446
V. Chiroli et al. / European Journal of Medicinal Chemistry 38 (2003) 441Á
/446
Table 1
Compound
Melting
point
1H-NMR (CDCl3) (ppm)
3 (meta
subst)
80Á
77Á
71Á
63Á
/
84 8C
79 8C
73 8C
64 8C
81 8C
10.04 (1H, s), 8.25 (1H, dd), 7.82 (1H, dd), 7.74Á
8.23 (1H, dd), 7.66 (1H, dt), 7.40 (2H, m), 7.30Á
8.24 (1H, dd), 7.67 (1H, t), 7.42 (1H, dd), 7.33Á7.14 (5H, m), 4.61 (2H, s), 2.33 (3H, s)
/
7.60 (3H, m), 7.45 (2H, m), 7.21 (2H, dd), 2.32 (3H, s)
4 (meta
subst)
/
/
7.15 (3H, m), 7.10 (1H, dd), 4.71 (2H, d), 2.32 (3H, s), 2.12 (1H, t)
5 (meta
subst)
/
/
NCX 4016
/
8.22 (1H, dd), 7.67 (1H, dt), 7.48 (1H, dt), 7.42 (1H, td), 7.33 (1H, dt), 7.26 (1H, d), 7.20 (2H, m), 5.45 (2H, s), 2.33
(3H, s)
3 (orto subst) 80Á
4 (orto subst) 115Á
115.2 8C
/
10.01 (1H, s), 8.20 (1H, dd), 7.98 (2H, m), 7.65 (1H, dt), 7.40 (3H, m), 7.21 (1H, dd), 2.31 (3H, s)
8.20 (1H, d), 7.83 (1H, t), 7.55 (1H, t), 7.42 (2H,d), 7.38 (1H, dd), 7.23(2H, m), 5.29 (1H, dt), 4.58 (2H, d); 2.30 (3H, s)
/
5 (orto subst) 108Á
/
110 8C 8.22 (1H, dd), 7.85 (1H, dt), 7.59 (3H, m), 7.30Á7.45 (3H, m), 4.86 (2H, s), 2.31(3H, s)
/
NCX 4040
3 (para subst) 78Á
4 (para subst) 70Á
5 (para subst) 91Á
86Á
/
88 8C
80 8C
73 8C
93 8C
54 8C
42 8C
8.18 (1H, dd), 7.77 (1H, dt), 7.58 (3H, m), 7.32 (3H, m), 5.61 (2H, s), 2.26 (3H, s)
10.19 (1H, s), 8.25 (1H, dd), 7.96 (1H, dd), 7.68 (2H, t), 7.45 (2H, m), 7.22 (2H, m), 2.29 (3H, s)
/
/
8.22 (1H, dd), 7.64 (1H, dt), 7.51 (1H, dd), 7.40Á
8.23 (1H, dd), 7.68 (1H, dt), 7.50(1H, dd), 7.40 (2H, t), 7.32Á
8.27 (1H, dd), 7.51 (1H, dt), 7.43Á7.20 (6H, m), 5.45 (2H, s), 2.32 (3H, s)
/7.25 (3H, m), 7.14 (2H, m), 4.61 (2H, s), 2.28 (3H, s), 2.05 (1H, s)
/
/7.18 (3H, m), 4.56 (2H, s), 2.30 (3H, s)
NCX 4060
9
52Á
/
/
39Á
/
8.08 (1H, dd), 7.72 (1H, t), 7.58 (1H, dt), 7.40 (1H, d), 7.30 (2H, m), 7.08 (1H, d), 5.40 (1H, d), 7.30 (2H, m), 7.08 (1H,
d), 5.40 (2H, s), 4.65 (2H, s), 2.21 (3H, s)
NCX 4050
12
109Á
oil
oil
/
110 8C 8.15 (1H, dd), 7.80 (1H, t), 7.60 (1H, t), 7.43Á7.25 (3H, m), 7.06 (1H, d), 5.55 (2H, s), 5.42 (2H, s), 2.25 (3H, s)
/
8.02 (1H, dd), 7.59 (1H, dt), 7.30 (1H, dd), 7.07(1H, dd), 4.43 (2H, t), 3.79 (4H, m), 3.63 (2H, t), 2.36 (3H, s)
8.00 (1H, dd), 7.53 (1H, dt), 7.29 (1H, dt), 7.07 (1H, dd), 4.58 (2H, t), 4.38 (2H, t), 3.75 (4H, t), 2.31 (3H, s)
NCX 4018
[13] J.L. Wallace, L.J. Ignarro, S. Fiorucci, Nat. Rev. Drug Discovery
While clinical trials currently ongoing will provide
more information on the action of NCX 4016 in patients
it is noteworthy that, unlike aspirin, in phase I studies
NCX 4016 has been found to spare the stomach at doses
producing clear COX inhibitory activity [26], therefore
providing further support to the concept of NO
cytoprotection.
1 (2002) 375Á
[14] M. Carini, G. Aldini, M. Orioli, R. Maffei Facino, J. Pharm.
Biomed. Anal. 29 (2002) 1061Á1071.
/383.
/
[15] M.N. Muscara, F. Lovren, W. McKnight, M. Dicay, P. Del
Soldato, C.R. Triggle, J.L. Wallace, Br. J. Pharmacol. 133 (2001)
1314Á
[16] G. Rossoni, B. Manfredi, V.D. Colonna, M. Bernareggi, F. Berti,
J. Pharmacol. Exp. Ther. 297 (2001) 380Á387.
[17] G. Rossoni, B. Manfredi, P. Del Soldato, F. Berti, Br. J.
Pharmacol. 137 (2002) 229Á236.
[18] G.M. Pieper, W. Siebeneich, C.L. Olds, C.C. Felix, P. Del
Soldato, Free Radic. Biol. Med. 32 (2002) 1143Á1156.
/1322.
/
/
References
/
[19] C. Napoli, G. Cirino, P. Del Soldato, R. Sorrentino, V. Sica, M.
[1] L. Jackson Roberts, II, J.D. Morrow, in: J.G. Hardman, L.E.
Limbird, A. Goodman Gilman (Eds.), Goodman and Gilman’s,
The Pharmacological Basis of Therapeutics, 10th ed., McGraw-
Condorelli, A. Pinto, L.J. Ignarro, Proc. Natl. Acad. Sci. USA 98
(2001) 2860Á2864.
/
[20] C. Napoli, G. Aldini, J.L. Wallace, F. de Nigris, R. Maffei
Facino, P. Abete, D. Bonaduce, G. Condorelli, F. Rengo, V. Sica,
F.P. D’Armiento, C. Mignogna, G. de Rosa, M. Condorelli, L.O.
Hill, USA, 2001, pp. 687Á
[2] J.R. Vane, Y.S. Bakhle, R.M. Botting, Annu. Rev. Pharmacol.
Toxicol. 38 (1998) 97Á120.
[3] L. Ma, P. Del Soldato, J.L. Wallace, Proc. Natl. Acad. Sci. USA
99 (2002) 13243Á13247.
[4] W.W. Zuurmond, Clin. Rheumatol. 20 (Suppl.) (2001) S6Á
[5] D. Mukherjee, S.E. Nissen, E.J. Topol, J. Am. Med. Assoc. 286
(2001) 954Á959.
[6] P. Del Soldato, R. Sorrentino, A. Pinto, Trends Pharmacol. Sci.
20 (1999) 319Á323.
[7] J.E. Keeble, P.K. Moore, Br. J. Pharmacol. 137 (2002) 295Á
[8] S. Moncada, Ann. N.Y. Acad. Sci. 811 (1997) 60Á69.
[9] A. Gasco, R. Fruttero, G. Sorba, Farmaco 51 (1996) 617Á
[10] P. DelSoldato, F. Sannicolo`, WO 95/30641.
[11] J.L. Wallace, Gastroenterology 112 (1997) 1000Á
[12] M. Carini, G. Aldini, R. Stefani, M. Orioli, R. Maffei Facino, J.
Pharm. Biomed. Anal. 26 (2001) 509Á518.
/
731.
/
Lerman, L.J. Ignaro, Proc. Natl. Acad. Sci. USA 98 (2002) 1689Á
/
1694.
[21] C.L. Wainwraight, A.M. Miller, L.M. Work, P. Del Soldato, Br.
/
/
S8.
J. Pharmacol. 135 (2002) 1882Á1888.
/
[22] S. Momi, M. Emerson, W. Paul, M. Leone, A.M. Mezzasoma, P.
/
Del Soldato, C.P. Page, P. Gresele, Eur. J. Pharmacol. 397 (2000)
177Á
[23] J.L. Williams, S. Borgo, I. Hasan, E. Castillo, F. Traganos, B.
Rigas, Cancer Res. 61 (2001) 3285Á3289.
[24] A.W. Bak, W. McKnight, P. Li, P. Del Soldato, A. Malignano, G.
Cirino, J.L. Wallace, Life Sci. 62 (1998) PL367ÁPL373.
[25] B. Rigas, J.L. Williams, Int. J. Oncol. 20 (2002) 885Á890.
[26] S. Fiorucci, L. Santucci, P. Gresele, R. Maffei Facino, P. Del
Soldato, A. Morelli, Gastroenterology 124 (2003) 600Á607.
/185.
/
/310.
/
/
/635.
/
/
1016.
/
/
/