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EP0664810A1 - 3,3-disubstituted tri- and tetracyclic indolin-2-ones useful for the treatment of cognitive disorders - Google Patents

3,3-disubstituted tri- and tetracyclic indolin-2-ones useful for the treatment of cognitive disorders

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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Withdrawn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)
French (fr)
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
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Filing date
Publication date
Application filed by DuPont Merck Pharmaceutical Co filed Critical DuPont Merck Pharmaceutical Co
Publication of EP0664810A1 publication Critical patent/EP0664810A1/en
Withdrawn legal-status Critical Current

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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

  • 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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Abstract

Compounds of formula (I) have been shown to enhance the release of the neurotransmitter acetylcholine, and thus may be useful as chemical intermediates and as pharmacological agents in the treatment of diseases of man, such as in Alheimer's Disease and other conditions involving learning and cognition, where subnormal levels of this neurochemical are found. The compounds of this invention have the structure shown in formula (I).

Description

TTTI--B
3,3-Disubstituted Tri- and Tetracyclic Indolin-2-ones Useful for the Treatment of Cognitive Disorders. Field of the Invention 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. Background Including Prior Art:
Increasingly there is a need for effective treatments for nervous systems disorders and neurological deficiencies. Many of these diseases correlate with increasing age due mainly to degenerative changes in the nervous system. Although in early stages of some diseases, certain systems are rather specifically affected (e.g., cholinergic systems in Alzheimer's Disease and Myasthenia Gravis, the dopaminergic system in Parkinson's Disease, etc.) multiple neurotransmitter systems deficiencies (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 sy ptomology that includes cognitive, neurological and effective/psychotic components (see Gottfries, Psychopharmacol., 86, 245 (1985) ) . 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., 1_, 313 (1985)) whereas neurological deficits (e.g. Parkinsonian symptoms) and mood/mental changes may be related to impairment of dopaminergic and serotonergic systems, respectively. Other neurological
-1- SUBSTITUTE SHEET deficits (e.g., Myasthenia Gravis) are related to cholinergic deficiencies in the peripheral nervous system.
Treatment strategies employed previously encompass 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. Except for 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.
European Patent Application 311,010 discloses that α,α-disubstituted aromatics or heteroaromatics of the formula :
or a salt thereof, are useful as cognition enhancers.
U.S. Patent No. 4,760,083 to Myers, et al. discloses that indolines of the following formula are useful for treatment of cognitive deficiencies:
-2- SUBSTITUTE SHEET
The references claim the necessity of two heteroaryl groups for activity.
European Patent Application No. 0 415 102 Al by Effland, et al. describes an invention related to the formula:
U.S. Patent No. 3,595,866 to D. E. Butler describes an invention of the formula:
European Patent Application No. 0 347 698 Al wherein Ting, et al. describes a compound of formula:
-3-
SUBSTITUTE SHEET
Patent WO 91/01/306 1991 discloses oxindole derivatives of formula:
useful for treating senile dementia, i. e. improving brain functions and activating and protecting brain metabolism. This reference only discloses imides and does not suggest alkyl or aryl substituted amides.
Summary of the Invention
Presently it has been found that certain 3,3- disubstituted tri- and tetracyclic indolin-2-ones enhance the stimulus-induced release of neurotrans- mitters, specifically acetylcholine in nervous tissue, and thus improve processes involved in learning and memorization of an avoidance task.
According to the present invention, there are provided compounds of formula:
-4-
SUBSTΓΠJTE SHEET
I or pharmaceutically acceptable salts thereof, wherein:
X is a single bond, 0, S, SO, SO2, CH2, CH2CH2, CH=CH, C=0, C(R7) (OR6), CH(0R6), -CONR6-, -NR6CO-, -CH2-NR6-, -NR6-CH2-, NR6, -C(R7)=N-7 -CH(R7)-N(R6)-, or -CR7-, -CH- when a is a single bond and b is a double bond;
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 -CR7- and when a is a single bond;
R1 is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl;
R2 is -(CH2)m-W, wherein m = 1-4, and W is selected from the group: (a) 2-, 3- or 4-pyridyl, (b) 2-, 4-, or 5-pyrimidinyl,
(c) 2-pyrazinyl,
(d) 3- or 4-pyridazinyl,
(e) 3- or 4-pyrazolyl,
(f) 2- or 3-furyl, (g) 2- or 3-tetrahydrofuranyl,
(h) 2- or 3-thienyl,
-5-
SUBSTITUTE SHEET (i) 3-indolyl,
(j) aryl unsubstituted or substituted with 1-3 R5, (k) 2-fluoro-4-pyridyl, or R2 is -(CH2)n-Y, wherein n = 1-6, and Y is selected from the group: -CH=CHC0 R7, -CH=CHCOR7, -CH=CHR7, -CH=C(R7)2, -CH=CH2f -CΞCC02R7, -C=CCOR7, -C=CR7, or -C≤CH, F, Cl, Br, OR6, N(R6)2, C02H, C02R7, CONHR7,
NHCHO, CONHR6, C0N(R )2, CN, -OCOR7, COR7, CHO, SR7, SOR7, SO2R7 or NO2;
R3 and R4 are each independently selected from the group:
H, alkyl of 1-6 carbons, alkenyl of 2-6 carbons, alkynyl of 2-6 carbons; cycloalkyl of 3-7 carbons, cycloalkylalkyl of 3-10 carbons, aryl unsubstituted or substituted with 1-3 R5, alkaryl of 1-10 carbons, provided that when a is a single bond R3 is =0, =CH2, =CH(R7), =C(R7)2, or (CH3)2, and provided that when a and b are each a single bond, then R3 and R4 are each independently selected from the group: =0, =CH2, =CH(R7), =C(R )2,
(CH3)2 ; or R3 and R4, taken together may form a saturated or unsaturated carbocyclic or heterocyclic ring, unsubstituted or substituted with 1-2 R5 substituents;
R-5 is selected from the group:
H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, alkaryl of 1-10 carbons, F, Cl, Br, I, OR6, NHR6, N(R6)2,
CO2H, C02R7, CONHR7, CON(R7)2, CN, COR7, CHO, SR7, SOR7, SO2R7, NO2 or -CH=CH-CH=CH- which
