WO1999051592A1 - Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1) - Google Patents
Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1) Download PDFInfo
- Publication number
- WO1999051592A1 WO1999051592A1 PCT/US1999/007606 US9907606W WO9951592A1 WO 1999051592 A1 WO1999051592 A1 WO 1999051592A1 US 9907606 W US9907606 W US 9907606W WO 9951592 A1 WO9951592 A1 WO 9951592A1
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- WO
- WIPO (PCT)
- Prior art keywords
- hydrogen
- lower alkyl
- independently
- indol
- phenyl
- Prior art date
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- 0 *NCC(B1)CNC2=C1C=C[C@]1C2=C1 Chemical compound *NCC(B1)CNC2=C1C=C[C@]1C2=C1 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- 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
Definitions
- This invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically, this invention relates to various indol-3-yl-cyclohexylamine derivatives useful for the treatment of such diseases.
- compositions which enhance the transmission of serotonin are useful for the treatment of many psychiatric disorders, including depression and anxiety.
- the first generation of non-selective serotonin-affecting drugs operated
- SSRIs selective serotonin reuptake inhibitors
- U.S. Patent No. 3,058,980 discloses the preparation of compounds having the following formula which are claimed to exhibit analgesic activity.
- PCT Patent No. WO 89-07596A discloses the preparation of compounds of the following formula which are active in a variety of central nervous system disorders, including depression and schizophrenia.
- U.S. Patent No. 4,612,312 discloses compounds of the following formula as being potentially useful as anxiolytic and antihypertensive agents.
- the present invention is directed to novel molecules which have the ability to act concomitantly at the 5-HT1A autoreceptors and with the 5-HT transporter. Such compounds are, therefore, potentially useful for the treatment of depression and other serotonin disorders.
- the compounds of the present invention are indol-3-yl-cyclohexyl amine derivatives represented by Formula I:
- R, and R 5 are each, independently, hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or trifluoromethyl;
- R 2 and R 4 are each, independently, hydrogen, lower alkyl, phenyl, or substituted phenyl;
- R 3 is hydrogen or lower alkyl
- X and Y are each, independently, O, NR 6 , or CH 2 , wherein R 6 is hydrogen, lower alkyl, phenyl, or substituted phenyl; or pharmaceutically acceptable salts thereof.
- the compounds of the present invention are those represented by
- R, and R 5 are each, independently, hydrogen, or halogen
- R 2 and R 4 are each hydrogen
- R 3 is hydrogen
- X and Y are each, independently, O or NR 6 , wherein R 6 is hydrogen; 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 straight and branched carbon chains containing 1-6 carbon atoms.
- halogen is meant to include fluorine, chlorine, bromine, and iodine.
- substituted phenyl may include substitution by halogen, lower alkyl, lower alkoxy and cyano groups.
- the compounds of Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base.
- Such salts prepared by methods well known to the art are 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.
- 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 prepared according to any one of Schemes 1-3 set forth below. In the Schemes, the intermediate compounds exemplified hereinafter are identified in parenthesis. The compound produced in each of the Schemes is identified by reference to the appropriate Example.
- the compounds of Formula I are generally prepared by the overall sequence indicated in Schemes 1-3 as follows. In the Schemes, the intermediate compounds exemplified hereinafter are identified in parenthesis. The compound produced in each of Schemes 1 to 3 is identified by reference to the appropriate Example.
- the trans isomer was isolated in 19% yield (0.22 g) as a white solid: 66-68 °C.
- the HCl salt of the trans isomer was prepared in ethyl acetate: mp 155 °C (dec). Elemental analysis for C 23 H 26 FN 3 O»HCl»0.75H 2 O'0.33EtOH Calc'd: C, 63.71; H, 6.85; N, 9.16.
- the trans isomer was isolated in 33% yield (0.32 g) as an oil.
- the fumarate salt of the trans isomer was prepared in isopropanol: mp 275-277 °C (dec). Elemental analysis for C 23 H 26 FN 3 O «0.5C 4 H 4 O 4 -0.3H 2 O Calc'd: C, 67.79; H, 6.51; N, 9.49.
- 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% foetal 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 m for 10 min., 4°C) in buffer (50 raM Tris; pH 7.5). The resulting pellets were aliquoted and - 11 - 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.
- 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 NaCl, 1 mM EDTA, 10 uM GDP, 500 mM DTT, pH 8.0).
- assay buffer 25 mM HEPES, 3 mM MgCl 2 , 100 mM NaCl, 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 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 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, - 13 - 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 in sterile liquid form compositions for parenteral administration.
