Studies on some 3(2H)-pyridazinone derivatives with antinociceptive activity

Article abstract of DOI:10.1002/(SICI)1521-4184(20004)333:4<79::AID-ARDP79>3.0.CO;2-S

Nineteen new [6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]acetamide (1- 10) and 3-[6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]propanamide (11-19) derivatives have been synthesized in this study. The structures of the compounds have been elucidated by the

Full text of DOI:10.1002/(SICI)1521-4184(20004)333:4<79::AID-ARDP79>3.0.CO;2-S

3(2H)-Pyridazinone Derivatives
79
Studies on Some 3(2H)-Pyridazinone Derivatives with Antinociceptive
Activity
a)
a)
a)
b)
Deniz S. Dogruer* , M. Fethi Sahin , Serdar Ünlü , and Shigeru Ito
a) Gazi University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, 06330, Ankara, Turkey
b) Institute for Medical and Dental Engineering Tokyo Medical and Dental University 2-3-10 Surugadai, Kanda, Chiyoda-Ku, Tokyo, Japan
Key Words : 3(2H)-Pyridazinone; antinociceptive activity; molecular connectivity
We have recently synthesized several benzoxazolinones
and benzothiazolinones carrying acetamide moieties at
position 3. We previously reported that N-[2-(4-methylpyrid-
inyl)]-2-[2(3H)-benzazolone-3-yl]acetamide and 4-[2-(6-
benzoyl-2-benzoxazolone-3-yl)acetyl]morpholine had sig-
Summary
Nineteen new [6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]-
acetamide (1–10) and 3-[6-(4-methoxyphenyl)-3(2H)-pyridazin-
one-2-yl]propanamide (11–19) derivatives have been synthesized
in this study. Thestructuresof thecompoundshavebeen elucidated
by their IR and NMR spectral data and elemental analysis. Anti-
nociceptive activity of the compounds has been investigated by
modified Koster’s Test in mice, using aspirin as a reference. All
the compounds (at 100 mg/kg dose) except 1 and 9 have been
found more potent than aspirin. Compound 6 in the group of
acetamide derivatives and compound 15 in the group of pro-
panamides exhibited the highest antinociceptive activity. In addi-
tion, thepropanamides havegenerally beenfound morepotent than
acetamides. In addition to these studies, the quantitative relation-
ships between some structural parameters (such as log P, parachor,
molar refractivity, and molecular connectivity indices) and antino-
ciceptive activity of the compounds have been investigated. Sta-
tistical regression analysis has shown a close relationship to exist
between the first-order molecular connectivity index (1χ) and the
antinociceptive activity.
nificant antinociceptive activity in comparison with the oth-
[7,8]
ers compounds synthesized
. In addition, we found that
3-[3-(4-phenylpiperazine-1-yl)propyl)]-2(3H)-benzothiaz-
olone was more active as antinociceptive than the other
[9]
synthesized compounds
.
In addition, various compounds incorporating a 3(2H)-
pyridazinone ring have been synthesized and their pharma-
[10–12]
cological activities have been reported
. Recently it was
reported that a considerable number of 3(2H)-pyridazinone
[6,13–18]
derivatives have analgesic activity
. Among these
compounds, one of the 3(2H)-pyridazinone derivatives, 4-
ethoxy-2-methyl-5-morpholino-3(2H)-pyridazinone (emorf-
azone) is a well-known analgesic and antiinflammatory agent
[13,14]
(Figure 1)
.
Introduction
Figure 1. Emorfazone.
Commonly used nonsteroidal antiinflammatory drugs
(NSAIDs) have significant side effects such as gastrointesti-
nal disorders and kidney damage. Therefore, the design of
new compounds with analgesic activity has attracted the
attention of medicinal chemists. As a result, there are many
studies in progress on analgesic-antiinflammatory com-
pounds.
Dal Piaz et al. subsequently synthesized 4-amino-2-methyl-
6-phenyl-5-vinyl-3(2H)-pyridazinone and discovered that
this compound is almost seven-fold more potent than emorf-
[15]
azone . Rohet and co-workers also synthesized some 4,6-
diphenyl-2-[3-(4-arylpiperazin-1-yl)propyl]-3(2H)-pyridaz-
inone derivatives and showed that these compounds have
trazodone-like analgesic activity . Santagati and co-work-
It was previously reported that various derivatives of
2-benzoxazolinone, 2-benzothiazolinone, and oxazolopyrid-
[6]
[1–5]
inone show significant analgesic activity
. A common
ers claimed that 2-substituted 4,5-dihalo-3(2H)-pyridazinone
derivatives have high analgesic activity. Additionally, all the
compounds that they synthesized exhibited almost no ulcero-
characteristic of these compounds is the N-substituted lactam
functional group. Another heterocyclic moiety which has this
functional group is the pyridazinone ring system. Many
authors previously reported that benzoxazolinone, oxazolo-
pyridinone, and pyridazinone derivatives bearing an aryl-
piperazine moiety at the side chain on the lactam nitrogen of
[16]
genic side effect . Rubat and co-workers stated that N-sub-
stituted 5-benzylidene-6-methyl-3-pyridazinone derivatives
also show analgesic activity
[17,18]
.
Consequently we have decided to change the heterocyclic
core of the compounds synthesized in our laboratory. There-
fore, the 3(2H)-pyridazinone ring has been chosen and 3(2H)-
pyridazinone derivatives carrying acetamide and propan-
amide moieties at position 2 of the pyridazinone ring have
been synthesized.
the rings have significant analgesic activity, and stressed the
[1,5,6]
significance of this structural feature
. In addition, some
authors claimed that these compounds exhibit better analge-
sic activity if they have a three carbon chain between the
nitrogen of the lactam and the amine component on the side
[5,6]
chain
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2000
0365-6233/00/0404/079 $17.50 +.50/0

80
Dogruer, Sahin, Ünlü, and Ito
The general structure of the compounds synthesized is
shown in Figure 2.
In addition, the quantitative relationships between some
physicochemical parameters (such as log P, parachor, molar
refractivity, and molecular connectivity indices) and antino-
ciceptive activity of the compounds have been investigated.
A good relationship has been found between the first-order
R = piperazines, piperidines
Figure 2. The chemical structure of the compounds synthesized.
1
molecular connectivity index ( χ) and antinociceptive activ-
ity by performing statistical regression analysis.
Table 1. Physical and chemical data of the compounds 1–19.
Arch. Pharm. Pharm. Med. Chem. 333, 79–86 (2000)

3(2H)-Pyridazinone Derivatives
Table 1. Continued
81
In the IR spectra of acetamide derivatives, carbonyl stretch-
ing bands of the amide function and pyridazinone ring were
seen at about 1665–1655 cm . However propanamide de-
Result and Discussion
–1
rivatives carbonyl stretching bands of the pyridazinone ring
–1
Chemistry
was seen at about 1670–1653 cm , carbonyl stretching of
–1 1
amide appeared at around 1644–1631 cm . H-NMR spec-
tral data of the compounds which were synthesized are pre-
sented in Table 2.
The title compounds were synthesized by the reaction of
appropriate amine derivatives with mixed anhydride struc-
tures which were obtained by reacting [6-(4-methoxy-
phenyl)-3(2H)-pyridazinone-2-yl]acetic acid or [6-(4-meth-
oxyphenyl)-3(2H)-pyridazinone-2-yl]propanoic acid in di-
chloromethane at 0 °C (ice-bath) with triethylamine and ethyl
chloroformate (Scheme 1). Analytical data are given in Ta-
ble 1.
Pharmacology
The antinociceptive activity of the compounds has been
investigated by modified Koster’s Test in mice, using aspirin
[23]
as a reference . All the compounds (at 100 mg/kg dose)
except 1 and 9 have been found more potent than aspirin.
Compound 6 in the group of acetamide derivatives and com-
pound 15 in the group of propanamides have exhibited the
highest antinociceptive activity among the others. Both of the
compounds have the 4-fluorophenylpiperazine moiety as
The synthesis of I, II, III, IV, V has already been reported
[19–22]
in the literature
. [6-(4-Methoxyphenyl)-3(2H)-pyri-
dazinone-2-yl]propanenitrile and the corresponding acid (VI,
VII) were prepared for the first time in this study.
Arch. Pharm. Pharm. Med. Chem. 333, 79–86 (2000)

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Dogruer, Sahin, Ünlü, and Ito
Arch. Pharm. Pharm. Med. Chem. 333, 79–86 (2000)

3(2H)-Pyridazinone Derivatives
83
Table 2. 1H-NMR spectroscopic data of the compounds 1–19.
—————————————————————————————————————————————————————————————
Comp.
1H-NMR (DMSO-d6): δ (ppm)
—————————————————————————————————————————————————————————————
1
2
3
4
5
6
7
8
9
8.03 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.04 (m, 3H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H);
5.01 (s, 2H, -CH2CO); 3.80 (s, 3H, -OCH3); 3.52 (t, 2H, piperazine 2-H); 3.45 (t, 2H, piperazine 6-H); 2.35 (t, 2H, piperazine 3-H);
2.26 (t, 2H, piperazine 5-H); 2.20 (s, 3H, -NCH3).
8.04 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.24 (t, 2H, phenyl 3-H, 5-H), 7.05 (d, 1H, pyridazine 4-H);
7.03 (d, 2H, p-methoxyphenyl 3-H, 5-H); 6.98 (d, 2H, phenyl 2-H, 6-H); 6.83 (t, 1H, phenyl 4-H); 5.10 (s, 2H, -CH2CO);
3.80 (s, 3H, -OCH3); 3.70 (t, 2H, piperazine 2-H); 3.61 (t, 2H, piperazine 6-H); 3.25 (t, 2H, piperazine 3-H); 3.15 (t, 2H, piperazine 5-H).
8.05 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.05 (m, 3H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H);
6.91 (m, 4H, phenyl 3-H, 4-H, 5-H, 6-H) 5.10 (s, 2H, -CH2CO); 3.80 (two separate singlets, 6H, -OCH3); 3.69 (t, 2H, piperazine 2-H);
3.60 (t, 2H, piperazine 6-H); 3.05 (t, 2H, piperazine 3-H); 2.95 (t, 2H, piperazine 5-H).
8.04 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.24 (t, 1H, phenyl 5-H), 7.04 (m, 3H, pyridazine 4-H,
p-methoxyphenyl 3-H, 5-H); 6.99 (dd, 1H, phenyl 2-H); 6.94 (dd, 1H, phenyl 4-H); 6.82 (dd, 1H, phenyl 6-H); 5.10 (s, 2H, -CH2CO);
3.80 (s, 3H, -OCH3); 3.70 (t, 2H, piperazine 2-H); 3.60 (t, 2H, piperazine 6-H); 3.30 (t, 2H, piperazine 3-H); 3.20 (t, 2H, piperazine 5-H).
8.04 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.25 (t, 2H, p-methoxyphenyl 3-H, 5-H);
7.00 (m, 5H, pyridazine 4-H , phenyl protons); 5.10 (s, 2H, -CH2CO); 3.80 (s, 3H, -OCH3); 3.70 (t, 2H, piperazine 2-H); 3.60 (t, 2H,
piperazine 6-H); 3.25 (t, 2H, piperazine 3-H); 3.15 (t, 2H, piperazine 5-H).
8.05 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.05 (m, 7H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H,
phenyl protons), 5.10 (s, 2H, -CH2CO); 3.80 (s, 3H, -OCH3); 3.71 (t, 2H, piperazine 2-H); 3.62 (t, 2H, piperazine 6-H); 3.18 (t, 2H,
piperazine 3-H); 3.08 (t, 2H, piperazine 5-H).
11.7 (s, 1H,amine salt); 8.04 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.66 (m, 2H, phenyl 3-H, 5-H);
7.47 (m, 3H, phenyl 2-H, 4-H, 6-H); 7.04 (m, 3H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H); 5.20–5.02 (two separate doublet, 2H,
-CH2CO); 4.38 (m, 3H, piperazine 2e-H, CH2); 4.16 (m, 1H, piperazine 6e-H); 3.80 (s, 3H, -OCH3); 3.47–2.90 (m, 6H, piperazine protons).
8.14 (m, 1H, pyridine 6-H); 8.03 (d, 1H, pyridazine 5-H); 7.81 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.57 (m, 1H, pyridine 4-H),
7.04 (d, 1H, pyridazine 4-H); 7.03 (d, 2H, p-methoxyphenyl 3-H, 5-H); 6.87 (d, 1H, pyridine 3-H); 6.68 (m, 1H, pyridine 5-H);
5.10 (s, 2H, -CH2CO); 3.80 (s, 3H, -OCH3); 3.60 (m, 8H, piperazine protons).
8.03 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.04 (d, 2H, p-methoxyphenyl 3-H, 5-H); 7.03 (d, 1H,
pyridazine 4-H); 5.05–4.95 (two separate doublet, 2H, -CH2CO); 4.27 (m,1H, piperidine 2e-H); 3.87 (m, 1H, piperidine 6e-H);
3.80 (s, 3H, -OCH3); 3.07 (m, 1H, piperidine 6a-H); 2.60 (m, 1H, piperidine 2a-H); 1.65 (m, 3H, piperidine 5e-H, 3e-H, 4-H);
1.15 (m, 1H, piperidine 5a-H); 0.90 (m, 1H, piperidine 3a-H) 0.80 (d, 3H, -CH3).
10
8.05 (d, 1H, pyridazine 5-H); 7.80 (d, 2H,p-methoxyphenyl 2-H, 6-H); 7.50 (m, 5H, phenyl protons); 7.02 (m, 3H, pyridazine 4-H,
p-methoxyphenyl 3-H, 5-H); 5.20–5.08 (two separate doublet, 2H, -CH2CO); 4.55 (m, 1H, piperidine 2e-H); 4.18 (m, 1H, piperidine 6e-H);
3.80 (s, 3H, -OCH3); 3.42 (m, 1H, piperidine 6a-H); 2.92 (m, 1H, piperidine 2a-H); 2.20 (m, 3H, piperidine 5e-H, 5a-H, 3e-H);
1.93 (m, 1H, piperidine 3a-H).
11
12
13
8.00 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.23 (t, 2H, phenyl 3-H, 5-H), 7.01 (d, 1H, pyridazine 4-H);
6.98 (d, 2H, p-methoxyphenyl 3-H, 5-H); 6.94 (d, 2H, phenyl 2-H, 6-H); 6.82 (t, 1H, phenyl 4-H); 4.34 (t, 2H, -NCH2CH2);
3.78 (s, 3H, -OCH3); 3.61 (m, 4H, piperazine 2-H, 6-H); 3.14 (t, 2H, piperazine 3-H); 3.07 (t, 2H, piperazine 5-H); 2.92 (t, 2H, -CH2CH2CO).
8.00 (d, 1H, pyridazine 5-H); 7.84 (d, 2H, p-methoxyphenyl 2-H, 6-H); 6.93 (m, 7H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H,
phenyl protons); 4.38 (t, 2H, -NCH2CH2); 3.80 (two separate singlets, 6H, -OCH3); 3.60 (m, 4H, piperazine 2-H, 6-H);
2.90 (m, 6H, piperazine 3-H, 5-H, -CH2CH2CO).
8.00 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.20 (t, 1H, phenyl, 5-H); 7.01 (d, 1H, pyridazine 4-H);
6.98 (d, 2H, p-methoxyphenyl 3-H, 5-H); 6.94 (dd, 1H, phenyl 2-H,); 6.89 (dd, 1H, phenyl 4-H); 6.82 (dd, 1H, phenyl 6-H);
4.38 (t, 2H -NCH2CH2); 3.78 (s, 3H, -OCH3); 3.58 (m, 4H, piperazine 2-H, 6-H); 3.20 (t, 2H, piperazine 3-H); 3.13 (t, 2H, piperazine 5-H);
2.92 (t, 2H, -CH2CH2CO).
14
15
16
8.00 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.24 (d, 2H, p-methoxyphenyl 3-H, 5-H); 7.01 (t, 1H, pyridazine 4-H);
6.98 (d, 2H, phenyl 3-H, 5-H); 6.94 (d, 2H, phenyl 2-H, 6-H); 4.34 (t, 2H, -NCH2CH2); 3.78 (s, 3H, -OCH3); 3.60 (m, 4H, piperazine 2-H,
6-H); 3.14 (t, 2H, piperazine 3-H); 3.07 (t, 2H, piperazine 5-H); 2.92 (t, 2H, -CH2CH2CO).
8.00 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.00 (m, 7H, pyridazine 4-H, p-methoxyphenyl 3-H, 5-H,
phenyl protons); 4.38 (t, 2H, -NCH2CH2); 3.80 (s, 3H, -OCH3); 3.60 (m, 4H, piperazine 2-H, 6-H); 3.04 (t, 2H, piperazine 3-H);
3.01 (t, 2H, piperazine 5-H); 2.91 (t, 2H, -CH2CH2CO).
8.00 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.43 (t, 1H, phenyl 5-H); 7.22 (dd, 1H, phenyl 2-H);
7.18 (dd, 1H, phenyl 4-H); 7.10 (dd, 1H, phenyl 6-H); 7.02 (d,1H, pyridazine 4-H); 6.98 (d, 2H, p-methoxyphenyl 3-H, 5-H);
4.35 (t, 2H, -NCH2CH2); 3.78 (s, 3H, -OCH3); 3.62 (m, 4H, piperazine 2-H, 6-H); 3.28 (t, 2H, piperazine 3-H); 3.20 (t, 2H, piperazine 5-H);
2.92 (t, 2H, -CH2CH2CO).
17
18
19
7.98 (d, 1H, pyridazine 5-H); 7.82 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.30 (m, 5H, phenyl protons); 7.05 (d, 2H, p-methoxyphenyl 3-H,
5-H); 7.00 (d, 1H, pyridazine 4-H); 4.30 (t, 2H, -NCH2CH2); 3.80 (s, 3H, -OCH3); 3.45 (m, 4H, piperazine 2-H, 6-H); 3.30 (s, 2H, -CH2-);
2.85 (t, 2H, -CH2CH2CO); 2.30 (m, 4H, piperazine 3-H, 5-H).
8.12 (m, 1H, pyridine 6-H) 8.00 (d, 1H, pyridazine 5-H); 7.80 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.55 (m, 1H, pyridine 4-H);
7.02 (d, 1H, pyridazine 4-H); 6.98 (d, 2H, p-methoxyphenyl 3-H, 5-H); 6.83 (d, 1H, pyridine 3-H); 6.67 (m, 1H, pyridine 5-H)
4.37 (t, 2H, -NCH2CH2); 3.78 (s, 3H, -OCH3); 3.50 (m, 8H, piperazine protons); 2.92 (t, 2H, -CH2CH2CO).
8.00 (d, 1H, pyridazine 5-H); 7.83 (d, 2H, p-methoxyphenyl 2-H, 6-H); 7.42 (m, 5H, phenyl protons), 7.00 (m, 3H, pyridazine 4-H,
p-methoxyphenyl 3-H, 5-H); 4.61 (m, 1H, piperidine 2e-H); 4.35 (t, 2H, -NCH2CH2); 4.12 (m, 1H, piperidine 6e-H) 3.80 (s, 3H, -OCH3);
3.32 (m, 1H, piperidine 6a-H); 2.95 (m, 2H, -CH2CH2CO); 2.85 (m, 1H, piperidine 2a-H); 2.10 (m, 3H, piperidine 5e-H, 5a-H, 3e-H);
1.85 (m, 1H, piperidine, 3a-H).
