Pyridofuropyrrolo[1,2-a]pyrimidines and pyridofuropyrimido[1,2-a]azepines: New chemical entities (NCE) with anticonvulsive and psychotropic properties

Article abstract of DOI:10.1039/c6ra02581a

Herein we report the synthesis of several new condensed furo[2,3-b]pyridines 3 from the 3-oxo derivatives of cyclopenta[c]pyridine, 5,6,7,8-tetrahydroisoquinoline and pyrano[3,4-c]pyridine 1. The obtained furo[2,3-b]pyridines 3 were used as starting materials for the synthesis of pyridofuropyrrolo[1,2-a]pyrimidines 4 and pyridofuropyrimido[1,2-a]azepines 5. Interestingly enough, derivatives of pyridofuropyrimido[1,2-a]azepines 5 exhibited significantly better anticonvulsant activity than the commercial drug ethosuximide (zarontin). Some of them showed a sedative effect, unlike ethosuximide.

Full text of DOI:10.1039/c6ra02581a

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PAPER
Pyridofuropyrrolo[1,2-a]pyrimidines and
pyridofuropyrimido[1,2-a]azepines: new chemical
entities (NCE) with anticonvulsive and psychotropic
properties†
Cite this: RSC Adv., 2016, 6, 32234
a
b
Samvel N. Sirakanyan, Athina Geronikaki, Domenico Spinelli,c
Ruzanna G. Paronikyan,a Irina A. Dzhagatspanyan,a Ivetta M. Nazaryan,a
Asmik H. Akopyana and Anush A. Hovakimyana
*
*
Herein we report the synthesis of several new condensed furo[2,3-b]pyridines 3 from the 3-oxo derivatives
of cyclopenta[c]pyridine, 5,6,7,8-tetrahydroisoquinoline and pyrano[3,4-c]pyridine 1. The obtained furo
[2,3-b]pyridines 3 were used as starting materials for the synthesis of pyridofuropyrrolo[1,2-a]pyrimidines
4 and pyridofuropyrimido[1,2-a]azepines 5. Interestingly enough, derivatives of pyridofuropyrimido[1,2-a]
azepines 5 exhibited significantly better anticonvulsant activity than the commercial drug ethosuximide
(zarontin). Some of them showed a sedative effect, unlike ethosuximide.
Received 28th January 2016
Accepted 6th March 2016
DOI: 10.1039/c6ra02581a
www.rsc.org/advances
by the occurrence of degenerative diseases such as Alzheimer’s
disease and other dementia types; which affect a third of people
over the age of 65.6 Especially, it becomes critical for people over
the age of 80, 25% of whom suffer from serious deterioration of
mental capacity. Loss of cognitive function could also be a result
of clinical conditions such as stroke, acute and chronic
inammation as well as intoxication, mental retardation in
children, cerebrovascular disease, alcoholic organic mental
disorders and many others.
The rst drug used as a nootropic was Piracetam. Now there
is a range of cognition-enhancing (nootropic) drugs that cover
a wide spectrum of mechanisms of action, including calcium
channel blockers, glutamatergic drugs, antioxidants, chol-
inomimetics and mnemotropic neuropeptides.7 Nevertheless,
all available nootropics suffer from signicant side effects,8 and
thus there is an urgent need for novel cognition enhancers
without such adverse reactions.
It is known from the literature that derivatives of fused pyr-
rolo[1,2-a]pyrimidinones and pyrimido[1,2-a]azepines (Fig. 1)
have a wide spectrum of biological activities such as anticon-
vulsive,9 antitubercular,10 HIV integrase inhibitory,11,12 bro-
blast growth factor receptor 1 kinase inhibitory,13 molluscicidal,
and larvicidal14 activities. At the same time, the condensed
system of pyridofuropyrrolo[1,2-a]pyrimidines and pyridofur-
opyrimido[1,2-a]azepines has never been described in the
literature (Fig. 2).
1. Introduction
Computer aided structure–activity relationship analysis and
molecular modelling are widely used in the nding and opti-
mization of new leads by today’s medicinal chemists.1 The
majority of available approaches are focused on a single
macromolecular target, the only pharmacological/biochemical
action, and/or compounds from the same chemical series.
The problem of applicability of the structure–activity relation-
ships found in compounds from one chemical series onto
compounds from another chemical series is in general still
under discussion.2 Moreover, the existing structure–activity
relationship/quantitative structure–activity relationship (SAR/
QSAR) methods deal with a single biological activity, whereas
in reality, every compound usually has both main and side
(sometimes also negative) pharmacological effects.3
Currently in the developed world, a continuous increase of
diseases linked to aging or to troubles related to mind problems
is observed. As people become older, there is a higher risk of
losing cognitive functions such as memory, attention span,
ability to concentrate and understand, orientation and
comprehension.4,5 Furthermore, long life can be accompanied
aScientic Technological Center of Organic and Pharmaceutical Chemistry of National
Academy of Sciences of Republic of Armenia, Institute of Fine Organic Chemistry of A. L.
Mnjoyan, Ave. Azatutyan 26, Yerevan, Armenia 0014. E-mail: shnnr@mail.ru
bAristotle University of Thessaloniki, School of Pharmacy, Thessaloniki 54124, Greece.
For this reason, and in continuation of our work15–18 on the
search for new biologically active heterocyclic compounds, we
have developed a method for the synthesis of these condensed
compounds, prepared a series of them, and studied their anti-
convulsant properties.
E-mail: geronik@pharm.auth.gr
c
`
Dipartimento di Chimica G. Ciamician, Alma Mater Studiorum-Universita di Bologna,
Via F. Selmi 2, Bologna 40126, Italy. E-mail: domenico.spinelli@unibo.it
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra02581a
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In the IR spectra of compounds 3, the absorption band of the
cyano group (2218–2223) characteristic for compounds 2 was
not observed. At the same time, the appearance of absorption
bands characteristic for the C]O (1664–1674 cmꢀ1) and NH2
(3330–3550 cmꢀ1) groups is an indication of the formation of
compounds 3.
Fig. 1 Structure of known compounds. R ¼ OH, Oalk, aryl; R1
¼
CO2Me, CONHC6H4-p-F; R + R1 ¼ substituted aryl and heteryl; n ¼ 1,
Their 1H NMR spectra in DMSO/CCl4 1/3 evidenced the
presence of the proton signals of the NH2 group at 5.70–5.75
ppm.
2, 3.
Aminoesters of furo[2,3-b]pyridines 3 still contain functional
groups, which can give new cyclization reactions. As a matter of
fact, with some lactams, in the presence of phosphorus oxy-
chloride, they led to the simultaneous closing reaction of the
two functional groups at once.9,14,24 As a result, new classes of
condensed heterocyclic systems of pyridofuropyrrolo[1,2-a]
pyrimidines 4 and pyridofuropyrimido[1,2-a]azepines 5 were
obtained with good or very good mean yields (>61 and 71%,
respectively) (Scheme 2).
Fig. 2 Structure of compounds 4 and 5 synthesized by us.
The course of the reaction can be represented as follows: at
the rst stage of the reaction, the chlorination of 2-pyrrolidi-
none (or of 2-azepanone) was carried out by the action of
phosphorus oxychloride with the formation of corresponding
amidochlorides, which were then able to react with the ami-
noesters of furo[2,3-b]pyridine. As a result of this reaction
amidines 1 were formed, which in turn were in equilibrium with
amidines 2. Further, an intramolecular cyclization took place,
leading to the formation of the desired products 4 and 5
(Scheme 2).9,14,24
The IR spectra of compounds 4 and 5 did not show the
characteristic bands of the amino group, but showed bands in
the range n 1671–1705 cmꢀ1 typical for the carbonyl group.
The 1H NMR spectra of compounds 4 and 5 did not show the
broad singlet of the NH2 group at 5.70–5.75 ppm, characteristic
for the initial compounds 3, nor the protons of the COOEt ester
group (the triplet of the CH2 group at 1.40–1.41 ppm, and the
quartet of the CH3 group 4.32–4.33 ppm). The structure of
compounds 4 and 5 was also supported by the MS and 13C NMR
data.
2. Results and discussion
2.1. Chemistry
As starting compounds, the already described 3-oxo derivatives
of cyclopenta[c]pyridine19 1a–c, 5,6,7,8-tetrahydroisoquinoline20
1d, e and pyrano[3,4-c]pyridine21 1f–i were used. All of these
starting materials are very interesting substrates, in fact, all of
them are decorated on adjacent carbon atoms of the pyridine
ring by two functional groups able to lead the way to
compounds with a new condensed ring (a furan ring), which in
turn will still contain other reactive groups useful for further
chemical transformations.
In fact, compounds 1, by simple interactions with ethyl
chloroacetate in the presence of potassium carbonate, were
converted with very good mean yields (>75.5%) into the corre-
sponding O-alkylated compounds 2,16,17,22,23 which in turn under
the action of sodium ethoxide cyclized, giving the fused furo
[2,3-b]pyridines 3 (ref. 16, 17, 22 and 23) via the Thorpe–Ziegler
reaction (Scheme 1).
We have observed that the cyclization process of the O-
alkylated derivatives 2 is very sensitive to humidity and to the
reaction time. As a result, we managed to implement the cycli-
zation only in super absolute ethanol (99.95%) reducing the
boiling time to 15–20 minutes: in such experimental conditions
very good mean yields (>76.5%) were obtained.
2.2. PASS predictions of neuroprotective activity
In silico study of the designed compounds was performed by
using the computer program PASS, which predicts the biolog-
ical activity spectra of compounds.
Scheme 1 Synthesis of ethyl 1-aminofuro[2,3-b]pyridine-2-carboxylates 3. (a) ClCH2CO2Et, K2CO2/DMF, 75–80 ꢁC, 2 h, mean yield: >75.5%; (b)
EtONa, reflux 15–20 min, mean yield: >76.5%. (1–3) a: X ¼ CH2, n ¼ 0, R ¼ H, R1 ¼ i-C3H7; b: X ¼ CH2, n ¼ 0, R ¼ H, R1 ¼ C4H9; c: X ¼ CH2, n ¼ 0,
R ¼ H, R1 ¼ Ph; d: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C3H7; e: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C4H9; f: X ¼ O, n ¼ 1, R ¼ R1 ¼ CH3; g: X ¼ O, n ¼ 1, R ¼ CH3,
R1 ¼ C2H5; h: X ¼ O, n ¼ 1, R ¼ CH3, R1 ¼ C4H9; i: X ¼ O, n ¼ 1, R ¼ CH3, R1 ¼ 2-furyl.
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Scheme 2 Synthesis of furopyrrolo[1,2-a]pyrimidines 4 and furopyrimido[1,2-a]azepines 5. (a) 2-Pyrrolidinone, POCl3, C2H4Cl2, reflux, 25 h,
mean yield: >61%; (b) 2-azepanone, POCl3, C2H4Cl2, reflux, 20 h, mean yield: >71.5%. (4) a: X ¼ CH2, n ¼ 0, R ¼ H, R1 ¼ i-C3H7; b: X ¼ CH2, n ¼ 0,
R ¼ H, R1 ¼ C4H9; c: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C3H7; d: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C4H9; e: X ¼ O, n ¼ 1, R ¼ R1 ¼ CH3; f: X ¼ O, n ¼ 1, R ¼
CH3, R1 ¼ C2H5; g: X ¼ O, n ¼ 1, R ¼ CH3, R1 ¼ C4H9; h: X ¼ O, n ¼ 1, R ¼ CH3, R1 ¼ 2-furyl. (5) a: X ¼ CH2, n ¼ 0, R ¼ H, R1 ¼ i-C3H7; b: X ¼ CH2,
n ¼ 0, R ¼ H, R1 ¼ C4H9; c: X ¼ CH2, n ¼ 0, R ¼ H, R1 ¼ Ph; d: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C3H7; e: X ¼ CH2, n ¼ 1, R ¼ H, R1 ¼ i-C4H9; f: X ¼ O, n ¼
1, R ¼ R1 ¼ CH3; g: X ¼ O, n ¼ 1, R ¼ CH3, R1 ¼ C2H5; h: X ¼ O, n ¼ 1, R ¼ CH3; R1 ¼ C4H9.
Table 1 Prediction results for the synthesized compounds
only the structural formula of a chemical compound is neces-
sary to obtain PASS predictions, this approach can be used at
Compoundsa
Predicted activity
Pa
the earliest stage of investigation (eventually also before the
synthesis of new compounds). Literature reports several exam-
ples of the successful use of the PASS approach for nding new
pharmacologically active species.29–34
4a
4c
4e
4f
4g
4h
Antineurotic
Antineurotic
Anticonvulsant
Anticonvulsant
Anticonvulsant
Neurodegenerative diseases
treatment
Anticonvulsant
Antiparkinsonian
Nootropic
Nootropic
Cognition disorders treatment
Nootropic
Cognition disorders treatment
Nootropic
Cognition disorders treatment
Nootropic
Cognition disorders treatment
Anticonvulsant
Nootropic
Cognition disorders treatment
Nootropic
Cognition disorders treatment
0.422
0.422
0.358
0.261
0.280
0.403
A biological activity spectrum for a substance is a list of
biological activities for which the probability to be revealed (Pa)
and the probability not to be revealed (Pi) are calculated. Pa and
Pi values are independent and their values vary from 0 to 1.25
The results of the prediction are valuable for the planning of the
experiment, but one should take into account some additional
factors, such as particular interest to certain kinds of activity,
desirable novelty of a substance, available facilities for experi-
mental testing, etc. Actually, each choice is always a compro-
mise between the desirable novelty of the studied substance
and the risk of obtaining a negative result in the testing. The
higher the Pa value, the lower the probability of false positives
in the set of compounds selected for biological testing.
The interpretation of PASS results could be presented as
follows. If Pa > 0.7, then the chance of nding this activity in the
experiments is high, but in many cases the compound may be
a close analogue of known pharmaceutical agents. If 0.5 < Pa <
0.7, the chance of nding the activity in the experiments is
lower, because the compound is not so similar to known
pharmaceutical agents. If Pa < 0.5, the chance of nding the
activity in the experiments is even lower; the compound has
a weak similarity with respect to the compounds from the
training set, but interestingly enough if the activity will be
experimentally observed, the compound may become a ‘New
Chemical Entity’ (NCE).
0.288
0.244
0.455
0.535
0.431
0.717
0.526
0.455
0.436
0.438
0.410
0.245
0.324
0.324
0.632
0.407
5a
5b
5c
5d
5e
5f
5g
5h
a
For compounds 4b and 4d the anticonvulsant activity was not
predicted.
Computer program prediction of activity spectra for
substances (PASS)25–28 is based on a robust analysis of structure–
activity relationships26 in a heterogeneous training set currently
including (version PASS 14) about 1 000 000 biologically active
compounds from different chemical series. This approach
(version PASS2014) can simultaneously predict 7000 different
biological activities with an accuracy prediction of 95%. Since
Biological activity spectra were predicted for all 16 synthe-
sized compounds 4 and 5 with PASS 9.1 version. The results in
Table 1 show that the anticonvulsant activity was predicted only
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Table 2 Anticonvulsant activity by pentilentetrazol antagonism and toxicity of the examined compounds 4c–h, 5a, 5b, 5f, and 5h
Compound
ED50a, mg kgꢀ1
LD50a, mg kgꢀ1
TD50a, mg kgꢀ1
TI
4.5
7.8
2.3
2.7
1.45
1.8
7.3
PI
1.4
1.5
1.5
4c
4d
4e
4f
4g
4h
5a
5b
38 ꢂ 4.0
32 ꢂ 3.7
80 ꢂ 2.5
74 ꢂ 2.9
120 ꢂ 4.4
110 ꢂ 3.1
48 ꢂ 3.9
62 ꢂ 4.4
135 ꢂ 3.5
30 ꢂ 3.8
155 ꢂ 2.56
170 ꢂ 2.4
250 ꢂ 3.0
180 ꢂ 3.3
200 ꢂ 3.5
175 ꢂ 3.9
200 ꢂ 3.2
350 ꢂ 4.1
2200 ꢂ 4.4
400 ꢂ 3.3
1400 ꢂ 3.8
1325 ꢂ 2.9
52 ꢂ 2.5
48 ꢂ 2.8
120 ꢂ 3.5
86 ꢂ 4.0
1.2
150 ꢂ 2.5
140 ꢂ 3.1
230 ꢂ 2.6
1000 ꢂ 3.8
240 ꢂ 2.6
1100 ꢂ 3.75
520 ꢂ 2.6
1.25
1.27
4.8
35.4
16.1
5f
5h
3.0
46.6
8.5
1.8
36.6
3.4
Ethosuximide
a
P ¼ 0.05 at the probability level.
Table 3 Anticonvulsant activity of compounds 4c, 4d, 5a, 5b and 5h
on the model of thiosemicarbazide (TSC) seizures
was carried out in experiments on outbred white mice weighing
18–22 g using two models of seizures caused by pentilentetrazol
(PTZ, metrazol, corazol) and by maximal electroshock (MES).
The PTZ induced test is considered an experimental model for
the clonic component of epilepsy seizures and prognostic
anxiolytic activities of the compounds.35–42 The MES test is used
as an animal model for the generalized tonic seizures of
epilepsy.36,37,40–45
The side effects of the compounds, such as neurotoxicity
(movement coordination disorder, myorelaxation, ataxia), were
also studied with “rotating rod”36,46 and acute toxicity tests. The
rotating rod performance test is a performance test based on
a rotating rod with forced motor activity being applied, usually
by a rodent. The test measures parameters such as riding time
(seconds) or endurance. In the test, a mouse is placed on
a horizontally oriented, rotating cylinder (rod) suspended above
a cage oor, which is low enough not to injure the animal, but
high enough to induce avoidance of fall. Mice naturally try to
stay on the rotating cylinder, or rotating rod, and avoid falling to
the ground. The length of time that a given animal stays on this
rotating rod is a measure of their balance, coordination, phys-
ical condition, and motor-planning. The speed of the rotating
rod is mechanically driven, and may either be held constant, or
accelerated.47
Latency of convulsions
induced by TSC, min
Dose, mg
Compound
kgꢀ1
M ꢂ m
Ib
Control
4c
4d
5a
5b
5h
—
74.8 ꢂ 3.5a
95.6 ꢂ 5.3
1.00
1.28
1.32
1.44
1.37
1.60
1.004
100
100
100
100
100
200
98.5 ꢂ 8.6
107.4 ꢂ 11.5
102.5 ꢂ 10.9
120.0 ꢂ 13.6
75.1 ꢂ 6.2
Ethosuximide
a
P ¼ 0.05 at the probability level. b I – an increase in the threshold.
for ve compounds (4e–h and 5f). The Pa values of these
compounds were less than 0.5, indicating that these
compounds, if truly active, could be new chemical entities.
Thus, PASS application to pyridofuropyrrolo[1,2-a]pyrimi-
dines 4 and pyridofuropyrimido[1,2-a]azepines 5 was able to
identify prospective pharmacological properties that could be
tested and eventually conrmed by experimental studies.
2.3. Biological assay
To determine the 50% effective (ED50, causing the anticon-
vulsant effect in 50% of animals, is calculated by the test
antagonism of PTZ), 50% neurotoxic (TD50, causing the
The study of anticonvulsant activity of 16 new pyridofuropyrrolo
[1,2-a]pyrimidines 4 and pyridofuropyrimido[1,2-a]azepines 5
Table 4 Effect of compounds 4c, 4d, 5a, 5b and 5h in the research activity in rats in the “open field” testa
Amount (absolute data during 5 min)
Dose, mg
Compound
kgꢀ1
Horizontal displacement
Vertical displacement
Cells
Control
4c
4d
5a
5b
5h
—
25.8 ꢂ 0.8
14.8 ꢂ 0.7
11.8 ꢂ 0.5
11.0 ꢂ 0.3
20.5 ꢂ 0.6
17.3 ꢂ 0.5
26.8 ꢂ 3.3
7.0 ꢂ 1.9
2.0 ꢂ 0.6
2.5 ꢂ 0.8
1.2 ꢂ 0.4
3.6 ꢂ 0.7
3.3 ꢂ 0.8
5.6 ꢂ 1.5
1.5 ꢂ 0.4
1.4 ꢂ 0.3
0.8 ꢂ 0.2
0.9 ꢂ 0.3
1.6 ꢂ 0.4
0.8 ꢂ 0.1
1.6 ꢂ 0.5
50
50
50
50
50
200
Ethosuximide
a
P ¼ 0.05 at a probability level.
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Table 5 Effect of compounds 4c, 4d, 5a, 5b and 5h on the state of “fear and despair” of mice in the EPM model (observation time 5 min)a
Time spent in
closed arms/s
Number of entries
into the closed arms
Time spent in the
center/s
Compound
Dose/mg kgꢀ1
Control
4c
4d
5a
5b
5h
—
278.2 ꢂ 15.8
254.4 ꢂ 11.2
257.8 ꢂ 14.7
242.6 ꢂ 8.6
246.0 ꢂ 10.2
267.8 ꢂ 12.4
245.2 ꢂ 32.3
3.0 ꢂ 0.2
3.2 ꢂ 0.3
3.8 ꢂ 0.5
1.2 ꢂ 0.1
4.4 ꢂ 0.6
4.0 ꢂ 0.5
3.0 ꢂ 0.8
21.8 ꢂ 2.5
45.6 ꢂ 1.1
42.2 ꢂ 8.9
57.4 ꢂ 3.7
54.8 ꢂ 4.6
32.3 ꢂ 2.7
25.4 ꢂ 7.4
100
100
100
100
100
200
Ethosuximide
a
P ¼ 0.05 at a probability level.
myorelaxed effect in 50% of animals, is calculated by the 7.0 and the number of sniffing cells was 1.5. Table 4 shows that
“rotating rod” test) and 50% lethal (LD50, causing death in 50% the tested compounds 4c, 4d, 5a, 5b and 5h at a 50 mg kgꢀ1 dose
of animals) doses, a statistical method of probability analysis by reduce the number of such movements, indicating a sedative
Litcheld and Wilcoxon36,48 was used. From a practical point of effect unlike ethosuximide, which does not exhibit this effect.
view, the therapeutic (TI ¼ LD50/ED50) and protective (PI ¼ The number of sniffing cells is almost unchanged, and this is
TD50/ED50) indexes were identied for the active compounds. apparently due to the lack of the anxiolytic effect.
Ethosuximide was used as a control.49
In order to assess fear, the methodology of the elevated plus
The evaluation of the anticonvulsant activity of all the syn- maze (EPM) developed by S. Pellow et al. (1986)53 was used. The
thesised compounds revealed that they, to different degrees, elevated plus maze test is one of the most widely used tests for
exhibit pentilentetrazol antagonism. The anticonvulsant effects measuring anxiety-like behaviour.54 The test is based on the
of the most active compounds (derivatives of pyrrolo[1,2-a] natural aversion of mice to open and elevated areas, as well as
pyrimidines 4c–h and derivatives of pyrimido[1,2-a]azepines 5a, on their natural spontaneous exploratory behaviour in novel
5b, 5f, and 5h) are presented in Table 2. The remaining environments due to unsuitability of their locomotor system to
compounds 4a, 4b, 5c–e, and 5g revealed weaker action in the jump. The apparatus consists of open arms and closed arms,
studied doses (up to 40%).
crossed in the middle perpendicularly to each other, and
The derivatives of pyrimido[1,2-a]azepines containing a butyl a centre area. Mice are given access to all of the arms and are
group, especially (5b and 5h), caused myorelaxation in higher allowed to move freely between them. The number of entries
doses and seem to be non-toxic. The ED50 values are higher than into the open arms and the time spent in the open arms are
that of reference drug compared to the derivatives of pyrrolo used as indices of open space-induced anxiety in mice.
[1,2-a]pyrimidines (4c–h). Moreover, these last compounds, in
Thus, administration of compounds 4c, 4d, 5a, 5b, and 5h
doses slightly higher than TD50, cause tremors and convulsions. compared with ethosuximide was accompanied by a complete
Furthermore, compounds 5b and 5h are less neurotoxic than lack of effect and mice stayed in the closed setting like the
the reference drug. Their therapeutic (TI) and protective (PI) control group, i.e., it is regarded as a manifestation of fear. In
indexes are much greater than those of the reference drug the control group (278.2 s), the animals were in a closed arm for
(Table 2). It should be mentioned that the compounds pre- almost most of the time of the observation. The number of
sented in Table 2 are more active than ethosuximide according entries into a closed arm is almost the same for both groups of
to the PTZ test, while in the test of maximal electroshock, not rats, the control and rats which received the compounds.
only the tested compounds but also the reference drug were not Interestingly, the time spent in the center is increased twofold
active.
for the tested compounds in contrast to ethosuximide used as
Next, the most active compounds with anticonvulsant a standard. The prolonged presence of animals in the center of
antagonism versus pentilentetrazol (4c, 4d, 5a, 5b and 5h) (Table the installation allows to consider some protective reaction,
3) were selected and studied on the model of thiosemicarbazide located on the border of “fear and despair” of the compounds
(TSC) seizures (affecting the exchange of GABA).36,50 It was studied (Table 5).
observed that these compounds at a 100 mg kgꢀ1 dose
increased the latency of convulsions induced by TSC to 1.5
times compared with the control. In this model, ethosuximide
(200 mg kgꢀ1) was not effective (Table 3).
3. Conclusions
Furthermore, these compounds were studied for their anxi-
olytic activity in some psychotropic models: such as “open eld”
and elevated plus maze (EPM). In the “open eld” test,51,52
which is a classic model for the evaluation of sedative, acti-
vating and anxiolytic properties, the number of the horizontal
displacement of the control group of rats was 25.8, vertical was
A method, working with good or very good mean yields, for the
synthesis of new classes of condensed heterocyclic systems,
pyridofuropyrrolo[1,2-a]pyrimidines 4 and pyridofuropyrimido
[1,2-a]azepines 5, has been developed. The anticonvulsant
activity combined with some psychotropic properties of the new
compounds was evaluated.
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The studied compounds exhibit protection against PTZ
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Ethyl [(5-cyano-3,3-dimethyl-8-ethyl-3,4-dihydro-1H-pyrano[3,4-
seizures, anti-thiosemicarbazide effects, as well as some
psychotropic effects.
c]pyridin-6-yl)oxy] acetate (2g). Yield 2.67 g (84%), mp 133–135
1
ꢁC. IR n/cmꢀ1: 2223 (C^N), 1752 (C]O). H NMR (300 MHz,
The biological assays evidenced that some of the studied
compounds showed a high anticonvulsant activity by antago-
nism with pentylenetetrazole. Thus, among the studied
compounds some derivatives of pyrimido[1,2-a]azepines 5 were
identied as highly active and with a toxicity lower than that of
ethosuximide. The anti-thiosemicarbazide effect was not
revealed by ethosuximide, in contrast to the selected
compounds 4c, 4d, 5a, 5b, 5h which increased the latency
period of TSC seizures by 1.5 fold. These ndings suggest some
GABA-ergic mechanism of action of the tested compounds.
According to the results of the psychotropic activity test, it is
obvious that the selected compounds have a sedative effect on
the model of “open eld” and a defense mechanism against the
fear in the EPM model, in contrast to ethosuximide. Thus, the
studied pyrimidine and azepine derivatives appear as prom-
ising New Chemical Entities (NCE) in the eld and could be lead
compounds for the development of new anticonvulsant agents
with psychotropic properties.
DMSO/CCl4, 1/3) d 1.21 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.26 (s, 6H,
C(CH3)2), 1.30 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 2.58 (q, J ¼ 7.4 Hz,
2H, CH2CH3), 2.78 (s, 2H, CH2), 4.18 (q, J ¼ 7.1 Hz, 2H,
OCH2CH3), 4.61 (s, 2H, OCH2), 4.92 (s, 2H, OCH2CO). Anal.
calcd for C17H22N2O4: C 64.14; H 6.96; N 8.80%. Found: C 64.03;
H 6.97; N 8.81%.
Ethyl [(8-butyl-5-cyano-3,3-dimethyl-3,4-dihydro-1H-pyrano[3,4-
c]pyridin-6-yl)oxy] acetate (2h). Yield 2.49 g (72%), mp 93–95 ꢁC.
IR n/cmꢀ1: 2222 (C^N), 1675 (C]O). 1H NMR (300 MHz,
DMSO/CCl4, 1/3) d 0.93 (t, J ¼ 7.3 Hz, 3H, CH2CH3), 1.27 (s, 6H,
C(CH3)2), 1.27 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.30–1.41 (m, 2H,
CH2CH3), 1.57–1.68 (m, 2H, CH2C2H5), 2.50–2.55 (m, 2H,
CH2C3H7), 2.78 (s, 2H, CH2), 4.17 (q, J ¼ 7.1 Hz, 2H, OCH2CH3),
4.62 (s, 2H, OCH2), 4.91 (s, 2H, OCH2CO). Anal. calcd for
C
19H26N2O4: C 65.88; H 7.56; N 8.09%. Found: C 65.78; H 7.54; N
8.11%.
4.1.2. General procedure for the synthesis of compounds
3b3g, and 3h. To a solution of sodium ethoxide [253 mg (11
mmol) in absolute ethanol (300 mL)], compound 2 (10 mmol)
was added. The mixture was reuxed for 15–20 min, cooled, and
poured onto ice. The formed crystals were ltered off, washed
with water, dried, and recrystallized from ethanol.
4. Experimental section
4.1. Chemistry
Ethyl 1-amino-5-butyl-7,8-dihydro-6H-cyclopenta[d]furo[2,3-b]
pyridine-2-carboxylate (3b). Yield 2.27 g (75%), mp 98–100 ꢁC.
1H NMR spectra were recorded in DMSO/CCl4 1/3 solution on
a Varian Mercury 300 V ꢃ 300 MHz spectrometer. Chemical
shis are reported as d (ppm) relative to TMS as the internal
standard. IR spectra were recorded on a Nicolet Avatar 330-FT-
IR spectrophotometer and the reported wavenumbers are
given in cmꢀ1. Mass spectra (MS) were recorded on an MX-
1321A spectrometer with direct entry of matter into the ion
source at an ionization energy 60 eV, m/z (Irel,%). All melting
points were determined in an open capillary and are uncor-
rected. Elemental analyses were performed on a EuroEA3000
Elemental Analyzer. All compounds showed $95% purity.
Compounds 2, 3a,15 2, 3c, 3d, 3i,16 2, 3e,22 2, and 3f (ref. 23)
have already been described.
4.1.1. General procedure for the synthesis of compounds
2b, 2g, and 2h. To a suspension of compound 1 (10 mmol) and
potassium carbonate (1520 mg, 11 mmol) in absolute DMF
(15 mL), ethyl chloroacetate (1350 mg, 11 mmol) was added
dropwise under stirring. The reaction mixture was maintained
at 75–80 ꢁC for 2 h, then cooled to room temperature and
poured into cold water. The resulting crystals were ltered off,
washed with water, dried, and re-crystallized from ethanol.
Ethyl [(1-butyl-4-cyano-6,7-dihydro-5H-cyclopenta[c]pyridin-3-
yl)oxy]acetate (2b). Yield 2.15 g (71%), mp 56–58 ꢁC. IR n/
cmꢀ1: 2218 (C^N), 1745 (C]O). 1H NMR (300 MHz, DMSO/
CCl4, 1/3) d 0.93 (t, J ¼ 7.3 Hz, 3H, CH2CH3), 1.28 (t, J ¼ 7.1 Hz,
3H, OCH2CH3), 1.27–1.39 (m, 2H, CH2CH3), 1.56–1.67 (m, 2H,
CH2C2H5), 2.13–2.24 (m, 2H, 6-CH2), 2.60 (t, J ¼ 7.4 Hz, 2H,
CH2C3H7), 2.86 (t, J ¼ 7.5 Hz, 2H, 7-CH2), 3.06 (t, J ¼ 7.6 Hz, 2H,
5-CH2), 4.17 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 4.89 (s, 2H,
OCH2CO). Anal. calcd for C17H22N2O3: C 67.53; H 7.33; N 9.26%.
Found: C 67.45; H 7.32; N 9.27%.
1
IR n/cmꢀ1: 3550, 3330 (NH2), 1674 (C]O). H NMR (300 MHz,
DMSO/CCl4, 1/3) d 0.95 (t, J ¼ 7.3 Hz, 3H, CH2CH3), 1.32–1.45
(m, 2H, CH2CH3), 1.40 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 1.63–1.75
(m, 2H, CH2C2H5), 2.15–2.27 (m, 2H, 7-CH2), 2.68–2.74 (m, 2H,
CH2C3H7), 2.89 (t, J ¼ 7.5 Hz, 2H, 6-CH2), 3.27 (t, J ¼ 7.6 Hz, 2H,
8-CH2), 4.32 (q, J ¼ 7.1 Hz, 2H, OCH2CH3), 5.70 (br s, 2H, NH2).
Anal. calcd for C17H22N2O3: C 67.53; H 7.33; N 9.26%. Found: C
67.64; H 7.32; N 9.29%.
Ethyl 1-amino-8,8-dimethyl-5-ethyl-8,9-dihydro-6H-furo[2,3-b]
pyrano[4,3-d]pyridine-2-carboxylate (3g). Yield 2.71 g (85%), mp
165–166 ꢁC. IR n/cmꢀ1: 3456, 3330 (NH2), 1665 (C]O). 1H NMR
(300 MHz, DMSO/CCl4, 1/3) d 1.29 (t, J ¼ 7.4 Hz, 3H, CH2CH3),
1.30 (s, 6H, C(CH3)2), 1.41 (t, J ¼ 7.1 Hz, 3H, OCH2CH3), 2.65 (q,
J ¼ 7.4 Hz, 2H, CH2CH3), 3.11 (s, 2H, CH2), 4.33 (q, J ¼ 7.1 Hz,
2H, OCH2CH3), 4.71 (s, 2H, OCH2), 5.74 (br s, 2H, NH2). Anal.
calcd for C17H22N2O4: C 64.14; H 6.96; N 8.80%. Found: C 64.04;
H 6.94; N 8.83%.
Ethyl 1-amino-8,8-dimethyl-5-butyl-8,9-dihydro-6H-furo[2,3-b]
pyrano[4,3-d]pyridine-2-carboxylate (3h). Yield 2.42 g (70%), mp
159–161 ꢁC. IR n/cmꢀ1: 3451, 3332 (NH2), 1664 (C]O). 1H NMR
(300 MHz, DMSO/CCl4, 1/3) d 0.97 (t, J ¼ 7.3 Hz, 3H, CH2CH3),
1.29 (s, 6H, C(CH3)2), 1.35–1.48 (m, 2H, CH2CH3), 1.40 (t, J ¼ 7.1
Hz, 3H, OCH2CH3), 1.65–1.76 (m, 2H, CH2C2H5), 2.61 (t, J ¼ 7.5
Hz, 2H, CH2C3H7), 3.11 (s, 2H, CH2), 4.33 (q, J ¼ 7.1 Hz, 2H,
OCH2CH3), 4.71 (s, 2H, OCH2), 5.75 (br s, 2H, NH2). Anal. calcd
for C19H26N2O4: C 65.88; H 7.56; N 8.09%. Found: C 65.80; H
7.54; N 8.06%.
4.1.3. General procedure for the synthesis of compounds
4a–h.
A mixture of furo[2,3-b]pyridine 3 (10 mmol), 2-
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pyrrolidinone (1700 mg, 20 mmol) and phosphorus oxychloride 2.41 (m, 2H, 11-CH2), 2.48 (s, 3H, CH3), 3.19 (s, 2H, CH2), 3.20 (t,
(1.86 mL, 20 mmol) in absolute 1,2-dichloroethane (50 mL) was J ¼ 7.9 Hz, 2H, 12-CH2), 4.20 (t, J ¼ 7.3 Hz, 2H, 10-CH2), 4.74 (s,
reuxed for 25 h. The solvent was distilled off to dryness and 2H, OCH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 19.6, 20.8,
water (50 mL) was added to the residue. The separated crystals 25.8, 31.7, 36.3, 46.5, 60.0, 68.6, 110.1, 123.7, 135.1, 139.6, 143.0,
were ltered off, washed with water, dried, and recrystallized 150.7, 153.5, 160.3, 160.7. Anal. calcd for C18H19N3O3: C 66.45;
from ethanol.
H 5.89; N 12.91%. Found: C 66.55; H 5.90; N 12.93%.
2,2-Dimethyl-5-ethyl-1,4,11,12-tetrahydro-2H-pyrano[400,300:40,50]
4-Isopropyl-2,3,10,11-tetrahydro-1H-cyclopenta[40,50]pyrido
[30,20:4,5]furo[3,2-d]pyrrolo[1,2-a]pyrimidin-7(9H)-one (4a). Yield pyrido[30,20:4,5]furo[3,2-d]pyrrolo[1,2-a]pyrimidin-8(10H)-one (4f).
2.01 g (65%), mp 209–211 ꢁC. IR n/cmꢀ1: 1671 (C]O). 1H NMR Yield 2.21 g (65%), mp 219–221 ꢁC. IR n/cmꢀ1: 1690 (C]O). 1H
(300 MHz, DMSO/CCl4, 1/3) d 1.31 (d, J ¼ 6.6 Hz, 6H, CH(CH3)2), NMR (300 MHz, DMSO/CCl4, 1/3) d 1.33 (s, 6H, C(CH3)2), 1.35 (t,
2.20–2.41 (m, 4H, 2-CH2, 10-CH2), 3.02 (t, J ¼ 7.4 Hz, 2H, 3-CH2), J ¼ 7.3 Hz, 3H, CH2CH3), 2.30–2.41 (m, 2H, 11-CH2), 2.74 (t, J ¼
3.19 (t, J ¼ 7.8 Hz, 2H, 11-CH2), 3.20 (sp, J ¼ 6.7 Hz, 1H, 7.3 Hz, 2H, CH2CH3), 3.20 (t, J ¼ 7.9 Hz, 2H, 12-CH2), 3.22 (s, 2H,
CH(CH3)2), 3.35 (t, J ¼ 7.6 Hz, 2H, 1-CH2), 4.18–4.24 (m, 2H, 9- CH2), 4.18–4.24 (t, J ¼ 7.3 Hz, 2H, 10-CH2), 4.79 (s, 2H, OCH2).
CH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 19.6, 21.0, 24.5, 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 11.3, 19.6, 25.8, 26.4, 31.7,
29.1, 31.1, 31.6, 32.8, 46.5, 109.2, 133.2, 135.5, 142.6, 149.6, 36.4, 46.5, 59.7, 68.5, 109.9, 123.1, 135.2, 139.7, 143.0, 150.7,
150.8, 160.7, 161.4, 161.8. Anal. calcd for C18H19N3O2: C 69.88; 157.9, 160.6, 160.7. Anal. calcd for C19H21N3O3: C 67.24; H 6.24;
H 6.19; N 13.58%. Found: C 69.95; H 6.20; N 13.56%.
N 12.38%. Found: C 67.13; H 6.25; N 12.41%.
4-Butyl-2,3,10,11-tetrahydro-1H-cyclopenta[40,50]pyrido[30,20:4,5]
5-Butyl-2,2-dimethyl-1,4,11,12-tetrahydro-2H-pyrano[400,300:40,50]
furo[3,2-d]pyrrolo[1,2-a]pyrimidin-7(9H)-one (4b). Yield 2.30 g pyrido[30,20:4,5]furo[3,2-d]pyrrolo[1,2-a]pyrimidin-8(10H)-one (4g).
1
(71%), mp 184–186 ꢁC. IR n/cmꢀ1: 1685 (C]O). H NMR (300 Yield 2.57 g (70%), mp 188–190 ꢁC. IR n/cmꢀ1: 1690 (C]O). 1H
MHz, DMSO/CCl4, 1/3) d 0.98 (t, J ¼ 7.3 Hz, 3H, CH2CH3), 1.37– NMR (300 MHz, DMSO/CCl4, 1/3) d 0.99 (t, J ¼ 7.3 Hz, 3H,
1.50 (m, 2H, CH2CH3), 1.70–1.80 (m, 2H, CH2C2H5), 2.23–2.41 CH2CH3), 1.33 (s, 6H, C(CH3)2), 1.39–1.52 (m, 2H, CH2CH3),
(m, 4H, 2-CH2, 10-CH2), 2.80 (t, J ¼ 7.5 Hz, 2H, CH2C3H7), 2.99 (t, 1.71–1.82 (m, 2H, CH2C2H5), 2.30–2.41 (m, 2H, 11-CH2), 2.66–
J ¼ 7.4 Hz, 2H, 3-CH2), 3.19 (t, J ¼ 7.9 Hz, 2H, 11-CH2), 3.34 (t, J ¼ 2.73 (m, 2H, CH2C3H7), 3.20 (t, J ¼ 7.9 Hz, 2H, 12-CH2), 3.22 (s,
7.6 Hz, 2H, 1-CH2), 4.18–4.24 (m, 2H, 9-CH2). 13C NMR (75 MHz, 2H, CH2), 4.18–4.25 (t, J ¼ 7.3 Hz, 2H, 10-CH2), 4.80 (s, 2H,
DMSO/CCl4, 1/3) d: 13.5, 19.6, 21.9, 24.4, 29.3, 29.8, 31.1, 31.6, OCH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 13.5, 19.6, 21.9,
34.9, 46.5, 109.1, 134.1, 135.4, 142.5, 149.3, 150.8, 156.9, 160.6, 25.8, 29.4, 31.7, 33.0, 36.5, 46.5, 59.8, 68.6, 110.1, 123.3, 135.2,
161.6. MS, m/z (Irel,%), [M+] 323 (4), 280 (100), 267 (1), 251 (9). 139.9, 143.1, 150.7, 157.3, 160.6, 160.7. Anal. calcd for
Anal. calcd for C19H21N3O2: C 70.57; H 6.55; N 12.99%. Found: C C21H25N3O3: C 68.64; H 6.86; N 11.44%. Found: C 68.53; H 6.88;
70.50; H 6.53; N 13.03%.
N 11.46%.
5-Isopropyl-1,2,3,4,11,12-hexahydropyrrolo[100,200:10,20]pyr-
2,2-Dimethyl-5-(2-furyl)-1,4,11,12-tetrahydro-2H-pyrano[400,300:40,50]
imido[40,50:4,5]furo[2,3-c]-isoquinolin-8(10H)-one (4c). Yield 2.23 pyrido[30,20:4,5]furo[3,2-d]pyrrolo[1,ꢁ2-a]pyrimidin-8(10H)-one
(4h).
g (69%), mp 236–238 ꢁC. IR n/cmꢀ1: 1690 (C]O). 1H NMR (300 Yield 2.75 g (73%), mp 343–345 C. IR n/cmꢀ1: 1687 (C]O). H
MHz, DMSO/CCl4, 1/3) d 1.28 (d, J ¼ 6.6 Hz, 6H, CH(CH3)2), NMR (300 MHz, DMSO/CCl4, 1/3) d 1.37 (s, 6H, C(CH3)2), 2.28–2.39
1.83–1.98 (m, 4H, 2,3-CH2), 2.29–2.40 (m, 2H, 11-CH2), 2.82– (m, 2H, 11-CH2), 3.21 (t, J ¼ 7.9 Hz, 2H, 12-CH2), 3.30 (s, 2H, CH2),
2.88 (m, 2H, 4-CH2), 3.18 (t, J ¼ 7.9 Hz, 2H, 12-CH2), 3.30–3.38 4.17–4.23 (t, J ¼ 7.3 Hz, 2H, 10-CH2), 5.14 (s, 2H, OCH2), 6.67 (dd,
(m, 3H, 1-CH2, CH(CH3)2), 4.17–4.23 (m, 2H, 10-CH2). 13C NMR J ¼ 3.5, 1.7 Hz, 1H, 4-CH, furyl), 7.22 (dd, J ¼ 3.5, 0.7 Hz, 1H, 3-CH,
(75 MHz, DMSO/CCl4, 1/3) d: 19.5, 20.8, 21.3, 22.4, 24.7, 26.5, furyl), 7.83 (dd, J ¼ 1.7, 0.7 Hz, 1H, 5-CH, furyl). 13C NMR (75 MHz,
30.4, 31.7, 46.4, 109.9, 125.1, 135.1, 143.5, 143.9, 150.8, 160.2, DMSO/CCl4, 1/3) d: 21.7, 25.8, 31.6, 36.5, 46.5, 60.0, 68.7, 107.8,
160.3, 164.9. Anal. calcd for C19H21N3O2: C 70.57; H 6.54; N 109.7, 110.1, 123.8, 135.0, 139.8, 140.9, 144.2, 152.7, 153.5, 155.7,
1
12.99%. Found: C 70.69; H 6.55; N 12.95%.
160.7, 161.9. Anal. calcd for C21H19N3O4: C 66.83; H 5.07; N 11.13%.
5-Isobutyl-1,2,3,4,11,12-hexahydropyrrolo[100,200:10,20]pyrimido Found: C 66.71; H 5.08; N 11.11%.
[40,50:4,5]furo[2,3-c]isoquinolin-8(10H)-one (4d). Yield 2.29
g
4.1.4. General procedure for the synthesis of compounds
(68%), mp 191–193 C. IR n/cmꢀ1: 1703 (C]O). H NMR (300 5a–h. A mixture of furo[2,3-b]pyridine 3 (10 mmol), 2-azepanone
MHz, DMSO/CCl4, 1/3) d 1.00 (d, J ¼ 6.6 Hz, 6H, CH(CH3)2), (2260 mg, 20 mmol) and phosphorus oxychloride (1.86 mL, 20
1.83–1.97 (m, 4H, 2,3-CH2), 2.21–2.40 (m, 3H, CH(CH3)2, 11- mmol) in absolute 1,2-dichloroethane (50 mL) was reuxed for
CH2), 2.68 (d, J ¼ 7.0 Hz, 2H, CHCH2), 2.76–2.82 (m, 2H, 4-CH2), 20 h. The solvent was distilled off to dryness and water (50 mL)
3.18 (t, J ¼ 7.9 Hz, 2H, 12-CH2), 3.31–3.37 (m, 2H, 1-CH2), 4.17– was added. The separated crystals were ltered off, washed with
4.23 (m, 2H, 10-CH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: water, dried, and recrystallized from ethanol.
1
ꢁ
19.6, 20.8, 22.2, 22.3, 25.2, 26.4, 27.1, 31.7, 42.9, 46.4, 109.9,
126.4, 135.0, 143.4, 143.6, 150.8, 159.7, 159.9, 160.3. Anal. calcd pyrido[300,200:40,50]furo[30,20:4,5]-pyrimido[1,2-a]azepin-7(9H)-one
for C20H23N3O2: C 71.19; H 6.87; N 12.45%. Found: C 71.08; H (5a). Yield 2.43 g (72%), mp 163–165 ꢁC. IR n/cmꢀ1: 1702 (C]O).
4-Isopropyl-2,3,10,11,12,13-hexahydro-1H-cyclopenta[400,500]
6.85; N 12.42%.
1H NMR (300 MHz, DMSO/CCl4, 1/3) d 1.31 (d, J ¼ 6.7 Hz, 6H,
2,2,5-Trimethyl-1,4,11,12-tetrahydro-2H-pyrano[400,300:40,50]pyr- CH(CH3)2), 1.76–1.93 (m, 6H, 10,11,12-CH2), 2.23–2.34 (m, 2H,
ido[30,20:4,5]furo[3,2-d]pyrrolo[1,2-a]pyrimidin-8(10H)-one (4e). 2-CH2), 3.02 (t, J ¼ 7.4 Hz, 2H, 3-CH2), 3.12–3.17 (m, 2H, 13-
Yield 2.28 g (70%), mp 251–253 ꢁC. IR n/cmꢀ1: 1700 (C]O). 1H CH2), 3.19 (sp, J ¼ 6.7 Hz, 1H, CH(CH3)2), 3.36 (t, J ¼ 7.6 Hz, 2H,
NMR (300 MHz, DMSO/CCl4, 1/3) d 1.33 (s, 6H, C(CH3)2), 2.30– 1-CH2), 4.41–4.46 (m, 2H, 9-CH2). 13C NMR (75 MHz, DMSO/
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CCl4, 1/3) d: 20.9, 24.5, 27.1, 28.7, 29.0, 31.1, 32.8, 36.6, 41.9, 3.22 (s, 2H, CH2), 4.41–4.46 (m, 2H, 10-CH2), 4.75 (c, 2H, OCH2). 13
C
109.2, 133.1, 135.1, 140.4, 149.7, 151.8, 160.9, 161.5, 161.8. Anal. NMR (75 MHz, DMSO/CCl4, 1/3) d: 20.8, 24.5, 25.8, 27.0, 28.7, 36.3,
calcd for C20H23N3O2: C 71.19; H 6.87; N 12.45%. Found: C 36.6, 41.9, 60.0, 68.6, 110.2, 123.7, 134.7, 139.7, 140.8, 151.7, 153.6,
71.10; H 6.85; N 12.48%.
160.4, 161.0. Anal. calcd for C20H23N3O3: C 67.97; H 6.56; N 11.89%.
4-Butyl-2,3,10,11,12,13-hexahydro-1H-cyclopenta[400,500]pyrido Found: C 68.05; H 6.57; N 11.91%.
[300,200:40,50]furo[30,20:4,5]-pyrimido[1,2-a]azepin-7(9H)-one (5b).
2,2-Dimethyl-5-ethyl-1,4,11,12,13,14-hexahydro-2H-pyrano
Yield 2.46 g (70%), mp 172–174 ꢁC. IR n/cmꢀ1: 1689 (C]O). 1H [4000,3000:400,500]pyrido[300,200:40,50]furo[30,20:4,5]pyrimido[1,2-a]aze-
NMR (300 MHz, DMSO/CCl4, 1/3) d 0.98 (t, J ¼ 7.3 Hz, 3H, pin-8(10H)-one (5g). Yield 2.76 g (75%), mp 224–226 ꢁC. IR n/
CH2CH3), 1.36–1.49 (m, 2H, CH2CH3), 1.69–1.93 (m, 8H, cmꢀ1: 1694 (C]O). 1H NMR (300 MHz, DMSO/CCl4, 1/3) d 1.34
CH2C2H5, 10,11,12-CH2), 2.23–2.33 (m, 2H, 2-CH2), 2.80 (t, J ¼ (s, 6H, C(CH3)2), 1.35 (t, J ¼ 7.4 Hz, 3H, CH2CH3), 1.76–1.94 (m,
7.6 Hz, 2H, CH2C3H7), 2.99 (t, J ¼ 7.4 Hz, 2H, 3-CH2), 3.11–3.16 6H, 11,12,13-CH2), 2.74 (q, J ¼ 7.4 Hz, 2H, CH2CH3), 3.14–3.20
(m, 2H, 13-CH2), 3.34 (t, J ¼ 7.6 Hz, 2H, 1-CH2), 4.40–4.45 (m, (m, 2H, 14-CH2), 3.23 (s, 2H, CH2), 4.41–4.47 (m, 2H, 10-CH2),
2H, 9-CH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 13.5, 21.9, 4.80 (s, 2H, OCH2). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 11.3,
24.4, 24.5, 27.1, 28.7, 29.2, 29.7, 31.1, 34.9, 36.6, 41.9, 109.2, 24.5, 25.8, 26.4, 27.1, 28.7, 36.4, 36.6, 41.9, 59.7, 68.6, 110.1,
134.1, 134.9, 140.4, 149.4, 151.8, 156.9, 160.9, 161.6. Anal. calcd 123.1, 134.8, 139.8, 140.9, 151.7, 158.0, 160.7, 161.0. Anal. calcd
for C21H25N3O2: C 71.77; H 7.17; N 11.96%. Found: C 71.90; H for C21H25N3O3: C 68.64; H 6.86; N 11.44%. Found: C 68.55; H
7.14; N 12.00%.
4-Phenyl-2,3,10,11,12,13-hexahydro-1H-cyclopenta[400,500]pyr-
6.85; N 11.47%.
5-Butyl-2,2-dimethyl-1,4,11,12,13,14-hexahydro-2H-pyrano
ido[300,200:40,50]furo-[30,20:4,5]pyrimido[1,2-a]azepin-7(9H)-one (5c). [4000,3000:400,500]pyrido-[300,200:40,50]furo[30,20:4,5]pyrimido[1,2-a]aze-
Yield 2.53 g (68%), mp 309 ꢁC. IR n/cmꢀ1: 1685 (C]O). 1H NMR pin-8(10H)-one (5h). Yield 2.69 g (68%), mp 150–152 ꢁC. IR
(300 MHz, DMSO/CCl4, 1/3) d 1.78–1.95 (m, 6H, CH2, 10,11,12- n/cmꢀ1: 1701 (C]O). 1H NMR (300 MHz, DMSO/CCl4, 1/3) d 0.99
CH2), 2.23–2.35 (m, 2H, 2-CH2), 3.13–3.20 (m, 2H, 13-CH2), 3.24 (t, J ¼ 7.3 Hz, 3H, CH2CH3), 1.33 (s, 6H, C(CH3)2), 1.38–1.51 (m,
(t, J ¼ 7.3 Hz, 2H, 3-CH2), 3.43 (t, J ¼ 7.5 Hz, 2H, 1-CH2), 4.41– 2H, CH2CH3), 1.71–1.94 (m, 8H, CH2C2H5, 11,12,13-CH2), 2.69
4.49 (m, 2H, NCH2), 7.38–7.51 and 7.83–7.88 (both m, 3H and (t, J ¼ 7.6 Hz, 2H, CH2C3H7), 3.13–3.20 (m, 2H, 14-CH2), 3.23 (s,
2H, Ph). 13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 24.4, 25.7, 26.9, 2H, CH2), 4.40–4.47 (m, 2H, 10-CH2), 4.80 (s, 2H, OCH2). 13C
28.6, 31.2, 31.8, 36.6, 42.1, 110.2, 127.9, 128.4, 128.5, 134.2, NMR (75 MHz, DMSO/CCl4, 1/3) d: 13.5, 21.9, 24.5, 25.8, 27.1,
135.9, 138.6, 140.3, 151.8, 152.0, 152.3, 161.5, 161.8. Anal. calcd 28.7, 29.4, 32.9, 36.5, 36.6, 41.9, 59.8, 68.6, 110.2, 123.3, 134.8,
for C23H21N3O2: C 74.37; H 5.70; N 11.31%. Found: C 74.47; H 139.9, 140.9, 151.8, 157.3, 160.7, 161.0. MS, m/z (Irel,%), [M+] 395
5.68; N 11.34%.
(28), 353 (100), 325 (14), 283 (10). Anal. calcd for C23H29N3O3: C
5-Isopropyl-1,2,3,4,11,12,13,14-octahydroazepino[100,200:10,20] 69.85; H 7.39; N 10.62%. Found: C 69.77; H 7.41; N 10.65%.
pyrimido[40,50:4,5]furo[2,3-c]isoquinolin-8(10H)-one (5d). Yield
2.57 g (73%), mp 183–185 ꢁC. IR n/cmꢀ1: 1702 (C]O). 1H NMR
4.2. PASS
(300 MHz, DMSO/CCl4, 1/3) d 1.28 (d, J ¼ 6.7 Hz, 6H, CH(CH3)2),
Prediction of biological activity spectra for the designed in silico
1.75–1.98 (m, 10H, 2,3-CH2 and 11,12,13-CH2), 2.82–2.88 (m,
compounds was performed by PASS version 2014.
2H, 4-CH2), 3.11–3.16 (m, 2H, 14-CH2), 3.33 (sp, J ¼ 6.7 Hz, 1H,
This version of PASS predicts simultaneously about 7000
CH(CH3)2), 3.32–3.38 (m, 2H, 1-CH2), 4.40–4.45 (m, 2H, 10-CH2).
types of biological activities with a mean accuracy of ꢄ95%
based on analysis of structure–activity relationships for the
training set, including information about 1 000 000 substances.
