WO1998056787A1 - 4-Phenylpiperidin-Derivate - Google Patents

4-Phenylpiperidin-Derivate Download PDF

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Publication number
WO1998056787A1
WO1998056787A1 PCT/NL1997/000328 NL9700328W WO9856787A1 WO 1998056787 A1 WO1998056787 A1 WO 1998056787A1 NL 9700328 W NL9700328 W NL 9700328W WO 9856787 A1 WO9856787 A1 WO 9856787A1
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WO
WIPO (PCT)
Prior art keywords
group
alkyl
compound according
acid
paroxetine
Prior art date
Application number
PCT/NL1997/000328
Other languages
English (en)
French (fr)
Inventor
Franciscus Bernardus Gemma Benneker
Frans Van Dalen
Jacobus Maria Lemmens
Theodorus Hendricus Antonium Peters
Frantisek PÍCHA
Original Assignee
Synthon B.V.
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
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Priority to CA002293247A priority Critical patent/CA2293247C/en
Priority to PL97336895A priority patent/PL188450B1/pl
Priority to PCT/NL1997/000328 priority patent/WO1998056787A1/de
Priority to JP50212699A priority patent/JP2002503248A/ja
Priority to PT97926276T priority patent/PT994872E/pt
Priority to TR2002/01156T priority patent/TR200201156T2/xx
Priority to US08/872,023 priority patent/US5874447A/en
Priority to EP97926276A priority patent/EP0994872B9/de
Priority to BR9714787-7A priority patent/BR9714787A/pt
Priority to DK97926276T priority patent/DK0994872T3/da
Priority to AT97926276T priority patent/ATE200781T1/de
Priority to SK1619-99A priority patent/SK283394B6/sk
Priority to KR1019997011625A priority patent/KR100543614B1/ko
Priority to CZ19994295A priority patent/CZ295301B6/cs
Priority to IL13336697A priority patent/IL133366A/xx
Application filed by Synthon B.V. filed Critical Synthon B.V.
Priority to ES97926276T priority patent/ES2155995T3/es
Priority to DE29724281U priority patent/DE29724281U1/de
Priority to EEP200200633A priority patent/EE200200633A/xx
Priority to HU0003141A priority patent/HUP0003141A3/hu
Priority to TR1999/03025T priority patent/TR199903025T2/xx
Priority to EEP199900570A priority patent/EE03970B1/xx
Priority to EP00203910A priority patent/EP1078925A1/de
Priority to AU31080/97A priority patent/AU3108097A/en
Priority to SI9730138T priority patent/SI0994872T1/xx
Priority to DE69704679T priority patent/DE69704679T2/de
Priority to UA99126690A priority patent/UA53707C2/uk
Priority to US09/200,743 priority patent/US7598271B1/en
Publication of WO1998056787A1 publication Critical patent/WO1998056787A1/de
Priority to NO19995455A priority patent/NO317371B1/no
Priority to IS5249A priority patent/IS1927B/is
Priority to BG103980A priority patent/BG64315B1/bg
Priority to HK00106418A priority patent/HK1027352A1/xx
Priority to GR20010400220T priority patent/GR3035784T3/el
Priority to US09/855,710 priority patent/US6900327B2/en
Priority to NO20033766A priority patent/NO20033766D0/no
Priority to NO20033765A priority patent/NO20033765D0/no
Priority to IS7098A priority patent/IS7098A/is
Priority to US12/358,997 priority patent/US20090326233A1/en

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon 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
    • 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
    • A61P25/22—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
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • 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

