WO1999051575A1 - N-aryloxyethyl-indoly-alkylamines utilisees pour le traitement de la depression (principes actifs de recepteurs du type 5-ht1a) - Google Patents

N-aryloxyethyl-indoly-alkylamines utilisees pour le traitement de la depression (principes actifs de recepteurs du type 5-ht1a) Download PDF

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Publication number
WO1999051575A1
WO1999051575A1 PCT/US1999/007621 US9907621W WO9951575A1 WO 1999051575 A1 WO1999051575 A1 WO 1999051575A1 US 9907621 W US9907621 W US 9907621W WO 9951575 A1 WO9951575 A1 WO 9951575A1
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WIPO (PCT)
Prior art keywords
indol
ethyl
yloxy
amine
fluoro
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PCT/US1999/007621
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English (en)
Inventor
Richard Eric Mewshaw
Dahui Zhou
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American Home Products Corporation
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Publication date
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU33861/99A priority Critical patent/AU3386199A/en
Priority to JP2000542296A priority patent/JP2002510675A/ja
Priority to EP99915317A priority patent/EP1070050A1/fr
Priority to CA002327359A priority patent/CA2327359A1/fr
Publication of WO1999051575A1 publication Critical patent/WO1999051575A1/fr

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    • 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
    • C07D401/12—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 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
    • A61P25/24—Antidepressants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • 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 compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems. More specifically, the present invention is directed to aryloxyethyl-indoly-alkylamine derivatives useful for the treatment of such diseases.
  • compositions which enhance neurotransmission of serotonin are useful for the treatment of many psychiatric disorders, including depression and anxiety.
  • the first generation of non-selective serotonin-affecting compounds operated
  • SSRIs selective serotonin reuptake inhibitors
  • the present invention relates to a new class of molecules which have the ability 35 to act concommitantly at the 5-HT1A autoreceptors and with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of anxiety or depression, as well as other serotonin disorders.
  • U.S. Patent No. 3,371,098 discloses sec. and tert. indolylethylamines useful as sedatives, anticonvulsants and analegesics.
  • U.S. Patent No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as alpha- 1-adrenergic receptor antagonists for the treatment of cardiovascular disorders.
  • EP 0722 941 A2 discloses the preparation of a series of hetero-oxy alkanamines of the following formula for the treatment of depression and other disorders for which serotonin uptake inhibitors are normally used. x I
  • Japanese Patents 05255302 and 09040648 disclose the following compounds which are reported to be useful for the treatment of central nervous system-related diseases, such as anxiety and depression.
  • the compounds of the present invention invention are aminomethyl benzoxezine indoles represented by Formula I:
  • R j is hydrogen, lower alkyl, or aryl
  • R 2 is hydrogen, lower alkyl, phenyl, or substituted phenyl
  • X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl group;
  • Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, they are not present at the ortho position; W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and n is 2-5; or pharmaceutically acceptable salts thereof.
  • the present invention is further derived to pharmaceutical compounds containing such compounds, as well as methods for alleviating symptoms of depression comprising administering the present compounds to a patient in need thereof.
  • the compounds of the present invention are those represented by
  • R j is hydrogen, methyl or aryl
  • R 2 is hydrogen
  • X and Y are each, independently, hydrogen, halogen or lower alkoxy, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydrofuranyl group; - 4 -
  • Z is hydrogen, halogen or lower alkoxy; with the proviso that when X, Y or Z are lower alkoxy they are not present at the ortho position; W is hydrogen or halogen; and n is 2-4; or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention are selected from the following:
  • lower alkyl and “lower alkoxy” are meant to include both straight and branched carbon chains containing 1 to 6 carbon atoms.
  • halogen is meant to include fluorine, chlorine, bromine, and iodine.
  • substituted phenyl is meant to include a phenyl moiety substituted with an alkyl, halogen, or alkoxy group.
  • aryl is meant to include aromatic radicals containing 6-12 carbon atoms.
  • the compounds of Formula I may advantageously be used in the form of the pharmaceutically acceptable acid addition salts thereof.
  • Such salts may be formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
  • inorganic or organic acids for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedis
  • the compounds of the present invention may be prepared by any suitable method known to those skilled in the art. However, the present compounds may be advantageously prepared according to any one of Schemes 1 to 10 set forth below. In the Schemes, the intermediate compounds discussed hereinafter are identified in parenthesis. The compound produced in each of Schemes 1 to 10 is identified with reference to the appropriate, corresponding Example.
  • the fumarate salt was prepared in ethanol: mp 121.5 -122°C: Elemental analysis for C I6 H 19 NO 2 » C 4 H 4 O 4
  • triphenylphosphine 2.6 g, 9.9 mmol
  • 2-chloroethanol 2-chloroethanol
  • DIAD diisopropyl azidodicarbimide
