Anti-alzheimer and anti-COX-2 activities of the newly synthesized 2,3'-bipyridine derivatives (II)

Article abstract of DOI:10.1080/10426500902917644

3-Amino-4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbohydrazides 3a,b were used as the starting materials in the present study. Our targets here were represented by the synthesis of several 3-amino-N'-4-arylmethylenes 5a,b, N-formamides 8a,b, ethyl im

Full text of DOI:10.1080/10426500902917644

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Phosphorus, Sulfur, and Silicon and the
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Anti-Alzheimer and Anti-COX-2 Activities
of the Newly Synthesized 2,3′-Bipyridine
Derivatives (II)
Fawzy A. Attaby a , Azza M. Abdel-Fattah a , Labeeb M. Shaif a
Mohamed M. Elsayed b
&
a Chemistry Department, Faculty of Science, Cairo University, Giza,
Egypt
b Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
Published online: 24 Feb 2010.
To cite this article: Fawzy A. Attaby , Azza M. Abdel-Fattah , Labeeb M. Shaif & Mohamed M.
Elsayed (2010) Anti-Alzheimer and Anti-COX-2 Activities of the Newly Synthesized 2,3′-Bipyridine
Derivatives (II), Phosphorus, Sulfur, and Silicon and the Related Elements, 185:3, 668-679, DOI:
10.1080/10426500902917644
To link to this article: http://dx.doi.org/10.1080/10426500902917644
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Phosphorus, Sulfur, and Silicon, 185:668–679, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902917644
ANTI-ALZHEIMER AND ANTI-COX-2 ACTIVITIES OF THE
NEWLY SYNTHESIZED 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
Fawzy A. Attaby,1 Azza M. Abdel-Fattah,1 Labeeb M. Shaif,1
and Mohamed M. Elsayed2
1Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
2Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
3-Amino-4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbohydrazides 3a,b were used as
the starting materials in the present study. Our targets here were represented by the synthesis
of several 3-amino-Nꢁ-4-arylmethylenes 5a,b, N-formamides 8a,b, ethyl imidoformate 10b,
N,N-dimethyl-Nꢁ-imidoformamides 12a,b, N-acetyl-N-acetamides 14a,b, 1,3,4-oxadiazole-
2-thiol 16a,b, pyrazolothienopyridines 20a,b, 2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-4-
aryl-6-pyridin-3-ylthieno[2,3-b]pyridin-3-amines 22a,b, 2-carbonyl-5-methyl-2,4-dihydro-
3H-pyrazol-3-ones 24a,b, and 2-carbonyl-pyrazolidine-3,5-diones 26a,b. The newly synthe-
sized heterocyclic compounds were tested as anti-Alzheimer and anti-COX-2 agents, and
their structures were elucidated by considering the data of IR, 1H NMR, mass spectra, and
elemental analyses.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords
N-Acetyl-N-acetamides; ethyl imidoformates; 1,3,4-oxadiazole-2-thiol;
3H-pyrazol-3-ones; pyrazolidine-3,5-diones; pyrazolothieno-pyridines
INTRODUCTION
The biological activities of thienopyridines have been reported as antimicrobial,1–3
anti-inflammatory,4 and ganadotropin-releasing hormone antagonizing activities,5 and they
also have neurotropic activity.6 Furthermore, pyridothienopyrimidines were reported to have
antiallergic,7 antiparasitic,8 antianaphylactic,9,10 and antimicrobial1 activity. The previously
mentioned findings have stimulated the interest for the synthesis of the title compounds.
In our previous recent work,11–21 we have reported several syntheses, characterizations,
reactions, and biological evaluations of 2-thioxo-hydropyridine-3-carbonitrile derivatives.
In this work, our goal is to use ethyl [(5-cyano-4-aryl-2,3ꢀ-bipyridin-6-yl)thio]acetates
1a,b15 and ethyl 3-amino-4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carboxylates 2a,b15
as synthons required for several chemical transformations as well as our medicinal chemistry
programs.
Received 17 December 2008; accepted 23 March 2009.
The authors thank the Cairo University, Faculty of Science, Chemistry Department, for the financial support
in this research.
Address correspondence to Prof. Dr. Fawzy A. Attaby, Chemistry Department, Faculty of Science, Cairo
University, Giza 12613, Egypt. E-mail: Fattaby@hotmail.com
668

