Synthesis, characterization and antihypertensive activity of pyridazinone derivatives

Article abstract of DOI:10.1016/j.ejmech.2010.02.003

Some 6-(substituted-phenyl)-2-(substitutedmethyl)-4,5-dihydropyridazin-3(2H)-one derivatives were synthesized by reacting 6-substituted-phenyl-4,5-dihydropyridazin-3(2H)-one with cyclic secondary amine under Mannich reaction conditions. The final compounds (15-70) were evaluated for antihypertensive activities by non-invasive method using Tail Cuff method. The compounds 16, 19, 24, 30, 39, 42 and 45 showed good antihypertensive activity.

Full text of DOI:10.1016/j.ejmech.2010.02.003

European Journal of Medicinal Chemistry 45 (2010) 2283–2290
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis, characterization and antihypertensive activity of
pyridazinone derivatives
*
Anees A. Siddiqui , Ravinesh Mishra, Mohammad Shaharyar
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Jamia Hamdard (Hamdard University), Hamdard Nagar, New Delhi-110062, (India)
a r t i c l e i n f o
a b s t r a c t
Article history:
Some 6-(substituted-phenyl)-2-(substitutedmethyl)-4,5-dihydropyridazin-3(2H)-one derivatives were
synthesized by reacting 6-substituted-phenyl-4,5-dihydropyridazin-3(2H)-one with cyclic secondary
amine under Mannich reaction conditions. The final compounds (15–70) were evaluated for antihy-
pertensive activities by non-invasive method using Tail Cuff method. The compounds 16, 19, 24, 30, 39,
42 and 45 showed good antihypertensive activity.
Received 9 December 2009
Received in revised form
29 January 2010
Accepted 1 February 2010
Available online 6 February 2010
Ó 2010 Elsevier Masson SAS. All rights reserved.
Keywords:
b
-Aroyl propionic acid
Pyridazinone
Antihypertensive activity
Non invasive method
1. Introduction
propionic acid in presence of Lewis acid, aluminium chloride. The
resulting b-benzoyl propionic acids (1–7) on hydrazinolysis gave
Pyridazinone derivatives were reported to exhibit diverse
pharmacological activities such as antidepressant [1], antihyper-
tensive [2,3], antithrombotic [4], anticonvulsant [5], cardiotonic
[6], antibacterial [7], diuretics [8], antiHIV [9] and anticancer [10].
Some pyridazinone derivatives like indolidan [11], bemoradan
[12], primobendan [13], levosimendan [14] (antihypertensive),
minaprine [15] (antidepressant), emorfazone [16] (antiin-
flammatory), and azanrinone [17] (cardiotonic), already appeared
in the clinical market. During our literature survey, it is observed
that various pyridazinone derivatives possess antihypertensive
activity due to vasorelaxant activity. Considering the 6-phenyl-
3(2H)-pyridazinone residue as the pharmacophoric group for the
activity, we have synthesized some new pyridazinone derivatives
and evaluated them for antihypertensive activity by non-invasive
method.
the pyridazinones (8–14). The pyridazinones were subjected to
Mannich reaction with cyclic secondary amine and formaldehyde
to get the final compounds (15–70) (Table 1).
3. Result and discussion
The final compounds (15–70) were structurally elucidated on
the basis of spectral data, explained with the example of compound
23. The IR spectra revealed presence of band at 1685 cmꢀ1 (C]O)
and 1600 cmꢀ1 (C]N). The 1H NMR showed singlet at
d
2.29 for
methyl group attached to phenyl ring. The two triplets at 2.62,
d
J ¼ 8.7 and 2.76, J ¼ 8.7 confirmed the presence of methylene group
at 4 and 5 position of pyridazinone ring respectively. The multiplets
at
methylene ring each for –CH2–N–CH2– and –CH2–O–CH2– moiety
respectively. The singlet at 4.78 is due to methylene group flanked
by two nitrogen atoms. In the aromatic region two double doublets
(dd) appeared at
d 2.80–3.10 and d 3.59–3.79 are indicative of 4 protons of
d
2. Chemistry
d
7.43, J ¼ 8.2 and 7.73, J ¼ 8.2 are due to equivalent
protons at H-30 & H-50 and H-20 & H-60 of p-disubstituted phenyl
ring attached at 6th position respectively. The mass spectrum
shows the presence of peak at m/z 287 accordance to the molecular
formula, C16H21N3O2. The structure is also supported by elemental
analysis data and 13C NMR data. The 13C NMR showed the peaks at
Some 6-(substituted-phenyl)-2-(substitutedmethyl)-4,5-dihy-
dropyridazin-3(2H)-one derivatives are synthesized according to
Scheme 1. The Friedel–Craft acylation of aromatic hydrocarbon
with succinic anhydride afforded the
b-substituted benzoyl
d
176 and
d 155 for carbonyl carbon (C-3) and tertiary carbon (C-6).
* Corresponding author. Tel.: þ91 11 26059688/5650; fax: þ91 11 27048685.
E-mail address: anees_56@yahoo.co.in (A.A. Siddiqui).
The other compounds are also identified in a similar manner,
0223-5234/$ – see front matter Ó 2010 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2010.02.003

2284
A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
R
O
Elementar (Vario EL III) using sulphanilic acid as a standard and
tugsten (VI) oxide as a combusting agent and analyses for C, H, N
were within ꢁ0.4% of the theoretical values.
O
Anhydrous AlCl
3
R
O
+
OH
O
O
4.1.1. General procedure for the synthesis of substituted b-aroyl
propionic acids (1–7)
1-7
Aromatic hydrocarbon Succinic anhydride
The substituted b-aroyl propionic acids (1–7) were synthesized
from respective aromatic hydrocarbon and characterized on the
basis of spectral data as per reported procedure [19,20].
NH NH .H O
2
2
2
R
4.1.2. General procedure for the synthesis of 6-substituted-phenyl-
R
4,5-dihydropyridazin-3(2H)-one (8–14)
HCHO
The appropriate substituted b-aroyl propionic acids were reac-
ted with hydrazine hydrate to get corresponding pyridazinone and
characterized on the basis of spectral data as per earlier reported
procedure [19,20].
Cyclic secondary amine
N
N
NH
N
1
O
R
O
4.1.3. General procedure for the preparation of 6-(substituted-
phenyl)-2-(substitutedmethyl)-4,5-dihydropyridazin-3(2H)-one
(15–70)
15-70
8-14
Compd no.
1,8
R
H
Compd no.
5,12
R
To a solution of 6-substituedphenyl-4,5-dihydropyridazine-
3(2H)-one (0.001 mol) in absolute ethanol (30 mL), formaldehyde
(37–41%) (1.5 mL) and cyclic secondary amine (0.001 mol) were
added and the contents refluxed for 24 h. After completion of the
reaction, ethanol was distilled off and the residue poured into
crushed ice and kept in refrigerator for overnight to separate out
the compound. The solid which separated out, was filtered and
recrystallized from ethanol.
CH2CH(CH3)2
2,9
CH3
OCH3
C2H5
6,13
C6H5
Cl
3,10
7,14
4,11
Scheme 1. Synthesis of 6-(substituted-phenyl)-2-(substitutedmethyl)-4,5-dihy-
dropyridazin-3(2H)-one derivatives.
4.1.3.1. 6-Phenyl-2-(morpholin-4-ylmethyl)-4,5-dihydropyridazin-
3(2H)-one (15). Morpholine was used as cyclic secondary amine for
Mannich reaction. Yield: 72%; m.p. 103–104 ꢂC; IR (KBr) ymax
(cmꢀ1): 2964 (CH), 1665 (C]O), 1446 (C]C); 1H NMR (CDCl3)
except compounds substituted with aromatic amines like indole,
phenothiazine, 1,2,4-triazole which showed the multiplet in
aromatic region.
The final compounds (15–70) were evaluated for antihyper-
tensive activity by non-invasive method using Tail Cuff method. The
results were shown in Table 1 and compared with standard drug,
hydralazine [18]. Compound number 16, 19, 24, 30, 39, 42 and 45
were found to show highly significant reduction in mean arterial
blood pressure but at higher dose in comparison to hydralazine.
On the basis of activity reported, it can be concluded that groups
like p-CH3, p-C2H5 in phenyl ring at 6-position increases the activity
as shown by the compound 16, 19, 24, 30, 39, 42 and 45. The various
cyclic secondary amine at 2-position in a methylene group does not
affect the antihypertensive activity. For example, the compound 16,
19, 30, 39, 42 and 45 possessing N-piperazine, N-phenothiazine,
N-(1,2,4-triazole), N-morpholine, N-(4-N-methylpiperazine) and
N-pyrrolidine at 2-position respectively showed good antihyper-
tensive activity.
d
(ppm): 2.60 (t, J ¼ 7.8, 2H, C–CH2), 2.73 (t, J ¼ 7.8, 2H, CH2–CO),
2.85–3.05 (m, 4H, 2 ꢃ CH2), 3.59–3.79 (m, 4H, CH2–O–CH2), 4.78 (s,
2H, –N–CH2–N–), 7.33–7.53 (m, 3H, Ar–H), 7.63–7.83 (m, 2H, Ar–H);
Ms (m/z): 273/274 (Mþ/Mþ þ 1), 187 (100%), 100 (60%), 96 (30%).
Anal. Calc. for C15H19N3O2: C: 65.91, H: 7.01, N: 15.37. Found: C:
65.88, H: 7.10, N: 15.32.
