3982 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 18
Albert et al.
1
(10) Barnes, P. J .; Baraniuk, J . N.; Belvisi, M. G. Neuropeptides in
the respiratory tract. Part I. Am. Rev. Respir. Dis. 1991, 144,
1187-1198.
91%). H NMR (DMSO-d6): δ 8.67-8.58 (m), 8.07-8.02 (m),
7.72-7.65 (m), 7.64-7.43 (m), 7.37-7.34 (m), 7.02-7.01 (m),
6.98-6.87 (m), 6.77-6.74 (m), 6.31-6.28 (d, J ) 9), 4.55-4.52
(m), 4.35-4.34 (m), 4.03-3.92 (m), 4.03-3.92 (m), 3.78-3.72
(m), 3.68 (s, 3H), 3.45-3.37 (m), 3.29-2.89 (m), 2.73 (s 3H),
2.59-2.49 (m), 1.91-1.78 (m), 1.58-1.46 (m). MS m/z ) 457
(M+).
N-[2-(S)-(3,4-Dich lor op h en yl)-4-oxobu tyl]-N-m eth yl-3-
cya n o-2-m eth oxy-1-n a p h th a m id e (35). Compound 34 (5.69
g, 12.45 mmol) was oxidized using oxalyl chloride (2.17 mL)
and DMSO (3.53 mL) and Et3N (7.0 mL) in DCM (200 mL)
using typical Swern conditions22 to afford the aldehyde (5.0 g,
88%) after column chromatography (5% methanol and DCM).
1H NMR (DMSO-d6): δ 9.70-9.64 (ap m), 8.67-8.57 (ap m),
8.07-7.97 (m), 7.80 (s 1H), 7.72-7.55 (m), 7.52-7.48 (m),
7.40-7.33 (m), 7.12-7.02 (m), 6.87-6.83 (m), 6.37-6.34 (d, J
) 9), 4.53-4.44 (m), 4.11-4.00 (m), 3.94-3.92 (m), 3.91-3.73
(m), 3.71 (s, 3H), 3.45-3.38 (m), 3.14 (s), 2.97-2.95 (d, J ) 6),
2.63 (s, 3H), 2.60-2.49 (m). MS m/z 455 (M+).
N-((S)-2-(3,4-Dich lor oph en yl)-4-(4-(2-oxo-1-piper idin yl)-
4-(N-m eth ylam in ocar bon yl))-1-piper idin yl)bu tyl)-N-m eth -
yl-3-cya n o-2-m eth oxy-1-n a p h th a m id e (5). Compound 23
(0.52 g, 2.19 mmol) and compound 35 (1.0 g, 2.19 mmol) were
dissolved in methanol (10 mL) and stirred for 15 min, and
then, acetic acid (0.5 mL) was added. The reaction mixture
was allowed to stir for 1 h. Next, NaBH3CN (0.21 g) was added
and the reaction was allowed to stir overnight. The reaction
was quenched with aqueous NaHCO3 and extracted with
DCM, washed with brine, dried (MgSO4), and purified by
chromatography (5% methanol in DCM) to give the title
compound (740 mg, 50%) as a solid, which was converted to
the citrate salt by combining with 1 equiv of citric acid in
methanol and then concentrated and dried under reduced
pressure. 1H NMR (DMSO-d6): δ 8.70-8.63 (m), 8.08-7.91
(m), 7.77-7.72 (m), 7.68 (s), 7.66-7.61 (m), 7.58-7.54 (m),
7.49-7.47 (m), 7.39-7.33 (m), 7.06-7.03 (m), 6.88-6.79 (m),
6.32-6.29 (d J ) 9), 4.55-4.47 (m), 4.12-3.99 (m), 3.92-3.88
(m), 3.82-3.77 (m), 3.69 (s, 3H), 3.46-3.30 (m), 3.17-3.06 (m),
2.99-2.72 (m), 2.65-2.56 (m), 2.22-2.10 (m), 1.79-1.77 (m),
1.67-1.63 (m). MS m/z 678 (M+). Anal. calcd for C36H41N5O4-
Cl2, 1 citric acid, 1.34 water: C, 56.36; H, 5.82; N, 7.82.
Found: C, 56.34; H, 5.73; N, 7.80. Data from 1H NMR
spectroscopy and HPLC indicated that the product existed as
a mixture of atropisomers.
