8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines : Highly potent in vivo AMPA antagonists

Article abstract of DOI:10.1016/S0960-894X(00)00054-8

A novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines were synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent affinities (IC₅₀ = 4 and 19 nM, respectively) and antagonist properties (IC₅₀ = 2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration with ED₅₀ values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00054-8

Bioorganic & Medicinal Chemistry Letters 10 (2000) 591±596
8-Methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno-
[1,2-e]pyrazines: Highly Potent In Vivo AMPA Antagonists
Serge Mignani,* Georg Andrees Bohme, Alain Boireau, Michel Cheve,
Dominique Damour, Marc-Williams Debono, Arielle Genevois-Borella,
Assunta Imperato, Patrick Jimonet, Jeremy Pratt, John C. R. Randle, Yves Ribeill,
Marc Vuilhorgne and Jean-Marie Stutzmann
RhoÃne-Poulenc S.A., RhoÃne-Poulenc Rorer, Centre de Recherche de Vitry-Alfortville, 13 quai Jules Guesde, BP 14,
94403 Vitry-sur-Seine Cedex, France
Received 6 December 1999; accepted 24 January 2000
AbstractÐA novel series of readily water soluble 8-methylureido-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazines were
synthesized. The -10-yl acetic acid ((+)-3) and -10-carboxylidene (4) derivatives exhibit potent anities (IC50=4 and 19 nM,
respectively) and antagonist properties (IC50=2 and 3 nM, respectively) at the ionotropic AMPA receptor. These compounds also
display anticonvulsant properties against both electrically and sound-induced convulsions in mice after ip, sc and iv administration
with ED50 values between 0.9 and 11 mg/kg, thus suggesting adequate brain penetration. # 2000 Elsevier Science Ltd. All rights
reserved.
It is now well established that l-glutamate is the major
fast excitatory neurotransmitter in the mammalian cen-
tral nervous system. Glutamate activates three major
types of postsynaptic ionotropic receptors, NMDA,
AMPA and kainate receptors, as well as several types of
metabotropic receptors. Excessive glutamate activation
has been shown to be linked to neurodegeneration and
cell death.1 The di€erent chemical classes of AMPA
receptor antagonists have been recently reviewed in the
literature.2,3
activity and in vivo anticonvulsant activity was docu-
mented in Xenopus oocytes and convulsive models in
outbred and genetically seizure-prone mice, respectively
(Tables 1 and 2).
Chemistry
The synthesis of the 7-, 8- and 9-substituted-imidazo-
indenopyrazino derivatives 2a±d,r±y is outlined in
Scheme 1. This route involves the reaction of the com-
mercially available or known substituted indenones
5a,d,s±v,x7±10 with bromine or CuBr giving 6a,d,s±v,x.
Treatment of 6a,d,s±v,x and 6b,c,r,w11±14 with ethyl imi-
dazol-2-carboxylate 915 gave 7a±d,r±x. Then, according
to Pathway A, the carboxamide derivatives 8a±d,s±u,w
were easily obtained by an aminolysis reaction. Finally,
an intramolecular ring closure reaction using HCl gave
2a±d, s±u,w. It has to be emphasized that the action of
7r,v,x with ammonium acetate in glacial acetic acid
yielded directly the cyclized derivative 2r,x and for the
synthesis of 2v followed by the action of HCl and ®nally
of para-nitrophenyl-N-methylcarbamate16 (Pathway B).
Compound 2y was prepared according to a previous
procedure described by us4 by the condensation of 6y
with N-methyl-1H-imidazole-2-carboxamide followed
by reaction with an excess imidazole (Pathway C).
