4-Alkynylphenyl imidazolylpropyl ethers as selective histamine H3- receptor antagonists with high oral central nervous system activity

Article abstract of DOI:10.1021/jm9802970

In search for potent and therapeutically useful H₃-receptor antagonists, we prepared novel 4-alkynylphenyl ether derivatives of 3-(1H- imidazol-4-yl)propanol in a convenient synthetic route. All compounds were tested for in vitro and in vivo H<

Full text of DOI:10.1021/jm9802970

J . Med. Chem. 1998, 41, 4171-4176
4171
4-Alk yn ylp h en yl Im id a zolylp r op yl Eth er s a s Selective Hista m in e H3-Recep tor
An ta gon ists w ith High Or a l Cen tr a l Ner vou s System Activity
Michael Krause,§ Xavier Ligneau,† Holger Stark,§ Monique Garbarg,‡ J ean-Charles Schwartz,‡ and
Walter Schunack*,§
Institut fu¨r Pharmazie I, Freie Universita¨t Berlin, Ko¨nigin-Luise-Strasse 2+4, D-14195 Berlin, Germany, Laboratoire
Bioprojet, 30 rue des Francs-Bourgeois, F-75003 Paris, France, and Unite´ de Neurobiologie et Pharmacologie
Mole´culaire (U. 109), Centre Paul Broca de l’INSERM, 2ter rue d’Ale´sia, F-75014 Paris, France
Received May 12, 1998
In search for potent and therapeutically useful H3-receptor antagonists, we prepared novel
4-alkynylphenyl ether derivatives of 3-(1H-imidazol-4-yl)propanol in a convenient synthetic
route. All compounds were tested for in vitro and in vivo H3-receptor antagonist activity as
well as for H3-receptor selectivity versus H1- and H2-receptors. The presented 4-alkynylphenyl
ethers are highly potent and selective H3 antagonists showing oral activity and improved brain
penetration. Particularly 4-ethynylphenyl 3-(1H-imidazol-4-yl)propyl ether (14a ) displays
striking in vitro and in vivo activity with a -log Ki value of 8.6 and an ED50 value of 0.12
mg/kg. At present 14a is the most potent H3-receptor antagonist in vivo and may therefore be
a potential drug for the therapy of H3-receptor-dependent diseases of the central nervous system
(CNS).
Ch a r t 1. Histamine H3-Receptor Antagonists
In tr od u ction
The histamine H3-receptor was demonstrated to be
located presynaptically on histaminergic neurons in the
central nervous system (CNS) where it regulates his-
tamine synthesis and release as an inhibitory autore-
ceptor.1,2 Inhibition of this negative feedback mecha-
nism by H3-receptor antagonists thus increases concen-
tration of the neurotransmitter histamine released.3
Moreover, H3-receptors function as heteroreceptors on
nonhistaminergic neurons in the brain and the periph-
ery inhibiting the release of neuropeptides4 and several
other neurotransmitters.5 In radiolabeling studies the
highest density of H3-receptors was found in distinct
areas of the CNS,6 and it is thus suggested that the
potential therapeutic role of H3-receptor antagonists
may be the treatment of various neurological and
psychiatric diseases, e.g., epilepsy, narcolepsy, schizo-
phrenia, or dementia.7
The first selective H3-receptor antagonist, thioper-
amide,8 which has become a useful tool for the phar-
macological investigation of H3-receptors, does not
appear to be suitable for clinical studies because of
hepatotoxicity that is probably related to its thiourea
group (Chart 1). Similar drawbacks are likely to occur
with the isothiourea derivative clobenpropit9 which is
more active than thioperamide in vitro but less effective
in vivo presumably as a consequence of limited bioavail-
ability (cf. Table 1). To circumvent the toxicological and
bioavailability problems at H3-receptors, a number of
histamine H3-receptor antagonists that are devoid of
sulfur-containing functionalities were developed, e.g.,
amides, carbamates, esters, ethers, guanidines, het-
eroaryl compounds,7 and less polar alkynes derived from
the marine natural product verongamine.10
The aim of the present study was to design potent
histamine H3-receptor antagonists that exhibit im-
proved oral bioavailability and brain penetration and
lack potentially toxic sulfur-containing functionalities.
The current research focused on imidazolylpropyl ethers
because their potency was clearly pointed out in previ-
ous studies. In particular, the para-iodinated benzylic
ether iodoproxyfan was selected for radiolabeling from
a series of recently described aliphatic imidazolylalkyl
ethers due to its in vitro potency and selectivity (Chart
1).6,11 In an attempt to explore structure-activity
relationships of H3-receptor ligands, Ganellin et al.
reported aromatic imidazolylalkyl ethers to be potent
H3-receptor antagonists that provide high in vitro
activity at H3-receptors.12 Thus, para-substituted phen-
yl ether derivatives such as 4-cyanophenyl 3-(1H-
imidazol-4-yl)propyl ether (UCL 1390; Chart 1) served
as lead compounds in the search for novel antagonists.
