USRE38200E1 - Indole-2,3-dione-3-oxime derivatives - Google Patents

Indole-2,3-dione-3-oxime derivatives Download PDF

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USRE38200E1
USRE38200E1 US09/956,892 US95689201A USRE38200E US RE38200 E1 USRE38200 E1 US RE38200E1 US 95689201 A US95689201 A US 95689201A US RE38200 E USRE38200 E US RE38200E
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methyl
dione
phenyl
isoquinoline
tetrahydro
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Frank Watjen
Jorgen Drejer
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NTG Nordic Transport Group AS
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Neurosearch AS
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    • 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
    • C07D471/04—Ortho-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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • A61P25/08—Antiepileptics; Anticonvulsants
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • 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
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • 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
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • 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
    • A61P25/22—Anxiolytics
    • 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
    • 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
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to novel indole-2,3-dione-3-oxime derivatives capable of antagonising the effect of excitatory amino acids, such as glutamate.
  • the invention also relates to a method of preparing the chemical compounds of the invention, to pharmaceutical compositions comprising the chemical compounds, and a method of treatment herewith.
  • EAA excitatory amino acids
  • NMDA N-methyl-D-aspartate
  • AMPA alfa-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid
  • This excitotoxic action is responsible for the loss of neurones in cerebrovascular disorders such as cerebral ischemia or cerebral infarction resulting from a range of conditions, such as thromboembolic or haemorrhagic stroke, cerebral vasospasm, hypoglycaemia, cardiac arrest, status epilepticus, perinatal asphyxia, anoxia such as from near-drowning, pulmonary surgery and cerebral trauma as well as lathyrism, Alzheimer's, and Huntington's diseases.
  • Compounds capable of blocking excitatory amino acid receptors are therefore considered useful for the treatment of the above disorders and diseases, as well as Amyotrophic Lateral Sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain and drug addiction.
  • ALS Amyotrophic Lateral Sclerosis
  • the invention provides the novel indole-2,3-dione-3-oxime derivatives described in claim 1 .
  • the invention relates to the use of a chemical compound of the invention for the preparation of a pharmaceutical composition.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the chemical compound of the invention together and a pharmaceutically acceptable excipient, carrier or diluent.
  • the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists.
  • the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
  • a cerebrovascular disorder lathyrism
  • Alzheimer's disease Huntington's diseases
  • schizophrenia Parkinsonism
  • epilepsy anxiety, pain or drug addiction.
  • the invention provides a method of treating disorders or diseases of living animals, including humans, which are responsive to excitatory amino acid receptor antagonists, comprising administering to a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
  • the invention provides a method of treating a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
  • a cerebrovascular disorder lathyrism
  • Alzheimer's disease Huntington's diseases
  • amyotrophic lateral sclerosis ALS
  • schizophrenia Parkinsonism
  • epilepsy anxiety, pain or drug addiction.
  • the invention relates to the use of the chemical compound of the invention in a method of treating a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists, said method comprising administering to a living animal body, including a human, in need thereof an effective amount of the chemical compound.
  • the invention relates to the use of the chemical compound of the invention in a method of treating a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
  • a cerebrovascular disorder lathyrism
  • Alzheimer's disease Huntington's diseases
  • amyotrophic lateral sclerosis ALS
  • schizophrenia Parkinsonism
  • epilepsy anxiety, pain or drug addiction.
  • the invention provides a method of preparing a chemical compound of the invention.
  • the present invention provides novel indole-2,3-dione-3-oxime derivatives.
  • the novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (I):
  • R 1 represents hydrogen, alkyl or benzyl
  • R 3 represents “Het”, or a group of the following formula
  • Het represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo; and
  • R 31 , R 32 , and R 33 independently represents hydrogen, alkyl, or hydroxyalkyl, and at least one of R 31 , R 32 , and R 33 independently represents (CH 2 ) n R 34 ;
  • R 34 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, CONR 35 R 36 or “Het”;
  • R 35 and R 36 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalky, aryl, aralkyl, or (CH 2 ) n —R 37 ;
  • R 37 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; or
  • R 35 and R 36 together with the N-atom to which they are attached form a saturated 5- to 6-membered, heterocyclic ring, optionally containing one additional N or O atom;
  • n 0, 1, 2, or 3;
  • R 5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , NO 2 , amino, alkyl, alkoxy, phenyl and SO 2 NR 51 R 52 ,
  • R 51 and R 52 each independently represents hydrogen or alkyl
  • R 51 and R 52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom;
  • A represents a ring of five to seven atoms fused with the benzo ring at the positions marked “a” and “b”, and formed by the following bivalent radicals:
  • R 6 represents hydrogen, alkyl or CH 2 CH 2 OH; or a pharmaceutically acceptable salt thereof.
