Novel α-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

Article abstract of DOI:10.1021/jm950304+

We have synthesized and evaluated azaquinoxalinediones 3a-c for their activity in inhibiting [³H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3- b]pyrazinedione derivatives 4, 7-10, 13, 15, and 16 showed some differences in comparison with those of the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the 7-nitro group of 1 · HCl was nearly coplanar with the quinoxaline ring, whereas the 6- imidazol1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones may be responsible for the selectivity against the glycine site. Among the series of azaquinoxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3- b]pyrazinedione (8c) exhibited a combination of the best affinity to the AMPA receptors with a K(i) value of 0.14 μM and selectivity against the glycine site (no affinity at 10 μM). In vivo, 8c also protected against sound- induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).

Full text of DOI:10.1021/jm950304+

J . Med. Chem. 1996, 39, 1331-1338
1331
Novel r-Am in o-3-h yd r oxy-5-m eth ylisoxa zole-4-p r op ion a te Recep tor An ta gon ists:
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of 6-(1H-Im id a zol-1-yl)-
7-n itr o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e a n d Rela ted Com p ou n d s
J unya Ohmori,†,‡ Hirokazu Kubota,† 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 April 24, 1995X
We have synthesized and evaluated azaquinoxalinediones 3a -c for their activity in inhibiting
[3H]AMPA binding from rat whole brain. It was found that the azaquinoxalinedione nucleus
functions as a bioisostere for quinoxalinedione in AMPA receptor binding. The detailed
structure-activity relationships of 6- and/or 7-substituted 2,3(1H,4H)-pyrido[2,3-b]pyrazinedi-
one derivatives 4, 7-10, 13, 15, and 16 showed some differences in comparison with those of
the corresponding substituted quinoxalinediones, including 6-(1H-imidazol-1-yl)-7-nitro-2,3-
(1H,4H)-quinoxalinedione (1) (YM90K). The X-ray study exhibited that conformation of the
7-nitro group of 1‚HCl was nearly coplanar with the quinoxaline ring, whereas the 6-imidazol-
1-yl group was rotated with respect to the aromatic ring. From the glycine site on NMDA
receptor binding study, it is indicated that bulkiness of 6-substituents on pyridopyrazinediones
may be responsible for the selectivity against the glycine site. Among the series of azaqui-
noxalinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione (8c) exhib-
ited a combination of the best affinity to the AMPA receptors with a Ki value of 0.14 µM and
selectivity against the glycine site (no affinity at 10 µM). In vivo, 8c also protected against
sound-induced seizure in DBA/2 mice (minimum effective dose, 10 mg/kg ip).
Excitatory amino acids (EAA), represented by L-
glutamate (L-Glu), are major excitatory neurotransmit-
ters in the mammalian central nervous system (CNS).1-3
It has recently become clear that excess EAA stimula-
tion causes degeneration of neurons, which is believed
to link a number of CNS diseases such as epilepsy, after
effects of cerebral ischemia, and Huntington’s and
F igu r e 1.
In a previous paper, we proposed the pharmacophore
for the AMPA receptor based on the structure-activity
relationships (SAR) of quinoxalinedione derivatives,
including compound 1,14,15 namely, functional groups
which possess moderately sized planar π-conjugation
systems and appropriate hydrophobicity (such as imi-
dazol-1-yl, nitro, or cyano group) are suitable for the
6-substituent of the 2,3(1H,4H)-quinoxalinedione nuclei,
whereas electron-withdrawing groups such as nitro,
trifluoromethyl, or cyano groups are suitable for the
7-substituent. Furthermore, it was revealed that 6,7-
disubstitution by the appropriate combination of sub-
stituents provided synergistically improved affinity for
AMPA receptors, whereas, 5,6- and 6,8-disubstitution
showed no improvement.
As part of our program to explore the AMPA receptor
pharmacophore, we have designed a series of azaqui-
noxalinediones (3, 4, 7-10, 13, 15, and 16) and inves-
tigated the structure-activity relationships of these
compounds in comparison with those of the correspond-
ing quinoxalinediones. Some compounds were evalu-
ated for selectivity against glycine sites on the NMDA
receptors with respect to the binding affinity. To further
investigate the pharmacophoric requirements for AMPA
receptor binding, conformation studies of 6- and/or 7-,
nitro- and/or imidazol-1-yl-substituted derivatives were
carried out.
Alzheimer’s diseases.4,5 Postsynaptic EAA receptors
have been classified into four main subtypes,6 namely,
the N-methyl-D-aspartate (NMDA), R-amino-3-hydroxy-
5-methylisoxazole-4-propionate (AMPA), kainate (KA),
and metabotropic glutamate receptor subtypes. AMPA
and KA receptors may be grouped collectively as non-
NMDA receptors.
During the design of new therapeutic agents for
neurodegenerative diseases based on the EAA hypo-
thesis, the NMDA subtype of the EAA receptors has
been the subject of intensive study.7-9 Within recent
years, competitive AMPA receptor antagonists10,11 have
received considerable attention for their therapeutic
potential in neurodegenerative disorders, based on
their physiological and pharmacological activities.12,13
Previously, we reported a potent and selective AMPA
receptor antagonist, 6-(1H-imidazol-1-yl)-7-nitro-2,3-
(1H,4H)-quinoxalinedione (1) (Figure 1),14,15 which
showed neuroprotective effects, i.e., anti-AMPA-induced
toxicity in cultured neurons16 and anticonvulsive activ-
ity and antiischemic effects in both global and focal
ischemia models.17-19 Compound 1 is now in clinical
studies.
† Yamanouchi Pharmaceutical Co. Ltd.
‡ Saitama University.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
0022-2623/96/1839-1331$12.00/0 © 1996 American Chemical Society

1332 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ohmori et al.
Sch em e 1a
Sch em e 3a
a
(a) cHNO3, H2SO4; (b) H2, Pd-C (10%); (c) (COOH)2, 4 N HCl.
Sch em e 4a
a
a
f
(a) (COOH)2, 4 N HCl; (b) NO2BF4, tetramethylene sulfone.
(a) (COOH)2, 4 N HCl; (b) HNO3, AcOH, Ac2O.
