Synthesis and in vitro Antibacterial Activity of Some Novel Fused Pyridopyrimidine Derivatives

Article abstract of DOI:10.1002/jhet.2420

Pyridopyrimidine derivatives 2, 5 and 7, 8, 9 were furnished by the reaction of compound 1 with a variety of reagents, namely, formic acid, acetic anhydride, phenyl isothiocyanate, phenyl isocyanate, carbon disulfide, acetamide and thioacetamide, which in turn were treated with hydrazine to give pyrazolopyridopyrimidine derivatives 4, 6 and 11, 12, 13. The potency of the results as antibacterial agents has been evaluated. Most of the tested products showed a highly inhibition zone against the two bacterial strains. All compounds have been characterized based on their IR,¹H-NMR and Mass spectra.

Full text of DOI:10.1002/jhet.2420

Month 2015
Synthesis and in vitro Antibacterial Activity of Some Novel Fused
Pyridopyrimidine Derivatives
Mahmoud Abd El Aleem Ali Ali El-Remaily,* O. M. El Hady, H. Salah Abo Zaid, and E. M. M. Abd El-Raheem
Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt
*
E-mail: mahmoudali201359@yahoo.com
Received October 14, 2014
DOI 10.1002/jhet.2420
Published online 00 Month 2015 in Wiley Online Library (wileyonlinelibrary.com).
Pyridopyrimidine derivatives 2, 5 and 7–9 were furnished by the reaction of compound 1 with a variety of
reagents, namely, formic acid, acetic anhydride, phenyl isothiocyanate, phenyl isocyanate, carbon disulfide,
acetamide and thioacetamide, which in turn were treated with hydrazine to give pyrazolopyridopyrimidine
derivatives 4, 6 and 11–13. The potency of the results as antibacterial agents has been evaluated. Most of
the tested products showed a highly inhibition zone against the two bacterial strains. All compounds have
1
been characterized based on their IR, H-NMR and Mass spectra.
J. Heterocyclic Chem., 00, 00 (2015).
1
INTRODUCTION
NH groups. H-NMR spectra of compounds 3 and 4
2
showed the following signals at δ 8.11, 8.14 ppm corre-
sponding to NH groups, respectively, to =CH group at
Pyridine nucleus and their fused heterocyclic systems
have attracted a great deal of interest over the years [1].
The pyrazolo[3,4-b]pyridines have promising biological
and chemotherapeutic importance. They are known to
inhibit VEGFR/PDGFR kinases [2] or glycogen synthesis
kinase-3 (GSK-3) [3], which play a key role in chronic
inflammatory processes [4], cancer [5] and Alzheimer’s
disease (AD) [6–9]. These compounds were also reported
as antimicrobial agents [10] and potent antitumor agents
8
.21 ppm for compound 3 and at 2.01ppm CH group of
3
compound 4. MS of compound 3 gave molecular ion peak
at m/z 206.
Compounds 5 and 6 were confirmed by the reaction of
compound 1 with hydrazine hydrate to afford compound
2
[15] that was used in the next step to produce com-
pounds 5 and 6 via the reaction with formic acid and
acetic anhydride. The formation of compounds 5 and 6
was assumed to proceed via the amide formation followed
by an intramolecular cyclization through compound 2,
respectively. IR spectra of compounds 5 and 6 showed
[11]. Compounds containing a fused pyrimidine ring have
significant biological activity, particularly in cancer and
virus research [12–14]. In view of the facts mentioned
previously and in conjunction with our previous interest
in preparing heterocyclic ring systems with wide expected
pharmaceutical and biological activities [15–25], we report
herein the synthesis and antibacterial evaluation of some
like new heterocyclic systems.
new absorption bands corresponding to NH groups at
2
À1
1
3
316–3174cm
respectively. Their H-NMR spectra
showed new signals corresponding to NH2 groups at
1
1.33, 11.37 ppm, respectively. MS of compound 5 and
6
gave molecular ion peaks at m/z 202 and 215, respec-
tively (Scheme 1).
Cyclocondensation of compound 1 with phenyl isocya-
nate, phenyl isothiocyanate, carbon disulfide and
thioacetamide afforded the corresponding pridopyrimidine
derivatives 7a,b, 8 and 9, respectively. The treatment of
compound 1 with Lawesson’s reagent (LR) also gave
thiazaphosphinine 10 in a good yield (Scheme 2). IR
spectra of compounds 7a,b–10 showed disappearance
RESULTS AND DISCUSSION
Chemistry. The presence of 2-amino-6-chloropyridine-
,5-dicarbonitrile 1 [1] moiety in our starting precursor
allows us to carry out some regioselective attack on the
amino- and chloro- groups by variety of reagents in one or
two steps.
3
The reaction of compound 1 with an excess of formic
acid, acetic anhydride or acetamide gave compounds 3
and 4, respectively, which, in turn, were allowed to react
with hydrazine hydrate to afford the corresponding
pyrazolopyridine derivatives 5 and 6, respectively. IR spec-
tra of compounds 3 and 4 showed new absorption bands
of absorption bands corresponding to NH groups and
2
showed new absorption bands corresponding to NH groups
À1
at 3185, 3183, 3186, 3183 and 3179cm , respectively.
