Synthesis of a novel water-soluble cleft-type cyclophane as an N-methyl-D-aspartate receptor antagonist

Article abstract of DOI:10.1248/cpb.57.95

Novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, 4,4′-bis({2-[N-(1,4,8,11-tetraazacy-clotetradecan-1-yl)acetyl] -N-phenethyl}aminoethoxy)diphenylmethane octahydrochloride (1, ACPCm) and 4,4′ bis({2-[N-(1,4,7,10-tetraazacyclododecan-1-

Full text of DOI:10.1248/cpb.57.95

January 2009
Notes
Chem. Pharm. Bull. 57(1) 95—98 (2009)
95
Synthesis of a Novel Water-Soluble Cleft-Type Cyclophane as an
N-Methyl-D-aspartate Receptor Antagonist
Takashi MASUKO, Tadashi KUSAMA, Rie NAMIKI, Koichi METORI, Yasuo KIZAWA, and
*
Muneharu MIYAKE
College of Pharmacy, Nihon University; 7–7–1 Narashinodai, Funabashi, Chiba 274–8555, Japan.
Received September 5, 2008; accepted October 18, 2008; published online October 21, 2008
Novel water-soluble N-methyl-D-aspartate (NMDA) receptor antagonists, 4,4ꢀ-bis({2-[N-(1,4,8,11-tetraazacy-
clotetradecan-1-yl)acetyl]-N-phenethyl}aminoethoxy)diphenylmethane octahydrochloride (1, ACPCm) and 4,4ꢀ-
bis({2-[N-(1,4,7,10-tetraazacyclododecan-1-yl)acetyl]-N-phenethyl}aminoethoxy)diphenylmethane octahydrochlo-
ride (2, ACPCn), were synthesized and the effect of these cleft-type cyclophanes on NMDA receptors was then
studied using voltage-clamp recordings of recombinant NMDA receptors expressed in Xenopus oocytes. ACPCm
(1) and ACPCn (2) inhibited macroscopic currents in the NR1/NR2A, NR1/NR2B, NR1/NR2C and NR1/NR2D
receptor subtypes in oocytes voltage-clamped at ꢁ70 mV. The IC50 values of ACPCm (1) and ACPCn (2) for
NR1/NR2A and NR1/NR2B receptors were 1.06 mM and, 0.92 mM and 1.47 mM and, 1.49 mM, respectively. The in-
hibition by these compounds was voltage-dependent, that is, the degree of inhibition was in the order of negative
holding potentials, ꢁ100 mVꢁꢁ70 mVꢁꢁ20 mV. These findings indicate that the cleft-type cyclophanes,
ACPCm (1) and ACPCn (2) directly act on the channel pore of the NMDA receptors.
Key words cleft-type cyclophane; N-methyl-D-aspartate receptor; Xenopus oocyte; voltage-clamped recording
The ionotropic glutamate receptors are ligand-gated ion cyclophanes ACCn3,4) and ATGDMAP5) which inhibited the
channels that mediate the vast majority of excitatory neuro- activity of the NR1/NR2A and NR1/NR2B receptors at
transmission in the brain. The three pharmacologically de- ꢀ70 mV. The IC50 values for ACCn and ATGDMAP were
fined classes of ionotropic glutamate receptor were originally 7.0 and 4.9 mM respectively against the NMDA receptors.
named after the reasonably selective agonists N-methyl-D-as- The inhibition of the activity of the NR1/NR2A and
partate (NMDA), a-amino-3-hydroxy-5-methyl-4-isoxazole NR1/NR2B receptors by N-(2-{4-[4-(2-{[(1,4,7,10-tetraaza-
propionate (AMPA), and kainite. It turned out that NMDA, cyclododec-1-yl)acetyl]-[2-(5-dimethylaminonaphtalene-1-
AMPA, and kainite receptor subunits are encoded by at least
six gene families as defined by sequence homology: a single
family for the AMPA receptors, two for kainite, and three for
NMDA.1) The NMDA receptor combines to form het-
eromeric complexes containing NR1 and NR2 subunits. The
NR1 subunit is ubiquitous and assembles with a second fam-
ily of subunits termed NR2, including NR2A, NR2B, NR2C
and NR2D.
