4′-Demethylepipodophyllotoxin Derivatives
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 2 601
6H, 3′,5′-OCH3), 3.55 (t, 1H, J ) 11.3 Hz, 13b-H), 3.32-3.18
1
116 °C. [R]20 ) -45.5 (c 0.910, CHCl3). H NMR (CDCl3) δ:
D
7.45-7.36 (m, 5H, CH2Ph), 7.21 (s, 1H, 5-H), 6.49 (s, 1H, 8-H),
6.38 (d, 1H, J ) 3.5 Hz, 4-H), 6.03 (br s, 2H, 2′,6′-H), 5.98 (d,
2H, J ) 7.6 Hz, CH2O2), 5.28 (s, 2H, CH2Ph), 5.18 (br t, 1H, J
) 5.3 Hz, NH), 4.44 (br t, 1H, J ) 8.3 Hz, 13a-H), 4.41 (d, 1H,
J ) 6.1 Hz, 1-H), 3.71 (s, 6H, 3′,5′-OCH3), 3.59 (dd, 1H, J )
8.3, 11.2 Hz, 13b-H), 3.37-3.24 (m, 3H, 2-H, CH2R), 2.86 (dd,
1H, J ) 3.5, 14.4 Hz, 3-H), 2.41 (m, 2H, CH2â), 2.21 (s, 6H,
N(CH3)2). MS (CI) m/z: 649 [M + H]+. HRMS (FAB+) m/z:
649.2388 [M + H+] C34H36N2O11 requires 649.2397 [M + H+].
(m, 4H, CH2R,γ), 3.00-2.73 (m, 5H, 2,3-H, NH, NH2), 1.80-
+
1.60 (m, 2H, CH2â). MS m/z: 635 [M + H]
.
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
[2-(N′,N′-Dimethylaminoethyl)]]carbamate (27a). White
amorphous solid. Yield 90%. Rf ) 0.30 (CH2Cl2/MeOH 85:15).
1
Mp ) 140-142 °C. [R]20 ) -64.0 (c 0.520, CHCl3). H NMR
D
(CDCl3) δ: 7.19 (s, 1H, 5-H), 6.48 (s, 1H, 8-H), 6.37 (d, 1H, J
) 3.5 Hz, 4-H), 6.01 (br s, 2H, 2′,6′-H), 5.96 (d, 2H, J ) 8.3
Hz, CH2O2), 5.19 (br s, 2H, 4′-OH, NH), 4.42 (br t, 1H, J ) 8.2
Hz, 13a-H), 4.35 (d, 1H, J ) 5.9 Hz, 1-H), 3.79 (s, 6H, 3′,5′-
OCH3), 3.55 (dd, 1H, J ) 8.2, 11.3 Hz, 13b-H), 3.32-3.21 (m,
3H, 2-H, CH2R), 2.87 (dd, 1H, J ) 3.5, 14.1 Hz, 3-H), 2.41 (m,
2H, CH2â), 2.20 (s, 6H, N(CH3)2). MS (CI) m/z: 515 [M + H]+.
HRMS (FAB+) m/z: 515.2043 [M + H+] C26H30N2O9 requires
515.2030 [M + H+].
11-Oxo-13-deoxo-4′-benzyloxycarbonyl-4′-demethyl-
epipodophyllotoxin 4-[N-[2-(N′,N′-Dimethylaminoethyl)]-
N-methyl]carbamate (22). Reaction time: 2 h. White amor-
phous solid. Yield: 78%. Rf ) 0.37 (CH2Cl2/MeOH 90:10). Mp
) 102-104 °C. [R]20D ) -42.5 (c 1.04, CHCl3). 1H NMR (CDCl3)
δ: 7.49-7.34 (m, 5H, CH2Ph), 7.25 (s, 1H, 5-H), 6.49 (s, 1H,
8-H), 6.36-6.45 (m, 1H, 4-H), 6.03 (br s, 2H, 2′,6′-H), 5.98 (d,
2H, J ) 6.9 Hz, CH2O2), 5.28 (s, 2H, CH2Ph), 4.51-4.40 (m,
2H, 1,13a-H), 3.71 (s, 6H, 3′,5′-OCH3), 3.59 (dd, 1H, J ) 8.1,
11.3 Hz, 13b-H), 3.65-3.55 (m, 2H, CH2R), 3.50-3.40 (m, 1
H, 2-H), 2.98 (s, 1.5H, NCH3 (rot.)), 2.92-2.87 (m, 1H, 3-H),
2.82 (s, 1.5H, NCH3 (rot.)), 2.56-2.47 (m, 2H, CH2â), 2.31 (br
s, 3H, N(CH3)2), 2.23 (br s, 3H, N(CH3)2). MS (CI) m/z: 663
[M + H]+.
