Design, synthesis, and structure-activity relationships of acetylene- based histamine H3 receptor antagonists

Article abstract of DOI:10.1021/jm980310g

New, potent, and selective histamine H₃ receptor antagonists have been synthesized by employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss operational scheme for side-chain substitution for optimizing the hydrophobic domain. Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas 26-31 are analogues prepared by incorporation of the trans-(±)-cyclopropane at the C-4 position of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S,2S)-cyclopropyl enantiomers of the most potent racemic compound 31 (K(i) = 0.33 ± 0.13 nM) demonstrated a stereopreference in H₃ receptor binding affinity for the (1R,2R) enantiomer 32 (K(i) = 0.18 ± 0.04 nM) versus the (1S,2S) enantiomer 33 (K(i) = 5.3 ± 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)-imidazole (32) is one of the most potent histamine H₃ receptor antagonists reported to date.

Full text of DOI:10.1021/jm980310g

J . Med. Chem. 1999, 42, 903-909
903
Design , Syn th esis, a n d Str u ctu r e-Activity Rela tion sh ip s of Acetylen e-Ba sed
Hista m in e H3 Recep tor An ta gon ists
Syed M. Ali,* Clark E. Tedford, Rosilyn Gregory, Michael K. Handley, Stephen L. Yates, Walter W. Hirth, and
J ames G. Phillips
Gliatech Inc., 23420 Commerce Park Road, Cleveland, Ohio 44122
Received May 18, 1998
New, potent, and selective histamine H3 receptor antagonists have been synthesized by
employing the use of (1) an appropriately positioned nonpolar acetylene spacer group, (2) either
a two-carbon straight chain linker or a conformationally restricting trans-cyclopropane ring
between the C-4 position of an imidazole headgroup and the acetylene spacer, and (3) a Topliss
operational scheme for side-chain substitution for optimizing the hydrophobic domain.
Compounds 9-18 are examples synthesized with the two-carbon straight chain linker, whereas
26-31 are analogues prepared by incorporation of the trans-(()-cyclopropane at the C-4 position
of an imidazole headgroup. Synthesis of both the (1R,2R)- and (1S,2S)-cyclopropyl enantiomers
of the most potent racemic compound 31 (Ki ) 0.33 ( 0.13 nM) demonstrated a stereopreference
in H3 receptor binding affinity for the (1R,2R) enantiomer 32 (Ki ) 0.18 ( 0.04 nM) versus the
(1S,2S) enantiomer 33 (Ki ) 5.3 ( 0.5 nM). (1R,2R)-4-(2-(5,5-Dimethylhex-1-ynyl)cyclopropyl)-
imidazole (32) is one of the most potent histamine H3 receptor antagonists reported to date.
Ch a r t 1
In tr od u ction
The discovery of the existence of a third type of
histamine receptor,1 the H3 receptor, and the develop-
ment of the subtype-selective agonist, (R)-R-methylhis-
tamine, and antagonist, thioperamide, have stimulated
a heightened interest in exploring the role of histamine
as a neurotransmitter.2 The histamine H3 receptor was
originally characterized as a presynaptic autoreceptor
that controls the synthesis and release of histamine.3
Thus, on histaminergic neurons at the presynaptic site,
activation of H3 receptors leads to an inhibition of
histamine synthesis from L-histidine and an inhibition
of histamine release. Contrarily, administration of the
H3 antagonist, thioperamide, has been shown to lead
to an increase in histamine levels in the rat anterior
hypothalamus, as determined by microdialysis.4
Evidence has since accumulated regarding the colo-
calization of modulating H3 heteroreceptors on seroton-
ergic,5 cholinergic,6 noradrenergic,7 dopaminergic,8 and
peptidergic9 neurons. The abundant distribution of H3
receptors in the central nervous system (CNS) and the
detection of histamine H3 heteroreceptors on entero-
chromaffin-like cells of rat stomach,10 as well as on
lung11 and cardiac tissues,12 have brought consideration
of the H3 receptor as significantly important in the con-
certed regulation of various (patho)physiological pro-
cesses.
Most pharmacological studies concerning antagonist
ligand modulation of the H3 receptor have focused on
the potential use of these agents in the treatment of
CNS disorders. Thioperamide (1) (Chart 1), the first
selective histamine H3 antagonist, has been shown to
have wake-promoting, arousal, and antiepileptic prop-
erties.13-15 Medicinal chemistry efforts initiated to
develop new, selective, and potent H3 receptor antago-
nists have focused much of their attention on improving
blood-brain barrier penetration. GT-2016 (2) has been
described as a prototype non-thiourea H3 antagonist
that exhibits good H3 receptor affinity and selectivity,
as well as excellent blood-brain barrier penetration and
dose-dependent increases in histamine release in the
cerebral cortex.16 As an outcome of the many structure-
activity relationship (SAR) efforts in this drug discovery
area, it has been suggested that H3 receptor antagonists
exhibit three common and essential structural fea-
tures: imidazole headgroup, spacer, and hydrophobic
tail group.17-19 These features are illustrated for GR-
175737 (3),20 clobenpropit (4),21 and the less potent
antagonist verongamine (5)22 (Chart 2).
The approach that we took to develop new, selective,
and potent H3 antagonists with good blood-brain bar-
rier penetration differs in several ways from previous
studies and is the subject of this full account of our
preliminary communication.23 First, an investigation of
the effect of using a nonpolar and linear acetylene
moiety as a spacer group was undertaken. A variety of
polar spacer groups such as amides, thioamides,
guanidines, ureas, thioureas, esters, carbamates, and
thiocarbamates have been shown to have utility for
synthesizing potent H3 antagonists. Second, we exam-
ined the outcome of replacing the two-carbon straight
chain linking the imidazole headgroup and the spacer,
an integral feature of many histamine-derived antago-
nists (illustrated for 3 and 5), with a conformationally
restricting trans chiral cyclopropane ring. The use of the
trans-cyclopropane linker can provide compounds that
can have either a (1R,2R) or (1S,2S) configuration.
10.1021/jm980310g CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/20/1999

904 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Ali et al.
