Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-06-13
2001-09-18
Rotman, Alan L. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C514S414000, C514S419000, C548S467000, C548S452000, C548S486000, C548S492000, C548S507000
Reexamination Certificate
active
06291683
ABSTRACT:
FIELD OF INVENTION
The present invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems. More specifically, the present invention is directed to aryloxyethyl-indoly-alkylamine derivatives useful for the treatment of such diseases.
BACKGROUND OF INVENTION
Pharmaceuticals which enhance 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 compounds operated through a variety of physiological means which caused them to possess numerous undesired side effects, such as dry mouth, blurred vision, and sedation due to multiple receptor activities. The more recently introduced compounds, i.e., 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. As SSRIs require several weeks before they exert their fill 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 fill antidepressant effect is observed, is due to the involvement of the 5-HT1A autoreceptors which suppress the firing activity of the 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 Le Poul et al.,
Arch. Pharmacol.,
352:141 (1995). Hence, it is believed that overriding this negative feedback by using 5HT1A antagonists would increase and accelerate the clinical antidepressant response. Recent studies by Artigas et al.,
Trends Neurosci.,
19:378-383, (1996) suggest that 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 concommitantly at the 5-HT1A autoreceptors and with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of anxiety or depression, as well as other serotonin disorders.
U.S. Pat. No. 3,371,098 discloses sec. and tert. indolylethylamines useful as sedatives, anticonvulsants and analegesics.
U.S. Pat. No. 5,436,264 discloses N-aryloxyalkyl-tryptamine-like compounds of the following formula as alpha-1-adrenergic receptor antagonists for the treatment of cardiovascular disorders.
EP 0722 941 A2 discloses the preparation of a series of hetero-oxy alkanamines of the following formula for the treatment of depression and other disorders for which serotonin uptake inhibitors are normally used.
Japanese Patents 05255302 and 09040648 disclose the following compounds which are reported to be usefull for the treatment of central nervous system-related diseases, such as anxiety and depression.
SUMMARY OF INVENTION
The compounds of the present invention invention are aminomethyl benzoxezine indoles represented by Formula I:
wherein:
R
1
is hydrogen, lower alkyl, or aryl;
R
2
is hydrogen, lower alkyl, phenyl, or substituted phenyl;
X and Y are each, independently, hydrogen, lower alky, lower alkoxy, or halogen, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyrrolyl, pyranyl, pyridinyl, dihydrofuranyl, furanyl, dioxanyl, oxazolyl, or isoxazolyl group;
Z is hydrogen, halogen, or lower alkoxy; with the proviso that when X, Y or Z represent lower alkoxy, they are not present at the ortho position;
W is hydrogen, halogen, lower alkoxy, lower alkyl, cyano, or a trifluoromethyl group; and
n is 2-5; or
pharmaceutically acceptable salts thereof.
The present invention is further derived to pharmaceutical compounds containing such compounds, as well as methods for alleviating symptoms of depression comprising administering the present compounds to a patient in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of the present invention are those represented by Formula I, wherein:
R
1
is hydrogen, methyl or aryl;
R
2
is hydrogen;
X and Y are each, independently, hydrogen, halogen or lower alkoxy, or together combine with the carbon atoms to which they are attached to complete a cyclopentyl, cyclohexyl, phenyl, pyridinyl, dioxanyl, oxazolyl, furanyl or dihydroflranyl group;
Z is hydrogen, halogen or lower alkoxy; with the proviso that when X, Y or Z are lower alkoxy they are not present at the ortho position;
W is hydrogen or halogen; and
n is 2-4; or
pharmaceutically acceptable salts thereof
Most preferably, the compounds of the present invention are selected from the following:
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine;
[2-(1H-Indol-4-yloxy)ethyl]-[3-(1H-indol-3-yl)-propyl]-amine;
[3-(1H-Indol-3-yl)-butyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine;
[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine;
[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-[3-(3-(5-fluoro-1-H-indol-3-yl)-propyl]-amine;
[2-(6-Fluorochroman-8-yloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]-amine;
[2-(6-Fluorochroman-8-yloxy)-ethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine;
[2-(6-Fluorochroman-8-yloxy)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine;
[2-(2,3-Dihydro-benzofuran-7-yloxy)-ethyl]-3-(5-fluoro-1H-indol-3-yl)-propyl]-amine;
[2-(Benzofuran-7-yloxyethyl]-[3-(5-fluoro-1H-indol-3-yl)-propyl]-amine;
[2-(5-Fluoro-2,3-dihydro-7-yloxy-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(indan-4-yloxy)-ethyl]-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(5,6,7,8-tetrahydro-naphthalen-1-yloxy)-ethyl]-amine;
[3-(1H-Indol-3-yl)-propyl]-[2-(naphthalen-1-yloxy)-ethyl]amine;
[3-(1H-Indol-3yl)-propyl]-(2-phenoxy-ethyl)-amine;
[3-(5-Fluoro-1H-indol-3yloxy)propyl]-[2-(indan-5yloxy)-ethyl]-amine;
[3-(1H-Indol-3-yl)-propyl]-[2-(quinolin-8-yloxy)-ethyl]-amine;
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-2-phenyl-ethyl]-amine; and
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-propyl]amine;
As used herein, the terms “lower alkyl” and “lower alkoxy” are meant to include both straight and branched carbon chains containing 1 to 6 carbon atoms. 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 alkyl, halogen, or alkoxy group. The term “a;ryl” is meant to include aromatic radicals containing 6-12 carbon atoms.
The compounds of Formula I may advantageously be used in the form of the pharmaceutically acceptable acid addition salts thereof. Such salts, which may be prepared by methods well known to those skilled in the art, may be formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicyclic, citric, gluconic, lactic, malic, mandelic, cinnarnic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-minobenzoic, glutamic, benzene-sulfonic, hydrochloric hydrobrornic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of the present invention may be prepared by any suitable method known to those skilled in the art. However, the present compounds may be advantageously prepared according to any one of Schemes 1 to 10 set forth below. In the Schemes, the intermediate compounds discussed hereinafter are
Mewshaw Richard E.
Zhou Dahui
American Home Products Corp
Desai Rita
Mazzarese Joseph M.
Rotman Alan L.
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