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.
  • the present invention is applied to the treatment of depression, OCD and panic.
  • compositions containing the salt of this invention may be formulated for administration by any route, and examples are oral, sub-lingual, rectal, topical, parenteral, intravenous or intramuscular administration. Preparations may, if desired, be designed to give slow release of the paroxetine salt.
  • the medicaments may, for example, be in the form of tablets, capsules, sachets, vials, powders, granules, lozenges, reconstitutable powders, or liquid preparations, for example solutions or suspensions, or suppositories.
  • 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 100 mg, for example 10 to 50 mg such as 10, 12.5, 15, 20, 25, 30 or 40 mg by a human patient. Most preferably unit doses contain 20 mg 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 400 mg 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, including formulations adapted for controlled or delayed release.
  • 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 utilised 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-0223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
  • Paroxetine salt, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer.
  • Example 1 Preparation of paroxetine hydriodide.
  • Example 8 Preparation of paroxetine hydriodide.
  • Paroxetine hydriodide 70 g was suspended in toluene (1200 ml) and heated to boiling point to form a solution. The solution was allowed to cool slowly and seeded until the product began to crystallise. After stirring for 3 more hours, the product was collected by filtration, washed with toluene and dried in vacuo. Yield 63.6 g
  • Example 11 Larger scale preparation of crystalline salt.
  • Paroxetine hexanoate (46 g), prepared as in Example 2, was heated to reflux in acetonitrile (400 ml) to form a solution. This solution was cooled, stirred and seeded with crystalline paroxetine hexanoate, whereupon the product began to crystallise within 1 hour. After leaving to stand overnight it was necessary to add more acetonitrile to mobilize the product, which was then filtered, . washed in acetonitrile, and dried at reduced pressure.
  • Hexanoic acid (0.8 ml) was added to a solution of paroxetine free base (2.1 g) in toluene (20 ml). The solvent was evaporated at 60°C to give a gum which solidified on further drying.
  • Example 14 Preparation of 2:1 salt of paroxetine with L- malic acid.
  • Example 15 Preparation of 1 : 1 salt of paroxetine with L-malic acid.
  • Example 18 Preparation of paroxetine adipate 1 : 1 salt.
  • Example 19 Preparation of paroxetine adipate 1 : 1 salt.
  • IR nujol mull Bands at: 1712, 1636, 1506, 1466, 1377, 1275, 1221, 1191, 1143, 1034, 929, 833, 540 cm: I .
  • Example 20 Preparation of paroxetine adipate.
  • Example 21 Preparation of paroxetine adipate 2: 1 salt.
  • Palmitic acid (0.75 g) was dissolved in toluene (10 ml) and mixed with a solution of paroxetine base (1 g) in toluene. The mixture was stirred at approximately 20°C for 1 hour then the solvent was removed by evaporation during which process the product crystallised. The crystals were dried at reduced pressure.
  • Palmitic acid (37.5 g) was dissolved in toluene (500 ml) and mixed with a solution of paroxetine base (52.5 g) in toluene (150 ml). The solvent was slowly removed by evaporation to cause the product to crystallise. The product, a white crystalline solid, was dried in a vacuum desiccator,
  • Paroxetine palmitate 60 g was dissolved in acetone (500 ml) by heating to reflux, and the solution allowed to cool. Seeds were added, whereupon crystallisation began almost immediately, and the mixture was stirred for 3 hours at approximately 20°C, adding further acetone as neccessary to keep the mixture at a suitable consistency for efficient stirring. The product was collected by filtration, washed with acetone and dried at reduced pressure. Yield 41.5g.
  • IR nujol mull Bands at 1644, 1464, 1206, 1042, 934, 836,822, 794,785, 720, 604, 540 cm '1 .
  • Example 25 Preparation of crystalline stearate salt.
  • Example 26 Larger scale preparation of crystalline salt.
  • Stearic acid 32 g was dissolved in toluene (300 ml) with heating to form a solution, and mixed with a solution of paroxetine base (42 g) in toluene (100 ml). The solvent was slowly removed by evaporation to cause the product to crystallise. The product, a white crystalline solid, was dried in a vacuum desiccator. Yield 70.31 g.
  • Paroxetine stearate 60 g was dissolved in acetone (800 ml) by heating to reflux, and the solution allowed to cool. The mixture started to crystallise and was stirred for 3 hours at approximately 20°C, adding further acetone as neccessary to keep the mixture at a suitable consistency for efficient stirring. The product was collected by filtration, washed with acetone and dried at reduced pressure. Yield 44.32 g.m. pt 80-82°C. IR nujol mull: Bands at 1641,1510,1464, 1246,1044 934 913,836, 787,721,677,579 cm' 1 .
  • Example 29 Preparation of ⁇ aroxetine-2-naphthoate A solution of paroxetine base in toluene (2.1 g in 10 ml) was added to a solution of 2- naphthoic acid (1.1 g) in methanol (50 ml). The reaction mixture was stirred at approximately 20°C and the solvents removed by low pressure distillation to afford a glassy white solid of non-crystalline paroxetine-2-naphthoate. This solid was triturated with heptane to afford a white crystalline solid, which was filtered, washed with heptane and dried at reduced pressure . Yield 2. l g
  • paroxetine base (4.2 g) in diethyl ether (20 ml) was added a solution of 1- naphthoic acid in diethyl ether (40 ml) and the mixture was stirred at ambient temperature. The solvent was removed by evaporation at low pressure to produce non-crystalline paroxetine- 1-naphthoate as a pale brown solid. To this solid was added a mixed solution of propan-2-ol (8 ml) and diethyl ether (30 ml), and the mixture was stirred and heated at gentle reflux. On cooling, crystalline paroxetine- 1-naphthoate precipitated from the solution as a white solid, which was isolated by filtration, and dried under vacuum.
  • Example 32 Preparation of paroxetine pamoate 1 : 1 salt.
  • IR nujol mull Bands at 1641, 1461, 1377, 1181, 1035, 829, 757 cm' 1 .
  • Example 37 Large scale preparation of crystalline salt
  • paroxetine base (4.2 g) in toluene (90 ml) was added to a suspension of salicylic acid (1.76 g) in water (28 ml), and the mixture was heated to reflux to form a solution. The water was removed by heating at reflux in a Dean and Stark apparatus, then the mixture was cooled and the solvent decanted. Residual solvent was removed by drying at reduced pressure and the resulting solid was stirred with heptane overnight, filtered under an atmosphere of nitrogen and dried to produce paroxetine salicylate as a pinkish powder.
  • paroxetine hydrochloride anhydrate (4.03 g, 11 rnmoles) and propan-2-ol (150 ml)
  • the mixture was heated to ensure total dissolution of paroxetine hydrochloride.
  • 4- hydroxybutyric acid sodium salt (1.39 g, 11 mmoles) in ethanol (100 ml).
  • the reaction mixture was stirred and a white precipitate formed. This precipitate was filtered and the filtrate was concentrated at a reduced pressure to afford a pink glassy solid of amorphous paroxetine 4-hydroxybutyrate.
  • Sample recrystallised from CHCI3 bands at circa 1651, 1538, 1511, 1489, 1467, 1396, 1220, 1189, 1133, 1075, 1034, 948, 927, 908, 837, 828, 806, 756, 743, 666, 612, 600, 580, 560 cm' 1 .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

