WO1997020558A1 - Use of 2-iminobenzothiazolines for treating parkinson's disease and parkinsonian syndromes - Google Patents
Use of 2-iminobenzothiazolines for treating parkinson's disease and parkinsonian syndromes Download PDFInfo
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- WO1997020558A1 WO1997020558A1 PCT/FR1996/001867 FR9601867W WO9720558A1 WO 1997020558 A1 WO1997020558 A1 WO 1997020558A1 FR 9601867 W FR9601867 W FR 9601867W WO 9720558 A1 WO9720558 A1 WO 9720558A1
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- trifluoromethoxybenzothiazoline
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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
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- 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
Definitions
- the present invention relates to a new therapeutic application of the compounds of formula:
- R represents a polyfluoroalkoxy or polyfluoroalkyl radical
- R- represents a hydrogen atom or an alkyl radical
- R2 represents a 2-propynyl, -alk-S (0) n-alk, -alk-SO2-NH2, -alk-SO2-NH2 or 4-phenylpiperazinylethyl radical
- n is 0, 1 or 2
- alk is alkyl containing 1 to 3C in a straight or branched chain, their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts.
- R is trifluoromethoxy, pentafluoroethoxy, trifluoromethyl or pentafluoroethyl and R-
- the compounds of formula (I) are useful in the treatment of convulsive phenomena, schizophrenic disorders, sleep disorders, phenomena related to cerebral ischemia, ALZHElMER disease, HUNTINGTON disease, Amyotrophic lateral sclerosis and olivopontocerebellar atrophy (EP374040, EP375510, EP408437, EP409692 and EP528968).
- 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 effectiveness of each compound is calculated by the ratio [dopamine level of the MPTP group + product to be tested] / [dopamine level of the MPTP group].
- mice 15 mg / kg of MPTP is injected 3 times at 2 hours and 30 minutes apart intraperitoneally into mice (C57BL6) weighing 19-25 g. Thirty minutes before the first MPTP injection, then 2 hours, 4 hours and 30 minutes and finally 7 hours after the first MPTP injection, 5 mg / kg of the product to be studied are administered orally. The mice are killed 24 hours. after the last MPTP injection. The st ⁇ atum is dissected and stored at -70 ° C until the time of its analysis. The dopamine levels are measured by high performance liquid chromatography with electrochemical detection. Statistical analyzes are performed using a variance analysis (ANOVA).
- ANOVA variance analysis
- the compounds of formula (I) have an efficiency coefficient equal to or greater than 1.80.
- salts with mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic salts such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theo- phillin-acetate, salicylate, phenolphthalmate, methylene-bis- ⁇ - oxynaphtoate or substitution derivatives of these derivatives.
- mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic salts such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theo- phillin-acetate, salicylate, phenolphthalmate, methylene-bis- ⁇ - oxynaphtoate or substitution derivatives of these derivatives.
- the medicaments consist of at least one compound of formula (I), an enantiomer, a diastereoisomer in free form or in the form of a salt. addition with a pharmaceutically acceptable acid, 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 drugs can 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, sac charose, lactose or silica, under a stream of argon.
- inert diluents such as starch, cellulose, sac charose, 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 dye, a coating (dragees) or a varnish.
- liquid compositions for oral administration there may be used pharmacologically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or the like. 'paraffin oil.
- inert diluents such as water, ethanol, glycerol, vegetable oils or the like. '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, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, 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 glycates 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, the duration of the treatment and 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.
- 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 the process for the preparation of medicaments useful in the treatment of Parkinson's disease and of parkinsonian syndromes consisting in mixing a compound of formula (I) or the pharmaceutically acceptable salts of this compound with one or more diluents and / or compatible and pharmaceutically acceptable adjuvants.
- 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 ⁇ e.
- Formula (I) a enantiomer, a diastereoisomer or a pharmaceutically acceptable salt of this compound.
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Abstract
The use of 2-iminobenzothiazolines of formula (II), wherein R is a polyfluoroalkoxy or polyfluoroalkyl radical, R1 is a hydrogen atom or a C1-4 alkyl radical, R2 is a 2-propynyl, -alk-S(O)n-alk, -alk-SO2-NH2, -alk-SO2-NHalk or 4-phenylpiperazinylethyl radical, n is 0, 1 or 2 and alk is alkyl, and enantiomers, diastereoisomers and pharmaceutically acceptable salts thereof, for treating Parkinson's disease and parkinsonian syndromes, is disclosed.
