WO1998035948A1 - 5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine - Google Patents

5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine Download PDF

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Publication number
WO1998035948A1
WO1998035948A1 PCT/US1998/001170 US9801170W WO9835948A1 WO 1998035948 A1 WO1998035948 A1 WO 1998035948A1 US 9801170 W US9801170 W US 9801170W WO 9835948 A1 WO9835948 A1 WO 9835948A1
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WO
WIPO (PCT)
Prior art keywords
halogen
alkyl
dihydro
ethoxy
dopamine
Prior art date
Application number
PCT/US1998/001170
Other languages
English (en)
Inventor
James Albert Nelson
Uresh Shantilal Shah
Richard Eric Mewshaw
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 BR9807230-7A priority Critical patent/BR9807230A/pt
Priority to AU60350/98A priority patent/AU722616B2/en
Priority to HU0001311A priority patent/HUP0001311A3/hu
Priority to CA002278757A priority patent/CA2278757A1/fr
Priority to IL13116098A priority patent/IL131160A0/xx
Priority to JP53574298A priority patent/JP2001511805A/ja
Priority to EP98903628A priority patent/EP0963372A1/fr
Priority to NZ336971A priority patent/NZ336971A/xx
Publication of WO1998035948A1 publication Critical patent/WO1998035948A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen 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
    • A61P25/14—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
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring

Definitions

  • This invention relates to N-substituted 5-aminoethoxy- 1 ,4-dihydroquinoxaline-2,3- diones which are dopamine D 2 agonists and therefore useful as antipsychotic agents and anti-parkinson agents.
  • Intrinsic activity is predicted using the ratio of the "low-affinity agonist" (Lo Ag) 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 dopamine autoreceptors results in reduced neuronal firing a well as inhibition of dopamine synthesis and release and therefore provide a means of controlling hyperactivity of the dopaminergic systems.
  • the compounds of this invention were also found to have high intrinsic activity and therefore they can behave as the natural neurotransmitter i.e. as full agonists. As such, they are useful in the treatment of diseases having abnormal concentrations of dopamine could be used as dopamine surrogates possibly in the treatment of Parkinson's disease.
  • the compounds of this invention are essentially free of extrapyramidal side effects.
  • R 1 and R 2 are independently selected from hydrogen, straight-chain and branched alkyl group having up to 10 carbon atoms or -(C ⁇ m A ⁇ where Ar is phenyl, naphthyl or thienyl, each optionally substituted by one or two substituents selected independently from C j -C 6 alkyl, halogen, -C 6 alkoxide and trifluoromethyl; or NR*R 2 is 1, 2, 3, 4-tetrahydroquinolin-l-yl or 1, 2, 3, 4- tetrahydroisoquinolin-2-yl; m is 1-5; n is 1 or 2;
  • Y is halogen, C,-C 6 alkyl, and C j -C 6 alkoxy; and the pharmaceutically acceptable salts thereof.
  • salts are prepared by methods well known to the art and are formed with both inorganic or organic acids including but not limited to 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.
  • inorganic or organic acids including but not limited to fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesul
  • the compounds of Formula I can be prepared by the overall sequence as follows:
  • N-(4-chloro-benzyl)-N-[2-(2,3- diamino-phenoxy)-ethyl]-2,2,2-trifluoro-acetamide N-(4-chloro-benzyl)-N-[2-(2,3-dioxo- l,2,3,4-tetrahydro-quinoxalin-5-yloxy)-ethyl]-2,2,2-trifluoro-acetamide (5b) was obtained a semi-solid material(47 %).
  • 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 analagous 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-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 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. In such form, 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.

