Synthesis of new pyridazinone derivatives and their affinity towards α1-α2-adrenoceptors

Article abstract of DOI:10.1016/S0968-0896(99)00046-2

A series of 3(2H)-pyridazinone derivatives was evaluated for their affinity in vitro towards α₁-α₂-adrenoceptors by radioligand receptor binding assays. All target compounds showed good affinities for the α₁-adrenoceptor (

Full text of DOI:10.1016/S0968-0896(99)00046-2

Bioorganic & Medicinal Chemistry 7 (1999) 933±941
Synthesis of New Pyridazinone Derivatives and their Anity
Towards ꢀ1±ꢀ2-Adrenoceptors
Stefano Corsano,a,* Giovannella Strappaghetti,a Roberta Barbaro,a Gino Giannaccini,b
Laura Bettib and Antonio Lucacchinib
a
Á
Istituto di Chimica e Tecnologia del Farmaco, Universita di Perugia, Via del Liceo 1, 06123 Perugia, Italy
Á
Dipartimento di Psichiatria, Neurobiologia, Farmacologia e Biotecnologie, Universita di Pisa, Via Bonanno 6, 56126 Pisa, Italy
b
Received 2 October 1998; accepted 18 January 1999
AbstractÐA series of 3(2H)-pyridazinone derivatives was evaluated for their anity in vitro towards a1±a2-adrenoceptors by
radioligand receptor binding assays. All target compounds showed good anities for the a1-adrenoceptor (with Ki values in the
subnanomolar range), and a gradual increase in anity was observed by increasing the polymethylene chain length of this series up
to a maximum of six and seven carbon atoms, when the fragment 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl is linked in 5
position of the 3(2H)-pyridazinone ring, while a slight decrease was found for the higher homologues. Increasing the chain length
when the 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinyl group is linked in 6 position of the 3(2H)-pyridazinone ring, had a di€erent
e€ect: there is the highest anity when the polymethylene chain is of four carbon atoms. The alkylic chain, a spacer between the two
major constituents of the molecule, can in¯uence the anity and the selectivity. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
The a1±a2-adrenoceptors (a1 AR and a2 AR) are mem-
bers of the superfamily of G protein coupled receptors.
Molecular cloning studies1,2 have shown that these
receptors have many common features which could
re¯ect their similar mechanisms of action.
In recent years, the search for new a1-adrenoceptor
antagonists has increased, in parallel with the develop-
ment of postsynaptically selective a-adrenoceptor
antagonists, due to their importance in the treatment of
The objective of our work has been the synthesis of new
hypertension3 and of benign prostatic hypertrophy4
compounds that are highly selective towards the a1-
receptor, as potential antihypertensive drugs, and as
(BPH).
molecular probes for the study of binding sites. In this
paper we report the synthesis and biological anity of
In the course of our studies on 3(2H)-pyridazinone
derivatives as potential antagonists of the a-adreno-
compounds in which the 3(2H)-pyridazinone ring has
ceptor, we have recently synthesized compounds 15 and
been linked in the 2-position with variations of 1-aryl-
piperazine, by a chain variable for 2 to 8 carbon atoms.
1a,6 which showed good activity towards a1-adreno-
ceptor. It is well known that the 1-arylpiperazines and
their 4-alkyl derivatives, such as Urapidil and SL89057
(2), are postsynaptic a-blockers with activity on BPH.
Chemistry
The synthesis of novel pyridazinone derivatives 3±28 are
reported in Scheme 1.
Compounds 38 and 10 were prepared by alkylation from
30a with 1-(2-methoxyphenyl)-piperazine or 1-(2-chloro-
phenyl)-piperazine respectively in isoamylic alcohol and
sodium carbonate. Compound 30a was prepared by
Key words: Pyridazinone; anity a1,a2-blocking; 1-arylpiperazine and
RAS.
Abbreviations: TBAB=tetrabutyl ammonium bromide; DMF=N,N-
Dimethylformamide.
*Corresponding author.
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00046-2

934
S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
Scheme 1.
treatment of the 4-chloro-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone 15 with 1,2-
dibromoethane using benzene, TBAB and KOH
according to the method of Yamada et al.9
Pharmacology
The pharmacological pro®le of compounds 3±28 was
evaluated for their anities towards a1- and a2-adreno-
ceptors by determining for each compound the ability to
displace [3H]-prazosin or [3H]-rauwolscine, respectively,
from speci®c binding sites on rat cerebral cortex.
Compounds 4, 11, 18 and 24 were prepared by alkyla-
tion of the 4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-
1-piperazinyl}-3(2H)-pyridazinone (1) or 6-{4-[2-(2-meth-
oxyphenoxy)-ethyl]-1-piperazinyl}-3(2H)-pyridazinone
(1a)6 with 1-(2-methoxyphenyl)-4-(3-chloropropyl)-piper-
azine (29c) or 1-(2-chlorophenyl)-4-(3-chloropropyl)-
piperazine (29d), in dry ethanol and sodium hydroxide
pellets. Intermediates 29c and 29d were prepared using
the method of J. Bourdais10 in DMF in the presence of
potassium carbonate.
Results and Discussion
In Table 1a±b are reported competition binding experi-
ments of compounds 3±28.
Relative to the Ki values observed for the a1-AR and a2-
AR, show that, all the synthesized compounds have
higher anities towards the a1-adrenoceptor than
towards the a2-adrenoceptor. In the series a gradual
increase in anity was observed by promoting the
polymethylene chain length up to a maximum of six or
seven carbon atoms, when the fragment 4-[2-(2-meth-
oxyphenoxy)-ethyl]-1-piperazinyl is linked in 5 position
of the 3(2H)-pyridazinone ring (compounds 7, 8 and 14,
15), while a slight decrease was found for the higher
homologues 9 and 16. Increasing the chain length when
the 4-[2-(2-methoxyphenoxy)-ethyl]-1-piperazinil group
was linked in 6 position of the 3(2H)-pyridazinone ring
had a di€erent e€ect: there is the highest anity when the
polymethylene chain has four carbon atoms (compounds
19 and 25). Thus, the position of the fragment 4-[2-(2-
methoxyphenoxy)-ethyl]-1-piperazinyl in¯uences the
anity and it is strictly dependent on the carbon-chain
length. In the series of compounds 3±16 a peak potency
was observed with a six or seven carbon chain, while in
Compounds 17 and 23 were prepared, using as starting
compound 1a by alkylation with 1-(2-methoxyphenyl)-
4-(2-chloroethyl)-piperazine (29a) or 1-(2-chloro-
phenyl)-4-(2-chloroethyl)-piperazine (29b) (prepared by
the method of J. Bourdais)10 in dry ethanol and sodium
hydroxyde pellets, respectively.
Alkylation of compound 1 with the dihalogenates with
polymethylene chain length from four to eight carbon
atoms, in acetone and potassium carbonate, gave the
intermediates 30b±f, which by reacting with 1-(2-
methoxyphenyl)-piperazine or 1-(2-chlorophenyl)-piper-
azine gave the compounds 5±9, 12±16, respectively.
For the synthesis of compounds 19±22 and 25±28 the
same procedure described above was used. Finally, the
intermediates 31a±d were prepared using the method
described for compounds 30b±f.