The PASS approach is described in more detail elsewhere.25,26
Recent news about PASS improvement and extension, as well as
several examples of PASS applications, may be found on the
PASS web-site.25
13C NMR (75 MHz, DMSO/CCl4, 1/3) d: 20.7, 21.3, 22.4, 24.5,
24.7, 26.5, 27.1, 28.7, 30.4, 36.7, 41.8, 109.9, 124.9, 134.6, 141.3,
144.0, 151.7, 160.3, 160.6, 164.9. Anal. calcd for C21H25N3O2: C
71.77; H 7.17; N 11.96%. Found: C 71.90; H 7.15; N 12.00%.
5-Isobutyl-1,2,3,4,11,12,13,14-octahydroazepino[100,200:10,20]pyr-
imido[40,50:4,5]furo[2,3-c]isoquinolin-8(10H)-one (5e). Yield 2.70 g
1
(74%), mp 192–194 C. IR n/cmꢀ1: 1705 (C]O). H NMR (300
ꢁ
MHz, DMSO/CCl4, 1/3) d 0.99 (d, J ¼ 6.6 Hz, 6H, CH(CH3)2),
4.3. Biological evaluation
1.75–1.97 (m, 10H, 2,3-CH2 and 11,12,13-CH2), 2.21–2.34 (m,
1H, CH(CH3)2), 2.68 (d, J ¼ 7.0 Hz, 2H, CHCH2), 2.76–2.82 (m, Biological investigations of all compounds described in the
2H, 4-CH2), 3.11–3.17 (m, 2H, 14-CH2), 3.32–3.38 (m, 2H, 1- paper were carried out using outbred white rats (Vistar line)
CH2), 4.40–4.45 (m, 2H, 10-CH2). 13C NMR (75 MHz, DMSO/ weighing 120 ꢂ 150 g and mice (Albino line) weighing 18 ꢂ 22 g
CCl4, 1/3) d: 20.8, 22.2, 22.4, 24.5, 25.2, 26.3, 27.1, 28.7, 36.7, of both sexes. All groups of animals were maintained at 25 ꢂ 2
41.8, 42.9, 109.9, 126.4, 134.6, 141.3, 143.8, 151.8, 159.8, 159.9, ꢁC in the same room, on a common food ration. All the exper-
160.6. Anal. calcd for C22H27N3O2: C 72.30; H 7.45; N 11.50%. imental protocols were approved by the Committee of Ethics of
Found: C 72.41; H 7.44; N 11.52%.
the Yerevan State Medical University (YSMU) (Yerevan, Arme-
2,2,5-Trimethyl-1,4,11,12,13,14-hexahydro-2H-pyrano[4000,3000:400,500] nia), followed the “Principles of laboratory animal care” and
pyrido[300,200:40,50]furo[30,20:4,5]pyrimido[1,2-a]azepin-8(10H)-one (5f). carried out in accordance with the European Communities
Yield 2.54 g (72%), mp 211–213 C. IR n/cmꢀ1: 1688 (C]O). H Council Directive of 24 November 1986 (86/609/EEC).55
1
ꢁ
NMR (300 MHz, DMSO/CCl4, 1/3) d 1.34 (s, 6H, C(CH3)2), 1.76–1.94
4.3.1. Evaluation of the anticonvulsant activity of the
(m, 6H, 11,12,13-CH2), 2.49 (s, 3H, CH3), 3.14–3.20 (m, 2H, 14-CH2), synthesized compounds. Pentylenetetrazole (PTZ) is a common
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convulsant agent used in animal models to investigate the the whole maze, as the fear of falling appeared. Normal animals
mechanisms of seizures.35–42 PTZ was injected subcutaneously prefer to spend most of their time in the closed (dark) arms of
at 90 mg kgꢀ1, which induced convulsions in 95% of animals the maze. The anxiolytic effect of the drug is estimated by the
(CD95%). Each animal was placed into an individual plastic cage increase of the number of entries into the open arm and the
for observation lasting 1 hour. Seizure and clonic convulsions time spent in them, without increasing the overall motor
were recorded. Substances were administered intraperitoneally activity. Studies were conducted on mice. The animal was
(i.p.) at doses of 10, 25, 50, 75, 100, 150, 200 mg kgꢀ1 in placed in the center of the installation – at the intersection of
carboxymethylcellulose and Tween-80 suspension 45 min the arms. The xed time spent in the closed arms and the
before the administration of PTZ and applying electrical stim- number of attempts to enter the center of the installation were
ulation. To the control animals the emulsion was injected. Every measured. The tested compounds (100 mg kgꢀ1) and reference
dose of each test compound was studied in 6 animals. As drug ethosuximide (200 mg kgꢀ1) were administered intraper-
a reference compound, the known antiepileptic drug ethosux- itoneally before the experiments. Control animals received an
imide (zarontin) was used.49
emulsier. The results were processed statistically (P ¼ 0.05).
MES test was used as an animal model for the generalized
4.3.3. Evaluation of the incoordination of movements in
tonic seizures of epilepsy.43–45 The parameters of MES were: 50 the rotating rod test and acute toxicity. Muscle relaxant prop-
mA, duration of 0.2 s, and oscillation frequency of 50 imp per s. erties were studied using the “rotating rod” test.36,46,47 Mice were
The anticonvulsant properties of compounds were assessed by placed on a horizontal rod 4 cm in diameter rotating at a speed
the prevention of tonic-extensor phase of convulsions.
of 5 revolutions per minute. The failure of animals under the
Thiosemicarbazide, being an antimetabolite of the GABA inuence of a substance to keep their balance on the rod for 2
inhibitor (glutamic acid decarboxylase) in the brain,36,50 was minutes was regarded as a manifestation of the lack of coor-
administered subcutaneously to mice at a dose of 18 mg kgꢀ1 as dination of movement. The compounds were injected i.p in
a 0.5% solution causing clonic convulsions in animals. Antith- doses of 25–1800 mg kgꢀ1
.
iosemicarbazide activity was evaluated on latency time of the
The acute toxicity (LD50), was determined by calculating the
onset of seizures. Substances were administered intraperito- number of dead animals aer 24 h of exposure (i.p. injection) in
neally (i.p.) at doses of 100 mg kgꢀ1 in carboxymethylcellulose doses of 100–2200 mg kgꢀ1. Ethosuximide was used as
suspension with Tween-80 45 min before administration of a control.
thiosemicarbazide. The comparative drug zarontin was given in
200 mg kgꢀ1 doses.
It should be mentioned that all experiments were performed
in compliance with the relevant laws and institutional guide-
4.3.2. Evaluation of the anxiolytic effect of the synthesized lines, and also the institutional committee(s) on animal exper-
compounds
imentation have approved the experiments.
Open eld test. An open eld apparatus (a square with a side
of 58 cm and a height of 20 cm) was used, the bottom of which is
divided into squares and has holes (cells). Within 5 minutes of
the experiment, the number of spontaneous horizontal
displacements (the intersection of squares), those sniffing cells
and those standing on their hind legs (vertical movement) in
the experimental and control groups of animals was
determined.51,52
Experiments were carried out in the daytime (in natural
light). Registration of spontaneous behaviour of each individual
animal was carried out for 5 min. The presence of sedating and
activating effects was judged by the number of horizontal (the
intersection of squares) and vertical (rising on their hind legs)
movements, while the anxiolytic effect was evaluated by the
number of examined cells from the experimental and control
groups of animals. For each compound, as well as for the
diazepam group used as the control, a group of eight animals
was used. Test compounds were administered to mice in the
most effective dose of 50 mg kgꢀ1 intraperitoneally as
a suspension with methylcarboxycellulose and Tween-80. The
compounds were administered to mice 45 minutes before
placing the animals in the “open eld” conditions.
Acknowledgements
The chemical part of this work was made possible in part by
a research grant from the Armenian National Science and
Education Fund (ANSEF, Chemorg-3824) based in New York,
USA. The biological part of this work was supported by the State
Committee Science MES RA, in frame of the research project
No. SCS “13-3D145”.
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