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WO1998045293A1 - Composes de pyrimido-isoquinoline a action anticonvulsive - Google Patents

Composes de pyrimido-isoquinoline a action anticonvulsive Download PDF

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Publication number
WO1998045293A1
WO1998045293A1 PCT/EP1998/002139 EP9802139W WO9845293A1 WO 1998045293 A1 WO1998045293 A1 WO 1998045293A1 EP 9802139 W EP9802139 W EP 9802139W WO 9845293 A1 WO9845293 A1 WO 9845293A1
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WO
WIPO (PCT)
Prior art keywords
pyrimido
dihydro
dimethoxy
isoquinolin
disorders
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.)
Ceased
Application number
PCT/EP1998/002139
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English (en)
Inventor
Barry Sidney Orlek
Peter Ainsworth
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SmithKline Beecham Ltd
Original Assignee
SmithKline Beecham Ltd
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Filing date
Publication date
Application filed by SmithKline Beecham Ltd filed Critical SmithKline Beecham Ltd
Priority to CA002286452A priority Critical patent/CA2286452A1/fr
Priority to JP54240998A priority patent/JP2001519798A/ja
Priority to EP98919259A priority patent/EP0973773A1/fr
Publication of WO1998045293A1 publication Critical patent/WO1998045293A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61P25/06—Antimigraine agents
    • 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
    • A61P25/20—Hypnotics; Sedatives
    • 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
    • A61P25/24—Antidepressants
    • 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

