Synthesis and pharmacology of conformationally restricted raloxifene analogues: Highly potent selective estrogen receptor modulators

Article abstract of DOI:10.1021/jm970688z

The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. In vivo structure- activity relationships and molecular

Full text of DOI:10.1021/jm970688z

1272
J . Med. Chem. 1998, 41, 1272-1283
Syn th esis a n d P h a r m a cology of Con for m a tion a lly Restr icted Ra loxifen e
An a logu es: High ly P oten t Selective Estr ogen Recep tor Mod u la tor s
Timothy A. Grese,* Lewis D. Pennington, J ames P. Sluka, M. Dee Adrian, Harlan W. Cole, Tina R. Fuson,
David E. Magee, D. Lynn Phillips, Ellen R. Rowley, Pamela K. Shetler, Lorri L. Short, Murali Venugopalan,
Na N. Yang, Masahiko Sato, Andrew L. Glasebrook, and Henry U. Bryant
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285
Received October 9, 1997
The 2-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator (SERM) which
is currently under clinical evaluation for the prevention and treatment of postmenopausal
osteoporosis. In vivo structure-activity relationships and molecular modeling studies have
indicated that the orientation of the basic amine-containing side chain of 1, relative to the
stilbene plane, is an important discriminating factor for the maintenance of tissue selectivity.
We have constructed a series of analogues of 1 in which this side chain is held in an orientation
which is orthogonal to the stilbene plane, similar to the low-energy conformation predicted for
raloxifene. Herein, we report on the synthesis of these compounds and on their activity in a
series of in vitro and in vivo biological assays reflective of the SERM profile. In particular, we
describe their ability to (1) bind the estrogen receptor, (2) antagonize estrogen-stimulated
proliferation of MCF-7 cells in vitro, (3) stimulate TGF-â3 gene expression in cell culture, (4)
inhibit the uterine effects of ethynyl estradiol in immature rats, and (5) potently reduce serum
cholesterol and protect against osteopenia in ovariectomized (OVX) rats without estrogen-like
stimulation of uterine tissue. These data demonstrate that one of these compounds, LY357489,
4, is among the most potent SERMs described to date with in vivo efficacy on bone and
cholesterol metabolism in OVX rats at doses as low as 0.01 mg/kg/d.
In tr od u ction
been investigated as a possible alternative to ERT.9 One
such compound, raloxifene (LY139481 HCl; 1), is in
advanced clinical trials for the prevention and treatment
of osteoporosis.10,11
The decreased production of ovarian steroids which
occurs after the climacteric has been linked to a number
of postmenopausal pathologies, particularly osteoporosis
and coronary artery disease.1,2 Although estrogen
replacement therapy (ERT) reduces the risks associated
with these pathologies, concerns relating to the in-
creased risk of endometrial cancer have necessitated the
development of therapeutic regimens in which the
uterine effects of estrogen are opposed by progestin
treatment.3 Side effects of progestin treatment, such
as resumption of menses, central nervous system dis-
turbances, and the possibility of attenuated cardiovas-
cular benefits, have significantly reduced patient com-
pliance.4 Furthermore, recent studies which suggest an
increased risk of breast and uterine cancer associated
with estrogen replacement therapy have stimulated the
search for treatment alternatives.5,6
Historically, a number of nonsteroidal compounds
which interact with the estrogen receptor (ER) have
been investigated as contraceptives and for the treat-
ment of breast cancer, uterine dysfunction, and other
disorders of the female reproductive system.7 Tamox-
ifen, originally developed as an estrogen antagonist and
widely utilized for the treatment of breast cancer, has
paradoxically been found to act as a partial estrogen
agonist in the uterus and to display estrogen agonist
effects in bone and in the cardiovascular system.8 More
recently, selective estrogen receptor modulators (SERMs)
which fully antagonize the effects of estrogen on uterine
and mammary tissue, while mimicking the effects of
estrogen on bone and the cardiovascular system, have
Pharmacologically, raloxifene is distinguished from
tamoxifen by its lack of proliferative effects in uterine
S0022-2623(97)00688-2 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

Synthesis of Raloxifene Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1273
F igu r e 1. Overlay of minimized structures of raloxifene (green carbons) and 3a (gray carbons).
Sch em e 1a
a
Reagents: (a) HCl, H2O, THF, reflux; (b) H2O2, Na2CO3 (see ref 24); (c) Et3N, EtOH, CH2Cl2; (d) DDQ, dichloroethane, 80 °C; (e)
AlCl3, EtSH, CH2Cl2; (f) TBDMSCl, Et3N, CH2Cl2; (g) NaH, (MeO)2CO, MeOH (see ref 25); (h) resorcinol, P(O)Cl3, toluene, 80 °C.
tissue.12,13 Other researchers have developed a series
of benzopyran-containing molecules (e.g. EM-800,14
CDRI-85/28715) which also exhibit this tissue specific-
ity.16 We have recently speculated that this difference
in biological activity may be related to a specific
structural property, that is, the orientation of the basic
amine-containing side chain with respect to the stilbene
plane.16 While in tamoxifen this side chain is coplanar
with the stilbene moiety, both molecular modeling and
X-ray crystallographic studies predict an orthogonal
orientation for the side chain in raloxifene (Figure 1).17
We have demonstrated that raloxifene analogues which
are forced to adopt the tamoxifen orientation exhibit a
tamoxifen-like biological profile, while analogues which
are conformationally locked in a raloxifene-like orienta-
tion maintain the raloxifene profile.18 Herein, we
describe the synthesis and biological activity of a series
of conformationally locked ER modulators which incor-
porate structural elements of both raloxifene and the
aforementioned benzopyrans. In particular, we disclose
LY357489, 4, an extremely potent SERM with in vivo
efficacy on bone and cholesterol metabolism at doses as
low as 0.01 mg/kg.
5-7 and a functionalized aryl Grignard reagent, 22,
allowed the utilization of methodology previously de-
veloped for the synthesis of 2,3-diarylisoflav-3-enes.21
Compound 5 was readily available by the silylation of
commercially available coumestrol.22 Thiacoumestans
6a -c were prepared by the condensation of a salicyl
aldehyde with thianaphthen-2-ones 10a ,b followed by
oxidation, demethylation, and silylation (Scheme 1a).23
This protecting group interchange was necessary, both
for ease of removal and to provide improved solubility
in later stages of the synthesis (vide supra). Compounds
10a ,b were in turn prepared either by hydrolysis of the
2-(dimethylamino)benzothiophene, 8,24,25 or from ben-
zothiophene via oxidation of the corresponding boronic
acid, 9.26 Naphthocoumarin 7 was prepared from car-
bomethoxytetralone 1227 via a von Pechman condensa-
tion,28 followed by protecting group interchange and
dehydrogenation (Scheme 1b).
Reduction of the tetracyclic coumarins 5-7 with
diisobutylaluminum hydride (DIBAL-H) then provided
the corresponding lactols 14-16 (Scheme 2).21 The silyl
protecting groups were required at this stage, since the
reduction was best carried out in toluene or toluene/
dichloromethane mixtures at low temperatures and the
corresponding methoxy-substituted coumarins had lim-
ited solubility under these conditions. In the benzofu-
ran-containing system, the lactol was isolated as a
mixture with the corresponding aldehyde tautomer 17,
and the yield of the reduction was significantly lower.
Presumably, the ring strain engendered by the incor-
poration of the smaller furan ring leads to a larger
proportion of the open form, which is prone to overre-
duction under the reaction conditions. For the ben-
zothiophene-containing system, significant amounts of
Ch em istr y
Compounds 2-4 were designed on the basis of mo-
lecular modeling studies of raloxifene and benzopyran-
containing SERMs which predicted an orthogonal ori-
entation of their respective side chains relative to the
stilbene plane.16 Overlay of the minimized structure of
compound 3 with raloxifene (Figure 1) indeed predicted
a similar topology.19,20
A retrosynthetic disconnection of the side chain of
compounds 2-4, leading to the tetracyclic coumarins

1274 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Grese et al.
Sch em e 2a
a
Reagents: (a) DIBAL-H, toluene, -100 to -70 °C; (b) phenol, (MgSO4), chlorobenzene or CH2Cl2, room temperature to reflux; (c)
THF, 0 °C to room temperature; (d) TBAF, THF; (e) PCC, Celite, CH2Cl2.
Sch em e 3a
starting material and overreduced product, 18, were
also obtained. Diol 18 could be recycled to 6 by
oxidation with PCC; however, partial oxidation to the
lactol 16 was not feasible. Conversion of the lactols to
the corresponding phenyl acetals 19-21 and displace-
ment with the aryl Grignard reagent 22 proceeded as
expected, and desilylation then provided the desired
compounds 2-4 in racemic form.21 Alternatively, con-
densation of 20a with (4-((trimethylsilyl)oxy)phenyl)-
magnesium bromide29 followed by selective removal of
the trimethylsilyl moiety provided monophenol 23
(Scheme 3). Mitsunobu alkylation with a variety of
N-hydroxyethylamines followed by desilylation then
provided analogues 3f-j containing modified side chains.
Finally, deshydroxy analogue 3d was prepared from 3a
by conversion to the bistriflate and palladium-catalyzed
transfer hydrogenation, and dimethoxy analogue 3e was
prepared by methylation of 3a with diazomethane
(Scheme 4).
a
Reagents: (a) (i) [4-[(trimethylsilyl)oxy]phenyl]magnesium
bromide, THF; (ii) K2CO3, MeOH; (b) HOCH2CH2Y, PPh3, DEAD,
toluene; (c) TBAF, THF.
Biologica l Testin g
In Vitr o. ER binding affinities were determined by
displacement of bound [3H]-17â-estradiol from MCF-7
treatment (Table 1, Figure 2). Selected compounds were
further evaluated in a 5-week, OVX rat model in which
effects on bone mineral density (BMD) were also exam-
ined.33 Bone-mineral density was assessed at the
proximal aspect of the tibia by quantitative computed
tomography (QCT) and is reported as percent protection
relative to sham-operated and OVX controls (Figure 3).
In vivo estrogen antagonist activity in the uterus was
determined in 21-day-old female Sprague-Dawley rats
dosed with a maximally stimulatory dose of 17R-
cell lysate for compounds 2-4 and are reported in Table
1.30 Antagonism of estrogen action in a mammary
tumor cell line was assayed via inhibition of MCF-7 cell
proliferation stimulated by 10-11 M 17â-estradiol and
IC50 values are also included in Table 1.31
In Vivo. Tissue-specific estrogen agonist effects were
examined in OVX rats,13 utilizing uterine weight,
uterine eosinophil peroxidase (EPO) activity,32 and
serum cholesterol levels as endpoints after 4 days of

Synthesis of Raloxifene Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1275
Sch em e 4a
raloxifene also stimulates a modest increase in uterine
wet weight, this increase is not dose related and is not
coincident with increases in other measures of uterine
hypertrophy such as epithelial cell height and total
estrogenicity.12a This uterine weight increase has there-
fore been attributed to water retention.12b The incon-
sistent correlation between elevation of uterine weight
and stimulation of other uterine parameters has led to
reliance on uterine EPO activity, a very sensitive
indicator of estrogen action in the uterus.32 Although
ethynylestradiol and tamoxifen both potently reduce
serum cholesterol, they also induce significant increases
in uterine EPO while raloxifene does not. All three
compounds induce significant increases in uterine weight,
although the effect of raloxifene is relatively modest and
is not dose related. We have used uterine EPO,
therefore, to discriminate compounds which demon-
strate a tamoxifen-like profile from those whose activity
parallels that of raloxifene.34,35
a
Reagents: (a) PhN(Tf)2, Et3N, DMF; (b) Pd(PPh3)4, dppp,
HCO2H, Et3N, DMF; (c) CH2N2, Et2O, MeOH.
ethynylestradiol (0.1 mg/kg) for 3 consecutive days.34
Test groups were also administered various doses of
compounds 2-4 15 min prior to ethynylestradiol dosing
for 3 days. Uterine weight/body weight ratios were
calculated for each animal and are reported as percent
inhibition (Figure 4).
As shown in Table 1, the conformationally restricted
SERMs generally mimic the effects of raloxifene on
uterine parameters and serum cholesterol. In contrast
to original the raloxifene series, in which the deshydroxy
congeners showed increased in vivo potency, changes
in the hydroxylation pattern of the benzothienoben-
zopyran (3a -d ) resulted in a reduction in potency.33
This distinction may reflect different efficiency or
selectivity of metabolic hydroxylation for the two series.
Similar to the raloxifene series,18 changing the base
from piperidine to other cyclic or acyclic amine func-
tionality reduced both potency and selectivity, with 3f-j
all showing increased evidence of uterine stimulation
relative to 3a .38 The piperidine-containing compounds
2, 3a -c, and 4 produce no significant increase in uterine
EPO or, unlike raloxifene, uterine weight. A similar
lack of uterine weight effects has previously been
reported for another series of benzopyran-containing
SERMs, but the relevance of this difference in compari-
son with raloxifene is unknown.16
Resu lts
In Vitr o. The in vitro results in Table 1 indicate the
importance of the hydroxy functionality of 2-4 for
optimal ER binding and inhibition of MCF-7 cell pro-
liferation. Comparison of the binding activities of 3b-e
with that of 3a reveals 6-20-fold decreases in relative
binding affinity (RBA) when either or both of the
hydroxy groups are replaced with a proton or converted
to methyl ethers. In parallel fashion, MCF-7 inhibitory
potency is decreased by 30-500-fold for the same
compounds. A similar importance has previously been
reported in the raloxifene series; however, unlike the
raloxifene series in which the 6-hydroxy functionality
is clearly more important for in vitro biological activity,
compounds 3b and 3c show only minor differentiation.35
The importance of the nature of the amine substitu-
ents with respect to in vitro estrogen antagonism is
demonstrated by the compounds 3f-j and is similar to
effects which have been reported in the raloxifene series,
with the piperidine base providing the optimum activ-
ity.18 Interestingly, the amine substituent has little
effect on the receptor binding observed for these com-
pounds and yet decreases MCF-7 inhibitory potency
3-50-fold relative to that observed for 3a .
Figure 2 demonstrates the surprising increase in in
vivo potency which was observed across the benzofuran
(2), benzothiophene (3a ), naphthalene (4) series. Al-
though similar to 3a and raloxifene in vitro, compound
4 (LY357489) demonstrated remarkable potency (ED50
) 0.02 mg/kg/d) for lowering serum cholesterol in the
OVX rat. Although the reasons for this increased
potency relative to 3a are unclear, other highly potent,
naphthalene-containing SERMs have been described
previously.37,39
Finally, the replacement of the benzothiophene sub-
structure of 3a with a benzofuran (2) or a naphthalene
(4) produces relatively minor effects on the in vitro
biological activity. The lower binding affinity observed
with 2 may be ascribed to the general intolerance of the
ER toward polar substitution.36 The replacement of the
benzothiophene core of raloxifene with a naphthalene
has previously been shown to provide compounds with
a similar pharmacological profile.37
Compounds 3a and 4 were further evaluated in an
OVX rat model of estrogen-deficiency-induced osteope-
nia. As shown in Figure 3, both 3a and 4 maintain the
ability of raloxifene and estrogen to prevent ovariec-
tomy-induced bone loss. In particular, LY357489, 4,
showed increased potency relative to raloxifene, with
significant effects at doses as low as 0.01 mg/kg/d.
Compounds 2, 3a , and 4 were also evaluated for
uterine estrogen antagonist activity in the immature rat
model as shown in Figure 4. In this model also,
LY357489, 4, showed improved potency (ED50 ) 0.05
mg/kg/d, raloxifene ED50 ) 0.55 mg/kg/d) and was even
able to reduce uterine weight below the level observed
for untreated controls. Compound 3a again showed
In Vivo. The in vivo data from the 4-day OVX rat
assay (Table 1, Figure 2) provide additional insights into
the effects of structural modifications on the complex
biological activities of SERMs. For example, tamoxifen
stimulates a dose dependent increase in uterine wet
weight as well as increases in other measures of uterine
stimulation such as epithelial cell height.12a Although

1276 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Grese et al.
Ta ble 1. In Vitro and in Vivo Biological Activity of Conformationally Restricted SERMs
a
b
RBA ) relative binding affinity by competition with [3H]-17â-estradiol. Average of at least two determinations. Values are (10%.
c Dose required to give 50% inhibition of a maximally effective (10-11) dose of 17â-estradiol. Average of at least three determinations.
d
Values are (10%. MED ) minimally effective dose (mg/kg body weight) at which a statistically significant (p e 0.05) increase in uterine
weight/body weight was observed. Activity at the MED is expressed as percent increase relative to OVX controls ( standard error. e MED
at which a significant (>5-fold increase relative to OVX control and value of Vmax g 10) increase in EPO activity was observed. Activity
at the MED is expressed as Vmax ( standard error. f Percent decrease in serum cholesterol relative to OVX controls ( standard error.
g
Statistically significant (p e 0.05) differences are denoted by an asterisk (*). Dose required to reduce serum cholesterol by 50% relative
to OVX controls. NA ) not active at the doses tested. 4-Hydroxytamoxifen, the primary biologically active metabolite of tamoxifen.
Not determined. Maximum dose tested ) 1.0 mg/kg. Maximum dose tested ) 3.0 mg/kg.
h
i
j
k
l
potency similar to that of raloxifene, while compound 2
was somewhat less effective.
structure-activity relationship observed in the ben-
zothiophene-containing series, 3, nicely parallels that
reported for raloxifene,18,35 although there is increased
dependence upon the degree of hydroxylation for in vivo,
as well as in vitro, potency.
Discu ssion
As part of our program to explore structure-activity
relationships in the raloxifene series, we discovered a
unique dependence upon the orientation of the basic
amine-containing side chain for the maintenance of full
estrogen antagonist activity in the uterus.16,18 Herein,
we have exploited this finding in the design of a new
series of SERMs in which the side chain is rigidly held
in an orthogonal orientation relative to a tetracyclic,
steroid-like core. Indeed, as described above, these
compounds function as full antagonists in the OVX rat
uterus without any evidence of intrinsic agonist activity
in that tissue. Nevertheless, as with raloxifene, they
maintain the ability to reduce serum cholesterol and
protect against ovariectomy-induced osteopenia. The
Surprisingly, substitution of oxygen or ethylene for
the benzothiophene sulfur revealed a marked depen-
dence of in vivo potency upon the nature of X (Scheme
1), with 4 (X ) CH2dCH2) > 3a (X ) S) > 2 (X ) O),
roughly correlated with increasing hydrophobicity of the
steroid-like nucleus. Most notably, shifting from the
benzothiophene to the naphthalene-containing nucleus
of 4 resulted in a significant boost in in vivo potency of
both agonist and antagonist activities, without a cor-
responding increase in in vitro effects. This shift may
reflect improved bioavailability for 4, although the
reasons for this improvement are unclear. Compound
4 maintains the hydroxylation pattern of 3a and ral-

