Discovery of 6-({4-[2-(4-tert-Butylphenyl)-1H-benzimidazol-4-yl]piperazin- 1-yl}methyl)quinoxaline(WAY-207024): An orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R)

Article abstract of DOI:10.1021/jm801572m

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4- piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes

Full text of DOI:10.1021/jm801572m

2148
J. Med. Chem. 2009, 52, 2148–2152
Brief Articles
Discovery of 6-({4-[2-(4-tert-Butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline
(WAY-207024): An Orally Active Antagonist of the Gonadotropin Releasing Hormone Receptor
(GnRH-R)
Jeffrey C. Pelletier,*,† Murty V. Chengalvala,‡ Joshua E. Cottom,‡ Irene B. Feingold,§ Daniel M. Green,† Diane B. Hauze,†
Christine A. Huselton,§ James W. Jetter,† Gregory S. Kopf,‡ Joseph T. Lundquist, IV,† Ronald L. Magolda,† Charles W. Mann,†
John F. Mehlmann,† John F. Rogers,† Linda K. Shanno,‡ William R. Adams,§ Cesario O. Tio,§ and Jay E. Wrobel†
Department of Chemical Sciences, Musculoskeletal Biology, and Drug Safety and Metabolism, Wyeth Research,
500 Arcola Road, CollegeVille, PennsylVania 19426
ReceiVed December 12, 2008
A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a
quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in
vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule
resulted in several structures with improved properties and culminated in the discovery of 6-({4-[2-(4-tert-
butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024). The compound was
shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral
administration.
Introduction
Gonadotropin releasing hormone (GnRH)a is a decameric
peptide synthesized and released in a pulsatile fashion from the
hypothalamus.1 The hormone stimulates the release of leutein-
izing hormone (LH) and follicle stimulating hormone (FSH)
from the anterior pituitary gland and these gonadotropins in turn
stimulate sex hormone synthesis and release into the general
circulation. Blocking the actions of GnRH via receptor super-
agonism, which downregulates the GnRH receptor over several
weeks, or direct antagonism has led to positive clinical results
for numerous hormone sensitive pathological conditions such
as prostate cancer, primary hirsutism, and uterine fibroids.2 All
marketed drugs, however, are small peptides and raise significant
issues such as parenteral administration, compliance, and safety.3
Alternatively, small molecule drug candidates frequently offer
Figure 1. Highly insoluble small molecule GnRH receptor antagonist
with affinity for rat and human receptors.
the advantages of oral activity, adjustable plasma drug levels,
and rapid discontinuation of treatment in the event of toxicity.
The emergence of small molecule GnRH receptor antagonists
in recent years offers the potential for alternative therapeutic
intervention.4 Several structural classes have emerged as potent
GnRH receptor antagonists.5 Bioavailability, however, has been
low (%F < 25) in most cases. In addition to this, receptor binding
affinity for small molecule antagonists has frequently shown
species selectivity, which has forced the in vivo evaluation of
many of these GnRH antagonists in expensive monkey models,
although some compounds showing activity in rat have been
documented.6 We recently reported the discovery of a 2-phenyl-
4-(1-piperazinyl)benzimidazole series of GnRH antagonists that
display high affinity for human and rat GnRH receptors.7 From
these efforts, a potent GnRH antagonist with an appended
quinoxaline-2,3-dione emerged as an advanced lead (1, Figure
1). The pharmaceutical properties of this lead, however, were
substandard due mainly to very low solubility (,1 µg/mL),
which precluded in vivo evaluation via oral administration. The
quinoxaline-2,3-dione portion of the molecule was most likely
responsible for the low solubility at pH ) 7.4.8 Attempts to
convert 1 into compounds with similar GnRH activity and
significantly improved properties are reported here. These efforts
led to the discovery of a high affinity GnRH antagonist with
plasma LH suppression properties following single oral dosing
in rats.
* To whom correspondence should be addressed. Phone: (484) 865-2912.
Fax: (484) 865-9399. E-mail: Pelletj@wyeth.com.
†
Department of Chemical Sciences.
Department of Musculoskeletal Biology.
Department of Drug Safety and Metabolism.
