Preparation of some fused pyridopyrimidine and pyridothienotriazine derivatives for biological evaluation

Article abstract of DOI:10.1080/104265090968118

Compounds 2 and 9 were formed using 3-(4-chloro-phenyl)-1-pyridin-2-yl propenone (1) and malononitrile or ethyl cyanoacetate, respectively. The pyridine derivative 2 was in turn used as a precursor for the preparation of some pyridopyrimidine and fused py

Full text of DOI:10.1080/104265090968118

This article was downloaded by: [University of Edinburgh]
On: 28 June 2012, At: 07:00
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
Preparation of Some
Fused Pyridopyrimidine
and Pyridothienotriazine
Derivatives for Biological
Evaluation
A. E. Rashad a , H. H. Sayed a , A. H. Shamroukh a &
H. M. Awad a
a Photochemistry Department, National Research
Centre, Dokki, Cairo, Egypt
b Department of Natural and Microbial Products,
National Research Centre, Dokki, Cairo, Egypt
Version of record first published: 19 Aug 2006
To cite this article: A. E. Rashad, H. H. Sayed, A. H. Shamroukh & H. M. Awad (2005):
Preparation of Some Fused Pyridopyrimidine and Pyridothienotriazine Derivatives
for Biological Evaluation, Phosphorus, Sulfur, and Silicon and the Related Elements,
180:12, 2767-2777
To link to this article: http://dx.doi.org/10.1080/104265090968118
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-
and-conditions
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.
The publisher does not give any warranty express or implied or make any
representation that the contents will be complete or accurate or up to
date. The accuracy of any instructions, formulae, and drug doses should be
independently verified with primary sources. The publisher shall not be liable
for any loss, actions, claims, proceedings, demand, or costs or damages
whatsoever or howsoever caused arising directly or indirectly in connection
with or arising out of the use of this material.

Phosphorus, Sulfur, and Silicon, 180:2767–2777, 2005
Copyright © Taylor & Francis Inc.
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/104265090968118
Preparation of Some Fused Pyridopyrimidine and
Pyridothienotriazine Derivatives for Biological Evaluation
A. E. Rashad
H. H. Sayed
A. H. Shamroukh
Photochemistry Department, National Research Centre, Dokki, Cairo,
Egypt
H. M. Awad
Department of Natural and Microbial Products, National Research
Centre, Dokki, Cairo, Egypt
Compounds
2 and 9 were formed using 3-(4-chloro-phenyl)-1-pyridin-2-yl
propenone (1) and malononitrile or ethyl cyanoacetate, respectively. The pyridine
derivative 2 was in turn used as a precursor for the preparation of some pyri-
dopyrimidine and fused pyridopyrimidine derivatives 3–8. On the other hand, the
pyridine derivative 9 was used for the preparation of thienopyridine derivatives 11
and 12. Nitrozation of compound 12 afforded pyridothienotriazine derivative 13.
Some of the prepared products showed potent antimicrobial activity.
Keywords Fused pyridopyrimidine; pyridine; pyridopyrimidine; pyridothienotriazine;
thienopyridine
INTRODUCTION
Pyridines, pyridopyrimidines, and their fused heterocyclic ring systems
are of current interest1−4 by virtue of their exceptional and versatile
biological activities as calcium antagonists,4 arteriolar vasodilators,5
antitumor agents,6 herbicide antidotes,7 antibacterial agents,8−10
diuretics,11,12 analgesics,13 CNS depressing agents,14 and hypotensive
agents.15,16 Similarly, pyridopyrimidine moiety was considered as the
best-known tyrosin kinase inhibitor for the treatment of chronic myel-
ogenous leukemia and drug resistance emerges by amplification of the
Received January 25, 2004; in final form March 8, 2005.
Address correspondence to A. E. Rashad, National Research Centre, Photochemistry
Department, Dokki, Cairo, Egypt. E-mail: aymnelzeny@yahoo.com
2767

