Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1995-09-18
1997-08-19
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
A61K 3153
Patent
active
056589050
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 94/00560 filed Mar. 18, 1994.
The present invention relates to the use of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and its pharmaceutically and veterinarily acceptable acid addition salts in therapy.
EP-A-0 021 121 describes a group of triazines, including 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, which are active in the treatment of disorders of the central nervous system, for example psychiatric and neurological disorders, and which are particularly useful as anticonvulsants for instance in the treatment of epilepsy. These triazines are non-depressant and are therefore advantageous compared with depressant anti-epileptics such as phenobarbitone. EP-A-0 247 892 describes 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine isethionate, a particularly preferred salt owing to its good solubility.
In mechanistic studies, 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine has been shown to produce a use-dependent block of voltage-sensitive sodium channels (Lang et at, 1993, J. Pharm. Exp. Therap., 266, 829; Lees, G. and Leach, M. J., 1993, Brain Res., 612, 190) and at anticonvulsant brain concentrations to inhibit the release of excitatory. amino acids, principally glutamate (Leach, M. J. et at, 1986, Epilepsia, 27, 490-497; Zhu, S. G. and McGee, E. G., 1990, Neurosci. Lett., 112, 348-351). Glutamate functions as an important neurotransmitter in the mammalian central nervous system and has also been identified as having specific actions in the peripheral nervous system. The known anticonvulsant effect of this compound has therefore been ascribed to its ability to act at voltage-sensitive sodium channels as an inhibitor of glutamate release.
Anxiety is a symptom associated with a wide range of clinical conditions. Conventional anxiety management includes treatment with sedative anxiolytics, examples of which are benzodiazepines such as diazepam (7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one). However, the clinical use of benzodiazepines is associated with adverse side-effects including dependence and ataxia. There is therefore a continuing need for new agents which are effective anxiolytics.
It has now surprisingly been found that 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and its salts are effective in controlling anxiety. Accordingly, the present invention provides the use in the preparation of a medicament for the treatment of anxiety or an anxiety disorder, of 3,5-diamino-6-(2,3-dichlorophenyt)-1,2,4-triazine or a pharmaceutically or veterinarily acceptable acid addition salt thereof.
3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine will hereinafter be referred to as compound A. Compound A and its salts will be referred to collectively as the present compounds. The present compounds are non-toxic at prophylactically and therapeutically effective doses. They have the important added advantage over benzodiazepines such as diazepam that their use does not give rise to dependence or to behavioural changes such as ataxia (see Example 1 and the Comparative Example which follow).
Suitable acid addition salts of compound A include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically and veterinarily acceptable. Examples of such salts include those formed with hydrochloric, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, fumaric, maleic, methanesulphonic, ethanesulphonic, oxaloacetic and isethionic acids. The salt with isethionic acid is preferred since it possesses particularly good solubility.
The present compounds may be prepared by a process which comprises cyciising the compound of formula (II): ##STR1## and, if desired, converting compound A thus obtained into a pharmaceutically or veterinarily acceptable acid addition salt.
The cyclisation is typically carried out by heating the compound of formula II under reflux in an alkanol, preferably a C.sub.1-4 alkanol, for example methanol or ethanol, in the presence of a strong base, for example potassium
REFERENCES:
British J. Pharmacol. III, Suppl. 205P (1994).
Epilepsia 32 (Suppl. 2) SA-S8 (1991).
Can. J. Neurol. Sci. 19 1 (Suppl.) (1992) 160-162.
Boll. Lega Ital. Epilespssia 70/71 (1990), 103-104.
Glaxo Wellcome Inc.
Spivack Phyllis G.
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