(3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol: A conformationally restricted analogue of the NRr2B subtype-selective NMDA antagonist (1S,2S)-1-(4-hydroxyphenyl)-2(4-hydroxy-4-phenylpiperidino)-1- propanol

Article abstract of DOI:10.1021/jm9707986

(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1)is a recently described antagonist of N-methyl-D-aspartate (NUDA) receptors containing the NR2B subunit. In the present study, the optimal orientation of compounds of this structural type for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule. Several of the new chromanol compounds have high affinity for the racemic [³H]CP-101,606 binding site on the NUDA receptor and protect against glutamate toxicity in cultured hippocampal neurons. The new ring caused a change in the stereochemical preference of the receptor - cis (erythro) compounds had better affinity for the receptor than the trans isomers. Computational studies suggest that steric interactions between the pendent methyl group and the phenol ring in the acyclic series determine which structures can best fit the receptor. The chromanol analogue, (3R,4S)- 3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol (12a, CP- 283,097), was found to possess potency and selectivity comparable to CP- 101,606. Thus 12a is a new tool to explore the function of the NR2B- containing NUDA receptors.

Full text of DOI:10.1021/jm9707986

1172
J . Med. Chem. 1998, 41, 1172-1184
(3R,4S)-3-[4-(4-F lu or op h en yl)-4-h yd r oxyp ip er id in -1-yl]ch r om a n -4,7-d iol:
A Con for m a tion a lly Restr icted An a logu e of th e NR2B Su btyp e-Selective
NMDA An ta gon ist (1S,2S)-1-(4-Hyd r oxyp h en yl)-2-
(4-h yd r oxy-4-p h en ylp ip er id in o)-1-p r op a n ol
Todd W. Butler, J ames F. Blake, J on Bordner, Paul Butler,† Bertrand L. Chenard,* Mary A. Collins,
Debra DeCosta, Mary J . Ducat, Michael E. Eisenhard, Frank S. Menniti, Martin J . Pagnozzi, Steven B. Sands,
Barbara E. Segelstein, Walter Volberg, W. Frost White, and Dayao Zhao
Central Research Division, Pfizer Inc., Groton, Connecticut 06340, and Department of Discovery Biology, Pfizer Central
Research, Sandwich, Kent CT13 9NJ , U.K.
Received November 24, 1997
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpiperidino)-1-propanol (CP-101,606, 1) is a
recently described antagonist of N-methyl-D-aspartate (NMDA) receptors containing the NR2B
subunit. In the present study, the optimal orientation of compounds of this structural type
for their receptor was explored. Tethering of the pendent methyl group of 1 to the phenolic
aromatic ring via an oxygen atom prevents rotation about the central portion of the molecule.
Several of the new chromanol compounds have high affinity for the racemic [3H]CP-101,606
binding site on the NMDA receptor and protect against glutamate toxicity in cultured
hippocampal neurons. The new ring caused a change in the stereochemical preference of the
receptorscis (erythro) compounds had better affinity for the receptor than the trans isomers.
Computational studies suggest that steric interactions between the pendent methyl group and
the phenol ring in the acyclic series determine which structures can best fit the receptor. The
chromanol analogue, (3R,4S)-3-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-4,7-diol
(12a , CP-283,097), was found to possess potency and selectivity comparable to CP-101,606.
Thus 12a is a new tool to explore the function of the NR2B-containing NMDA receptors.
In tr od u ction
(1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phenylpi-
peridino)-1-propanol (CP-101,606, 1) was recently de-
scribed as a potent N-methyl-D-aspartate (NMDA)
receptor antagonist with high selectivity for receptors
containing an NR2B subunit.1 The presence of the two-
carbon fragment linking the phenol and piperidine
groups allows for considerable conformational freedom
in 1. Thus little could be said regarding the optimal
orientation of compounds of this structural type for their
receptor. To better understand the conformational
requirements of the receptor, we designed and synthe-
sized a series of analogues which limited the rotational
19 was dibrominated with elemental bromine in CCl4.
Reaction of the dibromide 20 with excess 4-hydroxy-4-
freedom through introduction of a ring from the phenol
to the methyl group (2). Therefore we wish to describe
phenylpiperidine in refluxing ethanol gave the chromone
a series of chromanols which link the methyl group to
21. Sodium borohydride reduction gave the cis alcohol
22a along with a minor amount of 22b. Hydrogenolysis
of the benzyl ether, or tetrabutylammonium fluoride-
mediated desilylation, yielded the target compounds
the phenol ring via an oxygen atom. From this new
series of compounds, (3R,4S)-3-[4-(4-fluorophenyl)-4-
hydroxypiperidin-1-yl]chroman-4,7-diol (12a , CP-283,-
097) has emerged as an exciting new NMDA antagonist.
3a ,b.
The conversion of 20 into 21 deserves comment. It
is likely that this transformation initially proceeds by
dehydrohalogenation of 20 to the 3-bromochromone 23
(Scheme 2). Michael addition of the piperidine nucleo-
phile to 23 and subsequent rearrangement provide 21.4
However, related 3-bromochomones and 3-bromothio-
chromones have been reported to react with nucleo-
philes to form a variety of products resulting from initial
Michael addition and subsequent rearrangement, pyra-
none ring opening, or pyranone ring contraction.5 To
Ch em istr y2
On the basis of the structure-activity relations (SAR)
developed in the CP-101,606 series, we initially pre-
pared compounds with the 4-hydroxy-4-phenylpiperi-
dine fragment.3 The chromanols were efficiently pre-
pared from 7-[(triisopropylsilyl)oxy]- or 7-(benzyloxy)-
chroman-4-one (19) as outlined in Scheme 1. Compound
† Pfizer Central Research, U.K.
S0022-2623(97)00798-X CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/10/1998

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1173
Sch em e 1. Chromanol Synthesis
or
-
Sch em e 2. Rearrangement Sequence in the Conversion of 20 to 21
Sch em e 3
further support the mechanistic pathway and the
structure of 21, we have observed 23 in reactions which
have not been allowed to go to completion and have
independently converted 23 and 21. In addition, the
structure of the 3-piperidinochromones was secured by
an X-ray of chromanol 12a , as its 7-(p-bromobenzyl)
ether. This rearrangement reaction was used to prepare
related chromanols 6-10 and 13. Likewise the 6-fluo-
rochromanol analogue 18a was prepared commencing
with 3,3-dibromo-6-fluoro-7-[(triisopropylsilyl)oxy]chro-
man-4-one.
Two of the new chromanols, 3a and 10a , were
resolved into their enantiomers. Thus 3a was separated
into 4a and 5a via the N-Boc-alanine ester diastereo-
mers, 26 and 27, of the C-4 hydroxyl group of 22a , and
10a was separated into 11a and 12a via the N-Boc-
proline ester diastereomers, 28 and 29, respectively.
Additional analogues (14-17) were prepared as outlined
below.
The phenol methyl ether 14a was prepared directly
from 10a using methyl iodide and sodium hydride in
DMF. The 4-methoxychromane analogue 15a was
synthesized from 7-triisopropylsilyl (TIPS)-protected
intermediate 30 by methylation with sodium hydride
and methyl iodide in THF followed by desilylation with
tetrabutylammonium fluoride in THF. The 4-deoxy
compound 16 was prepared by reduction of the meth-
ylxanthate intermediate 32, prepared from 31. We
attempted to prepare the C-4 acetoxy analogue from 31
(Scheme 3). While the acetylation reaction proceeded
in good yield, deprotection did not afford the desired
4-acetoxychromane product. Hydrogenolysis of 33 gave
the C-4 reduced chromane 16 which was identical to the
xanthate reduction product. Apparently, C-4 substit-

1174 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
Sch em e 4
uents which are better leaving groups than hydroxy or
methoxy are unstable when the phenol is unmasked,
presumably through phenol-assisted ionization of the
C-4 substituent and quinone methide formation.6
the racemic [3H]CP-101,606 binding site. Furthermore,
the introduction of a piperidine C-4 hydroxyl group was
previously found to be essential to introduce an accept-
able separation of NMDA and R1 affinities.3 In this
conformationally restricted series, elimination of the
piperidine hydroxyl group did not increase R1-adrener-
gic receptor affinity. For example, compounds 6a and
8a each displace [3H]prazosin with IC50 g 5 µM.
Therefore, the new ring itself was sufficient to substan-
tially eliminate R1-adrenergic receptor affinity.
As compared to 1, the cis-chromanol 3a had only 2-3-
fold weaker affinity, even as a racemate. Thus the SAR
of the cis-chromanol series was more extensively ex-
plored. Initially, the enantiomers of 3a were evaluated.
The (+) enantiomer 5a had 3 times the affinity for the
receptor and 10 times the neuroprotective potency
against a glutamate challenge in neuronal cultures
compared to (-)-4a . In contrast, there was no difference
in activity between the enantiomers of 1.3 Thus the
receptor binding shows a greater sensitivity to absolute
stereochemistry for the rigid structures as a conse-
quence of their restricted conformational freedom.
Dimethylsulfoxonium ylide readily added to the in-
termediate chromenone 34 to afford 65% of the cyclo-
propyl ketone 35 (Scheme 4).7 Borohydride reduction
afforded a 4:1 mixture of cis and trans alcohols 36a ,b,
respectively. Ethanol recrystallization of the mixture
gave pure 36a .8 Catalytic hydrogenolysis of 36a gave
the cyclopropyl analogue 17a .
In Vitr o P h a r m a cology
The new compounds were initially evaluated in one
of two in vitro assays: (1) displacement of racemic [3H]-
CP-101,606 binding to rat forebrain membranes9 or (2)
inhibition of glutamate-induced neuron loss in primary
cultures of rat hippocampal neurons.10 The racemic [3H]-
CP-101,606 binding site1 resides with NMDA receptors
containing the NR2B subunit. The binding site overlaps
with that for the polyamines and is distinct from that
for the coagonists glutamate and glycine and from the
channel pore site labeled with [3H]TCP. There is a good
correlation between affinity at the racemic [3H]CP-101,-
606 binding site and neuroprotective potency in the
hippocampal neurons for a range of CP-101,606 ana-
logues. This suggests that neuroprotection is mediated
by the inhibition of hippocampal NMDA receptors
through interaction with the allosteric racemic [3H]CP-
101,606 binding site. Several observations are note-
worthy from the results of the present study (Table 1).
For example, comparison of the activities of the cis
compound 3a (equivalent to erythro relative stereo-
chemistry in acyclic series) and its trans isomer 3b
showed that the cis isomer had the greater neuropro-
tective efficacy. Since in the acyclic series, the threo
compounds were more potent NMDA antagonists, this
represents a crossover in receptor preference (see Mod-
eling Studies section). A second consequence of this
conformation-constraining exercise was the elimination
of R1-adrenergic receptor binding affinity. None of these
Manipulation of the spacer group connecting the
phenyl ring to the piperidine C-4 position retained
similar neuroprotective potency when the C-4 hydroxyl
group was not present (6a ), but in the presence of this
hydroxyl group (7a ) potency was reduced about 4-fold.
Consistent with this finding, elimination of the piperi-
dine hydroxyl group in the direct C-4 phenylpiperidine
(8a ) resulted in an improvement in neuroprotective
potency to IC50 ) 25 nM. When the spacer group was
extended to two carbons (9a ), the high potency was
retained even in the presence of the piperidine hydroxyl
group. These SAR observations closely follow those
previously described for 1 despite the reversal of relative
stereochemistry between the two series. Fluoro (10a )
or trifluoromethyl (13a ) para substitution on the phenyl
ring resulted in a small further enhancement in potency,
particularly for 10a (IC50 ) 5 nM). In following up the
high potency of 10a , further structural modifications
retained the 4-fluorophenyl group. Methylation of
either the phenol (14a ) or the benzylic (15a ) hydroxyl
groups or removal of the benzylic hydroxyl (16) resulted
in significant loss of NMDA antagonist activity. Intro-
duction of the cyclopropyl ring bridging C-2 and C-3 of
the chromanol (17a ) greatly reduced NMDA antagonist
potency. In contrast the C-6 fluorochromanol 18a was
noteworthy for possessing high receptor affinity and
neuroprotective potency. Thus fluorine substitution
adjacent to the phenolic hydroxyl group was well-
tolerated.
new compounds displaced [3H] prazosin with an IC50
<
1 µM (data not shown).11 Two examples are particularly
illustrative in this regard. Previously, we noted that a
two carbon spacer connecting the phenyl ring to C-4 of
the piperidine imparted significant R1 affinity to the
acyclic series.12 The corresponding chromanol com-
pound 9a had IC50 > 10 µM (32% inhibition at 10 µM)
in a radioligand binding assay employing [3H]prazosin
as the ligand while retaining high binding affinity to

