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5.1.28. (5R,9R,13S,14S)-17-Cyclopropylmethyl-6,7-didehydro-4,5-
epoxy-90-methoxy-50,60-dihydro-40H-pyrrolo[3,2,1-ij]quinolino-
[20,10:6,7]morphinan-3,14-diol (1k) methanesulfonate
Using the method A, 1-amino-7-methoxy-1,2,3,4-tetrahydro-
quinoline (7k) methanesulfonate was obtained from 7-methoxy-
1,2,3,4-tetrahydroquinoline (4k) hydrochloride (89%). 1H NMR
(DMSO-d6, 300 MHz) d: 1.95–2.09 (2H, m), 2.34 (3H, s), 2.67 (2H, t,
J = 6.6 Hz), 3.35 (2H, t, J = 5.5 Hz), 3.73 (3H, s), 6.55 (1H, dd, J = 2.5,
6.0 Hz), 6.67 (1H, d, J = 2.2 Hz), 7.01 (1H, d, J = 8.2 Hz), 10.09 (3H,
br s).
Using the method B, the title compound 1kꢀMeSO3H was ob-
tained from the compound 7kꢀMeSO3H and naltrexone (10a)
(92%). Mp 245–255 °C (dec). 1H NMR (DMSO-d6, 400 MHz) d:
0.41–0.55 (2H, m), 0.58–0.78 (2H, m), 1.04–1.16 (1H, m), 1.82
(1H, d, J = 11.5 Hz), 2.02–2.23 (2H, m), 2.32 (3.9H, s), 2.54–2.76
(3H, m), 2.82–2.95 (3H. m), 3.09 (1H, d, J = 12.4 Hz), 3.20–3.45
(4H, m), 3.75 (3H, s), 4.06 (1H, d, J = 6.0 Hz), 4.11–4.19 (1H, m),
4.21–4.30 (1H, m), 5.86 (1H, s), 6.25 (1H, br s), 6.33 (1H, d,
J = 7.7 H), 6.59 (1H, d, J = 8.2 Hz), 6.63 (1H, d, J = 8.2 Hz), 6.75 (1H,
d, J = 7.9 Hz), 8.90 (1.3H, br s), 9.20 (1H, br s). IR (KBr, cmꢁ1):
3400, 1620, 1514, 1462, 1433, 1373, 1296, 1257, 1178, 1116,
1048, 909, 845, 783. MS (free base, EI) m/z (M)+ = 484. Anal. Calcd
for C30H32N2O3ꢀ1.3MeSO3Hꢀ0.2H2O: C, 61.31; H, 6.18; N, 4.57; S,
6.80. Found: C, 61.15; H, 6.41; N, 4.82; S, 6.86.
4.05 (1H, d, J = 6.3 Hz), 4.11–4.17 (1H, m), 4.23–4.30 (1H, m),
5.86 (1H, s), 6.30 (1H, br s), 6.57 (1H, m), 6.61 (1H, d, J = 5.4 Hz),
6.65 (1H, d, J = 5.4 Hz), 6.66–6.68 (1H, m), 8.93 (1.3H, br s), 9.19
(1H, br s). IR (KBr, cmꢁ1): 3400, 2834, 1620, 1495, 1460, 1437,
1241, 1195, 1116, 1052, 926, 758. MS (FAB) m/z (M+H)+ = 485.
Anal. Calcd for C30H32N2O4ꢀ1.3MeSO3Hꢀ0.6H2O: C, 60.60; H, 6.24;
N, 4.52; S, 6.27. Found: C, 60.60; H, 6.44; N, 4.70; S, 6.52.
