Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure and benzodiazepine receptor binding

Article abstract of DOI:10.1016/S0223-5234(01)01239-9

In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and position of the substituents on the arylidene ring.

Full text of DOI:10.1016/S0223-5234(01)01239-9

Eur. J. Med. Chem. 36 (2001) 407–419
´
© 2001 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved
PII: S0223-5234(01)01239-9/FLA
Original article
Imidazo-thiazine, -diazinone and -diazepinone derivatives. Synthesis, structure
and benzodiazepine receptor binding
Katarzyna Kiec´-Kononowicza,*, Janina Karolak-Wojciechowskab, Christa E. Mu¨llerc,
Britta Schumacherc, Elzbieta Pe˛kalaa, Ewa Szyman´skaa
;
aDepartment of Chemical Technology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9,
PL-30-688 Krako´w, Poland
b
:
Institute of General and Ecological Chemistry, Technical University, Zwirki 36, PL-90-924 Ło´dz´, Poland
cPharmaceutical Institute Poppelsdorf, University of Bonn, Kreuzbergweg 26, D-53115 Bonn, Germany
Received 17 May 2000; revised 22 January 2001; accepted 23 March 2001
Abstract – In our search for new compounds acting on benzodiazepine receptors among the fused 2-thiohydantoin derivatives, a
series of arylidene imidazo[2,1-b]thiazines was synthesized. The 1,2- and 2,3- cyclized derivatives of mono- and di-substituted
Z-5-arylidene-2-thiohydantoins were examined (the X-ray crystal structure of Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-
b][1,3]thiazin-3(2H)-one was determined) and compared with the diphenyl derivatives. To investigate the influence of the type of
annelated ring on the biological activity, imidazo[2,1-b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives were obtained. The
method used in annelation (1,2- and 2,3-cyclized isomers with the exception of fused arylidene imidazothiazines), the substitution
pattern (arylidene towards diphenyl) as well as the character of the annelated ring had minor influence on the benzodiazepine
receptor affinity of the investigated compounds. It appears that the greatest influence on the biological activity has the character and
´
position of the substituents on the arylidene ring. © 2001 Editions scientifiques et me´dicales Elsevier SAS
benzodiazepine receptor / GABAA receptor / imidazo[2,1-b]thiazines / imidazo[2,1-b]pyrimidinone / imidazo[2,1-b]diazepinone
1. Introduction
dence, amnesia, oversedation and muscle relaxation
[4, 5]. As it would be useful to find partial agonists for
g-Aminobutyric acid acts on the g-aminobutyric
the benzodiazepine binding site of the GABAA recep-
acid-A chloride ion channel (GABAA receptor) con-
tor for therapeutic use, several research groups have
trolling the excitation of many central nervous system
developed and characterized such ligands comprising
pathways [1]. Various classes of compounds, such as
different chemical structures, including b-carboline
benzodiazepines, neurosteroids and barbiturates
(Abecarnil) [6], imidazopyridine (Alpidem) [7],
which interact with this macromolecular ionophore
quinoxalinone (Panadiplon) [8], pyridobenzimidazole
and modulate the action of g-aminobutyric acid on
[9] and imidazoquinoxaline [10, 11] structures. Fur-
the neuronal chloride flux, have a continuum of in-
ther, recent molecular biology studies, which demon-
trinsic activity ranging from full agonists (anxiolytic,
strated that the GABAA receptor is a hetero-
hypnotic and anticonvulsant agents) through antago-
oligomeric ligand-gated chloride channel consisting of
nists, to inverse agonists (proconvulsant and anxio-
a-, b-, g- and d-subunits, brought fresh impetus into
genic agents) [2, 3]. Partial agonists lie within this
this field of research concerning the identification of
continuum and may have reduced typical benzodi-
new selective ligands for certain subtypes of the
azepine-mediated side effects such as physical depen-
GABAA receptor [12].
We have recently reported on the annelated 2-thio-
hydantoin derivatives being benzylidene substituted
* Correspondence and reprints
E-mail address: mfkonono@kinga.cyf-kr.edu.pl
(K. Kiec´-Kononowicz).
imidazo[2,1-b]thiazoles, -thiazines and -thiazepines

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K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
teric replacement of sulfur with nitrogen yielding imi-
dazo[2,1-b]pyrimidinone derivative (11) (figure 3) as
well as enlargement of the annelated ring as in the
imidazo[2,1-b]diazepinone derivative (12) was also
investigated.
2. Chemistry
Figure 1. Structures of imidazo[2,l-b]thiazoles, -thiazines and
Bicyclic compounds of imidazo[2,1-b]thiazine type
5–8 were synthesized according to the procedures
outlined in Refs. [15, 16]. Thus, Z-5-arylidene-, cin-
namylidene-, or 5,5-diphenyl-2-thiohydantoins, re-
spectively, was reacted with 1,3-dibromopropane
under phase-transfer catalysis conditions (solid–liq-
uid) in acetone in the presence of potassium carbon-
ate and benzyltriethylammonium chloride as
phase-transfer catalysts (figure 2). The initial Z-5-
arylidene- and cinnamylidene-2-thiohydantoins were
prepared by Knoevenagel condensation of the appro-
priate aldehydes with 2-thiohydantoin [17]. Earlier it
was found by our research group [14, 16] that during
the reaction of 5-arylidene-2-thiohydantoins with 1,2-
dibromoethane two isomeric products were obtained:
the products of 1,2-substitution in minority (Yield:
3–10%) and of 2,3-substitution of 5-arylidene-2-thio-
hydantoin in majority (Yield: 22–51%). In an
-thiazepines.
with the general structure (1) given in figure 1, which
displayed micromolar affinity for the benzodiazepine
binding site of the GABAA receptors [13, 14]. Their
profile of action was characterized on the basis of the
GABAA shift [9] as partial agonists at the benzodi-
azepine-binding site of the GABAA receptors. Analy-
sis of the structure–activity relationships revealed
that thiazepine and thiazine derivatives were more
potent than the analogous thiazole derivatives. Re-
ceptor affinity was strongly dependent on the substi-
tution pattern of the benzylidene residue [13, 14].
In our present paper we report the further synthesis
and biological activity of bicyclic imidazo[2,1-
b]thiazines containing arylidene, cinnamylidene or
diphenyl substituents of type 5–8 (figure 2). Bioisos-
Figure 2. Synthesis of imidazo[2,1-b]thiazines 5–8; for substituents see table I.

