Structure-activity studies for a novel series of N-(arylethyl)-N- (1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-N-methylamines possessing dual 5- HT uptake inhibiting and α2-antagonistic activities

Article abstract of DOI:10.1021/jm960723m

In search of an α₂-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant with a more rapid onset of action, compound 3 was prepared and observed to possess high affinity for the α₂-receptor (K(i) = 6.71 nM) and

Full text of DOI:10.1021/jm960723m

© Copyright 1997 by the American Chemical Society
Volume 40, Number 7
March 28, 1997
Articles
Str u ctu r e-Activity Stu d ies for a Novel Ser ies of
N-(Ar yleth yl)-N-(1,2,3,4-tetr a h yd r on a p h th a len -1-ylm eth yl)-N-m eth yla m in es
P ossessin g Du a l 5-HT Up ta k e In h ibitin g a n d r2-An ta gon istic Activities
Michael D. Meyer,* Arthur A. Hancock, Karin Tietje, Kevin B. Sippy, Rajnandan Prasad, David M. Stout,
David L. Arendsen, B. Greg Donner, and William A. Carroll*
Neuroscience Research, Department 47C, Pharmaceutical Products Division, Abbott Park, Illinois 60064
Received October 15, 1996X
In search of an R2-antagonist/5-HT uptake inhibitor as a potential new class of antidepressant
with a more rapid onset of action, compound 3 was prepared and observed to possess high
affinity for the R2-receptor (Ki ) 6.71 nM) and the 5-HT uptake site (20.6 nM). A series of
tertiary amine analogs of 3 were synthesized and assayed for their affinity at both the R2-
receptor and the 5-HT uptake site. The structure-activity relationship reveals that a variety
of structural modifications to the arylethyl fragment are possible with retention of this dual
activity. On the tetralin portion, 5-OMe substitution and the (R) stereochemistry at C-1 are
optimal with alternate substitutions producing compounds retaining high affinity for the R2-
receptor but lacking affinity for the 5-HT uptake site. Data for several rigidified 5-O-alkyl
analogs suggests that the favored orientation of the oxygen lone pairs may be away from the
6-position of the tetralin.
In tr od u ction
concentrations following inhibition of metabolism or
reuptake. This has given rise to the concept that
blockade of these inhibitory receptors in conjunction
with monoamine reuptake inhibition might bring about
a more rapid onset of antidepressant action.5,7,8
The major pharmacological approach to the treatment
of depression currently consists of the chronic admin-
istration of agents that interfere with the primary
mechanisms of removal from the synapse of one or both
of the neurotransmitters norepinephrine (NE) and se-
rotonin (5-HT). Mechanistically, this occurs via inhibi-
tion of monoamine metabolism or neuronal reuptake.1
It is theorized that the resultant therapeutic response
is due to the facilitation of neurotransmission caused
by the increased synaptic availability of NE and/or
5-HT, and the subsequent adaptive biochemical changes
that take place at the receptor or postreceptor level.1,2,4b
The period of several weeks typically required for the
onset of antidepressant action with such agents has
been attributed to a feedback inhibition, via presynaptic
autoreceptors,3,4 of further NE and/or 5-HT release
caused by an acute rise in synaptic neurotransmitter
The role of the R2-autoreceptor in inhibiting the
release of NE has been well documented,6 and consider-
able evidence now exists implicating the desensitization
of R2-receptors as a key component in the onset of
efficacy of certain antidepressants.3,7-10 Indeed, the
coadministration of R2-antagonists with various anti-
depressants in animal studies has been shown to
accelerate â-5,7 and 5-HT2-receptor8 downregulation,
biochemical changes suggestive of an early onset of
action. The release of 5-HT, on the other hand, is
inhibited not only by activation of presynaptic 5-HT1-
autoreceptors4,11 but also R2-heteroreceptors.12 More-
over, the R2-antagonists yohimbine and idazoxan have
been shown to potentiate 5-HT release.12c,13 However,
contrary to the inhibitory effect of NE on 5-HT release,
X Abstract published in Advance ACS Abstracts, February 15, 1997.
S0022-2623(96)00723-6 CCC: $14.00 © 1997 American Chemical Society

1050 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Meyer et al.
Sch em e 1. Methods A-Ca
F igu r e 1.
a
Method A: R ) Me; X ) Cl, Br, OMs: i. Method B: R ) Me:
ii, iv. Method C: R ) H: iii, iv, v. Conditions: (i) Li2CO3, MeCN,
∆; (ii) EDCI, HOBt, THF; (iii) (COCl)2, CH2Cl2; (iv) BH3, THF; (v)
CH2O, NaCNBH3.
evidence suggests that hippocampal release of NE is
actually stimulated by 5-HT.14 Thus, 5-HT reuptake
inhibition may, by acutely increasing 5-HT concentra-
tions, activate not only 5-HT1-autoreceptors but also R2-
heteroreceptors indirectly by enhancing NE release.
Therefore, an agent with the dual profile of a 5-HT
reuptake inhibitor and an R2-antagonist15 might serve
to enhance synaptic concentrations of 5-HT relative to
that achievable through 5-HT uptake inhibition alone
and in turn produce a more effective antidepressant
response.
Sch em e 2. Methods D-Fa
Our search for a 5-HT uptake inhibitor/R2-antagonist
began with the phenethyl-1-(aminomethyl)tetralin (1,
Figure 1), identified through screening as possessing
high affinity for the R2-receptor (Ki ) 3.2 nM) with
modest potency at inhibiting 5-HT uptake (IC50 ) 160
nM). In an effort to enhance the potency of 1 at
inhibition of 5-HT uptake, consideration was given to
incorporating into 1 structural features common to other
5-HT uptake inhibitors from the literature. Indeed, the
class of compounds potent at inhibiting 5-HT uptake
encompasses a wide variety of structural types.16 In-
spection of molecular models, however, indicated that
good overlap could be achieved between the nitrogen
and the (methylenedioxy)phenyl of the potent uptake
inhibitor paroxetine 2 and the nitrogen and fluorophenyl
of 1. Thus, preparation of the methylenedioxy analog
of 1 resulted in compound 3, which possessed 8-fold
greater potency at inhibiting 5-HT uptake (IC50 ) 21
nM) and nearly equivalent R2 binding affinity (Ki ) 6.7
nM). At this point, an extensive SAR investigation was
initiated in an effort to explore in greater depth the
structural requirements for this dual activity. This
study has resulted in the development of a novel series
of structural analogs of 3 possessing high affinity for
the R2-receptor that also potently inhibit 5-HT uptake.
A preliminary account describing the in vitro pharma-
cological profile and putative antidepressant effects in
vivo of one member of this series, 40 (A-80426), has
recently appeared.17
a
Method D: i,ii. Method E: iii, i. v. Method F: v. Conditions:
(i) TMSCN, ZnI2; (ii) EtOH, HCl; (iii) DECNP, LiCN; (iv) p-TsOH,
benzene; (v) H2, RaNi.
ethyl fragment. The tertiary amines described in this
report were assembled by one of three different methods
(Scheme 1). Method A consisted simply of alkylation
of an [(N-methylamino)methyl]tetralin with the ap-
propriate arylethylhalide or mesylate. In method B, an
[(N-methylamino)methyl]tetralin was coupled to an
arylacetic acid fragment and the amide reduced. An
alternative method C entailed reaction of a primary
(aminomethyl)tetralin (R ) H) with an arylacetic acid
fragment, followed by reduction and alkylation of the
secondary amine.
1-(Aminomethyl)tetralin fragments were prepared
from the corresponding tetralones by either trimethyl-
silyl cyanide (TMSCN) or diethyl cyanophosphonate
(DECNP) addition, followed by elimination and reduc-
tion of the resulting dihydronaphthalene-1-carbonitrile
(Scheme 2). The choice of cyanide equivalent was
dictated by the propensity of the intermediate cyano-
hydrin to undergo elimination, with TMSCN being
favored for tetralones possessing an electron-donating
group para to the carbonyl, and DECNP being favored
for all other cases. Two previously undescribed tetral-
ones 5, and 7, were prepared via the elaboration of
known precursors 418 and 619 to the appropriate car-
boxylic acids followed by Friedel-Crafts cyclization
(Scheme 3).
Ch em istr y
Structure-activity relationship (SAR) studies on the
parent structure 3 entailed investigation of the aromatic
tetralin substitution pattern and absolute stereochem-
istry at C-1, alkyl substitution of the basic nitrogen, and
modification of the appended (methylenedioxy)phen-
The separate enantiomers with respect to the C-1
position of the tetralin ring were obtained by reaction
of racemic 5-OMe-tetralin-1-carboxylic acid 8 with (R)-

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1051
Sch em e 3a
Sch em e 5a
a
Conditions: (i) ClCO(CH2)2CO2Et, AlCl3; (ii) H2, 10% Pd/C;
(iii) LiAlH4; (iv) MsCl, Et3N; (v) KCN, EtOH; (vi) KOH, EtOH/
H2O; (vii) PPA, 100 °C.
Sch em e 4a
a
Conditions: (i) HCOCO2Me, TiCl4; (ii) BH3, THF; (iii)
C6H5NHCl, HO(CH2)2OH, 120 °C; (iv) MsCl, Et3N.
(A-80426), a new, efficient synthesis of the benzofuran
ring was developed. The existing methodology of
Barker,22 involving cyclization of an (aryloxy)acetalde-
hyde acetal, was initially investigated; however, poor
regioselectivity in the cyclization prompted us to develop
improved methodology. Condensation of the ethyl ester
of m-hydroxyphenylacetic acid 14 with methyl glyoxy-
late (Scheme 5) in the presence of titanium tetrachlo-
ride23,24 at 0 °C provided regioselectively in 80% yield
the desired 1,3,4-substituted hydroxy ester adduct 15.
Reduction with excess borane in tetrahydrofuran at
reflux provided in 99% yield a triol intermediate 16 that
upon heating in ethylene glycol at 120 °C with pyridine
hydrochloride cyclized to the desired benzofuran alcohol
17a in 40% yield,25 which was then activated as the
methanesulfonate 17b for coupling.
a
Conditions: (i) (COCl)2; (R)-phenylglycinol; (ii) (COCl)2; Et-
NMe2; (iii) (R)-pantolactone; (iv) LiAlH4; (v) MsCl, Et3N; (vi)
MeNH2; (vii) BH3, THF.
Resu lts a n d Discu ssion
phenylglycinol (Scheme 4, path A) and chromatographic
separation of the resultant diastereomeric amides 9a
and 10a . The amides were reduced to the secondary
amines 9b and 10b, and the absolute stereochemistry
was determined by X-ray analysis of a crystal of the HCl
salt of 10b, the secondary amine possessing the (R)
stereochemistry at the C-1 position. Removal of the
chiral auxiliary by catalytic hydrogenation yielded the
resolved primary amines. Once it was established that
the required absolute stereochemistry at C-1 was (R),
an enantioselective synthesis was developed (Scheme
4, path B). Racemic tetralin-1-carboxylic acid was
converted to its acid chloride, and treatment of the acid
chloride with dimethylethylamine provided the ketene
11 in situ. Addition of (R)-pantolactone20 then resulted
in a highly diastereoselective addition to yield exclu-
sively (>95%) the (R,R) diastereomer 12. Reduction of
the resulting ester-lactone intermediate (LiAlH4) fol-
lowed by activation of the alcohol as its mesylate ester21
and displacement with anhydrous methylamine yielded
the resolved [(N-methylamino)methyl]tetralin interme-
diate 13 in excellent chemical yield and enantiomeric
purity.
The tertiary amine analogs of 3 were assayed for their
affinity at the R2-receptor as well as for the ability to
inhibit 5-HT uptake in vitro. The SAR study reported
herein is broken into three parts: (1) substitution on
the tetralin ring; (2) modifications of the methylenedioxy
portion of the (methylenedioxy)phenethyl fragment; and
(3) nitrogen substitution. On the tetralin portion,
methoxy substitution was investigated at positions 5-8,
and the 5-position was further probed with a variety of
substituents differing in size and hydrogen-bonding
capacity. The results are summarized in Table 1. In
general, deviation from the 5-methoxy substitution
resulted in a loss of activity at inhibiting 5-HT uptake
ranging from 5.5-69 fold, whereas R2 binding was only
moderately affected. Interestingly, the 8-methoxy ana-
log 20 displayed slightly improved R2 affinity with
respect to 3, however it was nearly 2 orders of magni-
tude less active at inhibiting 5-HT uptake. The data
obtained on the hydrogen bond donating 5-hydroxy and
5-sulfonamido analogs 23 and 26 exemplify the impor-
tance of a Lewis basic functional group at this position
for potent 5-HT uptake inhibition. Also, increasing the
steric bulk at this position, as in the 5-ethoxy compound
24, exerts an adverse affect on 5-HT uptake inhibition.
The failure of the 5,6-dimethoxy analog 22 to demon-
strate potent 5-HT uptake inhibition could be due to an
The arylacetic acids and arylethyl halides and mesy-
lates used in this study were either known compounds
or prepared using well-established methodologies. For
one compound of particular interest from this study, 40

