[go: up one dir, main page]

WO1999016769A1 - Resolution de composes optiquement actifs - Google Patents

Resolution de composes optiquement actifs Download PDF

Info

Publication number
WO1999016769A1
WO1999016769A1 PCT/AU1998/000807 AU9800807W WO9916769A1 WO 1999016769 A1 WO1999016769 A1 WO 1999016769A1 AU 9800807 W AU9800807 W AU 9800807W WO 9916769 A1 WO9916769 A1 WO 9916769A1
Authority
WO
WIPO (PCT)
Prior art keywords
mianserin
toluoyl
optically pure
substantially optically
tartrate salt
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.)
Ceased
Application number
PCT/AU1998/000807
Other languages
English (en)
Inventor
Roy William Jackson
Kamani Rupika Subasinghe
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.)
Polychip Pharmaceuticals Pty Ltd
Monash University
Original Assignee
Polychip Pharmaceuticals Pty Ltd
Monash University
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 AUPO9445A external-priority patent/AUPO944597A0/en
Priority claimed from AUPP0713A external-priority patent/AUPP071397A0/en
Priority claimed from AUPP1468A external-priority patent/AUPP146898A0/en
Application filed by Polychip Pharmaceuticals Pty Ltd, Monash University filed Critical Polychip Pharmaceuticals Pty Ltd
Priority to AU93302/98A priority Critical patent/AU9330298A/en
Priority to EP98946144A priority patent/EP1017695A4/fr
Publication of WO1999016769A1 publication Critical patent/WO1999016769A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Definitions

