A novel route to isoquinoline[2,1-g][1,6]naphthyridine, pyrazolo[5,1-a]isoquinoline and pyridazino[4,5':3,4]pyrazolo[5,1-a]isoquinoline derivatives with evaluation of antitumor activities

Article abstract of DOI:10.5560/ZNB.2013-3101

(E)-2-Chloro-3-(2-cyanovinyl)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2, 1-a] isoquinoline-1-carbonitrile (5) was obtained by treatment of the 2-chloro-3-formylpyrido[2,1-a]isoquinoline derivative 3 with 2-(triphenylphosphoranylidene)acetonitrile (4). Treatment of 5 with sodium azide afforded the corresponding azido compound 6 which could be reduced by sodium dithionite to compound 7. A novel isoquinolino[2,1-g][1,6]naphthyridine derivative 11 was obtained by the reaction of phenyl isothiocyanate with the phosphorane compound 8, which was prepared by the reaction of compound 6 with triphenylphosphine. Treatment of 5 with amines 12a-c and thiophenols 14a-c in refluxing ethanol afforded the corresponding substitution products 13a-c and 15a-c, respectively. Also, the reaction of 1 with α-oxo hydroxamoyl chlorides 16 was reinvestigated, and the synthesized pyrazoloisoquinolines 19a-f and pyridazinopyrazoloisoquinolines 20a, e were screened for their in vitro antitumor activities.

Full text of DOI:10.5560/ZNB.2013-3101

A Novel Route to Isoquinoline[2,1-g][1,6]naphthyridine, Pyrazolo[5,1-a]
isoquinoline and Pyridazino[40,50:3,4]pyrazolo[5,1-a]isoquinoline
Derivatives With Evaluation of Antitumor Activities
Hamdi M. Hassaneena, Wagnat W. Wardkhanb and Yasmin Sh. Mohammedb
a
Department of Chemistry, Faculty of Science, Cairo University, Giza 12613, A. R. Egypt
National Organization for Drug Control and Research, Dokki, Giza, A. R. Egypt
b
Reprint requests to Prof. Hamdi M. Hassaneen. E-mail: hamdi 251@yahoo.com
Z. Naturforsch. 2013, 68b, 895 – 904 / DOI: 10.5560/ZNB.2013-3101
Received March 20, 2013
(E)-2-Chloro-3-(2-cyanovinyl)-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a] isoquinoline-
1-carbonitrile (5) was obtained by treatment of the 2-chloro-3-formylpyrido[2,1-a]isoquinoline
derivative 3 with 2-(triphenylphosphoranylidene)acetonitrile (4). Treatment of 5 with sodium azide
afforded the corresponding azido compound 6 which could be reduced by sodium dithionite to com-
pound 7. A novel isoquinolino[2,1-g][1,6]naphthyridine derivative 11 was obtained by the reaction
of phenyl isothiocyanate with the phosphorane compound 8, which was prepared by the reaction of
compound 6 with triphenylphosphine. Treatment of 5 with amines 12a–c and thiophenols 14a–c in re-
fluxing ethanol afforded the corresponding substitution products 13a–c and 15a–c, respectively. Also,
the reaction of 1 with α-oxo hydroxamoyl chlorides 16 was reinvestigated, and the synthesized pyra-
zoloisoquinolines 19a–f and pyridazinopyrazoloisoquinolines 20a, e were screened for their in vitro
antitumor activities.
Key words: Isoquinoline-1-acetonitrile, Naphthyridines, Pyrazoloisoquinolines,
Pyridazinopyrazoloisoquinolines, Hydroxamoyl Chlorides, Antitumor Activity
Introduction
Results and Discussion
Chemistry
Isoquinolines and their derivatives are impor-
tant constituents of pharmacologically active com-
2-Chloro-3-formyl-9,10-dimethoxy-4-oxo-6,7-dihy-
pounds, as these systems have shown a broad spec- dro-4H-pyrido[2,1-a]isoquinoline-1-carbonitril 3 was
trum of biological activities such as cardiovascular [1], prepared according to a literature procedure
anti-inflammatory [2], anti-depressant [3] and anti- (Scheme 1) [25]. The target compund 5, which
cancer [4 – 6]. Among them, pyrido[a]isoquinolines has not been reported hitherto, was prepared
are well known, and several methods for their prepa- in this study by stirring of 3 with 2-(triphenyl-
ration have been reported [7 – 12]. The present study phosphoranylidene)acetonitrile 4 in chloroform at
is a part of our program directed towards the syn- room temperature (Scheme 2). The structure of 5 was
thesis of fused isoquinoline derivatives [13 – 24]. The based on its elemental and spectral analyses. The 1H
aim of this study, on one hand is to introduce a sim- NMR spectrum showed two doublets at δ = 6.85 and
ple and convenient method for the synthesis of the ti- 7.75 ppm with a coupling constant J = 16 Hz that
tle compounds in good yields and on the other hand indicated a trans configuration for the vinylic protons,
to reinvestigate the proposed structures resulting from in addition to signals of a pyrido[2,1-a]isoquinoline
the reaction of isoquinoline-1-acetonitirile 1 with α- moiety. The mass spectrum of 5 showed the molecular
oxo hydroxamoyl chlorides 18a–f. Some of the syn- ion peak at m/z = 367, and its IR spectrum revealed
thesized compounds (19a–f and 20a, e) were tested bands at ν = 2245, 2214 and 1658 cm−1 assignable to
for antitumor activity against hepatocellular carcinoma cyano and amide carbonyl groups, respectively.
(HepG2), breast carcinoma (MCF-7) and colon carci-
noma (HCT).
