EP1053235A1 - Oxazole derivatives as serotonin-1a receptor agonists - Google Patents

Oxazole derivatives as serotonin-1a receptor agonists

Info

Publication number
EP1053235A1
EP1053235A1 EP99905632A EP99905632A EP1053235A1 EP 1053235 A1 EP1053235 A1 EP 1053235A1 EP 99905632 A EP99905632 A EP 99905632A EP 99905632 A EP99905632 A EP 99905632A EP 1053235 A1 EP1053235 A1 EP 1053235A1
Authority
EP
European Patent Office
Prior art keywords
carbon atoms
alkyl
compound
aryl
arylalkyl
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Withdrawn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
EP99905632A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Gerard Kelly
Lynne Padilla Greenblatt
Frances Christy Nelson
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Wyeth
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 EP1053235A1 publication Critical patent/EP1053235A1/en
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • A61P25/28—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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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

Definitions

  • This invention provides oxazole derivatives which are useful for the treatment of conditions related to or are affected by the 5-hydroxytryptamine-lA (5-HT1A) receptor subtype.
  • the compounds are particularly useful for the treatment of psychosis (e.g. schizophrenia), anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual dysfunction and memory deficits associated with Alzheimer's disease.
  • R- l is hydrogen, alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, benzyloxy, trifluoromethyl, chloro, bromo, or fluoro; a dashed line indicates an optional bond;
  • X is NR 4 , or no atom;
  • R-2 is alkyl of 1-6 carbon atoms, cycloalkyl of 3-8 carbon atoms, cycloalkylalkyl wherein the cycloalkyl moiety is 3-8 carbon atoms and the alkyl moiety is 1-6 carbon atoms, aryl of 5-12 carbon atoms, or arylalkyl of 6-12 carbon atoms;
  • R3 is aryl of 5-12 carbon atoms, arylalkyl of 6-12 carbon atoms, or heteroaryl of 5-12 ring atoms;
  • R4 is hydrogen or alkyl of 1-6 carbon atoms; or a pharmaceutically acceptable salt thereof, which are useful in the treatment of psychosis (e.g. schizophrenia), anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual - 2 - dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
  • psychosis e.g. schizophrenia
  • anxiety, depression and related CNS disorders and other conditions such as the treatment of alcohol and drug withdrawal, sexual - 2 - dysfunction and memory deficits associated with Alzheimer's disease and other dementias.
  • alkyl includes both straight chain and branched alkyl moieties.
  • the aryl, heteroaryl or aryl portion of arylalkyl may be optionally substituted.
  • Two substituents on the aromatic ring may be connected together to form another ring system.
  • An example of such a bicyclic system is an optionally substituted radical of the formula o
  • the aryl or the aryl portion of the arylalkyl substituent has 6 to 10 carbon atoms and is most preferably a phenyl or 1 ,4-benzodioxan-5-yl group.
  • the aryl or aryl portion may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, chloro, fluoro, bromo, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms.
  • heteroaryl ring contains 1-3 heteroatoms the same or different selected from oxygen, nitrogen, and sulfur and spefically preferred heteroaryl substituents are pyridyl, furyl, thienyl, quinolinyl, isoquinolinyl, or indolyl.
  • the heteroaryl moiety may be optionally mono-, di-, or tri- substituted with a substituent selected from the group consisting of alkyl of 1-6 carbon atoms, alkoxy of 1-6 carbon atoms, trifluoromethyl, chloro, fluoro, bromo, alkoxycarbonyl of 2-7 carbon atoms, alkylamino of 1-6 carbon atoms, and dialkylamino in which each of the alkyl groups is of 1-6 carbon atoms.
  • the pharmaceutically acceptable salts are those derived from organic and inorganic acids such as, but not limited to: acetic, lactic, citric, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methanesulfonic, toluenesulfonic and similarly known acceptable acids.
  • preferred members include those in which R 2 is alkyl, cycloalkyl, or cycloalkylalkyl; and those in which R 3 is aryl, and more preferably phenyl.
  • This invention also provides processes for preparing the compounds of formula (1) which comprise one of the following: a) reacting a compound of formula (8)
  • the amidoalkyl chloride of formula (3) may be prepared from the corresponding amine (5) using standard acylating conditions known to those skilled in the art of organic synthesis. 5 -
  • the alkyl chloride (5) is readily available, and may be prepared from the corresponding protected amino acid (6) using, for example, the Arndt-Eistert reaction.
  • reaction of the acid chloride of (6) with diazomethane and treatment of the resulting ⁇ - diazoketone (7) with HC1 affords the required product.
  • the chloroalkyloxazole (4) may be prepared from the ketoamide (3) by the action of a dehydrating agent such as POCI3.
  • a dehydrating agent such as POCI3.
  • the subsequent alkylation of (2) with the chloride (4) may be conducted in a suitable solvent (e.g. acetone), optionally utilizing a base (e.g. potassium carbonate or triethylamine) as an acid scavenger.
  • a suitable solvent e.g. acetone
  • a base e.g. potassium carbonate or triethylamine
  • the compounds of this invention are 5-HT1A agonists. Affinity for the serotonin 5-HTIA receptor was established in a standard pharmacological test procedure which measures the compound's ability to displace [ 3 H] 8-OH-DPAT binding in CHO cells stably transfected with human 5HT1 A 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 -80 C.
  • 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 5HT, 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.
  • a representative compound of this invention was evaluated in the standard pharmacological test procedure described above, and had a Ki of 4.4 nM, which demonstrates a high affinity for the 5-HT1A receptor. Based on the results of obtained in the standard pharmacological test procedure, the compounds of this invention are useful in 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.
  • 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-disintergrating 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 - 7 - 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.
  • projected daily dosages of the compounds of this invention are 0.1-2000 mg/kg for oral administration, preferrably 0.5-500 mg/kg; and 0.1-100 mg/kg for parenteral administration, preferrably 0.5-50 mg/kg. - 8 -
  • the tide compound was prepared using N-pivalyl-L-phenylalanylchloromethyl ketone (4 mmole) in the procedure described in example 2.
  • the product was obtained as a light yellow oil (2.24 mmole, 56% yield) after SiO 2 "flash" Chromatography.
  • the compound was prepared in 83% yield by substituting cyclohexylacetyl chloride (3 mmole) into the procedure outlined in example 1 above. This provided the titled compound as a light yellow oil (2.5 mmole) which was used without further purification.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Psychiatry (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
EP99905632A 1998-02-03 1999-02-02 Oxazole derivatives as serotonin-1a receptor agonists Withdrawn EP1053235A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US1751798A 1998-02-03 1998-02-03
US17517 1998-02-03
PCT/US1999/002210 WO1999038864A1 (en) 1998-02-03 1999-02-02 Oxazole derivatives as serotonin-1a receptor agonists

