J. Kossakowski et al. / Il Farmaco 60 (2005) 519–527
525
(
d, J = 8.8 Hz, 1 H, 5-H), 3.89, 3.86 (2 s, 6 H, 6-OCH3,
(m, 2 H, 3-COOCH ), 3.58–3.14 (m, 6 H, N(CH ) ), 2.87 (t,
2 2 3
2
-COOCH ), 2.63 (s, 3 H, 7-COCH ), 2.48 (s, 3 H, 3-CH ).
J = 6.0 Hz, 2H, 3-COOCH CH ), 2.59 (s, 3 H, 6-COCH ),
3
3
3
2 2 3
2
.58 (s, 3 H, 2-CH ), 1.39 (m, 6 H, 2 × CH CH ), 1.04 (t,
3 2 3
3
.3.10. 5-Bromo-7-hydroxy-6-methoxy
J = 7.0 Hz, 3 H, 5-OCH CH CH ); C H NO (375.4): calc.
C 67.19, H 7.79, N 3.73; found C 67.44, H 7.94, N 3.95.
2
2
3
21 29
5
-2-benzofurancarboxylic acid methyl ester (6a)
1
Yield 92%; m.p. 133–134 °C (methanol); H NMR
(
3
200 MHz, CDCl ): d 7.47 (s, 1 H, 3-H), 7.12 (s, 1 H, 4-H),
3
3
.4.4. 7-Acetyl-6-(O-ethyl-2′-diethylamino)-3-methyl-2-
benzofurancarboxylic acid methyl ester hydrochloride
2b)
Yield 75%; m.p. 161–163 °C (methanol/ethyl ether); H
.97 (s, 6 H, 6-OCH , 2-COOCH ); C H BrO (301.1): calc.
3 3 11 9 5
C 43.88, H 3.01; found C 43.85, H 3.02.
(
1
3
.3.11. 7-Methoxy-2-benzofurancarboxylic acid methyl
NMR (200 MHz, CDCl ): d = 12.37 (br.s, 1 H, NH), 7.67 (d,
J = 8.6 Hz, 1 H, 4-H), 7.09 (d, J = 8.8 Hz, 1 H, 5-H), 4.71 (t,
J = 4.4 Hz, 2 H, 6-OCH
3.32 (m, 6 H, N(CH ), 2.78 (s, 3 H, 7-COCH
3 H, 3-CH ), 1.46 (m, 6 H, 2 × CH CH ); C19 26ClNO ×
5
ester (7a)
3
1
Yield 95%; m.p. 72–73 °C (methanol), lit. 79 °C [27], H
NMR (200 MHz, CDCl ): d 7.53 (s, 1 H, 3-H), 7.25–7.20 (m,
2
2
2
), 3.96 (s, 3 H, 2-COOCH
3
), 3.52–
3
H, 4,6-H), 6.92 (d, J = 7.6 Hz, 1 H, 5-H), 4.02 (s, 3 H,
-COOCH3).
2
)
3
3
), 2.57 (s,
H
3
2
3
H O (401.9): calc. C 56.78, H 6.52, N 3.48; found C 56.62, H
2
3.4. Synthesis of O-(ethyl-N,N-diethylamino)substituted
6.83, N 3.57.
esters of benzofurancarboxylic acids
3
.4.5. 7-Acetyl-6-(O-ethyl-2′-diethylamino)-5-methoxy-3-
General procedure. A mixture of an appropriate benzo-
furancarboxylic acid ester, with free phenolic OH group
methyl-2-benzofurancarboxylic acid methyl ester hydro-
chloride (3b)
(1.8 mmol), N,N-diethyl-2-chloroethylamine hydrochloride
1
Yield 78%; m.p. 137–138 °C (methanol/ethyl ether); H
(7.2 mmol), anhydrous potassium carbonate (10 mmol) and
NMR (400 MHz, CDCl ): d = 12.07 (br.s, 1 H, NH), 7.15 (s,
3
Aliquat 336® (0.4 mmol) was suspended in anhydrous
acetone (20 ml) and refluxed with stirring for 16–20 h. When
the ester was alkylated, inorganic salts were removed by fil-
tration. The solvent was evaporated. The residue was purified
by column chromatography on silica gel (eluent: chloro-
form) and/or crystallized from appropriate solvent to give a
base. It was dissolved in methanol saturated with gaseous HCl.
The hydrochloride was precipitated by addition of diethyl
ether. The crude product was crystallized from methanol/ethyl
ether.
1
3
H, 4-H), 4.54 (m, 2 H, 6-OCH ), 3.99 (s, 3 H, 5-OCH ),
2 3
.97 (s, 3 H, 2-COOCH ), 3.53–3.24 (m, 6 H, N(CH ) ), 2.79
3
2 3
(s, 3 H, 7-COCH ), 2.58 (s, 3 H, 3-CH ), 1.47 (m, 6 H, 2 ×
3 3
CH CH ); C H ClNO (413.9): calc. C 58.06, H 6.77, N
3
2
3
20 28
6
.38; found C 58.07, H 6.52, N 3.49.
