Subtype-selective N-methyl-D-aspartate receptor antagonists: Synthesis and biological evaluation of 1-(heteroarylalkynyl)-4-benzylpiperidines

Article abstract of DOI:10.1021/jm000023o

4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-phenol (9) are potent NR1A/2B receptor antagonists (IC₅₀ values 0.17 and 0.10 μM, respectively). Administered intraperitoneally, they both potentia

Full text of DOI:10.1021/jm000023o

3408
J . Med. Chem. 2000, 43, 3408-3419
Su btyp e-Selective N-Meth yl-D-Asp a r ta te Recep tor An ta gon ists: Syn th esis a n d
Biologica l Eva lu a tion of 1-(Heter oa r yla lk yn yl)-4-ben zylp ip er id in es
J on L. Wright,* Tracy F. Gregory, Suzanne R. Kesten, Peter A. Boxer, Kevin A. Serpa, Leonard T. Meltzer, and
Lawrence D. Wise
Departments of Chemistry and Therapeutics, Pfizer Global Research, Ann Arbor, Michigan 48105
Stephen A. Espitia, Christopher S. Konkoy, Edward R. Whittemore, and Richard M. Woodward
CoCensys, Inc., 213 Technology Drive, Irvine, California 92618
Received J anuary 21, 2000
4-[4-(4-Benzylpiperidin-1-yl)but-1-ynyl]phenol (8) and 4-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-
phenol (9) are potent NR1A/2B receptor antagonists (IC50 values 0.17 and 0.10 µM, respectively).
Administered intraperitoneally, they both potentiated the activity of L-DOPA in the unilaterally
6-hydroxydopamine-lesioned (6-OHDA) rat, a model of Parkinson’s disease. However, compound
9 was not active orally, likely due to rapid first-pass metabolism of the phenol moiety. The
phenol was replaced by several bicyclic heterocyclic systems containing an NH group to function
as a H-bond donor in the hope that these would be less likely to undergo rapid metabolism. In
general, indoles, indazoles, benzotriazoles, indolones, and isatins gave analogues with weaker
NR1A/2B activity than the parent phenols, while benzimidazolones and benzimidazolinones
gave equipotent or more potent analogues. The preference for a para arrangement between
the H-bond donor and the linking acetylene moiety was confirmed, and a propyne link was
preferred over a butyne link. Substitution on the benzyl group or a 4-hydroxyl group on the
piperidine had little effect on NR1A/2B potency; however, 4-hydroxypiperidines demonstrated
slightly improved selectivity for NR1A/2B receptors versus R-1 adrenergic and dopamine D2
receptor affinity. From this study, 5-[3-(4-benzylpiperidin-1-yl)prop-1-ynyl]-1,3-dihydrobenzo-
imidazol-2-one (46b) was identified as a very potent, selective NR1A/2B receptor antagonist
(IC50 value 0.0053 µM). After oral administration at 10 and 30 mg/kg, 46b potentiated the
effects of L-DOPA in the 6-OHDA-lesioned rat and seemed to have improved oral bioavailability
but lower brain penetration compared to phenol 9.
In tr od u ction
glutamate toxicity may have a role in the neuronal
death in Parkinson’s disease and glutamate antagonists
might arrest this. Glutamate is involved in neural
signaling in the basal ganglia, which includes the
striatum and the substantia nigra. It is thus involved
in the changes that alter the normal functioning of
the basal ganglia circuitry in Parkinson’s disease.4 Use
of glutamate receptor antagonists might reverse these
changes in basal ganglia glutamatergic neurotrans-
mission. N-Methyl-D-aspartate (NMDA) receptors are
the predominant form of glutamate receptor in the basal
ganglia.5 Hence, NMDA receptor antagonists in par-
ticular may be useful for treating the symptoms of
Parkinson’s disease and may slow the progression of the
disease, although this is much more speculative.
Parkinson’s disease is characterized by motor dys-
function, in particular akinesia, bradykinesia, and
tremor. There is a clear correlation between degenera-
tion of substantia nigra dopaminergic neurons (the
etiology of which is unclear) and the severity of the
disease symptoms.1 Degeneration of these neurons leads
to dopamine depletion in the striatum, causing motor
dysfunction. Administration of L-dihydroxyphenylala-
nine (L-DOPA), the precursor to dopamine, ameliorates
the symptoms of the disease by replacing the shortage
of endogenous dopamine. However, L-DOPA therapy
causes unwanted side effects, such as dyskineasias and
psychiatric disturbances, and does not halt the progres-
sion of the disease. Hence there is a need for therapies
that reduce the side effects of L-DOPA use and slow the
progression of the disease.
Early NMDA receptor antagonists fell into three main
classes: competitive antagonists at the glutamate bind-
ing site, such as CGS 19755 (Selfotel)6 (1); noncompeti-
tive antagonists at the channel site, such as MK-8017
(2) and PCP8 (3) (“ion-channel blockers”); and glycine
site antagonists, such as ACEA 10219 (4). Competitive
NMDA receptor antagonists have been shown to poten-
tiate the effects of L-DOPA in animal models of Parkin-
son’s disease.10 In addition, MK-801 reverses L-DOPA-
induced motor fluctuations in rats with nigrostriatal
lesions.11 Unfortunately, many of these agents cause
The excitatory neurotransmitter L-glutamic acid
(glutamate) is known to be neurotoxic at high con-
centrations.2 For example, excess glutamate released
during ischemic events (such as stroke) overstimulates
glutamate receptors, raising intraneuronal calcium ion
concentrations to harmful levels.3 It is speculated that
* To whom correspondence should be addressed. Tel: 734-622-2732.
Fax: 734-622-5165. E-mail: jonathan.wright@pfizer.com.
10.1021/jm000023o CCC: $19.00 © 2000 American Chemical Society
Published on Web 08/17/2000

