Synthesis of novel 1-pyrazolylpyridin-2-ones as potential anti-inflammatory and analgesic agents

Article abstract of DOI:10.1002/ardp.200600197

A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3- carbonitriles, pyrazolo[3,4-b]pyridine-5-carbonitriles and pyrido[2,3-d] pyrimidine-6-carbonitriles have been synthesized and tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Compounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and biological data are reported.

Full text of DOI:10.1002/ardp.200600197

476
Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Full Paper
Synthesis of Novel 1-Pyrazolylpyridin-2-ones as Potential
Anti-Inflammatory and Analgesic Agents
Magda M. F. Ismail1, Yousry A. Ammar2, Heba S. A. El-Zahaby1, Sally I. Eisa1, and
Saber El-Sayed Barakat3
1 Pharmaceutical Chemistry Department, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City, Cairo,
Egypt
2 Chemistry Department, Faculty of Science, Al-Azhar University, Nasr City, Cairo, Egypt
3 Pharmaceutical Chemistry Department, Faculty of Pharmacy, Al-Azhar University, Nasr City, Cairo, Egypt
A new series of 4-alkyl/aryl-2-oxo-1-pyrazolyl-1,2-dihydropyridine-3-carbonitriles, pyrazolo[3,4-
b]pyridine-5-carbonitriles and pyrido[2,3-d]pyrimidine-6-carbonitriles have been synthesized and
tested for their anti-inflammatory and analgesic activities. Among the tested compounds, 3e
and 8b exhibited comparable anti-inflammatory activity to the standard (indomethacin). Com-
pounds 5, 7a, and 8b displayed potent analgesic activity. Detailed syntheses, spectroscopic and
biological data are reported.
Keywords: Analgesic activities / Anti-inflammatory / Condensed pyridone / 1-Pyrazolylpyridin-2-one /
Received: November 29, 2006; accepted: May 4, 2007
DOI 10.1002/ardp.200600197
of different 4-, 5-, and 6-substituents of the pyridine-2-one
nucleus on the biological activity.
Introduction
Antipyrine and its 4-amino derivative (amidopyrine)
were shown to exert antinociceptive and anti-inflamma-
tory activities in various test models. The 4-substitution
of antipyrine and derivatives of 4-aminoantipyrine
proved to be more active than the parent compounds [1].
On the other hand, 3-cyano-4,6-diarylpyridin-2-ones
exhibited marked anti-inflammatory and/or analgesic
activities [2]. Furthermore, many fused pyridine deriv-
atives such as pyrazolo[3,4-b]pyridines induced reduction
of pro-inflammatory cytokines and were found to possess
anti-inflammatory and analgesic activities [3, 4]. Several
reports revealed that pyrido[2,3-d]pyrimidine exerted
promising anti-inflammatory and analgesic activities
[5, 6]. Herein, we report the preparation and evaluation
of anti-inflammatory and analgesic activities of a new ser-
ies of 1-pyrazolyl-2-pyridone-3-carbonitriles and fused
analogs, with the objective of determining the influence
Results and discussion
Chemistry
The designed target compounds are depicted in
Schemes 1–3. The 4-alkyl-2-oxo-1,2-dihydropyridine-3-car-
bonitrile 2 was obtained through a one-pot reaction of
cyanoacetanilide 1 with acetaldehyde and malononitrile
in ethanol / piperidine [7–9]. On the other hand, reaction
of 1 with different arylidenes in presence of piperidine as
catalyst [10] afforded substituted 4-aryl-2-oxo-1,2-dihydro-
pyridine-3-carbonitriles 3a–e. Cyclocondensation of 1
with acetyl acetone or benzoyl acetone in ethanol using
catalytic amount of piperidine [8, 9] furnished 1-pyra-
zolyl-4-methyl-2-oxo-6-substituted-1,2-dihydropyridine-3-
carbonitriles 4a, b. It is important to emphasize that the
presence of the nitrile group at the 3-position of the pyri-
done ring activates the methyl group at position 4. Con-
densation of the 4-methyl group of compound 4a with
Correspondence: Magda M. F. Ismail, Pharmaceutical Chemistry De-
partment, Faculty of Pharmacy (Girls), Al-Azhar University, Nasr City,
Cairo 11754, Egypt.
