Design, synthesis, and monoamine transporter binding site affinities of methoxy derivatives of indatraline

Article abstract of DOI:10.1021/jm000329v

A series of methoxy-containing derivatives of indatraline 13a-f and 17 were synthesized, and their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding sites were determined. Introduction of a methoxy group to indatraline

Full text of DOI:10.1021/jm000329v

4868
J . Med. Chem. 2000, 43, 4868-4876
Design , Syn th esis, a n d Mon oa m in e Tr a n sp or ter Bin d in g Site Affin ities of
Meth oxy Der iva tives of In d a tr a lin e
Xiao-Hui Gu,† Han Yu,† Arthur E. J acobson,† Richard B. Rothman,‡ Christina M. Dersch,‡ Clifford George,§
J udith L. Flippen-Anderson,§ and Kenner C. Rice*,†
Laboratory of Medicinal Chemistry, Building 8, Room B1-23, National Institute of Diabetes and Digestive and Kidney
Diseases, National Institutes of Health, Bethesda, Maryland 20892-0815, Clinical Psychopharmacology Section, National
Institute on Drug Abuse, Addiction Research Center, Baltimore, Maryland 21224, and Laboratory for the Structure of Matter,
Naval Research Laboratory, Washington, D.C. 20375
Received August 1, 2000
A series of methoxy-containing derivatives of indatraline 13a -f and 17 were synthesized, and
their binding affinities for the dopamine, serotonin, and norepinephrine transporter binding
sites were determined. Introduction of a methoxy group to indatraline affected its affinity and
selectivity greatly. Except for the 4-methoxy derivative 13a ,which had the same high affinity
at the dopamine transporter binding site as indatraline, the other methoxy-containing analogues
(13b-f and 17) exhibited lower affinity than indatraline for the three transporter binding sites.
However, some of the analogues were more selective than indatraline, and the 6-methoxy
derivative 13c displayed the highest affinity for both the serotonin and norepinephrine
transporters. This compound retained reasonable affinity for the dopamine transporter and is
a promising template for the development of a long-acting inhibitor of monoamine transporters.
Such inhibitors have potential as medications for treatment, as a substitution medication, or
for prevention of the abuse of methamphetamine-like stimulants.
In tr od u ction
nizing methamphetamine-induced [3H]neurotransmitter
release.6 Herein we report the synthesis of a series of
methoxy-containing derivatives of indatraline and their
binding affinities for the dopamine transporter (DAT),
serotonin transporter (SERT), and norepinephrine trans-
porter (NET) binding sites (Table 1). The methoxy
function was chosen because it was amenable to being
readily converted to the phenol from which long-acting
inhibitors could be prepared.13 However, since we had
no way of predicting, a priori, which compound would
prove best for our further purposes, we prepared a
number of analogues.
The abuse of stimulants, such as methamphetamine
and amphetamine, is an outstanding national and
international1 public health problem;2 a considerable
number of adverse effects3 derive from that abuse
including the increased transmission of hepatitis and
HIV/AIDS.4,5 Drug therapy to prevent chronic stimulant
abuse or to block the effect of a stimulant is the subject
of considerable contemporary research by many re-
search groups.6 One approach, to find selective dopam-
ine reuptake inhibitors, is currently being evaluated as
a class of potential substitution medications for the
treatment of cocaine and methamphetamine abuse.7,8
We considered a different approach and hypothesized
that a compound that might be most useful as a
treatment agent would eliminate the transport of the
abused stimulant into nerve terminals.6 Such a drug
might be discovered by searching for a compound that
displayed good affinity for all three monoamine trans-
porters: the dopamine, serotonin, and norepinephrine
transporters.9-12 This high-affinity, nonselective drug
might eliminate methamphetamine’s reinforcing ef-
fects12 by blocking the transporters which are thought
to contribute to or modulate the effects of stimulant-
like drugs. Furthermore, if this drug were capable of
being converted to a long-acting depot medication,13 it
might also prevent craving and relapse for a consider-
able time.
Ch em istr y
Substituted 3,3-diphenylpropanoic acids 4a ,b were
synthesized in three steps from commercially available
benzaldehydes according to a modified literature method
(Scheme 1).15 Cyclization of 4a ,b occurred smoothly in
polyphosphoric acid (PPA)15 at 120 °C affording the
desired indanones 5a -c in good yield. It should be
pointed out that treatment of the acid chlorides of 4a ,b
with AlCl3 gave a very low yield of indanones (12-27%).
Cyclization of acid 4a gave indanone 5a in 68% yield
along with a 17% yield of lactone which arose from
demethylation and then intramolecular cyclization.
Cyclization of the acid 4b gave a 4:1 mixture of isomers
5b,c in 75% overall yield with 5b predominant. The
structure of the indanone 5b was confirmed by single-
crystal X-ray analysis (Figure 1).
The 6-methoxyindanones 7a -c were synthesized in
good to excellent yields by heating the corresponding
chalcones 6a -c in neat trifluoroacetic acid (TFA) in a
sealed tube (Scheme 2). Initial attempts to use PPA or
TFA at room temperature or reflux to effect the cycliza-
tion were unsuccessful. The trans-chalcones 6a -c were
prepared by base-catalyzed condensation of the ap-
Our present work is based on an indatraline template,
since indatraline has been shown to be a nonselective
monoamine reuptake inhibitor,14-16 capable of antago-
* To whom correspondence should be addressed. Tel: 301-496-1856.
Fax: 301-402-0589. E-mail: kr21f@nih.gov.
† NIDDK, NIH.
‡ NIDA, NIH.
§ Naval Research Laboratory.
10.1021/jm000329v This article not subject to U.S. Copyright. Published 2000 by the American Chemical Society
Published on Web 11/21/2000

Methoxy Derivatives of Indatraline
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4869
Sch em e 1a
Sch em e 2a
a
(a) ArCHO, KOH, EtOH-H2O; (b) TFA, sealed tube, 110-
120 °C; (c) excess CHCl3, 6 equiv NaOH, 2 equiv H2O, reflux; (d)
CH3I, K2CO3, acetone, rt.
a
(a) CNCH2CO2Et, piperidine, toluene, reflux; (b) 3,4-dichlo-
robromobenzene, Mg, toluene-ether; (c) HOAc-H2SO4-H2O (2:
1:1), reflux; (d) PPA, 110-120 °C.
F igu r e 2. X-ray structure for trans-1-azido-3-(3,4-dichlo-
rophenyl)-5-methoxyindan (11b) with displacement ellipsoids
drawn at the 30% probability level.
F igu r e 1. X-ray structure for 3-(3,4-dichlorophenyl)-5-meth-
oxyindan-1-one (5b) with displacement ellipsoids drawn at the
30% probability level. The lower occupancy atoms of the
disordered dichlorophenyl ring were omitted for clarity.
Others,15 and we,19 have shown that only the trans
isomer of 3-phenyl-1-indanamine is a potent inhibitor
for dopamine, serotonin, and norepinephrine uptake.
Thus, we developed a selective synthetic strategy to
obtain the desired trans-3-phenyl-1-indanamines. Treat-
ment of the alcohols 10a -f with diphenyl phosphorazi-
date (DPPA) in the presence of DBU following Thomp-
son’s procedure20,21 gave predominantly the trans-azides
11a -f in good yields (83-92%) and with high selectivity
(95:5-85:15). The undesired cis isomers were removed
by column chromatography. The anti configuration of
the desired azide 11b was unequivocally determined by
single-crystal X-ray analysis (Figure 2).
propriately substituted benzaldehydes and 3-methoxy-
acetophenone or 3,4-dimethoxyacetophenone.17 The requ-
isite benzaldehyde 9 was synthesized in 34% overall
yield from commercially available 2,3-dichlorophenol by
the Reimer-Tiemann reaction18 to introduce a formyl
group, followed by methylation of the hydroxyl group
with MeI and K2CO3 in acetone. It should be noted that
the 6-methoxyindanones 7a -c were not able to be
prepared by the same method as that described for
indanones 5a -c.
Reduction of the indanones 5a -c and 7a -c with
sodium borohydride gave, as expected, almost pure cis-
3-phenylindan-1-ols 10a -f in nearly quantitative yield.
With the desired substitution pattern in place, all that
remained was to reduce the azide and methylate the

4870 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Gu et al.
Sch em e 3a
Sch em e 4. Unsuccessful Synthesis of 17
Sch em e 5a
a
(a) p-TSA, PhH, reflux; (b) NBS, THF-H2O, rt; (c) MeNH2,
EtOH-H2O, reflux; (d) H2, 5% Pd/C, NaOAc‚3H2O, MeOH, rt.
a
danone 7a could be easily converted into compound 14
in 65% yield by treatment with Mn(OAc)3 and AcOH,26
we encountered great difficulty in transforming the
carbonyl group in 14 to a methylamino group. Various
reductive amination conditions were tried, but all failed
to give the desired compound presumably because of the
sensitivity of 14 to the reaction conditions.
Finally, compound 17 was synthesized from indanol
10c through the route shown in Scheme 5. Indanol 10c
was dehydrated with p-toluenesulfonic acid in refluxing
benzene27,28 to afford the unstable indene 15 as a
colorless liquid in quantitative yield. Indene 15 was
reacted immediately with NBS in aqueous THF29 to give
the expected bromohydrin 16a along with unexpected
ring-brominated bromohydrin 16b in 50% yield. The
latter was formed even when the amount of NBS was
reduced to less than 1 equiv. The mixture of 16a ,b was
treated with methylamine in refluxing aqueous etha-
nol30 to give the desired amino alcohol in moderate yield.
