A.R.A. Pires et al. / European Journal of Medicinal Chemistry 122 (2016) 291e301
297
[M ꢀ H]ꢀ, 337 [MþNa]þ.
H, 4.22; N, 5.12.
5.1.3.6. 5-(40-Fluorobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid (3e). The crude was prepared according to general procedure C
starting from 2e (500 mg,1.5 mmol) to afford 3e as a yellowish solid
(220 mg, 47%). m.p. 178e179 ꢁC. C17H11FO5. 1H NMR (400 MHz,
5.1.4.3. 5-(30-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid [2-(5-methoxy-1H-indol 3-yl)-ethyl]-amide (4b). The crude was
prepared according to general procedure D starting from 3b (0.6 g,
1.7 mmol) and 5-methoxytryptamine hydrochloride (323 mg,
1.7 mmol) and was recrystallized in ethyl acetate/toluene (9:1) to
afford 4b as a cream solid (456 mg, 49%). C28H23BrN2O5. m.p.
DMSO-d6)
d 5.24 (s, 2H, OCH2), 6.69 (s, 1H, COCH), 7.10 (d, 1H,
J ¼ 8.3 Hz, ArH), 7.20 (d, 1H, J ¼ 8.5 Hz, ArH), 7.18e7.28 (m, 2H, ArH),
7.63e7.77 (m, 2H, ArH), 7.72 (m, 1H, ArH). 13C NMR (100 MHz,
199e200 ꢁC. 1H NMR (400 MHz, DMSO-d6)
d
2.95 (t, 2H, J ¼ 6.8 Hz,
DMSO-d6)
d
69.3, 108.7, 110.6, 114.3, 114.7, 115.1 (d, JC-F ¼ 21.3 Hz),
CH2CH2NH), 3.57 (m, 2H, CH2CH2NH), 3.74 (s, 3H, OCH3), 5.27 (s, 2H,
OCH2), 6.69 (s, 1H, COCH), 6.73 (dd, 1H, J ¼ 2.4 Hz, J ¼ 8.7 Hz, ArH),
7.08 (d, 1H, J ¼ 1.8 Hz, ArH), 7.10 (d, 1H, J ¼ 8.3 Hz, ArH), 7.17 (d, 1H,
J ¼ 1.7 Hz, ArH), 7.23 (d, 1H, J ¼ 8.7 Hz, ArH), 7.26 (d, 1H, J ¼ 8.3 Hz,
ArH), 7.38 (m, 1H, ArH), 7.52 (d, 1H, J ¼ 8.0 Hz, ArH), 7.60 (d, 1H,
J ¼ 7.6 Hz, ArH), 7.77 (m, 1H, ArH), 7.91 (m, 1H), 9.19 (t, 1H,
J ¼ 5.2 Hz, CONH), 10.68 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
128.9 (d, JC-F ¼ 8.1 Hz), 133.0 (d, JC-F ¼ 2.8 Hz), 134.8, 157.5, 157.8,
158.6, 161.3, 161.6 (d, JC-F ¼ 242.9 Hz), 177.1. MS (ESI) m/z 313
[M ꢀ H]ꢀ.
5.1.3.7. 5-(30,40-Difluorobenzyloxy)-4-oxo-4H-chromene-2-
carboxylic acid (3f). The crude was prepared according to general
procedure C starting from 2f (196 mg, 0.5 mmol) to afford 3f as a
white solid (142 mg, 79%). C17H10F2O5. m.p. 198e199 ꢁC. 1H NMR
d
24.9, CH2 under DMSO, 55.2, 69.0, 100.2, 108.9, 110.7, 111.1, 111.2,
112.0, 112.1, 114.5, 121.7, 123.4, 125.6, 127.5, 129.4, 130.3, 130.5, 131.4,
(400 MHz, DMSO-d6)
1H, J ¼ 7.9 Hz, ArH), 7.23 (d, 1H, J ¼ 7.7 Hz, ArH), 7.42e7.54 (m, 2H,
ArH), 7.73e7.84 (m, 2H, ArH). 13C NMR (100 MHz, DMSO-d6)
68.6,
d
5.25 (s, 2H, OCH2), 6.74 (s,1H, COCH), 7.10 (d,
135.0, 139.7, 153.0, 153.6, 157.0, 157.6, 158.9, 176.6. MS (ESI) m/z 569
(
59.48; H, 4.46; N, 4.95; Found: C, 59.73; H, 4.29; N, 4.82.
