Quantitative structure-activity analyses of novel hydroxyphenylurea derivatives as antioxidants

Article abstract of DOI:10.1016/S0968-0896(98)00039-X

A series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed based on structures of natural antioxidants, vitamin E (α-tocopherol) and uric acid. They exhibited high inhibitory activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we analyzed their structure-activity relationships quantitatively. Electronic and steric effects of substituents on the phenolic hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the stabilization of an electron-deficient radical-type transition state. The steric shielding by ortho-substituents stabilized the phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate anion which could retard the formation of the transition state. Copyright (C) 1998 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(98)00039-X

BIOORGANIC &
MEDICINAL
CHEMISTRY
Bioorganic & Medicinal Chemistry 6 (1998) 849±868
Quantitative Structure±Activity Analyses of Novel
Hydroxyphenylurea Derivatives as Antioxidants
Kazuya Nakao,a Ryo Shimizu,a,* Hitoshi Kubota,b Mikiko Yasuhara,c
Yoshimasa Hashimura,c Toshikazu Suzuki,c Toshio Fujitad
and Hiroshi Ohmizub
aLead Generation Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532, Japan
bLead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89, Kashima, Yodogawa, Osaka 532, Japan
cLead Optimization Research Laboratory, Tanabe Seiyaku Co., Ltd., 2-2-50, Kawagishi, Toda 335, Japan
dDepartment of Agricultural Chemistry, Kyoto University, Kyoto 606-01, Japan
Received 29 August 1997; accepted 5 February 1998
AbstractÐA series of substituted hydroxyphenylureas was synthesized, the chemical structure of which was designed
based on structures of natural antioxidants, vitamin E (a-tocopherol) and uric acid. They exhibited high inhibitory
activity against lipid peroxidation. In order to gain an insight into the mechanism of the inhibition reaction, we ana-
lyzed their structure±activity relationships quantitatively. Electronic and steric e€ects of substituents on the phenolic
hydroxyl group were shown to be of importance in governing the inhibitory potency. An increase in the electron
donating property of substituents toward the phenolic hydroxyl group enhanced the antioxidative activity by the sta-
bilization of an electron-de®cient radical-type transition state. The steric shielding by ortho-substituents stabilized the
phenoxy radicals formed following the transition state. Derivatives having the carboxyl group were only weakly active
presumably because of an intermolecular ion-dipole interaction of the phenolic hydroxyl group with the carboxylate
anion which could retard the formation of the transition state. # 1998 Elsevier Science Ltd. All rights reserved.
Introduction
Active oxygen species and free radicals have been
recognized to play an important role in the initiation
and/or progression of various diseases such as ischemia-
reperfusion injury, atherosclerosis, and in¯ammatory
injury.1 Antioxidants are expected to be promising
drugs for treatment of these diseases by removing oxi-
dative stresses. For example, probucol 1, a well-known
reagent exhibiting antioxidative activity, is expected as a
therapeutic agent for atherosclerosis.2
Key words: Quantitative structure±activity relationship;
QSAR; hydroxyphenylurea; antioxidant.
*Corresponding author.
We noted the chemical structures of a-tocopherol (vita-
min E) 2 and uric acid 3, both of which exhibit an
0968-0896/98/$19.00 # 1998 Elsevier Science Ltd. All rights reserved
PII: S0968-0896(98)00039-X

850
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
interesting antioxidative activity. a-Tocopherol termi-
nates chain reactions of the lipid peroxidation by giving
a hydrogen atom from its phenolic hydroxyl group to
the peroxidized lipid radical and turns into the stable
tocopheroxy radical.3 For this mechanism, the para-
alkoxyphenol structure is an essential component of
a-tocopherol. Uric acid scavenges radical species and
the resultant urate radical is stabilized by delocalization
of the unpaired electron in the p electron system con-
taining urea substructures.4 The antioxidative nature of
these compounds could be governed by the readiness in
releasing the hydrogen as well as the stability of the
produced radicals. Based on these considerations, we
designed novel 2-hydroxy-5-methoxyphenylureas 4 by
combining substructural features of a-tocopherol and
uric acid as shown in Figure 1.
Chemistry
The compounds 5±57 were synthesized by combining
the substituted anilines 62 with the other substituted
anilines or amines (R-NH2) using triphosgene followed
by removal of the protecting group with methanolic
hydrogen chloride (Scheme 1).
The substituted anilines 62 were prepared by hydro-
genation of the substituted azobenzenes 61 or azidation
of the substituted benzenes 63 followed by reduction.
The amines (R-NH2) were purchased from commercial
sources or synthesized by alkylation and acylation of the
corresponding alcohols, amines, and halides.
Tetrahydroquinazoline derivative 58 was synthesized by
the synthetic route shown in Scheme 2. Cyclization of 69
was likewise carried out by using triphosgene under
weakly basic conditions. Those reactions are described
in the experimental section.
The corresponding radical species would be stabilized
by delocalization of the odd electron in the benzene ring
and the urea moiety. As we expected, the ®rst synthe-
sized compound, 1-(2-hydroxy-5-methoxyphenyl)-3-
phenylurea 5, exhibited antioxidative potency about 10
times higher than that of a-tocopherol. It was also
revealed that the potency of the derivatives varied with
substituent/structural modi®cations to various extents.
QSAR Parameters
Recently, Hansch and co-workers have shown that there
are a number of examples in which substituted phenols
display an inhibitory e€ect on biological reactions.5,6
The inhibitory mechanism involves free radical reactions
of substituted phenols which are governed mainly by
electronic characters of substituents. The electronic
e€ects of substituents are mostly represented by the s+
parameter, one of the variations of the Hammett s
including the through-resonance e€ect on the electron-
de®cient reaction center. It is de®ned according to the
reaction constants for the solvolysis of the substituted t-
cumyl chlorides.7 In this study, we ®rst examined the s+
value because we expected the antioxidative reaction
mechanism to be similar to mechanisms found by Hansch
and co-workers. In Table 1, the s+ values are listed along
with the s0 values8 which are supposed to represent for
the e€ect of the substituents devoid of the through-reso-
nance e€ect. The e€ect of ortho-substituents was analyzed
by assuming that it was primarily equivalent with that of
the corresponding para-substituents, which should be
adjusted/corrected according to the reduced through-
resonance e€ect with the use of an additional parameter,
In this paper, we report the relationship between
structure and activity in the inhibition of lipid peroxida-
tion of variously substituted hydroxyphenylureas 5±58
quantitatively, using free±energy related substituent
parameters as well as a quantum chemical index and
regression analyses. On the basis of this result, we pro-
pose a physicochemical mechanism of their anti-
oxidative activity.
‡
‡
ÁsRꢀˆ s
s0†.9 We used the combination of these
electronic parameters to clarify the inhibitory mechan-
ism of hydroxyphenylureas against lipid peroxidation.
To represent the steric e€ect of ortho-substituents on the
phenolic hydroxyl group, the Es(AMD) parameter
derived from the rate constants for the acidic hydrolysis
of ortho-substituted benzamides was used (Table 1).10
The Es(AMD) value of hydrogen is de®ned as the
reference (zero).
Figure 1. Design of hydroxyphenylurea derivatives.

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
851
Scheme 1. (a) (1) NaNO2, HCl, H2O, (2) substituted phenol, NaOH, H2O; (b) MOMCl, NaH DMF; (c) H2, Pd-C, EtOH; (d) (1) sec±
BuLi, THF, (2) TosN3, THF, (3) Na4P2O7, aq., (4) LiAlH4, THF; (e) R-NH2, triphosgene, Et3N,CH2Cl2; (f) concd HCl, MeOH.
Scheme 2. (a) Br2, CS2; (b) MOMCl, NaH, DMF; (c) H2, Pd-C, MeOH; (d) (1) n±BuLi, Et2O, (2) DMF; (e) (1) 3-(amino-
methyl)pyridine, benzene, (2) NaBH3CN, CH3CN; (f) triphosgene, Et3N, CH2Cl2; (g) concd HCl, MeOH.
The molecular hydrophobicity parameter, logP, of sub-
stituted diphenylureas (5±29) was estimated principally
by our empirical method to calculate the logP value of
substituted acetanilides.11,12 The di€erence in the logP
value, ÁlogP, between multisubstituted and unsub-
stituted diphenylureas (5±18) was assumed as being
nearly equal to the ÁlogP between multisubstituted and
unsubstituted acetanilides. Likewise, the ÁlogP value for
compounds 19±29 was taken as the summation of the
ÁlogP values for two substituted ring moieties. The
reference logP value of diphenylurea (3.00) was cited
from literature.13 The ÁlogP value is not identical to Áp,
in which p is the substituent hydrophobicity constant
de®ned from partition coecients of monosubstituted
benzenes. The ÁlogP value of multisubstituted benzene
is a composite of Æp and increments originated from
electronic, steric and intramolecular hydrogen-bonding
interactions between substituents. In compounds 30±56,
the logP value of corresponding phenylureas which have
no substituents on the phenyl ring and miscellaneous
substituents at the end of the urea moiety was calculated
using the CLOGP procedure.14,15 Thus, the logP value
for the all compounds was estimated by the summation
of ÁlogP and logP of diphenylurea or CLOGP of cor-
responding N-substituted phenylurea. The logP values
are listed in Table 2. Regression analyses were per-
formed by using the QREG93 program developed by
Asao et al.16
Molecular Orbital Calculations
To clarify the e€ect of the urea moiety against the anti-
oxidative activity and to assess the overall reactivity of
the hydroxyl group in hydroxyphenylurea derivatives
theoretically, quantum chemical calculations were per-
formed. For p-methoxyphenol and probucol 1, the
crystal structures in Cambridge Structural Database18
(entries MOPHLC19 and HAXHET,20 respectively)
were used as their initial coordinates. An initial con-
formation of vitamin E 2 was constructed based on the
crystal structure of 2,2,5,7,8-pentamethyl-6-hydroxy-
chroman (entry MOPHLB19). Initial coordinates of all
hydroxyphenylureas were constructed in the syn±syn

852
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Table 1. Physicochemical parameters for substituents
approximates the superdelocalizability for comparisons
of the reactivity of a corresponding position among a
series of compounds.23 The R(Ophenol) value was multi-
plied by 100 to scale them in an order similar to that of
other parameters.
+a
+a
0b
0b
+c
Substituents
sm
sp
sm
sp
ÁsR
Es
(AMD)d
Me
Et
0.07
0.06
0.06
0.31
0.30
0.26
0.07
0.07
0.07
0.13
0.13
0.17
0.19
0.17
0.09
1.16
1.33
2.78e
1.64f
0.40
0.55g
1.14
0.61i
t-Bu
C8H17
OMe
Ð
0.29f 0.08f 0.16f 0.13
0.78 0.06 0.16 0.62
0.81g 0.04g 0.14g 0.67
0.60 0.13 0.06 0.66
0.13h 0.60h 0.21h 0.03h 0.63
Results and Discussion
0.05
OC8H17
SMe
NHCONH-R
Ð
We designed and synthesized hydroxyphenylurea deri-
vatives referring to the antioxidative potencies and the
structural properties of vitamin E and uric acid. At
®rst, to clarify the e€ect of the urea moiety against the
inhibitory activity of lipid peroxidation, the stabilities of
p-methoxyphenol, probucol 1, vitamin E 2, and hydroxy-
phenylurea 5 were compared. The stabilities were
estimated by the energy di€erences between the ground-
states and the corresponding radicals (Table 3). The
energy di€erence of 5 was 2.3±5.1 kcal/mol less than the
others. Thus, a phenol having a urea moiety was more
stable in its radical form than those without ureas. Its
stability presumably arised from the delocalization of
an odd electron into the urea moiety. It was concluded
that 5 has higher antioxidative activity than other phe-
nolic derivatives owing to stabilization in the radical
form.
0.16
aTaken from ref. 7 or ref. 13.
bTaken from ref. 8 or ref. 17.
cÁsR+=sp
sp
.
+
0
dTaken from ref. 10.
eEs(AMD) value of t-Bu was approximated by Es value of t-Bu.
fThe values of C8H17 were approximated by the values of Bu.
gThe values of OC8H17 were approximated by the values of
OBu.
hThe values of these parameters were approximated by the
values of NHAc.
iEs(AMD) value of NHCONH-R was approximated by Es
value of NH2.
conformation on the basis of the crystal structure of 24
shown in Figure 2.18
To examine the substituent e€ects on the reactivity of
the phenolic hydroxyl group in transforming into the
phenoxy radical, we analyzed the ®rst set of diphenyl-
ureas with simple substituents such as alkyl, alkoxy, and
methylthio groups on the benzene ring A, where the
phenolic hydroxyl group is located. For 14 compounds
(5±18), eq (2) was formulated with Æs+ summed over
ortho-, meta-, and para-substituents.
The geometry of compounds was re®ned by semi-
empirical molecular orbital calculations with the PM3
Hamiltonian using the SPARTAN (version 4.1.1) soft-
ware.21 The calculations were performed with restricted
Hartree±Fock method for the ground-state compounds
and unrestricted Hartree±Fock for the radicals.
In the most stable conformation such as 24 (a) in Figure
3, an intramolecular hydrogen-bond formation is possi-
ble between the phenolic hydroxyl group and the urea
carbonyl. Since hydrogen-bonded hydroxyl group may
not be susceptible enough to react with the lipid peroxy
radicals, quantum chemical properties were calculated
for the meta-stable conformers such as 24 (b) where
the intramolecular hydrogen-bond formation is not
observed.
‡
logꢀ1=IC50† ˆ 0:59ꢀÆ0:41†Æs 0:24ꢀÆ0:23†ÆEs
ꢀAMD† ‡ 4:98ꢀÆ0:68†
n ˆ 14; s ˆ 0:30; r ˆ 0:80; F2;11 ˆ 9:91
ꢀ2†
In this and the following equations, n is the number of
compounds, s the standard deviation, r the correlation
coecient, and F the ratio between regression and
residual variances. The ®gure in parentheses is the 95%
con®dence interval.
The electron-releasing reactivity index of phenolic oxy-
gen, R(Ophenol), listed in Table 2, was calculated by eq
(1).22
The quality of eq (2) was just marginal and not as
good as one would like. Inspecting the correlation clo-
sely, we noted that the residual between observed and
calculated activity values was generally large for com-
pounds having the methoxyl group in the ortho-pos-
ition. In these compounds, the phenolic hydroxyl
group is sandwiched between the urea and methoxyl
groups except for compound 18. The through-resonance
RꢀOphenol† ˆ frꢀOphenol†= EHOMO  100
ꢀ1†
In eq (1), fr(Ophenol) is the frontier electron density at
the phenolic oxygen atom on the highest occupied
molecular orbital (HOMO) and EHOMO is the energy
level of the HOMO in eV. The R(Ophenol) index

