Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1996-03-26
1997-01-07
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
544182, C07D253075, A01N 43707
Patent
active
055917437
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to new derivatives of 3,5-dioxo-6 amino-(2H,4H)-1,2,4-triazine, their preparation and their therapeutic use.
In the search for new anxiolytic drugs having a non-benzodiazepine profile, the discovery and development of Buspirone has resulted in a large amount of work. In fact, during recent years, numerous compounds having an affinity for 5HT1A receptors have been claimed for their anxiolytic and/or antihypertensive activity (J. Peergaard, et al., Current opinion in therapeutic Patents, January 1993, 101-128).
The compounds of the present invention are characterized by their original structure, their powerful affinity for the 5HT1A receptor, and their pharmacological profile.
The compounds of the invention correspond to general formula I ##STR4## in which: R.sub.1 and R.sub.2, which are identical or different, represent hydrogen or a C.sub.1 -C.sub.6 alkyl radical, ##STR5## the Ar grouping in its turn representing an aromatic structure such as phenyl, naphthyl, pyrimidyl or pyridyl, possibly substituted by one or more groupings such as C.sub.1 -C.sub.3 alkyl, C.sub.1 -C.sub.3 alkoxy, hydroxy, trifluoromethyl or halogen. ##STR6## in which R represents hydrogen or a C.sub.1 -C.sub.3 alkyl grouping and X represents a nitrogen or carbon atom.
Furthermore, the invention covers the salts of the compounds of general formula I with pharmaceutically acceptable acids in the case of compounds of sufficient basicity, as well as the various enantiomers for the compounds having an asymmetric carbon.
The compounds of the invention can be obtained by a chemical process characterized by condensing a compound of general formula IV. ##STR7## with a compound of general formula V, ##STR8## the radicals R.sub.1, R.sub.2, n, and A having the same meaning in IV and V as in general formula I.
The compounds of general formula IV are themselves obtained in accordance with the invention as described below:
a) When R.sub.1 =R.sub.2 =H, by bromination of 3,5-dioxo-(2H,4H)-1,2,4-triazine by bromine in aqueous medium.
b) When R.sub.1 =R.sub.2 =alkyl, by alkylation of 3,5-dioxo(2H,4H)-1,2,4-triazine in the presence of sodium hydride in DMF by an alkyl halide, followed by bromination by the same method as a) above. For the alkylation it is necessary, as intermediate step, to isolate the mixture of monoalkyl compounds formed and to carry out the alkylation operation again under the same conditions in order to have a complete reaction.
c) When R.sub.1 =H and R.sub.2 =alkyl from 3,5-dioxo-(2H,4H)-1,2,4-triazine by: chloride presence of NaH in DMF, X representing Cl, Br or I
d) When R.sub.1 .noteq.R.sub.2 =alkyl, by alkylation of the compound obtained in accordance c/3 by an alkyl halide R.sub.1 X in the presence of NaH in DMF, X representing Br, Cl or I, followed by bromination as described previously.
e) When R.sub.1 =alkyl and R.sub.2 =H, by: glyoxylic acid with the thiosemicarbazide followed by a base treatment NaH in DMF, X representing Cl, Br or I
The preparation of the compounds I for which R.sub.1 =R.sub.2 =H can also be advantageously carried out by condensing the amine V with the brominated and acetylated compound VI ##STR9## and then treating the resultant derivative in acid medium such as hydrochloric acid or p-toluenesulfonic acid.
The compound VI is in its turn obtained by the acetylation with acetic anhydride or acetyl chloride of 6-bromo-3,5-dioxo-(2H,4H)-1,2,4-triazine.
The compounds V are commercial amines or can be obtained in conventional manner such as generation of the primary amine from the intermediate phthalimide.
The following examples illustrate the invention without limiting its scope.
The elementary analyses and the IR and NMR spectra confirm the structures of the compounds obtained by the invention.
EXAMPLE 1:
2,4-dimethyl-3,5-dioxo- (2H,
4H)-6-(4-(4-(3-trifluoromethylphenyl)piperazino)butylamino)-1,2,4-triazine 1. ##STR10## a) 2,4-dimethyl-3,5-dioxo(2H,4H)-1,2,4-triazine 1a.
To a 60% suspension of sodium hydride in paraffin oil (8.8 g; 0.22 mol) in DMF (100 ml), a solution of 3,
REFERENCES:
patent: 4931444 (1990-06-01), Van Wauve et al.
patent: 4985427 (1991-01-01), Waterhouse et al.
patent: 5023255 (1991-06-01), Ellis et al.
patent: 5424310 (1995-06-01), Fukami et al.
Lazurkevich et al., Growth activity of 6-substituted azauracils, Fiziol. Biokhim. Kul't. Rast. (1985), 17(1), pp. 48-54 1985.
Tzeng et al., 4-Azapteridines. 2[1]. Spectral, Chromatographic, and X-Ray Crystallographic Studies concerning the Mode of Covalent Addition to the Pyrazino[2,3-e]-as-triazine Ring system, J. Heterocyclic Chem., 23, (1986), pp. 33-42 1986.
Journal of Medicinal Chemistry, 35, No. 13, pp. 2369-2374 (1992); Jerzy L. Mokrosz et al., "Structure-activity relationship studies of central nervous system agents. 5. Effect of . . . ".
Couret Francoise
Dupont-Passelaigue Elisabeth
Faure Christian
Koek Wouter
Patoiseau Jean-Francois
Pierre Fabre Medicament
Rao Deepak R.
Shah Mukund J.
LandOfFree
3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives as 5HT.sub.1A ligan does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives as 5HT.sub.1A ligan, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and 3,5-dioxo-(2H,4H)-1,2,4-triazine derivatives as 5HT.sub.1A ligan will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1764361