WO2000035878A1 - Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a - Google Patents

Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a Download PDF

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Publication number
WO2000035878A1
WO2000035878A1 PCT/US1999/029881 US9929881W WO0035878A1 WO 2000035878 A1 WO2000035878 A1 WO 2000035878A1 US 9929881 W US9929881 W US 9929881W WO 0035878 A1 WO0035878 A1 WO 0035878A1
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WO
WIPO (PCT)
Prior art keywords
phenyl
compound
piperidin
ylmethyl
methoxy
Prior art date
Application number
PCT/US1999/029881
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English (en)
Inventor
Michael Gerard Kelly
Yvette Latko Palmer
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 CA002351859A priority Critical patent/CA2351859A1/fr
Priority to EP99965282A priority patent/EP1140838A1/fr
Priority to JP2000588140A priority patent/JP2002532473A/ja
Priority to BR9916185-0A priority patent/BR9916185A/pt
Priority to AU31231/00A priority patent/AU3123100A/en
Publication of WO2000035878A1 publication Critical patent/WO2000035878A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms

Definitions

  • novel arylpiperidine derivatives which are agonists and antagonists of the 5HT1A receptor subtype.
  • compounds of the present invention are useful for the treatment of central nervous system (CNS) disorders such as depression, anxiety, panic. OCD. sleep disorders, sexual dysfunction, alcohol and drug addiction, cognition enhancement, Alzheimer's disease. Parkinson's disease, obesity and migraine.
  • CNS central nervous system
  • R ] is aryl or heteroaryl:
  • A is NR 2 or CH 2 and B is NR 2 or CH 2 , provided that A is not equal to B;
  • R is hydrogen, alkyl, cycloalkyl. alkylcycloalkyl, heterocycloalkyl, alkylhetero- cycloalkyl, aryl, aralkyl. heteroaryl, alkylheteroaryl or COR3;
  • R3 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl. aryl or heteroaryl; n is an integer from 0 to 2. or a pharmaceutical salt thereof.
  • R ] is phenyl; 2-, 3- or 4-pyridyl; 2-pyrimidyl; benzodioxan-5-yl; indol-4-yl; 3-thienyl; l-, or 2-naphthyl.
  • R ] is phenyl or indol-4-yl.
  • R 2 is aralkyl, alkylheterocycloalkyl or COR3.
  • Alkyl' as used herein means a branched or straight chain having from 1 to 6 carbon atoms and more preferably from 1 to 4 carbon atoms.
  • exemplary alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • Lower alkyl refers to alkyl having from 1 to 6 carbon atoms.
  • Alkoxy' * as used herein means an alkyl-O group in which the alkyl group is as previously described.
  • exemplary alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and t-butoxy.
  • Aryl' as used herein means mono or bicyclic aromatic ring having from 6 to 10 carbon atoms. Monocyclic rings preferably have 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures.
  • Exemplary aryl groups include phenyl, naphthyl, and biphenyl. In some preferred embodiments aryl is phenyl, 1-naphthyl or 2-naphthyl. In still more preferred embodiments aryl is phenyl.
  • the aryl group may be substituted with one or more substituents. Substituted aryl groups preferably have one to three substituents.
  • Cycloalkyl as used herein means a monocyclic alkyl group having from 3 to 8 carbon atoms. In some preferred embodiments cycloalkyl may be substituted with from 1 to 3 substituents.
  • Heterocycloalkyl as used herein means a monocyclic alkyl group having from
  • heterocycloalkyl groups include piperidinyl, piperazinyl and morpholino.
  • heterocycloalkyl groups may be substituted with from 1 to 3 substituents.
  • Halogen as used herein means fluorine, chlorine, iodine and bromine.
  • Heteroaryl means 5 to 10 membered mono or bicyclic aromatic ring having from 1 to 3 heteroatoms selected from N, O and S. Monocyclic rings preferably have 5 or 6 members and bicyclic rings preferably have 8, 9 or 10 membered ring structures. Exemplary heteroaryls include pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, benzopyranyl and benzodioxanyl.
  • Preferred heteroaryl groups include thienyl, pyridyl, furyl, indolyl and benzodioxanyl. More preferred are heteroaryl groups including 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-furyl, 3-furyl, 3-indolyl, indol-4-yl and benzodiox- 5-yl.
  • the heteroaryl group may be substituted with one or more substituents. Substituted heteroaryl groups preferably have from 1 to 3 substituents.
