EP0703901A1 - Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase - Google Patents

Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase

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Publication number
EP0703901A1
EP0703901A1 EP94919032A EP94919032A EP0703901A1 EP 0703901 A1 EP0703901 A1 EP 0703901A1 EP 94919032 A EP94919032 A EP 94919032A EP 94919032 A EP94919032 A EP 94919032A EP 0703901 A1 EP0703901 A1 EP 0703901A1
Authority
EP
European Patent Office
Prior art keywords
lower alkyl
ethyl
compound
indol
treatment
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Withdrawn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
EP94919032A
Other languages
German (de)
English (en)
Inventor
Bernard Robin Boar
Dennis Mark O'shea
Ian David Tomlinson
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.)
AstraZeneca AB
Original Assignee
Astra AB
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 Astra AB filed Critical Astra AB
Publication of EP0703901A1 publication Critical patent/EP0703901A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/34—Oxygen atoms in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/32—Oxygen atoms
    • C07D209/38—Oxygen atoms in positions 2 and 3, e.g. isatin

Definitions

  • the present invention relates to novel compounds having therapeutic activity, intermediates for their preparation, processes for their preparation, pharmaceutical formulations containing said compounds and medicinal use of said compounds.
  • a major characteristic of Alzheimer's Disease is a marked central cholinergic dysfunction. This cholinergic deficit has been reported to correlate with cognitive impairment (P.T. Francis et al, New Engl. J. Med., 1985, 313, 7). Various attempts to increase central cholinergic activity and thereby reverse the cognitive deficits have, to date, met with only limited success.
  • THA 9-amino-l,2,3,4-tetrahydroacridine
  • the present invention is a.
  • a primary objective of the present invention is to provide structurally novel compounds which by virtue of their pharmacological profile enhance central cholinergic function and are of value in the treatment of the cognitive dysfunctions which may be associated with ageing or with conditions such as Alzheimer's Disease, Senile and related Dementias, Parkinson's Disease, Down's Syndrome and Huntington's Chorea.
  • This utility is manifested, for example, by the ability of these compounds to inhibit the enzyme acetylcholinesterase.
  • the compounds of this invention are, in general, highly potent and selective, have an improved duration of action and are, in general, less toxic than hitherto known compounds.
  • the present invention relates to a compound having the general formula (1)
  • n 3, 4, 5, 6 or 7;
  • X represents one or more substituents independently selected from hydrogen, lower alkyl, aryl, lower alkoxy, halogen, trifluoromethyl, nitro, -NHCOR where R is lower alkyl or aryl, - R- j ⁇ where R ⁇ and 2 are independently hydrogen or lower alkyl or together form a ring, or cycloalkyl, cycloalkenyl or bicycloalkyl either optionally further substituted by lower alkyl;
  • Y is CO or .
  • CR3R4 where R 3 and R 4 are independently
  • Z is lower alkyl
  • W represents one or more substituents independently selected from hydrogen, lower alkyl, lower alkoxy or halogen.
  • Preferred embodiments of this invention relate to compounds having the general formula (2)
  • n, X, W and Z are as previously defined above; or to compounds having the general formula (3)
  • n, X, W and Z are as previously defined above.
  • lower alkyl denotes a straight or branched alkyl group having from 1 to 6 carbon atoms.
  • examples of said lower alkyl include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl and straight- and branched- chain pentyl and hexyl.
  • cycloalkyl denotes a cyclic alkyl group having a ring size from C 3 to C- , optionally additionally substituted by lower alkyl.
  • examples of said cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclohexyl and cycloheptyl.
  • cycloalkenyl denotes a cyclic alkenyl group having a ring size from C 3 to C 7 , optionally additionally substituted by lower alkyl.
  • examples of said cycloalkenyl include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methylcyclohexenyl and cycloheptenyl.
  • lower alkoxy denotes a straight or branched alkoxy group having from 1 to 6 carbon atoms.
  • Examples of said lower alkoxy include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight- and branched-chain pentoxy and hexoxy.
  • halogen shall mean fluorine, chlorine, bromine or iodine.
  • aryl denotes a phenyl, furyl or thienyl group in which the ring is optionally further substituted by lower alkyl, lower alkoxy or halogen.
  • bicycloalkyl denotes a bicyclic alkyl group having a size from Cg to Cg, optionally additionally substituted by lower alkyl.
  • Examples of said bicycloalkyl include bicyclo [2.2.llheptyl, bicyclo[2.2.2]octyl and bicyclo[2.2.3]nonyl.
  • cyclic acetal denotes a cyclic acetal group having a ring size from C ⁇ to C 7 .
  • examples of said cyclic acetal include 1,3-dioxolanyl and 1,3-dioxanyl.
  • Preferred compounds according to the invention are those of general formula (2) or general formula (3) in which: n is 4, 5 or 6 is hydrogen or F, especially 4-F, and X is lower alkyl, especially methyl or ethyl, lower alkoxy, especially methoxy or ethoxy, cycloalkyl, especially Cg to C 7 cycloalkyl, F, aryl, especially phenyl, or -N 1 R 2 » especially 1 -pyrrol idinyl or 1- piperidinyl. More preferred compounds according to the invention are those of general formula (2) or general formula (3) in which the X substituent is at the 5- position.
