Bioisosteres of 9-carboxymethyl-4-oxo-imidazo[1,2-a]indeno-[1,2-e]pyrazin-2-carboxylic acid derivatives. Progress towards selective, potent in vivo AMPA antagonists with longer durations of action

Article abstract of DOI:10.1016/S0960-894X(00)00592-8

A novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyraz in-2-yl phosphonic acid 4i exhibited a stron

Full text of DOI:10.1016/S0960-894X(00)00592-8

Bioorganic & Medicinal Chemistry Letters 11 (2001) 127±132
Bioisosteres of 9-Carboxymethyl-4-oxo-imidazo[1,2-a]indeno-
[1,2-e]pyrazin-2-carboxylic Acid Derivatives.
Progress Towards Selective, Potent In Vivo AMPA Antagonists
with Longer Durations of Action
Patrick Jimonet, Georg Andrees Bohme, Jean Bouquerel, Alain Boireau,
Dominique Damour, Marc Williams Debono, Arielle Genevois-Borella,
Jean-Claude Hardy, Philippe Hubert, Franco Manfre,y Patrick Nemecek,
Jeremy Pratt, John C. R. Randle,{ Yves Ribeill,x Jean-Marie Stutzmann,
Marc Vuilhorgne and Serge MignaniÃ
Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, BP 14, F94403 Vitry-sur-Seine Cedex, France
Received 31 August 2000; revised 4 October 2000; accepted 24 October 2000
AbstractÐA novel series of 2- and 9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]pyrazin derivatives was synthesized. One of
them, the 9-(1H-tetrazol-5-ylmethyl)-4-oxo-5,10-dihydroimidazo[1,2-a]indeno[1,2-e]pyrazin-2-yl phosphonic acid 4i exhibited a
strong and a selective binding anity for the AMPA receptor (IC50=13 nM) and demonstrated potent antagonist activity
(IC50=6 nM) at the ionotropic AMPA receptor. This compound also displayed good anticonvulsant properties against electrically-
induced convulsions after ip and iv administration with ED50 values between 0.8 and 1 mg/kg. Furthermore, a strong increase in
potency was observed when given iv 3 h before test (ED50=3.5 instead of 25.6 mg/kg for the corresponding 9-carboxymethyl-2-
carboxylic acid analogue). These data con®rmed that there is an advantage in replacing the classical carboxy substituents by their
bioisosteres such as tetrazole or phosphonic acid groups. # 2001 Elsevier Science Ltd. All rights reserved.
Evidence suggests that glutamate, the major fast excita-
tory neurotransmitter in the central nervous system, is
involved in several neurodegenerative syndromes such
as Huntington's and Alzheimer's diseases, as well as in
brain ischemia and epilepsy.1 These processes are medi-
ated by NMDA, AMPA, kainate and metabotropic
receptors which in turn each comprise several sub-
classes.2 Blocking their activation is expected to have a
neuroprotective e€ect.3 AMPA antagonists have been
obtained from various chemical series such as quinox-
alines, heterocyclic-fused quinoxalinones, isatinoximes,
quinazolines, quinolones and decahydroisoquinolines.4
Representative examples are NBQX,5 YM90K,6 YM872,7
MPQX,8 ( )-LY2935589 or LY30016410 (Fig. 1). To
date, YM872 and LY300164 (talampanel) are the most
developed AMPA antagonists. These compounds have
reached in Phase I/II and Phase II clinical trials for
cerebrovascular ischemia, respectively.11
In the course of our e€orts to optimize the glutamate
receptor ligand imidazo[1,2-a]indeno[1,2-e]pyrazin-4-
one 1,12 we have previously published on some original
series of antagonists at the AMPA subtype of these
receptors such as the spiro-imidazo[1,2-a]indeno[1,2-e]-
pyrazin-4-ones (e.g., (+)-2)13 that are active at both the
glycine site of the NMDA and AMPA receptors, the 4-
oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-carboxylic acid
derivative 314 and the more recently described 8- and 9-
imidazo[1,2-a]indeno[1,2-e]pyrazin-9-acetic acids 4a and
4b15 which display high and selective anity at AMPA
receptors (Table 1).
ÃCorresponding author. Fax: +33-1-5571-8014; e-mail: serge.mignani
@aventis.com
yPresent address: Rhodia, Centre de Recherche de Lyon, Saint Fons,
France.
Encouraged by these results, we have now tried repla-
cing the two carboxylic moieties of 4a and 4b in order to
investigate further the structure±activity relationships
(SARs) in this family. Of particular interest was the
{Present address: Vertex Pharmaceuticals Incorporated, Cambridge,
MA 02139-4242, USA.
{Present address: Aventis Crop Science, Research Triangle Park,
North Carolina 27709, USA.
0960-894X/01/$ - see front matter # 2001 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00592-8

128
P. Jimonet et al. / Bioorg. Med. Chem. Lett. 11 (2001) 127±132
attempt to introduce a tetrazole ring and a phosphonic
acid group which are well known to be bioisosteres of
carboxylic acid functions16 and have led in several
cases to enhancements of potency, selectivity and/or
bioavailability.17
as outlined in Scheme 1. The 2-bromo indanones 6 were
obtained from indanones 519 using either bromide or
pyridinium perbromide monohydrate with a 36±100%
overall yield. Subsequent, regioselective condensation of
6 with the various 4-substituted-2-ethoxycarbonyl-
imidazoles 9±1120 and 12±15,21,24 in the presence of
potassium carbonate at re¯ux in acetone, a€orded ana-
logues of type 7 directly with low to excellent yields (25±
100%) or following simple hydrolysis and amidi®cation
protocols. Thus, the methylsulfonamide and phenyl-
sulfonamide analogues of 7 were obtained (38±52%
yield). Treatment of 7 with ammonium acetate in glacial
acetic acid or 5 N NH3/MeOH, at re¯ux, led to the cor-
responding 4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazines
derivatives 8 with moderate yield (30±60%). Finally, the
synthesis of 4c,d,g±k,22m±o was achieved by the hydrolysis
of the corresponding 4-oxo-imidazo[1,2-a]indeno[1,2-
e]pyrazine derivatives 8c,d,g±k,m±o using either acidic
(HBr, HCl) or basic conditions (NaOH) followed by the
action of HCl (40±80% yield). The expected compounds
4e and 4f were readily saponi®ed (NaOH) with 60 and
In this study, we describe the synthesis and the binding
properties of 4-oxo-imidazo[1,2-a]indeno[1,2-e]pyr-
azines 4c±o.18a,b We also report their anticonvulsant
e€ects in vivo, when administered by ip and iv routes, to
normal mice submitted to an electric shock (MES). The
in¯uence of bioisosteric replacement of carboxylic acids
in positions 2 and 9 of parent compounds 4a and 4b is
particularly studied with the objective of obtaining
potent AMPA antagonists with long durations of action.
Chemistry
The 4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazines 4c±o
were prepared following a four- or a ®ve-step synthesis
Figure 1.
Table 1. Binding studies and anticonvulsant pro®le by ip and iv route of 1, 4a±o, NBQX, YM90K and ( )-LY293558
a
Compound
Receptor anity IC50 nM
Anticonvulsant activity MES ED50b mg/kg
AMPA
NMDA/glycine
ip
iv
1
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
4m
4n
760
18
4
15
586
189
235
139
150
13
3000
7200
2100
537
62
1.2
2
2.3
5.6
10
Ð
Ð
3.5
1
4.7
2.2
1.9
5
Ð
0.5
0.5
2.0
Ð
5
Ð
Ð
2.9
0.8
2.5
3.8
Ð
5
>10,000
328
1200
2000
>10,000
2360
>10,000
>10,000
1600
147
30
31
12
5800
7200
6100
40
8.6
Ð
36
12
4
Ð
Ð
Ð
12
3.4
4o
NBQX
YM90K
100
140
350
600
>10,000
10,400
>10,000
(
)-LY293558
aIC50 values are mean of at least three determinations, each with at least three concentrations of tested compound in triplicate.
bED50 values are de®ned as the dose which protected 50% of the animals from a tonic convulsion (six male CD1 mice/dose of compound, with at
least three doses compared to a group receiving vehicle alone, pretreatment time by ip route: 30 min; iv route: 5 min, vehicle for ip: 1% Tween-80 in
water, vehicle for iv: saline.

P. Jimonet et al. / Bioorg. Med. Chem. Lett. 11 (2001) 127±132
129
90% yields, respectively. Hydrogenation of 4k in the
presence of a catalytic amount of Pd/C (10%) led to 4l
with a 50% yield.
On the basis of these binding data, the following SARs
could be highlighted: in position 9, replacement of the
carboxylic acid of 4a by several known bioisosteres, that
is tetrazole (4c), phosphonic acid (4d), N-methylcarbox-
amide (4e), N-methylsulfonylcarboxamide (4f) or
N-phenylsulfonylcarboxamide (4g), was only successful
for compound 4c by the introduction of the tetrazolyl
moiety. The AMPA binding anity was retained
(IC50=15 nM) but about a 10-fold decrease of selectiv-
ity versus the glycine/NMDA binding site was observed.
The other isosteric replacements led to more dramatic
changes reducing the potency of the AMPA ligands by a
factor of 8±32. In position 2, replacement of the carboxy
groups of 4a and 4b was performed with two com-
plementary objectives: either a bioisosteric modi®cation
as in position 9 in order to get improvements of the
pharmacodynamic pro®le, or a further exploration of
Biological Activity and SARs
In vitro studies
The binding anities for AMPA and glycine/NMDA
receptors were evaluated in in vitro binding assays using
[3H]-AMPA25 and [3H]-5,7-dichlorokynurenate ([3H]-
DCKA)26 as selective [3H]-ligands on rat cortical mem-
brane preparations. Results for compounds 1, 4a±o,
NBQX, YM90K and ( )-LY293558 are reported in
Table 1.
Scheme 1. Synthesis of 4c±o. Reagents and conditions: (a) 6c,e,h: Br2, CH2Cl2, rt, 1±5 h, 88±100%; 6d: pyridinium perbromide monohydrate, 50 ꢀC,
0.25 h, 77%; 6f: AcOH, HBr (47%), Br2, rt, 1 h, 84% then PhMe, N,N-dimethylformamide di-tert-butyl acetal, 80 ꢀC, 10 min, 36%; (b) K2CO3,
acetone, re¯ux, 1±4 h, 27±100%, 7c,d: 9, 7h,i: 11, 7j: 12, 7k: 10, 7m: 13, 7n: 14, 7o: 15; 7e: 9, K2CO3, 18-crown-6, acetone, re¯ux, 2 h, 26%; 7g: (1) 9,
K2CO3, acetone, re¯ux, 4 h, 90%; (2) 6 N HCl, dioxane, 89%; (3) CDI, THF, rt, 1.5 h then PhSO2NH2, NaH, THF, rt, 1 h, 65%; 7f: 9, K2CO3,
acetone, re¯ux, 4 h, 90% then 6 N HCl, dioxane, 89% then CDI, THF, rt, 0.5 h followed re¯ux, 0.5 h then MeSO2NH2, DBU, THF, rt, 18 h, 47%;
(c) 8c±h,j,k,m±o: AcONH4, AcOH, re¯ux, 1±7 h, 29±61%; 8i: 5 N NH3/MeOH, re¯ux, 16 h then AcONH4, AcOH, re¯ux, 16 h, 43%; (d) 4c,d,
.
.
.
4i HBr: HBr (30±47%), 3±20 h, re¯ux, 42±62% 4e 3H2O, 4f di-sodium salt: 1 N NaOH, H2O, dioxane, rt, 6 h, 63±92%; 4g: 1 N NaOH, H2O, diox-
.
.
