Synthesis, structure, and neuroprotective properties of novel imidazolyl nitrones

Article abstract of DOI:10.1021/jm991154w

A new series of imidazolyl nitrones spin traps has been synthesized and evaluated pharmacologically. The salient structural feature of these molecules is the presence of an imidazole moiety substituted by aromatic or heteroaromatic cycles. This connectivi

Full text of DOI:10.1021/jm991154w

J . Med. Chem. 2000, 43, 2165-2175
2165
Syn th esis, Str u ctu r e, a n d Neu r op r otective P r op er ties of Novel Im id a zolyl
Nitr on es
Alain Dhainaut,† Andre´ Tizot,† Eric Raimbaud,‡ Brian Lockhart,§ Pierre Lestage,§ and Solo Goldstein*,†
Chemistry Research Division A and Molecular Modeling Department, Institut de Recherches Servier,
11 rue des Moulineaux, 92150 Suresnes, France, and Cerebral Pathology Division,
Institut de Recherches Servier, 125 chemin de Ronde, 78290 Croissy sur Seine, France
Received August 27, 1999
A new series of imidazolyl nitrones spin traps has been synthesized and evaluated pharma-
cologically. The salient structural feature of these molecules is the presence of an imidazole
moiety substituted by aromatic or heteroaromatic cycles. This connectivity imparts to the nitrone
superior neuroprotective properties in vivo and in parallel reduced side effects and toxicity.
Thus compound 6a (a 2-phenylimidazolyl nitrone) administered intraperitoneally protects (80%)
mice from lethality induced by an intracerebroventricular administration of tert-butyl hydro-
peroxide (t-BHP) an oxidant capable of inducing neurodegenerative processes. Administration
of the archetypal nitrone phenyl-tert-butyl nitrone (PBN) at an equimolar dose also affords
some protection (60%) in this test. However, this activity is accompanied by hypothermia,
whereas no such effect is apparent for 6a . Moreover, previously prepared nonsubstituted or
alkyl-substituted imidazolyl nitrones were shown to be extremely toxic to rats in contrast to
the compounds prepared in this study. The observed activities in vivo correlate well with the
calculated partition coefficients (ClogP) and HOMO energy level.
In tr od u ction
occurs very easily, yielding nitroxide radical species,
which are generally much more stable (biochemically
less harmful) than the original free radical (Scheme 1).
Thus, phenyl tert-butyl nitrone (PBN) has been shown
to possess a neuroprotective action in several animal
models of brain ischemia, to decrease age-related protein
oxidation, and to improve memory when administered
chronically to mongolian gerbils.3,4
However, the operational mechanism of nitrones
might not exclusively reside in their capacity to directly
scavenge free radicals. Indeed, inhibition of inducible
nitric oxide synthase (iNOS) expression, as well as
cytokine production, modulation of calcium homeostasis,
glutamate regulation, and apoptosis have been docu-
mented throughout the literature.5
In the past decade, extensive research efforts in
pharmaceutical laboratories have been directed toward
pathologies implicating an oxidative stress. This dis-
turbance of equilibrium in favor of pro-oxidant systems
(oxidative damage potential) is extremely harmful to
tissues and organs, by virtue of irreversible molecular
modifications of polyunsaturated membrane lipids, pro-
teins, and nucleic acids.1 In particular, neurones in the
brain are very sensitive to oxidative damage due to high
levels of 20:4 and 22:6 membrane fatty acid, high oxygen
consumption, and low levels of protective antioxidant
enzymes or vitamin E.
Antioxidant systems become less efficient with age
due to progressive age-associated cellular damage, and
therefore, oxidative stress represents one of the most
critical pathophysiological factors to consider in the
aging brain, in cerebral ischemia, and in other neuro-
degenerative conditions. The initial biochemical impair-
ments in such diseases are caused by excessive amounts
of reactive free radicals, in particular, oxygen free
radicals, that can initiate chain reactions leading to the
propagation of chemical modifications of macromol-
ecules and ultimately to neuronal cell death.2
The above chemical and biochemical properties of
nitrones as well as their brain penetration and toxicity
are influenced by the substitution pattern of these
molecules.
For example, PBN (Figure 1) has a greater capacity
to cross the blood-brain barrier (BBB) compared with
pyridine N-oxide tert-butyl nitrone (POBN), an oxidated
pyridine analogue, as would be expected on the basis of
their lipophilicity. Moreover cyclic analogues of PBN
have revealed higher activity in a rat endotoxic shock
model than the parent compound.6,7 In an effort to
optimize their biological profile, a wide structural
diversity of nitrones has been synthesized and investi-
gated.8,9
It has been well-established that organic molecules
incorporating a nitrone moiety can act as free radical
trapping agents (spin traps) and are capable of opposing
oxidative challenges.3 Indeed, addition of free radicals
to the carbon-nitrogen double bond of such molecules
We have recently undertaken the design, synthesis,
and pharmacological evaluation of a nitrone series,
typified by 6a (Figure 1), possessing a substituted
imidazole moiety as the salient feature of their chemical
structure.10 It was anticipated that the presence of a
* Towhom allcorrespondence should be addressed.Tel: 33 155722599.
Fax: 33 155722430. E-mail: sgoldst@netgrs.com.
† Chemistry Research Division A.
‡ Molecular Modeling Department.
§ Cerebral Pathology Division.
10.1021/jm991154w CCC: $19.00 © 2000 American Chemical Society
Published on Web 05/04/2000

2166 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Dhainaut et al.
Sch em e 1
duction with diisobutylaluminum hydride in tetrahy-
drofuran at low temperature (aldehyde 5a was com-
mercially available). Finally, reaction with N-tert-
butylhydroxylamine hydrochloride in the presence of
sodium bicarbonate afforded the desired nitrones 6a -
q,s in good yield.
Alternatively, 4-trifluoromethylimidazoles 1r ,t af-
forded on treatment with 1 N sodium hydroxide the
corresponding 2-arylimidazole-4-carboxylic acids 3r ,t.
The Weinreb amides17a obtained directly from the acid
precursors by reaction with N,O-dimethylhydroxy-
lamine using 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetram-
ethyluronium tetrafluoroborate as the coupling agent,17b
led to aldehydes 5r ,t after reduction with lithium
aluminum hydride in tetrahydrofuran. Nitrones 6r ,t
were then obtained by the same procedure as described
above.
F igu r e 1. Spin traps: aryl and imidazolyl nitrones.
Nitrone 11 is related to nitrone 6a and might be
thought as formally arising from the interchange of the
substituents on the imidazole ring. Since unlike alde-
hyde 5a the related 4-phenylimidazole-2-carboxaldehyde
was not available, the procedure indicated in Scheme 3
was used to prepare the corresponding nitrone. Thus
commercially available phenylimidazole 7 in N,N-dim-
ethylformamide was reacted with trityl chloride in the
heterocyclic ring and extended conjugation would im-
prove the bioavailability and reduce the toxicity char-
acteristics of these nitrones in comparison to compounds
described in the literature. Indeed, high-level theoretical
calculations indicate that these molecules possess a
higher energy HOMO (highest occupied molecular or-
bital) and, depending on the substitution pattern, also
a lower energy LUMO (lowest unoccupied molecular
orbital) in comparison with PBN (vide infra).11 Since free
radicals react via their SOMO (single occupied molec-
ular orbital), improved spin trapping properties are
expected for both heteroatom radicals (SOMO-HOMO
control) and carbon atom radicals (SOMO-LUMO
control). Moreover, due to its conjugation with the
nitrone function, the imidazole ring might also partici-
pate in the reaction with free radical species.12 The
nitroxide radical species arising from the trapping of
free radicals by these compounds are expected to be even
more stable and less toxic than those derived from
nitrones described in the literature. In this respect it
should be stressed that the presence of an aromatic or
heteroaromatic substituent on the imidazole ring is
crucial. Indeed unsubstituted or alkyl-substituted imi-
dazoles13 turned out to be extremely toxic when admin-
istered to rats (vide infra). In addition, the BBB
penetration as well as clearance and metabolism of such
nitrones should be modulated by the nature of the
substituent on the imidazole ring and by the hydrogen-
bonding capabilities of this ring.14
18
presence of triethylamine to afford N-protected imi-
dazole 8.
The mixture was formylated using butyllithium in
N,N-dimethylformamide to afford 9, which was then
transformed into tritylated nitrone 10 in the usual
manner. Removal of the protecting group under acidic
conditions afforded the desired nitrone 11.18
Additionally the two N-methylated imidazolyl ni-
trones were obtained as depicted in Scheme 4. Thus
commercially available aldehyde 5a reacted with dim-
ethyl carbonate in the presence of K2CO3 and 18-crown-
619 to afford the corresponding N-methylated π and τ
aldehydes 12 and 13. After chromatographic separation
on silica each of these aldehydes was transformed by
the usual procedure into nitrones 14 and 15, respec-
tively. All compounds synthesized in these studies
showed spectroscopic characteristics and elemental
analysis consistent with their indicated structure (see
the Experimental Section).
Resu lts a n d Discu ssion
Herein we describe the synthesis and investigation
of aryl and heteroaryl substituted imidazolyl nitrones
in order to delineate compounds possessing improved
neuroprotective effects, a better BBB penetration, and
reduced secondary effects.
In general, the in vitro antioxidative properties of
nitrones are investigated by examining their capacity
to protect against Fe2+/H2O2-induced lipid peroxidation
and to preserve cell viability under oxidative stress.
All the nitrones described in the present study
demonstrated better results than PBN in a standard
lipid peroxidation test (the capacity of nitrones to inhibit
Fenton reaction mediated lipid peroxidation in mouse
cortical membranes was examined; results are not
shown). However, as already documented in the litera-
ture,3-5 and under the present conditions, no correlation
between the in vitro and in vivo profiles was found. On
the other hand, and albeit a more complex interpreta-
tion of the results, it is the later in vivo profile that
demonstrated interpretable information concerning the
neuroprotective properties of such compounds. Conse-
quently, in the present study we assessed the in vivo
properties of the synthesized nitrones by measuring
Ch em istr y
Two pathways starting with 4-trifluoromethylimida-
zoles15 have been used for the preparation of the
imidazolyl nitrones described in this study.
Indeed, the transformations of 4-trifluoromethylimi-
dazoles into the corresponding nitriles15,16 (pathway A)
or acids (pathway B) are well-known procedures. Thus
4-cyanoimidazoles 2b-q,s were prepared in good to
excellent yields by treatment of the corresponding
4-trifluoromethylimidazoles (1b-q,s) with dilute am-
monium hydroxide. The key intermediates, 5b-q,s
(corresponding aldehydes), were then obtained by re-

Neuroprotective Properties of Novel Imidazolyl Nitrones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2167
Sch em e 2a,b
a
Reagents: (i) NH4OH 5%; (ii) 1 N NaOH, ∆; (iii) TBTU/DIPEA/CH3NHOMe/CH2Cl2, rt; (iv) DIBALH/THF, -78 °C; (v) LiAlH4/THF,
b
-10 °C; (vi) t-BuNHOH‚HCl/NaHCO3/C2H5OH, ∆. Letter designation refers to substituents indicated in Table 1.
Sch em e 3a
An ideal nitrone would provide a significant protection
in the t-BHP test but without generating hypothermia
at protective doses. Thus compound 6a produced in the
above test nearly 80% survival without any significant
hypothermia at the tested doses, whereas the percent-
age survival provided by PBN (=60%) is accompanied
by a lowering of body temperature (=-1 °C).
Interestingly, compound 11, a regioisomer of 6a , is
devoid of any protective effects and also generates
hypothermia (=-1.5 °C). Moreover this compound,
found to be the most potent antioxidant in the lipid
peroxidation assay, is the best example for the fact that
such experiments are poorly representative when con-
sidering whole animals. Similarly, striking differences
are also observed when analyzing the results obtained
with the N-methylated imidazole regioisomers 14 and
15. Indeed, while no protection, but significant hypo-
thermia, was obtained with the former, a marked
protective effect (lower than with 6a but comparable
with PBN) with slight hypothermia was observed with
the latter; both these compounds demonstrated very low
activity in the lipid peroxidation test.
A close examination of the structures, indicated in
Table 1, reveals a clear dependence of the protective
effect and of the hypothermia on the nature of the
imidazole substituent. Thus compounds bearing naph-
thyl substituents (6b,c) demonstrated excellent protec-
tion but also significant hypothermia.
Molecules possessing heteroaromatic substituents on
the imidazole ring demonstrated an important decrease
in protection, despite the presence of hypothermia (6d -
a
Reagents: (i) trityl chloride/Et3N/DMF, rt; (ii) n-BuLi in
hexane/DMF, 0 °C; (iii) t-BuNHOH‚HCl/NaHCO3/EtOH, ∆; (iv)
AcOH/EtOH, rt.
their capacity to oppose lethality induced in mice by
intracerebroventricular (icv) injection of tert-butyl hy-
droperoxide (t-BHP), an oxidative agent known to
produce apoptotic-type neurodegeneration
20
(see the
Experimental Section for details). Since a major draw-
back of antioxidants described in the literature is the
potential induction of whole-body hypothermia at neu-
roprotective doses, the influence of all compounds on
body temperature was investigated (see the Experimen-
tal Section for details). Table 1 below summarizes the
biological results obtained with the various nitrones
described in this study, as well as their respective
HOMO energies21 and calculated partition coefficients
(ClogP).22

2168 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Dhainaut et al.
Sch em e 4a
trend is also observed in Figure 2. Indeed the more
active compounds in the t-BHP test have ClogP values
above 1, the optimum value being situated between 1.5
and 2.
Partial least squares algorithm (PLS, see Experimen-
tal Section) led to the following quantitative structure-
activity relationship equation for the t-BHP test:
% neuroprotection ) 33.2 × ClogP - 2.15 ×
EHOMO - 379.43 (1)
n ) 23 r2 ) 0.73 r ) 0.85 q2 ) 0.62
standard error of estimate ) 19.38
standard error of prediction cross-validated ) 22.71
a
Reagents: (i) (CH3O)2CO, K2CO3, 18-crown-6, ∆; (ii) chro-
The ClogP parameter alone explains 64% of the
activity variation in the t-BHP test (r2 ) 0.64), whereas
no correlation was observed with only HOMO energies.
A different perspective of the data was obtained by
plotting calculated protection levels (from eq 1) versus
measured activities (Figure 3, r2 ) 0.76, r ) 0.87). The
major outlier(s) from the fitted line appear to be
compounds 11 and 14, regioisomers of 6a and 15,
respectively. Besides the possible difference in experi-
mental lipophilicity, the different connectivity found in
11 and 14 might also induce changes in metabolic and
clearance factors which are not apparent in the above
equation. From a strictly quantitative point of view,
better correlations could be obtained by ignoring PBN
and outlier(s). However, it is more general and realistic
to take into consideration all studied nitrones and to
emphasize factors impacting on the pharmacological
profile.
The correlation involving hypothermia is shown in
Figure 4. Again the same two subsets, previously
described, can be distinguished. Molecules in the first
subset (PBN and substituted phenylimidazolyl nitrones)
display larger hypothermia effects than molecules in the
second subset. Electron-withdrawing-group substitution
in phenylimidazolyl nitrones leads to a dramatic in-
crease in hypothermia (e.g. 6l). The differences between
regioisomers (e.g. 6b and 6c, 6a and 11) are again
clearly apparent. Contrary to the t-BHP test, no mean-
ingful quantitative structure-activity relationship
(QSAR) could be obtained for the hypothermia effect.
However, the protective effect, as seen in the t-BHP test,
and hypothermia are clearly distinguishable, where the
best profile in this respect was demonstrated by 6a , 6c,
6t, and 15.
matographic separation SiO2, 230-400 mesh, toluene/AcOEt/THF,
94:5:1; (iii) t-BuNHOH‚HCl/NaHCO3/EtOH, ∆.
k ). Finally, substitution of the phenyl ring in 6a
maintained a high degree of protection with variable
levels of hypothermia (6l-t). It should be emphasized
that in our hands nitrones lacking substituents or
having alkyl substituents on the imidazole ring13 not
only were ineffective in the t-BHP test but also dem-
onstrated major toxicity. Indeed black urines, myore-
laxation, catatonia and tremors, were observed after
oral administration of these nitrones to rats (600 mg/
kg). No such effects were observed for our compounds
tested at an equivalent dose.
To gain a deeper understanding of the biological
behavior of these compounds, the dependence of the
neuroprotection and hypothermia on calculated physi-
cochemical parameters (ClogP and HOMO energies,
Table 1) was examined. The above correlations can be
conveniently visualized as in Figure 2, whereby the area
of the circle is directly proportional to the magnitude of
the determined biological effect (compounds without any
activities do not appear).
Two principal subsets can be distinguished (conver-
gent dotted lines): the first subset includes PBN and
phenylimidazolyl nitrones substituted by electron-
withdrawing groups. These compounds are character-
ized by their relatively low energy HOMO. The level of
neuroprotection observed in this subset is comparatively
large, PBN being the least effective; the second subset
includes unsubstituted phenylimidazolyl nitrones, phe-
nylimidazolyl nitrones substituted by electron-donor
groups, heteroaryl-substituted imidazolyl nitrones and
N-methylated imidazolyl nitrones. All these molecules
have a higher energy HOMO. Marked levels of protec-
tion were observed for 6a and related compounds,
whereas low or negligible central activities were ob-
served for the heteroaryl-substituted imidazolyl ni-
trones.
The two naphthyl isomers 6b and 6c, situated near
the convergence of the two dotted lines, have a high-
energy HOMO and exhibit excellent levels of protection.
There is clearly a trend toward higher protection
when the HOMO energy is higher and this is particu-
larly apparent for the second subset described above.
In general, lipophilic compounds are known to possess
higher central nervous system (CNS) activities and this
Con clu sion
A series of new aryl-substituted imidazolyl nitrones
was synthesized and evaluated in two in vivo tests.
These compounds proved to be better neuroprotective
agents (t-BHP test) with less hypothermia and toxicity
than previously described spin trappers (e.g. PBN and
unsubstituted and alkyl-substituted imidazolyl ni-
trones). The neuroprotective profile in vivo is strongly
dependent on ClogP calculated partition coefficient. An
additional parameter influencing biological behavior is
the HOMO energy level. A meaningful structure-
activity equation that links the above two parameters
with the percentage of neuroprotection could be obtained

Neuroprotective Properties of Novel Imidazolyl Nitrones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2169
Ta ble 1. Structure-Activity Profile

2170 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Ta ble 1 (Continued)
Dhainaut et al.
a
See also the Experimental Section. Nitrones were administered at 150 mg/kg, 30 min before injection of t-BHP. Indicated are percentage
survival at 2 h. Calculated from eq 1. c See also the Experimental Section. Indicated are temperature differences 30 min after 150
b
mg/kg ip administration of the corresponding nitrone. Negative value set to 0%. e To take into consideration differences in molecular
d
weight, figures in these columns were obtained by multiplying the actual measured values by the ratio of the molecular weight for the
compound under consideration and the highest molecular weight in the series (compound 6o).
inert atmosphere. Thin-layer chromatography (TLC) was
performed on Merck silica gel 60 F-254 plates, spots being
visualized by UV, light, or I2 vapors. HPLC analyses were
performed using Rainin pumps, a UV detector, and Hypersil
preparative columns. Normal and flash chromatography (FC)
was carried out using Merck silica gel (70-230 or 230-400
mesh). All final products were obtained as crystalline solids.
Yields are of purified compound and were not optimized.
Melting points were determined on a Bu¨chi 535 capillary
melting point apparatus and are uncorrected. 1H NMR spectra
were recorded on a AC 200, AM 300 or AMX 500 Bruker
spectrometer using CDCl3 or DMSO-d6 as solvent; chemical
shifts (δ) are reported in ppm relative to tetramethylsilane (0
ppm) and the following multiplicity abbreviations were used:
s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; bs,
broad signal. Elemental analyses were obtained on a Carlo
Erba 1108 combustion apparatus; chlorine elemental analyses
were performed with a Metler DL 70 titration potentiometer.
for the t-BHP test. Finally, it could be shown that the
neuroprotective effect and the hypothermia effect can
be separated.
Exp er im en ta l Section
Abbr eviation s: pyridine N-oxide tert-butyl nitrone (POBN),
tert-butyl hydroperoxide (t-BHP), phenyl tert-butyl nitrone
(PBN), inducible nitric oxide synthase (iNOS), single occupied
molecular orbital (SOMO), lowest unoccupied molecular orbital
(LUMO), highest occupied molecular orbital (HOMO), intrac-
erebroventricular (icv), blood-brain barrier (BBB), diisobuty-
laluminum hydride (DIBALH), 2-(1H-benzotriazol-1-yl)-1,1,3,3-
tetramethyluronium tetrafluoroborate (TBTU), central nervous
system (CNS), partial least squares (PLS), quantitative struc-
ture-activity relationships (QSAR), thin-layer chromatogra-
phy (TLC), flash chromatography (FC), Austin Method 1 (AM1),
diisopropylethylamine(DIPEA),N,N-dimethylformamide(DMF),
and tetrahydrofuran (THF).
Ch em ist r y. Unless indicated otherwise, reagents and
solvents were obtained from commercial sources and used as
received. When required, reactions were conducted under an
P r ep a r a tion of 4-Tr iflu or om eth ylim id a zoles 1 (Gen -
er a l P r oced u r e A). Compounds 1i, 1j, 1k , 1l, 1m , 1n , 1p ,

Neuroprotective Properties of Novel Imidazolyl Nitrones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2171
reaction is stirred for 20 h at room temperature. The precipi-
tated product is filtered, washed with water, and dried.
2-(2-Na p h t h yl)-4-t r iflu or om et h yl-1H -im id a zole (1b ):
1
Yield 4.5 g (53%); mp 142-144 °C; H NMR (DMSO-d6, 200
MHz) 8.6 (s, 1H), 8.2 (d, 1H), 8.1 (m, 4H), 7.6 (m, 2H). Anal.
(C14H9F3N2) C, H, N.
2-(1-Na p h t h yl)-4-t r iflu or om et h yl-1H -im id a zole (1c):
Yield 7.2 g (43%); mp >240 °C; 1H NMR (DMSO-d6, 200 MHz)
13.3 (bs, 1H), 8.8 (m, 1H), 8.1 (m, 3H), 7.85 (d, 1H), 7.6 (m,
3H). Anal. (C14H9F3N2) C, H, N.
2-(2-F u r yl)-4-tr iflu or om eth yl-1H-im id a zole (1d ): Yield
3.7 g (61%); mp 221-225 °C; 1H NMR (CDCl3, 200 MHz) 10.0
(m, 1H), 7.45, 7.35 (dd, 2H), 7.0 (d, 1H), 6.5 (dd, 1H). Anal.
(C8H5F3N2O) C, H, N.
2-(3-F u r yl)-4-tr iflu or om eth yl-1H-im id a zole (1e): Yield
1
7.5 g (79%); mp 177 °C; H NMR (DMSO-d6, 200 MHz) 13.1
(bs, 1H), 8.25 (m, 1H), 7.85 (m, 1H), 7.6 (m, 1H), 6.93 (m, 1H).
Anal. (C8H5F3N2O) C, H, N.
F igu r e 2. Plot of neuroprotective action vs ClogP and HOMO
energy for nitrones in Table 1. The circle area is proportional
to the percentage of protection in the t-BHP test. Labels
correspond to compounds 6a -f and 6k -t. (Compounds 6g-
j,m , 11, and 14, which do not reveal any protection, are not
shown.)
2-(3-Th ien yl)-4-tr iflu or om eth yl-1H-im ida zole (1f): Yield
1
7.1 g (51%); mp 222-223 °C; H NMR (DMSO-d6, 200 MHz)
13.1 (bs, 1H), 8.1 (dd, 1H), 7.87 (m, 2H), 7.65 (m, 1H). Anal.
(C8H5F3N2S) C, H, N, S.
2-(4-1H-Im idazolyl)-4-tr iflu or om eth yl-1H-im idazole (1g):
1
Yield 5.9 g (65%); mp 137-138 °C; H NMR (DMSO-d6, 200
MHz) 13.0-12.0 (bs, 2H), 7.75, 7.65, 7.60 (3s, 3H). Anal.
(C7H5F3N4) C, H, N.
2-(2-Th ia zolyl)-4-t r iflu or om et h yl-1H -im id a zole (1h ):
1
Yield 4.5 g (50%); mp 197-198 °C; H NMR (DMSO-d6, 200
MHz) 13.70 (bs, 1H), 8.05-7.9 (m, 2H), 8.0 (m, 1H). Anal.
(C7H4F3N3S) C, H, N, S.
2-(2-P yr id yl)-4-tr iflu or om eth yl-1H-im id a zole (1i): Yield
1
4.4 g (33%); mp 160-161 °C (lit.15 mp 156-157 °C); H NMR
(DMSO-d6, 300 MHz) 13.5 (bs, 1H), 8.65 (ddd, 1H), 8.10 (dt,
1H), 7.95 (td, 1H), 7.8 (dd, 1H), 7.45 (ddd, 1H). Anal. (C9H6F3N3)
C, H, N.
2-(3-P yr id yl)-4-tr iflu or om eth yl-1H-im id a zole (1j): Yield
7.3 g (55%); mp 228-229 °C (lit.15 mp 228-228.5 °C); 1H NMR
(DMSO-d6, 300 MHz) 13.5 (bs, 1H), 9.1 (dd, 1H), 8.6 (dd, 1H),
8.3 (ddd, 1H), 8.0 (d, 1H), 7.55 (ddd, 1H). Anal. (C9H6F3N3) C,
H, N.
2-(4-P yr idyl)-4-tr iflu or om eth yl-1H-im idazole (1k): Yield
3.2 g (48.5%); mp 210-214 °C (lit.15 mp 211-212 °C); 1H NMR
(DMSO-d6, 200 MHz) 13.6 (bs, 1H), 8.7 (d, 2H), 8.1 (s, 1H),
7.9 (d, 2H). Anal. (C9H6F3N3) C, H, N.
F igu r e 3. Plot of measured vs predicted neuroprotection (t-
BHP test, percentage survival). Predicted values were calcu-
lated from eq 1. Labels correspond to nitrones 6a -t.
2-(4-Nitr op h en yl)-4-tr iflu or om eth yl-1H-im id a zole (1l):
Yield 6.2 g (25%); mp 197 °C (lit.15 mp 195-196.5 °C); 1H NMR
(DMSO-d6, 200 MHz) 13.59 (bs, 1H), 8.4 (d, 2H), 8.2 (d, 2H),
8.05 (bs, 1H). Anal. (C10H6F3N3O2) C, H, N.
2-(4-Dim eth yla m in op h en yl)-4-tr iflu or om eth yl-1H-im i-
d a zole (1m ): Yield 2.1 g (13%); mp >240 °C (lit.15 mp 264-
1
265 °C); H NMR (DMSO-d6, 200 MHz) 12.75 (bs, 1H), 7.81
(d, 1H), 7.77 (s, 1H), 7.75 (d, 2H), 6.79 (d, 1H), 2.97 (s, 6H).
Anal. (C12H12F3N3) C, H, N.
2-(4-Flu or oph en yl)-4-tr iflu or om eth yl-1H-im idazole (1n ):
Yield 5.2 g (58%); mp 203-205 °C (lit.15 mp 206.5-207.5 °C);
1H NMR (DMSO-d6, 200 MHz) 13.2 (bs, 1H), 8.0 (dd, 2H), 7.9
(bs, 1H), 7.3 (dd, 2H). Anal. (C10H6F4N2) C, H, N.
2-(4-Tr iflu or om eth ylp h en yl)-4-tr iflu or om eth yl-1H-im -
id a zole (1o): Yield 6.7 g (39%); mp 223 °C; 1H NMR (DMSO-
d6, 300 MHz) 13.5 (bs, 1H), 8.2 (d, 2H), 8.02 (m, 1H), 7.82 (d,
2H). Anal. (C11H6F6N2) C, H, N.
F igu r e 4. Plot of induced hypothermia vs Clog P and HOMO
energy for nitrones in Table 1. The circle area is proportional
to the hypothermia effect (absolute value). Labels correspond
to compounds 6a -t.
2-(2-Ch lor oph en yl)-4-tr iflu or om eth yl-1H-im idazole (1p):
1
Yield 7.7 g (66%); mp 168-170 °C (lit.15 mp 165-167 °C); H
NMR (DMSO-d6, 200 MHz) 12.90 (bs, 1H), 7.9 (s, 1H), 7.8 (m,
1H), 7.6 (m, 1H), 7.5 (m, 2H). Anal. (C10H6ClF3N2) C, H, Cl,
N.
2-(3-Ch lor oph en yl)-4-tr iflu or om eth yl-1H-im idazole (1q):
Yield 8.9 g (88%); mp 189-191 °C (lit.15 mp 186.5-187.5 °C);
1H NMR (DMSO-d6, 200 MHz) 12.3 (m, 1H), 8.1 (s, 1H), 8.0
(s, 1H), 7.9 (dd, 1H), 7.7 (s, 1H), 7.6 (b, 1H). Anal. (C10H6-
ClF3N2) C, H, Cl, N.
1q, 1r , and 1t are described in the literature. Other compounds
described in this work have been synthesized in the same
manner using the procedure described below.
1,1-Dibromo-3,3,3-trifluoroacetone (1 equiv) is added to a
solution of NaOAc‚3H2O (2 equiv) in H2O (∼40 mL/100 mmol),
and the mixture is stirred and heated on a steam bath for 30
min. After cooling, the appropriate aldehyde (0.8 equiv) in
methanol (∼40 mL/100 mmol) containing concentrated am-
monium hydroxide (∼10 mL/100 mmol) is added and the
2-(4-Ch lor oph en yl)-4-tr iflu or om eth yl-1H-im idazole (1r ):
1
Yield 7.2 g (88%); mp 218-221 °C (lit.15 mp 228-230 °C); H

2172 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Dhainaut et al.
NMR (DMSO-d6, 200 MHz) 13.0 (m, 1H), 8.0 (d, 2H), 7.95 (s,
1H), 7.6 (d, 2H). Anal. (C10H6ClF3N2) C, H, Cl, N.
2-(4-Tr iflu or om eth ylph en yl)-4-cyan o-1H-im idazole (2o):
1
Yield 3.9 g (72%); mp 220-222 °C; H NMR (DMSO-d6, 300
MHz) 13.75 (bs, 1H), 8.35 (s, 1H), 8.2 (d, 2H), 7.9 (d, 2H). Anal.
(C11H6F3N3) C, H, N.
2-(p-Tolyl)-4-tr iflu or om eth yl-1H-im id a zole (1s): Yield
1
3.4 g (48%); mp 221-222 °C; H NMR (DMSO-d6, 200 MHz)
13.0 (bs, 1H), 7.9 (m, 3H), 7.3 (d, 2H), 2.4 (s, 3H). Anal.
(C11H9F3N2) C, H, N.
2-(2-Ch lor op h en yl)-4-cya n o-1H-im id a zole (2p ): Yield
1
3.0 g (52%); mp 153-154 °C; H NMR (DMSO-d6, 200 MHz)
2-(4-Me t h oxyp h e n yl)-4-t r iflu or om e t h yl-1H -im id a -
zole (1t): Yield 3.8 g (51%); mp 201-203 °C (lit.15 mp 204-
206 °C); 1H NMR (DMSO-d6, 200 MHz) 12.01 (bs, 1H), 7.9 (d,
2H), 7.8 (m, 1H), 7.05 (d, 2H), 3.8 (s, 3H). Anal. (C11H9F3N2O)
C, H, N.
P r ep a r a tion of 4-Cya n oim id a zoles 2 (Gen er a l P r oce-
d u r e B). Compounds 2d , 2f, 2g, and 2j are described in the
literature. Other compounds described in this work have been
synthesized in the same manner using the procedure described
below.
13.3 (bs, 1H), 8.25 (s, 1H), 7.8-7.4 (m, 4H). Anal. (C10H6ClN3)
C, H, N, Cl.
2-(3-Ch lor op h en yl)-4-cya n o-1H-im id a zole (2q): Yield
1
3.1 g (42%); mp 173-175 °C; H NMR (DMSO-d6, 200 MHz)
13.5 (bs, 1H), 8.25 (s, 1H), 7.99 (b, 1H), 7.90 (m, 1H), 7.48 (m,
2H). Anal. (C10H6ClN3) C, H, N, Cl.
2-(p-Tolyl)-4-cya n o-1H-im id a zole (2s): Yield 2.3 g (75%);
1
mp 226 °C; H NMR (DMSO-d6, 200 MHz) 13.4 (bs, 1H), 8.2
(s, 1H), 7.85 (d, 2H), 7.3 (d, 2H), 2.3 (s, 3H). Anal. (C11H9N3)
C, H, N.
The 4-trifluoromethylimidazoles 1 (1 equiv) in MeOH (10
mL/mmol) containing 5% ammonium hydroxide (20 mL/mmol)
were heated and stirred at 60 °C for 24 h, followed by
concentration of the reaction mixture under reduced pressure.
The precipitated product is filtered washed with water and
dried.
2-(2-Na p h th yl)-4-cya n o-1H-im id a zole (2b): Yield 2.4 g
(87%); mp 219 °C; 1H NMR (DMSO-d6, 200 MHz) 13.6 (bs, 1H),
8.6 (s, 1H), 8.4 (s, 1H), 8.10 (m, 4H), 7.60 (m, 2H). Anal.
(C14H9N3) C, H, N.
P r ep a r a tion of 4-Ca r boxyim id a zoles 3 (Gen er a l P r o-
ced u r e C). The 4-trifluoromethylimidazoles 1 (1 equiv) are
added to 2 N NaOH (∼2.5 mL/mmol) followed by stirring at
90 °C during 1 h. The reaction mixture is brought to pH 6
using 2 N HCl and the precipitated product is filtered, washed
with water, and dried.
2-(4-Ch lor op h en yl)-4-ca r boxy-1H-im id a zole (3r ): Yield
0.5 g (57%); mp 218 °C; 1H NMR (DMSO-d6, 200 MHz) 8.1 (d,
2H), 7.6 (s, 1H), 7.5 (d, 2H). Anal. (C10H7ClN2O2) C, H, N, Cl.
2-(4-Meth oxyph en yl)-4-car boxy-1H-im idazole (3t): Yield
2-(1-Na p h th yl)-4-cya n o-1H-im id a zole (2c): Yield 3.3 g
(62%); mp 239 °C; 1H NMR (DMSO-d6, 200 MHz) 13.5 (bs, 1H),
8.75 (m, 1H), 8.35 (s, 1H), 8.05 (d, 1H), 8.00 (m, 1H), 7.82 (dd,
1H), 7.60 (m, 3H). Anal. (C14H9N3) C, H, N.
1
2.9 g (85%); mp 233-235 °C; H NMR (DMSO-d6, 200 MHz)
8.0 (d, 2H), 7.85 (s, 1H), 7.1 (d, 2H), 3.85 (s, 3H). Anal.
(C11H10N2O3) C, H, N.
P r ep a r a tion of Wein r eb Am id es 4 (Gen er a l P r oced u r e
D). To a solution of the corresponding carboxylic acids 3 (1
equiv) in dichloromethane (∼10 mL/mmol) were added TBTU
(0.4 g/mmol, 1.1 equiv), diisopropylamine (0.64 mL/mmol), and
N,O-dimethylhydroxylamine (0.13 g/mmol, 1.8 equiv), followed
by stirring during 20 h at room temperature. The reaction
mixture is diluted with dichloromethane (15 mL/mmol) and
washed with water. The organic phase is dried on magnesium
sulfate, filtered, and concentrated in vacuo. After trituration
in diethyl ether the residue is filtered to afford the desired
product.
2-(2-F u r yl)-4-cya n o-1H-im id a zole (2d ): Yield 4.8 g (63%);
mp 225-229 °C (lit.16a mp 229-232 °C); 1H NMR (CDCl3, 200
MHz) 13.5 (bs, 1H), 8.2 (s, 1H), 7.9 (d, 1H), 7.0 (dd, 1H), 6.7
(dd, 1H). Anal. (C8H5N3O) C, H, N.
2-(3-F u r yl)-4-cya n o-1H-im id a zole (2e): Yield 0.4 g (51%);
1
mp 177-180 °C (lit.16b mp 198-202 °C); H NMR (DMSO-d6,
200 MHz) 13.3 (bs, 1H), 8.25 (d, 1H), 8.25 (s, 1H), 7.75 (t, 1H),
7.0 (d, 1H). Anal. (C8H5N3O) C, H, N.
2-(3-Th ien yl)-4-cya n o-1H-im id a zole (2f): Yield 5.6 g
1
(95%); mp 175 °C (lit.16b mp 198-202 °C); H NMR (DMSO-
d6, 200 MHz) 13.2 (bs, 1H), 8.1 (s, 1H), 8.02 (m, 1H), 7.55 (m,
2H). Anal. (C8H5N3S) C, H, N, S.
2-(4-Ch lor op h en yl)-4-(N-m eth yl-N-m eth oxya m in oca r -
bon yl)-1H-im id a zole (4r ): Yield 6.4 g (78%); mp 188-190
2-(4-1H-Im id a zolyl)-4-cya n o-1H-im id a zole (2g): Yield
2.0 g (77%); mp >240 °C (lit.16b mp >260 °C); 1H NMR (DMSO-
d6, 300 MHz) 13.05, 12.4 (bs, 2H), 8.3 (s, 1H), 8.05 (d, 1H),
7.95 (d, 1H). Anal. (C7H5N5) C, H, N.
1
°C; H NMR (CDCl3, 200 MHz) 11.4 (bs, 1H), 8.0 (d, 2H), 7.8
(s, 1H), 7.4 (d, 2H), 4.85 (s, 3H), 3.4 (s, 3H). Anal. (C12H12
ClN3O2) C, H, N, Cl.
-
2-(4-Meth oxyph en yl)-4-(N-m eth yl-N-m eth oxyam in ocar -
bon yl)-1H-im id a zole (4t): Yield 2.7 g (78%); mp 138-139 °C;
1H NMR (CDCl3, 200 MHz) 7.9 (d, 2H), 7.7 (s, 1H), 6.95 (d,
2H), 3.9 (s, 6H), 3.4 (s, 3H). Anal. (C13H15N3O3) C, H, N.
P r ep a r a tion of Im id a zolca r ba ld eh yd es 5. With the
exception of 5a , which is commercially available, all described
imidazolcarbaldehydes have been synthesized by one of the
two pathways described below.
2-(2-Th ia zolyl)-4-cya n o-1H-im id a zole (2h ): Yield 2.1 g
1
(76%); mp >240 °C; H NMR (DMSO-d6, 200 MHz) 14.1 (bs,
1H), 8.3 (s, 1H), 8.05 (d, 1H), 7.95 (d, 1H). Anal. (C7H4N4S) C,
H, N, S.
2-(2-P yr idyl)-4-cyan o-1H-im idazole (2i): Yield 2.7 g (84%);
1
mp 233 °C; H NMR (DMSO-d6, 200 MHz) 13.7 (bs, 1H), 8.7
(d, 1H), 8.25 (s, 1H), 8.15 (d, 1H), 8.0 (t, 1H), 7.5 (m, 1H). Anal.
(C9H6N4) C, H, N.
P a th w a y A: F r om Cya n oim id a zoles 2 (Gen er a l P r o-
ced u r e E). The corresponding cyanoimidazole (1 equiv) in
anhydrous THF (∼2 mL/mmol) is treated under argon at -
78 °C with 1.5 equiv of DIBALH (1.0 M in toluene), followed
by stirring for 30 min at - 45 °C and 1 h at 0 °C. Ethanol (0.5
mL/mmol) is added and the stirring is continued for 1 h at 0
°C. The reaction mixture is concentrated to dryness and the
residue is flash chromatographed to afford the desired product.
2-(3-P yr idyl)-4-cyan o-1H-im idazole (2j): Yield 4.8 g (86%);
1
mp 247 °C (dec) (lit.16b mp 215-218 °C); H NMR (DMSO-d6,
200 MHz) 13.6 (bs, 1H), 9.1 (d, 1H), 8.65 (dd, 1H), 8.35 (s, 1H),
8.30 (dt, 1H), 7.5 (s, 1H). Anal. (C9H6N4) C, H, N.
2-(4-P yr id yl)-4-cya n o-1H-im id a zole (2k ): Yield 2.1 g
1
(84%); mp >240 °C; H NMR (DMSO-d6, 200 MHz) 14.0 (bs,
1H), 8.8 (m, 2H), 8.4 (s, 1H), 7.95 (m, 2H). Anal. (C9H6N4) C,
H, N.
2-(2-Na p h t h yl)-1H-4-im id a zolca r ba ld eh yd e (5b ): FC
2-(4-Nitr op h en yl)-4-cya n o-1H-im id a zole (2l): Yield 3.8
g (74%); mp >240 °C; 1H NMR (DMSO-d6, 300 MHz) 13.6 (bs,
1H), 8.32 (d, 2H), 8.3 (s, 1H), 8.15 (d, 2H). Anal. (C10H6N4O2)
C, H, N.
2-(4-Dim eth ylam in oph en yl)-4-cyan o-1H-im idazole (2m ):
Yield 2.0 g (50%); mp >240 °C; 1H NMR (DMSO-d6, 200 MHz)
13.1 (bs, 1H), 7.7 (s, 1H), 7.45 (d, 2H), 6.80 (d, 2H), 2.9 (s, 6H).
Anal. (C12H12N4) C, H, N.
with a mixture of dichloromethane and ethanol (99:1); Yield
1
0.9 g (36%); mp 216 °C; H NMR (DMSO-d6, 300 MHz) 13.7
(bs, 1H), 9.85 (s, 1H), 8.55 (s, 1H), 8.3-7.95 (m, 4H), 8.04 (s,
1H), 7.57 (m, 2H). Anal. (C14H10N2O) C, H, N.
2-(1-Naph th yl)-1H-4-im idazolcar baldeh yde (5c): FC with
a mixture of dichloromethane and ethanol (99:1); Yield 3.4 g
1
(39%); mp >240 °C; H NMR (DMSO-d6, 200 MHz) 13.5 (bs,
1H), 9.7 (s, 1H), 8.3-7.65 (m, 7H), 8.1 (s, 1H). Anal. (C14H10N2O)
2-(4-F lu or op h en yl)-4-cya n o-1H-im id a zole (2n ): Yield
1
C, H, N.
2.7 g (67%); mp 216-218 °C; H NMR (DMSO-d6, 200 MHz)
13.7 (bs, 1H), 8.21 (s, 1H), 8.0 (dd, 2H), 7.35 (dd, 2H). Anal.
(C10H6FN3) C, H, N.
2-(2-F u r yl)-1H-4-im id a zolca r ba ld eh yd e (5d ): FC with a
mixture of dichloromethane and ethanol (97:3); Yield 0.5 g

Neuroprotective Properties of Novel Imidazolyl Nitrones
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11 2173
(49%); mp 215 °C; 1H NMR (DMSO-d6, 200 MHz) 13.3 (bs, 1H),
9.8 (s, 1H), 8.4 (s, 1H), 8.3-7.3 (m, 3H). Anal. (C8H6N2O2) C,
H, N.
2-(3-F u r yl)-1H-4-im id a zolca r ba ld eh yd e (5e): FC with a
mixture of dichloromethane and ethanol (97:3); Yield 1.9 g
(51%); mp 225 °C; 1H NMR (DMSO-d6, 200 MHz) 13.5 (bs, 1H),
9.7 (s, 1H), 8.4 (s, 1H), 8.2 (s, 1H), 7.7 (d, 1H), 7.0 (d, 1H).
Anal. (C8H6N2O2) C, H, N.
P a th w a y B: F r om Wein r eb Am id es (Gen er a l P r oce-
d u r e F ). A solution of the corresponding amide 4 (1 equiv) in
THF (∼8 mL/mmol) is cooled under argon at -10 °C followed
by addition of LiAlH4 (4 equiv, 110 mg/mmol) in one portion.
The reaction mixture is stirred for 2 h at 0 °C and then
hydrolyzed by addition of wet Na2SO4. All solids are filtered
out, the liquid is concentrated in vacuo, and the residue is
chromatographed to afford the desired product.
2-(4-Ch lor op h en yl)-1H -4-im id a zolca r b a ld eh yd e (5r ):
FC with a mixture of dichloromethane and ethanol (99:1); Yield
0.5 g (20%); mp 207 °C; H NMR (DMSO-d6, 300 MHz) 13.5
2-(3-Th ien yl)-1H-4-im id a zolca r ba ld eh yd e (5f): FC with
a mixture of dichloromethane and ethanol (99:1); Yield 0.6 g
(32%); mp 226 °C (dec); H NMR (DMSO-d6, 200 MHz) 13.6
1
1
(bs, 1H), 9.76 (s, 1H), 8.1 (bs, 2H), 8.1 (bs, 1H), 7.6 (d, 2H).
Anal. (C10H7ClN2O) C, H, N, Cl.
(bs, 1H), 9.8 (s, 1H), 8.4 (s, 1H), 7.9 (d, 1H), 7.7 (m, 2H). Anal.
(C8H6N2OS) C, H, N, S.
2-(4-Meth oxyp h en yl)-1H-4-im id a zolca r ba ld eh yd e (5t):
FC with a mixture of dichloromethane and methanol (99:1);
Yield 0.6 g (48.3%); mp >240 °C; H NMR (CDCl3, 200 MHz)
11.0 (m, 1H), 9.75 (s, 1H), 8.0 (d, 2H), 7.85 (s, 1H), 7.0 (d, 2H),
3.85 (s, 3H). Anal. (C11H10N2O2) C, H, N.
P r ep a r a tion of Im id a zolyln itr on es 6 (Gen er a l P r oce-
d u r e G). The corresponding imidazocarbaldehydes 5 (1 equiv),
tert-butylhydroxylamine hydrochloride (1.5 equiv, 180 mg/
mmol), and NaHCO3 (1.5 equiv, 120 mg/mmol) in ethanol (0.6
mL/mmol) are stirred under argon at 60 °C during 16 h.
The reaction mixture is diluted with dichloromethane (6 mL/
mmol). The organic phase is washed with water, dried on
MgSO4, and then concentrated in vacuo. The residual oil,
quickly taken up into diethyl ether, crystallizes to afford after
filtration the desired product.
2-(4-1H-Im id a zolyl)-1H-4-im id a zolca r ba ld eh yd e (5g):
FC with a mixture of dichloromethane and 2N ammoniacal
methanol (95:5); Yield 1.9 g (41%); mp >240 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.0, 12.4 (bs, 2H), 9.9 (s, 1H), 8.3 (s,
1H), 7.8 (s, 1H), 7.6 (s, 1H). Anal. (C7H6N4O) C, H, N.
2-(2-Th ia zolyl)-1H-4-im id a zolca r ba ld eh yd e (5h ): FC
with a mixture of dichloromethane and ethanol (98:2); Yield
2.3 g (45%); mp 199-201 °C; H NMR (DMSO-d6, 300 MHz)
14.0 (bs, 1H), 9.85 (s, 1H), 8.15 (bs, 1H), 8.0 (d, 1H), 7.9 (d,
1H). Anal. (C7H5N3SO) C, H, N, S.
1
1
2-(2-P yr id yl)-1H-4-im id a zolca r ba ld eh yd e (5i): FC with
a mixture of dichloromethane and methanol (98:2); Yield 1.2
1
g (46%); mp 170 °C; H NMR (DMSO-d6, 200 MHz) 13.7 (bs,
1H), 9.8 (s, 1H), 8.7 (d, 1H), 8.15 (td, 1H), 8.12 (s, 1H), 7.9 (td,
1H), 7.5 (dd, 1H). Anal. (C9H7N3O) C, H, N.
(Z)-r-(2-P h en yl-1H-im id a zol-4-yl) N-ter t-bu tyl n itr on e
(6a ): Yield 10.8 g (91%); mp 209-210 °C; 1H NMR (CDCl3,
200 MHz) 13.0 (bs, 1H), 7.95 (s, 1H), 7.8 (d, 2H), 7.65 (dd, 1H),
7.4-7.15 (m, 3H), 1.5 (s, 9H). Anal. (C14H17N3O) C, H, N.
(Z)-r-[2-(2-Na p h th yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
tr on e (6b): Yield 1.2 g (99%); mp 200-202 °C; 1H NMR
(CDCl3, 200 MHz) 13.0 (bs, 1H), 8.4 (s, 1H), 8.1 (dd, 1H), 7.95
(d, 1H), 7.9-7.5 (m, 4H), 7.6 (s, 1H), 7.5 (s, 1H), 1.6 (s, 9H).
Anal. (C18H19N3O) C, H, N.
2-(3-P yr id yl)-1H-4-im id a zolca r ba ld eh yd e (5j): FC with
a mixture of dichloromethane and ethanol (95:5); Yield 1.3 g
(51%); mp 175 °C; 1H NMR (DMSO-d6, 200 MHz) 13.2 (bs, 1H),
9.7 (s, 1H), 9.1 (s, 1H), 8.65 (m, 1H), 8.4 (m, 1H), 8.2 (s, 1H),
7.6 (m, 1H). Anal. (C9H7N3O) C, H, N.
2-(4-P yr id yl)-1H-4-im id a zolca r ba ld eh yd e (5k ): FC with
a mixture of dichloromethane and ethanol (95:5); Yield 1.1 g
(55%); mp 204 °C; 1H NMR (DMSO-d6, 200 MHz) 13.8 (bs, 1H),
9.8 (s, 1H), 8.7 (d, 2H), 8.15 (s, 1H), 7.9 (d, 2H). Anal.
(C9H7N3O) C, H, N.
2-(4-Nitr op h en yl)-1H-4-im id a zolca r ba ld eh yd e (5l): FC
with a mixture of dichloromethane and ethanol (95:5); Yield
1.4 g (36%); mp >240 °C; 1H NMR (DMSO-d6, 200 MHz) 13.8
(bs, 1H), 9.8 (s, 1H), 8.5 (d, 2H), 8.35 (s, 1H), 8.2 (d, 2H). Anal.
(C10H7N3O3) C, H, N.
2-(4-Dim et h yla m in op h en yl)-1H -4-im id a zolca r b a ld e-
h yd e (5m ): FC with a mixture of toluene and methanol (95:
5); Yield 1.0 g (70%); mp 220 °C; 1H NMR (DMSO-d6, 200 MHz)
13.5 (bs, 1H), 9.8 (s, 1H), 7.85 (d, 2H), 7.75 (s, 1H), 7.6 (d, 2H),
3.0 (s, 6H). Anal. (C12H13N3O) C, H, N.
(Z)-r-[2-(1-Na p h th yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
1
tr on e (6c): Yield 3.0 g (70%); mp 95 °C; H NMR (DMSO-d6,
300 MHz) 12.85 (bs, 1H), 9.05 (m, 1H), 8.5 (s, 1H), 8.05 (dd,
2H), 8.0 (s, 1H), 7.8 (dd, 1H), 7.65 (m, 3H), 1.55 (s, 9H). Anal.
(C18H19N3O) C, H, N.
(Z)-r-[2-(2-F u r yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n itr o-
n e (6d ): Yield 1.3 g (49%); mp 103 °C (dec); 1H NMR (DMSO-
d6, 200 MHz) 12.9 (bs, 1H), 8.4 (bs, 1H), 7.9 (s, 1H), 7.9 (d,
1H), 7.0 (d, 1H), 6.7 (m, 1H), 1.55 (s, 9H). Anal. (C12H15N3O2)
C, H, N.
(Z)-r-[2-(3-F u r yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n itr o-
1
n e (6e): Yield 1.0 g (71%); mp 160 °C (dec); H NMR (CDCl3,
2-(4-F lu or op h en yl)-1H -4-im id a zolca r b a ld eh yd e (5n ):
FC with a mixture of dichloromethane and ethanol (95:5); Yield
200 MHz), 7.89 (d, 1H, J ) 1.5 Hz), 7.58 (s, 1H), 7.37 (m, 1H,
J ) 1.2 Hz), 7.17 (s, 1H), 6.72 (d, 1H), 1.49 (s, 9H). Anal.
(C12H15N3O2) C, H, N.
(Z)-r-[2-(3-Th ien yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
tr on e (6f): Yield 0.6 g (58%); mp 197-198 °C; 1H NMR
(DMSO-d6, 200 MHz) 12.7 (bs, 1H), 8.4 (d, 1H), 8.0 (d, 1H, J
) 4.8 Hz), 7.85 (s, 1H), 7.6 (m, 2H, J ) 2.0 Hz), 1.5 (s, 9H).
Anal. (C12H15N3OS) C, H, N, S.
(Z)-r-[2-(4-1H-Im id a zolyl)-1H-im id a zol-4-yl] N-ter t-bu -
tyl n itr on e (6g): Yield 0.75 g (27%); mp 220 °C (dec); 1H NMR
(DMSO-d6, 200 MHz) 12.35 (bs, 2H), 8.2 (bs, 1H), 7.75 (bs, 1H),
7.75 (bs, 1H), 7.5 (bs, 1H), 1.45 (s, 9H). Anal. (C11H15N5O) C,
H, N.
1
2.0 g (67%); mp 202-203 °C; H NMR (DMSO-d6, 200 MHz)
13.5 (bs, 1H), 9.8 (s, 1H), 8.15 (s, 1H), 8.15 (dd, 2H), 7.4 (dd,
2H). Anal. (C10H7FN2O) C, H, N.
2-(4-Tr iflu or om et h ylp h en yl)-1H -4-im id a zolca r b a ld e-
h yd e (5o): FC with a mixture of dichloromethane and ethanol
(95:5); Yield 3.7 g (51%); mp 221 °C; 1H NMR (DMSO-d6, 200
MHz) 14.0 (bs, 1H), 9.8 (s, 1H), 8.25 (d, 2H), 8.15 (s, 1H), 7.9
(d, 2H). Anal. (C11H7F3N2O) C, H, N.
2-(2-Ch lor op h en yl)-1H -4-im id a zolca r b a ld eh yd e (5p ):
FC with a mixture of dichloromethane and methanol (96:4);
1
Yield 1.5 g (54%); mp 184-185 °C; H NMR (DMSO-d6, 300
MHz) 13.2 (bs, 1H), 9.75 (s, 1H), 8.15 (bs, 1H), 7.9 (dd, 1H),
7.62 (dd, 1H), 7.57 (td, 1H), 7.53 (td, 1H). Anal. (C10H7ClN2O)
C, H, N, Cl.
(Z)-r-[2-(2-Th ia zolyl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
1
tr on e (6h ): Yield 1.40 g (52%); mp 170 °C; H NMR (DMSO-
d6, 300 MHz) 13.4 (bs, 1H), 8.4 (s, 1H), 7.95 (d, 1H), 7.9 (s,
1H), 7.85 (d, 1H), 1.5 (s, 9H). Anal. (C11H14N4OS) C, H, N, S.
(Z)-r-[2-(2-P yr id yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
tr on e (6i): Yield 0.85 g (55%); mp 172-173 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.0 (bs, 1H), 8.65 (m, 1H), 8.35 (d, 1H),
8.15-7.75 (m, 3H), 7.45 (m, 1H), 1.5 (s, 9H). Anal. (C13H16N4O)
C, H, N.
(Z)-r-[2-(3-P yr id yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
tr on e (6j): Yield 1.1 g (60%); mp 174-176 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.1 (m, 1H), 9.1 (s, 1H), 8.65 (m, 1H),
2-(3-Ch lor op h en yl)-1H -4-im id a zolca r b a ld eh yd e (5q ):
FC with a mixture of dichloromethane and methanol (95:5);
Yield 1.4 g (45%); mp 178-180 °C; H NMR (DMSO-d6, 300
MHz) 13.55 (bs, 1H), 9.76 (s, 1H), 8.1 (d, 1H), 8.1 (s, 1H), 7.98
(m, 1H), 7.5 (m, 2H). Anal. (C10H7ClN2O) C, H, N, Cl.
2-(p-Tolyl)-1H-4-im id a zolca r ba ld eh yd e (5s): FC with a
mixture of dichloromethane and ethanol (96:4); Yield 0.15 g
(49%); mp 199-200 °C; 1H NMR (DMSO-d6, 200 MHz) 13.5
(bs, 1H), 9.8 (s, 1H), 8.1 (m, 3H), 7.3 (d, 2H), 2.3 (s, 3H). Anal.
(C11H10N2O) C, H, N.
1

2174 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 11
Dhainaut et al.
8.5 (m, 1H), 8.3 (m, 1H), 7.9 (s, 1H), 7.5 (m, 1H), 1.5 (s, 9H).
Anal. (C13H16N4O) C, H, N.
(c) Tr ityla ted Nitr on e 10. A solution of 7.3 g (17.6 mmol)
of 9, 3.2 g of tert-butylhydroxylamine hydrochloride, and 2.1
g of sodium bicarbonate in 20 mL of ethanol is heated and
stirred overnight at 60 °C. The reaction mixture is diluted with
200 mL of dichloromethane, followed by washing with water.
Drying of the organic phase (MgSO4), removal of the solvent
in vacuo, and crystallization from diethyl ether afforded 5.8 g
(68%) of the desired compound: mp 224-225 °C; 1H NMR
(DMSO-d6, 400 MHz) 7.68 (d, 2H), 7.45 (m, 13H), 7.33 (t, 1H),
7.16 (m, 6H), 0.95 (s, 9H). Anal. (C33H31N3O) C, H, N.
(Z)-r-[2-(4-P yr id yl)-1H-im id a zol-4-yl] N-ter t-bu tyl n i-
tr on e (6k ): Yield 0.9 g (57%); mp 239-241 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.2 (m, 1H), 8.7 (d, 2H, J ) 6.0 Hz),
8.5 (bs, 1H), 7.9 (d, 2H), 7.9 (s, 1H), 1.5 (s, 9H). Anal.
(C13H16N4O) C, H, N.
(Z)-r-[2-(4-Nitr op h en yl)-1H-im id a zol-4-yl] N-ter t-bu tyl
n itr on e (6l): Yield 1.0 g (61%); mp 253 °C; 1H NMR (DMSO-
d6, 200 MHz) 13.2 (bs, 1H), 8.5 (bs, 1H), 8.4 (d, 2H, J ) 8.5
Hz), 8.2 (d, 2H), 7.9 (m, 1H), 1.5 (s, 9H). Anal. (C14H16N4O3)
C, H, N.
(Z)-r-[2-(4-Dim eth yla m in op h en yl)-1H-im id a zol-4-yl] N-
ter t-bu tyl n itr on e (6m ): Yield 1.0 g (70%); mp 190-192 °C;
1H NMR (DMSO-d6, 300 MHz) 12.45 (bs, 1H), 8.3 (bs, 1H),
7.8 (s, 1H), 7.75 (d, 2H), 6.75 (d, 2H), 2.95 (s, 6H), 1.45 (s, 9H).
Anal. (C16H22N4O) C, H, N.
(Z)-r-[2-(4-F lu or op h en yl)-1H-im id a zol-4-yl] N-ter t-bu -
tyl n itr on e (6n ): Yield 2.0 g (73%); mp 192-194 °C; 1H NMR
(DMSO-d6, 300 MHz) 12.81 (bs, 1H), 8.4 (bs, 1H), 7.98 (dd,
2H), 7.85 (s, 1H), 7.3 (t, 2H), 1.49 (s, 9H). Anal. (C14H16FN3O)
C, H, N.
(Z)-r-[2-(4-Tr iflu or om eth ylph en yl)-1H-im idazol-4-yl] N-
ter t-bu t yl n it r on e (6o): Yield 2.0 g (86%); mp 226 °C; 1H
NMR (DMSO-d6, 200 MHz) 13.1 (bs, 1H), 8.5 (m, 1H), 8.2 (d,
2H), 7.8 (s, 1H), 7.8 (d, 2H), 1.5 (s, 9H). Anal. (C15H16F3N3O)
C, H, N.
(Z)-r-[2-(2-Ch lor op h en yl)-1H-im id a zol-4-yl] N-ter t-bu -
tyl n itr on e (6p ): Yield 1.3 g (73%); mp 132-134 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.2 (bs, 1H), 8.05 (bs, 1H), 8.05 (d, 1H),
7.66-7.4 (m, 4H), 1.5 (s, 9H). Anal. (C14H16ClN3O) C, H, N,
Cl.
(Z)-r-[2-(3-Ch lor op h en yl)-1H-im id a zol-4-yl] N-ter t-bu -
tyl n itr on e (6q): Yield 1.5 g (79%); mp 181-183 °C; 1H NMR
(DMSO-d6, 300 MHz) 12.95 (bs, 1H), 8.45 (bs, 1H), 8.02 (t, 1H),
7.92 (dt, 1H), 7.87 (s, 1H), 7.5 (t, 1H), 7.42 (ddd, 1H), 1.49 (s,
9H). Anal. (C14H16ClN3O) C, H, N, Cl.
(Z)-r-[2-(4-Ch lor op h en yl)-1H-im id a zol-4-yl] N-ter t-bu -
tyl n itr on e (6r ): Yield 0.48 g (72%); mp 212-215 °C; 1H NMR
(DMSO-d6, 200 MHz) 13.0 (bs, 1H), 8.5 (d, 1H), 8.0 (d, 2H),
7.85 (s, 1H), 7.6 (d, 2H), 1.5 (s, 9H). Anal. (C14H16ClN3O) C,
H, N, Cl.
(d ) Nitr on e 11. A solution of 5.6 g (11.5 mmol) of 10 in 60
mL of ethanol containing 5 mL of acetic acid is heated at reflux
during 5 h. The reaction mixture is concentrated under
reduced pressure, and dichloromethane is added, followed by
washing with 5% NaHCO3 and then with water. The organic
phase is dried over MgSO4 and concentrated. Crystallization
of the residual oil from diethyl ether affords 2.0 g (71%) of the
final compound 11: mp 166 °C; 1H NMR (DMSO-d6, 200 MHz)
13.1 (bs, 1H), 7.95 (s, 1H), 7.8 (d, 2H), 7.65 (dd, 1H), 7.4-7.15
(m, 3H), 1.5 (s, 9H). Anal. (C14H17N3O) C, H, N.
(Z)-r-[1-Meth yl-2-p h en yl-1H-im id a zol-5-yl] N-ter t-bu -
tyl n itr on e (14) a n d (Z)-r-[3-Meth yl-2-p h en yl-1H-im id a -
zol-5-yl] N-ter t-bu tyl n itr on e (15). (a ) Ca r ba ld eh yd es 12
a n d 13. Commercially available 5a (6.3 g, 36.6 mmol) in 70
mL of dimethyl carbonate containing 7.7 g of potassium
carbonate and 0.5 g of crown ether (18-crown-6) are stirred at
80 °C for 80 h. After cooling to room temperature, the
insolubles are filtered off and washed with a mixture of
dichloromethane and methanol (8:2). The filtrate and washings
are concentrated, and the residue is flash chromatographed
(SiO2, 230-400 mesh) using a mixture of toluene, ethyl
acetate, and tetrahydrofuran (94:5:1) to afford 1.5 g (22%) of
carbaldehyde 12 [mp 87-89 °C; 1H NMR (DMSO-d6, 300 MHz)
9.74 (s, 1H), 8.0 (s, 1H), 7.72 (m, 2H), 7.5 (m, 3H), 3.91 (s,
3H). Anal. (C11H10N2O) C, H, N] and 1.2 g (17.6%) of carbal-
dehyde 13 [mp 98-100 °C; 1H NMR (DMSO-d6, 500 MHz) 9.85
(s, 1H), 8.15 (s, 1H), 7.75 (dd, 2H), 7.5 (m, 3H), 3.8 (s, 3H).
Anal. (C11H10N2O) C, H, N].
(b) Nitr on e 14. Carbaldehyde 12 (1.4 g, 7.5 mmol), 1.4 g of
tert-butylhydroxylamine hydrochloride, and 1 g of sodium
bicarbonate in 10 mL of ethanol are heated and stirred at 60
°C during 16 h under an argon atmosphere. The reaction
mixture is diluted with 100 mL of dichloromethane, and the
organic phase is washed with water, dried (MgSO4), and then
concentrated under reduced pressure. The oily residue is
quickly taken up in ether to afford after crystallization 1.2 g
(62%) of product 14: mp 155-157 °C; 1H NMR (DMSO-d6, 300
MHz) 8.4 (s, 1H), 7.8 (s, 1H), 7.7 (dd, 2H), 7.55 (m, 3H), 3.75
(s, 3H), 1.55 (s, 9H). Anal. (C15H19N3O) C, H, N.
(Z)-r-[2-p-Tolyl-1H-im id a zol-4-yl] N-ter t-bu tyl n itr on e
(6s): Yield 10.8 g (86%); mp 174-176 °C; 1H NMR (CDCl3, 200
MHz) 12.7 (bs, 1H), 7.8 (d, 2H), 7.7 (bs, 1H), 7.5 (bs, 1H), 7.2
(d, 2H), 2.35 (s, 3H), 1.6 (s, 9H). Anal. (C15H19N3O) C, H, N.
(Z)-r-[2-(4-Meth oxyp h en yl)-1H-im id a zol-4-yl] N-ter t-
bu tyl n itr on e (6t): Yield 0.8 g (97%); mp 198-201 °C; 1H
NMR (DMSO-d6, 200 MHz) 12.7 (bs, 1H), 8.4 (bs, 1H), 7.95
(d, 2H, J ) 8.8 Hz), 7.85 (s, 1H), 7.05 (d, 2H), 3.8 (s, 3H), 1.5
(s, 9H). Anal. (C15H19N3O2) C, H, N.
(c) Nitr on e 15. The procedure described for 14 was again
employed: Yield 1.0 g (51%); mp 178-180 °C; 1H NMR
(DMSO-d6, 300 MHz) 8.45 (s, 1H), 7.8 (s, 1H), 7.7 (dd, 2H),
7.5 (m, 3H), 3.8 (s, 3H), 1.5 (s, 9H). Anal. (C15H19N3O) C, H,
N.
(Z)-r-[4-P h en yl-1H-im id a zol-2-yl] N-ter t-bu tyl n itr on e
(11). (a ) Tr ityla ted Im id a zole 8. To a solution containing
9.9 g (6.9 mmol) of commercially available 4-phenyl-1H-
imidazole (7) in 50 mL of DMF and 10 mL of triethylamine
was added under an argon atmosphere 21.3 g (7.6 mmol) of
trityl chloride in 150 mL of DMF. After stirring for 4 h at room
temperature 2.5 L of water is added and the obtained gummy
precipitate is triturated with ether. Filtering followed by
drying affords 25.0 g (94%) of the expected compound: mp
198-190 °C; 1H NMR (CDCl3, 200 MHz) 7.80 (d, 1H), 7.74 (s,
2H), 7.55 (s, 1H), 7.40 (m, 18H). Anal. (C28H22N2) C, H, N.
(b) Tr ityla ted Ca r ba ld eh yd e 9. 25 mL of n-BuLi (1.6 M
in hexane) is added over a 15 min period to a solution of 9.93
g (25.7 mmol) of 8 dissolved in 250 mL of anhydrous THF,
and the mixture is stirred under argon at 0 °C. After 2 h, 8
mL of DMF is added at 0 °C over a period of 5 min, followed
by stirring for 2 h more at room temperature. The THF is
removed in vacuo, water (250 mL) is added, followed by
extraction with dichloromethane. Drying (MgSO4), concentra-
tion in vacuo, and crystallization from diethyl ether afford 7.3
g (68.5%) of carbaldehyde 9: mp 187 °C; 1H NMR (DMSO-d6,
300 MHz) 9.20 (s, 1H), 7.79 (d, 2H), 7.54 (s, 1H), 7.43 (m, 11H),
7.32 (t, 1H), 7.17 (m, 6H). Anal. (C29H22N2O) C, H, N.
P h a r m a cology. ter t-Bu tyl Hyd r op er oxid e-Med ia ted
Leth a lity. The induction of lethality in mice via icv injection
of t-BHP was based on the method of Adams.20 Male NMRI
mice (30-35 g) were administered an icv injection of a 70%
solution of t-BHP (22 mg/kg/µl). The lethality was then asses-
sed at 1, 2, 5, and 24 h postinjection. In general, icv injection
induced convulsive behavior followed by progressive mortality
(6-10 animals) between 1 and 24 h. The protective action of
drugs on t-BHP-induced lethality was estimated by a 30 min
pretreatment with drug administered at 150 mg/kg (ip), in 0.2
mL saline/Tween solution. Results are expressed as the percen-
tage survival estimated from the number of lethalities of the
t-BHP-treated group relative to t-BHP/drug-treated group; n
) 10 animals per group, at the respective time intervals.
Effect on Bod y Tem p er a tu r e. The total body temperature
of NMRI mice (25-30 g) was assessed, with the aid of a rectal
probe, at 30, 60, 90, and 120 min following intraperitoneal (ip)
injection of the tested antioxidants (150 mg/kg ip/0.2 mL
Tween/saline solution). Results are expressed as the maximal

Neuroprotective Properties of Novel Imidazolyl Nitrones
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Ack n ow led gm en t. We thank Dr. J . P. Volland and
his staff for analytical and NMR data, Mr. N. Lebled
for excellent technical assistance in synthesis, the staff
of Cerebral Pathology Division for the pharmacological
testing, and Miss Nathalie Bre´gou for the skillful typing
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Su p p or tin g In for m a tion Ava ila ble: Analytical data.
This material is available free of charge via the Internet at
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