S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
Table 1. Anity towards a1- and a2-adenoceptors
935
(a)
Compound
n
X
Ki a1 (nM)
16.0‹1.7
Ki a2 (nM)
Ratio a2/a1
3
4
5
6
7
8
9
10
11
12
13
14
15
16
2
3
4
5
6
7
8
2
3
4
5
6
7
8
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-Cl
-Cl
-Cl
-Cl
-Cl
409.0‹35.7
245.0‹25.3
230.0‹20.0
15.0‹1.9
3.5‹0.4
25.5
17.0
53.0
3.8
2.3
3.2
6.5
5.0
7.8
4.0
6.4
6.0
2.7
4.0
14.5‹1.3
4.3‹0.3
3.9‹0.2
1.5‹0.1
1.4‹0.1
3.5‹0.4
58.8‹3.7
27.8‹3.0
10.0‹1.5
4.5‹0.2
4.2‹0.6
2.7‹0.3
5.6‹0.7
4.6‹0.5
22.7‹3.0
292.3‹30.2
219.0‹15.8
39.3‹5.3
29.0‹4.5
25.2‹3.8
7.4‹0.5
-Cl
-Cl
22.8‹2.5
Prazosin
Rauwolscine
0.24‹0.05
4.0‹0.3
(b)
17
18
19
20
21
22
23
24
25
26
27
28
2
3
4
5
6
7
2
3
4
5
6
7
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-OCH3
-Cl
-Cl
-Cl
-Cl
-Cl
38.0‹5.0
73.‹0.6
0.6‹0.1
12.9‹1.5
7.0‹0.8
2.3‹0.2
18.0‹2.0
6.8‹0.6
0.8‹0.1
7.0‹0.9
8.4‹1.2
15.0‹2.5
1261.0‹210.0
254.0‹40.3
62.0‹8.0
69.8‹9.2
71.8‹6.3
45.8‹6.3
370.0‹50.2
316.0‹40.3
69.4‹6.0
138.0‹25.0
138.8‹20.3
139.0‹15.3
33.2
34.8
103.3
5.4
10.2
20.0
20.5
46.5
86.7
20.0
16.5
9.3
-Cl
Prasosin
Rauwolscine
0.24‹0.05
4.0‹0.3
The Ki binding data were calculated as described in the Experimental section. The Ki values are mean‹SD of series separate assays, each performed
in triplicate. Inhibition constants (Ki) were calculated according to the equation of Cheng and Prouso€11 Ki=IC50/1+(L/Kd) when [L] is the ligand
concentration and Kd is dissociation constant. Kd of [3H]-prazosin binding to rat cortex membranes was 0.24 nM (a1) and Kd of [ H]-rauwolscine
3
binding to rat cortex membranes was 4 nM (a2).
the series of 17±28 the highest anity was observed
when the chain had four carbon atoms. It is evident
from these pharmacological results that the presence of
a methoxy group in the ortho position of the arylpiper-
azine fragment increases the anity more than a chlorine
atom. Moreover comparing the ratios of the Ki values
(a2/a1), one can readily see that the length of the alkyl
spacer has an e€ect on selectivity for both the 5- and 6-
substituent methoxy series (for example compound 19
shows the highest selectivity). Similar results have been
obtained for the 6-substituent chlorine series and little
e€ect was observed for 5-substituted chlorine series.
In conclusion, the length of the alkyl chain, a spacer
between the two major constituents of the molecule, can
in¯uence the anity and the selectivity.
Experimental Protocols
Biological methods
ꢀ1-Receptor binding. Rat cerebral cortex was homo-
genized in 20 volumes ice-cold 50 mM Tris±HCl bu€er
at pH 7.7 containing 5 mM EDTA (bu€er T1) in an

936
S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
ultra-turrax homogenizer. The homogenate was cen-
trifuged at 48000 g for 15 min at 4 ꢀC. The pellet (P1)
was suspended in 20 volumes of ice-cold bu€er T1. It
was then homogenized and centrifuged at 48000 g for
15 min at 4 ꢀC. The resulting pellet (P2) was frozen at
80 ꢀC until the time of assay.
dissociation constant. Kd of [3H]-prazosin binding to
cortex membranes was 0.24 nM (a1) and Kd of [3H]-
rauwolscine binding to cortex membranes was 4 nM (a2)
Experimental
The pellet was suspended in 20 volumes of ice-cold
50 mM Tris±HCl bu€er at pH 7.7 (T2 bu€er) and a1
binding assay was performed in triplicate by incubating
at 25 ꢀC for 60 min in 1 mL T2 bu€er containing aliquots
of the membrane fraction (0.2±0.3 mg protein) and
0.1 nM [3H]-prazosin in the absence or presence of
unlabeled 1 mM prazosin. The binding reaction was
terminated by ®ltering through Whatman GF/C glass
®ber ®lters under suction and washing twice with 5 mL
ice-cold Tris bu€er. The ®lters were placed in scintilla-
tion vials and 4 mL Ultima Gold MN Cocktail-Packard
solvent scintillation ¯uid was added. The radioactivity
was counted with an Packard 1600 TR scintillation
counter. Speci®c binding was obtained by subtracting
non-speci®c binding from total binding and was
approximated to 85±90% of the total binding.
Melting points were determined using a Ko¯er 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 theore-
tical values. Precoated Kiesegel 60 F254 plates (Merck)
were used for TLC. The corresponding hydrochlorides
were prepared by bubbling dry HCl into the dry solu-
tion of the compound.
General method A
4-Chloro-2-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (3). A mixture of (1 g, 2.3 mmol) of 4-
chloro-2-(2-chloroethyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30a), (0.45 g,
2.3 mmol) of 1-(2-methoxyphenyl)-piperazine, (0.3 g,
2.9 mmol) of dry sodium carbonate in 40 mL of iso-
amylic alcohol, was re¯uxed under stirring for 24 h,
after ®ltration, the solvent was removed under reduced
pressure, and the residue was puri®ed by chromato-
graphy on a silica gel column eluting with EtOH/
CH2Cl2 (4/96) to give a dense oil, (50%). 1H NMR
(CDCl3) d: 2.60±2.95 (m, 12H, 8H-pip., 2CH2), 3.05±
3.15 (m, 4H, H-pip.), 3.40±3.55 (m, 4H, H-pip.), 3.85 (s,
6H, 2-OCH3), 4.20 (t, J=6 Hz, 2H, CH2), 4.35 (t, J=
6 Hz, 2H, CH2), 6.80±7.00 (m, 8H, H-arom.), 7.60 (s, 1H,
H-pyrid.). The corresponding hydrochloride had mp:
128±129 ꢀC. Anal. calcd for C30H39ClN6O4. 2HCl: C,
54.93; H, 6.25; N, 12.81, found: C, 54.65; H, 6.04; N, 12.54.
ꢀ2-Receptor binding. Cerebral cortex was dissected from
rat brain and the tissue was homogenized in 20 volumes
of ice-cold 50 mM Tris±HCl bu€er at pH 7.7 containing
5 mM EDTA, as reported above (bu€er T1). The homo-
genate was centrifuged at 48000 g for 15 min at 4 ꢀC. The
resulting pellet was diluted in 20 volumes of 50 mM Tris±
HCl bu€er at pH 7.7 and used in the binding assay.
