Nonsteroidal selective glucocorticoid modulators: The effect of C-10 substitution on receptor selectivity and functional potency of 5-allyl-2,5-dihydro-2,2,4-trimethyl-lh-[1]benzopyrano[3,4-f]quinolines

Article abstract of DOI:10.1021/jm020335m

The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the glucocorticoid receptor is described. Substitution at the C-10 positi

Full text of DOI:10.1021/jm020335m

1016
J . Med. Chem. 2003, 46, 1016-1030
Non ster oid a l Selective Glu cocor ticoid Mod u la tor s: Th e Effect of C-10
Su bstitu tion on Recep tor Selectivity a n d F u n ction a l P oten cy of
5-Allyl-2,5-d ih yd r o-2,2,4-tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin es
Philip R. Kym,*,† Michael E. Kort,*,† Michael J . Coghlan,†,# J immie L. Moore,† Rui Tang,† J ames D. Ratajczyk,†
Daniel P. Larson,† Steven W. Elmore,† J ohn K. Pratt,† Michael A. Stashko,† H. Douglass Falls,† Chun W. Lin,†
Masake Nakane,† Loan Miller,† Curtis M. Tyree,‡ J effery N. Miner,‡ Peer B. J acobson,† Denise M. Wilcox,†
Phong Nguyen,† and Benjamin C. Lane†
Immunologic Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064-6061 and New Leads Discovery and Transcription Research, Ligand Pharmaceuticals, Inc.,
San Diego, California 92121
Received J uly 31, 2002
The preparation and characterization of a series of C-10 substituted 5-allyl-2,5-dihydro-2,2,4-
trimethyl-1H-[1]benzopyrano[3,4-f]quinolines as a novel class of selective ligands for the
glucocorticoid receptor is described. Substitution at the C-10 position of the tetracyclic core
with linear, two-atom appendages (OCH3, OCF2H, NHMe, SMe, CHdCH2, CtCH, CH2OH)
provided molecules of high affinity (Ki ) 2-8 nM) for the human glucocorticoid receptor (hGR)
with limited cross-reactivity with other steroid receptors (PR, MR, AR, ER). Optimal analogues
showed slightly less potent but highly efficacious E-selectin repression with reduced levels of
GRE activation efficacy in reporter gene assays relative to prednisolone. Preliminary SAR of
analogues containing substitution at the C-9 and C-10 positions identified the 9-OH, 10-OMe
analogue 50 and the 9-OH, 10-Cl analogue 58 as compounds that demonstrated potent, GR-
mediated inhibition in a conconavalin A stimulated T-cell proliferation assay in both rodent
and human whole blood monocytes. When evaluated for their in vivo effects in carrageenan-
induced paw edema in rats, 50, 58, and 10-OCF2H analogue 35 showed dose-dependent anti-
inflammatory effects (50, ED50 ) 16 mg/kg; 58, ED50 ) 15 mg/kg; 35, ED50 ) 21 mg/kg vs ED50
) 15 mg/kg for 18 and ED50 ) 4 mg/kg for prednisolone).
In tr od u ction
Having long been considered among the most potent
anti-inflammatory agents known, oral glucocorticoids
such as dexamethasone1 (dex, 1) and prednisolone2
(pred, 2) continue to represent the clinical gold standard
for treatment of numerous musculoskeletal, respiratory,
gastrointestinal, and dermatological disorders.3-5 Un-
fortunately, these beneficial anti-inflammatory and
receptor response elements9 (GREs) or inhibit transcrip-
immunomodulatory effects are counterbalanced by a
tion by repressing the activity of other transcription
broad spectrum of adverse events, the frequency and
factors such as NFkB10 or AP-1.11 Recently, it has been
severity of which tend to increase with increased dosage,
shown that these are discreet processes, and it has been
length of therapy, and systemic exposure. These del-
postulated that molecules that repress transcription
eterious side effects, which include osteoporosis,6 glucose
without activating GREs may lead to anti-inflammatory
intolerance,7 lipid redistribution, and acute psychosis,8
drugs with reduced side effect liabilities.12
have limited a more widespread therapeutic use of
The functional role played by the GR/ligand complex
synthetic glucocorticoids.
in the initiation or repression of transcriptional events
Over the past several years, an understanding of the
is determined predominantly by its topology, particu-
molecular mechanisms by which corticosteroids exert
larly the accessibility of key regions of this complex to
their biological effects has begun to emerge. Glucocor-
interact with various transcription factors, co-promoters,
ticoids bind to the glucocorticoid receptor (GR) where-
and co-repressor proteins.13 The conformation of the GR/
upon the resulting GR/ligand complex can either initiate
ligand complex is in turn determined by the manner in
transcription of specific target genes by binding to
which the receptor envelops the ligand, and minor
consensus sequences on DNA known as glucocorticoid
changes in ligand structure can lead to GR/ligand
complexes of varied tertiary structure which perform
different functions.14 Our goal is the discovery of
structurally novel, nonsteroidal small molecule modula-
tors of GR that mechanistically differentiate transcrip-
tional repression and activation pathways, ultimately
providing a superior anti-inflammatory agent with a
reduced iatrogenic profile.15-17
* To whom correspondence should be addressed: Michael Kort,
Abbott Laboratories, D-R4PM Bldg. AP10, 100 Abbott Park Road,
Abbott Park, IL 60064-6101; 847-935-4945; michael.e.kort@abbott.com;
Philip Kym, Abbott Laboratories, D-R4MF Bldg. AP10, 100 Abbott
Park Road, Abbott Park, IL 60064-6061; 847-935-4699; phil.r.kym@
abbott.com.
† Abbott Laboratories.
‡ Ligand Pharmaceuticals.
#
Present address: Eli Lilly and Co., Indianapolis, IN 46285
10.1021/jm020335m CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/19/2003

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1017
Sch em e 1a
Sch em e 2a
a
Reagents: (a) acetone, I2, 105 °C.
We have recently described the discovery of GR-
selective 1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-
f]quinolines (3) that are comparable to pred in rodent
in vivo models for rheumatoid arthritis and asthma.15
Introduction of a methyl ether group at the C-10
position of this pharmacophore imparted GR-selective
binding accompanied by enhanced GR-specific func-
tional potency for both reporter gene assays of repres-
sion and whole cell models of GR function. It was further
demonstrated that selective potentiation of GRE activa-
tion in this series could be achieved by judicious
structural modification of the C-5 substituent.16 Herein,
we describe a more extensive SAR associated with
D-ring functionality, concentrated on defining the op-
timal substitution pattern for potent, GR-selective
functional ligands.
a
Reagents: (a) H2, 10% Pd/C, THF, 92%; (b) Me3SiCl, N,O-
bis(trimethylsilyl)acetamide, CH3CN; acetone, I2, 105 °C, 73%; (c)
TBSCl, imidazole, THF, 23 °C, 60%; (d) Dibal-H, PhCH3, -78 °C;
(e) p-TsOH‚H2O, MeOH, 23 °C, 66% for 2 steps; (f) allyltrimeth-
ylsilane, BF3‚OEt2, CH2Cl2, -78 f 0 °C, 93%; (g) Bu4NF, THF,
23 °C, 91%.
Sch em e 3a
Ch em istr y
For the preparation of analogues bearing the desired
substitution pattern, we sought to develop a general
method for incorporation of the D-ring involving late-
state embellishment of a suitably functionalized AB-ring
precursor. To our disappointment, the modified Skraup
annulation reaction which provided highly regioselective
access to trimethylquinolines when executed with sub-
stituted aminocoumarins (e.g., 4 f 5, Scheme 1)15,18 was
neither selective nor efficient when performed with
model substrates 6 or 7. It was empirically determined
that the minimal structural requirement necessary to
retain regioselectivity in the Skraup reaction was the
presence of an unsaturated C-ring lactone, exemplified
by the decisive regioselection (10:1) in the annulation
of coumarin 8. On the basis of this observation, we
reasoned that increased diversity of substitution in the
D-ring might be best accomplished by installation of
functional groups that could be subsequently modified
or used to direct the incorporation of additional struc-
tural complexity. To this end, our synthetic target
became a core structure bearing latent C-10 hydroxyl
functionality which could presumably be converted to
a large number of C-10 alkyl ethers or further elabo-
rated, via the corresponding trifluoromethanesulfonate
derivative, to carbon- and nitrogen-substituted ana-
logues using palladium-catalyzed coupling methodology.
Construction of the desired tetracyclic core made
recourse to benzocoumarin 9 (Scheme 2), the synthesis
of which has been described elsewhere.15 Catalytic
hydrogenation of the nitroarene afforded aniline 10
which was regioselectively transformed to 1,2-dihydro-
2,2,4-trimethylquinoline 11 following in situ conversion
to the tris(trimethylsilyl) derivative. Controlled reduc-
a
Reagents: (a) Tf2O, Et3N, CH2Cl2, 78 f 23 °C, 91%; (b)
Cs2CO3, RX, DMF, 23 °C; (c) Pd(II), R3P, nucleophile; (d) LiAlH4,
Et2O, 0 f 23 °C, 47%; (e) Dibal-H, CH2Cl2, -78 f 0 °C, 93%; (f)
KHMDS, MeI, THF, 0 °C, 92%.
tion of the corresponding tert-butyldimethylsilyl (TBS)
protected coumarin 12 and acid-catalyzed acetalization
provided versatile intermediate 14. Exposure of this
methyl acetal to allyltrimethylsilane in the presence of
BF3•OEt2 produced C-5 allylated adduct 15, which was
immediately subjected to tetrabutylammonium fluoride
to provide 16 in excellent overall yield.
To rapidly assess the steric requirements of the “C-
10 pocket,” a series of alkyl ethers (18-23) was prepared
by treatment of phenol 16 with selected alkylating
agents (Scheme 3). Alternatively, 16 could be converted
to the triflate derivative 17 (Tf2O, Et3N, CH2Cl2), which
underwent further palladium-catalyzed elaboration to
provide 24-31.
While the C-5 allyl substituted phenol 16 served as a
convenient intermediate for the preparation of numer-
ous 10-substituted analogues, transformations demand-
ing especially harsh conditions required backtracking
to the more stable 1,2-dihydro-2,2,4-trimethylquinoline
11. For example, production of a C-10 difluoromethyl

1018 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Kym et al.
Sch em e 4a
Analogues bearing 9,10-disubstitution required de
novo synthesis from appropriately substituted arylbo-
ronic acids, as exemplified by the conversion of 2,3,6-
trimethoxyphenylboronic acid (44) to 9-hydroxy-10-
methoxy derivative 50 (Scheme 6). Selective differenti-
ation of the C-9 and C-10 phenol functionalities was
realized by protection of the more accessible 9-OH by
treatment with TBSCl and imidazole followed by me-
thylation of the remaining phenol with methyl iodide
and cesium carbonate (48 f 49). Additional D-ring
variants, particularly those decorated with one or more
halogen atoms or bearing functional groups at C-8 (55-
60, Figure 1), were similarly available via embellish-
ment of substituted 2-methoxyphenylboronic acids 44
and 51-54 using protocols outlined in Schemes 2, 3, and
6. Approaches presented in Scheme 3 applied to 50
provided access to 10-OMe analogues possessing differ-
ent C-9 substituents (63-70) designed to probe the “C-9
pocket” (Scheme 7).
a
Reagents: (a) BrF2CH, K2CO3, DMF, 80 °C, 43%; (b) NaH,
DMF, 0 °C, Me2NCSCl, 80 °C, 28%, (c) 275 °C, 59%; (d) Dibal-H,
PhCH3, -78 °C; (e) p-TsOH‚H2O, MeOH, 23 °C; (f) allyltrimeth-
ylsilane, BF3‚OEt2, CH2Cl2, -78 f 0 °C; 35: 58% for 3 steps; 36:
18% for 3 steps; (g) KOH, ethylene glycol, 170 °C; (h) Cs2CO3, MeI,
DMF, 0 °C, 34% for 2 steps.
Biologica l Eva lu a tion
As in our previous studies, receptor binding, E-
selectin repression, and glucocorticoid response element
(GRE) activation were relied upon for primary screen-
ing. Affinity for the R-isoform of hGR was evaluated in
a competition binding assay. Selectivity versus other
steroid receptors, particularly progesterone receptor,23,24
was routinely monitored. Each compound was then
further probed for its ability to functionally activate or
repress transcription in a cellular context using several
cotransfection assays.25,26
Sch em e 5a
The E-selectin cotransfection assay25 was used to
evaluate compounds for the effect on repression of
transcription mediated by nuclear factor κB (NFκB) or
activator protein-1 (AP-1). E-selectins are membrane-
bound cell adhesion proteins found only on endothelial
cells and are upregulated in response to infection or
tissue injury. The reporter plasmid used in this assay
contains an E-selectin promoter that has binding sites
for one NFκB and one AP-1 transcription factor placed
upstream of a luciferase expression cassette in HEPG2
cells. NFκB and AP-1 bind to the proximal promoter
region and are responsible for transmitting the effects
of inflammatory mediators tumor necrosis factor (TNF)
and interleukin-1 (IL-1) as well as the subsequent
upregulation of E-selectin gene expression. Glucocorti-
coids act to inhibit the inflammatory process in part by
interfering with the binding of both AP-1 and NFκB,
thereby repressing the expression of E-selectin and
other regulated genes.
a
Reagents: (a) Cs2CO3, Mel, DMF, 23 °C, 99%; (b) Br2, CHCl3/
AcOH, 55 °C; (c) H2, 10% Pd/C, dioxane, 65 °C, 67% for 2 steps;
(d) I2, acetone, 105 °C, 47%; (e) Dibal-H, PhCH3, -78 °C; (f)
p-TsOH‚H2O, MeOH, 23 °C; (g) allyltrimethylsilane, BF3‚OEt2,
CH2Cl2, -78 f 0 °C; 51% for 3 steps; (h) R’SnR3, Pd(dppf)Cl2,
NMP, 65 °C; for 42, 63%; for 43, 59%.
ether analogue (11 f 32 f 35, Scheme 4) necessitated
reaction of 11 with difluoromethylcarbene generated
from bromodifluoromethane in the presence of potas-
sium carbonate in DMF at 90 °C19 to generate the
desired linkage. Similarly, phenol 11 represented a
serviceable entry to sulfur-containing analogues. Py-
rolysis of O-aryl-N,N-dimethylthionocarbamate 33 ef-
fected Newman-Kwart rearrangement20,21 to give the
S-aryl N,N-dimethylthiocarbamate 34, which was fur-
ther converted to 37.
Oxygen functionality at C-10 also provided a handle
for more densely functionalized D-ring derivatives.
Regiochemistry enforced by the directing effects of the
10-OMe substituent provided access to 7,10-disubstitu-
tion via electrophilic bromination of 38 (Scheme 5).
Chemoselective reduction, Skraup reaction,18 and C-5
elaboration as previously described gave 41, which
reacted efficiently with organostannanes in the presence
of palladium catalyst22 to form C-7 alkyl substituted
analogues 42 and 43.
The GRE transcriptional activation assay27 provided
a mechanism for determining the facility of formation
of a receptor/ligand complex that would bind to GRE
signature sequences and initiate transcription. In this
cotransfection assay, the reporter plasmid contains a
portion of the mouse mammary tumor virus (MMTV)
promoter spliced upstream of a luciferase gene expres-
sion vector in CV-1 cells. The MMTV promoter contains
four GRE sites and the construct has no known affinity
for AP-1 or NFκB. Maximal efficacies of compounds in
both the E-selectin repression and GRE activation
assays are reported as a percentage of the maximal
response observed for dexamethasone and potency
values are calculated as the concentration at half-
maximal response for these curves.