Definitions

  • This invention relates to a novel method of treatment and to novel compounds for use in that method.
  • pyrimidoisoquinolinone derivatives of formula (I) below possess anti-convulsant activity and are therefore believed to be useful in the treatment and/or prevention of anxiety, mania, depression, panic disorders and/or aggresssion, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS).
  • the present invention provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggresssion, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post- traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction or amyotrophic lateral sclerosis (ALS); comprising administering to the sufferer in need thereof an effective or prophylactic amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof:
  • R is hydrogen or up to three substituents independently selected from halogen
  • R is hydrogen or Ci _g alkyl
  • R is R 3 or R 3 CO where
  • R is C3_7 cycloalkyl, phenyl or phenyl C ⁇ _ 6 alkyl in which the cyclic moieties are optionally substituted by up to three substituents independently selected from halogen, C j .g alkyl , C j _ 6 alkoxy, C j _ 6 alkylcarbonyl, hydroxy C ⁇ 6 alkyl and phenylcarbonyloxy C j _ 6 alkyl.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo.
  • Alkyl groups alone or as part of another group are typically methyl, ethyl, n- or is ⁇ -propyl, or n-, iso- or t-butyl.
  • Cycloalkyl groups are typically cyclopentyl, cyclohexyl or cycloheptyl.
  • R as hydrogen or methoxy
  • R ⁇ as hydrogen or methyl 3 R as cyclopentyl, phenyl, benzyl or phenyl substituted by one or two chloro, iodo, methyl, methoxy, w ⁇ -propyl,acetyl, hydroxymethyl or phenylcarbonyloxymethyl groups.
  • these compounds When synthesised, these compounds may be in salt form, and such salts also form part of this invention. Such salts may be used in preparing pharmaceutically acceptable salts.
  • the compounds and their salts may be obtained as solvates, such as hydrates, and these also form part of this invention.
  • administration of such compounds to a mammal may be by way of oral, parenteral, sub-lingual, nasal, rectal, topical, or transdermal administration.
  • a unit dose will normally contain 1 to 1000 mg, suitably 1 to 500 mg, for example an amount in the range of from 2 to 400 mg such as 2, 5, 10, 20, 30, 40, 50, 100i 200, 300 and 400 mg of the active compound.
  • Unit doses will normally be administered once or more than once per day, for example 1, 2, 3, 4, 5 or 6 times a day, more usually 1 to 4 times a day, such that the total daily dose is normally in the range, for a 70 kg adult of 1 to 1000 mg, for example 1 to 500 mg, that is in the range of approximately 0.01 to 15 mg/kg/day, more usually 0.1 to 6 mg/kg/day, for example 1 to 6 mg/kg/day.
  • the compound of formula (I) is administered in the form of a unit-dose composition, such as a unit dose oral, including sub-lingual, nasal, rectal, topical, transdermal or parenteral (especially intravenous) composition.
  • a unit dose oral including sub-lingual, nasal, rectal, topical, transdermal or parenteral (especially intravenous) composition.
  • compositions are prepared by admixture and are suitably adapted for oral or parenteral administration, and as such may be in the form of tablets, capsules, oral liquid preparations, powders, granules, lozenges, reconstitutable powders, injectable and infusable solutions or suspensions or suppositories.
  • Orally administrable compositions are preferred, in particular shaped oral compositions, since they are more convenient for general use.
  • Tablets and capsules for oral administration are usually presented in a unit dose, and contain conventional excipients such as binding agents, fillers, diluents, tabletting agents, lubricants, disintegrants, colourants, flavourings, and wetting agents.
  • the tablets may be coated according to well known methods in the art.
  • Suitable fillers for use include cellulose, mannitol, lactose and other similar agents.
  • Suitable disintegrants include starch, polyvinylpyrrolidone and starch derivatives such as sodium starch glycollate.
  • Suitable lubricants include, for example, magnesium stearate.
  • Suitable pharmaceutically acceptable wetting agents include sodium lauryl sulphate.
  • solid oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are, of course, conventional in the art.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Oral formulations also include conventional sustained release formulations, such as tablets or granules having an enteric coating.
  • fluid unit dose forms are prepared containing the compound and a sterile vehicle.
  • the compound depending on the vehicle and the concentration, can be either suspended or dissolved.
  • Parenteral solutions are normally prepared by dissolving the compound in a vehicle and filter sterilising before filling into a suitable vial or ampoule and sealing.
  • adjuvants such as a local anaesthetic, preservatives and buffering agents are also dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound of the invention.
  • the compositions will usually be accompanied by written or printed directions for use in the medical treatment concerned.
  • the present invention provides a pharmaceutical composition for use in the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggresssion, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and/or amyotrophic lateral sclerosis (ALS); which comprises a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.
  • ALS amyotrophic lateral sclerosis
  • the invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggresssion, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with AIDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy), tics (e.g.
  • epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer'
  • R is respectively R as defined for formula (I) or a group convertible to R with either
  • formula (II) is NR H (for compounds of formula (I) in which R is R CO),
  • R and R are respectively R and R as defined for formula (I) or a group
  • Reaction (a) is typically carried out by heating the reactants together, preferably under reflux in a suitable inert solvent, such as chloroform optionally in the presence of a tertiary amine base such as 2,6-lutidine.
  • a suitable inert solvent such as chloroform
  • a tertiary amine base such as 2,6-lutidine
  • Reaction (b) may be carried out under conventional conditions for condensing amines with acid chlorides, in the present case typically by mixing the reactants together at room temperature in a suitable inert solvent, such as chloroform optionally in the presence of a suitable tertiary amine base or catalyst such as N,N-dimethylamino-pyridine.
  • a suitable inert solvent such as chloroform
  • a suitable tertiary amine base or catalyst such as N,N-dimethylamino-pyridine.
  • the urea may be converted to an N-substituted barbituric acid by adding the urea to a mixture of sodium ethoxide and diethyl malonate in a suitable solvent, such as ethanol.
  • a suitable solvent such as ethanol.
  • the resultant barbituric acid may be heated with phosphorus oxychloride to obtain a compound of formula (II) in which X is chlorine.
  • Other halogen derivatives can be prepared by analogous procedures.
  • a compound of formula (LI) in which X is chlorine (which is a 6,7- dihydro-pyrimido-isoquinolin-4-one) may be prepared by reaction of phosphorus oxychloride with the corresponding 2,4-dione using a method similar to that of G.A.Howarth, Heterocycles, 1989, 29, 1929.
  • the dione may be prepared by heating an appropriately substituted N-phenylethyl cyanoacetamide in polyphosphoric acid.
  • R is hydrogen or up to three substituents independently selected from halogen
  • R is hydrogen or C ⁇ .g alkyl
  • R is C3.7 cycloalkyl, phenyl or phenyl C ⁇ _ 6 alkyl in which the cyclic moieties are optionally substituted by up to three substituents independently selected from halogen, C g alkyl, C j .g alkoxy, C j .g alkylcarbonyl, hydroxy C ⁇ 6 alkyl and phenylcarbonyloxy C j __ 6 alkyl.
  • a further aspect of this invention is the preparation of the above novel compounds by the
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising any novel compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier; and also the use of any novel compound of this invention, or a pharmaceutically acceptable salt or solvate thereof, as a therapeutic agent, in particular for the treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggression, disorders associated with a subarachnoid haemorrhage or neural shock, the effects associated with withdrawal from substances of abuse such as cocaine, nicotine, alcohol and benzodiazepines, disorders treatable and/or preventable with anti-convulsive agents, such as epilepsy including post-traumatic epilepsy, Parkinson's disease, psychosis, migraine, cerebral ischaemia, Alzheimer's disease and other degenerative diseases such as Huntingdon's chorea, schizophrenia, obsessive compulsive disorders (OCD), neurological deficits associated with ALDS, sleep disorders (including circadian rhythm disorders, insomnia & narcolepsy),
  • Giles de la Tourette's syndrome traumatic brain injury, tinnitus, neuralgia, especially trigeminal neuralgia, neuropathic pain, dental pain, cancer pain, inappropriate neuronal activity resulting in neurodysthesias in diseases such as diabetes, MS and motor neurone disease, ataxias, muscular rigidity (spasticity), temporomandibular joint dysfunction and amyotrophic lateral sclerosis (ALS).
  • N-Phenylethyl cyanoacetamide (0.5g) in polyphosphoric acid (20g) was heated at 110°C for 20h [as outlined in Hoechst patent US 4482556 (1984)]. The mixture was poured into water and then extracted with chloroform. The aqueous layer was neutralised with 40% NaOH, with ice cooling, and the product extracted into dichloromethane. The material (260mg) from the organic layer was dissolved in ethanol (5ml) and added to a freshly prepared solution of ethanoUc sodium ethoxide (73mg of sodium in ethanol 30ml). The mixture was stirred for 30 min and diethyl carbonate (2ml) was added. The mixture was heated under reflux for 6h and then ice was added and the pH adjusted to 7 with 5N HCl. The resultant white precipitate was removed by filtration and dried (0.19g).
  • WO 92/22293 discloses compounds having anti-convulsant activity, including inter alia the compound tr ⁇ n-?-(+)-6-acetyl-4S-(4-fluorobenzoylamino)- 3,4-dihydro-2,2-dimethyl-2H-l-benzopyran-3R-ol (hereinafter referred to as Compound A). It has been found that the compounds of WO 92/22293 bind to a novel receptor obtainable from rat forebrain tissue, as described in WO 96/18650 (SmithKline Beecham). The affinity of test compounds to the novel receptor site is assessed as follows.
  • Whole forebrain tissue is obtained from rats.
  • the tissue is first homogenised in buffer (usually 50mM Tris/HCl, pH 7.4).
  • the homogenised tissue is washed by centrifugation and resuspension in the same buffer, then stored at -70°C until used.
  • the affinity of the binding of test compounds to the novel site can be estimated by incubating together [3H] -Compound A and tissue in the presence of a range of concentrations of the compound to be tested.
  • the decrease in the level of specific [3H]- Compound A binding as a result of competition by increasing concentrations of the compound under test is plotted graphically, and non-linear regression analysis of the resultant curve is used to provide an estimate of compound affinity in terms of pKi value.
  • the maximal electroshock seizure (MEST) threshold test in rodents is particularly sensitive for detecting potential anticonvulsant properties 1 .
  • anticonvulsant agents elevate the threshold to electrically-induced seizures whilst proconvulsants lower the seizure threshold.
  • mice (naive male, Charles River, U.K. CD-I strain, 25 - 30g) are randomly assigned to groups of 10 - 20 and dosed orally or intraperitoneally at a dose volume of 10 ml/kg with various doses of compound (0.3 - 300 mg/kg) or vehicle. Mice are then subjected at 30 or 60 min post dose to a single electroshock (0.1 sec, 50Hz, sine wave form) administered via corneal electrodes. The mean current and standard error required to induce a tonic seizure in 50% (CC50) of the mice in a particular treatment group is determined by the 'up and down' method of Dixon and Mood (1948)2. Statistical comparisons between vehicle- and drug-treated groups are made using the method of Litchfield and Wilcoxon (1949)3.
  • the CC50 In control animals the CC50 is usually 14 - 18 mA. Hence the first animal in the control group is subjected to a current of 16 mA. If a tonic seizure does not ensue, the current is increased for a subsequent mouse. If a tonic convulsion does occur, then the current is decreased, and so on until all the animals in the group have been tested.
  • the percentage increase or decrease in CC50 for each group compared to the control is calculated.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Biomedical Technology (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Psychiatry (AREA)
  • Pain & Pain Management (AREA)
  • Psychology (AREA)
  • Addiction (AREA)
  • Anesthesiology (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Abstract

