Journal of Medicinal Chemistry
Article
spectra were acquired by the Analytical Department of Grenoble
University on an Esquire 300 Plus Bruker Daltonis instrument with a
nanospray inlet. Combustion analyses were performed at the Analytical
Department of Grenoble University, and all tested compounds have a
purity of at least 95%. Thin-layer chromatography (TLC) used
Macherey-Nagel silica gel F-254 plates (thickness 0.25 mm). Flash
chromatography used Merck silica gel 60, 200−400 mesh. Unless
otherwise stated, reagents were obtained from commercial sources and
were used without further purification.
Synthesis of Class I Compounds (4). To a solution of tryptamine
derivative in dry DMF (10 mL/mmol) were added successively the
carboxylic acid (1 equiv) in DMF (10 mL/mmol), HOBt (2 equiv),
triethylamine (5 equiv), and EDCI (2 equiv). The mixture was stirred
at room temperature for 24 h. The resulting solution was poured into
1 M HCl (15 mL) and extracted with CH2Cl2 (3 × 15 mL).
The combined organic layers were washed with saturated NaHCO3
(15 mL) and H2O (15 mL), dried over MgSO4, concentrated under
reduced pressure, and suspended in diethyl ether to afford compounds
4 as white solids.
5-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(6-Methoxy-1H-indol-3-yl)-ethyl]-amide (4a). Compound 4a was
purified by column chromatography, eluting with a CH2Cl2/EtOAc
(9:1 to 8:2) gradient. Yield 11%. mp 190−193 °C. 1H NMR (400 MHz,
DMSO): δ 2.93 (t, 2H, J = 7.7 Hz), 3.55 (q, 2H, J = 6.5 Hz), 3.74 (s,
3H), 5.24 (s, 2H), 6.64 (dd, 1H, J = 2.3 Hz, 8.6 Hz), 6.66 (s, 1H), 6.84
(d, 1H, J = 2.2 Hz), 7.05 (d, 1H, J = 2.2 Hz), 7.10 (d, 1H, J = 8.0 Hz),
7.25 (d, 1H, J = 8.4 Hz), 7.45 (d, 1H, J = 8.6 Hz), 7.58−7.63 (m, 4H),
7.76 (t, 1H, J = 8.4 Hz), 9.17 (t, 1H, J = 5.7 Hz), 10.62 (s, 1H). 13C
NMR (100 MHz, DMSO): δ 24.9, 55.1, 69.2, 94.5, 108.5, 108.9, 110.5,
111.4, 112.0, 114.5, 118.8, 120.6, 121.2, 121.6, 128.9, 131.2, 134.9,
136.3, 136.9, 153.6, 155.5, 157.0, 157.7, 158.8, 176.5. MS (ESI) m/z
545 [M − H]−, 581 [M + Cl]−. Anal. Calcd for C28H23BrN2O5: C,
61.44; H, 4.24; N, 5.12. Found: C, 61.05; H, 4.24; N, 4.91.
117.7, 118.1, 118.4, 120.5, 120.9, 121.1, 126.9, 127.4, 127.4, 127.7,
128.9, 131.2, 134.3, 134.7, 136.3, 136.4, 136.6, 155.7, 156.1, 156.8,
157.2, 157.5, 157.6, 161.2, 161.4, 175.3, 175.8. MS (ESI) m/z 547
[M + H]+. Anal. Calcd for C29H25BrN2O4: C, 63.86; H, 4.62; N, 5.14.
Found: C, 63.52; H, 4.47; N, 5.37.
5-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(5-Methoxy-1H-indol-3-yl)-ethyl]-methyl-amide (4e). Compound 4e
was purified by column chromatography, eluting with a CH2Cl2/
MeOH (99:1 to 98:2) gradient. 2:1 mixture of rotamers . Yield 29%.
1
mp 168−171 °C. H NMR (400 MHz, DMSO): δ 2.95−3.00 (m,
2H), 3.04 (s, 1.1H), 3.06 (s, 1.9H), 3.43 (s, 2H), 3.69−3.75 (m, 2H),
3.77 (s, 1H), 5.21 (s, 1.2H), 5.25 (s, 0.8H), 5.67 (s, 0.7H), 6.31
(s, 0.3H), 6.44−7.77 (m, 12H), 10.65 (s, 0.7H), 10.70 (s, 0.3H). 13C
NMR (100 MHz, DMSO): δ 22.2, 23.6, 32.9, 36.4, 47.9, 50.6, 54.8,
55.3, 69.2, 99.0, 100.2, 108.9, 109.1, 109.7, 110.2, 110.3, 110.6, 111.0,
111.04, 111.7, 112.0, 114.1, 120.5, 123.5, 124.2, 126.8, 127.5, 128.8,
131.1, 131.14, 131.2, 131.3, 134.3, 134.6, 136.3, 136.4, 152.8, 153.0,
155.5, 156.2, 156.7, 157.2, 157.5, 157.6, 161.1, 161.5, 175.3, 175.7. MS
(ESI) m/z 563 [M + H]+. Anal. Calcd for C29H25BrN2O5: C, 62.04; H,
4.49; N, 4.99. Found: C, 61.82; H, 4.55; N, 5.10.