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1019
Sch em e 6a
a
Reagents: (a) PdCl2(PPh3)2, Cs2CO3, DMF, 90 °C, 87%; (b) BBr3, CH2Cl2, -78 f 23 °C, 99%, (c) H2, 10% Pd/C, dioxane, 65 °C; (d) I2,
acetone, 105 °C, 54% for 2 steps; (e) TBSCl, imidazole, THF, 0 °C, 60%; (f) Cs2CO3, MeI, DMF, 0 °C, 93%; (g) Dibal-H, PhCH3, -78 °C;
(h) p-TsOH‚H2O, MeOH, 23 °C, 61% for 2 steps; (i) Bu4NF, THF, 23 °C, 99%; (j) allyltrimethylsilane, BF3‚OEt2, CH2Cl2, -78 f 0 °C, 79%.
Ta ble 1. Steric Mapping of the C-10 Pocketa
F igu r e 1. D-ring disubstituted analogues prepared from
functionalized 2-methoxyphenylboronic acids.
Sch em e 7a
a
Values with standard deviation represent the mean of two
experiments with triplicate determinations and values without
standard deviation represent a single experiment in triplicate.
Values with an asterisk represent the mean value of at least three
b
separate experiments in triplicate with standard error. All EC50
values were determined from full seven point, half-log concentra-
tion response curves. c Efficacies are represented as a percentage
a
Reagents: (a) Cs2CO3, RX, DMF, 0 °C; (b) Tf2O, Et3N, CH2Cl2,
d
of the maximal response of dexamethasone (100%). A hyphen
-78 f 23 °C, 91%; (c) Pd(OAc)2, dppe, CO, Et3N, MeOH/DMSO,
60 °C, 65%; (d) Dibal-H, CH2Cl2, -78 f 0 °C, 61%.
indicates a functional potency that was not calculated due to low
efficacy or a functional efficacy <20%.
While the aforementioned cotransfection assays were
the primary biochemical tools used in compound screen-
Resu lts a n d Discu ssion
ing for GR-mediated effects, promising analogues were
further evaluated for their effects on down-regulation
of T-cell proliferation induced by conconavalin A (con
A),28 an inhibitory process recognized for glucocorti-
coids.29 This assay was attractive to us since it could
easily be run using either human whole blood or rat
spleenocytes, thereby providing a potential measure of
species-specific effects. In addition, we have previously
observed an excellent correlation between activity in the
con A assay run using rat spleenocytes and in vivo
activity in the carrageenan paw edema assay,30 our
primary rodent model of inflammation. As before,
results are reported as a percentage of the maximal
response observed for dexamethasone and potency
values are calculated as the concentration at half-
maximal response for these curves.
Str u ctu r e-Activity Rela tion sh ip s. In our previous
disclosure, the systematic precession of a methyl ether
substituent about the periphery of the 5-aryl-1,2-dihy-
dro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline D-ring
demonstrated that C-10 substitution conferred remark-
able GR selectivity and functional activity in both in
vitro repression assays and in vivo models for asthma.15
Our present, more rigorous exploration of the C-10
pocket was initiated using a series of C-10 substituted
alkyl ethers of varying steric demand (Table 1). It
became immediately apparent that GR activity was
restricted to a narrowly defined subset of analogues of
comparable size: active derivatives 18 and 35, for
instance, differ only in the isosteric replacement of
methyl ether with difluoromethyl ether. Introduction of
less sterically encumbered functionality at C-10 (H in

1020 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Ta ble 2. Electronic Effect of C-10 Substituent on GR Activitya
Kym et al.
GRE activation
E-selectin repression
EC50 (nM)b eff (% dex)c
cmpd
R
GR Ki (nM)
EC50 (nM)b
eff (% dex)c
prednisolone
2.4 ( 0.3*
7.0 ( 0.1
5.2 ( 1.2
4.4 ( 1.0
6.9 ( 2.1
9.3 ( 0.7
140 ( 9
2.3 ( 0.6
18.0 ( 1.9
400 ( 87
8.0 ( 1.1*
32 ( 12
89 ( 19*
60 ( 1
60 ( 21
50 ( 4
92 ( 4
87 ( 8
7 ( 1
2.1 ( 0.2*
19 ( 9
18 ( 8
12 ( 4
59 ( 14
60 ( 6
467
19 ( 5
305
-
99 ( 1*
96 ( 3
92 ( 6
95 ( 4
89 ( 4
79 ( 5
30 ( 23
92 ( 1
22 ( 7
-
28
37
24
25
26
27
30
31
29
NHMe
SMe
vinyl
-CtCH
CN
CH2NH2
CH2OH
CH2OMe
CO2Me
123 ( 11
17 ( 0
130 ( 0
195 ( 120
d
-
61 ( 7
69 ( 22
5 ( 4
-
-
-
a
Values with standard deviation represent the mean of two experiments with triplicate determinations and values without standard
deviation represent a single experiment in triplicate. Values with an asterisk represent the mean value of at least three separate experiments
in triplicate with standard error. b All EC50 values were determined from full seven point, half-log concentration response curves. c Efficacies
d
are represented as a percentage of the maximal response of dexamethasone (100%). A hyphen indicates a functional potency that was
not calculated due to low efficacy or a functional efficacy <5%.
Ta ble 3. Receptor Cross-Reactivity of GR-Active Analoguesa
Ki (nM)
cmpd
R
GR
PR
MR
AR
2760*
ERc
b
prednisolone
2.4 ( 0.3*
33.8 ( 1.3
27.6 ( 4.9
2.5 ( 0.5*
2.2 ( 0.3
7.0 ( 0.1
5.2 ( 1.2
4.4 ( 1.0*
6.9 ( 2.1
9.3 ( 0.7
2.3 ( 0.6
-
37 ( 12
-
1370 ( 49
46 ( 23
35.8 ( 3.9
251 ( 31
93.8
1000†
1000†
1000†
1000†
1000†
1000†
1000†
1000†
1000†
1000†
1000†
62
16
18
35
28
37
24
25
26
30
H
OH
35.9
-
330 ( 56
1790 ( 480
349 ( 99
2920 ( 700
4740
435 ( 100
2400 ( 1060
1460 ( 490
192 ( 23
2060 ( 1150
1230 ( 510
96.3 ( 60.1
2590 ( 270
2460
OMe
OCF2H
NHMe
SMe
vinyl
-CtCH
57 ( 35
350 ( 220
-
239 ( 27
650 ( 600
-
CN
CH2OH
292 ( 49
1320 ( 500
a
Values with standard deviation represent the mean of two experiments with triplicate determinations and values without standard
deviation represent a single experiment in triplicate. Values with an asterisk represent the mean value of at least three separate experiments
b
in triplicate with standard error. A hyphen indicates a binding potency of >5000 nM. c Values with a dagger indicate that the mean Ki
values of at least three experiments were >1000 nM.
62; OH in 16) produced markedly decreased GR avidity
with concomitant ablation of functional activity in the
E-selectin repression and the GRE activation cotrans-
fection assays. An incremental increase in the size of
the alkyl ether group produced a similar diminution in
GR binding affinity and functional activity. Propargylic
substitution (21) would appear to represent the steric
threshold for acceptable GR binding potency; however,
this analogue was essentially inactive in cotransfection
assays.
The steric parameters of the C-10 pocket having been
established, we next sought to determine the tolerance
of hydrophilic substituents with the added objective of
improving the physicochemical properties of this oth-
erwise lipophilic pharmacophore. To this end, we pre-
pared molecules containing heteroatoms disposed either
R or â to the D-ring at C-10. When the R-position was
occupied by C, N, or S (24, 28, or 37, respectively), GR
binding potency and functional activity in cotransfection
repression assays were maintained (Table 2). The
spatial orientation of the C-10 substituent is also critical
for retention of functional agonism, as evidenced by the
diminished E-selectin potency of acetylene 25 and nitrile
26. In short, nonbranched two atom substituents ap-
pended to the C-10 position of the 5-allyl-1,2-dihydro-
2,2,4-trimethyl-5H-chromeno-[3,4-f]quinoline skeleton
provided optimal GR binding potency and E-selectin
repression activity. Of note, this subset of analogues
demonstrated transcriptional repression activity com-
parable to pred in the E-selectin assay, but was only
partially efficacious and considerably less potent than
pred in the GRE-mediated transactivation assay.
We next profiled the steroid receptor cross-reactivity
(Table 3) of preferred analogues (hGR Ki < 10 nM,
E-selectin EC50 > 50%). We have previously documented
the crucial role C-10 substitution plays in reducing the
affinity of 5-aryl-1,2-dihydro-2,2,4-trimethyl-5H-chro-
meno-[3,4-f]quinoline analogues for PR15 and indeed,
this appears to be a general feature of this tetracyclic
core irrespective of the C-5 substituent. For the C-5 allyl
series, C-10 unsubstituted analogue 62 binds GR and
PR with equal affinity while methyl ether 18 displays
potent GR binding (Ki ) 2.5 nM) and very weak PR
binding (Ki ) 1790 nM). All of the C-10 substituted

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1021
Ta ble 5. Effect of C-9 Substitution in D-Ring on GR Activitya
Ta ble 4. Species Selectivity in Conconavalin A T-Cell
Proliferation Assaya
conconavalin A
(rat)
conconavalin A
(human)
EC50
eff
EC50
(nM)b
eff
cmpd
R
(nM)b
(% dex)c
(% dex)c
predniso-
lone
18
35
28
19 ( 6*
97 ( 3* 25 ( 2*
95 ( 2*
OMe
48 ( 20* 100 ( 2* 780 ( 110* 82 ( 6*
OCF2H 85 ( 15 100 ( 3 563 ( 81
NHMe 48 ( 43 98 ( 0 418 ( 73
vinyl 90 ( 43* 97 ( 3* >1000*
65 ( 9
83 ( 9
24
56 ( 22*
a
Values with standard deviation represent the mean of two
experiments with triplicate determinations and values without
standard deviation represent a single experiment in triplicate.
Values with an asterisk represent the mean value of at least three
b
separate experiments in triplicate with standard error. All EC50
values were determined from full seven point, half-log concentra-
tion response curves. c Efficacies are represented as a percentage
of the maximal response of dexamethasone (100%).
analogues containing two-atom attachments are at least
100-fold selective for GR with 18 and 28 possessing the
most favorable cross-reactivity profiles. The C-5 allyl
substituent common to all of these analogues also
imparts considerable MR affinity (Table 3). In cotrans-
fection assays designed to ascertain MR agonism or
antagonism, potent binders of MR were found to not
function as MR agonists and had only weak activity as
MR antagonists.
Guided by the observed potency in the GR binding
assay and the level of GR-mediated transcriptional
repression in the E-selectin cotransfection assay, prom-
ising analogues were further evaluated using whole
blood assays with immunologically relevant endpoints
such as the con A-induced T-cell proliferation assay.
While demonstrating equivalent potency and compa-
rable efficacy (with 2-5-fold) relative to pred in the rat
con A assay, the 10-substituted compounds as a class
exhibited a species-selective potency biased toward
increased activity (approximately 10-fold) in rat spleen-
ocytes relative to human whole blood (Table 4). As a
class, the C-10 substituted compounds demonstrated
prednisolone equivalent efficacy, and potency within
2-5-fold of prednislone, but each analogue was less
efficacious and about 5-10-fold less potent in the
corresponding human experiment.
Toward the development of compounds with parallel
rat/human activity and in conjunction with 10-OMe
substitution, we reinvestigated the SAR of C-7, C-8, and
C-9, potential loci for beneficial interactions with GR.
Since it was known from our previous work that the GR
did not tolerate C-8 substituents larger than H or F and
that polar fucntionality at C-7 resulted in the oblitera-
tion of GR activity,15 our foray with the C-10 substituted
compounds was limited (Table 5). Interestingly, halo-
genation (F, Cl, Br) or introduction of polar substituents
(OH, CH2OH, or CO2Me) at C-9 led to retention of GR
binding potency was with a concurrent increase in PR
affinity. Though an improved receptor binding selectiv-
ity profile was observed with selected 7,10-disubstituted
analogues, this was offset by a loss of E-selectin repres-
a
Values with standard deviation represent the mean of two
experiments with triplicate determinations and values without
standard deviation represent a single experiment in triplicate.
Values with an asterisk represent the mean value of at least three
b
separate experiments in triplicate with standard error. All EC50
values were determined from full seven point, half-log concentra-
tion response curves. c Efficacies are represented as a percentage
d
of the maximal response of dexamethasone (100%). A hyphen
indicates a binding potency of >5000 nM, a functional potency that
was not calculated due to low efficacy, or a functional efficacy
<20%.
sion potency (Table 6). Only the C-9 hydroxyl analogue
50 (Table 5) maintained potent GR-specific functional
activity in the E-selectin repression assay. Furthermore,
50 was the only example that offered enhanced GR
affinity relative to 18, but at the expense of GR/PR
selectivity. With the 10-Cl analogue 58 (Table 6),
remarkable increases in GR binding and E-selectin
repression potency imparted by the C-9 hydroxyl group
were accompanied by an erosion of GR/PR selectivity.
In an attempt to restore the desired selectivity for GR
by leveraging the favorable cross-reactivity profile af-
forded by bromination at C-7 (see 41, Table 6), we
prepared trisubtituted D-ring analogue 61. Though 61
did not increase the GR/PR selectivity ratio as expected,
it did retain the potent transcriptional repression activ-
ity of the parent 9-hydroxy-10-chloro system. Perhaps
the most significant effect of 9-hydroxylation was to
overcome the issue of species specificity we had encoun-
tered in the con A assays (Table 7). For example, 50
and 58 demonstrated comparable inhibition of con
A-induced T-cell proliferation in rat spleenocyctes and
human whole blood, with the latter analogue exhibiting
potency equivalent to pred.
In Vivo Eva lu a tion . The in vivo activity of 18 in
acute and chronic rodent models of inflammation has
been previously documented.15 A comparable profile
relative to pred was observed (see Figure 2) upon oral
dosing the C-10 difluoromethyl ether 35, 50, and the
58 in the rat carrageenan induced paw edema (CPE)

1022 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Ta ble 6. Effect of C-9 Substitution in D-Ring on GR Activitya
Kym et al.
E-selectin repression
cmpd
R1
R2
R4
Br
Me
vinyl
H
GR Ki (nM)
PR Ki (nM)
EC50 (nM)b
eff (% dex)c
d
prednisolone
2.4 (0.3*
4.1 ( 1.9*
2.0 ( 0.1*
34 ( 7*
1.9 ( 0.3*
0.58 ( 0.09*
2.3 ( 0.2*
-
2.1 ( 0.2*
59 ( 4
81 ( 6
156 ( 10
45 ( 40
5.0 ( 2.0*
5.0 ( 1.0
99 ( 1*
96 ( 1
91 ( 7
89 ( 4
92
97 ( 1*
95 ( 1
41
42
43
60
58
61
OMe
OMe
OMe
Cl
Cl
Cl
H
H
H
H
OH
OH
-
-
450
61
H
Br
7.6 ( 2.1*
22.0 ( 6.6*
a
Values with standard deviation represent the mean of two experiments with triplicate determinations and values without standard
deviation represent a single experiment in triplicate. Values with an asterisk represent the mean value of at least three separate experiments
in triplicate with standard error. b All EC50 values were determined from full seven point, half-log concentration response curves. c Efficacies
d
are represented as a percentage of the maximaw response of dexamethasone (100%). A hyphen indicates a binding potency of >5000
nM, a functional potency that was not calculated due to low efficacy, or a functional efficacy <20%.
Ta ble 7. Effect of D-Ring Substitution on Species Selectivitya
conconavalin A (rat)
conconavalin A (human)
cmpd
R1
R2
EC50 (nM)b
eff (% dex)c
EC50 (nM)b
eff (% dex)c
prednisolone
19 ( 6*
48 ( 20*
78 ( 69
>1000
97 ( 3*
100 ( 2*
105 ( 3
37 ( 28
105 ( 3*
25 ( 2*
780 ( 110*
145 ( 61*
440 ( 62
29 ( 10
95 ( 2*
82 ( 6*
87 ( 1*
58 ( 11
87 ( 6
18
50
60
58
OMe
OMe
Cl
H
OH
H
Cl
OH
78 ( 58*
a
Values with standard deviation represent the mean of two experiments with triplicate determinations and values without standard
deviation represent a single experiment in triplicate. Values with an asterisk represent the mean value of at least three separate experiments
in triplicate with standard error. b All EC50 values were determined from full seven point, half-log concentration response curves. c Efficacies
are represented as a percentage of the maximal response of dexamethasone (100%).
Con clu sion
The SAR of D-ring substituted analogues of 5-allyl-
1,2-dihydro-2,2,4-trimethyl-5H-chromeno-[3,4-f]quino-
lines revealed several important effects of C-10 and C-9
substituents on GR-mediated activity. First, the optimal
C-10 substituent for obtaining GR-selective binding
affinity and potent E-selectin repression activity is a
linear appendage of two atoms. The advantageous effect
on GR activity conferred by this substitution pattern
appears to be linked to the isosteric volume occupied
by the substituent rather than its electronic character.
This is deduced from the similar profiles for GR activity
observed for the C-10 OMe, OCF2H, NHMe, SMe, vinyl,
F igu r e 2. Prednisolone, 18, 35, 50, and 58, dose-dependently
propargyl, CN, and CH2OH analogues. Compounds with
inhibit rat CPE.
larger or smaller C-10 substituents exhibit a decrease
in GR-mediated activity. Introduction of a 9-OH func-
tionality in combination with a 10-OMe or 10-Cl group
assay.30 An acute inflammatory response was generated
in Sprague-Dawley rats following injections of carra-
geenan in the hind paw; the resulting edema was
increases the potency of GR binding and E-selectin
repression, and provides analogues that demonstrate
quantified after 3 h by measuring the increase in volume
efficacious activity across test species in the conconava-
of the inflamed paw. Each of these compounds dose-
dependently inhibited edema in this model (35: ED50
) 21 mg/kg; 50: ED50 ) 16 mg/kg; 58: ED50 ) 15 mg/
kg) compared to an 1816 (ED50 ) 15 mg/kg) and pred
(ED50 ) 4 mg/kg). Moreover, the efficacy of the 9-hy-
droxy analogues 58 and 50 is noteworthy given that
these two analogues were devoid of species-specific
liabilities in vitro (con A assay).
lin A assay. It should be noted, however, that this
increase in GR potency comes with an apparent de-
crease in GR/PR selectivity. The most potent and
efficacious GR modulators were evaluated in vivo in the
rat carrageenan paw edema assay, and several ana-
logues showed an oral ED50 comparable to prednisolone.
Future work will focus on combining the optimal D-ring
substitution patterns with optimal C-5 substituents