—————————————————————————————————————————————————————————————
Arch. Pharm. Pharm. Med. Chem. 333, 79–86 (2000)

84
Dogruer, Sahin, Ünlü, and Ito
Table 3. Antinociceptive activity of the compounds 1–19.
Table 4. Molecular connectivity indices of the compound 1–19.
————————————————————————————
Compd
1χ 1χv 2χ 2χv
————————————————————————————
————————————————————————————
Compd
% Anti-
Compound
% Anti-
nociceptive
Activity
nociceptive
Activity
————————————————————————————
1
12,062
14,634
15,582
15,025
15,025
15,025
15,117
14,634
12,062
15,539
15,134
16,082
15,525
15,525
15,525
16,735
15,617
15,134
16,039
8,253
9,937
14,220
16,154
18,081
17,729
17,836
17,836
15,894
16,154
14,220
17,047
16,260
18,187
17,835
17,942
17,942
21.067
16,000
16,260
17,153
7,942
8,958
9,966
10,088
10,111
9,676
8,982
8,824
8,322
9,887
9,115
10,123
10,245
10,268
9,833
10,92
9,139
8,931
10,044
1
2
3
4
5
6
7
8
9
10
35
11
51*
65*
70*
59*
84*
76*
70*
68*
64*
41
2
42
12
3
10,469
10.210
10,210
10,038
10,383
9,800
50
13
4
61*
47
14
5
15
6
67*
60*
62*
33
16
7
17
18
8
19
9
8,566
59*
Aspirin
10
11
12
13
14
15
16
17
18
19
10,514
10,437
10,969
10,510
10,510
10,538
11,154
10,883
10,300
10,014
————————————————————————————
*p<0.05 (in comparison with control group).
amine component at the side chain. In addition, the propan-
amides have generally been found more potent than acet-
amides (Table 3).
Structure-Activity Relationships
Quantitative structure-activity relationships (QSARs) are
mathematical models which aim to predict the properties of
molecules from their structures. There are two basic kinds of
molecular predictors used in QSAR. One of them involves
parameters that bear a relation to free energy and usually
represent some important physicochemical properties of mol-
ecules, e.g., hydrophobic, electronic, and steric parameters.
The other category of molecular descriptor is the topological
————————————————————————————
Table 5. Log P, parachor, and molar refractivity values of the compounds
1–19.
——————————————————————————————
Compd
log P
Parachor (cm3)
Molar
index or numerical graph invariant which is produced directly
refractivity (cm3)
[24]
from molecular structure
.
——————————————————————————————
Molecular connectivity is a topological method used to
1
1.69 ± 0.73
3.00 ± 0.75
3.72 ± 0.77
3.96 ± 0.76
3.84 ± 0.75
3.29 ± 0.79
3.58 ± 0.74
2.09 ± 0.76
3.30 ± 0.69
3.43 ± 0.72
3.17 ± 0.73
3.89 ± 0.75
4.13 ± 0.74
4.01 ± 0.74
3.46 ± 0.78
4.49 ± 0.77
3.74 ± 0.72
2.25 ± 0.74
3.60 ± 0.70
722.5 ± 8.0
868.3 ± 8.0
918.5 ± 8.0
897.1 ± 8.0
897.1 ± 8.0
868.4 ± 8.0
906.9 ± 8.0
849.4 ± 8.0
727.0 ± 8.0
933.4 ± 8.0
906.9 ± 8.0
957.1 ± 8.0
935.7 ± 8.0
935.7 ± 8.0
907.1 ± 8.0
960.9 ± 8.0
945.5 ± 8.0
888.0 ± 8.0
972.0 ± 8.0
95.49 ± 0.5
116.18 ± 0.5
121.99 ± 0.5
120.78 ± 0.5
120.78 ± 0.5
116.05 ± 0.5
120.79 ± 0.5
114.62 ± 0.5
96.15 ± 0.5
describe the structure of a molecule by means of connectivity
m
indices ( χ ) that is known as a numerical descriptor. The
2
t
molecular connectivity index for a molecule is calculated
from the hydrogen-suppressed graph. The molecular connec-
tivity method is used to investigate the relationship between
3
4
5
the experimental values of physical or biological properties
[25,26]
and calculated connectivity indices
. In recent studies
6
the usefulness of molecular connectivity has been demon-
7
[27,28]
strated in the design of analgesics
. In this paper, some
8
structural parameters (such as log P, parachor, molar refrac-
tivity, and molecular connectivity indices) were studied for
possible correlation with antinociceptive activity of some
3(2H)-pyridazinone derivatives (Table 4 and Table 5). A
good collinearity between all parameters was found, and the
9
10
11
12
13
14
15
16
17
18
19
123.89 ± 0.5
120.79 ± 0.5
126.60 ± 0.5
125.39 ± 0.5
125.39 ± 0.5
120.66 ± 0.5
125.54 ± 0.5
125.39 ± 0.5
119.23 ± 0.5
128.50 ± 0.5
1
χ parameter had the best correlation with antinociceptive
activity. Therefore, the linear regression analysis was per-
1
formed between the χ parameter and antinociceptive activ-
1
ity. The following relationships were found between χ and
antinociceptive activity as the result of statistical regression
analysis.
1
2
Activity = (8.73 ± 1.81) χ – (72.27 ± 27.27) r = 0.58
1
2
——————————————————————————————
log Activity = (0.076 ± 0.013) χ + (0.616 ± 0.197) r = 0.67
Arch. Pharm. Pharm. Med. Chem. 333, 79–86 (2000)

3(2H)-Pyridazinone Derivatives
85
3-[6-(4-Methoxyphenyl)-3(2H)-pyridazinone-2-yl]propanenitrile
Acknowledgment
0.25 Mol of 6-(4-methoxyphenyl)-3(2H)-pyridazinone, 0.3 mol of tri-
ethylamine, 0.3 mol of acrylonitrile were added in 500 ml of water, heated
at 50–60 °C for 6 h and then stirred at the room temperature for 18 h. At the
end of this time, the solid was collected by filtration, washed with water to
neutral pH, dried, and crystallized from ethanol. Mp: 139 °C.
This study is financially sopported by Gazi University Research Fund
(Project No. 11/98–07).
Experimental Part
3-[6-(4-Methoxyphenyl)-3(2H)-pyridazinone-2-yl]propanoic Acid
Chemistry
0.01 Mol of 3-[6-(3-methoxyphenyl)-3(2H)-pyridazinone-2-yl]propane-
nitrile, in 10 N hydrochloric acid (50 ml) was stirred at the room temperature
for 2 h, then refluxed for 3 h. The reaction mixture was cooled and the
precipitate was collected by filtration, washed with water, dried, and crystal-
lized from ethanol-water. Mp: 173–174 °C.
All chemicals including piperazine and piperidine derivatives were ob-
tained from Aldrich Chemical Co. (Steinheim, Germany). Melting points
were determined with Electrothermal-9200 digital melting point apparatus
(Southend, Great Britain) and are uncorrected. IR spectra (KBr) of the
compounds were recorded on Bruker Vector 22 IR spectrometer. The 1H-
NMR spectra were recorded on Jeol 500 MHz-NMR spectrometer and a
Bruker 200 FT-NMR spectrometer using TMS as internal standard and
DMSO-d6. All chemical shifts were recorded as δ (ppm). Elemental analyses
were performed with Leco-932 (C,H,N,S-Elemental analyzer, St. Joseph,
USA) at Scientific and Technical Research Council of Turkey, Instrumental
Analysis Center (Ankara, Turkey), and the results were within the range of
± 0.4 % of calculated values.
Pharmacology
Local breed male albino mice (25.0 ± 5.0 g) were employed. All the
animals were left for two days in the laboratory for acclimatization before
the day of experiment and the last day they were given water only. Eachgroup
consisted of 6 mice.
Acetic acid (Merck AG), Carboxymethyl cellulose Sodium Salt (CMC Na)
(Aldrich), aspirin (Bayer), Gauge Calipers (Peacock, Ozaki Co., Tokyo)
were used.
Synthesis of [6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]acetamides
and 3-[6-(4-Methoxyphenyl)-3(2H)-pyridazinone-2-yl]propanamides
Antinociceptive Activity[23]
0.01 Mol of[6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]acetic acidor
3-[6-(4-methoxyphenyl)-3(2H)-pyridazinone-2-yl]propanoic acid in 40 ml
dichloromethane at 0 °C (ice-bath) was treated with triethylamine (3 ml) and
0.01 mol of ethyl chloroformate. After stirring the reaction mixture at 0 °C
for 15 min, 0.011 mol of an appropriate amine derivative was added to this
solution. The final mixture was stirred at 0–25 °C for 24 h and evaporated to
dryness then treated with either acetone or acetone-hexane mixture. All solid
materials thus obtained were dried and crystallized from appropriate sol-
vents illustrated in Table 1.
A modified Koster’s Test was used. Aspirin served as a reference. Test
compounds and reference were administered orally at 100 mg/kg dose as a
suspension in 0.2 ml of 0.5% CMC Na. Control animals received the same
volume of vehicles. One hour after the drug administration, every mouse was
treated with an aqueous acetic acid solution (3% w/v) injected intraperi-
toneally at a 300 mg/kg dose. Five minutes later, writhing movements were
counted for a period of 10 min. The mean writhing counts for each group
were used, in the antinociceptive activity calculation employing the follow-
ing equation.
n – n′
n
Antinociceptive activity (writhing inhibition %) =
× 100
6-(4-Methoxyphenyl)-4,5-dihydro-3(2H)-pyridazinone[20]
n = The mean writhing count of control group
n′ = The mean writhing counts of test groups
0.01 Mol of 4-(4-methoxyphenyl)-4-oxobutanoic acid and 0.015 mol of
hydrazine hydrate (0.85 ml; 55 %) in 30 ml ethanol were refluxed for 4 h.
The reaction mixture was cooled and the precipitate thus formed was col-
lected by filtration, dried, and crystallized from ethanol. Mp: 155–156 °C.
(Lit. mp: 151 °C).
Statistical Analysis
The differences between control and test groups were found statistically
significant by Mann-Whitney U test.
6-(4-Methoxyphenyl)-3(2H)-pyridazinone[20]
Structure-Activity Relationships
A solution of 0.043 mol bromine in 25 ml glacial acetic acid was added
dropwise to a solution of 0.039 mol of 6-(4-methoxyphenyl)-4,5-dihydro-
3(2H)-pyridazinone in 100 ml glacial acetic acid at 60–70 °C. Then, the
reaction mixture was refluxed for 3 h. After cooling to 5 °C, it was poured
into ice water and converted to the free base with ammonium hydroxide. The
precipitate was collected by filtration, washed with water until neutral, dried,
and crystallized from ethanol-water. Mp: 188 °C. (Lit. mp: 191 °C).
Statistical analysis of the results was performed using the SPSS version-6
computer program. The values of molecular connectivity index and valence
molecular connectivity index of nineteen compounds were calculated by our
group. To calculate molecular connectivity indices of compounds that were
synthesized, we used the values of connectivity delta (δ) and valence delta
(δv) that were reported by Kier and Hall[29,30]. The log P values were
calculated (determined) by ACD-log P version 1.0 computer program. The
values of the parachor and the molecular refractivity were calculated by
ACD-Chem Sketch version 2.51 computer program.
Ethyl [6-(4-Methoxyphenyl)-3(2H)-pyridazinone-2-yl]acetate[21]
0.025 Mol of 6-(4-methoxyphenyl)-3(2H)-pyridazinone, 0.0375 mol of
ethyl bromoacetate and 0.01 mol of anhydrous potassium carbonate in 25 ml
anhydrous DMF were stirred at room temperature for 1 h. The reaction
mixture was poured into ice water. The solid which separeted was collected
by fitration, dried, and crystallized from ethanol-water. Mp: 101 °C.
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