N-aryloxyethyl-indoly-alkylamines for the treatment of depression

Compounds useful for alleviating symptoms of depression are provided which have the following formula: wherein: PA1 R.sub.1 is hydrogen, lower alkyl or aryl; PA1 R.sub.2 is hydrogen, lower alkyl, phenyl or substituted phenyl; PA1 X and Y are each, independently, hydrogen, lower alkyl, lower alkoxy, or halogen, or together combine with the carbon atoms to which they are attached to complete a pyranyl, dihydrofuranyl, furanyl, or dioxanyl, group; PA1 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; PA1 W is hydrogen, halogen, lower alkyl, cyano or a trifluoromethyl group; and PA1 n is 2-5; or PA1 pharmaceutically acceptable salts thereof.

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 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 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. 
##STR1## 
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. 
##STR2## 
Japanese Patents 05255302 and 09040648 disclose the following compounds 
which are reported to be useful for the treatment of central nervous 
system-related diseases, such as anxiety and depression. 
##STR3## 
SUMMARY OF INVENTION 
The compounds of the present invention invention are aminomethyl 
benzoxezine indoles represented by Formula I: 
##STR4## 
wherein: R.sub.1 is hydrogen, lower alkyl, or aryl; 
R.sub.2 is hydrogen, lower alkyl, phenyl, or substituted phenyl; 
X and Y are each, independently, hydrogen, lower alkyl, 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.sub.1 is hydrogen, methyl or aryl; 
R.sub.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 dihydrofuranyl 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-(5-fluoro-1H-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]-ami 
ne; 
[2-(6-Fluorochroman-8-yloxy)-ethyl]-[2-(5-fluoro-1H-indol-3-yl)-ethyl]-amin 
e; 
[(2-(2,3-Dihydro-benzofuran-7-yloxy)-ethyl]-3-(5-fluoro-1H-indol-3-yl)-prop 
yl]-amine; 
[2-(Benzofuran-7-yloxy)-ethyl]-[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-ylo 
xy)-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-5-yloxy)-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 
"aryl" 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, 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 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 identified in parenthesis. The compound produced in each 
of Schemes 1 to 10 is identified with reference to the appropriate, 
corresponding Example. 
##STR5##

The present invention will now be illustrated by reference to the following 
specific, non-limiting examples. 
INTERMEDIATE 2 
[2-(2-Methoxy-phenoxy-ethyl]-benzyl-carbamic acid tert-butyl ester 
To a solution of (2-hydroxy-ethyl)-benzyl-carbamic acid tert-butyl ester 
(3.2 g, 12.6 mmol) and 2-methoxy phenol (1.0 g, 8.4 mmol) containing 
triphenylphosphine (3.3 g, 12.6 mmol) in anhydrous tetrahydrofuran (40 ml) 
was slowly added diisopropyl azodicarboxylate (2.5 g, 12.6 mmol). The 
reaction was allowed to stir for 18 hours, then poured into methylene 
chloride (250 ml) and washed with 1N sodium hydroxide (3.times.80 ml), 
dried over anhydrous magnesium sulfate, filtered and concentrated to a 
clear oil. The oil was dissolved in ether (70 ml) and hexanes were slowly 
added until the triphenylphosphine oxide precipitated. The solid was 
filtered and the solvent removed. The thick oil was then purified by 
column chromatography (15% ethyl aceate-hexanes) to afford 2.57 g (57.0%) 
of a clear oil: MS (EI) 358 m/e (M.sup.+). 
Elemental analysis for C.sub.21 H.sub.27 NO.sub.4 ; Calc'd: C, 70.56; H, 
7.61; N, 3.92; Found: C, 70.27; H, 7.58; N, 4.07. 
INTERMEDIATE 3 
[2-(2-Methoxy-phenoxy)-ethyl]-benzyl-amine 
To a solution of 2-(2-methoxy-phenoxy-ethyl]-benzyl-carbamic acid 
tert-butyl ester (18.0 g, 50.4 mmol) in methylene chloride (350 ml) was 
slowly added trifluoroacetic acid (60 ml). The reaction was stirred at 
room temperature for 12 hours, and then poured into 1 N sodium hydroxide 
(200 ml) and extracted with methylene chloride (3.times.150 ml). The 
combined organic layers were washed with 1 N sodium hydroxide (2.times.150 
ml) followed by water (2.times.100 mL), then dried over anhydrous 
magnesium sulfate, filtered, and the solvent removed under vacuum. 
Chromatography (5% methanol-methylene chloride) afforded 12.4 g (96%) of a 
clear oil. 
Elemental analysis for C.sub.16 H.sub.19 NO.sub.2 ; Calculated: C, 74.19; 
H, 7.24; N, 5.54; Found: C, 73.91; H, 7.28; N, 5.44. 
The fumarate salt was prepared in ethanol: mp 121.5-122.degree. C.: 
Elemental analysis for C.sub.16 H.sub.19 NO.sub.2.C.sub.4 H.sub.4 O.sub.4 
; Calc'd: C, 63.56; H, 6.27; N, 3.71; Found: C, 63.35; H, 6.16; N, 3.62. 
INTERMEDIATE 4 
N-Benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-propion-amide 
(4a) 
To a solution of 3-indole propionic acid (4.1 g, 21.7 mmol) and 
1-(3-dimethylamino-propyl)-3-ethylcarbodiimide hydrochloride (4.4 g, 23 
mmol) in methylene chloride (80 ml) was added a solution of 
2-(2-Methoxy-phenoxy)-ethyl]-benzyl-amine (3 g, 11.6 mmol) in methylene 
chloride (20 ml) at 0.degree. C. After 2 hours, the reaction mixture was 
poured into water (200 ml) and extracted with methylene chloride 
(2.times.50 ml). The combined organic layers were washed with 1N sodium 
hydroxide (50 ml), followed by water (2.times.50 ml). The organic layer 
was dried over anhydrous sodium sulfate, filtered, and the solvent removed 
under vacuum. Chromatography (5% methanol-methylene chloride) provided 3.3 
g (66.0%) of product as a white solid: mp 46.5-47.5.degree. C. MS EI m/e 
428 (M.sup.+). 
N-Benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-butyr-amide (4b) 
Replacing 3-indole propionic acid with 3-indole butyric acid (1.8 g, 8.9 
mmol) in (4a) above afforded 
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]buty-amide (1.3 
g; 78%) as a white foam. MS FAB m/e 443 (M+H).sup.+ MS FAB m/e 465 
(M+Na).sup.+. 
INTERMEDIATE 5 
Benzyl-[3-(1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-ethyl]amine (5a) 
To a solution of 
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-propion-amide 
in tetrahydrofuran (50 mL) at room temperature was added lithium aluminum 
hydride (1.8 g). The reaction was heated to reflux for 12 hours then 
allowed to cool to room temperature. The reaction was quenched with 
saturated ammonium chloride and the solid precipitates filtered through 
celite. The solvent was concentrated under vacuum and the product purified 
by chromatography (5% methanol-methylene chloride) to afford 2.0 g (86%) 
of product as a yellow oil. MS EI m/e 414 (M.sup.+). 
Elemental analysis for C.sub.27 H.sub.30 N.sub.2 O; Calc'd: C, 78.23; H, 
7.30; N, 6.76; Found: C, 77.53; H, 6.95; N, 6.90. 
Benzyl-[4-(1H-indol-3-yl)-butyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine (5b) 
Replacing 
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-propion-amide 
with 
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-butyl-amide (1. 
2 g, 2.7 mmol) in (5a) afforded 
N-benzyl-3-(1H-indol-3-yl)-N-[2-(2-methoxy-phenoxy)-ethyl]-butyl-amide 
(1.06 g, 91%) as a white oil. MS EI m/e 428 (M.sup.+). 
INTERMEDIATE 7 
5-Fluoro-indolyl-3-propylbromide 
A solution of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (Intermediate 6) 
prepared in accordance with the procedures set forth in Demerson et al., 
J. Med. Chem., 19:391-395 (1976). (25.4 g, 0.13 mol), carbon tetrabromide 
(65.5 g, 0.2 mol) and triphenylphosphine (52 g, 0.2 mol) in methylene 
chloride (156 ml) was allowed to stir for 2 hours. The solvent was 
evaporated and the product chromatographed (30% ethyl acetate-hexanes) to 
afford 33.5 g (99%) of product. 
INTERMEDIATE 8 
5-Fluoro-indolyl-3-propylazide 
A solution of 5-fluoro-indolyl-3-propylbromide (10.67 g, 41 mmol) and 
sodium azide (3.9 g, 60 mmol) in anhydrous N,N-dimethylformamide (60 ml) 
was allowed to stir at 60.degree. C. for 18 hours. The mixture was poured 
into water (150 ml), extracted with methylene chloride (3.times.150 ml), 
washed with water (3.times.100 ml). The organic layer was dried over 
sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (30% ethyl acetate-hexanes) afforded 8.10 g (89%) of 
product as a clear oil. 
Elemental analysis for C.sub.11 H.sub.11 FN.sub.3 ; Calc'd: C, 60.54; H, 
5.08; N, 25.67; Found: C, 60.62; H, 5.08; N, 25.84. 
INTERMEDIATE 9 
5-Fluoro-indolyl-3-propylamine 
A solution of 5-fluoro-indolyl-3-propylazide (8 g, 0.037 mol) and 10% 
palladium on carbon in ethanol was hydrogenated at 50 psi for 16 hours. 
The catalyst was filtered and the solvent removed under vacuum. The celite 
was washed with methanol (300 ml) and the solvent was removed under 
vacuum. Chromatography (15% methanol-methylene chloride plus ammonium 
hydroxide) afforded 4.33 g (61%) of product as a yellow solid: mp 
82-84.5.degree. C. 
Elemental analysis for C.sub.11 H.sub.13 FN.sub.2 ; Calc'd: C, 68.73; H, 
6.82; N, 14.57; Found: C, 68.82; H, 6.85; N, 14.49. 
INTERMEDIATE 10 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-Methoxy-phenoxy) 
ethyl]-benzylamine 
A solution of [2-(2-methoxy-phenoxy)-ethyl]-benzyl-amine (1.0 g, 3.9 mol), 
3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4 g, 5.8 mmol) and triethylamine 
(0.79 g, 7.8 mmol) in dimethylsulfoxide (40 ml) was allowed to stir for 16 
hours at 100.degree. C. The reaction mixture was poured into water (100 
ml) and extracted with methylene chloride (3.times.100 ml). The organic 
layer was washed with water (3.times.100 ml), dried over anhydrous sodium 
sulfate, filtered, and the solvent was removed under vacuum. 
