Estrogen receptor ligands. Part 6: Synthesis and binding affinity of dihydrobenzodithiins

Article abstract of DOI:10.1016/j.bmcl.2004.04.101

Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERα over ERβ, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model.

Full text of DOI:10.1016/j.bmcl.2004.04.101

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3753–3755
Estrogen receptor ligands. Part 6: Synthesis and binding affinity
of dihydrobenzodithiins
Qiang Tan,a,* Elizabeth T. Birzin,b Wanda Chan,b Yi Tien Yang,b Lee-Yuh Pai,b
Edward C. Hayes,b Carolyn A. DaSilva,b Frank DiNinno,a Susan P. Rohrer,b
James M. Schaefferb and Milton L. Hammonda
aDepartment of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, 800B-107, Rahway, NJ 07065, USA
bDepartment of Atherosclerosis and Endocrinology, Merck Research Laboratories, PO Box 2000, 800B-107, Rahway, NJ 07065, USA
Received 18 March 2004; revised 29 April 2004; accepted 30 April 2004
Available online
Abstract—Dihydrobenzodithiin compounds (1–6) were prepared to explore the expansion of the dihydrobenzoxathiin lead com-
pounds I–III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally
maintained a high degree of selectivity for ERa over ERb, however, they lacked the in vivo antagonism/agonism activity exhibited
by the lead class in an immature rat uterine growth model.
Ó 2004 Elsevier Ltd. All rights reserved.
The estrogen receptor is a nuclear hormone receptor,
which plays an important role in regulating the female
reproductive system, bone tissue, cardiovascular system,
and CNS. The concept of selective estrogen receptor
modulators (SERMs) has been widely explored as low-
risk yet an effective means to treat reproductive disor-
ders, estrogen-sensitive cancers, and osteoporosis.1;2 The
recent discovery of a new subtype of estrogen receptor,
ERb,3 and the anticipation of it possessing unique bio-
logical functions has prompted a new wave of effort
searching for subtype selective SERMs, or SERSMs
(Selective Estrogen Receptor Subtype Modulators).1c
preparation of dihydrobenzoxathiins, which is outlined
in Scheme 1. To this end, treatment of dithioketal
ketone 7 with NBS induced a series of tandem sulfur
bromination-migration, ring bromination, and aroma-
tization reactions leading to dithiin 8. Reductive cleav-
age of the alkyl group provided the previously
unknown, and pivotal synthon, 3,4-dimercaptophenol
(9). One of the freely exposed thiol groups in 9 was
selectively protected by a trityl group to give 10, whose
structure was confirmed by NOE experiments. We
found that the best conditions to influence this conver-
sion was the use of rotary evaporation under reduced
pressure to remove both the solvent (methylene chlo-
ride) and the HCl generated in situ in order to drive the
reaction to completion. A possible explanation for the
selectivity of the reaction is that in the absence of base
and presence of HCl, the thiol groups remain nonion-
ized and the inductively more nucleophilic one, para to
the phenol OH, reacted preferentially.
Previously we reported on
a new class of di-
hydrobenzoxathiin-based ERa selective SERMs or
SERAMs (Selective Estrogen Receptor Alpha Modula-
tors) (e.g. I–III).4 Since then, we have been engaged
in expanding the SAR of the class and now wish
to report the results obtained by replacing the
dihydrobenzoxathiin core with a dihydrobenzodithiin
core (1–6) (Fig. 1).
Coupling of the unprotected thiol group in 10 with
a-bromoketone 166 afforded 11. Utilization of the Kim
protocol (TFA–triethyl silane) led to the release of the
free thiol group and subsequent stereoselective, reduc-
tive cyclization gave rise to 12, the desired
dihydrobenzodithiin core, as judged by the small cou-
pling constant (J ¼ 3:4 Hz @ d ¼ 4:67 and 4.65 ppm)
between the two cis protons on the dithiin ring. Finally,
These compounds4e were synthesized utilizing the same
general strategy reported by Kim et al.4a;c;5 for the
Keywords: Estrogen receptor; Dihydrobenzodithiins; SERM; SERAM.
* Corresponding author. Tel.: +1-732-594-1276; fax: +1-732-594-9556;
e-mail: qiang_tan@merck.com
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.101

