Synthesis and antimicrobial activity of new pyridothienopyrimidines and pyridothienotriazines

Article abstract of DOI:10.1002/jccs.200200035

5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides (5a,b) were reacted with triethyl orthoformate or nitrous acid to give the corresponding pyrimidinones 6a,b and triazinones 7a,b. The reaction of 5a,b with acetic anhydride was carried o

Full text of DOI:10.1002/jccs.200200035

JournaloftheChineseChemicalSociety, 2002, 49, 223-231
223
Syn the sis and Antimicrobial Ac tiv ity of New Pyridothienopyrimidines and
Pyridothienotriazines
Abdu E. Abdel-Rahman, Etify A. Bakhite* and Elham A. Al-Taifi
ChemistryDepartment,FacultyofScience,AssiutUniversity,Assiut71516,Egypt
5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-carboxamides (5a,b) were re acted with
triethyl orthoformate or ni trous acid to give the cor re spond ing pyrimidinones6a,b and triazinones 7a,b. The
re ac tion of 5a,b with ace tic an hy dride was car ried out and its prod ucts were iden ti fied as a mix ture of
8-acetyl-9-aryl-2,7-dimethylpyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidine-4(3H)-one (9a,b) and related 5-
acetyl-4-aryl-3-biacetylamino-6-methylthieno[2,3-b]pyridine-2-carbonitrile(10a,b). Re ac tion of 7a with
some halocompounds af forded the N-alkylated triazinones8a-c.Chlorinationof6a,b and 9a,b with phos pho-
rus oxychloride pro duced 4-chloropyrimidines 11a-d which were used as pre cur sors for the rest of the tar get
heterocycles. Some of the pre pared com pounds were testedinvitrofortheirantimicrobialactivities.
INTRODUCTION
Scheme I
pyridine / heat
Thieno[2,3-b]pyridine ring sys tems have proved to be
an in ter est ing class of heterocycles. It has been re ported that
manyofitsderivativespossessgoodantibacterial,1-3 anti-
hypertensive4 andgonadotropin-releasinghormoneantago-
nizing5,6 activity.Pyridothienopyrimidinederivativeshave
found applicationsasanalgesics,7 antipyretics8 and anti-
inflammatories.9 Also, some pyridothienotriazines are known
to ex hibit antianaphylactic10 and antiallergic11 activity. In
view of these ben e fits and as a con tin u a tion of our pro gram
di rected to wards the syn the sis of new con densed thieno[2,3-
b]pyridines,12,13 we re port herein the syn the sis of the ti tle
compoundsandtheirevaluationregardingantimicrobialac-
tivity.
R
R
N
R
N
O
O
O
CN
CN
S
CH
+
CN
S
C
Piperidine
EtOH
+
S
O
H2N
H
2a,b
H
1a,b
3a,b
ClCH2CO NH2
AcO Na
R
R
O
O
N H2
CN
EtO Na
N
S
CO NH2
N
SCH2CONH2
5a,b
4a,b
1-5
a
R
OCH3
Cl
RESULTSANDDISCUSSION
b
Our ap proach to the syn the sis of the tar get com pounds
started from the reactionofarylmethylenecyanothioacet-
amides (1a,b) with acetylacetone which gave a mix ture of
dihydrothioxopyridines 2a,b and re lated tetrahydro thioxo-
pyridines 3a,b.14 Dehydrogenation of3a,btoafford2a,b was
achieved by heat ing in pyridine.14 The re ac tion of2a,b with
chloroacetamide by refluxing in eth a nol con tain ing so dium
acetategavethecorrespondingacetamidederivatives4a,b.
Thelattercompounds(4a,b) were cyclized into the key in ter-
mediates,5-acetyl-3-amino-4-aryl-6-methyl-thieno[2,3-b]-
pyridine-2-carboxamides(5a,b) upon boil ing with so dium
ethoxideinethanol(SchemeI).
formatebyrefluxinginaceticanhydrideledtotheformation
of pyrimidinones 6a,b in ex cel lent yields. The 1,2,3- tri a-
zinone analogs 7a,b were ob tained, in 85-87% yield, upon
treat ment of 5a,b in con cen trated sul fu ric acid with so dium
nitritewhereindiazotisationfollowedbyselfcouplingtook
place. The re ac tion of 7a with some halocompounds, namely
phenacyl bro mide, ethyl chloroacetate or chloroacetamide,
af forded the cor re spond ing N-alkylated triazinones8a-c in
84-92% yield (Scheme II).
When 5a,b were heated with ace tic an hy dride at re flux
tem per a ture for 8 hours, the prod ucts were iden ti fied as a
mixture8-acetyl-9-aryl-2,7-dimethylpyrido[3¢,2¢:4,5]thieno-
The cyclocondensation of 5a,b with triethyl ortho-

224 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Abdel-Rahman et al.
