5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines as potent, orally active, nonsteroidal progesterone receptor agonists: The effect of D-ring substituents

Article abstract of DOI:10.1021/jm9705770

Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to determine the effects of substitution at C(8) and C(9) on the progestational activity of this pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl group with variously substituted aryl groups resulted in optimization of the progestational activity, affording compounds with in vitro activity greater than that of progesterone as measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B). Binding affinities (K(i)) to hPR-A were subnanomolar in many cases. These in vitro effects were verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)- 1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline) was more potent than medroxyprogesterone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight assay using immature rats.

Full text of DOI:10.1021/jm9705770

J . Med. Chem. 1998, 41, 303-310
303
5-Ar yl-1,2-d ih yd r o-5H-ch r om en o[3,4-f]qu in olin es a s P oten t, Or a lly Active,
Non ster oid a l P r ogester on e Recep tor Agon ists: Th e Effect of D-Rin g
Su bstitu en ts
J ames P. Edwards,*,† Sarah J . West,† Keith B. Marschke,‡ Dale E. Mais,§ Marco M. Gottardis,§ and
Todd K. J ones†
Departments of Medicinal Chemistry, New Leads Discovery, and Endocrine Research, Ligand Pharmaceuticals, Inc.,
10275 Science Center Drive, San Diego, California 92121
Received August 28, 1997
Several 5-(4-chlorophenyl)-1,2-dihydro-5H-chromeno[3,4-f]quinolines were prepared to deter-
mine the effects of substitution at C(8) and C(9) on the progestational activity of this
pharmacophore. In combination with a halogen (F or Cl) at C(9), replacement of the C(5) aryl
group with variously substituted aryl groups resulted in optimization of the progestational
activity, affording compounds with in vitro activity greater than that of progesterone as
measured by a cotransfection assay using human progesterone receptor subtype-B (hPR-B).
Binding affinities (Ki) to hPR-A were subnanomolar in many cases. These in vitro effects were
verified in vivo using a rodent model. Compound 10 (LG120794, 9-chloro-5-(4-chlorophenyl)-
1,2-dihydro-2,2,4-trimethyl-5H-chromeno[3,4-f]quinoline) was more potent than medroxyproges-
terone acetate at counterpoising the effects of estradiol benzoate in the uterine wet weight
assay using immature rats.
In tr od u ction
Control of gene expression by intracellular receptors
(IRs) is regulated by small molecule naturally occurring
hormones.1 The ability of certain small molecules to
mimic (agonism) or to inhibit (antagonism) effects of
natural hormones provides an opportunity to influence
cell growth, cell differentiation, and other cellular
processes. IRs, including sex steroid receptors, are
therefore attractive targets for drug discovery.2 The
human progesterone receptor (hPR) is a member of a
subgroup within the IR superfamily that includes the
human androgen (hAR), estrogen (hER), glucocorticoid
(hGR), and mineralocorticoid (hMR) receptors. Like the
other members of this superfamily, after binding its
cognate ligand, progesterone (Figure 1), hPR binds to
specific hormone response elements (HREs) in target
genes and modulates gene transcription.1,3,4
Drugs that modulate the transcriptional activity of
hPR play important roles in medicine, and hPR agonists
F igu r e 1. RU486, progesterone, and 5-aryl-1,2-dihydro-2,2,4-
trimethyl-5H-chromeno[3,4-f]quinoline general structure 1.
have been used therapeutically for decades.5 For ex-
ample, medroxyprogesterone acetate (MPA), norgestrel,
and norethindrone are used in birth control formula-
tions, generally in combination with estrogen receptor
agonists;5,6 moreover, hPR agonists are also useful for
hormone replacement therapy (HRT)7 and the treat-
ment of certain carcinomas.8 All hPR modulators
(including hPR antagonists such as RU486, Figure 1)
either currently marketed or undergoing clinical trials
are steroids. Accordingly, these drugs display differing,
but substantial, levels of cross-reactivity with other sex
steroid receptors, particularly with hAR and hGR,6,9
which can lead to undesirable side effects. The op-
portunity therefore exists for the discovery of more
selective and efficacious hPR agonists and antagonists.
Utilizing the cotransfection assay1,2a,10 as a guide to
determining structure-activity relationships (SAR), we
have been pursuing the discovery of nonsteroidal hPR
modulators.11,12 A previous report from these labora-
tories demonstrated that certain 5-aryl-1,2-dihydro-5H-
chromeno[3,4-f]quinolines (1, R3 ) R4 ) H, Figure 1)
act as potent hPR agonists and reported optimization
of the structure of the 5-aryl substituent.13 This report
discloses a series of hPR agonists based on the 5-aryl-
1,2-dihydro-5H-chromeno[3,4-f]quinoline pharmacoph-
ore (1, Figure 1) that was designed to determine the
effects of D-ring substituents (R3-R4) upon hPR agonist
activity. This series of nonsteroidal hPR agonists has
yielded potent compounds with greatly improved activ-
* Address correspondence to this author. Phone: (619) 550-7723.
Fax: (619) 550-7249. E-mail: jedwards@ligand.com.
† Department of Medicinal Chemistry.
‡ Department of New Leads Discovery.
§ Department of Endocrine Research.
S0022-2623(97)00577-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/14/1998

304 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Edwards et al.
Sch em e 1a
F igu r e 2. Concentration-response curves for progesterone,
10, 16, and RU486. RU486 was run in the antagonist mode;
P ) progesterone. See the Experimental Section for details.
pounds 8-27 are racemic, and all biological data were
obtained using racemates.19
In Vitr o Biologica l Stu d ies
The ability of quinolines 8-27 to modulate hPR
activity in a cellular context was measured using a
cotransfection assay, and ligand binding affinity was
measured using a competitive binding assay using
baculovirus-expressed hPR-A in Sf21 cells as described
previously.11a,b The cotransfection assay is a tool for the
functional characterization of interactions of small-
molecule agonists or antagonists with IRs. Two plas-
mids, a receptor plasmid and a reporter plasmid, are
transiently introduced into mammalian cells that do not
normally express the IR of interest. In the experiments
described below, the receptor plasmid contained hPR-B
under constitutive control of the SV-40 promoter.20 The
reporter plasmid, MMTV-LUC, contained the cDNA for
firefly luciferase (LUC) under control of the mouse
mammary tumor virus (MMTV) long terminal repeat,
a conditional promoter containing a progesterone re-
sponse element (PRE).10 Progesterone and other ste-
roidal hPR agonists cause concentration-dependent
increases in luciferase activity in the hPR-B contrans-
fection assay, which can be reversed by known steroidal
hPR antagonists such as RU486 or ZK98299 (Figure 2).
Cross-reactivity with other sex steroid IRs was assessed
using similar hGR, hAR, hER, and hMR cotransfection
assays. Because the assays are cell-based, a measurable
response provides verification that the test compound
crosses the cell membrane.
a
(i) n-BuLi, THF, -78 °C, then (MeO)3B, rt; (ii) methyl 2-bromo-
5-nitrobenzoate, 5% (Ph3P)4Pd, DME, 2.0 M aq Na2CO3, 80 °C;
(iii) 20% KOH, EtOH, THF, rt; (iv) SOCl2, DCE, 80 °C; then AlCl3,
rt; (v) 10% Pd/C, H2, EtOAc/EtOH, rt; (vi) acetone, I2, 120-130
°C; (vii) ArLi, THF, -78 °C; (viii) BF3-OEt2, Et3SiH, CH2Cl2, rt.
ity over the parent series 1 (R3 ) R4 ) H). In addition,
the PR agonist effects have been demonstrated in vivo
by oral administration to rodents.
Ch em istr y
The synthetic route to compounds of structure 1 (R3
or R4 * H) is shown in Scheme 1. The key intermedi-
ates, benzocoumarins 5, were prepared by a modification
of Snieckus’ route to this type of structure.14 Thus,
lithium-halogen exchange of a bromoanisole 2 followed
by transmetalation afforded the 2-methoxybenzene bo-
ronic acids 3 in 75-95% yields. Palladium-catalyzed15
cross-coupling with commercial methyl 2-bromo-5-ni-
trobenzoate afforded the biphenyl esters 4 in 55-90%
yields. This conversion is notable in that it affords an
o,o′-disubstituted biphenyl, which is often problematic
in palladium-catalyzed cross-couplings. Conversion of
biphenyl esters 4 to benzocoumarins 5 followed a three-
step, two-pot protocol. Hydrolysis of the methyl esters
with ethanolic KOH afforded the biphenyl carboxylic
acids in 95-99% yields. Treatment of a suspension of
an acid in dichloroethane with SOCl2 at reflux afforded
the corresponding acid chloride; the reaction mixture
was then cooled to room temperature and treated with
AlCl3, which effected an intramolecular acylation with
concomitant O-demethylation to afford the nitrobenzo-
coumarins 5 in 95-99% yields.16 Hydrogenolysis over
palladium on carbon afforded the anilines, which were
converted to the 1,2-dihydro-2,2,4-trimethylquinolines
6 in moderate yields utilizing a Skraup cyclization.17
Treatment of 6 with an aryllithium reagent followed by
reduction of the intermediate hemiketals with BF3-
OEt2/Et3SiH18 afforded the 5-aryl-1,2-dihydro-5H-
chromeno[3,4-f]quinolines 8-27 in 30-75% yields. Com-
The hPR agonist data for 5-aryl-1,2-dihydro-5H-
chromeno[3,4-f]quinolines 8-27 are collected in Table
1. The data for three steroidal hPR agonists, proges-
terone, medroxyprogesterone acetate (MPA), and nore-
thindrone (entries 1-3), are shown for comparison.