3
.4.6. 6-(O-ethyl-2′-diethylamino)-7-(p-methoxy-
cinnamoyl)-3-methyl-2-benzofurancarboxylic acid methyl
ester hydrochloride (4b)
1
Yield 60%; m.p. 160–161 °C (methanol/ethyl ether); H
NMR (200 MHz, CDCl ): d 12.38 (br.s, 1 H, NH), 7.68 (d,
J = 8.8 Hz, 1 H, 4-H), 7.52 (m, 2 H, 5′-H, 6′-H), 7.40 (d,
J = 15.8 Hz, 1 H, 1′-H), 7.08 (m, 2 H, 2′-H, 5′-H), 6.91 (d,
3
3
.4.1. 6-Acetyl-5-(O-ethyl-2′-diethylamino)-2-methyl-3-
benzofurancarboxylic acid methyl ester (1f)
1
Yield 62%; m.p. 129–131 °C; H NMR (400 MHz,
J = 8.8 Hz, 2 H, 3′-H, 4′-H), 4.71 (m, 2 H, 6-OCH ), 3.90 (s,
CDCl ): d 7.75 (s, 1 H, 7-H), 7.56 (s, 1 H, 4-H), 4.72 (m, 2 H,
2
3
3
H, 2-COOCH ), 3.85 (s, 3 H, phenyl-OCH ), 3.42–3.18
5
2
×
-OCH ), 3.99 (s, 3 H, 3-COOCH ), 3.34 (m, 6 H, N(CH ) ),
.80 (s, 3 H, 6-COCH ), 2.63 (s, 3 H, 2-CH ), 1.48 (m, 6 H, 2
3
3
2
3
2 3
(
m, 6 H, N(CH ) ), 2.59 (s, 3 H, 3-CH ), 1.33 (t, J = 7.0 Hz,
2 3 3
3
3
6
6
H, 2 × CH CH ); C H ClNO (502.1): calc. C 64.60, H
2 3 27 32 6
.38, N 2.79; found C 64.79, H 6.36, N 3.03.
CH CH ); C H ClNO (383.9): calc. C 59.44, H 6.83, N
2
3
19 26
5
3.65; found C 59.54, H 6.97, N 3.70.
3
.4.7. 5-Bromo-7-(O-ethyl-2′-diethylamino)-6-methoxy-2-
3
.4.2. 6-Acetyl-5-(O-ethyl-2′-diethylamino)-2-methyl-3-
benzofurancarboxylic acid methyl ester (6b)
benzofurancarboxylic acid ethyl ester (1g)
1
1
Yield 58%; Oil; H NMR (400 MHz, CDCl ) d = 7.39 (s,
Yield 57%. Oil; H NMR (400 MHz, CDCl ): d 7.82 (s,
3
3
1
H, 3-H), 7.06 (s, 1 H, 4-H), 4.45 (s, 2 H, 7-OCH ), 3.87 (d,
1
5
H, 7-H), 7.53 (s, 1 H, 4-H), 4.43 (t, J = 6.4 Hz, 2 H,
-OCH ), 4.19 (t, J = 6.2 Hz, 2 H, 3-COOCH ), 2.85 (m, 6 H,
2
J = 9.2 Hz, 6 H, N(CH ) ), 1.19 (s, 6 H, 2 × CH CH ); C H
BrNO (400.3): calc. C 51.01, H 5.54, N 3.51; found C 51.16,
H 5.57, N 3.35.
2 3
2
3
17 22
2
2
N(CH ) ), 2.76 (s, 3 H, 6-COCH ), 2.65 (s, 3 H, 2-CH ), 1.25
5
2
3
3
3
(m, 6 H, 2 × CH CH ), 1.06 (t, J = 6.6 Hz, 3 H, 5-OCH CH );
2 3 2 3
C H NO (361.4): calc. C 66.46, H 7.53, N 3.88; found C
20
27
5
66.44, H 7.32, N 3.78.
3.5. Cytotoxicity
3
.4.3. 6-Acetyl-5-(O-ethyl-2′-diethylamino)-2-methyl-3-
The in vitro cell line screening utilizing 60 different human
tumor cell lines was carried out in National Institute of Health,
National Cancer Institute, Bethesda, USA. A 48 h continu-
ous drug exposure protocol was used and a sulforhodamine
benzofurancarboxylic acid n-propyl ester (1h)
1
Yield 60%; Oil; H NMR (400 MHz, CDCl ): d 7.80 (s,
3
1
H, 7-H), 7.45 (s, 1 H, 4-H), 4.08 (m, 2 H, 5-OCH ), 3.66
2