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Table 2. Physicochemical parameters of hydroxyphenylurea derivatives
853
Substituents
No. X1
X2
X3
X4
X5
Æs# ÆEs(AMD)
R(Ophenol
)
logP
ICOOR
5
OH
OH
OH
OH
OH
OH
OH
OH
H
H
H
OMe
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.75
0.08
0.13
0.78
0.57
0.87
0.88
0.92
0.91
0.91
0.89
0.94
0.86
0.81
0.61
0.61
1.01
0.61
0.61
1.77
1.94
3.39
2.25
1.01
1.16
1.01
1.01
0.40
0.787
0.341
0.402
0.803
0.576
0.803
0.793
0.837
0.795
0.847
0.911
0.861
0.723
0.589
1.95
1.92
1.76
5.23
2.52
2.26
2.66
3.43
5.48
1.75
5.03
5.02
0.99
1.72
0
0
0
0
0
0
0
0
0
0
0
0
0
0
6
7
OMe
H
H
8
H
OC8H17
SMe
OMe
OMe
OMe
OMe
OMe
OMe
OC8H17
OMe
OH
9
H
H
10
11
12
13
14
15
16
17
Me
Et
H
H
t-Bu
H
OH C8H17
OH OMe
OH OC8H17
H
H
H
OH
OH
OMe
OMe
H
H
OMe
OMe
18 OMe
Substituents
No. X2
Y1
Y2
Y3
Y4 Y5
Æs#
ÆEs(AMD) R(Ophenol
)
logP ICOOR
19
20
21
22
23
24
25
26
27
28
29
H
H
H
H
CF3
CO2H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
0.75
0.75
0.75
0.75
0.75
0.75
0.75
0.92
0.92
0.92
0.92
0.61
0.61
0.61
0.61
0.61
0.61
0.61
3.39
3.39
3.39
3.39
0.880
0.860
0.703
0.763
0.726
0.490
0.838
0.476
0.598
0.853
0.898
3.20
2.11
2.48
Ða
0
1
0
1
0
0
1
0
0
0
0
H
Me
H
H
H
H
H
CH=CHCO2H(trans)
Cl
OMe
H
H
H
2.90
1.94
1.99
Ða
H
H
H
H
H
H
OCH2CO2Et
NMe2
t-Bu
t-Bu
t-Bu
t-Bu
H
H
H
H
O(CH2)3NBu2
H
5.93
4.48
3.55
i-Pr
F
H
H i-Pr
H H
H
F
Substituents
No. X2
30 t-Bu
R
Æs#
ÆEs(AMD) R(Ophenol
)
logP ICOOR
2.92
0.92
3.39 0.905
0
(continued)

854
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Table 2Ðcontd
No. X2
R
Æs#
ÆEs(AMD) R(Ophenol
)
logP ICOOR
31
t-Bu
0.92
3.39
0.896
2.92
0
32
33
34
t-Bu
t-Bu
H
0.92
0.92
0.75
3.39
3.39
0.61
0.928
0.931
0.903
2.92
3.56
3.06
0
0
0
35
36
H
H
0.75
0.75
0.61
0.61
0.902
0.889
2.89
4.07
0
0
37
38
39
H
H
H
0.75
0.75
0.75
0.61
0.61
0.61
0.903
0.901
0.892
3.77
2.91
4.19
0
0
0
40
H
0.75
0.61
0.902
4.47
0
41
H
0.75
0.61
0.901
4.69
0

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
855
Table 2Ðcontd
42
H
0.75
0.61
0.901
4.98
0
43
44
H
H
0.75
0.75
0.61
0.61
0.901
0.901
1.56
1.10
0
0
45
46
H
H
0.75
0.75
0.61
0.61
0.902
0.902
2.56
3.85
0
0
47 OMe
0.91
1.01
0.986
2.86
0
48
49
t-Bu
t-Bu
0.92
0.92
3.39
3.39
0.934
0.977
4.32
5.67
0
0
50
51
t-Bu
t-Bu
0.92
0.92
3.39
3.39
0.932
0.946
5.33
0
2.12
0
(continued)

856
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Table 2Ðcontd
No. X2
R
Æs#
ÆEs(AMD) R(Ophenol
)
logP ICOOR
52
t-Bu
0.92
3.39
0.944
0.71
0
53
t-Bu
0.92
3.39
0.949
2.84
0
54
55
t-Bu
t-Bu
0.92
0.92
3.39
3.39
0.941
0.929
1.80
1.98
0
0
56
57
t-Bu
0.92
Ða
3.39
0.61
0.933
0.651
5.21
1
0
Ða
58
Ða
3.39
0.753
Ða
0
1
2
probucol
a-tocopherol
Ða
Ða
5.56
2.32
0.489
1.169
Ða
Ða
0
0
aThe values were not calculated because of missing parameters.
electronic e€ect between the ortho-methoxyl and the
phenolic hydroxyl groups may not be complete because
the coplanar conformation of the hydroxyl group may
be taken only with diculty. We therefore examined the
Equation (3) is improved signi®cantly over eq (2),
although the ÆEs(AMD) term is not signi®cant over the
95% level. In this equation, the coecient of ÆÁsR is
+
nearly equal to that of Æs+. This means that the
through-resonance e€ect almost does not exist in 2,6-
disubstituted phenols and that the e€ect does not con-
trol the reactivity of the phenolic hydroxyl group in
transforming into their radical species.
+
use of the parameter, ÁsR for ortho-substituents
de®ned above. In a way, this procedure is to apply the
Yukawa±Tsuno's one24 to the ortho-substituents. The
importance of the through-resonance e€ect could be
understood by comparison between the coecient of
Æs+ and that of ÆÁsR
Combining these two parameters, we used the Æs#
(sigma mixed),9 the sum of the s+ for meta- and para-
and the s0 for ortho-substituents, to formulate eq (4).
+
.
‡
‡
logꢀ1=IC50† ˆ 1:06ꢀÆ0:52†Æs
0:95ꢀÆ0:79†ÆÁsR
logꢀ1=IC50† ˆ 1:08ꢀÆ0:49†Æs# 0:16ꢀÆ0:18†ÆEs
0:16ꢀÆ0:19†ÆEsꢀAMD† ‡ 5:16ꢀÆ0:57†
n ˆ 14; s ˆ 0:24; r ˆ 0:89; F3;10 ˆ 12:60
ꢀ4†
ꢀAMD† ‡ 5:25ꢀÆ0:37†
ꢀ3†
nˆ14; sˆ0:23; rˆ0:89; F2;11 ˆ20:15

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
857
Figure 2. Crystal structure of 24.
Figure 4. Mechanism of termination of radical chain reaction
by hydroxyphenylurea derivatives.
are the values. The negative coecient of the
ÆEs(AMD) term in eq (4) indicates that the hydroxy-
phenylureas with the bulkier ortho-substituents show
higher inhibitory activity, although the steric e€ect is
not very important. After passing through the inter-
mediate state, the hydroxyphenylureas are transformed
to the corresponding phenoxy radicals. The phenoxy
radicals generated are stabilized more e€ectively by the
shielding e€ect of the bulkier ortho-substituents so that
it is less reactive to radicalize another lipid molecule.
Thus, the more sterically hindered hydroxyphenylureas
could have the higher antioxidative activity. In eq (4),
the Æs# term seems to represent the electron-donating
e€ect on increasing the reactivity of the phenolic
hydroxyl group turning into the corresponding phenoxy
radical and the ÆEs(AMD) term appears to show the
steric e€ect of substituents on the stability of the resul-
tant phenoxy radical.
Figure 3. Stable conformers of 24.
In eq (3) and (4), the ÆEs(AMD) term is not deleted
since it is signi®cant above the 95% level for the larger
set of compounds as will be shown below. The negative
coecient of Æs# shows that the electron-donating
e€ect including the through-resonance e€ect from para-
and meta-, but not from ortho-, substituents on the
electron-de®cient phenoxy radical enhances the inhibi-
tory activity. The mechanistic interpretation of this
e€ect is shown in Figure 4.
On approaching to the lipid peroxide radical, one of the
electrons of the O±H bond of the hydroxyphenylurea
tends to shift to the radical. In the transition complex,
phenolic oxygen is positively charged more or less.25,26
Enhancement of the electron-donating property of sub-
stituents could reduce the activation energy of this pro-
cess, leading to compounds showing the higher
inhibitory activity against the propagation of lipid per-
oxidation.
The addition of the logP term did not improve the
quality of the correlation, although the highly lipophilic
atmosphere of lipid peroxidation reaction expected to
imply the contribution of hydrophobicity of their inhi-
bitors. The use of the Æs0 value, instead of Æs+ and
Æs#, gave poorer correlations (s ˆ 0:33, r ˆ 0:73) and
in the correlation equation the ÆEs(AMD) term was
entirely insigni®cant (equations not shown).
The Es(AMD) value of ortho-substituents is de®ned so
that the bulkier are the substituents, the more negative
Table 3. Conformational energies and di€erences
To obtain more detailed information, we included 11
diphenylureas (19±29) having various substituents on
the non-phenolic benzene ring B. The electronic and
steric e€ects of substituents Y1±Y5 of the B ring on the
reactivity of the phenolic hydroxyl group of the A ring
were regarded as being insigni®cant because of their
distant location. Thus, the electronic and steric para-
meters of substituted phenylureido groups were taken to
be unchanged regardless of the substitution patterns on
the B ring to yield eq (5).
(kcal/mol)
ÁEc
a
b
No.
Egr
Erd
p-Methoxyphenol
58.99
107.53
178.67
63.88
36.54
85.74
22.45
21.79
19.72
17.39
1
2
5
158.95
46.49
aThe energies in the ground state.
bThe energies in the radical forms.
cÁE=Erd Egr.

858
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
logꢀ1=IC50† ˆ 1:14ꢀÆ0:39†Æs# 0:14ꢀÆ0:09†ÆEs
ꢀAMD† 1:19ꢀÆ0:27†ICOOR ‡ 5:30ꢀÆ0:29†
n ˆ 25; s ˆ 0:20; r ˆ 0:95; F3;21 ˆ 63:36
ꢀ5†
estimated ones within the range of experimental errors.
The surroundings in the brain homogenate where the
hydroxyphenylurea derivatives inhibit lipid peroxida-
tion are hydrophobic. Then it had been expected that
the hydrophobic derivatives would have approached to
the site of inhibition reaction more easily than the less
hydrophobic ones and that the former would have
exhibited higher potency. However the variations in the
hydrophobicity of compounds do not participate in the
activity variations.
The quality of the correlation in eq (5) formulated for
25 diphenylureas was much improved over that of eq
(4). The Æs# and ÆEs(AMD) terms, now signi®cant
above the 95% level, are similar to those in eq (4). In eq
(5), however, the addition of an indicator variable,
I
COOR, is required for an acceptable correlation. ICOOR
It was revealed that the inhibitory activities of hydroxy-
phenylurea derivatives were governed by electronic
steric e€ects on the ring A and that any structural con-
version around the ring B was rather tolerable except
for the negative e€ect of carboxylates. These ®ndings
were very important to rationally design novel com-
pounds with various pharmacological e€ects as well as
high antioxidative activities by modi®cation around the
ring B. For example, 1-(3-tert-butyl-2-hydroxy-5-meth-
oxyphenyl)-3-(2-cyclohexylethyl)-3-(4-dimethylamino-
phenyl)urea, one of the hydroxyphenylurea derivatives,
was found to inhibit low density lipoprotein oxidation
and acyl CoA: cholesterol acyltransferase.27
takes a value of unity for compounds having either car-
boxyl or ester substituent on the B ring, and takes zero
otherwise. The ester substituents are probably hydro-
lyzed into carboxylates by esterases involved during
incubation for 15 h with brain homogenate. The ICOOR
term in eq (5) shows that carboxylate derivatives are
about ten times less potent than derivatives otherwise
equivalent. Carboxylate exists in ionic form in the bu€er
solution and an intermolecular ion-dipole interaction
between the carboxylate anion and the phenolic hydroxyl
is possible. The carboxylate could prevent phenolic
hydroxyl from formation of the transition state with
lipid peroxides by the intermolecular ion-dipole asso-
ciation. This e€ect of carboxylates was represented by
the indicator variable ICOOR in eq (5).
The minute analyses of electronic e€ects of hydroxy-
phenylureas gave the mechanistic interpretation illu-
strated in Figure 4. This mechanism implies that the
reactivity index R(Ophenol) derived from the frontier
electron density at the HOMO level could work as the
parameter for the electronic e€ect of substituents on the
hydroxyl group. In order to validate this mechanistic
hypothesis, we performed correlation analysis using the
R(Ophenol) index. For 25 diphenylurea derivatives used
for eq (5), eq (7) was formulated with almost equivalent
coecients of ÆEs(AMD) and ICOOR terms and the
intercept in eq (5).
The facts that the coecients of the electronic and steric
terms in eq (5) is almost equivalent to those in eq (4) and
that no hydrophobicity term is signi®cant again in eq (5)
indicates that any structural variations beyond the urea
moiety may be made without signi®cant variations in
the activity if the substitution pattern is optimized on
the ring A. Thus, in order to examine the structural
conversion around the ring B without decrease of the
inhibitory activity, we synthesized various substituted-
ureido compounds (30±56) in which variations in elec-
tronic and steric e€ects of those substituents on the
phenolic hydroxyl on the A ring are also regarded as
being unchanged. The correlation analysis including
these compounds gave eq (6).
logꢀ1=IC50† ˆ1:36ꢀÆ0:67†RꢀOphenol
†
0:21ꢀÆ0:10†ÆEs
ꢀAMD† 1:28ꢀÆ0:34†ICOOR ‡ 5:08ꢀÆ0:48†
n ˆ 25; s ˆ 0:24; r ˆ 0:92; F3;21 ˆ 41:13
ꢀ7†
logꢀ1=IC50† ˆ 1:20ꢀÆ0:48†Æs# 0:14ꢀÆ0:07†ÆEs
ꢀAMD† 1:17ꢀÆ0:28†ICOOR ‡ 5:25ꢀÆ0:35†
n ˆ 52; s ˆ 0:26; r ˆ 0:88; F3;48 ˆ 56:81
ꢀ6†
For 54 hydroxyphenylureas including two compounds
57, 58 for which the Æs# parameters of substituents
were not available, eq (8) was formulated which is
practically equivalent to eq (7).
logꢀ1=IC50† ˆ1:01ꢀÆ0:57†RꢀOphenol
†
0:20ꢀÆ0:07†ÆEs
The inhibitory activity against the lipid peroxidation of
52 compounds was correlated with the same set of
parameters as those in previous equations for diphenyl-
ureas. Although logP values of these compounds were
widely spread between 0.71 (52) and 5.93 (27), no
hydrophobic e€ect was observed and the observed
activities of compounds 30±56 were identical to their
ꢀAMD† 1:16ꢀÆ0:31†ICOOR ‡ 5:26ꢀÆ0:46†
n ˆ 54; s ˆ 0:30; r ˆ 0:85; F3;50 ˆ 41:91
ꢀ8†
The ÆEs(AMD) term is signi®cant in eq (7) and (8) and
its coecient is almost equivalent with that in eq (5) and