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1023
virus (MMTV) promoter as we have previously described.15,27
Maximal efficacies of compounds in the E-selectin repression
and the GRE activation assays are reported as a percentage
of the maximal response observed for dexamethasone and
potency values are calculated as the concentration at half-
maximal response for these curves.
Hu m a n P BMC-In d u ced Con con a va lin A (Con A) P r o-
lifer a tion Assa y.28 Blood from a human donor (25 mL) was
placed in a heparin-treated 50 mL centrifuge tube and diluted
2-fold by adding an equal volume of 3% Dextran T500
(Pharmacia Biotech). After the sample stood for 20 min at
ambient temperature, the serum (about 35 mL) was trans-
ferred to a fresh 50 mL centrifuge tube. Histopaque-1077 (15
mL, Sigma) was overlaid to the tube and the tube was
centrifuged at 1400 rpm for 30 min at 25 °C. An interface was
collected and placed into a tube with 5 mL complete medium
(RPMI1640 with 10% fetal bovine serum and 50 µM â-mer-
captoethanol). The cells were washed and resuspended in
complete medium and plated into 96-well culture plates at
50000 cells per well.
After adding compounds to be tested, concanavalin A (con
A type IV-S, Sigma) was added to each well at 2.5 µg/mL and
incubated for 3 days in a CO2 incubator. To measure prolifera-
tion, 0.5 µCi/well of [3H]-thymidine (NEN Life Science Prod-
ucts) was added and incubated for an additional 6 h at 37 °C.
The cells were harvested onto glass fiber filter using a Tomtec
Cell Harvester 96. The glass fiber filter was counted via direct
â-counting method (Packard Matrix 9600).
Ra t Sp len ocyte-In d u ced Con con a va lin A P r olifer a -
tion Assa y. Sprague-Dawley rat spleens were dissected and
the splenocyte suspension was transferred to 50 mL centrifuge
tube. After large debris was removed, the cells were collected
by centrifugation at 1200 rpm for 10 min at 4 °C. Red blood
cells were removed from the splenocyte suspension by osmotic
shock, and the resulting cells were suspended in complete
medium. The cells were washed and resuspended in complete
medium and plated into 96-well culture plates at 50 000 cells
per well.
After compounds to be tested were added, con A was added
to each well at 2.5 µg/mL and incubated for 3 days in CO2
incubator. To measure proliferation, 0.5 µCi/well of [3H]-
thymidine was added and incubated for additional 6 h at 37
°C. The cells were harvested onto glass fiber filter using a
Tomtec Cell Harvester 96. The glass fiber filter was counted
via direct â-counting method (Packard Matrix 9600).
In Vivo Eva lu a tion : Ca r a geen a n P a w Ed em a (CP E)
Assa y.30 The effectiveness of selected compounds in a rodent
model of inflammation was evaluated using the rat carageenan
paw edema assay. Sprague-Dawley rats were given injections
of carrageenan in their hind paw stimulating an acute inflam-
matory response. The resulting edema is quantified after 3 h
by measuring the increase in the volume of the inflamed paw.
The effect of orally dosing our compounds on inhibiting the
edema was determined and an ED50 dose was calculated.
10-(ter t-Bu tyld im eth ylsiloxy)-5-oxo-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (12). Phenol
11 (2.44 g, 7.55 mmol) was dissolved in of dry THF (125 mL)
and the solution was cooled to 0 °C. Imidazole (1.55 g, 22.7
mmol) and TBSCl (1.70 g, 11.3 mmol) were added. A white
precipitate formed in the reaction mixture within 1 min of silyl
reagent addition. The reaction mixture was stirred overnight
without replenishing the cooling bath. The reaction mixture
was diluted with EtOAc (100 mL) and washed with 1 N HCl
(2 × 50 mL), saturated NaHCO3 (50 mL) and brine (50 mL).
The organic layer was dried (Na2SO4) and concentrated. The
resulting residue was purified by chromatography on silica gel
(gradient elution: 0-20% EtOAc/hexanes) to give 12 (1.97 g,
4.53 mmol, 60%) as an intensely yellow solid: mp 176-179
°C; 1H NMR (300 MHz, DMSO-d6) δ 8.76 (d, J ) 8.7 Hz, 1 H),
7.27 (t, J ) 7.9 Hz, 1 H), 6.96 (dd, J ) 8.0, 1.1 Hz, 1 H), 6.93
(d, J ) 8.6 Hz, 1 H), 6.74 (dd, J ) 8.1, 1.0 Hz, 1 H), 5.58 (br
d, J ) 1.3 Hz, 1 H), 4.23 (br s, 1 H), 2.12 (s, 3 H), 1.33 (s, 6 H),
1.04 (s, 9 H), 0.31 (s, 6 H); 13C NMR (300 MHz, DMSO-d6) δ
158.8, 152.3, 150.9, 145.8, 131.5, 130.1, 127.3, 126.0, 124.0,
with the ultimate goal of providing potent, GR-mediated
anti-inflammatory agents.
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were determined
with capillary apparatus and are uncorrected. Nuclear mag-
netic resonance spectra (1H at 300 MHz and 13C at 75 MHz)
were run as dimethyl sulfoxide-d6 solutions, unless otherwise
stated. Dimethyl sulfoxide-d6 was used as an internal stan-
dard. Mass spectra determinations were performed by the
Analytical Research Department, Abbott Laboratories. El-
emental analyses were performed by Robertson Microlit
Laboratories, Inc., Madison, NJ . Optical rotations were mea-
sured at 23 °C in chloroform. Analytical thin-layer chroma-
tography was done on 2 × 6 cm Kieselgel 60 F-254 plates
precoated with 0.25-mm-thick silica gel distributed by E.
Merck. Unless otherwise specified, column chromatography
was performed on silica gel (Kieselgel 60, 70-230 mesh) from
E. Merck. The term in vacuo refers to solvent removal using
a rotary evaporator at 30 mmHg. With the exception of amines,
solvents and reagents were purchased from Aldrich Chemical
Co. and were used without further purification unless other-
wise specified. All amines were dried over molecular sieves (4
Å) for at least 24 h prior to use. Tetrahydrofuran (THF) was
distilled from sodium benzophenone ketyl.
Recep tor Bin d in g Assa ys. Cytosol preparations of human
glucocorticoid receptor-R (GR-R) isoform and human proges-
terone receptor-A [PRA] have been described previously.31 Both
receptor cDNAs were cloned into baculovirus expression
vectors and expressed in insect SF21 cells. The GRX contains
Thr-Met-Glu-Tyr-Met-Pro-Met-Glu-Asp on its N-terminus.
[3H]-dexamethasone (Dex) (specific activity 82-86 Ci/mmol)
and [3H]-progesterone (Prog) (specific activity 97-102 Ci/
mmol) were purchased from Amersham Life Sciences (Arling-
ton Heights, IL).). Glass fiber type C multiscreen MAFC NOB
plates were from Millipore (Burlington, MA). Hydroxyapatide
Bio-Gel HTP gel was from Bio-Rad Laboratories (Hercules,
CA). Tris(hydroxymethyl)aminomethane (Tris), ethylenedi-
aminetetraacetic acid (EDTA), glycerol, dithiothreitol (DTT),
and sodium molybdate were obtained from Sigma Chemicals
(St. Louis, MO).
Human GR-R and PR-A binding reactions were performed
in Millipore multiscreen plates. For GR binding assays, [3H]-
Dex (∼35 000 dpm (∼0.9 nM)), GR cytosol (∼35 µg of protein),
test compounds and binding buffer (10 mM Tris HCl, 1.5 mM
EDTA, 10% glycerol, 1 mM DTT, 20 mM sodium molybdate,
pH 7.6 at 4 °C) were mixed in a total volume of 200 µL and
incubated at 4 °C overnight in a plate shaker. Specific binding
was defined as the difference between binding of [3H]-Dex in
the absence and in the presence of 1 µM unlabeled Dex. For
PR binding assays, [3H]-Prog (∼36 000 dpm (∼0.8 nM)) and
PRA cytosol (∼40 µg of protein) were used. Specific binding
was defined as the difference between binding of [3H]-Prog in
the absence and in the presence of 1 µM unlabeled Prog. After
an overnight incubation, 50 µL of hydroxyapatide (25% weight/
volume) slurry were added to each well and plates were
incubated for 15 min at 4 °C in a plate shaker. Plates were
suctioned with a Millipore vacuum manifold and each well was
rinsed with 300 µL of ice-cold binding buffer. Packard Micro-
scint-20 (250 µL) was added to each well and shaken at
ambient temperature for 20 min. The amount of radioactivity
was determined with a Packard TopCount plate reader. IC50
,
concentration of test compounds that inhibited 50% of specific
binding, was determined from the Hill analysis of the binding
curves. Ki of test compounds was determined using the Cheng-
Prusoff equation.32 The following radiolabeled standards were
used: dexamethasone (GR), progesterone (PR), aldosterone
(MR), testosterone (AR), and estrodiol (ER).
E-Selectin Rep r ession a n d GRE Activa tion Assa ys.
Transcriptional repression was evaluated using the E-selectin
cotransfection assay as has been previously described.15 GRE
mediated transcriptional activation was determined through
a cotransfection assay using a receptor plasmid containing
hGR and a reporter plasmid with the mouse mammary tumor

