Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone

Article abstract of DOI:10.1016/j.ejmech.2009.06.006

Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone are reported. An effect of substitution at 2-position of pyridazinone ring on vasodilatory potential has also been explored. The m

Full text of DOI:10.1016/j.ejmech.2009.06.006

European Journal of Medicinal Chemistry 44 (2009) 4441–4447
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European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and vasodilatory activity of some amide derivatives of
6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone
,
a
b
b
Ranju Bansal a , Dinesh Kumar , Rosalia Carron , Carmen de la Calle
*
a University Institute of Pharmaceutical Sciences, Panjab University, Sector 14, Chandigarh 160014, India
b
´
´
Departamento de Fisiologıa y Farmacologıa, Facultad de Farmacia, Campus ‘‘Miguel de Unamuno’’ E-37007 Salamanca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis and vasodilatory activity of some amide derivatives of 6-(4-carboxymethyloxyphenyl)-4,5-
dihydro-3(2H)-pyridazinone are reported. An effect of substitution at 2-position of pyridazinone ring on
vasodilatory potential has also been explored. The most active compound 6-[4-(2-oxo-2-pyrrolidin-1-yl-
ethoxy)phenyl]-2-(4-fluorophenyl)-4,5-dihydropyridazin-3(2H)-one (11) exhibited vasodilating activity
Received 5 December 2008
Received in revised form
28 May 2009
Accepted 4 June 2009
Available online 13 June 2009
in nanomolar range (IC50 ¼ 0.051
mM).
Ó 2009 Elsevier Masson SAS. All rights reserved.
Keywords:
Hypertension
Pyridazinones
Hydrazine derivatives
Vasodilatory activity
1. Introduction
pyridazinone, which is about 10 times more active venous and
arterial vasodilator in comparison with milrinone [10]. Encouraged
by these reports, we thought of synthesizing a new series of 6-
phenoxypyridazinones in which heteroatom oxygen is attached
directly to the 4-position of phenyl ring along with an extended 4-
substituent that placed heteroatom nitrogen further away from ring
to improve upon the vasodilatory activity.
Also, from medicinal chemistry research point of view, pyr-
idazinones offer a vulnerable ring system to researchers because of
easy functionalization at various ring positions. As the position 2
remained relatively unexplored in context with the antihyperten-
sive effects, several 2-substituted products have also been
prepared. Herein we report the synthesis and vasodilatory effects of
a new series of pyridazinones, in which carbamoyl derivatives of
6-phenoxypyridazinones have been prepared along with
2-substitution.
Hypertension is the most common cardiovascular disease and is
the major risk factor for coronary artery disease leading to
myocardial infarction and sudden cardiac death, heart failure,
stroke and renal failure [1,2]. Great efforts have been made on
obtaining novel antihypertensive agents acting on different
mechanisms to control blood pressure [3]. The studies on the
hydralazine group drugs led to the synthesis of many pyridazinone
and phthalazinone derivatives with a wide activity spectrum on
cardiovascular system [4].
Pharmacological activity of 4,5-dihydro-6-phenyl-3(2H)-pyr-
idazinones has been actively studied since long and are known for
their cardiovascular effects [5–7]. Considering that the 6-arylpyr-
idazinone structure is essential for the activity on cardiovascular
system, a number of studies have been performed on different
substitutions on both pyridazinone and aryl residues [8,9]. These
studies indicate that compounds having amino, acylamino, cyano
and halogen substituents on phenyl ring possess interesting anti-
hypertensive activity, e.g., levosimendan (1) [9] (Fig 1). This action
persisted for a longer duration in compounds possessing a 5-methyl
substituent on pyridazinone core. However RS-1893 (2) (Fig 1),
a 6-phenoxypyridazinone, has also been reported as an orally active
2. Chemistry
Various new pyridazinone derivatives have been synthesized
according to Schemes 1–3. Compounds 10–17 were synthesized by
fusing phenoxyacetic acid methyl ester (3) [11] with heterocyclic
amines such as pyrrolidine and piperidine to obtain 4 [12] and 5
[13] in the first step. The subsequent Friedel–Crafts acylation
reaction [14] and cyclocondensation of obtained
g-keto acids 6–9
with various hydrazine derivatives afforded corresponding pyr-
idazinones 10–17 as shown in Scheme 1. In the NMR spectra of all
* Corresponding author. Tel.: þ911722541142.
E-mail address: ranju29in@yahoo.co.in (R. Bansal).
0223-5234/$ – see front matter Ó 2009 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2009.06.006

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R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
CN
CN
the 2-unsubstituted ones 10 and 14 at d 2.59 ppm. Efforts to
incorporate 2-phenyl group in pyrrolidinyl and 2-p-fluorophenyl
moiety in piperidinyl series were unsuccessful.
An alternate route was adopted for the preparation of pyr-
idazinones 25–29, which are substituted with a heterocyclic amine
bearing an additional heteroatom. Contrary to Scheme 1, Friedel–
Crafts acylation of the phenol ester 3 was carried out instead of its
H
N
N
HN
O
N
Cl
O
O
H3C
N
N
amine substituted derivative to obtain
outlined in Scheme 2. Interestingly, a singlet for methyl protons of
–OCH2COOCH3 was absent in case of -methyl-
-keto acid 19 in 1H
g-keto acids 18 and 19 as
NH
HN
b
g
O
(1)
O
NMR spectrum. It seems that during Friedel–Crafts acylation, when
methylsuccinic anhydride was used, ester group at 4-position of
phenyl ring got hydrolyzed to an acid. The structure of compound
19 was further confirmed using 13C NMR spectroscopy. Thermal
fusion of 18 and 19 with morpholine, powdered imidazole,
a versatile pharmacophore possessing a variety of pharmacological
and enzymatic actions including inotropic and vasodilatory activi-
ties [15] and N-methylpiperazine and further cyclization reaction
(2)
Fig. 1. Structures of levosimendan (1) and RS-1893 (2).
these pyridazinone ring-bearing compounds, 4-CH2 and 5-CH2
protons characteristically resonated at their expected positions.
Methylene protons of 4-CH2 were quite downfield at
case of 2-substituted derivatives 11, 12, 15 and 16 in comparison to
d w 2.80 in
R
OCH3
b
O
OH
O
O
O
a
(4,5)
(3)
Phenol
c
R
R
O
O
O
O
d
R1
OH
N
N
O
O
R1
(6-9)
R2
O
(10-17)
Compd
No.
