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WO1998046574A1 - Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs - Google Patents

Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs Download PDF

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Publication number
WO1998046574A1
WO1998046574A1 PCT/EP1998/002172 EP9802172W WO9846574A1 WO 1998046574 A1 WO1998046574 A1 WO 1998046574A1 EP 9802172 W EP9802172 W EP 9802172W WO 9846574 A1 WO9846574 A1 WO 9846574A1
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WO
WIPO (PCT)
Prior art keywords
amine
phenyl
phthalazin
disorders
formula
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/EP1998/002172
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English (en)
Inventor
John David Harling
Hugh Jonathan Herdon
Barry Sidney Orlek
Mervyn Thompson
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SmithKline Beecham Ltd
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SmithKline Beecham Ltd
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Priority to CA002288171A priority Critical patent/CA2288171A1/fr
Priority to JP54349098A priority patent/JP2001518908A/ja
Priority to EP98920520A priority patent/EP0975605A1/fr
Publication of WO1998046574A1 publication Critical patent/WO1998046574A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/26—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings condensed with carbocyclic rings or ring systems
    • C07D237/30—Phthalazines
    • C07D237/34—Phthalazines with nitrogen atoms directly attached to carbon atoms of the nitrogen-containing ring, e.g. hydrazine radicals

Definitions

  • This invention relates to a novel method of treatment and to novel compounds for use in that method. 5
  • Leick, Chem. Ber., 1905, 38, 3923 describes the preparation of the compound phenyl-(4- 15 phenyl-phthalazin-l-yl)-amine.
  • 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,
  • OCD obsessive compulsive disorders
  • sleep disorders including circadian rhythm disorders, insomnia & narcolepsy
  • tics e.g. Giles de la Tourette's syndrome
  • traumatic brain injury e.g. Giles de la Tourette's syndrome
  • neuralgia especially trigeminal neuralgia
  • neuropathic pain e.g., neuropathic pain
  • dental pain e.g., cancer pain
  • MS motor neurone disease
  • ALS amyotrophic lateral sclerosis
  • the present invention provides a method of treatment and/or prophylaxis of anxiety, mania, depression, panic disorders and/or aggresssion, disorders associated with a 35 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) 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, C g alkyl, phenyl or Ci _g alkylphenyl.
  • R is hydrogen or C ⁇ .g alkyl
  • R is hydrogen or up to three substituents selected from halogen, CN, trifluoromethyl, trifluoromethoxy, C j .g alkyl, C ] _g alkoxy,
  • Ci.galkylcarbonyl Ci.galkoxycarbonyl, phenyl, phenoxy, phenylC ⁇ _4alkyl, benzyloxy, or benzoyl.
  • the compounds of use in this invention are typically optionally substituted phenyl- (pyridazinyl)-amines, especially (6-phenyl-pyridazin-3-yl)-amines, or optionally substituted phenyl-(phthalazinyl)-amines, especially (4-phenyl-phthalazin-l-yl)-amines.
  • the phenyl or pyridyl group P is typically mono or di-substituted by substituent R 3 when R 3 is other than hydrogen.
  • alkyl groups including alkyl groups that are part of another moiety, may be straight chain or branched.
  • Aromatic rings that are unsubstituted, including rings that are part of another moiety, may optionally be substituted with one or more substituents independently selected from halogen or C ⁇ .g alkyl, C j _g alkoxy or C ⁇ alkylcarbonyl.
  • Suitable halo substituents include fluoro, chloro, iodo and bromo.
  • R as hydrogen, phenyl or methylphenyl
  • R ⁇ represents a 3-substituent or a 3,5-disubstitution.
  • 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, 100, 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 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 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'
  • 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).
  • R is a substituent other than halogen (d) compounds of formula (I) in which Q is phthalazinyl, R is other than hydrogen and 3 R is phenyl, phenoxy, phenylC galley 1, benzyloxy, or benzoyl
  • the invention provides the use of a 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 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.
  • R is R as defined for formula (I) or a group convertible to R and P is defined for formula (I). with a compound of formula (El)
  • Y is a halogen, especially chloro, and the reaction is carried out by heating the reactants (II) and (HI) at around 100 °C. Further details of procedures for the preparation of compounds for use in this invention can be found in the references cited above and by study of the Examples below.
  • Phenyl-(4-phenyl-phthalazin-l-yl)-amine A stirred mixture of l-chloro-4-phenylphthalazine Dl (1.5g, 6.2mmol) and aniline (2.89g 31mmol) was heated to 100°C for 1 h. The mixture was cooled, chloroform added and the whole washed with 5% sodium hydroxide, water and dried (NaSO4) Evaporation in vacuo afforded a residue which on recrystallisation from ethanol gave the title compound as a pale yellow solid (0.52g). m.p. 230°C.
  • Example 6 The compounds of Examples 6 to 28 were prepared in a similar way to the method of Example 5.
  • Example 6 The compounds of Examples 6 to 28 were prepared in a similar way to the method of Example 5.
  • 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 [3Hj- 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.
  • the percentage increase or decrease in CC50 for each group compared to the control is calculated.
  • Drugs are suspended in 1% methyl cellulose.

