Synthesis and progesterone receptor antagonist activities of 6-aryl benzimidazolones and benzothiazolones

Article abstract of DOI:10.1016/S0960-894X(01)00554-6

Novel 6-aryl benzimidazolones and benzothiazolones were prepared and examined as bioisosteres of the recently reported 6-aryl dihydroquinolines (1) for progesterone receptor (PR) antagonist activities. PR antagonist activities increased when compounds 9c-f possessed a more lipophilic group at position-1 and pendent aryl moiety para to NH moiety. Furthermore, conversion of carbonyl moiety of 9e,f to the thio-carbonyl led to benzoimidazolethiones 15a,b with significantly improved potency and binding affinity.

Full text of DOI:10.1016/S0960-894X(01)00554-6

Bioorganic & Medicinal Chemistry Letters 11 (2001) 2747–2750
Synthesis and Progesterone Receptor Antagonist Activities of
6-Aryl Benzimidazolones and Benzothiazolonesy
Puwen Zhang,a,* Eugene A. Terefenko,a Jay Wrobel,a Zhiming Zhang,b Yuan Zhu,b
Jeffrey Cohen,b Keith B. Marschkec and Dale Maisc
aMedicinal Chemistry I, Chemical Sciences, Wyeth-Ayerst Research, Radnor, PA 19087, USA
bWomen’s Health Research Institute, Wyeth-Ayerst Research, Radnor, PA 19087, USA
cLigand Pharmaceuticals, San Diego, CA 92121, USA
Received 30 May 2001; accepted 6 August 2001
Abstract—Novel 6-aryl benzimidazolones and benzothiazolones were prepared and examined as bioisosteres of the recently repor-
ted 6-aryl dihydroquinolines (1) for progesterone receptor (PR) antagonist activities. PR antagonist activities increased when
compounds 9c–f possessed a more lipophilic group at position-1 and pendent aryl moiety para to NH moiety. Furthermore, con-
version of carbonyl moiety of 9e,f to the thio-carbonyl led to benzoimidazolethiones 15a,b with significantly improved potency and
binding affinity. # 2001 Elsevier Science Ltd. All rights reserved.
The progesterone receptor (PR) is one of the steroid
receptors that constitute a subclass of structurally rela-
ted intracellular gene regulators known as ‘ligand
dependent transcription factors’.1 PR agonists are
known to play an important role in women’s health and
have been used extensively in female contraception and
hormone replacement therapy. On the other hand, the
therapeutic potential of PR antagonists has not yet been
fully realized. A selective PR antagonist is potentially
useful for the treatment of hormone dependent cancers,2
nonmalignant chronic conditions such as uterine
fibroids,3 and endometriosis.4 However, many steroidal
PR antagonists, such as mifepristone, cross-react with
other steroid receptors such as glucocorticoid and
androgen receptors, thus preventing their chronic use.
The therapeutic opportunities presented by PR antago-
nists led us to search for novel, selective, nonsteroidal
PR antagonists. Several classes of the nonsteroidal PR
antagonists,5À8 including 6-aryl dihydroquinolines such
as 1,8b have been reported. In this report, we discuss
the synthesis and SAR of novel PR antagonists 6-aryl
benzimidazolones (5–16) and benzothiazolones (e.g.,
17a,b).
Synthesis
6-(3-Nitrophenyl) benzimidazolone (5) was prepared as
illustrated in Scheme 1. Acylation and nitration of 4-
bromoaniline followed by reduction yielded the acety-
*Corresponding author. Tel.: +1-610-341-3856; fax: +1-610-989-4588; e-mail: zhangp@war.wyeth.com
yPresented in preliminary form at XVI International Symposium on Medicinal Chemistry, Bologna, Italy, 18–22 September 2000.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00554-6

