Synthesis and biological activity of conformationally restricted analogs of milnacipran: (1S,2A)-1-Phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarboxamide, an efficient noncompetitive N-methyl-D-aspartic acid receptor antagonist

Article abstract of DOI:10.1021/jm960495w

We recently demonstrated that (±)-(Z)-2-(aminomethyl)-1-phenyl-N,N-diethylcyclopropanecarboxamide [milnacipran, (±)-1], an inhibitor of the reuptake of serotonin (5-HT), was a noncompetitive NMDA receptor antagonist. On the basis of the cyclopropane struc

Full text of DOI:10.1021/jm960495w

4844
J . Med. Chem. 1996, 39, 4844-4852
Syn th esis a n d Biologica l Activity of Con for m a tion a lly Restr icted An a logs of
Miln a cip r a n :
(1S,2R)-1-P h en yl-2-[(S)-1-a m in op r op yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e, a n
Efficien t Non com p etitive N-Meth yl-D-a sp a r tic Acid Recep tor An ta gon ist
Satoshi Shuto,*,† Shizuka Ono,† Yukako Hase,† Yoshihito Ueno,† Tomohiro Noguchi,‡ Kiyonori Yoshii,‡ and
Akira Matsuda†
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060, J apan, and Department of
Biochemical Engineering and Science, Kyushu Institute of Technology, Iizuka 820, J apan
Received J uly 8, 1996X
We recently demonstrated that (()-(Z)-2-(aminomethyl)-1-phenyl-N,N-diethylcyclopropanecar-
boxamide [milnacipran, (()-1], an inhibitor of the reuptake of serotonin (5-HT), was a
noncompetitive NMDA receptor antagonist. On the basis of the cyclopropane structure of (()-
1, conformationally restricted analogs with different stereochemistries, namely 1-phenyl-2-(1-
aminoalkyl)-N,N-diethylcyclopropanecarboxamindes (2, 3, en t-2, and en t-3), were designed and
synthesized. Among these analogs, 2a , 2b, and 2f, with (1S,2R,1′S)-configuration, were more
efficient than milnacipran as NMDA receptor antagonists; these compounds significantly
inhibited the binding of [3H]MK-801 at IC50 ) 0.35 ( 0.08, 0.20 ( 0.024, and 0.16 ( 0.02 µM,
respectively, and blocked the response of voltage-clamped oocytes to NMDA, surpassing the
effects of (()-1. Although both the 1′-methyl analog 2a and the 1′-vinyl analog 2f, like (()-1,
strongly inhibited 5-HT uptake in vitro, the corresponding 1′-ethyl analog 2b was devoid of
the inhibitory effect on 5-HT uptake, while it was about 30 times more potent as an NMDA
receptor antagonist than (()-1.
In tr od u ction
antagonist. Since our previous study showed that
modification of the functional groups of (()-1, such as
the aminomethyl or the diethylcarbamoyl group, did not
improve its activity,8 we planned to investigate the
effects of conformational changes of the molecule on its
activity. Therefore, we designed conformationally re-
stricted analogs of (()-1 and accordingly developed a
new method for restricting the conformation of cyclo-
propane derivatives.9a
Because of the potential involvement of NMDA (N-
methyl-D-aspartic acid) receptors in both chronic and
acute neurodegenerative disorders,1 there have been
attempts to develop novel agents that block the activa-
tion of NMDA receptors by glutamate or related exci-
tatory neurotransmitters.1-5
Recently, various noncompetitive and competitive
NMDA receptor antagonists have been developed, and
some have been shown to be effective in experimental
models of epilepsy and stroke.1-3 Unfortunately, non-
competitive inhibitors have had serious behavioral
effects4a,b and caused neuronal vacuolization,4c while
competitive inhibitors were often inactive in vivo be-
cause of poor transport to the brain.5 Therefore, the
development of another type of efficient NMDA receptor
antagonist is eagerly desired.
We previously reported that (()-(Z)-2-(aminomethyl)-
1-phenyl-N,N-diethylcyclopropanecarboxamide [mil-
nacipran, (()-1],6 as an efficient antidepressant due to
competitive inhibition of the re-uptake of serotonin (5-
HT) in the CNS,7 was a new class of noncompetitive
NMDA receptor antagonist.8 Although the binding
affinity of (()-1 for the NMDA receptor is not strong,
its characteristic structure is of importance for the
search of novel potent NMDA receptor antagonists other
than the known competitive and noncompetitive an-
tagonists.8 Therefore, we modified the structure of (()-
1, to increase its specific affinity for the NMDA receptor
as well to decrease its inhibitory effect on 5-HT re-
uptake, to develop a clinically useful NMDA receptor
We designed conformationally restricted analogs based
on the structural feature of (()-1, as shown in Figure
1. Adjacent substituents on a cyclopropane ring exert
significant mutual steric repulsion because they are
fixed in an eclipsed conformation relative to each other.
Consequently, the conformations of substituents on a
cyclopropane ring can be restricted by the steric effects
of adjacent substituents, especially when they are bulky
enough. Since the primary amino group of (()-1 is
essential for the binding to the NMDA receptor,8 we
presumed that the conformation of the aminomethyl
moiety would significantly affect the activity of the
compound. While the aminomethyl moiety is not very
bulky and may freely rotate to some extent, conformers
A and B may be preferable to conformer C, due to the
strong steric repulsion of the bulky N,N-diethylcarbam-
oyl group in conformer C, as shown in Figure 2.
Introducing an alkyl group into the R-position of the
amino function of (()-1 would prevent this rotation and
restrict the location of the amino group in space due to
its steric repulsion from the diethylcarbamoyl group.
Therefore, the conformation of the compounds can be
limited depending on the configuration of the alkyl
group introduced; conformer B would be predominant
in 2 and its enantiomer (en t-2), while conformer A
would be predominant in 3 and its enantiomer (en t-3),
* Author to whom correspondence should be addressed.
† Hokkaido University.
‡ Kyushu Institute of Technology.
X Abstract published in Advance ACS Abstracts, November 1, 1996.
S0022-2623(96)00495-5 CCC: $12.00 © 1996 American Chemical Society

New NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4845
F igu r e 1. Milnacipran and its conformationally restricted analogs.
F igu r e 2. Conformational restriction of milnacipran by introducing an alkyl group.
Resu lts a n d Discu ssion
Ch em istr y. We previously reported the stereoselec-
tive syntheses of four types of conformationally re-
stricted analogs of (()-1, namely, 2a and 2b, 3a and
3b, en t-2a and en t-2b, and en t-3a and en t-3b.9 In this
study, 2c-f were also synthesized from an optically
active cyclopropylcarbaldehyde 3, a key intermediate in
the synthesis of 2a and 2b, which was readily prepared
from (R)-epichlorohydrin (Scheme 1).
F igu r e 3. Molecular structures of the low-energy conformers
of 2b and 3b.
We previously recognized that addition reactions of
Grignard reagents on the cyclopropylcarbaldehyde 3
proceed from the least hindered si face in the bisected
s-trans conformation which is preferred due to the
peculiar stereoelectronic effects of the cyclopropane ring,
to give 1′S-products highly selectively.9 The Grignard
reaction of 3 with propyl-, isobutyl-, phenyl-, and
vinylmagnesium bromides in THF at -20 °C also gave
1′S-products 4c-g diastereoselectively in high yields.
Treatment of 4c-e with a NaN3/CBr4/Ph3P system in
DMF12 gave azido derivatives 5c-e stereoselectively in
good yields. This reaction gave the configuration-
retained azido products via the participation of a
neighboring group in intermediates I.9a However, when
isopropyl derivative 4g was treated under the same
reaction conditions, nucleophilic substitution did not
proceed, and 4g was recovered. This result is likely due
to steric hindrance around the 1′-position. On the other
hand, similar treatment of vinyl derivative 4f did not
give the desired 1′S-azide 5f, but SN2′ product 6 was
obtained as a mixture of E- and Z-isomers.
as shown in Figure 2. As the alkyl groups, we selected
methyl and ethyl groups, which would be bulky enough
to restrict the conformation of the compounds. We
carried out molecular orbital calculations on 2b and
3b.10 As shown in Figure 3, the calculated structures
of 2b and 3b supported our hypothesis.
Four types of conformationally restricted analogs with
different stereochemistries, namely, 2a and 2b, 3a and
3b, en t-2a and en t-2b, and en t-3a and en t-3b, were
synthesized with high stereoselectivity,11 starting from
(R)- or (S)-epichlorohydrins.9 X-ray crystallographic
analysis clearly showed that the conformations of 2 (en t-
2) and 3 (en t-3) were effectively restricted to conformers
B and A, respectively, as we hypothesized.9a
Among these conformationally restricted analogs,
(1S,2R)-1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethylcyclo-
propanecarboxamide (2a , PEDC) and (1S,2R)-1-phenyl-
2-[(S)-1-aminopropyl]-N,N-diethylcyclopropanecarbox-
amide (2b, PPDC) significantly inhibited the binding
of [3H]MK-801 to the NMDA receptor. Considering
these findings, to investigate the effects of the alkyl
group at the R-position of the amino group on the
biological activity, we synthesized other conformation-
ally restricted analogs of milnacipran (2c-f) with the
same stereochemistry as that of 2a and 2b.
