Synthesis and CNS activity of tricyclic theophylline derivatives. 8- substituted imidazo[2,1-f]theophyllines

Article abstract of DOI:10.1016/S0223-5234(99)00131-2

Based on previously described results of pharmacological in vitro and in vivo tests of some series of pyrimido- and diazepino-[2,1-f]theophylline derivatives, N8-unsubstituted, N8-benzyl and N8-arylpiperazino-alkyl derivatives of imidazo[2,1-f]theophyllines were synthesized and tested for their CNS activity. It has been shown that tricyclic [2,1-f]theophyllines possess sedative and analgesic activity. N8-Phenylpiperazinopropyl-1,3,6,7- tetrahydro-(8H)-imidazo[2,1-f]theophylline 6 showed significant anti- serotonin and long-lasting hypothermic effects. N8-Benzyl-1,3,6,8- tetrahydroimidazo-7-on[2,1-f]theophylline 8 possess anticonvulsant properties.

Full text of DOI:10.1016/S0223-5234(99)00131-2

Eur. J. Med. Chem. 34 (1999) 1085−1091
© 1999 Éditions scientifiques et médicales Elsevier SAS. All rights reserved
1085
Short communication
Synthesis and CNS activity of tricyclic theophylline derivatives.
8-substituted imidazo[2,1-f]theophyllines
Maciej Pawłowskia*, Anna Drabczyn´skab, Jacek Katlabia, Maria Gorczycaa, Danuta Malecc,
Jerzy Modzelewskic
aDepartment of Pharmaceutical Chemistry, Collegium Medicum of Jagiellonian University, 9 Medyczna St., 30-688 Kraków, Poland
bDepartment of Chemical Technology of Drugs, Collegium Medicum of Jagiellonian University, 9 Medyczna St., 30-688 Kraków, Poland
cDepartment of Pharmacodynamics School of Medicine, 4 Staszica St., 20-081 Lublin, Poland
(Received 26 April 1999; revised 13 June 1999; accepted 15 July 1999)
Abstract – Based on previously described results of pharmacological in vitro and in vivo tests of some series of pyrimido- and
diazepino-[2,1-f]theophylline derivatives, N8-unsubstituted, N8-benzyl and N8-arylpiperazino-alkyl derivatives of imidazo[2,1-f]theo-
phyllines were synthesized and tested for their CNS activity. It has been shown that tricyclic [2,1-f]theophyllines possess sedative and
analgesic activity. N8-Phenylpiperazinopropyl-1,3,6,7-tetrahydro-(8H)-imidazo[2,1-f]theophylline 6 showed significant anti-serotonin and
long-lasting hypothermic effects. N8-Benzyl-1,3,6,8-tetrahydroimidazo-7-on[2,1-f]theophylline 8 possess anticonvulsant properties. © 1999
Éditions scientifiques et médicales Elsevier SAS
imidazo[2,1-f]theophyllines / CNS activity of fused [2,1-f]theophyllines / arylpiperazinoalkylimidazo[2,1-f]theophyllines acting on CNS
1. Introduction
In this paper we would like to summarize the results of
our investigation on chemical and pharmacological prop-
erties of derivatives in which the third heterocyclic ring is
bound at position 7,8- of theophylline. In our initial
studies we found that some benzyl or dialkylamino-alkyl
derivatives of 1,3,6,7,8,9-hexahydropyrimido[2,1-f]theo-
phyllines and 1,3,6,7-tetrahydro-(9H)-pyrimid-8-on[2,1-
f]theophyllines (figure 1) changed the pharmacological
profile of the mother compound (theophylline) into seda-
tive, hypothermic, analgesic and neuroleptic-like activ-
ity [1–3].
Figure 1. Structure of 9-substituted 1,3,6,7,8,9-hexahydro-
(9H)-pyrimido[2,1-f]theophyllines and 1,3,6,7-tetrahydro-
(9H)-pyrimid-8-on[2,1-f]theophyllines.
These unexpected results seem to be related to the
presence of a heterocyclic six membered ring, as well as
to the basic alkylamino side chain substituted at the N9
position. Moreover, in preliminary screening it appeared
that among others, the most active are the derivatives
which contain arylpiperazino-propyl or its butyl homo-
logue as an N9-substituent. This observation prompted us
to synthesize the series of new compounds with seven, six
and five membered rings bound at position 7,8- of
theophylline and a piperazino-alkyl substituent at the N8,
N9 or N10 position, to study the influence of ring size and
kind of substituent in fused heterocyclic moieties on CNS
activity of investigated compounds.
The enlargement of the third heterocyclic ring lead to
1,3-diazepino- and 1,3-diazepin-9-on-[2,1-f]-theophylli-
nes [4] (figure 2).
*Correspondence and reprints

1086
Figure 2. Structure of 10-substituted 1,3,6,7,8,9-hexahydro-
(10H)-1,3-diazepino[2,1-f]theophyllines and 1,3,6,7,8,10-
hexahydro-1,3-diazepin-9-on[2,1-f]theophyllines.
Both investigated groups exhibit high CNS activity.
Particularly, N10-phenyl-piperazinopropyl-1,3,6,7,8,9-
hexahydro-(10H)-1,3-diazepino[2,1-f]theophylline showed
strong analgesic and sedative activity, but only slight
hypothermic and antiamphetamine effects [4].
Figure 4. Structure of 1-(2-pyrimido)-piperazinoalkyl deriva-
tives of tricyclic non-lactam and lactam system.
A similar mode of action was observed in the group of
pyrimidin-8-on[2,1-f]theophyllines with a double bond
between C6–C7 in the third ring [5] (figure 3).
2. Chemistry
Particularly, the N9-phenylpiperazinopropyl-derivate
of 1,3-dihydro-(9H)-pyrimid-8-on[2,1-f]theophylline in-
duced hypothermia and strongly decreased the spontane-
ous locomotor activity and amphetamine induced hyper-
activity [5].
Taking into account that various 1-aryl(heteroaryl)-
substituted piperazines have been reported to possess
agonistic activity on serotonin receptors [6], we also
investigated, in behavioral tests, the compounds with a
1-(2-pyrimido)-piperazinoalkyl substituent connected
with a non-lactam tricyclic system [7] and some of their
lactam analogues (1 and 2) (figure 4).
Following our research to verify the influence of the
third ring in tricyclic componds on the pharmacological
profile of CNS-activity, we undertook the synthesis of
N8-unsubstituted (3) and 8-arylpiperazinoalkyl deriva-
tives (4–7) of 1,3,6,7-tetrahydro-(8H)-imidazo[2,1-f]theo-
phylline.
In order to compare CNS-activity, previously obtained
N9-benzyl-1,3,6,7-tetrahydro-(9H)-pyrimid-8-on[2,1-f]
theophylline [1] with its analogue in which the five
member lactam ring is fused in the 7,8- position of
theophylline, N8-benzyl-1,3,6,8-tetrahydroimidazol-7-
on[2,1-f]theophylline 8 was synthesized.
9-{3-[4-(2-Pyrimidynyl)-1-piperazinyl]-propyl}-1,3,6,
7-tetrahydro-(9H)-pyrimid-8-on[2,1-f]theophylline (1
)
and 10-{3-[4-(2-pyrimidynyl)-1-piperazinyl]-propyl}-1,
3,6,7,8,10-hexahydro-1,3-diazepin-9-on[2,1-f]theophylli-
ne (2) were prepared according to the procedures de-
scribed previously [6].
In the reaction of 7-â-bromoethyl-8-bromotheo-
phylline [8] with ammonia 8-unsubstituted 1,3,6,7-
tetrahydro-(8H)-imidazo[2,1-f]theophylline, (3) was ob-
tained. Arylpiperazino-alkyl derivatives of 1,3,6,7-
tetrahydro-(8H)-imidazo[2,1-f]theophylline (4–7) were
obtained in a several step synthesis (figure 5).
8-â-Hydroxyethyl-1,3,6,7-tetrahydro-(8H)-imidazo-
[2,1-f]theophylline (I) and its homologue (Ia) were
prepared by condensation of 7-â-bromoethyl-8-bromo-
theophylline with 2-aminoethanol or 3-aminopropan-1-
ol. Compounds I and Ia, upon bromination with PBr3 in
CHCl3, yielded II and IIa. Aminolysis of compound II
and IIa with a double amount of phenylpiperazine or
2≠-pyrimidyl-piperazine in anhydrous toluene in the pres-
ence of K2CO3 gave the compounds 4–7.
N8-Benzyl-1,3,6,8-tetrahydroimidazol-7-on[2,1-f]theo-
phylline 8 was synthesized via cyclization of 8-benzyl-
aminotheophylline-7-acetic acid [9] in boiling acetic an-
hydride (figure 6).
3. Pharmacological results and discussion
The compounds 1–8 were evaluated for their influence
on the CNS. Their acute toxicity assessed in mice as the
LD50 (confidence limits) was as follows:
Figure 3. Structure of 9-substituted 1,3-dihydro-(9H)-
pyrimidin-8-on-[2,1-f]theophyllines.
Compound 1: 235 mg/kg (178–310)

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Figure 7. The influence of compounds (0.1 LD50) on sponta-
neous locomotor activity of mice.
Figure 5. Arylpiperazino-alkyl derivatives of 1,3,6,7-tetra-
hydro-(8H)-imidazo[2,1-f]theophylline (4–7).
Compound 2: 560 mg/kg (478–655)
Compound 3: 320 mg/kg (269–381)
Compound 4: 175 mg/kg (117–263)
Compound 5: 320 mg/kg (264–387)
Compound 6: 540 mg/kg (439–664)
Compound 7: 2 000 mg/kg
Compound 8: 2 000 mg/kg
The CNS effects of all these substances (1/10 LD50)
were studied in several tests, and it was observed that
substances 2, 3, 4, 6, 7 and 8 induced marked sedative
effects in the locomotor activity test (figure 7).
Compound 6 had the strongest action, which reduced
the activity of mice by about 90% (1/10 and 1/20 LD50).
Figure 6. N8-Benzyl-1,3,6,8-tetrahydroimidazol-7-on[2,1-f]
theophylline 8.
These doses of substance
6
also antagonized
amphetamine-induced hyperactivity in mice, but did not
change apomorphine-induced stereotypy or haloperidol-
induced catalepsy in rats. Compounds 4 and 6 also had
antiserotonin effects, as they diminished 5HTP-induced
head-twitch reactions of mice (table I). Hypothermic
action was observed after the administration of com-
pounds 1, 6, 7 and 8 (figure 8). The most apparent and
long-lasting effects were observed for compounds 6 and
8. Analgesic action in the hot plate test was induced in
mice by nearly all substances, except for compound 8
(table II).
These effects were of rather a short duration (up to
90 min after injection). Compound 8 had anticonvulsant
action in the pentetrazole test in mice, as it prevented the
tonic phase of the seizures and lethality of the animals.
Reserpine-induced hypothermia was slightly reversed by
substances 1, 3 and 4, and this action suggests some
antidepressant properties of these three substances. How-
Table I. The influence of the compounds (0.1 LD50) on the head
twitch responses of mice receiving L-5HTP (180 mg/kg i.p.).
Compound
Mean ± SE
number of head twitch responses
Tylose
11.4 ± 2.9
18.0 ± 4.3
14.5 ± 4.0
15.0 ± 4.2
3.6* ± 1.3
12.3 ± 5.5
1.8** ± 0.7
9.3 ± 3.2
1
2
3
4
5
6
7
8
12.7 ± 3.7
The compounds were injected 60 min before L-5HTP.
* P < 0.05, ** P < 0.01 (Student’s t-test).

1088
Figure 8. The influence of compounds (0.1 LD50) on body temperature of normothermic mice.
ever, we observed neurotoxic effects in the rota-rod test in
mice following injection of nearly all compounds tested.
pino[2,1-f]theophyllines (lactam structure) did not have a
significant influence on the direction of pharmacological
activity.
3. The potency of sedative action depends significantly
on the kind of N-substituted basic side chain. Variation of
the alkylamino substituents confirmed unequivocally that
the most apparent CNS activity was exerted by the
compounds with phenylpiperazinopropyl- or phenyl-
piperazinobutyl- substituents.
4. Conclusion
Analysing the results of our preliminary investigations
on chemical and pharmacological properties of tricyclic
theophylline derivatives from the point of view of
structure-activity relationships, it may be concluded that:
1. In contrast to mother theophylline, all investigated
tricyclic compounds generally exhibited a strong sedative
action, particularly those which contained the basic
aminoalkyl side chain, substituted on the third bound ring
at N8 of imidazole, N9 of pyrimidine and N10 of
diazepine. Their sedative properties were confirmed in a
number of behavioral tests (in mice).
4. Length reduction of the alkylene chain between
dialkylamino substituents and tricyclic substituents from
three or four to two carbon atoms resulted mostly in an
increase of toxicity.
5. The replacement of the phenylpiperazinoalkyl sub-
stituent with an (ω-4-pyrimidinyl)-piperazino-alkyl side
chain generally decreased the activity and revealed some
neurotoxic effects.
2. The replacement of the methylene group with a
carbonyl one in pyrimido[2,1-f]theophyllines or diaze-
Table II. The influence of the tested compounds on the reactivity of mice in the hot plate test.
Compound 0.1 LD50
Reaction time (s) of mice after injection (min)
30
60
90
120
Vehicle
8.9 ± 0.6
14.5*** ± 0.9
13.0*** ± 0.7
10.8 ± 0.6
14.7*** ± 1.0
13.4** ± 1.1
13.0** ± 1.0
14.7*** ± 1.1
10.1 ± 0.6
9.3 ± 0.6
13.4** ± 0.8
11.7 ± 0.9
13.8** ± 1.1
12.3* ± 0.8
12.9* ± 1.0
14.3** ± 1.2
13.2*** ± 1.0
10.9 ± 0.7
9.5 ± 0.7
15.1** ± 1.2
10.8 ± 0.6
10.4 ± 0.6
13.8* ± 1.1
11.2 ± 0.7
12.3 ± 1.2
10.6 ± 0.6
9.3 ± 0.5
9.1 ± 0.7
11.5 ± 0.9
10.4 ± 0.5
10.8 ± 0.7
13.4* ± 1.2
11.2 ± 0.8
11.5 ± 0.9
11.2 ± 0.8
10.2 ± 0.6
1
2
3
4
5
6
7
8
* P < 0.05; ** P < 0.02; *** P < 0.001 (Student’s t-test).

1089
6. All phenylpiperazinoalkyl substituted tricyclic [2,1-
f]theophyllines reduced the amphetamine induced hyper-
activity.
Pyrimido[2,1-f]theophyllines with phenylpiperazino-
alkyl side chains showed mainly analgesic and neuro-
leptic-like properties. The pyrimidinyl-piperazino ana-
logues exhibited agonistic activity on 5-HT1A receptors.
Their diazepino homologues exerted apparent analgesic
activity.
7. Some of previously described tricyclic theophylline
derivatives, evaluated for the affinities for 5-HT recep-
tors, were classified as postsynaptic antagonists or partial
agonists of 5-HT1A receptors [6].
5.1.2. 8-γ-Hydroxypropyl-1,3,6,7-tetrahydro-(8H)-imida-
zo[2,1-f]theophylline Ia
The title compound was obtained similarly to com-
pound I using 3-amino-1-propanol and isobutanol as a
solvent. The mixture was refluxed for 10 h. After refrig-
eration, the separated product was recrystallized. Yield
54%; m.p. 186–188 °C (isopropanol). Rf 0.74, UV λmax
nm 298.5 (log e 4.19). 1H-NMR 1.80–1.90 (m, 2H,
CH2CH2CH2) 3.34 (s, 3H, N3CH3), 3.48 (s, 3H, N1CH3),
3.49–3.55 (m, 2H, CH2OH), 3.66–3.71 (t, 2H, N8CH2),
3.92–3.98 (t, 2H, C7H2), 4.22–4.28 (t, 2H, C6H2). IR
(cm–1) 3 300–3 450 (OH), 2 800–2 950 (CH2)n, 1 650
(CO), 1 450 (CH2–N). Anal. C12H17O3N5; C, H, N.
Pyrimido[2,1-f-]theophyllines were also tested for af-
finity to adenosine receptors [10]. They were classified as
adenosine receptor subtype A1 antagonists.
Some of the presented data on tricyclic [2,1-f-]theo-
phyllines summarized in this article remains open to
further investigation.
5.1.3. 8-(â-Bromoethyl)-1,3,6,7-tetrahydro-(8H)-imida-
zo[2,1-f]theophylline II and 1,3-8-(γ-bromopropyl)-
1,3,6,7-tetrahydro-(8H)-imidazo[2,1-f]theophylline IIa
These two compounds were obtained similarly. To
0.01 mol of compound I or Ia, fourfold amounts of PBr3
in 25 cm3 of CHCl3 was added and refluxed for 5 h. Then
the solvent and the excess of PBr3 were distilled off under
reduced pressure and to the residue, water was added.
The mixture was alkalized with 10% NaOH (to pH 8).
The crude products were separated and recrystallized.
5. Experimental protocol
5.1. Chemistry
Melting points were determined on a Boetius apparatus
and are uncorrected. UV spectra were obtained on the
UV-VIS Lambda 12 spectrophotometer (Perkin Elmer)
(conc. 5 × 10–5 M/dm3 in methanol). IR spectra were
determined on the Specord M 80 spectrophotometer (Carl
Compound II. Yield 92%; m.p. 210–212 °C (ethanol).
Rf 0.87, UV λmax nm 298.5 (log e 4.20). H-NMR 3.36
1
(s, 3H, N3CH3), 3.51 (s, 3H, N1CH3), 3.60–3.65
(t, 2H, CH2Br), 3.76–3.81 (t, 2H, N8CH2), 4.02–4.08
(t, 2H, C7H2), 4.24–4.31 (t, 2H, C6H2). IR (cm–1)
2 800–2 950 (CH2)n, 1 650 (CO), 1 450 (CH2–N). Anal.
C11H14O2N5Br; C, H, N.
Compound IIa. Yield 94%; m.p. 162–164 °C (50°
ethanol). Rf 0.87, UV λmax nm 299.4 (log e 4.11).
1H-NMR 2.21–2.32 (m, 2H, CH2CH2CH2) 3.37 (s, 3H,
N3CH3), 3.52 (s, 3H, N1CH3), 3.47–3.54 (t, 2H, CH2Br),
3.88–3.95 (t, 2H, C7H2), 4.05–4.12 (t, 2H, C6H2). IR
(cm–1) 2 800–2 950 (CH2)n, 1 650 (CO), 1 450 (CH2–N).
Anal. C12H16O2N5Br; C, H, N.
1
Zeiss Jena) in KBr pellets. H-NMR spectra were ob-
tained on a Brucker AC200 F spectrometer in CDCl3
(except I measured in DMSO) solution using TMS as
internal standard. Chemical shifts are reported in δ units.
Coupling constants are reported in Herz. Elemental
analyses indicated by the symbols were within ± 0.4% of
the theoretical value. TLC was performed on Merck
plates (Kieselgel 60 F254 with S = benzene:acetone:
methanol (1:1:1) + 2 drops NH4OH.
5.1.1. 8-â-Hydroxyethyl-1,3,6,7-tetrahydro-(8H)-imidazo-
[2,1-f]theophylline I
5.1.4. 1,3,6,7-Tetrahydro-(8H)-imidazo[2,1-f]theophyl-
line 3
A mixture of 7-â-bromoethyl-8-bromotheophylline
(5.0 g; 0.014 mol), 2-aminoethanol (5 cm3; 0.08 mol) and
40 cm3 of ethanol was refluxed for 5 h. After refrigeration
the product was filtered off and recrystallized. Yield 69%;
m.p. 238–240 °C (ethanol). Rf 0.74, UV λmax nm 299.4
(log e 4.30). 1H-NMR 3.17 (s, 3H, N3CH3), 3.34 (s, 3H,
N1CH3), 3.30–3.36 (m, 2H, CH2OH), 3.57–3.64 (t, 2H,
N8CH2), 3.91–3.98 (t, 2H, C7H2), 4.05–4.12 (t, 2H,
C6H2), 4.82–4.86 (t, 1H, OH). IR (cm–1) 3 300 (OH),
2 800–2 950 (CH2)n, 1 650 (CO), 1 450 (CH2–N). Anal.
C11H15O3N5; C, H, N.
A mixture of 7-â-bromoethyl-8-bromotheophylline
(4.0 g; 0.011 mol), 5 cm3 of 25% ammonia and 15 cm3 of
ethanol was heated in an autoclave at 180–190 °C for 5 h.
Then the solution was evaporated and the residue was
refluxed with isopropanol to separate the inorganic salts.
The hot mixture was filtered off and the filtrate was
distilled off under reduced pressure. The crude product
was recrystallized from ethanol; m.p. 270–272 °C, yield
60%. Compound 3 was obtained by Eckstein et al. [11]
using another method.

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5.1.5. General procedure for compounds 4–7
5.1.5.5. 8-Benzyl-1,3,6,8-tetrahydroimidazol-7-on[2,1-
f]theophylline 8
Compounds 4–7 were obtained by aminolysis of com-
pounds II or IIa with double the amount of phenylpip-
erazine or 2≠-pyrimidynyl-piperazine. The reaction was
carried out in anhydrous toluene in the presence of a
stoichiometric amount of K2CO3 and refluxed for 5 h.
The inorganic salt was filtered off from the hot mixture
and the filtrate was refrigerated. The crystalline products
were filtered off and recrystallized.
A mixture of 8-benzylaminotheophyllino-7-acetic acid
(3.43 g; 0.01 mol) and 15 cm3 of acetic anhydride
was refluxed for 3 h. After cooling, the product was
separated by filtration, washed with a small amount of
methanol and recrystallized. Yield 50%, m.p. 216–
218 °C (methanol). Rf 0.92 (chloroform:methanol: 25%
NH4OH (8:2:0.25)), UV λmax nm 300.0 (log e 4.01)
1
(conc. 5 × 10–5 M/dm3 in chloroform). H-NMR 3.33
(s, 3H, N3CH3), 3.58 (s, 3H, N1CH3), 4.71 (s, 2H,
N8CH2C6H5), 4.93 (s, 2H, C6CH2), 7.33–7.48 (m, 5H,
C6H5). Anal. C16H15O3N5, C, H, N.
5.1.5.1. 8-{2-[4-(Phenyl)-1-piperazinyl]-ethyl}-1,3,6,7,-
tetrahydro-(8H)-imidazo[2,1-f]theophylline 4
Yield 52%; m.p. 164–166 °C (ethanol + butyl acetate).
Rf 0.80, UV λmax nm 244.0 (log e 4.09), 296.7 (log e
4.23). 1H-NMR 2.70–2.75 (m, 10H, CH2N(CH2)4N),
3.19 (t, J = 4.8, 2H, N8CH2), 3.37 (s, 3H, N3CH3), 3.51
(S, 3H, N1CH3), 3.99 (t, J = 7.7, 2H, C7H2), 4.22 (t, J =
7.8, 2H, C6CH2), 6.86–6.93 (m, 3H, 3≠,4≠,5≠-phenyl),
7.26 (m, 2H, 2≠,6≠-phenyl). Anal. C21H27O2N7, C, H, N.
5.2. Pharmacology
The experiments were performed on male Swiss mice
(19–26 g), and on Wistar rats (180–200 g), kept at ambi-
ent temperature on a 12 h light/dark schedule, with free
access to food and water before the experiments. The
experimental groups consisted of 5–8 animals each. All
investigated compounds were injected i.p., 1 h before the
test, as a suspension in 0.5% tylose solution.
5.1.5.2. 8-{2-[4-(2-Pyrimidynyl)-1-piperazinyl]-ethyl}-
1,3,6,7,-tetrahydro-(8H)-imidazo[2,1-f]theophylline 5
Yield 91%; m.p. 194–195 °C (toluene). Rf 0.50, UV
λmax nm 242.0 (log e 4.14), 301.0 (log e 3.99). 1H-NMR
2.55–2.70 (m, 10H, CH2N(CH2)4N), 3.37 (s, 3H,
N3CH3), 3.51 (s, 3H, N1CH3), 3.78 (t, J = 5.0, 2H,
N8CH2), 3.35–4.03 (m, 2H, C7H2), 4.18–4.26 (m, 2H,
C6CH2), 6.48 (m, J = 4.7, 1H, 5≠-pyrimidyl), 8.30 (d, J
= 4.8, 2H, 4≠,6≠-pyrimidyl). Anal. C19H25O2N9, C, H, N.
