Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists

Article abstract of DOI:10.1016/j.bmcl.2013.05.077

Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure-activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrat

Full text of DOI:10.1016/j.bmcl.2013.05.077

Bioorganic & Medicinal Chemistry Letters 23 (2013) 4388–4392
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Discovery of novel oxazolidinedione derivatives as potent
and selective mineralocorticoid receptor antagonists
a,
a
a
a
b
Christine Yang a, , Hong C. Shen , Zhicai Wu , Hong D. Chu , Jason M. Cox , Jaume Balsells ,
Alejandro Crespo c, Patricia Brown e, Beata Zamlynny e, Judyann Wiltsie d, Joseph Clemas d, Jack Gibson d,
Lisa Contino d, JeanMarie Lisnock d, Gaochao Zhou d, Margarita Garcia-Calvo d, Tom Bateman f, Ling Xu f,
Xinchun Tong f, Martin Crook e, Peter Sinclair a
⇑
⇑
a Department of Discovery Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
b Department of Process Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
c Department of Chemistry Modeling & Information, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
d Department of In Vitro Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
e Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
f Department of Drug Metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR)
antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and
microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hor-
mone receptor selectivity, and acceptable rat pharmacokinetics.
Received 21 March 2013
Revised 20 May 2013
Accepted 21 May 2013
Available online 4 June 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Mineralocorticoid receptor antagonist
Hypertension
The mineralocorticoid receptor (MR) is a nuclear hormone
receptor that regulates the expression of multiple genes involved
in cardiovascular disease and electrolyte homeostasis. MR is acti-
vated by aldosterone, which increases blood pressure through its
effects on natriuresis, with potential additional effects on the brain,
heart and vasculature.1 In visceral tissues, such as the kidney and
the gut, MR regulates sodium retention, potassium excretion and
water balance in response to aldosterone. Resistant hypertensive
patients frequently suffer from increased aldosterone levels, often
termed as ‘aldosterone breakthrough’, as a result of increases in
serum potassium or residual subtype I receptor activity of angio-
tensin II (AT1R).2 Hyperaldosteronism and aldosterone break-
through typically cause elevated blood pressure and congestive
heart failure (CHF), as well as enhanced MR activity. Hence, direct
antagonism of MR has a strong biological rational for treating
hypertension and CHF.
affinity.3 Due to the distinct functions of each nuclear hormone
receptor, it is imperative to develop selective MR antagonists to
minimize potential side effects as a result of interaction with other
nuclear hormone receptors.
Despite significant therapeutic advances in the treatment of
hypertension and heart failure, the current standard of care is sub-
optimal and there is a clear unmet medical need for additional
pharmacological interventions. Eplerenone and spironolactone
are two MR antagonists that are efficacious in treating cardiovas-
cular disease, particularly hypertension and heart failure.4 More-
over, multiple studies have shown that treatment with
spironolactone or eplerenone significantly lower systolic blood
pressure in hypertensive patients.5 In spite of their therapeutic
utility, there remain issues to overcome for both eplerenone and
spironolactone. For example, spironolactone elicits unwanted side
effects such as gynecomastia and menstrual irregularities due to its
AR and PR activity.6 Conversely, eplerenone is more selective
against other nuclear hormone receptors, but it lacks good MR po-
tency relative to spironolactone and requires b.i.d. dosing.7 As
such, we have embarked on a discovery program to identify effica-
cious and safe MR antagonists that possess the efficacy of spirono-
lactone and selectivity of eplerenone. Herein we report preliminary
results on the discovery of oxazolidinedione derivatives as a class
of novel, non-steroidal, and potent MR antagonists.8
Other receptors in the same receptor subclass are androgen
receptor (AR), glucocorticoid receptor (GR), estrogen receptor
(ER), and the progesterone receptor (PR). It should be noted that
both cortisol and corticosterone bind MR, and aldosterone is gener-
ally considered as the major endogenous ligand for MR with high
⇑
Corresponding authors. Tel.: +1 908 740 6593.
E-mail address: christine_yang@merck.com (C. Yang).
