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EP0664810A1 - 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

Info

Publication number
EP0664810A1
EP0664810A1 EP93923238A EP93923238A EP0664810A1 EP 0664810 A1 EP0664810 A1 EP 0664810A1 EP 93923238 A EP93923238 A EP 93923238A EP 93923238 A EP93923238 A EP 93923238A EP 0664810 A1 EP0664810 A1 EP 0664810A1
Authority
EP
European Patent Office
Prior art keywords
group
carbons
compound
single bond
mammal
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Withdrawn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
EP93923238A
Other languages
German (de)
English (en)
Inventor
Richard Alan Earl
Melvyn John Myers
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.)
Bristol Myers Squibb Pharma Co
Original Assignee
DuPont Merck Pharmaceutical Co
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 DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Publication of EP0664810A1 publication Critical patent/EP0664810A1/fr
Withdrawn legal-status Critical Current

Links

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

  • SHEET 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 physostig ine; neuropeptides like adrenocorticotropic hormone and vasopressin-related peptides.
  • L-DOPA treatment for Parkinson's Disease and cholinesterase inhibitor treatment for Myasthenia Gravis these treatment strategies have generally failed to enhance the residual function of the affected systems by enhancing the stimulus-induced release of neurotransmitters. Theoretically, 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 derivatives of formula:
  • a and b are each single or double bonds, provided that a is a single bond when b is a double bond, and that b is a single bond when a is double bond, and that b is a double bond when
  • 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 3 and R 4 are each independently selected from the group:
  • 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 ,
  • SUBSTITUTE SHEET attaches to an adjacent carbon atom forming a fused ring
  • R 6 is independently selected at each occurrence 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, -SO 2 -R 7 , and -COR 7 ;
  • R 7 is independently selected at each occurrence from the group: alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R 8 , and alkaryl of 1-10 carbons;
  • R8 is independently selected at each occurrence from the group:
  • R9 is independently selected at each occurrence from the group: H, alkyl of 1-6 carbons and aryl. Preferred fim odimp ⁇ tP
  • Preferred compounds of this invention are those of Formula I wherein, together or independently:
  • a is a single or a double bond
  • R 1 is 2-, 3- or 4-pyridyl, or 4- ⁇ yrimidinyl
  • R 2 is - ⁇ CH 2 ) m -W
  • R 2 is -(CH 2 ) n -Yr wherein n is 1 to 6, and
  • Y is selected from the group: CO 2 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:
  • Y is selected from the group: C0 2 R 7 , CN, and -OCOR 7 ;
  • R 5 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
  • SUBSTITUTE SHEET neurological dysfunction in a mammal comprising administering to the mammal a therapeutically effective amount of one or more of the above-described compounds.
  • 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 stereoisomer mixture, or a racemic mixture.
  • alkyl is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups 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, [4.3.0]bicyclononane, [4.4.O]bicyclodecane (decalin) , [2.2.2]bicyclooctane, and so forth.
  • 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; and "alkynyl” is intended to include hydrocarbon chains of
  • SUBSTITUTE SHEET 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; and "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 tetrahydronaphthyl (tetralin) .
  • 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, 0. 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.
  • heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable.
  • 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, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
  • 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.
  • 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.
  • Pharmaceutically acceptable salts 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..
  • the term "therapeutically 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 prepared according to the following schemes and examples, using appropriate materials and are further
  • 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 resulting anion is then alkylated with an appropriate alkyl halide (R 1 CH 2 ⁇ Hal) to give a compound of formula 5.
  • This process can then be repeated by treatment of a compound of formula 5 with a base, followed by addition of a second alkylating agent (R 2 -Hal) to produce a compound of Formula I.
