Quinazolin-4-one α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists: Structure-activity relationship of the C-2 side chain tether

Article abstract of DOI:10.1021/jm000522p

A series of 6-fluoro-3-(2-chlorophenyl)quinazolin-4-ones has been prepared, which contains a 2-fluorophenyl ring attached to C-2 by a variety of two-atom tethers. These compounds were used to probe the structure-activity relationship (SAR) for AMPA recept

Full text of DOI:10.1021/jm000522p

1710
J . Med. Chem. 2001, 44, 1710-1717
Qu in a zolin -4-on e r-Am in o-3-h yd r oxy-5-m eth yl-4-isoxa zolep r op ion ic Acid
(AMP A) Recep tor An ta gon ists: Str u ctu r e-Activity Rela tion sh ip of th e C-2 Sid e
Ch a in Teth er
Bertrand L. Chenard,* Willard M. Welch, J ames F. Blake, Todd W. Butler, Anthony Reinhold, Frank E. Ewing,
Frank S. Menniti, and Martin J . Pagnozzi
Global Research and Development, Groton Laboratories, Pfizer Inc., Groton, Connecticut 06340
Received December 7, 2000
A series of 6-fluoro-3-(2-chlorophenyl)quinazolin-4-ones has been prepared, which contains a
2-fluorophenyl ring attached to C-2 by a variety of two-atom tethers. These compounds were
used to probe the structure-activity relationship (SAR) for AMPA receptor inhibition. The
relative potencies of the new compounds ranged from 11 nM to greater than 10 µM. The
differential activity of the compounds was rationalized on the basis of alterations of the
2-fluorophenyl positioning (planar and radial) relative to the quinazolin-4-one ring based on
computational methods. From this effort, new AMPA receptor antagonists, containing the
methylamino tether group, have been identified.
In tr od u ction
the results of this study, which identified the methyl-
amino spacer as an optimal tether. It should be noted
that these quinazolin-4-ones exist as a stable isolable
pair of atropisomers.6 Previously, we showed that all
the AMPA receptor antagonist activity resides in a
single atropisomer. For this SAR evaluation, we worked
exclusively with racemic materials.
Hyperactivity of ionotropic glutamate receptors has
been implicated in the pathophysiological sequelae
which contributes to the cell death observed in many
neurodegenerative processes including ischemic stroke,
brain injury, and epilepsy.1 Thus, an intense effort has
been focused on the discovery of compounds that block
glutamate receptor function as a potential therapeutic
remedy for these ailments. Initially, the N-methyl-D-
aspartate (NMDA) receptor was targeted. However,
many issues of early drug candidates, relating to both
safety and physical properties, have made development
very difficult.2 More recently, attention has been di-
rected toward a second class of ionotropic glutamate
receptors, the R-amino-3-hydroxy-5-methyl-4-isoxazole-
propionic acid (AMPA) receptors, because prototype
antagonists have been efficacious in many in vivo
neurodegenerative models.3
In the course of our studies on the modulation of
glutamate receptor function, we identified potent non-
competitive AMPA receptor antagonists based on the
quinazolin-4-one template.4 Initial structure-activity
relationship (SAR) development taught that halogen
substitution at C-6 was well tolerated and a 2-substi-
tuted phenyl ring at N-3 was essential for good activity.
At C-2, a phenyl or pyridyl ring connected by a two-
carbon tether was also necessary for AMPA receptor
blockade because the parent structure, methaqualone
(C-2 methyl group), was inactive. On the basis of the
two-carbon tether, two potent series were identified
containing either the vinyl or hydroxyvinyl (enol) units.5
To better understand the SAR in this region of these
molecules, we prepared compounds that varied only in
the nature of the tether unit. For this investigation, 3-(2-
chlorophenyl)-6-fluoroquinazolin-4-one was used as the
template and a 2-fluorophenyl ring was connected to C-2
through the various tethering groups. We report here
Ch em istr y
Most of the new compounds were prepared from the
readily available intermediate 3-(2-chlorophenyl)-6-
fluoro-2-methylquinazolin-4-one (17).4 Condensation with
2-fluorobenzaldehyde in hot acetic acid and acetic
anhydride produced the vinyl-tethered derivative 1
(Scheme 1). Hydrogenation of the double bond afforded
the ethyl-linked derivative 2. Deprotonation of 17 with
LiHMDS or LDA and reaction with 2-fluorobenzalde-
hyde or ethyl 2-fluorobenzoate provided the correspond-
ing hydroxyethyl (3) and hydroxyvinyl (4) analogues,
respectively. Compound 3 was obtained as a separable
mixture of diastereomers (3a , 3b) due to the atropiso-
meric motif resident in these structures (see below and
Experimental Section). We have not determined the
relative stereochemistry of the isomers of 3. They are
identified on the basis of their elution sequence during
silica gel chromatographic purification, 3a eluting first.
DBU-induced elimination of the triflate derived from 4
yielded the acetylene-linked structure 5.
To access the methylamino analogue, the C-2 methyl
group of 17 was oxidized to the aldehyde (18) using the
two-step procedure of Vetilino and Coe.7 Reductive
amination with 2-fluoroaniline, 2-fluorobenzylamine,
and related anilines afforded the desired methylene-
amino and three-atom C-N-C-linked compounds 6 and
7, respectively (Scheme 2). The reductive amination
procedure with aniline analogues was somewhat slug-
gish (6, 12-16). Thus, it was often advantageous to
preform the intermediate imine under dehydrative
conditions with magnesium sulfate or with azeotropic
* To whom correspondence should be addressed. Phone: 860-441-
4548. Fax: 860-715-8234. E-mail:chenardbl@groton.pfizer.com.
10.1021/jm000522p CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/25/2001

AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1711
Sch em e 1a
a
(a) 2-Fluorobenzaldehyde, HOAc, NaOAc, Ac2O, reflux (57%). (b) H2, 10% Pd/C, EtOAc (66%). (c) LiHMDS, THF, 2-fluorobenzaldehyde,
-78 °C to room temperature [two diastereomers formed, 3a (19%), 3b (61%)]. (d) LDA, THF, ethyl 2-fluorobenzoate, -78 °C (40% of 4).
(e) 2,6-lutidine, CH2Cl2, Tf2O, -78 °C to room temperature; DBU, THF, -78 to -10 °C (93%).
Sch em e 2a
a
(a) DMFDMA, DMF, 140 °C (90%); NaIO4, THF, aqueous pH 7 buffer (97%). (b) Various reductive amination procedures (see
Experimental Section). (c) HOAc, Ac2O, reflux (37% of 10); HCOOH, Ac2O, THF (95%, R ) formyl); BH3-THF, THF (30% of 11).
removal of water. Reduction of the imine could also be
problematic. In several instances, we found that a
combination of sodium cyanoborohydride and sodium
triacetoxyborohydride was more effective than either
reducing agent alone (see Experimental Section). This
was an empirical observation; we have no satisfactory
explanation to rationalize the experimental results.
Two analogues of 6 were prepared with substitution
on the nitrogen atom of the tether group (Scheme 2).
The acetamide 10 was synthesized by acylation of 6 with
acetic anhydride. The N-methylated derivative 11 was
prepared by the two-step procedure of formylation with
in situ generated acetylformyl anhydride followed by
reduction with BH3-THF.
In an attempt to examine the activity of analogues
with a simple amide tether, aldehyde 18 was further
oxidized to its corresponding acid with sodium chlorite.8
Unfortunately, while the oxidation proceeded in the
desired manner, the product acid was unstable and
decarboxylated rapidly at ambient temperature in our
hands. A methoxy tether (8) was prepared by NBS
bromination of 17 to give 19 followed by nucleophilic
displacement with 2-fluorophenol (Scheme 3). Finally,
the aminomethyl linking group was prepared from the
readily available 3-(2-chlorophenyl)-6-fluoro-2-thioxo-
2,3-dihydro-1H-quinzaolin-4-one 20. Reaction of 20 with
POCl3 produced 2-chloro-2-(2-chlorophenyl)-6-fluoro-
quinazolin-4-one (21). Nucleophilic substitution with
2-fluorobenzylamine yielded the aminomethyl-tethered
analogue 9.
Biologica l Resu lts
Compounds were evaluated for their ability to block
kainate-induced 45Ca2+ influx into cultured rat cerebel-
lar granule cells, a process shown to be mediated by
AMPA receptors.9 This functional assay is sensitive to
both competitive and noncompetitive antagonists. Re-
sults are summarized in Table 1. The modifications to
the tether group had a profound effect on the AMPA
receptor antagonist activity, producing compounds with
more than a 1000-fold potency range. Among the nine
tethers examined, the vinyl, ethyl, acetylenyl, and
aminomethyl groups (1, 2, 5, 9) inhibited AMPA recep-
tor function within a 4-fold range (IC50s from 0.096 to
0.347 µM). It was somewhat surprising to observe
negligible activity with the hydroxyvinyl tether (4) in
light of potent activity previously observed with related
compounds.10
As a consequence of the chiral center introduced with
the hydroxyethyl tether (3) and the inherent thermal

1712 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Chenard et al.
Sch em e 3a
a
(a) NBS, CCl4, (BzO)2, reflux, light (35%). (b) 2-Fluorophenol, NaH, DMF (88%). (c) See Experimental Section for 20; POCl3, PCl5,
reflux (42%). (d) 2-Fluorobenzylamine, EtOH, reflux (45%).
Ta ble 1. Inhibition of Ca2+ Influx, Observed and Calculated Energy Differences Relative to 6, and Selected Torsion Angles as a
Function of the Tether Group in Quinazolin-4-ones
torsion angles, deg
a
b
∆∆Grel
,
∆Erot,
c
c
entry
A-B tether
IC50, µM
kcal/mol
kcal/mol
N3-C-A-Bc
C-A-B-Cph
A-B-Cph-CF
1
2
-CHdCH-
-CH2CH2-
-CH2CH(OH)-
-CH2CH(OH)-
-CdCH(OH)-
-CtC-
0.096 ( 0.022
0.160 ( 0.002
0.240 ( 0.010
1.18
1.49
1.47
2.35
168.4
178.6
178.5
178.9
160.3
75.9
3a f
3bf
4
>3.0d
>30d
0.282 ( 0.047
0.013 ( 0.001
>0.30d
>10d
5
6
7
8
1.82
0.0
0.140
177.9
171.5
8.8
164.5
178.3
-161.8
-CH2NH-
-CH2NHCH2-
-CH2O-
3.94
1.95
3.96
2.42
71.1
172.9
170.2
-81.9
73.0
-68.0
9
-NHCH2-
0.347 ( 0.128
2.4 ( 0.7
22 ( 3
NBQXe
GYKI 52466e
a
b
-RT ln(IC50compound/IC50compound 6). See text for explanation. ∆Erot is the energy required for the 2-fluorophenyl group to adopt
a conformation similar to the lowest energy conformation of 6. c Torsion angles measured in degrees for the lowest energy conformer.
Value represents the highest concentration tested at the stage of the program. e Reference standards provided to add perspective. f 3a
d
and 3b are diastereomers.
stability of the atropisomers in this series due to
restricted rotation of the N-3 (2-chlorophenyl) group, a
separable pair of diastereomers exist. These diastere-
omers were found to have differential activity (IC50 is
0.24 and >3.0 µM for 3a and 3b, respectively). It was
also interesting to note the loss of activity for the
methoxy-tethered analogue 8. The methylamino tether
(6) stood out among this survey with low nanomolar
inhibitory potency (IC50 ) 0.013 µM). The related one-
carbon-extended (C-N-C) analogue 7 was essentially
inactive.
We further extended the SAR of the methylamino
series by alkylating or acylating the linking group
nitrogen and through replacement of the 2-fluorophenyl
group with other substituted benzenes (Table 2). Entries
10 and 11 (N-acetyl, N-methyl) teach that the unsub-
stituted nitrogen is essential to the enhancement of
potency in 6. The short list of phenyl analogues (12-
16) demonstrates that the methylamino tether permits
modest substitution in this region while generally
maintaining good potency. The pyrrolidinylmethyl ana-
Ta ble 2. Inhibition of Ca2+ Influx with Analogues of 6
entry
R1
R2
IC50, µM
6
10
11
12
13
14
15
16
H
2-F
2-F
2-F
0.013 ( 0.001
acetyl
CH3
H
H
H
>3a
2.00 ( 0.03
0.042 ( 0.018
0.011 ( 0.004
0.213 ( 0.013
0.013 ( 0.001
0.26b
2-CN
3-CN
3-CH3
3-pyrrolidinylmethyl
3-NHC(O)CH3
H
H
a
Value represents the highest concentration tested at the stage
b
of the program. Single triplicate determination.
logue 15 is particularly attractive because both good
potency and solubility are achieved.11

AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1713
F igu r e 1. Two views of the overlap of 6 (orange, methylamino tether), 8 (magenta, methoxy tether), and 9 (green, aminomethyl
tether). Hydrogens attached to nonheteroatoms have have been omitted for clarity. The figure was generated via the Sybyl program
(SYBYL, version 6.6. Tripos Associates, Inc., 1699 S. Hanley Rd., Suite 303, St. Louis, MO 63144).
F igu r e 2. Two views of the overlap of 6 (orange methylamino tether), 1 (magenta, vinyl tether), and 5 (green, acetylene tether).
Hydrogens attached to nonheteroatoms have have been omitted for clarity. Bound conformations are depicted.
Molecu la r Mod elin g
play a large role in determining the potency of each
compound and that a nearly planar orientation of the
C-2 substituent is the preferred bioactive conformation.
Although the data set is small, the correlation between
biological and conformational energy differences is good
[R2 ) 0.94 (least-squares analysis of measured ∆∆Grel
vs ∆Erot, compound 5 omitted)]. One striking difference
between the observed and calculated values was found
for compound 5. We rationalized this difference on the
basis of the radial positioning of the 2-fluorophenyl ring
within the plane defined by the quinazolin-4-one. In the
case of the acetylene tether, the 2-fluorophenyl ring
maps to a unique position on a radius from the centroid
of the pyrimidin-4-one ring (Figure 2). As a result, even
though the 2-fluorophenyl ring of 5 adopts a conforma-
tion that is nearly coplanar with the quinazolin-4-one
ring in its lowest energy conformation (∆Erot ) 0.14 kcal/
mol), the linear nature of the acetylene tether prevents
the aryl substituent from achieving the radial position
that is optimal for AMPA receptor interaction. This
results in a substantial difference between ∆∆Grel and
To better understand the influence of the tethers on
AMPA receptor blockade for this series, we examined
overlays of computationally minimized structures. For
each of the compounds in the study, we located the
lowest energy conformation (in the gas-phase, Figure
1. To facilitate interpretation of the figures, relevant
torsion angles are provided in Table 1). Given the
potency of 6 (0.013 µM) relative to the other compounds
in the series (Table 1), we hypothesized that a nearly
planar conformation of the C-2 side chain attached to
the quinazolin-4-one ring afforded the best activity. Our
goal in carrying out the ab initio calculations was to
investigate the extent to which the SAR (Table 1) could
be explained by changes in the conformational energy
upon adopting the “active” conformation of 6. Accord-
ingly, for each of the compounds in the study, we located
constrained minima corresponding to a nearly planar
arrangement of pharmacophore groups, similar to the
lowest energy conformation of 6. These rotational
conformation energy differences (∆Erot) were compared
to the relative free energy difference between the IC50
for each compound compared to that of 6. This value
was obtained via ∆∆Grel ) -RT ln(K1/K6), where K1
corresponds to the measured IC50 of compound 1. For
example, from Table 1 the relative free energy difference
calculated from the biological activities between 1 and
6 is found to be ca. 1.18 kcal/mol. In comparison, the
energetic cost of 1 adopting a planar conformation is
computed to be 1.47 kcal/mol (∆Erot, Table 1). Similarly,
we find the experimental vs computed results for 2 to
be 1.49 vs 2.35 kcal/mol. Finally, for 8 and 9, the
experimental vs computed results are found to be 3.94
vs 3.96 kcal/mol and 1.95 vs 2.42 kcal/mol, respectively.
