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P. Jia et al. / European Journal of Medicinal Chemistry 44 (2009) 772e784
d, J ¼ 10.0 Hz, H1), 6.00 (1H, dd, J ¼ 10.0, 4.8 Hz, H2), 4.61
(1H, br s, H4a), 4.14 (1H, t, J ¼ 4.8 Hz, H3), 4.13 (1H, d,
J ¼ 15.2 Hz, H9a), 3.93 (2H, t, J ¼ 6.4 Hz, H40), 3.83 (3H,
s, OCH3), 3.81 (1H, d, J ¼ 15.2 Hz, H9b), 3.57 (2H, s,
CH2Ph), 3.35 (1H, br t, J ¼ 15.6, 13.2 Hz, H11a), 3.17 (1H,
br d, J ¼ 15.6 Hz, H11b), 2.68 (1H, dm, J ¼ 15.2 Hz, H4a),
2.57 (4H, q, J ¼ 6.8 Hz, NCH2CH3), 2.52e2.45(2H, m, H10),
2.06 (1H, m, H12a), 2.03e1.98 (1H, m, H4b), 1.80e1.73
(2H, m, H30), 1.68e1.62 (2H, m, H20), 1.51 (1H, d,
J ¼ 13.6 Hz, H12b), 1.08 (6H, t, J ¼ 6.8 Hz, NCH2CH3).
ESI-MS m/z: 507.5 [M þ H]þ.
6.1.9.13. 10-N-Demethyl-10-N-(6-(4-(morpholinomethyl)phe-
noxy)hexan-1-yl)-galanthamine (3m). Compound 3m was ob-
tained as a colorless oil in 47.1% yield. IR (CHCl3) n (cmꢁ1):
3553, 3026, 2930, 2855, 1612, 1509, 1437, 1285, 1265, 1243,
1
1116, 1058. H NMR (d, CDCl3): 7.21 (2H, d, J ¼ 8.8 Hz,
Hphenyl-3,5), 6.83 (2H, d, J ¼ 8.8 Hz, Hphenyl-2,6), 6.65 (1H,
d, J ¼ 8.0 Hz, H7), 6.61 (1H, d, J ¼ 8.0 Hz, H8), 6.09 (1H,
d, J ¼ 10.0 Hz, H1), 6.00 (1H, dd, J ¼ 10.0, 4.8 Hz, H2),
4.60 (1H, br s, H4a), 4.14 (1H, t, J ¼ 4.8 Hz, H3), 4.13 (1H,
d, J ¼ 15.6 Hz, H9a), 3.92 (2H, t, J ¼ 6.4 Hz, H60), 3.83
(3H, s, OCH3), 3.81 (1H, d, J ¼ 15.6 Hz, H9b), 3.69 (4H, t,
J ¼ 4.8 Hz, NCH2CH2O), 3.42 (2H, s, CH2Ph), 3.35 (1H, br
t, J ¼ 15.2, 13.8 Hz, H11a), 3.17 (1H, br d, J ¼ 15.2 Hz,
H11b), 2.68 (1H, dt, J ¼ 15.6, 1.6 Hz, H4a), 2.55e2.44 (2H,
m, H10), 2.43e2.41 (4H, m, NCH2CH2O), 2.06 (1H, m,
H12a), 2.03e1.97 (1H, m, H4b), 1.80e1.73 (2H, m, H50),
1.54e1.44 (5H, m, H12b, H20, H40), 1.38e1.32 (2H, m,
H30). 13C NMR (d, CDCl3): 158.22 (Cphenyl-1), 145.76
(C5a), 144.02 (C6), 133.06 (Cphenyl-4), 130.26 (Cphenyl-3,5),
129.37 (C8b), 127.55 (C8a, C2), 126.80 (C1), 121.93 (C8),
114.10 (Cphenyl-2,6), 111.16 (C7), 88.59 (C4a), 67.74 (C60),
66.86 (Cmor-2,6), 62.72 (C3), 61.93 (CH2Ph), 59.41 (C9),
57.58 (C10), 55.80 (OCH3), 53.39 (Cmor-3,5), 51.41 (C11),
48.27 (C4b), 32.79 (C12), 31.13 (C4), 29.13 (C50), 27.15
(C30), 27.00 (C20), 25.90 (C40). ESI-MS m/z: 549.5 [M þ H]þ.
