Investigations on the synthesis and pharmacological properties of amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-piperazinyl)propyl]-2,4- dioxo-1,2,3,4-tetra-hydropyrido[2,3-d]pyrimidine-5-carboxylic acid

Article abstract of DOI:10.1016/S0014-827X(99)00101-9

Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4- tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6-10) and their 1-[2- hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11-15) are described. Some of them displayed strong analgesic acti

Full text of DOI:10.1016/S0014-827X(99)00101-9

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 773–779
Investigations on the synthesis and pharmacological properties of
amides of 7-methyl-3-phenyl-1-[2-hydroxy-3-(4-phenyl-1-
piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-
pyrimidine-5-carboxylic acid
a,
c
yna Rajtar b,
´
Helena Sladowska *, Maria Sieklucka-Dziuba , Graz
;
Miros*law Sadowski c, Zdzis*law Kleinrok b
a Department of Chemistry of Drugs, Wroc*law Medical Uni6ersity, Tamka 1, 50-137, Wroc*law, Poland
b Department of Pharmacology, Medical School, Jaczewskiego 8, 20-090 Lublin, Poland
c Department of Hygiene, Medical School, Radziwi*l*lowska 11, 20-085 Lublin, Poland
Received 22 February 1999; accepted 23 September 1999
Abstract
Synthesis of amides of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (6–10) and
their 1-[2-hydroxy-3(4-phenyl-1-piperazinyl)propyl] derivatives (11–15) are described. Some of them displayed strong analgesic
activity. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Pyrido[2,3-d]pyrimidines; N-2-Hydroxy-3(4-phenyl-1-piperazinyl)propyl derivatives; Amides; Synthesis; Pharmacological activity
1. Introduction
similarity (imide moiety, pyridine ring), it seemed inter-
esting to state whether substitution of the above-
mentioned pharmacophoric group in position 1 of
compound 1 would distinctly influence its pharmaco-
logical activity (Fig. 1). In order to do this from a
chemical point of view, the subsitution of the ester
group in compound 1 by an amide group proved to be
It was stated previously [1] that compounds 1 and 2
were characterized by low toxicity and displayed anal-
gesic properties. Derivative 1 also weakly reduced hy-
perthermia induced by m-chlorophenylpiperazine
(antidepressant action).
These findings as well as the analgesic, anxiolytic,
sedative and anti-inflammatory activities of various
derivatives of pyrido[2,3-d]pyrimidine, obtained in our
department (e.g. Refs. [2–4]), encouraged us to con-
tinue the synthesis in this group of compounds. The
starting point for further investigations was our acci-
dental statement that the introduction of the 2-hy-
droxy-3-(4-phenyl-1-piperazinyl)propyl substituent at
the nitrogen atom of some 3,4-pyridinedicarboximides
gave non-toxic substances (LD50\2000 mg kg−1), dis-
playing very strong analgesic activity [4]. Because 3,4-
pyridinedicarboximides and 2,4-dioxo-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidines show some structural
Fig. 1.
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00101-9

´
774
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
Fig. 2.
necessary. According to statements made above the aim
of this paper was the synthesis of some amides 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-carboxylic acid (11–15) and evalu-
ation of their action on the CNS in preliminary phar-
macological tests. We hoped that the compounds ob-
tained would show (among others) stronger analgesic
properties in comparison with those of compound 1.
Furthermore, the 2-hydroxy-3(4-phenyl-1-piperazinyl)-
propyl substituent has similar structure to that of the
side chains of b-blockers. Therefore, we also evaluated
the influence of some amides on the arterial blood
pressure in rats.
stances with the following cyclic amines: pyrrolidine (6),
piperidine (7), morpholine (8), N-methyl- and N-
phenylpiperazines (9, 10). The amides 6–10 underwent
condensation with 2-hydroxy-3(4-phenyl-1-piperazinyl)-
propyl chloride in anhydrous ethanol and in the pres-
ence of potassium ethoxide. As a result derivatives
11–15 were obtained (Fig. 2).
The structures of all compounds synthesized were
1
confirmed by elemental and spectral analyses (IR, H
NMR).
3. Experimental
3.1. Chemistry
2. Chemistry
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 a Zeiss Jena specord model
IR 75 and H NMR spectra were determined in CDCl3
on a Tesla 587 A spectrometer (80 MHz) using TMS as
internal standard.
The starting material was ethyl 7-methyl-3-phenyl-
2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-pyrimidine-5-
carboxylate (3) [6]. It was subjected to acid hydrolysis
giving the corresponding pyrido-[2,3-d]pyrimidine-5-
carboxylic acid (4) [2,5]. Acid 4 was transformed into
the acid chloride 5 by heating with SOCl2 in anhy-
drous benzene solution. The last gave crystalline sub-
1

´
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
775
3.1.1. 7-Methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydro-
pyrido-[2,3-d]pyrimidine-5-carboxylic acid (4)
perature (r.t.) for 5 h. The separated product was
collected on a filter and after drying it was washed with
100 ml of distilled water. Only in the case of amide 10
was the solid substance first washed with ethanol (120
ml) and then with distilled water.
Ethyl
7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahy-
dro-pyrido[2,3-d]pyrimidine-5-carboxylate (3) (8 g) was
treated with a mixture of 480 ml of glacial acetic acid
and 240 ml of concentrated hydrochloric acid and
refluxed for 6 h. The acids were then distilled off under
reduced pressure and to the dry residue 200 ml of
distilled water were added. The separated product was
collected on a filter, washed with water, dried and
purified by crystallization from ethanol. After drying in
vacuo at 130° it melted \300°C. It had identical
physical and chemical properties to 7-methyl-3-
phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]pyri-
midine-5-carboxylic acid (C15H11N3O4=297.26) syn-
thesized previously [3,6].
All amides were purified by crystallization from
ethanol.
The properties of compounds 6–10 are listed in
1
Table 1 but the assignments of their H NMR spectra
are shown below.
1H NMR of 6: l=1.89 (m-4H), 3.05–3.13 (m-2H),
3.61–3.66 (m-2H, H of pyrrolidine), 2.69 (s-3H, CH3 in
7), 6.96 (s-1H, H in 6), 7.22–7.5 (m-5H, H arom), 10.5
(s-1H, NH).
1H NMR of 7: l=1.60 (m-6H), 2.7–4.06 (m-4H, H
of piperidine), 2.50, (s-3H, CH3 in 7), 6.86 (s-1H, H in
6), 7.17–7.56 (m-5H, H arom), 11.5 (s, broad, 1H,
NH).
3.1.2. Chloride of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic acid (5)
7-Methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropy-
rido[2,3-d]-pyrimidine-5-carboxylic acid (4 g) (4) was
treated with 60 ml of SOCl2 and 80 ml of anhydrous
benzene. The suspension was refluxed for 7 h. Benzene
and an excess of SOCl2 were distilled off under dimin-
ished pressure and 40 ml of anhydrous benzene were
added to the residue. Benzene was again evaporated in
vacuo. This procedure was repeated twice in order to
remove all traces of SOCl2. The crude product was used
for the reaction without further purification.
1H NMR of 8: l=2.68 (s-3H, CH3 in 7), 3.18 (t-2H),
3.59–3.92 (m-6H, H of morpholine), 6.88 (s-1H, H in
6), 7.20–7.52 (m-5H, H arom), 11.54 (s-1H, NH).
1H NMR of 9: l=2.31–2.62 (m-10H, 2×CH3+4H
of piperazine), 3.17–3.32 (t-2H), 3.66 (m-2H, H of
piperazine), 6.91 (s-1H, H in 6), 7.26–7.46 (m-5H, H
arom), 8.88 (s-1H, NH).
1H NMR of 10: l=2.62 (s-3H, CH3 in 7), 2.77–3.72
(m-6H) and 3.72–4.28 (m-2H, H of piperazine), 6.90–
7.42 (m-11H, H arom), 11.06 (s-1H, NH).
3.1.4. General procedure for obtaining amides of 7-
methyl-3-phenyl-1-[2-hydroxy-3(4-phenyl-1-
3.1.3. General procedure for obtaining amides of 7-
methyl-3-phenyl-2,4-dioxo-1,2,3,4-tetrahydropyrido-
[2,3-d]pyrimidine-5-carboxylic acid (6–10)
Chloride 5 (0.014 mol) obtained above was dissolved
in 80 ml of anhydrous benzene. To this solution 0.035
mol of a suitable cyclic amine (pyrrolidine, piperidine,
morpholine, N-methyl- and N-phenylpiperazines) was
introduced. The mixture was then stirred at room tem-
piperazinyl)propyl]-2,4-dioxo-1,2,3,4-tetrahydro-
pyrido[2,3-d]pyrimidine-5-carboxylic acid (11–15)
Potassium (0.01 mol) was dissolved in anhydrous
ethanol (150 ml) and to this solution 0.01 mol of a
suitable amide of 7-methyl-3-phenyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-5-carboxylic
was introduced. After dissolving the solid substance,
acid
Table 1
Properties of the investigated compounds
Comp. Formula (molecular weight) M.p. (°C) (solvent)
Yield (%) IR absorptions in KBr (cm−1
)
CO
OH or NH
Monsubstituted benzene
6
7
8
9
10
11
12
13
C19H18N4O3 (350.37)
C20H20N4O3 (364.39)
C19H18N4O4 (366.37)
C20H21N5O3 (379,41)
C25H23N5O3 (441,47)
C32H36N6O4 (568.66)
C33H38N6O4 (582.68)
C32H36N6O5 (584.66)
314–316 (ethanol)
333–335 (ethanol)
303–305 (ethanol)
312–314 (ethanol)
283–286 (ethanol)
198–201 (ethanol)
185–187 (ethanol)
75
60
55
65
50
44
45
1640, 1665, 1720 3060, 3100–3130 700, 770
1645, 1670, 1720 3060, 3100 700, 760
1640, 1680, 1730 3060, 3100–3120 705, 770
1650, 1670, 1715 3120, 3200
1660, 1680, 1730 3060, 3110
1650, 1670, 1725 3370–3420
1640, 1670, 1720 3360–3400
1640, 1670, 1720 3400–3420
700, 770
710, 770
700, 760
700, 760
700, 760
195–197 (methanol a 60
or ether)
14
15
C33H39N7O4 (597.698)
C38H41N7O4 (659.764)
209–211 (methanol)
226–228 (ethanol)
55
45
1650, 1680, 1730 3340–3400
1640, 1680, 1730 3360–3400
700, 770
700, 770
a Compound 13 crystallizes with 1 mol of CH3OH.

´
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
776
2-hydroxy-3(4-phenyl-1-piperazinyl)propyl
chloride
rats. The compounds were administered in doses equiv-
alent to 1/10, 1/20, 1/40, 1/80, 1/160, 1/320, 1/640,
1/1280 or 1/2560 of LD50. For all compounds 2000 mg
kg−1 was taken to be the initial dose. Control animals
received the equivalent volume of solvent. Each experi-
mental 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.
(0.012 mol) was added. The reaction mixture was
refluxed until the alkaline reaction disappeared. After
the filtration ethanol was distilled off to about 1/3 of its
original volume and left to crystallize. The separated
product (11–14) was collected on a filter. Only in the
case of amide 15 was the solid organic substance pre-
cipitated during the heating of the reagents. It was
collected on a filter, washed with distilled water and
dried.
An additional amount of 15 was isolated from the
filtrate (after evaporation of it to a small volume) and
added to the main product. All amides (11–15) were
purified by crystallization from the solvents given in
Table 1.
The properties of compounds 11–15 are listed in
1
Table 1 and the assignments of their H NMR spectra
are shown below.
1H NMR of 11: l=1.88 (m-4H), 3.6–3.65 (m-2H, H
of
pyrrolidine),
3.14–3.20
(m-6H,
4H
of
11. Arterial blood pressure in rats.
piperazine+2H of pyrrolidine), 2.56–2.73 m-9H
Acute toxicity was assessed by the methods of
Litchfield and Wilcoxon [7] and presented as the LD50
calculated from the mortality of mice after 24 h.
Motor coordination was measured according to the
method of Gross et al. [8]. The mice were placed for 2
min on the rod rotating with the speed of 4 rpm. 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 in circular photoresistor actometers (32 cm in
diameter). After the injection of the investigated com-
pounds the animals were placed in the actometers for 1
h. Each crossing of the light beam was recorded auto-
matically. The number of impulses was noted after 30
and 60 min.
Amphetamine hyperactivity in mice was induced by
D,L-amphetamine 2.5 mg kg−1 s.c. The investigated
compounds were injected 30 min before the am-
phetamine was administered. The locomotor hyperac-
tivity was measured 30 and 60 min later in the
photoresistor actometers.
Pain reactivity was measured by the ‘writhing syn-
drome’ test of Koster et al. [9]. The test was performed
in mice by the i.p. injection of a 0.6% solution of acetic
acid in a volume of 10 ml kg−1 60 min after the
administration of investigated compounds. The number
of writhing episodes was counted for 30 min after the
injection of 0.6% acetic acid.
; 4.33–4.64 (m-4H, Ha,b
of propyl+OH), 6.84–7.5 (m-11H, H arom).
1H NMR of 12: l=1.66 (m-6H), 3.75–3.90 (m-2H,
H of piperidine), 3.15–3.44 (m-6H, 4H of piper-
azine+2H
of
piperidine),
; 4.28–4.65 (m-4H, Ha,b
of propyl+OH), 6.85–7.50 (m-11H, H arom).
1H
NMR of 13: l=2.59–2.74,
; 3.16–3.26 (m-6H, 4H
2.56–2.73
(m-9H
(m-9H
of piperazine+2H of morpholine); 3.62 (m-2H); 3.73–
3.76, (m-4H, H of morpholine); 4.30–4.75, (m-4H, Ha,
b of propyl+OH); 6.84–7.46, m-11H (H arom).
1H NMR of 14: l=2.29–2.73 (m-16H, 2×CH3+8H
of piperazine+Ha of propyl), 3.15–3.20 (m-6H), 3.65–
3.95 (m-2H, H of piperazine), 4.15–4.77 (m-4H, Ha,b of
propyl+OH), 6.84–7.49 (m-11H, H arom).
1H
NMR
of
15:
l=2.58–2.76
m-9H
; 3.16–3.35 (m-10H, H
of piperazine), 3.77–4.85 (m-6H, 2H of piperazine+
Ha,b of propyl+OH), 6.86–7.52 (m-16H, H arom).
3.2. Pharmacology
Compounds 11, 12 and 14 were investigated
pharmacologically.
Pain reactivity was also measured in the ‘hot plate’
test according to the method of Eddy and Leimbach
[10]. Animals were placed individually on the metal
plate heated to 56°C. The time (s) of appearance of
the pain reaction (licking of the forepaws or jumping)
was measured. The experiments were performed 60
min after the administration of the investigated com-
pounds.
3.2.1. Materials and methods
The experiments were carried out on male and female
Albino-Swiss mice (body weight of 20–25 g) and male
Wistar rats (200–250 g). The compounds investigated
were administered intraperitoneally (i.p.) as suspensions
in 3% Tween 80 at a constant volume of 10 ml kg−1 in

´
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
777
Table 2
3.2.2. Statistics
Influence of the investigated compounds on the spontaneous locomo-
The results obtained were presented as means and
evaluated statistically using Student’s t-test or the exact
Fischer test.
tor activity in mice (n=8)
Comp. Dose
(part of LD50
Dose
No. of impulses9SEM after:
)
(mg kg−1
)
30 min
60 min
4. Results and discussion
Control
11
12
364.8970.8 554.4998.9
248.3911.3 375.7948.4
165.0942.2 * 187.0916.5 **
195.9922.0 * 257.8923.3 *
238.0926.0 324.4915.1 *
292.7940.7 472.09113.1
192.5933.3 * 262.1963.5 *
156.7948.0 * 270.5980.9 *
223.0923.5 322.1913.1 *
276.4935.6 397.4998.0
1/10
1/10
1/20
1/40
1/80
1/10
1/20
1/40
1/80
200.0
200.0
100.0
50.0
The LD50 values (i.p. in mice) for the tested com-
pounds 11, 12 and 14 are \2000 mg kg−1. It indicated
that the tested compounds were not toxic. Further-
more, none of the compounds in doses equivalent to
200 mg kg−1 showed neurotoxic properties as they did
not affect the motor coordination in the rota-rod test.
Compounds 12 and 14 suppressed the spontaneous
locomotor activity of mice during the 1 h observation
period up to the dose of 50 mg kg−1. Compound 11
was inactive in this test (Table 2). All compounds,
administered at a dose of 200 mg kg−1, did not affect
the excitatory action of amphetamine in mice, but they
possessed strong analgesic activity, assayed in the
‘writhing syndrome’ test up to the dose of 1.56 mg
kg−1 (11), 25 mg kg−1 (12) and 6.25 mg kg−1 (14)
(Table 3).
25.0
14
200.0
100.0
50.0
25.0
* PB0.05.
** PB0.01.
Anxiolytic properties were assessed by the ‘four
plates’ test in mice, according to Aron et al. [11], 60
min after the administration of investigated compounds
in doses, which had no effect on the spontaneous
locomotor activity. Mice were placed in cages with four
plate floors (11×7 cm) with a 4 mm gape between
each. After 15 s of adaptation the number of crossings
was counted during 1 min. Each crossing was punished
with direct current (180 V, 0.5 A) but not more than
every 3 s.
Strong analgesic properties of the investigated deriva-
tives were also confirmed in the ‘hot plate’ test. They
were active up to doses of 25 mg kg−1 (11), 100 mg
kg−1 (12) and 50 mg kg−1 (14) (Table 4). None of the
investigated compounds, administered at a dose of 200
mg kg−1, affected the pulse rate and arterial blood
Table 3
Pentetrazol seizures in mice were induced by pente-
trazol administration at a dose of 100 mg kg−1 s.c. 30
min after the injection of the investigated compounds.
The animals were observed during 30 min and the
number of mice developing clonic and tonic seizures as
well as mortality 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 Swinyard
et al. [12]. The criterion for the convulsive response was
the tonic extension of the hind limbs. The test was
performed 60 min after administration of the investi-
gated compounds.
Head twitch behaviour was induced by the adminis-
tration of 5-hydroxytryptophane (5-HTP) at a dose of
180 mg kg−1 i.p. 30 min after the investigated com-
pounds were administered. Animals were observed 60
min after 5-HTP administration [13].
Arterial blood pressure was determined according to
the method of Gerold and Tschirky [14] 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 inves-
tigated compounds.
Influence of the investigated compounds on the pain reactivity in the
‘writhing syndrome’ test in mice (n=8)
Comp.
Dose (part of LD50
)
Dose (mg kg−1
)
Mean no. of
writhings9SEM
Control
11
9.591.27
0 ***
1/10
1/20
1/40
1/80
1/160
1/320
1/640
1/1280
1/2560
1/10
1/20
1/40
1/80
1/160
1/10
1/20
1/40
1/80
200.0
100.0
50.0
25.0
12.5
6.25
3.12
1.56
0.78
200.0
100.0
50.0
25.0
12.5
200.0
100.0
50.0
25.0
12.5
6.25
3.12
0.590.32 ***
0.6790.38 ***
0.7490.24 ***
0.9590.32 ***
1.2590.55 ***
2.0090.41***
4.2090.62 **
6.7591.04
0 ***
0.2590.16 ***
0.3890.26 ***
3.3790.67 ***
4.7591.49
0 ***
0 ***
0 ***
1.0090.56 ***
3.0091.10**
4.1090.93 **
6.8790.59
12
14
1/160
1/320
1/640
** PB0.05.
*** PB0.01.

´
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
778
Table 4
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−1
)
Time of reaction on pain stimulus9SEM (s)
Control
11
4.0990.30
15.7091.10 ***
8.4691.33**
6.3790.70*
6.9590.77**
5.0290.45
8.7090.74***
6.8190.52***
5.7090.81
13.0090.90***
8.4691.46*
6.6790.71**
4.6790.33
1/10
1/20
1/40
1/80
1/160
1/10
1/20
1/40
1/10
1/20
1/40
1/80
200.0
100.0
50.0
25.0
12.5
200.0
100.0
50.0
200.0
100.0
50.0
12
14
25.0
* PB0.05.
** PB0.01.
*** PB0.001.
pressure in rats. In the remaining tests all the examined
amides were inactive.
effects as in the case of some 3,4-pyridinedicarbox-
imides, mentioned in Section 1. In both chemical groups
non-toxic substances were obtained, characterized by
very strong analgesic activity.
Except for 11, in both cases analgesic action was
associated with the weak suppression of the sponta-
neous locomotor activity of mice, but only at the high
doses (50–200 mg kg−1).
From the data presented above it follows that among
the three studied substances compound 11 (being the
pyrrolidinylamide derivative) showed the strongest se-
lective analgesic activity. Piperidinoamide 12 proved to
be the least active analgesic agent. It indicates that the
kind of amide group has influence on the strength of the
analgesic action.
The lead compound 1 showed low toxicity (LD50=
1561 mg kg−1), but in the rota-rod test it exerted weak
neurotoxic properties at the highest dose used (156.1 mg
kg−1), whereas amides 11, 12 and 14 did not reveal any
neurotoxic effects even at a dose of 200 mg kg−1. Ester
1 displayed analgesic properties in the ‘writhing syn-
drome’ test up to a dose of 25 mg kg−1 similar to amide
12, but in the case of 12 it was a very strong action.
