7
748 Journal of Medicinal Chemistry, 2006, Vol. 49, No. 26
Morrell et al.
thalic anhydride29 (7; 3.222 g, 15.56 mmol) was added to a
chloroform (200 mL) solution of 3,4,5-trimethoxybenzylidene-(3-
bromo-1-propylamine) (8; 4.919 g, 15.56 mmol), and the reaction
mixture was allowed to stir at room temperature for 16 h. The
precipitate was filtered, washed with chloroform (50 mL), and dried
to provide an off-white solid (∼0.5 g). The filtrate was concentrated
to a volume of 50 mL, and diethyl ether (20 mL) was added. The
precipitate was filtered and washed with diethyl ether (50 mL),
and the isolated precipitates were combined and dried to provide
an off-white solid (3.009 g, 37%): mp 142-145 °C. IR (KBr) 3082,
allowed to stir at room temperature for 4 h. The precipitate was
filtered, washed with chloroform (100 mL), and dried to provide
an off-white solid (4.048 g, 52%): mp 147-150 °C. IR (KBr) 2953,
-
1
1
1745, 1627, 1512, 1344, 1271, 1225, 1181, and 1051 cm ; H
NMR (CD OD) δ 8.88 (d, J ) 2.5 Hz, 1 H), 8.38 (dd, J ) 8.6 and
3
2.5 Hz, 1 H), 7.74 (dd, J ) 8.5 and 1.5 Hz, 1 H), 6.89 (d, J ) 9.0
Hz, 1 H), 6.81 (dd, J ) 9.0 and 2.9 Hz, 1 H), 6.31 (d, J ) 2.9 Hz,
1 H), 5.73 (d, J ) 6.5 Hz, 1 H), 4.84 (d, J ) 6.5 Hz, 1 H), 3.99
(m, 1 H), 3.68 (s, 3 H), 3.52 (s, 3 H), 3.44 (m, 2 H), 3.28 (m, 1 H),
2.23 (m, 1 H), 2.11 (m, 1 H); ESIMS m/z (rel intensity) 493/495
-
1
+
1749, 1629, 1592, 1526, 1465, 1351, 1239, 1171, and 1128 cm
;
(MH , 100/94). Anal. (C21
2 7
H21BrN O ) C, H, N.
1
H NMR (DMSO-d
.6 and 2.6 Hz, 1 H), 7.96 (d, J ) 8.7 Hz, 1 H), 6.26 (s, 2 H), 5.21
d, J ) 6.1 Hz, 1 H), 5.03 (d, J ) 6.1 Hz, 1 H), 3.98 (m, 1 H),
.63-3.55 (m, 11 H), 3.13 (m, 1 H), 2.21-2.07 (m, 2 H);
6
) δ 8.72 (d, J ) 2.6 Hz, 1 H), 8.41 (dd, J )
cis-4-Carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methox-
yphenyl)-7-nitro-1(2H)isoquinolone (21). 4-Nitrohomophthalic
anhydride29 (7; 4.563 g, 22.03 mmol) was added to a chloroform
(125 mL) solution of 4-methoxybenzylidene-(3-chloro-1-propy-
lamine) (13; 4.664 g, 22.03 mmol), and the reaction mixture was
allowed to stir at room temperature for 16 h. The precipitate was
filtered, washed with chloroform (50 mL), and dried to provide an
off-white solid (7.018 g, 76%): mp 163-164 °C. IR (KBr) 2957,
8
(
3
+
MALDIMS m/z (rel intensity) 523/525 (MH , 65/50), 478/480
+
(MH - COOH, 80/100). Anal. (C22
2 8
H23BrN O ) C, H, N.
cis-N-(3-Bromopropyl)-4-carboxy-3,4-dihydro-3-(2,3,4-tri-
methoxyphenyl)-7-nitro-1(2H)isoquinolone (17). 4-Nitrohomoph-
thalic anhydride29 (7; 2.948 g, 14.23 mmol) was added to a
chloroform (125 mL) solution of 2,3,4-trimethoxybenzylidene-(3-
bromo-1-propylamine) (9; 4.500 g, 14.23 mmol), and the reaction
mixture was allowed to stir at room temperature for 4.5 h. The
precipitate was filtered, washed with chloroform (50 mL), diethyl
ether (50 mL), and dried to provide an off-white solid (6.271 g,
-1
1
1739, 1633, 1528, 1347, 1296, 1256, and 1177 cm ; H NMR
(CD OD) δ 8.89 (d, J ) 2.5 Hz, 1 H), 8.38 (dd, J ) 8.7 and 2.6
3
Hz, 1 H), 7.98 (dd, J ) 8.7 and 1.0 Hz, 1 H), 6.97 (dd, J ) 6.7
and 2.1 Hz, 2 H), 6.76 (dd, J ) 6.8 and 2.1 Hz, 2 H), 5.25 (d, J )
6.3 Hz, 1 H), 4.90 (d, J ) 6.4 Hz, 1 H), 4.01 (m, 1 H), 3.70 (s, 3
H), 3.62 (m, 2 H), 3.26 (m, 1 H), 2.17 (m, 1 H), 2.04 (m, 1 H);
+
8
1
4%): mp 133-136 °C. IR (KBr) 2947, 1737, 1632, 1526, 1496,
ESIMS m/z (rel intensity) 419/421 (MH , 100/35). Anal. (C20
19
H -
-
1
1
465, 1418, 1348, 1294, 1179, and 1100 cm ; H NMR (CD
3
-
ClN
2
6 2
O ·0.75 H O) C, H, N.