Sample cotransfection experiment curves are depicted
in Figure 2. One of the most active D-ring-unsubsti-
tuted 5-aryl-1,2-dihydro-5H-chromeno[3,4-f]quinolines
tested when this study was initiated13 bore a 4-chlo-
rophenyl group at C(5) (LG120546, structure 1, R1
)
Cl, R2-4 ) H, compound 7), and the data for this
compound is also shown (entry 4). Using this compound
as a starting point, it was immediately evident that
compounds which bore a halogen atom at C(9) (entries
5 and 7) were more potent and efficacious hPR agonists

Novel Class of hPR Agonists: D-Ring Substituents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 305
Ta ble 1. hPR-B Agonist Activity in Cotransfected CV-1 Cells and Binding Affinities to Baculovirus-Expressed HPR-Aa
b,c
entry
ligand
R1
R2
R3
R4
EC50
efficacyd
Kib
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
progesterone
medroxyprogesterone acetate
norethindrone
2.89 ( 0.88
0.15 ( 0.08
2.2 ( 1.3
15 ( 1.1
8.1 ( 3.2
10 ( 9.1
9.0 ( 1.2
3.1 ( 0.9
7.4 ( 3.1
2.8 ( 0.7
2.7 ( 0.2
270 ( 70
5.0 ( 2.0
10 ( 2.9
15 ( 7.2
6.9 ( 1.8
5.2 ( 1.0
13 ( 5.4
3.6 ( 0.7
7.1 ( 1.3
7.4 ( 3.0
3.7 ( 0.5
9.4 ( 2.6
9.5 ( 2.8
100 ( 0
80 ( 4
3.5 ( 0.2
0.34 ( 0.04
1.87 ( 0.13
0.70 ( 0.12
0.32 ( 0.07
2.7 ( 0.6
0.59 ( 0.16
2.4 ( 0.5
2.2 ( 0.1
0.32 ( 0.11
0.49 ( 0.16
2.7 ( 0.5
0.37 ( 0.10
0.78 ( 0.33
1.3 ( 0.2
0.74 ( 0.08
0.59 ( 0.13
0.93 ( 0.27
0.48 ( 0.18
0.55
125 ( 6
77 ( 5
7
8
9
Cl
Cl
Cl
Cl
Cl
H
H
H
H
H
H
H
Cl
Me
H
Me
CF3
Me
H
H
H
F
H
F
H
Cl
OMe
F
F
F
F
F
F
F
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
108 ( 15
47 ( 7
110 ( 9
49 ( 3
82 ( 12
117 ( 7
97 ( 6
77 ( 11
149 ( 15
132 ( 27
102 ( 22
97 ( 8
83 ( 11
94 ( 4
95 ( 12
90 ( 12
140 ( 16
125 ( 14
73 ( 10
112 ( 3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
OMe
H
H
F
H
Br
OMe
H
H
H
H
Cl
F
H
H
Cl
Me
CF3
F
Me
Me
1.1
0.34
0.50
1.3 ( 0.4
a
b
Cotransfection experiment values represent at least triplicate determinations. Values are in nM, mean ( SEM, n g 2. If no SEM
is noted, value is from a single determination. c EC50 values represent the concentration required to give half-maximal activation for that
ligand. Efficacy expressed as percent relative to progesterone ) 100%.
d
Ta ble 2. Inhibition of Estradiol-Induced Uterine Wet Weight
relative to 7. Compound 8 (LG120748, entry 5), for
Gain in Immature Rats
example, displayed 2-fold better binding to hPR-A than
compd
% efficacya
did the parent compound 7 and better agonist efficacy
and potency in the cotransfection assay. The binding
affinity of 8 for hPR-A (Ki ) 0.32 nM) was more than 1
order of magnitude greater than that of progesterone
(Ki ) 3.5 nM). Compound 10 (LG120794) was similarly
more active than 7. In contrast, a C(8) fluoro (entry 6)
or C(9) methoxy (entry 8) group afforded potent com-
pounds with reduced efficacy. The SAR of the C(5) aryl
group for compounds bearing either a fluorine or
chlorine atom at C(9) was then investigated.
MPA
20
10
100
60
108
116
8
a
100% ) response to MPA at 1 mg/mouse.
group (entry 17). Surprisingly, a 4-methoxyphenyl
group at C(5) provided a compound with an EC50 of 13
nM (entry 18), 1 order of magnitude improvement over
the C(9) fluoro compound 15 (entry 12). Meta substit-
uents on the C(5) aryl were again well-tolerated (entries
19-22), providing compounds with potencies approach-
ing that of progesterone. Compound 24, bearing a
3-(trifluoromethyl)phenyl substituent at C(5), and com-
pound 25, bearing a 3-fluorophenyl substituent at C(5),
were the most active of the four (entries 21 and 22). The
combination of a p-halogen and a m-methyl group also
provided very potent compounds (entries 23 and 24).
The cross-reactivity with other IRs was also assessed.
Although several compounds (16, 17, 19, and 27)
displayed moderate hAR antagonist activity (200-500
nM), most were only weakly active at this receptor (IC50
> 3 µM). Interestingly, several of the C(9) chloro
derivatives also had moderate hGR agonist activity (e.g.,
22 and 23, EC50 ∼ 350-500 nM, 60-70% efficacy).
Activity on the hER and hMR was minimal (2-10 µM).
In the C(9) fluoro series (R3 ) H, R4 ) F), an
unsubstituted phenyl group at C(5) provided a com-
pound (12, entry 9) with comparable activity in the
functional assay (EC50 ) 7.4 nM) relative to 8, albeit
with reduced efficacy. Moving the chlorine atom of 8
over one position afforded compound 13 (LG120746,
entry 10), with greatly improved potency (EC50 ) 2.8
nM) compared to 8. The addition of an o-methyl group
to 8 also afforded a very potent hPR agonist (compound
14, entry 11); both 13 and 14 are equipotent to proges-
terone (entry 1). A 4-methoxyphenyl group at C(5)
afforded a compound with diminished binding affinity
and less potent and efficacious functional activity (entry
12): this result was consistent with the parent series
(R1 ) R2 ) H). Meta substituents on the C(5) aryl were
well-tolerated: methyl and trifluoromethyl also pro-
vided highly potent compounds (entries 13 and 14).
Notably, compound 16 (entry 13) was very active (EC50
) 5.0 nM, 149% efficacy), whereas the compound
bearing a 3-methylphenyl substituent in the C(9)-
unsubstituted series was much less active (EC50 ) 145
nM, 95% efficacy). The efficacies of several compounds
in this series were greater than that of progesterone
(see, for example, Figure 2).
In Vivo Biologica l Activity
Several of the nonsteroidal agonists of structure 1
were tested at a dose of 1.0 mg/animal for the ability to
counterpoise estradiol-induced uterine wet weight gain
in immature female Sprague-Dawley rats, and the
results from three of these experiments are shown in
Table 2. A 1.0 mg/animal dose affords maximal inhibi-
tion using MPA, which for comparison defined a 100%
response. As shown by the data, two compounds, 8
In the C(9) chloro series (R3 ) H, R4 ) Cl), an
unsubstituted phenyl group at C(5) provided a very
potent compound (entry 16), as did a 4-bromophenyl

306 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Edwards et al.
F igu r e 3. Effects of LG120794 (compound 10) on uterine wet
weights in estradiol benzoate (E-Bz)-primed 21-day-old im-
mature rats (control and E-Bz, n ) 6; all other groups, n ) 4;
*p < 0.05 vs E-Bz). Values represent mean ( SEM.