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  • Pharmacology & Pharmacy (AREA)
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  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
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  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Psychology (AREA)
  • Epidemiology (AREA)
  • Anesthesiology (AREA)
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Abstract

L'invention concerne un procédé de traitement ou de prophylaxie des maladies ou troubles suivants: anxiété, manie, dépression, troubles paniques ou comportement agressif, troubles associés à une hémorragie sous-arachnoïdienne ou à un choc nerveux, effets associés au sevrage de substances donnant lieu à des abus telles que cocaïne, nicotine, alcool et benzodiazépines, troubles pouvant être traités ou prévenus avec des agents anti-convulsifs tels que épilepsie incluant l'épilepsie post-traumatique, maladie de Parkinson, psychose, migraine, ischémie cérébrale, maladie d'Alzheimer et autres maladies dégénératives telles que chorée de Huntington, schizophrénie, troubles obsessionnels-compulsifs, déficits neurologiques associés au SIDA, troubles du sommeil (incluant troubles du rythme circadien, insomnie et narcolepsie), tics (maladie de Gilles de la Tourette, par exemple), lésion traumatique du cerveau, acouphène, névralgie, en particulier névralgie faciale, douleur névropathique, douleur dentaire, douleur cancéreuse, activité nerveuse inappropriée causant des neurodysthésies dans des maladies telles que diabète, sclérose en plaques et maladie du motoneurone, ataxies, rigidité musculaire (hypertonie spastique), dysfonction temporo-mandibulaire et sclérose latérale amyotrophique. Ce procédé comprend l'administration à la personne souffrante en ayant besoin d'une quantité active ou prophylactique d'un composé de formule (I) ou d'un sel ou solvate acceptable pharmaceutiquement de ce composé. Dans la formule (I), le système cyclique Q représente pyridazinyle ou phtalazinyle, le système cyclique P représente phényle ou pyridyle, R1 représente hydrogène, alkyle C¿1-6?, phényle ou alkyle C1-6 phényle, R?2¿ représente hydrogène ou alkyle C¿1-6, R?3 représente hydrogène ou jusqu'à trois substituants sélectionnés dans le groupe halogène, CN, trifluorométhyle, trifluorométhoxy, alkyle C¿1-6?, alcoxy C1-6, alkyle C1-6 carbonyle, alcoxy C1-6 carbonyle, phényle, phénoxy, phénylalkyle C1-4, benzyloxy ou benzoyle.
PCT/EP1998/002172 1997-04-16 1998-04-14 Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs Ceased WO1998046574A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
CA002288171A CA2288171A1 (fr) 1997-04-16 1998-04-14 Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs
JP54349098A JP2001518908A (ja) 1997-04-16 1998-04-14 ピリダジンおよびフタラジン誘導体、それらの製造方法および抗痙攣剤としてのそれらの使用
EP98920520A EP0975605A1 (fr) 1997-04-16 1998-04-14 Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9707693.9A GB9707693D0 (en) 1997-04-16 1997-04-16 Novel method of treatment
GB9707693.9 1997-04-16