Scheme II
Scheme IV
HC(OC2H5)3/Ac2O
NaNO /H2SO4
2
POCl3
5a,b
R
6a,b or 9a,b
R
R
R
O
O
O
O
N
R'
N
R'
N
O
N
N
morpholine
N
N
NH
N
S
NH
S
N
S
N
S
N
12
N
O
11a-d
Cl
7a,b
O
R = Cl, R' = H
6a,b
R
6,7
R
R'COCH2X
thiourea
R
N
R
a
b
OCH3
Cl
O
N
N
O
O
8
R
R'
N
R'
N
R'
NCH2COR'
a
b
c
OCH3 Ph
OCH3
OCH3 NH2
R"CH2X
N
S
N
OC2H5
NH
O
8a-c
S
N
S
SCH R"
2
S
14a-d
13a-d
11,13
R
R'
14
R
R'
R"
Scheme III
a
b
c
d
OCH3
Cl
OCH3 CH3
Cl CH3
H
H
a
b
c
d
OCH3
OCH3
OCH3 CH3
H
H
H
CO2C2H5
H
R
R
OCH3 CH3 CO2C2H5
O
O
hydrateinthelatterreaction.Thismaybeduetoanelectronic
or a steric fac tor. Con den sa tion of 15a,b with benzaldehyde
gave the phenyl hy dra zones 16a,b. The 3,5-dimethyl pyr-
azolylderivatives17a-d were pre pared, in 80-89% yield, by
the re act ing of com pounds 15a-dwith acetylacetone un der
neatconditions(SchemeV).
N
O
CH3
N(COCH3)2
Ac2O
5a,b
+
NH
N
S
N
S
C
N
9a,b
10a,b
9,10
R
a
OCH3
Cl
b
Scheme V
[3,2-d]pyrimidine-4(3H)-one (9a,b) and re lated 5-acetyl-4-
aryl-3-biacetylamino-6-methylthieno[2,3-b]pyridine-2-car-
bonitrile (10a,b)15 (Scheme III).
N2H4.H2O
11a-d
R
R
Thechlorinationofcompounds 6a,b and 9a,b with an
excessamountofphosphorusoxychlorideresultedinthefor-
mationofthecorresponding4-chloropyrimidinederivatives
11a-d in high yields. Com pound11bunderwentnucleophilic
dis place ment when treated with morpholine to give mor-
pholinoderivative12. Com pounds11a-d were re acted smoothly
with thiourea to fur nish the cor re spond ing pyrimidinthiones
13a-d. When 13a,c were al lowed to re act with methyl io dide
or ethyl chloroacetate, the S-alkylated prod ucts 14a-d were
ob tained in 75-89% yield (Scheme IV).
O
O
N
R'
N
R'
PhCHO
N
N
N
S
N
S
NHNH2
16a-d
15a-d
NHN=CHPh
Ac2CH2
R
O
15-17
R
R'
N
N
R'
N
a
b
c
OCH3
Cl
OCH3 CH3
H
H
N
N
S
On treat ment of 11a-d with an ex cess amount of hy-
drazine hy drate, only nucleophilic dis place ment of la bile
chlo rine at oms by the hydrazino group took place to give the
correspondinghydrazinocompounds15a-d in nearly quan ti-
ta tive yield. It is im por tant to note that the acetyl group of
compounds11a-d or 15a-d were not af fected by hydrazine
d
Cl CH3
17a-d
H3C
CH3
Heating of 15a-c with for mic or ace tic acid at re flux
temperatureresultedintheformationofmoderateyieldsof
s-triazolopyridothienopyrimidines 18a-d, re spec tively. An-

Pyridothieno-pyrimidines and -tri azines
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 225
Scheme VI
R
R
O
O
N
N
R'
N
N
N
R'
N
N
R"
N
CH2CO2Et
N
R
S
N
S
18a-f
CH2(CO2Et)2
R= OCH , R'= H
19,
3
R"CO2H
R
N2H4.H2O
15a-c
NaNO2 /
AcOH
O
O
N
N
R'
N
N
N
R'
N
CH2CONHNH2
N
N
S
N
S
N
N
20, R= OCH3, R'= H
21a, R = OCH3, R'= H
21b, R = Cl, R' = H
18
R
R'
R"
18
R
R'
R"
a
b
c
OCH3
Cl
OCH3 CH3
H
H
H
H
H
d
e
f
OCH3
Cl
H
H
CH3
CH3
OCH3 CH3 CH3
other s-triazoloderivative19 was ob tained upon fu sion of
15a with di ethyl malonate. Hydrazinolysis of 19 produced
the acethydrazide de riv a tive 20. Diazotisationof15a,b in
glacialaceticacidwithsodiumnitritesolutionproducedthe
tetrazoloderivatives21a,b in 73-76% yield (Scheme VI).
The struc tures of all newly syn the sized com pounds
wereelucidatedandconfirmedbyelementalanalyses,IR,1H
NMR and mass spec tral data (Ta ble 1).
Six teen com pounds were screened in vitro for their
antimicrobial activities against three strains of bacteria
(Serratia rhodenii, Echerichia coli and Micrococcus roseus)
andtwofungalspecies( Aspergillus fumigatus andPenicillium
oxalicum)usingthefilterpaperdiscmethod.16 Theresultsre-
vealedthatallthetestedcompoundsexhibitmoderatetovery
strongactivityagainstS. rhodenii and are in ac tive against E.
coli. Only six compounds (5b, 6a, 9b, 10b, 13d and 19)
showed mod er ate to very strong ac tiv ity against M. roseus.
