5-Benzylidene-1,2-dihydrochromeno[3,4-f]quinolines as selective progesterone receptor modulators

Article abstract of DOI:10.1021/jm020477g

A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited as highly potent progestins with more than 100-fold receptor selectivity over other steroid hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina versus breasts in a rodent model after oral administration.

Full text of DOI:10.1021/jm020477g

4104
J . Med. Chem. 2003, 46, 4104-4112
5-Ben zylid en e-1,2-d ih yd r och r om en o[3,4-f]qu in olin es a s Selective P r ogester on e
Recep tor Mod u la tor s
Lin Zhi,* Christopher M. Tegley, Barbara Pio, J ames P. Edwards, Mehrnouch Motamedi, Todd K. J ones,
Keith B. Marschke, Dale E. Mais, Boris Risek, and William T. Schrader
Discovery Research, Ligand Pharmaceuticals Inc., 10275 Science Center Drive, San Diego, California 92121
Received October 25, 2002
A series of 5-benylidene-1,2-dihydrochromeno[3,4-f]quinolines (4) were synthesized and tested
in bioassays to evaluate their progestational activities, receptor- and tissue-selectivity profiles
as selective progesterone receptor modulators (SPRMs). Most of the new analogues exhibited
as highly potent progestins with more than 100-fold receptor selectivity over other steroid
hormone receptors and LG120920 (7b) demonstrated tissue selectivity toward uterus and vagina
versus breasts in a rodent model after oral administration.
In tr od u ction
estradiol.7 There is a need for and a growing interest
in searching for selective pharmaceutical agents in the
area of steroid hormone receptors to improve safety
profiles of current drugs. In comparison with the success
of selective estrogen receptor modulators (SERMs),8 the
development of receptor- and tissue-selective progest-
erone receptor modulators (SPRMs) is in a very early
stage.9
The 5-substituted 1,2-dihydrochromeno[3,4-f]quino-
lines (1) have been demonstrated to be robust nonste-
roidal pharmacophores for human progesterone receptor
(hPR) modulators.10 One of the appealing series devel-
oped from the tetracyclic core contains a unique achiral
5-phenylmethylidene moiety. For example, LG120838
(2) exhibited highly potent progestational activity simi-
lar to steroidal progestin MPA (3) in rodent models via
oral administration.11 To further explore the structure-
activity relationship (SAR) around the 5-benzylidenes,
we synthesized a number of novel analogues (4) with a
fluorine substitution at the 9- or 7-position and evalu-
ated their biological activities as SPRMs in cotransfec-
tion, competitive binding assays and in an in vivo
model.12
Progestins and estrogens are two kinds of female
reproductive hormones with multiple target organs
beyond the reproductive system. Their biological actions
are mainly through activating their own transcription
factors: progesterone receptors (PR) and estrogen re-
ceptors (ER). Estrogen upregulates both isoforms of
progesterone receptor (PR-A and PR-B), while progestin
can suppress estrodial-stimulated ER activity in numer-
ous tissues through binding to PR-A or PR-B.1 The
coordinate role of progestins with estrogens compose the
intriguing biology of the two female hormones.2
Synthetic steroidal progestins, in combination with
estrogens, have been widely used in oral contraception
(OC), female hormone replacement therapy (HRT), and
the treatment of a number of female reproductive
disorders for decades.3 Addition of a progestin in
estrogen replacement therapy has proven to signifi-
cantly reduce endometrial cancer risk due to its anti-
estrogenic activity in the uterus.4 However, in breasts,
progestins demonstrate stimulative activity in addition
to the proliferative effect of estrogens. There has been
a potential breast cancer risk for women to have a long
term use of progestins in OC and HRT in combination
with estrogens, even though the clinical results have
been controversial.5 The latest results from the Women’s
Health Initiative confirmed the increased breast cancer
risk for women who used combined hormone prepara-
tion of conjugated equine estrogens and medroxyproges-
terone acetate (MPA, 3).6 Like the natural ligand
progesterone, all of the currently marketed progestins
possess some degree of cross-reactivities with other
steroid hormone receptors, which can cause potential
side-effects. The cross-reactivities of MPA with androgen
and glucocorticoid receptors might contribute to the
increased risk of cardiovascular diseases in women who
took the combination hormone preparation in the Wom-
en’s Health Initiative trials. It was reported that a new
steroidal progestin, trimegestone, had improved receptor
selectivity and also demonstrated a beneficial effect on
bone in an adult rat model when it was combined with
Ch em istr y
The syntheses of most analogues of structure 4 were
completed by a two-step general procedure described in
Scheme 1. Addition of a benzyl Grignard or organo-
lithium reagent to the tetracyclic lactone 510b provided
good to excellent yield of hemiacetal 6, and an acid-
catalyzed dehydration afforded the desired compounds
7-9 exclusively as Z-isomers under dim or yellow light
conditions.13 HCl salts of selected low melting point
analogues (7a and 7b) were prepared to increase
crystallinity of these compounds. A new synthetic route
was developed for analogue 15 (Scheme 2) since the
2-aminobenzyl Grignard or lithium reagent is not easily
accessible. The benzylic lithiation of 2-(methylamino)-
toluene was directed by the adjacent carbonate group
that formed in situ to give dianion 11.14 Addition of 11
to lactone 5b went smoothly to afford hemiacetal 12 in
high yield. Treatment of 12 with chloroformate provided
intermediate 13 with selective acylation of the phenol
oxygen and the aniline nitrogen but not the quinoline
* Address correspondence to this author. Phone: (858) 550-7663;
fax: (858) 550-7249; e-mail: lzhi@ligand.com.
10.1021/jm020477g CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/14/2003

Selective Progesterone Receptor Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4105
(2) gave the best progestational activity.11 To systemati-
cally investigate the biological effect of the ortho-
substitution, a number of 9-fluoro ortho-substituted
5(Z)-benzylidene analogues were evaluated (Table 1).
The testing results in both cotransfection and binding
assays clearly indicate that the electronic rather than
steric differences have a bigger impact on progestational
activity, and electron-rich groups result in better
progestins. The total electronic influence of the ortho-
substituents on the biological activity can be nicely
correlated between the EC50 mean value in hPR cotrans-
fection assay and the ordinary Hammett substituent
constants (σ-meta)17 (see Figure 2).
The SAR study around the 5-benzylidene moiety
generated a large number of highly potent progestins,
which motivated us to evaluate the scope of the ben-
zylidene pharmacophore. Our first attempt was to
evaluate pyridyl analogues (Table 1, 8). The assay
results indicated that the pyridine moiety was well
tolerated, and three out of four compounds (except 8c)
exhibited potent progestational activity. Expansion of
the benzylidene to five-member-ring heterocycle meth-
ylidenes is very successful, and 3-thiophene analogue
18b is one of the best hPR agonists in the series with
sub-nanomolar potency as well as 174% efficacy relative
to progesterone. Compound 18c also demonstrates
excellent activity.
F igu r e 1. The new progestins and reference compound.
nitrogen, presumably due to the steric hindrance of the
geminal dimethyl groups. Selective hydrolysis of the
carbonate 13 followed by a standard dehydration pro-
cedure afforded benzylidene product 14. The carbamate
in compound 14 that served as a methylamine precursor
was reduced by DIBAL-H in THF to afford the desired
product 15 in good yield.
Scheme 3 describes a novel general synthetic route
to prepare special benzylidene or heteroaryl meth-
ylidene compounds that were not available by the routes
described in Schemes 1 and 2. Treatment of lactone 5b
with Tebbe reagent15 afforded 5-methylidene compound
16, which was brominated with NBS to provide com-
pound 17 in moderate yield with the exclusive Z-olefin
configuration. Palladium-catalyzed cross-coupling reac-
tion16 of vinyl bromide 17 and boronic acids or tribu-
tyltin compounds gave analogues of structure 18 in 40-
70% yield without isomerization of the Z-olefin config-
uration.
In searching for SPRMs with full antiestrogenic
activity in uterus and diminished proliferative activity
in breasts, we evaluated the new progestins in the T47D
human breast cancer cell line.18 The results show that,
in contrast with steroidal progestins such as progest-
erone and MPA, our new analogues behaved as partial
agonists in the breast cell assay although they scored
as super agonists in CV-1 cotransfection assay.
The receptor selectivity profile of the new analogues
was examined by using other steroid hormone receptor
cotransfection and competitive binding assays. Tables
2 and 3 list the results of a group of representative
compounds. Most of them demonstrated more than 100-
fold selectivity toward hPR over human androgen
receptor (hAR) and human glucocorticoid receptor (hGR)
in binding affinities and transcriptional activities, as
well as over human mineralocorticoid receptor (hMR)
and human ER in the cotransfection assay, which makes
them superior in this regard compared to progesterone
and MPA.
Resu lts a n d Discu ssion
Our previous reports demonstrated that fluorine or
chlorine at C(9) significantly enhanced the hPR agonist
activity in the 5-aryl series,10b and compounds with a
m- or p-fluorine or an o-methyl group at the 5(Z)-
benzylidene phenyl ring had the highest efficacy in the
cotransfection assay.11 However, chlorine at C(9) also
increased glucocorticoid receptor binding affinity.10c To
access the similar enhancement effect on the 5-ben-
zylidene series, we prepared a number of analogues with
a fluorine substituent at C(9) or at the electronic
equivalent C(7) position in combination with the best
possible substitution in the benzylidene ring. Table 1
summarizes the SAR results of the new 5(Z)-ben-
zylidene analogues in the cotransfection and competitive
binding assays.
All of the 7-fluorine analogues (9a , 9b, 9c, and 9d )
have similar high efficacy (>160% of progesterone) and
demonstrated improved potency in the cotransfection
assay comparing to their corresponding 7-H analogues11
(only 2-Me analogue is shown in Table 1). The fluorine
enhancement on hPR agonist activity was also con-
firmed in the 9-fluorine series (data are not shown for
the 9-H analogues).
To characterize the tissue-selectivity profile of the new
progestins and reference compounds, we employed a
multi-endpoint adult rat model. In this assay, advantage
is taken of the fact that in the uterus and vagina,
estrogens induce a proliferation and increase in the
epithelial cell height, which can be antagonized by
progestins. In the breast, estrogens induce a prolifera-
tion of the ductal network while progestins stimulate
the growth of the lobular-alveolar end buds, which grow
from the distal end of the ducts. The assay is carried
out in ovariectomized female rats by treating them for
3 days with estrone or estrone plus varying doses of a
progestin. Proliferating cells or inhibition of proliferat-
ing cells were quantitated either by measurements of
cell height in sectioned and stained tissue samples or,
in the case of the breast, immuno-histochemically
labeled Brdu incorporated nuclei. Compound 7b was
We noticed in our initial study that the ortho-position
of the 5(Z)-benzylidene phenyl ring had more tolerance
for substitution, and the 2-methyl compound LG120838

4106 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Zhi et al.
Sch em e 1
Sch em e 2a
a
Reagents: (a) n-BuLi, THF, -70 °C, CO2; (b) n-BuLi; (c) 5b, THF; (d) ClCO2Me, pyridine, CH2Cl2, rt, 1 h; (e) Na2CO3, MeOH/H2O,
rt; (f) TsOH, CH2Cl2, rt, 2 h; (g) DIBAL-H, THF, rt, 2 h.
Sch em e 3
selected for the in vivo study based on its excellent
potency and good cross-reactivity profile in vitro (more
than 100-fold separation from other receptors as shown
in Table 3), relative ease of synthesis, and desirable
property for recrystallization. MPA was used as a
standard. Figure 3 shows the results of these measure-
ments for MPA and 7b. These results show that while
7b has similar potency and efficacy to MPA to inhibit

Selective Progesterone Receptor Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4107
Ta ble 1. Cell-Based Assay and Competitive Binding Data for the New Analoguesa
hPR agonist (mean ( SEM)b
T47D cells
CV-1 cells
EC50 (nM)c
no.
R1
R2
eff (%)
100
eff (%)
100
EC50 (nM)c
hPR-A binding Ki (nM)
progesterone
2.9 ( 0.9
0.15 ( 0.05
5.7 ( 3.7
2.1 ( 0.6
2.7 ( 0.5
4.0 ( 1.0
1.4 ( 0.7
5.3 ( 1.0
3.6 ( 0.3
2.0 ( 0.8
4.5 ( 1.3
4.0 ( 2.1
0.93 ( 0.24
6.2 ( 2.2
7.3 ( 3.1
12 ( 5
1.8 ( 0.3
3.5 ( 0.2
0.34 ( 0.04
0.66 ( 0.20
0.61 ( 0.06
5.5 ( 1.3
0.71 ( 0.16
1.5 ( 0.4
3
2
MPA
80 ( 7
166 ( 35
171 ( 49
170 ( 42
175 ( 22
163 ( 12
176 ( 15
178 ( 14
161 ( 17
123 ( 15
156 ( 13
154 ( 23
132 ( 13
190 ( 21
146 ( 13
147 ( 18
78 ( 20
90 ( 15
0.33 ( 0.05
H
2-MePh
45 ( 10
45
28 ( 2
9a
9b
9c
9d
7a
7b
7c
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
8a
8b
8c
8d
15
18a
18b
18c
7-F
7-F
7-F
7-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
9-F
Ph
11
3-FPh
51
18
4-FPh
36
8
9
2-MePh
Ph
2-MePh
2-EtPh
2-n-PrPh
2-i-PrPh
2-OMePh
2-SMePh
2-FPh
43
55 ( 9
49 ( 6
51
28 ( 9
19 ( 6
18
0.62 ( 0.39
0.55 ( 0.14
2.3 ( 0.91
1.6 ( 0.51
1.9 ( 0.8
46
59
43
54
40
8
3.8 ( 1.7
53
41
0.59 ( 0.06
0.62 ( 0.1
22.4 ( 8.2
16.4 ( 4.8
11.4 ( 4.3
2.6 ( 0.9
47
29
2-ClPh
2-BrPh
not available
9.0 ( 6.1
11 ( 4
37
62
72
56
49
46
40
49
59
56
48
64
50
97
48
2-CNPh
2-CHOPh
2-OCF3Ph
4-pyridyl
3-Me-4-pyridyl
2-pyridyl
3-Me-2-pyridyl
2-NMe2Ph
2-CF3Ph
3-thienyl
2-furyl
107 ( 19
136 ( 31
105 ( 8
11 ( 2
11 ( 6
190
6.4 ( 3.2
5.8 ( 3.6
2.0 ( 0.2
15 ( 5
4.9
4.6
44
1.5 ( 0.4
138 ( 3
50 ( 2
1.4 ( 0.5
9.2 ( 3.1
125 ( 18
172 ( 25
127 ( 14
174 ( 10
138 ( 37
4.5 ( 2.1
2.7 ( 1.1
14 ( 6
12
26
161
5.5
21
0.42 ( 0.06
1.2 ( 0.3
45.5 ( 9.6
1.3 ( 0.5
0.71 ( 0.20
1.7 ( 0.9
4.7 ( 1.5
a
Values with standard errors (SEM) represent the mean value of at least three separate experiments with triplicate determinations,
values without standard deviation represent N < 3. Agonist efficacies were compared to that of progesterone (100%). c All EC50 values
b
were determined from full dose-response curves ranging from 10-12 to 10-5 M.
Ta ble 2. Competitive Binding Data of 5-Benzylidene
Analogues with hPR, hAR, and hGRa
compound
hPR Ki (nM)
hAR Ki (nM)
hGR Ki (nM)
progesterone
3.5 ( 0.2
8.5 ( 3.1
2.9 ( 0.2
1456 ( 289
960 ( 202
>1000
30.5 ( 1.9
13.2 ( 1.8
321 ( 32
232 ( 40
207 ( 122
236 ( 60
270 ( 2
MPA
9a
0.34 ( 0.04
0.61 ( 0.06
1.5 ( 0.4
9d
7a
0.62 (0.39
0.55 ( 0.14
2.3 ( 0.91
3.8 ( 1.7
7b
>1000
7c
1589 ( 733
439 ( 7
7f
277 ( 59
386 ( 94
232 ( 53
874 ( 290
493 ( 14
84 ( 10
7g
0.59 ( 0.06
0.42 ( 0.06
1.4 ( 0.5
>1000
8b
>1000
8d
>1000
15
1.2 ( 0.3
819 ( 423
669 ( 206
>1000
18b
18c
1.3 ( 0.5
4.7 ( 1.5
140 ( 32
a
Values with standard errors (SEM) represent the mean value
of at least three separate experiments on receptor expressed in
SF12 cells in a baculovirus expression system.
Figu r e 2. Correlation between hPR EC50 of the new progestins
and Hammett substituent constants (σ-meta) of their 2′-
substituent at the 5-benzylidene moiety.
substituent of the benzylidene moiety correlates with
PR agonist potency. Heteroaromatic methylidenes such
as pyridyl, thienyl, and furyl methylidenes are well
tolerated to replace the 5-benzylidene group. Most of the
analogues showed improved selectivity toward hPR from
other steroid hormone receptors in comparison with
progesterone and MPA. In addition, LG120920 was
demonstrated to be a full agonist in the uterus and
vagina and a partial agonist in the breasts in a rodent
model.
estrone-induced epithelial cell height in both the uterus
and vagina, 7b has a greatly reduced potency and
efficacy at equivalent doses relative to MPA at inducing
the proliferative response in lobular-alveolar buds in the
breast.
In summary, the SAR around the 5-methylidene
moiety provided a large number of nonsteroidal proges-
tins that have low nanomolar potency in the cotrasfec-
tion assay as full agonists and as partial agonists in the
T47D assay. The Hammett σ constant of the ortho

4108 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Zhi et al.
Ta ble 3. Cross-Reactivity Profiles of Selected Analogues with hAR, hGR, hMR, and hERa
hAR effic
(%)b
hAR IC50
(nM)b
hGR effic hGR IC50
(%)b (nM)b
hMR effic hMR IC50
hER effic hER IC50
no.
P r
AR/PRe
GR/PRe
(%)b
(nM)b
ER/PRe
5
(%)b
(nM)b
ER/PRe
46 ( 7
37 ( 2
13 39 ( 8 >1000
>344
67
83 ( 14
14 ( 4
-
-
>1000
MPA 159 ( 10c
6.1 ( 1.0c
41 157 ( 22c
429 82
10 ( 1c
67 ( 10 1197 ( 852 >1000 46 ( 5c
924 ( 203c >1000
d
9a
9d
7a
7b
7c
7f
7g
8b
8d
15
18b
18c
60
-
900
-
250
119
212
387
181
39
-
-
>1000
-
-
>1000
>1000 89 ( 4
121 73 ( 16
228 84 ( 15
>1000 86 ( 10
>1000 81 ( 12
>1000 98 ( 1
>1000 99 ( 1
101 99 ( 1
556 88 ( 3
303 45
297 ( 24
2050 ( 319
650 ( 128
77 ( 11
90 ( 14
860 ( 110
245 ( 50
188 ( 72
320 ( 113
100
70 ( 9
1850 ( 500 >1000 41 ( 2 2443 ( 908 >1000
37 ( 7
38 ( 6
-
640 ( 150
-
-
-
-
>1000
>1000
167
-
-
-
-
-
>1000
>1000
>1000
>1000
>1000
255
820 ( 210
-
50 ( 4
334 ( 49
-
-
-
97
-
-
-
-
>1000 34
1885
-
-
-
139
54
>1000
-
-
-
71 ( 10
363 ( 120
511 44
1149
-
93 ( 4
60
203 ( 10
94
-
-
-
-
>1000
>1000
-
-
>1000
>1000
1500
119
141
64
-
52 ( 2
94 ( 4
215 ( 49
258 ( 86
63 ( 15 1900 ( 780 >1000 36 ( 10 3488 ( 1184 >1000
152 74 ( 9
109 ( 65
-
-
>1000 51
1273
749
a
Values with standard errors (SEM) represent the mean value of at least three separate experiments with triplicate determinations,
b
values without standard deviation represent N < 3. Antagonist efficacies were determined as a function (%) of maximal inhibition of a
standard agonist at EC50 value, and the IC50 values were determined from full dose-response curves ranging from 10-12 to 10-5 M.
c Agonist efficacy and EC50
.
Stands for the efficacy <20% or potency >5000 nM. e Potency ratio of the two receptors.
d
F igu r e 3. Inhibition of estrone-induced uterine or vaginal epithelial cell height (center and right panels) and proliferative induction
of lobular-alveolar buds in the breast (left panel) in the ovariectomized rat by compound 7b or MPA in three different doses (n
) 4 for all groups). All values represent the mean percent change ( SEM.
(Z)-9-Flu or o-5-(2-m eth ylben zyliden e)-1,2-dih ydr o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7b). This com-
pound was prepared by the general procedure from 2-meth-
ylbenzyl bromide (1.6 mL, 11 mmol) and lactone 5b (0.24 g,
0.78 mmol) in 86% yield as a yellow solid (0.26 g): mp 69-71
°C; 1H NMR (CDCl3) 8.16 (d, J ) 7.5, 1 H), 7.42 (d, J ) 8.4, 1
H), 7.36 (dd, J ) 9.0 and 1.8, 1 H), 7.28-7.10 (m, 3 H), 7.01
(dd, J ) 8.5 and 4.3, 1 H), 6.82 (td, J ) 8.3 and 3.0, 1 H), 5.88
(s, 1 H), 5.51 (s, 1 H), 4.18 (bs, 1 H), 2.28 (s, 3 H), 2.15 (s, 3 H)
and 1.33 (bs, 6 H). The HCl salt of 7b was made in a similar
fashion to that described in the preparation of 7a as yellow
solid:19 mp 191-193 °C; 1H NMR (CDCl3) 8.09 (d, J ) 8.0, 1H),
7.93 (d, J ) 7.5, 1H), 7.66 (d, J ) 8.3, 1H), 7.46 (dd, J ) 9.2
and 2.3, 1H), 7.30-7.24 (m, 1H), 7.20-7.17 (m, 2H), 7.08 (dd,
J ) 8.9 and 4.8, 1H), 7.03 (td, J ) 8.4 and 3.0, 1H), 5.94 (s,
1H), 5.72 (s, 1H), 2.27 (s, 3H), 2.25 (s, 3H), and 1.77 (bs, 6H).
