6-Aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones: A novel class of potent, selective, and orally active nonsteroidal progesterone receptor antagonists

Article abstract of DOI:10.1021/jm025555e

Novel 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones were synthesized and tested as progesterone receptor (PR) antagonists. These compounds were potent and showed good selectivity for PR over other steroid receptors such as the glucocorticoid and androgen receptors (e.g., greater than 80-fold selectivity at PR for 4h). Numerous 6-aryl benzoxazinones (e.g., 4h-j) were active orally in the uterine decidualization and component C3 assays in the rats. In these in vivo models, 4h had potencies comparable to mifepristone (1).

Full text of DOI:10.1021/jm025555e

© Copyright 2002 by the American Chemical Society
Volume 45, Number 20
September 26, 2002
Letters
nant chronic conditions such as fibroids,6,7 and en-
6-Ar yl-1,4-d ih yd r o-ben zo[d ][1,3]oxa zin -
2-on es: A Novel Cla ss of P oten t,
dometriosis.8,9
Mifepristone (1), a clinically available steroidal PR
antagonist, demonstrated potent activity at other ste-
roid receptors such as the glucocorticoid receptor (GR),
and this potentially limits its chronic use. Novel PR
antagonists that are structurally distinct from the
steroid class may have greater potential for selectivity
against other steroid receptors (e.g., GR).10-12 A number
of nonsteroidal PR antagonists have been reported.13-18
We have recently described novel PR antagonist 6-aryl
benzimidazolones (2) and PR agonist 6-aryl benzox-
azines (3).19,20 The structure-activity relationship (SAR)
studies from our reports indicated that the benzene-
fused heterocyclic core played an important role in PR
potency and functional activity. Further investigation
on other benzene-fused ring systems uncovered a novel
class of potent, selective, and orally active PR antago-
nists, 6-aryl-1,4-dihydrobenzoxazin-2-ones (4), which
will be discussed herein.
Selective, a n d Or a lly Active Non ster oid a l
P r ogester on e Recep tor An ta gon ists†
Puwen Zhang,*,‡ Eugene A. Terefenko,‡
Andrew Fensome,‡ J ay Wrobel,‡ Richard Winneker,§
Scott Lundeen,§ Keith B. Marschke,| and
Zhiming Zhang§
Chemical Sciences, Women’s Health Research Institute,
Wyeth Research, 500 Arcola Road,
Collegeville, Pennsylvania 19426, and
Ligand Pharmaceuticals, San Diego, California 92121
Received J une 11, 2002
Abstr a ct: Novel 6-aryl-1,4-dihydro-benzo[d][1,3]oxazin-2-ones
were synthesized and tested as progesterone receptor (PR)
antagonists. These compounds were potent and showed good
selectivity for PR over other steroid receptors such as the
glucocorticoid and androgen receptors (e.g., greater than 80-
fold selectivity at PR for 4h ). Numerous 6-aryl benzoxazinones
(e.g., 4h -j) were active orally in the uterine decidualization
and component C3 assays in the rats. In these in vivo models,
4h had potencies comparable to mifepristone (1).
In tr od u ction . The progesterone receptor (PR) is a
member of the intracellular superfamily of ligand-
dependent transcription factors.1 PR agonists play an
important role in female reproduction and have been
used extensively in female contraception and hormone
replacement therapy. PR antagonists, on the other
hand, have only found limited utility, and their thera-
peutic potential has not yet been fully realized. A
selective PR antagonist may be potentially useful in
female contraception2 and for the treatment of various
gynecological and obstetric diseases including hormone-
dependent breast and prostate cancers,3-5 nonmalig-
Ch em istr y. A general synthesis of 4a -m is described
in Scheme 1. Brofoxine 521 was reacted with a com-
mercially available substituted aryl boronic acid, using
a standard Suzuki coupling protocol, to afford the
desired target compounds 4. Alternatively, when the
pendent aryl boronic acid was not available, brofoxine
5 was converted to its corresponding boronic acid 6 by
a lithium-halogen exchange followed by quenching the
reaction solution with triisopropyl borate and then
† Presented in preliminary form at the 223rd ACS National Meeting,
Orlando, FL, April 7-11, 2002.