- 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 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 - 14 - 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)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Psychiatry (AREA)
- Medicinal Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pain & Pain Management (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA002327360A CA2327360A1 (fr) | 1998-04-08 | 1999-04-07 | Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1) |
AU34765/99A AU3476599A (en) | 1998-04-08 | 1999-04-07 | Indol-3-yl-cyclohexyl amine derivatives for the treatment of depression (5-ht1 receptor antagonists) |
JP2000542313A JP2002510682A (ja) | 1998-04-08 | 1999-04-07 | うつ病治療用のインドール−3−イル−シクロヘキシルアミン誘導体(5−ht1受容体拮抗薬) |
EP99916450A EP1070063A1 (fr) | 1998-04-08 | 1999-04-07 | Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1) |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US5724498A | 1998-04-08 | 1998-04-08 | |
US09/057,244 | 1998-04-08 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1999051592A1 true WO1999051592A1 (fr) | 1999-10-14 |
Family
ID=22009404
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/007606 WO1999051592A1 (fr) | 1998-04-08 | 1999-04-07 | Derives d'amine indol-3-yl-cyclhexyle utilises dans le traitement de la depression (antagonistes du recepteur 5-ht1) |
Country Status (6)
Country | Link |
---|---|
EP (1) | EP1070063A1 (fr) |
JP (1) | JP2002510682A (fr) |
CN (1) | CN1304409A (fr) |
AU (1) | AU3476599A (fr) |
CA (1) | CA2327360A1 (fr) |
WO (1) | WO1999051592A1 (fr) |
Cited By (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000040581A1 (fr) * | 1999-01-07 | 2000-07-13 | American Home Products Corporation | Derives de la 3,4-dihydro-2h benzo[1,4]oxazine |
WO2000040580A1 (fr) * | 1999-01-07 | 2000-07-13 | American Home Products Corporation | 3,4-dihydro-2h-benzo[1,4]oxazinyl-methyl[3-(1h-indol-3-yl)-alkyl]-amines |
US6221863B1 (en) | 1999-01-07 | 2001-04-24 | American Home Products Corp. | 3,4-dihydro-2H-benzo[1,4]oxazine derivatives |
WO2003068772A1 (fr) * | 2002-02-18 | 2003-08-21 | Glaxo Group Limited | Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique |
WO2004024723A1 (fr) * | 2002-09-12 | 2004-03-25 | Wyeth | Derives cycloalkylamine de 2,3-dihydro-1,4-benzodioxane antidepresseurs |
WO2004099191A2 (fr) * | 2003-05-02 | 2004-11-18 | Wyeth | Quinolines benzofuranyl et benzothienyl-piperazinyl et leurs procedes d'utilisation |
US6911445B2 (en) * | 2002-09-12 | 2005-06-28 | Wyeth | Antidepressant cycloalkylamine derivatives of heterocycle-fused benzodioxans |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3058980A (en) * | 1962-10-16 | Substitution products of benzo- | ||
US4612312A (en) * | 1984-07-30 | 1986-09-16 | Merrell Dow Pharmaceuticals Inc. | Glutarimide antianxiety and antihypertensive agents |
EP0303506A2 (fr) * | 1987-08-13 | 1989-02-15 | Glaxo Group Limited | Dérivés d'indole |
WO1991012252A1 (fr) * | 1990-02-13 | 1991-08-22 | Novo Nordisk A/S | Derives d'indole, preparation et utilisation de ces derives |
EP0478954A1 (fr) * | 1990-08-29 | 1992-04-08 | Merrell Pharmaceuticals Inc. | Antagonistes 5HT1A et 5HT1D de la sérotonine |
EP0666258A1 (fr) * | 1994-01-06 | 1995-08-09 | Bristol-Myers Squibb Company | Dérivés d'indolylcycloalkylamine et d'indolylcycloalkenylamine, leur préparation et leur utilisation comme agents antimigraines |
EP0714894A1 (fr) * | 1994-12-01 | 1996-06-05 | Eli Lilly And Company | 3-(1,2,3,6-Tétrahydro-(1-alkylénearyl)-4-pyridinyl)- et 3-(1-alkylenearyl)-4-pipéridinyl-1h-indoles: nouveaux agonistes 5-HT1f |
WO1996029075A1 (fr) * | 1995-03-20 | 1996-09-26 | Eli Lilly And Company | 5-substitue-3-(1,2,3,6-tetrahydropyridine-4-yl)- et 3-(piperidine-4-yl)-1h-indoles: nouveaux antagonistes 5-ht¿1f? |
-
1999
- 1999-04-07 CA CA002327360A patent/CA2327360A1/fr not_active Abandoned
