Organic Process Research & Development 2004, 8, 897−902
A Scaleable Synthesis of Fiduxosin
Anthony R. Haight,* Anne E. Bailey,† William S. Baker, Michael H. Cain, Richard R. Copp,‡ John A. DeMattei,§
Kelley L. Ford, Rodger F. Henry, Margaret C. Hsu, Robert F. Keyes, Steven A. King, Maureen A. McLaughlin,
Laura M. Melcher, William R. Nadler,| Patricia A. Oliver, Shyamal I. Parekh, Hemant H. Patel,# Louis S. Seif,
Mike A. Staeger, Gregory S. Wayne, Steven J. Wittenberger, and Weijiang Zhang3
GPRD Process Research and DeVelopment, Abbott Laboratories, Building R8/1, 1401 Sheridan Road,
North Chicago, Illinois 60064-6285, U.S.A.
Abstract:
Fiduxosin (1) has been under development at Abbott Labora-
tories for the treatment of benign prostatic hyperplasia. A
convergent strategy required methodologies for preparation of
an enantiomerically pure 3,4-cis-disubstituted pyrrolidine and
a 2,3,5-trisubstituted thienopyrazine in a regiospecific manner.
A [3+2] cycloaddition of an enantiopure azomethine ylide
followed by a diastereoselective crystallization was employed
to prepare the benzopyranopyrrolidine in high diastereomeric
and enantiomeric purity. Conditions for reduction of an O-aryl
lactone susceptible to epimerization were developed, and cy-
clization of the alcohol/phenol to the ether was accomplished
in high yield. The thienopyrazine was prepared by condensation
of methyl thioglycolate and a regiospecifically prepared 2-bromo-
3-cyano-5-phenylpyrazine. Conditions for effective halogen
substitutive deamination to prepare regiospecific trisubstituted
Figure 1. BPH antagonists.
pyrazines will be described.
blocking of the R1-adrenoreceptor sites can successfully treat
the physiological effects of BPH.3
The first R1-antagonists approved for the treatment of BPH
(terazosin,3 prazosin,4 and doxazosin5) had previously been
Introduction
introduced as therapies for hypertension. It is not surprising
then that cardiovascular side effects limited the dosing of
these agents for the treatment of BPH. Binding and functional
assays have demonstrated that the R1-adrenoreceptors are
composed of at least three native subtypes: R1a-, R1b-, and
R1d-adrenoreceptor sites with the R1a-site attributed to the
uroselectivity.6 Tamsulosin (Flomax), 2,7 was the first
compound designed with improved R1a/R1b-selectivity for the
treatment of BPH (Figure 1).
At Abbott, the R1a-antagonist fiduxosin (1) was found to
have improved uroselectivity relative to tamsulosin.8 To
further advance development of fiduxosin, a scaleable
synthetic route was necessary. We describe here our efforts
Benign prostatic hyperplasia (BPH), or the nonmalignant
enlargement of the prostate gland, is a disorder associated
with up to 80% of all males over the age of 60.1 Typical
symptoms of BPH include nocturia, increased frequency of
urination, and low urine flow caused, in part, by the
enlargement of the prostate gland and contraction of the
smooth muscle tissue surrounding the bladder neck. The
finding by Caine2 that the smooth muscle of the prostate
and bladder neck contains large numbers of R-adrenoreceptor
sites led to the experimental observation that the nonselective
R2/R1-adrenoreceptor antagonist, phentolamine, could ef-
fectively address the symptoms of BPH. Clinical evidence
with the selective R1-adrenoreceptor antagonist prazosin and
further functional studies have led to the recognition that
(3) Lepor, H.; Henry, D.; Laddu, A. R. Prostate 1991, 18, 345.
(4) Hedlund, H.; Andresson, K.-E.; Ek, A. J. Urol. 1983, 130, 275.
(5) Holme, J. B.; Christensen, M. M.; Rasmussen, P. C.; Jacobsen, F.; Nielsen,
J.; Norgaard, J. P.; Olesen, S.; Noer, L.; Wolf, H.; Husted, S. E. Scand. J.
Urol. 1994, 28, 77.
(6) Hieble, J. P.; Ruffolo, R. R. Exp. Opin. InVest. Drugs 1997, 6, 367. Meyer,
M. D.; Altenbach, R. J.; Bai, H.; Basha, F. Z.; Carroll, W. A.; Kerwin, J.
F.; Lebold, S. A.; Lee, E.; Pratt, J. K.; Sippy, K. B.; Tietje, K.; Wendt, M.
D.; Brune, M. E.; Buckner, S. A.; Hancock, A. A.; Drizin, I. J. Med. Chem.
2001, 44, 1971 and references therein.
* To whom correspondence should be addressed. E-mail: anthony.haight@
abbott.com.
† Present address: Hospira Inc., 275 N. Field Dr., Lake Forest, IL 60045.
‡ Present address: Quintessence Biosciences, 505 S. Rosa Rd., Madison, WI
53719.
§ Present address: Array Biopharma 1885 33rd St., Boulder, CO 80301.
| Present address: Industria Farmaceutica Serono, Via Luigi Einaudi, 11,
00012 Guidonia-Montecelio, Italy.
Present address: Vertex Pharmaceuticals, Boston, MA.
# Present address: Gujarat Industrial Chemicals, 388 620 Gujarat, India.
3 Present address: Theravance Inc., 901 Gateway Blvd. South, San Francisco,
CA 94080.
(7) Yamada, S.; Suzuki, M.; Tanaka, C.; Mori, R.; Kimura, R.; Inagaki, O.;
Honda, K.; Asano, M.; Takenaka, T.; Kawabe, K. Clin. Exp. Pharmacol.
Physiol. 1994, 21, 405.
(1) Bock, M. G.; Patane, M. A. Ann. Rep. Med. Chem. 2000, 35, 221. Garraway,
W. M.; Collins, G. N.; Lee, R. J. Lancet 1991, 338, 469.
(2) Caine, M.; Pfau, A.; Perlberg, S. Brit. J. Urol. 1976, 48, 255.
(8) Hancock, A. A.; Buckner, S. A.; Brune, M. E.; Esbenshade, T. A.; Ireland,
L. M.; Katwala, S.; Milicic, I.; Meyer, M. D.; Kerwin, J. F., Jr.; Williams,
M. J. Pharmacol. Exp. Ther. 2002, 300, 478.
10.1021/op049889k CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/16/2004
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