Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-12-30
2001-11-06
Ford, John M. (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
06313114
ABSTRACT:
FIELD OF INVENTION
This invention is directed to compounds useful in the treatment of neurological diseases caused by disorders of the serotonin-affected neurological systems. More specifically, the present invention is directed to compounds useful as anxiolytic and/or antidepressant agents.
BACKGROUND OF INVENTION
Pharmaceuticals which enhance the neurotransmission of serotonin (5-HT) are 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 recently 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., Le Poul et al.,
Arch. Pharmacol.,
352:141 (1995)). Hence, it is believed that overriding this negative feedback by using 5HT1A 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.
The present invention relates to a new class of molecules which have the ability to act at the 5-HT1A autoreceptors and concommitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
Compounds having antidepressant and anxiolytic activity due to their affinity for the 5HT1A autoreceptors are disclosed in, e.g., U.S. Pat. No. 3,717,634 which claims N-(heteroarcyclic)-piperazinylalkyl derivatives of azaspiroalkanediones Aryl and heteroaryl piperazinylalkyl carboxamides having 5HT1A activity are disclosed, e.g., in U.S. Pat. Nos. 5,106,849; 5,278,160; and 5,482,940.
Glutarimide derivatives having anxiolytic and antihypertensive activity are disclosed in U.S. Pat. No. 4,612,312.
Benzoxazine and thiazine derivatives useful for treating psychotic disorders and schizophrenia are disclosed in PCT Patent Application Publication No. WO 8907596-A. However, none of these patents disclose compounds which act at both the 5HT1A autoreceptors and the 5-HT-transporter.
SUMMARY OF INVENTION
The present invention is directed to compounds which are both active towards 5HT
1A
receptors and inhibit 5HT transport. Such compounds are useful in treating disorders relating to serotinin concentrations, such as anxiety and depression.
The present invention is directed to compounds of the formula:
wherein:
R is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl or substituted phenyl;
X and Y are each, independently, hydrogen, halogen, cyano, or alkoxy of 1 to 6 carbon atoms; and
m is 1 to 5;or
a pharmaceutically acceptable salt thereof.
The present invention is further directed to methods for allevating the symptoms of depression comprising administering to a patient in need thereof an antidepressant effective amount of a compound represented by the following formula:
wherein:
R is hydrogen, alkyl of 1 to 6 carbon atoms, phenyl, benzyl, or substituted phenyl;
X and Y are each, independently, hydrogen, halogen, cyano, or alkoxy of 1 to 6 carbon atoms; and
m is 1 to 5;or
a pharmaceutically acceptable salt thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the present compounds are those represented by the formula set forth above wherein:
R is hydrogen or alkyl of 1 to 4 carbon atoms;
X and Y are each, independently, hydrogen, halogen or cyano; and
m is 2 to 4; or
a pharmaceutically acceptable salt thereof.
Most preferably, the compounds of the present invention include:
(3,4)-Dihydro-2H-benzo[1,4]oxazine-2-yl-methyl)-[3-(1H-indo-3-yl)-propyl]-amine;
[3-(1H-Indol-3-yl)-propyl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-[3-(1H-indo-3-yl)-propyl]-amine;
(4-Benzyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-[3-(1H-indo-3-yl)-butyl]-amine;
[3-(5-Fluoro- 1H-indol-3-yl)-propyl]-(4-methyl-3,4-dihydro-2H-benzo[1,4]oxazin-2yl-methyl)-amine;
[3-(1H-Indol-3-yl)-propyl]-(4-benzyl-3,4-dihydro-2H-benzol[1 ,4]oxazin-2-yl-methyl)-amine;
[3-(1H-Indol-3-yl)-propyl]-(4-phenyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-isopropyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
[3-(1H-Indol-3-yl)-butyl]-(4-isopropyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-isobutyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-phenyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-butyl]-(4-phenyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-ethyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-propyl-3,4-dihydro-2H-benzo[1,4]oxazine-2-yl-methyl)-amine;
(7-Chloro-4-methyl-3,4-dehydro-2H-benzo[1,4]oxazin-2-yl-methyl)-[
3-5
-fluoro-1H-indol-3-yl)-propyl]-propyl-amine;
(3,4-Dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-[3-(5-fluoro-1H-indol-3-yl)-propyl-amine;
(7-Methoxy-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-(4-phenyl-3,4-dihydro-2H-benzo[1,4]oxazin-2-yl-methyl)-amine; and
(3,4-dihydro-2H-benzo[1,4]oxazin-3-yl-methyl)-[3(5-fluoro-1H-indol-3-yl)propyl]-amine.
As used herein, the terms “alkyl” and “alkoxy” are meant to include both straight and branched carbon chains. The term “halogen” is meant to include fluorine, chlorine, bromine and iodine. The term “substituted phenyl” is meant to include a phenyl moiety substituted with an alky, a halogen, or alkoxy group.
The pharmaceutically acceptable salts of the present compounds are those derived from such inorganic cations such as sodium, potassium and the like; organic bases, such as mono-, di- and trialkyl amines of 1 to 6 carbon atoms, per alkyl group and mono-, di- and trihydroxyalkyl amines of 1-6 carbon atoms per alkyl group; and organic and inorganic acids, such as acetic, lactic, citric, tartaric, succinic, maleic, malonic, gluconic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, methane sulfonic, and similarly known acceptable acids.
The compounds of the present invention may be prepared by any suitable method as will be recognized by one skilled in the art. However, the present compounds may be advantageously prepared according to any one of Schemes 1, 2, 3, or 4 set forth below.
In Schemes 1 to 4,
R may be methyl, ethyl, propyl, isopropyl or isobutyl;
R′ may be CO
2
Et or CH
2
OH;
R″ may be 3-indolyl-propyl or 3-indolyl-butyl;
X may be hydrogen, chlorine or methoxy;
Y may be hydrogen or fluorine;
Z may be hydrogen;
n is 2 or 3;and
m is 3 or 4.
Specific exemplification of the production of representative compounds of this
Mewshaw Richard E.
Zhou Dahui
Zhou Ping
American Home Products Corp
Ford John M.
Mazzarese Joseph M.
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