1
H-NMR spectra of compounds 7a,b–10 showed the fol-
lowing signals at δ 8.16, 8.26, 8.10, 8.11 and 8.26ppm cor-
responding to NH groups, respectively. MS of compounds
7a,b, 8 and 10 showed molecular ion peaks at m/z 300,
313, 254 and 380, respectively.
À1
corresponding to C=O at 1658, 1663cm , respectively,
and disappearance of absorption bands corresponding to
©
2015 HeteroCorporation

M. A. A. El-Remaily, O. M. El Hady, H. Salah Abo Zaid, and E. M. M. Abd El-Raheem
Vol 000
Scheme 1. Reaction of 2-amino-6-chloropyridine-3,5-dicarbonitrile with formic acid, acetic anhydride and acetamide.
Scheme 2. Reaction of 2-amino-6-chloropyridine-3,5-dicarbonitrile with phenyl isothiocyanate and other reagents.
The chlorine atom, attached to the pyridine nucleus at
hydrazine hydrate to give 3,5-diamino-1,7-dihydropyrazolo
7
–10 underwent substitution reaction with hydrazine
[3–29]pyrrolo[3,2-e]pyridine-6-carbonitrile 18 and 3,5-
diamino-1,7-dihydropyrazolo[3–29]pyrrolo[3,2-e]pyri-
dine-6-carboxamide 19, respectively. H-NMR spectra
of compounds 15 and 16 showed the following signals at δ
8.21 and 8.56 ppm corresponding to NH groups, respec-
tively, and compounds 18 and 19 showed the following sig-
hydrate to afford the corresponding compounds 11–14,
respectively. The structure of compounds 11–14 was con-
firmed by IR, H-NMR and MS, respectively. IR spectra
of compounds 11–14 showed new absorption bands corre-
sponding to NH groups at 3350–31659 cm . H-NMR
1
1
À1
1
2
spectra of compounds 11–14 showed the following signals
at δ 5.60, 5.57, 5.55, 5.52 and 5.28 ppm corresponding to
nals at δ 5.80 and 5.36ppm corresponding to NH groups,
respectively. MS of compound 16 showed molecular ion
peak at m/z 235.
2
NH groups, respectively. MS of compound 14 showed
2
molecular ion peak at m/z 377 (Scheme 2).
Compound 1 was allowed to react with chloroacetyl
chloride to yield pyridopyridine derivative 17, which in
turn was allowed to react with hydrazine to give N6,N6-di-
methyl-3,5-diamino-7-oxo-7,8-dihydro-1H-pyrazolo[3–29,1,8]-
naphthyridine-6-carboxamide 20. IR spectra of compounds
Alkylation of compound 1 with halo compounds (e.g.
chloroacetonitrile and chloroacetamide) in DMF as a solvent
gave the corresponding pyrrolopyridine derivatives 15 and
1
6, respectively, which, in turn, were allowed to react with
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Activity of Pyridopyrimidine Derivatives
1
7 and 20 showed new absorption bands corresponding to
37± 0.5°C for 24h. The inhibition zone of active com-
À1
C=O groups at 1662 and 1658cm , respectively.
pounds was measured in cm scale. The results shown in
Table 1 revealed that compounds 5, 7a, 7, 8, 9, 10, 12,
13, 14, 15 and 17 showed the highest inhibitory effect
against the two types of bacteria at the three used concen-
trations, while compounds 3 and 11a, showed moderate
activity. Compounds 4 and 21 showed high-inhibition zone
against a gram-positive bacteria and no activity against a
gram-negative bacteria. Compounds 6 and 18 showed high
inhibition zone against the two types of bacteria at high
concentration, but compound 22 showed high activity at
low concentration. On the other hand, compound 19
showed no bactericidal activity against either bacterial
strains (Table 1).
1
H-NMR spectra of compounds 17 and 20 showed the
following signals at δ 3.30 and 3.55ppm corresponding
to CH groups, respectively. Also the reaction of com-
pound 1 with ethyl chloroacetate or ethyl bromoacetate
afforded the N-substituted derivatives 21a,b which was
treated with morpholine to produce the cycled compound
3
1
2
,8-naphthyridine derivative 22. IR spectra of compounds
1a,b showed disappearance of absorption bands corre-
sponding to NH groups but showed appeared at
2
À1
1
3
399–3326 cm in compound 22. H-NMR spectra of
compounds 21a,b showed the following signals at δ 4.45
and 4.01 ppm corresponding to CH groups, respectively.
MS of compound 21a showed molecular ion peak at m/z
2
1
2
54. H-NMR spectra of compound 22 showed the follow-
ing signal at δ 5.30 ppm corresponding to NH group. MS
EXPERIMENTAL
2
of compound 22 showed molecular ion peak at m/z 356
All melting points were determined on a Kofler melting point
apparatus and were uncorrected. IR spectra were obtained on a
Shimadzou FTIR spectrometer (Shimadzou Corp., Kyoto, Japan).
(
Scheme 3).
Antibacterial activity.
Synthesis of new heterocyclic
compounds containing pyridine nucleus fused with other
heterocyclic rings is of considerable biological importance
including antibacterial activity [10].