6-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(5-Methoxy-1H-indol-3-yl)-ethyl]-amide (4f). Yield 41%. mp 192−
194 °C. 1H NMR (400 MHz, DMSO): δ 2.96 (t, 2H, J = 7.6 Hz), 3.59
(q, 2H, J = 7.2 Hz), 3.73 (s, 3H), 5.23 (s, 2H), 6.72 (dd, 1H, J =
2.4 Hz, 8.8 Hz), 6.81 (s, 1H), 7.08 (d, 1H, J = 2.3 Hz), 7.17 (d, 1H, J =
2.2 Hz), 7.23 (d, 1H, J = 8.8 Hz), 7.46 (d, 2H, J = 8.4 Hz), 7.51 (d,
1H, J = 3.2 Hz), 7.58 (dd, 1H, J = 3.2, 9.2 Hz), 7.62 (d, 2H, J = 8.4
Hz), 7.69 (d, 1H, J = 9.2 Hz), 9.24 (t, 1H, J = 5.6 Hz), 10.69 (s, 1H).
13C NMR (100 MHz, DMSO): δ 24.9, 55.3, 69.1, 100.2, 106.0, 109.5,
111.0, 111.2, 112.0, 120.4, 121.1, 123.4, 124.4, 124.7, 127.5, 129.8,
129.9, 131.4, 135.9, 149.9, 153.0, 155.6, 155.8, 158.9, 176.9, 177.0. MS
(ESI) m/z 546 [M − 1]+. Anal. Calcd for C28H23BrN2O5: C, 61.44; H,
4.24; N, 5.12. Found: C, 60.91; H, 4.22; N, 4.89.
5-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(1-Methyl-1H-indol-3-yl)-ethyl]-amide (4b). Compound 4b was
purified by column chromatography, eluting with a CH2Cl2/EtOAc
(95:5 to 9:1) gradient. Yield 19%. mp 177−180 °C. 1H NMR (400 MHz,
DMSO): δ 2.99 (t, 2H, J = 7.6 Hz), 3.57 (q, 2H, J = 7.0 Hz), 3.75 (s,
3H), 5.26 (s, 2H), 6.69 (s, 1H), 7.03 (t, 1H, J = 7.3 Hz), 7.12−7.17
(m, 2H), 7.22 (s, 1H), 7.27 (d, 1H, J = 8.4 Hz), 7.40 (d, 1H, J =
8.4 Hz), 7.60−7.66 (m, 5H), 7.79 (t, 1H, J = 8.4 Hz), 9.24 (t, 1H, J =
5.7 Hz). 13C NMR (100 MHz, DMSO): δ 24.6, 32.1, 69.1, 108.8,
109.5, 110.5, 110.7, 112.0, 114.4, 118.2, 118.3, 120.5, 121.0, 127.1,
127.4, 128.8, 131.1, 134.8, 136.2, 136.5, 153.5, 156.9, 157.6, 158.8,
176.4. MS (ESI) m/z 553 [M + Na]+. Anal. Calcd for C28H23BrN2O4·6/7
H2O: C, 61.50; H, 4.55; N, 5.12 . Found: C, 61.49; H, 4.40; N, 5.13 .
5-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(1H-Indol-3-yl)-ethyl]-methyl-amide (4c). Compound 4c was purified
by column chromatography, eluting with a CH2Cl2/MeOH (99:1 to
98:2). 6:4 mixture of rotamers. Yield 32%. mp 148−151 °C. 1H NMR
(400 MHz, DMSO): δ 3.02 (t, 2H, J = 7.1 Hz), 3.04 (s, 1.3H), 3.06
(s, 1.7H), 3.71 (t, 2H, J = 6.7 Hz), 5.23 (s, 1.2H), 5.25 (s, 0.8H), 6.05
(s, 0.6H), 6.31 (s, 0.4H), 6.60−7.76 (m, 12H), 10.81 (s, 0.6H), 10.87
(s, 0.4H). 13C NMR (100 MHz, DMSO): δ 15.1, 22.2, 23.8, 32.9, 36.4,
48.1, 50.9, 64.9, 69.3, 109.0, 109.1, 110.1, 110.3, 110.4, 110.9, 111.3,
111.4, 111.7, 112.0, 114.3, 114.6, 117.5, 118.0, 118.2, 118.3, 120.6,
120.8, 121.0, 123.0, 123.5, 126.6, 127.2, 128.9, 121.2, 134.4, 134.4,
134.7, 136.1, 136.2, 136.3, 136.4, 155.8, 156.2, 156.9, 157.2, 157.6,
157.7, 162.2, 161.6, 175.4, 175.8. MS (ESI) m/z 533 [M + H]+. Anal.
Calcd for C28H23BrN2O4: C, 63.29; H, 4.36; N, 5.27. Found: C, 63.45;
H, 4.50; N, 5.22.
6-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(1H-Indol-3-yl)-ethyl]-methyl-amide (4g). Yield 42%. mp 179−180 °C.
