Synthesis and histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles.

Article abstract of DOI:10.1016/S0968-0896(99)00253-9

The influence of lipophilic moieties attached to a 4-1H-imidazole ring on the histamine H3 receptor activity was systematically investigated. Series of 4-(n-alkyl)-1H-imidazoles and 4-(omega-phenylalkyl)-1H-imidazoles were prepared, with an alkyl chain varying from 2-9 methylene groups and from 1-9 methylene groups, respectively. The compounds were tested for their activity on the H3 receptor under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is proportional to chain length, ranging from a pA2 value of 6.3 +/- 0.2 for 4-(n-propyl)-1H-imidazole to a pA2 value of 7.2 +/- 0.1 for 4-(n-decyl)-1H-imidazole. For the series 4-(omega-phenylalkyl)-4H-imidazoles an optimum in H3 activity was found for the pentylene spacer: 4-(omega-phenylpentyl)-1H-imidazole has a pA2 value of 7.8 +/- 0.1.

Full text of DOI:10.1016/S0968-0896(99)00253-9

Bioorganic & Medicinal Chemistry 7 (1999) 3003±3009
Synthesis and Histamine H3 Receptor Activity of
4-(n-Alkyl)-1H-imidazoles and 4-(!-Phenylalkyl)-1H-imidazoles
Iwan J. P. De Esch,y Aziz Ga€ar, Wiro M. P. B. Menge and Henk Timmerman*
Leiden/Amsterdam Center for Drug Research (LACDR), Division of Medicinal Chemistry, Department of Pharmacochemistry,
Faculty of Chemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands
Received 3 May 1999; accepted 23 August 1999
AbstractÐThe in¯uence of lipophilic moieties attached to a 4-1H-imidazole ring on the histamine H3 receptor activity was sys-
tematically investigated. Series of 4-(n-alkyl)-1H-imidazoles and 4-(o-phenylalkyl)-1H-imidazoles were prepared, with an alkyl
chain varying from 2±9 methylene groups and from 1±9 methylene groups, respectively. The compounds were tested for their activity
on the H3 receptor under in vitro conditions. For the 4-(n-alkyl)-1H-imidazoles the activity is proportional to chain length, ranging
from a pA2 value of 6.3‹0.2 for 4-(n-propyl)-1H-imidazole to a pA2 value of 7.2‹0.1 for 4-(n-decyl)-1H-imidazole. For the series
4-(o-phenylalkyl)-4H-imidazoles an optimum in H3 activity was found for the pentylene spacer: 4-(o-phenylpentyl)-1H-imidazole
has a pA2 value of 7.8‹0.1. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
pharmacokinetic pro®les is only feasible if the molecular
structural features that are responsible for anity and
intrinsic activity are resolved.
The histamine H3 receptor has been shown to regulate
the neuronal synthesis of histamine and in addition
regulates its release into the synaptic cleft.1,2 Fur-
thermore, the H3 receptor acts as heteroreceptor,
controlling the release of other neurotransmitters (e.g.
dopamine, noradrenaline, serotonin, and acetylcho-
line).3 H3 receptors have been identi®ed in peripheral
tissues, but the highest densities of H3 receptors were
found in distinct areas of the central nervous system
(e.g. cortex, substantia nigra, and striatum) implying the
main pharmacological targets are found in the brain.4 It
has been speculated that H3 antagonists may provide
means for treating Alzheimer's disease, narcolepsy,
schizophrenia, epilepsy and obesity.5 A thorough inves-
tigation of the possible use of H3 ligands as therapeutic
agents in brain disorders is hampered by their poor
blood±brain-barrier penetration.6 Therefore, new
ligands are needed that can reach the central nervous
system. Rational design of compounds with improved
The most manifest feature of the SAR of H3 antagonists
is the crucial role of the 4-1H-substituted imidazole unit
present in all potent H3 ligands.7 Another pharmaco-
phoric element present in many H3 antagonists is a basic
nitrogen atom in the imidazole side-chain. It has been
suggested that this basic nitrogen atom interacts with an
aspartic acid residue of the receptor.8,9 However, a basic
group in the imidazole side-chain is not essential for H3
antagonism and several ligands have been developed
that lack a basic group in their imidazole side-chain.10,11
These compounds are thought to interact at the imida-
zole binding site and a putative hydrophobic pocket.8
Previously, our group has synthesised histamine analo-
gues to investigate the in¯uence of the length of the
alkyl chain (spacer), that connects the imidazole ring
with the amino group, on the H3 activity.12 Elongation
of the ethylene spacer of histamine resulted in com-
pounds with antagonistic activity and an optimal activ-
ity was found for the pentylene spacer, resulting in the
potent and selective H3 antagonist 4-(5-aminopentyl)-
1H-imidazole (impentamine).12 Attachment of lipo-
philic residues to the amino group signi®cantly
increased the H3 antagonistic activity, for example,
attachment of a benzyl group resulted in the potent
antagonist VUF4808 (Fig. 1, pA2=8.9).13 However,
Key words: Antagonists; neurologically active compounds; neuro-
transmitters and receptors.
* Corresponding author. Tel.: +31-20-4447580; fax: +31-20-
y4447610; e-mail: timmermn@chem.vu.nl
Present address: Drug Design Group, Department of Pharmacology,
University of Cambridge, Tennis Court Road, Cambridge CB2 1QJ,
UK.
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00253-9

3004
I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
Results
Chemistry
For the synthesis of the target compounds a general and
straightforward synthetic route was employed, starting
from the aldehyde precursors 1a±h and 2a±i (Scheme 1).
These aldehydes were reacted with (p-tolylsulfonyl)-
methyl isocyanide (TosMIC) in an [3+2] anionic
cycloaddition.16,17 The 4-tosyloxazolines 3a±h and 4a±i
precipitated from the reaction mixture in high yield
and were isolated by ®ltration. The oxazolines were
converted into the corresponding imidazoles with
ammonia in ethanol.
The aldehydes used were either commercially available
(aldehydes 1a±h and 2a,b) or prepared from readily
available starting materials (7, 8, 10, 11 and 12). Alde-
hydes 2c,e,g,i were obtained by Swern oxidation of the
corresponding alcohol and aldehyde 2d was synthesised
from the corresponding carboxylic acid 7, via LiAlH4
reduction and subsequent Swern oxidation (Scheme 2).
