July 2008
1057
from EtOH. After concentration of the filtrate, separation by centrifugal
chromatography (SiO2, 2—5% v/v CH2Cl2 in EtOH) also gave additional
pure products of (1R,2R)-7c and N,Nꢀ-dithiocarbamoyl derivative (1R,2R)-
7cc (entry 3).
N,Nꢂ-(1R,2R)-1,2-Cyclohexanediylbis(Nꢀ-3,4-dimethoxyphenylthi-
ourea) [(1R,2R)-7cc] After evaporation of the solvent, recrystallization
from EtOH afforded a pure product [(1R,2R)-7cc] (entry 4).
N-(cis-2-Aminocyclohexyl)-Nꢀ-tricyclo[3.3.1.13,7]dec-1-ylthiourea (cis-
7b) After evaporation of the solvent, flash column chromatography (SiO2,
CH2Cl2/EtOH/28% NH4OH, 980 : 15 : 5, v/v) gave pure products (cis-7b and
meso-7bb) (entry 7). An analytical sample was obtained by recrystallization
from MeOH.
Table 5. Antiviral Activity against HSV-1
EC50 (mg/ml)
CC50 (mg/ml)
CC50/EC50
(1R,2R)-7aa)
cis-7b
42.0
27.0
250
37.4
48.1
64.0
ꢄ320
ꢄ800
6
1.4
—
4
—
—
9b
ꢄ40
(1R,2R)-7aa
meso-7bb
Aciclovirb)
16.0
ꢄ40
0.2—0.9
a) This compound (1R,2R)-7a has been reported.1) b) Data were taken from ref.
13.
N,Nꢂ-(1R,2S)-rel-1,2-cyclohexanediylbis(Nꢀ-tricyclo[3.3.1.13,7]dec-1-
ylthiourea) (meso-7bb) and N,Nꢀ-Bis(tricyclo[3.3.1.13,7]dec-1-yl)thiourea
(8) After evaporation of the solvent, flash column chromatography (SiO2,
CH2Cl2/EtOH/28% NH4OH, 980 : 15 : 5, v/v) gave pure products (meso-7bb
and 8) (entry 8). Recrystallization from CH3CN gave an analytical sample of
meso-7bb.
molecule imparts at least a reversed physical property (an in-
creasing hydrophilic character) to the N-acylated product of
diamines. However, the trial compounds prepared in this
study [(1R,2R)-7d and (1R,2R)-10d] also possessed no sig-
nificant antiviral activity under the concentration of
40 mg/ml. Some of the antiviral active compounds by plaque
reduction assay are shown in Table 5. The N,Nꢀ-dicarbamoyl
derivative [(1R,2R)-7aa] possesses two adamantyl urea
moieties and has no basic primary amine functionality
in the molecule. In comparison with antiviral activity in
adamantyl derivatives such as 1-aminoadamantane4) and N-
N-(3-Aminocyclohexyl)-Nꢀ-tricyclo[3.3.1.13,7]dec-1-ylthiourea
(9b)
After evaporation of the solvent, flash column chromatography (SiO2,
CH2Cl2/EtOH/28% NH4OH, 980 : 15 : 5, v/v) gave pure products of 9b and
N,Nꢀ-dithiocarbamoyl derivative 9bb. For analytical use of 9b, recrystalliza-
tion from CH3CN was employed (entry 9).
N,Nꢂ-1,3-Cyclohexanediylbis[Nꢀ-tricyclo[3.3.1.13,7]dec-1-ylthiourea]
(9bb) After evaporation of the solvent, recrystallization from CHCl3 gave
a pure product 9bb (entry 10).
Preparation of 3-[[[(1R,2R)-2-Aminocyclohexyl]amino]carbonyl]-
pyrazinecarboxylic Acid [(1R,2R)-7d] A solution of acid anhydride 5
(1-adamantyl)thiourea,12) this fact is quite interesting for the (4.5 mmol) in acetone (20 ml) was added dropwise to a stirred solution of di-
amine (1R,2R)-1 (4.5 mmol) in acetone (20 ml) under the conditions shown
in Table 1 (entry 5). After cooling, the reaction mixture was filtrated to af-
ford a crude product. Recrystallization twice from EtOH–H2O gave a pure
product (1R,2R)-7d.
search of antiviral compounds (leads), providing useful infor-
mation for molecular modification of adamantane series.
However, since the plaque reduction assay applied in this
study offers no advantage in finding detailed information of
the mode of action of the antiviral compounds, we need to
make more precise experiments for further discussion.
Preparation of [(1R,2R)-7d]·HCl The reaction was carried out for
(1R,2R)-7d in a similar manner as that described above except for using dry
CH3CN as a solvent. The filtrated crude product from the reaction mixture
was suspended in MeOH (50 ml), added with 1 M HCl/EtOH (7 ml), and
evaporated under reduced pressure. The resulting material was recrystallized
from MeOH to give the desired [(1R,2R)-7d]·HCl (entry 6).
Experimental
The melting points were determined using a micro melting point appara-
tus (Yanagimoto MP-S3) without correction. IR spectra were measured by a
Preparation of 3-[[[(1R,2R)-2-Amino-1,2-diphenylethyl]amino]car-
Shimadzu FTIR-8100 IR spectrophotometer. Low- and high-resolution mass bonyl]pyrazinecarboxylic Acid [(1R,2R)-10d] This compound was also
spectra (LR-MS and HR-MS) were taken by the JEOL JMS HX-110 double- prepared in a similar manner to the compound (1R,2R)-7d. Crude product
focusing model equipped with a FAB ion source interfaced with a JEOL
was purified by recrystallization from H2O twice to give an analytically pure
l
JMA-DA 7000 data system. H- and 13C-NMR spectra were obtained by sample (1R,2R)-10d (entry 11).
