Some pyrrole substituted aryl pyridazinone and phthalazinone derivatives and their antihypertensive activities

Article abstract of DOI:10.1016/j.ejmech.2004.09.005

In this work, some 2-nonsubstituted/2-methyl-/2-(2-acetyloxyethyl)-6-[4- (substituted pyrrol-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone, derivatives and 2-nonsubstituted/2-methyl- 4-[4-(substituted pyrrol-1-yl)phenyl]-1(2H)- phthalazinone derivatives wer

Full text of DOI:10.1016/j.ejmech.2004.09.005

European Journal of Medicinal Chemistry 39 (2004) 1089–1095
www.elsevier.com/locate/ejmech
Laboratory note
Some pyrrole substituted aryl pyridazinone
and phthalazinone derivatives
and their antihypertensive activities
Seref Demirayak a,*, Ahmet Cagri Karaburun a, Rana Beis b
a Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Anadolu, 26470, Eskisehir, Turkey
b Department of Pharmacology, Faculty of Pharmacy, University of Anadolu, 26470, Eskisehir, Turkey
Received 14 May 2004; received in revised form 20 July 2004; accepted 6 September 2004
Available online 22 October 2004
Abstract
In this work, some 2-nonsubstituted/2-methyl-/2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazi-
none, derivatives and 2-nonsubstituted/2-methyl- 4-[4-(substituted pyrrol-1-yl)phenyl]-1(2H)-phthalazinone derivatives were synthesised by
reacting hexan-2,5-dion or 1-aryl-3-carbethoxypent-1,4-diones with corresponding 2-substituted/nonsubstituted 6-(4’-aminophenyl)-4,5-
dihydro-3(2H)-pyridazinone or 2-substituted/nonsubstituted-4-(4’-aminophenyl)-(2H)-phthalazinone under Paal–Knorr pyrrole synthesis
conditions. The antihypertensive activities of the compounds were examined both in vitro and in vivo. Some pyridazinone derivatives showed
appreciable activity.
© 2004 Elsevier SAS. All rights reserved.
Keywords: Pyridazinone; Phthalazinone; Pyrrole; Antihypertensive activity
1. Introduction
phosphodiesterase [18–20] and antiasthmatic effects [21–25]
on cardiovascular system. Considering the 6-aryl-3(2H)-
pyridazinone residue as the pharmacophoric group for the
activity [26,27], in this work; we aimed to obtain some new
derivatives of this class. Therefore, we focused on the forma-
tion of a ring system on the pharmacophoric pyridazinone
residue and its benzene condensed analogue phthalazinone
with a similar rationale of the cited studies above. For this
purpose, pyrrole moiety was selected.Although pyrrole or its
reduced form pyrrolidine exists in some antihypertensive
compounds such as, angiotensin converting enzyme (ACE)
inhibitors like kaptopril, enalapril and fosinopril, some ACE
II receptor antagonists [28], and Ca antagonist and vasodila-
tor bepridil, and moreover, pyrrole [29–31] substituted
arylpyridazinones were previously reported to possess hope-
ful activities on cardiovascular system, there is no evidence
showing that the pyrrole moiety is directly related with activ-
ity. However, it may be concluded that its role as contributor
to the pharmacological activity in those compounds is help-
ful. Using these features and as continuation to our work on
6-aryl-3(2H)-pyridazinones [9], in this study, we synthesised
some pyrrole substituted 6-aryl-3(2H)-pyridazinones and
Hypertension is not only the most common cardiovascular
disease and the principal cause of stroke but also leads to
disease of the coronary arteries with myocardial infarction
and sudden cardiac death, and is a major contributor to
cardiac failure, renal insufficiency [1]. As a consequence,
great efforts have been made on obtaining novel antihyper-
tensive agents acting on different mechanisms [2,3]. Espe-
cially the studies on the hydralazine group drugs I lead to the
synthesis of many pyridazinone and phthalazinone deriva-
tives II with a wide activity spectrum on cardiovascular
system [4,5]. Beside those reviewed, researches on pyridazi-
none derivatives and its analogues have still being carried on.
During our literature research, we observed that compounds
synthesised in the recent studies possessed notable antihy-
pertensive [6–9], platelet aggregation inhibitor [10–17],
* Corresponding author. Tel.: +90-222-3350580/3632;
fax: +90-222-3350750.
E-mail address: sdemiray@anadolu.edu.tr (S. Demirayak).