  • Suitable substituents include halogen, alkyl, hydroxy, alkoxy, amino, amido, nitro, alkylamino, alkylamido, perhaloalkyl, carboxyalkyl, carboxy, carbamide, dialkylamino and aryl.
  • Carbon number refers to the number of carbons in the carbon backbone and does not include carbon atoms occurring in substituents such as an alkyl or alkoxy substituents.
  • alkylcycloalkyl is an alkyl-cycloalkyl group in which alkyl and cycloalkyl are as previously described.
  • Pharmaceutically acceptable salts are the acid addition salts which can be formed from a compound of the above general formula and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid, and the like.
  • the compounds of this invention contain a chiral center, providing for various seteroisomeric forms of the compounds such as racemic mixtures as well as the individual optical isomers.
  • the individual isomers can be prepared directly or by asymmetric or stereospecific synthesis or by conventional separation of optical isomers from the racemic mixture.
  • a tert-butyl carbamate is an example of a suitable protection group (P) which can be removed by the action of acid.
  • P protection group
  • Deprotection to the amine, and subsequent reduction of the amide using lithium aluminum hydride or borane-tetrahydrofuran complex can afford the required unsubstituted product A.
  • the product may be alkylated with alkyl halides under the influence of a base such as sodium hydride or potassium carbonate to afford further derivatives, or alternatively may be acylated with carboxylic acid derivatives and the amide subsequently reduced under the above noted conditions to afford further derivatives.
  • 4-nipecotamide 4-(2-Methoxyphenyl)piperazine hydrochloride (5.0 g, 21.8 mmol) was added to a mixture of DAEC (4.18 g, 21.8 mmol), HOBT (1.3 equivalents, 3.83 g, 28.3 mmol) and N-t-butoxycarbonyl nipecotic acid (5 g, 21.8 mmol) in DMF (35 mL), and the resulting solution was treated with NMM (2.5 equivalents, 6.0 mL, 54.5 mmol) and stirred at ()°C for 16 hours.
  • Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of l-(2- methoxyphenyl)-4-piperidin-4-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 1 and triethylamine (2 equivalents, 1 mL) in CH 2 C1 2 (30 mL) and the solution stirred under N 2 at ()°C for 16 hours.
  • the mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL).
  • Example 6 l-(2-Methoxy-phenyl)-4-piperidin-3-ylmethyl-piperazine A solution of the amide from intermediate 4 (7.4 g, 21.8 mmol) and triethylamine (6 mL) in THF (100 mL) was treated with the dropwise addition of borane-THF (1.0 M, 76 mL) at 0°C under nitrogen. The mixture was refluxed for 16 hours and after cooling to 0°C, the reaction was terminated by the addition of 2N-HC1 (50 mL). After stirring for 1 hour, the solution was made basic with NaOH and the product extracted into ethyl acetate (3 x 35 mL).
  • Benzoyl chloride (0.49 g, 3.5 mmol) was added to a solution of l-(2- methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine ( 1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH C1, (30 mL) and the solution stirred under N, at 0°C for 16 hours.
  • the mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3 x 25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL).
  • Compounds of the present invention bind with very high affinity to the 5-HT1A receptor and consequently, they are useful for the treatment of central nervous system disorders such as depression, anxiety, sleep disorders, sexual dysfunction, alcohol and cocaine addiction, cognition enhancement and related problems in addition to the treatment of Alzheimer's disease, Parkinson's disease, obesity and migraine.
  • High affinity for the serotonin 5-HTIA receptor was established by testing the claimed compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with the human 5HT1A receptor.
  • Stably transfected CHO cells are grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. Cells are scraped off the plate, 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 are aliquoted and placed at -8()"C. On the day of assay, the cells are thawed on ice and resuspended in buffer.
  • the binding assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in 0.5% PEL Compounds are initially tested in a single point assay to determine percent inhibition at 1, 0.1 , and 0.01 mM, and Ki values are determined for the active compounds.