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P. Zhang et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2747–2750
lated o-phenylenediamine 2. Selective methylation of 2
via a reductive alkylation protocol9 afforded the alky-
lated o-phenylenediamine 3. Coupling of 3 with 3-
nitrophenyl boronic acid via a palladium catalyzed
Suzuki reaction and removal of acetyl moiety under an
acidic condition gave the desired o-phenylenediamine 4.
Ring closure of 4 with 1,10-carbonyl diimidazole pro-
vided the target compound 5 in good yield.
Mitsunobu protocol, provided 7 or 11. Removal of the
protecting groups from benzimidazolones 7 and 11
using TFA or isopropylamine gave compounds 8 or 12.
The cross-coupling of 8 or 12 with an appropriate aryl
boronic acid provided 6-aryl benzimidazolones 9a–f or
5-aryl benzimidazolones 13a,b in good yields.11
6-Aryl benzothiazol-2-ones and benzimidazole-2-
thiones 15–1711 were prepared as illustrated in Scheme
4. Briefly, 6-aryl benzimidazole-2-thiones 15a,b and 5-
aryl benzimidazole-2-thione 16 were prepared by heat-
ing a mixture of their corresponding benzimidazolones
and Lawesson’s reagents at reflux in toluene. 6-Aryl
benzothiazol-2-ones 17a,b were prepared from com-
6-Aryl benzimidazolones 9a–f and their 5-substituted
congeners 13a,b were more conveniently prepared from
the selectively protected benzimidazolones 610 and 1010
as depicted in Schemes 2 and 3, respectively. Alkylation
of 6 or 10, using a standard alkylation procedure or a
Scheme 1. Reagents and conditions: (a) Ac2O, reflux; (b) concd HNO3; (c) Fe, AcOH/H2O; (d) CH(OEt)3, reflux, EtOH, NaBH4; (e) ArB(OH)2,
Pd(Ph3P)4, K2CO3, toluene, EtOH/H2O, 85 ꢀC; (f) 1 N HCl, reflux; (g) CDI, THF.
Scheme 2. Reagents and conditions: (a) BnBr, KI, K2CO3, MeCN, 80 ꢀC or MeI, K2CO3, MeCN, rt; (b) R1OH, DEAD, Ph3P, THF, rt; (c) CH2Cl2,
TFA, rt; (d) ArB(OH)2, Pd(Ph3P)4, K2CO3, toluene, EtOH/H2O, 90 ꢀC.
Scheme 3. Reagents and conditions: (a) BnBr, KI, K2CO3, MeCN, 80 ꢀC; (b) isopropylamine, THF, rt; (c) ArB(OH)2, Pd(Ph3P)4, K2CO3, toluene,
EtOH/H2O, 90 ꢀC.

P. Zhang et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2747–2750
2749
quinolines as PR antagonists, we examined various
replacements for the dihydroquinoline core. Benzimida-
zolones and benzothiazolones were among the first
scaffolds examined. The compounds were evaluated for
their ability to inhibit progesterone induced PRE-luci-
ferase activity in CV-1 cells12 and/or inhibit progester-
one stimulated alkaline phosphatase activity in a T47D
human breast carcinoma cell line.13,14 The progesterone
receptor binding affinity of the novel compounds was
measured as previously reported.12,13
As shown in Table 1, 6-aryl 1-substituted benzimidazo-
lones such as 9c–f showed moderate PR antagonist
activity in the PRE-luciferase assay or in the alkaline
phosphatase assay. The potency of these compounds
was markedly affected by the substituent (R1) at posi-
tion-1 as demonstrated by 6-aryl benzimidazolones 5
and 9a–f. As size of substituent R1 increased from
methyl and ethyl to isopropyl and benzyl, the potency
of the compounds improved. These results suggested
that a lipophilic group or steric bulk at the position-1 is
favored.
Scheme 4. Reagents and conditions: (a) Lawesson’s reagent, toluene,
reflux; (b) ArB(OH)2, Pd(Ph3P)4, K2CO3, toluene, EtOH/H2O, 90 ꢀC.
The 1-substituted 5-aryl benzimidazolones 13a,b are at
least 6 times less potent than their 6-aryl congeners
(9e,f) in their PR activity and binding affinity. This
finding indicates that the favored position of pendent
aryl moiety is para to NH group.
mercially available 6-bromo benzothiazol-2-one (14)
and 3-nitro and 3-chloro phenyl boronic acids using
Suzuki coupling conditions.
6-Aryl benzimidazole-2-thiones 15a,b and 5-aryl benzi-
midazole-2-thione 16 were prepared and evaluated in
the T-47D alkaline phosphatase assay.13 From Table 1,
1-benzyl 6-aryl benzimidazole-2-thiones 15a,b showed
potent PR antagonist activity and their potency
Results and Discussion
6-Aryl dihydroquinolines such as 1 (Table 1) were
recently reported as nonsteroidal PR antagonists.8 In an
effort to improve the potency of 6-aryl dihydro-
Table 1. Activity and binding data of 6-aryl benzimidazolones and their analogues as PR antagonists
Compd
R
R1
R2
Y
PRE-luciferase
IC50 (nM)a
Alk. phos.
IC50 (nM)a
PR binding
Ki (nM)a
Mifepristone
1
0.3
42
0.2
41.0
1.1
20.0
5
9a
9b
9c
9d
9e
9f
13a
13b
15a
15b
16
NO2
Cl
Cl
NO2
Cl
Cl
NO2
Cl
NO2
Cl
NO2
Cl
Cl
NO2
Me
Me
Et
i-C3H7
i-C3H7
Bn
Bn
H
H
Bn
H
H
H
H
H
H
H
Bn
B
O
O
O
O
O
O
O
O
1529.0
1370.0
928
1000.0
1000.0
1000.0
29.2
73.1
112.8
62.0
>10,000
>10,000
NDb
106.0
135.7
412.0
257.3
3061.0
O>10,000
ND
ꢁ1000
525.0
521.0
714.0
>10,000
>10,000
17.0
3127.0
>10,000
150.0
n
H
H
Bn
S
S
S
Bn
H
ND
ND
265.0
326.0
10.0
30.0
ND
127.0
332.0
>10,000
460.7
83.8
17a
17b
aExperimental values represent the average of at least duplicate determinations.12À14 The standard deviations for these assays were typically ꢂ20%
of mean or less.
bND, not determined.