0960-894X/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2013.05.077

C. Yang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4388–4392
4389
Table 1
An in-house high-throughput screening identified compound
1a with modest MR activity in the human MR NH Pro assay
(IC50 = 6 M). This assay is a commercially available PathHunter™
In vitro SAR of R1 moiety in the human MR NH Pro assaya
l
protein–protein interaction assay that measures the ability of com-
pounds to antagonize full-length human MR binding to a coactiva-
tor peptide.9 In this assay, the average IC50 for spironolactone and
eplerenone is 11 nM and 244 nM, respectively. Hit 1a possesses at
least four distinct subgroups as colored in Figure 1. The optimiza-
tion strategy is to establish SAR with each of the four subgroups,
namely, R1–R3 and the oxazolidinedione core, as summarized in
Tables 1–4.
Prior to the optimization of R1 region in 1a (Table 1), the influ-
ence of the absolute configuration of 1a on MR antagonism was
found to be critical with the enantiomer of 1a being essentially
inactive (IC50 >40 lM). In addition, 3-OMe substitution of the ben-
zyl group (1b) improved the MR activity by sixfold compared to 1a.
The next discovery was that the methyl group present in the R3 re-
gion markedly enhanced the activity against MR (1c vs 1b and 1g
vs 1f). With this embedded methyl group in the R3 region, various
substitution of the benzyl group were explored (1h–1o are shown
as a subset), however, none exhibited superior activity to 1g. On
the other hand, the presence of the methyl group in the R1 region
of 1j and 1k did not present advantages over compound 1i in terms
of activity. Fused bicyclic aryl or heteroaryl methyl amine-derived
amides, in general, led to reduced MR activity (1p, 1jj, 1kk and 1ll),
except in the case of 1mm. The incorporation of monocyclic hete-
roaryls one or two carbons away from the amide group, as shown
by 1dd–1ii and 1nn–1qq, respectively, resulted in poor MR activ-
ity. The size variation of cycloalkyl groups adjacent to amide gave
MR activities within a few-fold of fluctuation (1x–1z). The addition
of a terminal phenyl group to cyclobutyl or cyclopropyl improved
potency as shown by 1aa–1cc. Lastly, aniline analogs (1q–1w) pro-
vided modest to good potency.
Table 2 summarizes the efforts to optimize the R2 region. The
removal of the benzyl group in this region resulted in a complete
loss of activity against MR (2a vs 1a). The binding pocket of R2 ap-
peared to be non-polar as hetereoaryl analogs (2b–2d, 2l and 2m)
led to significant loss of activity. In addition, the size of the binding
pocket may be small; larger fused bicyclic groups (2k, 2l and 2m),
or chlorine substitution (2h–2j) were associated with at least
eightfold decrease in MR potency. Lastly, the only acceptable sub-
stitution on the benzyl group appeared to be fluorine (2e–2g) de-
spite the loss of four to sixfold potency.
The SAR for the R3 area is depicted in Table 3. First, the phenyl
group in the R3 region of analog 1g contributed significantly to its
activity against MR. The absence of this group caused a ꢀ10-fold
loss of activity (3a vs 1g). Second, the chirality of the stereogenic
center in this region is important for biological activity against
MR. For example, diastereomer 3b is 10-fold less active than 1g.
Fluoro- and chloro-substitution (3c and 3d, respectively) main-
tained excellent activity. Cyclohexyl analog 3e was the most potent
MR antagonist that we found for this series with an IC50 of 14 nM.
By introducing a ring fused to the phenyl group, indanyl and tetra-
hydronaphthyl derivatives rendered IC50 of 33 and 170 nM, respec-
tively. Interestingly, 3h, a one-carbon homolog of 1g, was much
a
Values are based on the average of two experiments, each in 10-point titrations.
less active than 1g. A heterocyclic analog (3i), or pyridyl replace-
ment of the phenyl of 1g led to more than 50-fold loss of MR po-
tency. The combination of fluoro- and chloro-substituted phenyl
groups resulted in 3j, which displayed modest activity against MR.
The oxazolidinedione core was also a subject of modification
(Table 4). Almost all core modifications, as shown by analogs
Figure 1. Pharmacophore of the oxazolidinedione series.

4390
C. Yang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4388–4392
Table 2
Table 4
In vitro SAR of R2 moiety in the human MR NH Pro assaya
In vitro SAR of the oxazolidinedione core in the human MR NH Pro assaya
a
Values are based on the average of two experiments, each in 10-point titrations.
a
Values are based on the average of two experiments, each in 10-point titrations.
4a–4g, resulted in essentially a complete loss of activity against
MR, except for tertiary amide 4i, which only suffered a threefold
loss in potency compared to 4h.
