Highly selective aldose reductase inhibitors. 3. Structural diversity of 3-(arylmethyl)-2,4,5-trioxoimidazolidine-1-acetic acids

Article abstract of DOI:10.1021/jm960594+

Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by aldose reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of diabetic complications. Our attention is focused on finding compounds which inhibit

Full text of DOI:10.1021/jm960594+

684
J . Med. Chem. 1997, 40, 684-694
High ly Selective Ald ose Red u cta se In h ibitor s. 3. Str u ctu r a l Diver sity of
3-(Ar ylm eth yl)-2,4,5-tr ioxoim id a zolid in e-1-a cetic Acid s
Takayuki Kotani, Yasuhiro Nagaki, Akira Ishii, Yukari Konishi, Hisashi Yago, Seishi Suehiro,
Nobuhisa Okukado, and Kaoru Okamoto*
Institute of Bio-Active Science, Nippon Zoki Pharmaceutical Company Ltd., Kinashi, Yashiro-cho, Kato-gun,
Hyogo 673-14, J apan
Received August 19, 1996X
Accumulation of intracellular sorbitol, the reduced product of glucose, catalyzed by aldose
reductase (AR) (EC 1.1.1.21), is thought to be the cause of the development of diabetic
complications. Our attention is focused on finding compounds which inhibit AR without
significantly inhibiting aldehyde reductase (ALR) (EC 1.1.1.2). The uracil or 2,4-dioxoimida-
zolidine skeleton having the benzothiazolyl or 4-chloro-3-nitrophenyl group as an aryl part
indicated not only extremely high AR inhibitory activity but also AR selectivity. The ratio of
IC50(ALR)/IC50(AR) of 3-[(5-chlorobenzothiazol-2-yl)methyl]-1,2,3,4-tetrahydro-2,4-dioxopyrim-
idine-1-acetic acid (47d ) was more than 17 500. The uracil skeleton with the benzothiazolyl
moiety seemed to be the best combination for selective AR inhibition.
Ch a r t 1
In tr od u ction
The therapeutic potential as well as the discovery and
development of aldose reductase inhibitors (ARIs) for
the prevention of the secondary complications of diabe-
tes have been extensively reported.1-5 Although a
number of ARIs have so far been synthesized and
evaluated for their activities (Chart 1),2,6-9 only a few
aldose reductase (AR) (EC 1.1.1.21) selective inhibitors
have been found.10,11 To avoid the adverse effects of ARI
therapy, the AR selectivity is one of the most important
aspects as described by many reports.12-19 Although it
is not clear how aldehyde reductase (ALR) (EC 1.1.1.2)
works in diabetic patients, ALR would be one of the
important enzymes for reduction of many aldehydes,
counteraction and excretion of drugs,17 reduction of
3-deoxyglucosone (3-DG), which is an intermediate for
advanced glycation end products (AGEs),20 and metabo-
lism of methylglyoxal (MG).21
Our recent efforts22,23 have led to the discovery of 1a
(Chart 2), an orally active and highly potent ARI, which
is of interest because of its high AR inhibitory activity
and selectivity. It is presently being evaluated in a
clinical study. A new series of ARIs based on the 2,4,5-
trioxoimidazolidine-1-acetic acid framework and also the
structure-activity relationships (SAR) of 1 were previ-
ously reported.23 Introduction of the benzothiazolyl or
4-chloro-3-nitrophenyl group as an aryl portion was
extremely effective for high AR selectivity. Parallel to
the optimization of the aryl portion, the modification of
the 2,4,5-trioxoimidazolidine framework to the uracil or
2,4-dioxoimidazolidine core unit was investigated. Ka-
dor et al.24,25 have shown that the structural require-
ments for AR inhibitory activity consist of a nearly
planar structure with two hydrophobic (aromatic) re-
gions and a common region which is susceptible to
charge-transfer interactions. Therefore, it was neces-
sary to reinvestigate the core unit since the 2,4,5-
trioxoimidazolidine framework might play an important
role for AR selective inhibitory activity. AR selectivity
may be deeply influenced by the relative spatial position
of the nucleophilic charge-transfer and carboxylic acid
Ch a r t 2
moieties. In this paper, the conversion of the 2,4,5-
trioxoimidazolidine framework to the uracil or 2,4-
dioxoimidazolidine core unit and the results of the AR
and ALR inhibitory activities in various combinations
of the aryl moiety and the core unit are described.
Ch em istr y
The 2-methylidene derivative 9 was synthesized in
the following procedure. Treatment of 3-nitrobenzyl-
X Abstract published in Advance ACS Abstracts, February 1, 1997.
S0022-2623(96)00594-8 CCC: $14.00 © 1997 American Chemical Society

Highly Selective AR Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 685
Sch em e 1a
a
(a) Ethyl oxalyl chloride, Et3N, CH2Cl2, 0 °C; (b) 1 N NaOH, CH2Cl2; (c) Gly-OCH2CH2TMS (6), WSC‚HCl, CH2Cl2; (d) Ac2O, AcONa,
reflux; (e) nBu4NF, DMF.
Sch em e 2a
Sch em e 3a
a
(a) NaBH3CN, MeOH; (b) 10, Et2O; (c) HCl, AcOH, reflux.
Sch em e 4a
a
(a) OCNCH2COOEt (10), NaOH, H2O, EtOH, 0 °C; (b) Lawes-
son’s reagent, dioxane, reflux; (c) oxalyl chloride, CH2Cl2, rt; (d)
HCl, AcOH, reflux.
a
KNCO, HCl, H2O, reflux.
amine hydrochloride (3) with ethyl oxalyl chloride in the
presence of Et3N in CH2Cl2 gave the oxamate 4. The
oxamate 4 obtained was hydrolyzed and condensed with
glycine 2-(trimethylsilyl)ethyl ester (6) in the presence
of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hy-
drochloride (WSC‚HCl) to give the oxamide 7 as white
crystals. Introduction of the methylidene moiety26 was
achieved by the treatment of the oxamide 7 with acetic
anhydride and sodium acetate at refluxing temperature.
Deprotection of the ester 8 with nBu4NF gave the
desired carboxylic acid 9 as shown in Scheme 1.
The 2-thioxo derivative 14 was synthesized as shown
in Scheme 2. Condensation of 3 with ethyl isocyana-
toacetate (10) in an alkaline solution with vigorous
stirring gave the urea 11. The urea 11 was converted
to the thiourea 12 by using Lawesson’s reagent27 in
dioxane under reflux. Addition of oxalyl chloride to the
solution of the thiourea 12 in CH2Cl2 afforded the 4,5-
dioxo-2-thioxoimidazolidine-1-acetate derivative 13 which
was deprotected under acidic conditions to give the
carboxylic acid 14.
(15) with ethyl glycinate (16) in the presence of NaBH3-
CN in MeOH. The ester 17 was condensed with 10 to
give the trialkylated urea 18 whose ester groups were
hydrolyzed with AcOH and HCl to give the desired
carboxylic acid 19 (Scheme 3).
Ethyl 2,4-dioxoimidazolidine-1-acetate (21), the com-
mon intermediate for the preparation of 23a -d , was
obtained by refluxing a mixture of diethyl iminodiac-
etate (20) and KNCO under acidic conditions as shown
in Scheme 4. The hydantoin 21 was alkylated with the
benzyl bromide 22 in the presence of NaH, the alcohol
24 by the Mitsunobu reaction,28 or 2-(chloromethyl)-
benzothiazoles 25a ,b in the presence of NaBr and NaH
to give 23a -d . Acidic deprotection (AcOH and HCl)
afforded the carboxylic acids 26a -d as shown in Scheme
5.
The 5-methylidene derivative 30 was prepared in the
following procedure (Scheme 6). N-(3-Nitrobenzyl)-
serine methyl ester (28) was prepared by reductive
alkylation of 15 with serine methyl ester (27). Treat-
ment of the ester 28 with 10 gave the urea 29. Base-
catalyzed cyclization of 29 gave the carboxylic acid 30
in a quite low yield.
The hydantoin derivatives 19 and 26a -d were pre-
pared in moderate to good yields as shown in Schemes
3-5. N-(3-Nitrobenzyl)glycine ethyl ester (17) was
prepared by reductive alkylation of 3-nitrobenzaldehyde
The hydroxyhydantoin derivatives 36 and 40 were
synthesized in the procedures as shown in Schemes 7

686 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Kotani et al.
Sch em e 5a
a
(a) NaH, DMF, -10 °C-rt; (b) DEAD, PPh3, THF, 0 °C-rt; (c) NaBr, DMF, then NaH, DMF, -10 °C-rt; (d) HCl, AcOH, reflux.
Sch em e 6a
Sch em e 7a
a
(a) NaBH3CN, MeOH, 0 °C; (b) 10, Et2O, rt; (c) KOH, H2O,
EtOH, 0 °C-rt.
and 8, respectively. Condensation of (3-nitrobenzyl)-
urea (31) with 32 in 80% AcOH gave the 5-hydroxy-
2,4-dioxoimidazolidine derivative 33. Introduction of
the acetic acid unit to 33 was performed by condensation
with tert-butyl bromoacetate (34) in the presence of
KHCO3. Acid-catalyzed hydrolysis of the ester 35 with
4 N HCl/dioxane gave the carboxylic acid 36. Ethyl
5-hydroxy-2,4-dioxoimidazolidine-1-acetate (38), which
was prepared from ethyl ureidoacetate (37) and 32, was
alkylated with 3-nitrobenzyl bromide (22) to give 39.
Hydrolysis of the ester group with AcOH and HCl gave
the carboxylic acid 40.
a
(a) 80% AcOH, 80 °C; (b) BrCH2COOtBu (34), KHCO3, acetone;
(c) 4 N HCl/dioxane.
urea 41. Treatment of the urea 41 with malonyl
chloride in CH2Cl2 gave the barbituric acid derivative
42, which was saponified to give the acid 43 as shown
in Scheme 9.
Syntheses of the uracil compounds 47a -d and 51
were carried out as shown in Schemes 10 and 11. The
second alkylation of 4429 was performed by treatment
with 22 and 4-chloro-3-nitrobenzyl mesylate (46) in
DMF to give the dialkylated uracils 45a ,b, respectively.
