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WO1994009009A1 - Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs - Google Patents

Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs Download PDF

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Publication number
WO1994009009A1
WO1994009009A1 PCT/US1993/009476 US9309476W WO9409009A1 WO 1994009009 A1 WO1994009009 A1 WO 1994009009A1 US 9309476 W US9309476 W US 9309476W WO 9409009 A1 WO9409009 A1 WO 9409009A1
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WO
WIPO (PCT)
Prior art keywords
group
carbons
compound
single bond
mammal
Prior art date
Application number
PCT/US1993/009476
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English (en)
Inventor
Richard Alan Earl
Melvyn John Myers
Original Assignee
The Du Pont Merck Pharmaceutical Company
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 The Du Pont Merck Pharmaceutical Company filed Critical The Du Pont Merck Pharmaceutical Company
Priority to AU62422/94A priority Critical patent/AU6242294A/en
Priority to JP6510082A priority patent/JPH08502293A/ja
Priority to EP93923238A priority patent/EP0664810A1/fr
Publication of WO1994009009A1 publication Critical patent/WO1994009009A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/06—Peri-condensed systems
    • 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
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/06—Peri-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/06—Peri-condensed systems

Definitions

  • This invention relates to 3,3-disubstituted tri- and tetracyclic indolin-2-ones, to pharmaceutical compositions thereof, and methods of use in mammals to treat cognitive disorders, neurological dysfunction, and/or mood disturbances such as, but not limited to degenerative nervous system diseases. Additionally, these compounds can be used as reagents in studies on the biochemical mechanism of neurotransmitter diseases.
  • acetylcholine, dopamine, norepinephrine, serotonin are generally found at later stages of diseases such as senile dementia, multi-infarct dementia, Huntington's Disease, mental retardation, etc. This explains the generally observed multiple symptomology that includes cognitive, neurological and effective/psychotic
  • Deficits in the synthesis and release of acetylcholine in the brain are generally thought to be related to cognitive impairment (see Francis, et al., New England J. Med., 7 , 313 (1985)) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively.
  • neurological deficits e.g., Myasthenia Gravis
  • Other neurological deficits are related to cholinergic deficiencies in the peripheral nervous system.
  • vasoactive drugs like vincamine and pentoxifylline
  • metabolic enhancers like ergoloid mesylates, piracetam, and naftidrofuryl; neurotransmitter precursors like L-DOPA, choline, 5-hydroxytryptamine; transmitter
  • metabolizing enzyme inhibitors such as physostigmine; neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides. Except for L-DOPA
  • neurotransmitters .
  • Such an enhancement would improve the signal-to-noise ratio during chemical transmission for information, thereby reducing deficits in processes related to cognition, neurological function and mood regulation.
  • cognition enhancers are useful as cognition enhancers.
  • Patent WO 91/01/306 1991 discloses oxindole
  • X is -CH- or -CR 7 - and when a is a single bond
  • R 1 is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl
  • R 2 is -(CH 2 ) m -W
  • W is selected from the group:
  • R 2 is -(CH 2 ) n -Y
  • Y is selected from the group:
  • R 3 and R 4 are each independently selected from the group:
  • R 3 and R 4 taken together may form a saturated or unsaturated carbocyclic or heterocyclic ring, unsubstituted or substituted with 1-2 R 5 substituents;
  • R 5 is selected from the group:
  • alkyl of 1-6 carbons alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R 8 , alkaryl of 1-10 carbons, F, Cl, Br, I, OR 6 , NHR 6 , N(R 6 ) 2 ,
  • R 6 is independently selected at each occurrence
  • R 7 is independently selected at each occurrence
  • alkyl of 1-6 carbons aryl unsubstituted or substituted with 1-3 R 8 , and alkaryl of 1-10 carbons;
  • R 8 is independently selected at each occurrence
  • R 9 is independently selected at each occurrence
  • Preferred compounds of this invention are those of Formula I wherein, together or independently:
  • X is a single bond, O, S, SO, SO 2 , CH 2 , CH 2 CH 2 ,
  • R 1 is 2-, 3- or 4-pyridyl, or 4- ⁇ yrimidinyl
  • W is selected from the group:
  • R 2 is -(CH 2 ) n -Yr
  • n 1 to 6
  • Y is selected from the group:
  • R 7 , CN, COR 7 , CHO, -OCOR 7 ; R 3 and R 4 are each independently selected from the group:
  • R 5 is selected from the group:
  • More preferred compounds of this invention are those preferred compounds wherein:
  • R 2 is -(CH 2 ) m -W,
  • W is selected from the group:
  • R 2 is -(CH 2 ) n -Y,
  • Y is selected from the group:
  • This invention also provides pharmaceutical compositions comprising a suitable pharmaceutical carrier and an amount of one or more of the above-described compounds effective to treat cognitive or neurological dysfunction. Still further, this invention relates to a method of treating cognitive or neurological dysfunction in a mammal comprising
  • the compounds herein described may have asymmetric centers. All chiral, enantiomeric, diastereomeric, and racemic forms are included in the present invention.
  • the compounds of Formula (I) may be provided in the form of an individual stereoisomer, a non-racemic
  • alkyl is intended to include both branched and straight-chain saturated aliphatic
  • hydrocarbon groups having the specified number of carbon atoms having the specified number of carbon atoms.
  • alkoxy represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge;
  • cycloalkyl is intended to include saturated ring groups, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl;
  • biycloalkyl is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane,
  • alkenyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like;
  • alkynyl is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
  • Cycloalkyl-alkyl is intended to include cycloalkyl attached to alkyl.
  • Halo refers to fluoro, chloro, bromo, and iodo;
  • Counterion is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate, and the like.
  • aryl or “aromatic residue” is intended to mean phenyl or naphthyl;
  • carbocyclic is intended to mean any stable 5- to 7- membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic, for example, indanyl or
  • heterocycle is intended to mean a stable 5- to 7- membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which is either saturated or unsaturated, and which consists of carbon atoms and from 1 to 3 heteroatoms selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined
  • heterocyclic rings is fused to a benzene ring.
  • the heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure.
  • the heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such
  • heterocycles include, but are not limited to, pyridyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, quinolinyl, isoquinolinyl or
  • benzimidazolyl piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl,
  • substituted means that one or more hydrogen atom(s) on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded, and that the substitution results in a stable compound.
  • stable compound or “stable structure” is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • pharmaceutically acceptable salts refer to derivatives of the disclosed compounds that are modified by making acid or base salts. Examples include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids.
  • compositions of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences. 17th ed.,
  • terapéuticaally effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human subject that is being sought by a clinician or researcher.
  • the compounds of the present invention may be any organic compound having the same properties.
  • the compounds of the present invention may be any organic compound having the same properties.
  • Scheme 1 shows one process for the preparation of compounds of the present invention.
  • a compound of formula 2 is reacted in an inert solvent with chloroacetyl chloride to provide a compound of formula 3.
  • the solvent is preferably an aromatic hydrocarbon such as benzene or toluene or a
  • halohydrocarbon such as methylene chloride, 1,2-dichloroethane or chloroform.
  • the reaction temperature is not critical and generally ranges from about 20°C to about 120°C.
  • the reaction temperature is the reflux temperature of the solvent.
  • the temperature and duration of the alkylation reaction are not critical, and may be varied over a wide range from room temperature for 24 hours to 80°C for 3 hours. Preferred conditions are room temperature, and a duration of 2-3 hours. Equivalent amounts of the reagents can be used, but it is preferable to use the haloalkylating in a slight excess This method is disclosed by Myers and Nickolson, in US Patents
  • Suitable bases for generating the anion of a compound of formula 4 and 5 include, but are not limited to, sodamide, lithium diisopropylamide (LDA), sodium hydride, potassium tert-butoxide, sodium alkoxide, potassium alkoxide, potassium hydride, lithium 2, 2, 6, 6- tetramethylpiperidine, butyl lithium, sec-butyl lithium, tert--utyl lithium, and lithium- sodium-, or potassium hexamethyldisilazide.
  • LDA lithium diisopropylamide
  • the reaction can be conducted in an aprotic solvent, generally in an ether, such as but not limited to, tetrahydrofuran (THF), dioxane, glyme, diglyme, or diethyl ether.
  • THF tetrahydrofuran
  • dioxane glyme
  • diglyme diglyme
  • diethyl ether diethyl ether
  • the reaction can be run in dimethylformamide or dimethylacetamide.
  • the reaction can be carried out in a hydrocarbon solvent such as hexanes, heptane, cyclohexane, methylcyclohexane, benzene or toluene.
  • a hydrocarbon solvent such as hexanes, heptane, cyclohexane, methylcyclohexane, benzene or toluene.
  • the reactions can be conducted at a temperature from about -78°C to solvent reflux temperature.
  • phase-transfer catalysis e.g., phase-transfer catalysis
  • a solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, or chloroform in conjunction with a quaternary ammonium salt or a quaternary phosphonium salt in the presence of an aqueous base, such as sodium hydroxide or potassium hydroxide.
  • analytical HPLC may be collected as an oil, gum, or amorphous solid; or recrystallized from an appropriate solvent system; or further purified by chromatographic, sublimation, or distillation processes.
  • the compounds may exist as the "free base” or as an acid addition salt formed from pharmaceutically acceptable acids.
  • compounds of formula I may exist as racemates, diastereomeric mixtures, or their optically pure isomers.
  • the ester can be directly reduced to the alcohol, which can be
  • a nitrile can be oxidized to the corresponding amide using the procedure described by Noller, Org. Syn. Coll. Vol. II, p 586.
  • the same amide can be prepared from the corresponding ester by saponification,
  • MS mass spectra
  • HRMS high resolution mass spectra
  • Reagents were purchased from commercial sources and, where necessary, purified prior to use according to, the general procedures outlined by D. D. Perrin and W. L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988) .
  • Neurotransmitter release assay The neurotransmitter release activities of the compounds in this invention were determined as reported in Drug Development
  • mice Male Wistar rats (Charles River) weighing 175-200 grams were used . The rats were housed for at least seven days before the experiment in animal facility under 12/12 hour light/dark cycle. Deionized water and
  • Rats were decapitated and brains were removed immediately.
  • Slices (0.3 mm thick) from the parietal cortex were prepared manually using a recessed Lucite guide. Slices were subsequently cut into 0.25 ⁇ 0.25 mm squares with a Mcllwain tissue chopper.
  • Cerebral cortical slices (approximately 100 mg wet weight) were incubated in 10 ml Krebs-Ringer medium (KR) containing NaCl (116 mM), KCl (3 mM), CaCl 2 (1.3 mM), MgCl 2 (1.2 mM) , KH 2 PO 4 (1.2 mM), Na 2 SO 4 (1.2 mM), NaHCO 3 (25 mM) and glucose (11.0 mM) to which 10 mCi 3 H-choline (specific activity approximately 80 uCi/mM; Du Pont-NEN) and 10 nmol unlabeled choline had been added to give a final concentration of 1 mM.
  • KR Krebs-Ringer medium
  • the brain preparations were incubated for 30 minutes at 37°C under a steady flow of 95% 02/5% CO 2 . Under these conditions, part of the radioactive choline taken up by the preparation was converted into radioactive acetylcholine (ACh) by the cholinergic nerve endings stored in synaptic vesicles, and released upon depolarization by high potassium ion (K + ) containing media.
  • ACh radioactive acetylcholine
  • the slices were washed three times with non-radioactive KR medium and transferred to a superfusion apparatus to measure the drug effects on ACh release.
  • the superfusion apparatus consisted of 10 thermostated glass columns of 5
  • Each column was provided with a 4-way slider value (Beckmann Instruments) which allowed rapid change of low to high K + /KR-medium, and with two 10-channel 3-way values that were used to change from drug-free to drug-containing low and high K + /KR-medium.
  • Drug was added to the media by 100-fold dilutions of appropriate concentrations of the drug (in 0.9% saline) with either low- or high-K+/KR-medium .
  • the ratio of S2/S1 was a measure of the ability of the drug to enhance or depress stimulus-induced acetylcholine release.
  • Per cent acetylcholine (ACh) enhanced release caused by 10 mM of drug using this assay are shown in Table 5.
  • Alzheimer's Disease Parkinson 's Disease
  • senile dementia multi-infarct dementia
  • Huntington's disease mental disorders
  • Compounds of this invention can be administered to treat said deficiencies by means that produces contact of the active agent with the agent's site of action in the body of a mammal.
  • the compounds can be administered by any conventional means available for use in
  • the dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect.
  • the compounds of this invention can be orally
  • a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.
  • a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation was effective in obtaining the desired pharmacological effect.
  • compositions contain from about 1 mg to about 100 mg of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.
  • the active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions.
  • the compounds of this invention can also be administered parenterally in sterile liquid dose formulations .
  • Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar- coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the
  • Liquid dose forms for oral administration can contain coloring of flavoring agents to increase patient acceptance.
  • water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for
  • administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances.
  • suitable stabilizing agents such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents.
  • citric acid and its salts are also used.
  • solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences", A. Osol, a standard reference in the field.
  • a large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.
  • a mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is
  • the capsules were washed and dried.
  • the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of
  • microcrystalline cellulose 11 mg of starch, and 98.8 mg lactose.
  • Appropriate coatings may be applied to increase palatability or delayed adsorption.
  • the compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

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

Abstract

On a constaté que les composés de formule (I) améliorent la libération du neutrotransmetteur acétylcholine, et qu'ils peuvent ainsi être utiles comme intermédiaires chimiques et agents pharmacologiques dans le traitement des maladies chez l'homme, notamment la maladie d'Alzheimer et d'autres troubles affectant l'apprentissage et la cognition, dans lesquelles des quantités subnormales de ce composé neurochimique ont été constatées. Les composés de cette invention ont la structure de la formule (I).
PCT/US1993/009476 1992-10-13 1993-10-12 Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs WO1994009009A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU62422/94A AU6242294A (en) 1992-10-13 1993-10-12 3,3-disubstituted tri- and tetracyclic indolin-2-ones useful for the treatment of cognitive disorders
JP6510082A JPH08502293A (ja) 1992-10-13 1993-10-12 認識疾患の治療に有用な３，３−ジ置換された三環式および四環式インドリン−２−オン
EP93923238A EP0664810A1 (fr) 1992-10-13 1993-10-12 Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US96052292A 1992-10-13 1992-10-13
US07/960,522 1992-10-13

Publications (1)

Publication Number Publication Date
WO1994009009A1 true WO1994009009A1 (fr) 1994-04-28

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EP (1) EP0664810A1 (fr)
JP (1) JPH08502293A (fr)
AU (1) AU6242294A (fr)
CA (1) CA2146000A1 (fr)
IL (1) IL107251A0 (fr)
MX (1) MX9306337A (fr)
WO (1) WO1994009009A1 (fr)
ZA (1) ZA937604B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601856B2 (en) 2006-07-27 2009-10-13 Wyeth Benzofurans as potassium ion channel modulators
CN112624972A (zh) * 2019-09-24 2021-04-09 中国人民解放军军事科学院军事医学研究院 吖啶酮类化合物及医药用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0241006A2 (fr) * 1986-04-10 1987-10-14 E.I. Du Pont De Nemours And Company Indolines 3,3-disubstitués
EP0311010A2 (fr) * 1987-10-06 1989-04-12 The Du Pont Merck Pharmaceutical Company Composés aromatiques et hétéro-aromatiques alpha, alpha-disubstitués pour l'amélioration de la mémoire
WO1991013359A1 (fr) * 1990-02-28 1991-09-05 The Du Pont Merck Pharmaceutical Company Procede et compositions de tri de composes afin d'ameliorer les fonctions cholinergique, dopaminergique et serotoninergique

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0241006A2 (fr) * 1986-04-10 1987-10-14 E.I. Du Pont De Nemours And Company Indolines 3,3-disubstitués
US4760083A (en) * 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines
EP0311010A2 (fr) * 1987-10-06 1989-04-12 The Du Pont Merck Pharmaceutical Company Composés aromatiques et hétéro-aromatiques alpha, alpha-disubstitués pour l'amélioration de la mémoire
WO1991013359A1 (fr) * 1990-02-28 1991-09-05 The Du Pont Merck Pharmaceutical Company Procede et compositions de tri de composes afin d'ameliorer les fonctions cholinergique, dopaminergique et serotoninergique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7601856B2 (en) 2006-07-27 2009-10-13 Wyeth Benzofurans as potassium ion channel modulators
CN112624972A (zh) * 2019-09-24 2021-04-09 中国人民解放军军事科学院军事医学研究院 吖啶酮类化合物及医药用途

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IL107251A0 (en) 1994-01-25
ZA937604B (en) 1995-04-13
MX9306337A (es) 1995-01-31
JPH08502293A (ja) 1996-03-12
AU6242294A (en) 1994-05-09
CA2146000A1 (fr) 1994-04-28
EP0664810A1 (fr) 1995-08-02

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