Modified ibogaine fragments: Synthesis and preliminary pharmacological characterization of 3-ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5- b]benzothiophenes

Article abstract of DOI:10.1021/jm980156y

Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6- hexahydroazepino[4,5-b]indole, 5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors. All five derivatives, 9 and 17a-d, displayed 8-10-fold higher affinity at the DA transporter than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a) exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the lead compound. In keeping with their structural similarity to ibogaine, all five compounds displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds, 17a,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds displayed weak to poor affinities for μ and κ opioid receptors and for the NMDA receptor-coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5 may serve as useful substitutes for ibogaine.

Full text of DOI:10.1021/jm980156y

4486
J . Med. Chem. 1998, 41, 4486-4491
Mod ified Iboga in e F r a gm en ts:
Syn th esis a n d P r elim in a r y P h a r m a cologica l Ch a r a cter iza tion of
3-Eth yl-5-p h en yl-1,2,3,4,5,6-h exa h yd r oa zep in o[4,5-b]ben zoth iop h en es
Simon M. N. Efange,*,† Deborah C. Mash,‡ Anil B. Khare,† and Quinjie Ouyang‡
Departments of Radiology, Medicinal Chemistry, and Neurosurgery, Graduate Program in Neuroscience, University of
Minnesota, Minneapolis, Minnesota 55455, and Departments of Neurology and Molecular & Cellular Pharmacology,
University of Miami School of Medicine, Miami, Florida 33136
Received March 13, 1998
Five phenyl-substituted derivatives and analogues of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,
5, a major fragment of ibogaine (1), were synthesized and tested for binding to monoamine
transporters, the NMDA receptor-coupled cation channel, and dopamine and opioid receptors.
All five derivatives, 9 and 17a -d , displayed 8-10-fold higher affinity at the DA transporter
than ibogaine and noribogaine (4). At the serotonin transporter, two compounds (9 and 17a )
exhibited higher potency than ibogaine, while the rest had weaker binding affinities than the
lead compound. In keeping with their structural similarity to ibogaine, all five compounds
displayed weak to poor affinity for dopamine D1 and D2 receptors. However, two compounds,
17a ,c, demonstrated moderate binding affinities at dopamine D3 receptors. All five compounds
displayed weak to poor affinities for µ and κ opioid receptors and for the NMDA receptor-
coupled cation channel. Despite the qualitative differences, derivatives and analogues of 5
may serve as useful substitutes for ibogaine.
Ch a r t 1
In tr od u ction
Ibogaine (Chart 1, 1) is the major constituent of the
root of Tabernanthe iboga, a naturally occurring shrub
commonly found in West and Central Africa.1,2 In
African folk medicine, large quantities of this root were
consumed for initiation rites. In lower quantities, this
compound was used to combat fatigue during periods
of great physical exertion (reviewed in refs 3 and 4).
Pharmacological evaluation of this agent in laboratory
animals revealed unusual excitatory effects and local
anesthetic activity and confirmed its psychostimulant
activity.3
In humans, administration of ibogaine is followed by
a period of visualizations (lasting several hours), fol-
lowed by a longer cognitive phase of intense introspec-
tion. At the end of this period, some opiate and
psychostimulant addicts report alleviation or cessation
of craving, and a few have remained drug-free for
several years thereafter.5-9 Although these earlier
reports were anecdotal, methods for the treatment of
opiate and cocaine dependence with ibogaine were
patented by Lotsoff in 19855 and 1986,6 respectively.
Subsequent investigation of the antiaddictive activities
of 1 in animals (vide infra) has prompted the initiation
of limited human trials (IND 39,680).
Similarly, ibogaine reduces cocaine intake in mice,17
cocaine self-administration in rats,11,18 and cocaine-
induced locomotor activity in mice19 and rats.12 Ibogaine
has also been reported to attenuate alcohol intake by
alcohol-preferring rats.20 The compound may also re-
duce the rewarding effects of nicotine.21,22
In view of the exciting possibilities presented by this
alkaloid, we initiated a program to develop structurally
simple analogues of ibogaine for evaluation as potential
antiaddictive agents. This manuscript describes the
synthesis and preliminary biological characterization of
the first class of analogues produced by this effort.
In rats, ibogaine reduces intravenous morphine self-
administration10,11 and decreases morphine-induced lo-
comotor activity.12,13 In addition, ibogaine was found
to alleviate withdrawal in morphine-dependent rats.14-16
Ch em istr y
* Address inquiries to S. M. N. Efange, Department of Radiology,
Mayo Box 382, UMHC, 420 Delaware St. S.E., Minneapolis, MN 55455.