2768
A. E. Rashad et al.
development of a mutation.17 Also, pyridopyrimidines have antimi-
crobial activity against a number of bacteria and fungi.18,19 On the
other hand, certain pyridothienotriazines, inhibit the immunologically-
induced release of histamine.20 So, it is used clinically for the oral treat-
ment of asthma.21 These findings encouraged us to undertake the syn-
thesis of some newly pyridopyrimidine and pyridothienotriazine ring
systems in hoping that they could have some chemical and biological
interest.
DISCUSSION
Compounds 2 and 9 were used as starting materials for this study
and for further syntheses of other fused heterocyclic compounds. Thus,
on refluxing a mixture of 3-(4-chloro-phenyl)-1-pyridin-2-yl propenone
122,24 with malononitrile or ethyl cyanoacetate in the presence of
anhydrous ammonium acetate, gave compound 2 or 9, respectively
(Scheme 1). The structure of compounds 2 and 9 were confirmed with
spectral data. The IR spectra showed bands at (ν, cm−1): 3410, 3360
(NH2), and 2210 (CN) for compound 2 and 3250 (NH), 2210 (CN), and
1695 (CO) for compound 9. The 1H NMR spectra showed signals at (δ,
ppm): 6.80 (brs, 2H, NH2, exchangeable with D2O) for compound 2 and
10.20 (s, 1H, NH, exchangeable with D2O) for compound 9. The MS gave
the molecular ion peaks at m/z = 306 and 307 for compounds 2 and 9,
respectively.
On heating compound 2 with formic acid, it afforded pyrido[2,3-
d]pyrimidin-4-one derivative 3 (Scheme 1). Its IR spectrum showed
the absence of a cyano group and showed bands at (ν, cm−1): 3150
(NH) and 1700 (CO). Its 1H NMR spectrum gave signals at (δ,
ppm): 7.20–8.80 (m, 10H, Ar-H), and 11.20 (s, 1H, NH, exchangeable
with D2O). The reaction of compound 2 with carbon disulphide in
the presence of aqueous potassium hydroxide24 gave pyrido[2,3-
d]pyrimidine-2,4-dithione 4 (Scheme 1). The spectral data of compound
4 assigned its structure (cf. Experimental section). The latter com-
pound reacted with β-bromopropionic acid or chloroacetic acid to
afford pyrido[2ꢀ,3ꢀ:4,5]pyrimido[2,1-b][1,3]thiazine 5 or pyrido[2ꢀ,3ꢀ:4,5]
pyrimido[2,1-b][1,3]thiazole 6, respectively (Scheme 1). The IR spectra
showed bands at (ν, cm−1): 1700 and 1705 (CO) for compounds 5 and 6,
1
respectively. The H NMR spectra showed signals at (δ, ppm): 2.60 (t,
2H, CH2) and 3.00 (t, 2H, CH2) for compound 5 and 3.80 (s, 2H, CH2)
for compound 6. The MS spectra gave the molecular ion peaks at m/z =
436 and 422 for compounds 5 and 6, respectively. When compounds
5 or 6 were condensed with p-chlorobenzaldehyde, they afforded
compounds 7 or 8, respectively (Scheme 1). The latter compounds could

Pyridopyrimidines and Pyridothienotriazines
2769
be prepared directly via a one-pot reaction by treating compound 4 with
β-bromopropionic acid or chloroacetic acid and p-chlorobenzaldehyde.
The spectral data of compounds 7 and 8 assigned their structures (cf.
Experimental section) (Scheme 1).
SCHEME 1

2770
A. E. Rashad et al.
Thionation of compound 9 with phosphorus pentasulfide in dry
pyridine afforded the corresponding pyridinethione derivative 10
(Scheme 1); its MS spectra gave the molecular ion peak at m/z = 323.
Condensation of compound 10 with ethyl chloroacetate in the pres-
ence of sodium methoxide25 afforded 3-amino-thieno[2,3-b]pyridine-2-
carboxylic acid ethyl ester 11 (Scheme 1). The structure of compound
11 was confirmed with spectral data because the IR spectrum showed
1
bands at (ν, cm−1): 3400, 3350 (NH2), and 1725 (CO). The H NMR
spectra showed signals at (δ, ppm): 1.30 (t, 3H, CH3), 4.40 (q, 2H, CH2),
and 5.10 (brs, 2H, NH2 exchangeable with D2O); its MS spectra gave
the molecular ion peak at m/z = 409. The latter compound was am-
moniated to give its corresponding aminoamide derivative 12, which
annulated with nitrous acid to give 9-(4-chloro-phenyl)-7-pyridin-2-yl-
3H-pyrido[3ꢀ,2ꢀ:4,5] thieno[3,2-d][1,2,3] triazin-4-one (13) (Scheme 1).
The IR spectrum showed bands at (ν, cm−1): 3200 (NH) and 1675 (CO);
1H NMR spectrum showed signals at (δ, ppm): 10.40 (s, 1H, and NH
exchangeable with D2O).
BIOLOGICAL EVALUATION
The antimicrobial activity of some newly synthesized compounds 4, 7,
11, 12, and 13 were tested at concentration of 0.1 g/mL using dimethyl-
formamide as a solvent.
Microorganisms’ Species
Bacteria
∗Gram-negative bacteria, Escherichia coli
∗Gram-positive bacteria, Bacillus subtilis
Yeast: Candida albicans
Fungi: Aspergillus niger
Medium
The cap-assay method containing (g/L) peptone 6.0, yeast extract 3.0,
meat extract 1.5, glucose 1.0 and agar 20.0 were used. The medium
was sterilized and divided while hot (50–60◦C) in 15 mL portions among
sterile petri-dishes of 9 cm diameter and one mL of the spore suspension
of each microorganism was spread over the surface of the cold solid
medium placed in the petri-dish.
Method26
0.5 g of each the tested compounds was dissolved in 5 mL of dimethyl-
formamide. An amount of 0.1 mL of test solution was placed on watman

Pyridopyrimidines and Pyridothienotriazines
2771
TABLE I Antimicrobial Activity of Some Newly Synthesized
Compounds
Inhibition Zone (mm) Microorganism
Bacteria
Tested
compounds
Gram-negative Gram-positive
Fungi
Yeast
and standers Escherichia coli. Bacillus subtilis Aspergillus niger Candida albicans
Streptomycin
Erythromycin
Ampicillin
Amoxicillin
Fusidic Acid
4
7
11
12
13
+ + +
−
+ + +
+ + +
−
+
−
+ + +
−
−
++
++
−
−
−
−
−
−
+ + +
++
−
+ + +
+ + +
+
++
+
++
−
−
−
−
−
−
−
−
−
−
−
−
−
+ + +, Highly sensitive (inhibition zone = 21–25 mm). ++, Fairly sensitive
(inhibition zone = 16–20 mm). + Slightly sensitive (inhibition zone = 10–15 mm).
−, Not sensitive.
paper disc of 9 mm in diameter and the solvent was left to evaporate.
These saturated discs were placed carefully on the surface of the in-
oculated solid medium; each petri-dish contains at least 3 discs. The
petri-dishes were incubated at 5◦C for 1 h to permit good diffusion and
then were transferred to an incubator of 85◦C overnight, and then ex-
amined. The results were then recorded by measuring the inhibition
zone diameters (Table I).
Result
Among the tested compounds, it was noticed that compound 4 showed
more significant antibacterial and antifungal activity more than some
known drugs (standers) (Table I). Compound 7 demonstrated inhibitory
activity against Gram negative and yeast. On the other hand, com-
pounds 11, 12, and 13 showed no inhibitory effect on bacteria and fungi.
Experimental
All melting points are uncorrected and were measured using an Elec-
trothermal IA 9100 apparatus. Analytical data were performed by Vario
El Mentar apparatus, organic microanalysis section at the National Re-
search Centre. Their results were found to be in agreement with the

