Novel AMPA receptor antagonists: Synthesis and structure-activity relationships of 1-hydroxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)- quinoxalinedione and related compounds

Article abstract of DOI:10.1021/jm960387+

As part of our study of novel antagonists at the α-amino-3-hydroxy-5- methylisoxazole-4-propionate (AMPA) subtype of excitatory amino acid (EAA) receptors and the pharmacophoric requirements of the receptor, we designed and synthesized a series of 1-substituted 6-imidazolyl-7-nitro-, and 7- imidazolyl-6-nitroquinoxalinediones, as well as related compounds, 6a-j, 7, 11a-e, 15, and 17, which are 1- and 4-substituted analogues of 1 (YM90K), and evaluated their activity to inhibit [³H]AMPA binding from rat whole brain. On the basis of their structure-activity relationships (SAR), we deduced that the amide proton of the imidazolyl-near side of the quinoxalinedione nucleus is not essential for AMPA receptor binding, whereas that of the imidazolyl- far amide is. Further, the receptors possess size-limited bulk tolerance for their N-substituents on the imidazolyl-near amide portion. Moreover, we found that introduction of a hydroxyl group at the imidazolyl-near amide portion causes a severalfold improvement in AMPA receptor affinity over unsubstituted derivatives. Among the compounds, 1-hydroxy-7-(1H-imidazol-1-yl)-6-nitro- 2,3(1H,4H)-quinoxalinedione (11a) showed high affinity for AMPA receptor with a K(i) value of 0.021 μM, which is severalfold greater than that of 1 and NBQX (2) (1, K(i) = 0.084 μM; 2, K(i) = 0.060 μM). Compound 11a also showed over 100-fold selectivity for the AMPA receptor than for the N-methy]-D- aspartate (NMDA) receptor and the glycine site on NMDA receptor.

Full text of DOI:10.1021/jm960387+

J . Med. Chem. 1996, 39, 3971-3979
3971
Novel AMP A Recep tor An ta gon ists: Syn th esis a n d Str u ctu r e-Activity
Rela tion sh ip s of 1-Hyd r oxy-7-(1H-im id a zol-1-yl)-6-n itr o-2,3(1H,4H)-
qu in oxa lin ed ion e a n d Rela ted Com p ou n d s
J unya Ohmori,†,‡ Masao Shimizu-Sasamata,† Masamichi Okada,† and Shuichi Sakamoto*,†
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Company Limited, 21, Miyukigaoka,
Tsukuba, Ibaraki 305, J apan, and Course in Material Sciences, Graduate School of Science and Engineering,
Saitama University, Shimo-Ohkubo, Urawa, Saitama 338, J apan
Received May 31, 1996X
As part of our study of novel antagonists at the R-amino-3-hydroxy-5-methylisoxazole-4-
propionate (AMPA) subtype of excitatory amino acid (EAA) receptors and the pharmacophoric
requirements of the receptor, we designed and synthesized a series of 1-substituted 6-imidazolyl-
7-nitro-, and 7-imidazolyl-6-nitroquinoxalinediones, as well as related compounds, 6a -j, 7, 11a -
e, 15, and 17, which are 1- and 4-substituted analogues of 1 (YM90K), and evaluated their
activity to inhibit [3H]AMPA binding from rat whole brain. On the basis of their structure-
activity relationships (SAR), we deduced that the amide proton of the imidazolyl-near side of
the quinoxalinedione nucleus is not essential for AMPA receptor binding, whereas that of the
imidazolyl-far amide is. Further, the receptors possess size-limited bulk tolerance for their
N-substituents on the imidazolyl-near amide portion. Moreover, we found that introduction
of a hydroxyl group at the imidazolyl-near amide portion causes a severalfold improvement in
AMPA receptor affinity over unsubstituted derivatives. Among the compounds, 1-hydroxy-7-
(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxalinedione (11a ) showed high affinity for AMPA
receptor with a Ki value of 0.021 µM, which is severalfold greater than that of 1 and NBQX (2)
(1, Ki ) 0.084 µM; 2, Ki ) 0.060 µM). Compound 11a also showed over 100-fold selectivity for
the AMPA receptor than for the N-methyl-D-aspartate (NMDA) receptor and the glycine site
on NMDA receptor.
In tr od u ction
Neurodegenerative disorders such as global and focal
cerebral ischemia, Parkinson’s, Huntington’s, and Alzhei-
mer’s disease, and also epilespy often substantially
impair the patient’s ability to function in society.1 In
view of the lack of effective neuroprotective agents to
treat these disorders, the underlying mechanisms lead-
F igu r e 1.
(1H,4H)-quinoxalinedione (1, YM90K),18,19 and the oth-
ers (Figure 1).20-22 They have shown a variety of
neuroprotective effects; compound 1, for example, dis-
played anti-AMPA-induced toxicity in cultured neurons
and anticonvulsive activity and antiischemic effects in
both global and focal ischemia models.15-18,23
ing to these disorders have been studied to identify novel
target sites.2 During the last decades, it has become
clear that one of the main pathological processes of these
disorders is excess stimulation of excitatory amino acid
(EAA) receptors.3-11
Postsynaptic EAA receptors have been classified into
four main subtypes,12 namely the N-methyl-D-aspartate
(NMDA), R-amino-3-hydroxy-5-methylisoxazole-4-pro-
pionate (AMPA), kainate (KA), and metabotropic glu-
tamate receptor subtypes. AMPA and KA receptors
may be grouped collectively as non-NMDA receptors.
The cerebroprotective effects of the NMDA subtype of
EAA receptor antagonists have been well documented
in focal ischemia models5,6 but have been questioned in
global ischemia models.13,14 More recently, the AMPA
receptor has drawn much attention because of its
implication in the above diseases,7-11 especially in
neurodegeneration after cerebral ischemia.13-17 To
date, selective and competitive AMPA receptor antago-
nists were reported as candidate for therapeutic agents
include 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo[f]qui-
noxaline (2) (NBQX),7 6-(1H-imidazol-1-yl)-7-nitro-2,3-
We previously studied the structure-activity rela-
tionships (SAR) of imidazolylquinoxalinedione 1 and
related compounds with regard to the effect of substit-
uents on the benzene ring portion of the quinoxalinedi-
one nucleus19 and the pyridine ring portion of the
pyridopyrazinedione nucleus24 on binding activity for
AMPA receptors. We concluded that functional groups
which possess moderately sized π-conjugation systems
and appropriate hydrophobicity are suitable for the
6-substituents, while electron-withdrawing groups are
suitable for the 7-substituents. A combination of a
6-(1H-imidazol-1-yl) group and a 7-nitro group afforded
the best affinity for AMPA receptors in both series,
namely 2,3(1H,4H)-pyrido[2,3-b]pyrazinediones and 2,3-
(1H,4H)-quinoxalinediones. As part of our program to
discover potential AMPA receptor antagonists, we next
focused on the pyrazine ring portion of the quinoxa-
linedione nucleus. In the present paper we report the
synthesis of a series of 1-substituted 6-imidazolyl-7-
nitro-, and 7-imidazolyl-6-nitroquinoxalinediones as well
† Yamanouchi Pharmaceutical Co. Ltd.
‡ Saitama University.
X Abstract published in Advance ACS Abstracts, September 1, 1996.
S0022-2623(96)00387-1 CCC: $12.00 © 1996 American Chemical Society

3972 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ohmori et al.
Sch em e 1a
a
(a) RNH2; (b) imidazole, KOH, DMSO for 4a ,c-k , imidazole, DMF for 4b; (c) H2, Pd-C, H+; (d) (COOH)2, H+; (e) fHNO3, or NO2BF4;
(f) 4 N HCl for 6k .
as related compounds 6a -j, 7, 11a -e, 15, and 17 and
the evaluation on their activity in inhibiting [3H]AMPA
binding from rat whole brain. We also discuss the
pharmacophoric requirements of AMPA receptor with
respect to the pyrazinedione portion of the quinoxalines
on the basis of their SAR.
aniline 4i into quinoxaline 5i, deprotection of its benzyl
group occurred simultaneously in the reduction step.
The nitration of 5a -k in a concentrated H2SO4 or
Ac2O-AcOH-H2SO4 system gave 1-alkyl-7-(1-imida-
zolyl)-6-nitroquinoxalinediones 6a -c,e-k . The reaction
of 5k in Ac2O-AcOH-H2SO4 led ot nitration of the
6-position on the quinoxaline nucleus as well as acetyl-
ation of the 1-hydroxylethyl group at the same time. The
resulting compound 6k was hydrolyzed by acidic treat-
ment to give the desired 1-hydroxyethyl derivative 7.
The nitration of 5d , however, was sluggish in these
conditions. n-Decyl deriative 6d was obtained by nitra-
tion with nitronium tetrafluoroborate25 in tetrameth-
ylene sulfone at 100 °C in low isolated yield (14%).
As shown in Scheme 2, 1-hydroxy- or 1-alkoxy-6-nitro-
7-imidazolyl deriatives 11a -e were prepared as follows.