1052 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Ta ble 1. SAR of Aromatic Tetralin Ring
Meyer et al.
Ta ble 3. SAR of Rotationally Locked 5-Alkoxytetralins
R-2 binding
affinity Ki
5-HT uptake
inhibition IC50
(nM)a (95%
(nM)a (95%
no.
3
R
confidence limits)
confidence limits)
5-OMe
6.71
20.6
(3.05, 14.7)
(10.4, 41.0)
18
19
6-OMe
7-OMe
23.5b
469c
57.5
1420c
(35.5, 93.0)
2.88
(0.786, 10.6)
8.19
20
21
8-OMe
H
1430c
1090c
(3.99, 16.8)
22
23
5,6-di OMe (R)
5-OH
15.5c
757c
7.54
1240
(2.59, 22.0)
1.86
(212, 7250)
198
24
5-OEt (R)
(0.907, 3.81)
(57.6, 681)
25
26
5-SMe
5-NHSO2Me
21.0c
117c
19.0
658c
(0.424, 7.31)
6310
(3850, 10300)
2.89
(2.10, 3.98)
4.17
2
paroxetine
rauwolscine
napamezole
6.43
(2.29, 18.0)
>10,000c
887
(1.59, 11.0)
(454, 1730)
a
b
Number of determinations g 3. Number of determinations
) 2. c Number of determinations ) 1.
Ta ble 2. SAR of C-1 Stereochemistry
a
b
Number of determinations g 3. Number of determinations
) 2. c Number of determinations ) 1.
tethered back onto the 6-position of the tetralin, had
activity comparable to that of the more potent enanti-
omer 27. The corresponding benzofuran 31 was sig-
nificantly weaker at 5-HT uptake inhibition, indicative
of the importance of the Lewis basicity of the oxygen.
The methylenedioxy analog 29 displayed activity equiva-
lent to that of 30, bearing in mind that 29 was tested
as a racemate. In contrast to these findings, it is
interesting to note that the two compounds having the
tether to the 4-position, 32 and 33, were well over an
order of magnitude less potent at both the R2-receptor
and the 5-HT uptake site. These results suggest that
the oxygen lone pairs of the 5-methoxy may be oriented
away from the 6-position in binding to both of these
sites.
A brief examination into the importance of the N-alkyl
group was undertaken (Table 4). Although replacement
of methyl with ethyl led to only a slight drop in R2
affinity, 5-HT uptake inhibition was at least 10-fold
weaker. Larger groups such as cyclopropyl, methyl-
enecyclopropyl, and propargyl were dramatically weaker
even at the R2 site and hence were not evaluated for
5-HT uptake inhibition. The presence of a tertiary
amine, however, appears essential as the corresponding
secondary amine 34 displayed poor activity in both
assays.
R-2 binding
5-HT uptake
C-1 stereo-
affinity Ki (nM)a
inhibition IC50 (nM)a
no. chemistry (95% confidence limits) (95% confidence limits)
3
racemic
6.71
(3.05, 14.7)
1.70
(0.333, 8.63)
88.6
(410, 4170)
20.6
(10.4, 41.0)
12.7
(2.52, 64.3)
1310
27 (R)
28 (S)
(49.7, 158)
a
Number of determinations g 3.
unfavorable influence of the 6-methoxy group on the
orientation of the adjacent 5-methoxy substituent (vide
infra) and vice versa since 6-methoxy substitution is not
detrimental to activity when compared with the unsub-
stituted compound 21. From these results, 5-methoxy
substitution clearly provided the optimal combination
of activities on the tetralin portion. Evaluation of the
stereochemistry at C-1 of the tetralin for 3 (Table 2)
indicates that the majority of the activities at the R2-
receptor and the 5-HT uptake site resides in the (R)
enantiomer 27.
In order to examine the potential importance of the
binding orientation of the oxygen lone pairs of 3, several
rigidified 5-alkoxytetralins were prepared (Table 3). The
dihydrobenzofuran analog 30, where the alkyl group is
Modifications of the phenethyl appendage consisted
primarily of replacement of the methylenedioxy ring
with other heterocycles containing one or two hetero-

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
Ta ble 4. SAR of Nitrogen Substitution
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1053
absolute requirement; the indan derivative 44 retains
good affinity for both the 5-HT uptake site and the R2
binding site. The structural diversity tolerated in this
portion of the molecule allows for potential adjustment
of physiochemical parameters such as lipophilicity,
aqueous solubility, and the like; which in turn allows
for optimization of pharmaceutical properties such as
oral absorption and metabolic stability. Optimization
of these parameters resulted in the selection of 40 (A-
80426) for more in-depth pharmacological evaluation,
the results of which have been presented elsewhere.26,27
R-2 binding
5-HT uptake
inhibition IC50 (nM)a
affinity Ki (nM)a
no.
R
(95% confidence limits) (95% confidence limits)
27 Me
1.70
12.7
Exp er im en ta l Section
(0.333, 8.63)
(2.52, 64.3)
34 Hb
35 Etb
36 cyclopropyl
37 methylene
cyclopropyl
88.2c
414d
Ch em istr y. Proton NMR spectra were obtained on a
General Electric QE 300 or QZ 300 MHz instrument with
chemical shifts (δ) reported relative to tetramethylsilane as
internal standard. Melting points were determined on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Elemental analyses were performed either by
Oneida Research Services, Robertson Microlit Laboratories,
or the Analytical Department at Abbott Laboratories. Column
chromatography was carried out on silica gel 60 (230-400
mesh). Thin-layer chromatography (TLC) was performed
using 250 µm silica gel 60 glass-backed plates with F254 as
indicator. HPLC separations were done using a Waters
Associates Prep LC/System 500 liquid chromatograph. Optical
rotations were measured with a Perkin-Elmer 541 polarimeter.
X-ray crystal structures were obtained on a Rigaku AFC5R
diffractometer. All physical data and yields for final com-
pounds correspond to the indicated salt form unless otherwise
noted.
Meth od A. N-[2-(Ben zofu r an -6-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m et h yla m in e Met h a n esu lfon a t e (40, A-80426). Benzo-
furan-6-ethanol methanesulfonate ester (1.20 g, 5.0 mmol) and
N-[((R)-5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-
N-methylamine (for preparation, see method G) (1.03 g, 5.0
mmol) were combined in CH3CN (10 mL) with Li2CO3 (0.554
g, 7.5 mmol), and the reaction was heated to reflux for 48 h.
The reaction was quenched in H2O and extracted with Et2O
(2 × 100 mL). The organic phase was washed with water and
brine and dried (K2CO3). The solvent was evaporated, and the
resulting oily product was dissolved in EtOAc and treated with
1.1 equiv of MeSO3H. The product was collected and dried to
yield 1.70 g of 40 (76%): mp 191-193 °C; 1H NMR (CDCl3) of
the free base δ 1.6-2.0 (m, 4H), 2.4 (s, 3H), 2.3-3.0 (m, 9H),
3.81 (s, 3H), 6.67 (d, 1H), 6.72 (dd, 1H), 6.80 (d, 1H), 7.09 (m,
5.73c
158d
266d
NA
NA
54.3d
38 propargyl
184d
NA
a
b
Number of determinations g 3. Racemate. c Number of
d
determinations ) 2. Number of determinations ) 1.
atoms in various positions (Tables 5-7). The point of
attachment of the connecting ethyl chain to the phenyl
ring was held constant. In contrast to the sensitivity
of 5-HT uptake inhibitory activity to substitution changes
on the tetralin portion, modifications of both the position
and nature of the heteroatom were well tolerated.
Nitrogen, oxygen, and sulfur atoms were generally
interchangeable with only minor perturbations in activ-
ity. Indeed, even the indan 44 (Table 5) lacking a
heteroatom was quite active at 5-HT uptake inhibition.
Typically, the range in activity at 5-HT uptake inhibi-
tion spanned from approximately 2-fold more potent
than 27 for 54 and 60 to around 5-fold less active for a
variety of analogs of differing structure. Likewise, with
just a few exceptions nearly all compounds in this series
possessed high affinity for the R2-receptor, in the na-
nomolar range. Some interesting exceptions to these
observations, however, did manifest themselves. The
isobenzofuran 43, for example, was nearly 20-fold less
active at 5-HT uptake inhibition than either of the
isomeric dihydrobenzofurans 39 and 41. Also, the
related analogs 49, 53, and 54 with other atoms at this
position showed high affinity for the 5-HT uptake site.
Also noteworthy was the marked inactivity at the 5-HT
site of the two isomeric indoline trifluoromethane-
sulfonamides 52 and 58. These compounds were sub-
stantially weaker than the unsubstituted indolines 50
and 56 or methanesulfonamide derivatives 51 and 57.
All three trifluoromethanesulfonamides displayed poor
affinity for the R2-receptor, ranging between 25 and 35
times less potent than the corresponding methane-
sulfonamides.
Structure-activity studies on this series are best
summarized by division of the generic structure into a
left-hand (aminomethyl)tetralin fragment and a right-
hand arylethyl appendage. The left-hand substructure
is not at all tolerant of structural manipulation. 5-OMe
substitution is optimal, and only very modest changes
are at all tolerated. (R) stereochemistry at the one
stereocenter is required for both of the described activi-
ties. N-Methyl substitution of the basic amine is
required. By contrast, a significant degree of structural
modification is permitted on the pendant arylethyl
substructure. A large variety of fused heterocycles are
well tolerated. The presence of heteroatoms is not an
2H), 7.36 (s, 1H), 7.49 (d, 1H), 7.57 (d, 1H). Anal. (C24H31
NO5S) C, H, N.
-
Ben zofu r a n -6-eth a n ol Meth a n esu lfon a te Ester (17b).
3-Hydroxyphenylacetic acid (347 g, 2.28 mol) was esterified
by heating to reflux in EtOH (1.2 L) with concentrated H2SO4
(10 mL) for 5 h. The crude product was distilled at 160 °C (1
mm) to yield 391.7 g (95%) of 3-hydroxyphenylacetic acid ethyl
ester as a clear oil. To a mixture of 3-hydroxyphenylacetic
acid ethyl ester (225 g, 1.25 mol) and methyl glyoxalate (160
g) in CH2Cl2 (2 L) at 0 °C was added with vigorous stirring a
solution of TiCl4 (142 mL, 1.29 mol) in CH2Cl2 (800 mL). After
4 h at 0 °C the reaction was quenched by the addition of ice
(800 mL) to the flask followed by stirring for 30 min. The
layers were then separated, and the organic layer was dried
(MgSO4) and filtered through a short plug of silica gel, eluting
first with CH2Cl2 and then EtOAc. The EtOAc fraction was
washed through a fresh plug of silica gel and the solvent
evaporated to yield 265 g of 15 (80%) as a light clear oil. A
solution of 1.0 M BH3‚THF (2.66 L) was heated to reflux, the
heat source was removed, and compound 15 (254 g, 0.95 mol)
in THF (350 mL) was added at such a rate as to maintain a
gentle reflux (1.5 h). After the addition was complete, the
reaction was continued at reflux for 2.5 h, cooled in an ice bath,
and quenched by slow addition of MeOH (1 L). The solvent
was evaporated to yield 188 g of 16 (99%) as a colorless thick
oil. A solution of compound 16 (104 g) in ethylene glycol (800
mL) was heated to 120 °C and treated with pyridine hydro-

1054 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Ta ble 5. SAR of Arylethyl Side Chain
Meyer et al.
Ta ble 6. SAR of Arylethyl Side Chain
a
b
Number of determinations g 3. Number of determinations
) 2.
Ta ble 7. SAR of Arylethyl Side Chain
a
b
Number of determinations g 3. Number of determinations
) 2.
chloride (80 g), and the solution was heated to reflux for 30
min. The reaction was cooled, quenched on ice, and extracted
with ether (4 × 450 mL). The extracts were washed with 1 N
a
Number of determinations g 3.

