Synthesis and α1-antagonist activity of derivatives of 4-chloro-5-{4- [2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone

Article abstract of DOI:10.1016/S0223-5234(00)00161-6

The synthesis and evaluation of the biological activity of new 4-chloro- 5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic α-adrenoceptors of isolated rat vas deferens. (C) 2000 Editions scientifiques et medicales Elsevier SAS.

Full text of DOI:10.1016/S0223-5234(00)00161-6

Eur. J. Med. Chem. 35 (2000) 773−779
© 2000 Éditions scientifiques et médicles Elsevier SAS. All rights reserved
S0223523400001616/SCO
Short communication
Synthesis and α1-antagonist activity of derivatives of 4-chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone
Giovannella Strappaghettia*, Roberta Barbaroa, Gabrielle Maruccib
aDipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia , Via del Liceo 1, 06123, Perugia, Italy
bDipartimento di Scienze Chimiche, Università di Camerino, 62032, Camerino, Italy
Received 15 September 1999; revised and accepted 25 February 2000
Abstract – The synthesis and evaluation of the biological activity of new 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl}-
3(2H)-pyridazinone derivatives are reported. The blocking activity of these compounds was determined on the pre- and postsynaptic
α-adrenoceptors of isolated rat vas deferens. © 2000 Éditions scientifiques et médicles Elsevier SAS
α1-adrenoceptor antagonist / pyridazinone / structure–activity relationship / rat vas deferens
1. Introduction
In recent years the search for new α1-adrenoceptor
antagonists has increased with the development of
postsynaptically selective α-adrenoceptor antagonists due
to their importance in the treatment of hypertension [1],
and of benign prostatic hypertrophy (BPH) [2]. It is well
known that antihypertensive activity depends on a periph-
eral vasodilatation mediated by a postjunctional α1-
adrenoceptor block. In spite of their high α1 selectivity,
compounds like prazosin have side effects such as tachy-
Figure 1. Compounds bearing a linker of four or five combi-
nations.
wards α1-adrenoceptor and also to find out whether the
selectivity observed for molecules 1 and 1a depends on
their symmetrical structure, we considered it of interest to
synthesize compounds in which the 4-chloro-5-[4-(2-
methoxyphenoxyethyl)-1-piperazinyl]-3(2H)-pyridazinone
portion was substituted with different groups, and a
compound in which the flexibility of the chain was
reduced by the introduction of the amide group (figures 2
and 3).
cardia, which is connected with
a
presynaptic
α2-adrenolytic action [3, 4].
In the course of studies on 3(2H)-pyridazinone deriva-
tives as potential antagonists of α1-adrenoceptor, we have
in a previous work [5] synthesized a series of compounds
such as alkane-bridged [4-(phenoxyethyl)-1-piperazinyl]-
3(2H)-pyridazinones and tested them on the epididymal
or prostatic portion of the vas deferens to assess their α1-
and α2-adrenoceptor blocking properties. Compounds
bearing a linker of four or five carbon atoms (1 and 1a)
showed a good activity and selectivity towards the
α1-adrenoceptor (figure 1).
2. Chemistry
As an extension of this work, in order to better define
the structural requirements for optimum selectivity to-
Compounds 3 and 4 were prepared by alkylation of
compound 2 with 4-chloro-5-(4-methyl-piperazin-1-yl)-
2-(4-chlorobutyl)-pyridazin-3(2H)-one (11) or 4-chloro-
5-(4-methyl-piperazin-1-yl)-2-(5-chloropentyl)-pyridazin-
* Correspondence and reprints

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G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
Figure 2. Synthesis of 3–9.
3(2H)-one (11a), respectively, using two methods: ethanol
and sodium hydroxide pellets (method A) or acetone and
dry potassium carbonate (method B). No significantly
different yields were obtained from the two pathways.
The same procedures were used to prepare compounds 5,
6, 7 and 8, using as fragments 2-(4-chlorobutyl)-pyridazin-
3(2H)-one (12), 2-(5-chloropentyl)-pyridazin-3(2H)-one
(12a), 2-(4-chlorobutyl)-phthalazin-1(2H)-one (13) and
1-(4-chlorobutyl)-benzene (14), respectively. Compound
9 was prepared by alkylation of compound 15 with
piperidine in isoamyl alcohol and dry sodium carbonate.
Finally the condensation between 2-[4-chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-piperazin-1-yl}-pyridazin-3(2H)-
one-2-yl]-acetic acid (16) and 2-[phthalazin-1(2H)-one-
2-yl)]-ethylamine (17) in chloroform, ethyl chlorocarbon-
ate and triethylamine gave compound 10 (figure 3).
3. Pharmacology
The pharmacological profile of compounds 3–10 was
evaluated at α1- and α2-adrenoceptors on isolated rat vas
deferens tissues. Alpha1-adrenoceptor blocking activity
was assessed by antagonism of (–)-noradrenaline-induced
contractions of the epididymal portion: α2-adrenoceptor
blocking activity was determined by antagonism of the

G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
775
adrenoceptor is similar to that of compounds 1 and 1a.
Compound 5, in which the 4-chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-piperazin-1-yl}-pyridazin-3(2H)-
one was substituted with a pyridazin-3(2H)-one ring, the
activity and selectivity were preserved when the chain
joining the two major constituents of the molecule was
four carbon atoms, whereas selectivity decreases with the
lengthening of the chain by one carbon unit (compound
6). In compound 8, in which an aromatic ring is present,
the activity was preserved but not the selectivity, while
the activity disappeared with the presence of a piperidine
ring (compound 9). It is interesting to observe that there
was an increase of the activity and selectivity when the
4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-piperazin-
1-yl}-pyridazin-3(2H)-one portion was substituted with
the phthalazin-1(2H)-one ring (compound 7). While the
activity and selectivity towards α1-adrenoceptor showed
by compound 7 decrease with the introduction of an
amide group (compound 10).
Figure 3. Synthesis of 10.
clonidine-induced depression of the twitch responses of
the field prostatic portion of rat vas deferens. The
biological results were expressed as pKb values, calcu-
lated according to Drew [6].
In conclusion, from these results we advanced the
hypothesis that for
a
good selectivity towards
α1-adrenoceptor shown by compounds (1 and 1a) it is
necessary to have either a symmetrical structure, or
groups with a degree of steric hindrance capable of
coupling through further bonds with an accessory site
situated at an opportune distance from the active site.
Moreover, it is necessary that the linker joining the two
major constituents of the molecule shows a certain
flexibility.
4. Results and discussion
The biological results of compounds 3–10 are reported
in table I.
Relative to the observed pKb values for α1-AR α2-AR,
compounds 3 and 4 in which the 4-chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-piperazin-1-yl}-pyridazin-3(2H)-
one fragment was substituted with 4-chloro-5-(4-methyl-
5. Experimental protocols
piperazin-1-yl)-pyridazin-3(2H)-one
a
decrease of
selectivity was observed, although activity towards α1-
5.1. Biological methods
5.1.1. Blocking activity on the pre- and post-
Table I. Blocking activity on the pre- and postsynaptic adreno-
synaptic α-adrenoceptors of isolated rat vas deferens
Male albino rats (175–200 g) were killed by a sharp
blow on the head and both vasa deferentia were isolated
free from adhering connective tissue. A section of ap-
proximately 2 cm of the epididymal or prostatic portion
of the vas deferens was excised to study postsynaptic or
presynaptic α-blocking activity, respectively. The iso-
lated organs were mounted individually in baths of 20 mL
working volume containing Krebs solution of the follow-
ing composition: 118.4 mM NaCl, 4.7 mM KCl, 2.52 mM
CaCl2, 1.2 mM MgSO4·7H2O, 1.2 mM KH2PO4,
25.0 mM NaHCO3, 11.1 mM glucose. The concentration
of MgSO4·7H2O was reduced to 0.6 mM when the twitch
response to field stimulation was studied. The medium
was maintained at 37 °C and gassed with 95% O2/5%
CO2. The loading tension was 0.4 g or 0.5–0.8 g to assess
post- or presynaptic α-blocking activity, respectively, and
ceptors of isolated rat vas deferens.
Compound
α1
α2
Selectivity ratio
a
α1/α2
pKb
pKb
1b
1ab
3
4
5
6
7
8
9
6.83 ± 0.22
6.83 ± 0.09
6.78 ± 0.23
6.58 ± 0.13
6.94 ± 0.14
6.57 ± 0.20
7.86 ± 0.09
6.50 ± 0.26
inactive
<4.52
>100
>100
32
4.76 ± 0.20
5.28 ± 0.16
5.20 ± 0.08
<5
5.22 ± 0.10
5.04 ± 0.05
5.44 ± 0.17
inactive
25
>87
>22
>660
13
–
10
6.42 ± 0.15
5.18 ± 0.07
17
a The selectivity ratio is the antilog of the difference between the
pKb values at post- and presynaptic α-adrenoceptors. b These
values have been published in reference [5].

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G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
the contractions were recorded by means of force trans-
ducers connected to a two-channel Gemini 7070 poly-
graph. Field stimulation of the tissues was carried out by
means of two platinum electrodes placed near the top and
the bottom of the vas deferens at 0.1 Hz using square
pulses of 3 ms duration at a voltage of 10–15 V. The
stimulation voltage was fixed throughout the experi-
ments. Propanolol hydrochloride (1 µM) and cocaine
hydrochloride (10 µM) were present in the Krebs solution
throughout the experiments outlined below to block the
adrenergic ꢀ-receptor and neuronal and extraneuronal
uptake mechanisms, respectively. The biological results
were expressed as pKb values according to the following
equation:
values. Precoated Kiesegel 60 F254 plates (Merck) were
used for TLC. The corresponding hydrochlorides were
prepared by bubbling dry HCl into the dry solution of the
compound.
5.2.1. 4-Chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-pip-
erazin-1-yl}-2-{4-[4-chloro-5-(4-methyl-piperazin-1-yl)-
butyl}-pyridazin-3(2H)-one-2-yl]-pyridazin-3(2H)-one 3
5.2.1.1. General method
A: to 30 mL of dry ethanol was added 0.1 g (2.5 ×
10–3 mol) of sodium hydroxide pellets and 0.73 g (2.0 ×
10–3 mol) of 4-chloro-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-piperazin-1-yl}-pyridazin-3(2H)-one (2) [5], this
mixture was refluxed for 30 min. Then 0.64 g (2.0 ×
10-3 mol) of the 4-chloro-5-(4-methyl-piperazin-1-yl)-2-
(4-chlorobutyl)-pyridazin-3(2H)-one (11) dissolved in dry
ethanol was added, and this mixture was refluxed under
stirring for 24 h.
Kb = Ant /DR − 1
͓
͔
where Kb is the dissociation constant of the antagonist
and DR is the ratio of (–)-noradrenaline (NA) ED50 in the
presence and in the absence of the antagonist.
After evaporation under reduced pressure, the residue
was purified by flash-chromatography silica gel using as
eluent a stepwise gradient of ethanol (0–12%) in CH2Cl2.
A dense oil was obtained. Yield (0.65 g): 50%.
Postsynaptic α-blocking activity was determined on
the epididymal portion of the vas deferens. The tissue was
allowed to equilibrate for at least 30 min before the
addition of any drug. Cumulative dose–response curves
to (–)NA were obtained for each tissue at 30 min inter-
vals; a second curve was used as control. It was verified
that a third dose–response curve was always identical to
the second. Each antagonist was incubated for 30 min
before the initial challenge with NA. The dose ratio,
DR-1, was calculated at a concentration of 10–6 M and
the compounds tested at least five times at this concen-
tration.