Azido derivative 6 was prepared by stirring of 5
with sodium azide in a dioxane/water mixture for 3 h at
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
CO2Et
CO2Et
compound 7 was accomplished by stirring with sodium
dithionite in methanol/water mixture at room tempera-
ture for 24 h (Scheme 2). The structure of compound 7
was confirmed by elemental and spectral analyses. Its
IR spectrum revealed the absence of the azide stretch-
ing band, instead two new bands for the amino group
were clearly visible at 3367 and 3267 cm−1. Treat-
ment of 6 with triphenylphosphine in boiling ether
afforded the iminophosphorane 8 in good yield. The
IR spectrum of 8 revealed the absence of the azide
group, and its mass spectrum showed the molecular
ion peak at m/z = 608. Refluxing of iminophosphorane
8 with phenyl isothiocyanate in 1,2-dichlorobenzene
for 6 h afforded the novel 2,3-dimeth-oxy-8-oxo-
11-(phenylamino)-6,8-dihydro-5H- isoquinolino[2,1-
g][1,6]naphthyridine-10,13-dicarbonitrile (11) in 76%
yield (Scheme 3). It is proposed that the pathway of
the formation of the novel tetracyclic system 11 in-
volves an initial Aza-Wittig-type reaction between the
MeO
MeO
MeO
MeO
N
/ Δ
PhNO2
N
O
NC
NC
2
OH
1
POCl3 / DMF
MeO
MeO
N
O
NC
CHO
Cl
3
Scheme 1. Synthesis of 2-chloro-3-formylpyrido[2,1-a]iso-
quinoline 3.
room temperature (Scheme 2). Elemental analyses and iminophosphorane group and phenyl isothiocyanate to
spectral data were used to elucidate the structure of the give the reactive intermediate carbodiimide 9, which
product 6. Thus, the IR spectrum gave a band at ν = gives the intermediate 10 via intramolecular cycliza-
2125 cm−1 assignable to an azide group. Reduction tion by nucleophilic attack of the β-carbon atom of the
of the azido derivative 6 to the corresponding amino vinyl moiety. The latter yielded the final product 11
MeO
MeO
MeO
MeO
CN
CHCl3 / r. t.
+
N
O
N
O
PPh3
NC
CHO
NC
3
4
5
Cl
Cl
CN
NaN3 Dioxane / H2O
MeO
MeO
MeO
Na
2 S2 O4
N
O
N
O
MeOH / H2O
MeO
NC
NC
NH2
N3
7
6
CN
CN
Scheme 2. Synthesis of (E)-3-(2-cyanovinyl)pyrido[2,1-a]isoquinoline derivatives.
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
897
Scheme 3. Synthesis of isoquinolino[2,1-g][1,6]naphthyridine derivative 11.
via a proton shift (Scheme 3) [26]. Combustion anal-
It was claimed that 3-aroyl-3-hydroxyimino-2-
ysis and mass spectrum confirmed the molecular for- (6,7-dimethoxy-1,2,3,4-tetra-hydroisoquinolin-1-ylid-
mula C28H19N5O3. The IR spectrum of compound 11 ene)propanenitrile (18) can be obtained in good
revealed a band at 3255 cm−1 corresponding to anilino yield from the reaction of hydroxamoyl chlorides
NH. Its 1H NMR spectrum showed a singlet signal at 16a–f with 1 (Scheme 5) [27]. In our hands, stirring
δ = 8.58 corresponding to the proton of the pyridine of 1 with 16a in acetonitrile at room tempera-
ring at position 9.
ture afforded a product which gave analytical data
The chlorine atom in compound 5 showed high consistent with its formulation as 2-benzoyl-8,9-
reactivity towards nitrogen and sulfur nucleophiles. dimethoxy-5,6-dihydropyrazolo[5,1-a]isoquinoline-1-
Thus refluxing 5 with amine derivatives 12a–c in carbonitrile 19a. Mass spectral and combustion
ethanol for 6 h afforded the substitution products (E)- analysis data indicated its molecular formula as
2-(aralkylamino)-3-(2-cyanovinyl)-9,10-dimethoxy-4- C21H17N3O3. Similarly, 1 reacts with 16b–f to give
oxo-6,7-dihydro-4H-pyrido[2,1-a] isoquinoline-1-car- 19b–f. The IR spectra of compounds 19a–f were
bonitrile 13a–c (Scheme 4). Similarly, the substitution free of OH and NH bands. The reaction pathway that
products 15a–c were obtained by refluxing of 5 with seems to account for the formation of 19a–f from
sulfur nucleophiles 14a–c in ethanol in the presence reaction of 1 with 16a–f is outlined in Scheme 5. It
of triethylamine (Scheme 4). The structures of the is proposed that the reaction involves nucleophilic
products 13a–c and 15a–c were confirmed on the basis substitution to give 17a–f. The latter intermedi-
of elemental and spectral analyses (see Experimental ates tautomerize to give 18a–f, which cyclize via
Section).
elimination of water to give 19a–f. The structures
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898
H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
MeO
MeO
RNH2
R
N
O
-
a,
H5
C6
CH2
-
12
EtOH / Δ
H11
b, C6
13
NC
c,
-
H
3,4-(CH3 O)2 C6 3 CH2 CH2
NHR
CN
5
MeO
MeO
Ar
Ar-SH
N
S
O
14
a,
C
-
6 H5
EtOH / Δ
b, 4-MeC6 H4 -
-
c, 4-ClC6 H4
NC
15
Ar
CN
Scheme 4. Synthesis of (E)-3-(2-cyanovinyl)pyrido[2,1-a]isoquinoline derivatives 13 and 15.