Conversion of the parabanic acid skeleton to the
6-membered cyclic systems was attempted (Schemes
9-11). Compound 3 was treated with 10 to give the

Highly Selective AR Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 687
Sch em e 8a
enol ether. Thus, 48 was silylated with TMSCl and
hexamethyldisilazane (HMDS) at refluxing temperature
and alkylated with 22 in the presence of nBu4NI to give
49 as shown in Scheme 11. The uracil obtained was
alkylated again with ethyl bromoacetate and hydrolyzed
to give the carboxylic acid 51.
Resu lts a n d Discu ssion
Inhibitory activities of the target compounds 9, 14,
19, 26a -d , 30, 36, 40, 43, 47a -d , and 51 against rat
lens AR30 and rat kidney ALR31 were evaluated in a
spectrometric assay with DL-glyceraldehyde as the
substrate and NADPH as the cofactor. In vitro AR
inhibitory activities are expressed as the percentage of
inhibitions of the test compounds at 5.0 × 10-7, 1.0 ×
10-7, 5.0 × 10-8, 2.0 × 10-8, 1.0 × 10-8, and 5.0 × 10-9
M concentrations. ALR inhibitory activity was also
measured for the compounds which showed strong AR
inhibitory activity.
a
(a) 32, 80% AcOH, 80 °C; (b) 22, KHCO3, acetone; (c) HCl,
AcOH, reflux.
The (benzothiazol-2-yl)methyl moiety was introduced
into the uracil 44 by condensation with the appropriate
2-(chloromethyl)benzothiazole 25a ,b in the presence of
NaH or K2CO3 as shown in Scheme 10. Hydrolysis of
the esters 45a -d gave the desired carboxylic acids 47a -
d .
The parabanic acid 1a , 4,5-dioxo-2-thioxoimidazoli-
dine 14, 4-methylidene-2,5-dioxoimidazolidine 30, and
uracil 47a compounds showed strong AR inhibitory
activities with IC50 values of less than 1 × 10-7
M
For the preparation of the other uracil-type compound
51, uracil (48) was first alkylated with 22 via the TMS
(Tables 1 and 2). Among them, 1a and 47a showed
extremely weak inhibition for ALR. In addition, though
Sch em e 9a
a
(a) 10, NaOH, EtOH, H2O, 0 °C; (b) malonyl chloride, CH2Cl2, ambient temperature; (c) concentrated HCl, AcOH, reflux.
Sch em e 10a
a
(a) NaH, DMF, -10 °C-rt; (b) K2CO3, NaBr, DMF; (c) NaBr, DMF, then NaH, DMF, -10 °C-rt; (d) HCl, AcOH, reflux.

688 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Ta ble 1. Biological Data for 3-Nitrobenzyl-Substituted ARIs
Kotani et al.
Ta ble 3. AR and ALR Inhibitory Activities of 1, 2, 26a -d ,
and 47a -d
IC50 (M)
IC50(ALR)/
IC50(AR)
IC50 (M)
compd
1a
9
14
19
26a
30
36
ARa,b
ALRc,d
IC50(ALR)/
IC50(AR)
compd
ARa,b
ALRc,d
6.2 × 10-8
>1 × 10-4 (37.3%)
>1 × 10-4 (12.4%)
2.8 × 10-5
>1613
(17.7%)
1a
1b
2a
6.2 × 10-8
1.6 × 10-8
1.2 × 10-8
1.5 × 10-8
>1 × 10-4 (37.3%)
>1 × 10-4 (39.5%)
7.2 × 10-5
>1613
>6250
6000
2.5 × 10-8
1120
1813
71
(4.6%)
>1 × 10-4 (0.0%)
>1 × 10-4 (3.8%)
5.8 × 10-5
(38.2%)
2b
5.8 × 10-5
3867
3.2 × 10-8
26a
26b
26c
26d
47a
47b
47c
47d
(38.2%)
>1 × 10-4 (3.8%)
>1 × 10-4 (1.6%)
>1 × 10-4 (37.0%)
(5.0%)
>1 × 10-4 (19.0%)
>1 × 10-4 (11.0%)
1.5 × 10-6
2.4 × 10-8
>4167
>1613
40
(44.0%)
6.2 × 10-8
epalrestat
2.1 × 10-8
(47.5%)
3.4 × 10-8
2.5 × 10-8
1.1 × 10-8
5.7 × 10-9
>1 × 10-4 (17.4%)
>1 × 10-4 (26.5%)
>1 × 10-4 (39.3%)
>1 × 10-4 (32.0%)
>2941
>4000
>9091
>17544
a
b
IC50 value for rat lens AR. Parentheses indicated percent
inhibition of AR at 1 × 10-7 M. c IC50 value for rat kidney ALR.
Parentheses indicate percent inhibition of ALR at 1 × 10-4 M.
d
a
b
Ta ble 2. Biological Data for ARIs with 6-Membered
Heterocyclic Core Units
IC50 value for rat lens AR. Parentheses indicate percent
inhibition of AR at 1 × 10-7 M. c IC50 value for rat kidney ALR.
Parentheses indicate percent inhibition of ALR at 1 × 10-4 M.
d
IC50 (M)
IC50(ALR)/
IC50(AR)
compd
ARa,b
ALRc,d
Ch a r t 3
43
47a
51
(1.5%)
>1 × 10-4 (33.5%)
>1 × 10-4 (17.4%)
>1 × 10-4 (11.8%)
3.4 × 10-8
>2941
(27.8%)
a
b
IC50 value for rat lens AR. Parentheses indicate percent
inhibition of AR at 1 × 10-7 M. c IC50 value for rat kidney ALR.
Parentheses indicate percent inhibition of ALR at 1 × 10-4 M.
d
Sch em e 11a
a
(a) TMSCl, HMDS, reflux; (b) 22, nBu4NI, CH2Cl2, rt; (c) NaH,
DMF, below 0 °C, then BrCH2COOEt, 0 °C; (d) AcOH, concen-
trated HCl, reflux.
the 2,4-dioxoimidazolidine 26a showed moderate AR
inhibitory activity, it inhibited ALR only 3.8% at 1 ×
10-4 M concentration.
It was anticipated that the introduction of arylmethyl
moieties of ARIs, which showed high AR inhibitory
activity in the 2,4,5-trioxoimidazolidine-1-acetic acid
derivatives, into the 2,4-dioxoimidazolidine-1-acetic acid
or the 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-1-acetic
acid core unit would produce high AR inhibitory activity
without ALR inhibition. In other words, modification
of the aryl portion would enhance inhibitory activity
against AR without influencing ALR activity. There-
fore, the substituted benzothiazolyl or 4-chloro-3-nitro-
phenyl group was adopted as an aromatic substitution
as shown in Chart 3. As expected, introduction of the
benzothiazolyl or 4-chloro-3-nitrophenyl group into the
2,4-dioxoimidazolidine-1-acetic acid or the 1,2,3,4-tet-
rahydro-2,4-dioxopyrimidine-1-acetic acid core unit re-
sulted in high AR inhibitory activity. Results as shown
in Table 3. Unfortunately, the 2,4-dioxoimidazolidine-
1-acetic acid derivatives 26b-d showed lower enzyme
selectivity, though the 1,2,3,4-tetrahydro-2,4-dioxopy-
rimidine-1-acetic acid derivatives 47b-d had a tendency
to show higher enzyme selectivity. From the results of
AR and ALR inhibitory activities of 47c,d , it could be
deduced that introduction of the benzothiazolyl group
as an aryl moiety onto the 1,2,3,4-tetrahydro-2,4-dioxo-
pyrimidine-1-acetic acid core unit seemed to be the best
combination for selective AR inhibition. The IC50(ALR)/
IC50(AR) value of 5-chlorobenzothiazole derivative 47d
was more than 17 500. The compound 47d inhibits AR
almost completely without notable inhibition of ALR.
Free-Wilson-type neural network analysis of the
5-membered ring compounds 1a , 9, 19, 26a , 36 and 40
indicated that the carbonyl groups at C2 and C5 were
important functional groups for AR inhibitory activity.
Recently, X-ray crystallography studies of the human

Highly Selective AR Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 689
the AR inhibition and selectivity. The combination of
the 1,2,3,4-tetrahydro-2,4-dioxopyrimidine-1-acetic acid
core unit and a suitable aryl moiety such as the
substituted benzothiazolyl groups showed very high AR
inhibitory activity without ALR inhibition. This is
especially true for 3-[(5-chlorobenzothiazol-2-yl)methyl]-
1,2,3,4-tetrahydro-2,4-dioxopyrimidine-1-acetic acid (47d),
which showed the IC50 value of 5 × 10-9 M with the
IC50(ALR)/IC50(AR) value of 17 500. To apply ARI for
the treatment of diabetes complications clinically, long-
term administration would be required, and therefore,
enzyme selectivity is one of the most important indices.
Our compounds are ideal as an AR inhibitor at this
point because they showed selective inhibition for AR.
Exp er im en ta l Section
General information is given in the second series of this
paper.23
P r ep a r a tion of 3-(3-Nitr oben zyl)-2-m eth ylid en e-4,5-
d ioxoim id a zolid in e-1-a cetic Acid (9). Eth yl N-(3-Ni-
tr oben zyl)oxa m a te (4). A solution of ethyl oxalyl chloride
(4.5 mL, 40.3 mmol) in CH2Cl2 (30 mL) was added dropwise
to a suspension of 3 (7.00 g, 37.0 mmol) and Et3N (12.0 mL,
86.1 mmol) in CH2Cl2 (90 mL) at 0 °C. The mixture was
vigorously stirred at the same temperature for 4 h, poured into
H2O, and extracted several times with CH2Cl2. The combined
extracts were washed with brine, dried over Na2SO4, and
concentrated. After the residue was passed through a short
silica gel column, the eluent was condensed and recrystallized
from EtOH to give the oxamate 4 (6.90 g, 74%): mp 82-82.5
F igu r e 1. Superimposition of zopolrestat (blue), 1a (green),
and 47d (red).
AR complex with zopolrestat reported that 20Trp, 111Trp,
122Phe, and 300Leu played important roles in stabilizing
the ternary complex.32 111Trp and 298Cys were reported
to interact with carbonyl and/or imide groups in the core
portion. Hence, our interests were focused on confor-
mational differences among our ARIs and other ARIs.
