Synthesis and pharmacological evaluation of imidazoline sites I1 and I2 selective ligands

Article abstract of DOI:10.1016/S0968-0896(00)00280-7

Several series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline sites (I₁ and I₂) and α-adrenergic (α₁ and α₂) receptor ligands. Their pK_i values indicate that linkage of the imidazoline moiety at the 2-position with an aromatic substituent dramatically decreases α-adrenergic affinity. I₁ sites are more accessible by phenyl imidazolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(2′-methoxyphenyl)-imidazoline (17) is one of the best I₁ ligands ever reported (pK_i=8.53 and I₁/I₂>3388). On the other hand, I₂ selectivity increases in the presence of a methyl group in the para position. The original compound, 2-(3′-fluoro-4′-tolyl)-imidazoline (31) is a new potent ligand for the I₂ sites with high selectivity (pK_i=8.53 and I₂/I₁>3388). Copyright

Full text of DOI:10.1016/S0968-0896(00)00280-7

Bioorganic & Medicinal Chemistry 9 (2001) 585±592
Synthesis and Pharmacological Evaluation of Imidazoline
Sites I1 and I2 Selective Ligands
Maria Anastassiadou,a,* Saõda Danoun,a Louis Crane,a
Genevieve Baziard-Mouysseta,* Marc Payarda,* Daniel-Henri Caignard,b
Marie-Claire Rettorib and Pierre Renardb
a
Â
Â
Laboratoire de Chimie Pharmaceutique, Universite Paul Sabatier, Faculte de Pharmacie 35,
Ã
Chemin des Maraõchers, 31062 Toulouse Cedex 4, France
b
 Â
Societe ADIR. 1, rue Carle Hebert, 92415 Courbevoie Cedex, France
Â
Received 26 October 1999; accepted 26 September 2000
AbstractÐSeveral series of 2-aryl or heterocyclic-imidazoline compounds have been prepared and evaluated in vitro as imidazoline
sites (I1 and I2) and a-adrenergic (a1 and a2) receptor ligands. Their pKi values indicate that linkage of the imidazoline moiety at the
2-position with an aromatic substituent dramatically decreases a-adrenergic anity. I1 sites are more accessible by phenyl imida-
zolines substituted by a methyl or a methoxy group at the ortho or meta position. Indeed, 2-(20-methoxyphenyl)-imidazoline (17) is
one of the best I1 ligands ever reported (pKi=8.53 and I1/I2>3388). On the other hand, I2 selectivity increases in the presence of a
methyl group in the para position. The original compound, 2-(30-¯uoro-40-tolyl)-imidazoline (31) is a new potent ligand for the I2
sites with high selectivity (pKi=8.53 and I2/I1>3388). # 2001 Elsevier Science Ltd. All rights reserved.
Introduction
antihypertensive agent with high selectivity for I pre-
ferringsites, exhibits lower incidence and intensity of
sedation compared with the nonselective compound
clonidine and is also potent for a2-adrenoreceptors.22 2-
Benzofuranyl-imidazoline (2-BFI),23 as well as tracizo-
line10 and benazoline,10 have also been described as new
selective ligands for I sites over a-adrenergic receptors.
Pharmaceutical interest in imidazoline compounds began
with the discovery of tolazoline's (1) a-adrenergic proper-
ties.1 Subsequently, a large number of related structures
with a-adrenergic activity has been synthesized and used
in therapeutics.2À5 Aminoimidazoline derivatives are the
most well known imidazoline compounds and are used
principally as anti-hypertensive agents.6
To date, two main subclasses of imidazoline recognition
3
sites have been de®ned: the I1, bindingpreferably [ H]-
Since Bousquet and co-workers proposed the concept of
imidazoline-preferringsites ( I),7 some 15 years ago, the
design and synthesis of new molecules binding preferably
to I sites over a-adrenergic receptors have been brought
to practice.8À12 This new class of imidazoline recognition
sites appears to be responsible for a great number of
functions in various tissues and species.13 Recent studies
support their involvement in many cardiovascular,8,13À15
central nervous system (CNS)16,17 and pancreatic dis-
eases18À20 and suggest that high I selective substances
might lead to the development of new antiarhythmic,
antihypertensive, antidepressive or antidiabetic drugs with
minor lateral e€ects.21 The oxazoline rilmenidine, an
pNH2-clonidine and [3H]-clonidine,24À26 and the I2,
bindingpreferably [ 3H]-idazoxan.27À30 The I1 partici-
pate in blood pressure regulation13,31,32 whereas the I2
are mainly associated with the inhibition of the mono-
amine oxidase (MAO) enzyme in the CNS.33,34 The
antihypertensive e€ects of rilmenidine and moxonidine,
for instance, seem to be due to activation of I1-binding
sites in the rostral ventrolateral medulla (RVLM) of the
brain stem.13,35À37
As the functional roles of these two imidazoline subsites
are di€erent, the design and synthesis of I1 and I2 selec-
tive ligands are of great signi®cance. Therefore, the aim
of the present study was the synthesis and pharmaco-
logical evaluation of new I sites selective ligands without
a-adrenergic anities, which are selective for one of the
two imidazoline sites I1 or I2.
*Correspondingauthor. Tel.: +33-5-6155-1494; fax: +33-5-6225-
6881.
0968-0896/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(00)00280-7

586
M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
Our research project used as a startingpoint compound
2, obtained by removal of the methylene group between
the aromatic and imidazoline rings of 1 (Scheme 1). This
structural modi®cation resulted in increasinganity for
the imidazoline bindingsites while eliminatingpotency
for a-adrenergic receptors, a1 and a2 (Table 1).
Results
Chemistry
Compounds 3±13, 15, 18±25, 27±30 and 32±53 (Tables 2±
4) have been synthesized by nucleophilic addition of
ethylenediamine (EDA) to the correspondingaromatic
nitriles in the presence of catalytic amounts of a sulfur
reagent: P2S5,38 but CS2,39 or S40 may be also used
(Scheme 3).
In an e€ort to optimize these results, three diverse series
of imidazoline compounds have been prepared as shown
in Scheme 2.
The preparation of 20- or 40-aromatic halogenated imi-
dazolines has been attempted by addition of EDA to the
correspondingnitriles as described above. In this parti-
cular case, the formation of the imidazoline moiety does
not take place and the reaction observed is an aromatic
nucleophilic substitution (SNAr).42 2-Amino-ethyl-
amino-benzonitriles have been obtained in this fashion.
The ®rst one contains substituted phenyl-imidazolines
in the ortho, meta or para position (series I). The choice
of substituents was made with respect to their steric
e€ects and lipophilic properties (Me, Et, Pr and iPr, Bu,
and tBu), or electronic e€ects (Me, F, OMe. . .).
As benazoline10 and 2-BFI23 were recently described as
selective ligands for I2 sites over a adrenergic receptors, we
replaced in the series II and III the phenyl ringof 2 by a
naphthyl group or various heterocycles such as pyri-
dine, pyrazine, furane, thiophene, indole or quinoleine.
For these reasons, the synthesis of compounds 14, 16,
26 and 31 has been performed by addition of EDA to
the correspondingesters in the presence of trimethyl-
aluminium43 (Scheme 3). Compound 17 has also been
synthesized accordingto Scheme 3.
All these compounds were tested in vitro as imidazoline
bindingsites I1, I2, and a adrenergic receptors a1, a2
ligands (Scheme 2).
Pharmacology
Anities for compounds of the series I, II and III towards
a1- and a2-receptors as well as I1- and I2-bindingsites,
were determined from radioligand binding assays. The
results obtained are summarized in Tables 2±4. The
values are expressed as pKi anity constants.
Scheme 1.
Discussion
Table 1. pKi valuesa in bovine brain (I1), rabbit kidney (I2) and calf
cerebral cortex (a1 and a2) for compounds 1 and 2
The lack of a-adrenergic anity for almost all of com-
pounds prepared was our ®rst successful result. It seems
that linkage of the imidazoline moiety at position 2 with
an aromatic substituent generally eliminates a-adrener-
gic anity. In addition, 19 of the 53 derivatives pre-
pared show a high selectivity for the I sites with anities
reachingthe nanomolar scale.
Compound
pKi I1
pKi I2
pKi a1
pKi a2
Tolazoline 1
2
6.64
7.49
5.77
7.40
5.60
<5.00
6.74
<5.00
aValues are the mean of two experiments. The variability is less than 10%.
Havingaccomplished our ®rst goal, we then set out to
establish the structural factors that increase potency and
selectivity for one I subsite over the other.
I1-binding selectivity
We ®rst examined the in¯uence of di€erent substituents
on the phenyl ringof 2. As shown in Table 2, I1 sites
appear to bind preferably with phenyl-imidazoline ana-
logues substituted with a methyl or a methoxy group in
the ortho or meta positions. Indeed, compounds 3, 4, 17,
18 and 32 are all potent ligands for I1 bindingsites.
Compound 17 is the only one of this series also having
excellent I1 selectivity over both I2 sites and a-adrenergic
receptors. Amongdisubstituted compounds prepared,
compound 30 is very selective although its rather average
anity.
With regard to the series II and III (Tables 3 and 4), the
most potent and selective ligand obtained was compound
Scheme 2. Pharmacomodulation of the 2-2-phenyl-Á-2-imidazoline.

M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
587
Table 2. pKi valuesa in bovine brain (I1), rabbit kidney (I2) and calf cerebral cortex (a1 and a2) for compounds of series I
20
30
40
50
60
pKi I1
pKi I2
pKi a1
pKi a2
I1/I2
b
Compound
2
3
4
5
6
7
8
9
H
Me
H
H
H
H
H
H
H
H
Ph
H
F
H
H
OMe
H
H
H
SMe
H
H
H
H
H
H
Cl
H
Me
H
H
H
Me
H
Et
H
H
H
H
H
H
H
H
F
H
H
OMe
H
H
H
H
H
H
H
F
F
H
Cl
H
H
H
Me
H
Et
nPr
iPr
Bu
tBu
H
Ph
H
H
F
H
H
OMe
OPh
H
SMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
7.49
8.21
8.66
5.89
7.31
7.23
6.22
5.66
6.04
5.05
6.00
6.69
<5.00
<5.00
7.57
8.53
7.97
7.46
6.34
5.14
7.75
5.96
6.04
<5.00
7.00
5.00
5.25
<5.00
7.64
<5.00
8.27
<5.00
7.64
7.46
7.40
7.96
8.30
8.04
7.48
7.08
7.16
7.09
6.77
6.25
<5.00
8.00
7.00
7.64
7.43
5.00
7.75
8.28
7.34
<5.00
8.42
7.28
7.07
<5.00
7.00
7.11
5.31
6.77
5.30
8.53
8.21
6.57
8.30
8.26
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
6.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
5.11
<5.00
<5.00
6.89
<5.00
<5.00
NT
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
6.10
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
5.26
<5.00
<5.00
<5.00
<5.00
<5.00
NT
<5.00
<5.00
<5.00
<5.00
<5.00
<5.00
5.06
1.230
1.770
2.290
0.007
0.680
1.410
0.110
0.037
0.180
0.063
>10.00
0.049
<0.010
<0.002
1.380
3388
1.660
0.150
0.100
>1.380
0.210
0.048
0.090
Ð
1.000
0.008
0.871
<0.017
208
<0.0003
1.150
<0.030
0.218
0.158
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
CF3
OCF3
NHCOCH3
F
H
F
F
H
Me
H
OH
H
H
H
F
H
Me
tBu
H
H
H
F
H
F
H
Me
H
tBu
CN
O±CH2±O
<5.00
<5.00
<5.00
<5.00
aValues are the mean of two experiments. The variability is less than 10%.
bAntilogof the di€erence between p Ki I1 and pKi I2 values.
38. The anity of 38 was found to be equal to that of
compound 17 while its selectivity is much lower.
For compounds containingtwo substituents on the
phenyl ringof 2 (series I) excellent results have been
obtained. Compound 31 is obtained by introduction of
a ¯uoro group in the meta position of compound 5
(Table 2). This structural modi®cation leads to an
increase in anity and selectivity for I2 sites over both I1
and a-adrenergic receptors. Indeed compound 31 is one
of the best I2 ligands ever reported.
It is interestingto observe the di€erence in anity
between compounds 47 and 48 Substitution of one
hydrogen atom in the 3-position of 2-(2-thienyl)-imidazo-
line by a methyl group increases anity for both I1 and
I2 bindingsites, althouhg this compound is rather
selective for the I1 bindingsites.
In order to examine if the presence of a phenyl ringis
necessary to ensure high anity and selectivity for I2
sites, the phenyl ringof 2 has been replaced by other
aromatic substituents in the last two series of com-
pounds. These results are reported in Tables 3 and 4.
I2-Binding selectivity
For compounds of series I, the presence of a methyl
group in the para position of the phenyl ring, as in
compound 5, resulted in a remarkable increase in I2
selectivity compared to the ortho or meta analogues, 3
and 4 (Table 2). In a similar manner, a phenyl group in
the para position (i.e., compound 13), shows high
potency and good selectivity for the I2 bindingsites.
Increase of the alkyl chain length in the para position
leads to a signi®cant decrease in anity for I2 receptors
(compounds 7±11) (Table 2).
Benazoline (37), recently described as a selective ligand for
I sites, is highly potent for both I1 and I2 bindingsites.
Similar results have been obtained for compound 36.
As for molecules of the series III, the best results were
obtained for the quinoline analogues 50 and 51, for the
indolyl derivative 49 as well as for the 2-BFI 52, another

588
M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
Table 3. pKi valuesa in bovine brain (I1), rabbit kidney (I2) and calf
cerebral cortex (a1 and a2) for compounds of series II
Table 4. pKi valuesa in bovine brain (I1), rabbit kidney (I2) and calf
cerebral cortex (a1 and a2) for compounds of series III
b
b
Compound
Ar
pKi
I1
pKi
I2
pKi
a1
pKi I2/I1
a2
Compound
Het
pKi
I1
pKi
I2
pKi
a1
pKi
a2
I2/I1
41
42
6.60
6.00
6.17 <5.00 <5.00
5.91 <5.00 <5.00
2.700
36
8.82 8.82 <5.00 5.59 1.000
8.92 9.18 6.00 6.00 0.550
1.234
1.149
37 Benazoline
43
44
45
5.24
5.95
5.18 <5.00 <5.00
5.12 <5.00 <5.00
38
8.54 7.00 <5.00 6.70 34.67
6.760
39
40
<5.00 <5.00 <5.00 <5.00
Ð
6.39 <5.00 <5.00 <5.00 >24.5
7.05 7.94 >5.00 5.46 0.130
46
47
48
6.24
6.82
8.37
5.63 <5.00 <5.00
6.44 <5.00 <5.00
7.44 <5.00 <5.00
4.070
2.400
8.510
aValues are the mean of two experiments. The variability is less than
10%.
bAntilogof the di€erence between p Ki I1 and pKi I2 values.
potent ligand for the I sites. Although the three of them
present a high anity for the I2-bindingsites, their I2
selectivity is rather low compared to compounds 5 and 31.
49
50
51
52
53
7.28
7.34
6.84
7.49
5.13
8.57 <5.00
5.74
5.74
5.68
NT
0.050
0.033
0.023
0.050
0.170
Conclusion
8.82
5.82
As this has been clari®ed, 2-phenyl-imidazoline deriva-
tives do not generally bind to a-adrenergic receptors. It is
worth notingthat 19 of the 53 compounds reported herein
show a high anity and selectivity for the imidazoline
bindingsites. Amongthem, compound 17 is one of the
best I1 speci®c ligands. In a similar manner, the original
compound 31 is a new potent ligand for the I2 binding
sites with good selectivity. The naphthyl and hetero-
cyclic compounds 36±38 and 50±52, respectively, are
highly potent for the I sites, even more potent than their
phenyl-analogues 17 and 31, and exhibit rather moder-
ate selectivity. Therefore with respect to other aromatic
analogues, phenyl-imidazolines seem to be the most
selective derivatives for I1 and I2 sites.
8.47 <5.00
8.80
5.90
NT
5.57
6.40
aValues are the mean of two experiments. The variability is less than
10%.
bAntilogof the di€erence between p Ki I1 and pKi I2 values.
The ¯uoro-phenyl derivatives 14±16 do not obey this
rule. Compound 14, a rather bad ligand for the I sites,
binds preferably to the I2 over the I1 bindingsites.
Minor modi®cations to the structure of the molecules
can alter their I1/I2 pro®les.
With regard to the monosubstituted derivatives 17±19
and 21±22, we have concluded that 2-phenyl-imidazo-
lines substituted at the ortho position are highly selective
for the I1-subsites, whereas I2-subsites are more acces-
sible by phenyl derivatives containingthe substituent at
the para position. On the other hand, substitution in the
meta position of the phenyl ring(compounds 4, 6 and
18) results in maintainingpotency for both I1 and I2
bindingsites, but these compounds are less selective.
The ¯uoro and methyl derivatives 30, 31 and 32
(Table 2) containingexactly the same substituents on
the phenyl ringbut in di€erent positions, have totally
di€erent properties. Compound 30 is high selective for
the I1 sites, 31 for the I2 ones, while 32 is highly potent
for both of them (Scheme 4).
Therefore the variation in I1/I2 selectivity seems to be
due to the position of the methyl group. Indeed, for

M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
589
dried over anhydrous MgSO4. The solvent was removed
under reduced pressure and the crude free base was
collected and puri®ed by recrystallization from cyclohex-
ane. Yield 89%, mp 90ꢀC. H NMR (CDCl3) d 2.48 (s,
1
3H, CH3), 3.76 (s, 4H, 2CH2), 4.50 (s, 1H, NH), 7.14±7.47
(m, 4H, ArH). Anal. (C10H12N2) C, H, N.
Similarly, compounds 4,45 5,46 6±8, 9,41 10, 11,41 12,
13,41 15,45 18,47 19,48 20, 21,49 22,50 23±25, 27±30, 32,
33,51 34, 35,48 36,52 37,53 38±40, 41,54 42,54 43,55 44,56
45, 46,57 47,58 48,59 49, 50,60 51,61 52,62 and 53 were
prepared from the appropriate nitriles as previously
described. Physico-chemical data for already known
derivatives are in agreement with the literature. For all
new compounds prepared, physico-chemical data are
reported below.
Scheme 3. (a) Synthesis of imidazolines 3±13, 15, 18±25, 27±30, 32±53.
Reagents: (i) P2S5. (b) Synthesis of imidazolines 14, 16, 17, 26 and 31.
Reagents: (ii) trimethylaluminium.
2-(30 -Ethylpheꢀnyl)-4,5-dihydro-1H-imidazole (6). Yield
79%, mp <50 C. 1H NMR (CDCl3) d 1.19 (t, 3H, CH3),
2.61 (q, 2H, CH2CH3), 3.47 (s, 4H, 2CH2), 4.05 (s, 1H,
NH), 7.27±7.63 (m, 4H, ArH). Anal. (C11H14N2) C, H, N.
2-(40 -Ethylphenyl)-4,5-dihydro-1H-imidazole (7). Yield
98%, mp 136 ꢀC. 1H NMR (CDCl3) d 1.23 (t, 3H, CH3),
2.68 (q, 2H, CH2CH3), 3.74 (s, 4H, 2CH2), 4.70 (s, 1H,
NH), 7.22±7.67 (m, 4H, ArH). Anal. (C11H14N2) C, H, N.
Scheme 4.
compound 30 the methyl group is in the ortho position,
for 31 in the para and for 32 in the meta position.
2-(40-n-Propylphenyl)-4,5-dihydro-1H-imidazole (8). Yield
70%, mp 130 ꢀC. 1H NMR (CDCl3) d 0.92 (t, 3H, CH3),
1.62 (m, 2H, CH2CH3), 2.61 (t, 2H, ArCH2), 3.77 (s, 4H,
2CH2), 6.20 (s, 1H, NH), 7.22±7.69 (m, 4H, ArH). Anal.
(C12H16N2) C, H, N.
In this paper, we have reported new imidazoline-based
structures that are outstandingfor their anities and
unprecedented I1 or I2 selectivities. These compounds will
contribute to a better understandingof I sites charac-
terization and function.
2-(40-n-Butylphenyl)-4,5-dihydro-1H-imidazole (10). Yield
61%, mp 101 ꢀC. 1H NMR (CDCl3) d 0.90 (t, 3H, CH3),
1.34 (m, 2H, CH2CH3), 1.59 (m, 2H, CH2CH2CH3), 2.62
(t, 2H, ArCH2), 3.76 (s, 4H, 2CH2), 4.80 (s, 1H, NH),
7.21±7.68 (m, 4H, ArH). Anal. (C13H18N2) C, H, N.
Experimental
Chemistry
2-(20-Biphenyl)-4,5-dihydro-1H-imidazole (12). Yield 37%,
mp 109 ꢀC. 1H NMR (CDCl3) d 3.69 (s, 4H, 2CH2), 7.41±
7.78 (m, 10H, NH+ArH). Anal. (C15H14N2) C, H, N.
Meltingpoints were determined on a DSC-50 Shimadzu
apparatus. Infra-red spectra were recorded on a Perkin±
Elmer 983G spectrophotometer. All imidazoline-com-
pounds present the same IR absorption bands towards
2-(40 -Phenoxyphenyl)-4,5-dihydro-1H-imidazole (20).
Yield 56%, mp 129 ꢀC. 1H NMR (CDCl3) d 3.78 (s, 4H,
2CH2), 4.75 (s, 1H, NH), 6.99±7.74 (m, 9H, ArH). Anal.
(C15H14N2O) C, H, N.
1
3000 cmÀ1 (nCH, CH2, CH3) and 3150 cmÀ1 (nNH). H
NMR spectra were determined in the indicated solvent
with a 200 MHz spectrometer, and peak positions are
given as s (singlet), d (doublet), t (triplet), q (quadru-
plet) or m (multiplet). The microanalyses were per-
formed in the Microanalytical Laboratory of ENSCT in
Toulouse, France and the results obtained are within
Æ0.4% of the theoretical values. Reactions were moni-
tored by thin-layer chromatography (TLC) and product
mixtures were puri®ed by column chromatography
usingsilica egl 60 F-254,70±200 mesh. All yields are
calculated for analytical pure materials.
2-(40 -Tri¯uoromethylphenyl)-4,5-dihydro-1H-imidazole
(23). Yield 81%, mp 180 ꢀC. 1H NMR (CDCl3) d 3.79 (s,
4H, 2CH2), 4.55 (s, 1H, NH), 7.63±7.86 (m, 4H, ArH).
Anal. (C10H9F3N2) C, H, N.
2-(40-Tri¯uoromethoxyphenyl)-4,5-dihydro-1H-imidazole
(24). Yield 77%, mp 150 ꢀC. H NMR (CDCl3) d 3.60±
1
3.95 (m, 4H, 2CH2), 4.70 (s, 1H, NH), 7.23±7.80 (m, 4H,
ArH). Anal. (C10H9F3N2O) C, H, N.
2-(2-Tolyl)-4,5-dihydro-1H-imidazole (3).44
A stirred
mixture of 2-tolunitrile (2.64 g, 0.02 mol), ethylenedia-
mine (25 mL, 0.37 mol) freshly distilled on KOH, and
0.15gof P 2S5 was heated at 120 ꢀC in an oil bath for 4 h.
The reaction mixture was then cooled, poured into cold
water and extracted with CH2Cl2. The organic phase was
2-(40 -Acetamidophenyl)-4,5-dihydro-1H-imidazole (25).
Yield 87%, mp 272 ꢀC. H NMR (DMSO-d6) d 2.18 (s,
1
3H, CH3), 3.72 (s, 4H, 2CH2), 5.54 (s, 1H, Imid NH),
7.72±7.86 (m, 4H, ArH), 10.33 (s, 1H, CONH). Anal.
(C11H13N3O) C, H, N.

590
M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
2-(30,50 -Di¯uorophenyl)-4,5-dihydro-1H-imidazole (27).
Yield 57%, mp 131 ꢀC. 1H NMR (CDCl3) d 3.77 (s, 4H,
2CH2), 4.63 (s, 1H, NH), 6.81±7.25 (m, 3H, ArH). Anal.
(C9H8F2N2) C, H, N.
(5.34 g, 0.03 mol) in anhydrous toluene (100 mL) was
added at 0 ꢀC to a previously prepared solution of tri-
methylaluminium (3.17 g, 0.044 mol of a 2 M solution in
toluene) and ethylenediamine (2.64 g, 0.044 mol) in anhy-
drous toluene (100mL). The solution was heated under
re¯ux with stirringfor 10h. On cooling, water (12 mL)
was added followed by MeOH (30 mL) and CH2Cl2
(30 mL), and the mixture heated again under re¯ux for
15 min. The Al(OH)3 was then eliminated by ®ltration
and the organic layer was dried over MgSO4 and evapo-
rated in vacuo. The crude product obtained was extracted
with CH2Cl2. The extracts dried, the solvent removed
under reduced pressure and the crude free base was pur-
i®ed by recrystallization from cyclohexane. Yield 83%,
mp 161 ꢀC. 1H NMR (CDCl3) d 2.28 (s, 3H, CH3), 3.53 (s,
1H, NH), 3.76 (s, 4H, 2CH2), 7.15±7.39 (m, 3H, ArH).
Anal. (C10H11FN2) C, H, N.
2-(20 -Chloro-40 -¯uorophenyl)-4,5-dihydro-1H-imidazole
(28). Yield 40%, oil. 1H NMR (CDCl3) d 2.97, 3.16 (2m,
0
4H, 2CH2), 4.93 (s, 1H, NH), 6.46 (m, 1H, H5 ), 6.59 (m,
0
1H, H3 ), 7.35 (m, 1H, H6 ). Anal. (C9H8ClFN2) C, H, N.
0
2-(30 -Chloro-40 -¯uorophenyl)-4,5-dihydro-1H-imidazole
(29). Yield 41%, mp 109 ꢀC. H NMR (CDCl3) d 3.01,
1
0
3.28 (2t, 4H, 2CH2), 4.95 (s, 1H, NH), 6.75 (m, 1H, H5 ),
0
0
7.55 (m, 1H, H6 ), 7.72 (m, 1H, H2 ). Anal. (C9H8ClFN2)
C, H, N.
2-(20-Methyl-50-¯uorophenyl)-4,5-dihydro-1H-imidazole
(30). Yield 71%, mp 88ꢀC. H NMR (CDCl3) d 2.41 (s,
1
3H, CH3), 3.57 (s, 4H, 2CH2), 4.59 (s, 1H, NH), 6.92±7.11
(m, 3H, ArH). Anal. (C10H11FN2) C, H, N.
Compounds 14,63 16,53 and 17,64 were prepared as pre-
viously described.
2-(20-Fluoro-50-methylphenyl)-4,5-dihydro-1H-imidazole
(32). Yield 40%, mp 87 C. H NMR (CDCl3) d 2.31 (s,
3H, CH3), 3.74 (s, 4H, 2CH2), 5.39 (s, 1H, NH), 6.96±7.86
(m, 3H, ArH). Anal. (C10H11FN2) C, H, N.
2-(30,40 -Di¯uorophenyl)-4,5-dihydro-1H-imidazole (26).
A stirred mixture of 3,4-di¯uorothiobenzamide (2.78 g,
0.02 mol) and ethylenediamine (1.8 g, 0.03 mol) freshly
distilled on KOH, in toluene (50 mL) was heated under
re¯ux in an oil bath for 4 h. The reaction mixture was
then cooled, the solvent was evaporated in vacuo and
the crude free base was collected and puri®ed by
recrystallization from cyclohexane. Yield 45%, mp
ꢀ
1
2-(30-Cyano-20-methylphenyl)-4,5-dihydro-1H-imidazole
(34). Yield 78%, mp 144 ꢀC. 1H NMR (CDCl3) d 2.67 (s,
3H, CH3), 3.78 (s, 4H, 2CH2), 4.59 (s, 1H, NH), 7.29±7.65
(m, 3H, ArH). Anal. (C11H11N3) C, H, N.
154 ꢀC. H NMR (CDCl3) d 3.77 (s, 5H, NH+2CH2),
1
7.02±7.65 (m, 3H, ArH). Anal. (C9H8F2N2) C, H, N.
2-[10-(40-Methylnaphꢀthyl)]-4,5-dihydro-1H-imidazole (38).
Yield 16%, mp 149 C. 1H NMR (CDCl3) d 2.69 (s, 3H,
CH3), 3.75 (s, 5H, NH+2CH2), 7.27±8.65 (m, 6H, ArH).
Anal. (C14H14N2) C, H, N.
Pharmacology
The anity for the a1- and a2-adrenergic receptors was
determined by measurement of [3H]-Prazosin and [3H]-
RX 821002 displacement from membrane bindingsites of
calf cerebral cortex accordingto the methods previously
described by Glossman65 and Hudson66. Non-speci®c
bindingwas determined with 10 À5 M of phentolamine for
a1-ARs and with 10À5 M of yohimbine for a2-ARs.
2-[10 -(20 -Methoxynaphthyl)]-4,5-dihydro-1H-imidazole
(39). Yield 70%, mp 157 ꢀC. 1H NMR (DMSO-d6) d 1.92
(s, 3H, OCH3), 2.85 and 3.28 (2t, 4H, 2CH2), 6.73±7.6 (m,
6H, ArH), 8.15 (s, 1H, NH). Anal. (C14H14N2O) C, H, N.
2-[20 -(60 -Methoxynaphthyl)]-4,5-dihydro-1H-imidazole
(40). Yield 61%, mp 155 ꢀC. H NMR (CDCl3) d 3.84
I1- and I2-receptors bindingassays were performed
accordingto the methods previously described by Stef-
fen67 and Mac Kinnon.68
1
(s, 4H, 2CH2), 3.91 (s, 3H, OCH3), 4.85 (s, 1H, NH),
7.13±8.12 (m, 6H, ArH). Anal. (C14H14N2O) C, H, N.
1-Methyl - 4,5 -bis - [20 - (40,50 -dihydro -1H -imidazolyl)] -
imidazole (45). Yield 84%, mp 162 ꢀC. 1H NMR
(CDCl3) d 3.71 (s, 8H, 4CH2), 3.99 (s, 3H, CH3), 5.80 (s,
2H, NH), 7,41 (s, 1H, ArH). Anal. (C10H14N6) C, H, N.
I1-binding sites. Membranes from bovine adrenal glands
(0.6 mgprotein/mL) were incubated for 40 min with 4.8
nM [3H]-Clonidine at 22 ꢀC in bindingbu€er (PBS,
EGTA 0.5 mM, MgCl2 0.5 mM, 0.5% ascorbic acid, pH
7.4) and increasingconcentrations of competitors (12
concentrations in DMSO, 10À10 to 10À5 M) in the pre-
sence of 1 mM RX821002 to mask a2-ARs. Non-speci®c
bindingwas de®ned as [ 3H]-clonidine bindingin the
presence of 1 mM of S22687-1.
2-(50-Indolyl)-4,5-dihydro-1H-imidazole (49). Yield 60%,
mp 181 ꢀC. H NMR (CDCl3) d 2.50 (s, 1H, NH), 3.80
1
(s, 4H, 2CH2), 6.58±8.03 (m, 5H, ArH), 8.60 (s, 1H,
NH). Anal. (C11H11N3) C, H, N.
2-(90 -Xanthenyl)-4,5-dihydro-1H-imidazole (53). Yield
70%, mp 220 ꢀC. 1H NMR (CDCl3) d 3.30 (s, 1H, NH),
3.52 (s, 4H, 2CH2), 5.41 (s, 1H, CH), 7.04±7.37 (m, 8H,
ArH). Anal. (C16H14N2O) C, H, N.
I2-binding sites. Membranes from rabbit kidney cortex
(0.5 mg/mL) were incubated for 30 min with 4.7 nM
[3H]-Idazoxan at 22 ꢀC in bindingbu€er (Tris 50 mM,
EDTA 1 mM, MgCl2 2 mM, pH 7.5) and increasing
concentrations of competitors (10À10 to 10À5 M) in the
presence of 5 mM of Rauwolscine. 2-BFI was used to
de®ne non-speci®c binding.
2-(30-Fluoro-40-methylphenyl)-4,5-dihydro-1H-imidazole
(31). A solution of methyl 3-¯uoro-4-methyl benzoate

M. Anastassiadou et al. / Bioorg. Med. Chem. 9 (2001) 585±592
591
Acknowledgement
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