Synthesis and structure - Active relationship of 1-aryl-6,7-dimethoxy-1,2, 3,4-tetrahydroisoquinoline anticonvulsants

Article abstract of DOI:10.1248/cpb.58.1602

We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticonvulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported analogues. This novel series of isoquinolines was designed on the basis of well defined structure-active relationship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2) mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-1-(4′-methylphenyl)-6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline (6d) that displayed significant anticonvulsant activity. Computational studies helped to rationalize these obtained pharmacological results.

Full text of DOI:10.1248/cpb.58.1602

1602
Regular Article
Chem. Pharm. Bull. 58(12) 1602—1605 (2010)
Vol. 58, No. 12
Synthesis and Structure–Active Relationship of 1-Aryl-6,7-dimethoxy-
1,2,3,4-tetrahydroisoquinoline Anticonvulsants
Rosaria GITTO, ,a Laura DE LUCA,a Stefania FERRO,a Stefano AGNELLO,a Emilio RUSSO,b
*
a
Giovanbattista DE SARRO,b and Alba CHIMIRRI
b
a Dipartimento Farmaco-Chimico, Università di Messina; Viale Annunziata, 98168 Messina, Italy: and Dipartimento di
Medicina Sperimentale e Clinica, Università Magna Græcia; Viale Europa-Germaneto, 88100 Catanzaro, Italy.
Received July 20, 2010; accepted September 1, 2010; published online September 3, 2010
We have previously disclosed that some 6,7-dimethoxyisoquinoline derivatives are able to produce anticon-
vulsant effects in different animal models of epilepsy. Following these studies this paper describes the synthesis of
a small series of new 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines strictly related to previously reported
analogues. This novel series of isoquinolines was designed on the basis of well defined structure–active relation-
ship (SAR) information already acquired for this class of anticonvulsant agents. The pharmacological effects of
the new synthesized compounds were evaluated against audiogenic seizures in Dilute Brown non-Agouti (DBA/2)
mice. The preliminary pharmacological screening led to the identification of a new active molecule the 2-acetyl-
1-(4؅-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6d) that displayed significant anticonvulsant
activity. Computational studies helped to rationalize these obtained pharmacological results.
Key words isoquinoline; anticonvulsant; Dilute Brown non-Agouti mouse; molecular modeling
Epilepsy is commonly considered the result of an imbal- (AMPAR) subtype in a selective and non-competitive fash-
ance between excitatory and inhibitory “tone” leading to pe- ion.11—20) The most active compound of the series was the 2-
riodic and unpredictable seizures related to an abnormal dis- acetyl-1-(4Ј-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
charge of cerebral neurons. Epilepsy is one of the most com- droisoquinoline (1, Fig. 1) which showed both in in vivo and
mon neurological disorders, affecting ca. 1% of the popula- in vitro tests activity stronger than other known AMPAR an-
tion worldwide, and the incidence increases to 3% by the age tagonists such as GYKI 52466, talampanel, and CFM-2 (Fig.
of 75 years. Although most people become seizure-free with 1).17,21,22)
drug therapy, there is still a significant number of patients
Starting from the “lead compound” 1, in several previous
(30%) who are resistant to the currently available antiepilep- studies, we examined a large series of its analogues and re-
tic drugs whether used alone or in combination. The patho- ported a comprehensive structure–active relationship (SAR)
physiology of epilepsy is complex and several mechanisms studies concerning the influence of specific substituents on
play a role in epileptogenesis and epileptogenicity.1) The effi- tetrahydroisoquinoline skeleton; we found that the most ac-
cacy of anticonvulsant drugs may be connected with different tive derivatives are generally characterized by the presence of
molecular targets to reduce the excitability of neurons in- 2-acetyl substituent; moreover two methoxy substituents on
volved in seizure onset.2) The mechanism of action of cur- the benzene fused ring are crucial to produce pharmacologi-
rently available effective antiepileptics are: a) the induction cal effects.19) Furthermore our investigations suggested that
of a prolonged inactivation of the Naϩ channel; b) the block- the introduction of hydrophobic substituents at 4Ј-position of
ade of Ca2ϩ channel currents; c) the enhancement of the in- C-1 phenyl moiety (e.g. halogen atoms) could improve the
hibitory g-aminobutyrate (GABA)ergic neurotransmission or anticonvulsant efficacy against sound-induced seizures in
the modulation of excitatory glutamatergic neurotransmis- Dilute Brown non-Agouti (DBA/2) mice. These experimental
sion.3) With respect to this last pharmacological target, exten- evidences were confirmed by our computational studies in
sive studies have demonstrated that competitive and non- which we developed a 3-D pharmacophore model for non-
competitive antagonists of the ionotropic glutamate receptors competitive AMPAR antagonists.15) Herein we report the
(iGluRs) show promise in terms of their therapeutic potential synthetic approach and the preliminary anticonvulsant
for the prevention and treatment of the epilepsy.3—10)
screening in DBA/2 mice with the aim to explore other sub-
In our previous works, some isoquinoline derivatives were stitutions at the C-1 phenyl group and so to find new anticon-
found to have anticonvulsant activities in various seizure vulsant isoquinolines deepening SAR studies. Finally, we
models interacting with glutamate ionotropic a-amino-3-hy- tried to rationalize our findings by use a computational
droxyl-5-methyl-4-isoxazole propionate (AMPA) receptor approach.
Results and Discussion
As depicted in Chart 1 a small series of 2-acetyl-1-aryl-
6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives
(6a—f) was prepared following previously reported proce-
dures17,23) with slight modifications. In particular, we em-
ployed an efficient high-speed microwave-assisted synthetic
approach (Chart 1) optimizing the chemical yield and purity
Fig. 1. AMPA Receptor Antagonists as Anticonvulsant Agents
as well as greatly reducing the reaction times and solvent
∗ To whom correspondence should be addressed. e-mail: rgitto@unime.it
© 2010 Pharmaceutical Society of Japan

December 2010
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amount. In particular, in solvent-free conditions and starting azepines (GYKI 52466, CFM-2 and talampanel) as well as of
from amine 2 and suitable aldehyde 3a—f we prepared the other antiepileptic drugs such as gabapentin and valproate.25)
imine intermediates 4a—f which, in the same reactor, were
The biological results reported in Table 1 suggest that
transformed into 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroiso- these new synthesized compounds generally possess potency
quinolines (5a—f). Then compounds 5a—f were readily lower than “lead compound” 1.12,16) The analysis of ED50 val-
acetylated to give desired final compounds 6a—f. The struc- ues on clonic and tonic phases of the test (see Table 1) high-
tures of the obtained compounds were supported by elemen- lighted that the most active molecules of this new series of
tal analyses and spectroscopic measurements.
compounds were derivatives 5d and 6d bearing 4Ј-methyl
The anticonvulsant effects of the new 2-acetyl-1-aryl-6,7- substituent on C-1 phenyl ring. In particular, compound 6d
dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives (6a—f) exhibited an anticonvulsant potency better than that of GYKI
and the corresponding parent compounds 5a—f were evalu- 52466, the prototype of non-competitive AMPAR antagonists
ated against audiogenic seizures in DBA/2 mice, considered showing anticonvulsant efficacy. Moreover, the anticonvul-
an excellent animal model for generalized epilepsy and for sant effects of compound 6d were comparable to those of ac-
screening new anticonvulsant drugs.24) Table 1 reports the tive 2,3-benzodiazepine derivatives CFM-2 and talampanel,
pharmacological results for compounds 5a—f and 6a—f which has already undergone phase 1 and 2 trials for refrac-
compared with those of known non-competitive AMPA re- tory epilepsy, as well as amyotrophic lateral sclerosis and
ceptor antagonists such as isoquinoline 1 and 2,3-benzodi- Parkinson disease.21,22) It is interesting to note that in this ex-
perimental model of epilepsy the observed activity of com-
pound 6d exceeded that of valproate and gabapentin, two
drugs largely used in antiepileptic therapy. On the basis of
calculation of Log D7.4,26) predicted from a commercially
available program (advanced chemistry development/Lab),
we hypothesized that the hydrophobic character of methyl
substituent could positively contribute to the blood–brain
barrier crossing thus improving the anticonvulsant efficacy.
But we also observed a discrepancy of the potency between
3Ј-methyl-substituted derivative 6c and 4Ј-methyl-substituted
derivative 6d, so we decided to superimpose these two com-
pounds in our 3-D pharmacophore model developed for non-
competitive AMPAR antagonists.15) According to the previ-
ous reported pharmacophoric hypothesis five structural mo-
Reagents and conditions: (i) MW, 5 min, 90 °C, 100 W; (ii) TFA, MW,
5 min, 90 °C, 280 W; (iii) Ac2O, MW, 5 min, 70 °C, 150 W.
Chart 1
tifs control AMPAR recognition process; they are two hydro-
Table 1. Anticonvulsant Activity against Audiogenic Seizures in DBA/2 Mice and Estimated Log D7.4 Values of Tested Isoquinolines (1, 5a—f, and 6a—f)
ED50 mg/kga)
b)
Compd.
R1
R2
Log D7.4
Clonus
Tonus
1
4-Cl
Ac
H
H
H
H
1.44 (0.77—1.02)
Ͼ35
0.42 (0.31—0.54)
Ͼ35
14.3 (9.67—21.1)
8.38 (5.20—13.4)
10.3 (7.98—13.3)
Ͼ35
24.0 (14.3—40.1)
19.4 (14.1—26.7)
11.8 (6.78—20.5)
Ͼ35
5.98 (3.93—9.07)
16.5 (12.1—22.6)
25.1 (21.4—29.6)
3.92 (2.49—5.91)
7.41 (4.69—11.7)
3.27 (2.36—4.52)
9.90 (7.81—12.6)
21.5 (16.1—28.7)
3.40
1.31
1.25
1.76
1.88
1.38
1.39
2.24
2.24
3.27
3.27
2.72
2.72
—
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
3-CN
4-CN
3-Me
4-Me
3-OMe
4-OMe
3-CN
4-CN
3-Me
4-Me
3-OMe
4-OMe
—
Ͼ35
15.5 (11.2—21.5)
13.7 (9.28—20.3)
Ͼ35
H
H
Ͼ35
Ac
Ac
Ac
Ac
Ac
Ac
—
—
—
—
—
32.3 (28.7—35.3)
31.7 (21.9—45.7)
Ͼ35
6.63 (4.09—10.7)
30.9 (24.6—38.9)
Ͼ35
4.66 (2.80—7.46)
10.5 (7.15—15.3)
4.51 (3.40—5.99)
20.3 (13.7—30.2)
Ͼ35
CFM-2
GYKI 52466
Talampanel
Gabapentin
Valproate
—
—
—
—
—
—
—
a) All data were calculated according to the method of Litchfield and Wilcoxon. At least 32 animals were used to calculate each ED50 95% confidence limits are given in
parentheses. b) Log D data at pHϭ7.4 are predicted from a commercially available program (ACD/Lab).26)

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Vol. 58, No. 12
Fig. 2. Alignments of Compounds 6d (A) and 6c (B) into the Pharmacophoric Hypothesis (Hydrogen Bond Acceptor, HBA1 and HBA2; Hydrophobic
Aromatic Region, HYAr; Hydrophobic Group, HY1 and HY2; Excluded Volumes, E1, E2, E3)
gen-bond acceptors (HBA), one hydrophobic aromatic region EtOH to afford 1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines (5a—
f).
(HYAr), and two hydrophobic region (HY); moreover, in this
1-(3Ј-Cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5a):
model we described three excluded volumes (E1—E3) as
forbidden areas. Figure 2A displays the alignment of the
Yield: 45%; mp 135—137 °C. Rfϭ0.61 (CHCl3/MeOH; 90 : 10). 1H-NMR
(CDCl3) d: 2.78—3.15 (4H, m, CH2CH2), 3.66 (3H, s, OCH3), 3.89 (3H, s,
most active derivative compound 6d revealing that all favor-
able chemical features were well matched by this molecule
and the 4Ј-methyl substituent fits the HY2 chemical feature;
on the contrary in the case of the less active compound 6c we
found that in its best alignment into pharmacophoric hypoth-
esis the HY2 feature was lacking (see Fig. 2B). Considering
that the low active pairs of C-3Ј and C-4Ј substituted 2-
acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
derivatives (6a and 6b, 6e and 6f) were unable to fit all re-
quested chemical features, their pharmacological efficacy
was unaffected by the substituent shift from C-4Ј to C-3Ј po-
sition.
In conclusion, we have identified a new active compound
(6d) which shows significant anticonvulsant activity. On the
basis of our pharmacological data as well as our molecular
modeling studies, we also suggest that a methyl group at the OCH3), 3.87 (3H, s, OCH3), 5.03 (1H, s, CH), 6.26 (1H, s, ArH), 6.62 (1H,
4-position of the C-1 phenyl ring is the best substituent for
OCH3), 5.08 (1H, s, CH), 6.16 (1H, s, ArH), 6.66 (1H, s, ArH), 7.43—7.59
(4H, m, ArH). Anal. Calcd for C18H18N2O2: C, 75.45; H, 6.16; N, 9.52.
Found: C, 75.41; H, 6.26; N, 9.33.
1-(4Ј-Cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (5b):
Yield: 46%; mp 217—219 °C. Rfϭ0.52 (CHCl3/MeOH; 90 : 10). 1H-NMR
(CDCl3) d: 2.85—3.18 (4H, m, CH2CH2), 3.63 (3H, s, OCH3), 3.90 (3H, s,
OCH3), 5.42 (1H, s, CH), 6.07 (1H, s, ArH), 6.67 (1H, s, ArH), 7.44 (2H, d,
Jϭ8.24, ArH), 7.68 (2H, d, Jϭ8.24, ArH). Anal. Calcd for C18H18N2O2: C,
75.45; H, 6.16; N, 9.52. Found: C, 75.55; H, 6.31; N, 9.43.
6,7-Dimethoxy-1-(3Ј-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (5c):
Yield: 52%; mp 109—111 C. Rfϭ0.39 (CHCl3/MeOH; 90 : 10). 1H-NMR
(CDCl3) d: 2.33 (3H, s, CH3), 2.77—3.24 (4H, m, CH2CH2), 3.65 (3H, s,
OCH3), 3.88 (3H, s, OCH3), 5.01 (1H, s, CH), 6.26 (1H, s, ArH), 6.63 (1H,
s, ArH), 7.01—7.23 (4H, m, ArH). Anal. Calcd for C18H21NO2: C, 76.30; H,
7.47; N, 4.94. Found: C, 76.50; H, 7.61; N, 4.63.
6,7-Dimethoxy-1-(4Ј-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (5d):
Yield: 72%; mp 140—142 °C. Rfϭ0.20 (CHCl3/MeOH; 90 : 10). 1H-NMR
(CDCl3) d: 2.34 (3H, s, CH3), 2.73—3.26 (4H, m, CH2CH2), 3.64 (3H, s,
s, ArH) 7.13—7.24 (4H, m, ArH). Anal. Calcd for C18H21NO2: C, 76.30; H,
7.47; N, 4.94. Found: C, 76.22; H, 7.34; N, 4.90.
6,7-Dimethoxy-1-(3Ј-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
anticonvulsant efficacy of this new small series of 2-acetyl-1-
aryl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolines.
(5e): Yield: 62%; mp 97—99 °C. Rfϭ0.43 (CHCl3/MeOH; 90 : 10). 1H-
NMR (CDCl3) d: 2.74—3.26 (4H, m, CH2CH2), 3.65 (3H, s, OCH3), 3.78
(3H, s, OCH3) 3.88 (3H, s, OCH3), 5.02 (1H, s, CH), 6.28 (1H, s, ArH), 6.63
(1H, s, ArH) 6.80—7.27 (4H, m, ArH). Anal. Calcd for C18H21NO3: C,
72.22; H, 7.07; N, 4.68. Found: C, 72.42; H, 7.11; N, 4.70.
Experimental
Chemistry All starting materials and reagents commercially available
(Sigma-Aldrich Milan, Italy) were used without further purification. Mi-
crowave-assisted reactions were carried out in a CEM focused Microwave
Synthesis System. Melting points were determined on a Stuart SMP10 appa-
ratus and are uncorrected. Elemental analyses (C, H, N) were carried out on
a Carlo Erba Model 1106 Elemental Analyzer and the results are within
Ϯ0.4% of the theoretical values. Merck silica gel 60 F254 plates were used
for analytical TLC. Rfϭvalues were determined employing TLC plates and
using a CHCl3/MeOH mixture as eluent. 1H- and 13C-NMR spectra were
measured in CDCl3 with a Varian Gemini 300 spectrometer; chemical shifts
are expressed in d (ppm) relative to tetramethyl silane (TMS) as internal
standard and coupling constants (J) in Hz. All exchangeable protons were
confirmed by addition of deuterium oxide (D2O).
6,7-Dimethoxy-1-(4Ј-methoxyphenyl)-1,2,3,4-tetrahydroisoquinoline
(5f): Yield: 40%; mp 94—96 °C. Rfϭ0.25 (CHCl3/MeOH; 90 : 10). 1H-
NMR (CDCl3) d: 2.71—3.24 (4H, m, CH2CH2), 3.65 (3H, s, OCH3), 3.81
(3H, s, OCH3) 3.87 (3H, s, OCH3), 5.01 (1H, s, CH), 6.25 (1H, s, ArH), 6.62
(1H, s, ArH), 6.85 (2H, d, Jϭ8.51, ArH) 7.17 (2H, d, Jϭ8.51, ArH). 13C-
NMR (CDCl3) d: 29.4 and 41.0 (C-3 and C-4), 54.8 (OCH3), 55.9 (OCH3),
56.8 (OCH3), 60.3 (C-1) 111.0 and 111.9 (C-5 and C-8), 114.8 (C-3Ј,5Ј),
125.7 and 126.0 (C-4a and C-8a), 129.3 (C-2Ј,6Ј), 135.8 (C-1Ј), 147.5 and
148.8 (C-6, C-7), 158.1 (C-4Ј). Anal. Calcd for C18H21NO3: C, 72.22; H,
7.07; N, 4.68. Found: C, 72.34; H, 7.00; N, 4.61.
General Procedure for the Synthesis of 2-Acetyl-1-aryl-6,7-di-
methoxy-1,2,3,4-tetrahydroisoquinolines (6a—f) A solution of isoquino-
line derivative (5a—f) (1 mmol) in Ac2O (1 ml) was irradiated in a mi-
crowave oven at 150 W for 5 min at 70 °C; after cooling the reaction was
quenched by adding water and extracted with ethyl acetate (3ϫ5 ml). The
organic layer was dried over Na2SO4, and the solvent was removed until dry-
ness under reduced pressure. The oil residue was powdered with diethylether
and crystallized with EtOH to give 2-acetyl-1-aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline derivatives 6a—f.
General Procedure for the Synthesis of 1-Aryl-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinolines (5a—f)
A mixture of 2-(3Ј,4Ј-dimethoxy-
phenyl)ethylamine (2) (1.0 mmol) and suitable benzaldehyde derivative 3a—
f (1.2 mmol) was placed in a cylindrical quartz tube (f 2 cm), then stirred
and irradiated in a microwave oven at 100 W for 5 min at 90 °C; after cool-
ing to room temperature trifluoroacetic acid (2 ml) was added and the mix-
ture was irradiated at 280 W for 5 min at 90 °C. The reaction was quenched
by adding water, and the mixture was basified (pHϷ8—9) with sodium hy-
droxide (2 M aqueous) to give a solid. The crude product was powdered by
treatment with diethyl ether, filtered and purified by crystallization with
2-Acetyl-1-(3Ј-cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (6a): Yield 88%; mp 205—207 °C. Rfϭ0.74 (CHCl3/MeOH; 98 : 2). 1H-

December 2010
1605
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 guidelines
and the European Council Directive of laws and policies.20)
NMR (CDCl3) d: 2.19 (3H, s, CH3), 2.79—3.84 (4H, m, CH2CH2), 3.77
(3H, s, OCH3), 3.91 (3H, s, OCH3), 6.46 (1H, s, CH), 6.69 (1H, s, ArH),
6.87 (1H, s, ArH), 7.40—7.51 (4H, m, ArH). Anal. Calcd for C20H20N2O3:
C, 71.41; H, 5.99; N, 8.33. Found: C, 71.33; H, 5.80; N, 8.62.
Statistical Analysis Statistical comparisons between groups of control
and drug-treated animals were made using Fisher’s exact probability test (in-
cidence of the seizure phases). The ED50 values of each phase of audiogenic
seizures was determined for each dose of compound administered, and
dose–response curves were fitted using a computer program by Litchfield
and Wilcoxon’s method.27)
2-Acetyl-1-(4Ј-cyanophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (6b): Yield: 69%; mp 96—98 °C. Rfϭ0.66 (CHCl3/MeOH; 98 : 2). H-
1
NMR (CDCl3) d: 2.18 (3H, s, CH3), 2.72—3.72 (4H, m, CH2CH2), 3.76
(3H, s, OCH3), 3.89 (3H, s, OCH3), 6.46 (1H, s, CH), 6.68 (1H, s, ArH),
6.87 (1H, s, ArH), 7.36 (2H, d, Jϭ8.34, ArH), 7.57 (2H, d, Jϭ8.34 Hz,
ArH). 13C-NMR (CDCl3) d: 21.4 (CH3), 31.4 and 42.0 (C-3 and C-4), 53.3
(C-1), 55.8 (OCH3), 56.4 (OCH3), 110.9 and 111.9 (C-5 and C-8), 112.3
(CN), 118.9 (C-4Ј), 125.7 and 126.0 (C-4a and C-8a), 129.9 (C-2Ј,6Ј), 132.7
(C-3Ј,5Ј), 146.9 (C-1Ј), 148.3 and 149.2 (C-6 and C-7), 168.2 (CO). Anal.
Calcd for C20H20N2O3: C, 71.41; H, 5.99; N, 8.33. Found: C, 71.66; H, 5.90;
N, 8.30.
Acknowledgments Financial support for this research by MiUR
(Prin2008, grant number No. 20085HR5JK_002) is gratefully acknowl-
edged.
References
2-Acetyl-1-(3Ј-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (6c): Yield: 60%; mp 167—169 °C. Rfϭ0.63 (CHCl3/MeOH; 98 : 2).
1H-NMR (CDCl3) d: 2.17 (3H, s, CH3), 2.30 (3H, s, CH3), 2.77—3.71 (4H,
m, CH2CH2), 3.76 (3H, s, OCH3), 3.90 (3H, s, OCH3), 6.52 (1H, s, CH),
6.66 (1H, s, ArH), 6.86 (1H, s, ArH), 6.97—7.16 (4H, m, ArH). Anal. Calcd
for C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 73.60; H, 7.22; N,
4.26.
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2-Acetyl-1-(4Ј-methylphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line (6d): Yield: 58%; mp 184—186 °C. Rfϭ0.50 (CHCl3/MeOH; 98 : 2).
1H-NMR (CDCl3) d: 2.16 (3H, s, CH3), 2.32 (3H, s, CH3), 2.72—3.68 (4H,
m, CH2CH2), 3.75 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.51 (1H, s, CH),
6.65 (1H, s, ArH), 6.86 (1H, s, ArH), 7.07—7.15 (4H, m, ArH). 13C-NMR
(CDCl3) d: 21.3 (COCH3), 24.3 (CH3) 31.5 and 42.0 (C-3 and C-4), 55.3 (C-
1), 55.8 (OCH3), 56.4 (OCH3), 110.9 and 111.7 (C-5 and C-8), 125.8 and
126.5 (C-4a and C-8a), 127.9 (C-2Ј,6Ј), 129.7 (C-3Ј,5Ј), 138.2 (C-1Ј), 139.0
(C-4Ј), 148.3 and 149.2 (C-6 and C-7), 168.2 (CO). Anal. Calcd for
C20H23NO3: C, 73.82; H, 7.12; N, 4.30. Found: C, 74.00; H, 7.15; N, 4.31.
2-Acetyl-1-(3Ј-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (6e): Yield: 61%; mp 187—189 °C. Rfϭ0.31 (CHCl3/MeOH;
98 : 2). 1H-NMR (CDCl3) d: 2.17 (3H, s, CH3), 2.71—3.69 (4H, m,
CH2CH2), 3.76 (3H, s, OCH3), 3.76 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.53
(1H, s, CH), 6.65 (1H, s, ArH), 6.61—7.22 (5H, m, ArH). 13C-NMR
(CDCl3) d: 21.4 (COCH3), 31.4 and 42.3 (C-3 and C-4), 54.8 (OCH3), 55.6
(OCH3), 56.7 (OCH3), 57.1 (C-1), 110.2 and 111.8 (C-5 and C-8), 112.0 (C-
2Ј), 112.8 (C-4Ј), 120.9 and 132.7 (C-5Ј,6Ј), 125.7 and 126.0 (C-4a and C-
8a), 146.7 (C-1Ј), 148.2 and 149.4 (C-6 and C-7), 162.0 (C-3Ј) 168.5 (CO).
Anal. Calcd for C20H23NO4: C, 70.63; H, 6.79; N, 4.10. Found: C, 70.68; H,
6.66; N, 4.45.
2-Acetyl-1-(4Ј-methoxyphenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (6f): Yield: 66%; mp 107—109 °C. Rfϭ0.33 (CHCl3/MeOH;
98 : 2). 1H-NMR (CDCl3) d: 2.16 (3H, s, CH3), 2.69—3.65 (4H, m,
CH2CH2), 3.75 (3H, s, OCH3), 3.78 (3H, s, OCH3), 3.89 (3H, s, OCH3), 6.51
(1H, s, CH), 6.65 (1H, s, ArH), 6.79 (1H, s, ArH), 6.82 (2H, d, Jϭ8.44 Hz,
ArH), 7.17 (2H, d, Jϭ8.44 Hz, ArH). Anal. Calcd for C20H23NO4: C, 70.63;
H, 6.79; N, 4.10. Found: C, 70.70; H, 6.60; N, 4.31.
Pharmacology. Testing of Anticonvulsant Activity All experiments
were performed with DBA/2 mice which are genetically susceptible to
sound-induced seizures. DBA/2 mice (8—12 g; 21—25-d-old) were pur-
chased from Harlan Italy (Corezzana, Italy). Groups of 10 mice of either sex
were exposed to auditory stimulation 30 min following administration of ve-
hicle or each dose of drugs studied. The compounds were given intraperi-
toneally (i.p.) (0.1 ml/10 g of body weight of the mouse) as a freshly-pre-
pared 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 were 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 response 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
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