Synthesis of Raloxifene Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1277
F igu r e 2. Effects of 2, 3a , and 4 on serum cholesterol levels
in OVX rats. Cholesterol values are reported as the mean
percent decrease relative to OVX control ((SEM) with n g 5
for all groups. Raloxifene- and ethynylestradiol-treated groups
are included as internal standards. Observed effects at doses
of 2 g 1.0 mg/kg/d, 3a g 0.1 mg/kg/d, 4 g 0.01 mg/kg/d and
all doses of raloxifene or ethynyl estradiol differ significantly
from OVX control at P e 0.05.
F igu r e 3. Effects of raloxifene, 3a , and 4 on bone mineral
density (BMD) in the OVX rat. BMD values are reported as
percent protection ((SEM) relative to OVX controls, with sham
control values defined as 100% and OVX controls defined as 0
and n g 6 for each group. Observed effects at doses of 3a or
raloxifene g 1.0 mg/kg/d and doses of 4 or ethynyl estradiol g
0.01 mg/kg/d differ significantly from OVX control at P e 0.05.
others, cannot be excluded. Studies with other chiral,
nonsteroidal estrogen receptor modulators have indi-
cated that although the majority of the biological effects
reside in a single enantiomer, the racemates exhibit the
same qualitative profile of activity.14,44 Further studies
elucidating the biological effects of individual enanti-
omers of 4 will be reported in due course.
In conclusion, we have prepared a series of novel
raloxifene analogues in which the side chain is con-
strained in an orientation which approximates the low-
energy conformation predicted for the parent molecule.
We have demonstrated that this series of compounds
maintain the SERM profile of biological activity which
has previously been described for raloxifene, including
ER binding, inhibition of MCF-7 cell proliferation,
estrogen antagonist effects in the immature rat uterus,
and tissue-specific estrogen agonist effects on serum
cholesterol and bone in the OVX rat.12b,34 Finally, we
have demonstrated that one of these compounds,
LY357489, 4, is among the most potent SERMs de-
scribed to date with in vivo efficacy on bone and
cholesterol metabolism in OVX rats at doses as low as
0.01 mg/kg/d.
oxifene, and glucuronidation of the phenolic moieties is
thought to be the primary factor limiting the bioavail-
ability of raloxifene.40 Nevertheless, improved bioavail-
ability has been recently claimed for another series of
hydroxylated SERMs which are built upon a tetrahy-
dronaphthalene core unit.39 Further experimentation
will be necessary to determine if pharmacokinetics are
indeed responsible for this effect.
One alternative explanation involves the mechanisms
by which the ER controls gene transcription. It has
recently been proposed that the conformation of the
ER-ligand complex is dependent upon the nature of the
interacting ligand and that the distinct conformation
induced by a particular ligand affects differentially
which genes are transcriptionally activated.41,42 To the
extent that structural modification of the ligand disrupts
or alters this receptor-ligand conformation, different
sets of estrogen responsive genes may be influenced
positively or negatively, resulting in an altered biological
profile. We have explored the effects of LY357489, 4,
on TGF-â3 promoter activity in vitro, a candidate gene
which may be involved in the bone effects of raloxifene,
and found no significant increase in potency (Figure 5).43
Nevertheless, further evaluation of the effects 4 at the
transcriptional level in other promoter systems may be
warranted.
Exp er im en ta l Section
Ch em istr y. General experimental procedures have been
recently published.35 The abbreviations THF, DMF, DCE,
DMSO, DDQ, TBAF, and DEAD refer to tetrahydrofuran,
dimethylformamide, 1,2-dichloroethane, dimethyl sulfoxide,
2,3-dichloro-5,6-dicyano-1,4-benzoquinone, tetra-n-butylam-
monium fluoride, and diethyl azodicarboxylate, respectively.
All spectra were recorded in acetone-d6 unless otherwise
indicated. Elemental analyses were carried out by the Physi-
The compounds examined within this study were
prepared in racemic form, and therefore the biological
results reported herein must be interpreted with cau-
tion. The possibility that the individual enantiomers
may exert differential biological activities, functioning
synergistically in some tissues and antagonistically in

1278 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Grese et al.
HCl (615 mL) and heated at reflux for 12 h. The mixture was
neutralized with saturated NaHCO3, diluted with ether (1 L),
washed with saturated NaHCO3 (2 × 1 L) and brine (1 L),
dried (MgSO4), and concentrated. The residue was recrystal-
lized from ether to provide 52.7 g (81%) of the title compound:
1H NMR (CDCl3) δ 7.16 (d, J ) 9.7 Hz, 1H), 6.87 (d, J ) 2.9
Hz, 1H), 6.73 (dd, J ) 9.7, 2.9 Hz, 1H), 3.88 (s, 2H), 3.79 (s,
3H).
(()-6a ,11a -Dih yd r o-3,9-d im eth oxy-6H-[1]ben zoth ien o-
[3,2-c][1]ben zop yr a n -6-on e (11a ). To a stirred solution of
10a (20 g, 111 mmol) in a mixture of EtOH (100 mL) and CH2-
Cl2 (50 mL) was added 4-methoxysalicyl aldehyde (17.5 g, 115
mmol) followed by Et3N (567 mg, 784 mL, 5.6 mmol) at room
temperature. After 30 min, a solid began to precipitate, and
stirring was continued overnight. The mixture was then
diluted with cold hexane (1 L) and filtered to yield 28.7 g (82%)
of the title product as an off-white solid, pure by 1H NMR
analysis. An analytical sample was obtained by recrystalli-
zation from toluene as light yellow crystals, mp 157-165 °C
(dec): 1H NMR (CDCl3) δ 7.33 (d, J ) 8.6 Hz, 1H), 7.31 (d, J
) 8.1 Hz, 1H), 6.75 (d, J ) 2.4 Hz, 1H), 6.70 (m, 2H), 6.60 (d,
J ) 2.5 Hz, 1H), 5.22 (d, J ) 7.2 Hz, 1H), 4.33 (d, J ) 7.2 Hz,
1H), 3.79 (s, 3H), 3.76 (s, 3H); IR (CHCl3) 1759 cm-1; MS (FD)
m/e 314 (M+). Anal. (C17H14O4S) C, H.
(()-6a ,11a -Dih yd r o-9-m eth oxy-6H-[1]ben zoth ien o[3,2-
c][1]ben zop yr a n -6-on e (11c). The title compound was
prepared in 83% yield from 10a and salicyl aldehyde by a
method similar to that described for 11a : 1H NMR (CDCl3) δ
7.45 (d, J ) 7.5 Hz, 1H), 7.33 (m, 2H), 7.17 (m, 1H), 7.07 (d, J
) 8.1 Hz, 1H), 6.77 (d, J ) 2.4 Hz, 1H), 6.69 (dd, J ) 2.4, 8.5
Hz, 1H), 5.25 (d, J ) 7.4 Hz, 1H), 4.37 (d, J ) 7.3 Hz, 1H),
3.77 (s, 3H); 13C NMR (CDCl3) δ 166.4, 160.7, 150.8, 141.4,
130.1, 129.0, 127.7, 127.0, 124.9, 119.5, 117.2, 111.2, 108.3,
55.5, 50.6, 49.6; IR (CHCl3) 1766 cm-1; MS (FD) m/e 284 (M+).
Anal. (C16H12O3S) C, H.
3,9-Bis[(ter t-bu tyldim eth ylsilyl)oxy]-6H-[1]ben zoth ien o-
[3,2-c][1]ben zop yr a n -6-on e (6a ). A mixture of 11a (4.5 g,
14.3 mmol) and DDQ (3.4 g, 15 mmol) in DCE (100 mL) was
heated briefly to 80 °C, inducing the formation of a precipitate.
The mixture was filtered hot; the precipitate was rinsed with
CH2Cl2 and the mother liquor concentrated in vacuo. The
remnant was dissolved in hot CH2Cl2, filtered to remove
residual hydroquinone, and reconcentrated. The product was
recrystallized from toluene to provide 3.94 g (88%) of 9-meth-
oxy-6H-[1]benzothieno[3,2-c][1]benzopyran-6-one as white
needles, mp 220-221 °C: 1H NMR (acetone-d6/DMSO-d6) δ
8.41 (d, J ) 8.9 Hz, 1H), 7.82 (d, J ) 8.7 Hz, 1H), 7.74 (d, J )
2.3 Hz, 1H), 7.20 (dd, J ) 8.9, 2.4 Hz, 1H), 7.09 (d, J ) 2.4 Hz,
1H), 7.03 (dd, J ) 8.6, 2.4 Hz, 1H), 3.94 (s, 3H), 3.91 (s, 3H);
IR (KBr) 1717 cm-1; MS (FD+) m/e 312 (M+).
F igu r e 4. Effect of raloxifene, 2, 3a , and 4 on ethynylestradiol
(EE)-induced uterine weight increase in immature rats. Data
are reported as percent inhibition of uterine weight/body
weight ((SEM) relative to EE-treated controls, with vehicle
control values defined as 100% and EE-treated controls as 0
and n g 6 for each group. Observed effects at doses of 2 g 1.0
mg/kg/d and doses of 3a , 4, and raloxifene g 0.1 mg/kg/d differ
significantly from EE-treated controls at P e 0.05.
To a mechanically stirred slurry of the product prepared
above (12 g, 38.4 mmol) in CH2Cl2 (220 mL) was added
ethanethiol (11.9 g, 13.4 mL, 192 mmol) followed by aluminum
chloride (38.4 g, 288 mmol), portionwise. The reaction mixture
was stirred at ambient temperature for 5 h, cooled to 0 °C,
and quenched cautiously with THF (250 mL) followed by
saturated NaHC3 (250 mL). The mixture was diluted with
THF (1 L), the layers were separated, and the aqueous layer
was washed with THF (200 mL). The combined organic layers
were dried (Na2SO4) and concentrated to yield 11.1 g of crude
diphenol as a yellow solid, which was used without further
purification.
The crude product was slurried in CH2Cl2 (220 mL) and
treated with Et3N (20.2 g, 28 mL, 200 mmol) and tert-
butyldimethylsilyl chloride (20.3 g, 134.4 mmol). The mixture
was stirred at ambient temperature for 5 h, during which it
slowly became homogeneous. After dilution with hexane (600
mL), the mixture was washed with brine (600 mL) and the
aqueous layer was extracted with hexane (300 mL). The
combined organic layers were dried (Na2SO4) and concen-
trated, and the residue was recrystallized from hexane to
provide 18.0 g (91%) of the title compound as a fluffy white
solid, mp 142-144 °C: 1H NMR (CDCl3) δ 8.50 (d, J ) 8.7
Hz, 1H), 7.58 (d, J ) 8.5 Hz, 1H), 7.32 (d, J ) 2.1 Hz, 1H),
F igu r e 5. Effects of raloxifene, 1, and LY357489, 4, on TGF-
â3 promoter activity. Data are reported as the mean fold-
induction ((SEM) versus matched controls with n ) 3 for all
groups.
cal Chemistry Department of Lilly Research Laboratories and
are within (0.4% of theory unless otherwise noted.
6-Meth oxyth ia n a p h th en -2-on e (10a ).25 A solution of 824
(75.1 g, 360 mmol) in THF (600 mL) was treated with 1 N

Synthesis of Raloxifene Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1279
7.05 (dd, J ) 8.7, 2.1 Hz, 1H), 6.92 (d, J ) 2.2 Hz, 1H), 6.84
(dd, J ) 8.4, 2.2 Hz, 1H), 1.01 (s, 9H), 1.00 (s, 9H), 0.27 (s,
6H), 0.25 (s, 6H); 13C NMR (DMSO-d6) δ 158.4, 157.0, 154.6,
152.7, 149.6, 138.5, 130.5, 125.2, 124.6, 120.0, 117.6, 116.3,
112.7, 111.3, 108.0, 25.6, 25.6, 18.2, 18.2, -4.4, -4.4; IR
(CHCl3) 1717 cm-1; MS (FD) m/e 512 (M+). Anal. (C27H36O4-
SSi2) C, H.
(()-3,9-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-6-p h en oxy-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (20a ). To a solu-
tion of 15a (4.52 g, 8.78 mmol) and phenol (4.13 g, 43.9 mmol)
in CH2Cl2 (100 mL) was added anhydrous MgSO4 (4.5 g), and
the resultant slurry was stirred for 4 h at ambient tempera-
ture. The mixture was filtered and concentrated and the
residue dissolved in chlorobenzene and reconcentrated in vacuo
at approximately 70 °C. The residue was then dissolved in
CH2Cl2 (300 mL), washed with saturated Na2CO3 (3 × 300 mL)
and water (2 × 300 mL), dried (Na2SO4), and concentrated to
yield 5.16 g (99%) of the title compound as an amorphous solid
which was used without further purification: 1H NMR δ 7.67
(d, J ) 8.7 Hz, 1H), 7.50 (d, J ) 2.1 Hz, 1H), 7.4-7.5 (m, 4H),
7.23 (d, J ) 8.4 Hz, 1H), 7.08 (t, J ) 7.2 Hz, 1H), 6.99 (dd, J
) 8.7, 2.1 Hz, 1H), 6.67 (dd, J ) 8.4, 2.3 Hz, 1H), 6.62 (d, J )
2.3 Hz, 1H), 0.99 (s, 9H), 0.96 (s, 9H), 0.24 (s, 6H), 0.21 (s,
6H); 13C NMR δ 156.9, 153.3, 151.7, 139.9, 131.9, 124.5, 123.9,
121.7, 118.8, 113.7, 113.1, 112.7, 108.7, 90.7, 25.1, 25.1, 17.9,
-5.2, -5.2; MS (FD+) m/e 590 (M+). Anal. (C33H42O4SSi2) C,
H.
(()-3-[(ter t-Bu tyld im eth ylsilyl)oxy]-6-p h en oxy-6H-[1]-
ben zoth ien o[3,2-c][1]ben zop yr a n (20b). A solution of 15b
(1.59 g, 4.1 mmol) and phenol (5.29 g, 56 mmol) in chloroben-
zene (50 mL) was heated at reflux for 2.5 h. The mixture was
concentrated in vacuo at approximately 70 °C, dissolved in
additional chlorobenzene (50 mL), and reconcentrated to yield
1.9 g (100%) of the title compound as a pink solid which was
used without further purification: 1H NMR δ 8.05 (d, J ) 8.7
Hz, 1H), 7.85 (d, J ) 8.7 Hz, 1H), 7.3-7.6 (m, 8H), 7.14 (t, J
) 8.2 Hz, 1H), 6.75 (dd, J ) 8.7, 2.1 Hz, 1H), 6.69 (d, J ) 2.1
Hz, 1H), 1.00 (s, 9H), 0.26 (s, 6H).
3-[(ter t-Bu t yld im et h ylsilyl)oxy]-6H -[1]b en zot h ien o-
[3,2-c][1]ben zop yr a n -6-on e (6b). The title compound was
prepared from 6a,11a-dihydro-3-methoxy-6H-[1]benzothieno-
[3,2-c][1]benzopyran-6-one (11b)23 in three steps and 61%
overall yield by a method similar to that described for 6a : 1H
NMR δ 8.57 (d, J ) 7.8 Hz, 1H), 8.10 (d, J ) 8.0 Hz, 1H), 7.81
(d, J ) 8.2 Hz, 1H), 7.5-7.7 (m, 2H), 6.99 (m, 2H), 1.03 (s,
9H), 0.33 (s, 6H); IR (CHCl3) 1716 cm-1; MS (FD) m/e 382 (M+).
Anal. (C21H22O3SSi) C, H.
9-[(ter t-Bu t yld im et h ylsilyl)oxy]-6H -[1]b en zot h ien o-
[3,2-c][1]ben zop yr a n -6-on e (6c). The title compound was
prepared from 11c in three steps and 73% overall yield by a
method similar to that described for 6a : 1H NMR (CDCl3) δ
8.55 (d, J ) 8.5 Hz, 1H), 7.72 (d, J ) 8.7 Hz, 1H), 7.4-7.6 (m,
2H), 7.34 (m, 2H), 7.08 (dd, J ) 2.2, 8.8 Hz, 1H), 1.02 (s, 9H),
0.26 (s, 6H); IR (CHCl3) 1717 cm-1; MS (FD) m/e 382 (M+).
Anal. (C21H22O3SSi) C, H.
(()-3,9-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-6H -[1]b en -
zoth ien o[3,2-c][1]ben zop yr a n -6-ol (15a ). A solution of 6a
(2.0 g, 3.9 mmol) in toluene (200 mL) was cooled to -92 °C
and treated dropwise with a 1.0 M toluene solution of diisobu-
tylaluminum hydride (4.7 mL, 4.7 mmol) at a rate that
maintained the internal temperature below -89 °C. The
mixture was stirred for approximately 3 h as the temperature
gradually rose to -77 °C and then was quenched with MeOH
(5 mL) and 10% aqueous citric acid (50 mL). After dilution
with CH2Cl2 (200 mL), the mixture was washed with saturated
potassium sodium tartrate (100 mL), and the aqueous layer
was extracted with CH2Cl2 (2 × 200 mL). The combined
organic layers were washed with brine (300 mL), and the brine
wash was further extracted with CH2Cl2 (100 mL). The
organic layers were dried (Na2SO4) and concentrated, and the
remnant was chromatographed (silica gel, 1-15% EtOAc/
hexane) to yield 360 mg (18%) of starting material, 1.21 g (60%,
74% based on recovered starting material), of the titled
compound as a white crystalline solid (analytical sample
recrystallized from hexane/EtOAc, mp 162-164 °C) [1H NMR
δ 7.70 (d, J ) 9.0 Hz, 1H), 7.46 (d, J ) 2.1 Hz, 1H), 7.29 (d, J
) 8.1 Hz, 1H), 7.00 (dd, J ) 8.5, 1.8 Hz, 1H), 6.85 (br s, 1H),
6.6 (m, 2H), 6.39 (br s, 1H), 1.01 (s, 9H), 1.00 (s, 9H), 0.25 (s,
6H), 0.25 (s, 6H); 13C NMR δ 156.9, 153.3, 151.7, 139.9, 131.9,
124.5, 123.9, 121.7, 118.8, 113.7, 113.1, 112.7, 108.7, 90.7, 25.1,
25.1, 17.9, -5.2, -5.2; IR (CHCl3) 3540 cm-1; MS (FD+) m/e
514 (M+). Anal. (C27H38O4SSi2) C, H] and 260 mg (13%, 16%
based on recovered starting material) of diol 18 as an amor-
phous solid: 1H NMR (CDCl3) δ 7.73 (d, J ) 8.7 Hz, 1H), 7.29
(d, J ) 2.0 Hz, 1H), 7.16 (d, J ) 8.2 Hz, 1H), 6.98 (dd, J ) 8.7,
2.0 Hz, 1H), 6.5 (m, 3H), 6.30 (br s, 1H), 4.71 (s, 2H), 1.01 (s,
9H), 1.00 (s, 9H), 0.22 (s, 6H), 0.19 (s, 6H); IR (CHCl3) 3600,
3510 cm-1; MS (FD+) m/e 516 (M+).
(()-9-(ter t-Bu t yld im et h ylsilyl)oxy-6-p h en oxy-6H -[1]-
ben zoth ien o[3,2-c][1]ben zop yr a n (20c). The title com-
pound was prepared in 93% yield from 15c by a method similar
to that described for 20b: 1H NMR δ 7.76 (d, J ) 8.7 Hz, 1H),
7.60 (d, J ) 2.1 Hz, 1H), 7.56 (d, J ) 8.7 Hz, 1H), 7.1-7.5 (m,
10H), 1.04 (s, 9H), 0.30 (s, 6H).
(()-3,9-Dih ydr oxy-6-[4-[2-(1-piper idin yl)eth oxy]ph en yl]-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3a ). To a solution
of 20a (4.0 g, 6.7 mmol) in toluene (100 mL) at 0 °C was added
a 0.5 M THF solution of [4-[2-(1-piperidinyl)ethoxy]phenyl]-
magnesium bromide (prepared from the corresponding bro-
mobenzene and magnesium turnings, catalyzed by iodine in
THF, 27 mL, 13.5 mmol). The mixture was allowed to warm
to room temperature and stirred for 1.5 h. After being
quenched with water (300 mL), the mixture was extracted with
EtOAc (2 × 300 mL), and the organic layer was dried (Na2-
SO4) and concentrated. The residue was purified via chroma-
tography (silica gel, 3:1 hexane:EtOAc, 0.1% NH4OH) to give
3.85 g (82%) of the title compound as a colorless, gummy
solid: 1H NMR δ 7.45 (s, 1H), 7.2-7.3 (m, 4H), 6.8-6.9 (m,
3H), 6.68 (s, 1H), 6.51 (d, J ) 8.1 Hz, 1 H), 6.36 (s, 1H), 4.01
(t, J ) 6.0 Hz, 2H), 2.62 (t, J ) 6.0 Hz, 2H), 2.41 (m, 4H),
1.4-1.6 (m, 4H), 1.3-1.4 (m, 2H), 0.99 (s, 9H), 0.96 (s, 9H),
0.22 (s, 6H), 0.20 (s, 6H); MS (FD) m/e 702 (M+).
To a solution of the product of the above reaction (3.85 g,
5.5 mmol) in THF (150 mL) was added a 1.0 M THF solution
of TBAF (27.4 mL, 27.4 mmol). The solution was stirred at
ambient temperature for 2 h, diluted with EtOAc (300 mL),
and washed with saturated NH4Cl (300 mL). The aqueous
layer was washed with EtOAc (150 mL), and the combined
organic layers were washed with saturated NaHCO3 (300 mL),
dried (Na2SO4), and concentrated. The remnant was purified
by chromatography (silica gel, 1:1 hexane:EtOAc, 10% MeOH,
0.1% NH4OH) to give 2.35 g (90%) of the titled product as a
red foam. Crystallization from MeOH gave an off-white
powder, mp 242-245 °C (dec): 1H NMR δ 8.58 (br s, 2H), 7.35
(d, J ) 2.1 Hz, 1H), 7.26 (d, J ) 8.6 Hz, 2H), 7.17 (d, J ) 8.2
Hz, 1H), 7.16 (d, J ) 8.6 Hz, 1H), 6.84 (d, J ) 8.5 Hz, 2H),
6.80 (m, J ) 2.2 Hz, 1H), 6.63 (s, 1H), 6.46 (dd, J ) 8.2, 2.2
Hz, 1H), 6.35 (d, J ) 2.3 Hz, 1H), 4.02 (t, J ) 6.0 Hz, 2H),
2.63 (t, J ) 6.0 Hz, 2H), 2.42 (m, 4H), 1.4-1.6 (m, 4H), 1.3-
1.4 (m, 2H); 13C NMR (DMF-d7) δ 160.2, 159.9, 156.4, 153.2,
140.8, 132.8, 130.9, 129.6, 125.3, 124.6, 122.5, 115.2, 115.1,
(()-3-[(ter t-Bu tyldim eth ylsilyl)oxy]-6H-[1]ben zoth ien o-
[3,2-c][1]ben zop yr a n -6-ol (15b). The title compound was
prepared in 45% yield from 6b by a method similar to that
described for 15a : 1H NMR δ 7.96 (d, J ) 7.7 Hz, 1H), 7.83
(d, J ) 6.7 Hz, 1H), 7.3-7.8 (m, 3H), 6.91 (m, 1H), 6.62 (m,
2H), 1.00 (s, 9H), 0.26 (s, 6H); IR (CHCl3) 2958, 2932, 2861,
1616, 1594 cm-1; MS (FD) m/e 384 (M+). Anal. (C21H24O3-
SSi) C, H.
(()-9-[(ter t-Bu tyldim eth ylsilyl)oxy]-6H-[1]ben zoth ien o-
[3,2-c][1]ben zop yr a n -6-ol (15c). The title compound was
prepared in 49% yield from 6c by a method similar to that
described for 15a : 1H NMR δ 7.77 (d, J ) 8.6 Hz, 1H), 7.50
(d, J ) 2.1 Hz, 1H), 7.42 (m, 1H), 7.28 (m, 1H), 7.05 (m, 2H),
6.89 (m, 1H), 6.46 (m, 1H), 1.02 (s, 9H), 0.26 (s, 6H); IR (CHCl3)
2959, 2932, 2861, 1612, 1598 cm-1; MS (FD) m/e 384 (M+).
Anal. (C21H24O3SSi) C, H.