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1055
HCl, 1 N NaOH, and brine, dried (MgSO4), filtered, and
evaporated to yield 37.9 g of an oil that was distilled at 105-
110 °C (0.5 mm) to give 34.5 g of 17a (40%) as a colorless oil.
To a solution of 17a (6.74 g, 41.5 mmol) in CH2Cl2 (40 mL)
with NEt3 (6.37 mL, 45.7 mmol) at 0 °C was added a solution
of MsCl (3.38 mL, 43.6 mmol) in CH2Cl2 (10 mL), and the
reaction was stirred for 2 h at 0 °C to provide upon workup
10.0 g of 17b (100%) as a colorless oil.
60 mmol) over 10 min and the reaction allowed to proceed for
45 min at 5 °C. After workup and isolation, the resultant
cyanohydrin was heated in benzene (100 mL) to reflux with
p-TsOH (0.50 g, 2.6 mmol) for 2 h to give 7.81 g (84%) of the
title compound.
Meth od F . N-[(5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a -
len -1-yl)m eth yl]a m in e Hyd r och lor id e. 5-Methoxy-3,4-di-
hydronaphthalene-1-carbonitrile (16.7 g) was reduced under
4 atm of H2 with RaNi (34 g) in MeOH (225 mL) with NH3 (25
mL) at room temperature. Solvents were evaporated, and the
crude product was converted to the hydrochloride salt to
provide 7.15 g of the title compound.
Meth od B. N-[2-[3,4-(Meth ylen ed ioxy)p h en yl]eth yl]-
N-(1,2,3,4-t et r a h yd r on a p h t h a len -1-ylm et h yl)-N-m et h -
yla m in e Meth a n esu lfon a te (21). Step 1. N-(1,2,3,4-Tet-
rahydronaphthalen-1-ylmethyl)-N-methylamine hydrochloride
(prepared by methods D and F) (2.10 g, 10 mmol), 3,4-
(methylenedioxy)phenylacetic acid (2.0 g, 11 mmol), 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (2.30
g, 12 mmol), and 1-hydroxybenzotriazole (2.97 g, 22 mmol)
were combined in THF (30 mL) and stirred at room temper-
ature for 18 h. The reaction was quenched in water, extracted
with EtOAc (2 × 50 mL), washed successively with 10%
aqueous HCl, 5% NaHCO3, brine, and dried (MgSO4), and
evaporated to dryness to yield 3.2 g (95%) of the intermediate
amide. Step 2. The amide was treated with 1.0 M BH3‚THF
(38 mL) in THF (30 mL) at reflux for 5 h. The reaction was
quenched by addition of MeOH, evaporated to dryness, and
then treated at reflux for 1 h with MeOH (30 mL) and iPrOH
saturated with anhydrous HCl (15 mL). After evaporation,
basification, and extraction, the free base was converted to its
methanesulfonate salt and recrystallized from Et2O and EtOH
to yield 1.89 g of 21: mp 140-1 °C; 1H NMR (DMSO-d6) δ
1.6-1.9 (m, 4H), 2.28 (s, 3H), 2.6-3.4 (m, 9H), 5.95 (s, 2H),
6.7-7.3 (m, 7H), 9.0 (br s, 1H). Anal. (C22H29NO5S) C, H, N.
Meth od C. N-[2-[3,4-(Meth ylen ed ioxy)p h en yl]eth yl]-
N -[(5-m e t h o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)-
m eth yl]a m in e Hyd r och lor id e (34). Step 1. Oxalyl chlo-
ride (1.3 mL, 15 mmol) was added to a solution of 3,4-
(methylenedioxy)phenylacetic acid (1.80 g, 10 mmol) in 40 mL
of CH2Cl2 and 3 drops of DMF. After 45 min at 25 °C, the
solvent was evaporated. The resulting acid chloride was added
to a solution of N-[(5-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)methyl]amine hydrochloride (prepared by methods E and
F) (2.28 g, 10 mmol) in 40 mL of CH2Cl2 and 4.18 mL of NEt3.
After 2 h, the reaction was quenched in 100 mL 5% aqueous
NaHCO3, extracted with CH2Cl2, dried (MgSO4), and evapo-
rated to dryness to provide the intermediate amide. Step 2.
The amide was dissolved in 20 mL of THF and 22 mL of 1.0
M BH3‚THF was added. The reaction was refluxed for 4 h,
cooled to room temperature, and quenched by the addition of
5 mL of MeOH. The solvent was evaporated, and the residue
was dissolved in 20 mL of MeOH and 10 mL of saturated
iPrOH/HCl. The reaction was refluxed for 30 min and then
evaporated to dryness. The product was recrystallized from
EtOH to yield 2.60 g of 34: mp 178-80 °C; 1H NMR (DMSO-
d6) δ 1.6-1.9 (m, 4H), 2.34 (s, 3H), 2.4-3.6 (m, 7H), 3.88 (s,
3H), 3.9-4.1 (m, 2H), 5.99 (s, 2H), 6.73 (dd, 1H), 6.78-6.92
(m, 4H), 7.17 (t, 1H), 8.4 (br s, 2H). Anal. (C22H29NO6S‚1/
2H2O) C, H, N. Step 3. N-[2-[3,4-(Meth ylen ed ioxy)p h en yl]-
eth yl]-N-[(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
m et h yl]-N-m et h yla m in e Met h a n esu lfon a t e (3). The
secondary amine 34 (as the hydrochloride salt) (0.940 g, 2.50
mmol) was dissolved in MeOH (25 mL) and 37% aqueous
formaldehyde (6.9 mL). To the above solution was added 1.2
g of NaCNBH3, and the reaction was stirred at 25 °C for 2 h.
The reaction was quenched in 5% aqueous NaHCO3 solution
(100 mL), extracted with ether, dried (K2CO3), and evaporated
to dryness. The resulting oil was converted to its methane-
sulfonic acid salt, and the product recrystallized from EtOH
and Et2O to yield 0.830 g of 3: mp 159-61 °C; 1H NMR (CDCl3)
δ 1.7-2.2 (m, 4H), 2.5-3.5 (m, 9H), 2.85 (s, 3H), 3.00 (d, 3H),
3.82 (s, 3H), 5.94 (s, 2H), 6.7 (m, 5H), 7.15 (t, 1H), 10.9 (br s,
1H). Anal. (C23H31NO6S) C, H, N.
Resolu tion Meth od s: Step 1. (1S)- a n d (1R)-5-Meth -
oxy-1,2,3,4-tetr a h yd r on a p h th a len e-1-ca r boxylic (R)-(-)-
P h en ylglycin ol Am id es (9a a n d 10a ). 5-Methoxytetralin-
1-carboxylic acid (1.03 g, 5.00 mmol) was dissolved in CH2Cl2
(50 mL), and oxalyl chloride (0.65 mL) and DMF (2 drops) were
added. After 1 h at reflux, solvent and excess reagent were
evaporated. The resulting acid chloride was added to a
solution of (R)-(-)-2-phenylglycinol (0.823 g, 6.00 mmol) and
1.4 mL of NEt3 in CH2Cl2 (50 mL). After 1 h, the reaction
was quenched in dilute HCl, extracted with CH2Cl2, dried
(MgSO4), and evaporated to dryness. The resulting solid was
purified by chromatography over silica gel to yield 0.70 g of
(1R)-5-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic (R)-
(-)-phenylglycinol amide (10a ): mp 179-80 °C; 1H NMR
(CDCl3) δ 1.75-2.0 (m, 3H), 2.3 (m, 1H), 2.39 (dd, 1H), 2.6 (m,
1H), 2.80 (dt, 1H), 3.70 (t, 1H), 3.79 (m, 2H), 3.84 (s, 3H), 5.1
(m, 1H), 6.05 (m, 1H), 6.75 (d, 1H), 6.77 (d, 1H), 7.13 (m, 3H),
7.3 (m, 3H). Further elution yielded 0.65 g of (1S)-5-methoxy-
1,2,3,4-tetrahydronaphthalene-1-carboxylic (R)-(-)-phenyl-
glycinol amide (9a ): mp 181-3°C; NMR (CDCl3) δ 1.6-2.0 (m,
3H), 2.3 (m, 1H), 2.57 (t, 1H), 2.6 (m, 1H), 2.76 (dt, 1H), 3.73
(t, 1H), 3.7 (m, 2H), 3.83 (s, 3H), 5.07 (m, 1H), 6.08 (m, 1H),
6.76 (d, 1H), 6.81 (d, 1H), 7.13 (m, 3H), 7.3 (m, 3H). Step 2.
[(R)-2-P h en yl-2-[((R)-5-m eth oxy-1,2,3,4-tetr a h yd r on a p h -
th a len -1-yl)m eth yl]a m in o]eth a n ol Hyd r och lor id e (10b).
The (R,R) product 10a (7.18 g, 22 mmol) was dissolved in 100
mL of THF, 110 mL of 1.0 M BH3‚THF was added, and the
reaction was refluxed for 3.5 h. MeOH (50 mL) was then
added and the solvent evaporated. The residual product was
dissolved in methanol (50 mL) and iPrOH saturated with
HCl(g) (25 mL) and refluxed for 30 min. Solvent was evapo-
rated to yield 5.96 g of the desired product 10b as a white
solid: mp 157-8 °C; 1H NMR (CDCl3) δ 1.4 (m, 1H), 1.76 (m,
1H), 2.25 (m, 1H), 2.4 (m, 1H), 2.62 (m, 1H), 2.97 (m, 1H), 3.1
(m, 1H), 3.52 (m, 1H), 3.75 (s, 3H), 4.08 (m, 1H), 4.5 (m, 2H),
5.62 (m, 1H), 6.62 (d, 1H), 6.73 (d, 1H), 7.03 (t, 1H), 7.43 (m,
3H), 7.7 (m, 2H), 9.5 (br s, 1H), 9.7 (br s, 1H).
[(R)-2-P h en yl-2-[((S)-5-m eth oxy-1,2,3,4-tetr ah ydr on aph -
th a len -1-yl)m eth yl]a m in o]eth a n ol Hyd r och lor id e (9b).
The (S,R) product 9a (4.6 g, 14 mmol) was treated as described
in the preceding example to yield 4.0 g of 9b as a white solid:
1
mp 190-1 °C; H NMR (CDCl3) δ 1.6-2.0 (m, 3H), 2.25 (m,
1H), 2.43 (m, 1H), 2.7 (m, 1H), 3.07 (m, 1H), 3.5 (m, 1H), 3.77
(s, 3H), 4.02 (m, 1H), 4.4 (m, 2H), 5.5 (m, 1H), 6.62 (d, 1H),
6.63 (d, 1H), 7.03 (t, 1H), 7.43 (m, 3H), 7.68 (m, 2H), 9.1 (m,
1H), 10.1 (m, 1H).
[(R)-(5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]a m in e Hyd r och lor id e (10c). The amine 10b (3.22
g, 9.3 mmol) was dissolved in MeOH (100 mL) and treated
with H2 in the presence of Pd/C at 25 °C for 24 h. The reaction
was filtered and evaporated to yield 1.65 g of the title
compound 10c as a white solid: mp 266-7 °C; 1H NMR
(DMSO-d6) δ 1.6-1.9 (m, 4H), 2.45 (m, 1H), 2.62 (dt, 1H), 2.92
(dd, 1H), 3.04 (m, 2H), 3.77 (s, 3H), 6.80 (d, 1H), 6.86 (d, 1H),
7.13 (t, 1H), 8.07 (br s, 3H); [R]25 ) +26.7°.
D
[(S)-(5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]a m in e Hyd r och lor id e (9c). The amine 9b (3.89 g,
11.2 mmol) was dissolved in MeOH (100 mL), treated with H2
in the presence of Pd/C at 25 °C for 24 h, filtered, and
evaporated to dryness to yield 2.39 g of the title compound 9c
as a white solid, mp 267-9 °C; 1H NMR (DMSO-d6) δ 1.6-1.9
(m, 4H), 2.45 (m, 1H), 2.62 (dt, 1H), 2.92 (dd, 1H), 3.04 (m,
2H), 3.77 (s, 3H), 6.80 (d, 1H), 6.86 (d, 1H), 7.13 (t, 1H), 8.07
Meth od D. The trimethylsilyl cyanide additions were
conducted as previously described.28
Meth od E. 5-Meth oxy-3,4-d ih yd r on a p h th a len e-1-ca r -
bon itr ile. To a solution of 5-methoxy-1-tetralone (8.80g, 50
mmol) in anhydrous THF (50 mL) at 5 °C was added first LiCN
(0.50 g, 6.6 mmol) and then diethyl cyanophosphonate (9.1 mL,
(br s, 3H); [R]25 ) -25.6°.
D

