Phenylimidazolidin-2-one derivatives as selective 5-HT3 receptor antagonists and refinement of the pharmacophore model for 5-HT3 receptor binding

Article abstract of DOI:10.1021/jm970060o

A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties has been suggested on the basis of the similarity between the molecular electrostatic potential (MEP) of metoclopramide, a D₂ receptor antagonist with weak 5-HT₃ receptor antagonist properties, and zetidoline, a D₂ receptor antagonist. Starting from this premise, a series of phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl moiety were synthesized and evaluated for 5-HT₃ receptor radioligand binding affinity ([³H]-GR 43694). In vitro 5-HT₃ receptor antagonist activity was tested in the guinea pig ileum assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT₃ receptor antagonists in vivo as determined by inhibition of the Bezold-Jarisch reflex in the anesthetized rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicycloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4- yl)methyl]imidazolidin-2-one (58), in particular, displayed very high affinity for the 5-HT₃ receptor (K(i) of 0.038 nM) with a K(b) of 5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron, tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID₅₀ comparable to that of ondansetron (2.2 μg/kg iv) in the Bezold-Jarisch reflex. A molecular modeling study based on this structurally novel series of compounds allowed the refinement of previously reported 5-HT₃ receptor antagonist pharmacophore models.

Full text of DOI:10.1021/jm970060o

J . Med. Chem. 1997, 40, 3369-3380
3369
P h en ylim id a zolid in -2-on e Der iva tives a s Selective 5-HT3 Recep tor An ta gon ists
a n d Refin em en t of th e P h a r m a cop h or e Mod el for 5-HT3 Recep tor Bin d in g
Franco Heidempergher,† Antonio Pillan,‡ Vittorio Pinciroli,§ Fabrizio Vaghi,† Claudio Arrigoni,| Giorgio Bolis,‡
Carla Caccia,† Luciano Dho,† Robert McArthur,† and Mario Varasi*,†
CNS Research, Structure Based Drug Design-CAMD Unit, R&D-Analytical Chemistry, and Toxicology, Pharmacia & Upjohn,
Viale Louis Pasteur, 10, 20014 Nerviano (Milano), Italy
Received J anuary 31, 1997X
A possible bioisosterism between the benzamido and the phenylimidazolidin-2-one moieties
has been suggested on the basis of the similarity between the molecular electrostatic potential
(MEP) of metoclopramide, a D2 receptor antagonist with weak 5-HT3 receptor antagonist
properties, and zetidoline, a D2 receptor antagonist. Starting from this premise, a series of
phenylimidazolidin-2-one derivatives bearing a basic azabicycloalkyl or an imidazolylalkyl
moiety were synthesized and evaluated for 5-HT3 receptor radioligand binding affinity ([3H]-
GR 43694). In vitro 5-HT3 receptor antagonist activity was tested in the guinea pig ileum
assay (GPI). A number of high-affinity ligands were shown to be potent 5-HT3 receptor
antagonists in vivo as determined by inhibition of the Bezold-J arisch reflex in the anesthetized
rat. In general, the imidazolylalkyl derivatives were found to be more active than azabicy-
cloalkyls. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazolidin-2-one (58),
in particular, displayed very high affinity for the 5-HT3 receptor (Ki of 0.038 nM) with a Kb of
5.62 nM in the GPI assay, being more potent than the reference compounds (ondansetron,
tropisetron, granisetron, and BRL 46470) tested. 58 showed an ID50 comparable to that of
ondansetron (2.2 µg/kg iv) in the Bezold-J arisch reflex. A molecular modeling study based
on this structurally novel series of compounds allowed the refinement of previously reported
5-HT3 receptor antagonist pharmacophore models.
In tr od u ction
only well-established therapeutic indication of 5-HT3
receptor antagonists is as antiemetics, several lines of
evidence suggest a role of 5-HT3 receptor antagonists
in the treatment of central nervous system disorders
such as anxiety, schizophrenia, drug abuse and with-
drawal, and age-associated memory impairments.8 The
aim of this study was to design novel and potent 5-HT3
receptor antagonists, combining a molecular modeling
and traditional medicinal chemistry approach to develop
potential therapeutic agents for the treatment of che-
motherapy-induced emesis and CNS disorders.
Serotonin (5-hydroxytryptamine, 5-HT) acts as a
neurotransmitter, neuromodulator, and hormone, ex-
hibiting profound pharmacological activities both in the
central nervous system and in the periphery. 5-HT is
involved in numerous physiological and pathological
processes interacting with various distinct membrane
receptors. Four main 5-HT receptorial subclasses,
5-HT1, 5-HT2, 5-HT3, and 5-HT4, are characterized.1
These receptor subtypes have been confirmed by mo-
lecular biology techniques. Molecular cloning studies
have revealed the existence of additional receptor
subtypes such as 5-HT5, 5-HT6, and 5-HT7, but very
little pharmacological data are available, and their
physiological relevance is not yet clear.2 The majority
of the 5-HT receptors belongs to a G-protein-paired
receptor family. The 5-HT3 receptors, on the other
hand, are coupled directly to a cation channel and are
present within the central and peripheral nervous
system.3 Electrophysiological analysis of 5-HT3 receptor
function reveals that agonist interaction mediates the
opening of an ion channel permeable to monovalent
cations.4 The development of selective antagonists of
the 5-HT3 receptor subtype has attracted considerable
attention in recent years.5 For example, the 5-HT3
receptor antagonists, such as ondansetron6 and gran-
isetron,7 represent a major improvement in the phar-
macotherapy of emesis, which is a frequent, severe, and
sometimes incapacitating syndrome, associated with
cancer chemotherapy and anesthesia. Although the
Before the introduction of potent and selective 5-HT3
antagonists, metoclopramide was the drug of choice to
alleviate chemotherapy-induced nausea and vomiting.
Dopamine (D2) receptor blockade was originally thought
to underlie metoclopramide’s antiemetic activity.9 Sub-
sequently, the antiemetic action for this drug has been
linked to its relatively weak antagonism of 5-HT3
receptors, an action first reported for metoclopramide
in isolated rabbit heart.10 Modification of the basic side
chain of metoclopramide with the introduction of a
quinuclidine ring in place of the (diethylamino)ethyl
moiety led to the identification of the potent and
selective 5-HT3 receptor antagonist zacopride,11 which
is also endowed with potent antiemetic properties.12
Molecular modeling studies indicated that the mo-
lecular electrostatic potential (MEP) of metoclopramide
shows a remarkable similarity with that of zetidoline,
a potent dopamine D2 receptor antagonist, in a nearly
extended conformation.13 The close electronic similarity
between metoclopramide and zetidoline has been pro-
posed to account for their common D2 receptor antago-
nist properties. We observed that substructure A
(benzamide group) of metoclopramide can be considered
bioisoster of substructure B (phenylimidazolidin-2-one
† CNS Research.
‡ Structure Based Drug Design-CAMD Unit.
§ R&D-Analytical Chemistry.
| Toxicology.
X Abstract published in Advance ACS Abstracts, September 15, 1997.
S0022-2623(97)00060-5 CCC: $14.00 © 1997 American Chemical Society

3370 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Heidempergher et al.
F igu r e 1. Substructures of metoclopramide (A) and zetidoline
(B).
F igu r e 2. Electrostatic isopotential maps of substructure A
(bottom left) and substructure B (bottom right). Negative fields
are presented in cyan, neutral fields in yellow, and positive
fields in red. The superposition of substructure A (yellow) and
substructure B (red) at the top of the picture were obtained
by maximizing the surface overlap of the MEPs. For clarity
the two structures in the middle of the picture are reported
color coded by atom type in the same orientation of the bottom
pair. In both compounds the chloro and the carbonyl groups
are the main responsible for the definition of the negative part
(cyan) of the MEP in which the largest part of both molecules
is enveloped. Only the methyl of the metoxy group in A and
the N-methyl in B appear in the positive volume (red).
through 13C-NMR and NOE experiments. A structure-
activity (SAR) study of the present set of compounds
allowed the refinement of the reported pharmacophore
model for 5-HT3 receptor binding.
group) of zetidoline (Figure 1). This assumption was
supported by a qualitative comparison of the isopoten-
tial maps obtained through the semiempirical computer
modeling of substructures A and B (Figure 2).
Ch em istr y
The synthesis of 1-azabicyclo-3-phenylimidazolidin-
2-ones (21-39) (Table 3) is shown in Scheme 1. Reduc-
tive amination of quinuclidin-3-one, tropinone or
pseudopelletierine with the appropriate N-phenyl-1,2-
diaminoethane in presence of NaBH3CN as reducing
agent in refluxing methanol at pH 6 provided the
intermediates 1-20 (Table 1). Tropinone and pseudopel-
letierine afforded a mixture of endo and exo derivatives
that were separated by column chromatography. Imi-
dazolidinone ring closure was achieved employing 1,1′-
carbonyldiimidazole in refluxing THF, except for com-
pound 40 (Table 3). In this case, the concomitant steric
hindrance of the 2,5-disubstituted aromatic ring and of
the [3.3.1]azabicyclic moiety did not allow the cycliza-
tion. Ring closure was carried out via the carbamate
intermediate 20a and cyclization in refluxing pyridine
(Scheme 2). The endo/exo configuration assignment of
3′-substituted granatanes and tropanes was performed
These relationships led to the working hypothesis that
5-HT3 receptor antagonist properties should be con-
ferred to the molecule by linking the phenylimidazoli-
din-2-one group (substructure B) to the quinuclidine
ring. Compound 21 was synthesized to test this hy-
pothesis. This compound showed an affinity (Ki) of 2 (
0.16 nM to the 5-HT3 receptor and an ID50 of 79.9 µg/
kg, after iv administration, in the Bezold-J arisch reflex
response. These results encouraged us to explore
further other basic moieties such as tropane, granatane,
and (5-methyl-1H-imidazol-4-yl)methyl, which are known
to be present in different 5-HT3 antagonists such as
tropisetron and MDL 72222, granisetron, and GR 65630,
respectively.14,15 In addition, the phenylimidazolidin-
2-one group can be viewed as a cyclized phenylurea
moiety, which is present in several 5-HT3 antagonists,
such as compound I,16 BRL 46470,17 and DAU 6215.18
We report on the synthesis and the pharmacological
properties of phenylimidazolidin-2-one derivatives bear-
ing a basic imidazolylalkyl or an azabicycloalkyl moiety.
