Synthesis and biological activity of novel N-substituted 4-amino-6,7,8-trimethoxyquinazoline compounds

Article abstract of DOI:10.1007/s10593-007-0196-5

A series of N-substituted 4-amino-6,7,8-trimethoxyquinazoline derivatives has been synthesized from 4-chloro-6,7,8-trimethoxyquinazoline and aryl (or benzyl) amines using 2-propanol as a solvent. The starting material 4-chloro-6,7,8-trimethoxyquinazoline has been synthesized from natural gallic acid by a novel route. Their structures have been verified by elemental analysis and IR, ¹H, and ¹³C NMR spectroscopy. The title compounds have been evaluated for their in vitro antiproliferative activities against some cancer cells by the MTT method. Unfortunately, most of the compounds tested have exhibited a weaker anticancer activity than the reference standard drug PD153035.

Full text of DOI:10.1007/s10593-007-0196-5

Chemistry of Heterocyclic Compounds, Vol. 43, No. 10, 2007
SYNTHESIS AND BIOLOGICAL
ACTIVITY OF NOVEL N-SUBSTITUTED
4-AMINO-6,7,8-TRIMETHOXYQUIN-
AZOLINE COMPOUNDS
Gang Liu, Chunping Liu, Lin Sun, Rongjun Qu, Hou Chen, and Chunnuan Ji
A series of N-substituted 4-amino-6,7,8-trimethoxyquinazoline derivatives has been synthesized from
4-chloro-6,7,8-trimethoxyquinazoline and aryl (or benzyl) amines using 2-propanol as a solvent. The
starting material 4-chloro-6,7,8-trimethoxyquinazoline has been synthesized from natural gallic acid by a
1
novel route. Their structures have been verified by elemental analysis and IR, H, and 13C NMR
spectroscopy. The title compounds have been evaluated for their in vitro antiproliferative activities
against some cancer cells by the MTT method. Unfortunately, most of the compounds tested have
exhibited a weaker anticancer activity than the reference standard drug PD153035.
Keywords: gallic acid, quinazoline, anticancer.
Recently it has been shown that quinazoline compounds exhibit promising biological activity for
medicinal or pesticidal use [1–5]. As part of our ongoing research program on heterocyclic compounds, which may
serve as leads for designing novel antitumor referred to PD153035 as the leading compound, we were particularly
interested in 4-substituted quinazolines [6–12]. We considered the well-known activity of the quinazoline nucleus
in chemotherapy, where many of its substituted derivatives are effective antitumor agents [13-16].
HN
MeO
MeO
Br
N
N
PD153035
Furthermore, the more recent data reported that a broad class of quinazolines also acts as potent and
highly selective inhibitors of epidermal growth factor receptor (EGFR) or epidermal growth factor receptor
tyrosine kinase (EGFR-TK) [17–21]; the members of this class are expected to have great therapeutic potential in
the treatment of malignant and nonmalignant epithelial diseases [22, 23]. In view of these facts and in order to
__________________________________________________________________________________________
School of Chemistry and Materials Science, Ludong University, Yantai 264025, P. R. of China; e-mail:
shdliugang@yahoo.com.cn. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1521-1531,
September, 2007. Original article submitted June 4, 2007.
1290
0009-3122/07/4310-1290©2007 Springer Science+Business Media, Inc.

study the influence of position 4 and 8 substitution on antitumor activity, we have prepared a series of new
4-aryl(benzyl)amino-6,7,8-trimethoxyquinazolines from natural gallic acid hoping to discover more active ATP
site inhibitors.
The synthetic route to the target compounds is shown in the Scheme:
OH
OMe
OMe
HO
OH
MeO
OMe
MeO
OMe
HNO3
Me2SO4
MeOH
H2SO4
COOH
COOH
COOMe
2
1
3
OMe
OMe
OMe
MeO
OMe
MeO
OMe
MeO
OMe
NO2
H+
Sn/HCl
NO2
NH2
COOH
COOH
COOMe
5
4
6
OMe
OMe
MeO
MeO
MeO
MeO
N
N
HCONH2
POCl3
∆
NH
N
∆
O
Cl
7
8
OMe
MeO
MeO
N
R
NH2
N
i-PrOH
NHR
9a–s
9 a R = 4-Br·2HCl, c R = 3-Cl·HCl, d R = 3-Br, e R = 3-Br·HCl, f R = 3-F·HCl, g R = 3-F,
h R = 4-F, i R = 2-F·HCl, j R = 2-Cl-4-Br·HCl, k R = 3,4,5-(MeO)3·HCl, l R = 4-NO2·HCl,
m R = 3-NO2·HCl, n R = 2-NO2·HCl, o R = H, p R = 4-Cl·2HCl, q R = OH·2HCl,
H
.
,
2HCl
=
R
,
b
s
R
=
r
O
MeO
H
Me
R-(–)
R
=
Me
S-(+)
To the best of our knowledge, this is the first report on the synthesis of N-substituted 4-amino-
6,7,8-trimethoxyquinazoline compounds from natural gallic acid.
Nineteen new N-substituted 4-amino-6,7,8-trimethoxyquinazoline compounds were synthesized referred to
PD153035 as the leading compound.The structures of new compounds were confirmed by elemental analysis, IR,
1H and 13C NMR spectra.
1291

TABLE 1. Inhibitory Activity of 9a-s and 8 in a Concentration of 10 µM
Against PC3 Cancer Cells
Compound
Inhibition*, %
Compound
Inhibition*, %
9a
9b
9c
9d
9e
9f
19.5± 1.8
50.0± 4.3
26.7± 3.2
17.0± 2.3
22.2± 3.4
16.3± 2.4
12.1± 2.9
16.6± 1.9
18.1± 5.3
11.5± 4.8
35.0± 3.3
9l
34.5± 5.8
37.2± 1.4
22.8± 3.0
9.3± 3.1
9m
9n
9o
9p
19.4± 5.5
25.0± 6.1
35.5± 4.1
−7.44± 4.2
71.3 ± 4.7
87.5± 1.8
9q
9g
9h
9i
9r
9s
8
9j
PD153035*2
9k
_______
* Each value represents the mean ± SEM (n = 9). Significance levels
p < 0.1 (compounds 9a, b, d, f-h, k, m-p, r, s), p < 0.05 (compounds 9c, e,
i, j, l, q; 8, PD153035) as compared with the respective control.