6.1.9.11. 10-N-Demethyl-10-N-(6-(4-((diethylamino)methyl)-
phenoxy)hexan-1-yl)-galanthamine (3k). Compound 3k was
obtained as a colorless oil in 49.9% yield. IR (CHCl3) n
(cmꢁ1): 3556, 3026, 2929, 2855, 1611, 1509, 1437, 1286,
1265, 1242, 1059. 1H NMR (d, CDCl3): 7.26 (2H, d,
J ¼ 8.8 Hz, Hphenyl-3,5), 6.83 (2H, d, J ¼ 8.8 Hz, Hphenyl
-
2,6), 6.65 (1H, d, J ¼ 8.0 Hz, H7), 6.61 (1H, d, J ¼ 8.0 Hz,
H8), 6.09 (1H, d, J ¼ 10.0 Hz, H1), 6.00 (1H, dd, J ¼ 10.0,
4.8 Hz, H2), 4.61 (1H, br s, H4a), 4.14 (1H, t, J ¼ 4.8 Hz,
H3), 4.13 (1H, d, J ¼ 15.2 Hz, H9a), 3.93 (2H, t, J ¼ 6.4 Hz,
H60), 3.83 (3H, s, OCH3), 3.81 (1H, d, J ¼ 15.2 Hz, H9b),
3.57 (2H, s, CH2Ph), 3.35 (1H, br t, J ¼ 15.6, 13.2 Hz,
H11a), 3.17 (1H, br d, J ¼ 15.6 Hz, H11b), 2.68 (1H, dt,
J ¼ 15.2, 1.6 Hz, H4a), 2.57 (4H, q, J ¼ 6.8 Hz, NCH2CH3),
2.52e2.45 (2H, m, H10), 2.06 (1H, dd, J ¼ 13.6, 3.0 Hz,
H12a), 2.03e1.98 (1H, m, H4b), 1.80e1.73 (2H, m, H50),
1.53e1.44 (5H, m, H12b, H20, H40), 1.38e1.33 (2H, m,
H30), 1.08 (6H, t, J ¼ 6.8 Hz, NCH2CH3). 13C NMR (d,
CDCl3): 158.01 (Cphenyl-1), 145.68 (C5a), 143.95 (C6),
133.06 (Cphenyl-4), 130.10 (Cphenyl-3,5), 129.43 (C8b),
6.1.9.14. 10-N-Demethyl-10-N-(4-(3-(1-morpholinoethyl)phe-
noxy)butan-1-yl)-galanthamine (3n). Compound 3n was ob-
tained as a colorless oil in 48.3% yield. IR (CHCl3) n
(cmꢁ1): 3554, 3026, 2930, 2855, 1589, 1506, 1437, 1265,
1
1118, 1059. H NMR (d, CDCl3): 7.20 (1H, t, J ¼ 7.8 Hz,
Hphenyl-5), 6.88e6.86 (2H, m, Hphenyl-6, Hphenyl-2), 6.74 (1H,
d, J ¼ 7.8 Hz, Hphenyl-4), 6.65 (1H, d, J ¼ 8.0 Hz, H7), 6.61
(1H, d, J ¼ 8.0 Hz, H8), 6.09 (1H, d, J ¼ 10.4 Hz, H1), 6.00
(1H, dd, J ¼ 10.4, 4.8 Hz, H2), 4.61 (1H, br s, H4a), 4.17e
4.13 (2H, m, H9a, H3), 3.95 (2H, t, J ¼ 6.4 Hz, H40), 3.84
(1H, d, J ¼ 15.2 Hz, H9b), 3.82 (3H, s, OCH3), 3.68 (4H, t,
J ¼ 4.8 Hz, NCH2CH2O), 3.38 (1H, br t, J ¼ 14.8, 13.6 Hz,
H11a), 3.26 (1H, q, J ¼ 6.5 Hz, CHCH3), 3.19 (1H, br d,
J ¼ 14.8 Hz, H11b), 2.68 (1H, dm, J ¼ 15.6 Hz, H4a),
2.64e2.53 (2H, m, H10), 2.51e2.47 (2H, m, Hmor-3a,
Hmor-5a), 2.39e2.34 (2H, m, Hmor-3b, Hmor-5b), 2.09e2.05
(1H, m, H12a), 2.03e1.97 (1H, m, H4b), 1.81e1.76 (2H,
m, H30), 1.71e1.66 (2H, m, H20), 1.53 (1H, d, J ¼ 13.8 Hz,
H12b), 1.32 (3H, d, J ¼ 6.8 Hz). ESI-MS m/z: 535.5
[M þ H]þ.
