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...
51425311, 51425312, 51425411, 51425503, 514456, A61K 31535, A61K 31495, A61K 3135
Patent
active
061599727
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a product which comprises a combination of a selective 5-HT.sub.1A receptor antagonist, more specifically a (R)-5 carbamoyl-8-fluoro-3-N, N-disubstituted-amino-3,4-dihydro-2H-1-benzopyran, 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 whereby each of the components are in the form of the free base,solvate or pharmaceutically acceptable salt thereof. The present invention also relates to a process for the preparation of the inventive combination, pharmaceutical formulation comprising said combination and to the use of said combination by either concomitant administration or by separate 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 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 beneficial 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 5HT.sub.1A antagonist and a selective h5-5HT.sub.1B antagonist or partial agonist. Advantageously, treatment with the combination results in synergistic effects in increasing 5-HT transmission. 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). Antagonists of these receptors prevent this feed back regulation, resulting in enhanced release of 5-HT. Combined treatment with both types of receptor antagonists causes an synergistic effect as measured as the increase in 5-HT turnover in guinea pigs. This indicates that a selective blockade of somatodrendritic 5-HT.sub.1A receptors combined with a selective h5-HT.sub.1B receptor antagonist may offer a new rational for rapid onset of 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 potent selective h5-HT.sub.1B receptor antagonist) in combination with compound B (a potent selective 5-HT.sub.1A receptor antagonist) compared with the administration of compound A alone.
THE COMBINATION
Thus, by combining a first component (a) which is a selective 5-HT.sub.1A antagonist having the formula I ##STR3## wherein R.sub.1 is n-propyl or cyclobutyl, R.sub.2 is isopropyl, tertiary butyl, cyclobutyl, cyclopentyl or cyclohexyl, R.sub.3 is hydrogen and R.sub.4 is hydrogen or methyl and being in the (R)-enantiomer form, with a second component (b) which is a selective h5-HT.sub.1B antagonist or partial agonist having the formula II ##STR4## wherein X is CH.sub.2, O; Y is CONH, NHCO; ##STR5## 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 form of free bases, solvates, preferably hydrates, or pharmaceutically acceptable salts there
Berg Stefan
Ross Svante
Thorberg Seth-Olov
Astrazeneca AB
Jarvis William R. A.
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