Molecular modeling was employed to understand the potential
binding mode of the ozaxolidinedione derivatives. Figure 2 shows
the predicted binding orientation of compound 1g obtained by
molecular docking using the 1.95 Å MR X-ray structure 2A3I.10
The R1 substituent is located in the A-ring pocket, making a
Table 3
In vitro SAR of R3 moiety in the human MR NH Pro assaya
edge-to-face
p–p interaction with F829. The orientation and size
of R1 substituent are both critical for activity: from the electro-
philic potentials (blue iso-surface mesh in Fig. 2), positions 3 and
5 of the benzyl ring at R1 are favored. Thus, the OMe groups in
1g interact with R817 (resembling the sterol A-ring 3-keto group)
and non-conserved S810, resulting in the most potent substitu-
tions in R1. Hydrophobic substitutions in the R1 benzyl ring may
also be tolerated (1h, 1i and 1l), due to the hydrophobic nature
of the A-ring region. Incorporation of heteroaryl groups (1dd–1ii)
show reduced activity since the acceptor group is not placed cor-
rectly to interact with R817. Moreover, increasing the R1 substitu-
ent size (1jj–1qq) will reduce activity due to steric hindrance.
Finally, replacing the R1 benzyl group with a phenyl group, will fa-
vor substitutions at the 4 position with either halogen atoms or a
cyano group (1u or 1w).
Not only is the presence of a benzyl group in the R2 region cru-
cial for activity, but also its absolute configuration. The benzyl
group is placed in the sterol D-ring pocket and interacts with
L848, L938 and F941. The nature of the D-ring region is mostly
hydrophobic (green iso-surface mesh in Fig. 2), hence polar analogs
are less potent. Moreover, the benzyl ring completely fills the D-
ring pocket, making the small fluorine analog the only acceptable
substitution.
The methyl group in the R3 position of 1g contributes to MR
activity by forcing the molecule to adopt the preferred bound ori-
entation: the benzyl ring in R3 is placed parallel to the benzyl ring
a
in R2, making strong interactions. The other stereoisomer in R3
p–p
Values are based on the average of two experiments, each in 10-point titrations.

C. Yang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4388–4392
4391
Figure 2. Suggested binding mode of 1g within MR pocket: representative docking pose of compound 1g (green sticks) in 2A3I MR ligand binding crystal structure. Side
chains of residues located within 5 Å of 1g are represented as blue lines. The electrophilic (blue) and hydrophobic (green) potentials within the binding pocket are shown as
mesh representations. The dashed black lines illustrate atom pairs within hydrogen bond distance. Aldosterone crystal structure conformation is depicted as magenta lines
for comparison.
Table 5
Nuclear hormone receptor selectivity of 3f and 3j
Compd
MR
NH_PRO
IC50
GR
NH_PRO
EC50
GR
NH_PRO
M) IC50
AR
NH_PRO
EC50
AR
NH_PRO
M) IC50
ER
NH_PRO
EC50 M)
a
ER
NH_PRO
IC50 M)
a
ERb
NH_PRO
EC50
ERb
NH_PRO
IC50
PRb
NH_PRO
EC50
PRb
NH_PRO
IC50 (lM)
(
l
M)
(
l
(l
M)
(
l
(l
M)
(
l
(
l
(
l
M)
(
l
M)
l
M)
antagonist
agonist
antagonist
agonist
antagonist
agonist
antagonist
agonist
antagonist
agonist
antagonist
mode
mode
mode
mode
mode
mode
mode
mode
mode
mode
mode
Spironolactone 0.011
>20
>20
>20
>20
4.1
18
>20
11
>20
>20
>20
>20
0.67
>20
12
>20
>20
>20
>20
>20
>20
17
3.3
>20
>20
15
>20
>20
>20
>20
4.0
>20
8.1
3.6
Eplerenone
0.24
0.033
0.18
>20
>20
>20
3f
3j
>20
7.3
15
Table 6
Rat PK profiles of representative compoundsa
Compd
F (%)
Cl (mL/min/kg)
Vdss (L/kg)
Cmax
(
lM)
T1/2 (h)
AUCN iv, po (
lM h kg/mg)
1g
3f
3j
7
28
63
46
35
66
2.8
4.7
7.9
0.06
0.098
0.12
1.2
2.5
2.3
0.75, 0.05
0.89, 0.24
0.46, 0.24
a
Formulation: 1 mg/mL PEG 200: water (70:30). iv Dose: 1 mg/kg (n = 2). po Dose: 1 mg/kg (n = 3). Blood concentrations were determined by LC/MS/MS following protein
precipitation with acetonitrile.
will not promote this bound conformation, hence reducing its
activity against MR. The methyl group also interacts with MR by
protecting the backbone hydrogen-bond between hydrophobic
residues L769 and A773 located in helix 3. From the iso-surface
mesh in Figure 2, position 4 of the benzyl ring is ideal for substitu-
tion, as reported for compounds 3c and 3d. Compounds 3e–3g will
bind similarly with their R3 groups interacting with hydrophobic
residues located in helix 3 (L766, N770, L769 and A773), the loop
preceding helix 12 (V954 and F956) and helix 12 (L960). However,
the ethyl group in compound 3h will clash with helix 3. Interest-
ingly, the location of the benzyl ring in R3 coincides with the region
where aldosterone’s C-18 OH and C-21 OH groups are bound. This
orientation will prevent the formation of the canonical hydrogen
bond network (between the ligand, N770 in helix 3 and T945 in he-
lix 10) required for receptor activation,11 making the R3 region an
important feature contributing to the antagonism of MR.
The oxazolidinedione core binds in the hydrophobic C-ring re-
gion of the pocket and it is oriented perpendicular to both the ste-
rol plane and R2/R3 benzyl rings (Fig. 2). Although it does not
make any direct interaction with polar atoms of MR, the oxazoli-
dine core is essential for activity since it constrains the molecule
to adopt the desired bound conformation by placing the R1-3
groups in the correct pocket regions. The O-atom also makes an
important intramolecular hydrogen bond with the amide group
of R1 (Fig. 2). Removal of the O-atom or the carbonyl groups will
increase conformational flexibility of the molecule and disrupt the

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C. Yang et al. / Bioorg. Med. Chem. Lett. 23 (2013) 4388–4392
3. Funder, J. W. Annu. Rev. Med. 1997, 48, 231.
4. (a) The RALES Investigators N. Eng. J. Med. 1999, 341, 709; (b) Zannad, F.;
McMurray, J. J. V.; Krum, H.; van Veldhuisen, D. J.; Swedberg, K.; Shi, H.;
Vincent, J.; Pocock, S. J.; Pitt, B. N. Eng. J. Med. 2003, 348, 1309; (c) Funder, J. W.
Hypertens. Res. 2010, 33, 539.
5. (a) Calhoun, D. A.; White, W. B. J. Am. Soc. Hypertens. 2008, 2, 462; (b) The RALES
Investigators Am. J. Cardiol. 1996, 78, 902; (c) Bomback, A. S.; Muskala, P.; Bald,
E.; Chwatko, G.; Nowicki, M. Clin. Nephrol. 2009, 72, 449; (d) Williams, J. S. Nat.
Rev. Endocrinol. 2010, 6, 248; (e) Nishizaka, M. K.; Calhoun, D. A. Curr.
Hypertens. Rep. 2005, 7, 343; (f) Gaddam, K.; Corros, C.; Pimenta, E.; Ahmed, M.;
Denney, T.; Aban, I.; Inusah, S.; Gupta, H.; Lloyd, S. G.; Oparil, S.; Husain, A.;
Dell’Italia, L. J.; Calhoun, D. A. Hypertension 2010, 55, 1137; (g) Zannad, F.;
McMuray, J. J.; Drexler, H.; Drum, H.; van Veldhuisen, D. J.; Swedberg, K.; Shi,
H.; Vincent, J.; Pitt, B. Eur. J. Heart Fail. 2010, 12, 617.
6. De Gasparo, M.; Whitebread, S. E.; Preiswerk, G.; Jeunemaitre, X.; Corvol, P.;
Menard, J. J. Steroid Biochem. 1989, 32, 223.
7. De Gasparo, M.; Joss, U.; Ramjoe, H.; Whitebread, S.; Haenni, H.; Schenkel, L.;
Kraehenbuehl, C.; Biollas, M.; Grob, J.; Schmidlin, J.; Wieland, P.; Wehrli, H. U. J.
Pharmacol. Exp. Ther. 1987, 240, 650.
8. For other non-steroidal MR antagonists, see review: Meyers, M. J.; Hu, X. Expert
Opin. Ther. Pat. 2007, 17, 17.
9. http://www.discoverx.com/nhrs/prod-nhrs.php.