  • 5-HT1A Receptor Intrinsic Activity Assay is performed in a 96 well microtiter plate in a total volume of 250 ⁇ L. Non-specific binding is determined in the presence of 10 mM 5-HT, final ligand concentration is 1.5 nM. Following a 30 minute incubation at room temperature, the reaction is terminated by the addition of ice cold buffer and rapid filtration through a GF/B filter presoaked for 30 minutes in
  • the intrinsic activity of compounds of the present invention was established by testing the claimed compounds ability to reverse the stimulation of cyclic adenosinemonophosphate (cAMP) in CHO cells stably transfected with the human 5-HT 1 A receptor.
  • cAMP cyclic adenosinemonophosphate
  • Stably transfected CHO cells were grown in DMEM containing 10% heat inactivated FBS and non-essential amino acids. The cells are plated at a density of xl() 6 cells per well in a 24 well plate and incubated for 2 days in a CO 2 incubator. On the second day, the media is replaced with 0.5 mL treatment buffer (DMEM + 25 mM HEPES, 5 mM theophylline, 10 ⁇ M pargyline) and incubated for 10 minutes at 37°C. Wells are treated with forskolin (1 ⁇ M final concentration) followed immediately by the test compound (0.1 and 1 ⁇ M for initial screen) and incubated for an additional 10 minutes at 37°C.
  • DMEM + 25 mM HEPES 5 mM theophylline, 10 ⁇ M pargyline
  • compounds of the present invention exhibit high affinity for the 5HT1 A receptor subtype and exhibit intrinsic activity as evidenced by their ability to reverse stimulation of cyclic adenosinemonophosphate (cAMP). Accordingly, compounds of the present invention are useful for treatment of disorders of the central nervous system and may be administered to a patient suffering from one or more of said disorders. Treatment, as used herein, refers to the alleviation or amelioration of symptoms of a particular disorder in a patient. In addition, compounds of the present invention may be administered as part of a treatment regime that includes other agents which act on the central nervous system. In some preferred embodiments, compounds of the present invention are part of a combination therapy including a serotonin rcuptakc inhibitor.
  • Serotonin reuptake inhibitors useful in combination therapies of the present invention fluoxetine, fluvoxamine, paroxetine, sertraline and venlafaxine. Said agents may be administered at the same time, where they may be combined into a single dosage form, or at a different time, as compounds of the present invention, while still being part of the regime of the combination therapy. Compounds of the invention may be administered to a patient either neat or with a convention pharmaceutical carrier.
  • 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.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine. low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs.
  • the active ingredient 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.
  • suitable examples of 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
  • 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. Oral administration may be either liquid or solid composition form.
  • the pharmaceutical composition is in unit dosage form, e.g. as tablets or capsules.
  • the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient;
  • 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 dosage to be used in the treatment of a specific psychosis must be subjectively determined by the attending physician.
  • the variables involved include the specific psychosis or state of anxiety and the size, age and response pattern of the patient.
  • the novel method of the invention for treating conditions related to or are affected by the 5-HT 1 A receptor comprise administering to warm-blooded animals, including humans, an effective amount of at least one compound of Formula A and its non-toxic, pharmaceutically acceptable addition salts.
  • the compounds may be administered orally, rectally, parenterally or topically to the skin and mucosa.
  • the usual daily dose is depending on the specific compound, method of treatment and condition treated.
  • the usual daily dose is 0.01 - 1000 mg/Kg for oral application, preferably 0.5 - 500 mg/Kg, and 0.1 - 100 mg/Kg for parenteral application, preferably 0.5 - 50 mg/Kg.

