Synthesis and biological activity of pyrazolothienotetrahydroisoquinoline and [1,2,4]triazolo[3,4-a]thienotetrahydroisoquinoline derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.11.036

1-Hydrazino-3-thioxo-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (3) was subjected to react with bifunctional compounds namely: acetylacetone, ethyl cyanoacetate, ethyl benzoylactate, diethylmalonate and ethyl acetoacetate to produce pyrazololthienotetr

Full text of DOI:10.1016/j.ejmech.2010.11.036

European Journal of Medicinal Chemistry 46 (2011) 567e578
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological activity of pyrazolothienotetrahydroisoquinoline and
[1,2,4]triazolo[3,4-a]thienotetrahydroisoquinoline derivatives
*
Adel M. Kamal, Shaban M. Radwan, Remon M. Zaki
Chemistry Department, Faculty of Science Assiut University, Assiut 71516, Egypt
a r t i c l e i n f o
a b s t r a c t
Article history:
1-Hydrazino-3-thioxo-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (3) was subjected to react with
bifunctional compounds namely: acetylacetone, ethyl cyanoacetate, ethyl benzoylactate, diethylmalonate
and ethyl acetoacetate to produce pyrazololthienotetrahydroisoquinoline derivatives 6e11. Also, heating
of compound (3) with formic acid afforded triazolothienotetrahydroisoquinoline compound 5 which
Received 9 August 2010
Received in revised form
20 November 2010
Accepted 24 November 2010
Available online 1 December 2010
reacted with a-halogenated compounds to afford compounds 13aee. Compound 13c when heated with
triethylorthoformate afforded triazolo derivative 14. Also, compound 6 was used for synthesizing
compounds 18e20. Representative compounds of the synthesized triazolo and pyrazolothienotetrahy-
droisoquinoline products were tested and evaluated as antimicrobial agents.
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
Hydrazinotetrahydroisoquinoline
Pyrazolothienotetrahydroisoquinoline
Triazolothienotetrahydroisoquinoline
Antimicrobial activity
1. Introduction
Tetrahydroisoquinoline derivatives are a class of selective
estrogen receptor modulators (SERMs) have high binding affinity
and specificity exhibiting up to 50 folds for ERa over ERb and
attractive targets in the treatment of breast cancer and the devel-
opment of receptor-based breast cancer imaging agents for diag-
nostic use in biomedical imaging technique positron emission
tomography (PET) [21].
Tetrahydroisoquinolines were identified as anti-platelet aggre-
gation agents. The investigations of the anti-platelet aggregation
mechanism of tetrahydroisoquinolines indicated that in addition to
1,2,3,4-Tetrahydroisoquinoline (THIQ) was
a common core
structure of many alkaloids isolated from natural sources and
showed antitumor [1], antimicrobial [2], and other biological
activities [3e7]. The recent success in total synthesis of ectei-
nascidin 743 [8,9] and its human clinical trials [10,11] have shed
light on this class of natural products.
In 1990, the isolation of the ecteinascidins, a new family of
tetrahydroisoquinoline alkaloids [1] was reported from the marine
tunicate Ecteinascidin tubinata [12]. Among these compounds,
ecteinascidin 743 (Et-743, Yondelis TM, I) is presently in phase II/III
clinical trials due to its exceedingly low nanomolar activity against
different tumor cell lines (Fig. 1) [13e15]. It has been demonstrated
that Et-743 (I) binds to guanine in the minor groove of DNA at the
reactive C-21 carbinolamine position. The restricted natural avail-
ability of Et-743 (I) from the tunicate has been overcome through
semi-synthesis of multigram quantities from the more readily
available metabolite cyanosafracin B (IIa). Cyanosafracin B (IIa) is
available in kilogram quantities through bacterial fermentation.
The route, developed by Cuevas and Manzanares at PharmaMar,
supports current clinical trials [16,17]. Closely related to the ectei-
nascidins, safracins IIaec were isolated in 1983 from Pseudomonas
fluorescens and also display potent antimicrobial and antitumor
activities [18e20].
receptor and
b-adrenergic/a2-adrenergic receptor system [22].
2. Results and discussion
2.1. Chemistry
Reaction of 4-cyano-1-morpholin-4-yl-5,6,7,8-tetrahydroiso-
quinoline-3(2H)thione (1) with hydrazine hydrate under neat
condition followed by addition of ethanol afforded 1-hydrazino-3-
thioxo-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (3) with loss
of morpholine molecule instead of the expected 1-morpholin-4-yl-
3-hydrazino-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (2). The
structure of the produced compound 3 was elucidated on the basis
of 1H NMR spectra which revealed the appearance of signals
characteristic to NH2, NH group at
d 7.8 and 10.5 ppm respectively
with disappearance of signals characteristic to aliphatic protons of
morpholine ring. The structure of compound 3 also confirmed by
mass spectrum which show molecular ion peak at 220.08 (m/z).
* Corresponding author. Tel.: þ20 123106643.
E-mail address: remonch2003@yahoo.com (R.M. Zaki).
0223-5234/$ e see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.11.036

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A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
OMe
OMe
Me
HO
17
Me
16
18
G
H
HO
NH
HO
MeO
E
15
F
O5
H
H
C
S
4
O
6
7
OAc
H
Me
H
N
NMe
14
Me
11
3
NMe
H
8
A
13
N
MeO
1
H
21
H
O
O
R
22
HO
O
NH
Me
O
I. Ecteinascidin 743
NH2
IIa, Cyanosafarin B; R= CN
IIb, Safracin A; R=H
IIc, Safracin B; R=OH
OMe
Me
HO
H
OAc
H
N
Me
NMe
H
H
O
O
C
Nphth
III. phtalascidin 650
Fig. 1. Ecteinacidin 743, the safracins and phtalasidin 650.
Thus hydrazino compound 3 was used as a key intermediate for
of 5 showed the disappearance of signals characteristic for NH, NH2
synthesis of new fused heterocyclic systems condensed with tet-
rahydroisoquinoline moiety.
groups and appearance of new signals at
to CH triazole Scheme 1.
d
9.6 ppm corresponding
When compound 3 condensed with aromatic aldehydes namely
benzaldrhyde, p-anisaldehyde and p-chlorobenzaldehyde in
refluxed ethanol afforded the corresponding hydrazones 4aec.
Hydrazino derivative 3 underwent ring closure upon heating
with formic acid to give 5-thioxo-7,8,9,10-tetrahydro-1H[1,2,4]
triazolo[3,4-a]isoquinoline-6-carbonitrile (5). The structure of
compound 5 was confirmed using spectral analysis. IR spectrum of
compound 5 revealed the disappearance of absorption bands at
3280, 3200 cmꢀ1 characteristic for NH, NH2 groups. 1H NMR spectra
Condensation of hydrazino derivative 3 with different
bifunctional compounds namely acetylacetone, ethyl cyanoace-
tate, ethyl benzoylacetate and diethylmalonate yielded the
hydrazones as intermediate that can’t be separated and under-
went ring closure under the same conditions (in situ) except in
case of reaction with ethyl acetoacetate which hydrazone deriv-
ative 10 was separated and underwent ring closure by using
ethanolic sodium ethoxide solution to give a variety of pyrazolo
derivatives 6e11 Scheme 2.
CN
CN
S
CN H2NNH2.H2O
S
NH2
N
N
N
H2NHN
X
N
N
N
H
H
O
H
O
2
3
1
HCOOH
reflux
H
O
EtOH
CN
S
CN
X
N
HN
N
N
N
H
N
S
H
4 a-c
5
X: a= H, b= OCH3, c= Cl
Scheme 1. Synthesis of mercaptohydrazinoisoquinoline 3 and its condensation reactions with aromatic aldehydes and formic acid giving mercaptotriazolo, mercapto-p-chloro
benzylidenehydrazinyl derivatives 4a-c, 5.

A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
569
CN
CN
N
N
N
H
S
N
N
N
S
H
Ph
O
H C
CH
8
6
CH COCH COCH
CN
S
PhCOCH CO Et
H C
O
CN
S
N N
H
O
N
CH COCH CO Et
NCCH CO Et
H
H NHN
N
H
10
Et
CH (CO Et)
3
EtONa
CN
CN
S
HN
N
N
S
HN
N
N
CN
S
H
H
O
NH
N
N
O
O
N
H
O
7
9
H C
11
Scheme 2. Synthesis of mercatopyrazolotetrahydroisoquinolines 6-11.
Alkylation of 5-thioxo-7,8,9,10-tetrahydro-1H[1,2,4]triazolo[3,4-
a]isoquinoline-6-carbonitrile (5) with -halogenated carbonyl
Compound 16e was synthesized by an alternative method
through a reaction of 1-hydrazino-3-thioxo-5,6,7,8-tetrahydroiso-
quinoline-4-carbonitrile (3) with ethyl chloroacetate and fused
sodium acetate in refluxing ethanol to afford ethyl(4-cyano-1-
hydrazino-5,6,7,8-tetrahydroisoquinolin-3-ylsulfanyl)acetate (17).
Condensation of compound 17 with p-chlorobenzaldehyde affor-
ded ethyl-1-(2-p-chlorobenzylidene hydrazinyl)-4-cyano-5,6,7,8-
tetrahydroisoquinoline-3-sulfanyl-acetate (15b) which underwent
ThorpeeZiegler cyclization to afford ethyl-1-amino-5-(2-p-chlor-
obenzylidenehydrazinyl)-6,7,8,9-tetrahydrothieno[2,3-c]isoquino-
line-2-carboxy-late (16b). Compounds 15b, 16b prepared by the
two methods were identical in all aspects Scheme 5.
a
compounds in ethanol in the presence of sodium acetate furnished
compounds 12aee. Compounds 12aee underwent Thorpe-Ziegler
cyclization upon heating with ethanolic sodium ethoxide solution
to give 7-amino-6-substituted-8,9,10,11-tetrahydrothieno[2,3-c]
[1,2,4]triazolo[3,4-a]isoquino-line (13aee). 1,2,3,4-Tetrahydro-10-
oxopyrimido[40,50:4,5]thieno[2,3-c][1,2,4]triazolo [3,4-a]isoquino-
line (14) was synthesized via condensation of compound 13c with
triethylorthoformate Scheme 3.
