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• • 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
  • C07D211/08—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/18—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D211/20—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
  • C07D211/22—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 hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
• • 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
• • 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
• • 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
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • 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
  • A61P25/06—Antimigraine agents
• • 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
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/32—Alcohol-abuse
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
  • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
  • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
  • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
  • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring 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 atoms of the carbocyclic ring
  • C07D317/64—Oxygen atoms

Definitions

• the present invention relates to a novel compound, to processes for preparing it and to its use in treating medical disorders.
• Example 2 of US 4007196 describes the preparation of paroxetine by demethylation of the N-methyl derivative.
• Paroxetine free base is isolated as an oil by evaporation of a benzene solution.
• the free base is dissolved in ether and treated with a solution of maleic acid in ethyl ether to form a crystalline product, which is recrystallised from 99% ethanol-ether to give a maleate salt melting 136-8°C.
• a maleate salt melting 136-8°C Apart from the melting point, there is no characterizing data that allows an unambiguous assignment of structure.
• paroxetine maleate in which the ratio of paroxetine to maleic acid (by mole) is 1 : 1.
• paroxetine maleate in which the ratio of paroxetine to maleic acid (by mole) is 2: 1.
• the maleate anion may be associated with a proton (hydrogen atom) in addition to paroxetine or may be associated with another cation, for example an alkali metal or ammonium cation.
• the 1 : 1 salt may be described as paroxetine hydrogen maleate, while in the latter case the salt may be described as a mixed salt.
• novel salts of this invention are 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.
• novel salts of this invention are provided in crystalline form.
• the crystalline form exists as more than one polymorph. each polymorph forms another aspect of this invention.
• paroxetine (1:1) maleate Form A having a melting point of 139-141°C and having an IR or XRD spectrum substantially as disclosed in Example 1 below
• paroxetine (1 :1) maleate Form B having a melting point of 136-138°C and having an IR or XRD spectrum substantially as disclosed in Example 2 below.
• paroxetine maleates may be prepared by contacting appropriate stoichiometric amounts of the acid and paroxetine free base.
• the base is in solution, more preferably both are in solution.
• Mixed salts may be prepared by forming the precursor 1 : 1 salt in situ or using it pre-formed; and contacting it in solution with a solution containing the metal or ammonium ion.
• solvents are suitable for mobilising 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.
• the maleic acid may be added as a solid, but is preferably added as a solution in an organic solvent such as ethanol or ethyl acetate, or water, methanol, propan-2-ol, or acetone.
• the maleic acid may also be added in the form of a soluble salt, for example ammonium maleate, or the maleic acid salt of an amine, for example ethylamine or diethylamine.
• the concentration of paroxetine base is preferably in the range 5 to 50% weight/volume, more preferably in the range 10 to 30%.
• the concentration of maleic acid when used in solution is preferably in the range 0.1 to 5, preferably 0.5 to 2 molar. Elevated temperatures may be used to increase solubility.
• the salt may be isolated in solid form by conventional means from a solution thereof obtained as above.
• a non-crystalline salt may be prepared by precipitation from solution, spray drying and freeze drying of solutions, evaporating a solution to a glass, or vacuum drying of oils, or solidification of melts obtained from reaction of the free base and the acid.
• a crystalline salt 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.
• paroxetine maleate may be recrystallised from a variety of organic solvents, such as acetonitrile, butanone, sec-butanol, dichloromethane, ethanol, 3- pentanone, propan-2-ol and toluene.
• 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 reproducibility of the production process and the particle size distribution and form of the product.
• 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 (1 :1) maleate Form A may be prepared by crystallisation from a solution of paroxetine maleate, which may be prepared, for example, by mixing together a solution of paroxetine free base and a solution of maleic acid.
• an excess of maleic is used, for example a molar ratio between 1 : 1 and 1 : 1.5, preferably between 1.1 and 1.3.
• Suitable solvents include ethyl acetate, methanol, ethanol, propan-2-ol, propan-1-ol, sec- butanol, butan-1-ol, methyl isobutylketone, acetone and acetonitrile, or a mixture of solvents, including mixtures with toluene.
• the maleate Form B may be prepared by recrystallisation of Form A (or vice versa). More preferably, and advantageously, Form B is prepared directly by crystallisation in a similar manner to Form A, that is directly from a solution of paroxetine maleate, which may be prepared by mixing together a solution of paroxetine free base, typically as the final stage of a manufacturing process, and a solution of maleic acid.
• a solution of paroxetine maleate which may be prepared by mixing together a solution of paroxetine free base, typically as the final stage of a manufacturing process, and a solution of maleic acid.
• solvents include toluene, butanone, acetone and dichloromethane. Propan-2- ol may also be used.