-6-
SUBSTITUTE SHEET attaches to an adjacent carbon atom forming a fused ring;
R6 is independently selected at each occurrence from the group:
H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, alkaryl of 1-10 carbons, -SO2-R7, and -COR7;
R7 is independently selected at each occurrence from the group: alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, and alkaryl of 1-10 carbons;
R8 is independently selected at each occurrence from the group:
OR9, NHR9, N(R9)2, C02H, C02R9, CONHR9, CON(R9)2, CN, COR9, CHO, SR9, SOR9, S02R9, and NO2; and
R9 is independently selected at each occurrence from the group: H, alkyl of 1-6 carbons and aryl. Preferred fim odimpπtP
Preferred compounds of this invention are those of Formula I wherein, together or independently:
X is a single bond, 0, S, SO, SO2, CH2, CH2CH2, CH=CH, C=0, NR6;
a is a single or a double bond;
b is a single bond;
R1 is 2-, 3- or 4-pyridyl, or 4-ρyrimidinyl;
R2 is - <CH2) m-W,
-7-
SUBSTITUTE SHEET wherein m = 1-4, and W is selected from the group:
2-, 3- or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, or 2-pyrazinyl; or R2 is -(CH2)n-Yr wherein n is 1 to 6, and
Y is selected from the group: CO2R7, CN, COR7, CHO, -OCOR7;
R3 and R4 are each independently selected from the group:
H, alkyl of 1-6 carbon atoms or -CH=CH-CH=CH- to form a fused ring; and
R5 is selected from the group:
H, alkyl of 1-6 carbons, phenyl unsubstituted or substituted with 1-3 R8, F, Cl, Br, I, NO2 or -CH=CH-CH=CH- which attaches to an adjacent carbon forming a fused ring. More preferred compounds of this invention are those preferred compounds wherein:
X is 0, S, SO, SO2, CH2, CH2CH2, C=0;
R2 is -(CH2)m-W, wherein m = 1, and W is selected from the group: 2-, 3- or 4-pyridyl, and 4-pyrimidinyl; or R2 is -<CH2)n-ϊ, where n = 3-4, and
Y is selected from the group: C02R7, CN, and -OCOR7;
R3 and R4 are each H, or R3 and R4 join together forming a fused ring consisting of -CH=CH-
CH=CH-; and
R5 is selected from the group:
-8-
SUBSTITUTE SHEET H, Cl, Br, I, N02 or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring.
Specifically preferred are those compounds of Formula I which are:
(a) 2,2-Bis (4-pyridinylmethyl)-pyrrolo[3,2,1- kl]phenothiazin-l (2H)-one;
(b) 1, 1-Bis (4-pyridinylmethyl)-5, 6-dihydro-4H- pyrollo[3,2,1-ij]quinolin-2 (IH)-one;
(c) 2,2-Bis(4-pyridinylmethyl)-6,7-dihydro- indolofl,7-ab] [l]benzapin-l (2H)-one;
(d) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3.2.1- kl]phenoxazin-l (2H)-one;
(e) 2,3-Dihydro-6,6-bis(4-pyridinylmethyl)- pyrrolo[1,2,3-de]-1,4-benzothiazin-5(6H)-one;
(f) l,2-Dihydro-2-(4-pyridinylmethyl)-2- (pentanenitrile)-pyrrolo[3.2.1-kl]phenoxazin-1 (2H)- one, hydrobromide.
It should be recognized that the above-identified groups of compounds are preferred embodiments of this invention, but that their description herein is in no way intended to limit the overall scope of this invention.
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
-9-
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. Detailed Description of the Invention The compounds herein described may have asymmetric centers. All chiral, enantiomeric, diastereomeric, and racemic forms are included in the present invention.
Thus, the compounds of Formula (I) may be provided in the form of an individual stereoisomer, a non-racemic stereoisomer mixture, or a racemic mixture.
Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. When any variable occurs more than one time in any constituent or in Formula (I), or any other formula herein, its definition on each occurrence is independent of its definition at every other occurrence. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms. As used herein "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; and "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
-10-
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" as used herein 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. As used herein, "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) .
As used herein, the term "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. 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, tetrahydroquinolinyl, tetrahydroisoquinolinyl,
-11-
SUBSTITUTE SHEET decahydroquinolinyl, pyrazinyl, quinazzoyl, phthalazinyl, naphthyridinyl or octahydroisoquinolinyl.
The term "substituted", as used herein, 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.
By "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.
As used herein, "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. 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..
Mack Publishing Company, Easton, PA, 1985, p. 1418, the disclosure of which is hereby incorporated by reference. As used herein, 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. -Synthesis
The compounds of the present invention may be prepared according to the following schemes and examples, using appropriate materials and are further
-12-
SUBSTITUTE SHEET exemplified by the following specific examples. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare those compounds.
Scheme 1 shows one process for the preparation of compounds of the present invention. In this scheme 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. Preferably, the reaction temperature is the reflux temperature of the solvent. Next, fusion of a compound of formula 3 with anhydrous aluminum chloride at a temperature within a few degrees of the melting point of the compound of formula 3, but using a temperature no greater than about 200°C, affords a compound of formula 4. This reaction is disclosed in the following references which are herein incorporated by reference: Chem. Ber. 42, 2120 (1914), J. Chem. Soc. 1697 (1954), Te rahedron 2A, 6093 (1968) and i_M£j Chem. 15, 762 (1972) . See also, the references listed in Table I. Next, the anion of a compound of formula 4 is generated by treatment with a base, in an appropriate aprotic solvent and at a suitable temperature. The resulting anion is then alkylated with an appropriate alkyl halide (R1CH2~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 (R2-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
-13-
SUBSTITUTE SHEET 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 4,876,259 and 4,760,083, which are herein incorporated by reference.