2772
A. E. Rashad et al.
calculated values ( 0.3). The IR spectra (KBr) were recorded on a
Perkin-Elmer 1650 spectrophotometer. 1H NMR spectra were deter-
mined on a Jeol 300 MHz in DMSO-d6 or CDCl3 and the chemical
shifts were expressed in ppm relative to TMS as internal reference.
Mass spectra were run at 70 eV on EI + Q1 MSLMR UPLR.
6-Amino-4-(4-chloro-phenyl)-2-pyridin-2-yl-pyridine-5-
carbonitrile (2)
A mixture of 3-(4-chloro-phenyl)-1-pyridin-2-yl propenone 1 (2.43 gm,
0.01 mole) and malononitrile (0.66 gm, 0.01 mole) in 30 mL glacial acetic
acid containing anhydrous ammonium acetate (1.53 g, 0.02 mole) was
refluxed for 6 h. The reaction mixture was cooled and poured into water.
The formed solid was filtered off, dried, and recrystallized from ethanol
to give 2 in an 85% yield; m.p. 194–195◦C. IR spectrum (KBr, ν, cm−1):
1
3410, 3360 (NH2) and 2210 (CN); H NMR spectrum (CDCl3, δ ppm):
7.12–8.60 (m, 9H, Ar-H), 6.80 (s, 2H, NH2 exchangeable with D2O); MS,
m/z (%): 306 (M+, 100). Analysis for C17H11ClN4 (306.75): required C,
66.56; H, 3.61; Cl, 11.56; N, 18.26; found C, 66.33; H, 3.50; Cl, 11.55; N,
18.00.
5-(4-Chloro-phenyl)-7-pyridin-2-yl-3H-pyrido[2,3-d]pyrimidin-
4-one (3)
Compound 2 (1.12 gm, 4 mmol) was heated under reflux temperature
in formic acid (20 mL, 85%) for 12 h. The reaction mixture was cooled
and poured into water. The formed solid was filtered off, dried, and re-
crystallized from dioxane to give 3 in a 50% yield; m.p. 258–260◦C. IR
spectrum (KBr, ν, cm−1): 3150 (NH), and 1700 (CO); 1H NMR spectrum
(DMSO-d6, δ ppm): 7.20–8.80 (m, 10H, Ar-H), 11.2 (s, 1H, NH exchange-
able with D2O). MS, m/z (%): 334 (M+, 15.20). Analysis for C18H11ClN4O
(334.76): required C, 64.58; H, 3.31; Cl, 10.59; N, 16.74; found C, 64.35;
H, 3.30; Cl, 10.61; N, 16.60.
5-(4-Chloro-phenyl)-7-pyridin-2-yl-1H-pyrido[2,3-d]pyrimidine-
2,4-dithione (4)
To a solution of 2 (1.12 gm, 4 mmol) in a 5% alcoholic potassium hydrox-
ide (20 mL), carbon disulfide (10 mL) was added. The reaction mixture
was stirred for 1 h, followed by refluxing for 2 h. The reaction mixture
was cooled, poured into water, and neutralized with hydrochloric acid
(5 mL, 34%). The formed solid was filtered off, dried, and recrystallized
from dioxane to give 4 in a 60% yield; m.p. 234–235◦C. IR spectrum

