Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1988-09-09
1990-08-14
Friedman, Stanley J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514810, A61K 31415
Patent
active
049488031
DESCRIPTION:
BRIEF SUMMARY
This invention relates to a new medical use for certain chemical compounds and pharmaceutical compositions containing them. In particular it relates to the use in the treatment of subjects addicted, recovering from addiction, or liable to become addicted, to drugs or substances of abuse of compounds which act as antagonists of 5-hydroxytryptamine (5-HT) at receptors known in the art as 5-HT.sub.3, 5-HT'M' or 5-HT 'M'-like' receptors. Such receptors have been described for example by Fozard et al., Eur. J. Pharmacol., 1979, 59, 195-210; Ireland, Straughan and Tyers, Br. J. Pharmacol., 1982, 75, 16P; Humphrey, Neuropharm., 1984, 23, 1503-1570; Richardson et al., Nature, 1985, 316, 126-131; and Bradley et al., Neuropharm., 1986, 25, 563-576. Receptors of this type are now designated as 5-HT.sub.3 receptors.
5-HT receptors of this type are located, for example, on the terminals of afferent sensory neurones, in the isolated guinea-pig ileum preparation and are also present in the central nervous system. Compounds which act as antagonists of 5-HT at 5-HT.sub.3 receptors may be identified using standard tests, for example, in vitro by measuring their inhibition of the depolarising effect of 5-HT on the rat or rabbit isolated vagus nerve, or the tachycardia produced by 5-HT in the rabbit isolated heart or the contraction produced by 5-HT in the guinea-pig isolated ileum, or in vivo by measuring their effect on the Von Bezold-Jarisch reflex (induced by 5-HT) as described, for example, in the above-mentioned references.
A variety of compounds which act as antagonists of 5-HT at 5-HT.sub.3 receptors have been described in the art. The known compounds are generally azabicyclo derivatives and/or benzoic acid derivatives, or imidazole derivatives. Azabicyclo derivatives include compounds containing a bridged piperidyl group, such as a tropyl, pseudotropyl, homotropyl or quinuclidinyl group. An azabicyclo derivative preferably contains a carbocyclic or heterocyclic aromatic group linked, for example as an ester or amide, to the azabicyclic ring. The aromatic group may be for example an optionally substituted phenyl, indolyl, benzofuranyl, benzothienyl, benzisoxazolyl, indazolyl or pyrimidinyl group.
Benzoic acid derivatives which act as antagonists of 5-HT at 5-HT.sub.3 receptors include benzoates and benzamides. A benzoic acid derivative may for example be an ester or an amide formed with an azabicyclic group as defined above, or formed with a piperidyl group.
Such compounds have been disclosed inter alia in published UK Patent Application Nos. 2100259, 2125398, 2131420, 2132189, 2145416, 2152049, 2153821 and 2169292, published European Patent Application Nos. 111608, 116255, 158265, 191562, 200444, 210840, 214772, 219193, 221702, 226267, 227215, 230718, 235878 and 242973, and published Australian Patent Application No. 87/67121. The compounds disclosed in published European Patent Application Nos. 13138, 67615, and 94742 are described in published European Patent Application Nos. 215545 and 220011 as antagonists of 5-HT at 5-HT.sub.3 receptors.
The compounds disclosed in these specifications have been described as being of use in a variety of conditions, including migraine. However there is no disclosure in these specifications of compounds which are antagonists of 5-HT at 5-HT.sub.3 receptors being of use in the treatment of drug abuse.
We have now found that compounds which act as 5-HT antagonists at 5-HT.sub.3 receptors may be used in the treatment of subjects addicted, recovering from addiction, or liable to become addicted, to drugs or substances of abuse.
1,2,3,9-Tetrahydro-9-methyl-3-[(2-methylimidazol-1-yl)methyl]-4H-carbazol-4 -one and its salts and solvates, which are disclosed in published UK Patent Application No. 2153821A are however excluded from the present invention. It will be appreciated that general references hereinafter to "compounds which act as antagonists of 5-HT at 5-HT.sub.3 receptors" and to those compounds "disclosed in published UK Patent Application No. 2153821A" exclude 1,2,3,9-tetrahydro
REFERENCES:
patent: 4808581 (1989-02-01), Oxford et al.
patent: 4847281 (1989-07-01), Tyers
Friedman Stanley J.
Glaxo Group Limited
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