4.1.3.2. 6-Phenyl-2-(piperazin-1-ylmethyl)-4,5-dihydropyridazin-
3(2H)-one (16). Piperazine was used as cyclic secondary amine for
Mannich reaction. Yield: 52%; m.p.117–118 ꢂC; IR (KBr) ymax (cmꢀ1):
3325 (NH), 2964 (CH), 1661 (C]O), 1424 (C]C); 1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.7, 2H, C–CH2), 2.69–2.89 (m, 8H, 4 ꢃ CH2), 2.97
(t, J ¼ 7.7, 2H, CH2–CO), 5.2 (s, 2H, –N–CH2–N–), 7.26–7.36 (m, 3H,
Ar–H), 7.64–7.84 (m, 2H, Ar–H), 9.7 (s, 1H, NH); Ms (m/z): 272/273
(Mþ/Mþ þ 1), 187 (100%), 99 (40%). Anal. Calc. for C16H21N3O: C:
66.15, H: 7.40, N: 20.57. Fond: C: 66.08, H: 7.36, N: 20.49.
4. Experimental protocols
4.1.3.3. 6-Phenyl-2-(piperidin-1-ylmethyl)-4,5-dihydropyridazin-
3(2H)-one (17). Piperidine was used as cyclic secondary amine for
Mannich reaction. Yield: 48%; m.p. 104–106 ꢂC; IR (KBr) ymax
(cmꢀ1): 2933 (CH), 1677 (C]O), 1425 (C]C); 1H NMR (CDCl3)
4.1. Chemistry
Melting points were determined by open tube capillary method
and are uncorrected. Purity of the compounds was checked by thin
layer chromatography (TLC) plates (silica gel G) which were
visualized by exposing to iodine vapors and UV light. The FT-IR
spectra were recorded on Bio-rad FTS-135 spectrophotometer
using KBr pellets; ymax values are given in cmꢀ1. 1H NMR and 13C
NMR spectra were recorded on Bruker Spectrospin DPX 300 MHz
using CDCl3 as solvent and tetramethylsilane (TMS) as an internal
d
(ppm): 2.61 (t, J ¼ 7.8, 2H, C–CH2), 2.55–2.75 (m, 6H, 3 ꢃ CH2),
2.89 (t, J ¼ 7.8, 2H, CH2–CO), 2.92–3.04 (m, 4H, 2 ꢃ CH2), 5.2 (s, 2H,
–N–CH2–N–), 7.30–7.50 (m, 3H, Ar–H), 7.64–7.84 (m, 2H, Ar–H); Ms
(m/z): 271/272 (Mþ/Mþ þ 1), 187 (100%), 98 (40%), 96 (40%). Anal.
Calc. for C16H21N3O: C: 70.82, H: 7.80, N: 15.49. Found: C: 70.80, H:
7.75, N: 15.46.
standard. Chemical shifts are given in
d
(ppm) scale and coupling
4.1.3.4. 6-Phenyl-2-[(4-methylpiperazin-1-yl)methyl]-4,5-dihy-
dropyridazin-3(2H)-one (18). 1-Methylpiperazine was used as
cyclic secondary amine for Mannich reaction. Yield: 56%; m.p. 109–
110 ꢂC; IR (KBr) ymax (cmꢀ1): 3002 (CH), 1675 (C]O), 1500 (C]N);
constants (J values) are expressed in Hz. The FAB Mass spectra were
obtained on JEOL-JMS-DX 303 system, equipped with direct
inlet probe system. Elemental analysis was carried out on CHNS

A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
2285
Table 1
Mean arterial pressure (mm Hg) and substituents of compounds (15–70)
1
R
2
1
N
N
R
O
6
3
4
5
.
Compound (20 mg/kg)
MAP (Mean ꢁ SEM)
% Reduction in MAP
R
R1
Control
Toxic control
101.33 ꢁ 4.64
162.33 ꢁ 4.02**
96.16 ꢁ 4.70**
111.66 ꢁ 10.28**
94.16 ꢁ 6.36**
108 ꢁ 12.76**
97.5 ꢁ 6.18**
93.5 ꢁ 3.09**
136.66 ꢁ 1.76*
131.3 ꢁ 2.06**
99.5 ꢁ 5.54**
139.4 ꢁ 6.83ns
95.8 ꢁ 2.15**
104.6 ꢁ 2.78**
98.8 ꢁ 2.41**
105.6 ꢁ 3.86**
123.6 ꢁ 3.18**
110.8 ꢁ 2.65**
95.5 ꢁ 1.93**
114 ꢁ 6.60**
Hydralazinea
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
56
61
62
63
64
65
66
67
68
69
70
40.76
31.21
41.99
33.46
39.93
42.40
15.81
19.11
38.70
14.12
40.98
35.56
39.13
34.94
23.85
31.74
41.16
29.77
35.44
27.16
36.05
33.83
32.72
31.62
29.27
47.31
36.05
30.51
47.14
36.17
32.97
44.31
29.52
24.22
32.48
16.09
28.29
25.58
28.91
32.97
34.94
29.52
30.14
29.52
25.58
25.91
33.46
30.14
39.50
25.83
28.78
24.84
39.50
38.88
36.30
30.01
29.77
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
OCH3
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
C2H5
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
–CH2CH(CH3)2
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
Cl
Cl
Cl
Cl
Cl
N-Morpholine
N-Piperazine
N-Piperidine
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
N-Piperidine
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
104.8 ꢁ 3.92**
118 ꢁ 7.56**
N-Piperidine
103.8 ꢁ 4.59**
107.4 ꢁ 5.54**
109.2 ꢁ 7.32**
111 ꢁ 6.67**
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
114.8 ꢁ 6.28**
114.4 ꢁ 5.49**
113.4 ꢁ 4.79**
114.4 ꢁ 3.65**
120.8 ꢁ 3.66**
121 ꢁ 3.93**
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
N-Piperidine
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
108 ꢁ 7.92**
113.4 ꢁ 6.83**
98.2 ꢁ 7.25**
85.4 ꢁ 1.77**
103.8 ꢁ 4.43**
112.8 ꢁ 3.92**
85.8 ꢁ 1.11**
103.6 ꢁ 5.67**
108.8 ꢁ 3.77**
90.4 ꢁ 2.029**
114.4 ꢁ 5.54**
120.4 ꢁ 7.38**
115.6 ꢁ 4.79**
122 ꢁ 4.85**
N-Pyrrolidine
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
N-Piperidine
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
N-Piperidine
98.2 ꢁ 1.56**
99.2 ꢁ 2.57**
103.4 ꢁ 1.88**
113.6 ꢁ 7.78**
114 ꢁ 5.96**
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
N-(1,2,4-triazole)
N-Morpholine
N-Piperazine
123 ꢁ 4.02**
109.6 ꢁ 6.17**
136.2 ꢁ 2.90**
116.4 ꢁ 6.615**
120.8 ꢁ 4.07**
115.4 ꢁ 5.25**
108.8 ꢁ 5.00**
105.6 ꢁ 7.52**
N-Piperidine
N-(4-N-Methylpiperazine)
N-Phenothiazine
N-Indole
N-Pyrrolidine
N-(1,2,4-triazole)
Cl
Cl
Cl
All values were expressed as Mean ꢁ SEM (*p ꢄ 0.05), each group comprised of 5 animals (i.e. n ¼ 5).
Toxic control group was compared with control group. All the treatment groups were compared with toxic control group and p < 0.05 was considered to be significant.
**p < 0.01, *p < 0.05 and nsnon significant.
a
Dose of hydralazine was taken as 2.6 mg/kg [18].

2286
A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
1H NMR (CDCl3)
d
(ppm): 2.2 (s, 1H, N–CH3), 2.55 (t, J ¼ 7.9, 2H,
H-60), 9.3 (br s, 1H, NH); Ms (m/z): 286/287 (Mþ/Mþ þ 1). Anal. Calc.
for C16H22N4O: C: 67.11, H: 7.74, N: 19.56. Fond: C: 66.96, H: 7.64, N:
19.50.
C–CH2), 2.91 (t, J ¼ 7.9, 2H, CH2–CO), 2.92–3.10 (m, 4H, 2 ꢃ CH2),
3.25–3.35 (m, 4H, 2 ꢃ CH2), 5.20 (s, 2H, –N–CH2–N–), 7.29–7.49 (m,
3H, Ar–H), 7.60–7.80 (m, 2H, Ar–H); Ms (m/z): 286/287 (Mþ/
M
þ þ 1), 187 (100%), 99 (20%). Anal. Calc. for C16H22N4O: C: 67.11, H:
4.1.3.11. 6-(4-Methylphenyl)-2-(piperidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (25). Piperidine was used as cyclic
secondary amine for Mannich reaction. Yield: 41%; m.p. 123–
125 ꢂC; IR (KBr) ymax (cmꢀ1): 2936 (CH), 1660 (C]O), 1420 (C]C);
7.74, N: 19.56. Found: C: 67.10, H: 7.63, N: 19.46.
4.1.3.5. 6-Phenyl-2-(1,2-dihydro-10H-phenothiazin-10-ylmethyl)-
4,5-dihydropyridazin-3(2H)-one (19). Phenothiazine was used as
cyclic secondary amine for Mannich reaction. Yield: 64%; m.p.
88–90 ꢂC; IR (KBr) ymax (cmꢀ1): 2965 (CH), 1661 (C]O), 1631
1H NMR (CDCl3)
d
(ppm): 2.26 (s, 3H, CH3), 2.63 (t, J ¼ 7.8, 2H,
C–CH2), 2.58–2.78 (m, 6H, 3 ꢃ CH2), 2.90 (t, J ¼ 7.8, 2H, CH2–CO),
2.90–3.12 (m, 4H, 2 ꢃ CH2), 5.18 (s, 2H, –N–CH2–N–), 7.38 (dd,
J ¼ 8.4, 2H, H-30, H-50), 7.72 (dd, J ¼ 8.4, 2H, H-20, H-60); Ms (m/z):
285/286 (Mþ/Mþ þ 1). Anal. Calc. for C17H23N3O: C: 71.56, H: 8.12,
N: 14.72. Found: C: 71.38, H: 7.96, N: 14.52.