Binding assay was performed in triplicate, by incubating
aliquots of the membrane fraction (0.2±0.3 mg protein)
in Tris±HCl bu€er at pH 7.7 with approximately 2 nM
[3H]-rauwolscine in a ®nal volume of 1 mL. Incubation
was carried out at 25 ꢀC for 60 min. Non-speci®c bind-
ing was de®ned in the presence of 10 mM rauwolscine.
The binding reaction was concluded by ®ltration
through Whatman GF/C glass ®ber ®lters under
reduced pressure. Filters were washed four times with
5 mL aliquots of ice-cold bu€er and placed in scintilla-
tion vials. Speci®c binding was obtained by subtracting
non speci®c binding from total binding and approxi-
mated to 85±90% of total binding. The receptor-bound
radioactivity was measured as described above.
Compounds 5±10, 12±16 were synthesized following
general method A.
4-Chloro-2-{4-[4-(2-methoxyphenyl)-1-piperazinyl]butyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (5). By 4-chloro-2-(4-chlorobutyl)-5-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyr-
idazinone (30b) with 1-(2-methoxyphenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (7/93), a dense oil was
obtained (60%), 1H NMR (CDCl3) d: 1.50±1.65 (m, 2H,
CH2), 1.75±1.90 (m, 2H, CH2), 2.50 (t, J=8 Hz, 2H,
CH2), 2.60±2.80 (m, 8H, H-pip.), 2.90 (t, J=6 Hz, 2H,
CH2), 3.05±3.15 (m, 4H, H-pip.), 3.40±3.50 (m, 4H, H-
pip.), 3.85 (s, 6H, 2OCH3), 4.10±4.30 (m, 4H, 2CH2),
6.80±7.00 (m, 8H, H-arom.), 7.60 (s, 1H, H-pyrid.). The
corresponding hydrochloride had mp: 126±128 ꢀC.
Anal. calcd for C32H43ClN6O4. 3HCl: C, 53.35; H, 6.39;
N, 11.67, found: C, 53.31; H, 6.78; N, 11.36.
Compounds were dissolved in bu€er or DMSO (bu€er/
concentration of 2%) and added to the assay mixture. A
blank experiment was carried out to determine the e€ect
of the solvent on binding.
Protein estimation was based on a reported method,12
after solubilization with 0.75 N sodium hydroxide, using
bovine serum albumin as standard.
The concentration of tested compound that produces
50% inhibition of speci®c [3H]-prazosin or [3H]-rau-
wolscine binding (IC50) was determined by log-probit
analysis with seven concentrations of the displacer, each
performed in triplicate. Inhibition constants (Ki) were
calculated according to the equation:11 Ki=IC50/1+([L]/
Kd) where [L] is the ligand concentration and Kd its
4-Chloro-2-{5-[4-(2-methoxyphenyl)-1-piperazinyl]pentyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (6). From 4-chloro-2-(5-bromopentyl)-5-{4-

S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
937
[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (30c) with 1-(2-methoxyphenyl)-piperazine. Pur-
i®ed by chromatography on a silica gel column eluting
with EtOH/CH2Cl2 (5/95), a dense oil was obtained
is hygroscopic. Anal. calcd for C36H51ClN6O4.3HCl: C,
55.90; H, 6.98; N, 10.87, found: C, 55.78; H, 6.60; N,
10.73.
1
(30%). H NMR (CDCl3) d: 1.35±1.45 (m, 2H, CH2),
4-Chloro-2-{2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl}-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (10). From 4-chloro-2-(2-chloroethyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30a) with 1-(2-chlorophenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (6/94), a dense oil was
obtained (75%). 1H NMR (CDCl3) d: 2.70±2.80 (m, 8H,
H-pip.), 2.85±2.95 (m, 4H, 2CH2), 3.05±3.15 ( m, 4H, H-
pip), 3.40±3.50 (m, 4H, H-pip.), 3.90 (s, 3H, OCH3),
4.20 (t, J=6 Hz, 2H, CH2), 4.35 (t, J=6 Hz, 2H, CH2),
6.90±7.05 (m, 6H, H-arom.), 7.15±7.35 (m, 2H, H-
arom.), 7.65 (s, 1H, H-pyrid.). The corresponding hy-
drochloride had mp: 247±250 ꢀC. Anal. calcd for
C29H36Cl2N6O3. 2HCl: C, 52.74; H, 5.76; N, 12.70,
found: C, 52.63; H, 6.05; N, 12.46.
1.55±1.70 (m, 2H, CH2), 1.75±1.90 (m, 2H, CH2), 2.45 (t,
J=8 Hz, 2H, CH2), 2.55±2.65 (m, 8H, H-pip.), 2.95 (t,
J=6 Hz, 2H, CH2), 3.10±3.15 (m, 4H, H-pip.), 3.40±3.50
(m, 4H, H-pip.), 3.85 (s, 6H, 2-OCH3), 4.10±4.20 (m, 4H,
2CH2), 6.80±7.00 (m, 8H, H-arom.), 7.60 (s, 1H, H-
pyrid.). The corresponding hydrochloride had mp: 95±
98ꢀC. Anal. calcd for C33H45ClN6O4. 3HCl : C, 53.96; H,
6.54; N, 11.44, found: C, 54.20; H, 6.75; N, 11.65.
4-Chloro-2-{6-[4-(2-methoxyphenyl)-1-piperazinyl]hexyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (7). From 4-chloro-2-(6-chlorohexyl)-5-{4-
[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (30d) with 1-(2-methoxyphenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (6/94), a dense oil was
obtained (69%). 1H NMR (CDCl3) d: 1.30±1.40 (m, 4H,
2CH2), 1.50±1.65 (m, 2H, CH2), 1.70±1.85 (m, 2H,
CH2), 2.45 (t, J=8 Hz, 2H, CH2), 2.55±2.75 (m, 8H, H-
pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.10±3.20 (m, 4H, H-
pip), 3.40±3.50 (m, 4H, H-pip.), 3.85 (s, 6H, 2OCH3),
4.10±4.20 (m, 4H, 2CH2), 6.80±7.00 (m, 8H, H-arom.),
7.60 (s, 1H, H-pyrid.). The corresponding hydrochloride
had mp: 138±140 ꢀC. Anal. calcd for C34H47ClN6O4.
3HCl: C, 54.56; H, 6.68; N, 11.20, found: C, 55.00; H,
6.91; N, 11.32.
4-Chloro-2-{4-[4-(2-chlorophenyl)-1-piperazinyl]butyl}-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (12). From 4-chloro-2-(4-chlorobutyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30b) with 1-(2-chlorophenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (10/90), a dense oil was
obtained (35%). 1H NMR (CDCl3) d: 1.50±1.70 (m, 2H,
CH2), 1.85±2.00 (m, 2H, CH2), 2.55 (t, J=8 Hz, 2H,
CH2), 2.65±2.75 (m, 8H, H-pip.), 2.95 (t, J=6 Hz, 2H,
CH2), 3.05±3.15 (m, 4H, H-pip.), 3.40±3.50 (m, 4H, H-
pip.), 3.90 (s, 3H, OCH3), 4.10±4.20 (m, 4H, 2CH2),
6.95±7.10 (m, 6H, H-arom.), 7.15±7.35 (m, 2H, H-
arom.), 7.60 (s, 1H, H-pyrid.). The corresponding hy-
drochloride had mp: 127±130 ꢀC. Anal. calcd for
C31H40Cl2N6O3. 3HCl: C, 54.10; H, 6.10; N, 12.20,
found: C, 54.45; H, 6.41; N, 11.95.