1
H-NMR spectra were recorded on a Varian Gemini (Varian, Inc.,
Palo Alto, North Carolina, USA) at 200 MHz using TMS as an
internal reference and DMSO-d6 as a solvent. MS were obtained
on a Shimadzu GCMS-QP1000 mass spectrometer (Shimadzou
Corp.) at 70 ev. Purity and monitoring of synthesized compounds
were checked by protected TLC plates (E Merck Kieselgel 60
The synthesized compounds were dissolved in DMSO.
In order to ensure that the solvent had no effect on bacterial
growth or enzymatic activity, negative control tests were
performed using DMSO at the same concentrations.
The inhibitory effect of tested compounds 1–19, 21b
and 22 on the in vitro growth of two different types of
bacteria Bacillus cereus, a gram-positive bacteria (+ve),
and Pseudomonas aureginosa, a gram-negative bacteria
F
254). The structure of new products was confirmed by IR,
1
HNMR and MS. The precursor product 1 and compound 2 were
synthesized by the procedures reported in [1,15].
7
-Chloro-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-
carbonitrile (3). Compound 1 and in all experiments
0.005mol, 0.89 g), and excess of formic acid (10mL) was
(
(
Àve) was evaluated using agar diffusion method (cup
heated under reflux for 10h; the mixture was left to cool and
poured into ice cold water. The obtained solid product was
and plate method) [26–29]. All plates were incubated at
Scheme 3. Reaction of 2-amino-6-chloropyridine-3,5-dicarbonitrile with halogenated active methylenes.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. A. El-Remaily, O. M. El Hady, H. Salah Abo Zaid, and E. M. M. Abd El-Raheem
Vol 000
Table 1
Antibacterial activity of the tested pyridine derivatives 1–19, 21b, and 22.
Bacillus cereus
Pseudomonas aureginosa
Compound
10 000 ppm
30 000 ppm
50 000 ppm
10 000 ppm
30 000 ppm
50 000 ppm
3
4
5
6
1.1
1.5
2.0
—
2.0
1.6
1.5
2.0
1.6
—
1.8
1.7
1.6
1.5
—
1.0
1.4
1.5
—
—
—
1.6
—
1.8
—
1.4
—
2.0
—
1.1
—
1.2
3.5
1.6
1.6
1.2
1.2
1.0
1.7
3
1.9
1.1
1.1
1.5
1.8
2.0
—
2.2
3.0
1.1
1.8
1.7
1.4
2.0
2.0
2.5
1.7
1.0
1.7
1.0
2.0
1.8
—
7
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
a
b
1.7
1.9
1.3
1.8
1.2
1.5
2.0
1.4
1.2
1.3
1.1
1.3
—
1.5
2.0
2.1
1.0
1.8
—
1.6
1.5
1.2
2.1
0.9
1.8
—
1.2
1.8
1.7
1.3
2.0
1.3
1.8
1.5
1.0
1.8
1.1
1.6
1.5
—
0
1 a
2
3
4
5
6
7
8
1.0
—
—
1.5
1.5
9
1 b
2
—
1.8
—
—
—
1.6
1.5
—
—
—
—
—
filtered off, washed with water and crystallized from ethanol. Yield
8 6 6
175 (50%); Anal. Calcd. for C H N O (202): C, 47.53; H, 2.99;
N, 41.57. Found: C, 47.58; H, 2.99; N, 41.53.
À1
(
91%), pale yellow, mp 260°C; IR cm : 3205 (NH), 2220 (CN),
1
1
658 (CO); H-NMR: δ 8.60 (s, 1H, CHpyridine), 8.21 (s, 1H,
CHprymidine), 8.11 (s, 1H, NH); MS: m/z (100%): 206 (5.5%),
88 (53%), 178 (91.8%), 133 (100%); Anal. Calcd. for
OCl (206.5): C, 46.51; H, 1.46; N, 27.12; Cl, 17.16.
Found: C, 46.59; H, 1.43; N, 27.07; Cl, 17.10.
-Chloro-2-methyl-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidine-6-
3-Amino-7-methyl-5,6-dihydro-1H-pyrazolo[4’,3’:5,6]pyrido[2,3-
d]pyrimidin-5-one (6).
cm : 3316, 3179 (NH
Yield (60%), yellow, mp >360°C; IR
), 3141 (2NH), 1684 (CO); H-NMR: δ
À1
1
1
2
C H N
8 3 4
2
11.37 (s, 2H, 2NH), 8.34 (s, 1H, CHpyridine), 5.52 (br, 2H, NH ),
2.54 (s, 3H, CH3); MS: m/z (100%): 215 (0.8%), 189 (100%);
7
Anal. Calcd. for C H N O (216): C, 50.00; H, 3.73; N, 38.87.
9
8 6
carbonitrile (4). Method A Compound 1 (0.005 mol, 0.89g) and
excess of acetic anhydride (10 mL) were heated under reflux for 12 h,
the mixture was left to cool, and the solvent was evaporated. The
obtained solid product was washed with water and crystallized
from ethanol.
Found: C, 50.15; H, 3.63; N, 38.80.
General procedure for the preparation of compounds
(7a,b).