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1175
Ta ble 1. Binding Affinity at the Racemic [3H]CP-101,606
Binding Site and Potency for Neuroprotection against
NMDA-Induced Toxicity in Cultured Hippocampal Neurons
The enantiomers of 10a were separated, and consis-
tent with the previously resolved chromanol 3a , the (+)
enantiomer 12a was more potent than the (-) enanti-
omer 11a . In contrast, however, the absolute separation
of activity was marginal, 2-3-fold at best. At this time
we are unable to explain the relative lack of stereose-
lectivity of this putative receptor site on the NR2B
NMDA receptor. Nevertheless, with a binding affinity
of 18 nM and a neuroprotective potency of 4 nM, 12a
was more extensively evaluated. 12a at 1 µM did not
displace ligands for various receptors (including the
kainate and AMPA subtypes of glutamate receptors)
and uptake sites in the central nervous system (CNS).
The exception was the σ site labeled by [3H]DTG (79%
displacement at 1 µM, n ) 3).
The NMDA receptor is composed of multiple protein
subunits NR1 and NR2A-D.13 Expression studies
indicate the functional receptor is composed of at least
one NR1 subunit and one or more of the NR2 subunits.14
In the mammalian brain, the NR1 and NR2A subunits
are widely expressed. In contrast, NR2B subunit
expression is restricted to forebrain regions including
cortex, hippocampus, and dentate gyrus, whereas the
NR2C subunit is expressed in cerebellum, and the
NR2D subunit is restricted to midbrain. Thus, selectiv-
ity for the NR2B subtype of NMDA receptors was
assessed initially by comparison of neuroprotective
potencies against glutamate toxicity in cultured hip-
pocampal versus cerebellar granule neurons. 12a was
900-fold more potent for inhibition of hippocampal
neuron loss (IC50 ) 4 ( 0.6 nM) than for cerebellar
granule neuron loss (IC50 of 4500 ( 2500 nM). Selectiv-
ity was further assessed by determining potency and
efficacy for inhibition of NMDA-induced whole cell
currents in Xenopus oocytes expressing the NR1A
NMDA receptor subunit in combination with the NR2A,
NR2B, or NR2C subunit. In the oocytes transfected
with the NR2A or NR2C subunit, 12a inhibited only a
small fraction of the NMDA-induced current (e6 ( 3%
NR2A and 15 ( 5% NR2C of the maximal current; IC50’s
not obtained). In contrast, in the NR2B-transfected
cells, inhibition of current was nearly complete (82 (
2% inhibition of the maximal current) and had an IC50
of 206 ( 38 nM (Figure 1). Thus, the neuroprotective
selectivity for hippocampal neurons and the greater
potency and efficacy for inhibition of NMDA-induced
currents in oocytes expressing the NR2B subunit sup-
port the hypothesis that 12a , and this class of com-
pounds, is highly selective for NMDA receptors contain-
ing the NR2B subunit.
In Vivo P h a r m a cology of 12a
Compounds 11a and 12a were compared with 1 for
their ability to block haloperidol-induced catalepsy in
rats (Table 2).15 Haloperidol-induced blockade of dopam-
ine receptors in rats results in a cataleptic state in which
the animals will remain perched on an elevated bar for
extended periods. Several classes of NMDA receptor
antagonists have been shown to prevent the induction
of this cataleptic state. Thus, this procedure allows for
the comparative assessment of compounds for CNS
exposure upon peripheral administration of NMDA
receptor antagonists. 12a was equipotent with 1 when
given subcutaneously. In contrast to 1, 12a was also

1176 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
F igu r e 1. Dose-response relations for 12a at NMDA NR2A, -2B, and -2C receptors. 12a does not block NR2A or NR2C receptors
but blocks NR2B receptors with an IC50 ) 206 ( 38 nM.
Ta ble 2. In Vivo Activity of 1, 11a , and 12a
1
11a
12a
blockade of haloperidol-induced catalepsy in rat, ED50 ( SEM
0.4 ( 0.2 mg/kg, sc
1.1 ( 0.4 mg/kg, sc
6.8 ( 3.6 mg/kg, po
0.3 ( 0.5 mg/kg, sc
1.2 ( 0.4 mg/kg, po
4 (1-15), iv
blockade of NMDA-stimulated fos induction in mouse, ED50
(95% confidence interval)
1.0 (0.3-5), iv
blockade of CSD in rat protected/tested
(mg/kg iv bolus + mg/kgh iv infusion)
0/2 (0.2 + 0.2)
2/3 (0.6 + 0.6)
2/2 (2.0 + 2.0)
active after oral administration (albeit at 4-fold lesser
potency than when given subcutaneously). By either
route of administration, 12a was 3-5-fold more potent
than 11a .
noncompetitive NMDA receptor antagonists.18 One
current hypothesis links CSD to migraine headache.19
In the present study, CSD was induced by electrical
stimulation of the parietal cortex in anesthetized rats.
Efficacy to block the spread of induced CSD was
evaluated when 12a was administered intravenously as
a bolus followed by infusion. Three dose levels were
evaluated (0.2 mg/kg plus 0.2 mg/kg/h, 0.6 mg/kg plus
0.6 mg/kg/h, 2 mg/kg plus 2 mg/kg/h). At the highest
dose, 12a completely blocked CSD (n ) 2), while at the
lowest dose no effect was observed (n ) 2). At the 0.6
mg/kg dose, complete blockade of CSD was observed in
two of three rats.
To further probe the in vivo effects of these NMDA
receptor antagonists, we evaluated their ability to
prevent the induction of cfos in rats after peripheral
administration of NMDA. Mechanical injury, excito-
toxin exposure, and ischemia have been found to
increase the expression of the immediate early gene cfos
in neurons.16 Thus, elevated cfos expression may be
considered as a marker for brain injury. NMDA recep-
tor antagonists have been shown to prevent cfos induc-
tion due to neuronal injury.17 It has previously been
shown that 1, administered iv 30 min prior to intrap-
eritoneal administration of NMDA, blocked the induc-
tion of cfos in rat dentate gyrus.3 In the present study,
12a also blocked cfos induction with an ED50 of 4 mg/
kg, iv (Table 2). These data, together with the data on
blockade of haloperidol-induced catalepsy, indicate that
12a readily gains access to the brain and exerts phar-
macodynamic effects consistent with that of an NMDA
receptor inhibition. The in vivo efficacy of 12a is
comparable to that of 1 after subcutaneous administra-
tion, and in contrast to 1, 12a is active after oral
administration.
Mod elin g Stu d ies
The present study was undertaken to examine the
pharmacological effects of tethering the methyl sub-
stituent of compounds such as 1 onto the phenol ring.
By restricting the conformational options of such mol-
ecules, it was hoped that new insights could be obtained
regarding the most favorable spatial orientation of the
functional groups in this unique series of NMDA
antagonists. The potential pharmacological results are
further complicated by the known R1-adrenergic recep-
tor affinity resident in some conformations of the acyclic
structures.12 Thus NMDA and R1-adrenergic receptor
interactions may converge or diverge as a result of this
tethering exercise. In fact, two outcomes were ob-
served: first, the NMDA antagonist activity of the new
compounds was found to be greatest within the cis
products, an apparent change in conformational prefer-
ence for the receptor, and second, introduction of the
ring effectively eliminated R1-adrenergic affinity.
Finally, we evaluated 12a for efficacy in inhibiting
electrically induced cortical spreading depression (CSD)
in the rat. CSD is a propagating wave of cellular
depolarization which spreads across the cortical surface
at a rate of about 3-5 mm/min. NMDA receptor
activation has been reported to play an essential role
in the initiation and propagation of CSD, and CSD is
inhibited by glutamate- or glycine-site competitive and

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1177
F igu r e 2. Stereoimage of 1 (yellow) overlapped with 12a (green) and the erythro diastereomer of 1 (gray). All structures were
computed with the 6-31G(d)//6-31G(d) level of theory and are shown in their lowest energy states with the important elements of
the pharmacophore overlapped.
The apparent change in conformational preference of
the receptor upon introduction of the new ring teaches
much about the preferred orientation of these molecules
within the NMDA receptor site. The chromane ring in
compounds such as 12a exists in a somewhat flattened
chair conformation (at least in the solid state as
confirmed by the X-ray). Additionally, the large C-3
piperidine substituent assumes an equatorial position
which further limits conformational freedom. As these
rigid structures possess the highest intrinsic NMDA
activity, it is reasonable to conclude that they represent
an optimal conformation at their site of interaction with
the NMDA receptor. That being the case, we can
evaluate the conformation of the acyclic compounds 1
(threo) and its erythro diastereomer by mapping them
onto the rigid backbone of 12a .20 It was found that the
threo-1 could adopt a conformation very similar to 12a
but with two important differences (Figure 2). First,
the phenol aromatic ring in 1 sits orthogonal to the
chromanol phenol ring. Rotation of this ring to a nearly
coplanar position requires 1.27 kcal/mol. Second, the
pendent methyl group of 1 occupies a space below the
pyran ring of 12a . Apparently, there is sufficient
volume within this region of the receptor to allow the
methyl group a measure of freedom. In contrast, the
corresponding erythro diastereomer of 1 has a confor-
mational minimum in which the pendent methyl group
nicely overlaps with C-2 of the pyran ring (Figure 2).
Again, the phenol group is situated orthogonal to that
in 12a . In this case, however, rotation of the phenol
ring cannot be accommodated without a severe steric
interaction between the methyl group and the ortho
hydrogen of the phenol. Rotation of the phenol ring to
a nearly coplanar (compared to 1) orientation requires
ca. 6.0 kcal/mol. Thus, even though the erythro acyclic
structures possess the same stereochemistry as the
more active cis cyclic compounds 12a , they cannot
interact with the NMDA receptor without adopting an
energetically less favorable conformation.
This is the first time that introduction of a ring in an
NMDA antagonist structural series has resulted in a
change in stereochemical preference at the binding site.
However, the phenomenon has been observed for adr-
energic receptor interactions. For example, restricting
the rotation of isoproterenol and related compounds by
tying the ethanolamine side chain into a tetrahy-
dronaphthol ring demonstrated that the â-adrenergic
agonist activity which was greatest for erythro-isopro-
terenol was mirrored by the trans-tetrahydronaphthol
conformation.21 Studies comparing the adrenergic ac-
tivities of cis- and trans-benzocycloheptanols have also
been reported; however, no direct comparison with their
acyclic counterparts was described.22 Thus the cross-
over of receptor stereochemical preference upon intro-
duction of a ring tethering the ethanolamine side chain
first observed for adrenergic receptor interactions may
now be applied to this series of NR2B NMDA antago-
nists.
Con clu sion s
Previously it was found that replacement of the
pendent methyl group on 1 with ethyl or propyl resulted
in a loss of NMDA antagonist potency. Despite this
disappointing result, we continued to probe in this area

