Development of FUB 181, a selective histamine H3-receptor antagonist of high oral in vivo potency with 4-(ω-(arylalkyloxy)alkyl)-1H-imidazole structure

Article abstract of DOI:10.1002/(SICI)1521-4184(199806)331:6<211::AID-ARDP211>3.0.CO;2-P

A series of 4-(ω-(arylalkyloxy)alkyl)-1H-imidazoles and related sulphur-containing compounds have been prepared and evaluated for their histamine H₃-autoreceptor antagonist in vitro potency in an assay on synaptosomes of rat cerebral cortex. In addition, the in vivo potency has been determined from the changes in N(τ)-methylhistamine levels in brain after p.o. administration to mice. Compounds with different alkyl chains and various aryl moities have been synthesized and tested to explore structure- activity azol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives showed low to moderate H₃-receptor antagonist potency, whereas the corresponding allyl and propyl derivatives were compounds with high antagonist in vitro potency. Corresponding thioether or sulphoxide derivatives also showed antagonist activity. Additionally, some ether derivatives possessed high in vivo potency as well. The most active ether derivatives under in vivo conditions were 4-(3-(3-(4- fluorophenyl)propyloxy)propyl)-1H-imidazole (11b) and the corresponding chloro compound 11c (FUB 181) with ED₅₀ values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all compounds tested showed weak activity at histamine H₁ or H₂ receptors. Furthermore, the most promising ether FUB 181 exhibited low activity at adrenergic α₁, β(1/2), serotonergic 5-HT(2A), 5- HT₃, and muscarinic M₃ receptors. Time-course investigations of FUB 181 in mice showed a rapid mode of action with the highest value 3 h after p.o. application. Thus, FUB 181 appears to block histamine H₃ receptors potently and selectively.

Full text of DOI:10.1002/(SICI)1521-4184(199806)331:6<211::AID-ARDP211>3.0.CO;2-P

Development of FUB 181
211
Development of FUB 181, a Selective Histamine H -Receptor
3
Antagonist of High Oral in Vivo Potency with
4-(ω-(Arylalkyloxy)alkyl)-1H-imidazole Structure✩ 1)
a)
a)
b)
a)
a)
c)
Holger Stark *, Annette Hüls , Xavier Ligneau , Katja Purand , Heinz Pertz , Jean-Michel Arrang ,
c)
a)
Jean-Charles Schwartz , and Walter Schunack
a) Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany
b) Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, F-75003 Paris, France
c) Unité de Neurobiologie et Pharmacologie Moléculaire, Centre Paul Broca de l’INSERM (U109), 2ter rue d’Alésia, F-75014 Paris, France
Key Words: Histamine H receptor; antagonist; FUB 181; imidazolylpropyl ether
3
antagonists are necessary to characterize the pharmacological
and physiological functions of this receptor subtype. At pre-
Summary
sent, histamine H receptors have been identified as autore-
ceptors located presynaptically on the axon terminals of
3
A series of 4-(ω-(arylalkyloxy)alkyl)-1H-imidazoles and related
sulphur-containing compounds have been prepared and evaluated
for their histamine H3-autoreceptor antagonist in vitro potency in
an assay on synaptosomes of rat cerebral cortex. In addition, the
in vivo potency has been determined from the changes in Nτ-
methylhistamine levels in brain after p.o. administration to mice.
Compounds with different alkyl chains and various aryl moities
have been synthesized and tested to explore structure-activity
relationships. Within this series of novel antagonists, (1H-imid-
azol-4-yl)methyl and 2-(1H-imidazol-4-yl)ethyl ether derivatives
showed low to moderate H3-receptor antagonist potency, whereas
the corresponding allyl and propyl derivatives were compounds
with high antagonist in vitro potency. Corresponding thioether or
sulphoxide derivatives also showed antagonist activity. Addition-
ally, some ether derivatives possessed high in vivo potency as well.
The most active ether derivatives under in vivo conditions were
4-(3-(3-(4-fluorophenyl)propyloxy)propyl)-1H-imidazole (11b)
and thecorresponding chloro compound 11c (FUB 181) with ED50
values of 0.76 and 0.80 mg/kg, respectively. On the other hand, all
compounds tested showed weak activity at histamine H1 or H2
receptors. Furthermore, the most promising ether FUB 181 exhib-
ited low activity at adrenergic α1, β1/2, serotonergic 5-HT2A,
5-HT3, and muscarinic M3 receptors. Time-course investigations
of FUB 181 in mice showed a rapid mode of action with the highest
value 3 h after p.o. application. Thus, FUB 181 appears to block
histamine H3 receptors potently and selectively.
histaminergic neurones controlling histamine release and
[6]
synthesis by a negative feed-back mechanism . In addition,
H receptors have been found as heteroreceptors located on
3
non-histaminergic neurones in the central nervous system
[7]
(CNS) and on sympathetic, parasympathetic, and non-ad-
renergic non-cholinergic nerve fibres supplying the gastroin-
[8]
[9]
[10]
testinal , bronchial , and cardiovascular system , thus
modulating the effect on a number of different neurotransmit-
[11–15]
ters
. H receptors may also be located on endocrine
3
cells, e.g., enterochromaffin and enterochromaffin-like
[16, 17]
cells
. Their activation causes inhibition of release of
the respective mediators. Histamine H -receptor antagonists
3
have not yet been used clinically, but several therapeutic
indications for H -receptor antagonists have been pro-
3
[17–19]
posed
, e.g., various diseases or conditions of the CNS
like memory and learning deficits
disorders , and epilepsy
[20, 21]
, cognitive and sleep
[22]
[23]
.
The common structural features of different developments
in the field of highly potent antagonists led to a general
construction pattern for histamine H -receptor antago-
3
[18]
nists . A nitrogen-containing heterocycle connected with a
polar group via an alkyl chain seems to be of fundamental
importance for H -receptor antagonist activity. H -receptor
3
3
potency can be further increased by the introduction of a
lipophilic portion linked with the polar group via an addi-
tional alkyl spacer. Although some non-imidazoles such as
[24]
[25]
[26]
Introduction
betahistine , dimaprit , and clozapine
have some
antagonist potency, replacement of or variation on the imid-
During the last decade several synthetic attempts have been
azole ring to other nitrogen-containing ring systems were
[1–5]
carried out by various laboratories
to develop potent and
[27, 28]
generally accompanied by a dramatic loss of potency
.
selective antagonists of the histamine H -receptor subtype
3
On the other hand, various functional groups are tolerated as
polar groups without a decrease in H -receptor antagonist
[6]
first described by Arrang et al. in 1983 . Potent and selective
3
[29]
potency. Thus, different compounds such as amides
,
———
1) Presented in parts: XXIIIrd Annual Meeting of the European Histamine
Research Society (EHRS) (Abstract p. 120), Budapest, Hungary, May 18–21,
1994; XIIIth International Symposium on Medicinal Chemistry (Abstract
P134), Paris, France, September 19–23, 1994; 2nd European Congress of
Pharmaceutical Sciences (Free Communication FC22[42], poster P84[52]),
Berlin, September 29–October 1, 1994; VIIth Noordwijkerhout-Camerino
Symposium, Trends in Drug Research (Abstract P20), Noordwijkerhout, The
Netherlands, May 15–19, 1997.
[4, 30]
[31]
[32]
[32,
isothiourea
, guanidines , esters , carbamates
33]
[34]
, and oxadi-azoles
are suitable antagonists for H -re-
ceptors (for review see Leurs et al. , Stark et al. ). Since
the reference antagonist thioperamide and the highly active
3
[19]
[17]
compound clobenpropit showed some affinity for 5-HT
3
receptors, new leads were recommended for the evaluation of
[35]
H -receptor mediated functions . In previous studies, ben-
3
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
0365-6233/98/0606/0211 $17.50 +.50/0

212
Stark and co-workers
Figure 1. General construction pattern for this series of histamine H3-
receptor antagonists.
zyl ether derivatives of 4-(3-hydroxypropyl)-1H-imidazole
[36]
were shown to be highly effective compounds in vitro
.
Unfortunately, most of them were inactive in vivo. Only some
derivatives with voluminous aryl substituents or diphenyl-
methyl ethers showed remarkable in vivo potency. It might
be speculated that the attack of metabolizing enzymes is
hindered by these bulky substituents, but other reasons like
higher lipophilicity have also to be taken into account. Ra-
tional variations of these structures led to the compounds of
the present study. Most of the novel antagonists follow the
construction pattern containing an imidazole ring as a nitro-
gen-containing ring system and an ether functionality as polar
group (Figure 1). In this study structure-activity relationships
are discussed for a series of compounds with different spacers
and lipophilic groups containing an oxygen or sulphur moi-
ety. A series of 4-(ω-(arylalkyloxy)alkyl)-1H-imidazoles and
related sulphur-containing compounds have been developed.
Scheme 1. Synthesis of ether derivatives (except 10a, for details see text).
(a) i, NaH, dry toluene, 15-crown-5, 24 h, ambient temp.; ii, Cl-(CH2)m-R,
reflux; iii, 2N HCl, THF, 2 h, 70 °C.
imidazole protection by triphenylmethyl chloride, and reduc-
[42]
tion to the alcohol as described previously . The allyl
alcohol derivative 3 could be obtained by reduction of the
methyl ester of urocanic acid according to a procedure for
conversion of the corresponding amide to the amine pre-
[43]
viously described by Sellier et al. . The sodium alcoholates
of 1–4 were prepared by standard methods with sodium
hydride and activated with a catalytic amount of 15-crown-5
in an aprotic solvent like toluene.
The newly designed compounds were tested for their hista-
3
mine H -receptor antagonist in vitro potency in a [ H]hista-
3
mine-release assay on synaptosomes of rat cerebral
[37]
Addition of the corresponding arylalkyl halide to the trityl-
ated imidazolylalkyl alcoholates resulted in the desired ethers
in a tritylated form, except 4-(3-(2-phenylethyloxy)propyl)-
1H-imidazole (10a). In case of 10a elimination on 2-chloro-
1-phenylethane and formation of a stable styrene product
inhibited the synthesis of the desired ether 10a. To avoid
elimination, 2-phenyl ethanolate was combined with 4-(3-
chloropropyl)-1-(triphenylmethyl)-1H-imidazole hydro-
cortex . Furthermore, the H -receptor antagonist in vivo
3
potency was evaluated in brain after p.o. administration to
Swiss mice by examination of the central effect on the level
τ
[37]
of the main histamine metabolite, N -methylhistamine . In
order to investigate H -receptor selectivity, we have also
3
determined the activity at H and H receptors for most of the
1
2
compounds in functional assays on isolated organs of the
[38]
guinea pig . Compound FUB 181 (11c) was selected for
[44]
chloride, freshly prepared according to ref. . Nevertheless,
further pharmacological evaluation. It was tested in an addi-
the yield reached only 15% of the theoretical value in this
non-optimized reaction and resulted in 10a. The thioether 13
was prepared according to the method described for 10a with
sodium 3-phenyl propanethiolate. The corresponding sul-
tional functional assay on guinea pig ileum for its H -receptor
3
antagonist activity. Activity at adrenergic α , β , seroton-
1
1/2
ergic 5-HT , 5-HT , and muscarinic M receptors was de-
2A
3
3
termined to provide evidence with regard to receptor
phoxide 14 was obtained by oxidation of 13 using m-chloro-
selectivity and the potential use of the novel H -receptor
3
[45]
peroxybenzoic acid
.
antagonist as a therapeutic drug.
Finally, cleavage of the protecting group was performed by
[46]
refluxing in 2N HCl for 2 h in almost quantitative yields
Chemistry
with low amounts of side products. The etherderivativeswere
isolated, purified by rotary chromatography, and crystallized
as hydrogen maleates. Chemical data of the designed ethers
are given in Table 1. H NMR data of some compounds
selected by differences in chain lengths and substitution
patterns are given in the Experimental Part.
1-(Triphenylmethyl)-4-(ω-hydroxyalkyl)-1H-imidazoles
(1–4) were converted into ethers by Williamson reaction in
alkaline solution with different arylalkyl halides
(Scheme 1). Central building blocks of ethers were the
methyl (1), ethyl (2), allyl (3), and propyl (4) derivatives of
4-(ω-hydroxyalkyl)-1H-imidazoles protected in 1-position
by a triphenylmethyl group. The methanol derivative 1 was
1
[39]
Pharmacological Results and Discussion
prepared from 1,3-dihydroxyacetone and formamidine ace-
[40, 41]
tate in NH under pressure according to
and finally
3
Histamine H -Receptor Antagonist in Vitro Assay on Synap-
tosomes of Rat Cerebral Cortex
3
protected by triphenylmethyl chloride. The ethanol derivative
2 was obtained from 1,4-dihydroxybutanone and formamid-
[41]
ine acetate according to
and protected like before. The
The newly designed compounds were tested for their hista-
imidazole protected propanol derivative 4 was conveniently mine H -receptor antagonist potency in a functional assay on
3
[37]
prepared from urocanic acid by esterification, hydrogenation, synaptosomes of rat cerebral cortex . The influence of the
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

Development of FUB 181
213
Table 1. Structure, chemical data, and pharmacological data on histamine H3-receptor antagonist potency in vitro and in vivo in rodents.
—————————————————————————————————————————————————————————————–
No. Chain A Formula Mr Yield mp In Vitro In Vivo (p.o.)
X
m
R
(%) (°C) Ki (nM)a ED50 (mg/kg)b
—————————————————————————————————————————————————————————————–
5a
CH2
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
1
1
1
2
3
3
1
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
4
3
3
–
Ph
C11H12N2O•C4H4O4
304.3 56
372.3 45
358.9 42
327.3 75
346.4 32
91
90
75
81
92
>500
>500
>500
>500
>10
>10
>10
>10
5b CH2
3-F3C-Ph
1-Naphthyl
Ph
C12H11F3N2O•C4H4O4
C15H14N2O•C4H4O4•0.25 H2O
C12H14N2O•C4H4O4•0.5 H2O
C14H18N2O•C4H4O4
5c
6
CH2
CH2
7
(CH2)2
CH=CH-CH2
(CH2)3
(CH2)3
Ph
186 ± 11 n.d.c
3.8 ± 0.7
19 ± 6 >10
23 ± 5 1.0 ± 0.6
261 ± 76 >10
d
8
4-F-Ph
Ph
C15H17FN2O•C4H4O4
C13H16N2O•C4H4O4
376.4 18 130–132 81 ± 24
9e
332.3 50
346.4 15
422.5 25
366.9 40
374.4 20
436.5 45
364.9 68
382.9 24
394.9 38
439.3 36
428.4 45
428.4 35
374.4 21
394.9 50
441.0 25
396.4 30
429.3 28
410.5 48
415.0 25
374.4 41
385.5 53
61
90
10a
Ph
C14H18N2O•C4H4O4
10b (CH2)3
10c (CH2)3
10d (CH2)3
4-Ph-Ph
Ph-O
C20H22N2O•C4H4O4
131
96
C14H18N2O2•.C4H4O4•0.25 H2O
21 ± 3
0.84 ± 0.03
Ph-CH(CH3) C16H22N2O•C4H4O4
77
52 ± 18 ~10
67 ± 11 ~10
10e
11a
(CH2)3
(CH2)3
(Ph)2CH
Ph
C21H24N2O•C4H4O4
105
10 3
118
130
130
104
85
C15H20N2O•C4H4O4•0.25 H2O
C15H19FN2O•C4H4O4•0.25 H2O
C15H19ClN2O•C4H4O4
C15H19BrN2O•C4H4O4
C16H19F3N2O•C4H4O4
C16H19F3N2O•C4H4O4
C16H22N2O•C4H4O4
17 ± 3
7 ± 2
1.4 ± 0.6
11b (CH2)3
11cf (CH2)3
11d (CH2)3
4-F-Ph
0.76 ± 0.14
0.8 ± 0.2
1.4 ± 0.3
1.0 ± 0.1
2.8 ± 1.2
4.2 ± 2.2
2.9 ± 0.3
4-Cl-Ph
4-Br-Ph
4-F3C-Ph
3-F3C-Ph
4-H3C-Ph
13 ± 4
15 ± 4
23 ± 4
40 ± 9
24 ± 5
34 ± 7
11e
11f
11g
(CH2)3
(CH2)3
(CH2)3
125
116
111
101
119
111
125
96
11h (CH2)3
11i (CH2)3
11k (CH2)3
11l (CH2)3
4-H3CO-Ph C16H22N2O2•C4H4O4•0.25 H2O
4-Ph-Ph
3,4-F2-Ph
2,4-Cl2-Ph
1-Naphthyl
2-Naphthyl
Ph
C21H24N2O•C4H4O4• 0.25 H2O
C15H18F2N2O•C4H4O4
118 ± 19 >10
9 ± 2
2.4 ± 1.9
3.6 ± 1.5
C15H18Cl2N2O•C4H4O4
15 ± 3
11m (CH2)3
11n (CH2)3
C19H22N2O•C4H4O4
139 ± 29 ≥10
259 ± 88 ≥10
40 ± 11 ~10
34 ± 10 ~10
C19H22N2O•C4H4O4•0.25 H2O
C16H22N2O•C4H4O4
12
13
14
(CH2)3
(CH2)3
(CH2)3
Ph
C15H20N2S•C4H4O4•0.5 H2O
C15H20N2OS•C4H4O4•0.5 H2O
106
S(O)
O
Ph
401.5 36 128–130 186 ± 70 >10
6 ± 1g
UCL (CH2)3
1503g
4-O2N-Ph
UCL (CH2)3
1390g
O
–
4-NC-Ph
12 ± 3g
Thioperamide
Clobenpropit
4 ± 1h
1.0 ± 0.5h
0.6 ± 0.1h 26 ± 7h
—————————————————————————————————————————————————————————————
(a) functional assay in vitro on synaptosomes of rat cerebral cortex [37]; (b) in vivo assay 90 min after p.o. administration to mice, ED50 values were calculated
as mg free base • kg–1[37]; (c) n.d = not determined; (d) (E)-configured; (e) ref. [36]; (f) FUB 181; (g) ref. [47]; (h) ref. [31]
.
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

214
Stark and co-workers
[4,
spacer lengths, the structure of chains A and B (see Figure 1), tion, as observed previously with benzyl-like compounds
and of different lipophilic residues represented by unsubsti-
30, 36]
. Moreover, introduction of electron-releasing substit-
tuted or substituted phenyl rings as well as annulenes were uents led to ethers with remarkable H -receptor antagonist
3
examined in order to explore structure-activity relationships effect, e.g., methyl or methoxy groups (11g,h). These results
and to achieve potent H -receptor antagonists (Table 1).
also indicated that electronic parameters on the lipophilic
3
Whereas compounds with a 4-((ω-arylalkyloxy)methyl)- moiety of the molecule have less influence on receptor-ligand
1H-imidazole structure (5,6) did not show antagonist potency interaction than steric factors.
under in vitro conditions, compounds with longer chains for
Recently, a comparable class of 4-(ω-(aryloxy)alkyl)-1H-
[47]
spacer A presented moderate to potent H -receptor antago- imidazoles has been described . These structures also be-
3
nists, e.g., 4-(2-(3-phenylpropyloxy)ethyl)-1H-imidazole long to the general construction pattern of H -receptor
3
(7), 4-(3-(3-(4-fluorophenyl)propyloxy)prop-1-enyl)-1H- antagonists (Figure 1) with a missing spacer B. They are also
imidazole (8), or 4-(3-(ω-arylalkyloxy)propyl)-1H-imida- highly potent histamine H -receptor antagonists, e.g., UCL
3
zoles (9–12). For this reason, this study was focused on 1503 or UCL 1390.
compounds with a trimethylene moiety for chain A. In this
Exchange of the ether functionality by thioether (13) re-
group we have designed ethers with one (9), two (10a–c), sulted in a compound with slightly diminished potency,
three (10d,e,11a–n), or four (12) methylene groups for chain whereas the sulphoxide moiety in 14 reduced the activity
B, with side-chain branching (10d) or a heteroatom within the drastically.
side-chain (10c).
The benzyl derivative 9 was selected from a series of
previously designed compounds . This ether was intro-
duced to allow a direct comparison of the different substitu-
tion patterns in compounds with different chain lengths for
chain B. The unsubstituted ω-phenylalkyl derivatives with
different chain lengths for spacer B (7,9,10) have served as
Histamine H -Receptor Antagonist in Vivo Assay on Mice
Brain after p.o. Administration
3
[36]
All novel compounds showing promising in vitro results or
larger structural differences to other compounds were tested
for their central histamine H -receptor in vivo potency after
3
[37]
p.o. administration to mice (Table 1) . Ethers with one
parent compounds to provide a class of histamine H -receptor
3
methylene chain (5a–c,6) for chain A were not active in this
screening assay. These results were in agreement with the
respective in vitro results.
antagonists with different substitution pattern as novel lead.
Even side-chain branching (10d) and introduction of oxygen
as a linker (10c) was accepted by maintaining in vitro po-
tency. The development was focused on the preparation of a
series of various substituted compounds in order to correlate
Benzyl ether 9 with remarkable in vitro activity failed to
[36]
show H -receptor antagonist effect in vivo . Pharmaco-
3
kinetic reasons, e.g., malabsorption, distribution in peripheral
organs, poor blood-brain barrier penetration, or fast biodegra-
dation might be an explanation. A similar interpretation was
the influence of substituents with changes in H -receptor
antagonist potency. Unsubstituted derivatives (9,10a,11a,12)
showed high in vitro potency in the nanomolar concentration
3
[32]
already given for the radioligand iodoproxyfan . On the
range possessing rather homogeneous K values. Substitution
i
other hand, benzyl-like ethers with bulkier biphenyl or
naphthyl residues as lipophilic moieties showed meaningful
of the phenyl ring by another phenyl ring (10b,11i) led to a
reduction of potency in vitro. Thus, the introduction of the
biphenyl system compared to the phenyl ring was not advan- H -receptor in vivo potency (ED ≤ 4.0 mg/kg) as described
3
50
[36]
previously . Starting from this observation, the influence
of chains A, B, and of substituents on the lipophilic aryl
moiety was explored for in vivo potency.
tageous. A similar relationship could be found by comparison
of different naphthyl derivatives (5c,11m,n) to the phenyl
compounds: histamine H -receptor antagonist potency was
3
reduced by introduction of annulenes like naphthyl ring sys-
tems, whereas a diphenyl system maintains potency (10e).
Most probably steric reasons could be taken into account for
Unsubstituted phenyl derivatives of 4-(3-hydroxypropyl)-
1H-imidazole, which differ only in their lengths of chain B
(9,10a–e,11a–n,12), showed different pharmacological be-
diminished receptor-ligand interaction explaining the re- haviour in vivo: whereas methylene (9) and tetramethylene
duced potency at H receptors under in vitro conditions for (12) derivatives did not show H -receptor activity, di-
3
3
methylene (10a), dimethylene-oxy (10c), and trimethylene
derivatives with bulky substituents.
Introduction of a halogen atom in para-position of the (11a–h,k,l) derivatives proved to be H -receptor antagonists
3
with moderate to high potency. The three-membered chain B
phenyl ring (11b–d) slightly increased the H -receptor an-
3
tagonist in vitro potency compared to the unsubstituted de- seems to be most favourable in this series (10a,11a). The
rivative 11a, whereas other substituents showed no improve- unsubstituted phenylderivative 11a with a trimethylene chain
for chains A and B has served as parent structure leading to
novel compounds with different substitution pattern and vari-
ment (11e,g,h). However, introduction of a second fluorine
atom in meta-position (11k) failed to change effect of the
mono-substituted derivative 11b. That the second halogen ous lipophilic residues (10d,e,11b–n) and therefore to com-
pounds with different pharmacokinetic behaviours. Within
this series of 4-(3-(arylalkyloxy)propyl)-1H-imidazoles,
compounds with bulky residues like diphenyl (10e) or
substituent in ortho- or meta-position has almost no influence
on the in vitro activity was also concluded from comparison
of the mono- and dichlorinated compounds 11c,l. No signifi-
cant difference could be found between the different halogen naphthyl (11m,n) as well as side-chain branched derivatives
substitutions. (10d) presented reduced in vivo potency whereas 3-(ω-
Comparison of compounds 11e and 11f containing a tri- phenylalkyloxy)propyl derivatives show notable to high H -
3
fluoromethyl substituent showed that the para-position receptor antagonist in vivo potency. Opposite effects for
seemed to be slightly favourable compared to the meta-posi- bulky aryl moieties were observed in a comparable series of
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

Development of FUB 181
215
Table 2. Data of functional in vitro assays at histamine receptor subtypes of
selected compounds.
——————————————————————————————
benzyl and benzyl-like ethers. Introduction of smaller substit-
uents with electron-withdrawing (11b–f,11k,l) as well as
electron-releasing (11g,h) effects led to highly potent H -re-
3
H3 receptor
–log Kia
H2 receptor
–log Kb
H1 receptor
–log Kc
ceptor antagonists under in vivo conditions. The para-fluori-
nated ether 11b, the comparable chlorinated ether 11c and the
No.
dimethylene-oxy derivative 10c possessing ED values be-
——————————————————————————————
50
low 1 mg/kg belong to the most potent H -receptor antago-
3
5a
5b
<6.3
<6.3
<6.3
6.6
7.3
7.2
7.8
8.2
7.9
7.8
7.6
7.4
7.6
6.9
8.0
7.8
6.9
6.6
7.4
7.5
4.1
3.7
4.5
4.9
5.1
5.0
3.5
4.0
5.0
5.0
4.6
5.3
4.5
4.8
4.7
5.1
4.9
5.0
4.7
4.9
3.9
<4
nists in vivo reported so far. In contrast to in vitro results,
potency under in vivo conditions was decreased by introduc-
tion of a second halogen substituent (11k,l). The related
para-trifluoromethyl substituted ether 11e also presented
high in vivo potency. The meta-substituted derivative 11f was
slightly less active than the para-substituted derivative 11e
underlining the advantageous effect of para-substitution for
5c
5.0
4.9
4.8
4.7
5.2
5.4
5.3
5.3
5.1
5.6
5.3
5.5
5.7
5.7
6.3
5.4
5.5
5.5
10b
10d
10e
11a
11b
11c
11d
11e
11f
11g
11i
11k
11l
11m
11n
12
H -receptor antagonists in vivo. These results are in agree-
3
ment with structure-activity relationships described pre-
viously for in vitro activities. The sulphur-containing
derivatives 13,14 are moderately potent or devoid of measur-
able in vivo potency, respectively.
Selectivity
In addition to their H -receptor antagonist potency, the
3
effect of selected compounds was also tested at other hista-
mine receptors in order to exclude a cross-activity at these
closely related receptor-subtypes which could prevent the
pharmacological use of the new H -receptor antagonists. The
3
activity at H and H receptors was determined on isolated
1
2
[38]
13
organs of guinea pigs according to ref. . The compounds
possessing high potency at H receptors show low to moder-
ate affinity at other histamine receptor subtypes (Table 2):
——————————————————————————————
(a) functional assay on synaptosomes of rat cerebral cortex[37];(b) functional
3
assay on guinea pig atrium[38]; (c) functional assay on guinea pig ileum[38]
.
The potency at H -receptors predominated over that at the
3
other histamine receptor subtypes. The lowest selectivity
ratio was found for compound 11m, which is only 4 times
more potent at H than at H receptors. The H -receptor
(guinea pig ileum): α ). The low affinity of FUB 181 for
1
5-HT receptors should be underlined since a number of other
3
3
1
3
potency of most of the compounds tested was more than two H -receptor ligands, e.g., thioperamide and clobenpropit,
3
[35]
orders of magnitude higher than the activity at H or H
showed some affinity for this receptor subtype
.
1
2
τ
receptors. The selectivity ratio (H vs. H /H receptors) of
Furthermore the time-course of changes in N -methylhis-
tamine levels in mouse brain induced by oral administration
of 1.5 mg/kg FUB 181 were analyzed. Given at a dose
3
2
1
11b,c is about 630 and 400, respectively.
We decided to get further information on the activity of
compounds at other aminergic receptor systems, which is
important to assess for potential use as drugs. Compound 11c
(FUB 181) was selected for evaluation of its activity at
representing about twice its ED value (Table 1), FUB 181
elicited a maximal effect 3 h after its administration which
50
numerous membrane-receptors, including those H -receptors
3
on the guinea pig ileum. The functional tests were performed
[48]
[49]
according to Ligneau et al. and Schlicker et al. . Deriva-
tive FUB 181 was selected for the following reasons: high
H -receptorantagonist potency in vitro as well as in vivo, easy
3
large scale synthesis and as a lead structure for other closely
related derivatives (10a,c, 11a,b, 11d–l). 4-(3-(3-(4-Chlo-
rophenyl)propyloxy)propyl)-1H-imidazole (FUB 181, 11c)
_
showed the following data (x ± SEM, n = number of experi-
ments): –log K = 8.4 ± 0.09 (n = 13) at histamine H
B
3
[48]
receptors on guinea pig ileum , –log K = 6.0 ± 0.03 (n =
B
[48]
4) at adrenergic α receptors on rat aorta , –log K = 4.7
1
B
[48]
(n = 3) at β receptors on guinea pig atrium , –log K =
1/2
B
5.61 ± 0.05 (n = 5) at serotonergic 5-HT receptors on rat
2A
Figure 2. Changes in brain Nτ-methylhistamine level of mice receiving
FUB 181. Mice were sacrificed at various times after the p.o. administration
of vehicle or FUB 181 (1.5 mg/kg). Nτ-methylhistamine levels are expressed
in percent of increase as compared to levels in corresponding controls (133
± 5 ng/g). Means ± SEM of values from 24 mice.
[49]
tail artery , –log K = 5.05 ± 0.03 (n = 2) at serotonergic
B
[49]
5-HT receptors on guinea pig ileum , and –log K = 5.63
3
B
± 0.08 (n = 4) at muscarinic M receptors on guinea pig
3
[48]
ileum . The lowest selectivity ratio was about 250:1 (H
3
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

216
Stark and co-workers
ω
1-(Triphenylmethyl)-4-(3-hydroxyprop-1-enyl)-1H-imidazole (3)
was no more significant after 6 h (increase in N -methylhis-
tamine level expressed as % of control: 68 ± 7 (90 min after
p.o. administration), 86 ± 10 (180 min), 58 ± 5 (270 min), and
16 ± 7 (360 min) (Figure 2).
A solution of LiAlH4 in (8 mmol, 0.3 g) in 8 ml of abs. diethyl ether was
added dropwise at –30 °C to 3-(1-triphenylmethyl-1H-imidazol-4-yl)prop-
1-enoic acid (13 mmol, 5.0 g) in 50 ml of abs. THF. The temperature was
kept at –25 °C for 2 h. Then the reaction was quenched with a saturated
solution of NH4Cl. Evaporation of the dried organic extract under reduced
pressure resulted in a colourless oil which was crystallized and recrystallized
twice in abs. EtOH to obtain 3 (45%). mp. 214–215 °C, 1H NMR (DMSO-
d6): δ 7.10–7.42 (m; 16H, imidazole-2-H, 15 Ph-H), 6.89 (s; 1H, imidazole-
5-H), 6.55 (m; 2H, CH=CH), 4.69 (br*; 1H, OH), 4.02 (d; J = 4.5, 2H,
CH2-OH). Anal. (C25H22N2O•H2O) C, H, N: C calc. 78.1; found 78.6, N:
calc. 7.29; found 6.73.
Thus, the results proved that FUB 181 (11c), additionally
to its high potency, is a highly selective histamine H -receptor
3
antagonist. Recent pharmacological data of FUB 181 proved
its benefit compared to the reference ligands concerning the
[50]
influence on learning and memory behaviour
.
Conclusions
General Preparation of Ethers (except 8a)
In this study potential H -receptor antagonists with 4-(ω-
3
(arylalkyloxy)alkyl)-1H-imidazole structure and related
compounds were designed. We evaluated their in vitro activ-
ity in a functional test on synaptosomes of rat cerebral cortex
as well as their in vivo activity in brain after p.o. administra-
tion to mice. The novel compounds belonging to a general
Freshly prepared sodium alcoholate of 1-(triphenylmethyl)-4-hy-
droxymethyl-1H-imidazole[40,41], (1, 5 mmol, 1.70 g, for compounds 5–6),
1-(triphenylmethyl)-4-(2-hydroxyethyl)-1H-imidazole[41]
,
(2, 5 mmol,
1.77 g, for compound 7), 1-(triphenylmethyl)-4-(3-hydroxyprop-1-enyl)-
1H-imidazole (3, 5 mmol, 1.8 g, for compound 8), and 1-(triphenylmethyl)-
4-(3-hydroxypropyl)-1H-imidazole[42], (4, 5 mmol, 1.84 g, for compounds
9–12), prepared by standard methods with NaH, the corresponding arylalkyl
halides (6 mmol), and 15-crown-5 (0.1 g, 0.5 mmol) in 10 mL of dry toluene
were refluxed for 24 h. The solvent was evaporated under reduced pressure
and the residue dissolved in 10 mL of THF and 30 mL of 2N HCl. The
mixture was refluxed at 70 °C for 2 h. The organic solvent was evaporated
under reduced pressure, and triphenyl methanol was extracted with Et2O.
The aqueous layer was basified with K2CO3 and extracted 3 times with
100 mL of Et2O. The combined organic layers were dried (MgSO4) and
evaporated under reduced pressure. Purification of the residues by rotary
chromatography [eluent: CH2Cl2/MeOH/NH3 (25%) 80:19:1] gave colour-
less oils which were crystallized as hydrogen maleates from Et2O/EtOH.
Analytical data of selected compounds with various chain lengths and
different substitution patterns are given below.
construction pattern for H -receptor antagonists are ethers
3
with high in vitro and in vivo potencies. The most potent
compounds under in vivo screening conditions were 4-(3-(2-
(phenoxy)ethyloxy)propyl)-1H-imidazole (10c), 4-(3-(3-(4-
fluorophenyl)propyloxy)propyl)-1H-imidazole (11b), and its
chloro analogue (FUB 181, 11c). The optimal chain length
for spacer A was a trimethylene chain as well as a three
membered spacer for chain B. In this series a number of
compounds with different substituents showed high in vivo
potency (except the bulkier diphenyl or naphthyl derivatives
(10e,11m,11n) and the side-chain branched derivative 10d).
The designed ethers showed low activity at H and H recep-
1
2
tors proving their selectivity for H receptors. Investigations
on various other neurotransmitter receptors in functional
3
Preparation of 10a
studies ensured the high selectivity for H receptors of com-
pound FUB 181 (11c).
The designed compounds constitute as useful tools for
pharmacological investigations as well as leads for further
3
Thionyl chloride (6 mmol) was added dropwise at 0 °C to a solution of
compound 4 (2 g, 5.4 mmol) in 30 mL of THF. After stirring for 1 h at 0 °C
and 2 h at ambient temperature 150 mL of Et2O were added slowly. 4-(3-
Chloropropyl)-1-(triphenylmethyl)-1H-imidazole hydrochloride immedi-
ately crystallized and could be obtained in 90% yield[44] (mp 147 °C, CHN).
4-(3-Chloropropyl)-1-(triphenylmethyl)-1H-imidazole hydrochloride
(5 mmol, 2.13 g) and 2-phenylethanolate (15 mmol, 1.83 g, freshly prepared
with NaH by standard methods) in 10 mL of dry toluene were refluxed for
30 h. Deprotection, purification, and crystallization continued according to
the general procedure described above.
developments of histamine H -receptor antagonists and po-
3
tential drugs possessing oral potency.
Acknowledgment
This work was supported by the Biomedical & Health Research Pro-
gramme BIOMED of the European Union and by the Verband der Chemi-
schen Industrie, Fonds der Chemischen Industrie (Frankfurt/Main,
Germany).
4-(Phenylmethyloxy)methyl-1H-imidazole (5a)
1H NMR (DMSO-d6): δ 8.84 (s; 1H, imidazole-2-H), 7.59 (s; 1H, imid-
azole-5-H), 7.35 (m; 5H, 5Ph-H), 6.08 (s; 2H, maleic acid), 4.54 (m; 4H,
CH2-O-CH2). Anal. (C11H12N2O•C4H4O4) C, H, N.
Experimental Section
4-(2-Phenylethyloxy)methyl-1H-imidazole (6)
Chemistry. Melting points were determined on an Electrothermal IA
9000 digital melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a Bruker AC 300 (300 MHz) spectrometer. Chemical shifts
(δ) are expressed in ppm downfield from internal TMS as reference. Mass
spectra were obtained on an EI-MS Finnigan MAT CH7A and a Finnigan
MAT 711. Elemental analyses (C, H, N) were measured on Perkin-Elmer
240 B or Perkin-Elmer 240 C instruments and were within ±0.4% of
theoretical values unless otherwise indicated. TLC was performed on silica
gel F254 plates (Merck). Preparative, centrifugally accelerated, radial thin
layer chromatography was performed using a chromatotron 7924T (Harrison
Research) and glass rotors with 4 mm layers of silica gel 63–200 µm PF254
containing gypsum (Merck). Optimization of yields was performed only
diminutively.
1H NMR (DMSO-d6): δ 8.80 (s; 1H, imidazole-2-H), 7.53 (s; 1H, imid-
azole-5-H), 7.25 (m; 5H, 5Ph-H), 6.07 (s; 2H, maleic acid), 4.50 (s; 2H,
imidazole-CH2), 3.64 (t; J = 6.9, 2H, CH2-CH2-Ph), 2.84 (t; J = 6.8, 2H,
CH2-Ph). Anal. (C12H14N2O•C4H4O4•0.5 H2O) C, H, N.
4-(2-(3-Phenylpropyloxy)ethyl)-1H-imidazole (7)
1H NMR (DMSO-d6): 8.91 (s; 1H, imidazole-2-H), 7.42 (s; 1H, imid-
azole-5-H), 7.21 (m; 5H, 5Ph-H), 6.06 (s; 2H, maleic acid), 3.61 (t; J = 6.3,
2H, imidazole-CH2-CH2), 3.39 (t; J = 6.4, 2H, O-CH2-CH2-CH2), 2.89 (s;
2H, imidazole-CH2), 2.57 (m; 2H, CH2-CH2-Ph), 1.78 (m; 2H, CH2-Ph).
Anal. (C14H18N2O•C4H4O4) C, H, N.
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

Development of FUB 181
217
4-(3-(3-(4-Fluorophenyl)propyloxy)prop-1-enyl)-1H-imidazole (8)
4-(3-(3-Phenylpropylthio)propyl)-1H-imidazole (13)
Preparation according to 10a using sodium 2-phenylethanthiolate. 1H
NMR (DMSO-d6): δ 8.89 (s; 1H, imidazole-2-H), 7.41 (s; 1H, imidazole-5-
H), 7.24 (m; 5H, 5Ph-H), 6.04 (s; 2H, maleic acid), 2.71 (t; J = 7.6, CH2-S),
2.65 (t; 2H, CH2-S), 2.50 (m; 4H under solvent, imidazole-CH2, Ph-CH2)
1.81 (m; 4H, 2CH2). Anal. (C15H20N2S•C4H4O4•0.5 H2O) C, H, N.
1H NMR (DMSO-d6): δ 8.72 (s; 1H, imidazole-2-H), 7.55 (s; 1H, imid-
azole-5-H), 7.25 (m; hH, Ph-2-H, Ph-6-H), 7.09 (m; 2H, Ph-3-H, Ph-5-H),
6.55 (d; J = 16.3, 1H, imidazole-CH), 6.43 (m; 1H, imidazole-CH=CH), 6.17
(s; 2H, maleic acid), 4.10 (d; J = 4.8, 2H, CH-CH2), 3.43 (t; J = 6.3, 2H,
CH2-CH2-CH2), 2.64 (t; J = 7.6, 2H, CH2-Ph), 1.83 (m; 2H, CH2-CH2-Ph).
Anal. (C15H17N2O•C4H4O4) C, H, N.
4-(3-(3-Phenylpropylsulphoxy)propyl)-1H-imidazole (14)
4-(3-(2-Phenylethyloxy)propyl)-1H-imidazole (10a)
A suspension of 13 (1 mmol, 0.4 g), K2CO3 (0.5 g) and 3-chloroperoxy-
benzoic acid (2 mmol, 0.3 g) in 40 ml of dichloromethane was stirred for 2 h.
After evaporation under reduced pressure the residue was extracted several
times with EtOH. The ethanol extracts were purified and crystallized as
described above. 1H NMR (DMSO-d6): δ 8.87 (s; 1H, imidazole-2-H), 7.43
(s; 1H, imidazole-5-H), 7.25 (m; 5H, 5Ph-H), 6.05 (s; 2H, maleic acid),
2.76-2.50 (m; 8H, imidazole-CH2, Ph-CH2, CH2-SO-CH2), 1.95 (m; 4H,
2CH2). Anal. (C12H14N2O•C4H4O4•0.5 H2O) C, H, N.
1H NMR (DMSO-d6): δ 8.89 (s; 1H, imidazole-2-H), 7.16–7.33 (m, 6H,
imidazole-5-H, 5Ph-H), 6.04 (s; 2H, maleic acid), 3.59 (t; J = 6.9, 2H,
CH2-CH2-Ph), 3.41 (t; J = 6.2, 2H, CH2-O), 2.79 (t; J = 6.9, 2H, Ph-CH2),
2.64 (t; J = 7.6, imidazole-CH2), 1.85 (m; 2H, CH2-CH2-O). Anal.
(C14H18N2O•C4H4O4) C, H, N.
4-(3-(3-Phenylpropyloxy)propyl)-1H-imidazole (11a)
1H NMR (DMSO-d6): δ 8.92 (s; 1H, imidazole-2-H), 7.42 s; 1H, imid-
azole-5-H), 7.25 (m; 5H, 5Ph-H), 6.05 (s; 2H, maleic acid), 3.39 (t; J = 6.2,
2H, CH2-O), 3.36 (t; J = 6.3, 2H, CH2-O), 2.70 (m; 2H, imidazole-CH2),
2.61 (m; 2H, CH2-Ph); 1.81 (m; 4H, imidazole-CH2-CH2, CH2-CH2-Ph).
Anal. (C15H20N2O•C4H4O4•0.25 H2O) C, H, N.
Pharmacology. General Procedures
Histamine H3-Receptor Antagonist Potency on Synaptosomes of Rat
Cerebral Cortex
All novel compounds were tested for their histamine H3-receptor antago-
nist potency in an assay with K+-evoked depolarization-induced release of
[3H]histamine from synaptosomes of rat cerebral cortexaccordingtoGarbarg
4-(3-(3-(4-Fluorophenyl)propyloxy)propyl)-1H-imidazole (11b)
1H NMR (DMSO-d6): δ 8.94 (s; 1H, imidazole-2-H), 7.43 (s; 1H, imid-
azole-5-H), 7.23 (m; 2H, Ph-2-H, Ph-6-H), 7.09 (m; 2H, Ph-3-H, Ph-5-H),
6.05 (s; 2H, maleic acid), 3.36 (m; 4H, 2CH2-O), 2.64 (m; 4H, imidazole-
et al. [37]
.
Histamine H3-Receptor Antagonist Potency in Vivo on Mice Brain after p.o.
Administration
CH2,
CH2-Ph),
1.81
(m;
4H,
2CH2-CH2,-O). Anal.
(C15H19FN2O•C4H4O4•0.25 H2O) C, H, N.
The increase in Nτ-methylhistamine levels in Swiss mice brain after p.o.
application of the compound was selected to determine the histamine H3-re-
4-(3-(3-(4-Methoxyphenyl)propyloxy)propyl)-1H-imidazole (11h)
ceptor antagonist potency in vivo[37]
.
1H NMR (DMSO-d6): δ 8.89 (s; 1H, imidazole-2-H), 7.40 (s; 1H, imid-
azole-5-H), 7.09 (d; J = 8.5, 2H, Ph-3-H, Ph-5-H), 6.83 (d; J = 8.5, 2H,
Ph-2-H, Ph-6-H), 6.04 (s; 2H, maleic acid), 3.71 (s; 3H, OCH3), 3.35 (m; 4H,
CH2-O-CH2), 2.68 (t; J = 7.6, 2H, imidazole-CH2), 2.53 (t; J = 7.7, 2H,
CH2-Ph), 1.84 (q; J = 6.9, 2H, imidazole-CH2-CH2), 1.74 (q; J = 7.1,
CH2-CH2-Ph). Anal. (C16H22N2O2•C4H4O4•0.25 H2O) C, H, N.
In Vitro Screening on other Receptor Models
Histamine H1-receptor activity on the isolated guinea pig ileum as well as
H2-receptor activity on the isolated spontaneously beating guinea pig right
atrium were screened by standard methods described by Pertz and Elz [38]
.
Compound 11c was also tested for antagonist activity at peripheral histamine
H3 receptors (guinea pig ileum)[48], adrenergic α1 receptors (rat aorta)[48]
β1/2 receptors (guinea pig atrium)[48], 5-HT2A receptors (rat tail artery)[48]
,
,
4-(3-(3-(3,4-Difluorophenyl)propyloxy)propyl)-1H-imidazole (11k)
1H NMR (DMSO-d6): 8.89 (s; 1H, imidazole-2-H), 7.05–7.40 (m; 4H,
imidazole-5-H, 3Ph-H), 6.04 (s; 2H, maleic acid), 3.36 (m; 4H, 2CH2-O),
2.64 (m; 4H, imidazole-CH2, CH2-Ph), 1.81 (m; 4H, 2CH2-CH2,-O). Anal.
(C15H18F2N2O•C4H4O4) C, H, N.
5-HT3 receptors (guinea pig ileum)[49], and M3 receptors (guinea pig il-
eum)[48]. Each pharmacological test was performed at least in triplicate with
at least two animals, but the exact type of interaction had not been determined
in each case. Results are given as a mean.
4-(3-(3-(2,4-Dichlorophenyl)propyloxy)propyl)-1H-imidazole (11l)
References
1H NMR (DMSO-d6): δ 8.91 (s; 1H, imidazole-2-H), 7.57 (s; 1H, Ph-3-H),
7.41 (s; 1H, imidazole-5-H), 7.36 (s; 2H, Ph-4-H, Ph-5H), 6.05 (s; 2H, maleic
acid), 3.38 (m; 4H, 2CH2-O), 2.70 (m; 4H, imidazole-CH2, CH2-Ph), 1.80
(m; 4H, 2CH2-CH2,-O). Anal. (C15H18Cl2N2O•C4H4O4) C, H, N.
✩
Dedicated to Prof. Dr. G. Heinisch, Innsbruck, on the occasion of his
60th birthday.
[1] J.C. Schwartz, J.-M. Arrang, M. Garbarg, J.-M. Lecomte, C. R. Ganel-
lin, A. Fkyerat, W. Tertiuk, W. Schunack, R. Lipp, H. Stark, K. Purand,
PCT Int. Appl. WO 93/14070. 1992 [Chem. Abstr. 1994 120, 107004c].
4-(3-(3-(1-Naphthyl)propyloxy)propyl)-1H-imidazole (11m)
1H NMR (DMSO-d6): δ 8.93 (s; 1H, imidazole-2-H), 8.06 (d; J = 7.7, 1H,
naphthyl-8-H), 7.91 (dd; 3J5,6 = 7.3, 4J5,7 = 1.8, 1H, naphthyl-5-H), 7.77 (d;
J = 8.0, 1H, naphthyl-4-H), 7.57 - 7.49 (m; 2H, naphthyl-6-H, naphthyl-7-H),
7.43 (s; 2H, imidazole-5-H, naphthyl-2-H), 7.34 (d; J = 6.6, 1H, naphthyl-3-
H), 6.05 (s; 2H, maleic acid), 3.40 (m; 4H, CH2-O-CH2), 3.08 (t; J = 7.5,
CH2-naphthyl), 2.72 (t; J = 7.5, 2H, imidazole-CH2), 1.89 (m; 4H, imida-
zole-CH2-CH2, CH2-CH2-naphthyl). Anal. (C19H22N2O•C4H4O4) C, H, N.
[2] J.-M. Arrang, M. Garbarg, J.-C. Lancelot, J.-M. Lecomte, M. F. Robba,
J.-C. Schwartz, Eur. Pat. Appl. EP 494 010. 1990.
[3] C. R. Ganellin, S. K. Hosseini, Y. S. Khalaf, W. Tertiuk, J.-M. Arrang,
M. Garbarg, X. Ligneau, J.-C. Schwartz, J. Med. Chem. 1995, 38,
3342–3350.
[4] H. Van der Goot, M. J. P. Schepers, G. J. Sterk, H. Timmerman, Eur.
J. Med. Chem. 1992, 27, 511–517.
4-(3-(4-Phenylbutyloxy)propyl)-1H-imidazole (12)
[5] G. J. Durant, A. M. Khan, Patent PCT WO 93/20061. 1993.
1H NMR (DMSO-d6): 8.83 (s; 1H, imidazole-2-H), 7.36 (s, 1H, imid-
azole-5-H), 7.17–7.28 (m; 5H, 5Ph-H), 6.10 (s; 2H, maleic acid), 3.37 (m;
4H, 2CH2-O), 2.50–2.69 (m; 4H, imidazole-CH2, CH2-Ph), 1.82 (m; 2H,
imidazole-CH2-CH2), 1.56 (m; 4H, CH2-CH2-CH2-Ph). Anal.
(C16H22N2O•C4H4O4) C, H, N.
[6] J.-M. Arrang, M. Garbarg, J.-C. Schwartz, Nature (London) 1983, 302,
832–837.
[7] E. Schlicker, B. Malinowska, M. Kathmann, M. Göthert, Fundam. Clin.
Pharmacol. 1994, 8, 128–137.
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)

218
Stark and co-workers
[8] G. Coruzzi, G. Bertaccini, J.-C. Schwartz, Naunyn-Schmiedeberg’s
Arch. Pharmacol. 1991, 343, 225–227.
[31] H. Stark, M. Krause, J.-M. Arrang, X. Ligneau, J.-C. Schwartz, W.
Schunack, Bioorg. Med. Chem. Lett. 1994, 4, 2907–2912.
[32] H. Stark, K. Purand, A. Hüls, X. Ligneau, M. Garbarg, J.-C. Schwartz,
[9] M. Ichinose, C. D. Stretton, J.-C. Schwartz, P. J. Barnes, Br. J. Phar-
macol. 1989, 97, 13–15.
W. Schunack, J. Med. Chem. 1996, 39, 1220-1226.
[33] K. Purand, H. Stark, X. Ligneau, M. Garbarg, J.-C. Schwartz, W.
[10] M. Imamura, N. Seyedi, H. M. Lander, R. Levi, Circ. Res. 1995, 77,
Schunack, Eur. J. Pharm. Sci. 1994, 2, 140.
206–210.
[34] E. Schlicker, M. Kathmann, H. Bitschnau, I. Marr, S. Reidemeister, H.
Stark, W. Schunack, Naunyn-Schmiedeberg’s Arch. Pharmacol. 1996,
353, 482-488.
[11] K. Fink, E. Schlicker, M. Göthert, Adv. Biosci. 1991, 82, 125–126.
[12] E. Schlicker, K. Fink, M. Detzner, M. Göthert, J. Neural. Transm.
[Gen.Sect] 1993, 93, 1–10.
[35] R. Leurs, M. T. M. Tulp, W. B. P. Menge, M. J. P. Adolfs, O. P.
[13] J. Clapham, G. J. Kilpatrick, Br. J. Pharmacol. 1992, 107, 919–923.
Zuiderveld, H. Timmerman, Br. J. Pharmacol. 1995, 116, 2315–2321.
[36] A. Hüls, K. Purand, H. Stark, S. Reidemeister, X. Ligneau, J.-M.
Arrang, J.-C. Schwartz, W. Schunack, Arch. Pharm. Pharm. Med.
Chem. 1996, 329, 379-385.
[14] E. Schlicker, R. Betz, M. Göthert, Naunyn-Schmiedeberg’s Arch. Phar-
macol. 1988, 337, 588–590.
[15] J. L. Burgaud, N. Oudart, J. Pharm. Pharmacol. 1993, 45, 955–958.
[37] M. Garbarg, J.-M. Arrang, A. Rouleau, X. Ligneau, M. Dam Trung
Tuong, J.-C. Schwartz, C. R. Ganellin, J. Pharmacol. Exp. Ther. 1992,
263, 304–310.
[16] A. Bado, L. Moizo, J. P. Laigneau, M. J. M. Lewin, Am. J. Physiol.
1992, 262, G56–61.
[17] H. Stark, E. Schlicker, W. Schunack, Drugs Future 1996, 21, 507-520.
[38] H. Pertz, S. Elz, J. Pharm. Pharmacol. 1995, 47, 310-316.
[18] R. Lipp, H. Stark, W. Schunack in The Histamine Receptor, Receptor
Biochemistry and Methodology ( Eds.: J.-C. Schwartz, H. L. Haas)
Wiley-Liss, Inc.: New York, 1992; 16, pp 57-72.
[39] H. Meerwein in Methoden der organischen Chemie (Houben-Weyl);
Georg Thieme Verlag: Stuttgart, 1965, issue VI/3, pp 24-32.
[40] R. K. Griffith, R. A. DiPetro, Synthesis 1983, 576.
[19] R. Leurs, R. C. Vollinga, H. Timmerman, Prog. Drug Res. 1995, 45,
[41] P. Dziuron, W. Schunack, Arch. Pharm. (Weinheim) 1973, 306, 347–
107–165.
350.
[20] C. E. Tedfort, S. L. Yates, G. P. Pawlowski, J. W. Nalwalk, L. B. Hough,
M. A. Khan, J. G. Phillips, G. J. Durant, R. C. A. Frederickson, J.
Pharmacol. Exp. Ther. 1995, 275, 589–604.
[42] H. Stark, K. Purand, A. Hüls, X. Ligneau, M. Garbarg, J.-C. Schwartz,
W. Schunack, Eur. J. Pharm. Sci. 1994, 2, 106.
[43] C. Sellier, A. Buschauer, S. Elz, W. Schunack, Liebigs Ann. Chem.
1992, 317-323.
[21] K. I. Meguro, K. Yanai, N. Sakai, E. Sakurai, K. Maeyama, H. Sasaki,
T. Watanabe, Pharmacol. Biochem. Behav. 1995, 50, 321–325.
[44] C. Sellier, PhD thesis, Freie Universität Berlin, Germany, 1991.
[45] N. N., Janssen, J. Chim. Data Sheet No. 234.
[22] J. M. Monti, Life Sci. 1993, 53, 1331–1338.
[23] H. Yokoyama, K. Onodera, K. Iinuma, T. Watanabe, Eur. J. Pharma-
col. 1993, 234, 129–133.
[46] P. Sieber, B. Riniker, Tetrahedron Lett. 1987, 28, 6031-6034.
[47] C. R. Ganellin, A. Fkyerat, S. K. Hosseini, Y. S. Khalaf, A. Piripitsi,
W. Tertiuk, J.-M. Arrang, M. Garbarg, X. Ligneau, J.-C. Schwartz, J.
Pharm. Belg. 1995, 50, 179–187.
[24] J.M. Arrang, M. Garbarg, T. T. Quach, M. D. Trung Tuong,
E. Yeramian, J.-C. Schwartz, Eur. J. Pharmacol. 1985, 111, 73–84.
[25] J.-C. Schwartz, J.-M. Arrang, M. Garbarg, H. Pollard, Agents Actions
1990, 30, 13–23.
[48] X. Ligneau, M. Garbarg, M. L. Vizuete, J. Diaz, K. Purand, H. Stark,
W. Schunack, J.-C. Schwartz, J. Pharmacol. Exp. Ther. 1994, 271,
452–459.
[26] M. Kathmann, E. Schlicker, M. Göthert, Psychopharmacol. 1994, 116,
464–468.
[49] E. Schlicker, H. Pertz, H. Bitschnau, K. Purand, M. Kathmann, S. Elz,
W. Schunack, Inflamm. Res. 1995, 44, 296-300.
[27] K. Kiec-Kononowicz, X. Ligneau, H. Stark, J.-C. Schwartz, W.
Schunack, Arch. Pharm. (Weinheim) 1995, 328, 445–450.
[50] K. Onodera, S. Miyazaki, M. Imaizumi, H. Stark, W. Schunack,
Naunyn Schmiedeberg’s Arch. Pharmacol., in press.
[28] K. Kiec-Kononowicz, X. Ligneau, J.-C. Schwartz, W. Schunack, Arch.
Pharm. Pharm. Med. Chem. 1995, 328, 469–472.
[51] J.-M. Arrang, M. Garbarg, J.-C. Lancelot, J.-M. Lecomte, H. Pollard,
M. Robba, W. Schunack, J.-C. Schwartz, Nature (London) 1987, 327,
117–123.
[29] H. Stark, R. Lipp, J.-M. Arrang, M. Garbarg, X. Ligneau, J.-C.
Schwartz, W. Schunack, Eur. J. Pharm. Sci. 1995, 3, 95–104.
[52] A. Hüls, K. Purand, H. Stark, X. Ligneau, M. Garbarg, J.-C. Schwartz,
[30] C. R. Ganellin, B. Bang-Andersen, Y. S. Khalaf, W. Tertiuk, J.-M.
Arrang, M. Garbarg, X. Ligneau, A. Rouleau, J.-C. Schwartz, Bioorg.
Med. Chem. Lett. 1992, 2, 1231–1234.
W. Schunack, Eur. J. Pharm. Sci. 1994, 2, 139.
Received: April 9, 1998 [FP294]
Arch. Pharm. Pharm. Med. Chem. 331, 211–218 (1998)