Pyridopyrimidines and Pyridothienotriazines
2773
1
(KBr, ν, cm−1): 3300 (NH), 3250 (NH), 1200 (CS), 1220 (CS); H NMR
spectrum (DMSO-d6, δ ppm): 7.20–8.70 (9H, m, Ar-H), 9.80 (s, 1H, NH
exchangeable with D2O), 11.00 (s, 1H, NH exchangeable with D2O). MS,
m/z (%): 382 (M+, 14.68). Analysis for C18H11ClN4S2 (382.89): required
C, 56.46; H, 2.90; Cl, 9.26; N, 14.63; S, 16.75; found C, 56.53; H, 2.93;
Cl, 9.22; N, 14.48; S, 16.83.
4-(4-Chloro-phenyl)-2-pyridin-2-yl-5-thioxo-7,8-dihydro-
pyrido[2ꢀ,3ꢀ:4,5] pyrimido[2,1-b][1,3]thiazin-9-one (5)
A mixture of 4 (1.53 gm, 4 mmol) and β-bromopropionic acid (0.61 gm, 4
mmol) was refluxed in a mixture of glacial acetic acid/acetic anhydride
(3:1) containing anhydrous sodium acetate (0.35 gm, 4 mmol) for 3 h.
The reaction mixture was cooled and poured into water. The formed
solid was filtered off, dried and recrystallized from methanol to give
5 in a 55% yield; m.p. 204–205◦C. IR spectrum (KBr, ν, cm−1): 1700
(CO), 1180 (CS); 1H NMR spectrum (CDCL3, δ ppm): 2.60 (t, 2H, CH2),
3.00 (t, 2H, CH2), 7.00–8.80 (m, 9H, Ar-H). MS, m/z (%): 436 (M+, 8.23).
Analysis for C21H13ClN4OS2 (436.94): required C, 57.73; H, 3.0; Cl, 8.11;
N, 12.82; S, 14.68; found C, 57.53; H, 2.98; Cl, 8.26; N, 12.84; S, 17.73.
4-(4-Chloro-phenyl)-2-pyridin-2-yl-5-thioxo-pyrido[2ꢀ,3ꢀ:
4,5]pyrimido[2,1-b] [1,3]thiazol-8-one (6)
A mixture of 4 (1.53 gm, 4 mmol) and chloroacetic acid (0.56 gm, 4 mmol)
was refluxed in a mixture of glacial acetic acid/acetic anhydride (3:1)
containing anhydrous sodium acetate (0.35 gm, 4 mmol) for 3 h. The
reaction mixture was cooled and poured into water. The formed solid
was filtered off, dried, and recrystallized from methanol to give 6 in a
60% yield; m.p. 178–180◦C. IR spectrum (KBr, ν, cm−1): 1705 (CO),
1185 (CS); 1H NMR spectrum (CDCL3, δ ppm): 3.80 (s, 2H, CH2),
7.20–9.00 (m, 9H, Ar-H). MS, m/z (%): 422 (M+, 11.90). Analysis for
C20H11ClN4OS2 (422.92): required C, 56.80; H, 2.62; Cl, 8.38; N, 13.25;
S, 15.16; found C, 56.73; H, 2.71; Cl, 8.22; N, 13.28; S, 14.93.
Preparation of Compounds 7 and 8
Method A
8-(4-Chloro-benzylidene)-4-(4-chloro-phenyl)-2-pyridin-2-yl-5-
thioxo-7,8-dihydro-pyrido[2ꢀ,3ꢀ:4,5]pyrimido[2,1-b][1,3]thiazin-9-one
(7). A mixture of 5 (1.3 gm, 3 mmol) and p-chlorobenzaldhyde
(0.42 gm, 3 mmol) was refluxed in glacial acetic acid containing

