Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-06-04
1999-12-07
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
546 79, 546 98, 546 99, 540479, 540586, 514290, 514296, A61K 3146, A61K 3155, C07D47118
Patent
active
059984058
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel fused tropane-derivatives which are monoamine neurotransmitter, i.e dopamine, serotonin and noradrenaline, re-uptake inhibitors. In particular, the present invention relates to novel fused tropane-derivatives which are potent serotonin re-uptake inhibitors and therefore useful in the treatment of disorders or diseases responsive to the inhibition of serotonin re-uptake, such as depression and related disorders, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety and eating disorders.
BACKGROUND OF THE INVENTION
The brain consists of a plurality of neurons that communicate with each other via chemical messengers. Each neuron generates neurochemicals, referred to as neurotransmitters; and the neurotransmitters act at sites on the cellular membrane of neurons, the sites being referred to as receptors. One group of neurotransmitters, referred to as the monoamine neurotransmitters, includes serotonin, dopamine and noradrenaline.
Monoamine neurotransmitters are released into the synaptic cleft in order to stimulate postsynaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into presynaptic terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occur.
Noradrenalin and serotonin re-uptake inhibitors are currently used as pharmaceuticals in anti-depressant therapy (Desipramine, Nortriptyline, and Protriptyline are inhibitors of noradrenaline-reuptake and Imipramine and Amitriptyline are mixed serotonine-reuptake and noradrenaline-reuptake inhibitors).
The pathophysiology of major affective illness is poorly understood, and several neurotransmitters have been implicated in the pathophysiology of major depression. However, several lines of preclinical and clinical evidence indicate that an enhancement of serotonin-mediated neurotransmission might underlie the therapeutic effect of the most recent and currently used drugs in anti-depressant therapy: Fluoxetine, Citalopram and Paroxetine.
Paradoxical serotonin re-uptake inhibitors inhibit the serotonin transporter within minutes whereas their full anti-depressant effect is seen only after three to four weeks of treatment, indicating that re-uptake inhibition per se is not responsible for the antidepressant response, but rather that further adaptive changes underlie and/or contribute to their therapeutic effect. The delayed onset of anti-depressant effect is considered to be a serious drawback to currently used monoamine re-uptake inhibitors.
The compounds provided with the present invention are potent serotonin (5-hydroxy-tryptamine, 5-HT) re-uptake inhibitors. The compounds of the invention also have noradrenaline and dopamine re-uptake inhibiting activity, the serotonin re-uptake and the noradrenaline re-uptake inhibiting activity of the compounds of the invention being stronger than the dopamine re-uptake inhibiting activity of the compounds, see table below.
A strong dopamine re-uptake inhibiting activity is currently considered with the risk of undesirable central stimulating effects. On the other hand, an activating effect on the mesolimbic dopamine system is currently believed to underlay the commen mechanism of current antidepressant treatment by a mechanism which enhances the endogenous reward system. Compounds with a strong serotonin re-uptake inhibiting activity combined with a well balanced moderate dopamine re-uptake inhibiting activity may therefore provide agents with a rapid onset of anti-depressant effect.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and the compounds of the present invention are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, such as eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and an
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Dahl Bjarne Hugo
Jensen Leif Helth
Nielsen Elsbet .O slashed.stergaard
Olsen Gunnar M.
Scheel-Kruger J.o slashed.rgen
Kessinger Ann M.
NeuroSearch A/S
Shah Mukund J.
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