Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1995-01-04
1997-04-01
Clardy, S. Mark
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
549404, A61K 3135, C07D31120
Patent
active
056166109
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to the new compounds, (R)-5-carbamoyl-8-fluoro-3-N,N-disubstituted-amino-3,4-dihydro-2H-1-benzop yrans in the form of free base or pharmaceutically acceptable salts thereof, process for their preparation, pharmaceutical compositions containing said therapeutically active compounds and to the use of said active compounds in therapy.
An object of the invention is to provide compounds for therapeutic use, especially compounds having a highly selective affinity for a subgroup of 5-hydroxytryptamine receptors, namely the 5HT.sub.1A -receptor in the central nervous system (CNS) of mammals including man and which compounds at the same time shows antagonist activity.
It is also an object of the invention to provide compounds with a therapeutic effect after oral administration.
PRIOR ART
Halogenated-5-subst/unsubst carbamoyl-3-(N,N-disubstituted-amino)-3,4-dihydro-2H-1-benzopyrans intended for therapeutic use in the central nervous system, especially having 5-HT.sub.1A receptor affinity, are already disclosed in the international patent application WO 91/09853.
BACKGROUND OF THE INVENTION
Various central nervous system disorders such as depression, anxiety, etc. appear to involve the disturbance of the neurotransmitters noradrenaline (NA) and 5-hydroxytryptamine (5-HT), the latter also known as serotonin. The drugs most frequently used in the treatment of depression are believed to act by improving the neurotransmission of either or both of these physiological agonists. It appears that the enhancement of 5-HT neurotransmission primarily affects the depressed mood and anxiety, whereas the enhancement of noradrenaline neurotransmission affects the retardation symptoms occuring in depressed patients. The invention concerns compounds which have an effect on 5-HT neurotransmission.
Serotonin, or 5-HT, activity is thought to be involved in many different types of psychiatric disorders. For instance it is thought that an increase in 5-HT activity is associated with anxiety, while a decrease in 5-HT release has been associated with depression. Serotonin has in addition been implicated in such diverse conditions as eating disorders, gastrointestinal disorders, cardiovascular regulation and sexual behavior.
The 5-HT Receptors
The various effects of serotonin may be related to the fact that serotonergic neurons stimulate the secretion of several hormones, e.g. cortisol, prolactin, .beta.-endorphin, vasopressin and others. The secretion of each of these other hormones appears to be regulated on a specific basis by several different 5-HT (serotonin) receptor subtypes. With the aid of molecular biology techniques, to date these receptors have been classified as 5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4, 5-ht.sub.5, 5-ht.sub.6 and 5-ht.sub.7 with the 5-HT.sub.1 receptor further divided into the 5-HT.sub.1A, 5-HT.sub.1B, 5-HT.sub.1D, 5-HT.sub.1E and 5-HT.sub.1F subtypes. Each receptor subtype is involved in a different serotonin function and has different properties.
The 5-HT.sub.1A -subtype Receptors
With respect to the 5-HT1A subtype receptors, these receptors have also been further differentiated depending on their neuronal location thereby resulting in different modes of action and physiological functions. For example, the 5-HT.sub.1A inhibitory autoreceptor is located presynaptically on cellbodies of 5-HT neurons. When 5-HT or a 5-HT.sub.1A agonist activates such an inhibitory autoreceptor, the firing rate of the 5-HT neuron is depressed. Since the neuron does not fire, the release of 5-HT into the synapse is also decreased. In this case, a 5-HT.sub.1A agonist acts as an artificial transmitter substance mimicking the effect of 5-HT with the result of decreasing the release of 5-HT from the central nervous system neurons. The 5-HT.sub.1A agonist on the inhibitory autoreceptor thus acts as an anxiolytic or antianxiety drug.
The use of a 5-HT blocking agent at the autoreceptor will thus allow the neuron to increase its firing resulting in an increased release
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Evenden John L.
Hammarberg Eva M.
Hansson Hans S.
Hellberg Sven E.
Johansson Lars G.
Astra Aktiebolag
Cebulak Mary C.
Clardy S. Mark
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