E-mail: magda_f_ismail@yahoo.com
Fax: +20 20405 2968
dimethylformamide-dimethylacetal
xylene [8, 9, 11] produced the 4-enamine derivative 5.
Treatment of 1 with 4-anisaldehyde afforded the aryli-
(DMF-DMA)
in
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Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Novel 1-Pyrazolylpyridin-2-ones
477
d]oxazinone which rearranged directly to the pyrido[2,3-
d]pyrimidine derivatives 10a, b [9]. Pharmacological eval-
uation: The new pyridone derivatives 2, 3b,c,e, 4a,b, 5, 7a,
8b, 9b, 10b were screened for anti-inflammatory and
analgesic activities.
Pharmacology
Anti-inflammatory activity
The anti-inflammatory activity of the tested compounds
was evaluated against the reference drug (indomethacin)
at doses of 50 mg and 5 mg, respectively. Then, the effi-
cacy of the tested compounds was determined after 6 h
of administration, when the percentage of inhibition
reaches the maximum value (Table 1). Compounds 3e
and 8b exhibited strong anti-inflammatory activity com-
parable to the reference drug. Compounds 2, 3b,c, and 5
showed moderate activities. Mild to weak effects were
exerted by the other compounds. Compounds 2, 3b, and
3c showed a relative efficacy of RE = 0.7 compared to indo-
methacin. The electronic effect of the substituents on the
4-phenyl group seems not to influence the activity; com-
pound 3b bearing an electron-releasing group (3,4,5-tri-
methoxyphenyl) has the same RE as 3c having an elec-
tron-withdrawing group (4-chlorophenyl). Acetylation of
Scheme 1. Synthesis of compounds 1–3.
dine 6 which was allowed to react in a Michael–addition
fashion with cyanoacetamide or cyano-acetic acid hydra-
zide [12, 13] to afford the desired compounds 7a, b. Cyclo-
condensation of 3a, b with N2H46H2O [9, 13] under
reflux condition led to the additional fused pyridones,
pyrazolo[3,4-b]pyridines 8a, b. Acetylation of 3a, b using
acetic anhydride under stirring, furnished the 6-acet-
amido derivatives 9a, b. However, reflux of 3a, b with
Ac2O for 6 h gave the intermediate 4-imino-pyrido[2,3-
Scheme 2. Synthesis route of compounds 1–7.
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M. M. F. ismail et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Scheme 3. Synthesis route of compounds 3–10.
the 6-amino group of 3b abruptly reduced the anti-
inflammatory activity (9b, RE = 0.1), while its cyclocon-
densation with Ac2O yielded 10b with slightly enhanced
activity. It is worth mentioning that conversion of 4a to
the 4-enamine derivative 5 enhanced the anti-inflamma-
tory activity (RE = 0.6).
On the other hand, incorporation of the antipyrine
nucleus to pyridine at position 5 via a carboxamide
linker 7a unfortunately produced weak anti-inflamma-
tory activity, while cyclocondensation of 3b with hydra-
zine hydrate afforded 8b which possesses a potent anti-
inflammatory activity (RE = 0.9).
Conclusion
The ester function at position 5 of pyridine enhanced the
anti-inflammatory activity and acetylation of 6-amino-
pyridine reduced the anti-inflammatory activity. The 4-
enamine group imparted high analgesic activity approxi-
mately equal to that of indomethacin. Incorporation of
antipyrine to the 2-pyridone nucleus at position 5 via a
carboxamide linker produced a highly analgesic agent.
Pyrazolo[3,4-b]pyridine exerted both potent analgesic
and anti-inflammatory activities.
