EP1171439A1 - Derives d'azaindole destines au traitement de la depression - Google Patents

Derives d'azaindole destines au traitement de la depression

Info

Publication number
EP1171439A1
EP1171439A1 EP00923540A EP00923540A EP1171439A1 EP 1171439 A1 EP1171439 A1 EP 1171439A1 EP 00923540 A EP00923540 A EP 00923540A EP 00923540 A EP00923540 A EP 00923540A EP 1171439 A1 EP1171439 A1 EP 1171439A1
Authority
EP
European Patent Office
Prior art keywords
compound
formula
pharmaceutically acceptable
ring
halogen
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.)
Withdrawn
Application number
EP00923540A
Other languages
German (de)
English (en)
Inventor
Richard Eric Mewshaw
Kristin Lynne Meagher
Original Assignee
American Home Products Corp
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 Corp filed Critical American Home Products Corp
Publication of EP1171439A1 publication Critical patent/EP1171439A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—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, the present invention is directed to aryl piperazinyl cyclohexyl derivatives useful for the treatment of such disorders.
  • SSRIs selective serotonin reuptake inhibitors
  • X is H, halo, C,-C 4 alkoxy, C,-C 4 alkylthio, C,-C 4 alkyl, benzyloxy, hydroxy or carbaxamido;
  • Y is O, S or a bond;
  • n is 1-4;
  • Ar is 1-naphthyl, 2-naphthyl, phenyl or phenyl, mono-substituted with a substituent selected from the group consisting of halo, C M alkoxy, C M alkylthio, C M benzyloxy hydroxy or trifluoromethyl.
  • U.S. Patent No. 5,627,196 discloses compounds of the following formula as having effects on serotonin-related systems.
  • D is a residue which combines with the carbon atoms to which it is attached to complete a pyrrolyl, imidazolyl, pyridinyl, pyrazinyl, pyridazinyl or pyrimidinyl group;
  • X is hydrogen, phenyl, hydroxy or methoxy provided that X is hydrogen or phenyl where r is 0;
  • R is -NH-R
  • A may be:
  • R, and R 2 form a carbocyclic or heterocyclic ring of 5 to 7 atoms, wherein said ring may be saturated or unsaturated ;
  • X is independently hydrogen, cyano, carbamoyl, halogen or alkoxy; or pharmaceutically acceptable salts thereof.
  • Preferred compounds of the present invention are preferably those of Formula I, wherein:
  • R, and R j form a carbocyclic or heterocyclic ring of 5-6 atoms; and X is hydrogen; or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention are selected from the following:
  • alkoxy is meant to include both straight and branched carbon chains containing 1-6 carbon atoms.
  • halogen is meant to include fluorine, chlorine, bromine and iodine.
  • heterocyclic ring mean saturated or unsaturated rings containing one or more heteroatoms, preferably selected from oxygen, nitrogen and sulfur. Preferred examples contain, 5 or 6 atoms, particular examples, are 1,4-dioxane, pyrrole and pyridine.
  • carbocyclic ring means saturated or unsaturated carbon rings such as aryl or cycloalkyl, preferably containing 5 or 6 carbon atoms..
  • 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 which will be recognized by those skilled in the art. However, the present compounds may be advantageously prepared according to Scheme 1 set forth below.
  • the oxalate salt was prepared in ethanol: mp 202-205°C Elemental analysis for C 23 H 22 N 4 O » C 2 H 2 O 4 « 0.5H 2 O Calc'd: C, 72.80; H, 6.11; N, 14.77
  • the PCR cloning of the human 5-HT 1A receptor subtype from a human genomic library has been described previously by 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 IA .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 maintained 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.
  • frontal cortical membranes prepared from male Sprague-Dawley rats were incubated with 3 H-paroxetine (0.1 nM) for 60 min at 25°C. All tubes also contained either vehicle, test compound (one to eight concentrations), or a saturating concentration of fluoxetine (10 ⁇ M) to define specific binding. All reactions were terminated by the addition of ice cold Tris buffer followed by rapid filtration using a
  • 5-HT 1A cloned receptor membrane fragments (as used for 5-HT 1A receptor binding assays) were stored at -70°C. When needed, membranes were rapidly thawed, centrifuged at 40,000 x g for
  • 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 the present invention are active towards 5HT 1A 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 formula I for use in methods of treatment or therapy form further aspects of the present invention.
  • 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 in 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 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.
  • compositions comprising the compounds of formula I and a pharmaceutically acceptable carrier form a further aspect of the present invention.