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (I), above, wherein “Het” is a lactone ring of the general formula (VI):
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II):
  • R 1 represents hydrogen, alkyl or benzyl
  • Het represents a saturated or unsaturated, 4 to 7 membered, monocyclic, heterocyclic ring, which ring may optionally be substituted one or more times with substituents selected from the group consisting of halogen, alkyl, alkoxy, and oxo;
  • n 0, 1, 2, or 3;
  • R 5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , NO 2 , amino, alkyl, alkoxy, phenyl and SO 2 NR 51 R 52 ; wherein
  • R 51 and R 52 each independently represents hydrogen or alkyl
  • R 51 and R 52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom;
  • A represents a ring of five to seven atoms fused with the benzo ring at the positions marked “a” and “b”, and formed by the following bivalent radicals:
  • R 6 represents hydrogen, alkyl or CH 2 CH 2 OH.
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II), above, wherein
  • n 0, 1 or2;
  • R 5 represents phenyl or pyridyl, both of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , NO 2 , amino, alkyl, alkoxy, phenyl and SO 2 NR 51 R 52 ; wherein
  • R 51 and R 52 each independently represents hydrogen or alkyl
  • R 51 and R 52 together with the N-atom to which they are attached form a chain —(CH 2 ) m —,
  • m 2, 3, 4, 5 or 6.
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (III):
  • R 1 , R 5 , R 6 , “Het”, and n are as defined above.
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (II), wherein
  • Het is a lactone of the general formula (VII):
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (IV):
  • R 1 represents hydrogen, alkyl or benzyl
  • R 31 , R 32 , and R 33 independently represents hydrogen, alkyl, or hydroxyalkyl
  • R 31 , R 32 , and R 33 independently represents (CH 2 ) n R 34 ;
  • R 34 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, or CONR 35 R 36 ; wherein
  • R 35 and R 36 represents hydrogen, alkyl, alkenyl, alkynyl, hydroxyalkyl, cycloalkyl, aryl, aralkyl, or (CH 2 ) n —R 37 ;
  • R 37 represents hydroxy, carboxy, alkoxycarbonyl, alkenyloxycarbonyl, alkynyloxycarbonyl, cycloalkoxycarbonyl, cycloalkyl-alkoxycarbonyl, aryloxycarbonyl, or aralkoxycarbonyl; or
  • R 35 and R 36 together with the N-atom to which they are attached form a saturated 5- to 6-membered, heterocyclic ring, optionally containing one additional N or O atom;
  • n 0, 1, 2, or 3;
  • R 31 , R 32 , and R 33 represents hydrogen or alkyl, and two of R 31 , R 32 , and R 33 together form a lactone ring of the general formula (VI):
  • n 1, 2 or 3;
  • R 5 represents phenyl, naphthyl, thienyl, or pyridyl, all of which may be substituted one or more times with substituents selected from the group consisting of halogen, CF 3 , NO 2 , amino, alkyl, alkoxy, phenyl and SO 2 NR 51 R 52 ; wherein
  • R 51 and R 52 each independently represents hydrogen or alkyl
  • R 51 and R 52 together with the N-atom to which they are attached form a saturated 4- to 7-membered, monocyclic, heterocyclic ring, optionally containing one additional N or O atom;
  • A represents a ring of five to seven atoms fused with the benzo ring at the positions marked “a” and “b”, and formed by the following bivalent radicals:
  • R represents hydrogen, alkyl or CH 2 CH 2 OH
  • novel indole-2,3-dione-3-oxime derivatives may be described by the general formula (V):
  • R 1 , R 31 , R 32 , R 33 , R 5 , and R 6 are as defined under formula (IV) above.
  • alkyl designates a straight chain or a branched chain containing of from one to six carbon atoms (C 1 -C 6 alkyl), including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl and hexyl.
  • alkyl represents a C 1 -C 4 alkyl, preferably a C 1 -C 3 alkyl, most preferred methyl, ethyl, propyl or isopropyl.
