January 2010
N-Substituted Isoquinoline Derivatives as Potential AChE Inhibitors
59
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(3-fluorobenzyl)piperazin-1-yl]ethanone (14). Mp 88–90ꢁC,
yield 63%. 1H NMR (d, ppm, in CDCl3): 2.49–2.55 (m, 8H,
CH2), 2.76–2.86 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.47–3.49
(m, 2H, CH2), 3.76–3.82 (m, 2H, CH2), 3.85 (s, 3H, CH3O),
3.87 (s, 3H, CH3O), 4.65–4.68 (m, 2H, CH2), 6.61 (s, 1H,
ArH), 6.63 (s, 1H, ArH), 6.94–7.25 (m, 4H, ArH). Anal. Calcd
for C24H30FN3O3: C, 67.43; H, 7.07; N, 9.83. Found: C,
67.68; H, 7.11; N, 9.53.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(4-fluorobenzyl)piperazin-1-yl]ethanone (15). Mp 95–96ꢁC,
yield 72%. 1H NMR (d, ppm, in DMSO-d6): 2.34–2.47 (m,
8H, CH2), 2.64–2.76 (m, 2H, CH2), 3.19 (s, 2H, CH2), 3.37–
3.41 (m, 2H, CH2), 3.58–3.62 (m, 2H, CH2), 3.69 (s, 3H,
CH3O), 3.70 (s, 3H, CH3O), 4.48–4.61 (m, 2H, CH2), 6.72 (s,
1H, ArH), 6.75 (s, 1H, ArH), 7.09–7.32 (m, 4H, ArH). Anal.
Calcd for C24H30FN3O3: C, 67.43; H, 7.07; N, 9.83. Found: C,
67.52; H, 7.02; N, 9.77.
2-[4-(4-t-Butylbenzyl)piperazin-1-yl]-1-[3,4-dihydro-6,7-
dimethoxyisoquinolin-2(1H)-yl]ethanone (21). Mp 97–
99ꢁC, yield 80%. 1H NMR (d, ppm, in DMSO-d6): 1.29 (s,
9H, CH3), 2.41–2.47 (m, 8H, CH2), 2.70–2.81 (m, 2H, CH2),
3.15 (s, 2H, CH2), 3.36–3.57 (m, 4H, CH2), 3.70 (s, 6H,
CH3O), 4.50–4.55 (m, 2H, CH2), 6.77–6.82 (m, 2H, ArH),
7.46–7.53 (m, 4H, ArH). Anal. Calcd for C28H39N3O3: C,
72.23; H, 8.44; N, 9.02. Found: C, 72.47; H, 8.62; N, 9.14.
2-[4-(3,4-Dichlorobenzyl)piperazin-1-yl]-1-[3,4-dihydro-6,
7-dimethoxyisoquinolin-2(1H)-yl]ethanone (22). Mp 78–
1
80ꢁC, yield 34%. H NMR (d, ppm, in CDCl3): 2.41–2.55 (m,
8H, CH2), 2.76–2.84 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.44 (s,
2H, CH2), 3.75–3.82 (m, 2H, CH2), 3.85 (s, 3H, CH3O), 3.87
(s, 3H, CH3O), 4.64–4.67 (m, 2H, CH2), 6.62 (s, 1H, ArH),
6.63 (s, 1H, ArH), 7.14–7.42 (m, 3H, ArH). Anal. Calcd for
C24H29 Cl2N3O3: C, 60,25; H, 6.11; N, 8.78. Found: C, 60.32;
H, 6.06; N, 8.90.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(3-methylbenzylpiperazin-1-yl]ethanone (16). Mp 139–
2-[4-(2-Chloro-6-fluorobenzyl)piperazin-1-yl]-1-[3,4-dihydro-
6,7-dimethoxyisoquinolin-2(1H)-yl]ethanone (23). Mp 78–
1
141ꢁC, yield 55%. H NMR (d, ppm, in CDCl3): 2.34 (s, 3H,
1
80ꢁC, yield 71%. H NMR (d, ppm, in CDCl3): 2.53–2.57 (m,
CH3), 2.50–2.55 (m, 8H, CH2), 2.76–2.84 (m, 2H, CH2), 3.26
(s, 2H, CH2), 3.45 (s, 2H, CH2), 3.76–3.82 (m, 2H, CH2), 3.85
(s, 3H, CH3O), 3.87 (s, 3H, CH3O), 4.64–4.67 (m, 2H, CH2),
6.61 (s, 1H, ArH), 6.63 (s, 1H, ArH), 7.05–7.20 (m, 4H, ArH).
Anal. Calcd for C25H33N3O3: C, 70.89; H, 7.85; N, 9.92.
Found: C, 70.63; H, 7.71; N, 10.12.
8H, CH2), 2.74-2.86 (m, 2H, CH2), 3.23 (s, 2H, CH2), 3.69 (s,
2H, CH2), 3.70-3.81 (m, 2H, CH2), 3.85 (s, 3H, OCH3), 3.87
(s, 3H, CH3O), 4.64-4.67 (m, 2H, CH2), 6.61 (s, 1H, ArH),
6.63 (s, 1H, ArH), 6.95-7.20 (m, 3H, ArH). Anal. Calcd for
C24H29ClFN3O3: C, 62.40; H, 6.33; N, 9.10. Found: C, 62.72;
H, 6.48; N, 9.21.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(4-methylbenzyl)piperazin-1-yl]ethanone (17). Mp 94ꢁC
dec, yield 69%. 1H NMR (d, ppm, in CDCl3): 2.34 (s, 3H,
CH3), 2.46–2.54 (m, 8H, CH2), 2.74–2.86 (m, 2H, CH2), 3.26
(s, 2H, CH2), 3.46 (s, 2H, CH2), 3.75–3.82 (m, 2H, CH2), 3.85
(s, 3H, CH3O), 3.87 (s, 3H, CH3O), 4.64 (s, 2H, CH2), 6.61 (s,
1H, ArH), 6.63 (s, 1H, ArH), 7.13–7.23 (m, 4H, ArH). Anal.
Calcd for C25H33N3O3: C, 70.89; H, 7.85; N, 9.92. Found: C,
70.73; H, 7.69; N, 9.75.
2-[4-(2,4-Difluorobenzyl)piperazin-1-yl]-1-[3,4-dihydro-6,
7-dimethoxyisoquinolin-2(1H)-yl]ethanone (24). Mp 100–
1
102ꢁC, yield 66%. H NMR (d, ppm, in DMSO-d6): 2.40–2.48
(m, 8H, CH2), 2.64–2.76 (m, 2H, CH2), 3.19 (s, 2H, CH2),
3.45–3.48 (m, 2H, CH2), 3.58–3.62 (m, 2H, CH2), 3.69 (s, 3H,
CH3O), 3.70 (s, 3H, CH3O), 4.48–4.61 (m, 2H, CH2), 6.72 (s,
1H, ArH), 6.75 (s, 1H, ArH), 7.14–7.22 (m, 3H, ArH). Anal.
Calcd for C24H29F2N3O3: C, 64.70; H, 6.56; N, 9.43. Found:
C, 67.59; H, 6.77; N, 9.31.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(4-methoxybenzyl)piperazin-1-yl]-ethanone (18). Mp 94ꢁC
dec, yield 69%. 1H NMR (d, ppm, in CDCl3): 2.46–2.53 (m,
8H, CH2), 2.76–2.83 (m, 2H, CH2), 3.25 (s, 2H, CH2), 3.44 (s,
2H, CH2), 3.71 (s, 3H, CH3O), 3.75–3.85 (m, 5H, CH2 and
CH3O) 3.86 (s, 3H, CH3O), 4.64–4.68 (m, 2H, CH2), 6.61 (s,
1H, ArH), 6.63 (s, 1H, ArH), 6.83–7.23 (m, 4H, ArH). Anal.
Calcd for C25H33N3O4: C, 68.31; H, 7.57; N, 9.56. Found: C,
68.54; H, 7.43; N, 9.48.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(3-trifluoromethylbenzyl)piperazin-1-yl]ethanone (19). Mp
101–103ꢁC, yield 77%. 1H NMR (d, ppm, in DMSO-d6):
2.41–2.48 (m, 8H, CH2), 2.62–2.78 (m, 2H, CH2), 3.20 (s, 2H,
CH2), 3.50–3.53 (m, 2H, CH2), 3.57–3.62 (m, 2H, CH2), 3.69
(s, 3H, CH3O), 3.70 (s, 3H, CH3O), 4.48–4.62 (m, 2H, CH2),
6.71 (s, 1H, ArH), 6.75 (s, 1H, ArH), 7.57–7.61 (m, 4H, ArH).
Anal. Calcd for C25H30F3N3O3: C, 62.88; H, 6.33; N, 8.80.
Found: C, 62.71; H, 6.46; N, 8.94.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-(2,
4,6-trimethylbenzyl)piperazin-1-yl]ethanone (25). Mp 99–
101ꢁC, yield 78%. 1H NMR (d, ppm, in DMSO-d6): 2.17 (s,
3H, CH3), 2.26 (s, 6H, CH3), 2.34–2.44 (m, 8H, CH2), 2.64–
2.78 (m, 2H, CH2), 3.16 (s, 2H, CH2), 3.36 (s, 2H, CH2),
3.60–3.65 (m, 2H, CH2), 3.69 (s, 3H, CH3O), 3.70 (s, 3H,
CH3O), 4.62 (s, 2H, CH2), 6.71–6.77 (m, 4H, ArH). Anal.
Calcd for C27H37N3O3: C, 71.81; H, 8.26; N, 9.30. Found: C,
72.01; H, 8.33; N, 9.16.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-(4-phe-
nethylpiperazin-1-yl]ethanone (26). Mp 88–90ꢁC, yield 88%.
1H NMR (d, ppm, in CDCl3): 2.59–2.84 (m, 14H, CH2), 3.28
(s, 2H, CH2), 3.78–3.87 (m, 8H, CH2 and CH3O), 4.65–4.69
(m, 2H, CH2), 6.58–6.62 (m, 2H, ArH), 7.26–7.28 (m, 5H,
ArH). Anal. Calcd for C25H33N3O3: C, 70.89; H, 7.85; N,
9.92. Found: C, 70.95; H, 7.67; N, 9.81.
2-(4-trans-Cinnamylpiperazin-1-yl)-1-[3,4-dihydro-6,7-di-
methoxyisoquinolin-2(1H)-yl]ethanone (27). Mp 147–149ꢁC,
yield 73%. 1H NMR (d, ppm, in DMSO-d6): 2.41–2.48 (m,
8H, CH2), 2.64–2.76 (m, 2H, CH2), 3.01–3.07 (m, 2H, CH2),
3.19 (s, 2H, CH2), 3.35–3.60 (m, 2H, CH2), 3.69 (s, 3H,
CH3O), 3.70 (s, 3H, CH3O), 4.48–4.62 (m, 2H, CH2), 6.23–
6.53 (m, 2H, CH¼¼CH), 6.71 (s, 1H, ArH), 6.75 (s, 1H, ArH),
7.18–7.42 (m, 5H, ArH). Anal. Calcd for C25H31N3O3: C,
71.70; H, 7.64; N, 9.65. Found: C, 71.83; H, 7.45; N, 9.53.
1-[3,4-Dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl]-2-[4-
(4-trifluoromethylbenzyl)piperazin-1-yl]ethanone (20). Mp
102–104ꢁC, yield 75%. 1H NMR (d, ppm, in DMSO-d6):
2.41–2.48 (m, 8H, CH2) 2.64–2.78 (m, 2H, CH2), 3.19 (s, 2H,
CH2), 3.49–3.53 (m, 2H, CH2), 3.60–3.67 (m, 2H, CH2), 3.69
(s, 3H, CH3O), 3.71 (s, 3H, CH3O), 4.48–4.62 (m, 2H, CH2),
6.71 (s, 1H, ArH), 6.75 (s, 1H, ArH), 7.48–7.68 (m, 4H, ArH).
Anal. Calcd for C25H30F3N3O3: C, 62.88; H, 6.33; N, 8.80.
Found: C, 62.96; H, 6.52; N, 8.67.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet