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WO1997020850A1 - 3,4-DIHYDRO[1,2,4]THIADIAZINO[3,4-b]BENZOTHIAZOLE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME - Google Patents

3,4-DIHYDRO[1,2,4]THIADIAZINO[3,4-b]BENZOTHIAZOLE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME Download PDF

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Publication number
WO1997020850A1
WO1997020850A1 PCT/FR1996/001868 FR9601868W WO9720850A1 WO 1997020850 A1 WO1997020850 A1 WO 1997020850A1 FR 9601868 W FR9601868 W FR 9601868W WO 9720850 A1 WO9720850 A1 WO 9720850A1
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Prior art keywords
formula
compounds
preparation
ethyl
radical
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Application number
PCT/FR1996/001868
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French (fr)
Inventor
Alain Boireau
Marie-Christine Dubroeucq
Assunta Imperato
Patrick Jimonet
Serge Mignani
John Randle
Original Assignee
Rhone-Poulenc Rorer S.A.
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Application filed by Rhone-Poulenc Rorer S.A. filed Critical Rhone-Poulenc Rorer S.A.
Priority to AU76995/96A priority Critical patent/AU7699596A/en
Priority to JP9521026A priority patent/JP2000501407A/en
Priority to EP96939978A priority patent/EP0876378A1/en
Publication of WO1997020850A1 publication Critical patent/WO1997020850A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs

Definitions

  • the present invention relates to new compounds of formula:
  • R represents a polyfluoroalkyl radical
  • R- represents an alkyl radical
  • Hal represents a halogen atom
  • radicals and the alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain.
  • the polyfluoroalkyl radicals are preferably the trifluoromethyl, trrfluoro-2,2,2 ethyl and pentafluoroethyl radicals.
  • the compounds of formula (I) can be in the form of racemics, enantiomers or diastereoisomers. These compounds are also part of the invention
  • the compounds of formula (I) can be prepared by cyclization of a compound of formula.
  • R and R-j have the same meanings as in formula (I).
  • This cyclization is generally carried out in an oxidizing medium (bromine, iodine potassium triiodide, hydrogen peroxide for example), or in the presence of chloramine T (sodium salt of N-chloro-p.toluenesulfonamide), in an inert solvent such as an alcohol (methanol, ethanol for example), a chlorinated solvent (chloroform, methylene chloride for example), a aromatic solvent (benzene, toluene for example), a ketone (acetone for example), at a temperature between -30 ° C and the boiling temperature of the reaction medium.
  • an oxidizing medium bromine, iodine potassium triiodide, hydrogen peroxide for example
  • chloramine T sodium salt of N-chloro-p.toluenesulfonamide
  • an inert solvent such as an alcohol (methanol, ethanol for example), a chlorinated solvent (chloroform, methylene chloride for example), a aromatic solvent
  • the compounds of formula (I), their racemics, enantiomers and diastereoisomers can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
  • the compounds of formula (I) have interesting pharmacological properties. These compounds are useful for the treatment of PARKINSON disease and parkinsonian syndromes.
  • the activity of the compounds of formula (I) has been demonstrated in mice by measuring the reduction in the dopamine level of the st ⁇ atum induced by MPTP compared with that of the control animals.
  • the coefficient of efficacy of each compound is calculated by the ratio [dopamine level of the MPTP group + product to be tested] / [dopamine level of the MPTP group].
  • the compounds of formula (I) have an efficiency coefficient greater than 1.80.
  • the compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.
  • the medicaments consist of at least one compound of formula (I), in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active
  • the medicaments may be used orally or parenterally.
  • compositions for oral administration tablets, pills, powders (gelatin capsules, cachets) or granules can be used.
  • the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, saccharose, lactose or silica, under a stream of argon.
  • inert diluents such as starch, cellulose, saccharose, lactose or silica
  • These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish
  • liquid compositions for oral administration it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, 3 vegetable oils or l 'paraffin oil.
  • inert diluents such as water, ethanol, glycerol, 3 vegetable oils or l 'paraffin oil.
  • These compositions can include substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.
  • the sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions.
  • solvent or vehicle water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable.
  • These compositions can also contain adjuvants, in particular wetting agents, iso ⁇ tonics, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating into the composition of the sterilizing agents, by irradiation or by heating.
  • compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
  • compositions for topical administration can be, for example, creams, lotions, mouthwashes, nasal drops or aerosols.
  • the doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 50 and 400 mg per day orally for an adult with unit doses ranging from 25 to 200 mg of active substance.
  • the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
  • Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:
  • capsules containing 50 mg of active product having the following composition are prepared:
  • a solution for injection containing 10 mg of active product having the following composition is prepared:
  • the invention also relates to a method of treating a mammal and, in particular a man, presenting with PARKINSON disease or parkinsonian syndromes comprising the administration of an effective amount of a compound of formula (I).