None of the tested com pounds were ac tive against the two
fungal species used. However, concerning the structure-
action re la tion ship, it is ob served that: (i) the cyclized com-
pound 5bexhibitedmorepotencythanitsopenintermediate
4b; (ii)Thepyrimidinonederivative6a showed higher ac tiv-
ity than its triazinone an a logue7a; (iii) As the num ber of sul-
furatomsincreasesinthemoleculetheantibacterialactivi-
ties in crease, i.e. com pound13dpos sesses higher ac tiv ity
thantherelatedoxoanalogue9b (Table2).
EXPERIMENTAL
All m.p.’s are un cor rected and mea sured on a Gallenkamp
apparatus. IR spectra were recorded on a Shimadzu 470
IR-spectrophotometer (KBr; Vmax in cm -1 ); 1H-NMRspectra
on a Varian EM-390, 90 MHz spec trom e ter with TMS as in-
ter nal stan dard or on a Jeol LA 400 MHz FT-NMR spec trom-
eter( dinppm);MSonaJeolJMS-600massspectrometerand
elemental analyses on a Perkin-Elemer 240C elemental
analyser or on an Elementar Analysensystem GmbH VARIOEL
V2.3 July 1998 CHNS Mode.
Reaction of arylmethylenecyanothioacetamides (1a,b)
with acetylacetone; formation of com pounds 2a,b and 3a,b
Thisreactionwasperformedaccordingtothereported
procedure.14
(5-Acetyl-4-aryl-3-cyano-6-methylpyridin-2-ylthio)-
acetamides (4a,b)
A mix ture of 2a,b (0.1 mol), chloroacetamide (9.4 g,

226 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Abdel-Rahman et al.
Table 1. Characterization Data of the Prepared Compounds
Compd.
M.P (°C)
Formula*
(M.W.)
Spectral data
Yield (%)
4a
175-176
90
C18H17N3O3S
(355.4)
IR: 3400, 3300 (NH2); 2200 (Cº N); 1690 (C=O, acetyl); 1650 (C=O, amide). 1H
NMR (CDCl3): 7.26-7.28 (d, J = 8.5 Hz, 2H, ArH’s); 6.98-7.00 (d, J = 8.5 Hz, 2H,
ArH’s); 6.16 (br, 2H, NH2); 3.93 (s, 2H, SCH2); 3.84 (s, 3H, OCH3); 2.51 (s, 3H,
COCH3); 1.86 (s, 3H, CH3 at C-6).
4b
5a
198-199
93
C17H14ClN3O2S
(359.8)
IR: 3400, 3300 (NH2); 2200 (Cº N); 1690 (C=O, acetyl); 1650 (C=O, amide).
251-253
91
C18H17N3O3S
(355.4)
IR: 3450, 3400, 3300, 3200 (2NH2), 1690 (C=O, acetyl); 1640 (C=O, amide). 1H
NMR (CDCl3): 6.99-7.50 (dd, J1, J2 = 8.5 Hz, 4H, ArH’s); 5.67, 5.79 (2s, 4H, two
-NH2 groups); 3.86 (s, 3H, OCH3); 2.59(s, 3H, COCH3); 1.97 (s, 3H, CH3 at C-6).
IR: 3450, 3400, 3300, 3200 (2NH2); 1690 (C=O, acetyl ); 1640 (C=O, amide).
5b
6a
6b
277-278
92
C17H14ClN3O2S
(359.8)
>360
85
C19H15N3O3S
(356.4)
IR: 3200-2000 (br, NH), 1690 (C=O, acetyl ); 1650 (C=O, pyrimidinone).
350-352
89
C18H12ClN3O2S
(369.8)
IR: 3200-2000 (br, NH), 1690 (C=O, acetyl); 1650 (C=O, pyrimidinone). 1H NMR
(DMSO): 12.87 (br, 1H, NH); 8.06 (s, 1H, CH pyrimidine); 7.51-7.53 (d, J = 8.0
Hz, 2H, ArH’s); 7.35-7.37 (d, J = 8.0 Hz, 2H, ArH’s); 2.57 (s, 3H, COCH3); 2.04
(s, 3H, CH3 at C-7). MS: 370 (M+, 10%); 369 (M+-1, 34%); 368 (M+-2, 51%); 367
(M+-1-2H, 83%); 354 (M+-O, 39%); 352 (M+-1-OH, 100%).
7a
269-271
85
C18H14N4O3S
(366.4)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl ); 1650 (C=O, triazinone). 1H NMR
(CDCl3): 13.55 (br, 1H, NH); 7.02-7.34 (dd, J1, J2 = 8.0 Hz, 4H, ArH’s); 3.88 (s,
3H, OCH3); 2.69 (s, 3H, COCH3); 1.99 (s, 3H, CH3 at C-7).
7b
8a
8b
246-247
87
C17H11ClN4O2S
(370.8)
IR: 3200-2000 (br, NH), 1690 (C=O, acetyl); 1650 (C=O, triazinone).
246-247
84
C26H20N4O4S
(484.5)
IR: 1690 (2 C=O, ketones); 1660 (C=O, triazinone).