2-Amino-5-fluoronitrobenzene was treated with ethyl-
oxalyl chloride to give ethoxalyl derivative 8. Contrary
to our expectations, catalytic hydrogenation of 8 with
palladium on carbon until the consumption of 2 equiv
of hydrogen followed by workup26 resulted in a mixture
of desired 1-hydroxy-7-fluoroquinoxalinedione (9), start-
ing material 8, and an over-reduced 7-fluoroquinoxa-
linedione. On the other hand, 9 was prepared by
catalytic hydrogenation with iridium on carbon27 in
excellent yield without the byproduct. Compound 9 was
nitrated, and subsequent nucleophilic substitution of the
fluorine atom of 10 with imidazoles or triazole gave
1-hydroxyquinoxalinediones 11a ,d ,e. 1-Alkoxyquinoxa-
lines 11b,c were prepared by alkylation of the 1-hydroxy
gruop of 10 under basic condition, followed by the
treatment with imidazole.
Ch em istr y
1-Alkyl-7-imidazolyl-6-nitro derivatives were pre-
pared as shown in Scheme 1. Regiospecific nucleophilic
substitution at the ortho position of 4-chloro-2-fluoroni-
trobenzene 3a by treatment with various alkylamines
in alcoholic solvents followed by substitution at the para
position with imidazole in a presence of KOH in DMSO
afforded the corresponding 2-(alkylamino)-4-(1H-imi-
dazol-1-yl)nitrobenzenes 4a ,c-k . In the case of 3a with
3-aminopyrrolidine, the reaction gave the desired N-(3-
pyrrolidinyl)aniline with a substantial amount of un-
desired regioisomer, 2-(3-amino-1-pyrrolidinyl)benzene.
To avoid formation of the byproduct, we utilized a
1-protected pyrrolidine, 3-amino-1-benzylpyrrolidine, as
an amine component for the first substitution step and
subsequent imidazole substitution of the resulting
intermediate to yield benzylpyrrolidinylaniline 4i. Next
we attempted to examine the availability of 2,4-difluo-
ronitrobenzene (3b) as a starting material. Treatment
of 3b with an excess equivalent of aqueous ethylamine
in ethanol selectivity resulted in the ortho-substituted
derivative, which was then reacted with imidazole in
DMF, without KOH, to give N-ethyl-5-(1H-imidazol-1-
yl)-2-nitroaniline, 4b.
Hydrogenation of nitroaniline 4a -k with palladium
on carbon under atmospheric pressure followed by cyclic
condensation of the resulting diamines with oxalic acid
in refluxing 4 N HCl led to the formation of correspond-
ing 1-substituted quinoxalinedione derivatives 5a -k . In
the case of the transformation from benzylpyrrolidinyl-
Ethoxalylation of 3-fluoroaniline followed by nitration
yielded a mixture of nitrobenzene 12 with two regio
isomers, which were separated by silica gel chromatog-
raphy. Reduction of the nitro group of 12 into hydroxy-
lamine by Zn-NH4Cl treatment under Zinin’s condi-

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3973
Sch em e 2a
Sch em e 4a
a
(a) n-PrNH2; (b) H2, Pd-C; (c) (COOH)2, H+; (d) KNO3, H2SO4;
(e) imidazole.
(6a ), 1-ethyl- (6b), and 1-n-propylquinoxalinediones (6c)
showed AMPA receptor affinity (Ki ) 0.33, 0.19, and
0.14 µM, respectively) equipotent to or slightly less than
that of unsubstituted 1 (Ki ) 0.084 µM). To explore the
bulk tolerance of AMPA receptor for the substituents,
1-branched-alkyl (6e) and 1-cycloalkyl (6f) derivatives
were examined; these also showed affinity similar to
that of 1 (Ki ) 0.23 and 0.11 µM). In contrast, the
binding activity of the more lengthened analogues
1-(cyclohexylmethyl)quinoxalinedione (6g) and 1-n-dec-
ylquinoxalinedione (6d ) had about 1/10 and 1/100 times
the affinity of 1, respectively. These results indicated
that the imidazolyl-near amide proton on the quinoxa-
line nucleus is not essential for AMPA receptor binding
and that the receptor possesses size-limited bulk toler-
ance for the 1-substituents. We thus speculated that
the imidazolyl-near amide act as a hydrogen bond
acceptor, shown as a1 in the pharmacophore model in
Figure 2, rather than as a hydrogen donor.
a
(a) EtOCOCOCl, Et3N; (b) H2, Ir-C; (c) KNO3, H2SO4; (d)
M2SO4-K2CO3 for 11b, EtI-NaH for 11c; (e) imidazole for 11a -
c, 4-methylimidazole for 11d , and triazole-NaH for 11e.
Sch em e 3a
We next focused on the effect of a heteroatom at the
substituents for AMPA receptor binding. 1-Methoxy
(11b) and 1-ethoxy (11c) derivatives exhibited only a
severalfold decrease in AMPA affinity (Ki ) 0.38, 0.30
µM, respectively) compared to that of 1. Their binding
activity is closely similar to that of the topologically
corresponding alkyl analogues 6b and 6c. Compounds
6h and 7, which possess dimethylamino and hydroxy
groups at the end of 1-alkyl substituents, respectively,
displayed 5-10-fold less AMPA affinity than 1, these
values being even less than those of the corresponding
1-alkyl analogues 6e and 6c. The 1-(3-pyrrolidinyl) (6i),
1-(3-quinuclidinyl) (6j) derivatives also exhibited less
affinity than compound 1 and the 1-cyclohexyl deriva-
tive 6f. Thus, it can be speculated that the inner part
of the suggested bulk tolerate pocket of the AMPA
receptor for the substituents may be, at least in part, a
hydrophobic environment.
It is interesting that 1-hydroxy-7-(1H-imidazol-1-yl)-
6-nitro-2,3(1H,4H)-quinoxalinedione 11a , in which the
hydroxyl group is directly attached to the quinoxalinedi-
one nucleus, showed AMPA receptor affinity with a Ki
value of 0.021 µM, which is 3-4-fold greater than those
of compounds 1 and 2 (1, Ki ) 0.084 µM; NBQX (2), Ki
) 0.060 µM). To our knowledge, compound 11a pos-
sesses one of the highest AMPA receptor affinities
among existing ligands for this receptor.
a
f
(a) EtOCOCOCl, Et3N; (b) HNO3; (c) Zn, NH4Cl; (d) KNO3,
H2SO4; (e) imidazole.
tion28 and following workup led to formation of cyclized
compound 13, which was purified, nitrated, and then
treated with imidazole to give 1-hydroxy-6-imidazolyl-
7-nitroquinoxalinedione, 15 (Scheme 3).
The preparation of 1-n-propyl-6-imidazolyl-7-nitro-
quinoxaline (17) was carried out as follows. 2,5-Difluo-
ronitrobenzene was ortho substituted with n-propyl-
amine. The product was hydrogenated with palladium
on carbon under atmospheric pressure, and then cyclic-
condensed with oxalic acid to afford 1-propyl-6-fluoro-
quinoxaline (16). Subsequent nitration with KNO3 and
nucleophilic substitution with imidazole gave compound
17 (Scheme 4).
Resu lts a n d Discu ssion
The structure of the 1-substituted quinoxalinediones
and the results of radiobinding assays for AMPA recep-
tor29 are summarized in Tables 1 and 2. Affinities are
presented as Ki (µM) values. Initially we investigated
1-alkyl-7-imidazolyl-6-nitroquinoxalinediones, namely
4-alkyl derivatives of compound 1 (Table 1). 1-Methyl-
We then examined 1-substituted 6-imidazolyl-7-nit-
roquinoxaline derivatives 15 and 17, namely 1-substi-
tuted derivatives of compound 1. Both 1-hydroxyl (15)
and 1-n-propyl (17) derivatives displayed affinity 20-
30-fold weaker than that of the corresponding 7-imida-

3974 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ta ble 1. 1-Substituted 6- or 7-Imidazolylquinoxalinedione Derivatives
Ohmori et al.
compd
R1
R2
R3
AMPA receptor affinity Ki (µM)a
6a
6b
6c
6d
6e
6f
6g
7
6h
6i
6j
11a
11b
Me
Et
n-Pr
n-decyl
isopentyl
cyclohexyl
cyclohexylmethyl
HOCH2CH2
Me2NCH2CH2
3-pyrrolidinyl
3-quinuclidinyl
HO
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
1-imidazolyl
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
NO2
0.33 (0.33-0.34)
0.19 (0.19-0.19)
0.14 (0.13-0.14)
8.9 (8.8-9.0)
0.23 (0.22-0.25)
0.11 (0.10-0.12)
0.79 (0.77-0.81)
0.42 (0.41-0.44)
0.84 (0.80-0.88)
0.55 (0.51-0.59)
1.0 (1.0-1.1)
0.021 (0.019-0.023)
0.38 (0.36-0.40)
0.30 (0.29-0.32)
0.44 (0.39-0.51)
4.5 (4.2-4.7)
0.084 (0.083-0.086)
0.060 (0.058-0.061)
MeO
EtO
HO
n-Pr
11c
15
17
1 (YM90K)
2 (NBQX)
1-imidazolyl
1-imidazolyl
NO2
a
Ki values were determined by double experiments performed in triplicate. Values in parentheses are 95% confidence intervals.
