Classifications

• • 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
  • A61K31/41—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
• • 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.
• radicals and the alkyl and alkoxy portions contain 1 to 4 carbon atoms in a straight or branched chain.
• 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 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-tetrahydropy ⁇ dine) induces a syndrome similar to Parkinson's disease. This syndrome results from a degeneration of nigrost ⁇ atal dopaminergic neurons in primates (RS BURNS et al., Proc. Natl. Acad.
• 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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• Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Life Sciences & Earth Sciences (AREA)
• Biomedical Technology (AREA)
• Neurology (AREA)
• Neurosurgery (AREA)
• Engineering & Computer Science (AREA)
• Chemical & Material Sciences (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Pharmacology & Pharmacy (AREA)
• Organic Chemistry (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Psychology (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (3)

Publications (1)

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ID=9485069

Family Applications (1)

Country Status (6)

Family Cites Families (1)

• 1995
  • 1995-12-01 FR FR9514240A patent/FR2741804B1/fr not_active Expired - Fee Related
• 1996
  • 1996-11-26 EP EP96939977A patent/EP0863756A1/fr not_active Withdrawn
  • 1996-11-26 WO PCT/FR1996/001867 patent/WO1997020558A1/fr not_active Application Discontinuation
  • 1996-11-26 AU AU76994/96A patent/AU7699496A/en not_active Abandoned
  • 1996-11-26 JP JP9521025A patent/JP2000505060A/ja active Pending
  • 1996-11-27 ZA ZA969968A patent/ZA969968B/xx unknown

Non-Patent Citations (1)

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