1,2,4-thiadiazino[3,4-b]benzothiazole derivatives, and medicinal

Details 1,2,4-thiadiazino[3,4-b]benzothiazole derivatives, and medicinal 1,2,4-thiadiazino[3,4-b]benzothiazole derivatives, and medicinal

1993-12-07

1995-04-04

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

544 9, A61K 3154, C07D51304

Patent

active

054038375

DESCRIPTION:

BRIEF SUMMARY
DESCRIPTION OF THE INVENTION

The present invention relates to derivatives of formula: ##STR2## their salts, their preparation and medicinal products containing them.
Patent EP 374040 describes 2-iminobenzothiazoline derivatives which are active towards glutamate-induced convulsions.
In the formula (I),
In the above definitions and in those which will be mentioned below, the alkyl and alkoxy radicals and portions contain 1 to 4 carbon atoms in a linear or branched chain.
The polyfluoroalkyl radicals are preferably trifluoromethyl, 2,2,2-trifluoroethyl and pentafluoroethyl radicals.
The polyfluoroalkoxy radicals are preferably trifluoromethoxy, pentafluoroethoxy, 2,2,2-trifluoroethoxy and 1,1,2,2-tetrafluoroethoxy radicals.
The invention also relates to the addition salts of the compounds of formula (I) with inorganic or organic acids.
The compounds of formula (I) may be prepared by cyclisation of a derivative of formula: ##STR3## in which R and R.sub.1 have the same meanings as in the formula (I).
This cyclisation is generally carried out in an oxidizing medium (for example bromine, chlorine, iodine, potassium triiodide, hydrogen peroxide or chloramine-T) in an inert solvent such as an alcohol (for example methanol or ethanol), a chlorine-containing solvent (for example chloroform or methylene chloride), an aromatic solvent (for example benzene or toluene), or a ketone (for example acetone), at a temperature ranging from 20.degree. to 50.degree. C.
The derivatives of formula (II) may be obtained by hydrolysis of a derivative of formula: ##STR4## in which R and R.sub.1 have the same meanings as in the formula (I).
This hydrolysis is preferably carried out by means of a base such as an alkali metal carbonate (for example sodium or potassium), or an alkali metal hydroxide (for example sodium hydroxide or potassium hydroxide), in an inert solvent such as an alcohol, a ketone, water or a mixture of these solvents, at a temperature of between 20.degree. and 50.degree. C.
The derivatives of formula (III) may be obtained by reacting thioacetic acid with a derivative of formula: ##STR5## in which R and R.sub.1 have the same meanings as in the formula (I).
This reaction is preferably carried out in an inert solvent such as tetrahydrofuran, by means of triphenylphosphine and ethyl azodicarboxylate, at a temperature of between 0.degree. and 25.degree. C.
The derivatives of formula (IV) may be prepared by applying or adapting the method described in Patent EP409692.
The reaction mixtures obtained by the various methods described above are treated using conventional physical methods (evaporation, extraction, distillation, chromatography, crystallization and the like) or conventional chemical methods (formation of salts and the like).
The compounds of formula (I), in the form of a free base, may be optionally converted to the addition salts with an inorganic or organic acid, by reaction of such an acid in an organic solvent such as an alcohol, a ketone, an ether or a chlorine-containing solvent.
The compounds of formula (I) and their salts possess advantageous pharmacological properties. These compounds interfere with glutamatergic transmission and are therefore useful in the treatment and prevention of phenomena linked to glutamate. These phenomena are in particular epileptogenic and/or convulsive manifestations, schizophrenic disorders and in particular the deficiency forms of schizophrenia, sleep disorders, anxiety, phenomena linked to cerebral ischaemia as well as neurological disorders linked to aging where glutamate may be involved, such as Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis and olivopontocerebellar atrophy.
The antiglutamate activity of these products has been determined for convulsions induced by glutamate according to a technique inspired by that of I. P. LAPIN, J. Neural. Transmission, 54, 229-238 (1982); the injection of glutamate by the intracerobroventricular route being carried out according to a technique inspired by that of R. CHERMAT and P. SIMON, J. Pharmacol. (Pari

REFERENCES:
Krutak et al, Chemical Abstract, vol. 91, entry 192232a (1979).
Journal of Organic Chemistry, vol. 44, No. 22, (1979), pp. 3847-3858, J. J. Krutak et al., `Chemistry of Ethenesulfonyl Fluoride.
Chemische Berichte, vol. 100, pp. 2159-2163, H. Beecken `Uber die Cycloaddition heterocyclisher N-sulfinyl-amine an Bicyclo[2.2.1]hepten und Athoxyacetylen` (1967).

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