2356 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 7
1H, NHamidine), 8.51 (s, 1H, Harom.), 7.90 (d, 2H, J ) 8.64 Hz,
Jarak et al.
0.074 g (81%); mp >300 °C; IR (KBr) (νmax/cm-1) 3220, 3000,
1650, 1610; 1H NMR (DMSO-d6) (δ ppm) 12.58 (s, 1H,
NHquinolone), 9.86 (bs, 1H, NHamidine), 9.65 (bs, 1H, NHamidine),
9.11 (bs, 1H, NHamidine), 8.95 (s, 1H, Harom.), 8.85 (d, 1H, J )
8.44 Hz, Harom.), 8.11 (s, 1H, Harom.), 7.87 (d, 1H, J ) 8.60 Hz,
Hanilide), 7.87 (d, 1H, J ) 9.31 Hz, Harom.), 7.76 (d, 3H, J ) 8.65
Hz, 2Hanilide, 1Harom.), 4.077-4.007 (m, 1H, J ) 6.64 Hz, CHi-pr),
1.26 (d, 6H, J ) 6.32 Hz, 2CH3 i-pr); 13C NMR (DMSO-d6) (δ
ppm) 161.3, 159.3, 142.5, 138.4, 134.8, 132.3, 129.6, 129.4 (2C),
126.2, 124.5, 124.4, 121.0, 120.7, 120.2, 119.7 (2C), 45.0, 21.3
(2C). Anal. (C19H18BrCl2N3OS) C, H, N.
6-Cyano-N-[4′-(N′-isopropylamidino)phenyl]-3-chlo-
robenzo[b]thiophene-2-carboxamide hydrochloride (5f):
from 1f (0.7 g, 2.7 mmol) in dry toluene (40 mL), p-(N-
isopropyl)amidinoaniline (0.49 g, 2.3 mmol) in dry DMF (30
mL), and Et3N (0.56 mL, 4 mmol), after refluxing for 4 h and
recrystallization from a mixture of DMF and methanol (1:1):
H
arom.), 7.69 (d, 1H, J ) 8.61 Hz, Harom.), 7.59 (d, 1H, J ) 8.65
Hz, Harom.), 4.11-4.07 (m, 1H, J ) 6.39 Hz, CHi-pr), 3.39 (s,
3H, CH3), 1.35 (d, 6H, J ) 6.35 Hz, 2CH3 i-pr); 13C NMR
(DMSO-d6) (δ ppm) 161.6, 157.9, 141.7, 140.7, 138.0, 125.3,
132.7, 132.4, 128.3, 127.6, 125.7, 124.2, 123.8, 123.0, 116.75,
116.73, 45.1, 21.3 (2C), 21.08. Anal. (C20H20ClN3OS) C, H, N.
2-(N′-Isopropylamidino)-9-methoxy-6-oxo-5,6-dihydro-
[1]benzothieno[2,3-c]quinoline hydrochloride (6c): yield
0.074 g (81%); mp >300 °C; IR(KBr) (νmax/cm-1) 3400, 3100,
2920, 2840, 1670, 1640, 1600; 1H NMR (DMSO-d6) (δ ppm)
12.56 (s, 1H, NHquinolone), 9.71 (bs, 2H, NHamidine), 9.18 (bs, 1H,
NHamidine), 8.91 (s, 1H, Harom.), 8.85 (d, 1H, J ) 9.19 Hz, Harom.),
7.89 (s, 1H, Harom.), 7.875 (d, 1H, J ) 7.86 Hz, Harom.), 7.69 (d,
1H, J ) 8.47 Hz, Harom.), 7.325 (d, 1H, J ) 8.70 Hz, Harom.),
4.13-4.11 (m, 1H, J ) 5.04 Hz, CHi-pr), 4.08 (s, 3H, OCH3),
1.35 (d, 6H, J ) 5.98 Hz, 2CH3 i-pr); 13C NMR (DMSO-d6) (δ
ppm) 162.0, 159.7, 144.3, 141.2, 135.8, 131.5, 130.0, 128.9,
127.4, 124.6, 123.5, 117.2, 117.1, 116.5, 106.8, 56.2, 45.6, 21.8
(2C). Anal. (C20H20ClN3O2S) C, H, N.
0.39 g (39.2%) of white powder; mp 292-295 °C; IR (KBr) (νmax
/
cm-1) 3340, 3200, 3000, 2200, 1670, 1600; H NMR (DMSO-
d6) (δ ppm) 11.0 (s, 1H, NHamide), 9.51 (d, 1H, J ) 7.81 Hz,
NHamidine), 9.37 (bs, 1H, NHamidine), 9.00 (bs, 1H, NHamidine), 8.84
(s, 1H, Harom.), 8.13 (d, 1H, J ) 8.48 Hz, Harom.), 8.01 (dd, 1H,
J1 ) 8.46 Hz, J2 ) 1.32 Hz, Harom.), 7.93 (d, 2H, J ) 8.82 Hz,
Hanilide), 7.79 (d, 2H, J ) 8.81 Hz, Hanilide), 4.09-4.02 (m, 1H, J
) 6.58 Hz, CHi-pr), 1.29 (d, 6H, J ) 6.0 Hz, 2CH3 i-pr); 13C NMR
(DMSO-d6) (δ ppm) 161.1, 159.0, 142.3, 128.4, 136.7, 136.1,
129.4 (2C), 128.9, 128.6, 124.6, 123.7, 120.0, 199.7 (2C), 118.5,
109.7, 44.9, 21.3 (2C). Anal. (C20H18Cl2N4OS) C, H, N.
