EP1073636A1 - 4-amino-(ethylamino)-oxindol dopamin autorezeptor agoniste - Google Patents

4-amino-(ethylamino)-oxindol dopamin autorezeptor agoniste

Info

Publication number
EP1073636A1
EP1073636A1 EP99917423A EP99917423A EP1073636A1 EP 1073636 A1 EP1073636 A1 EP 1073636A1 EP 99917423 A EP99917423 A EP 99917423A EP 99917423 A EP99917423 A EP 99917423A EP 1073636 A1 EP1073636 A1 EP 1073636A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
hydrogen
pharmaceutically acceptable
compound
indol
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Withdrawn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
EP99917423A
Other languages
English (en)
French (fr)
Inventor
James Albert Nelson
Mira Ana Kanzelberger
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 EP1073636A1 publication Critical patent/EP1073636A1/de
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • 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
    • 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
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to a series of 4-amino-(ethylamino)-oxindoles having dopaminergic properties.
  • the compounds of the present invention are useful in treating various conditions affected by dopamine agonists, such as Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.
  • Intrinsic activity is predicted using the ratio of the "low-affinity agonist” (i.e., Low Ag) state of the receptor and the "high-affinity agonist” (i.e., HighAg) state of the receptor, i.e. LowAg HighAg. These ratios correlate with the agonist, partial agonist, and antagonist activities of a given compound. Such activities characterize the ability of a compound to elicit an antipsychotic effect.
  • WO 9109849 broadly discloses a series of indole-amine compounds, such as, compounds A and B below, that are disclosed as being useful as reverse transcriptase inhibitors for the treatment of AIDS.
  • the compounds of this invention are 4-amino-(ethylamino)-oxindoles represented by Formula I:
  • R 1 and R 2 are each, independently, hydrogen, CI .I Q alkyl, or (CH 2 ) m R 4 , wherein R 4 is phenyl or naphthyl which may be substituted by one or two substituents selected from the group consisting of C j .g alkyl, halogen, C g alkoxide and trifluoromethyl and m is 1 to 5; and R 3 is hydrogen or C j .g alkyl; or pharmaceutically acceptable salts thereof.
  • the compounds of this invention are dopamine agonists having various degrees of intrinsic dopaminergic activity. Some of these compounds are selective autoreceptor agonists, (i.e., partial agonists which activate only autoreceptors versus postsynaptic D2 dopamine receptors). As such, the present compounds provide functional modulation of the dopamine systems of the brain without causing an excessive blockade of the postsynaptic dopamine receptors. Such excessive blockades have been observed to be responsible for the serious side effects frequently exhibited by agents known to be clinically effective for the treatment of schizophrenia. Moreover, the compounds of this invention have a high degree of intrinsic activity and, therefore, they can behave as the natural neurotransmitter, i.e., as a full agonist. As such, they are useful in the treatment of diseases caused by abnormal concentrations of dopamine, such as Parkinson's disease. DETAILED DESCRIPTION OF THE INVENTION
  • the compounds of the present invention are those of Formula I, wherein: R 1 and R 2 are each, independently, CJ.JQ alkyl, or (CH 2 ) m R 4 , wherein R 4 is phenyl and m is 1 ; and
  • R 3 is hydrogen or Ci.g alkyl; or pharmaceutically acceptable salts thereof.
  • the compounds of the present invention may be selected from the group consisting of:
  • alkyl and alkoxy refer to either straight or branched chain alkyl and alkoxy groups, respectively.
  • halogen refers to chlorine, bromine, fluorine and iodine.
  • the compounds of the present invention may be used in the form of their pharmaceutically acceptable acid addition salts having the utility of the free base.
  • Such salts preparable by methods well known to those skilled in 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 the present invention are dopamine autoreceptor agonists which modulate the synthesis and release of the neurotranmitter dopamine. They are thus useful for treatment of disorders of the dopaminergic system, such as schzophrenia, Parkinson's disease and Tourette's syndrome.
  • the present compounds are also partial agonists at the postsynaptic dopamine D 2 receptor and are thus useful in the treatment of other conditions affected by such agonists, such as alcohol and drug addiction.
  • the compounds of the present invention may be prepared by any suitable, conventional method which will be recognized by one skilled in the art. However, it is preferred that the present compounds be prepared by the overall sequences depicted in Schemes I and II.
  • the invention provides a process for the preparation of a compound having the formula I or a pharmaceutically acceptable salt thereof, in which
  • X 1 is a removable protecting group or R 1 ;
  • X 2 is a removable protecting group or R 2 ;
  • X 3 is a removable protecting group or R 3 subject to the proviso that at least one of X 1 , X 2 and X 3 is a removable protecting group;
  • X 4 is 2-oxo-l,3-dihydro-indol-4-yl; is subjected to treatment to remove the removable protecting group or groups; or (b) a compound having the formula D
  • X 1 is a removable protecting group or R 1 ;
  • X 2 is a removable protecting group or R 2 ;
  • X 3 is a removable protecting group or R 3 ;
  • X 5 is a precursor for 2-oxo-l,3-dihydro-indol-4-yl; is subjected to treatment to convert X 5 into 2-oxo-l,3-dihydro-indol-4-yl; and where at least one of X 1 , X 2 and X 3 is a removable protecting group the reaction product is subjected to treatment to remove the removable protecting group or groups; or
  • X 1 is a removable protecting group or R 1 ;
  • X 2 is a removable protecting group or R 2 ; and
  • X 6 is a leaving group and, where at least one of X 1 and X 2 is a removable protecting group; the reaction product is subjected to treatment to remove the removable protecting group or groups; or
  • Trifluoroacetyl is preferably used as removable protecting group in process (a). It can be removed by suitable basic conditions, for example, with sodium hydroxide in methanol.
  • the compound of formula C may be prepared in various ways, for example, as the preliminary reaction product of step (b) or (c). Step (b) may use 3-chloro-lH- indol-4-yl as X 5 . Step (c) may be carried out in standard manner for the preparation of amines.
  • X 6 may be, for example, chloro, bromo, alkyl sulfonyloxy or arylsulfonyloxy.
  • the affinity for the dopamine autoreceptor was established by the standard experimental test procedure of Seemen and Schaus, European Journal of Pharmacology. 203:105-109 (1991). According to this procedure, homogenized rat striatal brain tissue was incubated with the appropriate 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 are therefore dopamine antireceptor agonists.
  • Such compounds 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.
  • 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-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.
  • any of the - 13 - solid carriers known to those skilled in the art may be used with the compounds of this invention.
  • Particularly suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion exchange resins.
  • Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs of the compounds of this invention.
  • the compounds 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.
  • 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 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.
  • Compositions for oral administration may be either liquid or solid composition form.
  • the pharmaceutical compositions containing the compounds of this invention are in unit dosage form, e.g., tablets or capsules.
  • the compositions may be sub-divided in unit doses containing appropriate quantities of the present compounds.
  • 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 amount of the compounds of this invention that is administered and the dosage regimen depends on a variety of factors, including the - 14 - weight, age, sex, and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the specific compound employed, and thus may vary widely.
  • the pharmaceutical compositions may contain the compounds of this invention in the range of about 0.1 to about 2000 mg, preferably in the range of about 0.5 to about 500 mg and more preferably between about 1 and about 100 mg.
  • Projected daily dosages of active compound are about 0.01 to about 100 mg/kg body weight. The daily dose can be conveniently administered two to four times per day.

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material 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)
  • Addiction (AREA)
  • Indole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP99917423A 1998-04-13 1999-04-12 4-amino-(ethylamino)-oxindol dopamin autorezeptor agoniste Withdrawn EP1073636A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US5883498A 1998-04-13 1998-04-13
US58834 1998-04-13
PCT/US1999/007967 WO1999052870A1 (en) 1998-04-13 1999-04-12 4-amino-(ethylamino)-oxindole dopamine autoreceptor agonists

Publications (1)

Publication Number Publication Date
EP1073636A1 true EP1073636A1 (de) 2001-02-07

Family

ID=22019205

Family Applications (1)

Application Number Title Priority Date Filing Date
EP99917423A Withdrawn EP1073636A1 (de) 1998-04-13 1999-04-12 4-amino-(ethylamino)-oxindol dopamin autorezeptor agoniste

Country Status (8)

Country Link
EP (1) EP1073636A1 (de)
JP (1) JP2002511450A (de)
CN (1) CN1297439A (de)
AR (1) AR014847A1 (de)
AU (1) AU3555099A (de)
CA (1) CA2327477A1 (de)
WO (1) WO1999052870A1 (de)
ZA (1) ZA992670B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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.
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

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4452808A (en) * 1982-12-07 1984-06-05 Smithkline Beckman Corporation 4-Aminoalkyl-2(3H)-indolones
GB8712073D0 (en) * 1987-05-21 1987-06-24 Smith Kline French Lab Medicament
WO1993023035A2 (en) * 1992-05-18 1993-11-25 Smithkline Beecham Plc Use of indolone derivatives for the treatment of memory disorders, sexual dysfunction and parkinson's disease
AU4088897A (en) * 1996-08-27 1998-03-19 American Home Products Corporation 4-aminoethoxy indolone derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9952870A1 *

Also Published As

Publication number Publication date
CN1297439A (zh) 2001-05-30
AU3555099A (en) 1999-11-01
ZA992670B (en) 2000-10-12
CA2327477A1 (en) 1999-10-21
WO1999052870A1 (en) 1999-10-21
AR014847A1 (es) 2001-03-28
JP2002511450A (ja) 2002-04-16

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Inventor name: MEWSHAW, RICHARD, ERIC

Inventor name: KANZELBERGER, MIRA, ANA

Inventor name: NELSON, JAMES, ALBERT

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