OD) δ 8.87 (d, J ) 2.5 Hz, 1 H), 8.39 (dd, J ) 8.6 and 2.5 Hz, 1
H), 7.79-7.76 (m, 1 H), 6.53 (d, J ) 8.8 Hz, 1 H), 6.47 (d, J )
cis-4-Carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(3-methox-
yphenyl)-7-nitro-1(2H)isoquinolone (22). 4-Nitrohomophthalic
anhydride29 (7; 3.914 g, 18.90 mmol) was added to a chloroform
(125 mL) solution of 3-methoxybenzylidene-(3-chloro-1-propy-
lamine) (14; 4.000 g, 18.90 mmol), and the reaction mixture was
allowed to stir at room temperature for 16 h. The precipitate was
filtered, washed with chloroform (100 mL), and dried to provide a
white solid (4.477 g, 57%): mp 154-157 °C. IR (KBr) 1743, 1633,
8
3
2
.8 Hz, 1 H), 5.63 (d, J ) 6.8 Hz, 1 H), 4.90 (d, J ) 7.0 Hz, 1 H),
.93 (m, 1 H), 3.83 (s, 3 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.49 (m,
H), 3.29 (m, 1 H), 2.25 (m, 1 H), 2.09 (m, 2 H); ESIMS m/z (rel
+
+
intensity) 545/547 (MNa , 100/97), 523/525 (MH , 21/22). Anal.
) C, H, N.
cis-N-(3-Bromopropyl)-4-carboxy-3,4-dihydro-3-(3,4-dimethox-
22 2 8
(C H23BrN O
-
1 1
yphenyl)-7-nitro-1(2H)isoquinolone (18). 4-Nitrohomophthalic
3
1527, 1489, 1348, and 1179 cm ; H NMR (CD OD) δ 8.89 (d,
anhydride29 (7; 5.165 g, 18.05 mmol) was added to a chloroform
J ) 2.5 Hz, 1 H), 8.38 (dd, J ) 8.6 and 2.6 Hz, 1 H), 7.99 (dd, J
) 8.6 and 1.0 Hz, 1 H), 7.14 (m, 1 H), 6.84 (ddd, J ) 8.3 and 2.4
Hz and 1.00 Hz, 1 H), 6.61 (m, 2 H), 5.28 (d, J ) 6.4 Hz, 1 H),
4.95 (d, J ) 6.4 Hz, 1 H), 4.05 (m, 1 H), 3.65 (s, 3 H), 3.61 (m,
(150 mL) solution of 3,4-dimethoxybenzylidene-(3-bromo-1-pro-
pylamine) (10) (3.739 g, 18.05 mmol) and the reaction mixture
was allowed to stir at room temperature for 3 h. The precipitate
was filtered, washed with chloroform (100 mL), and dried to provide
2 H), 3.29 (m, 1 H), 2.20-2.00 (m, 2 H); negative ion ESIMS m/z
-
an off-white solid (5.910 g, 66%): mp 161-163 °C. IR (KBr) 3046,
(rel intensity) 417/419 [(M-H) , 100/34]. Anal. (C20
2 6
H19ClN O )
1
1
751, 1633, 1520, 1352, 1259, 1178, 1146, and 1030 cm-1; H
C, H, N.
NMR (CD
.6 Hz, 1 H), 8.00-7.97 (m, 1 H), 6.78 (d, J ) 8.4 Hz, 1 H), 6.65
d, J ) 2.2 Hz, 1 H), 6.58 (dd, J ) 8.3 and 2.2 Hz, 1 H), 5.27 (d,
J ) 6.1 Hz, 1 H), 4.89 (d, J ) 6.1 Hz, 1 H), 3.99 (m, 1 H), 3.74
s, 3 H), 3.64 (s, 3 H), 3.48 (m, 2 H), 3.28 (m, 1 H), 2.27 (m, 1 H),
3
OD) δ 8.89 (d, J ) 2.5 Hz, 1 H), 8.38 (dd, J ) 8.6 and
cis-4-Carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(2-methox-
yphenyl)-7-nitro-1(2H)isoquinolone (23). 4-Nitrohomophthalic
anhydride29 (7; 3.914 g, 18.90 mmol) was added to a chloroform
(125 mL) solution of 2-methoxybenzylidene-(3-chloro-1-propy-
lamine) (15; 4.000 g, 18.90 mmol), and the reaction mixture was
allowed to stir at room temperature for 16 h. The precipitate was
filtered, washed with chloroform (100 mL) and diethyl ether (50
mL), and dried to provide an off-white solid (5.455 g, 69%): mp
159-162 °C. IR (KBr) 3076, 1753, 1626, 1525, 1489, 1352, 1289,
2
(
(
+
2.14 (m, 1 H); ESIMS m/z (rel intensity) 493/495 (MH , 100/96).
