EP0963372A1 - 5-aminoalkoxy-1,4-dihydrochinoxalin-2,3-dione als dopamin agonsisten - Google Patents

5-aminoalkoxy-1,4-dihydrochinoxalin-2,3-dione als dopamin agonsisten

Info

Publication number
EP0963372A1
EP0963372A1 EP98903628A EP98903628A EP0963372A1 EP 0963372 A1 EP0963372 A1 EP 0963372A1 EP 98903628 A EP98903628 A EP 98903628A EP 98903628 A EP98903628 A EP 98903628A EP 0963372 A1 EP0963372 A1 EP 0963372A1
Authority
EP
European Patent Office
Prior art keywords
halogen
alkyl
dihydro
ethoxy
dopamine
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Withdrawn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
EP98903628A
Other languages
English (en)
French (fr)
Inventor
James Albert Nelson
Uresh Shantilal Shah
Richard Eric Mewshaw
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 LLC
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 EP0963372A1 publication Critical patent/EP0963372A1/de
Withdrawn legal-status Critical Current

Links

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.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Biomedical Technology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP98903628A 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydrochinoxalin-2,3-dione als dopamin agonsisten Withdrawn EP0963372A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US80132497A 1997-02-18 1997-02-18
US801324 1997-02-18
PCT/US1998/001170 WO1998035948A1 (en) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydroquinoxaline-2,3-diones being dopamine agonists

Publications (1)

Publication Number Publication Date
EP0963372A1 true EP0963372A1 (de) 1999-12-15

Family

ID=25180799

Family Applications (1)

Application Number Title Priority Date Filing Date
EP98903628A Withdrawn EP0963372A1 (de) 1997-02-18 1998-01-13 5-aminoalkoxy-1,4-dihydrochinoxalin-2,3-dione als dopamin agonsisten

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)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8329698B2 (en) 2008-06-16 2012-12-11 MERCK Patent Gesellschaft mit beschränkter Haftung Quinoxalinedione derivatives which are activators of AMPK-activated protein kinase

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NO179551C (no) * 1987-11-10 1996-10-30 Novo Nordisk As Analogifremgangsmåte for fremstilling av terapeutisk virksomme kinoxalinforbindelser
DK715888D0 (da) * 1988-12-22 1988-12-22 Ferrosan As Quinoxalinforbindelser, deres fremstilling og anvendelse
US4975430A (en) * 1989-06-16 1990-12-04 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
PT99864B (pt) * 1990-12-21 1999-06-30 Schering Ag Processo para a preparacao de novas composicoes farmaceuticas contendo antagonistas de receptor de quisqualato
US5159083A (en) * 1990-12-28 1992-10-27 Neurogen Corporation Certain aminomethyl phenylimidazole derivatives; a class of dopamine receptor subtype specific ligands
EP0647137B1 (de) * 1992-06-22 2008-08-13 The Regents Of The University Of California Glycinrezeptorantagonisten und ihre verwendung
GB9419318D0 (en) * 1994-09-24 1994-11-09 Pfizer Ltd Therapeutic agents
ES2169102T3 (es) * 1994-10-14 2002-07-01 Merck Patent Gmbh (r)-(-)-2-(5-(4-fluorfenil)-3-piridilmetilaminometil)-cromano como agente activo sobre el sistema nervioso central.
ZA9610745B (en) * 1995-12-22 1997-06-24 Warner Lambert Co 4-Subsituted piperidine analogs and their use as subtype selective nmda receptor antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9835948A1 *

Also Published As

Publication number Publication date
HUP0001311A2 (hu) 2001-05-28
CA2278757A1 (en) 1998-08-20
AU6035098A (en) 1998-09-08
TW434230B (en) 2001-05-16
ZA981306B (en) 1999-08-17
KR20000071162A (ko) 2000-11-25
JP2001511805A (ja) 2001-08-14
BR9807230A (pt) 2000-04-25
NZ336971A (en) 2000-10-27
AR011669A1 (es) 2000-08-30
CN1248249A (zh) 2000-03-22
WO1998035948A1 (en) 1998-08-20
HUP0001311A3 (en) 2001-07-30
AU722616B2 (en) 2000-08-10
IL131160A0 (en) 2001-01-28

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