2774
A. E. Rashad et al.
anhydrous sodium acetate (0.35 gm, 4 mmol). The reaction mixture
was cooled and poured into water. The formed solid was filtered off,
dried, and recrystallized from acetic acid to give 7 in a 65% yield; m.p.
256–257◦C. IR spectrum (KBr, ν, cm−1): 1715 (CO), 1180 (CS); 1H NMR
spectrum (DMSO-d6, δ ppm): 3.40 (s, 2H, CH2), 7.20–9.20 (m, 13H,
Ar-H and 1H arylmethylene). MS, m/z (%): 559 (M+, 10.55). Analysis
for C28H16Cl2N4OS2 (559.49): required C, 60.11; H, 2.88; Cl, 12.67; N,
10.01; S, 11.46; found C, 60.00; H, 2.93; Cl, 12.60; N, 10.20; S, 11.35.
7-(4-Chloro-benzylidene)-4-(4-chloro-phenyl)-2-pyridin-2-yl-5-
thioxo-pyrido[2ꢀ,3ꢀ:4,5]pyrimido[2,1-b][1,3]thiazol-8-one (8). A mix-
ture of 6 (1.26 gm, 3 mmol) and p-chlorobenzaldhyde (0.42 gm, 3 mmol)
was refluxed in glacial acetic acid containing anhydrous sodium acetate
(0.35 gm, 4 mmol). The reaction mixture was cooled and poured into
water. The formed solid was filtered off, dried, and recrystallized from
acetic acid to give 8 in a 70% yield; m.p. 248–250◦C. IR spectrum (KBr,
ν, cm−1): 1710 (CO), 1188 (CS); 1H NMR spectrum (DMSO-d6, δ ppm):
7.10–9.00 (m, 13H, Ar-H and 1H arylmethylene). MS, m/z (%): 545
(M+, 17.22). Analysis for C27H14Cl2N4OS2 (545.46): required C, 59.45;
H, 2.59; Cl, 13.00; N, 10.27; S, 11.76; found C, 59.90; H, 2.52; Cl, 12.90;
N, 10.16; S, 11.50.
Method B
General procedure. Compound 7 or 8 was prepared directly by re-
fluxing compound 4 (4 mmol) and β-bromopropionic acid or chloroacetic
acid (4 mmol) and p-chlorobenzaldhyde (4 mmol) in a mixture of glacial
acetic acid/acetic anhydride (3:1) containing anhydrous sodium acetate
(1.2 gm, 8 mmol) for 3 h. Then the reaction mixture was cooled, poured
into water, and the precipitates that formed were filtered off, dried, and
recrystallized from an appropriate solvent to give 7 (72%) or 8 (84%),
respectively. The obtained products were identified by m.p. and TLC in
comparison with authentic samples from Method A.
4-(4-Chloro-phenyl)-6-oxo-2-pyridin-2-yl-1,6-dihydro-pyridine-
5-carbonitrile (9)
A mixture of compound 1 (1.2 gm, 5 mmol) and ethyl cyanoacetate (0.33
gm, 5 mmol) was refluxed in glacial acetic acid containing anhydrous
ammonium acetate (0.80 gm, 10 mmol) for 6 h. The reaction mixture was
cooled and poured into water. The formed solid was filtered off, dried,
and recrystallized from dioxane to give 9 in a 80% yield; m.p. 209–
211◦C. IR spectrum (KBr, ν, cm−1): 3250 (NH), 2210 (CN), 1695 (CO);
1H NMR spectrum (DMSO-d6, δ ppm): 6.7 (s, 1H, pyridine), 7.30–8.60

Pyridopyrimidines and Pyridothienotriazines
2775
(m, 8H, Ar-H), 10.2 (s, 1H, NH exchangeable with D2O); MS, m/z (%):
307 (M+, 100). Analysis for C17H10ClN3O (307.74): required C, 66.35;
H, 3.28; Cl, 11.52; N, 13.65; found C, 66.42; H, 3.30; Cl, 11.48; N, 13.56.
4-(4-Chloro-phenyl)-6-thioxo-2-pyridin-2-yl-1,6-dihydro-pyridine-5-
carbonitrile (10). A mixture of compound 9 (3.07 gm, 10 mmol) and
P2S5 (6.44 gm, 20 mmol) was refluxed in 50 mL of dry pyridine for 6
h. The reaction mixture cooled and poured into ice water. The solid
formed filtered off, dried, and recrystallized from dioxane to give 10 in
a 55% yield; m.p. 243–245◦C. IR spectrum (KBr, ν, cm−1): 3300 (NH),
2215 (CN), 1200 (CS); 1H NMR spectrum (DMSO-d6, δ ppm): 7.20–8.50
(m, 9H,Ar-H), 10.6 (s, 1H, NH exchangeable with D2O); MS, m/z (%):
323 (M+, 27.39). Analysis for C17H10ClN3S (323.80): required C, 63.06;
H, 3.11; Cl, 10.95; N, 12.98; S, 9.90; found C, 62.88; H, 3.20; Cl, 10.99;
N, 12.77; S, 9.63.
3-Amino-4-(4-chloro-phenyl)-6-pyridin-2-yl-thieno[2,3-
b]pyridine-2-carboxylic acid ethyl ester (11)
A mixture of 10 (3.23 gm, 10 mmol) and ethyl chloroacetate (2.50 mL,
20 mmol) was stirred in 50 mL of anhydrous ethanol containing sodium
ethoxide (2%) for 2 h, and then was refluxed with stirring for 4 h. The
reaction mixture was cooled and poured into ice water. The solid formed
was filtered off, dried, and recrystallized from methanol to give 11 in
a 56% yield; m.p. 197–198◦C. IR spectrum (KBr, ν, cm−1): 3400–3350
(NH2), 1725 (CO); 1H NMR spectrum (CDCl3, δ ppm): 1.30 (t, 3H, CH3),
4.40 (q, 2H, CH2), 5.10 (brs, 2H, NH2 exchangeable with D2O), 7.10–8.80
(m, 9H, Ar); MS, m/z (%): 409 (M+, 31.10). Analysis for C21H16ClN3O2S
(409.90): required C, 61.54; H, 3.93; Cl, 8.65; N, 10.25; S, 7.82; found C,
61.44; H, 3.86; Cl, 8.76; N, 10.32; S, 7.80.
3-Amino-4-(4-chloro-phenyl)-6-pyridin-2-yl-thieno[2,3-
b]pyridine-2-carboxylic acid amide (12)
Compound 11 (2.05 mL, 5 mmol) was dissolved in 50 mL of ethanol, and
then a current of NH3was passed at 0◦C tell saturation. The reaction
mixture was left in a refrigerator at −4◦C over night; the solid substance
was filtered off, washed with water, and recrystallized from dioxane to
give 12 in a 66% yield; m.p. 228–230◦C. IR spectrum (KBr, ν, cm−1):
1
3410–3360 (NH2), 1680 (CO); H NMR spectrum (DMSO-d6, δ ppm):
4.80 (brs, 2H, NH2 exchangeable with D2O), 7.30–8.90 (m, 9H, Ar-H),
9.30 (brs, 2H, NH2 exchangeable with D2O); MS, m/z (%): 380 (M+,
7.20). Analysis for C19H13ClN4OS (380.86): required C, 59.92; H, 3.44;

