Isoquinoline derivatives. Synthesis and antiarrhythmic properties of 1-nitrophenyl-6,7-dimethoxy-4-spirocyclopentane-1,2,3,4-tetrahydroisoquinolines

Full text of DOI:10.1023/A:1010487331476

Pharmaceutical Chemistry Journal
Vol. 34, No. 12, 2000
SEARCH FOR NEW DRUGS
ISOQUINOLINE DERIVATIVES. SYNTHESIS AND ANTIARRHYTHMIC
PROPERTIES OF 1-NITROPHENYL-6,7-DIMETHOXY-4-
SPIROCYCLOPENTANE-1,2,3,4-TETRAHYDROISOQUINOLINES
É. A. Markaryan,1 Zh. S. Arustamyan,1 S. V. Avetisyan,1 K. Zh. Markaryan,1
and T. O. Asatryan1
Translated from Khimiko-Farmatsevticheskii Zhurnal, Vol. 34, No. 12, pp. 5 – 7, December, 2000.
Original article submitted May 30, 2000.
Earlier we synthesized 4-spiro-substituted tetrahydroiso-
quinolines (THI) containing phenyl and benzyl groups with
methoxyl substituents in the 1 position [1 – 3]; we studied
CH3O
NaBH4
NH
HCl
· HCl
their effect on the cardiovascular system.
CH3O
In this paper, we present data on synthesis and study of
the antiarrhythmic properties of compounds III – Va – Vc
and VII, VIIIa, VIIIb, containing nitrophenyl groups.
As the starting reagent for the synthesis of the indicated
compounds, we used 1-(3,4-dimethoxyphenyl)-1-aminome-
thylcyclopentane (I) [1].
Và – Vc
NO2
POCl3
for para isomer
By acylation of amine I with acid chlorides of o-, m-,
p-nitrobenzoic acids (II) in the presence of pyridine, we ob-
tained the corresponding amides IIIa – IIIc in 70 – 88%
yield.
CH3O
CH3O
O
I +
C
N
CH
O2N
H
NO2
VIà, VIb
VIIà, VIIb
NaBH4
NO2
CH3O
+ Cl
C
O
NH2
CH3O
CH3O
CH3O
IIà – IIc
I
NH CH2
VIIIà, VIIIb
NO2
CH3O
CH3O
CH3O
Position of nitro group, II – VIII:a – meta, b – para, c – ortho.
POCl3
N
NH
By Bischler—Napieralski cyclization of amides III, we
obtained derivatives of 3,4-dihydroisoquinolines IV; by re-
duction of hydrochlorides of the latter with sodium
borohydride in methanol solution, we obtained the corre-
sponding tetrahydroisoquinolines V in 60 – 65% yield.
The noncyclic analogs of tetrahydroisoquinolines V (the
secondary amines VIII) were obtained by reduction of
Schiff’s bases VII, which in turn were synthesized by boiling
equimolar amounts of amine I with meta- and para-nitroben-
zaldehydes (VIa, VIb) in anhydrous benzene.
CH3O
· HCl
C
O
NO2
IVà – IVc
NO2
IIIà – IIIc
1
A. L. Mnjoyan Institute of Fine Organic Chemistry, National Academy
of Sciences of the Republic of Armenia, Yerevan.
632
0091-150X/00/3412-0632$25.00 © 2001 Plenum Publishing Corporation

Isoquinoline Derivatives
633
By cyclization of N-(p-nitrobenzylidene)-1-(3,4-dime-
thoxyphenyl)-1-aminomethylcyclopentane (VIIb) in the
presence of phosphorus oxychloride, we carried out an alter-
nate synthesis of compound Vb with 85.0% yield.
The purity and structure of the synthesized compounds
were monitored chromatographically and by IR, PMR, and
mass spectra.
tinued for two more hours at room temperature and then the
solvent was driven off. 50 ml water was added to the residue.
The product was extracted with 100 ml benzene and dried
over sodium sulfate. After the benzene was driven off, the
residue was converted to the hydrochloride (Table 1). IR
spectrum, nmax, cm – 1: 3350 (NH); 1590, 1610 (C=C arom.),
1360 – 1300 (NO2). Mass spectrum: M+ 368. PMR spectrum,
d, ppm: 1.6 – 2.0 m (8H, 4CH2), 3.8 s (6H, 2CH3O),
3.0 – 3.1 d (1H-CH), 3.3 d (2H-CH2N), 5.8 m (NH), 7.0 s
(2H arom.), 7.78 t (1H arom.), 8.2 – 8.6 m (3H arom.).
Vb, c were obtained similarly (Table 1).
EXPERIMENTAL CHEMICAL PART
The IR spectra were taken on a UR-20 (GDR) spectrom-
eter in vaseline oil. The PMR spectra were taken on a Varian
T-60 (USA) in DMSO; internal standard, tetramethylsilane;
the mass spectra were taken on an MKh-1303. TLC was car-
ried out on Silufol in the system benzene—acetone, 2 : 1; io-
dine vapors were used as the visualizing agent. The hydro-
chlorides were recrystallized from acetone; the melting
points were determined on a Boetius (GDR) apparatus. Ele-
mental analysis data for C, H, N, Cl correspond to the empir-
ical formulas.
1-(3,4-Dimethoxyphenyl)-1-(m-nitrobenzylideneamin
omethyl)cyclopentane (VIIa).
A
mixture of 4.7 g
(0.02 mole) amine I and 3.0 g (0.02 mole) m-nitroben-
zaldehyde VIa in 50 ml anhydrous benzene was boiled with a
water trap until liberation of water stopped. After the ben-
zene was driven off, the residue was crystallized from ether.
IR spectrum, nmax, cm – 1: 1680 (C=N), 1590, 1610 (C=C
arom.). PMR spectrum, d, ppm: 1.8 – 2.2 broad s (8H,
4CH2); 3.6 sec (2H, CH2N); 3.8 sec (6H, 2CH3O); 5.9 sec
|
1-(3,4-Dimethoxyphenyl)-1-[N-(m-nitrobenzoyl)-ami-
(1H, H –C = N); 6.4 sec (1H arom.); 6.9 m (2H arom.);
nomethyl]cyclopentane (IIIa).
A
mixture of 4.7 g
7.3 – 8.5 m (4H-m-NO2C5H4).
(0.02 mole) amine I and 1.6 g (0.02 mole) anhydrous
pyridine was added with stirring to 3.7 g (0.02 mole)
m-nitrobenzoic acid chloride in 50 ml benzene. The mixture
was boiled for 4 h. On cooling, the mixture was treated with
5% HCl to bring it to pH 2, then with water, then with a 5%
sodium hydroxide solution and again with water until it
tested neutral; then it was dried over sodium sulfate. The
benzene was driven off, the residue was crystallized from
Compound VIIb was obtained similarly (Table 1).
Cyclization of the Schiff’s base (VIIb). 15 ml of phos-
phorus oxychloride was added with shaking to a solution of
3.7 g (0.01 mole) VIIb in 100 ml anhydrous toluene. The
mixture was boiled for 5 h. The solvent was driven off. 20 ml
water was added to the residue and it was alkalinized with an
aqueous ammonia solution (pH 8) and extracted with ben-
zene. The benzene extracts were washed with water and
dried over sodium sulfate. After the benzene was driven off,
the residue was converted to the hydrochloride Vb. Yield,
3.4 g (85.0%); m.p. 229 – 231°C.
ether and then from acetone (Table 1). IR spectrum, nmax
,
cm – 1: 3360 (NH), 1640 (C=O), 1590, 1610 (C=C arom.),
1360 (NO2). PMR spectrum, d, ppm: 1.6 – 2.0 m (8H,
4CH2), 3.6 d (2H, CH2NH–C=O), 3.79 sec (6H, 2CH3O),
6.75 t (NH), 6.9 m (3H arom.), 7.6 – 8.5 m (4H, meta-
NO2C6H4).
N-(m-nitrobenzyl)-1-[1-(3, 4-dimethoxyphenyl)cyclop
entyl]methylamine (VIIIa). While maintaining the temper-
ature at 0 – 7°C, 0.85 g (0.025 mole) NaBH4 was added with
Amides IIIb, c were obtained similarly (Table 1).
6,7-Dimethoxy-1-(m-nitrophenyl)-4-spirocyclopentane-
3,4-dihydroisoquinoline hydrochloride (IVa). 15 ml of
freshly distilled phosphorus oxychloride was added with
shaking to a solution of 3.0 g (0.08 mole) amide IIIa in
100 ml anhydrous toluene. The mixture was boiled for 6 h
and then the solvent was driven off. An aqueous ammonia
solution (pH 8) was added to the residue and the product was
extracted with ether. The ether extracts were washed with
water and dried over sodium sulfate. The product was con-
verted to the hydrochloride by treatment with an ether solu-
tion of HCl. IR spectrum, dmax, cm – 1: 1680 (C=N), 1590,
1610 (C=C arom.), 1360 – 1300 (NO2). Mass spectrum: M+
366. IVb, c were obtained similarly (Table 1).
TABLE 1. Characteristics of Compounds Obtained
Com-
pound
Yield,
%
m.p.,
°C
Empirical
formula
Rf
IIIa
68.8
78.0
88.6
53.0
70.8
71.7
63.5
66.5
66.3
75.3
82.3
78.5
80.0
123 – 124
131 – 132
127 – 128
202 – 203
176 – 177
183 – 186
162 – 163
229 – 231
210 – 211
75 – 77
0.79
0.65
0.56
0.50
0.43
0.41
0.56
0.52
0.54
0.63
0.59
0.61
0.57
C21H24N2O5
C21H24N2O5
C21H24N2O5
IIIb
IIIc
IVa
C21H22N2O4 × HCl
C21H22N2O4 × HCl
C21H22N2O4 × HCl
C21H24N2O4 × HCl
C21H24N2O4 × HCl
C21H24N2O4 × HCl
C21H24N2O4
IVb
IVc
Va
Vb
Vc
6,7-Dimethoxy-1-(m-nitrophenyl)-4-spirocyclopentan
e-1,2,3,4-tetrahydroisoquinoline (Va) hydrochloride.
0.38 g (0.01 mole) NaBH4 were added with stirring at
0 – 4°C to a solution of 2.0 g (0.005 mole) dihydroisoqu-
inoline IVa in 100 ml anhydrous methanol. Stirring was con-
VIIa
VIIb
VIIIa
VIIIb
68 – 69
191 – 192
139 – 140
C21H24N2O4
C21H26N2O4 × HCl
C21H26N2O4 × HCl

634
É. A. Markaryan et al.
TABLE 2. Protective Effect of Compounds III – Va – Vc and VII,
VIIIa, b for Calcium Chloride Induced Arrhythmias
sexes weighing 180 – 220 g, with cardiac rhythm and con-
duction disorders induced by calcium chloride (200 mg/kg,
intravenously) or aconitine (30 mg/kg, intravenously [4, 5].
The test compounds in doses of 2.5 and 5 mg/kg and the ref-
erence drug isoptin (2.5 mg/kg) were injected into a thigh
vein 2 – 3 min before application of arrhythmogens. The
ECG were recorded in standard lead II before and after injec-
tion of the test compounds (until sinus rhythm was restored
or the animal died). The antiarrhythmic activity was assessed
from the decrease in the frequency of development of rhythm
and conduction disorders, and also from the survival rate of
Frequency:
Animal
sinus
Com-
pound
Dose,
mg/kg of animals
Number
deaths,
%
arrhy- ventricular rhythm
thmias fibrillation resto-
ration
200
10
10
9
1
90.0
Calcium
chloride
(control)
IIIa
IIIb
IIIc
IVa
IVb
IVc
Va
5
5
5
5
5
5
5
5
5
5
5
5
5
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
6
4
4
5
4
5
5
2
5
4
2
3
5
1
2
5
3
1
1
1
2
3
1
2
5
4
3
5
9
16.7
50.0
83.3
83.3
83.3
66.7
50.0
83.3
66.7
16.7
33.3
50.0
16.7
10.0
the animals.
We established that most of the studied compounds ex-
hibit antiarrhythmic action on the calcium chloride model for
arrhythmia (Table 2). The noncyclic analogs (IIIa, IIIb; VIIa,
VIIb; and VIIIa, VIIIb) were the most active, but they were
Vb
Vc
VIIa
VIIb
VIIIa
VIIIb
Isoptin
less active than isoptin.
Most of the studied compounds did not have any protec-
tive effect in aconitine-induced arrhythmias. Only when used
in combination with the action of compounds IIIa, Vc, and
VIIIb did aconitine induce a less pronounced cardiac rhythm
disorder (isolated ventricular and atrial extrasystoles without
development of cases of ventricular fibrillation).
2.5
10
10
stirring to a solution of 3.7 g (0.01 mole) compound VIIa in
100 ml absolute methanol. Stirring was continued for 4 h at
room temperature and then the methanol was driven off.
50 ml water was added to the residue. The product was ex-
tracted with benzene. The benzene extracts were washed
with water and dried over sodium sulfate. After the benzene
was driven off, the residue was converted to the hydrochlo-
ride (Table 1). PMR spectrum, d, ppm: 1.6 – 2.0 m (8H,
–(CH2)4), 3.8 sec (6H, 2CH3O), 4.2 d (2H, Ar–CH2–N),
6.6 – 6.8 m (3H arom.), 7.65 – 8.8 m (4H-m-NO2C6H4).
Compound VIIIb was obtained similarly (Table 1).
REFERENCES
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EXPERIMENTAL PHARMACOLOGICAL PART
The antiarrhythmic activity was studied on 119 ure-
thane-narcotized (1 g/kg, intraperitoneally) rats of both
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