Synthesis and pharmacological properties of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4- tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid

Article abstract of DOI:10.1016/S0014-827X(99)00099-3

The synthesis of 1-(4-substituted)butyl derivatives of amides of 7- methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5- carboxylic acid and the results of the preliminary pharmacological screening are described in this paper. Some of th

Full text of DOI:10.1016/S0014-827X(99)00099-3

www.elsevier.nl/locate/farmac
Il Farmaco 55 (2000) 6–12
Synthesis and pharmacological properties of 1-(4-substituted)butyl
derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid
a,
c
b
b
´
*
Helena Sladowska *, Maria Sieklucka-Dziuba , Robert Rejdak , Zdzislaw Kleinrok
a
*
*
Department of Chemistry of Drugs, Wroclaw Medical Uni6ersity, Tamka 1, 50-137 Wroclaw, Poland
b Department of Pharmacology, Medical School, Jaczewskiego 8, 20-090 Lublin, Poland
c
**
Department of Hygiene, Medical School, Radziwillowska 11, 20-085 Lublin, Poland
Received 22 February 1999; accepted 23 September 1999
Abstract
The synthesis of 1-(4-substituted)butyl derivatives of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-
d]pyrimidine-5-carboxylic acid and the results of the preliminary pharmacological screening are described in this paper. Some of
them showed a weak analgesic action and caused suppression of the spontaneous locomotor activity of mice. © 2000 Elsevier
Science S.A. All rights reserved.
Keywords: Pyrido[2,3-d]pyrimidines; (4-Substituted)butyl derivatives; Pharmacological activity
1. Introduction
and showed anxiolytic action in ‘four plates’ test. All
caused hypothermia in normothermic mice. Contrary to
compounds Ia,b, derivative Ic had high toxicity. In
continuing research in this series of compounds, we
stated recently [2] that the replacement of an ester
group by an amide one and introduction of a 2-hy-
droxy-3(4-phenyl-1-piperazinyl)propyl substituent in
position 1 of the appropriate 2,4-dioxo-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidine gave non-toxic substances
(IIa–c) characterized by a strong analgesic activity
(Fig. 2).
In a previous paper [1], the synthesis and properties
were reported for 1-[4-(4-aryl)- and 1-[4-[4-(2-pyrim-
idinyl)]-1-piperazinyl]butyl derivatives of ethyl 7-
methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-
d]pyrimidine-5-carboxylate (Ia–c) (Fig. 1).
In the pharmacological screening compounds Ia,b
depressed the spontaneous locomotor activity of mice
Fig. 1.
Fig. 2.
* Corresponding author.
0014-827X/00/$ - see front matter © 2000 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00099-3

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H. Sladowska et al. / Il Farmaco 55 (2000) 6–12
7
In correlation with these studies, we now synthesized
1-(4-substituted)butyl derivatives of amides of 7-methyl-
3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
midine-5-carboxylic acid (5–14) combining certain struc-
tural elements of both I and II. We hoped that the
obtained compounds would have a depressive influence
on the CNS of animals. Our expectations followed
(amongst others) from the presence in their structures of
4-aryl- or 4-(2-pyrimidinyl)-l-piperazinyl- and 2-(1,2,3,4-
tetrahydroisoquinolinyl)butyl substituents, characteris-
tic of the selective anxiolytics — Buspirone type [3–7]
as well as from the presence of pyrrolidinyl — or a
piperidinoamide moiety having influence on the analgesic
action of the appropriate 2,4-dioxo-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidines [2,8].
quinoline, 1-(2-aminoethyl) piperidine) in acetonitrile
solution and in the presence of anhydrous potassium
carbonate. The compounds described in this paper
(Fig. 3) are crystalline substances. Their structures were
confirmed by spectral (IR, 1H NMR) and elemental
analyses.
For pharmacological screening we chose four sub-
stances: 5–7 and 13, Three of them (5–7) are pyrrolidinyl-
amide derivatives. As follows from our earlier
investigations [2], pyrrolidinylamide of 1-[2-hydroxy-
3(4-phenyl-1-piperazinyl)]propyl-7-methyl-3-phenyl-2,4-
dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-car-
boxylic acid produced considerably stronger analgesic
effect than the corresponding piperidinoamide. Com-
pounds 5–7 differ from one another in the kind of the
substituents at the N-4 of piperazine bounded with the
butyl chain. These substituents (phenyl (5), o-
methoxyphenyl (6), CH3 (7)) have different electronic
and lipophilic features. Introducing them we wanted to
verify their possible influence on the CNS action. For
testing we also selected compound 13, being a piperidi-
noamide derivative containing in position 1 4-[2-(1,2,3,4-
tetrahydroisoquinolinyl)]butyl substituent. According
to Mokrosz et al. [7], the replacement of 4-substituted
piperazine in the side-chain of Buspirone by the 1,2,3,4-
tetrahydroisoquinolinyl group did not change its af-
finity to the 5HT1A receptors and pharmacological
profile. Based on this, we wanted to know whether this
replacement would be possible in this group of com-
pounds.
2. Chemistry
The starting materials for the synthesis of compounds
3–14 were the appropriate amides of 7-methyl-3-phenyl-
2,4 - dioxo - 1,2,3,4 - tetrahydropyrido[2,3 - d]pyri-
midine-5-carboxylic acid (1, 2) previously synthesized [2].
Their potassium salts were condensed with 1,4-dibro-
mobutane with the aim of obtaining 4-bromobutyl
derivatives (3, 4). This last reaction was carried out in
anhydrous DMF solution at room temperature. Then,
4-bromobutyl derivatives 3 and 4 were transformed into
the compounds 5–14 by heating with the suitable
amines (N-phenyl-, N-o-methoxyphenyl-, N-methyl-,
N-(2-pyrimidinyl)-piperazines,
1,2,3,4-tetrahydroiso-
Fig. 3.

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H. Sladowska et al. / Il Farmaco 55 (2000) 6–12
8
Table 1
Properties of the investigated compounds
Comp.
Formula
M.p. (°C) (solvent)
Yield (%)
IR absorptions in KBr (cm−1
)
(molecular wt.)
CO
Mono- and disubstituted
benzene
CH2
3
C23H25N4O3Br
(485.378)
C24H27N4O3Br
(499.404)
C33H38N6O3
(566.68)
C34H40N6O4
(596.71)
C28H36N6O3
(504.62)
C32H35N5O3
(537.64)
C30H40N6O3
(532.67)
C34H40N6O3
(580.71)
182–184 (ethanol)
175–178 (ethanol)
196–198 (ethanol)
179–182 (ethanol)
150–152 (ether)
60
1650, 1670,
1720
1650, 1680,
1720
1650, 1680,
1720
1640, 1680,
1720
1645, 1670,
1720
1650, 1670,
1725
1650, 1680,
1720
1650, 1680,
1715
1640, 1680,
1720
1650, 1680,
1720
1650, 1670,
1720
1650, 1680,
1720
700, 755
700, 760
700, 765
700, 760
700, 760
700, 750
700, 760
700, 760
700, 750
700, 760
700, 755
700, 760
2880, 2930
2840, 2920
2800, 2860, 2905
2800, 2910
2800, 2940
2900, 2920
2800, 2920
2800, 2900
2800, 2900
2840, 2900
2840, 2930
2840, 2910
4
70
5
75
6
60
7
60–65
40
8
176–180 (ether)
9
126–130 (petroleum ether)
199–201 (ethanol)
50
10
11
12
13
14
70
C35H42N6O4
(610.73)
120–123 (ether/petroleum
ether)
187–191 (methanol/ether)
50
C
32H38N8O3
55
(582.688)
C33H37N5O3
(551.67)
147–150 (ether)
55
C
31H42N6O3
120–124 (petroleum ether)
56–60
(546.69)
3. Experimental
der diminished pressure. The residue was treated with a
small amount of distilled water and the crystalline
substance was collected on a filter and purified.
The properties of compounds 3 and 4 are given in
3.1. Chemistry
1
All the results of the C, H, N determinations (carried
out by a Carlo Erba Elemental Analyzer model NA-
1500) were within 90.4% of the theoretical values. All
melting points are uncorrected. The IR spectra, in KBr
pellets, were measured with Zeiss Jena specord model
Table 1 and the assignments in their H NMR spectra
are presented below: 1H NMR of 3: l=1.77–2.14,
m-8H (H of pyrrolidine +Hb,g of butyl); 2.64, s-3H
(CH3 in 7); 3.04–3.20, t-2H (H of pyrrolidine); 3.41–
3.68, m-4H (H of pyrrolidine+Hd of butyl); 4.41,
t(distorted)-2H (Ha of butyl); 6.94, s-1H (H in 6);
7.17–7.57, m-5H (H arom.).
1
IR 75 and H NMR spectra were determined in CDCl3
on a Tesla 587 A spectrometer (80 MHz) using TMS as
internal standard.
1H NMR of 4: l=1.4–2.13, m-10H (H of pipe-
ridine+Hb,g of butyl); 2.63, s-3H (CH3 in 7); 3.13–
3.20, m-2H (H of piperidine): 3.43–4.17, m-4H (H of
piperidine+Hd of butyl): 4.42, t-2H (Ha of butyl);
6.89, s-1H (H in 6); 7.16–7.51, m-5H (H arom.).
3.1.1. General procedure for obtaining compounds 3
and 4
0.01 mol of potassium was dissolved in 150 ml of
anhydrous ethanol and to this solution 0.01 mol of the
appropriate amide (1 or 2) was added. After dissolving
the solid substance, ethanol was distilled off under
diminished pressure and a dry crystalline residue was
treated with 16 g of 1,4-dibromobutane in 60 ml of
anhydrous DMF. The obtained suspension was stirred
at room temperature until the alkaline reaction disap-
peared. Then 200 ml of ether were added to the reac-
tion mixture and it was stirred again for 1 h. After
filtration the solvents were evaporated completely un-
3.1.2. General procedure for obtaining compounds 5–14
To 0.003 mol of compound 3 or 4 in 75 ml of
anhydrous acetonitrile, 0.75 g of anhydrous potassium
carbonate and 0.0045 (5–7, 10–12), 0.005 (8, 13), 0.012
(9, 14) mol of the suitable amine (N-phenyl-, N-o-meth-
oxyphenyl-, N-methyl-, N-(2-pyrimidynyl)-piperazines,
1,2,3,4-tetrahydroisoquinoline, 1-(2-aminoethyl) pipe-
ridine) were added. The mixture was refluxed for 12 h.
Then, after filtration the solvent was evaporated under

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H. Sladowska et al. / Il Farmaco 55 (2000) 6–12
9
Wistar rats (200–250 g). Investigated compounds were
administered intraperitoneally (i.p.) as suspensions in 3%
Tween 80 in the constant volume of 10 ml/kg in mice and
5 ml/kg in rats. The compounds were administered in
doses equivalent to 1/10, 1/20 and 1/40 of LD50. Control
animals received the equivalent volume of solvent. Each
experimental group consisted of eight animals.
The following pharmacological tests were performed:
1. Acute toxicity in mice.
2. Motor coordination in the rota-rod test in mice.
3. Spontaneous locomotor activity in mice
4. Amphetamine-induced locomotor hyperactivity in
mice.
5. Pain reactivity in the ‘writhing syndrome’ test in
mice.
6. Pain reactivity in the ‘hot plate’ test in mice.
7. Anxiolytic properties in ‘four plates’ test in mice.
8. Pentetrazol-induced seizures in mice.
9. Maximal electric shock in mice
10. Head twitches induced by 5-hydroxytryptophane in
mice.
reduced pressure and the residue was purified by crystal-
lization from the solvent given in Table 1.
The properties of compounds 5–14 are presented in
Table 1, and the assignments in the 1H NMR spectra of
some of them are presented below:
1H NMR of 6: l=1.55–2.03, m-8H (H of pyrro-
lidine+Hb,g of butyl); 2.49–2.71, m-9H (CH3 in 7+
H2CꢀN(CH2ꢀ)2); 3.12–3.16. m-6H (H of pyrrolidine+H
of piperazine); 3.6–3.67, t-2H (H of pyrrolidine); 3.86,
s-3H (OCH3); 4.42, t-2H (Ha of butyl); 6.93–7.50, m-10H
(H arom.).
1H NMR of 7: l=1.41–1.92, m-8H (H of pyrro-
lidine+Hb,g of butyl); 2.28–2.62, m-16H (2×CH3+H
of piperazine+Hd of butyl); 3.04–3.13, t-2H and 3.61–
3.66, t(distorted)-2H (H of pyrrolidine); 4.30–4.40, t-2H
(Ha of butyl); 6.92, s-1H (H in 6); 7.19–7.52, m-5H (H
arom.).
1H NMR of 9: l=1.47–1.94, m-14H (H of pipe-
ridine+H of pyrrolidine)+Hb,g of butyl); 2.35–2.76,
m-13H (3×CH2+H of piperidine+CH3 in 7); 3.01–
3.14, t-2H and 3.60–3.66, t(distorted)-2H (H of pyrro-
lidine); 4.40–4.48, t-2H (Ha of butyl); 6.91, s-1H (H in
6); 7.19–7.49, m-5H (H arom.).
11. Arterial blood pressure in rats.
Acute toxicity was assessed by the methods of
Litchfield and Wilcoxon [9] and presented as LD50
calculated from the mortality of mice after 24 h.
Motor coordination was measured according to the
method of Gross et al. [10]. The effects were evaluated
15, 30, 45, 60, 75, 90 and 105 min after the administration
of the investigated compounds.
Spontaneous locomotor activity in mice was mea-
sured by the use of Digiscan Optical Animal Activity
Monitoring System (Omnitech Electronics, Inc., Colum-
bus, OH). Thirty minutes after injection of the investi-
gated compounds, mice were placed separately in
Plexiglas cages (20×20×30 cm) for 1 h. The apparatus
monitors animal locomotor activity via a grid of invisible
infrared light beams, which in an equal number traverse
the animal cage from front to back and from left to right.
Each crossing of the light beam was recorded automat-
ically and subjected to rapid analysis by the Digiscan
1H NMR of 10: l=1.30–2.00, m-10H (H of pipe-
ridine+Hb,g of butyl); 2.40–2.72, m-9H (CH3 in 7+
H2CꢀN(CH2ꢀ)2); 2.92–3.20, m-6H (H of piperazine+H
of piperidine); 3.88–4.13, m-2H (H of piperidine); 4.33–
4.50, t-2H (Ha of butyl); 6.88–7.5, m-11H (H arom.).
1H NMR of 11: l=1.30–2.00, m-10H (H of pipe-
ridine+Hb,g of butyl); 2.25–2.72, m-9H (CH3 in 7+
H2CꢀN(CH2ꢀ)2); 2.87–3.29, m-6H (H of piperazine+H
of piperidine); 3.74–4.08, m-5H (OCH3+H of pipe-
ridine); 4.25–4.50, t-2H (Ha of butyl); 6.88–7.45, m-10H
(H arom.).
1H NMR of 12: l=1.30–2.00, m-10H (H of pipe-
ridine+Hb,g of butyl); 2.27–2.89, m-9H (CH3 in 7+
H2CꢀN(CH2ꢀ)2); 2.90–4.07, m-8H (H of piperidine+H
of piperazine); 4.07–4.50, t(distorted)-2H (Ha of butyl);
6.40–6.51, t-1H; 8.25–8.31, d-2H (H of pyrimidine); 6.88,
s-1H (H in 6); 7.29–7.42, m-5H (H arom.).
1H NMR of 13: l=1.51–1.82, m-10H (H of pipe-
ridine+Hb,g of butyl); 2.61–3.05, m-9H (CH3 in 7+Hd
of butyl+H of tetrahydroisoquinoline); 3.05–3.25, m-
2H; 3.75–4.2, t-2H (H of piperidine): 3.65, s-2H (H of
tetrahydroisoquinoline); 4.27–4.65, t-2H (Ha of butyl);
6.87–7.44, m-10H (H arom.).
Analyzer using computer program OMNI-PRO, Version
2.40. Horizontal activity (the total number of beam
interruptions that occurred in the horizontal sensor
during observation time) was evaluated after 30 and 60
min.
Amphetamine hyperactivity in mice was induced by
D,L-amphetamine 2.5 mg/kg s.c. The investigated com
3.2. Pharmacology
pounds were injected 30 min before amphetamine was
administered. The locomotor hyperactivity was mea-
sured 30 and 60 min later in the Digiscan Optical Animal
Activity Monitoring System.
Compounds 5–7 and 13 were investigated pharmaco-
logically.
Pain reactivity was measured by the ‘writhing syn-
drome’ test of Koster et al. [11]. The test was performed
on mice by the i.p. injection of a 0.6% solution of acetic
3.2.1. Material and methods
The experiments were carried out on male and female
Albino–Swiss mice (body weight, 20–25 g) and male

´
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H. Sladowska et al. / Il Farmaco 55 (2000) 6–12
Table 2
Table 4
Acute toxicity of the investigated compounds (n=8)
Influence of the investigated compounds on the pain reactivity in
‘writhing syndrome’ test in mice (n=8)
Comp.
LD50 (mg/kg i.p.)
Confidence limit
Comp.
