Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1998-10-21
2000-12-12
Jarvis, William R. A.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
5142378, 51425311, 51425312, 51425411, 51425503, 514654, A61K 31535, A61K 31495, A61K 3150, A61K 31135
Patent
active
061599700
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a product which comprising a combination of a monoamine oxidase (MAO) inhibitor and a selective h5-HT.sub.1B receptor antagonist or partial agonist, more specifically a piperidyl- or piperazinyl-substituted 1,2,3,4-tetrahydronaphthalene or 3,4-dihydro-2H-1-benzopyran- derivative in the form of the free base solvates, or pharmaceutically acceptable salts thereof. The present invention also relates to a process for the preparation of the inventive combination, pharmaceutical formulation containing said combination and to the use of said combination by either concomitant administration or individual administration as an improvement of the treatment of affective disorders such as depression, anxiety, obsessive compulsive disorder (OCD), etc.
BACKGROUND OF THE INVENTION
Today, it is generally considered that antidepressants, including monoamine oxidase inhibitors (MAOI:s), take 2-4 weeks to reach their full clinical effect. In contrast, the side effects occur immediately. Thus, the slow onset of action of antidepressants leads to a vulnerable period for patients in which they experience the side effects, but not the therapeutic effects of drugs. There is often a heavy burden on the treating physician to persuade the patient to continue with the treatment during this period. Furthermore, in suicidal patients, as the onset of action is gradual, they may regain initiative without experiencing full reversal symptoms, leading to a window of risk for suicide and a frequent requirement for hospitalisation. An antidepressant with fast onset of action would not only be benificial due to the faster symptom reduction, but would also be more acceptable to patients and physicians and reduce the need for and duration of hospitalisation. The same long period to reach full clinical effect has been shown in the treatment of other affective disorders such as anxiety and OCD.
SUMMARY OF THE INVENTION
The present invention is directed, in part, to a combination of a MAO inhibitor and an antagonist or partial agonist of h5-HT.sub.1B receptor. Advantageously, treatment with the combination results in an enhanced release of 5HT.
The 5-HT transmission in the brain is negatively regulated by somatodrendritic 5-HT.sub.1A receptors (rate of cell firing) and the terminal h5-HT.sub.1B receptors (release of 5-HT). MAO inhibitors decrease the transmission of 5-HT by acting at both these sites. An antagonist of the terminal h5-HT.sub.1B receptors prevent the decrease in the 5-HT release at the nerve terminals resulting in an elevated concentration of synaptic 5-HT showing that antagonists of h5-HT.sub.1B receptors may have a clinical potential to improve the efficacy of MAO inhibitors and offer a new rational for rapid onset therapeutic actions.
BRIEF DESCRIPTION OF DRAWINGS
FIG. 1 shows the results of a functional h5-HT.sub.1B receptor assay.
FIG. 2 shows the effect of administering compound A (a monoamine oxidase inhibitor) in combination with compound B or C (a h5-HT.sub.1B antagonist or saline).
THE COMBINATION
Thus, by combining a first component (a) which is a monoamine oxidase inhibitor with a second component (b) which is a selective h5-HT.sub.1B antagonist or partial agonist having the formula I ##STR3## wherein X is CH.sub.2, O; Y is CONH, NHCO; ##STR4## R.sub.4 and R.sub.5 independently are H or C.sub.1 -C.sub.4 alkyl, as racemate, R-enantiomer or S-enantiomer, and said components (a) and (b) being in the in the form of free bases, solvates, preferably hydrates, or pharmaceutically acceptable salts thereof, a faster onset of action will occur and consequently, a more efficacious treatment of the patients.
In other preferred embodiments of the second component (b) are those compounds of formula I wherein X is CH.sub.2, and of those compounds, compounds wherein Y is NHCO, and of those compounds, compounds wherein R.sub.3 is morpholino. Compounds wherein R.sub.1 is hydrogen, methyl or ethyl and wherein R.sub.2 is hydrogen, methyl, ethyl, methoxy or bromo are preferre
Berg Stefan
Ross Svante
Thorberg Seth-Olov
Astrazeneca AB
Jarvis William R. A.
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