• Seeding with the desired polymorph may be incorporated into the process to ensure reliability of polymorph formation and to control crystal size distribution.
• Form B The processing properties of Form B are generally superior to those of Form A, since this polymorph is more granular and easier to filter, wash and dry. Consequently, this invention provides a particularly convenient manufacturing process for paroxetine (1 :1) maleate, in which unsuitable solvents are avoided and a solution of paroxetine free base is prepared in toluene and converted directly to the maleate salt.
• Known processes for the preparation of paroxetine utilize toluene as the solvent of choice.
• paroxetine maleate Form B disclosed herein there was no process available which had the convenience of using toluene solutions of free base as starting material, since treatment of such solutions generated paroxetine maleate in the form of an oil or gum.
• paroxetine maleate is to start with a salt of paroxetine with an organic acid, such as acetic acid, rather than using paroxetine free base.
• a salt of paroxetine with an organic acid such as acetic 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).
• the salt may obtained as a solvate, when during isolation from solution it becomes associated with the solvent in which it is dissolved. Any 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.
• water Prior to the isolation of the paroxetine maleate, water may be removed from the solution containing the salt 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 and propan-2-ol. It should also be appreciated that mixtures of solvents can also be used to aid the azeotropic removal of water.
• Paroxetine free base may be prepared according to the procedures generally outlined in US Patent No 4,007,196 and EP-B-0 223403. Maleic acid is 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.
• 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 lOOmg, WO 99/52901 P rC ⁇ T i /GB o 9 ? 9/01106
• 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 400mg of active ingredient calculated on a free base basis.
• the unit dose is taken once a day.
• Preferred unit dosage forms include tablets or capsules.
• 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.
• compositions include those described EP-B-0- 223403, and US 4,007,196 in which the products of the present invention may be used as the active ingredients.
• Paroxetine (1:1) Maleate Form B by recrystallization of Form A from butanone.
• paroxetine maleate Form A 0.5g
• butanone 4 ml
• the solution was allowed to cool slowly to room temperature to give a paroxetine maleate Form B as a granular white crystalline solid which was collected by filtration and dried in vacuo over phosphorous pentoxide.
• NMR showed a ratio of 1 : 1 for paroxetine : maleic acid, butanone content was approximately 0.1% by weight.
• IR nojol mull
• Paroxetine (1:1) Maleate Form A by recrystallization from acetonitrile.
• Paroxetine (1:1) Maleate Form B by recrystallization of Form A from toluene.
• paroxetine maleate Form A 0.5g
• toluene 8 ml
• a suspension of paroxetine maleate Form A (0.5g) in toluene (8 ml) was stirred vigorously with heating and approximately half the solvent was distilled off.
• a further 3 ml toluene was added and the reaction mixture cooled to room temperature. After 2 hours, the white solid which had formed was collected by filtration and dried, to afford paroxetine maleate
• Paroxetine (1:1) Maleate Form A by recrystallization from ethanol.
• Paroxetine (1:1) Maleate Form B by recrystallization of Form A from 3-pentanone.
• N-phenyloxycarbonyl paroxetine (5.00 kg ), potassium hydroxide flake (4.50 kg) and toluene (75.0 litres) was heated to reflux under a nitrogen atmosphere with good stirring over a period of 40 minutes. After stirring for 4 hr 45 min at reflux the contents of the reactor was allowed to cool to room temperature. Water (50 litres) was added and the mixture stirred for 30 minutes and then allowed to settle for 30 minutes. The lower aqueous layer was drained from the reactor and the remaining toluene solution was heated to reflux. Water was removed by heating to reflux with Dean and Stark apparatus. Toluene (11.5 litres) was added and a similar quantity of the reaction solvent removed by distillation.
• the remaining mixture was cooled to approximately 100°C, stirred vigorously, and a mixture of maleic acid (1.04 kg) and paroxetine maleate Form B (40 g) seed crystals added in four portions via a solids charging hopper.
• the temperature was reduced in stages whereupon crystallization commenced between 60°C and 50°C.
• the temperature was held at 40°C for two hours for the bulk of the crystallization to occur.
• NMR indicated a molar ratio 2: 1 paroxetine to maleic acid.
• Paroxetine maleate (1:1 or 2: 1) 20.00 mg based 30.0 mg based on free base on free base
• the tablets are made satisfactorily on a single punch or a Rotary press.
• Paroxetine maleate (1:1 or 2:1) 10 mg based on 20 mg based on 30 mg based on free base free base free base
• Paroxetine, Sodium Starch Glycollate and Dicalcium Phosphate Dihydrate are screened and mixed together in a suitable mixer.

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• 1999
  • 1999-04-09 JP JP2000543459A patent/JP2002511466A/ja active Pending
  • 1999-04-09 ID IDW20002033A patent/ID26879A/id unknown
  • 1999-04-09 AU AU34334/99A patent/AU3433499A/en not_active Abandoned
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  • 1999-04-09 SK SK1503-2000A patent/SK15032000A3/sk unknown
  • 1999-04-09 BR BR9909529-7A patent/BR9909529A/pt not_active Application Discontinuation
  • 1999-04-09 PL PL99343378A patent/PL343378A1/xx not_active Application Discontinuation
  • 1999-04-09 WO PCT/GB1999/001106 patent/WO1999052901A1/en not_active Application Discontinuation
  • 1999-04-09 KR KR1020007011214A patent/KR20010042552A/ko not_active Application Discontinuation
  • 1999-04-09 EP EP99915911A patent/EP1073652A1/en not_active Ceased
  • 1999-04-09 TR TR2000/02939T patent/TR200002939T2/xx unknown
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  • 1999-04-09 CA CA002327450A patent/CA2327450A1/en not_active Abandoned
• 2000
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