1056 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Meyer et al.
Met h od G, St ep 1: (R)-5-Met h oxy-1,2,3,4-t et r a h y-
d r on a p h t h a len e-1-ca r b oxylic Acid (R)-Dih yd r o-3-h y-
dr oxy-4,4-dim eth yl-2(3H)-fu r an on e Ester (12). 3,4-Dihydro-
5-methoxynaphthalene-1-carbonitrile (prepared by method E)
(54.8 g) was reduced with NaBH4 (22.4 g) in EtOH (600 mL)
at reflux for 1 h. After cooling, the reaction was poured onto
ice/HCl and extracted with CH2Cl2 (3×), and the organics were
washed with brine, dried (MgSO4), and evaporated to give 56
g of the saturated nitrile (99%). This nitrile was heated to
reflux for 20 h in 45% KOH (275 mL) and ethylene glycol (225
mL), cooled, poured onto ice/HCl, and extracted with CH2Cl2.
The organics were washed with brine and dried (MgSO4), and
solvents were evaporated to give 5-methoxy-1,2,3,4-tetrahy-
dronaphthalene-1-carboxylic acid (48 g, 78%). This acid (46.31
g, 224.6 mmol) was dissolved in toluene (1 L), and to the
solution was added oxalyl chloride (21.6 mL, 247 mmol) and
DMF (0.5 mL). After 1.5 h at 50 °C, the solution was cooled
to 10 °C and dimethylethylamine (73 mL, 674 mmol) was
added. The reaction was stirred at ambient temperature for
3 h and then cooled to -70 °C. (R)-Dihydro-3-hydroxy-4,4-
dimethyl-2(3H)-furanone (35.1 g, 269.5 mmol) was added, and
the reaction was stirred for 2 h, warming slowly to -30 °C.
The reaction was then poured into water and extracted with
Et2O. The combined organic extracts were washed with 5%
NaHCO3 and brine, dried over MgSO4, and evaporated to
dryness under reduced pressure. Trituration with 1:1 Et2O/
hexane yielded 61.68 g (86%) of 12 as a white solid: mp 74-
g, 10 mmol) as described in method C to yield 0.85 g of 18:
1
mp 135-6 °C; H NMR (DMSO-d6) δ 1.6-1.9 (m, 4H), 2.3 (s,
3H), 2.4-3.4 (m, 9H), 2.95 (d, 3H), 3.72 (s, 3H), 6.0 (s, 2H),
6.6-7.0 (m, 5H), 7.08 (t, 1H), 9.0 (br s, 1H). Anal. (C23H31
NO6S) C, H, N.
-
N-[(7-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)m e-
th yl]-N-m eth yl-N-[2-[3,4-(m eth ylen ed ioxy)p h en yl]eth yl]-
a m in e Meth a n esu lfon a te (19). [(7-Methoxy-1,2,3,4-tetra-
hydronaphthalen-1-yl)methyl]amine hydrochloride (prepared
from 7-methoxytetralone using methods E and F) (1.6 g, 7.0
mmol) was reacted with 3,4-(methylenedioxy)phenylacetic acid
(1.80 g, 10 mmol) as described in method C to yield 0.65 g of
19: mp 115-6 °C; 1H NMR (DMSO-d6) δ 1.6-1.9 (m, 4H), 2.3
(s, 3H), 2.4-3.4 (m, 9H), 2.95 (d, 3H), 3.74 (s, 3H), 6.0 (s, 2H),
6.6-7.0 (m, 5H), 7.0 (m, 1H), 9.0 (br s, 1H). Anal. (C23H31
NO6S) C, H, N.
-
N -[(8-Me t h oxy-1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)-
m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]eth -
yl]a m in e Meth a n esu lfon a te (20). [(8-Methoxy-1,2,3,4-tet-
rahydronaphthalen-1-yl)methyl]amine hydrochloride (pre-
pared according to methods D and F from 8-methoxytetralone29)
(0.53 g, 1.4 mmol) was reacted with 3,4-(methylenedioxy)-
phenylacetic acid (0.36 g, 2.0 mmol) as described in method C
to yield 0.44 g of 20: mp 113-5 °C; 1H NMR (free base, CDCl3)
δ 1.5-1.8 (m, 3H), 2.13 (m, 1H), 2.39 (s, 3H), 2.45-2.80 (m,
8H), 3.21 (m, 1H), 3.80 (s, 3H), 5.92 (s, 2H), 6.6-6.8 (m, 5H),
7.08 (t, 1H). Anal. (C23H31NO6S‚1/4 H2O) C, H, N.
N-[((R)-5,6-Dim eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl)m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]-
eth yl]am in e Meth an esu lfon ate (22). N-[((R)-5,6-Dimethoxy-
1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amine (prepared via
methods D and G) (0.70 g) was reacted with 3,4-(methylene-
dioxy)phenylacetic acid (0.80 g) by method C to yield 0.28 g of
22: mp 150-1 °C; 1H NMR (DMSO-d6) δ 11.68-1.90 (m, 5H),
2.32 (s, 3H), 2.5-2.8 (m, 2H), 2.85 (s, 3H), 3.1-3.5 (m, 5H),
3.68 (s, 3H), 3.79 (s, 3H), 6.00 (s, 2H), 6.70-7.05 (m, 6H), 9.0
(br s, 1H). Anal. (C24H33NO7S‚1/4H2O) C, H, N.
N -[(5-H yd r oxy-1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)-
m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]eth -
yl]a m in e Hyd r och lor id e (23). N-(5-Methoxy-1,2,3,4-tet-
rahydronaphthalen-1-yl)-N-methylamine hydrochloride (pre-
pared by methods E and F) (1.21 g, 5.0 mmol) was treated
with 4.0 g of BBr3 (20 mmol) in CH2Cl2 (50 mL) at 0 °C to
yield after isolation 1.13 g of the phenol intermediate. This
compound was then treated as described in method B to yield
0.88 g of 23 as a white solid: mp 235-7 °C; 1H NMR (DMSO-
d6) δ 1.7-2.1 (m, 4H), 2.4-3.5 (m, 9H), 2.93 (d, 3H), 6.00 (s,
2H), 6.6-7.0 (m, 6H), 9.37 (s, 1H), 9.8 (br s, 1H). Anal.
(C21H26ClNO3) C, H, N.
N-[((R)-5-E t h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]eth -
yl]a m in e Meth a n esu lfon a te (24). From 3,4-(methylene-
dioxy)phenylacetic acid (0.42 g) and N-[((R)-5-ethoxy-1,2,3,4-
tetrahydronaphthalen-1-ylmethyl)-N-methylamine (0.50 g) by
method B, 0.49 g of 24: mp 162-3 °C; 1H NMR (DMSO-d6) δ
1.32 (t, 3H), 1.7-1.9 (m, 4H), 2.31 (s, 3H), 2.4-3.4 (m, 9H),
2.93 (d, 3H), 4.0 (m, 2H), 6.0 (s, 2H), 6.7-7.0 (m, 5H), 7.13 (m,
1H), 9.1 (br s, 1H). Anal. (C24H33NO6S) C, H, N.
N-Meth yl-N-[2-[3,4-(m eth ylen ed ioxy)p h en yl]eth yl]-N-
[[5-(methylthio)-1,2,3,4-tetrahydronaphthalen-1-yl]methyl]-
a m in e Hyd r och lor id e (25). 5-Hydroxy-1-tetralone (20 g)
was added to NaH (3.7 g) in DMF (200 mL), followed by
dimethylthiocarbamyl chloride (18.3 g), and the reaction was
heated at 85 °C for 16 h to give 9.66 g of the thiocarbamate.
Upon 2 h of heating in mineral oil (100 mL) at 270 °C the
thiocarbamate underwent the Newmann-Kwart rearrange-
ment to give, after cooling and precipitation with cyclohexane,
8.44 g of 5-thiotetralone. The thiolate anion, prepared from
NaOH (6 g) in MeOH (90 mL), was alkylated with MeI (6 g)
to give 4.47 g of 5-(methylthio)tetralone. 5-(Methylthio)-
tetralone (0.38 g) was converted to 3,4-dihydro-5-(methylthio)-
naphthalene-1-carbonitrile (0.4 g) via method E, reduced to
the saturated nitrile with NaBH4 (0.23 g) in 1:1 EtOH/
dimethoxyethane (20 mL) for 17 h at room temperature, and
hydrolyzed by heating to reflux with 45% KOH (15 mL) in
ethylene glycol (12 mL) for 12 h to give 5-(methylthio)-1,2,3,4-
1
77 °C; H NMR (CDCl3) δ 0.97 (s, 3H), 1.17 (s, 3H), 1.7-2.2
(m, 4H), 2.7 (m, 2H), 3.80 (s, 3H), 3.98 (t, 1H), 4.01 (s, 2H),
4.40 (s, 1H), 6.72 (d, 1H), 6.83 (d, 1H), 7.12 (t, 1H). Step 2.
N-[((R)-5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]-N-m eth yla m in e Hyd r och lor id e (13). To LiAlH4
(14.7 g, 387.2 mmol) suspended in THF (400 mL) was added
61.65 g (196.6 mmol) of furanone ester 12 dissolved in THF
(200 mL) over 30 min. After an additional 1 h, the reaction
was quenched using the Fieser workup conditions, filtered
through Celite, and evaporated to dryness to yield 36.98 g
(98%) of alcohol as a colorless oil. 1H NMR (CDCl3) δ 1.54
(bs, 1H), 1.7-2.0 (m, 4H), 2.5-2.7 (m, 2H), 2.97 (m, 1H), 3.80
(d, 2H), 3.81 (s, 3H), 6.70 (d, 1H), 6.86 (d, 1H), 7.12 (t, 1H).
The above alcohol (36.98 g, 192.3 mmol) was dissolved in
CH2Cl2 (600 mL) and NEt3 (53.6 mL, 385 mmol). The solution
was cooled to 0 °C, and MsCl (17.85 mL, 230.7 mmol) was
added over 15 min. After 1 h at 0 °C, the reaction was poured
into water and extracted with CH2Cl2. The combined organic
extracts were washed with 5% NaHCO3 and brine, dried over
MgSO4, and evaporated to dryness to yield 49.05 g (94%) of
1
the title compound as a light yellow solid: mp 55-56 °C; H
NMR (CDCl3, 300 MHz) δ 1.7-2.0 (m, 4H), 2.56 (m, 1H), 2.75
(dt, 1H), 2.98 (s, 3H), 3.22 (m, 1H), 3.81 (s, 3H), 4.28 (t, 1H),
4.40 (dd, 1H), 6.71 (d, 1H), 6.81 (d, 1H), 7.12 (t, 1H). The
mesylate (49.0 g, 181 mmol) was dissolved in anhydrous
methylamine (125 mL) and allowed to stand in a tightly
stoppered container at 25 °C for 48 h. The vessel was cooled
on ice, and the stopper was removed. The reaction was
warmed to ambient temperature, and excess methylamine was
allowed to evaporate. The product was suspended in 2 N
NaOH and extracted with Et2O (2 × 150 mL). The ethereal
solution was extracted with 10% HCl (2 × 100 mL), and the
aqueous extracts were then basified to pH 12 with aqueous
NaOH. The aqueous suspension was extracted with CH2Cl2
(2 × 100 mL), and the organic phase was dried over K2CO3
and evaporated to yield 34.5 g of a colorless oil (93%). The oil
was dissolved in Et2O (500 mL) and treated with a saturated
solution of anhydrous HCl in EtOH. The resulting white solid
was collected and recrystallized from ethanol to yield 38.0 g
of 13: mp 214-215 °C; 1H NMR (DMSO-d6, 300 MHz) δ 1.65-
1.9 (m, 4H), 2.4-2.7 (m, 2H), 2.59 (s, 3H), 3.0-3.3 (m, 3H),
3.76 (s, 3H), 6.81 (d, 1H), 6.87 (d, 1H), 7.14 (t, 1H), 8.7 (bs,
2H).
N-[(6-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)m e-
th yl]-N-m eth yl-N-[2-[3,4-(m eth ylen ed ioxy)p h en yl]eth yl]-
a m in e Meth a n esu lfon a te (18). [(6-Methoxy-1,2,3,4-tetrahy-
dronaphthalen-1-yl)methyl]amine hydrochloride (prepared from
6-methoxytetralone via methods D and F) (1.5 g, 6.2 mmol)
was reacted with 3,4-(methylenedioxy)phenylacetic acid (1.80