179-180
92
C22H20N4O4S
(452.5)
IR: 1740 (C=O, ester); 1690 (C=O, acetyl); 1650 (C=O, triazinone). 1H NMR
(CDCl3): 7.31-7.33 (dd, J = 2 Hz, 2H, ArH’s); 6.98-7.00 (dd, J = 2 Hz, 2H,
ArH’s); 5.17 (s, 2H, NCH2); 4.21-4.26 (q, J = 7.0 Hz, 2H, OCH2); 3.86 (s, 3H,
OCH3); 2.67 (s, 3H, COCH3); 1.98 (s, 3H, CH3 at C-7); 1.20-1.25 (t, J = 7.0 Hz,
3H, CH3).
8c
9a
276-277
85
C20H17N5O4S
(423.5)
IR: 3400, 3200 (NH2), 1690 (C=O, acetyl ); 1660 (C=O, triazinone and amide).
>360
32
C20H17N3O3S
(379.4)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl); 1650 (C=O, pyrimidinone). 1H NMR
(DMSO): 12.73 (s, 1H, NH); 7.24-7.26 (d, J = 8.3 Hz, 2H, ArH’s); 6.98-7.00 (d, J
= 8.3 Hz, 2H, ArH’s); 3.81 (s, 3H, OCH3); 2.55 (s, 3H, COCH3); 2.11 (s, 3H, CH3
at C-2); 1.96 (s, 3H, CH3 at C-7).
9b
>360
30
C19H14ClN3O2S
(383.8)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl); 1650 (C=O, pyrimidinone).
10a
10b
203-204
47
C22H19N3O4S
(421.5)
IR: 2200 (Cº N), 1720 (2C=O, biacetylamino); 1690 (C=O, acetyl).
201-202
48
C21H16ClN3O3S
(425.9)
IR: 2200 (Cº N), 1720 (2C=O, biacetylamino); 1690 (C=O, acetyl). 1H NMR
(CDCl3): 7.41-7.43 (d, J = 8.3 Hz, 2H, ArH’s); 7.06-7.09 (d, J = 8.3 Hz, 2H,
ArH’s); 2.65 (s, 3H, COCH3); 2.04 (s, 3H, CH3 at C-6); 2.01(s, 6H, 2xCOCH3,
biacetylamino group). MS: 427 (M++1, 6%); 426 (M+, 12%); 425 (M+-1, 15%); 424
(M+-2, 26%); 384 (M++1-COCH3, 94%); 383 (M+- COCH3 62%); 382 (M+-1-
COCH3, 100%); 340 (M+-2COCH3, 100%); 42.9 (COCH3+,75%).

Pyridothieno-pyrimidines and -tri azines
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 227
11a
11b
208-209
86
C19H14ClN3O2S
(383.9)
IR: 1690 (C=O, acetyl).
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.36 (s, 1H, CH pyrimidine); 7.37-7.39
(d, J = 8.0 Hz, 2H, ArH’s); 7.23-7.26 (d, J = 8.0 Hz, 2H, ArH’s); 2.60 (s, 3H,
COCH3); 1.92 (s, 3H, CH3 at C-7).
192-193
87
C18H11Cl2N3OS
(388.3)
11c
172-173
80
C20H16ClN3O2S
(397.9)
IR: 1690 (C=O, acetyl ). 1H NMR (CDCl3): 7.22-7.24 (d, J = 8.3 Hz, 2H, ArH’s);
6.96-6.98 (d, J = 8.3 Hz, 2H, ArH’s); 3.80 (s, 3H, OCH3); 2.52 (s, 3H, COCH3);
2.07 (s, 3H, CH3 at C-2); 1.94 (s, 3H, CH3 at C-7).
11d
12
220-221
77
C19H13Cl2N3OS
(402.3)
IR: 1690 (C=O, acetyl).
183-184
89
C22H19ClN4O2S
(438.9)
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.36 (s, 1H, CH pyrimidine); 7.37-7.39
(d, J = 8.0 Hz, 2H, ArH’s); 7.23-7.26 (d, J = 8.0 Hz, 2H, ArH’s); 3.89-3.92 (t, J1J2
= 5Hz, J2J3 = 4 Hz, 4H, (CH2)2O); 3.79-3.81 (t, J1J2 = 5Hz, J2J3 = 4 Hz, 4H,
(CH2)2N); 2.60 (s, 3H, COCH3); 1.92 (s, 3H, CH3 at C-7).
13a
13b
13c
304-305
79
C19H15N3O2S2
(381.5)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl).
343-344
75
C18H12ClN3OS2
(385.9)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl).
354-355
82
C20H17N3O2S2
(395.5)
IR: 3200-2000 (br, NH), 1690 (C=O, acetyl). 1H NMR (CDCl3): 13.6 (s, 1H, NH);
7.0-7.5 (dd, J = 8.0 Hz, 4H, ArH’s); 3.8 (s, 3H, OCH3); 2.7 (s, 3H, COCH3); 2.2 (s,
3H, CH3 at C-2); 1.9 (s, 3H, CH3 at C-7).
13d
14a
385-386
77
C19H14ClN3OS2
(399.9)
IR: 3200-2000 (br, NH); 1690 (C=O, acetyl).
206-207
89
C20H17N3O2S2
(395.5)
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.6 (s, 1H, CH pyrimidine);7.0-7.4 (dd,
J = 8.5 Hz, 4H, ArH’s); 3.8 (s, 3H, OCH3); 2.8 (s, 3H, SCH3); 2.5 (s, 3H, COCH3);
2.0 (s, 3H, CH3 at C-7).