1
6-N′′-Isopropylamidino-N-[4′-(N′-isopropylamidino)-
phenyl]-3-chlorobenzo[b]thiophene-2-carboxamide di-
hydrochloride (5g). Compound 5g was prepared using the
method described for the preparation of 5a; from 4b (0.75 g,
2.5 mmol) in dry methoxyethanol (80 mL). The obtained imino
ether was collected by filtration after 7 days and suspended
in absolute ethanol (40 mL). Isopropylamine (1.8 mL, 21 mmol)
was added and the mixture was stirred at room temperature
for 3 days. Crude product was recrystallized from methanol
and then from water to yield 0.25 g (24.4%) of white crystals:
Methyl 2-(N′-isopropylamidino)-6-oxo-5,6-dihydro[1]-
benzothieno[2,3-c]quinolin-9-carboxylate hydrochloride
(6d): yield 0.083 g (83.5%); mp 280-283 °C; IR (KBr) (νmax
/
cm-1) 3200, 3020, 1710, 1670, 1650; 1H NMR (DMSO-d6) (δ
ppm) 12.70 (bs, 1H, NHquinolone), 9.72 (bs, 2H, NHamidine), 9.16
(bs, 1H, NHamidine), 9.11 (d, 1H, J ) 8.61 Hz, Harom.), 8.98 (s,
1H, Harom.), 8.97 (s, 1H, Harom.), 8.23 (dd, 1H, J1 ) 8.72 Hz, J2
) 1.61 Hz, Harom.), 7.90 (d, 1H, J ) 8.46 Hz, Harom.), 7.72 (d,
1H, J ) 8.64 Hz, Harom.), 4.12-4.08 (m, 1H, J ) 6.38 Hz,
CHi-pr), 3.96 (s, 3H, COOCH3), 1.36 (d, 6H, J ) 6.33 Hz,
2CH3 i-pr); 13C NMR (DMSO-d6) (δ ppm) 165.7, 161.5, 157.7,
141.3, 140.7, 138.3, 136.6, 134.6, 128.7, 128.4, 126.3, 125.8,
125.7, 124.2, 123.3, 116.9, 116.6, 52.6, 45.2, 21.3 (2C). Anal.
(C21H20ClN3O3S) C, H, N.
2-(N′-Isopropylamidino)-9-bromo-6-oxo-5,6-dihydro[1]-
benzothieno[2,3-c]quinoline hydrochloride (6e): yield
0.094 g (90%); mp >300 °C; IR (KBr) (νmax/cm-1) 3200, 3000,
2820, 2780, 1650, 1610; 1H NMR (DMSO-d6) (δ ppm) 12.70 (s,
1H, NHquinolone), 9.73 (s, 1H, Hamidine), 9.64 (s, 1H, NHamidine),
9.12 (s, 1H, NHamidine), 9.82 (d, 2H, J ) 8.56 Hz, Harom.), 8.66
(d, 1H, J ) 1.49 Hz, Harom.), 7.91 (d, 1H, J ) 6.99 Hz, Harom.),
7.89 (d, 1H, J ) 5.42 Hz, Harom.), 7.70 (d, 1H, J ) 8.63 Hz,
mp 306-308 °C; IR (KBr) (νmax/cm-1) 3320, 3180, 3000, 1670,
1
1610; H NMR (DMSO-d6) (δ ppm) 9.75-9.49 (bs, 6H, NHami
-
dine), 8.64 (s, 1H, Harom.), 8.15 (d, 1H, J ) 8.44 Hz, Harom.), 7.95
(d, 2H, J ) 8.83 Hz, Hanilid), 7.92 (d, 2H, J ) 8.76 Hz, Harom.),
7.80 (d, 2H, J ) 8.61 Hz, Hanilide), 4.06-4.02 (m, 2H, CHi-pr),
1.35 (d, 6H, J ) 6.62 Hz, 2CH3 i-pr), 1.29 (d, 6H, J ) 6.50 Hz,
2CH3 i-pr); 13C NMR (DMSO-d6) (δ ppm) 161.5, 161.3, 159.2,
142.4, 138.6, 136.5, 135.3, 129.5 (2C), 128.4, 125.9, 124.7,
122.9, 120.0, 119.9 (2C), 45.4, 45.1, 21.4 (2C), 21.3 (2C). Anal.
(C23H28Cl3N5OS) C, H, N.
General Method for the Synthesis of 6-Oxo-5,6-dihydro-
[1]benzothieno[2,3-c]quinoline (6a-g). A solution of 6-sub-
stituted N-[4′-(N′-isopropylamidino)phenyl]-3-chlorobenzo[2,3-
c]thiophene-2-carboxamide (5a-g) (0.24 mmol) in methanol
(10 mL) was irradiated at room temperature with 400-W high-
pressure mercury lamp using a Pyrex filter for 1.5 h. The air
was bubbled through the solution. The solution was concen-
trated and the obtained solid was filtered off and washed with
acetone. After recrystallization from methanol, white crystals
were obtained.