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
[2-(N′,N′-Dimethylaminoethyl)]-N-methyl]carbamate
(27b). White amorphous solid. Yield 94%. Rf ) 0.32 (CH2Cl2/
MeOH 90:10). Mp ) 133-135 °C. [R]20 ) -50.0 (c 0.750,
D
CHCl3). 1H NMR (CDCl3) δ: 7.25 (s, 1H, 5-H), 6.50 (s, 1H, 8-H),
6.42-6.38 (m, 1H, 4-H), 6.02 (s, 2H, 2′,6′-H), 5.97 (d, 2H, J )
6.0 Hz, CH2O2), 4.43 (br t, 1H, J ) 8.2 Hz, 13a-H), 4.37 (d,
1H, J ) 5.9 Hz, 1-H), 3.80 (s, 6H, 3′,5′-OCH3), 3.56 (dd, 1H, J
) 8.2, 11.2 Hz, 13b-H), 3.44-3.38 (m, 1H, CH2a), 3.40-3.20
(m, 2H, 2-H, CH2R), 2.98 (s, 1.5H, NCH3 (rot.)), 2.95-2.86 (m,
1H, 3-H), 2.81 (s, 1.5H, NCH3 (rot.)), 2.52-2.43 (m, 2H, CH2â),
2.28 (s 3H, N(CH3)2), 2.19 (s 3H, N(CH3)2). MS (CI) m/z: 529
[M + H]+. HRMS (FAB+) m/z: 529.2180 [M + H+] C27H32N2O9
requires 529.2186 [M + H+].
11-Oxo-13-deoxo-4′-benzyloxycarbonyl-4′-demeth-
ylepipodophyllotoxin 4-[N-(2-Aminoethyl)]carbamate (23).
Reaction time: 30 min. White amorphous solid. Yield 76%. Rf
) 0.12 (CH2Cl2/MeOH 90:10). Mp ) 114-116 °C. [R]20
)
D
-59.0 (c 0.350, CHCl3). 1H NMR (CDCl3) δ: 7.46-7.29 (m, 5H,
CH2Ph), 7.16 (s, 1H, 5-H), 6.47 (s, 1H, 8-H), 6.41-6.30 (m, 1H,
4-H), 6.02 (s, 2H, 2′,6′-H), 5.94 (d, 2H, J ) 7.8 Hz, CH2O2),
5.25 (s, 2H, CH2Ph), 4.49-4.32 (m, 2H, 1,13a-H), 3.69 (s, 6H,
3′,5′-OCH3), 3.57 (br t, 1H, J ) 8.7 Hz, 13b-H), 3.40-3.17 (m,
3H, 2-H, CH2â), 2.93-2.76 (m, 3H, 3-H, CH2R), 2.13 (br s, 3H,
NH, NH2). MS (CI) m/z: 621 [M + H]+.
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
(2-Aminoethyl)]carbamate (27c). White amorphous solid.
Yield: 65%. Rf ) 0.16 (CH2Cl2/MeOH 85:15). Mp ) 161-163
°C. [R]20D ) -76.5 (c 0.350, CHCl3). 1H NMR (CD3OD) δ: 7.02
(s, 1H, 5-H), 6.49 (s, 1H, 8-H), 6.35-6.26 (m, 1H, 4-H), 6.14
(s, 2H, 2′,6′-H), 5.93 (d, 2H, J ) 3.9 Hz, CH2O2), 4.60-4.37
(m, 2H, 1,13a-H), 3.73 (s, 6H, 3′,5′-OCH3), 3.60-3.43 (m, 1H,
13b-H), 3.40-3.20 (m, 4H, 2,3, CH2R), 3.15-2.94 (m, 2H,
CH2â). MS m/z: 487 [M + H]+. Anal. (C24H26N2O9) C, H, N.
