Benzimidazole derivatives as novel nonpeptide luteinizing hormone-releasing hormone (LHRH) antagonists. Part 2: Benzimidazole-5-sulfonamides

Article abstract of DOI:10.1016/j.bmcl.2004.10.090

The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC₅₀: 4.2 nM).

Full text of DOI:10.1016/j.bmcl.2004.10.090

Bioorganic & Medicinal Chemistry Letters 15 (2005) 805–807
Benzimidazole derivatives as novel nonpeptide luteinizing
hormone-releasing hormone (LHRH) antagonists. Part 2:
Benzimidazole-5-sulfonamides
Yingfu Li,a Mikayo Kataoka,a Miyuki Tatsuta,a Kayo Yasoshima,a
Takeshi Yura,a Klaus Urbahns,a Atsushi Kiba,b Noriyuki Yamamoto,b
Jang B. Guptab and Kentaro Hashimotoa,*
aDepartment of Chemistry, Research Center Kyoto, Bayer Yakuhin, Ltd, Kizu, Soraku, Kyoto 619-0216, Japan
bDepartment of Biology, Research Center Kyoto, Bayer Yakuhin, Ltd, Kizu, Soraku, Kyoto 619-0216, Japan
Received 3 September 2004; revised 28 October 2004; accepted 30 October 2004
Available online 21 November 2004
Abstract—The 2-cyclopropyl substituted benzimidazole 2 has been used as a starting point for further optimization of an LHRH
antagonist series. SAR studies revealed that a tert-butyl urea fragment connected through a simple carbon chain would improve
activity. Further modification of the benzylsulfonamide moiety led to the discovery of 23 (IC50: 4.2nM).
Ó 2004 Elsevier Ltd. All rights reserved.
1. Introduction
F
N
N
Nonpeptidic luteinizing hormone-releasing hormone
(LHRH) antagonists are interesting novel therapeutics
for hormone dependent disease states such as endome-
triosis, prostate cancer and benign prostate hyperpla-
sia.1 We previously reported the discovery of a new
class of benzimidazoles as functional LHRH antagonists
with submicromolar potency on both human and rat
receptors (1, IC50 = 0.12lM).2
H
N
S
S
O
O
N
1
IC50=0.14 µM (rat-lhrh, Ca2+)
0.12 µM (human-lhrh, Ca2+)
In this study, we would wish to report a related series of
compounds, exemplified by 2, that allowed for the dis-
covery of single digit nanomolar LHRH antagonists
(Fig. 1).
F
N
H
N
N
S
O
O
2
IC50=1.6 µM (rat-lhrh, Ca2+)
1.9 µM (human-lhrh, Ca2+)
2. Chemistry
The central intermediate 32 (Scheme 1) was coupled
to Boc-protected 3-amino propionic acid yielding the
Figure 1. Functional activity of C-linked compound 2.
corresponding amide 4, which was subjected to acid-
induced cyclization to furnish the benzimidazoles 5–8.
After deprotection, 8 was converted to tert-butylurea
10 (R1 = 4-F) using tert-butyl isocyanate.3 Similarly,
the alkyl or aryl urea derivatives 13–25 were obtained.
Compound 8 was coupled with 3,3-dimethyl butyric
Keywords: LHRH antagonist; Small molecule.
*
Corresponding author at present address: Bayer HealthCare AG.,
Pharma Research Center, D-42096 Wuppertal, FRG. Tel.: +49
(0)202 36 8131; fax: +49 (0)202 36 4624; e-mail: kentaro.
hashimoto@bayerhealthcare.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.10.090