Catalytic hydrogenation of azido derivatives 5c-e
with Pd-C in MeOH gave the target conformationally
restricted analogs 2c-e, which were isolated as hydro-
chlorides in good yields (Scheme 1).
We attempted to synthesize vinyl derivative 2f using
an oxidative 2,3-sigmatropic rearrangement reaction13
via vinylselenide 7 (Scheme 2). We initially thought

4846 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Shuto et al.
Sch em e 1a
a
Reagents: (a) RMgBr, THF; (b) NaN3, CBr4, Ph3P, DMF; (c) H2, Pd-C, MeOH.
Sch em e 2a
a
Reagents: (a) (1) (CF3CO)2O, MeCN, (2) NaBH4, (PhSe)2, EtOH; (b) t-BuO2CNH2, i-Pr2NH, NCS, MeOH.
Sch em e 3a
a
Reagents: (a) LiCH2CO2Et, THF; (b) NaBH4, MeOH; (c) pivaloyl chloride, py; (d) NaN3, Ph3P, CBr4, DMF; (e) NaOMe, MeOH; (f)
TsCl, DMAP, Et3N, CH2Cl2; (g) NaBH4, (PhSe)2, EtOH; (h) Ph3P, py, then NH4OH; (i) Boc2O, CH2Cl2; (j) H2O2, aqueous THF; (k) TFA,
MeOH; (l) H2, Pd-C, MeOH.
that the phenylseleno derivative 7 could be prepared
by treating 4f with PhSe-, since the nucleophilic
substitution reaction of 4f proceeded in an SN2′ manner
to give the corresponding exo-olefin product as described
above. In fact, treatment of 4f with NaSePh, prepared
from (PhSe)2 and NaBH4, in EtOH gave the SN2′
product 7 in 76% yield as a mixture of E- and Z-isomers.
When mixture 7 was treated with N-chlorosuccinimide
in the presence of tert-butyl carbamate and i-Pr2NH, an
oxidative 2,3-sigmatropic rearrangement proceeded to
give the 1′-vinyl derivative as a mixture of 1′-diastere-
omers in high yield. However, separation of the dia-
stereomeric mixture was unsuccessful.14
Next, we planned to construct the vinyl moiety via
the oxidative syn-elimination reaction of a phenylseleno
group after introduction of an amino function at the 1′-
position, as outlined in Scheme 3. Treatment of alde-
hyde 3 with a lithium enolate of EtOAc at -78 °C in
THF gave 1′S-addition product 10 and the correspond-
ing 1′R-diastereomer in 79% and 10% yields, respec-
tively. Reduction of the ester group of 10 with NaBH4
in MeOH gave alcohol 11 of which the primary hydroxyl
was protected selectively with a pivaloyl group to give
12 in high yield. The azido function was introduced at
this stage; treatment of 12 with the NaN3/CBr4/Ph3P
system in DMF12 gave desired azido derivative 13 in
excellent yield. After removal of the protecting group,
the hydroxyl was tosylated to give 15. Nucleophilic
substitution reaction of 15 with NaSePh in EtOH
afforded phenylseleno derivative 16 in 85% yield. Al-
though catalytic hydrogenation of 16 was unsuccessful,
when 16 was treated successively with Ph3P in pyridine
and NH4OH,15 the azide group was selectively reduced
to give the desired amino derivative 17, the amino group
of which was protected with a Boc group to give 18.
Treatment of 18 with H2O2 in aqueous THF at room
temperature gave the oxidative syn-elimination product
8 in 95% yield. Deprotection of 8 with TFA in aqueous
MeOH furnished the target 1′-vinyl derivative 2f, which
was isolated as a hydrochloride in 84% yield. Finally,
the stereochemistry at the 1′-position was confirmed to
be S, since the catalytic hydrogenation of 2f with Pd-C
in MeOH gave 1′S-ethyl derivative 2b (PPDC), the
stereochemistry of which was determined previously by
X-ray crystallographic analysis.9a
Biologica l Activity.16 It is important to determine
the stereochemistry of the conformationally restricted
analogs of (()-1 that strongly bind to the NMDA
receptor. Therefore, conformationally restricted analogs
with different stereochemistries, namely, 2a and 2b, 3a
and 3b, en t-2a and en t-2b, and en t-3a and en t-3b,
were evaluated in vitro for their binding affinity for the

New NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4847
Ta ble 1. Effects of Compounds on the NMDA Receptor Binding and the 5-HT Uptake
NMDA receptor bindinga
5-HT uptakeb
selectivity indexc
(5-HT/NMDA)
compound
configuration
2′-substituent
(IC50, µM)
(Ki, µM)
(()-1
6.3 ( 0.3
0.0085 ( 0.0006
0.014 ( 0.002
24 ( 0.9
2.4 ( 0.3
>100
0.0013
0.040
125
0.37
>12
0.0089
>12
>3.2
>9.1
37
>24
>5.9
0.14
2a
1S,2R,1′S
1S,2R,1′S
1S,2R,1′R
1S,2R,1′R
1R,2S,1′R
1R,2S,1′R
1R,2S,1′S
1R,2S,1′S
1S,2R,1′S
1S,2R,1′S
1S,2R,1′S
1S,2R,1′S
Me
Et
Me
Et
Me
Et
Me
Et
0.35 ( 0.08
0.20 ( 0.02
6.5 ( 0.5
2b
3a
3b
en t-2a
en t-2b
en t-3a
en t-3b
2c
8.2 ( 2.1
19 ( 1.8
0.17 ( 0.003
>100
8.2 ( 2.0
31 ( 0.1
>100
11 ( 0.05
1.0 ( 0.05
4.2 ( 0.2
>100
Pr
i-Bu
Ph
37 ( 3
2d
2e
2f
>100
17 ( 0.3
>100
Vinyl
0.16 ( 0.02
0.009.8 ( 0.005
0.61 ( 0.46
0.023 ( 0.0007
phencyclidine
ketameine
a
b
Assay was done with cerebral cortical synaptic membrane of rats using [3H]MK-801. Assay was done with cerebral cortical synaptic
membrane of rats using [3H]paroxetine. c The ratio: 5-HT uptake inhibition (Ki)/NMDA receptor binding (IC50).
NMDA receptor of cerebral cortical synaptic membrane
from rats, with [3H]MK-801 as a radioligand.17 The
results are shown in Table 1. Generally, conformation-
ally restricted analogs with (1S,2R)-configuration, 2a ,
2b, 3a , and 3b, showed more potent inhibitory effects
than the corresponding enantiomers, en t-2a , en t-2b,
en t-3a , and en t-3b. Notably, conformationally re-
stricted analogs with (1S,2R,1′S)-configuration, namely,
2a [(1S,2R)-1-phenyl-2-[(S)-1-aminoethyl]-N,N-diethyl-
cyclopropanecarboxamide, PEDC] and 2b [(1S,2R)-1-
phenyl-2-[(S)-1-aminopropyl]-N,N-diethylcyclopropan-
ecarboxamide, PPDC], significantly inhibited the binding
of [3H]MK-801 with IC50 values of 0.35 ( 0.08 and 0.20
( 0.02 µM, respectively, which were about 20- and 30-
fold stronger than that of (()-1 (IC50 ) 6.3 ( 0.3 µM).8
The corresponding diastereomers, 3a and 3b, had
weaker activities than those of 2a and 2b, and their IC50
values were similar to that of (()-1. All of the confor-
mationally restricted analogs with (1R,2S)-configura-
tion, en t-2a, en t-2b, en t-3a, and en t-3b, showed weaker
activity than (()-1.
On the basis of these results, we synthesized confor-
mationally restricted analogs with (1S,2R,1′S)-config-
uration, 2c-f, which have propyl, isobutyl, phenyl, and
vinyl groups at the 1′-position and evaluated their
binding affinity for the receptor. The results are also
summarized in Table 1. The binding affinity was
significantly affected by the alkyl group at the 1′-
position; introduction of groups bulkier than the ethyl
group clearly decreased the affinity for the receptor.
Notably, the 1′-vinyl derivative 2f [(1S,2R)-1-phenyl-2-
[(S)-1-amino-2-propenyl]-N,N-diethylcyclopropanecar-
boxamide, PPEDC] strongly bound to the receptor and
was more potent than 2a and 2b.
(PPDC), which also strongly bound to the NMDA
receptor, did not affect 5-HT uptake (Ki ) 24 ( 0.9 µM).
The effect of PPDC (2b) was about 1500 times less than
the effects of PEDC (2a ) and PPEDC (2f), although they
have the same stereochemistry. The enantiomer of
PEDC, en t-2a , which was only a weak NMDA receptor
antagonist, considerably inhibited the 5-HT uptake (Ki
) 0.17 ( 0.003 µM). All of the 1′-ethyl derivatives had
insignificant inhibitory effects on the 5-HT uptake,
regardless of their stereochemistry. On the other hand,
all of the 1′-methyl derivatives, except en t-3a , clearly
inhibited 5-HT uptake, and the potency depended on
their stereochemistries; 2a [(1S,2R,1′S-)-configuration]
> en t-2a [(1R,2S,1′R)-configuration] > 3a [(1S,2R,1′R)-
configuration] . en t-3a [(1R,2S,1′S)-configuration].
