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C. Gao et al. / Bioorg. Med. Chem. 18 (2010) 7507–7514
2.51 (m, 2H), 2.59 (m, 4H), 2.85 (t, 2H, 3J = 6.3 Hz), 3.47 (m, 4H),
3.66 (s, 6H), 4.43 (t, 2H, 3J = 6.3 Hz), 5.71 (s, 2H), 6.28 (br s, 2H),
6.42 (br s, 1H), 7.31 (m, 1H), 7.61–7.64 (m, 2H), 7.76 (m, 1H),
7.96 (m, 1H), 8.37 (m, 1H), 8.65 (br s, 1H), 10.40 (s, 1H); 13C
NMR (75 MHz, DMSO-d6) d: 35.0, 49.5, 51.2, 55.6, 56.7, 59.7,
98.8, 104.6, 115.9, 116.5, 117.2, 121.6, 121.9, 122.3, 127.2, 134.1,
134.6, 138.7, 139.4, 142.3, 161.5, 171.1, 176.9; HRMS calcd for
TLC indicated completion of reaction. The volatile parts were re-
moved under reduced pressure and water was added with rapid
stirring under ice-water bath. Yellow solids were obtained after fil-
tration. The products were purified by recrystallization from etha-
nol and ethyl acetate.
4.1.2.1. N-(10-(3,5-Dimethoxybenzyl)-9,10-dihydro-9-oxoacri-
C
29H34N3O6 [M+H]+ 520.2448, found 520.2427.
din-2-yl)-2-amino-acetamide hydrochloride (8a).
Yield
136 mg, 60%; yellow solids; mp 297–299 °C; 1H NMR (500 MHz,
DMSO-d6) d: 3.62 (s, 6H), 3.83 (m, 2H), 5.72 (s, 2H), 6.28 (m, 2H),
6.42 (m, 1H), 7.36 (m, 1H), 7.63 (m, 1H), 7.68 (m, 1H), 7.78 (m,
1H), 7.94 (m, 1H), 8.23 (br s, 3H), 8.38 (m, 1H), 8.68 (m, 1H),
10.82 (s, 1H); 13C NMR (125 MHz, DMSO-d6) d: 41.5, 49.6, 55.6,
98.9, 104.6, 116.3, 116.5, 117.5, 121.7, 122.0, 122.3, 127.0, 127.1,
4.1.1.4. 2-(Pyrrolidinopropionamido)-10-(3,5-dimethoxybenzyl)-
9,10-dihydro-acridinone (6d). Yield 218 mg, 90%; yellow
crystals; mp 236–238 °C; 1H NMR (300 MHz, DMSO-d6) d: 1.68 (br
s, 2H), 2.48–2.54 (m, 6H), 2.74 (t, 2H, 3J = 6.8 Hz), 3.67 (s, 6H), 5.71
(s, 2H), 6.29 (br s, 2H), 6.43 (br s, 1H), 7.33 (m, 1H), 7.60–7.65 (m,
2H), 7.75 (m, 1H), 7.98 (m, 1H), 8.38 (m, 1H), 8.65 (m, 1H), 10.33
(s, 1H); 13C NMR (75 MHz, DMSO-d6) d: 23.7, 36.7, 49.6, 52.1, 54.0,
55.6, 98.8, 104.6, 115.7, 116.5, 117.3, 121.6, 121.8, 122.3, 127.0,
127.2, 134.2, 134.6, 138.7, 139.4, 142.3, 161.4, 170.7, 176.9; HRMS
calcd for C29H32N3O4 [M+H]+ 486.2393, found 486.2386.
132.9, 134.8, 139.2, 139.3, 142.4, 161.5, 165.2, 176.9; IR (KBr, cm
ꢂ1
) m: 687, 756, 814, 1070, 1164, 1208, 1276, 1353, 1506, 1548,
1588, 1696, 2343, 2842, 2963, 3005, 3105, 3229, 3320; HRMS calcd
for C24H24N3O4Cl [MꢂCl]+ 418.1767, found 418.1758.
4.1.2.2. N-(10-(3,5-Dimethoxybenzyl)-9,10-dihydro-9-oxoacri-
4.1.1.5. 2-(Piperidinopropionamido)-10-(3,5-dimethoxybenzyl)-
din-2-yl)-3-amino-propionamide hydrochloride (8b).
Yield
9,10-dihydro-acridinone (6e).