14b
163-164
88
C23H21N3O4S2
(467.6)
IR: 1730 (C=O, ester); 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.74 (s, 1H, CH
pyrimidine); 7.31-7.33 (d, J = 8.5 Hz, 2H, ArH’s); 6.99-7.01 (d, J = 8.5 Hz, 2H,
ArH’s); 4.19-4.24 (q, J = 7.0 Hz, 2H, OCH2); 4.18 (s, 2H, SCH2); 3.89 (s, 3H,
OCH3); 2.68 (s, 3H, COCH3); 1.94 (s, 3H, CH3 at C-7); 1.24-1.28 (t, J = 7.0 Hz,
3H, CH3 of ester).
14c
14d
198-199
75
C21H19N3O2S2
(409.5)
IR: 1690 (C=O, acetyl).
152-153
78
C24H23N3O4S2
(481.6)
IR: 1730 (C=O, ester); 1690 (C=O, acetyl). 1H NMR (CDCl3): 7.0-7.4 (dd, J = 9.0
Hz, 4H, ArH’s); 4.1-4.3 (q, 2H, OCH2); 3.9 (s, 2H, SCH2); 3.7 (s, 3H, OCH3); 2.5
(s, 3H, COCH3); 2.2 (s, 3H, CH3 at C-2); 1.9 (s, 3H, CH3 at C-7); 1.1-1.3 (t, 3H,
CH3 of ester).
15a
15b
289-290
93
C19H17N5O2S
(379.4)
IR: 3400-3200 (NHNH2); 1690 (C=O, acetyl); 1640 (C=N).
292-293
92
C18H14ClN5OS
(383.9)
IR: 3400-3200 (NHNH2); 1690 (C=O, acetyl); 1640 (C=N). 1H NMR (DMSO):
9.12 (br, 1H, NH ); 8.08 (s, 1H, CH pyrimidine); 7.49-7.51 (d, J = 8.0 Hz, 2H,
ArH’s); 7.33-7.35 (d, J = 8.0 Hz, 2H, ArH’s); 4.96 (br, 2H, NH2); 2.56 (s, 3H,
COCH3); 2.02 (s, 3H, CH3 at C-7).
15c
15d
297-298
95
C20H19N5O2S
(393.5)
IR: 3400-3200 (NHNH2); 1690 (C=O, acetyl); 1640 (C=N).
323-324
91
C19H16ClN5OS
(397.9)
IR: 3400-3200 (NHNH2), 1690 (C=O, acetyl), 1640(C=N). 1H NMR (DMSO): 9.0
(br, 1H, NH); 7.2-7.6 (dd, J = 8.0 Hz, 4H, ArH’s); 5.1 (br, 2H, NH2); 2.6 (s, 3H,
COCH3); 2.1 (s, 3H, CH3 at C-2); 1.9 (s, 3H, CH3 at C-7).
16a
262-263
89
C26H21N5O2S
(467.5)
IR: 3200 (NH); 1690 (C=O, acetyl); 1640 (C=N).

228 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Abdel-Rahman et al.
16b
17b
282-283
C25H18ClN5OS
IR: 3200 (NH); 1690 (C=O, acetyl); 1640 (C=N).
85
244-245
(472.0)
C23H18ClN5OS
IR: 1690 (C=O, acetyl ).1H NMR (CDCl3): 8.7 (s, 1H, CH pyrimidine); 7.4-
7.8 (dd, J = 9.0 Hz, 2H, ArH’s); 6.1 (s, 1H, CH pyrazole); 2.7 (s, 3H,
COCH3); 2.8, 2.4 (2s, 6H, two -CH3 attached to pyrazole ring); 2.0 (s, 3H,
CH3 at C-7).
89
(447.9)
17c
247-248
80
C25H23N5O2S
(457.6)
IR: 1690 (C=O, acetyl ).1H NMR (CDCl3): 7.1-7.6 (dd, J = 9.0 Hz, 4H,
ArH’s); 6.3 (s, 1H, CH pyrazole); 3.9 (s, 3H, OCH3); 2.7 (s, 3H, COCH3);
2.5, 2.9 (2s, 6H, two -CH3 attached to pyrazole ring); 2.2 (s, 3H, CH3 at C-
2); 2.0 (s, 3H, CH3 at C-7).
17d
18a
209-210
C24H20ClN5OS
IR: 1690 (C=O, acetyl).
83
282-283
(462.0)
C20H15N5O2S
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 9.08 (s, 1H, CH pyrimidine);
8.43 (s, 1H, CH triazole); 7.45-7.47 (d, J = 8.0 Hz, 2H, ArH’s); 7.31-7.33
(d, J = 8.0 Hz, 2H, ArH’s); 3.91 (s, 3H, OCH3); 2.66 (s, 3H, COCH3); 2.05
(s, 3H, CH3 at C-9).
76
(389.4)
18b
275-276
79
C19H12ClN5OS
(393.9)
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 9.10 (s, 1H, CH pyrimidine);
8.46 (s, 1H, CH triazole); 7.47-7.49 (d, J = 8.0 Hz, 2H, ArH’s); 7.33-7.35
(d, J = 8.0 Hz, 2H, ArH’s); 2.69 (s, 3H, COCH3); 2.04 (s, 3H, CH3 at C-9).
