A novel series of (phenoxyalkyl)imidazoles as potent H3-receptor histamine antagonists

Article abstract of DOI:10.1021/jm960138l

[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X = NH, S, CH₂S, O) of previously described [[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X = NH, S) have been synthesized and evaluated for H₃-receptor histamine antagonism in vitro (K(i) for [³H]histamine release from rat cerebral cortex synaptosomes) and in vivo (ED₅₀ per os in mice on brain tele- methylhistamine levels). Encouraging results led to the synthesis and testing of a novel series of substituted (phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-1H- imidazole (10a, UCL 1390; K(i) = 12 nM, ED₅₀ = 0.54 mg/kg) and 4-[3-[4- (trifluoromethyl)-phenoxy]propyl]-1H-imidazole (10c, UCL 1409; K(i) = 14 nM, ED₅₀ = 0.60 mg/kg) have been selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the relationship between in vitro and in vivo potency is described by the equation log ED₅₀ = 0.47 log K(i) + 0.20 (r = 0.78).

Full text of DOI:10.1021/jm960138l

3806
J . Med. Chem. 1996, 39, 3806-3813
A Novel Ser ies of (P h en oxya lk yl)im id a zoles a s P oten t H3-Recep tor Hista m in e
An ta gon ists†
C. Robin Ganellin,* Abdellatif Fkyerat, Benny Bang-Andersen, Salah Athmani, Wasyl Tertiuk,
Monique Garbarg,‡ Xavier Ligneau,§ and J ean-Charles Schwartz‡
Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street,
London WC1H 0AJ , U.K., Unite´ 109 de Neurobiologie et Pharmacologie, Centre Paul Broca de l’INSERM,
2 ter rue d’Ale´sia 75014, Paris, France, and Laboratoire Bioprojet, 30 rue des Francs-Bourgeois 75003, Paris, France
Received February 13, 1996X
[[(4-Nitrophenyl)X]alkyl]imidazole isosteres (where X ) NH, S, CH2S, O) of previously described
[[(5-nitropyrid-2-yl)X]ethyl]imidazoles (where X ) NH, S) have been synthesized and evaluated
for H3-receptor histamine antagonism in vitro (Ki for [3H]histamine release from rat cerebral
cortex synaptosomes) and in vivo (ED50 per os in mice on brain tele-methylhistamine levels).
Encouraging results led to the synthesis and testing of a novel series of substituted
(phenoxyethyl)- and (phenoxypropyl)imidazoles. From the latter, 4-[3-(4-cyanophenoxy)propyl]-
1H-imidazole (10a , UCL 1390; Ki ) 12 nM, ED50 ) 0.54 mg/kg) and 4-[3-[4-(trifluoromethyl)-
phenoxy]propyl]-1H-imidazole (10c, UCL 1409; Ki ) 14 nM, ED50 ) 0.60 mg/kg) have been
selected as potential candidates for drug development. For 16 [(aryloxy)ethyl]imidazoles the
relationship between in vitro and in vivo potency is described by the equation log ED50 ) 0.47
log Ki + 0.20 (r ) 0.78).
Ch a r t 1
In tr od u ction
Histamine H3-receptors are presynaptic autoreceptors
which modulate the synthesis2 and release3 of histamine
in histaminergic neurones in the central nervous system
(CNS). The H3-receptors also appear to occur as het-
eroreceptors on nonhistaminergic axon terminals,4 modu-
lating the release of other important neurotransmitters
both in the CNS and the periphery (see previous paper5
for an extensive list of references).
The first potent and highly selective H3-receptor
histamine antagonist to be described6 was thioperamide
(1) (Chart 1), which has been widely used for investiga-
tion of the involvement and role of H3-receptors in
physiology. Although 1 is very potent in vitro (Ki ) 4.3
nM),6 relatively high doses are required in vivo (e.g.,
ED50 ca. 2 mg/kg ip, ca. 5 mg/kg po in rats)7 to enhance
histamine release in the brain. This could be due to
the pharmacokinetic properties of thioperamide and also
might suggest a possible low penetration of the blood-
brain barrier.
Unfortunately, thioperamide is not suitable for hu-
man studies because of potential liver toxicity, and no
H3-antagonist is yet available for investigation of the
role of H3-receptors in humans to confirm the potential
therapeutic applications for H3-receptor histamine an-
tagonists. An H3-antagonist entering the brain would
permit an increase in histamine transmission through
histaminergic pathways and thereby potentiate the role
of histamine in controlling the waking state and so act
as a stimulant.8,9 Histamine H3-receptor antagonists
could also increase locomotor activity10 and pituitary
hormone11 secretion, act as anticonvulsants12 and an-
tinociceptives,13 and suppress food intake.14
of thioperamide analogues. It was demonstrated that
replacement of the central piperidine ring of thioper-
amide by a two-methylene chain gave the cyclohexyl-
thiourea derived from histamine which was some 50
times less active than thioperamide.15 We demon-
strated that in such structures derived from histamine
it was possible to replace the cyclohexylthioureido group
by an aminoheterocycle (2) (Chart 1) with retention of
activity. It was also shown that introducing an electron-
withdrawing group into the heterocycle, e.g., nitropyr-
idyl or (trifluoromethyl)pyridyl (3, R ) NO2 or CF3),
We recently described5 a structure-activity analysis
†Presented in part at the 13th International Meeting on Medicinal
Chemistry, Paris, France, September 21, 1994, and at the 2nd
European Congress of Pharmaceutical Sciences,1 Berlin, Germany,
September 30, 1994.
‡ Centre Paul Broca de l’INSERM.
§ Laboratoire Bioprojet.
X Abstract published in Advance ACS Abstracts, August 15, 1996.
S0022-2623(96)00138-0 CCC: $12.00 © 1996 American Chemical Society

Phenoxyalkylimidazoles as Histamine Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3807
Ta ble 1. [[(5(4)-Nitrophenyl)X]alkyl]imidazoles and Their
Potencies as H3-Receptor Histamine Antagonists (Ki in Vitro for
[3H]Histamine Release from Rat Cerebral Cortex
Synaptosomes, and ED50 in Vivo in Mice for Effect on Brain
tele-Methylhistamine Levels)
phenyl. In pursuance of this idea, 4-[(4-nitrophenyl)-
heteroalkyl]-1H-imidazole isosteres (6-8) of compounds
3 and 4 were synthesized, and this was followed by a
series16 of substituted (phenoxyethyl)imidazoles (9). The
compounds have been tested for antagonism of hista-
mine inhibition of histamine release in vitro from rat
cerebral cortex synaptosomes (see below) and in vivo in
mice for their effect on the levels of the histamine
catabolite, tele-methylhistamine, in the brain. The
results are reported herein.
NO2
Y
(CH2)nX
HN
N
Ki ( SEM
(nM)
ED50 ( SEM
Ch em istr y
no.
n
X
Y
(mg/kg)a
NR-(4-Nitrophenyl)histamine (6) was synthesized from
histamine and 4-chloronitrobenzene (Scheme 1). 4-[2-
[(4-Nitrophenyl)thio]ethyl]-1H-imidazole (7) was pre-
pared from 4-(2-chloroethyl)-1H-imidazole17 and sodium
4-nitrophenylthiolate in dry DMF (Scheme 2). 4-[[[(4-
Nitrophenyl)methyl]thio]methyl]-1H-imidazole (8) was
synthesized from S-(imidazol-4-ylmethyl)isothiourea18
by displacement with 4-nitrobenzyl chloride (Scheme 3).
Most of the substituted phenoxyethylimidazoles (9)
were prepared in a Williamson synthesis (Scheme 2)
from 4-(2-chloroethyl)-1H-imidazole and the appropriate
phenoxide (generated with K2CO3 (method A) or NaH
(method B)) in dry DMF as indicated in Table 2. These
alkylation methods were not always satisfactory, how-
ever, and to obtain a more reproducible procedure it was
necessary to protect the imidazole ring. This was
effected in two ways, either by using trityl (triphenyl-
methyl) as for compounds 9p , r (Scheme 5) or by using
N,N-dimethylsulfamoyl (Scheme 6) exemplified by 9l.
Both routes involve a Mitsunobu type coupling19 be-
tween the N-protected 4(or 5)-(2-hydroxyethyl)imidazole
and the appropriate substituted phenol using triphen-
ylphosphine and diethyl azodicarboxylate (DEAD) in
THF (Scheme 5). The trityl or sulfamoyl groups were
subsequently cleaved off using aqueous HCl in hot THF.
The requisite 1-(triphenylmethyl)-4-(2 hydroxyethyl)-
imidazole was obtained by tritylation of 4-(2-hydroxy-
1
3
4
6
7
8
9a
thioperamide
4 ( 1b
29 ( 11c
4.8 ( 0.9c
23 ( 9
1.0 ( 0.5
ndd
2.6 ( 1.0
10.7 ( 2.8
2.7 ( 0.7
g10
2
2
2
2
1
2
NH
S
N
N
NH
S
SCH2
O
CH
CH
CH
CH
9 ( 3
313 ( 58
35 ( 6
0.66 ( 0.11
Calculated as the base. Reference 6. c Reference 5. Not
a
b
d
determined.
enhanced potency. Furthermore, replacing the amino
group attached to nitropyridine by thio gave a compound
(4, UCL 1199) which is as active in vitro as thioper-
amide. Although it was hoped that 4 would penetrate
the CNS more readily than thioperamide (since it has
one less N-H group) it was subsequently found to
actually be less active than thioperamide in vivo in the
mouse (Table 1).
In structure 2 the side chain is attached through an
amino group to the 2-position of pyridine (or other
heterocycle), maintaining the 1,3 relationship of nitro-
gen atoms (N-C-N) that exists in thiourea. One
compound (5), however, had the side chain attached to
the pyridine 4-position and yet was active (Ki ) 160 nM),
indicating that antagonists do not have to necessarily
retain the N-C-N relationship. This result established
a precedent for replacing dN by dCH, and it therefore
seemed worthwhile to replace the pyridine ring by
Sch em e 1
Sch em e 2
Sch em e 3
Sch em e 4

3808 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Ganellin et al.
Ta ble 2. Aryloxyalkylimidazoles and Their Potencies as H3-Receptor Histamine Antagonists (Ki in Vitro for [3H]Histamine Release
from Rat Cerebral Cortex Synaptosomes and ED50 in Vivo in Mice for Effect on Brain tele-Methylhistamine Levels) and Physical Data
R
(CH2)nO
HN
N
ED50 ( SEM
crystn
solvent
synth
scheme
no.
n ) 2
R
Ki ( SEM (nM)
(mg/kg)a
formulab
C11H11N3O3
mp (°C)
9a
9b
9c
9d
9e
9f
9g
9h
9i
4-NO2
3-NO2
4-CN
3-CN
2-CN
4-CO2Me
4-CO2Et
4-COMe
4-COEt
4-COPh
4-CON(CH2)5
4-Cl
35 ( 6
12 ( 2
0.66 ( 0.11
0.9 ( 0.4
1.2 ( 0.3
2.9 ( 2.0
g10
>>3
>10
3.2 ( 1.4
0.95 ( 0.08
2.6 ( 0.5
>10
0.78 ( 0.21
>10
197-200
174-178
181-183
189-190
170-171
116-118
160-162
178-182
185-187
193-194
130-131
197-199
115-116
162-165
163-164
105-109
178-181
188-189
178
MeOH
EtOH
2A
2B
2A
2B
2B
2A
2A
2A
5
2B
2B
6
2B
2B
2B
5
C11H11N3O3‚0.75C2H2O4
9 ( 5
C
C
C
12H11N3O
12H11N3O‚C2H2O4
12H11N3O‚0.95C2H2O4
H2O:MeOHc
EtOH:Et2Od
EtOH:Et2Od
H2O
39 ( 6
483 ( 95
5.1 ( 1.7
6 ( 1
C13H14N2O3‚CF3CO2H‚0.3H2O
C14H16N2O3‚0.8C2H2O4
C
C
C
2-PrOH:Et2O
MeOH:Et2Oe
2-PrOH:Et2O
MeOH:Et2Od
EtOH:Et2Og
2-PrOH
23 ( 5
13H14N2O2‚C2H2O4
14H16N2O2‚0.9C2H2O4
18H16N2O2‚1.3C2H2O4
3.7 ( 0.6
54 ( 13
338 ( 135
21 ( 3
9j
9k
9l
f
C17H21N3O2‚1.3C2H2O4
C
11H11ClN2O‚C2H2O4‚0.5H2O
C11H10Cl2N2O‚CF3CO2H
9m
9n
9o
9p
9q
9r
3,5-Cl2
4-Br
2,3,4,5,6-F5
4-CF3
4-OMe
4-Me
>500
24 ( 10
>500
68 ( 18
38 ( 12
56 ( 23
80 ( 16
19 ( 9
90 ( 27
137 ( 20
h
2.9 ( 0.5
∼10
C
11H11BrN2O‚1.1C2H2O4
EtOH:Et2O
EtOH:Et2Od
H2O
C11H7F5N2O‚1.2C2H2O4‚0.2H2O
C12H11F3N2O
>10
2.9 ( 1.5
2.3 ( 0.7
>10
C
C
C
C
12H14N2O2‚0.85C2H2O4
12H14N2O‚0.8C2H2O4
13H16N2O‚0.85C2H2O4
14H18N2O‚1.1C2H2O4
EtOH
2B
5
2B
2B
2B
2B
2-PrOH:Et2O
EtOH:Et2O
EtOH:Et2O
H2O:MeOHg
EtOH
9s
9t
4-Et
4-Pr
1.6 ( 0.6
1.5 ( 0.4
3.4 ( 1.1
168-171
157-158j
187-189
i
9u
9v
3,4-C4H4
2,3-C4H4
C15H14N2O‚0.1H2O
C15H14N2O‚0.75C2H2O4
k
n ) 3
10a
10b
10c
4-CN
4-F
4-CF3
12 ( 3
11 ( 2
14 ( 6
0.54 ( 0.23
4.9 ( 1.1
0.6 ( 0.2
C
C
13H13N3O‚0.1H2O
194-195
135-137
201-204
EtOH:Et2O
CHCl3
EtOH:Et2O
5
5
5
12H13FN2O‚0.07CHCl3
C13H13F3N2O‚1.1C2H2O4
a
b
d
g
h
i
Calculated as the base. C2H2O4 ) oxalic acid. c 1:3. 2:1. e 10:1. f Piperidinyl. 1:2. Purified by preparative HPLC. â-Naphthyl.
Lit.28 mp 151-152 °C. R-Naphthyl.
j
k
Sch em e 5
Sch em e 6
ethyl)-1H-imidazole (Scheme 5), the latter being syn-
thesized by the published method.20 As an alternative,
which directly furnished the protected (hydroxyethyl)-
imidazole, 1-(N,N-dimethylsulfamoyl)-2-(tert-butyldi-
methylsilyl)imidazole21 was lithiated and treated with
ethylene oxide (Scheme 6).
The Williamson synthesis was not successful when
applied to the higher homologues 10 since the requisite

Phenoxyalkylimidazoles as Histamine Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3809
4-(3-chloropropyl)-1H-imidazole23 underwent intramo-
lecular cyclization under the conditions of the reaction.
Instead, the (phenoxypropyl)imidazoles (10) were pre-
pared using the trityl-protected imidazole derivative
1-(triphenylmethyl)-4-(3-hydroxypropyl)imidazole in a
Mitsunobu type synthesis (Scheme 5). 1-(Triphenyl-
methyl)-4-(3-hydroxypropyl)imidazole was synthesized
from the commercially available urocanic acid (Scheme
4) via hydrogenation,22 followed by esterification with
ethanol in sulfuric acid, then reduction with LiAlH4 to
4-(3-hydroxypropyl)-1H-imidazole,23 and finally trityla-
tion (Scheme 5).
Resu lts a n d Discu ssion
The N-(4-nitrophenyl)histamine analogue 6 is active
(Table 1) as an H3-receptor histamine antagonist in vitro
(Ki ) 23 ( 9 nM) and is not significantly different from
the corresponding pyridyl derivative N-(5-nitropyrid-2-
yl)histamine 3 (R ) NO2) (Ki ) 29 ( 11 nM).5 This
finding establishes that it is not necessary to retain a
heterocycle for activity in the structural type repre-
sented by 3. This is also the case for the nitropyridyl
thioether 4 (Ki ) 4.8 ( 0.9 nM) in which the corre-
sponding nitrophenyl thioether 7 (Ki ) 9 ( 3 nM) is
slightly less active as an H3 antagonist in vitro but is
equiactive in vivo. The isomer 8, in which the S and
CH2 groups attached to the benzene ring are inter-
changed, is, by contrast, some 30-fold less active (Ki )
313 ( 58 nM) than 7 in vitro and also less active in
vivo (ED50 g10 mg/kg).
These results encouraged us to investigate the cor-
responding oxygen isostere, 4-[2-(4-nitrophenoxy)ethyl]-
1H-imidazole, 9a . This compound was found to be
somewhat less active than 7 in vitro (Ki ) 35 ( 6 nM),
but it is actually as active as thioperamide 1 in vivo
(ED50 ) 0.66 ( 0.11 mg/kg). This last result led us to
explore a series of phenoxy compounds in which the
effects of a variety of substituents have been examined.
Other electron-withdrawing groups in the 4-position
of structure 9, such as R ) CN, CF3, COR′, and halogen,
give compounds whose activities are in the range Ki )
3.7-68 nM, except for the piperidine amide 9k . The
position of substitution has been investigated. There
is not a large difference between 3- and 4-substituted
compounds (e.g., R ) NO2 or CN, 9b,d ). On the other
hand a 2-CN-substituted compound 9e is approximately
50-fold less active than the 4-CN derivative 9c, and the
presence of two substituents, as in the 3,5-dichloro
analogue 9m , also appears to be deleterious for activity.
With the published5 aminopyridine series 3, electron-
withdrawing substituents R appeared to be much better
for activity than electron-releasing groups. In the
present phenoxy series, electron-releasing groups (R )
OMe, Me, Et, Pr) also give active compounds (9q-t) (Ki
) 19-80 nM). The â-naphthyloxy compound 9u has
previously been investigated for histamine-like effects
(H1 receptor) and was described as having a “momentary
spasmodic effect” on the isolated guinea pig ileum.28 The
substituent effects in the 4-position span 2 orders of
magnitude in potency in vitro (Ki ) 3.7-338 nM), but
attempts to obtain meaningful multiparameter correla-
tions between physicochemical properties and antago-
nist potencies have not been successful.
P h a r m a cology
In Vitr o. The compounds were tested in vitro for
their antagonism of histamine at H3-receptors in an
assay with K+-evoked depolarization-induced release of
[3H]histamine from synaptosomes of rat cerebral cortex.
Rats were killed by decapitation, and synaptosomes
were obtained from the cerebral cortex, washed, and
resuspended in modified Krebs-Ringer’s bicarbonate
medium. The synaptosomes were allowed to synthesize
[3H]histamine during a 30 min incubation at 37 °C in
the presence of (3-4) × 10-7 M L-[3H]histidine, and then
they were washed to remove excess [3H]histidine and
to obtain a constant spontaneous [3H]histamine efflux,
as described.3 Synaptosomes were incubated for 2 min
with 30 mM K+. Unlabeled histamine (1 µM) alone, or
together with test compounds, was added 5 min before
the start of incubations, at the end of which [3H]-
histamine was assayed by liquid scintillation counting
of the supernatant liquid after isolation by ion-exchange
chromatography on Amberlite CG 50 columns.3
Inhibition-response curves were analyzed for deter-
mination of IC50 values of antagonists by fitting the data
with an iterative computer, least-squares method de-
rived from Parker and Waud.24 The apparent dissocia-
tion constants (Ki) of the antagonists were calculated
from the IC50 values, assuming a competitive antago-
nism and neglecting the effect of endogenous histamine
according to the equation of Cheng and Prusoff,25 Ki )
IC50/(1 + S/EC50), where S represents the concentration
of exogenous histamine (1 µM) and EC50 represents the
histamine concentration (62 nM) eliciting a half-
maximal inhibitory effect on K+-evoked release of [3H]-
histamine.
In Vivo. The compounds were tested in vivo by
administration as the salt form indicated in Table 2 as
a suspension in 1% methylcellulose per os to groups of
at least six male Swiss mice (weighing 18-22 g) as
described by Garbarg et al.26 The compounds were first
given at 10 mg/kg (calculated as free base), and then
further doses were selected based on the initial results.
The brain histamine turnover was determined by mea-
suring the level of the main metabolite of histamine,
tele-methylhistamine. Mice were fasted for 24 h before
po treatment, and 90 min after treatment, animals were
decapitated and the cerebral cortex was dissected out.
The cortex was homogenized in 10 volumes of ice-cold
perchloric acid (0.4 M). The tele-methylhistamine level
was measured by a radioimmunoassay described by
Garbarg et al.27 Treatment with 10 mg/kg thioperamide
furnished the maximal tele-methylhistamine level for
comparison with the level reached after the adminis-
tered drug, and the ED50 value was calculated.24
There is a wide divergence between some of the in
vitro and in vivo potencies. The esters 9f and 9g which
are very active in vitro are not active in vivo, but this
probably reflects hydrolysis in vivo to the corresponding
acid. Some compounds were not sufficiently active in
vivo for an ED50 to be determined. For the other 16
active compounds (where n ) 2), a trend is apparent
between Ki and ED50 values, shown in Figure 1. The
equation log ED50 ) 0.47 log Ki + 0.20 (n ) 16, r ) 0.78)
obtained by regression analysis describes this relation-
ship. The compounds constitute a chemically homoge-
neous set since they are all imidazolylethoxy derivatives
which only vary by the substituent in the phenoxy ring.
In general, compounds with low Ki values are the most
active in vivo, but there is quite a spread of results. The

3810 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Ganellin et al.
impact at 70 eV. IR spectra were obtained on a Perkin-Elmer
983 spectrometer. The NMR, MS, and IR spectral data of all
compounds were consistent with the assigned structures. All
final products had satisfactory (within (0.4%) C, H, and N
analyses unless otherwise indicated. Elemental analyses were
performed by A. A. T. Stones in the Department of Chemistry,
University College London.
Analytical thin-layer chromatography (TLC) was performed
using Merck Kieselgel 60F-254 plates using NH4OH:MeOH:
EtOAc (1:1:5) as the solvent system. Analytical high-pressure
liquid chromatography (HPLC) was performed on a Gilson
binary gradient apparatus with UV detection at 254 nm and
a (4 × 4 + 250 × 4 mm) Lichrosorb RP Select B 5 mm column
with a flow rate of 1 mL/min. Column chromatography was
conducted using Merck silica gel 60 (particle size 0.063-0.200
mm).
Sta r tin g Ma ter ia ls. Histamine dihydrochloride, 4-(hy-
droxymethyl)-1H-imidazole hydrochloride, and the appropriate
substituted phenols were from Aldrich Chemical Co. except
for N-(p-hydroxybenzoyl)piperidine which was synthesized
from p-hydroxybenzoic acid using acetyl as a protecting group
(Scheme 7).
F igu r e 1. Correlation of oral activity log ED50 (µmol/kg) on
brain tele-methylhistamine levels in mice with in vitro log Ki
(nM) on rat cerebral cortex synaptosomes for 16 [(aryloxy)-
ethyl]imidazoles 9a -e,h -j,l,n ,o,q,r ,t-v.
Nr-(4-Nitr op h en yl)h ista m in e Oxa la te (6). Histamine
base was liberated from the dihydrochloride with NaOEt in
EtOH by heating under reflux for 1 h, filtering, and evaporat-
ing under reduced pressure. The residue was suspended in
2-PrOH and filtered hot, and the extract was evaporated to
yield histamine. Histamine (1.46 g, 13 mmol), 1-chloro-4-
nitrobenzene (2.06 g, 13 mmol), and K2CO3 were heated with
stirring under reflux in 2-PrOH (10 mL). The mixture was
filtered and concentrated under reduced pressure, and the
resulting solid residue was chromatographed on silica gel
eluted with CHCl3 and MeOH (1:10). The purified product
was dissolved in the minimum amount of 2-PrOH (10 mL),
cooled, and filtered from silica. The filtrate was then evapo-
rated under reduced pressure to afford a solid: mp 165-168
°C; yield 0.85 g, 28%. The product was converted into the
oxalate salt in EtOH followed by addition of ether and then
recrystallized from EtOH:CHCl3 (10:1) to yield yellow
needles: mp 185-186 °C; UV (MeOH) λmax (nm) (log ꢀmax) 380
(4.25); 1H NMR (200 MHz, DMSO-d6 + D2O) δ 8.66 (s, 1H,
Im-2), 8.07 (d, J ) 7 Hz, 2H, Ph), 7.32 (s, 1H, Im-4(5)), 6.54
(d, J ) 7 Hz, 2H, Ph), 3.53 (t, 2H, CH2NH), 2.97 (t, 2H, ImCH2).
Anal. (C11H12N4O2, 1.25C2H2O4) H, N; C: found, 46.4; calcd,
47.0.
4-[2-[(4-Nitr oph en yl)th io]eth yl]-1H-im idazole (7). 4-Ni-
trothiophenol (1.86 g, 12 mmol) in DMF (10 mL) was stirred
with NaH (200 mg of 60% in paraffin oil, 5 mmol) at 20 °C for
1 h under N2, and then 4-(2-chloroethyl)-1H-imidazole hydro-
chloride17 (200 mg, 1.2 mmol) and Bu4NI (catalytic amount)
were added. The mixture was heated at 80 °C for 1 d, and
the solvent was then evaporated under reduced pressure. The
resulting residue was stirred in Et2O, filtered, and extracted
with dilute HCl. The aqueous extract was basified with K2-
CO3, and the product was extracted into CHCl3 and then
crystallized from EtOH: mp 167-168 °C (yield 135 mg, 45%);
1H NMR (400 MHz, DMSO-d6) δ 8.12 (m, 2H, Ph-3,5H), 7.55
(s, 1H, Im-2H), 7.49 (m, 2H, Ph-2,6H), 6.87 (s, 1H, Im-4(5)H),
3.35 (t, 2H, CH2O), 2.85 (t, 2H, Im-CH2). Anal. (C11H11N3O2S)
C, H, N.
reliability for prediction is not good, however, because
the ED50 values only span 1 order of magnitude al-
though the Ki values extend over 2 orders.
Analysis of the in vivo data is complex. The com-
pounds are administered perorally, and activity will be
affected by their ability to be absorbed and by their
biodistribution properties. Included in this is the
requirement for the compounds to cross the blood-brain
barrier to enter the brain. In this connection, these
phenoxy compounds should have a distinct advantage
for brain penetration over the previous heterocyclic
arylamines since they are less polar and have a lower
propensity for hydrogen bonding, factors which are
believed to be very important for encouraging brain
penetration.29,30
Higher homologues, 10a -c, are also active Ki ∼ 11-
14 nM (Table 2), and two of these have ED50’s 0.5-0.6
mg/kg. Indeed 10a (UCL 1390, R ) 4-CN) and 10c
(UCL 1409, R ) 4-CF3) have been selected for further
study as potential candidates for drug development.
Compound 10a appears to be relatively selective for H3
receptors; in a range of binding assays it was found to
have no significant affinity at 10-5 M for A1, â1, â2, AT1,
benzodiazepine, D1, D2, NMDA, and 5-HT1A receptors
or Ca L-channels. It produced <50% inhibition at 10-5
M on R1, M, and opiate receptors but had somewhat
more affinity (<50% at 10-6 M) at H1 and (<50% at 10-7
M) at R2 receptors.
Subsequent to this work, homologous aliphatic ethers
[[(aralkyloxy)propyl]imidazoles, 11] have been de-
scribed31 as H3-receptor histamine antagonists, the most
important of which is the new radiochemically labeled
ligand iodoproxyfan32 (11, m ) 1, R ) 4-I) which has Ki
) 5 nM.
4-[[(4-Nitr oben zyl)th io]m eth yl]-1H-im id a zole (8).
A
mixture of 4-(chloromethyl)-1H-imidazole hydrochloride33 (1.53
g, 10 mmol) and thiourea (0.76 g, 10 mmol) was heated in
EtOH (10 mL) under reflux for 15 min. EtOH (5 mL), H2O
(20 mL), and 4-nitrobenzyl chloride (200 mg, 1.16 mmol) were
added, and the mixture was cooled to 0-10 °C. A solution of
NaOH (1.44 g, 36 mmol) in H2O (14 mL) was added dropwise
under N2 at 0-10 °C, followed by stirring for 1 h at the same
temperature and for an additional 3 h at 20 °C. The precipi-
tate was collected and washed (H2O) to afford the title
compound: mp 88 °C; yield 190 mg, 65%; 1H NMR (400 MHz,
CDCl3) δ 8.09 (d, 2H, Ph-3,5H), 7.56 (s, 1H Im-2H), 7.40 (d,
2H, Ph-2,6H), 6.85 (s, 1H, Im-4(5)H), 3.69 (t, 2H, Im-CH2), 3.56
(t, 2H, CH2). Anal. (C11H11N3O2S) C, H, N.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points (mp) were taken in open
capillaries on an Electrothermal apparatus and are uncor-
rected. 1H NMR spectra were recorded on a Varian XL-200
(200 MHz) or VXR-400 (400 MHz) spectrometer, and chemical
shifts (ppm) are reported relative to the solvent peak (CHCl3
in CDCl3 at 7.24 ppm and DMSO in DMSO-d6 at 2.49 ppm) or
relative to TMS. Signals are designated as follows: s, singlet;
sbr, broad singlet; d, doublet; dd, doublet of doublets; t, triplet;
q, quadruplet; quint, quintet; m, multiplet. Mass spectra were
recorded by Dr. M. Mruzek on a VG 7070H double-focusing
spectrometer with a Finnigan Incos data system using electron-
Syn t h esis of Com p ou n d s 9a -v. The compounds were
synthesized according to the schemes and methods indicated

Phenoxyalkylimidazoles as Histamine Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3811
Sch em e 7
in Table 2. The conditions for these procedures are exemplified
below with compounds 9a (Scheme 2, method A), 9k (Scheme
2, method B), 9l (Scheme 6), and 9p (Scheme 5).
4-[2-(4-Ch lor oph en oxy)eth yl]-1H-im idazole Oxalate (9l).
1-(N,N-Dimethylsulfamoyl)-2-(tert-butyldimethylsilyl)imid-
azole21 (2 g, 6.92 mmol) in dry THF (20 mL) was cooled to -78
°C under N2, and a solution of n-butyllithium (1.5 M in hexane)
(6 mL, 9 mmol) was added slowly by syringe. The mixture
was stirred at -78 °C for 30 min, and then a solution of
ethylene oxide (1.52 g, 34 mmol, 5 equiv) in dry THF (10 mL)
was added at 0 °C. The mixture was stirred at 20 °C for 16 h,
then poured into cold water (20 mL), and evaporated under
reduced pressure. The product was extracted into CH2Cl2 (3
× 100 mL), dried (MgSO4), and evaporated under reduced
pressure to give an oil which was purified by column chroma-
tography (Et2O:petroleum ether, 1:1) to afford 1-(N,N-dimeth-
ylsulfamoyl)-2-(tert-butyldimethylsilyl)-4-(2-hydroxyethyl)-
imidazole (1.2 g, 52%): mp 133-134 °C (Et2O); 1H NMR (400
MHz, CDCl3) δ 7.27 (d, 1H, Im-4H), 3.90 (t, 2H, CH2O), 3.01
(t, 2H, Im-CH2), 2.99 (s, 6H, N(CH3)2), 0.99 (s, 9H, C(CH3)3),
0.76 (s, 6H, Si(CH3)2).
To the above carbinol (0.70 g, 2.10 mmol) in freshly distilled
THF (10 mL) were added triphenylphosphine (0.82 g, 3.15
mmol) and 4-chlorophenol (0.27 g, 2.10 mmol), and the mixture
was cooled and stirred for 5 min under N2. Diethyl azodicar-
boxylate (0.55 g, 3.15 mmol), in freshly distilled THF (6 mL),
was added slowly, and stirring was continued at 20 °C for 16
h. The solvent was then removed in vacuo, and the residue
was chromatographed on a column (EtOAc:hexane, 1:2) to give
1-(N,N-dimethylsulfamoyl)-2-(tert-butyldimethylsilyl)-5-[2-(4-
chlorophenoxy)ethyl]imidazole as an oil (0.3 g, 32%). The
latter (0.3 g, 0.675 mmol) in THF (10 mL) and 2 N HCl (10
mL) was heated at 80 °C for 5 h. The THF was removed under
reduced pressure, and the resulting mixture was washed
(Et2O), basified (K2CO3), and extracted with CHCl3. The
extract was dried and evaporated, and the resulting product
was purified by column chromatography (EtOAc:MeOH, 5:1).
The resulting oil (0.1 g, 0.35 mmol) was dissolved in 2-PrOH
(4 mL) and treated with oxalic acid (1.5 equiv) in 2-PrOH (3
mL), cooled, and diluted with Et2O to give the product, as
oxalate, which was collected by filtration and crystallized from
EtOH: yield 0.044 g, 32%; mp 197-199 °C; 1H NMR (400 MHz,
DMSO-d6) δ 8.30 (s, 1H, Im-2H), 7.32 (d, 2H, Ph-H), 7.20 (d,
2H, Ph-H), 6.98 (d, 1H, Im-4(5)H), 4.18 (t, CH2O), 3.03 (t, 2H,
Im-CH2).
4-[2-(4-Nitr oph en oxy)eth yl]-1H-im idazole (9a) (Meth od
A). 4-Nitrophenol (209 mg, 1.5 mmol), 4-(2-chloroethyl)-1H-
imidazole hydrochloride (251 mg, 1.4 mmol), K2CO3 (475 mg,
3 mmol), and NaI (catalyst) were stirred at 80 °C for 5 d in
DMF (5 mL). The reaction mixture was cooled, diluted with
Et2O (100 mL), and filtered. The filtrate was evaporated under
reduced pressure, and the resulting residue was subjected to
column chromatography on silica gel (first eluant CHCl3 and
second eluant CHCl3:MeOH, 9:1) to give the product which,
after crystallization (MeOH), had the following properties: mp
1
197-200 °C; yield 350 mg, 33%; H NMR (200 MHz, DMSO-
d6) δ 11.83 (s, 1H, NH), 8.16 (d, 2H, Ph-3,5H), 7.64 (s, 1H,
Im-2H), 7.13 (d, 2H, Ph-2,6H), 6.94 (s, 1H, Im-4(5)H), 4.28 (t,
2H, CH2O), 2.48 (t, 2H, Im-CH2).
4-[2-[4-(1-P ip e r id in ylca r b on yl)p h e n oxy]e t h yl]-1H -
im id a zole Oxa la te (9k ) (Meth od B). A suspension of
4-hydroxybenzoic acid (35 g, 0.25 mol) was heated in Ac2O (46.2
mL) under reflux for 6 h. The Ac2O was evaporated, and the
resulting residue was triturated in Et2O, filtered, and washed
with Et2O to give 4-acetoxybenzoic acid as a white solid (33.6
g, 75%) (lit.34 mp 189 °C): 1H NMR (200 MHz, CDCl3) δ 9.50
(s, 1H, COOH), 8.20 (d, 2H, Ph-3,5H), 7.25 (d, 2H, Ph-2,6H),
2.30 (s, 3H, CH3).
A mixture of 4-acetoxybenzoic acid (33.6 g, 0.19 mol) and
PCl5 (39.1 g, 0.19 mol) in Et2O (250 mL) was stirred at 20 °C
for 2 h. The solvent and phosphorus oxychloride were then
evaporated off, and the residue was dried in vacuo and washed
with dry Et2O to give 4-acetoxybenzoyl chloride (26.3 g, 71%):
1H NMR (200 MHz, DMSO-d6) δ 8.20 (d, 2H, Ph-3,5H), 7.25
(d, 2H, Ph-2,6H), 2.20 (s, 3H, CH3).
4-Acetoxybenzoyl chloride (1.7 g, 8.6 mmol) was added to a
solution of piperidine (1.40 g, 18 mmol) in water (5 mL) at
15-25 °C. The mixture was stirred for 2 h, treated with 2 N
NaOH (45 mL), stirred for 2 h, acidified at 0 °C with dilute
HCl, and stirred for 2 h. The resulting white precipitate of
1-(4-hydroxybenzoyl)piperidine was collected and washed twice
with water and had the following properties: mp 215-217 °C
(lit.35 mp 210 °C); yield 1.33 g, 76%; IR ν (cm-1) 3100 (br, OH),
1
1680 (s, CdO); H NMR (200 MHz, CDCl3) δ 7.14 (d, 2H, Ph-
3,5H), 6.70 (s, 2H, Ph-2,6H), 3.40 (m, 4H, NCH2), 1.48 (m, 6H,
CCH2C).
4-[2-[4-(Tr iflu or om e t h yl)p h e n oxy]e t h yl]-1H -im id -
a zole (9p ). A solution of 4-(2-hydroxyethyl)-1H-imidazole
hydrochloride20 (0.5 g, 4.46 mmol) and dry triethylamine (1.25
mL, 9 mmol) in DMF (10 mL) was treated with triphenyl-
methyl chloride (1.24 g, 4.46 mmol) in DMF (5 mL) under N2.
The reaction mixture was stirred at 20 °C for 2 h and then
poured onto crushed ice (50 g). The resulting solid was
collected by filtration, washed (H2O × 3), and crystallized
(EtOH:Et2O) to afford 1-(triphenylmethyl)-4-(2-hydroxy-
ethyl)imidazole: yield 1.10 g, 69%; 1H NMR (400 MHz, CDCl3)
δ 7.33-7.12 (m, 16H, Im-2H and Ph3C), 6.60 (s, 1H, Im-5H),
3.90 (t, 2H, CH2-O), 3.70 (s, 1H, OH), 2.75 (t, 2H, Im-CH2).
To 1-(triphenylmethyl)-4-(2-hydroxyethyl)imidazole (708 mg,
2 mmol) under N2 was added freshly distilled THF (15 mL),
4-(trifluoromethyl)phenol (340 mg, 2.1 mmol), and triphen-
ylphosphine (550 mg, 2.1 mmol). The resulting mixture was
cooled and stirred for 5 min, and then diethyl azodicarboxylate
(366 mg, 2.1 mmol) in THF (10 mL) was slowly added; stirring
was continued at 20 °C for 2 h under N2. The solvent was
then evaporated under reduced pressure, and the resulting
residue was subjected to chromatography on a silica gel column
using Et2O as an eluant to give 1-(triphenylmethyl)-4-[2-[4-
To 1-(4-hydroxybenzoyl)piperidine (1.23 g, 6 mmol) in dry
DMF (10 mL) was added NaH (60% in paraffin oil, 200 mg, 5
mmol). The mixture was stirred at 20 °C for 1 h under N2,
and then 4-(2-chloroethyl)-1H-imidazole hydrochloride (200
mg, 1.20 mmol) and Bu4NI (catalytic amount) were added. The
mixture was heated at 100 °C for 2 d, and the solvent was
then evaporated under reduced pressure. The oily residue was
stirred in Et2O and filtered. The excess of 1-(4-hydroxyben-
zoyl)piperidine was extracted in Et2O under acidic conditions
(dilute HCl). The aqueous solution was basified with K2CO3
and extracted with CHCl3. The extract was evaporated, and
the resulting residue was subjected to chromatography on a
silica gel column (first eluant CHCl3, second eluant CHCl3:
MeOH, 95:5). The resulting product was converted into the
oxalate and recrystallized from EtOH:Et2O (1:2): mp 130-
131 °C; yield 35 mg, 29%; 1H NMR (400 MHz, DMSO-d6) δ
8.39 (d, 1H, Im-2H), 7.31 (d, 2H, Ph-3,5H), 7.25 (d, 1H, Im-
4(5)H), 6.99 (d, 2H, Ph-2,6H), 4.24 (t, 2H, O-CH2), 3.46 (m,
4H, piperidine-2,6H), 3.05 (t, 2H, Im-CH2), 1.60 (m, 6H,
piperidine-3,4,5H).

3812 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19
Ganellin et al.
(trifluoromethyl)phenoxy]ethyl]imidazole which was recrystal-
lized from water: yield 0.75 g, 75%. A solution of 1-(triphen-
ylmethyl)-4-[2-[4-(trifluoromethyl)phenoxy]ethyl]imidazole (640
mg, 1.28 mmol) in THF (2 mL) and 2 N HCl (5 mL) was heated
at 70 °C during 2 h. The THF was then evaporated off under
reduced pressure, the resulting residue was washed (Et2O) and
basified (K2CO3), and the resulting white solid was filtered off
and washed (H2O × 3) to give 4-[2-[4-(trifluoromethyl)-
phenoxy]ethyl]-1H-imidazole: mp 105-109 °C; yield 281 mg,
35 mg, 77%; IR ν (cm-1) 3450 (b, N-H str), 2220 (s, CN str),
1H NMR (400 MHz, CDCl3) δ 7.90 (d, 2H, Ph-3,5H), 7.85 (m,
1H, Im-2H), 7.28 (d, 2H, Ph-2,6H), 7.08 (s, 1H, Im-4(5)H), 4.37
(t, 2H, CH2O), 3.11 (t, 3H, Im-CH2 and NH), 2.49 (quint, 2H,
CH2).
Ack n ow led gm en t. We thank Dr. J . M. Lecomte for
a grant (to A.F., S.A.) from Laboratoire Bioprojet, Paris,
and the Commission of the European Communities for
a grant from the Biomedical and Health Research
Programme Biomed 1 (CT92-1087). We thank the
following for synthesis of the compounds indicated: Dr.
S. K. Hosseini (6), Helen Magnusen (9j), and Vincenzo
Cannizzaro (9i,r ,u ). We thank Dr. K. Richardson,
Pfizer Central Research Sandwich, Kent, for providing
binding data on 10a .
1
85%; H NMR (400 MHz, CDCl3) δ 7.59 (s, 1H, Im-2H), 7.50
(d, 2H, Ph-3,5H), 6.93 (d, 2H, Ph-2,6H), 6.89 (s, 1H, Im-4(5)H),
5.90 (s, 1H, Im-NH), 4.25 (t, 2H, CH2O), 3.10 (t, 2H, Im-CH2).
4-[3-(4-Cyan oph en oxy)pr opyl]-1H-im idazole (10a). Uro-
canic acid (25 g, 0.18 mol) was hydrogenated22 with 10%
palladium on charcoal (2.5 g) in water (200 mL) at 40 °C for 4
h. The mixture was then cooled, filtered, and evaporated
under reduced pressure. The resulting white residue was
dissolved in EtOH (1 L), sulfuric acid (10 mL) was added, and
the reaction mixture was heated under reflux for 12 h and
then cooled and evaporated under reduced pressure to give
an oily residue. The latter was basified at 0 °C with saturated
NaHCO3 and extracted with CHCl3 (6 × 100 mL). The
combined extracts were dried (MgSO4) and then evaporated
to give ethyl 2-(imidazol-4-yl)propionate23 as an oil (29.2 g,
96%): IR ν (cm-1) 3500 (b, N-H), 1730 (s, CdO); 1H NMR (200
MHz, D2O) δ 7.70 (s, 1H, Im-2H), 6.40 (s, 1H, Im-4(5)H), 3.31
(q, 2H, OCH2), 2.20 (t, 2H, Im-CH2), 1.94 (t, 2H, CH2CO), 1.10
(t, 3H, CH3).
Refer en ces
(1) Ganellin, C. R.; Fkyerat, A.; Hosseini, S. K.; Tertiuk, W.;
Garbarg, M.; Ligneau, X.; Schwartz, J .-C. Design of Non-
Thiourea H3-Receptor Histamine Antagonists. Eur. J . Pharm.
Sci. 1994, 2, 93 (SC 10).
(2) Arrang, J .-M.; Garbarg, M.; Schwartz, J .-C. Auto-inhibition of
Histamine Synthesis Mediated by Pre-synaptic H3-Receptors.
Neuroscience 1987, 23, 149-157.
(3) Arrang, J .-M.; Garbarg, M.; Schwartz, J .-C. Auto-inhibition of
Brain Histamine Release Mediated by a Novel Class (H3) of
Histamine Receptor. Nature (London) 1983, 302, 832-837.
(4) Schlicker, E.; Malinowska, B.; Kathmann, M.; Go¨thert, M.
Modulation of Neurotransmitter Release via Histamine H3
Heteroreceptors. Fundam. Clin. Pharmacol. 1994, 8, 128-137.
(5) Ganellin, C. R.; Hosseini, S. K.; Khalaf, Y. S.; Tertiuk, W.;
Arrang, J .-M.; Garbarg, M.; Ligneau, X.; Schwartz, J .-C. Design
of Potent Non-Thiourea H3-Receptor Histamine Antagonists. J .
Med. Chem. 1995, 38, 3342-3350.
(6) Arrang, J .-M.; Garbarg, M.; Lancelot, J .-C.; Lecomte J .-M.;
Pollard, H.; Robba, M.; Schunack, W.; Schwartz, J .-C. Highly
Potent and Selective Ligands for Histamine H3-Receptors.
Nature (London) 1987, 327, 117-123.
(7) Garbarg, M.; Trung Tuong, M. D.; Gros, C.; Schwartz, J .-C.
Effects of Histamine H3-Receptor Ligands on Various Biochemi-
cal Indices of Histaminergic Neuron Activity in Rat Brain. Eur.
J . Pharmacol. 1989, 164, 1-11.
(8) Monti, J . M.; J antos, H.; Boussard, M.; Altier, H.; Orellana, C.;
Olivera, S. Effects of Selective Activation or Blockade of the
Histamine H3 Receptor on Sleep and Wakefulness. Eur. J .
Pharmacol. 1991, 205, 283-287.
The above ester (29.2 g, 0.17 mol) in freshly distilled THF
(200 mL) was added dropwise to a cooled suspension of LiAlH4
(7.8 g, 0.2 mol) in THF (100 mL), and the mixture was stirred
at 20 °C for 15 h. Then KOH (6 g) in water (24 mL) was added
dropwise with cooling; the resulting mixture was heated to
reflux, and the hot solution was filtered. The residue was
extracted with boiling THF (2 × 200 mL) and filtered. The
filtrate was dried (MgSO4) and concentrated under reduced
pressure, and the resulting 4-(3-hydroxypropyl)-1H-imidazole23
was converted into the oxalate in 2-propanol and then pre-
cipitated with Et2O: yield 28.9 g, 79%; 1H NMR (200 MHz,
D2O) δ 7.94 (s, 1H, Im-2H), 7.00 (s, 1H, Im-4(5)H), 3.14 (t, 2H,
CH2O), 2.06 (t, 2H, Im-CH2), 1.14 (quint, 2H, CH2).
A solution of 4-(3-hydroxypropyl)-1H-imidazole (2.0 g, 15.85
mmol) and dry triethylamine (5.5 mL, 54.3 mmol) in dry DMF
(15.6 mL) was treated with triphenylmethyl chloride (4.86 g,
17.4 mmol) in DMF (5 mL) under N2. The reaction mixture
was stirred at 20 °C for 2 h and then poured into crushed ice
(350 g). The resulting solid was collected by filtration, washed
(3×) with water, and purified by column chromatography using
CHCl3, followed by CHCl3:MeOH (1:1) as eluant to give
1-(triphenylmethyl)-4-(3-hydroxypropyl)imidazole: mp 132-
133 °C.
(9) Schwartz, J .-C.; Arrang, J .-M.; Garbarg, M.; Pollard, H.; and
Ruat, M. Histaminergic Transmission in the Mammalian Brain.
Physiol. Rev. 1991, 71, 1-51.
(10) Sakai, N.; Onodera, K.; Maeyama, K.; Yanai, K.; Watanabe, T.
Effects of Thioperamide, a Histamine H3-Receptor Antagonist,
on Locomotor Activity and Brain Histamine Content in Mast
Cell Deficient W/WV Mice. Life Sci. 1991, 48 2397-2404.
(11) Soe-J ensen, P.; Knigge, U.; Garbarg, M.; Kjoer, A.; Rouleau, A.;
Bach, F. W.; Schwartz, J .-C.; Warberg, J . Responses of Anterior
Pituitary Hormones and Hypothalamic Histamine to Blockade
of Histamine Synthesis and to Selective Activation or Inactiva-
tion of Presynaptic Histamine H3 Receptors in Stressed Rats.
Neuroendocrinology 1993, 57, 532-540.
(12) Yokoyama, H.; Onodera, K.; Iinuma, K.; Watanabe, T. Effect of
Thioperamide, a Histamine H3-Receptor Antagonist, on Electri-
cally Induced Convulsions in Mice. Eur. J . Pharmacol. 1993, 234,
129-133.
(13) Malmberg-Aillo, P.; Lamberti, C.; Ghelardini, C.; Giotti, A.;
Bartolini, A. Role of Histamine in Rodent Antinociception. Br.
J . Pharmacol. 1994, 111, 1269-1279.
(14) Ookuma, K.; Sakata, T.; Fukagawa, K.; Yoshimatsu, H.; Kuroka-
wa, M.; Machidori, H.; Fujimoto, K. Neuronal Histamine in the
Hypothalamus Suppresses Food Intake in Rats. Brain Res. 1993,
628, 235-242.
(15) A similar analysis of burimamide analogues has been carried
out by Vollinga et al.: Vollinga, R. C.; Menge, W. M. P. B.; Leurs,
R.; Timmerman, H. New Analogs of Burimamide as Potent and
Selective Histamine H3 Receptor Antagonists: The Effect of
Chain Length Variation of the Alkyl Spacer and Modifications
of the N-Thiourea Substituent. J . Med. Chem. 1995, 38, 2244-
2250. It was shown that the cyclohexylthiourea derived from
histamine was some 10-fold less active than burimamide as an
H3-receptor antagonist when tested on the guinea pig jejunum.
To 1-(triphenylmethyl)-4-(3-hydroxypropyl)imidazole (184
mg, 0.5 mmol) under N2 was added freshly distilled THF (5
mL), 4-cyanophenol (71 mg, 0.6 mmol), and triphenylphosphine
(157 mg, 0.6 mmol). The resulting mixture was cooled and
stirred for 5 min, diethyl azodicarboxylate (104 mg, 0.6 mmol)
in THF (3 mL) was slowly added, and stirring was continued
at 20 °C for 3 h under N2. The solvent was then evaporated
under reduced pressure, and the residue was subjected to
chromatography on a silica gel column (first eluant petroleum
spirit: Et2O (1:1); second eluant Et2O) to give 1-(triphenyl-
methyl)-4-[3-(4-cyanophenoxy)propyl]imidazole, which was re-
crystallized from EtOH:petroleum ether (1:1): mp 187-188
1
°C; yield 140 mg, 56%; H NMR (400 MHz, CDCl3) δ 7.55 (d,
2H, Ph-3,5H), 7.47 (s, 1H, Im-2H), 7.32-7.10 (m, 15H, Ph3C),
6.88 (d, 2H, Ph-2,6H), 6.56 (s, 1H, Im-5H), 4.01 (t, 2H, CH2O),
2.75 (t, 2H, Im-CH2), 2.18 (quint, 2H, CH2).
1-(Triphenylmethyl)-4-[3-(4-cyanophenoxy)propyl]imid-
azole (96 mg, 0.2 mmol) in THF (2 mL) and 2 N HCl (5 mL)
was heated at 70 °C during 6 h. The THF was then removed
under reduced pressure, and the residue was washed with
Et2O and basified (K2CO3), and the product was extracted into
CHCl3 and dried (MgSO4). The combined extracts were
evaporated under reduced pressure to give the product, 4-[3-
(4-cyanophenoxy)propyl]-1H-imidazole, as a white solid which
was crystallized from EtOH:Et2O (1:2): mp 194-195 °C; yield

Phenoxyalkylimidazoles as Histamine Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 19 3813
(16) Schwartz, J .-C.; Arrang, J . M.; Garbarg, M.; Lecomte, J . M.;
Ganellin, C. R.; Fykerat, A.; Tertiuk, W.; Schunack, W.; Lipp,
R.; Stark, H.; Purand, K. French Patent 2 686 084-A1, 1993.
(17) (a) Turner, R. A. Studies of Imidazole Compounds III. Synthesis
of 4-(2-Chloroethyl)-imidazole. J . Am. Chem. Soc. 1949, 71,
3476-3478. (b) Huebner, C. F. Studies of Imidazole Compounds
V. A New and Improved Synthesis of 4-(2-Substituted Amino-
ethyl)-imidazoles. J . Am. Chem. Soc. 1951, 73, 4667-4669.
(18) Sterk, G. J .; van der Goot, H.; Timmerman, H. Studies on
Histaminergic Compounds III. Synthesis and Histamine H2-
Activity of a Series of Corresponding Histamine and Dimaprit
Analogues. Arch. Pharm. (Weinheim) 1986, 319, 624-630.
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