Yield 220 mg, 88%; yellow
145 mg, 62%; yellow solids; mp 229–231 °C; 1H NMR (500 MHz,
DMSO-d6) d: 2.80 (t, 2H, 3J = 6.8 Hz), 3.12 (m, 2H), 3.66 (s, 6H),
5.71 (s, 2H), 6.28 (m, 2H), 6.42 (m, 1H), 7.33 (m, 1H), 7.60–7.66
(m, 2H), 7.76 (m, 1H), 7.97 (m, 1H), 8.04 (br s, 3H), 8.37 (m, 1H),
8.71 (m, 1H), 10.56 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d: 33.7,
35.5, 49.5, 55.6, 98.8, 104.6, 116.1, 116.6, 117.3, 121.6, 121.9,
122.2, 127.1, 127.2, 133.8, 134.7, 138.8, 139.4, 142.3, 161.4,
168.9, 176.9; HRMS calcd for C25H26N3O4Cl [MꢂCl]+ 432.1923,
found 432.1913.
crystals; mp 226–227 °C; 1H NMR (300 MHz, DMSO-d6) d: 1.39
(m, 2H), 1.50–1.51 (m, 4H), 2.40–2.51 (m, 6H), 2.63 (m, 2H), 3.66
(s, 6H), 5.71 (s, 2H), 6.28 (m, 2H), 6.42 (br s, 1H), 7.33 (m, 1H),
7.59–7.65 (m, 2H), 7.75 (m, 1H), 7.96 (m, 1H), 8.37 (m, 1H), 8.61
(m, 1H), 10.40 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d: 19.1, 24.5,
26.1, 34.5, 49.5, 54.2, 54.9, 55.6, 56.6, 98.8, 104.6, 115.7, 116.5,
117.4, 121.6, 121.9, 122.3, 127.0, 127.2, 134.1, 134.7, 138.7,
139.4, 142.3, 161.4, 170.9, 176.9; HRMS calcd for C30H34N3O4
[M+H]+ 500.2549, found 500.2527.
4.1.2.3. N-(10-(3,5-Dimethoxybenzyl)-9,10-dihydro-9-oxoacri-
4.1.1.6. 2-(Morpholinopropionamido)-10-(3,5-dimethoxyben-
din-2-yl)-4-amino-butyramide hydrochloride (8c).
Yield
zyl)-9,10-dihydro-acridinone (6f).
Yield 216 mg, 86%; yellow
145 mg, 60%; yellow solids; mp 270–271 °C; 1H NMR (300 MHz,
DMSO-d6) d: 1.91 (m, 2H), 2.48 (m, 2H, 3J = 6.8 Hz), 2.87 (m, 2H),
3.66 (s, 6H), 5.72 (s, 2H), 6.27 (m, 2H), 6.42 (m, 1H), 7.33 (m,
1H), 7.60–7.66 (m, 2H), 7.76 (m, 1H), 7.86 (br s, 3H), 7.96 (m,
1H), 8.37 (m, 1H), 8.66 (m, 1H), 10.34 (s, 1H); 13C NMR (75 MHz,
DMSO-d6) d: 23.5, 33.4, 38.9, 49.5, 55.6, 98.7, 104.6, 115.9, 116.6,
117.3, 121.6, 121.9, 122.2, 127.2, 134.0, 134.7, 138.8, 139.4,
142.3, 161.4, 170.9, 176.9; HRMS calcd for C26H28N3O4 [MꢂCl]+
446.2080, found 446.2079.
crystals; mp 199–200 °C; 1H NMR (300 MHz, DMSO-d6) d: 2.41 (m,
4H), 2.65 (m, 2H), 3.57 (m, 4H), 3.66 (s, 6H), 5.70 (s, 2H), 6.27 (m,
2H), 6.41 (br s, 1H), 7.32 (m, 1H), 7.62–7.64 (m, 2H), 7.75 (m, 1H),
7.96 (m, 1H), 8.37 (m, 1H), 8.61 (m, 1H), 10.30 (s, 1H); 13C NMR
(75 MHz, DMSO-d6) d: 34.4, 49.5, 53.5, 54.7, 55.6, 66.7, 98.8,
104.5, 115.7, 116.5, 117.3, 121.6, 121.8, 122.2, 127.0, 127.2, 134.1,
134.6, 138.7, 139.4, 142.3, 161.4, 170.6, 176.8; HRMS calcd for
C
29H32N3O5 [M+H]+ 502.2342, found 502.2334.