The endo/exo configuration and the conformation of the
azabicycloalkyl compounds were assigned by means of
coupling constants in 1H-NMR spectra and verified
1
by means of H-NMR. This aim was complicated by
conformational flexibility of these bicyclic rings. Indeed,
while the exo-3′-substituted ring adopts a chair confor-
mation, the endo-3′-substituted ring could adopt a
conformation varying from the normal chair to boat
depending on the size of the 3′-substituent in order to

5-HT3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21 3371
Sch em e 1
Ta ble 1. Physicochemical Data of Intermediates of 1-20
compd
R
R1
Cl
R2
R3
endo/exo
n
% yield
mp, °C
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
oil
formula
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
H
Cl
40
62
41
55
51
50
48
64
48
55
48
50
40
20
47
45
42
20
48
56
C15H22ClN3
C16H24ClN3O
C16H25N3O
C16H25N3
C15H22ClN3
C16H25N3S
C16H22N4
C15H21Cl2N3
C15H23N3
C16H22F3N3
C15H22N4O2
C15H22BrN3
C16H24ClN3
C16H24ClN3
C17H26ClN3O
OCH3
H
H
H
H
H
H
H
H
H
H
H
H
H
OCH3
CH3
H
SCH3
CN
Cl
H
CF3
NO2
Br
Cl
Cl
H
H
Cl
Cl
oil
endo
exo
endo
endo
endo
exo
1
1
1
1
2
2
2
2
82.5-85.5
62-64
45-48
60-63
oil
oil
oil
oil
OCH3
H
H
H
H
C16H25N3
C17H26ClN3
C17H26ClN3
C17H27N3
H
H
endo
endo
OCH3
C18H28ClN3O
relieve transannular steric interactions of the substitu-
ent with C6′/C7′ (tropanes) or C7′ (granatanes) hydro-
gens in the chair conformation.19,20 A complete stereo-
chemical study is possible through analysis of H3′ and
H1′/H5′ coupling constants, but we also verified the
endo/exo assignment through 13C-NMR (granatanes)21
and NOE (granatanes and tropanes) data. To our
knowledge, no one has verified the stereochemistry of
these bicyclic systems by NOE experiments. Free base
spectra of our tropane derivatives (33-36) show H3′ as
a triple triplet with coupling constants J ) 8.1, 8.1 Hz
(quintet like signal) for one stereoisomer (33, 35, 36)
and J ) 5.9, 11.8 Hz (septet like signal) for the other
(34). The signal of the bridgehead protons H1′/H5′ is a
multiplet from which J values could not be extracted
but with half-bandwidth larger for 33, 35, and 36 than

3372 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Heidempergher et al.
Sch em e 2
Sch em e 3
for 34 (∆ν1/2 ) 17 and 9 Hz, respectively). These data
suggest that 34 is an exo isomer in a normal chair
conformation, while 33, 35, and 36 are endo isomers in
a slightly flattened boat conformation (Scheme 1) in
which H3′ is placed in pseudo axial-axial and pseudo-
axial-equatorial relationship with C2′ and C4′ protons
and H1′/H5′ having a large coupling constant with H2′â/
H4′â protons due to an almost zero degree dihedral
angle between these protons. Steady state 1D-NOE
experiments performed on the N,N-dimethyl quaternary
ammonium iodide derivatives of 33 and 34 (75 and 76
respectively) confirmed configuration assignment. In
fact, irradiation of the N-methyl signal overlooking C6′/
C7′ (3.00 ppm in both compounds) enhances H6′â/H7′â
and H1′/H5′ signals in both 75 and 76; irradiation of
the N-methyl signal overlooking C3′ (3.12 ppm for 75,
3.29 ppm for 76) causes NOE enhancements of H1′/H5′
and H2′â/H4′â signals in both stereoisomers but of the
H3′ signal only in the case of endo derivative (75). 1H-
NMR spectra of all granatane derivatives (37-40) show
H3′ as a triple triplet with coupling constants J ) 6.2,
12.4 Hz, but H1′/H5′ signal is a narrow multiplet in the
case 38 and a broad doublet (J = 10 Hz) in the case of
37, 39, and 40. This pattern of coupling constants, as
in the case of tropanes, suggests that 38 is an exo isomer
in a “chair-chair” conformation and 37, 39, and 40 are
endo isomers in a “chair-boat”conformation20 (Schemes
1 and 2). Stereochemistry assignment was verified by
means of 13C-NMR and NOESY experiments performed
on compounds 38 and 37 as free bases. The 13C-NMR
spectra show C7′ chemical shifts at lower field for the
exo isomer 38 (20.0 ppm) with respect to the endo
isomer 37 (14.1 ppm) as previously reported,21 and the
NOESY spectra display H3′/H7′R cross peak for 38 and
H7′R/H2′R-H4′R cross peak for 37 in agreement with the
proposed configuration and conformation (Scheme 1).
The 1-(imidazolylalkyl)-3-phenylimidazolidin-2-ones
(56-70) (Table 3) were prepared according to the
procedure outlined in Scheme 3. The intermediates 41-
55 (Table 2) were prepared by alkylating the appropri-
ate 1-phenylimidazolidin-2-one with 4-(chloromethyl)-
5-methyl-1-(triphenylmethyl)-1H-imidazole [5-(chloro-
methyl)-1-(triphenylmethyl)-1H-imidazole to obtain 55]
in the presence of NaH at room temperature. Mild
deprotection of trityl derivatives in AcOH/H2O/THF at
reflux afforded 56-70. The two pairs of regioisomers
71, 72, and 73, 74 (Table 3) were prepared according to
Scheme 4 by direct alkylation of 59 in DMF at 0 °C in
the presence of NaH as base and the appropriate alkyl
halide. The imidazole substitution pattern was as-
signed using steady state 1D-NOE experiments through
irradiation of imidazole ring substituents. Irradiation
of the CH2 signal caused NOE enhancements of the
NCH3 and CH3 signals for 73 and only of the CH3 signal
for 74. Irradiation of the CH3 signal enhances the CH2
signal in 73 and the CH2 and NCH3 signals in 74.
Similar results were obtained for 71 and 72.
Molecu la r Mod elin g
Many pharmacophore models for the 5-HT3 receptor
antagonism have already been reported in the litera-
ture. However, substantial discrepancies between these
pharmacophore models can be noted because of the
different 5-HT3 compounds chosen and the different
methods used to build them. Bull et al.22 proposed three
necessary components for high 5-HT3 receptor affinity
on the basis of a critical examination of five pharma-
cophore models:23-27 an aromatic ring, a carbonyl group
directly attached to the aromatic ring, and a basic
nitrogen. The aromatic ring may be the benzene of a
benzoate or benzamide, or the five-atom ring of an
indole or indazole compound. The carbonyl group may
be substituted by a bioisosteric equivalent function, such
as a 1,2,4-oxadiazole ring.28 Clark et al.29 proposed a
pharmacophore model where the alignment of the
receptor element that interacts with the basic nitrogen
was judged to be a more critical factor than the
alignment of the nitrogen itself. In this pharmacophore
model, it is the lone pair of the nitrogen atoms and not
the nitrogens themselves, that is used for the superposi-

5-HT3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21 3373
Ta ble 2. Physicochemical Data of Intermediates 41-55
product
R
R1
Cl
Br
Cl
R2
R3
R4
% yield
mp, °C
formula
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
Cl
H
H
H
H
CH3
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
51
56
60
47
59
60
65
45
40
60
58
55
58
60
68
189-191
215-217
199-202
196-198
180-183
206 dec
178-180
165-168
180-183
133-135
174-176
185-187
173-176
170-173
162-166
C33H29ClN4O
C33H29BrN4O
C33H28Cl2N4O
C33H30N4O
C34H29N5O
C34H32N4OS
C34H32N4O
H
CN
SCH3
CH3
CH3
H
C35H34N4O
C33H29ClN4O
C33H29ClN4O
C34H29F3N4O
C33H29N5O3
C33H29FN4O
C34H32N4O2
C32H28N4
H
CF3
NO2
F
OCH3
H
H
H
H
H
H
Sch em e 4
tion of the molecules. In this case the lone pairs would
point to a specific atom on the receptor, but their
direction is not necessarily the same for all the com-
pounds. A molecular modeling study was performed in
order to verify whether the pharmacophore models cited
might be used for SAR study of the present class of
compounds. These compounds were submitted to a
systematic conformational analysis, and the distances
between the pharmacophore features described previ-
ously were measured during the complete scanning of
the torsional angles. No conformation of even the most
active structure of this series could be properly fitted
into any of the models proposed. For example, in the
reference model of Hibert et al.,24 the distance between
the centroid of the aromatic ring and the oxygen of the
carbonyl group, and the distance between the centroid
of the aromatic ring and the basic nitrogen, are 3.3 and
6.7 Å, respectively. On the other hand, we measured
4.1 and 7.0-8.8 Å in the case of compound 58, or 4.1
and 8.3-8.9 Å for the compound 28 of our series. In
addition, the substitution of the phenyl ring in the
present series is a crucial factor that can increase the
potency several times. This fact cannot be explained
by the previously reported models. An automated
pharmacophore builder, the APEX-3D, was used to
avoid any bias with the models cited. A set of four
5-HT3 antagonists was used to represent the major
different chemical classes of the 5-HT3 antagonists:
zacopride, ondansetron, granisetron, and tropisetron.
Compound 58 was chosen as representative of our series
of molecules. While the computational methodology
described in the experimental molecular modeling sec-
tion did not yield any meaningful pharmacophore model
when applied to the five structures, the same procedure,
applied only to zacopride, ondansetron, granisetron, and
tropisetron yielded a model that seems to be a compro-
mise between the models cited by Hibert et al.24 and
Clark et al.29 The elements of the pharmacophore are
as follows: the basic nitrogen, the receptor element that
interacts with the basic nitrogen, the carbonyl group,
and the aromatic ring. In spite of this good technical
result, the problem of the SAR remained still unsolved
because no structure of our series of compounds could
be fitted into this model. However, we envisaged that
this automatically generated model could be used as a
starting point for modeling studies if the rigorous
requirement for the aromatic ring (and/or its centroid
surrogate marker) was eliminated. Indeed, with this
proviso we found that many other known 5-HT3 antago-
nists could be superimposed to this revised model, which
uses only the carbonyl group and the basic nitrogen with
its lone pair pointing to the receptor atom as key points
for superimposition. In particular, the 5-HT3 antago-
nists MDL 72222, DAU 6215, BRL 46470, and com-
pound I were added in the superimposition of the model
previously defined by zacopride, ondansetron, granis-
etron, and tropisetron. Notably, BRL 46470 and com-
pound I have never been included in literature models
cited before. The analysis of this putative model of
bioactive conformations of eight compounds suggested
that, in addition to the features used for the super-
imposition, the presence of two hydrophobic sites could
refine the 5-HT3 antagonist pharmacophore model to
account for the activities of the training set (Figure 3).
The hydrophobic site, described already by Clark et al.29

3374 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Ta ble 3. Pharmacological Data of Compounds 21-40, and 56-74a
Heidempergher et al.
Bezold-J arisch
reflex 5-HT, 30 µg/kg iv
[3H]BRL 43694
endo/exo Ki nM ((SEM) nM ((SEM) 100 µg/kg iv
GPI Kb,
% of inhibn at
ID50 µg/kg
compd
R
R1
Cl
R2 R3
R4
R5
R6
n
iv (95% C. L.)
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
Cl
H
H
H
H
H
H
Cl
H
H
H
H
Cl
H
H
Cl
H
H
H
H
2 ((0.16)
40 (( 2.81)
6 ((0.48)
4 ((0.23)
210 ((12)
6 ((0.62)
30 ((1.51)
1 ((0.08)
8 ((0.63)
98 ((7.00)
10 ((0.60)
3 ((0.18)
25 ((0.95)
>10000
400 ((12)
12 ((0.97)
250 ((15)
360 ((39)
190 ((12)
>10000
0.5 ((0.02)
0.62 ((0.03)
0.038 ((0.001) 5.62 ((8.1)
3.4 ((0.12)
2.7 ((0.18)
1.6 ((0.98)
0.93 ((0.04)
0.42 ((0.02)
19 ((2.00)
290 ((18)
30.9 ((12)
60
-11
37
75
8
28
43
76
71
14
5
79.94 (54-98)
nc
nc
37.6 (31-46)
nc
nc
nc
OCH3
H
H
OCH3
CH3
H
SCH3
CN
Cl
33.1 ((8.4)
12 ((6.3)
H
H
H
H
H
H
H
H
214 ((93)
45 ((12)
21.4 ((9.5)
20.6 (11-31)
67.1 (34-93)
H
CF3
NO2
Br
Cl
Cl
H
H
Cl
Cl
H
H
Cl
Br
Cl
H
nc
nc
nc
nc
nc
nc
nc
nc
75.2 ((14)
38.3 ((16)
H
H
H
77.7
27
0
1
1
1
1
2
2
2
2
endo
exo
endo
endo
endo
exo
OCH3
H
-22
56
15
-21
22
5
87
89
93
95
88
88
86
86
29
5
H
H
H
nc
nc
nc
endo
endo
OCH3
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C2H5
H
12 ((1.6)
10.4 ((4.2)
5.26 (4.5-6.1)
6.5 (4.6-8.4)
2.2 (1.9-2.6)
3.9 (2.2-5.4)
32.2 (23-44)
28.6 (19-35)
3.1 (2.5-3.9)
3.4 (2.2-5.4)
nc
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
26.9 ((10)
134 ((45)
120 ((79)
45.7 ((12)
50.1 ((27)
CN
SCH3
CH3
CH3
H
CH3 CH3
H
H
H
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
Cl
H
H
nc
nc
CF3
NO2
F
OCH3
H
H
H
H
H
9.7 ((1.00)
6.6 ((0.51)
3.7 ((0.12)
3.6 ((0.18)
4 ((0.39)
67 ((3.00)
85 ((2.00)
55 ((1.00)
8.5 ((0.63)
68.5 ((12)
125 ((21)
88.3 ((17)
67.8 ((31)
45.4 ((23)
39
95
84
92
56
38
21
45
77
H
H
H
H
H
H
H
H
54 (46-64)
17.6 (12-24)
15.4 (12-19)
nc
nc
nc
CH3
CH3 C2H5
CH3
CH3 CH3
H
CH3
H
nc
63.8 ((27)
28.5 (18-41)
Ondansetron
Tropisetron
Granisetron
BRL 46470
1 ((0.09)
19.4 ((8.2)
9.33 ((6.8)
12.9 ((3.6)
22.0 ((7.4)
90
90
95
2.25 (1.6-2.9)
1.0 (0.9-1.2)
0.88 (0.6-1.1)
0.89 (0.3-4.7)
1.57 ((0.08)
0.35 ((0.02)
0.26 ((0.01)
90.5
a
None of the compounds showed affinity for D1, D2, R1, R2, M1+2, 5-HT1, 5-HT1A, 5-HT2, and 5-HT4 receptor binding sites (IC50 >10
µM), or agonistic (EC50 >1 µM) or antagonistic activity (Kb > 1 µM) on rat oesophagus preparation (5-HT4 receptor).
and located below the aromatic ring, is not shared by
all compounds.
activity relationship. The most potent antagonists could
be easily superimposed on this model. The compounds
from either imidazole and quinuclidine series, occupying
the two hydrophobic pockets with halogens or alkyl
groups (28, 58, and 63), display the highest potency.
Compounds with only one hydrophobic substituent on
the phenyl ring in a meta position from the imidazole
and quinuclidine series have a greater potency than the
corresponding unsubstituted structures (compare 21
and 29; 56 and 59). The same pattern of activity has
been reported for 5-HT3 receptor antagonists, belonging
to other chemical series.30,31 However, among the
compounds we prepared, the meta-substituted mol-
ecules have a potency lower than that of the corre-
The presence of the aromatic ring linked to the
carbonyl group does not appear to be essential for
affinity. As suggested by Bermudez et al.,17 this may
act as a “spacer” unit to ensure the optimal spatial
orientation of the other features. As we noted, the five-
atom aromatic ring of tropisetron may be substituted
by an imidazolone group (DAU 6215), by a urea group
(compound I), or by an aliphatic group (BRL 46470). The
affinity value of BRL 46470 toward 5-HT3 receptor
increased 6-fold with respect to tropisetron (Table 3).
The phenylimidazolidin-2-one derivatives lent support
to a model that qualitatively accounted for a structure-

5-HT3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21 3375
course fit the molecules from which they were derived,
but represents a redefined pharmacophore model in-
corporating features of the others. The most relevant
improvements of our model with respect to the models
reported in the literature previously are the definition
of the two important hydrophobic sites, and the fact that
the phenyl ring acts as a “spacer” unit and not as a
group interacting with the receptor.
P h a r m a cologica l Resu lts
As shown in Table 3, several compounds of this series
were selective 5-HT3 receptor antagonists displaying a
noticeable in vitro and in vivo activity. All of the active
molecules displaying high affinity for the 5-HT3 receptor
showed no affinity (IC50 > 10 µM) for adrenergic,
dopaminergic, muscarinic, and the other serotoninergic
receptors. In particular, no affinity was found for the
5-HT4 binding site in the rat striatum, and neither
5-HT4 agonist nor antagonist activity was detected in
the rat oesophagus preparation test (see the Experi-
mental Section). 1-(Imidazolylalkyl)-3-phenyl deriva-
tives were found to be more active than the correspond-
ing azabicycloalkane analogs. N-Alkylation of either
5-methyl-1H-imidazol-4-yl nitrogens as well as removal
of the 5-methyl substituent on the imidazolyl ring led
to a decrease in potency (compare analogs 71-74 to the
unalkylated analog 59 and 59 to 70, respectively).
Within the azabicycloalkane compounds, the quinucli-
dine and tropane (n ) 1) basic moieties led to more
potent compounds than the granatane (n ) 2) moiety.
Among the compounds tested, the exo compounds were
inactive (34) or less active (38) than the endo compounds
(33, 37), respectively. The ortho and para ring mono-
substitution decreased 5-HT3 receptor antagonist activ-
ity (25, 64, and 65). The meta substitution generally
increased both in vitro and in vivo 5-HT3 receptor
activity compared to the unsubstituted compounds (29,
36, 39, and 59). 2,5-disubstitution led to weak activity
(22, 35, and 40), while the 3,5-disubstituted compounds
(28, 58, and 63) were the most potent compounds of this
series. 1-(3,5-Dichlorophenyl)-3-[(5-methyl-1H-imida-
zol-4-yl)methyl]imidazolidin-2-one (58) was one of the
most potent 5-HT3 receptor antagonists reported so far.
This compound was a more potent 5-HT3 receptor
antagonist in vitro than the reference compounds tested
and showed in vivo activity comparable to that of
ondansetron (Table 3).
F igu r e 3. Superposition (without hydrogen) of zacopride,
ondansetron, granisetron, tropisetron, MDL 72222, DAU 6215,
BRL 46470, and compound I. The lone pair of the nitrogen
pointing at the receptor atoms are shown in yellow, the
nitrogen atoms in blue, and the carbonyl groups in red. The
hydrophobic sites (van der Waals surface) are in green. In this
model the direction of the lone pair is nearly perpendicular to
the plane of the aromatic rings.
F igu r e 4. Superposition (without hydrogen) of zacopride,
ondansetron, granisetron, tropisetron, MDL 72222, DAU 6215,
BRL 46470, compound I, and compounds 28, 58, 63, and 64.
The lone pair of the nitrogen pointing at the receptor atoms
are shown in yellow, the nitrogen atoms in blue, and the
carbonyl groups in red. The hydrophobic sites (van der Waals
surface) are in green. The van der Waals surface of the chloro
atom of compound 64 is shown in magenta.
sponding double-meta-substituted ones (28, 58, and 63).
In our model, the chloro atom of the para-substituted
inactive compounds 25 and 64 occupies the space located
between the two hydrophobic sites (Figure 4). As the
amino group of the benzene of zacopride is located in
this site, it is possible to formulate the hypothesis that
the presence of a receptor residue is able to give a polar
interaction with the ligand. The inactivity of the
compound bearing a chloro atom in the ortho position
to the phenyl ring (65) may be explained by the fact that
this substituent prevents the planarity between the
phenyl ring and the carbonyl group. As a consequence,
the halogen occupies a region out of the pharmacophoric
hydrophobic sites. The compounds of this series with
a tropane or granatane ring, and particularly the exo
derivatives when compared with the endo derivatives,
do not fit this model because of the greater distance
between the basic nitrogen and hydrophobic regions,
and this is in agreement with their lack of or low level
of affinity. It must be observed that this model does
not preclude those reported in the literature, which, of
Con clu sion s
Starting from the observation of the close electronic
similarity between the substructures of metoclopramide
and zetidoline, the substructure of the latter was linked
to basic moieties present in different 5-HT3 antagonists.
This work revealed novel and potent 5-HT3 receptor
antagonists as potential candidates as antiemetics or
psychotropic drugs. This new series of compounds
helped to refine a 5-HT3 antagonist pharmacophore
model that was used to perform a structure-activity
relationship study of the present class of compounds and
of some known 5-HT3 antagonists. The model obtained
in this study could be a useful tool for a rational design
of new potential 5-HT3 antagonists.
Exp er im en ta l Section
Ch em istr y. Melting points were determined in open glass
capillaries on a Buchi apparatus and are not corrected. 1H-
NMR and 13C-NMR spectra were recorded on a Varian VXR-

3376 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Heidempergher et al.
200 or VXR-400S spectrometer using the solvent as internal
standard. Chemical shifts are expressed in parts per million
(ppm). The complete 1H-NMR spectrum is listed for one
representative compound of each structural class, and only
signals of the differing parts are reported for the other
derivatives. When spectra were registered in different condi-
tions (solvent, hydrochloride, free base) within a structural
class, one full spectrum is reported for each experimental
condition. Steady state 1D-NOE (preirradiation time 4 s) and
NOESY (mixing time 0.5 s) experiments were performed on a
Varian VXR-400 at 27 °C in DMSO-d6 as solvent. Positive
ion fast bombardment (FAB), field desorption (FD), and
electronic impact (EI) mass spectra (MS) were obtained on a
Varian MAT 311-A and on a Finnigan TSQ 70 instrument.
Some compounds have been tested by direct exposure probe
technique (DEP) in order to increase the molecular ion
intensity. Elemental analyses were performed for new com-
pounds by a Carlo Erba 1106 instrument.Where elemental
analyses are indicated, the results were within 0.4% of the
theoretical values. Yields refer to the purified products and
are not optimized. Column chromatography was carried out
using silica gel 60, 230-400 mesh (Carlo Erba). Starting
materials that were not commercially available were prepared
according to procedures already published.
6.4-6.7 (m, 3H, H2′′ + H4′′ + H6′′), 7.04 (t, J ) 7.9 Hz, 1H,
H5′′); MS (EI) m/z (rel intensity) 293 (M+, 293), 153 (94), 140
(12), 124 (100), 96 (9). Anal. (C16H24ClN3) C, H, Cl, N.
Compounds 1-12 and 15-20 were similarly prepared.
Yields and analytical data are reported in Table 1. The 1H
NMR spectra and MS data are consistent with the assigned
structures.
Gen er a l P r oced u r e for Cycliza t ion of 1,2-Dia m in o-
eth a n es to Im id a zolid in -2-on es 21-39. The procedure is
reported for the preparation of 1-[1-azabicyclo[2.2.2]oct-3-yl]-
3-(3-chlorophenyl)imidazolidin-2-one hydrochloride (21). 1,1-
Carbonyldiimidazole (2.04 g, 0.0125 mol) was added to a
stirred solution of 1 (2.7 g, 0.0097 mol) in 10 mL of anhydrous
THF. The reaction mixture was refluxed for 8 h under
nitrogen atmosphere. After evaporation, the residue was
taken up in ethyl acetate, washed with saturated NaCl
solution, and dried over anhydrous Na2SO4. After filtration
and evaporation to dryness, the crude product was purified
by silica gel chromatography (CH2Cl2-MeOH-30% NH4OH,
180:20:2) as eluant, followed by treatment with an excess of a
solution of HCl in EtOH. The crude salt was collected by
filtration and recrystallized from anhydrous EtOH to give 2.3
g (69.3% yield) of the desired product (mp 234-239 °C): 1H-
NMR (200 MHz, DMSO-d6) 1.7-2.1 (m, 4H, CH2-5′ + CH2-
7′), 2.22 (m, 1H, H4′), 3.1-3.3 (m, 4H, CH2-6′ + CH2-8′), 3.3-
3.6 (m, 2H, CH2-2′), 3.6-3.9 (m, 4H, CH2-4 + CH2-5), 3.99 (m,
1H, H3′), 7.0-7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.74 (t, J ) 2.1
Hz, 1H, H2′′); MS (EI) m/z (rel intensity) 305 (M+, 10), 235
(13), 222 (12), 153 (7), 109 (100), 96 (24). Anal. (C16H20ClN3O‚
HCl) C, H, Cl, N.
Compounds 22-39 were prepared as hydrochlorides or free
bases according to the procedure described for 21 starting from
the appropriate intermediate (2-19).
1-[1-Aza b icyclo[2.2.2]oct -3-yl]-3-(5-ch lor o-2-m et h oxy-
p h en yl)im id a zolid in -2-on e, h yd r och lor id e (22): 75% yield
(mp 209-215 °C); 1H-NMR (200 MHz, DMSO-d6) 3.78 (s, 3H,
OCH3), 7.09 (d, J ) 8.7 Hz, 1H, H3′′), 7.2-7.4 (m, 2H, H4′′ +
H6′′); MS (EI) m/z (rel intensity) 335 (M+, 4), 265 (3), 252 (2),
168 (3), 109 (100), 96 (19). Anal. (C17H22ClN3O2‚HCl) C, H,
Cl, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Ar yl-
im id a zolid in -2-on es.32 (1) N-Ar yl-1,2-d ia m in oeth a n es.32
A
mixture of 2-bromoethylamine hydrobromide (0.1 mol) and the
aniline derivative (0.2 mol) in 40 mL of toluene was heated at
reflux temperature for 16 h and then cooled. A solution of 60
mL of water and 20 mL of 50% aqueous KOH was added, and
the layers were separated. The aqueous layer was saturated
with NaCl and extracted three times with toluene. The
combined organic layers were washed with saturated NaCl
solution, dried over anhydrous Na2SO4, filtered, and evapo-
rated to dryness. Column chromatography gave the pure
compounds.
(2) 1-Ar ylim id a zolid in -2-on es.32 To a solution of N-aryl-
1,2-diaminoethane derivative (0.3 mol) in 40 mL of anhydrous
THF, 1,1-carbonyldiimidazole (0.33 mol) was added under
nitrogen atmosphere. The solution was refluxed for 4 h and
then evaporated to dryness; the residue was taken up in ethyl
acetate, washed with saturated NaCl solution, and dried over
anhydrous Na2SO4. After filtration and evaporation to dry-
ness, the products were purified by crystallization from a
suitable solvent.
1-[1-Aza bicyclo[2.2.2]oct-3-yl]-3-(3-m eth oxyp h en yl)im i-
1
d a zolid in -2-on e (23): 63% yield (mp 120-133 °C); H-NMR
(200 MHz, CDCl3) 1.4-1.9 (m, 4H, CH2-5′ + CH2-7′), 2.00
(sestet, J ) 3.0 Hz, 1H, H4′), 2.7-3.1 (m, 5H, CH2-6′ + CH2-8′
+ H2′a), 3.30 (ddd, J ) 14.1, 9.7, 2.1 Hz, 1H, H2′b), 3.60 (m,
2H, CH2-5), 3.80 (s, 3H, OCH3), 3.82 (m, 3H, CH2-4 + H3′),
6.57 (m, 1H, H4′′), 6.95 (m, 1H, H6′′), 7.20 (t, J ) 8.3 Hz, 1H,
H5′′), 7.34 (t, J ) 2.2 Hz, 1H, H2′′); FD MS 301. Anal.
(C17H23N3O2) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of In ter m ed i-
a tes 1-20. This procedure is illustrated for the preparation
of N-[endo-8-methyl-8-azabicyclo[3.2.1]oct-3-yl]-N′-(3-chlo-
rophenyl)-1,2-diaminoethane (13) and N-[exo-8-methyl-8-
azabicyclo[3.2.1]oct-3-yl]-N′-(3-chlorophenyl)-1,2-diamino-
ethane (14). Tropinone (1.53 g, 0.01 mol) was added to a
stirred solution of N-(3-chlorophenyl)-1,2-diaminoethane (2.06
g, 0.01 mol) in 50 mL of anhydrous methanol kept under
nitrogen atmosphere. The pH was adjusted to 6 by addition
of AcOH. NaBH3CN (1.26 g, 0.02 mol) was added, and the
reaction mixture was refluxed 8 h, then cooled, and filtered.