1024 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Kym et al.
121.8, 119.6, 117.3, 115.3, 110.5, 109.5, 49.6, 28.0 (2), 25.8 (3),
21.0, 18.2, -4.0 (2); MS (DCI/NH3) m/z 422 (M + H)+. Anal.
(C25H31NO3Si) C, H, N.
1 M solution in THF, 1.20 mmol). After 1 h, the reaction
mixture was concentrated in vacuo and was resuspended in
EtOAc (25 mL). The solution was washed with water (10 mL)
and brine (10 mL), then was dried (Na2SO4). Filtration through
a short plug of silica gel and Celite afforded the phenol 16 (343
mg, 0.960 mmol, 91%) as a pale tan foam: 1H NMR (300 MHz,
DMSO-d6) δ 9.77 (s, 1 H), 8.10 (d, J ) 9.0 Hz, 1 H), 6.88 (t, J
) 8.0 Hz, 1 H), 6.58 (d, J ) 9.0 Hz, 1 H), 6.53 (d, J ) 8.0 Hz,
1 H), 6.35 (d, J ) 8.0 Hz, 1 H), 6.05 (s, 1 H), 5.89-5.72 (m, 2
H), 5.44 (s, 1 H), 5.03 (d, J ) 9.0 Hz, 1 H), 4.99 (d, J ) 16.0
Hz, 1 H), 2.50-2.40 (m, 1 H), 2. 25-2.18 (m, 1 H), 2.16 (s, 3
H), 1.16, (s, 3 H), 1.15 (s, 3 H); 13C NMR (125 MHz, DMSO-d6)
δ 159.6, 150.1, 148.3, 142.2, 136.0, 131.8, 128.2, 127.1, 126.7,
123.3, 117.7, 116.6, 115.7, 113.0, 111.9, 105.4, 55.6, 49.3, 35.9,
29.2, 28.6, 23.5; MS (DCI/NH3) m/z 334 (M + H)+; HRMS
(FAB) calcd for C22H23NO2 (M)+ 333.1729, found 333.1727.
Gen er a l P r oced u r e for C-5 Allyla tion of Cou m a r in s
(Meth od A). P r ep a r a tion of 10-(ter t-Bu tyld im eth ylsi-
loxy)-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-t r im et h yl-1H -[1]-
ben zop yr a n o[3,4-f]qu in olin e (15). To a solution of lactone
12 (500 mg, 1.26 mmol) in anhydrous toluene (70 mL) at -78
°C under N2 was added dropwise Dibal-H (2.02 mL of a 1.0 M
solution in heptane, 2.02 mmol) maintaining the temperature
at -78 °C. The resulting orange-red solution was stirred at
-78 °C for 1.5 h at which time TLC analysis of an aliquot
(quenched with satd. ammonium chloride) indicated conversion
to desired product.. Some lower Rf material (diol resulting from
over-reduction) was also observed. EtOAc (10 mL) was added
to the solution at -78 °C to quench the excess DIBAL-H
reagent (indicated by a color change of the solution from
orange-red to light yellow), followed by addition of saturated
aq. NH4Cl solution (15 mL). The reaction mixture was parti-
tioned between EtOAc (150 mL) and aqueous Rochelle’s salt
(sodium potassium tartrate, 40 mL) and the resulting mixture
was stirred vigorously until a clear separation of layers was
observed. The layers were separated and the organic layer was
washed with brine (20 mL), was dried (Na2SO4), and was
filtered. Removal of solvent gave the crude lactol 13 (10-(tert-
butyldimethylsiloxy)-5-hydroxy-2,5-dihydro-2,2,4-trimethyl-
1H-[1]benzopyrano[3,4-f]quinoline) as a light yellow foam (512
mg) which was used without further purification: MS (DCI/
NH3) m/z 423 (M- H2O + H)+.
10-(Tr iflu or om eth a n esu lfon yloxy)-5-(2-p r op en yl)-2,5-
d ih yd r o-2,2,4-tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in o-
lin e (17). To a solution of 16 (134 mg, 0.392 mmol) in CH2Cl2
(4 mL) at -78 °C was added triethylamine (165 µL, 1.17
mmol), followed by trifluoromethanesulfonic anhydride (73 µL,
0.43 mmol). The reaction mixture was allowed to slowly warm
to 23 °C over a period of 1.5 h. The reaction was quenched
with satd. aqueous ammonium chloride (5 mL) and extracted
EtOAc (2 × 15 mL). The combined organic layers were washed
with brine (5 mL), then were dried (Na2SO4) and were
concentrated. The resulting tan residue was purified by flash
chromatography (elution with 10% EtOAc/hexanes) to provide
1
the triflate (169 mg, 0.357 mmol, 91%) as a yellow solid: H
NMR (300 MHz, DMSO-d6) δ 7.52 (d, J ) 8.6 Hz, 1 H), 7.37
(t, J ) 8.3 Hz, 1 H), 7.10 (d, J ) 8.4 Hz, 1 H), 7.03 (dd, J )
8.6, 1.1 Hz, 1 H), 6.66 (d, J ) 8.6 Hz, 1 H), 6.48 (br s, 1 H),
5.91-5.74 (m, 2 H), 5.48 (br s, 1 H), 5.03 (dd, J ) 9.0, 1.1 Hz,
1 H), 4.93 (dd, J ) 16.0, 1.1 Hz, 1 H), 2.47-2.26 (m, 2 H), 2.19
(s, 3 H), 1.21 (s, 3 H), 1.18 (s, 3 H);13C NMR (125 MHz, DMSO-
d6) δ 164.9, 155.4, 151.7, 146.2, 139.6, 135.1, 130.2, 128.0,
127.3, 126.3, 119.2, 117.8, 115.7, 113.0, 110.5, 105.4, 90.8, 55.5,
49.0, 36.1, 29.7, 28.6, 23.8; MS (DCI/NH3) m/z 466 (M + H)+;
HRMS (FAB) calcd m/z for C23H22F3NO4S (M)+ 465.1122, found
465.1127.
The lactol 13 was dissolved in MeOH (30 mL) at 23 °C and
p-TsOH•H2O (50 mg, 25% w/w) was added portionwise as a
solid. The mixture was stirred for 14 h at 23 °C and then was
quenched with saturated aqueous sodium bicarbonate (10 mL)
and was extracted with EtOAc (2 × 50 mL). The organics
portions were combined and were washed with brine (20 mL)
and were dried (Na2SO4). Filtration and concentration provided
a yellow residue which was purified by flash chromatography
(elution with 5% EtOAc/CH2Cl2) to provide 10-(tert-butyldi-
methylsiloxy)-5-methoxy-2,5-dihydro-2,2,4-trimethyl-1H-[1]-
benzopyrano[3,4-f]quinoline (14) (314 mg, 0.832 mmol, 66%
over two steps) as a yellow foam: 1H NMR (300 MHz, DMSO-
d6) δ 7.90 (d, J ) 8.0 Hz, 1 H), 6.62 (d, J ) 8.4 Hz, 1 H), 6.54
(t, J ) 8.1 Hz, 2 H), 6.09 (br d, J ) 1.4 Hz, 1 H), 5.37 (s, 1 H),
3.16 (s, 3 H), 2.08 (s, 3 H), 1.19 (s, 3 H), 0.98 (s, 3 H), 0.83 (s,
9 H), 0.16 (s, 6 H); MS (DCI/NH3) m/z 406 (M - OCH3 + H)+.
A mixture of 14 (314 mg, 0.832 mmol) and allyltrimethyl-
silane (286 mg, 2.49 mmol) in CH2Cl2 (8 mL) was cooled to
-78 °C and treated with BF3•Et2O (305 µL, 2.49 mmol)
dropwise via syringe. The reaction mixture was allowed to
warm to 0 °C in an ice bath. At approximately -50 °C, the
solution turned a deep green color that faded upon warming.
After 30 min at 0 °C, the yellow-brown mixture was poured
into a rapidly stirring mixture of EtOAc (20 mL) and satd.
aq. NaHCO3 (10 mL), stirred for 30 min, and partitioned. The
aqueous phase was extracted with EtOAc (15 mL) and the
combined organic phases washed with brine, dried (MgSO4)
and concentrated. The residue was purified by flash chroma-
tography (gradient elution: 10-20% EtOAc/hexanes to provide
15 (296 mg, 0.774 mmol, 93%) as a colorless foam: 1H NMR
(300 MHz, DMSO-d6) δ 8.19 (d, J ) 8.9 Hz, 1 H), 6.95 (t, J )
8.1 Hz, 1 H), 6.61 (d, J ) 8.8 Hz, 1 H), 6.53 (d, J ) 8.0 Hz, 1
H), 6.30 (d, J ) 8.1 Hz, 1 H), 6.17 (br s, 1 H), 5.89-5.72 (m, 2
H), 5.44 (s, 1 H), 5.03 (d, J ) 9.0 Hz, 1 H), 4.99 (d, J ) 16.0
Hz, 1 H), 2.50-2.40 (m, 1 H), 2.25-2.18 (m, 1 H), 2.08 (s, 3
H), 1.19 (s, 3 H), 0.98 (s, 3 H), 0.83 (s, 9 H), 0.16 (s, 6 H); 13C
NMR (125 MHz, DMSO-d6) δ 159.6, 150.1, 148.3, 142.2, 136.0,
131.8, 128.2, 127.1, 126.7, 123.3, 117.7, 116.6, 115.7, 113.0,
111.9, 105.4, 72.8, 55.6, 49.3, 35.9, 29.2, 28.6, 21.1 (3), 11.0,
-4.0 (2); MS (DCI/NH3) m/z 448 (M + H)+; HRMS (FAB) calcd
m/z for C28H37NO2Si (M)+ 447.2594, found 447.2588.
Gen er a l P r oced u r e for C-9 or C-10 Eth er F or m a tion :
P h en ol O-Alk yla tion With Rep r esen ta tive Electr op h iles
(Meth od B). P r ep a r a tion of 10-Meth oxy-5-(2-p r op en yl)-
2,5-dih ydr o-2,2,4-tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in -
olin e (18). To a solution of 16 (1.79 g, 4.09 mmol) in DMF
(200 mL) at 0 °C was added cesium carbonate (2.70 g, 8.19
mmol), followed by the dropwise addition of iodomethane (0.28
mL, 4.50 mmol) over 15 min. The ice bath was removed and
the reaction stirred for 1 h. The reaction flask was placed back
in the ice bath and quenched with satd. aq. NH4Cl (100 mL)
and extracted with EtOAc (3 × 100 mL). The combined organic
layers were washed with 0.5 M HCl (50 mL), brine (50 mL),
dried (Na2SO4), and concentrated in vacuo, affording a dark
yellow oil. Purification by flash chromatography (elution with
10% EtOAc/hexanes) provided 18 (1.71 g, 3.80 mmol, 93%) as
1
a yellow solid: mp 55-57 °C; H NMR (300 MHz, DMSO-d6)
δδ 7.96 (d, J ) 8.3 Hz, 1 H), 7.07 (t, J ) 8.4 Hz, 1 H), 6.71 (d,
J ) 8.5 Hz, 1 H), 6.60 (d, J ) 8.6 Hz, 1 H), 6.52 (d, J ) 8.4 H
z, 1 H), 6.12 (br s, 1 H), 5.82 (m, 1 H), 5.76 (dd, J ) 10.3, 2.7
Hz, 1 H), 5.44 (br s, 1H), 5.01 (m, 2 H), 3.86 (s, 3 H), 2.44 (m,
1 H), 2.20 (m, 1 H), 2.16 (s, 3 H), 1.17 (s, 3 H), 1.16 (s, 3 H);
13C NMR (125 MHz, DMSO-d6) δ 156.1, 150.8, 145.5, 134.2,
133.5, 132.0, 127.4, 127.1, 126.9, 124.6, 117.1, 116.2, 115.9,
113.2, 110.3, 105.4, 73.3, 55.6, 49.6, 36.4, 28.9 (2), 23.9; MS
(DCI/NH3) m/z (M + H)+ 348. Anal. (C23H25NO2) C, H, N.
10-Eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (19). Prepared from 16
according to method B using iodoethane as the electrophile:
1H NMR (300 MHz, DMSO-d6) δ 8.04 (d, J ) 8.81 Hz, 1 H),
7.05 (t, J ) 8.14 Hz, 1 H), 6.68 (dd, J ) 8.14, 0.7 Hz, 1 H),
6.58 (d, J ) 8.81 Hz, 1 H), 6.50 (dd, J ) 7.8, 0.7 Hz, 1 H), 6.12
(d, J ) 1.36 Hz 1 H), 5.83-5.74 (m, 2 H), 5.44 (d, J ) 1.7 Hz,
1 H), 5.05-4.95 (m, 2 H), 4.18-4.02 (m, 2 H), 2.16 (s, 3 H),
1.42 (t, J ) 6.8 Hz, 2 H), 1.16 (d, J ) 4.4 Hz, 6 H); MS (APCI/
10-Hydr oxy-5-(2-pr op en yl)-2,5-dih yd r o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (16). Silyl ether 15 (507
mg, 1.05 mmol) was dissolved in THF (6 mL) at 23 °C and
was treated with tetrabutylammonium fluoride (1.20 mL of a

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1025
20.6, 14.0; MS (DCI/NH3) m/z 344 (M + H)+; HRMS calcd for
NH3) m/z 362 (M + H)+; HRMS calcd for C24H27NO2 (M+)
361.2042, found 361.2052. Anal. (C24H27NO2) C, H, N.
C
24H26NO 344.2014 (M+), found 344.2011. Anal. (C24H25NO)
C, H, N.
5-(2-P r op en yl)-10-(2-p r op en yloxy)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (20). Pre-
pared from 16 according to method B using allyl bromide as
the electrophile: 1H NMR (300 MHz, DMSO-d6) δ 8.01 (d, J )
8.45 Hz, 1 H), 7.05 (t, J ) 8.09 Hz, 1 H), 6.71 (d, J ) 8.45 Hz,
1 H), 6.58 (d, J ) 8.45 Hz, 1 H), 6.53 (dd, J ) 8.82, 0.74 Hz,
2 H), 6.08-6.20 (m, 2 H), 5.89-5.74 (m, 2 H), 5.42-5.48 (m, 2
H), 5.30 (dd, J ) 10.8, 1.5 Hz, 1 H), 5.0-4.99 (m, 2 H), 4.73-
4.60 (m, 2 H), 2.16 (s, 3 H), 1.16 (d, J ) 1.8 Hz 6 H); MS (ESI)
m/z 374 (M + H)+; HRMS calcd for C25H27NO2 (M+) 373.2042,
found 373.2050. Anal. (C25H27NO2) C, H, N.
10-Eth yn yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (25). A solution of tri-
flate 17 (25 mg, 0.054 mmol), tetrabutylammonium iodide (40
mg, 0.108 mmol), bis(triphenylphosphine)palladium chloride
(7.0 mg, 0.010 mmol), copper(I) iodide (3.8 mg, 0.020 mmol),
and triethylamine (0.15 mL, 0.717 mmol) in DMF (0.75 mL)
was treated with trimethylsilylacetylene (174 mg, 1.76 mmol).
The resulting solution was heated at 55 °C for 3 h, then was
diluted with EtOAc (20 mL) and filtered. The filtrate was
washed with satd. NH4Cl (6 mL), and the aqueous layer was
extracted with EtOAc (10 mL). The combined extracts were
dried (MgSO4), filtered, and concentrated. The residue was
purified by preparative TLC (2× elution with 10% EtOAc/
hexanes). Extraction of the silica gel with EtOAc provided the
intermediate trimethylsilyl acetylene: 1H NMR (300 MHz,
DMSO-d6) δ 8.36 (d, J ) 8.5 Hz, 1 H), 7.10-7.04 (m, 2 H),
6.90 (dd, J ) 7.8, 1.8 Hz, 1 H), 6.60 (d, J ) 8.5 Hz, 1 H), 6.36-
6.30 (m, 1 H), 5.83-5.76 (m, 2 H), 5.49-5.43 (m, 1 H), 5.04
(br d, J ) 10.5 Hz, 1 H), 4.97 (br d, J ) 17.3 Hz, 1 H), 2.39-
2.30 (m, 1 H), 2.28-2.20 (m, 1 H), 2.17 (d, J ) 1.4 Hz, 3 H),
1.18 (s, 3 H), 1.17 (s, 3 H), 0.26 (s, 9 H); MS (DCI/NH3) m/z
414 (M + H)+.
A solution of the silylacetylene in THF (2.5 mL) was treated
sequentially with glacial acetic acid (0.005 mL) and tetra-
butylammonium fluoride (0.050 mL of a 1.0 M solution in THF,
0.050 mmol). The solution was stirred at 23 °C for 8 h, then
was diluted with EtOAc (20 mL) and was washed with satd.
NH4Cl (6 mL). The aqueous layer was extracted with EtOAc
(10 mL) and the combined extracts were dried (MgSO4),
filtered, and concentrated. The residue was purified by pre-
parative TLC (2× elution with 10% EtOAc/hexanes) to give
25 (12 mg, 0.029 mmol, 54%) as a pale yellow foam: 1H NMR
(300 MHz, DMSO-d6) δ 8.27 (dd, J ) 8.5, 0.7 Hz, 1 H), 7.15 (t,
J ) 8.5 Hz, 1 H), 7.07 (d, J ) 8.5 Hz, 1 H), 6.91 (br d, J ) 7.1
Hz, 1 H), 6.62 (d, J ) 8.5 Hz, 1 H), 6.38-6.31 (m, 1 H), 5.82-
5.77 (m, 1 H), 5.49-5.44 (m, 1 H), 5.03 (br d, J ) 10.3 Hz, 1
H), 4.98 (br d, J ) 17.1 Hz, 1 H), 4.41 (s, 1 H), 2.49-2.40 (m,
2 H), 2.17 (s, 3 H), 1.18 (s, 6 H); 1H NMR (75 MHz, DMSO-d6)
δ 150.0, 146.5, 134.0, 133.6, 133.0, 128.7, 127.2, 126.5, 126.1,
126.0, 118.3, 117.2, 116.0, 115.9, 112.9, 84.3, 84.2, 73.61, 49.8,
36.6, 29.2, 29.0, 23.8; MS (DCI/NH3) m/z 342 (M + H)+; HRMS
(FAB) calcd for C24H23NO 341.1780 (M+), found 341.1788. Anal.
(C24H23NO•H2O) C, H, N.
10-Cya n o-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-t r im et h yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (26). A magnetically
stirred mixture of 17 (195 mg, 0.419 mmol), tetrakis(tri-
phenylphosphine)palladium(0) (36 mg, 0.031 mmol) and zinc
cyanide (36 mg, 0.31 mmol) in dioxane (4.0 mL) and water
(1.0 mL) was heated at 80 °C for 48 h under argon atmosphere.
The reaction was allowed to cool to ambient temperature, was
diluted with EtOAc (25 mL), and was washed with brine (15
mL). The aqueous layer was extracted with EtOAc (2 × 20
mL) and the organic layer was dried (MgSO4), filtered, and
concentrated. The crude material was purified by flash chro-
matography (elution with 10% EtOAc/hexanes) to give product
contaminated with starting triflate. The partially pure nitrile
further purified by preparative TLC (5× elution with 5%
EtOAc/hexanes) and the product isolated by EtOAc extraction
to provide 26 (17.3 mg, 0.0505 mmol, 12%) as an off yellow
foam: 1H NMR (300 MHz, DMSO-d6) δ 7.87 (d, 1H, J ) 8.5
Hz), 7.46 (dd, 1H, J ) 7.5 Hz, J ) 1.5 Hz), 7.27 (t, 1H, J ) 7.8
Hz), 7.19 (dd, 1H, J ) 8.1 Hz, J ) 1.4 Hz), 6.71 (d, 1H, J ) 8.5
Hz), 6.57 (m, 1H), 5.90 (dd, 1H, J ) 10 Hz, J ) 3.6 Hz), 5.82
(m, 1H), 5.49 (m, 1H), 5.04 (dm, 1H, J ) 10.5 Hz), 4.98 (dm,
1H, J ) 17.3 Hz), 2.38 (m, 1H), 2.30 (m, 1H), 2.19 (s, 3H),
1.20 (s, 3H), 1.19 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
150.3, 147.4, 133.9, 133.7, 133.3, 128.4, 127.3, 127.2, 127.0,
125.3, 122.3, 119.8, 117.4, 116.1, 113.8, 113.5, 104.4, 73.9, 59.7,
50.0, 36.9, 29.3, 23.7; MS (DCI/NH3) m/z 343 (M + H)+; HRMS
(FAB) calcd for C23H22N2O 342.1732 (M+), found: 342.1730.
Anal. (C23H22N2O) C, H, N.
5-(2-P r op en yl)-10-(2-p r op yn yloxy)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (21). Pre-
pared from 16 according to method B using propargyl bromide
as the electrophile: 1H NMR (300 MHz, DMSO-d6) δ 7.95 (d,
1H, J ) 8.46 Hz), 7.07 (t, 2H, J ) 8.0 Hz), 6.78 (d, 1H, J ) 7.7
Hz), 6.61 (d, 1H, J ) 8.9 Hz), 6.58 (d, 1H, J ) 8.9 Hz), 6.15 (d,
1H, J ) 2.5 Hz), 5.84 (m, 3H), 5.45 (s, 3H), 5.05 (m, 2H), 4.88
(t, 2H, J ) 2.8 Hz), 2.16 (s, 3H), 1.76 (d, 6H, J ) 2.2 Hz); MS
(DCI) m/z 372 (M + H)+; HRMS calcd for C25H25NO2 (M+)
371.1885, found 371.1898. Anal. (C25H25NO2) C, H, N.
10-(Cyclopr opylm eth yl)oxy-5-(2-pr open yl)-2,5-dih ydr o-
2,2,4-tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (22).
Prepared from 16 according to method B using cyclopropyl-
methyl bromide as the electrophile: 1H NMR (300 MHz,
DMSO-d6) δ 8.13 (d, 1H, J ) 8.8 Hz), 7.03 (t, 1H, J ) 8.1 Hz),
6.64 (dd, 1H, J ) 8.5, 1.1 Hz), 6.60 (d, 1H, J ) 8.8 Hz), 6.50
(dd, 1H, J ) 8.8, 1.1 Hz), 6.10 (d, 1H, J ) 1.7 Hz), 5.83-5.74
(m, 2H), 5.44 (d, J ) 1.7 Hz), 5.05-4.95 (m, 2H), 4.18-4.02
(m, 2H), 2.17 (s, 3H), 1.42 (t, 2H, J ) 6.8 Hz), 1.16 (d, 6H, J
) 4.4 Hz), 0.60 (m, 2H), 0.36 (m, 2 H); MS (APCI) m/z 388 (M
+ H)+; HRMS calcd for C27H31NO2 (M+) 387.5141, found
387.5139.
10-Ben zyloxy-5-(2-pr open yl)-2,5-dih ydr o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (23). Prepared from 16
according to method B using benzyl bromide as the electro-
phile: 1H NMR (300 mHz, DMSO-d6) δ 8.03 (d, 1H, J ) 8.81
Hz), 7.45 (d, 2H, J ) 7.31 Hz), 7.39 (t, 2H, J ) 7.71 Hz), 7.05
(t, 1H, J ) 8.06 Hz), 6.80 (d, 1H, J ) 8.86 Hz), 6.53 (t, 2H, J
) 8.86 Hz), 6.06 (s, 1H), 6.55 (m, 1H), 5.44 (s, 1H), 5.22 (q,
2H, J ) 41.7, 12.1 Hz), 5.00-5.04 (m, 2H), 2.16 (s, 3H), 1.16
9s, 3H), 1.14 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 155.0,
150.9, 145.5, 137.0, 134.2, 133.5, 132.1, 128.4, 127.7, 127.5,
127.4, 127.1, 126.9, 117.1, 116.1, 115.8, 113.7, 113.0, 110.6,
107.0, 73.4, 70.1, 49.7, 36.5, 28.9, 23.9; MS (ESI+) m/z 424 (M
+ H)+. Anal. (C29H29NO2) C, H, N.
5-(2-P r op en yl)-10-vin yl-2,5-d ih yd r o-2,2,4-tr im eth yl-1H-
[1]ben zop yr a n o[3,4-f]qu in olin e (24). A solution of triflate
17 (103 mg, 0.221 mmol) and [1,3-bis(diphenylphosphino)-
ferrocene]palladium dichloride dichloromethane complex (22
mg, 0.027 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was
treated with vinyl tributylstannane (119 mg, 0.376 mmol). The
solution was heated at 65 °C for 24 h, then cooled to 23 °C,
treated with satd. KF solution (2 mL), and extracted with
EtOAc (10 mL). The organic portion was washed with water
(4 mL) and brine (4 mL) then was dried (MgSO4) and
concentrated. The residue was purified by flash chromatog-
raphy (elution with 5% EtOAc/hexanes + 1% triethylamine)
to provide 17 (52 mg, 0.13 mmol, 58%) as a pale yellow foam:
1H NMR (300 mHz, DMSO-d6) δ 7.22 (d, J ) 8.5 Hz, 1 H),
7.19-7.13 (m, 2 H), 6.99 (dd, J ) 17.3, 10.8 Hz, 1 H), 6.83 (dd,
J ) 7.0, 2.2 Hz, 1 H), 6.63 (d, J ) 8.5 Hz, 1 H), 6.26-6.21 (m,
1 H), 5.87 (dd, J ) 10.3, 6.8 Hz, 1 H), 5.77 (dd, J ) 10.5, 3.4
Hz, 1 H), 5.76 (dd, J ) 17.3, 1.4 Hz, 1 H), 5.49-5.45 (m, 1 H),
5.33 (dd, J ) 10.3, 1.4 Hz, 1 H), 5.03 (dd, 1H, J ) 10.3, 1.8
Hz, 1 H), 4.98 (br d, J ) 17.3 Hz, 1 H), 2.47-2.42 (m, 1 H),
2.32-2.26 (m, 1 H), 2.18 (d, J ) 1.4 Hz, 3 H), 1.21 (s, 3 H),
1.15 (s, 3 H); 13CNMR (75 mHz, DMSO-d6) δ 150.4, 145.8,
137.6, 134.2, 133.5, 128.1, 127.3, 126.7, 123.3, 121.0, 117.0,
116.5, 116.4, 114.4, 113.1, 73.8, 59.6, 49.8, 36.0, 29.4, 28.8, 23.8,