Description
APPLICATION DE 2-IMINOBEN7OTHIA7QLINES DANS LE TRAITEMENT DU PARKINSON ET DES SYNDROMES PARK1NSONIENS APPLICATION OF 2-IMINOBEN7OTHIA7QLINES IN THE TREATMENT OF PARKINSON AND PARK1NSONIAN SYNDROMES
La présente invention concerne une nouvelle application thérapeutique des composés de formule :The present invention relates to a new therapeutic application of the compounds of formula:
dans laquelle R représente un radical polyfluoroalcoxy ou polyfluoroalkyle, R-| représente un atome d'hydrogène ou un radical alkyle, R2 représente un radical 2-propynyle, -alk-S(0)n-alk, -alk-S02-NH2, -alk-S02-NHalk ou 4-phénylpipérazinyléthyle, n est 0, 1 ou 2 et alk est alkyle contenant 1 à 3C en chaîne droite ou ramifiée, leurs énantiomères, leurs diastéréoisomères et leurs sels pharmaceutiquement acceptables.in which R represents a polyfluoroalkoxy or polyfluoroalkyl radical, R- | represents a hydrogen atom or an alkyl radical, R2 represents a 2-propynyl, -alk-S (0) n-alk, -alk-SO2-NH2, -alk-SO2-NH2 or 4-phenylpiperazinylethyl radical, n is 0, 1 or 2 and alk is alkyl containing 1 to 3C in a straight or branched chain, their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts.
Dans les définitions qui précédent et celles qui seront citées ci-après, sauf mention contraire, les radicaux et les portions alkyle et alcoxy contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée.In the above definitions and those which will be cited below, unless otherwise stated, the radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain.
De préférence R est trifluorométhoxy, pentafluoroéthoxy, trifluorométhyle ou pentafluoroéthyle et R-| est hydrogène, méthyle ou éthyle.Preferably R is trifluoromethoxy, pentafluoroethoxy, trifluoromethyl or pentafluoroethyl and R- | is hydrogen, methyl or ethyl.
Les composés de formule (I) sont utiles dans le traitement des phénomènes convulsifs, des troubles schizophréniques, des troubles du sommeil, des phénomènes liés à l'ischémie cérébrale, de la maladie d'ALZHElMER, de la maladie d'HUNTINGTON, de la sclérose latérale amyotrophique et de l'atrophie olivopontocérébelleuse (EP374040, EP375510, EP408437, EP409692 et EP528968).The compounds of formula (I) are useful in the treatment of convulsive phenomena, schizophrenic disorders, sleep disorders, phenomena related to cerebral ischemia, ALZHElMER disease, HUNTINGTON disease, Amyotrophic lateral sclerosis and olivopontocerebellar atrophy (EP374040, EP375510, EP408437, EP409692 and EP528968).
Il a maintenant été trouvé de manière surprenante que ces composés et leurs sels peuvent être utilisés dans le traitement de la maladie de PARKINSON et des syndromes parkinsoniens.It has now surprisingly been found that these compounds and their salts can be used in the treatment of PARKINSON disease and parkinsonian syndromes.