Compd
No.
R
R1
R 2
R
R1
R 2
N
N
N
N
F
4
5
11
12
13
14
15
16
17
H
H
--
--
--
--
--
--
--
--
H
N
N
N
H
N
N
6
H
CH3
H
H
N
7
CH3
H
H
N
N
N
N
8
H
N
N
9
CH3
H
H
N
H
N
CH3
H
10
Scheme 1. Synthetic routes to compounds 3–17. Reagents and conditions: (a) methyl chloroacetate; (b) pyrrolidine/piperidine; (c) aluminium chloride, succinic anhydride/methyl
succinic anhydride; and (d) hydrazine hydrate/phenylhydrazine hydrochloride/p-fluoro phenylhydrazine hydrochloride/2-hydrazine-2-imidazoline hydrobromide, absolute
ethanol.

R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
4443
R
R
OR
O
O
O
O
O
O
a
c
b
3
R1
OH
OH
N
O
O
NH
O
O
R1
(18,19)
R1
(20-24)
O
(25-29)
18
19
20,25
21,26
22,27
23,28
24,29
Compd
No.
N
N
N
N-CH3
N
O
N
O
N
N
R
CH3
H
H
R1
CH3
H
CH3
H
CH3
H
Scheme 2. Synthetic route to compounds 18–29. Reagents and conditions: (a) aluminium chloride, succinic anhydride/methyl succinic anhydride; (b) morpholine/imidazole/
N-methylpiperazine, 70 ꢂC; and (c) hydrazine hydrate, ethanol.
with hydrazine hydrate in aldehyde free ethanol gave the target
products 25–29. Efforts to synthesize 2-substituted derivatives of
these pyridazinones were unsuccessful and impure products were
obtained every time.
10.06 ppm for –NH proton of parent pyridazinone nucleus in NMR
spectrum of 30. A singlet of methyl ester was also absent. The
reaction of 18 with phenylhydrazine hydrochloride and 2-hydra-
zino-2-imidazoline hydrobromide in absolute ethanol resulted into
base catalyzed transesterification to form ethyl esters 31 and 32. In
NMR spectra a singlet for protons of methyl ester was conspicu-
Attempts to directly cyclize
g-keto acid 18 using hydrazine
derivatives resulted in the formation of some unusual compounds
30–32 as depicted in Scheme 3. A hydrazide pyridazinone 30 was
obtained on treatment of 18 with hydrazine hydrate, which is in
anology with the earlier literature reports regarding the formation
of hydrazides from phenyl esters [14]. The infrared peaks in the
region 3300–3100 and a broad band at 1680 cmꢀ1 represented the
N–H stretching and bending modes, respectively. Two broad
singlets for protons of hydrazino functionality were prominently
ously absent, and instead two peaks at wd 1.35 (t, 3H, -OCH2CH3)
and w4.3 (q, 2H, –OCH2CH3) were present, which indicated the
transesterification of methyl ester to ethyl ester [16]. It seems that
highly reactive hydrazine hydrate immediately formed hydrazide
in case of compound 30, while for 31 and 32, less reactive phe-
nylhydrazine and 2-hydrazino-2-imidazoline salts were not able to
form hydrazides and transesterification took place instead.
present at
d 4.06 (s, 2H, –NH2) and 8.71 (–NH, disappeared on
deuterium exchange) in addition to another broad singlet at
3. Pharmacology
The newly synthesized pyridazinone derivatives 10,11,13–15,17,
25–29; standard drug hydralazine and prototypical compound
SK&F 93741 were screened for vasodilatory activity as reported
earlier [17], using rat thoracic aortic rings, precontracted with
phenylephrine (10ꢀ6 M). Imidazolinyl derivatives 12 and 16 could
not be screened for vasodilatory activity because of poor solubility
profile.
18
b
a
OCH2CH3
NHNH2
O
O
O
O
The results are expressed as percentage of the maximal control
phenylephrine-induced responses. Maximal relaxation (Emax) and
pD2 (ꢀlog IC50
) values of various compounds to inhibit the
contractions induced by phenylephrine (10ꢀ6 M) are shown in
Table 1.
N
N
N
NH
Many compounds produced a concentration dependent inhibi-
tion of the contractile response of phenylephrine and some
produced vasorelaxation better than the standard drugs hydral-
azine and reference compound SK&F 93741 (Fig 2). Most active
R
O
(30)
O
(31,32)
compound 11 (IC50 ¼ 0.051
mM) exhibited vasodilating activity in
31, R =
32, R =
nanomolar range.
N
4. Results and discussion
N
H
In general, pyrrolidinyl substituted derivatives 10 and 11
exhibited potent vasorelaxant activity as shown in Table 1. 2-
p-Fluorophenyl substituted derivative 11 with pD2 ¼ 7.2 ꢁ 0.1
Scheme 3. Synthetic route to compounds 30–32. Reagents and conditions: (a)
hydrazine hydrate, ethanol and (b) phenylhydrazine hydrochloride/2-hydrazine-2-
imidazoline hydrobromide, absolute ethanol.
(IC50 ¼ 0.051
mM) showed appreciable vasodilatory activity in

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R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
Table 1
5. Experimental
Maximal response (Emax) and pD2 (ꢀlog IC50) values to inhibit the contractions
induced by phenylephrine (10ꢀ6 M). Values are expressed as means ꢁ SEM, n ¼ 4–8.
