Synthesis of novel thieno[2,3-c]pyridazines and related heterocycles

Article abstract of DOI:10.1007/PL00010290

The reaction of ethyl 2,3-dihydro-5,6-diphenyl-3-thioxopyridazine-4-carboxylate with ω-bromoacetophenones, chloro-N-arylacetamides, chloroacetonitrile, ethyl chloroacetate, or chloroacetone furnished the corresponding 4,5-diphenyl-3-hydroxy thieno [2,3-c]pyridazines. 2-Cyano-, 2-ethoxycabonyl-, and 2-acetyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazines were employed as precursors in the synthesis of some novel furo [2′,3′:4,5]thieno[2,3-c]pyridazines, pyrano-[2′,3′:4,5]thieno[2,3-c]pyridazines, and thieno[2,3-c]pyridazines. The antibacterial and antifungal activities of some of the compounds are reported.

Full text of DOI:10.1007/PL00010290

Monatshefte fuÈr Chemie 130, 1117±1128 (1999)
Synthesis of Novel Thieno[2,3-c]pyridazines
and Related Heterocycles
Ã
Shaban M. Radwan and Etify A. Bakhite
Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
Summary. The reaction of ethyl 2,3-dihydro-5,6-diphenyl-3-thioxopyridazine-4-carboxylate with
!-bromoacetophenones, chloro-N-arylacetamides, chloroacetonitrile, ethyl chloroacetate, or chloro-
acetone furnished the corresponding 4,5-diphenyl-3-hydroxy thieno [2,3-c]pyridazines. 2-Cyano-,
2-ethoxycabonyl-, and 2-acetyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazines were employed
as precursors in the synthesis of some novel furo [20,30:4,5]thieno[2,3-c]pyridazines, pyrano-
[20,30:4,5]thieno[2,3-c]pyridazines, and thieno[2,3-c]pyridazines. The antibacterial and antifungal
activities of some of the compounds are reported.
Keywords. Biological activity; Furo[20,30:4,5]thieno[2,3-c]pyridazines; Pyrano[20,30:4,5]thieno[2,3-
c]pyridazines; Thieno[2,3-c]pyridazines.
Synthese neuer Thieno[2,3-c]pyridazine und verwandter Heterocyclen
Zusammenfassung. Die Reaktion von Ethyl-2,3-dihydro-5,6-diphenyl-3-thioxo-pyridazin-4-
carboxylat mit !-Bromacetophenon, Chlor-N-arylacetamiden, Chloracetonitril, Ethylchloracetat
oder Chloraceton ergab die entsprechenden 4,5-Diphenyl-3-hydroxythieno[2,3-c]pyridazine. 2-
Cyano-, 2-Ethoxycabonyl- und 2-Acetyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine wurden als
0
0
0
0
È
Vorlaufer neuer Furo[2 ,3 :4,5]thieno[2,3-c]pyridazine, Pyrano[2 ,3 :4,5]thieno[2,3-c]pyridazine und
Thieno[2,3-c]pyridazine eingesetzt. Die antibakteriellen und fungistatischen Eigenschaften einiger
Verbindungen werden mitgeteilt.
Introduction
Pyridazine derivatives and heterocyclic annelated pyridazines continue to attract
interest due to a wide spectrum of biological activities [1±6]. In particular, some
thienopyridazines have been reported to possess considerable antiasthmatic [7] and
®brinolytic activities [8]. In view of the above facts and in continuation of our
program directed towards the synthesis of new polyheterocyclic systems containing
a thiophene moiety with potential biological properties [9±12], we synthesized the
title compounds and evaluated their antimicrobial properties.
Ã
Corresponding author