Chromatography (30% ethyl acetate-hexanes) afforded 0.94 g (58%) of 
product as a yellow oil. MS EI m/e 432 (M.sup.+). 
INTERMEDIATE 11 
2-(5-Fluoro-1H-indol-3-yl)ethanol 
To a solution of 5-fluoro-indol-3-acetic acid (4.3 g, 0.022 mol) in 
anhydrous THF (35 ml) was added LiAlH.sub.4 (1.0 M, 33 ml, 0.033 mol) at 
0.degree. C. The mixture was allowed to stir for 0.5 hours and, then 
quenched by saturated NH.sub.4 Cl solution. The mixture was then filtered 
through celite. The filtrate was washed with 1N NaOH (3.times.100 ml) and 
extracted with ethyl acetate (3.times.100 ml). The organic layer was dried 
over anhydrous sodium sulfate, filtered, and the solvent was removed under 
vacuum. Chromatography (10% methanol-methylene chloride) afforded 4.04 g 
(100%) of product as an off-white solid: mp 59-61.degree. C. 
Elemental analysis for C.sub.10 H.sub.10 FNO; Calc'd: C, 67.03; H, 5.63; N, 
7.82; Found: C, 66.71; H, 5.50; N, 7.74. 
INTERMEDIATE 12 
3-(5-Fluoro-1H-indol-3-yl)-ethylbromide 
To a solution of 2-(5-fluoro-1H-indol-3-yl)ethanol (4 g, 22.5 mmol) in 
methylene chloride (50 ml) was added carbon tetrabromide (11.2 g, 34 
mmol), followed by triphenylphosphine (8.8 g, 33 mmol) at room 
temperature. The reaction mixture was allowed to stir at room temperature 
for 2.5 hours. The solvent was removed under vacuum. Chromatography (30% 
ethyl acetate-hexanes) afforded 5.91 g (98%) of product as an off-white 
solid: mp 58-59.degree. C. 
Elemental analysis for C.sub.10 H.sub.9 FBrN; Calc'd: C, 49.61; H, 3.75; N, 
5.79; Found: C, 49.29; H, 3.73; N, 5.72. 
INTERMEDIATE 15 
2-(5-Fluoro-2-methoxy-phenoxy)ethylchloride 
A solution of 5-fluoro-2-methoxy-phenol (4.34 g, 31 mmol) prepared in 
accordance with the procedures set forth in Mancini et al., Synth. Comm., 
19:2001-2005 (1989), 1-bromo-2-chloroethane (8.9 ml, 107 mmol) and 
potassium carbonate (14.8 g, 106 mmol) in 2-butanone (60 ml) was refluxed 
for 24 hours. The mixture was poured into water (150 ml), extracted with 
methylene chloride (3.times.150 ml) and washed with brine (3.times.100 
ml). The organic layer was dried over sodium sulfate, filtered and the 
solvent was removed under vacuum. Chromatography (20% ethyl 
acetate-hexanes) afforded 4.77 g (76%) of product as a clear oil. 
Elemental analysis for C.sub.9 H.sub.10 FClO.sub.2 ; Calc'd: C, 52.83; H, 
4.93; Found: C, 52.79; H, 4.75. 
INTERMEDIATE 16 
2-(5-Fluoro-2-methoxy-phenoxy)ethylazide 
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylchloride (3.97 g, 19 mmol) 
and sodium azide (2.6 g, 39 mmol) in anhydrous N,N-dimethylformide (60 ml) 
was allowed to stir at 60.degree. C. for 18 hours. The mixture was poured 
into water (150 ml), extracted with methylene chloride (3.times.150 ml), 
washed with water (3.times.100 ml). The organic layer was dried over 
sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (20% ethyl acetate-hexanes) afforded 3.75 g (92%) of 
product as a clear oil. 
Elemental analysis for C.sub.9 H.sub.10 FN.sub.3 O.sub.2 ; Calc'd: C, 
51.18; H, 4.77; N, 19.90; Found: C, 51.35; H, 4.71; N, 20.06. 
INTERMEDIATE 17 
2-(5-Fluoro-2-methoxy-phenoxy)ethylamine 
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylazide (3.97 g, 0.019 mol) 
and triphenylphosphine (5.95 g, 0.023 mol) in tetrahydrofuran (80 ml) and 
water (1.5 ml) was allowed to stir for 18 hours at room temperature. The 
solvent was removed under vacuum. Chromatography (ethyl acetate) removed 
triphenylphosphine and triphenylphosphine oxide and (25-50% methanol-ethyl 
acetate plus ammonium hydroxide) afforded 3.14 g (90%) of product as a 
clear oil. MS EI m/e 185 (M.sup.+). 
INTERMEDIATE 18 
3-Indolyl-propionamide (18a) 
A solution of 3-indolepropionic acid (15 g, 79 mmol), 
1,1'-carbonyldimidazole (16.7 g, 100 mmol) in anhydrous tetrahydrofuran 
(150 ml) was allowed to stir for 1.5 hours at room temperature. Then 
NH.sub.3 was bubbled through the solution for 2.5 hours at room 
temperature. The solvent was removed under vacuum, and the residue was 
dissolved in ethyl acetate (500 ml). The organic solution was washed with 
water (3.times.150 ml), dried over anhydrous sodium sulfate, filtered, and 
the solvent was removed under vacuum. The white solid was collected and 
dried under vacuum 10.42 g (96%); mp 124-125.degree. C. MS EI m/e 188 
(M.sup.+). 
3-Indolyl-butyramide (18b) 
This compound was prepared in the manner described above for (18a), using 
3-indolebutyric acid and 1,1'-carbonyldimidazole. A 96% yield was obtained 
as a off-white solid: mp 86-87.degree. C. 
INTERMEDIATE 19 
3-Indolyl-propylamine (19a) 
To a solution of 3-indolyl-propionamide (5 g, 24.7 mmol) in tetrahydrofuran 
anhydrous (150 ml) was added lithium aluminum hydride (1.0 M solution in 
tetrahydrofuran; 100 ml) slowly. The reaction mixture was refluxed for 3 
hours, then was quenched by adding water (4 ml), 15% sodium hydroxide (4 
ml) and water (12 ml) at 0.degree. C. The mixture was filtered through 
celite and concentrated under vacuum. Chromatography (10% 
methanol-methylene chloride plus ammonium hydroxide) afforded 4.0 g (86%) 
of product as a white solid: mp 58-60.5.degree. C. MS EI m/e 174 
(M.sup..cndot.+). 
3-Indolyl-butylamine (19b) 
This compound was prepared in in the manner described above for (19a) using 
3-indolyl-butyramide and lithium aluminum hydride. A 75% yield was 
obtained as a yellow solid: mp 51-53.degree. C. 
INTERMEDIATE 20 
2-(1H-Indol-4-yloxy)ethylchloride 
To a solution of 4-hydroxyindole (4 g, 30 mmol), 2-chloroethanol (4.83 g, 
60 mmol), triphenylphosphine (15.7 g, 60 mmol) in anhydrous 
tetrahydrofuran (40 ml) was slowly added diisopropyl azodicarboxylate 
(12.1 g, 60 mmol). The reaction was allowed to stir for 2.5 hours at room 
temperature, then poured into methylene chloride (250 ml), washed with 
water (3.times.100 ml) and dried over anhydrous sodium sulfate. This 
material was filtered and the solvent was removed under vacuum. 
Chromatography (20% hexanes-ethyl acetate) to remove triphenylphosphine, 
(20% methylene chloride-hexanes) afforded 2.94 g (50%) of product as a 
white solid: mp 69.5-72.degree. C. 
INTERMEDIATE 21 
5-Hydroxy-(2,3)-dihydrobenzo[1,4]dioxine 
Pyrogallol (5 g, 0.04 mol) 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 dropwise. 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 was removed under 
vacuum. Chromatography (5% methanol-methylene chloride) afforded 2.74 g 
(45%) of product as a clear oil. MS EI m/e 152 (M.sup.+). 
INTERMEDIATE 22 
5-(2-Chloroethoxy)-(2,3)-dihydrobenzo[1,4]dioxane 
To solution of 5-hydroxybenzodioxane (1.0 g, 6.5 mmol) and 2-chloroethanol 
(0.79 g, 9.9 mmol), triphenylphosphine (2.6 g, 9.9 mmol) in 
tetrahydrofuran (50 ml) was slowly added diisopropyl azidodicarbimide 
(DIAD) (2.0 g, 9.8 mmol). After 2 hours, another 1.5 eq of 
triphenylphosphine, DIAD, and 2-chloroethanol was added thereto and the 
mixture stirred for another 2 hours. 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. 
This material was filtered, and the solvent removed under vacuum. 
Chromatography (20% ethyl acetate-hexanes) afforded 1.7 g (76%) of product 
as a white solid: mp 70.5-72.5.degree. C. 
Elemental analysis for C.sub.10 H.sub.11 ClO.sub.3 ; Cal'd C, 55.96; H, 
5.17; Found: C, 55.57; H, 5.20. 
INTERMEDIATE 23 
2-(2,3-Dihydrobenzo[1,4]dioxin-5-yloxy)ethylazide 
A solution of 5-(2-chloroethoxy)-(2,3)-dihydrobenzo[1,4]dioxane (4.6 g, 
0.02 mol) and sodium azide (2.78 g, 0.043 mol) in anhydrous 
N,N-dimethyl-formamide (100 ml) was allowed to stir for 18 hours at 
60.degree. C. The mixture was poured into water (200 ml), extracted with 
methylene chloride (3.times.100 ml). The organic layer was washed with 
water (3.times.150 ml), dried over anhydrous sodium sulfate, filtered, and 
the solvent removed under vacuum. Chromatography (20% ethyl 
acetate-hexanes) afforded 3.43 g (72%) of product as a clear oil. MS FAB 
m/e 221 (M.sup.+) 
INTERMEDIATE 24 
2-(2,3-Dihydrobenzo[-1,4]dioxin-5-yloxy)ethylamine 
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy)ethylazide (3.43 g, 
0.016 mol) and triphenylphosphine (6.3 g, 0.023 mol) in tetrahydrofuran 
(50 ml) and water (2 ml) was allowed to stir for 18 hours at room 
temperature. The solvent was removed under vacuum. Chromatography (30% 
methanol-methylene chloride plus ammonium hydroxide) afford 1.93 g (62%) 
of product as a yellow oil. MS FAB m/e 196 (M+H).sup.+. 