-14-
SUBSTITUTESHEET Scheme 1
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. 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
-15-
SUBSTITUTE SHEET toluene. Depending on the strength of the base, the reactions can be conducted at a temperature from about -78°C to solvent reflux temperature. Instead of running the reaction sequentially, one may at times, add two equivalents of base to the compounds of formula 4, followed by two to three equivalents of the alkylating agent. Alternatively, phase-transfer catalysis conditions may be used, employing a solvent such as benzene, toluene, xylene, dichloromethane, dichloro- ethane,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. This procedure is described by Bryant and Huhn, in US Patent 4,806,651 and in JL. Heterocyclic Chem. 20, 771 (1983) , which is herein incorporated by reference.
When the alkylation reaction is complete as evidenced by thin layer chromatography, excess anion is decomposed with saturated ammonium chloride solution, and the reaction is taken through an acid- base cycle to remove neutral starting materials. Purification of the basic product generally involves conventional purification techniques such as flash chromatography followed by recrystallization if necessary. The pure base (one spot on thin layer chromatography and 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. Additionally, 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 R2 is not the same as -CH2-R1 because 5 may be obtained uncontaminated by 4 or the dialkylated
-16-
SUBSTITUTE SHEET product. This procedure is fully described by Bryant and Huhn, US Patent 4,806,651, which is herein incorporated by reference.
Scheme 2
In addition to the Friedel-Crafts cycloalkylation illustrated by Scheme 1, compounds of the formula 4 may also be prepared by the general "azasulfonium ion" rearrangement methods of Gassman U.S. Patents 3,897,451 (1975), 3,996,264 (1976), and 3,972,894 (1976) which are herein incorporated by reference; see also J. Am. Chem. Soc.f ■___.. 5512 (1974), S n hes s 534 (1981) . This route is shown in Scheme 3.
-17-
SUBSTITUTE SHEET Scheme 3
Raney
Nickel
Other representative compounds of this invention can be synthesized by converting one Y group to another. For example, a compound of formula I which is an ester (Y = CO2R7) may be converted to the corresponding alcohol (Y = CH2OH) of formula I which can be further converted to an ether (Y = OR6) or the "reverse ester" (Y = CH2OCOR7) . For such a case, the ester can be saponified to give the acid (Y = CO2H) which can be reduced to the alcohol. Alternatively, 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, Orςr. 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. By substituting primary or
-18- SUBSTITUTE SHEET secondary amines for ammonia, other compounds of this invention may be prepared.
The compounds listed in Tables I and II may be used as starting materials for the preparation of compounds of this invention. The listed compounds are either commercially available or disclosed in the literature. These lists are not comprehensive, and are intended to illustrate the invention, not to limit it. All references in Tables are incorporated by reference.
Table I
Cmpd
No . St* X a* Q R3 R4 R5 R5 ' Reference
P5 CH2
-19- SUBSTITUTE SHEET P6 A CH2CH2 - - - - H H Commercial
P7 C S - H2 - - H H Acad. Sci.
Paris 265, 758 (1967) P8 C S - 0 - - H H J. Org. Chem.
36, 2437 (1971) P9 C 0 - H2 - - H sH J. Med. Chem.
33, 2019 (1990) ; EP 332,364 A2 P10 C CH2CH2 - H2 - - H H GB 897,052
Pll C CH2 - - - - H H J. Med. Chem
33, 2019 (1990) P12 C CH - - - - F H
P13 C CH2 - - - - F F
P14 D S S H2 H H H - -
P15 D CH2 s H2 H H OCH3 -
P16 D CH2 s H2 H H F -
P17 D CH2 S H2 H H H H GB 1,394,373
P18 D O s H2 CH3 H CH3 - EP 332,364 A2
P19 C CH2 - H - - H H
P20 C CH2 - H2 - H F
P21 C CH2 - H2 - - F F
P22 D CH2 S H H H CH3 - GB 1,394,373
P23 D . CH2N-Pr s H2 H CH3 H - J. Med. Chem.
34, 3187 (1991) P24 B CH2NH s - H H H - J. Med. Chem.
20, 209 (1977) P25 B CH2NCH3 s - H H H -
P26 B CH2NH s - H H Cl P27 B NS02Ph s - H H H - J. Am. Chem.
Soc. 69, 795
(1947) P29 D CH S H =0 H H H J. Org. Chem.
55, 560 (1990) P30 D s S O H H H H J. Med. Chem.
22, 1074 (1979)
-20-
SUBSTITUTE SHEET P28 D NH s 0 H =0 H H US 4,087,527
* s indicates single bond
St = structure commercial = commercially available
Cmpd. No. Struct. Q R3 R4 R5 R7 Reference
P35 F
Struct. = structure commercial = commercially available
examples
Analytical data were recorded for the compounds described below using the following general procedures. Proton NMR spectra were recorded on a Varian FT-NMR spectrometer (200 MHz or 300 MHz); chemical shifts were recorded in ppm (3) from an internal tetramethylsilane standard in deuterochloroform or deuterodimethylsulfoxide and coupling constants (J) are reported in Hz. Mass spectra (MS) or high resolution mass spectra (HRMS) were recorded on Finnegan MAT 8230 spectrometer or Hewlett Packard 5988A model spectrometer. Melting points are uncorrected. Boiling points are uncorrected.
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.
-21-
SUBSTIT-'JTE SKΞ51 L. F. Armarego, Purification of Laboratory Chemicals, 3rd ed., (New York: Pergamon Press, 1988) . Chromatography was performed on silica gel using the solvent systems indicated below. For mixed solvent systems, the volume ratios are given. Parts and percentages are by weight unless otherwise specified. Common abbreviations include: THF (tetrahydrofuran) , TBDMS (t-butyl-dimethylsilyl) , DMF (dimethylformamide) , Hz (hertz) TLC (thin layer chromatography) .All temperatures are given in degrees centigrade (°C) .