  • This invention relates to methods for separation of enantio ers of heterocyclic organic compounds, and in particular to methods for separation of enantiomers of mianserin and related compounds .
  • racemic mixtures of enantiomers during the synthesis of pharmacologically-active agents is a significant problem in the pharmaceutical industry. It is well known in the art that in many cases there is differential activity between the two enantiomers, and that in some cases deleterious side-effects are associated with one optical isomer but not with the other.
  • the complex structure of such molecules also means that their synthesis involves many steps, and consequently where chiral centres are present the compounds are usually prepared in the form of racemic mixtures.
  • the pharmacological activity is mediated by the binding of the pharmacological agent to a target site, which may be extracellular or intracellular .
  • the 3- dimensional interaction between the pharmaceutical agent and its target site results in the pharmacological action, either by stimulating a biological activity, or by blocking a biological activity which is mediated by the target site.
  • the more accurate the 3-dimensional fit between the pharmacological agent and its target site the more potent will be the pharmacological activity which results, and the lower the likelihood of unwanted side-effects.
  • Mianserin, ( ⁇ ) -1,2, 3,4, 10, 14b-hexahydro-2- methyldibenzo[c,f.pyrazino [1, 2- ⁇ ] azepine is an anti- depressant drug marketed under the name of Tolvin by Organon. Its synthesis was originally described in US Patent No.3534041 by Organon, and derivatives of mianserin are disclosed in British Patents No. 1498632 and No. 1498633. Normianserin (Chemical Abstracts No. 71936-92-0), also known as desmethylmianserin, has similar pharmacological activity to that of mianserin but is less potent (Pinder, 1985; Doggrell, 1985; Przegalinski et al, 1986).
  • a related class of dibenzo-pyrazino-azepines was disclosed in U.S. Patent No. 3,701,778 (van der Burg) . These compounds were selected to have anti-inflammatory, anti-serotonergic, anti-histamine and cardiovascular effects, while certain intermediates in their preparation were also pharmacologically active.
  • the compounds included oxazepines, thiazepines and diazepines, and a variety of synthetic routes for obtaining the desired products was set forth.
  • Mianserin and the closely related compound normianserin are serotonin antagonists, and in addition to their anti-depressant activity have anti-histamine activity, and therefore are useful in the treatment of allergies.
  • Synthetic methods for production of mianserin and normianserin result in a racemic mixture.
  • the (+) enantiomer of mianserin is either the active component of such mixtures, or has higher activity than the (-) enantiomer as a result of preferential binding to cell membranes .
  • anti-histamine agents which do not cross the blood-brain barrier, and consequently are non-sedating, for example terfenadine (Seldane; Hoechst Marion Roussel), astemizole (Hismanal; Janssen Pharmaceutica) and loratadine (Claritin; Schering Corporation) .
  • terfenadine Shieldane; Hoechst Marion Roussel
  • astemizole Hismanal; Janssen Pharmaceutica
  • loratadine loratadine
  • terfenadine interacts with certain anti-fungal drugs and antibiotics to cause life-threatening abnormalities of cardiac ventricular rhythm, as a result of inhibition by the anti-fungal agent or antibiotic of conversion of terfenadine to its active metabolite, terfenadine carboxylate (fexofenadine) .
  • Astemizole requires approximately a week to become effective, and therefore patients frequently exceed the recommended dose. This can result in abnormal heart rhythms or even cardiac arrest.
  • astemizole also interacts with certain anti- fungal agents and antibiotics in a similar manner to terfenadine, resulting in increased blood levels of atemizol. Elevated blood levels of loratadine can also result from such interactions, but so far no adverse cardiac effects have been reported. Thus there is a also a considerable need in the art for further non-sedating anti- histamine agents .
  • agents of this type which are currently in clinical use, only terfenadine and its metabolite fexofenadine, marketed under the name Allegra by Hoechst Marion Roussel, are chiral compounds, and both of these are marketed as racemates.
  • a method for separation of the enantiomers of terfenadine is described in International patent publication No. W095/31436 by Merrell Dow Pharmaceuticals Inc.