Abstract

L'invention se rapporte à des composés de la formule (A) pouvant être utilisés pour le traitement de troubles du système nerveux central, notamment l'anxiété, la dépression, les troubles paniques, la toxicomanie alcoolique ou la narcomanie, la dysfonction sexuelle, les troubles du sommeil, les troubles cognitifs, la maladie d'Alzheimer ou la maladie de Parkinson.
PCT/US1999/029881 1998-12-17 1999-12-16 Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a WO2000035878A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002351859A CA2351859A1 (fr) 1998-12-17 1999-12-16 Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a
EP99965282A EP1140838A1 (fr) 1998-12-17 1999-12-16 Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a
JP2000588140A JP2002532473A (ja) 1998-12-17 1999-12-16 ５−ｈｔ１ａ受容体活性を有する１，４−ピペラジン誘導体
BR9916185-0A BR9916185A (pt) 1998-12-17 1999-12-16 Derivados de 1,4-piperazina tendo atividade receptora de 5ht1a
AU31231/00A AU3123100A (en) 1998-12-17 1999-12-16 1,4-piperazine derivatives having 5ht1a receptor activity

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21347098A 1998-12-17 1998-12-17
US09/213,470 1998-12-17

Publications (1)

Publication Number Publication Date
WO2000035878A1 true WO2000035878A1 (fr) 2000-06-22

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PCT/US1999/029881 WO2000035878A1 (fr) 1998-12-17 1999-12-16 Derives de 1,4-piperazine agissant sur le recepteur de 5ht1a

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EP (1) EP1140838A1 (fr)
JP (1) JP2002532473A (fr)
AU (1) AU3123100A (fr)
BR (1) BR9916185A (fr)
CA (1) CA2351859A1 (fr)
WO (1) WO2000035878A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003053927A1 (fr) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Dérivé de piperazine
WO2005030188A2 (fr) * 2003-09-26 2005-04-07 Vertex Pharmaceuticals Incorporated Derives de phenyl-piperazine en tant que modulateurs des recepteurs muscariniques
US7943768B2 (en) * 2005-12-21 2011-05-17 Astrazeneca Ab Piperazine compounds useful as antagonists of C-C chemokines (Ccr2b and CcrS) for the treatment of inflammatory diseases
US8106074B2 (en) 2001-07-13 2012-01-31 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives for treating opiate dependence
EP2896624A1 (fr) 2007-03-28 2015-07-22 Atir Holding S.A. Composés hétérocycliques comme agents sérotoninergiques et dopaminergiques et leurs utilisations

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409081A1 (fr) * 1989-07-21 1991-01-23 F. Hoffmann-La Roche Ag Dérivés de bêta-lactame
EP0445026A1 (fr) * 1990-02-27 1991-09-04 Adir Et Compagnie Dérivés d'aminométhyl-pipéridine, leur procÀ©dé de préparation et les compositions pharmaceutiques qui les contiennent
WO1999006395A1 (fr) * 1997-07-29 1999-02-11 Zeneca Limited Composes pyridyle et pyrimidyle heterocycliques inhibant l'oxydo-squalene cyclase

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409081A1 (fr) * 1989-07-21 1991-01-23 F. Hoffmann-La Roche Ag Dérivés de bêta-lactame
EP0445026A1 (fr) * 1990-02-27 1991-09-04 Adir Et Compagnie Dérivés d'aminométhyl-pipéridine, leur procÀ©dé de préparation et les compositions pharmaceutiques qui les contiennent
WO1999006395A1 (fr) * 1997-07-29 1999-02-11 Zeneca Limited Composes pyridyle et pyrimidyle heterocycliques inhibant l'oxydo-squalene cyclase

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8106074B2 (en) 2001-07-13 2012-01-31 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives for treating opiate dependence
WO2003053927A1 (fr) * 2001-12-21 2003-07-03 Taisho Pharmaceutical Co.,Ltd. Dérivé de piperazine
WO2005030188A2 (fr) * 2003-09-26 2005-04-07 Vertex Pharmaceuticals Incorporated Derives de phenyl-piperazine en tant que modulateurs des recepteurs muscariniques
WO2005030188A3 (fr) * 2003-09-26 2005-08-04 Vertex Pharma Derives de phenyl-piperazine en tant que modulateurs des recepteurs muscariniques
US7563795B2 (en) 2003-09-26 2009-07-21 Vertex Pharmaceuticals Incorporated Phenyl-piperazine derivatives as modulators of muscarinic receptors
US7943768B2 (en) * 2005-12-21 2011-05-17 Astrazeneca Ab Piperazine compounds useful as antagonists of C-C chemokines (Ccr2b and CcrS) for the treatment of inflammatory diseases
EP2896624A1 (fr) 2007-03-28 2015-07-22 Atir Holding S.A. Composés hétérocycliques comme agents sérotoninergiques et dopaminergiques et leurs utilisations

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Publication number Publication date
BR9916185A (pt) 2001-09-04
EP1140838A1 (fr) 2001-10-10
CA2351859A1 (fr) 2000-06-22
JP2002532473A (ja) 2002-10-02
AU3123100A (en) 2000-07-03

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