Similarly to 11, 12, and 14 compound 1 was inactive
both as an anxiolytic agent, in the ‘four plates’ test, and
also as anticonvulsant (pentetrazole and the maximal
electric shock induced seizures in mice). Furthermore, 1
did not affect the excitatory action of amphetamine in
mice at a dose of 156.1 mg kg−1. The same effect was
observed after administration of amides in doses of 200
mg kg−1. Compounds 1, 11, 12 and 14 did not change
the number of head twitches induced by 5-HTP in mice.
From the data presented above it can be seen that
the described modifications of compound 1 caused
reduction in the toxicity (LD50 for 11, 12 and 14 \2000
mg kg−1), elimination of the neurotoxic properties in all
cases and, in the case of compounds 11 and 14, made
the substance more active as an analgesic agent. The
results obtained also indicate that the introduction of
the 2-hydroxy-3(4-phenyl-1-piperazinyl)-propyl group
on some 2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3-d]-
pyrimidine derivatives caused the same pharmacological
References
´
[1] H. Sladowska, Investigations on the synthesis and properties of
arylpiperazinylalkyl derivatives of some dihydro- and tetrahy-
dropyrido[2,3-d]pyrimidines, Farmaco 48 (1993) 77–84.
´
[2] H. Sladowska, A. Bartoszko-Malik, T. Zawisza, Investigations
on the reaction course of diethyl 2-chloro-6-methylpiridine-3,5-
dicarboxylate with N-amino and N-hydroxyalkyl derivatives of
thiourea, Farmaco 41 (1986) 899–912.
´
[3] H. Sladowska, A. Bartoszko-Malik, T. Zawisza, Synthesis and
properties of the derivatives of 2-alkylthio-4-oxo-3,4 (and 1,4)-
dihydropyrido[2,3-d]pyridmide-5- and -6-carboxylic acids, Far-
maco 45 (1990) 111–121.
´
[4] H. Sladowska, M. Sieklucka-Dziuba, L. Staniak, Z. Kleinrok,
Synthesis and properties of l-aryl(pyrimidinyl)piperazinylalkyl
derivatives of ethyl 3-phenyl-7-methyl-2,4-dioxo-1,2,3,4-tetrahy-
dropyrido[2,3-d]pyrimidine-5-carboxylate, Farmaco 49 (1994)
499–503.
´
[5] H. Sladowska, J. Potoczek, M. Sieklucka-Dziuba, G. Rajtar, Z.
Kleinrok, in press.
´
[6] H. Sladowska, A. Bartoszko-Malik, T. Zawisza, Synthesis and
properties of new derivatives of ethyl 7-methyl-2,4-dioxo-1,2,3,4-
tetrahydropyrido[2,3-d]pyrimidine-5-carboxylate, Farmaco 45
(1990) 101–110.
[7] I.T. Litchfield, F. Wilcoxon, A simplified method of evaluating
dose-effect experiments, J. Pharmacol. Exp. Ther. 96 (1949)
99–113.
[8] F. Gross, J. Tripod, R. Meier, Zur pharmakologischen Charak-
terisierung des Schlafmittels Doriden, Med. Wschr. 85 (1995)
305–309.

´
H. Sladowska et al. / Il Farmaco 54 (1999) 773–779
779
[9] R. Koster, M. Anderson, J.E. de Bear, Acetic acid for analgesic
screening, Fed. Proc. Fed. Am. Soc. Exp. Biol. 18 (1959) 412.
[10] N.B. Eddy, D. Leimbach, Synthetic analgesics, II. Dithienyl-
butenyl and dithienyl-butylamines, J. Pharmacol. Exp. Ther. 107
(1953) 385–389.
says of antiepileptic drugs in mice and rats, J. Pharmacol. Exp.
Ther. 106 (1952) 319–330.
[13] M. Nakamura, H. Fukushima, Effects of reserpine,
parachlorophenylalanine, 5,6-dihydroxytryptamine and fludi-
azepam on the head twitches induced by 5-hydroxytryptamine or
5-methoxytryptamine in mice, J. Pharm. Pharmacol. 30 (1978)
254–256.
)
[11] C. Aron, D. Simon, C. Larousse, J.R. Bıssier, Evaluation of a
rapid technique for detecting minor tranquilizers, Neuropharma-
cology 10 (1971) 459–469.
[14] M. Gerold, H. Tschirky, Measurement of blood pressure in
unanaesthetized rats, Artzneim. Forsch. 18 (1968) 1285–1287.
[12] E.A. Swinyard, W.C. Brown, L.S. Goodman, Comparative as-
.
.