I. Sánchez et al. / European Journal of Medicinal Chemistry 41 (2006) 340–352
347
12b), 139.2 (C, C-6a), 144.8 (C, C-7a), 146.8 (C, C-12). Anal.
Calcd for C19H21N3O2; C, 70.57; H, 6.55; N, 12.99. Found: C,
70.23; H, 6.88; N, 12.67.
cm–1: 3490 (OH), 2924 (NH), 1729 (C=N), 1260 (Ar–O), 1087
(C–O). H-NMR (CD3OD, 200 MHz) δ: 1.99 (bs, 5H, OH),
1
3.04 (s, 1H, CH-O), 3.24 (m, 2H, CH2O), 3.39 (s, 1H, CH-
O), 3.45 (m, 1H, CH-O), 4.23 (m, 4H, CH2-O), 7.11 (s, 1H,
C5-H), 7.18 (m, 2H, C9-H and C10-H), 7.41 (m, 1H, C7-H),
7.48 (m, 1H, C8-H), 7.87 (s, 1H, C12-H), 8.38 and 8.39 (m,
2H, C2-H and C6-H), 9.86 (bs, 2H, NH2). 13C-NMR (CD3OD,
50.3 MHz) δ: 48.1 (CH, CH-O), 61.5 (CH2, CH2O), 62.3
(CH2, CH2O), 63.1 (CH2, CH2O), 102.1 (CH, C-5), 109.8
(CH, C-9), 112.2 (CH, C-12), 116.1 (CH, C-7), 120.3 (CH,
C-8), 123.8 (CH, C-10), 126.1 (CH, C-2′), 132.3 (CH, C-6′),
134.8 (C, C-3a’), 136.1 (C, C-10a), 137.4 (C, C-11a), 138.1
(C, C-6a), 139.8 (C, C-12a), 140.3 (C, C-5a), 141.1 (C, C-
4a), 142.7 (C, C-11), 149.4 (C, C-7a), 178.1 and 178.9 (C,
C-4′). Anal.Calcd for C25H25P3N6O15; C, 40.45; H, 3.39; N,
11.32. Found: C, 40.41; H, 3.53; N, 11.11.
4.1.1.6. 11-(p-Fluorophenoxy-2,3-dihydro-1,4-dioxino[2,3-b]
acridine (11). Compound 11 (0.045 g, 64%) was obtained by
the general procedure (method C) from as the p-fluorophenol
(0.065 g, 0.6 mmol) and the acridine 32 (0.05 g, 0.19 mmol).
IR (KBr) υ cm–1: 1501 (Ar–H), 1189 (Ar–O), 1068 (C–O). 1H-
NMR (CDCl3, 200 MHz) δ: 4.39 (m, 4H, CH2O), 6.79 (m, 2H,
C2′-H and C6′-H), 7.40 (m, 2H, Ar), 7.67 (m, 2H, Ar), 7.99 (d,
J = 8.2 Hz, 1H, C10-H), 8.21 (d, J = 8.2 Hz, 1H, C7-H). 13C-
NMR (CDCl3, 50.3 MHz) δ: 64.3 and 64.4 (CH2, CH2O),
105.5 (CH, C-5), 112.8 (CH, C-7), 116.3 (C, C-10a), 116.5
(CH, d, J = 8 Hz, C-2′ and C-6′), 117.0 (CH, C-10), 119.3
(CH, C-12), 122.1 (CH, C-9), 125.1 (CH, C-8), 129.4 (CH,
d, J = 37 Hz, C-3′, C-5′), 144.8 (C, C-11a), 148.1, 148.9, and
149.5 (C, C-1′, C-11, C-4a, C-12a), 153.3 and 155.2 (C, C-5a,
C-6a), 158.6 (C, d, J = 265 Hz, C-4′). MS (m/z, %): 347 (M,
100), 252 (M-95, 14), 196 (3), 152 (6). Anal. (C21H14FNO3) C,
H, N. Anal.Calcd for C21H14FNO3; C, 72.62; H, 4.06; N, 4.03.
Found: C, 72.96; H, 4.34; N, 3.89.
4.1.1.9. 11-(Adenosin-5′-triphosphate)-9-bromo-2,3-dihydro-
1,4-dioxino[2,3-b]acridine (13b). Was prepared from the chlor-
oacridine 38 (130 mg, 0.37 mmol) as described above for 13a.
The residue was purified by silica gel column chromatography
(metanol/NH4OH) affording 75 mg (24% yield) of the com-
pound 13b as an oil. IR (KBr) υ cm–1: 3510 (OH, N–H),
2938 (NH), 1220 (Ar–O), 1082 (C–O). 1H-NMR (CD3OD,
200 MHz) δ: 2.01 (bs, 5H, OH), 3.12 (s, 1H, CH–O 3.29 (m,
2H, CH2O), 3.45 (s, 1H, CH–O), 4.30 (m, 4H, CH2–O), 7.08
(s, 1H, C5-H), 7.28 (m, 1H, Ar), 7.50 (m, 1H, C7-H), 7.56 (m,
1H, C8-H), 7.80 (s, 1H, C12-H), 8.30 (m, 2H, Ar), 8.98 (bs,
2H, NH2). This compound 13b was unstable.