4-Chloro-2-{7-[4-(2-methoxyphenyl)-1-piperazinyl]heptyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (8). From 4-chloro-2-(7-bromoheptyl)-5-{4-
[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (30e) with 1-(2-methoxyphenyl)-piperazine.
Puri®ed by chromatography on a silica gel column eluting
with EtOH/CH2Cl2 (6/94), a dense oil was obtained (75%).
1H NMR (CDCl3) d: 1.30±1.45 (m, 6H, 3CH2), 1.50±1.60
(m, 2H, CH2), 1.70±1.85 (m, 2H, CH2), 2.45 (t, J=8 Hz,
2H, CH2), 2.70±2.80 (m, 8H, H-pip.), 2.95 (t, J=6 Hz, 2H,
CH2), 3.10±3.20 (m, 4H, H-pip.), 3.40±3.50 (m, 4H, H-
pip.), 3.85 (s, 6H, 2-OCH3), 4.10±4.25 (m, 4H, 2CH2),
6.80±7.00 (m, 8H, H-arom.), 7.60 (s, 1H, H-pyrid.). The
corresponding hydrochloride had mp: 125±128 ꢀC. Anal.
calcd for C35H49ClN6O4. 3HCl: C, 55.35; H, 6.45; N,
11.07, found: C, 55.36; H, 7.00; N, 10.95.
4-Chloro-2-{5-[4-(2-chlorophenyl)-1-piperazinyl]pentyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (13). From 4-chloro-2-(5-bromopentyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30c) with 1-(2-chlorophenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (7/93), a dense oil was
obtained (40%). 1H NMR (CDCl3) d: 1.30±1.45 (m, 2H,
CH2), 1.50±1.70 (m, 2H, CH2), 1.75±1.85 (m, 2H, CH2),
2.45 (t, J=8 Hz, 2H, CH2), 2.65±2.75 (m, 8H, H-pip.),
2.90 (t, J=6 Hz, 2H, CH2), 3.05±3.15 (m, 4H, H-pip.),
3.35±3.45 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3), 4.10±
4.20 (m, 4H, 2CH2), 6.80±6.95 (m, 5H, H-arom.), 7.05
(d, 1H, H-arom.), 7.20 (t, 1H, H-arom.), 7.25±7.35 (m,
1H, H-arom.), 7.60 (s, 1H, H-pyrid.). The correspond-
ing hydrochloride had mp: 120±123 ꢀC. Anal. calcd for
C32H42Cl2N6O3. 4HCl: C, 49.56; H, 65.42; N, 10.80,
found: C, 49.62; H, 5.90; N, 10.95.
4-Chloro-2-{8-[4-(2-methoxyphenyl)-1-piperazinyl]octyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (9). From 4-chloro-2-(8-chlorooctyl)-5-{4-
[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyr-
idazinone (30f) with 1-(2-methoxyphenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (7/93), a dense oil was
obtained (40%). 1H NMR (CDCl3) d: 1.30±1.40 (m, 8H,
4CH2), 1.50±1.60 (m, 2H, CH2), 1.65±1.75 (m, 2H,
CH2), 2.45 (t, J=8 Hz, 2H, CH2), 2.60±2.70 (m, 8H, H-
pip.), 2.90 ( t, J=6 Hz, 2H, CH2), 3.10±3.20 (m, 4H, H-
pip.), 3.40±3.50 (m, 4H, H-pip.), 3.85 (s, 6H, 2OCH3),
4.10±4.30 (m, 4H, 2CH2), 6.70±7.00 (m, 8H, H-arom.),
7.60 (s, 1H, H-pyrid.). The corresponding hydrochloride
4-Chloro-2-{6-[4-(2-chlorophenyl)-1-piperazinyl]hexyl}-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (14). From 4-chloro-2-(6-chlorohexyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30d) with 1-(2-chlorophenyl)-piperazine.

938
S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (6/94), a dense oil was
obtained (58%). 1H NMR (CDCl3) d: 1.30±1.45 (m, 4H,
2CH2), 1.55±1.65 (m, 2H, CH2), 1.75±1.85 (m, 2H,
CH2), 2.45 (t, J=8 Hz, 2H, CH2), 2.65±2.75 (m, 8H, H-
pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.00±3.10 (m, 4H, H-
pip.), 3.35±3.45 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3),
4.10±4.20 (m, 4H, 2CH2), 6.80±6.95 (m, 5H, H-arom.),
7.05 (d, 1H, H-arom.), 7.20 (t, 1H, H-arom.), 7.25±7.35
(m, 1H, H-arom.), 7.60 (s, 1H, H-pyrid.). The corre-
sponding hydrochloride had mp: 219±222 ꢀC. Anal.
calcd for C33H44Cl2N6O3. 2HCl: C, 55.00; H, 6.40; N,
11.70, found: C, 55.11; H, 6.54; N, 11.57.
1H NMR (CDCl3) d: 1.60±1.75 (m, 2H, CH2), 1.80±1.90
(m, 2H, CH2), 2.50 (t, J=8 Hz, 2H, CH2), 2.70±2.80 (m,
8H, H-pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.10±3.20 ( m,
4H, H-pip.), 3.30±3.40 (m, 4H, H-pip.), 3.85 (s, 6H,
2OCH3), 4.10 (t, J=8 Hz, 2H, CH2), 4.20 (t, J=6 Hz,
2H, CH2), 6.80±7.00 (m, 9H, 8H-arom., 1H-pyrid.), 7.10
(d, 1H, H-pyrid.). The corresponding hydrochloride had
mp: 125±128 ꢀC. Anal. calcd for C32H44N6O4. 5HCl: C,
50.64; H, 6.46; N, 11.08, found: C, 50.58; H, 6.76; N,
10.95.
2-{5-[4-(2-Methoxyphenyl)-1-piperazinyl]pentyl}-6-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (20). From 2-(5-bromopentyl)-6-{4-[2-(2-meth-
oxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone
(31b) with 1-(2-methoxyphenyl)-piperazine. Puri®ed by
chromatography on a silica gel column eluting with
EtOH/CH2Cl2 (7/93), a dense oil was obtained (45%).
1H NMR (CDCl3) d: 1.40±1.50 (m, 2H, CH2), 1.60±1.70
(m, 2H, CH2), 1.80±1.90 (m, 2H, CH2), 2.50 (t, J=8 Hz,
2H, CH2), 2.70±2.80 (m, 8H, H-pip.), 2.95 (t, J=6 Hz,
2H, CH2), 3.10±3.20 (m, 4H, H-pip.), 3.25±3.35 (m, 4H,
H-pip.), 3.90 (s, 6H, 2OCH3), 4.10 (t, J=8 Hz, 2H,
CH2), 4.20 (t, J=6 Hz, 2H, CH2), 6.80±7.00 (m, 9H,
8H-arom., 1H-pyrid.), 7.10 (d, J=9 Hz, 1H, H-pyrid.).
