4-Dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols: synthesis and evaluation of analgesic, anti-inflammatory and platelet anti-aggregating activities

Article abstract of DOI:10.1016/S0014-827X(00)00007-0

A number of 4-dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols 2a-n were synthesized and tested in vivo for anti-inflammatory and analgesic activities and in vitro for platelet anti-aggregating activity. Dimethylaminoderivatives 2b, e, g showed good analgesic activity; almost all of them had strong platelet anti-aggregating properties at a final concentration of 1x10^-3 M; pyrazoles 2c, d, f-h showed weak anti-inflammatory activity. Copyright (C) 2000 Elsevier Science S.A.

Full text of DOI:10.1016/S0014-827X(00)00007-0

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 219–226
4-Dialkylamino-1-(5-substituted or unsubstituted
1-phenyl-1H-pyrazol-4-yl)butan-1-ols: synthesis and evaluation of
analgesic, anti-inflammatory and platelet anti-aggregating activities
Giulia Menozzi a,*, Luisa Mosti a, Luisa Merello a, Antonietta Piana b, Ugo Armani b,
Marco Ghia c, Marianna Angiola c, Francesca Mattioli c
a Dipartimento di Scienze Farmaceutiche, Uni6ersita` di Geno6a, Viale Benedetto XV 3, I-16132 Genoa, Italy
b Dipartimento di Medicina Interna, Centro di Ricerca sulla Trombosi, Uni6ersita` di Geno6a, Viale Benedetto XV 6, I-16132 Genoa, Italy
c Dipartimento di Medicina Interna, Sezione di Farmacologia e Tossicologia Clinica, Uni6ersita` di Geno6a, Viale Benedetto XV 6,
I-16132 Genoa, Italy
Received 29 July 1999; accepted 30 December 1999
Abstract
A number of 4-dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)butan-1-ols 2a–n were synthesized and
tested in vivo for anti-inflammatory and analgesic activities and in vitro for platelet anti-aggregating activity. Dimethyl-
aminoderivatives 2b, e, g showed good analgesic activity; almost all of them had strong platelet anti-aggregating properties at a
final concentration of 1×10−3 M; pyrazoles 2c, d, f–h showed weak anti-inflammatory activity. © 2000 Elsevier Science S.A. All
rights reserved.
Keywords: Pyrazole derivatives; Anti-inflammatory agents; Analgesic agents; Platelet anti-aggregating agents
1. Introduction
Part of our research concerns the synthesis of 1-aryl-
1H-pyrazole derivatives and the evaluation of their
anti-inflammatory and analgesic properties [1].
In a recent study, carried out at the Searle Research
and Development laboratories, a number of 1,5-di-
arylpyrazole derivatives were identified as potent and
In a previous paper, we reported the synthesis and
pharmacological results of a number of v-dialkyl-
aminoalkyl ethers of phenyl-(5-substituted 1-phenyl-
1H-pyrazol-4-yl)methanols (A) [5].
Several of these compounds exhibited good anti-noci-
ceptive activity in the writhing test in mice and weak
anti-inflammatory activity in the carrageenan-induced
edema assay in rats. The weakness of compounds A
towards any acid agent, which caused the cleavage of
the ether linkage, prevented their transformation into
water-soluble salts.
selective cyclo-oxygenase 2 inhibitors [2]. Among these
compounds, 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-
1H-pyrazol-1-yl]benzenesulfonamide (SC-58635, cele-
coxib) demonstrated potent, oral anti-inflammatory
activity and, after its approval in December 1998, it is
currently marketed in the USA [3].
Moreover, a Ciba–Geigy patent reports a series of
1-aryl-1H-pyrazoles bearing
a tetrahydropyridylhy-
droxyalkyl chain in position 4 of the heterocycle, en-
dowed with anti-inflammatory activity [4].
Therefore, so as to improve the pharmacological
profile of aminoethers A, we have now synthesized a
number of novel 1-aryl-1H-pyrazoles (2a–n), which
* Corresponding author. Tel.: +39-010-353 8361; fax: +39-010-
353 8358.
E-mail address: menozzi@unige.it (G. Menozzi)
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(00)00007-0

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G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
maintain basic side chain like derivatives A, but which
lack the ether linkage and bear an alcoholic function
instead of the phenyl ring, similar to the tetrahydropy-
ridylhydroxyalkyl derivatives reported in the above
mentioned patent. The removal of the oxygen bridge
led to acid-proof molecules which could be transformed
into the respective hydrochlorides.
Thus, aminoalcohols 2a–n were investigated in vivo
regarding their analgesic and anti-inflammatory proper-
ties; furthermore, as hydrochlorides, they were tested in
vitro as inhibitors of platelet aggregation.
3. Pharmacology and biology
All compounds 2 (free bases) were subjected to pre-
liminary in vivo pharmacological screening for:
“ analgesic activity, evaluated by writhing test and hot
plate test in mice;
“ anti-inflammatory activity, evaluated by car-
rageenan-induced paw edema in rats.
In addition, the same compounds (converted into
hydrochlorides) were tested in vitro for their inhibitory
activity on human platelet aggregation induced in
platelet-rich plasma (PRP) by adenosine diphosphate
(ADP), collagen or adrenaline.
2. Chemistry
1-Phenyl-1H-pyrazole-4-carbaldehyde (1a), first pre-
pared by Finar and later by other authors with different
methods [6a–c], was obtained via oxidation of its corre-
sponding carbinol [7] by pyridinium chlorochromate, as
described for aldeydes 1b–g [5].
4. Experimental
4.1. Chemistry
Starting from 1a–g, by reaction with 3-dimethy-
lamino- or 3-(1-piperidinyl)-propylmagnesium chloride,
the corresponding 4-dimethylamino-1-(5-substituted or
Melting points were determined with a Fisher–Johns
apparatus and are uncorrected. The IR spectra were
registered on a Perkin–Elmer 398 spectrophotometer in
CHCl3 as solvent. The 1H NMR spectra were registered
on a Varian Gemini 200 (200 MHz) spectrometer;
chemical shifts are reported as l (ppm) relative to TMS
as internal standard; J in Hz; CDCl3 as solvent. Ele-
mental analyses were performed using a Carlo Erba
Elemental Analyzer model 1106 and the results were
within 90.3% of the calculated values.
unsubstituted
1-phenyl-1H-pyrazol-4-yl)-butan-1-ols
(2a–g) and 4-(1-piperidinyl)-1-(5-substituted or unsub-
stituted 1-phenyl-1H-pyrazol-4-yl)-butan-1-ols (2h–n),
were obtained in generally good yields, according to
Scheme 1.
1
In the H NMR spectra of compounds 2b,h–n, hy-
droxylic proton resonated in the range of 7.2–8.4 l, as
a very broad singlet, which disappeared with deuterium
oxide. Dimethylaminoderivatives 2a,c–g did not give
any signals corresponding to the hydroxylic proton.
The methyne proton of the side chain of all compounds
2 resonated as a multiplet in the range of 4.5–5 l (data
are reported in Table 2).
4.1.1. Intermediates
Aldehydes 1a–g, used as intermediates for the syn-
thesis of title compounds, were prepared as already
described [5].
Scheme 1.

G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
221
Table 1
4-Dialkylamino-1-(5-substituted or unsubstituted 1-phenyl-1H-pyrazol-4-yl)-butan-1-ols (2a–n)
Comp.
R
NR2%
Yield(%)
M.p. (°C) or b.p. (°C) (mm Hg)
57–58 a
Molecular formula
Anal.
2a
2b
H
N(CH3)2
N(CH3)2
51
75
C15H21N3O
C16H23N3O
C, H, N
C, H, N
CH3
45–46 a
185–190 (0.4)
2c
2d
C2H5
N(CH3)2
N(CH3)2
71
83
74–75 b
177–180 (0.4)
C17H25N3O
C18H27N3O
C, H, N
C, H, N
(CH2)2CH3
53–54 a
160–165 (0.1)
2e
2f
CH(CH3)2
C(CH3)3
C6H5
N(CH3)2
N(CH3)2
N(CH3)2
79
90
68
84
106–107 b
119–120 b
114–115 b
88–89 a
C18H27N3O
C19H29N3O
C21H25N3O
C18H25N3O
C, H, N
C, H, N
C, H, N
C, H, N
2g
2h
H
2i
CH3
73
44
70
87
72
64
60–61 a
C19H27N3O
C20H29N3O
C21H31N3O
C21H31N3O
C22H33N3O
C24H29N3O
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
195–200 (0.05)
75–76 a
2j
C2H5
195–200 (0.1)
74–75 c
2k
2l
(CH2)2CH3
CH(CH3)2
C(CH3)3
C6H5
102–103 a
114–115 a
104–105 a
2m
2n
a From anhydrous diethyl ether–petroleum ether (b.p. 40–70°C).
b From anhydrous diethyl ether.
c From petroleum ether (b.p. 40–70°C).
4.1.2. 1-Phenylpyrazol-4-ylcarbaldehyde (1a)
Yield 91%, m.p. 85–86°C from anhydrous diethyl
A solution of aldehydes 1a–g (10 mmol) in anhydrous
tetrahydrofuran (40 ml) was added dropwise to
an ice-cooled solution of the appropriate 3-dialky-
lamino-1-propylmagnesium chloride, prepared from
magnesium turnings (0.48 g, 20 mmol) and 3-dialkyl-
amino-1-propylchloride (20 mmol) in the same solvent
(70 ml). The mixture was refluxed overnight, cooled at
0°C and diluted with diethyl ether (100 ml). Hydrochlo-
ric acid (30 ml, 3 M) was then added with vigorous
stirring. The organic layer, separated from the acid
phase, was again extracted with hydrochloric acid (2×
20 ml, 3 M). Then a 10% sodium hydroxide solution was
added to the combined acid extracts, previously washed
ether–petroleum ether (b.p. 40–70°C). IR (CHCl3):
1680 cm−1 1H NMR (CDCl3): 7.35–7.6 (m, 3H,
.
ar.), 7.7–7.8 (m, 2H, ar.), 8.21 (s, 1H, H-3), 8.44 (s,
1H, H-5), 9.96 (s, 1H, CHO). Anal. C10H8N2O (C,
H, N).
4.1.3. General procedure for the preparation of 4-
dimethylamino-1-(5-substituted or unsubstituted 1-
phenyl-1H-pyrazol-4-yl)-butan-1-ols (2a–g) and for
4-(1-piperidinyl)-1-(5-substituted or unsubstituted 1-
phenyl-1H-pyrazol-4-yl)-butan-1-ols (2h–n)

222
G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
twice with diethyl ether and cooled at 0°C, and the basic
mixture (pHꢀ10) was then thoroughly extracted with
diethyl ether (2a,b,d,h–n) or chloroform (2c,e–g). The
extracts were dried (MgSO4) and evaporated under
reduced pressure to give a residue, which was roughly
purified by flash chromatography on Florisil, using
diethyl ether (2a,b,d,h–n) or chloroform (2c,e–g) as
eluent. Compounds 2a,e–h,k–n were further purified by
recrystallization from a suitable solvent; 2b–d,i,j by
bulb to bulb distillation in vacuo, followed by recrystal-
lization from a suitable solvent.
were administered orally, at the initial dose of 200
mg/kg. Compounds which exhibited a statistically sig-
nificant activity at this dose were further tested at doses
decreasing by a factor of two.
4.2.1. Anti-inflammatory acti6ity
The carrageenan-induced paw edema test [8] was used
on groups of five rats. Sixty minutes after administering
the test compound, 0.1 ml of a 1% carrageenan solution
in saline was injected into the plantar surface of the
right hind paw of each rat. Paw volume, as determined
by measuring the amount of water displaced after
immersing the paw up to the lateral malleolus level, was
recorded immediately after the carrageenan injection
and again 3 h later. The difference between these two
values was taken as edema volume. The inhibition
percentage of the edema of treated rats, with respect to
controls, was calculated and compared to that which
Yields, m.p. or b.p. values and recrystallization sol-
vents are reported in Table 1.
4.2. Pharmacology
Pyrazoles 2a–n were screened in vivo for their anal-
gesic and anti-inflammatory activities. All compounds
Table 2
IR and 1H NMR spectral data of compounds 2a–n
Comp. IR (CHCl3)
(cm−1
1H NMR (CDCl3), l (ppm)
)
2a
2b
2c
2d
2e
3350, 2825, 2785 1.6–2.15 (m, 4H, 2CH2), 2.25 (s, 6H, (CH3)2N), 2.3–2.45 (m, 2H, CH2N), 4.7–4.8 (m, 1H, CHO), 7.15–7.25
(m, 1H, H-5 pyrazole), 7.35–7.45 (m, 2H, aromatic), 7.6–7.7 (m, 3H, aromatic), 7.89 (s, 1H, H-3 pyrazole)
3340, 2825, 2785 1.65–2.2 (m, 4H, 2CH2), 2.30 (s, 6H, (CH3)2N), 2.33 (s, 3H, CH3), 2.35–2.55 (m, 2H, CH2N), 4.6–4.7 (m, 1H,
CHO), 7.25 (br s, 1H, OH, disappears with D2O), 7.35–7.5 (m, 5H, C6H5), 7.64 (s, 1H, H-3 pyrazole)
3330, 2820, 2775 1.05 (t, J=7.5, 3H, CH3), 1.6–2.1 (m, 4H, 2CH2), 2.29 (s, 6H, (CH3)2N), 2.3–2.5 (m, 2H, CH2N), 2.65–2.85
(m, 2H, CH2), 4.6–4.7 (m, 1H, CHO), 7.3–7.5 (m, 5H, C6H5), 7.62 (s, 1H, H-3 pyrazole)
3370, 2820, 2780 0.81 (t, J=7.4, 3H, CH3), 1.3–2.1 (m, 6H, 3CH2), 2.29 (s, 6H, (CH3)2N), 2.3–2.5 (m, 2H, CH2N), 2.6–2.75
(m, 2H, CH2), 4.6–4.7 (m, 1H, CHO), 7.3–7.5 (m, 5H, C6H5), 7.64 (s, 1H, H-3 pyrazole)
3350, 2825, 2780 1.24 and 1.31 (2d, J=7.2, 6H, (CH3)2C), 1.65–2.1 (m, 4H, 2CH2), 2.30 (s, 6H, (CH3)2N), 2.35–2.55 (m, 2H,
CH2N), 3.12 (h, J=7.2, 1H, CHMe2), 4.75–4.85 (m, 1H, CHO), 7.3–7.5 (m, 5H, C6H5), 7.65 (s, 1H, H-3
pyrazole)
2f
3330, 2820, 2775 1.25 (s, 9H, (CH3)3C), 1.65–2.2 (m, 4H, 2CH2), 2.30 (s, 6H, (CH3)2N), 2.35–2.55 (m, 2H, CH2N), 4.9–5.0 (m,
1H, CHO), 7.3–7.45 (m, 5H, C6H5), 7.67 (s, 1H, H-3 pyrazole)
2g
2h
3330, 2825, 2780 1.45–2.0 (m, 4H, 2CH2), 2.26 (s, 6H, (CH3)2N), 2.3–2.5 (m, 2H, CH2N), 3.5–3.6 (m, 1H, CHO), 7.15–7.4 (m,
10H, 2C6H5), 7.86 (s, 1H, H-3 pyrazole)
3340, 2805, 2765 1.3–2.15 (m, 10H, 5CH2), 2.2–2.6 (m, 6H, 3CH2N), 4.65–4.8 (m, 1H, CHO), 7.15–7.25 (m, 1H, H-5 pyrazole),
7.35–7.5 (m, 2H, aromatic), 7.55–7.75 (m, 3H, aromatic), 7.91 (s, 1H, H-3 pyrazole), ꢀ8.4 (very br s, 1H, OH,
disappears with D2O)
2i
2j
2k
2l
3320, 2805, 2765 1.35–2.1 (m, 10H, 5CH2), 2.32 (s, 3H, CH3), 2.35–2.7 (m, 6H, 3CH2N), 4.55–4.65 (m, 1H, CHO), 7.3–7.5 (m,
5H, C6H5), 7.63 (s, 1H, H-3 pyrazole), 7.77 (br s, 1H, OH, disappears with D2O)
3320, 2805, 2765 1.06 (t, J=7.5, 3H, CH3), 1.4–2.1 (m, 10H, 5CH2), 2.3–2.85 (m, 8H, 3CH2N+CH2Me), 4.6–4.7 (m, 1H,
CHO), 7.3–7.55 (m, 5H, C6H5), 7.65 (s, 1H, H-3 pyrazole), 7.70 (br s, 1H, OH, disappears with D2O)
3320, 2805, 2765 0.82 (t, J=7.4, 3H, CH3), 1.3–2.1 (m, 12H, 6CH2), 2.3–2.8 (m, 8H, 3CH2N+CH2), 4.55–4.65 (m, 1H, CHO),
7.3–7.5 (m, 5H, C6H5), ꢀ7.6 (very br s, 1H, OH, disappears with D2O), 7.65 (s, 1H, H-3 pyrazole)
3320, 2805, 2765 1.25 and 1.33 (2d, J=7.2, 6H, (CH3)2C), 1.4–2.15 (m, 10H, 5CH2), 2.3–2.7 (m, 6H, 3CH2N), 3.11 (h, J=7.2,
1H, CHMe2), 4.75–4.85 (m, 1H, CHO), 7.3–7.5 (m, 6H, C6H5+OH, 1H disappears with D2O), 7.66 (s, 1H,
H-3 pyrazole)
2m
2n
3320, 2805, 2760 1.25 (s, 9H, (CH3)3C), 1.4–2.2 (m, 10H, 5CH2), 2.3–2.7 (m, 6H, 3CH2N), 4.85–4.95 (m, 1H, CHO), 7.25–7.45
(m, 5H, C6H5), 7.54 (br s, 1H, OH, disappears with D2O), 7.68 (s, 1H, H-3 pyrazole)
3330, 2805, 2765 1.35–2.0 (m, 10H, 5CH2), 2.25–2.6 (m, 6H, 3CH2N), 4.45–4.55 (m, 1H, CHO), 7.1–7.4 (m, 10H, 2C6H5), 7.81
(br s, 1H, OH, disappears with D2O), 7.86 (s, 1H, H-3 pyrazole)

G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
223
was produced by indomethacin (6 mg/kg p.o.), used as
5. Results and discussion
a reference standard.
5.1. Pharmacology
4.2.2. Analgesic acti6ity
As concerns the analgesic activity, 13 of the 14
compounds produced a statistically significant anti-
nociceptive effect in the acetic acid writhing test in mice.
The degree of protection ranged from 40 to 92% at a
dose of 200 mg/kg. The most active were compounds 2b,
e, g, which displayed a significant anti-nociceptive effect
also at a dose of 100 mg/kg (49, 39 and 40%, respec-
tively). Only compound 2n was inactive.
However, when the hot plate test was used on the rat
to verify the anti-nociceptive effect of the three com-
pounds that produced a greater than 80% protection in
the writhing test at the maximum dose, the degree of
protection at the same dose was markedly lower, being
31% for 2b, 35% for 2e and 19% for 2g. This discrepancy
between the results of the two tests might be attributed
to their different sensitivity: the writhing test is able to
detect both peripherally and centrally acting analgesics,
whereas the hot plate test has demonstrated to be
predictive of centrally acting analgesics [12].
The writhing test [9] was used on a group of six mice.
One hour after the administration of the test compound,
0.01 ml/g of a 0.6% acetic acid solution was injected
intraperitoneally in each mouse. The writhing move-
ments of each animal were counted for 10 min (between
the 5th and 15th minute after the injection of the
irritant). The anti-nociceptive effect was expressed as
the percentage of protection compared to the control
group. Indomethacin (6 mg/kg p.o.) was used as a
reference standard.
The hot plate test [10] was used on groups of five rats.