  • 6-Fluorochroman-8-carbaldehyde To a solution of 6-fluorochroman (0.7 g, 4.6 mmol) in anhydrous methylene chloride (20 ml) was added TiCl 4 (1.57 g, 8.3 mmol) and ⁇ , ⁇ '-dichloromethyl methyl ether (0.53 g, 4.6 mmol) slowly at 0°C. The reaction was allowed to reach room temperature slowly and stirred for 16 hours. The reaction mixture was poured into ice- water, extracted with methylene chloride (3 x 100 ml), washed with saturated sodium carbonate (5 x 150 ml) and brine (3 x 100ml).
  • This compound was prepared in the manner described for 45(a) above by replacing 4-indanol with 5,6,7,8-tetrahydro-l-naphthol (4 g, 0.027 mol) ) in 46% yield (2.57 g) as a clear oil.
  • This compound was prepared in the manner described for 45(a) above by replacing 4-indanol with 1-naphthol (5 g, 0.035 mol) ) in 82% yield (6.34 g) as a clear oil.
  • the oxalate salt was prepared in ethanol: mp 185-188°C Elemental analysis for C 19 H 20 F 2 N 2 O 2 » C 2 H 2 O 4
  • the oxalate salt was prepared in ethanol: mp 188-189°C Elemental analysis for C 19 H 21 FN 2 O 2 « C 2 H 2 O 4 « 0.25H 2 O Calc'd C, 59.04; H, 5.63; N, 6.62
  • the oxalate salt was prepared in ethanol: mp 197.5-198.5°C Elemental analysis for C 20 H 22 N 2 O 3 »C 2 H 2 O 4
  • the fumarate salt was prepared in isopropanol: mp 189.5-190.5°C
  • the oxalate salt was prepared in ethanol: mp 213-214°C
  • the oxalate salt was prepared in isopropanol: mp 214-215°C
  • the oxalate salt was prepared in ethanol: mp 201-203°C
  • the oxalate salt was prepared in THF: mp 181-183 °C
  • the fumarate salt was prepared in ethanol: mp 203-205°C Elemental analysis for C 23 H 24 N 2 O » 0.5C 4 H 4 O 4 «0.25H 2 O Calc'd: C, 73.78; H,6.56; N, 6.88
  • the PCR cloning of the human 5-HT 1A receptor subtype from a human genomic library has been described previously Chanda et al., Mol. Pharmacol.. 43:516 (1993).
  • a stable Chinese hamster ovary cell line expressing the human 5-HT 1A receptor subtype (5-HT 1A .CHO cells) was employed throughout this study. Cells were maintained in DMEM supplemented with 10% fetal calf serum, non-essential amino acids and penicillin/ streptomycin.
  • Cells were grown to 95-100% confluency as a monolayer before membranes were harvested for binding studies. Cells were gently scraped from the culture plates, transferred to centrifuge tubes, and washed twice by centrifugation (2000 rpm for 10 min., 4°C) in buffer (50 mM Tris; pH 7.5). The resulting pellets were aliquoted and placed at -80°C. On the day of assay, the cells were thawed on ice, and resuspended in buffer. Studies were conducted using [ 3 H]8-OH-DPAT as the radioligand. The binding assay was performed in 96 well microtiter plates in a final total volume of 250 ⁇ L of buffer.
  • the [ 35 S]-GTP ⁇ S binding assay was similar to that disclosed by Lazareno and Birdsall, Br. J. Pharmacol.. 109: 1120, (1993). Briefly, 5-HT 1A cloned receptor membrane fragments (as used for 5-HT 1A receptor binding assays) were stored at -70 °C until needed. When needed, membranes were rapidly thawed, centrifuged at 40,000 x g for 10 minutes and resuspended at 4 °C for 10 minutes in assay buffer (25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCI, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0).
  • assay buffer 25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCI, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0.
  • the following assays were performed by incubating the cells with DMEM containing 25 mM HEPES, 5 mM theophylline and 10 ⁇ M pargyline for a period of 20 minutes at 37°C. Functional activity was assessed by treating the cells with forskolin (1 uM final concentration) followed immediately by test compound (6 concentrations) for an additional 10 min at 37°C. In separate experiments, 6 concentrations of antagonist were preincubated for 20 min prior to the addition of 10 nM 8-OH-DPAT and forskolin. The reaction was terminated by removal of the media and addition of 0.5 ml -42- ice cold assay buffer. Plates were stored at -20°C prior to assessment of cAMP formation by a cAMP SPA assay (Amersham).
  • the compounds of the present invention are active towards 5HT1 A receptors and generally elevate serotonin levels by inhibiting 5-HT transport. Accordingly, the present compounds should be useful in treating disorders related to defects in serotonin concentration.
  • the compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers.
  • Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient. Any of the solid carriers known to those skilled in the art may be used with the compounds of this invention.
  • Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention.
  • the compounds of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo- regulators.
  • liquid carriers for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) and their derivatives and oils (e.g., fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carriers are used to prepare compositions for parenteral administration. - 44 -
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • Compositions for oral administration may be either in liquid or solid composition form.
  • the pharmaceutical compositions containing the compounds of this invention are in unit dosage form, e.g., tablets or capsules.
  • the compositions may be sub-divided in unit doses containing appropriate quantities of the present compounds.
  • the unit dosage forms can be packaged compositions, for example, packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids.
  • the unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
  • the therapeutically effective amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors, including the weight, age, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg.
  • Projected daily dosages of active compound are about 0.01 to about 100 mg/kg body weight. The daily dose can be conveniently administered two to four times per day.

