New synthetic approaches to estrogen receptor modulators: Imidazo[1,2-a]pyridines

Article abstract of DOI:10.1016/S0040-4039(03)00875-X

Constrained triarenes have been important templates for selective modulation of the estrogen receptor (ER). For our ER program, we sought an unexplored, synthetically accessible heterocyclic template capable of bearing a broad range of pharmacophores. Tra

Full text of DOI:10.1016/S0040-4039(03)00875-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4077–4080
New synthetic approaches to estrogen receptor modulators:
imidazo[1,2-a]pyridines
Hari S. Patel, James A. Linn, David H. Drewry, Daniel A. Hillesheim, William J. Zuercher and
William J. Hoekstra*
Discovery Research Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709-3398, USA
Received 28 February 2003; revised 31 March 2003; accepted 31 March 2003
Abstract—Constrained triarenes have been important templates for selective modulation of the estrogen receptor (ER). For our
ER program, we sought an unexplored, synthetically accessible heterocyclic template capable of bearing a broad range of
pharmacophores. Traditional approaches to these therapeutics such as raloxifene have relied on an alkoxy moiety to link the
arene-based scaffold to the modulating amine group. Alternatively, aryl halide-mediated introduction of alkylene or aryl side
chains has not been studied extensively. The synthetic incorporation of pharmacophoric side chains that are carbon-linked to a
novel imidazopyridine-based ER recognition motif is disclosed. © 2003 Elsevier Science Ltd. All rights reserved.
The genesis of triaryl template-based estrogen receptor
(ER) modulators was realized in the 1960s with the
discovery of the breast cancer therapeutic tamoxifen.1
Constraint of this key non-steroidal ER recognition
motif paved the way for the discovery of the benzothio-
phene raloxifene, an important second generation selec-
tive estrogen receptor modulator (SERM) for
prevention of osteoporosis in menopausal women.2 The
human estrogen receptor, a member of the nuclear
receptor superfamily of ligand-dependent transcription
factors, experiences a conformational change upon lig-
and binding to initiate a cascade of regulatory events
with its target genes.1 The biological effects of estrogen
are mediated by its two receptor subtypes, ERa and
ERb.3
genated compounds utilize alkoxide-linked pharma-
cophoric amine groups. In our medicinal chemistry
program, we aimed to introduce a variety of pharma-
cophores to a suitably-protected core using aryl halide
intermediates. This strategy furnished novel carbon-
linked moieties to a new, imidazopyridine-based ER
recognition motif. To this end, the synthesis of ER
binding imidazo[1,2-a]pyridines4 (1) are disclosed
herein.
The mechanism of cyclocondensation of 2-aminopy-
ridine with 2-haloketones to afford imidazopyridine
cores has been studied by Hand and Paudler.5 The
imidazopyridine template has been employed to prepare
potential pharmaceutical agents such as calcium chan-
nel blockers,6 GABA modulators,7 and cyclooxygenase-
2 (COX-2) inhibitors.8 For instance, synthesis of
2-(4-alkylsulfonylphenyl)-3-phenylimidazopyridines led
to the discovery of potent, selective COX-2 inhibitors
as promising anti-inflammatory agents.8 Indomethacin-
Whilst the two hydroxy groups of raloxifene serve as
anchors in ER’s ligand binding domain, selective effects
are attributed to interaction of the amine moiety with
Asp-351. Synthetic approaches to these types of trioxy-
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00875-X