We have previously reported the preparation of 10H-
imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one (1) with
moderate AMPA and NMDA/glycine anity (IC50=
0.76 and 3 mM, respecively; Table 1), and anti-
convulsant (Table 2) and neuroprotective properties.4
In an e€ort to increase the potency of 1, chemical opti-
mization was performed, and we describe herein the
synthesis and the structure±activity relationships of the
resulting substituted imidazo[1,2-a]indeno[1,2-e]pyr-
azine-4-ones 2a±y, (‹)3, (+)3, ( )3 and 45,6 (Schemes
1±3). These new compounds exhibit moderate to high
anity for the AMPA receptor. In vitro antagonist
*Corresponding author. Tel.: +33-1-5571-8305; fax: +33-1-5571-
8014; e-mail: serge.mignani@aventis.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00054-8

592
S. Mignani et al. / Bioorg. Med. Chem. Lett. 10 (2000) 591±596
Table 1. In vitro anities of 1 and 2a±y
R1=R2=H
Receptor anity
Receptor anity
Cmpd.
R
AMPAa
Position 8
NMDA/glycinea
Cmpd.
R
AMPAa
NMDA/glycinea
Position 8
1
-H
-F
-Br
-Cl
0.76
0.25
2
16
30
30
3
7.8
2j
2k
2l
2m
2n
2o
2p
2q
2r
-NHCOCH2Ph
-NHCONH2
-NHCONHMe
-NHCONHEt
-NHCONMe2
-NHCONHPh
0.18
1.25
0.018
0.086
0.037
0.62
0.11
0.13
3.3
100
>100
100
10
100
>100
100
>100
5.3
>100
2a
2b
2c
2d
2e
2f
2g
2h
2i
>100
>100
>100
>100
22
8.4
10
>100
-Me
-SO3H
-NH2
-NHCO2Et
-NHCOMe
-NHCOPh
5.6
-NHCONHCH2Ph
-NHCONH(CH2)2Ph
-OMe
0.67
3.25
0.45
2s
100
Position 9
Position 7
2t
2u
2v
-F
-Cl
0.9
17
0.3
100
100
2.3
2w
2x
2y
-Cl
-F
-Me
3
0.97
>100
0.18
1
2.1
-NHCONHMe
aIC50 values (in mM) are mean of at least three determinations, each with at least three concentrations of tested compound in triplicate.
Table 2. In vitro and in vivo activities of 1, (‹)-3, (+)-3, ( )-3, 4, YM90K and ( )-LY293559
Cmpd
Receptor anity
Anticonvulsant activity
Antagonist activityb
Position 8: R=MeNHCONHÐ
AMPAa
NMDA/glycinea
MESc,d
DBA/2c,e
(‹)-3
0.008
0.039
0.004
0.019
14
10
1.8 ip
1 iv
2 sc
0.6 ip
4.4 ip
0.9 ip
1.6 ip
0.02
0.0067
0.002
0.003
(
)-3
7 ip
(+)-3
10
1 ip
4
100
11 ip
5.6 iv
1
YM90K
0.76
0.35
0.6
3
10
>10
62 ip
12 ip, iv
4 ip
nt
15 ip
nt
1.8
0.26
0.23
(
)-LY293559
aIC50 values (in mM) are mean of at least three determinations, each with at least three concentrations of tested compound in triplicate.
bIC50 values (in mM, except for 1: Kb value in nM from ref 4) for inhibition of currents generated by 50 mM kainate in Xenopus oocytes injected with
rat brain mRNA.
cPretreatment time: ip and sc: 30 min., iv: 5 min; vehicle for ip and sc: 1% Tween-80 in water; vehicle for iv: saline.
dED50 values (in mg/kg) 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 plus one group receiving vehicle alone).
eED50 values (mg/kg) are de®ned as the dose which protected 50% of the animals from an audiogenically induced tonic convulsion (six DBA/2 mice/
dose with three doses plus vehicle treated group).

