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WO1998035942A1 - Derives de 4-aminoethoxyindazole - Google Patents

Derives de 4-aminoethoxyindazole Download PDF

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Publication number
WO1998035942A1
WO1998035942A1 PCT/US1998/001167 US9801167W WO9835942A1 WO 1998035942 A1 WO1998035942 A1 WO 1998035942A1 US 9801167 W US9801167 W US 9801167W WO 9835942 A1 WO9835942 A1 WO 9835942A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutically acceptable
alkoxy
halogen
phenyl
alkyl
Prior art date
Application number
PCT/US1998/001167
Other languages
English (en)
Inventor
Richard Eric Mewshaw
Anthonie Johan Verwijs
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 AU62461/98A priority Critical patent/AU6246198A/en
Publication of WO1998035942A1 publication Critical patent/WO1998035942A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
    • C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • This invention relates to 4-aminoethoxyindazole derivatives having dopamine D 2 agonist activity useful for antipsychotic effects and antiparkinsonism.
  • Intrinsic activity is predicted using the ratio of the "low-affinity agonist" (LowAg) state of the receptor and the "high-affinity agonist” (HighAg) state of the receptor, i.e. LowAg/HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound, which activities characterize a compounds ability to elicit an antipsychotic effect.
  • the compounds of this invention are dopamine agonists various degrees of intrinsic activity some of which are selective autoreceptor agonists, and therefore partial agonist (i.e. activate only autoreceptors versus postsynaptic D 2 dopamine receptors).
  • the compounds of this invention are essentially free from extrapyramidal side effects (EPS).
  • EPS extrapyramidal side effects
  • the compounds of this invention are 4-aminoethoxy-benzimidazole derivatives which are illustrated by Formula I below.
  • Y is hydrogen, halogen, or -C ⁇ alkoxy;
  • R 1 is hydrogen or C ⁇ -C 6 alkyl;
  • X is methylene, oxygen or carbonyl;
  • the compounds of this 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 this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotransmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schizophrenia,
  • Parkinson's disease and Tourette's syndrome Such agents are partial agonists at the postsynaptic dopamine D 2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
  • Affinity for the dopamine autoreceptor was established by a modification of the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology 203, 105-109, 1991, wherein homogenized rat striatal brain tissue is incubated with ⁇ H-quinpirole (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
  • the compounds of this invention effect the synthesis of the neurotransmitter dopamine and thus are useful in the treatment of dopaminergic disorders such as schizophrenia, Parkinson's disease, Tourette's Syndrome, alcohol addiction, cocaine addiction, and addiction to analogous drugs.
  • Applicable solid carriers for pharmaceutical compositions containing the compounds of this invention 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, emulsif ⁇ ers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • suitable pharmaceutical additives such as solubilizers, emulsif ⁇ ers, 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) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl
  • 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 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 and the size, age and response pattern of the patient.

Landscapes

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

Abstract

Cette invention concerne des agonistes de la dopamine D2 de la formule (I) dans laquelle Y représente hydrogène, halogène ou alcoxy C1-C6, et R1 représente hydrogène ou alkyle C¿1?-C6, X représente méthylène, oxygène ou carbonyle, Ar représente phényle ou thiényle, chacun facultativement substitué par 1 à 2 groupes choisis indépendemment parmi alcoxy C1-C6, alkyle C1-C6, halogène, trifluorométhyle et phényle, n=1-4, ou leurs sels pharmaceutiquement acceptables. Les agonistes de la dopamine D2 sont utiles dans le traitement de la schizophrénie, de la maladie de Gilles de la Tourette, de la toxicomanie et de l'alcoolisme, ils sont également utiles dans le traitement de la maladie de Parkinson.
PCT/US1998/001167 1997-02-18 1998-01-13 Derives de 4-aminoethoxyindazole WO1998035942A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU62461/98A AU6246198A (en) 1997-02-18 1998-01-13 4-aminoethoxyindazole derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80132597A 1997-02-18 1997-02-18
US08/801,325 1997-02-18