Analgesic activity
Experimental
The recorded results in Table 2 show equipotent analge-
sic effects (RE = 0.97) as compared with the reference
drug, displayed by 4-enamine derivative 5. In addition, 5-
pyrazolylcarbamoylpyridine 7a displayed a strong anal-
gesic activity (RE = 0.84). Pyrazolo[3,4-b]pyridine 8b as
well elicited potent analgesia (RE = 0.87), while moderate
to mild activities were exhibited by the other com-
pounds.
Elemental analyses (C, H, N) were performed on an Perkin-Elmer
2400 analyzer (Perkin-Elmer, Norwalk, CT, USA) at the Microana-
lytical Unit of Cairo University. All compounds were within
l 0.4% of the theoretical values. Melting points were determined
in open capillaries on an Electrothermal LA 9000 Series (Electro-
thermal Engineering Ltd., Essex, UK) and are uncorrected. TLC
chromatography was performed on precoated silica gel 60F 254
plates (Merck Co., Sofia, Bulgaria). Infrared spectra were
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Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Novel 1-Pyrazolylpyridin-2-ones
479
Table 1. The anti-inflammatory activities of test compounds (50 mg/kg) and indomethacin (5 mg/kg).
Compound
Paw oedema thickness (mm)
1 h
X l S.E.
% Oedema
inhibition
2 h
X l S.E.
% Oedema
inhibition
3 h
X l S.E.
% Oedema
inhibition
Control
2
3b
3c
3e
4a
4b
5
0.174 l 0.0044
0.078 l 0.0028*
0.077 l 0.0026*
0.09 l 0.0025*
0.042 l 0.0019*
0.145 l 0.0039*
0.13 l 0.0034*
0.087 l 0.0028*
0.040 l 0.0018*
–
0.190 l 0.0040
0.131 l 0.0035*
0.125 l 0.0033*
0.109 l 0.0034*
0.105 l 0.0019*
0.174 l 0.0040*
0.161 l 0.0041*
0.138 l 0.0030*
0.090 l 0.0026*
–
0.250 l 0.0052
0.192 l 0.0048*
0.191 l 0.0033*
0.192 l 0.0035*
0.156 l 0.0120*
0.233 l 0.0050*
0.240 l 0.0056*
0.205 l 0.0049*
0.140 l 0.0048*
–
55.2
55.7
54.59
75.8
16.6
24.2
50
34.2
34.2
4.6
44.7
8.4
15.2
27.3
5.6
23.2
23.6
23.2
37.6
6.8
4
18
44
Indometh.
77
Compound
Paw oedema thickness (mm)
4 h
X l S.E.
% Oedema
inhibition
5 h
X l S.E.
% Oedema
inhibition
6 h
X l S.E.
% Oedema
inhibition
Efficacy
Control
2
3b
3c
3e
4a
4b
5
0.160 l 0.0015
0.150 l 0.0026*
0.150 l 0.0100*
0.149 l 0.0020*
0.132 l 0.0029*
0.140 l 0.0033*
0.152 l 0.0053*
0.151 l 0.0029*
0.114 l 0.0035*
-
0.125 l 0.0013
0.100 l 0.0015*
0.092 l 0.0028*
0.100 l 0.0018*
0.089 l 0.0019*
0.125 l 0.0029*
0.121 l 0.0032*
0.121 l 0.0100*
0.088 l 0.0015*
-
0.105 l 0.0010
0.089 l 0.0011*
0.087 l 0.0026*
0.089 l 0.0016*
0.059 l 0.0018*
0.098 l 0.0022*
0.091 l 0.0031*
0.090 l 0.0028*
0.052 l 0.0013*
-
-
6.3
6.3
6.8
17.5
12.5
5
26.4
26.4
0
28.8
-
3.2
3.2
29.6
17.2
17.2
15.3
43.8
6.6
13.3
14.2
50
0.7
0.7
0.7
0.9
0.2
0.3
0.6
1
5.6
28.7
Indomethacin
Compound
Paw oedema thickness (mm)
% Oedema
1 h
% Oedema
2 h
3 h
X l S.E.