2750
P. Zhang et al. / Bioorg. Med. Chem. Lett. 11 (2001) 2747–2750
improved at least 6-fold over their benzimidazol-2-one
congeners (9e,f) in the alkaline phosphatase assay. The
similar binding affinities of 15b and dihydroquinoline 1
indicate that an appropriately substituted benzimida-
zole-2-thione core is a good bioisostere for dihy-
droquinoline core. Similar to the SAR trend observed in
the 6-aryl benzimidazolones, the 5-substituted benzimi-
dazole-2-thione congener 16 did not elicit any sig-
nificant activity as a PR antagonist.
8. (a) Zhi, L.; Tegley, C. M.; Pio, B.; West, S. J.; Marschke,
K. B.; Mais, D. E.; Jones, T. K. Bioorg. Med. Chem. Lett.
2000, 10, 415. (b) Pooley, C. L. F.; Edwards, J. P.; Goldman,
M. E.; Wang, M.; Marschke, K. B.; Crombie, D. L.; Jones, T.
J. Med. Chem. 1998, 41, 3461.
9. Crochet, R. A.; Dewitt, B. C. Synthesis 1974, 55.
10. Meanwell, N. A.; Sit, S. Y.; Gao, J.; Wong, H. S.; Gao,
Q.; Laurent, D. R.; Balasubramanian, N. J. Org. Chem. 1995,
60, 1565.
11. Analytical data of our potent PR antagonists. 6-(3-
Chloro-phenyl)-1-isopropyl-1,3-dihydro-benzoimidazol-2-one (9d).
A white solid: mp 164–165 ꢀC; H NMR (300 MHz, DMSO-
1
Changing the N-alkyl moiety to sulfur atom at position-
1 resulted in 6-aryl benzothiazolones 17a,b with similar
potency and PR binding compared to 6-aryl benzimi-
dazolones 9e,f. The activity of 6-aryl benzothiazolones
17a,b might be attributable to the lipophilic nature of
sulfur atom at position-1. This result was consistent
with the observation, described above, that a lipophilic
group is preferred at position-1.
d6) d 10.9 (s, 1H), 7.7 (bs, 1H), 7.65 (d, 1H, J=7.8 Hz), 7.51 (s,
1H), 7.46 (t, 1H, J=7.9 Hz), 7.38 (m, 1H), 7.29 (d, 1H,
J=8.1 Hz), 7.04 (d, 1H, J=8.1 Hz), 4.65 (m, 1H), 1.48 (d, 6H,
J=6.9 Hz). MS (ES) m/z ([MÀH]À, 285. Anal. calcd for
C16H15ClN2O: C, 67.02; H, 5.27; N, 9.77. Found: C, 67.40; H,
5.40; N, 9.43. 1-Benzyl-6-(3-chloro-phenyl)-1,3-dihydro-benzoi-
midazol-2-one (9e). A white solid: mp 168–169 ꢀC; 1H NMR
(300 MHz, DMSO-d6) d 11.0 (s, 1H), 7.66 (t, 1H, J=2.05 Hz),
7.58–7.5 (m, 1H), 7.45 (t, 2H, J=8.18 Hz), 7.37–7.22 (m, 7 H),
7.08 (d, 1H, J=8.18 Hz), 5.1 (s, 2H); MS (ES) m/z [MÀH]À,
In summary, a number of novel 6-aryl benzimidazo-
lones and benzothiazolones were examined as PR
antagonists. The SAR trends unveiled from this study
indicate that a lipophilic group at position-1 of the
benzimidazolone nuclei and the pendent aryl ring sub-
stituted para to the N–H moiety are critical for the