A mixture of compound 1 (0.005 mol, 0.89 g) and
phenylisocyanate or phenylisothiocyanate (0.005 mol) in a
solvent mixture of DMF and ethanol (20 mL) was heated
under reflux for 10 h; the mixture was left to cool and poured
into ice cold water. The obtained solid product was filtered
off, washed with water and crystallized from ethanol.
Method B A mixture of compound 1 (0.005 mol, 0.89g) acetamide
(
0.005mol) in trifluoroacetic acid (TFA) (20 mL) was heated under
reflux for 24h; the solvent was removed under reduced pressure.
The obtained solid product was crystallized from ethanol.
7-Chloro-4-imino-2-oxo-3-phenyl-1,2,3,4-tetrahydropyrido[2,3-
d]pyrimidine-6-carbonitrile (7a). Yield (77%), browen, mp 230°C;
IR cm : 3344, 3185 (2NH), 2230 (CN), 1655 (CO); H-NMR: δ
8.92 (s, 1H, CH pyridine), 8.16 (s, 1H, 1NHpyrimidine), 7.62–7.46 (m,
5H, phenyl), 5.37 (s, 1H, 1NH); MS: m/z (100%): 300 (0.9%), 119
À1
Yield (88%), yellow, mp 330°C; IR cm : 3453 (NH), 2230
À1
1
1
(
CN), 1663 (CO); H-NMR: δ 8.51 (s, 1H, CHpyridine), 8.14 (s,
1
H, NH), 2.01 (s, 3H, CH ). MS: m/z (100%): 221 (30%), 200
3
(
C
35%), 178 (53%), 149 (100%), 105 (59%); Anal. Calcd. for
OCl (220.5): C, 49.00; H, 2.28; N, 25.40; Cl, 16.07.
(
11%), 93 (100%); Anal. Calcd. for C14 H N OCl (297.5): C,
9
H
5
N
4
8 5
56.48; H, 2.71; N, 23.58; Cl, 11.21. Found: C, 56.47; H, 2.70; N,
Found: C, 49.00; H, 2.23; N, 25.35; Cl, 16.17.
General procedure for the preparation of compounds
23.50; Cl, 11.21.
-Chloro-4-imino-3-phenyl-2-thioxo-1,2,3,4-tetrahydropyrido[2,3-
d]pyrimidine-6-carbonitrile (7b). Yield (73%), yellow, mp 263°C;
IR cm : 3344, 3183 (2NH), 2226 (CN); H-NMR: δ 8.79 (s, 1H,
CHpyridine), 8.26 (s, 1H, 1NHpyrimidine), 7.64–7.41 (m, 5H, phenyl),
5.71 (s, 1H, 1NH); MS: m/z (100%): 313 (38%), 293 (19%), 185
(23%); Anal. Calcd. for C14H N SCl (313.5): C, 53.59; H, 2.57; N,
8 5
22.32; Cl, 11.30; S, 10.22. Found: 53.62; H, 2.50; N, 22.32; Cl,
11.35; S, 10.29.
7
5
4
and 6.
A mixture of the corresponding compounds 3 or
(0.004 mol) and hydrazine hydrate (10 mL) was refluxed
for 12 h, the solvent was removed under reduced pressure,
and the obtained residue was triturated with ice cold water
À1
1
(
10 mL). The precipitated solid was filtered off, washed with
water, dried and crystallized from ethanol.
-Amino-2,3,5,6-tetrahydro-1H-pyrazolo[4’,3’:5,6]pyrido[2,3-
d]pyrimidin-5-one (5). Yield (67%), dark yellow, mp >360°C;
3
À1
1
IR cm : 3297, 3174 (NH
1.33 (s, 2H, 2NH), 8.61 (s, 1H, CHpyridine), 8.22 (s, 1H,
CHprymidine), 5.59 (br, 2H, NH ), MS: m/z (100%): 202 (100%),
2
), 3140 (NH), 1685 (CO); H-NMR:
7-Chloro-2,4-dithioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-6-
carbonitrile (8). An equimolar ratio of compound 1 (0.005mol,
0.89g), potassium hydroxide (0.005 mol, 0.89g) and carbon
1
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2015
Synthesis and Activity of Pyridopyrimidine Derivatives
disulfide (0.005 mol, 0.89g) in DMF (20mL) was stirred at room
temperature for 48 h, and the reaction mixture was poured into ice
cold water. The obtained solid product was filtered off, washed
with water and crystallized from ethanol.
3-Amino-7-methyl-5,6-dihydro-1H-pyrazolo[4’,3’:5,6]pyrido[2,3-
d]pyrimidine-5-thione (13). Yield (65%), red, mp >360°C (dec);
À1
1
IR cm : 3350, 3165 (NH
2H, 2NH), 8.43 (s,1H, CHpyridine), 5.52 (br, 2H, NH
s, 3H, CH ); Anal. Calcd. for C S (232): C, 46.54; H,
.47; N, 36.18; S, 13.81. Found: C, 46.65; H, 3.37; N, 36.08; S, 13.90.
