Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1993-10-12
1995-07-18
Henley, III, Raymond
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514811, A61K 31495
Patent
active
054341566
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a new use of certain diphenylbutyl-piperazinecarboxamides, especially amperozide, 4-[4,4-bis(4-fluorophenyl)butyl]-N-ethyl-1-piperazinecarboxamide, and salts thereof, in the treatment of substance abuse disorders. More particularly, this invention relates to the amelioration of withdrawal symptoms and to modifying drug-seeking behaviour.
BACKGROUND OF THE INVENTION
Different classes of neuronal receptors and neurotransmitters in the brain have been implicated in the complex mechanisms underlying the compulsive drinking of alcohol. Experimental findings have favoured the opioid, dopaminergic, serotonergic, and benzodiazepine receptor subtypes. Whether the receptor category is pre- or postsynaptic in nature and whether neurotransmitter synthesis and/or release is equally involved in the manifestation of alcohol drinking is presently unknown.
Drug dependency is extremely difficult to escape. This is true whether the dependency is one based on ethanol, amphetamine, barbiturates, benzodiazepines, cocaine, nicotine, opioids, and phencyclidine or the like. Despite active research, there are as yet no drugs that specifically can antagonize for example the alcohol craving in alcohol-dependent subjects. Previous research demonstrated that for example serotonin uptake blockers (e.g. zimelidine, sertraline) reduce voluntary alcohol consumption in rats and humans. However, the mechanism of action of these compounds is not Well understood. There is considerable experimental evidence that the effects on alcohol intake may be an expression of a more general inhibiting role that serotonin plays in consummatory behaviour. Indeed serotonin uptake blockers and serotonin agonists have been shown to reduce a number of oral consummatory behaviours such as the intake of food as well as a variety of flavoured fluids such as alcohol.
The serotonin uptake blocker, sertraline, has been found to reduce alcohol intake in rats. Concurrent with the effect on alcohol drinking, however, sertraline lowered the intake of food and water and caused an overall decline in body weights (Gill K. et al., Alcohol 5:355-358, 1988; Myers R. D. and Quarfordt S. D., Pharmacol. Biochem. Behav. 40:923-28, 1991). Clearly, it is likely that the action of sertraline on alcohol intake is related to a serotonin uptake blocker's effect on oral consummatory behaviour. Hence, a decline also in the drinking of alcohol would not be unexpected. Furthermore, during the period following the sertraline treatment, the intake of alcohol rose toward the pretreatment level. There is accordingly a need for a more specific and effective agent to be used for treating abuse disorders.
SUMMARY OF THE INVENTION
It has now unexpectedly been found that diphenylbutyl-piperazinecarboxamides of the formula ##STR1## wherein
R.sub.1 and R.sub.2 are groups independently selected from the group of H, alkyl chains, straight or branched, with 1-10 carbon atoms, cycloalkyl with 3-8 carbon atoms, aralkyl with 7-9 carbon atoms, alkenyl with 2-10 carbon atoms, phenyl unsubstituted or substituted by one to three groups selected from halogen, especially F, Cl and Br, lower alkyl with 1-5 carbon atoms, lower alkoxy with with 1-5 carbon atoms, amine unsubstituted or substituted by one or two lower alkyl groups with 1-5 carbon atoms, --CF.sub.3 and --CN groups,
R.sub.3, R.sub.4, R.sub.5 and R.sub.6 are groups independently selected from H, lower alkyl having from 1-3 carbon atoms and phenyl,
R.sub.7 is selected from hydrogen, halogen especially F, Cl and Br, lower alkoxy with 1-3 carbon atoms and --CF.sub.3, and
X is O or S and pharmaceutically acceptable salts thereof,
This finding opens up a completely new method of treating dependence on drugs, alcohol, nicotine and the like. The actual substances have been found to be both chemically and pharmacologically different from those drugs suggested hitherto for the treatment of drug dependence.
Specifically the invention relates to the relief or prevention of a withdrawal syndrome resultin
REFERENCES:
patent: 4308387 (1981-12-01), Bjork et al.
patent: 4385057 (1983-05-01), Bjork et al.
patent: 4447433 (1984-05-01), Bjork et al.
Life Sciences, vol. 47, 1990, Eva Eriksson: "Amperozide, a putative anti-psychotic drug: uptake inhibition and release of dopamine in vitro in the rat brain" pp. 2111-2117, see especially p. 2116.
Pharmacology & Toxicology Supplement, vol. 1, 1990, J. Svartengren et al: "Receptor binding properties of amperozide," pp. 8-11.
Bjork Anders
Christensson Erik
Henley III Raymond
Pharmacia AB
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