Ta ble 2. 1-Hydroxyquinoxalinedione Derivatives
is essential for AMPA receptor binding. On the basis
of the experimental observation that 1-substituted-7-
imidazolyl-6-nitroquinoxalinedione 11b forms a salt
with imidazole, as stated in the Experimental Section,
we deduced that the amide might act as a proton donor
in a Coulombic interaction such as a2 as shown in Figure
2. The hypothetical anionic site on the receptor in the
above interaction could be a basic amino acid residue
such as a histidine or lysine residue. The slight affinity
compound 15 and 17 showed for the AMPA receptor
deserves an explanation. In previous papers, we sug-
gested that the AMPA receptor requires different struc-
tural features between 6- and 7-substituents of quinox-
alinediones for their binding to the receptors.19,24
Moreover, the ratios of the affinity of 15 versus 11a and
17 versus 6c are similar (1/20 and 1/30, respectively).
Therefore, 15 and 17 probably bind to the receptors in
an upside-down mode, in which 6- and 7-substituents
are less favorable.
AMPA receptor
compd
R1
R2
affinity Ki (µM)a
11d
11e
18
HO
HO
H
4-methyl-1-imidazolyl
1,2,4-triazol-1-yl
4-methyl-1-imidazolyl
1,2,4-triazol-1-yl
0.050 (0.049-0.052)
0.18 (0.17-0.18)
0.18 (0.17-0.19)
0.24 (0.23-0.25)
19
H
a
See Table 1.
These SAR clearly indicated that the pyrazinedione
portion of the quinoxalinedione nucleus plays an im-
portant role in AMPA receptor binding and that the
receptor requires different structural features with
respect to the imidazolyl-near and the imidazolyl-far
amide of the pyrazine portion of quinoxalinedione
nucleus, respectively.
The pharmacophore model of the pyrazine portion of
the quinoxalinedione described in Figure 2 possesses
some similarity to that of kynurenic acids, quinoxa-
linediones, and tetramic acids for the glycine site on the
NMDA receptor suggested by Leeson et al.31-33 This
similarity may explain why most known quinoxaline
derivatives have at least some affinity for both the
AMPA receptor and glycine site. Different pharma-
cophoric requirements of substituents on the benzene
portion of the quinoxaline nucleus may confer selectivity
to selected ligands such that they can bind the AMPA
receptor and glycine site on the NMDA receptor with
different affinity.19,22,24
F igu r e 2. Suggested pharmacophore model of AMPA recep-
tors for the binding of quinoxalinediones with respect to
pyrazine ring portion.
F igu r e 3.
zolyl-6-nitroquinoxalines 11a and 6c. We previously
reported that 6-(1H-imidazol-1-yl)-5-nitro-2,3(1H)-indo-
linedione (20) possesses no or negligible affinity for the
AMPA receptor (Ki > 100 µM) (Figure 3).30 These
results indicated that the imidazolyl-far amide proton
Since 1-hydroxyquinoxaline 11a exhibited better af-
finity than 1, we prepared and evaluated 1-hydroxy-7-
(1,2,4-triazolyl)- (11e) and 1-hydroxy-7-(4-methylimi-

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3975
Ta ble 3. Affinities of 11a , 1, and 2 for EAA Receptor Subtypes
Ki (µM)a
non-NMDA
receptor affinity
NMDA receptor affinity
AMPA
compd receptor
high-affinity
KA site
NMDA
binding site
glycine
binding site
11a
1
2
0.021
0.084
0.060
0.63 (0.61-6.65)
2.2 (2.1-2.2)
4.1 (3.9-4.3)
12 (7.8-19)
>100
>100
4.2 (3.6-4.9)
37 (34-40)
>100
a
See Table 1.
for KA site ) 0.63 µM). Selectivity of 11a between
AMPA receptor and both binding sites on NMDA
receptors was less than those of 1 and 2 but was
nevertheless largely retained (Ki,NMDA/Ki,AMPA ) 570,
Ki,glycine/Ki,AMPA ) 200, respectively).
F igu r e 4. Suggested pharmacophore model of AMPA recep-
tors for the binding of 1-hydroxyquinoxalinediones with respect
to pyrazine ring portion.
Con clu sion
dazolyl)quinoxalinediones (11d ) (Table 2). In the case
of triazolyl derivative 11e, its affinity was equipotent
to that of the corresponding 1-unsubstituted derivative
19. In contrast, 4-methylimidazolyl derivative 11d
exhibited 4-fold greater affinity than unsubstituted 18,
giving a relation similar to that between 11a and 1.
These results indicate that the introduction of a hy-
droxyl group to the nitrogen atom of imidazolyl-near
amide results in a severalfold improvement in affinity
for AMPA receptors, at least in the imidazolylquinoxa-
linedione derivatives.34
We synthesized a series of 1-substituted quinoxa-
linedione derivatives and evaluated their affinity for
AMPA receptors. On the basis of their SAR, we deduced
that the pyrazinedione portion of the quinoxalinedione
nucleus play an important role in AMPA receptor
binding. Further, the receptor requires different struc-
tural features with respect to the imidazolyl-near and
imidazolyl-far amide of the pyrazine portion of quinoxa-
linedione nucleus; namely, the amide proton of the
imidazolyl-near side of the quinoxalinedione nucleus is
not essential for the receptor binding whereas that of
the imidazolyl-far amide is. Further, the receptors
possess size-limited bulk tolerance for their N-substit-
uents on the imidazolyl-near amide portion. Moreover,
we found that introduction of a hydroxyl group at the
imidazolyl-near amide portion causes a severalfold
improvement in AMPA receptor affinity over that of
unsubstituted derivatives. Among the compounds, 1-hy-
droxy-7-(1H-imidazol-1-yl)-6-nitro-2,3(1H,4H)-quinoxa-
linedione (11a ) showed high affinity for the AMPA
receptor with a Ki value of 0.021 µM, which is several-
fold greater than that of 1 and NBQX (2).
The effects of the hydroxy group probably result from
its acting as a supplementary interaction site for AMPA
receptor binding, because the acidic proton at the
imidazolyl-near amide portion is not essential for AMPA
receptor binding and the introduction of a hydroxy into
the amide induced only a modest improvement in the
affinity. Such interactions are probably not as strong
as a Coulombic interaction. On these bases, several
explanations can be speculated for the effect of the
hydroxy group. First, the 1-hydroxyl group may con-
tribute to hydrogen bonding or another dipole-dipole
interaction such as hypothetical interaction b1 (Figure
4A) or b2 (Figure 4B). If the hydroxy group acts as a
hydrogen bond donor as b1, the distance between the
hydroxy group and the nucleus may be critical for the
interaction, since 1-hydroxyethyl derivative 7 displayed
less affinity than 1.22 On the other hand, compounds
6h -j, which have amino substituents at the 1-position,
possess weaker affinity than 1, and 1-alkoxy derivatives
11b,c showed no improvement over 1. Therefore, if the
hydroxy group acts as a hydrogen bond acceptor as b2,
it may be important that the direction of the lone pair
of the hydroxy group be constrained by intramolecular
hydrogen bonding as seen in Figure 4B. Second, the
expanded π-conjugation ring system of the quinoxa-
linedione nucleus by formation of pseudoring c in model
B (Figure 4) may contribute to the receptor binding
mediated by π-π or π-σ interaction. The favorable
effects of the hydroxyl group may have multiple causes.
Among the compounds, 1-hydroxy-7-imidazolyl-6-ni-
troquinoxalinedione (11a ), which showed the best af-
finity for AMPA receptor, was further characterized by
its affinity for some another EAA receptor subtypes,
high-affinity KA binding site,35 NMDA binding site,36
and strychnine-insensitive glycine site on NMDA recep-
Exp er im en ta l Section
Ch em istr y. Melting points were measured on a Yanaco
MP-3 melting point apparatus and are uncorrected. Unless
stated otherwise, 1H NMR spectra were measured with a
J EOL FX90Q, FX100, EX400, or GX500 spectrometer in
DMSO-d6 except where stated otherwise; chemical shifts are
expressed in δ units using tetramethylsilane as the standard
(in NMR description, s ) singlet, d ) doublet, t ) triplet, q )
quartet, qu ) quintet, se ) sextet, m ) multiplet, and br )
broad peak). Mass spectra were recorded with a Hitachi M-80
or J EOL J MS-DX300 spectrometer. Where elemental analyses
(C, H, Cl, N, S) are indicated only by symbols of the elements,
analytical results obtained for these elements were within
0.4% of the theoretical values except where stated otherwise.
All solvents were evaporated in vacuo, and precipitates were
dried under reduced pressure. The preparation of quinoxa-
linedione derivatives 1 and 18-20 has been reported previ-
ously.19
Gen er a l Met h od for P r ep a r a t ion of 3-Im id a zolyl-
a n ilin e 4a -k . The compounds were prepared by treatment
of 3a or 3b with alkylamines followed by imidazole.