1
6:4 mixture of rotamers. H NMR (400 MHz, DMSO): δ 2.97−3.06
(m, 5H), 3.64−3.71 (m, 2H), 5.22 (s, 1.2H), 5.23 (0.8H), 6.16
(s, 0.6H), 6.46 (s, 0.4H), 6.50−7.68 (m, 12H), 10.80 (s, 0.6H), 10.87
(s, 0.4H). 13C NMR (100 MHz, DMSO): δ 22.2, 23.7, 30.7, 32.8, 36.4,
48.1, 50.9, 68.9, 69.0, 106.1, 106.2, 109.2, 109.5, 110.0, 110.9, 111.3,
111.4, 117.4, 118.0, 118.2, 118.3, 120.2, 120.3, 120.8, 120.9, 121.0,
123.0, 123.5, 124.0, 124.3, 124.4, 126.6, 127.2, 129.8, 129.9, 131.4,
136.0, 136.1, 126.2, 149.8, 150.2, 155.5, 155.7, 157.9, 158.3, 161.3,
161.7, 175.9, 176.3, 206.5. MS (ESI) m/z 532 [M + H]+, 553 [M + Na]+.
Anal. Calcd for C28H23BrN2O4: C, 63.29; H, 4.36; N, 5.27. Found: C,
62.34; H, 4.87; N, 5.24.
6-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(Methyl-1H-indol-3-yl)-ethyl]-methyl-amide (4h). Yield 3%. mp
1
127−131 °C. 3:2 mixture of rotamers. H NMR (400 MHz, DMSO):
δ 2.95−3.10 (m, 2H), 3.05 (s, 1.2H), 3.08 (1.8H), 3.65 (s, 1.8H),
3.66−3.70 (m, 2H), 3.75 (s, 1.2H), 5.22 (s, 1.4), 5.23 (s, 0.6H), 6.03
(s, 0.7H), 6.47 (s, 0.3H), 6.86−7.70 (m, 12H). 13C NMR (100 MHz,
DMSO): δ 22.1, 23.4, 32.1, 32.2, 32.6, 36.4, 48.1, 51.0, 68.9, 106.1,
109.3, 109.4, 109.5, 109.6, 110.2, 117.7, 118.1, 118.4, 120.1, 120.3,
120.6, 121.0, 121.1, 123.9, 124.0, 124.3, 126.9, 127.4, 127.8, 129.7,
131.4, 136.0, 136.1, 136.4, 136.6, 149.7, 150.2, 155.5, 155.7, 157.8,
158.3, 161.3, 161.6, 175.8, 176.3. MS (ESI) m/z 545 [M + H]+, 567
[M + Na]+, 1111 [2M + Na]+. Anal. Calcd for C29H25BrN2O4: C,
63.86; H, 4.62; N, 5.14. Found: C, 63.60; H, 4.67; N, 5.37.
7-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(5-Methoxy-1H-indol-3-yl)-ethyl]-amide (4i). Yield 45%. mp 227−
229 °C. 1H NMR (400 MHz, DMSO): δ 2.95 (t, 2H, J = 7.6 Hz), 3.58
(q, 2H, J = 6.8 Hz), 3.74 (s, 3H), 5.27 (s, 2H), 6.71 (dd, 1H, J = 2.0 Hz,
8.4 Hz), 6.77 (s, 1H), 7.07 (d, 1H, J = 2.0 Hz), 7.16−7.24 (m, 4H), 7.45
(d, 2H, J = 8.0 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.97 (d, 1H, J = 8.8 Hz),
9.17 (t, 1H, J = 5.2 Hz), 10.68 (s, 1H). 13C NMR (100 MHz, DMSO):
δ 24.9, 55.3, 69.2, 100.1, 101.9, 110.5, 111.1, 111.2, 112.1, 115.7, 117.8,
121.3, 123.4, 126.5, 127.5, 129.9, 131.4, 131.5, 135.4, 153.0, 155.5,
156.8, 158.9, 163.1, 176.4. MS (ESI) m/z 531 [M − 15]+. Anal. Calcd
5-(4-Bromobenzyloxy)-4-oxo-4H-chromene-2-carboxylic Acid [2-
(1-Methyl-1H-indol-3-yl)-ethyl]-methyl-amide (4d). Compound 4d
was purified by column chromatography, eluting with a CH2Cl2/
MeOH (99:1 to 98:2) gradient. 6:4 mixture of rotamers. Yield 20%.
mp 150−153 °C. 1H NMR (400 MHz, DMSO): δ 2.97−3.04
(m, 2H), 3.09 (s, 3H), 3.68−3.77 (m, 5H), 5.23 (s, 1.2H), 5.25 (s,
0.8H), 5.95 (s, 0.6H), 6.32 (s 0.4H), 6.64−7.76 (m, 12H). 13C NMR
(100 MHz, DMSO): δ 22.0, 23.5, 32.1, 32.2, 32.9, 36.3, 48.1, 51.0,
69.2, 109.0, 109.4, 109.5, 110.2, 110.3, 111.8, 112.0, 114.2, 114.5,
9857
dx.doi.org/10.1021/jm401649j | J. Med. Chem. 2013, 56, 9849−9860