Thieno[2,3-c]pyridazine derivatives: Synthesis and antimicrobial activity

Article abstract of DOI:10.1080/10426500802014443

Thieno[2,3-c]pyridazine 2 was selected as the starting material for the synthesis of some novel 5-arylidene amino and 5-thiazolidine derivatives. The structures of the synthesized compounds were elucidated by elemental analyses and spectral data. The anti

Full text of DOI:10.1080/10426500802014443

This article was downloaded by: [RMIT University]
On: 04 July 2013, At: 07:18
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Phosphorus, Sulfur, and Silicon
and the Related Elements
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/gpss20
Thieno[2,3-c]pyridazine
Derivatives: Synthesis and
Antimicrobial Activity
Fatma El-Mariah a
a Department of Chemistry, Faculty of Girls, Ain
Shams University, Cairo, Egypt
Published online: 07 Oct 2008.
To cite this article: Fatma El-Mariah (2008) Thieno[2,3-c]pyridazine Derivatives:
Synthesis and Antimicrobial Activity, Phosphorus, Sulfur, and Silicon and the Related
Elements, 183:11, 2795-2806
To link to this article: http://dx.doi.org/10.1080/10426500802014443
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.

This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Phosphorus, Sulfur, and Silicon, 183:2795–2806, 2008
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500802014443
Thieno[2,3-c]pyridazine Derivatives: Synthesis
and Antimicrobial Activity
Fatma El-Mariah
Department of Chemistry, Faculty of Girls, Ain Shams University,
Cairo, Egypt
Thieno[2,3-c]pyridazine 2 was selected as the starting material for the synthesis of
some novel 5-arylidene amino and 5-thiazolidine derivatives. The structures of the
synthesized compounds were elucidated by elemental analyses and spectral data.
The antimicrobial and antifungal activities of the newly synthesized products were
measured against some microorganisms.
Keywords 5-Aminothieno [2, 3-c] pyridazine; 5-thiazolideno; antimicrobial activity, con-
densation with aldehydes, Mannish bases
INTRODUCTION
Derivatives of the thienopyridazine ring systems are known to pos-
sess potent biological and pharmacological properties.1 On the other
hand, derivatives of thiazolidinone have various pharmacological ac-
tivities such as antibacterial,2,3 antifungal,4 and anticancer.5 Hence, it
was thought that the incorporation of the latter heterocyclic moieties
into thienopyridazine moiety might modify their biological activity. The
present investigation, which is in continuation of our previous work6−9
on pyridazine, deals with the synthesis of different 5-substituted
aminothienopyridazines. We found that Mannich bases had antimicro-
bial and other additional activities.10–13
RESULTS AND DISCUSSION
For this purpose, 5-amino-6-benzoyl-3, 4-diphenylthieno [2, 3-c] pyri-
dazine 2 was prepared by reaction of 4-cyano-5, 6-diphenyl-pyridazine-
Received 28 December 2007; accepted 26 February 2008.
The author acknowledges the help of Dr. Gamal El-Sherbeny, Department of Microbi-
ology, Faculty of Science, El-Azhar University, Cairo, Egypt, for carrying out the antimi-
crobial activity.
Address correspondence to Fatma El-Mariah, Department of Chemistry, Faculty of
Girls, Ain Shams University, Cairo, Egypt. E-mail: fatma elmariah@yahoo.com
2795

2796
F. El-Mariah
3(2H)-thione14 1 with ω-chloroacetophenone in the presence of an ex-
cess amount of potassium carbonate anhydrous in refluxing acetone
(Scheme 1).
SCHEME 1
5-Amino derivative 2 reacted with an equimolecular quantity of the
appropriate aromatic aldehydes to give good yields of 5-arylidene and
heteroarylidene aminothienopyridazines 3a−l (Scheme 1).
The structure of compounds 3a−l was assigned on the basis of sat-
isfactory analytical and spectral data (see Experimental section for de-
tails).
Chloroacetylation of 5-amino derivative 2 with chloroacetyl chloride
in dry benzene in presence of few drops of pyridine at room temperature
afforded 5-chloroacetylamino derivative 4 (Scheme 2).

Thieno[2,3-c]pyridazine Derivatives
2797
SCHEME 2
The assignment of structure 4 was based on analytical and spec-
tral data. The IR spectrum revealed the presence of an NH group at
3384cm−1, ketonic carbonyl group at 1738cm–1, and amide carbonyl
–1
group at 1683cm
.
The thiocyanation of 5-chloroacetylamino derivatives 4 using am-
monium thiocyanate in absolute ethanol resulted in the formation of

2798
F. El-Mariah
the novel 5-thiazolidinone derivative 6 in high yield. The structure of 6
was established on the basis of analytical and spectral data. Its infrared
spectrum revealed the absence of thiocyanate functional group, in ad-
dition to the presence of NH and C O functional groups. Also, mass
spectrum showed a molecular ion peak at m/z = (506, 100%), which
is the base peak in the spectrum. The formation of 6 is assumed to
proceed via the formation of intermediate 5 followed by intramolecular
cyclization of amino group to the thiocyanate group (Scheme 2).
The reactivity of 5-thiazolidinone 6 towards some electrophilic
reagents was studied. Condensation of compound 6 with aromatic and
heteroaromatic aldehydes in refluxing ethanol yielded the correspond-
ing arylidene derivatives 7a−g. The structures of compounds 7a−g
were confirmed on the basis of their elemental analysis and spectral
data.
Straight forward hydroxymethylation of 6 by treatment with 37%
formaldehyde solution afforded 5’-hydroxymethyl derivative 8a (85%).
A similar reactivity is shown by the methylene-active thiazolidinone
6: the reaction of 6 with formaldehyde in the presence of secondary
amines namely pyrrolidine, piperidine, morpholine, diethylamine, and
diphenylamine proceeded smoothly to give the Mannich bases 8b−f, in
good yields. The structure of the Mannich bases 8b−f was established
from microanalytical data and spectral data. The infrared spectra of
these compounds show strong carbonyl stretching frequencies of cyclic
amides and benzoyl ketone.
Screening for Antimicrobial Activities
Applying the agar plate diffusion technique,15 the newly synthesized
compounds were screened in vitro for antimicrobial activity against rep-
resentative of Gram positive bacteria (Staphylococcus aureus, Bacillus
subtilis), Gram negative bacteria (Escherichia coli, Pseudomonas aerug-
inosa), yeast (Candida albicans), and fungi (Aspergillus niger). In this
method, a standard 5 mm sterilized filter paper disc, impregnated with
the compound (0.3 mg/ 0.1 mL of dimethyl formamide), was placed on
an agar plate seeded with the test organism. The plates were incubated
for 24 h at 37◦C for bacteria and 28◦C for fungi. The zone of inhibition of
bacterial and fungi growth around the disc was observed. The screening
results given in Table I.
The antimicrobial activity of the compounds against examined Gram
positive bacteria Staphylococcus aureus and Bacillus subtilis varied
from compound to the other. The synthesized compounds gave high
or moderate antimicrobial activity against both or one of examined
Gram positive bacteria, except that two compounds (3d, 3g) had no

Thieno[2,3-c]pyridazine Derivatives
2799
TABLE I Antibacterial and Antifungal Activity
Sample
no.
Staphylococcus Bacillus Escherichia Pseudomonas Candida Aspergillus
aureus
subtilis
coli
aeruginosa albicans
niger
2
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
4
6
7a
7b
7c
7d
7e
7f
7g
8a
8b
8c
8d
8e
8f
−-
++
−
++
−
++
++
−
−
−
−
−
−
++
++
−
++
−
−
−
++
−
++
−
−
−
++
−
−
−
++
−
++
++
−
++
−
−
−
++
−
−
−
−
++
−
−
−
++
−
++
++
++
++
++
++
++
++
++
−
++
−
−
−
++
−
−
−
−
++
−
−
−
−
++
−
−
−
−
++
−
−
−
−
++
−
−
−
+ + +
−
++
−
−
−
+ + +
++
−
−
−
++
++
−
−
−
−
++
−
−
−
++
++
++
++
++
+ + +
++
++
+ + +
++
+ + +
−
++
−
−
−
−
++
−
−
−
++
+ + +
++
+ + +
−
++
−
−
−
+ + +
++
−
−
−
−
−
−
+ + +
++
−
−
−
−
−
−
+ + +
++
+ + +
+ + +
−
+ + +
+ + +
+ + +
+ + +
−
−
−
−
−
−
−
−
−
−
Ciprofloxacin
Fungicide
Nystin
+ + +
−
−
−
+ + +
+ + +
Zone of inhibition: ++ = 15–20 mm; + + + = 25–30 mm; and − = no inhibition.
antimicrobial activity against the tested Gram positive bacteria. Only
twelve compounds showed high and/or moderate antimicrobial activity
against both examined Gram positive bacteria namely (3c, 3e, 3h, 6,
7b, 7f, 7g, 8a, 8b 8d, 8e, 8f). The highest antimicrobial activity against
Staphylococcus aureus were obtained by five compounds (6, 7g, 8b, 8d,
8f); this is because these compounds contain R = Imino - oxothiazoli-
dine, 5-Methyl-2-thienyl, Diethyl amino, 1-Pyrrolidino, 1-Morpholino,
respectively.Whereas, the highest antimicrobial activity against Bacil-
lus subtilis was obtained by two compounds only (8b, 8e), which con-
tained R = Diethylamino, 1- Piperidino, respectively.

2800
F. El-Mariah
On the other hand, all compounds showed high or moderate an-
timicrobial activity against Gram negative bacteria Escherichia coli
and had no effect against the other examined Gram negative Pseu-
domonas aeruginosa. The highest antimicrobial activity against Gram
negative bacteria Escherichia coli was obtained by six compounds,
namely 7a, 7g, 8b, 8d, 8e, and 8f; this is because these compounds con-
tain R=C6H4Cl(p-), 5-Methyl-2-thienyl, Diethylamino, 1-Pyrrolidino,
1-Piperidino, and 1-Morpholino, respectively. It should be mentioned
that compound (8b), which contains R = Diethylamino, gave the high-
est antimicrobial activity against all tested Gram positive bacteria, as
well as tested Gram negative bacteria Escherichia coli.
Furthermore, the antimicrobial activity of synthesized compounds
against the two examined fungi Candida albicans and Aspergillus niger
have been studied. The results indicated that all synthesized com-
pounds had no antimicrobial activity against the two examined fungi
Candida albicans and Aspergillus niger.
Finally, results of antimicrobial activity revealed that synthesized
compounds showed high antimicrobial activity against bacteria than
fungi. It could be concluded from these results that the biologically ac-
tive compounds are nearly as active as standard antibiotic Ciprofloxacin
against the tested Gram positive bacteria (Staphylococcus aureus and
Bacillus subtilis) and Gram negative bacteria (Escherichia coli) and
completely inactive against tested fungi.
EXPERIMENTAL
Melting points were determined in open glass capillaries and are un-
corrected. Elemental analyses were carried out in the microanalytical
laboratory of Faculty of Science, Cairo University. The IR spectra of
compounds were recorded on a Perkin-Elmer spectrophotometer model
1430 as potassium bromide pellets and frequencies are reported in
cm–1. The 1H-NMR spectra were recorded on Perkin-Elmer R12B spec-
trometer and chemical shifts δ are in ppm relative to internal TMS, and
mass spectra were recorded on a mass spectrometer HP model MS 5988
EL 70 eV. Reactions were routinely followed by thin layer chromatogra-
phy (TLC) on silica gel; F254 aluminum sheets (Merck). The spots were
detected by UV irradiation at 254−336 nm.
Compound 1 was synthesized as reported previously.14
5-Amino-6-benzyol-3,4-diphenylthieno[2,3-c]pyridazine 2
To a solution of 4-cyano-5, 6-diphenylpyridazine-3 (2H)-thione 1 (2.9 g,
10 mmol) in dry acetone (20 mL), ω-chloroacetophenone (1.55 g,

Thieno[2,3-c]pyridazine Derivatives
2801
10 mmol) and anhydrous potassium carbonate (2.0 g) were added. The
reaction mixture was refluxed for 3 h. The solvent was evaporated under
reduced pressure, and the residue was treated with cold water (100 mL).
The precipitate was filtered off, washed several times with cold water,
dried, and recrystallized from ethanol to yield 2, yield 2.5 g (86.2%), m.p.
221−222◦C; IR: 3383 (NH2), 1688 (C O) cm–1; MS: m/z (%) 407 (M+,
28), 303 (18), 286 (8), 105 (100), 77 (68). Anal. calcd. for C25H17N3OS:
C, 73.69; H, 4.21; N, 10.31 Found: C, 73.80; H, 4.10; N, 10.40.
5-Arylidene(heteroarylidene)amino-6-benzoyl-3,4-
diphenylthieno[2,3-c]pyridazines 3a–l—General
Procedure
A mixture of 5-amino derivative 2 (0.50 g., 1.22 mmol) and aromatic and
heteroaromatic aldehydes (1.22 mmol) in ethanol (10 mL) was refluxed
for 3 h and then allowed to cool. The solid product was collected and
recrystallized from ethanol.
3a (R Ph): Yield (0.41 g, 82%), m.p. 170−171◦C; IR: 1689 (C O),
1644 (C N) cm–1; MS: m/z (%) 496 (M+, 0.8), 394 (0.8), 317 (1), 288 (2),
105 (58), 77 (100). Anal. calcd. for C32H21N3OS: C, 77.55; H, 4.27; N,
8.48; Found: C, 77.30; H, 4.20; N, 8.60.
3b [R=C6H4OH (p-)]: Yield (0.38 g, 76%), m.p. 155−157◦C; IR:
3428(OH-phenolic), 1694 (C O), 1639 (C N) cm–1; MS: m/z (%) 510
(M+ − 1, 2), 493 (1), 287 (1), 120 (2), 105 (100), 94 (4), 77 (80), 76 (95).
Anal. calcd. for C32H21N3O2S: C, 75.13; H, 4.14; N, 8.21; Found: C, 74.90;
H, 4.20; N, 8.10.
3c [R C6H4OCH3 (p-)]: Yield (0.40 g, 80%), m.p. 205-207◦C; IR: 1693
(C O), 1641 (C N) cm–1; MS: m/z (%) 529 (M++3, 0.2), 391 (0.5), 135
(2), 107 (1), 105 (100), 77 (99), 76 (10). Anal. calcd. for C33H23N3O2S: C,
75.41; H, 4.41; N, 7.99; Found: C, 75.60; H, 4.50; N, 8.10.
3d [R = C6H4Cl (p-)]: Yield (0.41 g, 82%), m.p. 203−204◦C; IR:
1689(C O), 1643(C N) cm–1; MS: m/z (%) 530 (M+, 0.2), 524 (0.2), 412
(0.2), 308 (0.6), 139 (2), 112 (0.5), 105 (100), 77 (90), 76 (7). Anal. calcd.
for C32H20ClN3OS: C, 72.51; H, 3.80; N, 7.93; Found: C, 72.40; H, 3.80;
N, 7.80.
3e [R = C6H4NO2 (p−)]: Yield (0.39 g, 78%), m.p. 115−116◦C; IR:
1672 (C O), 1597 (C N), 1344(NO2) cm–1; MS: m/z (%) 540 (M+, 3), 436
(4), 418 (5), 288 (7), 123 (5), 105 (69), 77 (100); Anal. calcd. for C32H20N4
O3S: C, 71.10; H, 3.73; N, 10.36; Found: C, 71.30; H, 3.80; N, 10.20.
3f (R = 1-Naphthyl): Yield (0.30 g, 60%), m.p. 200−201◦C; IR: 1689
(C O), 1643 (C N) cm–1;MS: m/z (%): 546 (M+, 5), 344 (6), 289 (4), 129
(5), 105 (54), 77 (100) Anal. calcd. for C36H23N3OS: C, 79.24; H, 4.25; N,
7.70; Found: C, 79.10; H, 4.30; N, 7.80.

2802
F. El-Mariah
3g (R = 2-Pyrryl): Yield (0.38 g , 76%), m.p. 210−211◦C; IR: 1688
(C O), 1644 (C N) cm–1; MS: m/z (%) 484 (M+, 0.7), 419 (0.4), 407 (1),
392 (1), 315 (1), 287 (1), 105 (49), 92 (0.6), 77 (100). Anal. calcd. for
C30H20N4OS: C, 74.36; H, 4.16; N, 11.56; Found: C, 74.60; H, 4.10; N,
11.40.
3h (R=1-Methyl-2-pyrryl): Yield (0.35 g, 70%) m.p. 190−191◦C; IR:
1688 (C O), 1644 (C N) cm–1; MS: m/z (%) 498 (M+, 1), 421 (0.8), 316
(0.8), 301 (1), 288 (1), 209 (1), 105 (67), 77 (100). 1H-NMR (DMSO-d6): δ
8.14–8.06 (m, 3H, pyrryl protons), 7.71−7.63 (m, 5H, PhCO), 7.59−7.20
(m, 10H, 2 Ph), 5.06 (s, 1H, =CH ), 3.34 (s, 3H, CH3). Anal. calcd. for
C31H22N4OS: C, 74.67; H, 4.45; N, 11.24; Found: C, 74.50; H, 4.50; N,
11.10.
3i (R=2-Furyl): Yield (0.45 g, 90%), m.p. 180−181◦C; IR: 1687 (C O),
1644 (C N) cm1; MS: m/z (%) 486 (M+, 0.6), 408 (4), 391 (0.8), 287 (2),
105 (100), 94 (2), 77 (91). Anal. calcd. for C30H19N3O2S: C, 74.21; H,
3.94; N, 8.65; Found: C, 74.00; H, 4.00; N, 8.50.
3j (R=5-Methyl-2-furyl): Yield (0.4 g, 80%); m.p. 220−222◦C; IR: 1689
(C O), 1646 (C N) cm–1; MS: m/z (%) 495 (M+ − 4, 0.2), 419 (18), 408
(9), 391 (0.8), 390 (0.8), 387 (2), 375 (69), 309 (1), 288 (0.6) 232 (2),
204 (2), 105 (100); 1H-NMR (DMSO-d6): δ 8.11 (s, br, 2H, furyl protons),
7.81−7.68 (m, 5H, PhCO), 7.60−7.21 (m, 10H, 2Ph), 5.06 (s, 1H, =CH ),
3.35 (s, 3H, CH3). Anal. calcd. for C31H21N3O2S: C, 74.53; H, 4.24; N,
8.41. Found: C, 74.30; H, 4.20; N, 8.30.
3k (R=2-Thienyl): Yield (0.41 g, 82%), m.p. 195−196◦C; IR: 1689
(C O), 1643 (C N) cm–1; MS: m/z (%) 501 (M+, 0.5), 391 (0.6), 287 (1),
105 (64), 110 (1), 83 (0.5) 77 (100). Anal. calcd. for C30H19N3OS2: C,
71.83; H, 3.82; N, 8.38; Found: C, 72.00; H, 3.90; N, 8.50.
3l (R = 5-Methyl-2-thienyl): Yield (0.37g, 74%), m.p. 225−227◦C; IR:
1688 (C O), 1643 (C N) cm–1; MS: m/z (%) 516 (M+, 1), 391 (2), 288
(3), 126 (4), 105 (53), 98 (2), 77 (100). 1H-NMR (DMSO-d6): δ 8.14−8.06
(m, 2H, thienyl protons), 7.8−7.59 (m, 5H, PhCO), 7.28−7.21 (m, 10 H,
2Ph), 5.06 (s, 1H, CH ), 3.35 (s, 3H, CH3). Anal. calcd. for C31 H21 N3
OS2: C, 72.21; H, 4.11; N, 8.15; Found: C, 72.40; H, 4.20; N, 8.00.
Reaction of Compound 2 with Chloroacetyl Chloride
To a solution of compound 2 (4.1 g, 10 mmol) in dry benzene (10 mL),
dry pyridine (1 mL) and chloroacetyl chloride (1.13 g, 10 mmol) were
added. The reaction mixture was stirred at room temperature for 1
h (monitored by TLC). The solvent was then evaporated under re-
duced pressure, and the residue was treated with ice-cold water. The
solid product was collected and recrystallized from ethanol to give 5-
chloroacetylamino derivative 4, yield 3.5 g, 85%, m.p. 210−211◦C; IR:

Thieno[2,3-c]pyridazine Derivatives
2803
–1
3384 (NH), 1738 (C O, Ketonic), 1683 (C O, amide carbonyl) cm
.
Anal. calcd. for C27 H18 Cl N3 O2S: C, 67.00; H, 3.75; N, 8.68; Found: C,
67.20; H, 3.70; N, 8.80.
Synthesis of 5-[2-Imino-4-oxothiazolidin-3-yl]-6-benzoyl-3,4-
diphenyl thieno[2,3-c] pyridazine 6
A mixture of compound 4 (4.8 g, 10 mmol) and ammonium thiocyanate
(0.76 g, 10 mmol) in (96%) ethanol (20 mL) was heated under reflux for 1
h on water bath and left overnight at room temperature. The solid prod-
uct formed was collected, washed with water, and recrystallized from
ethanol to give 6, yield 4.0 g, 83%, m.p. 150−151◦C, IR: 3387 (NH), 1677
(C O, Cyclic), 1540(C N) cm–1; MS: m/z (%) 506 (M+, 100), 210 (75),
1
105 (54); H-NMR (DMSO-d6): δ 8.13−8.03 (m, 5H, PhCO), 7.70−7.22
(m, 10 H, 2 Ph), 5.05 (s, 2H, CH2), 4.50−4.36 (br, 1H, NH). Anal. calcd.
for C28 H18N4 O2S2: C, 66.38; H, 3.58; N, 11.06. Found: C, 66.60; H, 3.50;
N, 11.20.
Reaction of Compound 6 with Aromatic and Heteroaromatic
Aldehydes—General Procedure
A mixture of compound 6 (0.51 g., 1.0 mmol) and aromatic aldehydes
(1.0 mmol) in absolute ethanol was refluxed for 3 h and allowed to cool.
The solid product was collected, dried, and recrystallized from ethanol
to obtain compounds 7a−g.
7a [C6H4 Cl(p-)]: Yield (0.41 g, 80%), m.p. 210−212◦C; IR: 3421
–1
(NH), 3055, 1542 (C C), 1677 (C O, Ketonic), 1596 (C O, cyclic) cm
;
MS: m/z (%) 629 (M+, 6), 594 (8), 552 (14), 538 (0.9), 524 (13, 518(9),
517 (13), 503(9), 490 (16), 440(15), 413(13), 393 (100). Anal. calcd. for
C35H21ClN4O2S2: C, 66.82; H, 3.37; N, 8.91; Found: C, 67.00; H, 3.30;
N,8.80.
7b [R=C6H4NO2(p)-]: Yield (0.40 g, 78%), m.p. 123−124◦C; IR: 3100
(NH), 3061, 1522 (C C), 1667 (C O, Ketonic), 1600 (C O, Cyclic), 1345
(NO2) cm–1; MS: m/z (%) 639(M+, 15), 562 (22), 535 (29), 518 (12), 441
(20), 412 (29), 392(9), 288 (100). Anal. calcd. for C35H21N5O4S2: C, 65.71;
H, 3.31; N, 10.95; Found: C, 65.90; H, 3.40; N, 10.80.
7c (R = 2-Pyrryl): Yield (0.39 g, 76.5%), m.p. 250−252◦C; IR: 3420
–1
(NH), 3050, 1544 (C C), 1741 (C O, Ketonic), 1650 (C O, Cyclic) cm
;
MS: m/z (%) 580 (M+-3, 3), 475 (3), 439 (13), 410 (3),391 (17), 314(9),
286 (11), 211 (10), 192 (2), 126 (23), 105 (100). Anal. calcd. for C33H21N5
O2S2: C, 67.90; H, 3.63; N, 12.00. Found: C, 67.70; H, 3.70; N, 12.20.
7d (R = 1-Methyl-2-pyrryl): Yield (0.38, 74.5%), m.p. 230−231◦C; IR:
3429(NH), 3058, 1540 (C C), 1697 (C O, Ketonic), 1639 (C O, Cyclic),

2804
F. El-Mariah
1584 (C N) cm–1; MS: m/z (%) 597 (M+, 0.3), 595 (0.3), 493(2), 412 (0.6),
126 (2), 109 (0.6), 105(100), 77 (99). 1H-NMR (DMSO-d6): δ 9.59 (s, 1H,
NH), 8.15−8.08 (m, 5H, PhCO), 7.87−7.59 (m, 10H, 2Ph), 7.29−7.09
(m, 3H, Pyrryl protons), 5.89 (s, 1H, CH ), 3.38 (s, 3H, CH3). Anal.
calcd. for C34H23N5O2S2: C, 68.32; H,3.88; N, 11.72; Found: C, 68.50; H,
3.80; N, 11.50.
7e (R = 5-Methyl-2-furyl): Yield (0.35 g, 68.6%), m.p. 224−226◦C; IR:
3428 (NH), 3056, 1538 (C C), 1691 (C O, Ketonic), 1640 (C O, Cyclic)
cm–1; MS: m/z (%) 596 (M+−2, 0.19), 581 (0.7), 519 (0.2), 438 (0.5), 410
(4), 392 (6), 314 (1), 286 (1), 126 (30), 105 (100). 1H-NMR (DMSO-d6): δ
9.47 (s, 1H, NH), 8.14−8.11 (m, 5H, PhCO), 7.88−7.62 (m, 10H, 2Ph),
7.11−6.92 (m, 3H, furyl protons), 5.82 (s, 1H, =CH ), 3.46-3.41 (br, s,
3H, CH3). Anal. calcd. for C34H22N4 O3S2: C, 68.21; H, 3.70; N, 9.36.
Found: C, 68.40; H, 3.80; N, 9.20.
7f (R = 2-Thienyl): Yield (0.43 g, 84%), m.p. 226−227◦C; IR: 3425
–1
(NH), 2950, 1543 (C C), 1677 (C O, Ketonic), 1653 (C O, Cyclic) cm
;
MS: m/z (%) 600 (M+, 8), 523 (19), 517 (16), 495 (10), 440 (38), 391 (11),
314 (18), 287 (15), 236 (100). Anal. calcd. for C33H20N4 O2S3: C, 65.98;
H, 3.36; N, 9.33. Found C, 65.80; H, 3.30; N, 9.20.
7g (R= 5-Methyl-2-thienyl): Yield (0.32g, 62.7%), m.p. 234−236◦C;
IR: 3424 (NH), 3056, 1537 (C C), 1686 (C O, Ketonic), 1641 (C O,
Cyclic) cm–1; MS: m/z (%) 516 (M+1, 1), 440 (2), 415 (1), 391 (2), 223
(1), 126 (8), 105 (100). Anal. calcd. for C34H22N4O2S3: C, 66.42; H, 3.61;
N, 9.11; Found: C, 66.60; H, 3.70; N, 9.00.
Reaction of Compound 6 with Formaldehyde
To a solution of compound 6 (0.51 g, 1.0 mmol) in absolute ethanol
(10 mL), formaldehyde (1.0 mL, 37%) was added. The reaction mixture
was refluxed for 3 h. Upon cooling, the solid product was filtered, dried,
and recrystallized from ethanol to give 5ꢀ-hydroxymethyl derivative 8a,
yield 0.42 g, 82%, m.p. 140−141◦C; IR: 3393 (NH), 3250−2971 (OH-
broad), 2971 (CH2), 1677 (C O, Cyclic), 1543 (C N) cm–1; MS: m/z (%)
536 (M+, 0.8), 400 (0.8), 391(6) 286 (2), 209 (2), 145 (6), 105 (100). Anal.
calcd. for C29H20N4O3S2: C, 64.91; H, 3.76; N, 10.44. Found: C, 64.70;
H, 3.70; N, 10.30.
Reaction of Compound 6 with Secondary Amines/
Formaldehyde—General Procedure
To a solution of compound 6 (0.51 g, 1.0 mmol) in absolute ethanol (10
mL), mixture of secondary amine (1.0 mmol) and formaldehyde (1 mL,

Thieno[2,3-c]pyridazine Derivatives
2805
37%) was added. The reaction mixture was refluxed for 4 h. Upon cool-
ing, the crude compound was precipitated, filtered, dried, and recrys-
tallized from ethanol to obtain compound 8b−e.
8b (R=Diethylamino): Yield (0.42 g, 82%), m.p. 138−140◦C; IR: 3420
(NH), 2869 (CH2), 1651 (C O, Cyclic), 1584(C N), 1071 (3◦-amine)
cm–1; MS: m/z (%) 591(M+, 3), 519 (5), 505 (5), 486 (3), 434(3), 391(1),
290 (100), 286 (4), 209 (3), 202 (13), 115 (27). Anal. calcd. for C33H29N5
O2S2: C, 66.98; H, 4.94; N, 11.84; Found: C, 66.70; H, 4.80; N, 12.00.
8c (R = Diphenylamino): Yield (0.35 g, 68.6%), m.p. 204−205◦C; IR:
3382 (NH), 2910 (CH2) 1688 (C O, Ketonic), 1642 (C O, cyclic), 1591
(C N), 1198 (3◦-amine) cm–1; MS: m/z (%) 687 (M+, 5), 394 (7), 209
(6), 183 (6), 168 (33), 114 (9), 105 (8), 77 (47), 51 (100). Anal. calcd. for
C41H29N5O2S2: C, 71.59; H, 4.25; N, 10.18; Found: C, 71.80; H, 4.10; N,
10.00.
8d (R = 1-Pyrrolidino): Yield (0.37 g, 72.5%), m.p.; 122−123◦C; IR:
3436 (NH), 2874 (CH2), 1693 (C O, Ketonic), 1663 (C O, Cyclic), 1564
(C N), 1147 (3◦-amine) cm–1; MS: m/z (%) 589 (M+, 0.3), 391 (1), 286
1
(0.8), 114 (2), 105 (100), 86 (8), 77 (57). H-NMR (DMSO-d6): δ 8.64 (s,
1H, NH), 8.06−8.02 (m, 5H, PhCO), 7.70−7.05 (m, 10H, 2Ph), 6.61 (t,
1H, CH), 3.94 (t, 2H, CH2), 2.67−2.55 (m, 4H, 2CH2 − α-pyrrolidene
protons), 1.64 (s, 2H, CH2 − β-pyrrolidene protons), 1.41 (s, 2H, CH2 −
β-pyrrolidene protons). Anal. calcd. for C33H27N5 O2S2: C, 67.21; H,
4.62; N, 11.88; Found: C, 67.00; H, 4.50; N, 11.70.
8e (R = 1-Piperidino): Yield (0.38 g, 74%), m.p. 150−151◦C; IR: 3428
(NH), 2849 (CH2), 1694 (C O, Ketonic), 1663 (C O, Cyclic), 1567 (C N),
1161 (3◦-amine) cm–1; MS: m/z (%) 604(M+, 63), 507 (54), 443 (46), 230
(100), 210 (63), 135 (42). 1H-NMR (DMSO-d6): δ 8.55 (s, 1H, NH), 8.04
(m, 5H, PhCO), 7.58−7.03 (m, 10H, 2Ph), 6−5.6 (m, 1H, CH), 3.78 (d,
2H, CH2), 2.5 (s, 4H, 2CH2 − α-piperidino), 1.33 (d, 6H, 3CH2 − β, β,γ -
piperidino). Anal. calcd. for C34H29N5 O2S2: C, 67.64; H, 4.84; N, 11.60.
Found: C, 67.40; H, 5.00; N, 11.40.
8f (R = 1-Morpholino): Yield (0.39 g, 76.5%), m.p. 140−141◦C; IR:
3413 (NH), 2849 (CH2), 1693 (C O, Ketonic), 1665 (C O, Cyclic), 1564
(C N), 1151 (3◦ amine) cm–1; MS: m/z (%) 605 (M+, 5), 528 (24), 288
(26) 115 (24), 107 (48), 100 (100), 87 (67). Anal. calcd. for C33H27N5O3S2:
C, 65.43; H, 4.49; N, 11.56; Found: C, 65.20; H, 4.40; N, 11.40.
REFERENCES
[1] (a) M. Yamaguchi, T. Mavvyama, K. Kamei, M. Akima, T. Kuroki, M. Hamana, and
N. Ohi; Chem. Pharm. Bull. 43, 236 (1995); (b) R. S. Vartanyan, Zh. V. Kazavyan,
M. A. Sheiranyan, A. S. Agaronyan, and N. O. Stepanyan, Khim, Farm. Zh., 30, 29
(1996).

2806
F. El-Mariah
[2] B. K. Garnaik and R. K. Behera, Indian J. Chem. Sect. B, 27B (12), 1157−1158
(1988).
[3] E. V. Valdzimirskaya, O. T. Novikevich, and O. G. Demchuk, Farm. Zh. (Kiev), 6,
67−71 (1991).
[4] R. Lakhan and R. L. Singh, J. Agric. Food Chem., 39 (3), 580−583 (1991).
[5] S. Grasso, A. Chimirri, P. Monforte, G. Fenech, and M. Zappala, Farmaco, 41 (12),
713−721 (1986).
[6] A. Deeb, F. El-Mariah, and M. Hosny, Bioorg. Med. Chem. Lett., 14, 5013−5017
(2004).
[7] F. El-Mariah, M. Hosny, and A. Deeb, Phosphorus, Sulfur, and Silicon, 181, 809−818,
(2006).
[8] F. El-Mariah, M. Hosny, and A. Deeb, Phosphorus, Sulfur, and Silicon, 181,
2505−2517, (2006).
[9] M. Hosny, F. El-Mariah, and A. Deeb, Phosphorus, Sulfur, and Silicon, 182,
1475−1482, (2007).
[10] M. Kupinic, M. Medic-Saric, M. Movrin, and D. Maysinger, J. Pharm. Sci., 68 (4),
459−462 (1979).
[11] R.W. Daisley and V. K. Shah, J. Pharm. Sci., 73 (3), 407−408 (1984).
[12] S. N. Pandeya, D. Sriram, G. Nath, and E. De Clercq, Arzneim.-Forsch. /Drug Res.,
50 (1), 55−59 (2000).
[13] S. N. Pandeya, D. Sriram, G. Nath, and E. De Clercq, J. Pharm. Sci., 9, 25−31 (1999).
[14] (a) M. F. Ismail, N. A. Shams, and O. M. El-Sawy, Synthesis, 410 (1980); (b) A. Deeb,
S. Said, M. Hamed, and F. Yasin, J. Chin. Chem. Soc., 37, 287 (1990).
[15] A. W. Bauer, W. W. Mkriby, J. C. Sherris, and M. Turck, Am. J. Clin. Pathol., 45, 493
(1966).