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.62 (t, J ¼ 7.8, 2H, C–CH2), 2.99
(t, J ¼ 7.8, 2H, CH2–CO), 5.39 (s, 2H, –N–CH2–N–), 6.99–7.80 (m, 13H,
Ar–H); Ms (m/z): 385/386 (Mþ/Mþ þ 1). Anal. Calc. for C23H19N3OS:
C: 71.66, H: 4.97, N: 10.90. Found: C: 71.56, H: 4.88, N: 10.78.
4.1.3.12. 6-(4-Methylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-
4,5-dihydropyridazin-3(2H)-one (26). 1-Methylpiperazine was
used as cyclic secondary amine for Mannich reaction. Yield: 52%;
m.p. 119–120 ꢂC; IR (KBr) ymax (cmꢀ1): 3002 (CH), 1675 (C]O),
4.1.3.6. 6-Phenyl-2-(1H-indol-1-ylmethyl)-4,5-dihydropyridazin-
3(2H)-one (20). Indole was used as cyclic secondary amine for
Mannich reaction. Yield: 40%; m.p. 98–100 ꢂC; IR (KBr) ymax (cmꢀ1):
2998 (CH), 1680 (C]O), 1590 (C]N); 1H NMR (CDCl3)
d
(ppm): 2.63
1500 (C]N); 1H NMR (CDCl3)
d (ppm): 2.25 (s, 1H, N–CH3), 2.34
(t, J ¼ 7.6, 2H, C–CH2), 2.97 (t, J ¼ 7.6, 2H, CH2–CO), 5.30 (s, 2H, –N–
CH2–N–), 7.42–7.78 (m, 11H, Ar–H); Ms (m/z): 303/304 (Mþ/
Mþ þ 1). Anal. Calc. for C19H17N3O: C: 75.23, H: 5.65, N: 13.85.
Found: C: 75.18, H: 5.54, N: 13.72.
(s, 3H, CH3), 2.52 (t, J ¼ 7.7, 2H, C–CH2), 2.90 (t, J ¼ 7.7, 2H,
CH2–CO), 3.04–3.20 (m, 4H, 2 ꢃ CH2), 3.22–3.42 (m, 4H, 2 ꢃ CH2),
5.18 (s, 2H, –N–CH2–N–), 7.42 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.76
(dd, J ¼ 8.4, 2H, H-20, H-60); Ms (m/z): 300/301 (Mþ/Mþ þ 1). Anal.
Calc. for C17H24N4O: C: 67.97, H: 8.05, N: 18.65. Found: C: 67.84, H:
7.88, N: 18.54.
4.1.3.7. 6-Phenyl-2-(pyrrolidin-1-ylmethyl)-4,5-dihydropyridazin-
3(2H)-one (21). Pyrrolidine was used as cyclic secondary amine for
Mannich reaction. Yield: 43%; m.p. 118–120 ꢂC; IR (KBr) ymax
(cmꢀ1): 3006 (CH), 1682 (C]O), 1580 (C]N); 1H NMR (CDCl3)
4.1.3.13. 6-(4-Methylphenyl)-2-(1,2-dihydro-10H-phenothiazin-10-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (27). Phenothiazine was
used as cyclic secondary amine for Mannich reaction. Yield: 62%;
m.p. 100–102 ꢂC; IR (KBr) ymax (cmꢀ1): 3000 (CH), 1672 (C]O), 1510
d
(ppm): 2.61 (t, J ¼ 7.7, 2H, C–CH2), 2.95 (t, J ¼ 7.7, 2H, CH2–CO),
2.90–3.12 (m, 8H, 4 ꢃ CH2), 5.36 (s, 2H, –N–CH2–N–), 7.30–7.48 (m,
3H, Ar–H), 7.68–7.80 (m, 2H, Ar–H); Ms (m/z): 257/258 (Mþ/
Mþ þ 1). Anal. Calc. for C15H19N3O: C: 70.01, H: 7.44, N: 16.33.
Found: C: 69.88, H: 7.34, N: 16.22.
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.35 (s, 3H, CH3), 2.60 (t, J ¼ 7.8,
2H, C–CH2), 2.98 (t, J ¼ 7.8, 2H, CH2–CO), 5.40 (s, 2H, –N–CH2–N–),
6.92–7.78 (m, 12H, Ar–H); Ms (m/z): 399/400 (Mþ/Mþ þ 1). Anal.
Calc. for C24H21N3OS: C: 72.15, H: 5.30, N: 10.52. Found: C: 71.98, H:
5.28, N: 10.36.
4.1.3.8. 6-Phenyl-2-(1,2,4-triazolin-1-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (22). 1,2,4-Triazole was used as cyclic secondary
amine for Mannich reaction. Yield: 50%; m.p. 120–122 ꢂC; IR (KBr)
ymax (cmꢀ1): 3010 (CH), 1680 (C]O), 1590 (C]N); 1H NMR (CDCl3)
4.1.3.14. 6-(4-Methylphenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (28). Indole was used as cyclic secondary
amine for Mannich reaction. Yield: 44%; m.p. 105–107 ꢂC; IR (KBr)
ymax (cmꢀ1): 2995 (CH), 1680 (C]O), 1570 (C]N); 1H NMR (CDCl3)
d
(ppm): 2.66 (t, J ¼ 7.8, 2H, C–CH2), 3.0 (t, J ¼ 7.8, 2H, CH2–CO), 5.30
(s, 2H, –N–CH2–N–), 7.38–7.83 (m, 7H, Ar–H); Ms (m/z): 255/256
(Mþ/Mþ þ 1). Anal. Calc. for C13H13N5O: C: 61.17, H: 5.13, N: 27.43.
Found: C: 61.12, H: 4.98, N: 27.22.
d
(ppm): 2.36 (s, 3H, CH3), 2.64 (t, J ¼ 7.6, 2H, C–CH2), 2.98 (t, J ¼ 7.6,
2H, CH2–CO), 5.36 (s, 2H, –N–CH2–N–), 7.46–7.78 (m, 10H, Ar–H);
Ms (m/z): 317/318 (Mþ/Mþ þ 1). Anal. Calc. for C20H19N3O: C: 75.69,
H: 6.03, N: 13.24. Found: C: 75.46, H: 5.88, N: 13.12.
4.1.3.9. 6-(4-Methylphenyl)-2-(morpholin-4-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (23). Morpholine was used as cyclic
secondary amine for Mannich reaction. Yield: 68%; m.p.113–114 ꢂC;
IR (KBr) ymax (cmꢀ1): 3010 (CH), 1685 (C]O), 1600 (C]N); 1H NMR
4.1.3.15. 6-(4-Methylphenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (29). Pyrrolidine was used as cyclic
secondary amine for Mannich reaction. Yield: 39%; m.p.118–120 ꢂC;
IR (KBr) ymax (cmꢀ1): 3006 (CH), 1682 (C]O), 1580 (C]N); 1H NMR
(CDCl3)
d
(ppm): 2.29 (s, 3H, CH3), 2.62 (t, J ¼ 7.8, 2H, C–CH2), 2.76
(t, J ¼ 7.8, 2H, CH2–CO), 2.85–3.05 (m, 4H, 2 ꢃ CH2), 3.59–3.79
(m, 4H, CH2–O–CH2), 4.78 (s, 2H, –N–CH2–N–), 7.43 (dd, J ¼ 8.2, 2H,
H-30, H-50), 7.73 (dd, J ¼ 8.2, 2H, H-20, H-60); 13C NMR (CDCl3)
(CDCl3)
d
(ppm): 2.30 (s, 3H, CH3), 2.62 (t, J ¼ 7.9, 2H, C–CH2), 2.96
(t, J ¼ 7.9, 2H, CH2–CO), 3.08–3.28 (m, 8H, 4 ꢃ CH2), 5.24 (s, 2H, –N–
CH2–N–), 7.42 (dd, J ¼ 8.0, 2H, H-30, H-50), 7.78 (dd, J ¼ 8.0, H-20,
H-60); Ms (m/z): 271/272 (Mþ/Mþ þ 1). Anal. Calc. for C16H21N3O: C:
70.82, H: 7.80, N: 15.49. Found: C: 70.68, H: 7.74, N: 15.36.
d
(ppm): 176 (C-3), 155 (C-6), 140 (C-4), 129 (C-20, C-60), 128 (C-30,
C-50), 127 (C-10), 71.5 (C-200, C-600), 53.9 (C-300, C-500), 33.5 (C-4), 27.4
(C-5), 20.9 (CH3); Ms (m/z): 287/288 (Mþ/Mþ þ 1). Anal. Calc. for
C16H21N3O2: C: 66.88, H: 7.37, N: 14.62. Found: C: 66.72, H: 7.32, N:
14.56.
4.1.3.16. 6-(4-Methylphenyl)-2-(2,3-dihydro-1H-1,2,4-triazol-1-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (30). 1,2,4-Triazole was
used as cyclic secondary amine for Mannich reaction. Yield: 56%;
m.p.126–127 ꢂC; IR (KBr) ymax (cmꢀ1): 3020 (CH), 1675 (C]O),1600
4.1.3.10. 6-(4-Methylphenyl)-2-(piperazin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (24). Piperazine was used as cyclic
secondary amine for Mannich reaction. Yield: 52%; m.p. 122–
124 ꢂC; IR (KBr) ymax (cmꢀ1): 2970 (CH), 1664 (C]O), 1528 (C]C);
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.36 (s, 3H, CH3), 2.68 (t, J ¼ 7.7,
2H, C–CH2), 3.02 (t, J ¼ 7.7, 2H, CH2–CO), 5.32 (s, 2H, –N–CH2–N–),
7.40–7.84 (m, 6H, Ar–H); Ms (m/z): 269/270 (Mþ/Mþ þ 1). Anal.