B: a mixture of 0.73 g (2.0 × 10–3 mol) of 4-chloro-5-
{4-[2-(2-methoxyphenoxy)-ethyl]-piperazin-1-yl}-pyrida-
zin-3(2H)-one (2), 0.30 g (2.2 × 10–3 mol) of dry potas-
sium carbonate, 0.64 g (2.0 × 10–3 mol) of 4-chloro-5-(4-
methyl-piperazin-1-yl)-2-(4-chlorobutyl)-pyridazin-3(2H)-
one (11) in 30 mL of acetone was refluxed under stirring
overnight. After cooling, the inorganic salts were filtered
off, the solvent evaporated under vacuum and the residue
was purified by flash-chromatography silica gel, as de-
scribed above. Yield (0.77 g): 60%. 1H-NMR (CDCl3) δ:
1.70–1.85 (m, 4H, 2CH2), 2.35 (s, 3H, CH3), 2.50–2.60
(m, 4H, H-pip), 2.70–2.80 (m, 4H, H-pip.), 2.90 (t, J =
6 Hz, 2H, CH2), 3.30–3.50 (m, 8H, H-pip.), 3.85 (s, 3H,
OCH3), 4.10–4.30 (m, 6H, 3CH2), 6.80–7.00 (m, 4H,
H-arom.), 7.60 (s, 2H, H-pyrid.). The corresponding
hydrochloride had m.p.: 268–272 °C.
Presynaptic α-blocking activity was assessed by an-
tagonism with the adrenergic α2-receptor agonist cloni-
dine. Clonidine inhibits twitch responses of the field-
stimulated vas deferens by acting on the presynaptic
adrenergic α2-receptor. [7]. The procedure reported by
Drew [6] was therefore used. In other tissues the dose–re-
sponse curves were determined after 30 min incubation
with the antagonist. Each antagonist was tested at 10–5
M
concentration, and this concentration was investigated at
least five times. Dose ratio (DR) values were then
determined from the concentration causing 50% inhibi-
tion of the twitch response in the absence and presence of
the antagonist.
5.2.2. 4-Chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-pip-
erazin-1-yl}-2-{5-[4-chloro-5-(4-methyl-piperazin-1-yl)-
pentyl}-pyridazin-3(2H)-one-2-yl]-pyridazin-3(2H)-one 4
This compound was prepared by alkylation of 2 with
4-chloro-5-(4-methyl-piperazin-1-yl)-2-(5-chloropentyl)-
pyridazin-3(2H)-one (11a) using the two methods de-
scribed above. Purified by flash-chromatography silica
gel using as eluent a stepwise gradient of ethanol (0–12%)
in CH2Cl2. A dense oil was obtained. Yield: 50%.
1H-NMR (CDCl3) δ: 1.30–1.50 (m, 2H, CH2), 1.70–1.90
(m, 4H, 2CH2), 2.40 (s, 3H, CH3), 2.50–2.60 (m, 4H,
H-pip), 2.70–2.80 (m, 4H, H-pip.), 2.95 (t, J = 6 Hz, 2H,
CH2), 3.30–3.50 (m, 8H, H-pip.), 3.90 (s, 3H, OCH3),
5.2. Chemical synthesis
Melting points were determined using a Kofler hot-
stage apparatus and are uncorrected. The NMR spectra
were recorded with a Bruker AC 200 MHz instrument in
the solvent indicated below. The chemical shift values
(ppm) are relative to tetramethylsilane as internal stan-
dard. Elemental analyses are within ± 0.4 % of theoretical

G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
777
4.10–4.30 (m, 6H, 3CH2), 6.80–7.00 (m, 4H, H-arom.),
7.60 (s, 2H, H-pyrid.). The corresponding hydrochloride
had m.p.: 30–33 °C.