INTERMEDIATE 25 
6-Fluorochroman 
A mixture of 6-fluoro-4-chromanone (2 g, 12 mmol) and 10% palladium on 
carbon (1 g) in concentrated hydrochloric acid (20 ml) and ethanol (30 ml) 
was hydrogenated for 20 hours. The catalyst was filtered and the solvent 
removed under vacuum. The residue was dissolved in ethyl acetate (100 ml), 
washed with 1N NaOH (6.times.200 ml) and water (3.times.150 ml), dried 
over anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatagraphy (20% ethyl acetate-hexanes) afforded 1.41 g (77%) 
of product as a clear oil. MS EI m/e 152 (M.sup.+). 
INTERMEDIATE 26 
6-Fluorochroman-8-carbaldehyde 
To a solution of 6-fluorochroman (0.7 g, 4.6 mmol) in anhydrous methylene 
chloride (20 ml) was added TiCl.sub.4 (1.57 g, 8.3 mmol) and 
.alpha.,.alpha.'-dichloromethyl methyl ether (0.53 g, 4.6 mmol) slowly at 
0.degree. C. The reaction was allowed to reach room temperature slowly and 
stirred for 16 hours. The reaction mixture was poured into ice-water, 
extracted with methylene chloride (3.times.100 ml), washed with saturated 
sodium carbonate (5.times.150 ml) and brine (3.times.100 ml). The organic 
layer was dried over anhydrous sodium sulfate, filtered, and the solvent 
was removed under vacuum. The crude solid was collected and dried under 
the vacuum to afford 0.75 g (90%) of product as a yellow solid: mp 
55-57.degree. C. 
Elemental analysis for C.sub.10 H.sub.9 FO.sub.2 ; Calc'd: C, 66.66; H, 
5.04; Found: C, 66.64; H, 4.78. 
INTERMEDIATE 27 
6-Fluoro-8-hydroxychroman 
To a solution of 6-fluorochroman-8-carbaldehyde (8.6 g, 48 mmol), 
3-t-butyl-4-hydroxy-5-methylphenyl sulfide (100 mg) in anhydrous methylene 
chloride (60 ml) at 0.degree. C. was added 3-chloroperoxybenzoic acid 
(mCPBA) (12.4 g, 70 mmol) portionwise. The reaction mixture was allowed to 
reflux for 16 hours. The excess mCBPA was destroyed by adding 10% sodium 
sulfite. The benzoic acid was filtered and the filtrate was extracted with 
methylene chloride (3.times.150 ml) and washed with water (3.times.150 
ml). The organic layer was dried over anhydrous sodium sulfate and 
filtered. The solvent was removed under vacuum and the crude product (10.2 
g, 52 mmol) was dissolved in ethanol-water (200 ml, 1:1). To the above 
solution, sodium hydroxide (6.2 g, 160 mmol) was added at 0.degree. C. 
After 30 minutes, the ice bath was removed, and the reaction mixture was 
allowed to stir for 3 hours at room temperature. Ethanol was then 
evaporated. The residue was neutralized with concentrated hydrochloric 
acid, extracted with methylene chloride (3.times.150 ml), washed with 
saturated sodium bicarbonate (2.times.100 ml) and brine (2.times.100 ml). 
The organic layer was dried over sodium sulfate, filtered and the solvent 
was removed under vacuum. Chromatography (25% ethyl acetate-hexanes) 
afforded 6.9 g (79%) of product as a white solid: mp 62-63.degree. C. 
Elemental analysis for C.sub.9 H.sub.9 FO.sub.2 ; Calc'd: C, 64.28; H, 
5.39; Found: C, 64.31; H, 5.27. 
INTERMEDIATE 28 
2-(6-Fluorochroman-8-yloxy)ethylchloride 
A solution of 6-fluorochroman-8-carbaldehyde (5.5 g, 33 mmol), 
1-bromo-2-chloroethane (16.4 g, 114 mmol) and K.sub.2 CO.sub.3 (16 g, 114 
mmol) in 2-butanone (60 ml) was refluxed for 24 hours. The mixture was 
poured into water (150 ml), extracted with methylene chloride (3.times.150 
ml) and washed with brine (3.times.100 ml). The organic layer was dried 
over sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (20% ethyl acetate-hexanes) afforded 5.74 g of product as a 
white solid: mp 89-90.degree. C. 
Elemental analysis for C.sub.11 H.sub.12 FClO.sub.2 ; Calc'd: C, 57.28; H, 
5.24; Found: C, 57.15; H, 5.69. 
INTERMEDIATE 29 
2-(6-Fluorochroman-8-yloxy)ethylazide 
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (4.13 g, 0.018 mol) 
and sodium azide (2.33 g, 0.036 mol) in anhydrous DMF (60 ml) was allowed 
to stir at 60.degree. C. for 18 hours. The mixture was poured into water 
(150 ml), extracted with methylene chloride (3.times.150 ml) and washed 
with water (3.times.100 ml). The organic layer was dried over sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(20% ethyl acetate-hexanes) afforded 4.12 g (97%) of product as a clear 
oil. 
Elemental analysis for C.sub.11 H.sub.12 FN.sub.3 O.sub.2 ; Calc'd: C, 
55.69; H, 5.10; N, 17.71; Found: C, 55.44; H, 4.97; N, 17.88. 
INTERMEDIATE 30 
2-(6-Fluorochroman-8-yloxy)ethylamine 
A solution of 2-(6-fluorochroman-8-yloxy)ethylazide (4.12 g, 0.017 mol) and 
triphenylphosphine (6.83 g, 0.026 mol) in tetrahydrofuran (80 ml) and 
water (1.5 ml) was allowed to stir for 18 hours at room temperature. The 
solvent was removed under vacuum. Chromatography (ethyl acetate) removed 
triphenylphosphine and triphenylphosphine oxide and (40% 
methanol-methylene chloride plus ammonium hydroxide) afforded 3.45 g (94%) 
of product as a white solid: mp 68-70.degree. C. 
Elemental analysis for C.sub.11 H.sub.14 FNO.sub.2 ; Calc'd: C, 62.55; 
H,6.68; N, 6.63; Found: C,62.18; H, 6.54; N,6.63. 
INTERMEDIATE 31 
7-Methoxybezofuran 
A solution of 7-methyoxy-2-benzofurancarboxylic acid (5 g, 0.026 mol), 
copper (0.2 g) in quinoline (30 ml) was heated under reflux for 2 hours. 
The mixture was filtrated through the celite. The celite was washed with 
ethyl acetate. The solvent was removed under vacuum. Chromatography (25% 
ethyl acetate-hexanes) afforded 2.45 g (64%) of product as a yellow oil. 
MS EI m/e 148 (M.sup.+). 
INTERMEDIATE 32 
7-Hydroxybezofuran 
7-Methoxybenzofuran (1 g, 6.7 mmol) was dissolved in anhydrous methylene 
chloride (25 ml) in a 100 ml round-bottom flask. The flask was placed in 
an acetone-ice bath at -78.degree. C. The flask was fitted with a 
air-condenser. A solution of boron tribromide in methylene chloride (1 M, 
10 ml) was added carefully to the stirred solution through the condenser. 
The reaction was kept at -78.degree. C. for 6 hours and then was allowed 
to stir at room temperature overnight. The reaction was quenched by adding 
water (20 ml) and diluted with ethyl ether. The solvent was removed under 
vacuum. Chromatography (25% ethyl acetate-hexanes) afforded 0.47 g (52%) 
of product as a light-brown oil. MS EI m/e 134 (M.sup.+). 
INTERMEDIATE 33 
2-(Benzofuran-7-yloxy)-ethylchloride 
To a solution of 7-hydroxybenzofuran (0.47 g, 3.5 mmol), triphenylphosphine 
(2.3 g, 8.7 mmol) and 2-chloroethanol (0.7 g, 8.7 mmol) in tetrahydrofuran 
((50 ml) was slowly added diisopropyl azodicarboxylate (1.8 g, 8.7 mmol). 
The reaction was stirred at room temperature for 3 hours. THF was removed 
under vacuum. Chromatography (25% ethyl acetate-hexanes) afforded 0.58 g 
(84%) of product as a yellow oil. MS EI m/e 196 (M.sup.+). 
INTERMEDIATE 34 
2-(2,3-Dihydrobenzofuran-7-yloxy)ethylchloride 
A solution of 2-(benzofuran-7-yloxy)-ethylchloride (0.64 g) and 10% 
palladium on carbon in acetic acid (20 ml) was hydrogenated under 40 psi 
for 20 hours. The catalyst was filtered off and the solvent removed under 
vacuum. Chromatography (20% ethyl acetate-hexanes) afforded 0.39 g (60%) 
of product as a white solid: mp 49-52.degree. C. MS EI m/e 198 (M.sup.+). 
INTERMEDIATE 35 
2-(4-Fluorophenoxy)-acetaldehyde diethyl acetal 
To a suspension of NaOH (5.4 g, 0.134 mol) in anhydrous DMF (100 ml) was 
added 4-fluorophenol (10 g, 0.089 mol) at 0.degree. C. After H.sub.2 
evolution had ceased, bromo-acetaldehyde diethyl acetal (16 ml, 0.11 mol) 
was added. The reaction was heated at 160-170.degree. C. for 18 hours. The 
mixture was poured into ice-water, extracted with ethyl acetate 
(3.times.150 ml), washed with 1N NaOH (3.times.100 ml) and brine 
(3.times.100 ml). The organic layer was dried over anhydrous sodium 
sulfate and filtered. The solvent was removed under vacuum. Chromatography 
(25% ethyl acetate-hexanes) afforded 16.36 g (80%) of product as a clear 
oil. MS EI m/e 228 (M.sup.+). 
INTERMEDIATE 36 
5-Fluorobenzofuran 
To a mixture of benzene (200 ml) containing polyphosphoric acid (7.9 g, 
0.035 mol) was added 2-(4-fluoro-phenoxy)-acetaldehyde diethyl acetal (8 
g, 0.035 mol). The mixture was stirred vigorously while being heated to 
reflux for 2.5 hours. The reaction mixture was cooled to room temperature 
and decanted from the polyphosphoric acid. The solvent was removed under 
vacuum. Chromatography (5% ethyl acetate-hexanes) afforded 3.4 g (45%) of 
product as a clear oil. 