2776
A. E. Rashad et al.
Cl, 9.31; N, 14.71; S, 8.42; found C, 60.10; H, 3.38; Cl, 9.26; N, 14.74; S,
8.39.
9-(4-Chloro-phenyl)-7-pyridin-2-yl-3H-
pyrido[3ꢀ,2ꢀ:4,5]thieno[3,2-d] [1,2,3]triazin-4-one (13)
To a suspended solution of compound 12 (0.38 gm, 1 mmol) in
a mixture of concentrated sulfuric acid (5 mL, 95%) and glacial
acetic acid (10 mL) at 0–5◦C, a solution of sodium nitrite (3.00 g)
in water (5 mL) was added dropwise with continuous stirring over
20 min. After 2 h of stirring at room temperature the foamy mixture was
diluted with water, filtered off, and recrystallized from (DMF/EtOH) to
give 13 in a 50% yield; m.p. 266–268◦C. IR spectrum (KBr, ν, cm−1):
1
3200 (NH), 1675 (CO); H NMR spectrum (DMSO-d6, δ ppm): 7.10–
8.70 (m, 9H, Ar-H), 10.40 (s, 1H, NH exchangeable with D2O); MS, m/z
(%): 391 (M+, 13.40). Analysis for C19H10ClN5OS (391.83): required C,
58.24; H, 2.57; Cl, 9.05; N, 17.87; S, 8.18; found C, 58.00; H, 2.55; Cl,
9.15; N, 17.59; S, 8.00.
REFERENCES
[1] S. Wawzonek, J. Org. Chem., 41, 3149 (1976).
[2] J. Qurioga, B. Insuasty, A. Sanchez, M. Nogueras, and H. Meier, J. Heterocycl. Chem.,
19, 1045 (1992).
[3] R. Rodriguez, M. Suarez, E. Ochoa, A. Morales, L. Gnzalez, N. Martin, M. Quinteiro,
C. Seoane, and J. L. Soto, J. Heterocycl. Chem., 33, 45 (1996).
[4] J. Qurioga, A. Hormaza, B. Insuasty, J. A. Ortiz, A. Sanchez, and M. Nogueras, J.
Heterocycl. Chem., 35, 231 (1998).
[5] S. Kazda and R. Towart, Br. J. Pharmacol., 72, 582 (1981).
[6] H. Akimoto, T. Miwa, and K. Otsu, Japan patent 04, 235, 986 (1992); Chem. Abstr.
118, 23101a (1993).
[7] M. Bartz, R. Kober, R. Seele, T. Saup, N. Meyer, N. Walker, A. Landes, and H. Walter,
Canadian Patent Appl; 2,078,4767 (1993); Chem. Abstr., 120, 77293b (1994).
[8] B. S. Hulbert and B. F. Valenti, J. Med. Chem., 11, 708 (1968).
[9] C. G. Dave, P. R. Shah, V. B. Desai, and S. Srinivan, Indian J. Pharm. Sci., 44, 83
(1982); Chem. Abstr., 98, 53822z (1983).
[10] C. G. Dave, P. R. Shah, V. B. Desai, and S. Srinivan, Ind. J. Chem., 21B, 750 (1982);
Chem. Abstr., 98, 72042m (1983).
[11] M. A. Parish, R. D. Gilliom, W. P. Purcell, R. K. Brown, R. F. Sprok, and H. D. White,
J. Med. Chem., 25, 98 (1982).
[12] C. J. Blankely, L. R. Bennett, R. W. Flemming, R. D. Smith, D. K. Tessman, and
H. R. Kaplan, J. Med. Chem., 26, 403 (1983).
[13] C. G. Dave, P. R. Shah, G. K. Shah, P. S. Pandya, K. C. Dave, and V. J. Patel, Indian
J. Pharm. Sci., 48, 75 (1986); Chem. Abstr., 105, 218732y (1986).
[14] F. Herold, Acta Pol. Pharm., 42, 263 (1985); Chem. Abstr., 106, 156390y (1987).
[15] J. Soloducho, A. Morzikiewcz, T. Bobk iewicz-Kozlowsky, A. Olejnik, and A. Pieczyn-
ska, Pol. J. Pharmcol. Pharm., 35, 131 (1983); Chem. Abstr., 100, 34513t (1984).

Pyridopyrimidines and Pyridothienotriazines
2777
[16] J. Soloducho, A. Morzikiewcz, T. Bobk Iewicz-Kozlowsky, A. Olejnik, and A. Pieczyn-
ska, Pol. J. Pharmcol. Pharm., 37, 541 (1985); Chem. Abstr., 104, 141711k (1986).
[17] D. R. Huron, M. E. Corre, A. J. Kraker, C. L. Sawyers, and M. M. Mosser, Clinical
Cancer Research, 9, 1267 (2003).
[18] S. S. A. Kumar and K. Lalit, J. Heterocycl. Commun., 1, 89 (1994).
[19] T. H. Ouiroz, S. H. Ortega, and M. S. Garcia, J. Analytical Science, 15, 105 (1999).
[20] R. D. Youssefyeh, R. E. Brown, J. Wilson, U. Shah, H. Jones, B. Love, A. Khandwala,
M. J. Leibowitz, and P. Sonnino-Goldman, J. Med. Chem., 27, 1639 (1984).
[21] J. M. Quintela, C. Peinador, L. Botana, M. Estevez, and R. Riguera, Bioorganic &
Medicinal Chemistry, 5, 1543 (1997).
[22] H. H. Sayed, Egypt. J. Chem, 48(2), 223 (2005).
[23] F. A. Fahmy and H. H. Sayed, Egypt. J. Chem., 44, 365 (2001).
[24] S. A. Swelam, O. S. Abd-El Salam, and M. E. A. Zaki, J. Serb. Chem. Soc., 64, 655
(1999).
[25] H. Vieweg, S. Leistner, and G. Wagner, J. Pharmazie, 43, 358 (1988).
[26] A. A. Abou-Zeid, and Y. M. Shehata, Indian J. Pharmacy, 31, 72 (1969).