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
409
Figure 3. Synthesis of imidazo[2,l-b]pyrimidinone 11 and imidazo[2,l-b]diazepinone 12.
only 1.5 kcal mol−1. These observations appear to be
important in the interpretation of the structure–activ-
ity relationships.
analogous reaction with 1,3-dibromopropane the
products of l,2-substitution were obtained in very low
yields (ca. 1%) or sometimes even difficult to detect.
In the reaction of 1,3-dibromopropane with 5-cin-
namylidene-2-thiohydantoin, the products of 1,2- (5)
and 2,3-cyclization (6) were obtained in a 1:4 ratio in
the same way as in the case of 5,5-diphenyl-2-thiohy-
dantoin dialkylation with 1,3-dibromopropane where
the ratio of the products 7 and 8 equaled 1:5 [18]. The
dominance of the 2,3-cyclization products correlates
with their higher thermodynamical stability. The heat
of formation (AM1 approximation) for the major
products was found to be 3 kcal mol−1.
The structures of 5-cinnamylidene derivatives were
confirmed by X-ray structure determination of one
dominating product of cyclization (figure 4). The
molecule of 6m (in Z-configuration) contains two
coplanar border cycles, phenyl and bicyclic imida-
zothiazinone (inclined at 5.8°) joined by the spacer
ꢀC8(H)ꢁC7(H)ꢀC6(H)ꢁ. Both the cyclic parts are in
cis-configuration with respect to the three carbon-
atom chain. This is clear from the values of the
respective torsion angles: C7ꢀC8ꢀC21ꢀC26=
174.2(2)° defining the phenyl ring position and/or
C7ꢀC6ꢀC5ꢀC4=179.7(2)° for the bicyclic part. How-
ever, the respective trans-isomer is also thermody-
namically possible, as concluded from the
conformational analysis (molecular mechanics) for
the phenyl ring rotation (figure 5). The two minima
with almost equal energy at C7ꢀC8ꢀC21ꢀC26 about
180° (cis) and 0° (trans) possess an energy barrier of
Imidazo[2,1-b]pyrimidinone (11) and imidazo[2,1-
b]diazepinone (12) derivatives (figure 3) were pre-
pared by the cyclization of appropriate imi-
dazoline-4-one aminoacid derivatives 10a and 10b in
acetic acid anhydride. 5-ortho-Chloro-substituted
benzylidene 2-thiohydantoin was chosen as the initiat-
ing material as the ortho-chloro derivative (6b) be-
longed to the most active compounds. The required
intermediate derivatives 10a and 10b were obtained
according to the method described for the prepara-
tion of thiazolidinone derivatives [19]; thus 2-
methylthio derivative (9), prepared by alkylation of
Figure 4. The molecule of 6m.

410
K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
3. Biological assays
The compounds 5a–5c, 6f, 6h–6n, 11 and 12 were
investigated in radioligand binding assays in the rat
brain cortical membranes for their affinity to the
benzodiazepine binding sites of the GABAA receptor.
All the compounds were screened for their potency to
displace [3H]diazepam from its binding site in a single
concentration (table I), Ki values were determined for
compounds, which inhibited the radioligand binding
by more than 40% at a concentration of 25 mM. A
typical displacement curve for the most potent com-
pound of the series, 6b, is shown in figure 7. The
Scatchard plot showed that the inhibition of
[3H]diazepam binding was competitive (figure 7).
Figure 5. The strain energy of 6m as a function of phenyl ring
rotation round the C21ꢀC8 bond.
arylidene-2-thiohydantoin (4) with methyl iodide, was
reacted with 3-aminopropanoic acid or with 4-
aminobutanoic acid for the preparation of 10a and
10b, respectively. Treatment of 10a with acetic anhy-
dride yielded the N-acetyl derivative of the bicyclic
compound 11, while in the synthesis using 10b as an
intermediate imidazo[2,1-b]diazepinone 12 was ob-
tained. The structures of compounds 11 and 12 were
confirmed on the basis of elemental and spectral
analyses. The electron ionization mass spectra showed
4. Results and discussion
4.1. Structure–activity relationships
The results obtained for the newly screened com-
pounds are presented in table I. For comparison, the
results obtained earlier for compounds 6a–6e and 6g are
also included in table I [13]. The substitution pattern of
the arylidene ring in derivatives 6a–6l was shown to
influence the receptor affinity of the investigated com-
pounds significantly. This is visualized by the diagram
given in figure 8. The diagram was prepared by a
selection of seven derivatives displaying higher affinities
(table II). The lowest Ki values were found for deriva-
tives with a meta-substituted arylidene ring. The affinity
sequence for chloro substitution was observed to be
ortho<para<meta (figure 8).
1
the expected molecular ions for 11 and 12; in the H
NMR spectra, in addition to the common characteris-
tic signals for the bicyclic structures, in the case of
compound 11 a triproton singlet for the acetyl group
was found. The models of both molecules 11 and 12
are given in figure 6. These models were built for the
molecular modeling of ligand–receptor interactions
(see below). For all the compounds considered calcu-
lations of their log P values were carried out [20] for
a preliminarily estimate of their lipophilicity.
Analysis of the calculated lipophilic properties of the
examined imidazo[2,1-b]thiazines showed that the log P
values of most of the compounds (5a, 5b, 6a–6i and 6m)
Figure 6. Models of 11 and 12.

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
411
Table I. Inhibition of [3H]diazepam binding to rat brain by imidazo-thiazine 5–8, -pyrimidinone 11 and -diazepinone 12 derivatives.
a
Compound
R1
R2
m
%
References
Ki (mM) n=3
log P b
5a
o-OCH3
o-OCH3
o-Cl
m-Cl
p-Cl
p-NO2
m-NO2
p-OCH3
o-OCH3
m-OCH3
o-Cl
m-OꢀPh
p-CH(CH3)2
H
H
–
–
–
–
–
H
H
H
H
H
H
H
H
0
0
0
0
0
0
0
0
0
0
0
0
0
1
1
–
–
–
–
–
5495
[16]
[13]
[13]
[13]
[13]
[13]
–
[13]
–
–
–
–
–
–
–
n.d. c
\25
13 [13]
1.6 [13]
10.193.9
\25
1.84
2.08
2.76
2.90
2.76
2.04
2.10
2.20
2.02
2.28
3.39
3.91
3.54
2.52
2.77
2.57
2.74
0.53
1.44
3.21
6a
1.593.1
7394
6995
4992 d
099 e
6296
6496
6395
4396
3917
30913
28917
1091
1798
17916
196
6b
6c
6d
6e
6f
4.590.4
6.091.3
19.694.2
8.890.8
\25
6g
6h
p-OCH3
p-OCH3
6i
6j
m-Cl
H
H
H
H
-
–
–
–
–
6k
\25
6l
\25
5b
\25
6m
\25
7
8
[15, 21]
[15, 21]
–
–
–
\25
\25
11
12
1294
3196
n.d.
\25
\25
Diazepam
0.025 [13]
a Percent specific inhibition of [3H]diazepam binding to rat brain cortical membranes at drug concentration of 25 mM unless
otherwise stated.
b log P values calculated by means of the PALLAS program [20].
c Inhibition curve could not be determined because of solubility problems.
d Drug concentration of 40 mM.
e Drug concentration of 100 mM.
Figure 7. Radioligand binding curve and Scatchard plot of compound 6b; full curve could not be determined owing to the limited
solubility at higher concentrations.
were within the range of 1.84–2.90 required for the
CNS-active compounds (log P:2.5 [24]). Only the
log P values of compounds 6j–6l (3.39–3.91) were
higher. On the other hand, the calculated log P values of
the fused imidazo[2,1-b]pyrimidinone (11) and imidazo
[2,l-b]diazepinone (12) derivatives were lower (0.53–

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K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
Table II. Parameters for selected molecules used in Eqs. (1)
analysis are collected in table II and the results of the
calculation are presented by the following equation (Eq.
(2)):
and (2).
Compound
yo
ym
yp
log P
Ki
log Ki= −0.02yo−1.08ym−0.02yp+1.01 n=7 r=0.85
6b
6c
6d
6f
6g
6h
6i
0.76
2.76
2.90
2.76
2.10
2.20
2.02
2.28
13.0
1.6
10.1
4.5
6.0
19.6
8.8
0.77
0.11
(2)
0.73
Contrary to Eq. (1), the newly obtained Eq. (2) has an
acceptable r-value worth discussing further. In the pre-
vious investigations (see figure 8) it was found that the
position of the substituents on the benzylidene ring had
a great influence on the activity of the compounds (see,
e.g. o-, m-, p-chloro derivatives 6b, 6c and 6d), the
meta-substituted derivatives being the most potent (with
the lowest Ki values). This corresponds excellently with
the high negative contribution to the log Ki of the ym
positive constant for Cl in Eq. (2) (table II). Moreover
para-nitro-substituted derivative 6e, not used in this
correlation, was much less active (Ki>25) but owing to
the higher negative contribution weight for ym a NO2
group introduced in the meta-position gave the consid-
erably more active compound 6f. Derivatives containing
a methoxy substituent in the para-position (6g) (small
negative contribution for yp in Eq. (2) and negative
y-constant for OCH3) as well as di-substituted methoxy
derivatives 6h and 6i belong to the most active com-
pounds in this series. In these two di-substituted deriva-
tives different weights in Eq. (2) are compensated by the
opposite signs of yo and ym for OCH3 significantly.
However, di-substitution with chlorine as in compound
−0.03
−0.03
−0.03
−0.33
0.12
1.44) than required. Such compounds have additional
functional groups that may form hydrogen bonds, lead-
ing to the reduction of the in-brain penetration [25, 26].
The lipophilicity had a minor influence on the Ki values
as shown by a second-degree polynomial fit, with poor
agreement (Eq. (1)) describing the relationship between
log P values and log Ki for the seven derivatives in table
II.
log Ki=6.41 log P−1.37 log P2−6.46 n=7, r=0.43
(1)
At the same time, we have performed a QSAR study
to explain the measured differences in affinity of aryli-
dene derivatives. The multiple linear regression (MLR)
model [22] with Hansch’s constants corresponding to
substituents in the o-, m- or p-positions of the arylidene
ring was applied [23]. The values used in the correlation
Figure 8. Graphical representation of Ki values of compounds 6 (see tables I and II and figure 2) with different substitution patterns
(R1, R2) on the phenyl ring.

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
413
Figure 9. Binding interactions of Z-5-arylidene-, cinnamylidene imidazo[2,1-b]thiazines and Z-5-arylidene imidazo[2,1-
b]pyrimidinone and imidazo[2,1-b]diazepinone derivatives with Cook et al. [30] model of BZR active sites.
6j combining interesting properties of the ortho- and the
meta-substituted compounds 6b and 6c was unprofitable
(Ki>25).
quantum-chemistry calculations (see figures 4 and 6). It
should be noted that the torsional angle describing
non-planarity in low energy conformations (AM1 ap-
proximation) for 6a–6l deviated by 148°. Independently
of the arylidene ring substitution, the barrier of rotation
for the ring was found to be as low as 2 kcal mol−1. The
planarity criterion is not fulfilled by the inactive bicyclic
diphenyl derivatives 7 and 8 [15, 21]. This clearly indi-
cates that the volume of the arylidene moiety in the
Z-configuration presumably fills the size in the lipophilic
pocket (the black contour in figure 9a represents the
highly active molecule (6b)). On the other hand, com-
pound 6m, a derivative with a cinnamylidene moiety,
Introducing a longer spacer between the phenyl ring
and the bicyclic structure as in compounds 5b and 6m
had no effect on activity. Analogous effects were ob-
served for the diphenyl derivatives 7 and 8. Moreover, it
was found that the type of annelation of the thiazine
ring also had no effect on the activity of the cinnamyli-
dene and diphenyl derivative (see pairs of compounds 5b
and 6m, and 7 and 8). Replacement of the thiazine ring
by pyrimidinone or diazepinone as in structures 11 and
12 also had no effect on the activity of the compounds.
It means that both the molecules cannot fulfill all the
spatial conditions required by the receptor (see below).
,
which is about 3 A longer than benzylidene, and is
practically inactive (the grey contour in figure 9a). Thus,
the benzylidene group may act as the hydrophobic
p-electron fragment. Moreover, the mode of substitution
in this fragment is important with regard to space (see
Eq. (1)).
4.2. Interaction with the benzodiazepine receptor
The general concept of the structural requirements for
benzodiazepin receptor ligands was presented in form of
several models [27–29]. The models are characterized by
a size-limited lipophilic region with p–p interaction
volume, at least one hydrogen bond donor interaction
site and one hydrogen bond acceptor. Such a model
may be easily adapted to arylidene thiazolidinone
derivatives as it is presented below.
The molecules highly active at the benzodiazepine
receptor in most cases contain a planar or almost planar
core. In the compounds studied, bicyclic and arylidene
moieties are also nearly planar. This result was obtained
from crystallography, and geometry optimization by
In all the molecules discussed there are two groups
able to act as H-bond acceptors as confirmed by the
electrostatic potential (MEP) distribution showing two
common minima. The one minimum is localized at the
carbonyl oxygen, the second appears near the nitrogen
atom (N1). This is visualized in figure 10 showing MEP
distribution for one molecule (6b). In figure 9 these two
groups are marked as corresponding to the binding sites
A1 and A3 in the benzodiazepine receptor. Having in
view the A2 pharmacophoric point (H-bond acceptor),
derivatives 11 and 12 were svnthesized (figure 6). Espe-
cially compound 12 having a free NH group seemed to

414
K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
be interesting as a potential benzodiazepine receptor
ligand. However, superimposition with 6b (figure 10)
clearly indicates that for the Z-isomer of 12 this group
and the phenyl ring are cis-configurated in the molecule.
Consequently, the location of the H-bond acceptor in
the receptor model is not close to the NH group in the
molecule. The observed low activity of 12 supported this
hypothesis.
In conclusion, we have described the synthesis of
diphenyl and arylidene imidazothiazine, -diazinone and
-diazepinone derivatives and the evaluation of their
benzodiazepine receptor-binding activity. Analysis of
the 3D structure of the compounds obtained and the
structural requirements for benzodiazepine receptor
binding revealed that for the activity the presence of
diphenyl and cinnamylidene substituents as well as di-
azinone and diazepinone annelated rings was not advan-
tageous. As a result of the QSAR analysis of the
arylidene imidazothiazine derivatives it was found that a
negative y-value for the meta-substituent in the aryli-
dene group is an important parameter, which influences
the binding of the compounds to the benzodiazepine
receptors.
chloroform–ethyl acetate (1:1); (B) methylene chloride;
(C) chloroform–isopropanol–25% (aq.) ammonia
(9:11:2); and (D) toluene–acetone (20:1.5). Column
chromatography was performed on Merck silica gel 60
(70–230 mesh) using solvents (A) or (B). Electron im-
pact and electron spray mass spectra were recorded on
an AMD-604, or a Finningan MAT 95S spectrometer,
respectively, with a direct inlet. IR spectra were mea-
sured with an FTIR 410 spectrometer (Jasco) in KBr
pellets. The UV spectra were obtained for solutions of
10−4 mol L−1 concentration with a UV–vis-spectrometer
(UV–vis V-530 Jasco). The 1H NMR spectra were
performed on a Bruker AC-200F, a Bruker DPX 250
AVANCE or a VARIAN MERCURY 300 MHz spec-
trometer in DMSO-d6 using tetramethyl silane as an
internal standard (chemical shifts are reported in l
units. The elemental analyses were performed at the
Department of Pharmaceutical Chemistry of the Jagiel-
lonian University, Cracow (Poland) and were within
0.4% of the theoretical values.
The initial 2-thiohydantoins (4) were obtained as de-
scribed earlier or in analogy to the procedure described
in Ref. [17]. The following new derivatives were
prepared.
5. Experimental
5.1.1. Z-5-(3-Phenoxybenzylidene)-2-thiohydantoin
Cream-colored yellow crystals, m.p. (dec.) 200–
203 °C; the raw product was analytically pure, Yield:
5.1. Chemistry
1
90%; TLC: Rf (A) 0.90; H NMR (250 MHz): l=6.47
Melting points (m.p. (dec.)) were measured on Mel-
Temp. II (LD Inc. USA) and were not corrected. TLC
was performed on Merck silica gel GF254 precoated
TLC Al sheets; the solvent systems used were: (A)
(s, 1H, ArCHꢁ), 6.95–7.02 (m, 3H, 2%-H, 3%-H, 4%-H),
7.13 (t, J=7.5 Hz, 1H, 6%-H), 7.35–7.44 (m, 3H, 3¦-H,
4¦-H, 5¦-H), 7.52 (d, J=10 Hz, 2H, 2¦-H, 6¦-H), 12.22
(s, 1H, N1H), 12.39 (s, 1H, N3H); FTIR (w, cm−1): 3133
(NꢀH), 1728 (CꢁO), 1648 (ArCHꢁ), 1481, 1371, 1245,
1195, 954, 694. Anal. (C16H12N2O2S) C, H, N.
5.1.2. Z-5-[4-(2-Propylo)benzylidene]-2-thiohydantoin
Yellow crystals, m.p. (dec.) 217–220 °C from acetic
acid, Yield: 73%; TLC: Rf (A) 0.86; 1H NMR (300
MHz): l=1.21 (d, J=6.9 Hz, 6H, 2CH3), 2.92 (sept,
J=6.9 Hz, 1H, CH(CH3)2), 6.47 (s, 1H, ArCHꢁ), 7.30
(d, J=8.4 Hz, 2H, 3%-H, 5%-H), 7.68 (d, J=8.4 Hz, 2H,
2%-H, 6%-H); FTIR (w, cm−1): 3305 (NꢀH), 2958 (CꢀH),
1712 (CꢁO), 1645 (ArCHꢁ), 1479, 1363, 1178, 761. Anal.
(C13H14N2OS) C, H, N.
5.1.3. Z-5-(2,3-dichlorobenzylidene)-2-thiohydantoin
Yellow crystals, m.p. (dec.) 286–288 °C; the raw
product was analytically pure, Yield: 94%; TLC: Rf (D)
1
Figure 10. MEP distribution of compound 6b.
0.16; H NMR (300 MHz): l=6.55 (s, 1H, ArCHꢁ),

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
415
7.42 (t, J=8.0 Hz, 1H, 5%-H), 7.64 (dd, J=8.1 Hz, 1H,
4%-H), 7.72 (dd, J=7.5 Hz, 1H, 6%-H), 12.39 (br s, 2H,
N1H, N3H); FTIR (w, cm−1): 3141 (NꢀH), 2857 (CꢀH),
1731 (CꢁO), 1670 (ArCHꢁ), 1515, 1376, 1228, 908, 781.
Anal. (C10H6N2OSCl2) C, H, N.
Compounds 5a, 6a, 6d, 6e, 6f [16], 6b, 6c [13]. 6g [31]
and 5c, 6n [16, 21] were obtained as described earlier.
The new derivatives 6h–6l were prepared in analogy to
the procedures described in Ref. [4].
(60 mL). The mixture was stirred at room temperature
(r.t.) for two days. The solid was removed, washed with
water, and then subsequently with 1% NaOH and 1%
HCl solutions. The remaining solid was suspended in
chloroform (150 mL), stirred for 0.5 h, and the suspen-
sion was filtered. The solid was then discarded. The
chloroform filtrate was evaporated to dryness. The pre-
cipitate obtained was recrystallized from dioxane, Yield:
2.8 g (60%); m.p. (dec.) 218–220 °C; TLC: Rf (A) 0.57;
1H NMR (200 MHz): l=2.10–2.25 (m, 2H,
CH2CH2CH2), 3.26 (t, J=5.5 Hz, 2H, SCH2), 3.65 (t,
J=5.8 Hz, 2H, NCH2), 7.04 (s, 1H, ArCHꢁ), 7.46 (t,
J=8.0 Hz, 1H, 5%-H), 7.64 (dd, J=8.0 Hz, J=1.5 Hz,
1H, 4%-H), 8.69 (dd, J=8.0, 1.5 Hz, 1H, 6%-H); FTIR (w,
cm−1): 1716 (CꢁO), 1631 (ArCHꢁ), 1482 (CꢁN), 1461,
1238, 1166, 1151, 1122, 790. Anal. (C13H10N2OSCl2) C,
H, N.
5.1.4. Z-2-(2,4-Dimethoxybenzylidene)-6,7-dihydro-
5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one (6h)
This compound was obtained as yellow crystals after
purification using column chromatography performed
twice with eluent (A), Yield: 34%; m.p. (dec.) 204–
1
205 °C; TLC: Rf (A) 0.38; H NMR (200 MHz): l=
2.16 (def qi, 2H, CH2CH2CH2), 3.21 (t, J=5.4 Hz, 2H,
SCH2), 3.61 (t, J=5.7 Hz, 2H, NCH2), 3.82 (s, 3H,
2%-OCH3), 3.87 (s, 3H, 4%-OCH3), 6.61 (dd, J=6.5 Hz,
J=2.4 Hz, 1H, 5%-H), 6.66 (d, J=2.4 Hz, 1H, 3%-H),
7.12 (s, 1H, ArCHꢁ), 8.62 (d, J=6.8 Hz, 1H, 6%-H);
5.1.7. Z-2-(3-Phenoxybenzylidene)-6,7-dihydro-
5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one (6k)
Compound 6k was obtained as yellow crystals after
purification using column chromatography performed
with eluent (A), Yield: 31%; m.p. (dec.) 144–146 °C
FTIR (w, cm−1): 1692 (CꢁO), 1648 (ArCHꢁ), 1588, 1466
+
’
(CꢁN), 1270, 1238; MS; m/z: 304 [M ], 273, 245, 181,
176, 160, 146, 121, 100, 72. Anal. (C15H16N2O3S) C, H,
N.
1
(from acetonitrile); TLC: Rf (A) 0.65; H NMR (300
MHz): l=2.14–2.17 (m, 2H, CH2CH2CH2), 3.22 (t,
J=5.4 Hz, 2H, SCH2), 3.62 (t, J=5.6 Hz, 2H, NCH2),
6.82 (s, 1H, ArCHꢁ), 6.99–7.05 (m, 3H, 3¦-H, 4¦-H,
5¦-H), 7.16 (t, J=7.5 Hz, 1H, 5%-H), 7.38–7.46 (m, 3H,
4%-H, 2¦-H, 6¦-H), 7.85 (d, J=8.2 Hz, 1H, 6%-H), 7.97 (t,
J=1.8 Hz, 1H, 2%-H); FTIR (w, cm−1): 1714 (CꢁO),
1635 (ArCHꢁ), 1569, 1488 (CꢁN), 1230, 898, 759, 692.
Anal. (C19H16N2O2S) C, H, N.
5.1.5. Z-2-(3,4-Dimethoxybenzylidene)-6,7-dihydro-
5H-imidazo[2,1-b][1,3]thiazin-3(2H)-one (6i)
This compound was obtained as yellow crystals after
purification using column chromatography performed
with eluent (A), Yield: 36%; m.p. (dec.) 212–214 °C;
TLC: Rf (A) 0.45; 1H NMR (200 MHz): l=2.16 (def qi,
2H, CH2CH2CH2), 3.22 (t, J=5.4 Hz, 2H, SCH2), 3.62
(t, J=5.6 Hz, 2H, NCH2), 3.77 (s, 3H, 3%-OCH3), 3.81
(s, 3H, 4%-OCH3), 6.80 (s, 1H, ArCHꢁ), 7.02 (d, J=8.5
Hz, 1H, 5%-H), 7.71 (dd, J=8.5 Hz, J=1.5 Hz, 1H,
6%-H), 7.87 (d, J=1.5 Hz, 1H, 2%-H); FTIR (w, cm−1):
5.1.8. Z-2-[4-(2-Propylo)benzylidene]-6,7-dihydro-5H-
imidazo[2,1-b][1,3]thiazin-3(2H)-one (6l)
1710 (CꢁO), 1648 (ArCHꢁ), 1590, 1508, 1484 (CꢁN),
The compound was obtained as cream-colored yellow
crystals after purification using column chromatogaphy
performed consecutively with eluents (B) and (A), Yield:
40%; m.p. (dec.) 174–176 °C (from dioxane); TLC: Rf
+
’
1362, 1268, 1244, 1158, 1136, 1016; MS; m/z: 304 [M ],
289, 275, 261, 233, 176, 100, 72. Anal. (C15H16N2O3S) C,
H, N.
1
(A) 0.66; H NMR (200 MHz): l=1.20 (d, J=6.9 Hz,
5.1.6. Z-2-(2,3-Dichlorobenzylidene)-6,7-dihydro-5H-
imidazo[2,1-b][1,3]thiazin-3(2H)-one (6j)
A solution of 1,3-dibromopropane 3.08 g (0.015 mol)
in acetone (10 mL) was added dropwise to a stirred
suspension of 5-(2,3-dichlorobenzylidene)-2-thiohydan-
toin 4.11 g (0.015 mol), K2CO3 (6.0 g), and triethylben-
zylammonium chloride 0.45 g (0.0015 mol) in acetone
6H, (CH3)2), 2.05–2.22 (m, 2H, CH2CH2CH2), 2.90
(sept, J=6.9 Hz, 1H, CH(CH3)2), 3.23 (t, J=5.4 Hz,
2H, SCH2), 3.63 (t, J=5.7 Hz, 2H, NCH2), 6.81 (s, 1H,
ArCHꢁ), 7.30 (d, J=8.2 Hz, 2H, 3%-H, 5%-H), 8.05 (d,
J=8.2 Hz, 2H, 2%-H, 6%-H); FTIR (w, cm−1): 2954
(CꢀH), 1710 (CꢁO), 1631 (ArCHꢁ), 1486 (CꢁN), 1245,
1162, 890, 833. Anal. (C16H18N2OS) C, H, N.

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K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
5.1.9. Z-3-Cinnamylidene-6,7-dihydro-4H-imidazo-
[2,1-b][1,3]thiazin-2(3H)-one (5b) and
Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b]-
vacuo. The solid obtained was dissolved in 100 mL of
water, and the solution was acidified with 2% HCl
solution to pH 6–7. The obtained precipitate was
filtered off the next day to yield 6.34 g (72%) of intensive
yellow crystals of 10a, m.p. (dec.) 247–249 °C (from
[1,3]thiazin-3(2H)-one (6m)
A solution of 1,3-dibromopropane 2.02 g (0.01 mol)
in acetone (10 mL) was added dropwise to a stirred
suspension of 5-cinnamylidene-2-thiohydantoin 2.30 g
(0.01 mol), K2CO3 (4.0 g), and triethylbenzylammonium
chloride 0.3 g (0.001 mol) in acetone (40 mL). The
mixture was stirred at r.t. for two days. The solid was
removed, washed with water, and then with 1% NaOH
and 1% HCl solutions, and recrystallized from dioxane
to yield 230 mg (8.5%) of yellow crystals of 5b, m.p.
(dec.) 265-268 °C; TLC: Rf (A) 0.07; 1H NMR (200
MHz): l=2.27–2.32 (m, 2H, CH2CH2CH2), 3.23–3.26
(m, 2H, SCH2), 4.18 (t, J=5.8 Hz, 2H, NCH2), 6.55 (d,
J=12.2 Hz, 1H, ArCHꢁ), 7.16 (d, J=15.2 Hz, 1H,
ꢀCHꢁCHꢀCHꢁ), 7.34–7.50 (m, 4H, ꢀCHꢁCHꢀCHꢁ, 3%-
H, 4%-H, 5%-H), 7.62–7.67 (m, 2H, 2%-H, 6%-H); FTIR (w,
cm−1): 1673 (CꢁO), 1618 (ArCHꢁCHꢀCHꢁ), 1434
1
acetic acid); TLC: Rf (C) 0.15; H NMR (250 MHz):
l=2.46 (s, 2H, CH2COOH), 3.58 (s, 2H, NHCH2), 6.53
(s, 1H, ArCHꢁ), 7.20 (t, J=7.6 Hz, 1H, 4%-H), 7.33 (d,
J=7.6 Hz, 1H, 3%-H), 7.42 (def t, 1H, 5%-H), 8.18 (br s,
1H, NHCH2), 8.88 (br s, 1H, 6%-H), 11.38 (br s, 1H,
NH); FTIR (w, cm−1): 3297 (NH), 1706 (CꢁO), 1664
(ArCHꢁ), 1617, 1507, 1404, 1294, 1196, 1049, 989; MS;
+
’
m/z (electron spray): 293 [M ], 275, 258, 240, 198, 151.
Anal. (C13H13N3O3Cl) C, H, N.
Method A. The suspension of propanoic acid deriva-
tive 10a (1.5 g) in acetic acid anhydride (1.5 mL) and
pyridine (2.25 mL) was left to stand with continuous
stirring at r.t. for 3 days. The solid obtained was filtered
off and recrystallized from ethanol to give 0.73 g (53%)
of cream yellow crystals of 11.
(CꢁN), 1405, 1326, 1236, 1121, 976, 755; MS; m/z: 270
Method B. The suspension of propanoic acid deriva-
tive 10a (1.0 g) in 10 mL of acetic acid anhydride was
refluxed for 1.5 h. After cooling, the precipitate formed
was filtered off and recrystallized from ethanol to give
0.52 g (37%) of 11.
+
’
[M ], 192, 154, 142, 128, 114. Anal. (C15H14N2OS) C,
H, N.
The combined precipitates obtained from the dioxane
solution (precipitated with water) and from the acetone
filtrate were recrystallized from acetone to yield 1.0 g
(37%) of cream-colored yellow crystals of 6m, m.p.
1
M.p. (dec.) 213–217 °C; TLC: Rf (C) 0.43; H NMR
(250 MHz): l=2.77 (s, 3H, CH3), 2.87 (t, J=6.5 Hz,
2H, CH2CO), 4.13 (t, J=6.5 Hz, 2H, NCH2), 7.24 (s,
1H, ArCHꢁ), 7.43–7.55 (m, 2H, 4%-H, 5%-H), 7.63 (dd,
J=7.3 Hz, J=2.0 Hz, 1H, 3%-H). 8.72 (dd, J=7.3 Hz,
J=2.0 Hz, 1H, 6%-H); FTIR (w, cm−1): 1779, 1703
1
(dec.) 184–187 °C; TLC: Rf (A) 0.57; H NMR (200
MHz): l=2.05–2.25 (m, 2H, CH2CH2CH2), 3.21 (t,
J=5.6 Hz, 2H, SCH2), 3.61 (t, J=5.8 Hz, 2H, NCH2),
6.75 (d, J=11.3 Hz, 1H, ArCHꢁ), 7.17 (d, J=15.8 Hz,
1H, ꢀCHꢁCHꢀCHꢁ), 7.32–7.45 (m, 3H, 3%-H, 4%-H,
5%-H), 7.50 (d, J=11.3 Hz, 1H, ꢀCHꢁCHꢀCHꢁ), 7.57–
7.62 (m, 2H, 2%-H, 6%-H); FTIR (w, cm−1): 1702 (CꢁO),
1621 (ArCHꢁCHꢀCHꢁ), 1484 (CꢁN), 1467, 1228, 1160,
968, 950, 908, 686. Anal. (C15H14N2OS) C, H, N.
(CꢁO), 1648 (ArCHꢁ), 1591, 1401, 1240, 1199, 1035,
+
’
975, 680; MS; m/z (electron spray): 317 [M ] 277, 275,
240, 198, 186, 129, 116, 74; UV: umax (nm) (log m)
(methylene chloride): 378 (4.441), 359 (4.545), 242
(4.433). Anal. (C15H12N3O3Cl) C, H, N.
5.1.10. 8-Acetylo-Z-2-(2-chlorobenzylidene)-5,6,7,8-te
trahydro-imidazo[2,1-b]pirymidin-3(2H),5-dione (11)
Starting material in the synthesis of 11: [Z-5-
(2-Chlorobenzylidene)-4-oxoimidazolin-2-yl]-3-amino-
propanoic acid (10a) was obtained following the proce-
dure described in Ref. [19].
The suspension of 3-aminopropanoic acid (4.8 g,
0.054 mol) and potassium tert-butanolate (4.2 g, 0.036
mol) in 500 mL anhydrous ethanol was stirred at r.t. for
0.5 h. Then Z-5-(2-chlorobenzylidene)-2-methylthioimi-
dazolin-4-one (9) [32] (7.5 g, 0.0297 mol) was added and
the reaction mixture was refluxed for 4 h. From the
clear reaction mixture the solvent was evaporated in
5.1.11. Z-2-(2-Chlorobenzylidene)-5,6,7,8-tetrahydro-
imidazo[2,1-b][1,3]diazepin-3(2H),5-dione (12)
Starting material in the synthesis of 12: [Z-5-
(2-Chlorobenzylidene)-4-oxoimidazolin-2-yl]-4-amino-
butanoic acid (10b) was obtained following the proce-
dure described in Ref. [19] analogous to that performed
for 10a.
10b: cream-colored crystals (from ethanol), m.p. (dec.)
1
134–137 °C; TLC: Rf (C) 0.11; H NMR (250 MHz):
l=1.84 (m, 2H, CH2CH2COOH), 2.32 (t, J=7.2 Hz,
2H, CH2COOH), 3.30–3.50 (m, 2H, CH2NH), 6.58 (s,
1H, ArCHꢁ), 7.20 (dt, J=7.5 Hz, J=1.5 Hz, 1H, 5%-H),
7.32 (d, J=7.6 Hz, 1H, 3%-H), 7.4 (def t, 1H, 4%-H), 8.40

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
417
Table III. Crystal data, structure refinement parameters and
the summary of intensity data collection for 6m.
790 mL of tris(hydroxymethyl)aminomethane hydrochlo-
ride buffer (50 mM, pH 7.4), 10 mL of the compound
solution, 100 mL of rat cerebral cortical membrane
preparation with a protein concentration of ca. 100 mg
per tube, and 100 mL of [3H]diazepam solution, to give
a final concentration of 1 nM. Dimethyl sulfoxide was
necessary as the compounds possessed low water
solubility.
Incubations were carried out at 2 °C for 1 h and were
terminated by rapid filtration through glass fiber filters
(Schleicher & Schu¨ll GF 51) using a Brandel cell har-
vester M-24 (Brandel, Gaithersburg, Maryland, USA).
Empirical formula
Formula weight
Crystallization medium
Color
C15H14N2OS
270.34
acetone–dioxane (2:1)
cream-yellow
0.4×0.3×0.3
Crystal size (mm)
Unit cell dimensions
,
a (A)
8.632(2)
7.610(2)
20.635(4)
96.96(3)
1345.5(5)
4
1.335
2.074
3428
,
b (A)
,
c (A)
i (°)
3
,
V (A )
Molecules/unit cell
Three
5 mL washes with ice cold tris(hydrox-
Density calculated (Mg m−3
)
Linear absorption factor (mm−1
Reflections collected
)
ymethyl)aminomethane hydrochloride buffer were car-
ried out. Unlabeled diazepam (5 mM) was used to define
the non-specific binding. All compounds were tested in a
single concentration of 25 mM, in some cases 40 or 100
mM in at least three independent experiments each in
triplicate. Inhibition curves for the more potent com-
pounds were determined using at least 6–7 different
concentrations each in triplicate spanning a concentra-
tion range of 3–4 orders of magnitude. Three indepen-
dent experiments were carried out. The Ki values were
calculated from the IC50 values as described in Ref. [13].
Reflections observed [I\2|(I)]
R-index
2768
0.0602
1.135
Goodness-of-fit on F2
Secondary extinction factor g
0.0147(19)
(br s, 1H, NHCH2), 8.82 (br s, 1H, 6%-H), 10.75 (br s,
1H, NH); FTIR (w, cm−1): 1751, 1710 (CꢁO), 1617
(ArCHꢁ), 1420, 1345, 1289, 1242, 1184, 1089, 1006, 833,
764, 691, 635. Anal. (C14H14N3O3Cl) C, H, N.
The cyclization of butanoic acid derivative 10b was
performed as described in method A for compound 11.
12: yellow crystals (from ethanol), m.p. (dec.) 269–
5.3. X-ray diffraction analysis of
Z-2-cinnamylidene-6,7-dihydro-5H-imidazo[2,1-b][1,3]-
thiazin-3(2H)-one (6m)
1
271 °C; TLC: Rf (C) 0.77; H NMR (250 MHz): l=
2.05–2.19 (m, 2H, CH2), 2.59 (t, J=7.8 Hz, 2H,
CH2CO), 3.96 (t, J=7.3 Hz, 2H, NHCH2), 7.02 (s, 1H,
ArCHꢁ), 7.30–7.48 (m, 2H, 4%-H, 5%-H), 7.52 (d, J=7.8
Hz, 1H, 3%-H), 8.80 (d, J=8.0 Hz, 1H, 6%-H), 11.3 (s,
1H, NH); FTIR (w, cm−1): 3436, 3267 (NH), 1730, 1698
(CꢁO), 1636 (ArCHꢁ), 1586, 1449, 1384, 1282, 1092,
Crystals of 6m were obtained by slow evaporation of
an acetone–dioxane (2:1) solution. All the crystallo-
graphic data are given in table III. Preliminary crystallo-
graphic data were obtained from a KM4 four-cycle
diffractometer; the accurate cell dimensions were deter-
mined by the least-squares refinement from the angular
settings of 25 reflections located within 10<[<40°; a
crystal of 0.4×0.3×0.3 mm3 was applied to collect dif-
fraction data on KM4 diffractometer by the ꢀ/2[ scan
technique and using graphite monochromated Cu Ka
radiation at r.t. for [<84° [h:−11“11, k: 0“9, l:
9“26]; an absorption correction was not applied; the
intensity of the two standard reflections monitored every
100 reflections did not show significant fluctuations;
3428 reflections were measured, 2768 reflections were
considered observed using the criterion F0>4|(F0). The
+
’
880, 768, 694, 578; MS; m/z (electron impact): 289 [M ]
254, 74, 60, 57, 55; UV: umax (nm) (log m) (methylene
chloride): 388 (4.428), 368 (4.478), 359 (4.483), 244
(4.372). Anal. (C16H14N3O3Cl) C, H, N.
5.2. Benzodiazepine binding assays
Frozen rat brains were obtained from Pel-Freez®,
Rogers, Arkansas, USA. The cortex was dissected and
the inhibition of binding of [3H]diazepam to rat brain
cortical membranes were determined as described earlier
in Ref. [13]. The compounds were dissolved in dimethyl
sulfoxide and diluted further with tris(hydrox-
ymethyl)aminomethane hydrochloride buffer (50 mM,
pH 7.4); the final dimethyl sulfoxide concentration was
1%. In a final volume of 1 mL, each test tube contained
structure was solved by a direct method (SHELXTL-PC
)
[33]. E-map provided positions for all non-H-atoms;
full-matrix least-squares refinement was carried out on
F2s using anisotropic temperature factors for all non-H-
atoms; the positions of all H-atoms were from Dz-maps;

418
K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
misotropic thermal parameters of H-atoms were taken
as 1.5 times of the temperature factors for their parent-
atoms then the positions of H-atoms were refined in the
riding model, being finished at R1=0.0602, wR2=
0.1780 with w=1/[z2(Fo2)+(0.1128 P)2+0.2078 P] where
P=(F2o+F2c)/3 and empirical extinction correction co-
efficient g=0.0147(19), S=1.135 (173 parameter); final
gression Equations were computed by means of the
QSAR-PC:PAR program written by Coburn [22].
6. Supplementary material
Crystallographic data for structural analysis have
been deposited with the Cambridge Crystallographic
Data Centre, CCDC no. 140168. Copies of this infor-
mation may be obtained free of charge from The
Director, CCDC, 12 Union Road, Cambridge CB2
1EZ, UK (fax: +44-1223-336033; e-mail: deposit@
ccdc.cam.ac.uk or www: http://www.ccdc.cam.ac.uk).
changes D/zmin<0.01; Dzmin= −0.27 e A−3, Dzmax
=
0.22 e A−3. The atomic scattering factors were taken
from SHELXL-97 [34]. The X-ray structure analysis re-
sults are presented in the form of non-H-atoms coordi-
nates in table IV as well as in figure 1.
5.4. Computational procedures
The conformation analyses of 6m (starting with the
crystallographically obtained geometry) were carried out
using molecular mechanics methods using the PCMOD.6
program [35]. The energy was minimized after each 10°
clockwise rotation of two torsional angles in the 360°
range. The geometry of the molecules was optimized
with MOPAC 6.0 using AM1 Hamiltonians in an aqueous
environment (dielectric constants equals 78.4) [36]. The
molecular electrostatic distribution MEP was performed
using the MOLDEN [37] program. The values of log P for
the compounds investigated were calculated by means of
PALLAS (version 1.2) program [20]. Multiple Linear Re-
Acknowledgements
The authors wish to thank Mrs Maria Kaleta for
excellent technical assistance. The financial support for
the synthetic and computational parts of this research
carried out under the Polish State Committee for Scien-
tific Research, Grant No. 4 P05F 007 13 is gratefully
acknowledged.
References
[1] Smith G.B., Olsen R.W., Trends Pharmacol. Sci. 16 (1995)
162–168.
Table IV. Atomic coordinates (×104) and equivalent isotropic
[2] Sieghart W., Pharmacol. Rev. 47 (1995) 181–234.
[3] Gardner C.R., Prog. Neurobiol. 31 (1988) 425–476.
2
3
,
displacement parameters (A ×10 ) for 6m.
[4] Bellantuono C., Reggi V., Tognoni G., Garattini S., Drugs 19
x
y
z
U (equiv.)
(1980) 195–219.
[5] Petersen E.N., Jensen L.H., Diejer J., Honore T., Pharma-
S(1)
374(1)
−53(2)
865(2)
2225(2)
2208(3)
3226(2)
713(3)
5316(1)
8308(3)
7397(3)
8231(2)
9887(3)
10980(3)
9916(3)
11322 (3)
11444(3)
12932(3)
7566(3)
1937(1) 81(1)
copsychiatry 19 (1986) 4–6.
N(1)
C(2)
N(3)
C(4)
O(4)
C(5)
C(6)
C(7)
C(8)
C(9)
C(10)
C(11)
C(21)
C(22)
C(23)
C(24)
1273(1)
1687(1)
1939(1)
1660(1)
66(1)
60(1)
59(1)
65(1)
[6] Rickels K., Ballenger J.C., McDonald S., Noyes R., Sussman
N., Woods S., Patin J., Singer J., Psychopharmacol. Bull. 27
(1991) 171–179.
[7] George P., Rossey G., Depoortere H., Mompon B., Allen J.,
1767(1) 88(1)
1229(1) 63(1)
867(1) 71(1)
443(1) 70(1)
Wick A., Pharmacology 46 (Suppl.) (1991) 277–288.
[8] Petke J.D., Im H.K., Im W.B., Blakeman D.P., Pregenzer J.F.,
Jacobsen E.J., Hamilton B.J., Carter D.B., Mol. Pharmacol. 42
(1992) 294–301.
199(3)
−1231(3)
−1688(3)
3486(3)
2906(3)
2158(4)
−3120(3)
−4228(3)
−5606(4)
−5888(4)
124(1)
73(1)
[9] Maryanoff B.E., Ho W., McComsey D.F., Reitz A.B., Grous
P.P., Nortey S.O., Shank R.P., Dubinsky B., Taylor R.J.,
Gardocki J.F., J. Med. Chem. 38 (1995) 16–20.
2413(1) 70(1)
6176(4)
4678(3)
2838(1)
2442(2)
78(1)
84(1)
[10] Jacobsen E.J., TenBrink R.E., Stelzer L.S., Belonga K.L.,
Carter D.B., Im H.K., Im W.B., Sethy V.H., Tang A.H.,
VonVoigtlander P.F., Petke J.D., J. Med. Chem. 39 (1996)
158–175.
13249(3)
11950(4)
12377(5)
14061(5)
15346(4)
14942(3)
−312(1) 68(1)
−493(1) 79(1)
−874(1) 90(1)
−1092(1) 93(1)
−932(1) 89(1)
−547(1) 76(1)
[11] Jacobsen E.J., Stelzer L.S., TenBrink R.E., Belonga K.L.,
Carter D.B., Im H.K., Im W.B., Sethy V.H., Tang A.H.,
VonVoigtlander P.F., Petke J.D., Zhong W.-Z., Mickelson
J.W., J. Med. Chem. 42 (1999) 1123–1144.
C (25) −4796(4)
C(26) −3436(3)

K. Kiec´-Kononowicz et al. / European Journal of Medicinal Chemistry 36 (2001) 407–419
419
T., Madsen U. (Eds.), A Textbook of Drug Design and Devel-
[12] Huang Q., Liu R., Zhang P., He X., McKernan R., Gan T.,
opment, Harwood, Amsterdam, 1996, pp. 94–130.
Bennet D.W., Cook J.M., J. Med. Chem. 41 (1998) 4130–4142.
[25] Stein W.D., The Movement of Molecules Across Cell Mem-
[13] Geis U., Kiec´-Kononowicz K., Mu¨ller C.E., Sci. Pharm. 64
(1996) 383–390.
branes, Academic Press, New York, 1967, pp. 65–91.
[26] Chadha H.S., Abraham M.H., Mitchell R.C., Bioorg. Med.
[14] Kiec´-Kononowicz K., Karolak-Wojciechowska J., Mu¨ller C.E.,
Chem. Lett. 4 (1994) 2511–2516.
Geis U., Ksiaz; ek W., Szyman´ska E., J. Heterocyclic Chem. 36
(1999) 257–263.
[27] DiaZ-Arauzo H., Evoniuk G.E., Skotnicki P., Cook J.M., J.
Med. Chem. 34 (1991) 1754–1756.
[15] Kiec´-Kononowicz K., Zejc A., Mikołajczyk M., Zatorski A.,
Karolak-Wojciechowska J., Wieczorek M.W., Tetrahedron 36
(1980) 1079–1087.
[28] Villar H.O., Uyeno E.T., Toll L., Polgar W., Loew M.F., Mol.
Pharmacol. 36 (1989) 589–600.
[16] Kiec´-Kononowicz K., Karolak-Wojciechowska J., Phosphorus
Sulfur Silicon 73 (1992) 235–248.
[29] Karolak-Wojciechowska J., Lange J., Kwiatkowski W.,
Gniewosz M., Plenkiewicz J., Bioorg. Med. Chem. 2 (1994)
773–779.
[17] Shalaby A.F.A., Daboun H.A., Boghdadi S.S.M.Z., Z. Natur-
forsch. 29B (1974) 99–103.
[30] Zhang W., Koehler K.F., Zhang P., Cook J.M., Drug Des.
Discov. 12 (1995) 193–248.
[18] Kiec´-Kononowicz K., Synthesis, physicochemical and pharma-
cological properties of heterocyclic compounds obtained as the
result of hydantoin modifications, Associated Professor Thesis,
Krako´w, 1991.
[31] Kiec´-Kononowicz K., Karolak-Wojciechowska J., Robak J.,
Arch. Pharm. Pharm. Med. Chem. 330 (1997) 85–90.
[32] Kiec´-Kononowicz K., Szyman´ska E., Motyl M., Holzer W.,
Białecka A., Kasprowicz A., Pharmazie 53 (1998) 680–684.
[19] Unangst P.C., Connor D.T., Cetenko W.A., Sorensen R.J.,
Kosthan C.R., Sircan J.C., Wright C.D., Schirer D.J., Dyer
R.D., J. Med. Chem. 37 (1994) 322–328.
[33] Sheldrick G.M., SHELXTL PCMT, Siemens Analytical X-Ray
Instruments Inc. Madison, WI, USA, 1990.
[20] PALLAS for Windows 1.2, CompuDrug Chemistry Ltd, 1995.
[34] Sheldrick G.M., SHELXL-93, A FORTRAN-77 Program for the
Refinement of Crystal Structures from Diffaction Data, Uni-
versity of Go¨ttingen, Germany, 1993.
[21] Kiec´-Kononowicz K., Zejc A., Mikołajczyk M., Zatorski A.,
Karolak-Wojciechowska J., Wieczorek M.W., Tetrahedron 37
(1981) 409–415.
[35] PCMODEL, 6 Molecular Modeling Software for the IBM PC,
Serena Software, Bloomington, 1996.
[22] Coburn R.A., QSAR-PC Programme, BIOSOFT, Cambridge,
UK.
[36] MOPAC program version 6, QCPE No.455, Department of
Chemistry, Indiana University, Bloomington, IN 47405, 1990.
[23] Hansch C., Leo A., Substituent Constants for Correlation
Analysis in Chemistry and Biology, Wiley, New York, 1979.
[37]
MOLDEN,
http://www.caos.kun.nl/ꢀschaft/molden/molden.
[24] Liljefors T., Pettersson J., in: Krogsgaard-Larsen P., Liljefors
html.
.