* To whom correspondence should be addressed. Tel: (484)865-3856.
Fax: (484)865-9398. E-mail: Zhangp@wyeth.com.
‡ Chemical Sciences, Wyeth Research.
§ Women’s Health Research Institute, Wyeth Research.
| Ligand Pharmaceuticals.
10.1021/jm025555e CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/27/2002

4380 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20
Letters
Sch em e 1a
Ta ble 1. PR Functional Activities of 1 and 4a -m in CV-1
PRE-Luciferase and T47D Alkaline Phosphatase Assays
T47D alkaline
a
CV-1 PRE-luciferase
IC50 (nM)a
phosphatase
Reagents: (a) n-BuLi, THF, -78 °C; B(Oi-Pro)3, -78 °C; 3 N
compd
R
IC50 (nM)a
HCl, room temperature, 65%. (b) ArX, Pd(Ph3P)4, Na2CO3, DME/
H2O, 85 °C, N2, 40-80%. (c) ArB(OH)2, Pd(Ph3P)4, Na2CO3, DME/
H2O, 85 °C, N2, 40-80%.
1
0.30
3.8
500.0
9.3
642.0
9.9
38.3
2.6
15.9
55.0
37.0
98.8
6.7
0.13
8.2
300.0
30.0
30.0
17.0
4a
4b
4c
4d
4e
4f
4g
4h
4i
3-F
2-Cl
3-Cl
4-Cl
acidic workup. Boronic acid 6 was then coupled with
the appropriate aryl halide to afford 4.
3-CN
Resu lts a n d Discu ssion . Recently, we disclosed
6-aryl benzimidazolones and 6-aryl benzoxazines as PR
modulators.19,20 The biological profile changed from PR
antagonism to PR agonism when the benzoimidiazolone
ring was replaced by a benzoxazine scaffold. This finding
indicated that the benzene-fused heterocyclic ring played
an important role in the direction of SAR for these
series. To search for more potent and selective PR
modulators, we continued to examine other benzene-
fused scaffolds and discovered that 6-aryl benzoxazino-
nes are potent and selective PR antagonists.
These 6-aryl benzoxazinones were tested in an assay
using hPR/PRE-luciferase plasmid cotransfected CV-1
cells22 and in an alkaline phosphatase assay in the T47D
human breast carcinoma cell line.23,24 The results are
listed in Table 1. The nature of the substituent and
substitution pattern on the pendent 6-aryl group played
an important role in the PRE-luciferase activity of the
compounds. For example, 3-chlorophenyl benzoxazinone
4c (IC50 ) 9.3 nM) was over 50-fold more potent than
its 2- or 4-substituted congeners 4b,d (IC50 values were
greater than 500 nM) indicating that a substituent in
the 3-position of the 6-aryl moiety was favored. Conse-
quently, a number of compounds (4a ,e,f) with different
substituents at the 3-position of the 6-aryl group were
prepared and showed low nonamolar activity in the
PRE-luciferase assay (IC50 values were in the range of
3.8-38.3 nM).
Several 6-aryl disubstituted analogues (4g-k ) were
prepared. The SAR results in the PRE-luciferase assay
showed that 3,5-disubstituted compounds 4g,h were
more potent than the corresponding 3,4-disubstituted
analogues 4i,j. The 8-fluoro-substituted analogue 4k
was less active than its parent congener 4h . The good
potency seen with compounds 4l,m demonstrated that
the thiophene and furan ring systems could successfully
replace the substituted phenyl system.