4.1.1.7. 11-(3,4,5-Trimethoxybenzyloxy)-2,3-dihydro-1,4-dioxi-
no[2,3-b]acridine (12). Compound 12 (colorless oil, 0.16 g,
60% yield) was obtained using the general procedure (method
B) starting from 3,4,5-trimethoxybenzylalcohol (0.25 g, 1.24
mmol) and the chloroderivative 32 (0.17 g, 0.62 mmol). IR
(KBr) υ cm–1 (2 HCl): 3505 (N–H), 1204 (Ar–O), 1136 (C–O).
1H-NMR (CDCl3, 200 MHz) δ: 3.85 (m, 9H, CH3O), 4.25 (m,
4H, CH2O), 4.60 (s, CH2O), 6.62 (s, 2H, C2′-H and C6′-H),
7.33 (m, 5H, Ar), 8.22 (bs, 1H Ar). 13C-NMR (CDCl3,
50.3 MHz) δ: 55.6 (CH3, CH3O), 60.4 (CH3, CH3O), 63.7
(CH2, CH2O), 63.8 (CH2, CH2O), 64.7 (CH2, CH2O), 103.4
(CH, C-2′, C-6′), 112.2 (CH, C-5), 116.2 (C, C-10a), 116.6
(CH, C-12), 120.6 (CH, C-7), 124.2 (C, C-11a), 125.8 (CH,
C-9), 132.6 (CH, C-8), 137.0 (CH, C-10), 140.0 and 141.2
(C, C-4a, C-12a), 144.2 (C, C-5a, C-6a), 149.8 (C, C-11),
151,9 (C, C-1′), 152.8 (C, C-3′, C-4′, C-5′). MS (EI) (m/z, %)
4.1.1.10. 6,9-Dihydro-5H-dioxino[2,3-i]pyrido[4,3,2-kl]acri-
dine (14). A mixture of the acetal 39 (125 mg, 0.37 mmol) and
a catalytic amount of PTSA in dry toluene (20 ml) was stirred
in a 130 °C oil bath for 1 h. Then was allowed to room tem-
perature and the mixture was poured drop-wise into an aqueous
solution of ammonium hydroxide cooled to 0 °C and extracted
with ethyl acetate (3 × 20 ml). The organic layers were washed
with water, dried on sodium sulphate and the solvent was con-
centrated under reduced pressure. The residue was purified by
column chromatography using ethyl acetate 100% as eluent to
give the compound 14 as an orange solid (25 mg, 24% yield).
+
433 (M, 1), 368 (1), 252 (100), 253 (17), 197 (C10H13O4 , 59).
Anal.Calcd for C25H23NO6; C, 69.27; H, 5.35; N, 3.23. Found:
C, 69.01; H, 5.76; N, 3.56.
1
m.p. (hexane/ethyl acetate) 349–350 °C. H-NMR (CD3OD,
200 MHz) δ: 4.34 (s, 4H, CH2); 6.33 (s, 1H, C8-H); 7.01 (m,
2H, Ar); 7.16 (d, J = 6 Hz, 1H, C13-H); 7.38 (m, 1H, C9-H);
7.95 (d, J = 6 Hz, 1H, C10-H); 8.23 (d, J = 8 Hz, 1H, C3-H).
13C-NMR (CDCl3, 50.3 MHz) δ: 62.3 (CH2-O), 93.7 (CH, C-
8), 106.3 (CH, C-2), 112.5 (CH, C-10), 118.1 (CH, C-13),
123.6 (C, C-13a), 124.1 (C, Ar), 129.2 (CH, C-11 and C-12),
129.6 (CH, C-3), 136.4 (C, C-3a), 143.2 (CH, C-2), 144.3 (C,
C-7a, C-3b), 148.1 (C, C-8a and C-9a), 149.2 (C, C-13b).
Anal. Calcd for C17H12N2O2; C, 73.90; H, 4.38; N, 10.14.
Found: C, 73.21; H, 4.65; N, 9.89.
4.1.1.8. 11-(Adenosin-5′-triphosphate)-2,3-dihydro-1,4-dioxino
[2,3-b]acridine (13a).
A solution of chloroacridine 32
(120 mg, 0.44 mmol) and KI (103.5 mg, 0.62 mmol) in
CH3CN 10 ml was stirred under argon atmosphere at room
temperature for 60 minutes. After adenosin triphosphate diso-
dium salt (408 mg, 0.74 mmol) and Aliquat® (0.3 ml) in
CH3CN:H2O 1:1 (20 ml) were added and the mixture was in-
troduced in an ultrasonic irradiation bath for 24 h. Finally the
CH3CN was removed and the mixture was extracted with with
CH2Cl2. The resulting organic layers were dried, filtered and
concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (metanol /NH4OH) af-
fording 150 mg (46% yield) of the compound 13a. IR (KBr) υ
4.1.1.11. 6-(N,N-diethylaminoethyl)-6,9-dihydro-5H-dioxino
[2,3-i]pyrido[4,3,2-kl]acridine (15). Prepared from the com-
pound 14 (100 mg, 0.35 mmol) and 2-diethylaminoethyl chlor-