The corresponding hydrochloride had mp: 131±134 ꢀC.
Anal. calcd for C33H46N6O4. 5HCl: C, 51.27; H, 6.60;
N, 10.80, found: C, 51.47; H, 6.86; N, 10.55.
4-Chloro-2-{7-[4-(2-chlorophenyl)-1-piperazinyl]heptyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (15). From 4-chloro-2-(7-bromoheptyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30e) with 1-(2-chlorophenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (6/94), a dense oil was
obtained (75%). 1H NMR (CDCl3) d: 1.30±1.45 (m, 6H,
3CH2), 1.55±1.65 (m, 2H, CH2), 1.75±1.85 (m, 2H,
CH2), 2.40 (t, J=8 Hz, 2H, CH2), 2.60±2.70 (m, 8H, H-
pip.), 2.95 (t, 2H, CH2), 3.00±3.10 (m, 4H, H-pip.),
3.35±3.45 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3), 4.10±
4.20 (m, 4H, 2CH2), 6.80±6.95 (m, 5H, H-arom.), 7.05
(d, 1H, H-arom.), 7.20 (t, 1H, H-arom.), 7.25±7.35 (m,
1H, H-arom.), 7.60 (s, 1H, H-pyrid.). The correspond-
ing hydrochloride is hygroscopic. Anal. calcd for
C34H46Cl2N6O3. 4HCl: C, 50.82; H, 5.70; N, 10.40,
found: C, 50.86; H, 5.80; N, 10.26.
2-{6-[4-(2-Methoxyphenyl)-1-piperazinyl]hexyl}-6-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (21). From 2-(6-chlorohexyl)-6-{4-[2-(2-meth-
oxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone
(31c) with 1-(2-methoxyphenyl)-piperazine. Puri®ed by
chromatography on a silica gel column eluting with
EtOH/CH2Cl2 (10/90), a dense oil was obtained (47%).
1H NMR (CDCl3) d: 1.30±1.45 (m, 4H, 2CH2), 1.60±
1.70 (m, 2H, CH2), 1.80±1.90 (m, 2H, CH2), 2.45 (t,
J=8 Hz, 2H, CH2), 2.70±2.80 (m, 8H, H-pip.), 2.95 (t,
J=6 Hz, 2H, CH2), 3.10±3.20 (m, 4H, H-pip.), 3.25±
3.35 (m, 4H, H-pip.), 3.90 (s, 6H, 2OCH3), 4.10 (t,
J=8 Hz, 2H, CH2), 4.20 (t, J=6 Hz, 2H, CH2), 6.80±
7.00 (m, 9H, 8H-arom., 1H-pyrid.), 7.10 (d, J=9 Hz,
1H, H-pyrid.). The corresponding hydrochloride had
mp: 132±135 ꢀC. Anal. calcd for C34H48N6O4. 5HCl: C,
51.89; H, 6.70; N, 10.60, found: C, 51.75; H, 7.03; N,
10.34.
4-Chloro-2-{8-[4-(2-chlorophenyl)-1-piperazinyl]octyl}-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (16). From 4-chloro-2-(8-chlorooctyl)-5-
{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (30f) with 1-(2-chlorophenyl)-piperazine.
Puri®ed by chromatography on a silica gel column
eluting with EtOH/CH2Cl2 (6/94), a dense oil was
obtained (40%). 1H NMR (CDCl3) d: 1.30±1.45 (m, 8H,
4CH2), 1.50±1.60 (m, 2H, CH2), 1.65±1.75 (m, 2H,
CH2), 2.45 (t, J=8 Hz, 2H, CH2), 2.60±2.75 (m, 8H, H-
pip.), 2.90 (t, J=6 Hz, 2H, CH2), 3.10±3.20 (m, 4H, H-
pip.), 3.40±3.50 (m, 4H, H-pip.), 3.85 (s, 3H, OCH3),
4.10±4.30 (m, 4H, 2CH2), 6.70±6.90 (m, 5H, H-arom.),
7.05 (d, 1H, H-arom.), 7.20 (t, 1H, H-arom.), 7.25±7.35
(m, 1H, H-arom.), 7.60 (s, 1H, H-pyrid.). The corre-
sponding hydrochloride is hygroscopic. Anal. calcd for
C35H48Cl2N6O3. 3HCl: C, 53.82; H, 6.53; N, 10.76,
found: C, 53.91; H, 6.75; N, 10.83.
2-{7-[4-(2-Methoxyphenyl)-1-piperazinyl]heptyl}-6-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (22). From 2-(7-bromoheptyl)-6-{4-[2-(2-meth-
oxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone
(31d) with 1-(2-methoxyphenyl)-piperazine. Puri®ed by
chromatography on a silica gel column eluting with
EtOH/CH2Cl2 (10/90), a dense oil was obtained (70%).
1H NMR (CDCl3) d: 1.30±1.45 (m, 6H, 3CH2), 1.60±
1.85 (m, 4H, 2CH2), 2.70 (t, J=8 Hz, 2H, CH2), 2.75±
2.80 (m, 4H, H-pip.), 2.85±3.00 (m, 6H, 4H-pip., CH2 ),
3.20±3.30 (m, 4H, H-pip.), 3.35±3.40 (m, 4H, H-pip.),
3.90 (s, 6H, 2OCH3), 4.10 (t, J=8 Hz, 2H, CH2), 4.20 (t,
J=6 Hz, 2H, CH2), 6.85 (d, J=9 Hz, 1H, H-pyrid.),
6.80±7.00 (m, 8H, H-arom.), 7.10 (d, J=9 Hz, 1H, H-
pyrid.). The corresponding hydrochloride had mp:
Compounds 19±22 and 25±28 were prepared using the
general method A, starting from 6-(4-[2-(2-methoxy-
phenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone (1a).6
2-{4-[4-(2-Methoxyphenyl)-1-piperazinyl]butyl}-6-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (19). From 2-(4-chlorobutyl)-6-{4-[2-(2-meth-
oxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone
(31a) with 1-(2-methoxyphenyl)-piperazine. Puri®ed by
chromatography on a silica gel column eluting with
EtOH/CH2Cl2 (12/88), a dense oil was obtained (50%).

S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
939
137±140 ꢀC. Anal. calcd for C35H50N6O4. 5HCl: C, 52.48;
H, 6.87; N, 10.49, found: C, 52.75; H, 6.95; N, 10.64.
phenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone (31d)
with 1-(2-chlorophenyl)-piperazine. Puri®ed by chro-
matography on a silica gel column eluting with EtOH/
CH2Cl2 (15/85), a dense oil was obtained (65%). 1H
NMR (CDCl3) d: 1.30±1.45 (m, 6H, 3CH2), 1.50±1.65
(m, 2H, CH2), 1.70±1.85 (m, 2H, CH2), 2.45 (t, J=8 Hz,
2H, CH2), 2.65±2.75 (m, 8H, H-pip.), 2.90 (t, J=6 Hz,
2H, CH2), 3.05±3.15 (m, 4H, H-pip.), 3.25±3.40 (m, 4H,
H-pip.), 3.85 (s, 3H, OCH3), 4.00 (t, J=8 Hz, 2H, CH2),
4.15 (t, J=6 Hz, 2H, CH2), 6.85 (d, J=9 Hz, 1H, H-
pyrid.), 6.90±7.05 (m, 7H, H-arom.), 7.10 (d, J=9Hz,
1H, H-pyrid.), 7.20±7.35 (m, 1H, H-arom.). The corre-
sponding hydrochloride had mp: 137±140 ꢀC. Anal. calcd
for C34H47ClN6O3. 4HCl: C, 54.64; H, 6.92; N, 10.27,
found: C, 54.10; H, 6.65; N, 10.50.