Parmi les composés de formule (I) sont préférés les composé suivants :
- 3-(2-propynyl)-2-imino-6-trifluorométhoxybenzothιazoline,Among the compounds of formula (I), the following compounds are preferred: - 3- (2-propynyl) -2-imino-6-trifluoromethoxybenzothιazoline,
- -2-ιmιno-3-méthylthiomethyl-6-trifluorométhoxybenzothιazoline,- -2-ιmιno-3-methylthiomethyl-6-trifluoromethoxybenzothιazoline,
- 3-[2-(éthylthio)éthyl]-2-imιno-6-trifluorométhoxybenzothiazoline,- 3- [2- (ethylthio) ethyl] -2-imιno-6-trifluoromethoxybenzothiazoline,
- 3-[2-(éthylthιo)éthyl]-2-ιmιno-6-trιfluorométhylbenzothiazoline, - 3-[2-(éthylthιo)éthyl]-2-ιmιno-6-pentafluoroéthoxybenzothiazoline,- 3- [2- (ethylthιo) ethyl] -2-ιmιno-6-trιfluoromethylbenzothiazoline, - 3- [2- (ethylthιo) ethyl] -2-ιmιno-6-pentafluoroethoxybenzothiazoline,
- 2-imιno-3-[2-(méthylthio)propyl]-6-trifluorométhoxybenzothιazoline,- 2-imιno-3- [2- (methylthio) propyl] -6-trifluoromethoxybenzothιazoline,
- 2-ιmιno-3-(méthylsulfιnylméthyl)-6-tπfluorométhoxybenzothiazoline,- 2-ιmιno-3- (methylsulfιnylmethyl) -6-tπfluoromethoxybenzothiazoline,
- 2-imιno-3-[2-(methylsulfιnyl)ethyl]-6-trιfluorométhoxybenzothiazolιne,- 2-imιno-3- [2- (methylsulfιnyl) ethyl] -6-trιfluorométhoxybenzothiazolιne,
- 3-[2-(éthylsulfιnyl)ethyl]-2-ιmιno-6-trifluoromethoxybenzothiazolιne, - 2-imιno-3-[3-(methylsulfιnyl)propyl]-6-tπfluorométhoxybenzothιazolιne,- 3- [2- (ethylsulfιnyl) ethyl] -2-ιmιno-6-trifluoromethoxybenzothiazolιne, - 2-imιno-3- [3- (methylsulfιnyl) propyl] -6-tπfluorométhoxybenzothιazolιne,
- 2-ιmιno-3-[2-(methylsulfιnyl)propyl]-6-trιfluoromethoxybenzothιazolιne,- 2-ιmιno-3- [2- (methylsulfιnyl) propyl] -6-trιfluoromethoxybenzothιazolιne,
- 2-ιmιno-3-[2-(méthylsulfonyl)éthyl]-6-trιfluorométhoxybenzothιazoline,- 2-ιmιno-3- [2- (methylsulfonyl) ethyl] -6-trιfluoromethoxybenzothιazoline,
- 3-[2-(éthylsulfonyl)éthyl]-2-imιno-6-tπfluorométhoxybenzothiazoline,- 3- [2- (ethylsulfonyl) ethyl] -2-imιno-6-tπfluoromethoxybenzothiazoline,
- 3-[2-(éthylsulfonyi)éthyl]-2-imιno-6-pentafluoroéthylbenzothiazolιne, - 3-[2-(éthylsulfonyl)éthyl]-2-imιno-6-trιfluorométhylbenzothιazolιne,- 3- [2- (ethylsulfonyi) ethyl] -2-imιno-6-pentafluoroethylbenzothiazolιne, - 3- [2- (ethylsulfonyl) ethyl] -2-imιno-6-trιfluoromethylbenzothιazolιne,
- 3-[2-(methylthιo)ethyl]-2-ethylιmιno-6-tπfluorométhoxybenzothιazolιne,- 3- [2- (methylthιo) ethyl] -2-ethylιmιno-6-tπfluorométhoxybenzothιazolιne,
- 3-[2-(éthylsulfιnyl)ethyl]-2-methylιmιno-6-trιfluoromethoxybenzothιazolιne,- 3- [2- (ethylsulfιnyl) ethyl] -2-methylιmιno-6-trιfluoromethoxybenzothιazolιne,
- 2-(2-ιmιno-6-trιfluoromethoxybenzothtazolιn-3-yl)éthanesulfonamιde,- 2- (2-ιmιno-6-trιfluoromethoxybenzothtazolιn-3-yl) ethanesulfonamide,
N-méthyl-2-(2-ιmιπo-6-tπfluorométhoxybenzothιazolιn-3-yl)éthanesulfo namide,N-methyl-2- (2-ιmιπo-6-tπfluoromethoxybenzothιazolιn-3-yl) ethanesulfo namide,
- 2-ιmιno-3-[2-(4-phenylpιperazιnyl)éthyl]6-trιfluorométhoxybenzothiazolιne, leurs énantiomères, leurs diastéréoisomères et leurs sels pharmaceutiquement acceptables.- 2-ιmιno-3- [2- (4-phenylpιperazιnyl) ethyl] 6-trιfluorométhoxybenzothiazolιne, their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts.