To obtain selective, orally active, and centrally pene-
trating H3-receptor antagonists, we introduced alkynyl
moieties in the para-position of phenyl ether derivatives
of 3-(1H-imidazol-4-yl)propanol. The synthetical ap-
proach and pharmacological evaluation of those 4-alky-
nylphenyl ethers are presented, all of which were
screened for their in vitro and in vivo H3-receptor
* To whom correspondence should be addressed.
§ Freie Universita¨t Berlin.
† Laboratoire Bioprojet.
‡ Centre Paul Broca de l’INSERM.
S0022-2623(98)00297-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 09/18/1998

4172 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
Sch em e 1. Synthetic Pathways To Obtain 4-Alkynylphenols 10a -ea
a
(i) PCl5, benzene, 24 h at ambient temperature; (ii) t-BuOK, 18-crown-6, C6H12, 0 °C f reflux, 3 h; (iii) Me3SiBr or Me3SiI, CH2Cl2,
48 h at ambient temperature f 50 °C, 30 min, MeOH/H2O; (iv) EtSNa, DMF, reflux, 1 h; (v) MomCl, Et3N, Et2O, 48 h at ambient
temperature; (vi) HCtCR, PdIICl2(PPh3)2, CuI, Et3N, 1 h at ambient temperature; (vii) EtSNa, DMF, reflux, 1 h; (viii) HCl, MeOH, THF,
24 h at ambient temperature; (ix) Me3SiCl, Et3N, Et2O, reflux, 18 h; (x) Me3SiCtCMe, (η3-C3H5PdIICl)2, TBAF, THF, ambient temperature
f 50 °C, 15 min; (xi) identified by TLC but not isolated due to instability.
antagonist activity as well as for their H3-receptor
selectivity versus H1- and H2-receptors.
giving the corresponding ketones 1a ,b. In contrast to
4-propynylphenol (10b) the ethynyl analogue 10a was
found to be too labile to be isolated from solution due to
polymerization, although its formation was clearly
proved by means of TLC.
Ch em istr y
The classical route to prepare aromatic alkynes 8a ,b
proceeds from aromatic ketones 1a ,b which are con-
verted to gem-dichlorides 2a ,b by treatment with PCl5
(Scheme 1). â-Elimination of HCl may follow, and
vinylic chlorides 3a ,b are frequent side products. The
CtC triple bond formation is accomplished by succes-
sive dehydrohalogenation in the presence of potassium
tert-butanolate. Although this method was optimized
by means of phase-transfer catalysis as recently re-
ported,13 the alkynes 8a ,b were obtained with overall
yields of only about 20%. Cleavage of the phenol
protecting methyl ether was finally achieved by treat-
ment with sodium ethanethiolate in refluxing dimeth-
ylformamide14 because the procedure with trimethysilyl
bromide or iodide15 led to hydration of the triple bond
An efficient and mild alternative route is provided by
arylation of alkynes, known as the Heck reaction,16
which was achieved by treatment with an ”arylpalla-
dium” reagent (Scheme 1). The latter was generated
in situ by treatment of an aryl iodide (5, 6) with a
palladium(II)-triphenylphosphine complex in the pres-
ence of triethylamine and cuprous(I) iodide as cocata-
lyst.17 The reaction was facilitated by cuprous(I) iodide
so that it was completed after 30 min at room temper-
ature. Subsequent cleavage of the protecting groups,
either methyl or methoxymethyl (Mom),18 yielded the
stable internal alkynes 10c,d . As the trimethysilyl
protecting group of 9e was not stable under the hydro-
lytic conditions used,19 the labile terminal 4-alkynylphe-

Notes
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4173
Sch em e 2. Synthesis of 4-Alkynylphenyl Ethers 14a
Even desilylation of the alkyne 13e, which was expected
to occur quantitatively under these conditions, came
about just partially so that not only the unprotected
target compound 4-ethynylphenyl 3-(1H-imidazol-4-yl)-
propyl ether (14a ) was obtained (60% yield) but also its
trimethylsilyl-protected analogue 14e (30% yield), sepa-
ration of which was performed by means of column
chromatography.
P h a r m a cologica l Resu lts a n d Discu ssion
In Vitr o Testin g. The presented compounds were
tested for their antagonist potency at H3-receptors in
an assay with K+-evoked [3H]histamine release from
synaptosomes of rat cerebral cortex.23
The novel 4-alkynylphenyl ethers 14 show moderate
to high H3-receptor antagonist potency, which was found
to be dependent on the residue of the aromatic alkyne
(Table 1). The terminal alkyne 14a is the most potent
compound of this series, whereas substitution of the
aromatic alkyne decreased antagonist activity. It is
assumed that the affinity to H3-receptors is reduced
most likely due to steric effects as the methyl group in
14b led only to a slight decrease in potency as compared
to the bulkier propyl (14c), tert-butyl (14d ), and tri-
methylsilyl (14e) groups, respectively. The ethynyl
derivative 14a , however, which has a -log Ki value of
8.6 appears to be even more potent than the standard
H3-receptor antagonist thioperamide (-log Ki ) 8.4).8
The pronounced in vitro potency of 14a was further
substantiated in a functional H3-receptor assay on the
guinea pig ileum,6 in which it acts as a competitive
antagonist displaying a pA2 value of 8.1 ( 0.15 (xj (
SEM, n ) 16).