After evaporation, the residue was taken up with water,
basified with 20% NaOH solution, and extracted three times
with ethyl acetate. The organic layer was washed with
saturated NaCl solution, dried over anhydrous Na2SO4, and
evaporated to dryness after filtration. The residue was
purified by silica gel chromatography (CH2Cl2-MeOH-30%
NH4OH, 150:50:5) as eluant, to give 1.2 g of the endo product
13 as a white solid followed by 0.52 g of the exo compound 14
as a white solid. 13: 1H-NMR (200 MHz, CDCl3) 1.4-2.2 (m,
8H, CH2-2′ + CH2-4′ + CH2-6′ + CH2-7′), 2.26 (s, 3H, NCH3),
2.83 (m, 3H, ArNHCH2CH2 + H3′), 3.0-3.2 (m, 4H, ArNHCH2-
CH2 + H1′ + H5′), 4.3 (br s, 1H, ArNH), 6.4-6.7 (m, 3H, H2′′
+ H4′′ + H6′′), 7.06 (t, J ) 7.9 Hz, 1H, H5′′); MS (EI) m/z (rel
intensity) 293 (M+, 8), 153 (88), 140 (15), 124 (100), 96 (18).
Anal. (C16H24ClN3) C, H, Cl, N.
1-[1-Aza bicyclo[2.2.2]oct-3-yl]-3-(3-m eth ylp h en yl)im i-
1
d a zolid in -2-on e (24): 64% yield (mp 122-126 °C); H-NMR
(200 MHz, CDCl3): 2.33 (s, 3H, CH3), 6.84 (d, J ) 7.0 Hz, 1H,
H4′′), 7.1-7.3 (m, 2H, H5′′ + H6′′), 7.43 (s, 1H, H2′′); FD MS
285. Anal. (C17H23N3O) C, H, N.
1-[1-Aza b icyclo[2.2.2]oct -3-yl]-3-(4-ch lor op h en yl)im i-
1
d a zolid in -2-on e (25): 66% yield (mp 175-178 °C); H-NMR
(200 MHz, CDCl3): 7.26 (m, 2H, H3′′ + H5′′), 7.47 (m, 2H,
H2′′ + H6′′); FD MS 305. Anal. (C16H20ClN3O) C, H, Cl, N.
1-[1-Azabicyclo[2.2.2]oct-3-yl]-3-[3-(m eth ylth io)ph en yl]-
im id a zolid in -2-on e, h yd r och lor id e (26): 62% yield (mp 205
°C dec.). 1H-NMR (200 MHz, DMSO-d6) 2.44 (s, 3H, SCH3),
6.90 (m, 1H, H4′′), 7.25 (m, 2H, H5′′ + H6′′), 7.54 (s, 1H, H2′′);
MS (EI) m/z (rel intensity) 317 (M+, 17), 247 (7), 234 (11), 193
(9), 109 (100), 96 (20). Anal. (C17H23N3OS‚HCl) C, H, Cl, N,
S.
1-[1-Aza bicyclo[2.2.2]oct-3-yl]-3-(3-cya n op h en yl)im id a -
zolid in -2-on e (27): 58% yield (mp 163-167 °C); 1H-NMR (200
MHz, CDCl3): 7.2-7.5 (m, 2H, H4′′ + H5′′), 7.7-7.9 (m, 2H,
H2′′ + H6′′); FD MS 296. Anal. (C17H20N4O) C, H, N.
1-[1-Aza bicyclo[2.2.2]oct -3-yl]-3-(3,5-d ich lor op h en yl)-
im id a zolid in -2-on e, h yd r och lor id e h yd r a te (28): 72%
yield (mp 248.5-254 °C); 1H-NMR (200 MHz, DMSO-d6) 7.21
(t, J ) 1.7 Hz, 1H, H4′′), 7.64 (t, J ) 1.7 Hz, 2H, H6′′ + H2′′);
MS (EI) m/z (rel intensity) 339 (M+, 12), 269 (8), 256 (11), 109
(100), 96 (20). Anal. (C16H19Cl2N3O‚HCl‚H2O) C, H, Cl, N.
14: 1H-NMR (200 MHz, CDCl3) 1.3-1.6 (m, 4H, H2′â + H4′â
+ H6′R + H7′R), 1.77 (ddd, J ) 13.2, 5.6, 3.4 Hz, 2H, H2′R +
H4′R), 1.97 (m, 2H, H6′â + H7′â), 2.27 (s, 3H, NCH3), 2.73 (tt,
J ) 5.6, 11.2 Hz, 1H, H3′), 2.83 (m, 2H, ArNHCH2CH2), 3.0-
3.2 (m, 4H, ArNHCH2CH2 + H1′ + H5′), 4.3 (br s, 1H, ArNH),

5-HT3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21 3377
1-[1-Aza bicyclo[2.2.2]oct-3-yl]-3-p h en ylim id a zolid in -2-
on e (29): 83% yield (mp 140-143 °C); 1H-NMR (200 MHz,
CDCl3): 7.01 (m, 1H, H4′′), 7.31 (m, 2H, H3′′ + H5′′), 7.52 (m,
2H, H2′′ + H6′′); FD MS 271. Anal. (C16H21N3O) C, H, N.
1-[1-Aza b icyclo[2.2.2]oct -3-yl]-3-[3-(t r iflu or om et h yl)-
p h en yl]im id a zolid in -2-on e (30): 81% yield (mp 130.5-134.5
°C); 1H-NMR (200 MHz, CDCl3): 7.27 (d, J ) 7.9 Hz, 1H, H4′′),
7.42 (t, J ) 7.9 Hz, 1H, H5′′), 7.76 (m, 2H, H2′′ + H6′′); MS
(EI) m/z (rel intensity) 339 (M+, 26), 269 (16), 256 (19), 109
(100), 96 (17). Anal. (C17H20F3N3O) C, H, N.
13.0, 2.8 Hz, H2′R + H4′R), 1.8-2.1 (m, 5H, H6′â + H8′â +
H7′R + H2′â + H4′â), 2.40 (s, 3H, NCH3), 3.02 (br d, J ) 11.1
Hz, 2H, H1′ + H5′), 3.47 (m, 2H, CH2-5), 3.76 (m, 2H, CH2-4),
4.20 (tt, J ) 12.4, 6.2 Hz, 1H, H3′), 6.9-7.4 (m, 3H, H4′′ +
H5′′ + H6′′), 7.74 (t, J ) 2.1 Hz, 1H, H2′′); 13C-NMR (50 MHz,
CDCl3, free base) 14.1 (C7′), 24.4 (C6′ + C8′), 28.5 (C2′ + C4′),
40.1 (NCH3), 38.8, 42.6 (C4 + C5), 44.9 (C3′), 51.5 (C1′ + C5′),
115.1, 117.1, 121.9, 129.7 (C2′′ + C4′′ + C5′′ + C6′′), 134.5,
141.8 (C1′′ + C3′′), 156.9 (C2); MS (EI) m/z (rel intensity) 333
(M+, 21), 235 (3), 223 (7), 138 (100), 110 (70), 96 (82). Anal.
(C18H24ClN3O‚HCl) C, H, Cl, N.
exo-1-[9-Meth yl-9-a za bicyclo[3.3.1]n on -3-yl]-3-(3-ch lo-
r op h en yl)im id a zolid in -2-on e (38): 58% yield (mp 157.5-
161.5 °C); 1H-NMR (400 MHz, DMSO-d6) 1.3-1.5 (m, 4H, H6′R
+ H8′R + H2′R + H4′R), 1.62 (m, 1H, H7′â), 1.75 (m, 1H, H7′R),
1.8-2.1 (m, 4H, H6′â + H8′â + H4′â + H2′â), 2.39 (s, 3H,
NCH3), 2.83 (narrow m, 2H, H1′ + H5′), 3.44 (m, 2H, CH2-5),
3.77 (m, 2H, CH2-4), 4.56 (tt, J ) 12.4, 6.2 Hz, 1H, H3′), 6.9-
7.4 (m, 3H, H4′′ + H5′′ + H6′′), 7.77 (t, J ) 2.1 Hz, 1H, H2′′);
13C-NMR (50 MHz, CDCl3) 20.0 (C7′), 25.0 (C6′ + C8′), 30.2
(C2′ + C4′), 36.0, 42.5 (C4 + C5), 40.5 (NCH3), 45.5 (C3′), 53.3
(C1′ + C5′), 114.9, 117.2, 122.0, 129.7 (C2′′ + C4′′ + C5′′ +
C6′′), 134.5, 141.7 (C1′′ + C3′′), 156.8 (C2); MS (EI) m/z (rel
intensity) 333 (M+, 16), 235 (2), 223 (4), 138 (100), 110 (33),
96 (58). Anal. (C18H24ClN3O) C, H, N.
1-[1-Aza bicyclo[2.2.2]oct-3-yl]-3-(3-n itr op h en yl)im id a -
zolid in -2-on e, h yd r och lor id e (31): 52% yield (mp 220 °C
1
dec); H-NMR (200 MHz, DMSO-d6) 7.62 (t, J ) 8.2 Hz, 1H,
H5′′), 7.85 (m, 2H, H4′′ + H6′′), 8.63 (t, J ) 2.2 Hz, 1H, H2′′),
9.8 (br s, 1H, NH+); MS (EI) m/z (rel intensity) 316 (M+, 19),
286 (2), 246 (18), 233 (23), 109 (100), 96 (23). Anal.
(C16H20N4O3‚HCl) C, H, Cl, N.
1-[1-Aza b icyclo[2.2.2]oct -3-yl]-3-(3-b r om op h en yl)im i-
1
d a zolid in -2-on e (32): 72% yield (mp 132-136 °C); H-NMR
(200 MHz, CDCl3): 7.0-7.3 (m, 2H, H4′′ + H5′′), 7.47 (m, 1H,
H6′′), 7.70 (s, 1H, H2′′); FD MS 349. Anal. (C16H20BrN3O) C,
H, N.
en d o-1-[8-Meth yl-8-a za bicyclo[3.2.1]oct-3-yl]-3-(3-ch lo-
r op h en yl)im id a zolid in -2-on e, h yd r och lor id e (33): 68%
1
yield (mp 264-268 °C); H-NMR (200 MHz, DMSO-d6) 2.0-
en d o-1-[9-M e t h y l-9-a z a b i c y c lo [3.3.1]n o n -3-y l]-3-
p h en ylim id a zolid in -2-on e, h yd r och lor id e (39): 63% yield
2.5 (m, 8H, CH2-2′ + CH2-4′ + CH2-6′ + CH2-7′), 2.62 (d, J )
4.9 Hz, 3H, NCH3), 3.50 (m, 2H, CH2-5), 3.81 (m, 5H, CH2-4 +
H1′ + H5′ +H3′), 7.0-7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.76 (t,
J ) 2.1 Hz, 1H, H2′′), 9.7 (br s, 1H, NH+); 1H-NMR (200 MHz,
CDCl3, free base) 1.4-1.6 (m, 4H, H6′R + H7′R + H2′R +
H4′R), 2.10 (m, 2H, H6′â + H7′â), 2.20 (s, 3H, NCH3), 2.33
(dt, J ) 14.0, 8.1 Hz, 2H, H2′â + H4′â), 3.19 (m, ∆ν1/2 ) 17
Hz, 2H, H1′ + H5′), 4.11 (tt, J ) 8.1, 8.1 Hz, 1H, H3′), 6.9-
7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.54 (t, J ) 2.1 Hz, 1H, H2′′);
MS (EI) m/z (rel intensity) 319 (M+, 19), 223 (13), 196 (6), 124
(44), 96 (97), 82 (100). Anal. (C17H22ClN3O‚HCl) C, H, Cl, N.
exo-1-[8-Met h yl-8-a za b icyclo[3.2.1]oct -3-yl]-3-(3-ch lo-
r oph en yl)im idazolidin -2-on e, h ydr och lor ide h ydr ate (34):
70% yield (mp 239-243 °C); 1H-NMR (200 MHz, DMSO-d6)
1.75 (m, 2H, H2′â + H4′â), 1.95 (m, 2H, H6′R + H7′R), 2.2-
2.5 (m,4H, H2′R + H4′R + H6′â + H7′â), 2.64 (d, J ) 4.9 Hz,
3H, NCH3), 3.45 (m, 2H, CH2-5), 3.81 (m, 2H, CH2-4), 3.90 (m,
2H, H1′ + H5′), 4.17 (tt, J ) 5.9, 11.8 Hz, 1H, H3′), 6.9-7.5
(m, 3H, H4′′ + H5′′ + H6′′), 7.55 (t, J ) 2.1 Hz, 1H, H2′′);
1H-NMR (200 MHz, CDCl3, free base) 1.58 (ddd, J ) 12.8, 5.9,
3.3 Hz, 2H, H2′R + H4′R), 1.7-1.9 (m, 4H, H6′R + H7′R +
H2′â + H4′â), 2.07 (m, 2H, H6′â + H7′â), 2.28 (s, 3H, NCH3),
3.22 (m, ∆ν1/2 ) 9 Hz, 2H, H1′ + H5′), 3.43 (m, 2H, CH2-5),
3.73 (m, 2H, CH2-4), 4.20 (tt, J ) 11.8, 5.9 Hz, 1H, H3′), 6.9-
7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.60 (t, J ) 2.1 Hz, 1H, H2′′);
MS (EI) m/z (rel intensity) 319 (M+, 12), 223 (18), 196 (5), 124
(88), 96 (80), 82 (100). Αnal. (C17H22ClN3O‚HCl‚H2O) C, H,
Cl, N.
1
(mp 243-245.5 °C); H-NMR (400 MHz, DMSO-d6) 6.98 (m,
1H, H4′′), 7.30 (m, 2H, H3′′ + H5′′), 7.54 (m, 2H, H2′′ + H6′′);
FAB-MS m/z 300 (M + H)+. Anal. (C18H25N3O‚HCl) C, H, Cl,
N.
N-[en d o-9-Meth yl-9-a za bicyclo[3.3.1]n on -3-yl]-N-[(4-n i-
t r op h en oxy)ca r b on yl]-N′-(5-ch lor o-2-m et h oxyp h en yl)-
1,2-d ia m in oeth a n e (20a ). A solution of 4-nitrophenylchlo-
roformate (1.3 g, 0.0065 mol) in 5 mL of dichloromethane was
dropped at 0 °C to a solution of 20 (2 g; 0.0059 mol) and
triethylamine (0.99 mL, 0.0071 mol) in 30 mL of dichlo-
romethane. The mixture was stirred at 0 °C for 4 h, washed
with saturated NaCl solution, dried over anhydrous Na 2SO4,
and evaporated to dryness after filtration. The crude product
was purified by silica gel chromatography (EtOAc-MeOH-
TEA, 80:15:5) as eluant to give 2.54 g (86% yield) of an
1
amorphous yellow solid (mp 57-64 °C); H-NMR (200 MHz,
CDCl3): 0.8-2.3 (m, 10H, CH2-2′ + CH2-4′ + CH2-6′ + CH2-7′
+ CH2-8′), 2.47 (s, 3H, NCH3), 3.07 (d, J ) 10.9 Hz, 2H, H2′ +
H5′), 3.3-3.7 (m, 4H, NHCH2CH2), 3.81 (s, 3H, OCH3), 4.1-
4.7 (m, 2H, H3′ + NHCH2CH2), 6.5-6.7 (m, 3H, H3′′ + H4′′ +
H6′′), 7.37,8.27 (two m, 4H, PhNO2); MS (EI) m/ z (rel
intensity) 502 (M+, 3), 363 (22), 320 (34), 138 (100). Anal
(C25H31ClN4O5) C, H, Cl, N.
en do-1-[9-Meth yl-9-azabicyclo[3.3.1]n on -3-yl]-3-(5-ch lor o-
2-m eth oxyph en yl)im idazolidin -2-on e, Hydr och lor ide (40).
A solution of 20a (2.5 g; 0.005 mol) in 60 mL of anhydrous
pyridine was refluxed 56 h. The solution was evaporated to
dryness then purified by silica-gel chromatography (EtOAc-
MeOH-TEA, 80:15:5) as eluant followed by treatment with
an excess of a solution of HCl in EtOH. The crude salt was
ground with anhydrous EtOH to give 1.1 g (61% yield) of an
en do-1-[8-Meth yl-8-azabicyclo[3.2.1]oct-3-yl]-3-(5-ch lor o-
2-m et h oxyp h en yl)im id a zolid in -2-on e, h yd r och lor id e
(35): 41% yield (mp 224-228 °C); 1H-NMR (200 MHz, DMSO-
d6) 6.80 (d, J ) 7.9 Hz, 1H, H3′′), 7.12 (dd, J ) 7.9, 2.5 Hz,
1H, H4′′), 7.36 (d, J ) 2.5 Hz, 1H, H6′′); MS (EI) m/z (rel
intensity) 349 (M+, 32), 253 (17), 170 (10), 124 (100), 96 (70),
82 (66). Anal. (C18H24ClN3O2‚HCl) C, H, Cl, N.
amorphous solid (mp 95-103 °C):
1H-NMR (400 MHz, DMSO-
d6) 7.06 (d, J ) 8.8 Hz, 1H, H3′′), 7.23 (dd, J ) 8.8, 2.6 Hz,
1H, H4′′), 7.29 (d, J ) 2.6 Hz, 1H, H6′′); FD MS 363. Anal.
(C19H26ClN3O2‚HCl) C, H, Cl, N.
en d o-1-[8-Met h yl-8-a za b icyclo[3.2.1]oct -3-yl]-3-p h en -
ylim id a zolid in -2-on e, h yd r och lor id e (36): 68% yield (mp
252-257 °C); 1H-NMR (200 MHz, DMSO-d6) 6.99 (m, 1H, H4′′),
7.30 (m, 2H, H3′′ + H5′′), 7.54 (m, 2H, H2′′ + H6′′); MS (EI)
m/z (rel intensity) 285 (M+, 11), 189 (41), 162 (10), 124 (64),
96 (85), 82 (100). Anal. (C17H23N3O‚HCl) C, H, Cl, N.
en d o-1-[9-Meth yl-9-a za bicyclo[3.3.1]n on -3-yl]-3-(3-ch lo-
r op h en yl)im id a zolid in -2-on e, h yd r och lor id e (37): 62%
The quaternary ammonium iodide salts 75 and 76 were
prepared by addition of an excess of methyl iodide to a solution
of the corresponding free bases of 33 and 34 in MeOH. The
resulting precipitates were collected by filtration and ground
with acetone to give white solids.
en d o-1-[8-Dim eth yl-8-a za bicyclo[3.2.1]octyl]-3-(3-ch lo-
r op h en yl)im id a zolid in -2-on e, iod id e (75): 1H-NMR (400
MHz, DMSO-d6) 2.10 (m, 2H, H6′R + H7′R), 2.21 (d, J ) 17.0
Hz, 2H, H2′R + H4′R), 2.33 (m, 2H, H6′â + H7′â), 2.58 (ddd,
J ) 16.7, 9.4, 4.8 Hz, 2H, H2′â + H4′â), 3.00, 3.12 (two s, 6H,
N(CH3)2), 3.60 (m, 2H, CH2-5), 3.79 (m, 2H, CH2-4), 3.84 (m,
2H, H1′ + H5′), 4.14 (t, J ) 9.2 Hz, 1H, H3′), 7.0-7.5 (m, 3H,
H4′′ + H5′′ + H6′′), 7.77 (t, J ) 2.1 Hz, 1H, H2′′). Anal.
(C18H25ClIN3O) C, H, N.
1
yield (mp 243-249 °C); H-NMR (400 MHz, DMSO-d6) 1.3-
1.6 (m, 3H, H6′R + H8′R + H7′â), 1.8-2.3 (m, 7H, CH2-2′ +
CH2-4′ + H6′â + H8′â + H7′R), 2.79 (s, 3H, NCH3), 3.53 (m,
2H, CH2-5), 3.64 (br d, J ) 10.6 Hz, 2H, H1′ + H5′), 3.82 (m,
2H, CH2-4), 4.56 (tt, J ) 12.4, 6.2 Hz, 1H, H3′), 6.9-7.4 (m,
3H, H4′′ + H5′′ + H6′′), 7.74 (t, J ) 2.0 Hz, 1H, H2′′), 9.9 (br
1
s, 1H NH+); H-NMR (400 MHz, DMSO-d6, free base): 0.95
(m, 2H, H6′R + H8′R), 1.43 (m, 1H, H7′â), 1.56 (ddd, J ) 13.0,

3378 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21
Heidempergher et al.
exo-1-[8-Dim et h yl-8-a za b icyclo[3.2.1]oct -yl]-3-(3-ch lo-
r op h en yl)im id a zolid in -2-on e, iod id e (76): 1H-NMR (400
MHz, DMSO-d6) 1.84 (dd, J ) 13.4, 6.6 Hz, 2H, H2′R + H4′R),
2.07 (m, 2H, H6′R + H7′R), 2.35 (m, 2H, H6′â + H7′â), 2.52
(m, 2H, H2′â + H4′â), 3.00, 3.29 (two s, 6H, N(CH3)2), 3.55
(m, 2H, CH2-5), 3.80 (m, 2H, CH2-4), 3.90 (m, 3H, H3′ + H1′
+ H5′), 7.0-7.4 (m, 3H, H4′′ + H5′′ + H6′′), 7.72 (t, J ) 2.1
Hz, 1H, H2′′). Anal. (C18H25ClIN3O) C, H, N.
°C); 1H-NMR (200 MHz, DMSO-d6) 7.3-7.6 (m, 2H, H4′′ +
H5′′), 7.85 (m, 1H, H6′′), 8.00 (t, J ) 1.8 Hz, 1H, H2′′); MS
(EI) m/z (rel intensity) 281 (M+, 2), 200 (12), 187 (18), 96 (88),
95 (100). Anal. (C15H15N5O) C, H, N.
1-[(5-Met h yl-1H -im id a zol-4-yl)m et h yl]-3-[3-(m et h yl-
th io)p h en yl]im id a zolid in -2-on e (61): 89% yield (mp 185-
190 °C); 1H-NMR (200 MHz, CDCl3): 2.49 (s, 3H, SCH3), 6.93
(m, 1H, H4′′), 7.24 (m, 2H, H5′′ + H6′′), 7.54 (m, 1H, H2′′);
MS (EI) m/ z (rel intensity) 302 (M+, 76), 287 (8), 221 (11),
208 (76), 152 (50), 96 (100), 95 (80). Anal. (C15H18N4OS) C,
H, N, S.
1-[(5-Me t h yl-1H -im id a zol-4-yl)m e t h yl]-3-(3-m e t h yl-
p h en yl)im id a zolid in -2-on e (62): 88% yield (mp 216-221
°C); 1H-NMR (400 MHz, DMSO-d6) 2.26 (s, 3H, CH3-3′′), 6.78
(d, J ) 7.5 Hz, 1H, H4′′), 7.16 (t, J ) 7.5 Hz, 1H, H5′′), 7.35
(m, 2H, H2′′ + H6′′); MS (EI) m/z (rel intensity) 270 (M+, 35),
255 (6), 189 (7), 176 (43), 120 (50), 96 (72), 95 (100). Anal.
(C15H18N4O) C, H, N.
1-(3,5-Dim eth ylp h en yl)-3-[(5-m eth yl-1H-im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (63): 83% yield (mp 246-249
°C); 1H-NMR (200 MHz, DMSO-d6) 2.22 (s, 6H, CH3-3′′ + CH3-
5′′), 6.61 (s, 1H, H4′′), 7.17 (s, 2H, H2′′ + H6′′); MS (EI) m/z
(rel intensity) 284 (M+, 20), 269 (2), 203 (3), 190 (39), 134 (51),
96 (90), 95 (100). Anal. (C16H20N4O) C, H, N.
1-(4-Ch lor op h e n yl)-3-[(5-m e t h yl-1H -im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (64): 77% yield (mp 230-234
°C); 1H-NMR (200 MHz, DMSO-d6) 7.33 (m, 2H, H3′′ + H5′′),
7.57 (m, 2H, H2′′ + H6′′); MS (EI) m/z (rel intensity) 290 (M+,
12), 275 (2), 209 (2), 196 (16), 140 (18), 96 (80), 95 (100). Anal.
(C14H15ClN4O) C, H, Cl, N.
1-(2-Ch lor op h e n yl)-3-[(5-m e t h yl-1H -im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (65): 70% yield (mp 159.5-167.5
°C); 1H-NMR (400 MHz, DMSO-d6) 7.2-7.6 (m, 4H, H3′′ + H4′′
+ H5′′ + H6′′); MS (EI) m/z (rel intensity) 290 (M+, 54), 275
(21), 209 (13), 196 (25), 140 (18), 96 (75), 95 (100). Anal.
(C14H15ClN4O) C, H, Cl, N.
1-[(5-Me t h yl-1H -im id a zol-4-yl)m e t h yl]-3-(t r iflu or o-
m eth yl)im id a zolid in -2-on e (66): 84% yield (mp 205-209
°C); 1H-NMR (200 MHz, DMSO-d6) 7.2-7.7 (m, 3H, H4′′ + H5′′
+ H6′′), 8.12 (s, 1H, H2′′); MS (EI) m/z (rel intensity) 324 (M+,
33), 309 (6), 243 (6), 230 (13), 174 (19), 96 (78), 95 (100). Anal.
(C15H15F3N4O) C, H, N.
Gen er a l P r oced u r e for th e P r ep a r a tion of In ter m ed i-
a tes 41-54. The procedure is reported for the preparation of
1-[(5-methyl-1-(triphenylmethyl)-1H-imidazol-4-yl)methyl]-3-
(3-chlorophenyl)imidazolidin-2-one (41). 50% NaH (0.3
g,0.0062mol) was added at 0 °C to a stirred solution of 1-(3-
chlorophenyl)imidazolidin-2-one (1.2 g, 0.0061 mol) in 20 mL
of anhydrous DMF kept under nitrogen atmosphere. The
solution was stirred for 1 h at 60 °C, and then 4-(chloromethyl)-
5-methyl-1-(triphenylmethyl)-1H-imidazole (2.3 g, 0.0061 mol)
was added at room temperature. The mixture was stirred 6
h at 90 °C, cooled, poured into water, and extracted with CH2-
Cl2. The organic layer was washed with saturated NaCl
solution, dried over anhydrous Na2SO4, and evaporated to
dryness after filtration. The residue was purified by silica gel
chromatography (EtOAc as eluant) to give 2.1 g of the desired
product as a white solid. 1H-NMR (200 MHz, CDCl3) 1.47 (s,
3H, CH3-5′), 3.52 (m, 2H, CH2-5), 3.74 (m, 2H, CH2-4), 4.36 (s,
2H, CH2-4′), 6.9-7.5 (m, 19H, 3-Ph + H2′ + H4′′ + H5′′ +
H6′′), 7.57 (t, J ) 2.1 Hz, 1H, H2′′).; FD MS 532. Anal.
(C33H29ClN4O) C, H, Cl, N.
Compounds 42-54 were similarly prepared starting from
related 1-arylimidazolidin-2-ones. Compound 55 was prepared
employing 5-chloromethyl-1-(triphenylmethyl)-1H-imidazole as
alkylating agent. Yields and analytical data are given in Table
2. The 1H NMR spectra and MS data were consistent with
the assigned structures.
Typ ica l Dep r otection P r oced u r e of Tr ityl Der iva tives
to 1-(Im id a zolyla lk yl)-3-p h en ylim id a zolid in -2-on es (56-
70). The procedure is reported for the preparation of 1-(3-
chlorophenyl)-3-[(5-methyl-1H-imidazol-4-yl)methyl]imidazo-
lidin-2-one (56). A solution of 41 (2 g; 0.0038 mol) in AcOH
(30 mL), H2O (30 mL), and THF (30 mL) was heated at reflux
for 1 h. The solution was cooled and poured into 1 N HCl (100
mL) and washed with ethyl acetate. The aqueous layer was
basified with K2CO3 to pH 9 and then extracted with CH2Cl2.
The organic phase was washed with saturated NaCl solution,
dried over anhydrous Na2SO4, and, after filtration, evaporated
to dryness. The residue was ground with dry Et2O to obtain
0.8 g (73% yield) of the product as a white solid (mp 229.5-
232.5 °C dec): 1H-NMR (200 MHz, CDCl3) 2.28 (s, 3H, CH3-
5′), 3.50 (m, 2H, CH2-5), 3.75 (m, 2H, CH2-4), 4.35 (s, 2H, CH2-
4′), 6.9-7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.47 (s, 1H, H2′), 7.58
(t, J ) 2.1 Hz, 1H, H2′′); MS (EI) m/z (rel intensity) 290 (M+,
6), 275 (2), 209 (3), 196 (10), 140 (16), 96 (83), 95 (100). Anal.
(C14H15ClN4O) C, H, Cl, N.
1-[(5-Meth yl-1H-im idazol-4-yl)m eth yl]-3-(3-n itr oph en yl)-
im id a zolid in -2-on e (67): 88% yield (mp 227-231 °C); 1H-
NMR (200 MHz, DMSO-d6) 7.57 (dd, J ) 9.0, 7.4 Hz, 1H, H5′′),
7.80 (m, 2H, H6′′ + H4′′), 8.62 (t, J ) 2.3 Hz, 1H, H2′′); MS
(EI) m/z (rel intensity) 301 (M+, 20), 286 (4), 220 (3), 207 (5),
151 (6), 96 (86), 95 (100). Anal. (C14H15N5O3) C, H, N.
1-(3-F lu or op h e n yl)-3-[(5-m e t h yl-1H -im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (68): 90% yield (mp 220.5-223.5
1
°C); H-NMR (200 MHz, DMSO-d6) 6.78 (m, 1H, H4′′), 7.1-
7.7 (m, 3H, H5′′ + H6′′ + H2′′); FAB-MS m/z 275 (M + H)+.
Anal. (C14H15FN4O) C, H, N:
The following compounds were also prepared by the general
procedure described above.
1-(3-Met h oxyp h en yl)-3-[(5-m et h yl-1H -im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (69): 84% yield (mp 183-187
°C); 1H-NMR (200 MHz, DMSO-d6) 6.55 (ddd, J ) 8.1, 2.4, 0.9
Hz, 1H, H4′′), 7.03 (ddd, J ) 8.1, 2.0, 0.9 Hz, 1H, H6′′), 7.1-
7.5 (m, 2H, H2′′ + H5′′); FAB-MS m/z 287 (M + H)+. Anal.
(C15H18N4O2) C, H, N.
1-[(1H-Im id a zol-4-yl)m eth yl]-3-p h en ylim id a zolid in -2-
on e (70): 72% yield (mp 201-203 °C); 1H-NMR (400 MHz,
DMSO-d6) 3.38 (m, 2H, CH2-5), 3.74 (m, 2H, CH2-4), 4.27 (s,
2H, CH2-4′), 6.97 (m, 1H, H4′′), 7.01 (s, 1H, H5′), 7.30 (m, 2H,
H3′′ + H5′′), 7.56 (m, 3H, H2′ + H6′′ + H2′′); MS (EI) m/z (rel
intensity) 242 (M+, 100), 175 (3), 162 (64), 106 (86), 82 (90),
81 (79). Anal. (C13H14N4O) C, H, N.
1-(3-Br om op h e n yl)-3-[(5-m e t h yl-1H -im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (57): 88% yield (mp 233-238.5
1
°C); H-NMR (400 MHz, DMSO-d6) 2.15 (s, 3H, CH3-5′), 3.36
(m, 2H, CH2-5), 3.73 (m, 2H, CH2-4), 4.22 (s, 2H, CH2-4′), 7.1-
7.5 (m, 3H, H4′′ + H5′′ + H6′′), 7.43 (s, 1H, H2′), 7.92 (t, J )
2.1 Hz, 1H, H2′′), 11.8 (br s, 1H, NH-1′); FAB-MS m/z 335 (M
+ H)+. Anal. (C14H15BrN4O) C, H, Br, N.
1-(3,5-Dich lor op h en yl)-3-[(5-m eth yl-1H-im id a zol-4-yl)-
m eth yl]im id a zolid in -2-on e (58): 86% yield (mp 242-249
°C); 1H-NMR (200 MHz, DMSO-d6) 7.14 (t, J ) 1.8 Hz, 1H,
H4′′), 7.62(d, J ) 1.8 Hz. 2H, H2′′ + H6′′); MS (EI) m/z (rel
intensity) 324 (M+, 12), 309 (5), 243 (4), 230 (9), 174 (15), 96
(100), 95 (92). Anal. (C14H14Cl2N4O) C, H, Cl, N.
P r ep a r a tion of 1-[(1-Eth yl-4-m eth yl-1H-im id a zol-5-yl)-
m eth yl]-3-p h en ylim id a zolid in -2-on e, Hyd r och lor id e (71)
1-[(5-Meth yl-1H-im id a zol-4-yl)m eth yl]-3-p h en ylim id a -
zolid in -2-on e (59): 84% yield (mp 207-210.5 °C); H-NMR
(200 MHz, DMSO-d6) 6.96 (m, 1H, H4′′), 7.29 (m, 2H, H3′′ +
H5′′), 7.54 (m, 2H, H2′′ + H6′′); MS (EI) m/z (rel intensity)
256 (M+, 58), 241 (13), 175 (15), 162 (94), 106 (71), 96 (94), 95
(100). Anal. (C14H16N4O) C, H, N.
a n d
1-[(1-E t h yl-5-m et h yl-1H -im id a zol-4-yl)m et h yl]-3-
1
p h en ylim id a zolid in -2-on e, Hyd r och lor id e (72). 50% NaH
(0.198 g, 0.0041 mol) was added at 0 °C to a solution of 59 (1
g; 0.0039 mol) in 20 mL of anhydrous DMF kept under
nitrogen atmosphere. After 15 min, ethyl iodide (0.33 mL,
0.0041 mol) was dropped. Stirring was continued for 1 h at
room temperature. The mixture was poured into H2O and
extracted with CH2Cl2. The organic layer was washed with
1-(3-Cya n op h e n yl)-3-[(5-m e t h yl-1H -im id a zol-4-yl)-
m et h yl]im id a zolid in -2-on e (60): 84% yield (mp 221-226

5-HT3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 21 3379
saturated NaCl solution, dried over anhydrous Na2SO4, and
evaporated to dryness after filtration. The residue was
purified by silica gel chromatography using EtOAc-MeOH-
30% NH4OH (190:10:1) as eluant. Both the first eluted and
second eluted compounds were treated with an excess of a
solution of HCl in EtOH. The crude salts were collected by
filtration and recrystallized from anhydrous EtOH to afford
0.13 g of 71 (white solid, 10% yield, mp 227-230 °C) and 0.57
g of 72 (white solid, 40% yield, mp 225-230 °C).
71: 1H-NMR (400 MHz, DMSO-d6) 1.37 (t, J ) 7.3 Hz, 3H,
CH2CH3), 2.34 (s, 3H, CH3-4′), 3.36 (m, 2H, CH2-5), 3.78 (m,
2H, CH2-4), 4.16 (q, J ) 7.3 Hz, 2H, CH2CH3), 4.50 (s, 2H,
CH2-5′), 6.9-7.6 (m, 5H, Ph), 9.13 (s, 1H, H2′); MS (DEP) m/z
(rel intensity) 284 (M+, 54), 269 (5), 255 (6), 175 (11), 162 (5),
123 (100), 95 (27). Anal. (C16H20N4O‚HCl) C, H, Cl, N .
72: 1H-NMR (400 MHz, DMSO-d6) 1.37 (t, J ) 7.3 Hz, 3H,
CH2CH3), 2.32 (s, 3H, CH3-5′), 3.47 (m, 2H, CH2-5), 3.78 (m,
2H, CH2-4), 4.11 (q, J ) 7.3 Hz, 2H, CH2CH3), 4.44 (s, 2H,
CH2-4′), 6.9-7.6 (m, 5H, Ph), 9.11 (s, 1H, H2′); MS (DEP) m/z
(rel intensity) 284 (M+, 41), 269 (2), 255 (3), 124 (100), 95 (39).
Anal. (C16H20N4O‚HCl) C, H, Cl, N.
Following the general procedure described above 1-[(1,4-
dimethyl-1H-imidazol-5-yl)methyl]-3-phenylimidazolidin-2-
one, hydrochloride hemihydrate (73) (white solid, mp 219-
223 °C, 8% yield) and 1-[(1,5-dimethyl-1H-imidazol-4-yl)methyl]-
3-phenylimidazolidin-2-one, hydrochloride (74) (white solid, mp
250-270 °C dec, 47% yield) were obtained starting from 59
and employing methyl iodide as alkylating agent.
Molecu la r Mod elin g. The three-dimensional structures
of the compounds reported in Figures 3 and 4 were either built
from available structural fragments of the INSIGHTII version
2.3 software package (Biosym) or by referring to Cambridge
Structural Database. The database was accessed by the
substructure search feature of ISIS-Base (MDL). The built
structures were energy minimized by DISCOVER, version 2.9,
with molecular mechanics using gradient method and cvff.frc
force fields. The minimization was carried out until the rms
of gradients was less than 0.001 kcal/(mol A). The structures
were then submitted to a complete torsional angle search with
increment of 30°, for the bonds free to rotate, discarding the
conformations above 5 kcal/mol. The distance between the
pharmacophoric features of the present class of compounds was
measured in the Analysis module (Biosym). The conforma-
tions of the compounds used for the generation of automated
pharmacophoric pattern were submitted to the APEX-3D
software (Biosym) in MDL format. The alignment of com-
pounds to the pharmacophore model generated by APEX-3D
were done using the Search-Compare module of INSIGHTII.
The three-dimensional structures of the substructures A and
B were obtained by referring to fragments of compounds
reported in Cambridge Structural Database. The atomic
charges were computed by the program MOPAC using AM1
semiempirical method. The electrostatic isopotential surfaces
were calculated with DelPhi, version 2.3 (Biosym). The
potentials were expressed in kcal/mol, and the value of +1 was
represented in red, -1 in cyan, and 0 in yellow.
73: 1H-NMR (400 MHz, DMSO-d6) 2.33 (s, 3H, CH3-4′), 3.37
(m, 2H, CH2-5), 3.78 (m, 5H, CH2-4 + NCH3), 4.49 (s, 2H, CH2-
5′), 6.9-7.6 (m, 5H, Ph), 8.98 (s, 1H, H2′); MS (EI) m/z 270
(M+, 13), 255 (1), 175 (1), 110 (100), 109 (53). Anal.
(C15H18N4O‚HCl) C, H, Cl, N.
74: 1H-NMR (400 MHz, DMSO-d6) 2.29 (s, 3H, CH3-5′), 3.43
(m, 2H, CH2-5), 3.72 (s, 3H, NCH3), 3.78 (m, 2H, CH2-4), 4.43
(s, 2H, CH2-4′), 6.9-7.6 (m, 5H, Ph), 8.97 (s, 1H, H2′); MS (EI)
m/z (rel intensity) 270 (M+, 10), 255 (1), 175 (4), 162 (5), 109
(100). Anal. (C15H18N4O‚HCl) C, H, Cl, N.
P h a r m a cology. Bin d in g Assa ys. In vitro affinity of
compounds for central 5-HT3 receptor sites was determined
by their ability to displace the radioligand [3H]BRL 43694 in
the rat entorhinal cortex according to the method of Nelson
et al.33 The interaction with 5-HT4 receptor site was evaluated
by their ability to displace the radioligand [3H]GR113808 in
the rat striatum according to Grossman et al.34 Affinity for
R1, R2, D1, D2, 5-HT1A, 5-HT2 and M1+2 binding site was also
assessed in rat brain membrane using [3H]prazosin, [3H]-
yohimbine, [3H]SCH23390, [3H]-8-OH-DPAT, [3H]ketanserine,
and [3H]QNB as ligands according to established methods. The
analysis of binding data was carried out by the “Ligand”
computer program of Munson et al.35 Average Ki ((SEM)
values were calculated from at least three determinations of
displacement curves, each consisting of 10 concentrations in
triplicate.
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