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18 3409
Sch em e 1a
psychotomimetic, neurotoxic, and cardiovascular side
effects, which have limited their utility as drugs.12
Mammalian NMDA receptors are ligand-gated ion
channels composed of hetero-oligomeric combinations of
an NR1 subunit (found in eight splice variants) and at
least one of four NR2 subunits designated NR2A-
NR2D.13 The existence of distinct NMDA receptor
subtypes raises the possibility of finding subtype-
selective NMDA receptor modulators. Subtype-selective
NMDA antagonists might be useful in the treatment of
Parkinson’s disease (especially as an adjunct to L-DOPA)
without the side effects associated with many nonselec-
tive NMDA receptor antagonists. If a lower dose of
L-DOPA could be used, this may delay the onset of side
effects associated with its long-term use. Subtype-
selective NMDA antagonists have already been dem-
onstrated clinically to have reduced propensity for
psychotomimetic side effects compared to nonselective
NMDA receptor antagonists.14
a
(a) Pd(PPh3)4/pyrrolidine/50-80 °C; (b) NH2NH2‚xH2O/reflux.
support the hypothesis that NR1A/2B subtype-selective
antagonists could have utility for the treatment of
Parkinson’s disease as an add-on to L-DOPA. However,
compound 9 was not active after oral dosing, suggesting
low oral bioavailability. Preliminary pharmacokinetic
and metabolic studies indicated that these compounds
had good permeability across membranes but had short
half-lives in vivo. Further investigation revealed that
the phenol moiety was subject to rapid secondary
hydroxylation and conjugation. In this paper we discuss
the replacement of the phenol by heterocyclic NH-
containing rings that were expected to slow metabolism
and hence improve oral bioavailability.
In our previous paper,15 we had studied the SAR of a
novel NR1A/2B-selective antagonist 5 found via struc-
ture similarity searching of our compound library for
structural overlap with the NR2B-selective antagonists
ifenprodil (6) and haloperidol (7).
Ch em istr y
From this hit, the more potent phenols 8 and 9 were
developed. These compounds potentiated the effects of
L-DOPA in the 6-hydroxydopamine-lesioned rat, a model
of Parkinson’s disease, administered intraperitoneally
(ip), but had little effect by themselves. These data
Compounds 16a -20a , 16b, 18b, and 19b in Table 1
and 20b were prepared via the general synthesis
outlined in Scheme 1. The palladium-mediated coupling
of aryl halides to acetylenes 10a and 10b15 was most
reliably accomplished using Pd(PPh3)4 as catalyst with