  • the present invention also relates to processes for preparing the compound having formula (1) .
  • Said compound may be prepared by treating a compound of the general formula (4)
  • the process can be achieved, for example, by treating a compound of structure (4) with a l,n-dihaloalkane, in a suitable solvent such as toluene or 3-methyl-2-butanone or acetonitrile or acetone or dimethylsulphoxide or dimethylformamide in the presence of a base such as triethylamine or anhydrous potassium carbonate.
  • a suitable solvent such as toluene or 3-methyl-2-butanone or acetonitrile or acetone or dimethylsulphoxide or dimethylformamide
  • a base such as triethylamine or anhydrous potassium carbonate.
  • Such reaction should be conducted at a suitable temperature, normally between 0°C and 100°C, optionally in an inert atmosphere.
  • Some compounds of type (5) are known in the literature.
  • the intermediate (5) may either be isolated and purified and characterised using standard techniques or else may be reacted in a crude form with a compound of structure (6) .
  • Such reaction is preferably conducted in a suitable solvent such as dichloromethane or dimethylformamide in the presence of a base such as triethylamine or anhydrous potassium carbonate or an excess of compound (6), optionally with the addition of a catalytic amount of potassium iodide.
  • a suitable solvent such as dichloromethane or dimethylformamide
  • a base such as triethylamine or anhydrous potassium carbonate or an excess of compound (6)
  • a catalytic amount of potassium iodide optionally with the addition of a catalytic amount of potassium iodide.
  • the reaction should be conducted at a suitable temperature, normally between 0°C and 100°C, optionally in an inert atmosphere.
  • the required product (1) may then be isolated and purified and characterised using standard techniques. In the case of products wherein Y represents an acetal or cyclic acetal group, the corresponding products wherein
  • Y is .CO can be subsequently prepared by acid-catalysed
  • isatins systematic name lH-indole-2,3-diones
  • the isatins of structure (4) are, depending on the nature of the substituent(s) X, either compounds which have been previously described in the literature, or compounds which can be prepared by the straightforward application of known methods.
  • the Sandmeyer procedure (Organic Syntheses, Coll. Vol. I., p 327), in which an aniline, chloral hydrate and hydroxylamine are reacted together to give an intermediate isonitrosoacetanilide which is then cyclised to the isatin on treatment with strong acid, is a particularly useful method.
  • oxindoles systematic name l,3-dihydro-2H-indol-2- ones.
  • the oxindoles of structure (4) are, depending on the nature of the substituent(s) X, either known compounds or compounds which can be prepared using known methods.
  • the Gassman reaction (P.G. Gassman et al, J.Amer.Chem.Soc, 1974, 96, 5508 and 5512) constitutes a well-known and general synthesis of oxindoles.
  • n 5, 6 or 7 and X, Y and Hal are as defined
  • Method (c) represents a preferred process for the
  • the present invention also relates to pharmaceutical formulations containing a compound according to claim 1.
  • -Another object of the present invention is a compound according to claim 1 for use in therapy.
  • Still another object of the present invention is the use of a compound having the general formula (1)
  • n is 3 , 4 , 5 , 6 or 7 ;
  • X represents one or more substituents independently selected from hydrogen, lower alkyl, aryl, lower alkoxy, halogen, trifluoromethyl, nitro,
  • R- ⁇ and R 2 are independently hydrogen or lower alkyl or together form a ring, or cycloalkyl, cycloalkenyl or bicycloalkyl either optionally further substituted by lower alkyl;
  • Y is ⁇ .CO or CR 3 R 4 where R 3 and R ⁇ are independently
  • Z is lower alkyl
  • W represents one or more substituents independently selected from hydrogen, lower alkyl, lower alkoxy or halogen;
  • the present invention relates to a method for the treatment of central cholinergic dysfunction whereby a pharmacologically effective amount of a compound according to claim 1 is administered to a host in need of said treatment.
  • the compounds of general formula (1) of the present invention are useful in the treatment of various cognitive dysfunctions, such as those occurring in Alzheimer's disease. This utility is manifested by the ability of these compounds to inhibit the enzyme acetylcholinesterase.
  • the compounds of this invention potentiate cholinergic function in the brain such that when administered to rodents these compounds induce marked cholinergic effects such as tremor.
  • the administration in the novel method of treatment of this invention may conveniently be oral, rectal, or parenteral at a dosage level of, for example, about 0.0001 to 10 mg/kg, preferably about 0.001 to 1.0 mg/kg and especially about 0.01 to 0.2 mg/kg and may be administered on a regimen of 1 to 4 doses or treatments per day.
  • the dose will depend on the route of administration, a preferred route being by oral administration. It will be appreciated that the severity of the disease, the age of the patient and other factors normally considered by the attending physician will influence the individual regimen and dosage most appropriate for a particular patient.