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1057
tetrahydronaphthalene-1-carboxylic acid (0.35 g). In a modi-
fication of method B, reaction of 3,4-(methylenedioxy)-N-
methylphenethylamine (0.86 g) and 5-(methylthio)-1,2,3,4-
tetrahydronaphthalene-1-carboxylic acid (1.0 g) yielded 0.685
g of 25: mp 169-70 °C; 1H NMR (DMSO-d6) δ 1.7-2.0 (m,
6H), 2.30 (s, 3H), 2.44 (s, 3H), 2.4-3.5 (m, 8H), 5.98 (s, 2H),
6.7-6.9 (m, 3H), 7.1 (m, 2H), 7.20 (t, 1H), 9.1 (br s, 1H). Anal.
(C23H31NO5S2) C, H, N.
N-[(5-Meth a n esu lfon a m ido-1,2,3,4-tetr a h yd r on a ph th a -
len -1-yl)m et h yl]-N-m et h yl-N-[2-[3,4-(m et h ylen ed ioxy)-
p h en yl]et h yl]a m in e H yd r och lor id e (26). 5-Amino-1-
tetralone30 (1.02 g) was reacted with MsCl (0.80 g) and pyridine
(13 mL) to give 1.48 g (98%) of 5-methanesulfonamido-1-
tetralone that was benzylated with NaH and benzyl bromide
in DMF and elaborated onto the corresponding aminometh-
yltetralin via methods E and F. 3,4-(Methylenedioxy)phen-
ylacetic acid (0.568 g) and 1-(aminomethyl)-5-(N-benzyl-
methanesulfonamido)-1,2,3,4-tetrahydronaphthalene hydro-
chloride (1.14 g) were reacted by method C. The resulting
N-benzylated product was treated with 20% Pd/C (1.05 g) and
H2 (4 atm) in methanol for 4 h to yield 0.378 g of 26: mp 153-5
°C; 1H NMR (DMSO-d6) δ 1.65-2.1 (m, 6H), 2.55-3.55 (m,
7H), 2.91 (d, 3H), 3.37 (s, 3H), 5.93 (s, 2H), 6.7-7.0 (m, 3H),
7.2 (m, 3H), 9.0 (s, 1H), 9.9 (br s, 1H). Anal. (C22H29N2O4-
SCl) C, H, N.
N-[((R)-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]eth -
yl]a m in e Meth a n esu lfon a te (27). From 0.313 g (1.74 mmol)
3,4-(methylenedioxy)phenylacetic acid and 0.330 g of [(R)-(5-
methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]amine hy-
drochloride 10c (1.45 mmol) as described in method C to yield
0.382 g od 27: mp 169-70 °C; 1H NMR (CDCl3) δ 1.7-2.2 (m,
4H), 2.5-3.5 (m, 9H), 2.85 (s, 3H), 3.00 (d, 3H), 3.82 (s, 3H),
5.94 (s, 2H), 6.7 (m, 5H), 7.15 (t, 1H), 10.9 (br s, 1H). Anal.
(C23H31NO6S) C, H, N.
N-[((S)-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
m eth yl]-N-m eth yl-N-[2-[3,4-(m eth ylen edioxy)ph en yl]eth -
yl]a m in e Meth a n esu lfon a te (28). From 0.275 g (1.2 mmol)
of [(S)-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-
amine hydrochloride and 0.264 g (1.50 mmol) of 3,4-(methyl-
enedioxy)phenylacetic acid by method C to yield 0.280 g of
28: mp 169-70 °C; 1H NMR (CDCl3) δ 1.7-2.2 (m, 4H), 2.5-
3.5 (m, 9H), 2.85 (s, 3H), 3.00 (d, 3H), 3.82 (s, 3H), 5.94 (s,
(R)-6-[(N-Meth yla m in o)m eth yl]-N-[2-[3,4-(m eth ylen e-
d ioxy)p h en yl]et h yl]-6,7,8,9-t et r a h yd r on a p h t h o[1,2-b]-
fu r a n H yd r och lor id e (31). (R)-(+)-6-[(N-Methylamino)-
methyl]-2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan (0.50 g) and
3,4-(methylenedioxy)phenylacetic acid (0.38 g) were coupled
as in method B, step 1. The intermediate amide (0.52 g) and
DDQ (0.41 g) were heated at reflux in dioxane for 4 h to yield,
after column purification, 0.31 g of dehydrogenated intermedi-
ate. The amide was treated as in method B, step 2 with BH3‚
1
THF at reflux for 3 h to yield 0.23 g of 31: mp 240-2 °C; H
NMR (CD3OD) δ 1.85-2.1 (m, 5H), 2.9-3.6 (m, 8H), 3.05 (s,
3H), 5.94 (s, 2H), 6.73-6.90 (m, 3H), 6.78 (d, 1H), 7.13 (m,
1H), 7.43 (d, 1H), 7.74 (d, 1H). Anal. (C23H26ClNO3‚1/4H2O)
C, H, N.
tr a n s-6-[(N-Met h yla m in o)m et h yl]-N-[2-[3,4-(m et h yl-
en ed ioxy)p h en yl]eth yl]-2,3,3a ,4,5,6-h exa h yd r on a p h th o-
[1,8-bc]p yr a n Meth a n esu lfon a te (32) a n d cis-6-[(N-Me-
t h yla m in o)m et h yl]-N-[2-[3,4-(m et h ylen ed ioxy)p h en yl]-
eth yl]-2,3,3a ,4,5,6-h exa h ydr on a p h th o[1,8-bc]pyr a n Meth -
a n esu lfon a te (33). Ethyl (chroman-4-yl)acetate (6)19 (11.0
g) was reduced with LiAlH4 (3.6 g) in THF (500 mL) to give
9.83 g of an alcohol that was reacted with MsCl (4.6 mL) and
NEt3 (8.3 mL) in CH2Cl2 (250 mL) to yield 12 g of crude
mesylate. The mesylate was diplaced with KCN (5.87 g) by
heating to reflux in EtOH (250 mL) for 8 h, and then the nitrile
was hydrolyzed using 45% KOH (150 mL) in ethanol (200 mL)
to give upon acidification 5.51 g of the carboxylic acid in 57%
overall yield from 6. The carboxylic acid was cyclized with
PPA (140 mL) at 100 °C for 20 min to provide 7 (4.29 g) in
85% yield. Compound 7 was then elaborated according to
methods E and F to 6-(aminomethyl)-2,3,3a,4,5,6-hexahy-
dronaphtho[1,8-bc]pyran (0.524 g) that was reacted with 3,4-
(methylenedioxy)phenylacetic acid (0.470 g) by method C, step
1. The intermediate amides were separated by HPLC (55:45
hexane:EtOAc) into the cis (less polar) (0.210 g) and trans
(more polar) (0.340 g) products. The purified trans amide (0.44
g) was reduced and alkylated according to method C to yield
0.16 g of 32, mp 128-9 °C. The trans stereochemistry was
assigned by single-crystal X-ray analysis of 32. 1H NMR (free
base, CDCl3) δ 1.25-1.45 (m, 2H), 1.5-1.9 (m, 3H), 1.96 (m,
1H), 2.12 (m, 1H), 2.25-2.85 (m, 6H), 2.37 (s, 3H), 2.95 (m,
1H), 4.18 (m, 1H), 4.38 (m, 1H), 5.92 (s, 2H), 6.55-6.8 (m, 5H),
7.02 (t, 1H). Anal. (C24H31NO7S) C, H, N. The purified cis
amide (0.44 g) was elaborated according to method C to yield,
after chromatography and several recrystallizations from
EtOAc, 0.023 g of 33: mp 105-6 °C; 1H NMR (free base,
CDCl3) δ 1.15-1.35 (m, 2H), 1.67 (ddd, 1H), 1.95 (m, 2H), 2.13
(m, 1H), 2.34 (s, 3H), 2.4-2.8 (m, 7H), 3.03 (m, 1H), 4.14 (m,
1H), 4.38 (m, 1H), 5.92 (s, 2H), 6.58-6.75 (m, 4H), 6.85 (d,
1H), 7.03 (t, 1H). Anal. (C24H31NO7S‚0.75H2O) C, H, N.
N-Eth yl-N-[(5-m eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl)m et h yl]-N-[2-[3,4-(m et h ylen ed ioxy)p h en yl]et h yl]-
a m in e Hyd r och lor id e (35). From 3,4-(methylenedioxy)-
phenylacetic acid (1.20 g) and N-ethyl-N-[(5-methoxy-1,2,3,4-
tetrahydronaphthalen-1-yl)methyl]amine (1.50 g) by method
2H), 6.7 (m, 5H), 7.15 (t, 1H), 10.9 (br s, 1H). Anal. (C23H31
NO6S) C, H, N.
-
N -Me t h yl-N -[[5,6-(m e t h yle n e d ioxy)-1,2,3,4-t e t r a h y-
d r on a p h th a len -1-yl]m eth yl]-N-[2-[3,4-(m eth ylen ed ioxy)-
p h en yl]eth yl]a m in e Meth a n esu lfon a te (29). From 1.5 g
of [[5,6-(methylenedioxy)-1,2,3,4-tetrahydronaphthalen-1-yl]-
methyl]amine (prepared by methods D and F) and 1.45 g of
3,4-(methylenedioxy)phenylacetic acid by method C to yield
1.15 g of 29: mp 144-5 °C; 1H NMR (DMSO-d6) δ 1.6-1.9
(m, 4H), 2.3 (s, 3H), 2.5-3.4 (m, 9H), 2.92 (d, 3H), 6.0 (d, 2H),
6.7-7.0 (m, 5H), 9.1 (br s, 1H). Anal. (C23H29NO7S) C, H, N.
(R)-6-[(N-Meth yla m in o)m eth yl]-N-[2-[3,4-(m eth ylen e-
dioxy)ph en yl]eth yl]-2,3,6,7,8,9-h exa h yd r on a p h th o[1,2-b]-
fu r a n Meth a n esu lfon a te (30). Acylation of 5-bromo-2,3-
dihydrobenzofuran (4)18 (41.4 g) with ethylsuccinyl chloride
(43 mL) in the presence of AlCl3 (53.3 g) in dichloroethane (500
mL) at room temperature for 16 h gave 19.5 g of the keto-
ester as a white solid after workup. This solid was then
reduced under 4 atm of H2 with 10%Pd/C catalyst (3.9 g) in
EtOH (500 mL) to provide 12.4 g of an oil that was reacted for
3 h at room temperature with KOH (14 g) in 1:1 EtOH/H2O
(250 mL) to give 10.9 g of carboxylic acid upon acidification
with 12 N HCl. This acid was then cyclized with PPA (100
mL) by heating to 100 °C for 20 min to yield 7.6 g of 2,3,6,7,8,9-
hexahydronaphtho[1,2-b]furan-6-one (5). Compound 5 was
then elaborated to (R)-(+)-6-[(N-methylamino)methyl]-
2,3,6,7,8,9-hexahydronaphtho[1,2-b]furan using methods E
and G, and the resultant amine (0.80 g) and 3,4-(methylene-
dioxy)phenylacetic acid (0.64 g) were reacted by method B to
yield 0.33 g of 30: mp 185-6 °C; 1H NMR (DMSO-d6) δ 1.65-
1.9 (m, 4H), 2.29 (s, 3H), 2.85-3.0 (m, 5H), 3.05-3.6 (m, 9H),
4.50 (t, 2H), 5.99 (s, 2H), 6.7-7.1 (m, 5H), 9.0 (br s, 1H). Anal.
(C24H31NO7S) C, H, N.
1
B to yield, 1.50 g of 35: mp 140-1 °C; H NMR (DMSO-d6) δ
1.30 (t, 3H), 1.75 (m, 4H), 2.07 (m, 1H), 2.45 (m, 1H), 2.65 (m,
1H), 3.0 (m, 2H), 3.1-3.7 (m, 7H), 3.78 (s, 3H), 6.0 (s, 2H),
6.7-7.0 (m, 5H), 7.15 (t, 1H), 10.0 (br s, 1H). Anal. (C23H30
ClNO3) C, H, N.
-
N -C y c lo p r o p y l-N -[((R )-5-m e t h o x y -1,2,3,4-t e t r a -
h yd r on a p h t h a len -1-yl)m et h yl]-N-[2-[3,4-(m et h ylen ed i-
oxy)p h en yl]eth yl]a m in e Hyd r och lor id e (36). From 3,4-
(methylenedioxy)phenylacetic acid (0.63 g, 3.5 mmol) and
N-cyclopropyl-N-[((R)-5-methoxy-1,2,3,4-tetrahydronaphthalen-
1-yl)methyl]amine (0.80 g, 3.5 mmol) (prepared using method
G from cyclopropylamine and (R)-5-methoxy-1,2,3,4-tetra-
hydronaphthalene-1-methanol methanesulfonate ester) by
method B to yield, 0.87 g of 36: mp 100-103 °C; 1H NMR
(DMSO-d6) δ 0.8-1.2 (m, 4H), 1.7-1.9 (m, 3H), 2.05 (m, 1H),
2.42 (m, 1H), 2.70 (m, 1H), 2.95-3.20 (m, 3H), 3.25-3.70 (m,
4H), 3.78 (s, 3H), 6.00 (s, 2H), 6.70-7.00 (m, 5H), 7.17 (t, 1H),
9.85 (br s, 1H). Anal. (C24H30ClNO3) C, H, N.
N-(Cyclop r op ylm eth yl)-N-[((R)-5-m eth oxy-1,2,3,4-tet-
r a h yd r on a p h t h a len -1-yl)m et h yl]-N-[2-[3,4-(m et h ylen e-
d ioxy)p h en yl]eth yl]a m in e Hyd r och lor id e (37). From 3,4-