-Amino-4-imino-2-(4-methoxyphenyl)-1,2,4,4a,8,9a-
2
), 3145 (2NH); H-NMR: δ 11.38 (s,
2
), 2.52
À1
(
3
9 8 6
H N
Yield (88%), orange, mp 285°C; IR cm : 3347, 3186 (2NH),
1
3
2
230 (CN); H-NMR: δ 8.89 (s, 1H, CHpyridine), 8.10 (s, 2H,
6
2
NH); MS: m/z (100%): 254 (21%), 217 (10%), 175 (100%);
hexahydropyrazolo[4’,3’:5,6]-pyrido[2,3-d][1,3,2]thiazaphosphinine-
Anal. Calcd. for C H N S Cl (254.5): C, 37.72; H, 1.19; N,
8
3 4 2
À1
2
-sulfide (14). Yield (75%), brown, mp >360°C; IR cm : 3321,
2
2.00; Cl, 13.92. Found: C, 37.80; H, 1.15; N, 22.10; Cl, 13.82.
-Chloro-2-methyl-4-thioxo-3,4-dihydropyrido[2,3-d]pyrimidine-
-carbonitrile (9). A mixture of compound 1 (0.005 mol, 0.89g)
1
3
2
5
188 (NH ), 3143 (3NH), 2927 (CH)
; H-NMR: δ 11.27 (s, 2H,
NH), 8.81 (s, 1H, CHpyridine), 7.87–8.46 (m, 5H, NH+ phenyl)
.28 (br, 2H, NH ), 3.23 (s, 3H, CH ); MS: m/z (100%): 377
7
2
aliph.
6
or thioacetamide (0.005mol) in trifluoroacetic acid (TFA) (20 mL)
was heated under reflux for 24h, and the solvent was removed
under reduced pressure. The obtained solid product was
crystallized from ethanol.
2
3
(
3.5%), 379 (6.3%), 341(100%); Anal. Calcd. for
C H N OPS Cl (376): C, 44.67; H, 3.48; N, 22.33; S, 17.04.
14 10
4
2
Found: C, 44.60; H, 3.45; N, 22.36; S, 17.12.
À1
1
3-Amino-6-chloro-1H-pyrrolo[2–29]pyridine-2,5-dicarbo-
nitrile (15). A mixture of compound 1 (0.005 mol, 0.89 g) and
chloroacetonitrile (0.005 mol, 0.23 mL) in a solution of DMF was
heated under reflux for 10 h; the mixture was cooled down and
poured into ice cold water. The obtained solid product was
filtered off and crystallized from ethanol.
Yield (85%), red, mp >360°C; IR cm : 3183 (NH), 2225 (CN); H-
NMR: δ 8.66 (s, 1H, CHpyridine), 8.11 (s, 1H, 1NH), 2.01 (s, 3H, CH3);
Anal. Calcd. for C
4.98; S, 13.55. Found: C, 45.60; H, 2.10; N, 23.73; Cl, 14.98; S, 13.59.
-Chloro-6-cyano-4-imino-2-(4-methoxyphenyl)-1,4,4a,8a-
9 5 4
H N SCl (236.5): C, 45.67; H, 2.13; N, 23.67; Cl,
1
7
tetrahydro-2H-pyrido-2,3-d][1,3,2]thiazaphosphinine-2-sulfide (10). A
mixture of compound 1 (0.005 mol, 0.89 g) and Lawesson’s
reagent (0.005 mol, 2.1 g) in a mixture of dry p-xylene and
acetonitrile (20 mL) was heated under reflux for 10 h, the
solvent was removed under reduced pressure, and the obtained
residue was triturated with methanol (20 mL). The precipitate
was filtered off and crystallized from ethanol.
À1
Yield (58%), buff, mp 169–170°C; IR cm : 3407, 3343
1
(
NH ), 3235 (NH), 2211 (CN); H-NMR: δ 8.71 (s, 1H,
2
CHpyridine), 8.21 (s, 1H, NH), 3.5 (br, 2H, NH
17 (82%), 198 (100%), 187 (72%), 172 (67%); Anal. Calcd.
for C H N Cl (217.5): C, 49.67; H, 1.85; N, 32.18; Cl, 16.29.
2
), m/z (100%):
2
9
4 5
Found: C, 49.47; H, 1.90; N, 32.27; Cl, 16.35.
À1
3-Amino-6-chloro-5-cyano-1H-pyrrolo[2,3-b]pyridine-2-
Yield (65%), bright brown, mp 245°C; IR cm : 3340, 3179
carboxamide (16).
.89 g) in DMF (25 mL) was treated with chloroacetamide
0.005 mol, 0.54 mL). The reaction mixture was refluxed for
h and then left to cool. The precipitated product was filtered
off, dried and crystallized from ethanol
Yield (70%), brown crystal, mp 220°C; IR cm : 3427, 3333
A solution of compound 1 (0.005 mol,
(
2NH), 2927 (CH)aliph., 2228 (CN); 1H-NMR: δ 8.71 (s, 1H,
0
(
5
CHpyridine), 8.26 (s, 2H, 2NH), 7.91–7.26 (m, 4H, phenyl), 3.78
(
s, 3H, CH
3
); MS: m/z (100%): 380 (3.5%), 379 (6.3%), 341
(
100%); Anal. Calcd. for C H N OPS Cl (380.5): C, 44.16;
1
4
10
4
2
H, 2.55; N, 14.71; Cl, 9.31; S, 16.84. Found: C, 44.23; H, 2.55;
N, 14.70; Cl, 9.39; S, 16.94.