3410 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Wright et al.
Sch em e 2a
a
(a) Pd(PPh3)4/pyrrolidine; (b) Fe/H3O+/EtOH/reflux; (c) carbonyldiimiazole or thiocarbonyldiimidazole/THF.
pyrrolidine as base/solvent. 5-Bromoindole, 6-bromo-
indole (12), and 5-iodoisatin (13) were commercially
available, although 5-bromoindole coupled in very poor
yield. It was found that the 1-phenylsulfonyl derivative
1116 coupled in much higher yield with 10a and 10b,
and the phenylsulfonyl protecting group was removed
with ethanolic sodium hydroxide to give the free indole
analogues 16a and 16b. 6-Bromoindole (12) coupled
with 10a (without protection) to give 17a , albeit in poor
yield. 5-Iodoindazole (14)17 and 5-iodobenzotriazole (15),
the coupling partners for analogues 18a , 18b, 19a , and
19b, were both made via diazotization/iodination of
5-aminoindazole or 5-aminobenzotriazole, respectively.
Indolone analogues 21a and 21b were obtained by
hydrazine reduction18 of isatin derivatives 20a and 20b.
Benzimidazolones and benzimidazothiolones 46a , 46b,
47a , and 47b in Table 1 and 48-54 in Table 2 were
prepared as described in Scheme 2. The acetylenes
22-28 were synthesized as reported previously15 and
coupled, along with 10a and 10b , with commercially
available 2-nitro-4-bromoaniline (29) to give 30a , 30b,
and 31-37. Iron/HCl reduction allowed isolation of
the stable diamines 38a , 38b, and 39-45 that were
transformed to final products with carbonyl diimidazole
(46a , 46b, 48-54) or thiocarbonyl diimidazole (47a ,
47b) at room temperature in THF.
the resulting amine 59a cyclized under basic conditions
to give product 60a . Acetylene 10b was coupled with
5-bromo-2-nitrophenyl methyl carbonate (57) to give an
improved yield of coupled product 58b. This was reduced
and cyclized as above to give 60b. Some deformylation
occurred during the reduction step for both series;
mixtures of formyl product, cyclized product, and amino-
phenol were obtained that were separated by chroma-
tography.
Benzoxazinone analogue 63 (Table 1) was prepared
according to Scheme 4. 6-Hydroxy-2H-1,4-benzoxazin-
3(4H)-one (61)20 was triflated and coupled with butyne
10a using the Pd(PPh3)4/pyrrolidine conditions to give
coupled product 63. N-Monomethylbenzimidazolones 67
and 71 were prepared as outlined in Scheme 5. 5-Bromo-
N-methyl-2-nitroaniline (64), obtained by stirring 1,3-
dibromo-4-nitrobenzene21 with methylamine, was coupled
with propyne 10b under Pd(PPh3)2Cl2/Et3N/DMF/CuI
conditions (again use of pyrrolidine resulted in displace-
ment of the bromide). Iron/HCl reduction of the product
(65) followed by treatment with carbonyldiimidazole
gave benzimidazolone 67. Coupling of bromide 68, ob-
tained by methylation and formylation of commercially
available 2-nitro-4-bromoaniline, with propyne 10b
under Pd(PPh3)4/pyrrolidine conditions gave 69, which
could be reduced and cyclized to product 71 as above.
The benzimidazolinones 60a and 60b in Table 1 were
prepared as shown in Scheme 3. Acetylene 10a was
coupled with 5-bromo-2-nitrophenol (55)19 in moderate
yield and the product phenol 56 formylated to give 58a .
The Pd(PPh3)4/pyrrolidine conditions could not be used
here due to displacement of the activated bromine
substituent by pyrrolidine; Pd(PPh3)2Cl2/Et3N/CH2Cl2/
CuI conditions were employed instead. Iron/HCl condi-
tions were used to reduce the nitro group of 58a , and
P h a r m a cology
All compounds were tested for inhibitory activity at
NR1A/2A, NR1A/2B, and NR1A/2C receptors expressed
in Xenopus oocytes using electrophysiological tech-
niques.22 Compounds that possessed high antagonist
potency and selectivity for the NR1A/2B receptor were
further profiled in R-1 adrenergic (displacement of [3H]-