10. Molecular modeling was performed starting from the 1.95 Å MR structure with
bound corticosterone (PDB code 2A3I: Li, Y.; Suino, K.; Daugherty, J.; Xu, H. E.
Mol. Cell, 2005, 19, 367). The structure was prepared by removal of waters,
addition of hydrogens, and restrained energy minimization using Macromodel
(Macromodel 9.8.107, Schrödinger LLC, New York, NY). Electrophilic and
hydrophobic potentials were generated with Maestro (Maestro 9.1.107,
Scheme 1. Reagents and conditions: (a) CsF, DMF, 40 °C to rt, 3 days, 71%; (b) KOH,
EtOH, 46%, rt, overnight; (c) chiral SFC (OJ-H, 4.6 Â 100 mm, 5% MeOH/0.1% TFA/
CO2, 2.5 mL/min, 100 bar); (d) HATU, iPr2NEt, 3,5-dimethoxybenzylamine, DMF,
2 h, 72%; (e) 11, NaOH, THF, rt, overnight, 57%.
Schrödinger LLC, New York, NY) in
a
6 Å grid centered on the
crystallographic ligand. Molecular docking was performed by employing our
in-house docking routine FLOG (Miller, M. D.; Kearsley, S. K.; Underwood, D. J.;
Sheridan, R. P. J. Comput. Aided Mol. Des. 1994, 8, 153), which ranks pre-
calculated conformations of the target molecules in a 6 Å grid centered on the
crystallographic ligand. Conformations were generated using our in-house
metric matrix distance geometry algorithm JG (Kearsley, S. K. Merck & Co., Inc.,
unpublished). The conformations were subjected to energy minimization with
Macromodel using the MMFFs force field (Halgren, T. A. J. Comput. Chem. 1999,
20, 720). The representative docking pose reported in Figure 2 was selected by
visual inspection using SAR and was subjected to restrained energy
minimization (using Macromodel) to produce the model shown. Figure 2
was generated using Pymol (The Pymol Molecular Graphics System, version
1.4, Schrödinger LLC, New York, NY).
placement of the R2/R3 benzyl rings in the ligand binding pocket,
reducing its activity. Furthermore, the reported binding mode has
strain energy of 2 kcal/mol, which is thermally accessible at room
temperature.
The selectivity profiles of representative analogs 3f and 3j
against several nuclear hormone receptors, including AR, GR, ERa,
ERb, and PRb, are shown in Table 5. Compounds 3f and 3j demon-
strated acceptable selectivity, in particular, superior selectivity in
the AR antagonist mode assay with respect to spironolactone.
The rat pharmacokinetic (PK) profiles of compounds 1g, 3f and
3j are shown in Table 6. All compounds exhibited modest to high
clearance and acceptable IV exposure, with 1g showing poor oral
bioavailability. Interestingly, the structurally closely related and
more conformationally constrained analog 3g, improved the oral
bioavailability to 28%. The best oral bioavailability was observed
with 3j (63%). The preliminary PK studies demonstrated that the
oxazolidinedione represented a promising lead series.
11. Bledsoe, R. K.; Madauss, K. P.; Holt, J. A.; Apolito, C. J.; Lambert, M. H.; Pearce, K.
H.; Stanley, T. B.; Stewart, E. L.; Trump, R. P.; Willson, T. M.; Williams, S. P. J.
Biol. Chem. 2005, 280, 31283.