Calc. for C14H15N5O: C: 62.44, H: 5.61, N: 26.01. Found: C: 62.22, H:
5.48, N: 25.92.
1H NMR (CDCl3)
d
(ppm): 2.30 (s, 3H, CH3), 2.60 (t, J ¼ 7.9, 2H, CH2),
2.90 (t, J ¼ 7.9, 2H, CH2), 2.85–2.95 (m, 8H, 4 ꢃ CH2), 4.78 (s, 2H, –N–
CH2–N–), 7.22 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.74 (dd, J ¼ 8.4, 2H, H-20,

A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
2287
4.1.3.17. 6-(4-Methoxylphenyl)-2-(morpholin-4-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (31). Morpholine was used as cyclic
secondary amine for Mannich reaction. Yield: 53%; m.p.135–136 ꢂC;
IR (KBr) ymax (cmꢀ1): 2970 (CH), 1672 (C]O), 1452 (C]C); 1H NMR
secondary amine for Mannich reaction. Yield: 41%; m.p. 128–
130 ꢂC; IR (KBr) ymax (cmꢀ1): 3001 (CH), 1685 (C]O), 1600 (C]N);
1H NMR (CDCl3)
d
(ppm): 2.61 (t, J ¼ 7.8, 2H, C–CH2), 2.92 (t, J ¼ 7.8,
2H, CH2–CO), 2.94–3.14 (m, 8H, 4 ꢃ CH2), 3.90 (s, 3H, CH3O), 5.26 (s,
2H, –N–CH2–N–), 7.41 (dd, J ¼ 8.4, H-30, H-50), 7.79 (dd, J ¼ 8.4, H-20,
H-60); Ms (m/z): 287/288 (Mþ/Mþ þ 1). Anal. Calc. for C16H21N3O2:
C: 66.88, H: 7.37, N: 14.62. Found: C: 66.64, H: 7.14, N: 14.56.
(CDCl3)
d
(ppm): 2.48 (t, J ¼ 7.8, 2H, C–CH2), 2.73 (t, J ¼ 7.8, 2H,
CH2–CO), 2.80–3.0 (m, 4H, 2 ꢃ CH2), 3.50–3.70 (m, 4H, 2 ꢃ CH2),
3.85 (s, 3H, CH3O), 4.76 (s, 2H, –N–CH2–N–), 6.91 (dd, 2H, J ¼ 8.7,
H-30, H-50), 7.68 (dd, 2H, J ¼ 8.7, H-20, H-60); Ms (m/z): 303/304 (Mþ/
Mþ þ 1). Anal. Calc. for C16H21N3O3: C: 63.35, H: 6.98, N: 13.85.
Found: C: 63.10, H: 6.88, N: 13.66.
4.1.3.24. 6-(4-Methoxylphenyl)-2-(1,2,4-triazolin-1-ylmethyl)-4,5-
dihydropyridazin-3(2H)-one (38). 1,2,4-Triazole was used as cyclic
secondary amine for Mannich reaction. Yield: 58%; m.p.130–132 ꢂC;
IR (KBr) ymax (cmꢀ1): 3005 (CH), 1680 (C]O), 1580 (C]N); 1H NMR
4.1.3.18. 6-(4-Methoxylphenyl)-2-(piperazin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (32). Piperazine was used as cyclic
secondary amine for Mannich reaction. Yield: 46%; m.p. 127–
128 ꢂC; IR (KBr) ymax (cmꢀ1): 2972 (CH), 1678 (C]O), 1530 (C]C);
(CDCl3)
d
(ppm): 2.62 (t, J ¼ 7.9, 2H, C–CH2), 3.02 (t, J ¼ 7.9, 2H, CH2–
CO), 3.76 (s, 3H, CH3O), 5.34 (s, 2H, –N–CH2–N–), 7.36–7.86 (m, 6H,
Ar–H); Ms (m/z): 285/286 (Mþ/Mþ þ 1). Anal. Calc. for C14H15N5O2:
C: 58.94, H: 5.30, N: 24.55. Found: C: 58.72, H: 5.16, N: 24.36.
1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.6, 2H, C–CH2), 2.90 (t, J ¼ 7.6,
2H, CH2–CO), 2.90–3.10 (m, 8H, 4 ꢃ CH2), 3.8 (s, 3H, CH3O), 4.74 (s,
2H, –N–CH2–N–), 7.32 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.74 (dd, J ¼ 8.4,
2H, H-20, H-60), 9.30 (br s, 1H, NH); Ms (m/z): 302/303 (Mþ/Mþ þ 1).
Anal. Calc. for C16H22N4O2: C: 63.55, H: 7.33, N: 18.53. Fond: C:
63.38, H: 7.12, N: 18.44.
4.1.3.25. 6-(4-Ethylphenyl)-2-(morpholin-4-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (39). Morpholine was used as cyclic
secondary amine for Mannich reaction. Yield: 62%; m.p. 133–
135 ꢂC; IR (KBr) ymax (cmꢀ1): 2954 (CH), 1658 (C]O), 1448 (C]C);
1H NMR (CDCl3)
d (ppm): 0.92 (t, 2H, CH3), 2.54 (q, 2H, CH2), 2.60 (t,
4.1.3.19. 6-(4-Methoxylphenyl)-2-(piperidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (33). Piperidine was used as cyclic
secondary amine for Mannich reaction. Yield: 50%; m.p. 132–
134 ꢂC; IR (KBr) ymax (cmꢀ1): 2998 (CH), 1688 (C]O), 1455 (C]C);
J ¼ 7.9, 2H, C–CH2), 2.74 (t, J ¼ 7.9, 2H, CH2–CO), 2.86–3.06 (m, 4H,
2 ꢃ CH2), 3.58–3.78 (m, 4H, CH2–O–CH2), 5.16 (s, 2H, –N–CH2–N–),
7.42 (dd, J ¼ 8.2, 2H, H-30, H-50), 7.78 (dd, J ¼ 8.2, 2H, H-20, H-60); Ms
(m/z): 301/302 (Mþ/Mþ þ 1). Anal. Calc. for C17H23N3O2: C: 67.75, H:
7.69, N: 13.94. Found: C: 67.54, H: 7.46, N: 13.82.
1H NMR (CDCl3)
d
(ppm): 2.61 (t, J ¼ 7.8, 2H, C–CH2), 2.55–2.75
(m, 6H, 3 ꢃ CH2), 2.82 (t, J ¼ 7.8, 2H, CH2–CO), 2.86–3.10 (m, 4H,
2 ꢃ CH2), 3.86 (s, 3H, CH3O), 5.2 (s, 2H, –N–CH2–N–), 7.42
(dd, J ¼ 8.2, 2H, H-30, H-50), 7.78 (dd, J ¼ 8.2, 2H, H-20, H-60); Ms (m/
z): 301/302 (Mþ/Mþ þ 1). Anal. Calc. for C17H23N3O2: C: 67.75, H:
7.69, N: 13.94. Found: C: 67.55, H: 7.48, N: 13.76.
4.1.3.26. 6-(4-Ethylphenyl)-2-(piperazin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (40). Piperazine was used as cyclic
secondary amine for Mannich reaction. Yield: 50%; m.p. 137–
138 ꢂC; IR (KBr) ymax (cmꢀ1): 3338 (NH), 2968 (CH), 1668 (C]O); 1H
NMR (CDCl3)
d (ppm): 0.92 (t, 2H, CH3), 2.54 (q, 2H, CH2), 2.60
4.1.3.20. 6-(4-Methoxylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-
4,5-dihydropyridazin-3(2H)-one (34). 1-Methylpiperazine was used
as cyclic secondary amine for Mannich reaction. Yield: 56%; m.p.
135–137 ꢂC; IR (KBr) ymax (cmꢀ1): 2980 (CH), 1685 (C]O), 1590
(t, J ¼ 7.8, 2H, C–CH2), 2.80–2.86 (m, 8H, 4 ꢃ CH2), 2.96 (t, J ¼ 7.8, 2H,
CH2–CO), 5.24 (s, 2H, –N–CH2–N–), 7.32 (dd, J ¼ 8.5, 2H, H-30, H-50),
7.78 (dd, J ¼ 8.5, 2H, H-20, H-60), 9.6 (s, 1H, NH); Ms (m/z): 300/301
(Mþ/Mþ þ 1). Anal. Calc. for C17H24N4O: C: 67.97, H: 8.05, N: 18.65.
Found: C: 67.84, H: 7.88, N: 18.43.
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.20 (s,1H, N–CH3), 2.55 (t, J ¼ 7.9,
2H, C–CH2), 2.91 (t, J ¼ 7.9, 2H, CH2–CO), 2.92–3.10 (m, 4H, 2 ꢃ CH2),
3.20–3.40 (m, 4H, 2 ꢃ CH2), 3.86 (s, 3H, CH3O), 5.24 (s, 2H, –N–CH2–
N–), 7.35 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.76 (dd, J ¼ 8.4, 2H, H-20,
H-60); Ms (m/z): 316/317 (Mþ/Mþ þ 1). Anal. Calc. for C17H24N4O2:
C: 64.53, H: 7.65, N: 17.71. Found: C: 64.42, H: 7.53, N: 17.54.