L'invention porte sur une nouvelle méthode de traitement consistant à administrer au patient le nécessitant une dose efficace ou prophylactique d'un composé de formule (I) ou de ses sels ou solvates pharmacocompatibles. Dans ladite formule: R1 est H, ou jusqu'à trois substituants choisis indépendamment parmi halogène, C¿1-6? alkyle, C1-6 alkoxy, C1-6 alkylcarbonyle et hydroxy C1-6 alkyle, ou bien deux groupes R?1¿ forment un méthylènedioxy; R2 est H ou C¿1-6? alkyle, et R est R?3 ou R3¿CO, où R3 est C¿3-7? cycloalkyle, phényle ou phényle C1-6 alkyle dans lequel les fragments cycliques sont facultativement substitués par jusqu'à trois substituants choisis indépendamment parmi halogène, C1-6 alkyle, C1-6 alkoxy, C1-6 alkylcarbonyle, hydroxy C1-6 alkyle et phénylcarbonyloxy C1-6 alkyle. Ledit composé assure le traitement ou la prophylaxie de: l'anxiété, de la manie, de la dépression, des troubles liés à la panique ou au comportement agressif, des troubles associés à l'hémorragie méningée, au choc neural, des troubles liés à la désintoxication (cocaïne, nicotine, alcool et benzodiapézine) et pouvant être traités ou prévenus par des agents anticonvulsifs (dont l'épilepsie et l'épilepsie post traumatique), de la maladie de Parkinson, des psychoses, de la migraine, de l'ischémie cérébrale, de la maladie d'Alzheimer et autres affections dégénératives (dont la chorée de Huntingdon), de la schizophrénie, des névroses obsessionnelles, des troubles neurologiques associés au SIDA, des troubles du sommeil (dont les troubles du rythme circadien, l'insomnie et la narcolepsie), des tics (dont le syndrome de Gilles de la Tourette), des lésions traumatiques du cerveau, des acouphènes, des névralgies (y compris les névralgies faciales), des douleurs névropathiques, des douleurs dentaires, des douleurs cancéreuses, de l'activité anormale des neurones conduisant à la neurodysthésie dans des maladies telles que le diabète, des maladies de l'AM et des neurones moteurs, de l'ataxie, de la raideur musculaire (spasticité), du dysfonctionnement de l'articulation temporo-mandibulaire, et de la sclérose latérale amyotrophique.
PCT/EP1998/002139 1997-04-10 1998-04-03 Composes de pyrimido-isoquinoline a action anticonvulsive Ceased WO1998045293A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002286452A CA2286452A1 (fr) 1997-04-10 1998-04-03 Composes de pyrimido-isoquinoline a action anticonvulsive
JP54240998A JP2001519798A (ja) 1997-04-10 1998-04-03 抗痙攣作用を有するピリミド−イソキノリン化合物
EP98919259A EP0973773A1 (fr) 1997-04-10 1998-04-03 Composes de pyrimido-isoquinoline a action anticonvulsive