5.1. Chemistry
Compound (code)
Emax
pD2
The m.p.s reported are uncorrected, 1H NMR spectra were
recorded on Brucker AC-300F, 300 MHz instrument using Me4Si
(TMS) as the internal standard (chemical shifts in d, ppm). The IR
10 (DPJ-RG-1137)
11 (DPJ-RG-1169)
13b (DPJ-RG-1274)
14 (DPJ-RG-1189)
15b (DPJ-RG-1278)
17b (DPJ-RG-1276)
25b (DPJ-RG-1281)
26b (DPJ-RG-1288)
27b (DPJ-RG-1285)
28b (DPJ-RG-1287)
29b (DPJ-RG-1284)
Hydralazine
52.2 ꢁ 3.4a
61.8 ꢁ 4.6a
21.7 ꢁ 11.0
61.6 ꢁ 8.0a
16.2 ꢁ 5.9
29.8 ꢁ 12.8a
41.8 ꢁ 2.8a
17.6 ꢁ 12.5
3.7 ꢁ 3.5
5.9 ꢁ 0.1
7.2 ꢁ 0.1
–
5.9 ꢁ 0.2
spectra were recorded on a Perkin–Elmer 882 and Perkin–Elmer
spectrum RX 1, FT-IR spectrophotometer models using potassium
bromide pellets (ymax in cmꢀ1). The purity of compounds was
established by thin layer chromatography and elemental analyses
(C, H, N). Elemental analyses were carried out on a Perkin–Elmer-
2400 model CHN analyzer. Plates for TLC were prepared with silica
gel G according to Stahl’s method (E. Merck) using EtOAc as solvent
(activated at 110 ꢂC for 30 min) and were visualized by exposure to
iodine vapours. Anhydrous sodium sulfate was used as drying
agent. All solvents were dried and freshly distilled prior to use
according to standard procedures.
–
–
–
–
–
–
–
32.0 ꢁ 8.2
23.9 ꢁ 14.2
55.0 ꢁ 5.8
61.1 ꢁ 4.1
6.6 ꢁ 0.2
SK&F-93741
7.0 ꢁ 0.2
a
p < 0.05 versus DMSO.
b
The compounds, which did not produce 50% relaxation upto 10ꢀ5 M.
nanomolar range and was found 4.5 times and 1.7 times more
potent in comparison to standard drug hydralazine and reference
compound SK&F 93741, respectively. However 2-unsubstituted
5.1.1. General procedure for the synthesis of pyrrolidinyl/piperidinyl
substituted g-keto acids 6–9
A mixture of amide derivatives (4/5) (1.5 g, 8 mmol) and
requisite anhydride succinic anhydride (1.25 g, 12 mmol)/methyl-
succinic anhydride (1.0 g, 8 mmol) was added to a stirred solution
of aluminium chloride (5 g) in nitrobenzene (10 ml). The reaction
mixture was stirred manually under the anhydrous conditions for
20 min and then allowed to stand for 48 h at room temperature.
The mixture was decomposed with crushed ice and steam distilled
to remove nitrobenzene. The resultant hot solution was filtered and
then cooled in ice for precipitation. The solid product obtained was
filtered and washed thoroughly with distilled water. The solid
residue was dissolved in 10% aqueous sodium bicarbonate solution
and filtered off insoluble part. Acidification with concentrated
hydrochloric acid gave precipitate, which was filtered, washed with
water and recrystallized from methanol to afford the corresponding
compound 10 with pD2 ¼ 5.9 ꢁ 0.1 (IC50 ¼ 1.025
mM) was less
effective than standard and reference compounds in producing
vasorelaxation. Replacement of pyrrolidine with piperidine as in 14
with pD2 ¼ 5.9 ꢁ 0.1 (IC50 ¼ 0.91
mM) did not affect the vasodilatory
properties, whereas substitution of phenyl ring at 2-position in this
series resulted in substantial loss of vasodilatory activity
for compound 15, which produced only 16% maximal relaxation
(Table 1). Introduction of heterocyclic systems such as morpholine,
imidazole and N-methylpiperazine with an additional heteroatom
resulted in decreased vasodilatory activity in compounds 25, 27
and 29. Substitution of 5-methyl group in the compounds 13, 17, 26
and 28 also led to loss of activity.
Further investigations are required to elucidate the exact
mechanism of action of these pyridazinones, which probably is
mediated by phosphodiesterase 3 inhibition. However, the phar-
macological effects observed contribute to give information about
therapeutic interest of pyridazinone derivatives in hypertension.
g-keto acids 6–9.
5.1.1.1. 4-Oxo-4-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]butyric
acid (6). Yield: 39.17%; m.p. 196–198 ꢂC. IR: 2967, 1732, 1667, 1633,
1259, 1169, 925; 1H NMR (CDCl3 þ DMSO-d6): 1.86 (t, 2H, –CH2–,
pyrrolidine), 2.0 (t, 2H, –CH2–, pyrrolidine), 2.62 (t, 2H,
–COCH2CH2COOH), 3.20 (t, 2H, –COCH2CH2COOH), 3.44 (t, 2H, N–
CH2–, pyrrolidine), 3.51 (t, 2H, N–CH2–, pyrrolidine), 4.77 (s, 2H,
–OCH2–), 6.99 (d, 2H, CH, arom, Jo ¼ 8.31 Hz), 7.93 (d, 2H, CH, arom,
Jo ¼ 8.49 Hz) and 11.93 ppm (brs, 1H, –COCH2CH2COOH, dis-
appeared on deuterium exchange).
0
15
5.1.1.2. 3-Methyl-4-oxo-4-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]
30
butyric acid (7). Yield: 31.06%; m.p. 138–139 ꢂC. IR: 2976, 1737, 1672,
1629, 1599, 1263, 1174, 832; 1H NMR (CDCl3 þ DMSO-d6):
d 1.31
10
(d, 3H, –COCH(CH3)CH2COOH), 1.87 (s, 2H, –CH2–, pyrrolidine), 1.99
(p, 2H, –CH2–, pyrrolidine), 3.01 [m, 1H, –COCH(CH3)–CH(H)COOH],
3.14 [m, 1H, –COCH(CH3)CH(H)COOH], 3.41 [m, 1H, –COCH(CH3)–
CH2COOH], 3.52 (t, 4H, N–(CH2)2–, pyrrolidine], 4.71 (s, 2H, –OCH2–),
6.99 (d, 2H, CH, arom, Jo ¼ 8.59 Hz) and 7.96 ppm (d, 2H, CH, arom,
Jo ¼ 8.49 Hz).
45
11
14
Hydralazine
60
SK&F-93741
75
5.1.1.3. 4-Oxo-4-[4-(2-oxo-2-piperidin-1-yl-ethoxy)phenyl]butyric-
acid (8). Yield: 32.96%; m.p. 153–155 ꢂC. IR: 2932, 1722, 1677, 1627,
1508, 1249, 842; 1H NMR (CDCl3 þ DMSO-d6):
d
1.61 (m, 6H, 3 ꢃ –
-9
-8
-7
-6
Concentration (Log M)
-5
CH2–, piperidine), 2.71 (t, 2H, –COCH2CH2COOH), 3.25 (t, 2H,
–COCH2CH2COOH), 3.47 (t, 2H, N–CH2–, piperidine), 3.55 (t, 2H, N–
CH2–, piperidine), 4.79 (s, 2H, –OCH2–), 6.98 (d, 2H, CH, arom,
Jo ¼ 8.76 Hz) and 7.96 ppm (d, 2H, CH, arom, Jo ¼ 8.66 Hz).