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WO1998046574A1 true WO1998046574A1 (fr) 1998-10-22

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PCT/EP1998/002172 Ceased WO1998046574A1 (fr) 1997-04-16 1998-04-14 Derives de pyridazine et de phtalazine, leur procede de preparation et leur utilisation comme anti-convulsifs

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EP (1) EP0975605A1 (fr)
JP (1) JP2001518908A (fr)
CA (1) CA2288171A1 (fr)
GB (1) GB9707693D0 (fr)
WO (1) WO1998046574A1 (fr)

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207666B1 (en) * 1995-06-07 2001-03-27 Cell Pathways, Inc. Method for treating a patient having precancerous lesion with 4-phenylphthalazine derivatives
WO2004099177A1 (fr) * 2003-05-09 2004-11-18 Merck Sharp & Dohme Limited 1-phtalazinamines substituees en tant qu'antagonistes de vr-1
WO2007126957A2 (fr) 2006-03-31 2007-11-08 Novartis Ag Nouveaux composés
WO2007127475A3 (fr) * 2006-04-28 2008-11-06 Univ Northwestern Compositions et traitements contre des maladies démyélinisantes et des troubles de type douleur
EP2074998A3 (fr) * 2003-08-04 2009-10-07 Valery Khazhmuratovich Zhilov Utilisation de bioisostères cycliques des dérivés de système de purine pour le traitement des maladies causées par les troubles des systèmes nitrergiques et dopaminergiques
US7888357B2 (en) 2001-08-31 2011-02-15 Northwestern University Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death
US8063047B2 (en) 2004-11-02 2011-11-22 Centre National De La Recherche Scientifique (Cnrs) Pyridazine compounds and methods
WO2012037132A1 (fr) * 2010-09-14 2012-03-22 Exelixis, Inc. Dérivés de la phtalazine comme inhibiteurs de jak1
US8158627B2 (en) 2006-04-28 2012-04-17 Northwestern University Compositions and treatments using pyridazine compounds and cholinesterase inhibitors
US8367672B2 (en) 2004-11-02 2013-02-05 Universite De Strasbourg Pyridazine compounds, compositions and methods
WO2013019938A1 (fr) * 2011-08-02 2013-02-07 The Brigham And Women's Hospital, Inc. Dérivés de pyridazine en tant qu'activateurs d'eaat2
US9408845B2 (en) 2006-04-28 2016-08-09 Northwestern University Formulations containing pyridazine compounds

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EP0073161A1 (fr) * 1981-08-11 1983-03-02 Sanofi S.A. Nouveaux dérivés de la pyrazine actifs sur le système nerveux central
EP0382634A1 (fr) * 1989-02-07 1990-08-16 Elf Sanofi Nouveaux dérivés de la pyridazine, procédé de préparation et compositions pharmaceutiques en contenant
EP0514277A1 (fr) * 1991-05-16 1992-11-19 Sanofi Dérivés de 3-aminopyridazines actifs sur le système nerveux central
EP0534443A1 (fr) * 1991-09-26 1993-03-31 Mitsubishi Chemical Corporation Dérivés de la pyridazine 3,6-disubstituée

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GB2063249A (en) * 1979-10-09 1981-06-03 Mitsubishi Yuka Pharma 4-Phenylphthalazine derivatives
EP0073161A1 (fr) * 1981-08-11 1983-03-02 Sanofi S.A. Nouveaux dérivés de la pyrazine actifs sur le système nerveux central
EP0382634A1 (fr) * 1989-02-07 1990-08-16 Elf Sanofi Nouveaux dérivés de la pyridazine, procédé de préparation et compositions pharmaceutiques en contenant
EP0514277A1 (fr) * 1991-05-16 1992-11-19 Sanofi Dérivés de 3-aminopyridazines actifs sur le système nerveux central
EP0534443A1 (fr) * 1991-09-26 1993-03-31 Mitsubishi Chemical Corporation Dérivés de la pyridazine 3,6-disubstituée