General procedure for the preparation of compounds
À1
1
2
(NH ), 3229 (NH), 2218 (CN), 1636 (CO); H-NMR: δ 8.56 (s,
(
11a,b), (12), (13) and (14). A mixture of the corresponding
1H, NH), 8.33 (s, 1H, CHpyridine), 3.34 (br, 4H, 2NH ); MS:
2
compounds 7a,b, 8, 9 and 10 (0.004 mol) and hydrazine
hydrate (10 mL) was refluxed for 12 h; the solvent was
removed under reduced pressure, and the obtained residue was
triturated with ice cold water (10 mL). The precipitated solid
was filtered off, washed with water, dried and crystallized from
ethanol.
m/z (100%): 235 (4%), 160 (11%), 134 (100%); Anal. Calcd.
for C H N OCl (234.5): C, 45.88; H, 2.57; N, 29.72; Cl, 15.05.
9
6 5
Found: C, 45.90; H, 2.50; N, 29.60; Cl, 15.12.
N3,N3-Dimethyl-4-amino-7-chloro-6-cyano-2-oxo-1,2-dihydro[1,
8]naphthyridine-3-carboxamide (17).
To a cooled solution of
compound 1 (0.005 mol, 0.89 g) in DMF, chloroacetyl chloride was
added dropwise with stirring at room temperature for 2 h and then
refluxed for 3 h. The reaction mixture was cooled down and poured
onto ice cold water. The obtained solid product was filtered off,
dried and crystallized from ethanol.
3-Amino-5-imino-6-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[4’,3’:
5
,6]pyrido[2,3-d]pyrimidin-7-one (11a).
Yield (58%), yellow,
À1
mp >360°C; IR cm : 3321, 3172 (NH ), 3142 (3NH), 1685
2
1
(
CO); H-NMR: 11.50 (s, 2H, 2NH), 8.32 (s, 1H, CHpyridine),
.62–7.46 (m, 6H, NH + phenyl), 5.60 (br, 2H, NH ); Anal.
Calcd. for C14 O (293): C, 57.33; H, 3.78; N, 33.43. Found:
C, 57.23; H, 3.88; N, 33.40.
-Amino-5-imino-6-phenyl-5,6,7,8-tetrahydro-1H-pyrazolo[4’,3’:
7
2
À1
Yield (77%), brown crystal, mp 179°C; IR cm : 3398, 3287
11 7
H N
1
(
(
NH ), 3238 (NH), 2212 (CN), 1662 (CO); H-NMR: δ 8.07
2
2 3
s, 1H, CHpyridine), 7.30 (br, 3H, NH, NH ), 3.30 (s, 6H, 2CH )
3
MS: m/z (100%): 292 (50%), 149 (72%); Anal. Calcd. for
Cl (291.5): C, 49.41; H, 3.46; N, 24.01; Cl, 12.15.
5
,6]pyrido-[2,3-d]pyrimidine-7-thione (11b).
Yield (58%),
2
), 3140 (3NH);
À1
12 10 5 2
C H N O
yellow, mp >360°C; IR cm : 3321, 3199 (NH
1
Found: C, 49.41; H, 3.46; N, 24.01; Cl, 12.15.
H-NMR: 11.43 (s, 2H, 2NH), 8.35 (s, 1H, CHpyridine), 7.60–7.40
General procedure for the preparation of compounds 18,
(
m, 6H, NH + phenyl), 5.57 (br, 2H, NH ); Anal. Calcd. for
2
1
1
9 and 20.
A mixture of the corresponding compounds 15,
C H N
14 11 7
S (309): C, 54.36; H, 3.58; N, 31.69; S, 10.37. Found:
C, 54.47; H, 3.55; N, 31.59; S, 10.39.
-Amino-5,6,7,8-tetrahydro-1H-pyrazolo[4’,3’:5,6]pyrido[2,3-
d]pyrimidine-5,7-dithione (12). Yield (70%), brown, mp 230°C;
6 and 17 (0.004 mol) and hydrazine hydrate (10 mL) was
3
refluxed for 12 h; the solvent was removed under reduced
pressure, and the obtained residue was triturated with ice cold
water (10 mL). The precipitated solid was filtered off, washed
with water, dried and crystallized from ethanol.
3,5-Diamino-1,7-dihydropyrazolo[3,4-b]pyrrolo[3,2-e]pyridine-
6-carbonitrile (18). Yield (65%), dark yellow, mp >360°C; IR
À1
1
IR cm : 3318, 3199 (NH
NH), 8.37 (s, 1H, CHpyridine), 8.10 (s, 1H, 1NH), 5.55 (br, 2H,
NH ); Anal. Calcd. for C H N S (250): C, 38.39; H, 2.42; N,
2
), 3144 (3NH); H-NMR: δ 10.97 (s, 2H,
2
2
8 6 6 2
33.58; S, 25.62. Found: C, 38.30; H, 2.32; N, 33.65; S, 25.74.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

M. A. A. El-Remaily, O. M. El Hady, H. Salah Abo Zaid, and E. M. M. Abd El-Raheem
Vol 000
À1
1
cm : 3350,3241 (2NH ), 3165 (2NH); H-NMR: δ 11.12
REFERENCES AND NOTES
2
(
s, 2H, 2NH), 8.89 (s, 1H, CHpyridine), 5.8 (br, 4H, 2NH2);
Anal. Calcd. for C (213): C, 50.70; H, 3.31; N, 45.99.