1280 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Grese et al.
112.2, 109.6, 108.8, 108.7, 104.5, 77.6, 66.6, 58.3, 55.3, 26.5,
24.8; HRMS (FAB+) m/e calcd for C28H28NO4S 474.1739
(MH+), found 474.1726. Anal. (C28H27NO4S‚0.8H2O) C, H, N.
gas evolution ceased, N2 was bubbled through for 10 min to
remove excess diazomethane, and the mixture was concen-
trated. Radial chromatography of the residue (1:1 hexane:
EtOAc, 2% MeOH, under an NH3 atmosphere) provided 118
mg (37%) of the title compound as white crystals, mp 134-36
°C: 1H NMR δ 7.51 (d, J ) 2.2 Hz, 1H), 7.2-7.4 (m, J ) 8.6
Hz, 4H), 6.86 (m, 3H), 6.70 (s, 1H), 6.55 (dd, J ) 8.4, 2.3 Hz,
1H), 6.41 (d, J ) 2.4 Hz, 1H), 4.01 (t, J ) 6.0 Hz, 2H), 3.83 (s,
3H), 3.74 (s, 3H), 2.62 (t, J ) 6.0 Hz, 2H), 2.40 (m, 4H), 1.4-
1.6 (m, 4H), 1.3-1.4 (m, 2H); 13C NMR (CDCl3) δ 160.8, 159.2,
157.1, 152.6, 140.3, 131.6, 131.3, 130.5, 129.1, 124.3, 124.0,
121.7, 114.6, 114.0, 112.8, 107.6, 105.7, 102.3, 77.9, 65.8, 57.8,
55.5, 55.2, 54.9, 25.9, 24.1; MS (FD+) m/e 501 (M+). Anal.
(C30H31NO4S) C, H, N.
(()-3-H yd r oxy-6-[4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3b). The title
compound was prepared in two steps and 82% overall yield
from 20b by a method similar to that described for 3a . The
product was slurried in MeOH, trifluoroacetic acid was added
dropwise until all the material went into solution, the insoluble
material was filtered away, and the mother liquor was
concentrated in vacuo to yield 0.28 g (80%) of the TFA salt as
a fluffy orange solid: 1H NMR δ 7.95 (m, 1H), 7.38 (m, 1H),
7.2-7.3 (m, 5H), 6.90 (d, J ) 8.6 Hz, 2H), 6.76 (s, 1H), 6.51
(dd, J ) 2.2, 8.2 Hz, 1H), 6.38 (d, J ) 2.3 Hz, 1H), 4.44 (t, J )
4.9 Hz, 2H), 3.5-3.7 (m, 4H), 3.0-3.2 (m, 2H), 1.7-2.0 (m,
5H), 1.4-1.7 (m, 1H); IR (CHCl3) 3271, 3022, 3009, 1670, 1610
cm-1; HRMS (FAB) m/e calcd for C28H28NO3S (MH+) 458.1790,
found 458.1781. Anal. (C28H2NO3S‚CF3COOH‚1.2H2O) C, H,
N.
(()-9-H yd r oxy-6-[4-[2-(1-p ip er id in yl)et h oxy]p h en yl]-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3c). The title
compound was prepared in two steps and 56% overall yield
from 20c by a method similar to that described for 3a : 1H
NMR δ 6.7-7.4 (m, 12H), 4.02 (t, J ) 6.0 Hz, 2H), 2.63 (t, J )
6.0 Hz, 2H), 2.41 (m, 4H), 1.49 (m, 4H), 1.37 (m, 2H); IR (KBr)
2934, 1609 cm-1; HRMS (FAB) m/e calcd for C28H28NO3S
(MH+) 458.1790, found 458.1798. Anal. (C28H27NO3S‚0.5H2O)
C, H, N.
(()-6-[4-[2-(1-P ip er id in yl)et h oxy]p h en yl]-6H -[1]b en -
zoth ien o[3,2-c][1]ben zop yr a n (3d ). To a solution of the 3a
(500 mg, 1.06 mmol) in THF (25 mL) containing DMF (2 mL)
at room temperature was added Et3N (0.64 g, 0.69 mL, 6.36
mmol) followed by N-phenyltrifluoromethanesulfonimide (0.83
g, 2.33 mmol). The reaction mixture was stirred for 12 h and
warmed to 60 °C, and additional N-phenyltrifluoromethane-
sulfonimide (0.30 g, 0.85 mmol) was added. After 30 min, the
reaction mixture was cooled to ambient temperature and
concentrated, and the residue was purified by radial chroma-
tography (silica gel, 1:1 hexane:EtOAc, 1% MeOH under an
NH3 atmosphere) to afford 780 mg (100%) of the bistriflate as
a white foam: 1H NMR (MeOH-d4) δ 7.63 (d, J ) 8.8 Hz, 1H),
7.56 (d, J ) 2.5 Hz, 1H), 7.13 (dd, J ) 8.8, 2.7 Hz, 1H), 7.03
(d, J ) 8.8 Hz, 2H), 6.80 (d, J ) 8.9 Hz, 2H), 6.49 (d, J ) 2.5
Hz, 1H), 6.39 (d, J ) 8.7 Hz, 1H), 6.05 (dd, J ) 8.7, 2.6 Hz,
1H), 4.00 (t, J ) 5.5 Hz, 2H), 2.67 (m, 2H), 2.45 (m, 4H), 1.4-
1.6 (m, 4H), 1.3-1.4 (m, 2H); MS (FD) m/e 737 (M+).
A solution of the product of the above reaction (780 mg, 1.06
mmol), Pd(OAc)2 (42 mg, 0.19 mmol), 1,2-bis(diphenylphos-
phino)propane (149 mg, 0.36 mmol), formic acid (0.6 mL), and
Et3N (3.0 mL) in anhydrous DMF (40 mL) was stirred at
ambient temperature for 4 d. After concentration, the residue
was subjected chromatography (silica gel, 1:1 hexane:EtOAc,
2-10% MeOH, 0.1% NH4OH). Product-containing fractions
were concentrated and partitioned between CH2Cl2 (100 mL)
and saturated NaHCO3 (100 mL), and the aqueous layer was
extracted with CH2Cl2 (50 mL). The combined organic extracts
were dried (Na2SO4) and concentrated, and the residue was
purified by chromatography (silica gel, 1:1 hexane:EtOAc,
2-10% MeOH, 0.1% NH4OH) to give 267 mg (57%) of the title
compound as an oil which gave a white, crystalline solid, mp
107 °C, upon trituration with ether/hexane: 1H NMR (CDCl3)
δ 7.86 (d, J ) 7.4 Hz, 1H), 7.40 (m, 1H), 7.1-7.3 (m, 6H), 6.97
(t, J ) 7.3 Hz, 1H), 6.89 (d, J ) 8.1 Hz, 1H), 6.84 (d, J ) 8.6
Hz, 2H), 6.66 (s, 1H), 4.07 (t, J ) 6.1 Hz, 2H), 2.75 (t, J ) 6.1
Hz, 2H), 2.49 (m, 4H), 1.5-1.7 (m, 4H), 1.4-1.5 (m, 2H); 13C
NMR (CDCl3) δ 159.1, 151.6, 139.3, 137.1, 133.0, 131.5, 129.8,
129.1, 126.8, 124.6, 124.4, 123.7, 122.6, 121.5, 121.5, 119.3,
116.9, 114.6, 77.6, 65.7, 57.7, 54.9, 25.8, 24.0; MS (FD+) m/e
441 (M+). Anal. (C28H27NO2S) C, H, N.
(()-3,9-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-6-[4-h yd r ox-
yp h en yl]-6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (23). To
a solution of 20a (3.0 g, 5.08 mmol) in toluene (150 mL) at 0
°C was added a 0.4 M THF solution of [4-(trimethylsilyloxy)-
phenyl]magnesium bromide (prepared from the corresponding
bromobenzene and magnesium turnings, catalyzed by iodine,
in THF, 25.4 mL, 10.16 mmol).27 The mixture was allowed to
warm to room temperature and stirred for 1.5 h. After dilution
with ether (250 mL), the mixture was quenched with saturated
NH4Cl (250 mL), and the organic layer was dried (Na2SO4)
and concentrated. The residue was slurried in MeOH (100
mL), and ether was added until the mixture was homogeneous.
The solution was cooled to 0 °C and treated with anhydrous
K2CO3 (3 g) for 15 min. After dilution with ether (250 mL),
the mixture was filtered through Celite and washed with
saturated NH4Cl, and the aqueous layer was extracted with
additional ether (100 mL). The combined organic layers were
dried (Na2SO4) and concentrated, and the residue was purified
by chromatography (silica gel, 10:1 hexane:EtOAc). Recrys-
tallization from hexane provided 2.6 g (87%) of the title
compound as a light pink solid, mp 174-175 °C: 1H NMR δ
8.49 (s, 1H), 7.44 (d, J ) 2.2 Hz, 1H), 7.3-7.4 (m, 4H), 6.83
(dd, J ) 8.7, 2.2 Hz, 1H), 6.76 (d, J ) 8.5 Hz, 2H), 6.65 (s,
1H), 6.50 (dd, J ) 8.2, 2.3 Hz, 1H), 6.36 (d, J ) 2.3 Hz, 1H),
0.98 (s, 9H), 0.95 (s, 9H), 0.21 (s, 6H), 0.20 (s, 6H); 13C NMR
δ 158.7, 157.8, 153.9, 153.5, 140.9, 132.7, 131.6, 131.1, 129.9,
126.1, 124.7, 122.7, 119.3, 116.1, 114.4, 114.0, 113.9, 109.3,
78.3, 26.0, 25.9, 18.7, -4.3; IR (CHCl3) 3590, 3310 cm-1; MS
(FD+) m/e 590 (M+). Anal. (C33H42O4SSi2) C, H.
(()-3,9-D ih y d r o x y -6-[4-(2-d im e t h y la m in o e t h o x y )-
p h en yl]-6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3f).
A
toluene (30 mL) solution of 23 (450 mg, 0.76 mmol), triphen-
ylphosphine (799 mg, 3.1 mmol), and N,N-dimethylethanol-
amine (340 mg, 383 mL, 3.81 mmol) was treated with DEAD
(531 mg, 480 µL, 3.1 mmol) at ambient temperature, and the
mixture was stirred for 2 h. The mixture was then diluted
with ether (100 mL) and washed with saturated NH4Cl (100
mL), and the aqueous layer was washed with additional ether
(50 mL). The combined organic layers were dried (Na2SO4)
and concentrated. Chromatography (silica gel, 1:1 hexane:
EtOAc, 3% MeOH, 0.1% NH4OH) provided 357 mg (71%) of a
white foam: 1H NMR δ 7.45 (d, J ) 2.1 Hz, 1H), 7.27 (d, J )
8.6 Hz, 2H), 7.24 (m, 2H), 6.83 (m, 3H), 6.67 (s, 1H), 6.50 (dd,
J ) 8.2, 2.2 Hz, 1H), 6.36 (d, 2.2 Hz, 1H), 4.00 (t, J ) 5.9 Hz,
2H), 2.60 (t, J ) 5.9 Hz, 2H), 2.20 (s, 6H), 0.98 (s, 9H), 0.95 (s,
9H), 0.21 (s, 6H), 0.20 (s, 6H); MS (FD+) m/e 661.5 (M+).
A solution of the above product (328 mg, 0.50 mmol) in THF
(10 mL) was treated with 1.0 M TBAF in THF (2.5 mmol) for
2 h, diluted with saturated NH4Cl (100 mL), and extracted
with EtOAc (100 mL). The aqueous layer was washed with
EtOAc (50 mL), and the combined organic layers were washed
with saturated NaHCO3 (2 × 100 mL), dried (Na2SO4), and
concentrated. Radial chromatography (silica gel, 1:1 hexane:
EtOAc, 30% MeOH, under an NH3 atmosphere) provided 212
mg (99%) of the title compound, which crystallized from CCl4/
acetone as a pink solid, mp 130-140 °C (dec): 1H NMR δ 7.34
(d, J ) 2.1 Hz, 1H), 7.25 (d, J ) 8.6 Hz, 2H), 7.15 (m, 2H),
6.9-7.0 (m, 3H), 6.62 (s, 1H), 6.45 (dd, J ) 8.3, 2.3 Hz, 1H),
6.34 (d, J ) 2.2 Hz, 1H), 4.01 (t, J ) 5.8 Hz, 2H), 2.64 (t, J )
5.8 Hz, 2H), 2.30 (s, 6H); 13C NMR δ 160.0, 159.8, 156.0, 153.5,
(()-3,9-Dim eth oxy-6-[4-[2-(1-piper idin yl)eth oxy]ph en yl]-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3e). A solution
of 3a (300 mg, 0.633 mmol) in MeOH (75 mL) was treated with
a solution of diazomethane in ether/EtOH (approximately 16
mmol) at ambient temperature. The mixture was stirred until