4.1.3.27. 6-(4-Ethylphenyl)-2-(piperidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (41). Piperidine was used as cyclic
secondary amine for Mannich reaction. Yield: 48%; m.p. 147–
148 ꢂC; IR (KBr) ymax (cmꢀ1): 2968 (CH), 1678(C]O), 1465 (C]C);
1H NMR (CDCl3)
d (ppm): 0.90 (t, 3H, CH3), 2.54 (q, 2H, CH2), 2.60
4.1.3.21. 6-(4-Methoxylphenyl)-2-(1,2-dihydro-10H-phenothiazin-
10-ylmethyl)-4,5-dihydropyridazin-3(2H)-one (35). Phenothiazine
was used as cyclic secondary amine for Mannich reaction.Yield:
60%; m.p. 108–110 ꢂC; IR (KBr) ymax (cmꢀ1): 2986 (CH), 1664 (C]O),
(t, J ¼ 7.8, 2H, C–CH2), 2.58–2.74 (m, 6H, 3 ꢃ CH2), 2.82 (t, J ¼ 7.8, 2H,
CH2), 2.92–3.08 (m, 4H, 2 ꢃ CH2), 5.32 (s, 2H, –N–CH2–N–), 7.38
(dd, J ¼ 8.7, 2H, H-30, H-50), 7.78 (dd, J ¼ 8.7, 2H, H-20, H-60); Ms (m/
z): 299/300 (Mþ/Mþ þ 1). Anal. Calc. for C18H25N3O: C: 72.16, H:
8.42, N: 14.03. Found: C: 71.96, H: 8.24, N: 13.97.
1600 (C]N); 1H NMR (CDCl3)
d
(ppm): 2.62 (t, J ¼ 7.6, 2H, C–CH2),
2.99 (t, J ¼ 7.6, 2H, CH2–CO), 3.82 (s, 3H, CH3O), 5.40 (s, 2H, –N–
CH2–N–), 6.90–7.78 (m, 12H, Ar–H); Ms (m/z): 415/416 (Mþ/
Mþ þ 1). Anal. Calc. for C24H21N3O2S: C: 69.37, H: 5.09, N: 10.11.
Found: C: 69.18, H: 4.88, N: 9.92.
4.1.3.28. 6-(4-Ethylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-4,5-
dihydropyridazin-3(2H)-one (42). 1-Methylpiperazine was used as
cyclic secondary amine for Mannich reaction. Yield: 52%; m.p.
139–140 ꢂC; IR (KBr) ymax (cmꢀ1): 2970 (CH), 1680 (C]O), 1595
4.1.3.22. 6-(4-Methoxylphenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (36). Indole was used as cyclic secondary
amine for Mannich reaction. Yield: 46%; m.p. 116–118 ꢂC; IR (KBr)
ymax (cmꢀ1): 3005 (CH), 1680 (C]O), 1600 (C]N); 1H NMR (CDCl3)
(C]N); 1H NMR (CDCl3)
d (ppm): 0.96 (t, 2H, CH3), 1.18 (q, 2H, CH3),
2.2 (s, 1H, N–CH3), 2.50 (q, 2H, CH2), 2.62 (t, J ¼ 7.8, 2H, C–CH2), 2.91
(t, J ¼ 7.8, 2H, CH2–CO), 2.95–3.07 (m, 4H, 2 ꢃ CH2), 3.20–3.36
(m, 4H, 2 ꢃ CH2), 5.2 (s, 2H, –N–CH2–N–), 7.39 (dd, J ¼ 8.2, 2H, H-30,
H-50), 7.7 (dd, 2H, H-20, H-60); Ms (m/z): 314/315 (Mþ/Mþ þ 1). Anal.
Calc. for C18H26N4O: C: 68.76, H: 8.33, N: 17.82. Found: C: 68.66, H:
8.14, N: 17.76.
d
(ppm): 2.63 (t, J ¼ 7.7, 2H, C–CH2), 2.97 (t, J ¼ 7.7, 2H, CH2–CO),
3.80 (s, 3H, CH3O), 5.28 (s, 2H, –N–CH2–N–), 7.32–7.67 (m, 10H,
Ar–H); Ms (m/z): 333/334 (Mþ/Mþ þ 1). Anal. Calc. for C20H19N3O2:
C: 72.05, H: 5.74, N: 12.60. Found: C: 71.92, H: 5.54, N: 12.46.
4.1.3.29. 6-(4-Ethylphenyl)-2-(1,2-dihydro-10H-phenothiazin-10-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (43). Phenothiazine was
used as cyclic secondary amine for Mannich reaction. Yield: 60%;
4.1.3.23. 6-(4-Methoxylphenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (37). Pyrrolidine was used as cyclic

2288
A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
m.p.126–128 ꢂC; IR (KBr) ymax (cmꢀ1): 2968 (CH),1664 (C]O),1600
(C]N); 1H NMR (CDCl3)
(ppm): 1.02 (t, 2H, CH2), 2.54 (q, 2H, CH2),
2.60 (t, J ¼ 7.7, 2H, C–CH2), 2.96 (t, J ¼ 7.7, 2H, CH2–CO), 5.32 (s, 2H,
–N–CH2–N–), 6.96–7.82 (m, 12H, Ar–H); Ms (m/z): 413/414 (Mþ/
Mþ þ 1). Anal. Calc. for C25H23N3OS: C: 72.16, H: 5.61, N: 10.16.
Found: C: 71.92, H: 5.48, N: 9.98.
(m, H, –CH), 2.55–2.75 (m, 4H, 2 ꢃ CH2), 2.90 (t, J ¼ 7.8, 2H,
CH2–CO), 2.90–3.28 (m, 10H, 5 ꢃ CH2), 5.02 (s, 2H, –N–CH2–N–),
7.42 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.8 (dd, J ¼ 8.4, 2H, H-20, H-60); Ms
(m/z): 327/328 (Mþ/Mþ þ 1). Anal. Calc. for C20H29N3O: C: 73.36, H:
8.93, N: 12.83. Found: C: 73.23, H: 8.86, N: 12.76.
d
4.1.3.36. 6-(4-Isobutylphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-
4,5-dihydropyridazin-3(2H)-one (50). 1-Methylpiperazine was used
as cyclic secondary amine for Mannich reaction.Yield: 51%; m.p.
129–131 ꢂC; IR (KBr) ymax (cmꢀ1): 2995 (CH), 1680 (C]O), 1600
4.1.3.30. 6-(4-Ethylphenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (44). Indole was used as cyclic secondary
amine for Mannich reaction. Yield: 42%; m.p. 125–127 ꢂC; IR (KBr)
ymax (cmꢀ1): 3001 (CH), 1680 (C]O), 1600 (C]N); 1H NMR (CDCl3)
(C]N); 1H NMR (CDCl3)
d
(ppm): 0.78 (d, 6H, 2 ꢃ CH3), 1.76–1.88
d
(ppm): 0.88 (t, 2H, CH3), 2.52 (q, 2H, CH2), 2.60 (t, J ¼ 7.8, 2H,
(m, H, –CH), 2.50 (s, 3H, N–CH3), 2.60–2.70 (m, 4H, 2 ꢃ CH2), 2.85
(t, J ¼ 7.8, 2H, CH2–CO), 3.0–3.30 (m, 8H, 4 ꢃ CH2), 4.78 (s, 2H, –N–
CH2–N–), 7.35 (dd, J ¼ 8.5, 2H, H-30, H-50), 7.80 (dd, J ¼ 8.5, 2H, H-20,
H-60); Ms (m/z): 342/343 (Mþ/Mþ þ 1). Anal. Calc. for C20H30N4O: C:
70.14, H: 8.83, N: 16.36. Found: C: 69.88, H: 8.67, N: 16.18.
C–CH2), 2.96 (t, J ¼ 7.8, 2H, CH2–CO), 5.28 (s, 2H, –N–CH2–N–),
7.38–7.78 (m, 10H, Ar–H); Ms (m/z): 331/332 (Mþ/Mþ þ 1). Anal.
Calc. for C21H21N3O: C: 67.11, H: 6.39, N: 12.68. Found: C: 66.92, H:
6.12, N: 12.51.
4.1.3.31. 6-(4-Ethylphenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (45). Pyrrolidine was used as cyclic
secondary amine for Mannich reaction. Yield: 42%; m.p. 140–
142 ꢂC; IR (KBr) ymax (cmꢀ1): 3000 (CH), 1680 (C]O), 1600 (C]N);
4.1.3.37. 6-(4-Isobutylphenyl)-2-(1,2-dihydro-10H-phenothiazin-10-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (51). Phenothiazine was
used as cyclic secondary amine for Mannich reaction. Yield: 44%;
m.p.150–152 ꢂC; IR (KBr) ymax (cmꢀ1): 2998 (CH),1680 (C]O), 1602
1H NMR (CDCl3)
d
(ppm): 1.01 (t, 2H, CH3), 2.50 (t, 2H, CH2), 2.60
(C]N); 1H NMR (CDCl3)
d
(ppm): 0.80 (d, 6H, 2 ꢃ CH3), 1.76–1.94
(t, J ¼ 7.7, 2H, C–CH2), 2.94 (t, J ¼ 7.7, 2H, CH2–CO), 2.96–3.04 (m, 8H,
4 ꢃ CH2), 5.16 (s, 2H, –N–CH2–N–), 7.35–7.45 (m, 2H, Ar–H),
7.72–7.82 (m, 2H, Ar–H); Ms (m/z): 285/286 (Mþ/Mþ þ 1). Anal.
Calc. for C17H23N3O: C: 76.11, H: 6.39, N: 12.68. Found: C: 75.88, H:
6.28, N: 12.56.