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
859
Table 4. Inhibitory activities of lipid peroxidation of hydroxy-
phenylurea derivatives
(6), indicating that the steric e€ect of substituents on A
ring really exists inspite of its instability in eq (1)±(4).
log(I/IC50
Dev.
)
The antioxidative potencies, log(1/IC50), of probucol 1
and a-tocopherol 2 lacking the urea moiety were calcu-
lated by eq (8), as being 6.87 and 6.90, respectively. On
the average, these values overestimate the potencies
about 1.5 log unit higher than the observed values
(Table 3). Since eq (8) is derived based on QSAR of
hydroxyphenylureas, these di€erences are due to the
stabilization in the radical form by urea moiety as dis-
cussed previously. Thus, the introduction of the urea
moiety is expected to contribute to the activity
enhancement by about 30 times.
No.
IC50
(mM)
Obsd.
Calcd.
(eq (6))
Calcd.
(eq (8))
Dev.
5
0.43
6.00
2.80
0.37
0.81
0.39
0.28
0.14
0.44
0.25
0.30
0.33
0.65
2.40
0.30
10.10
0.31
6.50
0.44
0.59
11.30
0.13
0.14
0.16
0.15
0.13
0.16
0.07
0.15
0.42
1.30
2.40
0.41
1.50
0.54
0.16
1.20
1.20
0.26
1.10
0.85
0.15
0.09
0.16
0.16
0.14
0.16
0.38
0.15
0.15
0.19
2.00
2.60
0.38
4.40
4.13
6.37
5.22
5.55
6.43
6.09
6.41
6.55
6.85
6.36
6.60
6.52
6.48
6.19
5.62
6.52
5.00
6.51
5.19
6.36
6.23
4.95
6.89
6.85
6.80
6.82
6.89
6.80
7.15
6.82
6.38
5.89
5.62
6.39
5.82
6.27
6.80
5.92
5.92
6.59
5.96
6.07
6.82
7.05
6.80
6.80
6.85
6.80
6.42
6.82
6.82
6.72
5.70
5.59
6.42
5.36
5.38
6.24
5.24
5.55
6.27
6.02
6.54
6.58
6.83
6.66
6.48
6.48
6.52
6.42
6.28
6.24
5.07
6.24
5.07
6.24
6.24
5.07
6.83
6.83
6.83
6.83
6.83
6.83
6.83
6.83
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.24
6.48
6.83
6.83
6.83
6.83
6.83
6.83
6.83
6.83
5.66
Ða
0.13
0.02
0.00
0.16
0.07
0.13
0.03
0.02
0.30
0.12
0.04
0.04
0.23
0.66
0.28
0.07
0.27
0.12
0.12
0.01
0.12
0.06
0.02
0.03
0.01
0.06
0.03
0.32
0.01
0.14
0.35
0.62
0.15
0.42
0.03
0.56
0.32
0.32
0.35
0.28
0.17
0.58
0.57
0.03
0.03
0.02
0.03
0.41
0.01
0.01
0.11
0.04
Ða
6.18
5.73
5.87
6.19
5.96
6.43
6.45
6.78
6.51
6.32
6.41
6.33
6.19
5.93
6.27
5.09
6.09
4.99
6.12
5.88
5.07
6.42
6.54
6.80
6.85
6.85
6.84
6.88
6.88
6.29
6.29
6.28
6.29
6.29
6.28
6.29
6.29
6.29
6.29
6.29
6.29
6.29
6.46
6.88
6.92
6.88
6.89
6.89
6.90
6.89
6.88
5.72
6.04
6.70
6.87
6.90
0.19
0.51
0.32
0.24
0.13
0.02
0.10
0.07
0.15
0.28
0.11
0.15
0.00
0.31
0.25
0.09
0.42
0.20
0.24
0.35
0.12
0.47
0.31
0.00
0.03
0.04
0.04
0.27
0.06
0.09
0.40
0.66
0.10
0.47
0.01
0.51
0.37
0.37
0.30
0.33
0.22
0.53
0.59
0.08
0.12
0.03
0.09
0.47
0.08
0.07
0.16
0.02
0.45
0.28
1.51
1.52
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
1
Conclusion
We designed and synthesized novel hydroxyphenylureas
based on the structures of natural antioxidants, vitamin
E and uric acid. Quantitative analyses of their electronic
e€ects on the inhibition of lipid peroxidation gave us a
mechanistic interpretation. The structural requirements
for high antioxidative activity of hydroxyphenylureas
are: (1) electron-donating substituents on the benzene
ring where the phenolic hydroxyl group is located, (2)
bulky substituents at the ortho-positions of the phenolic
hydroxyl group, and (3) neither carboxylates nor esters
in their structures. The urea moiety seems to contribute
to the activity enhancement with a factor of 30 by sta-
bilizing its radical. Some of the hydroxyphenylurea
compounds studied here are now under pharmacologi-
cal investigation for the possibility as therapeutic agents
of diseases mentioned earlier in this paper.
Experimental
Inhibitory activity of lipid peroxidation
Probucol 1 was purchased from Daiichi Seiyaku Co.
Ltd. (Tokyo, Japan), and Deferoxamine mesylate
(Desferal) was from Chiba-Geigy Japan Ltd. (Hyogo,
Japan). a-Tocopherol 2, 2-thiobarbituric acid sodium
salt (TBA) and 3,5-di-tert-butyl-4-hydroxytoluene
(BHT) were purchased from Nacalai Tesque Co. Ltd.
(Kyoto, Japan). All other chemicals and materials used
were of the analytical grade available from local com-
mercial sources.
Adult male Sprague Dawley rats weighing 250±300 g
were obtained from Charles River, Japan Ltd. (Shi-
zuoka, Japan). Rats were sacri®ced by decapitation and
exsanguination. The entire brain was removed and
homogenized in 4 vol of cold 1/15 M phosphate bu€ered
saline (PBS, pH 7.4) and stored at 80 ꢁC until use.
Ða
Ða
Ða
Ða
2
Ða
Ða
aThe values were not calculated because of missing parameters.

860
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Immediately before the assay, the brain homogenate was
diluted to the fourfold volume with the PBS. Ten micro-
liters of each of the solutions containing various amounts
of antioxidants in dimethylsulfoxide (DMSO) were
added to and mixed with 1 mL of the brain homogenate.
The mixture was incubated with aeration at 37 ꢁC for
15 h. The lipid peroxidation level in the incubated
homogenate was measured as that of malonaldehyde
formed by peroxidation of unsaturated lipids. The
amount of malonaldehyde was measured as that of a red
pigment formed by the condensation with thiobarbituric
acid (TBA test) according to a method modi®ed from
that of Ohkawa et al.28 Five hundred microliters of
aqueous Desferal solution (®nal concentration: 1 mM)
and 250 mL of BHT solution dissolved in DMSO (®nal
concentration: 1 mM), both of which work as quenchers
of further peroxidation, were mixed with 1 mL of 20%
acetic acid and 1 mL of 1% aqueous TBA solution. The
quenching solution (2.75 mL) was added to and mixed
with the incubated homogenate. The mixture was
heated at 95 ꢁC for 20 min followed by cooling and
extraction with 4 mL of n-butanol. The ¯uorescence of
the n-butanol layer was measured at 536 nm (excitation)
and 552 nm (emission). The inhibition percentage of the
peroxidation was calculated from the di€erence in the
¯uorescence intensity between solutions from control
and treated homogenates. The IC50 value was calculated
by the Probit method from inhibitory percentage values
at the concentrations of 0, 0.1, 1, and 10 mM using an
appropriate commercial computer program.
for 15 min. The mixture was acidi®ed to pH 3 with concd
HCl, the resulting crystals were collected by ®ltration,
washed with water and dried. The crude crystals were
recrystallized from CHCl3±EtOH to yield 217 g (59%)
of 60 (X2=OMe, X3=H, X4=t-Bu). The solid of 60
(217 g, 0.691 mol) was added portionwise to a suspen-
sion of sodium hydride (NaH, 31.8 g, 0.829 mol, 60%
mineral oil suspended) in N,N-dimethylformamide
(DMF, 860 mL) at 0 ꢁC and stirred for 10 min at rt. To
the reaction mixture was added chloromethyl methyl
ether (MOMCl, 63 mL, 0.829 mol) dropwise at 0 ꢁC and
the resulting mixture was stirred at rt for 1 h. After
evaporation of DMF, the residue was extracted with
ethyl acetate (AcOEt), and the organic layer was washed
with brine, dried (MgSO4), and concd in vacuo. The
resulting crystals were recrystallized from Et2O-hexane
to a€ord 61 (X2=OMe, X3=H, X4=t-Bu, 168 g, 68%).
A mixture of 61 (168 g, 0.468 mol), 10% palladium on
carbon (3.0 g) and MeOH (1600 mL) was subjected to
hydrogenation using Parr apparatus (H2, 3.5 atm) for
2.5 h at room temperature. After removal of catalyst by
®ltration, the ®ltrate was concentrated in vacuo. The
residue was puri®ed on silica gel chromatography using
CHCl3/AcOEt (10:1) to a€ord 62 (X2=OMe, X3=H,
1
X4=t-Bu, 95.6 g, 85%): syrup; H NMR (d in CDCl3)
1.35 (s, 9H, CH3), 3.63 (s, 3H, CH3), 3.71 (s, 3H, CH3),
4.24 (br, 2H, NH2), 4.95 (s, 2H, CH2), 6.18 (d, 1H,
J=3 Hz, ArH-4), 6.26 (d, 1H, J=3 Hz, ArH-6); EIMS
m/z 239 (M+).
3,4,5-Trimethoxy-2-methoxymethoxyaniline (62; X2=OMe,
X3=OMe, X4=OMe). To a solution of 63 (X2=OMe,
X3=OMe, X4=OMe, 4.1 g, 18.0 mmol) in tetra-
hydrofuran (THF, 40 mL) was added dropwise sec-
butyllithium (1.875 M in cyclohexane, 10.5 mL,
19.8 mmol) at 78 ꢁC under nitrogen atmosphere and
the mixture was stirred for 45 min at the same tempera-
ture. To the reaction mixture was added dropwise a solu-
tion of p-toluenesulfonyl azide (TosN3, 3.9 g, 19.8 mmol)
in THF (10 mL) at 78 ꢁC under nitrogen atmosphere.
The mixture was stirred at the same temperature for
2.5 h and poured onto aqueous sodium pyrophosphate
(Na4P2O7 aq, 60 mL) at 0 ꢁC. After stirring the mixture
for 2 h at the same temperature, the insoluble materials
were removed by ®ltration, and the ®ltrate was extracted
with AcOEt. The combined organic layer was washed
with brine, dried (MgSO4), and concentrated in vacuo.
The residue was puri®ed with silica gel chromatography
using hexane/AcOEt (9:1). The fractions were collected
and concentrated in vacuo. The residue was dissolved to
THF (50 mL), added to a suspension of lithium alumi-
num hydride (LiAlH4, 1.15 g) in THF (50 mL) at 0 ꢁC
and stirred for 40 min at the same temperature. To the
mixture was added water (2.7 mL), 15% NaOH aq
(2.7mL), and water (8.1 mL) in this order. After the
insoluble materials were removed by ®ltration, the ®ltrate
Synthesis
Melting points were determined on Yamato melting
point apparatus and are uncorrected. Infrared spectra
were recorded on a Perkin±Elmer 1640 IR spectro-
photometer. Proton nuclear magnetic resonance (1H
NMR) spectra were recorded on a Hitachi R-90
(90 MHz) or a Bruker AC-200 (200 MHz) spectrometer
with tetramethylsilane as the internal standard. Mass
spectra were recorded on a Hitachi M-2000A spectro-
meter. Elemental analyses were performed on a Perkin±
Elmer 2400 II. Column chromatography was accom-
plished by using Kieselgel 60 (230±400 mesh, E. Merck)
with the indicated solvent system.
Preparation of the aniline 62
3-tert-Butyl-5-methoxy-2-methoxymethoxyaniline (62;
X2=OMe, X3=H, X4=t-Bu). To a solution of p-anisi-
dine (59, 153 g, 1.24 mol) in 25% HCl aq (1200 mL) was
added slowly NaNO2 (94 g, 1.36 mol) in water (300 mL)
under cooling with ice-water. The mixture was added
dropwise to a solution of 3-tert-butyl-4-hydroxyanisole
(BHA, 212 g, 1.18 mol) in NaOH aq (248 g in 1000 mL
of water) at 10 ꢁC and stirred at the same temperature