F igu r e 4. Effects of medroxyprogesterone acetate (MPA) on
uterine wet weights in estradiol benzoate (E-Bz)-primed 21-
day old immature rats (control and E-Bz, n ) 6; all other
groups n ) 4; *p < 0.05 vs E-Bz). Values represent mean (
SEM.
(LG120748) and 10 (LG120794), were at least as effica-
cious as MPA (108-116% response) in this single-dose
assay, whereas compound 20 was less efficacious (60%
response).
fluorine or chlorine atom (8-27, R4 ) F or Cl) to the
tetracyclic core of structure 1 afforded more active hPR
agonists (see Table 1). In addition, the influence of this
substituent outweighed the influence of the C(5) aryl
group, as demonstrated by the potent activity of 12, 15,
16, and 21, which bear C(5) substituents that afforded
compounds of moderate potency in the unsubstituted
series. Several of these compounds are as potent as and
more efficacious than progesterone in the hPR cotrans-
fection assay and bind to hPR-A at subnanomolar levels.
In addition, cross-reactivity with other IRs is minimal.
When administered orally to rodents, compound 10
(LG120794) is more potent and efficacious than MPA
at inhibiting estrogen-induced uterine wet weight gain.
These results and the results described in the preceding
paper13 demonstrate for the first time that nonsteroidal
ligands can act as potent and efficient agonists of the
human progesterone receptor in vitro and that the
activity observed in the cellular assays translates to that
observed in a rodent model in vivo. Although modeling
studies presented in the previous paper suggest that the
dihydroquinoline ring of 1 overlaps with the D-ring of
steroidal progestins, experimental evidence supporting
this hypothesis is lacking. In addition, there is cur-
rently no evidence suggesting that the steroidal and
nonsteroidal progestins bind to the exact same binding
site of hPR. The potent activity and excellent selectivity
of these molecules bode well for the discovery of more
selective and efficacious nonsteroidal hPR modulators
with improved cross-reactivity profiles relative to ste-
roidal progestins.
A range of doses of compound 10 was examined to
determine a dose-response curve for this agonist (Fig-
ure 3), using estradiol benzoate-primed animals. Com-
pound 10 had a significant blunting effect on uterine
wet weight gain at doses as low as 0.003 mg/animal,
compared to a minimally effective dose for MPA of 0.03
mg/animal (Figure 4). In addition, maximal inhibition
of estrogen-induced uterine wet weight gain using 10
was observed at 0.3 mg/animal, compared to 1.0 mg/
animal for MPA. These studies demonstrate that the
in vitro activity of the nonsteroidal hPR agonists
translates to the in vivo situation and that LG120794
is more effective than MPA in this animal model for
progestational action.
Discu ssion
Earlier studies had demonstrated that electron-
withdrawing groups at the meta and para positions of
the C(5) aryl substituent of 5-aryl-1,2-dihydro-5H-
chromeno[3,4-f]quinolines (1, R3 ) R4 ) H) afforded the
most potent hPR agonists. Other substituents on the
C(5) aryl group, such as methyl or methoxy, afforded
compounds with lower binding affinities (higher Ki’s)
and reduced hPR agonist activity. The most active
compounds in this earlier study displayed binding
affinities (Ki) of 0.4-1 nM and agonist potencies (EC50)
in the hPR-B cotransfection assay of 15-20 nM. Specif-
ically, a chlorine atom at the para-position of the C(5)
aryl moiety (7, R1 ) Cl, R2-4 ) H, entry 4, Table 1)
afforded a compound which displayed subnanomolar
binding to hPR-A (Ki ) 0.70 nM) and was a 15 nM
partial agonist in the hPR-B cotransfection assay.
The biological data for the compounds described in
this report demonstrate that the addition of a C(9)
Exp er im en ta l Section 21
Gen er a l Meth od 1. P r ep a r a tion of Bor on ic Acid s 3.
5-F lu or o-2-m eth oxyp h en ylbor on ic Acid (3a ). In a 200-
mL flask, a solution of 2-bromo-4-fluoroanisole (4.00 mL, 30.8
mmol) in THF (50 mL) was cooled to -78 °C. To this solution

Novel Class of hPR Agonists: D-Ring Substituents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 307
a 2.5 M solution of n-BuLi in hexanes (12.4 mL, 31 mmol, 1.0
equiv) was added dropwise over a 30-min period. The reaction
mixture was stirred at -78 °C for 60 min and treated with
trimethyl borate (10.5 mL, 92.4 mmol, 3.0 equiv). The reaction
mixture was allowed to slowly warm to room temperature (rt),
stirred overnight (12 h), and cooled to 0 °C. The solution was
treated with 5% HCl until the pH ) 6. The reaction mixture
was poured into saturated NH4Cl (80 mL) and extracted with
CH2Cl2 (3 × 100 mL). The extracts were washed with
saturated NH4Cl (1 × 80 mL), combined, dried (MgSO4),
filtered through a pad of Celite, and concentrated to afford
4.90 g (94%) of 3a as a white semisolid, which was used
without further purification: 1H NMR (acetone-d6) 7.47 (dd,
J ) 8.8, 3.3, 1H), 7.17 (m, 1H), 7.05 (dd, J ) 9.0, 3.9, 1H),
3.93 (s, 3H).
Purification by silica gel chromatography (hexane-EtOAc, 5:1)
afforded 0.51 g (34%) of 6a as a bright yellow solid: 1H NMR
(acetone-d6) 7.95 (d, J ) 8.7, 1H), 7.83 (dd, J ) 10.1, 2.9, 1H),
7.29 (dd, J ) 9.0, 4.9, 1H), 7.22 (d, J ) 8.7, 1H), 7.17 (m, 1H),
6.25 (br s, 1H), 5.54 (t, J ) 1.2, 1H), 2.06 (s, 3H), 1.30 (s, 6H),
13C NMR (acetone-d6) 160.2 (d, J C-F ) 239), 159.9, 148.2, 147.3,
132.9, 131.7, 125.3, 123.0, 121.9, 121.8, 119.1, 118.9 (d, J C-F
) 9.0), 115.6 (d, J C-F ) 25), 108.9 (d, J C-F ) 26), 51.0, 28.5,
21.6. Anal. (C19H16FNO2) C, H, N, F.
4-F lu or o-2-m eth oxyp h en ylbor on ic Acid (3b). Follow-
ing general method 1, from 2-bromo-5-fluoroanisole (5.50 g,
26.8 mmol, 1.0 equiv), 2.5 M n-BuLi in hexanes (10.7 mL, 27
mmol, 1.0 equiv), and trimethyl borate (9.1 mL, 80 mmol, 3.0
equiv) was obtained 4.22 g (93%) of 3b as a white solid, which
was used without further purification.
Gen er a l Meth od 2. P r ep a r a tion of Bip h en ylca r boxy-
la tes 4. Meth yl 5′-F lu or o-2′-m eth oxy-4-n itr o-2-bip h en yl-
ca r boxyla te (4a ). In a 250-mL flask, a solution of methyl
2-bromo-5-nitrobenzoate (5.00 g, 19.2 mmol) in DME (60 mL)
was treated with (Ph3P)4Pd (0.67 g, 0.58 mmol, 3.0 mol %).
The reaction mixture was stirred at rt for 10 min. A solution
of 3a (4.90 g, 29 mmol, 1.5 equiv) in EtOH (8 mL) was added
followed by 2.0 M Na2CO3 (29 mL, 58 mmol, 3 equiv). The
reaction mixture was heated to 80 °C for 6 h, cooled to rt,
poured into 2.0 M Na2CO3 (100 mL), and extracted with EtOAc
(3 × 100 mL). The extracts were washed with brine (1 × 100
mL), combined, dried (MgSO4), filtered, and concentrated to
an orange oil. Purification by silica gel chromatography
(hexane-EtOAc, 10:1) afforded 4.25 g (72%) of 4a as a yellow-
orange solid: 1H NMR (CDCl3) 8.73 (d, J ) 2.4, 1H), 8.39 (dd,
J ) 8.3, 2.4, 1H), 7.49 (d, J ) 8.3, 1H); 7.09 (dt, J ) 3.1, 8.5,
1 H); 7.00 (dd, J ) 8.5, 3.1, 1 H); 6.85 (dd, J ) 8.9, 3.2, 1 H);
3.76 (s, 3 H); 3.70 (s, 3 H).
Gen er a l Meth od 3. P r ep a r a tion of Diben zo[b,d ]p y-
r a n -6-on es 5. 2-F lu or o-8-n itr o-6H-d iben zo[b,d ]p yr a n -6-
on e (5a ). In a 200-mL flask, a solution of 4a (4.24 g, 13.9
mmol) in THF (50 mL) was cooled to 0 °C and treated with
EtOH (10 mL) and 20% KOH (10 mL). The reaction mixture
was allowed to warm to rt, stirred overnight, acidified to pH
) 10 with 10% HCl, and extracted with EtOAc (3 × 75 mL).