  • the pharmaceutical formulations comprising the compound of this invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral solutions or suspensions for parenteral administration; or as suppositories for rectal administration; or as suitable topical formulations.
  • Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described, for example, in "Pharmaceuticals - The Science of Dosage Form Design", M.E. Aulton, Churchill Livingstone, 1988.
  • the active substance may be admixed with an adjuvant/a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • an adjuvant/a carrier e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets.
  • the tablet can be coated with a polymer known to the man skilled in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the above- mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of supposi ⁇ tories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing from about 0.02% to about 20% by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
  • Solutions for parenteral applications by injection can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance, preferably in a concentration of from about 0.5% to about 10% by weight. These solutions may also contain stabili ⁇ zing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • EXAMPLE 9 l'-(5-Bromopentyl)-spiro[l,3-dioxolane-2,3'-[3H]-indol]- 2' (l'H)-one 13 C Nmr (CDC1 3 ) 25.1, 26.2, 32.0, 33.1, 39.1, 65.6, 101.8, 108.6, 122.9, 123.9, 124.7, 131.4, 143.7 and 173.0 ppm.
  • EXAMPLE 10 1'-(5-Bromopentyl)-5'-cyclohexyl-spiro[1,3-dioxolane- 2,3'-[3H]-indol]-2' (1 ⁇ )-one
  • the corresponding fumarate was prepared using fumaric acid in methanol.
  • EXAMPLE 18 5 ' -Cyc lohexyl - 1 ' - ( 5 - (N-ethyl -N-phenylmethylamino ) pentyl ) -spiro [1 , 3-dioxolane-2 , 3 ' - [3H] -indol 1 -2 ' d'H) -one
  • the title compound was prepared using the general method of Example 11 but employing N-methyl-N-phenylmethylamine.
  • Nmr (CDC1 3 ) 24.5, 26.8, 27.1, 35.5, 39.7, 42.0, 56.9, 62.2, 108.0, 121.8, 124.2, 124.4, 126.6, 127.5, 127.9, 128.6, 139.1, 144.4 and 174.6 ppm.
  • the title compound was prepared using the general method of Example 11 but employing N-ethyl-N-(4-fluorophenyl) methylamine.
  • EXAMPLE 30 1-(5-Bromopentyl)-5-phenyl-lH-indole-2,3-dione 13 C Ntar (CDC1 3 ) 25.4, 26.9, 32.1, 33.0, 40.1, 110.3, 118.1, 123.9, 126.5, 127.9, 129.0, 136.7, 137.3, 139.0, 149.9, 158.3 and 183.4 ppm.
  • EXAMPLE 31 1-(5-Bromopentyl)-5-phenyl-lH-indole-2,3-dione 13 C Ntar (CDC1 3 ) 25.4, 26.9, 32.1, 33.0, 40.1, 110.3, 118.1, 123.9, 126.5, 127.9, 129.0, 136.7, 137.3, 139.0, 149.9, 158.3 and 183.4 ppm.
  • EXAMPLE 31 1-(5-Bromopentyl)-5-phenyl-lH-in
  • EXAMPLE 33 1 - ( 5 - ( N-Ethyl -N-phen lmethylamino ) entyl ) - 5 - ( 1 - methylethyl ) -lH-indole-2 , 3-dione 13 C Ntar (CDC1 3 ) 11.7 , 23 .6, 24.5, 26.7 , 27 .0 , 33.3 , 40 .1, 47.3, 52.8, 58.1, 109.9, 117.7, 123.0, 126.5, 127.9, 128.6, 136.3, 140.0, 144.4, 149.1, 158.2 and 183.6 ppm.
  • Example 39 The product from Example 39 was treated by the general method of Example 7 to give the title compound.
  • Example 40 The product from Example 40 was treated by the general method of Example 15 to give the title compound.
  • Example 41 The product from Example 41 was treated by the general method of Example 19 to give the title compound.
  • Example 46 The product from Example 46 was treated according to the general method of Example 15 to give the title compound.
  • Example 32 The product from Example 32 (2.4g), 1,2-ethanedithiol (0.6ml) and p-toluenesulphonic acid (2.2g) were stirred overnight at room temperature in glacial acetic acid. The mixture was evaporated to dryness and the residue was further processed as in Example 1 to give the intermediate dithioacetal and thence the title compound.
  • Example 50 Using the general method of Example 50, the product of Example 33 was converted into the title compound.
  • Example 37 Using the general method of Example 50 but using tert- butanol rather than ethanol as the solvent for the second step, the product of Example 37 gave the title compound.
  • Example 52 The product from Example 52 (500mg), benzyl bromide (300mg) and anhydrous potassium carbonate (660mg) were stirred in dry dimethylformamide at room temperature to give the title compound.
  • Example 34 Using the general method of Example 50, the product of Example 34 was converted into the title compound. 13 C Ntar (CDC1 3 ) 11.7, 24.7, 26.7, 27.3, 36.1, 40.0, 47.3, 53.0, 55.8, 58.1, 108.4, 111.9, 112.1, 125.9, 126.6, 128.0, 128.7, 138.2, 140.1, 155.6 and 174.4 ppm.
  • composition 1 Composition 1 - Tablets
  • Example 14 lactose, cellulose and polyvinylpyrrolidone are sieved and blended.
  • the magnesium stearate is sieved and then blended into the above mixture. Compression using suitable punches then yields 1000 tablets each containing 2mg of the active ingredient. If desired, the obtained tablets can then be film coated.
  • Example 42 lactose, cellulose and part of the starch are mixed and granulated with 10% starch paste. The resulting mixture is dried and blended with the remaining starch, the polyvinylpyrrolidone and the sieved magnesium stearate. The resulting blend is then compressed to give 1000 tablets each containing 20mg of the active ingredient.
  • Example 53 The compound of Example 53 and the starch are sieved, blended together and then lubricated with the sieved magnesium stearate.
  • the blend is used to fill 1000 hard gelatine capsules of a suitable size. Each capsule contains lOmg of the active ingredient.