0223-5234/$ - see front matter © 2004 Elsevier SAS. All rights reserved.
doi:10.1016/j.ejmech.2004.09.005

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S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
1(2H)-phthalazinones and tested their antihypertensive
activities.
mentioned aminophenyl residue bearing derivatives were
reacted with suitable 1,4-dicarbonyl compounds, 8, in acetic
acid under Paal–Knorr pyrrole synthesis conditions to obtain
the aimed compounds as depicted in Figs. 1 and 2. In the
synthesis of the compounds, 13, unlike the synthesis of all
the other compounds, acetic anhydrite was added to the
reaction mixture in order to obtain 2-(2-acetyloxyethyl)-6-
[4-(substituted
pyrrole-1-yl)phenyl]-4,5-dihydro-3(2H)-
pyridazinones. The structures of the synthesised compounds
were elucidated by IR, 1H-NMR, EI-MS spectra and elemen-
tal analysis results. In the IR spectra, amide C=O stretching
bands of pyridazinone and phthalazinone ring systems,
which are characteristic for all compounds, were observed at
1660–1680 cm–1 and 1640–1660 cm–1 regions, respectively.
The stretching bands belonging to pyridazinones’ carbonyl
group observed in lower frequencies than phthalazinones’,
this shift might be attributed to the resonance in phthalazino-
nes. The other characteristic groups are the carbonyl group of
carbethoxy group on pyrrole ring, i.e. present in most of the
compounds, and the carbonyl group of acetyloxy residue of
compounds 13. As expected, they were observed at about
1700–1690 cm–1 and 1740 cm–1 regions, respectively. In the
NMR spectra of pyridazinone residue bearing compounds,
pyridazinone C4 and C5 protons resonated at 2.7 and
3.2 ppm, respectively. 2-Nonsubstituted pyridazinones’ N-H
peaks were observed at about 9 ppm. In compounds 13,
methyl and methylene protons of acetyloxy moiety charac-
teristically resonated at 2 ppm for methyl and 4.14 and
4.4 ppm for methylene groups. In phthalazinone residue
bearing compounds, characteristic phthalazinone C5 and C8
protons resonated as doublets at about 7.8 and 8.5 ppm,
respectively. However, phthalazinone C6,7 protons resonated
2. Chemistry
The syntheses of 6-[4-(substituted pyrrol-1-yl)phenyl]-
4,5-dihydro-3(2H)-pyridazinone, 9, 2-methyl-6-[4-(substi-
tuted pyrrol-1-yl)phenyl]-4,5-dihydro-3(2H)-pyridazinone,
11, 2-(2-acetyloxyethyl)-6-[4-(substituted pyrrol-1-yl)
phenyl]-4,5-dihydro-3(2H)-pyridazinone, 13, derivatives
along with 4-[4-(substituted pyrrol-1-yl)phenyl]-1(2H)-
phthalazinone, 10, and 2-methyl-4-[4-(substituted pyrrol-1-
yl)phenyl]-1(2H)-phthalazinone, 12, derivatives were aimed
in this work. 6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazi-
none, 3, 2-methyl-6-(4-aminophenyl)-4,5-dihydro-3(2H)-
pyridazinone, 5, 2-(2-hydroxyethyl)-6-(4-aminophenyl)-4,5-
dihydro-3(2H)-pyridazinone, 7, 4-(4-aminophenyl)-1-(2H)-
phthalazinone, 4, and 2-methyl-4-(4-aminophenyl)-1-(2H)-
phthalazinone, 6, required as starting material were readily
accomplished in high yields by refluxing the requisite c-keto
acid with hydrazine derivatives in ethanol [32–34]. Above-
Fig. 1. Syntheses of the starting compounds.

S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
1091
Fig. 2. Syntheses of the compounds.
as multiplets at about 8 ppm. 2-Nonsubstituted phthalazino-
nes’ N-H peaks were shifted and observed at about 13 ppm.
As denoted, pyridazinones’ N-H peaks were observed at
about 9 ppm, this situation may be attributable to the in-
creased acidity of the mentioned protons’ by comparison of
the more aromatic character bearing phthalazinone residue
with pyridazinone residue. All the other aromatic and ali-
phatic protons resonated as expected. In the EI-MS spectra,
molecular ion peaks were not obtained for compounds 10d
and 10e, for the other compounds the molecular peaks were
obtained, but molecular peak intensities were quite lower for
ester residue carrying compounds (almost lower than 5% for
all the compounds). This is an expected situation for ester
residue carrying compounds [35]. It is noteworthy that, in
these compounds, the peaks of the proposed fragments
formed with cleavage of the ester residue formed notable
peaks; even in compounds 10d, 10e and 12b M-46 fragment
formed the base peak.