The following examples and preparations are for illustrative purposes only and are not to be construed as limiting the invention.
Preparation 1
Pvrrolor3.2.1-kl1phenoxazin-1.2-dione To a solution of phenoxazine (21.05 g, 0.115 mole) in dichloroethane (125 ml) was added oxalyl chloride
(1.05 eq., 0.121 mole, 15.3 g, 10.52 ml) with stirring. The solution was heated to 50°C for one hour, then cooled to room temperature. A solution of aluminum chloride in nitrobenzene (1M, 1 eq., 0.115 mole, 115 ml) was added via addition funnel at room temperature. The solution was stirred for 6 hours, cooled with an ice bath, and quenched with IN HCl and water. More dichloroethane was added, and the organic solution was washed sequentially with water, aq. NaHC03 and brine, and dried over magnesium sulfate. The dichloroethane was removed via rotary evaporation, and 1000 ml of hexane was added to the resulting dark nitrobenzene solution to give dark violet crystals. The solid was filtered, and dried under vacuum to provide 19.95 g (0.084 mol, 73% yield) of the title compound, mp 218- 9 °C. MS (NH3/CI) m/e 238 (M+H) . Anal. Calcd for C14H7NO3: C, 70.89; H, 2.97; N, 5.90. Found: C, 70.62; H, 2.89; N, 5.82.
1.2-Dihydro-2- (4-me henylpγridiny1 )pyrrolo T .2.1- kllphenoxa^in-l (2 -one
To a mixture of the compound from Preparation 1 (2.38 g, 0.010 mole) in acetic anhydride (20 ml) was added acetic acid (2 ml) and 4-picoline (1.75 eq., 0.0175 mole, 1.63 g, 1.7 ml) . The mixture was heated to 110 °C, and held at this temperature for 45 min., at which time a red precipitate had formed. The reaction mixture was cooled to room temperature, and poured over ice. The solid was collected and washed with water. The material was dried under vacuum overnight to obtain 2.94 g (0.0094 mole, 94% yield) of the title compound, mp 240-5°C. MS (NH3/CI) m/e 313 (M+H) .
Preparation
-23-
SUBSTiTUTE SHEET 1.2-Dihvdro-2- ( -Pvridinylmethvl)pyrrolo r3.2.1- kllphenoxaz-Ln-l (2H)-one The product from Preparation 2 (3.0 g, 9.6 mmol) was weighed into a Parr™ shaker bottle, tetrahydrofuran (150 ml) was added, along with 160 mg of 20% Pd(0H)2 on carbon and 200 mg 10% Pd/C. The mixture was shaken under 55 psi of hydrogen for 4 hours, at which time the red color had faded. The reaction mixture was filtered to remove catalyst, and the solvent was removed by rotary evaporation. The residue was purified via column chromatography (silica gel, 5% methanol in ethyl acetate) , and the solid was recrystallized from ethyl acetate to give 1.902 g (6.1 mmol, 64% yield) of the title compound, mp 180-2 °C. iH- R (300 MHz, CDC13) 3 3.04 (dd, 1 H, J = 9, 14 Hz), 3.45 (dd, 1 H, J = 5, 14 Hz), 3.88 (dd, 1 H, J = 5, 9 Hz) , 6.43 (d, 1 H, J = 7 Hz), 6.70 (d, 1 H, J = 8 Hz), 6.83 (d, 1 H, J = 8 Hz), 6.88 (m, 1 H) , 7.00 (m, 2 H) , 7.13 (d, 2 H, J = 6 Hz) , 8.25 (dd, 1 H, J = 3, 7 Hz), 8.51 (d, 2 H, J = 6 Hz) . MS (NH3/CI) m/e 315 (M+H) . Anal. Calcd for C20H14N2O2: C, 76.42; H, 4.49; N, 8.91. Found: C, 76.23; H, 4.42, N; 8.81.
Example 193
2.2-Bis (4-Pvridiny 1 methyl -pyrrolo \ 3.2.1-kl 1 phenoxazin- l(2H)-one. To a solution of pyrro!o[3.2.1-kl]phenoxazin-l (2H) - one (486 mg, 2.18 mmol) in toluene (25 ml) was added 4-
-24- SUBSTITUTE SHEET picolyl chloride hydrochloride (2.2 eq., 4.8 mmol, 787 mg) and benzyltriethylammonium chloride (0.087 eq., 0.19 mmol, 43 mg) . While the mixture was stirred at room temperature, 50% aq. sodium hydroxide was added dropwise. The mixture was heated to 60°C for 2 hours, at which time TLC showed that all starting materials had been consumed. Water was added, and the dark brown reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with water, then brine, and the solution was dried over magnesium sulfate. After removal of solvent, the residue was purified via column chromatography (silica gel, 5% methanol in ethyl acetate) , and the solid was recrystallized from dichloromethane/hexane to give 471 mg (1.16 mmol, 53% yield) of the title compound, mp 199- 200°C. MS (NH3/CI) m/e 406 (M+H) . !H-NMR (300 MHz, CDCI3) 9 3.12 (d, 2 H, J = 13 Hz), 3.38 (d, 2 H, J = 13 Hz), 6.60 (d, 1 H, J = 8 Hz), 6.76 (m, 1 H) , 6.82 (d, 1 H, J = 8 Hz), 6.86 (d, 4 H, J = 6 Hz), 6.90- 6.98 (m, 3 H), 8.12 (m, 1 H) , 8.34 (d, 4 H, J = 6 Hz) . Anal. Cald for C26H19N3O2 : C, 77.02; H, 4.72; N, 10.36. Found: C, 76.81; H, 4.62; N, 10.28.