Consequently, it was suggested that the inhibitory
potency against the 5-HT uptake did not correlate with
that against NMDA receptor activation in these com-
pounds. These results also suggested that the confor-
mation of milnacipran binding to the NMDA receptor
was different from that binding to the 5-HT transporter.
We next investigated the effects of the conformation-
ally restricted analogs with different stereochemistries,
as well as (()-1, on the blockade of NMDA receptors
expressed by Xenopus oocytes. The oocyte expression
system has been used to investigate the pharmacological
aspects of neurotransmitter receptors, since Xenopus
oocytes not only translate microinjected exogenous
mRNA and assemble functional neurotransmitter re-
ceptors of voltage-gated channels but also are appropri-
ate for voltage-clamp experiments. Whole brain mRNA
was extracted from 10-day-old Wistar rats by the
guanidine/CsCl method, and the injected oocytes were
voltage-clamped with two glass electrodes filled with 3
M KCl, as previously described.18 The injected oocytes
were stimulated with 30 µM NMDA and 10 µM Gly in
the presence of the compounds tested at different
concentrations. All of the compounds tested, including
(()-1,19 decreased the responses to NMDA. The results
are summarized in Table 2. The conformationally
restricted analogs with (1S,2R,1′S)-configuration, 2a
and 2b, blocked the response significantly (IC50 ) 2.3
( 1.1 and 2.2 ( 2.1 µM, respectively). Although other
stereoisomers, 3, en t-2, and en t-3, as well as (()-1 also
clearly blocked the response, the effects were weaker
and those of 2a and 2b. Therefore, it is demonstrated
that the conformationally restricted analogs clearly
We next evaluated the inhibitory effects of the com-
pounds on the uptake of 5-HT by nerve terminals using
cerebral cortical synaptic membrane from rats, with [3H]-
paroxetine as a radioligand, since milnacipran [(()-1]
is a potent inhibitor of 5-HT uptake.7 As reported
previously,7 (()-1 significantly inhibited the 5-HT up-
take (Ki ) 0.0085 ( 0.0006 µM). Unfortunately,
(1S,2R,1′S)-1′-methyl derivative 2a (PEDC) and -vinyl
derivative 2f (PPEDC), which showed strong binding
to the NMDA receptor as described above, also signifi-
cantly inhibited 5-HT uptake (Ki ) 0.014 ( 0.002 and
0.023 ( 0.0007 µM, respectively), similar to (()-1.
Surprisingly, the corresponding 1′-ethyl derivative 2b

4848 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Shuto et al.
Ta ble 2. Blocking Effects of Compounds on the NMDA
though the potency of PPDC as an NMDA receptor
antagonist is about 30 times greater than that of the
lead compound, milnacipran, it does not inhibit 5-HT
uptake, which is the major effect of milnacipran. Thus,
we found a new method for restricting the conformation
of cyclopropane derivatives.
Receptors Produced by Oocytesa
compound
IC50 (µM) or inhibition (%)
1
53 (%)b
2a
2b
3a
3b
en t-2a
en t-2b
en t-3a
en t-3b
MK-801
2.3 ( 1.1 µM
2.2 ( 2.1 µM
50 ( 13 (%)c
51 ( 24 (%)c
51 ( 3 (%)c
39 ( 2.1 µM
59 ( 18 (%)c
51 ( 24 (%)c
98 (%)d
Exp er im en ta l Section
Melting points were determined on a Yanagimoto MP-3
micro-melting point apparatus and are uncorrected. The NMR
spectra were recorded with a J EOL EX-270 or -400 spectrom-
eter with tetramethylsilane as an internal standard. Chemical
shifts were reported in parts per million (δ), and signals are
expressed as s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), or br (broad). Mass spectra were measured on a
J EOL J MS-D300 spectrometer. Thin-layer chromatography
was done on Merck coated plate 60F254. Silica gel chromatog-
raphy was done with Merck silica gel 5715.
a
Estimated from the inhibition curves obtained from at least
b
three oocytes voltage-clamped at -50 mV. Inhibition at 10 µg/
mL. c Inhibition at 100 µg/mL. Inhibition at 0.1 µg/mL.
d
inhibit the function of the NMDA receptor, and there
were clear correlations between the inhibition of [3H]-
MK-801 binding and blockade of the NMDA receptors
by these compounds.20 The potency of the conforma-
tionally restricted analogs as NMDA antagonists de-
pended on their stereochemistry; in the order, 2
[(1S,2R,1′S)-configuration] > 3 [(1S,2R,1′R)-configura-
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxybu t yl]-N,N-d iet h yl-
cyclop r op a n eca r boxa m id e (4c). To a solution of 3 (245 mg,
1.0 mmol) in THF (8 mL) was slowly added PrMgBr (1.0 M in
THF, 2 mL, 2.0 mmol) at -20 °C under argon. The mixture
was stirred at the same temperature for 2 h and was quenched
with saturated NH4Cl (20 mL). After the mixture was
concentrated in vacuo, EtOAc and water were added, and then
the mixture was partitioned. The separated organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; EtOAc/hexane, 1:4) to
give 4c as an oil (251 mg, 87%): 1H NMR (500 MHz, CDCl3)
0.92 (3 H, t, J ) 7.0 Hz), 0.93 (3 H, t, J ) 7.0 Hz), 1.05 (1 H,
dd, J ) 5.5, 6.5 Hz), 1.14 (3 H, t, J ) 7.0 Hz), 1.26 (1 H, ddd,
J ) 6.5, 8.5, 9.0 Hz), 1.39-1.67 (4 H, m), 1.69 (1 H, dd, J )
5.5, 8.5 Hz), 3.12-3.17 (1 H, m), 3.32-3.46 (3 H, m), 3.52 (1
H, dq, J ) 14.0, 7.0 Hz), 5.41 (1 H, s), 7.18-7.30 (5 H, m);
HR-MS (EI) calcd for C18H27NO2 289.2042, found 289.2053.
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxy-3-m eth ylbu tyl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e (4d ). Compound 4d
was prepared as described above for 4c, with i-BuMgBr instead
of PrMgBr. After purification by column chromatography
(silica gel; EtOAc/hexane, 1:4), 4d was obtained as an oil (284
mg, 94%): 1H NMR (500 MHz, CDCl3) 0.90-0.94 (9 H, m),
1.04 (1 H, dd, J ) 5.5, 6.5 Hz), 1.14 (3 H, t, J ) 7.0 Hz), 1.24
(1 H, ddd, J ) 6.5, 8.5, 9.0 Hz), 1.37 (1 H, ddd, J ) 5.0, 8.5,
13.5 Hz), 1.61 (1 H, ddd, J ) 5.5, 8.5, 13.5 Hz), 1.68 (1H, dd,
J ) 5.5, 8.5 Hz), 1.88 (1 H, m), 3.20 (1 H, m), 3.33-3.55 (4H,
m), 5.42 (1H, s), 7.18-7.29 (5 H, m); HR-MS (EI) calcd for
C19H29NO2 303.2198, found 303.2206.
(1S,2R)-1-P h en yl-2-[(R)-1-h yd r oxy-1-p h en ylm et h yl]-
N,N-d iet h ylcyclop r op a n eca r b oxa m id e (4e). Compound
4e was prepared as described above for 4c, with PhMgBr
instead of PrMgBr. After purification by column chromatog-
raphy (silica gel; EtOAc/hexane, 1:4), 4e was obtained as a
white powder (309 mg, 96%): 1H NMR (500 MHz, CDCl3) 0.95
(3 H, t, J ) 7.0 Hz), 1.19 (3 H, t, J ) 7.0 Hz), 1.29 (1 H, dd, J
) 5.5, 6.0 Hz), 1.55 (1 H, ddd, J ) 6.0, 8.5, 9.5 Hz), 1.74 (1 H,
dd, J ) 5.5, 8.5 Hz), 3.40 (1 H, dq, J ) 14.0, 7.0 Hz), 3.46-
3.58 (3 H, m), 4.25 (1 H, dd, J ) 2.0, 9.5 Hz), 5.83 (1 H, d, J
) 2.0 Hz), 7.20-7.35 (8 H, m), 7.47 (2 H, d, J ) 7.5 Hz); HR-
MS (EI) calcd for C21H25NO2 323.1885, found 323.1893. Anal.
(C21H25NO2) C, H, N.
tion],
en t-2
[(1R,2S,1′R)-configuration],
en t-3
[(1R,2S,1′S)-configuration].
PPDC may be a desirable NMDA antagonist, since
milnacipran, the prototype of PPDC, has been shown
clinically to be an antidepressant free from serious side
effects21 and to be transportable to the brain. PPDC is
a strong and selective antagonist of the NMDA receptor;
with regard to the ratio of selectivity index [5-HT uptake
inhibition (Ki)/NMDA receptor binding (IC50)], (()-1 was
0.0013 and PPDC was 125, respectively. Furthermore,
PPDC may be easily transported to the brain because
it is more lipophilic than (()-1.
