WO1994029272A1 - 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 Download PDF

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Publication number
WO1994029272A1
WO1994029272A1 PCT/SE1994/000448 SE9400448W WO9429272A1 WO 1994029272 A1 WO1994029272 A1 WO 1994029272A1 SE 9400448 W SE9400448 W SE 9400448W WO 9429272 A1 WO9429272 A1 WO 9429272A1
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Prior art keywords
lower alkyl
ethyl
compound
indol
treatment
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Application number
PCT/SE1994/000448
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English (en)
Inventor
Bernard Robin Boar
Dennis Mark O'shea
Ian David Tomlinson
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Astra Aktiebolag
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Priority to JP7501642A priority Critical patent/JPH08511515A/ja
Priority to EP94919032A priority patent/EP0703901A1/fr
Priority to AU70108/94A priority patent/AU7010894A/en
Publication of WO1994029272A1 publication Critical patent/WO1994029272A1/fr
Priority to NO955074A priority patent/NO955074L/no
Priority to FI956074A priority patent/FI956074A0/fi

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    • 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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  • Organic Chemistry (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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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.
PCT/SE1994/000448 1993-06-16 1994-05-13 Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase WO1994029272A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
JP7501642A JPH08511515A (ja) 1993-06-16 1994-05-13 アセチルコリンエステラーゼの阻害剤としての１−置換イサチンおよびオキシンドール誘導体
EP94919032A EP0703901A1 (fr) 1993-06-16 1994-05-13 Derives de l'isatine a substitution 1 et de l'oxindole utiles comme inhibiteurs de l'acetylcholinesterase
AU70108/94A AU7010894A (en) 1993-06-16 1994-05-13 1-substituted isatin and oxindole derivatives as inhibitors of acetylcholinesterase
NO955074A NO955074L (no) 1993-06-16 1995-12-14 1-substituerte istain- og oksindolderivater som inhibitorer til acetylkolinesterase
FI956074A FI956074A0 (fi) 1993-06-16 1995-12-18 Asetyylikolinesteraasin inhibiittoreina toimivia 1-asemasta substituoituja isatiini- ja oksindolijohdannaisia

Applications Claiming Priority (2)

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SE19939302080A SE9302080D0 (sv) 1993-06-16 1993-06-16 New compounds
SE9302080-8 1993-06-16

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JP (1) JPH08511515A (fr)
AU (1) AU7010894A (fr)
CA (1) CA2164119A1 (fr)
FI (1) FI956074A0 (fr)
IS (1) IS4167A (fr)
NO (1) NO955074L (fr)
SE (1) SE9302080D0 (fr)
WO (1) WO1994029272A1 (fr)