5.1.31. (5R,9R,13S,14S)-17-Cyclopropylmethyl-6,7-didehydro-4,5-
epoxy-90-methyl-50,60-dihydro-40H-pyrrolo[3,2,1-ij]quinolino-
[20,10:6,7]morphinan-3,14-diol (1n) methanesulfonate
Using the method A, 1-amino-7-methyl-1,2,3,4-tetrahydro-
quinoline (7n) methanesulfonate was obtained from 7-methyl-
1,2,3,4-tetrahydroquinoline (4n) hydrochloride (86%). 1H NMR
(DMSO-d6, 300 MHz) d: 1.96–2.04 (2H, m), 2.26 (3H, s), 2.35 (3H,
s), 2.67-2.72 (2H, m), 3.35 (2H, t, J = 5.5 Hz), 6.78 (1H, dd, J = 0.8,
7.7 Hz), 6.89 (1H, s), 6.99 (1H, d, J = 7.7 Hz), 10.10 (3H, br s).
Using the method B, the title compound 1nꢀMeSO3H was ob-
tained from the compound 7nꢀMeSO3H and naltrexone (10a) benzo-
ate (90%). Mp 248 °C (dec). 1H NMR (DMSO-d6, 400 MHz) d: 0.40–
0.57 (2H, m), 0.58–0.79 (2H, m), 1.04–1.16 (1H, m), 1.84 (1H, d,
J = 12.3 Hz), 2.07–2.22 (2H, m), 2.32 (3.3H, s), 2.46 (3H, s), 2.53–
2.67 (3H, m), 2.78 (1H, d, J = 16.5 Hz), 2.84–2.97 (2H, m), 3.07–3.16
(1H, m), 3.21–3.32 (2H, m), 3.37–3.49 (2H, m), 4.06 (1H, d,
J = 6.0 Hz), 4.12–4.33 (2H, m), 5.88 (1H, s), 6.30 (1H, br s), 6.58–
6.65 (3H, m), 6.72 (1H, d, J = 7.1 Hz), 8.97 (1.1H, br s), 9.17 (1H, br
s). IR (KBr, cmꢁ1): 3400, 2926, 1657, 1562, 1510, 1460, 1433, 1296,
1195, 1116, 1052, 849, 785. MS (FAB) m/z (M+H)+ = 469. Anal. Calcd
for C30H32N2O3ꢀ1.1MeSO3Hꢀ0.7H2O: C, 63.64; H, 6.49; N, 4.77; S,
6.01. Found: C, 63.51; H, 6.58; N, 4.06; S, 6.06.
5.1.29. (5R,9R,13S,14S)-70-Chloro-17-cyclopropylmethyl-6,7-
didehydro-4,5-epoxy-50,60-dihydro-40H-pyrrolo[3,2,1-ij]quinolino-
[20,10:6,7]morphinan-3,14-diol (1l) methanesulfonate
Using the method A, 1-amino-5-chloro-1,2,3,4-tetrahydroquin-
oline (7l) methanesulfonate was obtained from 5-chloro-1,2,3,4-
tetrahydroquinoline (4l) hydrochloride (90%). 1H NMR (DMSO-d6,
300 MHz) d: 2.00–2.12 (2H, m), 2.33 (3H, s), 2.73 (2H, dd, J = 6.6,
6.6 Hz), 3.38 (2H, dd, J = 5.4, 5.4 Hz), 7.01 (1H, d, J = 8.4 Hz), 7.10
(1H, d, J = 7.2 Hz), 7.24 (1H, m), 10.05 (3H, br s).
Using the method B, the title compound 1lꢀMeSO3H was obtained
from the compound 7lꢀMeSO3H and naltrexone (10a) (62%). Mp
242 °C (dec). 1H NMR (DMSO-d6, 300 MHz) d: 0.40–0.46 (1H, m),
0.47–0.53 (1H, m), 0.60–0.66 (1H, m), 0.70–0.76 (1H, m), 1.05–1.13
(1H, m), 1.83–1.87 (1H, m), 2.14–2.28 (2H, m), 2.30 (3.6H, s), 2.55
(1H, d, J = 16.1 Hz Hz), 2.59–2.64 (1H, m), 2.67–2.77 (1H, m), 2.88–
3.00 (4H, m), 3.11 (1H, d, J = 11.6 Hz), 3.22–3.28 (1H, m), 3.36–3.46
(2H, m), 4.06 (1H, d, J = 6.4 Hz Hz), 4.12–4.18 (1H, m), 4.28–4.33
(1H, m), 5.90 (1H, s), 6.33 (1H, br s), 6.60 (1H, d, J = 8.1 Hz), 6.63
(1H, d, J = 8.1 Hz), 6.97 (1H, d, J = 8.5 Hz), 7.21 (1H, d, J = 8.4 Hz),
8.93 (1.2H, br s), 9.21 (1H, br s). IR (KBr, cmꢁ1):3858, 2942, 1639,
1505, 1469, 1432, 1378, 1324, 1203, 1115, 1044, 914, 861, 790. MS
(free base, EI) m/z (M)+ = 488. Anal. Calcd for C29H29ClN2O3ꢀ1.2
MeSO3Hꢀ0.4H2O: C, 59.31; H, 5.70; Cl, 5.80; N, 4.58; S, 6.29. Found:
C, 59.30; H, 5.90; Cl, 5.96; N, 4.52; S, 6.35.
