Synthesis and potent anticonvulsant activities of 4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid AMPA antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00561-8

The over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a] indeno[1,2-

Full text of DOI:10.1016/S0960-894X(00)00561-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2749±2754
Synthesis and Potent Anticonvulsant Activities of
4-Oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-8- and -9-carboxylic
(Acetic) Acid AMPA Antagonists
Jeremy Pratt, Patrick Jimonet, Georg Andrees Bohme, Alain Boireau,
Dominique Damour, Marc Williams Debono, Arielle Genevois-Borella,
John C. R. Randle,y Yves Ribeill,{ Jean-Marie Stutzmann,
Marc Vuilhorgne and Serge Mignani*
Aventis Pharma S.A., Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, B.P. 14, 94403 Vitry-sur-Seine Cedex, France
Received 22 June 2000; revised 20 September 2000; accepted 29 September 2000
AbstractÐThe over-stimulation of excitatory amino acid receptors such as the glutamate AMPA receptor has been suggested to be
associated with neurodegenerative disorders. Here we describe an original series of readily water soluble 4-oxo-imidazo[1,2-a]
indeno[1,2-e]pyrazin-8- and -9-carboxylic (acetic) acid derivatives. One of these compounds, 4f, exhibited nanomolar binding a-
nity, potent competitive antagonism at the ionotropic AMPA receptor and a long duration of anticonvulsant activity after adminis-
tration by parenteral route in vivo. # 2000 Elsevier Science Ltd. All rights reserved.
There is considerable evidence that the over-stimulation of
excitatory amino acid receptors, notably the glutamate
AMPA (2-amino-3-(3-hydroxy-5-methylisoxazole-4-)-
propionic acid) receptor may be involved in damage to
neuronal tissue during acute and chronic neurodegen-
erative disorders.1
AMPA antagonists described to date are members of
the following chemical families: (a) tricyclic derivatives;
(b) substituted quinoxalinediones; (c) quinolones; (e) isa-
tin oximes and (f) benzodiazepine derivatives.3 Repre-
sentative compounds that have reached some degree of
development include YM90K,4 MPQX,5 ( )-LY293558,6
and the non-competitive AMPA antagonist Talampanel
(LY300164) which appears to be the most advanced
clinically.7
The AMPA receptor complex is a ligand-gated ion
channel primarily permeable to Na+ and K+ which can
secondarily contribute to the entry into neurons of toxic
amounts of Ca2+ via a depolarization of the cells. This
leads to the removal of the Mg2+ block of the nmda
channel and to the opening of voltage-dependent Ca2+
channels. In addition, it has been shown in certain brain
areas such as the hippocampus that the AMPA recep-
tor-channel complex can lose one of its constitutive
protein sub-units in response to injury which renders it
Our investigations into the design of novel potent and
selective compounds belonging to this pharmacological
class started with the initial discovery of the anticonvulsant
and neuroprotective properties of imidazo[1,2-a]indeno
[1,2-e]pyrazin-4-one 1.8 We have previously described
two original series of competitive AMPA antagonists.
These were spiro-imidazo[1,2-a]indeno[1,2-e] pyrazin-4-
ones9 such as (+)-2, which recognize both the AMPA
receptor and the glycine site of the NMDA receptor,
and 4-oxo-imidazo[1,2 - a]indeno[1,2 - e]pyrazin - 2 - car-
boxylic acid derivatives10 such as 3, which demonstrate
selective binding anity for the AMPA receptor and
good activity in vivo in rodent models of convulsions
(Fig. 1).
directly permeable to Ca2+ 2
.
These ®ndings have led to an intensive search for
AMPA antagonists as potential neuroprotectants. The
*Corresponding author. Fax: +33-1-55-71-80-14;
e-mail: serge.mignani@aventis.com
yPresent address: Vertex Pharmaceuticals Incorporated, Cambridge,
MA 02139-4242, USA.
{Present address: Aventis Crop Science, Research Triangle Park, NC
27709, USA.
The present report describes the synthesis and the
pharmacological properties of a novel series of 8- and 9-
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00561-8

2750
J. Pratt et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2749±2754
Figure 1.
substituted carboxy- or carboxyalkyl-imidazo[1,2-a]in-
deno[1,2-e]pyrazines 4a±i.11,12 This original class of
AMPA receptor antagonists encompasses former com-
pounds that demonstrated moderate to high AMPA
binding anity in good correlation with antagonist
activity at functional AMPA receptors in vitro. Proper-
ties of the most relevant compounds are summarized in
Table 1, along with their in vivo anticonvulsant prop-
erties against electrically induced seizures in mice.
Structure±activity relationships (SARs) in this family
were identi®ed and led to the synthesis of 9-carboxy-
methyl-4,5-dihydro-4-oxo-imidazo-[1,2-a] indeno[1,2-
e]pyrazin-2-carboxylic acid 4f. This compound is
endowed with high binding anity for AMPA receptor
in rat brain membrane preparations (IC50= 4 nM) and
strong competitive antagonist activity as assessed by its
inhibitory activity on currents associated with AMPA
receptor activation (KB=5nM). Compound 4f is a very
ecient anticonvulsant when administered by i.p. route
to normal mice submitted to an electric shock (maximal
electroshock, MES) or to genetically seizure prone DBA/
2 mice submitted to sound with ED50s ꢀ 2 mg/kg. 4f also
shows high potency after i.v. and s.c. administration in
convulsion models induced by chemical substances, and
exhibited a long duration of action in the MES test.
Chemistry
The targeted 4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazines
4a±d,f±i were prepared from 2-bromo indanones 6a±
d,g,h following the reactions described in Scheme 1.
Compound 4e has been prepared in a similar way from
2-bromo-indanone with a 21% overall yield.10
Compounds 6a±d,g,h reacted with the imidazole-2-car-
boxylate derivatives 10j±l13 either under neat phase, in
toluene at re¯ux or using potassium carbonate as a base
in acetone at re¯ux. It led to the corresponding 2-sub-
stituted indanones 7a±d,f±i with moderate to good
Table 1. Binding studies, in vitro pharmacology and anticonvulsant pro®le by intraperitoneal route of 1, 4a±i, NBQX, YM90K and ( )-LY293558
Receptor anitya IC50 (nM)
Anticonvulsant activity ED50
(mg/kg i.p. (i.v.))
MESc
R1
R2
Compound
AMPA
NMDA
Antagonist activityb
H
H
H
H
H
9-CO2H
8-CO2H
9-CH2CO2H
8-CH2CO2H
H
9-CH2CO2H
8-CH2CO2H
9-CHMeCO2H
9-CH2CO2H
1
4a
4b
4c
4d
4e
4f
4g
760
3500
620
89
10,000
150
18
3000
21,000
10,000
>10,000
>10,000
83
1800
3252
2008
104
2644
29
5
214
53
23
31
260
230
62
Ð
>80
>80
Ð
H
-CO2H
-CO2H
-CO2H
-CO2H
-CH2CO2H
50
7200
1.2 (0.5)
16
19
2 (0.5)
36
12
611
450
4
140
350
600
>10,000
4100
2100
>10,000
10,400
>10,000
4h
4i
NBQX
YM90K
)-LY293558
(
4
aIC50 values are mean of at least three determinations, each with at least three concentrations of tested compound in triplicate.
bIC50 values (except for 1 and 4f: KB values in nM; 1 from ref 8) for inhibition of currents generated by 50 mM kainate in Xenopus oocytes injected
with rat brain mRNA.
cED50 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 (vehicle: 1% tween in water), pretreatment time by i.p. route: 30 min; i.v. route: 5 min.