effects of compounds were endothelium independent in na-
ture. It was found 9c and 9d were highest effective com-
pounds in this group. The following effective compounds are
9a, 9b and 9f. In consideration of the inhibition values
obtained, it is seen that the pyridazinone derivatives, 9, are
Table 1
Inhibitory effects of the compounds on isolated rat aorta
Compound (10–4 M)
% Inhibition of Phe contractions ( SEM)
38 4.2
9a
9b
29 6.8 *
9c
9d
9e
9f
48.8 7.9 *
44.2 4.5 *
25.2 6.5 *
36 3.9 *
10a
10b
10d
10e
11a
11b
11c
12b
13b
13c
13d
27 5.6
24.6 7.7 *
17.45 3.6
24.8 5.9
29 6.1
28.8 6.7 *
16.5 5.3
3. Results and discussion
27.6 6.5
33.9 8.3
The compounds were investigated for vasorelaxant effects
on isolated rat aorta. The results were shown in Table 1. Since
the endothelium layer was removed in our experiments, the
24.1 4.7
28.9 4.5
(* P < 0.05).

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S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
Table 2
4. Experimental protocols
Systolic blood pressures (mmHg)
Compound (20 mg/kg)
The mean of systolic blood pressure
4.1. Chemistry
Control
DMSO
Hydralazine a
9a
9b
9c
9d
9e
9f
10a
10b
10d
10e
11a
11b
107.29 6.94
105.2 3.66
Melting points were determined by using an Electrother-
83.59 6.39
80.05 4.25
83.07 3.15*
82.77 4.46
83.89 9.87
89.8 12.3
mal 9100 digital melting point apparatus and were uncor-
rected. Spectroscopic data were recorded on the following
instruments: FT-IR: Schimadzu 8400S spectrophotometer,
1H-NMR: Bruker DPX 400 NMR spectrometer. MS: VG
Zabspec Mass Spectrometer. Analyses for C, H, N were
within 0.4% of the theoretical values, Leco CHNS Analyser.
6-(4-Aminophenyl)-4,5-dihydro-3(2H)-pyridazinone,
(M.p.: 236–7 °C. Lit. [27] M.p: 237–8 °C), 2-methyl-6-(4-
aminophenyl)-4,5-dihydro-3(2H)-pyridazinone (M.p.: 216–
7 °C, Lit. [36] M.p.: 216–8 °C), 2-(2-hydroxyethyl)-6-(4-
aminophenyl)-4,5-dihydro-3(2H)-pyridazinone (M.p.: 147–
9 °C), 4-(4-aminophenyl)-1-(2H)-phthalazinone, (M.p.:
245–7 °C, Lit. [37] M.p.: 246–8 °C) 2-methyl-4-(4-
aminophenyl)-1-(2H)-phthalazinone (M.p.: 219–20 °C, Lit.
[38] M.p.: 220 °C) and 1-aryl-3-carbethoxy-1,4-pentadiones
[39] required as starting materials were prepared according
to the literature methods.
70.30 6.34*
93.07 3.55
100.72 3.70
82.34 1.82*
91.25 3.02
90.5 5.03
101.4 3.25
110.40 3.53
109.80 1.93
86.8 2.48*
97.96 4.96
89.80 1.83
11c
12b
13b
13c
13d
All the values were expressed as mean SEM (*P ≤ 0.05).
a Dose of hydralazine was taken as 2.6 mg/kg [43].
Some characteristics of the compounds are shown in
Table 3.
2-Nonsubstituted/2-methyl 6-(4’-substituted pyrrol-1-
yl)phenyl-4,5-dihydro-3(2H)-pyridazinone and 2-nonsubsti-
tuted/2-methyl 4-(4’-substituted pyrrol-1-yl)phenyl-1(2H)-
phthalazinone derivatives 9,10,11,12.
more active, i.e. not only the smallest of the synthesised
compounds in volume but also N-nonsubstituted pyridazi-
none derivatives. When reports in the literature on
N-nonsubstituted pyridazinone derivatives possessing higher
vasodilator activity were taken into account, we may con-
clude that a parallel result was obtained in our study.
A mixture of 3 or (4 or 5 or 6) (10 mmol) and an appro-
priate 8 (10 mmol) was refluxed in acetic acid for 1 h. The
reaction mixture was poured into ice water. The precipitate
formed was filtered and crystallised from ethanol-DMF mix-
ture.