5-(1H-Im id a zol-1-yl)-N-m eth yl-2-n itr oa n ilin e (4a ). To
an ice-cold solution of 4-chloro-2-fluoronitrobenzene (3a ) (3.00
g, 17.1 mmol) in ethanol (6 mL) was added dropwise aqueous
methylamine (40%, 6 mL). The reaction mixture was stirred
at same temperature for 1 h, allowed to warm to room
temperature, and then poured into water (50 mL). The
resulting precipitate was collected, washed with a small
amount of chilled ethanol-water solution, and then recrystal-
lized from methanol to give 3-chloro-N-methyl-5-nitroaniline
37
tor (Table 3). Compound 11a showed affinity sever-
alfold greater than that for 1 and 2 for both non-NMDA
receptors, AMPA receptor, and KA site, with AMPA
selectivity 30-fold greater than KA selectivity (Ki of 11a

3976 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ohmori et al.
(1.04 g, 33%). This orange-colored intermediate was added to
a solution of imidazole (3.76 g, 55.2 mmol) and KOH (85%,
0.54 g, 83.1 mmol) in DMSO (10 mL). The mixture was heated
at 120 °C for 2 h and then poured onto ice-water (60 g). The
resulting precipitate was collected and washed with water to
give 4a (1.11 g, 93%): 1H NMR δ 8.48 (s, 1H), 8.33 (br m, 1H),
8.19 (d, 1H), 7.94 (t, 1H), 7.15 (t, 1H), 7.08 (dd, 1H), 6.95 (d,
1H), 3.05 (d, 3H); MS (EI) m/ z 218 (M).
mL). The resulting precipitate was collected and washed with
water to give 4a (2.09 g, 97%): 1H NMR δ 8.31 (d, 1H), 8.14
(br m, 1H), 7.94 (t, 1H), 7.25-7.35 (m, 2H), 6.78 (d, 1H), 6.68
(dd, 1H), 3.39 (m, 2H), 1.42 (t, 3H); MS (EI) m/ z 232 (M).
Gen er a l Meth od for P r ep a r a tion of 1-Su bstitu ted -7-
im id a zolyl-6-n it r oq u in oxa lin ed ion es 6a -k . The com-
pounds were prepared by hydrogenation of the appropriate
o-nitroanilines 4a -k under atmospheric pressure using Pd-
C, followed by reaction with oxalic acid in 4 N HCl at reflux
temperature and then nitration by fuming HNO3 (6a -c,e-k )
or nitronium tetrafluoroborate (6d ).
5-(1H-Im idazol-1-yl)-2-n itr o-N-pr opylan ilin e (4c): 3 equiv
of n-propylamine was used in a place of aqueous methylamine;
1
90% from 3a (two steps); H NMR δ 8.48 (s, 1H), 8.32 (br s,
1H), 8.19 (d, 1H), 7.94 (s, 1H), 7.16 (s, 2H), 7.01 (dd, 1H), 3.44
(q, 2H), 1.69 (se, 2H), 0.98 (t, 3H); MS (EI) m/ z 246 (M).
N-Decyl-5-(1H-im idazol-1-yl)-2-n itr oan ilin e (4d): 3 equiv
of n-decylamine was used in a place of aqueous methylamine;
7-(1H-Im idazol-1-yl)-1-m eth yl-2,3(1H,4H)-qu in oxalin edi-
on e Hyd r och lor id e (5a ‚HCl). Imidazolylaniline 4a (1.08 g,
4.95 mmol) was hydrogenated in a solution of methanol (50
mL) and concentrated HCl (1.5 mL) under atmospheric pres-
sure using 10% palladium on carbon (0.11 g), filtered, and
evaporated to give suitably substituted phenylenediamine,
which was treated with oxalic acid (0.45 g, 4.95 mmol) in 4 N
HCl (15 mL) at reflux overnight. The resulting precipitate was
collected and washed with water to give 5a ‚HCl (1.20 g,
1
89% from 3a (two steps); H NMR δ 8.48 (s, 1H), 8.26 (br d,
1H), 8.19 (d, 1h), 7.93 (t, 1H), 7.17 (s, 1H), 7.15 (s, 1H), 7.01
(dd, 1H), 3.45 (q, 2H), 1.24-1.74 (m, 16H), 0.85 (t, 3H); MS
(EI) m/ z 344 (M).
5-(1H-Im id a zol-1-yl)-N-isop en tyl-2-n itr oa n ilin e (4e): 5
equiv of isopentylamine was used in a place of aqueous
methylamine; 99% from 3a (two steps); 1H NMR δ 8.48 (s, 1H),
8.19 (d, 1H), 8.19 (br s, 1H), 7.93 (t, 1H), 7.17 (m, 2H), 7.01
(dd, 1H), 3.46 (dd, 2H), 1.43-1.90 (m, 3H), 0.96 (d, 6H); MS
(EI) m/ z 274 (M).
1
87%): mp >300 °C; H NMR δ 12.26 (br s, 1H), 9.64 (s, 1H),
8.29 (s, 1H), 7.98 (s, 1H), 7.76 (s, 1H), 7.59 (d, 1H), 7.34 (d,
1H), 3.58 (s, 3H); MS (FAB) m/ z 243 (M + 1).
1-Eth yl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in oxa lin ed i-
on e h yd r och lor id e (5b‚HCl): 89% from 4b; 1H NMR δ 12.40
(br s, 1H), 9.87 (s, 1H), 8.35 (d, 1H), 7.94 (d, 1H), 7.83 (d, 1H),
7.61 (dd, 1H), 7.44 (d, 1H), 4.24 (q, 2H), 1.26 (t, 3H); MS (FAB)
m/ z 257 (M + 1).
N-Cycloh exyl-5-(1H-im id a zol-1-yl)-2-n itr oa n ilin e (4f):
3 equiv of cyclohexylamine at 60 °C was used in a place of
aqueous methylamine at ambient temperature; 91% from 3a
1
(two steps); H NMR δ 8.48 (t, 1H), 8.19 (d, 2H), 7.93 (t, 1H),
7-(1H-Im idazol-1-yl)-1-pr opyl-2,3(1H,4H)-qu in oxalin edi-
on e h yd r och lor id e (5c‚HCl): 93% from 4c; mp > 300 °C
7.16-7.22 (m, 2H), 7.00 (dd, 1H), 3.92 (m, 1H), 1.37-2.00 (m,
10H); MS (EI) m/ z 286 (M).
1
(H2O); H NMR δ 12.35 (br s, 1H), 9.79 (s, 1H), 8.31 (s, 1H),
N -(Cycloh e xylm e t h yl)-5-(1H -im id a zol-1-yl)-2-n it r o-
a n ilin e (4g): 3 equiv of cyclohexylmethylamine was used in
a place of aqueous methylamine; 85% from 3a (two steps); 1H
NMR δ 8.48 (s, 1H), 8.19 (d, 1H) 8.19 (br s, 1H), 7.93 (t, 1H),
7.17 (m, 2H), 7.01 (dd, 1H), 3.32 (t, 2H), 0.97-1.83 (m, 11H);
MS (EI) m/ z 300 (M).
7.92 (s, 1H), 7.78 (d, 1H), 7.59 (dd, 1H), 7.40 (d, 1H), 4.15 (t,
2H), 1.70 (se, 2H), 0.96 (t, 3H); MS (FAB) m/ z 271 (M + 1).
1-Decyl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in oxa lin ed i-
on e h yd r och lor id e (5d ‚HCl): 78% from 4d ; mp 183-186 °C
1
(H2O-HCl); H NMR δ 12.37 (br s, 1H), 9.82 (s, 1H), 8.32 (t,
1H), 7.93 (t, 1H), 7.71 (dd, 1H), 7.56 (d, 1H), 7.41 (d, 1H), 4.19
(t, 2H), 1.24-1.64 (m, 16H), 0.85 (t, 3H); MS (FAB) m/ z 369
(M + 1).
N-[2-(Dim eth yla m in o)eth yl]-5-(1H-im id a zol-1-yl)-2-n i-
tr oa n ilin e (4h ): 3 equiv of N,N-dimethylethylenediamine was
used in a place of aqueous methylamine; 84% from 3a (two
7-(1H -Im id a zol-1-yl)-1-isop en t yl-2,3(1H ,4H )-q u in ox-
a lin ed ion e h yd r och lor id e (5e‚HCl): 50% from 4e; mp >300
°C; 1H NMR δ 12.39 (br s, 1H), 9.83 (s, 1H), 8.33 (s, 1H), 7.94
(s, 1H), 7.56-7.69 (m, 2H), 7.42 (d, 1H), 4.20 (m, 2H), 1.57
(m, 3H), 0.96 (d, 6H); MS (FAB) m/ z 299 (M + 1).
1-Cycloh exyl-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-qu in ox-
a lin ed ion e h yd r och lor id e (5f‚HCl): 30% from 4f; mp >300
°C; 1H NMR δ 12.31 (br s, 1H), 9.81 (s, 1H), 8.28 (s, 1H), 7.92
(s, 1H), 7.90 (d, 1H), 7.56 (dd, 1H), 7.39 (d, 1H), 4.50 (m, 1H),
2.32-2.44 (br m, 2H), 1.36-1.77 (br m, 8H); MS (FAB) m/ z
311 (M + 1).
1
steps); H NMR δ 8.49 (s, 1H), 8.45 (t, 1H), 8.19 (d, 1H), 7.95
(s, 1H), 7.17 (d, 1H), 7.16 (s, 1H), 7.03 (dd, 1H), 3.50 (dd, 2H),
3.33 (d, 1H), 2.53 (d, 1H), 2.24 (s, 6H); MS (EI) m/ z 275 (M).
5-(1H -Im id a zol-1-yl)-2-n it r o-N -(1-b e n zyl-3-p yr r oli-
d in yl)a n ilin e (4i): 2 equiv of 1-benzyl-3-aminopyrrolidine was
used in a place of aqueous methylamine; 97% from 3a (two
steps). Spectral data for 3-chloro-2-nitroaniline intermedi-
ate: 1H NMR δ 8.25 (br d, 1H), 8.14 (d, 1H), 7.27-7.48 (m,
5H), 7.18 (d, 1H), 6.79 (dd, 1H), 4.33 (m, 1H), 3.72 (s, 2H),
2.30-2.92 (m, 6H); MS (EI) m/ z 331 (M).
5-(1H -Im id a zol-1-yl)-2-n it r o-N-(3-q u in u clid in yl)a n i-
lin e (4j): 2 equiv of 3-aminoquinuclidine dihydrochloride with
10 equiv of triethylamine was used in a place of aqueous
methylamine; 65% from 3a (two steps); 1H NMR δ 8.52 (br d,
1H), 8.48 (s, 1H), 8.21 (dd, 1H), 7.93 (t, 1H), 7.16 (t, 1H), 6.97-
7.09 (m, 2H), 4.02 (m, 1H), 3.41-3.56 (m, 2H), 2.41-2.77 (m,
4H), 1.96-2.06 (m, 1H), 1.44-2.06 (m, 4H); MS (EI) m/ z 313
(M).
N-(2-H yd r oxylet h yl)-5-(1H -im id a zol-1-yl)-2-n it r oa n i-
lin e (4k ): 2 equiv of ethanolamine was used in a place of
aqueous methylamine; 91% from 3a (two steps); 1H NMR δ
8.48 (s, 1H), 8.36 (br d, 1H), 8.18 (d, 1H), 7.93 (t, 1H), 7.16 (m,
2H), 7.00 (dd, 1H), 5.02 (t, 1H), 3.50-3.73 (m, 4H); MS (FAB)
m/ z 249 (M + 1).
N-Eth yl-5-(1H-im id a zol-1-yl)-2-n itr oa n ilin e (4b). To an
ice-cold solution of ethanol (10 mL) and aqueous ethylamine
(70%, 10 mL, excess equivalent) was added portionwise 2,4-
difluoronitrobenzene (3b) (3.00 g, 18.9 mmol). The reaction
mixture was stirred at same temperature for 30 min, allowed
to warm to room temperature, and then poured into water (100
mL). The resulting precipitate was collected and washed with
a small amount of chilled ethanol-water solution to give
N-ethyl-5-fluoro-2-nitroaniline (3.32 g, 96%). (Note: The
aniline was sublimed under reduced pressure.) This inter-
mediate (1.70 g, 9.23 mmol) was dissolved in a solution of
imidazole (6.28 g, 92.2 mmol) in DMF (20 mL). The mixture
was heated at 140 °C for 3 h and then poured into water (100
1-(Cycloh exylm eth yl)-7-(1H-im id a zol-1-yl)-2,3(1H,4H)-
qu in oxa lin ed ion e h yd r och lor id e (5g‚HCl): 87% from 4g;
1
mp >300 °C (H2O-HCl); H NMR δ 12.34 (br s, 1H), 9.72 (s,
1H), 8.28 (s, 1H), 7.92 (s, 1H), 7.75 (d, 1H), 7.57 (dd, 1H), 7.39
(d, 1H), 4.10 (d, 2H), 1.59-1.86 (m, 6H), 1.01-1.14 (m, 5H);
MS (FAB) m/ z 325 (M + 1).
1-[2-(Dim et h yla m in o)et h yl]-7-(1H -im id a zol-1-yl)-2,3-
(1H,4H)-qu in oxa lin ed ion e Dih yd r och lor id e (5h ‚2HCl):
86% from 4h ; mp 249-252 °C (H2O-HCl-iPrOH); 1H NMR δ
12.43 (s, 1H), 10.86 (br s, 1H), 10.04 (s, 1H), 8.48 (s, 1H), 8.05
(d, 1H), 7.94 (s, 1H), 7.67 (dd, 1H), 7.46 (d, 1H), 4.65 (t, 2H),
3.46 (s, 2H), 2.90 (s, 6H); MS (FAB) m/ z 300 (M + 1).
7-(1H-Im id a zol-1-yl)-1-(3-p yr r olid in yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e d ih yd r och lor id e (5i‚2HCl): 97% from 4i
(the deprotection of benzyl group occurred simultaneously in
1
the reduction step); H NMR δ 12.38 (br s, 1H), 9.95 (s, 1H),
8.43 (s, 1H), 7.92 (s, 1H), 7.37-7.69 (m, 3H), 5.71 (m, 1H), 4.55
(br m, 2H), 3.64 (br m, 4H); MS (FAB) m/ z 297 (M + 1).
7-(1H-Im idazol-1-yl)-1-(3-qu in u clidin yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e d ih yd r och lor id e (5j‚2HCl): 36% from 4j; 1H
NMR δ 12.23 (br s, 1H), 9.00 (s, 1H), 8.05 (s, 1H), 7.31-7.53
(m, 4H), 5.15-5.30 (m, 2H), 4.27-4.42 (m, 1H), 3.28-3.77 (s,
5H), 1.68-2.31 (s, 4H); MS (FAB) m/ z 338 (M + 1).
1-(2-Hydr oxyeth yl)-7-(1H-im idazol-1-yl)-2,3(1H,4H)-qu i-
n oxa lin ed ion e h yd r och lor id e (5k ‚HCl): 49% from 4k ; mp
>300 °C (H2O-HCl); 1H NMR δ 12.31 (br s, 1H), 9.87 (s, 1H),

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3977
8.36 (s, 1H), 7.98 (d, 1H), 7.92 (s, 1H), 7.62 (dd, 1H), 7.20 (d,
being stirred at ambient temperature for 2 h, the reaction
mixture was poured onto ice-water to give a precipitate which
was collected and recrystallized with DMF-water to give
6f‚H2SO4 (0.15 g, 16%): mp >300 °C (DMF-H2O); 1H NMR δ
12.46 (br s, 1H), 9.51 (s, 1H), 8.11 (s, 1H), 8.06 (s, 2H), 7.92 (s,
1H), 4.41 (t, 1H), 2.37 (br m, 2H), 1.38-1.76 (br m, 8H); MS
(FAB) m/ z 356 (M + 1). Anal. (C17H17N5O4‚H2SO4‚0.5H2O)
C, H, N, S.
1H), 4.32 (t, 2H), 3.71 (t, 2H); MS (FAB) m/ z 273 (M + 1).
Sod iu m
7-(1H -Im id a zol-1-yl)-1-m et h yl-6-n it r o-2,3-
(1H,4H)-qu in oxa lin ed ion a te (Na Sa lt of 6a ). To an ice-
cold solution of 5a (0.70 g, 2.51 mmol) in concentrated H2SO4
(7 mL) was added dropwise fumin gHNO3 (d ) 1.52, 0.11 mL,
2.64 mmol) with the temperature maintained below 10 °C.
After 2 h of stirring at ambient temperature, the reaction
mixture was poured onto ice-water and then made basic by
addition of aqueous NaOH (20%). The resulting precipitate
was collected and recrystallized with ethanol-water to give
1-Decyl-7-(1H-im idazol-1-yl)-6-n itr o-2,3(1H,4H)-qu in ox-
a lin ed ion e Hyd r och lor id e (6d ‚HCl). A solution of 5d (1.00
g, 2.47 mmol) and nitronium tetrafluoroborate25 (85%, 0.56 g,
3.58 mmol) in tetramethylene sulfone (8 mL) was heated at
100 °C for 30 min. After cooling, the reaction mixture was
poured onto ice-water and then neutralized by addition of
aqueous 1 N NaOH. The resulting precipitate was collected,
dissolved in 4 N HCl-MeOH, and then concentrated to give
crude product which was recrystallized from water-ethanol
to give 6d ‚HCl (0.15 g, 14%): mp 188-192 °C (MeOH); 1H
NMR δ 12.66 (br s, 1H), 9.51 (s, 1H), 8.20 (s, 1H), 8.05 (s, 1H),
7.94 (s, 1H), 7.91 (s, 1H), 4.08 (t, 2H), 1.62 (m, 2H), 1.24 (s,
14H), 0.85 (t, 3H); MS (FAB) m/ z 414 (M + 1). Anal.
(C21H27N5O4‚HCl) C, H, N; Cl: calcd, 7.88; found, 8.29.
