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ISSN 2291-6458 (Print), ISSN 2291-6466 (Online)
Research Article DOI:10.13179/canchemtrans.2014.02.04.0133
Synthesis of Some Novel Pyridazine, Thienopyridazine,
Pyrazolopyridine, Pyridopyrazolopyrimidine and
Pyridopyrazolotriazine Derivatives with Their Antimicrobial
Activity
Ismail M. M. Othman*, Hamdi M. Nasr, and Mohamed I. Hassan
Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut 71524, Egypt
Corresponding Author, E-mail: [email protected]
Received: May 15, 2014 Revised: June 28, 2014 Accepted: June 28, 2014 Published: June 29, 2014
Abstract: Coupling of compound 1 with diazotized aromatic amines in ethanol afforded the
arylhydrazones 3a,b. Fusion of 3a,b with active methylene derivatives 4a,b afforded the pyridazine
derivatives 6a–d. Also, when compounds 6b,c were reacted with elemental sulphur afforded the
thienopyridazine derivatives 7a,b. Treatment of compound 8 with hydrazine hydrate produced
pyrazolopyridine derivative 9. Pyridopyrazolopyrimidines (12–19) and pyridopyrazolotriazines 21, 22a,b
were achieved by the reaction of pyrazolopyridine with different reagents in basic media. The
antimicrobial activities of the new compounds were also evaluated. The newly synthesized compounds
were characterized by IR, 1H NMR and
13C-NMR spectral studies.
Keywords: Pyridazine; Thienopyridazine; Pyrazolopyridine; Pyridopyraz-Olopyrimidine,
Pyridopyrazolotriazine.
1. INTRODUCTION
Nitrogen-containing heterocyclic compounds are one of the most fruitful and extensively
developing fields of heterocyclic chemistry. These compounds exhibit various kinds of biological
activities. During the past decades increasing interest in the synthesis and biological activities of
pyridazine derivatives has been observed [1–3]. Pyridazine compounds have been reported to possess
varied biological activities such as antimicrobial [4], antihypertensive [5], anticancer [6], anti-
inflammatory[7] and antifungal activities [8]. These facts have prompted us to synthesize some novel
pyridazine derivatives. Recently, pyridazinone nucleus has been extensively studied in the search for new
and selective medicinal agents as drugs acting on the cardiovascular system [9]. Furthermore, a number of
thienopyridazines have been claimed to possess interesting biological and pharmacological activities such
as, anticancer [10], useful as NAD(P)H oxidase inhibitor [11], and identified as a new allosteric
modulator of the adenosine A1 receptor (A1AR)12
. Also, Pyrazolo [3,4-b]pyridines comprise a very
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interesting class of compounds because of their significant and versatile biological, and pharmacological
activities, such as antimicrobial [13], cardiovascular [14], antiviral [15] and antileishmanial [16]
activities. The pyrazolo[3,4-b]pyridine moieties represent important building blocks in both natural
and synthetic bioactive compounds [17]. They show anxiolytic activity along with Xanthine oxidase
inhibitors, cholesterol formation-inhibitor, and Anti-Alzheimer [18]. They also act as potent and selective
inhibitors of glycogen synthase kinase-3 (GSK-3) [19]. Moreover, fused heterocyclic containing
pyrazolopyridine systems have been described associated with several biological and medicinal activities
[20-23]. In connection with our efforts to synthesize fused heterocycles [24−27] from readily available
starting materials, we report here on the synthesis of some novel pyridazine, thienopyridazine,
pyrazolopyridine, pyridopyrazolopyrimidine and pyridopyrazolotriazine derivatives in order to investigate
the antimicrobial activity.
2. EXPERIMENTAL
All melting points are uncorrected. IR spectra (KBr) were recorded on a FTIR 5300 spectrometer
(, cm-1
). The 1H NMR and
13C-NMR spectra were recorded in DMSO-d6 at 200, 300 MHz on a Varian
Gemini NMR spectrometer (, ppm) using TMS as an internal standard. Elemental analyses were carried
out at the Microanalytical Center, Faculty of Science, Cairo University and Assiut University.
Microbiology screening was carried out in Botany Department, Faculty of Science, Al-Azhar University,
Assiut.
2.1 Preparation of Compounds 3a, b: General Procedure
A solution of 1 (0.01 mole ) in ethanol (30 mL) containing sodium acetate (2gm) was cooled to 0
ºC , stirred and treated gradually with cooled solution of aryl diazonium chloride (prepared from 0.01
mole of amine and the appropriate quantities of HCl and NaNO2). The solid product formed on standing
was collected and recrystallized from the proper solvent to give 3a, b.
N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-oxo-2-(2-(4-(N-(thiazol-2-
yl)sulfamoyl)phenyl)hydrazono)butanamide (3a)
It was obtained as yellow crystals from ethanol; yield 86 %; m.p. 158 ºC; IR (KBr) ν cm-1
3368,
3242, 3182 (3NH), 3057 (CH-arom.), 2946 (CH-aliph.), 1996, 1675, 1663 (3C=O); 1H NMR (DMSO-d6)
δ = 1.82 (s, 3H, CH3), 2.26 (s, 3H, CH3), 3.02 (s, 3H, NCH3), 6.89- 8.05 (m, 11H, Ar-H), 10.43 (s, 1H,
NH), 11.24 (s, 1H, NH), 13.52 (s, 1H, NH). Anal. Calc. For C24H23N7O5S2 (553.61): C, 52.07; H, 4.19; N,
17.71; S, 11.58%.Found: C, 52.22; H, 4.41; N, 17.92; S, 11.79%.