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
861
was concentrated in vacuo and the residue was diluted
with Et2O. The organic layer was washed with brine,
dried (MgSO4), ®ltered and concentrated in vacuo. The
residue was chromatographed on silica gel using hexane/
AcOEt (2:1) as an eluent to give 62 (X2=OMe,
for 1 h. To the solution was added Et2O and the result-
ing solid was collected by ®ltration. The solid was dis-
solved in saturated NaHCO3 aq and extracted with
CHCl3. The organic layer was dried (MgSO4), ®ltered
and concentrated in vacuo to give 2-(4-benzylpiperazin-
1-yl)ethylamine (1.2 g, 83%): syrup; 1H NMR (d in
CDCl3) 2.35±2.60 (m, 10H, CH2), 2.78 (t, 2H, J=6 Hz,
CH2), 3.51 (s, 2H, CH2), 7.20±7.35 (m, 5H, ArH); EIMS
m/z 219 (M+).
1
X3=OMe, X4=OMe, 2.5 g, 57%): syrup; H NMR (d
in CDCl3) 3.57 (s, 3H, CH3), 3.76 (s, 3H, CH3), 3.78 (s,
3H, CH3), 3.89 (s, 3H, CH3), 5.03 (s, 2H, CH2), 6.08 (s,
1H, ArH-6); EIMS m/z 243 (M+).
In the same manner, the other substituted methoxy-
methoxyanilines were obtained.
Urea formation and removal of the methoxymethyl
protecting group
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridyl-
methyl)urea (54). To a solution of triphosgene (5.58 g) in
CH2Cl2 (450 mL), the solution of 3-tert-butyl-5-meth-
oxy-2-methoxymethoxyaniline 62 (11.25 g, 47 mmol)
and triethylamine (20 mL) in CH2Cl2 (150 mL) were
added dropwise at 78 ꢁC and the reaction mixture
was warmed up to rt for 30 min. After removal of the
solvent, the residue was dissolved in CH2Cl2 (200 mL)
and the solution of 3-picolylamine (5.1 g, 47 mmol) and
triethylamine (10 mL) in CH2Cl2 (100 mL) was added
dropwise at rt. After stirring at the same temperature
for 1 h, the reaction mixture was washed with brine,
dried (MgSO4), ®ltered and concentrated in vacuo, and
the residue was chromatographed on silica using
CHCl3/MeOH (15:1). The crude crystals were recrys-
tallized from i-Pr2O-AcOEt to yield 14.0 g (80%) of
1-(3-tert-butyl-5-methoxy-2-methoxymethoxyphenyl)-3-
(3-pyridylmethyl)urea (72). To a solution of 72 (14.0 g,
37.4 mmol) in MeOH (150 mL) was added concd HCl
(6.8 mL) and the mixture was stirred at room tempera-
ture for 1 h. The resulting mixture was concd in vacuo
and the crude crystals were recrystallized from EtOH
to give 54 (11.2 g, 82%): mp 165±167 ꢁC; IR (KBr)
Preparation of the amine (R-NH2)
Commercially unavailable amines were synthesized by
alkylation or acylation of the corresponding alcohols,
amines and halides. The procedures are exempli®ed
by the syntheses of 4-(3-dibutylaminopropyl)oxy-
aniline, and 2-(4-benzylpiperazin-1-yl)ethylamine as
follows.
4-(3-Dibutylaminopropyl)oxyaniline. To a suspension of
NaH (1.15 g, 29.6 mmol, 60% mineral oil suspended) in
DMF (30 mL) was added dropwise p±aminophenol
(3.2 g, 29 mmol) and the mixture was stirred for 30 min
at room temperature. To the suspension was added
slowly N,N-dibutyl-3-chloropropylamine (6.0 g, 29 mmol)
at 0 ꢁC and the reaction mixture was stirred for 2 h at
room temperature. After the mixture was concentrated
in vacuo, the residue was extracted with AcOEt, the
organic layer was washed with brine, dried (MgSO4),
®ltered and concentrated in vacuo. The residue was
puri®ed on silica gel chromatography using CHCl3/
EtOH (20:1) to a€ord 4-(3-dibutylaminopropyl)oxy-
1
aniline (3.6 g, 44%): syrup; H NMR (d in CDCl3) 0.89
1
(t, 6H, J=7 Hz, CH3), 1.19±1.49 (m, 8H, CH2), 1.79±
1.93 (m, 2H, CH2), 2.40 (t, 4H, J=7 Hz, CH2), 2.57 (t,
2H, J=7 Hz, CH2), 3.40 (br, 2H, NH2), 3.92 (t, 2H,
J=6 Hz, CH2), 6.58±6.66 (m, 2H, ArH-2 and -6), 6.70±
6.78 (m, 2H, ArH-3 and -5); EIMS m/z 279 (M++1).
3311, 3200, 1653, 1600 cm 1; H NMR (d in DMSO-d6)
1.33 (s, 9H, CH3), 3.64 (s, 3H, CH3), 4.45±4.6 (m, 2H,
CH2), 6.47 (d, 1H, J=3 Hz, ArH-4), 6.85 (d, 1H,
J=3 Hz, ArH-6), 7.5±7.7 (m, 1H, NH), 7.95±8.1 (dd,
1H, J=5, 8 Hz, PyH-5), 8.46 (d, 1H, J=8 Hz, PyH-4),
8.75±8.9 (m, 3H, PyH-2, -6 and NH or OH); EIMS
+
.
m/z 329 (M ); Anal. Calcd for C18H23N3O3 HCl: C
2-(4-Benzylpiperazin-1-yl)ethylamine. A mixture of N-
benzyloxycarbonyl-2-iodoethylamine (6.9 g, 22.7 mmol),
N-benzylpiperazine (4.0 g, 22.7 mmol), and K2CO3
(15.7 g, 114 mmol) in hexamethylphosphoric triamide
(HMPA, 40 mL) was stirred overnight at room tem-
perature. The reaction mixture was diluted with water
and extracted with Et2O. The organic layer was washed
with brine, dried (MgSO4), ®ltered and concentrated in
vacuo, and the residue was puri®ed on silica gel chro-
matography using CHCl3/EtOH (15:1) to a€ord N-
benzyloxycarbonyl-2-(4-benzylpiperazin-1-yl)ethylamine
(5.6 g, 70%). A solution of N-benzyloxycarbonyl-2-(4-
benzylpiperazin-1-yl)ethylamine (2.3 g, 6.5 mmol) in 30%
HBr-AcOH (50 mL) was stirred at room temperature
59.09, H 6.61, N 11.49. Found: C 58.87, H 6.70, N
11.29.
In the same manner the following compounds were
obtained.
1-(2-Hydroxy-5-methoxyphenyl)-3-phenylurea (5). Mp
158±159 ꢁC; IR (KBr) 3310, 1604, 1565 cm 1; H NMR
1
(d in CDCl3+DMSO-d6) 3.76 (s, 3H, CH3), 6.49±6.54
(dd, 1H, J=3, 9 Hz, ArH-4), 6.85 (d, 1H, J=9 Hz, ArH-
3), 6.93±7.05 (m, 1H, ArH-40), 7.10 (d, 1H, J=3 Hz,
ArH-6), 7.25±7.34 (m, 2H, ArH-30 and -50), 7.43±7.48
(m, 2H, ArH-20 and -60), 8.16 (br, 1H, NH or OH), 8.57

862
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
(br, 1H, NH or OH); EIMS m/z 258 (M+); Anal. Calcd
for C14H14N2O3: C, 65.11, H, 5.46, N, 10.85. Found: C,
65.25, H, 5.36, N, 10.74.
for C15H16N2O3: C, 66.16, H, 5.92, N, 10.29. Found: C,
66.06, H, 5.79, N, 10.18.
1-(3-Ethyl-2-hydroxy-5-methoxyphenyl)-3-phenylurea (11).
1
1-(2-Hydroxy-4-methoxyphenyl)-3-phenylurea (6). Mp
164±166 ꢁC; IR (KBr) 3285, 1620, 1562 cm 1; H NMR
Mp 150±152 ꢁC; IR (Nujol) 3350, 3300, 1620 cm 1; H
1
NMR (d in CDCl3) 1.19 (t, 3H, J=7.6 Hz, CH3), 2.64
(q, 2H, J=7.6 Hz, CH2), 3.66 (s, 3H, CH3), 6.38 (d, 1H,
J=3 Hz, ArH-4), 6.56 (d, 1H, J=3 Hz, ArH-6), 7.02 (s,
1H, NH or OH), 7.07±7.16 (m, 1H, ArH-40), 7.16 (s, 1H,
NH or OH), 7.22±7.33 (m, 4H, ArH-20, -30, -50 and -60),
7.78 (s, 1H, NH or OH); EIMS m/z 286 (M+); Anal.
Calcd for C16H18N2O3: C, 67.12, H, 6.34, N, 9.78.
Found: C, 66.95, H, 6.10, N, 9.88.
(d in DMSO-d6) 3.67 (s, 3H, CH3), 6.30±6.43 (dd, 1H,
J=3, 9 Hz, ArH-5), 6.48 (d, 1H, J=3 Hz, ArH-3), 6.85±
7.02 (m, 1H, ArH-40), 7.17±7.34 (m, 2H, ArH-30 and -50),
7.42±7.52 (m, 2H, ArH-2 0 and 60), 7.85 (d, 1H, J=9 Hz,
ArH-6), 7.96 (s, 1H, NH or OH), 9.12 (s, 1H, NH or
OH), 9.92 (s, 1H, NH or OH); EIMS m/z 258 (M+);
Anal. Calcd for C14H14N2O3: C, 65.11, H, 5.46, N,
10.85. Found: C, 64.94, H, 5.35, N, 10.91.
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-phenylurea
1
1-(2-Hydroxy-3-methoxyphenyl)-3-phenylurea (7). Mp
153±155 ꢁC; IR (KBr) 3533, 3310, 1642, 1563 cm 1; H
(12). Mp 147±149 ꢁC; IR (Nujol) 3400, 3350, 1670 cm
;
1H NMR (d in CDCl3) 1.40 (s, 9H, CH3), 3.67 (s, 3H,
CH3), 6.38 (d, 1H, J=3 Hz, ArH-4), 6.77 (d, 1H,
J=3 Hz, ArH-6), 6.84 (s, 1H, NH or OH), 7.05 (s, 1H,
NH or OH), 7.08±7.15 (m, 1H, ArH-40), 7.23±7.33 (m,
4H, ArH-20, -30, -50 and -60), 7.65 (s, 1H, NH or OH);
EIMS m/z 314 (M+); Anal. Calcd for C18H22N2O3: C,
68.77, H, 7.05, N, 8.91. Found: C, 68.52, H, 6.90, N,
8.96.
1
NMR (d in DMSO-d6) 3.79 (s, 3H, CH3), 6.56±6.74 (m,
2H, ArH-4 and -5), 6.82±7.03 (m, 1H, ArH-40), 7.18±
7.35 (m, 2H, ArH-30 and -50), 7.42±7.52 (m, 2H, ArH-20
and -60), 7.68±7.80 (dd, 1H, J=3, 9 Hz, ArH-6), 8.21 (s,
1H, NH or OH), 9.06 (br, 1H, NH or OH), 9.34 (s, 1H,
NH or OH); EIMS m/z 258 (M+); Anal. Calcd for
C14H14N2O3: C, 65.11, H, 5.46, N, 10.85. Found: C,
65.32, H, 5.45, N, 10.82.
1-(2-Hydroxy-5-methoxy-3-octylphenyl)-3-phenylurea (13).
Mp 100±101 ꢁC; IR (Nujol) 3500, 3270, 1632,
1620 cm 1; 1H NMR (d in DMSO-d6) 0.83±0.95 (m, 3H,
CH3), 1.15±1.65 (m, 12H, CH2), 2.50±2.59 (m, 2H,
CH2), 3.66 (s, 3H, CH3), 6.30 (d, 1H, J=3 Hz, ArH-4),
6.92±6.99 (m, 1H, ArH-40), 7.23±7.31 (m, 2H, ArH-30
and -50), 7.43±7.47 (m, 2H, ArH-20 and -60), 7.50 (d, 1H,
J=3 Hz, ArH-6), 8.16 (s, 1H, NH or OH), 8.29 (s, 1H,
NH or OH), 9.34 (s, 1H, NH or OH); SIMS m/z 371
(M++1); Anal. Calcd for C22H30N2O3: C, 71.32, H,
8.16, N, 7.56. Found: C, 71.23, H, 8.11, N, 7.44.
1-(2-Hydroxy-5-octyloxyphenyl)-3-phenylurea (8). Mp
146±147 ꢁC; IR (Nujol) 3300, 3150, 1620, 1600 cm 1; 1H
NMR (d in DMSO-d6) 0.70±2.00 (m, 15H, CH3 and
CH2), 3.85 (t, 2H, J=6 Hz, CH2), 6.29±6.42 (dd, 1H,
J=3, 9 Hz, ArH-4), 6.73 (d, 1H, J=9 Hz, ArH-3), 6.86±
7.02 (m, 1H, ArH-40), 7.17±7.35 (m, 2H, ArH-30 and -50),
7.43±7.53 (m, 2H, ArH-20 and -60), 7.77 (d, 1H, J=3 Hz,
ArH-6), 8.17 (s, 1H, NH or OH), 9.33 (s, 1H, NH or
OH), 9.40 (s, 1H, NH or OH); EIMS m/z 356 (M+);
Anal. Calcd for C21H28N2O3: C, 70.76, H, 7.92, N, 7.86.
Found: C, 70.85, H, 7.89, N, 7.89.
1-(2-Hydroxy-3,5-dimethoxyphenyl)-3-phenylurea (14).
Mp 172±174 ꢁC; IR (Nujol) 3400, 3300, 1640 cm 1; H
1
1-(2-Hydroxy-5-methylthiophenyl)-3-phenylurea (9). Mp
162±164 ꢁC; IR (KBr) 3311, 1598, 1560 cm 1; H NMR
1
NMR (d in DMSO-d6) 3.68 (s, 3H, CH3), 3.79 (s, 3H,
CH3), 6.25 (d, 1H, J=3 Hz, ArH-4), 6.91±6.99 (m, 1H,
ArH-40), 7.23±7.31 (m, 2H, ArH-30 and -50), 7.42±7.46
(m, 2H, ArH-20 and -60), 7.45 (d, 1H, J=3Hz, ArH-6),
8.24 (s, 1H, NH or OH), 8.57 (s, 1H, NH or OH), 9.38
(s, 1H, NH or OH); SIMS m/z 289 (M++1); Anal.
Calcd for C15H16N2O4: C, 62.49, H, 5.59, N, 9.72.
Found: C, 62.19, H, 5.36, N, 9.64.
(d in DMSO-d6) 2.40 (s, 3H, CH3), 6.79±6.82 (m, 2H,
ArH-3, and -4), 6.88±7.05 (m, 1H, ArH-40), 7.19±7.36
(m, 2H, ArH-30 and -50), 7.43±7.53 (m, 2H, ArH-20 and -60),
8.15 (s, 1H, ArH-6), 8.21 (s, 1H, NH or OH), 9.31 (s,
1H, NH or OH), 10.0 (br, 1H, NH or OH); EIMS m/z
274 (M+); Anal. Calcd for C14H14N2O2S: C, 61.29, H,
5.14, N, 10.21. Found: C, 61.35, H, 4.95, N, 10.13.
1-(2-Hydroxy-5-methoxy-3-methylphenyl)-3-phenylurea
(10). Mp 173±176 ꢁC; IR (Nujol) 3300, 1635 cm
1-(2-Hydroxy-5-methoxy-3-octyloxyphenyl)-3-phenylurea
(15). Mp 66±68 ꢁC; IR (Nujol) 3400, 1670 cm
1
1
;
1H
;
1H
NMR (d in DMSO-d6) 2.20 (s, 3H, CH3), 3.67 (s, 3H,
CH3), 6.33 (d, 1H, J=3 Hz, ArH-4), 6.86±7.02 (m, 1H,
ArH-40), 7.18±7.35 (m, 2H, ArH-30 and -50), 7.43±7.53
(m, 2H, ArH-20 and -60), 7.58 (d, 1H, J=3Hz, ArH-6),
8.25 (s, 1H, NH or OH), 8.30 (s, 1H, NH or OH), 9.37
(s, 1H, NH or OH); EIMS m/z 272 (M+); Anal. Calcd
NMR (d in DMSO-d6) 0.80±1.90 (m, 15H, CH3 and
CH2), 3.67 (s, 3H, CH3), 3.96 (t, 2H, J=6 Hz, CH2),
6.22 (d, 1H, J=3 Hz, ArH-4), 6.85±7.03 (m, 1H, ArH-
40), 7.18±7.34 (m, 2H, ArH-30 and -50), 7.42±7.52 (m,
2H, ArH-20 and -60), 7.48 (d, 1H, J=3 Hz, ArH-6), 8.20
(s, 1H, NH or OH), 8.27 (s, 1H, NH or OH), 9.40 (s,