1-(2-H yd r oxyet h yl)-7-(1H -im id a zol-1-yl)-6-n it r o-2,3-
(1H,4H)-qu in oxa lin ed ion e Hyd r och lor id e (7‚HCl). (Ac-
etoxyethyl)quinoxaline 6k (0.25 g, 0.63 mmol) was treated with
4 N HCl at 100 °C for 30 min. After cooling, the reaction
mixture was evaporated, and the residue was recrystallized-
from i-PrOH to give 7‚HCl (0.20 g, 72%): mp >300 °C
(i-PrOH); 1H NMR δ 12.77 (br s, 1H), 9.56 (s, 1H), 8.28 (s, 1H),
8.15 (s, 1H), 8.06 (s, 1H), 7.91 (s, 1H), 4.25 (t, 2H), 3.67 (t,
2H); MS (FAB) m/ z 318 (M + 1). Anal. (C13H11N5O5‚HCl) C,
H, Cl; N: calcd, 19.80; found, 19.25.
1
the Na salt of 6a (0.29 g, 37%): mp >300 °C (H2O); H NMR
δ 7.82 (s, 1H), 7.60 (s, 1H), 7.35 (t, 1H), 7.19 (s, 1H), 7.04 (t,
1H), 3.52 (s, 3H); MS (FAB) m/ z 310 (M + Na + 1). Anal.
(C12H8N5O4‚Na‚2H2O) C, H, N.
Sod iu m 7-(1H -Im id a zol-1-yl)-1-isop en t yl-6-n it r o-2,3-
(1H,4H)-qu in oxa lin ed ion a te (Na sa lt of 6e): 32% from 5e;
1
mp 280-282 °C (H2O); H NMR δ 7.94 (s, 1H), 7.92 (s, 1H),
7.52 (s, 1H), 7.44 (s, 1H), 7.10 (s, 1H), 4.16 (t, 2H), 1.67 (qu,
1H), 1.50 (dd, 2H), 0.94 (d, 6H); MS (FAB) m/ z 366 (M + Na
+ 1). Anal. (C16H16N5O4‚Na) C, H, N.
1-(Cycloh exylm eth yl)-7-(1H-im id a zol-1-yl)-6-n itr o-2,3-
(1H,4H)-qu in oxa lin ed ion e (6g). The reaction mixture was
poured onto ice-water and then neutralized by addition of
aqueous NaOH (20%). The resulting precipitate was collected
and recrystallized with DMF-water to give 6g: 41% from 5g;
mp >300 °C (DMF-H2O); 1H NMR δ 12.39 (br s, 1 H), 7.95 (s,
1H), 7.89 (s, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.10 (s, 1H), 4.06
(d, 2H), 1.07-1.68 (m, 11H); MS (EI) m/ z 369 (M). Anal.
(C18H18N5O4‚0.75H2O) C, H; N: calcd, 18.34; found, 18.76.
7-(1H -Im id a zol-1-yl)-6-n it r o-1-(3-p yr r olid in yl)-2,3-
(1H,4H)-qu in oxa lin ed ion e (6i): 18% from 5i; mp 272-275
°C dec (H2O); 1H NMR δ 8.22 (s, 1H), 7.92 (s, 1H), 7.89 (s,
1H), 7.40 (s, 1H), 7.08 (s, 1H), 5.47 (m, 1H), 2.81-3.21 (m, 4H),
2.14 (m, 2H); MS (FAB) m/ z 343 (M + 1). Anal. (C15H14N6O4‚
2H2O) C, H, N.
4-(Eth oxa lyla m in o)-1-flu or o-3-n itr oben zen e (8). The
title compound was obtained in 71% yield from 2-amino-5-
fluoronitrobenzene by following the procedure described for
1-chloro-4-(ethoxalylamino)-3-nitrobenzene:26 1H NMR (CDCl3)
δ 11.78 (br, 1H), 8.87 (dd, 1H), 8.01 (dd, 1H), 7.47 (ddd, 1H),
4.47 (q, 2H), 1.46 (t, 3H); MS (EI) m/ z 256 (M).
7-(1H -Im id a zol-1-yl)-6-n it r o-1-(3-q u in u clid in yl)-2,3-
(1H,4H)-qu in oxa lin ed ion e (6j): 12% from 5j; mp >300 °C
1
(H2O); H NMR δ 7.96 (s, 1H), 7.93 (s, 1H), 7.46 (s, 1H), 7.36
1-Hyd r oxy-7-flu or o-2,3(1H,4H)-q u in oxa lin ed ion e (9).
(Ethoxalylamino)benzene 8 (10.0 g, 39.0 mmol) was hydroge-
nated in DMF (200 mL) under atmospheric pressure in a
presence of 5% iridium on carbon (0.50 g)27 until the consump-
tion of 2 equiv of hydrogen. The reaction mixture was filtered
and evaporated at 60 °C to give crude product which was
washed with solution of water and ethanol to give 9 (7.64 g,
(s, 1H), 7.10 (s, 1H), 4.65 (m, 1H), 3.97 (m, 1H), 2.99 (m, 2H),
2.80 (m, 2H), 2.15 (d, 1H), 1.90-2.00 (m, 2H), 1.61 (m, 1H),
1.35 (m, 1H), 1.24 (s, 1H); MS (FAB) m/ z 383 (M + 1). Anal.
(C18H18N6O4‚2H2O) C, H, N.
1-Eth yl-7-(1H-im id a zol-1-yl)-6-n itr o-2,3(1H,4H)-qu in ox-
a lin ed ion e Hyd r och lor id e (6b‚HCl). The crude 6b was
heated under reflux with 1 N HCl and then recrystallized from
water-ethanol to give 6b‚HCl: 46% from 5b; mp >300 °C
1
quantitative): mp 138-140 °C dec (EtOH-H2O); H NMR δ
12.13 (br s, 1H), 11.82 (br s, 1H), 7.12-7.31 (m, 2H), 6.99 (dd,
1H); MS (FAB) m/ z 197 (M + 1).
1
(H2O-EtOH); H NMR δ 12.71 (br s, 1H), 9.57 (s, 1H), 8.26
(s, 1H), 8.08 (s, 1H), 8.00 (s, 1H), 7.91 (s, 1H), 4.15 (q, 2H),
1.22 (t, 3H); MS (FAB) m/ z 302 (M + 1). Anal. (C13H11N5O4‚
HCl‚H2O) C, H, N, Cl.
7-(1H -Im id a zol-1-yl)-6-n it r o-1-p r op yl-2,3(1H ,4H )-q u i-
n oxa lin ed ion e h yd r och lor id e (6c‚HCl): 78% from 5c; mp
>300 °C (H2O-HCl); 1H NMR δ 12.81 (br s, 1H), 9.57 (s, 1H),
8.31 (s, 1H), 8.06 (d, 1H), 8.00 (s, 1H), 7.92 (d, 1H), 4.07 (t,
2H), 1.67 (se, 2H), 0.94 (t, 3H); MS (FAB) m/ z 316 (M + 1).
Anal. (C14H13N5O4‚HCl) C, H, N, Cl.
1-Hyd r oxy-7-flu or o-6-n itr o-2,3(1H,4H)-qu in oxa lin ed i-
on e (10). To an ice-cold solution of 9 (4.00 g, 20.4 mmol) in
concentrated H2SO4 (40 mL) was added portionwise KNO3
(2.27 g, 22.5 mmol) with the temperature maintained below
10 °C; the mixture was stirred at 0 °C for 1 h and then at
room temperature for 1 h. The reaction mixture was poured
onto ice-water (200 g), and resulting precipitate was collected
and washed with water to give 10 (3.64 g, 74%): mp 202 °C
(H2O); 1H NMR δ 12.32 (br s, 1H), 12.19 (br, 1H), 7.92 (d, 1H,
J ) 7.0 Hz), 7.50 (d, 1H, J ) 12.3 Hz); MS (FAB) m/ z 242 (M
+ 1).
1-(2-Ace t oxye t h yl)-7-(1H -im id a zol-1-yl)-6-n it r o-2,3-
(1H,4H)-qu in oxa lin ed ion e h yd r och lor id e (6k ‚HCl): an
Ac2O-AcOH-H2SO4 (5:1:1) solution was used in place of a
concentrated H2SO4 solvent; 54% from 5k ; mp 248-250 °C
1-Hyd r oxy-7-(1H-im id a zol-1-yl)-6-n itr o-2,3(1H,4H)-qu i-
n oxa lin ed ion e (11a ). A solution of 10 (2.61 g, 10.8 mmol)
and imidazole (3.68 g, 54.1 mmol) in DMF (50 mL) was heated
at 140 °C for 2 h, cooled to room temperature, and evaporated.
The resulting crude solid was washed with small amount of
water, methanol, and then chloroform and recrystallized from
DMF to yield 1.23 g of imidazole salt of 11a , which was
suspended in a solution of water (10 mL) and 1 N HCl (3.5
mL) and stirred at room temperature for 1 h, and the
suspension was collected and washed with water to afford 11a
1
(H2O); H NMR δ 12.43 (br s, 1H), 7.95 (d, 1H), 7.92 (s, 1H),
7.76 (s, 1H), 7.43 (s, 1H), 7.11 (s, 1H), 4.45 (t, 2H), 4.28 (t,
2H), 1.87 (s, 3H); MS (FAB) m/ z 360 (M + 1).