Table 1. Evaluation of in vitro antitumor activities of pyra-
zoloisoquinolines 19a–f and pyridazinopyrazoloisoquino-
lines 20a, e.
of 19a–f were further confirmed by their reaction
with hydrazine hydrate. For example, refluxing
of 19a, e with hydrazine hydrate in ethanol af-
forded the 9-aryl-2,3-dimethoxy-5,6-dihydro-pyri-
dazino[40,50:3,4]pyrazolo[5,1-a] isoquinolin-12-amin-
es 20a, e. The IR spectra of compounds 20 revealed
two bands at ca. 3340 and 3244 cm−1 assignable to
asymmetric and symmetric stretch of an amino group.
IC50 (µg)a
MCF-7
Compound
HepG2b
HCT
19a
19b
19c
19d
19e
19f
20a
20e
20.0
25.6
18.8
48.6
> 50
43.4
19.7
25.2
1.2
12.6
15.3
11.1
33.4
> 50
35.0
18.0
23.7
2.38
12.2
19.9
5.2
11.7
45.3
34.7
25.0
22.1
0.469
Antitumor activity
The cytotoxic potencies of the synthesized pyra-
zoloisoquinolines 19a–f and pyridazinopyrazoloiso-
quinolines 20a, e against a panel of human tumor cell
lines were investigated and compared with the ref-
erence drug Doxorubicin. The human tumor cell
line panel consisted of hepatocellular carcinoma
(HepG2), breast carcinoma (MCF-7) and colon car-
Doxorubicin
a
Cytotoxicity as IC50 for each cell line is the concentration of com-
pound which reduced the optical density of treated cells by 50%
with respect to untreated cells; b cell lines include hepatocellular car-
cinoma (HepG2), breast carcinoma (MCF-7) and colon carcinoma
(HCT).
cinoma (HCT). The results are summarized in Ta- 30 to 50 µg. Exceptionally, compound 19d was se-
ble 1. The cytotoxic potency of pyrazoloisoquino- lectively active against colon carcinoma cell lines
line derivatives substituted with 4-nitrobenzoyl (19d), (IC50 = 11.7 µg). Compounds bearing a phenyl, a 4-
thiophene-2-carbonyl (19e) and 2-naphthoyl (19f) at methoxybenzoyl and a 4-bromobenzoyl group at posi-
position 2 showed a weak, but distinct difference, and tion 2 (compounds 19a–c) and 20a, e displayed a broad
the IC50 values of these compounds ranged from spectrum of cytotoxic activities with IC50 value lower
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
899
MeO
MeO
MeO
N
NH
MeO
OH
N
OH
N
NC
NC
OH
N
R
O
Cl
R
O
18
17
1
+
R
O
16
R
MeO
MeO
MeO
a,
-
H5
C6
N
N
H2NNH2
-
b,
c,
H4
-
4-MeOC6
MeO
N
N
H4
4-BrC6
-
H4
4-NO2C6
2-thienyl
d,
e,
NC
H2 N
R
R
N
O
N
f,
2-naphthyl
20
Scheme 5. Synthesis of 2-aroylpyrazolo[5,1-a]isoquinoline derivatives.
19
than 25 µg against the three tumor cell lines. Inter- pyrido[2,1-a]isoquinoline-1-carbonitrile 2 [29], 2-chloro-3-
formyl-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido-[2,1-
a]isoquinoline-1-carbonitilie 3 [25], 2-(triphenylphosphor-
anylidene)acetonitrile 4 [30], hydroxamoyl chlorides 18a–
f [31, 32] were prepared according to the procedures in the
literature.
estingly, compound 19c exhibited a strong cytotoxic
effect against the HCT cell line with IC50 = 5.2 µg.
An overview of the cytotoxic activities data of all
examined compounds clearly confirmed that the 4-
bromobenzoyl-substituted pyrazolo-isoquinoline 19c
was most active against all tumor cell lines tested.
Synthesis of (E)-2-chloro-3-(2-cyanovinyl)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitrile (5)
Experimental Section
Melting points were determined on a Stuart melting point
To a solution of 2-(triphenylphosphoranylidene)aceto-
apparatus and are uncorrected. IR spectra were measured as nitrile (4, 5.64 g, 20.0 mmol) in chloroform (50 mL), 2-
KBr pellets on a FTIR Bruker-Vector 22 spectrophotometer. chloro-3-formyl-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-py-
The 1H NMR and 13C NMR spectra were recorded in rido[2,1-a]isoquinoline-1-carbonitilie (3, 6.88 g, 20.0
CDCl3 or [D6]DMSO on a Varian Mercury VXR 300 mmol) was added. The reaction mixture was stirred for
spectrometer (300 MHz for 1H NMR and 75 MHz for 13C 3 h at room temperature then evaporated to dryness under
NMR) using TMS as internal standard. Chemical shifts are reduced pressure. Ethanol (30 mL) was added to the residue,
reported in δ units (ppm). Mass spectra were measured and the solid formed was filtered, washed with ethanol
on a Shimadzu GCMS-Q-1000 EX mass spectrometer at and crystallized from DMF to give compound 5. Yellow
70 eV. Elemental analyses were performed at the Microana- crystals; m. p. 246 – 248 ◦C; yield: 6.24 g (85%). – IR
lytical Center, Cairo University. Isoquinoline-1-acetonitrile (KBr): ν = 2245 (CN), 2214 (CN), 1658 (C=O) cm−1
1 [28], 2-hydroxy-9,10-dimethoxy-4-oxo-6,7-dihydro-4H-
1H NMR (300 MHz, DMSO): δ = 2.91 (t, J = 7 Hz,
.
–
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
2H, CH2), 3.78 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.03 (t, (348.3): calcd. C 65.51, H 4.63, N 16.08; found C 65.32, H
J = 7 Hz, 2H, CH2), 6.85 (d, J = 16 Hz, 1H), 7.08 (s, 1H), 4.75, N 16.31.