1058 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Meyer et al.
1
(methylenedioxy)phenylacetic acid (0.59 g, 3.3 mmol) and
N-(cyclopropylmethyl)-N-[((R)-5-methoxy-1,2,3,4-tetrahy-
dronaphthalen-1-yl)methyl]amine (0.80 g, 3.3 mmol) (prepared
using method G from (cyclopropylmethyl)amine and (R)-5-
methoxy-1,2,3,4-tetrahydronaphthalene-1-methanol methane-
sulfonate ester) by method B to yield, 0.60 g of 37: mp 110-
yielded 0.77 g of 43: mp 162-164 °C; H NMR (DMSO-d6) δ
1.6-2.0 (m, 4H), 2.99 (d, 3H), 2.5-3.5 (m, 9H), 3.73 (s, 3H),
5.0 (m, 4H), 6.8-7.3 (m, 6H). Anal. (C24H33NO5S) C, H, N.
N-[2-(In d a n -5-yl)et h yl]-N-[((R)-5-m et h oxy-1,2,3,4-t et -
r a h yd r on a p h th a len -1-yl)m eth yl]-N-m eth yla m in e Meth -
a n esu lfon a te (44). From indan-5-acetic acid33 (1.0 g) and 13
(0.96 g) by method B to yield, 1.18 g of 44: mp 170-172 °C;
1H NMR (DMSO-d6), δ 1.7-2.1 (m, 6H), 2.31 (s, 3H), 2.4-3.5
(m, 13H), 2.96 (d, 3H), 3.77 (s, 3H), 6.82 (d, 1H), 6.87 (d, 1H),
7.0-7.3 (m, 4H), 9.1 (bs, 1H). Anal. (C25H35NO4S) C, H, N.
N-[2-(2,3-Dih yd r ob en zo[b]t h ien -5-yl)et h yl]-N-[((R)-5-
m et h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)m et h yl]-N-
m et h yla m in e Met h a n esu lfon a t e (45). From 2,3-dihy-
drobenzothiophene-5-acetic acid31 (0.80 g) and 13 (0.72 g) by
method B to yield, 0.33 g of 45: mp 158-159 °C; 1H NMR
1
111 °C H NMR (CDCl3) δ 0.50 (m, 2H), 0.82 (m, 2H), 1.30 (m,
1H), 1.90 (m, 1H), 2.00 (m, 1H), 2.42 (m, 1H), 2.58 (m, 1H),
2.80 (dt, 1H), 3.00-3.40 (m, 9H), 3.83 (s, 3H), 5.95 (d, 2H),
6.73 (m, 4H), 6.80 (d, 1H), 7.15 (t, 1H). Anal. (C25H32ClNO3)
C, H, N.
N-[((R)-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-yl)-
m eth yl]-N-[2-[3,4-(m eth ylen ed ioxy)p h en yl]eth yl]-N-p r o-
p a r gyla m in e Hyd r och lor id e (38). From 3,4-(methylene-
dioxy)phenylacetic acid (0.48 g, 2.7 mmol) and N-[((R)-5-
m et h oxy-1,2,3,4-t et r a h ydr on a ph t h a len -1-yl)m et h yl]-N-
propargylamine (0.61 g, 2.7 mmol) (prepared using method G
from propargylamine and (R)-5-methoxy-1,2,3,4-tetrahydronaph-
thalene-1-methanol methanesulfonate ester) by method B to
yield, 0.35 g of 38: mp 88-90 °C; 1H NMR (DMSO-d6) δ 1.65-
1.8 (m, 4H), 2.03 (m, 1H), 2.35-2.8 (m, 2H), 2.92-3.04 (m,
2H), 3.20-3.70 (m, 4H), 3.78 (s, 3H), 4.02 (m, 1H), 4.23-4.38
(m, 2H), 5.98 (s, 2H), 6.70-7.00 (m, 5H), 7.15 (t, 1H), 10.5 (br
s, 1H). Anal. (C24H28ClNO3‚3/4H2O) C, H, N.
N-[2-(2,3-Dih ydr oben zofu r an -6-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Hyd r och lor id e (39). Reaction of 3-hydroxy-
phenylacetic acid (40 g) with EtOH/H2SO4 gave the corre-
sponding ethyl ester (36.9 g) that was converted to the sodium
salt with 80% NaH (7.4 g) in DMF (250 mL) and alkylated
with bromoacetaldehyde diethyl acetal (37 mL) to give 49.6 g
of product after column chromatography. This acetal (20 g)
was then cyclized at 110 °C in PPA (5 g) and toluene (200 mL)
for 12 h to give after column chromatography 7.66 g (56%) of
a mixture of benzofuran-6-acetic acid ethyl ester and benzo-
furan-4-acetic acid ethyl ester in a 3:1 ratio. This mixture was
then hydrolyzed with aqueous 1 M NaOH. The crude mixture
of acids was recrystallized several times from hexane to
provide in 98% purity benzofuran-6-acetic acid (3.5 g) that was
reduced under 1 atm of H2 at room temperature using 10%
Pd/C to 2,3-dihydrobenzofuran-6-acetic acid. From 2,3-dihy-
drobenzofuran-6-acetic acid (0.31 g) and 13 (0.40 g) by method
B to yield, 0.31 g of 39: mp 227-229 °C; 1H NMR (CDCl3, 300
MHz) of the free base δ 1.6-2.0 (m, 4H), 2.38 (s, 3H), 2.4-3.0
(m, 9H), 3.17 (t, 2H), 3.81 (s, 3H), 4.54 (t, 2H), 6.68 (m, 3H),
6.80 (d, 1H), 7.10 (m, 2H). Anal. (C23H30NO2Cl) C, H, N.
N-[2-(2,3-Dih ydr oben zofu r an -5-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Meth a n esu lfon a te (41). 2,3-Dihydrobenzo-
furan-5-acetic acid31 (0.98 g, 5.5 mmol) and 13 (1.21 g, 5.0
mmol) were reacted according to method B to yield 1.29 g of
41: mp 161-163 °C; 1H NMR (CDCl3) δ 1.7-2.2 (m, 4H), 2.5-
3.5 (m, 9H), 2.86 (s, 3H), 3.00 (d, 3H), 3.18 (t, 2H), 3.81 (s,
3H), 4.55 (t, 2H), 6.71 (m, 3H), 6.94 (dd, 1H), 7.15 (m, 2H),
10.8 (bs, 1H). Anal. (C24H33NO5S) C, H, N.
(CDCl3
) of the free base δ 1.6-1.8 (m, 3H), 1.94 (m, 1H), 2.38
(s, 3H), 2.3-3.0 (m, 9H), 3.2-3.4 (m, 4H), 3.82 (s, 3H), 6.67
(d, 1H), 6.80 (d, 1H), 6.94 (dd, 1H), 7.1 (m, 3H). Anal. (C24H33
NO4S2) C, H, N.
-
N -[2-(Be n zo[b]t h ie n -5-yl)e t h yl]-N -[((R )-5-m e t h oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e Meth a n esu lfon a te (46). Reaction of 5-(bromometh-
yl)benzothiophene34 with LiCN/DMF for 4 h at room temper-
ature gave a nitrile that was directly hydrolyzed with 1:1 45%
KOH:EtOH at reflux to form benzothiophene-5-acetic acid.
This acid (0.90 g) and 13 (1.03 g) were coupled by method B,
substituting LiAlH4 for borane to yield 0.95 g of 46: mp 181-
1
182 °C; H NMR (CDCl3) δ 1.75-2.25 (m, 5H), 2.55 (m, 1H),
2.78 (m, 1H), 2.88 (s, 3H), 3.04 (d, 3H), 3.20-3.65 (m, 6H), 3.81
(s, 3H), 6.70 (m, 2H), 7.13 (t, 1H), 7.30 (m, 2H), 7.47 (d, 1H),
7.73 (d, 1H), 7.82 (d, 1H), 11.0 (bs, 1H). Anal. (C24H31NO4S2)
C, H, N.
N-[2-(1,1-Dioxoben zo[b]th ien -5-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Hyd r och lor id e (47). Benzothiophene-5-acetic
acid (see previous expermimental) was reduced with 1.0 M
BH3‚THF at 0 °C for 2 h and the resultant alcohol (0.6 g)
oxidized with m-CPBA (1.45 g) in CH2Cl2 (50 mL) for 4 h at
room temperature to give 0.66 g of a sulfone that was reacted
with methanesulfonyl chloride (0.26 mL) and NEt3 (0.48 mL)
in CH2Cl2 (4 mL) to provide 0.74 g of 1,1-dioxobenzothiophene-
5-ethanol methanesulfonate ester. From 1,1-dioxobenzo-
thiophene-5-ethanol methanesulfonate ester (0.37 g) and 13
(0.29) by method A to yield, 0.10 g of 47: mp 191-194 °C; 1H
NMR (DMSO-d6) δ 1.65-2.05 (m, 5H), 2.3-3.6 (m, 9H), 2.95
(d, 3H), 3.78 (s, 3H), 6.80 (d, 1H), 6.90 (d, 1H), 7.15 (t, 1H),
7.4 (d, 1H), 7.5-7.65 (m, 2H), 7.83 (d, 1H), 9.8 (br s, 1H). Anal.
(C23H28NO3SCl‚H2O) C, H, N.
N-[2-(1,1-Dioxo-2,3-d ih yd r oben zo[b]t h ien -5-yl)et h yl]-
N-[((R)-5-m et h oxy1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]-N-m eth yla m in e Hyd r och lor id e (48). 2,3-Dihy-
drobenzothiophene-5-acetic acid31 was reduced with 2.0 equiv
of BH3‚THF at 0 °C for 2 h, and the resultant alcohol was
converted to the bromide using CBr4/PPh3 and then oxidized
to the sulfone with m-CPBA. From 5-(2-bromoethyl)-1,1-dioxo-
2,3-dihydrobenzo[b]thiophene (0.315 g) and 13 (0.332 g) by
N -[2-(Be n zofu r a n -5-yl)e t h yl]-N -[(5-m e t h oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
a n esu lfon a te (42). 2,3-Dihydrobenzofuran-5-acetic acid was
oxidized with NBS and benzoyl peroxide in CCl4 to give
benzofuran-5-acetic acid. This acid (0.54 g) and 13 (0.57 g)
were reacted by method B to yield, 0.52 g of 42: mp 156-157
1
method A to yield, 0.147 g of 48: mp 225-226 °C; H NMR
(CD3OD) δ 1.8-2.0 (m, 4H), 2.5-2.9 (m, 2H), 3.0-3.6 (m, 14H),
3.81 (s, 3H), 6.8 (m, 2H), 7.15 (t, 1H), 7.4-7.5 (m, 2H), 7.7 (m,
1H). Anal. (C23
H30ClNO3S) C, H, N.
N-[2-(2,2-Dioxo-1,3-d ih yd r ob en zo[c]t h ien -5-yl)et h yl]-
N-[((R)-5-m et h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)-
m eth yl]-N-m eth yla m in e Meth a n esu lfon a te (49). 5-(2-
Hydroxyethyl)-2,2-dioxo-1,3-dihydrobenzo[c]thiophene (pre-
pared by the method of Grigg32 substituting 3-butyn-1-ol for
propargyl alcohol) was reacted with CBr4 and PPh3 to provide
5-(2-bromoethyl)-2,2-dioxo-1,3-dihydrobenzo[c]thiophene (0.275
g) that was coupled with 13 (0.242 g) by method A to give 0.237
g of 49: mp 169-71 °C; 1H NMR (DMSO-d6) δ 1.7-2.0 (m,
4H), 2.3 (s, 3H), 2.4-2.7 (m, 4H), 3.0 (s, 3H), 3.0-3.6 (m, 7H),
3.78 (s, 3H), 4.5 (m, 4H), 6.85 (m, 2H), 7.15 (m, 1H), 7.3 (m,
3H). Anal. (C24H33NO6S2) C, H, N.
1
°C; H NMR (CDCl3) of the free base δ 1.6-1.8 (m, 3H), 1.95
(m, 1H), 2.40 (s, 3H), 2.4-3.0 (m, 9H), 3.81 (s, 3H), 6.66 (d,
1H), 6.70 (d, 1H), 6.81 (d, 1H), 7.08 (t, 1H), 7.12 (dd, 1H), 7.4
(d, 1H), 7.41 (s, 1H), 7.59 (d, 1H). Anal. (C24H31NO6S) C, H,
N.
N-[2-(1,3-Dih yd r oisoben zofu r a n -5-yl)eth yl]-N-[((R)-5-
m et h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-yl)m et h yl]-N-
m eth yla m in e Meth a n esu lfon a te (43). Treatment of 1,3-
dihydroisobenzofuran-6-methanol32 (1.74 g) with PPh3 (3.23
g) and CBr4 (5.58 g) gave 2.1 g of the bromide that was then
diplaced with NaCN (0.97 g) in DMSO (10 mL) at room
temperature to yield 0.8 g of nitrile that was hydrolyzed with
2.5 M NaOH to provide 0.58 g of 1,3-dihydroisobenzofuran-5-
acetic acid. From 1,3-dihydroisobenzofuran-5-acetic acid (1.00
g) and 13 (0.95 g) by method B, substituting LiAlH4 for borane,
N-[(2,3-Dih yd r oin d ol-5-yl)et h yl]-N-[((R)-5-m et h oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e Bis(m eth a n esu lfon a te) (50). Indoline was N-ben-
zoylated with PhCOCl/NEt3 and then subjected to Friedel-