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Psychology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)

Abstract

Compounds of formula (I), wherein R is a polyfluoroalkyl radical, R1 is an alkyl radical and Hal is a halogen atom, are disclosed. The compounds of formula (I) are useful for treating Parkinson's disease and parkinsonian syndromes.

Description

DERIVES DE 3.4-DIHYDROh .2.41THIADIAZINθr3.4-b1BENZOTHIAZOLE. LEUR PREPARATION ET LES MEDICAMENTS LES CONTENANT DERIVATIVES OF 3.4-DIHYDROh .2.41THIADIAZINθr3.4-b1BENZOTHIAZOLE. THEIR PREPARATION AND THE MEDICINES CONTAINING THEM
La présente invention concerne de nouveaux composés de formule :The present invention relates to new compounds of formula:
Figure imgf000003_0001
Figure imgf000003_0001
leurs racemiques, leurs énantiomères et diastéréoisomères, leur préparation et les médicaments les contenanttheir racemics, their enantiomers and diastereoisomers, their preparation and the drugs containing them
Dans la formule (I), R représente un radical polyfluoroalkyle, R-| représente un radical alkyle et Hal représente un atome d'halogèneIn formula (I), R represents a polyfluoroalkyl radical, R- | represents an alkyl radical and Hal represents a halogen atom
Dans les définitions qui précèdent et celles qui seront citées ci-après, les radicaux et les portions alkyle contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée.In the above definitions and those which will be cited below, the radicals and the alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain.
Les radicaux polyfluoroalkyle sont de préférence les radicaux trifluorométhyle, trrfluoro-2,2,2 éthyle et pentafluoroethyle.The polyfluoroalkyl radicals are preferably the trifluoromethyl, trrfluoro-2,2,2 ethyl and pentafluoroethyl radicals.
Les composes de formule (I) peuvent se présenter sous forme de racemiques, d'enantiomeres ou de diastéréoisomères. Ces composes font également partie de l'inventionThe compounds of formula (I) can be in the form of racemics, enantiomers or diastereoisomers. These compounds are also part of the invention
Les composes de formule (I) peuvent être prépares par cyclisation d'un compose de formule .The compounds of formula (I) can be prepared by cyclization of a compound of formula.
Figure imgf000003_0002
Figure imgf000003_0002
dans laquelle R et R-j ont les mêmes significations que dans la formule (I).in which R and R-j have the same meanings as in formula (I).
Cette cyclisation s'effectue généralement en milieu oxydant (brome, iode triiodure de potassium, eau oxygénée par exemple), ou en présence de chloramine T (sel de sodium du N-chloro-p.toluènesulfonamide), au sein d'un solvant inerte tel qu'un alcool (méthanol, éthanol par exemple), un solvant chloré (chloroforme, chlorure de méthylène par exemple), un solvant aromatique (benzène, toluène par exemple), une cétone (acétone par exemple), à une température comprise entre -30°C et la température d'ébullition du milieu réactionnel.This cyclization is generally carried out in an oxidizing medium (bromine, iodine potassium triiodide, hydrogen peroxide for example), or in the presence of chloramine T (sodium salt of N-chloro-p.toluenesulfonamide), in an inert solvent such as an alcohol (methanol, ethanol for example), a chlorinated solvent (chloroform, methylene chloride for example), a aromatic solvent (benzene, toluene for example), a ketone (acetone for example), at a temperature between -30 ° C and the boiling temperature of the reaction medium.
Les dérivés de formule (II) peuvent être obtenus par application des méthodes décrites dans le brevet EP374040.The derivatives of formula (II) can be obtained by applying the methods described in patent EP374040.
