Azabicyclo derivatives and their use

Details Azabicyclo derivatives and their use Azabicyclo derivatives and their use

2001-05-15

2003-09-09

Hartley, Michael G. (Department: 1616)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C548S125000, C424S001810, C424S001850, C424S001890

Reexamination Certificate

active

06617459

ABSTRACT:

TECHNICAL FIELD
The present invention relates to azabicyclo derivatives in their labelled and unlabelled form. Furthermore, the present invention relates to the use of said derivatives in their labelled or unlabelled form in diagnostic methods, in particular for in vivo receptor imaging (neuroimaging).
BACKGROUND ART
WO 9713770 discloses 8-azabicyclo[3.2.1]oct-2-ene derivatives which are re-uptake inhibitors for the monoamine neurotransmitter serotonine (5-hydroxy-tryptamine, 5-HT) and therefore useful in the treatment of disorders or diseases which are caused, at least in part, by increase or decrease of the endogenous serotonine levels. Such disorders or diseases are e.g., depression and related disorders, obsessive compulsive disorders, panic disorders, memory deficits, attention deficit, hyperactivity disorder, obesity, anxiety and eating disorders.
Monoamine neurotransmitters (i.e. serotonine, dopamine, and noradrenaline) are produced in neurons and are released into the synaptic cleft upon stimulation of the presynaptic neuron. The neurotransmitter molecules can diffuse through the cleft and then bind to specific receptor molecules (transporters) located in the postsynaptic cell membrane. Binding to these receptors results in polarisation of the cell, i.e. transduction of the stimulus. The removal (or inactivation) of monoamine neurotransmitters from the synaptic cleft occurs mainly by a re-uptake mechanism into presynaptic nerve terminals. By inhibiting the re-uptake an enhancement of the physiological activity of monoamine neurotransmitters occurs.
Major depression is a common disorder, affecting approximately 1 in 6 individuals at some point in their lives. The pathophysiology of depression is poorly understood so far, and several neurotransmitters have been implicated in the pathophysiology of major depression. Inhibitors that block noradrenaline and serotonine re-uptake are currently used as pharmaceuticals in anti-depressant therapy. Several lines of preclinical and clinical evidence indicate that an enhancement of serotonine-mediated neurotransmission might underlie the therapeutic effect of the most recent and currently used drugs in anti-depressant therapy, such as fluoxetine, citalopram and paroxetine [P. Blier & C de Montigney;
TIPS
(Review) 1994 15 220-225].
Paradoxically, serotonine re-uptake inhibitors block the serotonine transporter within minutes after application 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 anti-depressant response, but rather that further adaptive changes underlie and/or contribute to their therapeutic effect [P. Willner;
Int. Review of Psychiatry
1990 2 141-156].
The serotonergic neural system of the brain has been shown to influence a variety of physiologic functions, and disturbance of this system has been made responsible for a variety of diseases and disorders such as eating disorders, depression, obsessive compulsive disorders, panic disorders, alcoholism, pain, memory deficits and anxiety. Included among these disorders are depression and related disorders such as pseudodementia or Ganser's syndrome, migraine, pain, bulimia, obesity, pre-menstrual syndrome or late luteal phase syndrome, alcoholism, tobacco abuse, panic disorder, anxiety, post-traumatic syndrome, memory loss, dementia of ageing, social phobia, attention deficit hyperactivity disorder (ADHD syndrome), chronic fatigue syndrome, premature ejaculation, erectile dysfunction, anorexia nervosa, disorders of sleep, autism, mutism or trichotillomania.
Currently the standard method for the diagnosis of depression is a consultation between physician e.g., psychiatrists and patient in order to evaluate the patient's emotional life. It is characteristic for depressed patients e.g. to lack initiative and interest, to possess a general feeling of sadness, and to have a feeling of guilt and worthlessness, to lack appetite and libido, and to suffer from sleeplessness. These symptoms can occur temporarily and with different intensity which makes it very difficult to determine the appropriate diagnosis and therapy. Therefore, psychiatrists have looked for objective laboratory or clinical tests that could confirm the diagnosis and possibly predict a response to treatment.
Recent research has focused on the biochemical backgrounds of the depression syndrome. It has been found that measurements of the regional cerebral blood-flow (rCBF) can be used to diagnose depression. In brains of depressed patients three areas showed significantly reduced rCBF (left dorsolateral prefrontal cortex, the left anterior cingulate cortex and the left angular gyrus). When depression is combined with cognitive impairment a decreased rCBF in the left medial prefrontal cortex and increased rCSF in the right cerebral vermis has been detected [Bench C J, Friston K J, Brown R G, Scott L C, Frackowiak R S & Dolan R J: The anatomy of melancholia-focal abnormalities of cerebral blood flow in major depression;
Psychol-Med.
1992 22 (3) 607-15; and Dolan R J, Bench C J, Brown R G, Scott L C, Friston K J & Frackowiak-R S: Regional cerebral blood flow abnormalities in depressed patients with cognitive impairment;
J. Neurol. Neurosurg. Psychiatry.
1992 56 (9) 768-73]. This method enables a physician to reliably detect a parameter that seems to correlate at least in a number of cases with pathologic depression. However, treatment with anti-depressant drugs is not reflected in changes of the rCBF, which means that a therapeutic effect can not be monitored by this method.
The study of serotonine re-uptake sites using emission tomography requires the use of radioligands which have desirable properties for in vivo receptor imaging. These criteria include ease of labelling with positron-emitting radio-nucleotides, low rates of peripheral metabolism, high selectivity for brain regions holding the neuroreceptor of interest, and relatively high specific
on-specific binding ratios. Despite the development of a number of radioligands for the serotonine transporter, none of these compounds satisfactorily meet all the criteria desired for an ideal ligand.
SUMMARY OF THE INVENTION
The novel compounds and their derivatives of this invention are very specific and selective binders to serotonine transporters. This allows to reliably determine the number of serotonine binding sites and related Kd values and the release of serotonine as well as the detection of changes in the serotonine metabolism in response to therapeutic drugs.
It is therefore an object of the present invention to provide a compound which can be used in the treatment or diagnosis of diseases or disorders that are related to changes in the serotonine levels in vivo and in vitro and which can be used as well to monitor the effect of a therapy.
Further, it is an object of the present invention to provide methods for diagnosing several disorders linked to decreased or increased neurotransmission of serotonine in vivo and in vitro using a specific detectable compound.
DETAILED DISCLOSURE OF THE INVENTION
It is an object of the present invention to provide a compound which can be used for treatment and/or diagnosing diseases or disorders that are related to changes in the serotonine levels in vivo and in vitro and which can be used as well to monitor the effect of a therapy. This object is solved by providing a labelled or unlabelled compounds derived from a compound having the formula (I):
or any of its enantiomers or any mixture thereof, or a pharmaceutically acceptable salt thereof; wherein
n is 0 or 1;
R is hydrogen, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, cycloalkyl, cycloalkylalkyl or 2-hydroxyethyl, alkylthio, alkylamino or a leaving group and
R
4
is
 phenyl which may be substituted one or more times with substituents selected from the group consisting of halogen, CF
3
, OCF
3
, CN, amino, alkylamino, nitro, alkyl, haloalkyl, hydroxyalkyl, cycloalkyl, alkenyl,

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