1026 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Kym et al.
10-Am in om et h yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-t r i-
m eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (27). To a mag-
netically stirred solution of the nitrile (40 mg, 0.116 mmol) in
Et2O (1 mL) at 0 °C was added lithium aluminum hydride (140
µL of a 1.0 M solution in Et2O, 0.140 mmol) under nitrogen.
The reaction was warmed to 23 °C and stirred for 6 h, then
was quenched by addition to satd. aq. sodium potassium
tartrate (2 mL). EtOAc (5 mL) was added and the mixture
stirred for 30 min. Water (1 mL) was added and the layers
were partitioned. The aqueous phase was extracted with ethyl
acetate (2 × 10 mL) and the combined organic layers were
washed with brine (8 mL), dried (MgSO4), filtered, and
concentrated. The residue was purified by preparative TLC
(2× elution with 15% EtOAc/hexanes) and the product isolated
by EtOAc extraction to provide 27 (19 mg, 0.055 mmol, 47%)
of as pale yellow foam: 1H NMR (300 MHz, DMSO-d6) δ 7.55
(d, J ) 8.5 Hz, 1 H), 7.19-7.11 (m, 2 H), 6.80 (dd, J ) 7.3, 1.8
Hz, 1 H), 6.64 (d, J ) 8.5 Hz, 1 H), 6.19-6.13 (m, 1 H), 5.81
(dd, J ) 10.5, 17.1 Hz, 1 H), 5.73 (dd, J ) 10.5, 3.4 Hz, 1 H),
5.49-5.43 (m, 1 H), 5.02 (br d, J ) 10.5 Hz, 1 H), 4.94 (d, J )
17.1 Hz, 1 H), 4.67-4.60 (m, 2 H), 3.93-3.85 (m, 2 H), 2.35-
2.26 (m, 2 H), 2.17 (s, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H); MS
(DCI/NH3) m/z 347 (M + H)+; HRMS (FAB) calcd for C23H26N2O
346.2045 (M+), found 346.2047. Anal. (C23H26N2O•H2O) C, H,
N.
10-H yd r oxym et h yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (30). A mag-
netically stirred solution of 29 (32 mg, 0.085 mmol) in CH2Cl2
(3 mL) was cooled to -78 °C and Dibal-H (0.400 mL of a 1.0
M solution in cyclohexane, 0.40 mmol) was added in dropwise
fashion. The temperature of the reaction was allowed to rise
to 0 °C over a period of 30 min. After 3.5 h, the reaction was
quenched by addition to aqueous Rochelle’s salt (3 mL) and
EtOAc (10 mL). Upon warming, the layers were partitioned
and the aqueous layer was extracted with EtOAc (3 × 15 mL).
The combined organic portions were dried (MgSO4), filtered,
and concentrated. The crude material was purified by pre-
parative TLC (2× elution with 10% EtOAc/hexanes) and the
product isolated by EtOAc extraction to provide 30 (8.0 mg,
0.023 mmol, 20%) as pale yellow foam: 1H NMR (300 MHz,
DMSO-d6) δ 7.47 (d, J ) 8.5 Hz, 1 H), 7.17-7.11 (m, 2 H),
6.80 (dd, J ) 7.3, 1.8 Hz, 1 H), 6.64 (d, J ) 8.5 Hz, 1 H), 6.19-
6.12 (m, 1 H), 5.81 (dd, J ) 17.1, 10.5 Hz, 1 H), 5.73 (dd, J )
10.5, 3.4 Hz, 1 H), 5.49-5.45 (m, 1 H), 5.32 (dd, J ) 6.3, 4.2
Hz, 1 H), 5.02 (br d, J ) 10.5 Hz, 1 H), 4.94 (d, J ) 17.1 Hz,
1 H), 4.65-4.60 (m, 2 H), 2.34-2.28 (m, 2 H), 2.17 (s, 3 H),
1.19 (s, 3 H), 1.16 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ
150.0, 145.7, 137.1, 134.3, 133.7, 133.5, 128.0, 127.3, 126.2,
124.3, 123.8, 117.0, 116.3, 116.0, 113.3, 73.6, 62.0, 49.8, 35.9,
29.4, 28.9, 23.9; MS (DCI/NH3) m/z 348 (M + H)+; HRMS
(FAB) calcd for C23H25NO2 347.1885 (M+), found 347.1897.
Anal. (C23H25NO2) C, H, N.
10-Met h yla m in o-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-t r i-
m eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (28). An ACE-
glass high-pressure vessel charged with aryltriflate 17 (165
mg, 0.360 mmol), palladium(II) acetate (1.6 mg, 0.007 mmol),
(S)-(-)-2,2′-bisphenylphospino)-1,1′-binaphthyl (5.5 mg, 0.008
mmol), sodium tert-butoxide (51 mg, 0.53 mmol), methylamine
(0.44 mL of 2.0 M solution in THF, 0.88 mmol) and toluene
(0.5 mL) was sealed and heated at 90 °C for 4 h. After cooling
the reaction to 0 °C, the solution was diluted with EtOAc (5
mL), and washed with 0.5 M HCl (2.5 mL). The organic layer
was separated, dried (Na2SO4), and concentrated to provide a
brown oil. Purification by flash chromatography (gradient
elution: 5%f12% EtOAc/hexanes) provided 28 (60 mg, 0.170
mmol, 47%) as light brown oil: 1H NMR (300 MHz, DMSO-
d6) δ 7.83 (d, J ) 8.5 Hz, 1 H), 6.94 (dd, J ) 7.5, 7.5 Hz, 1 H),
6.62 (d, J ) 8.5 Hz, 1 H), 6.28 (dd, J ) 7.5, 1.0 Hz, 1 H), 6.25
(dd, J ) 7.5, 1.0 Hz, 1 H), 6.05 (d, J ) 2.0 Hz, 1 H), 5.86-5.74
(m, 2 H), 5.67 (dd, J ) 10.0, 3.0 Hz, 1 H), 5.45 (s, 1 H), 5.40 (q,
J ) 5.0 Hz, 1 H), 5.03 (dd, J ) 9.0, 2.0 Hz, 1 H), 4.98 (dd, J )
15.0, 2.0 Hz, 1 H), 2.72 (d, J ) 5.0 Hz, 3 H), 2.60-2.53 (m, 1
H), 2.25-2.18 (m, 1 H), 2.16 (s, 3 H), 1.17, (s, 3 H), 1.15 (s, 3
H); 13C NMR (125 MHz, DMSO-d6) δ 150.6, 146.2, 145.0, 134.5,
133.6, 132.5, 127.6, 127.5, 124.2, 117.2, 117.0, 117.0, 113.3,
110.7, 106.1, 104.6, 73.5, 49.7, 35.5, 31.1, 29.3, 28.7, 23.9; MS
(DCI/NH3) m/z 347 (M + H)+; HRMS (FAB) calcd for C23H26N2O
346.2045 (M+), found 346.2049. Anal. (C23H26N2O) C, H, N.
10-Met h oxym et h yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (31). To a
magnetically stirred solution of the 30 (26 mg, 0.075 mmol)
in THF (2.0 mL) at 0 °C was added potassium hexamethyl-
disilazide (0.14 mL of a 1.0 M solution in hexane, 0.14 mmol).
The solution was stirred for 15 min then methyl iodide (13.8
mg, 0.097 mmol) was added and the reaction was allowed to
slowly come to ambient temperature. The reaction was
quenched with satd aq NH4Cl (2 mL) and then was extracted
with EtOAc (2 × 10 mL). The organic portions were dried
(MgSO4), filtered, and concentrated. The crude material was
purified by preparative TLC (2X elution with 10% EtOAc/
hexanes) and the product isolated by EtOAc extraction to
provide 31 (25 mg, 0.069 mmol, 92%) as pale yellow foam: 1H
NMR (300 MHz, DMSO-d6) δ 7.34 (d, J ) 8.5 Hz, 1 H), 7.17-
7.11 (m, 2 H), 6.85 (dd, J ) 7.4, 2.4 Hz, 1 H), 6.64 (d, J ) 8.5
Hz, 1 H), 6.23-6.18 (m, 1 H), 5.81 (d, J ) 10.2 Hz, 1 H), 5.77-
5.72 (m, 1 H), 5.46 (s, 1 H), 5.02 (br d, J ) 10.2 Hz, 1 H), 4.93
(br d, J ) 17.3 Hz, 1 H), 4.61 (d, J ) 11.2 Hz, 1 H), 4.43 (d, J
) 11.2 Hz, 1 H), 3.37 (s, 3 H), 2.37-2.31 (m, 1 H), 2.31-2.25
1
(m, 1 H), 2.17 (s, 3 H), 1.19 (s, 3 H), 1.17 (s, 3 H); H NMR
(300 MHz, DMSO-d6) δ 150.3, 145.8, 134.2, 133.8, 133.6, 132.7,
127.7, 127.3, 126.2, 125.1, 124.7, 117.0, 116.8, 116.7, 116.3,
113.5, 73.6, 72.8, 57.3, 49.8, 36.0, 29.4, 28.9, 23.9; MS (DCI/
NH3) m/z 362 (M + H)+; HRMS (FAB) calcd for C24H27NO2
361.2042 (M+), found 361.2047. Anal. (C24H27NO2) C, H, N.
10-Ca r bom eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-tr i-
m eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (29). To a deoxy-
genated solution of 17 (616 mg, 1.33 mmol), bis(diphenylphos-
phino)ethane (27 mg, 0.066 mmol), triethylamine (241 µL, 1.73
mmol), and methanol (0.5 mL) in DMSO (5.0 mL) was added
palladium acetate (15 mg, 0.066 mmol). The solution was
saturated with CO by bubbling a stream of gas into the
reaction mixture for 4 min at 23 °C. The reaction mixture was
then heated at 60 °C under CO atmosphere for 3 h. The
reaction was allowed to cool to 23 °C then was partitioned
between EtOAc (20 mL) and water (10 mL). The organic
portion was washed with water (7 mL) and brine (7 mL) and
then dried (Na2SO4). Filtration and concentration gave a black
residue which was purified by flash chromatography (elution
with 15% EtOAc/hexanes) to provide 29 (411 mg, 0.883 mmol,
66%) as a pale yellow foam: 1H NMR (300 MHz, DMSO-d6) δ
7.19-7.12 (m, 2 H), 7.02 (d, J ) 8.5 Hz, 1 H), 6.98 (dd, J )
5.5, 3.7 Hz, 1 H), 6.58 (d, J ) 8.5 Hz, 1 H), 6.31-6.27 (m, 1
H), 5.85-5.80 (m, 2 H), 5.45 (s, 1 H), 5.05 (dd, J ) 10.5, 1.5
Hz, 1 H), 4.98 (dd, J ) 17.3, 1.5 Hz, 1 H), 3.78 (s, 3 H), 2.36-
2.28 (m, 2 H), 2.18 (s, 3 H), 1.20 (s, 3 H), 1.16 (s, 3 H); MS
(DCI/NH3) m/z 376 (M + H)+; Anal. (C24H25NO3) C, H, N.
10-Diflu or om eth oxy-5-oxo-2,5-d ih yd r o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (32). A stirred suspen-
sion of 16 (47 mg, 0.127 mmol) and potassium carbonate (53
mg, 0.382 mmol) in DMF (2.5 mL) at 80 °C was treated with
bromodifluoromethane by bubbling a stream of the gaseous
reagent through the hot, stirred reaction mixture for 4 min.
The reaction mixture was heated for an additional 15 min then
cooled, diluted with 2:1 hexanes-Et2O (15 mL) and washed
with water (2 × 10 mL). The organic portions were washed
with brine (5 mL) and then dried (Na2SO4), filtered and
concentrated. The residue was purified by flash chromatog-
raphy (elution with 10% EtOAc/hexanes) to give 32 (23 mg,
0.055 mmol, 43%) as a white foam: 1H NMR (300 MHz, DMSO-
d6) δ 8.40 (d, J ) 9.1 Hz, 1 H), 7.43 (t, J ) 7.7 Hz, 1 H), 7.39
(t, J H-F ) 74 Hz, 1 H), 7.25 (d, J ) 9.1 Hz, 1 H), 7.18-7.12
(m, 2 H), 7.07 (br s, 1 H), 5.48 (br s, 1 H), 1.94 (s, 3 H), 1.24 (s,
6 H); MS (DCI/NH3) m/z 358 (M + H)+. Anal. (C20H17FNO3)
C, H, N.
10-Diflu or om eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e (35). Di-
fluoroether 35 was prepared from 32 according to method A:

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1027
1H NMR (300 MHz, DMSO-d6) δ 7.75 (d, J ) 9.0 Hz, 1 H),
7.20 (t, J H-F ) 74 Hz, 1 H), 7.15 (t, J ) 8.0 Hz, 1 H), 6.83 (dd,
J ) 8.0, 1.0 Hz, 1 H), 6.81 (dd, J ) 8.0, 1.0 Hz, 1 H), 6.63 (d,
J ) 9.0 Hz, 1 H), 6.28 (s, 1 H), 5.89-5.75 (m, 2 H), 5.46 (s, 1
H), 5.04 (dd, J ) 11.0, 2.0 Hz, 1 H), 4.96 (dd, J ) 17.0, 2.0 Hz,
1 H), 2.48-2.40 (m, 1 H), 2.29-2.20 (m, 1 H), 2.18 (s, 3 H),
1.17 (s, 6 H); 13C NMR (125 MHz, DMSO-d6) δ 151.4, 147.2,
146.2, 134.0, 133.7, 132.6, 127.2, 127.0, 127.0, 117.3, 116.9,
116.5, 116.2 (t, J C-F ) 310.1 Hz), 114.7, 114.2, 113.5, 112.6,
73.7, 49.8, 36.7, 29.2, 29.0, 23.8; MS (DCI/NH3) m/z 384 (M +
H)+; HRMS (FAB) calcd for C23H23F2NO2 383.1697 (M+), found
383.1693. Anal. (C23H23F2NO2) C, H, N.
5-(2-P r op en yl)-10-t h iom et h oxy-2,5-d ih yd r o-2,2,4-t r i-
m eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (37). A suspen-
sion of 36 (249 mg, 0.590 mmol) and KOH (90 mg, 1.20 mmol)
in ethylene glycol (6 mL) containing water (1.5 mL) was heated
at reflux (homogeneous solution) for 1.5 h. The solution was
cooled and poured onto ice (10 g). The mixture was acidified
(pH 4) with 10% HCl and was then extracted with CH2Cl2 (2
× 20 mL). The extracts were dried (Na2SO4), were filtered,
and were concentrated. The resulting residue was purified by
flash chromatography (elution with 5% EtOAc/CH2Cl2) to
provide nearly homogeneous thiophenol adduct (183 mg) as
an off-yellow solid that was used immediately: 1H NMR (300
MHz, DMSO-d6) δ 7.72 (d, J ) 8.0 Hz, 1 H), 7.08 (dd, J ) 7.6,
1.1 Hz, 1 H), 6.96 (t, J ) 7.5 Hz, 1 H), 6.67 (d, J ) 8.1 Hz, 1
H), 6.63 (dd, J ) 7.5, 1.2 Hz, 1 H), 6.28 (br s, 1 H), 5.88-5.70
(m, 2 H), 5.47 (br s, 1 H), 5.41 (s, 1H), 5.03 (dd, J ) 13.2, 1.3
Hz, 1 H), 4.98 (dd, J ) 18.4, 1.3 Hz, 1 H), 2.48-2.21 (m, 2 H),
2.17 (s, 3 H), 1.20 (s, 3 H), 1.17 (s, 3 H); MS (DCI/NH3) m/e
350 (M + H)+.
was washed with water (4 mL) and brine (4 mL) then was
dried (MgSO4) and concentrated. The residue was purified by
flash chromatography (elution with 5% EtOAc/hexanes) to
provide 42 (47 mg, 0.13 mmol, 63%) as a pale yellow foam: 1H
NMR (300 MHz, DMSO-d6) δ 7.92 (d, J ) 8.5 Hz, 1 H), 6.93
(d, J ) 8.5 Hz, 1 H), 6.59 (dd, J ) 5.5, 2.6 Hz, 1 H), 6.10 (s, 1
H), 5.90-5.76 (m, 2 H), 5.44 (s, 1 H), 5.07-4.90 (m, 2 H), 3.82
(s, 3 H), 2.17 (s, 3 H), 2.08 (s, 3 H), 1.99 (s, 3 H), 1.16 (s, 3 H),
1.15 (s, 3H); 13C NMR (300 MHz, DMSO-d6) δ 154.2, 148.5,
145.4, 134.5, 133.4, 131.9, 127.8, 127.4, 127.1, 118.2, 117.0,
116.3, 116.0, 113.1, 112.9, 104.8, 73.6, 55.5, 49.6, 36.5, 28.9,
28.8, 23.8, 15.0; MS (ESI) m/z 362 (M + H)+; HRMS (FAB)
calcd for C24H27NO2 361.2042 (M+), found 361.2045. Anal.
(C24H27NO2) C, H, N.
10-Met h oxy-7-vin yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (43). A solu-
tion of 41 (88 mg, 0.21 mmol) and (1,3-bis(diphenylphosphino)-
ferrocene)palladium (II) chloride‚dichloromethane complex (20
mg, 0.021 mmol) in 1-methyl-2-pyrrolidinone (2 mL) was
treated with vinyl tributylstannane (119 mg, 0.376 mmol). The
solution was heated at 65 °C for 24 h, then cooled to 23 °C,
treated with satd. KF solution (2 mL), and extracted with
EtOAc (10 mL). The organic portion was washed with water
(4 mL) and brine (4 mL) then was dried (MgSO4) and
concentrated. The residue was purified by flash chromatog-
raphy (elution with 5% EtOAc/hexanes + 1% triethylamine)
to provide 43 (46 mg, 0.12 mmol, 59%) as a pale yellow foam:
1H NMR (300 MHz, DMSO-d6) δ 7.82 (d, J ) 8.9 Hz, 1 H),
7.23 (d, J ) 8.9 Hz, 1 H), 6.78 (dd, J ) 11.0, 6.8 Hz, 1 H), 6.61
(d, J ) 8.9 Hz, 1 H), 6.49 (d, J ) 8.5 Hz, 1 H), 5.99 (d, J ) 1.7
Hz, 1 H), 5.74 (dd, J ) 7.6, 3.0 Hz, 1 H), 5.71-5.63 (m, 1 H),
5.57 (dd, J ) 7.6, 1.7 Hz, 1 H), 5.32 (s, 1 H), 5.00 (dd, J ) 9.3,
1.7 Hz, 1 H), 4.92 (dd, J ) 10.2, 1.7 Hz, 1 H), 4.83 (dd, J )
16.9, 1.7 Hz, 1 H), 3.75 (s, 3 H), 2.06 (s, 3 H), 1.53-1.41 (m, 2
H), 1.24-1.15 (m, 3 H), 1.05 (d, J ) 2.1 Hz, 1 H); 13C NMR
(300 MHz, DMSO-d6) δ 155.66, 147.91, 145.55, 134.17, 133.45,
131.98, 130.77, 127.37, 127.28, 123.88, 119.52, 117.21, 115.99,
115.80, 113.20, 113.18, 112.12, 105.59, 74.01, 55.59, 49.69,
36.40, 29.03, 28.83, 27.67, 26.19, 23.83, 13.55; MS (ESI) m/z
373 (M + H)+; HRMS (FAB) calcd for C25H27NO2 373.2042
(M+), found 373.2048. Anal. (C25H27NO2) C, H, N.
9-Hydr oxy-10-m eth oxy-5-(2-pr open yl)-2,5-dih ydr o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (50). To a
solution of lactone 49 (2.75 g, 6.09 mmol) in CH2Cl2 (750 mL)
at -78 °C under N2 was added dropwise 1 M DIBAL-H (15.2
mL of a 1.0 M solution in heptane, 15.2 mmol) maintaining
the temperature at -78 °C. The resulting orange-red solution
was stirred at -78 °C for 1 h at which time a TLC of an aliquot
(quenched with satd. NH4Cl) indicated conversion to desired
product.. A small amount of a lower Rf material (diol resulting
from over-reduction) was also seen. EtOAc (50 mL) was added
to the solution at -78 °C to quench the excess DIBAL-H
reagent (indicated by a color change of the solution from
orange-red to light yellow). The reaction mixture was parti-
tioned between EtOAc (600 mL) and satd. Rochelle’s salt
solution (200 mL) and the resulting mixture was stirred
vigorously until a clear separation of layers was observed (ca.
2 h). The layers were separated and the aqueous layer
extracted with EtOAc (3 × 100 mL). The organics portions
were combined, washed with brine (2 × 200 mL), dried (Na2-
SO4), filtered and concentrated to give the lactol as a light
yellow oil which was carried on without purification.
A solution of the crude thiophenol (183 mg) in DMF (10 mL)
at 0 °C was treated with cesium carbonate (50 mg, 0.153
mmol). After 10 min, a solution of iodomethane (25 mg, 0.176
mmol) in DMF (0.7 mL) was added, and the solution was
stirred at 0 °C for 30 min then at 23 °C for 2 h. The mixture
was diluted with 1:1 EtOAc-hexanes (100 mL) and was
washed with water (3 × 25 mL) then washed with brine (25
mL). The organic portion was dried (Na2SO4), was filtered, and
was concentrated. The resulting residue was purified by flash
chromatography (elution with 5% EtOAc/hexanes) to provide
37 (65 mg, 0.179 mmol, 34%) as an off-yellow solid: 1H NMR
(300 MHz, DMSO-d6) δ 7.82 (d, J ) 8.1 Hz, 1 H), 7.11 (t, J )
7.6 Hz, 1 H), 6.98 (br d, J ) 7.7 Hz, 1 H), 6.72 (br d, J ) 7.6
Hz, 1 H), 6.62 (d, J ) 8.0 Hz, 1 H), 6.27 (br s, 1 H), 5.88-5.70
(m, 2 H), 5.47 (br s, 1 H), 5.03 (dd, J ) 13.3, 1.1 Hz, 1 H), 4.99
(dd, J ) 18.3, 1.1 Hz, 1 H), 2.47 (s, 3 H), 2.46-2.33 (m, 1 H),
2.32-2.22 (m, 1 H), 2.18 (s, 3 H), 1.21 (s, 3 H), 1.17 (s, 3 H);
13C NMR (125 MHz, DMSO-d6) δ 150.5, 145.9, 134.2, 133.9,
133.6, 133.5, 127.3, 126.9, 126.5, 123.7, 120.5, 117.1, 116.6,
116.3, 114.2, 112.6, 73.9, 49.8, 35.8, 29.5, 28.9, 23.8, 16.5; MS
(DCI/NH3) m/e 364 (M + H)+; HRMS (FAB) calcd m/z for
C
23H25NOS: 363.1657 (M+), found 363.1663. Anal. (C23H25
NOS) C, H, N.
-
7-Br om o-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (41). Pre-
pared from 40 according to method A: 1H NMR (300 MHz,
DMSO-d6) δδ 7.93 (d, J ) 8.8 Hz, 1 H), 7.33 (d, J ) 9.2 Hz, 1
H), 6.71 (d, J ) 9.2 Hz, 1 H), 6.60 (d, J ) 8.5 Hz, 1 H), 6.25 (d,
J ) 1.5 Hz, 1 H), 5.94-5.80 (m, 2 H), 5.45 (s, 1 H), 5.0 (m, 2
H), 3.86 (s, 3 H), 2.17 (d, J ) 1.5 Hz, 3 H), 1.17 (s, 6 H). 13C
NMR (300 MHz, DMSO-d6) δ 155.3, 147.0, 146.0, 133.8, 133.6,
131.8, 129.5, 127.3, 127.2, 117.4, 116.0, 115.1, 113.2, 107.1,
102.6, 74.8, 55.9, 49.8, 29.0, 23.8; MS (APCI) m/z 426 (M +
H)+; HRMS (FAB) calcd for C23H2479BrNO2 426.3502 (M+),
found 426.3496. Anal. (C23H24BrNO2) C, H, N.
10-Meth oxy-7-m eth yl-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (42). A solu-
tion 41 (87 mg, 0.20 mmol) and (1,3-bis(diphenylphosphino)-
ferrocene)palladium (II) chloride‚dichloromethane complex (20
mg, 0.020 mmol) in DMF (2 mL) was treated with tetrameth-
yltin (63 mg, 0.35 mmol). The solution was heated at 65 °C
for 24 h, then cooled to 23 °C, treated with satd. KF solution
(2 mL), and extracted with EtOAc (10 mL). The organic portion
The lactol from the previous step was dissolved in MeOH
(50 mL) at 0° C and p-TsOH•H2O (700 mg, 25% w/w) was
added portionwise as a solid. The mixture was stirred for 14
h at 23 °C and then quenched with satd. aq. NaHCO3 (20 mL)
and extracted EtOAc (2 × 50 mL). The organics portions were
combined, washed with brine (50 mL), dried (Na2SO4), filtered,
and concentrated. Purification by flash chromatography (elu-
tion with 10% EtOAc/hexanes) provided the corresponding
methylacetal (1.75 g, 3.71 mmol, 61% over two steps) as a
white foam: 1H NMR (300 MHz, DMSO-d6) δ 7.99 (d, J ) 8.8
Hz, 1 H), 6.75-6.70 (m, 3 H), 6.27 (d, J ) 1.8 Hz, 1 H), 6.15
(s, 1 H), 5.46 (br s, 1 H), 3.63 (s, 3 H), 3.34 (s, 3 H), 2.18 (s, 3