J. Pratt et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2749±2754
2751
Scheme 1. Synthetic pathway for compounds 4a±d,f±i. Reaction conditions: (a) Br2, CHCl3 or CH2Cl2, 5 ꢂC to rt, 1±3 h, 33±100%; (b) 7a: 10j, neat phase,
130 ꢂC, 35%; 7b and 7d: 10j, PhMe, re¯ux, 6±26 h, 58±65.5%; 7c, 7f and 7h,i: 10j or 10k or 10l, K2CO3, acetone, re¯ux, 3±35 h, 33±67%; 7g: K2CO3, 18-
crown-6, DMF, 2 h, 85ꢂC then 16h, rt, 58%; (c) 8a,b: gNH3, MeOH, rt, 12h, 89±100%; (d) 9a,b: AcOH, re¯ux, 15h, 43±46.5%; (e) 9c,d and 9f±i:
AcONH4, AcOH, re¯ux, 4±16 h, 3±92%; (f) 4a,b: concd H2SO4, re¯ux, 2 h, 31±77% 4c: 8 N HCl, 40 ꢂC, 90h then 0.1N NaOH, 39.5%; 4d, 4g and 4i : 6 N
HCl, re¯ux, 2±16 h, 62±86.5%; 4f and 4h: 1 N NaOH, dioxane±water, 4 h, rt then 0.5±1 N HCl, 40±64%; 4g: 6 N HCl, dioxane, re¯ux, 5 h, 72%.
yields (33±67%). The carboxamide derivatives 8a,b were
obtained from the corresponding ester derivatives 7a
and 7b by action of ammonia gas in methanol with 89%
and 100% yields, respectively. Intramolecular ring clo-
sure reactions of 8a and 8b were carried out in glacial
acetic acid at re¯ux giving 9a and 9b with ꢁ40% yield.
Treatment of 7c,d,f±i with ammonium acetate in glacial
acetic acid at re¯ux directly led to the cyclized derivatives
9c,d,f±i with good yields (55±92%) for 9f±i, while a poor
yield (3±7%) was obtained for the preparation of 9c and
9d. Finally, the synthesis of 4a±d,f±i was achieved by
hydrolysis of 9a±d,f±i using either acid (H2SO4 or HCl)
or basic conditions (NaOH) followed by the action of
HCl. The carboxylic acid derivatives 4a±d,f±i were
obtained with moderate to good yields (31±86.5%).
The indanones 5c15 and 5h were easily obtained in
four/®ve-step synthesis from the commercially available
2-bromophenylacetic acid 11 as outlined in Scheme 2.
The key chemical steps were: (i) the direct carbon±carbon
coupling reaction of acrylic acid with 11 and 12 a€ording
13a and 13b with good yields (58±64%), and (ii) the
intramolecular cyclization reaction of 14a and 14b
under acidic reaction conditions (conc. H2SO4, H3PO4/
PCl5) giving 15a and 15b with 17 and 90% yields,
respectively.
The indanones 5d and 5g were prepared in a three-step
pathway from ethyl phenylacetate 16 via the synthesis
of 18 according to the sequence outlined in Scheme 3: (i)
acylation with 3-chloropropionyl chloride under stan-
dard Friedel±Craft's reaction conditions a€ording 17;
(ii) ring cyclization using concd H2SO4 giving 18; and (iii)
esteri®cation or amidi®cation of the carboxylic group
giving 5d or 5g, respectively.
The 2-bromo indanones 6a±d,g,h were prepared from the
corresponding indanones 5a,b,14 5c±d,g,h under standard
reaction conditions using bromine with 33±100% yields.