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6207666B1 (en) * 1995-06-07 2001-03-27 Cell Pathways, Inc. Method for treating a patient having precancerous lesion with 4-phenylphthalazine derivatives
US7888357B2 (en) 2001-08-31 2011-02-15 Northwestern University Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death
US8088774B2 (en) 2001-08-31 2012-01-03 Northwestern University Anti-inflammatory and protein kinase inhibitor compositions and related methods for downregulation of detrimental cellular responses and inhibition of cell death
WO2004099177A1 (fr) * 2003-05-09 2004-11-18 Merck Sharp & Dohme Limited 1-phtalazinamines substituees en tant qu'antagonistes de vr-1
US7329659B2 (en) 2003-05-09 2008-02-12 Merck Sharp & Dohme Limited Substituted-1-phthalazinamines as vr-1 antagonists
EP2074998A3 (fr) * 2003-08-04 2009-10-07 Valery Khazhmuratovich Zhilov Utilisation de bioisostères cycliques des dérivés de système de purine pour le traitement des maladies causées par les troubles des systèmes nitrergiques et dopaminergiques
US8367672B2 (en) 2004-11-02 2013-02-05 Universite De Strasbourg Pyridazine compounds, compositions and methods
US8933076B2 (en) 2004-11-02 2015-01-13 Centre National De La Recherche Scientifique (Cnrs) Pyridazine compounds, compositions and methods
US8063047B2 (en) 2004-11-02 2011-11-22 Centre National De La Recherche Scientifique (Cnrs) Pyridazine compounds and methods
US9663493B2 (en) 2004-11-02 2017-05-30 Northwestern University Pyridazine compounds, compositions and methods
US9527819B2 (en) 2004-11-02 2016-12-27 Northwestern University Pyridazine compounds, compositions and methods
EP2418202A1 (fr) 2006-03-31 2012-02-15 Novartis AG Nouveaux composés
WO2007126957A2 (fr) 2006-03-31 2007-11-08 Novartis Ag Nouveaux composés
EP2402319A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2404905A1 (fr) 2006-03-31 2012-01-11 Novartis AG Nouveaux composés
EP2301923A1 (fr) 2006-03-31 2011-03-30 Novartis AG Nouveaux composés
EP2402318A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteurs de la DGAT
EP2402317A1 (fr) 2006-03-31 2012-01-04 Novartis AG Inhibiteur de la DGAT
EP2402320A1 (fr) 2006-03-31 2012-01-04 Novartis AG Agents anorectiques
US8158627B2 (en) 2006-04-28 2012-04-17 Northwestern University Compositions and treatments using pyridazine compounds and cholinesterase inhibitors
US9408845B2 (en) 2006-04-28 2016-08-09 Northwestern University Formulations containing pyridazine compounds
WO2007127475A3 (fr) * 2006-04-28 2008-11-06 Univ Northwestern Compositions et traitements contre des maladies démyélinisantes et des troubles de type douleur
WO2012037132A1 (fr) * 2010-09-14 2012-03-22 Exelixis, Inc. Dérivés de la phtalazine comme inhibiteurs de jak1
WO2013019938A1 (fr) * 2011-08-02 2013-02-07 The Brigham And Women's Hospital, Inc. Dérivés de pyridazine en tant qu'activateurs d'eaat2
US9447075B2 (en) 2011-08-02 2016-09-20 The Brigham And Women's Hospital, Inc. Pyridazine derivatives as EAAT2 activators

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JP2001518908A (ja) 2001-10-16
GB9707693D0 (en) 1997-06-04
EP0975605A1 (fr) 2000-02-02

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