1178 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
Infrared spectra were recorded on a Perkin-Elmer 283B or
1420 spectrophotometer in chloroform solution unless other-
wise stated. Infrared spectra of KBr pellets were recorded on
a Nicolet 510 FT-IR by the diffuse reflectance method (DRIFTS).
Only strong bands are reported unless otherwise stated.
Proton NMR was obtained at 250 or 300 MHz with a Bruker
AM 250 or AM 300 or a Varian XL-300 instrument. NMR data
are reported in parts per million (δ) and are referenced to the
deuterium lock signal from the sample solvent (deuteriochlo-
roform unless otherwise stated). Optical rotations were
determined with a Perkin-Elmer 241 MC polarimeter. El-
emental analyses were determined by our own analytical group
or Schwarzkopf Microanalytical Laboratory, Woodside, NY.
Tetrahydrofuran was distilled from sodium benzophenone
ketyl immediately prior to use. All reactions were carried out
under a nitrogen atmosphere and were magnetically stirred
unless otherwise specified. Chromatographic purification
refers to flash column chromatography on silica gel.
3,3-Dibr om o-7-[(tr iisop r op ylsilyl)oxy]ch r om a n -4-on e
(20, R ) TIP S). Imidazole (3.71 g, 68.08 mmol) and 7-hy-
droxychroman-4-one36 (4.45 g, 27.11 mmol) were dissolved in
DMF (45 mL), and triisopropylsilyl chloride (6.5 mL, 30.4
mmol) in DMF (5 mL) was added dropwise over 5 min. The
mixture was stirred for 2 h and then poured into ice water
(100 mL). The solution was extracted with ether (2 × 100 mL),
and the combined organics were washed with 1 N LiCl (2 ×
100 mL) and brine. The organic phase was dried over CaSO4
and concentrated under reduced pressure. Volatile impurities
were removed by Kugelrohr distillation (100-110 °C pot
temperature, 0.5 mmHg) leaving behind 7.1 g (82%) of 7-[(tri-
isopropylsilyl)oxy]chroman-4-one (19, R ) TIPS) as a light-
yellow oil: NMR δ 7.78 (d, J ) 8.7 Hz, 1H), 6.52 (dd, J ) 8.7,
2.3 Hz, 1H), 6.39 (d, J ) 2.2 Hz, 1H), 4.49 (t, J ) 6.4 Hz, 2H),
2.74 (t, J ) 6.4 Hz, 2H), 1.34-1.19 (m, 3H), 1.08 (d, J ) 7.0
Hz, 18H); IR (KBr) 2945, 2867, 1685, 1605, 1268, 1163; FAB
m/e P+ calcd for (C18H28O3Si) 320.1807, observed m/e 320.1842.
The ketone was dissolved in CCl4 (170 mL), and bromine
(2.50 mL, 48.52 mmol) in CCl4 (30 mL) was added dropwise
over 20 min. The resulting dark-red solution was stirred for
an additional 30 min and then shaken with dilute aqueous
sodium bisulfite solution to consume unreacted bromine. The
organic phase was washed with saturated aqueous NaHCO3
and brine and then dried by filtration through phase separa-
tion paper. Concentration under reduced pressure gave 9.93
g (94%) of 20 (R ) TIPS) as a dark-orange oil which had the
following properties: NMR δ 7.88 (d, J ) 8.8 Hz, 1H), 6.64
(dd, J ) 8.8, 2.2 Hz, 1H), 6.46 (d, J ) 2.3 Hz, 1H), 4.69 (s,
2H), 1.33-1.21 (m, 3H), 1.09 (d, J ) 7.1 Hz, 18H); IR (KBr)
2941, 2863, 1693, 1602, 1271, 1247, 1167; FAB m/e P+ calcd
for (C18H26Br79Br81O3Si) 479.0076, observed m/e 479.0066.
3-(4-Hyd r oxy-4-p h en ylp ip er id in -1-yl)-7-[(tr iisop r op yl-
silyl)oxy]ch r om en -4-on e (21). A solution of 4-hydroxy-4-
phenylpiperidine (2.22 g, 12.50 mmol), 20 (R ) TIPS) (5.00 g,
10.45 mmol), and triethylamine (2.9 mL, 20.8 mmol) in
acetonitrile (150 mL) was stirred at ambient temperature
overnight (16 h). The reaction was concentrated and the
residue partitioned between ethyl acetate and water. The
organic phase was washed with water and brine, then dried
over CaSO4, and concentrated onto silica gel. Chromatography
using an ethyl acetate/hexane gradient (10-20%) gave 2.28 g
(54%) of 21 as a white solid. A portion recrystallized from
ethanol/ether: mp 163-163.5 °C; NMR δ 8.11 (d, J ) 8.8 Hz,
1H), 7.56-7.53 (m, 3H), 7.35 (t, J ) 7.5 Hz, 2H), 7.25 (t, J )
7.2 Hz, 1H), 6.88 (dd, J ) 8.8, 2.3 Hz, 1H), 6.80 (d, J ) 2.2 Hz,
1H), 3.45-3.41 (m, 2H), 2.98 (t, J ) 10.7 Hz, 2H), 2.39 (dt, J
) 13.0, 4.3 Hz, 2H), 1.86-1.82 (m, 3H), 1.35-1.19 (m, 3H),
1.10 (d, J ) 7.1 Hz, 18H); IR (KBr) 3437, 2950, 2870, 1635,
1615, 1600, 1447, 1285, 1247, 1200, 1185, 703, 690. Anal.
(C29H39NO4Si) C, H, N.
by introduction of a new ring tethering the methyl group
to the phenol ring. This strategy rigidly fixed the
benzylic hydroxyl and the piperidine ring fragment
relative to the phenol and allowed further refinement
of the pharmacophore which was crudely defined by 1.
We found that NMDA antagonist activity was most
pronounced with the cis configuration of the benzylic
hydroxyl and piperidine moieties on the pyran ring. The
SAR of the chromanols was explored, and in general,
the activity profile followed closely that previously
observed in the acyclic series. The SAR deviated from
the acyclic series in that the cis (erythro) compounds
were more potent for the cyclic compounds, and this
could be rationalized based on modeling studies which
demonstrated an energetically favorable overlap of the
threo acyclic compounds (e.g., 1) with the cis cyclic
compounds. However the corresponding erythro acyclic
compounds could not achieve similar overlap with the
cis cyclic compounds without incurring a severe steric
interaction between the pendent methyl group and the
phenol ring. An unanticipated benefit derived through
introduction of the new ring was a reduction in R1-
adrenergic receptor affinity. The attenuating effect was
sufficiently strong that even incorporation of an ethyl
spacer group between the phenyl and piperidine ring
(e.g., 9a ), a modification known to enhance R1-adren-
ergic receptor affinity, did not enhance R1 receptor
binding.
In the course of this study, the chromanol 12a (CP-
283,097) was identified as a potent NMDA antagonist
with high selectivity for the NR2B subtype of NMDA
receptors. Both in vitro and in vivo, 12a had a phar-
macological profile similar to that of 1 (CP-101,606) and
also had excellent oral activity.
The NMDA subtype of glutamate receptors has been
implicated in the pathogenesis of many neurodegenera-
tive conditions23 including stroke,24 traumatic head
injury,25 epilepsy,26 Parkinson’s disease,27 and Hunting-
ton’s disease.28 In addition, NMDA receptors play a role
in pain29 (especially chronic pain and the wind up
phenomenon30), migraine,31 ethanol withdrawal,32 drug
tolerance,33 and schizophrenia.34 As the neurodegen-
erative conditions are at some stage considered life-
threatening, early NMDA receptor-based therapy with
drug candidates with a low safety margin were evalu-
ated. Clinical development has been difficult for these
early candidates in part due to safety issues. Further-
more, indications such as migraine require drug can-
didates with a substantial safety margin. Our experi-
ence with 1 suggests that NMDA antagonists selective
for the NR2B subtype will have a much improved safety
profile compared to compounds which inhibit activity
at all NMDA receptors. Compounds such as 12a
represent a further improvement in profile due to
excellent oral bioavailability.35 Assuming that the
safety profile of NR2B-selective NMDA antagonists can
be demonstrated in a clinical setting, non-life-threaten-
ing conditions such as migraine will offer significant
new opportunities for these compounds. We are opti-
mistic that these new agents will test the boundaries
of NMDA antagonist-based therapy.
Continued elution of the column with 30-75% ethyl acetate/
hexanes gave 0.61 g (17%) of the desilylated product 3-(4-
hydroxy-4-phenylpiperidin-1-yl)-7-hydroxychromen-4-one. A
portion recrystallized from ethanol: mp 247-248 °C; NMR
(DMSO-d6) δ 10.68 (br s, 1H), 7.94 (d, J ) 8.8 Hz, 1H), 7.89
Exp er im en ta l Section
Gen er a l P r oced u r es. Melting points were taken with a
Thomas-Hoover melting point apparatus and are uncorrected.