Publications (1)

Publication Number Publication Date
EP1053235A1 true EP1053235A1 (en) 2000-11-22

Family

ID=21783033

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99905632A Withdrawn EP1053235A1 (en) 1998-02-03 1999-02-02 Oxazole derivatives as serotonin-1a receptor agonists

Country Status (6)

Country Link
EP (1) EP1053235A1 (ja)
JP (1) JP2002501920A (ja)
CN (1) CN1289333A (ja)
AU (1) AU2575399A (ja)
CA (1) CA2317515A1 (ja)
WO (1) WO1999038864A1 (ja)

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6242448B1 (en) * 1998-12-17 2001-06-05 American Home Products Corporation Trisubstituted-oxazole derivatives as serotonin ligands
US7053092B2 (en) 2001-01-29 2006-05-30 Otsuka Pharmaceutical Co., Ltd. 5-HT1a receptor subtype agonist
AR032641A1 (es) * 2001-01-29 2003-11-19 Otsuka Pharma Co Ltd Agonista de subtipo de receptor 5-ht 1a.
US8106074B2 (en) 2001-07-13 2012-01-31 Pierre Fabre Medicament Pyridin-2-yl-methylamine derivatives for treating opiate dependence
AR033485A1 (es) 2001-09-25 2003-12-26 Otsuka Pharma Co Ltd Sustancia medicinal de aripiprazol de baja higroscopicidad y proceso para la preparacion de la misma
US8703772B2 (en) 2001-09-25 2014-04-22 Otsuka Pharmaceutical Co., Ltd. Low hygroscopic aripiprazole drug substance and processes for the preparation thereof
AU2006206653A1 (en) * 2005-01-19 2006-07-27 Merck & Co., Inc. Aminomethyl beta-secretase inhibitors for the treatment of Alzheimer's disease
GB0516313D0 (en) * 2005-08-08 2005-09-14 Argenta Discovery Ltd Azole derivatives and their uses
CA2931219A1 (en) * 2013-12-20 2015-06-25 Laboratorios Del Dr. Esteve, S.A. Piperidine compounds having multimodal activity against pain

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH02167280A (ja) * 1988-08-15 1990-06-27 Glaxo Group Ltd ラクタム誘導体
US5162322A (en) * 1991-03-06 1992-11-10 A. H. Robbins Company, Incorporated Method of treating anxiety with 5-[(4-aryl or heteroaryl-1-piperazinyl]alkyl)-2-oxazolidinones

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9938864A1 *

Also Published As

Publication number Publication date
WO1999038864A1 (en) 1999-08-05
AU2575399A (en) 1999-08-16
JP2002501920A (ja) 2002-01-22
CA2317515A1 (en) 1999-08-05
CN1289333A (zh) 2001-03-28

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