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
863
1H, NH or OH); EIMS m/z 386 (M+); Anal. Calcd for
C22H30N2O4: C, 68.37, H, 7.82, N, 7.25. Found: C,
68.15, H, 7.80, N, 7.32.
N2O5 0.25CHCl3 H2O: C, 52.31, H, 4.68, N, 8.00.
Found: C, 52.64, H, 4.46, N, 8.01.
.
.
1-(2-Hydroxy-5-methoxyphenyl)-3-(4-methylphenyl)urea
(21). Mp 163±165 ꢁC; IR (KBr) 3302, 1606 cm
1
1-(2-Hydroxy-3-methoxy-5-octyloxyphenyl)-3-phenylurea
(16). Mp 115±117 ꢁC; IR (Nujol) 3300, 1660 cm
;
1H
1
;
1H
NMR (d in DMSO-d6) 2.23 (s, 3H, CH3), 3.66 (s, 3H,
CH3), 6.26±6.39 (dd, 1H, J=3, 9 Hz, ArH-4), 6.72 (d, 1H,
J=9 Hz, ArH-3), 7.03 (d, 2H, J=9 Hz, ArH-30 and -50),
7.31 (d, 2H, J=9 Hz, ArH-20 and -60), 7.75 (d, 1H,
J=3 Hz, ArH-6), 8.10 (s, 1H, NH or OH), 9.18 (s, 1H,
NH or OH), 9.36 (s, 1H, NH or OH); EIMS m/z 272
(M+); Anal. Calcd for C15H16N2O3: C, 66.16, H, 5.92,
N, 10.29. Found: C, 66.10, H, 5.85, N, 10.35.
NMR (d in DMSO-d6) 0.80±1.90 (m, 15H, CH3 and
CH2), 3.77 (s, 3H, CH3), 3.87 (t, 2H, J=6Hz, CH2), 6.23
(d, 1H, J=3Hz, ArH-4), 6.85±7.03 (m, 1H, ArH-40),
7.17±7.34 (m, 2H, ArH-30 and -50), 7.42±7.52 (m, 2H,
ArH-20 and -60), 7.47 (d, 1H, J=3Hz, ArH-6), 8.23 (s,
1H, NH or OH), 8.51 (s, 1H, NH or OH), 9.38 (s, 1H, NH
or OH); EIMS m/z 386 (M+); Anal. Calcd for
C22H30N2O4: C, 68.37, H, 7.82, N, 7.25. Found: C, 68.29,
H, 7.88, N, 7.19.
1-[4-(trans-Carboxyvinyl)phenyl]-3-(2-hydroxy-5-methoxy-
phenyl)urea (22). Mp 206 ꢁC; IR (Nujol) 3350, 1670,
1600 cm 1; 1H NMR (d in DMSO-d6) 3.66 (s, 3H, CH3),
6.38 (d, 1H, J=16 Hz, CH), 6.39 (dd, 1H, J=3, 9 Hz,
ArH-4), 6.74 (d, 1H, J=9 Hz, ArH-3), 7.49 (d, 2H,
J=9 Hz, ArH-30 and -50), 7.53 (d, 1H, J=16 Hz, CH),
7.61 (d, 2H, J=9 Hz, ArH-20 and -60), 7.77 (d, 1H,
J=3 Hz, ArH-6), 8.26 (s, 1H, NH or OH), 9.50 (s, 1H,
NH or OH), 9.60 (s, 1H, NH or OH), 12.22 (s, 1H,
CO2H); EIMS m/z 328 (M+); Anal. Calcd for
C17H16N2O5: C, 62.19, H, 4.91, N, 8.53. Found: C,
61.94, H, 4.81, N, 8.47.
1-(2-Hydroxy-3,4,5-trimethoxyphenyl)-3-phenylurea (17).
Mp 123±125 ꢁC; IR (Nujol) 3350, 3300, 1670 cm 1; H
1
NMR (d in DMSO-d6) 3.75 (s, 6H, CH3), 3.80 (s, 3H,
CH3), 6.87±7.03 (m, 1H, ArH-40), 7.19±7.35 (m, 2H,
ArH-30 and -50), 7.43±7.53 (m, 2H, ArH-20 and -60), 7.65
(s, 1H, ArH-6), 8.16 (s, 1H, NH or OH), 8.90 (s, 1H,
NH or OH), 9.31 (s, 1H, NH or OH); EIMS m/z 318
(M+); Anal. Calcd for C16H18N2O5: C, 60.37, H, 5.70,
N, 8.80. Found: C, 60.15, H, 5.66, N, 8.74.
1-(5-Hydroxy-2,4-dimethoxyphenyl)-3-phenylurea (18).
1
Mp 162±164 ꢁC; IR (KBr) 3372, 3280, 1664, 1597 cm
;
1-(4-Chlorophenyl)-3-(2-hydroxy-5-methoxyphenyl)urea
(23). Mp 184±186 ꢁC; IR (Nujol) 3300, 1620, 1595,
1H NMR (d in DMSO-d6) 3.76 (s, 3H, CH3), 3.82 (s,
3H, CH3), 6.70 (s, 1H, ArH-3), 6.86±7.03 (m, 1H, ArH-40),
7.18±7.35 (m, 2H, ArH-30 and -50), 7.42±7.53 (m, 2H,
ArH-20 and -60), 7.71 (s, 1H, ArH-6), 7.97 (s, 1H, NH or
OH), 8.49 (s, 1H, NH or OH), 9.16 (s, 1H, NH or OH);
EIMS m/z 288 (M+); Anal. Calcd for C15H16N2O4: C,
62.49, H, 5.59, N, 9.72. Found: C, 62.36, H, 5.49, N,
9.70.
1
1570 cm 1; H NMR (d in CDCl3+DMSO-d6) 3.71 (s,
3H, CH3), 6.33±6.46 (dd, 1H, J=3, 9 Hz, ArH-4), 6.77
(d, 1H, J=9 Hz, ArH-3), 7.18 (d, 2H, J=9 Hz, ArH-30
and -50), 7.42 (d, 2H, J=9 Hz, ArH-20 and -60), 7.53 (d,
1H, J=3 Hz, ArH-6), 8.12 (s, 1H, NH or OH), 8.80 (s,
1H, NH or OH), 8.95 (s, 1H, NH or OH); EIMS m/z
292 (M+); Anal. Calcd for C14H13N2O3Cl: C, 57.45, H,
4.48, N, 9.57. Found: C, 57.43, H, 4.43, N, 9.49.
1-(3-Tri¯uoromethylphenyl)-3-(2-hydroxy-5-methoxy-
phenyl)urea (19). Mp 155±157 ꢁC; IR (Nujol) 3300,
1630 cm 1; 1H NMR (d in DMSO-d6) 3.68 (s, 3H, CH3),
6.38 (dd, 1H, J=3, 9 Hz, ArH-4), 6.75 (d, 1H, J=9 Hz,
ArH-3), 7.20±7.53 (m, 3H, ArH-40, -50 and -60), 7.75 (d,
1H, J=3 Hz, ArH-6), 8.01 (s, 1H, NH or OH), 8.22 (s,
1H, ArH-20), 9.45 (s, 1H, NH or OH), 9.67 (s, 1H, NH
or OH); EIMS m/z 326 (M+); Anal. Calcd for
1-(2-Hydroxy-5-methoxyphenyl)-3-(4-methoxyphenyl)urea
1
(24). Mp 150±152 ꢁC; IR (Nujol) 3300, 3200, 1620 cm
;
1H NMR (d in DMSO-d6) 3.66 (s, 3H, CH3), 3.71 (s,
3H, CH3), 6.26±6.40 (dd, 1H, J=3, 9 Hz, ArH-4), 6.72
(d, 1H, J=9 Hz, ArH-3), 6.83 (d, 2H, J=9 Hz, ArH-30
and -50), 7.34 (d, 2H, J=9 Hz, ArH-20 and -60), 7.75 (d,
1H, J=3 Hz, ArH-6), 8.05 (s, 1H, NH or OH), 9.12 (s,
1H, NH or OH), 9.36 (s, 1H, NH or OH); EIMS m/z
288 (M+); Anal. Calcd for C15H16N2O4: C, 62.49, H,
5.59, N, 9.72. Found: C, 62.48, H, 5.40, N, 9.74.
.
C15H13N2O3F3 H2O: C, 52.33, H, 4.39, N, 8.14. Found:
C, 52.38, H, 4.29, N, 8.07.
1-(3-Carboxyphenyl)-3-(2-hydroxy-5-methoxyphenyl)urea
1
(20). Mp 173±175 ꢁC; IR (Nujol) 3310, 1670, 1600 cm
;
1-(4-Ethoxycarbonylmethoxyphenyl)-3-(2-hydroxy-5-meth-
oxyphenyl)urea (25). Mp 143±144 ꢁC; IR (KBr) 3350,
1740, 1680, 1600 cm 1; 1H NMR (d in CDCl3+DMSO-
d6) 1.29 (t, 3H, J=7 Hz, CH3), 3.71 (s, 3H, CH3), 4.24
(q, 2H, J=7 Hz, CH2), 4.55 (s, 2H, CH2), 6.39±6.52 (dd,
1H, J=3, 9 Hz, ArH-4), 6.80 (d, 1H, J=9 Hz, ArH-3),
6.81 (d, 2H, J=9 Hz, ArH-30 and -50), 7.10 (d, 1H,
1H NMR (d in DMSO-d6) 3.66 (s, 3H, CH3), 6.39 (dd,
1H, J=3, 9 Hz, ArH-4), 6.76 (d, 1H, J=9 Hz, ArH-3),
7.24±7.32 (m, 1H, ArH-50), 7.56±7.62 (m, 2H, ArH-40
and -60), 7.76 (d, 1H, J=3 Hz, ArH-6), 8.13 (s, 1H,
ArH-20), 8.59 (s, 1H, NH or OH), 9.75 (s, 1H, NH or
OH); SIMS m/z 303 (M++1); Anal. Calcd for C15H14

