Journal of Medicinal Chemistry
ARTICLE
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-phenyl-2,3,6,7,12,
12a-hezxahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,4-
dione (26). Compound 26 was prepared according to protocol e,
starting from 6 (50 mg) and iodobenzene (15 μL) and obtained after
purification by TLC (dichloromethane/methanol) as a white powder
(50 mg, 83%). LC tR = 5.91 min; MS (ESIþ) m/z = 452 [M þ H]þ; 1H
NMR (CD2Cl2) δ 8.01 (s, 1H), 7.66 (d, J = 6.6 Hz, 1H), 7.46 (m, 2H),
7.35 (m, 4H), 7.18 (m, 2H), 6.94 (dd, J = 8.0 and 1.7 Hz, 1H), 6.85 (d,
J = 1.7 Hz, 1H), 6.76 (d, J = 8.0 Hz, 1H), 6.29 (s, 1H), 5.92 (d, J = 7.8 Hz,
1H), 5.91 (d, J = 7.8 Hz, 1H), 4.56 (m, 2H), 4.30 (d, J = 17.0 Hz, 1H),
3.80 (dd, J = 15.9 and 4.7 Hz, 1H), 3.34 (dd, J = 16.0 and 11.3 Hz, 1H);
13C NMR (CD2Cl2) 23.49, 52.70, 56.50, 56.65, 101.36, 106.55, 107.32,
108.02, 111.10, 111.90, 118.57, 119.98, 120.62, 122.39, 125.10, 127.11,
129.14, 133.06, 135.75, 136.70, 139.04, 147.09, 147.74, 166.59, 167.76.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-thiophen-3-yl-2,3,6,
7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-
1,4-dione (27). Compound 27 was prepared according to protocol e,
starting from 6 (50 mg) and 3-iodothiophene (14 μL) and obtained after
purification by TLC (dichloromethane/methanol) as a white powder
(36 mg, 60%). LC tR = 6.11 min; MS (ESIþ) m/z = 458 [M þ H]þ; 1H
NMR (CD2Cl2) δ 8.16 (s, 1H), 7.65 (d, J = 6.8 Hz, 1H), 7.34 (m, 4H),
7.18 (m, 2H), 6.91 (dd, J = 8.0 and 1.7 Hz, 1H), 6.82 (d, J = 1.7 Hz, 1H),
6.73 (d, J = 8 Hz, 1H), 6.27 (s, 1H), 5.89 (d, J = 6.5 Hz, 1H), 5.88 (d, J =
6.5 Hz, 1H), 4.52 (m, 2H), 4.43 (d, J = 16.9 Hz, 1H), 3.82 (dd, J = 16.9
and 4.6 Hz, 1H), 3.34 (ddd, J = 15.9, 11.5, and 1.0 Hz, 1H); 13C NMR
(CD2Cl2) 23.59, 29.69, 52.31, 56.34, 56.51, 101.36, 106.18, 107.31,
108.01, 111.18, 114.48, 118.53, 119.94, 120.51, 122.35, 122.89, 124.91,
126.20, 132.99, 135.61, 136.57, 138.24, 147.13, 147.89, 165.40, 166.75.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(4-methoxyphenyl)-
2,3,6,7,12,12a-hexahydro-pyrazino[10,20:1,6]pyrido[3,4-b]
indole-1,4-dione (28). Compound 28 was prepared according to
protocol e, starting from 6 (50 mg) and 4-iodoanisole (31 mg) and
obtained after purification by TLC (dichloromethane/methanol) as a
white powder (30 mg, 47%). LC tR = 5.93 min; MS (ESIþ) m/z = 482
[M þ H]þ; 1H NMR (CD2Cl2) δ 8.17 (s, 1H), 7.65 (d, J = 6.6 Hz, 1H),
7.34ꢀ7.13 (m, 5H), 6.98 (d, J = 6.8 Hz, 2H), 6.93 (dd, J = 8.1 and 1.7 Hz,
1H), 6.85 (d, J = 1.7 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.27 (s, 1H), 5.91
(d, J = 7.6 Hz, 1H), 5.90 (d, J = 7.6 Hz, 1H), 4.53 (m, 2H), 4.25 (d, J =
17.0 Hz, 1H), 3.84 (s, 3H), 3.78 (dd, J = 16.0 and 4.7 Hz, 1H), 3.33 (dd, J
= 17.0 and 12.5 Hz, 1H); 13C NMR (CD2Cl2) 23.50, 55.48, 56.38, 56.52,
101.37, 106.22, 107.32, 108.01, 111.17, 113.69, 114.36, 118.54, 119.89,
120.49, 122.28, 126.21, 126.58, 132.97, 133.11, 135.82, 136.55, 147.10,
147.89, 158.54, 166.57, 167.28.