Anal. (C27H24FNO‚HCl) C, H, N.
(Z)-9-F lu or o-5-(2-eth ylben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7c). P r ep a r a -
tion of 2-Eth ylben zyl Br om id e. To a solution of 2-methyl-
benzyl alcohol (1.0 g, 8.2 mmol) in ether was added n-BuLi
(2.5 M in hexane, 6.5 mL, 16 mmol), and the resulting cloudy
mixture was heated at reflux for 4 h.20 Iodomethane (0.40 mL,
8.2 mmol) was added at room temperature and the reaction
was stirred for 1 h and quenched with water. Extraction with
EtOAc followed by chromatography afforded 2-ethylbenzyl
Exp er im en ta l Section
General experimental methods have been previously de-
scribed,10 and reported yields are not optimized. 1H NMR
spectra were obtained on a Bruker AC400 spectrometer at 400
MHz. General procedure for preparing 5(Z)-benzylidene com-
pounds 7-9 from lactones 5 and benzyl Grignard reagents
have also been described11
(Z)-9-Flu or o-5-ben zyliden e-1,2-dih ydr o-2,2,4-tr im eth yl-
5H-ch r om en o[3,4-f]qu in olin e (7a ). This compound was
prepared by the general procedure from benzylmagnesium
chloride (1.0 mL of a 1 M solution in Et20, 5 equiv) and lactone
5b (62 mg, 0.20 mmol) in 91% yield as a yellow solid (70 mg):
1H NMR (CDCl3) 7.75 (d, J ) 7.5, 2 H), 7.41 (d, J ) 8.4, 1H),
7.40-7.34 (m, 3H), 7.22 (t, J ) 7.3, 1H), 7.09 (dd, J ) 8.8 and
4.8, 1 H), 6.86 (td, J ) 8.3 and 3.0, 1H), 6.66 (d, J ) 8.4, 1H),
5.62 (s, 1H), 5.53 (s, 1H), 4.18 (bs, 1H), 2.12 (s, 3H) and 1.33
(bs, 6H). To a solution of 7a (70 mg, 0.18 mmol) in ether at 0
°C was added HCl (1.0 M in ether, 0.18 mL), and the
precipitate was filtered and recrystallized in methanol to give
the HCl salt of 7a as yellow crystalline solid:19 mp > 200 °C
1
dec; H NMR (CDCl3) 7.97 (d, J ) 8.4, 1H), 7.73 (d, J ) 7.3,
2H), 7.65 (d, J ) 8.4, 1H), 7.46 (dd, J ) 9.2 and 3.0, 1H), 7.40
(t, J ) 7.6, 2H), 7.28 (t, J ) 7.2, 1H), 7.18 (dd, J ) 8.8 and 4.4,
1H), 7.05 (td, J ) 8.3 and 3.0, 1H), 5.97 (s, 1H), 5.47 (s, 1H),
2.23 (s, 3H), and 1.77 (bs, 6H). Anal. (C26H22FNO‚HCl‚1/3CH4O)
C, H, N.

Selective Progesterone Receptor Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4109
alcohol as a colorless oil (0.36 g, 33%). The alcohol (0.36 g, 2.6
mmol) in ether (10 mL) was treated with PBr3 (0.70 g, 2.6
mmol) at room temperature for 10 min and was quenched with
satd NaHCO3. Extraction with EtOAc followed by chromatog-
raphy provided 2-ethylbenzyl bromide as colorless oil (0.53 g,
94%).
to give crude benzyl alcohol. The alcohol was treated with PBr3
under the condition described previously to provide 2-meth-
ylthiobenzyl bromide in 58% overall yield (0.69 g): 1H NMR
(CDCl3) 7.35 (d, J ) 7.0, 1H), 7.32-7.25 (m, 2H), 7.14 (m, 1H),
4.65 (s, 2H), and 2.52 (s, 3H).
Compound 7g was prepared by the general procedure from
2-methylthiobenzyl bromide (0.44 g, 2.0 mmol) and lactone 5b
(50 mg, 0.16 mmol) in 45% yield as a bright yellow solid (31
mg): mp 149-150 °C; 1H NMR (CDCl3) 8.17 (d, J ) 7.6, 1H),
7.41 (d, J ) 8.3, 1H), 7.35 (dd, J ) 9.8 and 2.8, 1H), 7.30-
7.17 (m, 3 H), 7.00 (dd, J ) 8.8 and 4.8, 1H), 6.83 (td, J ) 8.4
and 2.8, 1H), 6.67 (d, J ) 8.4, 1H), 6.15 (s, 1H), 5.54 (s, 1H),
4.20 (bs, 1H), 2.39 (s, 3H), 2.16 (s, 3H), and 1.35 (bs, 6H). Anal.
(C27H24FNOS) C, H, N.
Compound 7c was prepared by the general procedure from
2-ethylbenzyl bromide (0.20 g, 1.0 mmol) and lactone 5b (20
mg, 0.065 mmol) in 74% yield as a yellow foam (20 mg): 1H
NMR (CDCl3) 8.21 (d, J ) 7.5, 1H), 7.41 (d, J ) 8.3, 1H), 7.35-
7.22 (m, 2H), 7.20-7.13 (m, 2H), 7.00 (dd, J ) 8.8 and 4.3,
1H), 6.82 (td, J ) 8.4 and 2.9, 1H), 6.67 (d, J ) 8.4, 1H), 5.90
(s, 1H), 5.52 (s, 1H), 4.20 (bs, 1H), 2.61 (q, J ) 7.5, 2H), 2.14
(s, 3H), 1.34 (bs, 6H), and 1.13 (t, J ) 7.5, 3H). Anal. (C28H26
FNO) C, H, N.
-
(Z)-9-F lu or o-5-(2-flu or oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7h ). This com-
pound was prepared by the general procedure from 2-fluo-
robenzyl bromide (0.38 g, 2.0 mmol) and lactone 5b (50 mg,
0.16 mmol) in 65% yield as a yellow solid (42 mg): mp130-
132 °C; 1H NMR (CDCl3) 8.19-8.14 (m, 1H), 7.34 (d, J ) 8.4,
1H), 7.28 (dd, J ) 9.7 and 3.0, 1H), 7.18-7.08 (m, 2H), 6.99-
6.93 (m, 2H), 6.78 (td, J ) 8.1 and 3.0, 1H), 6.60 (d, J ) 8.4,
1H), 5.84 (s, 1H), 5.47 (s, 1H), 4.12 (s, 1H), 2.06 (s, 3H), and
1.26 (bs, 6H). Anal. (C26H21F2NO) C, H, N.
(Z)-9-Flu or o-5-(2-p r op ylben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7d ). P r ep a r a -
tion of 2-P r op ylben zyl Br om id e. This compound was made
from 2-methylbenzyl alcohol (1.0 g, 8.2 mmol) by the alkyla-
tion/bromide-conversion procedure as described in the prepa-
ration of 2-ethylbenzyl bromide. 2-Propylbenzyl alcohol was
obtained in 63% (0.75 g), and 2-propylbenzyl bromide was
isolated in 91% yield (1.0 g) as a colorless oil.
Compound 7d was prepared by the general procedure from
2-propylbenzyl bromide (0.21 g, 1.0 mmol) and lactone 5b (50
mg, 0.16 mmol) in 74% yield as a yellow solid (50 mg): mp
135-137 °C; 1H NMR (CDCl3) 8.25 (d, J ) 7.5, 1H), 7.41 (d, J
) 8.4, 1H), 7.34 (dd, J ) 9.2 and 3.0, 1H), 7.30-7.22 (m, 1H),
7.20-7.15 (m, 2H), 7.02 (dd, J ) 8.8 and 4.3, 1 H), 6.82 (td, J
) 8.4 and 2.9, 1H), 6.67 (d, J ) 8.4, 1H), 5.90 (s, 1H), 5.52 (s,
1H), 4.19 (bs, 1H), 2.54 (t, J ) 7.9, 2H), 2.13 (s, 3H), 1.60-
1.50 (m, 2H), 1.34 (bs, 6H), and 0.90 (t, J ) 7.3, 3H). Anal.
(C29H28FNO‚1/4H2O) C, H, N.
(Z)-9-F lu or o-5-(2-ch lor oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7i). This com-
pound was prepared by the general procedure from 2-chlo-
robenzyl chloride (0.32 g, 2.0 mmol) and lactone 5b (50 mg,
0.16 mmol) in 45% yield as a yellow solid (30 mg): mp 76-79
1
°C; H NMR (CDCl3) 8.29 (d, J ) 7.9, 1H), 7.43 (d, J ) 8.4,
1H), 7.40-7.35 (m, 2H), 7.31 (t, J ) 7.6, 1H), 7.15 (td, J ) 9.0
and 1.5, 1H), 7.04 (dd, J ) 8.9 and 4.9, 1H), 6.86 (td, J ) 8.5
and 2.9, 1H), 6.69 (d, J ) 8.4, 1H), 6.15 (s, 1H), 5.56 (s, 1H),
(Z)-9-F lu or o-5-(2-isop r op ylb en zylid en e)-1,2-d ih yd r o-
2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7e). P r ep a -
r a tion of 2-Isop r op ylben zyl Br om id e. To a solution of
2-isopropyl bromobenzene (2.5 g, 12 mmol) in THF (30 mL) at
-78 °C was added n-BuLi (2.5 M in hexane, 5.0 mL, 12 mmol),
and the mixture was warmed to -30 °C. A separate flask
charged with paraformaldehyde (1.7 g, 56 mmol) was heated
in 160 °C oil bath, and the monomeric formaldehyde gas was
bubbled by dry nitrogen through a tube to the reaction mixture
till the reaction went to completion. The mixture was quenched
with water, extracted with methylene chloride, and concen-
trated to afford crude 2-isopropylbenzyl alcohol (1.0 g, 56%).
The alcohol was converted to 2-isopropylbenzyl bromide by
PBr3, under the conditions described previously, in 90% yield.
Compound 7e was prepared by the general procedure from
2-isopropylbenzyl bromide (0.21 g, 1.0 mmol) and lactone 5b
(50 mg, 0.16 mmol) in 71% yield as an orange solid (48 mg):
4.23 (s, 1H), 2.16 (s, 3H), and 1.35 (bs, 6H). Anal. (C26H21
ClFNO) C, H, N.
-
(Z)-9-F lu or o-5-(2-br om oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7j). This com-
pound was prepared by the general procedure from 2-bro-
mobenzyl bromide (0.50 g, 2.0 mmol) and lactone 5b (50 mg,
0.16 mmol) in 81% yield as a yellow solid (60 mg): mp 82-84
1
°C; H NMR (CDCl3) 8.31 (dd, J ) 8.0 and 1.6, 1H), 7.58 (dd,
J ) 7.9 and 1.1, 1H), 7.44 (d, J ) 8.4, 1H), 7.40-7.31 (m, 2H),
7.12-7.03 (m, 2H), 6.85 (td, J ) 8.4 and 2.9, 1H), 6.69 (d, J )
8.4, 1H), 6.15 (s, 1H), 5.56 (s, 1H), 4.23 (s, 1H), 2.16 (s, 3H),
and 1.36 (bs, 6H). Anal. (C26H21BrFNO) C, H, N.
(Z)-9-F lu or o-5-(2-cya n oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7k ). To a solution
of o-tolunitrile (0.23 g, 2.0 mmoL) in THF at -78 °C was added
LiN(SiMe3)2 (1 M in THF, 2.2 mL), and the reaction was stirred
at -78 °C for 1 h. A solution of lactone 5b (0.15 g, 0.40 mmol)
in THF (2 mL) was added to give rise a deep red solution, and
the reaction was warmed to room temperature and quenched
with water. Extraction with EtOAc and removal of solvent
afforded crude hemiacetal 6, which was dehydrated under
acidic condition as that described in the general procedure to
give 7k (40 mg, 24%) as yellow solid: mp 100-102 °C; 1H NMR
(CDCl3) 8.44 (d, J ) 8.1, 1H), 7.65-7.57 (m, 2H), 7.45 (d, J )
8.4, 1H), 7.40 (dd, J ) 9.7 and 2.8, 1H), 7.24 (t, J ) 7.1, 1H),
7.09 (dd, J ) 8.9 and 4.7, 1H), 6.89 (td, J ) 8.1 and 3.0, 1H),
6.72 (d, J ) 8.4, 1H), 6.15 (s, 1H), 5.12 (s, 1H), 4.27 (s, 1H),
2.15 (s, 3H), and 1.36 (bs, 6H). Anal. (C27H21FN2O) C, H, N.
1
mp 156-158 °C; H NMR (CDCl3) 8.08 (dd, J ) 6.9 and 2.0,
1H), 7.40 (d, J ) 8.4, 1H), 7.37 (dd, J ) 9.6 and 2.8, 1H), 7.30-
7.17 (m, 3H), 6.96 (dd, J ) 8.4 and 4.8, 1H), 6.78 (td, J ) 8.0
and 3.2, 1H), 6.67 (d, J ) 8.4, 1H), 5.94 (s, 1H), 5.52 (s, 1H),
4.20 (bs, 1H), 3.10 (sept, J ) 6.9, 1H), 2.14 (s, 3H), 1.32 (bs,
6H), and 1.15 (d, J ) 6.9, 6H). Anal. (C29H28FNO) C, H, N.
(Z)-9-F lu or o-5-(2-m et h oxyb en zylid en e)-1,2-d ih yd r o-
2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7f). This
compound was prepared by the general procedure from
2-methoxybenzyl chloride (0.31 g, 2.0 mmol) and lactone 5b
(0.10 g, 0.33 mmol) in 55% yield as a yellow solid (75 mg): mp
80-83 °C; 1H NMR (CDCl3) 8.15 (dd, J ) 7.6 and 1.6, 1H),
7.38 (d, J ) 8.4, 1H), 7.33 (dd, J ) 10.0 and 2.8, 1H), 7.20 (dd,
J ) 8.4 and 1.6, 1H), 7.04-6.99 (m, 2H), 6.86 (d, J ) 8.0, 1H),
6.82 (td, J ) 8.0 and 3.2, 1H), 6.63 (d, J ) 8.4, 1H), 6.08 (s,
1H), 5.51 (s, 1H), 4.19 (bs, 1H), 3.80 (s, 3H), 2.14 (s, 3H), and
1.34 (bs, 6H). Anal. (C27H24FNO2) C, H, N.
(Z)-9-Flu or o-5-(2-for m ylben zyliden e)-1,2-dih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7l). To a solution
of compound 7k (21 mg, 0.050 mmol) in CHCl3 (3 mL) at -78
°C was added DIBAL-H (1.5 M in toluene, 0.05 mL, 0.075
mmol), and the reaction was warmed to room temperature and
stirred overnight. The reaction was quenched with water,
extracted with EtOAc, and concentrated. Chromatography
afforded 7l as a yellow foam (15 mg, 71%): 1H NMR (CDCl3)
10.21 (s, 1H), 8.00 (d, J ) 7.9, 1H), 7.85 (d, J ) 6.5, 1H), 7.58
(t, J ) 7.6, 1H), 7.42 (d, J ) 8.4, 1H), 7-38-7.31 (m, 2H),
6.91 (dd, J ) 8.8 and 4.8, 1H), 6.82 (td, J ) 8.2 and 2.9, 1H),
(Z)-9-F lu or o-5-(2-m eth ylth ioben zylid en e)-1,2-d ih yd r o-
2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7g). P r ep a -
r a tion of 2-Th iom eth oxyben zyl Br om id e. To a solution of
methyl 2-methylthio benzoate (1.0 g, 5.5 mmol) in THF (20
mL) at 0 °C was added LAH (0.48 g, 3.0 mmol), and the
reaction mixture was stirred for 30 min. The reaction was
quenched with water, extracted with EtOAc, and concentrated

4110 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
Zhi et al.
6.70 (d, J ) 8.4, 1H), 6.48 (s, 1H), 5.55 (s, 1H), 4.25 (bs, 1H),
2.15 (s, 3H), and 1.35 (bs, 6H). Anal. (C27H22FNO2‚1/3H2O) C,
H, N.
2H), 7.24 (t, J ) 7.6, 1H), 6.95 (m, 2H), 6.67 (d, J ) 8.4, 1H),
5.68 (s, 1 H), 5.55 (s, 1H), 4.19 (s, 1H), 2.13 (s, 3H), 1.36 (bs,
6H). Anal. (C26H22FNO) C, H, N.
(Z)-9-F lu or o-5-(2-tr iflu or om eth oxyben zylid en e)-1,2-d i-
h yd r o-2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (7m ).
This compound was prepared by the general procedure from
2-trifluoromethoxybenzyl bromide (0.51 g, 2.0 mmol) and
lactone 5b (0.10 g, 0.33 mmol) in 77% yield as a yellow solid
(Z)-7-F lu or o-5-(3-flu or oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (9b). This com-
pound was prepared by the general procedure from 2-fluo-
robenzyl bromide (189 mg, 1.0 mmol) and 5a (30 mg, 0.10
mmol) in 54% yield as a bright yellow solid (21 mg): mp 82-
1
1
(0.12 g): mp 147-149 °C; H NMR (CDCl3) 8.42 (d, J ) 7.4,
84 °C; H NMR (CDCl3) 7.73 (dd, J ) 9.4 and 1.8, 1H), 7.53
1H), 7.42 (d, J ) 8.4, 1H), 7.39-7.30 (m, 2H), 7.26-7.20 (m,
2H), 7.07 (dd, J ) 8.8 and 4.8, 1H), 6.86 (td, J ) 8.0 and 2.8,
1H), 6.68 (d, J ) 8.4, 1H), 6.00 (s, 1H), 5.55 (s, 1H), 4.21 (s,
1H), 2.10 (s, 3H), and 1.32 (bs, 6H). Anal. (C27H21F4NO2) C,
H, N.
(d, J ) 9.1, 1H), 7.51 (d, J ) 8.5, 1H), 7.45 (dd, J ) 6.5 and
2.3, 1H), 7.32 (td, J ) 8.0 and 6.3, 1H), 7.05-6.90 (m, 3H),
6.69 (d, J ) 8.5, 1H), 5.65 (s, 1H), 5.55 (s, 1H), 4.20 (bs, 1H),
2.12 (s, 3H), and 1.36 (bs, 6H). Anal. (C26H21F2NO) C, H, N.
(Z)-7-F lu or o-5-(4-flu or oben zylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (9c). This com-
pound was prepared by the general procedure from 4-fluo-
robenzyl chloride (0.19 g, 1.0 mmol) and lactone 5a (20 mg,
0.065 mmol) in 88% yield as a yellow solid (23 mg): mp 160-
(Z)-9-F lu or o-5-(4-p icolylid en e)-1,2-d ih yd r o-2,2,4-t r i-
m eth yl-5H-ch r om en o[3,4-f]qu in olin e (8a ). To a solution of
4-picoline (0.24 g, 2.5 mmol) and TMEDA (0.30 mL, 2.0 mmol)
in THF (4 mL) at -78 °C was added n-BuLi (2.4 M in hexane,
0.8 mL, 2.0 mmol), and the resulting orange solution was
stirred for 40 min.21 A solution of lactone 5b (31 mg, 0.10
mmol) in THF (1 mL) was added, and the reaction mixture
was stirred at -70 °C for 30 min. The reaction was quenched
with water, extracted, and concentrated. Chromatography
afforded hemiacetal 6 (R ) 4-pyridyl) as a yellow oil, which
was treated with TsOH by the general procedure to give 8a
(35 mg, 91%) as yellow solid: mp 147-149 °C; 1H NMR
(CDCl3) 8.56 (dd, J ) 4.8 and 1.3, 2H), 7.60 (dd, J ) 4.8 and
1.3, 2H), 7.45 (d, J ) 8.4, 1H), 7.39 (dd, J ) 9.7 and 3.0, 1H),
7.15 (dd, J ) 8.9 and 4.8, 1H), 6.91 (td, J ) 8.4 and 3.1, 1H),
6.73 (d, J ) 8.4, 1H), 5.57 (s, 1H), 5.54 (s, 1H), 4.26 (s, 1H),
2.10 (s, 3H), and 1.37 (bs, 6H). Anal. (C25H21FN2O) C, H, N.
(Z)-9-F lu or o-5-(3-m et h yl-4-p icolylid en e)-1,2-d ih yd r o-
2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (8b). This
compound was prepared in a similar fashion as that described
in the synthesis of 8a . Selective lithiation of 3,4-lutidine (0.32
g, 3.0 mmol) followed by addition to lactone 5b (31 mg, 0.10
mmol) and dehydration afforded 8b (27 mg, 67%) as a yellow
solid: mp 247-249 °C; 1H NMR (CDCl3) 8.46 (d, J ) 5.3, 1H),
8.38 (s, 1H), 8.05 (d, J ) 5.3, 1H), 7.46 (d, J ) 8.4, 1H), 7.38
(dd, J ) 9.7 and 2.8, 1H), 7.08 (dd, J ) 8.9 and 4.8, 1H), 6.89
(td, J ) 8.4 and 2.9, 1H), 6.73 (d, J ) 8.4, 1H), 5.84 (s, 1H),
5.55 (s, 1H), 4.27 (s, 1H), 2.24 (s, 3H), 2.14 (s, 3H), and 1.36
(bs, 6H). Anal. (C26H23FN2O) C, H, N.
(Z)-9-F lu or o-5-(2-p icolylid en e)-1,2-d ih yd r o-2,2,4-t r i-
m eth yl-5H-ch r om en o[3,4-f]qu in olin e (8c). This compound
was prepared in a similar fashion as that described in the
synthesis of 8a . Lithiation of 2-picoline (0.35 g, 3.8 mmol)
followed by addition to lactone 5b (31 mg, 0.10 mmol) and
dehydration afforded 8c (30 mg, 78%) as a yellow solid: mp
132-134 °C; 1H NMR (CDCl3) 8.57 (d, J ) 3.9, 1H), 8.30 (d, J
) 8.1, 1H), 7.72 (td, J ) 7.9 and 1.7, 1H), 7.44 (d, J ) 8.4,
1H), 7.39 (dd, J ) 9.8 and 2.9, 1H), 7.14-7.08 (m, 2H), 6.88
(td, J ) 8.5 and 2.8, 1H), 6.70 (d, J ) 8.4, 1H), 5.95 (s, 1H),
5.54 (s, 1H), 4.23 (s, 1H), 2.15 (s, 3H), and 3.15 (bs, 6H). Anal.