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J. Pratt et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2749±2754
Scheme 2. Synthetic pathway of indanones 5c and 5h. Reaction conditions: (a) KOH, CH2Cl2, TEBA, dimethyl disulfate, rt, 12 h then 1 N NaOH,
THF, rt, 4 h followed by 1 N HCl, 100%; (b) acrylic acid, Pd(OAc)2, for 13a: 11, Bu3N, tri-o-tolylphosphine, 100 ꢂC, 6 h, 64%; for 13b: 12, Na2CO3,
re¯ux, 35 h then 6 N HCl, 58%; (c) H2 (pressure of H2=17.6 psi), cat. Pd/C (10%), AcOH or DMF, 2±5 h, >98%; (d) 15a: concd H2SO4, 100 ꢂC,
18 h, 17%; 15b: H3PO4, PCl5, 130 ꢂC, 3 h, 90%; (e) EtOH, ClCOCOCl, rt, 1±4 h, 57±97%.
Scheme 3. Synthetic pathway of indanones 5d and 5g. Reaction conditions: (a) Cl(CH2)2COCl, AlCl3, CH2Cl2, rt, 24h, 9%; (b) concd H2SO4, 100 ꢂC,
1 h, 58%; (c) 5d: EtOH, MeSO3H, re¯ux, 2 h, 91%; 5g: CDI, gH2NMe, 10ꢂC to rt, 1 h, 67%.
Biology
receptor (IC50=7200 nM). On the other hand, intro-
duction of a carboxymethyl group in position 8 of 4e
decreased by 4-fold the binding anity at the AMPA
receptor (4g versus 4e) as did the introduction of a
1-carboxyethyl group in position 9 of 4e (4h versus 4f,
3-fold). The highest anity for the AMPA receptor was
®nally obtained by a methylene lengthening of the car-
bonyl group in position 2 of 4f which increased by 4.5-
fold the anity for the AMPA receptor (IC50=4 nM, 4i
versus 4f).
In vitro studies
The binding anities for AMPA and glycine/NMDA
receptors were evaluated in in vitro binding assays using
[3H]-AMPA16 and [3H]-5,7-dichlorokynurenate ([3H]-DC
KA)17 as selective H-ligands on rat cortical membrane
preparations. Results for compounds 1, 4a±i, NBQX,
YM90K and ( )-LY293559 are reported in Table 1. On
the basis of these binding data, the following SARs have
been identi®ed:
3
In comparison with NBQX, YM90K and ( )-LY293558,
the fused dicarboxylic-indenopyrazinone derivatives 4f
and 4i exhibit 8- to 150-fold higher anity at the AMPA
receptor while they retained the selectivity (ꢃ400-fold)
versus the glycine site of the NMDA receptor.
Introduction of a carbonyl group in position 9 of the imi-
dazo[1,2-a]indeno[1,2-e]pyrazin-4-one cycle 1 decreased
the binding at the AMPA receptor (5-fold, 4a versus 1)
whereas the introduction of the same group in position
8 did not modify the activity (4b versus 1). An interest-
ing improvement of the AMPA anity was achieved by
the introduction of a carboxymethyl moiety in position
9 of 1 (8.5-fold, 4c versus 1) but not in position 8 (4d
versus 1). This suggests that position 9 of the imidazo
[1,2 - a]indeno[1,2 - e]pyrazin - 4 - one cycle is critical to
obtain a high AMPA binding anity. Compounds 4a±c
exhibited lower potency than 1 for the glycine site (ꢃ3-
fold).
The antagonist activity of 1, 4a±i, NBQX, YM90K and
( )-LY293558 at AMPA receptors was determined using
kainate-evoked currents in Xenopus oocytes injected with
rat brain mRNAs as previously described18 (Table 1).
The compounds were screened for IC50 determination
using a supra-threshold and sub-maximal concentration
of kainate (50 mM). Compound 4f appeared to be the
most potent and was selected for further in depth
examination of its mechanism of action. This compound
antagonized kainate-induced responses in a competitive
manner as shown by the parallel rightward shift of the
concentration±response curve to kainate without
depression of the maximal response. Schild plot analysis
of this e€ect yielded a pA2 value of 8.3 (Fig. 2).
Introduction in the position 2 of 1 of a carbonyl group
increased the binding at both receptor subtypes (5-fold
for the AMPA receptor, 36-fold for the glycine/NMDA
receptor, 4e versus 1).
Given these preliminary results, the introduction of a
carboxymethyl group in position 9 of 4e, leading to
compound 4f, considerably increased the anity for the
AMPA receptor (IC50=18 nM) while retaining the
selectivity (400-fold) with respect to the glycine/NMDA
In vivo studies
As shown in Table 1, compounds 4f±i demonstrated
protective activity in vivo against maximal electroshock-

J. Pratt et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2749±2754
2753
Figure 2. Antagonism by compound 4f of AMPA receptor mediated currents. Left: concentration±response curves to kainate in the absence (white
circles) and in the presence of the following concentrations of 4f: triangles=3 nM; inverted triangles=10 nM; squares=30 nM; diamonds=100 nM.
Data are mean Æ SEM from n=3 cells. Right: pA2 determination using the Schild plot analysis: the anity constant (KB) was found by interpolating
log (DR-1) to zero.
induced (MES) convulsions in normal male CD1 mice
following intraperitoneal (i.p.) administration. Among
these compounds, 4f and 4i exhibited strong anti-
convulsant activities with ED50 of 1.2 and 2 mg/kg by
i.p. route, respectively. Given the high solubilities in
saline medium (ꢃ10 g/L) of their monosodium and dis-
odium salts, respectively, 4f and 4i could easily be
administered intravenously. Both compounds showed
ED50 values of 0.5 mg/kg when given 5 min before MES
challenge, suggesting adequate ADME by this route of
paramount importance for a potential use in patients
su€ering acute neurodegenerative a‚ictions such as
ischaemia or trauma. Of note, these two compounds dis-
play a ꢁ25-fold higher potency than their previously
described unsubstituted parent compound 18 and the 2-
carboxylic analogue 4e, and a 2- to 30-fold greater
activity than what was reported for NBQX, YM90K
and ( )-LY293558.
Figure 3. Duration of action of compound 4f in the mouse (i.v. and
s.c.) and in the rat (s.c.). Values are ED500s obtained from three groups
of six animals plus six control animals for each time point. Time is the
delay between administration of the compound and the electroshock
challenge.
The anticonvulsant pro®le of the most potent com-
pound in this series 4f was studied in somewhat greater
details. This compound exhibited a wide range of anti-
convulsant activity when assayed against chemoconvul-
sive agents such as pentylenetetrazole (a blocker of GABA
receptor complex), isoniazide (an inhibitor of glutamic
acid decarboxylase) and 4-aminopyridine (a K+ channel
blocker) by i.p. or s.c. routes (Table 2). 4f also had a
long duration of action in mouse (i.v. and s.c.) and rat
(s.c.) in the MES test as demonstrated in Figure 3.
dihydro-4-oxo-imidazo[1,2-a]indeno[1,2-e]pyrazin-2-
carboxylic acid derivatives exempli®ed by compound 4f
and its -2-acetic acid analogue 4i. Both compounds
possess high and selective binding anity for the
AMPA receptor (IC50 ꢀ 18 nM), and display potent
anticonvulsant activity in vivo following i.p. adminis-
tration (ED50 ꢀ 2 mg/kg). Compound 4f behaves as a
potent competitive antagonist at ionotropic AMPA-
type glutamate receptors, and nonetheless shows a long
duration of action following i.v. and s.c. administration
with ED50 remaining below 30 mg/kg 3 to 6 h post-
In conclusion, this study reports a novel series of readily
water soluble heterocyclic-fused 9-carboxymethyl-4,5-
Table 2. Anticonvulsant pro®le of 4f
MESa CD1
mouse ED50 (mg/kg)
MESa SD rat
ED50 (mg/kg)
Chemoconvulsive agentsb
in mouse ED50 (mg/kg)
(pretreatment time)
DBA/2c mouse ED50
(mg/kg)
0.5 i.v.