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
669
RESULTS AND DISCUSSION
3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbohydrazide (3a) was
synthesized via the reaction of ethyl [(5-cyano-4-phenyl-2,3ꢀ-bipyridin-6-yl)thio]acetates
1a15 with hydrazine hydrate under reflux for 3–5 h. The IR of this reaction product showed
no bands for CN and ester CO functions, while the newly formed NHNH2 functions were
detected (see the Experimental section). Thus, we concluded that the reaction most probably
proceeded via the cyclization of 1a giving 2a as an intermediate followed by the reaction
with hydrazine hydrate to give the carbohdrazide derivative 3a. The structure of 3a was fur-
ther confirmed chemically by its preparation authentically via the reaction of ethyl 3-amino-
4-aryl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carboxylate (2a) with hydrazine hydrate. The
mass spectrum of 3a gave peaks at m/z = 361 (30.4%) corresponding to the molecular
formula C19H15N5OS of the assigned structure; m/z = 330 (100%, M+ NHNH2); 302
(19.9%, M+ CONHNH2).
Similarly, 3-amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]-pyridine-2-
carbohydrazide (3b) was obtained by the reaction of either 1b or 2b with hydrazine
hydrate, and its structure was established by considering the data of IR and mass spectrum,
as well as elemental analyses (see the Experimental section).
The chemical reactivity and synthetic potentiality of both 3a,b were investigated via
their chemical reactions with several reagents. Thus, it has been found that 3a,b reacted
with (4-methoxybenzylidene)malononitrile (4) or anisaldehyde (6) in a pyridine/ethanol
mixture under reflux to afford the reaction product formulated as 5a,b, respectively, whose
chemical structures were confirmed by considering the data of IR and elemental analy-
ses (see the Experimental section). Moreover, the mass spectra of 5a,b gave m/z = 479
and 509, respectively, which corresponded to the molecular formulas C27H21N5O2S and
C28H23N5O3S of the assigned structures, in addition to several peaks corresponding to
fragments that confirm their structures.
In a further investigation of the chemical reactivity and synthetic potentiality of
NHNH2 group in each of 3a,b, several reactions with each of formic acid 7, triethyl ortho-
formate 9, dimethylformamide-dimethylacetal 11, and acetic anhydride 13 in a respective
manner to afford the corresponding pyridothienopyrimidines 8a,b–14a,b, respectively. The
IR and elemental analyses data was considered to elucidate the structure of these struc-
tures. Moreover, the mass spectral data was considered as a good physical tool to establish
the structures 8–14 as follows: For compounds 8a,b, it gave m/z = 399 (61.2%) and 429
(13.1%), which corresponded to the molecular formula C21H13N5O2S and C22H15N5O3S
of the assigned structures. Also, peaks at m/z = 370 (M+ CHO, 53.1%), 355 (M+
NHCHO, 100%) for 8a and 400 (35.5%), 385 (100%) for 8b confirm the presence of the
NH CHO group at the pyrimidine ring N atom. In addition to other peaks observed in
mass spectra and the data of IR and elemental analyses, the structural formula of each of
8a,b was confirmed (see Scheme 1 and the Experimental section). For compound 10a, it
gave m/z = 371 (100%), which corresponded to the molecular formula C20H13N5OS of the
assigned structure; 370 (50%, M+ H); 355 (17.1%, M+ NH2), 343 (11.3%, M+ CO),
342 (58.3%, 370 CO); 328 (5.5%, M+ CO NH); 313 (5%, 328 NH). These peaks
confirm the presence of NH2 on the pyrimidine N atom. The presence of N CH OEt
on pyrimidine N atom of 10b was confirmed by the detection of peaks at M+ CHNMe2
and M+ N CHNMe2. For compounds 14a,b in each case, it gave m/z = 469 and 499,
which corresponded to the molecular formula C25H19N5O3S and C26H21N5O4S, respec-
tively; M+ COCH3; M+ 2COCH3; M+ N(COCH3)2 in addition to several peaks that
further confirm 14a,b structure (see Scheme 1 and the Experimental section).

670
F. A. ATTABY ET AL.
Ar
N
NH2
OMe
NH
O
N
CN
Ar
CN
S
(Ar = C6H4-4-OMe)
N
5a,b
4
OMe-p-PhCHO
N
3a,b
6
Ar
N
N
S
EtOOC
NH
CHO
N
HCOOH
7
O
S
N
N
N
Ar
1a,b
N
8a,b
NH2NH2/EtOH
reflux 5h
Ar
N
N
NH2
N
N
O
S
CH(OEt)3
O
S
9
H2N NH
N
10a (Ar=C6H5)
H2N
Ar
3a,b
Ar
N
N
N
OEt
NH2NH2/EtOH
reflux 4h
O
S
N
N
N
10b (Ar=C6H4-4-OCH3)
N
Ar
N
CH3
CH3
S
N
N
EtOOC
N
H2N
O
Ar
S
N
DMF/DMA
2a,b
11
N
12a,b
Ar
CH3
N
COMe
N
N
COMe
Ac2O
O
S
N
13
N
14a,b
Ar = a, C6H5
b, C6H4-p-OMe
Scheme 1
The nucleophilic character of the N atom of NHNH2 group at the 3-position of each
of 3a,b was further investigated via their reaction with carbon disulfide (CS2) in pyridine
under reflux for 3–5 h. This reaction most probably proceeded through the attacking of
nucleophilic N at each of 3a,b and electrophilic C of carbon disulfide followed by hydrogen

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
671
disulfide removal in each case afforded 16a,b, respectively. The elemental analyses and
IR spectral data were considered to elucidate the structure of 16a,b and their mass spectra
to confirm their structure further, it gave m/z = 403 (100%) and 433 (100%), which
corresponded to the molecular formulas C20H13N5OS2 and C21H15N5O2S2 of the assigned
structures; M+ H; M+—oxadiazole-2-thiol in each case and other peaks that corresponded
to several fragments, which confirm the assigned structures
Further investigation for such nucleophilic character was performed via the reaction
of each of 3a,b with each of phenylisothiocyanate (17) and acetic acid (19) to afford
18a,b and 20a,b, respectively, whose structures were elucidated by considering data of the
elemental analyses, IR, and mass spectra (Scheme 2).
The work was extended to shed more light on both the synthetic potentiality and
position of –CONHNH2 in each of 3a,b. This target was obtained through their reactions
with each of pentan-2,4-dione (21), ethyl 3-oxobutanoate (23), and diethyl malonate (25)
Ar
NH2
SH
O
N
S
N
CS2 in pyridine
15
N
16a,b
N
Ar
N
NH2
NH
O
N
PhNCS in pyridine
17
3a,b
N
S
N
18a,b
MeOC
Ar
N
NH
O
AcOH
19
S
N
N
20a,b
Ar= a,C6H5
b,C6H4-p-OMe
Scheme 2