In a similar manner, the following compounds were prepared:
2, 3-Dihydro-6, 6-bis (4-pyridinylmethyl) - pyrrolo[1,2, 3-de]-1,4-benzothiazin-5 (6H) -one (Ex. 49) : mp 160-161 °C, MS (NH3/CI) m/e 374 (M+H) , 1-3-NMR (300 MHz, CDCI3) 9 2.44 (t, 2 H), 3.11 (d, 2 H, J = 12.9 Hz), 3.32 (d, 2 H, J = 12.8 Hz), 3.56 (t, 2 H) , 6.79 (d, 4 H, J = 1.5 Hz), 6.91 (m, 3 H) , 8.31 (d, 4 H, J = 1.5 Hz) . Anal. Calcd for :C22Hi9N30S: C, 70.75; H, 5.13; N, 11.25. Found: C, 70.32; H, 5.01; N, 11.04.
1, 1-Bis (4-pyridinylmethyl) -5, 6-dihydro-4H- pyrollo[3,2,l-ij]quinolin-2 (IH) -one (Ex. 1) : mp 140- 1°C, MS (CH4/CI) m/e 356 (M+H), 384 (M+29) , 1H-NMR (300 MHz, CDCI3) 9 1.45 (quin, 2 H, J = 6 Hz) , 2.42 (t, 2 H, J = 6 Hz), 3.11 (d, 2 H, J = 13 Hz), 3.26 (t, 2 H, J = 6
-25-
•r-.* tf
• i f- >»--ι--*-. Hz), 3.33 (d, 2 H, J = 13 Hz), 6.82 (d, 4 H, J = 6 Hz), 6.86 (d, 1 H, J = 7 Hz), 6.94 (t, 1 H, J = 7 Hz), 7.07 (d, 1 H, J = 7 Hz), 8.28 (d, 4 H, J = 6 Hz) . Anal. Calcd for C23H21N3O: C, 77.72; H, 5.96; N, 11.82. Found: C, 77.65; H, 5.79; N, 11.77.
2, 2-Bis (4-pyridinylmethyl) -pyrrolo [3, 2, 1- kl]phenothiazin-l (2H)-one (Ex. 169) : mp 190-1°C, MS (CH4/CI) m/e 422 (M+H), 450 (M+29) , -^H-NMR (300 MHz, CDCI3) 9 3.10 (d, 2 H, J = 13 Hz), 3.38 (d, 2 H, J = 13 Hz), 6.69 (d, 1 H, J = 7 Hz), 6.77- 7.08 (m, 5 H) , 6.86 (d, 4 H, J = 6 Hz), 8.34 (d, 4 H, J = 6 Hz), 8.58 (d, 1 H, J = 8 Hz) . Anal. Calcd for C26H19N3OS: C, 74.09; H, 4.54; N, 9.97. Found: C, 73.87; H, 4.34; N, 9.82. C,H,N. 2, 2-Bis (4-pyridinylmethyl) -6, 7-dihydro-indolo [1,7- ab] [l]benzapin-l (2H) -one dihydrochloride (Ex. 217) : mp" 274-6°C, MS (CH4/CI) m/e 418 (M+H), 446 (M+29), HRMS: m/e calcd 417.1841, m/e found 417.1836. Anal. Calcd for C2βH23 3θ»2HCl«H2θ: C, 66.14; H, 5.35; N, 8.26. Found: C, 66.14; H, 5.23; N, 8.15.
Example 200
1.2-Dihvdro-2- (4-Pvridinvlmethvl) -2- (pentanenitrile) - pvrrolo f 3.2.1-kll phenoxazin-1 (2H) -one . hvdrobromide To a slurry of sodium hydride (60% in oil, 176 mg, 4.4 mmol) in THF at room temperature was added the compound from Preparation 3 (2.2 mmol, 692 mg) , followed by 5-bromovaleronitrile (5 eq., 11 mmol, 1.78 g) . One
-26- SUBSTITUTE SHEET drop of ethanol was added, and the mixture was stirred at room temperature for 3 days. Methanol was added to decompose excess sodium hydride, and the solvents were removed by rotary evaporation. The residue was partitioned between ethyl acetate and water, then the product was extracted into IN HCl. The aqueous layer was basified, and the product was extracted into dichloromethane. Subsequent purification by column chromatography provided an oil, 475 mg, 55% yield. MS (NH3/CI) m/e 396 (M+H) . 1__-NMR (300 MHz, CDCI3) 9 1.25 (m, 2 H) , 1.61 (m, 2 H) , 1.88 (m, 1 H) , 2.13 (m, 1 H) , 2.25 (m, 2 H), 2.99 (d, 1 H, J = 13 Hz), 3.20 (d, 1 H, J = 13 Hz), 6.68 (d, 1 H, J = 8 Hz), 6.78 (d, 1 H, J = 8 Hz), 6.84 (d, 2 H, J = 6 Hz), 6.86 (m, 1 H) , 6.98 (m, 3 H) , 8.19 (dd, 1 H, J = 2, 7 Hz), 8.31 (d, 2 H, J = 6 Hz) . The compound was converted into a salt with hydrobromic acid, mp 239-45 °C. Anal. Calcd for C25H2iN3θ2 «2HBr«0.25H2θ: C, 62.44; H, 4.72; N, 8.74. Found: C, 62.61; H, 4.58; N, 8.64. By using the methods illustrated in the above examples, compounds in Tables III, IV and V can be prepared.
Table III
Ex. X Rl R2 R3 R4 a R5 mp°C. NO.
1 CH 4-pyr CH2~(4-pyr) H H s H 140-1
2 CH2 4-pyr CH2- (3-pyr) H H s H
3 CH2 4-pyr CH2- (2-pyr) H H s H
4 CH 4-pyr CH - (4-pyrim) H H s H
-27-
SUBSTITUTE SHEET 160-1
-29-
;EI
-32-
i-i— • — ! f*.