The aldehydes 2f and 2h were prepared by elongation of
aldehyde 2d and 2f, respectively, via a Wadsworth±
Emmons (Horner) reaction, catalytic hydrogenation
and subsequent reduction of the carboxylic esters by
diisobutylaluminum hydride (DIBALH) (Scheme 3).
Figure 1. Structures of some H3 receptor antagonists.
considering the activity of compounds like iodoproxifan
(pA2=8.3),14 it is not clear whether the amino group in
the impentamine derivatives is involved in binding to a
hydrogen-bonding acceptor site point of the receptor or
if the anity of these compounds is merely caused by
interaction with the imidazole binding site and a
hydrophobic pocket. The role of the lipophilic moiety of
H3 antagonists with respect to their potency has not yet
been investigated systematically.
Pharmacology
The histamine H3 antagonistic activities of the com-
pounds 5a±h and 6a±i were determined using an in vitro
test system based on the electrically evoked contractile
response of isolated guinea pig jejunum segments.18
Many new H3 antagonists have been synthesised using
readily available sca€olds like urocanic acid and hista-
mine.14,15 These approaches do not lead to series that
allow thorough SAR studies. However, our ongoing
molecular modelling studies prompted us to investigate
the role of the lipophilic moiety on H3 antagonistic
activity in more detail.8 Therefore, two series of com-
pounds were synthesised to explore the SAR of the
lipophilic tail of H3 antagonists. The contribution of
simple alkyl groups attached to the imidazole ring to the
H3 antagonistic activity was investigated in the ®rst ser-
ies. The e€ect of o-phenyl-alkyl groups attached to the
imidazole ring on the H3 activity was studied in a sec-
ond series. With these new series we ®ll a gap between
the SAR of the antagonists with a basic moiety in the
imidazole side-chain and the ligands that lack this
moiety, thereby enabling evaluation of the contribution
of the di€erent molecular structural features that are
responsible for anity and antagonistic activity.
Discussion and Conclusions
The 4-(n-alkyl)-1H-imidazoles have an antagonistic
activity on the histamine H3 receptor (Table 1) that
increases with chain length from pA2=6.3‹0.2 (for 4-
(n-propyl)-1H-imidazole (5a)) up to pA2=7.2‹0.1 (for
4-(n-decyl)-1H-imidazole (5h)). The remarkable activity
of such simple imidazole-containing compounds illus-
trates the important role of the imidazole nucleus for
binding to the H3 receptor. The increasing length of the
alkyl chain does not hinder the binding of these ¯exible
ligands. Entropy e€ects could be responsible for the
increase of activity with increasing alkyl chain length.
No optimum in activity was found. Further elongation
Scheme 1. Reagents: (i) TosMIC, NaCN, EtOH, 0ꢀC; (ii) EtOH/NH3; 120ꢀC; 15 bar.

I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
3005
Table 1. Histamine H3 receptor activity of 4-(n-alkyl)-1H-imidazoles
a
Compound
n
pA2 ‹SD
Impentamine
8.4‹0.2
6.3‹0.2
6.7‹0.1
6.4‹0.2
6.3‹0.2
6.6‹0.2
6.8‹0.1
7.1‹0.1
7.2‹0.1
5a
5b
5c
5d
5e
5f
2
3
4
5
6
7
8
9
Scheme 2. Reagents: (i) LiAlH4, Et2O; (ii) (COCl)2/DMSO, CH2Cl2,
55ꢀC; (iii) Et3N, CH2Cl2, 55ꢀC.
5g
5h
of the alkyl-chain of this series was not attempted due
to the poor solubilities of the higher 4-(n-alkyl)-1H-
imidazoles.
a
Histamine H3 receptor activity determined on isolated guinea pig
jejunum.15
For the 4-(o-phenylalkyl)-1H-imidazole series, a clear
optimum in H3 antagonistic activity was found (Table 2).
The low activity of 4-benzyl-1H-imidazole (6a, pA2=
5.8‹0.1) is enhanced by elongation of the linker between
the two aromatic rings, reaching an optimum in activity
for the pentylene linker, 4-(5-phenyl-pentyl)-1H-imida-
zole (6e, pA2=7.8‹0.1). Further elongation of the lin-
ker results in a decrease of H3 antagonistic activity,
leading to the weak antagonist 4-(9-phenyl-nonyl)-1H-
imidazole (6i, pA2=6.1‹0.2). During the preparation
of this paper compounds 5g, 6d and 6f were described
elsewhere by Stark and co-workers.19 In addition to
comparable in vitro activity, the authors reported that
these three compounds have high in vivo activity.
Table 2. Histamine H3 receptor activity of 4-(o-phenylalkyl)-1H-
imidazoles
a
Compound
n
pA2 ‹SD
6a
6b
6c
6d
6e
6f
6g
6h
6i
1
2
3
4
5
6
7
8
9
5.8‹0.1
5.9‹0.1
6.4‹0.3
7.5‹0.2
7.8‹0.1
7.7‹0.1
7.1‹0.2
6.5‹0.2
6.1‹0.2
The series of compounds presented in our study provide
additional insight into the contribution of the di€erent
molecular structural features that are responsible for H3
activity. Thus, by comparing the activities of 6g
(pA2=7.1) and VUF4808 (Fig. 1, pA2=8.9) it is evident
that the activity of the latter is caused not only by the
lipophilic moiety but that, in addition, the basic nitro-
gen in the side-chain is involved in interaction with a
hydrogen-bonding acceptor site point of the receptor.
Furthermore, the presented series of compounds allow
us to determine the relative position (with respect to the
imidazole binding site) of a hydrophobic pocket that is
available for binding H3 antagonists. These results
enable the construction of a qualitative model for the
binding of H3 antagonists, di€erent from existing mod-
a
Histamine H3 receptor activity determined on isolated guinea pig
jejunum.15
els in which the role of the basic nitrogen atom in
the imidazole side-chain is still prominent. We plan to
use such a model to design new H3 antagonists, that
may have better pharmacokinetic pro®les including
improved in vivo activities and lower toxicity.
Scheme 3. Reagents: (i) NaH, (2H5O)2P(O)CH2CO2CH3, THF, 0ꢀC; (ii) 10% Pd/C, H2, MeOH; (iii) DIBALH, CH2Cl2, 75ꢀC.