The doses corresponding to 0.1 LD50 of the com-
pounds were administered in all tests. The acute toxicity
of the compounds was assessed in mice as the LD50
calculated on the basis of mortality within 48 h [12].
Spontaneous locomotor activity and amphetamine-
induced hyperactivity in mice were observed in a photo-
resistor actometer for 30 min. Analgesic effects were
assessed in the hot plate (56 °C) test in mice, and body
temperature was measured with a thermistor thermometer
in the rectum of mice. Antipsychotic action was evaluated
in the tests of amphetamine (5 mg/kg s.c.)-induced
hyperactivity of mice and apomorphine (3 mg/kg s.c.)-
induced stereotypy in rats. Antiparkinsonian effects were
measured by investigation of the influence of the com-
pounds on haloperidol (1 mg/kg)-induced catalepsy in
rats. Anticonvulsant activity was assessed in pentetrazole
(90 mg/kg s.c.)-induced seizures in mice. The anti-
depressant action was evaluated using the test of
reserpine-induced hypothermia in mice (reserpine
2.5 mg/kg s.c., 20 h before injection of the investigated
substances, and then body temperature was measured at
30 min intervals for 3 h). The influence of the compounds
on serotonin neurotransmission was evaluated in the
head-twitch responses of mice following 5HTP injec-
tion [13, 14]. Neurotoxic properties were observed in the
rota-rod test [15, 16] in mice.
5.1.5.3. 8-{2-[4-(Phenyl)-1-piperazinyl]-propyl}-1,3,6,7,-
tetrahydro-(8H)-imidazo[2,1-f]theophylline 6
Yield 79%; m.p. 192–194 °C (toluene). Rf 0.75, UV
λmax nm 246.0 (log e 4.09), 299.0 (log e 4.09). 1H-NMR
1.84–1.92 (m, 2H, CH2CH2CH2), 2.44–2.63 (m, 10H,
CH2N(CH2)4N), 3.19 (t, J = 4.7, 2H, N8CH2), 3.35 (s,
3H, N3CH3), 3.47 (s, 3H, N1CH3), 3.86 (t, J = 8.0, 2H,
C7H2), 4.20 (t, J = 8.0, 2H, C6CH2), 6.84–6.93 (m, 3H,
3≠,4≠,5≠-phenyl), 7.24 (t, J = 7.8, 2H, 2≠,6≠-phenyl).
Anal. C22H29O2N7, C, H, N.
5.1.5.4. 8-{2-[4-(2-Pyrimidynyl)-1-piperazinyl]-propyl}-
1,3,6,7,-tetrahydro-(8H)-imidazo[2,1-f]theophylline 7
Yield 79%; m.p. 192–194 °C (toluene). Rf 0.59, UV
λmax nm 242.0 (log e 4.15), 301.0 (log e 3.94). 1H-NMR
1.84–1.92 (m, 2H, CH2CH2CH2), 2.43–2.53 (m, 10H,
CH2N(CH2)4N), 3.35 (s, 3H, N3CH3), 3.41 (t, J = 4.7,
2H, N8CH2), 3.49 (s, 3H, N1CH3), 3.75–3.92 (m, 2H,
C7H2), 4.21 (t, J = 8.0, 2H, C6CH2), 6.47 (t, J = 4.8, 1H,
5≠-pyrimidyl), 8.30 (d, J = 4.8, 2H, 4≠,6≠-pyrimidyl).
Anal. C20H27O2N9, C, H, N.
Statistical analysis was carried out using the Student’s
t-test (convulsions) and Mann-Whitney U test (catalepsy,
stereotypy).

1091
zyca M., Pol. J. Pharmacol. Pharm. 47 (1995) 169–173.
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