Fig. 2. Concentration–response curves for relaxation activity of compounds 10, 11, 14,
hydralazine and SK&F93741 on aortic rings obtained from Wistar rats. Each data point
represents the mean ꢁ SEM from four or eight experiments.

R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
4445
5.1.1.4. 3-Methyl-4-oxo-4-[4-(2-oxo-2-piperidin-1-yl-ethox-
Jm ¼ 1.75 Hz), 7.67 (dd, 2H, CH, arom, Jo ¼ 6.78 Hz, Jm ¼ 2.02 Hz) and
8.55 ppm (s, 1H, –NH, pyridazinone, disappeared on deuterium
exchange). Anal. Calc. for C17H21N3O3: C, 64.74; H, 6.71; N, 13.32%.
Found: C, 64.94; H, 6.74; N, 12.95%.
y)phenyl]-butyric-acid (9). Yield: 36.18%; m.p. 134–135 ꢂC. IR: 2926,
1719, 1677, 1629, 1442, 1252, 1186, 835; 1H NMR (CDCl3):
d 1.30 [d,
3H, –COCH(CH3)CH2COOH)], 1.64 (m, 6H, 3 ꢃ –CH2–, piperidine),
2.98 [m, 1H, –COCH(CH3)CH(H)COOH], 3.15 [m, 1H, –COCH–
(CH3)CH(H)COOH], 3.38 [m, 1H, –COCH(CH3)CH2COOH], 3.47 (t, 2H,
N–CH2–, piperidine), 3.56 [t, 2H, N–CH2–, piperidine], 4.77 (s, 2H,
–OCH2–), 6.99 (d, 2H, CH, arom, Jo ¼ 8.88 Hz) and 7.95 ppm (d, 2H,
CH, arom, Jo ¼ 8.76 Hz).
5.1.2.5. 6-[4-(2-Oxo-2-piperidin-1-yl-ethoxy)phenyl]-4,5-dihy-
dropyridazin-3(2H)-one (14). Yield: 59.84%; m.p. 220–221 ꢂC
(acetone/ether). IR: 3240, 3200, 3020, 1680, 1630, 1320, 1235 820;
1H NMR (CDCl3 þ DMSO-d6):
d
1.58 (m, 6H, 3 ꢃ –CH2–, piperidine),
2.59 (t, 2H, 4-CH2), 2.96 (t, 2H, 5-CH2), 3.49 (t, 2H, N–CH2–, piper-
idine), 3.56 (t, 2H, N–CH2–, piperidine), 4.73 (s, 2H, –OCH2–), 6.98
(dd, 2H, CH, arom, Jo ¼ 7.16 Hz, Jm ¼ 1.79 Hz), 7.66 (dd, 2H, CH, arom,
Jo ¼ 7.22 Hz, Jm ¼ 1.97 Hz) and 8.51 ppm (s, 1H, –NH, disappeared on
deuterium exchange). Anal. Calc. for C17H21N3O3: C, 64.74; H, 6.71;
N, 13.32%. Found: C, 64.97; H, 6.53; N, 13.44%.
5.1.2. General procedure for the synthesis of pyrrolidine/piperidine
substituted 6-(4-carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-
pyridazinone 10–17
Requisite hydrazine derivative (1 mmol) was added to a stirred
and refluxing solution of substituted g-keto acids 6–9 (1 mmol) in
aldehyde free ethanol (50 ml). The reaction mixture was further
refluxed for 8 h with continuous stirring (72 h reflux in case of 2-
hydrazino-2-imidazoline hydrobromide). The completion of the
reaction was monitored by TLC. The solvent was removed under
reduced pressure to obtain a solid residue. Ice-cold water was
added to it and the precipitate obtained was filtered off, washed
with ice-cold water, dried and recrystallized from appropriate
solvent to afford corresponding pyridazinone 10–17.
5.1.2.6. 6-[4-(2-Oxo-2-piperidin-1-yl-ethoxy)phenyl]-2-phenyl-4,5-
dihydropyridazin-3(2H)-one (15). Yield: 48.95%; m.p. 140–142 ꢂC
(ether). IR: 2923, 1671, 1602, 1514, 1333, 1242, 1012, 844. 1H NMR
(CDCl3 þ DMSO-d6):
d
1.60 (m, 6H, 3 ꢃ –CH2–, piperidine), 2.77 (t,
2H, 4-CH2), 3.06 (t, 2H, 5-CH2), 3.52 [m, 4H, N–(CH2)2–, piperidine],
4.73 (s, 2H, –OCH2), 6.98 (d, 2H, CH, arom, Jo ¼ 8.83 Hz), 7.26 (m, 1H,
4-CH, N-phenyl), 7.42 (t, 2H, 3-CH and 5-CH, arom, N-phenyl,
Jo ¼ 7.79 Hz), 7.59 (d, 2H, 2-CH and 6-CH, arom, N-phenyl,
Jo ¼ 8.50 Hz) and 7.77 ppm (d, 2H, CH, arom, Jo ¼ 8.81 Hz). Anal.
Calc. for C23H25N3O3: C, 70.56; H, 6.44; N, 10.73%. Found: C, 70.36;
H, 6.23; N, 10.50%.
5.1.2.1. 6-[4-(2-Oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-4,5-dihy-
dropyridazin-3(2H)-one (10). Yield: 66.49%; m.p. 178–179 ꢂC
(methanol). IR: 3193, 3068, 1666, 1609, 1514, 1349, 1249, 827; 1H
NMR (CDCl3 þ DMSO-d6):
d 1.86 (p, 2H, –CH2–, pyrrolidine), 1.98 (p,
2H, –CH2–, pyrrolidine), 2.59 (t, 2H, 4-CH2), 2.95 (t, 2H, 5-CH2), 3.52
[t, 4H, N–(CH2)2–, pyrrolidine], 4.67 (s, 2H, –OCH2–), 6.98 (dd, 2H,
CH, arom, Jo ¼ 7.24 Hz, Jm ¼ 1.95 Hz), 7.66 (dd, 2H, CH, arom,
Jo ¼ 6.78 Hz, Jm ¼ 2.05 Hz) and 8.75 ppm (s, 1H, –NH, disappeared
on deuterium exchange). Anal. Calc. for C16H19N3O3: C, 63.77; H,
6.35; N, 13.94%. Found: C, 63.59; H, 6.17; N, 14.19%.
5.1.2.7. 2-[4,5-Dihydro-1H-imidazol-2-yl]-6-{4-(2-oxo-2-piperidin-
1-yl-ethoxy)phenyl}-4,5-dihydropyridazin-3(2H)-one
(16). Yield:
44.42%; m.p. 215–216 ꢂC (water). IR: 2925, 1657, 1387, 1221; 1H
NMR (CDCl3 þ CF3COOD):
d
1.80 (brs, 6H, 3 ꢃ –CH2–, piperidine),
2.84 (brs, 2H, 4-CH2), 2.99 (brs, 2H, 5-CH2), 3.63 (brs, 2H, N–CH2–,
piperidine), 3.77 (brs, 2H, N–CH2–, piperidine), 3.91 (s, 4H, 2 ꢃ –
CH2–, imidazoline), 4.99 (s, 2H, –OCH2), 7.03 (d, 2H, CH, arom,
Jo ¼ 7.34 Hz) and 7.20 ppm (brs, 2H, CH, arom). Anal. Calc. for
C20H25N5O3$H2O: C, 59.83; H, 6.78; N, 17.45%. Found: C, 59.80; H,
6.76; N, 17.72%.
5.1.2.2. 6-[4-(2-Oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-2-(4-fluo-
rophenyl)-4,5-dihydropyridazin-3(2H)-one (11). Yield: 58.68%; m.p.
178–179 ꢂC (methanol). IR: 3190, 2879, 1660, 1645, 1510, 1332, 1257,
1184, 830; 1H NMR (CDCl3):
d 1.86 (p, 2H, –CH2–, pyrrolidine), 1.98
(p, 2H, –CH2–, pyrrolidine), 2.76 (t, 2H, 4-CH2), 3.06 (t, 2H, 5-CH2),
3.52 [t, 4H, N–(CH2)2–, pyrrolidine], 4.67 (s, 2H, –OCH2–), 6.99 (d,
2H, CH, arom, Jo ¼ 8.83 Hz), 7.09 (t, 2H, 3-CH and 5-CH, arom, N-p-
fluorophenyl, Jo ¼ 7.23 Hz), 7.55 ppm (m, 2H, 2-CH and 6-CH, arom,
N-p-fluorophenyl) and 7.74 ppm (d, 2H, CH, arom, Jo ¼ 8.78 Hz).
Anal. Calc. for C22H22N3O3 F: C, 66.82; H, 5.61; N, 10.63%. Found: C,
66.68; H, 5.40; N, 10.86%.
5.1.2.8. 5-Methyl-6-[4-(2-oxo-2-piperidin-1-yl-ethoxy)phenyl]-4,5-
dihydropyridazin-3(2H)-one (17). Yield: 65.06%; m.p. 164–165 ꢂC
(acetone/ether). IR: 3209, 3093.8, 2939, 1646, 1510, 1344, 1239,
1048, 829; 1H NMR (CDCl3):
d 1.31 [d, 2H, 5-CH(CH3)], 1.64 (m, 6H,
3 ꢃ –CH2–, piperidine), 2.61 (m, 1H, 4-CH2), 3.04 [m, 1H, 5-
CH(CH3)], 3.49 (s, 2H, N–CH2–, piperidine), 3.56 (s, 2H, N–CH2–,
piperidine), 4.73 (s, 2H, –OCH2–), 6.99 (d, 2H, CH, arom,
Jo ¼ 8.72 Hz), 7.67 (d, 2H, CH, arom, Jo ¼ 8.95 Hz) and 8.48 ppm (s,
1H, –NH, disappeared on deuterium exchange). Anal. Calc. for
C18H23N3O3: C, 65.63; H, 7.04; N, 12.76%. Found: C, 65.69; H, 6.69; N,
12.72%.
5.1.2.3. 2-[4,5-Dihydro-1H-imidazol-2-yl]-6-{4-(2-oxo-2-pyrrolidin-
1-yl-ethoxy)phenyl}-4,5-dihydropyridazin-3(2H)-one
(12). Yield:
30.99%; m.p. 226–228 ꢂC (water). IR: 3350, 2910, 1660, 1560, 1410,
1250, 840; 1H NMR (CDCl3 þ CF3COOD):
d 2.02 (p, 2H, –CH2–, pyr-
rolidine), 2.13 (p, 2H,–CH2, pyrrolidine), 2.80 (t, 2H, 4-CH2), 2.97 (t,
2H, 5-CH2), 3.63 [m, 4H, N–(CH2)2, pyrrolidine], 3.89 (s, 4H, 2 ꢃ –
CH2–, imidazoline), 4.83 (s, 2H, –OCH2–), 6.98 (d, 2H, CH, arom,
Jo ¼ 8.09 Hz), 7.17 (d, 2H, CH, arom, Jo ¼ 7.53 Hz) and 7.70 ppm (brs,
1H, –NH, imidazoline). Anal. Calc. for C19H23N5O3$H2O: C, 58.90; H,
6.50; N, 18.08%. Found: C, 59.02; H, 6.33; N, 17.82%.