The extracts were washed with brine (1 × 80 mL), combined,
dried (MgSO4), filtered, and concentrated to afford 3.68 g (91%)
of 5′-fluoro-2′-methoxy-4-nitro-2-biphenylcarboxylic acid as a
yellow solid. The crude acid was suspended in DCE (30 mL),
treated with SOCl2 (0.92 mL, 12.6 mmol, 1.0 equiv), and heated
to a gentle reflux for 90 min. The reaction vessel was cooled
to 0 °C, and AlCl3 (0.91 g, 6.8 mmol, 0.55 equiv) was added
portionwise. The reaction mixture was allowed to slowly warm
to rt, stirred for 5 h, and quenched with 5% HCl (100 mL).
The crude product was extracted with EtOAc (4 × 150 mL).
The extracts were washed with saturated NH4Cl (1 × 100 mL),
combined, dried (MgSO4), filtered, and concentrated to afford
3.19 g (99%) of 5a as a yellow solid: 1H NMR (DMSO-d6) 8.84
(d, J ) 2.3, 1H), 8.67 (m, 2H), 8.40 (d, J ) 9.2, 1H), 7.55 (m,
2H).
Gen er a l Meth od 4. P r ep a r a tion of Qu in olin es 6.
9-F lu or o-1,2-d ih yd r o-2,2,4-tr im eth yl-5-cou m a r in o[3,4-f]-
qu in olin e (6a ). In a 500-mL flask, a suspension of 2-fluoro-
8-nitro-6H-dibenzo[b,d]pyran-6-one (3.18 g, 12.2 mmol) in
EtOAc (300 mL) was treated with 10% Pd/C (2.0 g) and AcOH
(0.2 mL) and stirred under an atmosphere of H2 for 1 h. The
reaction mixture was filtered and the solids were rinsed with
acetone (200 mL). Concentration of the filtrate afforded 2.19
g (78%) of 8-amino-2-fluoro-6H-dibenzo[b,d]pyran-6-one as a
yellow solid. In a 200-mL resealable pressure tube, a suspen-
sion of 8-amino-2-fluoro-6H-dibenzo[b,d]pyran-6-one (1.10 g)
in acetone (100 mL) was treated with iodine (0.50 g) and
heated to 110 °C for 32 h. The reaction mixture was cooled to
rt, concentrated to remove the bulk of the acetone, and
dissolved in CH2Cl2 (200 mL). The organic layer was washed
with 0.5 N Na2S2O3 (2 × 200 mL) and saturated NaHCO3 (1
× 100 mL). The aqueous layers were extracted with CH2Cl2
(2 × 100 mL). The combined organic layers were dried (K2-
CO3), filtered, and concentrated to afforded an orange solid.
3-F lu or o-8-n itr o-6H-d iben zo[b,d ]p yr a n -6-on e (5b). In
a 200-mL round bottom flask, a solution of 2-bromo-5-ni-
trobenzoic acid (4.10 g, 16.7 mmol, 1.0 equiv) in DME (65 mL)
was treated with (Ph3P)4Pd (0.58 g, 0.50 mmol, 3.0 mol %).
The reaction mixture was stirred at rt for 10 min. A solution
of 3b (4.20 g, 25 mmol, 1.5 equiv) in EtOH (10 mL) was added
followed by 2.0 M Na2CO3 (30 mL). The reaction mixture was
heated to 80 °C for 6 h, cooled to rt, poured into 5% HCl (100
mL), and extracted with EtOAc (3 × 100 mL). The extracts
were washed with saturated NH4Cl (1 × 100 mL) and brine
(1 × 100 mL), combined, dried (MgSO4), filtered, and concen-
trated to an orange solid. The crude material was suspended
in DCE (80 mL), treated with SOCl2 (1.2 mL), and heated at
reflux for 90 min. The reaction mixture was cooled to rt,
treated with AlCl3 (0.4 g), and allowed to react overnight (11
h). The reaction mixture was poured into 20% KOH (80 mL)
and extracted with methylene chloride (3 × 80 mL). The
extracts were combined, dried (MgSO4), filtered, and concen-
trated to an orange oil. The crude material was dissolved in
methylene chloride (50 mL), adsorbed onto Celite (1 g), and
concentrated to a fluffy orange powder. This powder was
applied to a pad of silica gel in a 250-mL Buchner funnel (50
× 50 mm). The pad was rinsed with 100 mL of 2:1 hexane:
EtOAc, which was discarded, and then 400 mL of 1:1 hexane-
EtOAc. The filtrate was concentrated to afford 2.08 g (48%)
of 5b as an orange solid: 1H NMR (acetone-d6) 9.02 (d, J )
2.4, 1H), 8.71 (dd, J ) 8.8, 2.4, 1H), 8.65 (d, J ) 8.8, 1H), 8.53
(dd, J ) 9.6, 6.1, 1H), 7.34 (m, 2H).
8-F lu or o-1,2-d ih yd r o-2,2,4-tr im eth yl-5-cou m a r in o[3,4-
f]qu in olin e (6b). Following general method 4, from 5b (2.04
g, 7.9 mmol) and 10% Pd/C (0.4 g) was obtained 1.61 g (89%)
of 8-amino-3-fluoro-6H-dibenzo[b,d]pyran-6-one as a yellow
solid. The aniline was converted to the quinoline following
general method 4 to afford an orange solid. Purification by
silica gel chromatography (hexane-EtOAc, 5:1) afforded 0.46
g (21%) of 6b as a bright-yellow solid: 1H NMR (acetone-d6)
8.12 (dd, J ) 9.6, 5.9, 1H), 7.92 (d, J ) 9.6, 1H), 7.22 (d, J )
8.6, 1H), 7.11 (m, 2H), 6.1 (br s, 1H), 5.53 (d, J ) 1.2, 1H),
2.06 (s, 3H), 1.29 (s, 6H).
5-Ch lor o-2-m eth oxyp h en ylbor on ic Acid (3c). Following
general method 1, from 2c (2.00 g, 9.0 mmol, 1.0 equiv), 2.5
M n-BuLi in hexanes (3.62 mL, 9.0 mmol, 1.0 equiv), and
trimethyl borate (3.0 mL, 26 mmol, 2.9 equiv) was obtained
1.30 g of a white semisolid. This compound was used directly
with no further purification.
Met h yl 5′-Ch lor o-2′-m et h oxy-4-n it r o-2-b ip h en ylca r -
boxyla te (4c). Following general method 2, from methyl
2-bromo-5-nitrobenzoate (1.25 g, 4.8 mmol, 1.0 equiv), (Ph3P)4-
Pd (0.16 g, 0.14 mmol, 2.9 mol %), and 3c (1.30 g, 6.9 mmol,
1.5 equiv) was obtained 0.85 g (55%) of 4c as a yellow-orange
solid: 1H NMR (CDCl3) 8.73 (d, J ) 2.4, 1H), 8.38 (dd, J )
8.5, 2.5, 1H), 7.49 (d, J ) 8.5, 1H), 7.36 (dd, J ) 8.7, 2.5, 1H),
7.23 (d, J ) 2.5, 1H), 6.85 (d, J ) 8.7, 1H), 3.76 (s, 3H), 3.70
(s, 3H).
2-Ch lor o-8-n itr o-6H-d iben zo[b,d ]p yr a n -6-on e (5c). Fol-
lowing general method 3, from 4c (0.83 g, 2.6 mmol) was
obtained 0.75 g (95%) of the free acid, which was converted to
5c with SOCl2 (0.17 mL, 2.3 mmol) and AlCl3 (0.30 g, 2.5 mmol)
to afford 0.64 g (99%) of 5c: 1H NMR (acetone-d6) 9.04 (d, J )

308 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Edwards et al.
2.3, 1H), 8.73 (m, 2H), 8.51 (d, J ) 2.4, 1H), 7.72 (dd, J ) 8.6,
2.4, 1H), 7.50 (d, J ) 8.7, 1H).
(m, 2H), 5.65 (br s, 1H), 5.48 (d, J ) 1.4, 1H), 1.98 (d, J ) 1.4,
3H), 1.27 (s, 3H), 1.24 (s, 3H); 13C NMR (benzene-d6) 159.2 (d,
J C-F ) 238), 147.4, 146.3, 139.0, 134.5, 133.9, 130.5, 129.0,
128.7, 126.7 (d, J C-F ) 8.6), 124.8, 120.9, 119.9, 119.3 (d, J C-F
) 8.4), 115.6, 114.5 (d, J C-F ) 23), 109.2 (d, J C-F ) 24), 75.9,
50.9, 30.1, 29.2, 24.2. Anal. (C25H21ClFNO) C, H, N.
