2-Phenylspiroindenes: A novel class of selective estrogen receptor modulators (SERMs)

Article abstract of DOI:10.1016/S0960-894X(02)00985-X

A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to raloxifene (1) as an estrogen receptor ligand.

Full text of DOI:10.1016/S0960-894X(02)00985-X

Bioorganic& Medicinal Chemistry Letters 13 (2003) 479–483
2-Phenylspiroindenes: A Novel Class of Selective Estrogen
Receptor Modulators (SERMs)
Timothy A. Blizzard,* Jerry D. Morgan, II, Ralph T. Mosley, Elizabeth T. Birzin,
Katalin Frisch, Susan P. Rohrer and Milton L. Hammond
Merck Research Laboratories, RY800-B116, PO Box 2000, Rahway, NJ 07065, USA
Received 29 August 2002; accepted 11 October 2002
Abstract—A series of 2-phenylspiroindenes was prepared. The most active analogue (2) was found to be comparable in potency to
raloxifene (1) as an estrogen receptor ligand.
# 2002 Elsevier Science Ltd. All rights reserved.
Hormone replacement therapy (HRT) is widely used to
treat a variety of conditions, such as hot flashes and
osteoporosis, resulting from estrogen deficiency in post-
menopausal women.1 Although HRT is very effective, it
is also associated with some serious side-effects, includ-
ing blood clots and increased risk of cancer. The selec-
tive estrogen receptor modulators (SERMs) have
generated considerable interest due to their potential
ability to provide the benefits of estrogen without the
associated liabilities.2 The utility of SERMs is exempli-
fied by the use of Tamoxifen3 for the prevention and
treatment of breast cancer and raloxifene (1)4 for the
treatment and prevention of osteoporosis.4d,e Several
additional SERMs, such as lasofoxifene,5 fulvestrant,6
EM-652,7 ERA-923,8 and TSE-4248 are in late stages of
clinical trials for a variety of indications. Although the
current SERMs have clear advantages over conven-
tional HRT, they retain some of the disadvantages as
well. Clearly, an ‘ideal SERM’ has not yet emerged.
active compound.4b We speculated that this might also
be accomplished by constructing a spiroindene system
such as 2. Molecular modelling studies showed that 2
would overlap nicely with the active conformation of
raloxifene. We chose the simplified analogue 3 as our
initial synthetictarget.
The synthesis of 3 was accomplished using the synthetic
route outlined in Scheme 1.9 Alkylation of commercially
available anisindione 4 with methyl a-bromophenylace-
tate 5 under basicconditions afforded the desired alkyl-
ation product 6 in excellent yield (90% yield of
recrystallized product on 1.26 g scale). Hydrogenation
of 6 not only reduced the ketones but also resulted in
hydrolysis of the methyl ester to the desired carboxylic
acid 7 (due to lactonization of the intermediate benzylic
hydroxyl to form a lactone followed by hydrogenolysis
of the resulting benzylicester) in very good yield (74%
yield of crystalline product on 1.70 g scale). Conversion
of acid 7 to the acid chloride by reaction with PCl5 fol-
lowed by AlCl3 catalyzed Friedel–Crafts cyclization
afforded the desired ketone 8 in low and variable yield
We became interested in SERMs several years ago and
chose to focus initially on raloxifene isosteres. It was
known from X-ray crystal studies that the active con-
formation of raloxifene (1) was one in which the phe-
nylketone at C-3 of the benzothiophene was orthogonal
to the benzothiophene ring rather than coplanar.4c,f It
has been hypothesized that locking the aromatic rings in
this relative configuration by fusing the pendant phenyl
ring and the carbonyl linker might result in an especially
*Corresponding author. Fax: +1-732-594-9556; e-mail: tim_blizzard@
merck.com
0960-894X/03/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(02)00985-X

