Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1997-04-24
1998-08-18
Ramsues, Robert W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548161, 548164, A61K 31425, C07D27782
Patent
active
057959030
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR95/01392 filed Oct. 23, 1995.
The present invention relates to compounds of formula: ##STR2## to their salts, to their preparation and to the medicaments containing them.
In the formula (I), R represents a polyfluoroalkoxy or polyfluoroalkyl radical, and either R.sub.1 represents a hydrogen atom and R.sub.2 represents a hydroxyl radical, or R.sub.1 represents a hydroxyl radical and R.sub.2 represents a hydrogen atom.
The polyfluoroalkoxy radicals are preferably trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy and 1,1,2,2-tetrafluoroethoxy radicals. The polyfluoroalkyl radicals are preferably trifluoromethyl radicals.
In the preceding definitions and those which will be mentioned below, the alkyl and alkoxy radicals and portions contain 1 to 4 straight- or branched-chain carbon atoms.
The compounds of formula (I) in which R.sub.1 represents a hydrogen atom and R.sub.2 represents a hydroxyl radical can be prepared by reacting hydroxylamine hydrochloride with a corresponding 2-chloro-6-(polyfluoroalkoxy)- or -6-(polyfluoroalkyl)benzothiazole.
This reaction is carried out in an inert solvent such as a lower alcohol (for example, methanol), in the presence of a base such as an alkali metal hydroxide (for example, sodium hydroxide or potassium hydroxide), at the boiling temperature of the reaction mixture.
The 2-chloro-6-(polyfluoroalkoxy)- or -6-(polyfluoroalkyl)benzothiazoles can be obtained by application or adaptation of the methods described by S. Mignani et al., Synth. Commun., 22 (19), 2769-2780 (1992) and in the examples.
The compounds of formula (I) in which R.sub.1 represents a hydroxyl radical and R.sub.2 represents a hydrogen atom can be prepared by demethylation of a corresponding 2-amino-5-methoxy-6-(polyfluoroalkoxy)- or -6-(polyfluoroalkyl)benzothiazole.
This demethylation is generally carried out using excess hydrobromic acid, at the boiling temperature of the reaction mixture.
The 2-amino-5-methoxy-6-(polyfluoroalkoxy)- or -6-(polyfluoroalkyl)benzothiazoles can be obtained by application or adaptation of the methods described in the examples.
The reaction mixtures obtained by the various processes described above are treated according to conventional physical (evaporation, extraction, distillation, chromatography, crystallization, and the like) or chemical (formation of salts, and the like) methods.
The compounds of formula (I) in the free base form can optionally be converted to addition salts with an inorganic or organic acid, by reaction with such an acid in an organic solvent, such as an alcohol, a ketone, an ether or a chlorinated solvent.
The compounds of formula (I), for medicinal purposes, can be used as is or in the form of pharmaceutically acceptable salts, that is to say non-toxic at the use doses.
The addition salts with inorganic or organic acids, such as acetate, propionate, succinic, benzoate, fumarate, maleate, oxalate, methanesulphonate, isethionate, theophyllinacetate, salicylate, methylenebis-.beta.-oxynaphthoate, hydrochloride, sulphate, nitrate and phosphate, may be mentioned as examples of pharmaceutically acceptable salts.
The compounds of formula (I) and their salts exhibit advantageous pharmacological properties. These compounds interfere with glutamatergic transmission and are therefore useful in the treatment and the prevention of phenomena related to glutamate. These phenomena are in particular epileptogenic and/or convulsive manifestations, schizophrenic disorders, sleep disorders, anxiety, phenomena related to cerebral ischaemia, and neurodegenerative diseases and neurological disorders related to aging where glutamate may be involved, such as Alzheimer's disease, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosis, cranial and medullary traumas and olivopontocerebellar atrophy.
The antiglutamate activity of these products was determined with respect to convulsions induced by glutamate according to a technique inspired by that of I. P. Lapin, J. Neural. Transmission, 54, 229-238 (1982); injection of g
REFERENCES:
patent: 4370338 (1983-01-01), Mizoule
patent: 5008280 (1991-04-01), Gueremy et al.
patent: 5236940 (1993-08-01), Audiau et al.
Chapelle Philip
Gaillard Claude
Jimonet Patrick
Louvel Erik
Martinet Michel
Lutz Laura R. C.
Ramsues Robert W.
Rhone-Poulenc Rorer S.A.
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