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

Abstract

Cette invention concerne des composés de la formule (I) dans laquelle R1 et R2 sont sélectionnés indépendamment entre l'hydrogène, un groupe alkyle à chaîne droite et ramifiée présentant jusqu'à dix atomes de carbone ou -(CH¿2?)mAr où Ar représente phényle, naphtyle ou thiényle, chacun facultativement substitué par un ou deux substituants sélectionnés indépendamment entre alkyle C1-C6, halogène, alcoxyde C1-C6 et trifluorométhyle; ou NR?1R2¿ représente 1,2,3,4-tétrahydroquinoline-1-yl ou 1,2,3,4-tétrahydroisoquinoline-2-yl; m est compris entre 1 et 5; n représente 1 ou 2; Y représente halogène, alkyle C¿1?-C6 et alcoxy C1-C6; ou leurs sels pharmaceutiquement acceptables, lesquels constituent des agonistes de la dopamine D2 et sont par conséquentes utiles dans le traitement de psychoses et de la maladie de Parkinson's.
PCT/US1998/001170 1997-02-18 1998-01-13 5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine WO1998035948A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
BR9807230-7A BR9807230A (pt) 1997-02-18 1998-01-13 5-aminoalcóxi-1,4-diidroquinoxalina-2,3-dionas que são agonistas de dopamina
AU60350/98A AU722616B2 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists
HU0001311A HUP0001311A3 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists and pharmaceutical compositions containing them
CA002278757A CA2278757A1 (fr) 1997-02-18 1998-01-13 5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine
IL13116098A IL131160A0 (en) 1997-02-18 1998-01-13 5-Aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists
JP53574298A JP2001511805A (ja) 1997-02-18 1998-01-13 ドパミン作動薬である５−アミノアルコキシ−１，４−ジヒドロキノキサリン−２，３−ジオン
EP98903628A EP0963372A1 (fr) 1997-02-18 1998-01-13 5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine
NZ336971A NZ336971A (en) 1997-02-18 1998-01-13 5-Aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones useful as dopamine agonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80132497A 1997-02-18 1997-02-18
US08/801,324 1997-02-18

Publications (1)

Publication Number Publication Date
WO1998035948A1 true WO1998035948A1 (fr) 1998-08-20

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PCT/US1998/001170 WO1998035948A1 (fr) 1997-02-18 1998-01-13 5-aminoalcoxy-1,4-dihydroquinoxaline-2,3-diones en tant qu'agonistes de la dopamine

Country Status (14)

Country Link
EP (1) EP0963372A1 (fr)
JP (1) JP2001511805A (fr)
KR (1) KR20000071162A (fr)
CN (1) CN1248249A (fr)
AR (1) AR011669A1 (fr)
AU (1) AU722616B2 (fr)
BR (1) BR9807230A (fr)
CA (1) CA2278757A1 (fr)
HU (1) HUP0001311A3 (fr)
IL (1) IL131160A0 (fr)
NZ (1) NZ336971A (fr)
TW (1) TW434230B (fr)
WO (1) WO1998035948A1 (fr)
ZA (1) ZA981306B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009152909A1 (fr) 2008-06-16 2009-12-23 Merck Patent Gmbh Dérivés de quinoxalinedione