The parameter evaluated was the latency time for the
paw withdrawal after exposure to the hot plate surface
(55°C90.5); the maximum cut-off was 30 s. Latency
time was recorded before and 45 min after the drug was
administration. Morphine (15 mg/kg p.o.) was used as
a reference standard.
The low activity in the hot plate test associated with
potent anti-nociceptive properties in the writhing test is
in favor of a prevalent peripheral mechanism of action
without a central analgesic effect.
4.3. Biological assays
4.3.1. Platelet aggregation
Human blood samples from normal subjects were
drawn through a 19-gauge needle, avoiding carefully
prolonged venous stasis. None of these subjects was
treated with any drug known to influence the platelet
function.
Blood was collected in plastic tubes containing 3.8%
trisodium citrate aqueous solution. Platelet rich plasma
(PRP) was obtained by centrifuging the blood at 100×
g for 20 min. Platelet poor plasma (PPP) was obtained
by centrifuging the remaining blood at 1100×g for 15
min.
Five compounds produced a statistically significant
anti-inflammatory activity in the carrageenan-induced
edema assay in the rat. At the 200 mg/kg dose, the
degree of protection was 31% for 2c, 41% for 2d, 25%
for 2f, 29% for 2g and 38% for 2h. The most active
compounds 2d,h displayed a significant inhibition of the
paw edema also at the 100 mg/kg dose (22 and 24%,
respectively), whereas compounds 2c,f,g did not show
any statistically significant activity at such a dose.
The results of the pharmacological evaluation are
listed in Table 3.
Platelet count in PRP was maintained at 300 000/
mmc.
5.2. Biology
Platelet aggregation, performed in a Aggrecorder II
PA 3220 aggregometer (Menarini, Firenze, Italy), was
measured according to Born’s turbidimetric method [11]
and quantified by the maximal light transmission after
5 min.
A first sample of PRP was pre-incubated at 37°C for
2 min before the addition of the agonist (2 and 5 mM
adenosine diphosphate (ADP), collagen at final concen-
trations of 4 and 8 mg/ml, 5 mM adrenaline). A second
sample of PRP was incubated for 2 min with a solution
of the tested compound. Platelet aggregation was then
performed adding the agonist.
All the tested compounds, assayed at a concentration
of 1×10−3 M, remarkably inhibited the aggregation of
human platelets induced in platelet-rich plasma by 2 and
5 mM adenosine diphosphate (ADP), collagen at con-
centrations of 4 and 8 mg/ml, 5 mM adrenaline. Many of
them maintained good activity at a concentration of
1×10−4 M. Almost all compounds were more active
than acetylsalicylic acid at both concentrations.
The most active compounds were the 1,5-diphenyl-
substituted pyrazoles 2g (95–100% of inhibition at a
concentration of 1×10−3 M and 62–98% at 1×10−4
M) and 2n (93–100% at 1×10−3 M and 54–90% at
1×10−4 M). Derivatives 2g,n were also tested at a
concentration of 1×10−5 M, but at this dilution they
turned out to be inactive.
Comparing the maximal light transmission of the
aggregation curves obtained with and without the addi-
tion of the tested compound, the percentage of inhibi-
tion of platelet aggregation was calculated.

224
G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
Table 3
Anti-inflammatory and analgesic activities of compounds 2a–n
Comp.
Tested dose (mg/kg p.o.)
Anti-inflammatory activity a (% inhibition)
Analgesic activity (% protection)
Writhing test b
Hot plate test c
2a
2b
200
100
17
0
62 *,d
21
200
100
50
92 *,d
49 **,d
29
31 *,d
14
2c
2d
200
100
31 **,d
13
63 *,d
19
200
100
50
41 **,d
22 **,d
9
44 **,d
12
2e
200
100
50
16
87 *,d
39 **,d
25
35 *,d
15
2f
200
100
25 **,d
10
46 **,d
17
2g
200
100
50
29 **,d
12
83 *,d
40 **,d
17
19 *,d
8
2h
200
100
50
38 **,d
24 **,d
10
50 **,d
19
2i
200
100
0
63 *,d
25
2j
200
100
0
64 *,d
24
2k
2l
200
100
18
0
40 **,d
13
200
100
40 **,d
15
2m
200
100
16
67 *,d
23
2n
200
6
17
19
Indomethacin
Morphine
65 *,d
85 *,d
84 *,d
15
15
48 *,d
a Carrageenan-induced paw edema test (on groups of five rats).
b On groups of four mice.
c On groups of five rats.
d Statistical significance versus control group was evaluated by the Student’s test:
* PB0.01.
** PB0.05.

G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
225
Table 4
Platelet anti-aggregating activity of compounds 2a–n
Comp. Final concentration (M)
Inhibition of platelet aggregation induced by ADP, collagen and adrenaline in human plasma (%) a
ADP (5 mM)
ADP (2 mM)
Collagen (8 mg/ml)
Collagen (4 mg/ml)
Adrenaline (5 mM)
2a
2b
2c
2d
2e
2f
1×10−3
1×10−4
38
17
59
41
78
43
97
41
87
15
1×10−3
1×10−4
39
6
64
34
38
40
60
31
79
1
1×10−3
1×10−4
46
11
73
42
29
64
65
65
87
52
1×10−3
1×10−4
54
20
73
40
98
47
97
55
93
45
1×10−3
1×10−4
53
58
68
65
93
91
92
83
42
35
1×10−3
1×10−4
61
14
81
50
83
70
96
71
97
25
2g
1×10−3
1×10−4
1×10−5
100
62
6
100
98
19
95
68
4
98
89
5
100
83
6
2h
2i
1×10−3
1×10−4
54
9
77
47
94
39
93
45
88
78
1×10−3
1×10−4
62
39
85
54
82
25
92
66
94
73
2j
1×10−3
1×10−4
38
38
71
36
73
43
97
49
99
82
2k
2l
1×10−3
1×10−4
69
40
85
64
92
12
97
87
92
81
1×10−3
1×10−4
65
36
85
64
95
7
91
15
91
86
2m
2n
1×10−3
1×10−4
64
21
50
6
95
57
94
61
99
72
1×10−3
1×10−4
1×10−5
100
73
0
95
88
35
93
54
1
94
88
5
99
90
5
ASA
1×10−3
1×10−4
1×10−5
45
9
2
41
34
15
41
3
0
37
3
2
68
30
0
a Mean value of two determinations.
The results of the biological evaluation are listed in
Table 4.
effective compounds of the series (2b,e,g), seems to be
generally better for analgesic activity rather than the
1-piperidinyl moiety (compounds 2h–n) (Table 3).
The good analgesic properties of pyrazoles 2b,e,g do
not correlate with respective anti-inflammatory activi-
ties, which were weak or insignificant.
6. Conclusions
In summary, the results of the preliminary pharma-
cological tests which are reported above indicate that
aminoalcohols 2 have a predominant analgesic profile,
similar to aminoethers A [5]. However, the anti-noci-
ceptive properties of pyrazoles 2 seem to have increased
compared to analogues A. Furthermore, the dimethyl-
amino group, present in the side chain of the most
The strong platelet anti-aggregating activity of the
majority of compounds 2, not accompanied by remark-
able anti-inflammatory properties, could be justified by
a mechanism of selective cyclo-oxygenase-1 inhibition
[13]. This hypothesis could be supported by the obser-
vation that the two compounds 2g,n, endowed with the
greatest anti-platelet activity, have a diarylpyrazole

226
G. Menozzi et al. / Il Farmaco 55 (2000) 219–226
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skeleton, like many selective COX-2 inhibitors reported
in the above mentioned paper [2], but unlike these,
lacking the sulfonamide moiety, proved to be critical
for good COX-2 inhibitory activity.
The study of the action mechanism of new molecules
could be a topic for future investigations, to obtain
further information on the structure–activity relation-
ships of 1-aryl-1H-pyrazole derivatives.
Acknowledgements
We would like to thank A. Panaro for the micro-
analyses and F. Tuberoni and R. Raggio for the IR and
NMR spectra. C.N.R. (Rome) and Ministero dell’Uni-
versita` e della Ricerca Scientifica e Tecnologica (Cofi-
nanziamento Programma Nazionale) are gratefully
acknowledged for their financial support.
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