2-(N′-Isopropylamidino)-6-oxo-5,6-dihydro[1]-
benzothieno[2,3-c]quinoline hydrochloride (6a). Com-
pound 6a was prepared using the general method described
for the preparation of 6a-g; a solution of 5a (0.106 g, 0.25
mmol) in methanol (10 mL) was irradiated for 1 h. The formed
precipitate was filtered off and recrystallized from ethanol to
give 0.061 g (64%) of white crystals: mp >300 °C; IR (KBr)
(νmax/cm-1) 3060, 2940, 1650, 1620; 1H NMR (DMSO-d6) (δ
ppm) 12.62 (bs, 1H, NHquinolone), 9.72 (bs, 1H, NHamidine), 9.62
(bs, 1H, NHamidine), 9.18 (bs, 1H, NHamidine), 8.92 (d, 1H, J )
8.32 Hz, Harom.), 8.90 (d, 1H, J ) 1.69 Hz, Harom.), 8.23 (dd, 1H,
J1 ) 7.64 Hz, J2 ) 1.21 Hz, Harom.), 7.83 (dd, 1H, J1 ) 8.60 Hz,
J2 ) 1.74 Hz, Harom.), 7.69 (dd, 1H, J1 ) 7.02 Hz, J2 ) 1.06 Hz,
H
arom.), 4.12-4.09 (m, 1H, J ) 7.59 Hz, CHi-pr), 1.35 (d, 6H, J
) 6.29 Hz, CH3 i-pr); 13C NMR (DMSO-d6) (δ ppm) 161.9, 158.3,
143.6, 141.2, 134.8, 134.2, 134.0, 129.5, 129.1, 128.1, 127.3,
124.6, 123.7, 121.7, 117.3, 116.9, 45.6, 21.8 (2C). Anal. (C19H17-
BrClN3OS) C, H, N.
2-(N′-Isopropylamidino)-9-cyano-6-oxo-5,6-dihydro[1]-
benzothieno[2,3-c]quinoline hydrochloride (6f): yield
0.059 g (65%); mp >300 °C; IR (KBr) (νmax/cm-1) 3400, 3000,
2220, 1650, 1610; 1H NMR (DMSO-d6) (δ ppm) 12.47 (bs, 1H,
NHquinolone), 9.68 (bs, 3H, NHamidine), 9.13 (d, 1H, J ) 8.65 Hz,
Harom.), 8.91 (s, 2H, Harom.), 8.09 (d, 1H, J ) 8.64 Hz, Harom.),
7.89 (d, 1H, J ) 8.64, Harom.), 7.70 (d, 1H, J ) 8.64, Harom.),
4.15-4.11 (m, 1H, J ) 6.43 Hz, CHi-pr), 1.34 (d, 6H, J ) 6.32
Hz, CH3 i-pr); 13C NMR (δ ppm) (DMSO-d6) 161.7, 140.9, 138.2,
135.5, 131.8, 129.4, 129.1, 128.5, 127.3, 124.4, 123.6, 119.0,
117.2, 117.0, 110.1, 45.4 (2C), 21.4. Anal. (C20H17ClN4OS) C,
H, N.
2-(N′-Isopropylamidino)-9-(N′′-isopropylamidino)-6-
oxo-5,6-dihydro[1]benzothieno[2,3-c]quinoline dihydro-
chloride (6g). Compound 6g was prepared using the general
method described for the preparation of 6a-g; a solution of
5g (0.10 g, 0.19 mmol) in methanol (12 mL) was irradiated
for 1.5 h. The formed precipitate was filtered off and recrystal-
lized from methanol to yield 0.06 g (64%) of white crystals:
H
arom.), 7.67-6.55 (m, 2H, Harom.), 4.12-4.07 (m, 1H, CHi-pr),
1.28 (d, 6H, J ) 6.41 Hz, 2CH3 i-pr); 13C NMR (DMSO-d6) (δ
ppm) 161.1, 158.0, 141.4, 140.7, 135.3, 135.1, 133.4, 128.5,
127.9, 126.2, 126.0, 124.28, 124.24, 123.2, 116.8 (2C), 45.2, 21.4
(2C). Anal. (C19H18ClN3OS) C, H, N.
1
mp >300 °C; IR (KBr) (νmax/cm-1) 3040, 1650, 1640, 1610; H
NMR (DMSO-d6) (δ ppm) 12.82 (s, 1H, NHquinolone), 9.93 (d, 1H,
J ) 9.35 Hz, NHamidine), 9.20 (d, 1H, J ) 9.46 Hz, NHamidine),
9.80 (s, 1H, NHamidine), 9.78 (s, 1H, NHamidine), 9.39
2-(N′-Isopropylamidino)-9-methyl-6-oxo-5,6-dihydro[1]-
benzothieno[2,3-c]quinoline hydrochloride (6b): yield