Sch em e 2a
condensation of the resulting diamines with oxalic acid
gave the desired 6-substituted derivatives 7a -f. The
nitration of methoxy derivative 7a with fuming HNO3
in AcOH-Ac2O gave the 6-methoxy-7-nitro derivative
8a ; nitration of morpholino derivative 7b with KNO3
in concentrated H2SO4 yielded the 6-morpholino-7-nitro
derivative 8b. The nitration of 7c, however, was not
complete in these conditions. The preparation of 6-(1H-
imidazol-1-yl)-7-nitro derivative 8c was accomplished
by nitration with nitronium tetrafluoroborate22 in tet-
ramethylene sulfone at 120 °C. 6-Hydroxy derivative
9 was obtained by demethylation of methoxy derivative
7a in 48% HBr. Methylsulfonyl derivative 10 was
obtained by oxidation of methylthio derivative 7e with
hydrogen peroxide.
6-Methyl derivatives 13 were prepared in three steps,
namely, nitration of aniline 11, catalytic hydrogenation
of resulting nitropyridine 12, and subsequent cyclic
condensation with oxalic acid (Scheme 3).
7-Methyl (15a ) and 7-nitro (15b) derivatives were
prepared by the cyclic condensation of appropriate
diamines 14a 23 and 14b24 (Scheme 4). The compound
15b was nitrated with nitronium tetrafluoroborate in
tetramethylene sulfone at 130 °C to give the 6,7-dinitro
derivative 16.
Str u ctu r e-Activity Rela tion sh ip s. The struc-
tures of the azaquinoxalinediones and results of the
radioreceptor assay for AMPA receptors25 are sum-
marized in Tables 1-4. The affinities are presented as
Ki (µM) values or percent inhibition at 100 µM if the
compounds had weak potency.
a
(a) Nucleophile; (b) H2, Pd-C (10%), HCl; (c) H2, Ra Ni; (d)
(COOH)2, 4 N HCl; (e) nitration/fHNO3, Ac2O, AcOH for 8a ; KNO3,
H2SO4 for 8b; NO2BF4, tetramethylene sulfone for 8c; (f) 48% HBr;
(g) H2O2, AcOH.
The nonsubstituted azaquinoxalinediones, 2,3-pyrido-
[2,3-b]pyrazinedione (3a ) and 2,3-pyrido[2,3-c]pyra-
zinedione (3b), showed 22% and 32% inhibition of
[3H]AMPA binding at 100 µM, respectively. These are
weak but similar affinities with the lead compound
quinoxalinedione 17 (24% inhibition at 100 µM) (Table
1). The diazaquinoxalinedione, 6,7-pteridinedione (3c),
exhibited moderately improved affinity (62% inhibition
at 100 µM) compared to that of 17. These results
provide evidence that the introduction of a nitrogen
atom in the benzo ring of quinoxalinedione is tolerated
in AMPA receptor binding. In a previous paper, we
have revealed that a combination of some 6- and
7-substitutions to the 2,3-quinoxalinediones is signifi-
cantly effective in improving AMPA receptor binding
potency.15 Since 2,3-pyrido[2,3-b]pyrazinedione (3a )
served in the modification of both 6- and 7-positions,
we selected 3a as a lead for the following further
investigation.
Ch em istr y
Synthesis of the azaquinoxalinediones 3, 4, 7-10, 13,
15, and 16 is described in Schemes 1-4. The corre-
sponding diaminopyridines 2a ,b and pyrimidine 2c
were cyclized with oxalic acid in refluxing 4 N HCl to
give the desired compounds 3a -c (Scheme 1).20 This
reaction condition is commonly used in the following
method for construction of the pyrazinedione portion.
Nitration of compound 3a with fuming HNO3 in AcOH-
Ac2O gave the 6-nitro pyrazinedione 4 (Scheme 1).
Most of our 6-substituted derivatives and their 7-nitro
derivatives were prepared as shown in Scheme 2. The
versatile starting material 2-amino-6-chloro-3-nitropy-
ridine (5)21 was treated with several nucleophiles to
afford the corresponding derivatives 6a -e. Hydrogena-
tion of nitro derivatives 5 and 6e with Raney nickel and
6a -d with palladium on carbon followed by the cyclic

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1333
Ta ble 3. 6-Substituted Pyridopyrazinedione Derivatives
Ta ble 1. Azaquinoxalinediones and Quinoxalinedione
Ta ble 2. 7-Substituted Pyridopyrazinedione and
Quinoxalinedione Derivatives
Ta ble 4. 7-Nitro-6-substituted Pyridopyrazinedione and
Quinoxalinedione Derivatives
a
Ki values were determined by double experiments performed
in triplicate. Values in parentheses are 95% confindence
b
intervals. Inhibition at 100 µM.
Initially, monosubstituted analogues of pyridopyra-
zinedione were examined. The results of 7-substituted
derivatives 15a ,b and corresponding quinoxalinediones
18-20 are listed in Table 2, and those of 6-substituted
derivatives 4, 7a -f, 9, 10, and 13 are shown in Table
3.
As shown in Table 2, 7-nitro derivative 15b exhibited
a considerably enhanced potency, with a Ki value of 1.1
µM, similar to that of the corresponding nitroquinoxa-
linedione 19 (Ki ) 2.0 µM). On the basis of percent
inhibition of 3a at 100 µM (see Table 1), the activity of
15b was estimated as more than 100 times that of 3a .
7-Methyl derivative 15a showed moderately improved
affinity (74% inhibition at 100 µM) compared to those
of unsubstituted 3a and the corresponding quinoxa-
linedione 18.
Among 6-substituted pyridopyrazinediones, only nitro
derivative 4 (66% inhibition at 100 µM) and imidazol-
1-yl derivative 7c (76% inhibition at 100 µM, 25 (24-
26) µM of Ki value) showed improved affinity; however,
potency was less than that of the 7-substituted deriva-
a
b
See Table 1. Inhibition at 10 µM.
tive 15b and quinoxalinediones 20 and 19, respectively
(Table 3).
From the results of the remarkably enhanced affinity
of 7-nitro derivative 15b, we next synthesized and
evaluated 7-nitro-6-substituted pyridopyrazinediones
(Table 4). Introduction of methoxy (8a ), morpholino
(8b), and nitro (16) groups at the 6-position resulted in
little enhancement of potency. 6-(1H-Imidazol-1-yl)-7-
nitro-2,3(1H,4H)-pyrido[2,3-b]pyrazinedione (8c) showed
potent affinity (Ki value of 0.14 µM) which was 6-fold
more than that of 6,7-dinitropyridopyrazinedione 16,

1334 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ohmori et al.