  • cycloalkyl designates a cyclic alkyl containing of from three to seven carbon atoms (C 3 -C 7 cycloalkyl), including but not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • alkenyl designates a group containing of from two to six carbon atoms (C 2 -C 6 alkenyl), including at least one double bond, for example, but not limited to ethenyl, 1,2- or 2,3-propenyl, 1,2-, 2,3-, or 3,4-butenyl.
  • alkynyl designates a group containing of from two to six carbon atoms (C 2 -C 6 alkynyl), including at least one triple bond, for example, but not limited to ethynyl, 1,2- or 2,3-propynyl, 1,2-, 2,3- or 3,4-butynyl.
  • cycloalkyl-alkyl designates a cycloalkyl as defined above which is attached to an alkyl as also defined above, e.g. cyclopropylmethyl.
  • aryl designates an aromatic hydrocarbon, such as phenyl or naphthyl.
  • aralkyl designates an aryl as defined above which is attached to an alkyl as also defined above, e.g. benzyl.
  • alkoxy designates an alkyl-O— where alkyl is as defined above.
  • alkoxycarbonyl designates an alkyl-O-CO— where alkyl is as defined above.
  • cycloalkoxycarbonyl designates a cycloalkyl-O-CO— where cycloalkyl is as defined above.
  • cycloalkyl-alkoxycarbonyl designates a cycloalkyl-alkyl-O-CO— where cycloalkylalkyl is as defined above.
  • alkenyloxycarbonyl designates an alkenyl-O-CO— where alkenyl is as defined above.
  • alkynyloxycarbonyl designates an alkynyl-O-CO— where alkenyl is as defined above.
  • aryloxycarbonyl designates an aryl-O-CO— where aryl is as defined above.
  • aralkoxycarbonyl designates an aralkyl-O-CO— where aralkyl is as defined above.
  • halogen represents fluorine, chlorine, bromine and iodine.
  • amino represents NH 2 , NH-alkyl, or N-(alkyl) 2 , wherein alkyl is as defined above.
  • novel indole-2,3-dione-3-oxime derivatives of the invention is
  • novel indole-2,3-dione-3-oxime derivatives of the invention is N-(2-aminoethyl)-2,3-dione-3-oxime derivatives of the invention.
  • Racemic forms can be resolved into the optical antipodes by known methods, for example, by separation of diastereomeric salts thereof, with an optically active acid, and liberating the optically active amine compound by treatment with a base. Another method for resolving racemates into the optical antipodes is based upon chromatography on an optical active matrix. Racemic compounds of the present invention can thus be resolved into their optical antipodes, e.g., by fractional crystallisation of d- or I- (tartrates, mandelates, or camphorsulphonate) salts for example.
  • the chemical compounds of the present invention may also be resolved by the formation of diastereomeric amides by reaction of the chemical compounds of the present invention with an optically active activated carboxylic acid such as that derived from (+) or ( ⁇ ) phenylalanine, (+) or ( ⁇ ) phenylglycine, (+) or ( ⁇ ) camphanic acid or by the formation of diastereomeric carbamates by reaction of the chemical compound of the present invention with an optically active chloroformate or the like.
  • an optically active activated carboxylic acid such as that derived from (+) or ( ⁇ ) phenylalanine, (+) or ( ⁇ ) phenylglycine, (+) or ( ⁇ ) camphanic acid
  • the chemical compounds of the invention may exist in two forms, syn- and anti-form, depending on the arrangement of the substituents around the —C ⁇ N— double bond.
  • a chemical compound of the present invention may thus be the syn- or the anti-form, or it may be a mixture hereof.
  • novel indole-2,3-dione-3-oxime derivatives of the invention may be provided in any form suitable for the intended administration. Suitable forms include pharmaceutically (i.e. physiologically) acceptable salts.
  • Examples of pharmaceutically acceptable addition salts include inorganic and organic acid addition salts such as the hydrochloride, hydrobromide, phosphate, nitrate, perchlorate, sulphate, citrate, lactate, tartrate, maleate, fumarate, mandelate, benzoate, ascorbate, cinnamate, benzenesulfonate, methanesulfonate, stearate, succinate, glutamate, glycollate, toluene-p-sulphonate, formate, malonate, naphthalene-2-sulphonate, salicylate and the acetate.
  • Such salts are formed by procedures well known in the art.
  • acids such as oxalic acid, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining a chemical compound of the invention and its pharmaceutically acceptable acid addition salt.
