2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as potent androgen receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2006.11.047

The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl benzimidaz

Full text of DOI:10.1016/j.bmcl.2006.11.047

Bioorganic & Medicinal Chemistry Letters 17 (2007) 955–958
2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as
potent androgen receptor antagonists
Raymond A. Ng, Jihua Guan, Vernon C. Alford, Jr., James C. Lanter, George F. Allan,
Tifanie Sbriscia, Scott G. Lundeen and Zhihua Sui*
Johnson & Johnson Pharmaceutical Research and Development, LLC, Drug Discovery, 665 Stockton Drive, Exton, PA 19341, USA
Received 26 October 2006; revised 13 November 2006; accepted 14 November 2006
Available online 18 November 2006
Abstract—The synthesis and in vivo SAR of N-benzyl, N-aceto, and N-ethylene ether derivatives of 2-(2,2,2-trifluoroethyl)-5,6-
dichloro-benzimidazole as novel androgen receptor antagonists are described. SAR studies led to the discovery of 4-bromo-benzyl
benzimidazole 17 as a more potent androgen receptor antagonist in the rat prostate (ID50 = 0.13 mg/day), compared with bicalut-
amide (ID50 = 0.23 mg/day).
Ó 2006 Elsevier Ltd. All rights reserved.
Testosterone and dihydrotestosterone mediate protein
anabolism and affect basal metabolism through the
upregulation of the androgen receptor (AR).1 Andro-
gens have also been shown to increase libido in animal
models.2 Although androgens have many beneficial
effects and are important for gender dimorphism3 and
male development, endogenous androgens such as tes-
tosterone stimulate hyperplasia of the prostate and exac-
erbate androgen-dependent prostate cancer.4
N-substituted 2-(2,2,2-trifluoroethyl)-5,6-dichloro-benz-
imidazoles (Chart 2).
Target benzimidazoles were prepared by alkylation of 1
or 2 with substituted benzyl halides and potassium car-
bonate in DMF to afford compounds 6–12a and 16–52.
NC
F
O2N
F3C
O
O
O
S
F3C
N
H
N
H
Prostate cancer is the third leading cause of death for the
US men, behind heart disease and stroke. Early treat-
ment of the disease during the hormone-responsive stage
benefits patients with a 99.8% 5-year survival rate.5
Bicalutamide and flutamide, two non-steroidal antian-
drogens, are currently used for the treatment of andro-
gen-dependent prostate cancer6 (Chart 1).
OH
O
OH
hydroxy-flutamide
bicalutamide
Chart 1.
Cl
Cl
N
N
H
We are interested in selective androgen receptor ligands7
and have recently described the discovery of 5,6-dichlo-
robenzimidazole scaffold as androgen antagonists, of
which 2-(2,2,2-trifluoroethyl) derivatives (1) were more
potent than bicalutamide in both immature and mature
rat models.7f In this paper, we wish to report the results
of our studies on the synthesis and in vivo activity8 of
CF3
1
Cl
Cl
Cl
Cl
Cl
N
N
N
N
N
N
CF3
CF3
CF3
Cl
O
Keywords: Benzimidazoles; Androgen receptor antagonists;
Bicalutamide.
OR
R
R
*
Corresponding author. Tel.: +1 610 458 6985; fax: +1 610 458
8249; e-mail: zsui@prdus.jnj.com
Chart 2.
0960-894X/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2006.11.047

956
R. A. Ng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 955–958
Cl
Cl
that possessed good efficacy (6, 79% prostrate weight
N
N
a
b
1
inhibition). Although N-benzylation of 2 diminished
activity, the N-benzyl derivative of the ketone hydrate
5 (compound 8) showed good activity. Alkylation with
CH2-2-pyridinyl showed good activity as well (9, 10).
Interestingly, neither N-methyl nor N-ethyl derivative
of compound 13 showed efficacy, indicating that the effi-
cacy of the benzyl analogs was not due to the potential
metabolic cleavage of the benzyl moiety since methyl
and ethyl are more prone to oxidative cleavage by
P450s.
CF3
EtO2C
Cl
Cl
Cl
Cl
N
N
c
N
N
CF3
CF3
OH
OR
68-71
67
Scheme 1. Synthesis of 66–70. Reagents and conditions: (a)
BrCH2CO2Et, NaH, DMF (62%); (b) LiBH4, THF, EtOH (63%); (c)
ArOH, DBAD, PPh3, PhMe (65–74%).
The finding that the N-substituted benzimidazoles are
efficacious is quite significant. It further demonstrated
the divergent SARs between our series and bicaluta-
mide/flutamide. To achieve our goal to identify
androgen receptor antagonists that have comparable
efficacy in inhibiting prostate growth to that of
bicalutamide, we decided to further explore the sub-
stituent effect on the phenyl ring of the benzyl group
on the nitrogen of the benzimidazole. A variety of
substitutions around the aromatic ring was next
explored.
Compounds 53–66 were similarly synthesized from the
reaction of 1 with a-halo ketones in the presence of sodi-
um hydride in DMF (Scheme 1).
Previously, we reported the discovery of compounds 1,
2, and 5, which possess high (90–96%) prostate weight
inhibition in both immature and mature rats.7f Replace-
ment of the hydroxyl in 2 with a fluorine also gave a po-
tent compound (3) (81% prostrate weight inhibition at
1 mg/day). Compound 3 was tested in a dose-dependent
manner and the ID50 was 0.15 mg/d that is the same as
compound 2. However, toxicity was observed at the
3 mg/day dose (Table 1). Pentafluoro ethyl derivative 4
was exceedingly toxic and could not be tested. Having
completed the SAR studies on the side-chain modifica-
tions, we turned our attention to the effect of N-alkyl-
ation on potency in our series. Based on the literature
evidence for bicalutamide and flutamide, N-alkylation
usually leads to inactive or less-active analogs. Much
to our delight, N-benzylation of 1 provided a compound
Halogens such as Br, Cl, or F were tolerated at the 2- or
4-position, but not at the 3-position. Pentafluoro benzyl
derivative 24 abolished activity. Electron-donating
groups such as methyl or methoxy substituents generally
reduced activity. Trifluoromethyl substitution is well tol-
erated, with the most active (86% prostrate weight inhi-
bition) in the 2-position. Di-trifluoromethyl analog 30,
however, is inactive. Electron-withdrawing groups such
as nitro or nitrile were best at the 2-position. Interesting-
ly, a phenyl group is also well tolerated at the 2-position
(49). Pyridinyl derivatives were also prepared with the
nitrogen at the 2-position, showing the best activity
(50, 89% prostrate weight inhibition). Selected com-
pounds were tested in a dose-dependent manner, which
gives a more accurate assessment of activity. To our
delight, most compounds tested showed comparable
efficacy to that of the benchmark, bicalutamide. Unsub-
stituted benzyl derivative 6 had an ID50 of 0.37 mg/day,
compared to an ID50 of 0.23 mg/day for bicalutamide.
4-Bromobenzyl analog 17 (ID50 = 0.13 mg/day) is the
most active among the halogen-substituted analogs.
Based on single dose (2 mg/day) testing, pyridin-2-yl
analog 50 showed an 89% prostate weight inhibition,
and had an ID50 of 0.40 mg/day (Table 2).
Table 1.
Cl
Cl
X
N
Y
N
R
CF3
Compound
R
X
Y
H
PW inhibition %a
1
H
H
90
2
H
H
OH
F
96
3
H
H
81b
Toxic
94
4
H
F
F
5
H
OH
H
OH
H
6
Bn
Bn
Bn
79
49
7
H
OH
OH
H
Next, we extended the side chain off the benzimidazole
nitrogen by inserting a carbonyl group between the
nitrogen and the R-group (Table 3). Moderate activity
was observed when R-group is simple alkyl such as ethyl
ketone 53. Although unsubstituted acetophenone analog
55 had low activity (38% prostrate weight inhibition),
substitution with electron-withdrawing groups such as
nitro or fluorine at the 4-position restored activity (67–
71% prostrate weight inhibition). An electron-donating
group such as a methoxy substituent abolished activity.
Pyridin-2-yl analog 63 showed better activity than the
pyridin-3-yl analog 64. Thiophen-2-yl analog 65 showed
moderate activity. The most active compound in the
N-aceto series, pyridin-2-yl analog 63 was tested in a
8
OH
H
85
89
9
10
CH2–2-pyr
CH2–2-pyr
CH2CN
CH2OMe
H
H
OH
OH
OH
OH
OH
OH
84
54
11
12
Me
Me
Me
Me
Me
88
74
13
14
Me
Et
na
na
70
15
Bicalutamide
a Prostate weight inhibition
immature Sprague–Dawley rats. Dose = 2 mg/day. Normalized to
% in testosterone-treated castrated
control group administered with vehicle. (N = 3/group) (na = not
active).
b Dose = 1 mg/day.

R. A. Ng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 955–958
Table 3. Effect of N-aceto substitution
957
Table 2. Effect of benzyl substitution
Cl
N
Cl
Cl
CF3
CF3
N
N
N
Cl
O
R
R
Compound
R
PW inhibition %a
Compound
R
PW inhibition %a
ID50
s
53
54
Et
Ph
64
38
14
71
27
33
67
10
na
na
76
na
43
70
6
16
H
79
84
75
90
35
77
77
55
80
19
73
31
86
74
75
13
51
na
51
26
35
13
32
74
46
81
49
61
28
56
38
74
70
68
79
89
80
42
70
0.37
0.38
0.13
0.26
55
56
Ph, 3-NO2
Ph, 4-NO2
Ph, 4-Br
2-Br
4-Br
2-Cl
3-Cl
4-Cl
2-F
3-F
4-F
17
18
57
58
Ph, 4-Cl
Ph, 4-F
19
20
59
60
0.28
0.82
Ph, 2-OMe
Ph, 3-OMe
21
22
61
62
Ph, 2-OMe, 4-OMe
Pyridin-2-yl
Pyridin-3-yl
23
24
0.19
0.40
63
64
2,3,4,5,6-F
2-CH3
3-CH3
25
26
65
Bicalutamide
Thiophen-2-yl
27
28
2-CF3
3-CF3
4-CF3
a Prostate weight inhibition
immature Sprague–Dawley rats. Dose = 2 mg/day. Normalized to
control group administered with vehicle. (N = 3/group).
%
in testosterone-treated castrated
29
30
2-CF3, 4-CF3
2-OCH3
3-OCH3
4-OCH3
3-OCF3
4-OCF3
4-SCF3
31
32
33
34
Table 4. Effect of ethylene aryl ether substitution
35
36
Cl
Cl
CF3
N
N
37
38
4-SO2Me
2-CH2SO2Ph
4-OCH2Ph
2-NO2
39
40
R
0.95
41
42
3-NO2
4-NO2
4-OH
Compound
R
PW inhibition %a
43
44
66
67
OH
54
48
22
40
86
70
4-CO2Et
4-CO2H
2-CN
OPh(4-Cl)
OPh(3-F)
OPh(4-F)
OPh(4-CN)
45
46
68
69
47
48
3-CN
4-CN
2-Ph
70
Bicalutamide
49
50
0.55
0.40
a Prostate weight inhibition
immature Sprague–Dawley rats. Dose = 2 mg/day. Normalized to
control group administered with vehicle. (N = 3/group).
% in testosterone-treated castrated
Pyridin-2-yl
Pyridin-3-yl
Pyridin-4-yl
51
52
Bicalutamide
0.23
a Prostate weight inhibition
immature Sprague–Dawley rats. Dose = 2 mg/day. Normalized to
control group administered with vehicle. (N = 3/group).
% in testosterone-treated castrated
uct. Switching from DEAD to di-tert-butylazodicarb-
oxylate (DBAD) alleviated this problem.
Ethylene alcohol 66 showed moderate activity (54%
prostrate weight inhibition). 4-Fluoro-phenyl ether 69
was more active than the 3-fluoro-phenyl analog 68. In
general, extension of the side chain with an ethylene aryl
ether did not yield very active compounds, with the
exception of 4-cyano-phenyl ether 70 (86% prostrate
weight inhibition).
dose-dependent manner and the ID50 was 0.47 mg/day
(Table 4).
Since methylene methyl ether 11 showed good activity
(90% prostrate weight inhibition), extension of the side
chain to ethylene ether derivatives was briefly explored.
The preparation of compounds 67–71 begins with N-al-
kylation of 1 with ethyl bromoacetate and sodium hy-
dride in DMF. Reduction of the ethyl ester was
carried out with lithium borohydride. Initial attempts
to carry out a Mitsunobu displacement using diethyla-
zodicarboxylate (DEAD) were plagued with difficult
separation of the product from the hydrazide by-prod-
In summary, N-alkyl substitution, such as benzyl, aceto,
and ethylene ether side chains was explored. N-Aceto
and ethylene aryl ether derivatives generally did not im-
prove prostate antagonist activity. N-Benzylation of our
initial lead, 1, was well tolerated, particularly with halo-
gen (Cl, Br, F) substitution at the 2- or 4 position. 4-Bro-

958
R. A. Ng et al. / Bioorg. Med. Chem. Lett. 17 (2007) 955–958
T.; Mukherjee, A.; Zhu, Z.; Kirkovsky, L.; Miller, D. D.
Biophys. Res. Commun. 1998, 244, 1.
mobenzyl analog, 17, has an ID50 of 0.13 mg/d, which is
more potent than bicalutamide. The superior in vivo effi-
cacy of the novel benzimidazoles in reducing prostate
weight provided us with an excellent opportunity to select
a development candidate. Further biological evaluations
of the most potent compounds are underway.
7. (a) Zhang, X.; Li, X.; Allan, G.; Musto, A.; Lundeen, S. G.;
Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16, 3233; (b) Zhang,
X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.; Lundeen,
S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16, 5763; (c)
Zhang, X.; Li, X.; Allan, G. F.; Sbriscia, T.; Linton, O.;
Lundeen, S.G.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, in
press, doi:10.1016/j.bmcl.2006.10.035; (d) Lanter, J.; Fior-
deliso, J. J.; Jiang, W.; Allan, G. F.; Lai, M.; Hahn, D.;
Lundeen, S. G.; Sui, Z. Bioorg. Med. Chem. Lett. 2006, 16,
5646; (e) Lanter, J.; Fiordeliso, J. J.; Jiang, W.; Allan, G.
F.; Lai, M.; Hahn, D.; Lundeen, S. G.; Sui, Z. Bioorg. Med.
Chem. Lett. 2006, in press. doi:10.1016/j.bmcl.2006.09.086;
(f) Ng, R. A.; Guan, J.; Alford, Jr., V.C.; Lanter, J.; Allan,
G.; Sbriscia, T.; Linton, O.; Lundeen, S.; Sui, Z. Bioorg.
Med. Chem Lett. 2006, in press, doi:10.1016/
j.bmcl.2006.10.071.
8. Direct in vivo screening was used due to lack of
correlation between in vitro and in vivo assays in AR
areas. This was also observed by other laboratories. See:
(a) Yin, D.; He, Y.; Hong, S. S.; Marhefka, C.; Stourman,
N.; Kirkovsky, L.; Miller, D. D.; Dalton, J. T. Mol.
Pharmacol. 2003, 63, 211; (b) Yin, D.; Gao, W.; Kearbey,
J. D.; Xu, H.; Chung, K.; He, Y.; Marhefka, C. A.;
Veverka, K. A.; Miller, D. D.; Dalton, J. T. J. Pharmacol.
Exp. Ther. 2003, 304, 1334.
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