-' !TUT=
-33- SUBSTITUTE SHEET 09
mp
190-1
-34-
SUBSTITUTE SHEET
316 C=0 4-pyr CH2- (4-pyrim) H H
317 C=0 4-pyr CH2- (2-F-4- H H pyr)
318 C=0 4-pyr CH - (3-CN- H H
C6H5 )
319 C=0 4-pyr (CH2>3CN H H
320 C=0 4-pyr (CH2)4CN H H
321 C=0 4-pyr (CH2)5CN H H
322 C=0 4-pyr (CH2)3C02Et H H
323 C=0 4-pyr (CH2)4C02Et H H
324 C=0 4-pyr CH2-Ph H H
325 C=0 4-pyrim CH2- (4-pyr) H H
326 C=0 4-pyrim CH2- (3-pyr) H H
327 C=0 4-pyrim CH2- (2-pyr) H H
328 C=0 4-pyrim CH2- (4-pyrim) H H
329 C=0 4-pyrim CH2- (2-F-4- H H pyr)
330 C=0 4-pyrim CH2-(3-CN- H H
C6H5)
331 C=0 4-pyrim (CH2)3CN H H
332 C=0 4-pyrim (CH2)4CN H H
333 C=0 4-pyrim (CH2)5CN H H
334 C=0 4-pyrim (CH2) 3C02Et H H
335 C=0 4-pyrim (CH2)4C02Et H H
336 C=0 4-pyrim CH2-Ph H H
-39- SUkSTITUTE SHEET
400 4-pyrim CH2- (4-pyrim) (CH3)2 H CH3 CH3
401 4-pyrim CH2- (2-F-4-pyr) (CH3)2 H CH3 CH3
402 4-pyrim CH2- (3-CN-C6H5) (CH3)2 H CH3 CH3
403 4-pyrim (CH2)3CN (CH3)2 H CH3 CH3
404 4-pyrim (CH2)4CN (CH3)2 H CH3 CH3
405 4-pyrim (CH2)5CN (CH3)2 H CH3 CH3
406 4-pyrim (CH2)3C02Et (CH3)2 H CH3 CH3
407 4-pyrim (CH2)4C02Et (CH3)2 H CH3 CH3
408 4-pyrim CH2-Ph (CH3)2 H CH3 CH3
409 4-pyr CH2- (4-pyr) H H F H
410 4-pyr CH2- (3-pyr) H H F H
411 4-pyr CH2- (2-pyr) H H F H
412 4-pyr CH2- (4-pyrim) H H F H
413 4-pyr CH2- (2-F-4-pyr) H H F H
414 4-pyr CH2- (3-CN-C6H5) H H F H
415 4-pyr (CH2)3CN H H F H
416 4-pyr (CH2) 4CN H H F H
417 4-pyr (CH )sCN H H F H
418 4-pyr (CH2)3C02Et H H F H
419 4-pyr (CH2)4C02Et H H F H
420 4-pyr CH2-Ph H H F H
421 4-pyrim CH2- (4-pyr) H H F H
422 4-pyrim CH2- (3-pyr) H H F H
423 4-pyrim CH2- (2-pyr) H H F H
424 4-pyrim CH2- (4-pyrim) H H F H
425 4-pyrim CH2- (2-F-4-pyr) H H F H
426 4-pyrim CH2- (3-CN-C6H5) H H F H
427 4-pyrim (CH2)3CN H H F H
428 4-pyrim (CH2) 4CN H H F H
429 4-pyrim (CH )sCN H H F H
430 4-pyrim (CH2)3C02Et H H F H
431 4-pyrim (CH2)4C02Et H H F H
432 4-pyrim CH2-Ph H H F H
-42-
SUBST iTP .ςHEET Biochemical Test Procedure
Neurotransmitter release assay: The neurotransmitter releaεe activities of the compounds in this invention were determined as reported in Drug Development
Research. 19. 285-300 (1990) and iε a modification of the procedure deεcribed by Mulder, et al., Brain Res.. 70f 372 (1974) . These publications are herein incorporated by reference. Male Wistar ratε (Charleε River) weighing 175-200 gramε were used. The rats were houεed for at leaεt seven days before the experiment in animal facility under 12/12 hour light/dark cycle. Deionized water and standard rat chow (Purina) were available ad libitum. Rats were decapitated and brains were removed immediately. Sliceε (0.3 mm thick) from the parietal cortex were prepared manually uεing a receεεed Lucite guide. Slices were subεequently cut into 0.25 x 0.25 mm εquareε with a Mcllwain tiεεue chopper. Cerebral cortical εliceε (approximately 100 mg wet weight) were incubated in 10 ml Krebs-Ringer medium (KR) containing NaCl (116 mM) , KC1 (3 mM) , CaCl2 (1.3 mM) , MgCl2 (1.2 mM) , KH2PO4 (1.2 mM) , Na2S04 (1.2 mM) , NaHC03 (25 mM) and glucose (11.0 mM) to which 10 mCi 3H-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. The brain preparations were incubated for 30 minuteε at 37°C under a εteady flow of 95% 02/5% CO2. Under theεe conditions, part of the radioactive choline taken up by the preparation waε converted into radioactive acetylcholine (ACh) by the cholinergic nerve endingε εtored in synaptic vesicles, and released upon depolarization by high potasεium ion (K+) containing media. After labeling of the ACh εtores, the sliceε were waεhed three timeε with non-radioactive KR medium and tranεferred to a εuperfuεion apparatuε to measure the drug effects on ACh release. The εuperfusion apparatus consisted of 10 thermostated glass columns of 5 diameters that were provided with GF/F glasε fiber filters to support the sliceε (approximately 10 mg tiεεue/column) . Superfuεion waε carried out in KR-medium (0.3 ml/min.) containing 10 mM hemicholinium-3 (HC-3) . The HC-3 preventε the reuptake of choline formed during the εuperfusion from phospholipidε and releaεed 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 thermoεtated εtainleεε εteel coil before entering the superfusion column. Each column waε provided with a 4-way εlider 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.
After 15 min. of washout of non-specifically bound radioactivity, collection of 4 min. fractions was initiated. After three 4 min. collectionε, the original medium waε changed to a KR-medium in which the KC1 concentration haε been increaεed to 25 mM (high K+ -KR medium; SI) . Depolarization-induced stimulation of release by high K+/KR-medium lasted 4 min. Drug free low and high K+/KR-media were then substituted by drug- and vehicle-containing low- and high-K+/KR medium, and superfuεion was continued for three 4 min. collections with low K+/KR-medium, one 4 min. collection with high K+/KR-medium (S2) , and two 4 min. collections with low- K+/KR-medium.