Tel: (612) 626-6646. Fax: (612) 624-8495. E-mail: efang001@
maroon.tc.umn.edu.
The target compounds were synthesized as outlined
in Scheme 1. Briefly, chloromethylation of benzo-
thiophene provided 11 in 91% yield. Reaction of 11 with
sodium cyanide followed by reduction of the product 12
† University of Minnesota.
‡ University of Florida.
10.1021/jm980156y CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/30/1998

Modified Ibogaine Fragments
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4487
Sch em e 1a
conditioned avoidance, and induce hypothermia and
anorexigenic behavior in rodents.24 However, the com-
pound was devoid of neuroleptic activity when tested
in humans.25 Following the initial success of SCH12679
(7) in the treatment of aggressive mental retardation,26-28
Elliott et al.29 developed the corresponding 5-phenyl-
1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles in an effort
to increase the selectivity of this class of fused tricyclic
azepines. In mice, these compounds failed to exhibit
neuroleptic activity. However, two analogues, 3-methyl-
5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (9)
and 9-methoxy-3-methyl-5-phenyl-1,2,3,4,5,6-hexahy-
droazepino[4,5-b]indole (10), displayed antidepressant
activity.
Although the molecular mechanisms underlying the
antiaddictive activity of 1 are not known, the compound
displays moderate to high affinity for dopamine and
serotonin (5-HT) transporters,30 κ31-33 and µ opioid34
receptors, the MK-801 site on the NMDA receptor,33,35-40
σ-2 receptors,38,41-43 nicotine receptors,44,45 and voltage-
dependent Na+, K+, and Ca2+ channels.31 In the present
exploratory study, we compared the in vitro binding
profiles of 1 and its principal metabolite noribogaine (4)
with those of the previously described 9 and the isosteric
benzothiophenes 17a -d . Compound 9 was chosen over
5 for the same reasons cited by Elliott et al.23sthe
expectation that the phenyl group would restrict the
number of potential interaction sites. The benzo-
thiophenes were included to test the effects of isosteric
replacement. A summary of the radioligand binding
studies performed is presented in Table 1, and the
results of the assays are shown in Table 2. Inclusion
of literature values for SCH12679 (7) and SCH23390
(8) in Table 2 was prompted by the realization that the
6-5-7 fused azepines can be regarded as linearly
extended 3H-benzazepines. Linearly extended systems
such as lin-benzoguanosine have been used previously
to probe the dimensions of a given binding site.46 For
the purpose of this discussion, binding affinities are
defined as high (IC50 < 0.1 µM), moderate (IC50 ) 0.1-1
µM), weak (IC50 ) 1-10 µM), or poor (IC50 > 10 µM).
a
(a) CH2O (aq), HCl (g), concd HCl; (b) KCN, PTC, H2O, 90-
95 °C; (c) LiAlH4, ether, AlCl3, reflux; (d) Ac2O, Et3N; (e) BH3‚THF,
reflux; (f) styrene oxide, EtOH, reflux; (g) CF3CO2H, concd H2SO4
(cat.).
with LiAlH4 provided 13 in 20% yield from 11. Alter-
natively, commercially available 12 was reduced to 13
under similar conditions. Compound 13 was reacted
with acetic anhydride, and the resulting amide 14 was
reduced with BH3‚THF to provide the key intermediate
15 in 61% overall yield from benzothiophene. Typically,
the reaction of 15 with the styrene oxides produced 16
and a minor product resulting from the attack of the
amine at the more hindered carbon. The two were
easily separated by HPLC to provide 16 in yields of 30-
50%. Subsequent cyclization of the amino alcohols
16a -d proceeded smoothly to give the desired products
17a -d in yields of 46-58%. Typically, the cyclization
of the amino alcohols 16a -d was associated with a δ
0.1 upfield shift in the benzylic methine proton NMR
signal.
All five tricyclic compounds, 9 and 17a -d , displayed
comparable affinity for the dopamine transporter (DAT),
suggesting (1) that benzothiophene and indole are
bioisosteric at this site and (2) that a range of substit-
uents can be tolerated on the pendant phenyl group.
When compared to ibogaine and its metabolite, these
tricyclic analogues displayed 8-15-fold higher affinity
for the DAT. Since these tricyclic compounds are more
planar than ibogaine, it would be reasonable to conclude
that the cagelike isoquinuclidinyl fragment limits the
extent of interaction between ibogaine and the DAT.