% Oedema
inhibition
X l S.E.
inhibition
X l S.E.
inhibition
Control
7a
8b
9b
10b
Indomethacin
0.174 l 0.0044
0.137 l 0.0035*
0.051 l 0.0020*
0.160 l 0.0043*
0.138 l 0.0035*
0.040 l 0.0018*
–
0.190 l 0.0040
0.149 l 0.0032*
0.105 l 0.0024*
0.178 l 0.0046*
0.159 l 0.0041*
0.090 l 0.0026*
–
0.250 l 0.0052
0.9 l 0.0048*
0.183 l 0.0050*
0.249 l 0.0053*
0.239 l 0.0050*
0.140 l 0.0048*
–
21.3
70.6
8.1
44.3
77
21.5
44.7
6.3
16.3
52.6
8.4
26.8
0.4
4.4
44
Compound
Paw oedema thickness (mm)
4 h
X l S.E.
% Oedema
inhibition
5 h
X l S.E.
% Oedema
inhibition
6 h
X l S.E.
% Oedema
inhibition
Efficacy
Control
7a
8b
9b
10b
0.160 l 0.0015
0.160 l 0.0020*
0.140 l 0.0034*
0.159 l 0.0022*
0.157 l 0.0023*
0.130 l 0.0035*
–
–
20.7
0.6
1.8
28.7
0.15 l 0.0013
–
0.105 l 0.0010
0.096 l 0.0011*
0.068 l 0.017*
0.100 l 0.0015*
0.097 l 0.0014*
0.052 l 0.0013*
–
–
0.122 l 0.0017*
0.091 l 0.0019*
0.125 l 0.0019*
0.123 l 0.0018*
0.088 l 0.0015*
2.4
27.2
–
1.6
29.6
8.5
35.3
4.7
7.6
50
0.3
0.9
0.1
0.5
1
Indometh.
Significant difference from the control value at Pa 0.05; S.E. Standard error; Compounds 3a, 3d, 7b, 8a, 9a, and 10a were not eval-
uated due to low yields on preparation.
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M. M. F. ismail et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Table 2. The analgesic activity of the tested compounds (50 mg/kg) and indomethacin (5 mg/kg).
Compound
Reaction time (s)
0
30 min.
X l S.E.
Efficacy
1 h
X l S.E.
Efficacy
2 h
X l S.E.
Efficacy
X l S.E.
2
3b
3c
3e
7a
4a
4b
5
5.6 l 0.2*
5.9 l 0.4*
6.5 l 0.3*
6.4 l 0.4*
7.3 l 0.4*
5.4 l 0.3*
6.8 l 0.4
7.2 l 1.0*
5.6 l 0.2*
7.3 l 0.3
6.2 l 0.6*
7.9 l 0.4*
6.5 l 0.4* (15.2)
6.8 l 0.4* (15.2)
7.1 l 0.2* (9.2)
8.4 l 0.5* (31.2)
9.3 l 0.7* (27.3)
7.2 l 0.5* (33)
8.7 l .4 (27.9)
9.0 l 0.5* (25)
6.6 l 0.9* (17.8)
7.7 l 0.6* (5.4)
8.0 l 0.4* (29)
11.3 l 0.4* (43)
0.37
0.35
0.21
0.72
0.63
0.76
0.64
0.58
0.41
0.12
0.67
1.0
6.5 l 0.4* (16)
6.8 l 0.4* (15.2)
8.2 l 0.2* (26)
10.4 l 0.5* (62.5)
11.1 l 0.3* (52)
7.4 l 0.4* (37)
9.4 l 0.5 (38.2)
11.9 l 1.0* (65.2)
7.8 l 0.8*- (39.2)
8.0 l 0.7 (9.5)
0.37
0.19
0.33
0.80
0.67
0.47
0.49
0.84
0.50
0.12
0.69
1.0
6.5 l 0.4* (25.4)
7.4 l 0.1* (25.4)
8.2 l 0.3* (26)
0.20
0.31
0.32
0.43
0.84
0.25
0.38
0.97
0.40
0.15
0.87
1.0
8.6 l 0.5* (34.3)
12.2 l 0.4* (67.1)
6.5 l 0.8* (20.3)
8.9 l 0.4 (30.8)
12.8 l 0.5* (77.7)
7.4 l 0.5* (32.1)
8.2 l 0.1* (12.3)
10.6 l 0.5* (70)
14.2 l 0.4 (79.7)
9b
10b
8b
9.6 l 0.5* (54)
14 l 0.6 (77.2)
Indomethacin
Values between parentheses represent the increase of reaction time compared to zero time. Compounds 3a, 3d, 7b, 8a, 9a, and 10a
are not evaluated due to low yields on preparation. * Significant difference from the control value at P a 0.05; S.E. Standard error.