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  • Chemical & Material Sciences (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

L'invention concerne des composés servant à atténuer les symptômes de la dépression (principes actifs de récepteurs du type 5-HT1A). Ces composés sont représentés par la formule (I), dans laquelle R1 représente hydrogène, alkyle inférieur ou aryle; R2 représente hydrogène, alkyle inférieur, phényle ou phényle substitué; X et Y représentent chacun indépendamment hydrogène, alkyle inférieur, alcoxy inférieur ou halogène ou se combinent aux atomes de carbone auxquels ils sont liés, de façon à former un groupe cyclopentyle, cyclohexyle, phényle, pyrrolyle, pyranyle, pyridinyle, dihydrofuranyle, furanyle, dioxanyle, oxazolyle ou isoxazolyle; Z représente hydrogène, halogène ou alcoxy inférieur; à condition que lorsque X, Y ou Z représentent alcoxy inférieur, ils ne soient pas présents dans la position ortho; W représente hydrogène, halogène, alkyle inférieur, cyano ou un groupe trifluorométhyle; et n est compris entre 2 et 5. L'invention concerne également des sels pharmaceutiquement acceptables desdits composés.
PCT/US1999/007621 1998-04-08 1999-04-07 N-aryloxyethyl-indoly-alkylamines utilisees pour le traitement de la depression (principes actifs de recepteurs du type 5-ht1a) WO1999051575A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU33861/99A AU3386199A (en) 1998-04-08 1999-04-07 N-aryloxyethyl-indoly-alkylamines for the treatment of depression (5-ht1a receptor active agents)
JP2000542296A JP2002510675A (ja) 1998-04-08 1999-04-07 うつ病治療用のｎ−アリールオキシエチル−インドリル−アルキルアミン（５−ｈｔ１ａ受容体活性薬）
EP99915317A EP1070050A1 (fr) 1998-04-08 1999-04-07 N-aryloxyethyl-indoly-alkylamines utilisees pour le traitement de la depression (principes actifs de recepteurs du type 5-ht1a)
CA002327359A CA2327359A1 (fr) 1998-04-08 1999-04-07 N-aryloxyethyl-indoly-alkylamines utilisees pour le traitement de la depression (principes actifs de recepteurs du type 5-ht1a)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US5725298A 1998-04-08 1998-04-08
US09/057,252 1998-04-08

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WO1999051575A1 true WO1999051575A1 (fr) 1999-10-14

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EP (1) EP1070050A1 (fr)
JP (1) JP2002510675A (fr)
CN (1) CN1304403A (fr)
AU (1) AU3386199A (fr)
CA (1) CA2327359A1 (fr)
WO (1) WO1999051575A1 (fr)

Cited By (7)