2-{4-[4-(2-Chlorophenyl)-1-piperazinyl]butyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (25). From 2-(4-chlorobutyl)-6-{4-[2-(2-methoxy-
phenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone (31a)
with 1-(2-chlorophenyl)-piperazine. Puri®ed by chro-
matography on a silica gel column eluting with EtOH/
1
CH2Cl2 (13/87), a dense oil was obtained (30%). H
NMR (CDCl3) d: 1.55±1.75 (m, 2H, CH2), 1.80±1.95
(m, 2H, CH2), 2.55 (t, J=8 Hz, 2H, CH2), 2.65±2.70 (m,
8H, H-pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.10±3.20 (m,
4H, H-pip.), 3.30±3.40 (m, 4H, H-pip.), 3.90 (s, 3H,
OCH3), 4.10 (t, J=8 Hz, 2H, CH2), 4.25 (t, J=6 Hz,
2H, CH2), 6.85 (d, J=9 Hz, 1H, H-pyrid.), 6.90±7.10 (m,
7H, H-arom.), 7.15 (d, J=9 Hz, 1H, H-pyrid.), 7.20±
7.40 (m, 1H, H-arom.). The corresponding hydrochlo-
ride had mp: 115±118 ꢀC. Anal. calcd for C31H41
ClN6O3. 3HCl: C, 53.90; H, 6.37; N, 12.70, found: C,
53.84; H, 6.20; N, 11.95.
General method B
4-Chloro-2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (4). To 30 mL of dry ethanol was added
(0.1g, 2.5 mmol) of sodium hydroxide pellets, after was
2-{5-[4-(2-Chlorophenyl)-1-piperazinyl]pentyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (26). From 2-(5-bromopentyl)-6-{4-[2-(2-methoxy-
phenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone (31b)
with 1-(2-chlorophenyl)-piperazine. Puri®ed by chro-
matography on a silica gel column eluting with EtOH/
added
4-chloro-5-{4-[2-(2-methoxyphenoxy)-ethyl]-1-
piperazinyl}-3(2H)-pyridazinone (1) (0.9g, 2.5 mmol)
and the suspension was re¯uxed under stirring for
30 min, then 1-(2-methoxyphenyl)-4-(3-chloropropyl)-
piperazine (29c) (0.67 g, 2.5 mmol) dissolved in dry eth-
anol was added, after the reaction mixture was re¯uxed
under stirring for 15 h. After cooling and evaporation
under reduced pressure of the solvent, the residue was
puri®ed by chromatography on a silica gel, eluting with
EtOH/CH2Cl2 (7/93). A dense oil was obtained (45%).
1H NMR (CDCl3) d: 1.90±2.10 (m, 2H, CH2), 2.50 (t,
J=8 Hz, 2H, CH2), 2.60±2.80 (m, 8H, H-pip.), 2.90 (t,
J=6 Hz, 2H, CH2), 3.05±3.15 (m, 4H, H-pip.), 3.40±
3.50 (m, 4H, H-pip.), 3.85 (s, 6H, 2OCH3), 4.10±4.30
(m, 4H, 2CH2), 6.80±7.00 (m, 8H, H-arom.), 7.60 (s, 1H,
H-pyrid.). The corresponding hydrochloride had mp:
113±115 ꢀC. Anal. calcd for C31H41ClN6O4. 2HCl: C,
55.57; H, 6.42; N, 12.54, found: C, 55.83; H, 6.65; N, 12.70.
1
CH2Cl2 (14/86), a dense oil was obtained (35%). H
NMR (CDCl3) d: 1.40±1.45 (m, 2H, CH2), 1.50±1.70
(m, 2H, CH2), 1.75±1.90 (m, 2H, CH2), 2.40 (t, J=8 Hz,
2H, CH2), 2.65±2.70 (m, 8H, H-pip.), 2.90 (t, J=6 Hz,
2H, CH2), 3.05±3.15 (m, 4H, H-pip.), 3.30±3.40 (m, 4H,
H-pip.), 3.85 (s, 3H, OCH3), 4.05 (t, J=8 Hz, 2H, CH2),
4.15 (t, J=6 Hz, 2H, CH2), 6.85 (d, J=9 Hz, 1H, H-
pyrid.), 6.90±7.00 (m, 7H, H-arom.), 7.10 (d, J=9 Hz,
1H, H-pyrid.), 7.15±7.35 (m, 1H, H-arom.). The corre-
sponding hydrochloride had mp: 136±138 ꢀC. Anal.
calcd for C32H43ClN6O3. 4HCl: C, 52.87; H, 6.35; N,
11.30, found: C, 52.76; H, 6.20; N, 10.95.
2-{6-[4-(2-Chlorophenyl)-1-piperazinyl]hexyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (27). From 2-(6-chlorohexyl)-6-{4-[2-(2-methoxy-
phenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone (31c)
with 1-(2-chlorophenyl)-piperazine. Puri®ed by chro-
matography on a silica gel column eluting with EtOH/
4-Chloro-2-{3-[4-(2-chlorophenyl)-1-piperazinyl]propyl}-
5-{4-[2-(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-
pyridazinone (11). From 1 with 1-(2-chlorophenyl)-4-(3-
chloropropyl)-piperazine (29d). Puri®ed by chromato-
graphy on a silica gel column eluting with EtOH/
CH2Cl2 (8/92), a dense oil was obtained (30%). 1H
NMR (CDCl3) d: 2.00±2.15 (m, 2H, CH2), 2.55 (t,
J=8 Hz, 2H, CH2), 2.65±2.75 (m, 4H, H-pip.), 2.75±
2.85 (m, 4H, H-pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.05±
3.15 (m, 4H, H-pip.), 3.40±3.50 (m, 4H, H-pip.), 3.90 (s,
3H, OCH3), 4.15±4.30 (m, 4H, 2CH2), 6.90±7.10 (m,
6H, H-arom.), 7.15±7.35 (m, 2H, H-arom.), 7.60 (s, 1H,
H-pyrid.). The corresponding hydrochloride is hygro-
scopic. Anal. calcd for C30H38 Cl2N6O3. 3HCl: C, 50.68;
H, 5.80; N, 11.60, found: C, 50.28; H, 6.00; N, 11.25.