Considerable differences16,25 in potency and functional
activity were observed with the compounds in the T47D
alkaline phosphatase assay when compared to their
PRE-luciferase results. Most notably, compounds 4g,h ,l
were PR agonists with moderate potency in this assay
in contrast to being potent PR antagonists in the CV-1
PRE-luciferase assay. The discrepancy in the functional
preferences of the compounds from these two assays
may have resulted from the different cell background
or gene promoter context, though the mechanism is
unclear.26
3-OCH3
5-F, 3-Cl
5-F, 3-CN
4-F, 3-CN
4-F, 3-Cl
19.5
(500.0)b
(90.0)b
15.1
4j
23.0
4k c
4l
26.2
(61.1)b
8.0
4m
40.2
a
Experimental values represent the average of at least dupli-
cate determinations. The standard deviations for these assays were
typically (20% of mean or less. The efficacy was g90% unless
otherwise noted. The agonist efficacy for 4h in the T47D alkaline
phosphatase assay was 83%. The antagonist efficacy for 4l in the
b
PRE-luciferase assay was 60%. The number in parentheses
represented the EC50 values from the alkaline phosphatase assay.
c Compound 4k was prepared in a similar fashion as described in
Scheme 1 starting from the corresponding fluorine-substituted
analogue of 5.
Several additional noteworthy results emerged from
the T47D assay. The rearrangement of the fluorine atom
from position 5 to position 4 on the 6-aryl groups
(compare 4h with 4i and 4g with 4j) caused a change
from PR agonism to PR antagonism. Similarly, a one
atom change (oxygen to sulfur) caused a switch from
antagonism to agonism in furan congener 4m as com-
pared to thiophene analogue 4l.
Benzoxazinones 4a ,c,e,g-m were evaluated in the
ovariectomized mature female rat decidualization model27
and compared to mifepristone (1) (Figure 1 and Table
2). Analogues 4a ,g-m , containing a diverse array of
6-aryl moieties (i.e., substituted phenyl and heterocylic),
showed robust oral activity. Compounds 4h ,i,k were
similar to mifepristone (1) in potency while 4a ,j,l,m
were marginally less potent than 1. Interestingly,
6-(fluoro-cyanophenyl)-substituted analogue 4h 28,29 was
over 20-fold more potent than its des-fluorine congener
4e. This result suggested that the extra fluorine atom
on the 6-aryl group of 4h significantly improved its
pharmacokinetic properties over 4e since both com-
pounds had similar potency in the PRE-luciferase assay.
As illustrated by the data in Table 3, compound 4e was
cleared at a substantially higher rate than the fluorine-
substituted congener 4h when both were given at a
single 1 mg/kg intravenous dose to female rats. Fur-
thermore, the bioavailability in rats of 4h (72%) was
significantly greater than 4e (36%) suggesting that 4h
was also absorbed better than 4e. The other 6-(fluoro-
cyano)-substituted isomer 4i also demonstrated a con-
siderable boost in potency over des-fluoro parent 4e.

Letters
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 20 4381
Ta ble 4. Antagonist Cross-Activities of 1 and 4g,h ,j-m
IC50 (nM)
compd
PR
ER
AR
GR
MR
1a
0.3 (99) >1000 (40) 5 (7) 0.8 (98)
>1000 (77)
839
2369
2492
1386
4gb
4h b
4jb
2.6
15.9
37.0
6.7
NDc
319
2126
>10 000
>10 000
ND
1292 1756
207
280
129
2581
1856
4lb
4m b
40.2
ND
>10 000 >10 000
a
See ref 18 for the experimental data; values in the parentheses
b
represent percentage of efficacy. Experimental values represent
the average of at least duplicate determinations. The standard
deviation for these assays was typically (30% of mean or less.
The efficacy was g80% unless otherwise noted. See refs 18 and
24 for experimental details. c Not determined.
F igu r e 1. Representative dose-response curves for 4h and
1 in the rat uterine decidualization model. Overiectomized
mature rats were treated with vehicle (C), progesterone (P4,
5.6 mg/kg, SC), P4 + 1, and P4 + 4h for 7 days. Decidual
response (D/C) was measured 24 h after the final treatment
as described in ref 27. Each data point represents mean ( SE
from seven animals.
greater than 80-fold selectivity for PR over other steroid
receptors. More importantly, all benzoxazinones tested
had greater than 100-fold selectivity for PR over GR in
contrast to mifepristone, which was nearly equipotent
on both receptors. In addition, none of these compounds
showed any significant agonist activity at these steroid
receptors. When tested orally in a rat thymic involution
model,31 4h did not show any GR antagonist activity at
30 mg/kg indicating at least a 100-fold selectivity for
PR over GR in vivo.
Ta ble 2. Oral Activities of 1 and 4a ,c,e,g-m in Rat
Decidualization and C3 Models
decidualization
ED50 (mg/kg)a
component C3
ED50 (mg/kg)a
compd
1
0.3
1.5b
>30
7.0
1.7
NDc
ND
ND
ND
1.0
4.8
2.5
ND
ND
ND
These benzoxazinones demonstrated competitive bind-
ing when tested in a PR competition binding assay using
cytosol from the human T47D breast carcinoma cell
line.24 For example, compounds 4g,h had binding af-
finity (Ki) at PR of 5.5 and 25 nM, respectively.
Con clu sion . 6-Aryl benzoxazinones were evaluated
and found to be potent, selective, and orally active PR
antagonists. As a novel class of nonsteroidal PR an-
tagonists, 6-aryl benzoxazinones provided a substantial
selectivity advantage over mifepristone and were found
to be potentially useful as novel contraceptives and for
the treatment of hormone-dependent cancers, nonma-
lignant chronic conditions such as uterine fibroids, and
endometriosis.
4a
4c
4e
4g
4h
4i
4j
4k
4l
2.0b
0.3
0.6
1.0
0.6
1.7
4m
0.9
a
Experimental values represented the average of at least
duplicate determinations. The standard deviation for the decidu-
b
alization and C3 assays was typically (15% of mean or less. The
estimated ED50 value. c Not determined.
Ta ble 3. Pharmacokinetic Parameters of 4e,h in Female Rats
Following a 1 mg/kg IV Dosea
Ack n ow led gm en t. We thank Mr. Yuan Zhu, Mr.
J eff Cohen, and Mr. J eff Carver of the Women’s Health
Institute, Wyeth Research, for the technical assistance,
the Department of Analytical Chemistry of Chemical
Sciences, Wyeth Research, for analytical data, and Mr.
Cesario Tio, the Department of Drug Safety and Me-
tabolism, Wyeth Research, for the pharmacokinetic
data.
compd
t1/2 (hr)
AUC0f∞ (µg hr/mL)
Clp (L/hr kg)
4e
4h
0.6 ( 0.1
7.7 ( 2.2
0.46 ( 0.06
3.69 ( 1.42
2.18 ( 0.29
0.22 ( 0.06
a
Experimental values represented the average of three animals.
Similarly, 6-(fluoro-chloro) isomers 4g,j were over 15-
fold more potent than their des-fluoro parent 4c.
Selected compounds (4h -j) were tested in an ad-
ditional in vivo PR antagonist model, the adult ovariec-
tomized rat uterine component C3 assay.30 PR antago-
nists are known to reverse the progestin down-regulation
of estrogen-induced synthesis of complement component
C3 in the epithelial cells of the rat uterus. As shown in
Table 2, 4h ,j had comparable potency to mifepristone
(1) while 4i was marginally less potent.
Mifepristone (1) is also a potent GR antagonist (Table
4), and this is a cause of major concern with respect to
its chronic use. In this regard, the benzoxazinones
(4g,h ,j-m ) were tested for their cross-reactivities with
estrogen (ER), androgen (AR), glucocorticoid (GR), and
mineralocorticoid (MR) receptors18,24 and compared to
mifepristone (1). As illustrated in Table 4, the novel
benzoxazinones demonstrated good selectivity for PR
over other steroid receptors. For example, 4g,h showed
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and data of 4a -m . The procedures of rat uterine
decidualization and component C3 models. This material is
available free of charge via the Internet at http://pubs.acs.org.
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J M025555E