INTERMEDIATE 37 
5-Fluoro-2,3-dihydrobenzofuran 
A solution of 5-fluorobenzofuran and 10% palladium on carbon in acetic acid 
(25 ml) was hydrogenated under 50 psi for 12 hours. The catalyst was 
filtered through celite, and the celite was washed with methylene chloride 
(200 ml). The organic layer was washed with 1N NaOH (3.times.100 ml), 
brine (3.times.100 ml) and dried over anhydrous sodium sulfate. The 
solvent was removed under vacuum to afforded 2.59 g (85%) of product as a 
clear oil. 
INTERMEDIATE 38 
5-Fluoro-2,3-dihydrobenzofuran-7-carbaldehyde 
To a solution of 5-fluoro-2,3-dihydrobenzofuran (7 g, 0.051 mol) in 
anhydrous methylene chloride (40 ml) was added TiCl.sub.4 (9.5 ml, 0.087 
mol), followed by .alpha.,.alpha.'-dichloromethyl methyl ether (4.6 ml, 
0.051 mol) at 0.degree. C. The reaction was allowed to reach room 
temperature slowly and stirred overnight. The reaction mixture was poured 
into ice-water slowly, extracted with methylene chloride (3.times.100 ml) 
and washed with saturated sodium carbonate (5.times.100 ml), and brine 
(3.times.100 ml). The organic layer was dried over anhydrous sodium 
sulfate and filtered. Chromatography (25% ethyl acetate-hexanes) afforded 
3.29 g (39%) of product as a white solid: mp 103-104.degree. C. 
Elemental analysis for C.sub.9 H.sub.7 FO.sub.2 ; Calc'd: C, 65.06; H, 
4.75; Found: C, 65.01; H, 4.03. 
INTERMEDIATE 39 
5-Fluoro-7-hydroxy-2,3-dihydro-benzofuran 
To a solution of 5-fluoro-2,3-dihydrobenzofuran-7-carbaldehyde (3.29 g, 20 
mmol), 3-t-butyl-4-hydroxy-5-methylphenyl sulfide (100 mg) in anhydrous 
methylene chloride (40 ml) at 0.degree. C. was added 3-chloroperoxybenzoic 
acid (mCPBA) (8.5 g, 30 mmol) portionwise. The reaction mixture was 
refluxed for 16 hours. The excess mCBPA was destroyed by adding 10% sodium 
sulfite. The benzoic acid was filtered off and the filtrate was extracted 
with methylene chloride (3.times.100 ml) and washed with water 
(3.times.100 ml). The organic layer was dried over anhydrous sodium 
sulfate and filtered. The solvent was removed under vacuum and crude 
product was dissolved in ethanol-water (100 ml, 1:1). To the above 
solution, sodium hydroxide (2.11 g, 53 mmol) was added at 0.degree. C. 
After 30 minutes, the ice bath was removed, and the reaction mixture was 
allowed to stir for 3 hours at room temperature. Ethanol was evaporated 
and the residue was neutralized with concentrated hydrochloric acid. This 
mixture was extracted with methylene chloride (3.times.100 ml) and washed 
with saturated sodium bicarbonate (2.times.100 ml) and brine (2.times.100 
ml). The organic layer was dried over sodium sulfate, filtered and the 
solvent was removed under vacuum. Chromatography (30% ethyl 
acetate-hexanes) afforded 1.62 g (50%) of product as a white solid: mp 
102.5-103.5.degree. C. 
Elemental analysis for C.sub.8 H.sub.7 FO.sub.2 ; Calc'd: C, 62.34; H, 
4.58; Found: C, 62.19; H, 4.59. 
INTERMEDIATE 40 
2-(5-Fluoro-2,3-dihydro-benzofuran-7-yloxy)ethylchloride 
A solution of 5-fluoro-7-hydroxy-2,3-dihydro-benzofuran (1.6 g, 10 mmol), 
1-bromo-2-chloroethane (7.8 g, 55 mmol) and K.sub.2 CO.sub.3 (2.2 g, 16 
mmol) in 2-butanone (40 ml) was refluxed for 24 hours. The mixture was 
poured into water (150 ml), extracted with methylene chloride (3.times.150 
ml) and washed with brine (3.times.100 ml). The organic layer was dried 
over anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (25% ethyl acetate-hexanes) afforded 2.10 g of 
product as a white solid: mp 72.5-74.5.degree. C. 
Elemental analysis for C.sub.10 H.sub.10 FClO.sub.2 ; Calc'd: C, 55.44; H, 
4.65; Found: C, 55.37; H, 4.58. 
INTERMEDIATE 41 
2-(5-Fluoro-2,3-dihydrobenzofuran-7-yloxy)ethylazide 
A solution of 2-(5-fluoro-2,3-dihydro-benzofuran-7-yloxy)ethylchloride 
(2.05 g, 9.4 mmol) and sodium azide (1.23 g, 19 mol) in anhydrous DMF (30 
ml) was allowed to stir at 60.degree. C. for 24 hours. The mixture was 
poured into water (100 ml), extracted with methylene chloride (3.times.150 
ml), washed with water (3.times.100 ml). The organic layer was dried over 
sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (20% ethyl acetate-hexanes) afforded 2.0 g (95%) of product 
as a clear oil. MS ESI m/e 241 [M+1].sup.+ 
INTERMEDIATE 42 
2-(5-Fluoro-2,3-dihydrofuran-7-yloxy)ethylamine 
A solution of 2-(5-fluoro-2,3-dihydrobenzofuran-7-yloxy)ethylazide (1.98 g, 
89 mmol) and triphenylphosphine (2.8 g, 10.6 mmol) in tetrahydrofuran (50 
ml) and water (1.5 ml) was allowed to stir for 18 hours at room 
temperature. The solvent was removed under vacuum. Chromatography (ethyl 
acetate) removed triphenylphosphine and triphenylphosphine oxide and (40% 
methanol-methylene chloride plus ammonium hydroxide) afforded 2.0 g (100%) 
of product as a clear oil. MS ESI m/e 198 [M+1].sup.+ 
INTERMEDIATE 44 
4-Indanol 
A solution of 1 g of 2-(5-fluoro-2,3-dihydrofuran-7-yloxy)ethylamine 
(Intermediate 43) (Intermediate 44), prepared in the manner described by 
Ross et al., J. Am. Chem. Soc., 110:6471-6480 (1988) and 10% palladium on 
carbon in acetic acid (50 ml), was hydrogenated for 36 hours. The catalyst 
was filtered off through celite. The celite was washed with methylene 
chloride. The organic layer was washed with saturated sodium carbonate 
(3.times.150 ml), brine (3.times.150 ml) and dried over sodium sulfate. 
The solvent was removed under vacuum. Chromatography (30% ethyl 
acetate-hexanes) afforded 0.78 g (86%) of product as a clear oil. MS EI 
m/e 134 (M.sup.+). 
INTERMEDIATE 45 
2-(Indan-4-yloxy)-ethylchloride (45a) 
To a solution of 4-indanol (0.75 g, 5.6 mmol), triphenylphosphine (4.4 g, 
16.8 mmol), 2-chloroethanol (0.7 g, 8.7 mmol) in tetrahydrofuran (50 ml) 
was slowly added diisopropyl azodicarboxylate (1.8 g, 8.7 mmol). The 
reaction was stirred at room temperature for 3 hours and the solvent was 
removed under vacuum. Chromatography (25% ethyl acetate-hexanes) afforded 
0.58 g (84%) of product as a yellow oil. MS EI m/e 196 (M.sup.+). 
2-(5,6,7,8-Tetrahydronapthalen-1-yloxy)-ethylchloride (45b) 
This compound was prepared in the manner described for 45(a) above by 
replacing 4-indanol with 5,6,7,8-tetrahydro-1-naphthol (4 g, 0.027 mol)) 
in 46% yield (2.57 g) as a clear oil. 
Elemental analysis for C.sub.12 H.sub.15 ClO; Calc'd: C, 68.41; H, 7.17; 
Found: C, 68.37; H, 7.25. 
2-(Napthalen-1-yloxy)-ethylchloride (45c) 
This compound was prepared in the manner described for 45(a) above by 
replacing 4-indanol with 1-naphthol (5 g, 0.035 mol)) in 82% yield (6.34 
g) as a clear oil. 
Elemental analysis for C.sub.12 H.sub.11 ClO; Calc'd: C, 69.74; H, 5.37; 
Found: C, 69.64; H, 5.30. 
2-Phenoxy-ethylchloride (45d) 
This compound was prepared in the manner described above for 45(a) by 
replacing 4-indanol with phenol (5 g, 0.053 mol)) in 12% yield (1.03 g) as 
a clear oil. MS EI m/e 156 (M.sup.+). 
INTERMEDIATE 46 
2-(Indan-5-yloxy)-ethylchloride 
A solution of 5-indanol (5 g, 0.037 mol), 1-bromo-2-chloroethanol (8.02 g, 
0.056 mol) and potassium carbonate (7.7 g, 0.056 mol) in 2-butanone (40 
ml) was refluxed for 18 hours. The mixture was poured into water (100 ml), 
extracted with methylene chloride (3.times.150 ml) and washed with water 
(3.times.100 ml). The organic layer was dried over anhydrous sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(20% ethyl acetate-hexanes) afforded 3.2 g (43%) of product as a white 
solid: mp 45-46.degree. C. 
Elemental analysis for C.sub.11 H.sub.13 ClO; Calc'd: C, 67.18; H, 6.66; 
Found: C, 67.03; H, 6.57. 
INTERMEDIATE 47 
[3-(1H-Indol-3-yl)-propyl]-(2-hydroxyethyl)amine 
To a solution of 3-(1H-indol-3-yl)-propyl-amine (3.5 g, 18.6 mmol), 
2-chloro-thanol (1 g, 12.4 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir at 80.degree. C. for 12 hours. The mixture was poured 
into water (100 ml), extracted with methylene chloride (3.times.150 ml) 
and washed with water (3.times.100 ml). The organic layer was dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (15% methanol-methylene chloride) afforded 1.04 g 
(38%) of product as a yellow oil. MS EI m/e 218 (M.sup.+). 
INTERMEDIATE 48 
(2-Hydroxy-ethyl)-[3-(1H-indol-3-yl)-propyl]-carbamic acid-tert-butyl ester 
A solution [3-(1H-indol-3-yl)-propyl]-(2-hydroxyethyl)amine (1.05 g, 4.5 
mmol), di-tert-dicarbonate (5 g, 24 mmol) in anhydrous tetrahydrofuran (20 
ml) was heated at 80.degree. C. for 2 hours. The mixture was poured into 
water (100 ml), extracted with methylene chloride (3.times.150 ml) and 
washed with water (3.times.100 ml). The organic layer was dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (5% methanol-methylene chloride) afforded 0.86 g 
(56%) of product as a yellow oil. MS EI m/e 318 (M.sup.+). 
INTERMEDIATE 49 
2-Chloro-1-phenylethanol 
A solution of 2-chloroacetophenone (5 g, 0.032 mol), sodium borohydride 
(6.1 g, 0.16 mol) in tetrahydrofuran (30 ml) was allowed to stir at 
60.degree. C. for 18 hours. The reaction was quenched by water (200 ml) 
and stirred for another 2 hours. The mixture was extracted with methylene 
chloride (3.times.100 ml) and washed with water (3.times.150 ml). The 
organic layer was dried over sodium sulfate and filtered. The solvent was 
removed under vacuum and afforded 5.07 g(100%) of product as a clear oil. 
MS EI m/e 156 (M.sup.+). 
INTERMEDIATE 50 
2-(2-Methoxy-phenoxy)-2-phenyl-ethylchloride 
To a solution of guaiacol (2 g, 8.1 mmol), triphenylphosphine (6.4 g, 24 
mmol), and 2-chloro-1-phenylethanol (3.78 g, 24 mmol) in tetrahydrofuran 
(50 ml) was slowly added diisopropyl azodicarboxylate (4.18 g, 24 8mmol). 
The reaction was stirred at room temperature for 2 hours. Tetrahydrofuran 
was removed under vacuum. Chromatography (20% ethyl acetate-hexanes) 
afforded 3.30 g (78%) of product as a clear oil. MS EI m/e 262 (M.sup.+). 
INTERMEDIATE 51 
5-Fluoro-3-(3-p-toluenesulfonyloxypropyl)indole 
To a stirred solution of 3-(5-fluoro-1H-indol-3-yl)-propan-1-ol (2.90 g, 
15.0 mmol) in pyridine (15.0 mL) was added p-toluenesulfonyl chloride (7.1 
g, 37.5 mmol) at room temperature. After stirring for 30 minutes at room 
temperature, the reaction mixture was poured to 200 mL of ice water. The 
aqueous was extracted with ethyl acetate and the combined organic extracts 
were washed with 1N HCl and brine. The resulting material was dried over 
anhydrous sodium sulfate, filtered, and the solvent was concentrated under 
vacuum. The crude product was purified by silica gel column chromatography 
(ethyl acetate/hexane, 3/7) to give 4.1 g (79%) of the title compound as a 
solid: mp 74.degree. C. (Lit. mp 99.degree. C.; EP 464604 A2). 
INTERMEDIATE 52 
2-(2-Methoxy-phenoxy) propionitrile 
To a solution of guaiacol (5 g, 0.04 mol) in anhydrous N,N-dimethylformide 
(20 mL) was added sodium hydride (1.16 g, 0.048 mol). The mixture was 
allowed to stir at room temperature for 0.5 hours, followed by the 
addition of 2-bromopropionitrile (8.09 g, 0.06 mol). The mixture was 
allowed to stir for 4 hours at room temperature and quenched with water 
(20 ml). The mixture was extracted with methylene chloride (3.times.100 
ml), washed with water (3.times.100 ml) and the organic layer was dried 
over anhydrous sodium sulfate and filtered. The solvent was removed under 
vacuum. Chromatography (20% ethyl acetate-hexanes) afforded 3.91 g (55%) 
of product as a clear oil. MS EI m/e 177 (M.sup.+). 
INTERMEDIATE 53 
2-(2-Methoxy-phenoxy)propylamine 
To a solution of 2-(2-methoxy-phenoxy)-propionitrile (3.91 g, 0.022 mol) in 
anhydrous ethyl ether (30 ml) was added lithium aluminum hydride (1.0 M, 
44 ml, 0.044 mol). The mixture was heated at 65.degree. C. for 18 hours 
and the reaction was quenched with water (3 ml), 15% NaOH (3 ml) and water 
(9 ml). The resulting material was filtered through celite. The celite was 
washed with methanol (200 ml), and the solvent was removed under vacuum. 
Chromatography (10% methanol-methylene chloride) afforded 0.26 g (7%) of 
product as yellow oil. MS EI m/e 181 (M.sup.+). 
EXAMPLE 1 
[3-(1H-Indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine 
A mixture of 
benzyl-[3-(1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-ethyl]amine (2 g, 
4.7 mmol) and 5% palladium on carbon in ethanol was hydrogenated for 20 
hours. The catalyst was filtered off and the solvent removed under vacuum. 
Chromato-graphy (ethyl acetate-hexanes-methanol-ammonia hydroxide: 
4/4/1/1) affored 0.79 g (52%) of product as a white solid: mp 
101-102.degree. C. 
The fumarate salt was prepared in ethanol: mp 130-130.5.degree. C. 
Elemental analysis for C.sub.20 H.sub.24 N.sub.2 O.sub.2.C.sub.4 H.sub.4 
O.sub.4 ; Calc'd: C, 64.78; H, 6.46; N, 6.29; Found: C, 64.76; H, 6.23; N, 
6.21. 
[4-(1H-Indol-3-yl)-butyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine 
Hydrogenation of 
benzyl-[4-(1H-indol-3-yl)-butyl]-[2-(2-methoxy-phenoxy)-ethyl]-amine 
afforded 0.79 g (100%) of product as a clear oil. The oxalate salt was 
prepared from isopropanol: mp 167-168.degree. C. 
Elemental analysis for C.sub.20 H.sub.24 N.sub.2 O.sub.2.C.sub.4 H.sub.4 
O.sub.4 ; Calc'd: C, 64.47; H, 6.59; N, 6.54; Found: C, 64.44; H, 6.52; N, 
6.46. 
EXAMPLE 2 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-Methoxy-phenoxy)ethyl]-amine 
A mixture of [3-(5-fluoro-1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy) 
ethyl]-benzylamine (0.94 g, 2.2 mol) and 10% palladium on carbon (250 mg) 
in ethanol was hydrogenated for 20 hours. The catalyst was filtered off 
and the solvent was removed under vacuum. Chromatography (10% 
methanol-methylene chloride) afforded 0.63 g (85%) of product as an 
off-white solid: mp 125-126.degree. C. 
The oxalate salt was prepared in isopropanol: mp 146-149.degree. C. 
Elemental analysis for C.sub.20 H.sub.23 FN.sub.2 O.sub.2.C.sub.2 H.sub.2 
O.sub.4.0.5H.sub.2 O; Calc'd: C, 59.85; H, 5.94; N, 6.35; Found: C, 60.13; 
H, 5.67; N, 6.10. 
EXAMPLE 3 
[3-(5-Fluoro-1H-indol-3-yl)propyl]-[2-(5-fluoro-2-methoxy-phenoxy)-ethyl]-a 
mine 
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylchloride (0.3 g, 1.5 
mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.56 g, 2.9 mmol) in 
dimethylsulfoxide (20 ml) was allowed to stir for 12 h at 90.degree. C. 
The reaction mixture was poured into water (100 ml) and extracted with 
methylene chloride (3.times.100 ml). The organic layer was washed with 
water (3.times.150 ml), dried over anhydrous sodium sulfate, filtered and 
the solvent was removed under vacuum. Chromatography (10% 
methanol-methylene chloride) afforded 0.39 g (77%) of product as a white 
solid: mp 119-122.degree. C. 
The oxalate salt was prepared in ethanol: mp 175-177.degree. C.; Elemental 
analysis for C.sub.20 H.sub.22 F.sub.2 N.sub.2 O.sub.2.C.sub.2 H.sub.2 
O.sub.4 ; Calc'd: C, 58.66; H, 5.57; N, 6.22; Found: C, 58.29; H, 5.25; N, 
6.07. 
[2-(5-Fluoro-1H-indol-3-yl)ethyl]-[2-(5-fluoro-2-methoxy-phenoxy)-ethyl]-am 
ine (3b) 
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylamine (0.51 g, 2.8 mmol), 
2-(5-fluoro-1H-indol-3-yl)ethylchloride (0.44 g, 1.8 mmol) and 
triethylamine (0.29 g, 3 mmol) in dimethylsulfoxide (20 ml) was allowed to 
stir for 8 hours at 90.degree. C. The reaction mixture was poured into 
water (100 ml) and extracted with methylene chloride (3.times.100 ml). The 
organic layer was washed with water (3.times.150 ml), dried over anhydrous 
sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (5% methanol-methylene chloride) afforded 0.27 g (43%) of 
product as a brown oil. 
The oxalate salt was prepared in ethanol: mp 185-188.degree. C.; Elemental 
analysis for C.sub.19 H.sub.20 F.sub.2 N.sub.2 O.sub.2.C.sub.2 H.sub.2 
O.sub.4 ; Calc'd: C, 57.80; H, 5.08; N, 6.42; Found: C, 57.53; H, 4.95; N, 
6.36. 
EXAMPLE 4 
[2-(5-Fluoro-1H-indol-3-yl)ethyl]-[2-(5-fluoro-2-methoxy-phenoxy)-ethyl]-am 
ine 
A solution of 2-(5-fluoro-2-methoxy-phenoxy)ethylamine (0.41 g, 2.2 mmol), 
3-(2-bromoethyl)indole (0.25 g, 1.1 mmol) in dimethylsulfoxide (20 ml) was 
allowed to stir for 12 hours at 90.degree. C. The reaction mixture was 
poured into water (100 ml) and extracted with methylene chloride 
(3.times.100 ml). The organic layer was washed with water (3.times.150 
ml), dried over anhydrous sodium sulfate, filtered and the solvent was 
removed under vacuum. Chromatography (10% methanol-methylene chloride) 
afforded 0.15 g (34%) of product as a brown oil. 
The oxalate salt was prepared in ethanol: mp 188-189.degree. C.; Elemental 
analysis for C.sub.19 H.sub.21 FN.sub.2 O.sub.2.C.sub.2 H.sub.2 
O.sub.4.0.25H.sub.2 O; Calc'd C, 59.04; H, 5.63; N, 6.62; Found: C, 59.68; 
H, 5.49; N, 6.56. 