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1179
(s, 1H), 7.53 (d, J ) 7.8 Hz, 2H), 7.34 (t, J ) 7.6 Hz, 2H), 7.22
(t, J ) 7.2 Hz, 1H), 6.89 (dd, J ) 8.8, 2.1 Hz, 1H), 6.80 (d, J )
2.0 Hz, 1H), 4.97 (s, 1H), 3.32 (br d, J ) 10.8 Hz, 2H), 2.91 (t,
J ) 10.9 Hz, 2H), 2.14-2.05 (m, 2H), 1.69 (br d, J ) 12.7 Hz,
2H); IR (KBr) 3575, 3240, 2943, 2920, 2820, 1610, 1580, 1240.
Anal. (C20H19NO4) C, H, N.
(-)-(3R,4S)-3-(4-Hyd r oxy-4-p h en ylp ip er id in -1-yl)ch r o-
m a n -4,7-d iol (4a ) a n d (+)-(3S,4R)-3-(4-Hyd r oxy-4-p h e-
n ylp ip er id in -1-yl)ch r om a n -4,7-d iol (5a ). 1,1′-Carbonyldi-
imidazole (0.165 g, 1.018 mmol) in CH2
Cl2 (2 mL) was added
to a solution of N-t-Boc-D-alanine (0.190 g, 1.004 mmol) in CH2-
Cl2 (6 mL). After the mixture stirred for 1 h at ambient
temperature, 22a (R ) TIPS) (0.250 g, 0.503 mmol) was added,
and the reaction was stirred overnight (16 h). The reaction
was concentrated under reduced pressure and partitioned
between ethyl acetate and water. The organic phase was
washed with water and brine, dried over MgSO4, and concen-
trated onto silica gel. Chromatography using an ether/CH2-
Cl2 (5-10%) gradient elution gave 0.115 g (34%) of 2-N-t-Boc-
D-alanine 3R,4S-7-[(triisopropylsilyl)oxy]-3-[4-phenyl-4-hydroxy-
piperidin-1-yl]chroman-4-yl ester (26) as a white foam. A por-
tion recrystallized from ether/petroleum ether: mp 152.5-153
°C; NMR δ 7.46 (d, J ) 7.3 Hz, 2H), 7.34 (t, J ) 7.4 Hz, 2H),
7.27-7.22 (m, 1H), 7.15 (br d, J ) 8.2 Hz, 1H), 6.42 (dd, J )
8.1, 2.6 Hz, 1H), 6.34 (d, J ) 2.2 Hz, 1H), 6.18 (br s, 1H), 5.12
(d, J ) 6.5 Hz, 1H), 4.42-4.30 (m, 2H), 4.18 (t, J ) 10.9 Hz,
1H), 2.94-2.88 (m, 2H), 2.83-2.61 (m, 3H), 2.02 (dq, J ) 12.1,
4.2 Hz, 2H), 1.79-1.71 (m, 2H), 1.53 (s, 1H), 1.42-1.35 (m,
12H), 1.31-1.10 (m, 3H), 1.07 (d, J ) 6.9 Hz, 18H). Anal.
(C37H56N2O7Si) C, H, N. [R]D ) -112.3°, c ) 1.02 (CHCl3).
Continued elution of the column with 25% ether/CH2Cl2
gave 0.133 g (40%) of 2-N-t-Boc-D-alanine (3S,4R)-7-[(triiso-
propylsilyl)oxy]-3-[4-phenyl-4-hydroxypiperidin-1-yl]chroman-
4-yl ester (27) as a white foam. A portion recrystallized from
ether/petroleum ether: mp 146-147.5 °C; NMR δ 7.51 (d, J
) 7.9 Hz, 2H), 7.33 (t, J ) 7.5 Hz, 2H), 7.14 (d, J ) 8.2 Hz,
1H), 6.41 (dd, J ) 8.1, 2.2 Hz, 1H), 6.34 (d, J ) 2.3 Hz, 1H),
6.25 (s, 1H), 5.03 (d, J ) 7.8 Hz, 1H), 4.39-4.36 (m, 1H), 4.30-
4.23 (m, 2H), 3.07-2.95 (m, 1H), 2.88-2.82 (m, 4H), 2.17-
1.98 (m, 3H), 1.77-1.69 (m, 2H), 1.59 (s, 1H), 1.39 (s, 9H),
1.33-1.15 (m, 6H), 1.06 (d, J ) 7.3 Hz, 18H). Anal.
(C37H56N2O7Si) C, H, N. [R]D ) +115.7°, c ) 1.065 (CHCl3).
2-N-t-Boc-D-alanine (3R,4S)-7-[(triisopropylsilyl)oxy]-3-[4-
phenyl-4-hydroxypiperidin-1-yl]chroman-4-yl ester (26) (0.080
g, 0.12 mmol) in 0.32N sodium methoxide solution (10 mL)
was stirred for 30 min; then cesium fluoride was added in three
50-mg portions (0.150 g, 0.987 mmol) at 45-min intervals and
then stirred overnight (16h) at ambient temperature. The
reaction was concentrated, and the pH was adjusted to ∼8
using 1 N HCl and NaHCO3 solution. This was extracted with
ethyl acetate (2 × 20 mL); the extracts were washed with
brine, dried over MgSO4, and concentrated to give 0.390 g of
milky oil. Recrystallization from ethanol/ether yielded 0.0179
g (44%) of pure (-)-(3R,4S)-3-(4-hydroxy-4-phenylpiperidin-
1-yl)chroman-4,7-diol (4a ) as a cream-colored solid: mp 180-
181 °C; [R]D ) - 90.1°, c ) 0.425 (methanol). Enantiomeric
excess was determined to be 98 +% by NMR using the chiral
resolving agent (R)-(-)-2,2,2-trifluoro-1-(9-anthryl)ethanol in
deuterated acetonitrile.
3-(4-Hyd r oxy-4-p h en ylp ip er id in -1-yl)-7-[(tr iisop r op yl-
silyl)oxy]ch r om a n -4-ol (cis-22a a n d tr a n s-22b). Sodium
borohydride (1.58 g, 41.8 mmol) was added to a solution of 21
(2.0 g, 4.1 mmol) in ethanol (75 mL), and the mixture was
stirred for 21 h at ambient temperature. The reaction was
quenched with water and concentrated under reduced pres-
sure. The residue was partitioned between ethyl acetate and
water; the organic phase was washed with water and brine,
then dried over CaSO4, and concentrated to give 1.71 g of a
light-yellow solid. NMR showed a 7:1 mixture of cis and trans
diastereomers. This material was recrystallized from ether/
hexanes to give 1.0 g (50%) of cis-3-(4-hydroxy-4-phenylpip-
eridin-1-yl)-7-[(triisopropylsilyl)oxy]chroman-4-ol (22a ) as a
white solid: mp 145.5-146.5 °C; NMR δ 7.50 (d, J ) 7.3 Hz,
2H), 7.37 (t, J ) 7.5 Hz, 2H), 7.27 (t, J ) 7.2 Hz, 1H), 7.19 (d,
J ) 8.4 Hz, 1H), 6.50 (dd, J ) 8.3, 2.4 Hz, 1H), 6.36 (d, J )
2.3 Hz, 1H), 4.74 (d, J ) 3.3 Hz, 1H), 4.33 (dd, J ) 9.7, 3.3 Hz,
1H), 4.09 (t, J ) 10.5 Hz, 1H), 3.09 (br d, J ) 11.5 Hz, 1H),
2.90-2.71 (m, 4H), 2.20-2.08 (m, 3H), 1.86-1.78 (m, 2H), 1.64
(br s, 1H), 1.29-1.16 (m, 3H), 1.08 (d, J ) 6.9 Hz, 18H); 13C
NMR δ 157.40, 154.75, 147.90, 131.64, 128.49, 127.27, 124.47,
115.40, 113.46, 107.13, 70.94, 62.34, 61.78, 60.74, 47.07, 45.12,
38.46, 17.93, 12.65; IR (KBr) 3380, 2940, 2860, 1615, 1280,
1173, 1040. Anal. (C29H43NO4Si) C, H, N.
Chromatography of the recrystallization residues using an
ethyl acetate/hexanes gradient (20-60%) gave an additional
0.070 g (4%) of 22a followed by 0.27 g (14%) of a 5.6:1 mixture
of trans-3-(4-hydroxy-4-phenylpiperidin-1-yl)-7-[(triisopropyl-
silyl)oxy]chroman-4-ol (22b) and 22a as a yellow solid which
was used without further purification. Trans product: NMR
δ 7.48 (d, J ) 7.2 Hz, 2H), 7.39-7.23 (m, 4H), 6.51 (dd, J )
8.4, 2.4 Hz, 1H), 6.34 (d, J ) 2.3 Hz, 1H), 4.79 (d, J ) 8.1 Hz,
1H), 4.39 (dd, J ) 11.0, 3.4 Hz, 1H), 4.14-4.07 (m, 1H), 3.16-
3.08 (m, 1H), 2.90-2.73 (m, 4H), 2.20-1.98 (m, 2H), 1.80-
1.72 (m, 2H), 1.29-1.14 (m, 3H), 1.09 (d, J ) 6.9 Hz, 18H);
13C NMR δ 156.71, 154.48, 148.15, 128.83, 128.41, 127.15,
124.49, 117.29, 113.39, 107.21, 71.38, 64.77, 64.06, 63.40,
48.36, 43.03, 38.98, 17.94, 12.65.
cis-3-(4-Hyd r oxy-4-p h en ylp ip er id in -1-yl)ch r om a n -4,7-
d iol (3a ). Tetrabutylammonium fluoride in THF (1.95 mL,
1.95 mmol) was added to a stirring solution of 22a (0.94 g,
1.89 mmol) in THF (100 mL). After 1.5 h, the reaction was
concentrated directly onto silica gel and chromatographed
using an ethyl acetate/hexanes gradient (20-75%) followed by
pure ethyl acetate to yield 0.72 g of crude 3a as a light-yellow
solid. Recrystallization from ethanol/ether gave 0.54 g (84%)
of pure 3a as a white solid: mp 171.5-172.5 °C; NMR (DMSO-
d6) δ 9.41 (br s, 1H), 7.50 (d, J ) 7.9 Hz, 2H), 7.32 (t, J ) 7.6
Hz, 2H), 7.20 (t, J ) 7.2 Hz, 1H), 7.04 (d, J ) 8.3 Hz, 1H),
6.34 (dd, J ) 8.2, 2.3 Hz, 1H), 6.18 (d, J ) 2.2 Hz, 1H), 4.83
(m, 2H), 4.67 (s, 1H), 4.25 (dd, J ) 10.0, 2.5 Hz, 1H), 4.07 (t,
J ) 10.6 Hz, 1H), 3.02 (br d, J ) 10.4 Hz, 1H), 2.89 (br d, J )
10.4 Hz, 1H), 2.71 (q, J ) 11.1 Hz, 2H), 2.56 (br d, J ) 10.8
Hz, 1H), 1.97 (br t, J ) 11.7 Hz, 2H), 1.61 (br d, J ) 13.0 Hz,
2H); IR (KBr) 3420, 3280, 3160, 2940, 2910, 2830, 2800, 1625,
1600, 1470, 1165, 1130, 1045. Anal. (C20H23NO4‚0.25H2O) C,
H, N.
Similar treatment of 2-N-t-Boc-D-alanine (3S,4R)-7-[(triiso-
propylsilyl)oxy]-3-(4-phenyl-4-hydroxypiperidin-1-yl)chroman-
4-yl ester (27) gave (+)-(3S,4R)-3-(4-hydroxy-4-phenylpiperidin-
1-yl)chroman-4,7-diol (5a ): mp 180-181 °C; [R]D ) +89.6°, c
) 0.425 (methanol). Enantiomeric excess was determined to
be 98+% by NMR using the chiral resolving agent (R)-(-)-
2,2,2-trifluoro-1-(9-anthryl)ethanol in deuterated acetonitrile.
The following compounds were prepared using the same
general procedure as for the preparation of 3a .
6a : mp 166-168 °C (ethanol/ether); NMR (DMSO-d6) δ 9.27
(s, 1H), 7.27 (t, J ) 7.2 Hz, 2H), 7.19-7.14 (m, 3H), 6.99 (d, J
) 8.4 Hz, 1H), 6.31 (dd, J ) 8.2, 2.2 Hz, 1H), 6.14 (d, J ) 2.2
Hz, 1H), 4.75 (br s, 1H), 4.58 (br s, 1H), 4.14 (d, J ) 7.6 Hz,
1H), 4.01 (t, J ) 10.6 Hz, 1H), 3.13 (d, J ) 10.8 Hz, 1H), 3.01
(d, J ) 10.7 Hz, 1H), 2.50-2.43 (m partially obscured by
DMSO signal, 3H), 2.19-2.06 (m, 2H), 1.55-1.51 (m, 3H),
1.23-1.16 (m, 2H); IR (KBr) 3240, 2920, 2810, 1615, 1595,
1510, 1175, 1040, 705. Anal. (C21H25NO3) C, H, N.
3b was prepared using the procedure for 3a : mp 192.5-
193 °C (ethanol); NMR (DMSO-d6) δ 9.28 (s, 1H), 7.46 (d, J )
7.2 Hz, 2H), 7.29 (t, J ) 7.5 Hz, 2H), 7.18 (t, J ) 7.2 Hz, 1H),
7.10 (d, J ) 8.4 Hz, 1H), 6.33 (dd, J ) 8.3, 2.4 Hz, 1H), 6.13
(d, J ) 2.4 Hz, 1H), 5.18 (d, J ) 5.5 Hz, 1H), 4.75 (s, 1H), 4.54
(br t, J ) 5.2 Hz, 1H), 4.24 (dd, J ) 11.6, 4.9 Hz, 1H), 4.12
(dd, J ) 8.9, 2.5 Hz, 1H), 2.76-2.74 (m, 4H), 2.55 (m partially
obscured by DMSO signal, 1H), 1.93-1.75 (m, 2H), 1.54 (br d,
J ) 13.2 Hz, 2H); IR (KBr) 3400, 3265, 2950, 2820, 1630, 1605,
1510, 1490, 1165, 1127, 1010. Anal. (C20H23NO4) C, H, N.
7a : mp 181-182 °C (ethanol/ether); NMR (DMSO-d6) δ 9.36
(br s, 1H), 7.67-7.18 (m, 5H), 7.00 (d, J ) 8.4 Hz, 1H), 6.31

1180 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
(dd, J ) 8.1, 2.3 Hz, 1H), 6.14 (d, J ) 2.2 Hz, 1H), 4.72 (br s,
1H), 4.58 (br s, 1H), 4.17 (m, 2H), 3.98 (t, J ) 10.7 Hz, 1H),
2.90-2.82 (m, 1H), 2.71-2.67 (m, 3H), 2.67-2.44 (m, 3H),
1.50-1.39 (m, 4H); IR (KBr) 3320, 3150, 2940, 2910, 1620,
1600, 1160, 1120, 1080. Anal. (C21H25NO4‚H2O) C, H, N.
8a : mp 195-195.5 °C (ethanol/ether); NMR (DMSO-d6) δ
9.39 (s, 1H), 7.32 (m, 5H), 7.03 (d, J ) 8.3 Hz, 1H), 6.34 (dd,
J ) 8.2, 2.3 Hz, 1H), 6.17 (d, J ) 2.3 Hz, 1H), 4.84 (br s, 1H),
4.65 (br s, 1H), 4.21 (dd, J ) 10.2, 2.6 Hz, 1H), 4.08 (t, J )
10.6 Hz, 1H), 3.28 (br d, J ) 11.1 Hz, 1H), 3.18 (br d, J ) 11.1
Hz, 1H), 2.57-2.49 (m partially obscured by DMSO signal,
2H), 2.46-2.26 (m, 2H), 1.77-1.60 (m, 4H); IR (KBr) 3230,
2920, 2815, 1610, 1590, 1170, 1040, 700. Anal. (C20H23NO3)
C, H, N.
9a : mp 157-157.5 °C (ether/hexanes); NMR (DMSO-d6) δ
9.35 (s, 1H), 7.29-7.13 (m, 5H), 7.01 (d, J ) 8.3 Hz, 1H), 6.31
(dd, J ) 8.2, 2.4 Hz, 1H), 6.15 (d, J ) 2.4 Hz, 1H), 4.72 (d, J
) 4.3 Hz, 1H), 4.61 (s, 1H), 4.19 (d, J ) 7.8 Hz, 1H), 4.11 (s,
1H), 4.01 (t, J ) 10.6 Hz, 1H), 2.88-2.73 (m, 1H), 2.72-2.69
(m, 1H), 2.67-2.53 (m, 5H), 1.66-1.61 (m, 2H), 1.52 (br s, 4H).
Anal. (C22H27NO4) C, H, N.
3,3-Dibr om o-7-(ben zyloxy)ch r om a n -4-on e (20, R ) Bn ).
7-Hydroxychroman-4-one (56.8 g, 346 mmol), K2CO3 (110 g,
796 mmol), and benzyl bromide (42 mL, 350 mmol) in acetone
(1000 mL) were refluxed for 6 h. The reaction was filtered
through Celite and concentrated. The residue was dissolved
in ethyl acetate (500 mL) and washed with 1 N NaOH (2 ×
250 mL), water, and brine. Drying over MgSO4 and concen-
tration under reduced pressure gave 81.4 g (93%) of 7-(ben-
zyloxy)chroman-4-one (19, R ) Bn) as a tan solid. A portion
recrystallized from ethanol with hot filtration: mp 99-102 °C;
NMR δ 7.85 (d, J ) 9.0 Hz, 1H), 7.44-7.32 (m, 5H), 6.66 (dd,
J ) 9.0, 2.4 Hz, 1H), 6.49 (d, J ) 2.4 Hz, 1H), 5.09 (s, 2H),
4.52 (t, J ) 6.5 Hz, 2H), 2.76 (t, J ) 6.5 Hz, 2H). Anal.
(C16H14O3) C, H.
Bromine (35 mL) was added over 30 min to a solution of
19, (R ) Bn) in CCl4 (1600 mL) and ethyl acetate (700 mL).
The reaction was stirred for an additional 2 h to give a dark-
red solution which was carefully washed with a saturated
NaHCO3 solution that contained a small amount of sodium
bisulfite and brine. The organic phase was dried over MgSO4
and concentrated to give a sticky brown solid. This material
was recrystallized from ethanol/ether to yield 54.7 g (41%) of
3,3-dibromo-7-(benzyloxy)chroman-4-one (20, R ) Bn): mp
89-90 °C; NMR δ 7.96 (d, J ) 9.0 Hz, 1H), 7.43-7.36 (m, 5H),
6.79 (dd, J ) 9.0, 2.4 Hz, 1H), 6.57 (d, J ) 2.4 Hz, 1H), 5.12
(s, 2H), 4.71 (s, 2H). Anal. (C16H12Br2O3) C, H.
cis-3-[4-Hydr oxy-4-(4-flu or oph en yl)piper idin -1-yl]ch r o-
m a n -4,7-d iol (10a ). A solution of 4-hydroxy-4-(4-fluorophe-
nyl)piperidine (52.0 g, 266 mmol), 20 (R ) Bn; 54.7 g, 133
mmol), and triethylamine (38 mL, 270 mmol) in acetonitrile
(2.5 L) was stirred at ambient temperature overnight (16 h).
The light-yellow precipitate that formed was collected and
rinsed with water (3 × 150 mL) and ether (150 mL) to yield
55.4 g (93%) of 3-[4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-
7-(benzyloxy)chromen-4-one (34). A portion was recrystallized
from ethanol/THF to give a white solid: mp 220-221 °C; NMR
(DMSO-d6) δ 7.99 (d, J ) 8.9 Hz, 2H), 7.56-7.40 (m, 8H), 7.18-
7.08 (m, 4H), 5.25 (s, 2H), 5.06 (s, 1H), 3.60 (br s, 1H), 3.55-
3.35 (m, 1H), 3.10-2.95 (m, 2H), 2.15-2.00 (m, 2H), 1.71 (br
t, J ) 13.7 Hz, 2H); IR (KBr) 3407, 2822, 1627, 1615, 1592,
1509, 1448, 1310, 1260, 1243, 1219, 1183, 1128, 1095, 851, 835,
830, 701. Anal. (C27H24FNO4) C, H, N.
which was used without further purification. A portion
recrystallized from ethyl acetate/CHCl3: mp 194-195 °C;
NMR δ 7.56-7.30 (m, 8H), 7.06 (t with long-range coupling, J
) 8.7 Hz, 2H), 6.63 (dd, J ) 8.5, 2.4 Hz, 1H), 6.47 (d, J ) 2.4
Hz, 1H), 5.04 (s, 2H), 4.77 (d, J ) 4.5 Hz, 1H), 4.36 (dd, J )
10.4, 3.5 Hz, 1H), 4.13 (t, J ) 10.4 Hz, 1H), 3.82 (br s, 1H),
3.11 (br d, J ) 11.2 Hz, 1H), 2.92-2.71 (m, 4H), 2.21-2.06
(m, 2H), 1.87-1.73 (m, 2H), 1.54 (s, 1H); IR (KBr) 3519, 2951,
2856, 2839, 2824, 1617, 1587, 1503, 1465, 1403, 1382, 1270,
1259, 1236, 1170, 1115, 1099, 1072, 1044, 1017, 835, 821.
Anal. (C27H28FNO4) C, H, N.
10% Pd/C (0.160 g) was added to a solution of cis-3-[4-
hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-(benzyloxy)chroman-
4-ol (31) (0.80 g, 1.78 mmol) in methanol/acetic acid (40 mL/
0.8 mL), and the mixture was pressurized to 49 psi with
hydrogen gas. The reaction was shaken for 7.5 h at ambient
temperature, filtered through Celite, and concentrated under
reduced pressure. The resulting solid was stirred vigorously
for 1 h with a mixture of ether and saturated NaHCO3 solution.
The solids were filtered off and rinsed with water and then
ether to give 0.59 g (92%) of cis-3-[4-hydroxy-4-(4-fluorophe-
nyl)piperidin-1-yl]chroman-4,7-diol (10a ) as a white solid. A
sample recrystallized with hot filtration from ethanol: mp
159-160 °C; NMR (DMSO-d6) δ 7.55-7.49 (m, 2H), 7.11 (t, J
) 8.9 Hz, 2H), 7.02 (d, J ) 8.4 Hz, 1H), 6.32 (dd, J ) 8.3, 2.3
Hz, 1H), 6.15 (d, J ) 2.3 Hz, 1H), 5.10-4.50 (s @ 4.64 (1H)
overlapping br m (2H)), 4.23 (dd, J ) 10.3, 2.8 Hz, 1H), 4.04
(t, J ) 10.5 Hz, 1H), 2.99 (br d, J ) 10.8 Hz, 1H), 2.86 (br d,
J ) 10.7 Hz, 1H), 2.73-2.50 (m, 3H), 2.08-1.90 (m, 2H), 1.58
(br d, J ) 13.0 Hz, 2H); IR (KBr) 3578, 3344, 3194, 2950, 2860,
1617, 1602, 1511, 1260, 1236, 1172, 1170, 1162, 1118, 1072,
1040, 858, 832, 818. Anal. (C20H22FNO4‚0.25H2O) C, H, N.
13a : prepared by the procedure of 10a ; mp 189.5-190 °C
(ethanol/ether); NMR (DMSO-d6) δ 9.37 (s, 1H), 7.70 (AB
quartet, ∆ν1-3 ) 15.1 Hz, J ) 8.5 Hz, 4H), 7.03 (d, J ) 8.3 Hz,
1H), 6.33 (dd, J ) 8.1, 2.2 Hz, 1H), 6.16 (d, J ) 2.2 Hz, 1H),
5.06 (s, 1H), 4.79 (s, 1H), 4.66 (s, 1H), 4.37-4.25 (m, 1H), 4.06
(t, J ) 10.5 Hz, 1H), 3.02 (br d, J ) 9.5 Hz, 1H), 2.90 (br d, J
) 10.7 Hz, 1H), 2.76-2.50 (m, 3H), 1.98 (br t, J ) 11.4 Hz,
2H), 1.60 (br d, J ) 12.8 Hz, 2H); IR (KBr) 3589, 3380, 3212,
2945, 2858, 1619, 1598, 1512, 1330, 1260, 1239, 1214, 1181,
1170, 1167, 1162, 1132, 1117, 1071, 1037, 1015, 858, 840, 821.
Anal. (C21H22F3NO4‚0.50 H2O) C, H, N.
(-)-(3R,4S)-3-[4-Hyd r oxy-4-(flu or op h en yl)p ip er id in -1-
yl]ch r om a n -4,7-d iol (11a ) a n d (+)-(3S,4R)-3-[4-Hyd r oxy-
4-(4-flu or op h en yl)p ip er id in -1-yl]ch r om a n -4,7-d iol (12a ).
N-(tert-Butoxycarbonyl)-D-proline (4.80 g, 22.30 mmol), cis-3-
[4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-(benzyloxy)chro-
man-4-ol (31, see preparation of 10a ; 5.00 g, 11.12 mmol), 1-[3-
(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (4.26
g, 22.22 mmol), and 4-(dimethylamino)pyridine (1.36 g, 11.13
mmol) in CH2Cl2 (100 mL) were refluxed for 1.5 h to give a
light-yellow solution. This was concentrated under reduced
pressure, redissolved in ethyl acetate (200 mL), washed with
water (3 × 100 mL) and brine, dried over MgSO4, and
concentrated to give 8.1 g of a mixture of diastereomers of
pyrrolidine-1,2-dicarboxylic acid 2-{7-(benzyloxy)-3-[4-(4-fluo-
rophenyl)-4-hydroxypiperidin-1-yl]chroman-4-yl} ester 1-tert-
butyl ester as a white solid. This mixture was dissolved in
100 mL of 1:1 ether/isopropyl ether, and crystallization was
induced by scratching the flask with a spatula. This material
was refluxed with isopropyl ether (100 mL) for 30 min and
cooled and the solid filtered off to yield 3.29 g of pyrrolidine-
1,2-dicarboxylic acid (3R,4S)-2-{7-(benzyloxy)-3-[4-(4-fluorophe-
nyl)-4-hydroxy-piperidin-1-yl]chroman-4-yl} ester 1-tert-butyl
ester (28) which contained a small amount of pyrrolidine-1,2-
dicarboxyilic acid (3S,4R)-2-{7-(benzyloxy)-3-[4-(4-fluorophe-
nyl)-4-hydroxypiperidin-1-yl]chroman-4-yl} ester 1-tert-butyl
ester. Recrystallization of this material from ethyl acetate
gave 2.26 g (31% overall, 62% of theory) of pure 28 which NMR
showed to be a mixture of rotamers. This material was used
directly in the next step.
Sodium borohydride (10.6 g, 280 mmol) was added to a
solution of 3-[4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-
(benzyloxy)chromen-4-one (34) (12.5 g, 28.06 mmol) in a
mixture of THF (1000 mL) and ethanol (600 mL). After the
mixture stirred for 5 and 16 h, additional portions of sodium
borohydride (8.4 and 11 g) were added. After stirring for 40
h (total), the reaction was quenched with water and concen-
trated at 50 °C under reduced pressure. The resulting
material was rinsed with water (3 × 50 mL) and ether (50
mL) to yield 11.34 g (90%) of cis-3-[4-hydroxy-4-(4-fluorophe-
nyl)piperidin-1-yl]-7-(benzyloxy)chroman-4-ol (31) as a solid
Pyrrolidine-1,2-dicarboxylic acid (3S,4R)-2-{7-(benzyloxy)-
3-[4-(4-fluorophenyl)-7-hydroxypiperidin-1-yl]chroman-4-yl} es-

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1181
ter 1-tert-butyl ester (28) (2.15 g, 3.33 mmol) in THF (25 mL)
was added dropwise over 10 min to an ice-cooled slurry of
lithium aluminum hydride (0.15 g, 3.95 mmol) in THF (25 mL).
The cooling bath was removed, and the reaction was stirred
for 30 min at ambient temperature. The mixture was carefully
quenched with excess Na2SO4 decahydrate and then dried over
anhydrous Na2SO4. Filtration through Celite followed by
concentration under reduced pressure yielded a white paste
which was stirred for 10 min with 1:1 ether/hexanes (50 mL)
and filtered to give 1.14 g (77%) of (3R,4S)-3-[4-hydroxy-4-(4-
fluorophenyl)piperidin-1-yl]-7-(benzyloxy)chroman-4-ol. This
material had NMR spectrum identical to the racemic inter-
mediate 31 from the preparation of 10a and had [R]D ) -70.4°,
c ) 0.28 (methanol). Hydrogenation following the procedure
for 10a and recrystallization from ethanol/hexanes gave 0.385
g (42%) of (3R,4S)-3-[4-hydroxy-4-(4-fluorophenyl)piperidin-1-
yl]chroman-4,7-diol (11a ): [R]D ) - 84.1°, c ) 0.29 (methanol);
mp 166.5-167 °C; NMR (DMSO-d6) identical to that of 10a .
Anal. (C20H22FNO4‚0.25 H2O) C, H, N.
cis-3-[4-H yd r oxy-4-(4-flu or op h en yl)p ip er id in -1-yl]-7-
m et h oxych r om a n -4-ol (14a ). cis-3-[4-Hydroxy-4-(4-fluo-
rophenyl)piperidin-1-yl]chroman-4,7-diol (10a ) (0.225 g, 0.626
mmol) was added to an ice-cold slurry of hexanes-washed 60%
sodium hydride (0.275 g, 0.689 mmol) in DMF (2 mL). The
cooling bath was removed and the mixture stirred at room
temperature for 30 min; methyl iodide (0.043 mL, 0.689 mmol)
was added, and the stirring was continued for an additional
hour. The reaction was diluted with ethyl acetate and washed
with 1 N aqueous LiCl. The aqueous phase was back-extracted
twice with ethyl acetate. The organic extracts were combined
and washed with 1 N aqueous LiCl and brine, dried over
CaSO4, and concentrated to give 0.185 g (79%) of cis-3-[4-
hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-methoxychroman-
4-ol (14a ) as a white solid. A portion recrystallized from
methanol: mp 181-182 °C; NMR (DMSO-d6) δ 7.53 (dd, J )
9.0, 5.5 Hz, 2H), 7.13 (t, J ) 9.0 Hz, 3H), 6.49 (dd, J ) 8.5, 2.5
Hz, 1H), 6.34 (d, J ) 2.5 Hz, 1H), 4.88-4.87 (m, 2H), 4.70 (br
s, 1H), 4.28 (dd, J ) 10.0, 2.5 Hz, 1H), 4.09 (t, J ) 10.5 Hz,
1H), 3.71 (s, 3H), 3.02 (br d, J ) 10 Hz, 1H), 2.89 (br d, J )
10.5 Hz, 1H), 2.69 (symmetric multiplet, 2H), 2.58 (symmetric
multiplet, 1H), 1.95 (symmetric multiplet, 2H), 1.60 (br d,
J ) 13.5 Hz, 2H); IR (KBr) 3430, 3244, 2963, 2952, 2927,
2893, 2777, 1621, 1592, 1505, 1448, 1315, 1272, 1216, 1205,
1171, 1161, 1108, 1044, 970, 840, 811. Anal. (C21H24FNO4)
C, H, N.
cis-3-[4-H yd r oxy-4-(4-flu or op h en yl)p ip er id in -1-yl]-4-
m et h oxych r om a n -7-ol (15a ). cis-3-[4-Hydroxy-4-(4-fluo-
rophenyl)piperidin-1-yl]chroman-4,7-diol (10a ) (0.429 g, 1.194
mmol) was added to an ice-cold slurry of hexanes-washed 60%
sodium hydride (0.053 g, 1.31 mmol) in DMF (4 mL). This
mixture was stirred at room temperature for 30 min, triiso-
propylsilyl chloride (0.280 mL, 1.31 mmol) was added, and the
reaction mixture was stirred overnight (16 h). The reaction
was diluted with ethyl acetate and washed with 1 N aqueous
LiCl. The aqueous phase was back-extracted twice with ethyl
acetate. The organic extracts were combined and washed with
1 N aqueous LiCl and brine, dried over CaSO4, and concen-
trated onto silica gel. Flash chromatography using first CH2-
Cl2 and then 2% methanol/0.025% NH4OH/CH2Cl2 gave 0.360
g (58%) of cis-3-[4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-
7-[(triisopropylsilyl)oxy]-chroman-4-ol (30) as a white solid:
NMR δ 7.48 (d, J ) 5.5 Hz, 2H), 7.20 (d, J ) 8.5 Hz, 2H), 7.05
(t, J ) 8.5 Hz, 2H), 6.51 (dd, J ) 8.5, 2.5 Hz, 1H), 6.38 (d, J )
2.5 Hz, 1H), 4.76 (d, J ) 3.5 Hz, 1H), 4.34 (dd, J ) 10.5, 3.0
Hz, 1H), 4.11 (t, J ) 10.5 Hz, 1H), 3.11 (br d, J ) 11.0 Hz,
1H), 2.92-2.69 (m, 4H), 2.20-2.09 (m, 2H), 1.90-1.75 (m, 2H),
1.56 (s, 1H), 1.36-1.18 (m, 3H), 1.10 (d, J ) 6.5 Hz, 18H).
pressure and partitioned between CH2Cl2 and water. The pH
of the aqueous layer was adjusted to pH 8 by addition of first
saturated aqueous NH4Cl and then saturated aqueous NaH-
CO3. The organic phase was then washed with brine, dried
by filtration through phase separation paper, and concentrated
to give crude 3-[4-hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-
[(triisopropylsilyl)oxy]-4-methoxychromane as a yellow oil.
This material was dissolved in THF (9 mL), and 1.0 M (THF)
tetrabutylammonium fluoride solution (0.64 mL, 0.64 mmol)
was added. The reaction was stirred for 20 min at room
temperature, saturated aqueous NH4Cl (∼3 mL) was added,
the solvent was removed under reduced pressure, and satu-
rated aqueous NaHCO3 solution was added to bring the pH
to ∼8. This solution was extracted with CH2Cl2. The extract
was washed with brine, dried by filtering through phase
separation paper, and concentrated onto silica gel. Chroma-
tography using first CH2Cl2, then 0.5-1% methanol/CH2Cl2/
<0.5% NH4OH, and finally 3% methanol/CH2Cl2/<0.5% NH4-
OH gave 0.111 g (51%) of cis-3-[4-hydroxy-4-(4-fluorophenyl)-
piperidin-1-yl]-4-methoxychroman-7-ol (15a ) as a white solid.
A sample recrystallized from methanol: mp 203-205 °C; NMR
(DMSO-d6) δ 9.43 (s, 1H), 7.51 (dd, J ) 8.5, 5.5 Hz, 2H), 7.10
(t, J ) 9.0 Hz, 2H), 7.02 (d, J ) 8.0 Hz, 1H), 6.30 (dd, J ) 8.0,
2.0 Hz, 1H), 6.19 (d, J ) 2.0 Hz, 1H), 4.85 (s, 1H), 4.32 (s,
1H), 4.30-4.05 (m, 2H), 3.24 (s, 1H), 2.96-2.57 (m, 4H), 2.49
(symmetric multiplet, 2H), 1.67-1.50 (m, 2H). Anal. (C21H24
FNO4) C, H, N.
-
3-[4-(4-F lu or op h en yl)-4-h yd r oxyp ip er id in -1-yl]ch r o-
m a n -7-ol (16). cis-3-[4-Hydroxy-4-(4-fluorophenyl)piperidin-
1-yl]-7-(benzyloxy)chroman-4-ol (31, see preparation of 10a ;
1.00 g, 2.23 mmol) was added to an ice-cold slurry of hexanes
washed 60% sodium hydride (0.106 g, 2.67 mmol) in DMF (20
mL). The cooling bath was removed, and the mixture was
stirred at room temperature for 40 min during which time a
precipitate formed. Carbon disulfide (0.201 mL, 3.34 mmol)
was added; the solids quickly dissolved to give a clear yellow
solution which was stirred for 30 min, and then methyl iodide
(0.153 mL, 2.45 mmol) was added. After 30 min of additional
stirring, the reaction was diluted with ethyl acetate and
washed with 1 N aqueous LiCl. The aqueous phase was back-
extracted twice with ethyl acetate. The organic phases were
combined and washed with 1 N aqueous LiCl and brine, dried
over CaSO4, and concentrated onto silica gel. Flash chroma-
tography using an ethyl acetate/hexanes gradient (10-40%)
for elution gave 0.880 g (73%) of the crude methylxanthate 32
as an oily, yellow solid: NMR δ 7.51-7.30 (m, 7H), 7.19 (d, J
) 8.5 Hz, 1H), 7.03 (t, J ) 8.5 Hz, 2H), 6.58 (dd, J ) 8.5, 2.5
Hz, 1H), 6.40 (d, J ) 2.5 Hz, 1H), 5.35 (dd, J ) 4.5, 2.0 Hz,
1H), 5.01 (s, 2H), 4.46 (dt, J ) 11.0, 2.0 Hz, 1H), 3.97 (t, J )
10.5 Hz, 1H), 3.09 (symmetric multiplet, 1H), 3.00-2.64 (m,
4H), 2.47 (s, 3H), 2.20-1.93 (m, 2H), 1.74 (d with long-range
coupling, J ) 14.0 Hz, 2H), 1.51 (s, 1H); MS m/e P1+ calcd for
(C29H30FNO4S2) 540.1679, observed m/e 540.1693. This mate-
rial was used without further purification.
The crude xanthate 32 (0.465 g, 0.86 mmol), tri-n-butyltin
hydride (0.694 mL, 2.58 mmol), and AIBN (0.030 g) in toluene
(30 mL) were refluxed for 1.5 h and concentrated onto silica
gel. Chromatography using an ethyl acetate/hexanes gradient
(20-75%) for elution gave 0.310 g (83%) of 3-[4-(4-fluorophe-
nyl)-4-hydroxypiperidin-1-yl]-7-benxyloxychromane as a white
solid: NMR (DMSO-d6) δ 7.49 (dd, J ) 9.0, 5.5 Hz, 2H), 7.45-
7.37 (m, 5H), 7.10 (t, J ) 9.0 Hz, 2H), 6.98 (d, J ) 8.5 Hz,
1H), 6.51 (dd, J ) 8.5, 2.5 Hz, 2H), 6.39 (d, J ) 2.5 Hz, 1H),
5.03 (s, 2H), 4.86 (s, 1H), 4.29 (br d, J ) 10.5 Hz, 1H), 3.86
(symmetric multiplet, 1H), 2.91-2.60 (m, 7H), 1.99-1.78 (m,
2H), 1.58 (br d, J ) 13.5 Hz, 2H); MS m/e P+ calcd for (C27H28
-
FHO3) 434.2131, observed m/e 434.2109. This material was
used without further purification.
cis-3-[4-Hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-[(triiso-
propylsilyl)oxy]chroman-4-ol (30) (0.300 g, 0.582 mmol) was
added to an ice-cold slurry of hexanes-washed 60% sodium
hydride (0.053 g, 1.31 mmol) in THF (4 mL). After the mixture
stirred for 45 min at room temperature, methyl iodide (0.040
mL, 0.64 mmol) was added, and stirring was continued
overnight (18 h). The reaction was concentrated at reduced
3-[4-(4-Fluorophenyl)-4-hydroxypiperidin-1-yl]-7-(benzyl-
oxy)chromane (0.290 g, 0.669 mmol) in methanol/acetic acid
solution (50 mL/2 mL) was combined with 20% palladium
hydroxide on carbon (0.150 g), pressurized to 45 psi with
hydrogen gas, and shaken at room temperature for 3.5 h. The
reaction was filtered through Celite and concentrated. The

1182 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
residue was stirred with CH2Cl2 and saturated aqueous
NaHCO3. After the aqueous phase was discarded, methanol
was added to the organic phase to help dissolve the remaining
sticky solids. The resulting solution was concentrated onto
silica gel, and chromatography using 2-4% methanol/0.025%
NH4OH/CH2Cl2 as eluent gave 0.153 g (67%) of 3-[4-(4-
fluorophenyl)-4-hydroxypiperidin-1-yl]chroman-7-ol (16) as a
white foam. A portion recrystallized from 2-propanol: mp
200.5-201.5 °C; NMR (DMSO-d6) δ 9.17 (s, 1H), 7.52 (dd, J )
9.0, 5.5 Hz, 2H), 7.12 (t, J ) 9.0 Hz, 2H), 6.87 (d, J ) 8.5 Hz,
1H), 6.29 (dd, J ) 8.0, 2.5 Hz, 1H), 6.15 (d, J ) 2.5 Hz, 1H),
4.89 (s, 1H), 4.29 (br d, J ) 10.5 Hz, 1H), 3.82 (symmetric
multiplet, 1H), 2.90-2.60 (m, 7H), 1.89 (symmetric multiplet,
2H), 1.60 (br d, J ) 13.0 Hz, 2H); IR (KBr) 3422, 3264, 3065,
2944, 2924, 2833, 1619, 1598, 1509, 1479, 1464, 1223, 1155,
1139, 1118, 1098, 1038, 831. Anal. (C20H22FNO3) C, H, N.
gradient (10-50%) for elution. This yielded a white solid
which was recrystallized from ethyl acetate/hexanes to give
10.7 mg (40%) of cis-7a-[4-(4-fluorophenyl)-4-hydroxypiperidin-
1-yl]-1,1a,7,7a-tetrahydro-2-oxacyclopropa[b]naphthalene-4,7-
diol (17a ) as a fluffy white solid: mp 157-158 °C; NMR
(CDCl3:DMSO-d6, 3:1) δ 8.51 (s, 1H), 7.14 (d, J ) 7.3 Hz, 2H),
7.00-6.89 (m, 3H), 6.81 (t, J ) 7.0 Hz, 1H), 6.06 (dd, J ) 8.4,
2.4 Hz, 1H), 5.83 (d, J ) 2.2 Hz, 1H), 4.83 (d, J ) 8.0 Hz, 1H),
4.09 (d, J ) 8.0 Hz, 1H), 3.79 (s, 1H), 3.55 (dd, J ) 7.2, 4.0
Hz, 1H), 3.02-2.77 (m, 2H), 2.52 (br d, 1H), 2.33 (br d, 1H),
1.67-1.40 (m, 2H), 1.40-1.27 (m, 2H), 0.84 (dd, J ) 7.0, 4.0
Hz, 1H), 0.47 (long-range coupled t, J ) 7.0 Hz, 1H). Anal.
(C21H23NO4‚0.25H2O) C, H, N.
6-F lu or o-7-h yd r oxych r om a n -4-on e. 1,3-Dimethoxyben-
zene (1.0 mL, 7.64 mmol) and N-fluorobenzenesulfonimide
(2.41 g, 7.64 mmol) were stirred for 5 h at 60 °C to give a dark-
red oil. The reaction was cooled to room temperature and
stirred overnight with a mixture of ether and water. The ether
layer was washed with water and brine, dried over MgSO4,
and concentrated to an oily yellow solid. This material was
filtered through silica gel using 10% ether/hexanes to give
0.700 g (59%) of crude 1,3-dimethoxy-4-fluorobenzene.
This material (0.50 g, 3.2 mmol) was refluxed in 48%
hydrobromic acid/acetic acid (2 mL/2 mL) overnight (16 h). The
mixture was diluted with water and extracted into ether (3 ×
25 mL). The combined organics were washed with water and
brine, dried over MgSO4, and concentrated. Chromatography
using 15% ethyl acetate/hexanes gave 0.158 g (39%) of 90-
95% pure 4-fluororesorcinal as a waxy, light-yellow solid.
The solid was combined with 3-chloropropionic acid (0.13
g, 1.20 mmol) and triflic acid (1.0 mL) and heated for 4 h at
80 °C. The mixture was poured into water and extracted into
ether (3 × 20 mL). The extracts were washed with water and
brine, dried over MgSO4, and concentrated to a red pasty solid.
Sodium hydroxide (2 N, 15 mL) was added, and this mixture
was stirred at room temperature overnight (16 h). The
solution was acidified with 1 N HCl to pH 1-2 and extracted
with ethyl acetate (3 × 20 mL). The extracts were washed
with water and brine, dried over MgSO4, and concentrated onto
silica gel. Chromatography using 25% ethyl acetate/hexanes
gave 0.11 g (52% from fluororesorcinol) of 6-fluoro-7-hydroxy-
chroman-4-one as a white solid: mp 222-223 °C; NMR δ 7.39
(d, J ) 11.1 Hz, 1H), 6.49 (d, J ) 7.1 Hz, 1H), 4.46 (t, J ) 6.4
Hz, 2H), 2.67 (t, J ) 6.4 Hz, 2H). Anal. (C9H7FO3) C, H.
cis-7a -[4-(4-F lu or op h en yl)-4-h yd r oxyp ip er id in -1-yl]-1,-
1a ,7,7a -tetr a h yd r o-2-oxa cyclop r op a [b]n a p h th a len e-4,7-
d iol (17a ). Trimethylsulfoxonium iodide (0.721 g, 3.28 mmol)
was added to 60% sodium hydride (0.160 g, 4.00 mmol) which
had been rinsed three time with hexanes. Dimethyl sulfoxide
(16 mL) was added over 1 min to give a cloudy solution. 3-[4-
Hydroxy-4-(4-fluorophenyl)piperidin-1-yl]-7-(benzyloxy)chromen-
4-one (34, see preparation of 10a ; 0.100 g, 0.233 mmol) was
added, and the mixture was stirred at 50 °C for 1 h followed
by 2 h at room temperature to give a red-colored solution. The
reaction was diluted with water (75 mL) and extracted three
times with ethyl acetate. The combined extracts were washed
with water (2×) and brine, dried over CaSO4, and concentrated
directly into silica gel. Chromatography using first 10% and
then 20% ethyl acetate/hexanes gave 0.260 g (53%) of 4-(ben-
zyloxy)-7a-[4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl]-1a,7a-
dihydro-1H-2-oxacyclopropa[b]naphthalen-7-one (35) as a white
solid. A portion recrystallized from ethyl acetate/hexanes: mp
190-191 °C; NMR δ 7.82 (d, J ) 8.6 Hz, 1H), 7.53 (dd, J )
8.6, 1.3 Hz, 2H), 7.45-7.20 (m, 8H), 6.69 (dd, J ) 8.6, 2.4 Hz,
1H), 6.45 (d, J ) 2.3 Hz, 1H), 5.07 (s, 2H), 4.44 (dd, J ) 7.0,
4.3 Hz, 1H), 3.89 (dt, J ) 12.0, 2.6 Hz, 1H), 3.53 (dt, J ) 11.8,
2.5 Hz, 1H), 2.94 (br d, J ) 11.8 Hz, 1H), 2.82 (br d, J ) 11.4
Hz, 1H), 2.06-1.85 (m, 3H), 1.80-1.70 (m, 2H), 1.59 (t, J )
7.0 Hz, 1H), 1.40 (dd, J ) 6.9, 4.3 Hz, 1H). Anal. (C28H27
NO4) C, H, N.
-
Sodium borohydride (0.190 g, 5.00 mmol) was added to an
ice-cold solution of 4-(benzyloxy)-7a-[4-(4-fluorophenyl)-4-hy-
droxypiperidin-1-yl]-1a,7a-dihydro-1H-2-oxacyclopropa[b]naph-
thalen-7-one (35) (0.249 g, 0.54 mmol) in THF/ethanol (15 mL/
10 mL). The ice bath was removed, and the reaction stirred
for 24 h at room temperature. Water (3 mL) was added, and
the mixture was concentrated under reduced pressure. The
residue was dissolved in ethyl acetate (500 mL), washed with
water and brine, dried over CaSO4, and concentrated onto
silica gel. Flash chromatography using an ethyl acetate/
hexanes gradient (10-50%) for elution gave 0.185 g of a 3:1
mixture of cis and trans diastereomers of 1-[4-(benzyloxy)-7-
hydroxy-1,1a-dihydro-7H-2-oxacyclopropa[b]naphthalen-7a-yl]-
4-(4-fluorophenyl)piperidin-4-ol (36a ,b). This mixture was
recrystallized twice from ethanol/water (∼10:1) to afford 0.070
g (29%) of ∼93% pure cis-36a diastereomer as white needles:
mp 205-206 °C; NMR δ 7.55-7.23 (m, 11H), 6.66 (dd, J )
8.5, 2.5 Hz, 1H), 6.42 (d, J ) 2.5 Hz, 1H), 5.31 (dd, J ) 9.0,
1.6 Hz, 1H), 5.02 (s, 2H), 4.07 (dd, J ) 7.0, 4.0 Hz, 1H), 3.27
(dt, J ) 12.5, 2.7 Hz, 1H), 3.17 (dt, J ) 11.0, 2.5 Hz, 1H), 2.98
(d of multiplets, J ) 11.0 Hz, 1H), 2.80 (d of multiplets, J )
9.5 Hz, 1H), 2.07 (dd, J ) 13.0, 4.7 Hz, 1H), 1.96 (dd, J ) 13.0,
4.6 Hz, 1H), 1.83-1.70 (m, 2H), 1.80 (d, J ) 8.5 Hz, 1H), 1.58
(s, 1H), 1.17 (dd, J ) 6.7, 4.1 Hz, 1H), 0.96 (dt, J ) 7.0, 1.6
Hz, 1H). Anal. (C28H29NO4) C, H, N.
cis-3-[4-H yd r oxy-4-(4-flu or op h en yl)p ip er id in -1-yl]-6-
flu or och r om a n -4,7-d iol (18a ). 6-Fluoro-7-hydroxychroman-
4-one was reacted using the same reaction sequence as used
to prepare 10a to give cis-3-[4-hydroxy-4-(4-fluorophenyl)-
piperidin-1-yl]-6-fluorochroman-4,7-diol (18a ) as
a white
solid: mp 160-161 °C; NMR (DMSO-d6) δ 9.84 (br s, 1H), 7.50
(dd, J ) 8.9, 5.6 Hz, 2H), 7.11 (t, J ) 8.9 Hz, 2H), 6.95 (d, J )
11.4 Hz, 1H), 6.31 (d, J ) 7.7 Hz, 1H), 4.90 (br s, 1H), 4.86 (s,
1H), 4.62 (s, 1H), 4.20 (dd, J ) 10.3, 2.3 Hz, 1H), 4.02 (t, J )
10.5 Hz, 1H), 2.95 (br d, J ) 10.8 Hz, 1H), 2.85 (br d, J ) 10.9
Hz, 1H), 2.73-2.60 (m, 2H), 2.57-2.52 (m partially under
DMSO signal, 1H), 1.96-1.86 (m, 2H), 1.56 (br d, J ) 13.4
Hz, 2H); IR (KBr) 3573, 3278, 2944, 2862, 1632, 1605, 1524,
1512, 1297, 1266, 1246, 1234, 1222, 1172, 1163, 1115, 1074,
1016, 858, 830, 591, 543, 407. Anal. (C20H21F2NO4) C, H, N.
Com p u ta tion a l Meth od s. Restricted Hartee-Fock cal-
culations were carried out for the erythro and threo isomers
of 1 and 12a in the gas phase. The geometries for this series
of molecules were fully optimized by means of analytical
energy gradients37 with the 6-31G(d) basis set.38 The ab initio
molecular orbital calculations were carried out with the
Gaussian 94 series of programs on a Silicon Graphics com-
puter.39 For each isomer of 1 a variety of conformations were
generated corresponding to ca. 60° torsions about each rotat-
able bond not involving a terminal hydrogen. The lowest-
energy structures from this search were then used for further
study as described in the modeling section.
A mixture of cis-1-[4-(benzyloxy)-7-hydroxy-1,1a-dihydro-
7H-2-oxacyclopropa[b]naphthalen-7a-yl]-4-(4-fluorophenyl)pi-
peridin-4-ol (36a ) (0.033 g, 0.075 mmol) and 10% Pd/C (0.050
g) in methanol (50 mL) was pressurized to 43.5 psi with
hydrogen and shaken for 18 h at ambient temperature. The
reaction was filtered through Celite, concentrated onto silica
gel, and chromatographed using an ethyl acetate/hexanes
Biologica l Meth od s. Biological evaluation of the new
compounds was carried out according to published proce-
dures: neuroprotection against NMDA (or glutamate) in

Rigid Analogue of NR2B Subtype-Selective NMDA Antagonist
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7 1183
cultured hippocampal neurons,3 racemic [3H]CP-101,606 bind-
ing assay,1 blockade of haloperidol-induced catalepsy in rat,15
blockade of NMDA-induced cfos induction.3 Expression and
recordings of exogenous receptors in Xenopus oocytes are
similar to those described previously.40 External media con-
tained (in mM) 115 NaCl, 2.5 KCl, 0.4 BaCl2, 0.1 CaCl2, 10
HEPES, pH 7.5. Two-electrode voltage clamp (GeneClamp
500, Axon Instruments Inc.) was performed with 0.5-2 MΩ
electrodes filled with 3 M KCl. Bath volume of chamber was
∼150 µL, and chamber was perfused by gravity at ∼6 mL/
min. The CSD model is described below.
Block a d e of Cor tica l Sp r ea d in g Dep r ession in th e Ra t.
Male Sprague-Dawley rats (weight range 275-325 g) were
anesthetized with urethane (1500 mg/kg, ip). The left fermoral
artery and vein were cannulated for measurement of blood
pressure and removal of blood samples for blood gas analysis
and for infusion of compounds, respectively. Body tempera-
ture, measured rectally, was maintained at 37 ( 0.5 °C by
use of a thermostatic heating pad (Harvard Apparatus). The
spontaneously breathing animals were then turned prone, and
the head was fixed in a Koph stereotaxic frame. A craniotomy
(5 mm × 3 mm) was carefully drilled over the parietal cortex.
Two saline-filled glass electrodes [GC150F-10 (Clark Electro-
chemicals), tip approximately 10 mm, 1.5-2.0 mm apart], each
containing a Ag/AgCl wire, were inserted into the parietal
cortex (∼1.0 mm depth) to monitor DC potential. Two saline-
filled cannulaes, each containing a Ag/AgCl wire, were inserted
under the skin of the animals to serve as reference electrodes.
(5) It has been reported that 3-bromochromone and 3-bromothio-
chromone may react with nucleophiles to form a variety of
products resulting from initial Michael addition and subsequent
rearrangement, pyranone ring opening, or pyranone ring con-
traction. See, for example: Gammill, R. B.; Nash, S. A.; Mizsak,
S. A. The Addition of Amines to 3-Bromochromone and 6-Bro-
mofurochromone. An unexpected Ring Contraction of the Pyrone
Ring. Tetrahedron Lett. 1983, 24, 3435-3438. Gammill, R. B.;
Nash, S. A.; Bell, L. T.; Watt, W. A Novel Entry to Substituted
Chromones and Furochromones Through Cyclopropane Inter-
mediates. Tetrahedron Lett. 1992, 33, 997-1000. Nakazumi, H.;
Watanabe, S.; Maeda, K.; Kitao, T. Synthesis of 2-(Aminometh-
ylene)-2H,3H-1-benzothiophene-3-one form 3-Bromo-4H-1-ben-
zothiopyran-4-one as
Chem. Lett. 1990, 679-682.
a new Donor-Acceptor Chromophore.
(6) We also attempted to prepare the C-4 acetoxy product by
acylation of the C-7 TIPS-protected phenol 29. In this case
fluoride deprotection afforded only 10a and its trans epimer 10b.
This is consistent with the proposed rapid formation of a quinone
methide when a good C-4 leaving group is present and capture
with water upon workup. The same result was observed when
we attempted to introduce a C-4 benzoyl group.
(7) Corey, E. J .; Chaykovsky, M. Dimethyloxosulfonium Methylide
((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2).
Formation and Application to Organic Synthesis. J . Am. Chem.
Soc. 1965, 87, 1353-1364.
(8) The trans isomer 36b was not obtained 100% pure. Stereochem-
ical assignments for 36a and 36b followed from the NMR
decoupling experiments below. (Left) Irradiation at 5.31 ppm
results in loss of the 1.6-Hz coupling to the proton at 0.96 ppm.
(Right) Irradiation at 4.32 ppm results in loss of the 1.3-Hz
coupling to the proton at 5.06 ppm, loss of the 3.9-Hz coupling
to the proton at 1.08 ppm, and loss of the 7.6-Hz coupling to
proton at 0.99 ppm.
CSD was induced electrically in the parietal cortex by using
a
bipolar electrode (NEX-200, Rhodes). The stimulation
electrode was placed at 90° to the frontal recording electrode
and positioned so that it visibly touched but did not depress
the cortex. Electrocortical stimulation consisted of a train of
5-ms pulses at 40 Hz lasting for 2 s (Multistim System D-330,
Digitimer Ltd.). The threshold stimulation for CSD elicitation
was defined by varying the current (Isotim KA320, World
Precision Instruments). Once the threshold current was
determined (usually 0.1-0.2 mA), the current was increased
by 20%. Four control stimulations, at 10-min intervals, were
performed to ensure the reproducibility of initiating CSD. The
test compound was then administered as a loading bolus
followed by continuous infusion for 1.0 h. The speed of CSD
spread was calculated from the latency difference of the
negative DC shift at the rostral and caudal electrodes and the
distance between the electrodes.
(9) McCarthy, K. E.; Miller, S. A.; Chenard, B. L.; Butler, T. W.;
Dumont, M. L.; Stemple, J . Z. Synthesis of High-Specific Activity
Tritium and Optically Pure [14C]CP-101, 606. J . Labelled Com-
pds. Radiopharm. 1997, XXXIX, 973-985.
(10) Shalaby, I. A.; Chenard, B. L.; Prochniak, M. A.; Butler, T. W.
Neuroprotective Effects of the N-Methyl-D-Aspartate Receptor
Antagonists Ifenprodil and SL 82.0715 on Hippocampal Cells
in Culture. J . Pharmacol. Exp. Ther. 1992, 260, 925-932.
(11) For a description of the [3H]prazosin binding assay, see: Green-
grass, P.; Bremner, R. Binding Characteristics of Prazosin-H-3
to Rat-Brain Alpha-Adrenergic Receptors. Eur. J . Pharmacol.
1979, 55, 323-326.
Ack n ow led gm en t. The NMDA receptor clones were
a kind gift of Dr. S. Nakanishi, Kyoto University, J apan.
(12) See ref 3 and Chenard, B. L.; Shalaby, I. A.; Koe, B. K.; Ronau,
R. T.; Butler, T. W.; Prochnick, M. A.; Schmidt, A. W.; Fox, C.
B. Separation of R1-Adrenergic and N-Methyl-D-Aspartate
Antagonist Activity in a Series of Ifenprodil Compounds. J . Med.
Chem. 1991, 34, 3085-3090.
Su p p or tin g In for m a tion Ava ila ble: X-ray structure
determination data for the p-bromobenzyl ether of compound
12a (12 pages). Ordering information is given on any current
masthead page.
(13) Seeburg, P. H. The Molecular Biology of Mammalian Glutamate
Receptor Channels. Trends Neurosci. 1993, 16, 359-365.
(14) Monyer, H.; Sprengel, R.; Schoepfer, R.; Herb, A.; Higuchi, M.;
Lomeli, H.; Burnashev, N.; Sakmann, B.; Seeburg, P. Hetero-
meric NMDA Receptors: Molecular and Functional Distinction
of Subtypes. Science 1992, 256, 1217-1221. Kutsuwada, T.;
Kashiwabuchi, N.; Mori, H.; Sakimura, K.; Kushiya, E.; Araki,
K.; Meguro, H.; Masaki, H.; Kumanishi, T.; Arakawa, M.;
Mishina, M. Molecular Diversity of the NMDA Receptor Chan-
nel. Nature 1992, 358, 36-41. Chazot, P. L.; Coleman, S. K.;
Cik, M.; Stephenson, F. A. Molecular Characterization of N-
Methyl-D-aspartate Receptors Expressed in Mammalian Cells
Yields Evidence for the Coexistence of Three Subunit Types
within a Discrete Receptor Molecule. J . Biol. Chem. 1994, 269,
24403-24409.
(15) Schmidt, W. J .; Bubser, M. Anticataleptic Effects of the N-
Methyl-D-Aspartate Antagonist MK-801 in Rats. Pharmacol.
Biochem. Behav. 1989, 32, 621-623. Mehta, A. K.; Ticku, M. K.
Role of N-Methyl-D-Aspartate (NMDA) Receptors in Experi-
mental Catalepsy in Rats. Life Sci. 1990, 109, 128-133.
(16) For a review, see: Herrera, D. G.; Robertson, H. A. Activation
of c-fos in the Brain. Prog. Neurobiol. 1996, 50, 83-107.
(17) Dragunow, M.; Faull, R. L. M.; J ansen, K. L. R. MK-801, an
Antagonist of NMDA Receptors, Inhibits Injury-Induced cfos
Accumulation in Rat Brain. Neurosci. Lett. 1990, 109, 128-133.
Refer en ces
(1) Menniti, F.; Chenard, B.; Collins, M.; Ducat, M.; Shalaby, I.;
White, F. CP-101,606, a Potent Neuroprotectant Selective for
Forebrain Neurons. Eur. J . Pharmacol. 1997, 331, 117-126.
(2) Except where indicated, all new compounds were prepared as
racemates. The stereochemistry illustrated for all new com-
pounds was chosen based on the absolute stereochemistry of 12a
as defined by X-ray structure analysis of its p-bromobenzyl ether.
(3) Chenard, B. L.; Bordner, J .; Butler, T. W.; Chambers, L. K.;
Collins, M. A.; DeCosta, D. L.; Ducat, M. F.; Dumont, M. L.; Fox,
C. B.; Mena, E. E.: Menniti, F. S.; Neilsen, J .; Pagnozzi, M. J .;
Richter, K. E. G.; Ronau, R. T.; Shalaby, I. A.; Stemple, J . Z.;
White, W. F. (1S,2S)-1-(4-Hydroxyphenyl)-2-(4-hydroxy-4-phen-
ylpiperidino)-1-propanol: A Potent New Neuroprotectant Which
Blocks N-Methyl-D-Aspartate Responses. J . Med. Chem. 1995,
38, 3138-3145.
(4) Winter, C. W.; Hamilton, C. S. Substituted Chromones. J . Am.
Chem. Soc. 1952, 74, 3999-4001. Colonge, J .; Guyot, A. No 44.-
Etude sur les chromanones-4, III. Alcoylation et bromuration
des chromanones: passage aux chromones. Bull. Chim. Soc. Fr.
1958, 329-334. auf dem Keller, H. H.; Zymalkowski, F. 3-Amino-
chromanole-(4) als potentialle Sympathomimetika. Arch. Pharm.
(Weinheim) 1971, 304, 543-554.

1184 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 7
Butler et al.
Sonnenberg, J . L.; Mitchelmore, C.; MacGregor-Leon, P. F.;
Hempstead, J .; Morgan, J . I.; Curran, T. Glutamate Receptor
Agonists Increase the Expression of Fos, Fra, and AP-1 DNA
Binding Activity in the Mammalian Brain. J . Neurosci. Res.
1989, 24, 72-80. Le, F.; Wilce, P. A.; Hume, D. A.; Shanley, B.
C. Involvement of γ-Aminobutyric Acid and N-Methyl-D-Aspar-
tate Receptors in the Inhibitory Effect of Ethanol on Pentyle-
netetrazole-Induced cfos Expression in Rat Brain. J . Neurochem.
1992, 59, 1309-1315. Sharp, J . W.; Sagar, S. M.; Hisanaga, K.;
J asper, P.; Sharp, F. R. The NMDA Receptor Mediates Cortical
Induction of fos and fos-Related Antigens Following Cortical
Injury. Exp. Neurol. 1990, 109, 323-332.
(28) Greenamyre, J . T.; Penney, J . B.; Young, A. B.; D′Amato, C. J .;
Hicks, S. P.; Shoulson, I. Alterations in L-Glutamate Binding
in Alzheimer’s and Huntington’s Diseases. Science 1985, 227,
1496-1498. Young, A. B.; Greenamyre, J . T.; Hollingsworth, Z.;
Albin, R.; D’Amato, C.; Shoulson, I.; Penney, J . B. NMDA
Receptor Losses in Putamen from Patients with Huntington’s
Disease. Science 1988, 241, 981-983.
(29) Dickenson, A. H. Spinal Cord Pharmacology of Pain. Br. J .
Anaesth. 1995, 75, 193-200.
(30) For an overview and leading references to the wind up phenom-
enon and the potential use of NMDA antagonists as analgesics,
see: Dickenson, A. H. A Cure for Wind Up: NMDA Receptor
Antagonists as Potential Analgesics. Trends Pharmacol. Sci.
1990, 11, 307-309.
(31) Herrara, D. G.; Robertson, H. A. Application of Potassium
Chloride to the Brain Surface induces the c-fos Proto-Onco-
gene: Reversal by MK-801. Brain Res. 1990, 510, 166-170.
Lauritzen, M. Spreading Depression and Migraine. Path. Biol.
1992, 40, 332-337. Lauritzen, M. Pathophysiology of the
Migraine Aura. Brain 1994, 117, 199-210.
(18) Nellgard, B.; Weiloch, T. NMDA-Receptor Blockers But Not
NBQX, an AMPA Receptor Antagonist, Inhibit Spreading De-
pression in Rat Brain. Acta Physiol. Scand. 1992, 146, 467-
503.
(19) Lauritzen, M. Pathophysiology of the Migraine Aura: The
Spreading Depression Theory. Brain 1994, 117, 199-210.
(20) The conformation of 1 has been calculated and compared to that
obtained by X-ray analysis (see ref 3). The conformations are
essentially identical. Furthermore, the solution conformation of
1
(and its erythro diastereomer) can be approximated by
(32) For leading references, see: Liljequist, S. The Competitive
NMDA Receptor Antagonist, CGP 39551, Inhibits Ethanol
Withdrawal Seizures. Eur. J . Pharmacol. 1991, 192, 197-198.
(33) Trujillo, K. A.; Akil, H. Inhibition of Morphine Tolerance and
Dependence by the NMDA Receptor Antagonist MK-801. Science
1991, 251, 85-87.
(34) Deutsch, S. I.; Mastropaolo, J .; Schwartz, B. L.; Rosse, R. B.;
Morihisa, J . M. A “Glutamatergic Hypothesis” of Schizophrenia.
Clin. Neuropharmacol. 1989, 12, 1-13. Sherman, A. D.; David-
son, A. T.; Baruah, S.; Hegwood, T. S.; Waziri, R. Evidence of
Glutamatergic Deficiency in Schizophrenia. Neurosci. Lett. 1991,
121, 77-80.
(35) Personal communication from Dr. S. J aw. Details will be
published elsewhere.
(36) Koch, K.; Biggers, M. S. General Preparation of 7-Substituted
4-Chromanones: Synthesis of a Potent Aldose Reductase Inhibi-
tor. J . Org. Chem. 1994, 59, 1216-1218.
(37) Schlegel, H. B. Optimization of Equilibrium Geometries and
Transition Structures. J . Comput. Chem. 1982, 3, 214-218.
(38) 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.
(39) 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.;
Peng, C. Y.; Ayala, P. Y.; Chen, W.; Wong, M. W.; Andres, J . L.;
Replogle, E. S.; Gomperts, R.; Martin, 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.
application of the Karplus equation to the NMR coupling
constants for the benzylic proton.
(21) Nishikawa, M.; Kanno, M.; Kuriki, H.; Sugihara, H.; Motohashi,
M.; Itoh, K.; Miyashita, O.; Oka, Y.; Sanno, Y. Selective
â-Adrenoceptor Activities of Tetrahydronaphthalene Derivatives.
Life Sci. 1975, 16, 305-314. For a separate study on adrenergic
activity of the trans-tetrahydronaphthols, see: Macchia, B.;
Balsamo, A.; Breschi, M. C.; Lapucci, A.; Lucacchini, A.; Macchia,
F.; Manera, C.; Martinelli, A.; Martini, C.; Martinotti, E.;
Nencetti, S. Conformational Effects on the Activity of Drugs. 13.
A revision of Previously Proposed Models for the activation of
R- and â-Adrenergic Receptors. J . Med. Chem. 1992, 35, 1009-
1018.
(22) Lal, B.; Khanna, J . M.; Anand, N. Phenethylamine in a Rigid
Framework. 2,3-Substituted cis- and trans-6-Amino-6,7,8,9-
tetrahydro-5H-benzocyclohepten-5-ols. J . Med. Chem. 1971, 15,
23-27.
(23) Meldrum, B. Possible Therapeutic Application of Antagonists
of Excitatory Amino Acid Neurotransmitters. Clin. Sci. 1985,
68, 113-122. Greenamyre, J . T. The Role of Glutamate in
Neurotransmission and in Neurologic Disease. Arch. Neurol.
1986, 43, 1058-1063. Choi, D. W. Glutamate Neurotoxicity and
Diseases of the Central Nervous System. Neuron 1988, 1, 623-
634. Danysz, W.; Parsons, C. F.; Bresink, I.; Quack, G. Glutamate
in CNS Disorders. DN&P 1995, 8, 261-277.
(24) Muir, K. W.; Lees, K. R. Clinical Experience with Excitatory
Amino Acid Antagonist Drugs. Stroke 1995, 26, 503-513.
McCulloch, J . Glutamate Receptor Antagonists in Cerebral
Ischemia. J . Neural Transm. 1994, 43 (Suppl.), 71-79. Albers,
G. W.; Goldberg, M. P.; Choi, D. W. N-Methyl-D-Aspartate
Antagonists: Ready for Clinical Trial in Brain Ischemia? Ann.
Neurol. 1989, 25, 398-403.
(25) McIntosh, T. K. Novel Pharmacologic Therapies in the Treat-
ment of Experimental Traumatic Brain Injury: A Review. J .
Neurotrauma 1993, 10, 215-261.
(26) Meldrum, B. The Role of Glutamate in Epilepsy and Other CNS
Disorders. Neurology 1994, 44 (Suppl. 8), S14-S23.
(40) Stu¨hmer, W. Electrophysiological recordings from Xenopus
oocytes. Methods Enzymol. 1992, 207, 319-339. Sands, S. B.;
Costa, A. C. S.; Patrick, J . W. Barium permeability of neuronal
nicotinic receptor R7 expressed in Xenopus oocytes. Biophys. J .
1993, 65, 2614-2621.
(27) Greenamyre, J . T.; O’Brian, C. F. N-Methyl-D-Aspartate An-
tagonists in the Treatment of Parkinson’s Disease. Arch. Neurol.
1991, 48, 977-981. Starr, M. S. Glutamate/Dopamine D1/D2
Balance in the Basal Ganglia and Its Relevance to Parkinson’s
Disease. Synapse 1995, 19, 264-293.
J M9707986