S. Mignani et al. / Bioorg. Med. Chem. Lett. 10 (2000) 591±596
593
Scheme 1. Synthesis of 2a±d,r±y. Reagents and conditions: (a) 5a,d,s±v,x, Br2, 47% HBr, AcOH or CuBr, dioxane, 100 ꢀC, 41±100%; (b) 6a,d,r±x, 9,
base (NaH or DBU), DMF or toluene or neat phase or NaI:MeOH, rt-re¯ux, 13±43%; (c) 7a±d,s±u, w, 2.5±5 N, NH3:MeOH or NH3, MeOH, rt-
g
re¯ux, 34±94%; (d) 8a±d,s±u,w, 6±12 N, HCl, 5 ꢀC, 37±79%; (e) 7r,x, NH4Ac, AcOH, re¯ux, 56±62%; (i) 7v, NH4Ac, AcOH, re¯ux, (ii) 6 N HCl,
re¯ux until solubilization, (iii) p-nitrophenyl-N-methyl carbamate,15 followed by 0.5 N HCl, 30%; (f) (i) 6y, N-methyl-1H-imidazol-2-carboxamide,
DMF, 115 ꢀC, (ii) imidazole, neat phase, 160 ꢀC.
Scheme 2. Synthesis of 2,e,f±q. Reagents and conditions: (a) ClSO3H, rt, 86.5%; (b) KNO3, concd H2SO4, rt then H2 (1.2 bar), 0.1 N NaOH, cat.
Pd/C (10%), rt, 42.5%; (c) 2g: NaH, dioxane, 55 ꢀC then ClCO2Et, rt, 26%; 2h: Ac2O, DMF, Et3N, re¯ux, 93%; 2i,j: ClCOPh or ClCOCH2Ph,
Et3N, DMF, re¯ux, 20±69%; 2k±m,o±q: Et3N, DMF, R-NCO (R=Me3Si-Me-, Et-, Ph-, PhCH2 or Ph(CH2)2-), rt, 11±83%; 2n: Me2NCOCl,
DMAP, pyridine, rt, 15%.
Compound 2e was obtained from 1 by action of chloro-
sulfonic acid, whereas 2g±q were prepared in a three-
steps synthesis by regioselective nitration of 1 with
potassium nitrate followed by hydrogenation of the
nitro group in the presence of a catalytic amount of Pd/
C (10%), leading to 2f, and ®nally condensation of the
corresponding isocyanates (Scheme 2).
from the ester derivative 14 by preparative HPLC using
Chiracel OD as the stationary phase eluted by a 30:70
mixture of heptane:ethanol with 0.1% of TFA. Then,
compounds (+)-14 and ( )-14 were readily saponi®ed
by action of HCl giving (+)-3 [a2d0=+94.2 (DMF,
c=0.5)] and ( )-3 [a2d0= 83.8 (DMF, c=0.5)]. Com-
pound 4 was prepared from 12 by selective reduction of
the nitro group using concd HCl/SnCl2 followed by
condensation of methylisocyanate (Scheme 3).
Compound (‹)-3 was obtained by hydrolysis of 14 with
NaOH which was prepared in ®ve steps from 1: (a)
condensation of glyoxylic acid giving 10; (b) dehydra-
tion with ZnCl2-acetic anhydride giving 11; (c) regio-
selective nitration using KNO3 producing 12; (d)
reduction of both nitro and ethylenic groups using conc.
HCl/Fe leading to 13; (e) condensation of methyliso-
cyanate. The excellent AMPA anity of (‹)-3 (Table
2) prompted us to examine the enantiomers (+)-3 and
( )-3. They were prepared in an optically pure form
Biological Activity and SAR
In vitro binding studies
The anities for AMPA and NMDA/glycine recep-
tors were evaluated in in vitro binding assays on rat
cortical membrane preparations using [3H]-AMPA17

594
S. Mignani et al. / Bioorg. Med. Chem. Lett. 10 (2000) 591±596
Scheme 3. Synthesis of (‹) -3, (+)-3, ( )-3 and 4. Reagents and conditions: (a) HCOCO2H, NaH, DMF, rt then 1 N HCl, rt, 64%; (b) ZnCl2,
Ac2O, re¯ux, 23%; (c) KNO3, concd H2SO4, rt, 92%; (d) MeOH, concd HCl, Fe, 65 ꢀC, 83.5%; (e) MeNCO, K2CO3, DMF, 6 h, rt, 84.5%; (f) 1 N
NaOH, 35 ꢀC then 1 N HCl, 46%; (g) preparative HPLC (see text), (+)-14: 26%, ( )-14: 27%; (h) 8 N HCl, dioxane, 40 ꢀC, (+)-3: 67%, ( )-3:
63.5%, (i) SnCl2, concd HCl, 40 ꢀC, 94%; (j) MeNCO, K2CO3, DMF:dioxane 1:1, rt, 35%.
