A. Wu et al. / European Journal of Medicinal Chemistry 44 (2009) 4674–4680
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57.28, 56.99, 53.21, 53.10, 45.70, 37.95; FTIR (KBr, cmꢀ1): 3422,
2938, 2814, 2762, 1688, 1647, 1584, 1450, 1383, 1235, 1135, 1045,
786, 756, 696; HRMS (ESþ) calcd for C35H37N4O2 ([M þ H])þ
545.2917, found 545.2917.
J ¼ 5.2 Hz, 1H, Ar–NH), 6.78 (d, J ¼ 8.8 Hz, 1H, Ar–H), 6.17 (d,
J ¼ 6.8 Hz, 2H, 2C]CH), 4.23 (t, J ¼ 6.8 Hz, 2H, CH2N), 3.45 (q,
J ¼ 6.4 Hz,, 2H, Ar–NHCH2), 3.18 (d, J ¼ 6.8 Hz, 4H, 2NCH2CH), 2.56
(t, J ¼ 6.8 Hz, 2H, CH2N(CH3)2), 2.45 (d, J ¼ 6.8 Hz, 2H,
CH2N(CH2CH])2), 2.27 (s, 6H, N(CH3)2), 1.83–1.76 (m, 2H, CH2),
1.62–1.59 (m, 2H, CH2), 1.49–1.43 (m, 4H, CH2CH2); 13C NMR
(CD3COCD3, 100 MHz) dC: 164.01, 163.24, 150.40, 143.36, 142.36,
139.74, 134.08, 130.48, 129.90, 129.74, 128.13, 128.09, 127.37, 127.17,
127.10, 124.20, 122.82, 120.52, 109.06, 103.78, 57.02, 53.79, 52.67,
45.16, 43.35, 37.44, 31.77, 27.00, 26.88, 24.76, 22.47, 13.52; FTIR
(KBr, cmꢀ1): 2925, 2844, 1680, 1643, 1580, 1535, 1439, 1361, 1342,
1242, 1123, 767, 696; HRMS (ESþ) calcd for C52H55N4O2 ([M þ H])þ
767.4325, found 767.4337.
4.1.2.2. (E)-4-(3-(4-(2-(2-(Dimethylamino)ethyl)-1,3-dioxo-2,3-dihy-
dro-1H-benzo[de]isoquinolin-6-yl)piperazin-1-yl)prop-1-enyl)benzo-
nitrile (7b). Orange solid. Yield: 90%; m.p. 128.2–130.2 ꢁC; 1H NMR
(CDCl3, 400 MHz) dH: 8.58 (d, J ¼ 7.2 Hz, 1H, Ar–H), 8.52 (d,
J ¼ 8.0 Hz, 1H, Ar–H), 8.41 (d, J ¼ 8.4 Hz, 1H, Ar–H), 7.69 (t,
J ¼ 8.0 Hz, 1H, Ar–H), 7.62 (d, J ¼ 8.4 Hz, 2H, Ar–H), 7.49 (d,
J ¼ 8.4 Hz, 2H, Ar–H), 7.23 (d, J ¼ 8.0 Hz, 1H, Ar–H), 6.64 (d,
J ¼ 16.0 Hz, 1H, C]CH), 6.51–6.44 (m, 1H, Ar–H), 4.33 (t, J ¼ 7.2 Hz,
2H, CH2N), 3.36–3.33 (m, 6H, CHCH2N and CH2NCH2), 2.85 (s, 4H,
CH2NCH2), 2.67 (t, J ¼ 7.2 Hz, 2H, CH2N(CH3)2), 2.37 (s, 6H,
N(CH3)2); 13C NMR (CDCl3, 100 MHz) dC: 164.50, 164.01, 155.84,
141.22, 132.59, 132.47, 131.62, 131.15, 130.59, 130.21, 129.95, 126.82,
126.19, 125.64, 123.28, 118.85, 116.83, 114.97, 110.93, 60.73, 56.96,
53.32, 53.02, 45.66, 37.93; FTIR (KBr, cmꢀ1): 2933, 2814, 2762,
2214, 1695, 1651, 1584, 1569, 1450, 1368, 1231, 1131, 1038, 975, 778;
HRMS (ESþ) calcd for C30H32N5O2 ([M þ H])þ 494.2556, found
494.2542.