1118
S. M. Radwan and E. A. Bakhite
Results and Discussion
Syntheses
The thiation of ethyl 2,3-dihydro-5,6-diphenyl-4-oxopyridazine-4-carboxylate (1)
[13] using P2S5 in dry pyridine resulted in the formation of thioxo derivative 2
which was used as a starting material in the synthesis of the target heterocycles.
Thus, the reaction of 2 with halocompounds like !-bromo-acetophenones, chloro-
N-arylacetamides, or chloroacetonitrile in re¯uxing ethanol containing an
equimolar quantity of sodium acetate gave the corresponding S-alkylated products
3a±f. Cyclization of 3a±f to the corresponding thienopyridazines 4a±f was
achieved by re¯uxing the educts in ethanol containing an excess of fused sodium
acetate or catalytic amounts of sodium ethoxide. Compound 2 was also reacted
with ethyl chloroacetate and/or chloroacetone in the presence of fused sodium
acetate to give the thienopyridazines 4g, h. (Scheme 1). Reaction of the vicinal
hydroxycarbamoyl derivative 4c with ethyl chloroformate afforded the thienopyr-
idazine derivative 6 instead of the expected oxazine-2,4-dione 5 (Scheme 2).
An attempt to synthesize novel heterocyclic systems containing the furo-
[20,30:4,5]thieno[2,3-c]pyridazine moiety involved reaction of 4f with ethyl
chloroacetate in DMF at 100ꢀC for 2 h in the presence of K2CO3 to give ethyl-(2-
cyano-4,5-diphenylthieno[2,3-c]pyridazin-3-yloxy)-acetate (7); the reaction of 4f
3, 4
R
3, 4
R
a
b
c
COPh
e
f
CONHC6H4Cl( p)
CN
p-COC6H4Br
CONHPh
g
h
CO2Et
d
CONHC6H4Me( p)
COMe
Scheme 1

Thienopyridazines and Related Compounds
1119
Scheme 2
Scheme 3
with chloroacetonitrile under the same conditions afforded 3-amino-2-cyano-7,8-
diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine (8). Upon treatment with sodium
ethoxide in re¯uxing ethanol, 7 underwent Thorpe-Ziegler cyclization to furnish
ethyl 3-amino-7,8-diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine-2-carboxylate (9)

1120
S. M. Radwan and E. A. Bakhite
which could also be obtained by heating 4f with ethyl chloroacetate in DMF at
100ꢀC for 10 h in the presence of K2CO3. Heating of 9 with formamide resulted in
the formation of the pyrimidofurothienopyridazine derivative 10. The reaction of
9 with hydrazine hydrate gave the carbohydrazide 11, which on treatment
with sodium nitrite in glacial acetic acid yielded the corresponding carbonylazide
12. On re¯uxing of 12 in dry toluene, Curtius rearrangement to imidazolo-
[4,00500:4,5]furo[20,30:4,5]thieno[2,3-c]pyridazine 14 occurred via the intermediate
isocyanate derivative 13 (Scheme 3).
The present investigation was extended to the synthesis of novel pyrano-
[20,30:4,5]thieno[2,3-c]pyridazines starting from the vicinal hydroxyester 4g.
Re¯uxing of 4g in an ethanolic solution of sodium hydroxide resulted in hydrolysis
followed by spontanous decarboxylation to give 4,5-diphenyl-3-hydroxy-
thieno[2,3-c]pyridazine (16). The cycloaddition reaction of 16 with benzylidene-
malononitrile afforded 2-amino-3-cyano-4,8,9-triphenyl-4H-pyrano[20,30:4,5]-
thieno[2,3-c]pyridazine (17) in nearly quantitative yield. The condensation of 17
with triethyl orthoformate yielded methanimidate 18 which upon treatment with
hydrazine hydrate according to literature [14] did not give the pyrimidopyr-
anothienopyridazine 19, most probably due to -N=C- ®ssion, and compound 17
was recovered. Heating of 17 with acetic anhydride at re¯ux temperature led to the
formation of the monoacetyl derivative 20 (Scheme 4).
2-Acetyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4h) proved also to be
a versatile synthon for the preparation of other new thienopyridazines. Thus, its
condensation with hydroxylamine or thiosemicarbazide gave the corresponding
oxime 21 and thiosemicarbazone 22. An attempt to cyclize 21 to the isoxazolo-
Scheme 4

Thienopyridazines and Related Compounds
1121
Scheme 5
thienopyridazine 23 by heating with acetic anhydride failed, and the biacetyl
derivative 24 was isolated instead. The interaction of 22 with ethyl chloroacetate in
re¯uxing ethanol in the presence of fused sodium acetate produced the
thiazolidinone derivative 25 (Scheme 5).
The structural formulas of all newly synthesized compounds were con®rmed by
elemental and spectroscopic analyses (cf. Experimental). Moreover, the IR and 1H
NMR spectroscopic data revealed that compounds 4a±f and 16 exist predominantly
in their enol form. This fact was supported by the aforementioned behaviour of
compounds 4c, 4f, and 16 towards some reagents, such as ethyl chloroformate,
ethyl chloroacetate/chloroacetonitrile, or benzylidenemalononitrile.
Screening for antimicrobial activities
Compounds 3f, 4a, 4c, 4g, 7, 9, 14, 16, 17, and 20 were tested in vitro for their
antimicrobial activities against four straines of bacteria (Staphylococcus aureus,
Sarcina spp., Pseudomonas aeruginosa, Bacillus cereus) and four species of fungi
(Aspergillus fumigatus, Aspergillus niger, Aspergillus temcus, Fusarium solani)
using the ®lter paper disc method [15, 16]. The screening results given in Table 1
indicate that among the tested compounds only four (3f, 4a, 4c, and 16) showed
good growth inhibition against Sarcina spp. and Bacillus cereus. Compounds 3f
and 4c are also active against Staphylococcus aureus. However, concerning the
antifungal activities, only 4a showed a considerable activity against Aspergillus
fumigatus and Aspergillus temcus. The rest of the tested compounds showed no
activity against bacterial and fungal species under investigation.