(m, H, –CH), 2.52–2.72 (m, 4H, 2 ꢃ CH2), 2.90 (t, J ¼ 7.8, 2H,
CH2–CO), 4.78 (s, 2H, –N–CH2–N–), 7.42–7.89 (m, 12H, Ar–H);
Ms (m/z): 441/442 (Mþ/Mþ þ 1). Anal. Calc. for C27H27N3OS: C:
73.44, H: 6.16, N: 9.52. Found: C: 73.28, H: 5.96, N: 9.24.
4.1.3.38. 6-(4-Isobutylphenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (52). Indole was used as cyclic secondary
amine for Mannich reaction. Yield: 43%; m.p. 134–136 ꢂC; IR (KBr)
ymax (cmꢀ1): 2990 (CH), 1685 (C]O), 1600 (C]N); 1H NMR (CDCl3)
4.1.3.32. 6-(4-Ethylphenyl)-2-(1,2,4-triazolin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (46). 1,2,4-Triazole was used as cyclic
secondary amine for Mannich reaction. Yield: 51%; m.p.141–143 ꢂC;
IR (KBr) ymax (cmꢀ1): 3002 (CH), 1680 (C]O), 1600 (C]N); 1H NMR
d
(ppm): 0.85 (d, 6H, 2 ꢃ CH3), 1.70–1.86 (m, H, –CH), 2.28–2.52
(CDCl3)
d
(ppm): 1.18 (t, 2H, CH3), 2.59 (t, 2H, CH2), 2.66 (t, J ¼ 7.9,
(m, 2H, CH2), 2.62 (t, J ¼ 7.8, 2H, C–CH2), 2.92 (t, J ¼ 7.8, 2H,
CH2–CO), 5.02 (s, 2H, –N–CH2–N–), 7.32–7.89 (m, 10H, Ar–H);
Ms (m/z): 359/360 (Mþ/Mþ þ 1). Anal. Calc. for C23H25N3O: C: 76.85,
H: 7.01, N: 11.69. Found: C: 76.68, H: 6.86, N: 11.64.
2H, C–CH2), 3.01 (t, J ¼ 7.9, 2H, CH2–CO), 5.32 (s, 2H, –N–CH2–N–),
7.36–7.86 (m, 6H, Ar–H); Ms (m/z): 283/284 (Mþ/Mþ þ 1). Anal.
Calc. for C15H17N5O: C: 63.59, H: 6.05, N: 24.72. Found: C: 63.52, H:
5.82, N: 24.58.
4.1.3.39. 6-(4-Isobutylphenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (53). Pyrrolidine was used as cyclic
secondary amine for Mannich reaction. Yield: 40%; m.p. 136–
138 ꢂC; IR (KBr) ymax (cmꢀ1): 3000 (CH), 1680 (C]O), 1600 (C]N);
4.1.3.33. 6-(4-Isobutylphenyl)-2-(morpholin-4-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (47). Morpholine was used as cyclic
secondary amine for Mannich reaction. Yield: 38%; m.p. 152–
154 ꢂC; IR (KBr) ymax (cmꢀ1): 2998 (CH), 1675 (C]O), 1600 (C]N);
1H NMR (CDCl3)
d
(ppm): 0.80 (d, 6H, 2 ꢃ CH3), 1.78–1.92 (m, H,
1H NMR (CDCl3)
d
(ppm): 0.9 (d, 6H, 2 ꢃ CH3),1.75–1.85 (m, H, –CH),
–CH), 2.60 (t, J ¼ 7.7, 2H, C–CH2), 2.85 (t, J ¼ 7.7, 2H, CH2–CO),
2.69 (t, J ¼ 7.8, 2H, C–CH2), 2.92 (t, J ¼ 7.8, 2H, CH2–CO), 2.96–3.04
(m, 4H, 2 ꢃ CH2), 3.15–3.25 (m, 4H, 2 ꢃ CH2), 4.78 (s, 2H, –N–CH2–
N–), 7.34 (dd, J ¼ 8.2, 2H, H-30, H-50), 7.42 (dd, J ¼ 8.2, 2H, H-20,
H-60); Ms (m/z): 329/330 (Mþ/Mþ þ 1). Anal. Calc. for C19H27N3O2:
C: 69.27, H: 8.26, N: 12.76. Found: C: 69.12, H: 8.12, N: 12.58.
2.90–3.20 (m, 10H,
5
ꢃ
CH2), 5.1 (s, 2H, –N–CH2–N–),
7.42 (dd, J ¼ 8.6, 2H, H-30, H-50), 7.80 (dd, J ¼ 8.6, 2H, H-20, H-60);
Ms (m/z): 313/314 (Mþ/Mþ þ 1). Anal. Calc. for C19H27N3O: C: 72.81,
H: 8.68, N: 13.41. Found: C: 72.57, H: 8.48, N: 13.22.
4.1.3.40. 6-(4-Isobutylphenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4,5-
dihydropyridazin-3(2H)-one (54). 1,2,4-Triazole was used as cyclic
secondary amine for Mannich reaction. Yield: 53%; m.p. 144–
146 ꢂC; IR (KBr) ymax (cmꢀ1): 2998 (CH), 1678 (C]O), 1600 (C]N);
4.1.3.34. 6-(4-Isobutylphenyl)-2-(piperazin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (48). Piperazine was used as cyclic
secondary amine for Mannich reaction.Yield: 52%; m.p. 147–148 ꢂC;
IR (KBr) ymax (cmꢀ1): 3000 (CH), 1680 (C]O), 1590 (C]N); 1H NMR
1H NMR (CDCl3-d6)
d
(ppm): 0.82 (d, 6H, 2 ꢃ CH3), 1.85–1.95 (m, H,
(CDCl3)
d
(ppm): 0.89 (d, 6H, 2 ꢃ CH3), 1.74–1.86 (m, H, –CH), 2.62
–CH), 2.42–2.58 (m, 2H, CH2), 2.65 (t, J ¼ 7.9, 2H, C–CH2), 2.86
(t, J ¼ 7.9, 2H, CH2–CO), 4.79 (s, 2H, –N–CH2–N–), 7.40–7.86 (m, 6H,
Ar–H); Ms (m/z): 311/312 (Mþ/Mþ þ 1). Anal. Calc. for C17H21N5O:
C: 65.57, H: 6.80, N: 22.49. Found: C: 65.44, H: 6.68, N: 22.13.
(t, J ¼ 7.8, 2H, C–CH2), 2.70–2.86 (m, 8H, 4 ꢃ CH2), 2.92 (t, J ¼ 7.8, 2H,
CH2–CO), 4.79 (s, 2H, –N–CH2–N–), 7.42 (dd, J ¼ 8.3, 2H, H-30, H-50),
7.80 (dd, J ¼ 8.2, 2H, H-20, H-60), 8.10 (s, 1H, NH); Ms (m/z): 328/329
(Mþ/Mþ þ 1). Anal. Calc. for C19H28N4O: C: 69.48, H: 8.59, N: 17.06.
Fond: C: 69.24, H: 8.36, N: 16.86.
4.1.3.41. 6-(4-Biphenyl)-2-(morpholin-4-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (55). Morpholine was used as cyclic secondary
amine for Mannich reaction. Yield: 68%; m.p. 163–165 ꢂC; IR (KBr)
ymax (cmꢀ1): 2970 (CH), 1674 (C]O), 1556 (C]C); 1H NMR (CDCl3)
4.1.3.35. 6-(4-Isobutylphenyl)-2-(piperidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (49). Piperidine was used as cyclic
secondary amine for Mannich reaction. Yield: 48%; m.p.
137–138 ꢂC; IR (KBr) ymax (cmꢀ1): 3010 (CH), 1685 (C]O), 1600
d
(ppm): 2.62 (t, J ¼ 7.6, 2H, C–CH2), 2.96 (t, J ¼ 7.6, 2H, CH2–CO),
2.97–2.99 (m, 4H, 2 ꢃ CH2), 3.59–3.79 (m, 4H, CH2–O–CH2), 5.28
(s, 2H, –N–CH2–N–), 7.06–7.80 (m, 9H, Ar–H); Ms (m/z): 349/350
(C]N); 1H NMR (CDCl3)
d
(ppm): 0.80 (d, 6H, 2 ꢃ CH3), 1.80–1.90

A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
2289
(Mþ/Mþ þ 1). Anal. Calc. for C21H23N3O2: C: 72.18, H: 6.63, N: 12.03.
146–148 ꢂC; IR (KBr) ymax (cmꢀ1): 2995 (CH), 1685 (C]O), 1592
(C]N); 1H NMR (CDCl3)
(t, J ¼ 7.5, 2H, CH2–CO), 5.3 (s, 2H, –N–CH2–N–), 7.38–7.83 (m, 11H,
Ar–H); Ms (m/z): 331/332 (Mþ/Mþ þ 1). Anal. Calc. for C13H13N5O:
C: 68.87, H: 5.17, N: 21.13. Found: C: 68.62, H: 4.96, N: 20.94.