3754
Q. Tan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3753–3755
Figure 1.
Scheme 1. Synthesis of 1 and 2. Reagents and conditions: (a) NBS, methylene chloride, 40%. (b) Li, liquid ammonia, 98%. (c) Trityl chloride,
methylene chloride, then evaporate solvent 91%. (d) 16, triethyl amine, 51%. (e) TFA, triethyl silane, 65%. (f) MOMCl, NaH, THF. (g) TBAF, THF,
ca. 70% for two steps. (h) 1-Piperidineethanol, DIAD, triphenyl phosphine, THF. (i) 2 N HCl–MeOH–acetone, ca. 90% for two steps. (j) Mg, MeOH,
ca. 30%.
the piperidino ethyl side chain was installed by the use of
a Mitsunobu reaction, which in conjunction with pro-
tecting group manipulations provided 1. Subsequent
reduction of 1 provided 2. Similarly prepared were
compounds 3–6. (For more information on the prepa-
ration of relevant structures, see Refs. 4 and 5.)
the stimulatory effects on uterine tissue in the presence
and absence of estradiol.
In summary, the scope of the Kim protocol5 was
broadened by successfully applying it to the synthesis of
cis-di-substituted dihydrobenzodithiins. As with dihy-
drobenzoxathiins,4 the ERa selectivity of dihydrobenzo-
dithiins is thought to arise from the interaction of the
sulfur atom with the two discriminating residues of
protein binding cavities in ERa and ERb. However, the
replacement of the oxygen atom with a sulfur atom
significantly altered the size of the ring, which presum-
ably contributed to the reduction in binding affinity and
moreover, altered the native conformation of the aryl
appendages, which in turn dramatically impacted the
in vivo antagonism/agonism activity profile found in I–
III. Such a result is testimony to the very sensitive nature
of the estrogen receptor in response to the structural
As indicated in Table 1, racemic compounds 1–6
exhibited good affinity for ERa with an ERa/b selec-
tivity up to 40-fold, which is comparable to the dihy-
drobenzoxathiins I–III. Interestingly, the removal of the
bromine atom resulted in a significant decrease in the
binding affinity to ERa. Although compounds 1–6 do
inhibit estrogen-dependent growth of the MCF-7 cells,
they are substantially less potent than the di-
hydrobenzoxathiin class of compounds, and were found
to be devoid of either anti-estrogenic or estrogen-like
activity in an immature rat model designed to measure