Les composes de formule (I), leurs racemiques, énantiomères et diastéréoisomères peuvent être purifies par les méthodes connues habituelles, par exemple par cristallisation, chromatographie ou extraction.The compounds of formula (I), their racemics, enantiomers and diastereoisomers can be purified by the usual known methods, for example by crystallization, chromatography or extraction.
Les composés de formule (I) présentent des propriétés pharmacologiques intéressantes. Ces composés sont utiles pour le traitement de la maladie de PARKINSON et des syndromes parkinsoniens.The compounds of formula (I) have interesting pharmacological properties. These compounds are useful for the treatment of PARKINSON disease and parkinsonian syndromes.
II est connu que la neurotoxine MPTP (1 -methyl-4-phenyl-1 ,2,3,6-tétrahydro- pyπdine) induit un syndrome similaire à la maladie de Parkinson. Ce syn¬ drome resuite d'une dégéneration des neurones nigrostπataux dopaminergi- ques chez les primates (R. S. BURNS et coll., Proc. Natl. Acad. Sci., 80, 4546-4550 (1983), chez l'homme (J. W. LANGSTON et coll., Science, 219, 979-980 (1983)) et chez la souris (R. E. HEIKKILA et coll., Science, 224, 1451 -1453 (1984).It is known that the neurotoxin MPTP (1-methyl-4-phenyl-1, 2,3,6-tetrahydropyπdine) induces a syndrome similar to Parkinson's disease. This syn¬ drome results from a degeneration of nigrostπatal dopaminergic neurons in primates (RS BURNS et al., Proc. Natl. Acad. Sci., 80, 4546-4550 (1983), in humans (JW LANGSTON et al., Science, 219, 979-980 (1983)) and in mice (RE HEIKKILA et al., Science, 224, 1451 -1453 (1984).
L'activité des composés de formule (I) a ete mise en évidence chez la souris en mesurant la diminution du taux de dopamine du stπatum induite par la MPTP comparée à celle des animaux témoins. Le coefficient d'efficacité de chaque composé est calcule par le rapport [taux de dopamine du groupe MPTP+produit à tester] / [taux de dopamine du groupe MPTP].The activity of the compounds of formula (I) has been demonstrated in mice by measuring the reduction in the dopamine level of the stπatum induced by MPTP compared with that of the control animals. The coefficient of efficacy of each compound is calculated by the ratio [dopamine level of the MPTP group + product to be tested] / [dopamine level of the MPTP group].
On injecte, 3 fois à 2 heures et 30 minutes d'intervalle, 15 mg/kg de MPTP par voie mtrapeπtoneale a des souris (C57BL6) pesant 19-25 g. Trente minu¬ tes avant la première injection de MPTP, puis 2 heures, 4 heures et 30 minu- tes et enfin 7 heures après la première injection de MPTP on administre par voie orale 5mg/kg du produit a étudier. Les souris sont tuées 24 heures après la dernière injection de MPTP. Le stπatum est disséqué et conservé à -70°C jusqu'au moment de son analyse. Les taux de dopamine, sont mesures par chromatographie liquide haute performance avec une détection électrochimique. Les analyses statistiques sont effectuées en utilisant une analyse de vaπance (ANOVA).15 mg / kg of MPTP are injected 3 times at 2 hours and 30 minutes apart by mtrapeπtoneale route to mice (C57BL6) weighing 19-25 g. Thirty minutes before the first injection of MPTP, then 2 hours, 4 hours and 30 minutes and finally 7 hours after the first injection of MPTP, 5 mg / kg of the product to be studied is administered orally. Mice are killed 24 hours after the last MPTP injection. The stπatum is dissected and stored at -70 ° C until the moment of its analysis. Dopamine levels are measured by high performance liquid chromatography with electrochemical detection. Statistical analyzes are performed using a variance analysis (ANOVA).
Les composes de formule (I) présentent un coefficient d'efficacité supérieur à 1 ,80.The compounds of formula (I) have an efficiency coefficient greater than 1.80.
Les composes de formule (I) présentent une toxicité faible. Leur DL50 est supérieure a 50 mg/kg par voie IP chez la souris.The compounds of formula (I) have a low toxicity. Their LD50 is greater than 50 mg / kg by the IP route in mice.