18c
18d
18e
233-234
70
C21H17N5O2S
(403.5)
IR: 1690 (C=O, acetyl).
252-253
77
C21H17N5O2S
(403.5)
IR: 1690 (C=O, acetyl).
279-280
79
C20H14ClN5OS
(407.9)
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.98 (s, 1H, CH pyrimidine);
7.47-7.49 (d, J = 8.5 Hz, 2H, ArH’s); 7.33-7.35 (d, J = 8.5 Hz, 2H, ArH’s);
2.69 (s, 3H, COCH3); 2.68 (s, 3H, CH3 at C-3); 2.04 (s, 3H, CH3 at C-9).
18f
19
268-269
74
C22H19N5O2S
(417.5)
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 7.1-7.5 (dd, J = 8.0 Hz, 4H,
ArH’s); 3.8 (s, 3H, OCH3); 2.8 (s, 3H, COCH3); 2.6 (s, 3H, CH3 at C-3);
2.1 (s, 3H, CH3 at C-2); 2.0 (s, 3H, CH3 at C-9).
IR: 1730 (C=O); 1690 (C=O, acetyl).1H NMR (CDCl3): 9.04 (s, 1H, CH
pyrimidine); 7.32-7.34 (d, J = 8.5 Hz, 2H, ArH’s); 7.00-7.02 (d, J = 8.5
Hz, 2H, ArH’s); 4.20-4.26 (q, J = 7.0 Hz, 2H, OCH2); 4.05 (s, 2H, CH2);
3.91 (s, 3H, OCH3); 2.67 (s, 3H, COCH3); 1.97 (s, 3H, CH3 at C-9); 1.24-
1.28 (t, J = 7.0 Hz, 3H, -CH3 of ester). MS: 476 (M++1, 30%); 475 (M+,
100%); 474 (M+-1, 16%); 460 (M+-CH3, 94%); 432 (M+-COCH3, 9%); 388
(M+- CH2CO2C2H5 11%).
192-193
78
C24H21N5O4S
(475.5)
20
213-214
C22H19N7O3S
IR: 3450, 3300 (NHNH2); 1690 (C=O, acetyl); 1650 (C=O, hydrazide).
87
210-211
(461.5)
C18H14N4O3S
21a
IR: 1690 (C=O, acetyl). 1H NMR (CDCl3): 8.8 (s, 1H , CH pyrimidine);
7.0-7.5 (dd, J = 9.0 Hz, 4H, ArH’s); 4.0 (s, 3H, OCH3); 2.7 (s, 3H,
COCH3); 2.1 (s, 3H, CH3 at C-9).
73
(366.4)
21b
223-224
76
C17H11ClN4O2S IR: 1690 (C=O, acetyl).
(370.8)
* Satisfactory elemental analyses were obtained for all compounds.
0.1 mol) and CH3CO2Na.3H2O (15.0 g, 0.11 mol) in C 2H5OH
(300mL)washeatedunderrefluxfor2h. Theprecipitatethat
formed on cool ing was col lected and recrystallized from
C2H5OH to give fine white nee dles of 4a,b.
5-Acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]pyridine-2-
carboxamides (5a,b)
Asuspensionofcompound4a,b (0.03 mol) in C2H5OH
(100 mL) con tain ing dis solved Na (0.46 g, 0.02 mol) was

Pyridothieno-pyrimidines and -tri azines
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 229
Table 2. The Antimicrobial Activities of Some Representative
Compounds (diameter of inhibition zones)
added. The mix ture was stirred at 80 °C for 2 h and then di-
luted with H2O (10 mL). The pre cip i tate was col lected and
crystallizedfromC2H5OH to give 8a-c.
Compd.
No.
S.
E.
M.
A.
P.
rhodenii coli
roseus fumigatus oxalicum
Reaction of 5-acetyl-3-amino-4-aryl-6-methylthieno[2,3-b]-
pyridine-2-carboxamides (5a,b) with aceticanhydride;
for ma tion of com pounds 9a,b and 10a,b
4b
5b
6a
7a
8c
9b
10b
11c
12
13d
14b
15c
17d
18a
19
21
++
+++
++
+
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
+
-
++
++
-
-
+
+
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
++
-
-
-
-
-
-
Compounds5a,b(0.005 mol) in redistilled (CH3CO)2O
(20 mL) was heated un der re flux for 8 h. The solid that pre-
cipitatedaftercoolingwasfilteredoffandrecrystallizedfrom
C2H5OH. This compound was identified as 8-acetyl-
9-aryl-2,7-dimethylpyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimi-
dine-4(3H)-one (9a,b). The mother li quor of the above crude
prod uct was di luted with H2O (20 mL) to give a pre cip i tate
whichwascollectedandcrystallizedfromaqueousC2H5OH.
This prod uct was as signed as 5-acetyl-4-aryl-3- biacety ami-
no-6-methylthieno[2,3-b]pyridine-2-carbonitrile( 10a,b).
+
++
++
+
-
-
-
-
-
-
-
-
+
-
+++
++
+
+
+
+
+
+
+++
-
-
-
-
++
-
-
Tioconazole
(Tyrosyde)Ò
+++
+++
Chlorination of 6a,b and 9a,b; formation of
4-chloropyrimidines 11a-d; general procedure
- : No activity; +: moderate activity (inhibition zone 7-10 mm);
++: strong activity (inhibition zone 11-15 mm); +++: very strong
activity (inhibition zone 16-20 mm).
