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Borderless Science Publishing 504

Canadian Chemical Transactions Year 2014 | Volume 2 | Issue 4 | Page 504-517

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

mailto:[email protected]

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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)


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-dihydrothieno[3,4-d]pyridazine-1-carboxamide (7b)


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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Canadian Chemical Transactions Year 2014 | Volume 2 | Issue 4 | 04-517


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]pyrimidine-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 product, 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]triazine-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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