Antihypertensive activities of the compounds were tested
by using Tail–Cuff method. The results were shown in
Table 2. In the antihypertensive activity tests, when the blood
pressure values of the control group and DMSO, i.e. used for
solving the compounds, were compared, we may say that the
effect of this solvent on blood pressure is in a negligible
amount. In these test, hydralazine, which has a similar
chemical structure with our compounds, was used as control
antihypertensive. Although there is difference between the
dose of hydralazine and our compounds tested, when the
systolic blood pressure values obtained was compared, it is
seen that the most significant activity was observed for com-
pound 9f. Also, in these tests we may conclude that, in
analogy with the vasorelaxant activity tests, the most active
compound group seems to be the first members of the syn-
thesised series, i.e. N-nonsubstituted pyridazinones, 9. Be-
sides, it is seen that also the compounds 10d and 13b showed
significant activity.
9a IR(KBr)mmax(cm–1) : 3274(N-H), 1681(C=O), 1614-
1
1540(C=N, C=C). H-NMR(400 MHz)(CDCl3) d (ppm) :
2.18 (s, 6H), 2.82 (t, 2H, J = 8.12 Hz), 3.16 (t, 2H, J
= 8.18 Hz), 6.16 (s, 2H), 7.26 (d, 2H, J = 8.32 Hz), 7.92 (d,
2H, J = 8.37 Hz), 9.01 (bs, 1H).
9b IR(KBr)mmax(cm–1) : 3217(N-H), 1703(Ester C=O),
1
1681(C=O), 1618-1558(C=N, C=C). H-NMR(400 MHz)
(CDCl3) d (ppm) : 1.54 (t, 3H, J = 7.12 Hz), 2.58 (s, 3H), 2.80
(t, 2H, J = 8.23 Hz), 3.16 (t, 2H, J = 8.23 Hz), 4.49 (q, 2H, J
= 7.12 Hz), 6.97 (s, 1H), 7.22 (d, 2H, J = 7.92 Hz), 7.30-7.36
(m, 5H), 7.92 (d, 2H, J = 8.57 Hz), 9.03 (s, 1H). EI-MS: m/z:
401.80 M+, 401.16, 371.50, 115.09, 43.38 (%100).
9c IR(KBr)mmax(cm–1) : 3222(N-H), 1703(Ester C=O),
1
1681(C=O), 1612-1558(C=N, C=C). H-NMR(400 MHz)
(CDCl3) d (ppm) : 1.54 (t, 3H, J = 7.11 Hz), 2.42 (s, 3H), 2.58
(s, 3H), 2.81 (t, 2H, J = 8.21 Hz), 3.17 (t, 2H, J = 8.23 Hz),
4.49 (q, 2H, J = 7.12 Hz), 6.93 (s, 1H), 7.11 (d, 2H, J
= 8.64 Hz), 7.13 (d, 2H, J = 8.57 Hz), 7.35 (d, 2H, J
= 8.52 Hz), 7.92 (d, 2H, J = 8.53 Hz), 8.93 (bs, 1H).
When vasorelaxant activity was taken into consideration,
most active compounds are bearing methyl and methoxy
substitutions, while this substitution is the nitro group for
antihypertensive activity. Therefore, it is seen that there is no
meaningful difference between different substituent groups
and activity.
9d IR(KBr)mmax(cm–1) : 3211(N-H), 1693(Ester C=O),
1
1670(C=O), 1614-1533(C=N, C=C). H-NMR(400 MHz)
(CDCl3) d (ppm) : 1.54 (t, 3H, J = 7.23 Hz), 2.57 (s, 3H), 2.49
(s, 3H), 2.81 (t, 2H, J = 8.22 Hz), 3.17 (t, 2H, J = 8.25 Hz),

S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
1093
Table 3
Some characteristics of the compounds
Comp.
9a
9b
9c
9d
R1
R2
R3
M.p. (C)
290 Dec.
169–70
Yield (%)
22
Mol. Formula (Anal. C,H,N)