79Br), 571 (81Br) [MþNa]þ; Anal. Calcd for C28H23BrN2O5, H2O: C,
d
108.9, 110.7, 114.7, 115.1, 115.8 (d, JC-F ¼ 18.1 Hz), 117.4 (d, JC-
¼ 17.1 Hz), 123.2 (m), 134.7, 135.2, 148.0 (m), 150.0, 151.5, 157.4,
5.1.4.4. 5-(20-Fluorobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide (4c). The crude
was prepared according to general procedure D starting from 3c
(157 mg, 0.5 mmol) and was recrystallized in acetonitrile to afford
4c as a white solid (18 mg, 7%). C28H23FN2O5. m.p. 216e217 ꢁC. 1H
F
157.5, 161.5, 176.9. MS (ESI) m/z 331 [M ꢀ H]ꢀ.
5.1.3.8. 5-(40-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid (3g). The crude was prepared according to general procedure B
from 2g (1.7 g, 4.3 mmol) to afford 3g as a white solid (1.5 g, 90%).
NMR (400 MHz, DMSO-d6)
d
2.95 (t, 2H, J ¼ 7.5 Hz, CH2CH2NH), 3.56
C
17H11BrO5. Decomposition at 200 ꢁC. 1H NMR (400 MHz, DMSO-
(m, 2H, CH2CH2NH), 3.73 (s, 3H, OCH3), 5.29 (s, 2H, OCH2), 6.66 (s,
1H, COCH), 6.71 (m, 1H, ArH), 7.07 (m, 1H, ArH), 7.17e7.29 (m, 6H,
ArH), 7.41 (m, 1H), 7.78 (m, 1H, ArH), 7.95 (m, 1H, ArH), 9.21 (t, 1H,
J ¼ 5.5 Hz, CONH), 10.69 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6)
d6)
ArH), 6.76 (d, 1H, J ¼ 8.0 Hz, ArH), 7.08e7.20 (m, 4H, ArH), 7.28 (m,
1H, ArH). 13C NMR (100 MHz, DMSO-d6)
69.2, 108.9, 110.6, 114.7,
d
4.79 (s, 2H, OCH2), 6.29 (s, 1H, COCH), 6.64 (d, 1H, J ¼ 8.2 Hz,
d
115.2, 120.6, 128.9, 131.2, 135.1, 136.3, 151.2, 157.4, 157.7, 161.4, 176.7.
d
24.9, CH2 under DMSO, 55.3, 64.5 (d, JC-F ¼ 4.0 Hz), 100.1, 108.9,
MS (ESI) m/z 374 (79Br), 476 (81Br) [M]þ.
110.7, 111.1, 111.2, 112.1, 114.5,115.0 (d, JC-F ¼ 14.2 Hz), 123.4, 123.8 (d,
JC-F ¼ 14.2 Hz), 124.5 (d, JC-F ¼ 2.9 Hz), 127.5, 129.6 (d, JC-F ¼ 4.3 Hz),
129.8 (d, JC-F ¼ 8.3 Hz), 131.4, 135.0, 153.0, 153.6, 157.0, 157.7, 158.9,
159.6 (d, JC-F ¼ 245.2 Hz), 176.5. MS (ESI) m/z 485 [M ꢀ H]ꢀ, 487
[MþH]þ, 509 [MþNa]þ. Anal. Calcd for C28H23FN2O5, C, 69.13; H,
4.77; N, 5.76; Found: C, 69.09; H, 4.81; N, 6.13.
5.1.4. Synthesis of targeted compounds 4aeg
5.1.4.1. General procedure D. To a solution of tryptamine derivative
(1 equiv.) in DMF (10 mL/mmol) were added successively a solution
of acid derivative 3aeg (1 equiv.) in DMF (10 mL/mmol), HOBt
(2 equiv.), triethylamine (4 equiv.) and EDCI (2 equiv.). The mixture
was stirred overnight at room temperature. The resulting mixture
was poured into 1 M hydrochloric acid and extracted with ethyl
acetate. The combined organic layers were washed with sodium
bicarbonate and water, dried over anhydrous magnesium sulfate,
filtered and concentrated under reduced pressure.