In the design of conformationally restricted analogs,
it is imperative that the conformationally restricted
analogs and the lead compound be as similar as possible
in size, shape, and molecular weight.22 Conformation-
ally restricted analogs have usually been designed and
synthesized by introducing cyclic moieties into lead
compounds which were often rather bulky. Conse-
quently, their chemical and physical properties are often
changed. On the other hand, it has been considered that
an induced fit, namely conformational changes in both
the receptor and the ligand coming from their interac-
tion, is important for strong binding.22a The introduc-
tion of cyclic moieties to restrict the conformation may
make the compounds too rigid to be suitable for an
induced fit. On the basis of these considerations, our
method of restricting the conformation of a key func-
tional group by introducing a small alkyl group, such
as a methyl or ethyl group, would be efficient. The alkyl
groups introduced in the conformationally restricted
analogs may be effective for removing the undesirable
side effects when the lead compound interacts with
several binding sites. In fact, although the 1′-methyl
derivative PEDC (2a ) and -vinyl derivative PPEDC (2f)
are significantly active both as NMDA receptor antago-
nists and as 5-HT-uptake inhibitors, the corresponding
1′-ethyl derivative PPDC (2b), which is also an efficient
NMDA receptor antagonist, is almost inactive as a 5-HT
uptake inhibitor.
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxy-2-p r op en yl]-N,N-d i-
eth ylcyclop r op a n eca r boxa m id e (4f). Compound 4f was
prepared as described above for 4c, with vinylmagnesium
bromide instead of PrMgBr. After purification by column
chromatography (silica gel; EtOAc/hexane, 1:4), 4f was ob-
tained as a white powder (242 mg, 89%): 1H NMR (500 MHz,
CDCl3) 0.93 (3 H, t, J ) 7.0 Hz), 1.13 (1 H, dd, J ) 5.5, 6.5
Hz), 1.15 (3 H, t, J ) 7.0 Hz), 1.36 (1 H, ddd, J ) 6.5, 9.0, 9.5
Hz), 1.72 (1 H, dd, J ) 5.5, 9.0 Hz), 3.33-3.46 (3 H, m), 3.53
(1 H, dq, J ) 14.0, 7.0 Hz), 3.66 (1 H, dd, J ) 5.5, 9.5 Hz),
5.13 (1 H, d, J ) 10.5 Hz), 5.33 (1 H, d, J ) 16.0 Hz), 5.54 (1
H, s), 6.00 (1 H, ddd, J ) 5.5, 10.5, 16.0 Hz), 7.19-7.31 (5 H,
m); HR-MS (EI) calcd for C17H23NO2 273.1729, found 273.1712.
(1S,2R)-1-P h en yl-2-[(S)-1-h ydr oxy-2-m eth ylpr opyl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e (4g). Compound 4g was
In conclusion, we developed conformationally re-
stricted analogs of milnacipran [(()-1] and identified a
potent NMDA receptor antagonist, PPDC (2b). Al-

New NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4849
prepared as described above for 4c, with i-PrMgBr instead of
PrMgBr. After purification by column chromatography (silica
gel; EtOAc/hexane, 1:4), 4f was obtained as an oil (263 mg,
91%): 1H NMR (500 MHz, CDCl3) 0.92 (3 H, t, J ) 7.3 Hz),
0.99 (3 H, d, J ) 6.8 Hz), 1.02 (3 H, d, J ) 6.4 Hz), 1.08 (1 H,
dd, J ) 5.4, 6.6 Hz), 1.14 (3 H, t, J ) 7.3 Hz), 1.28 (1 H, ddd,
J ) 6.6, 8.8, 10.0 Hz), 1.73 (1 H, dd, J ) 5.4, 98.8 Hz), 1.85 (1
H, ddd, J ) 6.4, 6.4, 6.8 Hz), 2.90 (1 H, dd, J ) 6.4, 10.0 Hz),
3.33-3.54 (4 H, m), 7.19-7.31 (5 H, m); MS (EI) m/z 289
(MH+).
2.71 (1 H, m), 3.29 (1 H, dq, J ) 14.0, 7.0 Hz), 3.33-3.47 (3 H,
m), 7.20-7.30 (5 H, m), 9.06 (3 H, br s); MS (EI) m/z 288 (M+).
Anal. (C18H29ClN2O‚0.3H2O) C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-a m in o-3-m eth ylbu th yl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e h yd r och lor id e (2d ):
yield 43%; mp 198-199 °C; [R]27 ) +79.9 (c 0.670, CHCl3);
D
1H NMR (500 MHz, CDCl3) 0.89 (3 H, t, J ) 7.0 Hz), 0.95 (3
H, d, J ) 6.5 Hz), 0.98 (3 H, d, J ) 6.5 Hz), 1.08 (1 H, dd, J )
5.5, 6.0 Hz), 1.10 (3 H, t, J ) 7.0 Hz), 1.53 (1 H, ddd, J ) 6.0,
9.0, 9.0 Hz), 1.89 (1 H, dd, J ) 5.5, 9.0 Hz), 1.91-2.03 (2 H,
m), 2.13-2.19 (1 H, m), 2.72-2.79 (1 H, m), 3.29 (1 H, dq, N
) 14.0, 7.0 Hz), 3.34-3.47 (1 H, m), 7.19-7.30 (5 H, m), 9.07
(3 H, br s); MS (EI) m/z 302 (M+). Anal. (C19H31ClN2O‚0.1H2O)
C, H, N.
(1S,2R′)-1-P h en yl-2-[(S)-1-a zid ob u t yl]-N,N-d iet h ylcy-
clop r op a n eca r boxa m id e (5c). To a solution of 4c (289 mg,
1.0 mmol) in DMF (8 mL) were added at 0 °C NaN3 (1.24 g,
19 mmol), Ph3P (787 mg, 3.0 mmol), and CBr4 (995 mg, 3.0
mmol), and the mixture was stirred at room temperature for
3 h. Water was added, the resulting mixture was evaporated,
and then the residue was partitioned between brine and
EtOAc. The separated organic layer was dried (Na2SO4),
evaporated, and purified by column chromatography (silica gel;
hexane/EtOAc, 1:2) to give 5c as an oil (210 mg, 67%): 1H
NMR (500 MHz, CDCl3) 0.37 (3 H, t, J ) 7.0 Hz), 0.94 (1 H,
dd, J ) 5.0, 9.5 Hz), 0.97 (3 H, t, J ) 7.0 Hz), 1.12 (3 H, t, J
) 7.0 Hz), 1.42-1.61 (2 H, m), 1.66 (1 H, dd, J ) 5.0, 5.5 Hz),
1.72-1.77 (2 H, m), 1.96 (1 H, ddd, J ) 5.5, 9.5, 10.0 Hz), 2.90
(1 H, ddd, J ) 6.5, 6.5, 10.0 Hz), 3.03 (1 H, dq, J ) 14.0, 7.0
Hz), 3.17 (1 H, dq, J ) 14.0, 7.0 Hz), 3.53 (1 H, dq, J ) 14.0,
7.0 Hz), 3.71 (1 H, dq, J ) 14.0, 7.0 Hz), 7.20-7.32 (5 H, m);
HR-MS (EI) calcd for C18H26N4O 314.2106, found 314.2089.
(1S,2R)-1-P h en yl-2-[(S)-1-a zid o-3-m eth ylbu tyl]-N,N-d i-
eth ylcyclop r op a n eca r boxa m id e (5d ). Compound 5d was
prepared from 4d (240 mg, 0.792 mmol) as described above
for 5c. After purification by column chromatography (silica
gel; EtOAc/hexane, 1:2), 5d was obtained as an oil (243 mg,
94%): 1H NMR (500 MHz, CDCl3) 0.37 (3 H, t, J ) 7.0 Hz),
0.92 (3 H, d, J ) 6.5 Hz), 0.95 (1 H, dd, J ) 5.0, 9.5 Hz), 0.97
(3 H, d, J ) 6.5 Hz), 1.12 (3 H, t, J ) 7.0 Hz), 1.54 (1 H, ddd,
J ) 4.5, 9.5, 14.0 Hz), 1.65 (1H, dd, J ) 5.0, 6.5 Hz), 1.74 (1
H, ddd, J ) 4.5, 9.5, 14.0 Hz), 1.83-1.90 (1 H, m), 1.96 (1 H,
ddd, J ) 6.5, 9.5, 9.5 Hz), 2.92 (1 H, ddd, J ) 4.5, 9.5, 9.5 Hz),
3.03 (1 H, dq, J ) 14.0, 7.0 Hz), 3.16 (1 H, dq, J ) 14.0, 7.0
Hz), 3.53 (1 H, dq, J ) 14.0, 7.0 Hz), 3.71 (1 H, dq, J ) 14.0,
7.0 Hz), 7.20-7.32 (5 H, m); HR-MS (EI) calcd for C19H28N4O
328.2263, found 328.2256.