(C25H21FN2O) C, H, N.
(Z)-9-F lu or o-5-(3-m et h yl-2-p icolylid en e)-1,2-d ih yd r o-
2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (8d ). This
compound was prepared in a similar fashion as that described
in the synthesis of 8a . Selective lithiation of 2,3-lutidine (0.32
g, 3.0 mmol) followed by addition to lactone 5b (66 mg, 0.21
mmol) and dehydration afforded 8d (70 mg, 82%) as a yellow
solid: mp 194-195 °C; 1H NMR (CDCl3) 8.53 (d, J ) 3.8, 1H),
7.48 (d, J ) 7.1, 1H), 7.44 (d, J ) 8.4, 1H), 7.34 (dd, J ) 9.8
and 2.9, 1H), 7.07 (dd, J ) 7.7 and 4.8, 1H), 6.95 (dd, J ) 8.8
and 4.8, 1H), 6.80 (td, J ) 8.5 and 2.8, 1H), 6.70 (d, 1H), 5.94
(s, 1H), 5.53 (s, 1H), 4.22 (s, 1H), 2.31 (s, 3H), 2.26 (s, 3H),
and 1.34 (bs, 6H). Anal. (C26H23FN2O) C, H, N.
1
162 °C; H NMR (CDCl3) 7.85 (dd, J ) 8.9 and 5.6, 1H), 7.49
(d, J ) 8.4, 1H), 7.52 (dd, J ) 7.3 and 1.1, 1H), 7.08 (t, J )
8.8, 2H), 7.01-6.93 (m, 2 H), 6.67 (d, J ) 8.3, 1H), 5.63 (s,
1H), 5.54 (s, 1H), 4.20 (bs, 1 H), 2.11 (s, 3H), 1.29 (bs, 6H).
Anal. (C26H21F2NO) C, H, N.
(Z)-7-Flu or o-5-(2-m eth ylben zyliden e)-1,2-dih ydr o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (9d ). This com-
pound was prepared by the general procedure from 2-meth-
ylbenzyl bromide (185 mg, 1.0 mmol) and lactone 5a (30 mg,
0.10 mmol) in 50% yield as a yellow solid (20 mg): mp 150-
1
151 °C; H NMR (CDCl3) 8.35 (d, J ) 7.9, 1H), 7.50 (d, J )
8.4, 1H), 7.45 (t, J ) 5.6, 1H), 7.30 (m, 1H), 7.16 (m, 2H), 6.94
(m, 2H), 6.68 (d, J ) 8.4, 1H), 5.97 (s, 1H), 5.53 (s, 1H), 4.20
(bs 1H), 2.29 (s, 3H), 2.17 (s, 3H), 1.35 (br s, 6H). Anal. (C27H24
FNO) C, H, N.
-
(Z)-9-F lu or o-5-(2-d im et h yla m in ob en zylid en e)-1,2-d i-
h yd r o-2,2,4-tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (15).
To a solution of N-methyl-2-toluidine (0.30 g, 2.5 mmol) in THF
(10 mL) at -78 °C was added n-BuLi (1.6 M in hexane, 1.6
mL, 2.6 mmol), and the reaction mixture was warmed to -10
°C and then, saturated with CO2 gas. The mixture was
concentrated under reduced pressure, dissolved in THF (10
mL), and cooled back to -78 °C. Second portion of n-BuLi (1.6
mL) was added, and the resulting orange slurry was stirred
at -15 °C for 40 min and then cooled back to -78 °C again. A
solution of lactone 5b (0.10 g, 0.31 mmol) in THF (2 mL) was
added, and the reaction mixture was warmed slowly to -40
°C and quenched with water. The mixture was treated with
HCl (2 M, 6 mL) to hydrolyze the carbamate and neutralized
to pH > 9. Extraction with EtOAc followed by chromatography
afforded compound 12 as yellow oil (0.10 g, 93%). To a solution
of compound 12 (75 mg, 0.15 mmol) in CH2Cl2 (4 mL) were
added pyridine (0.5 mL) and methyl chloroformate (0.05 mL,
0.6 mmol), and the reaction was stirred for 10 min. The
reaction mixture was extracted with EtOAc, and the organic
layer was washed with satd NaHCO3 and brine and concen-
trated to afford compound 13 as crude mixture. A mixture of
compound 13 and satd Na2CO3 (5 mL) in MeOH/dioxane (1:1
mixture, 12 mL) was heated at 80 °C for 2 h and extracted
with EtOAc. The organic phase was washed with brine and
concentrated to provide crude intermediate, which was treated
with TsOH in CH2Cl2 (5 mL) for 2 h. The reaction was
quenched with 2 M NaHCO3 (5 mL) and extracted with EtOAc.
Chromatography afforded compound 14 (40 mg, 57%) as a
yellow foam: 1H NMR (CDCl3) 8.47 (d, J ) 7.5, 1H), 7.43 (d,
J ) 8.4, 1H), 7.41-7.33 (m, 2H), 7.24 (t, J ) 7.4, 1H), 7.12 (d,
J ) 9.6, 1H), 7.09 (dd, J ) 8.9 and 4.8, 1H), 6.87 (td, J ) 8.5
and 2.9, 1H), 6.69 (d, J ) 8.4, 1H), 5.72 (s, 1H), 5.52 (s, 1H),
4.23 (s, 1H), 3.60 (bs, 3H), 3.10 (bs, 3H), 2.08 (s, 3H), and 1.33
(bs, 6H). To a solution of compound 14 (40 mg, 0.085 mmol) in
CH2Cl2 (5 mL) at 0 °C was added DIBAL-H (1.5 M in toluene,
0.30 mL), and the reaction was stirred at room temperature
for 2 h. The reaction was quenched with water, extracted with
EtOAc, and concentrated. Chromatography afforded 15 (22 mg,
60%) as a yellow foam: 1H NMR (CDCl3) 8.24 (dd, J ) 7.7 an
1.2, 1H), 7.40 (d, J ) 8.3, 1H), 7.33 (dd, J ) 9.8 and 2.9, 1H),
(Z)-5-Ben zylid en e-7-flu or o-1,2-d ih yd r o-2,2,4-tr im eth yl-
5H-ch r om en o[3,4-f]qu in olin e (9a ). This compound was
prepared by the general procedure from benzylmagnesium
chloride (0.4 mL of a 1 M solution in Et20, 5 equiv) and lactone
5a (20 mg, 0.065 mmol) in 81% yield as a yellow solid (20
mg): mp 92-94 °C; 1H NMR (CDCl3) 7.87 (d, J ) 7.6, 2H),
7.49 (d, J ) 8.4, 1H), 7.45 (d, J ) 6.4, 1H), 7.39 (t, J ) 7.6,

Selective Progesterone Receptor Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19 4111
7.20 (t, J ) 7.5, 1H), 7.09 (t, J ) 7.6, 1H), 7.05-6.96 (m, 2H),
6.81 (t, J ) 5.4, 1H), 6.66 (d, J ) 8.4, 1H), 6.09 (s, 1H), 5.49 (s,
1H), 4.20 (bs, 1H), 2.63 (s, 6H), 2.11 (s, 3H), and 1.32 (bs, 6H).