Q. Tan et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3753–3755
Table 1. Human ER bindinga and inhibition of MCF-7 cell growth
3755
2. Representative SERMs: EVISTA: Grese, T. A.; Penning-
ton, L. D.; Sluka, J. P.; Adrian, M. D.; Cole, H. W.; Fuson,
T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler,
P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato,
M.; Glasebrook, A. L.; Bryant, H. U. J. Med. Chem. 1998,
41, 1272; NALVADEX: Jordan, V. C. Br. J. Pharmacol.
1993, 110, 507; EM-652, SCH57068: Labrie, M.; Labrie, C.;
Belanger, A.; Simard, J.; Giguere, V.; Tremblay, A.;
Tremblay, G. J. Steroid. Biochem. Mol. Biol. 2001, 79,
213; Lasofoxifene: Ke, H. Z.; Paralkar, V. M.; Grasser, W.
A.; Crawford, D. T.; Qi, H.; Simmons, H. A.; Pirie, C. M.;
Chidsey-Frink, K. L.; Owen, T. A.; Smock, S. L.; Chen, H.
K.; Jee, W. S. S.; Cameron, K. O.; Rosati, R. L.; Brown, T.
A.; DaSilva Jardine, P.; Thompson, D. D. Endocrinology
1998, 139, 2068; Bazedoxifene: Miller, C. P.; Collini, M. D.;
Tran, B. D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.;
Moran, R. A.; Henderson, R. A.; Bender, R. H. W.;
Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; Abou-
Gharbia, M. A. A.; Lyttle, C. R.; Komm, B. S. J. Med.
Chem. 2001, 44, 1654.
Compoundb
Binding affinity, IC50 (nM)
ERa/ERb (fold selective for
ERa)
MCF-7 inhibition
IC50 (nM)
1
4/161 (40)
15/583 (39)
4/87 (22)
152
564
114
67
2
3
4
5/111 (22)
18/266 (15)
21/326 (16)
0.8/45 (56)d
1.0/38 (38)f
4/115 (29)h
1.3/1.1 (1)j
5
123
112
3.0e
0.6g
0.4i
––
6
Ic
IIc
IIIc
Estradiol
a The single 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 re-
combinant human ERa and ERb proteins, with an incubation time of
3 h. In our experience, this assay provides IC50 values that are
reproducible to within a factor of 2–3.
3. (a) Kuiper, G. G. J. M.; Enmark, E.; Pelto-Huikko, M.;
Nilsson, S.; Gustafsson, J. A. Proc. Natl. Acad. Sci. U.S.A.
1996, 93, 5925; (b) Mosselman, S.; Polman, J.; Dijkema, R.
FEBS Lett. 1996, 392, 49.
b All new dihydrobenzodithiins are racemic and were characterized
spectroscopically.
c Chiral.
d Average of 36 measurements.
4. (a) Kim, S.; Wu, J. Y.; Birzin, E. T.; Frisch, K.; Chan, W.;
Pai, L.-Y.; Yang, Y. T.; Mosley, R. T.; Fitzgerald, P. M.
D.; Sharma, N.; Dahllund, J.; Thorsell, A.-G.; DiNinno,
F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L.
J. Med. Chem. 2004, 47, 2171; (b) Chen, H. Y.; Kim, S.;
Wu, J. Y.; Birzin, E. T.; Chan, W.; Yang, Y. T.; DiNinno,
F.; Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L.
Bioorg. Med. Chem. Lett. 2004, 14, 2551; (c) Kim, S.; Wu, J.
Y.; Chen, H. Y.; Birzin, E. T.; Chan, W.; Pai, L.-Y.; Yang,
Y. T.; Colwell, L.; Li, S.; Dahllund, J.; DiNinno, F.;
Rohrer, S. P.; Schaeffer, J. M.; Hammond, M. L. Bioorg.
Med. Chem. Lett. 2004, 14, 2741; (d) Tan, Q.; Birzin, E. T.;
Chan, W.; Yang, Y. T.; Pai, L.-Y.; Hayes, E. C.; DaSilva,
C. A.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J. M.;
Hammond, M. L. Bioorg. Med. Chem. Lett. 2004, 14,
in press; (e) DiNinno, F. P.; Chen, H. Y.; Kim, S.; Wu,
J. Y. International Patent WO200232377.
e Average of 7 measurements.
f Average of 101 measurements.
g Average of 5 measurements.
h Average of 2 measurements.
i Average of 2 measurements.
j Average of 130 measurements.
changes and has prompted future work toward under-
standing the SAR of the dihydrobenzoxathiin SERAM
platform.
References and notes
1. Recent reviews on SERMs: (a) Jordan, V. C. J. Med. Chem.
2003, 46, 883; (b) Jordan, V. C. J. Med. Chem. 2003, 46,
1081; (c) Meegan, M. J.; Lloyd, D. G. Curr. Med. Chem.
2003, 10, 181; (d) Miller, C. P. Curr. Pharm. Des. 2002, 8,
2089; (e) Bryant, H. U. Endocr. Metabol. Disord. 2002, 3,
231.
5. Kim, S.; Wu, J. Y.; Chen, H. Y.; DiNinno, F. Org. Lett.
2003, 5, 685.
6. Bromoketone 16 was obtained via a-bromination (THF,
PTAB, 0 °C to rt, 79%) of the corresponding ketone, which
was made according to the method in Ref. 4a,b.