672
F. A. ATTABY ET AL.
to build an additional pyrazole ring along NH NH2 group. Thus, it has been found that
3a reacted with 21, 23, and 25 in acetic acid under reflux for 3–5 h to afford the reaction
products 22a, 24a, and 26a, respectively. The IR of these reaction products showed the
bands of CO and NH2 functions, and their mass spectra gave m/z = 425, 427, and 429,
respectively, in addition to several fragments that elucidate the assigned structures further.
Considering all previously mentioned data in addition to that of elemental analyses,
these reaction products were formulated as 2-[(3,5-dimethyl-1H-pyrazol-1-yl)carbonyl]-
4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-3-amine (22a), 2-[(3-amino-4-phenyl-6-
pyridin-3-ylthieno[2,3-b]pyridin-2-yl)carbonyl]-5-methyl-2,4-dihydro-3H-pyrazol-3-one
(24a), and 1-{[3-amino-4-(4-phenyl)-6-pyridin-3-ylthieno[2,3-b]-pyridin-2-yl]carbonyl}-
pyrazolidine-3,5-dione (26a), respectively.
Similarly, compounds 22b, 24b, and 26b were obtained under the same above-
mentioned experimental conditions through the reaction of each 3a,b with each of 21, 23,
and 25, respectively (see Scheme 3).
Ar
NH2
O
S
N
N
CH3COCH2COCH3
21
N
H3C
CH3
N
22a,b
Ar
NH2
O
S
N
N
NH
CH3COCH2COOEt
23
3a,b
O
CH3
N
24a,b
Ar
NH2
O
S
N
NH
EtOOCCH2COOEt
25
N
O
O
N
26a,b
Ar= a,C6H5
b,C6H4-p-OMe
Scheme 3

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
673
Biological Evaluation: Anti-Alzheimer Activity
Compounds 5a,b, 8a,b, 10a,b, 12a,b, 14a,b, 16a,b, 18a,b, 20a,b, 22a,b, 24a,b,
and 26a,b with potency as anti-Alzheimer agents relative to Flurbiprofen are arranged in
descending order as follows: 3a, 26a, 8a, 22a, 5a, 20a, 18a, 16a, 14a, 10a, 12a, 18b,
16b, 20b, 5b, 12b, 10b, 3b, 24b, 8b, 14b, 22b, 26b. (For further details on the biological
activities of these compounds, see the Supplemental Materials and Figures S1–S5, available
online.)
EXPERIMENTAL
All melting points were uncorrected. IR (KBr discs) spectra were recorded on a
Shimadzu FTIR-8201PC Spectrophotometer. 1H NMR spectra were recorded on a Varian
Mercury 300 MHz and a Varian Gemini 200 MHz spectrometers using TMS as an internal
standard and CDCl3, DMSO-d6, and (CD3)2CO as solvents. Chemical shifts were expressed
as δ (ppm) units. Mass spectra were recorded on Shimadzu GCMS-QP1000EX using
an inlet type at 70 eV. The Microanalytical Center of Cairo University performed the
microanalyses.
Synthesis of 3a,b
Method A. A solution of each of 1a,b (1 g, 1 g; 0.0027 mol, 0.0025 mol) in
hydrazine hydrate (15 mL) and ethanol (20 mL) was heated under reflux for 5 h; the excess
solvents were evaporated. The solid was collected by filtration, dried, and crystallized from
the acetic acid to give 3a,b, respectively.
Method B. A solution of each of 2a,b (1 g, 1 g; 0.0027 mol, 0.0025 mol) in
hydrazine hydrate (15 mL) and ethanol (20 mL) was heated under reflux for 4 h; the excess
solvent was evaporated. The solid was collected by filtration, dried, and crystallized from
the acetic acid to give 3a,b, respectively.
3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridine-2-carbohydrazide (3a)
as yellow crystals (76%), mp = 270◦C; IR (ν cm−1): 3461, 3319, 3251 (NH & NH2), 3018
(aromatic-CH); MS: 361 (M+, 30.4% corresponding to the molecular formula C19H15N5OS
of the assigned structure), 330 (M+ NHNH2, 100%), 302 (M+ CONHNH2, 19.9%); 1H
NMR (DMSO-D6) (δppm): 4.46 (br, 2H, NH2); 5.83 (br, 2H, NH2); 7.51–8.67 (m, 9Hꢀs,
Aryl and pyridinyl Hꢀs); 9.19 (br, 1H, NH) and 9.37 (s, 1H, C5 H); Anal., Calcd./Found(%):
C(63.14/63.16) H(4.18/4.20) N(19.38/19.42) S(8.86/8.90).
3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b] pyridine-2-carbo-
hydrazide (3b) as yellow crystals (92%), mp = 252◦C; IR (ν cm−1): 3479, 3331, 3214
(NH & NH2), 3040 (aromatic-CH); MS: 391 (M+, 51.1% corresponding to the molecu-
lar formula C20H17N5O2S of the assigned structure), 360 (M+ NHNH2, 100%); Anal.,
Calcd./Found(%): C(61.37/61.40) H(4.38/4.42) N(17.89/17.91) S(8.18/8.22).
Synthesis of 5a,b
Method A. A solutionof eachof 3a,b (0.20g, 0.21g; 0.00055mol) and (4-methoxy-
benzylidene)malononitrile 4 (0.10g, 0.00055 mol) in pyridine (15 mL) and ethanol (20 mL)
was heated under reflux for 2 h; the excess solvent was evaporated. The solid was collected
by filtration, dried, and crystallized from the acetic acid to give 5a,b, respectively.