Found: C: 71.89, H: 6.44, N: 11.92.
d
(ppm): 2.66 (t, J ¼ 7.5, 2H, C–CH2), 3.0
4.1.3.42. 6-(4-Biphenyl)-2-(piperazin-1-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (56). Piperazine was used as cyclic secondary
amine for Mannich reaction. Yield: 47%; m.p. 162–164 ꢂC; IR (KBr)
ymax (cmꢀ1): 3325 (NH), 2964 (CH), 1661 (C]O), 1524 (C]C); 1H
4.1.3.49. 6-(4-Chlorophenyl)-2-(morpholin-4-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (63). Morpholine was used as cyclic
secondary amine for Mannich reaction. Yield: 70%; m.p. 178–
180 ꢂC; IR (KBr) ymax (cmꢀ1): 3010 (CH), 1685 (C]O), 1600 (C]N);
NMR (CDCl3)
d
(ppm): 2.61 (t, J ¼ 7.7, 2H, C–CH2), 2. 92 (t, J ¼ 7.7, 2H,
CH2–CO), 2.95–3.07 (m, 8H, 4 ꢃ CH2), 5.25 (s, 2H, –N–CH2–N–),
7.04–7.78 (m, 9H, Ar–H), 9.8 (br s, 1H, NH); Ms (m/z): 348/349 (Mþ/
M
þ þ 1). Anal. Calc. for C21H24N4O: C: 72.39, H: 6.94, N: 16.08. Fond:
1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.8, 2H, C–CH2), 2.73 (t, J ¼ 7.8,
C: 72.14, H: 6.78, N: 15.84.
2H, CH2–CO), 2.90–3.05 (m, 4H, 2 ꢃ CH2), 3.59–3.79 (m, 4H, CH2–O–
CH2), 4.28 (s, 2H, –N–CH2–N–), 7.37 (dd, 4H, J ¼ 8.4, H-30-H-50), 7.82
(dd, 2H, J ¼ 8.4, H-20, H-60); Ms (m/z): 307/309 (Mþ/Mþ þ 2). Anal.
Calc. for C15H18ClN3O2: C: 58.54, H: 5.89, N: 13.65. Found: C: 58.46,
H: 5.84, N: 13.36.
4.1.3.43. 6-(4-Biphenyl)-2-(piperidin-1-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (57). Piperidine was used as cyclic secondary
amine for Mannich reaction. Yield: 56%; m.p. 170–172 ꢂC; IR (KBr)
ymax (cmꢀ1): 2944 (CH), 1678(C]O), 1520 (C]C); 1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.8, 2H, C–CH2), 2.62–2.68 (m, 6H, 3 ꢃ CH2),
4.1.3.50. 6-(4-Chlorophenyl)-2-(piperazin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (64). Piperazine was used as cyclic
secondary amine for Mannich reaction. Yield: 62%; m.p. 166–
168 ꢂC; IR (KBr) ymax (cmꢀ1): 3005 (CH), 1685 (C]O), 1590 (C]N);
2.90–3.06 (m, 4H, 2 ꢃ CH2), 5.24 (s, 2H, –N–CH2–N–), 7.14–7.82
(m, 9H, Ar–H); Ms (m/z): 347/348 (Mþ/Mþ þ 1). Anal. Calc. for
C16H21N3O: C: 70.05, H: 6.94, N: 12.09. Found: C: 69.86, H: 6.82, N:
11.92.
1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.7, 2H, C–CH2), 2.86 (t, J ¼ 7.7,
2H, CH2–CO), 2.90–3.40 (m, 8H, 4 ꢃ CH2), 4.78 (s, 2H, –N–CH2–N–),
7.36 (dd, J ¼ 8.2, 2H, H-30, H-50), 7.65 (dd, J ¼ 8.2, 2H, H-20, H-60),
8.50 (s, 1H, –NH); Ms (m/z): 306/308 (Mþ/Mþ þ 2). Anal. Calc. for
C15H19ClN4O: C: 58.72, H: 6.24, N: 18.26. Fond: C: 58.56, H: 6.02, N:
18.16.
4.1.3.44. 6-(4-Biphenyl)-2-[(4-methylpiperazin-1-yl)methyl]-4,5-
dihydropyridazin-3(2H)-one (58). 1-Methylpiperazine was used as
cyclic secondary amine for Mannich reaction. Yield: 70%; m.p.
154–156 ꢂC; IR (KBr) ymax (cmꢀ1): 3010 (CH), 1684 (C]O), 1590
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.21 (s,1H, N–CH3), 2.54 (t, J ¼ 7.4,
2H, C–CH2), 2.96 (t, J ¼ 7.4, 2H, CH2–CO), 3.02–3.18 (m, 4H, 2 ꢃ CH2),
3.22–3.38 (m, 4H, 2 ꢃ CH2), 5.2 (s, 2H, –N–CH2–N–), 7.10–7.80
(m, 9H, Ar–H); Ms (m/z): 362/363 (Mþ/Mþ þ 1). Anal. Calc. for
C16H22N4O: C: 72.90, H: 7.23, N: 15.46. Found: C: 72.76, H: 6.98, N:
15.40.
4.1.3.51. 6-(4-Chlorophenyl)-2-(piperidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (65). Piperidine was used as cyclic
secondary amine for Mannich reaction. Yield: 58%; m.p. 152–
154 ꢂC; IR (KBr) ymax (cmꢀ1): 3010 (CH), 1680 (C]O), 1600 (C]N);
1H NMR (CDCl3)
d
(ppm): 2.65 (t, J ¼ 7.6, 2H, C–CH2), 2.90 (t, J ¼ 7.6,
2H, CH2–CO), 3.0–3.40 (m, 10H, 5 ꢃ CH2), 5.01 (s, 2H, –N–CH2–N–),
7.40 (dd, J ¼ 8.4, 2H, H-30, H-50), 7.70 (dd, J ¼ 8.4, 2H, H-20, H-60); Ms
(m/z): 305/307 (Mþ/Mþ þ 2). Anal. Calc. for C16H20ClN3O: C: 62.84,
H: 6.59, N: 13.74. Found: C: 62.75, H: 6.44, N: 13.68.
4.1.3.45. 6-(4-Biphenyl)-2-(1,2-dihydro-10H-phenothiazin-10-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (59). Phenothiazine was
used as cyclic secondary amine for Mannich reaction. Yield: 76%;
m.p. 166–168 ꢂC; IR (KBr) ymax (cmꢀ1): 2968 (CH), 1670 (C]O),1604
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.62 (t, J ¼ 7.6, 2H, C–CH2), 2.96
4.1.3.52. 6-(4-Chlorophenyl)-2-[(4-methylpiperazin-1-yl)methyl]-
4,5-dihydropyridazin-3(2H)-one (66). 1-Methylpiperazine was used
as cyclic secondary amine for Mannich reaction. Yield: 66%; m.p.
172–174 ꢂC; IR (KBr) ymax (cmꢀ1): 3005 (CH), 1685 (C]O), 1598
(t, J ¼ 7.6, 2H, CH2–CO), 5.26 (s, 2H, –N–CH2–N–), 6.80–6.98 (m, 9H,
phenyl protons), 7.14–7.78 (m, 9H, Ar–H); Ms (m/z): 461/462 (Mþ/
Mþ þ 1). Anal. Calc. for C23H19N3OS: C: 75.46, H: 5.02, N: 9.10.
Found: C: 75.18, H: 4.88, N: 8.88.
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.40 (s, 3H, N–CH3), 2.80 (t, J ¼ 7.8,
2H, C–CH2), 2.88 (t, J ¼ 7.8, 2H, CH2–CO), 2.90–3.20 (m, 8H,
4 ꢃ CH2), 4.79 (s, 2H, –N–CH2–N–), 7.40 (dd, J ¼ 8.6, 2H, H-30, H-50),
7.70 (dd, 2H, J ¼ 8.6, H-20, H-60); Ms (m/z): 320/322 (Mþ/Mþ þ 2).
Anal. Calc. for C16H21ClN4O: C: 59.90, H: 6.60, N: 17.46. Found: C:
59.64, H: 6.48, N: 17.26.
4.1.3.46. 6-(4-Biphenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (60). Indole was used as cyclic secondary amine
for Mannich reaction.Yield: 60%; m.p. 150–152 ꢂC; IR (KBr) ymax
(cmꢀ1): 2998 (CH), 1680 (C]O), 1602 (C]N); 1H NMR (CDCl3)
d
(ppm): 2.63 (t, J ¼ 7.5, 2H, C–CH2), 3.02 (t, J ¼ 7.5, 2H, CH2–CO),
5.02 (s, 2H, –N–CH2–N–), 7.12–7.76 (m, 15H, Ar–H); Ms (m/z): 379/
380 (Mþ/Mþ þ 1). Anal. Calc. for C19H17N3O: C: 79.13, H: 5.58, N:
11.07. Found: C: 78.86, H: 5.32, N: 10.86.
4.1.3.53. 6-(4-Chlorophenyl)-2-(1,2-dihydro-10H-phenothiazin-10-
ylmethyl)-4,5-dihydropyridazin-3(2H)-one (67). Phenothiazine was
used as cyclic secondary amine for Mannich reaction. Yield: 64%;
m.p. 190–192 ꢂC; IR (KBr) ymax (cmꢀ1): 3010 (CH), 1685 (C]O), 1602
4.1.3.47. 6-(4-Biphenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihydropyr-
idazin-3(2H)-one (61). Pyrrolidine was used as cyclic secondary
amine for Mannich reaction. Yield: 67%; m.p.174–176 ꢂC; IR (KBr) ymax
(cmꢀ1): 2998 (CH), 1685 (C]O), 1598 (C]N); 1H NMR (CDCl3)
(C]N); 1H NMR (CDCl3)
d
(ppm): 2.48 (s, 3H, N–CH3), 2.60 (t, J ¼ 7.7,
2H, C–CH2), 2.90 (t, J ¼ 7.7, 2H, CH2–CO), 4.78 (s, 2H, –N–CH2–N–),
7.15–7.55 (m, 12H, Ar–H); Ms (m/z): 419/421 (Mþ/Mþ þ 2). Anal.