a
(i) Boc2O, MeCN, Et3N, dioxane, H2O, DMAP, 2 h at ambient
temperature; (ii) PPh3, DEAD, THF, 72 h at ambient temperature;
(iii) NH3, MeOH, 6 h at ambient temperature; (iv) H2NNH2,
MeOH, 30 min at ambient temperature.
nol 10a was formed instead of 10e but could not be
isolated as mentioned above.
Synthesis of the desired trimethylsilyl-protected alkyne
10e was accomplished by Heck reaction using trimeth-
ylsilyl-protected 4-iodophenol (7) as substrate (Scheme
1). During the reaction the trimethylsilyl protecting
group of the phenol was cleaved, hence giving 10e
almost quantitatively in a tandem reaction.
Although gaseous propyne could have been used
effectively under these conditions, the Heck reaction did
not seem to be attractive for the synthesis of 10b due
to its problematic utilization. However, the fluoride-
mediated cross-coupling reaction of trimethylsilylpro-
pyne with 4-iodoanisole yielding 8b is an efficient
alternative to dehydrohalogenation (Scheme 1).20 Al-
though this cross-coupling reaction was reported to be
highly chemoselective in the presence of an unprotected
hydroxy group, we found protection of the phenol to be
essential because coupling of 4-iodophenol (4) failed to
give 10b. Compound 8b was deprotected by sodium
ethanethiolate in the final stage to give 10b with an
overall yield of 74%.
In Vivo Resu lts on Mice. The in vivo antagonist
activity at H3-receptors was screened in an assay
measuring the effect on brain histamine turnover after
oral application to mice.23
Corresponding to the effects observed in vitro, the
4-ethynylphenyl ether 14a showed improved potency as
compared to the internal alkyne derivatives 14b-e,
which are nevertheless highly effective H3-receptor
antagonists exhibiting about the same potency as thio-
peramide (Table 1). However, the striking CNS activity
following oral administration of 14a is clearly pointed
out by these results as it is approximately 6.5 times
higher on a molar basis than thioperamide. It is even
more potent than any other H3-receptor antagonist
published so far and might thus become a potential
therapeutic agent in neurology or psychiatry.
Scr een in g a t Oth er Hista m in e Recep tor Su b-
typ es. In addition, compounds 14a -e were tested for
their H1-receptor activity on the guinea pig ileum as well
as for their H2-receptor activity on the guinea pig
atrium.24 As a result, all compounds were observed to
be moderately or highly selective for the H3-receptor
versus H1- and H2-receptors, respectively (Table 1).
Particularly the most potent compound (14a ) exhibits
pronounced selectivity for the H3-receptor at a ratio of
approximately 6000/1 vs H1- and 1250/1 vs H2-receptors.
To obtain the desired 4-alkynylphenyl ethers 14, the
phenol precursors 10 were coupled to tert-butoxycarbo-
nyl (Boc)-protected 3-(1H-imidazol-4-yl)propanol (12)21
according to the Mitsunobu protocol (Scheme 2).22 The
Boc protection of the imidazole was readily accom-
plished at ambient temperature by means of di-tert-
butyl dicarbonate in the presence of 4-(N,N-dimethyl-
amino)pyridine. The Boc residue was primarily chosen
as protecting group because the commonly used trityl
group could not be cleaved without affecting the CtC
triple bond, neither hydrolytically under various acidic
conditions nor hydrogenolytically in the presence of
palladium on charcoal. However, cleavage of the Boc
group by methanolic ammonia or hydrazine at ambient
temperature proved to be ideal in this reaction sequence.
Con clu sion s
The presented 4-alkynylphenyl ether derivatives of
3-(1H-imidazol-4-yl)propanol were prepared in a mild
and convenient synthetic route providing almost quan-

4174 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
Ta ble 1. Chemical Data and Pharmacological Results of Screening for Histamine H3-Receptor Antagonist Activity and Selectivity
in vivo
in vitro
-log K
a
ED50 (mg kg-1
)
Kib (nM)
compd
R
yield (%) mpc (°C)
formula
Mr
xj ( SEM
xj ( SEM H3
H2
H1
b
d
e
14a
14b
14c
14d
14e
H
Me
Pr
t-Bu
SiMe3
60f
87
85
150
137
126
132
126
C14H14N2O‚C4H4O4‚0.25H2O
346.9
365.4
388.9
407.5
0.12 ( 0.07
1.3 ( 0.4
2.2 ( 0.9
2.2 ( 0.3
1.1 ( 0.3
1.0 ( 0.5g
26 ( 7i
2.3 ( 0.8
7.5 ( 1.2
140 ( 58
123 ( 17
36 ( 15
8.6 <4.8 <5.5
8.1 <4.7 <5.0
6.9 <4.7 <5.9
6.9 <4.6 <5.6
7.4 <4.6 <5.0
C
C
C
15H16N2O‚C4H4O4‚0.5H2O
17H20N2O‚C4H4O4‚0.25H2O
18H22N2O‚C4H4O4‚0.5H2O
95
30f
C17H22N2OSi‚C4H4O4‚0.75H2O 428.1
thioperamide
clobenpropit
4 ( 1h
0.6 ( 0.1j
a
b
In vivo screening on central H3-receptor activity after po application to mice.23 ED50 values expressed in mg of base kg-1
.
Functional
H3-receptor test in vitro on synaptosomes of rat cerebral cortex.23 c Crystallization solvent: Et2O/EtOH. Functional H2-receptor test on
d
guinea pig atrium.24 e Functional H1-receptor test on guinea pig ileum.24 f Compounds 14a ,e obtained from a single experiment. g Reference
h
i
j
12. Reference 8. Reference 11. Reference 6.
°C followed by an additional 3 h under reflux. After the
mixture was hydrolyzed on ice, the organic layer was sepa-
rated, washed (H2O), dried (MgSO4), and evaporated. The
resulting product was subjected to column chromatography
[eluent: CH2Cl2 (25%), light petroleum (75%)] to afford the
title compound as an oil which was crystallized from light
titative yields in each step, except for compounds 14a ,e
which were obtained together from a single experiment.
In vitro studies proved their H3-receptor antagonist
potency and selectivity for H3-receptors versus H1- and
H2-receptors. Furthermore, the new compounds display
high oral CNS activity with particularly the terminal
alkyne being 6.5 times more active on a molar basis
than thioperamide and more effective than any other
H3-receptor antagonist published to date. Although
increasing substitution of the alkyne reduced both in
vitro and in vivo activity, the internal alkynes proved
to be almost equipotent with thioperamide. These data
clearly indicate the efficacy of the structural modifica-
tions applied. Furthermore, the (trimethylsilyl)ethynyl
derivative 14e is, to our knowledge, the first compound
containing a silyl moiety which shows H3-receptor
antagonist activity.
1
petroleum (yield, 1.5 g, 25%): mp 29 °C; H NMR (CDCl3) δ
7.42 (d, J ) 8.7 Hz, 2H, Ph-2-H, Ph-6-H), 6.83 (d, J ) 8.7 Hz,
2H, Ph-3-H, Ph-5-H), 3.81 (s, 1H, Me), 2.99 (s, 1H, CtCH);
MS m/z 132 (M•+, 100), 117 (27), 89 (26); IR (KBr) ν˜ 3287 (s,
CtC-H), 2959 (m, C-H), 2838 (m, C-H), 2105 (m, CtC),
1605 (s, CdC), 1570 (w, CdC), 1507 (s, CdC). Anal. (C9H8O‚
0.2H2O) C, H, N.
4-Meth oxy-1-p r op yn ylben zen e (8b).26 Meth od A: Pre-
pared according to 8a (yield, 20%). Meth od B: To a solution
of 4-iodoanisole (5; 10 mmol, 2.34 g) in 40 mL of THF were
subsequently added (trimethylsilyl)propyne (10 mmol, 1.18 g),
TBAF (10 mmol, 2.61 g), and (η3-C3H5PdCl)2 (0.25 mmol, 0.09
g) followed by 15 min of stirring at 50 °C under argon
atmosphere. The cooled mixture was filtered and evaporated
under reduced pressure. The resulting product was purified
as described for 8a (yield, 1.1 g, 75%): mp 22 °C; 1H NMR
(CDCl3) δ 7.32 (d, J ) 8.8 Hz, 2H, Ph-2-H, Ph-6-H), 6.81 (d, J
) 8.8 Hz, 2H, Ph-3-H, Ph-5-H), 3.79 (s, 3H, O-Me), 2.03 (s,
3H, CtC-Me); MS m/z 146 (M•+, 43), 131 (18), 111 (100), 90
(22); IR (KBr) ν˜ 2955 (m, C-H), 2850 (m, C-H), 2043 (w, Ct
C), 1607 (s, CdC), 1567 (m, CdC), 1510 (vs, CdC). Anal.
(C10H10O‚0.25H2O) C, H, N.
4-Meth oxy-1-p en tyn ylben zen e (8c). To a solution of
4-iodoanisole (5; 20 mmol, 4.68 g) in 50 mL of Et3N were
subsequently added (PPh3)2PdCl2 (0.2 mmol, 0.14 g), CuI (0.2
mmol, 0.04 g), and pentyne (40 mmol, 2.72 g) followed by
stirring for 1 h at ambient temperature under Ar atmosphere.
The mixture was then filtered, concentrated under reduced
pressure, and subjected to column chromatography (eluent:
light petroleum). The product was obtained as a light-yellow
oil (yield, 3.4 g, 98%): 1H NMR (CDCl3) δ 7.32 (d, J ) 8.8 Hz,
2H, Ph-2-H, Ph-6-H), 6.81 (d, J ) 8.8 Hz, 2H, Ph-3-H, Ph-5-
H), 3.79 (s, 3H, O-Me), 2.36 (t, J ) 7.0 Hz, 2H, CtC-CH2),
1.63 (m, 2H, CH2-Me), 1.04 (t, J ) 7.4 Hz, 3H, CH2-Me); MS
m/z 174 (M•+, 85), 145 (100), 102 (13). Anal. (C12H14O) C, H,
N.
Exp er im en ta l Section
Ch em istr y. Gen er a l P r oced u r es. Melting points were
determined on an Electrothermal IA 9000 digital melting point
apparatus and are uncorrected. 1H NMR spectra were re-
corded on a Bruker AC 300 (300 MHz) spectrometer. Chemical
shifts are expressed in ppm downfield from internal Me4Si as
reference. 1H NMR data are reported in the order: multiplic-
ity (br, broad; s, singlet; d, doublet; t, triplet; m, multiplet; *,
exchangeable by D2O), number of protons, and approximate
coupling constants in hertz. A Finnigan MATCH/A (EI; 170
°C, 70 eV) or a Finnigan MAT CH5DF (FAB+; Xe, Me2SO/
glycerol) mass spectrometer was used. IR spectra were
obtained on a Perkin-Elmer spectrophotometer 297. Elemen-
tal analyses (C, H, N) were measured on a Perkin-Elmer 240
C instrument and were within (0.4% of the theoretical values
unless otherwise indicated. Analytical TLC was performed on
silica gel F254 plates (Merck). Preparative column chromatog-
raphy was carried out using silica gel, 63-200 µm (Merck).
1-Eth yn yl-4-m eth oxyben zen e (8a).25 A solution of 4-meth-
oxyphenylethanone (1a ; 50 mmol, 7.51 g) in 10 mL of benzene
was added to a suspension of PCl5 (50 mmol, 10.43 g) in 100
mL of benzene. The mixture was stirred for 24 h at ambient
temperature, hydrolyzed on ice, and extracted with light
petroleum (bp 50-70 °C). The organic layer was washed (H2O,
NaHCO3, H2O), dried (MgSO4), and evaporated to dryness. The
resulting oil (2a ; 44 mmol, 9.0 g) was dissolved in 40 mL of
cyclohexane and cooled in an ice bath. Then t-BuOK (88 mmol,
9.87 g) and 18-crown-6 (0.09 mmol, 23 mg) were added at 0-5
1-(3,3-Dim eth ylbu tyn yl)-4-m eth oxyben zen e (8d ): pre-
pared according to 8c; crystallized from light petroleum (yield,
1
93%); mp 39 °C; H NMR (CDCl3) δ 7.32 (d, J ) 8.8 Hz, 2H,
Ph-2-H, Ph-6-H), 6.79 (d, J ) 8.8 Hz, 2H, Ph-3-H, Ph-5-H),
3.78 (s, 3H, O-Me), 1.30 (s, 9H, t-Bu); MS m/z 188 (M•+, 81),
175 (100), 160 (21), 133 (11), 115 (15). Anal. (C13H16O) C, H,
N.

Notes
4-(Meth oxym eth oxy)-1-p en tyn ylben zen e (9c): prepared
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21 4175
3-H, Ph-5-H), 6.07 (s, 2H, Mal), 4.06 (m, 3H, O-CH2, CH), 2.82
(t, J ) 7.4 Hz, 2H, Im-CH2), 2.09 (m, 2H, Im-CH2-CH2); MS
m/z 226 (M•+, 12), 209 (1), 153 (1), 109 (100), 82 (36). Anal.
(C14H14N2O‚C4H4O4‚0.25H2O) C, H, N.
according to 8c (yield, 98%); oil; 1H NMR (CDCl3) δ 7.32 (d, J
) 8.7 Hz, 2H, Ph-2-H, Ph-6-H), 6.94 (d, J ) 8.7 Hz, 2H, Ph-
3-H, Ph-5-H), 5.16 (s, 2H, O-CH2), 3.47 (s, 3H, O-Me), 2.36 (t,
J ) 7.0 Hz, 2H, CtC-CH2), 1.61 (m, 2H, CH2-Me), 1.04 (t, J
) 7.4 Hz, 3H, CH2-Me); MS m/z 204 (M•+, 43), 145 (11), 45
(100). Anal. (C13H16O2) C, H, N.
3-(1H -Im id a zol-4-yl)p r op yl 4-P r op yn ylp h en yl E t h er
(14b). Triphenylphosphine (6 mmol, 1.57 g) was dissolved in
20 mL of THF under N2 atmosphere together with 12 (5 mmol,
1.13 g) and 10c (5 mmol, 0.80 g) and cooled in an ice bath.