1
CH2Cl2 (15/85), a dense oil was obtained (30%). H
NMR (CDCl3) d: 1.35±1.45 (m, 4H, 2CH2), 1.55±1.70
(m, 2H, CH2), 1.75±1.90 (m, 2H, CH2), 2.50 (t, J=8 Hz,
2H, CH2), 2.65±2.75 (m, 8H, H-pip.), 2.95 (t, J=6 Hz,
2H, CH2), 3.10±3.20 (m, 4H, H-pip.), 3.30±3.40 (m, 4H,
H-pip.), 3.85 (s, 3H, OCH3), 4.05 (t, J=8 Hz, 2H, CH2),
4.20 (t, J=6 Hz, 2H, CH2), 6.85 (d, J=9 Hz, 1H, H-
pyrid.), 6.90±7.15 (m, 7H, H-arom.), 7.20±7.25 (m, 1H,
H-pyrid.), 7.30±7.40 (m, 1H, H-arom.). The corre-
sponding hydrochloride had mp: 127±130 ꢀC. Anal.
calcd for C33H45ClN6O3. 3HCl: C, 55.10; H, 6.50; N,
11.70, found: C, 55.35; H, 6.81; N, 11.42.
Compounds 17, 18, 23 and 24 were prepared with the
same procedure described for compound 4 starting from
compound 1a.
2-{7-[4-(2-Chlorophenyl)-1-piperazinyl]heptyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (28). From 2-(7-bromoheptyl)-6-{4-[2-(2-methoxy-
2-{2-[4-(2-Methoxyphenyl)-1-piperazinyl]ethyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazinone

940
S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
(17). From 1a with 1-(2-methoxyphenyl)-4-(2-chloroethyl)-
piperazine (29a). Puri®ed by chromatography on a silica
gel column eluting with EtOH/CH2Cl2 (8/92), a dense
ammonium bromide (TBAB) using the method of
Yamada.9 The residue was puri®ed by chromatography
on a silica gel using EtOH/CH2Cl2 (4/96) (35%). H
NMR (CDCl3) d: 2.70±2.85 (m, 4H, H-pip.), 2.95 (t,
J=6 Hz, 2H, CH2), 3.40±3.50 (m, 4H, H-pip.), 3.70 (t.
J=6 Hz, 2H, CH2), 3.85 (s, 3H, OCH3), 4.20 (t, J=
6 Hz, 2H, CH2), 4.50 (t, J=6 Hz, 2H, CH2), 6.85±6.95
(m, 4H, H-arom.), 7.65 (s, 1H, H-pyrid.).
1
1
oil was obtained (50%). H NMR (CDCl3) d: 2.60±2.80
(m, 8H, H-pip.), 2.85±2.90 (m, 4H, 2CH2), 3.05±3.15
(m, 4H, H-pip.), 3.25±3.40 (m, 4H, H-pip.), 3.85 (s, 6H,
2OCH3), 4.15±4.30 (m, 4H, 2CH2), 6.80±6.95 (m, 9H,
8H-arom., 1H-pyrid.), 7.10 (d, J=9 Hz, 1H, H-pyrid.).
The corresponding hydrochloride had mp: 231±234 ꢀC.
Anal. calcd for C30H40N6O4. 2HCl: C, 57.98; H, 6.76;
N, 13.52, found: C, 57.67; H, 6.82; N, 13.70.
General method C
4-Chloro-2-(4-chlorobutyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30b). A mix-
ture of 1 g (20 mmol) of 1, 1-bromo-4-chlorobutane
(0.7 g, 30 mmol), dry potassium carbonate (0.56 g,
30 mmol) in 20 mL of the acetone, was re¯uxed under
stirring for 15 h. After the ®ltered residue was evapo-
rated under reduced pressure and was puri®ed by chro-
matography on silica gel eluting with EtOH/CH2Cl2
2-{3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl}-6-{4-[2-
(2-methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyrid-
azinone (18). From 1a with 1-(2-methoxyphenyl)-4-(3-
chloropropyl)-piperazine (29c). Puri®ed by chromato-
graphy on a silica gel column eluting with EtOH/
1
CH2Cl2 (10/90), a dense oil was obtained (35%). H
NMR (CDCl3) d: 2.10±2.20 (m, 2H, CH2), 2.65±2.80
(m, 8H, H-pip.), 2.85±2.95 (m, 4H, 2CH2), 3.20±3.30
(m, 4H, H-pip.), 3.35±3.40 ( m, 4H, H-pip.), 3.85 (s, 6H,
2OCH3), 4.10±4.30 (m, 4H, 2CH2), 6.80±7.00 (m, 9H,
8H-arom., 1H-pyrid.), 7.10 (d, 1H, H-pyrid.). The cor-
responding hydrochloride is hygroscopic. Anal. calcd
for C31H42N6O4. 2HCl: C, 58.60; H, 6.93; N, 13.23,
found: C, 58.27; H, 6.63; N, 12.95.
1
(3/97) (70%). H NMR (CDCl3) d: 1.75±2.05 (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.), 3.60 (t. J=6 Hz, 2H,
CH2), 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.)
Compounds 30c±f were prepared using the method
described for compound 30b.
2-{2-[4-(2-chlorophenyl)-1-piperazinyl]ethyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (23). From 1a with 1-(2-chlorophenyl)-4-(2-chloro-
ethyl)-piperazine (29b). Puri®ed by chromatography on
a silica gel column eluting with EtOH/CH2Cl2 (12/88), a
dense oil was obtained (45%). 1H NMR (CDCl3) d:
2.60±2.70 (m, 8H, H-pip.), 2.75±2.80 (m, 4H, 2CH2),
2.95±3.05 (m, 4H, H-pip.), 3.20±3.30 (m, 4H, H-pip.),
3.80 (s, 6H, 2OCH3), 4.05±4.25 (m, 4H, 2CH2), 6.75 (d,
J=9 Hz, 1H, H-pyrid.), 6.90±7.05 (m, 6H, H-arom.),
7.15 (d, J=9 Hz, 1H-pyrid.), 7.20±7.25 (m, 1H, H-
arom.), 7.35±7.45 (m, 1H, H-arom.). The corresponding
hydrochloride had mp: 228±232 ꢀC. Anal. calcd for
C29H37ClN6O3. 2HCl: C, 55.64; H, 6.23; N, 13.43,
found: C, 55.73; H, 6.40; N, 13.60.
4-Chloro-2-(5-bromopentyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30c). From 1
with 1,5-dibromopentane, reaction time 6 h, (50%). H
NMR (CDCl3) d: 1.40±1.60 (m, 2H, CH2), 1.70±2.00
(m, 4H, 2CH2), 2.70±2.80 (m, 4H, H-pip.), 2.90 (t,
J=6 Hz, 2H, CH2), 3.35±3.55 (m, 6H, 4H-pip., CH2),
3.90 (s, 3H, OCH3), 4.10±4.30 (m, 4H, 2CH2), 6.80±7.00
(m, 4H, H-arom.), 7.60 (s, 1H, H-pyrid.).
1
4-Chloro-2-(6-chlorohexyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30d). From 1
with 1-bromo-6-chlorohexane, reaction time 8 h, (50%).
1H NMR (CDCl3) d: 1.30±1.35 (m, 4H, 2CH2), 1.70±
1.90 (m, 4H, 2CH2), 2.70±2.80 (m, 4H, H-pip.), 2.90 (t,
J=6 Hz, 2H, CH2), 3.35±3.55 (m, 6H, 4H-pip., CH2),
3.90 (s, 3H, OCH3), 4.10±4.25 (m, 4H, 2CH2), 6.80±7.00
(m, 4H, H-arom.), 7.60 (s, 1H, H-pyrid.).