Subsequent brief hydrogenolysis in the presence of Pd/C
(a) NaBH4, MeOH, 0 °C-rt; (b) DPPA, DBU, THF, 0 °C-rt;
(c) H2, Boc2O, 5% Pd/C, EtOAc; (d) CH3I, NaH, DMF; (e) HCl-
EtOAc, rt; (f) ZnBr2, CH2Cl2, rt.
resulting amine. Hydrogenolysis of azides 11a -f over
Pd/C in the presence of (BOC)2O22 afforded the carbam-
ates which were subsequently methylated with NaH
and MeI in THF23 to provide N-methylcarbamates
12a -f in good yields. Initial attempts to use TFA to
cleave the BOC group from 12a -f were unsuccessful,
and a complex mixture resulted. Removal of the BOC
group from 12a ,c-e was achieved using a saturated
solution of HCl in EtOAc.24 However, this reagent
afforded complex mixtures on attempts to deprotect the
5-methoxy-containing derivatives 12b,f. The deprotec-
tion of 12b,f was smoothly accomplished in high yield
using ZnBr2 in dry CH2Cl2. The HCl salts of 13a -f
were purified by recrystallization from a mixture of
2-propanol and isopropyl ether.
Initial attempts to synthesize compound 17 failed
through the route shown in Scheme 4. Although in-
25

Methoxy Derivatives of Indatraline
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4871
Ta ble 1. Physical Properties and Binding Affinities of Indatraline Analoguesa
Ki ( SD (nM)
compd
13a
13b
13c
13d
13e
13f
mp (°C)
formula
DATb
SERTb
NETc
248-250 dec
193-195
C17H17Cl2NO‚HCl
1.7 ( 0.05
9.4 ( 0.44
11.6 ( 0.3
32 ( 2
63 ( 2
6.5 ( 0.5
1.1 ( 0.08
108 ( 4
27 ( 1.7
76.5 ( 5.3
15 ( 0.6
C
C
C
C
C
C
17H17Cl2NO‚HCl
240-242
17H17Cl2NO‚HCl
190-192 dec
212-214
17H17Cl2NO‚HCl
93 ( 9.3
18H19Cl2NO‚HCl‚0.5H2O
18H19Cl2NO‚HCl‚0.25H2O
17H17Cl2NO2‚HCl
788 ( 13
5.6 ( 0.5
61 ( 2
122 ( 6.1
102 ( 9.5
1686 ( 93
5.8 ( 0.4e
220-222 dec
268-270 dec
3.6 ( 0.18
1133 ( 21
1.7 ( 0.24e
17
8.1 ( 0.5
indatralined
0.42 ( 0.04e
a
The Ki values of the test agents were determined using protocols previously established in ref 31. bDAT and SERT binding sites
labeled with [125I]RTI-55. NET site labeled with [3H]nisoxetine. dPhysical data can be found in ref 15. Data from ref 31.
c
e
and sodium acetate, selectively removing the aromatic
bromine atom without affecting the aromatic chlorines,
afforded compound 17 in 23% overall yield. The relative
configuration of the three stereocenters was assigned
through NOE. The observed cross-peaks between the
CHOH at C2 and the Ar + indano CH at C3 and the
lack of a cross-peak between the NHMeCH at C1 and
any other proton in 17 except for the aromatic protons
were unambiguously indicative of the cis relationship
between the OH and the dichlorobenzene moiety and a
trans relationship between the OH and the NHMe
moiety. It was not possible to confirm the relative
stereochemistry of 17 by X-ray analysis because it was
not possible to grow a usable single crystal.
monomethoxy derivatives except for the 4-methoxy
analogue 13a . The low binding affinity of compound 13e
for the DAT binding site was surprising considering that
the difference between 13e,f was only the transposition
of a methoxy group from C5 to the dichlorobenzene ring.
This clearly illustrated the sensitivity of the binding site
in the DAT to structural modifications in the dichlo-
robenzene moiety of indatraline-like compounds. Com-
pound 17 was a selective compound with high affinity
for the SERT binding site and might prove useful as a
template for compounds capable of blocking a single
monamine transporter. From these SAR data it is
apparent that substitution in the C2-position or in the
dichlorobenzene ring inhibits binding at the DAT, but
there is much less effect on the SERT.
P h a r m a cology
Con clu sion s
The binding affinities (Ki) of compounds 13a -f and
17 for the DAT, SERT, and NET are summarized in
Table 1. Binding assays were determined in competition
studies using [125I]RTI-55 ([125I]-3â-(4′-iodophenyl)tro-
pane-2â-carboxylic acid methyl ester) to label the DAT
and SERT and [3H]nisoxetine to label the NET following
known procedures.31,32 For comparative purposes, bind-
ing data for indatraline are included.
Our results demonstrated that the introduction of a
methoxy group into indatraline greatly influences its
potency and selectivity for the three monoamine trans-
porters. We have found that an oxygenated moiety
outside of the aromatic ring in the indan skeleton is
deleterious to the affinity of the compound for the
transporters. Our synthesis of a series of methoxy-
containing derivatives of indatraline afforded com-
pounds that had high affinity for either the DAT or the
SERT. Only one compound, however, the C6-monosub-
stituted methoxy compound 13c, had high affinity for
both of those transporters, as well as for the NET. This
compound was formerly prepared and examined as an
antidepressant by Bøgesø et al.15 Its IC50 for synapto-
somal uptake inhibition was noted to be 2.5, 0.67, and
0.62 nM at DA, NE, and 5-HT, respectively; it was not
chosen for further pharmacological evaluation at that
time. Compound 13c will be the subject of our future
research since we believe that it is theoretically capable
of blocking the transport of methamphetamine-like
substrates to all of the monamine nerve terminals.
Furthermore, it can serve as a template for a potentially
long-acting depot preparation, which may be suitable
as a medication for the treatment or prevention of the
sequelae resulting from the abuse of methamphetamine-
like stimulants.
Resu lts a n d Discu ssion
In general, the binding affinity (Ki) of all the methoxy-
containing indatraline-like compounds decreased rela-
tive to indatraline, although one of them maintained
sufficiently high affinity for our purposes. A major loss
in affinity for the DAT was observed with compounds
13e and 17. In those compounds, a second oxygen
function was introduced in the molecule outside of the
aromatic part of the indan moiety. Compound 13a , with
a methoxy group in the 4-position, exhibited the highest
binding affinity for the DAT among these analogues (Ki
) 1.7 nM, equivalent to indatraline) and showed high
selectivity for DAT vs SERT or NET (37- and 16-fold,
respectively). All the other compounds with methoxy
substituents on the aromatic ring of the indan showed
progressively less affinity for the DAT the further
removed they were from that C4-position. Compound
13b, with a methoxy group in the C5-position, possessed
essentially equivalent, high binding affinities for the
DAT and SERT, although it had 6- and 16-fold lower
affinity than indatraline, respectively, at those trans-
porters. Remarkably, introduction of a methoxy group
in the 7-position (compound 13d ) resulted in an 18- and
257-fold decrease in binding affinity for the DAT and
SERT, respectively. The 5,6-dimethoxy compound 13f
had higher affinity for the DAT than any of the
Exp er im en ta l Section
Melting points were determined on a Thomas-Hoover capil-
lary apparatus and were uncorrected. Elemental analyses were
performed by Atlantic Microlabs, Atlanta, GA, and the results
were within (0.4% of the theoretical values for the elements
indicated. Chemical ionization mass spectra (CIMS) were
obtained using a Finnegan 1015 mass spectrometer. Electron
ionization mass spetra (EIMS) were obtained using a V.G.

4872 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Gu et al.
1
Micro Mass 7070F mass spectrometer. H NMR spectra were
viscous oil: 1H NMR (CDCl3) δ 7.45-6.77 (m, 7H), 4.67 (m,
1H), 4.24-4.11(m, 3H), 3.78(d, J ) 2.1 Hz, 3H), 1.15(dd, J )
2.1 Hz 6.9 Hz, 3H); CIMS (NH3) m/z 395 (M+ + NH4, 100).
recorded on a Varian Gemini-300 spectrometer. Chemical
shifts are expressed in parts per million (ppm) on the δ scale
relative to a tetramethylsilane (TMS) internal standard. Thin-
layer chromatography (TLC) was performed on 250-µm Anal-
tech GHLF silica gel plates. Flash column chromatography was
performed with Fluka silica gel 60 (220-240 mesh). No
attempt was made to optimize the reported yields.
2-Cya n o-3-(2-m eth oxyp h en yl)a cr ylic Acid Eth yl Ester
(2a ). The general method of Bøgesø33 was used with slight
modification. A solution of o-anisaldehyde (41 g, 0.3 mol), ethyl
cyanoacetate (41 g, 0.36 mol) and piperidine (2.0 mL) in
toluene (200 mL) was refluxed under a Dean-Stark trap for
1.5-2 h. After removal of the volatiles in vacuo, an orange oil
was obtained in quantitative yield, which solidified when
standing at ambient temperature. The product was used in
the next reaction without further purification. A sample for
analysis was obtained by recrystallization from EtOAc as pale-
yellow needles: 1H NMR (CDCl3) δ 8.77 (s, 1H), 8.31-6.95 (m,
4H), 4.38 (q, J ) 8.05 Hz, 2H), 3.91 (s, 3H), 1.39 (t, J ) 8.05
Hz, 3H); CIMS (NH3) m/z 232 (MH+, 100).
3-(3,4-Dich lor op h en yl)-3-(2-m et h oxyp h en yl)p r op ion -
ic Acid (4a ). The general method of Bøgesø33 was used with
slight modification. A mixture of crude 3a (26 g, 6.9 mmol),
AcOH (40 mL), concentrated H2SO4 (20 mL), and H2O (20 mL)
was refluxed with stirring for 26 h and then poured into ice.