7.75 (d, J = 16 Hz, 1H), 7.86 (s, 1H). – 13C NMR (75 MHz,
Synthesis of (E)-3-(2-cyanovinyl)-9,10-dimethoxy-4-oxo-
DMSO): δ = 27.19, 40.21, 55.72, 55.97, 79.24, 92.25,
2-((triphenylphosphoranylidene)-amino)-6,7-dihydro-
96.86, 110.89, 111.93, 117.44, 118.20, 120.87, 133.49,
4H-pyrido[2,1-a]isoquinoline-1-carbonitrile (8)
141.75, 146.77, 150.85, 152.36, 154.52, 159.24. – MS (EI,
70 eV): m/z(%) = 369 (34) [M+2]+, 367 (100) [M]+, 366
A solution of 6 (1.87 g, 5.0 mmol) and triphenylphosphine
(66). – C19H14ClN3O3 (367.8): calcd. C 62.05, H 3.84, Cl
9.64, N 11.43; found C 61.89, H 3.92, Cl 9.61, N 11.20.
(1.3 g, 5.0 mmol) in dry ether (25 mL) was refluxed for 1 h
and then cooled. The solid that precipitated was filtered,
washed with ethanol and crystallized from DMF to give com-
pound 8. Canary-yellow crystals; m. p. 270 – 272 ◦C; yield:
2.31 g (76%). – IR (KBr): ν = 2225 (CN), 2203 (CN), 1641
( C=O) cm−1. – 1H NMR (300 MHz, DMSO): δ = 2.85 (t,
J = 7 Hz, 2H, CH2), 3.70 (s, 3H, OMe), 3.84 (s, 3H, OMe),
4.00 (t, J = 7 Hz, 2H, CH2), 6.58 (d, J = 16 Hz, 1H), 7.04
(s, 1H), 7.43 (d, J = 16 Hz, 1H), 7.47 (s, 1H), 7.58 – 7.71
(m, 15H). – 13C NMR (75 MHz, DMSO): δ = 26.82, 40.32,
55.55, 55.78, 90.16, 90.30, 91.89, 109.02, 109.10, 110.68,
111.85, 118.14, 119.63, 120.19, 128.34, 128.96, 129.45,
129.13, 129.73, 132.12, 132.26, 132.66, 132.69, 133.06,
144.38, 146.54, 149.88, 152.00, 159.97, 160.65, 162.15. –
MS (EI, 70 eV): m/z(%) = 608 (15) [M]+, 262 (100). –
C37H29N4O3P (608.6): calcd. C 73.02, H 4.80, N 9.21, P
5.09; found C 72.84, H 4.65, N 9.06, P 5.31.
Synthesis of (E)-2-azido-3-(2-cyanovinyl)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitrile (6)
A solution of 5 (1.84 g, 5.0 mmol) in a dioxane-water
mixture (4 : 1 (v/v) 60 mL) was treated with a solution of
sodium azide (0.65 g, 10.0 mmol) in the same solvent mix-
ture. The reaction mixture was vigorously stirred for 3 h
at room temperature, then diluted with water (100 mL).
The solid that precipitated was collected and crystallized
from DMF to afford compound 6. Yellow crystals; m. p.
318 – 320 ◦C; yield: 1.48 g (79%). – IR (KBr): ν = 2230
(CN), 2214 (CN), 2125 ( N3), 1651 (C=O) cm−1. – 1H
NMR (300 MHz, DMSO): δ = 2.91 (t, J = 7 Hz, 2H, CH2),
3.99 (s, 3H, OMe), 4.02 (s, 3H, OMe), 4.15 (t, J = 7 Hz,
2H, CH2), 7.00 (d, J = 16 Hz, 1H), 7.19 (s, 1H), 7.78
(d, J = 16 Hz, 1H), 7.86 (s, 1H). – 13C NMR (75 MHz,
DMSO): δ = 27.09, 41.25, 55.70, 56.02, 80.41, 92.25, 96.74,
110.61, 112.35, 117.43, 118.13, 120.89, 133.26, 141.75,
146.78, 150.89, 152.36, 154.51, 159.49. – MS (EI, 70 eV):
m/z(%) = 346 (86) [M–N2]+, 331 (100). – C19H14N6O3
(374.3): calcd. C 60.96, H 3.77, N 22.45; found C 60.74, H
3.85, N 22.19.
Synthesis of 2,3-dimethoxy-8-oxo-11-(phenylamino)-
6,8-dihydro-5H-isoquinolino[2,1-g]-[1,6]naphthyridine-
10,13-dicarbonitrile (11)
Phenyl isothiocyanate (0.12 g, 1.0 mmol) was added to
a solution of 8 (0.61 g, 1.0 mmol) in 1,2-dichlorobenzene
(10 mL). The reaction mixture was refluxed for 6 h, and
then the solvent was removed under reduced pressure. The
solid was collected and crystallized from DMF to give com-
pound 11. Yellow crystals; m. p. 308 – 310 ◦C; yield: 0.34 g
(76%). – IR (KBr): ν = 3255 (NH), 2227 (CN), 2204
(CN), 1665 (C=O) cm−1. – 1H NMR (300 MHz, CDCl3):
δ = 2.90 (t, J = 7 Hz, 2H, CH2), 3.84 (s, 3H, OMe),
3.88 (s, 3H, OMe), 4.05 (t, J = 7 Hz, 2H, CH2), 7.05 (s,
1H), 7.10 – 7.99 (m, 6H), 8.58 (s, 1H), 9.52 (s, 1H, NH).
Synthesis of (E)-2-amino-3-(2-cyanovinyl)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitrile (7)
To a stirred suspension of 6 (1.87 g, 5.0 mmol) in a 4 :
1 MeOH:H2O (40 mL) mixture, sodium dithionite (4.0 g,
20.0 mol) was added portionwise. The reaction mixture was
stirred for 24 h, then poured into H2O (20 mL). The resulting
solid product was filtered, washed with water and crystallized
from DMF-EtOH to give compound 7. Yellow crystals; m. p.