Synthesis of Raloxifene Analogues
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8 1281
141.1, 133.0, 131.4, 130.2, 129.8, 125.3, 124.8, 122.6, 115.3,
115.2, 112.7, 109.7, 109.0, 104.8, 78.0, 66.6, 58.6, 45.8; IR (KBr)
3300 cm-1; HRMS (FAB+) m/e calcd for C25H24NO4S 434.1426
(MH+), found 434.1440. Anal. (C25H23NO4S‚H2O) C, H, N.
trated, and the residue was recrystallized from hexane to
provide 14.2 g (77%) of the title compound as a white powder,
mp 118-119 °C: 1H NMR (CDCl3) δ 7.90 (d, J ) 8.5 Hz, 1H),
7.82 (d, J ) 8.5 Hz, 1H), 7.10 (d, J ) 2.0 Hz, 1H), 6.97 (m,
2H), 6.90 (dd, J ) 8.5, 2.0 Hz, 1H), 1.03 (s, 9H), 1.02 (s, 9H),
0.28 (s, 6H), 0.25 (s, 6H); IR (CHCl3) 1733 cm-1; MS (FD+)
m/e 496 (M+). Anal. (C27H36O5Si2) C, H.
(()-3,9-Bis[(ter t-bu tyldim eth ylsilyl)oxy]-6H-ben zofu r o-
[3,2-c][1]ben zop yr a n -6-ol (14). The title compound was
prepared from 5 in 37% yield as a mixture with its aldehyde
tautomer (17) by a method similar to that described for 15a :
1H NMR δ 10.15 (s, 0.5H), 9.2 (br s, 0.5H), 7.99 (d, J ) 8.4 Hz,
1H), 7.56 (d, J ) 8.4 Hz, 1H), 7.50 (m, 0.5H), 7.09 (d, J ) 2.0
Hz, 1H), 6.96 (m, 1H), 6.6-6.7 (m, 2H), 6.55 (m, 0.5H), 1.01
(s, 9H), 1.00 (s, 9H), 0.27 (s, 6H), 0.25 (s, 6H); IR (CHCl3) 3550,
1663 cm-1; MS (FD) m/e 499 (MH+). Anal. (C27H38O5Si2) C,
H.
(()-3,9-Dih ydr oxy-6-[4-[2-(dieth ylam in o)eth oxy]ph en yl]-
6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3g). The title
compound was prepared in two steps and 66% overall yield
from 23 and N,N-diethylethanolamine by a method similar to
that described for 3f as a red solid, mp 118-123 °C (dec)
(acetone/ether): 1H NMR δ 7.35 (d, J ) 2.1 Hz, 1H), 7.26 (d,
J ) 8.6 Hz, 2H), 7.16 (d, J ) 8.1 Hz, 1H), 7.13 (d, J ) 8.5 Hz,
1H), 6.81 (m, 3H), 6.62 (s, 1H), 6.45 (dd, J ) 8.3, 2.3 Hz, 1H),
6.35 (d, J ) 2.2 Hz, 1H), 3.98 (t, J ) 6.2 Hz, 2H), 2.78 (t, J )
6.2 Hz, 2H), 2.56 (q, J ) 7.1 Hz, 4H), 0.97 (t, J ) 7.1 Hz, 6H);
13C NMR δ 160.2, 159.7, 155.9, 153.5, 141.1, 132.9, 131.5,
130.2, 129.9, 125.4, 124.8, 122.7, 115.2, 112.8, 109.6, 108.9,
104.8, 78.1, 67.5, 52.6, 48.3, 12.4; IR (KBr) 3311 cm-1; MS
(FD+) m/e 462 (MH+). Anal. (C27H27NO4S) C, H, N.
(()-3,9-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-6-p h en oxy-
6H-ben zofu r o[3,2-c][1]ben zop yr a n (19). The title com-
pound was prepared in 87% yield from 14 by a method similar
to that described for 20a : 1H NMR δ 7.1-7.7 (m, 8H) 6.6-6.9
(m, 3H), 1.01 (s, 9H), 1.00 (s, 9H), 0.28 (s, 6H), 0.25 (s, 6H).
(()-3,9-Dih yd r oxy-6-[4-[2-(1-p yr r olid in yl)e t h oxy]-
p h en yl]-6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3h ). The
title compound was prepared in two steps and 70% overall
yield from 23 and 1-(2-hydroxyethyl)pyrrolidine by a method
similar to that described for 3f as a white solid, mp 237-240
°C (dec) (hexane/EtOAc): 1H NMR (DMF-d7) δ 10.05 (br, 2H),
7.45 (d, J ) 2.0 Hz, 1H), 7.30 (d, J ) 8.4 Hz, 2H), 7.23 (d, J )
8.6 Hz, 1H), 7.19 (d, J ) 8.2 Hz, 1H), 6.91 (d, J ) 8.7 Hz, 2H),
6.86 (dd, J ) 8.9, 2.2 Hz, 1H), 6.74 (s, 1H), 6.51 (dd, J ) 8.2,
2.1 Hz, 1H), 6.40 (d, J ) 2.1 Hz, 1H), 4.14 (t, J ) 5.6 Hz, 2H),
(()-3,9-Dih ydr oxy-6-[4-[2-(1-piper idin yl)eth oxy]ph en yl]-
6H-ben zofu r o[3,2-c][1]ben zop yr a n (2). The title compound
was prepared in two steps and 65% overall yield from 19 by a
method similar to that described for 3a as a bright red foam,
which crystallized from CCl4: 1H NMR (DMF-d7) δ 10.00 (br
s, 1H), 9.83 (br s, 1H), 7.3-7.5 (m, 3H), 7.10 (s, 1H), 6.98 (d,
J ) 8.5 Hz, 2H), 6.7-6.9 (m, 3H), 6.54 (dd, J ) 8.1, 1.8 Hz,
1H), 6.42 (s, 1H), 4.10 (t, J ) 5.8 Hz, 2H), 2.67 (m, 2H), 2.44
(m, 4H), 1.4-1.6 (m, 4H), 1.3-1.4 (m, 2H); 13C NMR (DMF-
d7) δ 160.2, 159.9, 156.8, 156.4, 155.1, 147.2, 133.0, 129.5,
121.4, 119.5, 118.9, 115.1, 112.9, 109.2, 108.9, 108.3, 104.3,
2.96 (t, J ) 5.5 Hz, 2H), 2.6-2.8 (m, 4H), 1.6-1.8 (m, 4H); 13
C
NMR (DMF-d7) δ 160.2, 159.6, 156.4, 153.2, 140.8, 133.0, 130.8,
129.6, 125.2, 124.6, 122.4, 115.3, 115.1, 112.2, 109.7, 108.8,
104.5, 77.6, 66.8, 54.8, 54.7, 23.8; IR (KBr) 3286 cm-1; HRMS
(FAB+) m/e calcd for C27H26NO4S 460.1583 (MH+), found
460.1572. Anal. (C27H25NO4S‚0.5H2O) C, H, N.
98.7, 78.5, 66.5, 58.2, 55.3, 26.4, 24.6; IR (KBr) 3220 cm-1
;
HRMS (FAB+) m/e calcd for C28H28NO5 458.1967 (MH+), found
458.1974. Anal. (C28H27NO4S‚1.75H2O) C, N; H: calcd, 6.30;
found, 5.81.
(()-3,9-Dih yd r oxy-6-[4-[2-(1-m or p h olin yl)e t h oxy]-
p h en yl]-6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3i). The