The brown crystalline acid was filtered, and washed thor-
oughly with H2O. After coevaporation several times with
toluene, the brown acid was recrystallized from EtOAc to
afford 4a (14.5 g, 65%) as an off-white solid: 1H NMR (CDCl3)
δ 7.34-6.84 (m, 7H), 4.83 (t, J ) 7.0 Hz, 8.16 Hz, 1H), 3.77 (s,
3H, OCH3), 3.04 (m, 2H); CIMS (NH3) m/z 342 (M+ + NH4,
100).
3-(3,4-Dich lor op h en yl)-3-(3-m et h oxyp h en yl)p r op ion -
ic Acid (4b). Prepared from 3b in 72% yield as a white solid
by a procedure similar to that described for 4a : 1H NMR
(CDCl3) δ 7.40-6.82 (m, 7H), 4.86 (t, J ) 7.0 Hz, 8.2 Hz, 1H),
3.79 (s, 3H, OCH3), 3.05 (m, 2H); CIMS (NH3) m/z 342 (M+
NH4, 100).
+
3-(3,4-Dich lor oph en yl)-4-m eth oxyin dan -1-on e (5a). PPA
(30 g) was placed in a dry flask and heated to 90 °C under an
atmosphere of Ar. Acid 4a (980 mg, 3 mmol) was added, and
the reaction mixture was stirred at 110 °C for 3 h. The mixture
was poured into ice-H2O and extracted with EtOAc, The
combined extracts were washed successively with H2O, 5%
NaOH solution and brine, dried over Na2SO4, and concentrated
in vacuo to give a brown oil, which was purified by column
chromatography on silica gel (petroleum ether/EtOAc 10:1f8:
1) to afford 5a (625 mg, 68%) as a pale-yellow syrup: 1H NMR
(CDCl3) δ 7.48-6.87 (m, 6H), 4.33 (t, J ) 6.8 Hz, 1H), 3.72 (s,
3H, OCH3), 3.2 (q, J ) 7.8 Hz, 19.5 Hz, 1H), 2.56 (m, 1H);
EIMS m/z 306 (M+, 45), 292 (M+ - 15, 80), 215 (100).
3-(3,4-Dich lor op h en yl)-5-m eth oxyin d a n -1-on e (5b) a n d
3-(3,4-Dich lor oph en yl)-7-m eth oxyin dan -1-on e (5c). A mix-
ture of acid 4b (7.0 g, 21.53 mmol) and PPA (28 g) was heated
at 110 °C for 4 h under an atmosphere of Ar, then poured into
a mixture of ice-H2O and extracted with EtOAc. The combined
extracts were washed successively with H2O, 5% NaOH
solution and brine, dried over Na2SO4, and concentrated in
vacuo to give a brown solid, which was purified by column
chromatography on silica gel (petroleum ether/EtOAc 8:1f3:
1) to afford 5b (3.902 g, 59%) as a pale-yellow solid. At the
same time 5c (0.847 g, 13%) was obtained as a yellow solid.
5b (the less polar component): mp 169-171 °C; 1H NMR
(CDCl3) δ 7.76 (d, J ) 9 Hz, 1H), 7.39 (d, J ) 7.8 Hz, 1H), 7.24
(d, J ) 1.8 Hz, 1H), 7.00-6.94 (m, 2H), 6.63 (s, 1H), 4.47 (dd,
J ) 3.9 Hz, 7.8 Hz, 1H), 3.82 (s, 3H), 3.21 (dd, J ) 7.8 Hz, 8.7
Hz, 1H), 2.59 (q, J ) 3.9 Hz, 1H); EIMS m/z 306 (M+, 100). 5c
(the more polar component): mp 124-126 °C; 1H NMR (CDCl3)
δ 7.54 (t, J ) 7.8 Hz, 1H), 7.38 (d, J ) 7.8 Hz, 1H), 7.12 (d, J
) 2.1 Hz, 1H), 6.96 (dd, J ) 2.1 Hz, 9 Hz, 1H), 6.86 (d, J ) 7.8
Hz, 1H), 6.77 (d, J ) 7.8 Hz, 1H), 4.46 (dd, J ) 3.9 Hz, 7.8 Hz,
1H), 4.00 (s, 3H), 3.2 (dd, J ) 7.8 Hz, 8.7 Hz, 1H), 2.60 (dd, J
) 3.9 Hz, 1H); EIMS m/z 306 (M+, 100).
3-(3,4-Dich lor op h e n yl)-1-(3-m e t h oxyp h e n yl)p r op e -
n on e (6a ). To a stirred mixture of 3-methoxyacetophenone
(15.1 g, 0.1 mol) and 3,4-dichlorobenzaldehyde (17.5 g, 0.1 mol)
in EtOH (250 mL) was slowly added a solution of KOH (18.3
g) in H2O (120 mL) at 0 °C. The reaction mixture was stirred
at ambient temperature for 2 h. The pale-yellow solid product
(27.52 g, 89%) was collected by filtration, washed with EtOH,
and dried in air overnight: mp 116-118 °C; 1H NMR (CDCl3)
δ 7.74-7.14 (m, 9H), 3.89 (s, 3H); EIMS m/z 307 (M+).
3-(3,4-Dich lor o-1-m eth oxyph en yl)-1-(3-m eth oxyph en yl)-
p r op en on e (6b). Prepared in 69% yield from 3,4-dichloro-2-
methoxybenzaldehyde as a yellow solid by a procedure similar
to that described for 6a : 1H NMR (CDCl3) δ 7.99-7.13 (m,
8H), 3.90 (s, 3H), 3.89 (s, 3H); EIMS m/z 336 (M+, 15), 305
(M+ - 31, 100).
2-Cya n o-3-(3-m eth oxyp h en yl)a cr ylic Acid Eth yl Ester
(2b). The title compound was prepared as a red oil in
quantitative yield from m-anisaldehyde by a procedure similar
to that described for 2a . 2b was used without further purifica-
tion. A sample for analysis was obtained after purification by
column chromatography on silica gel (petroleum ether/EtOAc
10:1): 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.61 (d, J ) 2.1 Hz,
1H), 7.52 (d, J ) 7.8 Hz, 1H), 7.41 (t, J ) 7.8 Hz, 8.7 Hz, 1H),
7.13-7.10 (dd, J ) 2.1 Hz, 7.8 Hz, 1H), 4.39 (m, 2H), 3.87 (s,
3H), 1.40 (t, J ) 8.7 Hz, 3H); CIMS (NH3) m/z 232 (MH+, 100).
2-Cya n o-3-(3,4-d ich lor op h en yl)-3-(2-m eth oxyp h en yl)-
p r op ion ic Acid E t h yl E st er (3a ). The general method of
Bøgesø33 was used with slight modification. A 250-mL two-
necked flask was equipped with a dropping funnel and an
efficient refluxing condenser attached to a potassium carbonate
tube. In the flask were placed magnesium turnings (0.96 g,
0.04 g atom), a crystal of iodine and 30 mL of dry ether. A
solution of 4-bromo-1,2-dichlorobenzene (9.0 g 40 mmol) in 50
mL of anhydrous ether was added at a rate which maintained
rapid refluxing. The mixture was stirred and heated under
reflux for an additional 1.5 h. A solution of 2a (4.62 g, 20 mmol)
in Et2O (50 mL) was added to the above solution at ambient
temperature. The mixture was refluxed for 1 h, then poured
into a mixture of ice (200 g) and concentrated H2SO4 (20 mL).
The organic phase was separated, and the aqueous phase was
extracted with EtOAc. The combined extracts were washed
with H2O and brine, dried over Na2SO4, and concentrated in
vacuo to afford 3a (10.16 g, 135%) as a red oil, which was used
in the next reaction without further purification. A sample for
analysis was obtained by column chromatography on silica gel
(petroleum ether/EtOAc 10:1) as a pale-yellow viscous oil: 1H
NMR (CDCl3) δ 7.47-6.88 (m, 7H), 5.00 (dd, J ) 7.8 Hz, 10.8
Hz, 1H), 4.43 (dd, J ) 7.8 Hz, 10.8 Hz, 1H), 4.13 (t, J ) 8.1
Hz, 2H), 3.85 (s, 3H),1.13(q, J ) 8.1 Hz, 3H); CIMS (NH3) m/z
395 (M+ + NH4, 100), 361 (M - 17, 35); EIMS m/z 377(M+,
18), 265 (M - 112, 95), 159 (100).
2-Cya n o-3-(3,4-d ich lor op h en yl)-3-(3-m eth oxyp h en yl)-
p r op ion ic Acid Eth yl Ester (3b). As in the preparation of
3a , magnesium turnings (2.76 g, 0.115 g atom), a crystal of
iodine and 50 mL of dry Et2O were placed in the flask. A
solution of 4-bromo-1,2-dichlorobenzene (22.9 g, 100 mml) in
50 mL of anhydrous Et2O was added at a rate which main-
tained rapid refluxing. The mixture was stirred and heated
under reflux for 1 h after the addition. A solution of 2b (10.5
g, 45.5 mmol) in dry toluene (50 mL) was added to the above
solution at ambient temperature. The mixture was refluxed
for 2 h, then poured into a mixture of ice (200 g) and
concentrated H2SO4 (20 mL). The organic phase was separated,
and the aqueous phase was extracted with EtOAc. The
combined extracts were washed with H2O and brine, dried over
Na2SO4, and concentrated in vacuo. The residual oil was
purification by column chromatography on silica gel (petroleum
ether/EtOAc 10:1) to afford 3b (14.2 g, 83%) as a pale-yellow
3-(3,4-Dich lor op h en yl)-1-(3,4-d im eth oxyp h en yl)p r op e-
n on e (6c). Prepared in 91% yield from 2,3-dimethoxyac-
etophenone as a yellow solid by a procedure similar to that

Methoxy Derivatives of Indatraline
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4873
described for 6a : 1H NMR (CDCl3) δ 8.05-7.10 (m, 8H), 3.93
(s, 3H), 3.88 (s, 3H); EIMS m/z 336 (M+).