127.47 (C8a, C2), 126.81 (C1), 121.91 (C8), 114.03 (Cphenyl
-
2,6), 111.06 (C7), 88.62 (C4a), 67.72 (C60), 62.00 (CH2Ph,
C3), 57.69 (C9), 56.56 (OCH3), 55.78 (C10), 51.44 (C11),
48.34 (C4b), 46.29 (2 NCH2CH3), 32.84 (C12), 29.62 (C4),
29.18 (C50), 27.31 (C30), 27.06 (C20), 25.95 (C40), 11.35 (2
NCH2CH3). ESI-MS m/z: 535.5 [M þ H]þ.
6.1.9.12. 10-N-Demethyl-10-N-(4-(4-(morpholinomethyl)phe-
noxy)butan-1-yl)-galanthamine (3l). Compound 3l was ob-
tained as a colorless oil in 62.5% yield. IR (CHCl3) n
(cmꢁ1): 3554, 3027, 2930, 2853, 1612, 1509, 1437, 1286,
1
1264, 1243, 1116, 1058. H NMR (d, CDCl3): 7.21 (2H, d,
J ¼ 8.8 Hz, Hphenyl-3,5), 6.81 (2H, d, J ¼ 8.8 Hz, Hphenyl-2,6),
6.65 (1H, d, J ¼ 8.0 Hz, H7), 6.62 (1H, d, J ¼ 8.0 Hz, H8),
6.07 (1H, d, J ¼ 10.4 Hz, H1), 6.01 (1H, dd, J ¼ 10.4, 4.8 Hz,
H2), 4.60 (1H, br s, H4a), 4.18 (1H, d, J ¼ 15.6 Hz, H9a),
4.14 (1H, t, J ¼ 4.8 Hz, H3), 3.94 (2H, t, J ¼ 6.4 Hz, H40),
3.86 (1H, d, J ¼ 15.6 Hz, H9b), 3.82 (3H, s, OCH3), 3.70 (4H,
t, J ¼ 4.8 Hz, NCH2CH2O), 3.45 (2H, s, CH2Ph), 3.40 (1H, br
t, J ¼ 15.2, 13.2 Hz, H11a), 3.21 (1H, br d, J ¼ 15.2 Hz,
H11b), 2.68 (1H, dm, J ¼ 15.6 Hz, H4a), 2.64e2.55 (2H, m,
H10), 2.47e2.41 (4H, m, NCH2CH2O), 2.07 (1H, m, H12a),
2.03e1.98 (1H, m, H4b), 1.80e1.75 (2H, m, H30), 1.73e1.67
(2H, m, H20), 1.56 (1H, d, J ¼ 13.2 Hz, H12b). ESI-MS m/z:
521.4 [M þ H]þ.
6.1.9.15. 10-N-Demethyl-10-N-(6-(3-(1-morpholinoethyl)phe-
noxy)hexan-1-yl)-galanthamine (3o). Compound 3o was ob-
tained as a colorless oil in 45.8% yield. IR (CHCl3) n
(cmꢁ1): 3556, 3026, 2930, 2855, 1585, 1506, 1437, 1265,
1
1118, 1058. H NMR (d, CDCl3): 7.20 (1H, t, J ¼ 8.0 Hz,
Hphenyl-5), 6.88e6.87 (2H, m, Hphenyl-6, Hphenyl-2), 6.75 (1H,
d, J ¼ 8.0 Hz, Hphenyl-4), 6.66 (1H, d, J ¼ 8.0 Hz, H7), 6.62
(1H, d, J ¼ 8.0 Hz, H8), 6.09 (1H, d, J ¼ 10.0 Hz, H1),
6.00 (1H, dd, J ¼ 10.0, 4.8 Hz, H2), 4.60 (1H, br s, H4a),
4.14 (1H, d, J ¼ 15.6 Hz, H9a), 4.13 (1H, t, J ¼ 4.8 Hz, H3),