  • Metal salts of a chemical compound of the invention includes alkali metal salts, such as the sodium salt, of a chemical compound of the invention containing a carboxy group.
  • the chemical compound of the invention may be provided in solved or dissolved form together with a pharmaceutically acceptable solvents such as water, ethanol and the like.
  • a pharmaceutically acceptable solvents such as water, ethanol and the like.
  • solved forms are considered equivalent to dissolved forms for the purposes of this invention.
  • the invention provides novel pharmaceutical compositions comprising a therapeutically effective amount of the chemical compound of the invention.
  • a chemical compound of the invention for use in therapy may be administered in the form of the raw chemical compound, it is preferred to introduce the active ingredient, optionally in the form of a physiologically acceptable salt in a pharmaceutical composition together with one or more excipients, carriers and/or diluents.
  • the invention provides pharmaceutical compositions comprising the chemical compound of the invention or a pharmaceutically acceptable salt or derivative thereof together with one or more pharmaceutically acceptable carriers therefor and, optionally, other therapeutic and/or prophylactic ingredient.
  • the carrier(s) must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • compositions those suitable for oral, rectal, nasal, topical (including buccal and sub-lingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration, or in a form suitable for administration by inhalation or insufflation.
  • compositions and unit dosages thereof may thus be placed into the form of pharmaceutical compositions and unit dosages thereof, and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles, and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • Compositions containing ten (10) milligrams of active ingredient or, more broadly, 0.1 to one hundred (100) milligrams, per tablet, are accordingly suitable representative unit dosage forms.
  • the chemical compound of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a chemical compound of the invention or a pharmaceutically acceptable salt of a chemical compound of the invention.
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and more dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavouring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain from five or ten to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term “perparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as a mixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized moulds, allowed to cool, and thereby to solidify.
  • compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid preparations include solutions, suspensions, and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • the chemical compound according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavours, stabilising and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavours, stabilisers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the chemical compound according to the invention may be formulated as ointments, creams or lotions, or as a transdermal patch.
  • Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents.
  • Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilising agents, dispersing agents, suspending agents, thickening agents, or colouring agents.
  • compositions suitable for topical administration in the mouth include lozenges comprising the active agent in a flavoured base, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
  • Solutions or suspensions are applied directly to the nasal cavity by conventional means, for example with a dropper, pipette or spray.
  • the compositions may be provided in single or multi-dose form. In the latter case of a dropper or pipette, this may be achieved by the patient administering an appropriate, predetermined volume of the solution or suspension. In the case of a spray, this may be achieved for example by means of a metering atomising spray pump.
  • Administration to the respiratory tract may also be achieved by means of an aerosol formulation in which the active ingredient is provided in a pressurised pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide, or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by provision of a metered valve.
  • the active ingredients may be provided in the form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • a powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidone (PVP).
  • PVP polyvinylpyrrolidone
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin, or blister packs from which the powder may be administered by means of an inhaler.
  • the compound In compositions intended for administration to the respiratory tract, including intranasal compositions, the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • compositions adapted to give sustained release of the active ingredient may be employed.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in package form.
  • Tablets or capsules for oral administration and liquids for intravenous administration and continuous infusion are preferred compositions.
  • novel indole-2,3-dione-3-oxime derivatives and the pharmaceutically acceptable salts of the invention possess valuable therapeutic properties.
  • novel indole-2,3-dione-3-oxime derivatives of the invention are excitatory amino acid antagonists and useful in the treatment of disorders or diseases of mammals, including humans, which are responsive to excitatory amino acid receptor antagonists.
  • excitatory amino acid antagonists and useful in the treatment of disorders or diseases of mammals, including humans, which are responsive to excitatory amino acid receptor antagonists.
  • the same biological activity applies to physiologic metabolites of the novel indole-2,3-dione-3-oxime derivatives of the invention.
  • the chemical compound of this invention is useful in the treatment of central nervous system disorders related to their biological activity. More particularly the novel indole-2,3-dione-3-oxime derivatives of the invention show strong excitatory amino acid (EAA) antagonising properties at the AMPA ((RS)-alfa-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) binding site.
  • EAA excitatory amino acid
  • the chemical compound of this invention may accordingly be administered to a subject, including a human, in need of treatment, alleviation, or elimination of a disorder or disease associated with the biological activity of the compound.
