2210
J. T. Link et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2209–2212
Although inefficient, an alternate route resulted in the
preparation of sulfonamide 3 (Scheme 2). Aniline 10 was
alkylated with benzyl bromide and Suzuki coupling with
3H-benzo[c][1,2]oxaborol-1-ol 12 yielded alcohol 13.
Hydrogenation removed one benzyl group, reduced the
nitro group, and provided alcohol 14. Conversion of the
alcohol to the mesylate followed by spontaneous cycli-
zation provided the tricyclic sulfonamide 3. Tricyclic
sulfonamide 3 was unstable and was stored prior to
assay at low temperature ()78 ꢁC). Room temperature
storage, either neat or in solution, lead to numerous
uncharacterized decomposition products.
N
N
Y
X
O
S
O
O
S
O
N
N
H
H
5
3
Figure 2. Proposed cyclization.
The synthesis of a cyclization precursor 9 (X ¼ Br)
began with 2-methyl-3-nitroaniline 6, which was con-
verted to aniline 7 by sulfonylation followed by nitro
group reduction (Scheme 1). Reductive amination with
2-bromobenzaldehyde followed by a second reductive
amination with benzaldehyde provided bromide 9.
Attempted cyclization under precedented conditions
lead to reduction (rather than ring closure) and deliv-
ered dibenzylanilino-sulfonamide 4.7 The failure of this
reaction may be due to the instability of the desired
product 3, however the testing of sulfonamide 4 revealed
it to be a potent GR modulator. Furthermore, it has
reasonable properties for a lead structure including
no rule of five violations,8 low molecular weight
(MW ¼ 380.5), c log P ¼ 4.5, and a polar surface area
consistent with membrane permeability.9
A more efficient preparation of the dibenzylanilines
related to 4 begins with 2-methyl-3-nitroaniline 15
(Scheme 3). Reductive amination with an aldehyde, like
16, provided monoalkyl anilines like 17 in high yield.
Alkylation with a reactive alkyl halide, for example, a
benzyl halide, then yielded nitroarenes such as 18.
Reduction and sulfonylation provided dialkyl sulfon-
amides like 19.
Compounds were assayed in binding assays against a
panel of human nuclear hormone receptors monitoring
the displacement of radiolabeled dexamethasone.9
Functional activity was measured in a reporter cell line
(GRAF) genetically engineered to express h-GR, the
glucocorticoid response element, and a reporter gene
encoding a secreted form of alkaline phosphatase.10
Br
R1
N-(3-Dibenzylamino-2-methyl-phenyl)-methanesulfon-
amide 4 is a potent binder of the human glucocorticoid
receptor (h-GR) with an IC50 ¼ 28 nM (Table 1). It has
good selectivity for this receptor over the human pro-
gesterone receptor (h-PR) (>100·), mineralocorticoid
receptor (h-MR>10·), androgen receptor (h-AR>6·),
estrogen receptor (h-ERa>100·, and thyroid-hormone
receptor (h-TRa and h-TRb > 100ꢀ). Evaluation of
sulfonamide 4 in the GRAF assay indicated it is an
antagonist with moderate potency (IC50 ¼ 250 nM).
N-(5-Benzyl-5,6-dihydro-phenanthridin-3-yl)-methane-
sulfonamide 3 showed excellent h-GR binding potency
(IC50 ¼ 20 nM). However, its instability precluded fur-
ther potency determinations and analog synthesis, so we
focused our attention on sulfonamide 4. Ultimately we
were able to optimize the in vitro properties of the series
as shown by dihalide 19.
HN
c
d
O
S
O
R2
N
H
6 R1 = NO2, R2 = NH2
7 R1 = NH2, R2 = NHSO2Me
a, b
8
e
N
N
Br
O O
S
O
S
O
N
N
H
H
4
9
Scheme 1. (a) MsCl, pyr, rt, 2 h; (b) H2 (1 atm), 10% Pd on carbon,
EtOAc, rt, 2 h, 84% (two steps); (c) 2-bromobenzaldehyde, AcOH,
DCE, rt, 4 h; Na(OAc)3BH, 12 h, 64%; (d) benzaldehyde, AcOH,
DCE, rt, 4 h; Na(OAc)3BH, 12 h, 14%; (e) Pd(OAc)2, P(o-tol)3,
Cs2CO3, DMA, 85 ꢁC, 12 h, 22%.
SAR studies of dialkyl anilines related to sulfonamide 4
indicated aryl groups, particularly benzyl groups, are
O
B
NH2
12
OH
OH
Br
a
d
b
c
N
N
N
HN
Br
NO2
O
O
S
N
NO2
NO2
NH2
HO
H
10
11
13
14
3
Scheme 2. (a) BnBr, i-Pr2Net, DMF, 120 ꢁC, 12 h, 75%; (b) Pd(PPh3)4, 12, Na2CO3, EtOH, tol, 80 ꢁC, 7 h, 95%; (c) H2, 10% Pd/C, EtOAc, rt, 4 h, 9%;
(d) MsCl, pyr, rt, 12 h, 13%.