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
CH3
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
C
16H17N3O
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
H
-C6H5
66
24H23N3O3
25H25N3O3
25H25N3O4
24H22ClN3O3
24H22N4O5
20H17N3O
-C6H4-p-CH3
-C6H4-p-OCH3
-C6H4-p-Cl
-C6H4-p-NO2
CH3
233–234
210–212
261–263
303–305
310 Dec.
242–245
247–248
249–250
272–274
288–290
110–111
146–147
201–203
240–243
219–220
198–199
78–80
59
83
9e
9f
95
55
10a
10b
10c
10d
10e
10f
11a
11b
11c
12a
12b
12c
13a
13b
13c
13d
13e
15
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
H
-C6H5
38
28H23N3O3
29H25N3O3
29H25N3O4
28H22ClN3O3
28H22N4O5
17H19N3O
-C6H4-p-CH3
-C6H4-p-OCH3
-C6H4-p-Cl
-C6H4-p-NO2
CH3
18
95
90
42
25
COOCH2CH3
COOCH2CH3
H
-C6H5
45
25H25N3O3
25H24ClN3O3
21H19N3O
-C6H4-p-Cl
CH3
45
32
COOCH2CH3
COOCH2CH3
H
-C6H5
31
29H25N3O3
29H24ClN3O3
20H23N3O3
28H29N3O5
29H31N3O5
28H28ClN3O5
28H28N4O7
-C6H4-p-Cl
CH3
48
21
COOCH2CH3
COOCH2CH3
COOCH2CH3
COOCH2CH3
-C6H5
92–94
37
-C6H4-p-CH3
-C6H4-p-Cl
-C6H4-p-NO2
103–105
157–158
139–140
41
57
43
4.49 (q, 2H, J = 7.10 Hz), 6.96-6.98 (m, 3H), 7.21 (d, 2H, J
= 8.55 Hz), 7.32 (d, 2H, J = 8.52 Hz), 7.92 (d, 2H, J
= 8.53 Hz), 8.97 (bs, 1H).
10c IR(KBr)mmax(cm–1): 3248(N-H), 1680-1660(Ester
C=O, C=O), 1602-1556(C=N, C=C). H-NMR(400 MHz)
1
(DMSO-d6) d (ppm) : 1.48 (t, 3H, J = 7.11 Hz), 2.42 (s, 3H),
2.58 (s, 3H), 4.48 (q, 2H, J = 7.09 Hz), 6.88 (s, 1H), 7.12 (d,
2H, J = 8.75 Hz), 7.17 (d, 2H, J = 8.68 Hz), 7.60 (d, 2H, J
= 8.52 Hz), 7.78 (d, 1H, J = 8.03 Hz), 7.83 (d, 2H, J
= 8.51 Hz), 8.08 (m, 2H), 8.50 (d, 1H, J = 8.25 Hz), 13.00 (s,
1H).
9e IR(KBr)mmax(cm–1) : 3205(N-H), 1693(Ester C=O),
1
1670(C=O), 1622-1556(C=N, C=C). H-NMR(400 MHz)
(CDCl3) d (ppm) : 1.54 (t, 3H, J = 7.11 Hz), 2.58 (s, 3H), 2.82
(t, 2H, J = 8.21 Hz), 3.18 (t, 2H, J = 8.23 Hz), 4.49 (q, 2H, J
= 7.12 Hz), 6.96 (s, 1H), 7.14 (d, 2H, J = 8.59 Hz), 7.29 (d,
2H, J = 8.59 Hz), 7.34 (d, 2H, J = 8.57 Hz), 7.94 (d, 2H, J
= 8.56 Hz), 8.80 (s, 1H). EI-MS: m/z: 435.59 M+, 408.70,
409.89, 408.70, 406.06 (%100), 364.23, 115.34.
10d IR(KBr)mmax(cm–1) : 3202(N-H), 1687(Ester C=O),
1
1658(C=O), 1606-1558(C=N, C=C). H-NMR(400 MHz)
(DMSO-d6) d (ppm) : 1.45 (t, 3H, J = 7.09 Hz), 2.55 (s, 3H),
3.85 (s, 3H), 4.40 (q, 2H, J = 7.09 Hz), 6.77 (s, 1H), 6.96 (d,
2H, J = 8.79 Hz), 7.20 (d, 2H, J = 8.67 Hz), 7.57 (d, 2H, J
= 8.32 Hz), 7.78 (d, 1H, J = 8.01 Hz), 7.83 (d, 2H, J
= 8.31 Hz), 8.08 (m, 2H), 8.51 (d, 1H, J = 8.27 Hz), 13.07 (s,
1H). EI-MS: m/z: 456.91, 455.85, 454.60, 451.86, 449.29
(%100), 190.09.
9f IR(KBr)mmax(cm–1) : 3199(N-H), 1697(Ester C=O),
1672(C=O), 1595-1558(C=N, C=C), 1515, 1342(N=O). 1H-
NMR(400 MHz)(DMSO-d6) d (ppm) : 1.53 (t, 3H, J
= 7.08 Hz), 2.58 (s, 3H), 2.69 (t, 2H, J = 8.14 Hz), 3.21 (t, 2H,
J = 8.25 Hz), 4.49 (q, 2H, J = 7.08 Hz), 6.96 (s, 1H), 7.27 (d,
2H, J = 8.84 Hz), 7.33 (d, 2H, J = 8.50 Hz), 7.83 (d, 2H, J
= 8.50 Hz), 7.99 (d, 2H, J = 8.84 Hz), 10.96 (s, 1H).