Calc. for C23H18ClN3OS: C: 65.78, H: 4.32, N: 10.01. Found: C: 65.52,
H: 4.16, N: 9.84.
d
(ppm): 2.63 (t, J ¼ 7.8, 2H, C–CH2), 2.96 (t, J ¼ 7.8, 2H, CH2–CO),
3.02–3.18 (m, 8H, 4 ꢃ CH2), 5.40(s, 2H, –N–CH2–N–), 7.16–7.82 (m, 9H,
Ar–H); Ms (m/z): 333/334 (Mþ/Mþ þ 1). Anal. Calc. for C15H19N3O: C:
75.65, H: 6.95, N: 12.60. Found: C: 75.48, H: 6.92, N: 12.48.
4.1.3.54. 6-(4-Chlorophenyl)-2-(1H-indol-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (68). Indole was used as cyclic secondary
amine for Mannich reaction. Yield: 38%; m.p. 146–148 ꢂC; IR (KBr)
ymax (cmꢀ1): 2998 (CH), 1680 (C]O), 1600 (C]N); 1H NMR (CDCl3)
4.1.3.48. 6-(4-Biphenyl-4-yl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4,5-
dihydropyridazin-3(2H)-one (62). 1,2,4-Triazole was used as
cyclic secondary amine for Mannich reaction. Yield: 59%; m.p.
d
(ppm): 2.62 (t, J ¼ 7.8, 2H, C–CH2), 2.86 (t, J ¼ 7.8, 2H, CH2–CO), 4.79
(s, 2H, –N–CH2–N–), 7.35–7.80 (m, 10H, Ar–H); Ms (m/z): 337/339

2290
A.A. Siddiqui et al. / European Journal of Medicinal Chemistry 45 (2010) 2283–2290
(Mþ/Mþ þ 2). Anal. Calc. for C19H16ClN3O: C: 67.56, H: 4.77, N: 12.44.
pulse rate was observed. Once the ‘‘pulse level ready’’ signal
appeared, the BP recording button was pressed and the mean
arterial BP was recorded. Albino rats (body weight 200–250 g)
were used in present study. Rats were assigned to groups of five
animals in each. Each compound (20 mg/kg body weight) was
injected intraperitoneally after suspending in 1% carboxymethyl
cellulose (CMC) solution. The mean arterial blood pressure was
recorded after 1 h.
Found: C: 67.32, H: 4.65, N: 12.26.
4.1.3.55. 6-(4-Chlorophenyl)-2-(pyrrolidin-1-ylmethyl)-4,5-dihy-
dropyridazin-3(2H)-one (69). Pyrrolidine was used as cyclic
secondary amine for Mannich reaction. Yield: 63%; m.p. 166–
168 ꢂC; IR (KBr) ymax (cmꢀ1): 2998 (CH), 1680 (C]O), 1600 (C]N);
1H NMR (CDCl3)
d
(ppm): 2.60 (t, J ¼ 7.6, 2H, C–CH2), 2.90 (t, J ¼ 7.6,
2H, CH2–CO), 2.95–3.20 (m, 8H, 4 ꢃ CH2), 4.78 (s, 2H, –N–CH2–N–),
7.36 (dd, J ¼ 8.2, 2H, H-30, H-50), 7.60 (dd, J ¼ 8.2, 2H, H-20, H-60); Ms
(m/z): 291/293 (Mþ/Mþ þ 2). Anal. Calc. for C15H18ClN3O: C: 61.75,
H: 6.22, N: 14.40. Found: C: 61.61, H: 6.02, N: 14.26.
4.2.5. Statistical analysis of data
The statistical analysis was performed using GRAPHPAD
INSTAT 3 software (Graph Pad Software Inc, San Diego, CA). Data
obtained from animal experiments were expressed as arithmetic
mean ꢁ SEM. The comparison between various groups was
performed by one-way analysis of variance (ANOVA), and the
effect in treatment groups were compared with toxic control
4.1.3.56. 6-(4-Chlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-4,5-
dihydropyridazin-3(2H)-one (70). 1,2,4-Triazole was used as cyclic
secondary amine for Mannich reaction. Yield: 48%; m.p. 136–
138 ꢂC; IR (KBr) ymax (cmꢀ1): 2990 (CH), 1675 (C]O), 1598 (C]N);
group by Dunnet multiple comparison test. < 0.05 was
p
1H NMR (CDCl3)
d
(ppm): 2.65 (t, J ¼ 7.8, 2H, C–CH2), 2.95 (t, J ¼ 7.8,
considered to be significant [*p 0.05; **p < 0.01]. The
<
2H, CH2–CO), 4.79 (s, 2H, –N–CH2–N–), 7.42–7.80 (m, 6H, Ar–H);
Ms (m/z): 289/291 (Mþ/Mþ þ 2). Anal. Calc. for C13H12ClN5O: C:
53.89, H: 4.17, N: 24.17. Found: C: 53.66, H: 4.12, N: 23.96.
percentage reduction in BP for all the treatment groups was also
calculated and compared.
Acknowledgements
4.2. Pharmacology
The authors are thankful to Jamia Hamdard, New Delhi, India for
providing facility for the research work.
4.2.1. Procurement, identification, and housing of animals
Albino rats (body weight 200–250 g) were supplied by Central
Animal House facility of Hamdard University and kept under
References
standard laboratory conditions in 12
h light/dark cycle at
25 ꢂC ꢁ 2 ꢂC. Animals were provided with pellet diet (Lipton,
Calcutta, India) and water ad libitum. They were marked for easy
identification.
[1] A. Coelho, E. Sotelo, E. Ravina, Tetrahedron 59 (2003) 2477–2484.
[2] S. Demirayak, A.C. Karaburun, R. Beis, Eur. J. Med. Chem. 39 (2004) 1089–1095.
[3] A.A. Siddiqui, S.M. Wani, Ind. J. Chem. 43B (2004) 1574–1579.
[4] A. Monge, P. Parrado, M. Font, E.F. Alvarez, J. Med. Chem. 30 (6) (1987)
1029–1035.
[5] C. Rubat, P. Coudert, B. Refouvelet, P. Tronche, P. Bastide, Chem. Pharm. Bull. 38
(11) (1990) 3009–3013.
[6] I. Sircar, R.E. Weishaar, D. Kobylarz, W.H. Moos, J.A. Bristol, J. Med. Chem. 30
(1987) 1955–1962.
[7] J.G. Longo, I. Verde, M.E. Castro, J. Pharm. Sci. 82 (1993) 286–290.
[8] A. Akahane, H. Katayama, T. Mitsunaga, J. Med. Chem. 42 (1999) 779–783.
[9] D.G.H. Livermone, R.C. Bethell, N. Cammack, J. Med. Chem. 36 (1993)
3784–3794.
4.2.2. Conditioning/training of animals
For conducting the BP measurement studies, the animals were
kept in a restrainer for 10 min every day for one week. This exercise
was done to avoid the fluctuation in blood pressure due to
aggressive behavior of animal while keeping into the restrainer for
measuring the activity.
[10] W. Malinka, A. Redzicka, O. Lozach, Il Farmaco 59 (2004) 457–462.
[11] K. Abouzid, M.A. Hakeem, O. Khalil, Y. Maklad, Bioorg. Med. Chem. 16 (2008)
382–389.
[12] D.W. Combs, M.S. Rampulla, S.C. Bell, D.H. Klaubert, A.J. Tobia, R. Falotico,
B. Haertlein, C.L. Weiss, J.B. Moore, J. Med. Chem. 22 (1990) 380–386.
[13] D.W. Robertson, N.D. Jones, J.H. Krushinski, G.D. Pollock, J.K. Swartzendruber,
J. Scott Hayes, J. Med. Chem. 30 (1987) 623–627.
[14] S. Archan, W. Toller, Curr. Opin. Anesthesiol 21 (1) (2008) 78–84.
[15] E. Sotelo, A. Coelho, E. Ravina, Tetrahedron Lett. 44 (2003) 4459–4462.
[16] A.A. Siddiqui, S.R. Ahmad, S.A. Hussain, Acta. Pol. Pharm. 64 (2) (2008)
223–228.
4.2.3. Induction of hypertension in normotensive rats
After recording the initial BP of rats, the animals were divided
into groups of 5 animals each. One group was taken as control.
Hypertension was induced in the remaining groups by subcuta-
neous injection of methyl prednisolone acetate (20 mg/kg/wk) for 2
weeks as per method reported by Krakoff et al. [21].
4.2.4. Measurement of mean blood pressure of rats
[17] A.A. Siddiqui, Ashok, S.M. Wani, Ind. J. Heterocycl. Chem. 13 (2004) 257–260.
[18] R.E. Borchard, C.D. Barnes, L.G. Eltherington, Drug Dosage in Laboratory
Animals: A Handbook, third ed. The Telford Press Inc., New Jersey, 1991.
[19] M.S.Y. Khan, A.A. Siddiqui, Ind. J. Chem. 39B (2000) 614–620.
[20] A.A. Siddiqui, M. Islam, M. Asif, C. Asthana, J. Ultra. Chem. 3 (2) (2007)
176–178.
[21] L.R. Krakoff, R. Selvadurai, E. Sytter, Effect of methylprednisolone upon arterial
pressure and the renin angiotensin system in the rat. Am. J. Physiol. 228 (1975)
613–617.
Mean arterial blood pressure was measured in conscious rats
using CODA Non Invasive Blood Pressure Recorder by Tail–Cuff
method (Kent Scientific Corporation, USA). The restrainer carrying
the rat was placed in the BP instrument with tail protruding out.
The tail was gently placed in contact with a transducer membrane,
which was connected to the digital BP display panel. The instru-
ment was then turned on and allowed to stabilize until steady