Drug waε added to the media by 100-fold dilutionε of appropriate concentrationε of the drug (in 0.9% saline) with either low- or high-K+/KR-medium.
All superfusion fractions were collected in liquid εcintillation counting vialε. After εuperfusion, the sliceε were removed from the superfusion columns and extracted with 1.0 ml of 0.IN HCl. Liquiscint (NEN) εcintillation cocktail (12 ml) waε added to εuperfuεion fractions and extractε, and the εamples were counted in a Packard Tricarb Liquid Scintillation Counter. No corrections were made for quenching.
The ratio of S2/S1 (as compared to controls where no drug was present during S2) waε a eaεure of the ability of the drug to enhance or depreεs stimulus- induced acetylcholine releaεe. Per cent acetylcholine (ACh) enhanced release caused by 10 mM of drug using this aεεay are εhown in Table 5.
Utility
The foregoing teεt reεultε εuggest that the compounds of this invention have utility in the treatment of cognitive disorders and/or neurological function deficits and or mood and mental disturbanceε in patientε εuffering from nervouε εyεtem diεorderε like Alzheimer's Diεease, Parkinson'ε Diεeaεe, εenile dementia, multi-infarct dementia, Huntington'ε disease, mental retardation, Myasthenia Gravis, etc. The above- described in vitro assay is recognized as aiding in the identification of drugs useful in the treatment of cognitive disorderε and/or neurological function deficitε and or mood and mental diεturbanceε in patientε εuffering from nervous syεtem disorders like Alzheimer's Disease, Parkinson'ε Diεeaεe, εenile dementia, multi- infarct dementia, Huntington'ε diεeaεe, mental retardation, Myaεthenia Graviε, etc. Cook et al., Drug
-45- SUBSTITUTE SHEET Development Research. 1£, 301-304 (1990), Nickolson et al., Druσ Development Research. 19. 285-300 (1990) and DeNoble et al., Pharmacology Biochemistry & Behavior. 36r 957-961 (1990), all have shown via the above- deεcribed in vitro aεsay that the drug DuP 996, which has the chemical name 3,3-bis (4-pyridinylmethyl)-1- phenylindolin-2-one (linopirdine) , is useful in the treatment of cognition dysfunction.
Formulations Compounds of this invention can be administered to treat said deficiencieε by meanε that produceε contact of the active agent with the agent's εite of action in the body of a mammal. The compoundε can be adminiεtered by any conventional meanε 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 adminiεtration and εtandard pharmaceutical practice.
The doεage adminiεtered will vary depending on the uεe and known factorε 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 εy ptomε; kind of concurrent treatment; frequency of treatment; and deεired effect. For uεe in the treatment of εaid diseases or conditions, the compounds of thiε invention can be orally adminiεtered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a doεe of 0.01 to 10 mg/kg in divided doεes one to four times a day, or in εuεtained release formulation was effective in obtaining the desired pharmacological effect. Dosage forms (compositionε) εuitable for adminiεtration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be
-46- SUBSTITUTE SHEET preεent in an amount of about 0.5 to 95% by weight baεed on the total weight of the composition.
The active ingredient can be administered orally is solid doεage formε, εuch aε capsules, tablets and powders; or in liquid forms such as elixirε, εyrupε, and/or εuεpenεionε. The compounds of this invention can also be administered parenterally in εterile liquid doεe formulationε.
Gelatin capεuleε can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, εteric acid, or celluloεe derivativeε. Similar diluentε can be uεed to make compreεεed tablets. Both tablets and capsuleε can be manufactured as εuεtained release products to provide for continuous release of medication over a period of time. Compressed tablets can be εugar- coated or film-coated to aεk any unpleasant taste, or uεed to protect the active ingredientε from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.
Liquid dose forms for oral administration can contain coloring of flavoring agentε to increaεe patient acceptance.
In general, water, pharmaceutically acceptable oilε, saline, aqueous dextrose (glucoεe) , and related εugar εolutionε and glycolε, εuch as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutionε. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if neceεεary, butter εubstances. Antioxidizing agents, εuch as sodium biεulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
-47- SUBSTITUTE SHEET Suitable pharmaceutical carriers are deεcribed in "Remington'ε Pharmaceutical Sciences", A. Osol, a εtandard reference in the field.
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 capsuleε each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magneεium εtearate.
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 waε pumped into gelatin to form εoft gelatin capεuleε containing 100 mg of the active ingredient. The capεules were washed and dried.
Tablets A large number of tablets are prepared by conventional procedureε 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 coatingε may be applied to increase palatability or delayed adsorption. The compounds of thiε invention may alεo be uεed aε reagents or standards in the biochemical study of neurological function, dyεfunction, and disease.