L'exemple suivant illustre l'invention.The following example illustrates the invention.
EXEMPLE 1EXAMPLE 1
A 20 ml d'une solution methanolique de chloramine T tπhydrate (2 g) à -30°C, on ajoute, en environ 10 minutes, 2,5 g de chlorhydrate de 3-(2- ethylthιoethyl)-2-ιmιno-6-trιfluorométhyl-benzothιazolιne. La reaction est poursuivie 30 minutes a la même température. Après réchauffement à une température voisine de 20°C, l'insoluble orange est sépare par filtration et le filtrat traite avec 200 ml d'éther éthylique. Le précipite jaunâtre forme est isole par filtration (2,4 g) Apres recristallisation dans un mélange d'acetonitπle et d'éthanol absolu (12/1 en volumes respectivement), on obtient 0,68 g d'hydrate du chlorure de 2-ethyl-8-trιfluoromethyl-3,4- dιhydro[1 ,2,4]thιadιazιno[3,4-b]benzothιazolιum sous forme de poudre blanc casse sublimant a 178°C [Spectre 1 H dans DMSO ,T=300K, δ en ppm (300 MHz) : 1 ,43 (3H, t, J=7Hz, CH3), 3,57 (2H, q, J=7Hz, SCH2), 3,88 et 4,04 (1 H chacun, respectivement dt, J=13 et 5Hz, et ddd, J=13-8 et 4Hz, SCHp), 4,60 et 4,77 (1 H chacun, respectivement ddd, J=14-8 et 4Hz et dt, J=14 et 5Hz, NCHp), 7,72 (1 H, d, J=8Hz, CH arom.), 7,88 (1 H, d, J=8Hz, CH arom.), 8,35 (1 H, s, CH arom ), Analyse C12H12CIF3N2S2; 1 ,0 H20; % calcule : C : 42,29; H - 3,55; Cl : 10,40, F : 16,72; N 8,22; trouve C : 41 ,9; H : 3,0; Cl : 1 1 ,2; F - 17,1 ; N : 8,0].To 20 ml of a methanolic solution of chloramine T tπhydrate (2 g) at -30 ° C, 2.5 g of 3- (2- ethylthιoethyl) -2-ιmιno-6 hydrochloride are added in about 10 minutes -trιfluorométhyl-benzothιazolιne. The reaction is continued for 30 minutes at the same temperature. After heating to a temperature in the region of 20 ° C., the insoluble orange is separated by filtration and the filtrate is treated with 200 ml of ethyl ether. The yellowish precipitate formed is isolated by filtration (2.4 g) After recrystallization from a mixture of acetonitrile and absolute ethanol (12/1 by volume respectively), 0.68 g of hydrate of 2- chloride is obtained. ethyl-8-trιfluoromethyl-3,4- dehydro [1, 2,4] thιadιazιno [3,4-b] benzothιazolιum in the form of white powder breaks sublimating at 178 ° C [ 1 H spectrum in DMSO, T = 300K, δ in ppm (300 MHz): 1.43 (3H, t, J = 7Hz, CH 3 ), 3.57 (2H, q, J = 7Hz, SCH 2 ), 3.88 and 4.04 (1 H each , respectively dt, J = 13 and 5Hz, and ddd, J = 13-8 and 4Hz, SCHp), 4.60 and 4.77 (1 H each, respectively ddd, J = 14-8 and 4Hz and dt, J = 14 and 5Hz, NCHp), 7.72 (1 H, d, J = 8Hz, CH arom.), 7.88 (1 H, d, J = 8Hz, CH arom.), 8.35 (1 H , s, CH arom), Analysis C12H12CIF3N2S2; 1.0 H2O; % calculate: C: 42.29; H - 3.55; Cl: 10.40, F: 16.72; N 8.22; finds C: 41.9; H: 3.0; Cl: 1 1, 2; F - 17.1; N: 8.0].
La 3-(2-ethylthιoéthyl)-2-ιmιno-6-trιfluoromethyl-benzothιazolιne peut être obtenue selon le protocole décrit dans le brevet EP374040. 97/20850 PCI /FR96/018683- (2-ethylthιoethyl) -2-ιmιno-6-trιfluoromethyl-benzothιazolιne can be obtained according to the protocol described in patent EP374040. 97/20850 PCI / FR96 / 01868
Les médicaments sont constitues par au moins un composé de formule (I), à l'état pur ou sous forme d'une composition dans laquelle il est associé à tout autre produit pharmaceutiquement compatible, pouvant être inerte ou physiologiquement actif Les médicaments peuvent être employés par voie orale ou parentérale.The medicaments consist of at least one compound of formula (I), in the pure state or in the form of a composition in which it is associated with any other pharmaceutically compatible product, which may be inert or physiologically active The medicaments may be used orally or parenterally.