In the central nervous system (CNS), the NMDA receptor
plays a critically important role in a variety of neurophysio-
logical phenomena, including neuronal development, synap-
tic plasticity, and excitotoxicity. Glutamate is known to be
neurotoxic under certain circumstances, in particular when
energy supply is compromised. Thus some researchers now
believe that the neurodegeneration associated with a variety
of acute and chronic disorders (ischemic stroke, Parkinson’s
disease, Alzheimer’s disease, dementia, etc.) may be caused
in part by overactivation of glutamate receptors. Alzheimer’s
disease is a neurodegenerative disorder characterized by irre-
versible, progressive loss of memory followed by complete
dementia. The cognitive decline is accompanied by impaired
performance of daily activities, behavior, speech and visual-
spatial perception. Glutamate excitotoxicity as a result of
blockade of glutamate uptake into astrocytes by Ab aggre-
gates induces excessive Ca influx through mainly the NMDA
receptors, followed by neuronal cell death.2) The NMDA re-
ceptor subtype has been found to play a key role in glutamate
promotion of synaptic plasticity, long-term potentiation and
neuronal cell death.1)
Fig. 1. Previously (ACCn and ATGDMAP) and Currently (ACPCm (1)
We previously reported the synthesis of two cleft-type and ACPCn (2)) Reported NMDA Receptor Antagonists
∗ To whom correspondence should be addressed. e-mail: miyake.muneharu@nihon-u.ac.jp
© 2009 Pharmaceutical Society of Japan

96
Vol. 57, No. 1
sulfonylamino)ethyl]amino}ethoxy)benzyl]phenoxy}ethyl)- 1,4,7,10-tris(tert-butoxycarbonyl)-1,4,7,10-tetraazacyclodo-
2-(1,4,7,10-tetraazacyclotridec-1-yl)-N-[2-(5-dimethyl- decane (7)6) and EDC by a method similar to that of ACPCm
aminonaphtalene-1-sulfonylamino)ethyl]acetamide (DNCn) (1). The effects of ACPCm (1) and ACPCn (2) on the
and N-(2-{4-[4-(2-{[(1,4,7,10-tetraazacyclododec-1-yl)- NMDA receptors were studied using voltage-clamped
acetyl]-[2-(toluene-4-sulfonylamino)ethyl]amino}ethoxy)- recordings of recombinant NMDA receptors expressed in
benzyl]phenoxy}ethyl)-2-(1,4,7,10-tetraazacyclotridec-1-yl)- Xenopus oocytes. We measured the effects of 10 mM ACPCm
N-[2-(toluene-4-sulfonylamino)ethyl]acetamide (TsDCn), (1) and ACPCn (2) on responses to glutamate (10 mM, with
both of which have two sulfonamide groups, was stronger 10 mM glycine) at the NR1/NR2 receptors containing differ-
than that of ACCn.4) In the present study, we attempted to ent NR2 subunits, namely NR2A, NR2B, NR2C and NR2D,
synthesize more potent cleft-type cyclophanes than ACCn in oocytes voltage-clamped at ꢀ70 mV. Both ACPCm (1)
and ATGDMAP (Fig. 1).
and ACPCn (2) inhibited macroscopic currents at all NMDA
receptor subtypes and the inhibition of the NR1/NR2A and
NR1/NR2B receptors by these cleft-type cyclophanes was
Results and Discussion
We introduced a phenethylamino group as a spacer in the slightly more potent than inhibition of the NR1/NR2C and
cleft-type cyclophane (ACCn) to increase molecular rigidity NR1/NR2D receptor subtypes (Fig. 2). The dose-dependency
and enhance affinity towards the NMDA receptor. Further of the inhibition by both compounds for the NR1/NR2A
analysis revealed that ACPCm (1) and ACPCn (2), which and NR1/NR2B receptors at ꢀ70 mV was then investigated.
form hydrophobic structures with a diphenylmethane skele- The IC50 values of ACPCm (1) and ACPCn (2) for the
ton and two phenethylamine groups, and which have two NR1/NR2A receptors were 1.06 mM and 0.92 mM, and for the
cyclic polyamines as the hydrophilic group, exhibit more po- NR1/NR2B receptors were 1.47 mM and 1.49 mM, respectively
tent NMDA inhibitory activity than ACCn and ATGDMAP.