864
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
J=3 Hz, ArH-6), 7.32 (d, 2H, J=9 Hz, ArH-20 and -60),
8.01 (s, 1H, NH or OH), 8.40 (s, 1H, NH or OH), 8.97
(br, 1H, NH or OH); EIMS m/z 360 (M+); Anal. Calcd
for C18H20N2O6: C, 59.99, H, 5.59, N, 7.76. Found: C,
59.61, H, 5.55, N, 7.58.
(m, 1H, PyH-5), 7.26 (d, 1H, J=3 Hz, ArH-6), 7.48 (d,
1H, J=8 Hz, PyH-3), 8.0±8.15 (m, 1H, PyH-4), 8.25±
8.35 (m, 1H, PyH-6), 9.93 (s, 1H, NH or OH), 11.25 (s,
1H, NH or OH); EIMS m/z 315 (M+); Anal. Calcd for
.
C17H21N3O3 HCl: C, 58.04, H, 6.30, N, 11.94. Found:
C, 57.91, H, 6.34, N, 11.70.
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(4-dimethyl-
aminophenyl)urea (26). Mp 196±199 ꢁC; IR (KBr) 2957,
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridyl)
1
2557, 1677, 1572 cm 1; H NMR (d in DMSO-d6) 1.36
urea (31). Mp 200±202 ꢁC; IR (Nujol) 3170, 1715 cm
;
1
(s, 9H, CH3), 3.10 (s, 6H, CH3), 3.68 (s, 3H, CH3), 6.48
(d, 1H, J=3 Hz, ArH-4), 7.19 (d, 1H, J=3 Hz, ArH-6),
7.55±7.65 (m, 4H, ArH-20, -30, -50 and -60), 8.65 (s, 1H,
1H NMR (d in DMSO-d6) 1.36 (s, 9H, CH3), 3.68 (s,
3H, CH3), 6.52 (d, 1H, J=3 Hz, ArH-4), 7.24 (d, 1H,
J=3 Hz, ArH-6), 7.93 (dd, 1H, J=5, 9 Hz, PyH-5), 8.36
(d, 1H, J=9 Hz, PyH-4), 8.50 (d, 1H, J=5 Hz, PyH-6),
8.81 (s, 1H, NH or OH), 9.13 (d, 1H, J=2 Hz, PyH-2),
10.72 (s, 1H, NH or OH); EIMS m/z 315 (M+); Anal.
NH or OH), 9.75 (s, 1H, NH or OH); EIMS m/z 357
+
.
(M ); Anal. Calcd for C20H27N3O3 HCl: C, 60.98, H,
7.16, N, 10.67. Found: C, 60.94, H, 7.15, N, 10.54.
.
Calcd for C17H21N3O3 HCl: C, 58.04, H, 6.30, N, 11.94.
Found: C, 58.13, H, 6.55, N, 11.85.
1-[4-(3-Dibutylaminopropyl)oxyphenyl]-3-(3-tert-butyl-2-
hydroxy-5-methoxyphenyl)urea (27). Mp 150±153 ꢁC; IR
1
(KBr) 2960, 1670, 1610 cm
;
1H NMR (d in CDCl3)
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(4-pyridyl)
urea (32). Mp 193±195 ꢁC; IR (KBr) 3520, 3480, 2952,
0.88 (t, 6H, J=7.2 Hz, CH3), 1.20±1.35 (m, 4H, CH2),
1.41 (s, 9H, CH3), 1.60±1.80 (m, 4H, CH2), 2.10±2.30
(m, 2H, CH2), 2.90±3.05 (m, 4H, CH2), 3.10±3.25 (m,
2H, CH2), 3.63 (t, 2H, CH2), 3.72 (s, 3H, CH3), 6.54 (d,
1H, J=3 Hz, ArH-4), 6.55 (d, 2H, J=9 Hz, ArH-30 and
-50), 6.70 (d, 1H, J=3 Hz, ArH-6), 7.36 (d, 2H, J=9 Hz,
ArH-20 and -60), 8.65 (s, 1H, NH or OH), 9.08 (s, 1H,
NH or OH); EIMS m/z 515 (M+); Anal. Calcd for
1
1723, 1610, 1587 cm 1; H NMR (d in DMSO-d6) 1.36
(s, 9H, CH3), 3.69 (s, 3H, CH3), 6.55 (d, 1H, J=3 Hz,
ArH-4), 7.23 (d, 1H, J=3 Hz, ArH-6), 7.95 (d, 2H,
J=7.2 Hz, PyH-2 and -6), 8.05 (br, 1H, NH or OH),
8.59 (d, 2H, J=7.2 Hz, PyH-3 and -5), 8.98 (s, 1H, NH
or OH), 11.59 (s, 1H, NH or OH); EIMS m/z 315 (M+);
.
.
Anal. Calcd for C17H21N3O3 HCl 1.5H2O: C, 53.90, H,
6.65, N, 11.09. Found: C, 53.88, H, 6.58, N, 10.73.
.
.
C29H45N3O4 HCl 0.25H2O: C, 64.42, H, 8.67, N, 7.77.
Found: C, 64.42, H, 8.44, N, 7.97.
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-cyclohexyl-
urea (33). Mp 147±148 ꢁC; IR (KBr) 3375, 2932,
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(2,6-diiso-
propylphenyl)urea (28). Mp 193±195 ꢁC; IR (KBr) 3323,
1
1572 cm 1; H NMR (d in CDCl3) 1.12±2.00 (m, 10H,
1
2965, 1639, 1556 cm 1; H NMR (d in DMSO-d6) 1.16
CH2), 1.41 (s, 9H, CH3), 3.50±3.70 (m, 1H, CH), 3.64 (s,
3H, CH3), 5.24 (d, 1H, J=7.8 Hz, NH), 6.06 (d, 1H,
J=3 Hz, ArH-4), 6.33 (s, 1H, NH or OH), 6.73 (d, 1H,
J=3 Hz, ArH-6), 8.70 (s, 1H, NH or OH); EIMS m/z
320 (M+); Anal. Calcd for C18H28N2O3: C, 67.47, H,
8.81, N, 8.74. Found: C, 67.42, H, 9.02, N, 9.00.
(d, 12H, J=7 Hz, CH3), 1.34 (s, 9H, CH3), 3.10±3.24
(m, 2H, CH), 3.65 (s, 3H, CH3), 6.46 (d, 1H, J=3 Hz,
ArH-4), 7.07±7.31 (m, 4H, ArH-6, -30, -40 and -50), 8.19
(s, 1H, NH or OH), 8.56 (s, 1H, NH or OH), 8.61 (s,
1H, NH or OH); EIMS m/z 398 (M+); Anal. Calcd for
C24H34N2O3: C, 72.33, H, 8.60, N, 7.03. Found: C,
72.33, H, 8.59, N, 6.92.
1-(2-Hydroxy-5-methoxyphenyl)-3-diphenylmethylamino-
ethylurea (34). Mp 198±201 ꢁC; IR (Nujol) 3350, 3290,
1
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(2,4-di¯uoro-
phenyl)urea (29). Mp 153±154 ꢁC; IR (KBr) 3334,
1670, 1650 cm
;
1H NMR (d in DMSO-d6) 2.80±3.00
(m, 2H, CH2), 3.30±3.50 (m, 2H, CH2), 3.62 (s, 3H, CH3),
5.40 (s, 1H, CH), 6.32 (dd, 1H, J=3, 9 Hz, ArH-4), 6.74
(d, 1H, J=9 Hz, ArH-3), 7.10±7.80 (m, 12H, ArH and
NH or OH), 7.66 (d, 1H, J=3 Hz, ArH-6), 8.06 (s, 1H,
1
1640 cm
;
1H NMR (d in CDCl3) 1.40 (s, 9H, CH3),
3.71 (s, 3H, CH3), 6.48 (d, 1H, J=3 Hz, ArH-4), 6.76±
6.88 (m, 2H, ArH-50 and -60), 6.80 (d, 1H, J=3 Hz, ArH-
6), 6.90 (s, 1H, NH or OH), 7.02 (s, 1H, NH or OH),
7.12 (s, 1H, NH or OH), 7.80±7.95 (m, 1H, ArH-30);
EIMS m/z 350 (M+); Anal. Calcd for C18H20 N2O3F2:
C, 61.71, H, 5.75, N, 8.00. Found: C, 61.80, H, 5.71, N,
7.84.
NH or OH), 9.43 (s, 1H, NH or OH); SIMS m/z 392
+
.
.
(M +1); Anal. Calcd for C23H25N3O3 HCl 0.25H2O:
C, 63.88, H, 6.18, N, 9.72. Found: C, 64.03, H, 6.09, N,
9.67.
1-(2-Hydroxy-5-methoxyphenyl)-3-[2-(4-phenylpiperadin-
1-yl)ethyl]urea (35). Mp 172±174 ꢁC; IR (Nujol) 3350,
1670, 1650, 1610 cm 1; H NMR (d in DMSO-d6) 3.10±
3.35 (m, 6H, CH2), 3.50±3.70 (m, 4H, CH2), 3.63 (s, 3H,
CH3), 3.81 (d, 2H, J=9 Hz, CH2), 6.34 (dd, 1H, J=3,
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(2-pyridyl)
urea (30). Mp 185±187 ꢁC; IR (KBr) 3096, 1696, 1652,
1540 cm 1; 1H NMR (d in DMSO-d6) 1.36 (s, 9H, CH3),
3.69 (s, 3H, CH3), 6.55 (d, 1H, J=3 Hz, ArH-4), 7.22
1