Ch a r t 2
Sch em e 2a
a
(a) n-BuLi-TMEDA, R-I, 55 °C, 24-36 h; (b) 1 N HCl, 90 °C,
1 h.
Sch em e 3a
Sch em e 1a
a
(a) LiAlH4 (1.5 equiv), THF, 0 °C, 1.5 h; (b) Swern oxidation,
77% (two steps); (c) CBr4, Ph3P, CH2Cl2, 3 h, 90%; (d) n-BuLi (4
equiv), THF, 2.5 h, 92%.
Ch a r t 3
a
(a) PPh3, CBr4, CH2Cl2, 0 °C, 3 h, 90%; (b) n-BuLi (2 equiv),
THF, -78 °C, 2.5 h, 91%.
Therefore, the most potent of these derivatives was
prepared in both enantiomeric pure forms in order to
determine if these compounds exhibited different recep-
tor binding affinities due to their opposite stereochem-
ical configuration. Finally, H3 receptor binding affinity
of the new acetylene-containing ligands was optimized
by preparing compounds with aliphatic hydrophobic tail
groups following Topliss tree guidelines.24 Thus, the
SAR studies described herein were determined by in-
dependently modifying the linker and the hydrophobic
tail, keeping the acetylene spacer as a constant.
NaH to generate the carbanion of 8 gave no reaction.
Reactions using n-BuLi in THF, but performed in the
presence of HMPA (1 equiv), gave good yields and
required no heating.
Ch em istr y
The acetylene 8 is prepared in straightforward man-
ner from known aldehyde 6 by standard treatment with
CBr4 and triphenylphosphine to give vinyl dibromide 7
followed by treatment with 2 equiv of n-BuLi at -78
°C to provide 8 (Scheme 1).23 The series of compounds
9-18 (Table 1) containing the two-carbon straight chain
linker between the imidazole headgroup and the acety-
lene spacer was prepared by alkylation of the corre-
sponding acetylene carbanion of 8 with the requisite
aliphatic iodides followed by trityl deprotection (Scheme
2).
The most productive reaction conditions for the alky-
lation of 8 were determined to be generation of the
carbanion of 8 with n-BuLi-TMEDA complex in THF
at -20 °C followed by reaction with 1.5 equiv of aliphatic
iodides at room temperature (1 h) and then at 55 °C for
24-36 h (Scheme 2). Typical yields for these reactions
ranged from 60% to 90% and were very substrate-
dependent. Alkylations using KHMDS, NaHMDS, or
The racemic cyclopropane-containing terminal acety-
lene 22 was used as starting material for the prepara-
tion of the series of compounds 26-31 (Table 2),
containing the cyclopropane bridge between the imida-
zole headgroup and the acetylene spacer. The synthesis
of the key acetylene intermediate 22 (Scheme 3) is
similar to the preparation of its straight chain analogue
8 but proceeds from the racemic mixture of trans-butyl
2-(1-(triphenylmethyl)-1H-imidazol-4-yl)cyclopropane-
carboxylate (19).25 The alkylation reactions with 22 and
subsequent trityl deprotection of products were per-
formed in a fashion similar to that of the straight chain
series. Chiral (1R,2R)-32 and (1S,2S)-33 (Table 2) were
prepared from the corresponding enantiomerically pure
esters 23 and 24 (Chart 3), respectively. These esters
were obtained in gram quantities by resolution of the
racemic mixture 19 using a chiral column.26 The abso-

Acetylene-Based Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 905
Ta ble 1. In Vitro Histamine H3 Receptor Binding Affinities of
Compounds 9-18
Ta ble 2. In Vitro Histamine H3 Receptor Binding Affinities of
Compounds 26-33
compd
R
Ki (nM)
compd cyclopropane config
R
Ki (nM)
9
10
11
12
13
14
15
16
17
18
H
66.3 ( 5.5
79 ( 22
CH2CH3
(CH2)2CH3
26
27
28
29
30
31
32
33
(()-cyclopropyl
(()-cyclopropyl
(()-cyclopropyl
(()-cyclopropyl
(()-cyclopropyl
(()-cyclopropyl
(CH2)2CH3
5.1 ( 0.8
6.5 ( 1.5
1.43 ( 0.3
1.8 ( 1.0
15.9 ( 0.6
0.33 ( 0.13
0.12 ( 0.04
5.3 ( 0.5
27 ( 7.5
3.7 ( 1.1
0.9 ( 0.3
2.9 ( 0.2
3.5 ( 1.0
0.8 ( 0.04
5.6 ( 1.0
2.8 ( 0.7
(CH2)2CH(CH3)2
(CH2)2-cyclo-C5H9
(CH2)2-cyclo-C6H11
(CH2)4C6H5
(CH2)2CH(CH3)2
(CH2)2-cyclo-C5H9
(CH2)2-cyclo-C6H11
(CH2)4C6H5
(CH2)2-tert-butyl
(CH2)4CH3
(CH2)2-tert-butyl
(1R,2R)-cyclopropyl (CH2)2-tert-butyl
(1S,2S)-cyclopropyl (CH2)2-tert-butyl
(CH2)6CH3
lipophilic aromatic or a cycloalkyl substituent.17-19,21,29
However, acetylenic compounds containing longer car-
bon chains and with only alkyl substitution such as 17
and 18 are as potent as 14 and 15 which contain shorter
chains accompanied by cyclohexyl or phenyl substitu-
ents. Interestingly, the unsubstituted terminal acety-
lene 9, which is derived from deprotection of our key
synthetic intermediate 8, shows approximately the same
binding affinity as 10 (66.3 ( 5.5 vs 79 ( 22 nM).
Recently, a new series of H3 receptor antagonists that
contain a chiral cyclopropane bridge as an integral
structural feature has been prepared.28 Therefore, it was
anticipated that cyclopropyl replacement of the two-
carbon straight chain between the imidazole headgroup
and the acetylene spacer in compounds from Table 1
would produce conformationally restricted analogues
that would also exhibit a stereopreference in their
binding affinities for the H3 receptor. Table 2 shows the
H3 receptor binding data for all racemic and chiral
cyclopropyl-containing compounds prepared in this study.