(R/S)-5-(4-Ch lor op h en yl)-8-flu or o-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 (9). Following gen-
eral method 5, from 6b (61 mg, 0.20 mmol) was obtained an
orange oil, which was purified by silica gel chromatography
(hexane-EtOAc, 16:1) to afford 33 mg (41%) of 9 as a clear
oil: 1H NMR (benzene-d6) 7.25 (d, J ) 8.2, 1H), 7.22 (dd, J )
8.6, 6.2, 1H), 7.00 (d, J ) 8.4, 2H), 6.86 (d, J ) 8.4, 2H), 6.84
(s, 1H), 6.71 (dd, J ) 9.4, 3.5, 1H), 6.49 (td, J ) 8.5, 2.7, 1H),
6.30 (d, J ) 8.3, 1H), 5.13 (d, J ) 0.7, 1H), 3.37 (br s, 1H),
1.70 (d, J ) 0.7, 3H), 1.00 (s, 6H); 13C NMR (benzene-d6) 163.2
(d, J C-F ) 245), 152.7 (d, J C-F ) 10), 145.7, 138.9, 134.5, 134.0,
130.4, 129.4, 129.1, 129.0, 124.2, 124.0 (d, J C-F ) 10.0), 121.8,
121.1, 120.0, 115.8, 109.7 (d, J C-F ) 22), 105.8 (d, J C-F ) 23),
76.2, 50.9, 30.0, 29.1, 24.1. Anal. (C25H21ClFNO) C, H, N.
(R/S)-9-Ch lor o-5-(4-ch lor op h en yl)-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 (10). This compound
was prepared via general method 5 from compound 6c (0.27
g, 0.83 mmol) to afford 165 mg (47%) of compound 10 as a
white solid: 1H NMR (acetone-d6) 7.60 (d, J ) 2.5, 1H), 7.58
(d, J ) 8.4, 1H), 7.27 (d, J ) 8.6, 2H), 7.22 (d, J ) 8.6, 2H),
6.96 (dd, J ) 8.5, 2.5, 1H), 6.94 (s, 1H), 6.84 (d, J ) 8.4, 1H),
6.81 (d, J ) 8.5, 1H), 5.7 (br s, 1H), 5.49 (d, J ) 1.1, 1H), 1.99
(d, J ) 1.1, 3H), 1.27 (s, 3H), 1.24 (s, 3H); 13C NMR (acetone-
d6) 150.5, 148.3, 140.8, 135.1, 134.7, 131.5, 130.4, 129.6, 129.3,
128.1, 128.0, 127.9, 125.3, 122.9, 120.3, 119.9, 116.6, 116.5,
76.3, 51.6, 30.5, 29.7, 24.5. Anal. (C25H21Cl2NO) C, H, N, Cl.
(R/S)-5-(4-Ch lor op h en yl)-1,2-d ih yd r o-9-m eth oxy-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (11). This com-
pound was prepared via general method 5 from compound 6d
(61 mg, 0.19 mmol) to afford 28 mg (35%) of compound 11 as
a white solid: 1H NMR (benzene-d6) 7.40 (d, J ) 8.4, 1H), 7.24
(d, J ) 2.8, 1H), 7.12 (d, J ) 8.4, 2H), 6.89 (d, J ) 8.4, 2H),
6.88 (s, 1H), 6.87 (d, J ) 8.6, 1H), 6.50 (dd, J ) 8.6, 2.9, 1H),
5.12 (d, J ) 1.0, 1H), 3.38 (br s, 1H), 3.30 (s, 3H), 1.75 (d, J )
1.0, 3H), 0.99 (s, 6H); 13C NMR (benzene-d6) 155.8, 146.0,
145.6, 139.6, 134.3, 133.8, 130.8, 130.6, 129.4, 128.9, 128.3,
126.2, 124.7, 122.0, 120.1, 118.9, 115.6, 113.6, 75.8, 55.4, 50.9,
30.1, 29.1, 24.3. Anal. (C26H24ClNO2) C, H, N.
9-Ch lor o-1,2-d ih yd r o-2,2,4-tr im eth yl-5-cou m a r in o[3,4-
f]qu in olin e (6c). Following general method 4, from 5c (0.64
g, 2.3 mmol) and 10% Pd/C (0.2 g) was obtained 0.50 g (88%)
of 8-amino-6-chloro-6H-dibenzo[b,d]pyran-6-one as a yellow
solid. The aniline was converted to the quinoline following
general method 4 to afford an orange solid. Purification by
silica gel chromatography (hexane-EtOAc, 5:1) afforded 0.14
g (21%) of 6c as a bright-yellow solid: 1H NMR (acetone-d6)
8.10 (d, J ) 2.4, 1H), 8.00 (d, J ) 8.7, 1H), 7.39 (dd, J ) 8.7,
2.3, 1H), 7.26 (d, J ) 8.8, 1H), 7.23 (d, J ) 8.6, 1H), 5.55 (s,
1H), 2.06 (s, 3H), 1.30 (s, 6H).
2,5-Dim eth oxyp h en ylbor on ic Acid (3d ). Following gen-
eral method 1, from 1-bromo-2,5-dimethoxybenzene (2.00 mL,
13.3 mmol), 2.5 M n-BuLi in hexanes (5.34 mL, 13 mmol), and
trimethyl borate (4.5 mL, 40 mmol) was obtained 2.43 g (99%)
of a white semisolid which was used without further purifica-
tion.
Meth yl 2′,5′-Dim eth oxy-4-n itr o-2-bip h en ylca r boxyla te
(4d ). Following general method 2, from methyl 2-bromo-5-
nitrobenzoate (2.46 g, 9.46 mmol), (PPh3)4Pd (0.33 g, 0.28
mmol), and 3d (2.42 g, 13 mmol) was obtained 2.08 g (69%) of
4d as a white solid: 1H NMR (CDCl3) 8.70 (d, J ) 2.4, 1H),
8.37 (dd, J ) 8.4, 2.5, 1H), 7.52 (d, J ) 8.5, 1H), 6.92 (dd, J )
8.8, 3.0, 1H), 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.67 (s,
3H).
2-Met h oxy-8-n it r o-6H -d ib en zo[b,d ]p yr a n -6-on e (5d ).
Following general method 3, from 4d (2.07 g) was obtained
1.93 g (99%) of the free acid, which was converted to 5d with
SOCl2 (0.47 mL, 6.4 mmol) and AlCl3 (0.67 g, 5.0 mmol) to
afford 1.71 g (99%) of 5d as an orange powder: 1H NMR
(acetone-d6) 9.04 (d, J ) 2.4, 1H), 8.74 (d, J ) 8.9, 1H), 8.69
(dd, J ) 8.9, 2.4, 1H), 7.92 (d, J ) 2.9, 1H), 7.41 (d, J ) 9.0,
1H), 7.30 (dd, J ) 9.0, 2.9, 1H), 3.97 (s, 3H).
1,2-Dih yd r o-9-m et h oxy-2,2,4-t r im et h yl-5-cou m a r in o-
[3,4-f]qu in olin e (6d ). Following general method 4, from 5d
(1.71 g, 6.3 mmol) and 10% Pd/C (0.60 g) was obtained 1.27 g
(80%) of 8-amino-2-methoxy-6H-dibenzo[b,d]pyran-6-one as a
white solid. The aniline was converted to the quinoline
following general method 4 to afford an orange solid. Purifica-
tion by silica gel chromatography (hexane-EtOAc, 4:1) af-
forded 0.25 g (15%) of 6d as a yellow solid: 1H NMR (CDCl3)
7.73 (d, J ) 8.6, 1H), 7.35 (d, J ) 2.8, 1H), 7.23 (d, J ) 8.9,
1H), 7.00 (d, J ) 8.6, 1H), 6.92 (dd, J ) 8.9, 2.8, 1H), 5.57 (s,
1H), 4.29 (br s, 1H), 3.88 (s, 3H), 2.11 (d, J ) 1.1, 3H), 1.33 (s,
6H).
Gen er a l Meth od 5. P r ep a r a tion of Dih yd r oqu in olin es
8-27. (R/S)-5-(4-Ch lor oph en yl)-9-flu or o-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 (8). In a 20-mL
2-neck flask, a solution of 4-bromochlorobenzene (230 mg, 1.20
mmol, 6.0 equiv) in THF (2 mL) was cooled to -78 °C and
treated with a 2.5 M solution of n-BuLi in hexanes (0.48 mL,
1.2 mmol, 6.0 equiv). The reaction mixture was stirred at -78
°C for 1 h. A solution of 6a (61 mg, 0.20 mmol) in THF (1
mL) was added via syringe; the reaction mixture was stirred
at -78 °C for 3 h and quenched with 1:1 MeOH-H2O (2 mL).