Definitions

  • the present invention relates to a group of tri-substituted, 4-phenylpiperidines, to a process for preparing such compounds, to a medicament comprising such compounds, and to the use of such compounds for the manufacture of a medicament .
  • Paroxetine has been used as a therapeutic agent in the form of a salt with pharmaceutically acceptable acids.
  • the first clinical trials were conducted with the acetate salt.
  • paroxetine hydrochloride A known useful salt of paroxetine is the hydrochloride . This salt is considered to be the active substance in several marketed pharmaceutical products, e.g. Paxil or Seroxat . A number of forms of paroxetine hydrochloride have been described:
  • EP 223403 discloses paroxetine hydrochloride hemihydrate and pharmaceutical compositions based thereon. Most of these known salts of paroxetine have unsuitable physico-chemical characteristics for ensuring safe and efficient handling during production thereof and formulation into final forms, since they are unstable (acetate, maleate) and possess undesirable hygroscopi- city.
  • crystalline paroxetine hydrochloride hemihydrate approaches these problems, but as stated in WO 95/16448, its limited photostability causes undesired colouration during classical wet tabletting procedure. Moreover, crystalline paroxetine hydrochloride hemihydrate exhibits only limited solubility in water.
  • the aqueous solubility is low, for example less than 3 g/ml , the dissolution rate at in vivo administration could be rate-limiting in the absorption process.
  • the aqueous solubility of the paroxetine hemihydrate at room temperature exceeds this threshold by a relatively small margin.
  • an object of the present invention is to provide a compound with improved characteristics.
  • the present invention comprises a compound, and pharmaceutically acceptable salts, having the formula I:
  • - R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl
  • - R 1 represents hydrogen, trifluoro (C ) alkyl, alkyl or alkynyl ,
  • - X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, - R 2 represents:
  • phenyl group optionally substituted by one or more of the following groups :
  • the inventors have found that these compounds exhibit good stability and very high solubility. This yields the advantage that high concentrations of the compound are obtainable in small volumes.
  • the R group is preferably the 3,4 methylenedioxyphenyl group of the formula:
  • the X group is preferably a fluorine group attached to position 4 in the phenyl ring.
  • the R 2 group preferably represents a C1-C4 alkyl group, and most preferably represents a C1-C2 alkyl group in order to provide an optimum solubility.
  • the compounds can have a solubility at about 20 °C of at least about 10 mg/ml water, preferably having a solubility in water of at least 100, for example 500 and most preferably of at least 1000 mg/ml water.
  • a process for preparing a compound as above comprising the steps of mixing together a 4 phenylpiperidine compound, a salt and/or a base thereof having the formula II:
  • - R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl ,
  • - R represents hydrogen, trifluoro (C ⁇ _. ) alkyl, alkyl or alkynyl
  • - X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, . with a sulfonic acid of the general formula R_-S0 3 H, wherein R 2 represents: - a C1-C10 alkyl group,
  • phenyl group optionally substituted by one or more of the following groups:
  • the compounds of the invention can be prepared from the free base of the 4 phenylpiperidine, having the formula II, this preferably being paroxetine, by treatment with a sulfonic acid as defined above in a suitable solvent to form a solution of the desired acid addition salt, whereafter this is precipitated out of the solution.
  • the forming of a solution may preferably ' proceed at temperatures from about 0 °C to the boiling point of the solvent .
  • the solution may be purif ied by treatment of activated charcoal , silica gel , kieselguhr or other suitable materials .
  • the solution of a salt of the invention can be formed by dissolution of a salt of 4 phenyl piperidine having the formula II with an organic sulfonic acid .
  • the compounds of the invention may be prepared from a paroxetine C1 -C5 carboxylate , such as the acetate , by addition of corresponding organic sulfonic acid to the solution of the said carboxylate , as follows :
  • a medicament for use as a medicament and, according to a fifth aspect, a medicament comprising this compound, and to the use thereof for treating depressions, obsessive compulsive disorders, panic disorders, bulimia, anorexia, pain, obesity, senile demential, migraine, anorexia, social phobia, depressions arising from pre-menstrual tension.