The racemic mixture of compounds 26-31 demonstrates
approximately equipotent H3 receptor binding affinity
in comparison to their straight chain congeners. The
racemic mixture 30 is 4-5 times less potent than 15.
However, the racemic mixtures of cyclopentyl derivative
28 and the tert-butyl analogue 31 have the best activi-
ties within the cyclopropyl series and follow the trend
shown in the straight chain series. Since the racemate
31 exhibited the highest potency, each of the chiral
enantiomers was prepared. The (1R,2R)-cyclopropane
32 (Ki ) 0.18 ( 0.04 nM) was at least 1 order of
magnitude more potent than its (1S,2S) analogue 33 (Ki
) 5.3 ( 0.5 nM). Compound 32 is one of the most potent
H3 receptor antagonists prepared to date. Apparently,
the combination of the (1R,2R) configuration of the
cyclopropyl ring with the nonpolar but linear acetylene
spacer places the tert-butyl-containing hydrophobic tail
in a preferred orientation with the imidazole head-
group.30
lute configurations of the cyclopropane ring of deriva-
tives 23 and 24 were established from the X-ray crystal
structure obtained for sultam derivative 25.27
Resu lts a n d Discu ssion
Our previous SAR studies28 and results obtained by
others17,18 have demonstrated the usefulness of incor-
porating aliphatic hydrocarbon side chains into the
hydrophobic tail. However, for this new series of acety-
lene-containing H3 antagonists, a more systematic ap-
proach was used to maximize our chances of synthesiz-
ing the most potent compounds in this series by
employing a Topliss operational scheme for side-chain
substitution.24 In the straight chain series, compound
10 was chosen as the base compound for these studies.
The rationale for this choice came from molecular
modeling studies which were discussed in a preliminary
account of this work.23 The H3 receptor binding data for
all of the compounds containing a two-carbon straight
chain between the imidazole headgroup and the acety-
lene spacer are reported in Table 1. The base compound
10 had H3 receptor binding affinity of Ki ) 79 ( 22 nM,
whereas its methyl-substituted analogue 11 had a Ki )
27 ( 7.5 nM. On the premise that a +π (hydrophobic)
effect would be the most probable, compounds 12 and
17 were synthesized in which an isopropyl group or a
n-propyl group, respectively, replaced the methyl group
of 11. Both compounds exhibited improvements in
binding affinity with respect to 10 and 11. Because an
increase in activity was observed, the +π branch of the
Topliss tree was followed and the cyclopentyl derivative
13 prepared. This derivative also exhibited improved
binding affinity with a Ki ) 0.95 ( 0.3 nM. As suggested
by Topliss,24 the cyclohexyl and phenethyl analogues 14
and 15 were synthesized. These compounds showed no
improvement in activity and suggested that the opti-
mum hydrophobicity (π factor) had been obtained with
the cyclopentyl substitution in 13.
Since the optimum π value had been obtained with
13, it remained to be determined if activity could be
increased with increasing -σ* values; therefore, ana-
logue 16 was prepared. The bulky tert-butyl substitution
was tolerated quite well, and 16 exhibited a Ki ) 0.8 (
0.1 nM.
Several SAR studies involving the development of new
H3 receptor antagonists have focused on optimizing
receptor affinity by studying the influence of chain
length between a polar spacer group and either a
P h a r m a cology. The H3 antagonist properties of
compounds 13, 14, and 32 were evaluated in vitro for
their ability to block the H3 agonist-induced inhibition
of norepinephrine (NE) release from cardiac synapto-
somes. In this experimental design, an H3 agonist
produces complete blockade of K+-induced NE release
via action at presynaptic H3 heteroreceptors. Coincu-
bation of compound 13, 14, or 32 with an H3 agonist
resulted in complete attenuation of the agonist-induced
modulation of NE release.23,31 Furthermore, compound

906 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Ali et al.
138.9, 137.9, 129.7, 128.1, 118.5, 89.2, 32.5, 25.9. Anal.
(C26H22N2Br2) C, H, N.
32 was also found to attenuate H3 agonist-induced
inhibition of the neurogenic contractions of the isolated
guinea pig jejunum. These studies clearly demonstrate
functional H3 antagonist activity for compounds 13, 14,
and 32.23,31
4-Bu t-3-yn yl-1-(tr ip h en ylm eth yl)im id a zole (8). n-BuLi
(2.5 M in hexane, 50 mL, 0.125 mol) was added to a solution
of 7 (16.0 g, 0.03 mol) in dry tetrahydrofuran (400 mL) at -78
°C. Stirring was continued for 2.5 h, and the mixture was
treated with aqueous saturated solution of ammonium chlo-
ride. The reaction mixture was extracted with ethyl acetate,
and the organic layer was separated, washed with water, and
dried (Na2SO4). Purification by flash column chromatography
(EtOAc/hexanes, 3:8) gave 8 as a solid: 10.0 g (91%); mp 126-
128 °C; 1H NMR (300 MHz, CD3OD) δ 8.83 (s, 1H), 7.42 (s,
1H), 2.95 (t, J ) 6.9 Hz, 2H), 2.60 (dt, J ) 2.4 and 6.9 Hz,
2H), 2.36 (t, J ) 2.4 Hz, 1H); 13C NMR (300 MHz, CDCl3) δ
134.9, 128.9, 117.7, 82.8, 71.6, 24.8, 18.8. Anal. (C26H22N2) C,
H, N.
Gen er a l P r oced u r e for th e Alk yla tion of Acetylen es
8 a n d 22. n-BuLi (2.5 M, 1.3 equiv) was added to TMEDA
(1.3 equiv) at 0 °C. The mixture was stirred at 0 °C for 30 min
and cooled to -20 °C. A 1.0 M solution of acetylene (8 or 22)
(1.0 equiv) in tetrahydrofuran was added to the n-BuLi-
TMEDA complex. After 45 min a solution of alkyl iodide (1.5
equiv) in tetrahydrofuran was added, and the reaction was
stirred at 55 °C for 24-36 h. The reaction mixture was treated
with water and extracted with ethyl acetate. The organic layer
was separated, washed with water, and dried (Na2SO4). The
crude product was purified by flash column chromatography
(EtOAc/hexanes, 1:1) to afford pure products in 60-90% yield.
Syn th esis of (1R,2R)-4-(2-(5,5-Dim eth ylh ex-1-yn yl)cy-
clop r op yl)im id a zole (32) a n d Gen er a l P r oced u r e for th e
Rem ova l of th e Tr ip h en ylm eth yl P r otectin g Gr ou p . A
solution of (1R,2R)-4-(2-(5,5-dimethylhex-1-ynyl)cyclopropyl)-
1-(triphenylmethyl)imidazole (2.5 g, 5.5 mmol) in ethanol (20
mL) and hydrochloric acid (2.0 N, 35 mL) was heated at 85-
90 °C for 20-30 min. The mixture was cooled to room
temperature and filtered. The filtrate was basified (NaHCO3)
and extracted (EtOAc). The organic layer was separated,
washed with water, and dried (Na2SO4). The crude product
was purified by flash column (EtOAc/MeOH, 99:1) and gave
32 as a waxy solid: 1.14 g (96%).
Con clu sion s
New potent and selective classes of histamine H3
receptor antagonists have been identified from SAR
studies that employed the use of (1) a nonpolar acetylene
spacer group, (2) conformationally restricting cyclopro-
pane ring attachment at the C-4 position of an imidazole
headgroup, and (3) a Topliss operational scheme for
side-chain substitution. The combination of acetylene
spacer, trans-cyclopropane ring incorporation, and ali-
phatic hydrophobic side-chain substitution provided a
new series of potent H3 receptor antagonists.
Exp er im en ta l Section
All reagents were obtained from commercial suppliers and
were used without further purification. Solvents used were
either AR or HPLC grade. Thin-layer chromatography was
performed on K6F silica gel 60A. Preparative column chro-
matography was performed on silica gel (230-400 µm) under
pressure. Melting points were obtained on a Fisher-J ohns
melting point apparatus and are uncorrected. 1H and 13C NMR
spectra were recorded on a Varian VXR 300-MHz spectrom-
eter. Chemical shifts are reported in ppm (δ) relative to
internal standard tetramethylsilane. All J values are given
in hertz (Hz). High-resolution (EI) mass spectra were recorded
on a KRATOS MS 50 spectrometer at 70 eV. All compounds
gave correct HRMS. HPLC analysis was performed on a
Perkin-Elmer Quanternary 200 Ic pump using a reverse-phase
column (Phenomenex Prodigy, 5-µm o.d.S(2), 150- × 4.6-mm
i.d.) for compounds 9-18. Compounds 26-33 were analyzed
on a Perkin-Elmer Quanternary 200 Ic pump using a chiral
column (Chiralcel, 10-µm o.d.) polysaccharide type (250- × 4.6-
mm i.d.).
4-Bu t-3-yn ylim id a zole (9). Acetylene 8 (0.15 g) was trityl-
1
deprotected and gave acetylene 9 as an oil: 0.04 g (86%); H
NMR (300 MHz, CD3OD) δ 8.83 (s, 1H), 7.42 (s, 1H), 2.95 (t,
J ) 6.9 Hz, 2H), 2.60 (dt, J ) 2.4 and 6.9 Hz, 2H), 2.36 (t, J
) 2.4 Hz, 1H); 13C NMR (300 MHz, CD3OD) δ 134.9, 128.9,
117.7, 82.8, 71.6, 24.8, 18.8; HRMS (EI) calcd for C7H8N2
120.6875, found 120.069.
4-Hex-3-yn ylim id a zole (10). Acetylene 8 (0.2 g, 0.55
mmol) was treated with iodoethane (0.13 g, 0.83 mmol) and
gave the alkylated acetylene (0.18 g), which was subsequently
trityl-deprotected giving acetylene 10 as an oil: 0.04 g (49%,
overall yield); 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 6.83
(s, 1H), 2.80 (t, J ) 7.2 Hz, 2H), 2.45 (m, 2H), 2.15 (m, 2H),
1.08 (t, J ) 7.2 Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 134.4,
118.0, 82.5, 79.0, 69.0, 26.5, 19.2, 14.2, 12.4; HRMS (EI) calcd
for C9H11N2 (M - 1) 147.09222, found 147.09231.
4-Hep t-3-yn ylim id a zole (11). Acetylene 8 (0.14 g, 0.38
mmol) was treated with iodopropane (0.1 g, 0.57 mmol) and
gave alkylated acetylene (0.13 g), which was trityl-deprotected
and gave the alkylated acetylene 11 as an oil: 0.06 g (87%,
overall yield); 1H NMR (300 MHz, CDCl3) δ 9.33 (brs, 1H), 7.55
(s, 1H), 6.83 (s, 1H), 2.79 (t, J ) 7.2 Hz, 2H), 2.47 (t, J ) 7.2
Hz, 2H), 2.10 (t, J ) 7.2 Hz, 2H), 1.46 (m, 2H), 0.92 (t, J ) 7.2
Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 135.7, 134.4, 117.8,
80.9, 79.6, 26.6, 22.4, 20.7, 19.2, 13.4; HRMS (EI) calcd for
C10H13N2 (M -1)161.10788,found 161.10771.Anal.(C14H18N2O4-
(maleate salt)) C, H, N.
4-(7-Meth yloct-3-yn yl)im id a zole (12). Acetylene 8 (0.21
g, 0.59 mmol) was treated with 1-iodo-3-methylbutane (0.18
g, 0.88 mmol) providing the alkylated acetylene (0.09 g), which
was trityl-deprotected and gave acetylene 12 as an oil: 0.03 g
(25%, overall yield); Rf 0.3 (EtOAc/MeOH, 95:5); 1H NMR (300
MHz, CDCl3) δ 7.55 (s, 1H), 6.82 (s, 1H), 5.96 (brs, 1H), 2.78
(t, J ) 7.2 Hz, 2H), 2.45 (t, J ) 7.2 Hz, 2H), 2.12 (t, J ) 7.5
A representative method for the synthesis of all compounds
is illustrated in General Procedure for the Alkylation of
Acetylenes 8 and 22. Most compounds are oils and turned to
sticky solids at room temperature after a few days.