1-[2-(Dim eth yla m in o)eth yl]-7-(1H-im id a zol-1-yl)-6-n i-
t r o-2,3(1H ,4H )-q u in oxa lin ed ion e d ih yd r och lor id e (6h ‚
2HCl): an Ac2O-AcOH-H2SO4 (5:1:1) solution was used in
place of a concentrated H2SO4 solvent; 29% from 5h ; mp 284-
1
287 °C (H2O-HCl); H NMR δ 12.56 (br s, 1H), 9.28 (s, 1H),
1
(33%): mp 281-283 °C; H NMR δ 12.58 (br s, 1H), 8.26 (s,
8.11 (s, 1H), 8.05 (d, 1H), 7.99 (s, 1H), 7.75 (d, 1H), 4.54 (t,
2H), 3.46 (m, 2H), 2.88 (m, 6H); MS (FAB) m/ z 345 (M + 1).
Anal. (C15H16N6O4‚2HCl‚0.25H2O) C, H, N, Cl.
1H), 8.04 (s, 1H), 7.60 (s, 1H), 7.57 (t, 1H), 7.27 (s, 1H); MS
(FAB) m/ z 290 (M + 1). Anal. (C11H7N5O5‚1.5H2O) C, H, N.
Im id a zoliu m 7-(1H-Im id a zol-1-yl)-1-m eth oxy-6-n itr o-
2,3(1H,4H)-qu in oxa lin ed ion a te (Im id a zole Sa lt of 11b).
The solution of 10 (0.25 g, 1.04 mmol), dimethyl sulfate (0.16
g, 1.24 mmol), and K2CO3 (0.17 g, 1.23 mmol) in DMSO (5 mL)
was heated at 60 °C for 30 min. The reaction mixture was
1-Cycloh exyl-7-(1H-im id a zol-1-yl)-6-n it r o-2,3(1H,4H)-
qu in oxa lin ed ion e Su lfa te (6f‚H2SO4). To an ice-cold solu-
tionof 5f (0.70 g, 2.02 mmol) in concentrated H2SO4 (7 mL)
was added dropwise fuming HNO3 (d ) 1.52, 0.10 mL, 2.41
mmol) with the temperature maintained below 10 °C. After

3978 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20
Ohmori et al.
poured into water, and the resulting precipitate was collected
and washed with water to give 1-methoxyquinoxalinedione
intermediate (0.10 g, 38%): mp >300 °C; H NMR δ 7.79 (d,
δ 11.56 (br s, 1H), 8.34 (dd, 1H, J ) 5.7 Hz, J ′ ) 9.4 Hz), 8.12
(dd, 1H, J ) 2.9 Hz, J ′ ) 10.9 Hz), 7.35 (ddd, 1H, J ) 2.9 Hz,
J ′ ) 8.6 Hz, J ′′ ) 10.3 Hz), 4.37 (q, 2H), 1.35 (t, 3H); MS (EI)
m/ z 256 (M). 5-(Ethoxalylamino)-1-fluoro-2-nitrobenzene: 1H
NMR δ 11.31 (br s, 1H), 7.42-7.84 (m, 3H), 4.33 (q, 2H), 1.35
(t, 3H); MS (EI) m/ z 256 (M). 3-(Ethoxalylamino)-1-fluoro-
2-nitrobenzene: 1H NMR δ 11.44 (br s, 1H), 8.21 (t, 1H, J )
9.1 Hz), 7.98 (dd, 1H, J ) 2.6 Hz, J ′ ) 16.6 Hz), 7.85 (ddd,
1H, J ) 1.1 Hz, J ′ ) 2.6 Hz, J ′′ ) 10.3 Hz), 4.37 (q, 2H), 1.35
(t, 3H); MS (EI) m/ z 256 (M).
1-Hyd r oxy-6-flu or o-2,3(1H,4H)-qu in oxa lin ed ion e (13).
In a water bath, to a solution of 12 (6.20 g, 24.2 mmol) and
NH4Cl (5.64 g, 105 mmol) in water (40 mL) and DMF (120
mL) was added portionwise powdered zinc (5.70 g, 87.2 mmol)
with the temperature maintained below 35 °C.28 The reaction
mixture was filtered and washed with hot DMF (100 °C), and
the filtrate was allowed to cool to room temperature. The
resulting precipitate was removed, and the solution was
evaporated to afford crude solid, which was recrystallized from
methanol-DMF to give 13 (2.73 g, 57%): 1H NMR δ 12.28 (br
s, 1H), 7.90 (dd, 1H, J ) 5.7 Hz, J ′) 10.9 Hz), 7.00-7.26 (m,
2H); MS (FAB, Neg) m/ z 195 (M - 1).
1
1H, J ) 7.5 Hz), 7.41 (d, 1H, J ) 12.5 Hz), 3.97 (s, 3H). An
NOE between the methyl group and H-8 was observed: MS
(FAB) m/ z 256 (M + 1).
The same procedure as described for 11a was used for the
preparation of 11b from the intermediate, except the aqueous
HCl treatment in the workup (66% from the intermediate):
mp 212-215 °C (H2O); 1H NMR δ 12.25 (br s, 1H), 7.95 (s,
1H), 7.94 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 7.46 (s, 1H), 7.10
(s, 1H), 7.02 (s, 2H), 4.00 (s, 3H); MS (FAB) m/ z 304 (M + 1).
Anal. (C12H9N5O5‚C3H3N2‚0.5H2O) C, H, N.
1-E t h oxy-7-(1H-im id a zol-1-yl)-6-n it r o-2,3(1H,4H)-q u i-
n oxa lin ed ion e (11c). Under argon atmosphere, sodium
hydride [60% suspension in mineral oil (0.083 g, 2.07 mmol)
from which the mineral oil was removed by extraction with
n-hexane] was suspended in DMSO (5 mL). 1-Hydroxyqui-
noxaline 10 (0.50 g, 2.07 mmol) was added to the solution and
stirred at room temperature for 30 min. To the reaction
mixture was added dropwise ethyl iodide (0.32 g, 2.05 mmol),
and then the mixture was gradually heated up to 120 °C,
cooled to room temperature, diluted with water (10 mL), and
acidified with 1 N HCl to pH 5-6. The resulting precipitate
was collected and washed with boiling water to give a solid,
which was purified by short column chromatography (metha-
nol eluent) to give 1-ethoxyquinoxaline intermediate (0.23 g,
1-Hyd r oxy-6-flu or o-7-n itr o-2,3(1H,4H)-qu in oxa lin ed i-
on e (14). The title compound was prepared by the method
described for 10: 16% from 13; mp 208 °C dec; 1H NMR δ 12.59
(br s, 1H), 12.12 (br s, 1H), 8.04 (d, 1H, J ) 7.9 Hz), 7.16 (d,
1H, J ) 13.0 Hz); MS (FAB) m/ z 242 (M + 1).
1
41%): mp 267-269 °C; H NMR δ 12.29 (s, 1H), 7.91 (d, 1H,
1-Hyd r oxy-6-(1H-im id a zol-1-yl)-7-n itr o-2,3(1H,4H)-qu i-
n oxa lin ed ion e (15). The title compound was prepared by
the method described for 11a : 48% from 14; mp 285 °C dec
J ) 6.5 Hz), 7.52 (d, 1H, J ) 12.0 Hz), 4.23 (q, 2H), 1.37 (t,
3H). An NOE between the ethyl group and H-8 was ob-
served: MS (FAB) m/ z 270 (M + 1).
1
(H2O); H NMR δ 12.08 (br s, 1H), 8.13 (s, 1H), 7.92 (s, 1H),
The same procedure as described for 11a was used for
preparation of 11c from the intermediate (30% from the inter-
7.43 (s, 1H), 7.20 (s, 1H), 7.13 (m, 1H); MS (FAB) m/ z 290 (M
+ 1). Anal. (C11H7N5O5‚0.5H2O) C, H, N.
1
mediate): mp 189-190 °C (DMF-H2O); H NMR δ 12.45 (s,
6-F lu or o-1-p r op yl-2,3(1H,4H)-qu in oxa lin ed ion e (16).
The N-propylaniline intermediate was prepared by the method
described for corresponding intermediate of 4b using 2,5-
difluoronitrobenzene in a place of 2,4-difluoronitrobenzene:
82% from starting material; 1H NMR δ 7.95 (br, 1H), 7.88 (dd,
1H), 7.23-7.26 (m, 1H), 6.83 (dd, 1H), 3.26 (t, 2H), 1.76 (se,
2H), 1.06 (t, 3H); MS (EI) m/ z 198 (M). The title compound
was prepared by the method described for 5a : 86% from the
1H), 7.95 (s, 2H), 7.52 (s, 1H), 7.45 (s, 1H), 7.11 (s, 1H), 4.26
(q, 2H), 1.34 (t, 3H); MS (FAB) m/ z 318 (M + 1). Anal.