Alternatively, the higher affinity of the tricyclic com-
pounds (relative to ibogaine and noribogaine) may result
from the interaction of the pendant phenyl group with
a hydrophobic pocket. In that case, the lower affinity
of ibogaine at the DAT may derive not from its cagelike
structure but from its inability to benefit from this
additional interaction.
Resu lts a n d Discu ssion
Despite its apparent complexity, the skeleton of
ibogaine can be broken down into a number of easily
identifiable fragments. Two of the most obvious ones
are tryptaminyl and isoquinuclidinyl. Previously, tro-
pan-3-ylindoles, synthesized as abbreviated ibogaine
analogues, have been found to display comparable or
slightly higher affinity for a number of molecular targets
other than ibogaine.23 However, for the current study
we chose a third fragment represented by 1,2,3,4,5,6-
hexahydroazepino[4,5-b]indole (5). This fragment was
chosen because it contains the tryptaminyl fragment
and a portion of the isoquinuclidinyl fragment and is
thus intermediate in structure between ibogaine and
these two principal components. A review of the
literature showed that 5 and its derivatives had been
developed as conformationally restricted tryptamine
analogues.24 In rats, some derivatives of 5 were found
to elicit many of the symptoms associated with trypta-
mine. One of these compounds, 6-methyl-1,2,3,4,5,6-
hexahydroazepino[4,5-b]indole (6, U-22,394A), was found
to antagonize aggressive behavior in fighting mice, block
In contrast to the DAT, the serotonin transporter
(SERT) was more discriminating. Among the tricyclic
compounds, 9 displayed the highest affinity for the
SERT. Moreover, only this compound displayed com-
parable affinity for both DAT and SERT. Compound

4488 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Efange et al.
Ta ble 1. Radioligand Binding Assays for Modified Ibogaine Fragments
binding site
radioligand
nonspecific
tissue
striatum
striatum
striatum
ref
Dopaminergic
D1 receptor
D2 receptor
[3H]SCH23390
(+)-butaclamol
(+)-butaclamol
(+)-butaclamol
(+)-butaclamol
(-)-cocaine
48
49
41
50
51
[3H]YM-09151-2
[3H]haloperidol
[3H]-(+)-7-OH-DPAT
D3 receptor
DA transporter
ventral striatum
striatum
[
125I]RTI-121
Glutamatergic
NMDA receptor complex
[3H]-(+)-MK801
(+)-MK801
caudate
36
Opioidergic
κ
µ
[3H]U69593
naloxone
naloxone
insular Ctx
thalamus
52
53
[3H]DAMGO
Serotonergic
(-)-cocaine
5-HT transporter
[
125I]RTI-55
occipital Ctx
54
Ta ble 2. Relative Affinities (IC50 ( SD, µM) of 3-Ethyl-5-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]benzothiophenes and Reference
Compounds at Selected Molecular Targets
DAT
(WIN35,428)
SERT
(RTI-55)
D1
D2
D3
µ
κ
NMDA
(MK801)
target
(SCH23390) (YM-09151-2) (7-OH-DPAT)
(DAMGO)
(U69593)
9
17a
17b
17c
0.18 ( 0.005 0.19 ( 0.001
0.14 ( 0.003 0.30 ( 0.001
20 ( 1.6
3 ( 0.05
5 ( 0.05
5 ( 0.06
70 ( 0.09
>10a
27.2 ( 0.35
5.0 ( 0.07
3.5 ( 0.28
3.1 ( 0.14
5.0 ( 0.21
>10a
4.2 ( 0.02
0.6 ( 0.01
2.0 ( 0.28
0.6 ( 0.04
2.0 ( 0.14
>10a
3.1 ( 0.82
2.2 ( 0.08
5.0 ( 0.33
3.1 ( 0.57
54.5 ( 4.5
21.2 ( 2.5
1.3 ( 0.21
12.5 ( 0.07
16.2 ( 1.53
15.9 ( 1.80
ND
42 ( 1.2
46.6 ( 8
32 ( 0.30
81 ( 1.6
0.21 ( 0.02
0.25 ( 0.01
4.30 ( 0.01
1.10 ( 0.002
17d
0.25 ( 0.001 1.20 ( 0.002
ibogaine
4.11 ( 0.45a
0.59 ( 0.09a
0.04 ( 0.01a
ND
3.76 ( 0.22b 25.0 ( 0.57a 5.2 ( 0.24a
noribogaine 3.35 ( 0.50a
>10a
>10a
>10a
0.16 ( 0.01b 4.24 ( 0.28a 31.4 ( 5.43a
ND
ND
SCH23390
SCH12679
ND
ND
0.0043c
0.491d
ND
5.218
ND
ND
ND
ND
ND
ND
ND
a
b
d
Reference 32. Reference 55. c Reference 56. Reference 47. Values shown for reference compounds are Ki ( SD, µM; ND, not
determined.