The reaction mixture was allowed to warm to rt, poured into
H2O (8 mL), and extracted with EtOAc (3 × 12 mL). The
extracts were washed with brine (1 × 10 mL), combined, dried
(MgSO4), filtered, and concentrated. Purification by silica gel
chromatography (hexane-EtOAc, 4:1) afforded the hemiketal
adduct, which was not characterized. The adduct was dis-
solved in CH2Cl2 (1 mL) and treated with Et3SiH (0.16 mL,
1.0 mmol, 5.0 equiv) and BF3-OEt2 (0.12 mL, 1.0 mmol, 5.0
equiv). After stirring for 3 h, the reaction mixture was
quenched by the addition of saturated NaHCO3 (2 mL), poured
into saturated NaHCO3 (8 mL), and extracted with EtOAc (3
× 10 mL). The extracts were washed with brine (1 × 10 mL),
combined, dried (MgSO4), filtered, and concentrated to an
orange oil. Purification by silica gel chromatography (hexane-
EtOAc, 16:1) afforded 60 mg (75%) of 8 as a white solid: 1H
NMR (acetone-d6) 7.55 (d, J ) 8.4, 1H), 7.34 (dd, J ) 10.0,
2.8, 1H), 7.25 (m, 4H), 6.91 (s, 1H), 6.84 (d, J ) 8.5, 1H), 6.75
(R/S)-9-F lu or o-1,2-d ih yd r o-2,2,4-t r im et h yl-5-p h en yl-
5H-ch r om en o[3,4-f]qu in olin e (12). This compound was
prepared via general method 5 from compound 6a (60 mg, 0.19
mmol) to afford 44 mg (70%) of compound 12 as a white solid:
1H NMR (benzene-d6) 7.30 (d, J ) 7.6, 1H), 7.23 (dd, J ) 9.6,
3.0, 1H), 7.17 (d, J ) 8.3, 1H), 6.99 (s, 1H), 6.95 (t, J ) 7.6,
2H), 6.86 (t, J ) 7.6, 1H), 6.73 (dd, J ) 8.6, 4.9, 1H), 6.50 (td,
J ) 8.6, 3.0, 1H), 6.24 (d, J ) 8.3, 1H), 5.10 (s, 1 H), 3.40 (br
s, 1H), 1.77 (d, J ) 1.2, 3H), 0.99 (s, 3H), 0.98 (s, 3H); 13C NMR
(benzene-d6) 159.1 (d, J C-F ) 237), 147.8, 146.3, 140.5, 133.7,
130.9, 129.4, 129.1, 128.7, 128.5, 126.9 (d, J C-F ) 8.0), 124.7,
121.2, 120.0, 119.3 (d, J C-F ) 8.6), 115.5, 114.4 (d, J C-F ) 23),
109.1 (d, J C-F ) 25), 76.6, 50.9, 39.2, 24.2. (Anal. (C25H22
FNO) C, H, N.
-
(R/S)-5-(3-Ch lor op h en yl)-9-flu or o-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 (13). This compound
was prepared via general method 5 from compound 6a (50 mg,
0.16 mmol) to afford 46 mg (70%) of compound 13 as a colorless
solid: 1H NMR (acetone-d6) 7.55 (d, J ) 8.4, 1H); 7.35 (dd, J
) 9.9, 2.9, 1H), 7.20 (m, 4H), 6.93 (s, 1H), 6.84 (d, J ) 8.4,
1H), 6.81 (dd, J ) 8.5, 5.0, 1H), 6.73 (td, J ) 8.5, 2.9, 1H),
5.67 (br s, 1H), 5.49 (s, 1H), 1.99 (s, 3H), 1.27 (s, 3H), 1.24 (s,
3 H); 13C NMR (acetone-d6) 159.2 (d, J C-F ) 236), 147.8, 143.5,
134.8, 134.6, 130.7, 129.9, 129.1, 128.9, 127.8, 127.1 (d, J C-F
) 7.9), 125.0, 119.7, 119.6, 119.4 (d, J C-F ) 9.0), 116.1, 114.2
(d, J C-F ) 24), 109.1 (d, J C-F ) 25), 75.7, 51.2, 29.7, 29.4, 24.1.
Anal. (C25H21ClFNO) C, H, N.
(R/S)-5-(4-Ch lor o-3-m eth ylph en yl)-9-flu or o-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 (14). This
compound was prepared via general method 5 from compound

Novel Class of hPR Agonists: D-Ring Substituents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 309
6a (50 mg, 0.16 mmol) to afford 42 mg (62%) of Compound 14
as a colorless solid: 1H NMR (benzene-d6) 7.28 (dd J ) 9.6,
2.9, 1H), 7.19 (m, 3H), 6.99 (m, 2H), 6.93 (s, 1H), 6.76 (dd, J )
8.7, 4.9, 1H), 6.57 (td, J ) 8.4, 2.9, 1H), 6.27 (d, J ) 8.4, 1H),
5.15 (s, 1H), 3.43 (br s, 1H), 1.96 (s, 3H), 1.80 (d, J ) 1.0, 3H),
1.01 (s, 6H); 13C NMR (benzene-d6) 159.2 (d, J C-F ) 237), 147.5,
146.3, 139.3, 136.5, 134.7, 133.9, 131.6, 130.5, 129.5, 129.2,
128.0, 126.7 (d, J C-F ) 8.3), 124.8, 121.0, 119.9, 119.3 (d, J C-F
) 8.6), 115.6, 114.6 (d, J C-F ) 23), 109.2 (d, J C-F ) 24), 75.9,
50.9, 30.0, 29.2, 24.2, 20.3. Anal. (C26H23ClFNO) C, H, N.
(R/S)-9-F lu or o-1,2-d ih yd r o-5-(4-m eth oxyp h en yl)-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (15). This com-
pound was prepared via general method 5 from compound 6a
(60 mg, 0.19 mmol) to afford 45 mg (58%) of compound 15 as
a clear film: 1H NMR (benzene-d6) 7.39 (dd, J ) 9.4, 2.8, 1H),
7.30 (d, J ) 8.6, 2H), 7.07 (s, 1H), 6.86 (dd, J ) 8.8, 4.0, 1H),
6.63 (d, J ) 8.6, 2H), 6.62 (m, 1H), 6.35 (d, J ) 8.2, 1H), 5.22
(s, 1H), 3.48 (br s, 1H), 3.19 (s, 3H), 1.93 (d, J ) 1.2, 3H), 1.09
(s, 3H), 1.08 (s, 3H) (the C(10)H is obscured by the benzene
singlet); 13C NMR (benzene-d6) 160.1, 159.1 (d, J C-F ) 237),
147.8, 146.3, 133.6, 132.4, 131.4, 130.5, 129.5, 127.1 (d, J C-F
) 8.5), 124.7, 121.3, 119.9, 119.4 (d, J C-F ) 8.5), 115.4, 114.4
(d, J C-F ) 25), 114.3, 109.1 (d, J C-F ) 23), 76.5, 54.8, 50.9,
30.2, 29.1, 24.2. Anal. (C26H24FNO2) C, H, N.
2.5, 1H), 6.94 (s, 1H), 6.83 (d, J ) 8.5, 1H), 6.76 (d, J ) 8.5,
1H), 5.63 (br s, 1H), 5.46 (d, J ) 1.1, 1H), 1.98 (s, 3H), 1.26 (s,
3H), 1.24 (s, 3H); 13C NMR (benzene-d6) 150.4, 140.4, 133.7,
130.7, 129.3, 129.1, 128.9, 128.6, 128.3, 127.9, 127.6, 127.2,
124.6, 122.7, 120.7, 119.9, 119.7, 115.5, 76.7, 50.9, 30.1, 29.2,
24.2. Anal. (C25H22ClNO) C, H, N.
(R/S)-5-(4-Br om op h en yl)-9-ch lor o-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 (20). This compound
was prepared via general method 5 from compound 6c (50 mg,
0.15 mmol) to afford 23 mg (32%) of compound 20 as a white
solid: 1H NMR (acetone-d6) 7.59 (d, J ) 2.4, 1H), 7.58 (d, J )