(C13H11N5O5‚1.25H2O) C, H, N.
1-H yd r oxy-7-(4-m et h yl-1H -im id a zol-1-yl)-6-n it r o-2,3-
(1H,4H)-qu in oxalin edion e Hydr och lor ide (11d ‚HCl). The
same procedure as described for 11a was used except the
product was recrystallized from excess 1 N HCl in the
workup: 41% from 10; mp >300 °C (HCl); 1H NMR δ 12.78 (s,
1H), 12.37 (br s, 1H), 9.37 (s, 1H), 8.21 (s, 1H), 7.89 (s, 1H),
7.73 (s, 1H), 2.37 (s, 3H); MS (FAB) m/ z 304 (M + 1). Anal.
(C12H9N5O5‚HCl) C, H, N, Cl.
1
intermediate; H NMR δ 12.07 (br s, 1H), 7.35-7.51 (m, 1H),
6.92-7.14 (m, 2H), 4.05 (t, 2H), 1.63 (se, 2H), 0.94 (t, 3H); MS
(FAB) m/ z 223 (M + 1).
6-(1H -Im id a zol-1-yl)-7-n it r o-1-p r op yl-2,3(1H ,4H )-q u i-
n oxa lin ed ion e (17). The nitroquinoxaline intermediate was
prepared by the method described for 10: 95% from 16; 1H
NMR δ 12.48 (br s, 1H), 8.00 (d, 1H, J ) 6.8 Hz), 7.14 (d, 1H,
J ) 11.7 Hz), 4.09 (t, 2H), 1.67 (se, 2H), 0.96 (t, 3H); MS (FAB)
m/ z 268 (M + 1). The title compound was prepared by the
method described for 11a : 98% from the intermediate; mp
1-Hyd r oxy-7-(1H-1,2,4-tr ia zol-1-yl)-6-n itr o-2,3(1H,4H)-
qu in oxa lin ed ion e (11e). Under argon atmosphere, sodium
hydride [60% suspension in mineral oil (0.21 g, 5.25 mmol)
from which the mineral oil was removed by extraction with
n-hexane] was suspended in DMSO (5 mL). Triazole (0.14 g,
2.03 mmol) was added to the solution and stirred at room
temperature for 30 min, and then 10 (0.40 g, 1.66 mmol) was
added. The reaction mixture was heated at 150 °C overnight,
cooled to room temperature, diluted with water (10 mL), and
acidified with 1 N HCl to pH 4. The resulting precipitate was
collected, washed with water and methanol, and recrystallized
from DMF-water to give 11e (0.19 g, 40%): mp >300 °C
1
158-160 °C (H2O); H NMR δ 12.51 (br s, 1H), 8.13 (s, 1H),
7.91 (s, 1H), 7.42 (s, 1H), 7.21 (s, 1H), 7.10 (s, 1H), 4.14 (t,
2H), 1.70 (se, 2H), 0.97 (t, 3H); MS (FAB) m/ z 316 (M + 1).
Anal. (C14H13N5O4‚1.25H2O) C, H, N.
Biology. Ra d iobin d in g Assa y. Inhibition of the specific
binding of [3H]AMPA, [3H]KA, NMDA-sensitive [3H]Glu, and
strychnine-insensitive [3H]Gly to brain membraines in vivo
was evaluated using standard procedures.
The binding of [3H]AMPA was conducted with crude mem-
branes of rat whole brain in the presence of 100 mM KSCN
as described by Honore et al.29 [3H]KA binding was performed
using crude membranes from rat cortex.35 [3H]Glu and [3H]-
Gly bindings were examined using Triton X-100-treated
membranes of whole brain except cerebellum.36,37 Final ligand
concentrations were as follows: [3H]AMPA, 43 nM; [3H]KA, 4
nM; [3H]Glu, 10 nM; [3H]Gly, 35 nM.
1
(DMF-H2O); H NMR δ 12.54 (s, 1H), 12.24 (s, 1H), 9.07 (s,
1H), 8.26 (s, 1H), 7.93 (s, 1H), 7.75 (s, 1H); MS (FAB) m/ z
297 (M + 1). Anal. (C10H6N6O5‚0.25H2O) C, H, N.
3-(Eth oxalylam in o)-1-flu or o-4-n itr oben zen e (12). 3-(Eth-
oxalylamino)-1-fluorobenzene was obtained in 62% yield from
3-fluoroaniline by following the procedure described for 1-chloro-
4-(ethoxalylamino)-3-nitrobenzene:26 1H NMR δ 10.96 (br s,
1H), 7.31-7.78 (m, 3H), 6.90-7.12 (m, 1H), 4.35 (q, 1H), 1.35
(t, 3H); MS (EI) m/ z 211 (M).
To an ice-cold solution of the intermediate (7.90 g, 37.3
mmol) in AcOH-Ac2O solution (1:1, 90 mL) was added
dropwise fuming HNO3 (d ) 1.52, 10.0 mL, 241 mmol) with
the temperature maintained below 20 °C. The solution was
stirred at room temperature for 5 h and poured onto ice-water.
The resulting precipitate was collected and washed with water
to give a crude mixture, which was purified by column
chromatography (CHCl3 eluent) to give 12 (less polar isomer,
6.80 g, 71%), 5-(ethoxalylamino)-1-fluoro-2-nitrobenzene (more
polar isomer, 0.034 g, 0.3%), and 3-(ethoxalylamino)-1-fluoro-
2-nitrobenzene (most polar isomer, 2.31 g, 24%). 12: 1H NMR
IC50 values were determined from logit-log analysis, and
Ki values were determined using the Cheng-Prusoff relation-
ship.
Ack n ow led gm en t. We thank Professor H. Nohira
of Saitama University and Drs. N. Inukai, K. Murase,
T. Mase, S. Usuda, S. Tsukamoto, T. Yamaguchi, and
K. Koshiya of Institute for Drug Discovery Research,
Yamanouchi Pharmaceutical Co., Ltd., for their encour-

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 20 3979
(20) Ornstein, P. L.; Arnold, M. B.; Augenstein, N. K.; Lodge, D.;
Leander, J . D.; Schoepp, D. (3SR, 4aRS, 6RS, 8aRS)-6-[2-(1H-
Tetrazole-5-yl)ethyl]decahydroisoquinoline-3-carboxylic Acid: A
Structurally Novel, Systemically Active, Competitive AMPA
Receptor Antagonist. J . Med. Chem. 1993, 36, 2046-2048.
(21) Bigge, C. F.; Malone, T. C.; Boxer, P. A.; Nelson, C. B.; Ortwein,
D. F.; Schelkun, R. M.; Retz, D. M.; Lescosky, L. J .; Borosky, S.
A.; Vartanian, M. G.; Schwarz, R. D.; Campbell, G. W.; Ro-
bichaud, L. J .; Watjen, F. Synthesis of 1,4,7,8,9,10-Hexahydro-
9-methyl-6-nitropyrido[3,4-f]quinoxaline-2,3-dione and Related
Quinoxalinediones: Characterization of R-Amino-3-hydroxy-5-
methyl-4-isoxazolepropionic Acid (and N-Methyl-D-aspartate)
Receptor and Anticonvulsant Activity. J . Med. Chem. 1995, 38,
3720-3740.
(22) Desos, P.; Lepagnol, J . M.; Morain, P.; Lestage, P.; Cordi, A. A.
Structure-Activity Relationship in a Series of 2(1H)-Quinolones
Bearing Different Acid Function in the 3-Position: 6,7-Dichloro-
2(1H)-oxoquinoline-3-phosphonic Acid, a New Potent and Selec-
tive AMPA/Kainate Antagonist with Neuroprotective Properties.
J . Med. Chem. 1996, 39, 197-206.
(23) Okada, M.; Hidaka, K.; Togami, J .; Ohno, K.; Tada, S.; Ohmori,
J .; Sakamoto, S.; Yamaguchi, T. R-Amino-3-hydroxy-5-methyl-
isoxazole-4-propionate (AMPA) Excitatory Amino Acid Receptor
Antagonistic Properties of YM900 (6-(1-Imidazolyl)-7-nitroqui-
noxaline-2,3(1H,4H)-dione). 22nd Annual Meeting Society for
Neuroscience, Anaheim, October 1992; Abstract 44.15.
(24) Ohmori, J .; Kubota, H.; Shimizu-Sasamata, M.; Okada, M.;
Sakamoto, S. Novel R-amino-3-hydroxy-5-methylisoxazole-4-
propionate Receptor Antagonists: Synthesis and Structure-
Activity Relationships of 6-(1H-Imidazol-1-yl)-7-nitro-2,3(1H,4H)-
pyrido[2,3-b]pyrazinedione and Related Compounds. J . Med.
Chem. 1996, 39, 1331-1338.
agement and helpful discussion. We also thank Mr. K.
Hidaka, S. Yatsugi, J . Togami, and Ms. S. Kawasaki-
Yatsugi for biological experiments and the staff of the
Structure Analysis Department for measurement of
NMR and mass spectra and elemental analyses in
Institute for Drug Discovery Research, Yamanouchi
Pharmaceutical Co., Ltd.
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