Les composes de formule (I), leurs énantiomères, leurs diastéréoisomères et leurs sels pharmaceutiquement acceptables peuvent être préparés selon les procédés décrits dans les brevets EP374040, EP375510, EP408437, EP409692 et EP528968.
Il est connu que la neurotoxine MPTP (1 -methyl-4-phényl-1 ,2,3,6-tetrahydro- pyπdine) induit un syndrome similaire a la maladie de Parkinson. Ce syn¬ drome resuite d'une degeneration 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).The compounds of formula (I), their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts can be prepared according to the methods described in patents EP374040, EP375510, EP408437, EP409692 and EP528968. 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 syndrome 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 composes 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 a celle des animaux témoins. Le coefficient d'efficacité de chaque compose est calcule par le rapport [taux de dopamine du groupe MPTP+produit a 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 effectiveness 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 a 2 heures et 30 minutes d'intervalle, 15 mg/kg de MPTP par voie intrapéritonéale 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 à étudier Les souris sont tuées 24 heures après la dernière injection de MPTP. Le stπatum est dissèque et conserve à -70°C jusqu au moment de son analyse Les taux de dopamine, sont mesures par chromatographie liquide haute performance avec une détection electrochimique. Les analyses statistiques sont effectuées en utilisant une analyse de vaπance (ANOVA).15 mg / kg of MPTP is injected 3 times at 2 hours and 30 minutes apart intraperitoneally into mice (C57BL6) weighing 19-25 g. Thirty minutes before the first MPTP injection, then 2 hours, 4 hours and 30 minutes and finally 7 hours after the first MPTP injection, 5 mg / kg of the product to be studied are administered orally. The mice are killed 24 hours. after the last MPTP injection. The stπatum is dissected and stored at -70 ° C until the time of its analysis. The 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 égal ou supérieur a 1 ,80.The compounds of formula (I) have an efficiency coefficient equal to or greater than 1.80.
Comme sels pharmaceutiquement acceptables peuvent être notamment cites les sels d'addition avec les acides minéraux tels que chlorhydrate, sulfate, nitrate, phosphate ou organiques tels que acétate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, théo- philline-acetate, salicylate, phenolphtalmate, methylène-bis-β-oxynaphtoate ou des dérives de substitution de ces dérives.As pharmaceutically acceptable salts, mention may in particular be made of addition salts with mineral acids such as hydrochloride, sulfate, nitrate, phosphate or organic salts such as acetate, propionate, succinate, oxalate, benzoate, fumarate, maleate, methanesulfonate, isethionate, theo- phillin-acetate, salicylate, phenolphthalmate, methylene-bis- β- oxynaphtoate or substitution derivatives of these derivatives.
Les médicaments sont constitues par au moins un compose de formule (I), un énantiomère, un diastereoisomere sous forme libre ou sous forme d'un sel
d'addition avec un acide pharmaceutiquement acceptable, 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), an enantiomer, a diastereoisomer in free form or in the form of a salt. addition with a pharmaceutically acceptable acid, 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 drugs can be used orally or parenterally.
Comme compositions solides pour administration orale, peuvent être utilisés des comprimes, des pilules, des poudres (capsules de gélatine, cachets) ou des granules. 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 vernis.As 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, sac charose, 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 dye, a coating (dragees) or a varnish.