Then diethyl azodicarboxylate (6 mmol, 0.95 mL) was added
dropwise followed by additional stirring for 72 h at ambient
temperature. Evaporation under reduced pressure and puri-
fication by column chromatography (eluent: EtOAc) afforded
the Boc-protected product 13b which was deprotected by
stirring in 25 mL of methanolic NH3 (10%) at ambient
temperature for 6 h. The residue was concentrated under
reduced pressure and subjected to column chromatography
[eluent: CH2Cl2 (90%), MeOH (10%)] to give the title com-
pound as an oil, which was crystallized as hydrogen maleate
from EtOH/Et2O: 1H NMR (Me2SO-d6) δ 8.88 (s, 1H, Im-2-
H), 7.42 (s, 1H, Im-5-H), 7.30 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-
6-H), 6.87 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.04 (s, 2H,
Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.78 (t, J ) 7.5 Hz, 2H,
Im-CH2), 2.06 (m, 2H, Im-CH2-CH2), 2.00 (s, 3H, Me); MS m/z
240 (M•+, 16), 158 (100), 109 (100), 82 (23). Anal. (C15H16N2O‚
C4H4O4‚0.5H2O) C, H, N.
1-(3,3 -Dim e t h ylb u t yn yl)-4 -(m e t h oxym e t h oxy)b e n -
zen e (9d ): prepared according to 8c (yield, 98%); oil; 1H NMR
(CDCl3) δ 7.31 (d, J ) 8.8 Hz, 2H, Ph-2-H, Ph-6-H), 6.93 (d, J
) 8.8 Hz, 2H, Ph-3-H, Ph-5-H), 5.16 (s, 2H, CH2), 3.46 (s, 3H,
O-Me), 1.30 (s, 9H, t-Bu); MS m/z 218 (M•+, 49), 203 (10), 173
(27), 45 (100). Anal. (C14H18O2‚0.2H2O) C, H, N.
4-(Met h oxym et h oxy)-1-[(t r im et h ylsilyl)et h yn yl]b en -
zen e (9e): prepared according to 8c (yield, 79%); oil; 1H NMR
(CDCl3) δ 7.39 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-6-H), 6.95 (d, J
) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 5.17 (s, 2H, CH2), 3.47 (s, 3H,
O-Me), 0.24 (s, 9H, Si-Me3); MS m/z 234 (M•+, 41), 219 (15),
189 (17), 130 (25), 45 (100). Anal. (C13H18O2Si) C, H, N.
4-P r op yn ylp h en ol (10b). A solution of 8b (20 mmol, 3.0
g) in 100 mL of DMF was heated together with EtSNa (50
mmol, 4.21 g) under reflux for 1 h. The resulting suspension
was then concentrated under reduced pressure, extracted with
CH2Cl2, filtered, and evaporated again. Column chromatog-
raphy (eluent: CH2Cl2) afforded the title compound as a light-
yellow oil (yield, 2.67 g, 98%): 1H NMR (CDCl3) δ 7.27 (d, J )
8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.81 (d, J ) 8.6 Hz, 2H, Ph-2-H,
3-(1H -Im id a zol-4-yl)p r op yl 4-p en t yn ylp h en yl et h er
(14c): prepared according to 14b; crystallized as hydrogen
1
Ph-6-H), 5.22 (br*, 1H, OH), 2.02 (s, 3H, Me); MS m/z 132 (M•+
100), 103 (18). Anal. (C9H8O‚0.8H2O) C, H, N.
,
maleate from EtOH/Et2O; H NMR (Me2SO-d6) δ 8.89 (s, 1H,
Im-2-H), 7.43 (s, 1H, Im-5-H), 7.30 (d, J ) 8.6 Hz, 2H, Ph-2-
H, Ph-6-H), 6.87 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.05 (s,
2H, Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.79 (t, J ) 7.4 Hz,
2H, Im-CH2), 2.36 (t, J ) 7.0 Hz, 2H, CtC-CH2), 2.06 (m,
2H, Im-CH2-CH2), 1.53 (m, 2H, CH2-Me), 0.98 (t, J ) 7.3 Hz,
3H, Me); MS m/z 268 (M•+, 13), 131 (6), 109 (100), 82 (14). Anal.
(C17H20N2O‚C4H4O4‚0.25H2O) C, H, N.
4-P en tyn ylp h en ol (10c). Meth od A: Prepared according
to 10b (yield, 98%). Meth od B: To a solution of 9c (10 mmol,
2.04 g) in 20 mL of THF was added 5 mL of 10% methanolic
HCl followed by stirring at ambient temperature for 24 h.
Removal of the solvent under reduced pressure and purifica-
tion by column chromatography (eluent: CH2Cl2) afforded the
product as a light-yellow oil (yield, 1.52 g, 95%): 1H NMR
(CDCl3) δ 7.27 (d, J ) 8.7 Hz, 2H, Ph-3-H, Ph-5-H), 6.74 (d, J
) 8.7 Hz, 2H, Ph-2-H, Ph-6-H), 4.99 (s*, 1H, OH), 2.36 (t, J )
7.0 Hz, 2H, CtC-CH2), 1.61 (m, 2H, CH2-Me), 1.04 (t, J )
7.3 Hz, 3H, CH2-Me); MS m/z 160 (M•+, 79), 131 (100). Anal.
(C11H12O‚0.25H2O) C, H, N.
4-(3,3-Dim eth ylbu tyn yl)p h en ol (10d ). Meth od A: Pre-
pared according to 10b (yield, 95%). Meth od B: Prepared
according to 10c (yield, 90%); crystallized from light petroleum;
mp 90 °C; 1H NMR (CDCl3) δ 7.26 (d, J ) 8.6 Hz, 2H, Ph-3-H,
Ph-5-H), 6.73 (d, J ) 8.6 Hz, 2H, Ph-2-H, Ph-6-H), 4.86 (br*,
1H, OH), 1.30 (s, 9H, t-Bu); MS m/z 174 (M•+, 57), 159 (100),
144 (13). Anal. (C12H14O) C, H, N.
4-(3,3-Dim et h ylbu t yn yl)p h en yl 3-(1H -im id a zol-4-yl)-
p r op yl eth er (14d ): prepared according to 14b; crystallized
as hydrogen maleate from EtOH/Et2O; 1H NMR (Me2SO-d6) δ
8.90 (s, 1H, Im-2-H), 7.43 (s, 1H, Im-5-H), 7.27 (d, J ) 8.7 Hz,
2H, Ph-2-H, Ph-6-H), 6.87 (d, J ) 8.7 Hz, 2H, Ph-3-H, Ph-5-
H), 6.06 (s, 2H, Mal), 4.01 (t, J ) 6.1 Hz, 2H, O-CH2), 2.80 (t,
J ) 7.5 Hz, 2H, Im-CH2), 2.07 (m, 2H, Im-CH2-CH2), 1.27 (s,
9H, t-Bu); MS m/z 282 (M•+, 14), 267 (4), 159 (7), 109 (100), 82
(11). Anal. (C18H22N2O‚C4H4O4‚0.5H2O) C, H, N.
3-(1H-Im id a zol-4-yl)p r op yl 4-[(Tr im eth ylsilyl)eth yn yl]-
p h en yl Eth er (14e). This was prepared according to 14b.
The Boc-protected product 13e was deprotected by stirring in
25 mL of methanolic hydrazine solution (10%) at ambient
temperature for 30 min. The residue was concentrated under
reduced pressure and subjected to column chromatography
[eluent: CH2Cl2 (90%), MeOH (10%)] to separate the title
compound from 14a giving it as an oil which was crystallized
as hydrogen maleate from EtOH/Et2O: 1H NMR (Me2SO-d6)
δ 8.86 (s, 1H, Im-2-H), 7.42 (m, 3H, Im-5-H, Ph-2-H, Ph-6-H),
6.93 (d, J ) 8.5 Hz, Ph-3-H, Ph-5-H), 6.06 (s, 2H, Mal), 4.06
(t, 2H, O-CH2), 2.81 (t, J ) 7.3 Hz, 2H, Im-CH2), 2.09 (m, 2H,
Im-CH2-CH2), 0.23 (s, 9H, Si-Me3); MS m/z 298 (M•+, 6), 283
(3), 175 (5), 147 (4), 109 (100), 82 (23); IR (KBr) ν˜ 3432 (br),
3141 (m), 2957 (m, C-H), 2877 (m, C-H), 2155 (w, CtC), 1574
(vs, CdC), 1510 (vs, CdC). Anal. (C17H22N2OSi‚C4H4O4‚
0.75H2O) C, N; H: calcd, 6.48; found, 6.04.
4-[(Tr im eth ylsilyl)eth yn yl]p h en ol (10e): prepared from
(4-iodophenoxy)trimethylsilane (7) according to 8c; crystallized
from light petroleum (yield, 85%); mp 68 °C; 1H NMR (CDCl3)
δ 7.33 (d, J ) 8.6 Hz, 2H, Ph-3-H, Ph-5-H), 6.72 (d, J ) 8.6
Hz, 2H, Ph-2-H, Ph-6-H), 5.43 (br*, 1H, OH), 0.23 (s, 9H, Si-
Me3); MS m/z 190 (M•+, 31), 175 (100), 116 (13). Anal. (C11H14
-
OSi) C, H, N.
4-(3-Hyd r oxyp r op yl)-1H-im id a zole-1-ca r boxylic Acid
1,1-Dim eth yleth yl Ester (12).27 3-(1H-Imidazol-4-yl)pro-
panol (11; 10 mmol, 3.7 g)11 was dissolved in 20 mL of MeCN
and 5 mL of dioxane/H2O (1:1). After addition of 5 mL of Et3N,
DMAP (1 mmol, 0.12 g), and Boc2O (12 mmol, 2.62 g), the
solution was stirred at ambient temperature for 2 h followed
by evaporation to dryness. The residue was subjected to
column chromatography [eluent: CH2Cl2 (90%), MeOH (10%)]
to give the title compound as an oil which crystallized at 4 °C
(yield, 2.21 g, 97%): mp 76-78 °C; 1H NMR (Me2SO-d6) δ 8.08
(s, 1H, Im-2-H), 7.21 (s, 1H, Im-5-H), 4.47 (t, J ) 5.1 Hz, 1H,
OH), 3.43 (m, 2H, O-CH2), 2.50 (t, J ) 7.7 Hz, 2H, Im-CH2),
1.71 (m, 2H, Im-CH2-CH2), 1.56 (s, 9H, t-Bu); MS m/z (FAB+)
227 (M + H•+, 17), 171 (81), 127 (40), 109 (15), 81 (11). Anal.
(C11H18N2O3‚0.5H2O) C, H, N.
P h a r m a cology. Gen er a l Meth od s: Hista m in e H3-Re-
cep tor Assa y on Syn a p tosom es fr om Ra t Cer ebr a l Cor -
tex. The new compounds were tested for their H3-receptor
antagonist activity at least in triplicate in an assay with K+-
evoked depolarization-induced release of [3H]histamine from
synaptosomes according to Garbarg et al.23
Hista m in e H3-Recep tor An ta gon ist Activity in Vivo in
Mou se. In vivo testing of all compounds was performed at
least in triplicate after oral administration to Swiss mice as
described by Garbarg et al.23
4-Eth yn ylph en yl 3-(1H-im idazol-4-yl)pr opyl eth er (14a):
for preparation see 14e; crystallized as hydrogen maleate from
In Vitr o Scr een in g a t Oth er Hista m in e Recep tor s. All
compounds were screened in duplicate for histamine H2-recep-
tor activity at isolated spontaneously beating guinea pig right
1
EtOH/Et2O; H NMR (Me2SO-d6) δ 8.89 (s, 1H, Im-2-H), 7.42
(m, 3H, Im-5-H, Ph-2-H, Ph-6-H), 6.94 (d, J ) 8.4 Hz, 2H, Ph-

4176 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 21
Notes
(12) Ganellin, C. R.; Fkyerat, A.; Bang-Andersen, B.; Athmani, S.;
Tertiuk, W.; Garbarg, M.; Ligneau, X.; Schwartz, J .-C. A Novel
Series of (Phenoxyalkyl)imidazoles as Potent H3-Receptor His-
tamine Antagonists. J . Med. Chem. 1996, 39, 3806-3813.
(13) Dehmlow, E. V.; Lissel, M. Preparation of Alkynes from Alkyl
Halides with Solid Potassium tert.-Butoxide and Crown Ether.
Liebigs Ann. Chem. 1980, 1-13.
atrium as well as for H1-receptor activity at isolated guinea
pig ileum by standard methods described by Hirschfeld et al.24
Ack n ow led gm en t. We greatly acknowledge the gift
of 3-(1-trityl-1H-imidazol-4-yl)propanol kindly provided
by Dr. J .-M. Lecomte (Bioprojet, Paris, France). This
work was supported by the Biomedical Health and
Research Programme of the European Community and
by the Verband der Chemischen Industrie, Fonds der
Chemischen Industrie (Frankfurt/Main, Germany).
(14) Feutrill, G. I.; Mirrington, R. N. Demethylation of Aryl Methyl
Ethers with Thioethoxide Ion in Dimethyl Formamide. Tetra-
hedron Lett. 1970, 1327-1328.
(15) J ung, M. E.; Lyster, M. A. Quantitative Dealkylation of Alkyl
Ethers via Treatment with Trimethylsilyl Iodide. A New Method
for Ether Hydrolysis. J . Org. Chem. 1977, 42, 3761-3764.
(16) Dieck, H. A.; Heck, F. R. Palladium Catalyzed Synthesis of Aryl,
Heterocyclic and Vinylic Acetylene Derivatives. J . Organomet.
Chem. 1975, 93, 259-263.
(17) Sonogashira, K.; Tohda, Y.; Hagihara, N. A Convenient Synthesis
of Acetylenes: Catalytic Substitutions of Acetylenic Hydrogen
with Bromoalkenes, Iodoarenes, and Bromopyridines. Tetrahe-
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(18) Rall, G. J . H.; Oberholzer, M. E.; Ferreira, D.; Roux, D. G. Crown
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(19) Takahashi, S.; Kuroyama, Y.; Sonogashira, K.; Hagihara, N. A
Convenient Synthesis of Ethynylarenes and Diethynylarenes.
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(21) Grehn, L.; Ragnarsson, U. A Convenient Method for the Prepa-
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(22) Mitsunobu, O. The Use of Diethyl Azodicarboxylate and Tri-
phenylphosphine in Synthesis and Transformation of Natural
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(23) Garbarg, M.; Arrang, J .-M.; Rouleau, A.; Ligneau, X.; Dam Trung
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