1a and 47d were constructed by CAChe (ver. 3.8, CAChe
Scientific) using zopolrestat as a template and mini-
mized by molecular mechanics implemented in CAChe.
Superimposition of zopolrestat with 1a and 47d is
diagrammed in Figure 1. The carbonyl oxygens at C2
of 1a and 47d are located so as to interact with 298Cys
in the same manner as zopolrestat. The carbonyl
oxygen of zopolrestat, the C4 carbonyl oxygen of 1a , and
the C5 carbonyl oxygen of 47d seem to occupy the spatial
positions to allow interaction with 111Trp of AR. Petrash
et al. reported that 298Cys could potentially function as
the proton donor.32 The most significant difference
between zopolrestat and 1a or 47d seems to be the
presence or absence of the benzo group in the core unit.
Although accurate molecular modeling has not yet been
studied, some of the other ARIs without AR specificity
would occupy the same region of the benzo group of
zopolrestat. This region may be an important binding
site for ALR, and therefore, weak ALR inhibition of 1a
can logically be expected as shown in Figure 1.
1
°C; H NMR (DMSO-d6) δ 1.28 (t, J ) 7.1 Hz, 3H, CH3), 4.26
(q, J ) 7.1 Hz, 2H, OCH2), 4.47 (d, J ) 6.2 Hz, 1H, NCH2),
7.64 (dd, J ) 8.1, 7.6 Hz, 1H, Ar-H), 7.76 (d, J ) 7.6 Hz, 1H,
Ar-H), 8.13 (d, J ) 8.1 Hz, 1H, Ar-H), 8.17 (s, 1H, Ar-H), 9.61
(t, J ) 6.2 Hz, 1H, CONH); IR (KBr, cm-1) 3284 (NH), 1745
(CdO), 1687 (CdO), 1535 (NO2), 1350 (NO2).
N-(3-Nitr oben zyl)oxa m ic Acid (5). A mixture of the
oxamate 4 (8.85 g, 35.1 mmol) and 1 N NaOH (175 mL, 175
mmol) in CH2Cl2 (270 mL) was vigorously shaken in
a
separatory funnel for 15 min. The aqueous layer was filtered
off to remove the insoluble material. Acidification of the
filtrate gave the white solid, which was filtered and dried
under reduced pressure to afford the oxamic acid 5 (6.96 g,
88%): mp 167-168 °C; 1H NMR (DMSO-d6) δ 4.45 (d, J ) 6.2
Hz, 1H, NCH2), 7.64 (dd, J ) 8.2, 7.7 Hz, 1H, Ar-H), 7.74 (d,
J ) 7.7 Hz, 1H, Ar-H), 8.13 (d, J ) 8.2 Hz, 1H, Ar-H), 8.16 (s,
1H, Ar-H), 9.16 (t, J ) 6.2 Hz, 1H, CONH), 13.50 (br s, 1H,
COOH); IR (KBr, cm-1) 3539 (NH), 3373 (OH), 1718 (CdO),
1684 (CdO), 1541, 1520 (NO2), 1354 (NO2).
Glycin e 2-(Tr im eth ylsilyl)eth yl Ester (6). WSC‚HCl
(12.91 g, 67.4 mmol) was added to a mixture of Z-Gly-OH
(10.07 g, 48.1 mmol), 2-(trimethylsilyl)ethanol (5.80 mL, 47.4
mmol), and DMAP (0.37 g, 0.3 mmol) in CH2Cl2 (200 mL) at 0
°C. The mixture was stirred at ambient temperature for 19
h, poured into H2O, and extracted several times with CH2Cl2.
The combined extracts were washed with brine, dried (Na2-
SO4), and concentrated. The residue was subjected to the next
reaction step without further purification.
A mixture of the ester obtained above and 10% Pd/C (0.97
g) in EtOAc (100 mL) was stirred at room temperature under
H2 atmosphere for 4 h. The catalyst was removed by filtration,
and the filtrate was concentrated. The residual oil was
chromatographed on silica gel (hexane-EtOAc ) 1/1) to afford
6 (8.18 g, 97%): mp 175-180 °C dec; 1H NMR (CDCl3) δ 0.05
(s, 9H, Si-CH3), 0.90-1.05 (m, 2H, CH2-Si), 3.38 (s, 2H, NCH2-
CO2), 4.15-4.25 (m, 2H, OCH2); IR (KBr, cm-1) 3290 (NH),
1741 (CdO), 1647 (CdO).
N-[[[2-(Tr im eth ylsilyl)eth oxy]ca r bon yl]m eth yl]-N′-(3-
n itr oben zyl)oxa m id e (7). A mixture of the oxamic acid 5
(6.96 g, 31.0 mmol), 6 (6.8 g, 39.1 mmol), and DMAP (0.10 g,
0.1 mmol) in CH2Cl2 (150 mL) was treated with WSC‚HCl (8.62
g, 45.0 mmol) at 0 °C. The mixture was stirred at ambient
temperature for 20 h, poured into H2O, and extracted several
Con clu sion
A number of modifications of the 2,4,5-trioxoimida-
zolidine framework to the uracil or hydantoin core unit
were investigated. It was found that the conversion of
the 2,4,5-trioxoimidazolidine framework to the uracil or
2,4-dioxoimidazolidine core unit was effective for high
AR inhibition without ALR inhibition. The steric
hindrance of the core unit plays an important role for
AR selective inhibitory activity. The results of the AR
and ALR inhibitory activities of various combinations
of the aryl moiety with the core unit suggested that both
the aryl moiety and the core unit were necessary for

690 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Kotani et al.
times with CH2Cl2. The combined extracts were washed with
brine, dried over Na2SO4, and concentrated. Purification by
column chromatography on silica gel (hexane-EtOAc ) 1/1)
followed by recrystallization from hexane-EtOAc (50-30 mL)
7.52 (dd, J ) 7.9, 7.9 Hz, 1H, Ar-H), 7.71 (d, J ) 7.9 Hz, 1H,
Ar-H), 8.08 (d, J ) 7.9 Hz, 1H, Ar-H), 8.16 (s, 1H, Ar-H); IR
(KBr, cm-1) 3349 (NH), 1739 (CdO), 1533 (NO2), 1345 (NO2).
Eth yl 3-(3-Nitr oben zyl)-4,5-dioxo-2-th ioxoim idazolidin e-
1-a ceta te (13). To a solution of the thiourea 12 (2.50 g, 8.8
mmol) in CH2Cl2 (10 mL) was added dropwise a solution of
oxalyl chloride (1.0 mL, 11.5 mmol) in CH2Cl2 (10 mL) at room
temperature. The mixture was stirred for 8 h and concen-
trated in vacuo. The crude product was passed through a short
silica gel pad to afford the 2-thioparabanic acid derivative 13,
which was used in the next reaction step without further
purification: 1H NMR (DMSO-d6) δ 1.20 (t, J ) 7.0 Hz, 3H,
CH3), 4.16 (q, J ) 7.0 Hz, 2H, OCH2), 4.65 (s, 2H, NCH2CO2),
5.19 (s, 2H, CH2Ar), 7.65 (dd, J ) 8.0, 8.0 Hz, 1H, Ar-H), 7.83
(dd, J ) 8.0, 2.4 Hz, 1H, Ar-H), 8.15 (dd, J ) 8.0, 2.4 Hz, 1H,
Ar-H), 8.26 (dd, J ) 2.4, 2.4 Hz, 1H, Ar-H).
3-(3-Nit r ob en zyl)-4,5-d ioxo-2-t h ioxoim id a zolid in e-1-
a cetic Acid (14). The crude thioparabanic acid derivative 13
was treated with AcOH (4.5 mL) and concentrated HCl (1.5
mL) at refluxing temperature for 1 h. After concentration of
the mixture, another portion of AcOH (4.5 mL) and concen-
trated HCl (1.5 mL) was added to the residue. The resulting
mixture was refluxed for an additional 1 h. After concentra-
tion, the solid was recrystallized from EtOH-hexane to give
the carboxylic acid 14 (0.23 g, 54% yield based on the thiourea
12): mp 188-188.5 °C; 1H NMR (DMSO-d6) δ 4.56 (s, 2H,
NCH2CO2), 5.20 (s, 2H, CH2Ar), 7.65 (dd, J ) 8.0, 7.7 Hz, 1H,
Ar-H), 7.83 (d, J ) 7.7 Hz, 1H, Ar-H), 8.16 (d, J ) 8.0 Hz, 1H,
Ar-H), 8.26 (s, 1H, Ar-H), 13.38 (br s, 1H, COOH); IR (KBr,
cm-1) 3000 (OH), 1784 (CdO), 1722 (CdO), 1531 (NO2), 1435
(CdS), 1346 (NO2); MS m/z 323 (M+). Anal. (C12H9N3O6S) C,
H, N.
P r ep a r a tion of 1-(3-Nitr oben zyl)-2,4-d ioxoim id a zoli-
d in e-3-a cetic Acid (19). Eth yl [(3-Nitr oben zyl)a m in o]-
a ceta te (17). A solution of 15 (12.60 g, 83.4 mmol) in MeOH
(50 mL) was added to a suspension of 16 (16.20 g, 125 mmol)
and NaBH3CN (8.50 g, 123 mmol) in MeOH (50 mL) at 0 °C.
The mixture was stirred at ambient temperature for 24 h.
Concentration of the reaction mixture gave a crude solid, which
was chromatographed on a silica gel column (hexane-EtOAc
) 1/1) to give the ethyl ester 17 (8.70 g, 44%): 1H NMR (CDCl3)
δ 1.29 (t, J ) 7.0 Hz, 3H, CH3), 3.41 (s, 2H, NCH2CO2), 3.92
(s, 2H, CH2Ar), 4.21 (q, J ) 7.0 Hz, 2H, OCH2), 7.50 (dd, J )
8.0, 8.0 Hz, 1H, Ar-H), 7.70 (d, J ) 8.0 Hz, 1H, Ar-H), 8.12 (d,
J ) 8.0 Hz, 1H, Ar-H), 8.23 (s, 1H, Ar-H); IR (KBr, cm-1) 3300
(NH), 1738 (CdO), 1527 (NO2), 1350 (NO2).