1028 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Kym et al.
H), 1.28 (s, 3 H), 1.08 (s, 3 H), 1.00 (s, 9 H), 0.22 (s, 3 H), 0.16
(s, 3 H); 13C NMR (75 MHz, DMSO-d6) δ 145.7, 143.6, 143.1,
132.5, 128.2, 127.5, 126.3, 118.1, 117.8, 117.4, 115.9, 114.7,
112.5, 96.0, 59.3, 54.4, 49.7, 30.0, 28.0, 25.6, 22.0, 18.0, -4.6,
13C NMR (125 MHz, DMSO-d6) δ 148.8, 146.2, 145.2, 143.4,
134.3, 134.0, 133.5, 127.3, 127.0, 123.8, 117.1, 116.2, 115.3,
114.0, 112.8, 73.9, 49.9, 49.7, 35.7, 29.5, 28.9, 23.9; MS (DCI/
NH3) m/z 368 (M + H)+; HRMS (FAB) calcd for C22H22ClNO2
367.1339 (M+), found 367.1336. Anal. (C22H22ClNO2) C, H, N.
-4.8; MS (DCI/NH3) m/z 469 (M + H)+. Anal. Calcd for C27H37
-
NO4Si: C, 69.34; H, 7.97; N, 3.10. Found C, 69.00; H, 8.05; N,
3.03.
9-Br om o-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (59). 1H NMR
(300 MHz, DMSO-d6) δ 7.93 (d, J ) 8.8 Hz, 1 H), 7.33 (d, J )
8.5 Hz, 1 H), 6.67 (d, J ) 8.5 Hz, 1 H), 6.65 (d, J ) 8.5 Hz, 1
H), 6.36 (d, J ) 1.1 Hz, 1 H), 5.88-5.74 (m, 2 H), 5.46 (s, 1 H),
5.05-4.95 (m, 2 H), 3.62 (s, 3 H), 2.18 (d, J ) 1.1 Hz, 3 H),
1.19 (s, 3 H), 1.16 (s, 3 H); 13C NMR (300 MHz, DMSO-d6) δ
152.7, 150.8, 146.5, 134.0, 133.6, 132.1, 130.0, 127.3, 126.1,
119.3, 117.4, 116.2, 115.0, 114.6, 114.0, 109.5, 73.7, 59.6, 49.9,
36.7, 29.4, 29.1, 23.9; MS (DCI/NH3) m/z 428 (M + H)+; HRMS
(FAB) calcd for C23H24BrNO279Br 425.0990 (M+), found 425.0998;
HRMS (FAB) calcd for C23H24NO281Br 427.0970 (M+), found
427.0974. Anal. (C23H24BrNO2) C, H, N.
To a solution of the crude methylacetal (1.75 g, 3.74 mmol)
in THF (100 mL) at 0 °C was added dropwise tetrabutylam-
monium fluoride (3.74 mL of a 1.0 M solution in THF, 3.74
mmol) over 15 min. The reaction was quenched by the addition
of satd ammonium chloride (50 mL) and exracted with EtOAc
(3 × 50 mL). The combined organics were washed with brine
(2 × 30 mL), dried (Na2SO4), filtered, and concentrated.
Purification by flash chromatography (elution with 30% EtOAc/
hexanes) provided the phmethyl acetal (1.30 g, 3.71 mmol,
99%) as a white foam: 1H NMR (300 MHz, DMSO-d6) δ 8.78
(s, 1 H), 7.98 (d, J ) 8.8 Hz, 1 H), 6.70 (d, J ) 8.8 Hz, 1 H),
6.65 (m, 2 H), 6.20, (br s, 1 H), 6.16 (s, 1 H), 5.45 (br s, 1 H),
3.65 (s, 3 H), 3.31 (s, 3 H), 2.18 (s, 3 H), 1.26 (s, 3 H), 1.08 (s,
3 H); 13C NMR (75 MHz, DMSO-d6) δ 145.5, 143.8, 141.3,
132.5, 128.4, 127.6, 126.3, 117.4, 117.4, 116.3, 114.7, 114.0,
112.3, 95.9, 59.3, 54.4, 49.7, 30.1, 28.1, 22.0, 22.0; MS (DCI/
NH3) m/z 354 (M + H)+. Anal. Calcd for C21H23NO4: C, 71.37;
H, 6.56; N, 3.96. Found C, 71.01; H, 6.75; N, 3.71.
Allylation of the methyl acetal was carried out according to
method A to provide 50: 1H NMR (300 MHz, DMSO-d6) δ 8.69
(s, 1 H), 7.92 (d, J ) 8.5, 1 H), 6.62 (d, J ) 8.5 Hz, 1 H), 6.62
(d, J ) 8.5 Hz, 1 H), 6.48 (d, J ) 8.5, 1 H), 6.16 (d, J ) 1.7 Hz,
1 H), 5.81 (ddt, J ) 17.3, 10.3, 6.6 Hz, 1 H), 5.67 (dd, J ) 9.8,
3.3 Hz), 5.44 (s, 1 H), 5.02 (dd, J ) 10.3, 1.8 Hz, 1 H), 4.98
(dd, J ) 17.3, 1.8 Hz, 1 H), 2.47-2.41 (m, 1 H), 2.34-2.27 (m,
1 H), 2.16 (s, 3 H), 1.18 (s, 3 H), 1.16 (s, 3 H); 13C NMR (75
MHz, DMSO-d6) δ 145.8, 145.1, 143.9, 142.9, 134.4, 133.4,
132.7, 127.5, 126.5, 117.8, 117.0, 116.3, 116.1, 114.3, 113.6,
112.4, 73.3, 59.3, 49.7, 36.4, 29.2, 28.9, 23.9; MS (DCI/NH3)
m/z 364 (M + H)+. Anal. (C23H24N2O2) C, H, N.
9-F lu or o-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (55). 1H NMR
(300 MHz, DMSO-d6) δ 7.87 (d, J ) 8.5 Hz, 1 H), 7.00 (dd, J
) 8.8, 2.2 Hz, 1 H), 6.64 (d, J ) 8.1 Hz, 1 H), 6.63 (d, J ) 8.8
Hz, 1 H), 6.31 (d, J ) 1.1 Hz, 1 H), 5.90-5.80 (m, 1 H), 5.79-
5.75 (m, 1 H), 5.46 (s, 1 H), 5.05-4.95 (m, 2 H), 3.79 (s, 3 H),
2.17 (d, J ) 1.1 Hz, 1 H), 1.17 (s, 6 H); MS (DCI/NH3) m/z 366
(M + H)+; HRMS (FAB) calcd for C23H24FNO2 366.1869 (M+),
found 366.1869. Anal. (C23H24FNO2) C, H, N.
9-Ch lor o-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (56). 1H NMR
(300 MHz, DMSO-d6) δ 7.93 (d, J ) 8.5 Hz, 1 H), 7.20 (d, J )
8.5 Hz, 1 H), 6.70 (d, J ) 8.5 Hz, 1 H), 6.64 (d, J ) 8.5 Hz, 1
H), 6.36-6.33 (m, 1 H), 5.84-5.79 (m, 2 H), 5.48-5.42 (m, 1
H), 5.03 (br d, J ) 10.5 Hz, 1 H), 4.98 (br d, J ) 17.1 Hz, 1 H),
3.65 (s, 3 H), 2.49-2.39 (m, 1 H), 2.35-2.26 (m, 1 H), 2.18 (s,
3 H), 1.19 (s, 3 H), 1.17 (s, 3 H); MS (ESI) m/z 382 (M + H)+;
HRMS (FAB) calcd for C23H24ClNO2 381.1495 (M+), found:
381.1488. Anal. (C23H24ClNO2) C, H, N.
10-Ch lor o-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-tr im eth yl-
1H-[1]ben zop yr a n o[3,4-f]qu in olin e (60). 1H NMR (300
MHz, DMSO-d6) δ 7.93 (d, J ) 8.6 Hz, 1 H), 7.12-7.10 (m, 2
H), 6.90-6.84 (m, 1 H), 6.65 (d, J ) 8.8 Hz, 1 H), 6.36 (br s, 1
H), 5.90-5.75 (m, 2 H), 5.47 (br s, 1 H), 5.05 (dd, J ) 10.5, 2.1
Hz, 1 H), 4.97 (dd, J ) 17.3, 1.7 Hz, 1 H), 2.47-2.26 (m, 2 H),
2.16 (s, 3 H), 1.23 (s, 3 H), 1.17 (s, 3 H); 13C NMR (125 MHz,
DMSO-d6) δ 151.6, 146.3, 133.9, 133.6, 133.5, 128.2, 127.2,
127.1, 126.7, 124.5, 123.1, 117.2, 116.5, 116.1, 114.8, 112.9,
74.0, 49.8, 36.1, 29.4, 28.9, 23.8; MS (DCI/NH3) m/z 352 (M +
H)+; HRMS (FAB) calcd for C22H22ClNO 351.1390 (M+), found
351.1385. Anal. (C22H22ClNO) C, H, N.
7-Br om o-10-ch lor o-9-h yd r oxy-5-(3-p r op en yl)-2,2,4-tr i-
m et h yl-1H -2,5-d ih yd r o-[1]b en zop yr a n o[3,4-f]q u in olin e
1
(61). H NMR (300 MHz, DMSO-d6) δ 10.03 (s, 1 H), 7.90 (d,
J ) 8.5 Hz, 1 H), 7.00 (app s, 2 H), 6.63 (d, J ) 8.4 Hz, 1 H),
6.43 (br s, 1 H), 5.92-5.77 (m, 2 H), 5.47 (br s, 1 H), 5.11-
4.97 (m, 1 H), 2.44-2.26 (m, 2 H), 2.19 (s, 3 H), 1.22 (s, 3 H),
1.18 (s, 3 H); MS (DCI/NH3) m/z 448 (M + H)+; HRMS (FAB)
calcd for C22H2177BrClNO2 445.0444 (M+), found 445.0436;
HRMS (FAB) calcd for C22H2179BrClNO2 447.0424 (M+), found
447.0413. Anal. (C22H21BrClNO2) C, H, N.
5-(2-P r op en yl)-2,5-d ih yd r o-2,2,4-tr im eth yl-1H-[1]ben -
zop yr a n o[3,4-f]qu in olin e (62). 1H NMR (300 MHz, DMSO-
d6) δ 7.66 (dd, J ) 7.7, 1.5 Hz, 1 H), 7.47 (d, J ) 8.5 Hz, 1 H),
7.11 (t, J ) 7.7 Hz, 1 H), 6.97 (t, J ) 7.7 Hz, 1 H), 6.84 (dd, J
) 8.1, 1.4 Hz, 1 H), 6.66 (d, J ) 8.5 Hz, 1 H), 6.24-6.18 (m, 1
H), 5.86 (dd, J ) 9.8, 3.3 Hz, 1 H), 5.84-5.79 (m, 1 H), 5.48-
5.42 (m, 1 H), 5.03 (br d, J ) 10.3 Hz, 1 H), 4.99 (br d, J )
17.3 Hz, 1 H), 2.47-2.39 (m, 1 H), 2.17 (s, 3 H), 2.15 (m, 1 H),
1.21 (s, 3 H), 1.13 (s, 3 H); MS (ESI) m/z 318 (M + H)+; HRMS
calcd for C22H23NO 317.1780 (M+), found 317.1765. Anal.
(C22H23NO) C, H, N.
9,10-Dim et h oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-t r i-
m eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (63). Prepared
from 50 according to method B using methyl iodide as the
electrophile: 1H NMR (300 MHz, DMSO-d6) δ 7.93 (d, J ) 8.5
Hz, 1 H), 6.82 (d, J ) 8.8 Hz, 1 H), 6.61 (dd, J ) 4.4, 4.4 Hz,
2 H), 6.22 (d, J ) 1.4 Hz, 1 H), 5.83 (ddt, J ) 16.9, 10.3, 3.1
Hz, 1 H), 5.70 (dd, J ) 10.3, 3.3 Hz, 1 H), 5.44 (s, 1 H), 5.44-
4.96 (m, 2 H), 3.77 (s, 3 H), 3.67 (s, 3 H), 2.16 (s, 3 H), 1.17 (s,
3 H), 1.16 (s, 3 H); MS (ESI) m/z 378 (M + H)+; HRMS (FAB)
calcd for C24H27NO3 377.1991 (M+), found 377.2001. Anal.
(C23H24N2O2) C, H, N.
8-F lu or o-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (57). 1H NMR
(300 MHz, DMSO-d6) δ 7.85 (d, J ) 8.5 Hz, 1 H), 7.15-7.09
(m, 2 H), 6.62 (d, J ) 8.5 Hz, 1 H), 6.27-6.22 (m, 1 H), 5.83-
5.77 (m, 2 H), 5.49-5.44 (m, 1 H), 5.03 (br d, J ) 10.0 Hz, 1
H), 4.95 (br d, J ) 17.0 Hz, 1 H), 3.65 (s, 3 H), 2.47-2.40 (m,
1 H), 2.33-2.26 (m, 1 H), 2.18 (s, 3 H), 1.20 (s, 3 H), 1.15 (s, 3
H); MS (ESI) m/z 366 (M + H)+; HRMS (FAB) calcd for C23H24
-
9-Eth oxy-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zop yr a n o[3,4-f]qu in olin e (64). Pre-
pared from 50 according to nethod B using iodoethane as the
electrophile: 1H NMR (300 MHz, DMSO-d6) δ 7.94 (d, J ) 8.8
Hz, 1 H), 6.79 (d, J ) 8.8 Hz, 1 H), 6.60 (d, J ) 8.8 Hz, 1 H),
6.55 (d, J ) 8.8, 1 H), 6.45 (s, 1 H), 5.85 (ddt, J ) 17.3, 10.3,
6.6 Hz, 1 H), 5.43 (d, J ) 9.2 Hz), 5.16 (s, 1 H), 5.09 (dd, J )
10.3, 1.1 Hz, 1 H), 5.06 (dd, J ) 17.3, 1.1 Hz, 1 H), 4.91 (s, 1
H), 4.06-3.97 (m, 2 H), 2.62-2.52 (m, 1 H), 2.31-2.15 (m, 1
H), 2.24 (s, 3 H), 1.35 (t, J ) 7.0 Hz, 3 H), 1.26 (s, 3 H), 1.07
(s, 3 H); MS (DCI/NH3) m/z 392 (M + H)+; HRMS (FAB) calcd
FNO2 365.1791 (M+), found 365.1795. Anal. (C23H24FNO2) C,
H, N.
10-Ch lor o-9-h yd r oxy-5-(2-p r op en yl)-2,5-d ih yd r o-2,2,4-
tr im eth yl-1H-[1]ben zopyr an o[3,4-f]qu in olin e (58). 1H NMR
(300 MHz, DMSO-d6) δ 9.34 (s, 1 H), 7.87 (s, J ) 8.8 Hz, 1 H),
6.72 (d, J ) 8.9 Hz, 1 H), 6.66 (d, J ) 8.4 Hz, 1 H), 6.58 (d, J
) 8.9 Hz, 1 H), 6.21 (br s, 1 H), 5.81-5.71 (m, 1 H), 5.62 (dd,
J ) 10.6, 3.0 Hz, 1 H), 5.41 (br s, 1 H), 4.98 (dd, J ) 10.5, 2.1
Hz, 1 H), 4.93 (dd, J ) 16.9, 2.2 Hz, 1 H), 2.42-2.34 (m, 1 H),
2.26-2.20 (m, 1 H), 2.11 (s, 3 H), 1.16 (s, 3 H), 1.11 (s, 3 H);