Dose
(part of LD50
Dose (mg/kg)
Mean no. of
writhings9SEM
5
6
7
389.5
244.5
304.8
405.7
139.5–694.2
92.8–443.9
248.0–374.7
321.9–511.4
)
Control
5
7.590.8
13
1/10
1/20
1/40
1/10
1/10
1/20
1/10
1/20
1/40
38.95
19.47
9.73
24.45
30.48
15.24
40.57
20.28
10.14
3.290.5***
4.590.4**
6.191.8
6.491.6
3.891.2*
7.590.6
2.790.8***
4.890.6*
6.591.1
6
7
acid in a volume of 10 ml/kg, 60 min after the adminis-
tration of investigated compounds. The number of
writhing episodes was counted for 30 min after the
injection of 0.6% acetic acid.
13
Pain reactivity was also measured in the ‘hot plate’
test according to the method of Eddy and Leimbach
[12]. Animals were placed individually on the metal
plate heated to 56°C. The time(s) for the appearance
of the pain reaction (licking of the forepaws or jump-
ing) was measured. The experiments were performed 60
min after the administration of the investigated com-
pounds.
Anxiolytic properties were assessed by the ‘four
plates’ test in mice, according to Aron et al. [13], 60
min after the administration of investigated compounds
in doses that had no effect on the spontaneous loco-
motor activity. Mice were placed in the cages with four
plates in the floors (11×7 cm) with a 4 mm gap between
each. After 15 s of adaptation the number of crossings
was counted for 1 min. Each crossing was punished
with direct current (180 V, 0.5 A) but not more often
than every 3 s.
* PB0.05.
** PB0.01.
*** PB0.001.
developing clonic and tonic seizures as well as mortal-
ity was recorded in that period.
Maximal electric shock was induced by means of
alternating current (50 Hz, 25 mA, 0.2 s) with the use
of ear clip electrodes according to the method of Swin-
yard et al. [14]. The criterion for the convulsive re-
sponse was the tonic extension of the hind limbs. The
test was performed 60 min after administration of the
investigated compounds.
Head twitch behavior was induced by the adminis-
tration of 5-hydroxytryptophane (5-HTP) at a dose of
180 mg/kg i.p. 30 min after the investigated compounds
were administered. Animals were observed 60 min after
5-HTP administration.
Arterial blood pressure was determined according to
the method of Gerold and Tschirky [15] using the
UGO-BASILE equipment (blood pressure recorder,
Cat. No. 8006). Systolic blood pressure on the tail
artery was measured 30 min after administration of the
investigated compounds.
Pentetrazol seizures in mice were induced by pente-
trazol administration at a dose of 100 mg/kg s.c. 30
min after the investigated compounds. The animals
were observed during 30 min and the number of mice
Table 3
Influence of the investigated compounds on the spontaneous locomo-
tor activity in mice (n=8)
Comp. Dose
Dose
No. of impulses9SEM after:
3.2.2. Statistics
(part of (mg/kg)
The results obtained were presented as means and
evaluated statistically using Student’s t-test or exact
Fischer’s test.
LD50
)
30 min
60 min
Control
5
3925.09522.7
2154.09349.5*
3445.09326.7
6389.89854.6
3328.79435.45**
4963.29538.2
1/10
1/20
1/10
1/20
1/40
1/10
1/10
1/20
38.95
19.47
24.45
12.22
6.11
30.48
40.57
20.28
6
1125.89362.0*** 2147.59431.4***
4. Results and discussion
1976.19650.4*
3261.09823.4
4120.59452.5
2224.29488.0*
3966.39842.7
2789.19492.8**
4829.09387.4
6566.69707.7
3326.89757.9*
6884.39634.2
7
13
The LD50 values for the investigated compounds 5–7
and 13 after their i.p. administration in mice are
presented in Table 2. They indicate that the tested
substances were quite toxic with LD50 values between
244.5 and 405.7 mg/kg. The most toxic derivative was 6
(LD50=244.5 mg/kg). None of the investigated com-
* PB0.05.
** PB0.01.
*** PB0.001.

´
H. Sladowska et al. / Il Farmaco 55 (2000) 6–12
11
Table 5
Influence of the investigated compounds on the pain reactivity in ‘hot plate’ test in mice (n=8)
Comp.