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
865
.
8.8 Hz, ArH-4), 6.74 (d, 1H, J=8.8 Hz, ArH-3), 6.86 (t,
1H, J=7 Hz, ArH-40), 6.99 (d, 2H, J=8 Hz, ArH-30 and
-50), 7.26 (m, 2H, ArH-20 and -60), 7.38 (br, 1H, NH or
OH), 7.64 (d, 1H, J=3 Hz, ArH-6), 8.12 (s, 1H, NH or
OH), 11.01 (s, 1H, NH or OH); EIMS m/z 370 (M+);
.
Anal. Calcd for C20H26N4O3 HCl: C, 59.03, H, 6.69, N,
13.77. Found: C, 58.78, H, 6.66, N, 13.61.
2.0HCl H2O: C, 58.80, H, 6.58, N, 10.16. Found: C,
59.08, H, 6.41, N, 10.27.
1-{2-[4-Bis(4-¯uorophenyl)methylpiperadin-1-yl]ethyl}-3-
(2-hydroxy-5-methoxyphenyl)urea (40). Mp 203±205 ꢁC;
IR (KBr) 3389, 3230, 2310, 1664 cm 1; H NMR (d in
DMSO-d6+D2O) 2.55±2.80 (br, 4H, CH2), 3.20±3.30
(m, 2H, CH2), 3.35±3.50 (m, 6H, CH2), 3.64 (s, 3H,
CH3), 4.75 (s, 1H, CH), 6.38 (dd, 1H, J=3, 9 Hz, ArH-
4), 6.73 (d, 1H, J=9 Hz, ArH-3), 7.19 (t, 4H, J=9 Hz,
ArH), 7.53 (dd, 4H, J=6, 9 Hz, ArH), 7.58 (d, 1H,
J=3 Hz, ArH-6); SIMS m/z 497 (M++1); Anal. Calcd
1
1-{2-[4-(3-Tri¯uoromethylphenyl)piperadin-1-yl]ethyl}-3-
(2-hydroxy-5-methoxyphenyl)urea (36). Mp 181±182 ꢁC;
1
IR (Nujol) 3300, 1660 cm 1; H NMR (d in DMSO-d6)
3.15±3.30 (m, 8H, CH2), 3.53±3.56 (m, 2H, CH2), 3.63
(s, 3H, CH3), 3.96±4.01 (m, 2H, CH2), 6.32 (dd, 1H,
J=3, 9 Hz, ArH-4), 6.71 (d, 1H, J=9 Hz, ArH-3), 7.16
(d, 1H, J=7.6 Hz, ArH-60), 7.28±7.32 (m, 2H, ArH-20
and -40), 7.48 (t, 1H, J=8 Hz, ArH-50), 7.65 (d, 1H,
J=3 Hz, ArH-6), 8.07 (s, 1H, NH or OH), 9.41 (s, 1H,
.
.
for C27H30N4O3F2 2.0HCl H2O: C, 55.20, H, 5.83, N,
9.54. Found: C, 55.31, H, 5.57, N, 9.49.
1-(2-Hydroxy-5-methoxyphenyl)-3-[2-(4-diphenylmethylene-
piperidin-1-yl)ethyl]urea (41). Mp 124±127 ꢁC; IR
(Nujol) 3380, 3300, 1680 cm 1; H NMR (d in DMSO-
1
NH or OH), 10.56 (br, 1H, NH or OH); EIMS m/z
+
.
438 (M ); Anal. Calcd for C21H25N4O3F3 HCl: C,
d6) 2.25±2.50 (m, 10H, CH2), 3.15±3.30 (m, 2H, CH2),
3.62 (s, 3H, CH3), 6.30 (dd, 1H, J=3, 9 Hz, ArH-4), 6.66
(d, 1H, J=9 Hz, ArH-3), 6.85±6.95 (m, 1H, NH), 7.05±
7.15 (m, 4H, ArH), 7.15±7.35 (m, 6H, ArH), 7.60 (d, 1H,
J=3 Hz, ArH-6), 8.02 (s, 1H, NH or OH), 9.32 (s, 1H,
NH or OH); EIMS m/z 457 (M+); Anal. Calcd for
C28H31N3O3: C, 73.49, H, 6.83, N, 9.18. Found: C,
73.09, H, 6.71, N, 8.99.
53.11, H, 5.52, N, 11.80. Found: C, 53.11, H, 5.48, N,
11.85.
1-{2-[4-(4-Chlorophenyl)piperadin-1-yl]ethyl}-3-(2-hyd-
roxy-5-methoxyphenyl)urea (37). Mp 183±186 ꢁC; IR
1
(Nujol) 3250, 1660, 1590 cm
;
1H NMR (d in D2O
+TFA+DMSO-d6) 3.40±3.50 (m, 4H, CH2), 3.60±3.75
(m, 8H, CH2), 3.76 (s, 3H, CH3), 6.65±6.71 (dd, 1H,
J=3, 9 Hz, ArH-4), 6.90 (d, 1H, J=9 Hz, ArH-3), 7.19
(d, 1H, J=3 Hz, ArH-6), 7.26 (d, 2H, J=9 Hz, ArH-30
and -50), 7.46 (d, 2H, J=9 Hz, ArH-20 and -60); EIMS
1-{2-[4-Bis(4-¯uorophenyl)methylenepiperidin-1-yl]ethyl}-
3-(2-hydroxy-5-methoxyphenyl)urea (42). Mp 128±131 ꢁC;
IR (Nujol) 3380, 3300, 1680, 1600, 1595 cm 1; 1H NMR
(d in DMSO-d6) 2.25±2.35 (m, 4H, CH2), 2.35±2.60 (m,
6H, CH2), 3.15±3.25 (m, 2H, CH2), 3.62 (s, 3H, CH3),
6.30 (dd, 1H, J=3, 9 Hz, ArH-4), 6.67 (d, 1H, J=9 Hz,
ArH-3), 6.85±6.95 (m, 1H, NH), 7.15±7.25 (m, 8H,
ArH), 7.60 (d, 1H, J=3 Hz, ArH-6), 8.02 (s, 1H, NH or
OH), 9.31 (s, 1H, NH or OH); SIMS m/z 494 (M++1);
Anal. Calcd for C28H29N3O3F2: C, 68.14, H, 5.92, N,
8.51. Found: C, 67.83, H, 5.96, N, 8.38.
+
.
m/z 404(M ); Anal. Calcd for C20H25N4O3 Cl HCl: C,
54.43, H, 5.94, N, 12.69. Found: C, 54.36, H, 5.94, N,
12.69.
1-(2-Hydroxy-5-methoxyphenyl)-3-{2-[4-(4-methoxyphe-
nyl)piperain-1-yl]ethyl}urea (38). Mp 183±185 ꢁC; IR
1
(Nujol) 3350, 3300, 3200, 1640 cm
;
1H NMR (d in
DMSO-d6) 3.10±3.45 (m, 6H, CH2), 3.50±3.80 (m, 6H,
CH2), 3.63 (s, 3H, CH3), 3.70 (s, 3H, CH3), 6.33 (dd,
1H, J=3, 9 Hz, ArH-4), 6.73 (d, 1H, J=9 Hz, ArH-3),
6.88 (d, 2H, J=9 Hz, ArH-30 and -50), 7.03 (d, 2H,
J=9 Hz, ArH-20 and -50), 7.33 (br, 1H, NH or OH), 7.64
(d, 1H, J=3 Hz, ArH-6), 8.09 (s, 1H, NH or OH), 10.90
(br, 1H, NH or OH); EIMS m/z 400 (M+); Anal. Calcd
1-(2-Hydroxy-5-methoxyphenyl)-3-[N-2-(4-methoxyphenyl)
ethyl-N-methyl]aminopropylurea (43). Mp 185±187 ꢁC;
IR (Nujol) 3240, 2620, 1670, 1600 cm 1; H NMR (d in
DMSO-d6) 1.80±1.95 (m, 2H, CH2), 2.79 (s, 3H, CH3),
2.92±3.18 (m, 8H, CH2), 3.62 (s, 3H, CH3), 3.72 (s, 3H,
CH3), 6.32 (dd, 1H, J=3, 9 Hz, ArH-4), 6.70 (d, 1H,
J=9 Hz, ArH-3), 6.88 (d, 2H, J=9 Hz, ArH-20 and -60),
7.12 (m, 1H, NH), 7.21 (d, 2H, J=9 Hz, ArH-30 and -
50), 7.63 (d, 1H, J=3 Hz, ArH-6), 8.00 (s, 1H, NH or
OH), 9.42 (s, 1H, NH or OH); SIMS m/z 388 (M++1);
1
.
for C21H28N4O4 2.0HCl: C, 53.28, H, 6.39, N, 11.83.
Found: C, 53.39, H, 6.29, N, 11.73.
1-(2-Hydroxy-5-methoxyphenyl)-3-[2-(4-diphenylmethyl-
piperadin-1-yl)ethyl]urea (39). Mp 200±202 ꢁC; IR (Nujol)
1
3390, 3260, 2400, 1665 cm
;
1H NMR (d in DMSO-
.
Anal. Calcd for C21H29N3O4 HCl: C, 59.50, H, 7.13, N,
9.91. Found: C, 59.47, H, 7.19, N, 9.90.
d6+D2O) 2.70±2.90 (br, 4H, CH2), 3.15±3.30 (m, 2H,
CH2), 3.35±3.50 (m, 6H, CH2), 3.64 (s, 3H, CH3), 4.80
(s, 1H, CH), 6.38 (dd, 1H, J=3, 9 Hz, ArH-4), 6.73 (d,
1H, J=9 Hz, ArH-3), 7.24±7.41 (m, 6H, ArH), 7.53±
7.56 (m, 4H, ArH), 7.58 (d, 1H, J=3 Hz, ArH-6);
1-(2-Hydroxy-5-methoxyphenyl)-3-[N-2-(3,4-dimethoxy-
phenyl)ethyl-N-methyl]aminopropylurea (44). Mp 143±
144 ꢁC; IR (KBr) 3260, 2950, 2630, 1670, 1610 cm 1; 1H
NMR (d in DMSO-d6) 1.85±1.95 (m, 2H, CH2), 2.79 (d,
+
.
EIMS m/z 460 (M ); Anal. Calcd for C27H32N4O3

866
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
3H, J=4 Hz, CH3), 2.93±3.23 (m, 8H, CH2), 3.62 (s, 3H,
CH3), 3.72 (s, 3H, CH3), 3.75 (s, 3H, CH3), 6.32 (dd,
1H, J=3, 9 Hz, ArH-4), 6.71 (d, 1H, J=9 Hz, ArH-3),
6.77±6.82 (dd, 1H, J=2, 8 Hz, ArH-60), 6.88 (d, 1H,
J=8 Hz, ArH-50), 6.91 (d, 1H, J=2 Hz, ArH-20), 7.16
(m, 1H, NH), 7.62 (d, 1H, J=3 Hz, ArH-6), 8.02 (s, 1H,
N4O3: C, 68.15, H, 8.24, N, 12.72. Found: C, 67.99,
H, 8.45, N, 12.57.
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-[2-(4-di-
phenylmethylpiperadin-1-yl)ethyl]urea (49). Mp 169±
175 ꢁC; IR (KBr) 3312, 1655 cm
1
;
1H NMR (d in
NH or OH), 9.45 (s, 1H, NH or OH); SIMS m/z 418
+
DMSO-d6+D2O) 1.34 (s, 9H, CH3), 2.60±2.80 (br, 4H,
CH2), 3.20±3.35 (m, 2H, CH2), 3.35±3.55 (m, 6H, CH2),
3.65 (s, 3H, CH3), 4.68 (s, 1H, CH), 6.52 (d, 1H,
J=3 Hz, ArH-4), 6.78 (d, 1H, J=3 Hz, ArH-6), 7.23±
7.53 (m, 10H, ArH); EIMS m/z 516 (M+); Anal. Calcd
.
(M +1); Anal. Calcd for C22H31N3O5 HCl: C, 58.21,
H, 7.11, N, 9.26. Found: C, 57.91, H, 7.16, N, 9.13.
1-(2-Hydroxy-5-methoxyphenyl)-3-[3-(4-phenylpiperadin-
1-yl)propyl]urea (45). Mp 189±191 ꢁC; IR (Nujol) 3350,
.
.
for C31H40N4O3 2.0HCl H2O: C, 61.28, H, 7.30, N,
9.22. Found: C, 61.36, H, 7.44, N, 8.95.
1
3150, 1650 cm
;
1H NMR (d in DMSO-d6) 1.90±2.10
(m, 2H, CH2), 3.10±3.30 (m, 6H, CH2), 3.40±3.70 (m,
4H, CH2), 3.63 (s, 3H, CH3), 3.70±3.90 (m, 2H, CH3),
6.32 (dd, 1H, J=3, 9 Hz, ArH-4), 6.71 (d, 1H, J=9 Hz,
ArH-3), 6.86 (t, 1H, J=7 Hz, ArH-40), 7.00 (d, 2H,
J=8 Hz, ArH-30 and -50), 7.14 (br, 1H, NH), 7.20±7.30
(m, 2H, ArH-20 and -60), 7.63 (d, 1H, J=3 Hz, ArH-6),
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-[3-(4-di-
phenylmethylpiperadin-1-yl)propyl]urea (50). Mp 173±
175 ꢁC; IR (Nujol) 3270, 1655, 1600 cm 1; H NMR (d
1
in CDCl3) 1.36 (s, 9H, CH3), 1.9±2.1 (m, 2H, CH2), 2.5±
3.5 (m, 12H, CH2), 3.68 (s, 3H, CH3), 4.24 (s, 1H, CH),
6.55 (d, 1H, J=3 Hz, ArH-4), 6.67 (d, 1H, J=3 Hz,
ArH-6), 7.1±7.35 (m, 11H, ArH and NH or OH), 8.50
8.00 (s, 1H, NH or OH), 10.81 (br, 1H, NH or OH);
+
.
EIMS m/z 384 (M ); Anal. Calcd for C21H28N4O3 HCl:
C, 59.92, H, 6.94, N, 13.31. Found: C, 59.73, H, 7.05, N,
13.32.
(s, 1H, NH or OH), 8.90 (s, 1H, NH or OH); SIMS
+
.
m/z 531 (M +1); Anal. Calcd for C32H42N4O3 HCl:
C, 67.77, H, 7.64, N, 9.88. Found: C, 67.60, H, 7.62,
N, 9.92.
1-(2-Hydroxy-5-methoxyphenyl)-3-[3-(4-diphenylmethyl-
piperadin-1-yl)propyl]urea (46). Mp 181±183 ꢁC; IR
1
(Nujol) 3380, 3280, 1660 cm 1; H NMR (d in CDCl3)
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(2-chloro-
ethyl)urea (51). Mp 126±128 ꢁC; IR (KBr) 3353, 2961,
1.8±1.95 (m, 2H, CH2), 2.30±2.55 (m, 2H, CH2), 2.80±
2.95 (m, 2H, CH2), 3.05±3.20 (m, 6H, CH2), 3.40±3.55
(m, 2H, CH2), 3.62 (s, 3H, CH3), 4.45 (s, 1H, CH), 6.31
(dd, 1H, J=3, 9 Hz, ArH-4), 6.70 (d, 1H, J=9 Hz, ArH-
3), 7.10±7.15 (m, 1H, NH), 7.20±7.35 (m, 6H, ArH),
7.42±7.46 (m, 4H, ArH), 7.61 (d, 1H, J=3 Hz, ArH-6),
7.99 (s, 1H, NH or OH), 9.42 (s, 1H, NH or OH); SIMS
m/z 475 (M++1); Anal. Calcd for C28H34N4
1
1628 cm
;
1H NMR (d in CDCl3) 1.40 (s, 9H, CH3),
3.5±3.7 (m, 4H, CH2), 3.71 (s, 3H, CH3), 5.51 (br, 1H,
NH or OH), 6.41 (d, 1H, J=3 Hz, ArH-4), 6.68 (s, 1H,
NH or OH), 6.78 (d, 1H, J=3 Hz, ArH-6); EIMS m/z
300 (M+); Anal. Calcd for C14H21N2O3Cl: C, 55.91, H,
7.04, N, 9.31. Found: C, 56.07, H, 7.28, N, 9.11.
.
.
O3 2.0HCl H2O: C, 59.47, H, 6.77, N, 9.91. Found: C,
59.55, H, 6.70, N, 10.08.
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(2,3-di-
hydroxypropyl)urea (52). Mp 118±123 ꢁC; IR (Nujol)
3350, 3300, 2850, 1630, 1610 cm
1
;
1H NMR (d in
1-(2-Hydroxy-3,5-dimethoxyphenyl)-3-(2-diphenylmethyl-
aminoethyl)urea (47). Mp 183±185 ꢁC; IR (KBr) 3300,
1670 cm
3.10±3.20 (m, 2H, CH2), 3.50±3.60 (m, 2H, CH2), 3.75
(s, 3H, CH3), 3.84 (s, 3H, CH3), 5.57 (s, 1H, CH), 6.42
(d, 1H, J=2.5 Hz, ArH-4), 6.96 (d, 1H, J=2.5 Hz, ArH-
6), 7.44±7.56 (m, 10H, ArH); SIMS m/z 422 (M++1);
.
Anal. Calcd for C24H27N3O4 HCl: C, 62.95, H, 6.16, N,
9.18. Found: C, 62.59, H, 6.17, N, 8.92.
CDCl3+DMSO-d6) 1.40 (s, 9H, CH3), 2.30 (br, 2H,
CH2), 3.3±3.5 (m, 2H, CH2), 3.55±3.7 (m, 2H, CH2),
3.72 (s, 3H, CH3), 3.99 (m, 1H, CH), 6.2±6.4 (m, 1H,
NH), 6.41 (d, 1H, J=3 Hz, ArH-4), 6.68 (d, 1H,
J=3 Hz, ArH-6), 7.93 (s, 1H, NH or OH), 8.81 (s, 1H,
NH or OH); SIMS m/z 313 (M++1); Anal. Calcd for
C15H24N2O5: C, 57.68, H, 7.74, N, 8.97. Found: C,
57.62, H, 7.76, N, 8.80.
1
;
1H NMR (d in D2O+TFA+DMSO-d6)
4-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-1-phenyl-
semicarbazide (53). Mp 160±162 ꢁC; IR (Nujol) 3370,
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-[2-(4-benz-
ylpiperadin-1-yl)ethyl]urea (48). Mp 134±135 ꢁC; IR
1
3340, 1660, 1605 cm 1; H NMR (d in CDCl3) 1.41 (s,
1
(Nujol) 3350, 3300, 1610 cm
;
1H NMR (d in
9H, CH3), 3.69 (s, 3H, CH3), 6.34 (d, 1H, J=3 Hz,
ArH-4), 6.59 (s, 1H, NH), 6.75 (d, 1H, J=3 Hz, ArH-
6), 3.89 (d, 2H, J=7 Hz, ArH-30 and -50), 7.01 (t, 1H,
J=7 Hz, ArH-40), 7.26 (s, 1H, NH or OH), 7.26±7.34
(m, 2H, ArH-20 and -60), 7.83 (s, 1H, NH or OH);
EIMS m/z 329 (M+); Anal. Calcd for C18H23N3O3: C,
CDCl3) 1.42 (s, 9H, CH3), 2.4±2.7 (m, 10H, CH2),
3.2±3.4 (m, 2H, CH2), 3.48 (s, 2H, CH2), 3.74 (s, 3H,
CH3), 5.45 (m, 1H, NH), 6.42 (d, 1H, J=3 Hz, ArH-
4), 6.77 (d, 1H, J=3 Hz, ArH-6), 7.29 (m, 7H, ArH);
SIMS m/z 441 (M++1); Anal. Calcd for C25H36