17a was 2-fold weaker at the latter binding site, while
phenyl group, a more extensive study is needed to
clearly define structure-activity relationships at this
binding site.
17b,c displayed between 4- and 17-fold lower affinity
for the SERT than DAT. Since the larger discrepancy
between DAT and SERT is associated with substitution
of the pendant phenyl group, we conclude that the DAT
contains a larger hydrophobic pocket than the SERT.
While the tricyclic analogues typically displayed lower
affinity for SERT than for DAT, ibogaine, and particu-
larly noribogaine, demonstrated higher affinity for
SERT than for DAT, clearly underscoring the impor-
tance of the hydroxyl group in the interaction with
SERT.
At the dopamine D1 receptor, both ibogaine and
noribogaine displayed decidedly poor affinity. Despite
the structural similarity between the 3H-benzazepines
(such as SCH23390 and SCH12679) and the fused
tricyclic azepines (9 and 17a -d ), the latter displayed
weak to poor affinity for the D1 receptor. In previous
studies of the structurally analogous 3-benzazepines,47
C7- and C8-hydroxy groups were found to play a critical
role in the interaction with the D1 receptor. Conse-
quently, we conclude that the poor affinity of the fused
tricyclic compounds, 9 and 17a -d , may be attributed
to the absence of hydroxyl groups at the corresponding
C9- and C10-positions. This conclusion is supported by
molecular modeling studies which demonstrated that
the C7- and C8-positions of SCH23390 are eclipsed by
the benzo portion of 17a (data not shown). While
ibogaine and noribogaine also displayed poor affinity for
dopamine D1 and D2 receptors, four (17a -d ) out of five
tricyclic compounds displayed weak affinity for D2
receptors and two (17a ,c) of the four compounds clearly
exhibited moderate affinity for dopamine D3 receptors.
Although it would appear that the D3 receptor is
sensitive to single-point substitution on the pendant
At the µ opioid receptor, noribogaine was a moderately
potent ligand while ibogaine, 9, and 17a -c showed
weak to poor affinity. On the other hand, noribogaine
and 17a showed weak affinity for κ opioid receptors
while all other compounds showed poor affinity for this
site. The 20-fold disparity in the potencies of ibogaine
and its principal metabolite 1 clearly suggests that a
hydroxyl group (or suitable bioisostere thereof) is re-
quired for binding to the µ opioid receptor. Finally,
ibogaine, noribogaine, and the tricyclic azepines (9 and
17a -d ) were all relatively poor inhibitors of [3H]NMDA
binding. However, ibogaine appeared to display higher
affinity for this site than all the other compounds (Table
1).
Although the molecular mechanisms underlying the
antiaddictive activity of ibogaine remain unclear, the
present investigation clearly shows that the fused
tricyclic azepines 9 and 17a -d recognize many of the
same molecular targets as ibogaine and/or noribogaine.
Consequently, the biological actions of 9 and 17a -d
may be expected to demonstrate striking similarities
with those of ibogaine and/or noribogaine. To explore
this possibility, studies have been initiated to investi-
gate the effects of 17a -d on cocaine self-administration
in rodents. These studies will be reported at a later
date.
Exp er im en ta l Section
Gen er a l. Synthetic intermediates were purchased from
Aldrich Chemical Co., Inc. (Milwaukee, WI) and Lancaster
Synthesis (Windham, MA) and were used as received. Sol-
vents were distilled immediately before use.

Modified Ibogaine Fragments
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23 4489
Standard handling techniques for air-sensitive materials
were employed throughout this study. Preparative chroma-
tography was performed on a Harrison Research chromatotron
using Merck 60 PF254 silica gel. Analytical TLC was per-
formed on Analtech GHLF silica gel plates, and the chromato-
grams were visualized by UV and/or methanolic iodine.
