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 PDF

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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
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Application number
PCT/US1999/007606
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English (en)
Inventor
Richard Eric Mewshaw
Ping Zhou
Original Assignee
American Home Products Corporation
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
Application filed by American Home Products Corporation filed Critical American Home Products Corporation
Priority to AU34765/99A priority Critical patent/AU3476599A/en
Priority to CA002327360A priority patent/CA2327360A1/fr
Priority to JP2000542313A priority patent/JP2002510682A/ja
Priority to EP99916450A priority patent/EP1070063A1/fr
Publication of WO1999051592A1 publication Critical patent/WO1999051592A1/fr

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    • 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)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Pain & Pain Management (AREA)
  • General Chemical & Material Sciences (AREA)
  • Psychiatry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

On décrit des composés qui sont efficaces dans le traitement des troubles des symptômes neurologiques affectés par la sérotonine (le récepteur 5-HT1A étant actif), ces composés étant représentés par la formule (I). Dans cette formule, R1 et R5 représentent chacun indépendamment, hydrogène, halogène, alcoxy inférieur, alkyle inférieur, cyano ou trifluorométhyle; R2 et R4 représentent chacun indépendamment hydrogène, alkyle inférieur, phényle ou phényle substitué; R3 représente hydrogène ou alkyle inférieur; et X et Y représentent chacun indépendamment O, NR6 ou Ch2, R6 représentant hydrogène, alkyle inférieur, phényle ou phényle substitué. Cette invention concerne lesdits composés de formule (I) ainsi que leurs sels pharmaceutiquement acceptables. formule (I)
PCT/US1999/007606 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) WO1999051592A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
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)
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)
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)

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WO1999051592A1 true WO1999051592A1 (fr) 1999-10-14

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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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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?

Patent Citations (8)

* Cited by examiner, † Cited by third party
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?

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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

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JP2002510682A (ja) 2002-04-09
CA2327360A1 (fr) 1999-10-14
AU3476599A (en) 1999-10-25
EP1070063A1 (fr) 2001-01-24
CN1304409A (zh) 2001-07-18

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