4.1.3. General procedure for the synthesis of 7e and 9a
To a solution of compound 6/8 (0.142 mmol) in CHCl3 (2 mL), 4-(4-
(3,3-diphenylallyl)piperazin-1-yl)benzoic acid (68 mg, 0.170 mmol),
prepared by using the previously reported method [27,34,44], EDCI
(65 mg, 0.340 mmol) and DMAP (41 mg, 0.340 mmol) were added.
The solutionwas stirred at room temperature under nitrogen for 48 h
and then concentrated. The residue was purified on silica gel column
chromatography by using CH2Cl2/CH3OH 50:1 (v/v) as the eluent,
affording 7e/9a as bright yellow–orange red solids.
4.1.2.3. (E)-2-(2-(Dimethylamino)ethyl)-6-(4-(3-(4-(dimethylamino)-
phenyl)allyl)piperazin-1-yl)-1H-benzo[de]isoquinoline-1,3(2H)-dione
(7c). Orange red solid. Yield: 85%; m.p. 125.7–127.7 ꢁC; 1H NMR
(CDCl3, 400 MHz) dH: 8.58 (dd, J1 ¼7.2 Hz, J2 ¼ 0.8 Hz, 1H, Ar–H),
8.52 (d, J ¼ 8.0 Hz, 1H, Ar–H), 8.42 (dd, J1 ¼8.4 Hz, J2 ¼ 0.8 Hz, 1H,
Ar–H), 7.68 (q, J1 ¼7.6 Hz, J2 ¼ 0.8 Hz, 1H, Ar–H), 7.32 (d, J ¼ 8.8 Hz,
2H, Ar–H), 7.22 (d, J ¼ 8.0 Hz, 1H, Ar–H), 6.70 (d, J ¼ 8.8 Hz, 2H, Ar–
H), 6.52 (d, J ¼ 15.6 Hz, 1H, C]CH), 6.16–6.09 (m, 1H, Ar–H), 4.33 (t,
J ¼ 7.2 Hz, 2H, CH2N), 3.33–3.29 (m, 6H, CHCH2N and CH2NCH2),
2.97 (s, 6H, Ar–N(CH3)2), 2.84 (s, br, 4H, CH2NCH2), 2.66 (t,
J ¼ 7.2 Hz, 2H, CH2N(CH3)2), 2.37 (s, 6H, N(CH3)2); 13C NMR (CDCl3,
100 MHz) dC: 164.54, 164.04, 150.19, 133.63, 132.64, 131.11, 130.37,
129.96, 127.31, 126.18, 125.56, 125.25, 123.22, 121.35, 116.61, 114.92,
112.45, 61.34, 56.97, 53.12, 53.09, 45.68, 40.49, 37.94; FTIR (KBr,
cmꢀ1): 2933, 2807, 2755, 1688, 1654, 1584, 1521, 1446, 1346, 1231,
1116, 1042, 964, 782, 756; HRMS (ESþ) calcd for C31H38N5O2
([M þ H])þ 512.3026, found 512.3026.