L'invention concerne un sel de paroxétine avec un acide choisi dans le groupe comprenant les acides hydrobromique, hydro-iodique, hexanoïque, malique, aspartique, adipique, palmitique, stéarique, éthylènediamine-tétracétique (EDTA), naphtoïque, naphtalène-sulfonique, pamoïque, gluconique, salicylique, hydroxynaphtoïque et hydroxybutyrique. Ce sel est utile pour le traitement et la prophylaxie de certains troubles du système nerveux central.
EP99938439A 1998-08-08 1999-08-06 Sels de paroxetine Withdrawn EP1102764A1 (fr)

Applications Claiming Priority (33)

Application Number Priority Date Filing Date Title
GBGB9817337.0A GB9817337D0 (en) 1998-08-08 1998-08-08 Novel compound
GBGB9817311.5A GB9817311D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817335 1998-08-08
GBGB9817310.7A GB9817310D0 (en) 1998-08-08 1998-08-08 Novel compound
GB9817312 1998-08-08
GBGB9817323.0A GB9817323D0 (en) 1998-08-08 1998-08-08 Novel compound
GBGB9817367.7A GB9817367D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817324 1998-08-08
GB9817337 1998-08-08
GB9817308 1998-08-08
GBGB9817338.8A GB9817338D0 (en) 1998-08-08 1998-08-08 Novel compound
GB9817315 1998-08-08
GBGB9817312.3A GB9817312D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817308.1A GB9817308D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817338 1998-08-08
GBGB9817313.1A GB9817313D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817310 1998-08-08
GBGB9817314.9A GB9817314D0 (en) 1998-08-08 1998-08-08 Novel compounds
GB9817323 1998-08-08
GBGB9817335.4A GB9817335D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817324.8A GB9817324D0 (en) 1998-08-08 1998-08-08 Novel compounds
GBGB9817315.6A GB9817315D0 (en) 1998-08-08 1998-08-08 Noel compound
GB9817313 1998-08-08
GB9817314 1998-08-08
GB9817311 1998-08-08
GB9817367 1998-08-08
GB9817318 1998-08-10
GB9817319 1998-08-10
GBGB9817319.8A GB9817319D0 (en) 1998-08-10 1998-08-10 Novel compounds
GBGB9817318.0A GB9817318D0 (en) 1998-08-10 1998-08-10 Novel compounds
GBGB9823834.8A GB9823834D0 (en) 1998-10-30 1998-10-30 Novel compounds
GB9823834 1998-10-30
PCT/GB1999/002588 WO2000008016A1 (fr) 1998-08-08 1999-08-06 Sels de paroxetine