∆Erot
.
Taken in concert, the radial and planar positioning
of this ring are likely to account for most of the observed
differences in biological activity for the molecules of this
series. The most dramatic example illustrating this
point compares 6 and 8. In this instance, the unfavor-
able interactions between the lone pairs of electrons on
the oxygen atom of the tether with N-1 of the quinazo-
lin-4-one contribute to a relatively high energy require-
ment to bring the 2-fluorophenyl ring into planar
alignment. However, once done, the radial positioning
of this ring is nearly superimposable with the structure
of 6. Thus, nearly all of the potency difference (∆∆Grel
)
between 8 and 6 can be captured in the calculated ∆Erot
value.
The agreement between the computed and measured
results suggests that conformational energy changes

1714 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Chenard et al.
deuterium lock signal for the solvent deuteriochloroform unless
otherwise indicated. Chromatography refers to flash chroma-
tography on silica gel unless otherwise indicated. Solvent
evaporation (or concentration or removal) implies concentra-
tion at reduced pressure with the use of a rotary evaporator.
Con clu sion s
The pharmacophore for the quinazolin-4-one class of
noncompetitive AMPA receptor antagonists may be
viewed as consisting of three elements: the quinazolin-
4-one ring with its small C-6 substituent, the orthogonal
N-3 phenyl ring, which must contain a single ortho
substituent, and the aryl ring attached to C-2 through
a two-atom spacer. In this study, we have examined the
consequences of modifying the tether unit while retain-
ing a two-atom connector. As the identity of the three
pharmacophoric elements was retained throughout the
series, we have been able to isolate the impact of tether
changes on biological activity. AMPA receptor blockade
was found to vary more than 1000-fold and the methyl-
amino tether was identified as the linking unit that
conferred the greatest potency.
To rationalize the differences in potency among these
relatively similar compounds, we conducted molecular
modeling experiments. Inspection of minimized struc-
tures revealed first that 6 likely exists as a nearly
planar array of the quinazolin-4-one and 2-fluorophenyl
rings, assisted in adopting this conformation by a
hydrogen bond between the tether NH and N-1 of the
quinazolin-4-one. The facility with which the other
compounds in the series could adopt this same planar
arrangement was found to directly correlate with an-
tagonist activity at the AMPA receptor. Thus, rotational
positioning of the 2-fluorophenyl ring relative to the
quinazolin-4-one ring could account for most of the
difference in potency between 6 and the other com-
pounds which we compared.
This correlation was generally good but could not
completely account for the activity differences. We
hypothesize that radial positioning of the 2-fluorophenyl
ring likely accounts for much of the remaining differ-
ence. This is most dramatically illustrated with the
acetylene-tethered compound 5 where the 2-fluoro-
phenyl ring is nearly coincident with the quinazolin-4-
one plane, but the activity remained 10-fold weaker
than 6.
Modulation of AMPA receptor activity remains an
important target for neuroprotective therapy, and new
compounds with increased potency and improved phys-
icochemical properties are desired. The observations
relating the positioning of the three elements of the
quinazolin-4-one noncompetitive AMPA receptor phar-
macophore should be of considerable assistance in the
design of related structures with favorable affinity for
the AMPA receptor.
E-3-(2-Ch lor op h en yl)-6-flu or o-2-[2-(2-flu or op h en yl)vi-
n yl]-3H-qu in a zolin -4-on e (1). A solution of 3-(2-chlorophen-
yl)-6-fluoro-2-methyl-3H-quinazolin-4-one (17, 0.432 g, 1.50
mmol) of 2-fluorobenzaldehyde (0.248 g, 0.22 mL, 2.00 mmol)
and sodium acetate (0.20 g) were dissolved in a mixture of 5
mL of glacial acetic acid and 1.0 mL of acetic anhydride, and
the mixture was heated at reflux overnight. A second aliquot
of 2-fluorobenzaldehyde (0.11 mL, 1.0 mmol) was added, and
reflux was continued for 6 h. The acetic acid solvent was then
removed at reduced pressure, and the residues were parti-
tioned between aqueous NaHCO3 and CHCl3. The aqueous
layer was extracted with CHCl3, and the combined organic
extracts were washed with brine, dried over MgSO4, treated
with decolorizing carbon, and concentrated to a solid. This solid
was taken up in 1:1 ethyl ether/pentane, filtered, and air-dried
1
to give 0.338 g (57%) of 1; mp 199-200 °C. H NMR: δ 8.04
(d, J ) 15 Hz, 1H), 7.91 (m, 1H), 7.80 (dd, J ) 12, 2.0 Hz, 1H),
7.62 (m, 1H), 7.46-7.53 (m, 3H), 7.35-7.39 (m, 1H), 7.23-
7.28 (m, overlapping CHCl3, 2H), 6.98-7.07 (m, 2H), 6.40 (d,
J ) 16 Hz, 1H). Anal. (C22H13ON2ClF2) C, H, N.
3-(2-Ch lor oph en yl)-6-flu or o-2-[2-(2-flu or oph en yl)-eth yl]-
3H-qu in a zolin -4-on e (2). To a solution of 1 (98 mg, 0.25
mmol) dissolved in 15 mL of ethyl acetate was added 50 mg of
10% Pd/C. The mixture was hydrogenated at 1 atm for 6 h, at
which time the reaction was shown to be complete by the
disappearance of the starting material peak in the MS of the
mixture. The catalyst was filtered off, and the solvent was
evaporated. The residues were dissolved in ethyl ether, and
excess of a solution of HCl gas in ethyl ether was added.
Crystallization occurred from
a clear solution. After the
mixture was stirred for 90 min, the crystals were filtered and
washed with dry ethyl ether and air-dried to give 65 mg (66%)
of 2; mp 166-169 °C. 1H NMR: δ 7.88 (dd, J ) 8.3, 2.9 Hz,
1H), 7.74 (dd, J ) 8.7, 4.5 Hz, 1H), 7.57 (d, J ) 8.2 Hz, 1H),
7.39-7.51 (m, 3H), 7.08-7.20 (m, 3H), 6.90-6.99 (m, 2H), 3.10
(t, J ) 7.9 Hz, 2H), 2.62 (m, 2H). Anal. (C22H15ON2ClF2)
C, H, N.
Dia ster eom er s of 3-(2-Ch lor op h en yl)-6-flu or o-2-[2-(2-
flu or op h en yl)-2-h yd r oxy-eth yl]-3H-qu in a zolin -4-on e (3a
a n d 3b). A solution of 17 (0.50 g, 1.73 mmol) in THF (50 mL)
was cooled to -78° C, and 1.0 M lithium bis(trimethylsilyl)-
amide (1.90 mL, 1.90 mmol) was added to give a dark-
burgundy mixture. The anion solution was stirred at 0 °C for
1 h and then returned to -78 °C, and 2-fluorobenzaldehyde
(0.21 mL, 1.99 mmol) in THF (10 mL) was added dropwise
over 1 min. The resulting orange solution was stirred at room
temperature for 30 min, saturated aqueous NH4Cl solution
was added, and the mixture was extracted with ethyl acetate
(50 mL). The extract was washed with dilute sodium bisulfite
solution and brine, dried over MgSO4, and concentrated to an
orange foam (0.72 g). The foam was chromatographed, eluting
with 10% ethyl acetate/hexanes to give 0.134 g (19%) of the
first diastereomeric isomer of 3-(2-chlorophenyl)-6-fluoro-2-[2-
(2-fluorophenyl)-2-hydroxy-ethyl]-3H-quinazolin-4-one (3a ) as
a colorless oil. Dissolution of this oil in ethyl ether/hexanes
(∼1:2) and concentration gave a white crystalline solid; mp
Exp er im en ta l Section
Com p u ta tion a l Meth od s. Restricted Hartree-Fock cal-
culations were carried out for compounds 1, 2, 5, 6, 8, and 9.
The geometries for these series of molecules were fully
optimized by means of analytical energy gradients12 with the
6-31G(d) basis set13 in the gas phase. The ab initio molecular
orbital calculations were carried out with the Gaussian 94
series of programs on a Silicon Graphics computer.14 For each
molecule a variety of conformations were generated corre-
sponding to ca. 60° torsions about each rotatable bond not
involving a terminal hydrogen.
Gen er a l P r oced u r es. All nonaqueous reactions were run
under an atmosphere of dry nitrogen and stirred with a
magnetic stir bar unless otherwise stated. All melting points
are uncorrected. All 1H NMR spectra were recorded at 250,
300, or 400 MHz and are reported in ppm (δ) calibrated to the
1
148-149 °C. H NMR: δ 7.93 (dd, J ) 8.3, 2.9 Hz, 1H), 7.78
(dd, J ) 9.1, 4.8 Hz, 1H), 7.63-7.52 (m, 3H), 7.49-7.43 (m,
2H), 7.36-7.31 (m, 1H), 7.25-7.19 (sym mult, 1H), 7.14 (dt,
J ) 7.5, 1.1 Hz, 1H), 6.95 (ddd, J ) 10.4, 8.1, 1.2 Hz, 1H),
5.57 (br dd, J ) 9.1, 2.1 Hz, 2H), 2.72 (dd, J ) 17.4, 2.5 Hz,
1H), 2.63 (dd, J ) 17.4, 9.1 Hz, 1H). Anal. (C22H15ClF2N2O2‚
0.25 H2O) C, H, N.
Continued elution with 10% ethyl acetate/hexanes gave
0.435 g (61%) of the second diastereomeric isomer 3b as a
yellow oil. Repeated dissolution of the oil in ethyl ether/
hexanes (∼1:2) and concentration gave a yellow solid; mp 137-
1
138 °C. H NMR: δ 7.93 (dd, J ) 7.9, 3.1 Hz, 1H), 7.78 (dd,
J ) 9.1, 4.8 Hz, 1H), 7.60 (dd, J ) 7.9, 1.7 Hz, 1H), 7.57-7.51

AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1715
(m, 2H), 7.46 (dt, J ) 7.7, 1.9 Hz, 1H), 7.40 (dt, J ) 7.7, 1.5
Hz, 1H), 7.26-7.20 (m, partially overlapping CHCl3, 1H), 7.14-
7.10 (m, 2H), 6.96 (ddd, J ) 10.8, 8.3, 1.0 Hz, 1H), 5.65 (br s,
1H), 5.59 (dd, J ) 7.5, 3.7 Hz, 1H), 2.71 (dd, J ) 17.0, 2.9 Hz,
1H), 2.66 (dd, J ) 17.0, 7.6 Hz, 1H). Anal. (C22H15ClF2N2O2)
C, H, N.
all at once. The mixture warmed slightly to the touch and was
stirred for 1 h at ambient temperature. The reaction was
filtered through Celite, and the pad was rinsed with ethyl
acetate. The phases were separated from the filtrate, and the
aqueous layer was extracted with ethyl acetate. The combined
organic phase was washed with brine, dried over MgSO4, and
concentrated to afford 0.802 g (97%) of 3-(2-chlorophenyl)-6-
fluoro-3,4-dihydroquinazolin-4-one-2-carboxaldehyde (18) as a
1:2 mixture of free aldehyde and hydrate. 1H NMR: δ 9.52 (s)
[CHO], 8.20-7.45 (m, 7 H), 6.75 (d, J ) 7.4 Hz) [hydrate OH]
and 6.49 (d, J ) 8 Hz) [hydrate OH], 5.14 (t, J ) 7.5 Hz)
[hydrate methine CH]. This partially hydrated aldehyde was
used without further purification.
3-(2-Ch lor op h en yl)-6-flu or o-2-[(2-flu or op h en yla m in o)-
m eth yl]-3H-qu in a zolin -4-on e (6). A mixture of 18 (0.40 g,
1.32 mmol), o-fluoroaniline (0.130 mL, 0.134 mmol), and
anhydrous MgSO4 (2 g) in methanol (20 mL) was stirred at
ambient temperature for 18 h, then refluxed for 3 h to give a
pink-red slurry of the imine intermediate. To this crude imine
was added sodium cyanoborohydride (0.40 g, 6.36 mmol) and
sodium triacetoxyborohydride (0.56 g, 2.64 mmol), and stirring
was continued for an additional 18 h. The reaction was
concentrated and partitioned between ethyl acetate and
saturated aqueous NaHCO3 solution. The organic phase was
dried over MgSO4 and concentrated to a light-pink oil. The oil
was chromatographed, eluting with a 10-20% ethyl acetate/
hexanes gradient to give 0.363 g (69%) of 6 as a white solid;
mp 179-180 °C. 1H NMR: δ 7.91 (dd, J ) 8.3, 2.9 Hz, 1H),
7.84 (dd, J ) 9.1, 4.8 Hz, 1H), 7.65 (dd, J ) 7.5, 1.9 Hz, 1H),
7.56-7.49 (m, 3H), 7.37 (dd, J ) 7.5, 1.7 Hz, 1H), 6.97 (ddd,
J ) 12.0, 8.1, 1.4 Hz, 1H), 6.89 (br t, J ) 7.4 Hz, 1H), 6.63
(ddt, J ) 7.9, 4.8, 1.6 Hz, 1H), 6.42 (sym mult, 1H), 3.90 (ABq,
∆ν1-3 ) 35.3 Hz, J ) 17.2 Hz, 2H). Anal. (C21H14ClF2N3O‚0.25
H2O) C, H, N.
3-(2-Ch lor op h en yl)-6-flu or o-2-[(2-flu or oben zyla m in o)-
m eth yl]-3H-qu in a zolin -4-on e (7). A mixture of 18 (0.20 g,
0.66 mmol), o-fluorobenzylamine (0.075 mL, 0.66 mmol), and
sodium triacetoxyborohydride (0.20 g, 0.94 mmol) in 1,2-
dichloroethane was stirred at room temperature for 18 h. The
mixture was concentrated, and the residue was partitioned
between ethyl acetate and saturated aqueous NaHCO3. The
organic layer was washed with brine, dried over MgSO4, and
concentrated to a yellow oil (0.277 g). The oil was chromato-
graphed, eluting with 20-30% ethyl acetate/hexanes to give
0.209 g (77%) of 7 as a colorless oil. Crystallization was induced
by addition of a few drops of ethyl ether and scratching,
resulting in a white solid product; mp 98-100 °C. 1H NMR: δ
7.89 (dd, J ) 8.3, 2.9 Hz, 1H), 7.75 (dd, J ) 9.2, 5.0 Hz, 1H),
7.57 (dd, J ) 7.9, 1.7 Hz, 1H), 7.51-7.40 (m, 3H), 7.32-7.26
(m, 2H), 7.23-7.16 (m, 1H), 7.05 (dt, J ) 7.5, 1.0 Hz, 1H), 6.97
(ddd, J ) 10.0, 8.1, 1.3 Hz, 1H), 3.81 (ABq, ∆ν1-3 ) 25.7 Hz,
J ) 13.5 Hz, 2H), 3.40 (ABq, ∆ν1-3 ) 19.5 Hz, J ) 16.6 Hz,
2H). Anal. (C22H16ClF2N3O) C, H, N.
Z-3-(2-Ch lor op h en yl)-6-flu or o-2-[2-(2-flu or op h en yl)-2-
h yd r oxyvin yl]-3H-qu in a zolin -4-on e (4). A solution of di-
isopropylamine (0.183 mL, 1.39 mmol) in THF (10 mL) was
chilled to -78 °C, and butyllithium (0.405 mL, 1.01 mmol, 2.5
N) was added. The solution was stirred for 10 min, then 17
(0.309 g, 1.07 mmol) dissolved in THF (3 mL) was added via
syringe. The reaction turned deep-red and was stirred for 45
min at -78 °C. In a separate vessel, ethyl 2-fluorobenzoate
(1.70 g, 10.1 mmol) was dissolved in THF (30 mL) and chilled
to -78 °C. The red anion solution was rapidly transferred via
cannula into the cold ester solution (less than 1 min). The
reaction was stirred at -78 °C for 30 min, then it was
quenched with saturated aqueous NaHCO3 and allowed to
warm to room temperature. The solvent was removed at
reduced pressure, and the residue was partitioned between
ethyl acetate and water. The phases were separated, and the
aqueous phase was extracted with ethyl acetate. The combined
organic phase was washed with brine, dried over MgSO4, and
concentrated. The residue was triturated with ethyl ether, and
a yellow solid was collected to afford 0.176 g, (40%) of 4; mp
1
218-219 °C. H NMR: δ 7.85 (dd, J ) 2, 8 Hz, 1 H), 7.76 (dt,
J ) 2, 8 Hz, 1 H), 7.63 (dd, J ) 2, 7 Hz, 1 H), 7.54-7.46 (m,
2 H), 7.43 (dd, J ) 3, 7 Hz, 1 H), 7.42-7.30 (m, 3 H), 7.15 (t,
J ) 8 Hz, 1 H), 6.95 (dd, J ) 8, 11 Hz, 1 H), 5.18 (s, 1 H).
Anal. (C22H13ClF2N2O2) C, H, N.
3-(2-Ch lor op h en yl)-6-flu or o-2-[(2-flu or op h en yl)-eth yn -
yl]-3H-qu in a zolin -4-on e (5). A solution of 4 (0.050 g, 0.12
mmol) and 2,6-lutidine (0.020 g, 0.18 mmol) in CH2Cl2 (15 mL)
was chilled to -78 °C. Triflic anhydride (0.021 mL, 0.12 mmol)
in CH2Cl2 (5 mL) was added via syringe. The reaction was
stirred for 2.5 h at -78 °C, then warmed to ambient temper-
ature and stirred for 1 h. The dark-yellow solution was poured
onto saturated aqueous Na2CO3 and vigorously stirred for 30
min. The organic layer was separated and washed with brine,
dried over MgSO4 and concentrated to a brown oil (crude
triflate). This oil was dissolved in THF (10 mL) and chilled to
-78 °C. DBU (0.037 mL, 0.24 mmol) was dissolved in THF (5
mL) and added dropwise via syringe. The mixture was stirred
1.5 h at -78 °C and then 1 h at 10 °C. The reaction was poured
into an ice cold mixture of 1 N HCl (10 mL) and ethyl acetate
(50 mL). Phases were separated and the organic layer was
washed with water, saturated aqueous Na2CO3, and brine. The
organic layer was further dried over MgSO4 and concentrated
to a brown oil. The oil was chromatographed, eluting with 10%
ethyl acetate/hexane to give a solid that was triturated with
hexane to afford 0.045 g (93%) of 5 as a tan solid; mp 200-
1
205 °C. H NMR: δ 7.97 (dd, J ) 3, 8 Hz, 1 H), 7.86 (dd, J )
5, 9 Hz, 1 H), 7.62 (dd, J ) 2, 9 Hz, 1 H), 7.56-7.44 (m, 4 H),
7.34 (dq, J ) 2, 8 Hz, 1 H), 7.20 (t, J ) 7 Hz, 1 H), 7.05 (t,
J ) 8 Hz, 1 H), 6.98 (t, J ) 9 Hz, 1 H). Anal. (C22H11ClF2N2O‚
H2O) C, N; H: calcd, 3.19; found, 2.77.
2-Br om om eth yl-3-(2-ch lor oph en yl)-6-flu or o-3H-qu in azo-
lin -4-on e (19). A solution of 3-(2-chlorophenyl)-6-fluoro-2-
methyl-3H-quinazolin-4-one (1.00 g, 3.46 mmol) in 15 mL of
CCl4 was treated with recrystallized N-bromosuccinimide
(0.678 g, 3.81 mmol) and a catalytic amount of benzoyl
peroxide. The mixture was heated at reflux and irradiated with
a 100 W floodlamp for 3 h. The mixture was then cooled in ice
and filtered, and the filtrate was concentrated. The residue
was chromatographed, eluting with 2:1 hexane/ethyl acetate
to give 0.443 g (35%) of 19; mp 165-167 °C. 1H NMR: δ 7.89-
7.92 (m, 1H), 7.74-7.78 (m, 1H), 7.59-7.61 (m, 1H), 7.49-
7.55 (m, 4H), 4.06 (dd, J ) 11, 167 Hz, 2H). Anal. (C15H9ON2-
BrClF) C, H, N.
3-(2-Ch lor oph en yl)-6-flu or o-2-(2-flu or oph en oxym eth yl)-
3H-qu in a zolin -4-on e (8). To a solution of 2-fluorophenol
(0.112 mg, 1.0 mmol) in 3 mL of DMF was added oil-free NaH
(40 mg, 1.0 mmol) all at once. After the foaming had subsided,
19 (60 mg, 0.16 mmol) dissolved in 3 mL of DMF was added
and the reaction mixture was stirred at room temperature
overnight. The reaction mixture was diluted with ethyl acetate,
and the resulting solution was washed three times with water
3-(2-Ch lor op h en yl)-6-flu or o-3,4-d ih yd r oqu in a zolin -4-
on e-2-ca r boxa ld eh yd e (18). A mixture of 17 (1.0 g, 3.46
mmol) and dimethylformamide dimethyl acetal (0.92 mL, 6.92
mmol) in dimethylformamide (4 mL) was heated to 140 °C for
24 h. The reaction was cooled to ambient temperature and
concentrated at reduced pressure. The dark residue was
triturated with methanol, and the bright-yellow crystalline
solid that formed was collected and dried to give 1.075 g (90%)
of 3-(2-chlorophenyl)-6-fluoro-2-(2-(dimethylamino)vinyl)-3,4-
dihydroquinazolin-4-one; mp 210-211 °C. 1H NMR: δ 7.86 (d,
J ) 12.3 Hz, 1 H), 7.79 (dd, J ) 3, 8.5 Hz, 1 H), 7.61-7.54 (m,
1 H), 7.51-7.29 (m, 5 H), 4.06 (d, J ) 12.3 Hz, 1 H), 2.80 (br
s, 6 H). Anal. (C18H15ClFN3O) C, H, N.
To a well-stirred mixture of sodium periodate (2.24 g, 10.47
mmol) in aqueous pH 7 buffer (10 mL) and tetrahydrofuran
(10 mL) was added 3-(2-chlorophenyl)-6-fluoro-2-(2-(dimethyl-
amino)vinyl)-3,4-dihydro-quinazolin-4-one (0.90 g, 2.62 mmol)

1716 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11
Chenard et al.
to remove the DMF. The organic solution was washed with
brine, dried over MgSO4, and concentrated. The residue was
crystallized from 1:1 ethyl ether/pentane to give 1.028 g (88%)
of 8; mp 139-141 °C. 1H NMR: δ 7.92 (d, J ) 2.1 Hz, 1H),
7.78-7.81 (m, 1H), 7.38-7.56 (m, 5H), 6.83-7.02 (m, 4H), 4.77
(dd, J ) 12.4, 67.6 Hz, 2H). Anal. (C21H13O2N2ClF2) C, H, N.
concentrated directly onto silica gel. The product was purified
by chromatography, eluting with a 10-30% ethyl acetate/
hexanes gradient to give 0.36 g (95%) of N-[3-(2-chlorophenyl)-
6-fluoro-4-oxo-3,4-dihydro-quinazolin-2-ylmethyl]-N-(2-fluo-
rophenyl)formamide as a white solid; mp 145-146.6 °C. 1H
NMR: δ 8.38 (d, J ) 2.1 Hz, 1H), 7.87 (dd, J ) 8.3, 2.9 Hz,
1H), 7.68 (dd, J ) 8.7, 4.8 Hz, 1H), 7.64-7.62 (m, 1H), 7.58
(dt, J ) 7.7, 1.9 Hz, 1H), 7.54-7.42 (m, 4H), 7.33-7.25 (m,
1H), 7.21-7.12 (m, 2H), 4.50 (ABq, ∆ν1-3 ) 209.1 Hz, J ) 17.2
Hz, 2H). Anal. (C22H14ClF2N3O2) C, H, N.
3-(2-Ch lor op h en yl)-6-flu or o-2-t h ioxo-2,3-d ih yd r o-1H-
qu in a zolin -4-on e (20). A solution of 5-fluoroanthranilic acid
(2.159 g, 13.9 mmol) and of 2-chlorophenylisothiocyanate (1.81
mL, 2.35 g, 13.9 mmol) in 21 mL of glacial acetic acid was
heated at reflux. After 1 h, a solid began to separate from the
reaction mixture, and after 2.5 h, no starting 5-fluoranthranilic
acid could be detected by TLC (silica, ethyl acetate). The
reaction mixture was cooled, and the acetic acid was evapo-
rated to give a yellow crystalline solid. This solid was taken
up in ethyl ether, filtered, and washed twice with ethyl ether
The formamide (0.10 g, 0.235 mmol) was dissolved in THF
(5 mL), and borane-THF (1.25 mL, 1.25 mmol, 1 N in THF)
was added. The resulting mixture was stirred at room tem-
perature for 18 h. Methanol was added to quench the excess
borane, and the mixture was concentrated onto silica gel. The
product was purified by chromatography, eluting with 10%
ethyl acetate/hexanes to give 29 mg (30%) of 11 as a colorless
oil. Crystallization was induced by warming with hexanes (∼2
mL) to afford white needles; mp 126-127 °C. 1H NMR: δ 7.89
(dd, J ) 8.7, 2.9 Hz, 1H), 7.73 (dd, J ) 8.7, 5.0 Hz, 1H), 7.54-
7.44 (m, 2H), 7.38-7.29 (m, 3H), 6.97-6.85 (m, 3H), 6.81-
6.75 (m, 1H), 4.06 (ABq, ∆ν1-3 ) 40.7 Hz, J ) 16.4 Hz, 2H),
2.93 (s, 3H). Anal. (C22H16ClF2N3O) C, H, N.
1
and air-dried to give 3.68 g (86%) of 20; mp 295-297 °C. H
NMR: δ 7.13-7.15 (m, 1H), 7.31-733 (m, 1H), 7.39-7.67 (m,
4H), 7.80-7.82 (m, 1H). Anal. (C14H8ON2SClF) C, H, N, S.
2-Ch lor o-3-(2-ch lor op h en yl)-6-flu or o-3H-qu in a zolin -4-
on e (21). A solution of 20 (1.50 g, 4.90 mmol) in 11.0 mL of
POCl3 was treated with PCl5 (1.70 g, 8.17 mmol), and the
mixture was refluxed for 2.5 h. The reaction was concentrated,
and the residues were taken up in ethyl acetate and extracted
with water and brine. The organic phase was dried over MgSO4
and concentrated to leave a crystalline solid. This solid was
taken up in ethyl ether, filtered, washed with ethyl ether, and
air-dried to give 0.640 g (42%) of 21; mp 160-161 °C. 1H
NMR: δ 7.92-7.90 (m, 1H), 7.77-7.72 (m, 1H), 7.63-7.61 (m,
1H), 7.58-7.45 (m, 3H), 7.40-7.36 (m, 1H). Anal. (C14H7ON2-
Cl2F) C, H, N.
2-{[3-(2-Ch lor op h en yl)-6-flu or o-4-oxo-3,4-d ih yd r oqu in -
a zolin -2-ylm eth yl]a m in o}ben zon itr ile (12). A mixture of
18 (0.20 g, 0.66 mmol), o-cyanoaniline (0.083 g, 0.70 mmol),
and p-toluenesulfonic acid (0.012 g, 0.063 mmol) in toluene
(20 mL) was refluxed for 18 h with azeotropic removal of water
(Dean-Stark trap). The reaction mixture was concentrated to
afford the crude imine as a red oil. The crude imine was
dissolved in anhydrous methanol (10 mL), and sodium cy-
anoborohydride (0.20 g, 3.18 mmol), sodium triacetoxyboro-
hydride (0.28 g, 1.32 mmol), and anhydrous MgSO4 (1 g) were
added. This mixture was stirred at ambient temperature for
6 days, then concentrated and partitioned between ethyl
acetate and saturated aqueous NaHCO3. The organic phase
was dried over MgSO4 and concentrated to an orange-red oil.
The oil was chromatographed, eluting with a 15-25% ethyl
acetate/hexanes gradient to give 0.145 g (54%) of 12 as a red
oil. Dissolution and concentration from ethyl ether gave a red
solid; mp 169-170 °C (melt which solidified to a material that
3-(2-Ch lor op h en yl)-6-flu or o-2-(2-flu or oben zyla m in o)-
3H-qu in a zolin -4-on e (9). To a solution of 21 (0.267 g, 0.87
mmol) in 5 mL of absolute ethanol was added 2-fluorobenzyl-
amine (0.2 mL, 0.216 g., 1.73 mmol). The reaction was refluxed
overnight, then the mixture was cooled and concentrated. The
residues were partitioned between ethyl acetate and 1 N HCl.
The aqueous layer was extracted one time with ethyl acetate,
and the combined organic extracts were washed with brine,
dried over MgSO4, and evaporated. The residue was crystal-
lized from ethyl ether to give 157 mg (45%) of 9; mp 163-165
1
1
further melted at 178-180 °C). H NMR: δ 7.92 (dd, J ) 8.3,
°C. H NMR: δ 7.77-7.73 (m, 1H), 7.60-7.64 (m, 1H), 7.42-
2.9 Hz, 1H), 7.87 (dd, J ) 9.1, 4.8 Hz, 1H), 7.68 (dd, J ) 7.9,
1.9 Hz, 1H), 7.59-7.50 (m, 3H), 7.43-7.38 (m, 2H), 7.33-7.28
(sym mult, 1H), 6.70 (dt, J ) 7.5, 0.8 Hz, 1H), 6.40 (d, J ) 8.7
Hz, 1H), 3.93 (ABq, ∆ν1-3 ) 33.2 Hz, J ) 17.0 Hz, 2H). Anal.
(C22H14ClFN4O) C, H, N.
7.52 (m, 3H), 7.32-7.40 (m, 3H), 7.18-7.26 (m, 1H), 7.04-
7.08 (m, 1H), 6.96-7.01 (m, 1H). Anal. (C21H14ON3ClF2)
C, H, N.
N-[3-(2-Ch lor op h en yl)-6-flu or o-4-oxo-3,4-d ih yd r oqu in -
azolin -2-ylm eth yl]-N-(2-flu or oph en yl)acetam ide (10). Ace-
tic acid (2 mL), 6 (0.10 g, 0.25 mmol) and acetic anhydride (10
mL) were combined and refluxed overnight. The reaction was
cooled and poured into saturated aqueous NaHCO3 (50 mL)
and ethyl acetate (50 mL) and stirred for 30 min at ambient
temperature. The phases were separated, and the organic layer
was washed with aqueous NaHCO3, dried over MgSO4, and
concentrated. The residue was chromatographed, eluting with
30% ethyl acetate/hexane to afford 0.041 g (37%) of 10 as a
pale-greenish solid; mp 144-147 °C. The compound exists as
3-{[3-(2-Ch lor op h en yl)-6-flu or o-4-oxo-3,4-d ih yd r oqu in -
a zolin -2-ylm eth yl]a m in o}ben zon itr ile (13). A mixture of
18 (0.150 g, 0.50 mmol), glacial acetic acid (10 mL), 3-ami-
nobenzonitrile (0.050 g, 0.42 mmol), and anhydrous Na2SO4
(0.71 g, 5 mmol) was stirred at ambient temperature overnight.
TLC indicated that the imine had formed (Rf ) 0.43, silica,
30% ethyl acetate/hexane, UV detection). Sodium triacetoxy-
borohydride (0.267 g, 1.26 mmol) was added, and the reaction
was allowed to stir over the weekend (72 h). The mixture was
poured into saturated aqueous NaHCO3 and repeatedly ex-
tracted with ethyl acetate. The combined organic layer was
dried over MgSO4 and concentrated to afford a yellow solid.
This solid was triturated with 50% ethyl ether/isopropyl ether
to give 0.133 g (78%) of 13 as an off-white solid; mp 225-228
1
about a 2:1 mixture of rotomers as indicated by the H NMR
spectrum: δ 7.88 (dd, J ) 3, 8 Hz, 1H), 7.74 (br s, 1 H), 7.56
(br s, 1 H), 7.52-7.47 (m, 5 H), 7.35-7.30 (m, 1 H), 7.20-7.11
(m, 2 H), [4.45 (br d, J ) 270 Hz) and 4.35 (ABq, δν1-3 ) 534
Hz, J ) 15 Hz) total of 2H], 1.94 S, 3 H). Anal. (C23H16
ClF2N3O2) C, H, N.
-
1
°C. H NMR: δ 7.93 (dd, J ) 3, 8 Hz, 1 H), 7.87 (dd, J ) 4.5,
8.5 Hz, 1 H), 7.70 (dd, J ) 1.5, 7.5 Hz, 1 H), 7.62-7.52 (m, 4
H), 7.40 (dd, J ) 1.5, 7.5 Hz, 1 H), 7.20 (t, J ) 8 Hz, 1 H), 6.97
(d, J ) 7.5 Hz, 1 H), 6.80 (dd, J ) 2, 8 Hz, 1 H), 6.66 (s, 1 H),
3.88 (ABq, ∆ν1-3 ) 39.5 Hz, J ) 17 Hz, 2 H). Anal. (C22H14
ClFN4O‚0.5 H2O) C, H, N.
3-(2-Ch lor op h en yl)-6-flu or o-2-(m -t olyla m in om et h yl)-
3H-qu in a zolin -4-on e (14). A mixture of 18 (0.20 g, 0.66
mmol), m-toluidine (0.075 mL, 0.70 mmol), and anhydrous
MgSO4 (1 g) in methanol (10 mL) were stirred at room
temperature for 1 h to give a pink-orange slurry. To this crude
imine was added sodium cyanoborohydride (0.20 g, 3.18 mmol)
3-(2-Ch lor op h en yl)-6-flu or o-2-{[(2-flu or op h en yl)-m eth -
yla m in o]m eth yl}-3H-qu in a zolin -4-on e (11). Formic acid
(0.57 mL, 15.1 mmol) and acetic anhydride (1.5 mL, 16.8 mmol)
were stirred at room temperature for 30 min. A solution of 6
(0.36 g, 0.90 mmol) in THF (20 mL) was added, and the
mixture was stirred at room temperature for 2 h. A second
batch of acetylformyl anhydride was separately prepared
(identical reagent stoichiometry as above) and added to the
mixture. The reaction was stirred 18 h, then it was concen-
trated. The residue was taken up in ethyl acetate and washed
with saturated NaHCO3 and brine, dried over MgSO4, and
-

AMPA Receptor Antagonists
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 11 1717
and sodium triacetoxyborohydride (0.28 g, 1.32 mmol), and
stirring was continued for an additional 15 min. The reaction
was concentrated, and the residue was partitioned between
ethyl acetate and saturated aqueous NaHCO3. The organic
phase was dried over MgSO4 and concentrated to a light-brown
oil (0.27 g) that was chromatographed, eluting with a 10-20%
ethyl acetate/hexanes gradient to give 0.176 g (68%) of 14 as
a tan solid; mp 167-168 °C. 1H NMR: δ 7.91 (dd, J ) 8.3, 2.9
Hz, 1H), 7.80 (dd, J ) 9.1, 4.8 Hz, 1H), 7.65 (dd, J ) 7.9, 1.7
Hz, 1H), 7.56-7.47 (m, 3H), 7.36 (dd, J ) 7.5, 1.7 Hz, 1H),
7.02 (t, J ) 7.7 Hz, 1H), 6.54 (d, J ) 7.5 Hz, 1H), 6.40 (s, 1H),
6.34 (dd, J ) 7.9, 2.1 Hz, 1H), 3.84 (ABq, ∆ν1-3 ) 47.3 Hz,
J ) 17.2 Hz, 2H). Anal. (C22H17ClFN3O‚0.125 H2O) C, H, N.
3-(2-Ch lor op h en yl)-6-flu or o-2-[(3-p yr r olid in -1-ylm eth -
ylp h en yla m in o)m eth yl]-3H-qu in a zolin -4-on e (15). A mix-
ture of 18 (0.50 g, 1.65 mmol), 3-pyrrolidin-1-ylmethylaniline
(0.291 g, 1.65 mmol), and anhydrous Na2SO4 (2.3 g, 16.5 mmol)
in CH2Cl2 (20 mL) was refluxed for 24 h. The mixture was
diluted with water and stirred for 20 min. The phases were
separated, and the organic phase was washed with saturated
aqueous NaHCO3 and brine, dried over MgSO4, and concen-
trated to afford 0.61 g of crude imine. The imine was dissolved
in ethanol (20 mL), and 10% Pd/C (0.61 g) and formic acid (2.6
mL, 69.7 mmol) were added. The reaction was stirred at
ambient temperature for 3 h, and then saturated aqueous
NaHCO3 was added. The mixture was filtered through Celite,
and the filtrate was concentrated to remove most of the
ethanol. The milky aqueous residue was extracted with ethyl
acetate. The organic phase was washed with water and brine,
dried over MgSO4, and concentrated. The residue was chro-
matographed, eluting with 10% methanol/0.5% ammonium
hydroxide/CHCl3 to give 0.322 g (53%) of 15 as an off-white
foam; mp 105-110 °C. 1H NMR: δ 7.92 (dd, J ) 3, 8 Hz, 1 H),
7.80 (dd, J ) 5, 9 Hz, 1 H), 7.66 (dd, J ) 2, 7 Hz, 1 H), 7.59-
7.50 (m, 3 H), 7.39 (dd, J ) 2, 7 Hz, 1 H), 7.08 (t, J ) 8 Hz, 1
H), 6.69 (br s, 1 H), 6.66 (d, J ) 7.5 Hz, 1 H), 6.40 (d, J - 8
Hz, 1 H), 5.13 (s, 1 H), 3.94 (dd, J ) 5, 17 Hz, 1 H), 3.81 (dd,
J ) 4.5, 17 Hz, 1 H), 3.59 (br s, 2 H), 2.58 (br s, 4 H), 1.80 (br
s, 4 H). Anal. (C26H24ClFN4O‚H2O) C, N; H: calcd, 5.45; found,
5.04.
Refer en ces
(1) Greenamyrre, J . T. The role of glutamate in neurotransmission
and in neurologic disease. Arch. Neurol. 1986, 43, 1058-1063.
Danysz, N.; Parsons, C. G.; Bresink, I.; Quack, G. Glutamate in
CNS disorders. Drug News Perspect. 1995, 8, 261-277.
(2) Muir, K. W.; Lees, K. R. Clinical experience with excitatory
amino acid antagonist drugs. Stroke 1995, 26, 503-513.
(3) Bigge, C. F.; Nikam, S. S. AMPA receptor agonists, antagonists
and modulatorsstheir potential for clinical utility. Expert Opin.
Ther. Pat. 1997, 7, 1099-1114.
(4) Welch, W. M.; Ewing, F. E.; Huang, J .; Menniti, F. S.; Pagnozzi,
M. J .; Kelly, K.; Seymour, P. A.; Guanowsky, V.; Guhan, S.;
Guinn, M. R.; Critchett, D.; Lazzaro, J .; Ganong, A. H.; DeVries,
K. M.; Staigers, T. L.; Chenard, B. L. Atropisomeric quinazolin-
4-one derivatives are potent noncompetitive R-amino-3-hydroxy-
5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists.
Bioorg. Med. Chem. Lett. 2001, 11, 177-181.
(5) Chenard, B. L.; Menniti, F. S.; Pagnozzi, M. J .; Shenk, K. D.;
Ewing, F. E.; Welch, W. M. Methaqualone derivatives are potent
noncompetitive AMPA receptor antagonists. Bioorg. Med. Chem.
Lett. 2000, 10, 1203-1205.
(6) As described in ref 4, all activity resides in the S isomer. Full
details of the equilibration kinetics will be published separately.
Newell, L. M.; Sekhar, V. C.; DeVries, K. M.; Staigers, T. L.;
Finneman, J . I. Determination of the activation parameters for
atropisomerization of (S)-3-(2-chlorophenyl)-2-[2-(6-diethylami-
nomethylpyridin-2-yl)-vinyl]-6-fluoro-3H-quinazolin-4-one. J .
Chem. Soc., Perkin Trans. 1, submitted.
(7) Vetelino, M. G.; Coe, J . W. A mild method for the conversion of
activated aryl methyl groups to carboxaldehydes via the un-
catalyzed periodate cleavage of enamines. Tetrahedron Lett.
1994, 35, 219-222.
(8) Bal, B. S.; Childers, W. E., J r.; Pinnick, H. W. Oxidation of R,â-
unsaturated aldehydes. Tetrahedron 1981, 37, 2091-2096.
(9) Menniti, F. S.; Chenard, B. L.; Collins, M. B.; Ducat, M. F.;
Elliott, M. L.; Ewing, F. E.; Huang, J . I.; Kelly, K. A.; Lazzaro,
J . T.; Pagnozzi, M. J .; Weeks, J . L.; Welch, W. M.; White, W. F.
Characterization of the binding site for a novel class of noncom-
petitive AMPA receptor antagonists. Mol. Pharmacol. 2000, 58,
1310-1317.
(10) A possible rationale for the lack of AMPA receptor antagonist
activity of 4 has been proposed in ref 5.
(11) The good solubility noted for 15 was an empirical observation.
Solubility was not experimentally quantified.
(12) Schlegel, H. B. Optimization of Equilibrium Geometries and
Transition Structures. J . Comput. Chem. 1982, 3, 214-218.
(13) Francl, M. M.; Pietro, W. J .; Hehre, W. J .; Binkley, J . S.; Gordon,
M. S.; DeFrees, D. J .; Pople, J . A. Self-Consistent Molecular
Orbital Methods. XXIII. A Polarization-Type Basis Set for
Second-Row Elements. J . Chem. Phys. 1982, 77, 3654-3665.
(14) Frisch, M. J .; Trucks, G. W.; Schlegel, H. B.; Gill, P. M. W.;
J ohnson, B. G.; Robb, M. A.; Cheeseman, J . R.; Keith, T.;
Petersson, G. A.; Montgomery, J . A.; Raghavachari, K.; Al-
Laham, M. A.; Zakrzewski, V. G.; Ortiz, J . V.; Foresman, J . B.;
Cioslowski, J .; Stefanov, B. B.; Nanayakkara, A.; Challacombe,
M.; Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres,
J . L.; Replogle, E. S.; Gomperts, R.; Martin, R. L.; Fox, D. J .;
Binkley, J . S.; Defrees, D. J .; Baker, J .; Stewart, J . P.; Head-
Gordon, M.; Gonzalez, C.; Pople, J . A. Gaussian 94, revision B.3;
Gaussian, Inc.: Pittsburgh, PA, 1995.
N-(3-{[3-(2-Ch lor op h en yl)-6-flu or o-4-oxo-3,4-d ih yd r o-
qu in azolin -2-ylm eth yl]-am in o}ph en yl)acetam ide (16). This
compound was prepared by following the procedure to make
7, giving a 29% yield (after chromatographic purification
eluting with a 25-50% ethyl acetate/hexanes gradient). The
analytical sample was prepared by trituration with 10:1 ethyl
ether/ethyl acetate to afford 16 as an off-white solid; mp
167.5-169.5 °C. 1H NMR δ 7.91 (dd, J ) 8.3, 3.1 Hz, 1H), 7.83
(dd, J ) 9.1, 4.8 Hz, 1H), 7.65 (dd, J ) 7.9, 1.9 Hz, 1H), 7.56-
7.47 (m, 3H), 7.38 (dd, J ) 7.1, 2.0 Hz, 1H), 7.10-7.02 (m,
3H), 6.61 (d, J ) 7.9 Hz, 1H), 6.24 (d, J ) 6.6 Hz, 1H), 3.86
(ABq, ∆ν1-3 ) 47.7 Hz, J ) 17.2 Hz, 2H), 2.12 (s, 3H). Anal.
(C23H18ClFN4O2) C, H, N.
J M000522P