10e IR(KBr)mmax(cm–1) : 3249(N-H), 1672(Ester C=O),
10a IR(KBr)mmax(cm–1): 3295(N-H), 1664(C=O), 1606-
1654(C=O), 1606-1556(C=N, C=C). H-NMR(400 MHz)
1
1
1519(C=N, C=C). H-NMR(400 MHz)(CDCl3) d (ppm) :
(DMSO-d6) d (ppm) : 1.46 (t, 3H, J = 7.08 Hz), 2.57 (s, 3H),
4.40 (q, 2H, J = 7.04 Hz), 6.93 (s, 1H), 7.28 (d, 2H, J
= 8.53 Hz), 7.46 (d, 2H, J = 8.50 Hz), 7.60 (d, 2H, J
= 8.23 Hz), 7.80 (d, 1H, J = 7.70 Hz), 7.85 (d, 2H, J
= 8.22 Hz), 8.08 (m, 2H), 8.51 (d, 1H, J = 8.18 Hz), 13.08 (s,
1H). EI-MS: m/z: 458.65, 457.02, 455.04, 453.13 (%100),
189.28.
2.26 (s, 6H), 6.18 (s, 2H), 7.61 (d, 2H, J = 8.30 Hz), 7.94 (d,
2H, J = 8.29 Hz), 8.09-8.06 (m, 3H), 8.78 (m, 1H), 11.26 (s,
1H). EI-MS: m/z: 315.65 M+, 314.75 M-1, 189.54, 162.85,
43.41, 41.42 (%100).
10b IR(KBr)mmax(cm–1): 3294(N-H), 1693(Ester C=O),
1
1654(C=O), 1600-1556(C=N, C=C). H-NMR(400 MHz)
(DMSO-d6) d (ppm) : 1.46 (t, 3H, J = 7.09 Hz), 2.57 (s, 3H),
4.40 (q, 2H, J = 7.10 Hz), 6.89 (s, 1H), 7.27-7.41 (m, 5H),
7.59 (d, 2H, J = 8.39 Hz), 7.78 (d, 1H, J = 7.65 Hz), 7.83 (d,
2H, J = 8.38 Hz), 8.08 (m, 2H), 8.50 (d, 1H, J = 7.67 Hz),
13.07 (s, 1H).
10f IR(KBr)mmax(cm–1) : 3205(N-H), 1693(Ester C=O),
1650(C=O), 1606-1556(C=N, C=C), 1508, 1338(N=O). 1H-
NMR(400 MHz)(DMSO-d6) d (ppm) : 1.53 (t, 3H, J
= 7.10 Hz), 2.58 (s, 3H), 3.85 (s, 3H), 4.50 (q, 2H, J
= 7.10 Hz), 6.97 (s, 1H), 7.23 (d, 2H, J = 8.69 Hz), 7.60 (d,

1094
S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
2H, J = 8.32 Hz), 7.83 (d, 1H, J = 8.01 Hz), 7.78 (d, 2H, J
= 8.31 Hz), 7.85 (d, 2H, J = 8.70 Hz), 8.10 (m, 2H), 8.49 (d,
1H, J = 8.27 Hz), 13.05 (s, 1H).
(400 MHz)(DMSO-d6) d (ppm) : 1.44 (t, 3H, J = 7.08 Hz),
2.08 (s, 3H), 2.49 (s, 3H), 2.70 (t, 2H, J = 8.15 Hz), 3.15 (t,
2H, J = 8.11 Hz), 4.15 (t, 2H, J = 5.45 Hz), 4.37 (q, 2H, J
= 7.10 Hz), 4.46 (t, 2H, J = 5.47 Hz), 6.89 (s, 1H), 7.21-7.46
(m, 5H), 7.49 (d, 2H, J = 8.25 Hz), 8.03 (d, 2H, J = 8.25 Hz).
13c IR(KBr)mmax(cm–1) : 1735(Acetyl C=O), 1699(Ester
C=O), 1672(C=O), 1575-1533(C=N, C=C). 1H-NMR
(400 MHz)(DMSO-d6) d (ppm) : 1.48 (t, 3H, J = 7.10 Hz),
2.10 (s, 3H), 2.49 (s, 3H), 2.78 (t, 2H, J = 8.20 Hz), 3.16 (t,
2H, J = 8.22 Hz), 4.15 (t, 2H, J = 5.45 Hz), 4.36 (q, 2H, J
= 7.12 Hz), 4.42 (t, 2H, J = 5.10 Hz), 6.90 (s, 1H), 7.15 (d,
2H, J = 8.50 Hz), 7.30 (d, 2H, J = 8.50 Hz), 7.49 (d, 2H, J
= 8.25 Hz), 8.02 (d, 2H, J = 8.27 Hz).