Comme compositions liquides pour administration orale, on peut utiliser des solutions, des suspensions, des émulsions, des sirops et des elixirs pharma- ceutiquement acceptables contenant des diluants inertes tels que l'eau, l'éthanol, le glycerol, les 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, there may be used pharmacologically acceptable solutions, suspensions, emulsions, syrups and elixirs containing inert diluents such as water, ethanol, glycerol, vegetable oils or the like. '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 émulsions. Comme solvant ou véhicule, on peut employer l'eau, le propylèneglycol, un polyethyleneglycol, 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 à 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 glyceπdes semisynthétiques ou des polyethyleneglycols.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, isotonic agents, emulsifiers, dispersants and stabilizers. Sterilization can be done in several ways, for example by sanitizing filtration, by incorporating sterilizing agents into the composition, 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 glycates 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 recherche, 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, the duration of the treatment and 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 comprimes doses à 50 mg de produit actif ayant la composition suivante :Prepared according to the usual technique, 50 mg tablets of active product having the following composition:
- Compose de formule (I) 50 mg- Compound of formula (I) 50 mg
- Mannitol 64 mg - Cellulose microcπstalline 50 mg- Mannitol 64 mg - Cellulose microcπstalline 50 mg
- Polyvidone excipient 12 mg- Polyvidone excipient 12 mg
- Carboxymethylamidon sodique 16 mg- Carboxymethylamidon 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, polyéthyleneglycol 6000, dioxyde de titane (72-3,5-24,5) q.s.p. 1 comprime pellicule termine a 245 mg
Exemple B- Mixture of methylhydroxypropylcellulose, polyethylene glycol 6000, titanium dioxide (72-3,5-24,5) qs 1 compressed film ends 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:
- Compose 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 le procède de préparation de médicaments utiles dans le traitement de la maladie de Parkinson et des syndromes parkinsoniens consistant a mélanger un compose de formule (I) ou les sels pharmaceutiquement acceptables de ce compose avec un ou plusieurs diluants et/ou adjuvants compatibles et pharmaceutiquement acceptables.The invention also relates to the process for the preparation of medicaments useful in the treatment of Parkinson's disease and of parkinsonian syndromes consisting in mixing a compound of formula (I) or the pharmaceutically acceptable salts of this compound with one or more diluents and / or compatible and pharmaceutically acceptable adjuvants.
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 compose αe .ormule (I), un énantiomère, un diastereoisomère ou un sel pharmaceutiquement acceptable de ce compose.
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 αe. Formula (I), a enantiomer, a diastereoisomer or a pharmaceutically acceptable salt of this compound.
Claims
REVENDICATIONS
1 - Application d'un composé de formule (I)1 - Application of a compound of formula (I)
R2 R 2
dans laquelle R représente un radical polyfluoroalcoxy ou polyfluoroalkyle, R-| représente un atome d'hydrogène ou un radical alkyle, R2 représente un radical 2-propynyle, -alk-S(0)n-alk, -alk-S02-NH2, -alk-S02-NHalk ou 4-phénylpipérazinyléthyle, n est 0, 1 ou 2 et alk est alkyle contenant 1 à 3C en chaîne droite ou ramifiée, étant entendu que, sauf mention contraire, les radicaux ou portions alkyle et alcoxy contiennent 1 à 4 atomes de carbone en chaîne droite ou ramifiée, leurs énantiomères, leurs diastéréoisomères et leurs sels pharmaceutiquement acceptables pour la préparation d'un médicament utile pour le traitement de la maladie de PARKINSON ou des syndromes parkinsoniens.in which R represents a polyfluoroalkoxy or polyfluoroalkyl radical, R- | represents a hydrogen atom or an alkyl radical, R2 represents a 2-propynyl, -alk-S (0) n-alk, -alk-SO2-NH2, -alk-SO2-NH2 or 4-phenylpiperazinylethyl radical, n is 0, 1 or 2 and alk is alkyl containing 1 to 3C in a straight or branched chain, it being understood that, unless otherwise stated, the alkyl or alkoxy radicals or portions contain 1 to 4 carbon atoms in a straight or branched chain, their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts for the preparation of a medicament useful for the treatment of PARKINSON disease or parkinsonian syndromes.
2 - Application selon la revendication 1 pour la préparation des composés de formule (I) pour lesquels R est trifluorométhoxy, pentafluoroéthoxy, trifluorométhyle ou pentafluoroéthyie et R-j est hydrogène, méthyle ou éthyle.2 - Application according to claim 1 for the preparation of compounds of formula (I) for which R is trifluoromethoxy, pentafluoroethoxy, trifluoromethyl or pentafluoroethyie and R-j is hydrogen, methyl or ethyl.