1122
S. M. Radwan and E. A. Bakhite
Experimental
All melting points are uncorrected and were measured on a Fisher-John apparatus. IR spectra:
Shimadzu 470 IR-spectrophotometer (KBr; ꢀmax in cmꢁ1); 1H NMR spectra: Varian EM-390,
90 MHz, TMS as internal standard (ꢁ in ppm); MS: Jeol JMS-600; elemental analyses: Perkin-Elmer
240C elemental analyser. The results of the analyses were in good agreement with the calculated
values.
Ethyl 2,3-dihydro-5,6-diphenyl-3-oxopyridazine-4-carboxylate (1)
1 was prepared according to Ref. [13].
Ethyl 2,3-dihydro-5,6-diphenyl-3-thioxopyridazine-4-carboxylate (2; C19H16N2O2S)
A mixture of 3.2 g 1 (0.01 mol) and 2.22 g P2S5 (0.01 mol) in 25 cm3 dry pyridine was heated under
re¯ux for 5 h. The reaction mixture was cooled, poured onto 50 cm3 cold H2O, and acidi®ed with dil.
HCl. The precipitated solid was collected and crystallized from ethanol to give 2 in the form of
yellow needles.
Yield: 2.4 g (70%); m.p.: 230ꢀC; IR: ꢀmax ˆ 3100 (NH), 2900±2750 (SH), 1720 (C=O)cmꢁ1
;
1H NMR (DMSO-d6): ꢁ ˆ 13.5 (s, 1H, NH), 7.0±7.5 (m, 10H, ArH), 4.0±4.4 (q, 2H, CH2), 1.2±1.5
(t, 3H, CH3) ppm.
Reaction of thioxopyridazine 2 with halocompounds; general procedure
A mixture of 1.68 g 2 (0.005 mol), 0.68 g sodium acetate trihydrate (0.005 mol), and the respective
halocompound (0.005 mol) in 30 cm3 ethanol was re¯uxed for 2 h. The product which separated on
cooling was collected and recrystallized from the proper solvent to give 3a±f.
Ethyl 5,6-diphenyl-3-phenacylthiopyridazine-4-carboxylate (3a; C27H22N2O3S)
Prepared from 2 and phenacyl bromide; yield: 1.8 g (79%); m.p.: 124±126ꢀC (methanol); IR:
1
ꢀmax ˆ 1720 (C=O, ester), 1680 (C=O)cmꢁ1; H NMR (CDCl3): ꢁ ˆ 7.0±8.3 (m, 15H, ArH), 5.1 (s,
2H, SCH2), 4.0±4.3 (q, 2H, OCH2), 0.9±1.2 (t, 3H, CH3) ppm.
Ethyl 3-p-bromophenacylthio-5,6-diphenylpyridazine-4-carboxylate (3b; C27H21BrN2O3S)
Prepared from 2 and p-bromophenacyl bromide; yield: 2.35 g (85%); m.p.: 150±151ꢀC (ethanol); IR:
ꢀmax ˆ 1720 (C=O, ester), 1680 (C=O) cmꢁ1
.
Ethyl 5,6-diphenyl-3-phenylcarbamoylmethylthiopyridazine-4-carboxylate (3c; C27H23N3O3S)
Prepared from 2 and chloro-N-phenylacetamide; yield: 2.0 g (85%); m.p.: 145±146ꢀC (ethanol); IR:
ꢀmax ˆ 3300 (NH), 1720 (C=O, ester), 1670 (C=O, amide) cmꢁ1; 1H NMR (CDCl3): ꢁ ˆ 10.6 (s, 1H,
NH), 7.0±7.7 (m, 15H, ArH), 4.0 (s, 2H, SCH2), 4.2±4.5 (q, 2H, OCH2), 1.1±1.4 (t, 3H, CH3) ppm.
Ethyl 5,6-diphenyl-3-p-tolylcarbamoylmethylthiopyridazine-4-carboxylate (3d; C28H25N3O3S)
Prepared from 2 and chloro-N-p-tolylacetamide; yield: 2.1 g (87%); m.p.: 160±161ꢀC (ethanol); IR:
ꢀmax ˆ 3300 (NH), 1720 (C=O, ester), 1670 (C=O, amide) cmꢁ1
.