11a IR(KBr)mmax(cm–1) : 1662(C=O), 1614-1515(C=N,
1
C=C). H-NMR(400 MHz)(DMSO-d6) d (ppm) : 2.14 (s,
6H), 2.69 (t, 2H, J = 8.22 Hz), 3.19 (t, 2H, J = 8.22 Hz), 3.49
(s, 3H), 5.97 (s, 2H), 7.48 (d, 2H, J = 8.54 Hz), 8.05 (d, 2H, J
= 8.54 Hz).
11b IR(KBr)mmax(cm–1) : 1693(Ester C=O), 1658(C=O),
1606-1558(C=N, C=C). 1H-NMR(400 MHz)(CDCl3) d
(ppm) : 1.54 (t, 3H, J = 7.11 Hz), 2.58 (s, 3H), 2.80 (t, 2H, J
= 8.20 Hz), 3.14 (t, 2H, J = 8.17 Hz), 3.60 (s, 3H), 4.49 (q,
2H, J = 7.11 Hz), 6.98 (s, 1H), 7.20 (d, 2H, J = 8.45 Hz),
7.30-7.37 (m, 5H,), 7.92 (d, 2H, J = 8.50 Hz).
13d IR(KBr)mmax(cm–1) : 1739(Acetyl C=O), 1690-
1677(Ester C=O, C=O), 1602-1558(C=N, C=C). 1H-
NMR(400 MHz)(DMSO-d6) d (ppm) : 1.44 (t, 3H, J
= 7.08 Hz), 2.08 (s, 3H), 2.48 (s, 3H), 2.69 (t, 2H, J
= 8.23 Hz), 3.15 (t, 2H, J = 8.21 Hz), 4.14 (t, 2H, J
= 5.45 Hz), 4.38 (q, 2H, J = 7.09 Hz), 4.42 (t, 2H, J
= 5.49 Hz), 6.89 (s, 1H), 7.23 (d, 2H, J = 8.55 Hz), 7.42 (d,
2H, J = 8.55 Hz), 7.49 (d, 2H, J = 8.55 Hz), 8.03 (d, 2H, J
= 8.53 Hz). EI-MS: m/z: 521.83 M+1, 521.07M+, 432.68,
431.54, 334.76, 73.28, 55.38, 43.38 (%100).
11c IR(KBr)mmax(cm–1) : 1697(Ester C=O), 1672(C=O),
1606-1552(C=N, C=C). 1H-NMR(400 MHz)(CDCl3) d
(ppm) : 1.54 (t, 3H, J = 7.11 Hz), 2.58 (s, 3H), 2.79 (t, 2H, J
= 8.23 Hz), 3.14 (t, 2H, J = 8.17 Hz), 3.64 (s, 3H), 4.49 (q,
2H, J = 7.11 Hz), 6.96 (s, 1H), 7.15 (d, 2H, J = 8.53 Hz), 7.30
(d, 2H, J = 8.45 Hz), 7.34 (d, 2H, J = 8.47 Hz), 7.96 (d, 2H, J
= 8.50 Hz). EI-MS: m/z: 449.86 M+1, 448.95 M+, 420.46,
101.21, 41.91 (%100).
12a IR(KBr)mmax(cm–1) : 1643(C=O), 1581-1577(C=N,
1
C=C). H-NMR(400 MHz)(CDCl3) d (ppm) : 2.30 (s, 6H),
13e IR(KBr)mmax(cm–1) : 1735(Acetyl C=O), 1690-
1680(Ester C=O, C=O), 1595-1560(C=N, C=C), 1514,
1342(N=O). 1H-NMR(400 MHz)(DMSO-d6) d (ppm) : 1.45
(t, 3H, J = 7.08 Hz), 2.08 (s, 3H), 2.51 (s, 3H), 2.70 (t, 2H, J
= 8.23 Hz), 3.15 (t, 2H, J = 8.50 Hz), 4.14 (t, 2H, J
= 5.45 Hz), 4.40 (q, 2H, J = 7.15 Hz), 4.42 (t, 2H, J
= 5.42 Hz), 7.17 (s, 1H), 7.47 (d, 2H, J = 8.91 Hz), 7.56 (d,
2H, J = 8.55 Hz) , 8.06 (d, 2H, J = 8.54 Hz), 8.19 (d, 2H, J
= 8.92 Hz).