Anal. (C28H27FN2O‚1/2H2O) C, H, N.
binding assays are progesterone for hPR-A, DHT for hAR, and
dexamethasone for hGR.
Ma ter ia l a n d Meth od s for Mu ltien d P oin t Ra t Assa y.
This assay will be described in greater detail elsewhere, but
briefly the assay is a modification as described previously.22
Briefly, 4-week old female rats were ovariectomized an allowed
to recover 1 week prior to dosing for 3 days with either vehicle,
estrone (10ug per rat) or estrone plus progestin (0.1, 1, and
10 mg/kg, oral). On the morning of the fourth day, rats were
given a single intraperitoneal injection of 5-bromo-2′-deoxy-
uridine (Brdu), which incorporates into proliferating cells
DNA. Animals were sacrificed 2 h later and breast, uterine
and vagina tissues isolated and paraffin embedded. The
uterine and vagina tissues were sectioned and stained, and
the epithelial cell height was measured using ImagePro
software. The breast tissue was sectioned, deparaffinized, and
subjected to immuno-histochemistry steps which first tags the
Brdu within the DNA and second tags the Brdu antibody with
a secondary antibody which is fluorescent tagged. The lobular-
alveolar buds, which are under progestin control, were identi-
fied and the amount of labeled nuclei quantified and expressed
as a proliferating index.
9-F lu or o-5-m et h ylid en e-1,2-d ih yd r o-2,2,4-t r im et h yl-
5H-ch r om en o[3,4-f]qu in olin e (16). Treatment of lactone 5b
(0.99 g, 3.2 mmol) with Tebbe reagent (0.5 M in toluene, 7
mL) by the literature condition15 afforded compound 16 in 30%
yield as a yellow solid: 1H NMR (CDCl3) 7.39 (d, J ) 8.4, 1H),
7.33 (dd, J ) 7.5 and 2.5, 1H), 6.94 (dd, J ) 8.7 and 4.5, 1H),
6.85 (td, J ) 8.1 and 2.5, 1H), 6.66 (d, J ) 8.4, 1H), 5.51 (s,
1H), 5.07 (s, 1H), 4.45 (s, 1H), 2.15 (s, 3H), and 1.30 (s, 6H).
9-F lu or o-5(Z)-br om om eth ylid en e-1,2-d ih yd r o-2,2,4-tr i-
m eth yl-5H-ch r om en o[3,4-f]qu in olin e (17). Compound 16
(0.10 g, 0.33 mmol) was treated with NBS (30 mg, 0.33 mmol)
in DMF (2 mL) at room temperature for 10 min, and standard
workup followed by chromatography provided compound 17
(65 mg, 51%) as a yellow foam: 1H NMR (CDCl3) 7.40 (d, J )
8.4, 1H), 7.33 (dd, J ) 7.4 and 2.8, 1H), 7.10 (dd, J ) 8.8 and
4.8, 1H), 6.86 (td, J ) 8.0 and 2.8, 1H), 6.67 (d, J ) 8.4, 1H),
5.52 (s, 1H), 5.45 (s, 1H), 4.19 (s, 1H), 2.08 (s, 3H), and 1.29
(s, 6H).
9-F lu or o-5(Z)-(2-tr iflu or om eth ylben zylid en e)-1,2-d ih y-
d r o-2,2,4-t r im et h yl-5H -ch r om en o[3,4-f]q u in olin e (18a ).
To a solution of compound 17 (20 mg, 0.052 mmol) in DME (4
mL) was added Pd(PPh3)4 (2 mg, 3 mol %), and the mixture
was stirred at room temperature for 15 min. A solution of
2-trifluoromethylbenzeneboronic acid (15 mg, 0.078 mmol) in
DME (1 mL) and CsF (24 mg, 0.15 mmol) were added to the
reaction mixture. The reaction was heated at 80 °C for 2 h,
quenched with NaHCO3 (satd aqueous), and extracted with
EtOAc. Removal of solvent and chromatography of the crude
mixture afforded 18a (12 mg, 53%) as yellow foam: 1H NMR
(CDCl3) 8.52 (d, J ) 8.0, 1H), 7.64 (d, J ) 8.0, 1H), 7.58 (t, J
) 8.0, 1H), 7.43 (d, J ) 8.4, 1H), 7.37 (dd, J ) 9.0 and 2.9,
1H), 7.28 (t, J ) 8.0, 1H), 7.04 (dd, J ) 9.0 and 4.8, 1H), 6.85
(td, J ) 9.0 and 2.9, 1H), 6.70 (d, J ) 8.4, 1H), 6.02 (s, 1H),
5.55 (s, 1H), 4.23 (s, 1H), 2.08 (s, 3H), and 1.33 (bs, 6H). Anal.
(C27H21F4NO‚H2O) C, H, N.
9-Flu or o-5(Z)-(3-th ien ylm eth yliden e)-1,2-dih ydr o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (18b). This com-
pound was prepared from the coupling reaction of compound
17 (50 mg, 0.13 mmol) and 3-thienylboronic acid (25 mg, 0.20
mmol) as that described in the synthesis of 18a in 38% yield
(19 mg) as orange oil: 1H NMR (CDCl3) 7.61 (d, J ) 2.7, 1H),
7.49 (dd, J ) 5.0 and 1.4, 1H), 7.40 (d, J ) 8.4, 1H), 7.34 (dd,
J ) 9.4 and 2.1, 1H), 7.30 (dd, J ) 4.8 and 3.0, 1H), 7.08 (dd,
J ) 8.7 and 4.8, 1H), 6.85 (td, J ) 8.1 and 3.2, 1H), 6.65 (d, J
) 8.4, 1H), 5.70 (s, 1H), 5.52 (s, 1H), 4.18 (s, 1H), 2.10 (s, 3H),
and 1.34 (bs, 6H). Anal. (C24H20FNOS) C, H, N.
Refer en ces
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9-F lu or o-5(Z)-(2-fu r ylm et h ylid en e)-1,2-d ih yd r o-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (18c). This com-
pound was prepared from the coupling reaction of compound
17 (25 mg, 0.065 mmol) and 2-(tributylstannyl)furan (24 mg,
0.065 mmol) as that described in the synthesis of 18a in 67%
yield (16 mg) as yellow solid: mp 89-91 °C; 1H NMR (CDCl3)
7.40 (d, J ) 8.4, 1H), 7.36 (d, J ) 1.6, 1H), 7.34 (dd, J ) 9.6
and 2.8, 1H), 7.08 (dd, J ) 8.8 and 4.8, 1H), 6.93 (d, J ) 3.3,
1H), 6.86 (td, J ) 8.9 and 2.5, 1H), 6.64 (d, J ) 8.4, 1H), 6.51
(t, J ) 2.6, 1H), 5.72 (s, 1H), 5.52 (s, 1H), 4.18 (s, 1H), 2.10 (s,
3H), and 1.33 (bs, 6H). Anal. (C24H20FNO2) C, H, N.
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described previously.10 The agonist activity was determined
by examining the LUC expression (normalized response), and
the efficacy readout was a relative value to the maximal LUC
expression produced by a reference agonist, e.g., progesterone
for hPR, dihydrotestosterone (DHT) for hAR, dexamethasone
for hGR, aldosterone for hMR, estradiol for hER. All the
cotransfection experiments were carried out in 96-well plates
by automation (Beckman Biomomek automated workstation).
R ecep t or Bin d in g Assa ys. The preparation of receptor
binding assays for hPR-A, hGR, and hAR were described
previously,10 and the radioligands used in the competative

4112 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 19
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J M020477G