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimés, des pilules, des poudres (capsules de gélatine, cachets) ou des granulés. Dans ces compositions, le principe actif selon l'invention est mélange à un ou plusieurs diluants inertes, tels que amidon, cellulose, sac- charose, lactose ou silice, sous courant d'argon. Ces compositions peuvent également comprendre des substances autres que les diluants, par exemple un ou plusieurs lubrifiants tels que le stéarate de magnésium ou le talc, un colorant, un enrobage (dragées) ou un vernisAs solid compositions for oral administration, tablets, pills, powders (gelatin capsules, cachets) or granules can be used. In these compositions, the active principle according to the invention is mixed with one or more inert diluents, such as starch, cellulose, saccharose, lactose or silica, under a stream of argon. These compositions can also comprise substances other than diluents, for example one or more lubricants such as magnesium stearate or talc, a colorant, a coating (dragees) or a varnish
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des emulsions, des sirops et des elixirs pharma¬ ceutiquement acceptables contenant des diluants inertes tels que l'eau, l'ethanol, le glycérol, 3 huiles végétales ou l'huile de paraffine. Ces com¬ positions peuvent comprendre des substances autres que les diluants, par exemple des produits mouillants, edulcorants, épaississants, aromatisants ou stabilisants.As liquid compositions for oral administration, it is possible to use solutions, suspensions, emulsions, syrups and pharmaceutically acceptable elixirs containing inert diluents such as water, ethanol, glycerol, 3 vegetable oils or l 'paraffin oil. These compositions can include substances other than diluents, for example wetting products, sweeteners, thickeners, flavorings or stabilizers.
Les compositions stériles pour administration parentérale, peuvent être de préférence des solutions aqueuses ou non aqueuses, des suspensions ou des emulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyéthylèneglycol, des huiles végétales, en particulier l'huile d'olive, des esters organiques injectables, par exemple l'oléate d'éthyle ou d'autres solvants organiques convenables. Ces compositions peuvent également contenir des adjuvants, en particulier des agents mouillants, iso¬ tonisants, émulsifiants, dispersants et stabilisants. La stérilisation peut se faire de plusieurs façons, par exemple par filtration aseptisante, en incorpo rant a la composition des agents stérilisants, par irradiation ou par chauffage. Elles peuvent également être préparées sous forme de compositions solides stériles qui peuvent être dissoutes au moment de l'emploi dans de l'eau stérile ou tout autre milieu stérile injectable Les compositions pour administration rectale sont les suppositoires ou les capsules rectales qui contiennent, outre le produit actif, des excipients tels que le beurre de cacao, des glycérides semisynthétiques ou des polyéthylèneglycols.The sterile compositions for parenteral administration can preferably be aqueous or non-aqueous solutions, suspensions or emulsions. As solvent or vehicle, water, propylene glycol, polyethylene glycol, vegetable oils, in particular olive oil, injectable organic esters, for example ethyl oleate or other organic solvents can be used. suitable. These compositions can also contain adjuvants, in particular wetting agents, iso¬ tonics, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by aseptic filtration, by incorporating into the composition of the sterilizing agents, by irradiation or by heating. They can also be prepared in the form of sterile solid compositions which can be dissolved at the time of use in sterile water or any other sterile injectable medium. The compositions for rectal administration are suppositories or rectal capsules which contain, in addition to the active product, excipients such as cocoa butter, semisynthetic glycerides or polyethylene glycols.