Nonsteroidal Selective Glucocorticoid Modulators
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6 1029
for C26H27NO3 391.2147 (M+), found 391.2138. Anal. (C26H27
NO3) C, H, N.
-
mixture was then heated at 60 °C under CO atmosphere for 3
h. The reaction was allowed to cool to 23 °C then was
partitioned between EtOAc (15 mL) and water (5 mL). The
organic portion was washed with water (5 mL) and brine (5
mL) and then dried (Na2SO4). Filtration and concentration
gave a black residue which was purified by flash chromatog-
raphy (elution with 15% EtOAc/hexanes) to provide 69 (205
10-Meth oxy-5-(2-p r op en yl)-9-(2-p r op en yloxy)-2,5-d ih y-
d r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e
(65). Prepared from 50 according to method B using allyl
1
bromide as the electrophile: H NMR (300 MHz, DMSO-d6) δ
7.93 (d, J ) 9.0 Hz, 1 H), 6.83 (d, J ) 8.8 Hz, 1 H), 6.61 (d, J
) 9.0 Hz, 1 H), 6.59 (d, J ) 8.8 Hz, 1 H), 6.23 (d, J ) 1.5 Hz,
1 H), 6.15-6.02 (m, 1 H), 5.81 (ddt, J ) 17.3, 10.3, 6.6 Hz, 1
H), 5.67 (dd, J ) 9.8, 3.3 Hz), 5.45 (s, 1 H), 5.44 (dd, J ) 16.0,
2.0 Hz, 1 H), 5.27 (dd, 10.6, 2.0 Hz, 1 H), 5.03 (dd, J ) 10.3,
1.8 Hz, 1 H), 4.98 (dd, J ) 17.3, 1.8 Hz, 1 H), 4.56-4.53 (m, 1
H), 2.47-2.41 (m, 1 H), 2.34-2.27 (m, 1 H), 2.16 (s, 3 H), 1.17
(s, 3 H), 1.16 (s, 3 H); MS (DCI/NH3) m/z 404 (M + H)+; HRMS
(FAB) calcd for C26H29NO3 403.2147 (M+), found 403.2150.
Anal. (C26H29NO3) C, H, N.
1
mg, 0.442 mmol, 65%) as a pale yellow foam: H NMR (300
MHz, DMSO-d6) δ 7.92 (d, J ) 8.1 Hz, 1 H), 6.48 (d, J ) 8.3
Hz, 1 H), 6.75 (d, J ) 8.2 Hz, 1 H), 6.65 (d, J ) 8.2 Hz, 1 H),
6.33 (br s, 1 H), 5.90-5.75 (m, 2 H), 5.46 (br s, 1 H), 5.04 (dd,
J ) 10.5, 1.0 Hz, 1 H), 4.98 (dd, J ) 15.4, 1.0 Hz, 1 H), 3.82 (s,
3 H), 3.67 (s, 3 H), 2.54-2.42 (m, 1 H), 2.38-2.27 (m, 1 H),
2.18 (s, 3 H), 1.19 (s, 3 H), 1.16 (s, 3 H); 13C NMR (100 MHz,
DMSO-d6) δ 166.1, 156.5, 154.6, 146.3, 133.9, 133.5, 131.9,
129.0, 127.2, 126.2, 119.1, 118.1, 117.4, 116.2, 114.5, 114.0,
113.0, 74.0, 60.7, 51.8, 49.8, 36.8, 29.4, 29.0, 23.8; MS (DCI/
NH3) m/z 406 (M + H)+; HRMS (FAB) calcd for C25H27NO4
405.1940 (M)+, found 405.1939. Anal. (C25H27NO4) C, H, N.
9-Hyd r oxym eth yl-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih y-
d r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e
(70). A magnetically stirred solution of 69 (32 mg, 0.085 mmol)
in CH2Cl2 (3 mL) was cooled to -78 °C and Dibal-H (0.400
mL of a 1.0 M solution in cyclohexane, 0.40 mmol) was added
in dropwise fashion. The temperature of the reaction was
allowed to rise to 0 °C over a period of 30 min. After 3.5 h, the
reaction was quenched by addition to aqueous Rochelle’s salt
(3 mL) and EtOAc (10 mL). Upon warming, the layers were
partitioned and the aqueous layer was extracted with EtOAc
(3 × 15 mL). The combined organic portions were dried
(MgSO4), filtered, and concentrated. The crude material was
purified by preparative TLC (2× elution with 10% EtOAc/
hexanes) and the product isolated by EtOAc extraction to
provide 69 (24 mg, 0.069 mmol, 61%) as pale yellow foam: 1H
NMR (500 MHz, DMSO-d6) δ 7.93 (d, J ) 8.2 Hz, 1 H), 7.16
(d, J ) 8.3 Hz, 1 H), 6.67 (d, J ) 8.1 Hz, 1 H), 6.63 (d, J ) 8.3
Hz, 1 H), 6.27 (br s, 1 H), 5.87-5.75 (m, 2 H), 5.44 (br s, 1 H),
5.03 (br d, J ) 10.3 Hz, 1 H), 4.98 (br d, J ) 15.1 Hz, 1 H),
4.97-4.93 (m, 1 H), 4.57-4.48 (m, 2 H), 3.59 (s, 3 H), 2.55-
2.46 (m, 1 H), 2.30-2.22 (m, 1 H), 2.19 (s, 3 H), 1.19 (s, 3 H),
1.16 (s, 3 H);13C NMR (125 MHz, DMSO-d6) δ 154.0, 150.2,
145.9, 134.2, 133.4, 132.1, 128.9, 127.4, 126.6, 125.9, 117.2,
116.8, 116.3, 115.6, 113.9, 112.6, 73.6, 60.0, 58.1, 49.8, 36.4,
29.4, 28.9, 23.9; MS (DCI/NH3) m/z 378 (M + H)+; HRMS
(FAB) calcd m/z for C24H27NO3 377.1991 (M)+, found 377.1985.
Anal. (C24H27NO3) C, H, N.
10-Meth oxy-5-(2-p r op en yl)-9-(2-p r op yn yloxy)-2,5-d ih y-
d r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e
(66). Prepared from 50 according to method B using propargyl
1
bromide as the electrophile: H NMR (300 MHz, DMSO-d6) δ
7.92 (d, J ) 8.8 Hz, 1 H), 6.88 (d, J ) 8.8 Hz, 1 H), 6.62 (d, J
) 8.8 Hz, 1 H), 6.61 (d, J ) 8.8, 1 H), 6.24 (d, J ) 1.7 Hz, 1 H),
5.81 (ddt, J ) 17.3, 10.3, 6.6 Hz, 1 H), 5.72 (dd, J ) 9.8, 3.3
Hz), 5.44 (s, 1 H), 5.03 (dd, J ) 10.3, 1.8 Hz, 1 H), 4.99 (dd, J
) 17.3, 1.8 Hz, 1 H), 4.79 (d, J ) 2.3 Hz, 2 H), 3.57 (t, J ) 2.3
Hz, 1 H), 2.47-2.41 (m, 1 H), 2.34-2.27 (m, 1 H), 2.16 (s, 3
H), 1.17 (s, 3 H), 1.16 (s, 3 H); MS (DCI/NH3) m/z 402 (M +
H)+; HRMS (FAB) calcd for C26H27NO3 401.1991 (M+), found
401.1978. Anal. (C26H27NO3) C, H, N.
9-Cya n om eth oxy-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih y-
d r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e
(67). Prepared from 50 according to method B using chloro-
acetonitrile as the electrophile: 1H NMR (300 MHz, DMSO-
d6) δ 7.92 (d, J ) 9.1 Hz, 1 H), 6.95 (d, J ) 8.2 Hz, 1H), 6.66
(d, J ) 8.3 Hz, 1 H), 6.63 (d, J ) 9.1 Hz, 1 H), 6.26 (d, J ) 2.4
Hz, 1 H), 5.45 (s, 1 H), 5.12 (s, 2 H), 5.05-4.97 (m, 1 H), 5.01
(s, 1 H), 3.69 (s, 3 H), 2.46-2.40 (m, 1 H), 2.30-2.23 (m, 1 H),
2.17 (s, 3 H), 1.18 (s, 3 H), 1.17 (s, 3 H); 13C NMR (100 MHz,
DMSO-d6) δ 146.6, 146.2, 145.0, 134.1, 133.6, 133.5, 132.6,
127.3, 126.6, 118.6, 117.2, 116.8, 116.2, 115.2, 114.4, 113.7,
112.4, 73.5, 60.1, 60.1, 55.5, 49.8, 36.7, 29.3, 29.0, 23.9; MS
(DCI/NH3) m/z 403 (M+H)+; HRMS (FAB) calcd for C25H26N2O3
402.1914 (M+), found 402.1947. Anal. (C25H26N2O3) C, H, N.
10-Met h oxy-9-t r iflu or om et h a n esu lfon yloxy-5-(2-p r o-
p en yl)-2,5-d ih yd r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o-
[3,4-f]qu in olin e (68). To a solution of 50 (268 mg, 0.784
mmol) in CH2Cl2 (9 mL) at -78 °C was added triethylamine
(330 µL, 2.34 mmol), followed by trifluoromethanesulfonic
anhydride (146 µL, 0.860 mmol). The reaction mixture was
allowed to slowly warm to 23 °C over a period of 1.5 h. The
reaction was quenched with satd. aq. NH4 (0 mL) and extracted
EtOAc (2 × 20 mL). The combined organic layers were washed
with brine (5 mL), then were dried (Na2SO4) and were
concentrated. The resulting tan residue was purified by flash
chromatography (elution with 10% EtOAc/hexanes) to provide
68 (338 mg, 0.714 mmol, 91%) as a white solid: 1H NMR (300
MHz, DMSO-d6) δ 7.52 (d, J ) 8.6 Hz, 1 H), 7.37 (t, J ) 8.3
Hz, 1 H), 7.03 (dd, J ) 8.6, 1.1 Hz, 1 H), 6.66 (d, J ) 8.6 Hz,
1 H), 6.48 (br s, 1 H), 5.91-5.74 (m, 2 H), 5.48 (br s, 1 H), 5.03
(dd, J ) 9.0, 1.1 Hz, 1 H), 4.93 (dd, J ) 16.0, 1.1 Hz, 1 H),
3.84 (s, 3 H), 2.47-2.26 (m, 2 H), 2.19 (s, 3 H), 1.21 (s, 3 H),
1.18 (s, 3 H);13C NMR (125 MHz, DMSO-d6) δ 162.7, 153.4,
150.2, 146.2, 140.7, 138.2, 130.6, 127.9, 127.3, 124.1, 118.5,
116.8, 114.4, 113.3, 109.4, 106.7, 74.0, 88.2, 56.0, 47.3, 33.9,
29.4, 26.1, 22.3; MS (DCI/NH3) m/z 496 (M + H)+; HRMS
(FAB) calcd for C24H24F3NO5S 362.1756 (M)+, found 362.1749.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures for the preparation of 9-11, 33-34, 36, 38-40, 44,
46-49, and 54 along with characterization data. This informa-
tion is free of charge via the Internet at http://pubs.acs.org.
Refer en ces
(1) Cohen, E. M. Dexamethasone [9R-fluoro-11â,17R,21-trihydroxy-
16R-methyl pregna-1,4-diene-3, 20-dione]. Anal. Profiles Drug
Subst. 1973, 2, 163-197.
(2) Ali, S. L. Prednisolone. Anal. Profiles Drug Subst. Excipients
1992, 21, 415-500.
(3) Barnes, P. J . Anti-inflammatory actions of glucocorticoids:
molecular mechanisms. Clinical Science 1998, 94, 557-572.
(4) Andersson. P.-B.; Goodkin, D. E. Glucocorticosteroid therapy for
multiple sclerosis: a critical review. J . Neuro. Sci. 1998, 160,
16-25.
(5) Schimmer, B. P.; Parker, K. L. Adrenocorticotropic hormone;
adrenocortical steroids and their synthetic analogs; inhibitors
of the synthesis and actions of adrenocortical hormones. In
Goodman & Gilman’s The Pharmacological Basis of Therapeu-
tics, 9th ed.; J . G. Hardman, L. E. Limbird, P. B. Molinoff and
R. W. Ruddon, Eds.; McGraw-Hill: New York, 1996; pp 1459-
1485.
(6) Gennari, C. Differential Effect of Glucocorticoids on calcium
absorption and bone mass. Br. J . Rheumatol. 1993, 32, 11-14.
(7) Andrews, R. C.; Walker, B. R. Glucocorticoids and insulin
resistance: old hormones, new targets. Clin. Sci. 1999, 513-
523.
(8) Remesar, X.; Fernandez-Lopez, J . A.; Alemany, M. Steroid
hormones and the control of body weight. Med. Res. Rev. 1993,
13(5), 623-631.
9-Ca r bom eth oxy-10-m eth oxy-5-(2-p r op en yl)-2,5-d ih y-
d r o-2,2,4-t r im et h yl-1H -[1]b en zop yr a n o[3,4-f]q u in olin e
(69). To a deoxygenated solution of 68 (308 mg, 0.667 mmol),
bis(diphenylphosphino)ethane (14 mg, 0.033 mmol),triethyl-
amine (120 µL, 0.870 mmol), and methanol (0.3 mL) in DMSO
(3.0 mL) was added palladium acetate (6 mg, 0.033 mmol).
The solution was saturated with CO by bubbling a stream of
gas into the reaction mixture for 4 min at 23 °C. The reaction

1030 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 6
Kym et al.
(9) Adcock, I. M. Ligand-induced differentiation of glucocorticoid
receptor (GR) transrepression and transactivation. Biochem. Soc.
Trans. 1996, 24(2), 267S.
(20) Newman, M. S.; Karnes, H. A. Conversion of phenols to thiophe-
nols via dialkylthiocarbamates. J . Org. Chem. 1966, 31, 3980-
3984.
(21) Kwart, H.; Evans, E. R.. The vapor phase rearrangement of
thionocarbamates. J . Org. Chem. 1966, 31, 410-413.
(22) Cacchi, Sandro; Ciattini, P.; Morera, E.; Ortar, G. Palladium-
catalyzed carbonylation of aryl triflates. Synthesis of arenecar-
boxylic acid derivatives from phenols. Tetrahedron Lett. 1986,
27, 3931-3934.
(23) Edwards, J . P.; West, S. J .; Marschke, K. B.; Mais, D. E.;
Gottardis, M. M.; J ones, T. K. 5-Aryl-1,2-dihydro-5H-chromeno-
[3,4-f]quinolines as potent, orally active, nonsteroidal progest-
erone receptor agonists: the effect of D-ring substituents. J . Med.
Chem. 1998, 41, 303-310.
(24) Zhi, L.; Tegley, C. M.; Kallel, E. A.; Marschke, K. B.; Mais, D.
E.; Gottardis, M. M.; J ones, T. K.; 5-Aryl-1,2-dihydrochromen-
[3,4-f]quinolines: A novel class of nonsteroidal human proges-
terone receptor agonists. J . Med. Chem. 1998, 41, 291-302.
(25) Thiesen, H.-J . From transient cotransfections to the transcription
repressor assay (TRA). Immunol. Methods Man. 1997, 1, 315-
322.
(10) van der Burg, B.; Liden, J .; Okret, S.; Delaunay, F.; Wissink,
S.; van der Saag, P. T.; Gustafsson, J .-A. Nuclear factor-kappa
B repression in antiinflammation and immunosuppression by
glucocorticoids. Trends Endocrinol. Metab. 1997, 8, 152-157.
(11) J onat, C.; Rahmsdorf, H. J .; Park, K. K.; Cato, A. C.; Gebel, S.;
Ponta, H.; Herrlich, P. Antitumor promotion and antiinflam-
mation: down-modulation of AP-1 (Fos/J un) activity by gluco-
corticoid hormone. Cell 1990, 62, 1189-1204.
(12) Wade, E. J .; Heck, S.; Cato, C. B. Glucocorticoid receptor-
activator protein-1 interactions in drug design. Biochem. Soc.
Trans. 1995, 23, 3(4), 946-52.
(13) Evans, R. M. Molecular characterization of the glucocorticoid
receptor. Recent Prog. Horm. Res. 1989, 45, 1-27.
(14) Katzenellenbogen, J . A.; Katzenellenbogen, B. S. Nuclear hor-
mone receptors: ligand-activated regulators of transcription and
diverse cell responses. Chem. Biol. 1996, 3(7), 529-536.
(15) Coghlan, M. J .; Kym, P. R.; Elmore, S. W.; Wang, A. W.; Luly,
J . R.; Wilcox, D. M.; Lin, C. W.; Stashko, M. A.; Miner, J . N.;
Tyree, C.; Nakane, M.; J acobson, P. B.; Lane, B. L. Synthesis
and characterization of nonsteroidal ligands for the glucocorti-
coid receptor: selective quinoline derivatives with prednisolone-
equivalent functional activity. J . Med. Chem. 2001, 44, 2879-
2885.
(16) Elmore, S. W.; Coghlan, M. J ., Anderson, D. D.; Pratt, J . K.;
Wang, A. X.; Kym, P. R.; Green, B. E.; Stashko, M. A.; Lin, C.
W.; Tyree, C. M.; Miner, J . N.; J acobson, P. B.; Wilcox, D. M.;
Luly, J . R.; Lane, B. C. Nonsteroidal selective glucocorticoid
modulators: the effect of C-5 alkyl substitution on the tran-
scriptional activation/repression profile of 2,5-dihydro-10-meth-
oxy- dihydro-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines.
J . Med. Chem. 2001, 44, 4481-4491.
(17) Coghlan, M. J .; Kort, M. E. Novel ligands of steroid hormone
receptors. Expert Opin. Ther. Pat. 1999, 9, 1523-1536.
(18) Eisch, J . J .; Dluzniewski, T. Mechanism of the Skraup and
Doebner-von Miller quinoline syntheses: cyclization of R,â-
unsaturated N-aryliminium salts via 1,3-diazetidinium ion
intermediates. J . Org. Chem. 1989, 54, 1269-1274.
(19) Fokin, A. V.; Kolomiyets, A. F. Some new approaches to
modifying aromatic and heteroaromatic compounds by means
of fluorine-containing substituents. J . Fluorine Chem. 1988,
247-261.
(26) White, R.; Parker, M. Analysis of cloned factors. Transcr. Factors
1993, 143-179.
(27) Guido, E. C.; Delorme, E. O.; Clemm, D. L.; Stein, R. B.; Rosen,
J .; Miner, J . N. Determinants of promoter-specific activity by
glucocorticoid receptor. Mol. Endocrinol. 1996, 10, 1178-1190.
(28) Goodwin, J . S. Modulation of conconavalin-A-induced suppressor
cell activation by prostaglanding E2. Cell. Immunol. 1980, 49,
421-425.
(29) Wang, S.; Huang, J .; Wang, S. In vitro glucocorticoid inhibition
of steroid-treated residual circulatory human lymphocytes. Cell.
Immunol. 1981, 65, 43-51.
(30) Sedgwick, A. D.; Edwards, J . C. W. Animal models Of inflam-
mation. Immunopharmacol. Microcirc. 1994, 189-202.
(31) Pathirana, C.; Stein, R. B.; Berger, T. S.; Fenical, W.; Ianiro,
T.; Mais, D. E.; Torres, A.; Goldman, M. E. Nonsteroidal Human
Progesterone Receptor Modulators From the Marine Alga Cy-
mopolia Barbata. Mol. Pharmacol. 1995, 47, 630-635.
(32) Cheng, Y.-C.; Prusoff, W. H. Relation Between the Inhibition
Constant K1 and the Concentration of Inhibitor Which Causes
Fifty Percent Inhibition (I50) of an Enzymic Reaction. Biochem.
Pharmacol. 1973, 22, 3099-3108.
J M020335M