N-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2-(2-(4-(N-(4,5-dimethyloxazol-2-
yl)sulfamoyl)phenyl)hydrazono)-3-oxobutanamide (3b)
It was obtained as brown crystals from ethanol; yield 82%; m.p. 174ºC; IR (KBr): υ cm−1
3384,
3267, 3126 (3NH), 3072 (CH-arom.), 2965 (CH-aliph.), 1695, 1664, 1645 (3CO); 1H NMR (DMSO-d6): δ
= 1.72 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.46 (s, 3H, CH3), 3.17 (s, 3H, NCH3), 6.90-
7.98 (m, 9H, Ar-H), 9.93 (s, 1H, NH), 11.66 (s, 1H, NH), 13.43 (s, 1H, NH). Anal. Calc. For C26H27N7O6S
(565.60): C, 55.21; H, 4.81; N, 17.33; S, 5.67%.Found: C, 55.41; H, 4.59; N, 17.54; S, 5.88%.
2.2 Preparation of Compounds 6a-d: General Procedure
An equimolar amount of either 3a (0.01 mole) or 3b (0.01 mole) in ammonium acetate (2 gm)
was added to either malononitrile (4a) (0.01 mole) or ethyl cyanoacetate (4b) (0.01 mole). The reaction
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mixture, in each case, was fused for 1h. Then left to stand at room temperature and triturated with ethanol.
The solid product so formed, in each case, was collected by filtration and recrystallized from the proper
solvent to give 6a-d.
5-Cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-6-imino-4-methyl-1-(4-(N-
(thiazol-2-yl)sulfamoyl)phenyl)-1,6-dihydropyrid- azine-3-carboxamide (6a)
It was obtained as brown crystals from DMF/ethanol; yield 68%; m.p. 267ºC; IR (KBr) ν cm-1
3375, 3332, 3254 (3NH), 3057 (CH-arom.), 2945 (CH-aliph.), 2205 (CN), 1662, 1647 (2CO); 1
H NMR
(DMSO-d6) δ = 1.85 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.11 (s, 3H, NCH3), 7.25- 8.12 (m, 12H, Ar-H+
NH), 10.15 (s, 1H, NH), 11.82 (s, 1H, NH). 13
C NMR (DMSO-d6) δ C = 10.54, 13.15, 34.61 (3CH3),
116.12 (CN), 102.92, 104.42, 112.38, 117.45, 123.23, 125.65, 130.23, 131.44, 133.10, 136.42, 137.31,
138.46, 143.11, 150.26, 155.15, 160.56 (Ar-C), 167.21, 169.75 (2CO); Anal. Calc. For C27H23N9O4S2
(601.66): C, 53.90; H, 3.85; N, 20.95; S, 10.66%.Found: C, 53.68; H, 3.64; N, 20.72; S, 10.87%.
5-Cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-methyl-6-oxo-1-(4-(N-
(thiazol-2-yl)sulfamoyl)phenyl)-1,6-dihydropyrid- azine-3-carboxamide (6b)
It was obtained as brown crystals from ethanol /dioxane; yield 59%; m.p. 254ºC; IR (KBr) ν cm-1
3349, 3207 (2NH), 3068 (CH-arom.), 2935 (CH-aliph.), 2198 (CN), 1688, 1670, 1653 (3C=O); 1H NMR
(DMSO-d6) δ = 1.57 (s, 3H, CH3), 2.23 (s, 3H, CH3), 3.02 (s, 3H, NCH3), 7.22- 8.08 (m, 12H, Ar-H+
NH), 10.85 (s, 1H, NH). Anal. Calc. For C27H22N8O5S2 (602.64): C, 53.81; H, 3.68; N, 18.59; S,
10.64%.Found: C, 53.58; H, 3.89; N, 18.82; S, 10.86%.
5-Cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-(4-(N-(4,5-dimethyloxazol-2-
yl)sulfamoyl)phenyl)-6-imino-4-methyl-1,6-dihydr- opyridazine-3-carboxamide (6c)
It was obtained as green crystals from DMF/ethanol; yield 66%; m.p. 273ºC; IR (KBr): υ cm−1
3348, 3215, 3192 (3NH), 3060 (CH-arom.), 2934 (CH-aliph.), 2193 (CN), 1668, 1647 (2CO); 1
H NMR
(DMSO-d6): δ = 1.46 (s, 3H, CH3), 2.15 (s, 3H, CH3), 2.26 (s, 3H, CH3), 2.48 (s, 3H, CH3), 3.05 (s, 3H,
NCH3), 7.18- 7.98 (m, 11H, Ar-H+ 2NH), 11.32 (s, 1H, NH). Anal. Calc. For C29H27N9O5S (613.65): C,
56.76; H, 4.43; N, 20.54; S, 5.23%.Found: C, 56.95; H, 4.64; N, 20.76; S, 5.44%.
5-Cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-1-(4-(N-(4,5-dimethyloxazol-2-
yl)sulfamoyl)phenyl)-4-methyl-6-oxo-1,6-dihydro- pyridazine-3-carboxamide (6d)
It was obtained as green crystals from DMF/ethanol; yield 67%; m.p. 270ºC; IR (KBr): υ cm−1
3363, 3181 (2NH), 3053 (CH-arom.), 2933 (CH-aliph.), 2203 (CN), 1686, 1670, 1658 (3CO); 1
H NMR
(DMSO-d6): δ = 1.27 (s, 3H, CH3), 2.24 (s, 3H, CH3), 2.38 (s, 3H, CH3), 2.47 (s, 3H, CH3), 3.11 (s, 3H,
NCH3), 7.27- 8.22 (m, 10H, Ar-H+ NH), 11.21 (s, 1H, NH). Anal. Calc. For C29H26N8O6S (614.63): C,
56.67; H, 4.26; N, 18.23; S, 5.22%.Found: C, 56.88; H, 4.47; N, 18.45; S, 5.43%.
2.3 Preparation of Compounds 7a, b: General Procedure
A mixture of compound 6b or 6c (0.01 mole), elemental sulphur (0.01 mole) in ethanol (30 ml)
and dimethylformamide (5 mL) containing triethylamine (0.5 mL) was heated under reflux for 7 h. then
cooled, poured into crushed ice and acidified with HCl. The solid product, formed in each case, was
filtered off and recrystallized from the proper solvent to give 7a, b.
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5-Amino-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-oxo-3-(4-(N-(thiazol-2-
yl)sulfamoyl)phenyl)-3,4-dihydrothieno[3,4-d]pyri-dazine-1-carboxamide (7a)
It was obtained as dark brown crystals from dioxane; yield 58%; m.p. 297ºC; IR (KBr) ν cm-1
3425, 3348 (NH2), 3256, 3188 (2NH), 3045 (CH-arom.), 2928 (CH-aliph.), 1672, 1665, 1644 (3C=O); 1H
NMR (DMSO-d6) δ = 2.26 (s, 3H, CH3), 3.15 (s, 3H, NCH3), 5.16 (s, 1H, NH2), 6.24 (s, 1H, CH-
thiophene), 7.11- 8.15 (m, 12H, Ar-H+ NH), 11.38 (s, 1H, NH). 13
C NMR (DMSO-d6) δ C = 12.21, 34.42
(2CH3), 103.92, 112.12, 115.18, 117.84, 121.57, 124.45, 125.88, 129.63, 130.14, 131.18, 132.84, 133.35,
136.68, 138.68, 146.62, 150.36, 154.45, 160.41 (Ar-C), 165.47, 168.36, 175.52 (3CO); Anal. Calc. For
C27H22N8O5S3 (634.71): C, 51.09; H, 3.49; N, 17.65; S, 15.16%.Found: C, 51.30; H, 3.69; N, 17.86; S,
15.37%.
5-Amino-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-(4-(N-(4,5-dimethyloxazol-2-
yl)sulfamoyl)phenyl)-4-imino-3,4-dihydro- thieno[3,4-d]pyridazine-1-carboxamide (7b)
It was obtained as green crystals from DMF/ethanol; yield 55%; m.p. 284ºC; IR (KBr): υ cm−1
3412, 3377 (NH2), 3252, 3175 (NH), 3075 (CH-arom.), 2947 (CH-aliph.), 1668, 1652 (2CO); 1
H NMR
(DMSO-d6): δ = 1.72 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.36 (s, 3H, CH3), 3.02 (s, 3H, NCH3), 5.20 (s, 1H,
NH2), 7.21- 8.12 (m, 12H, Ar-H+ 2NH + CH-thiophene), 11.17 (s, 1H, NH). Anal. Calc. For
C29H27N9O5S2 (645.71): C, 53.94; H, 4.21; N, 19.52; S, 9.93%.Found: C, 53.73; H, 4.42; N, 19.75; S,
9.70%.
3-Amino-4-(4-chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-6-methyl-
1H-pyrazolo[3,4-b]pyridine-5-carboxamide (9)
Amixture of pyridinethione 8 (0.01 mole) and excess of hydrazine hydrate (3 mL) was heated
under reflux for 1/2 h, then ethanol (20 mL) was added and complete reflux for 14 h. The solid product
that formed was collected by filtration and recrystallized from dioxane to give 9 as yellow crystals, yield
69%; m.p. 305 ºC. IR (KBr): υ cm−1
3427, 3358 (NH2), 3274, 3212 (2NH), 3060 (CH-arom.), 2954 (CH-
aliph.), 1673, 1650 (2CO). 1H NMR (DMSO-d6): δ = 1.88 (s, 3H, CH3), 2.16 (s, 3H, CH3), 3.01 (s, 3H,
NCH3), 4.32 (s, 2H, NH2), 6.88 –7.75 (m, 9H, Ar-H), 9.44 (s, 1H, NH), 12.25 (s, 1H, NH). 13
C NMR
(DMSO-d6) δ C = 11.64, 22.48, 36.12 (3CH3), 91.52, 104.33, 122.64, 123.24, 125.65, 127.47, 129.34,
130.51, 132.34, 133.28, 135.75, 136.32, 149.22, 150.74, 152.55, 162.17 (Ar-C), 166.37, 168.16 (2CO);
Anal. Calc. for C25H22ClN7O2 (487.94): C, 61.54; H, 4.54; Cl, 7.27; N, 20.09%.Found: C, 61.76; H, 4.75;
Cl, 7.50; N, 20.30%.