2-{3-[4-(2-chlorophenyl)-1-piperazinyl]propyl}-6-{4-[2-(2-
methoxyphenoxy)ethyl]-1-piperazinyl}-3(2H)-pyridazin-
one (24). From 1a with 1-(2-chlorophenyl)-4-(3-chloro-
propyl)-piperazine (29d). Puri®ed by chromatography
on a silica gel column eluting with EtOH/CH2Cl2 (12/
4-Chloro-2-(7-bromoheptyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30e). From 1
1
1
88), a dense oil was obtained (35%). H NMR (CDCl3)
with 1,7-dibromoheptane, reaction time 7 h, (75%). H
d: 2.05±2.25 (m, 2H, CH2), 2.65±2.75 (m, 6H, 4H-pip.,
CH2), 2.80±2.95 (m, 6H, 4H-pip, CH2), 3.15±3.25 (m,
4H, H-pip.), 3.30±3.40 (m, 4H, H-pip.), 3.85 (s, 3H,
OCH3), 4.10±4.25 (m, 4H, 2CH2), 6.85 (d, J=9 Hz, 1H,
H-pyrid.), 6.90±7.10 (m, 7H, H-arom.), 7.15±7.25 (m,
1H, H-pyrid.), 7.30±7.40 (m, 1H, H-arom.). The corre-
sponding hydrochloride had mp: 189±192 ꢀC. Anal.
calcd for C30H39ClN6O3. 2HCl: C, 56.30; H, 6.72; N,
13.13, found: C, 56.11; H, 6.40; N, 12.97.
NMR (CDCl3) d: 1.30±1.50 (m, 6H, 3CH2), 1.70±1.90
(m, 4H, 2CH2), 2.70±2.80 (m, 4H, H-pip.), 2.90 (t,
J=6 Hz, 2H, CH2), 3.40±3.50 (m, 6H, 4H-pip., CH2),
3.85 (s, 3H, OCH3), 4.05±4.20 (m, 4H, 2CH2), 6.80±7.00
(m, 4H, H-arom.), 7.60 (s, 1H, H-pyrid.).
4-Chloro-2-(8-bromooctyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30f). From 1
1
with 1,8-dibromooctane, reaction time 18 h, (50%). H
NMR (CDCl3) d: 1.20±1.45 (m, 8H, 4CH2), 1.60±1.90
(m, 4H, 2CH2), 2.75±2.85 (m, 4H, H-pip.), 2.95 (t,
J=6 Hz, 2H, CH2), 3.25±3.50 (m, 6H, 4H-pip., CH2),
3.90 (s, 3H, OCH3), 4.00±4.20 (m, 4H, 2CH2), 6.80±7.00
(m, 4H, H-arom.), 7.60 (s, 1H, H-pyrid.).
4-Chloro-2-(2-chloroethyl)-5-{4-[2-(2-methoxyphenoxy)-
ethyl]-1-piperazinyl}-3(2H)-pyridazinone (30a). This
compound was prepared from 1, with 1,2-dibromo-
ethane in benzene, potassium hydroxide and tetrabutyl

S. Corsano et al. / Bioorg. Med. Chem. 7 (1999) 933±941
941
Compounds 31a±d were prepared using the general
method C starting compound 1a.
CH2), 4.20 (t, J=6 Hz, 2H, CH2), 6.80 (d, J=9 Hz, 1H,
H-pyrid.), 6.90±7.00 (m, 4H, H-arom.), 7.10 (d,
J=9 Hz, 1H, H-pyrid.).
2-(4-Chlorobutyl)-6-{4-[2-(2-methoxyphenoxy)ethyl]-1-
piperazinyl}-3(2H)-pyridazinone (31a). Reaction time
1
20 h, (70%). H NMR (CDCl3) d: 1.50±2.00 (m, 4H,
Acknowledgements
2CH2), 2.70±2.85 (m, 4H, H-pip.), 3.00 (t, J=6 Hz, 2H,
CH2), 3.30±3.40 (m, 4H, H-pip.), 3.60 (t, J=8 Hz, 2H,
CH2), 3.90 (s, 3H, OCH3), 4.10 (t, J=8 Hz, 2H, CH2),
4.20 (t, J=6 Hz, 2H, CH2), 6.80 (d, J=9 Hz, 1H, H-
pyrid.), 6.90±7.00 (m, 4H, H-arom.), 7.10 (d, J=9 Hz,
1H, H-pyrid.).
Financial support (40%) provided by the Ministry of
University and Scienti®c and Technological Research
(MURST) is acknowledged. Thanks are due to Dr. C.
Santi for NMR analysis and the aid in the structure
elucidation.
2-(5-Bromopentyl)-6-{4-[2-(2-methoxyphenoxy)ethyl]-1-
piperazinyl}-3(2H)-pyridazinone (31b). Reaction time
20 h, (70%). H NMR (CDCl3) d: 1.40±1.60 (m, 2H,
CH2), 1.75±2.00 (m, 4H, 2CH2), 2.70±2.85 (m, 4H, H-
pip.), 2.95 (t, J=6 Hz, 2H, CH2), 3.30±3.50 (m, 6H, 4H-
pip., CH2), 3.90 (s, 3H, OCH3), 4.05 (t, J=8 Hz, 2H,
CH2), 4.25 (t,J=6 Hz, 2H, CH2), 6.85 (d, 1H, H-pyrid.),
6.90±7.00 (m, 4H, H-arom.), 7.10 (d, 1H, H-pyrid.).
References
1
1. Strader, C. D.; Sigal, I. S.; Dixon, R. A. F. Faseb, J 1989, 3,
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2-(6-Chlorohexyl)-6-{4-[2-(2-methoxyphenoxy)ethyl]-1-
piperazinyl}-3(2H)-pyridazinone (31c). Reaction time
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2CH2), 1.75±1.90 (m, 4H, 2CH2), 2.70±2.80 (m, 4H, H-
pip.), 3.00 (t, J=6 Hz, 2H, CH2), 3.30±3.40 (m, 4H, H-
pip.), 3.55 (t, J=8 Hz, H, CH2), 3.90 (s, 3H, OCH3),
4.05 (t, J=8 Hz, 2H, CH2), 4.25 (t, J=6 Hz, 2H, CH2),
6.85 (d, J=9 Hz, 1H, H-pyrid.), 6.90±7.00 (m, 4H, H-
arom.), 7.10 (d, J=9 Hz, 1H, H-pyrid.).
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1
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2-(7-Bromoheptyl)-6-{4-[2-(2-methoxyphenoxy)ethyl]-1-
piperazinyl}-3(2H)-pyridazinone (31d). Reaction time
20 h, (50%). H NMR (CDCl3) d: 1.30±1.50 (m, 6H,
3CH2), 1.70±1.90 (m, 4H, 2CH2), 2.70±2.80 (m, 4H, H-
pip.), 2.90 (t, J=6 Hz, 2H, CH2), 3.30±3.50 (m, 6H, 4H-
pip., CH2), 3.95 (s, 3H, OCH3), 4.05 (t, J=8 Hz, 2H,
1
12. Lowry, O. H.; Rosenbrough, N. J.; Farr, A. L.; Randall,
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