Also compound 4c reacts with a-halogenated carbonyl compounds
inethanolin thepresenceof fusedsodiumacetateto affordcompounds
15aee. Compounds 15aee underwent ThorpeeZiegler cyclization
reaction upon refluxing with ethanolic sodium ethoxide solution
to give 1-amino-2-substituted-5-(2-p-chlorobenzylidenehydrazinyl)-
6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline (16aee) Scheme 4.
In analogues manner, reaction of compound 6 with a-halogenated
carbonylcompoundsinethanolinthepresenceofsodiumacetategave
S-alkylated products 18aee. Compounds 18aee underwent Thor-
peeZiegler cyclization reaction to give 2-substituted-1-amino-5-
C N
C N
+
C H3 C O O Na
X
Y
/ stirring
EtO H
N
N
N
S
Y
S
HN
N
N
5
12a-e
C H3 C O O Na
EtO Na/EtO H
/ reflux
EtO H
N
O
N H2
Y
13c
H C(OEt)3/ AcO H
N H
N
N
N
S
N
N
N
S
14
13a-e
X =C l, B r
Y : a= C N , b= C O 2Et, c=C O N H 2, d= C O C H 3, e= C O Ph
Scheme 3. Synthesis of triazolothienotetrahydroisoquinolines 13a-e.

570
A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
Cl
CN
Cl
CN
S
CH3CO2Na
EtOH/reflux
+
X
Y
N
N
N
H
N
H
S
N
H
N
15a-e
Y
4c
EtONa/EtOH
X= Cl, Br
Y: a= CN, b= CO2Et, c= CONH2, d= COCH3, e= COPh
Cl
NH2
N
N
H
N
S
Y
16a-e
Scheme 4. Synthesis of -p-chlorobenzylidenehydrazinylthienotetra hydroisoquinolines 16a-e.
CN
CN
S
ClCH2CO2Et/ AcONa
H2NNH
N
17
SCH2CO2Et
H2NNH
N
H
3
p-ClPhCHO/ EtOH
Cl
NH2
K2CO3/ EtOH
Cl
CN
SCH2CO2Et
N
CO2Et
N
N
S
N
H
N
N
H
16b
15b
Scheme 5. An alternative method for synthesis of ethyl-amino-p-chlorobenzylidenehydrazinyl thienotetrahydroisoquinolinecarboxylate 16b.
morpholin-4-yl-6,7,8,9-tetrahydrothieno[2,3-c]isoquinoline (19aee).
Also compounds 19aee were obtained directly from pyrazolylthione
3. Pharmacology
derivative 6 using
a-halogenated compounds in refluxing ethanol in
3.1. Antimicrobial activity
the presence of anhydrous potassium carbonate. Heating compound
19c with triethylorthoformate yielded 5-(3,5-dimethylpyrazol-1-yl)-
1,2,3,4-tetrahydropyrimido[40,50:4,5]thieno[2,3-c]isoquinolin-8(9H)-
one (20) Scheme 6.
Some of the synthesized compounds in this work were chosen
and screened in vitro for their antimicrobial activity against some
strainsof bacteria andfungi Tables1 and2, 2. The antifungal activities
CN
CN
CH3COONa
+
X
Y
EtOH / reflux
N
N
N
S
Y
N
N
N
S
H
H3C
CH3
H3C
CH3
18a-e
6
X
Y
EtONa/EtOH
K2CO3
EtOH/ reflux
NH2
18c
N
O
HC(OEt)3/ AcOH
Y
NH
N
N
N
S
S
N
N
N
H3C
CH3
H3C
CH3
20
19a-e
X=Cl, Br
Y: a= CN, b= CO2Et, c=CONH2, d= COCH3, e= COPh
Scheme 6. Synthesis of pyrazolothienotetra hydroisoquinolines 19a-e.

A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
571
of tested compounds were evaluated by the reported method [23]
using 2% concentration of selected compounds in DMSO as
a solvent. The inhibition zone (mm) was compared with clotrimazole
as a reference. In the case of antibacterial activities also the
concentrationof testedcompounds was2%andtheinhibition zone in
(mm) was compared with chloramphenicol as a reference.
3.2. Conclusion
The tested compounds of novel synthesized triazolo and pyr-
azolothienotetrahydro isoquinolines showed antibacterial and anti-
fungal activities. For example, compound 3 showed antibacterial
against moststrainseither gram(þve) bacteria such as Bacilluscereus,
Staphylococcus aureus and Micrococcus luteus or gram (ꢀve) bacteria
such as Escherichia coli. Also, compound 3 showed antifungal activity
against certain fungi like Candida albicans, Trichophyton rubrum,
Fusarium oxysporum and Aspergillus niger. For triazolo derivatives, It’s
noticeable that 5-substituted-mercapto-6-cyano-7,8,9,10-tetrahydro
[1,2,4]triazolo[3,4-a]isoquinoline compounds 12aee have antibac-
terial effect higher than the cyclized 7-amino-6-substituted-
8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]triazolo[3,4-a]isoquinoline
compounds 13aee in most cases except for 12a, 13a towards Serratia
marcescens and E. coli which the amino derivatives have the higher
effect. In case of pyrazolo derivatives different results were observed,
the cyclized 1-amino-2-substituted-5-(3,5-dimethylpyrazol-1-yl)-
6,7,8,9-tetrahydro thieno[2,3-c]isoquinoline 19aee showed equal (or
higher in some cases) antibacterial activities than 3-sub-
stitutedsulfanyl-1-(3,5-dimethylpyrazol-1-yl)-5,6,7,8-tetrahydro
isoquinoline-4-carbonitrile 18aee. It’s noticeable that presence of
carbonitrile group in triazolo and pyrazolo derivatives 12a, 13a, 17a
and 18a increases their antibacterial activity towards S. marcescens.
While the triazolo derivatives show higher antibacterial activity
towards B. cereus and M. luteus. The benzoyltriazolo derivatives show
the highest antifungal activity than the other tested compounds
especially towards Aspergillus flavus and A. niger.
On the other hand, 1-hydrazino-3-thioxo-5,6,7,8-tetrahydroiso-
quinoline-4-carbo-nitrile (3) showed remarkable antifungal activi-
ties towards most tested fungi. In triazolo derivatives only 6-cyano-
7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]isoquinoline-5-sulfanylace-
tophenone (12e) and 7-amino-6-benzoyl-8,9,10,11-tetrahydrothieno
[2,3-c][1,2,4]triazolo[3,4-a]isoquinoline (13e) have significant anti-
fungal activity towards most strains but in case of pyrazolo deriva-
tives 17d, 18d showed higher antifungal activities than the other
pyrazolo substituents.
4. Experimental
All melting points are uncorrected and measured on a Fisher-John
apparatus. IR spectra were recorded with a PerkineElmer 1430
Spectrophotometer using KBr wafer technique.1H NMR and 13C NMR
spectra were obtained on a Varian EM-390 (90 MHz) and Joel
400 MHz spectrometer in CDCl3, DMSO-d6 and CF3CO2D using Me4Si
as internal standard, and chemical shifts are expressed as ppm. Mass
spectra were measured on a Jeol-JMS 600 spectrometer. Analytical
data were obtained on Elementar Analysensysteme GmbH-VarioEL
V.3 microanalyzer in the central lab of Assiut University. 1-Morpho-
lin-4-yl-3-mercapto-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile
(1) wasprepared accordingto reported procedure [24]. Numberingof
carbon atoms used in 13C NMR analysis is shown in Fig. 2.
4.1. 1-Hydrazino-3-thioxo-5,6,7,8-tetrahydroisoquinoline-4-
carbonitrile (3)
Compound 1 (2.75 g, 0.01 mol) and hydrazine hydrate (3 mL,
0.06 mol) was fused for 1 h then ethanol (10 mL) was added and

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A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
reflux continued for additional 1 h. The yellow precipitate, which
formed, was filtered off and recrystallized from a mixture of
ethanol/dioxane as yellow crystals in 73% yield. M.p.: 298e300 ꢁC.
IR (cmꢀ1 KBr)
n
¼ 3450, 3290, 3190 (NH, NH2), 2200 (CN), 2930 (CH
aliphatic), 1640 (C]N), 1250 (C]S). 1H NMR (400 MHz, DMSO-d6):
dppm ¼ 1.65e1.70 (m, 2H, CH2), 2.05e2.15 (m, 4H, 2CH2), 2.70e2.75
(m, 2H, CH2), 7.50e7.80 (s br, 3H, NH þ NH2 disappeared by D2O),
9.50 (s, 1H, NH disappeared by D2O). 13C NMR (400 MHz, DMSO-
d6): dppm ¼ 170.90 (C]S), 152.40 (C-3), 152.30 (C-9), 115.60 (CN),
105.70 (C-8), 99.00 (C-4), 21.20e40.80 (m, 4CH2). MS m/z (%):
220.08 (Mþ, 100), 217.07 (38.20), 202.05 (44.90), 190.05 (71.40),
170.07 (39.10). 162.03 (21.50), 104.05 (24.60). Anal. Calcd. for:
C10H12N4S: C, 54.52; H, 5.49; N, 25.43; S, 14.55%. Found: C, 54.32; H,
5.70; N, 25.25; S, 14.72%.
4.2. 1-(2-Arylidenehydrazinyl)-3-thioxo-5,6,7,8-
tetrahydroisoquinoline-4-carbo nitrile (4aec)
General procedure: Compound 3 (1 g, 4.5 mmol) was fused with
the appropriate aromatic aldehyde (2 mL) for 5 min then ethanol
(5 mL) was added and reflux continued for additional 2 h. The solid
precipitate, which formed, was filtered off and recrystallized from
dioxane.