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Publication number Priority date Publication date Assignee Title
JP2003530319A (ja) * 2000-02-11 2003-10-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング インドル−３−イル誘導体
FR2845992A1 (fr) * 2002-10-16 2004-04-23 Pf Medicament Derives de 3-(cyclopenten-1yl)-benzyl-ou3-(cyclopenten-1yl)- heteroarylmethyl-amines et leur utilisation a titre de medicaments pour le traitement de la schizophrenie
WO2004074281A1 (fr) * 2003-02-18 2004-09-02 Merck Patent Gmbh Benzofuranoxyethylamines servant d'antidepresseurs et d'anxiolytiques
WO2006061376A1 (fr) * 2004-12-08 2006-06-15 Solvay Pharmaceuticals B.V. Derives d'aryloxyethylamine a action combinee d'agonisme partiel des recepteurs de la dopamine-d2 et d'inhibition du recaptage de la serotonine
WO2003011210A3 (fr) * 2001-07-31 2007-10-25 Astrazeneca Ab Derives d'aryl heteroalkalylamine et leur utilisation en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
US7371769B2 (en) 2004-12-07 2008-05-13 Solvay Pharmaceuticals B.V. Tetrahydropyridin-4-yl indoles with a combination of affinity for dopamine-D2 receptors and serotonin reuptake sites
US8101619B2 (en) 2004-12-08 2012-01-24 Solvay Pharmaceuticals B.V. Phenylpiperazine derivatives with a combination of partial dopamine-D2 receptor agonism and serotonin reuptake inhibition

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DE10305739A1 (de) * 2003-02-11 2004-08-19 Merck Patent Gmbh Benzofuranderivate

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NELSON,D.L.: "Structure-Activity Relationships at 5-HT1A Recpeotrs: Binding Profiles and Intrinsic Activity", PHARMACOL.BIOCHEM.BEHAV., vol. 40, 1991, pages 1041 - 1051, XP002114414 *
SLEIGHT A J ET AL: "IDENTIFICATION OF 5-HYDROXYTRYPTAMINE1A RECEPTOR AGENTS USING A COMPOSITE PHARMACOPHORE ANALYSIS AND CHEMICAL DATABASE SCREENING", NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY, vol. 343, 1 January 1991 (1991-01-01), pages 109 - 116, XP000650292 *

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2003530319A (ja) * 2000-02-11 2003-10-14 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフトング インドル−３−イル誘導体
JP4938194B2 (ja) * 2000-02-11 2012-05-23 メルク パテント ゲゼルシャフト ミット ベシュレンクテル ハフツング インドル−３−イル誘導体
WO2003011210A3 (fr) * 2001-07-31 2007-10-25 Astrazeneca Ab Derives d'aryl heteroalkalylamine et leur utilisation en tant qu'inhibiteurs de la synthase de l'oxyde nitrique
US7163957B2 (en) 2002-10-16 2007-01-16 Pierre Fabre Medicament 3-(Cyclopenten-1-yl)-benzyl-or 3-(cyclopenten-1-yl)-heteroarylmethyl-amine derivatives and use thereof as medicines for treating schizophrenia
JP2006508080A (ja) * 2002-10-16 2006-03-09 ピエール、ファーブル、メディカマン ３−（シクロペンテン−１−イル）−ベンジル−または３−（シクロペンテン−１−イル）−ヘテロアリールメチルアミン誘導体および統合失調症を治療するための医薬としてのそれらの使用
CN1319962C (zh) * 2002-10-16 2007-06-06 皮埃尔法布雷医药公司 3－(环戊烯－1－基)－苄基(或杂芳基甲基)胺衍生物及其制备治疗精神分裂症的药物的用途
US7235568B2 (en) 2002-10-16 2007-06-26 Pierre Fabre Medicament 3-(cyclopenten-1-yl)-benzyl-or 3-(cyclopenten-1-yl)-heteroarylmethyl-amine derivatives and use thereof as medicines for treating schizophrenia
WO2004035561A1 (fr) * 2002-10-16 2004-04-29 Pierre Fabre Medicament Derives de 3-(cyclopenten-1-yl)-benzyl- ou 3-(cyclopenten-1-yl)-heteroarylmethyl-amines et leur utilisation a titre de medicaments pour le traitement de la schizophrenie
FR2845992A1 (fr) * 2002-10-16 2004-04-23 Pf Medicament Derives de 3-(cyclopenten-1yl)-benzyl-ou3-(cyclopenten-1yl)- heteroarylmethyl-amines et leur utilisation a titre de medicaments pour le traitement de la schizophrenie
WO2004074281A1 (fr) * 2003-02-18 2004-09-02 Merck Patent Gmbh Benzofuranoxyethylamines servant d'antidepresseurs et d'anxiolytiques
US7425574B2 (en) 2003-02-18 2008-09-16 Merck Patent Gesellschaft Mit Beschrankter Haftung Benzofuran oxyethylamines as antidepressants and anxiolytics
AU2004213097B2 (en) * 2003-02-18 2010-06-24 Merck Patent Gmbh Benzofuran oxyethylamines serving as antidepressant drugs and anxiolytic drugs
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CN1304403A (zh) 2001-07-18
AU3386199A (en) 1999-10-25
EP1070050A1 (fr) 2001-01-24
CA2327359A1 (fr) 1999-10-14

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