and [3H]-5,7-dichlorokynurenate ([3H]-DCKA)18 as
selective 3H-ligands. Results for compounds 1, 2a±y,
(‹)-3, (+)-3, ( )-3, 4, and the two representative
AMPA antagonists YM90K19 and ( )-LY29355920 are
reported in Tables 1 and 2. On the basis of these data,
the following structure±activity relationships were high-
lighted: the position and the nature of the substituents
pertaining to the imidazo[1,2-a]indeno[1,2-e]pyrazine-4-
one cycle 1 are crucial. Thus, introduction of various
substituents such as halogens (Br, Cl), the methyl group
and the electron-withdrawing group SO3H in position 8
decreased the binding at the AMPA receptor (2.5±40-
fold, 2b±e versus 1) whereas the introduction of a ¯uor-
ine atom gave the compound 2a which is up to 3-fold
more potent than 1. Compounds 2a±e exhibited the
greatest AMPA anities but had lower potency for the
glycine site (30- to >50-fold). Introduction of either an
electron-donating group NH2 (2f) or an acetylamino
group (2h) reduced the binding (4- to 7-fold) at the
AMPA receptor. Replacement of the methyl group of
2h by a phenyl (2i), a benzyl (2j) or an ethoxygroup (2g)
highly reinforced the AMPA anity (5- to 18-fold, 2j
and 2g versus 2h).
1H-imidazol-1-yl ring on the quinoxalinedione series
a€orded selective AMPA antagonist derivatives as
YM90K, we decided to prepare the compound 2s. This
compound exhibited poor anities for both AMPA and
glycine/NMDA receptors.
We next turned our attention to explore the e€ects of
substitutions at positions 7 and 9, on receptor anities.
Moving the N-methyl ureido moiety from 8 to 9 (2l
versus 2v) resulted in a 17-fold lower anity at the
AMPA receptor. The same e€ect applies to the 9-¯uoro
derivative (2t versus 2a) but not for the 9-chloro deri-
vative (2u) which retained the poor AMPA potency (2u
versus 2c). In comparison with 2d, introduction of a
methyl group in position 7 (compound 2y) resulted in
poor activity at the AMPA receptor and a weak potency
at the NMDA/glycine receptor whereas introduction of
a ¯uorine atom a€orded 2x which combined moderate
AMPA and NMDA/glycine anities (IC50±1 mM). In
comparison with 2c, introduction of a chlorine atom in
position 7 (2w) increased both AMPA and glycine/
NMDA anities (5- and >500-fold, respectively).
Starting from the most potent derivative 2l, the 10-sub-
stituted acid derivatives (‹)-3 and 4 have been pre-
pared. Introduction of a carboxymethyl moiety in
position 10 of 2l improved the AMPA anity 20-fold
((‹)-3 versus 2l) and maintained the hgh selectivity
versus NMDA/glycine site (1700-fold). Whereas intro-
duction of an E-carboxylidene moiety retained the
AMPA potency and the selectivity against the NMDA/
glycine receptor (4 versus 2l). The dextrorotatory isomer
(+)-3 displayed a 10-fold greater potency at the AMPA
receptor (IC50=0.004 mM) than did ( )-3 (IC50=0.039
The most signi®cant improvement on the AMPA
potency involved the introduction of N-alkylated and
N,N0-dialkylated ureido groups such as methyl, ethyl,
benzyl, or phenylethyl which markedly increased the
AMPA binding by 6- to 20-fold (2l±q). A potent urea
derivative (2l) displayed an IC50 of 18 nM while it also
retained a high selectivity versus the glycine-binding site
(>5000). Introduction of a methoxy group in position 8
as in 2r led to moderate combined AMPA and glycine/
NMDA anities (IC50±4 mM). Since the presence of a

S. Mignani et al. / Bioorg. Med. Chem. Lett. 10 (2000) 591±596
595
mM), while the selectivity versus the NMDA/glycine
receptor was more than 250-fold for both isomers.