480
T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 13 (2003) 479–483
Scheme 1. Reagents and conditions: (i) K2CO3, DMF, 50 ꢀC, 15 m, 90%; (ii) H2, Pd(OH)2/C, EtOAc, EtOH, AcOH, 68 h, 74%; (iii) PCl5, CH2Cl2,
0 ꢀC, 1 h; (iv) AlCl3, CH2Cl2, 0 ꢀC, 45 m, 25% from 7; (v) NaBH4, MeOH, THF, 14 h; (vi) TsOH, benzene, reflux, 2 h, 12–24% from 8; (vii) BBr3,
CH2Cl2, 2 h, 40%.
(8 appears to be unstable to chromatography, perhaps
due to residual HCl generated in the cyclization).
Reduction of the ketone with NaBH4 followed by acid-
catalyzed dehydration yielded olefin 9. Finally, removal
of the methyl ether protecting group with BBr3 afforded
the desired spirocycle 3. Despite the fact that 3 is a
relatively simple analogue of raloxifene, lacking both
the second phenolic hydroxyl group and the basic side
chain, it had very good activity in an ER binding assay
(Table 1). We were therefore encouraged to continue in
this area.
Crafts cyclization afforded the desired cyclic ketone 15
which was immediately reduced with NaBH4 followed
by acid-catalyzed dehydration to afford the penultimate
intermediate 16 in 13% overall (for the four steps from
14) yield. Removal of the methyl ether protecting
groups with BBr3 afforded the desired spiroindene 10 in
54% yield.
Similarly, reaction of 4 with 17 (prepared in essentially
quantitative yield by NBS bromination of commercial
methyl 3-methoxyphenylacetate)10 afforded the desired
alkylation product 18 in excellent yield. Hydrogenation
of 18 afforded the desired carboxylic acid 19 in 72%
recrystallized yield. Conversion of acid 19 to the acid
chloride by reaction with PCl5 followed by AlCl3 cata-
lyzed Friedel–Crafts cyclization afforded the desired
cyclic ketone 20 which was immediately reduced with
NaBH4 followed by acid-catalyzed dehydration to
afford the penultimate intermediate 21 in 6% overall
(from 19) yield. Removal of the methyl ether protecting
groups with BBr3 afforded spiroindene 11 in 80% yield.
We next turned our attention to the more complex
analogues 10 and 11, which each have an additional
phenolichydroxyl group. Compounds 10 and 11 were
prepared by the routes outlined in Schemes 2 and 3,
respectively. Reaction of 4 with 12 (prepared in essen-
tially quantitative yield by NBS bromination of com-
mercial methyl 4-methoxyphenylacetate)10 afforded the
desired alkylation product 13 in quantitative yield.
Hydrogenation of 13 not only reduced the ketones but
also resulted in hydrolysis of the methyl ester to the
desired carboxylic acid 14 in modest yield. The yield was
a bit lower than usual in this case due to incomplete
reduction (some monoketone was isolated as a by-pro-
duct). Conversion of acid 14 to the acid chloride by
reaction with PCl5 followed by AlCl3 catalyzed Friedel–
We were very pleased to find that 10 was significantly
more active than 3 in the ER binding assay (Table 1).
Interestingly, though, the meta substituted analogue 11
was slightly less active than 3 despite the presence of the
additional hydroxyl group.
The availability of ketone 15, an intermediate in the
synthesis of 10, allowed us to explore the effect of alkyl
substitution at C-3 of the spiroindene. Reaction of 15
with methylmagnesium chloride followed by dehy-
dration with p-toluenesulfonicaicd afforded the 3-
methyl-spiroindene 22 in low yield. Deprotection of 22
then provided the desired 3-methylspiroindene diol 23.
Introduction of the methyl group at C-3 resulted in a
slight decrease in ER binding affinity (Scheme 4).
Table 1. Estrogen receptor binding affinities (IC50
)
Binding affinity IC50 (nM)a
Compd
Human ERa
Human ERb
Rat ERa
Rat ERb
1
2
1.8
1.0
12
1.9
0.7
1.7
3.4
2.7
nd
1.1
3
24
4.3
28
19
21
2.1
23
5.9
nd
nd
34
10
11
23
26
28
34
29
1.2
>10,000
1070
15
2.2
The low overall yield of the syntheticroutes outlined in
Schemes 1–3 prompted us to examine an alternative
route. It has been reported that indene can be di-alky-
lated with a dibromide under basicconditions to afford
spiroindenes.11 We hypothesized that this route could
be applied to 2-phenylindenes to afford compounds like
2. Indeed, reaction of 2-phenylindene 24 with a,a0-
>10,000
58
31
>10,000
429
12
>10,000
114
16
aThe IC50 values were generated in an estrogen receptor ligand binding
assay. This scintillation proximity assay was conducted in NEN Basic
Flashplates using tritiated estradiol and full length recombinant
human ER-alpha and ER-beta proteins.