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US6306851B1 (en) 1999-05-04 2001-10-23 American Home Products Corporation Cyclocarbamate and cyclic amide derivatives
US6319912B1 (en) 1999-05-04 2001-11-20 American Home Products Corporation Cyclic regimens using 2,1-benzisothiazoline 2,2-dioxides
US6329416B1 (en) 1999-05-04 2001-12-11 American Home Products Corporation Combination regimens using 3,3-substituted indoline derivatives
US6339098B1 (en) 1999-05-04 2002-01-15 American Home Products Corporation 2,1-benzisothiazoline 2,2-dioxides
US6358948B1 (en) 1999-05-04 2002-03-19 American Home Products Corporation Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
US6358947B1 (en) 1999-05-04 2002-03-19 American Home Products Corporation Tetracyclic progesterone receptor modulator compounds and methods
US6369056B1 (en) 1999-05-04 2002-04-09 American Home Products Corporation Cyclic urea and cyclic amide derivatives
US6380178B1 (en) 1999-05-04 2002-04-30 American Home Products Corporation Cyclic regimens using cyclocarbamate and cyclic amide derivatives
US6380235B1 (en) 1999-05-04 2002-04-30 American Home Products Corporation Benzimidazolones and analogues
US6399593B1 (en) 1999-05-04 2002-06-04 Wyeth Cyclic regimens using cyclic urea and cyclic amide derivatives
US6407101B1 (en) 1999-05-04 2002-06-18 American Home Products Corporation Cyanopyrroles
US6417214B1 (en) 1999-05-04 2002-07-09 Wyeth 3,3-substituted indoline derivatives
US6423699B1 (en) 1999-05-04 2002-07-23 American Home Products Corporation Combination therapies using benzimidazolones
US6436929B1 (en) 1999-05-04 2002-08-20 Wyeth Cyclothiocarbamate derivatives as progesterone receptor modulators
US6462032B1 (en) 1999-05-04 2002-10-08 Wyeth Cyclic regimens utilizing indoline derivatives
US6498154B1 (en) 1999-05-04 2002-12-24 Wyeth Cyclic regimens using quinazolinone and benzoxazine derivatives
US6509334B1 (en) 1999-05-04 2003-01-21 American Home Products Corporation Cyclocarbamate derivatives as progesterone receptor modulators
US6759408B2 (en) 1999-05-04 2004-07-06 Wyeth Combination regimens using progesterone receptor modulators
WO2004087658A1 (fr) * 2003-03-31 2004-10-14 Ucb, S.A. Derives d'indolone-acetamide, leurs procedes de preparation et leurs utilisations
US6906090B1 (en) 1998-03-06 2005-06-14 Astrazeneca Ab Compositions and methods for treating mycobacterial diseases
WO2005118561A1 (fr) * 2004-05-27 2005-12-15 Ucb, S.A. Derives de benzoxazolone, procedes permettant de les preparer et de les utiliser
WO2006008067A1 (fr) * 2004-07-22 2006-01-26 Ucb, S.A. Derives d'indolone, leurs procedes de preparation et leurs utilisation
US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity
US7317037B2 (en) 2004-08-09 2008-01-08 Wyeth Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof
EP1891954A2 (fr) 1998-09-30 2008-02-27 Takeda Pharmaceutical Company Limited Agents pour améliorer le pouvoir de vidange de la vessie
WO2010090680A1 (fr) * 2008-12-15 2010-08-12 Wyeth Llc Agonistes de cb2 de type oxindole substitué
CN103242332A (zh) * 2013-05-13 2013-08-14 江西科技师范大学 1-n酰基取代吲哚酮衍生物
CN104530065A (zh) * 2013-05-13 2015-04-22 江西科技师范大学 1-n酰基取代吲哚酮衍生物的应用
US10154988B2 (en) 2012-11-14 2018-12-18 The Johns Hopkins University Methods and compositions for treating schizophrenia
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
US10806717B2 (en) 2013-03-15 2020-10-20 The Johns Hopkins University Methods and compositions for improving cognitive function
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BR112015013675B1 (pt) 2012-12-13 2022-04-26 H. Lundbeck A/S Composição compreendendo vortioxetina e donepezil e usos dos mesmos