N,N′-Bis[(eth oxyca r bon yl)m eth yl]-N-(3-n itr oben zyl)-
u r ea (18). To a solution of the ester 17 (5.20 g, 21.8 mmol)
in ether (50 mL) was added a solution of 10 (2.6 mL, 23.2
mmol) in ether (50 mL) at room temperature. After being
stirred for 15 h, the mixture was concentrated and the residue
was directly chromatographed on a silica gel column (hexane-
EtOAc ) 1/1) to afford the urea 18 (7.93 g, 99%): 1H NMR
(CDCl3) δ 1.26 (t, J ) 7.0 Hz, 3H, CH3), 1.27 (t, J ) 7.0 Hz,
3H, CH3), 3.99 (s, 2H, NCH2CO2), 4.04 (s, 2H, NCH2CO2), 4.19
(q, J ) 7.0 Hz, 4H, OCH2), 4.68 (s, 2H, CH2Ar), 5.35 (t, J )
5.0 Hz, 1H, CONH), 7.55 (dd, J ) 7.0, 7.0 Hz, 1H, Ar-H), 7.70
(d, J ) 7.0 Hz, 1H, Ar-H), 8.14 (d, J ) 7.0 Hz, 1H, Ar-H), 8.15
(s, 1H, Ar-H); IR (KBr, cm-1) 3353 (NH), 1745 (CdO), 1741
(CdO), 1527 (NO2), 1350 (NO2).
1
gave the oxamide 7 (4.41 g, 37%): mp 99-100.5 °C; H NMR
(DMSO-d6) δ 0.13 (s, 9H, Si-CH3), 0.80-1.00 (m, 2H, CH2-Si),
3.84-3.90 (m, 2H, NCH2CO2), 4.10-4.20 (m, 2H, OCH2), 4.56
(d, J ) 6.3 Hz, 2H, CH2Ar), 7.63 (dd, J ) 8.1, 7.6 Hz, 1H, Ar-
H), 7.74 (d, J ) 7.6 Hz, 1H, Ar-H), 8.13 (d, J ) 8.1 Hz, 1H,
Ar-H), 8.16 (s, 1H, Ar-H), 9.08 (t, J ) 4.4 Hz, 1H, CONH),
9.56 (t, J ) 6.3 Hz, 1H, CONH); IR (KBr, cm-1) 3294 (NH),
1751 (CdO), 1655 (CdO), 1535 (NO2), 1348 (NO2).
2-(Tr im eth ylsilyl)eth yl 2-Meth ylid en e-3-(3-n itr oben -
zyl)-4,5-d ioxoim id a zolid in e-1-a ceta te (8). A mixture of the
oxamide 7 (4.90 g, 12.8 mmol) and AcONa (3.35 g, 40.8 mmol)
in Ac2O (50 mL) was refluxed for 2 days. During the reaction,
the color of the mixture changed from colorless to dark brown.
The reaction mixture was neutralized with saturated NaHCO3
and extracted three times with EtOAc. The combined extracts
were washed with saturated NaHCO3 and brine, dried over
Na2SO4, and concentrated under reduced pressure. The
residual solid was chromatographed on silica gel (hexane-
EtOAc ) 10/1) and recrystallized from hexane-EtOAc to give
1
8 (2.19 g, 42%): mp 110-112 °C; H NMR (CDCl3) δ 0.04 (s,
9H, Si-CH3), 0.95-1.05 (m, 2H, CH2-Si), 4.10 (d, J ) 5.2 Hz,
1H, CH2d), 4.17 (d, J ) 5.2 Hz, 1H, CH2d), 4.20-4.30 (m,
2H, OCH2), 4.43 (s, 2H, NCH2CO2), 5.02 (s, 2H, CH2Ar), 7.57
(dd, J ) 8.2, 7.7 Hz, 1H, Ar-H), 7.63 (d, J ) 7.7 Hz, 1H, Ar-
H), 8.13 (s, 1H, Ar-H), 8.19 (d, J ) 8.2 Hz, 1H, Ar-H); IR (KBr,
cm-1) 1753 (CdO), 1741 (CdO), 1728 (CdO), 1527 (NO2), 1356
(NO2).
2-Meth yliden e-3-(3-n itr oben zyl)-4,5-dioxoim idazolidin e-
1-a cetic Acid (9). To a solution of 8 (0.76 g, 1.87 mmol) in
THF (20 mL) and hexane (10 mL) was added a solution of nBu4-
NF (1 M solution, 2.0 mL, 2.0 mmol) in THF at room
temperature. The mixture was vigorously stirred for 2.5 h.
The reaction mixture was acidified with 2 N HCl and extracted
three times with EtOAc. The extracts were dried over Na2-
SO4 and concentrated. Recrystallization from EtOH gave the
1
carboxylic acid 9 (0.20 g, 33%): mp 160-160.5 °C; H NMR
(DMSO-d6) δ 4.10 (s, 2H, NCH2CO2), 4.47 (s, 1H, CH2d), 4.52
(s, 1H, CH2d), 4.70 (d, J ) 16.2 Hz, 1H, CH2Ar), 4.80 (d, J )
16.2 Hz, 1H, CH2Ar), 7.65 (dd, J ) 8.4, 8.2 Hz, 1H, Ar-H),
7.83 (d, J ) 8.2 Hz, 1H, Ar), 8.16 (d, J ) 8.4 Hz, 1H, Ar-H),
8.24 (s, 1H, Ar-H), 12.96 (br s, 1H, COOH); IR (KBr, cm-1
)
3020 (OH), 1740 (CdO), 1684 (CdO), 1533 (NO2), 1348 (NO2);
MS m/z 305 (M+). Anal. (C13H11N3O6‚0.9H2O) C, H, N.
P r ep a r a tion of 3-(3-Nitr oben zyl)-4,5-d ioxo-2-th ioxoim -
id a zolid in e-1-a cet ic Acid (14). N-[(E t h oxyca r b on yl)-
m eth yl]-N′-(3-n itr oben zyl)u r ea (11). Ethyl isocyanatoac-
etate (10; 6.0 mL, 53.5 mmol) was added dropwise to a solution
of 3-nitrobenzylamine hydrochloride (3; 10.0 g, 53.0 mmol) and
NaOH (2.10 g, 52.5 mmol) in H2O (50 mL) and EtOH (100 mL)
with vigorous stirring at 0 °C. After being stirred for 1.5 h,
the precipitate was filtered and washed well with H2O to give
a solid, which was recrystallized from EtOH (200 mL) to give
the urea 11 (10.70 g, 76%) as white crystals: mp 141.5-142
1
°C; H NMR (DMSO-d6) δ 1.18 (t, J ) 7.0 Hz, 3H, CH3), 3.78
(d, J ) 6.0 Hz, 2H, NCH2CO2), 4.08 (q, J ) 7.0 Hz, 2H, OCH2),
4.34 (d, J ) 6.1 Hz, 2H, CH2Ar), 6.45 (t, J ) 6.0 Hz, 1H,
CONH), 6.87 (t, J ) 6.1 Hz, 1H, CONH), 7.61 (dd, J ) 7.7, 7.7
Hz, 1H, Ar-H), 7.71 (d, J ) 7.7 Hz, 1H, Ar-H), 8.09 (d, J ) 7.7
Hz, 1H, Ar-H), 8.10 (s, 1H, Ar-H); IR (KBr, cm-1) 3334 (NH),
1722 (CdO), 1597 (NO2), 1346 (NO2).
1-(3-Nitr oben zyl)-2,4-d ioxoim id a zolid in e-3-a cetic Acid
(19). A mixture of the urea 18 (6.58 g, 17.9 mmol) in AcOH
(21 mL) and concentrated HCl (7 mL) was refluxed for 3 h
with vigorous stirring. The mixture was concentrated, and
AcOH (21 mL) and concentrated HCl (7 mL) were added. The
resulting mixture was refluxed for an additional 2 h. Evapo-
ration of the solvent yielded a crude solid, which was washed
with H2O and recrystallized from EtOH (30 mL) to give the
carboxylic acid 19 (3.68 g, 70% yield) as white crystals: mp
168-170 °C; 1H NMR (DMSO-d6) δ 4.08 (s, 2H, NCH2CO2),
4.12 (s, 2H, NCH2CON), 4.68 (s, 2H, CH2Ar), 7.67 (dd, J )
8.6, 7.7 Hz, 1H, Ar-H), 7.76 (d, J ) 7.7 Hz, 1H, Ar-H), 8.16 (s,
1H, Ar-H), 8.17 (d, J ) 8.6 Hz, 1H, Ar-H), 13.20 (br s, 1H,
COOH); IR (KBr, cm-1) 3100 (OH), 1774 (CdO), 1745 (CdO),
1714 (CdO), 1533 (NO2), 1359 (NO2); MS m/z 293 (M+). Anal.
(C12H11N3O6) C, H, N.
N-[(E t h oxyca r b on yl)m et h yl]-N′-(3-n it r ob en zyl)t h io-
u r ea (12). The urea 11 (3.00 g, 11.2 mmol) was treated with
Lawesson’s reagent (5.00 g, 12.4 mmol) in 1,4-dioxane (30 mL)
at refluxing temperature for 1.5 h. During the reaction, the
color of the solution changed from colorless to brown. The
mixture was poured into H2O and extracted several times with
EtOAc. The combined extracts were washed with brine, dried
over Na2SO4, and concentrated. The residue was chromato-
graphed on silica gel (hexane-EtOAc ) 1/1) to afford the
thiourea 12 (2.50 g, 79%): 1H NMR (CDCl3) δ 1.28 (t, J ) 7.0
Hz, 3H, CH3), 4.20 (q, J ) 7.0 Hz, 2H, OCH2), 4.41 (d, J ) 4.9
Hz, 2H, NCH2CO2), 4.90 (s, 2H, CH2Ar), 7.18 (br s, 1H, CONH),

Highly Selective AR Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 691
P r ep a r a tion of 3-(Ar ylm eth yl)-2,4-d ioxoim id a zolid in e-
1-a cet ic Acid s (26). E t h yl 2,4-Dioxoim id a zolid in e-1-
a ceta te (21). To a solution of 20 (50.0 mL, 285 mmol) and
KNCO (46.72 g, 576 mmol) in H2O (500 mL) was added
dropwise concentrated HCl (48 mL, 576 mmol) over the period
of 1 h with vigorous stirring at room temperature. After being
refluxed for 2 h, the mixture was allowed to cool to room
temperature and extracted three times with EtOAc. The
combined extracts were dried over Na2SO4 and concentrated.
The residual solid was recrystallized from EtOH (100 mL) to
give the hydantoin 21 (32.49 g, 61%): mp 92-93.5 °C; 1H NMR
(DMSO-d6) δ 1.21 (t, J ) 7.0 Hz, 3H, CH3), 3.97 (s, 2H, NCH2-
CO2), 4.08 (s, 2H, NCH2CON), 4.13 (q, J ) 7.0 Hz, 2H, OCH2),
10.96 (br s, 1H, NH); IR (KBr, cm-1) 3188 (NH), 1770 (CdO),
1713 (CdO).
Eth yl 3-(3-Nitr oben zyl)-2,4-d ioxoim id a zolid in e-1-a c-
eta te (23a ). A solution of the hydantoin 21 (0.82 mg, 4.38
mmol) in DMF (30 mL) was added dropwise to a suspension
of NaH (60 wt % in oil, 221 mg, 5.51 mmol) in DMF (20 mL)
over a period of 30 min maintaining the temperature below 0
°C. The mixture was stirred at the same temperature for an
additional 1 h. A solution of the benzyl bromide 22 (1.30 g,
4.38 mmol) in DMF (30 mL) was added dropwise to the
reaction mixture at 0 °C. After stirring for 2 h, the mixture
was poured into ice-cooled 2 N HCl with vigorous stirring. The
resulting mixture was extracted several times with EtOAc. The
combined extracts were washed twice with brine, dried over
Na2SO4, and concentrated to give a residue, which was
chromatographed on a silica gel column (hexane-EtOAc ) 3/1)
to give the ester 23a (1.32 g, 94%): 1H NMR (DMSO-d6) δ 1.19
(t, J ) 7.0 Hz, 3H, CH3), 4.12 (s, 2H, NCH2CO2), 4.14 (q, J )
7.0 Hz, 2H, OCH2), 4.18 (s, 2H, NCH2CON), 4.74 (s, 2H, CH2-
Ar), 7.66 (dd, J ) 9.0, 7.8 Hz, 1H, Ar-H), 7.73 (d, J ) 7.8 Hz,
1H, Ar-H), 8.14 (s, 1H, Ar-H), 8.16 (d, J ) 9.0 Hz, 1H, Ar-H),
10.99 (br s, 1H, CONHCO); IR (neat, cm-1) 1732 (CdO), 1703
(CdO), 1533 (NO2), 1350 (NO2).
to a suspension of NaH (60 wt % in oil, 0.25 g, 6.25 mmol) in
DMF (10 mL) at -10-0 °C. After stirring at the same
temperature for 2 h, a mixture prepared by the treatment of
the benzothiazole 25a (0.78 g, 4.19 mmol) with NaBr (0.79 g,
4.57 mmol) in DMF (40 mL) at room temperature for 30 min
was added at 0 °C. The resulting mixture was stirred at
ambient temperature for 16 h, poured into ice-cooled 2 N HCl,
and extracted three times with EtOAc. The combined extracts
were washed with brine, dried over Na2SO4, and concentrated.
The residual oil was chromatographed on silica gel (hexane-
EtOAc ) 2/1) and recrystallized from EtOH (50 mL) to give
the ester 23c (1.23 g, 73%): mp 133-135 °C; 1H NMR (DMSO-
d6) δ 1.21 (t, J ) 7.0 Hz, 3H, CH3), 4.15 (q, J ) 7.0 Hz, 2H,
OCH2), 4.19 (s, 2H, NCH2CO2), 4.22 (s, 2H, NCH2CON), 5.08
(s, 2H, CH2Ar), 7.45 (dd, J ) 8.2, 7.8 Hz, 1H, Ar-H), 7.63 (dd,
J ) 7.8, 0.8 Hz, 1H, Ar-H), 8.08 (dd, J ) 8.2, 0.8 Hz, 1H, Ar-
H); IR (KBr, cm-1) 1721 (CdO), 1717 (CdO).
P r ep a r a tion of 5-Meth ylid en e-1-(3-n itr oben zyl)-2,4-
d ioxoim id a zolid in e-3-a cetic Acid (30). Meth yl 3-Hy-
d r oxy-2-[(3-n itr oben zyl)a m in o]p r op ion a te (28). A solu-
tion of 15 (12.64 g, 8.36 mmol) in MeOH (50 mL) was added
to a suspension of 27 (12.69 g, 8.17 mmol) in MeOH (50 mL)
at 0 °C. After stirring for 30 min at 0 °C, a solution of NaBH3-
CN (0.78 g, 11.3 mmol) in MeOH (50 mL) was added. The
resulting mixture was stirred at ambient temperature for 15
h, poured into saturated NaHCO3, and extracted several times
with EtOAc. The combined extracts were washed with satu-
rated NaHCO3, dried over Na2SO4, and concentrated. The
residual oil was chromatographed on a silica gel column
(hexane-EtOAc ) 1/1) to give 28 (3.46 g, 17%): 1H NMR
(CDCl3) δ 2.51 (br s, 1H, OH), 3.44 (dd, J ) 6.6, 4.6 Hz, 1H,
OCH2), 3.68 (dd, J ) 10.9, 6.2 Hz, 1H, OCH2), 3.78 (s, 3H,
OCH3), 3.75-7.80 (m, 1H, NCHCO), 3.82 (d, J ) 13.6 Hz, 1H,
CH2Ar), 4.04 (d, J ) 13.6 Hz, 1H, CH2Ar), 7.51 (dd, J ) 7.9,
7.6 Hz, 1H, Ar-H), 7.79 (d, J ) 7.6 Hz, 1H, Ar-H), 8.14 (d, J )
7.9 Hz, 1H, Ar-H), 8.27 (s, 1H, Ar-H); IR (neat, cm-1) 3334
(OH), 1738 (CdO), 1527 (NO2), 1352 (NO2).
3-(3-Nitr oben zyl)-2,4-d ioxoim id a zolid in e-1-a cetic Acid
(26a ). The ester 23a (1.70 g, 5.29 mmol) was treated with
AcOH (12 mL) and concentrated HCl (4 mL) at refluxing
temperature for 1 h. After condensation, the mixture was
treated again with AcOH (12 mL) and concentrated HCl (4
mL) under reflux for an additioal 1 h. The resulting mixture
was poured into ice-cooled EtOAc-aqueous NaOH and ex-
tracted several times with cold 10% aqueous NaOH. The
combined aqueous layer was acidified with concentrated HCl
and extracted several times with EtOAc. The combined
extracts were dried over Na2SO4 and concentrated. The
residual solid was recrystallized from EtOH (200 mL) to give
the carboxylic acid 26a (0.35 g, 44%): mp 165-166 °C; 1H
NMR (DMSO-d6) δ 4.08 (s, 2H, NCH2CO2), 4.10 (s, 2H, NCH2-
CON), 4.73 (s, 2H, CH2Ar), 7.65 (dd, J ) 7.9, 7.4 Hz, 1H, Ar-
H), 7.74 (d, J ) 7.9 Hz, 1H, Ar-H), 8.14 (s, 1H, Ar-H), 8.16 (d,
N′-[(E t h oxyca r b on yl)m et h yl]-N-[2-h yd r oxy-1-(m et h -
oxyca r bon yl)eth yl]-N-(3-n itr oben zyl)u r ea (29). Ethyl iso-
cyanatoacetate (10; 1.9 mL, 16.9 mmol) was added to a solution
of the ester 28 (3.46 g, 13.6 mmol) in ether (50 mL) at room
temperature. Immediately after addition, a white solid pre-
cipitated. After stirring vigorously for 7 h, the precipitated
solid was filtered and washed with ether. Recrystallization
from hexane-EtOAc (60-20 mL) gave the urea 29 (4.15 g,
1
80%) as white crystals: mp 88.5-90.5 °C; H NMR (DMSO-
d6) δ 1.16 (t, J ) 7.1 Hz, 3H, CH3), 3.56 (s, 3H, OCH3), 3.65-
3.75 (m, 2H, NCH2CO2), 3.76 (d, J ) 5.5 Hz, 2H, OCH2), 4.05
(q, J ) 7.1 Hz, 2H, OCH2), 4.58 (t, J ) 5.5 Hz, 1H, CH), 4.66
(d, J ) 18.1 Hz, 1H, CH2Ar), 4.76 (d, J ) 18.1 Hz, 1H, CH2-
Ar), 4.97 (br s, 1H, OH), 7.00 (t, J ) 5.5 Hz, 1H, CONH), 7.61
(dd, J ) 8.0, 7.6 Hz, 1H, Ar-H), 7.83 (d, J ) 7.6 Hz, 1H, Ar-
H), 8.10 (d, J ) 8.0 Hz, 1H, Ar-H), 8.27 (s, 1H, Ar-H); IR (KBr,
cm-1) 3388 (OH), 3332 (NH), 1745 (CdO), 1630 (CdO), 1527
(NO2), 1352 (NO2).
J ) 7.4 Hz, 1H, Ar-H), 13.09 (br s, 1H, COOH); IR (KBr, cm-1
)
2990 (OH), 1789 (CdO), 1732 (CdO), 1686 (CdO), 1525 (NO2),
1351 (NO2); MS m/z 277 (M+ - OH). Anal. (C12H11N3O6) C,
H, N.
5-Meth yliden e-1-(3-n itr oben zyl)-2,4-dioxoim idazolidin e-
3-a cetic Acid (30). To a solution of KOH (0.38 g, 6.54 mmol)
in H2O (70 mL) and EtOH (30 mL) was added a solution of
the urea 29 (2.53 g, 6.13 mmol) at 0 °C. The mixture was
stirred at ambient temperature for 24 h and washed three
times with EtOAc. After acidification with concentrated HCl,
the aqueous layer was extracted several times with EtOAc.