compounds’ ability to elicit good PR antagonist activ-
ity. Furthermore, replacement of a carbonyl moiety
with a thio-carbonyl group at position-2 significantly
improved potency and binding affinity of 6-aryl benzi-
midazole-2-thiones. These findings proved valuable in the
design of our next generation of more potent PR antago-
nists, which will be the subject of future disclosure.
.
333. Anal. calcd for C20H15ClN2O 0.4 H2O: C, 70.24; H, 4.66;
N, 8.19. Found: C, 70.27; H, 4.56; N, 8.00. 1-Benzyl-6-(3-nitro-
phenyl)-1,3-dihydro-benzoimidazol-2-one (9f). A white solid:
mp 202–203 ꢀC; 1H NMR (300 MHz, DMSO-d6) d 11.2 (s,
1H), 8.38 (t, 1H, J=1.97 Hz), 8.15 (dd, 1H, J=7.83, 1.97 Hz),
8.80 (d, 1H, J=7.83 Hz), 7.72 (t, 1H, J=7.83 Hz), 7.56 (bs,
1H), 7.43–7.22 (m, 6H), 7.13 (d, 1H, J=7.83 Hz), 5.1 (s, 2H);
À
.
MS (ES) m/z [MÀH] , 344. Anal. calcd for C20H15N3O3 0.25
H2O: C, 68.66; H, 4.46; N, 12.01. Found: C, 68.42; H, 4.44; N,
11.77. 1-Benzyl-6-(3-chlorophenyl)-1,3-dihydro-2H-benzimida-
ꢀ
1
zole-2-thione (15a). A yellow solid: mp 211–212 C; H NMR
(300 MHz, DMSO-d6) d 12.99 (s, 1H), 7.70 (t, 1H, J=1.7 Hz),
7.64 (m, 1H), 7.58–7.61 (m, 1H), 7.25–7.54 (m, 9H), 5.59 (s,
2H); MS (ESI) m/z [MÀH]À, 349. Anal. calcd for
C20H15ClN2S: C, 68.46; H, 4.31; N, 7.98. Found: C, 68.07; H,
4.23; N, 7.88. 1-Benzyl-6-(3-nitrophenyl)-1,3-dihydro-2H-benzi-
midazole-2-thione (15b). A yellow solid: mp 244–245 ꢀC; 1H
NMR (300 MHz, DMSO-d6) d 13.08 (s, 1H), 8.43 (s, 1H), 8.20
(dd, 1H, J=8.2, 1.7 Hz), 8.12 (d, 1H, J=7.8 Hz), 7.72–7.78
(m, 2H), 7.62 (d, 1H, J=8.3 Hz), 7.25–7.43 (m, 6H), 5.62 (s,
2H); MS (ESI) m/z [MÀH]À, 360. Anal. calcd for
Acknowledgements
We are grateful for the assistance of the Department of
Analytical Chemistry of Wyeth-Ayerst Research for
elemental analyses, NMR and mass spectroscopy data.
.
C20H15ClN2S 0.2 H2O: C, 65.81; H, 4.25; N, 11.51. Found: C,
65.56; H, 4.11; N, 11.29. 6-(3-Chloro-phenyl)-3H-benzothiazol-
A
white solid: mp 195–196 ꢀC; 1H NMR
2-one (17a).
(300 MHz, DMSO-d6)
References and Notes
d
11.95 (s, 1H), 7.96 (d, 1H,
J=1.17 Hz), 7.7 (t, 1H, J=1.76 Hz), 7.62–7.59 (m, 2H), 7.46
(t, 1H, J=7.65 Hz), 7.4–7.38 (m, 1H), 7.18 (d, 1H,
J=8.24 Hz); MS (EI) m/z (M+), 261. Anal. calcd for
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A
brown solid: mp 276–277 ꢀC; 1H NMR
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8.21–8.08 (m, 3H), 7.78–7.69 (m, 2H), 7.24 (d, 1H,
J=9.23 Hz); MS (ES) m/z [MÀH]À, 271. Anal. calcd for
.
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