*2 The standard compound was prepared for comparison of activity.
The in vitro antitumor activities of these compounds were evaluated against PC3, BGC823, and Bcap-37
cells by the MTT method. The results for title compounds 9a–s and 8 against PC3 cells are summarized in
Table 1.
Unfortunately, most of the test compounds exhibited less anticancer activity than the reference standard
drug PD153035. The compounds 9b, k, m, r, and 8 (4-chloro-6,7,8-trimethoxyquinazoline) showed weak
inhibitory activity against PC3 cells. The data given in Table 1 indicate that the change of substituents of the
quinazoline ring affects the antitumor activity. When the 6,7,8-position was substituted by the methoxy group, the
compounds generally had less antitumor activities than 6,7-dimethoxy-substituted compounds. When position 4
in the quinazoline ring was substituted by a different aryl or benzyl moiety, the compounds generally had a
potential anticancer activity, such as 9b, k, m, and r with as inhibition of 50.0, 35.0, 37.2, and 35.5% against PC3
cells in the concentration of 10 µM. All the title compounds showed lower or no activities against Bcap-37 and
BGC823 cells, the results of the antitumor activity against these cells were not listed.
The compounds 9d and 9e (R = 3-bromophenyl) differ from PD153035 only by the substituent in position
8, showing that introduction of an additional methoxy group lowers the activity against tumor cells PC3
(Table 1).
So, we can conclude that position 8 without substitution had a very important effect on antitumor activity.
To the following research we should consider other positions, such as 2, 3, or 5.
The chiral compounds 9r and 9s exhibited a very different antitumor activity against PC3 cells (Table 1).
(R)-4-(α-Methylbenzylphenyl)amino-6,7,8-trimethoxyquinazoline 9r showed a weak inhibitory activity against
PC3 cells (35.5% in a concentration of 10 µM), and (S)-4-(α-methylbenzylphenyl)amino-6,7,8-trimethoxy-
quinazoline 9s demonstrated no activity in the same concentration. In our following research, we can think of
different chiral moieties in position 4.
In summary, N-substituted 4-amino-6,7,8-trimethoxyquinazoline derivatives 9a-s were synthesized by a
novel method from gallic acid. The compounds were evaluated for their in vitro antitumor activities against PC3,
Bcap37, and BGC823 cells by the MTT method. Compounds 9b, k, m, r, and 8 inhibited PC3 cells by 50.0, 35.0,
37.2, 35.5, and 71.3% in a concentration of 10 µM. Unfortunately, the other tested compounds exhibited low
anticancer activity.
1292

TABLE 2. Characteristics of Compounds 9a-s
Found, %
——————
Calculated, %
Com-
pound*
Empirical
formula
mp, °C
Yield*2, %
C
N
H
9a
9b
9c
C17H16BrN3O3·2HCl
C25H25N3O5·2HCl
C17H16ClN3O3·HCl
C17H16BrN3O3
43.82
44.09
57.60
57.70
53.50
53.42
52.21
52.32
47.69
47.85
55.69
55.82
61.97
62.00
61.85
62.00
55.66
55.82
43.96
44.28
54.67
54.86
51.73
51.98
51.71
51.98
52.18
51.98
66.56
66.45
48.53
48.77
4.18
3.92
5.03
5.23
4.57
4.48
4.35
4.13
4.25
4.02
4.72
4.68
4.85
4.90
4.88
4.90
4.86
4.68
3.76
3.50
5.61
5.52
4.52
4.36
4.55
4.36
4.57
4.36
5.95
5.89
4.63
4.33
9.04
9.07
8.16
8.07
10.74
10.99
10.98
10.77
10.02
9.85
11.35
11.49
12.59
12.76
12.63
12.76
11.31
11.49
9.01
9.11
9.55
9.60
14.12
14.26
14.32
14.26
14.29
14.26
12.93
12.91
170-173
160-162
51.7
46.8
61.2
19.9
65.6
60.4
36.1
55.4
63.8
66.2
64.4
54.3
34.5
32.7
64.0
41.9
58.0
48.9
61.4
172 (dec.)
126-127
9d
9e
C17H16BrN3O3·HCl
C17H16FN3O3·HCl
C17H16FN3O3
180 (dec.)
232-234
9f
9g
9h
9i
252-254
C17H16FN3O3
184-186
C17H16FN3O3·HCl
C17H15BrClN3O3·HCl
C20H23N3O6·HCl
C17H16N4O5·HCl
C17H16N4O5·HCl
C17H16N4O5·HCl
C18H19N3O3
194 (dec.)
178 (dec.)
195 (dec.)
212 (dec.)
204-206
9j
9k
9l
9m
9n
9o
9p
9q
9r*3
9s*4
210 (dec.)
173-175
C17H16ClN3O3·2HCl
C17H17N3O4·2HCl
C19H21N3O3
9.97
10.04
10.52
10.50
12.23
12.38
175 (dec.)
153 (dec.)
207-209
51.24
51.01
67.31
67.24
67.43
67.24
5.04
4.78
5.97
6.24
6.23
6.24
C19H21N3O3
12.37
12.38
205-206
_______
* Physical state: pale yellow solid (compounds 9a, c−i, l−n, p, q), yellow
solid (compounds 9b, k), white solid (compounds 9j, o, r, s).
*2 Yields of isolated products.
*3 [α]D22 -213° (c = 0.01 mol/l, EtOH).
*4 [α]D22 +208° (c = 0.01 mol/l, EtOH).
EXPERIMENTAL
Unless otherwise indicated, all common reagents and solvents were used as obtained from commercial
supplies without further purification. All melting points of the products were determined on a XT-4 binocular
microscope (Beijing Tech Instrument Co., China) and are not corrected. The IR spectra were recorded on a
Bruker VECTOR22 spectrometer in KBr disks. 1H and 13C NMR spectra were recorded on a spectrometer Varian-
Inova 500 (500 and 125 MHz respectively) at room temperature in DMSO-d6 using TMS as an internal standard.