EXAMPLE 5 
[3-(5-Fluoro-1H-indol-3-yl)propyl]-[2-(1H-indol-4-yloxy)-ethyl]-amine 
A solution of 2-(1H-indol-4-yloxy)ethylchloride (0.7 g, 3.6 mmol), 
5-fluoro-indolyl-3-propylamine (1.0 g, 5.4 mmol) in dimethylsulfoxide (20 
ml) was allowed to stir for 12 hours at 90.degree. C. The reaction mixture 
was poured into water (100 ml) and extracted with methylene chloride 
(3.times.100 ml). The organic layer was washed with water (3.times.150 
ml), dried over anhydrous sodium sulfate, filtered and the solvent was 
removed under vacuum. Chromatography (5%-10% methanol-methylene chloride) 
afforded 0.54 g (43%) of product as a white solid: mp 70-73.degree. C. 
The oxalate salt was prepared in ethanol: mp 183.5-185.degree. C.; 
Elemental analysis for C.sub.21 H.sub.22 FN.sub.3 O.C.sub.2 H.sub.2 
O.sub.4 ; Calc'd C, 62.53; H, 5.48; N, 9.51; Found: C, 62.31; H, 5.38; N, 
9.35. 
[2-(1H-Indol-4-yloxy)ethyl]-[3-(1H-indol-3-yl)-propyl]amine (5b) 
This compound was prepared in the manner described above for Example 5 
using 2-(1H-indol-4-yloxy)ethylchloride and 3-indolyl-propylamine in 65% 
yield as an off-white solid: mp 109-111.degree. C. The oxalate salt was 
prepared in isopropanol: mp 200.5-202.degree. C. 
Elemental analysis for C.sub.21 H.sub.23 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 
; Calc'd: C, 65.19; H, 5.95; N, 9.92; Found: C, 64.89, H, 6.00; N, 9.81. 
[3-(1H-Indol-3-yl)butyl]-[2-(1H-indol-4-yloxy)ethyl]amine (5c) 
This compound was prepared in the manner described above for Example 5 
using 2-(1H-indol-4-yloxy)ethylchloride and 3-indolyl-butylamine in 43% 
yield as an off-white solid: mp 70-73.degree. C. 
The oxalate salt was prepared in ethanol: mp 183.5-185.degree. C. Elemental 
analysis for C.sub.22 H.sub.25 N.sub.3 O.C.sub.2 H.sub.2 O.sub.4 ; Calc'd: 
C, 62.58; H, 5.48; N, 9.52; Found: C, 62.31; H, 5.38; N,9.35. 
EXAMPLE 6 
[2-(2,3-Dihydrobenzo[1,4]dioxin-5-yloxy)-ethyl]-[2-(1H-indol-3-yl)-ethyl]am 
ine 
A solution of 2-(2,3-dihydrobenzo[1,4]dioxin-5-yloxy) ethylamine (0.38 g, 
1.9 mmol), 3-(2-bromoethyl)-indole (0.24 g, 1.1 mmol) and triethylamine 
(0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to 
stir for 14 hours at 90.degree. C. The mixture was poured into water (100 
ml) and extracted with methylene chloride (3.times.100 ml). The organic 
layer was washed with water (3.times.150 ml), dried over anhydrous sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.19 g 
(52%) as a yellow oil. 
The oxalate salt was prepared in ethanol: mp 197.5-198.5.degree. C.; 
Elemental analysis for C.sub.20 H.sub.22 N.sub.2 O.sub.3.C.sub.2 H.sub.2 
O.sub.4 ; Calc'd: C, 61.63; H, 5.64; N, 6.53; Found: C, 61.36; H, 5.46; N, 
6.45s. 
EXAMPLE 7 
[2-(2,3-Dihydro-benzo[1,4]dioxin-5-yloxy)-ethyl]-[3-(5-fluoro-1H-indol-3-yl 
)-propyl]-amine 
A solution of 5-(2-chloroethoxy)-(2,3)-dihydrobenzo[1,4]dioxane (0.75 g, 
3.5 mmol), 3-(5-fluoro-1H-indol-3-yl)-propylamine (1.0 g, 5.2 mmol) and 
triethylamine (0.35 g, 3.5 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir for 14 hours at 100.degree. C. The mixture was poured 
into water (100 ml) and extracted with methylene chloride (3.times.100 
ml). The organic layer was washed with water (3.times.150 ml), dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (5% -10% methanol-methylene chloride plus ammonium 
hydroxide) afforded 0.10 g (52%) of product as a yellow oil. 
The fumarate salt was prepared in isopropanol: mp 189.5-190.5.degree. C.; 
Elemental analysis for C.sub.21 H.sub.23 FN.sub.2 O.sub.3.0.5C.sub.4 
H.sub.4 O.sub.4.0.5H.sub.2 O; Calc'd: C, 64.74; H, 5.88; N, 6.54; Found: 
C, 64.01; H, 5.95; N, 6.36. 
EXAMPLE 8 
[2-(6-Fluorochroman-8-yloxy)ethyl]-[2-(1H-indol-3-yl)ethyl]-amine 
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (0.41 g, 2.2 mmol), 
3-(2-bromoethyl)indole (0.25 g, 1.1 mmol) and triethylamine (0.23 g, 2.2 
mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to stir for 12 
hours at 90.degree. C. The mixture was poured into water (100 ml) and 
extracted with methylene chloride (3.times.100 ml). The organic layer was 
washed with water (3.times.150 ml), dried over anhydrous sodium sulfate, 
filtered and the solvent was removed under vacuum. Chromatography (10% 
methanol-methylene chloride plus ammonium hydroxide) afforded 0.15 g (34%) 
of product as a yellow oil. 
The oxalate salt was prepared in ethanol: mp 213-214.degree. C.; Elemental 
analysis for C.sub.21 H.sub.23 FN.sub.2 O.sub.2.C.sub.2 H.sub.2 O.sub.4 ; 
Calc'd: C, 62.11; H,5.67; N, 6.30; Found: C, 62.26; H, 5.71; N, 6.19. 
EXAMPLE 9 
[2-(6-Fluorochroman-8-yloxy)ethyl]-[3-(5-fluro-1H-indol-3-yl)propyl]-amine 
(9a) 
A solution 2-(6-fluorochroman-8-yloxy)ethylchloride (0.25 g, 7.1 mmol), 
3-(5-fluoro-1H-indol-3-yl)-propylamine (0.42 g, 2.2 mmol) and 
triethylamine (0.22 g, 2.2 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir for 14 hours at 90.degree. C. The mixture was poured 
into water (100 ml) and extracted with methylene chloride (3.times.100 
ml). The organic layer was washed with water (3.times.150 ml), dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (10% methanol-methylene chloride plus ammonium 
hydroxide) afforded 0.25 g (60%) as a white solid: mp 137-138.5.degree. C. 
The oxalate salt was prepared in isopropanol: mp 214-215.degree. C.; 
Elemental analysis for C.sub.22 H.sub.24 F.sub.2 N.sub.2 
O.sub.2.1.5C.sub.2 H.sub.2 O.sub.4 ; Calc'd: C, 57.58; H, 5.22; N, 5.31; 
Found: C, 57.75; H, 5.07; N, 5.51. 
[2-(6-Fluorochroman-8-yloxy)ethyl]-[2-(5-fluro-1H-indol-3-yl)ethyl]-amine 
(9b) 
A solution of 2-(6-fluorochroman-8-yloxy)ethylchloride (0.26 g, 1.1 mmol), 
2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.45 g, 2.1 mmol) and triethylamine 
(0.30 ml, 2.1 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to 
stir for 14 hours at 90.degree. C. The mixture was poured into water (100 
ml) and extracted with methylene chloride (3.times.100 ml). The organic 
layer was washed with water (3.times.150 ml), dried over anhydrous sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.19 g 
(48%) of product as a yellow oil. 
The oxalate salt was prepared in ethanol: mp 201-203.degree. C.; Elemental 
analysis for C.sub.21 H.sub.22 F.sub.2 N.sub.2 O.sub.2.1C.sub.2 H.sub.2 
O.sub.4 ; Calc'd: C, 59.70; H, 5.23; N, 6.05; Found: C, 59.48; H, 5.08; N, 
5.88. 
EXAMPLE 10 
[2-(2,3-Dihydrobenzofuran-7-yloxy)ethyl]-[3-(5-fluoro-1H-indol-3-yl)propyl] 
amine 
A solution of 2-(2,3-dihydrobenzofuran-7-yloxy)ethylchloride (0.38 g, 1.9 
mmol), 3-(5-fluoro-1H-indol-3-yl)propylamine (0.93 g, 4.8 mmol), 
triethylamine (0.48 g, 4.8 mmol) in anhydrous DMSO (20 ml) was allowed to 
stir at 90.degree. C. for 12 hours. The mixture was poured into water (100 
ml) and extracted with methylene chloride (3.times.100 ml). The organic 
layer was washed with water (3.times.150 ml), dried over anhydrous sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(10% methanol-methylene chloride plus ammonium hydroxide) afforded 0.52 g 
(77%) of product as a yellow oil. 
The oxalate salt was prepared in ethanol: mp 158-160.degree. C.; Elemental 
analysis for C.sub.21 H.sub.23 FN.sub.2 O.sub.2.C.sub.2 H.sub.2 O.sub.4 ; 
Calc'd: C, 63.82; H, 5.78; N, 5.95; Found: C, 63.45; H, 5.74; N,5.76. 
EXAMPLE 11 
[2-(Benzofuran-7-yloxy)ethyl]-[3-(5-fluoro-1H-indol-3-yl)propyl]amine 
A solution of 2-(benzofuran-7-yloxy)-ethylchloride (0.58 g, 2.9 mmol), 
3-(5-fluoro-1H-indol-3-yl)propylamine (1.4 g, 7.4 mmol) and triethylamine 
(0.74 g, 7.4 mmol) in anhydrous DMSO (20 ml) was allowed to stir at 
90.degree. C. for 12 hours. The mixture was poured into water (100 ml) and 
extracted with methylene chloride (3.times.100 ml). The organic layer was 
washed with water (3.times.150 ml), dried over anhydrous sodium sulfate, 
filtered and the solvent was removed under vacuum. Chromatography (7% 
methanol-methylene chloride) afforded 0.31 g (30%) of product as a 
light-brown oil. 
The oxalate salt was prepared in THF: mp 181-183.degree. C.; Elemental 
analysis for C.sub.21 H.sub.21 FN.sub.2 O.sub.2.1C.sub.2 H.sub.2 O.sub.4 ; 
Calc'd: C, 62.39; H, 5.24; N, 6.33; Found: C, 62.07; H, 5.24; N, 6.45. 
