B. Marvania et al. / Bioorg. Med. Chem. 19 (2011) 1987–1998
1997
8.45–8.46 (1H, m, ArH), 8.52 (1H, s, ArH), 8.57, 8.83, 9.85 (each 1H,
s, exchangeable, 3 Â NH). Anal. (C25H22Cl3FN6O): C, H, N.
5.8.13. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3,4,
5-trimethoxyphenylamino)quinazolin-6-yl)urea (21n)
Compound 21n was synthesized from 14 (freshly prepared from
13, 1.00 g, 3.2 mmol) and N4-(3,4,5-trimethoxyphenyl)quinazolin-
4,6-diamine (20n, 0.42 g, 1.3 mmol) in dry THF (25 mL) containing
triethylamine (0.9 mL): yield 0.49 g (66%); mp 154–155 °C (dec);
5.8.8. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3,4-dichloro-
phenylamino)quinazolin-6-yl)urea (21i)
Compound 21i was synthesized from 14 (freshly prepared from
13, 1.00 g, 3.2 mmol) and N4-(3,4,-dichlorophenyl)quinazolin-4,6-
diamine (20i, 0.40 g, 1.3 mmol) in dry THF (25 mL) containingtrieth-
ylamine (0.9 mL): yield 0.55 g (71%); mp 225–226 °C (dec); 1H NMR
(DMSO-d6) d 3.67–3.73 (8H, m, 4 Â CH2), 6.74 (2H, d, J = 8.8 Hz,
2 Â ArH), 7.34 (2H, d, J = 8.8 Hz, 2 Â ArH), 7.61–7.63 (1H, m, ArH),
7.75–7.77 (1H, m, ArH), 7.87–7.90 (2H, m, 2 Â ArH), 8.28–8.29 (1H,
m, ArH), 8.47–8.48 (1H, m, ArH), 8.57 (1H, s, ArH) 8.58, 8.86, 9.91
(each 1H, s, exchangeable, 3 Â NH). Anal. (C25H22Cl4N6O): C, H, N.
1H NMR (DMSO-d6)
d 3.33 (3H, s, Me), 3.67–3.72 (8H, m,
4 Â CH2), 3.80 (6H, s, 2 Â Me), 6.74 (2H, d, J = 9.0 Hz, 3 Â ArH),
7.28 (2H, s, 2 Â ArH), 7.34 (2H, d, J = 9.0 Hz, 2 Â ArH), 7.73 (1H, d,
J = 8.9 Hz, ArH), 7.85–7.88 (1H, dd, J = 2.0 Hz, J = 8.9 Hz, ArH), 8.42
(1H, d, J = 2.0 Hz, ArH), 8.49 (1H, s, ArH) 8.56, 8.81, 9.58 (each
1H, s, exchangeable, 3 Â NH). Anal. (C28H30Cl2N6O4ÁH2O): C, H, N.
5.8.14. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3-ethynyl-
phenylamino)quinazolin-6-yl)urea (21o)
5.8.9. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3-bromo-4-
fluorophenylamino)quinazolin-6-yl)urea (21j)
Compound 21o was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(3-ethynylphenyl)quinazolin-4,6-dia-
mine (20o, 0.68 g, 2.6 mmol) in dry THF (35 mL) containing trieth-
ylamine (1.8 mL): yield 0.75 g (52%); mp 164–165 °C (dec); 1H
NMR (DMSO-d6) d 3.67–3.73 (8H, m, 4 Â CH2), 4.19 (1H, s, CH),
6.73 (2H, d, J = 8.8 Hz, 2 Â ArH), 7.20–7.21 (1H, m, ArH), 7.34 (2H,
d, J = 8.8 Hz, 2 Â ArH), 7.37–7.41 (1H, m, ArH), 7.73–7.76 (1H, m,
ArH), 7.88–7.90 (2H, m, 2 Â ArH), 8.03–8.04 (1H, m, ArH), 8.44–
8.45 (1H, m, ArH), 8.52 (1H, s, ArH) 8.58, 8.82, 9.78 (each 1H, s,
exchangeable, 3 Â NH). Anal. (C27H24Cl2N6OÁH2O): C, H, N.
Compound 21j was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(3-bromo-4-fluorophenyl)quinazolin-
4,6-diamine (20j, 0.87 g, 2.6 mmol) in dry THF (35 mL) containing
triethylamine (1.8 mL): yield 0.25 g (17%); mp 175–176 °C (dec);
1H NMR (DMSO-d6) d 3.73–3.75 (8H, m, 4 Â CH2), 6.76 (2H, d,
J = 8.8 Hz, 2 Â ArH), 7.36 (2H, d, J = 8.8 Hz, 2 Â ArH), 7.41–7.43
(1H, m, ArH), 7.77 (1H, d, J = 9.2 Hz, ArH), 7.87–7.90 (2H, m,
2 Â ArH), 8.26 (1H, dd, J = 2.2 Hz, J = 9.2 Hz, ArH), 8.48 (1H, d,
J = 2.2 Hz ArH), 8.54 (1H, s, ArH), 8.63, 8.89, 9.86 (each 1H, s,
exchangeable, 3 Â NH). Anal. (C25H22BrCl2FN6OÁ1.5H2O): C, H, N.
5.8.15. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(4-phenoxy-
phenylamino)quinazolin-6-yl)urea (21p)
5.8.10. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(4-chloro-3-
(trifluoromethyl)phenylamino)quinazolin-6-yl)urea (21k)
Compound 21k was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(4-chloro-3-(trifluoromethyl)phenyl)
quinazolin-4,6-diamine (20k, 0.80 g, 2.6 mmol) in dry THF (35 mL)
containing triethylamine (1.8 mL): yield 0.80 g (52%); mp 220–
221 °C (dec); 1H NMR (DMSO-d6) d 3.67–3.73 (8H, m, 4 Â CH2),
6.73 (2H, d, J = 8.8 Hz, 2 Â ArH), 7.34 (2H, d, J = 8.8 Hz, 2 Â ArH),
7.71–7.73 (1H, m, ArH), 7.76–7.92 (1H, m, ArH), 7.85–7.88 (1H, m,
ArH), 8.27–8.31 (1H, m, ArH), 8.43–8.44 (1H, m, ArH), 8.51–8.52
(1H, m, ArH), 8.56 (1H, s, ArH) 8.57, 8.87, 10.05 (each1H, s, exchange-
able, 3 Â NH). Anal. (C26H22Cl3F3N6OÁ0.5H2O): C, H, N.
Compound 21p was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(4-phenoxyphenyl)quinazolin-4,6-
diamine (20p, 0.85 g, 2.6 mmol) in dry THF (35 mL) containing tri-
ethylamine (1.8 mL): yield 0.30 g (33%); mp 143–144 °C (dec); 1H
NMR (DMSO-d6) d 3.31–3.71 (8H, m, 4 Â CH2), 6.72–6.74 (2H, m,
2 Â ArH), 7.01–7.07 (4H, m, 4 Â ArH), 7.10–7.14 (1H, m, ArH),
7.32–7.41 (4H, m, 4 Â ArH), 7.71–7.73 (1H, m, ArH), 7.81–7.90 (3H,
m, 3 Â ArH), 8.41–8.42 (1H, m, ArH), 8.46 (1H, s, ArH) 8.58, 8.80,
9.73 (each 1H, s, exchangeable, 3 Â NH). Anal. (C31H28Cl2N6O2ÁH2O):
C, H, N.
5.8.16. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3-chloro-4-
(pyridin-2-ylmethoxy)phenylamino)quinazolin-6-yl)urea (21q)
Compound 21q was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(3-chloro-4-(pyridin-2-ylmeth-
oxy)phenyl)quinazolin-4,6-diamine (20q, 0.98 g, 2.6 mmol) in dry
THF (35 mL) containing triethylamine (1.8 mL): yield 0.90 g (56%);
mp 156–157 °C (dec); 1H NMR (DMSO-d6) d 3.68–3.74 (8H, m,
4 Â CH2), 5.30 (2H, s, CH2), 6.74 (2H, d, J = 9.0 Hz, 2 Â ArH), 7.25–
7.27 (1H, m, ArH), 7.34 (2H, d, J = 9.0 Hz, 2 Â ArH), 7.37–7.39 (1H,
m, ArH), 7.58–7.60 (1H, m, ArH), 7.69–7.74 (2H, m, 2 Â ArH), 7.86–
7.91 (2H, m, 2 Â ArH), 8.01–8.02 (1H, m, ArH), 8.42–8.42 (1H, m,
ArH), 8.48 (1H, s, ArH), 8.60–8.61 (1H, m, ArH) 8.57, 8.80, 9.72 (each
1H, s, exchangeable, 3 Â NH). Anal. (C31H28Cl3N7O2Á1.5H2O): C, H, N.
5.8.11. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3-chloro-4-
methoxyphenylamino)quinazolin-6-yl)urea (21l)
Compound 21l was synthesized from 14 (freshly prepared from
13, 2.00 g, 6.5 mmol) and N4-(3-chloro-4-methoxyphenyl)quinazo-
lin-4,6-diamine (20l, 0.78 g, 2.6 mmol) in dry THF (35 mL) contain-
ing triethylamine (1.8 mL): yield 1.0 g (69%); mp 168–169 °C (dec);
1H NMR (DMSO-d6) d 3.69–3.72 (8H, m, 4 Â CH2), 3.87 (3H, s, Me),
6.73 (2H, d, J = 8.6 Hz, 2 Â ArH), 7.17–7.19 (1H, m, ArH), 7.34 (2H,
d, J = 8.6 Hz, 2 Â ArH), 7.72–7.73 (2H, m, 2 Â ArH), 7.85–7.87 (1H,
m, ArH), 7.96–7.97 (1H, m, ArH), 8.42–8.43 (1H, m, ArH), 8.47
(1H, s, ArH) 8.56, 8.79, 9.70 (each 1H, s, exchangeable, 3 Â NH).
Anal. (C26H25Cl3N6O2ÁH2O): C, H, N.
5.8.12. 1-(4-(Bis(2-chloroethyl)amino)phenyl)-3-(4-(3-methoxy-
phenylamino)quinazolin-6-yl)urea (21m)
5.9. Biological experiments
Compound 21m was synthesized from 14 (freshly prepared
from 13, 2.50 g, 8.1 mmol) and N4-(3-methoxyphenyl)quinazolin-
4,6-diamine (20m, 0.87 g, 3.2 mmol) in dry THF (35 mL) containing
triethylamine (2.2 mL): yield 1.1 g (65%); mp 159–160 °C (dec); 1H
NMR (DMSO-d6) d 3.69–3.71 (8H, m, 4 Â CH2), 3.78 (3H, s, Me),
6.68–7.70 (1H, m, ArH), 6.73 (2H, d, J = 9.0 Hz, 2 Â ArH), 7.26–
7.28 (1H, m, ArH), 7.33 (2H, d, J = 9.0 Hz, 2 Â ArH), 7.45–7.46 (1H,
m, ArH), 7.52–7.53 (1H, m, ArH), 7.73 (1H, d, J = 9.0 Hz, ArH),
7.90 (1H, dd, J = 2.1 Hz, J = 9.0 Hz, ArH), 8.42 (1H, d, J = 2.1 Hz,
ArH), 8.50 (1H, s, ArH) 8.57, 8.81, 9.65 (each 1H, s, exchangeable,
3 Â NH). Anal. (C26H26Cl2N6O2ÁH2O): C, H, N.
5.9.1. Cytotoxicity assays
The effects of the newly synthesized compounds on cell growth
were determined in T-cell acute lymphocytic leukemia CCRF-CEM)
and their resistant subcell lines (CCRF-CEM/Taxol and CCRF-CEM/
VBL) by the XTT assay28 and human solid tumor cells (i.e., breast
carcinoma MX-1 and colon carcinoma HCT-116) by the SRB assay29
in a 72 h incubation using a microplate spectrophotometer as de-
scribed previously.30 After the addition of phenazine methosul-
fate-XTT solution at 37 °C for 6 h, absorbance at 450 and 630 nm
was detected on a microplate reader (EL 340; Bio-Tek Instruments
Inc., Winooski, VT). The cytotoxicity of the newly synthesized