  • a disorder or disease associated with the biological activity of the compound includes especially cerebral ischaemia, cerebral infarction, excitatory amino acid dependent, including glutamate and/or aspartate dependent Lathyrism, Alzheimer's and Huntington's diseases, Amyotropic Lateral sclerosis, phychosis, Parkinsonism, epilepsy, anxiety, pain (migraine), drug addiction and convulsions.
  • the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment of a disorder or disease of a mammal, including a human, which disorder or disease is responsive to glutamic and/or aspartic acid receptor antagonists.
  • the invention relates to the use of a chemical compound of the invention for the manufacture of a pharmaceutical composition for the treatment a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
  • a cerebrovascular disorder lathyrism
  • Alzheimer's disease Huntington's diseases
  • schizophrenia Parkinsonism
  • epilepsy anxiety, pain or drug addiction.
  • the invention provides a method of treating disorders or diseases of living animals, including humans, which are responsive to excitatory amino acid receptor antagonists, comprising administering to a living animal body, including a human, in need thereof an effective amount of a chemical compound of the invention.
  • the invention provides a method of treating a cerebrovascular disorder, lathyrism, Alzheimer's disease, Huntington's diseases, amyotrophic lateral sclerosis (ALS), schizophrenia, Parkinsonism, epilepsy, anxiety, pain or drug addiction.
  • a cerebrovascular disorder lathyrism
  • Alzheimer's disease Huntington's diseases
  • amyotrophic lateral sclerosis ALS
  • schizophrenia Parkinsonism
  • epilepsy anxiety, pain or drug addiction.
  • Suitable dosage ranges are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and especially 30-100 milligrams daily, dependent as usual upon the exact mode of administration, form in which administered, the indication toward which the administration is directed, the subject involved and the body weight of the subject involved, and further the preference and experience of the physician or veterinarian in charge.
  • novel indole-2,3-dione-3-oxime derivatives of the invention may be prepared by conventional methods of chemical synthesis, e.g. those described in the working examples.
  • the starting materials for the processes described in the present application are known or may readily be prepared by conventional methods from commercially available chemicals.
  • the end products of the reactions described herein may be isolated by conventional techniques, e.g. by extraction, crystallisation, distillation, chromatography, etc.
  • the invention provides a method of preparing a chemical compound of the invention which comprises the step of reacting a compound having the general formula
  • R 3 and m have the meanings set forth above, optionally followed by converting the thus obtained compound to another compound of the invention or to a pharmaceutically acceptable salt hereof by using conventional methods.
  • the isoquinoline salt (3.9 mmol) was dissolved in acetic acid (10 mL) and sodium borohydride (0.15 g, 3.97 mmol) was added. After stirring for 24 h, the reaction mixture was diluted with a mixture of ethyl acetate and water and potassium carbonate was added portion-wise to neutralise the acetic acid. The aqueous layer was extracted with ethyl acetate (2x), washed with saturated NaCl, dried over MgSO 4 , filtered and evaporated.
  • N-ethyl-5-bromo-8-nitro-1,2,3,4-tetrahydroisoquinoline was prepared according to the same procedure. M.p. 52-53° C.
  • 8-amino-2-methyl-5-phenyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride m.p. 210-21° C.
  • 8-amino-2-methyl-5-(4-fluorophenyl)-1,2,3,4-tetrahydro-isoquinoline m.p. 141° C.
  • 8-amino-2-methyl-5-(4-trifluoromethylphenyl)-1,2,3,4-tetrahydro-isoquinoline m.p. 132-134° C.
  • 8-amino-2-methyl-5-(4-chlorophenyl)-1,2,3,4-tetrahydro-isoquinoline hydrochloride m.p. 213-215° C.
  • N-(2-bromoethoxy)phtalimide was prepared analogously from 1,2-dibromoethane and N-hydroxyphtalimide.
  • ⁇ -Phthalimidooxy- ⁇ -butyrolactone (1.0 g, 4 mmol) was added to hydrochloric acid (1M, 10 mL) at reflux. After 5 min. at reflux for 5 min and the reaction was cooled down on an ice bath and filtered. The filtrate was evaporated to dryness. Toluene was added and residual water removed axeotropic distillation. 0.75 g of the desired material was obtained.
  • GLU L-glutamate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • NMDA N-methyl-D-aspartate
  • quisqualate receptors kainate receptors.
  • AMPA has been known for several years to be a potent and selective agonist at the traditionally named quisqualate receptors. Activation of quisqualate receptors by AMPA is associated with Na + influx and K + efflux leading to depolarisation.