674
F. A. ATTABY ET AL.
Method B. A solution of each of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and 4-
methoxybenzaldehyde 6 (0.075 g, 0.00055 mol) in pyridine (15 mL) and ethanol (20 mL)
was heated under reflux for 2 h. Excess solvent was evaporated. The solid was collected by
filtration, dried, and crystallized from the acetic acid to give 5a,b, respectively.
3-Amino-Nꢀ-[(4-methoxyphenyl)methylene]-4-methoxyphenyl-6-pyridin-3-yl-
thieno[2,3-b]pyridine-2-carbohydrazide (5a) as yellow crystals (96%), mp = 299◦C;
IR (ν cm−1): 3477, 3290 (NH2), 3149 (NH), 3048 (aromatic-CH) and 1629 (CO); MS:
479 (M+, 68.3% corresponding to the molecular formula C27H21N5O2S of the assigned
structure), 330 (M+ NHN CH C6H4 p OMe, 100%); Anal., Calcd./Found(%):
C(67.62/67.65) H(4.41/4.44) N(14.60/14.63) S(6.69/6.71).
3-Amino-Nꢀ-[(4-methoxyphenyl)methylene]-4-methoxyphenyl-6-pyridin-3-yl-
thieno[2,3-b]pyridine-2-carbohydrazide (5b) as yellow crystals (90%), mp = 298◦C;
IR (ν cm−1): 3472, 3281 (NH2), 3150 (NH), 3032 (aromatic-CH) and 1627 (CO);
MS: 508 (M+, 21% which corresponds to the molecular formula C28H22N5O3S
of the assigned structure), 333 (M+
(M+
CONHN CH C6H4-p-OMe, 100%), 360
NHN CH C6H4-p-OMe, 42.8%); Anal., Calcd./Found(%): C(66.00/66.03)
H(4.55/4.58) N(13.74/13.77) S(6.29/6.31).
Synthesis of 8a,b
A solution of each of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and formic acid (15 mL)
was heated under reflux for 6 h. The excess formic acid was evaporated and cooled. The
solid was collected by filtration, dried, and crystallized from the ethanol to give 8a,b,
respectively.
N-[9-(4-Phenyl)-4-oxo-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyra-midin-
3(4H)-yl]formamide (8a) as white crystals (87%), mp = 300–302◦C; IR (ν cm−1):
3222 (NH), 3055 (aromatic-CH) and 1715–1683 (twoCO); MS: 399 (M+, 61.2%
corresponding to the molecular formula C21H13N5O2S of the assigned structure), 370
(M+ CHO, 53.1%), 356 (M+ NCHO, 72.9%), 355 (M+ NHCHO, 100%), 300 (M+
CON(CH)NHCHO, 77.7%); Anal., Calcd./Found(%): C(63.15/63.18) H(3.28/3.30)
N(17.53/17.57) S(8.03/8.06).
N-[9-(4-Methoxyphenyl)-4-oxo-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]-py-
rimidin-3(4H)-yl]formamide (8b) as yellow crystals (83%), mp = 292◦C; IR (ν cm−1):
3427 (NH), 3063 (aromatic-CH) and 1681 (CO); MS: 429 (M+, 13.1% corresponding to the
molecular formula C22H15N5O3S of the assigned structure), 400 (M+ CHO, 35.5%), 386
(M+ NCHO, 31.8%), 385 (M+ NHCHO, 100%), 331 (M+ CON(C)NHCHO, 90.7%);
Anal., Calcd./Found(%): C(61.53/61.55) H(3.52/3.56) N(16.31/16.34) S(7.47/7.50).
Synthesis of 10a,b
A solution of each of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and triethylorthoformate
(10 mL) was heated under reflux for 4 h; the excess triethylorthoformate was evaporated
and cooled. The solid was collected by filtration, dried, and crystallized from acetic acid to
give 10a,b, respectively.
3-Amino-9-phenyl-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-4(3H)
-one (10a) as orange crystals (77%), mp = 318–320◦C; IR (ν cm−1): 3329, 3254 (NH2),
3050 (aromatic-CH) and 1674 (CO); MS: 371 (M+, 100% corresponding to the molecular
formula C20H13N5OS of the assigned structure), 370 (M+ H, 50.3%), 355 (M+ NH2,