- 1999-04-07 EP EP99916450A patent/EP1070063A1/fr not_active Withdrawn
- 1999-04-07 JP JP2000542313A patent/JP2002510682A/ja active Pending
- 1999-04-07 CN CN99807010A patent/CN1304409A/zh active Pending
- 1999-04-07 AU AU34765/99A patent/AU3476599A/en not_active Abandoned
- 1999-04-07 WO PCT/US1999/007606 patent/WO1999051592A1/fr not_active Application Discontinuation
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
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US3058980A (en) * | 1962-10-16 | Substitution products of benzo- | ||
US4612312A (en) * | 1984-07-30 | 1986-09-16 | Merrell Dow Pharmaceuticals Inc. | Glutarimide antianxiety and antihypertensive agents |
EP0303506A2 (fr) * | 1987-08-13 | 1989-02-15 | Glaxo Group Limited | Dérivés d'indole |
WO1991012252A1 (fr) * | 1990-02-13 | 1991-08-22 | Novo Nordisk A/S | Derives d'indole, preparation et utilisation de ces derives |
EP0478954A1 (fr) * | 1990-08-29 | 1992-04-08 | Merrell Pharmaceuticals Inc. | Antagonistes 5HT1A et 5HT1D de la sérotonine |
EP0666258A1 (fr) * | 1994-01-06 | 1995-08-09 | Bristol-Myers Squibb Company | Dérivés d'indolylcycloalkylamine et d'indolylcycloalkenylamine, leur préparation et leur utilisation comme agents antimigraines |
EP0714894A1 (fr) * | 1994-12-01 | 1996-06-05 | Eli Lilly And Company | 3-(1,2,3,6-Tétrahydro-(1-alkylénearyl)-4-pyridinyl)- et 3-(1-alkylenearyl)-4-pipéridinyl-1h-indoles: nouveaux agonistes 5-HT1f |
WO1996029075A1 (fr) * | 1995-03-20 | 1996-09-26 | Eli Lilly And Company | 5-substitue-3-(1,2,3,6-tetrahydropyridine-4-yl)- et 3-(piperidine-4-yl)-1h-indoles: nouveaux antagonistes 5-ht¿1f? |
Non-Patent Citations (2)
Title |
---|
CLIFFE,I.A. ET AL.: "Advances in 5-HT1A Antagonist Search", DRUGS FUTURE, vol. 18, 1993, BARCELONA, pages 631 - 642, XP002114577 * |
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 (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000040581A1 (fr) * | 1999-01-07 | 2000-07-13 | American Home Products Corporation | Derives de la 3,4-dihydro-2h benzo[1,4]oxazine |
WO2000040580A1 (fr) * | 1999-01-07 | 2000-07-13 | American Home Products Corporation | 3,4-dihydro-2h-benzo[1,4]oxazinyl-methyl[3-(1h-indol-3-yl)-alkyl]-amines |
US6221863B1 (en) | 1999-01-07 | 2001-04-24 | American Home Products Corp. | 3,4-dihydro-2H-benzo[1,4]oxazine derivatives |
WO2003068772A1 (fr) * | 2002-02-18 | 2003-08-21 | Glaxo Group Limited | Composes presentant une affinite avec des recepteurs de type 5ht1 et leur utilisation therapeutique |
US7244726B2 (en) | 2002-02-18 | 2007-07-17 | Glaxo Group Limited | Heterocyclic compounds possessing affinity at 5HT1 -type receptors and use thereof in therapy |
WO2004024723A1 (fr) * | 2002-09-12 | 2004-03-25 | Wyeth | Derives cycloalkylamine de 2,3-dihydro-1,4-benzodioxane antidepresseurs |
US6911445B2 (en) * | 2002-09-12 | 2005-06-28 | Wyeth | Antidepressant cycloalkylamine derivatives of heterocycle-fused benzodioxans |
US7041697B2 (en) | 2002-09-12 | 2006-05-09 | Wyeth | Antidepressant cycloalkylamine derivatives of 2,3-dihydro-1,4-benzodioxan |
US7488751B2 (en) | 2002-09-12 | 2009-02-10 | Wyeth | Antidepressant cycloalkylamine derivatives of 2,3-dihydro-1,4-benzodioxan |
WO2004099191A2 (fr) * | 2003-05-02 | 2004-11-18 | Wyeth | Quinolines benzofuranyl et benzothienyl-piperazinyl et leurs procedes d'utilisation |
WO2004099191A3 (fr) * | 2003-05-02 | 2005-02-10 | Wyeth Corp | Quinolines benzofuranyl et benzothienyl-piperazinyl et leurs procedes d'utilisation |
US7276603B2 (en) | 2003-05-02 | 2007-10-02 | Wyeth | Benzofuranyl-and benzothienyl-piperazinyl quinolines and methods of their use |
Also Published As
Publication number | Publication date |
---|---|
EP1070063A1 (fr) | 2001-01-24 |
CN1304409A (zh) | 2001-07-18 |
CA2327360A1 (fr) | 1999-10-14 |
AU3476599A (en) | 1999-10-25 |
JP2002510682A (ja) | 2002-04-09 |
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