title compound was prepared in two steps and 77% overall
yield from 23 and 1-(2-hydroxyethyl)morpholine by a method
similar to that described for 3f as a red solid, mp 147-153 °C
(dec) (acetone/ether): 1H NMR δ 7.35 (d, J ) 2.1 Hz, 1H), 7.25
(d, J ) 8.6 Hz, 2H), 7.16 (d, J ) 8.3 Hz, 1H), 7.14 (d, J ) 8.6
Hz, 1H), 6.81 (m, 3H), 6.62 (s, 1H), 6.46 (dd, J ) 8.2, 2.2 Hz,
1H), 6.35 (d, J ) 2.2 Hz, 1H), 4.04 (t, J ) 5.7 Hz, 2H), 3.56 (t,
J ) 4.7 Hz, 4H), 2.68 (t, J ) 5.7 Hz, 2H), 2.47 (t, J ) 4.3 Hz,
4H); 13C NMR δ 160.0, 159.7, 155.9, 153.5, 141.1, 132.9, 131.4,
129.8, 129.7, 125.4, 124.8, 122.6, 115.2, 112.8, 109.6, 108.9,
104.7, 78.0, 67.2, 66.5, 58.1, 54.7; IR (KBr) 3471 cm-1; MS
(FD+) m/e 475 (MH+). Anal. (C27H25NO5S‚0.25H2O) C, H, N.
(()-3,9-Dih ydr oxy-6-[4-[2-(2-oxo-1-pyr r olidin yl)eth oxy]-
p h en yl]-6H-[1]ben zoth ien o[3,2-c][1]ben zop yr a n (3j). The
title compound was prepared in two steps and 50% overall
yield from 23 and 1-(2-hydroxyethyl)-2-pyrrolidinone by a
method similar to that described for 3f as a red solid, mp 150-
160 °C (dec) (acetone solvate): 1H NMR (MeOH-d4) δ 7.21 (m,
3H), 7.11 (d, J ) 8.3 Hz, 1H), 7.02 (d, J ) 8.7 Hz, 1H), 6.80 (d,
J ) 8.6 Hz, 2H), 6.71 (dd, J ) 8.6, 2.2 Hz, 1H), 6.51 (s, 1H),
6.37 (dd, J ) 8.2, 2.3 Hz, 1H), 6.25 (d, J ) 2.3 Hz, 1H), 4.04 (t,
J ) 5.2 Hz, 2H), 3.57 (t, J ) 5.2 Hz, 2H), 3.48 (t, J ) 7.1 Hz,
2H), 2.28 (t, J ) 8.1 Hz, 2H), 2.14 (s, 6H, CH3CO) 1.91 (quintet,
J ) 7.5 Hz, 2H); 13C NMR (MeOH-d4) δ 178.0, 160.2, 160.0,
156.2, 153.9, 141.7, 133.7, 131.9, 130.9, 130.3, 125.6, 125.0,
122.7, 115.6, 115.4, 113.4, 109.8, 109.0, 104.9, 78.6, 66.6, 49.7,
43.4, 31.8, 30.7, 18.9; IR (CHCl3) 1680 cm-1; MS (FD+) m/e
474 (MH+). Anal. (C27H23NO5S‚(CH3)2CO) C, H, N.
(()-2-Meth oxy-8-h yd r oxy-11,12-d ih yd r o-5H-ben zo[b]-
n a p h th o[2,1-d ]p yr a n -5-on e (13). To a solution of 1-car-
bomethoxy-6-methoxy-2-tetralone (12)27 (18.0 g, 76.8 mmol)
and resorcinol (8.9 g, 80.7 mmol) being stirred at ambient
temperature in toluene (450 mL) was added POCl3 (12.0 g,
7.3 mL, 18.3 mmol) dropwise, and the mixture was warmed
to 80 °C for 12 h. After being cooled to room temperature,
the mixture was poured into water (500 mL) and filtered, and
the precipitate was rinsed with ether. The filtrate layers were
separated, the aqueous layer was extracted with EtOAc (3 ×
500 mL), and the combined organic layers were dried (Na2-
SO4) and concentrated. Recrystallization of the residue from
MeOH provided 16.0 g (71%) of the title compound as a yellow
solid, mp 244-249 °C (dec): 1H NMR (DMSO-d6) δ 10.55 (br
s, 1H), 8.24 (d, J ) 8.6 Hz, 1H), 7.75 (d, J ) 8.7 Hz, 1H), 6.6-
7.0 (m, 4H), 3.76 (s, 3H), 2.8-3.0 (m, 4H); 13C NMR (DMSO-
d6) δ 170.3, 160.3, 158.3, 158.1, 153.3, 147.7, 137.5, 127.4,
125.8, 122.5, 114.5, 112.6, 112.4, 110.9, 101.4, 54.6, 26.3, 22.7;
IR (KBr) 3250, 1676, 1618 cm-1; MS (FD+) m/e 294 (M+).
Anal. (C18H14O4) C, H.
2,8-Bis[(ter t-bu tyldim eth ylsilyl)oxy]-5H-ben zo[b]n aph -
th o[2,1-d ]p yr a n -5-on e (7). To a mechanically stirred slurry
of 13 (4.17 g, 14.2 mmol) in CH2Cl2 (100 mL) was added
ethanethiol (3.53 g, 3.95 mL, 56.8 mmol) followed by aluminum
chloride (9.0 g, 67.5 mmol), portionwise. The reaction mixture
was stirred at ambient temperature for 5 h, cooled to 0 °C,
and quenched cautiously with THF (100 mL) followed by
saturated NaHCO3 (100 mL). The mixture was diluted with
THF (100 mL), the layers were separated, and the aqueous
layer was washed with THF (100 mL). The combined organic
layers were dried (Na2SO4) and concentrated to yield 3.6 g of
crude diphenol as a yellow solid, which was used without
further purification.
3,9-Bis[(ter t-bu tyld im eth ylsilyl)oxy]-6H-ben zofu r o[3,2-
c][1]ben zop yr a n -6-on e (5). Coumestrol (10 g, 37.3 mmol)
was slurried in CH2Cl2 (600 mL), cooled to 0 °C, and treated
with Et3N (24.9 g, 34.3 mL, 246 mmol) and tert-butyldimeth-
ylsilyl chloride (24.7 g, 164 mmol). The mixture was warmed
to ambient temperature and stirred overnight, during which
it slowly became homogeneous. After dilution with ether (800
mL), the mixture was washed with brine (800 mL) and the
aqueous layer was extracted with ether (500 mL). The
combined organic layers were dried (Na2SO4) and concen-
The crude product was slurried in CH2Cl2 (100 mL) and
treated with Et3N (8.6 g, 11.9 mL, 85.2 mmol) and tert-
butyldimethylsilyl chloride (8.6 g, 56.8 mmol). The mixture
was stirred at ambient temperature for 5 h, during which it