3006
I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
Experimental
sphere. Gradually, methyl diethylphosphonoacetate
(8.9 g, 42.4 mmol) was added. After stirring the reaction
mixture for 30 min, 5-phenyl-pentanal (2d) (6.9 g,
42.4 mmol) was added dropwise. After additional stir-
ring for 15 min, saturated aqueous ammonium chloride
(100 mL) was added. The reaction mixture was extrac-
ted with diethyl ether (3Â100 mL) and the combined
organic layers were washed with saturated aqueous
sodium chloride (100 mL), dried over anhydrous sodium
sulfate, ®ltered and concentrated under reduced pres-
sure. The residue was puri®ed by column chromato-
graphy (EtOAc:hexane, 1:4, v/v) to yield 8.0 g (86%) of
a slightly-yellow oil. Rf 0.66 (EtOAc:hexane, 1:4, v/v).
1H NMR (CDCl3) d 1.41±1.72 (m, 4H), 2.28 (m, 2H),
2.60 (t, J=6.7 Hz, 2H), 3.65 (s, 3H), 5.80 (d, J=16.0 Hz,
1H), 6.94 (dt, J=16.0, 7.2 Hz, 1H), 7.23 (m, 5H).
General procedure
1H and 13C NMR spectra were recorded on a Bruker
AC-200 spectrometer (unless indicated otherwise) with
tetramethylsilane as an internal standard. Melting points
(mp) were determined on an Electrothermal IA9200
apparatus and are uncorrected. Elemental analyses were
performed by the Department of Microanalysis, Gronin-
gen University, Groningen, The Netherlands. Solvents
were puri®ed and dried by standard procedures.
4-Phenyl-butanal (2c). A solution of oxalyl chloride
(3.5 g, 28 mmol) and anhydrous dichloromethane (60 mL)
was cooled to 55ꢀC under a nitrogen atmosphere.
DMSO (4.3 g, 55 mmol), dissolved in anhydrous dichloro-
methane (25 mL), was added dropwise. After stirring for
5 min, 4-phenyl-butanol (8) (3.8 g, 25 mmol) dissolved in
anhydrous dichloromethane (10 mL) was added drop-
wise. After additional stirring for 15 min, triethylamine
(12.7 g, 125 mmol) was added. The mixture was allowed
to warm to room temperature and was subsequently
washed with an aqueous solution of HCl (1 N, 75 mL).
The aqueous layer was extracted with dichloromethane
(3Â75 mL) and the combined organic layers were
washed with saturated aqueous sodium chloride (75 mL),
dried over anhydrous sodium sulfate, ®ltered and con-
centrated under reduced pressure to yield a colourless
Methyl 7-phenyl-heptanoate (15). To methyl 7-phenyl-
2(E)-heptenoate (13) (8.0 g, 37 mmol) in methanol
(50 mL) was added 10% Pd/C (800 mg) and the result-
ing suspension was stirred overnight in a hydrogen
atmosphere (10 bar). The Pd(C) catalyst was removed
by ®ltration over hy¯o and the volatiles were evapo-
rated in vacuo to yield 7.4 g (91%) of a colourless oil.
1H NMR (CDCl3) d 1.33 (m, 4H), 1.60 (m, 4H), 2.28 (t,
J=8.0 Hz, 2H), 2.58 (t, J=7.9 Hz, 2H), 3.65 (s, 3H),
7.32±7.80 (m, 5H).
7-Phenyl-heptanal (2f). To a cooled ( 75ꢀC) stirred
solution of methyl 7-phenyl-heptanoate (15) (7.4 g,
33 mmol) in anhydrous dichloromethane (250 mL) was
added DIBALH (35 mL of a 1 M solution in dichlor-
omethane) dropwise. After stirring the solution for
30 min, saturated aqueous Rochelle salt (100 mL) was
added. The mixture was allowed to warm up to room
temperature and washed with diethyl ether. The com-
bined organic layers were washed with an aqueous HCl
solution (1 M, 100 mL) and saturated aqueous sodium
chloride (100 mL), dried over anhydrous sodium sulfate,
®ltered and concentrated under reduced pressure. The
product was isolated as a slightly-yellow oil. Yield: 4.9 g
(77%); 1H NMR (CDCl3) d 1.28 (m, 4H), 1.54 (m, 4H),
2.33 (dt, J=8.0, 2.2 Hz, 2H), 2.52 (t, J=7.9 Hz, 2H),
7.02±7.28 (m, 5H), 9.69 (t, J=2.2 Hz, 1H).
1
oil. Yield: 3.7 g (99%); H NMR (CDCl3) d 1.95 (m,
2H), 2.44 (dt, J=2.0, 7.1 Hz, 2H), 2.62 (t, J=8.1 Hz,
2H), 7.08±7.33 (m, 5H), 9.75 (d, J=2.0 Hz, 1H).
5-Phenyl-pentanol (9). A suspension of lithiumalumi-
niumhydride (4.3 g, 0.11 mol) in anhydrous diethyl ether
(100 mL) was cooled to 0ꢀC under a nitrogen atmo-
sphere. Gradually, 5-phenyl-pentanoic acid (7) (10.1 g,
56 mmol) was added. The suspension was allowed to
warm to room temperature and stirred overnight. After
cooling to 0ꢀC, water (100 mL) was added cautiously.
The reaction mixture was poured into aqueous sulfuric
acid (5%, 400 mL). The aqueous layer was extracted
with diethyl ether (3Â200 mL) and the combined
organic layers were washed with saturated aqueous
sodium chloride (150 mL), dried over anhydrous sodium
sulfate, ®ltered and concentrated under reduced pressure
1
to yield a colourless oil. Yield: 9.3 g (100%); H NMR
(CDCl3) d 1.42 (m, 2H), 1.61 (m, 4H), 2.62 (t, J=
8.0 Hz, 2H), 3.62 (t, J=7.8 Hz, 2H), 7.08±7.37 (m, 5H).
8-Phenyl-octanal (2g). Analogous to the preparation of
2c, using 8-phenyl-octanol (11). Yield: 63.3%; Rf 0.67
1
(EtOA:hexane, 1:4, v/v). H NMR (CDCl3) d 1.30 (m,
6H), 1.59 (m, 4H), 2.39 (dt, J=2.4, 6.7 Hz, 2H), 2.58 (t,
J=7.0 Hz, 2H), 7.08±7.34 (m, 5H), 9.75 (t, J=2.4Hz, 1H).
5-Phenyl-pentanal (2d). Analogous to the preparation of
1
2c, using 5-phenyl-pentanol (9). Yield: 100%; H NMR
(CDCl3) d 1.64 (m, 4H), 2.45 (m, 3H), 2.63 (m, 2H),
7.00±7.29 (m, 5H), 9.68 (s, 1H).
Methyl 9-phenyl-2(E)-nonenoate (14). Analogous to the
preparation of 13, using 7-phenyl-heptanal (2f). Yield:
79.3%; Rf 0.67 (EtOAc:hexane, 1:4, v/v); 1H NMR
(CDCl3) d 1.28 (m, 6H), 1.53 (m, 4H), 2.12 (m, 2H),
2.52 (t, J=8.0 Hz, 2H), 3.63 (s, 3H), 5.73 (d, J=16.0 Hz,
1H), 6.90 (dt, J=16.0, 6.9 Hz, 1H), 7.02±7.28 (m, 5H).
6-Phenyl-hexanal (2e). Analogous to the preparation of
2c, using 6-phenyl-hexanol (10). Yield: 67.0%; 1H NMR
(CDCl3) d 1.35 (m, 2H), 1.60 (m, 4H), 2.33 (dt, J=2.2,
8.0 Hz, 2H), 2.53 (t, J=7.4 Hz, 2H), 6.98±7.28 (m, 5H),
9.69 (t, J=2.2 Hz, 1H).
Methyl 9-phenyl-nonanoate (16). Analogous to the pre-
paration of 15, using methyl 9-phenyl-2(E)-nonenoate
1
Methyl 7-phenyl-2(E)-heptenoate (13). A suspension of
THF (75 mL) and NaH (1.9 g of a 60% oil dispersion,
46.7 mmol) was cooled to 0ꢀC under a nitrogen atmo-
(14). Yield: 91.0%; H NMR (CDCl3) d 1.21 (m, 8H),
1.52 (m, 4H), 2.22 (t, J=7.6 Hz, 2H), 2.51 (t, J=8.0 Hz,
2H), 3.58 (s, 3H), 7.02±7.25 (m, 5H).

I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
3007
9-Phenyl-nonanal (2h). Analogous to the preparation of
2f, using methyl 9-phenyl-nonanoate (16). Yield: 97%;
1H NMR (CDCl3) d 1.22 (m, 8H), 1.54 (m, 4H), 2.35 (t,
J=8.2 Hz, 2H), 2.53 (t, J=7.6 Hz, 2H), 6.99±7.28 (m,
5H), 9.70 (s, 1H).
J=6.7 Hz, 1H), 5.03 (q, J=6.7 Hz, 1H), 6.97 (s, 1H),
7.34 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H).
5-(n-Nonyl)-4-tosyl-2-oxazoline (3g). Yield: 97.1%; mp
116.9±117.7ꢀC; H NMR (CDCl3) d 0.88 (t, J=7.0 Hz,
1
3H), 1.25 (m, 14H), 1.68 (m, 2H), 2.42 (s, 3H), 4.75 (d,
J=6.8 Hz, 1H), 5.04 (q, J=6.8 Hz, 1H), 6.95 (s, 1H),
7.35 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H).
10-Phenyl-decanal (2i). Analogous to the preparation of
2c, using 10-phenyl-decanol (12). The crude yellow
coloured product was puri®ed by column chromato-
graphy (EtOAc:hexane, 1:4, v/v) to give 95% of a col-
5-(n-Decyl)-4-tosyl-2-oxazoline (3h). Yield: 87.8%; mp
105.8±106.4ꢀC; H NMR (CDCl3) d 0.88 (t, J=7.0 Hz,
1
1
ourless oil. Rf 0.69 (EtOAc:hexane, 1:4, v/v); H NMR
(CDCl3) d 1.27 (m, 10H), 1.60 (m, 4H), 2.40 (dt, J=2.4,
6.8 Hz, 2H), 2.59 (t, J=8.2 Hz, 2H), 7.08±7.33 (m, 5H),
9.75 (t, J=2.4 Hz, 1H).
3H), 1.22 (m, 16H), 1.65 (m, 2H), 2.43 (s, 3H), 4.72 (d,
J=6.7 Hz, 1H), 5.03 (q, J=6.7 Hz, 1H), 6.98 (s, 1H),
7.37 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H).
5-(Benzyl)-4-tosyl-2-oxazoline (4a). Yield: 95.7%; mp
93.8±96.7ꢀC; H NMR (CDCl3) d 2.40 (s, 3H), 3.00 (m,
2H), 4.82 (d, J=6.7 Hz, 1H), 5.30 (q, J=6.7 Hz, 1H),
6.91 (s, 1H), 7.11±7.38 (m, 7H), 7.77 (d, J=8.0 Hz, 2H).
General procedure for the preparation of 5-(n-alkyl)-
4-tosyl-2-oxazolines and 5-(!-phenylalkyl)-4-tosyl-2-
oxazolines
1
To a stirred suspension of tosylmethyl isocyanide
(20.0 mmol)
and
the
corresponding
aldehyde
5-(2-Phenyl-ethyl)-4-tosyl-2-oxazoline (4b). Yield: 75.8%;
mp 87.2±88.2ꢀC; 1H NMR (CDCl3) d 1.99 (m, 2H), 2.44
(s, 3H), 2.78 (m, 2H), 4.79 (d, J=6.7 Hz, 1H), 5.07 (q,
J=6.7 Hz, 1H), 7.00 (s, 1H), 7.01±7.40 (m, 7H), 7.78 (d,
J=8.2 Hz, 2H).
(20.5 mmol) in absolute ethanol (200 mL) at 0ꢀC was
added ®nely powdered sodium cyanide (30 mg,
1.0 mmol). For a moment the reaction mixture became
clear followed by precipitation of the product. Ten min
after the addition of sodium cyanide, the suspension
was ®ltered. The product was washed with ether:hexane
(20 mL, 1:1, v/v) and dried in vacuo.