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H. S. Patel et al. / Tetrahedron Letters 44 (2003) 4077–4080
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based anti-inflammatory agents have been synthesized
as well.9 The key, annulation step in the synthesis of
our ER-targeted imidazopyridines required 2-aminopy-
ridines and bromine-substituted benzoin-derived pre-
cursors 2 to furnish variably-substituted tetracyclic
intermediates 3 (Eq. (1)). Synthetic details are presented
below.
pKi=5.95). Thus, methyl ether deprotection and Heck
coupling of the resultant phenol with 4-methoxystyrene
proceeded smoothly to 8a. Experimental details for
conversion of 6 to 8a are included.12 The versatility of
this general strategy renders the intermediates 7a–c
suitable for Suzuki and Sonogashira couplings as well
(Eq. (3), products 913 and 1014).
Styryl-appended target 8a was prepared as follows (Eq.
(2)). Friedel–Crafts acylation of anisole by polyphos-
phoric acid-activated 4-bromophenylacetic acid (5)10
and bromination in dioxane11 of this acetophenone
intermediate furnished a-bromoketone 6. The bis-elec-
trophile 6 was cyclo-condensed with variably-substi-
tuted 2-aminopyridines in acetonitrile to isolate key
bromoarene intermediates 7a–c (for 7c, ERa SPA bind-
ing pKi=6.50, ERb SPA binding pKi=5.00; for estra-
diol, ERa pKi=8.70, ERb pKi=8.56). Since one
initiative of our synthesis was to introduce a variety of
moieties at the bromine-containing position of 7a–c,
feasibility of methyl ether unmasking using harsh boron
tribromide was studied and effected prior to palladium-
mediated carbonꢀcarbon bond formation toward prod-
ucts exemplified by 8a (ERa pKi=5.50; ERb
In summary, we have described a practical, five-step
synthesis of novel, estrogen-receptor binding imi-
dazo[1,2-a]pyridines. As an application of this chem-
istry, key bromoarene intermediates 7a–c were carried
forward to biologically interesting ER modulators such
as 8a. Given the facility of the Heck, Suzuki, and
Sonogashira couplings with the phenolic intermediates
7a–c, these aryl bromides offer promise for metal-
directed homologation using Stille and Buchwald
methodologies as well. These transformations will be
studied in due course. The synthesis of potential phar-
macophoric side chains that are carbon-linked15 to the
imidazopyridine core represents a general methodology
that may be applicable to a number of triarene-type ER
modulator templates.
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H. S. Patel et al. / Tetrahedron Letters 44 (2003) 4077–4080
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Acknowledgements
tolylphosphine (4.5 mg, 0.18 equiv.), then evacuated and
back-filled with nitrogen. 4-Methoxystyrene (14 mL, 1.2
equiv.), Et3N (25 mL, 2 equiv.), DMF (0.5 mL), and
MeCN (1 mL) were delivered via syringe and the mixture
stirred at 85°C for 7 h, cooled, and evaporated. The
crude product was purified over silica gel via MPLC
(EtOAc/DCM) to yield 2-(hydroxyphenyl)-3-(4-{[E]-2-
[4-methoxyphenyl]ethenyl}phenyl)imidazo[1,2-a]pyridine
We thank Dr. David W. Gray of GlaxoSmithKline
Discovery Research Biology for biological data.
1
References
(8a, 30.7 mg, 88% yield) as a dark yellow solid. H NMR
(400 MHz, DMSO-d6): l 9.50 (s, 1H), 8.07–8.05 (d, 1H),
7.75–7.73 (d, 2H), 7.61 (s, 1H), 7.59–7.56 (d, 2H), 7.47–
7.41 (m, 4H), 7.34–7.30 (d, 1H), 7.29–7.25 (t, 1H), 7.21–
7.17 (d, 1H), 6.97–6.95 (d, 2H), 6.87–6.84 (t, 1H),
6.69–6.68 (d, 2H), 3.77 (s, 3H). IR (neat, cm−1): 3028,
2958, 2929, 2851, 1725, 1656, 1633, 1607, 1510, 1487,
1442, 1391, 1344, 1249, 1173, 1105, 1026, 838, 754. MS
(high-resolution, M+H+): C28H22N2O2, calculated
419.1759; observed, 419.1759.
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4. Krohnke, F.; Kickhoffen, B.; Thomas, C. Chem. Ber.
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13. For 9: A 16×125 mm screw-capped vial was charged with
7a (30 mg, 82 mmol), (1,1%-bis(diphenylphos-
phino)ferrocene)palladium chloride (6.2 mg, 0.1 equiv.),
K2CO3 (22.7 mg, 2 equiv.), 4-fluorophenylboronic acid
(23 mg, 2 equiv.), then evacuated and back-filled with
nitrogen and THF (2.5 mL). The reaction mixture was
stirred at 65°C for 18 h, cooled, concentrated and diluted
with EtOAc (75 mL). The organic layer was washed with
brine (100 mL), and dried over MgSO4, and evaporated.
The crude product was purified over silica gel via MPLC
(EtOAc/DCM) to afford 2-(hydroxyphenyl)-3-(4%-fluoro-
1,1%-biphenyl-4-yl)imidazo[1,2-a]pyridine (9, 24.6 mg,
79% yield) as a white flaky solid. 1H NMR (300 MHz,
DMSO-d6): l 9.52 (s, 1H), 8.10–8.07 (d, 1H), 7.89–7.82
(m, 4H), 7.65–7.62 (d, 1H), 7.58–7.55 (d, 2H), 7.47–7.44
(d, 2H), 7.37–7.26 (m, 3H), 6.90–6.85 (t, 1H), 6.72–6.69
(d, 2H). IR (neat, cm−1): 1161, 1528, 1508, 1486, 1440,
1390, 1345, 1274, 1237, 1161, 1102, 1024, 1006, 825, 753.
MS (high-resolution, M+H+): C25H17FN2O, calculated,
381.1403; observed, 381.1425.
10. Anstead, G. M.; Katzenellenbogen, J. A. J. Med. Chem.
1988, 31, 1754.
11. Boswell, G. E.; Musso, D. L.; Kelley, J. L.; Soroko, F.
E.; Cooper, B. R. J. Heterocyclic Chem. 1996, 33, 33.
12. Compound 8a was synthesized from 6 as follows: A
solution of 6 (1.92 g, 4.99 mmol) and 2-aminopyridine
(0.52 g, 1.1 equiv.) in MeCN (100 mL) was heated at
90°C for 18 h. The solution was evaporated and the crude
product was purified over silica gel-60 via medium pres-
sure liquid chromatography (MPLC; EtOAc/DCM) to
afford 0.99 g (52% yield) of a fine off-white powder. A
solution of this product (0.65 g, 1.7 mmol) in DCM (65
mL) was cooled to −20°C in a MeOH/ice bath. Under
nitrogen, BBr3 was added slowly (10 mL of 1.0 M DCM,
5.9 equiv.). After 2 h the reaction mixture was warmed to
rt (4 h), and quenched with MeOH (50 mL). The reaction
was concentrated, filtered through silica gel (EtOAc/
DCM) and evaporated to give 7a (0.60 g, 97% yield) as a
pale yellow/red powder. A 16×125 mm screw-capped vial
was charged with 7a (30 mg, 82 mmol), tris(dibenz-
ylidineacetone)dipalladium (7.5 mg, 0.09 equiv.), tris-o-
14. For compound 10: A 16×125 mm screw-capped vial was
charged with 7a (30 mg, 82 mmol), tris(dibenzylideneace-
tone)dipalladium(0) (15.0 mg, 0.2 equiv.), triphenylphos-
phine (806 mg, 0.4 equiv.), and copper(I) iodide (3.1 mg,
0.2 equiv.), and then evacuated and back-filled with
nitrogen. A solution of 1-ethynyl-4-methoxybenzene (53.3
mL, 5 equiv.), Et3N (50.0 mL, 4.3 equiv.), and 1,4-dioxane