5.1.4.5. 5-(30-Fluorobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide (4d). The crude
was prepared according to general procedure D starting from 3d
(370 mg, 1.2 mmol) and was washed with diethyl ether to afford 4d
as a white solid (300 mg, 51%). C28H23FN2O5. Decomposition at
260 ꢁC. 1H NMR (400 MHz, DMSO-d6)
d
2.95 (t, 2H, J ¼ 7.6 Hz,
5.1.4.2. 5-(20-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide (4a). The crude
was prepared according to general procedure D starting from 3a
(103 mg, 0.3 mmol) and 5-methoxytryptamine hydrochloride
(105 mg, 0.55 mmol) and was purified by flash silica column
chromatography, using dichloromethane/methanol (95:5) as
eluent to afford 4a as a white solid (36 mg, 24%). C28H23BrN2O5.
CH2CH2NH), 3.57 (m, 2H, CH2CH2NH), 3.75 (s, 3H, OCH3), 5.29 (s,
2H, OCH2), 6.69 (s, 1H, COCH), 6.71 (dd, 1H, J ¼ 2.4 Hz, J ¼ 8.7 Hz,
ArH), 7.08 (d, 1H, J ¼ 2.3 Hz, ArH), 7.11 (d, 1H, J ¼ 8.3 Hz, ArH), 7.15
(m, 1H, ArH), 7.17 (d, 1H, J ¼ 2.2 Hz, ArH), 7.23 (d, 1H, J ¼ 8.8 Hz,
ArH), 7.26 (d, 1H, J ¼ 8.0 Hz, ArH), 7.41e7.49 (m, 2H, ArH), 7.57 (m,
1H, ArH), 7.77 (m, 1H, ArH), 9.19 (t, 1H, J ¼ 5.8 Hz, CONH), 10.68 (s,
1H, NH). 13C NMR (100 MHz, DMSO-d6)
d 24.9, CH2 under DMSO,
m.p. 204e205 ꢁC. 1H NMR (400 MHz, DMSO-d6)
d
2.95 (t, 2H,
55.3, 69.1, 100.1, 108.8, 110.6, 111.0, 111.1, 112.0, 112.1, 113.4 (d, JC-
J ¼ 7.6 Hz, CH2CH2NH), 3.56 (m, 2H, CH2CH2NH), 3.74 (s, 3H, OCH3),
5.23 (s, 2H, OCH2), 6.69 (s, 1H, COCH), 6.71 (dd, 1H, J ¼ 2.4 Hz,
J ¼ 8.8 Hz, ArH), 7.08 (d, 1H, J ¼ 2.3 Hz, ArH), 7.12e7.18 (m, 2H, ArH),
7.23 (d, 1H, J ¼ 8.6 Hz), 7.26e7.35 (m, 2H, ArH), 7.50 (m, 1H, ArH),
7.67 (m, 1H, ArH), 7.80 (m, 1H, ArH), 8.12 (m, 1H, ArH), 9.20 (t, 1H,
J ¼ 5.7 Hz, CONH), 10.7 (s, 1H, NH). 13C NMR (500 MHz, DMSO-d6)
¼ 22.6 Hz), 114.1 (d, JC-F ¼ 21 Hz), 114.5, 122.4 (d, JC-F ¼ 2.6 Hz),
F
123.4, 127.5, 130.2 (d, JC-F ¼ 8.4 Hz), 131.4, 135.0, 139.8 (d, JC-
¼ 7.9 Hz), 153.0, 153.6, 157.0, 157.6, 158.9, 161.3 (d, JC-F ¼ 242.9 Hz),
F
176.6. MS (ESI) m/z 487 [MþH]þ.
5.1.4.6. 5-(40-Fluorobenzyloxy)-4-oxo-4H-chromene-2-carboxylic
acid [2-(5-methoxy-1H-indol-3-yl)-ethyl]-amide (4e). The crude
was prepared according to general procedure D starting from 3e
(180 mg, 0.6 mmol) and 5-methoxytryptamine hydrochloride
(114 mg, 0.6 mmol) and was precipitated with diethyl ether to
afford 4e as a yellow solid (118 mg, 50%). C28H23FN2O5. m.p.
d
24.9, CH2 under DMSO, 55.3, 69.7, 100.1, 108.8, 110.8, 111.1, 111.2,
112.0, 112.1, 114.5, 121.1, 123.4, 127.6, 127.9, 129.2, 129.6, 131.4, 132.2,
135.2, 135.8, 153.0, 153.7, 157.1, 157.5, 158.9, 176.6. MS (ESI) m/z 547
(
79Br), 549 (81Br) [MþH]þ, 545 (79Br), 547 (81Br) [M ꢀ H]ꢀ. Anal.
Calcd for C28H23BrN2O5, C, 61.43; H, 4.24; N, 5.12; Found: C, 61.74;