5-(3-Phenyl-propyl)-4-tosyl-2-oxazoline (4c). Yield: 68.7%;
mp 113.8±115.4ꢀC, H NMR (CDCl3) d 1.73 (m, 4H),
1
2.44 (s, 3H), 2.65 (t, J=7.0 Hz, 2H), 4.71 (d, J=6.6 Hz,
1H), 5.07 (q, J=6.6 Hz, 1H), 6.95 (s, 1H), 7.09±7.32 (m,
5H), 7.35 (d, J=8.0 Hz, 2H), 7.78 (d, 8.0 Hz, 2H).
5-(n-Propyl)-4-tosyl-2-oxazoline (3a). Yield: 83.3%; mp
110.5±111.6ꢀC; H NMR (CDCl3) d 0.96 (t, J=7.3 Hz,
1
3H), 1.48 (m, 2H), 1.63 (m, 2H), 2.43 (s, 3H), 4.74 (d,
J=5.4 Hz, 1H), 5.07 (q, J=5.4 Hz, 1H), 6.94 (s, 1H),
7.37 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H).
5-(4-Phenyl-butyl)-4-tosyl-2-oxazoline (4d). Yield: 65.0%;
1
labile product; H NMR (CDCl3) d 1.48 (m, 2H), 1.66
(m, 4H), 2.42 (s, 3H), 2.62 (t, J=7.5 Hz, 2H), 4.73 (d,
J=4.0 Hz, 1H), 5.03 (q, J=6.5 Hz, 1H), 6.94 (s, 1H),
7.07±7.44 (m, 7H), 7.79 (d, J=8.5 Hz, 2H).
5-(n-Butyl)-4-tosyl-2-oxazoline (3b). Yield: 77.3%; mp
101.1±103.0ꢀC; 1H NMR (CDCl3) d 0.89 (t, J=7.00 Hz,
3H), 1.38 (m, 4H), 1.68 (m, 2H), 2.43 (s, 3H), 4.72 (d,
J=6.00 Hz, 1H), 5.02 (q, J=6.00 Hz, 1H), 6.95 (s, 1H),
7.35 (d, J=7.60 Hz, 2H), 7.80 (d, J=7.60 Hz, 2H).
5-(5-Phenyl-pentyl)-4-tosyl-2-oxazoline (4e). Yield: 85.6%;
mp 104.2±105.4ꢀC; H NMR (CDCl3) d 1.40 (m, 4H),
1
1.65 (m, 4H), 2.43 (s, 3H), 2.60 (t, J=7.6 Hz, 2H), 4.72
(d, J=6.5 Hz, 1H), 5.05 (q, J=6.5 Hz, 1H), 6.94 (s,1H),
7.08±7.30 (m, 5H), 7.34 (d, J=8.0 Hz, 2H), 7.80 (d,
J=8.0 Hz, 2H).
5-(n-Pentyl)-4-tosyl-2-oxazoline (3c). Yield: 76.7%;
mp 117.1±118.3ꢀC; 1H NMR (CDCl3) d 0.88 (t, J=
7.00 Hz, 3H), 1.31 (m, 6H), 1.64 (m, 2H), 2.42 (s, 3H),
4.73 (d, J=6.00 Hz, 1H), 5.04 (q, J=6.00 Hz, 1H), 6.94
(s, 1H), 7.34 (d, J=8.00 Hz, 2H), 7.80 (d, J=8.00 Hz,
2H).
5-(6-Phenyl-hexyl)-4-tosyl-2-oxazoline (4f). Yield: 54%;
1
product unstable; H NMR (CDCl3) d 1.29 (m, 6H),
1.54 (m, 4H), 2.34 (s, 3H), 2.53 (t, J=7.6 Hz, 2H), 4.69
(d, J=6.8 Hz, 1H), 5.06 (q, J=6.8 Hz, 1H), 6.90 (s, 1H),
6.99±7.19 (m, 5H), 7.29 (d, J=8.0 Hz, 2H), 7.74 (d,
J=8.0 Hz, 2H).
5-(n-Hexyl)-4-tosyl-2-oxazoline (3d). Yield: 87.2%; mp
104.5±105.6ꢀC; 1H NMR (CDCl3) d 0.86 (t, J=7.00 Hz,
3H), 1.25 (m, 8H), 1.64 (m, 2H), 2.43 (s, 3H), 4.74 (d,
J=6.00 Hz, 1H), 5.04 (q, J=6.00 Hz, 1H), 6.95 (s, 1H),
7.37 (d, J=7.40 Hz, 2H), 7.80 (d, J=7.40 Hz, 2H).
5-(7-Phenyl-heptyl)-4-tosyl-2-oxazoline (4g). Yield: 88.0%;
mp 101.4±102.2ꢀC; H NMR (CDCl3) d 1.30 (m, 8H),
1
5-(n-Heptyl)-4-tosyl-2-oxazoline (3e). Yield: 92.7%; mp
118.2±119.0ꢀC; 1H NMR (CDCl3) d 0.85 (t, J=6.67 Hz,
3H), 1.20 (m, 10H), 1.65 (m, 2H), 2.44 (s, 3H), 4.73 (d,
J=6.70 Hz, 1H), 5.04 (q, J=6.70 Hz, 1H), 6.95 (s, 1H),
7.36 (d, J=8.0 Hz, 2H), 7.82 (d, J=8.0 Hz, 2H).
1.61 (m, 4H), 2.45 (s, 3H), 2.60 (t, J=8.2 Hz, 2H), 4.74
(d, J=6.8 Hz, 1H), 5.02 (q, J=6.8 Hz, 1H), 6.95 (s, 1H),
7.08±7.32 (m, 5H), 7.36 (d, J=8.0 Hz, 2H), 7.80 (d,
J=8.0 Hz, 2H).
5-(8-Phenyl-octyl)-4-tosyl-2-oxazoline (4h). Yield: 66.4%;
1
5-(n-Octyl)-4-tosyl-2-oxazoline (3f). Yield: 78.3%; mp
100.4±101.5 C; H NMR (CDCl3) d 0.88 (t, J=6.8 Hz,
mp 98.4±99.3ꢀC; H NMR (CDCl3) d 1.22 (m, 10H),
1.57 (m, 4H), 2.38 (s, 3H), 2.53 (t, J=7.3 Hz, 2H), 4.68
(d, J=6.6 Hz, 1H), 4.98 (q, J=6.6 Hz, 1H), 6.89 (s, 1H),
ꢀ
3H), 1.21 (m, 12H), 1.64 (m, 2H), 2.42 (s, 3H), 4.73 (d,
1

3008
I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
7.04±7.27 (m, 5H), 7.30 (d, J=8.0 Hz, 2H), 7.74 (d, J=
8.0 Hz, 2H).
4-(n-Heptyl)-imidazole (hydrogen oxalate) VUF 5526
(5e). Yield: 55.4%; mp 186.1±186.6ꢀC; 1H NMR
(DMSO-d6) d 0.84 (t, J=6.7 Hz, 3H), 1.25 (m, 8H), 1.58
(m, 2H), 2.60 (t, J=8.0 Hz, 2H), 7.26 (s, 1H), 8.58 (s,
1H); 13C NMR (DMSO-d6) d 13.713, 21.823, 24.069,
27.954 (2x), 28.109, 30.917, 115.625, 133.454, 133.712,
5-(9-Phenyl-nonyl)-4-tosyl-2-oxazoline (4i). Yield: 69.3%;
mp 94.0±95.1ꢀC; H NMR (CDCl3) d 1.28 (m, 12H),
1
1.63 (m, 4H), 2.43 (s, 3H), 2.58 (t, J=7.4 Hz, 2H), 4.74
(d, J=6.6 Hz, 1H), 5.04 (q, J=6.6 Hz, 1H), 6.95 (s, 1H),
7.08±7.32 (m, 5H), 7.36 (d, J=8.0 Hz, 2H), 7.81 (d,
J=8.0 Hz, 2H).
.
163.914. Anal. calcd for C10H18N2 0.8C2H2O4: C, 58.47;
H, 8.29; N, 11.76. Found: C, 58.64; H, 8.38; N, 11.71.
4-(n-Octyl)-imidazole (hydrogen oxalate) VUF 5467 (5f).
Yield: 47.1%; mp 190.2±190.7ꢀC; 1H NMR (DMSO-d6)
d 0.85 (t, J=7.0 Hz, 3H), 1.23 (bs, 10H), 1.58 (m, 2H),
2.57 (t, J=6.8 Hz, 2H), 7.18 (s, 1H), 8.48 (s, 1H); 13C
NMR (DMSO-d6) d 13.73, 21.85, 24.32, 28.07 (2Â),
28.37, 28.42, 31.01, 115.88, 133.56, 133.96, 164.04. Anal.
General procedure for the preparation of 4-(n-alkyl)-1H-
imidazoles and 4-(!-phenylalkyl)-1H-imidazoles
In a stainless steel bomb, a solution of the correspond-
ing oxazoline (15.0 mmol) and a saturated solution of
ammonia in abs ethanol (120 mL) was heated at 120ꢀC
for 25 h. The pressure increased to about 12 atm. After
cooling, the solvent was removed under reduced pres-
sure. The dark, oily residue was dissolved in ethyl acet-
ate:dichloromethane (150 mL, 4:1, v/v) and washed with
saturated aqueous sodium chloride (5Â50 mL). The
organic layer was dried over sodium sulfate, ®ltered and
concentrated under reduced pressure. The isolated oil
was puri®ed on a silica gel column with CH2Cl2:MeOH
(5:1, v/v) as eluent (for all products: 0.6< Rf<0.7). The
product was crystallized as hydrogen oxalate from
acetone:CH3CN.
.
calcd for C11H20N2 0.8C2H2O4: C, 59.98; H, 8.63; N,
11.10. Found: C, 60.12; H, 8.69; N, 11.13.
4-(n-Nonyl)-imidazole (hydrogen oxalate) VUF 5528
(5g). Yield: 47.2%; mp 191.0ꢀC; H NMR (DMSO-d6)
1
d 0.87 (t, J=6.8 Hz, 3H), 1.23 (bs, 12H), 1.58 (m, 2H),
2.58 (t, J=6.9 Hz, 2H), 7.32 (s, 1H), 8.78 (s, 1H); 13C
NMR (DMSO-d6) d 13.723, 21.852, 23.758, 27.803,
28.091 (2Â), 28.417, 28.632, 31.029, 115.337, 133.347,
.
133.430, 163.378. Anal. calcd for C6H10N2 1.0C2H2O4:
C, 60.20; H, 8.71; N, 10.17. Found: C, 60.52; H, 8.80; N,
10.15.
4-(n-Propyl)-imidazole (hydrogen oxalate) VUF 5522
(5a). Yield: 44.7%; mp 153.5±153.9ꢀC; 1H NMR
(DMSO-d6) d 0.83 (t, J=7.3 Hz, 3H), 1.57 (m, 2H), 2.58
(t, J=6.7 Hz, 2H), 7.32 (s, 1H), 8.80 (s, 1H), 13.24 (bs,
2.9H); 13C NMR (DMSO-d6) d 13.046, 21.158, 25.613,
115.353, 133.142, 135.349, 163.786. Anal. calcd for
4-(n-Decyl)-imidazole (hydrogen oxalate) VUF 5529
(5h). Yield: 68.6%; mp 193.7±194.2ꢀC; 1H NMR
(DMSO-d6) d 0.85 (bs, 3H), 1.20 (bs, 14H), 1.58 (m,
2H), 2.59 (m, 2H), 7.24 (s, 1H), 8.66 (s, 1H); 13C NMR
(400 MHz; 80ꢀC; DMSO-d6) d 13.425, 21.641, 24.400,
28.0182, 28.0972, 28.2474, 28.2991, 28.5372, 28.5599,
30.893, 115.796, 133.358, 134.182, 163.379. Anal. calcd
.
C6H10N2 1.0C2H2O4: C, 47.62; H, 5.97; N, 13.75.
Found: C, 47.64; H, 5.69; N, 13.78.
.
for C13H24N2 0.8C2H2O4: C, 62.55; H, 9.20; N, 9.99.
Found: C, 62.59; H, 9.30; N, 10.03.
4-(n-Butyl)-imidazole (hydrogen oxalate) VUF 5523
ꢀ
1
(5b). Yield: 63.1%; mp 155.6 C; H NMR (DMSO-d6)
d 0.89 (t, J=7.3 Hz, 3H), 1.30 (m, 2H), 1.58 (m, 2H),
2.62 (t, J=7.0 Hz, 2H), 7.28 (s, 1H), 8.69 (s, 1H), 12.23
(bs, 2H); 13C NMR (DMSO-d6) d 13.318, 21.226,
23.502, 29.930, 115.402, 133.373, 133.473, 164.012.