The extracts were concentrated and purified by chromatogra-
phy on a silica gel column (CHCl3-MeOH ) 3/1) to give the
carboxylic acid 30 (0.10 g, 5%): mp 169-171 °C; 1H NMR
(DMSO-d6) δ 4.24 (s, 2H, NCH2CO2), 5.01 (s, 2H, CH2Ar), 5.15
(d, J ) 2.6 Hz, 1H, CH2d), 5.35 (d, J ) 2.6 Hz, 1H, CH2d),
7.66 (dd, J ) 8.1, 7.7 Hz, 1H, Ar-H), 7.75 (d, J ) 7.7 Hz, 1H,
Ar-H), 8.17 (d, J ) 8.1 Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 13.32
(br s, 1H, COOH); IR (KBr, cm-1) 3000 (OH), 1738 (CdO), 1718
(CdO), 1662 (CdO), 1527 (NO2), 1354 (NO2); MS m/z M+ was
not detected. Anal. (C13H11N3O6) C, H, N.
Eth yl 3-(4-Ch lor o-3-n itr oben zyl)-2,4-d ioxoim id a zoli-
d in e-1-a ceta te (23b). A solution of DEAD (5.2 mL, 33.0
mmol) in THF (30 mL) was added to a solution of the alcohol
24 (5.13 g, 27.3 mmol), the ester 21 (4.70 g, 25.2 mmol), and
PPh3 (8.68 g, 33.1 mmol) in THF (30 mL) at 0 °C. The mixture
was stirred at ambient temperature for 24 h. The reaction
mixture was poured into H2O and extracted several times with
EtOAc. The combined extracts were washed with brine, dried
over Na2SO4, and concentrated. The residue was chromato-
graphed on silica gel (hexane-EtOAc ) 3/1) and recrystallized
twice from EtOH-H2O to give the ethyl ester 23b (7.01 g,
1
78%): mp 76-77 °C; H NMR (DMSO-d6) δ 1.20 (t, J ) 7.1
Hz, 3H, CH3), 4.11 (s, 2H, NCH2CO2), 4.14 (q, J ) 7.1 Hz, 2H,
OCH2), 4.18 (s, 2H, NCH2CON), 4.69 (s, 2H, CH2Ar), 7.60 (d,
J ) 8.3 Hz, 1H, Ar-H), 7.77 (d, J ) 8.3 Hz, 1H, Ar-H), 7.97 (s,
1H, Ar-H); IR (KBr, cm-1) 1770 (CdO), 1732 (CdO), 1713
(CdO), 1527 (NO2), 1333 (NO2).
P r ep a r a tion of 5-Hyd r oxy-1-(3-n itr oben zyl)-2,4-d ioxo-
im id a zolid in e-3-a cetic Acid (36). Ben zyl 2-(Ben zyloxy)-
2-h yd r oxya ceta te (32). A mixture of glyoxylic acid mono-
hydrate (110 g, 1.20 mol), benzyl alcohol (500 mL, 4.80 mol),
Eth yl 3-[(4-Ch lor oben zoth ia zol-2-yl)m eth yl]-2,4-d ioxo-
im id a zolid in e-1-a ceta te (23c). A solution of the hydantoin
21 (0.78 g, 4.19 mmol) in DMF (30 mL) was added dropwise

692 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5
Kotani et al.
and p-TsOH‚H2O (100 mg) in toluene was refluxed for 2 h on
a Dean-Stark apparatus. After cooling, the mixture was
washed twice with H2O. The organic phase was dried over
Na2SO4 and concentrated. The residual oil was distilled to
give 32 (204.9 g, 63%): bp 95-100 °C/1 mmHg; 1H NMR
(CDCl3) δ 3.73 (d, J ) 11.4 Hz, 1H, OH), 4.68 (d, J ) 11.9 Hz,
1H, CH2), 4.82 (d, J ) 11.9 Hz, 1H, CH2), 5.04 (d, J ) 11.4
Hz, 1H, CH), 5.23 (d, J ) 5.1 Hz, 1H, CH2), 5.25 (d, J ) 5.1
Hz, 1H, CH2), 7.25-7.37 (m, 10H, Ar-H).
hydantoin derivative 39 (17.2 g, 62%): mp 101-102 °C; 1H
NMR (CDCl3) δ 1.29 (t, J ) 7.2 Hz, 3H, CH3), 4.14 (d, J )
18.0 Hz, 1H, CH2CO2), 4.22 (q, J ) 7.2 Hz, 2H, OCH2), 4.27
(d, J ) 18.0 Hz, 1H, CH2CO2), 4.30 (d, J ) 8.0 Hz, 1H, OH),
4.74 (d, J ) 15.0 Hz, 1H, CH2Ar), 4.77 (d, J ) 15.0 Hz, 1H,
CH2Ar), 5.35 (d, J ) 8.0 Hz, 1H, CH), 7.51 (dd, J ) 8.2, 7.9
Hz, 1H, Ar-H), 7.70 (d, J ) 7.9 Hz, 1H, Ar-H), 8.16 (d, J ) 8.2
Hz, 1H, Ar-H), 8.19 (s, 1H, Ar-H); IR (KBr, cm-1) 3413 (OH),
1713 (CdO), 1525 (NO2), 1352 (NO2).
5-H yd r oxy-1-(3-n it r ob en zyl)im id a zolid in e-2,4-d ion e
(33). A solution of the urea 31 (78.0 g, 0.40 mol) and 32 (120.0
g, 0.44 mol) in 80% AcOH (500 mL) was stirred at 80 °C for 2
h. After removal of the solvent, the mixture was coevaporated
with toluene. The residue was chromatographed on silica gel
(CHCl3-EtOAc ) 1/1) followed by recrystallization from
hexane-EtOAc (1/1) to give the hydantoin derivative 33 (48.9
5-Hyd r oxy-3-(3-n itr oben zyl)-2,4-d ioxoim id a zolid in e-1-
a cetic Acid (40). A mixture of the ester 39 (15.0 g, 45 mmol)
in AcOH (45 mL) and concentrated HCl (15 mL) was refluxed
for 2 h. The mixture was concentrated, and the residue was
allowed to stand at room temperature to give a solid. The solid
was filtered, washed well with Et2O, and recrystallized from
EtOH-H2O (1/1) to give the carboxylic acid 40 (8.10 g, 59%):
1
1
g, 62%): mp 155-158 °C; H NMR (DMSO-d6) δ 4.50 (d, J )
mp 153-155 °C; H NMR (DMSO-d6) δ 3.90 (d, J ) 18.0 Hz,
16.2 Hz, 1H, CH2Ar), 4.59 (d, J ) 16.2 Hz, 1H, CH2Ar), 5.07
(d, J ) 8.1 Hz, 1H, CH), 7.03 (d, J ) 8.1 Hz, 1H, OH), 7.63
(dd, J ) 8.3, 7.9 Hz, 1H, Ar-H), 7.78 (d, J ) 7.9 Hz, 1H, Ar-
H), 8.12 (dd, J ) 8.3, 2.2 Hz, 1H, Ar-H), 8.17 (d, J ) 2.2 Hz,
1H, Ar-H); IR (KBr, cm-1) 3373 (OH), 1757 (CdO), 1718 (CdO),
1540 (NO2), 1346 (NO2).
1H, CH2CO2), 4.16 (d, J ) 18.0 Hz, 1H, CH2CO2), 4.73 (d, J )
15.6 Hz, 1H, CH2Ar), 4.78 (d, J ) 15.6 Hz, 1H, CH2Ar), 5.24
(s, 1H, CH), 7.20 (br s, 1H, OH), 7.66 (dd, J ) 8.0, 7.6 Hz, 1H,
Ar-H), 7.76 (d, J ) 7.6 Hz, 1H, Ar-H), 8.14-8.17 (m, 2H, Ar-
H), 13.00 (br s, 1H, COOH); IR (KBr, cm-1) 3533 (OH), 1776
(CdO), 1713 (CdO), 1527 (NO2), 1350 (NO2); MS m/z 310 ([M
+ H]+). Anal. (C12H11N3O7) C, H, N.
ter t-Bu tyl 5-Hyd r oxy-1-(3-n itr oben zyl)-2,4-d ioxoim id -
a zolid in e-3-a ceta te (35). A mixture of the hydantoin 33
(12.5 g, 50 mmol), 34 (9.0 mL, 60 mmol), and KHCO3 (10.0 g,
100 mmol) was refluxed for 8 h. After removal of the insoluble
material, the filtrate and washings were concentrated. The
residue was dissolved in EtOAc, washed with H2O and brine,
dried over Na2SO4, and concentrated. The residual gum was
chromatographed on silica gel (EtOAc) and recrystallized from
P r ep a r a tion of 3-(3-Nitr oben zyl)-2,4,6-tr ioxoh exa h y-
d r op yr im id in e-1-a cetic Acid (43). N-[(Eth oxyca r bon yl)-
m eth yl]-N′-(3-n itr oben zyl)u r ea (41). Ethyl isocyanatoac-
etate (10; 6.0 mL, 53.5 mmol) was added dropwise to a solution
of 3 (10.0 g, 53.0 mmol) and NaOH (2.10 g, 52.5 mmol) in H2O
(50 mL) and EtOH (100 mL) with vigorous stirring at 0 °C.
After stirring for 1.5 h, the precipitate was filtered, washed
well with H2O, and recrystallized from EtOH (200 mL) to give
the urea 41 (10.70 g, 76%) as white crystals: mp 141.5-142
1
hexane-EtOAc to give 35 (12.4 g, 68%): mp 117-118 °C; H
NMR (CDCl3) δ 1.41 (s, 9H, CH3), 4.09 (d, J ) 17.5 Hz, 1H,
CH2CO2), 4.12 (d, J ) 17.5 Hz, 1H, CH2CO2), 4.58 (d, J ) 16.2
Hz, 1H, CH2Ar), 4.68 (d, J ) 16.2 Hz, 1H, CH2Ar), 5.29 (d, J
) 6.4 Hz, 1H, CH), 7.36 (d, J ) 6.4 Hz, 1H, OH), 7.65 (dd, J
) 8.2, 7.8 Hz, 1H, Ar-H), 7.79 (d, J ) 7.8 Hz, 1H, Ar-H), 8.14
(dd, J ) 8.2, 1.7 Hz, 1H, Ar-H), 8.20 (d, J ) 1.7 Hz, 1H, Ar-
H); IR (KBr, cm-1) 3430 (OH), 1732 (CdO), 1705 (CdO), 1531
(NO2), 1350 (NO2).