10-(4-Chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-8-methyl-4-phenyl-
2-(p-tolyl)pyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxamide (12)
A mixture of compound 9 (0.01 mole) and 3-phenyl-1-(p-tolyl) prop-2-en-1-one (0.01 mole) in
ethanol (30 mL) containing a few drops of piperidine was heated under reflux for 8 h. The solid product
formed after cooling was collected by filtration and recrystallized from ethanol to give (12; 70%) as
yellow crystals; m.p. 195 oC; IR (KBr) ν cm
-1 3255 (NH), 3070 (CH-arom.), 2943 (CH-aliph.), 1692, 1657
(2C=O); 1H NMR (DMSO-d6) δ = 1.78 (s , 3H, CH3), 2.28 (s , 3H, CH3), 2.32 (s , 3H, CH3), 3. 12 (s, 3H,
NCH3), 6.87- 7.96 (m, 19H, Ar-H+ CH-pyrimidine), 9.87 (s, 1H, NH). Anal. Calc. for C41H32ClN7O2
(690.19): C, 71.35; H, 4.67; Cl, 5.14; N, 14.21%.Found: C, 71.56; H, 4.89; Cl, 5.36; N, 14.43%.
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2-Amino-10-(4-chlorophenyl)-3-cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-
8-methyl-4-phenylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxamide (14)
A mixture of compound 9 (0.01 mole) and benzylidinemalononitrile (0.01 mole) in ethanol (30
mL) containing a few drops of piperidine was heated under reflux for 8 h. The solid product formed after
cooling was collected by filtration and recrystallized from ethanol to give 14 as pale yellow crystals from
ethanol; yield 50%; m.p. 208ºC; IR (KBr) ν cm-1
3400, 3365 (NH2), 3225 (NH), 3050 (CH-arom.), 2926
(CH-aliph.), 2215 (CN), 1680, 1645 (2CO); 1
H NMR (DMSO-d6) δ = 1.92 (s, 3H, CH3), 2.18 (s, 3H,
CH3), 3.04 (s, 3H, NCH3), 6.98- 7.94 (m, 16H, Ar-H+ NH2), 10.12 (s, 1H, NH). 13
C NMR (DMSO-d6) δ C
= 11.89, 13.44, 34.36 (3CH3), 115.96 (CN), 88.67, 104.48, 106.31, 122.28, 123.13, 126.65, 127.21,
128.43, 128.85, 129.46, 130.10, 130.23, 130.74, 131.44, 132.77, 133.10, 136.38, 137.43, 139.29, 148.16,
158.82, 159.25, 161.21 (Ar-C), 166.94, 169.25 (2CO); Anal. Calc. for C35H26ClN9O2 (640.09): C, 65.67;
H, 4.09; Cl, 5.54; N, 19.69%. Found: C, 65.87; H, 4.32; Cl, 5.76; N, 19.81%.
2.4 Preparation of Compounds 16-19: General Procedure
To a solution of 9 (0.01 mole) in ethanol (25 mL) containing piperidine (0.5 mL), either acetyl
acetone (0.01 mol), ethyl acetoacetate (0.01 mol), ethyl cyanoacetate (0.01 mol) or malononitrile (0.01
mol) was added. The reaction mixture, in each case, was heated under reflux for 7 h, then cooled, poured
into crushed ice and acidified with HCl. The solid product, formed in each case, was filtered off and
recrystallized from dioxane to afford 16-19.
10-(4-Chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-2,4,8-
trimethylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxamide (16)
It was obtained as brown crystals, yield 60%; m.p. 225ºC; IR (KBr): υ cm−1
3227 (NH), 3052
(CH-arom.), 2943 (CH-aliph.), 1672, 1654 (2CO) ; 1H NMR (DMSO-d6): δ = 1.35 (s, 6H, 2CH3), 2.24 (s,
3H, CH3), 2.33 (s, 3H, CH3), 3.14 (s, 3H, NCH3), 7.03- 7.99 (m, 10H, Ar-H + CH-pyrimidine), 9.68 (s,
1H, NH). 13
C NMR (DMSO-d6) δ C = 12.46, 16.41, 21.74, 24.33, 36.18 (5CH3), 102.69, 104.86, 108.58,
122.43, 123.45, 125.22, 128.68, 128.39, 129.57, 132.12, 133.49, 134.13, 136.35, 138.78, 145.47, 149.46,
154.51, 157.62, 160.35, (Ar-C), 165.26, 168.28 (2CO); Anal. Calc. for C30H26ClN7O2 (552.03): C, 65.27;
H, 4.75; Cl, 6.42; N, 17.76 %.Found: C, 65.48; H, 4.96; Cl, 6.63; N, 17.96%.