  • a substantially optically pure (+) -mianserin comprising the steps of:
  • a substantially optically pure (-) -mianserin comprising the steps of :
  • (+) -di-p-toluoyl-D-tartaric acid is referred to throughout the specification as the (+) -di- p-toluoyl-D-tartrate salt of mianserin, or simply as the (+) -di-p-toluoyl-D-tartrate salt .
  • the initial crystallisation step in either is performed using a ratio of mianserin to (-)-di-p- toluoyl-L-tartaric acid or (+) -di-p-toluoyl-D-tartaric acid (as appropriate) of 1:2-2.2.
  • the crystallisation steps are performed using hot absolute ethanol as solvent.
  • a method wherein the mother liquor remaining after the substantially optically pure crystals of the (-)-di-p- toluoyl-L-tartrate or (+) -di-p-toluoyl-D-tartrate salt form is subjected to treatment to isolate (+) -mianserin or (-)- mianserin, respectively.
  • Treatment of the mother liquor typically involves a molar ratio of mianserin to the tartaric acid enantiomer of about 1:1.1.
  • treatment to isolate (-)- mianserin comprises the steps of :
  • the treatment to isolate (+) -mianserin comprises the steps of :
  • the basification step is performed using 10% sodium hydroxide.
  • the final purification step may suitably be performed by extraction with ethyl acetate,
  • the method is also applicable to the preparation of mianserin-like compounds in optically pure form.
  • a mianserin-like compound is a compound prepared from mianserin as a precursor.
  • a purified enantiomer of mianserin prepared by the method of the invention may be used as starting material for preparation of a substantially pure (+) or (-) enantiomer, as appropriate, of a mianserin-like compound.
  • the mianserin- like compound is selected from the group consisting of compounds of general formula I :
  • Y H, CN or —(CH.) n — 1C.N .
  • R 3 H or lower alkyl
  • R 4 H, lower alkyl, or lower acyl.
  • a substantially optically pure (+)- or (-) -mianserin-like compound comprising the steps of:
  • (+)- or (-) -mianserin can be converted to (+) or (-) 2- cyanonormianserin by reaction with a cyanogen halide, preferably cyanogen bromide. Typically this reaction is conducted in dry benzene under an atmosphere of nitrogen. The product may be extracted with a 1:1 mixture of benzene and ether. - li ⁇
  • (+) or (-)-2- cyanonormianserin can be converted to (+)- or (-)-2- carboxamidino-1, 2,3,4,10, 14b-hexahydrodibenzo [c, f] pyrazino- [1,2- ⁇ ] azepine by reaction with an alkylhaloaluminium amide.
  • the alkylhaloaluminium amide is methylchloroaluminium amide generated in situ from trimethylaluminium and ammonium chloride.
  • (+) or (-)-2- cyanonormianserin can be converted to (+)- or (-)- normianserin, where necessary, and (+)- or (-) -mianserin- like compounds of the general formula I are prepared by:
  • R 1 is as defined above, and L is a leaving group selected from the group consisting of CH 3 0, CH 3 S, CH 3 S0 2 , S0 3 H, and 3,5-dimethylpyrazol-l-yl,
  • step (f) reacting N-cyanonormianserin with H 2 S as in step (c), reacting the thus-formed product with methyl iodide in a second step, and reacting the product of the second step with R ⁇ NH,
  • a substantially optically pure (+)- or (-) -mianserin-like compound Preferably the mianserin-like compound is FCC-5. More preferably, the compound is the (-) -enantiomer of FCC-5.
  • a pharmaceutical composition comprising (+)- or (-) -mianserin or a (+)- or (-)- mianserin-like compound and a pharmaceutically acceptable carrier .
  • a method for the treatment of disturbances of 5-hydroxytryptamine metabolism and/or h stamine metabolism in a mammal comprising the step of administering to a mammal suffering from such disturbance a pharmacologically effective amount of a substantially optically pure (+)- or (-) -mianserin-like compound.
  • a substantially optically pure (+) or (-) -mianserin-like compound in the treatment of disturbances of 5-hydroxytryptamine metabolism and/or histamine metabolism.
  • an eighth aspect of the present invention there is provided use of a substantially optically pure (+) or (-) -mianserin-like compound in the preparation of a medicament for the treatment of disturbances of 5-hydroxytryptamine metabolism and/or histamine metabolism.
  • (+) Tartaric acid (0.30 g, 0.0019 ol) dissolved in hot absolute ethanol (5 ml) was added with stirring to a hot solution of racemic mianserin (0.5 g, 0.0018 mol) in absolute ethanol (10 ml) .
  • the salt separated as white crystals.
  • the salt was fractionally recrystallised, and after three recrystallisations material with almost constant rotation of [ ⁇ ] D +38.6° was obtained.
  • the mother liquors yielded material of [ ⁇ ] D -20°.
  • Liberation of free mianserin by base treatment of the salt with [ ⁇ ] D +38.6° gave material with [ ⁇ ] +48.8°.
  • (+) and (-) isomers of FCC-5 were prepared in two steps from (+) and (-) isomers of mianserin.
  • Each isomer of mianserin was first converted to 2-cyanonormianserin (2-Cyano-1,2,3,4,10, 14b-hexahydrodibenzo- [c, f]pyrazino [1,2- ⁇ ] azepine) using cyanogen bromide in benzene.
  • 2-cyanonormianserin was then converted to FCC-5 according to the method of Garigipati (Garigipati, 1990) .
  • the (+) and (-) isomers of FCC-5 were prepared as described in Example 4. Other compounds used were histamine diphosphate and mepyramine maleate (Sigma, MO, USA). Saline (NaCl, 0.9% w/v) was used as the vehicle for all drugs. FCC-5 was dissolved in saline at a concentration of 1 mM, and the solution was sonicated and slightly warmed to aid solubility. Concentrations of the test compounds are expressed as molar concentrations .
  • Guinea pigs were killed instantly by exposure to halothane and exsanguination. An approximate 2 cm length of ileum was removed and mounted in a 15 mL organ bath containing Krebs solution of the following composition (mM) : NaCl 97.0, KC1 3.0, CaC12 1.89, MgSo4 1.0, KH2P04
  • Figure 1 shows the time course for the recovery during washing of the antagonism of histamine by both FCC-5 isomers and mepyramine (15 min contact time) .
  • the response of the ileum to histamine was significantly antagonised in the presence of either isomer of FCC-5 (10 nM) , after
  • the antihistaminic properties of the isomers of FCC-5 have been demonstrated in vitro for the first time. Both isomers of FCC-5 produced potent antagonism of contractile responses to histamine in the isolated guinea pig ileum, an effect mediated by HI receptors.
  • a distinguishing characteristic of the antihistaminic effect of FCC-5 (-) -isomer in the isolated ileum was the relatively rapid onset of this effect, within 15 min, and the subsequent lack of return of responses to histamine following washing of the tissue to remove the antagonist.
  • the effect of FCC-5 (+) -isomer or mepyramine could be fully reversed with washing.
  • FCC-5 (-) -isomer produces a non-competitive type of antagonism or a specific antihistaminic effect with slow dissociation of FCC-5 (-) -isomer from its Hi binding sites.
  • FCC-5 (+) -isomer acts more like a competitive Hi receptor antagonist, similarly to mepyramine.
  • racemic FCC-5 which also showed powerful and long-lasting antihistamine properties in vitro and in vivo, particularly in the .guinea pig respiratory system.
  • Our results with FCC-5 (-) -isomer suggest that this compound is a nonsedating antihistamine which has significant therapeutic potential for the treatment of allergic disease.
  • the purified enantiomers provided by the method of the invention are useful in the treatment of disturbances of 5-hydroxytryptamine and/or histamine metabolism in a mammal, hence they are useful as non- sedating anti-histamines for the treatment of asthma or an allergic condition and in the treatment of conditions such as depression, hypertension, congestive heart failure, migraine, anxiety, schizophrenia, gastrointestinal disturbances, diarrhoea and emesis.
  • Przegalinski E., Rawlow, A., and Dohnal-Borak, L. Polish J. Pharmacol. Pharm., 1986 38 69-75.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention concerne des procédés de séparation d'énantiomères de miansérine ou de composés du type miansérine au moyen d'acide (+)- ou (-)-di-p-toluoyl-(L) ou (D) tartrique. L'invention a également pour objet des composés du type miansérine (+) ou (-) optiquement purs et des préparations pharmaceutiques renfermant ces composés. En outre, l'invention concerne des procédés pour le traitement des troubles du métabolisme de la 5-hydroxytrytamine et de l'histamine, ainsi que pour le traitement d'affections telles que dépression, hypertension, insuffisance cardiaque congestive, migraines, anxiété, schizophrénie, troubles gastro-intestinaux, diarrhée, asthme ou allergie. Le composé du type miansérine présente la formule (1) dans laquelle X = CH2, O, S ou NR4, et Y = H, CN ou est de formule (2), Z = O, S ou NR2.
PCT/AU1998/000807 1997-09-26 1998-09-25 Resolution de composes optiquement actifs Ceased WO1999016769A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU93302/98A AU9330298A (en) 1997-09-26 1998-09-25 Resolution of optically-active compounds
EP98946144A EP1017695A4 (fr) 1997-09-26 1998-09-25 Resolution de composes optiquement actifs

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
AUPO9445 1997-09-26
AUPO9445A AUPO944597A0 (en) 1997-09-26 1997-09-26 Resolution of optically-active compounds
AUPP0713 1997-12-03
AUPP0713A AUPP071397A0 (en) 1997-12-03 1997-12-03 Resolution of optically-active compounds
AUPP1468 1998-01-23
AUPP1468A AUPP146898A0 (en) 1998-01-23 1998-01-23 Resolution of optically-active compounds

Publications (1)

Publication Number Publication Date
WO1999016769A1 true WO1999016769A1 (fr) 1999-04-08

Family

ID=27158043

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU1998/000807 Ceased WO1999016769A1 (fr) 1997-09-26 1998-09-25 Resolution de composes optiquement actifs

Country Status (2)

Country Link
EP (1) EP1017695A4 (fr)
WO (1) WO1999016769A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058353A3 (fr) * 2002-12-24 2004-09-23 Amedis Pharm Ltd Utilisation therapeutique d'inhibiteurs selectifs de recaptage de noradrenaline
CN118852173A (zh) * 2024-09-23 2024-10-29 南京桦冠生物技术有限公司 一种盐酸米安色林新晶型及其制备方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1838767A (en) * 1966-03-12 1968-09-05 N. V. Organon New biologically active derivatives of piperazine and process for the manufacture thereof
WO1988007997A1 (fr) * 1987-04-10 1988-10-20 Monash University DERIVES AZEPINO DE 1,2,3,4,10,14b-HEXAHYDRODIBENZO [c,f] PYRAZINO-[1,2-a] ET ANALOGUES 10-AZA, 10-OXA AND 10-THIA ANALOGUES
EP0421823A2 (fr) * 1989-10-05 1991-04-10 Sankyo Company Limited Composés tétracycliques à activité anti-allergique et anti-asthmatique, leur préparation et utilisation

Family Cites Families (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL129434C (fr) * 1966-03-12
NL154511B (nl) * 1967-07-07 1977-09-15 Organon Nv Werkwijze ter bereiding van piperazinederivaten, werkwijze ter bereiding van een farmaceutisch preparaat, dat een dergelijke verbinding bevat en vormstukken bereid volgens deze werkwijze.
NL7107667A (fr) * 1971-06-04 1972-12-06
NL179906C (nl) * 1974-02-09 1986-12-01 Akzo Nv Werkwijze voor het bereiden van 1,2,3,4,10,14b-hexahydrodibenzo(c,f)pyrazino (1,2-a)azepine derivaten.
DE3008716A1 (de) * 1980-03-07 1981-09-24 Licentia Patent-Verwaltungs-Gmbh, 6000 Frankfurt Verfahren zum transformatorischen ansteuern eines als stellglied arbeitenden schalttransistors eines gleichspannungswandlers
JP2892574B2 (ja) * 1990-10-04 1999-05-17 三共株式会社 光学活性なヘテロ四環系化合物
JPH05194522A (ja) * 1991-10-23 1993-08-03 Sankyo Co Ltd ヘテロ四環性化合物
JPH07247286A (ja) * 1994-01-18 1995-09-26 Sankyo Co Ltd 含窒素環状化合物の光学分割方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU1838767A (en) * 1966-03-12 1968-09-05 N. V. Organon New biologically active derivatives of piperazine and process for the manufacture thereof
AU3975768A (en) * 1968-06-26 1970-01-08 Piperazine derivatives
WO1988007997A1 (fr) * 1987-04-10 1988-10-20 Monash University DERIVES AZEPINO DE 1,2,3,4,10,14b-HEXAHYDRODIBENZO [c,f] PYRAZINO-[1,2-a] ET ANALOGUES 10-AZA, 10-OXA AND 10-THIA ANALOGUES
EP0421823A2 (fr) * 1989-10-05 1991-04-10 Sankyo Company Limited Composés tétracycliques à activité anti-allergique et anti-asthmatique, leur préparation et utilisation

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
ACTA PSYCHIATR. SCAND., 1985, 72 (Suppl. 320), R.M. PINDER, "Adrenoreceptor Interactions of the Enantiomers and Metabolites of Mianserin: Are they Responsible for the Antidepressant Effect?", pages 1-9. *
BULL. CHEM. SOC. JPN., 69, (1996), H. TOMORI et al., "Facile Optical Resolution of a Dibenzopyrazinoazepine Derivative and the Nature of Molecular Recognition of Amines by Chiral 2.3-Di-O-(Arylcarbonyl) Tartaric Acids", pages 3581-3590. *
CHEMICAL ABSTRACTS, 124:176146, "Optical Resolution of Nitrogen-Containing Cyclic Compound"; & JP,A,07 247 286 (SANKYO CO LTD) 26 September 1995. *
See also references of EP1017695A4 *
THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS, Vol. 278, E. KOYAMA et al., "Identification of Human Cytochrome P450 Isoforms Involved in the Stereoselective Metabolism of Mianserin Enantiomers", pages 21-30. *
VOGEL'S TEXTBOOK OF PRACTICAL ORGANIC CHEMISTRY, 5th Ed., Section 5.19, Resolution of Racemates, pages 809-810, Experiment 5.219, pages 812-813. *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004058353A3 (fr) * 2002-12-24 2004-09-23 Amedis Pharm Ltd Utilisation therapeutique d'inhibiteurs selectifs de recaptage de noradrenaline
CN118852173A (zh) * 2024-09-23 2024-10-29 南京桦冠生物技术有限公司 一种盐酸米安色林新晶型及其制备方法