7.35 (m, 3H), 7.10-7.06 (dd, J ) 1.8 Hz, 8.7 Hz, 1H), 6.89-
6.86 (m, 1H), 6.44 (s, 1H), 5.25 (t, J ) 6.9 Hz, 1H), 4.12 (t, J
) 7.8 Hz, 1H), 3.73 (s, 3H), 3.05-2.96 (m, 1H), 1.94-1.85 (m,
1H); EIMS m/z 308 (M+, 100), 291 (M+ - 17, 45).
3-(3,4-Dich lor op h en yl)-6-m eth oxyin d a n -1-on e (7a ).15
A
solution of 6a (3.17 g, 10.3 mmol) in TFA (20 mL) in a sealed
glass tube was heated at 120-130 °C for 4 h. After removal of
the solvent in vacuo, the residual oil was poured into ice-H2O
and extracted with EtOAc. The combined extracts were
washed with saturated aqueous NaHCO3 and brine, then dried
over Na2SO4, and concentrated in vacuo to afford a yellow oil,
which was crystallized from isopropyl ether to give 7a (2.78
g, 88%) as a white solid: mp 80-82 °C (lit.15 mp 67-69 °C);
1H NMR (CDCl3) δ 7.49-6.94 (m, 6H), 4.51-4.47 (m, 1H), 3.88
(s, 3H), 3.31-3.20 (m, 1H), 2.65-2.58 (m, 1H); EIMS m/z 307
(M+).
3-(3,4-Dich lor o-2-m eth oxyp h en yl)-6-m eth oxyin d a n -1-
on e (7b). Prepared from 6b in 58% yield as a white solid by
a procedure similar to that described for 7a : 1H NMR (CDCl3)
δ 7.26-7.13 (m, 4H), 6.77 (d, J ) 7.8 Hz, 1H), 4.84-4.80 (dd,
J ) 3.9 Hz, 7.8 Hz, 1H), 3.87 (s, 3H), 3.73 (s, 3H), 3.28-3.19
(dd, J ) 7.8 Hz, 19.5 Hz, 1H), 2.69-2.62 (dd, J ) 3.9 Hz, 19.5
Hz, 1H); EIMS m/z 336 (M+, 100), 321 (M+ - 15, 75).
cis-3-(3,4-Dich lor op h en yl)-6-m eth oxyin d a n -1-ol (10c).15
Prepared from 9c in 97% yield as a white solid by a procedure
similar to that described for 10a : 1H NMR (CDCl3) δ 7.38 (d,
J ) 7.8 Hz, 1H), 7.33 (d, J ) 2.1 Hz, 1H), 7.06 (dd, J ) 2.1 Hz,
7.8 Hz, 1H), 7.01 (s, 1H), 6.83 (s, 2H), 5.24 (t, 7.8 Hz, 1H),
4.10 (t, J ) 7.8 Hz, 1H), 3.83 (s, 3H), 3.06-2.97 (m, 1H), 1.92-
1.82 (m, 1H); CIMS (NH3) m/z 310 (MH+, 100).
cis-3-(3,4-Dich lor op h en yl)-7-m eth oxyin d a n -1-ol (10d ).
Prepared from 9d in 100% yield as a white solid by a procedure
similar to that described for 10a : 1H NMR (CDCl3) δ 7.37-
6.46 (m, 6H), 5.21 (t, J ) 6.9 Hz, 1H), 4.17 (t, J ) 7.8 Hz, 1H),
3.05-2.91 (m, 1H), 1.90-1.85 (m, 1H); EIMS m/z 308 (M+).
cis-3-(3,4-Dich lor o-2-m eth oxyph en yl)-6-m eth oxyin dan -
1-ol (10e). Prepared from 9e in 95% yield as a white solid by
a procedure similar to that described for 10a : 1H NMR (CDCl3)
δ 7.36-6.28 (m, 5H), 5.13 (t, J ) 6.9 Hz, 1H), 4.11 (t, J ) 7.8
Hz, 1H), 3.83 (s, 3H), 3.71 (s, 3H), 3.2-2.86 (m, 1H), 1.89-
1.83 (m, 1H); EIMS m/z 339(M+).
3-(3,4-Dich lor op h en yl)-5,6-d im eth oxyin d a n -1-on e (7c).
Crude 7c was prepared from 6c in 70% yield by a procedure
similar to that described for 7a . The residual oil was purified
by column chromatography on silica gel (hexanes/EtOAc
8:1f3:1) to afford 7c as a white solid: 1H NMR (CDCl3) δ 7.39
(d, J ) 7.8 Hz, 1H), 7.23 (s, 2H), 6.95 (m, 1H), 6.61 (s, 1H),
4.46-4.43 (dd, J ) 3.0 Hz, 7.8 Hz, 1H), 3.95 (s, 3H), 3.87 (s,
3H), 3.25-3.16 (dd, J ) 7.8 Hz, 18.6 Hz, 1H), 2.59-2.52 (dd,
J ) 3 Hz, 18.6 Hz, 1H); CIMS (NH3) m/z 354 (M+ + NH4, 100),
337 (M+, 50), 320 (M+ - 15, 75); EIMS m/z 336 (M+, 100).
3,4-Dich lor o-2-h yd r oxyben za ld eh yd e (8).34 NaOH (24 g,
0.6 mol) was added to a solution of 2,3-dichlorophenol (16.3 g,
0.1 mol), CHCl3 (150 mL) and H2O (3.6 mL, 0.2 mol) at ambient
temperature. The reaction mixture was refluxed for 4 h,
diluted with H2O (250 mL) and EtOAc (100 mL), and the
organic phase was separated. The aqueous phase was acidified
with 1 N HCl to pH 1 and back-extracted with EtOAc. The
combined extracts were washed with H2O, dried over Na2SO4,
and concentrated in vacuo to give a brown oil, which was
purified by column chromatography on silica gel (petroleum
ether/EtOAc 10:1) to afford 8 (9.8 g, 51.3%) as a white solid:
1H NMR (CDCl3) δ 9.88 (s, 1H, CHO), 7.45 (d, J ) 7.8 Hz,
1H), 7.18 (d, J ) 9.0 Hz, 1H); EIMS m/z 191 (M+).
cis-3-(3,4-Dich lor op h e n yl)-5,6-d im e t h oxyin d a n -1-ol
(10f). Prepared from 9f in 100% yield as a white solid by a
procedure similar to that described for 10a : 1H NMR (CDCl3)
δ 7.38 (d, J ) 7.8 Hz, 1H), 7.21 (d, J ) 2.1 Hz, 1H), 6.95 (s,
2H), 6.43 (s, 1H), 4.95-4.92 (dd, J ) 1.8 Hz, 6.9 Hz, 1H), 4.50
(t, J ) 7.8 Hz, 1H), 3.91 (s, 3H), 3.78 (s, 3H), 2.65-2.59 (m,
1H), 2.34-2.27 (m, 1H); EIMS m/z 339 (M+).
t r a n s-1-Azid o-3-(3,4-d ich lor op h e n yl)-6-m e t h oxyin -
d a n (11c). Diphenyl phosphorazidate (2.463 g, 8.95 mmol) was
added to a solution of 10c (1.974 g, 6.39 mmol) in dry THF
(30 mL). The mixture was stirred 10 min and cooled to 0 °C.
DBU (1.34 mL, 8.95 mmol) was added dropwise via syringe
and the reaction mixture was allowed to warm to room
temperature overnight. The mixture was partitioned between
H2O (50 mL) and Et2O (50 mL), and the aqueous phase was
extracted with Et2O. The combined extracts were washed with
brine, dried over Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(hexanes/EtOAc 30:1) to yield 11c (1.982 g, 93%) as a pale-
yellow oil: 1H NMR (CDCl3) δ 7.37 (d, J ) 7.8 Hz, 1H), 7.22
(d, J ) 2.1 Hz, 1H), 6.98-6.89(m, 4H), 4.98-4.95 (dd, J ) 1.8
Hz, 6.9 Hz, 1H), 4.67 (t, J ) 7.8 Hz, 1H), 3.84 (s, 3H), 2.65-
2.58 (m, 1H), 2.35-2.27 (m, 1H); EIMS m/z 333 (M+), 304 (M+
- 28), 291 (M+ - 43).
t r a n s-1-Azid o-3-(3,4-d ich lor op h e n yl)-4-m e t h oxyin -
d a n (11a ). Prepared from 10a in 87% yield as an oil by a
procedure similar to that described for 11c: 1H NMR (CDCl3)
δ 7.35 (d, J ) 7.8 Hz, 1H), 7.29-7.23 (m, 2H), 7.00-6.98 (dd,
J ) 1.8 Hz, 8.7 Hz, 1H), 6.82 (d, J ) 8.7 Hz, 1H), 6.57 (d, J )
7.8 Hz, 1H), 5.25 (d, J ) 6.9 Hz, 1H), 4.52 (t, J ) 8.7 Hz, 1H),
3.86 (s, 3H), 2.58-2.52 (m, 1H), 2.65-2.12 (m, 1H); CIMS
(NH3) m/z 308 (M+ - 28).
t r a n s-1-Azid o-3-(3,4-d ich lor op h e n yl)-5-m e t h oxyin -
d a n (11b). Prepared from 10b in 92% yield as a pale-yellow
oil by a procedure similar to that described for 11c: 1H NMR
(CDCl3) δ 7.40-7.36 (dd, J ) 3.9 Hz, 7.8 Hz, 2H), 7.25 (d, J )
1.8 Hz, 1H), 7.01-6.98 (dd, J ) 1.8 Hz, 8.7 Hz, 1H), 6.89-
6.86 (dd, J ) 1.8 Hz, 8.7 Hz, 1H), 6.49 (s, 1H), 4.98 (m, 1H),
4.49 (t, J ) 7.8 Hz, 1H), 3.75 (s, 3H), 2.64-2.56 (m, 1H), 2.34-
2.25 (m, 1H); EIMS m/z 333 (M+, 35), 304 (M+ - 28, 45), 291
(M+ - 43, 100).