10-(4-Chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyra-zol-4-yl)-4-hydroxy-2,8-
dimethylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimidine-9-carboxamide (17)
It was obtained as buff crystals, yield 51%; m.p. 222ºC; IR (KBr): υ cm−1
3500 (OH), 3249 (NH),
3065 (CH-arom.), 2923 (CH-aliph.), 1660, 1647 (2CO); 1H NMR (DMSO-d6): δ = 1.38 (s, 3H, CH3), 2.30
(s, 3H, CH3), 2.41 (s, 3H, CH3), 3.11 (s, 3H, NCH3), 7.12- 7.89 (m, 10H, Ar-H + CH-pyrimidine ), 9.27
(s, 1H, NH), 11.53 (s, 1H, OH). Anal. Calc. for C29H24ClN7O3 (554.00) : C, 62.87; H, 4.37; Cl, 6.40; N,
17.70%.Found: C, 62.65; H, 4.58; Cl, 6.62; N, 17.91%.
2-Amino-10-(4-chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-
hydroxy-8-methylpyrido[2',3':3,4]pyrazolo[1,5-a]pyrimi- dine-9-carboxamide (18)
It was obtained as pale yellow crystals, yield 52%; m.p. 237ºC; IR (KBr): υ cm−1
3500 (OH),
3420, 3375 (NH2), 3200 (NH), 3042 (CH-arom.), 2928 (CH-aliph.), 1664, 1652 (2CO) ; 1H NMR
(DMSO-d6): δ = 1.86 (s, 3H, CH3), 2.43 (s, 3H, CH3), 3.05 (s, 3H, NCH3), 7.16- 7.95 (m, 12H, Ar-H +
NH2+ CH-pyrimidine), 9.62 (s, 1H, NH), 11.25 (s, 1H, OH). Anal. Calc. for C28H23ClN8O3 (554.99): C,
60.60; H, 4.18; Cl, 6.39; N, 20.19%.Found: C, 60.82; H, 4.39; Cl, 6.60; N, 20. 42%.
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2,4-Diamino-10-(4-chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihyd-ro-1H-pyrazol-4-yl)-8-
methylpyrido[2',3':3,4]pyrazolo[1,5-a]pyramidine-9-carboxamide (19)
It was obtained as pale yellow crystals, yield 68%; m.p. 226ºC; IR (KBr): υ cm−1
3430, 3382 (2NH2),
3237 (NH), 3066 (CH-arom.), 2945 (CH-aliph.), 1667, 1648 (2CO) ; 1H NMR (DMSO-d6): δ = 1.26 (s, 3H,
CH3), 2.25 (s, 3H, CH3), 3.15 (s, 3H, NCH3), 6.86 (s, 2H, NH2), 7.24- 7.98 (m, 12H, Ar-H + NH2+ CH-
pyrimidine), 10.38 (s, 1H, NH). Anal. Calc. for C28H24ClN9O2 (554.00): C, 60.70; H, 4.37; Cl, 6.40; N,
22.75%.Found: C, 60.92; H, 4.58; Cl, 6.63; N, 22.56%.
2.5 Preparation of Compounds 21, 22a, b: General Procedure
To a cold solution (0-5ºC) of either ethyl acetoacetate (0.01 mole), malononitrile (0.01 mole) or
ethyl cyanoacetate (0.01 mole) in ethanol (30 mL) containing sodium acetate (2 gm), solution of
diazonium chloride 20 (prepared by adding a cold solution of sodium nitrite (0.01 mol) to a solution of
aminopyrazole 9 (0.01 mole) in HCl (3 mL) with continuous stirring) was added. The reaction mixture, in
each case, was left at room temperature for 2 h with stirring. The solid produ- ct, formed in each case, was
filtered off and recrystallized from the proper solvent to yield 21, 22 a,b.
3-Acetyl-10-(4-chlorophenyl)-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-4-
hydroxy-8-methylpyrido[2',3':3,4]pyrazolo[5,1-c] [1,2,4] triazine-9-carboxamide (21)
It was obtained as brown crystals from DMF / ethanol, yield 61%; m.p. > 300 ºC. IR (KBr): υ
cm−1
3500 (OH), 3216 (NH), 3055 (CH-arom.), 2932 (CH-aliph.) 1715, 1678, 1654 (3CO); 1H NMR
(DMSO-d6): δ = 1.22 (s, 3H, CH3), 2.12 (s, 3H, CH3), 2.35 (s, 3H, COCH3), 3.02 (s, 3H, NCH3), 6.92 -
7.83 (m, 10H, Ar-H+ OH), 10.17 (s, 1H, NH). 13
C NMR (DMSO-d6) δ C = 10.31, 22.65, 27.83, 34.25
(4CH3), 101.81, 105.65, 122.82, 125.14, 126.32, 129.39, 129.77, 132.51, 133.47, 134.72, 135.15, 136.23,
148.36, 151.41, 154.55, 158.64, 159.15, 160.11, (Ar-C), 167.42, 169.22, 190.39 (3CO); Anal. Calc. for
C29H23ClN8O4 (583.00): C, 59.74; H, 3.98; Cl, 6.08; N, 19.22%.Found: C, 59.95; H, 3.75; Cl, 6.29; N,
19.43%.