5.2.6. 4-Chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-
piperazin-1-yl}-2-(4-phenylbutyl)-pyridazin-3(2H)-one 8
This compound was prepared by alkylation of 2 with
1-(4-chlorobutyl)-benzene (14) using method A. Purified
by flash-chromatography silica gel using as eluent a
stepwise gradient of ethanol (0–5%) in CH2Cl2. A dense
oil was obtained. Yield: 30%. 1H-NMR (CDCl3) δ:
1.60–1.90 (m, 4H, 2CH2), 2.60 (t, J = 6 Hz, 2H, CH2),
2.65–2.75 (m, 4H, H-pip.), 2.90 (t, J = 6 Hz, 2H, CH2),
3.30–3.45 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3), 4.10–4.20
(m, 4H, 2CH2), 6.80–7.00 (m, 4H, H-arom.), 7.10–7.30
(m, 5H, H-arom.), 7.60 (s, 1H, H-pyrid.). The corre-
sponding hydrochloride had m.p.: 27–30 °C.
5.2.3. 4-Chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-piperazin-1-yl}-2-{4-
[pyridazin-3(2H)-one-2-yl]-butyl}-pyridazin-3(2H)-one 5
This compound was prepared by alkylation of 2 with
2-(4-chlorobutyl)-pyridazin-3(2H)-one (12) using method
B. Purified by chromatography silica gel using as eluent
a stepwise gradient of ethanol (0–8%) in CH2Cl2. A dense
oil was obtained. Yield: 40%. 1H-NMR (CDCl3) δ:
1.70–1.90 (m, 4H, 2CH2), 2.70–2.80 (m, 4H, H-pip.),
2.95 (t, J = 6 Hz, 2H, CH2), 3.40–3.50 (m, 4H, H-pip.),
3.90 (s, 3H, OCH3), 4.10–4.20 (m, 6H, 3CH2), 6.80–7.00
(m, 5H, 4H-arom., 1H-pyrid.), 7.15 (dd, J = 9 Hz e 5 Hz,
1H, H-pyrid.), 7.6 (s, 1H, H-pirid.), 7.75 (dd, J = 5 Hz e
2 Hz, 1H, H-pyrid.). The corresponding hydrochloride
had m.p.: 35–38 °C.
5.2.7. 4-Chloro-5-{4-[2-(2-
methoxyphenoxy)-ethyl]-piperazin-1-yl}-
2-[4-(piperidin-1-yl)-butyl]-pyridazin-3(2H)-one 9
This compound was prepared by alkylation of 0.45 g
(1.0 × 10–3 mol) 4-chloro-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-piperazin-1-yl}-2-(4-chlorobutyl)-pyridazin-3(2H)-
one 15 [8] with 0.10 g (1.2 × 10–3 mol) of piperidine
0.20 g (1.2 × 10–3 mol) dry sodium carbonate in 15 mL of
isoamyl alcohol. This mixture was refluxed under stirring
for 24 h. After evaporation under reduced pressure, the
residue was purified by flash-chromatography silica gel
using as eluent a stepwise gradient of ethanol (0–50%) in
CH2Cl2. A dense oil was obtained. Yield (0.176 g): 35%.
1H-NMR (CDCl3) δ: 1.40–1.60 (m, 2H, CH2-piperid.),
1.70–1.90 (m, 10H, 2CH2-piperid., 3CH2), 2.55–2.80 (m,
10H, 4H-pip., 2CH2-piperid.), 2.90 (t, J = 6 Hz, 2H,
CH2), 3.40–3.50 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3),
4.10–4.25 (m, 4H, 2CH2), 6.80–7.00 (m, 4H, H-arom.),
7.60 (s, 1H, H-pyrid.). The corresponding hydrochloride
had m.p.: 235–238 °C.