3,4-Dich lor o-2-m eth oxyben za ld eh yd e (9). To a solution
of 8 (5.8 g, 30.4 mmol) in dry acetone (100 mL) were added
successively K2CO3 (8.42 g, 61 mmol) and MeI (8.8 g, 62 mmol).
The reaction mixture was stirred at room temperature over-
night. After removal of the volatiles in vacuo, the residue was
partitioned between H2O (150 mL) and Et2O (100 mL). The
aqueous phase was extracted with Et2O. The combined ex-
tracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The brown residue was purified by
column chromatography on silica gel (petroleum ether/EtOAc
20:1) to afford 9 (4.86 g, 78.1%) as a white solid: 1H NMR
(CDCl3) δ 10.32 (s, 1H, CHO), 7.72 (d, J ) 8.4 Hz, 1H), 7.38
(d, J ) 8.4 Hz, 1H), 4.03 (s, 3H); CIMS (NH3) m/z 222 (M+
17, 100).
+
cis-3-(3,4-Dich lor op h en yl)-4-m eth oxyin d a n -1-ol (10a ).
NaBH4 (231 mg, 6.08 mmol) was added portionwise to a
solution of ketone 5a (1.868 g, 6.08 mmol) in 20 mL MeOH at
0 °C. The resulting reaction mixture was stirred at room
temperature for 2 h, and the solvent was removed in vacuo.
The residue was partitioned between H2O and Et2O. The
aqueous phase was extracted with Et2O. The combined ex-
tracts were washed with brine, dried over Na2SO4, and
concentrated in vacuo to give crude 10a (1.925 g, 100%) as a
colorless syrup, which was used in the next step without
further purification: 1H NMR (CDCl3) δ 7.38-6.45 (m, 6H),
5.23 (t, J ) 6.9 Hz, 1H), 4.14 (t, J ) 7.8 Hz, 1H), 3.78 (s, 3H),
3.06-2.94 (m, 1H), 1.93-1.82 (m, 1H); EIMS m/z 308 (M+).
cis-3-(3,4-Dich lor op h en yl)-5-m eth oxyin d a n -1-ol (10b).
Prepared from 9b in 100% yield as a white solid by a procedure
similar to that described for 10a : 1H NMR (CDCl3) δ 7.40-
t r a n s-1-Azid o-3-(3,4-d ich lor op h e n yl)-7-m e t h oxyin -
d a n (11d ). Prepared from 10d in 85% yield as a colorless oil
by a procedure similar to that described for 11c: 1H NMR
(CDCl3) δ 7.38 (d, J ) 7.8 Hz, 1H), 7.32-7.24 (m, 2H), 7.01-
6.98 (dd, J ) 1.8 Hz, 8.7 Hz, 1H), 6.83 (d, J ) 8.7 Hz, 1H),
6.54 (d, J ) 7.8 Hz, 1H), 5.28 (d, J ) 6.9 Hz, 1H), 4.51 (t, J )
8.7 Hz, 1H), 3.91 (s, 3H), 2.59-2.52 (m, 1H), 2.67-2.16 (m,
1H); CIMS (NH3) m/z 308 (M+ - 28); EIMS m/z 333 (M+, 10),
291 (M+ - 43, 100).
tr a n s-1-Azido-3-(3,4-dich lor o-2-m eth oxyph en yl)-6-m eth -
oxyin d a n (11e). Prepared from 10e in 82% yield as a syrup

4874 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Gu et al.
by a procedure similar to that described for 11c: 1H NMR
(CDCl3) δ 7.14 (d, J ) 8.7 Hz, 1H), 6.99 (s, 1H), 6.89 (s, 2H),
6.75 (d, J ) 8.7 Hz, 1H), 5.02-4.98 (m, 1H), 4.84 (t, J ) 7.8
Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 2.66-2.58 (m, 1H), 2.38-
2.28 (m, 1H); EIMS m/ z 363 (M+, 20), 335 (M+ - 28, 25), 320
(M+ - 43, 53).
tr a n s-1-Azid o-3-(3,4-d ich lor op h en yl)-5,6-d im eth oxyin -
d a n (11f). Prepared from 10f in 87% yield as a red oil by a
procedure similar to that described for 11c: 1H NMR (CDCl3)
δ 7.41-7.39 (d, J ) 7.8 Hz, 1H), 7.23 (d, J ) 2.1 Hz, 1H), 6.96
(s, 2H), 6.46 (s, 1H), 4.98-4.95 (dd, J ) 1.8 Hz, 6.9 Hz, 1H),
4.49 (t, J ) 7.8 Hz, 1H), 3.94 (s, 3H), 3.79 (s, 3H), 2.68-2.60
(m, 1H), 2.35-2.26 (m, 1H); EIMS m/z 363 (M+, 13), 335 (M+
- 28, 10), 321 (M+ - 43, 100).
tr a n s-[3-(3,4-Dich lor o-2-m eth oxyp h en yl)-6-m eth oxyin -
d a n -1-yl]m eth ylca r ba m ic Acid ter t-Bu tyl Ester (12e). A
solution of azide 11e (1.85 g, 5.08 mmol) and BOC2O (1.55 g,
7.11 mmol) in EtOAc (40 mL) was added to a mixture of 5%
Pd/C in EtOAc (20 mL) which had been presaturated with
hydrogen. The reaction mixture was shaken in a Parr hydro-
genation apparatus at 35 psi for 3 h. After filtering off the
catalyst, the filtrate was concentrated in vacuo to give a white
solid, which was filtered through a short silica gel column
(hexanes/EtOAc 10:1f6:1). The white foam was used in the
next reaction.
tr a n s-[3-(3,4-Dich lor op h en yl)-5,6-d im et h oxyin d a n -1-
yl]m eth ylca r ba m ic Acid ter t-Bu tyl Ester (12f). Prepared
from 11f in 88% yield as a white foam by a procedure similar
to that described for 12e: 1H NMR (CDCl3) δ 7.42 (d, J ) 7.8
Hz, 1H), 7.32 (m, 1H), 7.06 (m, 1H), 6.75 (s, 1H), 6.48 (s, 1H),
4.44-4.39 (m, 1H), 3.89 (s, 3H), 3.79 (s, 3H), 2.58 (s, 3H), 2.48
(brs, 1H), 2.34-2.28 (m, 1H), 1.51 (s, 9H); EIMS m/z 451 (M+),
396 (100).
[3-(3,4-Dich lor op h en yl)-4-m eth oxyin d a n -1-yl]m eth yl-
a m in e (13a ). HCl gas was bubbled into a solution of 12a (601
mg, 1.43 mmol) in dry EtOAc (50 mL) at 0 °C for 5 min, and
then the mixture was stirred at room temperature for 1 h.
After removal of the solvent in vacuo, the residue was
partitioned between H2O and EtOAc. The aqueous phase was
extracted once with EtOAc, then neutralized with 20% NaOH
to pH 8, and extracted with EtOAc. The combined extracts
were washed with brine, dried over Na2SO4, and concentrated
in vacuo to give a viscous oil, which was converted into the
HCl salt with 2 N ethereal HCl. The salt was recrystallized
from 2-PrOH-iPr2O to afford 13a (428 mg, 83.4%) as a white
solid: mp 248-250 °C dec; 1H NMR (HCl salt, CDCl3 + DMSO-
d6) δ 7.55 (d, J ) 7.8 Hz, 1H), 7.40 (t, J ) 7.8 Hz, 1H), 7.34 (d,
J ) 8.4 Hz, 1H), 7.11 (d, J ) 2.1 Hz, 1H), 6.93-6.88 (m, 2H),
4.88 (t, J ) 6.6 Hz, 1H), 4.71-4.66 (dd, J ) 3.6 Hz, 8.4 Hz,
1H), 3.68 (s, 3H), 2.83-2.73 (m, 1H), 2.61 (s, 3H), 2.44-2.36
(m, 1H); CIMS (NH3) m/z 322 (M+). Anal. (C17H17Cl2NO‚HCl)
C, H, N.
The above product (1.49 g, 3.4 mmol) was dissolved in dry
DMF (20 mL). To this solution was added NaH powder (429
mg, 17 mmol) at 0 °C. The reaction mixture was stirred at
room temperature for 2.5 h, then CH3I (3 mL) was added at 0
°C. The mixture was allowed to warm to room temperature
overnight. The mixture was partitioned between H2O and
Et2O. The aqueous phase was extracted with Et2O. The
combined extracts were washed with brine, dried over Na2-
SO4, and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel (hexanes/
EtOAc 10:1f5:1) to afford 12e in 85% yield as a white foam:
1H NMR (CDCl3) δ 7.08 (d, J ) 8.7 Hz, 1H), 6.92 (d, J ) 7.8
Hz, 1H), 6.83-6.76 (m, 2H), 6.64 (m, 1H), 6.02 (brs, 1H), 4.77-
(m, 1H), 3.84 (s, 3H), 3.81(s, 3H), 2.62 (s, 3H), 2.51 (brs, 1H),
2.33-2.24 (m, 1H); CIMS (NH3) m/z 469 (M+ + 17), 452 (M+).
