Anticancer Anthranilates
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 26 8251
9H), 8.27 (m, 1H), 8.49 (m, 1H), 9.55 (s, 1H, NH); IR (Nujol)
3323 (NH), 1695 (CO), 1613, 1588 cm-1. Anal. (C20H15F3N2O3)
C, H, N.
3277 (NH), 1702 (CO), 1623, 1587 cm-1. Anal. (C18H11-
ClF3N3O2) C, H, N.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic acid
3-Chlorophenyl Ester (28). Following the general procedure,
the title compound was obtained from 6b and 3-chlorophenol:
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
4-Methylthiophenyl Ester (19). Following the general pro-
cedure, the title compound was obtained from 6a and 4-me-
thylthiophenol: 0.328 g, yield 81%; mp 112-114 °C (isopropyl
ether/MeOH 3:1); 1H NMR (DMSO-d6) δ 3.45 (s, 3H, CH3),
7.28-7.88 (m, 9H), 8.29 (m, 1H), 8.50 (m, 1H), 9.54 (s, 1H,
NH); IR (Nujol) 3317 (NH), 1697 (CO), 1612, 1591 cm-1. Anal.
(C20H15F3N2O2S) C, H, N.
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
2-Chlorophenyl Ester (20). Following the general procedure,
the title compound was obtained from 6a and 2-chlorophenol:
0.306 g, yield 78%; mp 132-134 °C (isopropyl ether); 1H NMR
(DMSO-d6) δ 7.30 (m, 1H), 7.51 (m, 4H), 7.56 (m, 1H), 7.72
(m, 2H), 7.87 (m, 1H), 8.35 (m, 1H), 8.48 (m, 1H), 9.49 (s, 1H,
NH); IR (Nujol) 3323 (NH), 1704, 1614, 1596 cm-1. Anal.
(C19H12ClF3N2O2) C, H, N.
1
0.268 g, yield 68%; mp 68-70 °C (isopropyl ether); H NMR
(DMSO-d6) δ 7.34 (m, 1H), 7.69-7.47 (m, 4H), 8.13 (m, 1H),
8.51 (s, 1H), 8.74 (m, 3H), 10.43 (s, 1H, NH); IR (Nujol) 3288
(NH), 1703 (CO), 1610, 1588 cm-1. Anal. (C18H11ClF3N3O2) C,
H, N.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic Acid
4-Chlorophenyl Ester (29). Following the general procedure,
the title compound was obtained from 6b and 4-chlorophenol:
1
0.315 g, yield 80%; mp 86-88 °C (isopropyl ether); H NMR
(DMSO-d6) δ 7.35 (m, 1H), 7.53 (d, J ) 8.2 Hz, 2H), 7.69 (d, J
) 8.2 Hz, 2H), 8.10 (m, 1H), 8.52 (s, 1H), 8.79 (m, 3H), 10.45
(s, 1H, NH); IR (Nujol) 3283 (NH), 1695 (CO), 1610, 1584 cm-1
Anal. (C18H11ClF3N3O2) C, H, N.
.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic Acid
2,4-Dichlorophenyl Ester (30). Following the general pro-
cedure, the title compound was obtained from 6b and 2,4-
dichlorophenol: 0.368 g, yield 86%; mp 116-118 °C (isopropyl
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
3-Chlorophenyl Ester (21). Following the general procedure,
the title compound was obtained from 6a and 3-chlorophenol:
1
ether); H NMR (DMSO-d6) δ 7.36 (s, 1H), 7.73 (s, 2H), 8.00
1
0.314 g, yield 80%; mp 80-82 °C (isopropyl ether); H NMR
(s, 1H), 8.13 (m, 1H), 8.52 (s, 1H), 8.79 (m, 3H), 10.34 (bs, 1H,
NH); IR (Nujol) 3298 (NH), 1716 (CO), 1610, 1587 cm-1. Anal.
(C18H10Cl2F3N3O2) C, H, N.
(DMSO-d6) δ 7.32 (m, 3H), 7.48 (m, 3H), 7.60 (m, 1H), 7.73
(m, 1H), 7.85 (m, 1H), 8.29 (m, 1H), 8.49 (m, 1H), 9.51 (s, 1H,
NH); IR (Nujol) 3322 (NH), 1700 (CO) cm-1. Anal. (C19H12-
ClF3N2O2) C, H, N.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic Acid
Pyridin-3-yl Ester (31). Following the general procedure, the
title compound was obtained from 6b and 3-hydroxypyridine:
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
4-Chlorophenyl Ester (22). Following the general procedure,
the title compound was obtained from 6a and 4-chlorophenol:
1
0.278 g, yield 77%; mp 96-98 °C (isopropyl ether); H NMR
(DMSO-d6) δ 4.05 (s, 3H, CH3), 7.36 (m, 1H), 7.71 (m, 1H),
8.01 (m, 1H), 8.13 (m, 1H), 8.52 (s, 1H), 8.69 (m, 2H), 8.78 (m,
3H), 10.42 (s, 1H, NH); IR (Nujol) 3263 (NH), 1722 (CO), 1597
cm-1. Anal. (C17H11F3N4O2) C, H, N.
1
0.362 g, yield 92%; mp 84-85 °C (isopropyl ether); H NMR
(DMSO-d6) δ 7.30 (m, 1H), 7.40 (m, 2H), 7.46 (d, J ) 8.8 Hz,
2H), 7.64 (d, J ) 8.8 Hz, 2H), 7.73 (m, 1H), 7.85 (m, 1H), 8.29
(m, 1H), 8.49 (m, 1H), 9.51 (s, 1H, NH); IR (Nujol) 3321 (NH),
1697 (CO) 1613, 1592 cm-1. Anal. (C19H12ClF3N2O2) C, H, N.
Acknowledgment. The authors thank the Devel-
opmental Therapeutics Program of the National Cancer
Institute, Bethesda, MD, for providing the in vitro and
in vivo antitumor screening data.
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
2,4-Dichlorophenyl Ester (23). Following the general pro-
cedure, the title compound was obtained from 6a and 2,4-
dichlorophenol: 0.291 g, yield 68%; mp 100-102 °C (isopropyl
1
ether/MeOH 3:1); H NMR (DMSO-d6) δ 7.31 (m, 1H), 7.48-
Supporting Information Available: Experimental de-
tails and structural assignment for compounds 3 and 4.
Elemental analyses, spectral data, and tables of NCI’s in vitro
testing results. This material is available free of charge via
7.85 (m, 7H), 8.35 (m, 1H), 8.49 (m, 1H), 9.47 (s, 1H, NH); IR
(Nujol) 3325 (NH), 1698 (CO) 1628, 1588 cm-1. Anal. (C19H11-
Cl2F3N2O2) C, H, N.
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
2,4,6-Trichlorophenyl Ester (24). Following the general
procedure, the title compound was obtained from 6a and 2,4,6-
trichlorophenol: 0.259 g, yield 56%; mp 120-122 °C (isopropyl
ether/MeOH 3:1); 1H NMR (DMSO-d6) δ 7.32 (m, 3H), 7.54
(m, 2H), 7.77 (m, 2H), 7.91 (m, 1H), 7.99 (s, 1H), 8.43 (m, 1H),
8.49 (m, 1H), 9.45 (s, 1H, NH); IR (Nujol) 3328 (NH), 1724
(CO) 1613, 1593 cm-1. Anal. (C19H11Cl3F3N2O2) C, H, N.
References
(1) Shime, H.; Kariya, M.; Orii, A.; Momma, C.; Kanamori, T.;
Fukuhara, K.; Kusakari, T.; Tsuruta, Y.; Takakura, K.; Nikaido,
T.; Fujii, S. Tranilast inhibits the proliferation of uterine
leiomyoma cells in vitro through G1 arrest associated with the
induction of p21(waf1) and p53. J. Clin. Endocrinol. Metab. 2002,
87, 5610-5617.
(2) Yashiro, M.; Murahashi, K.; Matsuoka, T.; Nakazawa, K.;
Tanaka, H.; Osaka, H.; Koyama, T.; Ohira, M.; Chung, K. H.
Tranilast (N-3,4-dimethoxycinamoyl anthranilic acid): A novel
inhibitor of invasion-stimulating interaction between gastric
cancer cells and orthotopic fibroblasts. Anticancer Res. 2003, 23,
3899-904.
(3) Mo, H.; Tatman, D.; Jung, M.; Elson, C. E. Farnesyl anthranilate
suppresses the growth, in vitro and in vivo, of murine B16
melanomas. Cancer Lett. 2000, 157, 145-153.
N-(2-(Trifluoromethyl)pyridin-4-yl)anthranilic Acid
Pyridin-3-yl Ester (25). Following the general procedure, the
title compound was obtained from 6a and 3-hydroxypyridine:
1
0.298 g, yield 83%; mp 66-68 °C (isopropyl ether); H NMR
(DMSO-d6) δ 7.31 (m, 1H), 7.47 (m, 2H), 7.65 (m, 1H), 7.74
(m, 1H), 7.86 (m, 2H), 8.33 (m, 1H), 8.49 (m, 1H), 8.63 (s, 1H),
9.52 (s, 1H, NH); IR (Nujol) 3260 (NH), 1713 (CO), 1613, 1597
cm-1. Anal. (C18H12F3N3O2) C, H, N.
(4) (a) Sebolt-Leopold, J. S.; Dudley, D. T.; Herrera, R.; Van
Becelaere, K.; Wiland, A.; Gowan, R. C.; Tecle, H.; Barrett, S.
D.; Bridges, A.; Przybranowski, S.; Leopold, W. R.; Saltiel, A. R.
Blockade of the MAP kinase pathway suppresses growth of colon
tumors in vivo. Nat. Med. 1999, 5, 810-816. (b) Allen, L. F.;
Sebolt-Leopold, J.; Meyer, M. B. CI-1040 (PD184352), a targeted
signal transduction inhibitor of MEK (MAPKK). Semin. Oncol.
2003, 30, 105-116.
(5) (a) Manley, P. W.; Furet, P.; Bold, G.; Bru¨ggen, J.; Mestan, J.;
Meyer, T.; Schnell, C. R.; Wood, J. Anthranilic Acid Amides: A
Novel Class of Antiangiogenic VEGF Receptor Kinase Inhibitors
J. Med. Chem. 2002, 45, 5687-5693. (b) Manley, P. W.; Bold,
G.; Bru¨ggen, J.; Fendrich, G.; Furet, P.; Mestan, J.; Schnell, C.
R.; Stolz, B.; Meyer, T.; Meyhack, B.; Stark, W.; Strauss, A.;
Wood, J. Advances in the structural biology, design and clinical
development of VEGF-R kinase inhibitors for the treatment of
angiogenesis. Biochim. Biophys. Acta 2004, 1697, 17-27.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic Acid
3-Methoxyphenyl Ester (26). Following the general proce-
dure, the title compound was obtained from 6b and 3-meth-
oxyphenol: 0.285 g, yield 73%; mp 76-78 °C (isopropyl ether);
1H NMR (DMSO-d6) δ 4.05 (s, 3H, CH3), 7.08 (m, 2H), 8.09
(m, 1H), 8.51 (m, 3H), 8.68 (m, 4H), 10.62 (s, 1H, NH); IR
(Nujol) 3286 (NH), 1700 (CO), 1614, 1586 cm-1. Anal.
(C19H14F3N3O3) C, H, N.
2-(2-(Trifluoromethyl)pyridin-4-ylamino)nicotinic Acid
2-Chlorophenyl Ester (27). Following the general procedure,
the title compound was obtained from 6b and 2-chlorophenol:
1
0.248 g, yield 63%; mp 64-66 °C (isopropyl ether); H NMR
(DMSO-d6) δ 7.38 (m, 1H), 7.68 (m, 3H), 8.16 (m, 1H), 8.53 (s,
1H), 8.68 (m, 1H), 8.83 (m, 2H), 10.41 (s, 1H, NH); IR (Nujol)