EXAMPLE 12 
[2-(5-Fluoro-2,3-dihydro-7-yloxy)-ethyl]-[2-(5-fluro-1H-indol-3-yl)-ethyl]- 
amine 
A solution of 2-(5-fluoro-2,3-dihydrofuran-7-yloxy) ethylamine (0.40 g, 2.1 
mmol), 2-(5-fluoro-1H-indol-3-yl)-ethylamine (0.25 g, 1.0 mmol) and 
triethylamine (0.29 ml, 2.1 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir for 14 hours at 90.degree. C. The mixture was poured 
into water (100 ml) and extracted with methylene chloride (3.times.100 
ml). The organic layer was washed with water (3.times.100 ml), dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (5% methanol-methylene chloride plus ammonium 
hydroxide) afforded 0.2 g (54%) of product of product as a yellow oil. 
The oxalate salt was prepared in ethanol: mp 209.5-210.5.degree. C.; 
Elemental analysis for C.sub.20 H.sub.20 F.sub.2 N.sub.2 
O.sub.2.1.5C.sub.2 H.sub.2 O.sub.4 ; Calc'd: C, 55.98; H, 4.70; N, 5.68; 
Found: C, 55.53; H, 4.44; N, 5.72. 
EXAMPLE 13 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(indan-4-yloxy)-ethyl]-amine (13a) 
A solution of 2-(indan-4-yloxy)-ethylchloride (0.58 g, 2.9 mmol), 
3-(5-fluoro-1H-indol-3-yl)-propylamine (1.4 g, 7.4 mmol) and triethylamine 
(1 ml, 7.4 mmol) in anhydrous dimethylsulfoxide (20 ml) was allowed to 
stir for 12 hours at 90.degree. C. The mixture was poured into water (100 
ml) and extracted with methylene chloride (3.times.100 ml). The organic 
layer was washed with water (3.times.100 ml), dried over anhydrous sodium 
sulfate, filtered and the solvent was removed under vacuum. Chromatography 
(7% methanol-methylene chloride) afforded 0.31 g (30%) of product as a 
brown oil. 
The oxalate salt was prepared in tetrahydrofuran: mp 220-222.degree. C.; 
Elemental analysis for C.sub.22 H.sub.25 FN.sub.2 O.C.sub.2 H.sub.2 
O.sub.4 ; Calc'd: C, 65.10; H, 6.15; N, 6.33; Found: C, 64.74; H, 6.14; N, 
6.11. 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(5,6,7,8-etrahydro-naphthalen-1-ylox 
y)-ethyl]-amine (13b) 
This compound was prepared in the manner described above for Example 13 by 
replacing 2-(indan-4-yloxy)-ethylchloride with 
2-(5,6,7,8-tetrahydronapthalen-1-yloxy)-ethylchloride (0.6 g, 2.8 mmol) in 
29% yield (0.3 g) as a yellow oil. 
The fumarate salt was prepared in ethanol: mp 203-205.degree. C.; Elemental 
analysis for C.sub.23 H.sub.27 FN.sub.2 O.0.5C.sub.4 H.sub.4 O.sub.4 ; 
Calc'd: C, 70.73; H,6.89; N, 6.60; Found: C, 70.49; H, 6.87; N, 6.52. 
[3-(1H-indol-3-yl)-propyl]-[2-(naphthalen-1-yloxy)-ethyl]-amine (13c) 
This compound was prepared in the manner described above for Example 13 by 
replacing 2-(indan-4-yloxy)-ethylchloride with 
2-(napthalen-1-yloxy)-ethylchloride (0.6 g, 2.8 mmol), and 
3-(5-fluoro-1H-indol-3-y-)-propylamine with 3-(1H-indol-3-yl)-propylamine 
(1.35 g, 7.2 mmol) in 85% yield (1.42 g) as a yellow solid: mp 
119-120.degree. C. 
The fumarate salt was prepared in ethanol: mp 203-205.degree. C.; Elemental 
analysis for C.sub.23 H.sub.24 N.sub.2 O.0.5C.sub.4 H.sub.4 
O.sub.4.0.25H.sub.2 O Calc'd: C, 73.78; H,6.56; N, 6.88; Found: C, 73.74; 
H,6.47; N, 6.89. 
[3-(1H-indol-.sup.3 -yl)-propyl]-[2-phenoxy-ethyl]-amine (13d) 
This compound was prepared in the manner described above for Example 13 by 
replacing 2-(napthalen-1-yloxy)-ethylchloride with 2-phenoxy-ethylchloride 
(0.59 g, 3.8 mmol) in 100% yield (1.08 g) as a yellow oil. 
The fumarate salt was prepared in ethanol: mp 203-205.degree. C.; Elemental 
analysis for C.sub.19 H.sub.22 N.sub.2 O.C.sub.4 H.sub.4 O.sub.4 ; Calc'd: 
C, 67.30; H, 6.38; N, 6.82; Found: C, 67.01; H, 6.30; N, 6.73. 
EXAMPLE 14 
[3-(5-Fluoro-1H-indol-3-yloxy)-proyl]-[2-(indan-5-yloxy)-ethyl]-amine 
A solution of 2-(indan-5-yloxy)-ethylchloride (0.7 g, 3.5 mmol), 
3-(5-fluoro-1H-indol-3-yl)-propylamine (1.01 g, 5.3 mmol) and 
triethylamine (0.53 g, 5 mmol) in anhydrous dimethylsulfoxide (20 ml) was 
allowed to stir for 12 hours at 90.degree. C. The mixture was poured into 
water (100 ml) and extracted with methylene chloride (3.times.100 ml). The 
organic layer was washed with water (3.times.100 ml), dried over anhydrous 
sodium sulfate, filtered and the solvent was removed under vacuum. 
Chromatography (5-10% methanol-methylene chloride) afforded 0.53 g (43%) 
of product as a yellow oil. 
The fumarate salt was prepared in ethanol: mp 179-180.degree. C.; Elemental 
analysis for C.sub.22 H.sub.25 FN.sub.2 O.0.5C.sub.4 H.sub.4 O.sub.4 ; 
Calc'd: C, 69.46; H, 6.68; N, 6.75; Found: C, 69.19; H, 6.67; N, 6.72. 
EXAMPLE 15 
[3-(1H-Indol-3-yl)-propyl]-[2-(quinolin-8-yloxy)ethyl]-amine 
To a solution of (2-hydroxy-ethyl)-[3-(1H-indol-3-yl)-propyl]-carbamic 
acid-tert-butyl ester (0.86 g, 2.7 mmol), triphenylphosphine (0.71 g, 2.7 
mmol) and 8-hydroxy-quinoline (0.26 g, 2.7 mmol) in tetrahydrofuran (50 
ml) was slowly added diisopropyl azodicarboxylate (0.55 g, 2.7 mmol). The 
reaction was stirred at room temperature for 3 hours. Tetrahydrofuran was 
removed under vacuum. Chromatography (5% methanol-methylene chloride) 
afforded a yellow solid, which was dissolved in methylene chloride (30 
ml). To this solution was added a trifluoroacetic acid solution (4 ml in 
10 ml methylene chloride). The reaction mixture was allowed to stir for 2 
h at room temperature. The mixture was then quenched with saturated sodium 
carbonate and extracted with methylene chloride (3.times.100 ml). The 
organic layer was dried over anhydrous sodium sulfate and filtered. The 
solvent was removed under vacuum. Chromatography (10-15% 
methanol-methylene plus ammonium hydroxide) afforded 0.17 g (18%) of 
product as a light-yellow oil. 
The HCl salt was prepared in ethyl acetate: mp 83-86.degree. C.; Elemental 
analysis for C.sub.22 H.sub.23 N.sub.3 O.HCl.1.25H.sub.2 O; Calc'd: C, 
65.34; H, 6.60; N, 10.39; Found: C, 65.24; H, 6.69; N, 10.47. 
EXAMPLE 16 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)-2-phenyl-ethyl]- 
amine 
A solution of 2-(2-methoxy-phenoxy)-2-phenyl-ethylchloride (0.71 g, 2.7 
mmol), 2-(5-fluoro-1H-indol-3-yl)-ethylamine (1.04 g, 5.4 mmol) and 
triethylamine (0.75 ml, 5.4 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir for 12 hours at 90.degree. C. The mixture was poured 
into water (100 ml) and extracted with methylene chloride (3.times.100 
ml). The organic layer was washed with water (3.times.100 ml), dried over 
anhydrous sodium sulfate, filtered, and the solvent was removed under 
vacuum. Chromatography (7% methanol-methylene chloride plus ammonium 
hydroxide) afforded 0.15 g (13%)of parouduct of product as a yellow oil. 
The citrate salt was prepared in ethyl ether: mp 64.5-67.degree. C.; 
Elemental analysis for C.sub.20 H.sub.20 F.sub.2 N.sub.2 O.sub.2.C.sub.6 
H.sub.8 O.sub.7.1.5H.sub.2 O; Calc'd: C, 60.27; H, 6.01; N, 4.39; Found: 
C, 59.96; H, 6.00; N, 4.39. 
EXAMPLE 17 
[3-(5-Fluoro-1H-indol-3-yl)-propyl]-[2-(2-methoxy-phenoxy)propyl]amine 
A solution of 2-(2-methoxy-phenoxy)propylamine (0.26 g, 1.2 mmol), 
5-fluoro-3-(3-p-toluenesulfonyloxypropyl)indole (0.26 g, 0.81 mol) and 
triethylamine (0.13 g, 1.2 mmol) in anhydrous dimethylsulfoxide (20 ml) 
was allowed to stir for 8 hours at 90.degree. C. The mixture was poured 
into water (100 ml) and extracted with methylene chloride (3.times.100 
ml). The organic layer was washed with water (3.times.100 ml), dried over 
anhydrous sodium sulfate, filtered and the solvent was removed under 
vacuum. Chromatography (10% methanol-methylene chloride plus ammonium 
hydroxide) afforded 0.1 g (36%) of product of product as a yellow oil. 
The oxalate salt was prepared in 1-propanol: mp 143-146.degree. C.; 
Elemental analysis for C.sub.20 H.sub.20 F.sub.2 N.sub.2 O.sub.2.C.sub.2 
H.sub.2 O.sub.4 1H.sub.2 O; Calc'd: C, 59.47; H, 6.29; N, 6.03; Found: C, 
59.34; H, 5.87; N, 5.96. 
The activity of the present compounds is demonstrated by the following 
standard pharmacological test procedures. 