Thienopyridazines and Related Compounds
1123
Ethyl 3-p-chlorophenylcarbamoylmethylthio-5,6-diphenylpyridazine-4-carboxylate
(3e: C27H22ClN3O3S)
Prepared from 2 and chloro-N-p-chlorophenylacetamide; yield: 2.1 g (83%); m.p.: 150±152ꢀC
(ethanol); IR: ꢀmax ˆ 3300 (NH), 1720 (C=O, ester), 1670 (C=O, amide) cmꢁ1
.
Ethyl 3-cyanomethylthio-5,6-diphenylpyridazine-4-carboxylate (3f; C21H17N3O2S)
Prepared from 2 and chloroacetonitrile; yield: 1.5 g (80%); m.p.: 202±203ꢀC (benzene); IR:
ꢀmax ˆ 2210 (C:N), 1730 (C=O, ester)cmꢁ1; 1H NMR (CDCl3): ꢁ ˆ 7.0±7.7 (m, 15H, ArH), 5.4 (s,
2H, SCH2), 4.2±4.5 (q, 2H, OCH2), 1.1±1.4 (t, 3H, CH3) ppm.
4,5-Diphenyl-3-hydroxy-2-substituted-thieno[2,3-c]pyridazines 4a±f; general procedure
A) To a suspension of 3a±f (0.005 mol) in 30 cm3 abs. ethanol, 1.65 g fused sodium acetate
(0.02 mol) or sodium ethoxide solution (0.3 g sodium in 15 cm3 abs. ethanol) was added. The
resulting mixture was re¯uxed for 3 h, cooled, diluted with 50 cm3 H2O, and acidi®ed with dil. HCl.
The solid formed was collected and crystallized from ethanol to give 4a±f.
B) A mixture of 1.68 g 2 (0.005 mol), 1.65 g fused sodium acetate (0.02 mol), and the respective
halocompound (0.005 mol) in 35 cm3 ethanol was re¯uxed for 10 h. The reaction mixture was diluted
with 50 cm3 H2O and acidi®ed with dil. HCl. The solid product formed was collected and
crystallized from ethanol to give 4a±f. The products obtained by the two synthetic routes are
identical in all aspects.
2-Benzoyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4a; C25H16N2O2S)
Obtained by cyclization of 3a (yield: 90%) or by reaction of 2 with phenacyl bromide (yield: 75%);
1
m.p.: 198±199ꢀC; IR: ꢀmax ˆ 3350 (OH), 1620 (C=O) cmꢁ1; H NMR (CDCl3): ꢁ ˆ 13.2 (br, 1H,
OH), 7.3±8.3 (m, 15H, ArH) ppm.
2-p-Bromobenzoyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4b; C25H15BrN2O2S)
Obtained by cyclization of 3b (yield: 95%) or by reaction of 2 with p-bromophenacyl bromide
(yield: 77%); m.p.: 253±255ꢀC; IR: ꢀmax ˆ 3350 (OH), 1620 (C=O) cmꢁ1
.
4,5-Diphenyl-3-hydroxy-2-phenylcarbamoylthieno[2,3-c]pyridazine (4c; C25H17N3O2S)
Obtained by cyclization of 3c (yield: 84%) or by reaction of 2 with chloro-N-phenylacetamide (yield:
1
72%); m.p.: 266±267ꢀC; IR: ꢀmax ˆ 3300±3100 (OH, NH), 1620 (C=O) cmꢁ1; H NMR (DMSO):
ꢁ ˆ 10.5 (s, 1H, NH), 7.1±7.8 (m, 16H, ArH and OH) ppm.
4,5-Diphenyl-3-hydroxy-2-p-tolylcarbamoylthieno[2,3-c]pyridazine (4d; C26H19N3O2S)
Obtained by cyclization of 3d (yield: 86%) or by reaction of 2 with chloro-N-p-tolylacetamide
(yield: 77%); m.p.: > 300ꢀC; IR: ꢀmax ˆ 3300±3100 (OH, NH), 1620 (C=O) cmꢁ1
.
2-p-Chlorophenylcarbamoyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4e; C25H16ClN3O2S)
Obtained by cyclization of 3e (yield: 84%) or by reaction of 2 with chloro-N-p-chlorophenyl-
acetamide (yield: 75%); m.p.: 282±284ꢀC; IR: ꢀmax ˆ 3300±3100 (OH, NH), 1620 (C=O) cmꢁ1
.