4.11 (s, 3H), 6.12 (s, 2H), 7.56 (d, 2H, J = 8.44 Hz), 7.88 (d,
2H, J = 8.45 Hz), 7.94-8.00 (m, 3H), 8.72-8.75 (m, 1H).
12b IR(KBr)mmax(cm–1) : 1699(Ester C=O), 1645(C=O),
1585-1519(C=N, C=C). 1H-NMR(400 MHz)(CDCl3) d
(ppm) : 1.59 (t, 3H, J = 7.12 Hz), 2.70 (s, 3H), 4.14 (s, 3H),
4.55 (q, 2H, J = 7.12 Hz), 7.04 (s, 1H), 7.32-7.41 (m, 5H),
7.52 (d, 2H, J = 8.37 Hz), 7.84 (m, 3H), 8.00 (m, 2H), 8.75 (d,
1H, J = 7.72 Hz). EI-MS: m/z: 463.32 M+, 434.11 (%100),
233.17, 189.80, 42.88.
12c IR(KBr)mmax(cm–1): 1697(Ester C=O), 1641(C=O),
1583-1556(C=N, C=C). 1H-NMR(400 MHz)(CDCl3) d
(ppm) : 1.46 (t, 3H, J = 7.10 Hz), 2.58 (s, 3H), 4.10 (s, 3H),
4.42 (q, 2H, J = 7.11 Hz), 6.96 (s, 1H), 7.28 (d, 2H, J
= 8.37 Hz), 7.46 (d, 2H, J = 7.72 Hz), 7.60 (d, 2H, J
= 7.75 Hz), 7.86-8.00 (m, 5H), 8.72-8.75 (m,1H).
4.2. Pharmacology
Male wistar rats between 200 and 300 g were killed by
cervical dislocation. For the endothelium-denuded rings,
segments of thoracic aorta (3–5 mm) were gently rubbed to
remove the endothelium. Using a resting tension of 1 g,
tissues were set up in 10-ml organ baths containing Krebs–
Henseleit solution at 37 °C and bubbled with 95% O2–5%
CO2. To assess phenylephrine (10–6 M) (Sigma, St. Louis,
MO) induced contractions, isometric transducers and
Gemini recorders (Ugo Basile, Varese, Italy) were used for
recording organ responses [40]. Rings of aorta were precon-
tracted with phenylephrine (Phe) (10–6 M) and exposed to
acetylcholine (ACh) (10–6 M) to test endothelium-dependent
relaxations (EDR) [41]. Test material was dissolved in
DMSO. Compounds were applied to the organ bath at a
concentration of 10–4 M.
5.1. 2-(2-Acetyloxyethyl)-6-(4’-substituted pyrrol-1-yl)
phenyl-4,5-dihydro-3(2H)-pyridazinones 13
A mixture of 7 (10 mmol) and an appropriate 8 (10 mmol)
was refluxed in acetic acid for 45 min then excess acetic
anhydrite was added and heated for 15 min. The reaction
mixture was poured into ice water. The precipitate formed
was filtered and crystallised from diethyl ether–ethanol mix-
ture.
13a IR(KBr)mmax(cm–1)
:
1739(Acetyl C=O),
1
1670(C=O), 1541-1516(C=N, C=C). H-NMR(400 MHz)
(CDCl3) d (ppm) : 2.10 (s, 3H), 2.20 (s, 6H), 2.70 (t, 2H, J
= 8.12 Hz), 3.15 (t, 2H, J = 8.16 Hz), 4.14 (t, 2H, J
= 5.65 Hz). 4.42 (t, 2H, J = 5.69 Hz), 6.16 (s, 2H), 7.47 (d,
2H, J = 8.32 Hz), 8.05 (d, 2H, J = 8.37 Hz).
Systolic blood pressure was measured in conscious rats
using Tail–Cuff method [42]. Wistar rats (body weight 200–
250 g) were used in the present study. Rats were assigned to
groups of five animals each. The compounds were dissolved
in DMSO. The compounds at the dose level of 20 mg/kg
body weight were injected intraperitoneally. The Tail–Cuff
13b IR(KBr)mmax(cm–1) : 1741(Acetyl C=O), 1695(Ester
C=O), 1672(C=O), 1604-1558(C=N, C=C). 1H-NMR

S. Demirayak et al. / European Journal of Medicinal Chemistry 39 (2004) 1089–1095
1095
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Acknowledgements
Authors are grateful to Anadolu University, Commission
of Scientific Research Projects for the support of this work.
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