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
1
675
17.1%), 343 (M+ CO, 11.3%), 342 (M+ NNH, 58.3%); H NMR (DMSO-D6) (δ
ppm): 6.038 (s, 2H, NH2); 7.51–9.45 (m, 11H, phenyl, pyridinyl, and C2(H)); Anal.,
Calcd./Found(%): C(64.68/64.70) H(3.53/3.58) N(18.86/18.70) S(8.63/8.66).
Ethyl(4-oxo-9-(4-methoxyphenyl)-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno-[3,2-d]
pyrimidin-3(4H)-yl)imidoformate (10b) as yellow crystals (78%), mp = 242◦C; IR (ν
cm−1): 3040 (aromatic-CH) and 1665 (CO); MS: 457 (M+, 100% corresponding to the
molecular formula C24H19N5O3S of the assigned structure), 455 (M+ 2H, 72.6%), 400
1
(M+ COEt, 52.1%); H NMR (DMSO-D6) (δ ppm): 1.35 (t, 3H, CH2CH3); 3.86
(s, 3H, OCH3); 4.42 (q, 2H, -CH2CH3); 7.08–7.05 (d, 2H, J = 8.1 Ar Hꢀs); 7.71–7.68
(d, 2H, J = 8.1 Ar Hꢀs); 8.05–9.45 (m, 7H, pyridinyl, C2(H) and N CH OEt); Anal.,
Calcd./Found(%): C(63.01/63.05) H(4.19/4.22) N(15.31/15.34) S(7.01/7.05).
Synthesis of 12a,b
A solution of each of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and dimethylfor-
mamidedimethylacetal (0.07 g, 0.00055 mol) in dry xylene (15 mL) was heated under
reflux for 5 h. The excess solvent was evaporated and cooled. The solid was collected by
filtration, dried, and crystallized from dioxane to give 12a,b, respectively.
N,N-Dimethyl-Nꢀ-(4-oxo-9-phenyl-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno-[3,2-d]
pyrimidin-3(4H)-yl)imidoformamide (12a) as pale yellow crystals (70%), mp =
284◦C; IR (ν cm−1): 3038 (aromatic-CH) and 1655. (CO); MS: 426 (M+, 14.1%
corresponding to the molecular formula C23H18N6OS of the assigned structure), 355 (M+
1
N CHN(CH3)2, 100%); H NMR (DMSO-D6) (δ ppm): 2.94 (s, 3H, N(CH3)2); 3.00
(s, 3H, N(CH3)2); 7.50–9.44 (m, 12H, Ar, pyridinyl Hꢀs, C2(H), C8(H) and N CHNMe2);
Anal., Calcd./Found(%): C(64.77/64.80) H(4.25/4.29) N(19.70/19.73) S(7.52/7.55).
N,N-Dimethyl-Nꢀ-(4-oxo-9-methoxyphenyl-7-pyridin-3-ylpyrido[3ꢀ,2ꢀ:4,5]thieno
[3,2-d]pyrimidin-3(4H)-yl)imidoformamide (12b) as pale yellow crystals (72%),
mp = 264◦C; IR (ν cm−1): 3048 (aromatic-CH) and 1662 (CO); MS: 456 (M+, 61.4%
corresponding to the molecular formula C24H20N6O2S of the assigned structure), 399 (M+
CHN(CH3)2, 90.9%), 358 (M+ CHNN CHN(CH3)2, 31.8%); 1H NMR (DMSO-D6)
(δ ppm): 2.987 (s, 6H, N(CH3)2); 3.869 (s, 3H, OCH3); 7.073 (d, 2H, J = 8.4 Hz Ar Hꢀs);
7.702 (d, 2H, J = 8.4 Ar Hꢀs) and 8.029–9.429 (m, 7H, pyridinyl Hꢀs, C2(H) and C8(H)
and N CHNMe2); Anal., Calcd./Found(%): C(63.14/63.16) H(4.42/4.44) N(18.41/18.44)
S(7.02/7.05).
Synthesis of 14a,b
A solution of each of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and acetic anhydride
(15 mL) was heated under reflux for 6 h. The excess solvent was evaporated and cooled.
The solid was collected by filtration, dried, and crystallized from the proper acetic acid to
give 14a,b, respectively.
N-Acetyl-N-(9-phenyl-2-methyl-4-oxo-7-pyridin-3-yl-1,4-dihydropyrido-[3ꢀ,2ꢀ:
4,5]thieno[3,2-d]pyrimidin-3(2H)-yl)acetamide (14a) as pale yellow crystals (78%),
mp = 270◦C; IR (ν cm−1): 3023 (aromatic-CH) and 1736, 1690 (CO); MS: 469 (M+,
43.4% corresponding to the molecular formula C25H19N5O3S of the assigned structure),
426 (M+ COCH3, 26.7%), 383 (M+ 2COCH3, 100%), 369 (M+ N (COCH3)2,
13.5%); 1H NMR (DMSO-D6) (δppm): 1.908 (s, 3H, CH3); 2.245 (s, 3H, COCH3); 2.488