  • a compound of the invention as a reagent in further syntheses. More specifically, the compounds of the present invention can be used as a start reagent for forming further acid addition salts, for example for providing further paroxetine acid addition salts, by reacting with a suitable reagent, i.e. with a corresponding acid.
  • a suitable reagent i.e. with a corresponding acid.
  • paroxetine acetate proceeds as follows :
  • the preparation of a further salt, as above, results in this further salt having a high purity.
  • the inventors have shown that such salts have a surprisingly high purity.
  • the compounds of the present invention can react with a base, such as an inorganic and/or an organic base, to form (liberate) free bases of the corresponding compounds.
  • a base such as an inorganic and/or an organic base
  • the free bases liberated from the compounds of the present invention have surprisingly higher purity than if prepared by known methods which is especially important in case of their use for production of pharmaceuticals .
  • the new compounds of the first aspect of the invention can also form hydrates and/or solvates by a contact with a corresponding reaction partner, i ⁇ e. with water and/or with a solvent.
  • a corresponding reaction partner i ⁇ e. with water and/or with a solvent.
  • further salts, hydrates and solvates for example these of paroxetine, are the: hydrochloride oxalate dihydrate hydrobromide succinate trihydrate hydroiodide tartrate hexahydrate acetate citrate methanolate propionate embonate ethanolate maleate hemihydrate fumarate hydrate
  • the inventors have shown that such salts have a surprisingly high purity.
  • bases which can be employed in the preparation of the free bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine and such like.
  • the compounds according to the present invention exhibit high solubility, they can be dosed, for example injected, in a high concentration, low volume solution, this method of dosing being particularly advantageous with certain patients, such as manic depressives and such like, i.e. patients who are unable or unwilling to swallow medicine.
  • compositions according to the present invention comprise a compound of the invention alone or together with a pharmaceutically acceptable carrier or diluent.
  • the preferred formulations are those for oral administration (tablets, capsules) but formulations for parenteral or topical administration are also within the scope of the invention.
  • the high water solubility of the compounds of the invention enables high dissolution rates in solid dosage forms based on the compounds of the invention to be obtained, during the in vitro release as well as good bioavailability after peroral application jLn vivo.
  • the tablets containing compounds of the present invention can be prepared both by tabletting procedure in which water is present (e.g. aqueous granulation) as well as by tabletting processing it which water is absent (direct compression, dry granulation) and may be coated by any suitable means of coating.
  • a seeding crystal of paroxetine methane sulfonate was made as follows:
  • Paroxetine p-toluene sulfonate from paroxetine 5.0 g (15 mmol) of paroxetine was dissolved in 25 ml of hot ethylacetate.
  • Paroxetine p-chlorobenzene sulfonate from paroxetine 1.1 g (3.3 mmol) of paroxetine was dissolved in 3 ml of hot ethylacetate.
  • Paroxetine acetate from paroxetine methane sulfonate 1.0 g (2.4 mmol) of paroxetine methane sulfonate in 5 ml of hot iso-propanol. To this solution was added 0.2 g (3.2 mmol) of acetic acid. The mixture was 0 placed at 4 °C overnight after which a solid was precipitated. The solid was filtered off and washed 3 times with 10 ml of ether and dried in a vacuumoven. 0.5 g (1.3 mmol) off white crystals were obtained 5 Yield 54%
  • the purity of the compound obtained was 99.5% (HPLC) .
  • the compounds of the invention are crystalline, with defined melting points, DSC curves and IR spectra. It cannot be excluded that, under different conditions of their formation and under specific conditions, they could exist also in other crystalline or polymorph modifications which may differ from those as described herein.
  • the compounds of the invention are also generally very stable and non-hygroscopic.
  • the present invention comprising acid addition salts with organic sulfonic acids are substantially free of the bound organic solvent.
  • the amount of bound organic solvent should be less than 2.0% (w/w) as calculated on the anhydrous basis. They nevertheless may contain crystallization water and also unbound water, that is to say water which is other than water of crystallization.
  • Table 2 and 3 examples of results of . hygroscopicity tests and stability tests ( in comparison with known salts of paroxetine) are presented.
  • paroxetine maleate m.p.: 128-130°C.
  • paroxetine acetate m.p.: 123-125°C.
  • H 3 , IH 2.50-3.00 (m, H 4 , H 2a ⁇ , H 6a ⁇ , 3H); 3.05-3.75 (m, H 2 H 6 H 7 , 3H);