-48- SUBSTITUTE SHEET

Claims

What is claimed is:
1. A compound of formula:
or pharmaceutically acceptable salts thereof,
wherein: X is a single bond, O, S, SO, SO2, CH2, CH2CH2,
CH=CH, C=O, C(R7)(OR6), CH(OR6), -CONR6-, -NR6CO-, -CH2-NR6-, -NR6-CH2-, NR6, -C(R7)=N-, -CH(R7)-N(R6)-, or -CR7-, -CH- when a is a single bond and b is a double bond; 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 -CR7- and when a is a single bond;
R1 is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl; R2 is -(CH2)m-W,
wherein m = 1-4,
and W is selected from the group:
(a) 2-, 3- or 4-pyridyl,
(b) 2-, 4-, or 5-pyrimidinyl,
(c) 2-pyrazinyl,
(d) 3- or 4-pyridazinyl, (e) 3- or 4-pyrazolyl,
(f) 2- or 3-furyl,
(g) 2- or 3-tetrahydrofuranyl, (h) 2- or 3-thienyl,
(i) 3-indolyl,
(j) aryl unsubstituted or substituted with 1-3 R5,
(k) 2-fluoro-4-pyridyl, or
R2 is -(CH2)n-Y,
wherein n = 1-6,
and Y is selected from the group:
-CH=CHCO2R7, -CH=CHCOR7, -CH=CHR7, -CH=C(R7)2, -CH=CH2, -C≡CCO2R7, -C=CCOR7, -C≡CR7, or -C=CH, F, Cl, Br, OR6, N(R6)2, CO2H, CO2R7, CONHR7, NHCHO, CONHR6, CON(R7)2, CN, -OCOR7, COR7,
CHO, SR7, SOR7, SO2R7 or NO2;
R3 and R4 are each independently selected from the group:
H, alkyl of 1-6 carbons, alkenyl of 2-6 carbons, alkynyl of 2-6 carbons; cycloalkyl of 3-7 carbons, cycloalkylalkyl of 3-10 carbons, aryl unsubstituted or substituted with 1-3 R5, alkaryl of 1-10 carbons, provided that when a is a single bond R3 is =O, =CH2, =CH(R7),
=C(R7)2, or (CH3)2, and
provided that when a and b are each a single bond, then R3 and R4 are each independently selected from the group: =O, =CH2, =CH(R7), =C(R7)2, (CH3)2 ; or
R3 and R4, taken together may form a saturated or unsaturated carbocyclic or heterocyclic ring, unsubstituted or substituted with 1-2 R5 substituents;
R5 is selected from the group:
H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, alkaryl of 1-10 carbons, F, Cl, Br, I, OR6, NHR6, N(R6)2, CO2H, CO2R7, CONHR7, CON(R7)2, CN, COR7, CHO, SR7, SOR7, SO2R7, NO2 or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring;
R6 is independently selected at each occurrence
from the group:
H, alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, alkaryl of 1-10 carbons, -SO2-R7, and -COR7;
R7 is independently selected at each occurrence
from the group:
alkyl of 1-6 carbons, aryl unsubstituted or substituted with 1-3 R8, and alkaryl of 1-10 carbons;
R8 is independently selected at each occurrence
from the group:
OR9, NHR9, N(R9)2, CO2H, CO2R9, CONHR9,
CON(R9)2, CN, COR9, CHO, SR9, SOR9, SO2R9, and NO2; and R9 is independently selected at each occurrence
from the group:
H, alkyl of 1-6 carbons and aryl.
A compound of Claim 1 wherein:
X is a single bond, O, S, SO, SO2, CH2, CH2CH2,
CH=CH, C=O, NR6; a is a single or a double bond; b is a single bond;
R1 is 2-, 3- or 4-pyridyl, or 4-pyrimidinyl; R2 is -(CH2)m-W,
wherein m = 1-4, and
W is selected from the group:
2-, 3- or 4-pyridyl, 2-, 4-, or 5-pyrimidinyl, or 2-pyrazinyl; or
R2 is -(CH2)n-Y,
wherein n is 1 to 6, and
Y is selected from the group:
CO2R7, CN, COR7, CHO, -OCOR7;
R3 and R4 are each independently selected from the group:
H, alkyl of 1-6 carbon atoms or -CH=CH-CH=CH- to form a fused ring; and
R5 is selected from the group:
H, alkyl of 1-6 carbons, phenyl unsubstituted or substituted with 1-3 R8, F, Cl, Br, I, NO2 or -CH=CH-CH=CH- which attaches to an adjacent carbon forming a fused ring.
3. A compound of Claim 2 wherein: X is O, S, SO, SO2, CH2, CH2CH2, C=O;
R2 is -(CH2)m-W,
wherein m = 1, and
W is selected from the group:
2-, 3- or 4-pyridyl, and 4-pyrimidinyl; or
R2 is -(CH2)n-Y,
where n = 3-4, and
Y is selected from the group:
CO2R7, CN, and -OCOR7;
R3 and R4 are each H, or R3 and R4 join together forming a fused ring consisting of -CH=CH- CH=CH-; and R5 is selected from the group:
H, Cl, Br, I, NO2 or -CH=CH-CH=CH- which attaches to an adjacent carbon atom forming a fused ring. 4. The compounds of Claim 1 which are:
(a) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3,2,1- kl]phenothiazin-1(2H)-one;
(b) 1,1-Bis(4-pyridinylmethyl)-5,6-dihydro-4H- pyrollo[3,2,1-ij]quinolin-2(IH)-one;
(c) 2,2-Bis(4-pyridinylmethyl)-6,7-dihydroindolo[l,7-ab][1]benzapin-l(2H)-one;
(d) 2,2-Bis(4-pyridinylmethyl)-pyrrolo[3.2.1- kl]phenoxazin-1(2H)-one; (e) 2,3-Dihydro-6,6-bis(4-pyridinylmethyl)- pyrrolo[1,2,3-de]-1,
4-benzothiazin-5(6H)-one;
(f) 1,2-Dihydro-2-(4-pyridinylmethyl)-2- (pentanenitrile)-pyrrolo[3.2.1-kl]phenoxazin-1(2H) one, hydrobromide.
5. A pharmaceutical composition comprising a
pharmaceutically suitable carrier and a
therapeutically effective amount of a compound of Claim 1.
A pharmaceutical composition comprising a
pharmaceutically suitable carrier and a
therapeutically effective amount of a compound of Claim 2.
A pharmaceutical composition comprising a pharmaceutically suitable carrier and a therapeutically effective amount of a compound of Claim 3.
8. A pharmaceutical composition comprising a
pharmaceutically suitable carrier and a therapeutically effective amount of a compound of Claim 4.
9. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 1.
10. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 2.
11. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 3.
12. A method of treating a neurolgical disorder in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Claim 4.
EP93923238A 1992-10-13 1993-10-12 3,3-disubstituted tri- and tetracyclic indolin-2-ones useful for the treatment of cognitive disorders Withdrawn EP0664810A1 (en)

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