676
F. A. ATTABY ET AL.
(s, 3H, COCH3); 7.514–9.488 (m, 10H, Ph and pyridinyl Hꢀs); Anal., Calcd./Found(%):
C(63.68/63.70) H(4.49/4.52) N(14.85/14.89) S(6.80/6.86).
N-Acetyl-N-(9-[4-methoxyphenyl]-2-methyl-4-oxo-7-pyridin-3-yl-1,4-di-hydro-
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d]pyrimidin-3(2H)-yl)acetamide (14b) as pale yellow
crystals (73%), mp = 260◦C; IR (ν cm−1): 2982 (aromatic-CH) and 1741, 1696 (CO); MS:
499 (M+, 39.9% corresponding to the molecular formula C26H21N5O4S of the assigned
structure), 456 (M+ COCH3, 9.3%), 413 (M+ 2COCH3, 100%); 1H NMR (DMSO-D6)
(δ ppm): 2.29 (s, 3H, CH3); 2.40 (s, 6H, 2COCH3); 3.86 (s, 3H, OCH3); 7.10–7.07 (d, 2H, J
= 8.7, Ar Hꢀs); 7.77–7.74 (d, 2H, J = 8.7, Ar Hꢀs); 8.16–9.46 (m, 5H, pyridinyl and C8(H));
Anal., Calcd./Found(%): C(62.26/62.30) H(4.62/4.65) N(13.96/14.00) S(6.39/6.42).
Synthesis of 16a,b
A solution of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and carbon disulfide (5 mL) in
pyridine (15 mL) was heated under reflux for 5 h, cooled, poured onto ice-cold water,
and neutralized with drops of acetic acid. The solid was collected by filtration, dried, and
crystallized from the ethanol to give 16a,b, respectively.
5-[3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl]-1,3,4-oxa-dia-
zole-2-thiol (16a) as orange crystals (67%), mp = 310–312◦C; IR (ν cm−1): 3476,
3352 (NH2), 3053 (aromatic-CH); MS: 403 (M+, 100% corresponding to the molec-
ular formula C20H13N5OS2 of the assigned structure), 326 (M+ C6H5, 15.7%), 302
(M+ CONNCSH, 13.4%); Anal., Calcd./Found (%): C(59.54/59.58) H(3.25/3.28)
N(17.36/17.39) S(15.89/15/92).
5-{3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl}-1,3,
4-oxadiazole-2-thiol (16b) as orange crystals (72%), mp = 264◦C; IR (ν cm−1): 3474,
3362 (NH2), 3047 (aromatic-CH); MS: 433 (M+, 100% corresponding to the molecular
formula C21H15N5O2S2 of the assigned structure), 432 (M+ H, 15.3%), 417 (M+
NH2, 16.7%), 332 (M+ CONNCSH, 17.6%); Anal., Calcd./Found(%): C(58.18/58.20)
H(3.49/3.52) N(16.16/16.19) S(14.79/14.82).
Synthesis of 18a,b
A solution of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and phenylisothiocyanate (0.07 g,
0.00055 mol) in pyridine (15 mL) was heated under reflux for 5 h, cooled, poured onto ice-
cold water, and neutralized with drops of acetic acid. The solid was collected by filtration,
dried, and crystallized from the ethanol to give 18a,b, respectively.
2-(5-Anilino-1,3,4-oxadiazol-2-yl)-4-phenyl-6-pyridin-3-ylthieno[2,3-b]-pyridin-
3-amine (18a) as yellow crystals (78%), mp = >330◦C; IR (ν cm−1): 3446, 3270
(NH2), 3202 (NH) 3058 (aromatic-CH); MS: 462 (M+, 59.0% corresponding to the
molecular formula C26H18N6OS of the assigned structure), 385 (M+ H,C6H5, 82.1%),
330 (M+ NN CNHC6H5, 100%), 301 (M+ H,CONHN CNHC6H5, 66.7%); Anal.,
Calcd./Found(%): C(67.52/67.57) H(3.92/3.96) N(18.17/18.20) S(6.93/6.97).
2-(5-Anilino-1,3,4-oxadiazol-2-yl)-4-methoxyphenyl-6-pyridin-3-ylthieno-[2,3-
b]pyridin-3-amine (18b) as orange crystals (70%), mp = 190◦C; IR (ν cm−1): 3473,
3359 (NH2), 3219 (NH), 3054 (aromatic-CH); MS: 492 (M+, 10.9% corresponding to the
molecular formula C27H20N6O2S of the assigned structure), 360 (M+ NN CNHC6H5,

