D. H. Boschelli et al. / Bioorg. Med. Chem. 16 (2008) 405–412
411
hexane to all ethyl acetate provided 103 mg (26%) of 14,
mp 144–145 ꢁC. 1H NMR (400 MHz, TFA/DMSO-d6) d
3.35 (s, 3H), 3.77 (m, 2H), 4.38 (m, 2H), 7.40 (s, 1H),
7.60–7.65 (m, 2H), 7.73 (d, J = 9 Hz, 1H), 7.92 (s, 1H),
8.67 (d, J = 9Hz, 1H), 9.16 (s, 1H); MS 388.0 (MꢀH)ꢀ.
Analysis for C19H15Cl2N3O2: calcd C, 58.78; H, 3.89; N,
10.82. Found: C, 58.86; H, 3.90; N, 10.76.
amine in 8% yield as a white solid, mp 165–167 ꢁC, fol-
lowing flash column chromatography eluting with 30%
methanol in dichloromethane. 1H NMR (400 MHz,
DMSO-d6) d 1.76 (m, 2H), 2.17 (s, 6H), 2.33 (t,
J = 6 Hz, 2H), 2.90 (s, 3H), 3.26 (m, 2H), 3.84 (s, 3H),
3.97 (s, 3H), 6.37 (s, 1H), 6.77 (s, 1H), 7.21 (s, 1H),
7.63 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.27 (s, 1H);
MS 474.1 (MꢀH)+. Analysis for C23H25Cl2N5O2Æ1.0
H2O: calcd C, 56.10; H, 5.53; N, 14.22. Found: C,
55.97; H, 5.68; N, 14.23. Via the procedure used to pre-
pare 15 (use of 1-methyl-2-pyrrolidinone as solvent), 18
was obtained from 2 and 3-dimethylamino-1-propyl-
amine in 44% yield as a white solid, mp 163–165 ꢁC, fol-
lowing flash column chromatography eluting with a
gradient of 5% methanol in dichloromethane to 1%
aqueous ammonium hydroxide in 25% methanol in
dichloromethane. Analysis for C23H25Cl2N5O2Æ1.4
H2O: calcd C, 55.29; H, 5.61; N, 14.02. Found: C,
55.51; H, 5.54; N, 14.01.
5.1.14. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-{[3-(4-methylpiperazin-1-yl)propyl]amino}-3-quino-
linecarbonitrile (15). A mixture of 2 (200 mg, 0.51mmol)
and 1-(3-aminopropyl)-4-methylpiperazine (512 mg,
3.25 mmol) in 1.0 mL of 1-methyl-2-pyrrolidinone was
heated at 105 ꢁC for 29 h. The reaction mixture was
cooled to room temperature and treated with saturated
aqueous sodium bicarbonate for 1 h. The precipitate
was filtered, washed with water, and air-dried, then puri-
fied by flash chromatography, eluting with a gradient of
5% methanol in dichloromethane to 25% methanol in
dichloromethane. Trituration with ethyl ether containing
several drops of dichloromethane provided 158 mg (59%)
5.1.18. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{[3-
(dimethylamino)propyl]-(methyl)amino]-6-methoxy-3-quin-
olinecarbonitrile (19). Via the procedure used to prepare
16, 19 was obtained from 2 and N,N,N0-trimethyl-1,3-
propanediamine in 27% yield as a light yellow solid, mp
1
of 15 as an off-white solid, mp 215–217 ꢁC. H NMR
(400 MHz, DMSO-d6) d 1.80 (m, 2H), 2.20 (m, 2H),
2.92–2.49 (complex m, 10H), 3.28 (s, 3H), 3.84 (s, 3H),
3.99 (s, 3H), 6.68 (s, 1H), 6.76 (s, 1H), 7.22 (s, 1H), 7.64
(s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.29 (s, 1H); MS 529.2
(MꢀH)+. Analysis for C26H30Cl2N6O2: calcd C, 58.98;
H, 5.71; N, 15.87. Found: C, 59.09; H, 5.77; N, 15.70.
1
116–117 ꢁC. H NMR (400 MHz, DMSO-d6) d 1.68 (m,
2H), 2.10 (s, 6H), 2.21 (t, J = 7 Hz, 2H), 2.90 (s, 3H),
3.85 (s, 3H), 3.99 (s, 3H), 7.10 (s, 1H), 7.27 (s, 1H),
7.72 (s, 1H), 8.33 (s, 1H), 9.51 (s, 1H); MS 486.2
(MꢀH)ꢀ. Analysis for C24H27Cl2N5O2: calcd C, 59.02;
H, 5.57; N, 14.34. Found: C, 58.89; H, 5.67; N, 13.94.