1282 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 8
Grese et al.
slowly became homogeneous. After dilution with ether (250
mL), the mixture was washed with brine (250 mL) and the
aqueous layer was extracted with ether (150 mL). The
combined organic layers were dried (Na2SO4) and concen-
trated, and the residue was recrystallized from hexane to
provide 5.3 g (74%) of the title compound as a yellow solid,
mp 145-147 °C: 1H NMR (CDCl3) δ 8.37 (d, J ) 8.6 Hz, 1H),
7.58 (d, J ) 9.3 Hz, 1H), 6.83 (s, 1H), 6.81 (m, 2H), 6.72 (d, J
) 2.4 Hz, 1H), 2.8-3.0 (m, 4H), 1.00 (s, 18H), 0.27 (s, 6H),
0.24 (s, 6H); MS (FD) m/e 508 (M+).
of Lilly Research Laboratories (analytical and spectral
data and support).
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(3) Cust, M. P.; Gangar, K. F.; Whitehead, M. I. Oestrogens and
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(6) Beresford, S. A. A.; Weiss, N. S.; Voigt, L. F.; McKnight, B. Risk
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Chem. 1994, 1, 61-104. (c) Chander, S. K.; Sahota, S. S.; Evans,
T. R. J .; Luqmani, Y. A. The biological evaluation of novel
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antiestrogens and approaches to the prevention of breast cancer.
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(8) J ordan, V. C. A current view of tamoxifen for the treatment and
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(9) For recent reviews, see: (a) Grese, T. A.; Dodge, J . A. Estrogen
receptor modulators: effects in non-traditional target tissues.
Annu. Rep. Med. Chem. 1996, 31, 181-190. (b) Kauffman, R.
F.; Bryant, H. U. Selective estrogen receptor modulators. Drug
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T. Tissue-selective actions of estrogen analogs. Bone 1995, 17,
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(10) J ones, C. D.; J evnikar, M. G.; Pike, A. J .; Peters, M. K.; Black,
L. J .; Thompson, A. R.; Falcone, J . F.; Clemens, J . A. Anties-
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arylbenzo[b]thiophene derivatives leading to [6-hydroxy-2-(4-
hydroxyphenyl)benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]-
phenyl]methanone hydrochloride (LY156758), a remarkably
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(11) (a) Draper, M. W., Flowers, D. E.; Huster, W. J .; Neild, J . A.;
Harper, K. D.; Arnaud, C. A controlled trial of raloxifene
(LY139481) HCl: Impact on bone turnover and serum lipid
profile in healthy postmenopausal women. J . Bone Miner. Res.
1996, 11, 835-842. (b) Delmas, P. D.; Bjarnason, N. H.; Mitlak,
B. H.; Ravoux, A.-C.; Shah, A. S.; Huster, W. J .; Draper, M.;
Christiansen, C. Effects of raloxifene on bone mineral density,
serum cholesterol concentrations, and uterine endometrium in
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(12) (a) Sato, M.; Rippy, M. K.; Bryant, H. U. Raloxifene, tamoxifen,
nafoxidine, or estrogen effects on reproductive and nonrepro-
ductive tissues in ovariectomized rats. FASEB J . 1996, 10, 905-
912. (b) Black, L. J .; Sato, M.; Rowley, E. R.; Magee, D. E.;
Bekele, A.; Williams, D. C.; Cullinan, G. J .; Bendele, R.;
Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J . D.;
Bryant, H. U. Raloxifene (LY139481 HCl) prevents bone loss
and reduces serum cholesterol without causing uterine hyper-
trophy in ovariectomized rats. J . Clin. Invest. 1994, 93, 63-69.
(13) Another group has recently described proliferative effects in
uterine tissue from immature rats treated with raloxifene:
Ashby, J .; Odum, J .; Foster, J . R. Activity of raloxifene in
immature and ovariectomized rat uterotrophic assays. Regul.
Toxicol. Pharm. 1997, 25, 226-231. Our data from both im-
mature and ovariectomized rats, reported herein and else-
where,12,18,34 do not support their findings or conclusions.
A sample of the above product (7.0 g, 13.8 mmol) and DDQ
(3.3 g, 14.5 mmol) in DCE (100 mL) was heated at reflux
overnight, inducing the formation of a precipitate. The
mixture was cooled to room temperature, diluted with hexane
(300 mL), filtered through Celite, and concentrated. The
remnant was partitioned between hexane:ether (1:1, 200 mL)
and water (200 mL), and the organic layer was dried (MgSO4),
concentrated, and recrystallized from hexane to provide 5.5 g
(79%) of the title product as a tan solid, mp 154-156 °C: 1H
NMR (CDCl3) δ 9.69 (d, J ) 9.4 Hz), 8.80 (s, 2H), 8.01 (d, J )
9.5 Hz), 7.34 (dd, J ) 9.3,2.5 Hz, 1H), 7.28 (d, J ) 5.4 Hz,
1H), 6.90 (m, 2H), 1.05 (s, 9H), 1.03 (s, 9H), 0.29 (s, 12H); IR
(CHCl3) 1711, 1622, 1604 cm-1; MS (FD) m/e 506 (M+). Anal.
(C29H38O4Si2) C, H.
(()-2,8-Bis[(ter t-bu tyld im eth ylsilyl)oxy]-5H-ben zo[b]-
n a p h th o[2,1-d ]p yr a n -5-ol (16). The title compound was
prepared from 7 in 82% yield by a method similar to that
described for 15a as a white solid, mp 188-190 °C (hexane/
ether): 1H NMR (CDCl3) δ 7.98 (d, J ) 9.1 Hz, 1H), 7.86 (d, J
) 8.8 Hz, 1H), 7.79 (d, J ) 8.6 Hz, 1H), 7.75 (d, J ) 8.2 Hz,
1H), 7.23 (d, J ) 2.3 Hz, 1H), 7.18 (dd, J ) 9.0, 2.4 Hz, 1H),
7.06 (d, J ) 7.4 Hz, 1H), 6.67 (m 2H), 3.24 (d, J ) 7.7 Hz, 1H),
1.04 (s, 9H), 1.02 (s, 9H), 0.27 (s, 6H), 0.27 (s, 6H); IR (CHCl3)
3574 cm-1; MS (FD) m/e 508 (M+). Anal. (C29H40O4Si2)
Calcd: C, 68.44; H, 7.94. Found: C, 68.63; H, 8.11.
(()-2,8-Bis[(ter t-b u t yld im et h ylsilyl)oxy]-5-p h en oxy-
5H-ben zo[b]n a p h th o[2,1-d ]p yr a n (21). The title compound
was prepared in 95% yield from 16 by a method similar to
that described for 20a : 1H NMR δ 7.9-8.1 (m, 4H), 7.61 (s,
1H), 7.3-7.5 (m, 3H), 7.2-7.3 (m, 3H), 7.11 (t, J ) 7.3 Hz,
1H), 6.74 (dd, J ) 8.5, 2.3 Hz, 1H), 6.62 (d, J ) 2.4 Hz, 1H),
1.03 (s, 9H), 0.99 (s, 9H), 0.29 (s, 6H), 0.24 (s, 6H); MS (FD)
m/e 584 (M+).
(()-2,8-Dih ydr oxy-5-[4-[2-(1-piper idin yl)eth oxy]ph en yl]-
5H-ben zo[b]n a p h th o[2,1-d ]p yr a n (4). The title compound
was prepared in two steps and 81% overall yield from 21 by a
method similar to that described for 3a as a white solid, mp
158-161 °C (ether): 1H NMR δ 7.89 (d, J ) 8.7 Hz, 1H), 7.77
(d, J ) 8.7 Hz, 1H), 7.68 (m, 2H), 7.23 (d, J ) 2.4 Hz, 1H),
7.09 (m, 3H), 6.97 (s, 1H), 6.71 (d, J ) 8.7 Hz, 2H), 6.49 (dd,
J ) 8.3, 2.4 Hz, 1H), 6.36 (d, J ) 2.3 Hz, 1H), 3.95 (t, J ) 6.0
Hz, 2H), 2.60 (t, J ) 6.0 Hz, 2H), 2.40 (m, 4H), 1.4-1.5 (m,
4H), 1.3-1.4 (m, 2H); 13C NMR δ 159.5, 159.5, 155.8, 153.9,
135.0, 132.4, 130.1, 128.0, 126.7, 125.6, 125.4, 125.3, 124.7,
121.4, 119.9, 116.1, 114.8, 111.0, 110.1, 105.5, 75.8, 66.1, 58.3,
55.3, 26.3, 24.7; IR (KBr) 2934 cm-1; MS (FD) m/e 468 (MH+).
Anal. (C30H29NO4‚H2O) C, H, N.
Biologica l Assa ys. Methods utilized for the ER binding,
MCF-7 proliferation, 4-day and 5-week OVX rat assays have
been recently described.35 Procedures for the immature rat
assay have also been published elsewhere.45 Stimulation of
TGF-â3 promoter activity was assayed in HeLa cells which
had been cotransfected with a TGF-â3/luciferase reporter
plasmid and an expression plasmid (pCMVER) encoding the
human ER by the published procedure.43
Ack n ow led gm en t. The authors thank Dr. Chris
Schmid for helpful discussions and suggestions. The
authors also thank Kennan Fahey, Dr. David Mitchell,
and Robert Murff for the preparation of starting materi-
als and intermediates. The authors also acknowledge
the contributions of the Physical Chemistry Department

Synthesis of Raloxifene Analogues
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J M970688Z