1124
S. M. Radwan and E. A. Bakhite
2-Cyano-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4f; C19H11N3OS)
Obtained by cyclization of 3f (yield: 70%) or by reaction of 2 with chloroacetonitrile (yield: 67%);
1
m.p.: 240±242ꢀC; IR: ꢀmax ˆ 3450 (OH), 22000 (C:N)cmꢁ1; H NMR (DMSO-d6): ꢁ ˆ 7.2±7.5
(m, 11H, ArH and OH) ppm.
Reaction of thioxopyridazine 2 with ethyl chloroacetate or chloroacetone:
formation of thienopyridazines 4g, h; general procedure
A mixture of 3.36 g 2 (0.01 mol), 3.3 g fused sodium acetate (0.04 mol), and ethyl chloroacetate or
chloroacetone (0.01 mol) in 45 cm3 ethanol was heated under re¯ux for 6 h. The reaction mixture was
diluted with 50 cm3 H2O and acidi®ed with dil. HCl. The precipitate formed was collected and
crystallized from ethanol to afford 4g or 4f, respectively.
4,5-Diphenyl-2-ethoxycarbonyl-3-hydroxythieno[2,3-c]pyridazine (4g; C21H16N2O3S)
Yield: 2.8 g (74%); m.p.: 190±191ꢀC; IR: ꢀmax ˆ 3200 (OH), 1650 (C=O) cmꢁ1; 1H NMR (CDCl3):
ꢁ ˆ 10.3 (s, 1H, OH), 7.1±7.6 (m, 10H, ArH), 4.3±4.5 (q, 2H, OCH2), 1.3±1.5 (t, 3H, CH3) ppm; MS:
‡
‡
‡
‡
m/z (%) ˆ 376 (M , 58), 375 (M -H, 84), 346 (M -H-C2H5, 39), 300 (M ‡H-C6H5, 100), 299
‡
‡
(M -C6H5, 17), 77 (C6H5 , 12).
2-Acetyl-4,5-diphenyl-3-hydroxythieno[2,3-c]pyridazine (4h; C20H14N2O2S)
Yield: 2.4 g (69%); m.p.: 178±180ꢀC; IR: ꢀmax ˆ 3400 (OH), 1620 (C=O) cmꢁ1; 1H NMR (CDCl3):
ꢁ ˆ 7.1±7.5 (m, 11H, ArH and OH), 2.6 (s, 3H, CH3) ppm.
Thienopyridazine 6 (C28H21N3O4S)
A suspension of 0.42 g 4c (0.001 mol) in 10 cm3 ethyl chloroformate was heated under re¯ux for 2 h.
The precipitate which formed after cooling was collected and recrystallized from ethanol to give
colourless needles of 6.
Yield: 0.42 g (74%); m.p.: 220±221ꢀC; IR: ꢀmax ˆ 3380 (NH), 1760 (C=O, ester), 1660 (C=O,
1
amide) cmꢁ1; H NMR (DMSO-d6): ꢁ ˆ 10.6 (s, 1H, NH), 7.0±7.8 (m, 15H, ArH), 3.6±4.0 (q, 2H,
OCH2), 0.8±1.2 (t, 3H, CH3) ppm.
Ethyl-(2-cyano-4,5-diphenylthieno[2,3-c]pyridazine-3-yloxy)-acetate (7; C23H17N3O3S)
To a mixture of 3.3 g 4f (0.01 mol) and 1.23 g ethyl chloroacetate (0.01 mol) in 20 cm3 DMF, 2.76 g
anhydrous K2CO3 (0.02 mol) were added. The reaction mixture was heated on a water bath for 2 h,
cooled, and diluted with 30 cm3 H2O. The solid thus precipitated was collected and recrystallized
from aqueous ethanol to give 7.
Yield: 3.1 g (74%); m.p.: 150ꢀC; IR: ꢀmax ˆ 2200 (CN), 1740 (C=O) cmꢁ1
.
3-Amino-2-cyano-7,8-diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine (8; C21H12N4OS)
8 was prepared by reaction of 4f with chloroacetonitrile in analogy to the method described above.
The product was crystallized from methanol and identi®ed as 8.
Yield: 2.0 g (54%); m.p.: 270ꢀC; IR: ꢀmax ˆ 3300, 3200 (NH2), 2200 (C:N) cmꢁ1
.