(1S,2R)-1-P h en yl-2-[(R)-1-a zid o-1-p h en ylm eth yl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e (5e). Compound 5e was
prepared from 4e (130 mg, 0.40 mmol) as described above for
5c. After purification by column chromatography (silica gel;
EtOAc/hexane, 1:2), 5e was obtained as an oil (132 mg, 95%
yield): 1H NMR (500 MHz, CDCl3) 0.19 (3 H, t, J ) 7.0 Hz),
1.10 (3 H, t, J ) 7.0 Hz), 1.23 (1 H, dd, J ) 5.0, 9.0 Hz), 2.00
(1 H, dd, J ) 5.0, 6.5 Hz), 2.10 (1 H, dq, 14.0, 7.0 Hz), 2.36 (1
H, ddd, J ) 6.5, 9.0, 9.0 Hz), 2.95 (1 H, dq, J ) 14.0, 7.0 Hz),
3.21 (1 H, dq, J ) 14.0, 7.0 Hz), 3.28 (1 H, dq, J ) 14.0, 7.0
Hz), 4.28 (1 H, d, J ) 9.0 Hz), 7.17-7.43 (10 H, m); HR-MS
(EI) calcd for C21H24N4O 348.1950, found 348.1942.
Gen er a l P r oced u r e for th e Red u ction of Azid o De-
r iva tives. A mixture of 5c-e (1.00 mmol) and 10% Pd-
charcoal (50 mg) in MeOH (10 mL) was stirred under atmo-
spheric pressure of hydrogen at room temperature for 1.5 h,
and then the catalyst was filtered off. The filtrate was
evaporated, and the residue was purified by column chroma-
tography (silica gel; CHCl3/MeOH/28% NH4OH, 90:20:0.5) to
give free amines 2c-e as oil. The oil was partitioned between
CHCl3 and 1 N NaOH, and then the CHCl3 phase was washed
twice with brine, dried (Na2SO4), and evaporated. The residue
was dissolved in MeOH (1 mL), the solution was put on a
column of Diaion WA-30 resin (2 × 8 cm, Cl- form), and the
column was developed with MeOH. The solvent was evapo-
rated, and the residue was treated with ether to give white
crystals of 2c-e as hydrochlorides.
(1S,2R)-1-P h en yl-2-[(R)-1-a m in o-1-p h en ylm eth yl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e h yd r och lor id e (2e):
yield 88%; mp 149-150 °C; [R]27 ) -104.9 (c 0.610, CHCl3);
D
1H NMR (500 MHz, CDCl3) 0.18 (3 H, t, J ) 7.0 Hz), 1.01 (3
H, t, J ) 7.0 Hz), 1.08-1.12 (1 H, m), 1.83-1.86 (1 H, m), 2.08-
2.18 (1 H, m), 2.42-2.47 (1 H, m), 2.89 (1 H, dq, J ) 14.0, 7.0
Hz), 3.09 (1 H, dq, J ) 14.0, 7.0 Hz), 3.23 (1 H, dq, J ) 14.0,
7.0 Hz), 4.07-4.09 (1 H, m), 7.11-7.57 (10 H, m), 8.91 (3 H,
br s); MS (EI) m/z 322 (M+). Anal. (C21H27ClN2O‚0.8H2O) C,
H, N.
(E a n d Z)-(1R,2S)-1-P h en yl-2-[3-(p h en ylselen o)-1-p r o-
p en yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e (7). A mix-
ture of 4f (220 mg, 0.806 mmol) and (CF3CO)2O (145 µL, 1.05
mmol) in MeCN (10 mL) was stirred at room temperature for
1 h under argon. The resulting solution was added to a
NaSePh solution, which was prepared by stirring a mixture
of NaBH4 (95 mg, 2.5 mmol) and (PhSe)2 (328 mg, 1.05 mmol)
in EtOH (15 mL) at room temperature for 1 h, and the mixture
was heated under reflux for 16 h under argon. The resulting
mixture was evaporated, and the residue was partitioned
between CH2Cl2 and water. The separated organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; MeOH/CHCl3, 1:6) to
give 7 as an oil (252 mg, 76%); 1H NMR (500 MHz, CDCl3)
0.51 (t, J ) 7.0 Hz), 0.52 (t, J ) 7.0 Hz), 1.02-1.10 (m), 1.08
(t, J ) 7.0 Hz), 1.67 (dd, J ) 5.5, 6.0 Hz), 1.70 (dd, J ) 5.0, 6.0
Hz), 2.49 (ddd, J ) 6.0, 9.0, 9.5 Hz), 2.58 (ddd, J ) 6.0, 9.5,
9.5 Hz), 2.89 (dq, J ) 14.0, 7.0 Hz), 2.89-3.54 (m), 3.15 (dq, J
) 14.0, 7.0 Hz), 3.41 (dq, J ) 14.0, 7.0 Hz), 3.49 (dq, J ) 14.0,
7.0 Hz), 3.53 (d, J ) 7.5 Hz), 3.78 (d, J ) 7.5 Hz), 5.00 (dd, J
) 9.5, 10.5 Hz), 5.09 (1 H, dd, J ) 9.5, 15.0 Hz), 5.72 (dt, j )
10.5, 7.5 Hz), 5.88 (dt, J ) 15.0, 7.5 Hz), 7.16-7.50 (m); HR-
MS (EI) calcd for C23H27NOSe 413.1257, found 413.1237.
(1R,2S)-1-P h en yl-2-[1-(ter t-bu toxyca r bon yl)a m in o]-2-
pr open yl]-N,N-dieth ylcyclopr opan ecar boxam ides (8 an d
9). To a solution of 7 (150 mg, 0.364 mmol), t-BuO2CNH2 (128
mg, 1.09 mmol), and i-PrNH2 (0.38 mL, 2.2 mmol) in MeOH
(0.5 mL) was added at 0 °C under argon NCS (146 mg, 1.09
mmol), and the mixture was stirred at room temperature for
2 h. The resulting mixture was evaporated and the residue
was partitioned between diethyl ether and water. The sepa-
rated organic layer was washed with brine, dried (Na2SO4),
evaporated, and purified by column chromatography (silica gel;
hexane/EtOAc, 5:1) to give the mixture of 8 and 9 as an oil
(135 mg, 99%, 8:9 ) 1:6): 1H NMR (500 MHz, CDCl3) 0.54 (br
t, J ) 7.0 Hz), 0.77 (br t, J ) 7.0 Hz), 1.12-1.20 (m), 1.40-
1.50 (m), 1.57-1.62 (m), 1.83 (dd, J ) 8.0, 16.0 Hz), 3.07 (dq,
J ) 14.0, 7.0 Hz), 3.12-3.23 (m), 3.28 (dq, J ) 14.0, 7.0 Hz),
3.32 (dq, J ) 14.0, 7.0 Hz), 3.36 (dq, J ) 14.0, 7.0 Hz), 3.38
(dq, J ) 14.0, 7.0 Hz), 3.52 (dq, J ) 14.0, 7.0 Hz), 3.61 (dq, J
) 14.0, 7.0 Hz), 3.80-3.90 (m), 4.30-4.40 (1 H, m), 4.95 (br
s), 5.11 (d, J ) 10.5 Hz), 5.12 (d, J ) 10.0 Hz), 5.18 (d, J )
17.0 Hz), 5.20 (d, J ) 17.0 Hz), 5.87 (br s), 6.03-6.10 (m), 7.18-
7.31 (m); MS (EI) m/z 372 (M+).
(1S,2R)-1-P h en yl-2-[(S)-1-h yd r oxy-2-(eth oxyca r bon yl)-
eth yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e (10). To a
solution of HN(TMS)2 (3.93 mL, 18.6 mmol) in THF (20 mL)
was added dropwise BuLi solution (1.66 M in hexane, 11.2 mL,
18.6 mmol) at -10 °C under argon. After 20 min the solution
was cooled to -78 °C and EtOAc (1.86 mL, 18.6 mmol) was
added dropwise, and then the solution was stirred for 20 min
at the same temperature. A solution of 3 (3.8 g, 15.5 mmol)
(1S,2R)-1-P h en yl-2-[(S)-1-a m in obu tyl]-N,N-d ieth ylcy-
clop r op a n eca r boxa m id e h yd r och lor id e (2c): yield 95%;
mp 205-207 °C; [R]27D ) +86.7 (c 0.766, MeOH); 1H NMR (500
MHz, CDCl3) 0.90 (3 H, t, J ) 7.5 Hz), 1.10 (3 H, t, J ) 7.0
Hz), 1.06-1.09 (1 H, m), 1.43-1.65 (3 H, m), 1.90 (1 H, dd, J
) 6.0, 9.0 Hz), 2.01-2.09 (1 H, m), 2.24-2.31 (1 H, m), 2.65-

4850 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Shuto et al.
in THF (20 mL) was added dropwise to the solution, and the
resulting solution was stirred at the same temperature for 2
h. The cooling bath was removed, and the reaction mixture
was quenched by an addition of saturated NH4Cl (10 mL).
After the mixture was concentrated in vacuo, EtOAc and water
were added, and then the mixture was partitioned. The
separated organic layer was washed with brine, dried (Na2-
SO4), evaporated, and purified by column chromatography
(silica gel, hexane/EtOAc, 2:1) to give 10 as an oil (4.1 g, 79%)
and the corresponding 1′R-diastereomer as an oil (0.49 g, 10%).
10: 1H NMR (500 MHz, CDCl3) 0.89 (3 H, t, J ) 7.0 Hz), 1.14
(3 H, t, J ) 7.0 Hz), 1.17 (1 H, dd, J ) 5.5, 6.5 Hz), 1.27 (3 H,
t, J ) 7.0 Hz), 1.37 (1 H, ddd, J ) 6.5, 8.5, 9.0 Hz), 1.63 (1 H,
dd, J ) 5.5, 8.5 Hz), 2.58 (1 H, dd, J ) 6.0, 15.0 Hz), 2.70 (1
H, dd, J ) 7.5, 15.0 Hz), 3.34 (1 H, dq, J ) 14.0, 7.0 Hz), 3.35
(1 H, dq, J ) 14.0, 7.0 Hz), 3.43 (1 H, dq, J ) 14.0, 7.0 Hz),
3.51 (1 H, dq, J ) 14.0, 7.0 Hz), 3.62-3.67 (1 H, m), 4.16 (2 H,
q, J ) 7.0 Hz), 5.40 (1 H, br s), 7.19-7.30 (5 H, m); MS (EI)
m/z 333 (M+). Anal. (C19H27NO4) C, H, N.
(28% in MeOH, 2.5 mL), and the resulting mixture was stirred
at room temperature for 15 h under argon and then neutral-
ized with AcOH. The resulting mixture was evaporated, and
the residue was partitioned between EtOAc and water. The
separated organic layer was washed with brine, dried (Na2-
SO4), evaporated, and purified by column chromatography
(silica gel; EtOAc/hexane, 3:1) to give 14 as a white powder
(1.04 g, 99%): 1H NMR (500 MHz, CDCl3) 0.44 (3 H, t, J )
7.0 Hz), 1.13 (3 H, t, J ) 7.0 Hz), 1.10-1.14 (1 H, m), 1.58 (1
H, dd, J ) 5.5, 6.0 Hz), 1.83 (1 H, br s), 1.87-2.08 (3 H, m),
3.08 (1 H, dq, J ) 14.0, 7.0 Hz), 3.18-3.29 (2 H, m), 3.50 (1 H,
dq, J ) 14.0, 7.0 Hz), 3.65 (1 H, dq, J ) 14.0, 7.0 Hz), 3.84 (2
H, t, J ) 6.0 Hz), 7.21-7.33 (5 H, m); MS (EI) m/z 385 (M+).
Anal. (C22H33N4O2) C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-azido-3-(tosyloxy)pr opyl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e (15). A mixture of 14
(400 mg, 1.27 mmol), TsCl (606 mg, 3.18 mmol), Et3N (0.89
mL, 6.4 mmol), and DMAP (20 mg, 0.16 mmol) in CH2Cl2 (10
mL) was stirred at room temperature for 15 h, and then water
and CH2Cl2 were added. The separated organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; EtOAc/hexane, 1:3) to
give 15 as an oil (592 mg, 99%): 1H NMR (500 MHz, CDCl3)
0.49 (3 H, t, J ) 7.0 Hz), 1.10 (3 H, t, J ) 7.0 Hz), 1.20 (1 H,
dd, J ) 5.0, 9.5 Hz), 1.41 (1 H, dd, J ) 5.0, 6.5 Hz), 1.68 (1 H,
ddd, J ) 6.5, 9.5, 9.5 Hz), 1.92-1.99 (1 H, m), 2.03-2.10 (1 H,
m), 2.45 (3 H, s), 3.09 (1 H, dq, J ) 14.0, 7.0 Hz), 3.19-3.26 (2
H, m), 3.46 (1 H, dq, J ) 14.0, 7.0 Hz), 3.55 (1 H, dq, J ) 14.0,
7.0 Hz), 4.11-4.16 (1 H, m), 4.19-4.24 (1 H, m), 7.22-7.36 (7
H, m), 7.80 (2 H, d, J ) 8.0 Hz); MS (EI) m/z 470 (M+). Anal.
(C24H30N4O4S‚0.1H2O) C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-azido-3-(ph en ylselen o)pr opyl]-
N,N-d ieth ylcyclop r op a n eca r boxa m id e (16). A mixture of
(PhSe)2 (165 mg, 0.528 mmol) and NaBH4 (60 mg, 1.58 mmol)
in EtOH (10 mL) was stirred at room temperature for 1 h
under argon, to which a solution of 15 (190 mg, 0.404 mmol)
in EtOH (4 mL) was added. The resulting mixture was stirred
at room temperature for 15 h and then evaporated. The
residue was partitioned between diethyl ether and water. The
separated organic layer was washed with brine, dried (Na2-
SO4), evaporated, and purified by column chromatography
(silica gel; EtOAc/hexane, 1:3) to give 16 as an oil (156 mg,
85%): 1H NMR (500 MHz, CDCl3) 0.41 (3 H, t, J ) 7.0 Hz),
1.01 (1 H, dd, J ) 5.0, 9.5 Hz), 1.13 (3 H, t, J ) 7.0 Hz), 1.54
(1 H, dd, J ) 5.0, 6.5 Hz), 1.87 (1 H, ddd, J ) 6.5, 9.5, 9.5 Hz),
2.02-2.11 (2 H, m), 2.91-2.97 (1 H, m), 3.02-3.15 (3 H, m),
3.20 (1 H, dq, J ) 14.0, 7.0 Hz), 3.50 (1 H, dq, J ) 14.0, 7.0
Hz), 3.64 (1 H, dq, J ) 14.0, 7.0 Hz), 7.20-7.31 (8 H, m), 7.51-
7.53 (2 H, m); MS (EI) m/z 456 (M+). Anal. (C23H28N4O4Se)
C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-a m in o-3-(p h en ylselen o)p r o-
p yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e (17). A mix-
ture of 16 (400 mg, 1.27 mmol) and Ph3P (180 mg, 0.69 mmol)
in pyridine (2 mL) was stirred at room temperature for 1 h,
28% NH4OH (2 mL) was added, and then the mixture was
stirred at room temperature for 12 h. The resulting mixture
was evaporated, and the residue was partitioned between
diethyl ether and water. The separated organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; CHCl3/MeOH/28% NH4-
OH, 90:10:0.2) to give 17 as an oil (70 mg, 93%): 1H NMR
(500 MHz, CDCl3) 0.83 (3 H, t, J ) 7.0 Hz), 1.09 (1 H, dd, J )
5.0, 6.5 Hz), 1.13 (3 H, t, J ) 7.0 Hz), 1.20 (1 H, ddd, J ) 6.5,
9.0, 9.5 Hz), 1.49 (1 H, dd, J ) 5.0, 9.0 Hz), 1.85-2.01 (2 H,
m), 2.22 (2 H, br s), 2.54 (1 H, ddd, J ) 5.0, 8.0, 9.5 Hz), 2.99
(1 H, ddd, J ) 6.5, 9.5, 12.0 Hz), 3.09 (1 H, ddd, J ) 5.5, 9.5,
12.0 Hz), 3.28 (1 H, dq, J ) 14.0, 7.0 Hz), 3.31 (1 H, dq, J )
14.0, 7.0 Hz), 3.42 (1 H, dq, J ) 14.0, 7.0 Hz), 3.53 (1 H, dq, J
) 14.0, 7.0 Hz), 7.17-7.69 (10 H, m); HR-MS (EI) calcd for
C23H30N2OSe 430.1523, found 413.1497.
Th e 1′-d ia ster eom er of 10: 1H-NMR (500 MHz, CDCl3)
0.80 (3 H, t, J ) 7.0 Hz), 1.11 (3 H, t, J ) 7.0 Hz), 1.25 (3 H,
t, J ) 7.0 Hz), 1.38 (1 H, ddd, J ) 6.5, 6.5, 9.0 Hz), 1.48 (1 H,
dd, J ) 5.5, 6.5 Hz), 1.57 (1 H, dd, J ) 5.5, 9.0 Hz), 2.61 (1 H,
dd, J ) 8.5, 16.0 Hz), 2.87 (1 H, dd, J ) 4.0, 16.0 Hz), 3.25-
3.51 (4 H, m), 3.43 (1 H, d, J ) 4.0 Hz), 4.15 (2 H, q, J ) 7.0
Hz), 4.26-4.30 (1 H, m), 7.19-7.31 (5 H, m); MS (EI) m/z 333
(M+).
(1S,2R)-1-P h en yl-2-[(S)-1,3-d ih yd r oxyp r op yl]-N,N-d i-
eth ylcyclop r op a n eca r boxa m id e (11). A mixture of NaBH4
(4.50 g, 119 mmol) and 10 (3.97 g, 11.9 mmol) in MeOH (40
mL) was stirred for 2 h at room temperature and then heated
under reflux for 1 h. The mixture was cooled to room
temperature and quenched by an addition of AcOH, and the
resulting mixture was evaporated. The residue was parti-
tioned between EtOAc and water. The separated organic layer
was washed with brine, dried (Na2SO4), evaporated, and
purified by column chromatography (silica gel; MeOH/CHCl3,
1:6) to give 11 as a white powder (766 mg, 96%): 1H NMR
(500 MHz, CDCl3) 0.92 (3 H, t, J ) 7.0 Hz), 1.05 (1 H, dd, J )
5.5, 6.5 Hz), 1.15 (3 H, t, J ) 7.0 Hz), 1.33 (1 H, ddd, J ) 6.5,
8.5, 9.0 Hz), 1.71 (1 H, dd, J ) 5.5, 8.5 Hz), 1.81-1.93 (2 H,
m), 2.61 (1 H, br s), 3.32-3.53 (5 H, m), 3.79-3.87 (2 H, m),
5.83 (1 H, br s), 7.17-7.35 (5 H, m); MS (EI) m/z 291 (M+).