F igu r e 3. Conformation of 1‚HCl in the crystalline state as
established by X-ray analysis.
F igu r e 2. Anticonvulsant effects of 8c and 1 on sound-induced
seizure in DBA/2 mice. Vertical bars represent the mean (SE
(N ) 8).
nearlycoplanar with the quinoxaline ring (dihedral
angle C16-C15-N8-O4: 167°), whereas the 6-imida-
zol-1-yl group was rotated with respect to the ring
(dihedral angle C15-C16-N9-C19: 102°). This con-
formation probably reflects conjugational constraints in
each substituent. The modification of 19 or 20 into 1
resulted in a synergistically improved affinity; the
torsion of the 6-imidazolyl group is therefore at least
tolerated in the AMPA receptor binding.
about 10 times that of 15b, and close to that of the
corresponding substituted quinoxalinedione 1 (Ki )
0.084 µM). In both the series, 2,3(1H,4H)-pyrido[2,3-
b]pyrazinediones and 2,3(1H,4H)-quinoxalinediones, the
combination of 6-(1H-imidazol-1-yl) group and 7-nitro
group afforded the best affinity for AMPA receptors.
Although some quinoxaline derivatives are recognized
as AMPA receptor antagonists, the general lack of
specificity of most of them in distinguishing between
AMPA receptor and glycine site on the NMDA receptor
is known.15,26,27 Thus we evaluated the selectivity of
7-nitro-6-substituted pyridopyrazinedione with respect
to binding affinity (Table 4).28 6-Methoxypyridopyra-
zinedione 8a displayed high affinity for both the glycine
sites, with a Ki value of 0.37 µM, and AMPA receptors,
with a Ki value of 0.70 µM. However, 6-nitro derivative
16, 6-morpholino derivative 8b, and 6-(1H-imidazol-1-
yl) derivative 8c showed little or no affinity for the
glycine site. As the compounds which have bulkier
6-substituents showed less potent glycine site affinity,
and as it is known that most quinoxalinediones and
kynurenic acids which are glycine antagonists have
small 5-, 6-, and 7-substituents,26 selectivity for the
glycine site may result from the bulkiness of 6-substit-
uents on pyridopyrazinediones 16 and 8b,c. Like the
corresponding quinoxalinedione 1,15 compound 8c showed
a combination of the best affinity for the AMPA recep-
tors (Ki value of 0.14 µM) and selectivity against the
glycine site (no inhibition at 10 µM) in this series of
pyridopyrazinediones. Thus, these findings verify that
appropriate 6-substituents such as the 1H-imidazol-1-
yl group in these classes of compounds not only function
in improving AMPA receptor binding potency but also
distinguish between AMPA receptor and glycine site.
In in vivo activity in preventing audiogenic seizure
in the DBA/2 mouse,29 the compound 8c exhibited a
minimum effective dose of 10 mg/kg ip when adminis-
tered at 15 min prior to sound exposure, which is close
to that of 1 (3 mg/kg ip) (Figure 2).
Since we were interested in the difference between
6- and 7-nitropyridopyrazinediones (4 and 15b) in
AMPA receptor affinity, we modeled their molecular
conformation utilizing MOPAC30 and included 6-nitro-
quinoxaline 19. The calculated optimum conformations
of 4, 15b, and 19 are illustrated in Figure 4. The nitro
group and the aromatic ring of compound 4 exhibited a
dihedral angle of 130°, while those of 15b and 19, which
showed more enhanced potency, were nearly horizontal
(179° for 15b and 177° for 19), similar to the conforma-
tion of the nitro of 1. These conformational differences
can probably be accounted for as follows. The conjuga-
tion between the nitro group and aromatic ring con-
strains the conformation of 15b and 19 into the copla-
nar, whereas coulombic repulsion between the lone pair
of the pyridine nitrogen atom and the nitro group
oxygen atom led to the twisted conformation of 4.
Because of their different activities, we next focused
our attention on the conformation of 6-imidazolylpyri-
dopyrazinedione 7c and 6-imidazolylquinoxalinedione
20. The optimization of compound 20 by MOPAC
calculation led to two planar conformations with the
dihedral angles of 179° and 1° between the imidazolyl
group and pyridopyrazinedione ring, respectively, and
each showed the same internal energy. Since we
observed little difference in the same two planar con-
formations (0° and 180°) and in internal energy (0.39
kcal difference), the different affinity between 7c and
20 can not be explained by molecular planarity such as
in the case of 6-nitropyridopyrazine 4 or 6-imidazolyl-
7-nitroquionoxaline 1.
On this basis, several interpretations of the SAR on
AMPA affinity could be considered. First, the less
improved affinity of 6-nitropyridopyrazine 4 may be
caused by its twisted conformation. Because this tor-
sional restriction is in contrast to the torsional tolerance
of the imidazolyl group of 6,7-disubstituted 1 in improv-
ing the affinity, the SAR may reflect the different
pharmacophore between the first and second substitu-
Con for m a tion Stu d y. In order to investigate the
conformations of the 6-imidazolyl and 7-nitro groups
to AMPA receptor binding in 6,7-disubstituted deriva-
tives, X-ray crystallographic analysis of the hydrochlo-
ride salt of quinoxalinedione 1 was carried out. The
solved crystalline structure of 1‚HCl is illustrated in
Figure 3. Conformation of the 7-nitro group of 1 was

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1335
that conformation of the 7-nitro group of 1‚HCl was
nearly coplanar with the quinoxaline ring, whereas the
6-imidazol-1-yl group was rotated with respect to the
aromatic ring. Glycine site binding study of selected
compounds indicated that bulkiness of 6-substituents
on pyridopyrazinediones may be responsible for selec-
tivity against the glycine site. Among this series of
pyridopyrazinediones, 6-(1H-imidazol-1-yl)-7-nitro-2,3-
(1H,4H)-pyrido[2,3-b]pyrazinedione (8c), an aza ana-
logue of 1, was found to combine potent affinity for
AMPA-type non-NMDA EAA receptor and selectivity to
the glycine binding site on the NMDA receptor.31 In
vivo, 8c also showed protection against sound-induced
seizure in DBA/2 mice.
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 not corrected. Unless
1
stated otherwise, H NMR spectra were measured in DMSO-
d6 or CDCl3 with either a J EOL FX90Q or FX100 spectrometer;
chemical shifts are expressed in δ units using tetramethylsi-
lane as the standard (in NMR description: s ) singlet, d )
doublet, t ) triplet, q ) quartet, 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, analytical
results obtained for these elements were within 0.4% of the
theoretical values except where stated otherwise. All solutions
were dried over anhydrous sodium sulfate, and the solvent was
evaporated under reduced pressure.
The preparation of quinoxalinedione derivatives 1 and 17-
20 has been reported previously.15
Gen er a l Meth od for P r ep a r a tion of Aza qu in oxa lin ed i-
on es. 2,3(1H,4H)-Pyridopyrazinediones 3a -c were prepared
by reaction of the appropriate diamines with oxalic acid in 4
N HCl at reflux temperature.
F igu r e 4. Conformations of nitro-substituted derivatives (a
for 15b, b for 19, and c for 4) calculated by MOPAC with PM3
Hamiltonian.
2,3(1H,4H)-P yr id o[2,3-b]p yr a zin ed ion e (3a ).20 Diami-
nopyridine 2a (3.7 g, 34.3 mmol) was treated with oxalic acid
(3.4 g, 37.8 mmol) in 4 N HCl (20 mL) at reflux for 3 h. The
resulting precipitate was collected and washed with water to
give 3a (3.9 g, 70%): mp >300 °C (DMF-H2O); 1H NMR δ
7.80 (dd, 1H), 7.24 (dd, 1H), 6.86 (dd, 1H); MS (EI) m/ z 163
(M). Anal. (C7H5N3O2) C,H,N.
ents or between the nitro and imidazolyl group at the
6- or 7-position of the derivatives. The torsion of the
nitro group certainly diminishes the conjugation system;
it will also decrease the electron-withdrawing effects on
the acidities of the amide proton of the ring and/or
π-electron distribution on the aromatic ring, which may
be favorable for the receptor binding. The assumption
corresponds to the SAR, that is, the electron-withdraw-
ing property of the 7-substituents improves AMPA
receptor affinity.15 Second, since neither substitution
for 3a with nitro, 4, nor imidazolyl, 7c, at the 6-position
resulted in less improved affinity than those of 15b, 19,
and 20, the 6-substituents of monosubstituted pyridopy-
razinediones may not be able to contribute to the
favorable interaction with AMPA receptor, as compared
to 7-substituents of monosubstituted pyridopyrazinedi-
ones and quinoxalinediones and 6-substituents of di-
substituted derivatives. This may reflect the existence
of a pyridine nitrogen atom at the ortho position which
could cause Coulombic repulsion or affect the π-electron
distribution on the aromatic nuclei. Possibly, the SAR
on AMPA affinity may be caused by multiple reasons.
2,3(1H,4H)-P yr id o[2,3-c]p yr a zin ed ion e (3b): 48% from
2b; mp >300 °C (H2O); 1H NMR δ 12.48 (brs, 2H), 8.48 (s,
1H), 8.36 (d, 1H), 7.42 (d, 1H); MS (EI) m/z 163 (M). Anal.
(C7H5N3O2‚0.9HCl) C,H,N.
6,7(5H,8H)-P ter id in ed ion e (3c): 62% from 2c; mp >300
1
°C (DMF-H2O); H NMR δ 12.64 (brs, 1H), 12.06 (brs, 1H),
8.61 (s, 1H), 8.37 (s, 1H); MS (EI) m/z 164 (M). Anal.
(C7H5N3O2‚0.1H2O) C,H,N.
6-Nitr o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e (4). To
an ice-cold solution of 3a (1.2 g, 7.48 mmol) in a mixture of
acetic anhydride (12 mL) and acetic acid (2.4 mL) was added
dropwise fuming HNO3 (d ) 1.52, 0.93 mL, 22.4 mmol). The
reaction mixture was stirred at 50 °C for 1 h. The resulting
precipitate was collected and washed with water to give 4 (0.49
g, 28%): mp >300 °C (DMF-H2O); 1H NMR δ 12.82 (brs, 1H),
12.44 (s, 1H), 8.06 (d, J ) 8.0 Hz, 1H), 7.64 (d, J ) 8.3 Hz,
1H); MS (EI) m/z 208 (M). Anal. (C7H4N4O4‚0.1H2O) C,H,N.
2-Am in o-6-m eth oxy-3-n itr op yr id in e (6a ). Sodium (0.20
g, 8.70 mmol) was dissolved in methanol (20 mL). 2-Amino-
6-chloro-3-nitropyridine (5)21 (1.30 g, 7.49 mmol) was added
to the solution and refluxed for 2 h. The resulting precipitate
was collected and washed with a little methanol to give 6a
(0.89 g, 70%): mp 170-171 °C (methanol); 1H NMR δ 8.26 (d,
1H), 8.16 (br, 2H), 6.15 (d, 1H), 3.91 (s, 3H); MS (EI) m/z 169
(M).
Con clu sion
This study showed that the nitrogen atoms in the
pyridine and pyrimidine rings of azaquinoxalinediones
are tolerated in AMPA receptor binding. The detailed
SAR of a series of 6- and/or 7-substituted pyrido[2,3-b]-
pyrazinediones for the AMPA receptor binding showed
some differences from that of the corresponding substi-
tuted quinoxalinediones. The X-ray study exhibited
2-Am in o-6-m or p h olin o-3-n itr op yr id in e (6b). A solution
of 5 (2.00 g, 11.5 mmol) and morpholine (1.51 mL, 17.3 mmol)
in methanol (20 mL) was stirred at room temperature over-
night. The resulting precipitate was collected and washed
with a little methanol to give 6b (1.92 g, 74%): mp 155-158

1336 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ohmori et al.
1
1
°C (methanol); H NMR δ 8.08 (d, 1H), 7.84 (br, 2H), 6.32 (d,
°C (DMF-H2O); H NMR δ 12.82 (s, 1H), 11.98 (s, 1H), 8.08
(s, 1H), 4.00 (s, 3H); MS (FAB) m/z 239 (M + 1). Anal.
(C8H6N4O5‚0.1DMF) C,H,N.
1H) 3.68 (s, 8H); MS (EI) m/z 244 (M).
2-Am in o-6-(1H-im id a zol-1-yl)-3-n itr op yr id in e (6c).