4.1.3.1. 2-(2-(Dimethylamino)ethyl)-6-(4-(4-(4-(3,3-diphenylallyl)
piperazin-1-yl)benzoyl)piperazin-1-yl)-1H-benzo[de]isoquinoline-
1,3(2H)-dione (7e). Bright yellow solid. Yield: 60%; m.p. 99.5–
101.5 ꢁC; 1H NMR (CDCl3, 400 MHz) dH: 8.61 (d, J ¼ 7.2 Hz, 1H,
Ar–H), 8.54 (d, J ¼ 8.0 Hz, 1H, Ar–H), 8.43 (d, J ¼ 8.4 Hz, 1H, Ar–H),
7.73 (t, J ¼ 8.0 Hz, 1H, Ar–H), 7.43–7.34 (m, 5H, Ar–H), 7.32–7.28 (m,
5H, Ar–H), 7.25–7.22 (m, 1H, Ar–H), 7.18 (d, J ¼ 6.8 Hz, 2H, Ar–H),
6.91 (d, J ¼ 8.8 Hz, 2H, Ar–H), 6.26 (t, J ¼ 7.2 Hz, 1H, C]CH), 4.33 (t,
J ¼ 7.2 Hz, 2H, CH2N), 3.98 (s, 4H, CH2NCH2), 3.30–3.27 (m, 8H,
N(CH2CH2)2N), 3.15 (d, J ¼ 6.8 Hz, 2H, CHCH2N), 2.67 (t, J ¼ 7.2 Hz,
2H, CH2N(CH3)2), 2.61 (s, 4H, CH2NCH2), 2.37 (s, 6H, N(CH3)2); 13C
NMR (CDCl3, 100 MHz) dC: 170.94, 164.40, 163.94, 155.28, 153.44,
144.55, 141.89, 139.53, 132.44, 131.28, 129.96, 129.84, 129.76, 129.18,
128.25, 128.19, 127.41, 127.28, 127.25, 126.28, 126.03, 125.84, 124.96,
123.87,117.52,115.38, 114.57, 57.28, 56.92, 53.23, 52.92, 48.19, 45.72,
38.00; FTIR (KBr, cmꢀ1): 2933, 2814, 1695, 1654, 1584, 1509, 1387,
1368, 1279, 1235, 1135, 1019, 786, 756, 696; HRMS (ESþ) calcd for
C46H49N6O3 ([M þ H])þ 733.3866, found 733.3851.
4.1.2.4. (E)-6-(4-Cinnamylpiperazin-1-yl)-2-(2-(dimethylamino)ethyl)-
1H-benzo[de]isoquinoline-1,3(2H)-dione (7d). Khaki solid. Yield:
85%; m.p. 164.6–166.6 ꢁC; 1H NMR (CDCl3, 400 MHz) dH: 8.58 (dd,
J1 ¼7.6 Hz, J2 ¼ 0.8 Hz, 1H, Ar–H), 8.52 (d, J ¼ 8.0 Hz, 1H, Ar–H), 8.42
(dd, J1 ¼8.8 Hz, J2 ¼ 0.8 Hz, 1H, Ar–H), 7.69 (q, J1 ¼8.4 Hz,
J2 ¼ 0.8 Hz, 1H, Ar–H), 7.42 (d, J ¼ 7.2 Hz, 2H, Ar–H), 7.36–7.32 (m,
2H, Ar–H), 7.28–7.22 (m, 2H, Ar–H), 6.62 (d, J ¼ 16 Hz, 1H, C]CH),
6.38–6.31 (m,1H, Ar–H), 4.33 (t, J ¼ 7.2 Hz, 2H, CH2N), 3.34–3.32 (m,
6H, CHCH2N and CH2NCH2), 2.85 (s, br, 4H, CH2NCH2), 2.66 (t,
J ¼ 7.2 Hz, 2H, CH2N(CH3)2), 2.37 (s, 6H, N(CH3)2); 13C NMR (CDCl3,
100 MHz) dC: 164.52, 164.03, 155.98, 136.77, 133.52, 132.62, 131.12,
130.31, 129.95, 128.62, 127.66, 126.36, 126.18, 126.08, 125.59, 123.24,
116.69, 114.94, 61.04, 56.97, 53.21, 53.07, 45.68, 37.94; FTIR (KBr,
cmꢀ1): 2962, 2807, 2762, 1688, 1651, 1584, 1509, 1450, 1391, 1365,
1246, 1120, 1042, 971, 782, 760, 693; HRMS (ESþ) calcd for
C29H33N4O2 ([M þ H])þ 469.2604, found 469.2600.