282 – 284 ◦C; yield: 1.37 g (79%). – IR (KBr): ν = 3367,
3267 ( NH2), 2225 (CN), 2198 (CN), 1639 (C=O) cm−1. –
1H NMR (300 MHz, DMSO): δ = 2.88 (t, J = 7 Hz, 2H,
CH2), 3.51 (s, 3H, OMe), 3.88 (s, 3H, OMe), 4.00 (t, J =
7 Hz, 2H, CH2), 6.86 (d, J = 16 Hz, 1H), 7.07 (s, 1H), 7.21
(s, 2H, NH2), 7.75 (d, J = 16 Hz, 1H), 7.81 (s, 1H). – 13C
NMR (75 MHz, DMSO): δ = 26.85, 40.35, 55.67, 55.89,
79.17, 92.25, 96.85, 110.85, 111.93, 117.34, 117.97, 120.68,
133.38, 141.61, 146.73, 150.70, 152.33, 154.38, 159.13. –
–
13C NMR (75 MHz, CDCl3): δ = 26.80, 40.37, 55.66,
55.90, 86.73, 93.73, 110.23, 110.81, 112.09, 115.44, 117.41,
118.14, 121.55, 123.70, 128.74, 130.62, 133.45, 138.53,
143.81, 146.87, 152.43, 154.27, 155.57, 158.49. – MS (EI,
70 eV): m/z(%) = 449 (100) [M]+, 448 (54). – C26H19N5O3
(449.4): calcd. C 69.48, H 4.26, N 15.58; found C 69.71, H
4.22, N 15.63.
Synthesis of (E)-2-amino-3-(2-cyanovinyl)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitriles 13a–c
General procedure: A mixture of compound 5 (1.10 g,
MS (EI, 70 eV): m/z(%) = 348 (100) [M]+. – C19H16N4O3 3.0 mmol) and an amine 12a–c (3.0 mmol) in absolute EtOH
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
901
(50 mL) was refluxed for 6 h in the presence of triethyl- NMR (75 MHz, CDCl3): δ = 27.59, 36.92, 39.32, 51.00,
amine (0.4 mL). The solvent was evaporated and the residue 55.74, 55.80, 56.12, 56.23, 82.16, 95.54, 100.87, 110.17,
cooled. The resulting solid product was collected, washed 111.55, 111.81, 112.00, 117.63, 118.23, 120.19, 120.99,
with ethanol and crystallized from CH3CN to give com- 129.32, 132.53, 142.00, 147.69, 148.02, 149.11, 150.35,
pounds 13a–c.
152.79, 155.81, 159.98. – MS (EI, 70 eV): m/z(%) = 512
(14) [M]+, 348 (100), 163 (91). – C29H28N4O5 (512.5):
calcd. C 67.96, H 5.51, N 10.93; found C 67.69, H 5.48, N
11.02.
(E)-2-(Benzylamino)-3-(2-cyanovinyl)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitrile (13a)
Synthesis of (E)-2-(arylthio)-3-(2-cyanovinyl)-9,10-dimeth-
oxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-
1-carbonitriles 15a–c
Yellow crystals; m. p. 160 – 161 ◦C; yield: 1.02 g (78%).
– IR (KBr): ν = 3249 (NH), 2225 (CN), 2210 (CN), 1669
(C=O) cm−1. – 1H NMR (300 MHz, CDCl3): δ = 2.91 (t,
J = 7 Hz, 2H, CH2), 3.82 (s, 3H, OMe), 3.83 (s, 3H, OMe),
General procedure: These compounds were prepared as
4.04 (t, J = 7 Hz, 2H, CH2), 4.74 (s, 2H, CH2), 6.71 (d, previously described for the synthesis of 13 using arylthi-
J= 16 Hz, 1H), 6.78 – 6.83 (m, 6H), 6.86 (s, 1H), 7.26 (d, ols 14 in the presence of triethylamine (0.4 mL) instead
J = 16 Hz, 1H), 7.75 (s, 1H). – 13C NMR (75 MHz, CDCl3): of amines 12. The resulting solid products were collected,
δ = 26.71, 41.02, 49.63, 55.76, 55.98, 83.35, 101.02, 110.96, washed with ethanol and crystallized from CH3CN to give
112.35, 115.36, 116.45, 118.13, 119.27, 127.50, 127.96, compounds 15a–c.
128.33, 129.02, 134.52, 136.89, 138.92, 146.24, 152.10,
(E)-3-(2-Cyanovinyl)-9,10-dimethoxy-4-oxo-2-(phenylthio)-
152.68, 156.02. – MS (EI, 70 eV): m/z(%) = 438 (9) [M]+,
6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
398 (85), 91 (100). – C26H22N4O3 (438.4): calcd. C 71.22,
nitrile (15a)
H 5.06, N 12.78; found C 71.12, H 4.94, N 12.93.
Yellow crystals; m. p. 166 – 168 ◦C; yield: 1.03 g (78%).
(E)-3-(2-Cyanovinyl)-2-(cyclohexylamino)-9,10-dimethoxy-
4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
nitrile (13b)
– IR (KBr): ν = 2214 (CN), 2209 (CN), 1645 (C=O) cm−1
.