.
ane, rt, 20 h then 1 N HCl, rt, 2 h, 49%; 4h,j, 4m HCl, 4n HCl: 6 N HCl, rt, 2±16h, 66±79%; 4k HCl: cHCl/AcOH, re¯ux, 48 h, 54%; 4o: 12 N HCl,
re¯ux, 64 h, 54%; (e) 4l: 4k, H2 (pressure: 73.5 psi), 0.3 N NaOH, Pd/C (10%), rt, 12 h then 1 N HCl until pH=7, 50%.

130
P. Jimonet et al. / Bioorg. Med. Chem. Lett. 11 (2001) 127±132
the SAR in this position by lengthening and/or con-
straining the carboxyalkyl-like chain. The introduction
of a phosphonic acid as a substitute for the carboxylic
acid of 4a and 4b induced in both cases a lower potency
leading to compounds with moderate anities (4h and
4j, IC50=147±150 nM). Pursuing the lengthening of the
carboxyalkyl chain by the introduction of either a car-
boxyethyl group or the unsaturated E-carboxylidene
moiety decreased the potency for the AMPA receptor
by about 10-fold (4l and 4k versus 4b). We next turned
our attention to explore the e€ects of introducing 2-, 3-,
or 4-carboxyphenyl moieties. Moving the carboxylic
acid around the phenyl ring from position 2 to positions
3 and 4 (4m±o) increased the AMPA anity with IC50's
as low as 12, 40 and 100 nM, respectively. Interestingly,
the most potent derivative 4m demonstrated the same
level of AMPA binding potency and selectivity against
the glycine site of the NMDA receptor as the parent
carboxylic acid 4a, thus showing room for possible
drastic modi®cations in position 2 of this series of
AMPA ligands.
In vivo studies
Compounds 4c±e,h±n demonstrated moderate to good
in vivo activities against MES-induced convulsions28 in
normal mice following ip (30 min before challenge) or iv
administration (5 min before challenge) with ED50
values between 0.8 and 8.6 mg/kg. Among these com-
pounds, 4i displayed the strongest anticonvulsant prop-
erties with an ED50 of 1 and 0.8 mg/kg by ip and iv
route, respectively.
The duration of action of several of the most potent
compounds in this series (4a±c,e,h±k,m) was studied in
the MES test (pre-treatment time: 3 h) following iv
administration in the mouse. As shown in Table 2, the
compounds 4i and 4h demonstrated long durations of
action with ED50's of 3.5 mg/kg. Compared to the par-
ent compound 4a, replacement of the carboxy group by
a phosphonic acid in position 2 (compound 4h) led to a
dramatic increase of potency after a 3 h pre-treatment
(ED50=3.5 versus 25.6 mg/kg iv). This combines with
about a 10-fold decrease of anity for the AMPA
receptor, thus the improvement of in vivo potency is
impressive; it suggests the superiority of the phosphonic
over the carboxylic moiety for in vivo activity and a
long duration of action, in this series. This superiority is
also evident by comparing 4j and 4b: despite a 36-fold
lower binding potency, the phosphonic analogue 4j only
displayed a 2-fold decrease of anticonvulsant activity
after 30 min (ip) or 5 min (iv) and similar protective
e€ect administered iv 3 h before challenge to the car-
boxylic derivative 4b. The other modi®cations in posi-
tion 2 were less critical leading to compounds with
similar in vivo potency and duration of action to the
parent carboxylic acids (4k,m versus 4a,b). In position 9,
replacement of the carboxymethyl group by a 1H-tetra-
zol-5-yl moiety while it did not induce any signi®cant
change in 4c compared to 4a, but when combined with
the introduction of a phosphonic acid in position 2 as in
4i versus 4h, both in vitro and in vivo potency enhance-
ments were observed giving the very potent and selective
AMPA antagonist 4i with a duration of action lasting at
least 3 h. This contrasts with YM90K where, 3 h post-
administration, the ecacious dose exceeded 40 mg/kg.
The iv administration of 4i was also largely facilitated
by its high solubility in saline solution (ꢁ10 g/L).
In comparison with NBQX, YM90K and (±)-LY293558,
the fused 2,9-disubstituted-4,10-dihydro-4-oxo-4H-imi-
dazo[1,2-a]indeno[1,2-e]pyrazines 4c,i,m exhibited a 10-
to 40-fold higher potency at the AMPA receptor while
they retained a good selectivity versus the glycine site of
the NMDA receptor (between 36- and 480-fold). In
addition, 4c,i,m were about 50-fold more potent for the
AMPA receptor than the unsubstituted derivative 1.
The functional activity of 4i at AMPA receptors was
determined using kainate-evoked currents in Xenopus
oocytes injected with human recombinant GluR1+
GluR2 mRNA. The potency of this ligand at AMPA
receptors was examined using current response analysis
as previously described.27 Compound 4i antagonized
kainate-induced responses in a concentration-dependent
manner showing an IC50 value of 6 nM (Fig. 2) versus
260 and 230 nM (rat cortex mRNA) for YM90K and
(±)-LY293558, respectively.
Table 2. Duration of action of compounds 4a±c,e,h±k,m and YM90K
in the mouse (iv, 3 h post-administration)
a
Compound
Anticonvulsant activity ED50 mg/kg
4a
4b
25.6
28
4c
4e
4h
4i
In. 40
>2 0
3.5
3.5
4j
4k
4m
YM90K
22.4
25.6
15
>4 0
aED50 values are de®ned as the dose which protected 50% of the ani-
mals from a tonic convulsion (six male CD1 mice/dose of compound,
with at least three doses compared to a group receiving vehicle alone
(vehicle: saline).
Figure 2. Antagonist activity of compound 4i against functional
responses mediated by AMPA receptors in voltage clamped oocytes.
Data are meanÆSD response of three oocytes in the presence of the
indicated concentration of 4i.

P. Jimonet et al. / Bioorg. Med. Chem. Lett. 11 (2001) 127±132
131
In conclusion, this study reports a novel series of 2- and
9-disubstituted heterocyclic-fused 4-oxo-indeno[1,2-e]-
pyrazines. The best biological activities were obtained
with a phosphonic acid group in position 2 and either a
carboxymethyl or a (1H-tretrazol-5-yl) methyl group in
position 9 of the 5H,10H-imidazo[1,2-a]indeno[1,2-e]-
pyrazine-4-one ring. Compound 4i possesses one of the
highest anities for the AMPA receptor (IC50=13 nM),
a good selectivity against the glycine site of the NMDA
receptor (ꢁ180-fold) and also exhibits potent anti-
convulsant e€ects following ip and iv administration at
doses below 1 mg/kg with a long duration of action
compared to the carboxylic acid analogues 4a and 4b. In
addition, 4i exhibits very potent antagonist intrinsic
activity against AMPA receptor-mediated responses in
Xenopus oocytes (IC50=6 nM). This compound cer-
tainly represents one of the very few soluble and long
lasting AMPA antagonists reported to date. Therefore,
in the imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one series, it
seems to be advantageous from a pharmacodynamic
point of view to replace the classical carboxy sub-
stituents by their bioisosteres such as a tetrazole or a
phosphonic acid group as far as this chemical modi®ca-
tion is tolerated by the receptor site.
A. R.; Lodge, D.; Leander, J. D. Bioorg. Med. Chem. Lett.
1999, 9, 1953.
11. (a) Anderson, B. A.; Harn, N. K.; Hansen, M. M.; Hark-
ness, A. R.; Lodge, D.; Leander, J. D. Bioorg. Med. Chem.
Lett. 1999, 9, 1953. (b) Wojciech, D. Drugs 2000, 3, 84 and
references cited therein.
12. Mignani, S.; Aloup, J.-C.; Blanchard, J.-C.; Bohme, G. A.;
Boireau, A.; Damour, D.; Debono, M. W.; Dubroeucq,
M.-C.; Genevois-Borella, A.; Imperato, A.; Jimonet, P.; Pratt,
J.; Randle, J. C. R.; Reibaud, M.; Ribeill, Y.; Stutzmann, J.-
M. Drug. Dev. Res. 1999, 48, 121.
13. Jimonet, P.; Boireau, A.; Cheve, M.; Damour, D.; Gene-
vois-Borella, A.; Imperato, A.; Pratt, J.; Randle, J. C. R.;
Ribeill, Y.; Stutzmann, J.-M.; Mignani, S. Bioorg. Med. Chem.
Lett. 1999, 9, 2921.
14. Stutzmann, J.-M.; Bohme, G. A.; Boireau, A.; Damour,
D.; Debono, M. W.; Genevois-Borella, A.; Imperato, A.; Jim-
onet, P.; Pratt, J.; Randle, J. C. R.; Ribeill, Y.; Vuilhorgne,
M.; Mignani, S. Bioorg. Med. Chem. Lett. 2000, 10, 1133.
15. Pratt, J.; Jimonet, P.; Bohme, G. A.; Boireau, A.;
Damour, D.; Debono, M. W.; Genevois-Borella, A.; Randle,
J. C. R.; Ribeill, Y.; Stutzmann, J.-M.; Vuilhorgne, M.;
Mignani, S. Bioorg. Med. Chem. Lett. 2000, 10, 2749.
16. Lipinski, C. A. Annu. Rep. Med. Chem. 1986, 27, 283 and
references cited therein.
17. (a) For examples, see: Auberson, Y. P.; Acklin, P.; Bis-
cho€, S.; Moretti, R.; Ofner, S.; Schutz, M.; Veenstra, S.
Bioorg. Med. Chem. Lett. 1999, 9, 249. (b) Marshall, W. S.;
Goodson, T.; Cullinan, G. J.; Swanson-Bean, D.; Haisch,
K. D.; Rinkema, L. E.; Fleisch, J. H. J. Med. Chem. 1987, 30,
682. (c) Kraus, J. L. Pharmacol. Res. Commun. 1983, 15, 183.
18. (a) All the new compounds described herein have been
fully characterized using 1H NMR, IR and mass spectro-
scopies, and have given satisfactory elemental analyses (C, H,
N). As examples, data obtained for the most potent in vivo
compounds 4i and 4k are reported in ref 22. (b) Aloup, J.-C.;
Audiau, F.; Barreau, M.; Damour, D.; Genevois-Borella, A.;
Hardy, J.-C.; Jimonet, P.; Manfre, F.; Mignani, S.; Bouquerel,
J.-C.; Nemecek, P.; Ribeill, Y. Patent applications WO96/
31511; Chem. Abstr. 126:8136 and WO97/25328; Chem. Abstr.
127:176439.
Acknowledgements
We thank S. Beccari, F. Chenot, F. Gay, R. Kerphir-
ique, B. Martin, A. Renaudon, M. Roux and J.-C.
Szmigel for technical assistance.
References and Notes
19. (a) The indanone 5c was prepared in a six-step pathway
from the commercially available 2-bromophenyl-acetonitrile
16 according to the sequence outlined in Scheme 2. No
attempt has been conducted to locate the position of the ben-
zyl group attached to the tetrazole ring of 17, 18 and 5c. (b)
The 4-diethylphosphonomethyl-indanone 5d was prepared
using an Arbuzov±Michaelis reaction by the condensation of
triethylphosphite with (4-bromomethyl)indanone23 in xylene
at re¯ux (8 h) with 63% yield. (c) The 4-carboxy-
methylindanone 5f was obtained in a three-step synthesis from
2-bromophenylacetic acid via a Heck reaction with acrylic acid
[(Pd(OAc)2/tri-o-tolylphosphine)], followed by hydrogenation
of the double bound (Pd/C) and ®nally a Friedel±Craft
cyclization (concd H2SO4) with 11% overall yield. Esteri®ca-
tion of 5f (EtOH/ClCOCOCl) gave 5h with 57% yield,
1. (a) For recent reviews, see: Satkowski, M.; Attwell, D.
Trends Neurosci. 1994, 17, 359. (b) Danysz, W.; Parsons, C. G.;
Bresink, I.; Quack, G. Drug News Perspect. 1995, 8, 261. (c)
Doble, A. Pharmacol. Ther. 1999, 81, 163 and references cited
therein.
2. Nakanishi, S. Science 1992, 258, 597 and references cited
therein.
3. For a recent review, see: Nature 1999, 399(Suppl), and
references cited therein.
4. For a recent review, see: Chimirri, A.; Gitto, R.; Zappala,
M. Exp. Opin. Ther. Patents 1999, 9, 557 and references cited
therein.
5. Sheardown, M. J.; Nielsen, E. O.; Hansen, A. J.; Jacobsen,
P.; Honore, T. Science 1990, 247, 571.
6. Ohmori, J.; Sakamoto, S.; Kubota, H.; Shimizu-Sasamata,
M.; Okada, M.; Kawasaki, S.; Hidaka, K.; Togami, J.; Fur-
uya, T.; Murase, K. J. Med. Chem. 1994, 37, 467.
7. Habert, A.; Takahashi, M.; Yamaguchi, T.; Hjelstuen, M.;
Haraldseth, O. Brain Res. 1998, 811, 63.
8. Turski, L.; Huth, A.; Scheardown, M.; Wiegand, F.;
Jacobsen, P.; Ottow, E. Proc. Natl. Acad. Sci. U.S.A. 1998, 95,
10960.
9. Ornstein, P. L.; Arnold, M. B.; Augenstein, N. K. J. Med.
Chem. 1993, 36, 2046.
10. Anderson, B. A.; Harn, N. K.; Hansen, M. M.; Harkness,
Scheme 2. Synthesis of 5c: (a) NaN3, NH4Cl, DMF, 100 ꢀC, 6 h,
83.5%; (b) BrCH2Ph, K2CO3, acetone, re¯ux, 5 h, 100%; (c) acrylic
acid, Pd(OAc)2, Et3N, tri-o-tolylphosphine, 100 ꢀC, 16 h, 92%; (d) H2
(pressure: 22 psi), Pd/C (10%), NaOH/H2O, 1.5 h, 84%; (e) H2SO4
(95%), 100 ꢀC, 0.5 h, 64%; (f) BrCH2Ph, K2CO3, acetone, re¯ux, 5 h,
100%.

132
P. Jimonet et al. / Bioorg. Med. Chem. Lett. 11 (2001) 127±132
whereas the action of the methylamine with 5f (CDI/THF)
a€orded 5e with 75% yield (Structure, see Scheme 1).
20. 9: Branco, P. S.; Prabhakar, S.; Lobo, A. M.; Williams, D.
Tetrahedron 1992, 48, 6335. 10: 4-(3-Ethoxy-3-oxo-1-pro-
penyl)-imidazole-2-carboxylate (10) was prepared in three-step
synthesis from commercially available 2,5-dihydro-2,5-dime-
thoxy furfurylamine via a Cornforth±Huang-cyclization reac-
tion with 17.5% overall yield (Vuilhorgne, M.; Bouquerel, J.;
Mignani, S. Syn. Lett. 2000, submitted for publication). 11: 2-
Ethoxycarbonyl-imidazole-4-phosphonate (11) was prepared
in one-step synthesis by the condensation of hydroxy-
iminoglycine ethyl ester (Gregory, G. I.; Seale, P. W.; War-
burton, W. K.; Wilson, M. J. J. Chem. Soc., Perkin Trans. 1
1973, 47) with diethyl ethylphosphonate (Daniel, T.; McMils,
M. C.; Chamberlin, A., Cotman, C. W. Brain Res. 278, 1983,
137) with 17% yield, Canton, T.; Bohme, G. A.; Boireau, A.;
Mignani, S.; Jimonet, P.; Vuilhorgne, M.; Debono, M.-W.; Le
Guern, S.; Laville, M.; Briet, D.; Roux, M.; Stutzmann, J.-
M.; Pratt, P. J. Pharmacol. Exp. Ther. 2000, submited for
publication.
between the methylene group attached to the tetrazole and H8,
H10 on the other. MS (FAB, Gly/SGly): m/z 386 (MH+). IR
(KBr) cm 1: 3250±2100, 1695, 1210, 975, 925. Elemental ana-
lysis: % calcd C 38.65, H 2.81, N 21.03; found C 38.45, H 2.8,
.