Acknowledgements
We thank S. Baudouin, D. Briet, V. Brut, M.-A.
Coleno, R. Kerphirique, B. Martin and M. Roux for
technical assistance.
Functional studies
The antagonist activity of (‹)-3, ( )-3, (+)-3, 4 and 1
at the AMPA receptor were determined using kainate-
evoked currents in Xenopus oocytes injected with rat
brain mRNAs following classical electrophysiological
methods as previously described.21 The antagonist e-
cacy of these compounds at the AMPA receptor was
compared to that of the competitors YM90K and ( )-
LY 293559. All drugs were solubilized in concentrated
form (10 to 10 M) in water or dimethyl-sulfoxide
and then diluted to the desired concentration in the
recording medium. IC50 values were determined against
a submaximal concentration of the agonist and calcu-
lated by a non-linear least square regression procedure
according to a sigmoidal equation (Graphpad Prism
2.01). Compounds (+)-3, ( )-3 and 4 showed potent
and selective antagonist activity at the AMPA receptor
(see Table 2).
References and Notes
1. For a recent review, see: Doble, A. Pharmacol. Ther. 1999,
81, 163, and references cited therein.
2. Bigge, C. F.; Nikam, S. S. Exp. Opin. Ther. Patents 1997, 7,
1099.
3. Chimirri, A.; Gitto, R.; Zappala, M. Exp. Opin. Ther.
Patents 1999, 9, 557, and references cited therein.
4. 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.
5. Aloup, J.-C.; Audiau, F.; Barreau, M.; Damour, D.; Jim-
onet, P.; Genevois-Borella, A.; Jimonet, P.; Mignani, S.;
Ribeill, Y. Patent Applications, WO 94/07893, WO 95/26349
and WO 95/26350 (Chem. Abstr. 121: 83376; 124:146197 and
124: 146198, respectively).
3
2
6. 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 compounds
(‹)-3 and 4. (‹)-3: NMR (250 MHz , DMSO) d: 2.62 (1H,
dd, J=8 and 17 Hz, H1 ), 2.68 (3H,d, J=4.5 Hz, NMe), 3.15 (1H,
0
dd, J=4 and 17 Hz, H1 ), 4.38 (1H, dd, J=4 and 8 Hz, H10),
6.08 (1H, br.q NH), 7.38 (1H, dd, J=1.8 and 9 Hz, H7), 7.53
(1H, br.s , H2), 7.66 (1H, d, J=9 Hz, H6), 7.72 (1H, d, J=1.8 Hz,
H9), 8.1 (1H, br.s, H1), 8.7 (1H, s, ureido NH), 12.15 (1H, very
br.s, NH5). Attributions were secured thanks to NOE's obser-
vation. Strong enhancements were obtained between H1 and
In vivo studies
Compounds (‹)-3, (+)-3, ( )-3 and 4 demonstrated
potent in vivo activities at doses ꢁ11 mg/kg against
both MES-induced22 convulsions in male CD1 mice
(following ip, sc and iv administrations) and audiogenic
convulsions in DBA/2 mice23 (following ip adminis-
tration), 5 or 30 min before challenges (Table 2). Com-
pound 2l exhibited low in vivo potency in both models
(ED50>100 mg/kg ip) showing the crucial role of the
acid group in position 10 of the 10H-imidazo[1,2-a]in-
deno[1,2-e]pyrazin-4-one cycle. Thus, (+)-3e was found
to be a highly potent anticonvulsant (ED50ꢁ1 mg/kg ip)
in both in vivo models, unlike the levorotatory isomer
( )-3e which was between 5- and 7-fold less potent than
(+)-3 (ip route). Compound 4 was respectively 10- and
1.7-fold less potent than (+)-3 by ip administration in
MES and DBA/2, tests respectively. Compound (+)-3e
displayed a higher level of potency than YM90K and
( )-LY293558 (4±12-fold in MES test, 17-fold in DBA/
2 test) than the unsubstituted parent compound 1 (60-
fold in MES test). In addition, (‹)-3 and 4 demon-
strated high anticonvulsant activities by iv route in the
MES test with ED50s of ꢂ1±6 mg/kg and this route of
administration was facilited by their high solubility in
saline solution (7±10 g/L).