  • 3 H-AMPA is a selective radioligand for labelling the ionotropic quisqualate (AMPA) receptors.
  • Cerebral cortex from male Wistar rats (150-200 g) is homogenised for 5-10 sec in 20 ml Tris-HCl (30 mM, pH 7.4) using an Ultra-TurraxTM homogeniser. The suspension is centrifuged at 27,000 ⁇ g for 15 minutes and the pellet is washed three times with buffer (centrifuged at 27,000 ⁇ g for 10 minutes). The washed pellet is homogenised in 20 ml of buffer and incubated on a water bath (of 37° C.) for 30 minutes to remove endogenous glutamate and then centrifuged for 10 minutes at 27,000 ⁇ g. The pellet is then homogenised in buffer and centrifuged at for 10 minutes at 27,000 ⁇ g. The final pellet is resuspended in 30 ml buffer and the preparation is frozen and stored at ⁇ 20° C.
  • the membrane preparation is thawed and centrifuged at 2° C. for 10 minutes at 27,000 ⁇ g.
  • the pellet is washed twice with 20 ml 30 mM Tris-HCl containing 2.5 mM CaCl 2 , pH 7.4, using an Ultra-TurraxTM homogeniser and centrifuged for 10 minutes at 27,000 ⁇ g.
  • the final pellet is resuspended in 30 mM Tris-HCl containing 2.5 mM CaCl 2 and 100 mM KSCN, pH 7.4 (100 ml per g of original tissue) and used for binding assays.
  • the 550 ⁇ l samples are added 5 ml of ice-cold buffer and poured directly onto WhatmanTM GF/C glass fibre filters under suction and immediately washed with 5 ml of ice-cold buffer.
  • the 240 ⁇ l samples are filtered over glass fibre filter using a SkatronTM cell harvester.
  • the filters are washed with 3 ml ice-cold buffer.
  • the amount of radioactivity on the filters is determined by conventional liquid scintillation counting. Specific binding is total binding minus non-specific binding.
  • the test value is given as the IC 50 (the concentration ( ⁇ M) of the test substance which inhibits the specific binding of 3 H-AMPA by 50%).

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7288653B2 (en) 1999-05-19 2007-10-30 Painceptor Pharma Corporation Inhibitors of proton-gated cation channels and their use in the treatment of ischaemic disorders
US20100041691A1 (en) * 2006-09-12 2010-02-18 Neurosearch A/S Pharmaceutical compositions comprising combinations of an ampa/kainate antagonistic compound and an inhibitor of a multidrug resistance protein

Families Citing this family (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA54403C2 (uk) * 1996-10-01 2003-03-17 Н'Юросерч А/С Похідні індол-2,3-діон-3-оксиму, фармацевтична композиція, спосіб лікування розладу чи захворювання ссавців, у тому числі людини та спосіб одержання похідних індол-2,3-діон-3-оксиму
DE69922936T2 (de) 1998-03-31 2005-12-08 Neurosearch A/S Verwendung von indol-2,3-dione-3-oximderivate als ampa-antagonisten
CN1298704C (zh) * 2000-01-24 2007-02-07 神经研究公司 具有神经营养活性的靛红衍生物
IT1318636B1 (it) * 2000-07-21 2003-08-27 Roberto Pellicciari Derivati dell'acido 2- o 3- tenoico ad attivita' antagonista deirecettori del glutammato.
JP2004523543A (ja) * 2001-02-15 2004-08-05 ニューロサーチ、アクティーゼルスカブ 神経栄養活性を有する化合物とドパミン活性を増加させる化合物の組み合わせ作用によるパーキンソン病の治療法
MXPA04000358A (es) 2001-07-13 2004-05-04 Pharmacia & Up John Company Hexahidroazepino (4,5-g) indoles e indolinas como ligandos del receptor 5-ht.