Table 3. Physicochemical data of synthesized compounds.
mixture was allowed to cool and the separated solid was filtered
and crystallized (Table 3).
2: IR (cm– 1): 3336 (broad, NH2), 2210 (CN), 1688, 1660 (C=O). 1H-
NMR (DMSO-d6): d 2.09 (s, 3H, CH3-pyrazole), 2.41 (s, 3H, CH3-pyri-
dine), 3.20 (s, 3H, NCH3), 7.37–7.58 (m, 5H, PhH), 8.34 (bs, 2H,
NH2, D2O exchangeable).
Formulae
Mp
(8C)
Yield
(%)
Solvent
Compound
C19H16N6O2
C27H24N6O5
C24H17ClN6O2
C27H25N5O5
C26H22ClN5O4
C19H18N4O2
C24H20N4O2
C22H23N5O2
C22H20N4O2
C25H22N6O4
C25H23N7O4
C25H21N7O3
C27H25N7O5
C27H22N6O4
C29H26N6O6
C27H22N6O4
C29H26N6O6
178–180 65
177–180 82
317–320 47
159–161 40
232–234 39
217–219 63
237–240 32
143–145 43
137–139 59
157–160 32
159–162 33
223–225 29
308–310 30
258–260 24
192–195 63
237–240 33
205–207 31
EtOH
EtOH
Dioxan
MeOH
EtOH
EtOH
EtOH
MeOH
MeOH
EtOH
2
3b
3c
3d
3e
4a
4b
5
6-Amino-3,5-dicyano-1-(1,5-dimethyl-2-phenyl-3(1H)-
pyrazolon-4-yl)-4-substitutedphenyl-2(1H)-pyridone 3b,c;
and 6-amino-3-cyano-1-(1,5-dimethyl-2-phenyl-3(1H)-
pyrazolon-4-yl)-5-ethoxycarbonyl-4-substitutedphenyl-
6
7a
7b
8a
8b
9a
9b
10a
10b
2(1H)-pyridone 3d, e
EtOH
A mixture of equimolar amounts (0.01 mol) of compound 1
(2.7 g) and the appropriate arylidene derivatives in ethanol
(20 mL) containing few drops of piperidine was refluxed for 3 h.
The reaction mixture was allowed to cool, and the solid so
obtained was filtered and crystallized from the appropriate sol-
vent (Table 3).
Dioxan
Dioxan
Dioxan
EtOH
Dioxan
EtOH
3b: IR (cm– 1): 3496 broad (NH2), 2216 (CN), 1664, 1642 (C=O),
1H-NMR (DMSO-d6): d 2.14 (s, 3H, CH3), 3.24 (s, 3H, NCH3) 3.75 (s,
3H, OCH3), 3.82 (s, 6H, 26OCH3), 6.93 (s, 2H, ArH), 7.39–7.58 (m,
5H, Ph-H), 8.49 (s, 2H, NH2, D2O exchangeable), MS (m/z,%): 512
[M+] (21.0), 122 (100) 405 (10.2), 364 (9.07), 107 (5.52).
3c: IR (cm– 1): 3445, 3277 (NH2), 2213 (CN), 1680, 1664 (C=O),
MS (m/z,%): 456 [M+] (26.08), 458 [M+2] (68.75), 56 (100), 336
(30.70), 302 (27.51), 199 (11.70).
recorded on Pye Unicam SP 1000 IR spectrophotometer (Thermo-
electron, Egelsbach, Germany). H-NMR spectra were recorded
1
on Varian Gemini EM-300 MHz NMR spectrophotometer (Varian,
Fort Collins, CO, USA). DMSO-d6 was used as solvent, TMS was
used as internal standard, and chemical shifts were measured in
d ppm. Mass spectra were recorded on Varian MAT 311-A 70 eV
(Varian). 2-(Arylidene) malononitrile [14] 3a was prepared
according to the reported method [10]. MF: CHNO; mp. 307–
3108C; yield: 55.5%.
3d: IR (cm– 1): 3333, 3269 (NH2), 2254 (CN), 1636 (CO-N), 1719
1
(COO), H-NMR (DMSO-d6): d 1.05 (t, 3H, COOCH2CH3, J = 6.9 Hz),
2.15 (s, 3H, CH3), 3.28 (s, 3H, NCH3), 3.78 (q, 2H, COOCH2CH3, J =
6.9 Hz), 3.81 (s, 3H, OCH3), 7.00–7.25 (2d, 4H, ArH, AB system J =
9 Hz), 7.37–7.58 (m, 5H, Ph-H), 8.48 (s, 2H, NH2, D2O exchange-
able).
Synthesis
3e: IR (cm– 1): 3448, 3261 (NH2), 2210 (CN), 1670 (CO-N), 1700
1
6-Amino-3,5-dicyano-1-(1,5-dimethyl-2-phenyl-3(1H)-
(COO), H-NMR (DMSO-d6): d 1.51 (t, 3H, COOCH2CH3, J = 7.0 Hz),
pyrazolon-4-yl)-4-methyl-2(1H)-pyridone 2
2.31 (s, 3H, CH3), 3.19 (s, 3H, NCH3), 4.11 (q, 2H, COOCH2CH3, J =
7.0 Hz), 7.29 (d, 2H, AB system J = 9 Hz), 7.36 (d, 2H, AB system J =
9 Hz), 7.39–7.56 (m, 5H, Ph-H), 9.36 (s, 2H, NH2, D2O exchange-
able).
A mixture of equimolar amounts (0.01 mol) of 1 (2.7 g), acetalde-
hyde (0.4 g) and malononitrile (0.6 g) in ethanol (20 mL) contain-
ing few drops of piperidine was refluxed for 3 h. The reaction
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Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Novel 1-Pyrazolylpyridin-2-ones
481
1-(1,5-Dimethyl-2-phenyl-3-(1H)-pyrazolon-4-yl)-3-
3-Amino-5-cyano-7-(1,5-dimethyl-2-phenyl-3(1H)-
pyrazolon-4-yl)-4-substituted-phenyl-1H,7H-
pyrazolo[3,4-b]pyridin-6-ones 8a, b
cyano-4-methyl-6-substituted-2(1H)-pyridones 4a, b
A mixture of equimolar amounts (0.01 mol) of compound 2
(2.7 g) and acetyl acetone (1 mL) or benzoyl acetone (1.6 g) in
ethanol (20 mL) containing a few drops of piperidine was
refluxed for 3 h. The reaction mixture was cooled and the solid
so obtained was filtered and crystallized (Table 3).
A mixture of the appropriate 3a, b (0.01 mol) and hydrazine
hydrate (0.5 mL, 90%) in ethanol (20 mL) was refluxed for 3 h.
The reaction mixture was cooled and the solid so obtained was
filtered and crystallized (Table 3).
4a: IR (cm– 1): 2218 (CN), 1660 (C=O), 1H-NMR (DMSO-d6): d 2.10
(s, 3H, CH3-pyrazole), 2.30 (s, 3H, CH3), 2.40 (s, 3H, CH3), 3.10 (s,
3H, NCH3), 6.40 (s, 1H, H-5), 7.30–7.60 (m, 5H, Ph-H). 4b: IR (cm–
1): 2211 (CN), 1665 (C=O), MS (m/z,%): 396 [M+] (15), 56 (100), 275
(9.30), 140 (16.34), 77 (37.33).
1
8a: H-NMR (DMSO-d6): d 2.15 (s, 3H, CH3), 3.22 (s, 3H, NCH3)
3.86 (s, 3H, OCH3), 5.32 (s, 2H, NH2, D2O exchangeable), 7.15–7.52
(m, 10H, 9ArH & NH).
8b: IR (cm– 1): 3378, 3211, 3138 (NH, NH2), 2212 (CN), 1660,
1
1623 (C=O), H-NMR (DMSO-d6): d 2.15 (s, 3H, CH3), 3.22 (s, 3H,
NCH3) 3.76, 3.83 (2s, 9H, 36OCH3) 5.55 (bs, 2H, NH2, D2O
exchangeable), 6.92 (s, 2H, ArH), 7.37–7.51 (m, 6H, 5 Ph-H & NH),
MS (m/z,%): 527 [M+] (100), 528 [M+1] (38.2), 526 [M-1] (78.3), 392
(43.10), 356 (63.70).
3-Cyano-1-(1,5-dimethyl-2-phenyl-3(1H)-pyrazolon-4yl)-
4-[(2-di-methylamino)-vinyl]-6-methyl-2(1H)-pyridone 5
A mixture of equimolar amounts (0.01 mol) of 4a (3.3 g) and
DMF-DMA (1.2 g) in xylene (20 mL) was refluxed for 4 h. The reac-
tion mixture was cooled, washed with diethylether, and the sep-
arated solid was crystallized (Table 3).
6-Acetamido-[3,5-dicyano-1-(1,5-dimethyl-2-phenyl-
3(1H)pyrazolon-4-yl)-4-substitutedphenyl-2(1H)-
pyridones 9a, b
A mixture of 3a or 3b (0.01 mol) and acetic anhydride (15 mL)
was stirred for 2 h at room temperature. The solid so obtained
was filtered and crystallized (Table 3).
5: IR (cm– 1): 1661 (C=O), 2200 (CN), 1H-NMR (DMSO-d6): d 2.10 (s,
3H, CH3-pyrazole), 2.25 (s, 3H, CH3), 3.20 (s, 3H, NCH3-pyrazole),
3.24, 3.39 (2s, 6H, 26NCH3), 5.10 (d, 1H, N-CH=), 6.44 (s, 1H, H-5),
7.35–7.90 (m, 6H, 5 Ph-H & 1H CH=C), MS (m/z,%): 389 [M+] (5.17),
56 (100), 334 (16.20), 93 (13.15), 77 (33.51).
9a: IR (cm– 1): 3456 (NH), 2222 (CN), 1690, 1670 (C=O).
9b: IR (cm– 1): 3436 (NH), 2215 (CN), 1679, 1623 (C=O). 1H-NMR
(DMSO-d6): d 1.90 (s, 3H, CH3), 2.14 (s, 3H, COCH3), 3.26 (s, 3H,
NCH3), 3.75 (s, 3H, OCH3), 3.83 (s, 6H, 26OCH3), 6.93 (s, 2H, ArH),
7.39–7.55 (m, 5H, Ph-H), 8.50 (s, 1H, NH, D2O-exchangeable).
1,5-Dimethyl-4-[2-cyano-3-(4-methoxyphenyl)-
acrylamido]-2-phenyl-3(1H)-pyrazolone 6
A mixture of equimolar amounts (0.01 mol) of compound 1
(2.7 g), p-anisaldehyde (1.3 g) and sodium ethoxide (0.7 g) in etha-
nol (10 mL) was refluxed for 1 h. The reaction mixture was
cooled and the solid so obtained was filtered and crystallized
(Table 3).
6-Cyano-8-(1,5-dimethyl-2-phenyl-3(1H)pyrazolon-4-yl)-
2-methyl-5-substituted phenyl-3H,8H-pyrido[2,3-
d]pyrimidine-4,7diones 10a, b
A mixture of the appropriate 3a or 3b (0.01 mol) and acetic anhy-
dride (15 mL) was refluxed for 6 h, cooled, and then poured into
cold water. Then, a few drops of HCl were added and the solid so
obtained was filtered and crystallized (Table 3).
Alternative procedure: A mixture of the appropriate 9a or 9b
(0.01 mol) and acetic anhydride (15 mL) was refluxed for 5 h and
then proceeded as before.
6: IR (cm– 1): 3195 (NH), 2213 (CN), 1657 (C=O), 1H-NMR (DMSO-
d6): d 2.17 (s, 3H, CH3), 3.14 (s, 3H, NCH3) 3.86 (s, 3H, OCH3), 7.14–
8.00 (m, 9H, ArH), 8.22 (s, 1H, CH=), 9.51 (s, 1H, NH, D2O
exchangeable).
10a: IR (cm– 1): 3424 (NH), 2217 (CN), 1660 (C=O), 1H-NMR
(DMSO-d6): d 1.90, 2.04 (2s, 6H, 26CH3), 3.29 (s, 3H, NCH3), 3.85 (s,
3H, OCH3), 7.12–7.49 (m, 10H, 9ArH & NH, D2O exchangeable).
10b: IR (cm– 1): 3446 (NH), 2215 (CN), 1677 (C=O), 1H-NMR
(DMSO-d6): d 1.90, 1.98 (2s, 6H, 26CH3), 3.03 (s, 3H, NCH3), 3.76 (s,
3H, OCH3), 3.85 (s, 6H, 26OCH3), 6.93 (s, 2H, ArH), 7.07-7.59 (m,
6H, 5 Ph-H & NH, D2O exchangeable), MS (m/z,%): 552 [M-2] (7.75),
89 (100), 524 (8.11), 368 (25.70), 236 (23.50), 313 (34.83).
6-Amino-5-[(1,5-dimethyl-2-phenyl-3(1H)-pyrazolon-4-
yl)-aminocarbonyl]-3-cyano-4-(4-methoxyphenyl)-2(1H)-
pyridone 7a; and 1,6-diamino-5-[(1,5-dimethyl-2-phenyl-
3(1H)-pyrazolon-4-yl)-aminocarbonyl]-3-cyano-4-(4-
methoxyphenyl)-2(1H)-pyridone 7b
A mixture of equimolar amounts (0.01 mol) of compound 6
(3.8 g) and cyanoacetamide (0.86 g) or cyanoacetic acid hydra-
zide (0.9 g) and sodium ethoxide (0.7 g) in ethanol (20 mL) was
refluxed for 3 h, then cooled and poured into cold water. A few
drops of HCl were added and the separated solid was filtered and
crystallized (Table 3).
Pharmacological evaluation
Materials: Eighty adult albino rats of both sexes weighing (120–
150 g) and eighty mice weighing (20–25 g) were obtained from
animal house lab, Nile company, Cairo, Egypt and acclimatized
for one week in the animal facility that has a 12 h light/dark
cycles with controlled temperature (21–238C). Normal rat chow
and water were made available, carrageenan sodium (1%,
Sigma), tween 80 (2%), saline, distilled water, and indomethacin
cap (lot No 0.30687, MUB, Egypt). Dial micrometer; Baty and Co.
Ltd, Sussex, England.
7a: IR (cm– 1): 3448, 3306, 3171, (NH2, NH), 2208 (CN), 1698
(C=O).
7b: IR (cm– 1): 3332, 3203 (NH2, NH), 2208 (CN), 1690 (C=O), 1H-
NMR (DMSO-d6): d 2.36 (s, 3H, CH3), 3.10 (s, 3H, NCH3), 3.85 (s, 3H,
OCH3), 6.92–7.53 (m, 11H, 9ArH & NH2), 11.48 (s, 1H, NHCO),
11.81 (s, 2H, NH2, D2O exchangeable).
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482
M. M. F. ismail et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 476–482
Preparation of samples
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i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com