Melting points were determined on a Mel-Temp melting point
apparatus and are uncorrected. 1H NMR spectra were re-
corded on an IBM Brucker spectrometer at 200 MHz. NMR
spectra are referenced to the deuterium lock frequency of the
spectrometer. Under these conditions, the chemical shifts (in
N-2-(Ben zo[b]th ien -3-yl)eth yl-N-eth yla m in e (15). Com-
pound 14 (0.85 g, 3.88 mmol) was refluxed in 1 M BH3‚THF
(20 mL) for 18 h. Upon cooling, the reaction mixture was
acidified with 2 N HCl (20 mL). The mixture was adjusted to
pH 8 with 2 M NaOH (aq) and partitioned between water and
CH2Cl2 (50 mL). The CH2Cl2 extracts were dried over Na2SO4
and concentrated under reduced pressure to yield a residue
which was refluxed in 6 N HCl for 6 h. Finally, the resulting
mixture was cooled to room temperature, made alkaline by
treatment with NaOH pellets, and extracted with CH2Cl2 (2
× 50 mL). The combined organic extracts were dried over
Na2SO4 and concentrated to provide 0.52 g (65%) of the product
as a syrup: 1H NMR (CDCl3) δ 1.09 (t, 3H, J ) 7 Hz, -CH3),
2.68 (q, 2H, J ) 7 Hz, CH3-CH2-), 3.01 (m, 2H, CH2-NH),
3.63 (t, J ) 6 Hz, 2H, CH2-CH2-NH), 6.29 (br s, 1H, NH),
7.15 (s, 1H, CH-S), 7.25-7.39 (m, 2H, phenyl), 7.75-7.88 (m,
2H, phenyl).
3-Nitr ostyr en e Oxid e. A solution of 3-nitrostyrene (1.0
g, 6.70 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath.
3-Chloroperoxybenzoic acid (57% pure) (2.23 g, 7.38 mmol) was
added in one batch, and the stirring was continued with cooling
for 2 h. The ice bath was removed, and stirring was continued
at room temperature for an additional 16 h. The reaction
mixture was concentrated to a residue and diluted with CCl4
(20 mL). Precipitated m-chlorobenzoic acid was removed by
filtration, and the filtrate was washed with a 50:50 mixture
of 5% aqueous NaHCO3 and 5% aqueous NaHSO3 (100 mL).
The organic extract was dried over Na2SO4 and concentrated
under reduced pressure to yield 0.70 g (64%) of a yellow oil:
1H NMR (CDCl3) δ 2.81 (m, 1H, CH), 3.20 (m, 1H, CH-), 3.97
(m, 1H, -CH-), 7.62 (m, 2H, phenyl), 8.16 (m, 2H, phenyl).
1
ppm) of residual solvent in the H NMR spectra are found to
be as follows: CHCl3, 7.26; DMSO, 2.56; HOD, 4.81. The
following abbreviations are used, where appropriate, to de-
scribe the peak splitting patterns: br ) broad, s, ) singlet, d
) doublet, t ) triplet, q ) quartet, m ) multiplet. Both low-
and high-resolution mass spectometry were performed on an
AEI MS-30 instrument. Elemental analyses were performed
by Atlantic Microlab, Inc., Norcross, GA.
3-(Ch lor om eth yl)ben zo[b]th iop h en e (11). HCl(g) was
bubbled vigorously through a mixture of thianaphthene (17.0
g, 126.68 mmol), 37% aqueous formaldehyde (15 mL), and
concentrated HCl (15 mL) until the reaction temperature rose
to 65 °C. At this time, the flow of HCl gas was reduced to a
slow stream which was maintained for 1.5 h. The reaction
mixture was diluted with H2O (50 mL) and subsequently
extracted with ether (2 × 50 mL). The combined ethereal
extracts were dried over Na2SO4 and concentrated under
reduced pressure to yield a straw-colored liquid: 21.0 g
(90.7%); 1H NMR (CDCl3) δ 4.90 (s, 2H, CH2-Cl), 7.25 (s, 1H,
CH-S), 7.45 (m, 2H, phenyl), 7.88 (m, 2H, phenyl).
3-Br om ostyr en e Oxid e. A solution of 3-bromostyrene (1.0
g, 5.46 mmol) in CH2Cl2 (10 mL) was cooled in an ice bath.
3-Chloroperoxybenzoic acid (57% pure) (1.82 g, 6.01 mmol) was
added in one batch, and the stirring was continued with cooling
for 2 h. The ice bath was removed, and stirring was continued
at room temperature for an additional 16 h. The reaction
mixture was concentrated to a residue and diluted with CCl4
(20 mL). Precipitated m-chlorobenzoic acid was removed by
filtration, and the filtrate was washed with a 50:50 mixture
of 5% aqueous NaHCO3 and 5% aqueous NaHSO3 (100 mL).