AU2003250323A1 (en) * 2002-08-22 2004-03-11 Neurosearch A/S A method of preparing enantiomers of indole-2,3-dione-3-oxime derivatives
GB0507298D0 (en) 2005-04-11 2005-05-18 Novartis Ag Organic compounds
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US20080108622A1 (en) * 2006-10-19 2008-05-08 Eisenach James C Combination therapy for the treatment of pain
US20080108603A1 (en) * 2006-10-19 2008-05-08 Eisenach James C Combination therapy for the treatment of pain
WO2010104324A2 (ko) * 2009-03-10 2010-09-16 한국과학기술연구원 베타-아밀로이드 집적체 및 피브릴에 우수한 결합 친화도를 가지는 할로겐화 이소인돌론 화합물, 및 이의 제조 방법 및 용도
CN102653538A (zh) * 2011-03-04 2012-09-05 爱斯医药科技(南京)有限公司 Spd-502的制备方法
WO2016176463A1 (en) * 2015-04-29 2016-11-03 Janssen Pharmaceutica Nv Indolone compounds and their use as ampa receptor modulators
BR112017023147B1 (pt) 2015-04-29 2024-04-30 Rapport Therapeutics, Inc Derivados de azabenzimidazóis, seus usos como moduladores do receptor de ampa e composições farmacêuticas
JP6804469B2 (ja) 2015-04-29 2020-12-23 ヤンセン ファーマシューティカ エヌ．ベー． ベンゾイミダゾロン及びベンゾチアゾロン化合物並びにａｍｐａ受容体調節因子としてのそれらの使用
CN107567452B (zh) 2015-04-29 2020-07-07 詹森药业有限公司 咪唑并哌嗪和吡唑并嘧啶以及它们作为ampa受体调节剂的用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0529636A1 (en) * 1991-08-28 1993-03-03 Neurosearch A/S Novel isatinoxime derivatives, their preparation and use
WO1994026747A1 (en) * 1993-05-13 1994-11-24 Neurosearch A/S Ampa antagonists and a method of treatment therewith
EP0633262A1 (en) * 1993-07-07 1995-01-11 Neurosearch A/S Novel isatineoxime derivatives, their preparation and use
WO1996008495A1 (en) * 1994-09-14 1996-03-21 Neurosearch A/S Fused indole and quinoxaline derivatives, their preparation and use
WO1996008494A1 (en) * 1994-09-14 1996-03-21 Neurosearch A/S Indole-2,3-dione-3-oxime derivatives, their preparation and use
US5721230A (en) 1993-05-10 1998-02-24 Hoffmann-La Roche Inc. Substituted pyrroles

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE69677B1 (en) * 1989-12-11 1996-10-02 Neurosearch As Isatine derivatives their preparation and use
TW281669B (cs) * 1993-02-17 1996-07-21 Chugai Pharmaceutical Co Ltd
UA54403C2 (uk) * 1996-10-01 2003-03-17 Н'Юросерч А/С Похідні індол-2,3-діон-3-оксиму, фармацевтична композиція, спосіб лікування розладу чи захворювання ссавців, у тому числі людини та спосіб одержання похідних індол-2,3-діон-3-оксиму

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0529636A1 (en) * 1991-08-28 1993-03-03 Neurosearch A/S Novel isatinoxime derivatives, their preparation and use
US5721230A (en) 1993-05-10 1998-02-24 Hoffmann-La Roche Inc. Substituted pyrroles
WO1994026747A1 (en) * 1993-05-13 1994-11-24 Neurosearch A/S Ampa antagonists and a method of treatment therewith
EP0633262A1 (en) * 1993-07-07 1995-01-11 Neurosearch A/S Novel isatineoxime derivatives, their preparation and use
WO1996008495A1 (en) * 1994-09-14 1996-03-21 Neurosearch A/S Fused indole and quinoxaline derivatives, their preparation and use
WO1996008494A1 (en) * 1994-09-14 1996-03-21 Neurosearch A/S Indole-2,3-dione-3-oxime derivatives, their preparation and use
US5801174A (en) * 1994-09-14 1998-09-01 Neurosearch A/S Fused indole and quinoxaline derivatives, their preparation and use
US5917053A (en) * 1994-09-14 1999-06-29 Neurosearch A/S Indole-2,3-dione-3-oxime derivatives, their preparation and use

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
JPET, Nielsen et al., vol. 289(3), pp. 1492-1501, 1999. *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7288653B2 (en) 1999-05-19 2007-10-30 Painceptor Pharma Corporation Inhibitors of proton-gated cation channels and their use in the treatment of ischaemic disorders
US20080269230A1 (en) * 1999-05-19 2008-10-30 Painceptor Pharma Corporation Inhibitors of proton-gated cation channels and their use in the treatment of ischaemic disorders
US20100041691A1 (en) * 2006-09-12 2010-02-18 Neurosearch A/S Pharmaceutical compositions comprising combinations of an ampa/kainate antagonistic compound and an inhibitor of a multidrug resistance protein

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