12. The mixture of diethyl a-benzylmalonate (41 g, 164 mmol) and CsF (49.8 g) in
90 mL of DMF was heated at 40 °C with vigorous air bubbling for 3 days. The
resulting mixture was diluted with ethyl acetate (800 mL) and washed with
water (1 L Â 3). The organic layer was concentrated and then purified by
biotage (5–20% ethyl acetate in hexanes) to give the diethyl
a-benzyl a-
hydroxy malonate (31 g, 117 mmol, 71%) as a colorless oil. 1H NMR (300 MHz,
CDCl3) d: 7.22–7.26 (m, 5H), 4.23 (q, J = 7.2 Hz, 4H), 3.80 (br, 1H), 3.35 (s, 2H),
1.26 (t, J = 7.2 Hz, 6H). To diethyl
a-benzyl a-hydroxy malonate (6.3 g,
24 mmol) in 50 mL of EtOH (anhydrous) was added KOH (1.5 g). The mixture
was stirred at rt over night. After removing the solvent in vacuo, the residue
was taken up with 100 mL of ethyl acetate and 150 mL of water. The organic
layer was removed. To the aqueous layer containing the potassium salt of the
desired product was added 0.2 N HCl until pH = 2. The mixture was extracted
with 200 mL ethyl acetate. The organic layer was dried with magnesium
sulfate and concentrated to give the acid (2.6 g, 11 mmol, 46%) as a colorless
oil. The racemic acid was then purified by chiral SFC (OJ-H, 4.6 Â 100 mm, 5%
MeOH/0.1% TFA/CO2, 2.5 mL/min, 100 bar) to give (2R)-2-benzyl-3-ethoxy-2-
hydroxy-3-oxopropanoic acid as a single enantiomer (1.0 g, the first eluting
peak). The assignment of the absolute configuration is based on vibrational
circular dichroism (details in supporting information). LC/MS 261.1 (M+23). To
a mixture of (2R)-2-benzyl-3-ethoxy-2-hydroxy-3-oxopropanoic acid (112 mg,
0.47 mmol), 3,5-dimethoxybenzylamine (86 mg, 0.51 mmol) and HATU
(197 mg, 0.52 mmol) was added DMF (4 mL) and Hünig base (67 mg,
0.52 mmol). The mixture was stirred at rt for 2 h. To the mixture was added
ethyl acetate and water. The organic layer was washed with water twice, and
dried with magnesium sulfate. After removal of the solvent, the residue was
purified by biotage (10–30% ethyl acetate in hexanes) to give ethyl (2R)-2-
benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxy-3-oxopropanoate
(132 mg, 0.34 mmol, 72%) as a colorless oil. To a mixture of ethyl (2R)-2-
benzyl-3-[(3,5-dimethoxybenzyl)amino]-2-hydroxy-3-oxopropanoate (40 mg,
0.10 mmol) and isocyanate 11 (80 mg, 0.54 mmol) in 4 mL of THF was added
NaOH (solid, 50 mg) at rt. The mixture was under vigorous stirring for
overnight. Filtered, and washed with ethyl acetate. The filtrate was
concentrated, taken up by DMSO, and purified by Gilson (30–100%
acetonitrile/water/0.05% TFA) to give 1g (28 mg, 0.057 mmol, 57%) as a white
solid. LC/MS 489.0 (M+1). 1H NMR (300 MHz, CDCl3) d: 7.20–7.29 (m, 8H), 7.01
(d, J = 7.0 Hz, 2H), 6.80 (t, J = 5.5 Hz, 1H), 6.42 (t, J = 2.0 Hz, 1H), 6.35 (d,
J = 2.0 Hz, 2H), 5.06 (q, J = 7.0 Hz, 1H), 4.44 (dd, J = 5.5, 14.5 Hz, 1H), 4.36 (dd,
J = 5.5, 15.0 Hz, 1H), 3.79 (s, 6H), 3.65 (d, J = 14.0 Hz, 1H), 3.40 (d, J = 14.5 Hz,
1H), 1.54 (d, J = 7.0 Hz, 3H).
A representative synthesis of oxazolidinedione analogs is illus-
trated in Scheme 1.12 The
a-hydroxylation of malonate 6 occurred
by applying vigorous air bubbling over 3 days, to afforded desired
hydroxylated intermediate 7, which then underwent a monohy-
drolysis to yield monocarboxylic acid 8. Chiral super critical fluid
chromatography (SFC) separation provided the chiral acid 9, which
subsequently coupled with 3,5-dimethoxybenzylamine to gener-
ate amide 10. The final oxazolidinedione formation was accom-
plished by using isocyanate 11 in the presence of solid NaOH in
THF. It should be noted that the oxazolidinedione is particularly
unstable under basic aqueous conditions.
In conclusion, we have identified novel oxazolidinedione
amides as potent antagonists for MR. Systematic SAR studies led
to several compounds with excellent selectivity over other nuclear
hormone receptors, and representative compounds also displayed
reasonable PK profiles in rats. Further investigations of the series
will be reported in due course.
References and notes
1. Fardella, C.; Miller, W. Annu. Rev. Nutr. 1996, 16, 443.
2. McKelvie, R. S.; Yusuf, S.; Pericak, D.; Avezum, A.; Burns, R. J.; Probstfield, J.;
Tsuyuki, R. T.; White, M.; Rouleau, J.; Latini, R.; Maggioni, A.; Young, J.; Pogue, J.
Circulation 1999, 100, 1056.