[3-(3,4-Dich lor op h en yl)-6-m eth oxyin d a n -1-yl]m eth yl-
a m in e (13c).15 Prepared from 12c in 86% yield by a procedure
1
similar to that described for 13a : mp 240-242 °C; H NMR
(CDCl3) δ 7.41-6.78 (m, 6H), 4.44 (t, J ) 7.2 Hz, 1H), 4.26-
4.23 (m, 1H), 3.82 (s, 3H), 3.51 (s, 3H), 2.49-2.41 (m, 1H),
2.31-2.20 (m, 1H); CIMS (NH3) m/z 322 (M+). Anal. (C17H17
Cl2NO‚HCl) C, H, N.
-
[3-(3,4-Dich lor op h en yl)-7-m eth oxyin d a n -1-yl]m eth yl-
a m in e (13d ). Prepared from 12d in 83% yield by a procedure
similar to that described for 13a : mp 190-192 °C dec; 1H NMR
(CDCl3) δ 7.38-6.70 (m, 4H), 6.75 (d, J ) 8.7 Hz, 1H), 6.53 (d,
J ) 7.8 Hz, 1H), 4.53 (t, J ) 7.8 Hz, 1H), 4.48-4.45 (m, 1H),
3.87 (s, 3H), 2.46 (s, 3H), 2.56-2.48 (m, 1H), 2.17-2.06 (m,
1H); CIMS m/z 322 (M+), 288 (M+ - 34). Anal. (C17H17Cl2NO‚
HCl) C, H, N.
[3-(3,4-Dich lor o-2-m eth oxyp h en yl)-6-m eth oxyin d a n -1-
yl]m eth yla m in e (13e). Prepared from 12e in 81% yield by a
procedure similar to that described for 13a : mp 212-214 °C;
1H NMR (CDCl3) δ 7.13 (d, J ) 8.7 Hz, 2H), 6.89-6.84 (m,
2H), 6.74 (d, J ) 7.8 Hz, 1H), 4.88 (t, J ) 8.7 Hz, 1H), 4.67
(dd, J ) 3.0, 7.8 Hz, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 2.77-2.64
(m, 1H), 2.61 (s, 3H), 2.41-2.31 (m, 1H); EIMS m/z 352 (M+),
336 (M+ - 15), 320 (M+ - 31). Anal. (C18H19Cl2NO2‚HCl‚
0.5H2O) C, H, N.
tr a n s-[3-(3,4-Dich lor op h en yl)-4-m et h oxyin d a n -1-yl]-
m eth ylca r ba m ic Acid ter t-Bu tyl Ester (12a ). Prepared
from 11a in 90% yield as a white foam by a procedure similar
to that described for 12e: 1H NMR (CDCl3) δ 7.30 (d, J ) 7.8
Hz, 1H), 7.14 (s, 1H), 6.88-6.74 (m, 4H), 6.07 (brs, 1H), 4.52
(d, J ) 7.8 Hz, 1H), 3.69 (s, 3H), 2.59 (s, 3H) 2.49-2.41 (m,
1H), 2.28 (m, 1H). 1.50 (s, 9H); CIMS (NH3) m/z 439 (M+
17), 422 (M+), 405 (M+ - 15), 383 (M+ - 39), 291 (100).
+
tr a n s-[3-(3,4-Dich lor op h en yl)-5-m et h oxyin d a n -1-yl]-
m eth ylca r ba m ic Acid ter t-Bu tyl Ester (12b). Prepared
from 11b in 87% yield as a pale-yellow syrup by a procedure
[3-(3,4-Dich lor op h en yl)-5-m eth oxyin d a n -1-yl]m eth yl-
a m in e (13b). A mixture of 12b (1.69 g, 4 mmol) and anhy-
drous ZnBr2 (1.81 g, 8 mmol) in dry CH2Cl2 (20 mL) was stirred
at room temperature under Ar for 5 h. After evaporation of
the solvent in vacuo, the residual syrup was purified by column
chromatography on silica gel (hexanes/EtOAc 10:1-5:1, fol-
lowed by CH2Cl2/MeOH 10:1) to yield a pale-yellow oil, which
was converted into the HCl salt by treatment with ethereal
HCl. The salt was recrystallized from 2-PrOH-iPr2O to afford
1
similar to that described for 12e: H NMR (CDCl3) δ 7.34 (d,
J ) 8.7 Hz, 1H), 7.16 (d, J ) 7.8 Hz, 2H), 6.93-6.83 (m, 2H),
6.52 (s, 1H), 4.45-4.40 (m, 1H), 3.74 (s, 3H), 2.57 (s, 3H), 2.48-
2.43 (m, 1H), 2.36-2.27 (m, 1H), 1.50 (s, 9H); CIMS (NH3) m/z
439 (M+ + 17), 422 (M+), 405 (M+ - 15), 383 (M+ - 39), 291
(100).
tr a n s-[3-(3,4-Dich lor op h en yl)-6-m et h oxyin d a n -1-yl]-
m eth ylca r ba m ic Acid ter t-Bu tyl Ester (12c). Prepared
from 11c in 93% yield as a white foam by a procedure similar
1
13b (1.31 g, 92%) as a pale-yellow solid: mp 193-195 °C; H
1
to that described for 12e: H NMR (CDCl3) δ 7.26 (d, J ) 8.7
NMR (CDCl3) δ 7.56 (d, J ) 8.4 Hz, 1H), 7.41 (d, J ) 8.1 Hz,
1H), 7.27 (d, J ) 2.1 Hz, 1H), 7.05 (dd, J ) 1.8, 8.1 Hz, 1H),
6.93 (dd, J ) 2.1, 8.4 Hz, 1H), 6.51 (d, J ) 1.8 Hz, 1H), 4.87
(d, J ) 7.2 Hz, 1H), 4.70 (t, J ) 8.1 Hz, 1H), 3.73 (s, 3H), 2.97-
2.90 (m, 1H), 2.78 (s, 3H), 2.51-2.40 (m, 1H); CIMS (NH3) m/z
322 (M+). Anal. (C17H17Cl2NO‚HCl) C, H, N.
Hz, 1H), 7.15 (d, J ) 7.8 Hz, 2H), 6.92-6.81 (m, 2H), 6.53 (s,
1H), 4.43-4.41 (m, 1H), 3.72 (s, 3H), 2.58 (s, 3H), 2.50-2.42
(m, 1H), 2.37-2.24 (m, 1H), 1.49 (s, 9H); CIMS (NH3) m/z 439
(M+ + 17), 291 (100).
tr a n s-[3-(3,4-Dich lor op h en yl)-7-m et h oxyin d a n -1-yl]-
m eth ylca r ba m ic Acid ter t-bu tyl Ester (12d ). Prepared
from 11d in 86% yield as a white foam by a procedure similar
[3-(3,4-Dich lor op h en yl)-5,6-d im et h oxyin d a n -1-yl]m e-
th yla m in e (13f). Prepared from 12f in 88% yield by a
procedure similar to that described for 13b: mp 220-222 °C
1
to that described for 12e: H NMR (CDCl3) δ 7.08 (d, J ) 8.7
1
Hz, 1H), 6.92 (d, J ) 7.8 Hz, 1H), 6.83-6.76 (m, 2H), 6.64 (m,
1H), 6.02 (brs, 1H), 4.77 (m, 1H), 3.84 (s, 3H), 3.81 (s, 3H),
2.62 (s, 3H, NCH3), 2.51 (brs, 1H), 2.33-2.24 (m, 1H), 1.41 (s,
9H); CIMS (NH3) m/z 469 (M+ + NH4), 452 (M+).
dec; H NMR (CDCl3) δ 7.88 (d, J ) 8.7 Hz, 1H), 7.74 (d, J )
2.1 Hz, 1H), 7.65 (s, 1H), 7.51-7.48 (dd, J ) 2.1, 8.7 Hz, 1H),
6.98 (s, 1H), 5.05 (t, J ) 7.8 Hz, 1H), 4.30 (s, 3H), 4.12 (s, 3H),
3.71 (m, 1H), 3.23-3.18 (m, 1H), 3.15 (s, 3H), 2.92-2.84 (m,

Methoxy Derivatives of Indatraline
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25 4875
1H); CIMS (NH3) m/z 352 (MH+), 321 (M+ - 31). Anal. (C18H19
Cl2NO2‚HCl‚0.25H2O) C, H, N.
-
°C dec; 1H NMR (CDCl3) δ 7.39 (d, J ) 8.7 Hz, 1H), 7.18 (d, J
) 1.8 Hz, 1H), 7.00-6.93 (m, 3H), 6.87-6.83 (dd, J ) 1.8 Hz,
7.8 Hz, 1H), 4.53 (d, J ) 6.9 Hz, 1H), 4.44 (pseudo t, J ) 4.8
Hz, 6.9 Hz, 1H), 4.01 (d, J ) 4.8 Hz, 1H). 3.84 (s, 3H), 2.61 (s,
3H); NOE cross-peaks (DMSO) δ 4.5 (NMeCH, cross-peak with
δ 3.3 (water), 3 cross-peaks with aromatic protons δ 6.9-7.2),
4.65 (Ar + indano CH, cross-peak with CHOH), 4.8 (CHOH,
cross-peaks with Ar + indano CH and water); CIMS m/z 339
(MH+). Anal. (C17H17Cl2NO2‚HCl) C, H, N.
2-Acet oxy-3-(3,4-d ich lor op h en yl)-6-m et h oxyin d a n -3-
on e (14). A mixture of Mn(OAc)3‚2H2O (22 g, 80 mmol) and
AcOH (14.4 g, 240 mmol) in 300 mL benzene was refluxed for
1 h. Solid 7a (6.2 g, 20 mmol) was added, and the resulting
mixture was refluxed overnight. After cooling to room tem-
perature, the mixture was diluted with EtOAc and washed
successively with 1 N HCl, saturated NaHCO3 and brine. The
organic phase was dried over Na2SO4, and concentrated in
vacuo to give 10.5 g of a red oil. The oil was purified by flash
chromatography on silica gel (petroleum ether/EtOAc 6:1f4:
1) to afford 14 (4.75 g, 65%) as a red syrup: 1H NMR (CDCl3)
δ 7.45-7.03 (m, 6H), 5.34 (d, J ) 5.1 Hz, 1H), 4.37(d, J ) 1.2
Sin gle-Cr ysta l X-r a y An a lysis of 3-(3,4-Dich lor op h e-
n yl)-5-m eth oxyin d a n -1-on e (5b) a n d tr a n s-1-Azid o-3-(3,4-
d ich lor op h en yl)-5-m et h oxyin d a n (11b ). 3-(3,4-Dich lo-
r op h en yl)-5-m eth oxyin d a n -1-on e (5b): C16H12O2Cl2, fw )
307.16, monoclinic space group P21/c; a ) 8.444(2), b ) 6.578-
(1), c ) 26.081(4) Å; â ) 98.74(1)°; V ) 1431.7(4) Å3, Z ) 4,
Hz, 1H), 3.88 (s, 3H), 2.19 (s, 3H); CIMS (NH3) m/z 382 (M+
17, 100), 365 (M+, 10), 324 (M+ - 41, 100).
+
F
calc ) 1.425 mg mm-3; λ(Cu KR) ) 1.54178 Å, µ ) 4.06 mm-1
,
1-(3,4-Dich lor op h en yl)-5-m eth oxy-1H-in d en e (15). A
solution of 10c (309 mg, 1 mmol) and p-toluenesulfonic acid
(80 mg) in anhydrous benzene was refluxed for 30 min. The
reaction mixture was washed twice with H2O. The combined
aqueous phases were extracted with Et2O. The combined
organic phases were dried over Na2SO4 and concentrated in
vacuo to afford 15 (310 mg, 100%) as a colorless oil, which was
immediately used in the next reaction: 1H NMR (CDCl3) δ
7.31 (d, J ) 8.7 Hz, 1H), 7.17 (d, J ) 2.1 Hz, 1H), 7.09 (d, J )
8.7 Hz, 1H), 6.96-6.85 (m, 3H), 6.74-6.70 (dd, J ) 2.1 Hz,
7.8 Hz, 1H), 6.54-6.51 (dd, J ) 2.1 Hz, 6.0 Hz, 1H). 4.49 (s,
1H), 3.83 (s, 3H); EIMS m/z 291 (M+).
2-Br om o-3-(3,4-d ich lor op h en yl)-6-m eth oxyin d a n -1-ol
(16a ). The indene 15 (1.07 g, 3.67 mmol) was dissolved in 50%
(v:v) aqueous THF (50 mL), and NBS (382 mg, 2.14 mmol) was
added to the above solution at 0 °C. The resulting reaction
mixture was stirred at room temperature under an atmosphere
of nitrogen for 3 h. Additional NBS (240 mg, 1.35 mmol) was
added to the mixture, and the mixture was stirred at room
temperature overnight. After dilution with EtOAc, the reaction
mixture was washed with water, 5% aqueous NaHCO3 and
brine. The organic phase was dried over Na2SO4 and concen-
trated in vacuo to give a brown oil, which was purified by flash
chromatography on silica gel (hexanes/EtOAc 10:1f5:1).
Compound 16a (the least polar component) (200 mg, 14%) was
obtained as a white solid along with dibrominated compound
16b (the more polar component) (615 mg, 36%) as a white
foam. 16a : 1H NMR (CDCl3) δ 7.45 (d, J ) 7.8 Hz, 1H), 7.35
(d, J ) 1.8 Hz, 1H), 7.12-7.08 (dd, J ) 1.8 Hz, 7.8 Hz, 1H),
7.01 (d, J ) 2.1 Hz, 1H), 6.88-6.84 (dd, J ) 2.1 Hz, 8.7 Hz,
1H), 6.79 (d, J ) 8.7 Hz, 1H), 5.32 (d, J ) 7.8 Hz, 1H), 4.25 (d,
J ) 8.7 Hz, 1H), 3.96 (t, J ) 8.7 Hz, 1H), 3.84 (s, 3H), 2.31
(brs, 1H); 13C NMR (CDCl3) δ 160.59, 143.35, 140.86, 133.33,
132.12, 131.08, 130.84, 128.35, 125.68, 116.33, 108.26, 81.78,
63.75, 55.86, 55.74; EIMS m/z 388 (M+, 70), 307 (M+ - Br,
100). 16b: 1H NMR (CDCl3) δ 7.36 (d, J ) 8.7 Hz, 1H), 7.09-
7.03 (m, 2H), 6.93-6.83 (m, 2H), 5.35 (d, J ) 7.8 Hz, 1H), 4.59
(d, J ) 8.7 Hz, 1H), 4.22 (t, J ) 8.7 Hz, 1H), 3.86 (s, 3H), 2.34
(brs, 1H); EIMS m/z 466 (M+, 35), 388 (M+ - Br, 90), 307 (M+
- 2Br, 100).
F(000) ) 632, T ) 295 K.
t r a n s-1-Azid o-3-(3,4-Dich lor op h e n yl)-5-m e t h oxyin -
d a n (11b): C16H13N3OCl2, fw ) 334.19, triclinic space group
P1; a ) 7.582(1), b ) 9.940(1), c ) 11.284(2) Å; R ) 103.49(2),
â ) 106.38(2), γ ) 95.22(2)°; V ) 782.0(2) Å3, Z ) 2, Fcalc
)
1.419 mg mm-3; λ(Cu KR) ) 1.54178 Å, µ ) 3.772 mm-1, F(000)
) 344, T ) 295 K. The following parameters are common to
5b and 11b and where different they are indicated by
enclosure in brackets [ ] for [11b].
A clear colorless 0.54 × 0.52 × 0.15 [0.35 × 0.25 × 0.06]
mm crystal was used for data collection on an automated
Bruker P4 diffractometer equipped with an incident beam
monochromator. Lattice parameters were determined from 30
[35] centered reflections within 11° < 2θ < 65° [10° < 2θ <
73°]. The data collection range had a {(sin θ)/λ}max ) 0.55.
Three standards, monitored after every 97 reflections, exhib-
ited random variations with deviations up to (1.9 [2.5]%
during the data collection. A set of 3276 [2663] reflections was
collected in the θ/2θ scan mode and ω scan rate (a function of
count rate) from 7.5 to 30.0°/min. There were 1964 [2133]
unique reflections. Corrections were applied for Lorentz,
polarization, and absorption effects. The structure was solved
with SHELXTL35 and refined with the aid of the SHELX97
system of programs. The full-matrix least-squares refinement
on F2 varied 232 [199] parameters: atom coordinates and
anisotropic thermal parameters for all non-H atoms. H atoms
were included using a riding model [coordinate shifts of C
applied to attached H atoms, C-H distances set to 0.96-0.93
Å, H angles idealized, Uiso(H) were set to 1.2-1.5Ueq(C)]. Final
residuals were R1 ) 0.049 [0.055] for the 1764 [1763] observed
data with Fo >4σ(Fo) and 0.054 [0.065] for all data. Final
difference Fourier excursions of 0.31 and -0.21 [0.29 and
-0.45] eÅ-3
.
In 5b the dichlorophenyl group is disordered such that the
atoms may be located on an alternate position with occupan-
cies of 0.57 and 0.43 for the major and minor positions. Tables
of coordinates, bond distances and angles, and anisotropic
thermal parameters have been deposited with the Crystal-
lographic Data Centre, Cambridge CB2 1EW, England.
1-(3,4-Dich lor oph en yl)-5-m eth oxy-3-m eth ylam in oin dan -
2-ol (17). A mixture of 16a ,b (1:2.57, respectively, 1.2 g) was
dissolved in EtOH (40 mL), and 40% aqueous methylamine
(40 mL) was added. The resulting solution was refluxed for 4
h. The volatiles were removed under reduced pressure, and
the residue was partitioned between Et2O and H2O. The
aqueous phase was extracted with Et2O. The combined organic
phases were washed with brine, dried over Na2SO4, and
concentrated in vacuo. The residue was filtered through a short
silica gel column to afford 550 mg of a yellow oil, which was
taken up in MeOH (20 mL). 5% Pd/C (65 mg) and NaOAc‚
3H2O (330 mg, 2.4 mmol) were added to the above solution
and the reaction mixture was shaken in a Parr hydrogenation
apparatus at 35 psi for 25 min. After filtration off the catalyst,
the filtrate was concentrated in vacuo. The residue was
converted into the HCl salt by treatment with HCl-MeOH.
The salt was recrystallized from 2-PrOH-iPr2O to afford 17
as a white solid (238 mg, 23.3% overall yield): mp 268-270
Ack n ow led gm en t. We thank Dr. Noel Whittaker
and Dr. Wesley White for mass spectral analyses and
Drs. Timothy Caldwell and Herman Yeh (all from
NIDDK, NIH) for their aid with the interpretation of
the NOE data. We also thank the National Institute on
Drug Abuse (NIDA) for partial support of this research.
The X-ray crystallographic work was supported in part
by NIDA and the Office of Naval Research.
Su p p or tin g In for m a tion Ava ila ble: Crystal data and
structure refinement, atomic coordinates, bond lengths and
angles, anisotropic displacement parameters, hydrogen coor-
dinates and isotropic displacement parameters, and torsion
angles of 5b and 11b. This material is available free of charge
via the Internet at http://pubs.acs.org.

4876 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 25
Gu et al.