N 20.93. 4k HCl (RPR 127759): NMR (250 MHz, DMSO) d:
3.8 (2H, s, CH2), 4 (2H, s, H10), 6.65 (1H, d, J=16 Hz,
CHˆCH, trans), 7.25 (1H, dd, J=8 and 1.5 Hz, H8), 7.4 (1H,
t, J=8 Hz, H7), 7.6 (1H, d, J=16 Hz, CHˆCH, trans), 7.85
(1H, dd, J=8 and 1.5 Hz, H6), 8.45 (1H, s, H1), 12.7 (1H, br.s,
H5). Stereochemistry of the double bond (E) was easily
deduced from the value (J=16 Hz) of the vicinal coupling
constant while the expected NOEs were observed between the
CH2COOH and H8, H10 on the one hand and between H1, H10
and the CHˆCH protons on the other. MS (CI, NH3): m/z
352 (MH+). IR (KBr) cm 1: 3380, 3200±2300, 1695, 1680.
Elemental analysis: % calcd C 55.75, H 3.64, N 10.84; found C
55.7, H 3.84, N 10.8.
23. Nakada, Y.; Ohno, S.; Yoshimoto, M.; Yura, Y. Agric.
Biol. Chem. 1978, 42, 1365.
24. 21a: Verbruggen, C.; De Craeker, S.; Rajan, P.; Jiao, X.-
Y.; Borloo, M.; Smith, K.; Fairlamb, A. H.; Haemers, A.
Bioorg. Med. Chem. Lett. 1996, 6, 253. 21b and 21d were
prepared in a two-step synthesis from the corresponding ethyl
4-bromoacetylbenzoate (Desideri, N.; Conti, C.; Sestili, I. M.;
Tomao, P.; Stein, M. L.; Orsi, N. Antiviral Chem. Chemother.
1992, 3, 195) and ethyl 2-bromoacetylbenzoate (Viti, G.;
Giannotti, D.; Nannicini, R.; Ricci, R.; Pestellini, V. J. Het-
erocycl. Chem. 1991, 28, 379) by the condensation with difor-
mylimide sodium salt (MeCN, 80 ꢀC, 3±16 h) followed by the
action of 5% solution of HCl in ethanol (rt, 3 h) with 33 and
50% overall yield, respectively. 21c: Pratesi, P.; Grana, E.;
Villa, L. Farmaco 1973, 28, 753.
21. The 2-ethoxycarbonyl imidazole derivatives 12±15 were
easily prepared in a one-step synthesis with 27±73% yields
(Scheme 3).
Scheme 3. Synthesis of 12±15. Reagents and conditions: (a) AcOH,
AcONa, 95 ꢀC, 3±3.5 h, 12: 69%, 13: 73%, 14: 53.5%, 15: 27%.
25. Honore, T.; Drejer, J. J. Neurochem. 1988, 51, 457.
26. Canton, T.; Doble, A.; Miquet, J.-M.; Jimonet, P.; Blan-
chard, J.-C. J. Pharm. Pharmacol. 1992, 44, 812.
27. Debono, M. W.; Le Guern, J.; Canton, T.; Doble, A.;
Pradier, L. Eur. J. Pharmacol. 1993, 235, 283.
.
22. 4i HBr (RPR 121879): NMR (250 MHz, DMSO) d: 4.1
(2H, s, H10), 4.45 (2H, s, CH2), 7.2 (1H, dd, J=8 and 1.5 Hz,
H8), 7.45 (1H, t, J=8 Hz, H7), 7.8 (1H, dd, J=8 and 1.5 Hz,
H6), 8.2 (1H, s, H1), 12.45 (1H, br.s, H5). Attributions were
secured thanks to NOE observation. Strong enhancements
were obtained between H1 and H10 on the one hand, and
28. Swinyard, E. A.; Brown, W. C.; Goodmann, L. S. J.
Pharmacol. Exp. Ther. 1952, 106, 319.