Publications (1)

Publication Number Publication Date
WO1998035942A1 true WO1998035942A1 (fr) 1998-08-20

Family

ID=25180801

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/US1998/001167 WO1998035942A1 (fr) 1997-02-18 1998-01-13 Derives de 4-aminoethoxyindazole
PCT/US1998/002413 WO1998035943A1 (fr) 1997-02-18 1998-02-13 Derives du 4-aminoethoxyindazole

Family Applications After (1)

Application Number Title Priority Date Filing Date
PCT/US1998/002413 WO1998035943A1 (fr) 1997-02-18 1998-02-13 Derives du 4-aminoethoxyindazole

Country Status (11)

Country Link
EP (1) EP0960101A1 (fr)
JP (1) JP2001512458A (fr)
KR (1) KR20000071125A (fr)
CN (1) CN1248246A (fr)
AR (1) AR011137A1 (fr)
AU (2) AU6246198A (fr)
BR (1) BR9807397A (fr)
CA (1) CA2278746A1 (fr)
IL (1) IL131159A0 (fr)
WO (2) WO1998035942A1 (fr)
ZA (1) ZA981307B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005116027A2 (fr) * 2004-05-26 2005-12-08 Pfizer Limted Nouveaux derives indazole et indolone et leur utilisation pharmaceutique
US10590086B2 (en) 2014-11-03 2020-03-17 Iomet Pharma Ltd. Pharmaceutical compound

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021630A1 (fr) * 1993-03-18 1994-09-29 Merck Sharp & Dohme Limited Derives d'indazole a action neuroleptique
WO1994021626A1 (fr) * 1993-03-18 1994-09-29 Merck Sharp & Dohme Limited Derives d'indazole

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994021630A1 (fr) * 1993-03-18 1994-09-29 Merck Sharp & Dohme Limited Derives d'indazole a action neuroleptique
WO1994021626A1 (fr) * 1993-03-18 1994-09-29 Merck Sharp & Dohme Limited Derives d'indazole

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 114, no. 3, 21 January 1991, Columbus, Ohio, US; abstract no. 23858x, MOSTI LUISA ET AL.: "4-substituted 1-phenyl-1H-indazoles with analgetic, antinflammatory, antipyretic and local anesthetic activities." page 697; column 2; XP002063971 *
CHEMICAL ABSTRACTS, vol. 117, no. 23, 7 December 1992, Columbus, Ohio, US; abstract no. 225909n, MOSTI LUISA ET AL.: "4-substituted 1-methyl-1-H-indazoles with analgesic, antiinflammatory and antipyretic activities" page 36; column 2; XP002063970 *
FARMACO, vol. 45, no. 4, - 1990, pages 415 - 429 *
FARMACO, vol. 47, no. 5, 1992, pages 567 - 584 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005116027A2 (fr) * 2004-05-26 2005-12-08 Pfizer Limted Nouveaux derives indazole et indolone et leur utilisation pharmaceutique
WO2005116027A3 (fr) * 2004-05-26 2006-04-13 Pfizer Limted Nouveaux derives indazole et indolone et leur utilisation pharmaceutique
US10590086B2 (en) 2014-11-03 2020-03-17 Iomet Pharma Ltd. Pharmaceutical compound
US11130738B2 (en) 2014-11-03 2021-09-28 Iomet Pharma Ltd. Pharmaceutical compound

Also Published As

Publication number Publication date
AU6273398A (en) 1998-09-08
IL131159A0 (en) 2001-01-28
JP2001512458A (ja) 2001-08-21
EP0960101A1 (fr) 1999-12-01
AU6246198A (en) 1998-09-08
ZA981307B (en) 1999-08-17
CN1248246A (zh) 2000-03-22
AR011137A1 (es) 2000-08-02
WO1998035943A1 (fr) 1998-08-20
KR20000071125A (ko) 2000-11-25
BR9807397A (pt) 2000-03-14
CA2278746A1 (fr) 1998-08-20

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