Applications Claiming Priority (2)

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GBGB9707251.6A GB9707251D0 (en) 1997-04-10 1997-04-10 Novel method and compounds
GB9707251.6 1997-04-10

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WO1998045293A1 true WO1998045293A1 (fr) 1998-10-15

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JP (1) JP2001519798A (fr)
CA (1) CA2286452A1 (fr)
GB (1) GB9707251D0 (fr)
WO (1) WO1998045293A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7501512B2 (en) 2003-07-08 2009-03-10 Smithkline Beecham Corporation Chemical compounds
WO2012037782A1 (fr) * 2010-09-20 2012-03-29 Glaxo Group Limited Composés tricycliques, leurs procédés de préparation et leurs utilisations
US12168011B2 (en) 2022-02-21 2024-12-17 Verona Pharma Plc Formulation production process
US12251384B1 (en) 2023-06-26 2025-03-18 Verona Pharma Plc Particulate composition

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EP0370379A1 (fr) * 1988-11-19 1990-05-30 Hoechst Aktiengesellschaft Compositions pharmaceutiques contenant des dérivés di-terpénoidiques de labdane et des dérivés de la pyrimido(6,1-a)isoquinolin-4-one et leur application
US5114944A (en) * 1991-04-12 1992-05-19 A. H. Robins Company Incorporated 2-phenylpyrazolo[1,5-a]pyrimidine-3-acetic acid derivatives exhibiting therapeutic effects

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7501512B2 (en) 2003-07-08 2009-03-10 Smithkline Beecham Corporation Chemical compounds
WO2012037782A1 (fr) * 2010-09-20 2012-03-29 Glaxo Group Limited Composés tricycliques, leurs procédés de préparation et leurs utilisations
US8871928B2 (en) 2010-09-20 2014-10-28 Glaxo Group Limited Tricyclic compounds, preparation methods, and their uses
US12168011B2 (en) 2022-02-21 2024-12-17 Verona Pharma Plc Formulation production process
US12409180B2 (en) 2022-02-21 2025-09-09 Verona Pharma Plc Formulation production process
US12251384B1 (en) 2023-06-26 2025-03-18 Verona Pharma Plc Particulate composition

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EP0973773A1 (fr) 2000-01-26
JP2001519798A (ja) 2001-10-23
GB9707251D0 (en) 1997-05-28
CA2286452A1 (fr) 1998-10-15

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