3 - Application d'un composé choisi parmi les composé suivants :3 - Application of a compound chosen from the following compounds:
- 3-(2-propynyl)-2-imino-6-trifluorométhoxybenzothiazoline,- 3- (2-propynyl) -2-imino-6-trifluoromethoxybenzothiazoline,
- -2-imino-3-méthylthiométhyl-6-trifluorométhoxybenzothiazoline, - 3-[2-(éthylthio)éthyl]-2-imino-6-trifluorométhoxybenzothiazoline,- -2-imino-3-methylthiomethyl-6-trifluoromethoxybenzothiazoline, - 3- [2- (ethylthio) ethyl] -2-imino-6-trifluoromethoxybenzothiazoline,
- 3-[2-(éthylthio)éthyl]-2-imino-6-trifluorométhylbenzothiazoline,- 3- [2- (ethylthio) ethyl] -2-imino-6-trifluoromethylbenzothiazoline,
- 3-[2-(éthylthio)éthyi]-2-imino-6-pentaf!uoroéthoxybenzothiazoline,- 3- [2- (ethylthio) ethy] -2-imino-6-pentaf! Uoroethoxybenzothiazoline,
- 2-imino-3-[2-(méthylthio)propyl]-6-trifluorométhoxybenzothiazoline,- 2-imino-3- [2- (methylthio) propyl] -6-trifluoromethoxybenzothiazoline,
- 2-imino-3-(méthylsulfinylméthyl)-6-trifluorométhoxybenzothiazoline, - 2-imino-3-[2-(méthylsulfinyl)éthyl]-6-trifluorométhoxybenzothiazoline,
- 3-[2-(éthylsulfιnyl)éthyl]-2-ιmιno-6-trιfluoromethoxybenzothiazoline,- 2-imino-3- (methylsulfinylmethyl) -6-trifluoromethoxybenzothiazoline, - 2-imino-3- [2- (methylsulfinyl) ethyl] -6-trifluoromethoxybenzothiazoline, - 3- [2- (ethylsulfιnyl) ethyl] -2-ιmιno-6-trιfluoromethoxybenzothiazoline,
- 2-imιno-3-[3-(méthylsulfιnyl)propyl]-6-trιfluorométhoxybenzothiazolιne,- 2-imιno-3- [3- (methylsulfιnyl) propyl] -6-trιfluorométhoxybenzothiazolιne,
- 2-ιmιno-3-[2-(méthylsulfιnyl)propyl]-6-trifluorométhoxybenzothiazoline,- 2-ιmιno-3- [2- (methylsulfιnyl) propyl] -6-trifluoromethoxybenzothiazoline,
- 2-imιno-3-[2-(méthylsulfonyl)éthyl]-6-trifluorométhoxybenzothιazoline, - 3-[2-(éthylsulfonyl)éthyl]-2-ιmιno-6-trifluorométhoxybenzothιazoline,- 2-imιno-3- [2- (methylsulfonyl) ethyl] -6-trifluoromethoxybenzothιazoline, - 3- [2- (ethylsulfonyl) ethyl] -2-ιmιno-6-trifluoromethoxybenzothιazoline,
- 3-[2-(éthylsulfonyl)éthyl]-2-ιmιno-6-pentafluoroéthylbeπzothιazolιne,- 3- [2- (ethylsulfonyl) ethyl] -2-ιmιno-6-pentafluoroethylbeπzothιazolιne,
- 3-[2-(éthylsulfonyl)éthyl]-2-ιmιno-6-trιfluorométhylbenzothiazolιne,- 3- [2- (ethylsulfonyl) ethyl] -2-ιmιno-6-trιfluorométhylbenzothiazolιne,
- 3-[2-(méthylthιo)éthyl]-2-éthylιmιno-6-tπfluorométhoxybenzothιazoline,- 3- [2- (methylthιo) ethyl] -2-ethylιmιno-6-tπfluoromethoxybenzothιazoline,
- 3-[2-(éthylsulfιnyl)éthyl]-2-methylιmιno-6-trιfluorométhoxybenzothιazolιne, - 2-(2-ιmιno-6-tπfluoromethoxybenzothιazolιn-3-yl)éthanesulfonamιde,- 3- [2- (ethylsulfιnyl) ethyl] -2-methylιmιno-6-trιfluorométhoxybenzothιazolιne, - 2- (2-ιmιno-6-tπfluoromethoxybenzothιazolιn-3-yl) ethanesulfonamιde,
N-methyl-2-(2-ιmιno-6-trιfluoromethoxybenzothιazolιn-3-yl)éthanesulfo namide,N-methyl-2- (2-ιmιno-6-trιfluoromethoxybenzothιazolιn-3-yl) ethanesulfo namide,
- 2-imιno-3-[2-(4-phenylpιperazιnyl)éthyl]6-tπfluorométhoxybenzothιazolιne, leurs énantiomères, leurs diastéréoisomères et leurs sels pharmaceutiquement acceptables pour la préparation d'un médicament utile pour le traitement de la maladie de PARKINSON ou des syndromes parkinsoniens.- 2-imιno-3- [2- (4-phenylpιperazιnyl) ethyl] 6-tπfluorométhoxybenzothιazolιne, their enantiomers, their diastereoisomers and their pharmaceutically acceptable salts for the preparation of a drug useful for the treatment of PARKINSON disease or syndromes Parkinson's.