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
677
63.8%), 358 (360–2H, 100%), 330 (M+ NH2, CONN CNHC6H5, 65.5%); Anal.,
Calcd./Found(%): C(65.84/65.87) H(4.09/4.12) N(17.06/17.09) S(6.51/6.55).
Synthesis of 20a,b
A solution of 3a,b (0.20 g, 0.21 g; 0.00055 mol) in acetic acid (15 mL) was heated
under reflux for 5 h. The excess solvent was evaporated and cooled. The solid was collected
by filtration, dried, and crystallized from acetic acid to give 20a,b, respectively.
1-Acetyl-8-(4-phenyl)-6-pyridin-3-yl-1,2-dihydro-3H-pyrazolo[3ꢀ,4ꢀ:4,5]-thieno
[2,3-b]pyridin-3-one (20a) as pale yellow crystals (69%), mp = 322◦C; IR (ν cm−1): 3311
(NH), 3055 (aromatic-CH), 1710, 1667 (acetyl and amidic CO); MS: 386 (M+, 26.8%
corresponding to the molecular formula C21H14N4O2S of the assigned structure), 385 (M+
H, 100%), 328 (M+ H, NCOCH3, 11.0%); Anal., Calcd./Found(%): C(65.27/65.30)
H(3.65/3.70) N(14.50/14.54) S(8.30/8.33).
1-Acetyl-8-(4-methoxyphenyl)-6-pyridin-3-yl-1,2-dihydro-3H-pyrazolo-[3ꢀ,4ꢀ:4,
5]thieno[2,3-b]pyridin-3-one (20b) as yellow crystals (79%), mp = >330◦C; IR (ν cm−1):
3313 (NH), 3006 (aromatic-CH), 1708, 1662 (CO); MS: 416 (M+, 29% corresponding to
the molecular formula C22H16N4O3S of the assigned structure), 415 (M+ H, 41.9%), 399
(M+ H, NH211.3%), 386 (M+ OCH3, 21%); Anal., Calcd./Found(%): C(63.45/63.48)
H(3.87/3.90) N(13.45/13.49) S(7.70/7.73).
Synthesis of 22a,b
A solution of 3a,b (0.20 g, 0.21 g; 0.00055 mol) in acetylacetone (10 mL) was heated
under reflux for 6 h. The reaction mixture was triturated with ethanol (5 mL) and then left
to cool. The solid was collected by filtration, dried, and crystallized from the ethanol to
give 22a,b, respectively.
2-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-phenyl-6-pyridin-3-ylthieno[2,3-
b]pyridin-3-amine (22a) as yellow crystals (87%), mp = 200◦C; IR (ν cm−1):
3480, 3326 (NH2), 3031 (aromatic-CH), 1640 (CO); MS: 425 (M+, 64.3% corre-
sponding to the molecular formula C24H19N5OS of the assigned structure), 330 (M+
NC(CH3)CHC(CH3)N, 33.3%); Anal., Calcd./Found(%): C(67.74/67.77) H(4.50/4.54)
N(16.46/16.50) S(7.54/7.59).
2-[(3,5-Dimethyl-1H-pyrazol-1-yl)carbonyl]-4-methoxyphenyl-6-pyridin-3-yl
thieno[2,3-b]pyridin-3-amine (22b) as yellow crystals (90%), mp = 242◦C; IR (ν cm−1):
3476, 3313 (NH2), 2957 (aromatic-CH), 1681 (CO); MS: 455 (M+, 55.8% corresponding
to the molecular formula C25H21N5O2S of the assigned structure), 360 (M+ -pyrazolyl
ring, 25.8%), 358 (360 -2H, 100%); 1H NMR (DMSO-D6) (δppm): 2.26 (s, 3H, CH3); 2.50
(s, 3H, CH3) 3.86 (s, 3H, OCH3); 6.22 (s, 2H, NH2); 7.05–9.45 (m, 10H, Ar Hꢀs, pyridinyl
Hꢀs and C4(H)); Anal., Calcd./Found(%): C(65.92/65.97) H(4.65/4.69) N(15.37/15.40)
S(7.04/7.07).
Synthesis of 24a,b
A solution of 3a,b (0.20 g, 0.21 g; 0.00055 mol) and ethyl acetoacetate (0.07 g,
0.00055 mol) in acetic acid (15 mL) was heated under reflux for 5 h. The excess solvent
was evaporated and cooled. The solid was collected by filtration, dried, and crystallized
from the acetic acid to give 24a,b, respectively.