3-(1-(Tr ip h en ylm eth yl)im id a zol-4-yl)p r op a n a l (6). To
a solution of oxalyl chloride (2.0 M solution, 194 mL, 0.39 mol)
in dichloromethane (300 mL) was added dimethyl sulfoxide
(55 mL, 0.78 mol) dropwise at - 78 °C. The mixture was stirred
at -78 °C for 10 min, and a solution of 3-(1-(triphenylmethyl)-
imidazol-4-yl)propan-1-ol (102 g, 0.28 mol) in dichloromethane
(800 mL) was added. Stirring was continued at -78 °C for 10
min. Triethylamine (155 mL, 1.1 mol) was added and the
reaction brought to room temperature. The organic layer was
separated, washed with water, and dried (Na2SO4). Purifica-
tion by flash column chromatography (EtOAc/hexane, 1:1) gave
1
6 as a white solid: 100 g (99%); mp 94-95 °C; H NMR (300
MHz, CDCl3) δ 9.86 (brt, J ) 1.5 Hz, 1H), 7.45 (m, 10H), 7.20
(m, 6H), 6.65 (s, 1H), 2.99 (m, 4H).
4-(4,4-Dibr om obu t-3-en yl)-1-(tr ip h en ylm eth yl)im id a -
zole (7). Triphenylphosphine (2.59 g, 9.85 mmol) was added
in portions to a 0 °C solution of carbon tetrabromide (2.17 g,
6.56 mmol) in dichloromethane (5 mL). The reaction mixture
was stirred at 0 °C for 20 min. A solution of 6 (1.2 g, 3.28 mmol)
in dichloromethane (5 mL) was added. Stirring was continued
at 0 °C for 3 h and treated with aqueous saturated sodium
bicarbonate solution. The organic layer was separated, washed
with water, and dried (Na2SO4). The crude product was
purified by flash column chromatography (EtOAc/hexane, 1:9)
1
giving 7 as a solid: 1.52 g (90%); mp 115-116 °C; H NMR
(300 MHz, CDCl3) δ 7.41 (s, 1H), 7.33 (m, 9H), 7.12 (m, 6H),
6.54 (s, 1H), 6.34 (t, J ) 7.2 Hz, 1H), 2.67 (t, J ) 7.2 Hz, 1H),
2.42 (dd, J ) 7.2 Hz, 2H); 13C NMR (300 MHz, CDCl3) δ 142.0,

Acetylene-Based Histamine H3 Receptor Antagonists
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5 907
Hz, 2H), 1.37 (m, 1H), 0.85 (d, J ) 6.9 Hz, 6H); 13C NMR (300
MHz, CDCl3) δ 135.7, 134.4, 117.9, 81.2, 79.4, 37.9, 27.1, 26.5,
22.4, 22.1, 19.2, 16.7; HRMS (EI) calcd for C12H17N2 (M - 1)
189.13918, found 189.13966.
Step 2. Dimethyl sulfoxide (2.68 mL, 37.8 mmol) was added
dropwise (30 min) to a solution of oxalyl chloride (2.0 M
solution, 9.4 mL, 18.9 mmol) in dichloromethane (20 mL) at
- 78 °C. A solution of alcohol from step 1 (4.8 g (crude), 12.6
mmol) in CH2Cl2 (80 mL) was added over 30 min at -78 °C.
Stirring was continued for 30 min, and then triethylamine (7.1
mL, 50.4 mmol) was added dropwise. At that time the cooling
bath was removed, and the reaction was warmed to room
temperature and treated with an aqueous saturated am-
monium chloride solution. The organic layer was separated,
dried (MgSO4), filtered, and evaporated in vacuo. The crude
aldehyde was purified by flash column chromatography (EtOAc/
hexanes, 1:3) and gave 20 as a white solid: 3.2 g (77% (two
steps)); 1H NMR (300 MHz, CDCl3) δ 9.24 (d, J ) 4.8 Hz, 1H),
7.30 (m, 10H), 7.11 (m, 6H), 6.64 (s, 1H), 2.49 (m, 1H), 2.26
(m, 1H), 1.62 (m, 2H).
(()-4-(2-(2,2-Dibr om ovin yl)cyclop r op yl)-1-(tr ip h en yl-
m eth yl)im id a zole (21). To a solution of carbon tetrabromide
(10.2 g, 30.6 mmol) in dichloromethane (100 mL) at 0 °C was
added triphenylphosphine (16.1 g, 61.4 mmol) in portions over
20 min. Stirring was continued at 0 °C for 30 min. A solution
of 20 (5.8 g, 15.34 mmol) in dichloromethane (30 mL) was
added. After 40 min the reaction mixture was treated with an
aqueous saturated ammonium chloride solution. The organic
layer was separated, washed with water, and dried (Na2SO4).
The crude product was filtered rapidly through a silica gel
column (EtOAc/hexane, 1:3) to give 21 as a white solid: 7.3 g
(90%); mp 188-190 °C; 1H NMR (300 MHz, CDCl3) δ 7.30 (m,
10H), 7.11 (m, 6H), 6.58 (s, 1H), 5.89 (d, J ) 9.3 Hz, 1H), 1.99
(m, 2H), 1.42 (m, 1H), 1.02 (m, 1H); 13C NMR (300 MHz,
CDCl3) δ. 142.0, 140.5, 139.7, 137.9, 129.7, 128.1, 117.7, 86.5,
25.4, 18.3, 15.0. Anal. (C27H22N2Br2) C, H, N.
(()-4-(2-Eth yn ylcyclop r op yl)-1-(tr ip h en ylm eth yl)im i-
d a zole (22). A solution of 21 (4.2 g, 7.86 mmol) in tetrahy-
drofuran (50 mL) was treated with n-BuLi (2.5 M in hexane,
12.6 mL, 31.4 mmol) at - 78 °C. The reaction mixture was
stirred for 2.5 h or until HPLC analysis showed the reaction
to be complete and then quenched by the addition of saturated
NH4Cl. The reaction mixture was extracted (EtOAc), and the
organic layer was separated, dried (MgSO4), and evaporated
in vacuo. The crude product was purified by flash column
chromatography (EtOAc/hexane, 1:4) and gave 22 as a white
solid: 2.9 g (98%); mp 157-158 °C; 1H NMR (300 MHz, CDCl3)
δ 7.26 (m, 10H), 7.11 (m, 6H), 6.62 (s, 1H), 2.11 (m, 1H), 1.83
(d, J ) 2.1 Hz, 1H), 1.64 (m, 1H), 1.35 (m, 1H), 1.17 (m, 1H);
13C NMR (300 MHz, CDCl3) δ. 142.2, 139.4, 138.1, 129.8, 128.1,
118.1, 86.4, 64.6, 19.5, 16.2, 9.1.
(±)-4-(2-P en t-1-yn ylcyclop r op yl)im id a zole (26). Acety-
lene 22 (0.1 g, 0.27 mmol) was treated with 1-iodopropane (0.07
g, 0.4 mmol) to give the alkylated acetylene (0.07 g), which
was trityl-deprotected and gave acetylene 26 as an oil: 0.02 g
(49%, overall yield); 1H NMR (300 MHz, CDCl3) δ 7.51 (s, 1H),
6.81 (s, 1H), 2.10 (m, 2H), 2.02 (m, 1H), 1.46 (t, J ) 7.2 Hz,
2H), 1.41 (m, 1H), 1.15 (m, 1H), 1.05 (m, 1H), 0.97 (d, J ) 7.2
Hz, 3H); 13C NMR (300 MHz, CD3OD) δ 139.4, 135.9, 115.9,
82.2, 77.4, 23.5, 21.5, 19.6, 16.5, 13.7, 10.6; HRMS (EI) calcd
for C11H15N2 (M - 1) 175.12352, found 175.12380.
4-(6-Cyclop en tylh ex-3-yn yl)im id a zole (13). Acetylene 8
(0.21 g, 0.38 mmol) was treated with cyclopentylethyl iodide
(0.2 g, 0.88 mmol) to give the alkylated acetylene (0.09 g),
which was trityl-deprotected and gave acetylene 13 as an oil:
0.04 g (33%, overall yield); Rf 0.4 (EtOAc/MeOH, 95:5); 1H
NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 6.84 (s, 1H), 2.79 (t, J
) 7.2 Hz, 2H), 2.46 (t, J ) 7.2 Hz, 2H), 2.15 (t, J ) 7.2 Hz,
2H), 1.0-1.8 (m, 11H); 13C NMR (300 MHz, CD3OD) δ 134.8,
117.6, 83.2, 78.5, 40.6, 36.6, 33.4, 26.2, 25.5, 19.2, 18.6; HRMS
(EI) calcd for C14H19N2 (M - 1) 215.15483, found 215.15497.
4-(6-Cycloh exylh ex-3-yn yl)im id a zole (14). Acetylene 8
(0.5 g, 1.3 mmol) was treated with cyclohexylethyl iodide (0.72
g, 2.8 mmol) to give alkylated acetylene (0.38 g) which was
trityl-deprotected and gave acetylene 14 as an oil: 0.18 g (73%,
overall yield); 1H NMR (300 MHz, CDCl3) δ 7.54 (s, 1H), 6.82
(s, 1H), 2.78 (t, J ) 7.1 Hz, 2H), 2.45 (m, 2H), 2.10 (m, 2H),
1.64 (m, 5H), 1.34 (t, J ) 7.1 Hz, 2H), 1.19 (m, 4H), 0.84 (m,
2H); 13C NMR (300 MHz, CDCl3) δ 134.4, 118.2, 100.0, 84.4,
79.4, 36.6, 36.5, 32.8, 26.5, 26.4, 26.1, 19.1, 16.1; HRMS (EI)
calcd for C15H21N2 (M - 1) 229.17047, found 229.17127. Anal.
(C19H26N2O4(maleate salt)) C, H, N.
4-(8-P h en yloct-3-yn yl)im id a zole (15). Acetylene 8 (0.2 g,
0.55 mmol) was treated with 4-phenyl-1-iodobutane (0.21 g,
0.82 mmol) and gave the alkylated acetylene (0.17 g), which
was trityl-deprotected and gave acetylene 15 as an oil: 0.07 g
(49%, overall yield); Rf 0.5 (EtOAC/MeOH, 95:5); 1H NMR (300
MHz, CDCl3) δ 7.65 (s, 1H), 7.42 (m, 2H), 7.23 (m, 3H), 6.94
(s, 1H), 2.94 (t, J ) 6.9 Hz, 2H), 2.71 (t, J ) 7.2 Hz, 2H), 2.54
(m, 2H), 2.36 (m, 2H), 2.1 (m, 2H), 1.8 (m, 2H); HRMS (EI)
calcd for C17H19N2 (M - 1) 251.15483, found 251.15428.
4-(7,7-Dim eth yloct-3-yn yl)im id a zole (16). Acetylene 8
(0.2 g, 0.55 mmol) was treated with 3,3-dimethyl-1-iodobutane
(0.26 g, 1.2 mmol) to give the alkylated acetylene (0.07 g),
which was trityl-deprotected and gave acetylene 16 as an oil:
0.02 g (14%, overall yield); Rf 0.5 (EtOAc/MeOH, 95:5); 1H
NMR (300 MHz, CDCl3) δ 7.70 (s, 1H), 6.86 (s, 1H), 2.85 (t, J
) 6.9 Hz, 2H), 2.76 (t, J ) 7.2 Hz, 2H), 2.07 (m, 2H), 1.46 (m,
2H), 1.02 (s, 9H); HRMS (EI) calcd for C13H21N2 (M + 1)
205.17047, found 205.1700.
4-Non -3-yn ylim id a zole (17). Acetylene 8 (0.21 g, 0.59
mmol) was treated with 1-iodopentane (0.18 g, 0.88 mmol) to
give the alkylated acetylene (0.18 g), which was trityl-
deprotected and gave acetylene 17 as an oil: 0.07 g (62%,
overall yield); 1H NMR (300 MHz, CDCl3) δ 7.57 (s, 1H), 6.84
(s, 1H), 2.79 (t, J ) 7.2 Hz, 2H), 2.47 (t, J ) 7.2 Hz, 2H), 2.12
(t, J ) 7.2 Hz, 2H), 1.46 (m, 2H), 1.31 (m, 4H), 0.87 (t, J ) 6.9
Hz, 3H); 13C NMR (300 MHz, CDCl3) δ 135.5, 134.2, 118.1,
81.4, 79.5, 31.1, 28.7, 26.4, 22.2, 19.1, 18.7, 14.0; HRMS (EI)
calcd for C12H19N2 (M + 1) 191.15483, found 191.15483.
4-Un d ec-3-yn ylim id a zole (18). Acetylene 8 (0.20 g, 0.55
mmol) was treated with 1-iodoheptane (0.27 g, 1.2 mmol) to
give the alkylated acetylene (0.18 g), which was trityl-
deprotected and gave acetylene 18 as an oil: 0.08 g (81%,
overall yield); 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H), 6.83
(s, 1H), 2.78 (t, J ) 7.2 Hz, 2H), 2.46 (m, 2H), 2.14 (m, 2H),
1.46 (m, 2H), 1.26 (m, 8H), 0.86 (t, J ) 6.9 Hz, 3H); 13C NMR
(300 MHz, CDCl3) δ 135.4, 134.3, 117.6, 81.3, 79.2, 31.6, 28.9,
28.7, 26.2, 22.5, 19.0, 18.6, 14.0; HRMS (EI) calcd for C14H21N2
(M - 1) 217.17047, found 217.17128.
(()-2-(1-(Tr ip h e n ylm e t h yl)im id a zol-4-yl)cyclop r o-
p a n eca r ba ld eh yd e (20). Step 1. Lithium aluminum hydride
(1.0 M solution in THF, 16.66 mL, 16.66 mmol) was added to
a solution of butyl 2-(1-(triphenylmethyl)imidazol-4-yl)cyclo-
propanecarboxylate (5 g, 11.1 mmol) in dry tetrahydrofuran
(50 mL) at 0 °C. The reaction mixture was stirred at 0 °C for
1.5 h. The mixture was treated with water (0.4 mL), 10%
sodium hydroxide (0.4 mL), and water (1.2 mL). The suspen-
sion was filtered through Celite and washed with ethyl acetate.
The filtrate was dried (MgSO4), filtered, and evaporated in
vacuo to give the crude alcohol (4.8 g).
(()-4-(2-(5-Meth ylh ex-1-yn yl)cyclopr opyl)im idazole (27).
Acetylene 22 (0.1 g, 0.27 mmol) was treated with 1-bromo-3-
methylbutane (0.8 g, 0.54 mmol) to give the alkylated acetylene
(0.07 g), which was trityl-deprotected and gave acetylene 27
as an oil: 0.02 g (37%, overall yield); 1H NMR (300 MHz,
CDCl3) δ 7.80 (s, 1H), 6.80 (s, 1H), 2.12 (m, 3H), 1.61 (m, 3H),
1.35 (q, J ) 7.2 Hz, 1H), 1.27 (brm, 1H), 1.16 (m, 1H), 0.85 (d,
J ) 6.6 Hz, 6H); 13C NMR (300 MHz, CD3OD) δ 137.9, 134.4,
114.9, 81.3, 38.0, 27.2, 22.2, 18.3, 16.7, 16.0, 9.7; HRMS (EI)
calcd for C13H17N2 (M - 1) 201.13918, found 201.13958.
(()-4-(2-(4-Cyclop en tylbu t-1-yn yl)cyclop r op yl)im id a -
zole (28). Acetylene 22 (0.2 g, 0.5 mmol) was treated with
cyclopentylethyl iodide (0.07 g, 0.4 mmol) to give the alkylated
acetylene (0.85 g), which was trityl-deprotected and gave
1
acetylene 28 as an oil: 0.04 g (33%, overall yield); H NMR
(300 MHz, CD3OD) δ 7.51 (s, 1H), 6.81 (s, 1H), 2.14 (m, 2H),
2.04 (m, 1H), 1.88 (m, 1H), 1.80 (m, 2H), 1.65-1.39 (m, 7H),

908 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 5
Ali et al.
1.17-1.02 (m, 4H); 13C NMR (300 MHz, CD3OD) δ 137.9, 134.5,
114.9, 81.14, 39.3, 35.4, 32.2, 25.0, 18.1, 15.9, 9.7; HRMS (EI)
calcd for C15H19N2 (M - 1) 227.15483, found 227.15589.
25 mM Tris buffer containing 145 mM NaCl (pH 7.4, 4 °C).
Competition experiments were analyzed, and Ki’s were deter-
mined using the equation: Ki ) IC50/(1 + ([ligand]/Kd).
(()-4-(2-(4-Cycloh exylb u t -1-yn yl)cyclop r op yl)im id a -
zole (29). Acetylene 22 (0.17 g, 0.45 mmol) was treated with
2-cyclohexyl-1-iodoethane (0.13 g, 0.54 mmol) to give the
alkylated acetylene (0.06 g), which was trityl-deprotected and
gave acetylene 29 as an oil: 0.02 g (21%, overall yield); 1H
NMR (300 MHz, CD3OD) δ 7.51 (s, 1H), 6.81 (s, 1H), 2.14 (m,
2H), 2.04 (m, 1H), 1.72 (m, 5H), 1.42 (m, 1H), 1.35 (m, 3H),
1.29-1.02 (m, 5H), 0.9 (m, 2H); 13C NMR (300 MHz, CD3OD)
δ 137.9, 134.3, 114.8, 81.2, 36.8, 36.6, 32.9, 26.6, 26.2, 18.3,
Ack n ow led gm en t. We gratefully acknowledge Dr.