806
R1
Y. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 805–807
Table 1. Functional activity of compounds 5–10 and 12–18
R1
NHBn
NH2
NHBn
H
N
H
N
a
S
S
NH
R2
1
3
O
O
F
O
O
N
N
O
H
N
X
4
3
R
S
O
O
b
R1
N
N
Cmpd
X
R
IC50 (lM)
H
N
S
R2
r-lhrh
h-lhrh
O
O
5
6
7
CH2
CHMe
CH2
–CH2CH3
–CH3
–CH2NH2
>10
0.69
>10
>10
0.39
>10
8 : R1=4-F, R2=(CH2)2NH-Boc
c
9 : R1=4-F, R2=(CH2)2NH-COCH2(t-Bu)
10 : R1=4-F, R2=(CH2)2NH-CONH(t-Bu)
11 : R1=4-F, R2=(CH2)3CO2Me
d
H
N
O
8
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
0.54
0.74
2.6
O
O
O
O
O
O
O
e
12 : R1=4-F, R2=(CH2)3CONt-Bu
H
N
9
0.84
Scheme 1. Reagents and conditions: (a) RCO2H, WSCI, HOBt,
triethylamine, THF, rt, 90%; (b) compound 8, HOAc, 90°C, 70%,
compound 11, HOAc, 90°C, 41%; (c) 4N HCl, dioxane, rt, 99%, then,
tert-butylacetyl chloride, triethylamine, CH2Cl2, rt, 38%; (d) 4N HCl,
dioxane, rt, 99%, then isocyanic acid tert-butylester, triethylamine,
CH2Cl2, rt, 56%; (e) 1N LiOH, THF, rt, 37%, then, tert-butylamine,
WSCI, HOBt, triethylamine, THF, rt, 71%.
H
N
H
N
10
12
13
14
15
16
17
0.012
0.23
0.020
0.40
0.15
0.69
0.11
0.18
0.066
H
N
H
N
H
N
0.079
0.38
acid furnishing 9. Diaminosulfonamide 3 was coupled
and cyclized with glutaric acid monomethyl ester to give
benzimidazole 11. Hydrolysis and renewed amide for-
mation furnished compound 12.
H
N
H
N
H
N
H
N
0.030
0.083
0.053
3. Results and discussion
H
N
H
N
All synthesized compounds were evaluated as functional
antagonists on cells transfected with rat and human
receptors, respectively (Tables 1 and 2).2 All IC50 values
indicate the mean of two experiments each run in tripli-
cate. The geometry of the propyl substituent appeared
to directly influence the biological activity of 2. Whereas
the n-propyl compound 5 was inactive, the isopropyl
derivative showed a 5-fold improvement in potency
(6). Interestingly, despite the inactivity of 5 and the pri-
mary amine 7, the Boc-protected amine 8 retained acti-
vity, prompting us to investigate the SAR of the
carbamate even further. Whereas the tert-butyl acet-
amide 9 showed similar potency, the isomeric pivaloate
12 was less potent. The corresponding tert-butyl urea 10
was the first example of a double-digit nanomolar com-
pound. Taken together, the SAR observed among 8–10
and 12 clearly indicates the importance of two hydro-
gen-bond donors for optimal interaction with the
LHRH receptor. Similar ureas with bulky substitutents
have been described by other groups.4 Substituting the
tert-butyl group with other alkyl substitutents such as
isopropyl (13), ethyl (14) or neopentyl (15) reduced
activity. Similarly, chain prolongation (16) diminished
potency, suggesting the importance of the correct spatial
orientation of the bulky aliphatic group. Interestingly
however, this group can be replaced by a phenyl substit-
uent, and the ortho-substituted derivatives 17/18 repre-
sent two further examples of double digit nanomolar
LHRH antagonists.
O
F
H
N
H
N
O
O
Cl
H
N
H
N
18
CH2
0.050
0.083
This discovery prompted us to re-investigate the
SAR of the sulfonamide side chain within the
tert-butyl urea class (Table 2). Similar to the SAR
described in our previous communication, electron-
withdrawing substituents in para-position were pre-
ferred. ortho-(20, 24), meta-(21, 22) or electron
donating substituents (25) clearly reduced potency.
In contrast to trends observed in our earlier series
however, merely exchanging 10Õs F-atom by a chloro
substituent led to 23, which was the first single-
digit nanomolar LHRH inhibitor within the series,
improving potency of our initial lead by three orders
of magnitude.
In summary, we have identified a novel series of nonpep-
tide LHRH antagonists that could be optimized towards

