D. J. Blythin et al. / Bioorg. Med. Chem. Lett. 12 (2002) 3161–3165
3165
Table 6. Amino acid derivatives in the 2R series
Shih, N.-Y.; Piwinski, J. J. Bioorg. Med. Chem. Lett. 2000, 10,
2329.
Compd
Y
NK1 Ki (nM)
NK2 Ki (nM)
7. Ting, P. C.; Lee, J. F.; Anthes, J. C.; Shih, N.-Y.; Piwinski,
J. J. Bioorg. Med. Chem. Lett. 2000, 10, 2333.
8. Bernstein, P. R.; Aharony, D.; Albert, J. S.; Andisik, D.;
Barthlow, H. G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.;
Dembofsky, B. T.; Koether, G.; Kosmider, B. J.; Kirkland,
K.; Ohnmacht, C. J.; Potts, W.; Rumsey, W. L.; Shen, L.;
Shenvi, A.; Sherwood, S.; Stollman, D.; Russell, K. Bioorg.
Med. Chem. Lett. 2001, 11, 2769.
20a
20b
20c
20d
20e
20f
S-Phg
R-Phg
S-Phe
R-Phe
S-Tyr
S-Trp
143
42
11
21
32
70
16
1.1
1.1
3.2
7.0
28
9. Desai, M. C.; Lefkowitz, S. L.; Thadeio, P. F.; Longo,
K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
10. After this project was begun a PCT application issued to
Fujisawa Pharmaceutical Co., Ltd., Japan WO97/22597 cov-
ering certain 2-aryl-substituted piperazines as neurokinin
antagonists. As far as we are aware, no literature publications
have appeared describing their work.
11. Godek, D. M.; Rosen, T. J. WO 91/18878. Chem. Abstr.
1992, 116, 106106.
12. Roderick, W. R.; Platte, H. J.; Pollard, C. B. J. Med.
Chem. 1966, 9, 181.
13. Cheng, Y. C.; Prusoff, W. H. Biochem. Pharmacol. 1973,
22, 3099.
14. We thank Dr. K. McCormick for developing the resolu-
tion methodology.
Scheme 6. (a) N-BOC-Z-CO2H, HOBT, Et3N, DEC; (b) 4 M HCl in
dioxane.
15. Watson, S. P. Br. J. Pharmacol. 1983, 80, 205.
16. Hall, J. M.; Morton, I. K. M. Br. J. Pharmacol. 1991, 102,
511.
17. Maggi, C. A.; Patacchini, R.; Robero, P.; Mali, A. Eur. J.
Pharmacol. 1989, 166, 435.
Acknowledgements
The authors would like to thank Mr. W. Tom for
developing the procedure described in reference 12, Mr.
C. Rizzo and Mr. S. Tozzi for the in vitro functional
assay data, Mr. Z. Zhan and Mr. C. Richard for the
NK1 and NK2 binding data, and Dr. J. Kaminski and
Ms. L. Weber for help with the X-ray structure repre-
sentation.
18. Ellis, J. L.; Undem, B. J.; Kays, J. S.; Ghanekar, S. V.;
Barthlow, H. G.; Buckner, C. K. J. Pharmacol. Exper. Ther.
1993, 267, 95.
19. Furchgott, R. F. Pharmacol. Rev. 1955, 7, 183.
20. Compound 15, mp 153–154 ꢀC, [a]23.9=À53.9ꢀ (3.54 mg
in 2 mL MeOH), was crystallized from 95% EtOH. Crystal
data: C20H28Cl2N2O4, M=431.46, orthorhombic, space
˚
˚
˚
group P212121, a=14.118(2) A, b=26.022(5) A, c=6.058(1) A,
V=2226(1) A , Z=4, Dcalcd=1.287 g cmÀ3, m(Cu Ka radiation,
3
˚
l=1.5418 A)=28.9 cmÀ1, crystal size: 0.03ꢁ0.06ꢁ0.60 mm.
˚
Intensity data (2640 non-equivalent reflections, ymax=75ꢀ)
were recorded on an Enraf-Nonius CAD4 diffractometer. The
crystal structure was solved by direct methods. Full-matrix
least-squares refinement of atomic positional and thermal
parameters (anisotropic C, Cl, N, O, fixed H contributions)
converged (max. shift:esd=0.03) at R=0.045 (Rw=0.058)
over 1446 reflections with I>2.0s(I). Crystallographic data
(excluding structure factors) have been deposited with the
Cambridge Crystallographic Data Centre, deposition number
CCDC 175702. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK (fax: +44–1223–336033; e-mail: deposit@ccdc.
cam.ac.uk).
References and Notes
1. Presented at the 221st National Meeting of the American
Chemical Society, San Diego, CA, April 1–5, 2001; MEDI
244.
2. Regoli, D.; Boudon, A.; Fauchere, J.-L. Pharmacol. Rev.
1994, 46, 551.
3. Advenier, C.; Lagente, V.; Boichot, E. Eur. Respir. J. 1997,
10, 1892.
4. Chapman, R. W.; Hey, J. A.; McLeod, R.; Minnicozzi, M.;
Rizzo, C. A. Drug News Perspect. 1998, 11, 480.
5. Gerspacher, M.; von Sprecher, A. Drugs Future 1999, 24, 883.
6. Reichard, G. R.; Ball, Z. T.; Aslanian, R.; Anthes, J. C.;