(11) Burkholder, T. P.; Kudlacz, E. M.; Maynard, G. D.; Liu, X.-G.;
Le, T.-B.; Webster, M. E.; Horgan, S. W.; Wenstrup, D. L.;
Freund, D. W.; Boyer, F.; Bratton, L.; Gross, R. S.; Knippenberg,
R. W.; Logan, D. E.; J ones, B. K.; Chen, T.-M.; Geary, J . L.;
Correll, M. A.; Poole, J . C.; Mandagere, A. K.; Thompson, T. N.;
Hwang, K.-K. Synthesis and structure-activity relationships for
a series of substituted pyrrolidine NK1/NK2 receptor antagonists.
Bioorg. Med. Chem. Lett. 1997, 7, 2531-2536.
(12) Ting, P. C.; Lee, J . F.; Anthes, J . C.; Shih, N. Y.; Piwinski, J . J .
Synthesis of substituted 4(Z)-(methoxyimino)pentyl-1-pipe-
ridines as dual NK1/NK2 inhibitors. Bioorg. Med. Chem. Lett.
2001, 11, 491-494.
(13) Shah, S. K.; Hale, J . J .; MacCoss, M.; Dorn, C. P., J r.; Qi, H.;
Miller, D. J .; Finke, P. E.; Meurer, L. C.; Cascieri, M. A.;
Sadowski, S.; Metzger, J . M.; Eiermann, G. J .; Forrest, M. J .;
MacIntyre, D. E.; Mills, S. G. Discovery of spiroindolinopiperi-
dine derivatives as potent, orally active dual antagonists of NK1
and NK2 receptors. Abstr. Pap.-Am. Chem. Soc. 2000, 220,
MEDI-195.
(14) Greenfeder, S.; Cheewatrakoolpong, B.; Billah, M.; Egan, R. W.;
Keene, E.; Murgolo, N. J .; Anthes, J . C. The neurokinin-1 and
neurokinin-2 receptor binding sites of MDL103,392 differ.
Bioorg. Med. Chem. 1999, 7, 2867-2876.
(15) Reichard, G. A.; Ball, Z. T.; Aslanian, R.; Anthes, J . C.; Shih, N.
Y.; Piwinski, J . J . The design and synthesis of novel NK1/NK2
dual antagonists. Bioorg. Med. Chem. Lett. 2000, 10, 2329-2332.
(16) Bernstein, P. R.; Aharony, D.; Albert, J . S.; Andisik, D.; Barth-
low, H. G.; Bialecki, R.; Davenport, T.; Dedinas, R. F.; Dembo-
fsky, 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. Discovery of novel, orally active dual
NK1/NK2 antagonists. Bioorg. Med. Chem. Lett. 2001, 11, 2769-
2773.
(17) Rumsey, W. L.; Aharony, D.; Bialecki, R. A.; Abbott, B. M.;
Barthlow, H. G.; Caccese, R.; Ghanekar, S.; Lengel, D.; McCar-
thy, M.; Wenrich, B.; Undem, B.; Ohnmacht, C.; Shenvi, A.;
Albert, J . S.; Brown, F.; Bernstein, P. R.; Russell, K. Pharma-
cological characterization of ZD6021:
a novel, orally active
antagonist of the tachykinin receptors. J . Pharmacol. Exp. Ther.
2001, 298, 307-315.
(18) Sebok, P.; Timar, T.; Eszenyi, T.; Patonay, T. The first synthesis
of 7-alkylthio-2,2-dimethyl-2H-chromenes, the sulfur analogues
of natural and synthetic precocenes. Synthesis 1994, 8, 837-
840.
(19) Pitchen, P.; Dunach, E.; Deshmukh, M. N.; Kagan, H. B. An
efficient asymmetric oxidation of sulfides to sulfoxides. J . Am.
Chem. Soc. 1984, 106, 8188-8193.
(20) Wood, J . L.; Khatri, N. A.; Weinreb, S. M. A direct conversion of
esters to nitriles. Tetrahedron Lett. 1979, 51, 4907-4910.
(21) Miller, S. Preparation of Bicyclic Heterocycles as Neurokinin A
Antagonists. 1995, WO 9515961 A9515961 19950615.
(22) Mancuso, A.; Huang, S.; Swern, D. Oxidation of Long-Chain and
Related Alcohols to Carbonyls by Dimethyl Sulfoxide “Activated”
by Oxalyl Chloride. J . Org. Chem. 1978, 43, 2480-2482.
(23) Buckner, C. K.; Liberati, N.; Dea, D.; Lengel, D.; Stinson-Fisher,
C.; Campbell, J .; Miller, S.; Shenvi, A.; Krell, R. D. Differential
blockade by tachykinin NK1 and NK2 receptor antagonists of
bronchoconstriction induced by direct-acting agonists and the
indirect-acting mimetics capsaicin, serotonin and 2-methyl-
serotonin in the anesthetized guinea pig. J . Pharmacol. Exp.
Ther. 1993, 267, 1168-1175.
(24) Saria, A.; Lundberg, J . M.; Skofitsch, G.; Lembeck, F. Vascular
protein leakage in various tissues induced by substance P,
capsaicin, bradykinin, serotonin, histamine and by antigen
challenge. Naunyn-Schmiedeberg’s Arch. Pharmacol. 1983, 324,
212-218.
(25) Clayden, J .; Pink, J . H. Concerted rotation in a tertiary aromatic
amide: towards a simple molecular gear. Angew. Chem., Int.
Ed. 1998, 37, 1937-1939.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for the synthesis of 36a -k , 37a -g, 38b-f, 39a -e, and
40a -e. This material is available free of charge via the
Internet at http://pubs.acs.org.
Refer en ces
(1) Ribeiro-Da-Silva, A.; McLeod, A. L.; Krause, J . E. Neurokinin
receptors in the CNS. Handb. Chem. Neuroanat. 2000, 16, 195-
240.
(2) Stout, S. C.; Owens, M. J .; Nemeroff, C. B. Neurokinin-1 receptor
antagonists as potential antidepressants. Annu. Rev. Pharmacol.
Toxicol. 2001, 41, 877-906.
(3) Chahl, L. A.; Urban, L. A. New developments in tachykinin
research. Pharmacol. Rev. Commun. 1999, 10, 197-203.
(4) Swain, C.; Rupniak, N. M. J . Progress in the development of
neurokinin antagonists. Annu. Rep. Med. Chem. 1999, 34, 51-
60.
(5) Gerspacher, M.; Von Sprecher, A. Dual neurokinin NK1/NK2
receptor antagonists. Drugs Future 1999, 24, 883-892.
(6) Gao, Z.; Peet, N. P. Recent advances in neurokinin receptor
antagonists. Curr. Med. Chem. 1999, 6, 375-388.
(7) Sakurada, T.; Sakurada, C.; Tan-No, K.; Kisara, K. Neurokinin
receptor antagonists: therapeutic potential in the treatment of
pain syndromes. CNS Drugs 1997, 8, 436-447.
(26) Ahmed, A.; Bragg, R. A.; Clayden, J .; Lai, L. W.; McCarthy, C.;
Pink, J . H.; Westlund, N.; Yasin, S. A. Barriers to rotation about
the chiral axis of tertiary aromatic amides. Tetrahedron 1998,
54, 13277-13294.
(27) Manuscript in preparation.
(28) For compounds that displayed nonpurely competitive antago-
nism, affinity could be approximately evaluated by monitoring
the magnitude of the maximum tissue relaxation response (%
of control response) to increasing agonist concentration following
incubation of the tissue with the antagonist at a given concen-
tration. Thus, higher antagonist affinity would be indicated by
greater suppression (lower percentage of control response) at
lower concentration. For compounds showing this type of
behavior, observations were as follows: 38b, 37% at 30 nM; 38c,
42% at 10 nM; 38d , 17% at 10 nM; and 38f, 42% at 100 nM.
(8) Shenvi, A. B.; Aharony, D.; Brown, F. J .; Buckner, C. K.;
Campbell, J . B.; Dedinas, R. F.; Gero, T. W.; Green, R. C.; J acobs,
R. T.; Kusner, E. J .; Miller, S. C.; Ohnmacht, C.; Palmer, W.;
Smith, R.; Steelman, G.; Ulatowski, T.; Veale, C.; Walsh, S.
Abstracts of Papers, Part 1, 214th National Meeting of the
American Chemical Society, Las Vegas, NV, Sept 7-1, 1997;
American Chemical Society: Washington, DC, 1997; MEDI 264.
(9) Advenier, C.; J oos, G.; Molimard, M.; Lagente, V.; Pauwels, R.
Role of tachykinins as contractile agonists of human airways in
asthma. Clin. Exp. Allergy 1999, 29, 579-584.