4-(Benzyl)-imidazole (hydrogen oxalate) VUF 5511 (6a).
Yield: 31.4%; mp 172.7±175.4ꢀC; 1H NMR (DMSO-d6)
d 3.98 (s, 2H), 7.20 (s, 1H), 7.25 (m, 5H), 8.50 (s, 1H),
9.73 (s, 1H); 13C NMR (DMSO-d6) d 30.407, 116.341,
126.228, 128.252, 133.273, 134.019, 138.297, 164.572.
.
.
Anal. calcd for C7H12N2 1.0C2H2O4: C, 49.97; H, 6.50;
N, 12.81. Found: C, 50.04; H, 6.66; N, 12.80.
Anal. calcd for C10H10N2 0.75C2H2O4: C, 61.19; H,
5.14; N, 12.41. Found: C, 61.08; H, 4.69; N, 12.28.
4-(n-Pentyl)-imidazole (hydrogen oxalate) VUF 5524
(5c). Yield: 52.8%; mp 179.8±180.4ꢀC, 1H NMR
(DMSO-d6) d 0.83 (t, J=7.5 Hz, 3H), 1.28 (m, 4H), 1.59
(m, 2H), 2.58 (t, J=7.6 Hz, 2H), 7.21 (s, 1H), 8.55 (s,
1H), 10.22 (bs, 1.6H); 13C NMR (DMSO-d6) d 13.614,
21.511, 24.074, 27.653, 30.356, 115.674, 133.464, 133.776,
4-(2-Phenylethyl)-imidazole (hydrogen oxalate) VUF
5512 (6b). Yield: 55.9%; mp 183.0±183.4ꢀC; H NMR
1
(DMSO-d6) d 2.91 (m, 4H), 7.13 (s, 1H), 7.14±7.33 (m,
5H), 8.52 (s, 1H), 10.74 (s, 2.2H); 13C NMR (DMSO-d6)
d 26.196, 33.918, 115.825, 125.818, 128.033, 128.83,
133.261, 133.541, 140.447, 164.548. Anal. calcd for
.
.
164.216. Anal. calcd for C8H14N2 0.8C2H2O4: C, 54.84;
H, 7.48; N, 13.32. Found: C, 54.80; H, 7.52; N, 13.22.
C11H12N2 0.8C2H2O4: C, 61.96; H, 5.61; N, 11.47.
Found: C, 62.03; H, 5.81; N, 11.42.
4-(n-Hexyl)-imidazole (hydrogen oxalate) VUF 5466
(5d). Yield: 39.8%; 1H NMR (DMSO-d6) d 0.86 (t,
J=6.8 Hz, 3H), 1.27 (m, 6H), 1.58 (m, 2H), 2.60 (t,
J=7.7 Hz, 2H), 7.28 (s, 1H), 8.70 (s, 1H), 11.14 (bs,
1H); 13C NMR (DMSO-d6) d 13.683, 21.737, 23.855,
27.779, 27,818, 30.616, 115.428, 133.385, 133.517,
4-(3-Phenyl-propyl)-imidazole (hydrogen oxalate) VUF
5513 (6c). Yield: 74.4%; mp 186.1±187.9ꢀC; H NMR
1
(DMSO-d6) d 1.91 (m, 2H), 2.62 (m, 4H), 7.04±7.38 (m,
5H), 7.41 (s, 1H), 8.78 (s, 1H), 9.45 (bs, 2.8H); 13C
NMR (DMSO-d6) d 23.372, 29.315, 34.013, 115.262,
125.479, 127.952, 132.920, 133.262, 141.009, 163.541.
.
.
163.777. Anal. calcd for C9H16N2 1.1 C2H2O4: C, 53.54;
H, 7.30; N, 11.15. Found: C, 53.62; H, 7.37; N, 11.21.
Anal. calcd for C12H14N2 1.0C2H2O4: C, 60.86; H, 5.84;
N, 10.14. Found: C, 60.97; H, 5.81; N, 10.08.

I. J. P. De Esch et al. / Bioorg. Med. Chem. 7 (1999) 3003±3009
3009
.
4-(4-Phenyl-butyl)-imidazole (hydrogen oxalate) VUF
5514 (6d). Yield: 60.9%; mp 178.9±180.6ꢀC; H NMR
for C18H26N2 1.0C2H2O4: C, 66.64; H, 7.83; N, 7.77.
Found: C, 66.65; H, 7.81; N, 7.93.
1
(DMSO-d6) d 1.59 (m, 4H), 2.61 (m, 4H), 6.81 (bs, 1H).
7.09±7.36 (m, 6H), 8.51 (s, 1H); 13C NMR (DMSO-d6)
d 23.985, 27.699, 30.117, 34.501, 115.707, 125.432,
128.002, 133.489, 133.694, 141.775, 164.346. Anal. calcd
for C13H16N2 0.75C2H2O4: C, 65.03; H, 6.59; N, 10.46.
Found: C, 65.02; H, 6.64; N, 10.37.
Acknowledgement
.
This research was in part (IDE) supported by the Dutch
Technology Foundation (STW).
4-(5-Phenyl-pentyl)-imidazole (hydrogen oxalate) VUF
5515 (6e). Yield: 86.2%; mp 167.1±168.2ꢀC; H NMR
1
References
(DMSO-d6) d 1.32 (m, 2H), 1.61 (m, 4H), 2.59 (m, 4H),
7.07±7.34 (m, 6H), 7.60 (bs, 1H), 8.73 (s, 1H); 13C NMR
(DMSO-d6) d 23.738, 27.637 (2Â), 30.308, 34.684,
115.390, 125.386, 127.978, 128.022, 133.299, 133.405,
141.908, 163.709. Anal. calcd for C14H18N2 1.0C2H2O4:
C, 63.14; H, 6.62; N, 9.20. Found: C, 63.12; H, 6.62; N,
9.15.
1. Arrang, J.-M.; Garbarg, M.; Schwartz, J.-C. Neuroscience
1985, 15, 553.
2. Arrang, J.-M.; Garbarg, M.; Schwartz, J.-C. Nature 1983,
302, 832.
3. Schlicker, E.; Katmann, M. In The Histamine H3 Receptor;
A Target for New Drugs; Leurs, R.; Timmerman, H., Eds.;
Elsevier Science B.V.: Amsterdam, 1998; p 13.
4. Arrang, J.-M.; Garbarg, M.; Lancelot, J.-C.; Lecomte, J.-M.;
Pollard, H.; Robba, M.; Schunack, W.; Schwartz, J.-C. Nature
1987, 327, 117.
5. Leurs, R.; Blandina, P.; Tedford, C.; Timmerman, H. TiPS
1998, 19, 177.
6. Garbarg, M.; Trung Tuong, M. D.; Gros, C.; Schwartz,
J.-C. Eur. J. Pharmacol. 1989, 164, 1.
7. Leurs, R.; Vollinga, R. C. H. T. Prog. Drug Res. 1995, 45,
107.
8. De Esch, I. J. P.; Nederkoorn, P. H. J.; Timmerman, H. In
The Histamine H3 Receptor; A Target for New Drugs; Leurs,
R.; Timmerman, H., Eds.; Elsevier Science B.V.: Amsterdam,
1998; pp 223±241.
.
4-(6-Phenyl-hexyl)-imidazole (hydrogen oxalate) VUF
5516 (6f). Yield: 40.9%; mp 184.1±185.6ꢀC; H NMR
1
(DMSO-d6) d 1.30 (m, 4H), 1.56 (m, 4H), 2.68 (m, 4H),
7.08±7.37 (m, 6H), 8.53 (s, 1H), 8.59 (bs, 1H); 13C NMR
(DMSO-d6) d 24.135, 27.920, 27.980, 28.039, 30.632,
34.849, 115.683, 125.349, 127.967, 128.007, 133.424,
.
133.750, 142.002, 164.311. Anal. calcd for C15H20N2 0.75
C2H2O4: C, 66.98; H, 7.32; N, 9.47. Found: C, 66.93; H,
7.33; N, 9.44.
4-(7-Phenyl-heptyl)-imidazole (hydrogen oxalate) VUF
5517 (6g). Yield: 83.0%; mp 164.9±166.3ꢀC; H NMR
1
9. Oliveira, L.; Paiva, A. C. M.; Vriend, G. J. Comp. -Aided
Mol. Design 1993, 7, 649.
(DMSO-d6) d 1.28 (m, 6H), 1.56 (m, 4H), 2.58 (m, 4H),
7.08±7.34 (m, 6H), 8.72 (s, 1H), 9.77 (bs, 1H); 13C NMR
(DMSO-d6) d 23.683, 27.762, 28.031, 28.193, 28.282,
30.732, 34.881, 115.270, 125.343, 127.971, 128.002,
133.285, 133.355, 142.039, 163.607. Anal. calcd for
10. Krause, M.; Ligneau, X.; Stark, H.; Garbarg, M.;
Schwartz, J.-C.; Schunack, W. J. Med. Chem. 1998, 41, 4171.
11. Ali, S. M.; Tedford, C. E.; Gregory, R.; Handley, M. K.;
Yates, S. L.; Hirth, W. W.; Phillips, J. G. J. Med. Chem. 1999,
5, 903.
.
C16H22N2 1.0C2H2O4: C, 65.04; H, 7.28; N, 8.43.
Found: C, 65.12; H, 7.22; N, 8.44.
12. Vollinga, R. C.; Menge, W. M. P. B.; Leurs, R.; Timmer-
man, H. J. Med. Chem. 1995, 38, 266.
13. Van de Stolpe, A.; Menge, W. M. P. B.; Timmerman, H.
Substituted aminoalkylimidazoles; new potent histamine H3
antagonists. 11th Noordwijkerhout-Camerino Symposium,
Trends in drug research, 11±15 May 1997, p 27.
14. Huls, A.; Purand, K.; Stark, H.; Reidemeister, S.; Ligneau,
X.; Arrang, J.-M.; Schwartz, J.-C.; Schunack, W. Arch.
Pharm. Med. Chem. 1996, 329, 379.
15. Clitherow, J. W.; Beswick, P.; Irving, W. J.; Scopes, D. I.
C.; Barnes, J. C.; Clapham, J.; Brown, J. D.; Evans, D. J.;
Hayes, A. G. Bioorg. Med. Chem. Lett. 1996, 6, 833.
16. Ten Have, R.; Huisman, M.; Meetsma, A.; Van Lusen, A.
M. Tetrahedron 1997, 53, 11355.
17. Horne, D. A.; Yakushijin, K.; Buchi, G. Heterocycles
1994, 39, 139.
18. Vollinga, R. C.; Zuiderveld, O. P.; Scheerens, H.; Bast, A.;
Timmerman, H. Meth. Find. Exp. Clin. Pharmacol. 1992, 14,
747.
4-(8-Phenyl-octyl)-imidazole (hydrogen oxalate) VUF
5518 (6h). Yield: 96.4%; mp 139.9±147.1ꢀC; H NMR
1
(DMSO-d6) d 1.24 (m, 8H), 1.56 (m, 4H), 2.58 (m, 4H),
6.98 (bs, 1.6H), 7.03±7.40 (m, 6H), 8.79 (s, 1H); 13C
NMR (DMSO-d6) d 23.651, 27.745, 28.055, 28.362,
28.482, 30.763, 34.902, 115.226, 125.332, 127.963,
127.993, 133.259, 133.319, 142.047, 163.332. Anal. calcd
.
for C17H24N2 1.0C2H2O4: C, 65.88; H, 7.56; N, 8.09.
Found: C, 65.78; H, 7.61; N, 8.09.
4-(9-Phenyl-nonyl)-imidazole (hydrogen oxalate) VUF
5519 (6i). Yield: 87.4%; mp 157.2±159.5ꢀC; H NMR
1
(DMSO-d6) d 1.25 (m, 10H), 1.56 (m, 4H), 2.58 (m, 4H),
7.05±7.33 (m, 6H), 8.00 (bs, 1H), 8.72 (s, 1H); 13C NMR
(DMSO-d6) d 23.738, 27.787, 28.079, 28.395, 28.582,
28.621, 30.780, 34.910, 115.289, 125.339, 127.965,
128.005, 133.284, 133.384, 142.058, 163.497. Anal. calcd
19. Stark, H.; Ligneau, X.; Arrang, J.-M.; Schwartz, J.-C.;
Schunack, W. Bioorg. Med. Chem. Lett. 1998, 8, 2011.