1
°C; H NMR (DMSO-d6) δ 1.18 (t, J ) 7.0 Hz, 3H, CH3), 3.78
(d, J ) 6.0 Hz, 2H, NCH2CO2), 4.08 (q, J ) 7.0 Hz, 2H, OCH2),
4.34 (d, J ) 6.1 Hz, 2H, CH2Ar), 6.45 (t, J ) 6.0 Hz, 1H,
CONH), 6.87 (t, J ) 6.1 Hz, 1H, CONH), 7.61 (dd, J ) 7.7, 7.7
Hz, 1H, Ar-H), 7.71 (d, J ) 7.7 Hz, 1H, Ar-H), 8.09 (d, J ) 7.7
Hz, 1H, Ar-H), 8.10 (s, 1H, Ar-H); IR (KBr, cm-1) 3334 (NH),
1722 (CdO), 1597 (NO2), 1346 (NO2).
5-Hyd r oxy-1-(3-n itr oben zyl)-2,4-d ioxoim id a zolid in e-3-
a cetic Acid (36). A solution of 35 (3.60 g, 10.0 mmol) in 4 N
HCl/dioxane (50 mL) was stirred at room temperature for 1
day and concentrated. The residue was crystallized by addi-
tion of CHCl3 and rinsed with CHCl3 to give 36 (0.80 g, 26%)
Eth yl 3-(3-Nitr oben zyl)-2,4,6-tr ioxoh exa h yd r op yr im i-
d in e-1-a ceta te (42). A solution of malonyl chloride (3.2 mL,
32.9 mmol) in CH2Cl2 (10 mL) was added dropwise to a
suspension of the urea 41 (8.60 g, 32.2 mmol) in CH2Cl2 (100
mL) at 0 °C. The mixture was stirred at the same temperature
for 4.5 h, neutralized with saturated NaHCO3, and extracted
three times with EtOAc. The combined extracts were washed
with brine, dried over Na2SO4, and concentrated in vacuo. The
residue was chromatographed on silica gel (hexane-EtOAc )
1/1) to give the barbituric acid derivative 42 (6.70 g, 60%): mp
115-116.5 °C; 1H NMR (DMSO-d6) δ 1.18 (t, J ) 7.1 Hz, 3H,
CH3), 4.00 (br s, 2H, COCH2CO), 4.12 (q, J ) 7.1 Hz, 2H,
OCH2), 4.50 (s, 2H, NCH2CO2), 5.06 (s, 2H, CH2Ar), 7.63 (dd,
J ) 8.0, 7.5 Hz, 1H, Ar-H), 7.78 (d, J ) 7.5 Hz, 1H, Ar-H),
8.14 (d, J ) 8.0 Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-H); IR (KBr,
cm-1) 1749 (CdO), 1714 (CdO), 1682 (CdO), 1527 (NO2), 1352
(NO2).
3-(3-Nitr oben zyl)-2,4,6-tr ioxoh exa h yd r op yr im id in e-1-
a cetic Acid (43). A mixture of the ester 42 (2.98 g, 8.53
mmol), AcOH (9 mL), and concentrated HCl (3 mL) was
refluxed for 2 h. After concentration, the residue was treated
again with AcOH (9 mL) and concentrated HCl (3 mL) with
refluxing for 1 h. Condensation gave a solid, which was
washed well with H2O and recrystallized from EtOH to give
the carboxylic acid 43 (1.90 g, 67%): mp 89-90 °C dec; 1H
NMR (DMSO-d6) δ 4.00 (br s, 2H, COCH2CO), 4.41 (s, 2H,
NCH2CO2), 5.05 (s, 2H, CH2Ar), 7.62 (dd, J ) 8.0, 7.2 Hz, 1H,
Ar-H), 7.78 (d, J ) 7.2 Hz, 1H, Ar-H), 8.13 (d, J ) 8.0 Hz, 1H,
Ar-H), 8.20 (s, 1H, Ar-H), 13.06 (br s, 1H, COOH); IR (KBr,
cm-1) 2970 (OH), 1716 (CdO), 1531 (NO2), 1354 (NO2); MS
m/z 321 (M+). Anal. (C13H11N3O7‚0.6H2O) C, H, N.
1
as a solid: mp 123-125 °C; H NMR (DMSO-d6) δ 4.09 (d, J
) 17.6 Hz, 1H, CH2CO2), 4.13 (d, J ) 17.6 Hz, 1H, CH2CO2),
4.58 (d, J ) 16.2 Hz, 1H, CH2Ar), 4.68 (d, J ) 16.2 Hz, 1H,
CH2Ar), 5.20 (s, 1H, CH), 7.36 (br s, 1H, OH), 7.65 (dd, J )
8.1, 7.8 Hz, 1H, Ar-H), 7.79 (d, J ) 7.8 Hz, 1H, Ar-H), 8.14 (d,
J ) 8.1 Hz, 1H, Ar-H), 8.20 (s, 1H, Ar-H), 13.13 (br s, 1H,
COOH); IR (KBr, cm-1) 1782 (CdO), 1718 (CdO), 1529 (NO2),
1352 (NO2); MS m/z 310 ([M + H]+). Anal. (C12H11N3O7) C,
H, N.
P r ep a r a tion of 5-Hyd r oxy-3-(3-n itr oben zyl)-2,4-d ioxo-
im id a zolid in e-1-a cetic Acid (40). Eth yl 5-Hyd r oxy-2,4-
d ioxoim id a zolid in e-1-a ceta te (38). A solution of 37 (58.5
g, 0.40 mol) and 32 (130.0 g, 0.48 mol) in 80% AcOH (500 mL)
was stirred at 80 °C for 2 h. The mixture was concentrated
and coevaporated with toluene. The residue was chromato-
graphed on silica gel (EtOAc-CH2Cl2) followed by recrystal-
lization from hexane-EtOAc (1/1) to give the hydantoin
derivative 38 (37.6 g, 47%): mp 107-108 °C; 1H NMR (DMSO-
d6) δ 1.20 (t, J ) 7.0 Hz, 3H, CH3), 3.88 (d, J ) 18.0 Hz, 1H,
CH2CO2), 4.13 (dq, J ) 7.0, 1.0 Hz, 2H, OCH2), 4.14 (d, J )
18.0 Hz, 1H, CH2CO2), 5.07 (d, J ) 8.4 Hz, 1H, CH), 7.01 (d,
J ) 8.4 Hz, 1H, OH), 11.04 (s, 1H, NH); IR (KBr, cm-1) 3460
(NH), 3260, 1786 (CdO), 1720 (CdO).
Eth yl 5-Hyd r oxy-3-(3-n itr oben zyl)-2,4-d ioxoim id a zo-
lid in e-1-a ceta te (39). A mixture of 38 (20.0 g, 0.10 mol), 22
(26.0 g, 0.12 mol), and KHCO3 (20.0 g, 0.20 mol) in acetone
(250 mL) was refluxed for 10 h. After removal of the solvent,
the mixture was dissolved in EtOAc and washed with H2O and
brine. The organic phase was dried over Na2SO4 and concen-
trated. The residue was chromatographed on silica gel
(EtOAc) and crystallized by addition of Et2O to give the
P r ep a r a tion of 3-(Ar ylm eth yl)-1,2,3,4-tetr a h yd r o-2,4-
d ioxop yr im id in e-1-a cetic Acid s (47). Eth yl 1,2,3,4-Tet-
r a h yd r o-3-(3-n it r ob en zyl)-2,4-d ioxop yr im id in e-1-a ce-
ta te (45a ). A solution of 44 (2.31 g, 11.7 mmol) in DMF (40
mL) was added dropwise to a suspension of NaH (60 wt % in

Highly Selective AR Inhibitors
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 5 693
oil, 0.58 g, 14.5 mmol) in DMF (30 mL) while maintaining the
temperature below 0 °C. After stirring for 1.5 h, a solution of
22 (3.42 g, 11.6 mmol) in DMF (70 mL) was added at 0 °C.
The mixture was stirred at 0 °C for 2 h, poured into H2O, and
extracted several times with EtOAc. The combined extracts
were washed with brine, dried, and concentrated. The residue
was chromatographed on silica gel (hexane-EtOAc ) 1/1) and
recrystallized from EtOH to give 45a (1.86 g, 48%): mp 105-
5.08 (s, 2H, CH2Ar), 5.65 (d, J ) 8.0 Hz, 1H, COCHdC), 7.68
(dd, J ) 7.7, 7.7 Hz, 1H, Ar-H), 7.78 (d, J ) 7.7 Hz, 1H, Ar-
H), 7.86 (d, J ) 8.0 Hz, 1H, COCdCH), 8.19 (d, J ) 7.7 Hz,
1H, Ar-H), 8.20 (s, 1H, Ar-H), 11.39 (br s, 1H, NH); IR (KBr,
cm-1) 3007 (NH), 1707 (CdO), 1666 (CdO), 1533 (NO2), 1346
(NO2).
Eth yl 1,2,3,4-Tetr a h yd r o-1-(3-n itr oben zyl)-2,4-d ioxo-
p yr im id in e-3-a ceta te (50). A suspension of 49 (5.91 g, 23.9
mmol) in DMF (100 mL) was added to a suspension of NaH
(60 wt % in oil, 1.21 g, 30.3 mmol) in DMF (20 mL) while
maintaining the temperature below 0 °C. The mixture was
stirred at the same temperature for 3 h. A solution of ethyl
bromoacetate (2.7 mL, 24.3 mmol) in DMF (20 mL) was added
dropwise to the above mixture. After stirring for 2.5 h, the
mixture was poured into H2O and extracted several times with
EtOAc. The combined extracts were washed with brine, dried
over Na2SO4, and concentrated. The residue was chromato-
graphed on silica gel (hexane-EtOAc ) 1/1) and recrystallized
from EtOH (40 mL) to give the dialkylated uracil 50 (3.15 g,
1
107 °C; H NMR (DMSO-d6) δ 1.17 (t, J ) 7.1 Hz, 3H, CH3),
4.14 (q, J ) 7.1 Hz, 2H, CH2), 4.60 (s, 2H, NCH2CO2), 5.10 (s,
2H, CH2Ar), 5.86 (d, J ) 7.9 Hz, 1H, COCHdC), 7.63 (dd, J )
7.6, 7.6 Hz, 1H, Ar-H), 7.71 (d, J ) 7.6 Hz, 1H, Ar-H), 7.75 (d,
J ) 7.9 Hz, 1H, COCdCH), 8.11 (s, 1H, Ar-H), 8.13 (d, J )
7.6 Hz, 1H, Ar-H); IR (KBr, cm-1) 1730 (CdO), 1697 (CdO),
1664 (CdO), 1531 (NO2), 1350 (NO2).