Les compositions pour administration topique peuvent être par exemple des crèmes, lotions, collutoires, gouttes nasales ou aérosols.The compositions for topical administration can be, for example, creams, lotions, mouthwashes, nasal drops or aerosols.
Les doses dépendent de l'effet recherché, de la durée du traitement et de la voie d'administration utilisée ; elles sont généralement comprises entre 50 et 400 mg par jour par voie orale pour un adulte avec des doses unitaires allant de 25 à 200 mg de substance active.The doses depend on the desired effect, on the duration of the treatment and on the route of administration used; they are generally between 50 and 400 mg per day orally for an adult with unit doses ranging from 25 to 200 mg of active substance.
D'une façon générale, le médecin déterminera la posologie appropriée en fonction de l'âge, du poids et de tous les autres facteurs propres au sujet à traiter.In general, the doctor will determine the appropriate dosage based on age, weight and all other factors specific to the subject to be treated.
Les exemples suivants illustrent des médicaments selon l'invention :The following examples illustrate medicaments according to the invention:
Exemple AExample A
On prépare, selon la technique habituelle, des comprimés dosés à 50 mg de produit actif ayant la composition suivante :Tablets containing 50 mg of active product having the following composition are prepared according to the usual technique:
- Composé de formule (I) 50 mg- Compound of formula (I) 50 mg
- Mannitol 64 mg - Cellulose microcristalline 50 mg- Mannitol 64 mg - Microcrystalline cellulose 50 mg
- Polyvidone excipient 12 mg- Polyvidone excipient 12 mg
- Carboxyméthylamidon sodique 16 mg- Carboxymethyl starch sodium 16 mg
- Talc 4 mg- Talc 4 mg
- Stéarate de magnésium 2 mg - Silice colloïdale anhydre 2 mg- Magnesium stearate 2 mg - Colloidal anhydrous silica 2 mg
- Mélange de méthylhydroxypropylcellulose, polyéthylèneglycol 6000, dioxyde de titane (72-3,5-24,5) q.s.p. 1 comprimé pellicule terminé à 245 mg Exemple B- Mixture of methylhydroxypropylcellulose, polyethylene glycol 6000, titanium dioxide (72-3,5-24,5) qs 1 film-coated tablet finished at 245 mg Example B
On prépare, selon la technique habituelle, des gélules dosées à 50 mg de produit actif ayant la composition suivante :Using the usual technique, capsules containing 50 mg of active product having the following composition are prepared:
- Composé de formule (I) 50 mg - Cellulose 18 mg- Compound of formula (I) 50 mg - Cellulose 18 mg
- Lactose 55 mg- Lactose 55 mg
- Silice colloïdale 1 mg- Colloidal silica 1 mg
- Carboxyméthylamidon sodique 10 mg- Carboxymethyl starch sodium 10 mg
- Talc 10 mg - Stéarate de magnésium 1 mg- Talc 10 mg - Magnesium stearate 1 mg
Exemple CExample C
On prépare une solution injectable contenant 10 mg de produit actif ayant la composition suivante :A solution for injection containing 10 mg of active product having the following composition is prepared:
- Composé de formule (I) 10 mg - Acide benzoïque 80 mg- Compound of formula (I) 10 mg - Benzoic acid 80 mg
- Alcool benzylique 0,06 cm3- Benzyl alcohol 0.06 cm3
- Benzoate de sodium 80 mg- Sodium benzoate 80 mg
- Ethanol à 95 % 0,4 cm3- 95% ethanol 0.4 cm3
- Hydroxyde de sodium 24 mg - Propylène glycol 1 ,6 cm3- Sodium hydroxide 24 mg - Propylene glycol 1.6 cm3
- Eau q.s.p. 4 cm3- Water q.s.p. 4 cm3
L'invention concerne également une méthode de traitement d'un mammifère et, notamment l'homme, présentant la maladie de PARKINSON ou des syndromes parkinsoniens comprenant l'administration d'une quantité efficace d'un composé de formule (I). The invention also relates to a method of treating a mammal and, in particular a man, presenting with PARKINSON disease or parkinsonian syndromes comprising the administration of an effective amount of a compound of formula (I).

