Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-05-30
1999-11-02
Ford, John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544182, C07D253075, A61K 3153
Patent
active
059771062
DESCRIPTION:
BRIEF SUMMARY
The subject of the present invention is novel 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives functionalized at the 2-position, their preparation and their therapeutic use.
Within the framework of the search for new anxiolytic medicaments with a non-benzodiazepine profile, the discovery and the development of buspirone have triggered a large number of studies. Numerous observations make it possible to associate a dysfunction of the serotoninergic system with certain psychiatric pathologies such as anxiety or depression (M. Hamon, H. Gozlan, Medecine/Sciences 1993, 9, 21-30). Thus, during the past few years, numerous compounds with affinity towards the 5HT.sub.1A receptors have been claimed for their benefit in human therapy and more particularly for their anxiolytic activity (J. Peergaard et al., current opinion in therapeutic patents, January 1993, 101-128).
3,5-dioxo-6-amino-(2H,4H)-1,2,4-triazine derivatives have been claimed by the applicant for their application in human therapy (FR filing No. 93,08259/06.07.93).
The compounds of the present invention are characterized by their novel structure, their potent affinity towards the 5HT.sub.1A receptor and their pharmacological profile.
The compounds of the invention correspond to the formula I, ##STR2## in which R.sub.1 represents hydrogen, a (C.sub.1 -C.sub.4) alkyl, phenyl (C.sub.1 -C.sub.4 alkyl) or phenyl radical, the phenyl ring being optionally substituted by one or more groups such as (C.sub.1 -C.sub.3) alkyl, hydroxyl, trifluoromethyl or halogen, ##STR3## the Ar group itself representing an aromatic structure such as phenyl, naphthyl, pyrimidyl, pyridyl, optionally substituted by one or more groups such as (C.sub.1 -C.sub.3) alkyl, (C.sub.1 -C.sub.3) alkoxy, hydroxyl, trifluoromethyl or halogen, ##STR4## in which R represents hydrogen or a (C.sub.1 -C.sub.3) alkyl group and X represents a nitrogen or carbon atom.
In addition, the invention covers the salts of compounds of general formula I with pharmaceutically acceptable acids, as well as the various enantiomers in the case of compounds having an asymmetric carbon.
In particular, n can take the values 2, 3 or 4.
The compounds of the invention may be obtained according to two different synthesis routes.
Method A
It is characterized in that:
1--a compound of general formula IV ##STR5## in which R.sub.1 is as defined in the formula I, is treated with a dihalogenated derivative of formula V halogen, preferably respectively chlorine for Hal and bromine for Hal'. The reaction is carried out in dimethylformamide in the presence of sodium hydride.
2--After acid hydrolysis, treatment is performed with a derivative of formula VI or VII ##STR6## in which Ar, R and X are as defined in the formulae I, II and III.
The reaction is performed by heating in toluene or xylene or in butanol in the presence of triethylamine.
3--Treatment is optionally performed with a derivative R.sub.2 Y in which R.sub.2 is as defined in the formula I and Y representing chlorine, bromine or iodine, in dimethyl formamide in the presence of sodium hydride.
Method B
It is characterized in that:
1--A compound of formula VIII: ##STR7## in which R.sub.1 is as defined in the formula I, is treated with an alkyl halide R.sub.2 Y, in dimethylformamide in the presence of sodium hydride.
2--Deacetylation is performed in acid medium such as paratoluenesulfonic acid in ethanol.
3--Treatment is performed with a dihalogenated compound V as defined above, in dimethylformamide in the presence of sodium hydride, then with a derivative VI or VII, as defined above.
The intermediate and final compounds may be, if desired, purified according to one or more purification methods chosen from extraction, filtration, silica gel chromatography and crystallization.
The raw materials used in the processes described above are commercially or easily accessible to persons skilled in the art according to processes described in the literature.
The following examples illustrate the invention without limiting its scope.
The elemental analyses and the IR and NMR spectra con
Couret Fran.cedilla.oise
Dupont-Passelaigue Elisabeth
Faure Christian
Koek Wouter
Patoiseau Jean-Fran.cedilla.ois
Ford John M.
Pierre Fabre Medicament
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