8.3, 1H), 7.42 (d, J ) 8.5, 2H), 7.16 (d, J ) 8.5, 2H), 6.94 (dd,
J ) 8.2, 2.4, 1H), 6.92 (s, 1H), 6.84 (d, J ) 8.4, 1H), 6.77 (d, J
) 8.4, 1H), 5.68 (br s, 1H), 5.48 (s, 1H), 1.98 (s, 3H), 1.27 (s,
3H), 1.24 (s, 3H); 13C NMR (benzene-d6) 150.0, 146.3, 139.4,
133.9, 132.0, 130.7, 130.0, 129.0, 128.0, 127.9, 127.0, 124.7,
122.9, 122.7, 120.4, 119.8, 119.6, 115.7, 75.9, 50.9, 30.0, 29.2,
24.1. Anal. (C25H21BrClNO) C, H, N.
(R/S)-9-Ch lor o-1,2-d ih yd r o-5-(4-m eth oxyp h en yl)-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (21). This com-
pound was prepared via general method 5 from compound 6c
(40 mg, 0.12 mmol) to afford 21 mg (41%) of compound 21 as
a white solid: 1H NMR (acetone-d6) 7.59 (d, J ) 2.5, 1H), 7.56
(d, J ) 8.5, 1H), 7.11 (d, J ) 8.7, 2H), 6.94 (d, J ) 8.7, 2H),
6.94 (dd, J ) 8.5, 2.4, 1H), 6.89 (s, 1H), 6.82 (d, J ) 8.5, 1H),
6.75 (m, 1H), 5.61 (br s, 1H), 5.45 (s, 1H), 3.69 (s, 3H), 1.99 (s,
3H), 1.26 (s, 3H), 1.23 (s, 3H); 13C NMR (benzene-d6) 160.1,
150.5, 146.3, 133.6, 132.3, 131.1, 130.5, 129.4, 128.3, 127.9,
127.6, 127.4, 124.6, 122.6, 120.8, 119.8, 115.5, 114.3, 76.6, 54.8,
50.9, 30.2, 29.2, 24.2. Anal. (C26H24ClNO2) C, H, N.
(R/S)-9-Ch lor o-5-(3-ch lor op h en yl)-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 (22). This compound
was prepared via general method 5 from compound 6c (40 mg,
0.12 mmol) to afford 19 mg (37%) of compound 22 as a white
solid: 1H NMR (acetone-d6) 7.61 (d, J ) 2.3, 1H), 7.59 (d, J )
9.0, 1H), 7.25 (m, 4H), 6.95 (m, 2H), 6.85 (d, J ) 8.3, 1H), 6.83
(d, J ) 7.3, 1H), 5.72 (br s, 1H), 5.50 (s, 1H), 2.00 (s, 3H), 1.28
(s, 3H), 1.26 (s, 3H); 13C NMR (benzene-d6) 150.0, 146.3, 142.8,
135.1, 134.0, 130.1, 129.8, 128.8, 128.1, 127.9, 127.0, 126.9,
124.7, 122.7, 120.4, 119.9, 119.7, 115.8, 75.8, 50.9, 29.9, 29.3,
24.0. Anal. (C25H21Cl2NO) C, H, N.
(R/S)-9-Ch lor o-1,2-d ih yd r o-2,2,4-t r im et h yl-5-(3-m et h -
ylp h en yl)-5H-ch r om en o[3,4-f]qu in olin e (23). This com-
pound was prepared via general method 5 from compound 6c
(20 mg, 0.06 mmol) to afford 10 mg (41%) of compound 23 as
a white solid: 1H NMR (acetone-d6) 7.59 (d, J ) 2.4, 1H), 7.58
(d, J ) 9.1, 1H), 7.19 (m, 2H), 6.95 (m, 3H), 6.92 (s, 1H), 6.83
(d, J ) 8.5, 1H), 6.78 (d, J ) 8.5, 1H), 5.64 (br s, 1H), 5.51 (s,
1H), 2.20 (s, 3H), 2.05 (s, 3H), 1.27 (s, 3H), 1.24 (s, 3H); 13C
NMR (benzene-d6) 150.5, 146.3, 140.5, 138.3, 133.7, 130.8,
129.7, 129.5, 129.4, 128.8, 127.9, 127.6, 127.2, 126.4, 124.6,
122.7, 120.8, 120.0, 119.7, 115.6, 76.8, 50.9, 30.0, 29.3, 24.2,
21.6. Anal. (C26H24ClNO) C, H, N.
(R/S)-9-Ch lor o-1,2-d ih yd r o-2,2,4-tr im eth yl-5-[3-(tr iflu o-
r om eth yl)ph en yl]-5H-ch r om en o[3,4-f]qu in olin e (24). This
compound was prepared via general method 5 from compound
6c (40 mg, 0.83 mmol) to afford 21 mg (38%) of compound 24
as a white solid: 1H NMR (acetone-d6) 7.61 (d, J ) 2.3, 1H),
7.52 (m, 4H), 7.07 (s, 1H), 6.99 (m, 2H), 6.87 (d, J ) 8.3, 1H),
6.84 (d, J ) 8.3, 1H), 5.73 (br s, 1H), 5.51 (s, 1H), 2.01 (s, 3H),
1.27 (s, 6H); 13C NMR (benzene-d6) 149.9, 146.4, 141.8, 134.2,
131.9, 131.2 (q, J C-F ) 33), 129.7, 129.3, 128.9, 126.8, 126.5,
(R/S)-9-F lu or o-1,2-d ih yd r o-5-(3-m et h ylp h en yl)-2,2,4-
tr im eth yl-5H-ch r om en o[3,4-f]qu in olin e (16). This com-
pound was prepared via general method 5 from compound 6a
(31 mg, 0.10 mmol) to afford 18 mg (46%) of compound 16 as
a clear film: 1H NMR (benzene-d6) 7.25 (dd, J ) 9.6, 2.9, 1H),
7.20 (d, J ) 10.0, 2H), 7.02 (s, 1H), 6.91 (t, J ) 7.6, 1H), 6.77
(m, 1H), 6.71 (d, J ) 7.6, 2H), 6.51 (td, J ) 8.4, 2.9, 1H), 6.25
(d, J ) 8.3, 1H), 5.11 (s, 1H), 3.39 (br s, 1H), 1.92 (s, 3H), 1.82
(s, 3H), 1.00 (s, 3H), 0.99 (s, 3H); 13C NMR (benzene-d6) 159.1
(d, J C-F ) 237), 147.9, 146.3, 140.6, 138.2, 133.7, 131.1, 129.8,
129.4, 128.7, 128.3, 126.9 (d, J C-F ) 8.8), 126.4, 124.7, 121.3,
120.0, 119.3 (d, J C-F ) 8.6), 115.5, 114.4 (d, J C-F ) 24), 109.2
(d, J C-F ) 24), 76.7, 50.9, 30.0, 29.1, 24.2, 21.6. Anal. (C26H24
FNO) C, H, N.
-
(R/S)-9-F lu or o-1,2-d ih yd r o-2,2,4-tr im eth yl-5-[3-(tr iflu o-
r om eth yl)ph en yl]-5H-ch r om en o[3,4-f]qu in olin e (17). This
compound was prepared via general method 5 from compound
6a (60 mg, 0.19 mmol) to afford 43 mg (51%) of compound 17
as a clear film: 1H NMR (acetone-d6) 7.58 (d, J ) 8.5, 1H),
7.54 (s, 1H), 7.51 (m, 3H), 7.36 (dd, J ) 10.0, 2.9, 1H), 7.04 (s,
1H), 6.86 (d, J ) 8.5, 1H), 6.83 (dd, J ) 8.7, 5.0, 1H), 6.74 (td,
J ) 8.6, 2.9, 1H), 5.70 (br s, 1H), 5.51 (s, 1H), 2.01 (d, J ) 1.2,
3H), 1.27 (s, 6H); 13C NMR (CDCl3): 158.5 (d, J C-F ) 238),
146.4, 145.8, 141.0, 134.4, 131.7, 130.7 (q, J C-F ) 32), 129.2,
128.7, 128.5, 125.8 (d, J C-F ) 8.6), 125.2 (q, J C-F ) 4.0), 125.0
(q, J C-F ) 3.6), 124.2, 124.2 (q, J C-F ) 273), 120.5, 119.9, 118.7
(d, J C-F ) 8.6), 115.7, 114.2 (d, J C-F ) 23), 108.7 (d, J C-F
)
25), 75.2, 50.9, 29.6, 29.2, 24.0. Anal. (C26H21F4NO) C, H, N.