11-Oxo-13-deoxo-4′-benzyloxycarbonyl-4′-demethyl-
epipodophyllotoxin 4-[N-[2-(N′,N′-Dimethylaminopro-
pyl)]]carbamate (24). Reaction time: 1.30 h. White amor-
phous solid. Yield 79%. Rf ) 0.14 (CH2Cl2/MeOH 90:10). Mp
) 102-104 °C. [R]20 ) -51.0 (c 0.500, CHCl3). 1H NMR
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
[3-(N′,N′-Dimethylaminopropyl)]]carbamate (27d). White
amorphous solid. Yield: 81%. Rf ) 0.16 (CH2Cl2/MeOH 85:
D
(CDCl3) δ: 7.48-7.30 (m, 5H, CH2Ph), 7.19 (s, 1H, 5-H), 6.48
(s, 1H, 8-H), 6.38 (d, 1H, J ) 3.4 Hz, 4-H), 6.02 (s, 2H, 2′,6′-
H), 5.95 (d, 2H, J ) 6.4 Hz, CH2O2), 5.45 (br s, 1H, NH), 5.27
(s, 2H, CH2Ph), 4.49-4.33 (m, 2H, 1-H, 13a-H), 3.70 (s, 6H,
3′,5′-OCH3), 3.58 (t, 1H, J ) 9.8 Hz, 13b-H), 3.41-3.19 (m,
3H, 2-H, CH2R), 2.85 (dd, 1H, J ) 4.0, 14.0 Hz, 3-H), 2.38-
2.30 (m, 2H, CH2γ), 2.23 (s, 3H, N(CH3)2), 2.21 (s, 3H, N(CH3)2),
1.80-1.65 (m, 2H, CH2â). MS m/z: 663 [M + H]+. HRMS
(FAB+) m/z: 663.2539 [M + H+] C35H38N2O11 requires 663.2554
[M + H+].
15). Mp ) 103-105 °C. [R]20 ) -68.0 (c 0.285, CHCl3). 1H
D
NMR (CDCl3) δ: 7.03 (s, 1H, 5-H), 6.49 (s, 1H, 8-H), 6.37 (d,
1H, J ) 3.5 Hz, 4-H), 6.01 (s, 2H, 2′,6′-H), 5.96 (d, 2H, J ) 7.5
Hz, CH2O2), 5.80 (br s, 1H, 4′-OH), 4.45 (t, 1H, J ) 7.7 Hz,
13a-H), 4.36 (d, 1H, J ) 5.6 Hz, 1-H), 3.79 (s, 6H, 3′,5′-OCH3),
3.57 (dd, 1H, J ) 8.5, 11.1 Hz, 13b-H), 3.39-3.21 (m, 3H, 2-H,
CH2R), 3.20-3.08 (m, 1H, 2-H), 2.85 (dd, 1H, J ) 3.5, 14.6
Hz, 3-H), 2.72 (s, 6H, N(CH3)2), 2.26-2.10 (m, 2H, CH2γ),
2.00-1.85 (m, 2H, CH2â). MS m/z: 529 [M + H]+. HRMS
(FAB+) m/z: 529.2180 [M + H+] C27H32N2O9 requires 529.2186
[M + H+]. Anal. (C27H32N2O9) C, H, N.