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H. S. Patel et al. / Tetrahedron Letters 44 (2003) 4077–4080
(0.5 mL) were delivered via syringe, and the mixture stirred
at 110°C for 16 h. The reaction mixture was cooled,
concentrated, and then diluted with EtOAc (50 mL). The
solution was washed twice with brine (50 mL), and dried
over MgSO4. The crude reaction mixture was purified over
silica gel via MPLC (MeOH/DCM) to yield 2-(hydroxy-
phenyl)-3-(4-{[4-methoxyphenyl]ethynyl}phenyl)imidazo-
[1,2-a]pyridine (10, 62 mg, 90% yield) as a white solid. H
NMR (300 MHz, DMSO-d6): l 9.56 (s, 1H), 8.13–8.10 (d,
1H), 7.71–7.69 (d, 2H), 7.66–7.63 (d, 1H), 7.56–7.51 (m,
4H), 7.42–7.39 (d, 2H), 7.35–7.30 (t, 1H), 7.03–7.00 (d, 2H),
6.93–9.89 (t, 1H), 6.73–6.70 (d, 2H), 3.81 (s, 3H). IR (neat,
cm−1): 2962, 2926, 1649, 1603, 1510, 1441, 1393, 1258, 1172,
1139, 1091, 1021, 797, 755. MS (high-resolution, M+H+):
C28H20N2O2, calculated, 417.1603; observed, 417.1625.
15. For an example of a carbon-linked basic side chain to a
naphthimidazole core, see: Kuo, S.-C.; Ibuka, T.; Huang,
L.-J.; Lien, J.-C.; Yean, S.-R.; Huang, S.-C.; Lednicer, D.;
Morris-Natschke, S.; Lee, K.-H. J. Med. Chem. 1996, 39,
1447.
1