The organic extract was dried over Na2SO4 and concentrated
under reduced pressure to yield 0.80 g (64%) of a yellow oil:
1H NMR (CDCl3) δ 2.74 (m, 1H, CH), 3.14 (m, 1H, CH-), 3.82
(m, 1H, -CH-), 7.21 (m, 2H, phenyl), 7.42 (m, 2H, phenyl).
3′,4′-Dich lor ostyr en e Oxid e. To an ice-cooled solution of
3′,4′-dichlorostyrene (1.20 g, 6.93 mmol) in CH2Cl2 (20 mL) was
added mCPBA (57% pure) (2.31 g, 7.62 mmol) in one batch,
and stirring was continued with cooling for 2 h. The ice bath
was removed, and stirring was continued at room temperature
for an additional 16 h. The reaction mixture was diluted with
hexane (50 mL) and concentrated to 1.24 g (95%) of a clear
liquid. (Note: The material obtained was impure by TLC but
was used without any further purification.)
P r oced u r e A: Syn t h esis of Am in o Alcoh ols 16a -d .
N-[2-(Ben zoth ien -3-yl)eth yl]-N-eth yl-N-(2-h ydr oxy-2-ph en -
yl)eth yla m in e (16a ). A mixture of compound 15 (0.50 g, 2.44
mmol) and styrene oxide (0.32 g, 2.93 mmol) was refluxed in
EtOH (5 mL) for 3 h. The reaction mixture was concentrated
under reduced pressure and the crude product was purified
by radial flow chromatography [hexane (90)-acetone (10):Et3N
(1)] to yield 0.32 g (43%) of a pale-yellow oil: 1H NMR (CDCl3)
δ 1.17 (t, 3H, -CH3), 2.26-3.08 (m, 8H, all methylene Hs),
4.44 (br s, 1H, -OH), 4.66 (dd, 1H, CH-OH), 7.17 (s, 1H, CH-
S), 7.46 (m, 7H, phenyl), 7.76-7.91 (m, 2H, phenyl).
N-E t h yl-N-[2-(b en zot h ien -3-yl)et h yl]-N-[2-h yd r oxy-2-
(3-br om op h en yl)eth yl]a m in e (16b): procedure A, mobile
phase for radial flow chromatography, hexane (83):acetone
(17):Et3N (1); yield, 30%; 1H NMR (CDCl3) δ 1.14 (t, 3H, CH3),
2.23-3.16 (m, 8H, all methylene Hs), 4.05 (br s, 1H, OH), 4.55
(dd, 1H, CH-OH), 7.15 (s, 1H, CH-S), 7.18-7.80 (m, 8H,
phenyl).
3-(Cya n om et h yl)b en zo[b]t h iop h en e (12). Potassium
cyanide (6.65 g, 102.14 mmol) and benzyltriethylammonium
chloride (23.26 g, 227.78 mmol) were dissolved in H2O (50 mL)
in a round-bottomed flask fitted with a stirrer, reflux con-
denser, and a dropping funnel. 3-(Chloromethyl)thianaph-
thene (15.0 g, 82.12 mmol) was added dropwise with cooling
(water bath) to the well-stirred mixture, and the resulting
emulsion was heated at 90-95 °C for 1 h. The reaction
mixture was diluted with water (50 mL) and extracted with
CH2Cl2 (2 × 50 mL). The organic extracts were combined,
dried over Na2SO4, and concentrated to a residue. The crude
product was purified by radial flow chromatography [hexane
(9)-acetone (1)] to obtain 4.0 g (28%) of a pale-colored
crystalline solid: 1H NMR (CDCl3) δ 3.69 (s, 2H, CH2-Cl),
7.25-7.91 (m, 5H, aryl).
2-(Ben zo[b]th ien -3-yl)eth yla m in e (13). To a stirring
slurry of lithium aluminum hydride (1.16 g, 30.32 mmol) in
dry ether (50 mL) was added, under N2, a slurry of aluminum
chloride (4.04 g, 30.32 mmol) in dry ether (50 mL). After 5
min, a solution of 3-(cyanomethyl)thianaphthene (5.25 g, 30.32
mmol) in ether (50 mL) was slowly added over 10 min. Upon
completion of the addition, the resulting mixture was refluxed
for 22 h, cooled, neutralized with a 20% aqueous solution of
Rochelle’s salt, and extracted with ethyl acetate (3 × 100 mL).