(19) Yu, H.; Rothman, R. R.; Dersch, C. M.; Partilla, J . S.; J acobson,
A. E.; Rice, K. C. Unpublished results.
Refer en ces
(1) Topp, L.; Hando, J .; Dillon, P.; Roche, A.; Solowij, N. Ecstasy
use in Australia: patterns of use and associated harm. Drug
Alcohol Dependence 1999, 55, 105-115.
(2) Crome, H. B. Treatment interventions - looking towards the
millennium. Drug Alcohol Dependence 1999, 55, 247-263.
(3) Yui, K.; Goto, K.; Ikemoto, S.; Ishiguro, T. Stress induced
spontaneous recurrence of methamphetamine psychosis: the
relation between stressful experiences and sensitivity to stress.
Drug Alcohol Dependence 2000, 58, 67-75.
(4) Hoffman, J . A.; Klein, H.; Eber, M.; Crosby, H. Frequency and
intensity of crack use as predictors of women’s involvement in
HIV-related sexual risk behaviors. Drug Alcohol Dependence
2000, 58, 227-236.
(5) Sorensen, J . L.; Copeland, A. L. Drug abuse treatment as an
HIV prevention strategy: a review. Drug Alcohol Dependence
2000, 59, 17-31.
(6) Rothman, R. B.; Partilla, J . S.; Bauman, M. H.; Dersch, C. M.;
Carroll, F. I.; Rice, K. C. Neurochemical neutralization of
methamphetamine with high-affinity nonselective inhibitors of
biogenic amine transporters: a pharmacological strategy for
treating stimulant abuse. Synapse 2000, 35, 222-227.
(7) Baumann, M. H.; Char, G. U.; deCosta, B. R.; Rice, K. C.;
Rothman, R. B. GBR12909 attenuates cocaine-induced activation
of mesolimbic dopamine neurons in the rat. J . Pharmacol. Exp.
Ther. 1994, 271, 1216-1222.
(20) Thompson, A. S.; Humphrey, G. R.; DeMarco, A. M.; Mathre, D.
J .; Grabowski, E. J . J . Direct conversion of activated alcohols to
azides using diphenyl phosphorazidate. A practical alternative
to Mitsunobu reaction. J . Org. Chem. 1993, 58, 5886-5888.
(21) Lautens, M.; Rovis, T. Selective functionalization of 1,2-dihy-
dronaphthalenols leads to a concise, stereoselective synthesis
of setraline. Tetrahedron 1999, 55, 8967-8976.
(22) Saito, S.; Nakajima, H.; Inaba, M.; Moriwake, T. One-pot
transformation of azido-group to N-(t-butoxycarbonyl)amino
group. Tetrahedron Lett. 1989, 30, 837-838.
(23) Snider, B. B.; Lin, H. Total synthesis of (-)-FR901483. J . Am.
Chem. Soc. 1999, 121, 7778-7786.
(24) Cavelier, F.; Enjalbal, C. Studies of selective Boc removal in the
presence of silyl ethers. Tetrahedron Lett. 1996, 37, 5131-5134.
(25) Nigam, S. C.; Mann, A.; Taddei, M.; Wermuth, G. Selective
removal of the tert-butoxycarbonyl group from secondary
amines: ZnBr2 as the deprotecting agent. Synth. Commun. 1989,
19, 3139-3142.
(26) Demir, A. S.; Camkerten, N.; Akgun, H.; Taneyli, C.; Mahasneh,
A. S.; Watt, D. S. Oxidation of aryl alkyl ketones to R-acyloxy,
R-(camphorsulfonyloxy), or R-hydroxy derivatives using manga-
nese(III) acetate in combination with carboxylic acids or (1S)-
(+)-10-camphorsulfonic acid. Synth. Commun. 1990, 20, 2279-
2289.
(8) Villemagne, V.; Rothman, R. B.; Yokoi, F.; Rice, K. C.; Matecka,
D.; Clough, D. J .; Dannals, R. F.; Wong, D. F. Doses of GBR
12909 which suppress cocaine self-administration in non-human
primates substantially occupy DA transporters as measured by
(27) Nguy, N. M.; Chiu, I. C.; Kohn, H. Synthesis and reactivity of
6- and 7-methoxyindano[1,2-b]aziridines. J . Org. Chem. 1987,
52, 1649-1655.
[
11C]WIN35,428 PET scans. Synapse 1999, 32, 44-50.
(28) Winter, J . C.; Godse, D. D.; Gessner, P. K. Synthesis of 5- and
6-methoxyindene. J . Org. Chem. 1965, 30, 3231-3233.
(29) Takahashi, M.; Ogasawara, K. Lipase-mediated resolution of
trans-1-azidoindan-2-ols: a new route to optically pure cis-1-
aminoindan-2-ol. Synthesis 1996, 954-958.
(30) Heier, R. F.; Dolak, L. A.; Duncan, J . N.; Hyslop, D. K.; Lipton,
M. F.; Martin, I. J .; Mauragis, M. A.; Piercey, M. F.; Nichols, N.
F.; Schreur, P. J . K. D.; Smith, M. W.; Moon, M. W. Synthesis
and biological activities of (R)-5,6-dihydro-N,N-dimethyl-4H-
imidazo[4,5,1-ij]quinolin-5-amine and its metabolites. J . Med.
Chem. 1997, 40, 639-646.
(9) Munzar, P.; Baumann, M. H.; Shoaib, M.; Goldberg, S. R. Effects
of dopamine and serotonin-releasing agents on methamphet-
amine discrimination and self-administration in rats. Psychop-
harmacology 1999, 141.
(10) Munzar, P.; Laufert, M. D.; Kutkat, S. W.; Novakova, J .;
Goldberg, S. R. Effects of various serotonin agonists, antagonists,
and uptake inhibitors on the discriminative stimulus effects of
methamphetamine in rats. J . Pharmacol. Exp. Ther. 1999, 291,
239-250.
(11) Munzar, P.; Goldberg, S. R. Noradrenergic modulation of the
discriminative-stimulus effects of methamphetamine in rats.
Psychopharmacology 1999, 143, 293-301.
(12) Kuczenski, R.; Segal, D. S.; Cho, A. K.; Melega, W. Hippocampus
norepinephrine, caudate dopamine and serotonin, and behavioral
responses to the stereoisomers of amphetamine and metham-
phetamine. J . Neurosci. 1995, 15, 1308-1317.
(13) Glowa, J . R.; Fantegrossi, W. E.; Lewis, D. B.; Matecka, D.; Rice,
K. C.; Rothman, R. B. Sustained Decrease in Cocaine-Main-
tained Responding in Rhesus Monkeys with 1[2-[Bis(4-fluo-
rophenyl)methoxy]ethyl]-4-(3-hydroxyl-3-phenylpropyl)piperazi-
nyl Decanoate, a Long-Acting Ester Derivative of GBR 12909.
J . Med. Chem. 1996, 39, 4689-4691.
(14) Hyttel, J .; Larsen, J . J . Neurochemical profile of Lu 19-005, a
potent inhibitor of uptake of dopamine, noradrenaline, and
serotonin. J . Neurochem. 1985, 44, 1615-1622.
(15) Bøgesø, K. P.; Christensen, A. V.; Hyttel, J .; Liljefors, T.
3-Phenyl-1-indanamines. Potential antidepressant activity and
potent inhibition of dopamine. Norepinephrine, and serotonin
uptake. J . Med. Chem. 1985, 28, 1817-1828.
(16) Negus, S. S.; Brandt, M. R.; Mello, N. K. Effects of the long-
acting monamine reuptake inhibitor indatraline on cocaine self-
administration in rhesus monkeys. J . Pharmacol. Exp. Ther.
1999, 291, 60-69.
(31) Rothman, R. B.; Cadet, J . L.; Akunne, H. C.; Silverthorn, M. L.;
Baumann, M. H.; Carroll, F. I.; Goodman, C. B.; Rice, K. C.; de
Costa, B. R.; Partilla, J . S.; Wang, J .-B.; Uhl, G. R.; Glowa, J .
R.; Dersch, C. M. Studies of the biogenic amine transporters.
IV. Demonstration of a multiplicity of binding sites in rat
caudate membranes for the cocaine analogue [125I]RTI-55. J .
Pharmacol. Exp. Ther. 1994, 270, 296-309.
(32) Lewis, D. B.; Matecka, D.; Zhang, Y.; Hsin, L. W.; Dersch, C.
M.; Stafford, D.; Glowa, J . R.; Rothman, R. B.; Rice, K. C.
Oxygenated analogues of 1-[2-(diphenylmethoxy)ethyl]- and 1-[2-
[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)pipera-
zines (GBR 12935 and GBR 12909) as potential extended-action
cocaine-abuse therapeutic agents. J . Med. Chem. 1999, 42,
5029-5042.
(33) Bøgesø, K. P. Neuroleptic Activity and Dopamine-Uptake Inhibi-
tion in 1-Piperazine-3-phenylindans. J . Med. Chem. 1983, 26,
935-947.
(34) Maier, L.; Diel, P. J . Organic Phosphorus Compounds. 94.
Preparation, Physical and Biological Properties of Aminoaryl-
methylphosphonic and -Phosphonous Acids. Phosphorus, Sulfur,
Silicon Relat. Elem. 1991, 57, 57-64.
(17) McDonald, E.; Smith, P. Electrocyclic reactions of protonated
chalcones; synthesis of 3-aryl-indan-1-ones. J . Chem. Soc., Perkin
Trans. I 1980, 837-842.
(18) J ung, M. E.; Lazarova, T. I. New efficient method for the total
synthesis of (S,S)-isodityrosine from natural amino acids. J . Org.
Chem. 1999, 64, 2976-2977.
(35) Sheldrick, G. M. SHELXTL, version 5.1; Bruker Analytical X-ray
Instruments: Madison, WI, 1997.
J M000329V