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315959A2 (fr) * 1987-11-10 1989-05-17 Novo Nordisk A/S Quinoxalines et leur préparation et application
EP0377112A1 (fr) * 1988-12-22 1990-07-11 Novo Nordisk A/S Composés quinoxaline, leur préparation et utilisation
WO1990015606A1 (fr) * 1989-06-16 1990-12-27 The State Of Oregon Acting By And Through The State Board Of Education On Behalf Of The Oregon Health Sciences University Cnqx et ses analogues comme therapeutiques pour les maladies nerveuses degeneratives
WO1992011012A1 (fr) * 1990-12-21 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen Utilisation d'antagonistes des recepteurs de quisqualate pour le traitement de la maladie de parkinson
WO1992012134A2 (fr) * 1990-12-28 1992-07-23 Neurogen Corporation Certains derives de phenylimidazole aminomethyle; nouvelle classe de ligands a specificite de sous-type de recepteur de dopamine
WO1994000124A1 (fr) * 1992-06-22 1994-01-06 Eckard Weber Antagonistes des recepteurs de glycine et leur utilisation
WO1996009295A1 (fr) * 1994-09-24 1996-03-28 Pfizer Limited Derives de quinoxaline utiles en therapie
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
WO1997023216A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315959A2 (fr) * 1987-11-10 1989-05-17 Novo Nordisk A/S Quinoxalines et leur préparation et application
EP0377112A1 (fr) * 1988-12-22 1990-07-11 Novo Nordisk A/S Composés quinoxaline, leur préparation et utilisation
WO1990015606A1 (fr) * 1989-06-16 1990-12-27 The State Of Oregon Acting By And Through The State Board Of Education On Behalf Of The Oregon Health Sciences University Cnqx et ses analogues comme therapeutiques pour les maladies nerveuses degeneratives
WO1992011012A1 (fr) * 1990-12-21 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen Utilisation d'antagonistes des recepteurs de quisqualate pour le traitement de la maladie de parkinson
WO1992012134A2 (fr) * 1990-12-28 1992-07-23 Neurogen Corporation Certains derives de phenylimidazole aminomethyle; nouvelle classe de ligands a specificite de sous-type de recepteur de dopamine
WO1994000124A1 (fr) * 1992-06-22 1994-01-06 Eckard Weber Antagonistes des recepteurs de glycine et leur utilisation
WO1996009295A1 (fr) * 1994-09-24 1996-03-28 Pfizer Limited Derives de quinoxaline utiles en therapie
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
WO1997023216A1 (fr) * 1995-12-22 1997-07-03 Warner-Lambert Company Analogues de piperidine a substitution en position 4 et utilisation de ces derniers en tant qu'antagonistes selectivement actifs contre les sous-types du recepteur de nmda

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BENES,F.M.: "Development of the Glutamate, GABA and Dopamine Systems in Relation to NRH-Induced Neurotoxicity", BIOL.PSYCHIATRY, vol. 38, 1995, NEW YORK, pages 783 - 787, XP002065087 *
JAEN J C ET AL: "DOPAMINE AUTORECEPTOR AGONISTS AS POTENTIAL ANTIPSYCHOTICS. 1 (AMINOALKOXY)ANILINES", JOURNAL OF MEDICINAL CHEMISTRY, vol. 31, no. 8, August 1988 (1988-08-01), pages 1621 - 1625, XP000674393 *
OLNEY,J.W. ET AL.: "Glutamate Receptor Dysfunction and Schizophrenia", ARCH.GEN.PSYCHIATRY, vol. 52, December 1995 (1995-12-01), CHICAGO, pages 998 - 1007, XP002065088 *
STARR,M.S. ET AL.: "Facilitation of dopamine D1 receptor -but not dopamine D1/D2 receptor-dependent locomotion by glutamate antagonists in the reserpine-treated mouse", EUR.J.PHARMACOL., vol. 250, 1993, AMSTERDAM, pages 239 - 246, XP002065089 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009152909A1 (fr) 2008-06-16 2009-12-23 Merck Patent Gmbh Dérivés de quinoxalinedione

Also Published As

Publication number Publication date
ZA981306B (en) 1999-08-17
IL131160A0 (en) 2001-01-28
HUP0001311A3 (en) 2001-07-30
AU722616B2 (en) 2000-08-10
KR20000071162A (ko) 2000-11-25
EP0963372A1 (fr) 1999-12-15
NZ336971A (en) 2000-10-27
TW434230B (en) 2001-05-16
CA2278757A1 (fr) 1998-08-20
CN1248249A (zh) 2000-03-22
BR9807230A (pt) 2000-04-25
AR011669A1 (es) 2000-08-30
AU6035098A (en) 1998-09-08
HUP0001311A2 (hu) 2001-05-28
JP2001511805A (ja) 2001-08-14

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