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2383
CH3O-7), 6.49 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.76 (s,
1H, H-8), 7.28–7.30 (m, 5H, Ar). Anal. (C24H28N2O4)
C, H, N.
CH2), 2.72–3.64 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.90 (s, 3H, CH3O-7), 6.49 (s, 1H, H-1), 6.66 (s, 1H,
H-5), 6.77 (s, 1H, H-8), 7.21–7.30 (m, 5H, Ar). Anal.
(C23H26N2O4) C, H, N.
4.1.7. 1-(4-Bromophenyl)-6,7-dimethoxy-2-[oxo(piperi-
din-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (22). Mp
94–96 °C. Yield 48%. H NMR: d 1.18–1.60 (m, 6H,
CH2), 2.69–3.65 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.89 (s, 3H, CH3O-7), 6.44 (s, 1H, H-1), 6.65 (s, 1H,
H-5), 6.70 (s, 1H, H-8), 7.16 (d, 2H, J = 8.5, H20–H60),
7.43 (d, 2H, J = 8.5, H30–H50). Anal. (C24H27BrN2O4)
C, H, N.
4.1.15. 1-(4-Bromophenyl)-6,7-dimethoxy-2-[oxo(pyrroli-
din-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (30). Mp
97–99 °C. Yield 46%. H NMR: d 1.42–1.91 (m, 4H,
CH2), 2.69–3.66 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.89 (s, 3H, CH3O-7), 6.45 (s, 1H, H-1), 6.66 (s, 1H,
H-5), 6.72 (s, 1H, H-8), 7.17 (d, 2H, J = 8.0, H20–H60),
7.43 (d, 2H, J = 8.0, H30–H50). Anal. (C23H25BrN2O4)
C, H, N.
1
1
4.1.8. 1-(4-Chlorophenyl)-6,7-dimethoxy-2-[oxo(piperi-
din-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (23). Mp
88–90 °C. Yield 47%. H NMR: d 1.25–1.64 (m, 6H,
CH2), 2.70–3.65 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.90 (s, 3H, CH3O-7), 6.44 (s, 1H, H-1), 6.65 (s, 1H,
H-5), 6.72 (s, 1H, H-8), 7.22 (d, 2H, J = 8.2, H20–H60),
7.29 (d, 2H, J = 8.2, H30–H50). Anal. (C24H27ClN2O4)
C, H, N.
4.1.16. 1-(4-Chlorophenyl)-6,7-dimethoxy-2-[oxo(pyrroli-
din-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (31). Mp
91–93 °C. Yield 45%. H NMR: d 1.43–1.93 (m, 4H,
CH2), 2.70–3.65 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.89 (s, 3H, CH3O-7), 6.45 (s, 1H, H-1), 6.67 (s, 1H, H-
5), 6.73 (s, 1H, H-8), 7.21 (d, 2H, J = 8.2, H20–H60), 7.30
(d, 2H, J = 8.2, H30–H50). Anal. (C23H25ClN2O4) C, H, N.
1
1
4.1.9. 1-(4-Fluorophenyl)-6,7-dimethoxy-2-[oxo(piperidin-
1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (24). Mp 140–
142 °C. Yield 46%. 1H NMR: d 1.25–1.62 (m, 6H,
CH2), 2.70–3.60 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.89 (s, 3H, CH3O-7), 6.45 (s, 1H, H-1), 6.65 (s, 1H,
H-5), 6.73 (s, 1H, H-8), 6.96–7.01 (m, 4H, Ar). Anal.
(C24H27FN2O4) C, H, N.
4.1.17. 1-(4-Fluorophenyl)-6,7-dimethoxy-2-[oxo(pyrroli-
din-1-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline (32). Mp
76–78 °C. Yield 43%. H NMR: d 1.42–1.91 (m, 4H,
CH2), 2.76–3.65 (m, 8H, CH2), 3.75 (s, 3H, CH3O-6),
3.89 (s, 3H, CH3O-7), 6.46 (s, 1H, H-1), 6.66 (s, 1H,
H-5), 6.74 (s, 1H, H-8), 6.99–7.28 (m, 4H, Ar). Anal.
(C23H25FN2O4) C, H, N.
1
4.1.10. 6,7-Dimethoxy-2-[morpholin-4-yl(oxo)acetyl]-1-
phenyl-1,2,3,4-tetrahydroisoquinoline (25). Mp 153–
155 °C. Yield 51%. 1H NMR: d 2.73–3.71 (m, 12H,
CH2), 3.75 (s, 3H, CH3O-6), 3.90 (s, 3H, CH3O-7),
6.48 (s, 1H, H-1), 6.67 (s, 1H, H-5), 6.76 (s, 1H, H-8),
7.25–7.31 (m, 5H, Ar). Anal. (C23H26N2O5) C, H, N.
4.2. Pharmacology
4.2.1. Testing of anticonvulsant activity. All experiments
were performed with DBA/2 mice which are genetically
susceptible to sound-induced seizures.20 DBA/2 mice (8–
12 g; 22 to 25 days old) were purchased from Harlan
Italy (Corezzano, Italy). Groups of 10 mice of either
sex were exposed to auditory stimulation 30 min follow-
ing administration of vehicle or each dose of drugs stud-
ied. The compounds were given intraperitoneally (ip)
(0.1 mL/10 g of body weight of the mouse) as a freshly
prepared solution in 50% dimethylsulfoxide (DMSO)
and 50% sterile saline (0.9% NaCl). Individual mice were
placed under a hemispheric perspex dome (diameter
58 cm), and 60 s was allowed for habituation and assess-
ment of locomotor activity. Auditory stimulation (12–
16 kHz, 109 dB) was applied for 60 s or until tonic
extension occurred, and induced a sequential seizure re-
sponse in control DBA/2 mice, consisting of an early
wild running phase, followed by generalized myoclonus
and tonic flexion and extension sometimes followed by
respiratory arrest. The control and drug-treated mice
were scored for latency to and incidence of the different
phases of the seizures. The experimental protocol and all
the procedures involving animals and their care were
conducted in conformity with the Institutional Guide-
lines and the European Council Directive of laws and
policies.
4.1.11. 1-(4-Bromophenyl)-6,7-dimethoxy-2-[morpholin-
4-yl(oxo)acetyl]-1,2,3,4-tetrahydroisoquinoline (26). Mp
161–163 °C. Yield 53%. 1H NMR: d 2.72–3.72 (m,
12H, CH2), 3.75 (s, 3H, CH3O-6), 3.90 (s, 3H, CH3O-
7), 6.43 (s, 1H, H-1), 6.66 (s, 1H, H-5), 6.69 (s, 1H, H-
8), 7.16 (d, 2H, J = 8.2, H20–H60), 7.43 (d, 2H, J = 8.5,
H30–H50). Anal. (C23H25BrN2O5) C, H, N.
4.1.12. 1-(4-Chlorophenyl)-6,7-dimethoxy-2-[morpholin-
4-yl(oxo)acetyl]-1,2,3,4-tetrahydroisoquinoline (27). Mp
1
99–100 °C. Yield 52%. H NMR: d 2.76–3.72 (m, 12H,
CH2), 3.75 (s, 3H, CH3O-6), 3.89 (s, 3H, CH3O-7),
6.43 (s, 1H, H-1), 6.65 (s, 1H, H-5), 6.81 (s, 1H, H-8),
7.25 (d, 2H, J = 8.5, H20–H60), 7.29 (d, 2H, J = 8.5,
H30–H50). Anal. (C23H25ClN2O5) C, H, N.
4.1.13. 1-(4-Fluorophenyl)-6,7-dimethoxy-2-[morpholin-4-
yl(oxo)acetyl]-1,2,3,4-tetrahydroisoquinoline (28). Mp
191–193 °C. Yield 48%. 1H NMR: d 2.73–3.72 (m, 12H,
CH2), 3.75 (s, 3H, CH3O-6), 3.90 (s, 3H, CH3O-7), 6.45
(s, 1H, H-1), 6.66 (s, 1H, H-5), 6.69 (s, 1H, H-8), 6.73–
7.27 (m, 4H, Ar). Anal. (C23H25FN2O5) C, H, N.
4.2.2. Statistical analysis. Statistical comparisons be-
tween groups of control and drug-treated animals were
made using Fisher’s exact probability test (incidence of
the seizure phases). The ED50 values of each phase of
4.1.14. 6,7-Dimethoxy-2-[oxo(pyrrolidin-1-yl)acetyl]-1-
phenyl-1,2,3,4-tetrahydroisoquinoline (29). Mp 114–
116 °C. Yield 42%. 1H NMR: d 1.43–1.92 (m, 4H,