4-Amino-10-(4-chlorophenyl)-3-cyano-N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-
8-methylpyrido[2',3':3,4]pyrazolo[5,1-c][1,2,4]tri- azine-9-carboxamide (22a)
It was obtained as brown crystals from dioxane; yield 65%; m.p. > 300 ºC; IR (KBr) ν cm-1
3380,
3364 (NH2), 3228 (NH), 3054 (CH-arom.), 2928 (CH-aliph.), 2217 (CN), 1669, 1648 (2C=O); 1H NMR
(DMSO-d6) δ = 1.38 (s, 3H, CH3), 2.23(s, 3H, CH3), 3.03 (s, 3H, NCH3), 6.55 ( s, 2H, NH2), 6.88- 7.74
(m, 9H, Ar-H), 9.17 (s, 1H, NH). Anal. Calc. for C28H21ClN10O2 (564.99): C, 59.52; H, 3.75; Cl, 6.28; N,
24.79%.Found: C, 59.73; H, 3.96; Cl, 6.49; N, 24.58%.
Ethyl4-amino-10-(4-chlorophenyl)-9-((1,5-dimethyl-3-oxo-2-phenyl-2,3- dihydro-1H-pyrazol-4-
yl)carbamoyl)-8-methylpyrido[2',3':3,4]pyrazolo[5,1-c][1,2,4]triazine-3-carboxylate (22b)
It was obtained as buff crystals from dioxane; yield 57%; m.p. 275 ºC; IR (KBr) ν cm-1
3346,
3320 (NH2), 3218 (NH), 3058 (CH-arom.), 2925 (CH-aliph.), 1720, 1682, 1656 (3C=O); 1H NMR
(DMSO-d6) δ = 1.34 (t, 3H, CH3), 2.45 (s, 3H, CH3), 2.77 (s, 3H, CH3), 3.14 (s, 3H, NCH3), 4.07 (q, 2H,
CH2), 6.72 ( s, 2H, NH2), 7.32- 7.87 (m, 9H, Ar-H), 9.76 (s, 1H, NH). Anal. Calc. for C30H26ClN9O4
(612.04): C, 58.87; H, 4.28; Cl, 5.79; N, 20.60%.Found: C, 58.65; H, 4.50; Cl, 5.48; N, 20.82%.
3. RESULTS AND DISCUSSION
Treatment of N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)-3-oxobutanamide
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(1) [28] with diazonium salt has been reported. So, we observed that coupling of compound 1 with
diazotized aromatic amines in ethanol buffered with sodium acetate at 0 ºC afforded the aryl hydrazones
[24,29] 3a,b based on their spectral data. For example, the 1H NMR spectrum of 3a showed the presence
of a multiple signal at δ = 6.89- 8.05 ppm corresponding to aromatic protons and three signals at δ =
10.43, 11.24 and 13.52 ppm corresponding to 3NH groups, It should be emphasized here that the signal
corresponding to NH function of hydrazo group appears at downfield at δ = 13.52 ppm due to the
intramolecular hydrogen bonding with carbonyl group. The IR spectrum of the same product further
supports the hydrozo structure. So, the obtained arylhydrazones have been utilized as starting materials
for preparing the targeted pyridazine ring system. Fusion of aryl hydrazones 3a,b with either
malononitrile (4a) or ethyl cyanoacetate (4b) in the presence of ammonium acetate over melting point for
one hour afforded the pyridazine derivatives 6a–d. The structures of 6a-d were confirmed based on
elemental analysis and spectral data. Thus, the IR spectrum of compound 6a, for example, indicated the
presence of the absorption band of the CN functional group at υ 2205 cm−1
. The 1H NMR spectrum of
compound 6a revealed the presence of a multiplet signal at δ = 7.25- 8.12 ppm corresponding to aromatic
protons, NH group and singlet signals at δ 10.15, 11.82 ppm assigned to 2NH groups beside the signals
assigned to CH3 protons in the molecule. Also, 13
C NMR of the structure revealed signals at 10.54, 13.15,
34.61 ppm (3CH3), 116.12 ppm (CN), 167.21, 169.75 ppm (2C=O), in addition to the sp2 carbon atoms as
in the experimental section. (Scheme 1 and Experimental part).
N
N
O
CH3
CH3
Ph
NH
O O
CH3
N
N
O
CH3
CH3
Ph
NH
O
NN
CH3
Ar
X
CN
N
N
O
CH3
CH3
Ph
NH
O O
CH3
NNH
Ar
N
N
O
CH3
CH3
Ph
NH
OCH
3
N
NH
Ar
OH
X
CN
Ar-N=NCl
3
1
CNCH2XAcONH4
5
4a,x = CN
b,x = COOC2H5
2, 3 a, Ar= C6H4- SO2NH-thiazol-2-yl
b, Ar= C6H4-SO2NH-(4,5-dimethyloxazol-2-yl)
6 a, Ar= C6H4-SO2NH-thiazol-2-yl , X= NH
b, Ar= C6H4-SO2NH-thiazol-2-yl , X=O
c, Ar= C6H4-SO2NH-(4,5-dimethyloxazol-2-yl) , X= NH
Ar= C6H4-SO2NH-(4,5-dimethyloxazol-2-yl) , X= Od,
a-d
a,b
6
2
Scheme 1: Synthesis of pyridazines
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The formation of 6 from 3 is assumed to proceed via intermediate of non isolable 5. The
pyridazine derivatives 6b,c were used as starting material to obtain some fused azines [30]. Thus, the
dihydropyridazines 6b,c were reacted with elemental sulphur in ethanol containing little amount of
triethylamine to afford the thienopyridazine derivatives 7a,b. The structures of 7a,b were confirmed
based on elemental analysis and spectral data. The IR spectrum of compound 7a, for example, exhibited
the disappearance of the absorption band due to the CN function group and the appearance of absorption
band due to the NH2 functional group at υ 3425, 3348 cm−1
. 1
H NMR spectrum of compound 7a revealed
a singlet signal at δ 5.16 ppm assigned to NH2, singlet signal at δ 6.24 ppm assigned to CH-thiophene and
a multiplet signals at δ 7.11- 8.15 ppm assigned to aromatic protons, Also, 13
C NMR of the structure
revealed signals at 12.21, 34.42 ppm (2CH3) , 165.47, 168.36, 175.52 ppm (3C=O), and absence of CN
carbon atom, in addition to the sp2 carbon atoms as in the experimental section (Scheme 2 and
Experimental part).
S
EtOH / T. E. A
S
NN
NH2
X
N
N
O
CH3
CH3
Ph
NH
O
Ar
7
6 b,c
a, Ar= C6H4-SO2NH-thiazol-2-yl , X=O
b, Ar= C6H4-SO2NH-(4,5-dimethyloxazol-2-yl) , X= NH
Scheme 2: synthesis of thienopyridazines
7 a,b
This work was extended to study the reactivity of 827
towards hydrazine hydrate as binucleophile.
Thus, treatment of 8 with hydrazine hydrate in boiling ethanol afforded a sulfur free reaction product 9.
The IR spectrum of this reaction product showed the presence of absorption peaks at υ cm−1
3427, 3358
(NH2), 3274, 3212 (2NH) and the absence of any absorption peak in the range of 2190- 2250 cm−1
due to
CN group. The 1H NMR spectrum of 9 revealed the presence of two protons as a singlet at δ = 4.32 ppm
assignable to the NH2 group and signals at δ = 9.44, 12.25 ppm assigned to 2NH beside the other protons
in their proper positions (Scheme 3).
NH
N
N
O
CH3CH
3
Ph
O
NH
CH3
S
CN
Cl
NH2NH
2
NNH
N
N
O
CH3
CH3
Ph
O
N
NH
CH3
Cl
NH2
98
EtOH
reflux
Scheme 3: synthesis of pyrazolopyridine
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Aim to prepare polyfunctionally substituted polycondensed pyridines, we report synthesis of
several new pyridopyrazolopyrimidines via reaction of aminopyrazolopyridine 9 with non-symmetrical
double bond system and with different active methylene reagents. Thus, the aminopyrazolopyridine 9
reacted with arylidineacetophenone to give pyridopyrazolopyrimidine derivative 12. The analytical and
spectral data are in agreement with the proposed structure (Scheme 4 and Experimental part). Formation
of 12 is assumed to proceed via an initial Michael addition of the endocylic NH in 9 with
arylidineacetophenone followed by intramolecular cyclodehydration and spontaneous auto-oxidation
under the reaction conditions. It should be pointed out that the reaction of 9 with arylidineacetophenone
might involve the exocyclic amino group. However, the involvement of the endocyclic pyrazole-NH was
considered based on the literature [31, 32] reported that the ring NH in aminopyrazole is the most reactive
center in the molecule. Similarly, the reaction of 9 with benzylidinemalononitrile in ethanolic piperidine
afforded the pyridopyrazolo-pyrimidine derivative 14. The IR spectrum of 14 exhibited the presence of
the absorption band due to the CN function group. The formation of compound 14 is assumed to proceed
via an initial Michael addition of the endocylic NH in 9 to the active double bond in
benzylidinemalononitrile to yield the intermediate 13 followed by intramolecular cyclization and
aromatized by a loss of hydrogen molecule to the final product 14 (Scheme 4).
N
N
O
CH3CH
3
PhN
O
N
NH
CH3
Cl
N
Ph
H
CN
NNH2
Ph
CN
CN
Ar
O
Ph
EtOH / Pip.
EtOH / Pip.
-H2O
-H2
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
NH2
Ph
CN
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
Ar
Ph
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
Ar
Ph
ArO
N
NH2
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
Ph
9
10
..
11
14
10, 11 and 12 , Ar = C6H4-CH3-p
13
12
Scheme 4: Synthesis of pyridopyrazolopyrimidines
Our investigation was extended to include the reactivity of the aminopyrazole 9 towards active
methylene compounds, namely, acetyl acetone, ethyl acetoacetate, ethyl cyanoacetate in ethanolic
piperidine to yield pyridopyrazolopyrimidine derivatives 16-18 [33], and with malononitrile to yield the
diaminopyridopyrazolopyrimidine derivative 19. The structures of 16–19 were confirmed based on
elemental analysis and spectral data (cf. Scheme 5 and Experimental part).
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N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
CH3
CH3
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
CH3
OH
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
OH
NH2
N
N
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
NH2
NH2
CH3COCH
2COCH
3
COOC2H
5
COCH3
COOC2H
5
CN
CNNC
EtOH / Pip.
EtOH / Pip.
EtOH / Pip.
N
NH2
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
CH3
CH3O
-H2O
9
15 16
17
18
19
Scheme 5: Synthesis of pyridopyrazolopyrimidines
The IR spectrum of 16, for example, indicated the absence of the absorption band due to the NH2
group. The 1H NMR spectrum of the same product revealed the absence of any signals may be attributed
to NH2 and pyrazole-NH protons. Furthermore, the structure of compound 16 was supported by 13
C NMR
spectrum (Scheme 5 and Experimental part).
The formation of compound 16 is assumed to proceed via the condensation of the endocylic NH
in 9 with acetyl acetone followed by intramolecular cyclization through dehydration (Scheme 5).
Moreover, the diazotization of 9 and its reactions with active methylene reagents have been studied to
develop a synthetic approach to polyfunctionality substituted fused heterocycles. Thus, coupling of
different active methylene reagents such as ethyl acetoacetate, malononitrile and ethyl cyanoacetate with
diazotized amino group in compound 9 afforded the pyridopyrazolotriazine derivatives 21 and 22a,b. 1
H
NMR spectra of 21 revealed the disappearance of the signal corresponding to NH2 group. Also, the 13
C
NMR of compound 21 revealed a signal at high downfield at 190.39 ppm assigned to acetyl carbonyl
group (cf. Scheme 6 and Experimental part).
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NHNN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
N2Cl
N
NN
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
NH2
X
N
NN
NN
N
N
O
CH3
CH3
Ph
NH
O
CH3
Cl
OH
COCH3
NaNO2 / HCl
X CN
EtOH / CH3COONa
CH3COCH
2COOC
2H
5
EtOH / CH3COONa
9
21
22 a, x = CN
b, x = COOC2H5
+ -
20
Scheme 6: Synthesis of pyridopyrazolotriazines
22a,b
3.1 Antimicrobial Activity
Thirteen compounds were screened in vitro for their antimicrobial activities against two strains of
bacteria (Gram positive bacteria; Bacillus cereus (G + ve), and Gram negative bacteria; Klebsiella
pneumonia (G − ve) and one fungal specie (Aspergillus flavus) using the filter paper disc method [34].
The filter paper disc method was performed in nutrient agar for bacteria and Dox agar for fungi. These
agar media were inoculated with 0.5 mL of the 24 h. liquid cultures. Filter paper discs (5mm diameter)
saturated with each compound solution (10 mg/mL of DMSO) was placed on the indicated agar media.
The incubation time was (48 h at 37 °C for bacteria and 72 h at 28 °C for fungi). Discs saturated with
DMSO were used as control. Ciprofloxacin flucoral was used as a reference substance. The diameter of
inhibition zones (mm) were measured and recorded. The results revealed that all the tested compounds
were found to possess various antimicrobial activities towards the entire microorganisms used (Table 1).
Compound 7a exhibited the highest inhibitory activity against Bacillus cereus (G +ve), compound 12 was
found to be very active against Klebsiella pneumonia (G − ve). In addition, compounds 6a, 12, 21
revealed a moderate activity against Bacillus cereus (G +ve). Compounds 6, 16 showed a moderate
activity against Klebsiella pneumonia (G -ve), compounds 9, 19 showed a moderate activity against
Aspergillus flavus. Moreover, compounds 3a, 6b, 7b, 14, 16 and 22a showed the lowest inhibitory
activity against Bacillus cereus (G +ve), compounds 3a, 6a, 7a, 17, 19 and 22a are less active towards
Klebsiella pneumonia (G -ve). Whereas compounds 6a, 7a, 12, 17 exhibited the lowest inhibitory activity
towards Aspergillus flavus. The results indicated that most of the synthesized compounds exhibited
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noticeable antimicrobial activity, and that the bacterial isolates were less active to the synthesized
compounds than the fungal specie.
Table1. Antimicrobial activities of some newly synthesized compounds.
Compd. Gram positive bacteria Gram negative bacteria Fungi
No.
Bacillus Klebsiella Aspergillus
cereus pneumonia flavus
3a + + -
6a ++ + +
6b + - -
7a +++ + +
7b + - -
9 - ++ ++
12 ++ +++ +
14 + - -
16 + ++ -
17 - + +
19 - + ++
21 ++ - -
22a + + -
DMF - - -
Ciprofloxacin ++++ ++++ ++++
Flucoral
Inhibition Zone = 0.1 - 0.5 cm beyond control = + (slightly active); Inhibition Zone = 0.6 - 1.0 cm beyond
control = + + (moderately active); Inhibition Zone = 1.1 - 1.5 cm beyond control = + + + (highly active);
Inhibition Zone = 0.0 cm beyond control = − (inactive).
4. CONCLUSION
The achieved derivatives of new hydrazo, pyridazine, thienopyridazine, pyrazolopyridine,
pyridopyrazolopyrimidine, and pyridopyrazolotriazine that are expected to have biological activities,
have been synthesized and their structures confirmed by their spectral data, elemental analyses, and
with some chemical reactions.
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The authors declare no conflict of interest
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