–
1H NMR (300 MHz, CDCl3): δ = 2.90 (t, J = 7 Hz,
2H, CH2), 3.86 (s, 3H, OMe), 3.92 (s, 3H, OMe), 4.02 (t,
Yellow crystals; m. p. 212 – 214 ◦C; yield: 1.01 g (78%). J = 7 Hz, 2H, CH2), 6.77 (s, 1H), 6.95 – 7.21 (m, 6H), 7.81
– IR (KBr): ν = 3299 (NH), 2228 (CN), 2209 (CN), 1665 (s, 1H), 7.85 (d, J = 16 Hz, 1H). – 13C NMR (75 MHz,
(C=O) cm−1. – 1H NMR (300 MHz, CDCl3): δ = 1.24 CDCl3): δ = 27.27, 40.21, 55.96, 56.09, 93.70, 102.39,
(m, 10H), 2.91 (t, J = 7 Hz, 2H, CH2), 3.80 (s, 3H, OMe), 110.01, 111.90, 116.95, 117.77, 118.79, 122.94, 129.34,
3.86 (s, 3H, OMe), 4.01 (t, J = 7 Hz, 2H, CH2), 4.20 (m, 129.83, 130.15, 132.04, 138.22, 143.12, 147.59, 150.02,
1H), 5.90 (d, 1H, NH), 6.82 (s, 1H), 6.85 (d, J = 16 Hz, 150.44, 153.00, 158.41. – MS (EI, 70 eV): m/z(%) = 441
1H), 7.47 (d, J = 16 Hz, 1H), 7.75 (s, 1H). – 13C NMR (100) [M]+, 440 (92), 364 (74). – C25H19N3O3S (441.4):
(75 MHz, CDCl3): δ = 24.81, 24.99, 26.75, 33.75, 40.40, calcd. C 68.02, H 4.34, N 9.52, S 7.25; found C 67.86, H
55.85, 55.97, 56.46, 82.13, 102.45, 111.25, 112.64, 115.23, 4.52, N 9.34, S 7.19.
115.61, 117.86, 118.71, 133.59, 137.24, 146.70, 150.64,
(E)-3-(2-Cyanovinyl)-9,10-dimethoxy-4-oxo-2-(p-tolylthio)-
151.22, 152.49, 156.33. – MS (EI, 70 eV): m/z(%) = 430
6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-1-carbo-
(36) [M]+, 390 (100), 333 (78). – C25H26N4O3 (430.5):
nitrile (15b)
calcd. C 69.75, H 6.09, N 13.01; found C 69.79, H 5.82, N
13.14.
Yellow crystals; m. p. 196 – 197 ◦C; yield: 1.06 g (78%).
– IR (KBr): ν = 2214 (CN), 2207 (CN), 1644 (C=O) cm−1
1H NMR (300 MHz, CDCl3): δ = 2.28 (s, 3H, Me),
2.91 (t, J = 7 Hz, 2H, CH2), 3.87 (s, 3H, OMe), 3.92 (s,
3H, OMe), 4.22 (t, J = 7 Hz, 2H, CH2), 6.76 (s, 1H),
.
(E)-3-(2-Cyanovinyl)-2-((3,4-dimethoxyphenethyl)amino)-
9,10-dimethoxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]iso-
quinoline-1-carbonitrile (13c)
–
Yellow crystals; m. p. 92 ◦C; yield: 1.18 g (77%). – IR 7.06 – 7.36 (m, 5H), 7.80 (s, 1H), 7.98 (d, J = 16 Hz, 1H).
(KBr): ν = 3260 (NH), 2225 (CN), 2207 (CN), 1657 (C=O)
–
13C NMR (75 MHz, CDCl3): δ = 20.88, 27.27, 40.22,
cm−1. – 1H NMR (300 MHz, CDCl3): δ = 2.87 (t, J = 7 Hz, 55.96, 56.09, 93.70, 102.39, 110.01, 111.90, 116.95, 117.77,
2H, CH2), 2.91 (t, J = 7 Hz, 2H, CH2), 3.76 (t, J = 7 Hz, 2H, 118.79, 122.94, 129.34, 129.83, 130.15, 132.04, 138.22,
CH2), 3.81 (s, 3H, OMe), 3.83 (s, 3H, OMe), 3.94 (s, 3H, 143.12, 147.59, 150.02, 150.44, 153.00, 158.41. – MS (EI,
OMe), 3.97 (s, 3H, OMe), 4.12 (t, J = 7 Hz, 2H, CH2), 4.98 70 eV): m/z(%) = 455 (76) [M]+, 415 (66), 91 (100). –
(s, 1H, NH), 6.70 (d, J = 16 Hz, 1H), 6.74 – 6.77 (m, 3H), C26H21N3O3S (455.4): calcd. C 68.56, H 4.65, N 9.23, S
6.81 (s, 1H), 7.23 (d, J = 16 Hz, 1H), 7.73 (s, 1H). – 13C 7.03; found C 68.48, H 4.70, N 9.21, S 6.87.
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902
H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
(E)-2-((4-Chlorophenyl)thio)-3-(2-cyanovinyl)-9,10-dimeth-
oxy-4-oxo-6,7-dihydro-4H-pyrido[2,1-a]isoquinoline-
1-carbonitrile (15c)
C22H19N3O4 (389.4): calcd. C 67.86, H 4.92, N 10.79; found
C 67.62, H 5.12, N 10.96.
2-(4-Bromobenzoyl)-8,9-dimethoxy-5,6-dihydropyrazolo-
[5,1-a]isoquinoline-1-carbonitrile (19c)
Yellow crystals; m. p. 174 – 176 ◦C; yield: 1.08 g (76%).
– IR (KBr): ν = 2215 (CN), 2209 (CN), 1652 (C=O) cm−1
.