  • 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
  • Suitable bases for generating the anion of a compound of formula 4 and 5 include, but are not limited to, sodamide, lithium diisopropyla ide (LDA) , sodium hydride, potassium tert-butoxide, sodium alkoxide, potassium alkoxide, potassium hydride, lithium 2, 2, 6, 6- tetramethylpiperidine, butyl lithium, sec-butyl lithium, i ⁇ -ct-butyl lithium, and lithium- sodium-, or potassium hexamethyldisilazide.
  • LDA lithium diisopropyla ide
  • 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. Addition ⁇ ally, the reaction can be run in dimethylformamide or dimethylacetamide. However, if the compounds are soluble in a nonpolar solvent, the reaction can be carried out in a hydrocarbon solvent such as hexanes, heptane, cyclohexane, methylcyclohexane, benzene or
  • compounds of formula I may exist as racemates, diastereo eric mixtures, or their optically pure isomers.
  • Compounds of formula 5 may also be prepared according to Scheme 2. This procedure is particularly useful when R 2 is not the same as -CH 2 -R 1 because 5 may be obtained uncontaminated by 4 or the dialkylated
  • the ester can be directly reduced to the alcohol, which can be subsequently acylated with an acid halide or anhydride, or by coupling the alcohol to an acid using dicyclohexylcarbodiimide, carbonyl diimidazole, or some other coupling agent.
  • a nitrile can be oxidized to the corresponding amide using the procedure described by Noller, Or ⁇ r. Syn. Coll. Vol. II, p 586.
  • the same amide can be prepared from the corresponding ester by saponification, activation of carboxyl, and reaction with ammonia or ammonia derivatives.
  • 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.
  • Neurotransmitter release assay The neurotransmitter relea ⁇ e activities of the compounds in this invention were determined as reported in Drug Development
  • the brain preparations were incubated for 30 minute ⁇ at 37°C under a ⁇ teady flow of 95% 02/5% CO 2 .
  • part of the radioactive choline taken up by the preparation wa ⁇ converted into radioactive acetylcholine (ACh) by the cholinergic nerve ending ⁇ ⁇ tored in synaptic vesicles, and released upon depolarization by high potas ⁇ ium ion (K + ) containing media.
  • the slice ⁇ were wa ⁇ hed three time ⁇ with non-radioactive KR medium and tran ⁇ ferred to a ⁇ uperfu ⁇ ion apparatu ⁇ to measure the drug effects on ACh release.
  • the ⁇ uperfusion apparatus consisted of 10 thermostated glass columns of 5 diameters that were provided with GF/F glas ⁇ fiber filters to support the slice ⁇ (approximately 10 mg ti ⁇ ue/column) .
  • Superfu ⁇ ion wa ⁇ carried out in KR-medium (0.3 ml/min.) containing 10 mM hemicholinium-3 (HC-3) .
  • the HC-3 prevent ⁇ the reuptake of choline formed during the ⁇ uperfusion from phospholipid ⁇ and relea ⁇ ed ACh, which would be converted into unlabeled ACh and released in preference to the pre-formed labeled ACh.
  • the medium was delivered by a 25-channel peristaltic pump (Ismartec by Brinkman) and warmed to 37°C in a thermo ⁇ tated ⁇ tainle ⁇ ⁇ teel coil before entering the superfusion column.
  • Each column wa ⁇ provided with a 4-way ⁇ lider 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 wa ⁇ added to the media by 100-fold dilution ⁇ of appropriate concentration ⁇ of the drug (in 0.9% saline) with either low- or high-K+/KR-medium.
  • the ratio of S2/S1 (as compared to controls where no drug was present during S2) wa ⁇ a ea ⁇ ure of the ability of the drug to enhance or depre ⁇ s stimulus- induced acetylcholine relea ⁇ e.
  • Per cent acetylcholine (ACh) enhanced release caused by 10 mM of drug using this a ⁇ ay are ⁇ hown in Table 5.
  • te ⁇ t re ⁇ ult ⁇ uggest that the compounds of this invention have utility in the treatment of cognitive disorders and/or neurological function deficits and or mood and mental disturbance ⁇ in patient ⁇ ⁇ uffering from nervou ⁇ ⁇ y ⁇ tem di ⁇ order ⁇ like Alzheimer's Di ⁇ ease, Parkinson' ⁇ Di ⁇ ea ⁇ e, ⁇ enile dementia, multi-infarct dementia, Huntington' ⁇ disease, mental retardation, Myasthenia Gravis, etc.
  • Formulations Compounds of this invention can be administered to treat said deficiencie ⁇ by mean ⁇ that produce ⁇ contact of the active agent with the agent's ⁇ ite of action in the body of a mammal.
  • the compound ⁇ can be admini ⁇ tered by any conventional mean ⁇ available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but are generally administered with a pharmaceutical carrier selected on the basis of the chosen route of admini ⁇ tration and ⁇ tandard pharmaceutical practice.
  • the do ⁇ age admini ⁇ tered will vary depending on the u ⁇ e and known factor ⁇ 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 ⁇ y ptom ⁇ ; kind of concurrent treatment; frequency of treatment; and de ⁇ ired effect.