5.2.4. 4-Chloro-5-{4-[2-(2-methoxy-
phenoxy)-ethyl]-piperazin-1-yl}-2-{5-[pyridazin-
3(2H)-one-2-yl]-pentyl}-pyridazin-3(2H)-one 6
This compound was prepared by alkylation of 2 with
2-(5-chloropentyl)-pyridazin-3(2H)-one (12a) using
method B. Purified by flash-chromatography silica gel
using as eluent a stepwise gradient of ethanol (0–6%) in
CH2Cl2. A dense oil was obtained. Yield: 50%. 1H-NMR
(CDCl3) δ: 1.20–1.50 (m, 2H, CH2), 1.70–2.00 (m, 4H,
2CH2), 2.70–2.85 (m, 4H, H-pip.), 2.95 (t, J = 6 Hz, 2H,
CH2), 3.40–3.50 (m, 4H, H-pip.), 3.90 (s, 3H, OCH3),
4.10–4.20 (m, 6H, 3CH2), 6.80–7.00 (m, 5H, 4H-arom.,
1H-pyrid.), 7.10 (dd, J = 9 Hz e 5 Hz, 1H, H-pirid.), 7.60
(s, 1H, H-pyrid.), 7.75 (dd, J = 5 Hz e 2 Hz, 1H,
H-pyrid.). The corresponding hydrochloride had m.p.:
232–235°C.
5.2.8. N1-{2-[1(2H)-phthalazin-1-yl}ethyl]-
2-(4-cloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-
5.2.5. 4-Chloro-5-{4-[2-(2-methoxy-
piperazin-1-yl}-pyridazin-3-one-2-yl)-acetamide 10
Ethyl chlorocarbonate 1.10 g (5.1 × 10–3 mol) was
added dropwise to a stirred and cooled (0 °C) solution of
2.10 g (5.0 × 10–3 mol) acid 16 and 0.51 g (5.0 × 10–3 mol)
of triethylamine in 60 mL of chloroform, followed after
30 min by the addition of a solution of 0.95 g (5.0 ×
10–3 mol) of amine 17 [9] in 15 mL of chloroform. The
resulting reaction mixture was stirred for 7 h at room
temperature and then was evaporated under reduced
pressure. The residue was purified by flash-
chromatography silica gel using as eluent a stepwise
gradient of ethanol (0–10%) in CH2Cl2. A solid was
phenoxy)-ethyl]-piperazin-1-yl}-2-[4-[phthalazin-
1(2H)-one-2-yl]-butyl}-pyridazin-3(2H)-one 7
This compound was prepared by alkylation of 2 with
2-(4-chlorobutyl)-phthalazin-1(2H)-one
(13)
using
method B. Purified by chromatography silica gel using as
eluent a stepwise gradient of ethanol (0–5%) in CH2Cl2.
A dense oil was obtained. Yield: 60%. 1H-NMR (CDCl3)
δ: 1.80–2.00 (m, 4H, 2CH2), 2.70–2.85 (m, 4H, H-pip.),
2.95 (m, 2H, CH2), 3.40–3.50 (m, 4H, H-pip.), 3.85 (s,
3H, OCH3), 4.10–4.30 (m, 6H, 3CH2), 6.80–7.00 (m, 4H,
H-arom.), 7.60 (s, 1H, H-pyrid.), 7.70–7.85 (m, 3H,
H-phthalaz.), 8.1 (s, 1H, H-phthalaz.), 8.35–8.45 (m, 1H,
H-phthalaz). The corresponding hydrochloride had m.p.:
72–75 °C
1
obtained. m.p.: 100–105 °C. Yield (1.12 g): 40%. H-
NMR (CDCl3) δ: 2.70–2.80 (m, 4H, H-pip.), 2.95 (t, J =
6 Hz, 2H, CH2), 3.40–3.50 (m, 4H, H-pip.), 3.70 (t, J =

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G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
6 Hz, 2H, CH2), 3.90 (s, 3H, OCH3), 4.20 (t, J = 6 Hz,
2H, CH2), 4.40 (t, J = 6 Hz, 2H, CH2), 4.80 (s, 2H, CH2),
6.80–7.00 (m, 4H, H-arom.), 7.10 (s, 1H, NHCO),
7.60–7.90 (m, 4H, 3H-phthalaz., 1H-pyrid.), 8.15 (s, 1H,
H-phthalaz.), 8.4 (m, 1H, H-phthalaz.). The correspond-
ing hydrochloride had m.p.: 105–108°C.