A
solution of 5 (16.4 g, 94.6 mmol) was treated with imidazole
(64.4 g, 946 mmol) in DMF (300 mL) at 120 °C for 1 h. The
reaction mixture was cooled down to ambient temperature and
poured in water (300 mL). The resulting precipitate was
collected and washed with water to give 6c (15.5 g, 80%): mp
235-236 °C (methanol); 1H NMR δ 8.57 (d, 1H), 8.56 (d, 1H),
8.18 (brs, 2H), 7.95 (t, 1H), 7.16 (q, 1H), 7.16(d, 1H); MS (EI)
m/z 205 (M).
6-Mor p h olin o-7-n it r o-2,3(1H ,4H )-p yr id o[2,3-b]p yr a -
zin ed ion e (8b). To an ice-cold solution of 7b (0.29 g, 1.17
mmol) in concentrated H2SO4 (3 mL) was added KNO3 (0.12
g, 3.89 mmol) portionwise, and the reaction mixture was
stirred at 90 °C for 1 h. The solution was poured onto ice,
and the resulting precipitate was collected and washed with
water. The solid was recrystallized from DMF-water to give
8b (0.38 g, 65%): mp >300 °C (DMF-H2O); 1H NMR δ 12.57
(s, 1H), 11.86 (s, 1H), 8.01 (s, 1H), 3.70 (m, 4H), 3.33 (br, 4H);
MS (FAB) m/z 294 (M + 1). Anal. (C11H11N5O5) C,H,N.
6-(1H-Im id a zol-1-yl)-7-n it r o-2,3(1H,4H)-p yr id o[2,3-b]-
p yr a zin ed ion e Hyd r och lor id e (8c‚HCl). A solution of 7c
(1.01 g, 3.56 mmol) and nitronium tetrafluoroborate22 (85%,
1.35 g, 8.90 mmol) in tetramethylene sulfone (10 mL) was
heated at 120 °C for 4 h. The solution was poured onto water
(10 mL) and neutralized with 1 N NaOH. The resulting
precipitate was collected and washed with hot water. The solid
was suspended in water and mixed with 1 N HCl (3.6 mL).
After the mixture was stirred for 0.5 h, the solid was collected
and washed with water and ethanol followed by recrystalli-
zation with DMF-water to give 8c‚HCl (0.63 g, 57%): mp
2-Am in o-3-n itr o-6-(m eth ylth io)p yr id in e (6e). A solu-
tion of 5 (2.00 g, 11.5 mmol) was treated with aqueous sodium
mercaptan (15%, 5.92 mL, 6.51 mmol) in methanol (20 mL)
at room temperature overnight. The resulting precipitate was
collected and washed with methanol to give 6e (1.72 g, 81%):
1
mp 135-137 °C (methanol); H NMR δ 8.17 (d, 1H), 8.10 (br,
2H), 6.64 (d, 1H), 2.56 (s, 3H); MS (EI) m/z 185 (M).
Gen er a l Met h od for P r ep a r a t ion of 6-Su b st it u t ed
P yr id op yr a zin ed ion es. 6-Substituted-2,3(1H,4H)-pyrido-
[2,3-b]pyrazinediones 7a -e were prepared by hydrogenation
of the appropriate 2-amino-3-nitropyridines under atmospheric
pressure using Pd-C (7a -d ) or Raney nickel (7e,f) to give the
diamines followed by reaction with oxalic acid in 4 N HCl at
reflux temperature to give the corresponding 6-substituted 2,3-
(1H,4H)-pyrido[2,3-b]pyrazinediones.
1
>300 °C (DMF-H2O); H NMR δ 13.16 (brs, 1H), 12.74 (brs,
1H), 9.53 (m, 1H), 8.46 (s, 1H), 8.07 (m, 1H), 7.87 (m, 1H); MS
(FAB) m/z 275 (M + 1). Anal. (C10H6N6O4‚HCl‚0.2H2O)
C,H,N,Cl.
6-Meth oxy-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e (7a ).
A solution of 6a (0.88 g, 5.20 mmol) in ethanol (20 mL) was
hydrogenated under atmospheric pressure with 10% Pd-C as
catalyst. The suspension was filtered, and the filtrate was
evaporated. To a solution of this residue in 4 N HCl (12 mL)
was added oxalic acid (0.47 g, 5.20 mmol), and the mixture
was refluxed overnight. The resulting precipitate was collected
and washed with water. The solid was recrystallized from
DMF-water to give 7a (0.57 g, 57%): mp >300 °C (DMF-
6-Hydr oxy-2,3(1H,4H)-pyr ido[2,3-b]pyr azin edion e [2,3,6-
(1H,4H,5H)-P yr id o[2,3-b]p yr a zin etr ion e] (9). A solution
of 7a (0.25 g, 1.29 mmol) in aqueous HBr (48%, 5 mL) was
refluxed for 4 h and then stirred at room temperature
overnight. The reaction mixture was diluted with water (100
mL), and the resulting precipitate was collected and washed
with water. Recrystalliaztion of the solid from DMF-water
gave 9 (0.16 g, 70%): mp >300 °C (DMF-H2O); 1H NMR δ
12.69 (s, 1H), 11.77 (s, 1H), 10.65 (br, 1H), 7.38 (d, J ) 8.6
Hz, 1H), 6.41 (d, J ) 8.4 Hz, 1H); MS (FAB) m/z 180 (M + 1).
Anal. (C7H5N3O3‚0.1H2O) C,H,N.
1
H2O); H NMR δ 12.26 (s, 1H), 11.83 (s, 1H), 7.44 (d, J ) 8.6
Hz, 1H), 6.58 (d, J ) 8.6 Hz, 1H), 3.83 (s, 3H); MS (FAB) m/z
194 (M + 1). Anal. (C8H7N3O3) C,H,N.
6-Mor p h olin o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e
(7b): 32% from 6b; mp >300 °C (DMF-H2O); 1H NMR δ 12.01
(s, 1H), 11.71 (s, 1H), 7.33 (d, J ) 8.6 Hz, 1H), 6.60 (d, J ) 8.8
Hz, 1H), 3.65-3.75 (m, 4H), 3.35-3.41 (m, 4H); MS (FAB) m/z
249 (M + 1). Anal. (C11H12N4O3‚0.6H2O) C,H,N.
6-(N-Meth ylam in o)-2,3(1H,4H)-pyr ido[2,3-b]pyr azin edi-
on e h yd r och lor id e (7d ‚HCl): 61% from 2-amino-6-(N-me-
thylamino)-3-nitropyridine (6d );21 mp >300 °C (DMF-H2O);
1H NMR δ 11.86 (br, 2H), 7.30 (d, J ) 8.6 Hz, 1H), 6.96 (br,
1H), 6.36 (d, J ) 8.6 Hz, 1H), 2.78 (s, 3H); MS (FAB) m/z 193
(M + 1). Anal. (C8H7N3O2‚HCl) C,H,N,Cl.
6-(Meth ylsu lfon yl)-2,3(1H,4H)-pyr ido[2,3-b]pyr azin edi-
on e (10). To a solution of 7e (0.20 g, 0.96 mmol) in acetic
acid (2 mL) was added aqueous hydrogen peroxide (30%, 0.36
mL, 3.17 mmol), and the mixture was stirred at room tem-
perature overnight. The solution was diluted with water (15
mL), and the resulting precipitate was collected and recrystal-
lized from DMF-water to give 10 (0.12 g, 52%): mp >300 °C
1
(DMF-H2O); H NMR δ 12.51 (br, 2H), 7.78 (d, 1H), 7.62 (d,
1H), 3.22 (s, 3H); MS (FAB) m/z 242 (M + 1). Anal.
(C8H7N3O4S) C,H,N,S.
6-(Me t h ylt h io)-2,3(1H ,4H )-p yr id o[2,3-b]p yr a zin e d i-
on e (7e). A solution of 6e (1.68 g, 9.07 mmol) in methanol
(30 mL) was hydrogenated under atmospheric pressure with
Raney nickel as catalyst. The suspension was filtered, and
the filtrate was evaporated. To a solution of the residue in 4
N HCl (18 mL) was added oxalic acid (0.82 g, 9.07 mmol), and
the mixture was refluxed overnight. The resulting precipitate
was collected and washed with water. The solid was recrys-
tallized from DMF-water to give 7e (1.06 g, 56%): mp >300
2-Am in o-6-m eth yl-3-n itr op yr id in e (12). To an ice-cold
solution of 11 (23.0 g, 212 mmol) in concentrated H2SO4 (100
mL) was added dropwise concentrated HNO3 (70%, d ) 1.43,
13.4 mL, 212 mmol). The ice bath was removed, and the
solution spontaneously heated to about 50 °C and then cooled.
The reaction mixture was additionally stirred at room tem-
perature for 2 h and poured onto ice. The solution was
adjusted to pH 4-5 by aqueous NaOH, and the resulting
precipitate was collected and washed with hot water to give
12 (15.4 g, 47%): 1H NMR δ 8.64 (m, 2H), 8.25 (d, 1H), 6.64
(d, 1H), 2.71 (s, 3H); MS (GC-EI) m/z 153 (M).
6-Meth ylp yr id o[2,3-b]p yr a zin e-2,3-d ion e (13). A solu-
tion of 12 (7.60 g, 49.7 mmol) in ethanol (80 mL) was
hydrogenated under atmospheric pressure with 10% Pd-C as
catalyst. The suspension was filtered, and the filtrate was
evaporated. To a solution of this residue in 4 N HCl (54 mL)
was added oxalic acid (4.30 g, 47.8 mmol), and the mixture
was refluxed overnight. The resulting precipitate was collected
and washed with water. The solid was recrystallized from
DMF-water to give 13 (2.90 g, 33%): mp >300 °C (DMF-
H2O); 1H NMR δ 11.98 (m, 2H), 7.36 (d, 1H), 6.99 (d, 1H), 2.40
(s, 3H); MS (EI) m/z 177 (M). Anal. (C8H7N3O2) C,H,N.
7-Meth yl-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e (15a ).
A solution of 2,3-diamino-5-methylpyridine (14a )23 (4.60 g,
37.4 mmol) and oxalic acid (3.40 g, 37.8 mmol) in 4 N HCl (50
mL) was refluxed overnight. The resulting precipitate was
collected and washed with water to give 15a (4.9 g, 74%): mp
1
°C (DMF-H2O); H NMR δ 12.31 (s, 1H), 11.90 (s, 1H), 7.37
(d, J ) 8.4 Hz, 1H), 7.02 (d, J ) 8.4 Hz, 1H), 3.32 (s, 3H); MS
(FAB) m/z 210 (M + 1). Anal. (C8H7N3O2S) C,H,N,S.
6-Ch lor o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e (7f):
57% from 5; mp >300 °C (DMF-H2O); 1H NMR δ 12.51 (s,
1H), 12.05 (s, 1H), 7.47 (d, J ) 8.4 Hz, 1H), 7.18 (d, J ) 8.2
Hz, 1H); MS (FAB) m/z 198 (M + 1). Anal. (C7H4N3O2-
Cl‚0.5DMF) C,H,N,Cl.
6-Meth oxy-7-n itr o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed i-
on e (8a ). To an ice-cold solution of 7a (0.50 g, 2.59 mmol) in
a mixture of acetic anhydride (5 mL) and acetic acid (5 mL)
was added dropwise fuming HNO3 (0.16 mL, 3.89 mmol), and
the reaction mixture was stirred at 90 °C for 1 h. The solution
was poured onto ice, and the resulting precipitate was collected
and washed with water. The solid was recrystallized from
DMF-water to give 8a (0.38 g, 62%). The NOE was observed
between the aromatic proton and the amide proton but not
methoxy proton in NMR study of this compound: mp >300

Novel AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1337
>300 °C; 1H NMR δ 12.22 (s, 1H), 11.94 (s, 1H), 7.88 (m, 1H),
7.24 (m, 1H), 3.30 (s, 3H); MS (EI) m/z 177 (M). Anal.
(C8H7N3O2‚0.5H2O) C,H,N.
spectra, and elemental analyses in Institute for Drug
Discovery Research, Yamanouchi Pharmaceutical Co.
Ltd.
7-Nitr o-2,3(1H,4H)-p yr id o[2,3-b]p yr a zin ed ion e (15b):
81% from 2,3-diamino-5-nitropyridine (14b);24 mp >300 °C; 1H
NMR δ 12.93 (br, 1H), 12.21 (br, 1H), 8.86 (d, J ) 2.9 Hz, 1H),
8.40 (d, J ) 2.9 Hz, 1H); MS (EI) m/z 208 (M). Anal.
(C7H4N4O4) C,H,N.
Su p p or tin g In for m a tion Ava ila ble: Crystal data, frac-
tional coordinates, bond lengths, bond angles, and torsional
angles for compound 1 (4 pages). Ordering information is
given on any current masthead page.
6,7-Din itr o-2,3(1H,4H)-pyr ido[2,3-b]pyr azin edion e (16).
A solution of 15b (0.59 g, 2.83 mmol) and nitronium tetrafluo-
roborate22 (85%, 0.53 g, 3.39 mmol) in tetramethylene sulfone
(6 mL) was heated at 130 °C for 2 h. The solution was poured
onto water (10 mL), and the resulting precipitate was collected.
The solid was recrystallized from water to give 16 (0.32 g,
45%): mp 265 °C dec (H2O); 1H NMR δ 13.30 (s, 1H), 12.60 (s,
1H), 8.12 (s, 1H); MS (EI) m/z 253 (M). Anal. (C7H3N5O6)
C,H,N.
Refer en ces
(1) Curtis, C. R.; Watkins, J . C. The Excitation and Depression of
Spinal Neurons by Structurally Related Amino Acids. J . Neu-
rochem. 1960, 6, 117-141.
(2) Krnjevic, K.; Phillis, J . W. Iontophoretic Studies of Neurons in
the Mammalian Cerebral Cortex. J . Physiol. 1963, 165, 274-
304.
(3) Takeuchi, A.; Takeuchi, N. The Effect on Crayfish Muscle of
Iontophoretically Applied Glutamate. J . Physiol. 1964, 170, 296-
317.
(4) Choi, D. W. Glutamate Neurotoxicity and Diseases of the
Nervous System. Neuron 1988, 1, 623-634.
(5) Olney, J . W. Excitotoxic Amino Acids and Neuropsychiatric
Disorders. Annu. Rev. Pharmacol. Toxicol. 1990, 30, 47-71.
(6) Monghan, D. T.; Bridges, R. J .; Cotman, C. W. The excitatory
Amino Acid Receptors: Their Classes, Pharmacology, and
Distinct Properties in the Function of the Central Nervous
System. Annu. Rev. Pharmacol. Toxicol. 1989, 29, 365-402.
(7) Smith, S. E.; Durmuller, N.; Meldrum, B. S. The non-N-methyl-
D-aspartate receptor Antagonists, GYKI 52466 and NBQX are
Anticonvulsant in Two Animal Models Of Epilepsy. Eur. J .
Pharmacol. 1991, 201, 179-183.
(8) Park, C. K.; Nehls, D. G.; Graham, B. S. The Glutamate
Antagonist MK-801 Reduces Focal Ischemic Brain Damage in
the Rat. Annu. Neurol. 1988, 24, 543-551.
(9) Buchan, A. M.; Li, H.; Cho, S.; Pulsinelli, W. A. Blockade of the
AMPA Receptor Prevents CA1 Hippocampal Injury Following
Severe but Transient Forebrain Ischemia in Adult Rats. Neu-
rosci. Lett. 1991, 132, 255-258.
Molecu la r Mod elin g. The conformation of the compounds
was optimized by the PM3 method with MMOK parameter as
implemented in the MOPAC30 Ver. 6.0 program. For these
computations, the molecular modeling package MOLGRAPH-
MS (Daikin Industry Ltd., J apan) on an IRIS/INDIGO work-
station (SiliconGraphics) was used.
X-r a y Cr ysta llogr a p h ic An a lysis of 1‚HCl. Suitable
crystals for X-ray diffraction studies formed from H2O with
space group symmetry of P21/n and cell constants of a ) 9.613-
(1) Å, b ) 9.093(1) Å, c ) 14.154(1) Å, â ) 90.20(1)° for Z ) 4,
and a calculated density of 1.662 g/cm3. A Rigaku AFC-5R
automatic four-circle diffractometer equipped with graphite-
monochromated Cu KR radiation (λ ) 1.541 84 Å) was used
for data collection and θ - 2θ scan technique. Of the 1831
reflections with 2θ < 120° at a scanning rate of 8° (2θ) min-1
,
1727 were observed (|F| > 3σ|F|). Three reference reflections
showed no significant intensity deterioration throughout the
data collection. The intensities were corrected for Lorentz and
polarization factors but not for absorption and secondary
extinction.
(10) Honore, T.; Davies, S. T.; Drejer, J .; Fletcher, E. J .; J acobsen,
P.; Lodge, D.; Nielsen, F. E. Quinoxalinediones: Potent Com-
petitive Non-NMDA Glutamate Receptor Antagonists. Science
1988, 241, 701-703.
(11) Sheardown, M. J .; Nielsen, E. Φ.; Hansen, A. J .; J acobsen, P.;
The structure was solved by direct methods using the
computer program SHELXS86.31 All hydrogen atoms were
located on a difference Fourier map. The structure was refined
by block-diagonal least-squares calculations with anisotropic
(isotropic for hydrogen atoms) thermal parameters to a final
R value of 0.039 (RW ) 0.047).
Biology. Ra d iobin d in g Assa y. Inhibition of the specific
binding of [3H]AMPA and strychnine-insensitive [3H]Gly to
brain membranes in vitro was evaluated using standard
procedures. The binding of [3H]AMPA was conducted with
crude membranes of rat whole brain in the presence of 100
mM KSCN as described by Honore et al.25 [3H]Gly binding was
examined using Triton X-100-treated membranes of whole
brain except cerebellum.28 Final ligand concentrations were
as follows: [3H]AMPA, 43 nM, and [3H]Gly, 35 nM.
Honore,
T.
2,3-Dihydroxy-6-nitro-7-sulfamoyl-benzo(F)-
quinoxaline: A Neuroprotectant for Cerebral Ischemia. Science
1990, 247, 571-574.
(12) Kaku, D. A.; Goldberg, M. P.; Choi, D. W. Antagonism of non-
NMDA Receptors Augments the Neuroprotective Effect Of
NMDA Receptor Blockade in Cortical Cultures Subjected to
Prolonged Deprivation of Oxygen and Glucose. Brain Res. 1991,
554, 344-347.
(13) J udge, M. E.; Sheardown, M. J .; J acobsen, P.; Hanore, T.
Protection against Post-ischemic Behavioral Pathology by the
R-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA)
Antagonist 2,3-Dihydroxy-6-nitro-7-sulfamoylbenz(f)quinoxaline-
(NBQX) in the Gerbil. Neurosci. Lett. 1991, 133, 291-294.
(14) Sakamoto, S.; Ohmori, J .; Shimizu-Sasamata, M.; Okada, M.;
Kawasaki, S.; Yatsugi, S.; Hidaka, K.; Togami, J .; Tada, S.;
Usuda, S.; Murase, K. Imidazolylquinoxaline-2,3-diones: Novel
and Potent Antagonists of a-Amino-3-hydroxy-5-methylisoxazole-
4-propionate (AMPA) excitatory Amino Acid Receptor. XIIth
International Symposium on Medicinal Chemistry, Basel, Swit-
zerland, September 1992; Abstract 28.
(15) Ohmori, J .; Sakamoto, S.; Kubota, H.; Shimizu-Sasamata, M.;
Okada, M.; Kawasaki, S.; Hidaka, K.; Togami, J .; Furuya, T.;
Murase, K. 6-(1H-Imidazol-1-yl)-7-nitro-2,3-(1H,4H)-quinoxa-
linedione Hydrochloride (YM90K) and Related Compounds:
Structure-Activity Relationships for the AMPA-type Non-NMDA
receptor. J . Med. Chem. 1994, 37, 467-475.
(16) 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.
(17) Yatsugi, S.; Kawasaki, S.; Katoh, M.; Takahashi, M.; Koshiya,
K.; Shimizu-Sasamata, M. Effect of a Novel AMPA Antagonist
YM900 and Other Excitatory Amino Acid Antagonists on the
Delayed Neuronal Death in the Gerbil Hippocampus. J . Cereb.
Blood Flow Metab. 1993, 13 (Suppl. 1), S635.
(18) Shimizu-Sasamata, M.; Kawasaki, S.; Yatsugi, S.; Ohmori, J .;
Sakamoto, S.; Koshiya, K.; Usuda, S.; Murase, K. The Neuro-
protective Actions of YM-900, a Novel and Potent R-Amino-3-
hydroxy-5-methylisoxazole-4-propionate (AMPA) Receptor An-
tagonist, in a Gerbil Global Ischemia Model and a Rat Focal
Ischemia Model. 22nd Annual Meeting Society for Neuroscience,
Anaheim, October 1992; Abstract 44.14.
IC50 values were determined from logit-log analysis, and
Ki values were determined using the Cheng-Prushoff rela-
tionship.
Au d iogen ic Seizu r es in DBA/2 Mice. Test compounds
were given ip to groups of eight male DBA/2 mice (21-28 days
old, weight 10-12 g) per dose level 15 min prior to challenge
with auditory stimulation (12 kHz at 120 dB).29 Seizure
response was assessed on the following scale: 0 ) no response,
1 ) wild running, 1 ) clonus, 1 ) tonic, and 1 ) respiratory
arrest; maximum score ) 4, and minimum score ) 0.
Ack n ow led gm en t. We thank Professor H. Nohira
of Saitama University and Drs. N. Inukai, K. Murase,
T. Tamura, S. Usuda, and S. Tsukamoto of Institute for
Drug Discovery Research, Yamanouchi Pharmaceutical
Co. Ltd., for their encouragement and helpful discus-
sion. We also thank Dr. T. Furuya for X-ray analysis,
Mr. J . Togami for AMPA binding assay, Mr. A. Kohara
for glycine binding assay, and the staff of the Structure
Analysis Department for measurement of NMR, mass

1338 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Ohmori et al.
(19) Shimizu-Sasamata, M.; Kawasaki-Yatsugi, S.; Okada, M.; Saka-
moto, S.; Yatsugi, S.; Togami, J .; Hatanaka, K.; Ohmori, J .;
Koshiya, K.; Usuda, S.; Murase, K. YM90K: Pharmacological
Characterization as a Selective and Potent R-Amino-3-hydroxy-
5-methylisoxazole-4-propionate (AMPA)/Kainate Receptor An-
tagonist. J . Pharmacol. Exp. Ther. 1996, 276, 84-92.
(20) Compound 3a has been synthesized by an alternative procedure;
see: Winterfeld, K.; Wildersohn, M. 2,3-Dichlor- und 2,3,7-
Trichlor-5-aza-chinoxalin. Arch. Pharm. (Weinheim, Ger.) 1970,
303, 44-48.
(27) Leeson, P. D.; Baker, R.; Carling, R. W.; Curtis, N. R.; Moore,
K. W.; Williams, B. J .; Foster, A. C.; Donald, A. E.; Kemp, J . A.;
Marshall, G. R. Kynurenic Acid Derivatives. Structure-Activity
Relationships for Excitatory Amino Acid Antagonism and Iden-
tification of Potent and Selective Antagonists at the Glycine Site
on the N-Methyl-D-aspartate Receptor. J . Med. Chem. 1991, 34,
1243-1252.
(28) Monahan, J . B.; Corpus, V. M.; Hood, W. F.; Thomas, J . W.;
Compton, R. P. Characterization of a [3H]Glycine Recognition
Site as a Modulatory Site of the N-methyl-D-Aspartate Receptor
Complex. J . Neurochem. 1989, 53, 370-375.
(29) De Sarro, G. B.; Meldrum, B. S.; Nistico, G. Anticonvulsant
Effects of Some Calcium Entry Blockers in DBA/2 Mice. Br. J .
Pharmacol. 1988, 93, 247-256.
(30) Stewart, J . J . P. MOPAC: A Semiempirical Molecular Orbital
program. J . Comput.-Aided Mol. Des. 1990, 4, 1-105.
(31) Sheldrick, G. H. SHELXS86 Program for Crystal Structure
Solution; University of Gottingen: Federal Republic of Germany,
1986.
(21) Steinmetz, G.; Thiele, K. German Pat. Appl. DE 2000563, 1970.
(22) Fieser, L. F.; Fieser, M. Reagents for Organic Synthesis I; J ohn
Wiley and Sons, Inc.: New York, 1967; pp 742-743.
(23) Brooks, W.; Day, A. R. Derivatives of 1H-imidazo[4,5-b]pyridine.
J . Heterocycl. Chem. 1969, 6, 759-760.
(24) Hunger, A.; Keberle, H.; Rossi, A.; Hoffmann, K. Swiss Pat. Appl.
CH 386442, 1965.
(25) Honore, T.; Lauridsen, J .; Krogsgaard-Larsen, P. The binding
of [3H]AMPA, a Structural Analogue of Glutamic Acid, to Rat
Brain Membranes. J . Neurochem. 1982, 38, 173-178.
(26) Leeson P. D.; Iversen L. L. The Glycine Site on the NMDA
Receptor: Structure-Activity Relationships and Therapeutic
Potential. J . Med. Chem. 1994, 37, 4053-4067.
J M950304+