0
0
0
H10, H1 on the one hand and between H9 and H1 , H10, ureido
NH on the other, thus con®rming the skeletal arrangement. MS
(FAB, Gly/SGly): m/z 354 (MH+); IR (KBr) cm 1: 1675, 1640,
1555. Elemental analysis: % calcd C 57.79, H 4.28, N 18.82;
found C 57.80, H 4.30, N 19.80. 4: NMR (250 MHz, DMSO)
d: 2.64 (3H, d, J=4 Hz, NH), 6.10 (1H, br.q, NH), 6.98 (1H, s,
0
H1 ), 7.52 to 7.68 (3H, m, H2, H6 and H7), 8.3 (1H, d, J=1.5 Hz,
H9), 8.42 (1H, br.s, H1), 8.8 (1H, s, ureido NH), 12.65 (very br.s,
NH5). The relative stereochemistry of the double bond has been
obtained by NOE experiments. Strong NOE was observed
between H1 and H1. MS (FAB, Gly/SGly): m/z 352 (MH+).
0
IR (KBr) cm 1: 1687, 1675, 1655, 1560. Elemental analysis: %
calcd C 58.12, H 3.73, N 19.93; found C 58, H 4, N 20.
7. Compound 5s: Coates, W.; Kruse, L. I. US Patent Appli-
cation US 88-149743, Chem. Abstr. 112, 118861
8. Compound 5t: Olivier, O.; Marechal, E. Bull. Soc. Chim. Fr.
1973, 11, 3092.
9. Compound 5v was prepared from commercially available 4-
amino-indan-2-one by action of acetyl chloride in presence of
TEA at rt with 48% yield.
In conclusion, this study reports a novel series of het-
erocyclic-fused indeno[1,2-e]pyrazin-4-one derivatives
(+)-3 and 4 possessing high and selective anities for
the AMPA receptor (IC50<20 nM). They also exhibit
potent anticonvulsant e€ects following ip, sc and iv
administrations (ED50 ꢁ 11 mg/kg), suggesting an
excellent passage of the blood-brain barrier. To our
knowledge, compound (+)-3 possesses one of the high-
est anities for the AMPA receptors (IC50=4 nM)
identi®ed to date associated with high anticonvulsant
potency (ED50 ꢁ 1 mg/kg ip).
10. Compound 5x: Seka, R.; Kellerman, W. Chem. Ber. 1942,
1730.
11. Compound 6b: Blade, R. J. Eur. Patent Application EP
346107, (Chem. Abstr. 113), 6180
12. Compound 6c and 6w: Knabe, B.; Lang, H. J.; Granzer, E.
Ger. Patent Application DE 76-2640358, (Chem. Abstr. 88,
190817).
13. Compound 6r: Srivastava, S.; Kumar, P.; Thakur, S. N.;
Sahay, L. K.; Srivastava, J. N. J. Indian Chem. Soc. 1989, 66, 276.
14. Compound 6y: Peglion, J.-L.; Goument, B.; Millan, M.;
Newman, A.; Dekeyne, A. Eur. Patent Application EP 906912,
(Chem. Abstr. 130), 282085.

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S. Mignani et al. / Bioorg. Med. Chem. Lett. 10 (2000) 591±596
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