(R/S)-9-Flu or o-5-(4-flu or o-3-m eth ylph en yl)-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 (18). This
compound was prepared via general method 5 from compound
6a (38 mg, 0.12 mmol) to afford 25 mg (51%) of compound 18
as a white foam: 1H NMR (benzene-d6) 7.25 (dd, J ) 8.6, 2.8,
1H), 7.17 (d, J ) 8.2, 1H), 7.10 (dd, J ) 7.4, 1.8, 1H), 6.96 (m,
1H), 6.92 (s, 1H), 6.74 (dd, J ) 8.9, 4.9, 1H), 6.58 (t, J ) 8.9,
1H), 6.54 (td, J ) 8.5, 2.9, 1H), 6.24 (d, J ) 8.2, 1H), 5.13 (s,
1H), 3.40 (br s, 1H), 1.82 (d, J ) 1.6, 3H), 1.79 (d, J ) 1.1,
3H), 0.99 (s, 6H); 13C NMR (benzene-d6) 161.6 (d, J C-F ) 256),
159.2 (d, J C-F ) 237), 147.6, 146.3, 136.1, 133.8, 132.2 (d, J C-F
125.5 (q, J C-F ) 8), 125.4 (q, J C-F ) 4), 124.7, 124.2 (q, J C-F
)
) 5.4), 130.8, 129.3, 128.4 (d, J C-F ) 8.2), 126.8 (d, J C-F
8.7), 125.2 (d, J C-F ) 18), 124.8, 121.1, 119.9, 119.3 (d, J C-F
)
)
273), 119.9, 119.6, 115.8, 75.6, 50.9, 29.6, 29.4, 24.0. Anal.
(C26H21ClF3NO) C, H, N.
8.5), 115.6, 115.3 (d, J C-F ) 22), 114.5 (d, J C-F ) 23), 109.2 (d,
J C-F ) 25), 76.0, 50.9, 30.0, 29.2, 24.2, 14.7 (d, J C-F ) 3.0).
Anal. (C26H23F2NO) C, H, N.
(R/S)-9-Ch lor o-1,2-d ih yd r o-2,2,4-t r im et h yl-5-p h en yl-
5H-ch r om en o[3,4-f]qu in olin e (19). This compound was
prepared via general method 5 from compound 6c (75 mg, 0.23
mmol) to afford 61 mg (68%) of compound 19 as a white solid:
1H NMR (acetone-d6) 7.58 (d, J ) 2.3, 1H), 7.56 (s, 1H), 7.27
(d, J ) 8.6, 2H), 7.22 (m, 4H), 7.19 (m, 1H), 6.94 (dd, J ) 8.5,
(R/S)-9-Ch lor o-5-(3-flu or op h en yl)-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 (25). This compound
was prepared via general method 5 from compound 6c (40 mg,
0.12 mmol) to afford 25 mg (50%) of compound 25 as a white
solid: 1H NMR (acetone-d6) 7.61 (d, J ) 2.4, 1H), 7.59 (d, J )
8.4, 1H), 7.29 (m, 1H), 7.04 (d, J ) 7.9, 1H), 6.97 (m, 4H), 6.85
(d, J ) 8.5, 1H), 6.80 (d, J ) 8.5, 1H), 5.69 (br s, 1H), 5.50 (s,
1H), 2.01 (s, 3H), 1.27 (s, 3H), 1.25 (s, 3H); 13C NMR (benzene-
d6) 163.6 (d, J C-F ) 246), 150.1, 146.3, 143.3 (d, J C-F ) 6.5),

310 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Edwards et al.
(b) Horwitz, K. B.; Wei, L. L.; Sedlacek, S. M.; D’arville, C. N.
Progestin Action and Progesterone Receptor Structure in Human
Breast Cancer: A Review. Recent Prog. Horm. Res. 1985, 41,
249-316. (c) Haller, D. G.; Glick, J . H. Progestational Agents
in Advanced Breast Cancer: An Overview. Semin. Oncol. 1986,
13 (Suppl. 4), 2-8. (d) Santen, R. J .; Manni, A.; Harvey, H. A.;
Redmond, C. Endrocrine Treatment of Breast Cancer in Women.
Endocrinol. Rev. 1990, 11, 221-265.
134.0, 130.3 (d, J C-F ) 8.3), 130.0, 129.0, 128.3, 128.0, 127.9,
126.9, 124.6 (d, J C-F ) 6.5), 122.7, 120.4, 119.9, 119.7, 115.9
(d, J C-F ) 22), 115.7, 115.6 (d, J C-F ) 22), 75.9, 50.9, 39.9,
29.3, 24.0. Anal. (C25H21ClFNO) C, H, N.
(R/S)-9-Ch lor o-5-(4-ch lor o-3-m eth ylph en yl)-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 (26). This
compound was prepared via general method 5 from compound
6c (100 mg, 0.31 mmol) to afford 75 mg (56%) of compound 26
as a white solid: 1H NMR (acetone-d6) 7.60 (d, J ) 2.4, 1H),
7.57 (d, J ) 8.5, 1H), 7.23 (m, 2H), 7.00 (m, 2H), 6.91 (s, 1H),
6.84 (d, J ) 8.2, 1H), 6.79 (d, J ) 8.5, 1H), 5.68 (br s, 1H),
5.48 (s, 1H), 2.23 (s, 3H), 1.99 (s, 3H), 1.27 (s, 3H), 1.25 (s,
3H); 13C NMR (acetone-d6) 150.2, 147.8, 139.8, 136.4, 134.7,
134.4, 132.0, 130.1, 129.5, 128.9, 128.4, 127.6, 127.5, 124.7,
127.4, 124.8, 122.5, 119.9, 119.3, 116.1, 75.9, 51.2, 29.8, 29.3,
24.1, 20.2. Anal. (C26H23Cl2NO) C, H, N.
(9) (a) Pollow, K.; J uchem, M.; Grill, H.-J .; Elger, W.; Beier, S.;
Henderson, D.; Schmidt-Gollwitzer, K.; Manz, B. Gestodene: A
Novel Synthetic ProgestinsCharacterization of Binding to Re-
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(10) Berger, T. S.; Parandoosh, Z.; Perry, B. W.; Stein, R. B.
Interaction of Glucocorticoid Analogues with the Human Glu-
cocorticoid Receptor. J . Steroid Biochem. Mol. Biol. 1992, 41,
733-738.
(R/S)-9-Ch lor o-5-(4-flu or o-3-m eth ylph en yl)-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 (27). This
compound was prepared via general method 5 from compound
6c (40 mg, 0.12 mmol) to afford 22 mg (43%) of Compound 27
as a white solid: 1H NMR (acetone-d6) 7.59 (d, J ) 2.6, 1H),
7.57 (d, J ) 8.6, 1H), 7.12 (d, J ) 8.1, 1H), 6.99 (m, 1H), 6.96
(dd, J ) 8.2, 2.4, 1H), 6.90 (s, 1H), 6.84 (d, J ) 8.4, 1H), 6.77
(d, J ) 8.5, 1H), 5.68 (br s, 1H), 5.48 (s, 1H), 2.14 (s, 3H), 1.99
(s, 3H), 1.25 (s, 3H), 1.24 (s, 3H); 13C NMR (benzene-d6) 161.6
(d, J C-F ) 256), 150.2, 146.3, 135.9 (d, J C-F ) 3.7), 133.8, 132.2
(d, J C-F ) 5.4), 130.6, 129.2, 128.3 (d, J C-F ) 8), 127.9, 127.8,
127.2, 125.3 (d, J C-F ) 18), 124.7, 122.7, 120.6, 119.8, 119.7,
115.6, 115.3 (d, J C-F ) 22), 76.1, 50.9, 30.0, 29.2, 24.2, 14.7 (d,
J C-F ) 3.6). Anal. (C26H23ClFNO) C, H, N.
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Progesterone Receptor Modulators from the Marine Alga Cy-
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see: (a) Combs, D. W.; Reese, K.; Phillips, A. Nonsteroidal
Progesterone Receptor Ligands. 1. 3-Aryl-1-benzoyl-1,4,5,6-
tetrahydropyridazines. J . Med. Chem. 1995, 38, 4878-4879. (b)
Combs, D. W.; Reese, K.; Cornelius, L. A.; Gunnet, J . W.; Cryan,
E. V.; Granger, K. S.; J ordan, J . J .; Demarest, K. T. Nonsteriodal
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Progesterone Receptor Binding of Steroidal and Nonsteroidal
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E.; Gottardis, M. M.; J ones, T. K. 5-Aryl-1,2-dihydrochromeno-
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Snieckus, V.; J osephy, P. D. Sequential Directed Ortho Meta-
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(16) Alternatively, direct coupling of 3 with 2-bromo-5-nitrobenzoic
acid obviated the need for the hydrolysis step, and 5b was
prepared in this way; however, in practice the methyl esters were
easier to purify and handle.
(17) Manske, R. H. F.; Kulka, M. The Skraup Synthesis of Quinolines.
Organic Reactions; 1953; Vol. 7, Chapter 2.
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(19) The preparation, resolution, and biological evaluation of enan-
tiomerically pure compounds from this series will be the subject
of a future report.
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J M9705770