Claims

REVENDICATIONS
1 - Composés de formule1 - Compounds of formula
Figure imgf000009_0001
Figure imgf000009_0001
dans laquelle R représente un radical polyfluoroalkyle, R-| représente un radical alkyle et Hal représente un atome d'halogène, étant entendu que les radicaux et les portions alkyle contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée, leurs racemiques, leurs énantiomères et diastéréoisomères.in which R represents a polyfluoroalkyl radical, R- | represents an alkyl radical and Hal represents a halogen atom, it being understood that the radicals and the alkyl portions contain 1 to 4 carbon atoms in a straight or branched chain, their racemics, their enantiomers and diastereoisomers.
2 - Composes de formule (I) selon la revendication 1 pour lesquels R représente un radical trifluorométhyle, trifluoro-2,2,2 éthyle ou pentafluoroéthyle.2 - Compounds of formula (I) according to claim 1 for which R represents a trifluoromethyl, trifluoro-2,2,2 ethyl or pentafluoroethyl radical.
3 - Procédé de préparation des composés de formule (I) selon la revendication 1 caractérise en ce que l'on cyclise un dérivé de formule :3 - Process for the preparation of the compounds of formula (I) according to claim 1, characterized in that a derivative of formula is cyclized:
Figure imgf000009_0002
Figure imgf000009_0002
dans laquelle R et R-| ont les mêmes significations que dans la revendication 1.in which R and R- | have the same meanings as in claim 1.
4 - Le chlorure de 2-éthyl-8-tπfluorométhyl-3,4-dιhydro[1 ,2,4]thiadιazιno[3,4- bjbenzothiazolium.4 - 2-Ethyl-8-tπfluoromethyl-3,4-dehydro chloride [1,2,4] thiadιazιno [3,4- bjbenzothiazolium.
5 - Médicament contenant en tant que principe actif au moins un composé de formule (I) selon la revendication 1.5 - Medicinal product containing as active principle at least one compound of formula (I) according to claim 1.
6 - Médicament contenant en tant que principe actif du chlorure de 2-éthyl-8- trιfluorométhyl-3,4-dιhydro[1 ,2,4]thιadιazιπo[3,4-b]benzothιazolιum. 6 - Medicinal product containing as active ingredient 2-ethyl-8-trιfluoromethyl-3,4-dehydro [1,2,4] thιadιazιπo [3,4-b] benzothιazolιum chloride.
PCT/FR1996/001868 1995-12-01 1996-11-26 3,4-DIHYDRO[1,2,4]THIADIAZINO[3,4-b]BENZOTHIAZOLE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME WO1997020850A1 (en)

Priority Applications (3)

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AU76995/96A AU7699596A (en) 1995-12-01 1996-11-26 3,4-dihydro{1,2,4}thiadiazino{3,4-b}benzothiazole derivatives, preparation thereof and drugs containing same
JP9521026A JP2000501407A (en) 1995-12-01 1996-11-26 3,4-Dihydro [1,2,4] thiadiazino [3,4-b] benzothiazole derivative, method for producing the same, and drug containing the same
EP96939978A EP0876378A1 (en) 1995-12-01 1996-11-26 3,4-DIHYDRO 1,2,4]THIADIAZINO 3,4-b]BENZOTHIAZOLE DERIVATIVES, PREPARATION THEREOF AND DRUGS CONTAINING SAME

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9514241 1995-12-01
FR95/14241 1995-12-01

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001194A1 (en) * 1991-07-04 1993-01-21 Rhone-Poulenc Rorer S.A. 1,2,4-THIADIAZINO[3,4-b]BENZOTHIAZOLE DERIVATIVES, THEIR PREPARATION, AND DRUGS CONTAINING SAME

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993001194A1 (en) * 1991-07-04 1993-01-21 Rhone-Poulenc Rorer S.A. 1,2,4-THIADIAZINO[3,4-b]BENZOTHIAZOLE DERIVATIVES, THEIR PREPARATION, AND DRUGS CONTAINING SAME

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