4.1.3.2. N-(6-(2-(2-(Dimethylamino)ethyl)-1,3-dioxo-2,3-dihydro-1H-
benzo[de]isoquinolin-6-ylamino)hexyl)-4-(4-(3,3-diphenylallyl)piper-
azin-1-yl)benzamide (9a). Orange red solid. Yield: 60%; m.p. 85.6–
87.6 ꢁC; 1H NMR (DMSO-d6, 400 MHz) dH: 8.69 (d, J ¼ 8.4 Hz, 1H,
Ar–H), 8.40 (d, J ¼ 7.2 Hz, 1H, Ar–H), 8.23 (d, J ¼ 8.8 Hz, 1H, Ar–H),
8.14 (t, J ¼ 5.2 Hz, 1H, Ar–H), 7.74 (t, J ¼ 4.2 Hz, 1H, Ar–H), 7.70–7.62
(m, 3H, Ar–H), 7.41 (t, J ¼ 7.2 Hz, 2H, Ar–H), 7.35–7.22 (m, 4H, Ar–H),
7.21–7.19 (m, 2H, Ar–H), 7.14–7.12 (m, 2H, Ar–H), 6.88 (d, J ¼ 8.8 Hz,
2H, Ar–H), 6.72 (d, J ¼ 8.8 Hz, 1H, Ar–H), 6.18 (t, J ¼ 6.4 Hz, 1H,
C]CH), 4.10 (t, J ¼ 7.2 Hz, 2H, CH2N), 3.35 (d, J ¼ 6.4 Hz, 2H,
CONHCH2), 3.24–3.21 (m, 6H, CH2NCH2 and NHCH2), 3.00 (d,
J ¼ 6.8 Hz, 2H, NCH2CH), 2.46–2.45 (m, 6H, CH2NCH2 and
CH2N(CH3)2), 2.18 (s, 6H, N(CH3)2), 1.71–1.65 (m, 2H, CH2), 1.55–1.51
(m, 2H, CH2), 1.50–1.42 (m, 4H, CH2CH2); 13C NMR (DMSO-d6,
100 MHz) dC: 166.24, 164.21, 163.32, 153.03, 151.13, 143.62, 142.04,
139.62, 134.77, 131.11, 129.92, 129.85, 129.08, 128.80, 128.75, 127.77,
127.37, 126.76, 124.62, 124.42, 122.26, 120.55, 113.95, 107.87, 104.19,
57.12, 52.98, 47.69, 45.82, 43.25, 29.73, 28.26, 26.83, 26.73; FTIR
(KBr, cmꢀ1): 3280, 3044, 2925, 2844, 1680, 1639, 1576, 1543, 1502,
1450, 1391, 1361, 1290, 1238, 1120, 1005, 771, 695; HRMS (ESþ)
calcd for C48H55N6O3 ([M þ H])þ 763.4336, found 763.4332.
4.1.2.5. 6-(6-(Bis(3,3-diphenylallyl)amino)hexylamino)-2-(2-(dimethy-
lamino)ethyl)-1H-benzo[de]isoquinoline-1,3(2H)-dione (9b). Viscous
orange solid. Yield: 85%; m.p. 76.8–78.8 ꢁC; 1H NMR (CD3COCD3,
400 MHz) dH: 8.56 (dd, J1 ¼0.8 Hz, J2 ¼ 8.4 Hz, 1H, Ar–H), 8.46 (dd,
J1 ¼1.2 Hz, J2 ¼ 7.6 Hz, 1H, Ar–H), 8.34 (d, J ¼ 8.8 Hz, 1H, Ar–H),
7.61 (dd, J1 ¼1.2 Hz, J2 ¼ 8.4 Hz, 1H, Ar–H), 7.39–7.31 (m, 6H, Ar–
H), 7.26–7.22 (m, 6H, Ar–H), 7.17–7.13 (m, 8H, Ar–H), 6.97 (t,