The PCR cloning of the human 5-HT.sub.1A receptor subtype from a human 
genomic library has been described previously Chanda et al., Mol. 
Pharmacol., 43:516 (1993). A stable Chinese hamster ovary cell line 
expressing the human 5-HT.sub.1A receptor subtype (5-HT.sub.1A.CHO cells) 
was employed throughout this study. Cells were maintained in DMEM 
supplemented with 10% fetal calf serum, non-essential amino acids and 
penicillin/streptomycin. 
Cells were grown to 95-100% confluency as a monolayer before membranes were 
harvested for binding studies. Cells were gently scraped from the culture 
plates, transferred to centrifuge tubes, and washed twice by 
centrifugation (2000 rpm for 10 min., 4.degree. C.) in buffer (50 mM Tris; 
pH 7.5). The resulting pellets were aliquoted and placed at -80.degree. C. 
On the day of assay, the cells were thawed on ice, and resuspended in 
buffer. Studies were conducted using [.sup.3 H]8-OH-DPAT as the 
radioligand. The binding assay was performed in 96 well microtiter plates 
in a final total volume of 250 .mu.L of buffer. Competition experiments 
were performed by using 7 concentrations of unlabelled drug and a final 
ligand concentration of 1.5 nM. Non-specific binding was determined in the 
presence of 10 .mu.M 5HT. Saturation analysis was conducted by using 
[.sup.3 H]8-OH-DPAT at concentrations ranging from 0.3-30 nM. Following a 
30 minute incubation at room temperature, the reaction was terminated by 
the addition of ice cold buffer and rapid filtration using a M-96 Brandel 
Cell Harvester (Gaithersburg, Md.) through a GF/B filter presoaked for 30 
minutes in 0.5% polyethyleneimine. 
A protocol similar to that used by Cheetham et al., Neuropharmacol. 32:737, 
(1993) was used to determine the affinity of compounds for the serotonin 
transporter. Briefly, frontal cortical membranes prepared from male 
Sprague-Dawley rats were incubated with .sup.3 H-paroxetine (0.1 nM) for 
60 min at 25.degree. C. All tubes also contained either vehicle, test 
compound (one to eight concentrations), or a saturating concentration of 
fluoxetine (10 .mu.M) to define specific binding. All reactions are 
terminated by the addition of ice cold Tris buffer followed by rapid 
filtration using a Tom Tech filtration device to separate bound from free 
.sup.3 H-paroxetine. Bound radioactivity was quantitated using a Wallac 
1205 Beta Plate.RTM. counter. Nonlinear regression analysis was used to 
determine IC.sub.50 values which were converted to Ki values using the 
method disclosed in Cheng and Prusoff, Biochem. Pharmacol., 22:3099, 
(1973); Ki=IC50/((Radioligand conc.)/(1+KD)). 
The [.sup.35 S]-GTP.gamma.S binding assay was similar to that disclosed by 
Lazareno and Birdsall, Br. J. Pharmacol., 109:1120, (1993). Briefly, 
5-HT.sub.1A cloned receptor membrane fragments (as used for 5-HT.sub.1A 
receptor binding assays) were stored at -70.degree. C. until needed. When 
needed, membranes were rapidly thawed, centrifuged at 40,000.times.g for 
10 minutes and resuspended at 4.degree. C. for 10 minutes in assay buffer 
(25 mM HEPES, 3 mM MgCl.sub.2, 100 mM NaCl, 1 mM EDTA, 10 .mu.M GDP, 500 
mM DTT, pH 8.0). These membranes were then incubated for 30 min at 
30.degree. C. with [.sup.35 S]GTPgS (1 nM) in the presence of vehicle, 
test compound (one to eight concentrations), or excess 8-OH-DPAT to define 
maximum agonist response. All reactions were terminated by the addition of 
ice cold Tris buffer followed by rapid filtration using a Tom Tech.RTM. 
filtration device to separate bound [.sup.35 S]GTPgS from free compound. 
Agonists produce an increase in the amount of bound [.sup.35 S]GTPgS 
whereas antagonists produce no increase in binding. Bound radioactivity 
was counted and analyzed as above. 
The following assays were performed by incubating the cells with DMEM 
containing 25 mM HEPES, 5 mM theophylline and 10 .mu.M pargyline for a 
period of 20 minutes at 37.degree. C. Functional activity was assessed by 
treating the cells with forskolin (1 uM final concentration) followed 
immediately by test compound (6 concentrations) for an additional 10 min 
at 37.degree. C. In separate experiments, 6 concentrations of antagonist 
were preincubated for 20 min prior to the addition of 10 nM 8-OH-DPAT and 
forskolin. The reaction was terminated by removal of the media and 
addition of 0.5 ml ice cold assay buffer. Plates were stored at 
-20.degree. C. prior to assessment of cAMP formation by a cAMP SPA assay 
(Amersham). 
The compounds tested correspond to those prepared in Examples 1 to 17 
above. The of the procedure are set forth in Table 1. 
TABLE 1 
______________________________________ 
Example 5-HT.sub.1A 
ST(K.sub.i,nM,or 
GTP.gamma.S ED.sub.50 
cAMP ED.sub.50 
No. (Ki,nM) %Inhib.@.1.mu.M) (EMax%) (EMax%) 
______________________________________ 
1a 1.97 22 13.0 (80%) 
1.32 (94%) 
1b 7.72 25 44.0 (60%) 
2 1.34 0.48 41.6 (77%) 4.28 (97%) 
3a 35.0 0.97 -- 4.71 (99%) 
3b 47.9 49% (100)% -- 
4 91.4 28.0 -- -- 
5a 1.50 0.57 2.0 (90%) -- 
5b 2.47 14 4.0 (66%) -- 
5c 4.22 18 25.8 (59%) -- 
6 5.80 12.0 (100%) -- 
7 0.68 0.08 15.7 (75%) 1.11(90%) 
8 8.53 4.5 36 (49%) -- 
9a 26.6 0.84 121 (0%) 49 (0%) 
9b 29.2 4.5 -- 234 (0%) 
10 1.63 0.74 4.72 (80%) -- 
11 1.55 3.03 2.93 (99.9%) -- 
12 35.1 12.0 -- -- 
13a 76.9 71% -- -- 
13b 170.3 40 -- -- 
13c 16.8 34% -- -- 
13d 9.20 26% -- -- 
14 158.4 56 -- -- 
15 0.54 24 3.0 (76%) -- 
16 43.9 21.0 -- -- 
17 14.50 16.0 236 (97.5%) -- 
______________________________________ 
As demonstrated by the results set forth above, the compounds of the 
present invention are active towards 5HT1A receptors and generally elevate 
serotonin levels by inhibiting 5-HT transport. Accordingly, the present 
compounds should be useful in treating disorders related to defects in 
serotonin concentration. 
The compounds of this invention may be administered orally or parenterally, 
neat or in combination with conventional pharmaceutical carriers. 
Applicable solid carriers can include one or more substances which may 
also act as flavoring agents, lubricants, solubilizers, suspending agents, 
fillers, glidants, compression aids, binders or tablet-disintegrating 
agents or an encapsulating material. In powders, the carrier is a finely 
divided solid which is in admixture with the finely divided active 
ingredient. In tablets, the active ingredient is mixed with a carrier 
having the necessary compression properties in suitable proportions and 
compacted in the shape and size desired. The powders and tablets 
preferably contain up to 99% of the active ingredient. Any of the solid 
carriers known to those skilled in the art may be used with the compounds 
of this invention. Particularly suitable solid carriers include, for 
example, calcium phosphate, magnesium stearate, talc, sugars, lactose, 
dextrin, starch, gelatin, cellulose, methyl cellulose, sodium 
carboxymethyl cellulose, polyvinylpyrrolidone, low melting waxes and ion 
exchange resins. 
Liquid carriers may be used in preparing solutions, suspensions, emulsions, 
syrups and elixirs of the compounds of this invention. The compounds of 
this invention can be dissolved or suspended in a pharmaceutically 
acceptable liquid carrier such as water, an organic solvent, a mixture of 
both or pharmaceutically acceptable oils or fat. The liquid carrier can 
contain other suitable pharmaceutical additives such as solubilizers, 
emulsifiers, buffers, preservatives, sweeteners, flavoring agents, 
suspending agents, thickening agents, colors, viscosity regulators, 
stabilizers or osmo-regulators. Suitable examples of liquid carriers for 
oral and parenteral administration include water (particularly containing 
additives as above, e.g., cellulose derivatives, preferably sodium 
carboxymethyl cellulose solution), alcohols (including monohydric alcohols 
and polyhydric alcohols, e.g., glycols) and their derivatives and oils 
(e.g., fractionated coconut oil and arachis oil). For parenteral 
administration, the carrier can also be an oily ester such as ethyl oleate 
and isopropyl myristate. Sterile liquid carriers are used to prepare 
compositions for parenteral administration. 
Liquid pharmaceutical compositions which are sterile solutions or 
suspensions can be utilized by, for example, intramuscular, 
intraperitoneal or subcutaneous injection. Sterile solutions can also be 
administered intravenously. Compositions for oral administration may be 
either in liquid or solid composition form. 
Preferably, the pharmaceutical compositions containing the compounds of 
this invention are in unit dosage form, e.g., tablets or capsules. In such 
form, the compositions may be sub-divided in unit doses containing 
appropriate quantities of the present compounds. The unit dosage forms can 
be packaged compositions, for example, packeted powders, vials, ampoules, 
prefilled syringes or sachets containing liquids. Alternatively, the unit 
dosage form can be, for example, a capsule or tablet itself, or it can be 
the appropriate number of any such compositions in package form. 
The therapeutically effective amount of the compounds of this invention 
that is administered and the dosage regimen depends on a variety of 
factors, including the weight, age, sex, and medical condition of the 
subject, the severity of the disease, the route and frequency of 
administration, and the specific compound employed, and thus may vary 
widely. However, it is believed that the pharmaceutical compositions may 
contain the compounds of this invention in the range of about 0.1 to about 
2000 mg, preferably in the range of about 0.5 to about 500 mg and more 
preferably between about 1 and about 100 mg. Projected daily dosages of 
active compound are about 0.01 to about 100 mg/kg body weight. The daily 
dose can be conveniently administered two to four times per day. 
The present invention may be embodied in other specific forms without 
departing from the spirit and essential attributes thereof and 
accordingly, reference should be made to the appended claims, rather than 
to the foregoing specification, as indicating the scope of the invention.