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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)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • General Chemical & Material Sciences (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente invention se rapporte à de nouveaux composés ayant la formule générale (I) dans laquelle n vaut 3, 4, 5, 6 ou 7; X représente un ou plusieurs substituants sélectionnés indépendamment parmi hydrogène, alkyle inférieur, aryle, alcoxy inférieur, halogène, trifluorométhyle, nitro, -NHCOR où R représente alkyle inférieur ou aryle, -NR1R2 où R1 et R2 représentent indépendamment hydrogène ou alkyle inférieur ou forment un anneau, ou cycloalkyle, cycloalcényle ou bicycloalkyle, l'un et l'autre éventuellement également substitués par alkyle inférieur; Y représente (a) ou (b) où R3 et R4 représentent indépendamment hydrogène, alkyle inférieur, alcoxy inférieur ou forment un acétal cyclique; Z représente alkyle inférieur; et W représente un ou plusieurs substituants indépendamment sélectionnés parmi hydrogène, alkyle inférieur, alcoxy inférieur ou halogène; l'invention se rapporte également à des stéréo-isomères et à des isomères optiques et des racémates de ces composés dans lesquels ces isomères existent, ainsi qu'à des sels d'addition d'acide pharmaceutiquement acceptables de ceux-ci et à des solvates de ceux-ci ayant une activité thérapeutique, à leurs intermédiaires de préparation, à leurs procédés de préparation, aux formulations pharmaceutiques contenant ces composés et à l'utilisation médicinale de ces composés.
EP94919032A 1993-06-16 1994-05-13 Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase Withdrawn EP0703901A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
SE19939302080A SE9302080D0 (sv) 1993-06-16 1993-06-16 New compounds
SE9302080 1993-06-16
PCT/SE1994/000448 WO1994029272A1 (fr) 1993-06-16 1994-05-13 Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase

Publications (1)

Publication Number Publication Date
EP0703901A1 true EP0703901A1 (fr) 1996-04-03

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Country Status (9)

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EP (1) EP0703901A1 (fr)
JP (1) JPH08511515A (fr)
AU (1) AU7010894A (fr)
CA (1) CA2164119A1 (fr)
FI (1) FI956074A7 (fr)
IS (1) IS4167A (fr)
NO (1) NO955074L (fr)
SE (1) SE9302080D0 (fr)
WO (1) WO1994029272A1 (fr)

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EP2018874A2 (fr) 1998-08-07 2009-01-28 Targacept, Inc. compositions pharmaceutiques pour la prévention et le traitement de troubles du système nerveux central comprenant un analogue de la nicotine et un inhibiteur de l'acétylcholinestérase
WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
WO2014090929A1 (fr) 2012-12-13 2014-06-19 H. Lundbeck A/S Compositions comprenant de la vortioxétine et du donépézil
WO2014144801A1 (fr) 2013-03-15 2014-09-18 Agenebio Inc. Procédés et compositions pour améliorer la fonction cognitive

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CA2320757A1 (fr) * 1998-03-06 1999-09-10 Astrazeneca Ab Nouvelle utilisation
CN1535682A (zh) 1998-09-30 2004-10-13 ����ҩƷ��ҵ��ʽ���� 改善膀胱排泄能力的药物
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WO2011100373A1 (fr) 2010-02-09 2011-08-18 The Johns Hopkins University Procédés et compositions pour améliorer la fonction cognitive
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AU7010894A (en) 1995-01-03
WO1994029272A1 (fr) 1994-12-22
CA2164119A1 (fr) 1994-12-22
NO955074D0 (no) 1995-12-14
SE9302080D0 (sv) 1993-06-16
FI956074A0 (fi) 1995-12-18
NO955074L (no) 1996-02-07
JPH08511515A (ja) 1996-12-03
FI956074A7 (fi) 1995-12-18
IS4167A (is) 1994-12-17

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