5.1.3. General procedure for the synthesis 4-(4-
(methoxycarbonylmethoxyphenyl)-4-oxobutyric acids 18, 19
A
mixture of phenoxyacetic acid methyl ester 3 (1.0 g,
6.02 mmol) and succinic anhydride (1.0 g, 9.99 mmol)/methyl-
succinic anhydride (1.0 g, 8.76 mmol) was added to a stirred solu-
tion of aluminium chloride (3 g) in nitrobenzene (6 ml). The
reaction mixture was stirred manually under the anhydrous
conditions for 20 min and was allowed to stand for 48 h at room
temperature. The reaction contents were decomposed with
crushed ice and steam distilled to remove nitrobenzene. Hot solu-
tion was filtered and filtrate cooled in ice for complete precipita-
tion. The precipitate obtained was filtered and washed thoroughly
with distilled water. The resulting solid was dissolved in 10%
aqueous sodium bicarbonate solution and filtered off insoluble
5.1.2.4. 5-Methyl-6-[4-(2-oxo-2-pyrrolidin-1-yl-ethoxy)phenyl]-4,5-
dihydropyridazin-3(2H)-one (13). Yield: 63.29%; m.p. 158–159 ꢂC
(methanol). IR: 3213, 2927, 1680, 1655, 1514, 1453, 1347, 1256, 829;
1H NMR (CDCl3 þ DMSO-d6):
d 1.30 [d, 3H, 5-CH(CH3)], 1.86 (p, 2H,
–CH2–, pyrrolidine), 1.97 (p, 2H, –CH2–, pyrrolidine), 2.63 (m, 2H, 4-
CH2), 3.04 [m, 1H, 5-CH(CH3)], 3.52 (t, 4H, N–(CH2)2–, pyrrolidine],
4.67 (s, 2H, –OCH2–), 6.99 (dd, 2H, CH, arom, Jo ¼ 7.28 Hz,

4446
R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
part. Acidification of the filtrate with concentrated hydrochloric
acid gave precipitate, which was filtered, washed with water, dried
and recrystallized from methanol to afford the corresponding
off, washed with ice-cold water, dried and recrystallized from
appropriate solvent to afford corresponding pyridazinones 25–29.
g
-keto acids 18, 19.
5.1.5.1. 6-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]-4,5-dihy-
dropyridazin-3(2H)-one (25). Yield: 70.88%; m.p. 191–192 ꢂC
(acetone). IR: 3269, 2916, 1681, 1605, 1335, 1237, 1110, 849; 1H NMR
5.1.3.1. 4-(4-(Methoxycarbonylmethoxyphenyl)-4-oxobutyric
acid (18). Yield: 49.93%; m.p. 124–126 ꢂC. IR: 3252, 1735, 1669,
1603, 1509, 1244, 1175, 1084, 847, 815; 1H NMR (CDCl3 þ DMSO-d6):
(CDCl3 þ DMSO-d6):
d 2.60 (t, 2H, 4-CH2), 2.96 (t, 2H, 5-CH2), 3.64
(m, 8H, N–(CH2)2– and O–(CH2)2–, morpholine), 4.74 (s, 2H, –OCH2–
), 6.98 (d, 2H, CH, arom, Jo ¼ 8.72 Hz), 7.67 (d, 2H, CH, arom,
Jo ¼ 8.68 Hz) and 8.44 ppm (s, 1H, –NH, disappeared on deuterium
exchange). Anal. Calc. for C16H19N3O4: C, 60.56; H, 6.03; N, 13.24%.
Found: C, 60.43; H, 5.90; N, 12.90%.
d
2.26 (t, 2H, –COCH2CH2COOH), 3.26 (t, 2H, –COCH2CH2COOH),
3.82 (s, 3H, –COOCH3), 4.72 (s, 2H, –OCH2–), 6.95 (d, 2H, CH, arom,
Jo ¼ 8.74 Hz) and 7.97 ppm (d, 2H, CH, arom, Jo ¼ 8.74 Hz).
5.1.3.2. 4-(4-Carboxymethoxyphenyl)-3-methyl-4-oxobutyric
acid (19). Yield: 34.61%; m.p. 178–179 ꢂC. IR: 2918, 1720, 1706, 1673,
1597, 1428, 1256, 1174, 1078, 844; 1H NMR (CDCl3 þ DMSO-d6):
5.1.5.2. 5-Methyl-6-[4-(2-morpholin-4-yl-2-oxoethoxy)phenyl]-4,5-
dihydropyridazin-3(2H)-one (26). Yield: 43.19%; m.p. 220–221 ꢂC
(ethanol). IR: 3198, 2927, 1677, 1612, 1514, 1424, 1337, 1247, 1107,
d
1.25 [d, 3H, –COCH(CH3)CH2COOH], 2.98 [m, 2H,
–COCH(CH3)CH2COOH], 3.40 (m, 1H, –COCH(CH3)CH2COOH), 4.68
(s, 2H, –OCH2–), 6.97 (dd, 2H, CH, arom, Jo ¼ 8.96 Hz, Jm ¼ 1.76 Hz)
and 7.95 ppm (dd, 2H, CH, arom, Jo ¼ 7.26 Hz, Jm ¼ 1.64 Hz). 13C NMR
832. 1H NMR (CDCl3 þ DMSO-d6):
d 1.28 [d, 3H, 5-CH(CH3)], 2.57 (m,
2H, 4-CH2), 3.05 [m, 5H, 5-CH(CH3) and N–(CH2)2–, morpholine],
3.84 [t, 4H, O–(CH2)2–, morpholine], 4.55 (s, 2H, –OCH2–), 6.94 (d,
2H, CH, arom, Jo ¼ 8.93 Hz), 7.66 (d, 2H, CH, arom, Jo ¼ 8.78 Hz) and
9.70 ppm (s, 1H, –NH, disappeared on deuterium exchange). Anal.
Calc. for C17H21N3O4: C, 61.62; H, 6.39; N,12.68%. Found: C; 61.95; H,
6.55; N, 12.47%.
(CDCl3 þ DMSO-d6):
d 17.03 [–CH(CH3)], 34.59 (CH2), 41.31 (CH),
64.64 (–OCH2–), 114.07 (2 ꢃ –CH–, arom), 129.88 (C and 2 ꢃ CH,
arom), 161.45 (C, arom), 169.69 (-COOH), 177.32 (–COOH) and
196.30 ppm (C]O).
5.1.4. General procedure for the synthesis of morpholine/imidazole/
5.1.5.3. 6-[4-(2-Imidazol-1-yl-2-oxoethoxy)phenyl]-4,5-dihydropyr-
idazin-3(2H)-one (27). Yield: 64.85%; m.p. 235–236 ꢂC (acetone).