Craig J . Mossman (University of Kansas) for determin-
ing the optical rotation of compounds 32 and 33 and
Gary Pawlowski for the in vitro binding data of com-
pounds 9 and 13.
Su p p or tin g In for m a tion Ava ila ble: 1H NMR spectra,
high-resolution mass spectra, and HPLC purity data for new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
16.3, 16.1, 9.8; HRMS (EI) calcd for
241.17047, found 241.17079.
C16H22N2 (M - 1)
(()-4-(2-(6-P h en ylh ex-1-yn yl)cyclopr opyl)im idazole (30).
Acetylene 22 (0.1 g, 0.27 mmol) was treated with 4-phenyl-1-
iodobutane (0.1 g, 0.4 mmol) to give the alkylated acetylene
(0.11 g), which was trityl-deprotected and gave acetylene 30
as an oil: 0.054 g (63%, overall yield); 1H NMR (300 MHz,
CDCl3) δ 7.50 (s, 1H), 7.28-7.15 (m, 5H), 6.79 (s, 1H), 2.60 (t,
J ) 7.8 Hz, 2H), 2.15 (dt, J ) 1.5 and 6.9 Hz, 2H), 2.07 (m,
1H), 1.69 (m, 2H), 1.52 (m, 3H), 1.25 (m, 1H), 1.13 (m, 1H);
13C NMR (300 MHz, CD3OD) δ 142.3, 136.6, 134.1, 128.3,
125.7, 114.8, 81.2, 35.4, 30.5, 28.5, 18.6, 17.6, 16.2, 10.0; HRMS
(EI) calcd for C18H19N2 (M - 1) 263.15482, found 263.15373.
Refer en ces
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brain histamine release mediated by a novel class (H3) of
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(()-4-(2-(5,5-Dim et h ylh ex-1-yn yl)cyclop r op yl)im id a -
zole (31). Acetylene 22 (0.1 g, 0.27 mmol) was treated with
3,3-dimethyl-1-iodobutane (0.1 g, 0.4 mmol) to give the alky-
lated acetylene (0.04 g), which was trityl-deprotected and gave
1
acetylene 31 as an oil: 0.02 g (35%, overall yield); H NMR
(300 MHz, CDCl3) δ 7.64 (s, 1H), 6.81 (s, 1H), 2.08 (m, 3H),
1.52 (brm, 1H), 1.41 (m, 2H), 1.22 (m, 1H), 1.14 (m, 1H), 0.87
(s, 9H); 13C NMR (750 MHz, CD3OD) δ 137.6, 134.3, 114.9,
80.9, 78.1, 43.3, 36.8, 30.3, 18.1, 16.0, 14.3, 9.8; HRMS (EI)
calcd for C14H21N2 (M + 1) 217.17047, found 217.17120. Anal.
(C18H24N2O4(maleate salt)) C, H, N.
(+)-(1R,2R)-4-(2-(5,5-Dim eth ylh ex-1-yn yl)cyclop r op yl)-
im id a zole (32). The (1R,2R) enantiomer of acetylene 22 (4.5
g, 12.1 mmol) was treated with 3,3-dimethyl-1-iodobutane (3.8
g, 18 mmol) to give the alkylated acetylene (3.0 g), which was
trityl-deprotected and gave acetylene 32 as an oil: 1.4 g (54%,
overall yield); mp 173-175 °C; [R]20D ) +140 (c ) 0.5, MeOH);
1H NMR (300 MHz, CDCl3) δ 7.49 (s, 1H), 6.77 (s, 1H), 2.07
(m, 3H), 1.49 (m, 1H), 1.41 (m, 2H), 1.19 (m, 1H), 1.12 (m,
1H), 0.85 (s, 9H); 13C NMR (300 MHz, CDCl3) δ 138.4, 134.6,
115.1, 81.2, 77.8, 43.3, 30.2, 28.9, 18.5, 15.8, 14.2, 9.5; HRMS
(EI) calcd for C14H19N2 (M - 1) 215.15483, found 215.15501.
Anal. (C18H24N2O4(maleate salt)) C, H, N.
(-)-(1S,2S)-4-(2-(5,5-Dim eth ylh ex-1-yn yl)cyclop r op yl)-
im id a zole (33). The (1S,2S) enantiomer of acetylene 22 (0.4
g, 1.07 mmol) was treated with 3,3-dimethyl-1-iodobutane (0.29
g, 1.6 mmol) to give the alkylated acetylene (0.25 g), which
was trityl-deprotected and gave acetylene 33 as an oil: 0.09 g
(41%, overall yield); [R]20D ) -131 (c ) 0.83, MeOH); 1H NMR
(300 MHz, CDCl3) δ 7.64 (s, 1H), 6.81 (s, 1H), 2.08 (m, 3H),
1.54 (m, 1H), 1.42 (m, 2H), 1.25 (m, 1H), 1.16 (m, 1H), 0.85 (s,
9H); 13C NMR (300 MHz, CDCl3) δ 137.9, 134.5, 115.1, 81.0,
78.0, 43.2, 30.2, 28.9, 18.1, 15.0, 14.2, 9.6; HRMS (EI) calcd
for C14 H19N2 (M - 1) 215.15483, found 215.15386.
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receptor affinity was determined in rat cortical membranes
using the H3 agonist ligand [3H]-NR-methylhistamine (78.9 Ci/
mmol; DuPont NEN Research Products, Boston, MA). The
binding assay was carried out in propylene tubes in a total
volume of 0.2 mL of 50 mM Na+ phosphate buffer (pH 7.4),
containing 75-100 µg of tissue protein and 0.8-1.2 nM [3H]-
NR-methylhistamine. Compounds (1-2 mg) were dissolved in
water or a small aliquot (80 µL) of 10% HCl. Compounds were
further diluted with water to the desired concentration.
Nonspecific binding was accounted for by the inclusion of
thioperamide (10 µM). The samples were incubated for 40 min
at 25 °C. Samples were filtered through glass fiber filters,
presoaked with 0.3% poly(ethylenimine), using an Inotech cell
harvester. The filters were rapidly washed three times with
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Acetylene-Based Histamine H3 Receptor Antagonists
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