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1059
1
Crafts acetylation using AcCl and AlCl3 in CH2Cl2 at reflux.
6-Acetyl-N-benzoylindoline (1.33 g, 5.00 mmol) was then added
to a solution of thallium trinitrate (2.45 g, 5.50 mmol) in MeOH
(12.5 mL) with 60% HClO4 (2.5 mL) and the reaction allowed
to proceed for 4 h at room temperature to provide N-benzoyl-
2,3-dihydroindolyl-5-acetic acid methyl ester (1.36 g, 93%).
This ester was hydrolyzed with LiOH in THF/H2O to give
N-benzoyl-2,3-dihydroindolyl-5-acetic acid and this acid (0.98
g) reacted with 13 (0.85 g) by method B to yield the intermedi-
ate N-benzyl analog of the title compound as its dihydrochlo-
ride salt. Hydrogenation of this intermediate using a palla-
dium catalyst in MeOH afforded 0.60 g of 50: mp 207-208
209 °C; H NMR (CDCl3) of the free base δ 1.5-2.0 (m, 6H),
2.38 (s, 3H), 2.4-3.0 (m, 7H), 2.88 (s, 3H), 3.81 (s, 3H), 4.68
(s, 4H), 6.67 (d, 1H), 6.80 (d, 1H), 7.1 (m, 4H). Anal.
(C25H36N2O6S2‚0.5H2O) C, H, N.
N -[2-(N -T r i flu o r o m e t h a n e s u lfo n a m i d o -1,3-d i h y -
d r oisoin d ol-5-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-tetr a h y-
d r on a p h th a len -1-yl)m eth yl]-N-m eth yla m in e Meth a n e-
su lfon a te (55). N-[2-(1,3-Dihydroisoindol-5-yl)ethyl]-N-[((R)-
5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)methyl]-N-
methylamine (53) (0.340 g) was dissolved in CH2Cl2 (10 mL)
and treated with NEt3 (0.68 mL, 5 mmol) and trifluoromethane-
sulfonic anhydride (0.85 g) to yield 0.158 g of 55: mp 210 °C;
1H NMR (CDCl3) of the free base δ 1.5-2.0 (m, 6H), 2.38 (s,
3H), 2.4-3.0 (m, 7H), 3.81 (s, 3H), 4.88 (s, 4H), 6.67 (d, 1H),
6.79 (d, 1H), 7.05-7.20 (m, 4H). Anal. (C24H29N2F3O3S) C,
H, N.
1
°C; H NMR (DMSO-d6) δ 1.7-2.0 (m, 4H), 2.3 (s, 6H), 2.4-
2.7 (m, 2H), 2.96 (d, 3H), 3.0-3.7 (m, 12H), 3.77 (s, 3H), 6.82
(d, 1H), 6.88 (d, 1H), 7.1-7.4 (m, 4H), 9.2 (bs, 2H). Anal.
(C25H38N2O7S2) C, H, N.
N-[2-(N-Met h a n esu lfon a m id o-2,3-d ih yd r oin d ol-5-yl)-
eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl)m eth yl]-N-m eth ylam in e Meth an esu lfon ate (51). From
N-methanesulfonamido-2,3-dihydroindole-5-acetic acid (pre-
pared by the same sequence as outlined for example 50) (1.14
g) and 13 (0.90 g) by method B to yield 0.98 g of 51: mp 202-
203 °C; 1H NMR (DMSO-d6) δ 1.7-1.9 (m, 4H), 2.7 (s, 3H),
2.4-2.6 (m, 2H), 2.93 (d, 3H), 2.95 (s, 3H), 2.9-3.6 (m, 9H),
3.78 (s, 3H), 3.92 (m, 2H), 6.81 (d, 1H), 6.87 (d, 1H), 7.07-7.3
(m, 4H), 9.1 (bs, 1H). Anal. (C25H36N2O6S2) C, H, N.
N-[2-[N-(Tr iflu or om eth an esu lfon am ido)-2,3-dih ydr oin -
dol-5-yl]eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-tetr ah ydr on aph -
t h a len -1-yl)m et h yl]-N-m et h yla m in e Met h a n esu lfon a t e
(52). From N-(trifluoromethanesulfonamido)-2,3-dihydroin-
dole-5-acetic acid (prepared by the same sequence as example
50) (1.00 g, 3.2 mmol) and 13 (0.78 g, 3.2 mmol) by method B
gave 0.47 g of 52: mp 83 °C; 1H NMR (DMSO-d6) δ 11.65-1.9
(m, 4H), 2.32 (s, 3H), 2.38-2.8 (m, 2H), 2.97 (s, 3H), 3.10-
3.80 (m, 7H), 3.78 (s, 3H), 3.90-4.10 (m, 2H), 4.20-4.28 (m,
2H), 6.81 (d, 1H), 6.87 (d, 1H), 7.10-7.40 (m, 4H), 9.0 (br s,
1H). Anal. (C25H33N2O6S2F3) C, H, N.
N-[2-(1,3-Dih ydr oisoin dol-5-yl)eth yl]-N-[((R)-5-m eth oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e d ih yd r och lor id e (53). 5-Methoxycarbonylisoindoline
hydrochloride35 (5.0 g) was reacted with benzoyl chloride (3.96
g) and NEt3 (9.9 mL) in CH2Cl2 (150 mL) to give 5.89 g of
benzamide (89%) that was subjected to ester hydrolysis with
LiOH‚H2O (2.6 g) in 2:1 THF/H2O (120 mL) to give 5.1 g (92%)
of the corresponding carboxylic acid. This acid (2.6 g) was
converted to the acid chloride with oxalyl chloride (1.48 g) in
CH2Cl2 (75 mL) and then reacted with diazomethane to give
2.64 g of diazo ketone (94%) that was rearranged by the
addition of Ag2O (1 g) in portions over 3 h to a solution of the
diazo ketone in EtOH (60 mL) at reflux to provide 2.0 g of
N-benzoyl-1,3-dihydroisoindol-5-yl acetic acid ethyl ester (73%).
Hydrolysis of this ester (2.6 g) with LiOH.H2O (1.1 g) in 2:1
THF/H2O (60 mL) gave N-benzoyl-1,3-dihydroisoindol-5-ylace-
tic acid (2.00 g, 7.1 mmol) that was coupled with 13 (1.55 g)
by method B to yield the intermediate N-benzyl analog (2.62
g). Hydrogenation of this intermediate using a palladium
catalyst in MeOH afforded 0.83 g of 53: mp 188 °C; 1H NMR
(CD3OD) δ 1.88 (m, 5H), 3.05-3.30 (m, 5H), 3.45 (m, 5H), 3.80
(s, 3H), 4.62 (m, 4H), 6.83 (m, 2H), 7.16 (t, 1H), 7.40 (m, 3H).
Anal. (C23H30N2O‚2HCl‚0.5H2O) C, H, N.
N-[2-(N-Met h a n esu lfon a m id o-1,3-d ih yd r oisoin d ol-5-
yl)et h yl]-N-[((R)-5-m et h oxy-1,2,3,4-t et r a h yd r on a p h t h a -
len -1-yl)m eth yl]-N-m eth ylam in e Meth an esu lfon ate Hem i-
h yd r a te (54). 5-(Methoxycarbonyl)isoindoline hydrochloride35
(3.93 g) was reacted with MsCl (2.54 g) and NEt3 (7.8 mL) in
CH2Cl2 (150 mL) to give 4.47 g of the sulfonamide (95%) that
was reduced with LiAlH4 (1.3 g) in THF (60 mL) at room
temperature over 75 min to provide 3.52 g (94%) of the
corresponding alcohol. The alcohol was then converted to the
mesylate with MsCl (2.1 g) and NEt3 (4.3 mL) in CH2Cl2 and
the mesylate displaced with 0.5 M LiCN/DMF (30 mL) at room
temperature for 1 h to give 2.47 g of the nitrile. This nitrile
was then hydrolyzed with 45% KOH (20 mL) in EtOH (50 mL)
at reflux for 1 h to yield N-methanesulfonamido-1,3-dihy-
droisoindole-5-acetic acid (2.25 g, 75%). This acid (1.0 g) was
reacted with 13 (1.05 g) by method B to yield 0.77 g of 54: mp
N-[2-(2,3-Dih yd r oin d ol-6-yl)eth yl]-N-[((R)-5-m eth oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e Dih yd r och lor id e (56). From (2-oxoindolin-6-yl)acetic
acid36 (700 mg) and 13 (800 mg) by method B to yield, 360 mg
of 56: 1H NMR (CDCl3) δ 1.50-2.25 (m, 8H), 2.50 (m, 4H),
2.76 (m, 4H), 2.99 (t, 2H), 3.54 (t, 2H), 3.81 (m, 3H), 6.54 (m,
1.5H), 6.68 (m, 1H), 6.80 (m, 1H), 7.05 (m, 1.5H). Anal.
(C23H30N2O‚2HCl‚0.5H2O) C, H, N.
N-[2-(N-Met h a n esu lfon a m id o-2,3-d ih yd r oin d ol-6-yl)-
eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-tetr a h yd r on a p h th a len -
1-yl)m et h yl]-N-m et h yla m in e Met h a n esu lfon a t e (57).
Methanesulfonamido-2,3-dihydroindole-6-methanol37 was con-
verted to N-methanesulfonamido-2,3-dihydroindole-6-acetic
acid via the method used in example 54, and the acid (0.983
g) and 13 (0.846 g) were reacted by method B to yield 1.12 g
of 57: mp 163-165 °C; 1H NMR (DMSO-d6) δ 1.7-1.9 (m, 5H),
2.4-3.6 (m, 16H), 3.35 (s, 3H), 3.77 (s, 3H), 3.93 (m, 2H), 6.82
(d, 2H), 6.86 (d, 2H), 6.95 (t, 1H), 7.1-7.3 (m, 3H), 9.0 (br s,
1H). Anal. (C25H36N2O6S2) C, H, N.
N-[2-[N-(Tr iflu or om eth an esu lfon am ido)-2,3-dih ydr oin -
dol-6-yl]eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-tetr ah ydr on aph -
th a len -1-yl)m eth yl]-N-m eth yla m in e Meth a n esu lfon a te
(58). Indole-6-carboxylic acid methyl ester38 (5.39 g, 30 mmol)
in acetic acid (75 mL) at 15 °C was reduced with NaCNBH3
(5.39 g, 90 mmol) to give 3.69 g of the indoline. This indoline
was converted to the trifluoromethanesulfonamide with triflic
anhydride and NEt3, elaborated on as in example 53 to
N-(trifluoromethanesulfonamido)-2,3-dihydroindole-6-acetic acid
(0.928 g) and reacted with 13 (0.725 g) by method B to yield
0.654 g of 58: mp 140-141 °C; 1H NMR (DMSO-d6) δ 1.8 (m,
4H), 2.4-2.7 (m, 2H), 2.95 (s, 3H), 3.0-3.5 (m, 7H), 3.3 (s, 3H),
3.78 (s, 3H), 4.2 (m, 2H), 6.8 (d, 1H), 6.87 (d, 1H), 7.15 (m,
2H), 7.3 (m, 2H). Anal. (C25H33F3N2O6S2) C, H, N.
5-[2-[[(R)-5-Met h oxy-1,2,3,4-t et r a h yd r on a p h t h a len -1-
yl)m et h yl)m et h yl]a m in o]et h yl]-1,3-d ih yd r oin d ol-2-on e
Meth a n esu lfon a te (59). From 5-(2-chloroethyl)-2,3-dihy-
droindol-2-one39 (1.4 g) and 13 (1.2 g) by method A to yield,
1
0.44 g of 59: mp 133-134 °C; H NMR (DMSO-d6) δ 1.6-2.0
(m, 5H), 2.4-3.5 (m, 8H), 2.31 (s, 3H), 2.97 (d, 3H), 3.48 (s,
2H), 3.78 (s, 3H), 6.7-7.2 (m, 6H), 9.1 (bs, 1H), 9.87 (s, 1H).
Anal. (C24H32N2O5S‚H2O) C, H, N.
N-[2-(Ben zoxa zol-6-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
a n esu lfon a te (60). 3-Hydroxy-4-nitrobenzyl alcohol40 was
converted to 3-hydroxy-4-nitrophenylacetic acid using the
method employed in example 43, and the acid (0.711 g) and
13 (0.725 g) were reacted by method B. The intermediate
product was hydrogenated using a palladium catalyst in EtOH
to yield an intermediate aminophenol. Treatment of this
intermediate with triethyl orthoformate at reflux for 18 h
yielded 0.54 g of 60: mp 139-141 °C; 1H NMR (CDCl3) δ 1.7-
2.3 (m, 5H), 2.5-3.6 (m, 8H), 2.89 (s, 3H), 3.06 (d, 3H), 3.82
(s, 3H), 6.7 (m, 2H), 7.13 (t, 1H), 7.27 (dd, 1H), 7.55 (bs, 1H),
7.72 (d, 1H), 8.09 (s, 1H), 11.0 (bs, 1H). Anal. (C23H30N2O5S)
C, H, N.
N-[2-(2-Meth ylben zoxazol-6-yl)eth yl]-N-[((R)-5-m eth oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e Meth a n esu lfon a te (61). 3-Hydroxy-4-nitrophenyl-
acetic acid (see example 60 for preparation) (1.70 g) and 13
(2.00 g) were reacted by method B. The product was reduced