5.1.15. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-[(2-methoxyethylamino]-3-quinolinecarbonitrile (16).
A mixture of 2 (250 mg, 0.64 mmol) and 2-methoxyethyl-
amine (1 mL) was heated at 105 ꢁC in a sealed tube for
6 h. The reaction mixture was cooled to room tempera-
ture, diluted with ethyl acetate, and washed with brine.
The organic layer was dried over sodium sulfate, filtered,
and concentrated. The residue was stirred with ethyl ace-
tate then filtered to give 170 mg (45%) of 16 as a white so-
Acknowledgments
The authors acknowledge the Wyeth Analytical Chemi-
cal Technology Department for the spectral data and
pharmaceutical profiling results, Dr. Ana Carolina Bar-
rios Sosa for the repreparation of 18, the Wyeth Drug
Safety and Metabolism Department for the nude mouse
microsome stability and plasma level determinations,
members of the Wyeth Oncology Department for the
kinase profiling data and Carlo Etienne for assistance
with the xenograft studies. We also thank Drs. Dennis
Powell, Kim Arndt, Jay Gibbons, Phil Frost and Tarek
Mansour for their support.
1
lid, mp 165–166 ꢁC. H NMR (400 MHz, DMSO-d6) d
3.30 (s, 3H), 3.42 (m, 2H), 3.59 (t, J = 6 Hz, 2H), 3.84
(s, 3H), 3.97 (s, 3H), 5.90 (s, 1H), 6.84 (s, 1H), 7.22 (s,
1H), 7.66 (s, 1H), 7.70 (s, 1H), 8.30 (s, 1H), 9.32 (s,
1H); MS 445.1 (MꢀH)ꢀ. Analysis for C21H20Cl2N4O3:
calcd C, 56.39; H, 4.51; N, 12.53. Found: C, 56.11; H,
4.37; N, 12.17.
5.1.16. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-6-meth-
oxy-7-[(3-morpholin-4-ylpropyl)amino]-3-quinolinecar-
bonitrile (17). Via the procedure used to prepare 15,
17 was obtained from 2 and 4-(3-aminopropyl)morphol-
ine in 59% yield as an off-white solid, mp 220–221 ꢁC.
1H NMR (400 MHz, DMSO-d6) d 1.80 (m, 2H), 3.35–
2.48 (complex m, 6H), 3.24–3.35 (m, 2H), 3.36 (m, 4H),
3.84 (s, 3H), 3.98 (s, 3H), 7.33 (s, 1H), 6.60 (s, 1H), 6.79
(s, 1H), 7.21 (s, 1H), 7.65 (s, 1H), 7.70 (s, 1H), 8.30 (s,
1H), 9.28 (s, 1H); MS 516.1 (MꢀH)+. Analysis for
C25H27Cl2N5O3: calcd C, 58.14; H, 5.27; N, 13.56. Found:
C, 58.28; H, 5.40; N, 13.67.
References and notes
1. Schwartzberg, P. L. Oncogene 1998, 17, 1463.
2. Frame, M. C. Biochim. Biophys. Acta 2002, 1602, 114.
3. Parsons, S. J.; Parsons, J. T. Oncogene 2004, 23, 7906.
4. Summy, J. M.; Gallick, G. E. Clin. Cancer Res. 2006, 12,
1398.
5. Alvarez, R. H.; Kantarjian, H. M.; Cortes, J. E. Cancer
2006, 107, 1918.
6. Chen, T.; George, J. A.; Taylor, C. C. Anti-Cancer Drugs
2006, 17, 123.
7. Mitra, S. K.; Schlaepfer, D. D. Curr. Opin. Cell Biol. 2006,
18, 516.
8. Avizienyte, E.; Wyke, A. W.; Jones, R. J.; McLean, G. W.;
Westhoff, M. A.; Brunton, V. G.; Frame, M. C. Nat. Cell
Biol. 2002, 4, 632.
5.1.17. 4-[(2,4-Dichloro-5-methoxyphenyl)amino]-7-{[3-
(dimethylamino)propyl]amino}-6-methoxy-3-quinolinecar-
bonitrile (18). Via the procedure used to prepare 16, 18
was obtained from 2 and 3-dimethylamino-1-propyl-