K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
867
65.63, H, 7.04, N, 12.76. Found: C, 65.51, H, 7.38, N,
12.49.
45 min at the same temperature, 10% acetic acid aq
(100 mL) was added and extracted with Et2O. The
organic layer was washed with brine, dried (MgSO4),
®ltered and concentrated in vacuo. The residue was
chromatographed on silica gel using hexane/AcOEt
(10:1) as an eluent to give 68 (5.1 g, 40%): mp 62±64 ꢁC;
1H NMR (d in CDCl3) 1.37 (s, 9H, CH3), 3.65 (s, 3H,
CH3), 3.84 (s, 3H, CH3), 4.91 (s, 2H, CH2), 6.03 (s, 1H,
ArH), 10.34 (s, 1H, CHO); EIMS m/z 267 (M+). A
mixture of 68 (5.0 g, 18.7 mmol) and 3-(amino-
methyl)pyridine (3.0 g, 28.1 mmol) was stirred at 95 ꢁC
for 3 h. After the mixture had cooled to room tempera-
ture, acetonitrile (40 mL) and molecular sieves 3A were
added to remove water in the mixture. To the mixture
was added sodium cyanoborohydride (2.35 g,
37.4 mmol) at 0 ꢁC. The mixture was neutralized with
15% HCl/dioxane (pH 6.5±7.0). After stirring for 4 h,
molecular sieves were removed by ®ltration and the ®l-
trate was concentrated in vacuo. The residue was diluted
with AcOEt and washed with brine, dried (MgSO4), ®l-
tered and concentrated in vacuo. The residue was chro-
matographed on silica gel using CHCl3/EtOH (20:1) as
an eluent to give 69 (2.2 g, 33%): mp 60±65 ꢁC; 1H
NMR (d in CDCl3) 1.37 (s, 9H, CH3), 3.65 (s, 3H, CH3),
3.76 (s, 3H, CH3), 3.81 (s, 2H, CH2), 3.87 (s, 2H, CH2),
4.95 (s, 2H, CH2), 6.22 (s, 1H, ArH), 7.21±7.25 (m, 1H,
PyH-5), 7.65±7.70 (m, 1H, PyH-4), 8.49±8.56 (m, 2H,
PyH-2 and -6); EIMS m/z 359 (M+). To the solution of
69 (2.12 g, 5.9 mmol) and triethylamine (3.3 mL) in
CH2Cl2 (200 mL) was added a solution of triphosgene
(610 mg, 2.1 mmol) in CH2Cl2 (10 mL) dropwise at
78 ꢁC and the reaction mixture was warmed to room
temperature for 30 min. The reaction mixture was
washed with brine, dried (MgSO4), ®ltered and con-
centrated in vacuo, and the residue was chromato-
graphed on silica using CHCl3/EtOH (20:1). The crude
crystals were recrystallized from Et2O to yield 735 mg
(32%) of 70. To a solution of 70 (560 mg, 1.45 mmol) in
MeOH (15 mL) was added concd HCl (1.0 mL) and the
mixture was stirred at 35 ꢁC for 4 h. The resulting mix-
ture was concentrated in vacuo and the crude crystals
were recrystallized from EtOH to give 58 (410 mg,
1-(3-tert-Butyl-2-hydroxy-5-methoxyphenyl)-3-(3-pyridyl-
ethyl)urea (55). Mp 172±175 ꢁC; IR (KBr) 3350,
1636 cm 1; 1H NMR (d in DMSO-d6) 1.32 (s, 9H, CH3),
2.92±3.08 (m, 2H, CH2), 3.40±3.55 (m, 2H, CH2), 3.63
(s, 3H, CH3), 6.45 (d, 1H, J=3 Hz, ArH-4), 6.73 (d, 1H,
J=3 Hz, ArH-6), 7.00±7.15 (m, 1H, NH), 8.01 (dd, 1H,
J=5, 8 Hz, PyH-5), 8.50 (d, 1H, J=8 Hz, PyH-4), 8.69
(s, 1H, NH or OH), 8.80 (d, 1H, J=5 Hz, PyH-6), 8.88
(s, 1H, PyH-2); EIMS m/z 343 (M+); Anal. Calcd for
.
C19H25N3O3 HCl: C, 60.07, H, 6.90, N, 11.06. Found:
C, 59.86, H, 6.86, N, 10.97.
Ethyl 7-[3-(3-tert-butyl-2-hydroxy-5-methoxyphenyl)
ureido]-7-phenylheptanoate (56). Mp 93±95 ꢁC; IR
1
(KBr) 3320, 2940, 1642 cm
;
1H NMR (d in CDCl3)
1.24 (t, 3H, J=7 Hz, CH3), 1.2±1.9 (m, 8H, CH2), 1.39
(s, 9H, CH3), 2.27 (t, 2H, J=7 Hz, CH2), 3.67 (s, 3H,
CH3), 4.11 (q, 2H, J=7 Hz, CH2), 4.6±4.8 (m, 1H,
CH), 5.40 (d, 1H, J=7 Hz, NH), 6.17 (s, 1H, NH or
OH), 6.47 (s, 1H, ArH-4), 6.73 (d, 1H, J=3 Hz, ArH-
6), 7.2±7.4 (m, 5H, ArH), 8.24 (s, 1H, NH or OH);
SIMS m/z 471 (M++1); Anal. Calcd for C27H38N2O5:
C, 68.91, H, 8.14, N, 5.95. Found: C, 68.95, H, 8.42,
N, 5.74.
1-(2-Hydroxy-4,5-methylenedioxyphenyl)-3-(3-pyridyl-
methyl)urea (57). Mp 167±170 ꢁC; IR (KBr) 3050,
1
1663 cm
;
1H NMR (d in DMSO-d6) 4.45 (d, 2H,
J=5 Hz, CH2), 5.84 (s, 2H, CH2), 6.50 (s, 1H, ArH-3),
7.38±7.55 (m, 1H, NH), 7.46 (s, 1H, ArH-6), 7.97 (dd,
1H, J=5, 8 Hz, PyH-5), 8.03 (s, 1H, NH or OH), 8.39
(d, 1H, J=8 Hz, PyH-4), 8.73±8.82 (m, 2H, PyH-2 and -
6), 9.58 (br, 1H, NH or OH); SIMS m/z 288 (M++1);
.
Anal. Calcd for C14H13N3O4 HCl: C, 51.94, H, 4.36, N,
12.98. Found: C, 51.99, H, 4.31, N, 12.87.
7-tert-Butyl-8-hydroxy-5-methoxy-2-oxo-3-(3-pyridyl-
methyl)-1,2,3,4-tetrahydroquinazoline (58). To a solution
of 60 (X2=OMe, X3=H, X4=t-Bu, 28.4 g, 0.10 mol) in
carbon disul®de (CS2, 500 mL) was added dropwise
bromine (6.0 mL, 0.10 mol) at room temperature. After
stirring at the same temperature for 2 h, the reaction
mixture was diluted with Et2O, washed with water and
brine, dried (MgSO4), ®ltered and concentrated in vacuo
to a€ord 65 (29.5 g, 81%). In the same manner as the
alkylation by MOMCl and the hydrogenation as
described above, 67 was obtained from 65. To a solution
of 67 (15.3 g, 48 mmol) in Et2O (300 mL) was added n-
butyllithium (2.3 M in hexane, 54.5 mL, 125 mmol)
dropwise at 78 ꢁC and the mixture was stirred for 1 h
at the same temperature. To the resulting mixture was
added a solution of DMF (9.6 mL, 124 mmol) at
78 ꢁC. After the reaction mixture was stirred for
75%): mp 228±231 ꢁC; IR (Nujol) 1665, 1610 cm 1; H
1
NMR (d in DMSO-d6) 1.34 (s, 9H, CH3), 3.69 (s, 3H,
CH3), 4.36 (s, 2H, CH2), 4.75 (s, 2H, CH2), 6.39 (s,
1H, ArH), 7.95±8.10 (dd, 1H, J=5, 8 Hz, PyH-5), 8.44
(s, 1H, PyH-2), 8.50 (d, 1H, J=8 Hz, PyH-4), 8.85 (d,
1H, J=5 Hz, PyH-6), 8.89 (s, 1H, NH or OH); EIMS
+
.
m/z 341 (M ); Anal. Calcd for C19H23N3O3 HCl: C,
60.39, H, 6.40, N, 11.12. Found: C, 60.21, H, 6.37, N,
10.98.
Acknowledgements
The authors sincerely thank Professor Corwin Hansch
for helpful discussions. They are grateful to Drs Kazuo

868
K. Nakao et al./Bioorg. Med. Chem. 6 (1998) 849±868
Matsumoto, Keisuke Kawashima, Kimiaki Hayashi,
Yasuhiko Ozaki, Masahiko Seki and Osamu Sakurai
for useful suggestions and comments. They wish to
thank Masakatsu Sugahara and Kuniharu Suzumura
for their skillful experiments. They are indebted to
Kimio Okamura and Hajime Hiramatsu for the X-ray
crystallographic analysis.
Example 2.
Álog P ˆ log Pꢀ‰derivative 48Š† log Pꢀ‰N-
substituted phenylureaŠ†
a
b
ˆ log Pꢀ‰acetanilide 12Š†
log Pꢀ‰acetanilideŠ†
ˆ 1:59 1:16 ˆ 0:43
d
log Pꢀ‰derivative 48Š† ˆ CLOGPꢀ‰N-substituted phenylureaŠ† ‡Á log P
ˆ 3:89 ‡ 0:43 ˆ 4:32
aEstimated by our empirical method. bMeasured value (Fujita,
T.; Iwasa, J.; Hansch, C. J. Am. Chem. Soc. 1964, 86, 5175±
5180). cCited from reference 13. dCalculated by CLOGP
method.
References and Notes
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5778±5782.
16. Asao, M.; Nakao, K.; Shimizu, R.; Nishioka, T.; Fujita, T.
submitted to Japan Chemistry Program Exchange (http://
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6. Hansch, C.; Gao, H. Chem. Rev. 1997, 97, 2995±3059.
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Example 1.
26. Das, P. K.; Encinas, M. V.; Steenken, S.; Scaiano, J. C. J.
Am. Chem. Soc. 1981, 103, 4162±4166.
Álog P ˆ log Pꢀ‰derivative 14Š† log Pꢀ‰diphenylureaŠ†
a
b
ˆ log Pꢀ‰acetanilide 14Š† log Pꢀ‰acetanilideŠ†
27. Yasuhara, M.; Saito, K.; Kubota, H.; Ohmizu, H.; Suzuki,
T. Biol. Pharm. Bull. 1997, 20, 1056±1060.
ˆ ꢀ 0:09† 1:16 ˆ 1:25
c
log Pꢀ‰derivative 14Š† ˆ log Pꢀ‰diphenylureaŠ† ‡ Álog P
28. Ohkawa, H.; Ohishi, N.; Yagi, K. Anal. Biochem. 1979, 95,
351±358.
ˆ 3:00 ‡ ꢀ 1:25† ˆ 1:75