Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-12-06
1998-09-01
Cooney, Jr., John M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514810, 514811, 514812, 514813, A01N 4364
Patent
active
058011714
DESCRIPTION:
BRIEF SUMMARY
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 triazine compounds, including 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine, and acid addition salts thereof, 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. The compounds are non-depressant and are therefore advantageous compared with depressant antiepileptics 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 at anticonvulsant brain concentrations to inhibit the release of excitatory amino acids, principally glutamate (Leach, M. J. et al. (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 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 as an inhibitor of glutamate release.
A number of currently available drugs that produce effects on mood, thought or feeling have a well-recognized potential for addiction and misuse; see for example Chapter 22 in Goodman and Gilman's "The Pharmacological Basis of Therapeutics", eighth edition, McGraw-Hill, Inc. (1992). One of the hazards in the use of such a drug is that some individuals eventually develop a dependence on it; they continue to take it in the absence of medical indications, often despite adverse social and medical consequences, and behave as though its effects were essential for continued well-being. The intensity of this need may vary from a mild desire to a craving or compulsion to use the drug and, when its availability is uncertain, individuals may exhibit a preoccupation with its procurement.
A further aspect of drug use and misuse is drug tolerance, which is manifested as a reduction in a particular effect upon repeated exposure to a drug at constant dose, or the need for an increased dose of a drug to maintain a given effect. A related phenomenon is reverse tolerance (sensitisation), whereby the repeated administration of a given drug produces an increase in a particular effect.
No successful clinical management yet exists for drug dependence or drug tolerance, despite the significant problems caused by each for the individual and for society. There is therefore a need for effective ways of treating drug dependence and tolerance.
It has now surprisingly been found that 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine and its pharmaceutically and veterinarily acceptable acid addition salts are effective in controlling drug dependence and tolerance. Accordingly, the present invention provides the use of 3,5-diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine or a pharmaceutically or veterinarily acceptable acid addition salt thereof in the preparation of a medicament for
3,5-Diamino-6-(2,3-dichlorophenyl)-1,2,4-triazine will hereinafter be referred to as compound A. Compound A and its acid addition salts will be referred to collectively as the present compounds.
Suitable acid addition salts of compound A include those formed with either organic or 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 or isethionic acid. The salt with isethionic acid is preferred since it possesses particularly good solubility.
The present compounds may be pr
REFERENCES:
Leach et al: "Neurochemical and Behavioural Aspects of Lamotrigine," EPILEPSIA, vol. 32, No. SUP2, 1991, pp. S4-S8.
Oonnell et al: "The Effect of Lamotrigine Upon Development of Cortical Kindled Seizures in the Rat," Neuropharmacology, vol. 30, No. 3, Mar. 1991, pp. 253-258.
Weiss et al: "Chronic Carbamazepine Inhibits the Development of Local Anaesthetic Seizures Kindled by Cocaine and Lidocaine," vol. 497, No. 1, 11 Sep. 1989, pp. 72-79.
The Merck Index, Eleventh Edition, 1989, "Lamotrigine", p. 844.
Cooney Jr. John M.
Glaxo Wellcome Inc
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