Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-30
2001-04-24
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C544S105000
Reexamination Certificate
active
06221863
ABSTRACT:
FIELD OF THE INVENTION
This invention is directed to compounds useful in the treatment of neurological disease caused by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically, the present invention is directed to 3,4-Dihydro-2H-benzo[1,4]oxazine derivatives useful as anxiolytic and/or antidepressant agents.
BACKGROUND OF THE INVENTION
Compounds which enhance the neurotransmission of serotonin (5-HT) are known to be useful for the treatment of many psychiatric disorders, including depression and anxiety. The first generation of non-selective serotonin-affecting drugs operated through a variety of physiological means which caused them to possess numerous undesired side effects. The more currently prescribed drugs, the selective serotonin reuptake inhibitors (SSRIs), act predominately by inhibiting 5-HT, which is released at the synapses, from being actively removed from the synaptic cleft via a presynaptic serotonin transport carrier. Since SSRIs require several weeks before they exert their full therapeutic effect, this 5-HT blockade mechanism cannot fully account for their therapeutic activity. It is speculated that this two week induction which occurs before a full antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of 5-HT neurons, causing a dampening of the therapeutic effect. Studies suggest that after several weeks of SSRI administration, a desensitization of the 5-HT autoreceptors occurs allowing a full antidepressant effect in most patients (see e.g., LePoul et al.,
Arch. Pharmacol.,
352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT
1
A antagonists would potentially increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al.,
Trends Neurosci.,
19:378-383 (1996) suggest a combination of 5-HT1A activity and inhibition of 5-HT uptake within a single molecular entity can achieve a more robust and fast-acting antidepressant effect.
U.S. Pat. No. 3,058,980 discloses the preparation of compounds of the following formula which are known to exhibit analgesic activity.
WO 8907596-A discloses the preparation of compounds having the following formula which are active in a variety of CNS disorders, including depression and schizophrenia.
U.S. Pat. No. 4,612,312 discloses compounds of the following formula as anxiolytic and antihypertensive agents.
SUMMARY OF THE INVENTION
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommnitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
The compounds of this invention are 3,4-dihydro-2H-benzo[1,4]oxazine derivatives represented by Formula I:
wherein:
R
1
is hydrogen or halogen;
R
2
is hydrogen, alkoxy or carboximide;
R
3
is hydrogen, alkyl, alkylaryl, aryl or substituted aryl;
R
4
is hydrogen, CN, halogen or carboximide; and
X is CH or N; or pharmaceutically acceptable salts thereof.
REFERENCES:
patent: 3058980 (1962-10-01), Berg et al.
patent: 4612312 (1986-09-01), Hibert et al.
patent: 8907596 (1989-08-01), None
patent: WO99/51592 (1999-10-01), None
Le Puol et al.,Arch. Pharmacol, 352:141 (1995).
Artigas et al.,Trends Neurosci., 19:378-383 (1996).
Bourlot, Anne-Sophie, et al.,New Substituted, 1,4-Benzosazine Derivatives with Potential Intracellular Calcium ActivityJ. Med. Chem 1998, 41. pp. 3142-3158.
Mewshaw Richard E.
Shah Uresh S.
American Home Products Corp.
Nagy Michael R.
Raymond Richard L.
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