JEOL JNM A-500. Chemical shifts were expressed in d ppm downfield
Preparation of [(1R,2R)-10d]·HCl A solution of acid anhydride 5
(2 mmol) in dry CH3CN (10 ml) was added to a stirred solution of diamine
from an internal tetramethylsilane (TMS) signal for lH-NMR and the carbon
signal of the corresponding solvent [CDCl3 (77.00 ppm) and dimethyl sul- (1R,2R)-3 (2 mmol) in dry CH3CN (20 ml) under the conditions shown in
foxide (DMSO)-d6 (39.50 ppm)] for 13C-NMR. In D2O, the chemical shifts Table 1 (entry 12). The resulting mixture was filtrated to give crude mixed
were referenced to 3-(trimethylsilyl)propionic acid-d4 sodium salt (TSP-d4). products of (1R,2R)-10d and N,Nꢀ-diacyl derivative (1R,2R)-10dd, the mix-
Microanalyses were performed with a Yanaco MT-6 CHN corder. Routine
ture of which was suspended in EtOH (12 ml) and added with 1 M HCl/EtOH
monitoring of reactions was carried out using precoated Kieselgel 60F254 (16 ml) with stirring for 1 h. At the beginning of the addition of HCl, the re-
plates (E. Merck). Centrifugal or flash column chromatography was per- action mixture became a transparent solution, and then precipitation gradu-
formed on silica gel (Able-Biott or Fuji Silysia FL40D, respectively) with a ally occurred. After cooling the mixture, filtration of the precipitated mate-
UV detector. Commercially available starting materials were used without rial gave (1R,2R)-10dd in a 14% yield. The filtrate was evaporated and the
further purification.
General Procedure for Addition of Iso(thio)cyanate to Diamines
residue was purified by recrystallization to afford the product (1R,2R)-10d
(entry 12).
A
solution of a diamine (2—5 mmol) and an appropriate iso(thio)cyanate
3,3ꢀ-[[(1R,2R)-1,2-Diphenyl-1,2-ethanediyl]bis(iminocarbonyl)]bis-
(molar ratios listed in Table 1) in an appropriate solvent (20—60 ml) was pyrazine-carboxylic Acid [(1R,2R)-10dd] White solid: mp 174—175 °C
stirred at room temperature or refluxed for the indicated time (Table 1). Ex- (from HCl–EtOH); HR positive ion FAB-MS, Calcd for C26H21N6O6
cept for the synthesis of (1R,2R)-7c, after the evaporation of the solvent of (MꢃH)ꢃ: 513.1523. Found: 513.1526. IR (KBr) cmꢂ1: ca. 3400 br (OH),
the reaction mixture, purification of the residue by recrystallization or flash
3295 (CONH), ca. 3000—2500 br (COOH), 1720 (COOH), 1650 (CONH).
chromatography afforded the pure product. Physical and spectroscopic data 1H-NMR (DMSO-d6) d: 5.70 (2H, dt, Jꢁ8.5, 2.1 Hz, PhCH), 7.15 (2H, dt,
are listed in Tables 2—4.
Jꢁ7.3, 1.2 Hz, p-Ph), 7.22 (4H, dt, Jꢁ7.3, 1.2 Hz, m-Ph), 7.39 (4H, dd,
Jꢁ7.3, 1.2 Hz, o-Ph), 8.78 (2H, d, Jꢁ2.4 Hz, H6ꢀ), 8.81 (2H, d, Jꢁ2.4 Hz,
N,Nꢂ-(1R,2R)-1,2-Cyclohexanediylbis[Nꢀ-tricyclo[3.3.1.13,7]dec-1-
ylurea] [(1R,2R)-7aa] This compound was prepared from diamine H5ꢀ), 9.67 (2H, d, Jꢁ8.4 Hz, NH). 13C-NMR (DMSO-d6) dC: 57.08 (PhCH),
(1R,2R)-1 and isocyanate 4a at a ratio of 1 : 2.1 and purified by recrystalliza-
tion from EtOH (entry 1 in Table 1). The physical and spectroscopic data for 143.96 (C6ꢀ), 145.93 (C5ꢀ), 147.57 (C3ꢀ), 162.94 (CONH), 166.63 (COOH).
this compound have already been reported.1)
Anal. Calcd for C26H20N6O6·1.8H2O: C, 57.31; H, 4.37; N, 15.42. Found: C,
N,Nꢂ-(1R,2R)-1,2-Cyclohexanediylbis[Nꢀ-tricyclo[3.3.1.13,7]dec-1-yl- 57.37; H, 4.37; N, 15.19.
127.15 (p-Ph), 127.53 (o-Ph), 128.02 (m-Ph), 139.63 (4ꢀ-Ph), 142.69 (C2ꢀ),
thiourea] [(1R,2R)-7bb] This product was obtained by recrystallization
from EtOH (entry 2).
Preparation of N,Nꢀ-[(1R,2R)-1,2-Diphenyl-1,2-ethanediyl]bisdecan-
amide [(1R,2R)-10ee] n-Decanoyl chloride 6 (2 mmol) was added to a
N-[(1R,2R)-2-Aminocyclohexyl]-Nꢀ-(3,4-dimethoxyphenyl)thiourea stirred mixture of diamine (1R,2R)-3 (2 mmol) and Na2CO3 (3.5 mmol) at
[(1R,2R)-7c] After the reaction was completed, the precipitated crude room temperature under an N2 atmosphere. After refluxing for 5 h, the reac-
product of the title compound was filtrated and purified by recrystallization
tion mixture received addition of saturated aqueous NaHCO3 (30 ml), ex-
Mibu, Nobuko