E t h yl 3-[(4-Ch lor ob en zot h ia zol-2-yl)m et h yl]-1,2,3,4-
tetr a h yd r o-2,4-d ioxop yr im id in e-1-a ceta te (45c). A solu-
tion of the uracil 44 (0.89 g, 4.49 mmol) in DMF (20 mL) was
added to a suspension of NaH (60 wt % in oil, 0.29 g, 7.25
mmol) in DMF (10 mL) at -10 °C. After stirring for 30 min,
a mixture prepared by the treatment of 4-chloro-2-(chloro-
methyl)benzothiazole (25a ) (0.96 g, 4.40 mmol) with NaBr
(0.55 g, 5.35 mmol) in DMF (20 mL) at room temperature for
30 min was added dropwise to the reaction mixture at -10
°C. The resulting mixture was stirred for an additional 2.5 h
and poured into H2O. The precipitate was filtered and washed
well with H2O and hexane. The crude solid was chromato-
graphed on silica gel (hexane-EtOAc ) 1/1) to give the ester
45c (0.56 g, 34%): mp 151-152.5 °C dec; 1H NMR (DMSO-d6)
δ 1.18 (t, J ) 7.0 Hz, 3H, CH3), 4.15 (d, J ) 7.0 Hz, 2H, OCH2),
4.63 (s, 2H, NCH2CO2), 5.43 (s, 2H, CH2Ar), 5.90 (d, J ) 8.0
Hz, 1H, CHd), 7.43 (dd, J ) 8.0, 8.0 Hz, 1H, Ar-H), 7.61 (d, J
) 8.0 Hz, 1H, Ar-H), 7.80 (d, J ) 8.0 Hz, 1H, CHd), 8.04 (d,
J ) 8.0 Hz, 1H, Ar-H); IR (KBr, cm-1) 1705 (CdO), 1661
(CdO).
1
40%): mp 97-98 °C; H NMR (DMSO-d6) δ 1.16 (t, J ) 7.1
Hz, 3H, CH3), 4.10 (q, J ) 7.1 Hz, 2H, CH2), 4.54 (s, 2H, NCH2-
CO), 5.10 (s, 2H, CH2Ar), 5.88 (d, J ) 7.9 Hz, 1H, COCHdC),
7.68 (dd, J ) 8.3, 7.6 Hz, 1H, Ar-H), 7.77 (d, J ) 7.6 Hz, 1H,
Ar-H), 8.02 (d, J ) 7.9 Hz, 1H, COCdCH), 8.18 (d, J ) 8.3
Hz, 1H, Ar-H), 8.22 (s, 1H, Ar-H); IR (KBr, cm-1) 1757 (CdO),
1716 (CdO), 1670 (CdO), 1533 (NO2), 1348 (NO2).
1,2,3,4-Tetr a h yd r o-1-(3-n itr oben zyl)-2,4-d ioxop yr im i-
d in e-3-a cetic Acid (51). A mixture of the ethyl ester 50 (2.29
g, 6.87 mmol), AcOH (9 mL), and HCl (3 mL) was refluxed for
1.5 h. After being concentrated, the mixture was refluxed
again with AcOH (9 mL) and HCl (3 mL) for 2 h and
condensed. The residual solid was filtered, washed well with
H2O, and recrystallized from EtOH-EtOAc (100-40 mL) to
give the carboxylic acid 51 (1.82 g, 87%): mp 200-201.5 °C;
1H NMR (DMSO-d6) δ 4.46 (s, 2H, NCH2CO), 5.10 (s, 2H, CH2-
Ar), 5.86 (d, J ) 7.9 Hz, 1H, COCHdC), 7.68 (dd, J ) 8.1, 7.7
Hz, 1H, Ar), 7.78 (d, J ) 7.7 Hz, 1H, Ar), 8.00 (d, J ) 7.9 Hz,
1H, COCdCH), 8.18 (d, J ) 8.1 Hz, 1H, Ar), 8.22 (s, 1H, Ar),
12.99 (br s, 1H, OH); IR (KBr, cm-1) 2900 (OH), 1741 (CdO),
1705 (CdO), 1524 (NO2), 1350 (NO2); MS m/z 305 (M+). Anal.
(C13H11N3O6) C, H, N.
P u r ifica tion of En zym es. The procedures employed for
isolation of rat lens AR and rat kidney ALR are reported in
the previous publications.22,23
En zym e Assa y. In vitro AR and ALR inhibition assays
were conducted according to the method reported else-
where.22,23
Neu r a l Netw or k An a lysis. Free-Wilson-type neural
network analysis of the 5-membered ring compounds 1a , 9,
19, 26a , 36, and 40 was carried out with PSDD33 (Perceptron
Simulator for Drug Design) running on a Macintosh Quadra
950 workstation. The inhibitory activity is expressed as five
classes based on the percentage of inhibition at 1 × 10-7 M.
Active classes 1, 2, 3, 4, and 5 indicate less than 20% inhibition,
20-40% inhibition, 40-60% inhibition, 60-80% inhibition,
and more than 80% inhibition, respectively. As the structural
descriptor, the Free-Wilson descriptors for three carbonyl
groups were used. Classification using ALS-type training
patterns were used for calculation.
Molecu la r Mod elin g. An active conformation of zopol-
restat was obtained from PDB (1MAR).34 1a and 47a were
constructed by CAChe (ver. 3.8, CAChe Scientific) using
zopolrestat as a template and minimized by molecular me-
chanics implemented in CAChe. The carboxylic acid moieties
of zopolrestat, 1a , and 47a were superimposed.
E t h yl 3-[(5-Ch lor ob en zot h ia zol-2-yl)m et h yl]-1,2,3,4-
tetr a h yd r o-2,4-d ioxop yr im id in e-1-a ceta te (45d ). A mix-
ture of 44 (1.75 g, 8.83 mmol), 25b (1.96 g, 8.99 mmol), K2CO3
(1.33 g, 9.62 mmol), and NaBr (0.98 g, 9.52 mmol) in DMF
(40 mL) was stirred at 80 °C for 4 h. The mixture was poured
into ice-H2O, and the precipitate was filtered and washed well
with H2O and hexane. The crude solid was recrystallized from
EtOH (60 mL) to give the ester 45d (2.01 g, 67%): mp 138-
1
138.5 °C dec; H NMR (DMSO-d6) δ 1.19 (t, J ) 7.0 Hz, 3H,
CH3), 4.15 (d, J ) 7.0 Hz, 2H, OCH2), 4.62 (s, 2H, NCH2CO2),
5.41 (s, 2H, CH2Ar), 5.91 (d, J ) 7.8 Hz, 1H, CHd), 7.49 (dd,
J ) 8.6, 2.0 Hz, 1H, Ar-H), 7.80 (d, J ) 7.8 Hz, 1H, CHd),
8.05 (d, J ) 2.0 Hz, 1H, Ar-H), 8.11 (d, J ) 8.6 Hz, 1H, Ar-H);
IR (KBr, cm-1) 1751 (CdO), 1728 (CdO), 1685 (CdO).
1,2,3,4-Tetr a h yd r o-3-(3-n itr oben zyl)-2,4-d ioxop yr im i-
d in e-1-a cetic Acid (47a ). A mixture of 45a (1.60 g, 4.80
mmol), AcOH (6 mL), and HCl (2 mL) was refluxed for 2 h.
After concentration, the residue was refluxed again with AcOH
(6 mL) and HCl (2 mL) for 2 h. Condensation of the reaction
mixture gave a crude solid, which was washed well with H2O
and recrystallized from EtOH to give the carboxylic acid 47a
1
(1.39 g, 95%) as white crystals: mp 161-161.5 °C; H NMR
(DMSO-d6) δ 4.50 (s, 2H, NCH2CO2), 5.10 (s, 2H, CH2Ar), 5.83
(d, J ) 7.9 Hz, 1H, COCHdC), 7.62 (dd, J ) 7.9, 7.9 Hz, 1H,
Ar-H), 7.72 (d, J ) 7.9 Hz, 1H, Ar-H), 7.73 (d, J ) 7.9 Hz, 1H,
COCdCH), 8.12 (s, 1H, Ar-H), 8.13 (d, J ) 7.9 Hz, 1H, Ar-H),
13.20 (br s, 1H, COOH); IR (KBr, cm-1) 2980 (OH), 1734
(CdO), 1703 (CdO), 1537 (NO2), 1350 (NO2); MS m/z 305 (M+).
Anal. (C13H11N3O6) C, H, N.
P r ep a r a tion of 1,2,3,4-Tetr a h yd r o-1-(3-n itr oben zyl)-
2,4-d ioxop yr im id in e-3-a cetic Acid (51). 1-(3-Nitr oben -
zyl)u r a cil (49). A suspension of 48 (5.29 g, 47.2 mmol) and
TMSCl (12.0 mL, 94.6 mmol) in hexamethyldisilazane (HMDS)
(100 mL) was refluxed for 2 h. The clear solution was
concentrated under reduced pressure (ca. 5 mmHg). To the
residue was added a solution of the bromide 22 (14.00 g, 47.3
Su p p or tin g In for m a tion Ava ila ble: Melting point, 1H
NMR, IR, and MS data for compounds 23d , 26b-d , 45b, and
47b-d (3 pages). Ordering information is given on any
current masthead page.
n
mmol) and Bu4NI (1.11 g, 3.0 mmol) in CH2Cl2 (100 mL). The
resulting mixture was stirred at room temperature for 4 days
and poured into H2O. The precipitate was filtered, washed
well with H2O and EtOAc, and dried to give the benzyluracil
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