Dose (part of LD50
)
Dose (mg/kg)
Time of reaction on pain stimulus9SEM (s)
Control
5
6.291.1
9.390.7*
7.690.9
6.092.0
11.191.4**
8.391.6
1/10
1/20
1/10
1/10
1/20
1/10
1/20
38.95
19.47
24.45
30.48
15.24
40.57
20.28
6
7
13
9.290.6*
6.590.8
* PB0.05.
** PB0.01.
pounds had neurotoxic properties at the dose of 38.95
(5), 24.45 (6), 30.48 (7), 40.57 (13) mg/kg as they did
not affect the motor coordination in the rota-rod test.
Compounds 5 and 13 suppressed spontaneous locomo-
tor activity during a 1 h observation period at the
highest dose used 38.95 (5), 40.57 (13) mg/kg. Com-
pound 6 was active in this test up to the dose of 12.22
mg/kg. Derivative 7 did not affect spontaneous locomo-
tor activity (Table 3). Furthermore compounds 5, 7 and
13 possessed analgesic activity assayed in the ‘writhing
syndrome’ test. Compounds 5 and 13 were active up to
a dose of 19.47 (5), 20.28 (13) mg/kg, and 7 at a dose of
30.48 mg/kg (Table 4). Analgesic activity of compounds
5, 7 and 13 was confirmed in a ‘hot plate’ test at doses
of 38.95 (5), 30.48 (7), 40.57 (13) mg/kg. Derivative 6
did not show analgesic activity in both tests performed
(Table 5). In the remaining tests all investigated com-
pounds were inactive.
From the presented results it follows that 6, being a
(4-o-methoxyphenyl-1-piperazinyl)butyl derivative of
the appropriate pyrrolidinylamide, proved to be, con-
trary to 5 (without the OCH3 group), the least active
and the most toxic compound. Piperidinoamide 13,
containing in position 1 4-[2-(1,2,3,4-tetrahydroiso-
quinolinyl)]butyl substituent, was the least toxic com-
pound and similar to 5, active in three tests.
In spite of the differences in the structures, com-
pounds 5 and 13 have the same pharmacological
profile. Their LD50 values are also similar. The small
differences in the strength of action, e.g. in the
‘writhing syndrome’ test, may be explained by the fact
that piperidinoamide produces a weaker analgesic effect
than pyrrolidinylamide. This indicates that at least in
two tests (‘writhing syndrome’ and ‘hot plate’), the
replacement of the N-substituted piperazinyl group by
1,2,3,4-tetrahydroisoquinolinyl one in this series of
compounds is possible. Amide 7, containing a small
lipophilic methyl group at the nitrogen atom in position
4 of the piperazine, showed only analgesic activity in
two tests at the highest dose used. But in the ‘writhing
syndrome’ test it has a weak action.
The investigated compounds have the same activity
profile as 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)]propyl
derivatives (IIa–c) but they are considerably more toxic
in comparison with IIa–c (LD50 for IIa–c were \2000
mg/kg [2]. The last compounds showed strong analgesic
properties in the ‘writhing syndrome’ test up to a dose
of 1.56 (IIa), 25 (IIb), or 6.25 mg/kg (IIc). This indi-
cates that in this test, compounds 5, 7 and 13 were less
active than IIa,c. In comparison with IIb, derivatives 5
and 13 indeed an exerted analgesic effect in lower
doses, but particularly in the case of 13 (at the dose of
20.28 mg/kg) it was a weak action. A weak activity was
also displayed by 7. In the ‘hot plate’ test compounds
IIa–c were active as strong analgesic agents up to doses
of 25 (IIa), 100 (IIb) and 50 mg/kg (IIc). The investi-
gated compounds showed a weak activity in this test.
This might be due (among others) to the fact that in
comparison with IIb and IIc they could not be adminis-
tered in higher doses because of their toxicity. Com-
pounds IIb,c suppressed weakly the spontaneous
locomotor activity of mice up to a dose of 50 mg/kg.
The tested compounds (with the exception of 13) gave
stronger effect in this test in lower doses. Substances
5–7 and 13 were also more toxic in comparison with
Ia,b (LD50 for Ia,b were as follows: 1600 (Ia), 1800
mg/kg (Ib) but less toxic than Ic (LD50 for Ic=183.7
mg/kg) [1]). Contrary to Ia,b they were devoid of
anxiolytic activity, but with the exception of 6 they
showed weak analgesic properties. The comparison of
the activity of compound 5 (amide) with the action of
Ia (ester) indicates that in this case, the amide group
causes the analgesic effect.
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