Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-11-30
1996-10-15
Weddington, Kevin E.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514218, 5142358, 514248, 514255, 514357, 514360, 514810, 514811, 514812, 514813, A61K 31495
Patent
active
055654550
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/SE93/00339 filed 04/19/93.
FIELD OF THE INVENTION
The present invention relates to a new use of certain pyridyl- and pyrimidyl-substituted bisphenylalkylpiperazines in the treatment of substance abuse disorders. More particularly, this invention relates to the amelioration of withdrawal symptoms and to modify drug-seeking behaviour.
BACKGROUND OF THE INVENTION
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. There is a need, therefore for an agent decreasing or overcoming such addiction and, if possible reducing or eliminating the symptoms related to the withdrawal of such drugs or substances of abuse.
Different classes of neuronal receptors and neurotransmitters in the brain have been implicated in the complex mechanisms underlying for example the compulsive drinking of alcohol. Experimental findings have favoured the opioid, dopaminergic, serotonergic, and benzodiazepine receptor subtypes.
Based upon a large number of genetic and pharmacological studies, serotonin (5-ET) containing neurons in the limbic-midbrain and limbic-forebrain pathways are seemingly involved, in part, in the fundamental mechanisms underlying for example alcohol drinking.
A number of reports have established that 5-HT uptake blockers significantly attenuate ethanol intake in rats. For example, zimelidine (The Merck Index 11th Ed., No. 10024) was found to have a potent inhibitory effect on voluntary ethanol consumption in rats. In human trials, zimelidine was shown to increase the number of abstinent days and to produce a slight reduction in the number of daily drinks. There is ample evidence that serotonin is involved in the regulation of both food and fluid intake. Zimelidine was found to attenuate the ingestion of food and alcohol concomitantly. It is possible, therefore, that zimelidine's action is mediated through more global effects on consummatory behaviour rather than specific effects on ethanol reinforcement.
Buspirone (The Merck Index 11th Ed., No. 1493), a partial 5-HT.sub.1A agonist, has been found to be effective for the treatment of anxiety. Buspirone was reported to attenuate significantly the consumption of alcohol by monkeys. In a clinical trial comparing buspirone to placebo in alcohol-dependent individuals, there was a lower drop-out rate in the buspirone-treated group, which also reported fewer signs of craving.
Amperozide (The Merck Index 11th Ed., No. 612), a 5-HT.sub.2 antagonist, was reported to significantly attenuate the intake of alcohol in rats without affecting neither consumption of food nor level of body weight.
SUMMARY OF THE INVENTION
It has now surprisingly been found that bisphenylalkylpiperazines of formula ##STR1## and the pharmaceutically acceptable acid addition salts thereof, wherein R.sub.1 and R.sub.2 are the same or different and selected from hydrogen or halogen; alkyl having 1 to 5 carbon atoms; ##STR2## wherein R.sub.5 is selected from hydrogen, alkyl having 1 to 5 carbon atoms or halogen; R.sub.6 and R.sub.7 are the same or different and selected from hydrogen, halogen, alkyl having 1 to 5 carbon atoms, alkoxy having 1 to 5 carbon atoms, hydroxy, cyano, nitro, trifluoromethyl, COOR.sub.8, CONR.sub.9 R.sub..sub.10 or COB; wherein R.sub.8 is hydrogen or alkyl having 1 to 5 carbon atoms; R.sub.9 and R.sub.10 are the same or different and selected from hydrogen, alkyl having 1 to 5 carbon atoms or cycloalkyl having 3 to 8 carbon atoms; ##STR3## wherein m is 1, 2, 3, or 4; R.sub.11 is selected from hydrogen or alkyl having from 1 to 5 carbon atoms;
and when used in the foregoing definitions the term alkyl is meant to include straight and branched hydrocarbon groups; the term alkoxy is meant to include straight and branched alkoxy groups; the term halogen is meant to include fluoro, chloro and bromo,
are unexpectedly effective and specific in the treatment of individuals addicted to drugs o
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patent: 4766215 (1988-08-01), Abou-Gharbia et al.
patent: 4937245 (1990-06-01), Fex et al.
Andersson Gunnar
Bjork Anders
Pharmacia AB
Weddington Kevin E.
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