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EP1891954A2 (fr) 1998-09-30 2008-02-27 Takeda Pharmaceutical Company Limited Agents pour améliorer le pouvoir de vidange de la vessie
US6608068B2 (en) 1999-05-04 2003-08-19 Wyeth Indoline derivatives
WO2000066555A1 (fr) * 1999-05-04 2000-11-09 American Home Products Corporation Derives de thio-oxindole
US6339098B1 (en) 1999-05-04 2002-01-15 American Home Products Corporation 2,1-benzisothiazoline 2,2-dioxides
US6355648B1 (en) 1999-05-04 2002-03-12 American Home Products Corporation Thio-oxindole derivatives
US6358948B1 (en) 1999-05-04 2002-03-19 American Home Products Corporation Quinazolinone and benzoxazine derivatives as progesterone receptor modulators
US6358947B1 (en) 1999-05-04 2002-03-19 American Home Products Corporation Tetracyclic progesterone receptor modulator compounds and methods
US6369056B1 (en) 1999-05-04 2002-04-09 American Home Products Corporation Cyclic urea and cyclic amide derivatives
US6380178B1 (en) 1999-05-04 2002-04-30 American Home Products Corporation Cyclic regimens using cyclocarbamate and cyclic amide derivatives
US6380235B1 (en) 1999-05-04 2002-04-30 American Home Products Corporation Benzimidazolones and analogues
US6391907B1 (en) 1999-05-04 2002-05-21 American Home Products Corporation Indoline derivatives
US6399593B1 (en) 1999-05-04 2002-06-04 Wyeth Cyclic regimens using cyclic urea and cyclic amide derivatives
US6407101B1 (en) 1999-05-04 2002-06-18 American Home Products Corporation Cyanopyrroles
US6417214B1 (en) 1999-05-04 2002-07-09 Wyeth 3,3-substituted indoline derivatives
US6423699B1 (en) 1999-05-04 2002-07-23 American Home Products Corporation Combination therapies using benzimidazolones
US6436929B1 (en) 1999-05-04 2002-08-20 Wyeth Cyclothiocarbamate derivatives as progesterone receptor modulators
US6441019B2 (en) 1999-05-04 2002-08-27 Wyeth Cyclocarbamate and cyclic amide derivatives
US6462032B1 (en) 1999-05-04 2002-10-08 Wyeth Cyclic regimens utilizing indoline derivatives
US6498154B1 (en) 1999-05-04 2002-12-24 Wyeth Cyclic regimens using quinazolinone and benzoxazine derivatives
US6503939B2 (en) 1999-05-04 2003-01-07 Wyeth Combination regimens using 3,3-substituted indoline derivatives
US6509334B1 (en) 1999-05-04 2003-01-21 American Home Products Corporation Cyclocarbamate derivatives as progesterone receptor modulators
US6521657B2 (en) 1999-05-04 2003-02-18 Wyeth Thio-oxindole derivatives
US6544970B2 (en) 1999-05-04 2003-04-08 Wyeth Cyclic regimens utilizing indoline derivatives
US6562857B2 (en) 1999-05-04 2003-05-13 Wyeth Cyanopyrroles
US6566358B2 (en) 1999-05-04 2003-05-20 Wyeth Cyclocarbamate derivatives as progesterone receptor modulators
US6583145B1 (en) 1999-05-04 2003-06-24 Wyeth Thio-oxindole derivatives
WO2000066556A1 (fr) * 1999-05-04 2000-11-09 American Home Products Corporation Derives d'indoline utilises comme antagonistes de progesterone
US6693103B2 (en) 1999-05-04 2004-02-17 Wyeth 1,2,3,4-tetrahydro-2-thioxo-quinolinyl and 1,2,3,4-tetrahydro-2-oxo-quinolinyl derivatives as progesterone receptor modulators
US6713478B2 (en) 1999-05-04 2004-03-30 Wyeth Cyclocarbamate derivatives as progesterone receptor modulators
US6329416B1 (en) 1999-05-04 2001-12-11 American Home Products Corporation Combination regimens using 3,3-substituted indoline derivatives
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US6946454B2 (en) 1999-05-04 2005-09-20 Wyeth Thio-oxindole derivatives
US6759408B2 (en) 1999-05-04 2004-07-06 Wyeth Combination regimens using progesterone receptor modulators
US6982261B2 (en) 1999-05-04 2006-01-03 Wyeth Cyanopyrroles
US7081457B2 (en) 1999-05-04 2006-07-25 Wyeth Cyclothiocarbamate derivatives as progesterone receptor modulators
US7186745B2 (en) 2001-03-06 2007-03-06 Astrazeneca Ab Indolone derivatives having vascular damaging activity
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US7645887B2 (en) 2003-03-31 2010-01-12 Ucb Pharma, S.A. Indolone-acetamide derivatives, processes for preparing them and their uses
US7964593B2 (en) 2003-03-31 2011-06-21 Ucb Pharma, S.A. Indolone-acetamide derivatives, processes for preparing them and their uses
WO2005118561A1 (fr) * 2004-05-27 2005-12-15 Ucb, S.A. Derives de benzoxazolone, procedes permettant de les preparer et de les utiliser
US8293775B2 (en) 2004-05-27 2012-10-23 Ucb Pharma, S.A. Benzoxazolone derivatives, processes for preparing them and their uses
US7632856B2 (en) 2004-07-22 2009-12-15 Ucb Pharma, S.A. Indolone derivatives, processes for preparing them and their uses
WO2006008067A1 (fr) * 2004-07-22 2006-01-26 Ucb, S.A. Derives d'indolone, leurs procedes de preparation et leurs utilisation
US7317037B2 (en) 2004-08-09 2008-01-08 Wyeth Progesterone receptor modulators comprising pyrrole-oxindole derivatives and uses thereof
WO2010090680A1 (fr) * 2008-12-15 2010-08-12 Wyeth Llc Agonistes de cb2 de type oxindole substitué
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CN103242332B (zh) * 2013-05-13 2015-11-04 江西科技师范大学 1-n酰基取代吲哚酮衍生物
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CN103242332A (zh) * 2013-05-13 2013-08-14 江西科技师范大学 1-n酰基取代吲哚酮衍生物
US10159648B2 (en) 2015-05-22 2018-12-25 Agenebio, Inc. Extended release pharmaceutical compositions of levetiracetam
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NO955074D0 (no) 1995-12-14
IS4167A (is) 1994-12-17
JPH08511515A (ja) 1996-12-03
CA2164119A1 (fr) 1994-12-22
NO955074L (no) 1996-02-07
FI956074A (fi) 1995-12-18
FI956074A0 (fi) 1995-12-18
EP0703901A1 (fr) 1996-04-03
AU7010894A (en) 1995-01-03
SE9302080D0 (sv) 1993-06-16

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