4 - Application selon l'une des revendications 1 à 3 pour obtenir un médicament contenant 25 a 200 mg de matière active.
4 - Application according to one of claims 1 to 3 to obtain a medicament containing 25 to 200 mg of active material.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP9521025A JP2000505060A (en) | 1995-12-01 | 1996-11-26 | Use of 2-iminobenzothiazolines for treating Parkinson's disease and Parkinson's syndrome |
| EP96939977A EP0863756A1 (en) | 1995-12-01 | 1996-11-26 | Use of 2-iminobenzothiazolines for treating parkinson's disease and parkinsonian syndromes |
| AU76994/96A AU7699496A (en) | 1995-12-01 | 1996-11-26 | Use of 2-iminobenzothiazolines for treating parkinson's disease and parkinsonian syndromes |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR95/14240 | 1995-12-01 | ||
| FR9514240A FR2741804B1 (en) | 1995-12-01 | 1995-12-01 | APPLICATION OF 2-IMINOBENZOTHIAZOLINES IN THE TREATMENT OF PARKINSON'S DISEASE AND PARKINSONIAN SYNDROMES |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1997020558A1 true WO1997020558A1 (en) | 1997-06-12 |
Family
ID=9485069
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/FR1996/001867 WO1997020558A1 (en) | 1995-12-01 | 1996-11-26 | Use of 2-iminobenzothiazolines for treating parkinson's disease and parkinsonian syndromes |
Country Status (6)
| Country | Link |
|---|---|
| EP (1) | EP0863756A1 (en) |
| JP (1) | JP2000505060A (en) |
| AU (1) | AU7699496A (en) |
| FR (1) | FR2741804B1 (en) |
| WO (1) | WO1997020558A1 (en) |
| ZA (1) | ZA969968B (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374040A1 (en) * | 1988-12-15 | 1990-06-20 | Rhone-Poulenc Sante | 2-Imino-benzothiazoline derivatives, processes for their preparation and medicaments containing them |
-
1995
- 1995-12-01 FR FR9514240A patent/FR2741804B1/en not_active Expired - Fee Related
-
1996
- 1996-11-26 WO PCT/FR1996/001867 patent/WO1997020558A1/en not_active Application Discontinuation
- 1996-11-26 EP EP96939977A patent/EP0863756A1/en not_active Withdrawn
- 1996-11-26 AU AU76994/96A patent/AU7699496A/en not_active Abandoned
- 1996-11-26 JP JP9521025A patent/JP2000505060A/en active Pending
- 1996-11-27 ZA ZA969968A patent/ZA969968B/en unknown
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0374040A1 (en) * | 1988-12-15 | 1990-06-20 | Rhone-Poulenc Sante | 2-Imino-benzothiazoline derivatives, processes for their preparation and medicaments containing them |
Non-Patent Citations (1)
| Title |
|---|
| A. BENAZZOUZ ET AL.: "Riluzole prevents MPTP-induced parkinsonism in the Rhesus monkey: a pilot study.", EUR. J. PHARMACOL., vol. 284, no. 3, 1995, pages 299 - 307, XP000600898 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU7699496A (en) | 1997-06-27 |
| FR2741804A1 (en) | 1997-06-06 |
| EP0863756A1 (en) | 1998-09-16 |
| ZA969968B (en) | 1997-06-13 |
| FR2741804B1 (en) | 1998-01-02 |
| JP2000505060A (en) | 2000-04-25 |
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