Reddish-brown crystals; m. p. 260 – 262 ◦C; yield: 1.73 g
(79%). – IR (KBr): ν = 2211 (CN) cm−1. – 1H NMR
(300 MHz, DMSO): δ = 3.08 (t, J = 7 Hz, 2H, CH2), 3.76
(s, 3H, OMe), 3.86 (s, 3H, OMe), 4.24 (t, J = 7 Hz, 2H,
CH2), 7.10 (s, 1H), 7.60 (s, 1H), 7.85 (d, J = 7.5 Hz,
2H), 7.88 (d, J = 7.5 Hz, 2H) ppm. – 13C NMR (75 MHz,
DMSO): δ = 27.09, 42.69, 55.58, 55.79, 69.46, 107.36,
111.88, 116.11, 116.41, 124.86, 125.62, 128.88, 131.59,
133.73, 138.88, 147.29, 147.93, 150.90, 159.55. – MS (EI,
70 eV): m/z(%) = 439 (100) [M+2]+, 437 (97) [M]+. –
C21H16BrN3O3 (438.2): calcd. C 57.55, H 3.68, Br 18.23,
N 9.59; found C 57.51, H 3.54, Br 18.16, N 9.72.
–
1H NMR (300 MHz, CDCl3): δ = 2.91 (t, J = 7 Hz,
2H, CH2), 3.86 (s, 3H, OMe), 3.90 (s, 3H, OMe), 4.28 (t,
J = 7 Hz, 2H, CH2), 6.79 (s, 1H), 6.99 (d, J = 16 Hz, 1H),
7.21 – 7.46 (m, 4H), 7.82 (s, 1H), 7.88 (d, J = 16 Hz, 1H).
–
13C NMR (75 MHz, CDCl3): δ = 27.29, 40.20, 55.85,
56.12, 93.36, 101.52, 109.78, 112.57, 117.00, 117.94, 119.21,
123.16, 129.24, 130.01, 130.25, 132.31, 139.16, 143.31,
147.88, 150.31, 150.45, 153.09, 158.70. – MS (EI, 70 eV):
m/z(%) = 477 (43) [M+2]+, 475 (100) [M]+, 364 (96). –
C25H18ClN3O3S (475.8): calcd. C 63.10, H 3.81, Cl 7.45, N
8.83, S 6.72; found C 63.25, H 3.99, Cl 7.36, N 8.61, S 6.84.
Synthesis of 2-aroyl-8,9-dimethoxy-5,6-dihydropyrazolo-
[5,1-a]isoquinoline-1-carbonitriles 19a–f
8,9-Dimethoxy-2-(4-nitrobenzoyl)-5,6-dihydropyrazolo-
[5,1-a]isoquinoline-1-carbonitrile (19d)
General procedure: A mixture of equimolar amounts of
isoquinoline-1-acetonitrile 1 and hydroxamoyl chloride 16
(5 mmol each) was stirred for 2 h in acetonitrile (30 mL) at
room temperature, during which time the compounds dis-
solved, and the product 19 precipitated. The solids were
collected and crystallized from CH3CN to give compounds
19a–f.
Yellowish-green crystals; m. p. 258 – 260 ◦C; yield: 1.58 g
(78%). – IR (KBr): ν = 2182 (CN), cm−1. – 1H NMR
(300 MHz, DMSO): δ = 3.09 (t, J = 7 Hz, 2H, CH2), 3.75
(s, 3H, OMe), 3.83 (s, 3H, OMe), 4.29 (t, J = 7 Hz, 2H,
CH2), 7.11 (s, 1H), 7.57 (s, 1H), 8.01 (d, J = 7.5 Hz, 2H),
8.13 (d, J = 7.5 Hz, 2H). – 13C NMR (75 MHz, DMSO): δ =
27.09, 42.71, 55.49, 55.70, 69.35, 107.39, 111.75, 116.10,
116.42, 124.86, 125.65, 128.97, 131.46, 133.74, 139.23,
148.55, 149.82, 152.10, 160.04. – MS (EI, 70 eV): m/z(%) =
404 (38) [M]+, 150 (100). – C21H16N4O5 (404.3): calcd. C
62.37, H 3.99, N 13.86; found C 62.15, H 4.12, N 13.74.
2-Benzoyl-8,9-dimethoxy-5,6-dihydropyrazolo[5,1-a]iso-
quinoline-1-carbonitrile (19a)
Dark-green crystals; m. p. 256 – 258 ◦C; yield: 1.36 g
(76%). – IR (KBr): ν = 2202 (CN) cm−1. – 1H NMR
(300 MHz, DMSO): δ = 3.10 (t, J = 7 Hz, 2H, CH2),
3.79 (s, 3H, OMe), 3.85 (s, 3H, OMe), 4.26 (t, J = 7 Hz,
2H, CH2), 7.11 (s, 1H), 7.65 – 7.96 (m, 6H). – MS (EI,
70 eV): m/z(%) = 359 (100) [M]+, 358 (59). – C21H17N3O3
(359.3): calcd. C 70.18, H 4.77, N 11.69; found C 70.05, H
4.70, N 11.83.
8,9-Dimethoxy-2-(thiophene-2-carbonyl)-5,6-dihydropyra-
zolo[5,1-a]isoquinoline-1-carbonitrile (19e)
Yellowish-brown crystals; m. p. 264 – 266 ◦C; yield:
1.41 g (77%). – IR (KBr): ν = 2210 (CN) cm−1. – 1H
NMR (300 MHz, DMSO): δ = 3.12 (t, J = 7 Hz, 2H, CH2),
3.77 (s, 3H, OMe), 3.84 (s, 3H, OMe), 4.41 (t, J = 7 Hz,
2H, CH2), 7.12 (s, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.62 (s,
1H), 7.86 (d, J = 7.5 Hz, 1H), 8.11 (d, J = 7.5 Hz, 1H).
– MS (EI, 70 eV): m/z(%) = 365 (100) [M]+, 111 (52). –
C19H15N3O3S (365.3): calcd. C 62.46, H 4.14, N 11.50, S
8.76; found C 62.35, H 4.20, N 11.59, S 8.58.
8,9-Dimethoxy-2-(4-methoxybenzoyl)-5,6-dihydropyrazolo-
[5,1-a]isoquinoline-1-carbonitrile (19b)
Green crystals; m. p. 262 – 264 ◦C; yield: 1.50 g (77%).
– IR (KBr): ν = 2205 (CN) cm−1. – 1H NMR (300 MHz,
DMSO): δ = 3.07 (t, J = 7 Hz, 2H, CH2), 3.76 (s, 3H, OMe),
3.82 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.25 (t, J = 7 Hz,
2H, CH2), 7.09 (s, 1H), 7.18 (d, J = 7.5 Hz, 2H), 7.58
(s, 1H), 7.88 (d, J = 7.5 Hz, 2H). – 13C NMR (75 MHz,
DMSO): δ = 27.21, 42.51, 55.53, 55.64, 55.71, 69.83,
8,9-Dimethoxy-2-(2-naphthoyl)-5,6-dihydropyrazolo-
[5,1-a]isoquinoline-1-carbonitrile (19f)
Pale-green crystals; m. p. 172 – 173 ◦C; yield: 1.60 g
107.49, 112.06, 114.14, 116.31, 116.65, 118.40, 128.88, (78%). – IR (KBr): ν = 2209 (CN) cm−1. – 1H NMR
133.47, 138.78, 147.93, 148.84, 150.83, 159.71, 161.33. – (300 MHz, DMSO): δ = 3.12 (t, J = 7 Hz, 2H, CH2), 3.81
MS (EI, 70 eV): m/z(%) = 389 (100) [M]+, 328 (86). – (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.34 (t, J = 7 Hz, 2H,
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H. M. Hassaneen et al. · Naphthyridines and Isoquinolines
903
CH2), 7.13 (s, 1H), 7.57 – 8.55 (m, 8H). – MS (EI, 70 eV): 2,3-Dimethoxy-9-(thiophen-2-yl)-5,6-dihydropyridazino-
m/z(%) = 409 (4) [M]+, 154 (100). Anal. for C25H19N3O3 [40,50:3,4]pyrazolo[5,1-a]isoquinolin-12-amine (20e)
(409.4): calcd. C 73.34, H 4.68, N 10.26; found C 73.39, H
Yellow crystals; m. p. 268 – 270 ◦C; yield: 1.36 g (72%).
– IR (KBr): ν = 3475, 3348 ( NH2) cm−1. – 1H NMR
(300 MHz, DMSO): δ = 2.82 (t, J = 7 Hz, 2H, CH2), 3.17 (t,
J = 7 Hz, 2H, CH2), 3.76 (s, 3H, OMe), 3.85 (s, 3H, OMe),
5.62 (s, 2H, NH2), 7.04 (s, 1H), 7.16 (s, 1H), 7.23 (t, J =
7.5 Hz, 1H), 7.64 (d, J = 7.5 Hz, 1H), 8.45 (d, J = 7.5 Hz,
1H). – MS (EI, 70 eV): m/z(%) = 379 (4) [M]+, 365 (100).
– C19H17N5O2S (379.3): calcd. C 60.15, H 4.52, N 18.46, S
8.43; found C 60.01, H 4.70, N 18.55, S 8.67.
4.79, N 9.98.
Synthesis of 9-aryl-2,3-dimethoxy-5,6-dihydropyridazino-
[40,50:3,4]pyrazolo[5,1-a]isoquinolin-12-amines 20
General procedure: A mixture of a 2-aroyl-8,9-dime-
thoxy-5,6-dihydropyrazolo[5,1-a]isoquinoline-1-carbonitri-
le 19a, e (5 mmol) in ethanol (30 mL) and hydrazine hydrate
99% (0.7 g, 14 mmol) was refluxed for 6 h, during which the
corresponding pyridazino-[40,50:3,4]pyrazoloisoquinoline
20a, e precipitated. The resulting solid products were
collected, washed with ethanol and crystallized from DMF
to give compounds 20.
In vitro cytotoxicity assays
The cells were propagated in Dulbecco’s modified Eagle’s
medium (DMEM) supplemented with 10% heat-inactivated
fetal calf serum, 1% L-glutamine, HEPES buffer, and
50 µg mL−1 gentamycin. The cells were maintained at 37 ◦C
in a humidified atmosphere with 5% CO2. The cytotoxicity
assay was carried out using 100 µL of cell suspension, con-
taining 10,000 cells seeded in each well of a 96-well mi-
2,3-Dimethoxy-9-phenyl-5,6-dihydropyridazino-
[40,50:3,4]pyrazolo[5,1-a]isoquinolin-12-amine (20a)
Yellow crystals; m. p. 280 – 282 ◦C; yield: 1.31 g (70%). crotiter plate (Falcon, NJ, USA). Fresh medium containing
– IR (KBr): ν = 3340, 3244 ( NH2) cm−1. – 1H NMR different dilutions of the test sample was added after 24 h of
(300 MHz, DMSO): δ = 2.81 (t, J = 7 Hz, 2H, CH2), 3.16 (t, seeding. Control cells were incubated without test sample.
J = 7 Hz, 2H, CH2), 3.77 (s, 3H, OMe), 3.86 (s, 3H, OMe), The microtiter plates were incubated at 37 ◦C in a humidi-
5.62 (s, 2H, NH2), 7.06 (s, 1H), 7.19 (s, 1H), 7.45 – 8.62 (m, fied incubator with 5% CO2 for a period of 48 h. Three wells
5H). – MS (EI, 70 eV): m/z(%) = 373 (7) [M]+, 149 (100). were used for each concentration of the test sample. The cell
– C21H19N5O2 (373.4): calcd. C 67.55, H 5.13, N 18.76; cytotoxic effect of each tested compound was determined us-
found C 67.51, H 4.92, N 18.83.
ing MTT assay [33].
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