powder (42 mg, 65%). LC tR = 6.55 min; MS (ESIþ) m/z =
486ꢀ488 [M þ H]þ; 1H NMR (CD2Cl2) δ 8.34 (s, 1H), 7.65 (d, J =
6.5 Hz, 1H), 7.44ꢀ7.05 (m, 7H), 6.91 (dd, J = 7.9 and 1.7 Hz, 1H), 6.84
(d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.29 (s, 1H), 5.90 (d, J = 6.7
Hz, 1H), 5.89 (d, J = 6.7 Hz, 1H), 4.54 (m, 2H), 4.28 (d, J = 16.7 Hz,
1H), 3.78 (dd, J = 16.0 and 4.8 Hz, 1H), 3.34 (dd, J = 15.9 and 11.4 Hz,
1H); 13C NMR (CD2Cl2) 23.35, 52.62, 56.30, 56.47, 101.39, 106.10,
107.35, 108.04, 111.18, 118.54, 119.98, 120.58, 122.38, 123.05, 125.29,
126.17, 127.14, 130.19, 132.99, 134.43, 135.55, 136.54, 141.17, 147.18,
147.92, 166.55, 166.93.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-thiophen-2-yl-2,3,6,
7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-1,
4-dione (31). Compound 31 was prepared according to protocol e,
starting from 6 (50 mg) and 2-iodothiophene (15 μL) and obtained after
purification by TLC (dichloromethane/methanol) as a white powder
(15 mg, 25%). LC tR = 6.38 min; MS (ESþ) m/z = 458 [M þ H]þ; 1H
NMR (CD2Cl2) δ 8.04 (s, 1H), 7.65 (d, J = 6.3 Hz, 1H), 7.33 (m, 1H),
7.18ꢀ7.08 (m, 4H), 6.98 (m, 1H), 6.90 (dd, J = 7.9 and 1.7 Hz, 1H),
6.80 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.9 Hz, 1H), 6.24 (s, 1H), 5.90 (d, J =
7.3 Hz, 2H), 4.62 (m, 2H), 4.50 (d, J = 17.0 Hz, 1H), 3.87 (dd, J = 16.0
and 4.5 Hz, 1H), 3.33 (m, 1H); 13C NMR (CD2Cl2) 23.92, 26.69, 51.19,
56.18, 56.75, 101.37, 106.11, 107.22, 108.02, 111.12, 112.76, 118.54,
120.00, 120.40, 120.57, 122.45, 126.18, 132.84, 135.57, 136.60, 140.44,
147.16, 147.91, 163.44, 165.51.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(4-trifluoromethylp-
henyl)-2,3,6,7,12,12a-hexahydropyrazino[10,20:1,6]pyrido-
[3,4-b]indole-1,4-dione (32). Compound 32 was prepared accord-
ing to protocol e, starting from 6 (50 mg) and 4-iodobenzotrifluoride
(19 μL) and obtained after purification by TLC (dichloromethane/
methanol) as a white powder (21 mg, 30%). LC tR = 6.90 min; MS
(ESIþ) m/z = 520 [M þ H]þ; 1H NMR (CD2Cl2) δ 8.16 (s, 1H), 7.74
(d, J = 8.5 Hz, 2H), 7.65 (m, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.34 (m, 1H),
7.18 (m, 2H), 6.92 (dd, J = 8.0 and 1.7 Hz, 1H), 6.84 (d, J = 1.7 Hz, 1H),
6.75 (d, J = 8.0 Hz, 1H), 6.31 (s, 1H), 5.90 (d, J = 7.0 Hz, 1H), 5.89 (d, J =
7.0 Hz, 1H), 4.63 (d, J = 16.6 Hz, 1H), 4.55 (dd, J = 11.4 and 4.6 Hz, 1H),
4.34 (d, J = 16.6 Hz, 1H), 3.80 (dd, J = 16.0 and 4.9 Hz, 1H), 3.37 (dd, J =
16 and 12.4 Hz, 1H); 13C NMR (CD2Cl2) 23.30, 52.36, 56.26, 56.50,
101.40, 106.04, 107.38, 108.03, 111.20, 118.54, 120.01, 120.64, 122.42,
124.01 (q, J = 288.75 Hz), 124.84, 126.16, 126.18 (q, J = 3.75 Hz),
128.42 (q, J = 32.8 Hz), 132.97, 135.44, 136.55, 143.14, 147.21, 147.92,
166.67, 166.90.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(4-chlorophenyl)-2,3,
6,7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole
-1,4-dione (33). Compound 33 was prepared according to protocol e,
starting from 6 (50 mg) and 1-chloro-4-iodobenzene (32 mg) and
obtained after purification by TLC (dichloromethane/meth-
anol) as a white powder (18 mg, 28%). LC tR = 6.54 min; MS
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(4-butylphenyl)-2,3,
6,7,12.12a-hexahydropyrazino[10,20:1.6]pyrido[3,4-b]indole
-1,4-dione (29). Compound 29 was prepared according to protocol e,
starting from 6 (50 mg) and 4-nbutylbenzene (35 mg) and obtained
after purification by TLC (dichloromethane/methanol) as a white
powder (32 mg, 48%). LC tR = 7.49 min; MS (ESIþ) m/z = 508 [M
þ H]þ; 1H NMR (CD2Cl2) δ 8.25 (s, 1H), 7.65 (d, J = 6.5 Hz, 1H),
7.33ꢀ7.13 (m, 7H), 6.92 (dd, J = 8 and 1.7 Hz, 1H), 6.85 (d, J = 1.7 Hz,
1H), 6.74 (d, J = 8 Hz, 1H), 6.29 (s, 1H), 5.90 (d, J = 7.0 Hz, 1H), 5.89
(d, J = 7.0 Hz, 1H), 4.53 (m, 2H), 4.27 (d, J = 17 Hz, 1H), 3.79 (dd,
J = 16.0 and 4.7 Hz, 1H), 3.32 (dd, J = 15.9 and 11.3 Hz, 1H), 2.67 (t, J =
1
(ESIþ) m/z = 486ꢀ488 [M þ H]þ; H NMR (CD2Cl2) δ 8.16 (s,
1H), 7.65 (m, 1H), 7.45 (d, J = 8.7 Hz, 2H), 7.34 (m, 3H), 7.17 (m, 2H),
6.91 (dd, J = 7.9 and 1.7 Hz, 1H), 6.83 (d, J = 1.7 Hz, 1H), 6.74 (d, J = 7.9
Hz, 1H), 6.27 (s, 1H), 5.90 (d, J = 7.4 Hz, 1H), 5.89 (d, J = 7.4 Hz, 1H),
4.50 (m, 2H), 4.27 (d, J = 16.7 Hz, 1H), 3.78 (dd, J = 16.0 and 5.0 Hz,
1H), 3.33 (dd, J = 14.9 and 12.4 Hz, 1H); 13C NMR (CD2Cl2) 23.37,
29.70, 52.67, 56.32, 56.47, 101.38, 107.34, 108.02, 111.17, 118.54,
119.96, 120.60, 122.37, 126.17, 126.32, 129.21, 132.42, 132.99,
135.57, 136.55, 138.64, 147.16, 147.90, 166.52, 167.02.
7.7 Hz, 2H), 1.65 (m, 2H), 1.40 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H); 13
C
NMR (CD2Cl2) 13.72, 22.37, 23.44, 29.70, 33.56, 35.13, 53.07, 56.29,
56.55, 101.36, 106.19, 107.32, 108.02, 111.20, 118.55, 119.89, 120.43,
122.26, 124.95, 125.28, 126.21, 126.43, 129.13, 129.43, 133.12, 135.78,
136.55, 137.76, 142.29, 147.09, 147.89, 166.51, 167.34.
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-(3-chlorophenyl)-2,
3,6,7,12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole
-1,4-dione (30). Compound 30 was prepared according to protocol e,
starting from 6 (50 mg) and 4-iodonitrobenzene (16.5 μL) and obtained
after purification by TLC (dichloromethane/methanol) as a white
(6R,12aR)-6-Benzo[1,3]dioxol-5-yl-2-pyridin-3-yl-2,3,6,7,
12,12a-hexahydropyrazino[10,20:1,6]pyrido[3,4-b]indole-
1,4-dione (34). Compound 34 was prepared according to protocol e,
starting from 6 (50 mg) and 3-iodopyridine (27 mg) and obtained after
purification by TLC (dichloromethane/methanol) as a white powder
(26 mg, 43%). LC tR = 4.90 min; MS (ESIþ) m/z = 453 [M þ H]þ; 1H
NMR (CD2Cl2) δ 8.66 (br s, 1H), 8.55 (br d, J = 3.2 Hz, 1H), 8.25
(s, 1H), 7.76 (m, 1H), 7.64 (m, 1H), 7.42 (m, 1H), 7.33 (m, 1H), 7.18
3235
dx.doi.org/10.1021/jm1014617 |J. Med. Chem. 2011, 54, 3222–3240