WO1998035948A1 - 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists - Google Patents

5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists 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)
French (fr)
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 EP98903628A priority Critical patent/EP0963372A1/de
Priority to IL13116098A priority patent/IL131160A0/xx
Priority to CA002278757A priority patent/CA2278757A1/en
Priority to NZ336971A priority patent/NZ336971A/xx
Priority to JP53574298A priority patent/JP2001511805A/ja
Priority to AU60350/98A priority patent/AU722616B2/en
Priority to BR9807230-7A priority patent/BR9807230A/pt
Priority to HU0001311A priority patent/HUP0001311A3/hu
Publication of WO1998035948A1 publication Critical patent/WO1998035948A1/en

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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)
  • 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)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Psychology (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
PCT/US1998/001170 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists WO1998035948A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
EP98903628A EP0963372A1 (de) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydrochinoxalin-2,3-dione als dopamin agonsisten
IL13116098A IL131160A0 (en) 1997-02-18 1998-01-13 5-Aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists
CA002278757A CA2278757A1 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists
NZ336971A NZ336971A (en) 1997-02-18 1998-01-13 5-Aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones useful as 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
AU60350/98A AU722616B2 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists
BR9807230-7A BR9807230A (pt) 1997-02-18 1998-01-13 5-aminoalcóxi-1,4-diidroquinoxalina-2,3-dionas que são agonistas de dopamina
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

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 (en) 1998-08-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/001170 WO1998035948A1 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists

Country Status (14)

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

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009152909A1 (en) 2008-06-16 2009-12-23 Merck Patent Gmbh Quinoxalinedione derivatives

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315959A2 (de) * 1987-11-10 1989-05-17 Novo Nordisk A/S Chinoxalinverbindungen und deren Herstellung und Verwendung
EP0377112A1 (de) * 1988-12-22 1990-07-11 Novo Nordisk A/S Chinoxalin-Verbindungen, ihre Herstellung und Verwendung
WO1990015606A1 (en) * 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 and its analogs as therapeutics for degenerative neural diseases
WO1992011012A1 (de) * 1990-12-21 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen Verwendung von quisqualat-rezeptor-antagonisten zur behandlung des morbus parkinson
WO1992012134A2 (en) * 1990-12-28 1992-07-23 Neurogen Corporation Certain aminomethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
WO1994000124A1 (en) * 1992-06-22 1994-01-06 Eckard Weber Glycine receptor antagonists and the use thereof
WO1996009295A1 (en) * 1994-09-24 1996-03-28 Pfizer Limited Quinoxaline derivatives useful in therapy
EP0707007A1 (de) * 1994-10-14 1996-04-17 MERCK PATENT GmbH ZNS wirksame Amino(thio)ether-Derivate
WO1997023216A1 (en) * 1995-12-22 1997-07-03 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0315959A2 (de) * 1987-11-10 1989-05-17 Novo Nordisk A/S Chinoxalinverbindungen und deren Herstellung und Verwendung
EP0377112A1 (de) * 1988-12-22 1990-07-11 Novo Nordisk A/S Chinoxalin-Verbindungen, ihre Herstellung und Verwendung
WO1990015606A1 (en) * 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 and its analogs as therapeutics for degenerative neural diseases
WO1992011012A1 (de) * 1990-12-21 1992-07-09 Schering Aktiengesellschaft Berlin Und Bergkamen Verwendung von quisqualat-rezeptor-antagonisten zur behandlung des morbus parkinson
WO1992012134A2 (en) * 1990-12-28 1992-07-23 Neurogen Corporation Certain aminomethyl phenylimidazole derivatives; a new class of dopamine receptor subtype specific ligands
WO1994000124A1 (en) * 1992-06-22 1994-01-06 Eckard Weber Glycine receptor antagonists and the use thereof
WO1996009295A1 (en) * 1994-09-24 1996-03-28 Pfizer Limited Quinoxaline derivatives useful in therapy
EP0707007A1 (de) * 1994-10-14 1996-04-17 MERCK PATENT GmbH ZNS wirksame Amino(thio)ether-Derivate
WO1997023216A1 (en) * 1995-12-22 1997-07-03 Warner-Lambert Company 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists

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 (en) 2008-06-16 2009-12-23 Merck Patent Gmbh Quinoxalinedione derivatives

Also Published As

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

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