Y. Li et al. / Bioorg. Med. Chem. Lett. 15 (2005) 805–807
807
Table 2. Functional activity of compounds 19–25
References and notes
1. Goulet, M. T. In Annual Reports in Medicinal Chemisty;
Bristol, J. A., Ed.; Academic: New York, 1995; Vol. 30, pp
169–178.
2. Hashimoto, K.; Tatsuta, M.; Kataoka, M.; Yasoshima, K.;
Shogase, Y.; Shimazaki, M.; Yura, T.; Li, Y.; Yamamoto,
N.; Gupta, J. B.; Urbahns, K. Bioorg. Med. Chem. Lett.
submitted for publication.
N
H
N
R1
H
N
N
S
H
N
O
O
O
Cmpd
R1-ArCH2
IC50 (lM)
3. Fonseca, T.; Gigante, B.; Gilchrist, T. L. Tetrahedron 2001,
57, 1793. Typical procedure to prepare 2-[2-(3-tert-butyl-
r-lhrh
0.31
h-lhrh
ureido)-ethyl]-1H-benzoimidazole-5-sulfonamide
deriva-
19
20
0.49
tives (synthesis of compound 10): A solution of {2-[2-
benzylamino-5-(4-fluoro-benzylsulfamoyl)-phenylcarbamo-
yl]-ethyl}-tert-butylcarbamate 4 (505mg, 0.910mmol) in
10mL of acetic acid was heated at 90°C for 3h. After
cooling to room temperature, the mixture was concentrated
in vacuo, to give crude compound 8. The crude mixture was
diluted in 10mL of CH2Cl2 and treated with 4N HCl/1,4-
dioxane to give a white precipitate as the deprotected
benzimidazole HCl salt. After filtering, and drying under
reduced pressure, the HCl salt (100mg, 0.210mmol) was
suspended in 1.5mL of CH2Cl2. To the suspension was
added triethylamine (0.0590mL) and tert-butyl isocyanate
(62.6mg, 0.630mmol) and the mixture was stirred at room
temperature for 2h. The mixture was diluted with CH2Cl2
and the organic layer was washed with water and brine.
After removing the solvent, the residue was triturated with
ether to give the desired 1-benzyl-2-[2-(3-tert-butyl-ureido)-
ethyl]-1H-benzoimidazole-5-(4-fluorobenzyl)sulfonamide10
(70.7mg, 63% yield for two steps) as a white precipitate. 1H
NMR (500MHz, DMSO-d6) d 1.19 (9H, s), 2.95–2.98 (2H,
t, J = 6.6Hz), 3.44–3.47 (2H, t, J = 6.9Hz), 3.93–3.94 (1H,
d, J = 6.0Hz), 5.56 (2H, s), 5.79 (1H, s), 5.83–5.85 (1H, t,
J = 6.0Hz), 7.04–7.07 (2H, t, J = 9.14Hz), 7.11–7.13 (2H, d,
J = 6.9Hz), 7.24–7.35 (5H, m), 7.61–7.67 (2H, dd, J = 8.5
Hz, 21Hz), 8.03–8.05 (2H, m).
F
0.45
0.11
0.75
0.17
F
F
21
F
CF3
22
23
24
25
0.051
0.0039
0.014
0.20
0.057
0.0042
0.022
0.34
Cl
Cl
Cl
MeO
the single-digit nanomolar range. The compounds exhi-
bit a tert-butyl urea fragment as a prerequisite, indispen-
sable for high potency.
4. Sasaki, S.; Cho, N.; Nara, Y.; Harada, M.; Endo, S.;
Suzuki, N.; Furuya, S.; Fujino, M. J. Med. Chem. 2003, 46,
113.