(Fig. 3). A cyclic polyamine, CP2323 (cyclam) inhibited
The NMDA antagonists ACPCm (1) and ACPCn (2) were macroscopic currents at NR1/NR2 containing NR2A and
synthesized as shown in Chart 1. A pentafluorophenyl ester NR2B subunits, though CP2222 (cyclen) did not show any
function in compound (3)3) was converted into amide (4, effects. No significant difference in inhibition effect was ob-
90%) after treatment of pentafluorophenyl ester with 2- served between ACPCm (1) and ACPCn (2).7) The inhibition
phenylethylamine in the presence of triethylamine (TEA) in curve (solid line) represents a sigmoidal curve that fits to the
CH2Cl2, followed sequentially by reduction with borane di- data with a Hill coefficient (0.8—1.2) using the PRISM 4
methyl sulfide complex (BH3·DMS) to the corresponding software program (GraphPad Software Inc., San Diego, CA,
amine (5, 92%). The amine was converted into 8 by treat- U.S.A.). To clarify the mechanism of inhibition by ACPCm
ment with 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1) and ACPCn (2), we tried to determine whether these
hydrochloride (EDC) and 1-carboxymethyl-1,4,8,11-tris(tert- cleft-type cyclophane produce voltage-dependent inhibition
butoxycarbonyl)-1,4,8,11-tetraazacyclotetradecane (6). Fi- of NMDA receptors. The effects of ACPCm (1) and ACPCn
nally, deprotection of 8 with concentrated HCl in THF re- (2) were studied using the NR1/NR2A and NR1/NR2B re-
sulted in the desired compound ACPCm (1) in quantitative ceptors expressed in Xenopus oocytes voltage-clamped at
yield. ACPCn (2) was synthesized from 1-carboxymethyl- ꢀ20 and ꢀ100 mV (Fig. 4). Inhibition by ACPCm (1) and
Chart 1

January 2009
97
ACPCn (2) became prominent at ꢀ100 mV compared to the
inhibition at ꢀ20 mV. The results suggest that the inhibition
caused by ACPCm (1) and ACPCn (2) is voltage-dependent,
and that both compounds act as an open channel blocker.
There are a few NMDA receptor antagonists available for
clinical use, and only ketamine and more importantly me-
mantine, act as channel blockers. The IC50 values for keta-
mine and memantine are 1.4 and 1.0 mM respectively against
NMDA receptors expressed in Xenopus oocyte using volt-
age-clamp recording.4,8) The degree of inhibition by ACPCm
(1) (IC50, 1.06 mM) and ACPCn (2) (IC50, 0.92 mM) against
the NR1/NR2A receptor was as potent as meantime, a thera-
peutic drug for Alzheimer’s disease. Further investigations is
now in progress to synthesize ACPCm (1) or ACPCn (2) de-
rivatives that display stronger inhibitory effects on NMDA
receptors by changing various side chains.
Experimental
Melting points were determined using the Yanagimoto melting point ap-
paratus Yanaco MP and are uncorrected. 1H-NMR spectra were recorded on
a JEOL JNM-ECX500 spectrometer containing tetramethylsilane as the
standard. Mass spectra (MS) were measured on a JEOL JMS-GC mate in-
strument. Adult female Xenopus laevis were chilled on ice, and the prepara-
tion and maintenance of oocytes were performed as described previously.4,10)
Capped cRNAs were prepared from linearized cDNA templates using
mMessage mMachine kits (Ambion, Austin, TX, U.S.A.). Oocytes were in-
jected with NR1A and NR2 cRNAs at a ratio of 1 : 5 (0.2—4 ng of NR1A
plus 1—20 ng of NR2). Macroscopic currents were recorded with a two-
electrode voltage-clamp using the Dual Electrode Voltage Clamp Amplifier
CEZ-1250 (Nihon Koden, Tokyo, Japan). Electrodes were filled with 3 M
KCl. Oocytes were continuously superfused (ca. 5 ml/min) with a Mg2ꢂ-free
saline solution (96 mM NaCl, 2 mM KCl, 1.8 mM BaCl2, 10 mM HEPES, pH
7.5). This solution contained BaCl2 rather than CaCl2, and, in most experi-
ments, oocytes were injected with Kꢂ-1,2-bis(2-aminophenoxy)ethane-
N,N,Nꢃ,Nꢃ-tetraacetic acid (BAPTA; 100 nl of 40 mM solution at pH 7.5) on
the day of recording to eliminate Ca2ꢂ-activated Clꢀ currents.4,9) Glutamate
and glycine were purchased from Wako Pure Chemical Industries, Ltd.
(Osaka, Japan). BAPTA were purchased from Sigma (St. Louis, MO,
U.S.A.).
Fig. 2. Effects of ACPCm (1) and ACPCn (2) on NMDA Receptors at
ꢀ70 mV
Representative traces showing the effects of 10 mM ACPCm (1) and ACPCn (2) on
the NR1/NR2A receptors. The effects of 10 mM ACPCm (1) and ACPCn (2) were deter-
mined in oocytes expressing NMDA (NR1/NR2A, NR1/NR2B, NR1/NR2C and
NR1/NR2D). Currents were evoked by 10 mM glutamate with 10 mM glycine and volt-
age-clamped at ꢀ70 mV. Macroscopic currents in the presence of cleft-type cyclophane
were expressed as a percentage of the control response at the NMDA receptors. Data
represent the meanꢆS.E.M. from 4 or 5 oocytes.
4,4ꢀ-Bis(N-phenethylcarbamoylmethoxy)diphenylmethane (4)
A
mixture of 3 (648 mg, 1 mmol), 2-phenylethylamine (242 mg, 2 mmol), and
TEA (0.28 ml, 2 mmol) in CH2Cl2 (40 ml) was stirred at room temperature.
After 2 h, the reaction mixture was diluted with CH2Cl2 (100 ml). The or-
ganic phase was washed with H2O and dried over MgSO4, and evaporated to
afford a white solid, which was chromatographed on silica gel column with
CHCl3 : MeOH (10 : 1) and then EtOAc as an eluent to give a white solid
(470 mg, 90%). An analytical sample was obtained by recrystallizing this
material from EtOAc–hexane, yielding colorless needles, mp 124—125 °C.
1H-NMR (CDCl3) d: 2.83 (4H, t, Jꢄ7.0 Hz), 3.57—3.62 (4H, m), 3.88 (2H,
s), 4.43 (4H, s), 6.58 (2H, br), 6.77 (4H, d, Jꢄ8.8 Hz), 7.09 (4H, d,
Jꢄ8.8 Hz), 7.13—7.15 (4H, m), 7.21—7.29 (6H, m). HR-FAB-MS m/z:
523.2596 [MꢂH]ꢂ (Calcd for C33H35N2O4: 523.2596). Anal. Calcd for
C33H34N2O4: C, 75.84; H, 6.56; N, 5.36. Found: C, 75.81; H, 6.56; N, 5.30.
4,4ꢀ-{Bis[2-(N-phenethyl)]aminoethoxy}diphenylmethane (5) A mix-
ture of 4 (340 mg, 0.65 mml) in tetrahydrofuran (THF) (20 ml) was stirred at
room temperature under N2 atmosphere. BH3·DMS (0.78 ml, 7.8 mmol) was
added and the reaction mixture was stirred for 24 h at 80 °C, then cooled to
room temperature. A 0.7 M hydrogen chloride–MeOH solution (5 ml) was
added, and the reaction mixture refluxed for 1 h, and evaporated. The residue
was adjusted to pH 11 with excess 25% NH4OH. The mixture was extracted
with CH2Cl2 (20 mlꢅ3). The combined organic phases were washed with
H2O and dried over Na2SO4. Removal of the solvent afforded a yellow oil,
which was chromatographed on silica gel column with CHCl3 : MeOH
(10 : 1) as the eluent to give a colorless oil (314 mg, 92%). 1H-NMR (CDCl3)
d: 2.83 (4H, t, Jꢄ7.3 Hz), 2.93—2.96 (4H, m), 3.00 (4H, t, Jꢄ5.4 Hz), 3.85
(2H, s), 4.03 (4H, t, Jꢄ5.4 Hz), 6.78 (4H, d, Jꢄ8.5 Hz), 7.06 (4H, d,
Jꢄ8.5 Hz), 7.20—7.22 (6H, m), 7.26—7.31 (4H, m). HR-FAB-MS m/z:
495.3013 [MꢂH]ꢂ (Calcd for C33H39N2O2: 495.3011).
Fig. 3. Inhibitory Curves of ACPCm (1) and ACPCn (2) on NMDA Re-
ceptors at ꢀ70 mV
Concentration–inhibition curves for ACPCm (1) and ACPCn (2) were determined at
the NR1/NR2A and NR1/NR2B receptors, voltage-clamped at ꢀ70 mV. Responses to
10 mM glutamate with 10 mM glycine measured in the presence of ACPCm (1) and
ACPCn (2) are expressed as a percentage of the control response at each receptor type.
Data represent meanꢆS.E.M. from 4 oocytes. Solid line represents a sigmoidal curve
that fits to the data with a Hill coefficient (0.8—1.2).
Fig. 4. Voltage-Dependent Inhibition by ACPCm (1) and ACPCn (2) of
NMDA Receptor Currents
The effects of 1 mM ACPCm (1) and ACPCn (2) on the NR1/NR2A and NR1/NR2B
receptors, were measured at ꢀ20 and ꢀ100 mV. Data represent the meanꢆS.E.M. from
4 or 5 oocytes for each subunit combination.
1-Carbonylmethyl-4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraaza-
cyclotetradecane (6) A mixture of benzyl bromoacetate (435 mg, 1.9

98
Vol. 57, No. 1
mmol), 1,4,8-tris(tert-butoxycarbonyl)-1,5,8,11-tetraazacyclotetradecane10)
(475 mg, 0.95 mmol) and K2CO3 (131 mg, 0.95 mmol) in MeCN (5 ml) was
stirred at 80 °C under N2 atmosphere for 12 h. After insoluble inorganic salts
were removed by filtration, the filtrate was concentrated under reduced pres-
sure. The residue was purified by column chromatography on silica gel with
EtOAc : hexane (1 : 2) to give 1-benzyloxycarbonylmethyl-4,8,11-tris(tert-
butoxycarbonyl)-1,5,8,11-tetraazacyclotetradecane (573 mg, 94%) as a vis-
cous oil. [1H-NMR (CDCl3) d: 1.41 and 1.43 (27H, 2s), 1.61—1.69 (2H, m),
1.82—1.92 (2H, m), 2.62—2.67 (2H, m), 2.80—2.85 (2H, m), 3.20—3.40
(12H, m), 3.41 (2H, s), 5.24 (2H, s), 7.32—7.38 (5H, m). HR-FAB-MS m/z:
649.4178 [Mꢂ1]ꢂ (Calcd for C34H57N4O8: 649.4176).] A solution of the oil
in THF (2 ml) was hydrogenated over 10% Pd–C (20 mg) at room tempera-
ture for 24 h under H2 atmosphere. The catalyst was filtered through a pad of
celite. The filtrate was concentrated to dryness to give a colorless oil
temperature. After 24 h, the reaction mixture was evaporated, and the result-
ing precipitate was triturated with THF and collected by filtration to give (1,
ACPCm) (60 mg, 100%) as a white solid. 1H-NMR (D2O) d: 1.53—1.62
(8H, m), 2.40—3.31 (42H, m), 3.50—3.70 (8H, m), 3.84 (2H, s), 4.12
(2H, m), 6.70—6.73 (2H, m), 6.77—6.80 (2H, m), 7.06—7.18 (14H, m).
HR-FAB-MS m/z: 975.6915 [Mꢀ8HClꢂH]ꢂ (Calcd for C57H87N10O4:
975.6911). Anal. Calcd for C57H86N10O4·8HCl: C, 54.03; H, 7.48; N, 11.06.
Found: C, 54.05; H, 7.64; N, 11.14.
4,4ꢀ-Bis({2-[N-(1,4,7,10-tetraazacyclododecan-1-yl)acetyl]-N-phen-
ethyl}aminoethoxy)diphenylmethane Octahydrochloride (2, ACPCn)
To a solution of 9 (80 mg, 0.052 mmol) in THF (1 ml) was added concen-
trated HCl (0.2 ml) at room temperature, and the reaction mixture was
stirred for 24 h, then concentrated under reduced pressure to give a white
solid, which was washed with THF and Et2O to give (2, ACPCn) (62 mg,
100%). 1H-NMR (D2O) d: 2.60—2.94 (40H, m), 3.41 (2H, t, Jꢄ4.9 Hz),
3.46 (4H, t, Jꢄ4.9 Hz), 3.59 (2H, t, Jꢄ5.1 Hz), 3.70 (2H, m), 3.93—
3.95 (2H, m), 4.07 (2H, t, Jꢄ5.1 Hz), 6.69 (2H, d, Jꢄ8.6 Hz), 6.77
(2H, d, Jꢄ8.6 Hz), 7.04—7.17 (14H, m). HR-FAB-MS m/z: 919.6283
[Mꢀ8HClꢂH]ꢂ (Calcd for C53H79N10O4: 919.6286). Anal. Calcd for
C53H78N10O4·8HCl: C, 52.57; H, 7.16; N, 11.57. Found: C, 52.65; H, 7.28;
N, 11.37.
1
(492 mg, 100%). H-NMR (CDCl3) d: 1.46 and 1.47 (27H, 2s), 1.73—1.77
(2H, m), 1.83—1.88 (2H, m), 2.62 (2H, br), 2.75 (2H, br), 3.28 (2H, s),
3.31—3.40 (12H, m). HR-FAB-MS m/z: 559.3706 [MꢂH]ꢂ (Calcd for
C27H51N4O8: 559.3706).
4,4ꢀ-Bis[2-(N-{2-[4,8,11-tris(tert-butoxycarbonyl)-1,4,8,11-tetraazacy-
clotetradecan-1-yl]acetyl}-N-phenethyl)aminoethoxy]diphenylmethane
(8) A mixture of 5 (248 mg, 0.5 mmol), 6 (558 mg, 1 mmol), EDC
(230 mg, 1.2 mmol) and TEA (0.168 ml, 1.2 mmol) in CH2Cl2 (50 ml) was
stirred at room temperature for 24 h. The reaction mixture was washed with
H2O and dried over MgSO4. The solvent was evaporated, and the residue
was chromatographed on silica gel with EtOAc : MeOH (9 : 1) to give a col-
Acknowledgments We thank Drs. S. Nakanishi, P. H. Seeburg and M.
Mishina for the kind supply of glutamate receptor clones. This work was
supported by a Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan (T.M.).
1
orless amorphous (100 mg, 13%). H-NMR (CDCl3) d: 1.41 (18H, s), 1.42
(36H, s), 1.60—2.30 (12H, m), 2.56—2.60 (2H, m), 2.69—2.90 (8H, m),
3.20—3.37 (26H, m), 3.59—3.72 (8H, m), 3.84 (2H, s), 3.95 (2H, t,
Jꢄ4.9 Hz), 4.11 (2H, t, Jꢄ4.9 Hz), 6.74 (2H, d, Jꢄ8.6 Hz), 6.79 (2H, d,
Jꢄ8.6 Hz),7.05 (2H, d, Jꢄ8.6 Hz), 7.06 (2H, d, Jꢄ8.6 Hz), 7.16—7.32
(10H, m). HR-FAB-MS m/z: 1575.9996 [MꢂH]ꢂ (Calcd for C87H134N10O16:
1576.0057). Anal. Calcd for C87H134N10O16: C, 66.30; H, 8.57; N, 8.89.
Found: C, 66.34; H, 8.77; N, 9.00.
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1
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s), 1.46 (18H, s), 2.86—3.73 (48H, m), 3.84 (2H, s), 4.03 (2H, t, Jꢄ4.9 Hz),
4.13 (2H, t, Jꢄ4.9 Hz), 6.77 (2H, d, Jꢄ8.6 Hz), 6.80 (2H, d, Jꢄ8.6 Hz),
7.04—7.07 (4H, m), 7.20—7.23 (6H, m), 7.25—7.29 (4H, m). HR-FAB-MS
m/z: 1519.9415 [MꢂH]ꢂ (Calcd for C83H127N10O16: 1519.9431). Anal. Calcd
for C83H126N10O16: C, 65.58; H, 8.36; N, 9.21. Found: C, 65.86; H, 8.64; N,
9.00.
4,4ꢀ-Bis({2-[N-(1,4,8,11-tetraazacyclotetradecan-1-yl)acetyl]-N-phen-
ethyl}aminoethoxy)diphenylmethane Octahydrochloride (1, ACPCm)
8 (76 mg, 0.048 mmol) was dissolved in THF (0.2 ml), to which concen-
trated HCl (0.2 ml) was added. The reaction mixture was stirred at room