678
F. A. ATTABY ET AL.
2-[(3-Amino-4-phenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)carbonyl]-5-meth
yl-2,4-dihydro-3H-pyrazol-3-one (24a) as yellow crystals (86%), mp = >330◦C; IR (ν
cm−1): 3386 (NH2), 3148 (NH), 3058 (aromatic-CH), 1681 (CO); MS: 427 (M+, 15.3%
corresponding to the molecular formula C23H17N5O2S of the assigned structure), 386 (M+
COCH, 24.0%), 385 (M+ CH3CNH, 92.9%); Anal., Calcd./Found(%): C(64.62/64.66)
H(4.01/4.05) N(16.38/16.40) S(7.50/7.54).
2-[(3-Amino-4-methoxyphenyl-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl)-carbon
yl]-5-methyl-2,4-dihydro-3H-pyrazol-3-one (24b) as yellow crystals (70%), mp =
>330◦C; IR (ν cm−1): 3422, 3363 (NH2), 3068 (aromatic-CH), 1682, 1662 (two CO);
MS: 441 (M+ NH2 54.2%), 440 (M+ NH2, H,), 439 (M+ NH2, 2H, 100%); Anal.,
Calcd./Found(%): C(63.01/63.06) H(4.19/4.22) N(15.31/15.35) S(7.01/7.07).
Synthesis of 26a,b
A solution of 3a,b (0.20 g, 0.21 g, 0.00055 mol) and diethyl malonate (0.09 g,
0.00055 mol) in acetic acid (15 mL) was heated under reflux for 5 h. The excess solvent
was evaporated and cooled. The solid was collected by filtration, dried, and crystallized
from the acetic acid to give 24a,b, respectively.
1-{[3-Amino-4-(4-phenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl]carbonyl}
pyrazolidine-3,5-dione (26a) as pale yellow crystals (77%), mp = 280◦C; IR (ν cm−1):
3262, 3203 (NH2), 3052 (aromatic-CH), 1673, 1634 (two CO); MS: 428 (M+ H, 5.1%),
427 (M+ 2H, 12.6%), 314 (M+ NH2, NCOCH2CONH, 10.0%); 1H NMR (DMSO-D6)
(δ ppm): 2.50 (s, 2H, CH2); 6.01 (s, 2H, NH2); 7.49–9.40 (m, 11H, Phenyl, pyridinyl
Hꢀs and NH); Anal., Calcd./Found(%): C(61.53/61.56) H(3.52/3.55) N(16.31/16.35)
S(7.47/7.52).
1-{[3-Amino-4-(4-methoxyphenyl)-6-pyridin-3-ylthieno[2,3-b]pyridin-2-yl]car-
bonyl}pyrazolidine-3,5-dione (26b) as yellow crystals (67%), mp = 300–302◦C; IR
(ν cm−1): 3485, 3362 (NH2), 3246 (NH), 2958 (aromatic-CH), 1716, 1671. (two CO);
MS: 458 (M+ H, 21.7%), 457 (M+ 2H, 43%), 415 (M+ H, CONH, 85.7%), 360
(M+ NCOCH2CONH, 100%), 332 (M+ CONCOCH2CONH, 9.2%), 316 (M+ NH2,
CONCOCH2CONH, 15.0%); Anal., Calcd./Found(%): C(60.12/60/.16) H(3.73/3.78)
N(15.24/15.27) S(6.98/7.01).
REFERENCES
1. A. M. Hussin, F. A. Abu-Shanab, and E. A. Ishak, Phosphorus, Sulfur, and Silicon, 159, 55
(2000).
2. F. A. Attaby and A. M. Abdel-Fattah, Phosphorus, Sulfur, and Silicon, 155, 253 (1999).
3. A. E. Abdel-Rahman, E. A. Bakhite, and E. A. Al-Taifi, J. Chin. Chem. Soc., 49, 223 (2002).
4. G. P. Moloney, Molecules, 6, M203 (2001).
5. S. Furuga, N. Choh, N. Suzuki, and T. Imada, PCT Int. Appl. WO 00000493(2002); Chem.
Abstr., 132, 64179s (2000).
6. A. Krauze, S. Germame, O. Eberlins, I. Sturms, V. Klusa, and G. Duburs, Eur. J. Med. Chem.,
34, 301 (1999).
7. J. M. Quintela, C. Peinador, C. Veiga, L. Gonzales, L. M. Botana, A. Alfonso, and R. Riguera,
Bioorg. Med. Chem., 6, 1911 (1998).
8. J. M. Quintela, C. Peinador, L. Gonzales, R. Iglesias, A. Parama, F. Alvares, M. L. Sanmartin,
and R. Riguera, Eur. J. Med. Chem., 38, 265 (2003).

ACTIVITIES OF 2,3ꢁ-BIPYRIDINE DERIVATIVES (II)
679
9. G. Wagner, S. Leistner, H. Vieweg, U. Krasselt, and J. Prantz, Pharmazie, 48, 342 (1993).
10. N. Boehm, U. Krasselt, S. Leistner, and G. Wagner, Pharmazie, 47, 897 (1992).
11. Fawzy A. Attaby, M. M. Ramla, and H. Takeda, Phosphorus, Sulfur, and Silicon, 183, 2956
(2008).
12. A. M. Abdel-Fattah, M. A. Elneairy, M. N. Eldin, and F. A. Attaby; Phosphorus, Sulfur, and
Silicon, 183, 1592 (2008).
13. A. M. Abdel-Fattah, M. A. Elneairy, M. N. Eldin, and F. A. Attaby, Afindad, 534, 163 (2008).
14. A. M. Abdel-Fattah, L. M. Shaif, and Fawzy A. Attaby; Phosphorus, Sulfur, and Silicon, 183,
2443 (2008).
15. F. A. Attaby, A. M. Abdel-Fattah, L. M. Shaif, and M. M. Elsayed, Phosphorus, Sulfur, and
Silicon, 185, 129 (2010).
16. F. A. Attaby, A. H. H. Elghandour, M. A. Ali, and Y. M. Ibrahem, Phosphorus, Sulfur, and
Silicon, 181, 1 (2006).
17. F. A. Attaby, A. H. H. Elghandour, M. A. Ali, and Y. M. Ibrahem, Phosphorus, Sulfur, and
Silicon, 181, 1087 (2006).
18. F. A. Attaby, A. H. Elghandour, M. A. Ali, and Y. M. Ibrahem, Phosphorus, Sulfur, and Silicon,
182, 133 (2007).
19. F. A. Attaby, A. H. H. Elghandour, M. A. Ali, and Y. M. Ibrahem, Phosphorus, Sulfur, and
Silicon, 182, 695 (2007).
20. F. A. Attaby, M. M. Ramla, and E. M. Gouda, Phosphorus, Sulfur, and Silicon, 182, 517 (2007).
21. F. A. Attaby, S. M. Eldin, M. A. A. Elneairy, and A. K. K. Elouh, Phosphorus, Sulfur, and
Silicon, 179, 2205 (2004).