T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 13 (2003) 479–483
481
Scheme 2. Reagents and conditions: (i) K2CO3, DMF, 50 ꢀC, 15 m, 100%; (ii) H2, Pd(OH)2/C, EtOAc, EtOH, AcOH, 23 h, 44%; (iii) PCl5, CH2Cl2,
0 ꢀC, 1 h; (iv) AlCl3, CH2Cl2, ꢁ20 ꢀC, 1 h then 0 ꢀC, 75 m; (v) NaBH4, MeOH, THF, 2.5 h; (vi) TsOH, benzene, reflux, 2 h, 13% from 14; (vii) BBr3,
CH2Cl2, 2 h, 54%.
Scheme 3. Reagents and conditions: (i) K2CO3, DMF, 50 ꢀC, 20 m, 88%; (ii) H2, Pd(OH)2/C, EtOAc, EtOH, AcOH, 39 h, 72%; (iii) PCl5, CH2Cl2,
0 ꢀC, 1 h; (iv) AlCl3, CH2Cl2, 0 ꢀC, 90 m; (v) NaBH4, MeOH, THF, 2 h; (vi) TsOH, benzene, reflux, 2 h, 6% from 19; (vii) BBr3, CH2Cl2, 2 h, 80%.
Scheme 4. Reagents and conditions: (i) PCl5, CH2Cl2, 0 ꢀC, 75 m; (ii) AlCl3, CH2Cl2, 0 ꢀC, 75 m; (iii) MeMgCl, THF, 90 m; (iv) TsOH, benzene,
reflux, 2 h, 6% from 14; (v) BBr3, CH2Cl2, 2 h, 53%.
dibromoxylene 25 under phase transfer conditions
afforded the parent spiroindene 26 in low yield. Simi-
larly, reaction of 24 with dibromide 2712 under the same
conditions resulted in spiro-alkylation with deprotection
to afford the hydroxy-spiroindene 28 in very low yield.
Not surprisingly, 26 and 28 were significantly less active
than 10.
optimize the yield of the problematicspiro-alkylation.
LAH reduction of the known indanone 2913 followed by
dehydration of the resulting alcohol with p-toluene-
sulfonicacid afforded a mixture of the isomeric2-phe-
nylindenes 31 and 32. Since deprotonation of 31 or 32
affords the same indenyl anion, no attempt was made to
separate the two isomers. Alkylation of 31/32 with
dibromide 25 afforded the expected mixture of spiro-
indenes 21 and 33 in very low yield.14 Deprotection of
33 afforded the spiroindene diol 34. Diol 34 was less
active than 10 but was comparable to the isomeric diol
11. The low overall yield of 34 combined with the una-
Although the overall yield of the spiroalkylation route
was disappointing in the examples outlined in Scheme 5,
we decided to try to apply it to the synthesis of 11 and
the isomericspiroindene 35 with the hope that we could

482
T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 13 (2003) 479–483
Scheme 5. Reagents and conditions: (i) THF, 50% aq NaOH, PhCH2N(CH3)4Cl, 22 h, 50 ꢀC, 16%; (ii) THF, 50% aq NaOH, PhCH2N(CH3)4Cl, 23
h, 50 ꢀC, 5%.
voidable production of two isomeric spiroindenes
prompted us to abandon this route (Scheme 6).15
methyl ester to afford acid 38 in good yield. The acid
chloride was formed by reaction of 38 with PCl5 and
treated in situ with AlCl3 to effect cyclization to the
ketone 40 in 24% yield. This cyclization reaction was
plagued by a fragmentation reaction that afforded by-
product 39 in 50% yield as a mixture of olefin isomers.
To date, we have been unable to find conditions which
avoid this undesirable side reaction.
The disappointing results obtained with the spiro-alkyl-
ation sequence prompted us to return to the original
sequence for the synthesis of the fully elaborated spiro-
indene 2 (Scheme 7). Selective deprotection of the
known anisindione derivative 3516 with sodium thio-
methoxide under an argon atmosphere17 afforded the
desired phenol 36 in good yield. A one-pot selective
alkylation of 36 at the indandione carbon with bromide
12 followed by alkylation of the phenol with N-chloro-
acetyl-piperidine18 provided the advanced intermediate
37 in very good yield. As expected, catalytic hydro-
genation of 37 reduced the ketones and hydrolyzed the
Cyclic ketone 40 was reduced with NaBH4 and the
resulting alcohol was treated with toluenesulfonic acid
to effect elimination to the olefin 41. Reduction of the
amide with LAH proceeded smoothly to afford the ter-
tiary amine. However, deprotection of the methyl ethers
proved to be problematic. The yield of the desired spiro-
Scheme 6. Reagents and conditions: (i) LiAlH4, THF, 86%; (ii) TsOH, benzene, reflux, 22%; (iii) 25, THF, 50% aq NaOH, PhCH2N(CH3)4Cl, 54
h, 50 ꢀC, 35% combined yield of 21 and 33; (iv) NaSMe, DMF, 100 ꢀC, 22 h, 5% from 31/32.
Scheme 7. Reagents and conditions: (i) NaSMe, NaHCO3, DMF, 130 ꢀC, Ar atmosphere, 58%; (ii) 12, NaHCO3, DMF, 25 ꢀC, 2 h, then N-chlor-
oacetyl-piperidine, K2CO3, 55 ꢀC, 3 h, 83%; (iii) H2, Pd(OH)2/C, EtOAc, EtOH, AcOH, 69 h, 78%; (iv) PCl5, CH2Cl2, 0 ꢀC; (v) AlCl3, CH2Cl2, 0 ꢀC,
24% (also isolated 50% yield of 39 as a mixture of 1,2- and 2,3- olefin isomers); (vi) NaBH4, THF; (vii) TsOH, benzene, reflux, 52%; (viii) LiAlH4,
THF; (ix) BBr3, CH2Cl2, 4%.

T. A. Blizzard et al. / Bioorg. Med. Chem. Lett. 13 (2003) 479–483
483
indene 2 was very low due to the formation of several
rearrangement products. However, it was possible to
isolate sufficient quantities of 2 for biological eval-
uation. We were pleased to find that 2 is an extremely
potent estrogen receptor ligand, perhaps slightly more
potent than raloxifene.
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It is clear from the data in Table 1 that the 2-phenyl-
spiroindenes can bind very efficiently to human estrogen
receptors. The binding data for the rat and human
receptors generally parallel each other with the excep-
tion of the methyl-indene analogue 23 which appears to
be significantly more potent in the rat. The most active
compound, 2, has binding affinity that is comparable to,
or perhaps slightly better than, raloxifene (1) itself. Even
the less complex analogues such as 3, 10, and 11 are
potent estrogen receptor ligands. The binding data con-
firm the anticipated importance of the position of the
phenolic hydroxyl groups. The most active compounds,
2 and 10, have hydroxyl groups in the same orientation
as in 1. The next most active compounds, 3 and 11, have
the A-ring hydroxyl in the same position as in 1 but
either lack the pendant ring hydroxyl, as in 3, or have it
shifted over one carbon, as in 11. Shifting both hydroxyl
groups, as in 34, results in a further decrease in binding
activity. The parent compound, 28, which lacks both
hydroxyl groups, is essentially inactive. Incorporation
of the raloxifene side chain into compound 10, as in
analogue 2, results in only a slight increase in binding
affinity. Addition of a methyl group at C-3 of 10, as in
23, results in only a slight decrease in binding suggesting
that there may be room at this position for small sub-
stituents. Further results in this area will be reported in
future communications from this laboratory.
9. All new compounds were characterized by LC–MS and
1
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TBDPS ether of 3-4,dimethylphenol using the procedure
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Z.; Lakshmikantham, M. V.; Lyon, M.; Cava, M. P. J. Org.
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described in Scheme 3. The structure of the other isomer was
confirmed by an NOE experiment.
15. Similar results were obtained when this sequence was
applied to the synthesis of 16 and its isomer (corresponding to
33). In this case, the yield of the spiro-alkylation reaction was
so low that deprotection of the product was not attempted and
the sequence was not completed.
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