5.1.32. (5R,9R,13S,14S)-90-Bromo-17-cyclopropylmethyl-6,7-
didehydro-4,5-epoxy-50,60-dihydro-40H-pyrrolo[3,2,1-ij]-
quinolino[20,10:6,7]morphinan-3,14-diol (1o) methanesulfonate
Using the method A, 1-amino-7-bromo-1,2,3,4-tetrahydroquin-
oline (7o) methanesulfonate was obtained from 7-bromo-1,2,3,4-
tetrahydroquinoline (4o) hydrochloride (75%), and using the meth-
od B, the title compound 1oꢀMeSO3H was obtained from compound
7oꢀMeSO3H and naltrexone (1a) hydrochloride (81%). Mp 250 °C
(dec). 1H NMR (DMSO-d6, 300 MHz) d: 0.39–0.57 (2H, m), 0.58–
0.80 (2H, m), 1.03–1.19 (1H, m), 1.85 (1H, d, J = 11.5 Hz), 2.07–2.25
(2H, m), 2.31 (3.6H, s), 2.53–2.79 (3H, m), 2.82–2.98 (3H, m), 3.11
(1H, d, J = 12.1 Hz), 3.22–3.32 (1H, m), 3.35–3.48 (2H, m), 3.53 (1H,
d, J = 16.5 Hz), 4.08 (1H, d, J = 6.3 Hz), 4.11–4.23 (1H, m), 4.27–4.40
(1H, m), 5.92 (1H, s), 6.37 (1H, br s), 6.60–6.66 (2H, m), 6.79 (1H, d,
J = 7.7 Hz), 7.05 (1H, d, J = 7.7 Hz), 8.94 (1.2H, br s), 9.25 (1H, br s).
IR (KBr, cmꢁ1): 3412, 2954, 1640, 1504, 1465, 1432, 1367, 1325,
1199, 1115, 1046, 913, 844, 782. MS (FAB) m/z (M+H)+ = 533. Anal.
Calcd for C29H29BrN2O3ꢀ1.2MeSO3Hꢀ0.7H2O: C, 54.84; H, 5.36; Br,
12.08; N, 4.24; S, 5.82. Found: C, 54.84; H, 5.52; Br, 12.02; N, 4.18;
S, 5.94.
5.1.30. (5R,9R,13S,14S)-17-Cyclopropylmethyl-6,7-didehydro-4,
5-epoxy-80-methoxy-50,60-dihydro-40H-pyrrolo[3,2,1-ij]quinolino-
[20,10:6,7]morphinan-3,14-diol (1m) methanesulfonate
5.1.33. (5R,9R,13S,14S)-80-Bromo-17-cyclopropylmethyl-6,7-
didehydro-4,5-epoxy-3-methoxy-50,60-dihydro-40H-pyrrolo[3,2,1-
ij]quinolino[20,10:6,7]morphinan-14-ol (1p) methanesulfonate
Using the method A, 1-amino-6-bromo-1,2,3,4-tetrahydroquin-
oline (7p) methanesulfonate was obtained from 6-bromo-1,2,3,4-
tetrahydroquinoline (4p) hydrochloride (82%). 1H NMR (DMSO-
d6, 300 MHz) d: 1.95–2.04 (2H, m), 2.34 (3H, s), 2.73–2.77 (2H,
m), 3.35–3.39 (2H, m), 6.98 (1H, d, J = 8.8 Hz), 7.31 (1H, s), 7.37
(1H, dd, J = 2.5, 7.7 Hz), 10.03 (3H, br s).
Using the method B, the title compound 1pꢀMeSO3H was ob-
tained from the compound 7pꢀMeSO3H and 3-O-methylnaltrexone
(10b) (73%). Mp 220–222 °C (dec). 1H NMR (DMSO-d6, 400 MHz) d:
0.41–0.51 (2H, m), 0.60–0.67 (1H, m), 0.70–0.77 (1H, m), 1.07–1.18
(1H, m), 1.87 (1H, d, J = 12.7 Hz), 2.08–2.26 (2H, m), 2.29 (3H, s),
Using the method A, 1-amino-6-methoxy-1,2,3,4-tetrahydro-
quinoline (7m) methanesulfonate was obtained from 6-methoxy-
1,2,3,4-tetrahydroquinoline (4m) hydrochloride (82%). 1H NMR
(DMSO-d6, 300 MHz) d: 1.94–2.01 (2H, m), 2.34 (3H, s), 2.51–2.77
(2H, m), 3.32 (2H, t, J = 5.5 Hz), 3.71 (3H, s), 6.71 (1H, d, J = 3.0 Hz),
6.80 (1H, dd, J = 3.0, 9.1 Hz), 7.05 (1H, d, J = 9.1 Hz), 9.96 (3H, br s).
Using the method B, the title compound 1mꢀMeSO3H was ob-
tained from the compound 7mꢀMeSO3H and naltrexone (10a)
(75%). Mp 218 °C (dec). 1H NMR (DMSO-d6, 400 MHz) d: 0.40–
0.53 (2H, m), 0.60–0.66 (1H, m), 0.69–0.77 (1H, m), 1.04–1.12
(1H, m), 1.83 (1H, d, J = 11.2 Hz), 2.08–2.22 (2H, m), 2.30 (3.9H,
s), 2.50–2.76 (3H, m), 2.86–2.98 (4H, m), 3.11 (1H, d, J = 11.7 Hz),
3.17 (1H, dd, J = 6.8, 20.0 Hz), 3.33–3.47 (2H, m), 3.68 (3H, s),