Found: C, 50.75; H, 3.36; N, 45.89.
,5-Diamino-1,7-dihydropyrazolo[3,4-b]pyrrolo[3,2-e]pyridine-
[
1] Duindam, A.; Lishinsky, V. L.; Sikkema, D. J. Synth Commun
993, 23, 2605.
2] Dai, Y.; Hartandi, K.; Soni, N. B.; Pease, L. J.; Reuter, D. R.;
9 7 7
H N
1
[
3
Olson, A. M.; Osterling, D. J.; Doktor, S. Z.; Albert, D. H.; Bouska, J. J.;
Glaser, K. B.; Marcotte, P. A.; Stewart, K. D.; Davidsen, S. K.;
Michaelides, M. R. Bioorg Med Chem Lett 2008, 18, 386.
[3] Witherington, J.; Bordas, V.; Garland, S. L.; Hickey, D. M. B.;
Lfe, R. J.; Liddle, J.; Saunders, M. D.; Smith, G.; Ward, R. W. Bioorg
Med Chem Lett 2003, 13, 1577.
6
-carboxamide (19).
Yield (68%), yellow, mp >360°C; IR
À1
1
cm : 3317, 3210 (3NH2), 3171 (2NH); 1621 (CO); H-NMR: δ
1
1.36 (s, 2H, 2NH), 8.33 (s, 1H, CHpyridine), 5.39 (br, 6H, 3NH
Anal. Calcd. for C O (231): C, 46.75; H, 3.92; N, 42.41.
Found: C, 46.85; H, 3.90; N, 42.35.
2
);
9 9 7
H N
[
[
[
4] Ghosh, S.; Karin, M. Cell 2002, 109, S91.
5] Peifer, M.; Polakis, P. Science 2000, 287, 1606.
6] Bhatt, R.; Xue, Y.; Berg, S.; Hellberg, S.; Ormö, M.; Nilsson, Y.;
N6,N6-Dimethyl-3,5-diamino-7-oxo-7,8-dihydro-1H-pyrazolo[3,4-
b][1,8]-naphthyridine-6-carboxamide (20). Yield (75%), yellow,
mp 280°C; IR cm : 3427, 3313 (NH2), 3183 (NH), 1628 (CO); H-
NMR: δ 11.54 (s, 2H, 2NH), 8.22 (s, 1H, CHpyridine), 5.29 (br, 4H,
2
À1
1
Radesáter, A.-C.; Jerning, E.; Markgren, P.-O.; Borgegàrd, T.; Nylöf, M.;
Giménez-Cassina, A.; Hernández, F.; Lucas, J. L.; Díaz-Nido, J.; Ávila, J.
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[7] Mourad, C.; Abdelouahid, S.; Elena, S.; Olivier, L.; Laurent, M.;
Marco-Contelles, J. Bioorg Med Chem Lett 2009, 9, 4566.
NH ), 3.55 (s, 6H, 2CH ); Anal. Calcd. for C H N O (287): C,
2 3 12 13 7 2
5
0.17; H, 4.56; N, 34.13. Found: C, 50.20; H, 4.45; N, 34.10.
General procedure for the preparation of compounds
[8] Abdelouahid, S.; Carolina, V.; de los Rios, C.; Bastida, A.;
(
21a,b).
A solution of compound 1 (0.005 mol, 0.89 g) in
Chioua, M.; Gonzalez-Lafuente, L.; Colmena, I.; Gandia, L.; Romero, A.;
del Barrio, L. Bioorg Med Chem 2011, 19, 122.
[9] Abdelouahid, S.; Marco-Contelles, J.; Soriano, E.; Alvarez-
Perez, M.; Chioua, M.; Romero, A.; Gonzalez-Lafuente, L.; Gandia, L.;
Roda, J. M.; Lopez, M. G. Bioorg Med Chem 2010, 18, 5861.
10] Tedder, M. E.; Nie, Z.; Margosiak, S.; Chu, S.; Feher, V. A.;
Almassy, R.; Appelt, K.; Yager K. M. Bioorg Med Chem Lett 2004, 14, 3165.
11] Lin, R.; Connolly, P. J.; Lu, Y.; Chin, G.; Li, S.; Yu, Y.;
Huang, S.; Li, X.; Emanuel, S. L.; Middleton, S. A.; Gruninger, R. H.;
Adams, M.; Fuentes-Pesquera, A. R.; Greenberger, L. M. Bioorg Med
Chem Lett 2007, 17, 4292.
ethanol and sodium ethoxide (25 mL) was treated with ethyl
chloroacetate and ethyl bromoacetate (0.005 mol), respectively.
The reaction mixture was refluxed for 7 h and then left to
cool. The precipitated product was filtered off, dried and
crystallized from ethanol.