4.2.1. 1-(2-Benzylidenehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroisoquinoline-3(2H)-thione (4a)
Obtained from compound 3 and beꢀn1zaldehyde as green crystals
in 82% yield. M.p. 310e312 ꢁC. IR (cm KBr)
n
¼ 3450 (NH), 3020
(CH aromatic), 2920, 2850 (CH aliphatic), 2200 (CN), 1610 (C]N),
1255 (C]S). 1H NMR (90 MHz, CF3CO2D): dppm ¼ 1.90e2.00 (m, 2H,
CH2), 2.60e2.70 (m, 4H, 2CH2), 3.00e3.05 (m, 2H, CH2), 7.60e7.90
(m, 5H, ArH), 8.65 (s, 1H, N]CH). 13C NMR (400 MHz, DMSO-d6):
dppm ¼ 173.20 (C]S), 154.57 (C-3), 154.25 (C-9), 145.20 (CH]N),
127.25e134.20 (5C-aromatic), 118.15 (CN), 106.48 (C-8),
20.01e40.54 (4CH2 cyclohexeno). Anal. Calcd. for: C17H16N4S: C,
66.21; H, 5.23; N, 18.17; S, 10.40%. Found: C, 66.00; H, 5.45; N, 18.25;
S, 10.30%.
4.2.2. 4-Cyano-1-(2-p-methoxybenzylidenehydrazinyl)-5,6,7,8-
tetrahydroiso quinoline-3(2H)-thione (4b)
Obtained from compound 3 and p-anisaldehyde as yellow
crystals in 84% yield. M.p. 316e318 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3400 (NH),
3030 (CH aromatic), 2920 (CH aliphatic), 2200 (CN), 1610 (C]N),
1250 (C]S). 1H NMR (90 MHz, CF3CO2D): dppm ¼ 2.00e2.10 (m, 2H,
CH2), 2.65e2.70 (m, 4H, 2CH2), 3.00e3.05 (m, 2H, CH2), 4.10 (s, 3H,
CH3) 7.20, 7.80 (2d, J ¼ 9.0, 8.4 Hz, 4H, p-sub ArH), 8.6 (s, 1H, N]
CH). MS m/z (%): 338.21 (Mþ, 9.3), 204.98 (100), 189.96 (8.70),
150.03 (11.30), 134.03 (26.30), 76.96 (26.80). Anal. Calcd. for:
C18H18N4OS: C, 63.88; H, 5.36; N, 16.55; S, 9.47%. Found: C, 64.00; H,
5.25; N, 16.45; S, 9.60%.
4.2.3. 1-(2-p-Chlorobenzylidenehydrazinyl)-3-thioxo-5,6,7,8-
tetrahydroisoquinoline-4-carbonitrile (4c)
Hydrazino compound
3 (1 g, 4.5 mmol) and p-chlor-
obenzaldehyde (0.63 g, 4.5 mmol) was refluxed in ethanol (20 mL) in
presence of piperidine for 2 h. The solid precipitate, which formed,
was filtered off and recrystallized from dioxane as orange crystals in
82% yield. M.p.: 348e350 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3450 (NH), 3050 (CH
aromatic), 2920 (CH aliphatic), 2210 (CN), 1620 (C]N), 1260 (C]S).
1H NMR (90 MHz, CF3CO2D): dppm ¼ 1.90e1.95 (m, 2H, CH2),
2.60e2.70 (m, 4H, 2CH2), 3.15e3.20 (m, 2H, CH2), 7.40, (d, J ¼ 7.5 Hz,
2H, p-sub. ArH), 7.80 (d, J ¼ 10.5 Hz, 2H, p-sub. ArH), 8.50 (s, 1H, N]
CH). 13C NMR (400 MHz, DMSO-d6): dppm ¼ 176.38 (C]S),157.62 (C-
3), 157.00 (C-9), 144.26 (CH]N), 128.55e133.63 (5C-aromatic),
120.25 (CN), 106.34 (C-8), 20.15e40.50 (4CH2 cyclohexeno). Anal.

A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
573
6
6
6
1
2
5
3
1
2
5
1
2
5
10
1 1
3
10
N
4
8
3
N
8
N
4
9
4
9
8
7
7
9
7
HN
N
N
N
S
S
N
H
H2N
13 12
N
N
S
N
1 0
19 O
O
H
H
11
3
5
9
Fig. 2. Numbering of carbon atoms for compounds 3,5 and 9.
Calcd. for: C17H15ClN4S: C, 59.56; H, 4.41; Cl,10.34; N,16.34; S, 9.35%.
Found: C, 59.32; H, 4.60; Cl, 10.50, N, 16.28; S, 9.30%.
4.4.3. 1-(3-Phenyl-5-oxo-4,5-dihydropyrazol-1-yl)-3-thioxo-
5,6,7,8-tetrahydroiso quinoline-4-carbonitrile (8)
Obtained from compound 3 and ethyl benzoylacetate which was
4.3. 5-Thioxo-7,8,9,10-tetrahydro-1H[1,2,4]triazolo[3,4-a]
isoquinoline-6-carbo nitrile (5)
recrystallized from a mixture of ethanol/dioxane as pale brown
crystals in 63% yield. M.p.: 310e312 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3120 (NH),
3050 (CH aromatic), 2920, 2850 (CH aliphatic), 2200 (CN), 1630
(CO), 1600 (C]N), 1250 (C]S). 1H NMR (90 MHz, DMSO-d6):
dppm ¼ 1.80e1.90 (m, 4H, 2CH2), 2.45e2.55 (m, 4H, 2CH2), 2.70 (s,
Hydrazino derivative 3 (1 g, 4.5 mmol) and formic acid (10 mL)
was refluxed for 1/2 h. The solid product, which formed, was
filtered off and recrystallized from ethanol as white crystals in 80%
2H, CH2CO), 7.30e7.90 (m, 5H, ArH), 10.50 (s, 1H, NH pyridine). 13
C
yield. M.p.: >360 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3120 (NH), 2950 (CH
NMR (400 MHz, DMSO-d6): dppm ¼ 178.58 (C]S), 170.37 (C-3),
168.85 (C-12), 159.70 (C-9), 122.78e134.53 (5C-aromatic), 118.00
(CN), 49.85 (CH2 pyrazole), 22.26e40.58 (4CH2 cyclohexeno). Anal.
Calcd. for: C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20%. Found:
C, 65.32; H, 4.74; N, 16.24; S, 9.00%.
aliphatic), 2200 (CN), 1615 (C]N), 1250 (C]S). 1H NMR (90 MHz,
DMSO-d6): dppm ¼ 1.65e1.80 (m, 4H, 2CH2), 2.75e2.85 (m, 4H,
2CH2), 9.70 (s, 1H, CH triazole), 10.90 (s, 1H, NH pyridine). 13C NMR
(400 MHz, DMSO-d6): dppm ¼ 178.43 (C]S), 152.76 (C-3), 149.76
(C-9), 137.38 (C-10), 122.63 (C-11), 105.87 (C-8), 99.96 (C-4),
22.21e42.52 (4CH2 cyclohexeno). MS m/z (%): 230.09 (Mþ, 41.30),
185.08 (34), 183.12 (100), 107.12 (21), 93.12 (42), 83.17 (20), 77.09
(49), 69.10 (29). Anal. Calcd. for: C11H10N4S: C, 57.37; H, 4.38; N,
24.33; S, 13.92%. Found: C; 57.50, H, 4.18; N, 24.55; S, 13.77%.
4.4.4. 4-Cyano-1-(3,5-dioxopyrazol-1-yl)-5,6,7,8-
tetrahydroisoquinoline-3(2H)-thione (9)
Obtained from compound 3 and diethylmalonate which was
recrystallized from dioxane as pale yellow crystals in 88% yield.
M.p.: 328e330 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3220, 3120 (2NH), 2920, 2850
4.4. Synthesis of pyrazolo compounds (6e11)
(CH aliphatic), 2200 (CN), 1730, 1685 (2CO), 1600 (C]N), 1210 (C]
S). 1H NMR (90 MHz, DMSO-d6): dppm ¼ 1.80e1.90 (m, 4H, 2CH2),
2.60e2.65 (m, 2H, CH2), 2.70e2.80 (m, 2H, CH2), 4.70 (s, 2H, CH2
General procedure: A mixture of 1-hydrazino-3-thioxo-5,6,7,8-
tetrahydroisoquinoline-4-carbonitrile (3) (1 g, 4.5 mmol) and active
methylene compound (20 mmol) was fused for 1 h then absolute
ethanol (20 mL) was added dropwise and reflux continued for
additional 2 h. The solid product, which formed, was filtered off and
recrystallized from the proper solvent.
pyrazole), 9.80 (s, 1H, NH pyrazole), 10.30 (s, 1H, NH pyridine). 13
C
NMR (400 MHz, DMSO-d6): dppm ¼ 180.72 (C]S), 174.15 (C-13),165.
24 (C-13), 158.95 (C-12), 150.54 (C-9), 119.18 (C-10), 110.85 (C-8),
51.80 (C-11), 21.32e38.65 (4CH2 cyclohexeno). Anal. Calcd. for:
C13H12N4O2S: C, 54.15; H, 4.20; N, 19.43; S, 11.12%. Found: C, 54.35;
H, 4.00; N, 19.65; S, 11.25%.
4.4.1. 4-Cyano-1-(3,5-dimethylpyrazol-1-yl)-5,6,7,8-
tetrahydroisoquinoline-3(2H)-thione (6)
4.4.5. Ethyl-3-[(4-cyano-3-thioxo-5,6,7,8-tetrahydroisoquinolin-1-
yl)hydrazono] butyrate (10)
Obtained from compound 3 and acetylacetone which was
recrystallized from dioxanꢀe1as brilliant yellow crystals in 86% yield.
Obtained from compound 3 and ethyl acetoacetate which was
recrystallized from ꢀd1ioxane as orange crystals in 73% yield. M.p.:
M.p.: 322ꢀ324 ꢁC. IR (cm KBr)
n
¼ 3120 (NH), 2950, 2820 (CH
aliphatic), 2210 (CN), 1600 (C]N), 1200 (C]S). 1H NMR (90 MHz,
CF3CO2D): dppm ¼ 1.95e2.05 (m, 4H, 2CH2), 2.50, 2.70 (2s sharp, 6H,
2CH3 pyrazole), 2.60e2.65 (m, 2H, CH2), 3.10e3.15 (m, 2H, CH2),
6.60 (s, 1H, CH pyrazole). Mass spectrum m/z (%): 284.02 (Mþ, 100),
283.03 (33), 251.04 (90), 241.99 (37), 227.99 (12), 210.04 (7), 115.93
(5). Anal. Calcd. for: C15H16N4S: C, 63.35; H, 5.67; N, 19.70; S, 11.27%.
Found: C, 63.57; H, 5.73; N, 20.00; S, 1138%.
208e210 ꢁC. IR (cm KBr)
n
¼ 3350, 3120 (2NH), 2920, 2850 (CH
aliphatic), 2200 (CN), 1740 (CO ester), 1600 (C]N), 1220 (C]S). 1H
NMR (90 MHz, CDCl3): dppm ¼ 1.30 (t, J ¼ 7.5 Hz, 3H, CH3 ester),
1.70e1.80 (m, 4H, 2CH2), 2.30 (s sharp, 3H, CH3), 2.50e2.60 (m, 2H,
CH2), 3.30e3.40 (m, 2H, CH2), 3.65 (s, 2H, CH2CO), 4.10 (q, J ¼ 6.0 Hz,
2H, CH2 ester), 8.10 (s, 1H, NH hydrazone), 10.25 (s, 1H, NH pyri-
dine). Anal. Calcd. for: C16H20N4O2S: C, 57.81; H, 6.06; N, 16.85; S,
9.65%. Found: C, 58.00; H, 5.93; N, 17.05; S, 9.84%.
4.4.2. 1-(5-Amino-3-oxo-2,3-dihydropyrazol-1-yl)-3-thioxo-
5,6,7,8-tetrahydroiso quinoline-4-carbonitrile (7)
Obtained from compound 3 and ethyl cyanoacetate which was
recrystallized from a mixture of ethanol/dioxane as brown crystals
4.4.6. 1-(3-Methyl-5-oxo-4,5-dihydropyrazol-1-yl)-3-thioxo-
5,6,7,8-tetrahydroiso quinoline-4-carbonitrile (11)
A solution of compound 10 (0.33 g, 1 mmol) in absolute ethanol
(20 mL) and few drops of sodium ethoxide solution were refluxed
for 20 min. The solid precipitate, which formed, was filtered off
and recrystallized from ethanol as brown crystals in 53% yield.
in 72% yield. M.p.: 318e320 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3250, 3240, 3120
(NH, NH2), 2200 (CN), 1700 (C]O), 1600 (C]N), 1200 (C]S). 1H
NMR (90 MHz, CF3CO2D): dppm ¼ 2.10e2.20 (m, 4H, 2CH2), 2.85e3.95
(m, 4H, 2CH2), 5.15 (s, 1H, CH pyrazole). 13C NMR (400 MHz, DMSO-
d6): dppm ¼ 179.88 (C]S), 166.20 (C-3), 162.38 (C-13), 154.54 (C-9),
118.76 (C-10), 110.87 (C-8), 92.24 (C-11), 22.84e41.36 (4CH2 cyclo-
hexeno). Anal. Calcd. for: C13H13N5OS: C, 54.34; H, 4.56; N, 24.37; S,
11.16%. Found: C, 54.15; H, 4.66; N, 24.50; S, 11.25%.
M.p.: 312e314 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3120 (NH), 2920, 2850 (CH
aliphatic), 2210 (CN), 1640 (CO), 1600 (C]N), 1230 (C]S). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.10 (s, 3H, CH3), 1.60e1.70 (m, 4H, 2CH2),
2.20e2.25 (m, 2H, CH2), 2.75e2.80 (m, 2H, CH2), 4.00 (s, 2H, CH2),
11.00 (s, 1H, NH pyridine). 13C NMR (400 MHz, DMSO-d6):

574
A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
dppm ¼ 177.73 (C]S), 161.23 (C-3), 159.41 (C-9), 156.90 (C-13),
119.12 (C-10), 111.52 (C-8), 50.78 (CH2 pyrazole), 21.35e43.68
(4CH2 cyclo-hexeno), 15.30 (CH3 pyrazole). Anal. Calcd. for:
C14H14N4OS: C, 58.72; H, 4.93; N, 19.57; S, 11.20%. Found: C, 58.85;
H, 5.10; N, 19.70; S, 11.38%.
NMR (90 MHz, CDCl3): dppm ¼ 1.80e1.90 (m, 4H, 2CH2), 2.75e2.80
(m, 2H, CH2), 3.05e3.10 (m, 2H, CH2), 4.70 (s, 2H, CH2), 7.30e7.90
(m, 5H, ArH), 9.20 (s, 1H, CH triazole). MS m/z (%): 347.43 (Mþ ꢀ 1,
30.70), 99.26 (100), 83.89 (8.60), 73.37 (34.80). Anal. Calcd. for:
C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20%. Found: C, 65.34; H,
4.75; N, 15.96; S, 9.38%.
4.5. Alkylation of 5-thioxo-7,8,9,10-tetrahydro-1H[1,2,4]triazolo
[3,4-a]isoquinoline-6-carbonitrile (12aee)
4.6. Cyclization of 5-substitutedmercapto-6-cyano-7,8,9,10-
tetrahydro[1,2,4] triazolo[3,4-a]isoquinoline (13aee)
General procedure: A mixture of 5 (1.00 g, 4 mmol) and of
alkylating agent (4 mmol) in presence of fused sodium acetate
(1.20 g, 1.50 mmol) was stirred in ethanol (30 mL) for 1/4 h. A white
precipitate, which formed on cooling and dilution with water, was
filtered off and recrystallized from ethanol.
4.6.1. Method A
General procedure: A solution of the alkylated compound 12aee,
(1 mmol) in absolute ethanol (20 mL) and few drops of sodium
ethoxide solution (prepared from 0.5 g of clean sodium on 20 mL
absolute ethanol) were refluxed for 10 min. The solid precipitate
which formed on cold or dilution with water was filtered off and
recrystallized from the proper solvent.
4.5.1. 6-Cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-5-sulfanyl acetonitrile (12a)
Obtained from 6-cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline (5) and chloroacetonitrile which was recrystallized
from ethanol as pale yellow crystals in 54% yield. M.p.: 230e232 ꢁC.
4.6.1.1. 7-Amino-8,9,10,11–tetrahydrothieno[2,3-c][1,2,4]triazolo[3,4-
a]isoquino-line-6-carbonitrile (13a). Obtained from compound 12a
which was recrystallized from DMSO as white needles in 84% yield.
M.p.: 320e322 ꢁC.
IR (cmꢀ1 KBr)
n
¼ 2950, 2850 (CH aliphatic), 2210 (CN), 1610 (C]N).
Anal. Calcd. for: C13H11N5S: C, 57.98; H, 4.12; N 26.00; S 11.91%.
Found: C, 58.10; H, 4.25; N, 25.82; S, 11.82%.
4.6.1.2. Ethyl-7-amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]tri-
azolo[3,4-a] isoquinolin-6-acetate (13b). Obtained from compound
12b which was recrystallized from dioxane as white needles in 75%
yield. M.p.: 248e250 ꢁC.
4.5.2. Ethyl-6-cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-5-sulfanyl acetate (12b)
Obtained from compound 5 and ethyl chloroacetate which was
recrystallized from ethanol as white crystals in 60% yield. M.p.:
180e182 ꢁC. IR (cmꢀ1 KBr)
n
¼ 2920, 2850 (CH aliphatic), 2200 (CN),
4.6.1.3. 7-Amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]triazolo[3,4-
a]isoquinoline-6-carboxamide (13c). Obtained from compound 12c
which was recrystallized from ethanol as white needles in 81%
yield. M.p.: 272e274 ꢁC.
1660 (CO ester), 1610 (C]N). MS m/z (%): 315.97 (Mþ, 100), 269.97
(68), 241.05 (22), 215.94 (7), 160.97 (8). Anal. Calcd. for:
C15H16N4O2S: C, 56.95; H, 5.10; N,17.71; S,10.13%. Found: C, 57.10; H,
5.25; N, 17.54; S, 10.25%.
4.6.1.4. 6-Acetyl-7-amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]tri-
azolo[3,4-a]iso quinoline (13d). Obtained from compound 12d
which was recrystallized from DMSO as white needles in 87% yield.
M.p.: 268e270 ꢁC.
4.5.3. 6-Cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-5-sulfanyl acetamide (12c)
Obtained from compound 5 and chloroacetamide which was
recrystallized from ethanꢀo1l as pale yellow crystals in 58% yield.
M.p.: 218e220 ꢁC. IR (cm KBr)
n
¼ 3400, 3350 (NH2), 2920 (CH
4.6.1.5. 7-Amino-6-benzoyl-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]
triazolo[3,4-a]isoquinoline (13e). Obtained from compound 12e
which was recrystallized from ethanol as yellow needles in 91%
yield. M.p.: 292e294 ꢁC.
aliphatic), 2210 (CN), 1660 (CO amide), 1610 (C]N). 1H NMR
(90 MHz, DMSO-d6): dppm ¼ 1.65e1.75 (m, 4H, 2CH2), 2.80e2.90 (m,
2H, CH2), 3.30e3.40 (m, 2H, CH2), 3.90 (s, 2H, CH2), 7.20 (s, 2H,
NH2), 9.60 (s, 1H, CH triazole). Anal. Calcd. for: C13H13N5OS: C,
54.34; H, 4.56; N, 24.37; S, 11.16%. Found: C, 54.52; H, 4.63; N, 24.50;
S, 11.00%.
4.6.2. Method B
A mixture of 5-thioxo-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-6-carbo-nitrile (5) (1 g, 4 mmol) and alkylating agent
(4 mmol) in presence of fused sodium acetate (1.2 g, 1.5 mmol) was
refluxed in ethanol (30 mL) for 2 h. A white precipitate is formed on
hot filtered off, dried and recrystallized from the proper solvent.
4.5.4. 6-Cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-5-sulfanyl acetone (12d)
Obtained from compound 5 and chloroacetone which was
recrystallized from ethanol as pale yellow crystals in 62% yield.
M.p.: 268e270 ꢁC. IR (cmꢀ1 KBr)
n
¼ 2920, 2850 (CH aliphatic), 2210
4.6.2.1. 7-Amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]triazolo[3,4-
a]isoquinoline-6-carbonitrile (13a). Obtained from triazolo com-
pound 5 and chloroacetonitrile which was recrystallized froꢀm1
DMSO as white needles in 76% yield. M.p.: 320e322 ꢁC. IR (cm
(CN), 1710 (C]O), 1600 (C]N). 1H NMR (90 MHz, CDCl3):
dppm ¼ 1.70e1.90 (m, 4H, 2CH2), 2.30 (s sharp, 3H, CH3), 2.70e2.80
(m, 2H, CH2), 2.90e3.05 (m, 2H, CH2), 4.00 (s, 2H, CH2), 9.20 (s, 1H,
CH triazole). MS m/z (%): 285.85 (100), 283.87 (36.50), 269.89 (15),
250.87 (30), 242.9 (39), 115.88 (10), 76.96 (13). Anal. Calcd. for:
C14H14N4OS: C, 58.72; H, 4.93; N, 19.57; S, 11.20%. Found: C, 58.55;
H, 5.05; N, 19.70; S, 11.00%.
n
KBr) ¼ 3350, 3250, 3100 (NH2), 2920, 2850 (CH aliphatic), 2200
(CN), 1645 (C]N). 1H NMR (CF3CO2D): dppm ¼ 2.10e2.15 (m, 2H,
CH2), 3.10e3.20 (m, 4H, 2CH2), 3.55e3.60 (m, 2H, CH2), 9.60 (s, 1H,
CH triazole). Anal. Calcd. for: C13H11N5S: C 57.98; H 4.12; N 26.00; S
11.91%. Found: C, 57.75; H, 4.25; N; 26.16; S, 11.84%.
4.5.5. 6-Cyano-7,8,9,10-tetrahydro[1,2,4]triazolo[3,4-a]
isoquinoline-5-sulfanyl acetophenone (12e)
4.6.2.2. Ethyl-7-amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]tri-
azolo[3,4-a] isoquinoline-6-acetate (13b). Obtained from compound
5 and ethyl chloroacetate which was recrystallized from dioxane as
white needles in 69% yield. M.p.: 248e250 ꢁC. IR (cmꢀ1 KBr)
Obtained from compound 5 and phenacyl bromide which was
recrystallized from ethanol as pale yellow crystals in 85% yield.
M.p.: 176e178 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3050 (CH aromatic), 2920, 2850
(CH aliphatic), 2210 (CN), 1675 (unsaturated CO), 1600 (C]N), 1H
n
¼ 3450, 3320 (NH2), 2920 (CH aliphatic); 1660 (CO ester), 1610

A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
575
(C]N). 1H NMR (CF3CO2D): dppm ¼ 1.40 (t, J ¼ 9.0 Hz, 3H, CH3),
4.8. Alkylation of 1-(2-p-Chlorobenzylidenehydrazinyl)-3-thioxo-
5,6,7,8-tetra hydroisoquinoline-4-carbonitrile (15aee)
2.10e2.20 (m, 2H, CH2), 3.15e3.30 (m, 4H, 2CH2), 3.60e3.70 (m, 2H,
CH2), 4.40 (q, J ¼ 7.5 Hz, 2H, CH2), 9.60 (s, 1H, CH triazole). Mass
spectrum m/z (%): 315.87 (Mþ, 58), 298.13 (42), 269.84 (100),
243.88 (56), 241.01 (64), 214.95 (94),199.88 (36),181.01 (56),134.86
(25), 116.93 (58). Anal. Calcd. for: C15H16N4O2S: C 56.95; H 5.10; N
17.71; S 10.13%. Found: C, 57.10; H, 4.98; N, 17.85; S, 10.00%.
General procedure: A mixture of p-chlorobenzylidene derivative
4c (0.5 g, 1.5 mmol) and alkylating agent (1.5 mmol) in presence of
fused sodium acetate (0.6 g, 6.8 mmol) in ethanol (20 mL) was
refluxed for 2 h. The solid product, which formed, was filtered off
and recrystallized from ethanol.
4.6.2.3. 7-Amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]triazolo[3,4-
a]isoquinoline-6-carboxamide (13c). Obtained from compound 5
and chloroacetamide which was recrystallized from ethꢀa1nol as
4.8.1. 1-(2-p-Chlorobenzylidenehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3-thiomethylcyanide (15a)
white needles in 75% yield. M.p.: 272e274 ꢁC. IR (cm
KBr)
Obtained from compound 4c and chloroacetonitrile as white
n
¼ 3350, 3300, 3250 (2NH2), 2950 (CH aliphatic), 1665 (C]O). 1H
crystals in 81% yield. M.p. 188e190 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3300 (NH),
NMR (90 MHz, DMSO-d6): dppm ¼ 1.70e1.75 (m, 2H, CH2),
2.80e2.90 (m, 4H, 2CH2), 3.10e3.20 (m, 2H, CH2), 6.90 (s, 2H,
CONH2), 7.30 (s, 2H, NH2), 9.50 (s, 1H, CH triazole). 13C NMR
(400 MHz, DMSO-d6): dppm ¼ 169.56 (C]O amide), 155.36 (C-3),
154.83 (C-7), 150.26 (C-9), 144.00 (C-10), 133.05 (C-12), 122.35 (C-
11), 93.65 (C-8), 19.85e45.30 (4CH2 cyclohexeno). MS m/z (%):
287.05 (Mþ, 16.60), 286.40 (Mþ ꢀ 1, 28.10), 269.65 (48.20), 248.85
(27.20), 240.71 (29.30), 213.58 (15.70), 190.81 (16.30), 149.84 (100),
104.29 (27.80), 90.89 (34.60). Anal. Calcd. for: C13H13N5OS: C, 54.34;
H, 4.56; N, 24.37; S, 11.16%. Found: C, 54.50; H, 4.68; N, 24.46; S,
11.00%.
3050 (CH aromatic), 2950, 2850 (CH aliphatic), 2190 (CN),1630 (C]
N). 1H NMR (90 MHz, DMSO-d6): dppm ¼ 1.70e1.75 (m, 4H, 2CH2),
2.50e2.55 (m, 2H, CH2), 3.25e3.30 (m, 2H, CH2), 4.40 (s, 2H,
CH2CN), 7.40 (d, J ¼ 10.5 Hz, 2H, p-sub ArH), 7.65 (d, J ¼ 7.5 Hz, 2H,
p-sub ArH), 8.40 (s, 1H, CH]N), 10.70 (s, 1H, NH). Anal. Calcd. for:
C19H16ClN5S: C, 59.76; H, 4.22; Cl, 9.28; N, 18.34; S, 8.40%. Found: C,
59.65; H, 4.45; Cl, 9.50; N, 18.18; S, 8.22%.
4.8.2. Ethyl-1-(2-p-chlorobenzylidenehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3-sulfanylacetate (15b)
Method A: Obtained from compound 4c and ethyl chloroacetate
as white crystals in 78% yield. M.p.: 186e188 ꢁC.
4.6.2.4. 6-Acetyl-7-amino-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]tri-
azolo[3,4-a]iso quinoline (13d). Obtained from compound 5 which
was recrystallized from DMSO as white needles in 74% yield. M.p.
Method B: A mixture of compound 17 (0.61 g, 2 mmol) and p-
chlorobenzaldehyde (0.28 g, 2 mmol) was refluxed in ethanol
(20 mL) for 2 h. The solid product, which formed, was filtered off and
recrystallized from ethanol as white crystals in 80% yield. M.p.:
268e270 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3420, 3300, 3100 (NH2), 2950 (CH
aliphatic), 1680 (CO), 1610 (C]N). Anal. Calcd. for: C14H14N4OS: C,
58.72; H, 4.93; N, 19.57; S, 11.20%. Found: C, 58.84; H, 4.86; N, 19.42;
S, 11.36%.
186e188 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3320 (NH), 3030 (CH aromatic), 2920
(CH aliphatic), 2200 (CN), 1720 (CO ester), 1640 (C]N). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.30 (t, J ¼ 9.0 Hz, 3H, CH3 ester), 1.70e1.80
(m, 4H, 2CH2), 2.60e2.65 (m, 2H, CH2), 3.75e3.80 (m, 2H, CH2), 4.00
(s, 2H, CH2CO), 4.40 (q, J ¼ 6.0 Hz, 2H, CH2 ester), 7.30 (d, J ¼ 9.0 Hz,
2H, p-sub ArH), 7.70(d, J ¼ 9.0 Hz, 2H, p-sub ArH), 8.70 (s,1H, CH]N),
11.20 (s, 1H, NH). Anal. Calcd. for: C21H21ClN4O2S: C, 58.80; H, 4.93;
Cl, 8.27; N,13.06; S, 7.48%. Found: C; 59.00; H, 4.85; N,12.95; S, 7.63%.
4.6.2.5. 7-Amino-6-benzoyl-8,9,10,11-tetrahydrothieno[2,3-c][1,2,4]
triazolo[3,4-a]isoquinoline (13e). Obtained from compound 5 and
phenacyl bromide which was recrystallized fromꢀe1thanol as yellow
needles in 86% yield. M.p.: 292e294 ꢁC. IR (cm KBr)
n
¼ 3450,
3350 (NH2), 2950 (CH aliphatic); 1640 (CO). 1H NMR (90 MHz,
CF3CO2D): dppm ¼ 2.00e2.10 (m, 2H, CH2), 3.10e3.15 (m, 4H, 2CH2),
3.50e3.55 (m, 2H, CH2), 7.80e8.10 (m, 5H, ArH), 9.50 (s, 1H, CH
triazole). 13C NMR (400 MHz, DMSO-d6): dppm ¼ 185.50 (C]O),
171.85 (C-3), 156.25 (C-7), 154.00 (C-9), 145.25 (CH triazole),
127.75e135.14 (5C-aromatic), 123.75 (C-11), 92.69 (C-8), 99.80
(C-4), 21.94e42.35 (4CH2 cyclohexeno). Anal. Calcd. for:
C19H16N4OS: C, 65.50; H, 4.63; N, 16.08; S, 9.20%. Found: C, 65.65; H,
4.52; N, 15.95; S, 9.34%.
4.8.3. 1-(2-p-Chlorobenzylidinehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3-sulfanylacetamide (15c)
Obtained from compound 4c and chloroacetamide as white
crystals in 75% yield. M.p.: 264e266 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3420,
3320, 3120 (NH, NH2), 3050 (CH aromatic), 2920 (CH aliphatic),
2210 (CN), 1670 (CO amide), 1600 (C]N). 1H NMR (90 MHz, DMSO-
d6): dppm ¼ 1.80e1.90 (m, 4H, 2CH2), 2.75e2.80 (m, 2H, CH2),
3.30e3.40 (m, 2H, CH2), 3.90 (s, 2H, CH2), 6.8 (s, 2H, NH2), 7.50 (d,
J ¼ 10.5 Hz, 2H, p-sub ArH), 7.80 (d, J ¼ 7.5 Hz, 2H, p-sub ArH), 8.40
(s, 1H, CH), 11.00 (s, 1H, NH). Anal. Calcd. for: C19H18ClN5OS: C,
57.07; H, 4.54; Cl, 8.87; N, 17.51; S, 8.02%. Found: C, 56.95; H, 4.66;
Cl, 9.00; N, 17.61; S, 7.85%.
4.7. 1,2,3,4-Tetrahydropyrimido[40,50:4,5]thieno[2,3-c][1,2,4]
triazolo[3,4-a]isoquinolin-10(11H)-one (14)
Compound 13c (0.6 g, 2 mmol) and trietyl orthoformate (2 mL)
and few drops of glacial acetic acid were refluxed for 1/2 h. The
precipitated solid, which formed, was filtered off and recrystallized
from dioxane as white crystals in 68% yield. M.p.: >360 ꢁC. IR (cmꢀ1
4.8.4. 1-(2-p-Chlorobenzylidine)hydrazinyl-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3-sulfanylacetone (15d)
Obtained from compound 4c and chloroacetone as white crys-
n
tals in 83% yield. M.p.: 256e258 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3300 (NH),
KBr) ¼ 3100 (NH), 2920, 2850 (CH aliphatic), 1660 (CO imide),
1575 (C]N). 1H NMR (90 MHz, CF3CO2D): dppm ¼ 2.10e2.30 (m, 4H,
2CH2), 3.10e3.20 (m, 2H, CH2), 3.80e3.90 (m, 2H, CH2), 8.90 (s, 1H,
CH pyrimidine), 9.70 (s, 1H, CH triazole). 13C NMR (400 MHz,
DMSO-d6): dppm ¼ 172.71 (C-3), 166.05 (CONH), 163.80 (C-7), 152.98
(C-9), 149.13 (CH]N pyrimidine), 145.25 (C-10), 126.86 (C-12),
124.35 (C-11), 92.86 (C-8), 99.70 (C-4), 22.25e43.85 (4CH2 cyclo-
hexeno). MS m/z (%): 297.93 (Mþ, 85), 284.05 (81.50), 251.09 (63),
108.65 (28), 89.87 (52), 79.06 (51), 70.04 (72), 59.86 (72), 56.87
(100). Anal. Calcd. for: C14H11N5OS: C, 56.55; H, 3.73; N, 23.55; S,
10.78%. Found: C, 56.34; H, 3.85; N, 23.32; S, 10.86%.
3030 (CH aromatic), 2930 (CH aliphatic), 2210 (CN), 1720 (CO ester),
1640 (C]N). 1H NMR (90 MHz, DMSO-d6): dppm ¼ 1.90e2.00 (m,
4H, 2CH2), 2.40e2.45 (m, 3H, CH3), 2.60e2.65 (m, 2H, CH2),
3.35e3.40 (m, 2H, CH2), 4.40 (s, 2H, CH2), 7.50 (m, J ¼ 9.0 Hz, 2H, p-
sub ArH), 7.80, (m, J ¼ 7.5 Hz, 2H, p-sub ArH), 8.3 (s, 1H, CH]N),
10.80 (s, 1H, NH). MS m/z (%): 400.33 (Mþ þ 2, 38.9), 398.33 (Mþ,
100), 355.24 (35), 343.24 (15), 341.24 (47), 261.21 (34.50), 260.22
(24), 218.22 (66), 216.21 (23). Anal. Calcd. for: C20H19ClN4OS: C,
60.22; H, 4.80; Cl, 8.89; N, 14.04; S, 8.04%. Found: C, 60.00; H, 4.92;
Cl, 9.03; N, 13.88; S, 8.20%.

576
A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
4.8.5. 1-(2-p-Chlorobenzylidenehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3-sulfanylacetophenone (15e)
C19H18ClN5OS: C, 57.07; H, 4.54; Cl, 8.87; N,17.51; S, 8.02%. Found: C,
56.95; H, 4.66; Cl, 9.00; N, 17.23; S, 7.85%.
Obtained from compound 4c and phenacyl bꢀro1mide as orange
crystals in 85% yield. M.p.: 248e250 ꢁC. IR (cm KBr)
n
¼ 3350
4.9.4. 2-Acetyl-1-amino-5-(2-p-chlorobenzylidinehydrazinyl)-
6,7,8,9-tetrahydro thieno[2,3-c]isoquinoline (16d)
(NH), 3050 (CH aromatic), 2920, 2850 (CH aliphatic), 2200 (CN),
1670 (unsaturated CO), 1560 (C]N). 1H NMR (90 MHz, DMSO-d6):
dppm ¼ 1.70e1.80 (m, 4H, 2CH2), 2.50e2.55 (m, 2H, CH2), 3.25e3.30
(m, 2H, CH2), 5.00 (s, 2H, CH2 doesn’t disappear by D2O), 7.20e8.10
(m, 9H, ArH), 8.30 (s, 1H, CH), 11.00 (s, 1H, NH disappears by D2O).
Anal. Calcd. for: C25H21ClN4OS: C, 65.14; H, 4.59; Cl, 7.69; N, 12.15; S,
6.96%. Found: C, 65.28; H, 4.63; Cl, 7.82; N, 12.25; S, 7.10%.
Obtained as orange crystals when the solid precipitate was
recrystallized from dioxane in 85% yield. M.p.: 294e296 ꢁC. IR
(cmꢀ1 KBr)
n
¼ 3500, 3400, 3280 (NH, NH2), 3050 (CH aromatic),
2920, 2850 (CH aliphatic),1670 (CO),1610 (C]N). 1H NMR (90 MHz,
CF3CO2D): dppm ¼ 1.85e1.95 (m, 4H, 2CH2), 2.50e2.55 (m, 2H, CH2),
2.60 (s sharp, 3H, CH3), 3.20e3.30 (m, 2H, CH2), 7.30 (d, J ¼ 9.0 Hz,
2H, p-substituted ArH), 7.80 (d, J ¼ 7.5 Hz, 2H, p-substituted ArH),
8.50 (s, 1H, CH]N). Anal. Calcd. for: C20H19ClN4OS: C, 60.22; H,
4.80; Cl, 8.89; N,14.04; S, 8.04%. Found: C, 60.37; H, 4.67; Cl, 9.04; N,
14.24; S, 7.90%.
4.9. Cyclization of 3-substitutedmercapto-1-(2-p-
chlorobenzylidinehydrazinyl)-4-cyano-5,6,7,8-
tetrahydroisoquinoline (16aee)
General procedure:
A
solution of (1 mmol) of alkylated
4.9.5. 1-Amino-2-benzoyl-5-(2-p-chlorobenzylidenehydrazinyl)-
6,7,8,9-tetrahydro thieno[2,3-c]isoquinoline (16e)
compound 15aee in absolute ethanol (20 mL) and few drops of
sodium ethoxide solution (prepared from 0.5 g of clean sodium on
20 mL absolute ethanol) were refluxed for 20 min. The solid
precipitate which was formed on cold or dilution with water
filtered off, dried and recrystallized from the proper solvent.
Obtained as red crystals when the solid precipitate was recrys-
tallized from dioxane in 81% yield. M.p.: 284e286 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3500, 3300, 3250 (NH, NH2), 3050 (CH aromatic), 2920, 2850
(CH aliphatic), 1650 (CO), 1600 (C]N). 1H NMR (90 MHz, DMSO-
d6): dppm ¼ 1.70e1.80 (m, 4H, 2CH2), 2.35e2.40 (m, 2H, CH2),
3.20e3.25 (m, 2H, CH2), 7.30e7.80 (m, 9H, ArH), 8.00 (s, 2H, NH2),
8.20 (s, 1H, CH]N), 10.80 (s, 1H, NH). MS m/z (%): 462.13 (27),
460.30 (Mþ, 18), 391.16 (45), 390.05 (42.50), 386.18 (100), 389.3
(25), 388.35 (56), 386.18 (100), 372.28 (23), 357.13 (26), 325.25 (26),
323.34 (49), 322.35 (61), 286.92 (34), 259.24 (21), 201.05 (22),
163.10 (20), 149.04 (61), 143.03 (28), 119.12 (26), 118.05 (22), 104.99
(32),101.05 (24), 97.12 (37). Anal. Calcd. for: C25H21ClN4OS: C, 65.14;
H, 4.59; Cl, 7.69; N, 12.15; S, 6.96%. Found: C, 65.34; H, 4.76; Cl, 7.54;
N, 12.03; S, 7.14%.
4.9.1. 1-Amino-5-(2-p-chlorobenzylidenehydrazinyl)-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carbonitrile (16a)
Obtained as pale yellow crystals when the solid precipitate was
recrystallized from ethanol-dioxane mixture as in 80% yield. M.p.:
232e234 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3400, 3350, 3150 (NH2), 2920, 2850
(CH aliphatic), 2210 (CN), 1620 (C]N). 1H NMR (90 MHz, DMSO-
d6): dppm ¼ 1.70e1.80 (m, 4H, 2CH2), 2.50e2.55 (m, 2H, CH2),
3.25e3.30 (m, 2H, CH2), 6.10 (s, 2H, NH2), 7.50 (d, J ¼ 9.6 Hz, 2H, p-
substituted ArH), 7.80 (d, J ¼ 6.6 Hz, 2H, p-substituted ArH), 8.30 (s,
1H, CH]N), 10.50 (s, 1H, NH). Anal. Calcd. for: C19H16ClN5S: C,
59.76; H, 4.22; Cl, 9.28; N, 18.34; S, 8.40%. Found: C, 59.68; H, 4.43;
Cl, 9.50; N, 18.17; S, 8.20%.
4.10. Ethyl(4-cyano-1-hydrazino-5,6,7,8-tetrahydroisoquinolin-3-
ylsulfanyl)acetate (17)
4.9.2. Ethyl-1-amino-5-(2-p-chlorobenzylidenehydrazinyl)-6,7,8,9-
tetrahydro thieno[2,3-c]isoquinoline-2-carboxylate (16b)
A mixture of 1-hydrazino-3-thioxo-5,6,7,8-tetrahydroisoquino-
line-4-carbonitrile (3) (1 g, 4.50 mmol), ethyl chloroacetate
(0.55 mL, 4.50 mmol) and fused sodium acetate (0.6 g, 6.80 mmol)
in ethanol (20 mL) was refluxed for 2 h. The solid precipitate, which
formed on cold, was filtered off and recrystallized from ethanol as
white needles in 84% yield. M.p.: 120e122 ꢁC. IR (cmꢀ1 KBr)
Obtained as white crystals when the solid precipitate wꢀas1
recrystallized from ethanol in 73% yield. M.p.: 228e230 ꢁC. IR (cm
KBr)
n
¼ 3500, 3350, 3250 (NH, NH2), 3070 (CH aromatic), 2920, 2830
(CH aliphatic), 2200 (CN), 1645 (CO unsaturated ester), 1590 (C]N).
1H NMR (90 MHz, DMSO-d6): dppm ¼ 1.10 (t, J ¼ 9.0 Hz, 3H, CH3 ester),
1.70e1.80 (m, 4H, 2CH2), 2.50e2.55 (m, 2H, CH2), 3.2e3.25 (m, 2H,
CH2), 4.20 (q, J ¼ 4.5 Hz, 2H, CH2), 5.90 (s, 2H, NH2 disappears by
D2O), 7.40 (d, J ¼ 6.0 Hz, 2H, p-substituted ArH), 7.8 (d, J ¼ 9.0 Hz, 2H,
p-substituted ArH), 8.20 (s,1H, CH]N),10.10 (s,1H, NH disappeared
by D2O). 13C NMR (400 MHz, DMSO-d6): dppm ¼ 166.30 (C]O ester),
156.22 (C-7), 153.34 (C-9), 136.86 (CH]N), 126.16e134.02 (5C-
aromatic), 115.28 (C-8), 111.15 (C-4), 95.32 (C-11), 59.95 (CH2 ester),
23.52e39.34 (4CH2 cyclohexeno), 15.10 (CH3 ester). Anal. Calcd. for:
C21H21ClN4O2S : C, 58.80; H, 4.93; Cl, 8.27; N, 13.06; S, 7.48%. Found:
C, 58.68; H, 5.04; Cl, 8.42; N, 13.25; S, 7.70%.
n
¼ 3450, 3380, 3320 (NH2, NH), 2190 (CN), 1740 (CO ester). 1H NMR
(90 MHz, DMSO-d6): dppm ¼ 1.20 (t, J ¼ 7.5 Hz, 3H, CH3), 1.75e1.85
(m, 4H, 2CH2), 2.40e2.45 (m, 4H, 2CH2), 3.40 (s, 2H, SCH2), 4.15 (q,
J ¼ 4.5 Hz, 2H, CH2), 6.60 (s, 2H, NH2), 8.10 (s, 1H, NH). Anal. Calcd.
for: C14H18N4O2S: C, 54.88; H, 5.92; N, 18.29; S, 10.47%. Found: C,
54.68; H, 6.00; N, 18.40; S, 10.54%.
4.11. Alkylation of 1-(3,5-dimethylpyrazol-1-yl)-4-cyano-5,6,7,8-
tetrahydroiso quinoline-3(2H)-thione (6): formation of (18aee)
General procedure: A mixture of pyrazolo derivative 6 (0.58 g,
2 mmol) and alkylating agent (2 mmol) in presence of fused sodium
acetate (0.75 g, 8.50 mmol) in ethanol (20 mL) was refluxed for 2 h.
The solid product, which formed on cooling, was filtered off and
recrystallized from ethanol.
4.9.3. 1-Amino-5-(2-p-chlorobenzylidenehydrazinyl)-6,7,8,9-
tetrahydrothieno[2,3-c]isoquinoline-2-carboxamide (16c)
Obtained as orange crystals when the solid precipitate was
recrystallized from ꢀe1thanol/dioxane mixture in 76% yield. M.p.:
280e282 ꢁC. IR (cm KBr)
n
¼ 3450, 3300, 3200 (NH, NH2), 3050
4.11.1. 3-Cyanomethylsulfanyl-1-(3,5-dimethylpyrazol-1-yl)-
5,6,7,8-tetrahydro isoquinoline-4-carbonitrile (18a)
(CH aromatic), 2920, 2850 (CH aliphatic), 1640 (CO amide), 1570
(C]N). 1H NMR (90 MHz, DMSO-d6): dppm ¼ 1.80e1.90 (m, 4H,
2CH2), 2.60e2.70 (m, 2H, CH2), 3.15e3.20 (m, 2H, CH2), 6.70 (s, 4H,
2NH2 disappeared by D2O), 7.30 (d, J ¼ 7.5 Hz, 2H, p-substituted
ArH), 7.70 (d, J ¼ 6.6 Hz, 2H, p-substituted ArH), 8.20 (s, 1H, CH]N),
11.00 (s, 1H, NH disappeared by D2O). Anal. Calcd. for:
Obtained from compound 6 and chloroacetꢀo1nitrile as white
crystals in 89% yield. M.p.: 142e144 ꢁC. IR (cm KBr)
n
¼ 2950,
2850 (CH aliphatic), 2200 (CN), 1630 (C]N). 1H NMR (90 MHz,
CDCl3): dppm ¼ 1.80e1.95 (m, 4H, 2CH2), 2.35, 2.40 (2s sharp, 6H,
2CH3), 2.70e2.75 (m, 2H, CH2), 3.00e3.10 (m, 2H, CH2), 4.00 (s, 2H,

A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
577
CH2CN), 6.00 (s, 1H, CH pyrazole). MS m/z (%): 323.97 (Mþ, 23.8),
322.95 (Mþ ꢀ 1, 100), 284.02 (32.3), 282.98 (27.9), 280.98 (19.1),
251.01 (19.5). Anal. Calcd. for: C17H17N5S: C, 63.13; H, 5.30; N, 21.65;
S, 9.91%. Found: C, 63.35; H, 5.18; N, 21.76; S, 9.71%.
(CH aliphatic), 2200 (CN), 1640 (C]N). 1H NMR (90 MHz, CDCl3):
dppm ¼ 1.70e1.80 (m, 4H, 2CH2), 2.15, 2.25 (2s sharp, 6H, 2CH3),
2.55e2.30 (m, 2H, CH2), 3.10e3.2 (m, 2H, CH2), 5.00 (s, 2H, NH2),
5.90 (s, 1H, CH pyrazole). Anal. Calcd. for: C17H17N5S: C, 63.13; H,
5.30; N, 21.65; S, 9.91%. Found: C, 63.25; H, 5.12; N, 21.48; S, 10.15%.
4.11.2. Ethyl[4-cyano-1-(3,5-dimethylpyrazol-1-yl)-5,6,7,8-
tetrahydroisoquinolin-3-ylsulfanyl]acetate (18b)
4.12.1.2. Ethyl-1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetra-
hydrothieno[2,3-c] isoquinolin-2-carboxylate (19b). Obtained as
pale yellow crystals in 80% yield. M.p.: 168e170 ꢁC. IR (cmꢀ1 KBr)
Obtained from compound 6 and ethyl chloroacetate as white
needles in 85% yield. M.p.: 140e142 ꢁC. IR (cmꢀ1 KBr)
n
¼ 2950 (CH
aliphatic), 2210 (CN), 1745 (CO ester), 1620 (C]N). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.15 (t, J ¼ 9.0 Hz, 3H, CH3 ester), 1.80e1.90
(m, 4H, 2CH2), 2.20, 2.25 (2s sharp, 6H, 2CH3), 2.65e2.70 (m, 2H,
CH2), 2.90e2.95 (m, 2H, CH2), 3.95 (s, 2H, CH2CO), 4.10 (q, J ¼ 7.5 Hz,
2H, CH2 ester), 5.90 (s, 1H, CH triazole). Anal. Calcd. for:
C19H22N4O2S: C, 61.60; H, 5.99; N,15.12; S, 8.65%. Found: C, 61.45; H,
6.14; N, 15.27; S, 8.78%.
n
¼ 3400, 3320 (NH2), 2920, 2850 (CH aliphatic), 1670 (CO ester),
1610 (C]N). 1H NMR (90 MHz, CDCl3): dppm ¼ 1.45 (t, J ¼ 7.5 Hz, 3H,
CH3 ester), 1.85e1.95 (m, 4H, 2CH2), 2.35, 2.40 (2s sharp, 6H, 2CH3),
2.70e2.75 (m, 2H, CH2), 3.35e3.40 (m, 2H, CH2), 4.40 (q, J ¼ 6.0 Hz,
2H, CH2 ester), 6.05 (s,1H, CH triazole), 6.40 (s, 2H, NH2). MS m/z (%)
370.31 (Mþ, 79), 344.41 (21), 343.04 (100), 342.11 (24), 330.59 (29),
329.11 (70), 327.87 (36), 315.04 (35), 300.72 (21), 295.13 (24),
282.88 (46.50), 281.79 (35), 268.63 (45), 255.77 (60.50). Anal. Calcd.
for: C19H22N4O2S: C, 61.60; H, 5.99; N, 15.12; S, 8.65%. Found: C,
61.76; H, 6.14; N, 14.95; S, 8.50%.
4.11.3. 2-[4-Cyano-1-(3,5-dimethylpyrazol-1-yl)-5,6,7,8-
tetrahydroisoquinoline-3-ylsulfanyl]acetamide (18c)
Obtained from compound 6 and chloroacetamide as white
crystals in 79% yield. M.p.: 200e202 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3450,
4.12.1.3. 1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahy-
3350, 3200 (NH2), 2920, 2850 (CH aliphatic), 2210 (CN), 1670 (CO
amide), 1620 (C]N). 1H NMR (90 MHz, CDCl3): dppm ¼ 1.75 (m, 4H,
2CH2), 2.20, 2.25 (2s sharp, 6H, 2CH3), 2.65 (m, 2H, CH2), 2.95 (m,
2H, CH2), 3.80 (s, 2H, CH2CO), 5.90 (s, 1H, CH pyrazole), 6.40 (s, 2H,
NH2). Anal. Calcd. for: C17H19N5OS: C, 59.80; H, 5.61; N, 20.51; S,
9.39%. Found: C, 59.95; H, 5.74; N, 20.27; S, 9.56%.
drothieno[2,3-c]iso-quinolin-2-carboxamide (19c). Obtainꢀe1d as
yellow needles in 89% yield. M.p.: 258e260 ꢁC. IR (cm
KBr)
n
¼ 3450, 3400, 3300, 3120 (2NH2), 2920, 2850 (CH aliphatic), 1650
(CO amide), 1600 (C]N). 1H NMR (90 MHz, DMSO-d6):
dppm ¼ 1.75e1.80 (m, 4H, 2CH2), 2.25, 2.30 (2s sharp, 6H, 2CH3),
2.60e2.65 (m, 2H, CH2), 3.45e3.50 (m, 2H, CH2), 6.10 (s, 1H, CH
pyrazole), 7.00 (s, 2H, NH2), 7.30 (s, 2H, NH2 amide). Anal. Calcd. for:
C17H19N5OS: C, 59.80; H, 5.61; N, 20.51; S, 9.39%. Found: C, 60.02; H,
5.43; N, 20.36; S, 9.46%.
4.11.4. 1-(3,5-Dimethylpyrazol-1-yl)-3-(2-oxopropylsulfanyl)-
5,6,7,8-tetrahydro isoquinoline-4-carbonitrile (18d)
Obtained from compound 6 and chloroacetone as pale yellow
crystals in 92% yield. M.p.: 128e130 ꢁC. IR (cmꢀ1 KBr)
n
¼ 2920,
4.12.1.4. 2-Acetyl-1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tet-
rahydrothieno[2,3-c]isoquinoline (19d). Obtained as yellow crystals
2850 (CH aliphatic), 2210 (CN), 1715 (CO), 1620 (C]N). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.85e1.95 (m, 4H, 2CH2), 2.25, 2.30, 2.35
(3s sharp, 9H, 3CH3), 2.65e2.70 (m, 2H, CH2), 2.95e3.00 (m, 2H,
CH2), 4.00 (s, 2H, CH2), 5.90 (s, 1H, CH pyrazole). Anal. Calcd. for:
C18H20N4OS: C, 63.50; H, 5.92; N, 16.46; S, 9.42%. Found: C, 63.36; H,
6.12; N, 16.28; S, 9.60%.
in 93% yield. M.p.: 178e180 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3400, 3280 (NH2),
2920, 2850 (CH aliphatic), 1660 (CO), 1600 (C]N). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.80e1.90 (m, 4H, 2CH2), 2.15, 2.20, 2.40
(3s sharp, 9H, 3CH3), 2.55e2.60 (m, 2H, CH2), 3.25 (m, 2H, CH2),
5.90 (s, 1H, CH pyrazole), 7.10 (s, 2H, NH2). MS m/z (%): 340.81 (Mþ,
25), 339.81 (Mþ ꢀ 1, 100), 324.81 (25), 297.93 (38), 283.91 (14),
253.97 (10). Anal. Calcd. for: C18H20N4OS: C, 63.50; H, 5.92; N,16.46;
S, 9.42%. Found: C, 63.40; H, 6.05; N, 16.58; S, 9.24%.
4.11.5. 1-(3,5-Dimethylpyrazol-1-yl)-3-(phenyl-2-
oxoethylsulfanyl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile
(18e)
Obtained from compound 6 and phenacyl bromide as white
4.12.1.5. 1-Amino-2-benzoyl-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-
tetrahydrothieno [2,3-c]isoquinoline (19e). Obtained as brilliant
yellow needles in 85% yield. M.p.: 218e220 ꢁC. IR (cmꢀ1 KBr)
crystals in 75% yield. M.p.: 180e182 ꢁC. IR (cmꢀ1 KBr)
n
¼ 2950 (CH
aliphatic), 2210 (CN), 1690 (unsaturated CO), 1600 (C]N). 1H NMR
(90 MHz, CDCl3): dppm ¼ 1.70e1.80 (m, 4H, 2CH2), 2.00, 2.20 (2s
sharp, 6H, 2CH3), 2.55 (m, 2H, CH2), 2.95 (m, 2H, CH2), 4.65 (s, 2H,
CH2CO), 5.80 (s, 1H, CH pyrazole), 7.30e8.00 (m, 5H, ArH). Anal.
Calcd. for: C23H22N4OS: C, 68.63; H, 5.51; N, 13.92; S, 7.97%. Found:
C, 68.75; H, 5.27; N, 14.14; S, 8.16%.
n
¼ 3450, 3300 (NH2), 3030 (CH aromatic), 2920, 2850 (CH
aliphatic), 1645 (unsaturated CO), 1600 (C]N). 1H NMR (90 MHz,
CF3CO2D): dppm ¼ 1.95e2.05 (m, 4H, 2CH2), 2.40, 2.60 (2s sharp, 6H,
2CH3), 2.45e2.50 (m, 4H, 2CH2), 6.80 (s,1H, CH pyrazole), 7.70e7.90
(m, 5H, ArH). Mass spectrum m/z (%): 401.38 (Mþ, 25), 322.09 (27),
261.27 (26), 184.3 (20.50), 167.22 (21), 149.1 (27), 109.24 (22), 82.15
(38), 71.09 (100). Anal. Calcd. for: C23H22N4OS: C, 68.63; H, 5.51; N,
13.92; S, 7.97%. Found: C, 68.75; H, 5.37; N, 14.10; S, 8.12%.
4.12. Cyclization of 3-substitutedsulfanyl-1-(3,5-dimethylpyrazol-
1-yl)-5,6,7,8-tetrahydroisoquinoline-4-carbonitrile (19aee)
4.12.1. Method A
4.12.2. Method B
General procedure: A solution of compound 18aee (1 mmol) in
absolute ethanol (20 mL) and few drops of sodium ethoxide solu-
tion were refluxed for 20 min. The solid precipitate which was
formed on cold or dilution with water filtered off, dried and re-
crystallized from ethanol.
General procedure: A mixture of pyrazolo derivative 6 (0.58 g,
2 mmol) and alkylating agent (2 mmol) in presence of anhydrous
potassium carbonate (0.70 g, 5 mmol) in ethanol (20 mL) was
refluxed for 3 h. The solid product, which formed on cooling, was
filtered off and recrystallized from ethanol.
4.12.1.1. 1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahy-
drothieno[2,3-c]iso-quinolin-2-carbonitrile (19a). Obtained as the
above procedure to afford greenish yellow needles in 84% yield.
4.12.2.1. 1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahydro-
thieno[2,3-c]iso-quinoline-2-carbonitrile
(19a). Obtained
from
compound 6 and chloroacetonitrile as greenish yellow crystals in
M.p.: 194e196 ꢁC. IR (cmꢀ1 KBr)
n
¼ 3300, 3220 (NH2), 2920, 2850
77% yield. M.p.: 194e196 ꢁC.

578
A.M. Kamal et al. / European Journal of Medicinal Chemistry 46 (2011) 567e578
4.12.2.2. Ethyl-1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetra-
hydrohieno[2,3-c]isoquinoline-2-carboxylate (19b). Obtained from
compound 6 and ethyl chloroacetate as pale yellow crystals in 72%
yield. M.p.: 168e170 ꢁC.
3) loaded with 10 mL of the solution under investigation (200 mL/
disc, 2.0%). The discs were placed on the surface of the fungal
cultures which were incubated at 30 ꢁC. The diameter of the inhi-
bition zone around each disc was measured. The previous method
was used for determining antibacterial activity too.
4.12.2.3. 1-Amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tetrahy-
drothieno[2,3-c]iso-quinoline-2-carboxamide (19c). Obtained from
compound 6 and chloroacetamide as pale yellow crystals in 76%
yield. M.p.: 258e260 ꢁC.
Acknowledgments
The authors are very grateful to Prof Dr. Ali Abd El-Hafez, The
chairman of Chemistry Department for all facilities who provided
us, and very grateful too to Prof Dr. Abd El-Aal Moubasher and Prof.
Dr. Ahmed Moharam, Department of Botany, Faculty of Science,
Assiut University, for performing the antimicrobial evaluation.
4.12.2.4. 2-Acetyl-1-amino-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-tet-
rahydrothieno[2,3-c]isoquinoline (19d). Obtained from compound 6
and chloroacetone as yellow crystals in 87% yield. M.p.: 178e180 ꢁC.
4.12.2.4. 1-Amino-2-benzoyl-5-(3,5-dimethylpyrazol-1-yl)-6,7,8,9-
tetrahydrothieno [2,3-c]isoquinoline (19e). Obtained from compound
6 and phenacyl bromide as yellow crystals in 78% yield. M.p.:
218e220 ꢁC.
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The fungal species were previously isolated from cases of
human dermatophytosis (Moubasher et al., 1993) [25]. The fungi
were grown in sterilized 9-cm Perti dishes containing Sabouraud’s
Dextrose Agar (SDA) supplemented with 0.05% chloramphenicol to
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