  • the compounds of thi ⁇ invention can be orally admini ⁇ tered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight.
  • a do ⁇ e of 0.01 to 10 mg/kg in divided do ⁇ es one to four times a day, or in ⁇ u ⁇ tained release formulation was effective in obtaining the desired pharmacological effect.
  • Dosage forms (composition ⁇ ) ⁇ uitable for admini ⁇ tration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be
  • the active ingredient can be administered orally is solid do ⁇ age form ⁇ , ⁇ uch a ⁇ capsules, tablets and powders; or in liquid forms such as elixir ⁇ , ⁇ yrup ⁇ , and/or ⁇ u ⁇ pen ⁇ ion ⁇ .
  • the compounds of this invention can also be administered parenterally in ⁇ terile liquid do ⁇ e formulation ⁇ .
  • Gelatin cap ⁇ ule ⁇ can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, ⁇ teric acid, or cellulo ⁇ e derivative ⁇ . Similar diluent ⁇ can be u ⁇ ed to make compre ⁇ ed tablets. Both tablets and capsule ⁇ can be manufactured as ⁇ u ⁇ tained release products to provide for continuous release of medication over a period of time. Compressed tablets can be ⁇ ugar- coated or film-coated to a ⁇ k any unpleasant taste, or u ⁇ ed to protect the active ingredient ⁇ from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.
  • a suitable carrier such as but not limited to lactose, starch, magnesium stearate, ⁇ teric acid, or cellulo ⁇ e derivative ⁇ .
  • Similar diluent ⁇ can be u ⁇ ed to make compre ⁇ ed tablets. Both tablets and capsule ⁇ can be manufactured as ⁇ u ⁇ tained release products to provide for continuous release of medication
  • Liquid dose forms for oral administration can contain coloring of flavoring agent ⁇ to increa ⁇ e patient acceptance.
  • water, pharmaceutically acceptable oil ⁇ , saline, aqueous dextrose (gluco ⁇ e) , and related ⁇ ugar ⁇ olution ⁇ and glycol ⁇ , ⁇ uch as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solution ⁇ .
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if nece ⁇ ary, butter ⁇ ubstances.
  • Antioxidizing agents ⁇ uch as sodium bi ⁇ ulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents.
  • citric acid and its salts, and EDTA are also used.
  • parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:
  • Capsules A large number of units capsules are prepared by filling standard two-piece hard gelatin capsule ⁇ each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magne ⁇ ium ⁇ tearate.
  • Soft Gelatin Capsules A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement wa ⁇ pumped into gelatin to form ⁇ oft gelatin cap ⁇ ule ⁇ containing 100 mg of the active ingredient. The cap ⁇ ules were washed and dried.
  • a digestible oil such as soybean, cottonseed oil, or olive oil
  • Tablets A large number of tablets are prepared by conventional procedure ⁇ so that 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 coating ⁇ may be applied to increase palatability or delayed adsorption.
  • the compounds of thi ⁇ invention may al ⁇ o be u ⁇ ed a ⁇ reagents or standards in the biochemical study of neurological function, dy ⁇ function, 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)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (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).
EP93923238A 1992-10-13 1993-10-12 Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs Withdrawn EP0664810A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US96052292A 1992-10-13 1992-10-13
US960522 1992-10-13
PCT/US1993/009476 WO1994009009A1 (fr) 1992-10-13 1993-10-12 Indolin-2-ones tri- et tetracycliques 3,3-disubstituees utiles dans le traitement de troubles cognitifs

Publications (1)

Publication Number Publication Date
EP0664810A1 true EP0664810A1 (fr) 1995-08-02

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Country Status (8)

Country Link
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)

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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

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4760083A (en) * 1986-04-10 1988-07-26 E. I. Dupont De Nemours & Company 3,3-disubstituted indolines
US5173489A (en) * 1986-04-10 1992-12-22 The Dupont Merck Pharmaceutical Co. α,α-disubstituted aromatics and heteroaromatics as cognition enhancers
US5278045A (en) * 1990-02-28 1994-01-11 Du Pont Merck Pharmaceutical Company Method and compositions to screen compounds for enhancement of the cholinergic, dopaminergic and serotonergic function

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9409009A1 *

Also Published As

Publication number Publication date
ZA937604B (en) 1995-04-13
AU6242294A (en) 1994-05-09
MX9306337A (es) 1995-01-31
CA2146000A1 (fr) 1994-04-28
WO1994009009A1 (fr) 1994-04-28
IL107251A0 (en) 1994-01-25
JPH08502293A (ja) 1996-03-12

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