Tropane-derivatives, their preparation and use

Details Tropane-derivatives, their preparation and use Tropane-derivatives, their preparation and use

2001-03-21

2002-05-28

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

Reexamination Certificate

active

06395748

ABSTRACT:

The present invention relates to novel tropane-derivatives which are valuable monoamine neurotransmitter, i.e dopamine, serotonin and noradrenaline, re-uptake inhibitors and the use of the novel tropane derivatives for the treatment of disorders or diseases responsive to the inhibition of monoamine neurotransmitter re-uptake, such as Parkinson's disease, depression, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders and drug addiction or misuse, including cocaine abuse.
BACKGROUND OF THE INVENTION
The brain consists of a plurality of neurons that communicate with each other via chemical messengers. Each neuron generates neurochemicals or neurotransmitters which act at sites being referred to as receptors on the cellular membrane of neurons. One group of neurotransmitters, referred to as the monoamine neurotransmitters, includes serotonin, dopamine and noradrenaline.
Monoamine neurotransmitters are released into the synaptic cleft between neurons in order to stimulate postsynaptic receptor activity. The removal (or inactivation) of monoamine neurotransmitters occurs mainly by a reuptake mechanism into the presynaptic terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occur.
The serotonergic neural system of the brain have been shown to influence a variety of physiologic functions, and compounds having serotonin re-uptake inhibiting activity are predicted to have the ability to treat in mammals, including humans, a variety of disorders associated with this neural system, for example eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Included among these disorders are disorders related to depression, such as pseudodementia or Ganser's syndrome, migraine pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, tobacco abuse, panic disorder, post-traumatic syndrome, memory loss, dementia of ageing, acquired immunodeficency syndrome dementia complex, memory dysfunction in ageing, social phobia, attention deficit hyperactivity disorder, chronic fatigue syndrome, premature ejaculation, erectile difficulty, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
The pathophysiology of major affective illness is poorly understood, and several neurotransmitters have been implicated in the pathophysiology of major depression.
Mixed noradrenalin and serotonin re-uptake inhibitors, such as Imipramine and Amitriptyline and noradrenaline-reuptake inhibitors, such as Desipramine, Nortriptyline, and Protriptyline are currently used pharmaceuticals in anti-depressant therapy. Moreover, 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 currently used 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.
A strong dopamine re-uptake inhibiting activity is considered with the risk of undesirable central stimulating effects. On the other hand, an activating effect on the mesolimbic dopamine system is 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 compounds of the present invention are also valuable dopamine reuptake inhibitors and are as such considered useful for the treatment of Parkinsonism, depression, obesity, narcolepsy, drug addiction or misuse, including cocaine abuse, attention-deficit hyperactivity disorders, Gilles de la Tourettes disease and senile dementia. Dopamine re-uptake inhibitors enhances indirectly via the dopamine neurones the release of acetylcholin and are therefore also useful for the treatment of memory deficits, e.g. in Alzheimers disease, presenile dementia, memory dysfuntion in ageing, and chronic fatigue syndrome. Noradrenaline re-uptake inhibitors are considered useful for enhancing attention, alertness, arousal, vigilance and for treating depression.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide novel tropane-derivatives which are monoamine neurotransmitter re-uptake inhibitors and therefore useful for the treatment of disorders such as Parkinson's disease, depression and related diseases, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders, drug addiction or misuse, including cocaine abuse.
Another object of the present invention is to provide novel pharmaceutical compositions containing the novel tropane-derivatives.
Still another object of the invention is to provide a method of treating diseases or disorders responsive to the inhibition of monoamine neurotransmitter re-uptake, such as Parkinsonism, depression and related diseases, obsessive compulsive disorders, panic disorders, dementia, memory deficits, attention deficit hyperactivity disorder, obesity, anxiety, eating disorders, drug addiction or misuse, including cocaine abuse.
Other objects will become apparent hereinafter to one skilled in the art.
The Present Invention
The invention then, inter alia, comprises the following, alone or in combination:
A compound having the formula,
or any mixture thereof, or a pharmaceutically acceptable salt thereof;
wherein
R is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl;
R
3
is CH
2
—X—R′, wherein X is O, S, or NR″, wherein R″ is hydrogen, or alkyl, and R′ is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, or —CO-alkyl;
R
4
is
phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, alkoxy, cycloalkoxy, alkyl, cydoalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;
3,4-mothylenedioxyphenyl;
benzyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;
heteroaryl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl; or
naphthyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, CN, alkoxy, cycloalkoxy, alkyl, cycloalkyl, alkenyl, alkynyl, amino, nitro, heteroaryl and aryl;
a compound as above which is
2-methoxymethyl-3-(3,4-dichlorophenyl)-tropane,
2-isopropoxymethyl-3-(3,4-dichlorophenyl)-tropane,
2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane,
2-cyclopropylmethyloxymethyl-3-(3,4-dichlorophenyl)-tropane,
2-methoxymethyl-3-(4-chlorophenyl)-tropane,
N-Normethyl-2-methoxymethyl-3-(4-chlorophonyl)-tropane,
2-ethoxymethyl-3-(4-chlorophenyl)-tropane,
N-normethyl-2-methoxymethyl-3-(3,4-dichlorophenyt)-tropane,
N-normethyl-2-ethoxymethyl-3-(3,4-dichlorophenyl)-tropane,
N-Normethyl-2-ethoxymethyl-3-(4-chlorophonyl)-tropane,
2-ethylthiomethyl-3-(3,4-dichlorophenyl)-tropane,
2-cyclopropylmethyloxymethyl-3-(4-chlorophenyl)-tropane, or
N-normethyl-2-cyclopropylmethyloxymethyl-3-(4

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