Benzophenone derivatives and related compounds as potent histamine H3-receptor antagonists and potential PET/SPECT ligands

Article abstract of DOI:10.1002/1521-4184(200102)334:2<45::AID-ARDP45>3.0.CO;2-2

Para-substituted aromatic ethers with benzophenone or related structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety were prepared by Mitsunobu-type ether synthesis or S_NAr reaction. Most of the title compounds possess high antagonist potency in histamine H₃-receptor assays in vitro as well as in vivo in mouse CNS following oral administration. After defining 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl phenyl methanone as a new lead, structure-activity relationships were investigated for this new class of compounds. Substitution of the meta′-position of the benzophenone moiety with halogen atoms (e.g., iodine, fluorine) led to compounds with high antagonist potency in vitro as well as in vivo (K_i = 9.3 and 4.3 nM, ED₅₀ = 0.7 and 0.47 mg/kg p.o., 18 and 12, respectively). A receptor profile of several functional in vitro assays for several biogenic amine receptors for the meta′-iodinated derivative demonstrated high selectivity toward the histamine H₃ receptor.

Full text of DOI:10.1002/1521-4184(200102)334:2<45::AID-ARDP45>3.0.CO;2-2

Benzophenone Derivatives and Related Compounds
45
Benzophenone Derivatives and Related Compounds as
Potent Histamine H -Receptor Antagonists and Potential
3
PET/SPECT Ligands1)
a,b)
c)
a)
a)
a)
d)
b)
Astrid Sasse , Xavier Ligneau , Bassem Sadek , Sigurd Elz , Heinz H. Pertz , C. Robin Ganellin , Jean-Michel Arrang ,
b)
a)
e)
Jean-Charles Schwartz , Walter Schunack , and Holger Stark *
a) Institut für Pharmazie, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany
b) Unité de Neurobiologie et Pharmacologie Moléculaire, Centre Paul Broca de l’INSERM (U. 109), 2ter rue d’Alésia, 75014 Paris, France
c) Laboratoire Bioprojet, 30 rue des Francs-Bourgeois, 75003 Paris, France
d) Department of Chemistry, Christopher Ingold Laboratories, University College London, 20 Gordon Street, London WC1H 0AJ, UK
e) Institut für Pharmazeutische Chemie, Biozentrum, Johann Wolfgang Goethe-Universität Frankfurt am Main, Marie-Curie-Strasse 9,
60439 Frankfurt am Main, Germany
Key Words: Histamine; H receptor; PET; SPECT; benzophenone
3
deficit hyperactivity disorder (ADHD), and Alzheimer’s dis-
ease . In order to study CNS disorders, non-invasive imag-
Summary
[9]
ing in vivo techniques such as Single Photon Emission
Computed Tomography (SPECT) and Positron Emission To-
mography (PET) are highly beneficial . For these neuro-
imaging techniques radiolabeled ligands with high affinity as
well as selectivity for the investigated receptor are needed.
Para-substituted aromatic ethers with benzophenone or related
structural elements and a 3-(1H-imidazol-4-yl)propyloxy moiety
were prepared by Mitsunobu-type ether synthesis or SNAr reac-
tion. Most of the title compounds possess high antagonist potency
in histamine H3-receptor assays in vitro as well as in vivo in mouse
CNS following oral administration. After defining 4-(3-(1H-imid-
azol-4-yl)propyloxy)phenyl phenyl methanone as a new lead,
structure-activity relationships were investigated for this new class
of compounds. Substitution of the meta′-position of the benzophe-
none moiety with halogen atoms (e.g., iodine, fluorine) led to
compounds with high antagonist potency in vitro as well as in vivo
(Ki = 9.3 and 4.3 nM, ED50 = 0.7 and 0.47 mg/kg p.o., 18 and 12,
respectively). A receptor profile of several functional in vitro
assays for several biogenic amine receptors for the meta′-iodinated
derivative demonstrated high selectivity toward the histamine H3
receptor.
[10]
Although a large number of histamine H -receptor ligands
3
[8,11]
[12,13]
has been described, e.g., thioperamide
, FUB 372
,
[14]
and ciproxifan (Chart 1, Table 1), and radioligands such
125
as [ I]iodoproxyfan for in vitro binding studies have been
[15]
developed , suitable radiolabeled compounds for PET and
SPECT are still lacking. Certain prerequisites for suitable
compounds have to be met. First of all, the ligand should
possess high affinity and selectivity for the histamine H
3
receptor, it should be able to cross the blood-brain barrier,
thus showing high potency in the CNS, and it must contain
an atom or functional group which is suitable for radio-
labeling such as –F, –I, –SCH or –OCH at a final step of
3
3
the synthesis. Unfortunately, previous developments have
[16–21]
Introduction
met these prerequisites with limited success
. Accord-
ing to published methods these structures may be radiola-
Histamine H and H receptors are well-known targets for
selective antagonists . A third histamine receptor, termed
1
2
18
11
[3]
beled by exchange or derivatisation to give [ F], [ C], or
123
123
[17,18]
[
[
I]labeled ligands
. Among other compounds,
H receptor, was identified as auto- and heteroreceptor in the
3
[19] 18
[20]
11
[4]
I]iodoproxyfan , [ F]VUF 5000 , and [ C]UCL
central nervous system (CNS) . Activation of presynapti-
[21]
1829 have been described (Chart 1), but biodistribution
cally localized histamine H receptors by histamine leads to
3
[5]
studies revealed only low uptake into the brain.
an inhibition of the release of various neurotransmitters
including histamine and to an inhibition of the synthesis of
histamine in histaminergic neurons . In vivo, histamine
[6]
In this study histamine H -receptor antagonists are de-
3
[7]
scribed which have been developed after defining a novel
lead and subsequent variation of the lead compound in order
to assess structure-activity relationships. As fluorinated and
iodinated derivatives showed high in vitro as well as in vivo
H -receptor antagonists inhibit the negative feedback of his-
3
[8]
tamine on its own synthesis and release
.
Several therapeutic applications have been proposed for
H -receptor antagonists such as schizophrenia, attention-
3
potency at histamine H receptors in rodents, further devel-
3
———
opment for use as PET or SPECT ligand are proposed. Bind-
ing experiments and a broad funtional receptor profile have
been performed for the most promising compound.
1)
Presented in part at the XVIth International Symposium on Medicinal
Chemistry, Bologna/Italy, September 18-22, 2000[1] and WO 96/29 315[2]
.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 2001
0365-6233/01/0202/0045 $17.50 +.50/0

46
Stark and co-workers
Chart 1
Table 1. Chemical structure and results of pharmacological assays of histamine H3-receptor antagonists 1–19 in vitro as
well as in vivo in rodents.
———————————————————————————————————————————————————
No.
n
R1
X
R2
Ki (nM)a
ED50 (mg/kg)b
± s.e.m.
± s.e.m.
———————————————————————————————————————————————————
1
0
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
H
CO
C6H5
C6H5
54 ± 13
3.2 ± 0.5
n.d.c
2.6 ± 0.5
0.9 ± 0.1
6.7 ± 2.5
0.18 ± 0.07
2
H
CO
3
CO-C6H5
H
4
H
H
H
H
H
H
H
H
H
F
CO-CH=CH
CH=CH-CO
CO
C6H5
8.3 ± 1.4
55 ± 13
12 ± 2
5
C6H5
~20
6
C6H11
0.88 ± 0.31
1.6 ± 0.4
7
CO
2-benzofuranyl
2-thienyl
4-F-C6H4
4-F-C6H4
4-F-C6H4
3-F-C6H4
C6H5
n.d.c
8
CO
4.3 ± 1.4
4.6 ± 1.2
54 ± 22
95 ± 30
4.3 ± 1.1
n.d.c
1.0 ± 0.6
9
CO
0.71 ± 0.2
3.7 ± 1.3
10
C=NOH
SO2
11
2.9 ± 1.0
12
CO
0.47 ± 0.25
3-10 (αd ~ 0.4)
13
CO
14
F
C=NOH
CO
C6H5
39 ± 10
n.d.c
n.d.c
~10
15
H
H
H
H
H
4-H3CO-C6H4
3-H3CO-C6H4
4-I-C6H4
3-I-C6H4
2-I-C6H4
4.5 ± 2.1
3.6 ± 1.6
16
CO
17
CO
14 ± 5
~10
0.70 ± 0.34
~25
18
CO
9.3 ± 2.0
263 ± 68
4 ± 1
19
CO
Thioperamidee
FUB 372f
Ciproxifang
Imoproxifanh
1.0 ± 0.5
1
1
1
H
H
H
CO
CH3
0.8 ± 0.2
0.49 ± 0.09
0.26 ± 0.03
0.24 ± 0.06
0.14 ± 0.03
0.034 ± 0.009
CO
cyclopropyl
CH3
C=NOH
———————————————————————————————————————————————————
a Functional H3-receptor assay on synaptosomes of rat cerebral cortex[30] b Central H3-receptor screening after p.o. administration
to mice[30] c n.d. = not determined; d α = intrinsic activity (histamine: α = 1.0); e Ref.[11] f Ref.[12,13] g Ref. [14] h Ref. [29]
;
;
;
;
;
.
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

Benzophenone Derivatives and Related Compounds
47
Chemistry
Ether 1 was prepared from 4-(2-chloroethyl)-1H-imid-
[22]
azole
, ethers 2–19 were built up from trityl-protected
[23]
2-(1H-imidazol-4-yl)ethanol
or 3-(1H-imidazol-4-yl)-
[15]
propanol by reaction of corresponding substituted phenols
[24]
orfluorobenzenes bya Williamson , Mitsunobu type (Gen-
eral Method A) , or S Ar (General Method B)
[25]
[26]
reaction,
N
respectively, and subsequent deprotection of the imidazole
ring (2–19) (Scheme 1). The appropriate phenols for Mitsun-
obu synthesis were prepared by different synthetic pathways
(Scheme 2, 3). α,β-Unsaturated ketones (4a, 5a) were pre-
pared by an aldol condensation of the appropriate ketone and
aldehyde. Substituted 4-hydroxybenzophenone precursors6c
and 16c–19c were synthesized from phenol and the corre-
sponding benzoic acid (Scheme 2). First, the phenyl esters
(6b, 16b–19b) were formed by standard methods, then a Fries
[27]
rearrangement
using AlCl at moderate temperature was
3
conducted for the formation of the 4-hydroxybenzophenone
derivatives (6c, 16c–19c). 2-Benzofuranyl 4-hydroxyphenyl
methanone (7b) was constructed up by reaction of 4-
methoxyacetophenone bromide and salicylaldehyde and sub-
sequent demethylation under mild conditions using boron
[28]
tribromide (Scheme 3) . Oximes (10, 14) were prepared as
[29]
described for imoproxifan
from their corresponding ke-
tones (9, 13) with hydroxylamine hydrochloride and sodium
carbonate in ethanol (Scheme 4).
Scheme 1. Synthesis of ethers 1–9, 11-13, and 15–19 by Williamson,
Mitsunobu (General Method A) or SNAr (General Method B) type reaction.
Trit = Trityl; (i) Ph3P, DEAD, THF, ambient temperature, 3 d; (ii) 2N HCl,
THF, reflux, 2 h; (iii) 15-crown-5, toluene, 70 °C, 8 h; (iv) NaH (60%), DMF,
ambient temperature, 1 h; (v) TBAI, DMF, 100 °C, 48 h.
Pharmacological Results and Discussion
Histamine H -receptor antagonist properties were investi-
3
gated in vitro in a functional model on synaptosomes of rat
3
[30]
cerebral cortex, measuring [ H]-histamine release . All
investigated compounds displayed affinity in the nanomolar
concentration range (Table 1). The novel compounds were
τ
also screened for their ability to modulate N -methylhis-
tamine levels in mouse brain cortex after p.o. administra-
[30]
tion . Unsubstituted benzophenone derivatives were
investigated first in order to select a new lead structure.
Variation of the chain length of the alkyl spacer between the
imidazole nucleusand the benzophenone moiety (1, 2) clearly
favored the three carbon methylene spacer (2) in agreement
Scheme 2. Synthesis of ketones 6c and 16c–19c by esterification and Fries
rearrangement. (i) Et3N, Et2O, reflux, 1 h; (ii) 6b, 16b: AlCl3, 80 °C, 30 min;
17b, 18b: AlCl3, nitrobenzene, 45 °C, 4 d.
with former observations on other classes of histamine H -re-
3
[22,31]
[32]
ceptor ligands with an ether
or carbamate
moiety.
The para-position for acyl substitution on the phenyl ring has
Scheme 3. Synthesis of benzofurane precursors 7a and 7b. (i) K2CO3, DMF, 120 °C, 3 h; (ii) BBr3, CH2Cl2, –80 °C → ambient temperature, 72 h.
Scheme 4. Synthesis of oximes 10 and 14. (i) NH2OH × HCl, Na2CO3, EtOH, 60 °C, 9 h.
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

48
Stark and co-workers
already been shown to lead to highly active compounds, e.g., increased in vivo antagonist activity after p.o. administration
[12,13]
to mice (ED = 0.47 mg/kg).
FUB 372 and ciproxifan (Table 1)
. The present find-
50
On substitution of the phenyl ring bound to the alkyl ether
moiety with fluorine in the meta-position (13), partial agonist
activity of low potency was observed under in vivo condi-
tions. The corresponding oxime 14 showed low antagonist
potency in vitro as well as in vivo. Recently this striking
partial agonist behavior has also been observed for a related
ings, demonstrating higher potency for para-substituted 2
than for meta-substituted 3, are in line with these results.
Compound 2 (K = 3.2 nM, ED = 0.9 mg/kg p.o.) is
i
50
equipotent with thioperamide, the reference histamine H -re-
3
ceptor antagonist. Compound 2 was thus defined as the novel
parent compound, and related compounds, as well as deriva-
tives of 2, were synthesized and investigated pharmacologi-
cally. Insertion of a vinyl group (4, 5) next to the carbonyl
moiety led to very different pharmacological potencies de-
pending on the position of the vinyl group. For compound 4
the carbonyl moiety remained on the phenyl ether side of the
molecule, and the in vitro antagonist potency was only low-
ered slightly compared to the lead 2. Interestingly, in vivo
[33]
class of meta-substituted phenyl ethers . As agonism is not
favorable for ligands in PET or SPECT imaging due to more
complex binding behavior of (partial) agonists in general, no
efforts were made to further investigate the structure-activity
relationships of this pharmacologically different class of
compounds. However, compounds derived from lead 2 with
high antagonist potency in vitro as well as in vivo, possessing
an atom that could be radiolabeled, such as the fluorine in 9
and 12, were further investigated.
antagonist potency of 4 was increased (ED = 0.18 mg/kg,
50
p.o.) and it is equipotent with FUB 372. In the other case
where the vinyl group is positioned next to the phenyl ether
moiety (5), a drop in in vitro and especially in in vivo potency
occurred. The observed different activities of 4 and 5 seem to
be related to the position of the carbonyl group within the
molecule, given that the electronic properties of 4 and 5 are
quite similar, since both represent comparable mesomeric
systems.
Introduction of a methoxy group in para′- or meta′-position
led to low in vivo potency (15, 16). Substitution with iodine
in para′-, meta′-, or ortho′-positions (17–19) showed very
interesting potency patterns. Whereas iodoproxyfan, a com-
[34]
monly used radioligand for binding studies , does not
possess central in vivo activity and was not suitable as a
[19]
SPECT ligand , the meta′-iodo substituted derivative 18
displayed high in vitro as well as in vivo antagonist potency.
The para′-substituted analogue 17 was about equipotent in
vitro, but showed highly decreased potency in vivo, which
might be caused by pharmacokinetic properties of para′-iodo
substitution of the phenyl ring. Ortho′-substituted 19 had only
moderate potency in vitro as well as in vivo. The ligand–re-
ceptor interaction which is determined in vitro might be
hindered by steric parameters of the ortho′-positioned iodine
in 19 shielding the carbonyl group or forcing the phenyl group
into another position. The importance of the position of the
carbonyl group has been discussed for 4, 5, 10, and 11, and
in vitro results of 18 and 19 further strengthen the hypothesis
that the carbonyl group of these compounds plays an impor-
tant role in the close ligand-receptor interaction. Compound
18 was selected for further investigation. For this reason, a
detailed functional receptor profile for several neurotransmit-
Exchange of the phenyl ring attached to the phenoxy car-
bonyl group with cyclohexyl (6) or heteroaromatics (7, 8)
hardly influenced H -receptor antagonist potency. In vitro,
3
exchange by cyclohexyl (6) led to a decrease of potency,
whereas in vivo no significant change was observed, presum-
ably due to increased lipophilicity and consequently en-
hanced penetration through the blood–brain barrier.
2-Thienyl substitution did not increase in vitro or in vivo
potency with 8 being equipotent to the lead 2.
Thus, compound 2 seemed to be a most promising structure
for further investigation into the structure-activity relation-
ships of this new class of compounds. Derivatives and ana-
logues of 2 were prepared with special interest in fluorinated,
methoxylated or iodinated compounds which could be trans-
formed to their corresponding radiolabeled potential PET or
SPECT ligands.
ter receptors as well as H -receptor binding experiments with
3
Introduction of an electron-withdrawing fluoro-substitutent
in para-position did not significantly affect in vitro and in
vivo potency when compared to 2. Unfortunately, transfor-
mation of the carbonyl group to an oxime moiety (10) de-
3
[ H](R)-α-methylhistamine on membranes of rat cerebral
cortex and a functional peripheral H -receptor assay on
3
guinea-pig were performed (Figure 1). Compound 18 dis-
played a high H -receptor selectivity, as its potency at H
3
3
creased histamine H -receptor potency in vitro as well as in
3
receptors was at least 100 times higher than at the other
vivo. Recently, this transformation was described as a possi-
receptors investigated including H and H receptors.
1
2
bility to increase H -receptor potency of ketones (e.g., FUB
3
[29]
372 → imoproxifan , cf. Table1), although this is not gen-
[29]
erally applicable . An exchange of the carbonyl moiety of
9 by a sulfone (11) also led to a decrease in H -receptor
3
18
18
potency. Compound 9 was [ F]-labeled ([ F]FUB 272) and
evaluated as a potential PET ligand . However, the labeled
[21]
compound was poorly taken up by the brain and distributed
homogeneously, indicating that it is not suitable in this form
for PET studies. Nevertheless, fluoro substitution was well
tolerated with regard to histamine H -receptor assays in vitro
3
and in vivo in rodents (K = 4.6 nM, ED = 0.71 mg/kg p.o.);
i
50
Figure 1. Functional receptor profile and binding data of compound 18.
a Histamine H3-receptor potency in a binding assay on rat cerebral cortex
thus diverse positions of fluoro substitution were investi-
gated. On changing the fluorine atom from para′- to meta′-
position (12), high in vitro potency was maintained, with
b
membranes; functional assay on synaptosomes of rat cerebral cortex
synaptosomes; c functional assay on guinea-pig ileum.
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

Benzophenone Derivatives and Related Compounds
49
NH3 atmosphere). Purefractionswerecrystallizedasfreebaseorashydrogen
chloride, hydrogen maleate, or hydrogen oxalate from EtOH/Et2O.
Conclusion
Benzophenone derivatives and related compounds contain-
ing a 3-(1H-imidazol-4-yl)propoxy moiety were investigated
General Method B (SNAr-type Ether Synthesis)
3-(1-(Triphenylmethyl)-1H-imidazol-4-yl)propanol[15] (5 mmol, 1.84 g)
was stirred for 2 h with NaH (6 mmol, 240 mg of 60% suspension in paraffin
oil) under Ar in 20 mL of dry toluene. Then a catalytic amount of 15-crown-5
(0.5 mmol, 0.1 g) and the appropriately substituted fluorobenzene (6 mmol)
in 5 mL of toluene were added at ambient temperature and the mixture heated
to 70 °C for 8 h. The solvent was evaporated, water was carefully added, and
it was then heated to reflux in 20 mL of 2N HCl and 40 mL of THF for 2 h.
Purification and crystallization were continued as described in General
Method A.
for their histamine H -receptor antagonist potency. Two
3
pharmacological assays were used to screen the potency of
the novel compounds in vitro as well as in vivo. After defining
a new lead structure (2) with high antagonist potency in vitro
and in vivo, structural variations were performed in order to
obtain structure-activity relationships for this new class of
compounds. Substitution with iodine (18) or fluorine (12) in
the meta′-position led to compounds showing high histamine
H -receptor potency in vitro as well as in vivo (K = 9.3 and
3
i
General Method C (Preparation of Esters)
4.3 nM, ED = 0.7 and 0.47 mg/kg p.o., respectively). These
50
compounds might be used as pharmacological tools for
SPECT or PET studies when labeled with [ I] or [ F]. For
The appropriate carboxylic acid (50 mmol) was transformed into the
carboxylic acid chloride with thionyl chloride (75 mmol) in 50 mL of THF
by heating the mixture to reflux for 30 min. The solvent was removed under
reduced pressure. The crude reaction product was directly added to a solution
of phenol (50 mmol) and Et3N (55 mmol) in 50 mL of Et2O and heated to
reflux for 1 h. The precipitate was filtered, dissolved in H2O and extracted
with Et2O. The combined organic phases were washed with a saturated
solution of K2CO3, 0.2N HCl, and brine, dried with Na2SO4, and concen-
trated.
123
18
meta′-iodinated compound 18 histamine H -receptor binding
3
studies and a functional receptor profile were determined,
establishing high affinity and selectivity for the histamine H
receptor.
3
Acknowledgment
General Method D (Fries Reaction I)
We gratefully thank H. Magnusen, S. Athmani, A. Hüls, and K. Purand for
the preparation of compounds 1–3, 6, and 9 and D. Dumoulin for technical
assistance in pharmacological experiments. This work was supported by the
Biomedical & Health Research Programme (BIOMED) of the European
Union, Fonds der Chemischen Industrie, Verband der Chemischen Industrie,
Frankfurt/Main, Germany, and Deutsche Pharmazeutische Gesellschaft,
DPhG-Stiftung zur Förderung des wissenschaftlichen Nachwuchses, Ger-
many.
The phenyl ester (30 mmol) obtained from General Method C was mixed
with AlCl3 (150 mmol), stirred for 30 min at ambient temperature, and then
heated to 80 °C for 30 min. The crude product was taken up in cold 0.5N HCl
and extracted with Et2O and CH2Cl2. The organic phases were dried
(Na2SO4) and concentrated. The resulting dark oil was purified by column
chromatography (eluent: CH2Cl2). Pure fractions were crystallized from
solvents as indicated.
General Method E (Fries Reaction II)
Experimental
The phenyl ester (30 mmol) obtained from General Method C and AlCl3
(150 mmol) were dissolved in 30 mL of nitrobenzene, warmed to 45 °C, and
stirred for 4 days. Work-up procedure as described in General Method D.
Chemistry
General Procedures. Melting points were determined on an Electrother-
mal IA 9000 digital or a Büchi 512 melting point apparatus and are uncor-
rected. 1H NMR spectra were recorded on a Brucker DPX 400 Avance
(400 MHz) spectrometer. Chemical shifts (δ) areexpressedinppmdownfield
from internal Me4Si as reference. Mass spectra were obtained on an EI-MS
Finnigan MAT CH7A. Elemental analyses (C, H, N) were measured for all
final compounds on Perkin-Elmer 240 B or Perkin-Elmer 240 C instruments
and were within ±0.4% of the theoretical values. Preparative, centrifugally
accelerated, rotatory chromatography was performed using a Chromatotron
7924T (Harrison Research) and glass rotors with 4 mm layers of silica gel
60 F254 containing gypsum (Merck). Column chromatography was carried
out using silica gel 63-200 µm (Macherey, Nagel & Co.). Thin layer chro-
matography (TLC) was performed on silica gel F254 plates (Merck).
4-(2-(1H-Imidazol-4-yl)ethyloxy)phenyl Phenyl Methanone (1)
4-Hydroxybenzophenone (12 mmol, 2.38 g) in dry DMF (10 mL) was
stirred with sodium hydride (6 mmol, 240 mg of 60% suspension in paraffin
oil) for 1 h at room temperature. Then 4-(2-chloroethyl)-1H-imidazole
hydrochloride[22] (1.2 mmol, 200 mg) and tetrabutylammonium iodide (cata-
lytic amount) were added and the mixture was heated at 100 °C for 48 h. The
mixture was then evaporated, acidified (2N HCl), washed (3 ×) with Et2O,
basified with K2CO3, and extracted with Et2O (3 ×). The combined ether
extracts were dried, concentrated, and the residue was treated with oxalic
acid in 2-propanol to yield the solid as hydrogen oxalate. The latter was
recrystallized from MeOH/Et2O. Yield: 25%. Anal. (C18H16N2O2 × 1.3
C2H2O4); Mr = 409.3; mp 193 °C; 1H NMR (DMSO-d6): δ 8.62 (s, 1H), 7.86
(d, J = 8.6 Hz, 2H), 7.78-7.59 (m, 5H), 7.36 (s, 1H), 7.13 (d, J = 8.7 Hz, 2H),
4.80 (t, J = 6.0 Hz, 2H), 3.28 (t, J = 7.3 Hz, 2H); C, H, N.
General Method A (Mitsunobu-type Ether Synthesis)
Triphenylphosphine (6 mmol, 1.57 g), 2-(1-(triphenylmethyl)-1H-imid-
azol-4-yl)ethanol[23] (5 mmol, 1.77 g) or 3-(1-(triphenylmethyl)-1H-imid-
azol-4-yl)propanol[15] (5 mmol, 1.84 g), and 6 mmol of the corresponding
phenol derivative were dissolved in 15 mL of freshly distilled THF under Ar
atmosphere and cooled in an ice bath. Diethyl azodicarboxylate (DEAD)
(6 mmol, 0.95 mL) was added dropwise. The mixture was stirred for 16–72 h
at ambient temperature. Then the solvent was removed under reduced
pressure and the crude reaction product purified by column chromatography
(eluent: EtOAc). Pure fractions were detritylated by heating to reflux in
20 mL of 2N HCl and 40 mL of THF for 2 h. THF was evaporated under
reduced pressure and the aqueous residue washed with Et2O. The aqueous
phase was basified with K2CO3 and extracted with Et2O and CH2Cl2. The
organic layer was separated and the solvent evaporated. The crude product
was subjected to rotatory chromatography (eluent: CH2Cl2/MeOH (90/10),
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Phenyl Methanone (2)
Prepared from (4-fluorophenyl)phenylmethyl chloride according to Gen-
eral Method B. Yield: 30%. Anal. (C19H18N2O2 × C4H4O4 × 0.25 H2O); Mr
= 426.9; mp 126 °C; 1H NMR (DMSO-d6): δ 8.87 (s, 1H), 7.75 (d, J = 8.6
Hz, 2H), 7.70-7.53 (m, 5H), 7.31 (s, 1H), 7.07 (d, J = 8.7 Hz, 2H), 6.04 (s,
2H), 4.13 (t, J = 6.1 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.10 (m, 2H); C, H, N.
3-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Phenyl Methanone (3)
Prepared from 3-hydroxybenzophenone according to General Method A,
crystallized from 2-propanol and recrystallized from MeOH. Yield: 40%.
Anal. (C19H18N2O2 × C2H2O4 × 0.2 H2O); Mr = 336.0; mp 155 °C; 1H NMR
(DMSO-d6): δ 8.38 (s, 1H), 7.65–7.57 (m, 5H), 7.46 (t, 1H), 7.24–7.21 (m,
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

50
Stark and co-workers
2H), 7.22 (s, 1H), 4.05 (t, J = 6.2 Hz, 2H), 2.74 (t, J = 7.6 Hz, 2H), 2.07 (m,
2H); C, H, N.
cooling to –80 °C by addition of dry MeOH (25 mL). The solvents were
evaporated under reduced pressure and the residue taken up with water. On
neutralizationwithK2CO3 2-benzofuranyl 4-hydroxyphenyl methanone (7b)
crystallized and was recrystallized from EtOH. Yield: 80%: For the final
step, 7b was treated according to General Method A. Yield: 80%. Anal.
(C21H19N2O3 × C4H4O4 × 0.5 H2O); Mr = 471.5; mp 155 °C; 1H NMR
(DMSO-d6): δ 8.84 (s, 1H), 8.06 (d, J = 8.8 Hz, 2H), 7.87 (s, 1H), 7.77 (m,
2H), 7.55 (dd, J = 7.8 Hz, 1H), 7.40 (m, 2H), 7.13 (d, J = 8.7 Hz, 2H), 6.04
(s, 2H), 4.17 (t, J = 6.1 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.15 (m, 2H); C, H,
N.
1-(4-Hydroxyphenyl)-3-phenyl-2-propen-1-one (4a)
4-Hydroxyacetophenone (40 mmol, 5.5 g) was dissolved in 30 mL of
water, 15 mL of EtOH, and 10 mL of 6N NaOH and stirred for 30 min at
ambient temperature. Then benzaldehyde (42 mmol, 4.5 g) dissolved in
H2O/EtOH (2/1) was added slowly. The mixture was heated to reflux for 72 h
and then acidified with 6N HCl. The crystalline product was filtered and
recrystallized from EtOH. Yield. 80%; mp 173 °C (174 °C[35]); 1H NMR
(DMSO-d6): δ 10.42 (s, 1H), 8.09 (d, J = 8.5 Hz, 2H), 7.94–7.86 (m, 3H),
7.69 (d, J = 15.6 Hz, 1H), 7.49-7.45 (m, 3H), 6.92 (d, J = 8.5 Hz, 2H).
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 2-Thienyl Methanone (8)
Prepared from 4-fluorophenyl 2-thienyl methanone according to General
Method B. Yield: 10%. Anal. (C17H16N2O2S × C2H2O4); Mr = 402.4; mp
175 °C; 1H NMR (DMSO-d6): δ 8.47 (s, 1H), 8.08 (d, J = 5.1 Hz, 1H), 7.84
(d, J = 8.7 Hz, 2H), 7.72 (d, J = 3.1 Hz, 1H), 7.28 (t, J = 4.3 Hz, 1H), 7.24
(s, 1H), 7.10 (d, J = 8.8 Hz, 2H), 4.13 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 7.6 Hz,
2H), 2.09 (m, 2H); C, H, N.
1-(4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl)-3-phenyl-2-propen-1-one (4)
Prepared from 4a according to General Method A. Yield: 65%. Anal.
(C21H20N2O2 × C2H2O4 × 0.75 H2O); Mr = 436.0; mp 169 °C; 1H NMR
(DMSO-d6): δ 8.91 (s, 1H), 8.17 (d, J = 8.8 Hz, 2H), 7.94 (d, J = 15.6 Hz,
1H) 7.90–7.87 (m, 2H), 7.71 (d, J = 15.6 Hz, 1H), 7.48–7.43 (m, 3H), 7.08
(d, J = 8.8 Hz, 2H), 4.15 (t, J = 6.1 Hz, 2H), 2.83 (t, J = 7.5 Hz, 2H), 2.13
(m, 2H); C, H, N.
4-Fluorophenyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Methanone (9)
3-(4-Hydroxyphenyl)-1-phenyl-2-propen-1-one (5a)
Prepared from bis(4-fluorophenyl)methylchloride according to General
Method B. Yield: 9%. Anal. (C19H17N2O2 × C4H4O4); Mr = 440.4; mp
127 °C; 1H NMR (DMSO-d6): δ 8.97 (s, 1H), 7.76 (m, 4H), 7.41 (m, 3H),
7.09 (d, J = 8.6 Hz, 2H), 6.06 (s, 2H), 4.14 (t, J = 6.1 Hz, 2H), 2.84 (t, J =
7.4 Hz, 2H), 2.14 (m, 2H); C, H, N.
Prepared from 4-hydroxybenzaldehyde and acetophenone as described for
4a. Yield. 80%; mp 183 °C (184 °C[35]); 1H NMR (DMSO-d6): δ 10.10 (s,
1H), 8.13 (d, J = 7.6 Hz, 2H), 7.75–7.70 (m, 4H), 7.67–7.64 (m, 1H), 7.56
(t, J = 7.6 Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H).
3-(4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl)-1-phenyl-2-propen-1-one (5)
4-Fluorophenyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Methanone
Prepared from 5a according to General Method A. Yield: 40%. Anal.
(C21H20N2O2 × 0.5 C2H2O4 × 0.75 H2O); Mr = 391.0; mp 187 °C; 1H NMR
(DMSO-d6): δ 9.00 (s, 1H), 8.14 (d, J = 7.5 Hz, 2H), 7.87–7.83 (m, 3H), 7.77
(d, J = 18.6 Hz, 1H), 7.70–7.65 (m, 1H), 7.60–7.56 (m, 2H), 7.47 (s, 1H),
4.11 (t, J = 6.0 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.12 (m, 2H); C, H, N.
Oxime (10)
Ketone 9 (free base, 1 mmol, 0.32 g), hydroxylamine hydrochloride
(5 mmol, 0.35 g), and Na2CO3 (6 mmol, 0.64 g) were dissolved in 25 mL of
dry EtOH and heated to 60 °C for 9 h. After filtration of inorganic salts, the
solvent was evaporated under reduced pressure. The product was purified by
column chromatography (eluent: CH2Cl2/MeOH (90/10); NH3 atmosphere)
and crystallized as hydrogen maleate from EtOH/Et2O. Yield: 70%. Anal.
(C19H18FN3O2 × C4H4O4); Mr = 455.5; mp 126 °C; 1H NMR (DMSO-d6):
δ 11.29/11.17 (2s, 1H), 8.86 (s, 1H), 7.41–7.20 (m, 6H), 7.02 (s, 1H), 6.92
(d, J = 8.5 Hz, 2H), 6.04 (s, 2H), 4.02 (t, J = 6.1 Hz, 2H), 2.80 (t, J = 7.6 Hz,
2H), 2.07 (m, 2H); C, H, N.
Phenyl Cyclohexanecarboxylate (6a)
Prepared from cyclohexanecarboxylic acid according to General Method
C. Yield: 91%; b.p. 163 °C/21 Torr (163 °C/21 Torr[36]); 1H NMR (DMSO-
d6): δ 7.40 (m, 2H), 7.25 (t, J = 7.4 Hz, 1H), 7.10 (d, J = 7.5 Hz, 2H), 2.60
(m, 1H), 1.99-1.21 (m, 10H).
Cyclohexyl 4-Hydroxyphenyl Methanone (6b)
4-Fluorophenyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Sulfone (11)
Prepared from 6a according to General Method D and crystallized from
light petroleum. Yield: 35%; mp 98 °C (98 °C[37]); 1H NMR (DMSO-d6): δ
10.31 (s, 1H), 7.83 (d, J = 8.7 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 3.34 (m,
1H), 1.81-1.19 (m, 10H).
Prepared from bis(4-fluorophenyl) sulfone according to General Method
B. Yield: 38%. Anal. (C18H17FN2O3S × HCl); Mr = 396.9; mp 235 °C; 1H
NMR (DMSO-d6): δ 8.83 (s, 1H), 8.02-7.98 (m, 2H), 7.87 (d, J = 8.7 Hz,
2H), 7.45 (m, 3H), 7.13 (d, J = 8.7 Hz, 2H), 4.09 (t, J = 6.0 Hz, 2H), 2.79 (t,
J = 7.5 Hz, 2H), 2.09 (m, 2H); C, H, N.
Cyclohexyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Methanone (6)
Prepared from 6b according to General Method A. Yield: 80%. Anal.
(C19H24N2O2 × C4H4O4); Mr = 428.5; mp 103 °C; 1H NMR (DMSO-d6): δ
8.86 (s, 1H), 7.91 (d, J = 8.8 Hz, 2H), 7.42 (s, 1H), 7.02 (d, J = 8.7 Hz, 2H),
6.04 (s, 2H), 4.10 (m, 3H), 2.79 (t, J = 7.4 Hz, 2H), 2.09 (m, 2H), 1.76-1.20
(m, 10H); C, H, N.
3-Fluorophenyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Methanone (12)
Prepared from 3-fluorophenyl 4-fluorophenyl methanone according to
General Method B. Yield: 15%. Anal. (C19H17FN2O2 × C4H4O4 × 0.25
H2O); Mr = 445.0; mp 127 °C; 1H NMR (DMSO-d6): δ 8.84 (s, 1H), 7.76 (d,
J = 8.6 Hz, 4H), 7.62-7.45 (m, 5H), 7.42 (s, 1H), 7.10 (d, J = 8.7 Hz, 2H),
6.04 (s, 2H), 4.14 (t, J = 6.1 Hz, 2H), 2.82 (t, J = 7.5 Hz, 2H), 2.11 (m, 2H);
C, H, N.
2-Benzofuranyl 4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl Methanone (7)
To a solution of 4-methoxyacetophenone bromide (8.7 mmol, 2.0 g) and
salicylaldehyde (8.7 mmol, 1.06 g) in 30 mL of dry DMF, K2CO3 (8.7 mmol,
1.2 g) was added slowly (1 h) under nitrogen atmosphere. It was then heated
to 100 °C for 3 h. The solvent was evaporated under reduced pressure and
the oily residue taken up in a saturated solution of K2CO3. The precipitate
was filtered, washed with H2O, and recrystallized from EtOH (7a). The
reaction product 7a (12 mmol, 3.2 g) was dissolved in 40 mL of dry CH2Cl2
and cooled to –80 °C under Ar atmosphere. BBr3 (40 mL of a 1 mol/L
solution in CH2Cl2) (40 mmol, 10 g) was added slowly, maintaining the
temperature below –60 °C. After complete addition of BBr3, the mixture was
stirred for 72 h at ambient temperature. The reaction was quenched after
2-Fluoro-4-(3-(1H-imidazol-4-yl)propyloxy)phenyl Phenyl Methanone (13)
Prepared from 2,4-difluorophenyl phenyl methanone according to General
Method B. Yield: 30%. Anal. (C19H17FN2O2 × C4H4O4 × H2O); Mr = 458.5;
mp 146 °C; 1H NMR (DMSO-d6): δ 8.83 (s, 1H), 7.68 (m, 2H), 7.63 (dd, J
= 7.22/7.11 Hz, 1H), 7.50 (m, 3H), 7.17 (s, 1H), 7.11 (d, J = 10.9 Hz, 1H),
6.94 (d, J = 7.59 Hz, 1H), 6.04 (s, 2H), 3.99 (t, J = 5.6 Hz, 2H), 2.27 (t, J =
7.4 Hz, 2H), 1.71 (m, 2H); C, H, N.
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

Benzophenone Derivatives and Related Compounds
51
2-Fluoro-4-(3-(1H-imidazol-4-yl)propyloxy)phenyl Phenyl Methanone
Phenyl 3-Iodobenzoate (18a)
Oxime (14)
Prepared from 3-iodobenzoic acid according to General Method C. Yield:
62%; mp 57 °C; 1H NMR (DMSO-d6): δ 8.41 (s, 1H), 8.12 (m, 2H),
7.49–7.28 (m, 6H).
Prepared from 13 as described for 10. Yield: 65%. Anal. (C19H18FN3O2 ×
C2H2O4 × 0.25 H2O); Mr = 433.9; mp 197 °C; 1H NMR (DMSO-d6): δ 11.40
(s, 1H), 8.86 (s, 1H), 8.13 (s, 1H), 7.43-7.33 (m, 5H), 7.01 (d, J = 10.5 Hz,
1H), 6.89-6.82 (m, 3H), 4.03 (t, J = 6.1 Hz, 2H), 2.66 (t, J = 7.5 Hz, 2H),
2.07 (m, 2H); C, H, N.
4-Hydroxyphenyl 3-Iodophenyl Methanone (18b)
Prepared from 18a according to General Method E and crystallized from
light petroleum. Yield: 33%; mp 188 °C; 1H NMR (DMSO-d6): δ 10.50 (s,
1H), 7.99 (d, J = 7.9 Hz, 1H), 7.95 (s, 1H), 7.67-7.64 (m, 3H), 7.34 (t, J =
7.7 Hz, 1H), 6.91 (d, J = 8.6 Hz, 1H).
4-Hydroxyphenyl 4-Methoxyphenyl Methanone (15a)
Bis(4-hydroxyphenyl)methanone (15 mmol, 3.2 g) was dissolved in 50 mL
of an aqueous solution of potassium hydroxide (10%). Dimethyl sulfate
(15 mmol, 1.9 g) was added dropwise, the mixture was stirred for 30 min at
ambient temperature and for an additional 30 min at 100 °C. It was acidified
with 2N HCl and extracted with Et2O. The solvent was evaporated, the
product purified by column chromatography (eluent: CH2Cl2/MeOH
(90/10)), and crystallized from EtOH. Yield: 33%; mp 154 °C (151 °C[38]);
1H NMR (DMSO-d6): δ 10.31 (s, 1H), 7.68 (d, J = 8.7 Hz, 2H), 7.62 (d, J =
8.6 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 3.85 (s, 3H).
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 3-Iodophenyl Methanone (18)
Prepared from 18b according to General Method A. Yield: 66%. Anal.
(C19H17IN2O2 × HCl); Mr = 468.7; mp 179 °C; 1H NMR (DMSO-d6): δ 9.03
(s, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.97 (s, 1H), 7.73 (d, J = 8.7 Hz, 2H), 7.67
(d, J = 7.8 Hz, 1H), 7.48 (s, 1H), 7.36 (t, J = 7.8 Hz, 1H), 7.09 (d, J = 8.8 Hz,
2H), 4.14 (t, J = 6.2 Hz, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.14 (m, 2H); C, H, N.
Phenyl 2-Iodobenzoate (19a)
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 4-Methoxyphenyl Methanone (15)
Prepared from 2-iodobenzoic acid according to general method C. 19a was
a yellow oil at room temp. and crystallized at 4 °C. Yield: 60%; 1H NMR
(DMSO-d6): δ 8.10 (d, J = 8.0 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.71 (t, J =
8.0 Hz, 1H), 7.54-7.50 (m, 2H), 7.40-7.33 (m, 4H).
Prepared from 15a according to General Method A. Yield: 50%. Anal.
(C20H20N2O3 × HCl); Mr = 373.5; mp 189 °C; 1H NMR (DMSO-d6): δ 9.02
(s, 1H), 7.70 (m, 4H), 7.48 (m, 1H), 7.07 (m, 4H), 4.13 (t, J = 6.3 Hz, 2H),
3.86 (s, 3H), 2.84 (t, J = 7.6 Hz, 2H), 2.13 (m, 2H); C, H, N.
4-Hydroxyphenyl 2-Iodophenyl Methanone (19b)
Prepared from 19a according to General Method E and crystallized from
light petroleum. Yield: 51%; mp 112 °C; 1H NMR (DMSO-d6): δ 10.60 (s,
1H), 7.94 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 8.7 Hz, 2H), 7.52 (t, J = 7.5 Hz,
1H), 7.32 (d, J = 7.5 Hz, 1H), 7.26 (t, J = 7.3 Hz, 1H), 6.88 (d, J = 8.7 Hz,
2H).
Phenyl 3-Methoxybenzoate (16a)
Prepared from 3-methoxybenzoic acid according to General Method C.
Yield: 71%; mp 62 °C (61 °C[38]); 1H NMR (DMSO-d6): δ 7.73 (d, J = 7.6
Hz, 1H), 7.61 (s, 1H), 7.53 (t, J = 8.0 Hz, 1H), 7.48 (t, J = 7.8 Hz, 2H),
7.34–7.30 (m, 2H), 7.28 (d, J = 7.7 Hz, 2H), 3.86 (s, 3H).
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 2-Iodophenyl Methanone (19)
4-Hydroxyphenyl 3-Methoxyphenyl Methanone (16b)
Prepared from 19b according to General Method A. Yield: 55%. Anal.
(C19H17IN2O2 × C4H4O4); Mr = 548.3; mp 98 °C; 1H NMR (DMSO-d6): δ
8.87 (s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.65 (d, J = 8.7 Hz, 2H), 7.54 (t, J =
7.5 Hz, 1H), 7.43 (s, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.28 (t, J = 7.7 Hz, 1H),
7.06 (d, J = 8.8 Hz, 1H), 6.05 (s, 2H), 4.12 (t, J = 6.1 Hz, 2H), 2.81 (t, J =
7.5 Hz, 2H), 2.10 (m, 2H); C, H, N.
Prepared from 16a according to General Method D and crystallized from
light petroleum. Yield: 17%; mp 134 °C (138 °C[38]); 1H NMR (DMSO-d6):
δ 10.42 (s, 1H), 7.67 (d, J = 8.7 Hz, 2H), 7.45 (t, J = 7.8 Hz, 1H), 7.21–7.17
(m, 3H), 6.89 (d, J = 8.7 Hz, 2H), 3.81 (s, 3H).
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 3-Methoxyphenyl Methanone (16)
Pharmacology
Prepared from 16b according to General Method A. Yield: 65%. Anal.
(C20H20N2O3 × C4H4O4); Mr = 452.5; mp 115 °C; 1H NMR (DMSO-d6): δ
8.90 (s, 1H), 7.75 (d, J = 8.7 Hz, 2H), 7.45 (m, 2H), 7.20 (m, 3H), 7.07 (d, J
= 8.8 Hz, 2H), 6.06 (s, 2H), 4.14 (t, J = 6.1 Hz, 2H), 3.82 (s, 3H), 2.82 (t, J
= 7.5 Hz, 2H), 2.12 (m, 2H); C, H, N.
General Procedures
Histamine H3-Receptor Antagonist Potency in Vitro on Synaptosomes of Rat
Cerebral Cortex
Compounds were tested for their histamine H3-receptor antagonist potency
in an assay using K+-evoked depolarization induced release of [3H]histamine
Phenyl 4-Iodobenzoate (17a)
from synaptosomes of rat cerebral cortex according to Garbarg et al.[30]
.
Prepared from 4-iodobenzoic acid according to General Method C. Yield:
25%; mp 129 °C (133 °C[39]) 1H NMR (DMSO-d6): δ 8.00 (d, J = 8.3 Hz,
2H), 7.87 (d, J = 8.3 Hz, 2H), 7.47 (m, 2H), 7.30 (m, 3H).
Histamine H3-Receptor Potency in Vitro on Guinea-Pig Ileum
Histamine H3-receptor potency was measured by concentration-dependent
inhibition of electrically evoked twitches of isolated guinea-pig ileum seg-
ments induced by (R)-α-methylhistamine in the presence of the antagonist
4-Hydroxyphenyl 4-Iodophenyl Methanone (17b)
as described previously[34]
.
Prepared from 17a according to general method E and crystallized from
light petroleum. Yield: 18%; mp 185 °C; 1H NMR (DMSO-d6): δ 10.44 (s,
1H), 7.90 (d, J = 8.2 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 8.3 Hz,
2H), 6.88 (d, J = 8.6 Hz, 2H).
Histamine H3-Receptor Binding Assay on Membranes of Rat Cerebral
Cortex
Displacement of [3H](R)-α-methylhistamine binding was performed on
membranes of rat cerebral cortex as described by Garbarg et al.[30]
.
4-(3-(1H-Imidazol-4-yl)propyloxy)phenyl 4-Iodophenyl Methanone (17)
Histamine H3-Receptor Potency in Vivo in Mouse
Prepared from 17b according to General Method A. Yield: 63%. Anal.
(C19H17IN2O2); Mr = 432.3; mp 187 °C; 1H NMR (DMSO-d6): δ 7.92 (d, J
= 8.3 Hz, 2H), 7.71 (d, J = 8.7 Hz, 2H), 7.50 (s, 1H), 7.45 (d, J = 8.4 Hz, 2H),
7.06 (d, J = 8.8 Hz, 2H), 6.83 (s, 1H), 4.10 (t, J = 6.2 Hz, 2H), 2.64 (m, 2H),
2.03 (m, 2H); C, H, N.
In vivo testing was performed after p.o. administration of the compounds
to male Swiss mice as described by Garbarg et al.[30]. Brain histamine
turnover was assessed by measuring the level of the main metabolite of
histamine, Nτ-methylhistamine.
Arch. Pharm. Pharm. Med. Chem. 334, 45–52 (2001)

52
Stark and co-workers
In Vitro Screening at Other Neurotransmitter Receptors
[18] W. Vaalburg, N.H. Hendrikse, E.F. de Fries, Ann. Med. 1999, 31,
432–437.
Histamine H2-receptor activity on the isolated spontaneously beating
guinea-pig right atrium, histamine H1-receptor activity on the isolated
guinea-pig ileum, and adrenergic α1D-receptor activity on rat aorta were
assessed by standard methods described by Hirschfeld et al.[40]. Muscarinic
M3-receptor assay on guinea-pig ileum, adrenergic β1/2-receptor assay on
guinea-pig right atrium, and serotonergic 5-HT2A-receptor assay on rat tail
artery were performed as described by Pertz and Elz.[41] Serotonergic 5-
HT1B-receptor potency was determined on guinea-pig iliac artery according
to Pertz[42] and serotonergic 5-HT3-receptor activity was conducted on
[19] A.D. Windhorst, H. Timmerman, R.P. Klok, F.G.J. Custers, W.M.P.B.
Menge, R. Leurs, H. Stark, W. Schunack, E.G.J. Gielen, M.J.P.G. van
Kroonenburgh, J.D.M. Herscheid, Nucl. Med. Biol. 1999, 26, 651–659.
[20] A.D. Windhorst, H. Timmerman, R.P. Klok, W.M.P.B. Menge, R.
Leurs, J.D.M. Herscheid, Bioorg. Med. Chem. 1999, 7, 1761–1767.
[21] M. Ponchant, S. Demphel, C. Fuseau, C. Coulomb, M. Bottleander,
J.-C. Schwartz, H. Stark, W. Schunack, S. Athmani, C.R. Ganellin, C.
Crouzel. In: XIIth International Symposium on Radiopharmaceutical
Chemistry 1997, Uppsala, Sweden, (June 15–19, 1997) pp. 605–608.
guinea-pig ileum as described by Elz and Keller[43]
.
[22] C.R. Ganellin, A. Fkyerat, B. Bang-Andersen, S. Athmani, W. Tertiuk,
M. Garbarg, X. Ligneau, J.-C Schwartz, J. Med. Chem. 1996, 39,
3806–3813.
References
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[23] P. Dziuron, W. Schunack, Arch. Pharm. (Weinheim) 1973, 306, 347–
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Reidemeister, S. Athmani, C.R. Ganellin, N. Pelloux-Léon, W. Tertiuk,
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