Publications (1)

Publication Number Publication Date
EP1102764A1 true EP1102764A1 (fr) 2001-05-30

Family

ID=27585627

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99938439A Withdrawn EP1102764A1 (fr) 1998-08-08 1999-08-06 Sels de paroxetine

Country Status (2)

Country Link
EP (1) EP1102764A1 (fr)
WO (1) WO2000008016A1 (fr)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000078290A2 (fr) * 1999-06-22 2000-12-28 Smithkline Beecham P.L.C. Nouvelle preparation
PT1109806E (pt) * 1999-07-01 2004-02-27 Italfarmaco Spa Complexos de paroxetina com ciclodextrinas ou derivados de ciclodextrinas

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8430581D0 (en) * 1984-12-04 1985-01-09 Ferrosan As Treatment
EP0223403B1 (fr) * 1985-10-25 1993-08-04 Beecham Group Plc Dérivé de pipéridine, sa préparation et son utilisation comme médicament
CA2206592A1 (fr) * 1996-05-30 1997-11-30 Shu-Zhong Wang Methode de preparation de chlorhydrate de paroxetine amorphe
HU221921B1 (hu) * 1996-07-08 2003-02-28 Richter Gedeon Vegyészeti Gyár Rt. N-benzil-piperidin- és tetrahidropiridinszármazékok és eljárás azok előállítására
EP0994872B9 (fr) * 1997-06-10 2001-12-05 Synthon B.V. Composes 4-phenylpiperidine
JP2002505254A (ja) * 1998-02-06 2002-02-19 スミスクライン・ビーチャム・パブリック・リミテッド・カンパニー パロキセチン塩

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0008016A1 *

Also Published As

Publication number Publication date
WO2000008016A1 (fr) 2000-02-17

Similar Documents

Publication Publication Date Title
EP0223403B1 (fr) Dérivé de pipéridine, sa préparation et son utilisation comme médicament
CA2451028C (fr) Formes polymorphes de chlorhydrate de 1-¬4-(5-cyanoindol-3-yl)butyl|-4-(2-carbamoylbenzofuran-5-yl)piperazi ne
US20010023253A1 (en) Novel compound
US5859045A (en) Crystalline -! 3R 4R-trans-7 methoxy 2,2-dimethyl1-3-phenyl 1-4 4-12 pyrrolidin-1 -Y1!ethoxyl 1!chromane hydrogen fumarate
EP1053234A1 (fr) Sels de paroxetine
AU3433499A (en) Paroxetine maleate
EP1102764A1 (fr) Sels de paroxetine
US20030028027A1 (en) Paroxetine maleate
AU710334B2 (en) Crystalline (-)-3R,4R-trans-7-methoxy-2,2-dimethyl -3-phenyl-4-(4-(2-(pyrrolidin-1-yl)ethoxy)phenyl)chromane, hydrogen fumarate
SK13622000A3 (sk) Kryštalická forma paroxetínu, farmaceutický prostriedok a použitie
CZ20002845A3 (cs) Soli paroxetinu
MXPA00009884A (en) Paroxetine maleate
AU2528899A (en) Salts of paroxetine
BG104973A (bg) Пароксетин 10-камфорсулфонат за лечение на cns заболявания
US20010008940A1 (en) Novel process
WO2000078752A1 (fr) Procede de production de chlorhydrate de paroxetine
MXPA00007719A (en) Salts of paroxetine
CZ20003722A3 (cs) Maleat paroxetinu
WO2001025201A1 (fr) Procede de preparation de produit intermediaire de paroxetine
WO2001012623A1 (fr) Procede de preparation d'hydrochlorure de paroxetine anhydre
MXPA00010435A (en) Paroxetine 10-camphorsulfonate for treatment of cns disorders
CZ20003343A3 (cs) Krystalická forma paroxetinu
EP1412350A1 (fr) Sel d'isethionate de paroxetine, procede de preparation et utilisation dans le traitement de la depression
WO2000032596A1 (fr) Sels amines de paroxetine

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20010213

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

17Q First examination report despatched

Effective date: 20010814

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20011227