LETTER
Improved Synthesis of a New Nonpeptidic Inhibitor of Human Neutrophil Elastase
301
Expert. Opin. Ther. Pat. 1999, 9, 869-895 and the literature
cited therein.
anate 17 followed by the addition reaction of benzyl alco-
hol to the formed isocyanate 17.8
(5) Veale, C. A.; Bernstein, P. R.; Bohnert, C. M.; Brown, F. J.;
Bryant, C.; Damewood, Jr. J. R.; Early, R.; Feeney, S. W.;
Edwards, P. D.; Gomes, B.; Hulsizer, J. M.; Kosmider, B. J.;
Krell, R. D.; Moore, G.; Salcedo, T. W.; Shaw, A.; Silberstein,
D. S.; Steelman, G. B.; Stein, M.; Strimpler, A.; Thomas, R.
M.; Vacek, E. P.; Williams, J. C.; Wolanin, D. J.; Woolson, S.
J. Med. Chem. 1997, 40, 3173-3181.
Synthesis of 15 from 10 was also improved as described
in Scheme 3b. The previous method consisting of 6 steps
via 18 and 19 was replaced by a new 4 step-synthesis via
aminoketone 14 as described in Scheme 2.
All the steps were carried out without column chromatog-
raphy on silica gel. Thus, practical synthesis of ONO-
6818 (1), the first clinical candidate for an orally active
non-peptidic inhibitor of HNE, was successfully carried
out. This method involves the unexplosive Lossen
rearrangement of 5 instead of an explosive Curtius re-
arrangement and the direct coupling reaction of Weinreb
amide 11 and the anion of 12 to form the right half 14.
(6) A communication and a full paper are being submitted to J.
Med. Chem.
(7) Brown, F. J.; Andisik, D. W.; Bernstein, P. R.; Bryant C. B.;
Ceccarelli, C.; Damewood, Jr. J. R.; Edwards, P. D.; Earley,
R. A.; Feeney, S.; Green, R. C.; Gomes, B.; Kosmider, B. J.;
Krell, R. D.; Shaw, A.; Steelman, G. B.; Thomas, R. M.;
Vacek, E. P.; Veale, C. A.; Tuthill, P. A.; Warner, P.;
Williams, J. C.; Wolanin, D. J.; Woolson S. A. J. Med. Chem.
1994, 37, 1259-1261.
(8) Veale, C. J.; Bernstein, P. R.; Bryant, C.; Ceccarelli, C.;
Damewood, Jr. J. R.; Earley, R.; Feeney, S. W.; Gomes, B.;
Kosmider, B. J.; Steelman, G. B.; Thomas, R. M.; Vacek, E.
P.; Williams, J. C.; Wolanin, D. J.; Woolson, S. J. Med.
Chem. 1995, 38, 98-108.
Full details regarding the right half will be reported in due
course.9
References and Notes
(1) Travis, J.; Dubin, A.; Potempa, J.; Watorek, W.; Kurdowska,
A. Ann. N.Y. Acad. Sci. 1991, 624, 81-86.
(9) Full details regarding the right half will be reported in J.
Heterocycl. Chem.
(2) Janoff, A. Am. Rev. Respir. Dis. 1985, 132, 417-433.
(3) Jackson, A. H.; Hill, S. L.; Afford, S. C.; Stockley, R. A. J.
Respir. Dis. 1984, 65, 114-124.
Article Identifier:
(4) For a comprehensive review of synthetic HNE inhibitors, see:
Metz W. A.; Peet N. P. Exp. Opin. Ther. Patents 1999, 9, 851-
868 and the literature cited therein. Skiles J. W.; Jeng A. Y.
1437-2096,E;2001,0,02,0299,0301,ftx,en;Y17100ST.pdf
Synlett 2001, No. 2, 299–301 ISSN 0936-5214 © Thieme Stuttgart · New York