D2O exchange was used to confirm the assignment of the signals of NH protons. Elemental analysis
1293

was performed by an Elementar Vario-III CHN analyzer. Specific rotation was determined on a WZZ-2A
automatically polarimeter (Beijing Tech Instrument Co., China). The following compounds were prepared as
described in the literature: 3,4,5-trimethoxybenzoic acid (2): white solid, yield 81.4%; mp 159-161°C (lit. [24],
mp 160-162°C); methyl 3,4,5-trimethoxybenzoate (3): white needles, yield 69.5%; mp 75-76°C (lit. [25],
mp 82-84°C).
TABLE 3 IR Spectra of Compounds 9a-s
Com-
pound
IR, cm-1
ν
δAr−H
804.3
+
9a
3415.5 (N−H2 ); 3010.9 (Ar−H); 2947.2 (asCH3); 2847.0 (sCH3);
1627.9-1489.1 (quinaz. skeleton vibr.); 1288.5 (asAr−O−C);
1128.4 (sAr−O−C)
+
9b
9c
3416.3 (N−H2 );3010.9 (Ar−H); 2949.2 (asCH3); 2850.8 (sCH3);
763.8
785.0
1626.0-1473.6 (Ar skeleton vibr.); 1286.5 (asAr−O−C); 1124.5 (sAr−O−C)
+
3418.6 (N−H2 ); 3012.8 (Ar−H); 2947.2 (asCH3); 2846.9 (sCH3);
1627.9-1487.1 (quinaz. skeleton vibr.); 1288.5 (asAr−O−C);
1126.4 (sAr−O−C)
9d
9e
3307.9 (N−H); 3010.9 (Ar−H); 2941.4 (asCH3); 2852.7 (sCH3);
1627.9-1487.1 (quinaz. skeleton vibr.); 1288.5 (asAr−O−C);
1126.4 (sAr−O−C)
788.9
786.9
+
3419.8 (N−H2 ); 3010.9 (Ar−H); 2945.3 (asCH3); 2848.9 (sCH3);
1626.0-1487.1 (quinaz. skeleton vibr.); 1286.5 (asAr−O−C);
1126.4 (sAr−O−C)
+
9f
3414.2 (N−H2 ); 3012.8 (Ar−H); 2951.1 (asCH3); 2852.6 (sCH3);
1627.9-1489.1 (Ar skeleton vibr.); 1288.5 (asAr−O−C); 1134.1 (sAr−O−C)
9g
9h
3369.4 (N−H); 3074.5 (Ar−H); 2933.7 (asCH3); 2833.4 (sCH3);
1618.3−1454.3 (Ar skeleton vibr.); 1271.1 (asAr−O−C); 1118.7 (sAr−O−C)
3356.1 (N−H); 3016.7 (Ar−H); 2947.2 (asCH3); 2856.6 (sCH3);
1626.0-1487.1 (quinaz. skeleton vibr.); 1282.7 (asAr−O−C);
1126.4 (sAr−O−C)
788.9
759.9
+
9i
3363.9 (N−H2 ); 2945.3 (asCH3); 2854.7 (sCH3);
1629.9-1487.1 (quinaz. skeleton vibr.); 1257.6 (asAr−O−C);
1126.4 (sAr−O−C); 1010.7 (C−F)
+
9j
9k
9l
3365.8 (N−H2 ); 3014.7 (Ar−H); 2945.3 (asCH3); 2848.9 (sCH3);
1626.0-1487.1 (Ar skeleton vibr.); 1286.5 (asAr−O−C); 1126.4 (sAr−O−C)
+
3419.8 (N−H2 ); 2947.2 (asCH3); 2839.2 (sCH3);
1633.7-1456.3 (Ar skeleton vibr.); 1284.6 (asAr−O−C); 1130.3 (sAr−O−C)
+
3365.8 (N−H2 ); 3010.9 (Ar−H); 2951.1 (asCH3); 2839.0 (sCH3);
1627.9-1514.1 (Ar skeleton vibr.); 1487.1 (asNO2); 1340.5 (sNO2);
1284.6 (asAr−O−C); 1130.3 (sAr−O−C)
+
9m
9n
3419.8 (N−H2 ); 3014.7 (Ar−H); 2947.2 (asCH3); 2843.1 (sCH3);
1631.8-1469.8 (Ar skeleton vibr.); 1485.2 (asNO2); 1346.3 (sNO2);
1284.6 (asAr−O−C); 1120.6 (sAr−O−C)
+
3387.8 (N−H2 ); 3018.6 (Ar−H); 2945.3 (asCH3); 2845.0 (sCH3);
792.7
1624.0-1458.2 (Ar skeleton vibr.); 1489.0 (asNO2); 1355.9 (sNO2);
1286.5 (asAr−O−C); 1130.3 (sAr−O−C)
9o
9p
9q
3234.6 (N−H); 3001.2 (Ar−H); 2937.6 (asCH3); 2831.5 (sCH3);
800.5
806.3
1614.4-1454.3 (Ar skeleton vibr.); 1282.7 (asAr−O−C); 1128.4 (sAr−O−C)
+
3419.8 (N−H2 ); 3010.9 (Ar−H); 2947.2 (asCH3); 2852.7 (sCH3);
1627.9-1471.7 (Ar skeleton vibr.); 1286.5 (asAr−O−C); 1130.3 (sAr−O−C)
+
+
3419.8 (N−H2 ); 3226.9 (O−H2 ); 3030.2 (Ar−H); 2949.2 (asCH3);
2854.7 (sCH3); 1626.0-1473.6 (Ar skeleton vibr.); 1273.0 (asAr−O−C);
1128.4 (sAr−O−C)
9r
9s
3261.6 (N−H); 3026.3 (Ar−H); 2972.3, 2933.7 (asCH3+CH2); 2831.5 (sCH3);
1612.5-1477.5 (Ar skeleton vibr.); 1280.7 (asAr−O−C); 1120.6 (sAr−O−C)
3242.3 (N−H); 3028.2 (Ar−H); 2972.3, 2935.7 (asCH3+CH2); 2831.5 (sCH3);
1612.5-1477.5 (Ar skeleton vibr.); 1311.6 (asAr−O−C); 1130.3 (sAr−O−C)
702.1
700.2
_________
* Quinaz. − quinazoline.