Com pound 6a,b or 9a,b (0.005 mol) in an excess
amount of POCl3 (15 mL) was heated un der re flux for 4 h.
The cooled re ac tion mix ture was poured with vig or ous stir-
ring onto ice H2O. The solid that sep a rated was col lected and
crystallizedfromC2H5OH as white nee dles of 11a-d.
heated un der re flux for 20 min. The pre cip i tated solid was
col lected and recrystallized from C2H5OH to give yel low
crys tals of5a,b.
8-Acetyl-9-(4¢-chlorophenyl)-7-methyl-4-morpholinopyrido-
[3¢,2¢:4,5]thieno[3,2-d]pyrimidine (12)
A mix ture of11b (0.39 g, 0.001 mol) and morpholine (2
mL) was heated gently for 1 h. and then triturated with
C2H5OH(10mL).Theprecipitatewhichformedaftercooling
was col lected and recrystallized from CH3OH to give white
nee dles of12.
8-Acetyl-9-aryl-7-methylpyrido[3¢,2¢:4,5]thieno[3,2-d]-
pyrimidine-4(3H)-ones (6a,b)
A mix ture of5a,b (0.01 mol) and HC(OC2H5)3 (4 mL)
in redistilled (CH3CO)2O (20 mL) was heated un der re flux
for 3 h. The solid that formed on cool ing was col lected and
recrystallized from C2H5OH as colour less plates of 6a,b.
Reaction of 11a-d with thiourea; formation of
pyrimidinethiones 13a-d
8-Acetyl-9-aryl-7-methypyrido[3¢,2¢:4,5]thieno[3,2-d]-
1,2,3-triazine-4(3H)-ones (7a,b)
A mix ture of 11a-d (0.003 mol) and thiourea (0.38 g,
0.005 mol) in C2H5OH (20 mL) was heated un der re flux for 3
h. The pre cip i tated solid was col lected, dis solved in warm
10% NaOH so lu tion and fil tered. The clear fil trate was acid i-
fied with CH3CO2Hwherebyayellowprecipitateseparated.
It was col lected and crys tal lized from C2H5OH-CHCl3 mix-
ture to give yel low nee dles of13a-d.
So dium ni trite so lu tion (12 mL, 10%, 0.015 mol) was
added to a so lu tion of5a,b (0.01 mol) in conc. H2SO4 (5 mL)
andglacialCH3CO2H (5 mL) at 0°C over 5 min utes with stir-
ring. The solid thus pre cip i tated was col lected and crys tal-
lized from C2H5OH as white crys tals of7a,b.
Reaction of 7a with some halocompounds; formationof
triazinones 8a-c
A so lu tion of7a (0.36 g, 0.001 mol) in HCON(C2H5)2
(7 mL) was stirred for a while with an hy drous K2CO3 (0.4 g),
and then the respective halocompound (0.001 mol) was
Alkylation of 13a,c; formation of thioethers 14a-d
To a sus pen sion of13a,c (0.002 mol) and CH3CO2Na.
3H2O (0.4 g, 0.003 mol) in C2H5OH (20 mL), methyl io dide
or ethyl chloroacetate (0.002 mol) was added. The re sult ing

230 J. Chin. Chem. Soc., Vol. 49, No. 2, 2002
Abdel-Rahman et al.
mixture was heated under reflux for 1 h. The solid that
formed on cool ing was col lected and recrystallized from
C2H5OH as colour less nee dles of 14a-d.
8-Acetyl-7-aryl-9-methyltetrazolo[1¢¢,5¢¢-c]pyrido[3¢,2¢:4,5]-
thieno[3,2-e]pyrimidines (21a,b)
To a so lu tion of 15a,b (0.001 mol) in gla cial CH3CO2H
(15 mL) at 0 °C, a cold so lu tion of NaNO2 10% (7 mL, 0.01
mol) was added with stir ring over 10 mins. The pre cip i tate
thatseparatedwascollectedandcrystallizedfromC 2H5OH to
give white crys tals of 21a,b.
Reaction of 11a-d with hydrazine hydrate; formation of
4-hydrazinopyrimidines 15a-d; general procedure
Amixtureof11a-d (0.02 mol) and hydrazine hy drate (2
mL, 0.04 mol) in C2H5OH (50 mL) was heated un der re flux
for 2 h. The sep a rated prod uct was col lected and recrys tal-
lized from dioxane to give white crys tals of 15a-d.
Biological Screening
ThefilterpaperdiscmethodwasperformedinNutrient
agar for bac te ria and Dox agar for fungi. These agar me dia
were in oc u lated with 0.5 mL of the 24 h. liq uid cul tures. Fil-
ter pa per discs (5 mm di am e ter) sat u rated with each com-
pound so lu tion (10 mg/mL of DMSO) were placed on the in-
di cated agar me dia. The in cu ba tion time was 48 h (at 37 °C
for bac te ria and at 28 °C for fungi). Discs sat u rated with
DMSO were used as con trol. Tioconazole (TyrosydeÒ) was
used as a ref er ence sub stance. The di am e ter of in hi bi tion
zones (mm) were mea sured and re corded.