11-Oxo-13-deoxo-4′-benzyloxycarbonyl-4′-demethyl-
epipodophyllotoxin 4-[N-[3-(N′,N′-Dimethylaminopropyl)]-
N-methyl]carbamate (25). Reaction time: 1 h. White amor-
phous solid. Yield: 65%. Rf ) 0.30 (CH2Cl2/MeOH 90:10). Mp
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
[3-(N′,N′-Dimethylaminopropyl)]-N-methyl]carbamate
(27e). White amorphous solid. Yield: 73%. Rf ) 0.10 (CH2Cl2/
) 124-126 °C. [R]20 ) -46.0 (c 0.410, CHCl3). 1H NMR
D
(CDCl3) δ: 7.48-7.31 (m, 5H, CH2Ph), 7.24 (s, 0.5H, 5-H (rot.)),
7.05 (s, 0.5H, 5-H (rot.)), 6.50 (s, 1H, 8-H), 6.41 (d, 1H, J ) 3.8
Hz, 4-H), 6.03 (s, 2H, 2′,6′-H), 5.97 (d, 2H, J ) 6.0 Hz, CH2O2),
5.27 (s, 2H, CH2Ph), 4.62-4.50 (m, 1H, 13a-H), 4.45 (d, 1H, J
) 7.6 Hz, 1-H), 3.70 (s, 6H, 3′,5′-OCH3), 3.68-3.54 (m, 1H,
13b-H), 3.48-3.44 (m, 0.5H, CH2R (rot.)), 3.40-3.20 (m, 1.5H,
CH2R (rot.)), 3.15-3.00 (m, 2H, 2,3-H), 2.95 (s, 1.5H, NCH3
(rot.)), 2.80 (s, 1.5H, NCH3 (rot.)), 2.68 (s, 6H, N(CH3)2), 2.30-
2.10 (m, 2H, CH2γ), 1.87-1.60 (m, 2H, CH2â). MS (CI) m/z:
677 [M + H]+. HRMS (FAB+) m/z: 677.2725 [M + H+]
C36H40N2O10 requires 677.2710 [M + H+].
MeOH 85:15). Mp ) 135-137°C. [R]20 ) -67.0 (c 0.468,
D
CHCl3). 1H NMR (CDCl3) δ: 7.23 (s, 0.5H, 5-H (rot.)), 7.02 (s,
1H, 5-H (rot.)), 6.51 (s, 1H, 8-H), 6.41 (d, 1H, J ) 3.6 Hz, 4-H),
6.01 (s, 2H, 2′,6′-H), 6.97 (d, 2H, J ) 7.0 Hz, CH2O2), 5.47 (br
s, 1H, 4′-OH), 4.46 (t, 1H, J ) 5.8 Hz, 13a-H), 4.38 (d, 1H, J
) 5.3 Hz, 1-H), 3.79 (s, 6H, 3′,5′-OCH3), 3.59 (br t, 1H, J ) 9.9
Hz, 13b-H), 3.30-3.04 (m, 3H, 2-H, CH2R), 2.95 (s, 1.5H, NCH3
(rot.)), 2.81 (s, 6H, N(CH3)2), 2.78 (s, 1.5H, NCH3 (rot.)), 2.77-
2.70 (m, 3H, 3-H, CH2γ), 2.23-2.07 (m, 2H, CH2â). MS (CI)
m/z: 543 [M + H]+. HRMS (FAB+) m/z: 543.2346 [M + H+]
C28H34N2O10 requires 543.2342 [M + H+]. Anal. (C28H34N2O9):
C, H, N.
11-Oxo-13-deoxo-4′-benzyloxycarbonyl-4′-demethyl-
epipodophyllotoxin 4-[N-(3-Aminopropyl)]carbamate (26).
Reaction time: 30 min. White amorphous solid. Yield 60%. Rf
) 0.10 (CH2Cl2/MeOH 90:10). Mp ) 92-94 °C. [R]20D ) -33.5
(c 0.475, CHCl3). 1H NMR (CDCl3) δ: 7.46-7.30 (m, 5H,
CH2Ph), 7.13 (s, 1H, 5-H), 6.47 (s, 1H, 8-H), 6.40-6.30 (m, 1H,
4-H), 6.01 (br s, 2H, 2′,6′-H), 5.95 (d, 2H, J ) 7.2 Hz, CH2O2),
5.26 (s, 2H, CH2Ph), 4.47-4.30 (m, 2H, 1-H, 13a-H), 3.78 (s,
11-Oxo-13-deoxo-4′-demethylepipodophyllotoxin 4-[N-
(3-Aminopropyl)]carbamate (27f). White amorphous solid.
Yield: 75%. Rf ) 0.10 (CH2Cl2/MeOH 85:15). Mp ) 165-167
°C. [R]20D ) -24.5 (c 0.430, DMSO). 1H NMR (CD3OD) δ: 6.97
(s, 1H, 5-H), 6.50 (s, 1H, 8-H), 6.30 (d, 1H, J ) 3.5 Hz, 4-H),
6.15 (s, 2H, 2′,6′-H), 5.94 (d, 2H, J ) 3.0 Hz, CH2O2), 4.60-