IR: 3212, 3120, 2928, 1672, 1615, 1429, 1344, 1244, 1061, 824; 1H
N-methylpiperazine substituted
g-keto acids 20–24
A mixture of requisite -keto acid 18/19 (0.3 g, 1.13 mmol) and
g
morpholine (0.3 ml)/imidazole (0.5 g, 7.34 mmol)/1-methyl-
piperazine (0.3 ml) was fused together at 70 ꢂC for 5 h. To the
fused reaction mixture ice-cold water was added to remove any
excess amine and contents were further cooled for complete
precipitation. The solid thus obtained in case of compounds 20
and 22 was filtered, washed with water, dried and recrystallized
NMR (CDCl3 þ DMSO-d6):
d 2.55 (t, 2H, 4-CH2), 2.94 (t, 2H, 5-CH2),
4.62 (s, 2H, –OCH2–), 6.93 (d, 2H, CH, arom, Jo ¼ 8.64 Hz), 7.08 (s, 2H,
4-CH and 5-CH, imidazole), 7.68 (d, 2H, CH, arom, Jo ¼ 8.22 Hz), 7.82
(s, 1H, 2-CH, imidazole) and 10.37 ppm (s, 1H, –NH, disappeared on
deuterium exchange). Anal. Calc. for C15H14N4O3: C, 60.39; H, 4.73;
N, 18.78%. Found: C, 60.11; H, 4.62; N, 18.57%.
from methanol to afford the corresponding substituted
acid. However, 3-methyl -keto acids 21, 23 and N-methylpiper-
azine substituted -keto acid 24 were obtained as a sticky mass
after washing with water and were used as such for further
cyclization.
g-keto
g
5.1.5.4. 6-[4-(2-Imidazol-1-yl-2-oxoethoxy)phenyl]-5-methyl-4,5-
dihydropyridazin-3(2H)-one (28). Yield: 35.80%; m.p. 232–233 ꢂC
(ethanol). IR: 3220, 3115, 2929, 1673,1610,1342,1244,1061, 878; 1H
g
NMR (CDCl3 þ DMSO-d6):
d 1.25 [d, 3H, 5-CH(CH3)], 2.56 (m, 2H, 4-
CH2), 3.05 [m, 1H, 5-CH(CH3)], 4.61 (s, 2H, –OCH2–), 6.93 (d, 2H, CH,
arom, Jo ¼ 8.58 Hz), 7.07 (s, 2H, 4-CH and 5-CH, imidazole), 7.67 (d,
2H, CH, arom, Jo ¼ 8.82 Hz), 7.80 (s, 1H, 2-CH, imidazole) and
10.25 ppm (s, 1H,–NH, disappeared on deuterium exchange). Anal.
Calc. for C16H16N4O3:C, 61.53; H, 5.16; N, 17.94%. Found: C, 61.27; H,
4.99; N, 17.91%.
5.1.4.1. 4-[4-(2-Morpholin-4-yl-2-oxoethoxy)phenyl]-4-oxobutyric
acid (20). Yield: 35.91%; m.p. 85–88 ꢂC. IR: 3269, 2921, 1684, 1607,
1436, 1237, 1110, 850; 1H NMR (CDCl3 þ DMSO-d6):
d 2.70 (t, 2H,
–COCH2CH2COOH), 3.10 [t, 4H, N–(CH2)2–, morpholine], 3.23 (t, 2H,
–COCH2CH2COOH), 3.85 [t, 4H, O–(CH2)2–, morpholine], 4.58 (s, 2H,
–OCH2–), 6.97 (d, 2H, CH, arom, Jo ¼ 8.57 Hz) and 7.94 ppm (d, 2H, CH,
arom, Jo ¼ 8.76 Hz).
5.1.5.5. 6-[4-[2-(4-Methylpiperazin-1-yl)-2-oxoethoxy]phenyl}-4,5-
dihydropyridazin-3(2H)-one (29). Yield: 40.29%; m.p. 160–161 ꢂC
(acetone). IR: 3049, 2916, 1660, 1612, 1338, 1219, 1130, 838; 1H NMR
5.1.4.2. 4-[4-(2-Imidazol-1-yl-2-oxoethoxy)phenyl]-4-oxobutyric
acid (22). Yield: 71.34% m.p. 172–173 ꢂC. IR: 3145, 1705, 1670, 1600,
1418, 1343, 1244, 1160, 1052, 825; 1H NMR (CDCl3 þ DMSO-d6):
(CDCl3 þ DMSO-d6):
d 2.30 (t, 3H, N-CH3), 2.41 (m, 4H, CH3–N–
(CH2)2–, N-methylpiperazine), 2.59 (t, 2H, 4-CH2), 2.96 (t, 2H, 5-
CH2), 3.62 (m, 8H, N–(CH2)2–, N-methylpiperazine), 4.74 (s, 2H,
–OCH2–), 6.98 (dd, 2H, CH, arom, Jo ¼ 9.60 Hz, Jm ¼ 2.89 Hz), 7.67
(dd, 2H, CH, arom, Jo ¼ 9.70 Hz, Jm ¼ 2.90 Hz) and 8.64 ppm (s, 1H,
–NH, disappeared on deuterium exchange). Anal. Calc. for
C17H22N4O3:C, 61.80; H, 6.71; N, 16.96%. Found: C, 61.55; H, 6.41; N,
16.81%.
d
2.92 (t, 2H, –COCH2CH2COOH), 3.45 (t, 2H, –COCH2CH2COOH),
4.88 (s, 2H, –OCH2–), 7.04 (d, 2H, CH, arom, Jo ¼ 8.51 Hz), 7.45 (s, 3H,
imidazole), 8.03 (d, 2H, CH, arom, Jo ¼ 8.59 Hz) and 8.78 ppm (brs,
1H, –NH, disappeared on deuterium exchange).
5.1.5. General procedure for the synthesis of morpholine/imidazole/
N-methylpiperazine substituted derivatives of 6-(4-
carboxymethyloxyphenyl)-4,5-dihydro-3(2H)-pyridazinone 25–29
Hydrazine hydrate (1 ml, 99%) was added to a stirred and
5.1.6. [4-(6-Oxo-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy]-acetohy-
drazide (30). Hydrazine hydrate (1.0 ml, 99%) was added to a stirred
and refluxing solution of 18 (0.6 g, 2.25 mmol) in aldehyde free
ethanol (50 ml). The reaction mixture was further refluxed for 2 h
with continuous stirring. The reaction was monitored with TLC for
the disappearance of starting material. Afterwards, the reaction
mixture was concentrated to half of the volume and left overnight
in refrigerator for crystallization. The crystals obtained were
refluxing solution of required substituted
g-keto acids 20–24
(1.5 mmol) in aldehyde free ethanol (50 ml). The reaction mixture
was further heated under reflux for 10 h with continuous stirring.