Also Published As

Publication number Publication date
EP1017695A4 (fr) 2002-01-16
EP1017695A1 (fr) 2000-07-12

Similar Documents

Publication Publication Date Title
DK2200610T3 (en) ADMINISTRATION OF PIMAVANSERIN WITH OTHER AGENTS
KR100299734B1 (ko) 1,4-(디페닐알킬)피페라진유도체
JP6782255B2 (ja) ヒストンデアセチラーゼ阻害薬及び組成物並びにそれらの使用の方法
EP1499589B1 (fr) Derives de n-¬phenyl(piperidin-2-yl)methyl|benzamide, leur preparation et leur application en therapeutique
EP4324828A1 (fr) Composés d'acide carboxylique aromatique substitués bicycliques
EP3519418B1 (fr) Dérivés de pipéridine pontés
TW201920166A (zh) 二氫吡咯並吡啶衍生物
CN1481360A (zh) 蕈毒碱拮抗剂
EP0558487B1 (fr) Preparation et utilisation de composes de piperidine
US6124287A (en) Imidazo[1,2-a]quinoxalin-4-amines active as adenosine antagonists, process for their preparation and pharmaceutical compositions thereof
SK32597A3 (en) 2,7-substituted octahydro-1h-pyrido[1,2-a]pyrazine derivatives
US5049637A (en) 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino-[1,2-a]azepino derivatives and 10-aza, 10-oxa and 10-thia analogues
PT98773B (pt) Processo para a preparacao de di-hidropirido/4,3-d/pirimidinas substituidas na posicao 4 e de composicoes farmaceuticas analgesicas e antiinflamatorias que as contem
NZ248776A (en) Imidazole-substituted piperidine derivatives; pharmaceutical compositions and preparatory methods
WO1999016769A1 (fr) Resolution de composes optiquement actifs
EP3233799B1 (fr) Ligands du récepteur d2 de la dopamine
HU211156A9 (en) Condensed diazepinones
US5874458A (en) 2,3-dihydro-1H-isoindole derivatives and their use as serotonin reuptake inhibitors
AU2013221406B2 (en) Peripherally restricted diphenyl purine derivatives
AU9330298A (en) Resolution of optically-active compounds
EP2277882A1 (fr) Composés pipéridiniques, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
NL8603236A (nl) Optisch actieve 2-chloor-12-(3-dimethylamino-2-methyl-propyl)-12h-dibenzod,g1,3,6dioxazocinen en een werkwijze voor de bereiding ervan.
CZ20023694A3 (cs) Tosylátové soli 4-(p-fluorfenyl)-piperidin-3-methanolů
EP1748043B1 (fr) Composés 1,1-pyridinyloxycyclopropanamines polysubstitués, leur procédé de préparation et les compositions pharmaceutiques qui les contiennent
JP3033181B2 (ja) ９―ジアシルアミノテトラヒドロアクリジン誘導体

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GD GE GH GM HR HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 93302/98

Country of ref document: AU

WWE Wipo information: entry into national phase

Ref document number: 1998946144

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: KR

WWE Wipo information: entry into national phase

Ref document number: 09509311

Country of ref document: US

WWP Wipo information: published in national office

Ref document number: 1998946144

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

NENP Non-entry into the national phase

Ref country code: CA

WWW Wipo information: withdrawn in national office

Ref document number: 1998946144

Country of ref document: EP