Landscapes

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

Abstract

L'invention concerne des composés utilisés dans le traitement de maladies en rapport avec les troubles des systèmes neurologiques liés à la sérotonine, tel que la dépression et l'anxiété. Ces composés sont représentés par la formule (I), dans laquelle R1 et R2 forment un noyau carbocyclique ou hétérocyclique de 5 à 7 atomes, ledit noyau pouvant être saturé ou non saturé ; X est indépendamment hydrogène, cyano, carbamoyl, halogène ou alcoxy, ou des sels pharmaceutiquement acceptables desdits composés.
EP00923540A 1999-04-22 2000-04-20 Derives d'azaindole destines au traitement de la depression Withdrawn EP1171439A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US29673699A 1999-04-22 1999-04-22
US296736 1999-04-22
PCT/US2000/010628 WO2000064898A1 (fr) 1999-04-22 2000-04-20 Derives d'azaindole destines au traitement de la depression

Publications (1)

Publication Number Publication Date
EP1171439A1 true EP1171439A1 (fr) 2002-01-16

Family

ID=23143341

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00923540A Withdrawn EP1171439A1 (fr) 1999-04-22 2000-04-20 Derives d'azaindole destines au traitement de la depression

Country Status (8)

Country Link
EP (1) EP1171439A1 (fr)
JP (1) JP2002543079A (fr)
CN (1) CN1348451A (fr)
AR (1) AR028475A1 (fr)
AU (1) AU4364400A (fr)
BR (1) BR0010693A (fr)
CA (1) CA2367681A1 (fr)
WO (1) WO2000064898A1 (fr)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN100338062C (zh) * 2002-03-28 2007-09-19 卫材株式会社 作为c－Jun N－末端激酶抑制剂的氮杂吲哚类化合物
CA2585857A1 (fr) 2004-11-26 2006-06-01 Janssen Pharmaceutica N.V. Derives d'isoxazoline-indole avec effet antipsychotique et anxiolytique ameliore
WO2008063888A2 (fr) 2006-11-22 2008-05-29 Plexxikon, Inc. Composés modulant l'activité de c-fms et/ou de c-kit et utilisations associées
WO2009012283A1 (fr) 2007-07-17 2009-01-22 Plexxikon Inc. Composés et procédés pour la modulation des kinases et leurs indications
SG173178A1 (en) 2009-04-03 2011-09-29 Hoffmann La Roche Propane- i-sulfonic acid {3- [5- (4 -chloro-phenyl) -1h-pyrrolo [2, 3-b] pyridine-3-carbonyl] -2, 4-difluoro-pheny l } -amide compositions and uses thereof
EP3141252B8 (fr) 2009-06-17 2019-03-13 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
NZ629615A (en) 2009-11-06 2016-01-29 Plexxikon Inc Compounds and methods for kinase modulation, and indications therefor
CN103492381A (zh) 2010-12-16 2014-01-01 沃泰克斯药物股份有限公司 流感病毒复制的抑制剂
EA028821B9 (ru) 2011-02-07 2018-10-31 Плексксикон, Инк. Соединения и способы для модуляции киназ, а также показания к их применению
TWI558702B (zh) 2011-02-21 2016-11-21 普雷辛肯公司 醫藥活性物質的固態形式
UA118010C2 (uk) 2011-08-01 2018-11-12 Вертекс Фармасьютікалз Інкорпорейтед Інгібітори реплікації вірусів грипу
US9150570B2 (en) 2012-05-31 2015-10-06 Plexxikon Inc. Synthesis of heterocyclic compounds
AU2014348840B2 (en) 2013-11-13 2019-06-06 Vertex Pharmaceuticals Incorporated Inhibitors of influenza viruses replication
EP3851437A3 (fr) 2013-11-13 2021-11-03 Vertex Pharmaceuticals Incorporated Procédés de préparation de dérivés de h-pyrrolo[2,3-b]pyridine
WO2016183120A1 (fr) 2015-05-13 2016-11-17 Vertex Pharmaceuticals Incorporated Inhibiteurs de la réplication des virus de la grippe
WO2016183116A1 (fr) 2015-05-13 2016-11-17 Vertex Pharmaceuticals Incorporated Procédés de préparation d'inhibiteurs de réplication des virus de la grippe

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5521197A (en) * 1994-12-01 1996-05-28 Eli Lilly And Company 3-<1-alkylenearyl>-4-<1,2,3,6-tetrahydropyridinyl>-and 3-<1-alkylenearyl>-4-piperidinyl-1h-indoles: new 5-HT1F agonists
US5576321A (en) * 1995-01-17 1996-11-19 Eli Lilly And Company Compounds having effects on serotonin-related systems
US5627196A (en) * 1995-01-17 1997-05-06 Eli Lilly And Company Compounds having effects on serotonin-related systems

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0064898A1 *

Also Published As

Publication number Publication date
CN1348451A (zh) 2002-05-08
CA2367681A1 (fr) 2000-11-02
JP2002543079A (ja) 2002-12-17
WO2000064898A1 (fr) 2000-11-02
AR028475A1 (es) 2003-05-14
AU4364400A (en) 2000-11-10
BR0010693A (pt) 2002-02-05

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