Anal. (C21 ) C, H, N.
2 7
H21BrN O
cis-N-(3-Bromopropyl)-4-carboxy-3,4-dihydro-3-(2,3-dimethox-
yphenyl)-7-nitro-1(2H)isoquinolone (19). 4-Nitrohomophthalic
anhydride29 (7; 3.258 g, 15.73 mmol) was added to a chloroform
-1
1
1248, 1162, and 759 cm ; H NMR (CD OD) δ 8.89 (d, J ) 2.5
3
(125 mL) solution of 2,3-dimethoxybenzylidene-(3-bromo-1-pro-
Hz, 1 H), 8.37 (dd, J ) 8.6 and 2.5 Hz, 1 H), 7.71 (m, 1 H), 7.26
(m, 1 H), 6.96 (d, J ) 8.1 Hz, 1 H), 6.77 (m, 2 H), 5.78 (d, J ) 6.5
Hz, 1 H), 4.86 (d, J ) 6.4 Hz, 1 H), 4.01 (m, 1 H), 3.74 (s, 3 H),
pylamine) (11; 4.500 g, 15.73 mmol), and the reaction mixture was
allowed to stir at room temperature for 16 h. The precipitate was
filtered, washed with chloroform (50 mL), diethyl ether (50 mL),
and dried to provide an off-white solid (6.737 g, 87%): mp 161-
3.63 (m, 2 H), 3.22 (m, 1 H), 2.16 (m, 1 H), 2.04 (m, 1 H); ESIMS
+
m/z (rel intensity) 419/421 (MH , 100/34). Anal. (C20
0.25 H O) C, H, N.
2
H
19ClN
2
O
6
·
1
1
63 °C. IR (KBr) 2947, 1745, 1630, 1524, 1481, 1345, 1274, and
-
1 1
179 cm ; H NMR (CD
3
OD) δ 8.87 (d, J ) 2.5 Hz, 1 H), 8.40
6-(3-Bromopropyl)-5,6-dihydro-7,8,9-trimethoxy-3-nitro-5,-
11-dioxo-11H-indeno[1,2-c]isoquinoline (24). Thionyl chloride
(1.5 mL) was added to a solution of cis-N-(3-bromopropyl)-4-
carboxy-3,4-dihydro-3-(2,3,4-trimethoxyphenyl)-7-nitro-1(2H)iso-
quinolone (17; 0.500 g, 0.955 mmol) in benzene (50 mL). The
reaction mixture was heated at reflux for 30 min, allowed to cool
to room temperature, and concentrated. The residue was diluted
with nitrobenzene (10 mL) and chilled in an ice bath, and aluminum
chloride was added (0.255 g, 1.910 mmol). The reaction mixture
was removed from the bath and heated at 100 °C for 1 h. Water
(
dd, J ) 8.6 and 2.5 Hz, 1 H), 7.80 (dd, J ) 8.7 and 2.9 Hz, 1 H),
.93 (dd, J ) 8.2 and 1.3 Hz, 1 H), 6.82 (t, J ) 8.1 Hz, 1 H), 6.35
dd, J ) 7.9 and 1.4 Hz, 1 H), 5.75 (d, J ) 6.8 Hz, 1 H), 4.94 (d,
J ) 6.5 Hz, 1 H), 3.98 (m, 1 H), 3.81 (s, 6 H), 3.51 (m, 2 H), 3.26
m, 1 H), 2.26 (m, 1 H), 2.11 (m, 1 H); ESIMS m/z (rel intensity)
6
(
(
+
493/495 (MH , 100/100). Anal. (C21
2 7
H21BrN O ) C, H, N.
cis-N-(3-Bromopropyl)-4-carboxy-3,4-dihydro-3-(2,5-dimethox-
yphenyl)-7-nitro-1(2H)isoquinolone (20). 4-Nitrohomophthalic
anhydride29 (7; 3.258 g, 15.73 mmol) was added to a chloroform
(
125 mL) solution of 2,5-dimethoxybenzylidene-(3-bromo-1-pro-
(100 mL) was added, and the solution was extracted with CHCl
(3 × 50 mL). The combined organic layer was washed with sat aq
3
pylamine) (12; 4.500 g, 15.73 mmol), and the reaction mixture was