4.1.1.7. 2-[(4-Hydroxyl-piperidino)propionamido]-10-(3,5-dimeth-
oxybenzyl) 9,10-dihydro-acridinone (6g). Yield 227 mg,
4.1.2.4. N-(10-(3,5-Dimethoxybenzyl)-9,10-dihydro-9-oxoacri-
din-2-yl)-5-amino-pentylamide hydrochloride (8d).
Yield
88%; yellow crystals; mp 222–223 °C; 1H NMR (300 MHz, DMSO-
d6) d: 1.40 (m, 2H), 1.73 (m, 2H), 2.09 (m, 2H), 2.49 (m, 2H), 2.64
(m, 2H), 2.77 (m, 2H), 3.46 (m, 1H), 3.67 (s, 6H), 4.58 (br s, 1H),
5.71 (s, 2H), 6.28 (br s, 2H), 6.42 (br s, 1H), 7.33 (m, 1H), 7.59–
7.65 (m, 2H), 7.75 (m, 1H), 7.96 (m, 1H), 8.38 (m, 1H), 8.63 (m,
1H), 10.39 (s, 1H); 13C NMR (75 MHz, DMSO-d6) d: 34.9, 35.0,
49.6, 51.2, 54.3, 55.6, 66.8, 98.8, 104.6, 115.7, 116.5, 117.3, 121.6,
121.9, 122.3, 127.0, 127.2, 134.1, 134.6, 138.7, 139.4, 142.3,
161 mg, 65%; yellow solids; mp 242–243 °C; 1H NMR (500 MHz,
DMSO-d6) d: 1.61–1.70 (m, 4H), 2.40 (m, 2H, 3J = 6.8 Hz), 2.82 (m,
2H), 3.66 (s, 6H), 5.71 (s, 2H), 6.28 (m, 2H), 6.42 (m, 1H), 7.32
(m, 1H), 7.60–7.64 (m, 2H), 7.75 (m, 1H), 7.91 (br s, 3H), 7.99 (m,
1H), 8.36 (m, 1H), 8.67 (m, 1H), 10.31 (s, 1H); 13C NMR
(125 MHz, DMSO-d6) d: 22.5, 26.9, 36.0, 39.2, 49.4, 55.6, 98.7,
104.6, 116.0, 116.4, 117.2, 121.5, 122.0, 122.1, 127.2, 127.3,
133.9, 134.8, 138.7, 139.2, 142.2, 161.4, 171.7, 177.1; HRMS calcd
for C27H30N3O4 [MꢂCl]+ 460.2236, found 460.2238.
161.5, 170.8, 176.9; HRMS calcd for
516.2499, found 516.2488.
C
30H34N3O5 [M+H]+
4.1.2.5. N-(10-(3,5-Dimethoxybenzyl)-9,10-dihydro-9-oxoacri-
4.1.2. General preparation of compound 8
To a solution of Boc-amino acid in dry THF (10 mL) was added
HOBt (81 mg, 0.6 mmol), DIC (76 mg, 0.6 mmol) and 2-amino-10-
din-2-yl)-6-amino-hexylamide hydrochloride (8e).
Yield
178 mg, 70%; yellow solids; mp 195–197 °C; 1H NMR (300 MHz,
DMSO-d6) d: 1.38 (m, 2H), 1.60–1.64 (m, 4H), 2.37 (m, 2H), 2.79
(m, 2H), 3.66 (s, 6H), 5.71 (s, 2H), 6.28 (m, 2H), 6.42 (m, 1H),
7.33 (m, 1H), 7.60–7.65 (m, 2H), 7.75 (m, 1H), 7.91 (br s, 3H),
7.99 (m, 1H), 8.37 (m, 1H), 8.67 (m, 1H), 10.28 (s, 1H); 13C NMR
(125 MHz, DMSO-d6) d: 25.1, 26.0, 27.2, 36.5, 39.2, 49.5, 55.7,
98.9, 104.6, 115.9, 116.4, 117.1, 121.6, 121.8, 122.3, 127.2, 134.2,
134.5, 138.7, 139.4, 142.3, 161.4, 171.6, 176.9; HRMS calcd for
(3,5-dimethoxybenzyl)-9,10-dihydro-acridinone
4
(180 mg,
0.5 mmol). The reaction suspension was stirred under nitrogen
overnight at room temperature. The volatile parts were removed
under reduced pressure and compound 7 was obtained by column
chromatography. Compound 7 was suspended and stirred in ethyl
acetate (15 mL), and then hydrochloride (3 M, 8 mL) was added
dropwise. The suspension was stirred at room temperature until
C
28H32N3O4 [MꢂCl]+ 474.2393, found 474.2393.