Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-12-30
2001-03-13
Fan, Jane (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S323000, C514S255030, C546S277400, C546S201000, C544S373000
Reexamination Certificate
active
06200994
ABSTRACT:
FIELD OF INVENTION
This invention relates to compounds useful for the treatment of diseases affected by disorders of the serotonin-affected neurological systems, such as depression and anxiety. More specifically, the present invention is directed to 1,4-disubstituted cyclohexane derivatives for the treatment of such disorders.
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.
U.S. Pat. No. 5,468,767 reports a series of substituted indoles of the following formula for the treatment of disorders associated with dysfunction in serotonergic neurotransmission, including depression
wherein R
1
is hydrogen or C
1-4
alkyl;
R
2
is C
1-4
alkyl or (CH
2
)
p
Ar;
m is zero or 1;
n is an integer from 1 to 3; and
p is zero or an integer from 1 to 4.
U.S. Pat. No. 5,622,951 discloses a series of piperazine derivatives of the following formula for the treatment of CNS disorders, including depression
wherein R is hydrogen or one or two lower alkyl groups;
R
1
and R
2
are each the same or different mono- or bicyclic aryl or heteroaryl radicals;
R
3
is hydrogen, one or two of the same or different lower alkyl groups or a spirocycloalkyl group; and
n is 1 or 2 and m is 1 to 3 and the total of n+m is 2, 3 or 4.
PCT Publication No. WO 93/10092 discloses a series substituted 1,3-cycloalkenes and cycloalkanes useful in the treatment of dopaminergic disorders.
SUMMARY OF INVENTION
The compounds of this invention are arylpiperazinyl-cyclohexyl indole derivatives represented by Formula I:
X is carbon or nitrogen;
R
1
and R
2
are each, independently, hydrogen, halogen, CF
3
, alkyl, alkoxy, or MeSO
2
;
R
3
is hydrogen, halogen, or alkyl;
R
4
is hydrogen, alkyl, alkylaryl, or aryl; and
R
5
is hydrogen, halogen, CF
3
, CN, carbamide, or alkoxy; or
pharmaceutically acceptable salts thereof.
DETAILED DESCRIPTION OF THE INVENTION
Preferably, the compounds of the present invention are those of Formula I, wherein:
X is carbon;
R
1
and R
2
are each, independently, hydrogen or alkoxy;
R
3
is hydrogen;
R
4
is hydrogen; and
R
5
is halogen; or
pharmaceutically acceptable salts thereof.
More preferably, the compounds of the present invention are selected from:
5-Fluoro-3-{(1,4-cis)-4-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-cyclohexyl}-1H-indole; and
5-Fluoro-3-{(1,4-trans)-4-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]cyclohexyl}-1H-indole.
As used herein, the terms “alkyl” and “alkoxy” are meant to include both straight and branched carbon chains containing 1-6 carbon atoms. The term “aryl” is meant to include aromatic radicals of 6-12 carbon atoms. The term “halogen” is meant to include fluorine, chlorine, bromine and iodine.
The compounds of this Formula I also may be used in the form of a pharmaceutically acceptable acid addition salt having the utility of the free base. Such salts, prepared by methods well known to the art, are formed with both inorganic or organic acids, for example: fumaric, maleic, benzoic, ascorbic, pamoic, succinic, bismethylenesalicylic, methanesulfonic, ethanedisulfonic, acetic, oxalic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaconic, glycolic, p-aminobenzoic, glutamic, benzene-sulfonic, hydrochloric, hydrobromic, sulfuric, cyclohexylsulfamic, phosphoric and nitric acids.
The compounds of the present invention may be prepared by any suitable method which will be recognized by those skilled in the art. However, the present compounds may be advantageously prepared according to Scheme 1 set forth below.
Specific exemplification of the production of representative compounds of this invention is given in the following procedures.
INTERMEDIATE 1
4-(5-Fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal
5-Fluoroindole (4.96 g, 0.036 mol), 1,4-cyclohexanedione monoethylene ketal (7.17 g, 0.046 mol) and potassium hydroxide (6 g, 0.043 mol) were heated to reflux in 70 ml of methanol for 6 hours. The reaction was cooled and the product was isolated by filtration and washed with water to give 8.59 g (86%) of product as a white solid: mp 153-155° C.
INTERMEDIATE 2
4-(5-Fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal
A mixture of 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-ethylene ketal (8.5 g) and 10% palladium on carbon (2.72 g) in ethanol (200 ml) was hydrogenated for 5 hours. The catalyst was filtered off and the solvent removed under vacuum. Chromatography (methanol-methylene chloride) afforded 7.55 g (82%) of product as a white solid: mp 183-185° C.
INTERMEDIATE 3
4-(5-Fluoro-1H-3-indolyl)-cyclohexanone
A solution of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone ethylene ketal (2.8 g, 10 mmol) in 2 L (1:1) tetrahydrofuran-hydrochloric acid (1N) was allowed to stir at room temperature for 16 hours. The solvent was evaporated under vacuum. The crude product was dissolved in ethyl acetate, and washed with 1N sodium hydroxide (3×150 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (40% ethyl acetate-hexanes) afforded 2.1 g (91%) of product as yellow solid: mp 112-114° C.
INTERMEDIATE 4
5-Fluoro-3-{(1,4-cis)-4-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-cyclohexyl}-1H-indole
A solution of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone (1.32 g, 5.7 mmol), 4-hydroxy-4-(3-methoxy-thiophen-2-yl)-piperidine, produced according to the procedures set forth in U.S. Pat. No. 5,525,600 (0.5 g, 2.5 mmol), sodium triacetoxyborohydride (1.82 g, 8.6 mmol) and acetic acid (0.65 ml, 11 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (10% methanol-ethyl acetate) afforded 0.52 g (22%) of product as a white foam; MS EI m/e 428 (M
+
).
INTERMEDIATE 5
5-Fluoro-3-{(1,4-trans)-4-[4-(3-methoxy-thiophen-2-yl)-3,6-dihydro-2H-pyridin-1-yl]-cyclohexyl}-1H-indole
The trans compound was isolated at
Baudy Reinhardt B.
Mewshaw Richard E.
American Home Products Corp
Fan Jane
Mazzarese Joseph M.
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