[
N1-(6-Chloro-3,5-dicyano-2-pyridyl)-2-chloroacetamide
[
À1
(
(
(
(
(
21a). Yield (85%), brown crystal, mp 230°C; IR cm : 3183
1
NH), 2206 (CN), 1635 (CO); H-NMR: δ 9.47 (s, 1H, NH), 8.90
s, 1H, CHpyridine), 4.45 (s, 2H, CH
84%), 138 (85%), 95 (100%); Anal. Calcd. for C
254): C, 42.38; H, 1.58; N, 21.97; Cl, 27.80. Found: C, 42.28; H,
2
); MS: m/z (100%): 254
[
[
12] De Clercq, E. J Med Chem 1986, 29, 1561.
13] Jones, A. S.; Sayers, J. R.; Walker, R. T.; De Clercq, E. J. Med
9 4
H
N
4
OCl
2
Chem 1988, 31, 268.
14] Griengl, H.; Wanek, E.; Schwarz, W.; Streicher, W.;
Rosenwirth, B.; De Clercq, E. J. Med Chem 1987, 30, 1199.
15] Soliman, A. M. J Heterocycl Chem 2011, 48, 592.
[16] Soliman, A. M.; Sultan, A. A.; El-Shafei, A. K. Monatsh Chem
1995, 126, 615.
1
.48; N, 21.99; Cl, 27.93.
[
N1-(6-Chloro-3,5-dicyano-2-pyridyl)-2-bromoacetamide
À1
(
21b). Yield (88%), yellow, mp 360°C (dec.); IR cm : 3185
[
1
(
NH), 2227 (CN), 1649 (CO); H-NMR: δ 9.77 (s, 1H, NH),
8
.98 (s, 1H, CHpyridine), 4.01 (s, 2H, CH ); Anal. Calcd. for
2
C H N OCl Br (298.5): C, 36.09; H, 1.35; N, 18.71; Cl, 11.84;
[17] Sultan, A. A.; Soliman, A. M.; El-Shafei, A. K. Phosphorus
Sulfur Silicon 1994, 97, 1.
9
4 4
Br, 26.66. Found: C, 36.19; H, 1.30; N, 18.71; Cl, 11.83; Br, 26.66.
-Amino-3,7-dimorpholino-1,2,3,4-tetrahydro[1,8]-naphthyridin-
-carbonitrile (22). An equimolar ratio of compound 21a,b
0.0017 mol, 0.45g), triethyamine (0.0034mol, 0.4 mL) and
[
[
[
[
18] Soliman, A. M. Synth Commun 2000, 30, 1269.
19] Soliman, A. M.; El-Saghier, A. M. Synth Commun 2001, 31, 2149.
20] Soliman, A. M. J Heterocycl Chem 2002, 39, 1.
4
6
(
21] Soliman, A. M.; Khodairy, A.; Ahmed, E. A. Phosphorus Sul-
morphline (0.005 mol), was heated under reflux in a mixture of
ethanol and THF (20mL) for 6 h, concentrated and left to cool
down. The obtained solid product was filtered off and crystallized
from ethanol.
fur Silicon 2003, 178, 649.
[22] Soliman, A. M.; Mohamed, S. K.; El Remaily, M. A. A.;
Abdel-Ghany H. E. J Med Chem 2012, 47, 138.
[23] Soliman, A. M.; Sultan, A. A.; El Remaily, M. A. A.; Abdel-
Ghany H. Synth Commun 2012, 42, 2748.
[24] Mohamed, S. K.; Soliman, A. M.; El Remaily, M. A. A.;
Abdel-Ghany H. Chem Sci J 2013, 4, CSJ-110.
À1
Yield (85%), bright yellow, mp 220°C; IR cm : 3399, 3326
1
(
NH
2
), 3218 (NH), 2202 (CN), 1644 (CO) H-NMR: δ 8.80 (s, 1H,
2
NH), 8.27 (s, 1H, CHpyridine), 5.30 (br, 2H, NH ), 3.75–3.72 (t, 8H,
[25] (a) Mohamed, S. K.; Soliman, A. M.; El Remaily, M. A. A.;
4
CH ), 3.68–3.65 (t, 8H, 4CH ); MS: m/z (100%): 356 (13%), 323
2
2
Abdel-Ghany, H. J Heterocycl Chem 2013, 50, 1425; (b) El Remaily,
M. A. A.; Mohamed, S. K. Tetrahedron 2014, 70, 270; (c) El Remaily,
M. A. A. Tetrahedron 2014, 70, 2971.
(
10%), 161 (13%), 149 (100%); Anal. Calcd. for C H N O (356)
17 20 6 3
C, 59.28; H, 7.02; N, 4.40. Found: C, 59.08; H, 7.08; N, 24.48.
[26] Jawetz, E.; Melnick, J. L.; Adelberg, E. A. Review of Medical
Microbiology; Lang Medical Pulication: Los Altos, CA, 1974.
[
[
27] Grayer, J. R.; Harbone, J. B. Phytochemistry 1994, 37 19.
28] Muanza, D. N.; Kim, B. W.; Euler, K. L.; Williams, L. Pharm
Acknowledgments. The authors are in deep gratitude for
Miss Dalia Ahmed Abd El Raheem in Botany Department,
Faculty of Science, Sohag University, Egypt, for the evaluation
of bacterial inhibiting effects.
Biol 1994, 32, 337.
[
29] Iroi, O. N.; Moo-Young, M.; Anderson, W. A. Pharm Biol
1996, 34, 87.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet