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WO1998035946A1 - Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2) - Google Patents

Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2) Download PDF

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Publication number
WO1998035946A1
WO1998035946A1 PCT/US1998/000623 US9800623W WO9835946A1 WO 1998035946 A1 WO1998035946 A1 WO 1998035946A1 US 9800623 W US9800623 W US 9800623W WO 9835946 A1 WO9835946 A1 WO 9835946A1
Authority
WO
WIPO (PCT)
Prior art keywords
dihydro
alkyl
benzoimidazol
pharmaceutically acceptable
ethoxy
Prior art date
Application number
PCT/US1998/000623
Other languages
English (en)
Inventor
Richard Eric Mewshaw
James Albert Nelson
Uresh Shantilal Shah
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 JP53572998A priority Critical patent/JP2001511804A/ja
Priority to EP98903469A priority patent/EP0964853A1/fr
Priority to CA002278747A priority patent/CA2278747A1/fr
Priority to HU0001262A priority patent/HUP0001262A3/hu
Priority to IL13115698A priority patent/IL131156A0/xx
Priority to BR9807703-1A priority patent/BR9807703A/pt
Priority to NZ337271A priority patent/NZ337271A/xx
Priority to AU60234/98A priority patent/AU744443B2/en
Publication of WO1998035946A1 publication Critical patent/WO1998035946A1/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
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/26—Oxygen atoms
    • 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 a series of 4-aminoalkoxy-l,3-dihydrobenzoimidazol-2- ones having dopaminergic properties and thus have utility in treating Parkinson's disease, Tourette's syndrome, schizophrenia, and alcohol and drug addiction.
  • the compounds of this invention are dopamine agonists having various degrees of intrinsic activity and are essentially free from extrapyramidal side effects. Some of the compounds are selective autoreceptor agonists, and therefore partial agonists (i.e. activate only autoreceptors versus postsynaptic D2 dopamine receptors). Efforts to induce antipsychotic activity with dopamine autoreceptor agonists have been successful (Dorsini et al., Adv. Biochem. PsychopharmacoL, 16, 645-648, 1977; Tamminga et al., Science, 200, 567-568; and Tamminga et al, Psychiatry, 398-402, 1986).
  • the invention compounds provide functional modulation of the dopamine systems of the brain without the excessive blockade of the postsynaptic dopamine receptors which have been observed to be responsible for the serious side effects frequently exhibited by agents found otherwise clinically effective for the treatment of schizophrenia.
  • Activation of the dopamine autoreceptors results in reduced neuronal firing a well as inhibition of dopamine synthesis and release and therefore provides 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 such as schizophrenia, Parkinson's disease and Tourette's syndrome. Such agents are partial agonists at the postsynaptic dopamine D2 receptor and are thereby useful in the treatment of alcohol and drug addiction.
  • Ciba-Geigy discloses compounds represented by the compound of the formula below which have both ⁇ and ⁇ -adrenergic properties and are useful as cardiovascular and antihypertensive agents.
  • R 1 is hydrogen or C ⁇ -C 6 alkyl
  • R 2 is selected from hydrogen, straight-chain and branched Ci-Cio alkyl, cyclohexylmethyl or -(CH 2 ) m Ar where Ar is phenyl, naphthyl, thienyl, furanyl or pyridinyl, each optionally substituted by one or two substituents selected independently from - alkyl, halogen, C,-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;
  • R 3 is hydrogen or C,-C 6 alkyl
  • Y is halogen, - alkyl, and - alkoxy
  • the pharmaceutically acceptable salts thereof can be formed with an invention compound and a pharmaceutically acceptable acid including, but not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, acetate, fumarate, succinate, citrate, maleate, lactate, and benzoate salts.
  • the compounds of this invention are dopamine autoreceptor agonists, that is, they serve to modulate the synthesis and release of the neurotranmitter 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.
  • the compounds of Formula I are generally prepared by the overall sequence depicted in Schemes I -IV.
  • R 1 and R 2 is hydrogen
  • Scheme I outlines a procedure to prepare an invention compound where R 3 is H.
  • Scheme II shows a synthetic route for invention compounds where R 3 is not H.
  • Scheme III shows a synthetic route for invention compounds where neither of R 1 and R 2 is H.
  • Scheme IV shows the procedure used to prepare an intermediate where Y is Cl.
  • the fumarate salt was prepared by adding a solution of the free base (165 mg) in warm isopropanol (15 mL) to an excess of fumaric acid in warm isopropanol (20 mL). Upon completion of addition crystals began forming and the mixture was allowed to cool to room temperature and the crystals filtered to afford 203 mg of fumarate salt, mp 201.5-202.5 °C; MS ESI m/e 298 (M+H + ).
  • Intrinsic activity is predicted using die 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.
  • 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 3 H-quinpirole (Quin.) and various concentrations of test compound, filtered and washed and counted in a Betaplate scintillation counter.
  • High affinity for the dopamine D-2 receptor was established by the standard experimental test procedure of Fields, et al., Brain Res., 136. 578 (1977) and Yamamura et al., eds., Neurotransmitter Receptor Binding, Raven Press, N.Y.
  • compositions of this invention may be administered neat or with a pharmaceutical carrier to a patient in need thereof.
  • the pharmaceutical carrier may be solid or liquid.
  • 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 n 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.
  • 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 a 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, preferable 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. Oral administration may be as either a liquid or a solid dosage form.
  • the compounds of this invention may be administered rectally in the form of a conventinal suppository.
  • the compounds of this invention may be formulated into an aqueous or partrially aqueous solution, which can then be utilized in die form of an aerosol.
  • the compounds of this invention may also be administered transdermally through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin.
  • the carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices.
  • the creams and ointments may be viscous liquid or semi-solid emulsions of either the oil in water or water in oil type.
  • Pastes comprised of absorptive powders dispersed in petroleum or hydrophilic petroleum containing the active ingredient may also be suitable.
  • a variety of occlusive devices may be used to realease the active ingredient into the blood stream such as a semipermeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient. Other occlusive devices are known in d e literature.
  • the dosage to be used in the treatment of a specific patient suffering a dopamine imbalance must be subjectively determined by the attending physician.
  • the variables involved include the severity of the dysfunction, and the size, age, and response pattern of the patient.
  • 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 die active ingredient;
  • the unit dosage form can be packaged compositions, for example packed 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.

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

Abstract

L'invention concerne des composés de la formule (I) ou bien un sel pharmaceutiquement acceptable de ceux-ci. Dans cette formule, R1 est hydrogène ou alkyle C¿1?-C6; R?2¿ est choisi parmi hydrogène, alkyle C¿1?-C10 à chaîne droite ou ramifié, cyclohexyméthyle ou bien -(CH2)mAr où Ar est phényle, napthyle, thiényle, furanyle ou pyridinyle, éventuellement substitués par un ou deux substituants choisis indépendamment parmi alkyle C1-6, halogène, alcoxy C1-C6 et trifluorométhyle; ou bien NR?1R2¿ est 1,2,3,4-tétrahydroquinoléin-1-yle ou 1,2,3,4-tétrahydroisoquinoléin-2-yle; m vaut 1-5; n vaut 1 ou 2; R3 est hydrogène ou alkyle C¿1?-C6; Y est halogène, alkyle C1-C6, et alcoxy C1-C6. Ces composés sont des agonistes des autorécepteurs de la dopamine et à ce titre sont utiles dans le traitement de la schizophrénie, de la maladie de Parkinson, de la maladie de Gilles de La Tourette, de l'alcoolisme et de la toxicomanie.
PCT/US1998/000623 1997-02-18 1998-01-13 Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2) WO1998035946A1 (fr)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP53572998A JP2001511804A (ja) 1997-02-18 1998-01-13 ４−アミノアルコキシ−１，３−ジヒドロベンゾイミダゾール−２−オン誘導体、それらの調製およびそれらのドパミン自己受容体（ｄ▲下２▼）作動薬としての使用
EP98903469A EP0964853A1 (fr) 1997-02-18 1998-01-13 Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2)
CA002278747A CA2278747A1 (fr) 1997-02-18 1998-01-13 Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2)
HU0001262A HUP0001262A3 (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one deriatives, their preparation and their use as dopamine autoreceptor (d2) agonists
IL13115698A IL131156A0 (en) 1997-02-18 1998-01-13 4-Aminoalkyl-1,3-dihydrobenzoimidazol-2-one derivatives their preparation and their use as dopamine autoreceptor (d2) agonists
BR9807703-1A BR9807703A (pt) 1997-02-18 1998-01-13 Derivados de 4-aminoalcóxi-1,3-diidrobenzoimidazol-2-ona, suas preparações e seus usos como agonistas (d2) auto-receptores da dopamina
NZ337271A NZ337271A (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives and their use as dopamine autoreceptor (D2) agonists
AU60234/98A AU744443B2 (en) 1997-02-18 1998-01-13 4-aminoalkoxy-1,3-dihydrobenzoimidazol-2-one derivatives, their preparation and their use as dopamine autoreceptor (D2) agonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US80187097A 1997-02-18 1997-02-18
US08/801,870 1997-02-18

Publications (1)

Publication Number Publication Date
WO1998035946A1 true WO1998035946A1 (fr) 1998-08-20

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PCT/US1998/000623 WO1998035946A1 (fr) 1997-02-18 1998-01-13 Derives 4-aminoalcoxy-1,3-dihydrobenzoimidazol-2-ones, leur preparation et leur utilisation comme agonistes de l'autorecepteur de la dopamine (d2)

Country Status (14)

Country Link
EP (1) EP0964853A1 (fr)
JP (1) JP2001511804A (fr)
KR (1) KR20000071160A (fr)
CN (1) CN1138761C (fr)
AR (1) AR011138A1 (fr)
AU (1) AU744443B2 (fr)
BR (1) BR9807703A (fr)
CA (1) CA2278747A1 (fr)
HU (1) HUP0001262A3 (fr)
IL (1) IL131156A0 (fr)
NZ (1) NZ337271A (fr)
TW (1) TW383303B (fr)
WO (1) WO1998035946A1 (fr)
ZA (1) ZA981310B (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008708A1 (fr) * 1990-11-20 1992-05-29 Fisons Plc Amines biologiquement actives
WO1993023385A1 (fr) * 1992-05-19 1993-11-25 Fisons Plc Amines actives sur le plan biologique
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
EP0771801A1 (fr) * 1995-11-06 1997-05-07 American Home Products Corporation Dérivés de chromanne
WO1998008843A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation Derives de 4-aminoethoxy-indolone utilises en tant qu'agonistes du recepteur d2 de la dopamine
WO1998008819A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation Derives de 4-aminoethoxy indolone

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008708A1 (fr) * 1990-11-20 1992-05-29 Fisons Plc Amines biologiquement actives
WO1993023385A1 (fr) * 1992-05-19 1993-11-25 Fisons Plc Amines actives sur le plan biologique
EP0707007A1 (fr) * 1994-10-14 1996-04-17 MERCK PATENT GmbH Dérivés d'amino(thio)éther agissant sur le système nerveux central
EP0771801A1 (fr) * 1995-11-06 1997-05-07 American Home Products Corporation Dérivés de chromanne
WO1998008843A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation Derives de 4-aminoethoxy-indolone utilises en tant qu'agonistes du recepteur d2 de la dopamine
WO1998008819A1 (fr) * 1996-08-27 1998-03-05 American Home Products Corporation Derives de 4-aminoethoxy indolone

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
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 *
WEINSTOCK J. ET AL.: "Synthesis and evaluation of non-catechol D-1 and D-2 dopamine receptor agonists: Benzimidazol-2-one, benzoxazol-2-one, and the highly potent benzothiazol-2-one 7-ethylamines", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 7, July 1987 (1987-07-01), pages 1166 - 1176, XP002020804 *

Also Published As

Publication number Publication date
CA2278747A1 (fr) 1998-08-20
EP0964853A1 (fr) 1999-12-22
IL131156A0 (en) 2001-01-28
HUP0001262A3 (en) 2002-04-29
AU6023498A (en) 1998-09-08
CN1252060A (zh) 2000-05-03
TW383303B (en) 2000-03-01
CN1138761C (zh) 2004-02-18
HUP0001262A2 (hu) 2001-04-28
JP2001511804A (ja) 2001-08-14
ZA981310B (en) 1999-08-17
BR9807703A (pt) 2000-05-02
KR20000071160A (ko) 2000-11-25
NZ337271A (en) 2001-01-26
AR011138A1 (es) 2000-08-02
AU744443B2 (en) 2002-02-21

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