1 s.c.
1.2 i.p.
0.4 i.v.
1 s.c.
4.8 i.p.
Pentylenetetrazole: 1.7 i.p. (30 min)
Isoniazide: 1.5 s.c. (0 min)
4-Aminopyridine: ꢁ16 s.c. (30 min)
0.8 i.p.
aED50 values are de®ned as the dose which protected 50% of the animals from a tonic convulsion (six male animals/dose of compound, with at least
three doses compared to a group receiving vehicle alone (1% tween in water) when given by i.v. (5 min before MES) or s.c. and i.p. (30 min before
MES).
bPentylenetetrazole: 150 mg/kg s.c.; isoniazide: 200 mg/kg i.p.; 4-aminopyridine: 15 mg/kg i.p.
cED50 values are de®ned as the dose which protected 50% of the animals from tonico-clonic convulsions (vehicle: 1% tween in water), pretreatment
time: 30 min.

2754
J. Pratt et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2749±2754
administration. The broad anticonvulsant pro®le of this
compound con®rms the involvement of AMPA recep-
tors in epileptogenic processes and highlights the inter-
est of new AMPA antagonists as potential treatments
against epilepsy and acute or chronic neurodegenerative
diseases.
10. 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, in press.
11. Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.;
Genevois-Borella, A.; Jimonet, P.; Mignani, S.; Ribeill, Y.
Patent Applications WO 95/26349 (Chem. Abstr. 124:146197).
Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.; Gene-
vois-Borella, A.; Hardy, J.-C.; Jimonet, P.; Manfre, F.;
Mignani, S.; Ribeill, Y. Patent Applications WO 96/31511
and WO 97/25328 (Chem. Abstr. 126:8136 and 127:176439,
respectively).
12. All compounds described herein gave satisfactory spectro-
scopic and elemental analysis data. As an example, we report
below a full description of what was obtained for compound 4f:
1H NMR (250 MHz, DMSO) d: 3.7 (2H, s, CH2COOH), 4 (2H,
s, H10), 7.2 (1H, br.d, J=8 Hz, H8), 7.35 (1H, t, J=8Hz, H7), 7.8
(1H, br.d, J=8Hz, H6), 8.5 (1H, s, H1), 12.45 (1H, br.s, NH5).
Strong NOEs were observed between H10 and H1, CH2COOH
in one hand and between H8 and CH2COOH on the other,
thus con®rming the previous attributions. MS (CI/NH3): m/z
326 (MH+). IR (KBr) cm 1: 3120, 3075, 2950, 2875, 1720,
1680. Elemental analysis: % calcd C 59.08, H 3.41, N 12.92;
found C 59.2, H 3.5, N 12.8.
13. 10j: Galeazzi, E.; Guzman, A.; Nava, J. L.; Liu, Y.;
Maddox, M. L.; Muchowski, J. M. J. Org. Chem. 1995, 60,
1090. 10k: Branco, P. S.; Sundaresan, P.; Lobo, A. M.; Wil-
liams, D. J. Tetrahedron 1992, 48, 6335. 10l: The imidazole 10l
was prepared in one-step synthesis by the action of ethyl
(ethylthio)iminoacetate tetra¯uoroborate (Yamanaka, H.;
Mizugaki, M.; Sakamoto, T.; Sagi, M.; Nakagawa, Y.;
Takayama, H.; Ishibashi, M.; Miyazaki, H. Chem. Pharm.
Bull. 1983, 4549) with ethyl 4-aminoacetoacetate chlorhydrate
(Orr, D. E.; Miah, A. J. Chem. Ind. 1983, 10, 392) in the pre-
sence of sodium acetate with 66% yield (AcOH, 95 ꢂC, 3 h);
yellow solid, mp 88 ꢂC.
Acknowledgements
We thank S. Beccari, D. Briet, V. Brut, F. Gay, B. Just,
B. Martin and M. Roux for technical assistance.
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