In vivo pharmacological activity requires compounds with
intrinsic biological target efficacy as well as exposure to the
target of interest. Starting with compound 1 as a lead, we sought
to alter the structure in such a way as to maintain GnRH affinity
and antagonist efficacy while improving molecular properties
‡
§
a Abbreviations: GnRH, gonadotropin releasing hormone; FSH, follicle
stimulating hormone; LH, leuteinizing hormone; PAMPA, phosphatidyl-
choline artificial membrane permeability assay; rLM, rat liver microsome.
10.1021/jm801572m CCC: $40.75
2009 American Chemical Society
Published on Web 03/09/2009

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 2149
Scheme 1. Preparation of Quinoxalin-2-one and Quinoxaline-2,3-dione GnRH Antagonistsa
a Conditions: (a) methylamine or 3-(pyridyl)methylamine, DMF, 56-95%; (b) H2, Pt/C, MeOH, 37-100%; (c) 1,1′-oxalyldiimidazole, THF, 40-60%;
(d) glycine methyl ester hydrochloride, MP-carbonate resin, DMF, 82%.
Scheme 2. Preparation of the 4-Quinoxaline and 5-Quinoxaline GnRH Antagonistsa
a Conditions: (a) 40% aq glyoxal, MeOH, 38-93%.
Scheme 3. Preparation of Quinoline and Dimethoxyquinoxaline
that would lead to enhanced absorption/stability that, in turn,
GnRH Antagonistsa
should lead to increased exposure following oral administration.
Compounds were evaluated in several high throughput in vitro
assays that provided data to assist in the determination of
compounds likely to have reasonable in vivo exposure levels.
The assays included aqueous solubility in pH ) 7.4 buffer,
phosphatidylcholine artificial membrane permeability assay
(PAMPA) to assess intestinal absorption, and rat liver mi-
crosome (rLM) half-life determination for the assessment of first
pass metabolism following absorption. Taken together, these
experiments have been shown to be reliable indicators of plasma
exposure levels.9 Their use as part of the screening process for
a Conditions: (a) quinoline-6-carboxaldehyde or quinoline-7-carboxal-
dehyde, NaBH(OAc)3, DCM, 25-30%.
potential in vivo candidates is rapid and requires fewer resources
than performing single day pharmacokinetic profiling on all
compounds with suitable GnRH activity.
Compound preparation is shown in Schemes 1-4. The
3-fluoro-4-nitrophenyl derivative 11, prepared as described
earlier,7a was treated with methylamine, 3-(pyridyl)methylamine,
or glycine methyl ester hydrochloride in the presence of resin
bound tertiary amine to afford the o-nitroamine products of
nucleophilic aromatic substitution. The nitro group of each
product was catalytically reduced to the phenylenediamines.
After reduction compound 12 spontaneously closed to the
desired product 5, while the other intermediates were treated
with 1,1′-oxalyldiimidazole to provide the corresponding qui-
noxaline-2,3-diones 2 and 3 (Scheme 1).
Preparation of the quinoxalines 6 and 9 was attained by
reacting previously disclosed phenylenediamines 13a and 13b7a
with aqueous glyoxal in methanol (Scheme 2). Quinolines 7
and 8 were obtained by reductive amination of piperazine 147a
with quinoline-6-carboxaldehyde10 and quinoline-7-carboxal-
dehyde,11 respectively (Scheme 3). Finally, preparation of the
azaquinoxalinedione 4 began with vinylation of commercially
available 2-amino-5-bromo-3-nitropyridine 15 followed by
reduction of the nitro group to the pyridinediamine with tin(II)
chloride dihydrate and sodium borohydride.12 Reaction of the
intermediate with oxalyldiimidazole followed by oxidation of

2150 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Brief Articles
Scheme 4. Preparation of Azaquinoxalinedione GnRH Antagonista
a Conditions: (a) vinyltributyltin, Pd(TPP)4, LiCl, Tol, N2, 100 °C, 77%; (b) SnCl2 ·2H20, NaBH4, EtOAc, t-BuOH, 60 °C, 82%; (c) 1,1′-oxalyldiimidazole,
THF, 79%; (d) OsO4, NaIO4, 1,4-dioxane, H2O, 26%; (e) 14, NaBH(OAc)3, NMP, 23%.
the vinyl group provided the aldehyde 16, which was reacted
with piperazine 14 to give the desired product (Scheme 4).
Detailed description of the in vitro affinity and functional
assays was reported earlier.7a Affinity of the small molecule
antagonists for human and rat GnRH receptors was assessed
with recombinant protein expressed in whole cells in competition
with radioiodinated (D-Trp6)-GnRH. Relative affinity was
measured as percent inhibition of binding and/or as IC50’s.
Human functional data was obtained as inhibition of tritiated
inosotol phosphates following treatment of cells overexpressing
the GnRH receptor with the agonist (D-Trp6)-GnRH. Functional
rat activity was assessed through inhibition of leuteinizing
hormone (LH) release from primary rat pituitary cells following
stimulation with (D-Trp6)-GnRH.
As mentioned earlier, the quinoxaline-2,3-dione portion of
lead compound 1 is the most likely source of extremely low
solubility of this molecule. It is also a flexible area of the
molecule in terms of GnRH activity as shown previously.7a
Hence, efforts to enhance the in vitro pharmaceutical profile
while retaining biological activity centered on this appended
heterocycle. The initial approach to solubility improvement was
the exchange of an H-bond donor for a methyl group. As seen
in Table 1, this did not have a detrimental effect on GnRH
activity nor did it help solubility to any significant degree (e.g.,
2, hGnRH binding IC50 ) 3.5 nM, sol @ pH 7.4 , 1 µg/mL).
Addition of a solubilizing group to this compound, such as
3-pyridylmethyl (e.g., 3, Table 1), also had little effect on
solubility. Replacement of the quinoxalinedione with a pyri-
dopyridazinedione (4, Table 1), however, provided a molecule
with enhanced human GnRH affinity and rat efficacy compared
to the lead compound. This modification also significantly
enhanced solubility (4 µg/mL) compared to the lead but it had
disappointing membrane permeability (Pe < 0.1 × 10-6 cm/s).
Conversion of the quinoxaline-2,3-dione into other functional
groups was examined next. Removal of a single carbonyl led
to a compound with suitable GnRH properties but poor
microsomal stability, solubility, and membrane permeability (see
5, Table 1). The quinoxaline 6 also showed good human in vitro
GnRH affinity and efficacy properties and moderate rat in vitro
activity (see Table 1). It also showed increased solubility and
membrane permeability over the original lead. Additional
analogues of the quinoxaline, including 6- and 7-methylquino-
lines (7 and 8) and the one-carbon transposed quinoxaline, 9,
were less active in the in vitro GnRH assays.
and 3 as extremely low (<1.0 µg/mL), hence they were not
considered for in vivo studies. Compounds 4 and 5 displayed
exceptionally poor membrane permeability properties with
Pe app < 0.1 × 10-6 cm/s in both cases (reasonable permeability
requires Pe
> 0.1 × 10-6 cm/s), indicating that they were
app
poor choices for further evaluation. The final remaining
candidate, compound 6, displayed low solubility (2 µg/mL) that
was still considerably higher than the quinoxaline-2,3-dione lead
1. In addition, quinoxaline 6 displayed moderate membrane
permeability properties and rat liver microsome stability (see
Table 1). We reasoned that the improved permeability and
microsomal stability might offset the low, but detectable
solubility in our assays. Hence, compound 6 was chosen for in
vivo PK evaluation via oral and iv administration. Table 2 shows
the results of these experiments in castrated rats. The quinoxaline
6 was absorbed well following oral administration with a
bioavailability of 74% (F%). Plasma half-lives following iv
(t1/2 ) 2.7 h) and oral (t1/2 ) 3.7 h) administration were similar,
indicating oral absorption of compound was not rate limiting.
In addition, oral exposure was high (AUC0-∞ ) 6637 ng·h/
mL) as was volume of distribution (Vss ) 6.1 L/kg) and plasma
clearance (Clp ) 38 mL/min/kg), indicating test material was
easily dispersed from plasma to the surrounding tissue. These
PK data indicated 6 would be an excellent candidate for in vivo
serum hormone suppression studies in castrated rats.
Serum LH levels in intact animals generally oscillate over
several hours so detection can be unreliable and variable.
Orchidectomized animals show stable elevated levels of this
hormone due to interruption of the testosterone feed back loop
that controls GnRH secretion. GnRH antagonists are known to
suppress these LH levels. Hence, castrated rats were given a
single oral dose of quinoxaline 6 (30 mg/kg, oral gavage, vehicle
) 2% Tween 80), and plasma samples were analyzed for LH
concentrations during the 24 h that followed. As Figure 2 shows,
compound 6 successfully lowered serum LH levels starting at
1 h post dosing and this effect lasted for at least 6 h. After
24 h, LH levels had returned to vehicle treated group levels.
This clearly indicates the quinoxaline is an orally active
antagonist of GnRH in rats.
In addition to GnRH activity, compound 6 was assessed in
vitro for broad off-target activity (65 receptors and enzymes),
including the hERG potassium channel, at 2 µM. Some activity
at the histamine H2, nonselective opioid, and neurokinin NK2
receptors was noted. The Ki data are summarized in Table 2.
No activity was observed at the hERG potassium channel.
The goal of this research was to convert a small molecule
GnRH antagonist lead with poor in vitro pharmaceutical
properties, particularly solubility at pH ) 7.4, into an advanced
lead with improved properties resulting in higher exposure
following oral administration in rats while maintaining GnRH
activity at or near the activity of the lead (1, Figure 1). The
quinoxaline-2,3-dione portion of lead compound 1 was eventu-
To determine a suitable candidate for in vivo testing, GnRH
activity and structure property (SPR) assessments were analyzed.
Strong potency in the human GnRH assays (binding IC50 < 20
nM, hIP IC50 < 100 nM) as well as moderate to strong activity
in the rat assays (binding IC50 < 100 nM, LH release IC50
<
500 nM) were required for additional testing. Compounds 2-6
fit these criteria. Analysis of in vitro pharmaceutical properties
within this subgroup indicated solubility (at pH ) 7.4) of 2

Brief Articles
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7 2151
Table 1. In Vitro GnRH Binding, Functional, and Pharmaceutical Profiling Dataa
a GnRH binding and functional data are the average of at least two runs performed in triplicate. b Binding to overexpressed human or rat GnRH receptors.
c Compound induced IP reduction in whole cells following stimulation with (D-Trp6)-GnRH. d Compound induced reduction in LH release from primary rat
pituitary cells stimulated with (D-Trp6)-GnRH. e See ref 9 for experimental details. f rLM ) rat liver microsome (see ref 9 for experimental details). g PAMPA
) phosphatidylcholine artificial membrane permeability assay (see ref 9 for experimental details).
ally modified to provide the quinoxaline, 6 (WAY-207024), a
molecule with potent GnRH receptor affinity (hGnRH IC50
12 nM, rGnRH IC50 ) 71 nM) and functional activity (hIP IC50
) 28 nM, rLH release IC50 ) 350 nM). This compound showed
)

2152 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 7
Table 2. Pharmacokinetic Parameters for Compound 6 in Castrated
Brief Articles
References
Ratsa b
,
(1) (a) Matsuo, H.; Baba, Y.; Nair, R. M. G.; Arimura, A.; Schally, A. V.
Structure of the porcine LH-and FSH-releasing hormone. I. Proposed
amino acid sequence. Biochem. Biophys. Res. Commun. 1971, 43,
1334–1339. (b) Schally, A. V.; Arimura, A.; Kastin, A. J.; Matsuo,
H.; Baba, Y.; Redding, T. W.; Nair, R. M. G.; Debeljuk, L.
Gonadotropin-releasing hormone. One polypeptide regulates secretion
of luteinizing and follicle-stimulating hormones. Science 1971, 173,
1036–1038. (c) Millar, R. P.; Lu, Z.-L.; Pawson, A. J.; Flanagan, C. A.;
Morgan, K.; Maudsley, S. R. Gonadotropin-releasing hormone recep-
tors. Endocr. ReV. 2004, 25, 235–275.
(2) Moreau, J.-P.; Delavault, P.; Blumberg, J. Luteinizing hormone-
releasing hormone agonists in the treatment of prostate cancer: a review
of their discovery, development, and place in therapy. Clin. Ther. 2006,
28, 1485–1508.
(3) Zhu, Y.-F.; Chen, C.; Struthers, R. S. Nonpeptide gonadotropin
releasing hormone antagonists. In Annual Reports in Medicinal
Chemistry; Doherty, A., Ed.; Academic Press: San Diego, 2004; Vol.
39, pp 99-110.
administration
method
iv
po (gavage)
dose (mg/kg)
vehicle
t1/2 (h)
Clp (mL/min/kg)
Vss (L/kg)
AUC0-∞ (ng·h/mL) 447
t1/2 (h)
Cmax (ng/mL)
Tmax (h)
AUC0-∞ (ng·h/mL)
bioavailability (F%)
a Values represent an average of three animals per dosed group. b Dosed
in free form.
1
20
DMSO/PEG200 (20/80) 2% Tween 80/0.04 N HCl
2.7
38
6.1
3.7
1333
2.0
6637
74
(4) Chengalvala, M. V.; Pelletier, J. C.; Kopf, G. S. GnRH agonists and
antagonists in cancer therapy. Curr. Med. Chem. Anti-Cancer Agents
2003, 3, 399–410.
(5) Betz, S. F.; Zhu, Y.-F.; Chen, C.; Struthers, R. S. Non-Peptide
Gonadotropin-Releasing Hormone Receptor Antagonists. J. Med.
Chem. 2008, 51, 3331–3348.
(6) (a) Young, J. R.; Huang, S. X.; Walsh, T. F.; Wyvratt, M. J., Jr.;
Yang, Y. T.; Yudkovitz, J. B.; Cui, J.; Mount, G. R.; Ren, R. N.;
Wu, T.-J.; Shen, X.; Lyons, K. A.; Mao, A.-H.; Carlin, J. R.;
Karanam, B. V.; Vincent, S. H.; Cheng, K.; Goulet, M. T.
2-Arylindoles as gonadotropin releasing hormone (GnRH) antago-
nists: optimization of the tryptamine side chain. Bioorg. Med. Chem.
Lett. 2002, 12, 827–832. (b) Anderes, K. L.; Luthin, D. R.; Castillo,
R.; Kraynov, E. A.; Castro, M.; Nared-Hood, K.; Gregory, M. L.;
Pathak, V. P.; Christie, L. C.; Paderes, G.; Vazir, H.; Ye, Q.; Anderson,
M. B.; May, J. M. Biological characterization of a novel, orally active
small molecule gonadotropin-releasing hormone (GnRH) antagonist
using castrated and intact rats. J. Pharmacol. Exp. Ther. 2003, 305,
688–695. (c) Li, H.; Anderes, K. L.; Kraynov, E. A.; Luthin, D. R.;
Do, Q.-Q.; Hong, Y.; Tompkins, E.; Sun, E. T.; Rajapakse, R.; Pathak,
V. P.; Christie, L. C.; Vazir, H.; Castillo, R.; Gregory, M. L.; Castro,
M.; Nared-Hood, K.; Paderes, G.; Anderson, M. B. Discovery of a
Novel, Orally Active, Small Molecule Gonadotropin-Releasing Hor-
mone (GnRH) Receptor Antagonist. J. Med. Chem. 2006, 49, 3362–
3367.
(7) (a) Pelletier, J. C.; Chengalvala, M.; Cottom, J.; Feingold, I.; Garrick,
L.; Green, D.; Hauze, D.; Huselton, C.; Jetter, J.; Kao, W.; Kopf, G.;
Lundquist, J., IV.; Mann, C.; Mehlmann, J.; Rogers, J.; Shanno, L.;
Wrobel, J. 2-Phenyl-4-piperazinylbenzimidazoles: Orally active inhibi-
tors of the gonadotropin releasing hormone (GnRH) receptor. Bioorg.
Med. Chem. 2008, 16, 6617–6640. (b) Green, D. M.; Pelletier, J. C.;
Goljer, I.; Andraka, D.; Chengalvala, M.; Shanno, L.; Hurlburt, W.
Parallel Synthesis of 2-Aryl-4-aminobenzimidazoles and Their Evalu-
ation as Gonadotropin Releasing Hormone Antagonists. J. Comb.
Chem. 2009, 11, 117–125.
(8) Fray, J. M.; Bull, D. J.; Carr, C. L.; Gautier, E. C. L.; Mowbray, C. E.;
Stobie, A. Structure-activity relationships of 1,4-dihydro-(1H,4H)-
quinoxaline-2,3-diones as N-methyl-D-aspartate (glycine site) receptor
antagonists. 1. Heterocyclic substituted 5-alkyl derivatives. J. Med.
Chem. 2001, 44, 1951–1962.
(9) Di, L.; Kerns, E. H. Application of Pharmaceutical Profiling Assays
for Optimization of Drug-Like Properties. Curr. Opin. Drug DiscoVery
DeV. 2005, 8, 495–504.
(10) Fakhfakh, M. A.; Fournet, A.; Prina, E.; Mouscadet, J.-F.; Franck,
X.; Hocquemiller, R.; Figadere, B. Synthesis and biological evaluation
of substituted quinolines: potential treatment of protozoal and retroviral
co-infections. Bioorg. Med. Chem. 2003, 11, 5013–5023.
Figure 2. Suppression of rat serum LH levels following a single oral
dose of compound 6 (30 mg/kg). Vehicle ) 2% Tween 80. LH levels
in both groups adjusted to 100 at t ) 0 h.
Table 3. Off-Target Biochemical Selectivity Data for 6
biochemical targeta
Ki (nM)
hGnRH/off-target Ki ratiosb
nonselective opioid
neurokinin 2 (NK2)
histamine 2 (H2)
550
330
850
50
30
77
a Human protein used in all cases. b Based on hGnRH Ki ) 11 nM.
solubility improvements over the lead even though it was still
low in terms of potential drug candidacy (∼2 µg/mL). Com-
pound 6 also showed moderate liver microsome stability (t1/2
) 16 min) and PAMPA membrane diffusion characteristics (Pe
) 0.23 × 10-6 cm/s). The combination of desirable intrinsic
GnRH activity and an improved in vitro pharmaceutical profile
with the quinoxaline supported in vivo testing. Single dose oral
and iv pharmacokinetics indicated the compound had high
bioavailability and exposure (see Table 2). As expected, rats
treated orally with compound 6 showed profound suppression
of LH that lasted for up to 24 h. Thus we were able to maintain
GnRH activity in a lead molecule while modifying the structure
to improve properties for better oral exposure and higher
bioavailability.
(11) Plobeck, N.; Delorme, D.; Wei, Z.-Y.; Hua, Y.; Zhou, F.; Schwartz,
P.; Gawell, L.; Gagnon, H.; Pelcman, B.; Schmidt, R.; Yu, S. Y.;
Walpole, C.; Brown, W.; Zhou, E.; Laberre, M.; Payza, K.; St-Onge,
S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.; Roberts,
E. New Diarylmethylpiperazines as Potent and Selective Nonpeptidic
δ Opioid Receptor Agonists with Increased In Vitro Metabolic
Stability. J. Med. Chem. 2000, 43, 3878–3894.
Acknowledgment. We thank Drs. Magid Abou-Gharbia,
Richard Lyttle, Richard Winneker, and Len Freedman for their
support of this program. We also thank Li Di and Ed Kerns for
in vitro pharmaceutical profiling and the Department of Analyti-
cal Chemistry for compound characterization.
(12) Cai, S. X.; Huang, J.-C.; Espitia, S. A.; Tran, M.; Ilyin, V. I.;
Hawkinson, J. E.; Woodward, R. M.; Weber, E.; Keana, J. F. W. 5-(N-
Oxyaza)-7-substituted-1,4-dihydroquinoxaline-2,3-diones: Novel, Sys-
temically Active and Broad Spectrum Antagonists for NMDA/glycine,
AMPA, and Kainate Receptors. J. Med. Chem. 1997, 40, 3679–3686.
Supporting Information Available: Experimental details, purity
data for compounds 2-9, experimental data for compounds 2-5,
1
and 7-9, copies of H NMR and 13C NMR spectra, and HPLC
analysis for compound 6. This material is available free of charge
via the Internet at http://pubs.acs.org.
JM801572M