1294

TABLE 4. 1H NMR Spectra of Compounds 9a−s
Com-
pound
δ, ppm (J, Hz)*
9a
9b
11.53 (1H, s, NH); 8.76 (1H, s, H-2 quinaz.); 8.14 (1H, s, H-5 quinaz.);
7.71 (4H, s, Ph); 4.05-4.02 (9H, 3s, 3OCH3)
11.45 (1H, s, NH); 8.68 (1H, s, H-2 quinaz.); 8.22 (1H, d, J = 7.45, H-5 DBF);
8.09 (1H, s, H-5 quinaz.); 8.03 (1H, s, H-1 DBF); 7.88 (1H, s, H-4 DBF);
7.72 (1H, d, J = 7.45, H-8 DBF); 7.58-7.55 (1H, m, H-7 DBF);
7.47-7.45 (1H, m, H-6 DBF); 4.04-3.93 (12H, 4s, 4OCH3)
9c
9d
9e
9f
11.43 (1H, s, NH); 8.81 (1H, s, H-2 quinaz.); 8.10 (1H, s, H-5 quinaz.);
7.90 (1H, s, H-2 Ph); 7.71 (1H, d, J = 9.15, H-4 Ph); 7.56-7.53 (1H, m, H-5 Ph);
7.41 (1H, d, J = 9.15, H-6 Ph); 4.05-4.02 (9H, 3s, 3OCH3)
11.51 (1H, s, NH); 8.81 (1H, s, H-2 quinaz.); 8.13 (1H, d, J = 4.0, H-2 Ph);
8.02 (1H, s, H-5 quinaz.); 7.76 (1H, d, J = 8.05, H-4 Ph); 7.54 (1H, d, J = 8.05, H-6 Ph);
7.48 (1H, t, J = 4.0, H-5 Ph); 4.05-4.02 (9H, 3s, 3OCH3)
11.62 (1H, s, NH); 8.81 (1H, s, H-2 quinaz.); 8.20 (1H, s, H-5 quinaz.);
8.03 (1H, s, H-2 Ph); 7.77 (1H, d, J = 8.0, H-4 Ph); 7.54 (1H, d, J = 8.0, H-6 Ph);
7.48 (1H, t, J = 4.0, H-5 Ph); 4.03-4.02 (9H, 3s, 3OCH3)
11.63 (1H, s, NH); 8.81 (1H, s, H-2 quinaz.); 8.21 (1H, s, H-5 quinaz.);
7.73 (1H, d, J = 10.9, H-4 Ph); 7.73 (1H, d, J = 8.0 Hz, H-6 Ph);
7.57-7.54 (1H, m, H-5 Ph); 7.20 (1H, t, J = 4.0, H-2 Ph); 4.07-4.03 (9H, 3s, 3OCH3)
9g
9.69 (1H, s, NH); 8.56 (1H, s, H-2 quinaz.); 7.88 (1H, d, J = 12.05, H-4 Ph);
7.71 (1H, s, H-5 quinaz.); 7.63 (1H, d, J = 8.0, H-6 Ph); 7.44-7.43 (1H, m, H-5 Ph);
6.96 (1H, t, J = 4.0, H-2 Ph); 4.01-3.93 (9H, 3s, 3OCH3)
9h
9i
11.61 (1H, s, NH); 8.73 (1H, s, H-2 quinaz.); 8.17 (1H, s, H-5 quinaz.);
7.74-7.71 (2H, m, H-3,5 Ph); 7.38-7.34 (2H, m, H-2,6 Ph); 4.05-4.02 (9H, 3s, 3OCH3)
11.82 (1H, s, NH); 8.72 (1H, s, H-2 quinaz.); 8.23 (1H, s, H-5 quinaz.);
7.56-7.36 (4H, m, H-3,4,5,6 Ph); 4.06-4.03 (9H, 3s, 3OCH3)
9j
8.71 (1H, s, H-2 quinaz.); 8.04 (1H, s, H- 5 quinaz.); 8.00 (1H, d, J = 2.3, H-3 Ph);
7.74 (1H, d, J = 8.6, H-5 Ph); 7.54 (1H, d, J = 8.6, H-6 Ph); 4.03-4.02 (9H, 3s, 3OCH3)
9k
11.52 (1H, s, NH); 8.75 (s, 1H, H-2 quinaz.); 8.17 (1H, s, H-5 quinaz.);
7.09 (2H, s, H-1,6 Ph); 4.06-4.02 (9H, 3s, 3OCH3); 3.81 (6H, s, 3,5-2CH3 phenyl);
3.71 (3H, s, 4-CH3 phenyl)
9l
11.21 (1H, s, NH); 8.82 (1H, s, H-2 quinaz.); 8.36 (2H, d, J = 8.6, 3,5-H Ph);
8.15 (2H, d, J = 8.6, 2,6-H Ph); 8.06 (1H, s, H-5 quinaz.); 4.06-4.02 (9H, 3s, 3OCH3)
9m
11.84 (1H, s, NH); 8.86 (1H, s, H-2 quinaz.); 8.72 (1H, s, H-2 Ph);
8.29 (1H, d, J = 9.15, H-4 Ph); 8.26 (1H, s, H-5 quinaz.); 8.18 (1H, d, J = 9.7, H-6 Ph);
7.82-7.79 (1H, m, H-5 Ph); 4.08-4.03 (9H, 3s, 3OCH3)
9n
9o
9p
9q
9r
12.01 (1H, s, NH); 8.66 (1H, s, H-2 quinaz.); 8.18 (1H, s, H-5 quinaz.);
8.17 (1H, d, J = 7.45, H-3 Ph); 7.90 (1H, t, J = 9.15, H-4 Ph);
7.77 (1H, d, J = 7.45, H-6 Ph); 7.65 (1H, t, J = 7.75, H-5 Ph); 4.06-4.02 (9H, 3s, 3OCH3)
8.60 (1H, t, J = 5.7, NH); 8.36 (1H, s, H-2 quinaz.); 7.54 (1H, s, H-5 quinaz.);
7.37-7.31 (4H, m, H-2,3,5,6 Ph); 7.23 (1H, t, J = 7.45, H-4 Ph);
4.79 (2H, d, J = 5.7, CH2); 3.97-3.87 (9H, 3s, 3OCH3)
11.57 (1H, s, NH); 8.75 (1H, s, H-2 quinaz.); 8.23 (1H, s, H-5 quinaz.);
7.77 (2H, d, J = 8.6, H-3,5 Ph); 7.57 (2H, d, J = 8.6, H-2,6 Ph);
4.06-4.02 (9H, 3s, 3OCH3)
11.42 (1H, s, NH); 9.75 (1H, s, OH); 8.66 (1H, s, H-2 quinaz.); 8.15 (1H, s, H-5 quinaz.);
7.43 (2H, d, J = 8.6, H-3,5 Ph); 6.87 (2H, d, J = 8.6, H-2,6 Ph);
4.03-4.00 (9H, 3s, 3OCH3)
8.31 (1H, s, H-2 quinaz.); 8.22 (1H, d, J = 7.45, NH); 7.64 (1H, s, H-5 quinaz.);
7.42 (2H, d, J = 7.45, Ph H-2,6); 7.32 (2H, t, J = 7.45, H-3,5 Ph);
7.21 (1H, t, J = 7.45, H-4 Ph); 5.62 (1H, p, J = 7.45, CH); 3.96-3.87 (9H, 3s, 3OCH3);
1.60 (3H, d, J = 7.45, CH3)
9s
8.31 (1H, s, H-2 quinaz.); 8.22 (1H, d, J = 7.45, NH); 7.64 (1H, s, H-5 quinaz);
7.42 (2H, d, J = 7.45, H-2,6 Ph); 7.32 (2H, t, J = 7.45, H-3,5 Ph);
7.21 (1H, t, J = 7.45, H-4 Ph); 5.62 (1H, p, J = 7.45, CH); 3.96-3.87 (9H, 3s, 3OCH3);
1.60 (3H, d, J = 6.9, CH3)
_________
* Quinaz. − quinazoline; DBF − dibenzofuran.
1295

TABLE 5. 13C NMR Spectra of Compounds 9a-s
Com-
pound
δ, ppm
1
2
9a
158.9 (C-2 quinaz.); 154.5 (C-6 quinaz.); 149.6 (C-9 quinaz.); 148.2 (C-7 quinaz.);
142.1 (C-8 quinaz.); 136.5 (quinaz. C-10); 132.2 (2C, C-3,5 Ph); 127.3 (2C, C-2,6 Ph);
109.9 (C-4 Ph); 100.6 (C-5 quinaz.); 62.7, 61.9, 57.8 (3C, 6,7,8-site OCH3 quinaz.)
9b
156.3 (C-2 quinaz.); 154.0 (C-6 quinaz.); 150.9 (C-9 quinaz.); 148.9 (C-7 quinaz.);
147.7 (C-13 DBF); 145.3 (C-2 DBF); 141.4 (C-8 quinaz.); 127.7 (C-11 DBF);
123.5 (C-12 DBF); 123.3 (C-7 DBF); 123.1 (C-6 DBF); 121.3 (C-5 DBF);
111.7 (C-10 quinaz.); 111.4 (C-8 DBF); 108.6 (C-4 DBF); 103.6 (C-1 DBF);
99.8 (C-5 quinaz.); 62.0, 61.3, 56.9 (3C, 6,7,8-site OCH3 quinaz.);
56.3 (2-site OCH3 DBF)
9c
9d
9e
9f
158.4 (C-2 quinaz.); 153.9 (C-6 quinaz.); 149.2 (C-9 quinaz.); 147.6 (C-7 quinaz.);
138.1 (C-8 quinaz.); 132.8 (C-3 Ph); 130.4 (C-5 Ph); 126.2 (C-4 Ph); 124.2 (C-2 Ph); 123.0
(C-6 Ph); 109.3 (C-10 quinaz.); 99.8 (C-5 quinaz.);
62.0, 61.2, 57.1 (3C, 6,7,8-site OCH3 quinaz.)
159.0 (C-2 quinaz.); 154.5 (C-6 quinaz.); 149.8 (C-9 quinaz.); 148.2 (C-7 quinaz.);
138.8 (C-8 quinaz.); 131.3 (C-3 Ph); 129.7 (C-5 Ph); 127.7 (C-4 Ph); 124.1 (C-2 Ph);
121.8 (C-6 Ph); 109.9 (C-10 quinaz.); 100.6 (C-5 quinaz.);
62.7, 61.9, 57.7 (3C, 6,7,8-site OCH3 quinaz.)
158.5 (C-2 quinaz.); 154.0 (C-6 quinaz.); 149.1 (C-1 Ph); 147.7 (C-9 quinaz.);
141.5 (C-7 quinaz.); 138.8 (C-8 quinaz.); 130.7 (C-5 Ph); 129.1 (C-3 Ph); 127.1 (C-4 Ph);
123.6 (C-2 Ph); 121.2 (C-6 Ph); 109.3 (C-10 quinaz.); 100.2 (C-5 quinaz.);
62.1, 61.3, 57.2 (3C, 6,7,8-site OCH3 quinaz.)
161.4 (C-2 quinaz.); 159.0 (C-6 quinaz.); 154.6 (C-9 quinaz.); 149.7 (C-7 quinaz.);
148.3 (C-8 quinaz.); 131.0 (C-3 Ph); 130.9 (C-5 Ph); 121.1 (C-4 Ph); 112.5 (C-2 Ph);
112.3 (C-6 Ph); 109.9 (C-10 quinaz.); 100.7 (C-5 quinaz.);
62.7, 61.9, 57.8 (3C, 6,7,8-site OCH3 quinaz.)
9g
9h
9i
162.7 (C-2 quinaz.); 160.7 (C-6 quinaz.); 156.1 (C-9 quinaz.); 151.4 (C-7 quinaz.);
146.0 (C-8 quinaz.); 129.7 (C-3 Ph); 129.6 (C-5 Ph); 117.4 (C-4 Ph); 111.1 (C-2 Ph);
109.6 (C-6 Ph); 108.4 (C-10 quinaz.); 97.6 (C-5 quinaz.);
61.6, 60.7, 56.2 (3C, 6,7,8-site OCH3 quinaz.)
161.7 (C-2 quinaz.); 159.8 (C-6 quinaz.); 159.1 (C-1 Ph); 154.5 (C-9 quinaz.);
149.7 (C-7 quinaz.); 148.1 (C-8 quinaz.); 142.1 (C-4 Ph); 133.3 (C-1 Ph);
127.7, 127.6 (2C, C-2,6 Ph); 116.2, 116.1 (2C, C-3,5 Ph); 109.7 (C-10 quinaz.);
100.7 (C-5 quinaz.); 62.7, 61.8, 57.8 (3C, 6,7,8-site OCH3 quinaz.)
159.3 (C-2 quinaz.); 157.8 (C-6 quinaz.); 155.9 (C-9 quinaz.); 153.9 (C-7 quinaz.);
149.2 (C-2 Ph); 147.7 (C-8 quinaz.); 141.7 (C-1 Ph); 129.3 (C-5 Ph); 128.6 (C-4 Ph);
116.3 (C-6 Ph); 116.2 (C-3 Ph); 108.9 (C-10 quinaz.); 100.2 (C-5 quinaz.);
62.0, 61.2, 57.1 (3C, 6,7,8-site OCH3 quinaz.)
9j
164.8 (C-4 quinaz.); 159.8 (C-2 quinaz.); 154.7 (C-7 quinaz.); 154.4 (C-8 quinaz.);
153.3 (C-6 quinaz.); 147.2 (C-1 Ph); 138.8 (C-9 quinaz.); 137.7 (C-3 Ph); 137.5 (C-5 Ph);
136.6 (C-2 Ph); 126.4 (C-6 Ph); 114.1 (C-4 Ph); 105.1 (C-10 quinaz.);
104.9 (C-5 quinaz.); 67.4, 66.7, 62.3 (3C, 6,7,8-site OCH3 quinaz.)
9k
159.0 (C-2 quinaz.); 154.5 (C-6 quinaz.); 153.3 (2C, C-3,5 Ph); 149.6 (C-9 quinaz.);
148.1 (C-7 quinaz.); 136.6 (C-8 quinaz.); 132.8 (C-4 Ph); 109.7 (C-10 quinaz.);
103.5 (2C, C-2,6 Ph); 100.8 (C-5 quinaz.); 62.7, 61.2, 60.7 (3C, 6,7,8-site OCH3 quinaz.);
57.8 (4-site OCH3 Ph); 56.6 (2C, 3,5-site OCH3 Ph)
9l
157.8 (C-2 quinaz.); 153.6 (C-6 quinaz.); 149.7 (C-9 quinaz.); 147.4 (C-7 quinaz.);
143.9 (C-4 Ph); 124.4 (2C, 3,5-C Ph); 123,2 (2C, C-2,6 Ph); 110.5 (C-10 quinaz.);
99.3 (C-5 quinaz.); 62.0, 61.2, 56.9 (3C, 6,7,8-site OCH3 quinaz.)
9m
159.1 (C-2 quinaz.); 154.6 (C-6 quinaz.); 149.8 (C-3 Ph); 148.3 (C-9 quinaz.);
142.3 (C-7 quinaz.); 138.6 (C-8 quinaz.); 131.2 (C-5 Ph); 130.7 (C-6 Ph); 121.3 (C-4 Ph);
119.5 (C-2 Ph); 110.1 (C-10 quinaz.); 100.8 (C-5 quinaz.);
62.7, 61.9, 57.9 (3C, 6,7,8-site OCH3 quinaz.)
9n
158.7 (C-2 quinaz.); 153.9 (C-6 quinaz.); 149.3 (C-9 quinaz.); 147.8 (C-7 quinaz.);
146.3 (C-8 quinaz.); 144.8 (C-5 Ph); 134.3 (C-2 Ph); 128.9 (C-3 Ph); 128.1 (C-4 Ph);
125.2 (C-6 Ph); 109.3 (C-10 quinaz.); 99.9 (C-5 quinaz.);
62.0, 61.2, 57.1 (3C, 6,7,8-site OCH3 quinaz.)
1296

TABLE 5. (continued)
1
2
9o
159.1 (C-4 quinaz); 153.1 (C-2 quinaz.); 152.2 (C-6 quinaz.); 147.6 (C-1 Ph);
146.3 (C-9 quinaz.); 140.9 (C-7 quinaz.); 140.2 (C-8 quinaz.); 128.8 (2C, C-3,5 Ph);
127.7 (2C, C-2,6 Ph); 127.3 (C-4 Ph); 111.7 (C-10 quinaz.); 98.5 (C-5 quinaz.);
62.2, 61.4, 56.7 (3C, 6,7,8-site OCH3 quinaz.); 42.1 (CH2)
9p
9q
158.4 (C-2 quinaz.); 153.7 (C-6 quinaz.); 149.3 (C-9 quinaz.); 147.5 (C-7 quinaz.);
135.8 (C-4 Ph); 128.6 (2C, C-3,5 Ph); 126.4 (2C, C-2,6 Ph); 109.9 (C-10 quinaz.);
100.2 (C-5 quinaz.); 62.0, 61.2, 57.2 (3C, 6,7,8-site OCH3 quinaz.)
158.3 (C-2 quinaz.); 156.1 (C-6 quinaz.); 153.7 (C-9 quinaz.); 149.1 (C-7 quinaz.);
147.3 (C-8 quinaz.);141.6 (C-4 Ph); 127.6 (C-1 Ph); 126.3 (2C, C-3,5 Ph);
115.2 (2C, C-2,6 Ph); 109.1 (C-10 quinaz.); 100.2 (C-5 quinaz.);
61.9, 61.2, 57.1 (3C, 6,7,8-site OCH3 quinaz.)
9r
9s
158.3 (C-4 quinaz.); 153.0 (C-2 quinaz.); 152.2 (C-6 quinaz.); 147.6 (C-1 Ph);
146.3 (C-9 quinaz.); 145.4 (C-7 quinaz.); 140.9 (C-8 quinaz.); 128.8 (2C, C-3,5 Ph);
127.1 (C-4 Ph); 126.6 (2C, C-2,6 Ph); 111.6 (C-10 quinaz.); 98.7 (C-5 quinaz.);
62.2, 61.4, 56.9 (3C, 6,7,8-site OCH3 quinaz.); 49.6 (CH); 22.9 (CH3)
158.3 (C-4 quinaz.); 153.0 (C-2 quinaz.); 152.2 (C-6 quinaz.); 147.6 (C-1 Ph);
146.3 (C-9 quinaz.); 145.4 (C-7 quinaz.); 140.9 (C-8 quinaz.); 128.8 (2C, C-3,5 Ph);
127.1 (C-4 Ph); 126.6 (2C, C-2,6 Ph); 111.6 (C-10 quinaz.); 98.7 (C-5 quinaz.);
62.2, 61.4, 56.9 (3C, 6,7,8-site OCH3 quinaz.); 49.6 (CH); 22.9 (CH3)
Methyl 3,4,5-Trimethoxy-2-nitrobenzoate (4). To a stirred solution of methyl 3,4,5-trimethoxy-
benzoate (2.0 g, 8.8 mmol) in AcOH (10 ml) at room temperature was carefully added fuming HNO3 (2.5 ml)
during 30 min. After addition of the acid, the solution stirred for 1-2 h. The reaction mixture was then poured into
ice water (60 ml). The solid obtained was filtered off, washed with water, dried, and recrystallized from
EtOH−H2O (2:1, v:v). Pale yellow needles, yield 25.4%; mp 62-63°C. IR spectrum, ν [δ], cm-1: 012.8 (Ph−H),
2962.7 (asCH3), 2846.9 (sCH3), 1718.6 (C=O), 1579.7–1496.8 (Ph skeleton vibration), 1544.9 (asNO2), 1344.4
(sNO2), 1232.5 (asPh−O−C), 1112.9 (sPh−O−C), [866.0 (Ar–H)]. 1H NMR, δ, ppm: 7.34 (1H, s, PhH); 3.94-3.89
13
(9H, 3s, 3OCH3); 3.83 (3H, s, COOCH3). C NMR, δ, ppm: 163.3 (C=O), 154.7 (C-5 Ph), 146.2 (C-3 Ph), 145.5
(C-4 Ph), 139.6 (C-2 Ph), 117.7 (C-1 Ph), 109.2 (C-6 Ph), 63.1 (4-OCH3), 61.6 (5-OCH3), 57.1 (3-OCH3), 53.7
(COOCH3). Found, %: C 48.57; H 5.02; N 4.91. C11H13NO7. Calculated, %: C 48.71; H 4.83; N 5.16.
3,4,5-Trimethoxy-2-nitrobenzoic Acid (5). A stirred solution of methyl 3,4,5-trimethoxy-
2-nitrobenzoate (14.0 g, 50 mmol) in 0.8 mol/l NaOH (120 ml, 100 mmol) and 95% EtOH (60 ml) was heated at
45-50°C in a water bath for 2 h. Then the reaction mixture was cooled by ice water, and concentrated
hydrochloric acid was added dropwise with stirring while maintaining the temperature at 20°C for the mixture pH
2-3. The solid obtained was filtered off, washed with water, dried, and recrystallized from EtOH. Pale yellow
needles, yield 92.3%; mp 160-161°C. IR spectrum, ν [δ], cm−1: 3107.3-2538.3 (OH+Ph−H), 2953.0 (asCH3),
2850.8 (sCH3), 1695.4 (C=O), 1577.8-1496.8 (Ph skeleton vibration), 1546.9 (asNO2), 1340.5 (sNO2), 1246.0
(asPh−O−C), 1116.8 (sPh−O−C), [725.2 (Ar−H)]. 1H NMR, δ, ppm: 7.32 (1H, s, PhH); 3.93–3.88 (9H, 3s, 3OCH3).
13C NMR, δ, ppm: 164.1 (C=O), 154.5 (C-5 Ph), 145.8 (C-3 Ph), 145.3 (C-4), 139.8 (C-2 Ph), 118.8 (C-1 Ph),
109.3 (C-6 Ph), 63.1 (4- OCH3), 61.5 (5-OCH3), 57.0 (3-OCH3). Found, %: C 46.77; H 4.14; N 5.32. C10H11NO7.
Calculated, %: C 46.70; H 4.31; N 5.45.
2-Amino-3,4,5-trimethoxybenzoic Acid (6). A mixture of powder Sn (5.3 g, 45 mmol) and concentrated
hydrochloric acid (18 ml) was stirred for 4-5 h at room temperature, and 3,4,5-trimethoxy-2-nitrobenzoic acid
(2.6 g, 10 mmol) was added to the solution. The reaction mixture was carefully heated to 80°C in a water bath
while maintaining the temperature for 20 min. Then concentrated hydrochloric acid (5 ml) was added into the
reaction mixture while maintaining the temperature for 10 min. The reaction mixture was cooled by ice bath and
stirred for 10 min. The precipitated complex stannic double salt was filtered off and washed with a little
concentrated hydrochloric acid. The white solid obtained was stirred with portions of 10% K2CO3 solution until
1297

it dissolved with pH 9-10 and the mixture was alkaline, whereupon a grayish precipitate appeared. It was removed
by filter and washed with 10% K2CO3 solution. The solution was neutralized with acetic acid to pH 2-3 while
maintaining the temperature below 20°C. The white solid obtained was filtered off, washed with water, dried, and
recrystallized from EtOH-H2O (1:1, v:v). White needles, yield 61.7%; mp 126-128°C. IR spectrum, ν [δ], cm-1:
3487.3, 3379.3 (NH2), 3200-2400 (O−H+Ph−H+asCH3+sCH3), 1670.4 (C=O), 1575.8-1458.2 (Ph skeleton
1
vibration), 1273.0 (asPh−O−C), 1149.6 (sPh−O−C), 744.5 (Ar−H). H NMR, δ, ppm: 7.07 (1H, s, PhH);
13
3.82-3.70 (9H, 3s, 3OCH3); 3.45 (1H, s, NH). C NMR, δ, ppm: 169.4 (C=O), 147.6 (C-5 Ph), 142.9 (C-3 Ph),
141.6 (C-4 Ph), 140.4 (C-2 Ph), 1109.3 (C-1 Ph), 104.5 (C-6 Ph), 60.9 (4-OCH3), 60.6 (5-OCH3), 56.6 (3-OCH3).
Found, %: C 52.74; H 5.63; N 6.02. C10H13NO5. Calculated, %: C 52.86; H 5.77; N 6.16.
6,7,8-Trimethoxyquinazolin-4-one (7). A mixture of 2-amino-3,4,5-trimethoxybenzoic acid (1.1 g,
5 mmol) and excess of formamide (4 ml) was stirred at 130–140°C for 5 h. After the reaction was over, a suitable
amount of water was added dropwise to the reaction mixture to dissolve the excess of formamide at 100°C. The
gray solid obtained was filtered off, washed with water, dried, and recrystallized from EtOH. Pale brown crystal,
yield 55.4%; mp 220-222°C. IR spectrum, ν[δ], cm-1: 3304.1 (NH), 3163.3 (OH), 3200-2400 (O−H+Ar–
H+asCH3+sCH3), 1664.6 (C=O), 1612.5-1473.6 (quinazolone skeleton vibration), 1286.5 (asAr–O–C), 1126.4
(sAr–O–C), [798.5 (Ar–H)]. 1H NMR, δ, ppm: 12.21 (1H, s, NH); 8.01 (1H, s, H-2 quinazolone); 7.35 (1H, s, H-5
quinazolone); 3.95–3.88 (9H, 3s, 3OCH3). 13C NMR, δ, ppm: 160.6 (C=O), 152.7 (C-2 quinazolone), 148.3 (C-6
quinazolone), 147.7 (C-8 quinazolone), 143.3 (C-7 quinazolone), 139.0 (C-9 quinazolone), 119.2 (C-10
quinazolone), 101.7 (C-5 quinazolone), 62.4, 61.4, 56.4 (3C, 6,7,8-OCH3 quinazolone). Found, %: C 56.18;
H 5.18; N 12.04. C11H12N2O4. Calculated, %: C 55.93; H 5.12; N 11.86.
4-Chloro-6,7,8-trimethoxyquinazoline (8). A solution of 6,7,8-trimethoxyquinazolin-4-one (0.6 g,
2.5 mmol) and four drops of N,N-dimethylaniline in POCl3 (25 ml) was heated at reflux for 3 h. POCl3 was
removed by distillation at reduced pressure and the residue was diluted with 20 ml CHCl3 and treated with 30 g
ice-water. To the mixture was added saturated potassium carbonate solution with stirring until the mixture
acquired pH 4-5. The organic layer was separated and the residue was extracted twice with 40 ml CHCl3, dried by
MgSO4, concentrated by distillation, and recrystallized from petroleum ether (bp 60–90°C). Pale gray solid, yield
62.5%; mp 101-103°C. IR spectrum, ν [δ], cm–1: 3099.6 (Ar–H), 2945.3 (asCH3), 2845.0 (sCH3), 1602.9-1467.8
(quinazoline skeleton vibration), 1246.0 (asAr–O–C), 1136.1 (sAr–O–C), [786.9 (Ar–H)]. 1H NMR, δ, ppm: 8.93
(1H, s, H-2 quinaz.); 7.29 (1H, s, H-5 quinaz.); 4.06-4.01 (9H, 3s, 3OCH3). 13C NMR, δ, ppm: 158.9 (C-2
quinaz.), 154.3 (C-4 quinaz.), 150.9 (C-6 quinaz.), 148.1 (C-9 quinaz.), 146.3 (C-7 quinaz.), 142.7 (C-8 quinaz.),
120.1 (C-10 quinaz.), 98.6 (C-5 quinaz.), 62.2, 61.1, 56.3 (3C, 6,7,8-OCH3 quinaz.). Found, %: C 52.02; H 4.21;
N 10.94. C11H12N2O4. Calculated, %: C 51.88; H 4.35; N 11.00.
N-Substituted 4-amino-6,7,8-trimethoxyquinazoline 9a-s (Tables 2-5). A solution of 4-chloro-
6,7,8-trimethoxyquinazoline (3.0 mmol) and aryl (or benzyl) amines (3.0 mmol) in i-PrOH (30 ml) was stirred
under reflux for 4-12 h. Upon completion of the reaction, as monitored by TLC, the solid was filtered off, washed
with 2-propanol, dried, and recrystallized from EtOH–H2O to give the title compounds. Most of them were
hydrochlorides. If not more solid appeared after the reaction was complete, the solvent was removed under
reduced pressure and the residue was washed with cool water, filtered off, and purified by silica gel column
chromatography (petroleum ether–ethyl acetate, 5:1, v:v) to give the title compounds. Most of them were free
organic bases. So, sometimes we could get both bases and their hydrochlorides in the same reaction.
MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay of cancer cell proliferation
[26]. All tested compounds were dissolved in DMSO (1-100 µM solution) and subsequently diluted in the culture
medium before treatment of the cultured cells. The tested cells were plated in 96-well plates at a density 2×103
cells/well/100 µl of the proper culture medium and treated with the compounds at 1-100 µM for 72 h. In parallel,
the cells treated with 0.1% DMSO served as a control. The MTT assay (Roche Molecular Biochemicals,
1465-007) was performed 30 h later according to the instructions provided by Roche. This assay is based on the
cellular cleavage of MTT into formazan, which is soluble in cell culture medium. The absorbance caused by
1298

formazan was measured at 595 nm with a microplate reader (Bio-Rad, model 680), which is directly proportional
to the number of living cells in culture. Three types of cells were used in these assays, PC3 (prostate cancer),
BGC 823 (human gastric cancer), and Bcap37 (breast cancer) cell lines, provided by ATCC and cultivated in
RPMI 1640 (for PC3, BGC823, and Bcap37) supplemented with 10% fetal bovine serum. Tissue culture reagents
were obtained from Gibco BRL.
This work was financially supported by the Scientific Research Foundation project in Ludong University
of China.
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