The combined organic extracts were dried over Na2SO4 and
concentrated under reduced pressure to yield the amine as a
syrup. The corresponding amine hydrochloride was obtained
by treating the free base with a solution of methanolic HCl:
1
yield of hydrochloride, 4.61 g (71%); H NMR (CDCl3) δ 1.43
(s, 2H, -NH2), 3.00 (m, 4H, -CH2-CH2-), 7.11 (s, 1H, CH-
S), 7.36 (m, 2H, phenyl), 7.72-7.86 (m, 2H, phenyl).
2-(Ben zo[b]th ien -3-yl)eth yla ceta m id e (14). Acetic an-
hydride (2.0 mL, 21.15 mmol) and Et3N (1.77 mL, 12.69 mmol)
were added to a solution of 2-(benzo[b]thien-3-yl)ethylamine
(0.75 g, 4.23 mmol) in DMF (5 mL). The reaction mixture was
stirred for 18 h at room temperature, diluted with H2O (25
mL), and extracted with CH2Cl2 (2 × 25 mL). The organic
extracts were dried over Na2SO4 and concentrated to a residue
to provide 0.88 g (94%) of a viscous liquid: 1H NMR (CDCl3)
δ 1.88 (s, 3H, -CH3), 3.00 (m, 2H, -CH2-), 3.54 (m, 2H, CH2-
NH), 6.29 (br s, 1H, NH), 7.10 (s, 1H, CH-S), 7.25-7.37 (m,
2H, phenyl), 7.72-7.86 (m, 2H, phenyl).
N-E t h yl-N-[2-(b en zot h ien -3-yl)et h yl]-N-[2-h yd r oxy-2-
(3-n itr op h en yl)eth yl]a m in e (16c): procedure A, mobile

4490 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 23
Efange et al.
phase for radial flow chromatography, hexane (83):acetone
(17):Et3N (1); yield, 46%; 1H NMR (CDCl3) δ 1.22 (t, 3H, CH3),
2.14-3.60 (m, 8H, all methylene Hs), 4.64 (br s, 1H, OH-),
4.66 (dd, 1H, CH-OH), 7.14 (s, 1H, CH-S), 7.30-8.25 (m, 8H,
phenyl).
N-E t h yl-N-[2-(ben zot h ien -3-yl)et h yl]-N-[2-h yd r oxy-2-
(3,4-d ich lor op h en yl)eth yl]a m in e (16d ): procedure A, mo-
bile phase for radial flow chromatography, acetone (5):hexane
(95):Et3N (1); yield, 43%; 1H NMR (CDCl3) δ 1.15 (t, 3H, CH3-
), 2.42 (dd, 2H, CH2-CHOH), 2.60-3.15 (m, 6H, CH2-), 4.05
(bs, 1H, OH), 4.55 (dd, 1H, -CHOH), 7.16 (s, 1H, phenyl), 7.18
(s, 1H, thienyl), 7.30-7.52 (m, 4H, phenyl), 7.75 (d, 1H,
phenyl), 7.82 (d, 1H, phenyl).
P r oced u r e B: Syn th esis of Hexa h yd r oa zep in o[4,5-b]-
ben zoth iop h en es. 3-Eth yl-5-p h en yl-1,2,3,4,5,6-h exa h y-
d r oa zep in o[4,5-b]ben zoth iop h en e (17a ). Compound 16a
(0.30 g, 1 mmol) was refluxed for 3 h in a mixture of CF3COOH
(5 mL) and H2SO4 (100 µL). After cooling to room temperature,
the reaction mixture was diluted with water (10 mL), adjusted
to pH 8 with solid NaHCO3, and extracted with EtOAc (2 ×
50 mL). The EtOAc extracts were dried over Na2SO4 and
concentrated under reduced pressure to provide the free amine
as a yellow oil. The latter was converted to the corresponding
hydrochloride with methanolic HCl and recrystallized from
i-PrOH-ether to yield 160 mg (57%) of a yellowish brown
solid: mp 92-96 °C dec; 1H NMR (CDCl3) δ 1.10 (t,3H, J ) 7
Hz, CH3-CH2-), 2.77 (q, 2H, J ) 7 Hz, CH3-CH2-), 2.80 (m,
2H, azepinyl), 3.20 (m, 4H, azepinyl), 4.49 (dd, 1H, benzylic
amide-HCl) were custom synthesized by Dr. Kenner Rice
(Laboratory of Medicinal Chemistry, NIDDK, Bethesda, MD).
All other unlabeled drugs were purchased from Research
Biochemicals, Inc., Natick, MA.
All binding assays were conducted as described previously
(see Table 1 for references). The ability of modified ibogaine
fragments to inhibit binding to neuroreceptors or transporters
was first assessed at doses of 100 nM and 10 µM. Positive
controls were routinely assayed in parallel using specific
reference drugs with known affinities (Table 1). Assay tubes
were incubated under the specified conditions and filtered
through Whatman 934AH filters on Millipore manifolds.
Nonspecific binding was defined as the cpm bound in the
presence of a saturating concentration of an established
competing ligand. Test compounds were considered active at
a given receptor site if the level of inhibition of radioligand
binding was equal to or greater than 50% inhibition at the 10
µM dose. To accurately determine potency values, full com-
petition curves were obtained at relevant binding sites using
10-15 concentrations of ibogaine (1) or noribogaine (4).
Ligand competition data were analyzed using the DRUG
program of EBDA/LIGAND (Biosoft, Elsevier).
Refer en ces
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methine), 7.19-7.67 (m, 9H, phenyl); CIMS calcd for C20H21
NS m/z 307.1395 (M+), found 307.1419 (100%). Anal. (C20H21
NS‚HCl‚H2O) C, H, N.
-
-
3-E t h yl-5-(3-b r om op h en yl)-1,2,3,4,5,6-h exa h yd r oa ze-
p in o[4,5-b]ben zoth iop h en e h yd r och lor id e (17b): proce-
dure B, mobile phase for chromatography, hexane (83):acetone
(17):Et3N (1); yield, 65%; mp (HCl) 169-173 °C (i-PrOH-
ether); 1H NMR (CDCl3) δ 1.08 (t, 3H, J ) 7 Hz, CH3-CH2-),
2.74 (q, 2H, J ) 7 Hz, CH3-CH2-), 2.84 (m, 2H, azepinyl),
3.14 (m, 4H, azepinyl), 4.42 (dd, 1H, benzylic methine), 7.20-
7.69 (m, 8H, phenyl); CIMS calcd for C20H20BrNS m/z 385.0500
(M+), found 385.0484 (42.68%). Anal. (C20H20BrNS‚HCl‚H2O)
C, H, N.
3-Eth yl-5-(3-n itr oph en yl)-1,2,3,4,5,6-h exah ydr oazepin o-
[4,5-b]ben zoth iop h en e h yd r och lor id e (17c): procedure B,
purified by chromatography, hexane (83)-acetone (17):Et3N
(1); yield, 46%; mp (HCl) 168-171 °C (i-PrOH-ether); 1H NMR
(CDCl3) δ 1.08 (t, 3H, J ) 7 Hz, CH3-CH2-), 2.74 (q, 2H, J )
7 Hz, CH3-CH2-), 2.94 (m, 2H, azepinyl), 3.11 (m, 4H,
azepinyl), 4.55 (dd, 1H, benzylic methine), 7.25-8.27 (m, 8H,
phenyl); CIMS calcd for C20H20N2O2S m/z 352.1246 (M+), found
352.1227 (84.20%). Anal. (C20H20N2O2S‚HCl‚3/4H2O) C, H, N.
3-Eth yl-5-(3,4-dich lor oph en yl)-1,2,3,4,5,6-h exah ydr oaze-
p in o[4,5-b]ben zoth iop h en e (17d ). Concentrated H2SO4
(300 µL) was added to a solution of 16d (1.1 g, 2.79 mmol) in
CF3COOH (20 mL), and the resulting solution was refluxed
for 1 h under N2. The reaction mixture was diluted with ice-
cold water, carefully adjusted to pH 8 with 2 N NaOH solution,
and extracted with CH2Cl2 (2 × 50 mL). The organic extracts
were dried over anhydrous Na2SO4 and passed through silica
gel column (eluting with 10% acetone:hexane). Concentration
of the eluent yielded a pale-yellow liquid (670 mg, 58%). The
free base was converted to its hydrochloride with methanolic
HCl and recrystallized from methanol-ether to yield a yellow
solid (560 mg, 53%): mp 154-156 °C; 1H NMR (CDCl3) δ 1.07
(t, 3H, J ) 7 Hz, CH3-), 2.70 (q, J ) 7 Hz, 2H, CH3-CH2-),
2.80-3.22 (m, 6H, azepinyl), 4.41 (dd, 1H, J ) 1.5 Hz, J ) 8
Hz, benzylic methine), 7.17-7.70 (m, 7H, phenyl); CIMS calcd
for C20H19Cl2NS m/z 375.0615 (M+), found 375.0610 (59.04%).
Anal. (C20H19Cl2NS‚HCl‚H2O) C, H, N.
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