The completion of the reaction was monitored by TLC. The solvent
was removed under reduced pressure to obtain a solid residue. Ice-
cold water was added to it and the precipitate obtained was filtered

R. Bansal et al. / European Journal of Medicinal Chemistry 44 (2009) 4441–4447
4447
filtered off, washed with cold ethanol, dried and recrystallized from
ethanol to afford 30. Yield: 68.33%; m.p. 208–210 ꢂC. IR: 3240, 3200,
1680, 1510, 1340, 1245, 1160, 750; 1H NMR (CDCl3 þ DMSO-d6):
(1.8 mM), KH2PO4 (1.2 mM) and glucose (11 mM). After excess of fat
and connective tissue was removed, the aorta were cut into rings
(4–5 mm in length), mounted under the basal tension of 2 g in 5 ml
organ baths containing PSS and attached to force-displacement
transducers to measure isometric contractile force. The tissue bath
was maintained at 37 ꢂC and bubbled with O2/CO2 (95:5) gas
mixture. Each preparation was allowed to equilibrate for at least
90 min prior to initiation of experimental procedures and during
this period the incubation media were changed every 20 min.
After equilibration aortic rings were contracted by single
concentration of phenylephrine (l0ꢀ6 M). When the contractions
were stable, compounds were added in progressively increasing
cumulative concentrations (10ꢀ8–10ꢀ5 M) at 30 min intervals. Only
one compound was tested in each ring. All compounds were
initially dissolved in dimethyl sulfoxide (DMSO) to prepare
a 10ꢀ2 M stock solution. Further solutions were made in PSS.
All the results are expressed as means ꢁ the standard error of
the mean (SEM). The response of the aortic rings to all compounds
was expressed as a percentage of the initial contraction to 10ꢀ6 M
phenylephrine. Dose–response curves were analyzed by
a sigmoidal curve-fitting analysis to give the pD2 value (the drug
concentration exhibiting 50% of the Emax expressed as negative log
molar) and Emax value (the maximal effect).
d
2.55 (t, 2H, 4-CH2), 2.94 (t, 2H, 5-CH2), 4.06 (s, 2H, –NH2), 4.58 (s,
2H, –OCH2–), 6.96 (d, 2H, CH, arom, Jo ¼ 8.49 Hz), 7.66 (d, 2H, CH,
arom, Jo ¼ 7.66 Hz), 8.71 (s, 1H, –NH, disappeared on deuterium
exchange) and 10.06 ppm (s, 1H, –NH, pyridazinone, disappeared
on deuterium exchange). Anal. Calc. for C12H12N4O3: C, 54.95; H,
5.38; N, 21.36%. Found: C, 54.75; H, 5.56; N, 21.58%.
5.1.7. [4-(6-Oxo-1-substituted-1,4,5,6-tetrahydropyridazin-3-
yl)phenoxy]-acetic acid ethyl ester 31, 32
Requisite hydrazine derivative (2 mmol) was added to a stirred
and refluxing solution of 18 (0.5 g, 1.88 mmol) in aldehyde free
ethanol (50 ml). The reaction mixture was further refluxed for 12 h
with continuous stirring (72 h reflux in case of 2-hydrazino-2-
imidazoline hydrobromide). The reaction was monitored with TLC
for the disappearance of starting material. Afterwards, the solvent
was removed under reduced pressure to obtain a solid residue. Ice-
cold water was added to it and the precipitate obtained was filtered
off, washed with ice-cold water, dried and recrystallized from an
appropriate solvent to afford corresponding pyridazinones 31, 32.
5.1.7.1. [4-(6-Oxo-1-phenyl-1,4,5,6-tetrahydropyridazin-3-yl)phenoxy]-
acetic acid ethyl ester (31). Yield: 46.84%; m.p. 94–95 ꢂC (ether). IR:
2911, 1756, 1728, 1675, 1597, 1513, 1331, 1245, 1179, 1074, 832; 1H
Acknowledgements
NMR (CDCl3 þ DMSO-d6):
d 1.30 (t, 3H, –OCH2CH3), 2.72 (t, 2H, 4-
The authors are thankful to Council of Scientific and Industrial
Research (CSIR), India for financial support.
CH2), 3.06 (t, 2H, 5-CH2), 4.28 (q, 2H, –OCH2CH3), 4.66 (s, 2H,
–OCH2–), 6.94 (d, 2H, CH, arom, Jo ¼ 8.81 Hz), 7.27 (m, 1H, 4-CH,
arom, N-phenyl), 7.42 (t, 2H, 3-CH and 5-CH, arom, N-phenyl,
Jo ¼ 7.80 Hz), 7.58 (d, 2H, 2-CH and 6-CH, arom, N-phenyl,
Jo ¼ 8.80 Hz) and 7.77 ppm (d, 2H, CH, arom, Jo ¼ 8.86 Hz). Anal.
Calc. for C20H20N2O4: C, 68.16; H, 5.72; N, 7.95%. Found: C, 67.93; H,
5.58; N, 7.66%.
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dropyridazin-3-yl]phenoxy}acetic acid ethyl ester (32). Yield:
25.13%; m.p. 215–216 ꢂC (water). IR: 2920, 1738, 1667, 1508, 1406,
1236, 1086, 703; 1H NMR (CDCl3 þ CF3COOD):
d 1.37 (t, 3H,
–OCH2CH3), 2.82 (s, 2H, 4-CH2), 2.99 (s, 2H, 5-CH2), 3.91 (s, 4H, 2 ꢃ –
CH2–, imidazoline), 4.39 (q, 2H, –OCH2CH3), 4.76 (s, 2H, –OCH2–),
6.97 (m, 2H, CH, arom, Jo ¼ 7.65 Hz) and 7.19 ppm (brs, 2H, CH,
arom). Anal. Calc. for C17H20N4O4$H2O: C, 59.28; H, 5.85; N, 16.27%.
Found: C, 59.34; H, 6.12; N, 15.96%.
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5.2. Vasodilatory activity
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Vasodilatory activity of newly synthesized compounds was
studied using descending thoracic aortic rings of wistar rats pre-
contracted with phenylephrine (10ꢀ6 M) [17]. Wistar rats of either
sex weighing 300–400 g were killed by a blow on the head. The
descending thoracic aorta was rapidly dissected and placed in
a physiological saline solution (PSS) of the composition: NaCl
(118 mM), KCI (4.75 mM), NaHCO3 (25 mM), MgSO4 (1.2 mM), CaCl2