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Psychiatry (AREA)
  • Obesity (AREA)
  • Hospice & Palliative Care (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/NL1997/000328 1997-06-10 1997-06-10 4-Phenylpiperidin-Derivate WO1998056787A1 (de)

Priority Applications (37)

Application Number Priority Date Filing Date Title
HU0003141A HUP0003141A3 (en) 1997-06-10 1997-06-10 4-phenylpiperidine derivatives, process for producing them and pharmaceutical compositions containing them
DE69704679T DE69704679T2 (de) 1997-06-10 1997-06-10 4-phenylpiperidin-derivate
PCT/NL1997/000328 WO1998056787A1 (de) 1997-06-10 1997-06-10 4-Phenylpiperidin-Derivate
JP50212699A JP2002503248A (ja) 1997-06-10 1997-06-10 ４−フェニルピペリジン化合物
PT97926276T PT994872E (pt) 1997-06-10 1997-06-10 Composto de 4-fenilpiperidina
TR2002/01156T TR200201156T2 (tr) 1997-06-10 1997-06-10 4-Fenilpiperidin bileşimleri.
US08/872,023 US5874447A (en) 1997-06-10 1997-06-10 4-Phenylpiperidine compounds for treating depression
EP97926276A EP0994872B9 (de) 1997-06-10 1997-06-10 4-phenylpiperidin-derivate
BR9714787-7A BR9714787A (pt) 1997-06-10 1997-06-10 Compostos de 4- fenilpiperidina e processo para sua preparação
DK97926276T DK0994872T3 (da) 1997-06-10 1997-06-10 4-phenylpiperidin-forbindelser
AT97926276T ATE200781T1 (de) 1997-06-10 1997-06-10 4-phenylpiperidin-derivate
SK1619-99A SK283394B6 (sk) 1997-06-10 1997-06-10 Zlúčeniny 4-fenylpiperidínu a jej farmaceuticky prijateľné soli, spôsob ich prípravy, liečivo s ich obsahom a ich použitie
KR1019997011625A KR100543614B1 (ko) 1997-06-10 1997-06-10 4-페닐피페리딘 화합물
TR1999/03025T TR199903025T2 (xx) 1997-06-10 1997-06-10 4-Fenilpiperidin bile�imleri.
IL13336697A IL133366A (en) 1997-06-10 1997-06-10 4-Phenylpiperidine compounds, process for their preparation and uses thereof
PL97336895A PL188450B1 (pl) 1997-06-10 1997-06-10 Pochodne 4-fenylopiperydyny, sposób wytwarzania pochodnych 4-fenylopiperydyny, zastosowanie pochodnej 4-fenylopiperydyny oraz środek farmaceutyczny
ES97926276T ES2155995T3 (es) 1997-06-10 1997-06-10 Compuestos de 4-fenilpiperidina.
DE29724281U DE29724281U1 (de) 1997-06-10 1997-06-10 4-Phenylpiperidin-Verbindungen
EEP200200633A EE200200633A (et) 1997-06-10 1997-06-10 Meetod triasendatud 4-fenüülpiperidiinühendi soola ja aluse vormide saamiseks, saadud soola ja aluse vormid
CA002293247A CA2293247C (en) 1997-06-10 1997-06-10 4-phenylpiperidine compounds
CZ19994295A CZ295301B6 (cs) 1997-06-10 1997-06-10 Deriváty 4-fenylpiperidinu, způsob jejich přípravy, jejich použití a lék je obsahující
EEP199900570A EE03970B1 (et) 1997-06-10 1997-06-10 4-fenüülpiperidiinühend, selle valmistamine ja kasutamine ning seda sisaldav ravim
EP00203910A EP1078925A1 (de) 1997-06-10 1997-06-10 4-Phenylpiperidin-Derivate
AU31080/97A AU3108097A (en) 1997-06-10 1997-06-10 4-phenylpiperidine compounds
SI9730138T SI0994872T1 (de) 1997-06-10 1997-06-10
UA99126690A UA53707C2 (uk) 1997-06-10 1997-10-06 Похідні 4-фенілпіперидину, спосіб їх отримання (варіанти) і фармацевтична композиція
US09/200,743 US7598271B1 (en) 1997-06-10 1998-11-30 Crystalline paroxetine methane sulfonate
NO19995455A NO317371B1 (no) 1997-06-10 1999-11-08 4-Fenylpiperidinforbindelser
IS5249A IS1927B (is) 1997-06-10 1999-11-16 4-fenýlpíperidín efnasambönd
BG103980A BG64315B1 (bg) 1997-06-10 1999-12-10 4-фенилпиперидинови соли, метод за получаването им и използването им като лекарствено средство
HK00106418A HK1027352A1 (en) 1997-06-10 2000-10-10 4-phenylpiperidine compounds
GR20010400220T GR3035784T3 (en) 1997-06-10 2001-04-26 4-phenylpiperidine compounds
US09/855,710 US6900327B2 (en) 1997-06-10 2001-05-16 4-phenylpiperidine compounds
NO20033765A NO20033765D0 (no) 1997-06-10 2003-08-25 4-Fenylpiperidinforbindelser
NO20033766A NO20033766D0 (no) 1997-06-10 2003-08-25 4-Fenylpiperidinforbindelser
IS7098A IS7098A (is) 1997-06-10 2004-01-08 4-fenýlpíperidín efnasambönd
US12/358,997 US20090326233A1 (en) 1997-06-10 2009-01-23 4-phenylpiperidine compounds

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
PCT/NL1997/000328 WO1998056787A1 (de) 1997-06-10 1997-06-10 4-Phenylpiperidin-Derivate
US08/872,023 US5874447A (en) 1997-06-10 1997-06-10 4-Phenylpiperidine compounds for treating depression

Publications (1)

Publication Number Publication Date
WO1998056787A1 true WO1998056787A1 (de) 1998-12-17

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/NL1997/000328 WO1998056787A1 (de) 1997-06-10 1997-06-10 4-Phenylpiperidin-Derivate

Country Status (26)

Country Link
US (4) US5874447A (de)
EP (2) EP1078925A1 (de)
JP (1) JP2002503248A (de)
KR (1) KR100543614B1 (de)
AT (1) ATE200781T1 (de)
AU (1) AU3108097A (de)
BG (1) BG64315B1 (de)
BR (1) BR9714787A (de)
CA (1) CA2293247C (de)
CZ (1) CZ295301B6 (de)
DE (2) DE29724281U1 (de)
DK (1) DK0994872T3 (de)
EE (2) EE03970B1 (de)
ES (1) ES2155995T3 (de)
GR (1) GR3035784T3 (de)
HK (1) HK1027352A1 (de)
HU (1) HUP0003141A3 (de)
IL (1) IL133366A (de)
IS (2) IS1927B (de)
NO (3) NO317371B1 (de)
PL (1) PL188450B1 (de)
PT (1) PT994872E (de)
SI (1) SI0994872T1 (de)
SK (1) SK283394B6 (de)
TR (2) TR199903025T2 (de)
WO (1) WO1998056787A1 (de)

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2336364A (en) * 1998-07-02 1999-10-20 Smithkline Beecham Plc Paroxetine methanesulfonate
WO1999052901A1 (en) * 1998-04-09 1999-10-21 Smithkline Beecham Plc Paroxetine maleate
WO2000001692A1 (en) * 1998-07-02 2000-01-13 Smithkline Beecham Plc Salts of paroxetine
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WO2002017921A2 (en) * 2000-08-28 2002-03-07 Synthon B.V. Paroxetine compositions and processes for making the same
WO2002022609A1 (fr) * 2000-09-14 2002-03-21 Asahi Glass Company, Limited Procede de production de sel de paroxetine sensiblement exempt de solvant organique
WO2003020717A1 (en) * 2001-08-02 2003-03-13 Spurcourt Limited Paroxetine isethionate salt, process of preparation and use in the treatment of depression
US9925174B2 (en) 2002-03-07 2018-03-27 Boehringer Ingelheim International Gmbh Administration form for the oral application of 3-[(2-{[4-(hexyloxycarbonyl-amino-imino-methyl)-phenylamino]-methyl}-1-methyl-1 H-benzimidazol acid ethyl ester and the salts thereof
WO2003082804A1 (en) * 2002-03-28 2003-10-09 Synthon B.V. Venlafaxine besylate
US8501777B2 (en) 2005-10-13 2013-08-06 Nsab, Filial Af Neurosearch Sweden Ab, Sverige 3,5-disubstituted phenyl-piperidines as modulators of dopamine neurotransmission
US11598776B2 (en) 2011-06-03 2023-03-07 Eisai R&D Management Co., Ltd. Biomarkers for predicting and assessing responsiveness of thyroid and kidney cancer subjects to lenvatinib compounds
RU2616610C2 (ru) * 2012-01-31 2017-04-18 Эйсай Ар Энд Ди Менеджмент Ко., Лтд. Производное пароксетина
US8933100B2 (en) 2012-01-31 2015-01-13 Eisai R&D Management Co., Ltd. Paroxetine derivative
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WO2013115163A1 (ja) * 2012-01-31 2013-08-08 エーザイ・アール・アンド・ディー・マネジメント株式会社 パロキセチン誘導体
US11207308B2 (en) 2012-04-04 2021-12-28 Prilenia Neurotherapeutics Ltd. Pharmaceutical compositions for combination therapy
US10259791B2 (en) 2014-08-28 2019-04-16 Eisai R&D Management Co., Ltd. High-purity quinoline derivative and method for manufacturing same
US11090386B2 (en) 2015-02-25 2021-08-17 Eisai R&D Management Co., Ltd. Method for suppressing bitterness of quinoline derivative
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