5.2.12. 2-(5-Chloropentyl)-pyridazin-3(2H)-one 12a
This compound was prepared by alkylation of
pyridazin-3(2H)-one with 1-bromo-5-chloropentane us-
ing method A. Purified by flash-chromatography silica
gel using as eluent a stepwise gradient of ethanol (0–2%)
in CH2Cl2. A dense oil was obtained. Yield: 65%.
1H-NMR (CDCl3) δ: 1.40–1.60 (m, 2H, CH2), 1.75–2.05
(m, 4H, 2CH2), 3.50 (t, J = 6 Hz, 2H, CH2), 4.15 (t, J =
6 Hz, 2H, CH2), 6.90 (dd, J = 9 Hz e 2 Hz, 1H, H-pyrid.),
7.15 (dd, J = 9 Hz e 5 Hz, 1H, H-pyrid.), 7.75 (dd, J =
5 Hz e 2 Hz, 1H, H-pyrid.).
5.2.9. 4-Chloro-5-(4-methyl-piperazin-
1-yl)-2-(4-chlorobutyl)-pyridazin-3(2H)-one 11
A mixture of 1.0 g (1.0 × 10–2 mol) of 1-methyl-
piperazine, 1.6 g (1.0 × 10–2 mol) of 4,5-dichloropyridozin
3(2H)-one and 1.0 g (1.0 × 10–2 mol) of KHCO3 in
25 mL of ethanol, was refluxed under stirring overnight.
The inorganic salts were filtered off, the solvent evapo-
rated under vacuum and the residue was purified by
flash-chromatography silica gel using as eluent a stepwise
gradient of ethanol (0–10%) in CH2Cl2 (yield: 35%)
obtaining 4-chloro-5-(4-methyl-piperazin-1-yl)-pyridazin-
3(2H)-one, which was alkylated with 1-bromo-4-
chlorobutane using method A. Purified by flash-
chromatography silica gel using as eluent a stepwise
gradient of ethanol (0–4%) in CH2Cl2. A dense oil was
obtained. Yield (1.59 g): 50%. 1H-NMR (CDCl3) δ:
1.70–2.00 (m, 4H, 2CH2), 2.35 (s, 3H, CH3), 2.50–2.60
(m, 4H, H-pip.), 3.40–3.50 (m, 4H, H-pip.), 3.65 (t, J =
6 Hz, 2H, CH2), 4.20 (t, J = 6 Hz, 2H, CH2), 7.60 (s, 1H,
H-pyrid.).
5.2.13. 2-(4-Chlorobutyl)-phthalazin-1(2H)-one 13
This compound was prepared by alkylation of
phthalazin-1(2H)-one with 1-bromo-4-chlorobutane us-
ing method B. Purified by flash-chromatography silica
gel using as eluent a stepwise gradient of ethanol (0–2%)
in CH2Cl2. A dense oil was obtained. Yield: 65%.
1H-NMR (CDCl3) δ: 1.70–2.10 (m, 4H, 2CH2), 3.60 (t,
J = 6 Hz, 2H, CH2), 4.30 (t, J = 6 Hz, 2H, CH2),
7.60–7.80 (m, 3H, H-phthalaz.), 8.10 (s, 1H, H-phthalaz.),
8.35–8.45 (m, 1H, H-phthalaz.).
5.2.14. 2-[4-Chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-
piperazin-1-yl}-pyridazin-3(2H)-one-2-yl]-acetic acid 16
5.2.10. 4-Chloro-5-(4-methyl-piperazin-
To a solution of 0.18 g (8.0 × 10–3 mol) sodium in
80 mL of dry ethanol there was added 2.91 g (8.0 ×
10–3 mol) of 4-chloro-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-piperazin-1-yl}-pyridazin-3(2H)-one (2), this mix-
ture was stirred and heated under reflux for 30 min. After
cooling this mixture, was added dropwise 1.33 g (8.0 ×
10–3 mol) of ethyl bromoacetate. After the addition was
complete, the reaction mixture was heated under reflux
for 24 h and filtered to remove sodium bromide. The
filtrate was evaporated under vacuum and the residue was
purified by chromatography silica gel using as eluent a
stepwise gradient of ethanol (0–10%) in CH2Cl2. A dense
oil was obtained corresponding to ethyl 2-[4-chloro-5-{4-
[2-(2-methoxyphenoxy)-ethyl]-piperazin-1-yl}-pyridazin-
1-yl)-2-(5-chloropentyl)-pyridazin-3(2H)-one 11a
This compound was prepared by alkylation of 4-chloro-
5-(4-methyl-piperazin-1-yl)-pyridazin-3(2H)-one
with
1-bromo-5-chloropentane using method A. Purified by
flash-chromatography silica gel using as eluent a stepwise
gradient of ethanol (0–4%) in CH2Cl2. A dense oil was
1
obtained. Yield: 55%. H-NMR (CDCl3) δ: 1.40–1.60
(m, 2H, CH2), 1.70–2.00 (m, 4H, 2CH2), 2.40 (s, 3H,
CH3), 2.50–2.70 (m, 4H, H-pip.), 3.40–3.50 (m, 4H,
H-pip.), 3.60 (t, J = 6 Hz, 2H, CH2), 4.15 (t, J = 6 Hz, 2H,
CH2), 7.60 (s, 1H, H-pyrid.).
5.2.11. 2-(4-Chlorobutyl)-pyridazin-3(2H)-one 12
This compound was prepared by alkylation of
pyridazin-3(2H)-one with 1-bromo-4-chlorobutane using
both methods A or B. Purified by flash-chromatography
silica gel using as eluent a stepwise gradient of ethanol
(0–2%) in CH2Cl2. A dense oil was obtained. Yield: 60%
1
3(2H)-one-2-yl]-acetate . Yield (2.02 g): 60%. H-NMR
(CDCl3) δ: 1.20–1.35 (t, 3H, CH3), 2.70–2.80 (m, 4H,
H-pip.), 2.90 (t, J = 6 Hz, 2H, CH2), 3.40–3.50 (m, 4H,
H-pip), 3.90 (s, 3H, OCH3), 4.10–4.30 (m, 4H, 2CH2),
4.80 (s, 2H, CH2), 6.80–7.00 (m, 4H, H-arom.), 7.65 (s,
1H, H-pirid.). This compound was treated with NaOH
2 N in EtOH and was refluxed under stirring for 4–5 h
followed by acidification with acetic acid gave the
corresponding acid. M.p.: 135–138 °C.
1
with method A, yield: 70% with method B. H-NMR
(CDCl3) δ: 1.75–2.05 (m, 4H, 2CH2), 3.60 (t, J = 6 Hz,
2H, CH2), 4.20 (t, J = 6 Hz, 2H, CH2), 6.90 (dd, J = 9 Hz
e 2 Hz, 1H, H-pyrid.), 7.20 (dd, J = 9 Hz e 5 Hz, 1H,
H-pyrid.), 7.75 (dd, J = 5 Hz e 2 Hz, 1H, H-pyrid.).

G. Strappaghetti et al. / Eur. J. Med. Chem. 35 (2000) 773–779
779
[2] Hieble J.P., Boyce A.J., Caine M., Fed. Proc. 45 (1986) 2609–2615.
Acknowledgements
[3] Langer S.Z., Cavero I., Massingham R., Hypertension (Dallas) 2
(1980) 372–382.
Financial support provided by the Ministry of Univer-
sity Scientific and Technological Research (MURST) is
acknowledged.
[4] Colucci W.S., Ann. Intern. Med. 97 (1982) 67–77.
[5] Corsano S., Scapicchi R., Strappaghetti G., Marucci G., Paparelli F.,
Eur. J. Med. Chem. 30 (1995) 71–75.
[6] Drew M.G., Eur. J. Pharmacol. 42 (1997) 123–130.
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