8-Acetyl-9-aryl-4-benzylidenehydrazino-7-methylpyrido-
[3¢,2¢:4,5]thieno[3,2-d]pyrimidines (16a,b)
A mixture of 15a,b (0.002 mol) and benzaldehyde
(0.02 mL, 0.002 mol) in C 2H5OH (25 mL) was refluxed for 3
h. The solid that pre cip i tated on cool ing was col lected and
recrystallized from dioxane to give white crys tals of16a,b.
Cyclocondensation of 15a-d with acetylacetone; formation
of 3,5-dimethylpyrazole derivatives17a-d
Compounds 15a-d (0.001 mol) in acetylacetone (5
mL), were gently heated un der re flux for 4 h. The re ac tion
mix ture was triturated with C2H5OH (5 mL) and then left to
cool. The pre cip i tate was col lected and recrystallized from
C2H5OH as white nee dles of17a-d.
Received September 25, 2001.
Key Words
Thienopyridines; Pyridothienopyrimidines;
Pyridothienotriazines; Triazolopyridothienopyrimidines;
Tetrazolopyridothienopyrimidines; Antimicrobial
activity.
Reaction of 15a-c with formic or aceticacid;formation
of s-triazolopyridothienopyrimidines 18a-f
Compounds15a-c (0.001 mol) in for mic acid 85% or
gla cial ace tic acid (15 mL) was heated un der re flux for 5 h.
Thesolidthatprecipitatedoncoolingwascollectedandcrys-
tal lized from C2H5OH to give white nee dles of18a-f.
REFERENCES
1. Shraideh, Z.; Sallal, A.-K. Biomed. Lett. 1997, 54, 233.
2. Gilis, P. M.; Haemers, A.; Bollaert, W. Eur. J. Med.
Chem. 1980, 15, 185.
3. Bompart, J.; Giral, L.; Malicorne, G.; Puygrenier, M. Eur.
J. Med. Chem. 1987, 22, 139.
Ethyl (8-acetyl-7-(4¢-methoxyphenyl)-9-methyl-s-triazolo-
[4¢¢,3¢¢-c]pyrido[3¢,2¢:4,5]thieno[3,2-d]pyrimidin-3-yl)-
acetate (19)
Com pound15a (1.52 g, 0.004 mol) in di ethyl malonate
(15mL)washeatedunderrefluxfor2h.Thereactionmixture
was triturated with C2H5OH (20 mL) whereby a white solid
precipitated. ItwascollectedandrecrystallizedfromC2H5OH
to give 19.
4. Adachi, I.; Hiramatsu, Y. Jap. Pat. 03,52,890, 1991:
Chem. Abstr. 1991, 115, 71573.
5. Furuya, S.; Takeyru, N.; Matsumoto, H. Jap. Pat.
09,169,766, 1997: Chem. Abstr. 1997, 127, 176416.
6. Furuya, S.; Choh, N.; Suzuki, N.; Imada, T. PCT Int.
Appl. WO. 000,00,493, 2000: Chem. Abstr. 2000, 132,
64179.
7. Dave, C. G.; Shah, P. R.; Dave, K. C.; Patel, V. J. J. In dian
Chem. Soc. 1989, 66, 48.
8. Bousquent, E.; Romero, G.; Guerrera, F.; Caruso, A.;
Roxas, M. A. Farmaco Ed. Sci. 1985, 40, 869.
9. Leistner, S.; Wagener, G.; Guestscharo, M.; Glusa, E.
Pharmazie 1986, 41, 54.
Reaction of 19 with hydrazine hydrate;formationof
acethydrazide 20
A mix ture of 19 (0.48 g, 0.001 mol) and hydrazine hy-
drate (0.5 mL, 0.01 mol) in C2H5OH (15 mL) was heated un-
der re flux for 2 h and then left to cool. The pre cip i tated solid
was col lected and recrystallized from C2H5OH to give 20.

Pyridothieno-pyrimidines and -tri azines
J. Chin. Chem. Soc., Vol. 49, No. 2, 2002 231
10. Wag ner, G.; Leistner, S.; Vieweg, H.; Krasselt, U.; Prantz,
J. Pharmazie 1993, 48, 514.
Thabet, E. A. Phosphorus,SulfurandSilicon 2000, 166,
149.
11. Youssefyeh, R. D.; Brown, R. E.; Wil son, J.; Shah, U.;
Jones, H.; Loev, B.; Khandwala, A.; Leibowitz, M. J.;
Sonnino-Goldman, P. J. Med. Chem. 1984, 27, 1639.
12. Bakhite, E. A.; Abdel-Rahman, A. E.; Mohamed, O. S.;
Thabet, E. A. Pharmazie 2000, 55, 577.
14. Eldin, S. M. Z. Naturforsch. 1999, 54b, 674 and ref er-
ences therein.
15. Awad, I. M. A.; Abdel-Rahman, A. E.; Bakhite, E. A.
Phosphorus,SulfurandSilicon 1991, 61, 305.
16. Kalyoncuoglu, N.; Rollas, S.; Sur-Altiner, D.; Yegenoglu,
Y.; Ang, O. Pharmazie 1992, 47, 769.
13. Abdel-Rahman, A. E.; Bakhite, E. A.; Mohamed, O. S.;