Thienopyridazines and Related Compounds
1125
Ethyl 3-amino-7,8-diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine-2-caboxylate (9; C23H17N3O3S)
A) A suspension of 4.15 g 7 (0.01 mol) in sodium ethoxide solution (1.0 g sodium in 100 cm3 abs.
ethanol) was heated under re¯ux for 10 min. The solid product separating on cooling was collected
and recrystallized from ethanol to give 9.
Yield: 3.5 g (84%); m.p.: 252±254ꢀC; IR: ꢀmax ˆ 3450, 3330 (NH2), 1660 (C=O) cmꢁ1; 1H NMR
(DMSO-d6): ꢁ ˆ 7.1±7.6 (m, 10H, ArH), 5.9 (s, 2H, NH2), 4.1±4.4 (q, 2H, OCH2), 1.2±1.5 (t, 3H,
‡
‡
‡
‡
CH3) ppm; MS: m/z (%) ˆ 417 (M ‡2, 13), 416 (M ‡1, 37), 415 (M , 88), 414 (M -H, 84), 413
‡
‡
(M -2H, 100), 385 (M -H-C2H5, 17).
B) To a mixture of 3.3 g 4f (0.01 mol) and 1.23 g ethyl chloroacetate (0.01 mol) in 20 cm3 DMF,
2.76 g anhydrous K2CO3 (0.02 mol) was added. The reaction mixture was heated on a water bath for
10 h, cooled, and diluted with 15 cm3 H2O. The solid precipitated was collected and crystallized
from ethanol to give 9 in 70% yield (2.9 g). The products obtained by the two synthetic routes are
identical in all aspects.
3,4-Dihydro-6,7-diphenyl-4-oxopyrimido[400,500:40,50]furo[20,30:4,5]thieno[2,3-c]pyridazine
(10; C22H12N4O2S)
A solution of 0.41 g 9 (0.001 mol) in 15 cm3 formamide was heated under re¯ux for 4 h. The
precipitate separating after cooling was collected and recrystallized from DMF to give 10.
Yield: 0.3 g (70%); m.p.: >300ꢀC; IR: ꢀmax ˆ 3200±2400 (br, NH), 1660 (C=O) cmꢁ1; MS: m/z
‡
‡
‡
‡
‡
(%) ˆ 396 (M , 35), 394 (M -2H, 80), 481 (M -NH, 40), 380 (M -O, 100), 370 (M -CN, 85).
3-Amino-7,8-diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine-2-carbohydrazide (11; C21H15N5O2S)
A suspension of 4.15 g 9 (0.01 mol) in 10 cm3 hydrazine hydrate 99% (0.2 mol) was heated under
re¯ux for 3 h. The reaction mixture was titurated with 25 cm3 ethanol and left to cool. The solid
which formed was collected and recrystallized from dioxane to give 11.
Yield: 3.5 g (87%); m.p.: 295±297ꢀC; IR: ꢀmax ˆ 3420, 3300, 3200, 3150 (2NH2, NH), 1620
(C=O) cmꢁ1
.
3-Amino-7,8-diphenylfuro[20,30:4,5]thieno[2,3-c]pyridazine-2-carbonylazide (12; C21H12N6O2S)
3.5 cm3 chilled sodium nitrite solution (10%, 0.005 mol) was added dropwise to a solution of 2.0 g 11
(0.005 mol) in 10 cm3 glacial acetic acid at 5±10ꢀC during 5 min. with stirring. The reaction mixture
was allowed to stand at room temperature for 1 h and then diluted with 25 cm3 H2O. The precipitate
which formed was collected, dried in air, and used in the next step without puri®cation.
Yield: 1.6 g (77%); m.p.: 230ꢀC (dec.); IR: ꢀmax ˆ 3450, 3300 (NH2), 2130 (N3), 1660
(C=O) cmꢁ1
.
5,6-Diphenyl-1H-imidazolo[400,500:40,50]furo[20,30:4,5]thieno[2,3-c]pyridazine-2(3H)-one
(14; C21H12N4O2S)
A solution of 0.41 g 12 (0.001 mol) in 15 cm3 dry toluene was heated under re¯ux for 3 h. The
precipitate separating upon cooling was collected and recrystallized from DMF to give 14.
Yield: 0.2 g (52%); m.p.: 293±295ꢀC; IR: ꢀmax ˆ 3300±3100 (2NH), 1680 (C=O) cmꢁ1
.
4,5-Diphenyl-3-hydroxythieno[2,3-c]pyridazine (16; C18H12N2OS)
A solution of 3.8 g 4g (0.01 mol) in 40 cm3 ethanolic sodium hydroxide solution (7%) was
heated under re¯ux for 5 h and left to cool. The reaction mixture was diluted with 40 cm3 H2O

1126
S. M. Radwan and E. A. Bakhite
and acidi®ed with dil. HCl. The precipitated product was collected and crystallized from ethanol
to give 16.
Yield: 1.3 g (42%); m.p.: 230±231ꢀC; IR: ꢀmax ˆ 3500±2500 (br, OH) cmꢁ1
.
2-Amino-3-cyano-4,8,9-triphenyl-4H-pyrano[20,30:4,5]thieno[2,3-c]pyridazine (17; C28H18N4OS)
To a mixture of 1.52 g 16 (0.005 mol) and 0.77 g benzylidenemalononitrile (0.005 mol) in 20 cm3
ethanol, few drops of piperidine were added. The reaction mixture was heated under re¯ux for 1 h.
The solid that precipitated while hot was ®ltered and recrystallized from dioxane to give white
crystals of 17.
Yield: 2.15 g (94%); m.p.: 281±282ꢀC; IR: ꢀmax ˆ 3480±3300 (NH2), 2200 (C:N) cmꢁ1, 1H NMR
(DMSO-d6: ꢁ ˆ 7.1±7.6 (m, 15H, ArH), 6.8 (s, 2H, NH2), 5.1 (s, 1H, CH pyran); MS: m/z (%) ˆ 460
‡
‡
‡
‡
‡
(M ‡2, 17), 458 (M , 100), 457 (M -H, 83), 456 (M -2H, 40), 77 (C6H5 , 27).
3-Cyano-4,8,9-triphenyl-4H-pyrano[20,30:4,5]thieno[2,3-c]pyridazine-2-methanimidate
(18; C31H22N4O2S)
A suspension of 2.29 g 17 (0.005 mol) in 15 cm3 triethyl orthoformate was heated under re¯ux for 3 h
and allowed to cool. The precipitated solid was ®ltered and recrystallized from ethanol to give white
crystals of 18.
Yield: 2.1 g (82%); m.p.: 220±222ꢀC; IR: ꢀmax ˆ 2200 (C:N), 1600 (C=N) cmꢁ1
;
1H NMR
(DMSO-d6: ꢁ ˆ 7.1±7.6 (m, 15H, ArH), 6.8 (s, 1H, N=CH), 5.2 (s, 1H, CH pyran), 4.1±4.5 (q, 2H,
OCH2), 1.2±1.5 (t, 3H, CH3) ppm.
Monoacetyl derivative 20 (C30H20N4O2S)
A solution of 2.29 g 17 (0.005 mol) in 25 cm3 acetic anhydride was heated under re¯ux for 4 h. The
reaction mixture was cooled, diluted with 20 cm3 H2O, and allowed to stand at room temperature for
2 h. The solid formed was collected and crystallized from acetic acid to give yellow crystals of 20.
Yield: 1.5 g (60%); m.p.: > 300ꢀC; IR: ꢀmax ˆ 3200 (NH), 2200 (C:N), 1710 (C=O) cmꢁ1; MS:
‡
‡
‡
‡
m/z (%) ˆ 500 (M , 31), 458 (M -COCH3, 47), 381 (M -COCH3-C6H5, 100), 77 (C6H5 , 15).
Oxime derivative 21 (C20H15N3O2S)
A mixture of 1.73 g 4h (0.005 mol), 0.35 g hydroxylamine Á HCl (0.005 mol), and 1.36 g sodium
acetate trihydrate (0.01 mol) in 30 cm3 ethanol was heated under re¯ux for 3 h. The solid formed
after cooling was collected and recrystallized from methanol to give 21.
Yield: 1.5 g (81%); m.p.: 298±299ꢀC; IR: ꢀmax ˆ 3450 (OH), 3250 (OH), 1600 (C=N) cmꢁ1
.
Diacetyl derivative 24 (C24H19N3O4S)
A solution of 0.72 g 21 (0.002 mol) in 10 cm3 acetic anhydride was heated under re¯ux for 4 h and
then diluted with 15 cm3 H2O. The solid precipitated was collected and recrystallized from methanol
to give 24 as pale yellow needles.
1
Yield: 0.65 g (73%); m.p.: 217±218ꢀC; IR: ꢀmax ˆ 1770 (C=O), 1600 (C=N) cmꢁ1; H NMR
(CDCl3): ꢁ ˆ 7.1±7.5 (m, 10H, ArH), 2.4 (s, 3H, CH3), 2.2 (s, 3H, CH3), 1.5 (s, 3H, CH3) ppm.
Thiosemicarbazone derivative 22 (C21H17N5OS2)
To a mixture of 3.46 g 4h (0.01 mol) and 0.91 g thiosemicarbazide (0.01 mol) in 30 cm3 ethanol, few
drops of acetic acid were added. The reaction mixture was heated under re¯ux for 3 h and left to

Thienopyridazines and Related Compounds
1127
Table 1. Antibacterial and antifungal activities; -: no inhibition zone
Staph.
aureus
Sarcina Pseud.
Bacillus Asp.
Asp.
Asp.
Fusa.
solani
spp.
aeurgin. cereus fumigatus
niger
temc.
3f
12
±
11
16
14
±
±
±
±
±
±
±
±
±
±
±
±
17
24
12
±
±
±
±
±
±
±
±
±
±
±
±
14
±
8
±
±
±
±
±
±
±
±
22
±
±
±
±
±
±
±
±
±
±
12
4a
4c
9
±
16
±
4g
7
±
±
±
±
±
9
±
±
±
±
14
16
17
20
Trosyd
±
±
±
±
±
10
±
14
±
±
±
±
±
±
±
±
7
22
21
16
cool. The product that precipitated was ®ltered and recrystallized from methanol to give yellow
needles of 22.
Yield: 3.5 g (83%); m.p.: 235±237ꢀC; IR: ꢀmax ˆ 3500±3100 (OH, NH2, NH), 1600 (C=N) cmꢁ1
.
Thiazolidinone derivative 25 (C23H17N5O2S2)
To a suspension of 2.20 g 22 (0.005 mol) and 0.62 g ethyl chloroacetate (0.005 mol) in 30 cm3
ethanol, 1.64 g fused sodium acetate (0.02 mol) were added. The resulting mixture was heated under
re¯ux for 4 h. The precipitate which formed on cooling was ®ltered and recrystallized from dioxane
to give 25 as orange needles.
1
Yield: 2.0 g (71%); m.p.: > 300ꢀC; IR: ꢀmax ˆ 3450 (OH), 3100 (NH), 1700 (C=O) cmꢁ1; H
NMR (TFA): ꢁ ˆ 7.2±7.7 (m, 11H, ArH‡OH), 4.2 (s, 2H, SCH2), 2.8 (s, 3H, CH3) ppm.
Biological screening
The ®lter paper disc method [15, 16] was employed in nutrient agar for bacteria and dox agar for
fungi. The eagar media were inoculated with 0.5 ml of the 24 h liquid cultures. Filter paper discs
(5 mm diameter) saturated with each compound solution (10 mg/1 ml of DMSO) were placed on the
indicated agar media. The incubation time was 48 h at 28ꢀC. Discs saturated with DMSO were used
as control. Trosyd was used as a reference substance. The diameters of inhibition zones (mm) were
measured and are recorded in Table 1.
References
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vol 27, Elsevier, Amsterdam, p 1; (b) Heinisch G, Kopelent H (1992) In: Ellis GP, West GB (eds)
Progress in Medicinal Chemistry, vol 29. Elsevier, Amsterdam, p 141
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(1997) J Med Chem 40: 1417
[3] Kuhla DE, Campbell HF, Studt WL, Faith WC (1989) US Pat: 4,826,835; (1989) Chem Abstr
111: 174114r
[4] Iwase N, Morinaka Y, Tamao Y, Kanaiama T, Yamada K (1993) Eur Pat: 534, 443; Chem Abstr
119: 249963t

1128
S. M. Radwan and E. A. Bakhite: Thienopyridazines and Related Compounds
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Received November 19, 1998. Accepted (revised) March 5, 1999