Aryloxy piperidinyl derivatives for the treatment of depression

Details Aryloxy piperidinyl derivatives for the treatment of depression Aryloxy piperidinyl derivatives for the treatment of depression

2001-11-15

2003-08-26

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...

C514S339000, C514S323000, C546S277400, C546S201000

Reexamination Certificate

active

06610712

ABSTRACT:

This invention relates to new aryloxy indole derivatives as pharmaceuticals which are useful for the treatment in mammals of diseases affected by disorders of the serotonin-affected neurological systems, such as depression, anxiety, panic disorder, obsessive-compulsive disorder, sleep disorders, sexual dysfunction, alcohol and drug, addiction, Alzheimer's disease, Parkinson's disease, obesity and migraine, as well as methods of enhancing cognition.
BACKGROUND OF THE INVENTION
EP 0714894 A1 discloses the preparation of compounds of formula II as new 5-HT
1f
agonist for the treatment of migraine headaches. EP 429341 A2 claims compounds of formula III as having serotonin transporter activity. A recent publication by Malleron et al. was also reported based around formula I [J. Med. Chem. 36, 1194 (1993)]. EP 722941 A2 discloses compounds having effects on serotonin-related systems of formula IV.
Pharmaceuticals which enhance serotonergic neurotransmission are of useful benefit 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 functions which endowed them with several side effect liabilities. The more currently prescribed drugs, the selective serotonin (5-HT) 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 per se cannot 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-HT
1A
autoreceptors which suppress the firing activity of 5-HT neuron, 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. Recent studies by Artigas et al. (Trends Neurosci., 1996, 19, 378-383) suggest a combination of 5-HT
1A
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-HT
1A
autoreceptors and concomitantly with the 5-HT transporter. Such compounds are therefore potentially useful for the treatment of depression as well as other serotonin disorders.
SUMMARY OF INVENTION
The compounds of this invention are aryloxy piperidinyl indoles represented by Formula I:
R
1
and R
2
may each be hydrogen or an alkyl of from 1 to 6 carbon atoms or an alkoxy group of from 1 to 6 carbon atoms; or
R
1
and R
2
may be concatenated to comprise another ring system wherein the ring contains a total of 5-7 ring members;
X is selected from hydrogen, halogen, cyano, C
1
-C
6
alkoxy;
Z is (CH
2
)n or carbonyl;
n is 0, 1 or 2;
the dashed line indicates an optional double bond; or a pharmaceutically acceptable salt thereof.
Ring systems formed by the concatenation of R
1
and R
2
are understood to contain the carbon or oxygen atoms of the R
1
and R
2
groups and can being saturated or unsaturated, including fused alkyl, pyran, or dioxan ring systems. With the phenyl ring to which they are bound, the concatenated rings can form the moieties:
One group of compounds of this invention comprises compounds of the formula:
wherein X is selected from H, halogen, cyano, C
1
-C
6
alkoxy; Z is (CH
2
)n or carbonyl;
and n is 0, 1 or 2; or a pharmaceutically acceptable salt thereof.
Another group of compounds of this invention comprises those of the formula:
wherein X is H, halogen, cyano, C
1
-C
6
alkoxy, or a pharmaceutically acceptable salt thereof.
A further group of compounds of this invention, and pharmaceutically acceptable salts thereof, are represented by the formula:
wherein X and Z are as defined above.
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, salicyclic, 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 Formula I are generally prepared by the overall sequence indicated in Scheme 1 and 2 as follows:
The following examples for preparation of intermediates and invention compounds are included for illustrative purposes and are not to be construed as limiting to this disclosure in any way. Those skilled in the art of organic synthesis may be aware of still other synthetic routes to the invention compounds. The reagents and intermediates used herein are either commercially available or prepared according to standard literature procedures.
Intermediate 1
1-(2-Chloroethoxy)-2-methoxybenzene.
To a solution of 2-methoxyphenol (14.4 g, 116 mmol) in 2-butanone (200 mL) was added bromochloroethane (69.0 g, 480 mmol) followed by the addition of potassium carbonate (40.0 g, 280 mmol). The reaction mixture was mechanically stirred and heated to reflux for 24 h, then cooled to room temperature. The solids were filtered off and the solvent was removed under vacuum. The residue was dissolved in diethyl ether and washed with 10% of NaOH, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by silica gel column chromatography (25% EtOAc/hexane) afforded 7.55 g (35%) of a solid: mp 36-38°C. (Lit.
2
41-43° C,);
1
H NMR (DMSO, 400 MHz), 3.75 (s, 3H), 3.91 (dd, 2H), 4.20 (dd, 2H), 6.86-6.99 (m, 4H); MS (EI) m/z 186 (M
+
).
Intermediate 2
5-(2-Chloroethoxy)-indane.
Replacing 2-methoxyphenol with commercially available 5-hydroxyindane and using the above procedure afforded the title compound in 43% yield as a white solid: mp 45-46° C.
Elemental Analysis Calcd for C
11
H
13
OCl Theory: C, 67.18; H, 6.66 Found: C, 67.03; H, 6.57
Intermediate 3
5-Hydroxy-(2,3)-dihydrobenzo[1,4]dioxan
Pyrogallol (5 g, 0.04 mmol) was dissolved in 2-butanone (600 mL) to which potassium carbonate (1.82 g, 0.013 mol) was added. The mixture was stirred at reflux while 1,2-dibromoethane (2.48 g, 1.14 mL, 0.013 mol) was slowly added drop wise. The reaction was allowed to stir overnight and then cooled to room temperature. The mixture was poured into water (100 mL) and extracted with methylene chloride (200 mL). The organic layer was dried over anhydrous sodium sulfate, filtered, and the solvent removed under vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.74 g (45%) of a clear oil.
Intermediate 4
5-(2-Chloroethoxy)-(2,3)-dihydrobenzo[1,4]dioxan
To solution of 5-hydroxy benzodioxan (1 g, 6.5 mmol) and 2-chloroethanol (0.79 g, 9.9 mmol), triphenylphosphine (2.6 g, 9.9 mmol) in THF (50 mL) was slowly added diisopropylazidodicarbimide (DIAD) (2.0 g, 9.8 mmol). After 2 h, another 1.5 eq of triphenylphosphine, DIAD, and 2-chloroethanol was added and the reaction stirred for another 2 h. The reaction mixture was poured into water (100 mL), and extracted with methylene chloride (100 mL). The organic layer was separated and dried over anhydrous magnesium sulfate, filtered, and the solvent removed under vacuum. Chromatography (ethyl acetate-hexane: 1:4) afforded 1.7 g (76%) or a white solid: mp 70.5-72.5° C.
Elemental Analysis for C
10
H
11
ClO
3
Theory: C, 55.96; H, 5.17 Found: C, 55.57; H, 5.20
Intermediate 5
(5-Fluoro-1H-indol-3-yl)-pyridin-4-yl-methanol
To a stirred solution of 5-fluoroindole (3.10 g, 23.0 mmol) in methanol (10.0 mL) was adde

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