Anal. (C17H25NO3‚0.2H2O) C, H, N.
(1S,2R-)-1-P h en yl-2-[(S)-1-h yd r oxy-3-(p iva loyloxy)p r o-
p yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e (12). A mix-
ture of 11 (1.60 g, 5.50 mmol) and pivaloyl chloride (1.26 mL,
7.59 mmol) in pyridine (30 mL) was stirred at 0 °C for 1.5 h
under argon, and then water was added. The resulting
mixture was evaporated, and the residue was partitioned
between EtOAc and water. The separated organic layer was
washed with brine, dried (Na2SO4), evaporated, and purified
by column chromatography (silica gel; EtOAc/hexane, 1:3) to
give 12 as an oil (1.81 g, 88%): 1H NMR (500 MHz, CDCl3)
0.91 (3 H, t, J ) 7.0 Hz), 1.03 (1 H, dd, J ) 5.5, 6.5 Hz), 1.13
(3 H, t, J ) 7.0 Hz), 1.18 (9 H, s), 1.29 (1 H, ddd, J ) 6.5, 8.5,
9.0 Hz), 1.70 (1 H, dd, J ) 5.5, 8.5 Hz), 1.89-2.03 (2 H, m),
3.23-3.28 (1 H, m), 3.31-3.46 (3 H, m), 3.51 (1 H, dq, J )
14.0, 7.0 Hz), 4.24 (2 H, t, J ) 6.5 Hz), 7.20-7.31 (5 H, m);
MS (EI) m/z 375 (M+). Anal. (C22H33NO4) C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-a zid o-3-(p iva loyloxy)p r op yl]-
N,N-d iet h ylcyclop r op a n eca r b oxa m id e (13). Compound
13 was prepared from 12 (1.50 g, 4.0 mmol) as described above
for 5c. After purification by column chromatography (silica
gel; EtOAc/hexane, 1:2), 13 was obtained as an oil (1.46 g,
91%): 1H NMR (500 MHz, CDCl3) 0.41 (3 H, t, J ) 7.0 Hz),
1.06 (1 H, dd, J ) 5.0, 9.0 Hz), 1.12 (3 H, t, J ) 7.0 Hz), 1.21
(9 H, s), 1.59 (1 H, dd, J ) 5.0, 6.5 Hz), 1.92 (1 H, ddd, J )
6.5, 9.0, 9.5 Hz), 1.98-2.13 (2 H, m), 3.07 (1 H, dq, J ) 4.0,
7.0 Hz), 3.11-3.15 (1 H, m), 3.19 (1 H, dq, J ) 14.0, 7.0 Hz),
3.49 (1 H, dq, J ) 14.0, 7.0 Hz), 3.67 (1 H, dq, J ) 14.0, 7.0
Hz), 4.19-4.29 (2 H, m), 7.21-7.32 (5 H, m); MS (EI) m/z 400
(M+). Anal. (C22H34N4O3) C, H, N.
(1S,2R)-1-P h en yl-2-[(S)-1-[(ter t-bu toxycar bon yl)am in o]-
3-(p h en ylselen o)p r op yl]-N,N-d iet h ylcyclop r op a n eca r -
boxa m id e (18). A mixture of 17 (400 mg, 1.27 mmol) and
Boc2O (960 mg, 2.11 mmol) in CH2Cl2 (35 mL) was stirred at
room temperature for 5 h, and then water and CH2Cl2 were
added. The organic layer separated was washed with brine,
(1S,2R)-1-P h en yl-2-[(S)-1-a zid o-3-h yd r oxyp r op yl]-N,N-
d ieth ylcyclop r op a n eca r boxa m id e (14). To a solution of
13 (1.33 g, 3.33 mmol) in MeOH (30 mL) was added NaOMe

New NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24 4851
dried (Na2SO4), evaporated, and purified by column chroma-
tography (silica gel; EtOAc/hexane, 1:3) to give 18 as a white
powder (1.02 g, 92%): 1H NMR (500 MHz, CDCl3) 0.57 (3 H,
br t), 1.13 (3 H, t, J ) 7.0 Hz), 1.19-1.34 (2 H, m), 1.41 (9 H,
s), 1.72-1.78 (1 H, m), 2.03-2.12 (1 H, m), 2.32-2.42 (1 H,
m), 2.92 (1 H, ddd, J ) 7.0, 9.0, 12.0 Hz), 3.01 (1 H, ddd, J )
5.0, 9.5, 12.0 Hz), 3.06-3.15 (1 H, m), 3.27 (1 H, dq, J ) 14.0,
7.0 Hz), 3.38 (1 H, dq, J ) 14.0, 7.0 Hz), 3.44-3.52 (1 H, m),
3.56 (1 H, dq, J ) 14.0, 7.0 Hz), 4.94 (1 H, br s), 7.17-7.29 (8
H, m), 7.47-749 (2 H, m); MS (EI) m/z 530 (M+). Anal.
(C28H38N2O3Se) C, H, N.
tine (10 µM). Incubations were stopped by rapid filtration over
GF/C glass-fiber filters that were presoaked in a solution of
0.1% polyethylenimine for at least 1 h before use. Filters were
washed with cold Tris-HCl buffer (4 mL × 3), and specific
binding was defined as bound radioactivity.
Ack n ow led gm en t . We are grateful to Messrs.
Daisuke Mochizuki, Ryuichi Tsujita, and Hironao Taka-
da and Mrs. Kanako Yamashita for their help and
encouraging discussions. We are also grateful to Daiso
Co., Ltd. for their gift of chiral epichlorohydrins.
(1S,2R)-1-P h en yl-2-[(S)-1-[(ter t-bu toxycar bon yl)am in o]-
2-p r op en yl]-N,N-d ieth ylcyclop r op a n eca r boxa m id e (8). A
mixture of 18 (680 mg, 1.28 mmol) and aqueous H2O2 (30%,
1.2 mL) in THF (25 mL) was stirred at room temperature for
5 days, and then water and CH2Cl2 were added. The separated
organic layer was washed with brine, dried (Na2SO4), evapo-
rated, and purified by column chromatography (silica gel;
CHCl3/MeOH, 20:1) to give 8 as a white powder (449 mg,
95%): 1H NMR (500 MHz, CDCl3) 0.54 (3 H, br t, J ) 7.0 Hz),
1.12-1.20 (1 H, m), 1.13 (3 H, t, J ) 7.0 Hz), 1.42 (9 H, s),
1.46-1.50 (1 H, m), 1.83 (1 H, dd, J ) 8.0, 16.0 Hz), 3.07 (1 H,
dq, J ) 14.0, 7.0 Hz), 3.32 (1 H, dq, J ) 14.0, 7.0 Hz), 3.36 (1
H, dq, J ) 14.0, 7.0 Hz), 3.61 (1 H, dq, J ) 14.0, 7.0 Hz), 3.80-
3.90 (1 H, m), 4.95 (1 H, br s), 5.11 (1 H, d, J ) 10.5 Hz), 5.20
(1 H, d, J ) 17.0 Hz), 6.03-6.10 (1 H, m), 7.18-7.30 (5 H, m);
HR-MS (EI) calcd for C22H32N2O3 372.2413, found 372.2419.
(1S,2R)-1-P h en yl-2-[(S)-1-a m in o-2-p r op en yl]-N,N-d i-
eth ylcyclop r op a n eca r boxa m id e (2f). A mixture of 19 (100
mg, 0.268 mmol) and aqueous TFA (90%, 3 mL) in MeOH (4.5
mL) was stirred at room temperature for 15 h. The pH of the
mixture was adjusted to about 10 with 3 M KOH, and then
CH2Cl2 was added. The separated organic layer was washed
with brine, dried (Na2SO4), evaporated, and purified by column
chromatography (silica gel; CHCl3/MeOH/28% NH4OH, 80:20:
0.2) to give an oil. The oil was dissolved in MeOH (1 mL),
which was put on a column of Diaion WA-30 resin (1 × 5 cm,
Cl- form), and the column was developed with MeOH. The
solvent was evaporated, and the residue was treated with
diethyl ether to give white crystals of 2f as hydrochloride (40
Refer en ces
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(4) (a) Willetts, J .; Balster, R. L.; Leander, J . D. The behavioral
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anticonvulsant potency of (()-2-amino-5-phophonopentanoic acid
and (()-2-amino-7-phophonoheptanoic acid. Neuroscience 1983,
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(6) Compound (()-1 had previously been called “midalcipran”.
However, since the clinical studies began, the name “milnacip-
ran” has generally been used for (()-1.
(7) (a) Briley, M. Midalcipran hydrochloride. Drugs Future 1986,
11, 21-23. (b) Moret, C.; Charveron, M.; Finberg, J . P. M.;
Cozinier, J .; M. Briley, M. Biochemical profile of midalcipran
(F-2207). (Z)-1-Phenyl-1-diethylaminocarbonyl-2-aminometh-
ylcyclopropane hydrochloride, a potential fourth generation
antidepressant drug. Neuropharmacology 1985, 24, 1211-1219.
(c) Bonnaud, B.; Cousse, H.; Mouzin, G.; Briley, M.; Stenger, A.;
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(8) Shuto, S.; Takada, H.; Mochizuki, D.; Tsujita, R.; Hase, Y.; Ono,
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2968.
mg, 50%): mp 185-188 °C; [R]27 ) +83.7 (c 0.680, MeOH);
D
1H NMR (500 MHz, CDCl3) 0.91 (3 H, t, J ) 7.0 Hz), 1.09 (1
H, dd, J ) 6.0, 6.5 Hz), 1.11 (3 H, t, J ) 7.0 Hz), 1.72 (1 H,
ddd, J ) 6.5, 9.0, 10.0 Hz), 1.88 (1 H, dd, J ) 6.0, 9.0 Hz),
3.20 (1 H, dd, J ) 7.0, 10.0 Hz), 3.30 (1 H, dq, J ) 14.0, 7.0
Hz), 3.34-3.49 (3 H, m), 5.42 (1 H, d, J ) 10.5 Hz), 5.54 (1 H,
d, J ) 17.5 Hz), 6.35 (1 H, ddd, J ) 7.0, 10.5, 17.5 Hz), 7.20-
7.31 (5 H, m), 9.20 (3 H, br s); MS (EI) m/z 272 (M+). Anal.
(C17H25ClN2O‚0.2H2O) C, H, N.
Ca ta lytic Hyd r ogen a tion of 2f. Compound 2f (hydro-
chloride, 3.2 mg) was partitioned between CHCl3 (5 mL) and
1 M NaOH (2 mL). The separated organic layer was washed
with brine, dried (Na2SO4), and evaporated. A mixture of the
residue and 10% Pd-charcoal (1 mg) in MeOH (2 mL) was
stirred under atmospheric pressure of hydrogen at room
temperature for 1.5 h, and then the catalyst was filtered off.
The filtrate was evaporated to give 2b as an oil (2.5 mg, 78%):
1H NMR (500 MHz, CDCl3) 0.81 (3 H, t, J ) 7.0 Hz), 0.95 (3
H, t, J ) 7.5 Hz), 1.11-1.15 (1 H, m), 1.13 (3 H, t, J ) 7.0 Hz),
1.19-1.27 (1 H, m), 1.47 (1 H, dd, J ) 5.0, 9.0 Hz), 1.48-1.55
(1 H, m), 1.59-1.67 (1 H, m), 2.31-2.34 (3 H, m), 3.26 (1 H,
dq, J ) 14.0, 7.0 Hz), 3.29 (1 H, dq, J ) 14.0, 7.0 Hz), 3.45 (1
H, dq, J ) 14.0, 7.0 Hz), 3.57 (1 H, dq, J ) 14.0, 7.0 Hz), 7.16-
7.29 (5 H, m); MS (EI) m/z 274 (M+).
Bin d in g Assa y. The binding affinity for the NMDA
receptors was investigated according to previously reported
methods.17
Assa y w ith Volta ge-Cla m p ed Oocytes. The blocking
effects of the compound on the NMDA receptors were inves-
tigated according to previously reported methods.18
(9) (a) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Takada, H.;
Yamashita, K.; Matsuda, A. Conformational restriction by
repulsion between adjacent substituents of a cyclopropane
ring: design and enantioselective synthesis of 1-phenyl-2-(1-
aminoalkyl)-N,N-diethylcyclopropanecarboxamides as potent
NMDA receptor antagonists. J . Org. Chem. 1996, 61, 915-923.
(b) Ono, S.; Shuto, S.; Matsuda, A. Highly stereoselective
nucleophilic addition to cyclopropyl carbonyls: the facial selec-
tivity in the cyclopropyl ketones is opposite to that in the
corresponding aldehyde. Tetrahedron Lett. 1996, 37, 221-224.
(c) Shuto, S.; Ono, S.; Hase, Y.; Kamiyama, N.; Matsuda, A.
Synthesis of (+)- and (-)-milnaciprans and their conformation-
ally restricted analogs. Tetrahedron Lett. 1996, 37, 641-644.
In h ibitor y Effects on th e Up ta k e of 5-HT. Under
various concentrations of the compounds, cerebral cortical
synaptic membrane from rats was incubated at 20 °C for 45
min in the presence of [3H]paroxetine (2 nM) in 50 mM Tris-
HCl (pH 7.4) containing NaCl (120 mM) and KCl (5 mM).
Nonspecific binding was determined by the addition of femoxe-
(10) Calculations were performed by
a semiempirical quantum
method, PM3 in Spartan (Version 4.0) programs on a Silicon
Graphics IRIS Indy R4600 PC.

4852 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 24
Shuto et al.
(11) The enantiomeric purity of these conformationally restricted
analogs was 96% ee, as measured by HPLC with a Chiralcel-
OJ column (Daicel Chemical Co., Ltd.); see ref 9a.
(12) Yamamoto, I.; Sekine, M.; Hata, T. One-step synthesis of
5′-azide-nucleosides. J . Chem. Soc., Perkin Trans. 1980, 306-
310.
(18) (a) Yoshii, K.; Kurihara, K. Inward rectifier produced by Xenopus
oocytes injected with mRNA extracted from carp olfactory
epithelium. Synapse 1989, 3, 234-238. (b) Yoshii, K.; Yu, L.;
Mixter-Mayne, K.; Davidson, N.; Lester, H. A. Equilibrium
properties of mouse-torpedo acetylcholine receptor hybrids
expressed in Xenopus oocyte. J . Gen. Physiol. 1987, 90, 553-
557. (c) Kawano, H.; Sashihara, S.; Mita, T.; Ohno, K.; Kawa-
mura, M.; Yoshii, K. Phenytoin, an antiepileptic drug, competi-
tively blocked non-NMDA receptors produced by Xenopus oocytes.
Neurosci. Lett. 1994, 166, 183-186.
(19) Although the binding affinity of milnacipran for the NMDA
receptor has been reported previously (ref 8), its effect on the
NMDA receptor under voltage-clamp conditions with Xenopus
oocytes has not been investigated.
(20) Preliminary results with the NMDA receptors expressed by
Xenopus oocytes suggested that PPCD has a blockade mecha-
nism different from that of MK-801; for example, the time
constant of the recovery of NMDA responses from channel
blockade by PPCD was about 5 s, which was greatly faster than
that with MKI-801 (90 min, reported by Huettner and Beam;
ref 2d).
(21) Studies on the binding of (()-1 to a wide range of receptors have
shown that it completely lacks affinity for neurotransmitter
receptors (ref 7). In a preliminary experiment, we evaluated
the binding affinity of PPDC for 5-HT1A, 5-HT2, D1, D2, and
mACh receptors. PPDC did not show any significant binding
to any of the neurotransmitter receptors tested, except for the
NMDA receptor.
(22) (a) Silverman, R. B. The organic chemistry of drug design and
drug action; Academic Press: San Diego, CA, 1992. (b) Kozikows-
ki, A., Eds. Drug design for neuroscience; Raven Press: New
York, 1993.
(13) (a) Shea, R. G.; Fitzner, J . N.; Fankhauser, J . E.; Hopkns, P. B.
Direct conversion of allylic selenides to protected allylic amines.
J . Org. Chem. 1984, 49, 3647-3650. (b) Futzner, J . N.; Shea,
R. G.; Fankhauser, J . E.; Hopkins, P. B. Asymmetric carbon to
nitrogen bond formation using optically active allylic selenides:
a new general method for the synthesis of N-protected optically
active R-amino acids. J . Org. Chem. 1985, 50, 417-419. (c)
Hassan, A. E. A.; Matsuda, A. [2,3]-Sigmatropic rearrangement
of the allylic selenides to allylic amines in sugar moiety of
pyrimidine nucleosides: synthesis of 3′-amino-2′,3′-dideoxy-2′-
methylidenecytidine. Heterocycles 1992, 34, 657-661. (d) Has-
san, A. E. A.; Shuto, S.; Matsuda, A. Chemical reactivity of the
sugar moiety of 2′-deoxy-2′-methylidene pyrimidine nucleo-
sides: synthesis of 3′-amino-2′,3′-dideoxy-2′-methylidene pyrim-
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(14) The ratio of the mixture was 1:6. We later recognized that the
minor product was the desired 2′S-diastereomer 8 by comparing
the 1H NMR spectrum of the diastereomeric mixture with that
of pure 8 prepared by another procedure, as shown in Scheme
3.
(15) Mungall, W. S.; Greene, G. L.; Heavner, G. A.; Letsinger, R. L.
Use of the azido group in the synthesis of 5′-terminal aminode-
oxythymidine oligonucleotides. J . Org. Chem. 1975, 40, 1659-
1662.
(16) All of the conformationally restricted analogs were isolated as
hydrochlorides, which were used in the biological evaluation.
(17) Asano, T.; Ikegaki, I.; Satoh, S.; Mochizuki, D.; Hidaka, H.;
Suzuki, Y.; Shibuya, M.; Sugita, K. Blockade of intracellular
actions of calcium may protect against ischaemic damage to the
gerbil brain. Br. J . Pharmacol. 1991, 103, 1935-1938.
J M960495W