1060 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7
Meyer et al.
with H2 over a palladium catalyst in EtOH to yield an
aminophenol that was heated in triethyl orthoacetate at reflux
for 1 h to yield 1.15 g of 61: mp 159-161 °C; 1H NMR (CDCl3)
of the free base δ 1.6-2.0 (m, 5H), 2.39 (s, 3H), 2.4-3.0 (m,
8H), 2.61 (s, 3H), 3.80 (s, 3H), 6.66 (d, 1H), 6.80 (d, 1H), 7.08
(d, 1H), 7.12 (dd, 1H), 7.31 (d, 1H), 7.52 (d, 1H). Anal.
(C24H32N2O5S) C, H, N.
N-[2-(Ben zoxa zol-5-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
an esu lfon ate (62). 4-Hydroxy-3-nitrophenylacetic acid41 (1.17
g) and 13 (1.20 g) were reacted by method B. The product
was hydrogenated using a palladium catalyst in EtOH to yield
an aminophenol that was treated with triethyl orthoformate
at reflux for 1 h to yield 1.24 g of 62: mp 175-177 °C; 1H
NMR (CDCl3) of the free base δ 1.6-1.8 (m, 3H), 1.93 (m, 1H),
2.39 (s, 3H), 2.4-3.0 (m, 9H), 3.81 (s, 3H), 6.67 (d, 1H), 6.80
(d, 1H), 7.09 (t, 1H), 7.22 (dd, 1H), 7.47 (d, 1H), 7.62 (d, 1H),
8.08 (s, 1H). Anal. (C23H30N2O5S) C, H, N.
(32%) was obtained. This acid (0.33 g) and 13 (0.31 g) were
reacted by method B. The crude borane reduction product, in
lieu of treatment with HCl, was evaporated, suspended in
Et2O, and treated with TMEDA (1.2 equiv) at reflux for 4 h to
yield 0.23 g of 66: mp 153-154 °C; 1H NMR (DMSO-d6) δ 1.7-
1.9 (m, 4H), 2.3 (s, 3H), 3.0 (d, 3H), 3.1-3.5 (m, 9H), 3.77 (s,
3H), 6.83 (d, 1H), 6.87 (d, 1H), 7.15 (t, 1H), 7.5 (dd, 1H), 7.97
(d, 1H), 8.04 (d, 1H), 9.3 (bs, 1H). Anal. (C23H29ClN2O4S2) C,
H, N.
N-[2-(2-Am in oben zoth ia zol-5-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Bis(m eth a n esu lfon a te) (67). 4-Aminophen-
ylacetic acid (20 g) and ammonium thiocyanate (20 g) were
dissolved in AcOH (300 mL), and the mixture was cooled to
15 °C, treated with Br2 (6.8 mL) in AcOH (10 mL), and then
stirred at room temperature for 4 h to give 23.4 g of 2-ami-
nobenzothiazole-5-acetic acid. This acid (1.15 g) and 13 (1.30
g) were reacted by method B, substituting 4 equiv of TMEDA
for the HCl treatment to decompose the intermediate borane
complex to give 0.97 g of 67: mp 200-202 °C; 1H NMR (DMSO-
d6) δ 1.4-2.0 (m, 6H), 2.47 (s, 3H), 2.4-3.0 (m, 7H), 3.81 (s,
3H), 5.1 (bs, 2H), 6.65 (d, 1H), 6.80 (d, 1H), 7.09 (t, 1H), 7.14
(dd, 1H), 7.44 (bs, 1H), 7.47 (d, 1H). Anal. (C24H35N3O7S3) C,
H, N.
6-[2-[[((R)-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-
yl)m eth yl]m eth yla m in o]eth yl]-3H-ben zoxa zol-2-on e Hy-
d r och lor id e (68). 3-Hydroxy-4-nitrophenylacetic acid (see
example 60 for preparation) (0.91 g) and 13 (1.0 g) were reacted
by method B. The product was reduced with H2/Pd in EtOH
to give an aminophenol that was reacted with 1,1′-carbonyl-
diimidazole in THF at reflux for 2 h to yield 0.49 g of 68: mp
147-149 °C; 1H NMR (CDCl3) of the free base δ 1.55-2.0 (m,
4H), 2.39 (s, 3H), 2.4-3.0 (m, 9H), 3.81 (s, 3H), 6.67 (d, 1H),
6.80 (d, 1H), 6.97 (m, 2H), 7.1 (m, 2H), 8.7 (bs, 1H). Anal.
(C22H27ClN2O3) C, H, N.
N-[2-(2-Meth ylben zoxazol-5-yl)eth yl]-N-[((R)-5-m eth oxy-
1,2,3,4-t e t r a h yd r on a p h t h a le n -1-yl)m e t h yl]-N -m e t h yl-
a m in e Meth a n esu lfon a te (69). 4-Hydroxy-3-nitrophenyl-
acetic acid41 (1.70 g) and 13 (2.00 g) were reacted by method
B. The product was treated with H2/Pd in EtOH to yield an
amino-phenol that was heated in triethyl orthoacetate at reflux
for 1 h to yield 1.36 g of 69: mp 178-179 °C; 1H NMR (DMSO-
d6) δ 1.7-1.9 (m, 4H), 2.31 (s, 3H), 2.60 (s, 3H), 2.96 (d, 3H),
2.9-3.6 (m, 9H), 3.79 (s, 3H), 6.81 (d, 1H), 6.89 (d, 1H), 7.16
(t, 1H), 7.29 (dd, 1H), 7.65 (m, 2H), 9.2 (bs, 1H). Anal.
(C24H32N2O5S) C, H, N.
N-[2-(Ben zim idazol-5-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr a h yd r on a p h th a len -1-yl)m eth yl]-N-m eth yla m in e Bis-
(m eth a n esu lfon a te) (63). 4-Aminophenylacetic acid was
esterified with H2SO4/MeOH and then converted to the amide
using Ac2O/pyridine. 4-N-Acetamidophenylacetic acid methyl
ester (12.4 g) was nitrated by addition to a chilled mixture of
70% HNO3 (19 mL) and Ac2O (210 mL) prepared at -10 °C to
give 15 g of yellow solid that was exhaustively hydrolyzed with
5 N HCl to provide 4-amino-3-nitrophenylacetic acid. This acid
(0.97 g) and 13 (1.0 g) were reacted by method B. The product
was hydrogenated using a palladium catalyst in EtOH to give
a dianiline that was refluxed with formic acid (1.2 equiv) in
10% aqueous HCl for 1 h to yield 0.61 g of 63: mp 162-164
1
°C; H NMR (CDCl3) of the free base δ 1.6-1.8 (m, 3H), 1.94
(m, 1H), 2.39 (s, 3H), 2.4-3.0 (m, 9H), 3.80 (s, 3H), 6.67 (d,
1H), 6.81 (d, 1H), 7.08 (t, 1H), 7.13 (dd, 1H), 7.47 (bs, 1H),
7.59 (bs, 1H), 8.01 (s, 1H), 9.5 (bs, 1H). Anal. (C24H35N3O7S2)
C, H, N.
N-[2-(Ben zoth iazol-6-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
a n esu lfon a te (64). Compound 66 (0.70 g) was reduced under
4 atm H2 using 10% Pd/C in MeOH with NaOAc to provide
0.44 g 64, mp 165-167 °C. 1H NMR (CDCl3) of the free base
δ 1.4-2.0 (m, 6H), 2.47 (s, 3H), 2.4-3.1 (m, 7H), 3.80 (s, 3H),
6.67 (d, 1H), 6.80 (d, 1H), 7.09 (t, 1H), 7.35 (m, 2H), 7.80 (s,
1H), 8.04 (d, 1H), 8.91 (s, 1H). Anal. (C23H30N2O4S2‚1/4H2O)
C, H, N.
N-[2-(2-Meth ylben zoth ia zol-6-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Meth a n esu lfon a te (65). 4-Aminophenylace-
tic acid (2.88 g) was iodinated with ICl (2.83 g) in CH2Cl2 (20
mL) to give 2.82 g (56%) of 4-amino-3-iodophenylacetic acid.
This iodo compound (1.46 g) was reacted with 1,1′-bis(di-
phenylphosphino)ferrocene (55 mg), CuO (0.28 g), thioaceta-
mide (0.38 g), and tris(dibenzylideneacetone)dipalladium(0)
(0.46 mg) in DMF (5 mL)42 at 60 °C for 6 h to provide 0.51 g
of 2-methylbenzothiazole-6-acetic acid methyl ester that was
hydrolyzed with LiOH in THF/H2O to the corresponding acid.
2-Methylbenzothiazole-6-acetic acid (0.62 g) and 13 (0.78 g)
were reacted by method B. The crude borane reduction
product, in lieu of treatment with HCl, was evaporated,
suspended in ether, and treated with TMEDA (tetramethyl-
ethylenediamine) (1.2 equiv) at reflux for 4 h to yield 0.56 g of
5-[2-[[((R)-5-Meth oxy-1,2,3,4-tetr a h yd r on a p h th a len -1-
yl)m et h yl]m et h yla m in o]et h yl]-3H -im id a zol-2-on e H y-
d r och lor id e (70). 4-Amino-3-nitrophenylacetic acid (see
example 63 for preparation) (1.34 g) and 13 (1.50 g) were
reacted by method B. The product was treated with H2/Pd in
EtOH to give a dianiline that was reacted with 1,1′-carbon-
yldiimidazole in THF at reflux for 2 h to yield 0.33 g of 70:
mp 192-196 °C; 1H NMR (DMSO-d6) δ 1.6-1.9 (m, 4H), 2.4-
3.5 (m, 9H), 2.9 (d, 3H), 3.77 (s, 3H), 6.85 (m, 5H), 7.12 (t,
1H), 9.8 (bs, 1H), 10.08 (s, 1H), 10.17 (s, 1H). Anal. (C22H28
-
ClN3O2‚0.75H2O) C, H, N.
N-[2-(Qu in olin -7-yl)et h yl]-N-[((R)-5-m et h oxy-1,2,3,4-
tetr a h yd r on a p h th a len -1-yl)m eth yl]-N-m eth yla m in e Di-
h yd r och lor id e (71). From 7-acetylquinoline43 was obtained
quinoline-7-acetic acid by the method of J ones.44 Quinoline-
7-acetic acid (1.84 g, 11 mmol) and 13 (2.42 g, 10.0 mmol) were
1
65: mp 164-167 °C; H NMR (DMSO-d6) δ 1.7-1.9 (m, 6H),
1
2.55-3.65 (m, 6H), 2.31 (s, 3H), 3.0 (d, 3H), 3.78 (s, 3H), 6.8-
6.9 (m, 2H), 7.15 (t, 1H), 7.43 (dd, 1H), 7.95 (d, 1H), 8.0 (d,
1H), 9.1 (br s, 1H). Anal. (C24H32N2O4S2) C, H, N.
reacted by method B to yield 0.91 g of 71: mp 87-90 °C; H
NMR (DMSO-d6) δ 1.8 (m, 4H), 2.4-2.7 (m, 2H), 3.0 (s, 3H),
3.2-3.8 (m, 7H), 3.8 (s, 3H), 6.8 (d, 1H), 6.9 (d, 1H), 7.15 (t,
1H), 7.9 (m, 2H), 8.2 (m, 2H), 8.95 (d, 1H), 9.17 (d, 1H). Anal.
(C24H30Cl2N2O‚0.75H2O) C, H, N.
N-[2-(2-Ch lor oben zoth ia zol-6-yl)eth yl]-N-[((R)-5-m eth -
o x y -1,2,3,4-t e t r a h y d r o n a p h t h a le n -1-y l)m e t h y l]-N -
m eth yla m in e Meth a n esu lfon a te (66). To 2-aminobenzo-
thiazole-6-acetic acid (see example 67 for preparation) was
added formic acid (16.5 mL) and then AcOH (6.3 mL) and 12
N HCl (12.3 mL), and the mixture was cooled to 0 °C. An
aqueous solution of NaNO2 (2.16 g) was added over 10 min
and stirred for 30 min, and then this mixture was added to a
solution of CuCl (4.02 g) in 12 N HCl (18.6 mL) and water
(42.5 mL) at 10 °C followed by heating to 60 °C for 10 min.
Following workup, 2.17 g of 2-chlorobenzothiazole-6-acetic acid
N-[2-(Isoqu in olin -7-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
a n esu lfon a te (72). From 7-acetylisoquinoline45 was obtained
isoquinoline-7-acetic acid by the method of J ones.44 isoquino-
line-7-acetic acid (0.56 g) and 13 (0.72 g) reacted by method B
was obtained 0.45 g of 72: 1H NMR (CDCl3) of the free base δ
1.55-2.0 (m, 5H), 2.4-3.1 (m, 11H), 3.81 (s, 3H), 6.67 (d, 1H),
6.80 (d, 1H), 7.07 (t, 1H), 7.6 (m, 2H), 7.77 (m, 2H), 8.48 (d,
1H), 9.2 (s, 1H). Anal. (C24H30Cl2N2O‚H2O) C, H, N.

Dual 5-HT Uptake Inhibitors/ R2-Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 7 1061
(8) Crews, F. T.; Scott, J . A.; Shorstein, N. H. Rapid Down-
Regulation of Serotonin2 Receptor Binding During Combined
Administration of Tricyclic Antidepressant Drugs and R2 An-
tagonists. Neuropharmacology 1983, 22, 1203-1209.
(9) (a) Smith, C. B.; Garc´ıa-Sevilla, J . A.; Hollingsworth, P. J . R2-
Adrenoceptors in rat brain are decreased after long-term tricyclic
anti-depressant drug treatment. Brain Res. 1981, 210, 413-418.
(b) Cohen, R. M.; Ebstein, R. P.; Daly, J . W.; Murphy, D. L.
N-[2-(Qu in olin -6-yl)et h yl]-N-[((R)-5-m et h oxy-1,2,3,4-
tetr a h yd r on a p h th a len -1-yl)m eth yl]-N-m eth yla m in e Hy-
d r och lor id e Dih yd r a te (73). Quinoline-6-acetic acid44 (1.0
g) and 13 (0.95 g) were reacted by method B to yield 0.79 g of
1
73: mp 137-139 °C; H NMR (DMSO-d6) δ 1.6-2.7 (m, 7H),
2.95 (d, 3H), 3.2-3.7 (m, 6H), 3.79 (s, 3H), 6.80 (d, 1H), 6.92
(d, 1H), 7.15 (t, 1H), 7.85-8.3 (m, 4H), 8.82 (m, 1H), 9.14 (m,
1H). Anal. (C24H30ClN2O‚2H2O) C, H, N).
Chronic Effects of
a Monoamine Oxidase-Inhibiting Anti-
depressant: Decreases in Functional R-Adrenergic Autoreceptors
Precede the Decrease in Norepinephrine-Stimulated Cyclic
Adenosine 3′:5′-Monophosphate Systems in Rat Brain. J . Neu-
rosci. 1982, 2, 1588-1595.
N-[2-(Qu in oxa lin -6-yl)eth yl]-N-[((R)-5-m eth oxy-1,2,3,4-
tetr ah ydr on aph th alen -1-yl)m eth yl]-N-m eth ylam in e Meth -
a n esu lfon a te (74). 4-Amino-3-nitrophenylacetic acid (see
example 63 for preparation) (0.97 g) and 13 (1.0 g) were reacted
by method B. The product was hydrogenated over palladium
in EtOH to yield a dianiline that was reacted with 2,3-
dihydroxy-1,4-dioxane to yield 0.88 g of 74: mp 192 °C; 1H
NMR (DMSO-d6) δ 1.7-2.0 (m, 4H), 2.3 (s, 3H), 2.4-3.6 (m,
9H), 3.03 (d, 3H), 3.79 (s, 3H), 6.84 (d, 1H), 6.90 (d, 1H), 7.16
(t, 1H), 7.85 (dd, 1H), 8.1 (m, 2H), 8.96 (m, 2H), 9.1 (bs, 1H).
Anal. (C24H31N3O4S) C, H, N.
Biology. Binding to R2-receptors obtained from rat cortical
membranes was determined by displacement of [3H]rauwols-
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determine the inhibition of uptake of [3H]serotonin in synap-
tosomes from rat cortex followed our published procedure.46
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Ack n ow led gm en t. The authors would like to thank
J im Leonard (deceased) for preparative HPLC separa-
tions, Dr. Lou Seif for performing catalytic hydrogena-
tions, and Dr. Steve Spanton and Roger Henry for X-ray
crystal structure analyses.
Su p p or tin g In for m a tion Ava ila ble: X-ray report data
for compounds 10b and 32 (35 pages). Ordering information
is given on any current masthead page.
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