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18 3411
Sch em e 3a
a
(a) Pd(PPh3)2Cl2/Et3N/CH2Cl2/CuI/reflux; (b) Et2OCCl/K2CO3/MeCN; (c) Fe/HCl/H2O/EtOH/reflux; (d) K2CO3/MeCN/reflux.
Sch em e 4a
a
(a) Tf2NPh/Et3N/THF; (b) Pd(PPh3)4/pyrrolidine/50 °C.
prazosin from rat brain cortical membranes)23 and
dopamine D2 (displacement of [3H]raclopride from rat
brain striatal membranes)24 receptor binding assays.
Compounds with potency and selectivity for NR1A/2B
receptors were tested orally in the 6-hydroxydopamine-
lesioned rat, a model of Parkinson’s disease, for in-
creases in the number of contraversive (away from the
side of lesion) rotations produced by L-DOPA (10 mg/kg
sc) over a 6-h period.25
activity at all three receptor subtypes. As these struc-
tures were derived from ifenprodil (R-1 adrenergic
receptor antagonist) and haloperidol (dopamine D2
antagonist), R-1 adrenergic and dopamine D2 receptor
affinities were determined for key analogues.
Our previous studies concluded that a hydrogen-bond
donor was required on the right-hand phenyl ring for
potent activity at NR1A/2B receptors. In addition, a para
arrangement between the hydrogen-bond donor and the
linking acetylene moiety was preferred. Hence these
requirements were considered when choosing potential
phenol replacements. These previous studies had also
indicated that the acetylene-containing link should be
propyne or butyne; pentyne reduced NR1A/2B potency.
Resu lts a n d Discu ssion
Our goals were to identify analogues of 8 and 9 with
potent activity at NR1A/2B and weak activity at NR1A/
2A and NR1A/2C receptors. Selectivity would demon-
strate a unique interaction at NR1A/2B receptors;
channel blockers, for example, generally have similar
Compounds 16a and 17a in Table 1 explored the use
of indole as a phenol replacement. When attached to

3412 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Wright et al.
Sch em e 5a
a
(a) Pd(PPh3)2Cl2/Et3N/DMF/CuI/50 °C; (b) Fe/H3O+/EtOH/reflux; (c) CDI/THF; (d) Pd(PPh3)4/pyrrolidine; (e) NaH/THF/reflux.
the butyne via the 5-position (16a ) or 6-position (17a ),
the compounds had relatively weak NR1A/2B activity,
with a preference for the 5-connected indole 16a . In this
case the propyne-linked analogue of 5-indole 16b was
very weak, with an NR1A/2B IC50 value of 15 µM. The
indole NH may not be acidic enough to form strong
H-bonds; hence the butynyl indazole analogue 18a and
benzotriazole analogue 19a were prepared. Both com-
pounds were significantly more potent at NR1A/2B
receptors, suggesting again that strong H-bond donor
ability is beneficial to NR1A/2B activity. As before, the
propyne analogues 18b and 19b were slightly weaker
at NR1A/2B receptors. All these compounds were highly
selective for NR1A/2B receptors versus NR1A/2A and
NR1A/2C receptors - in most cases the selectivity
exceeded 100-fold. This selectivity clearly separated
these compounds from traditional, nonselective NMDA
receptor antagonists such as channel blockers.
With the knowledge that a relatively acidic NH was
preferred for potent NR1A/2B activity, the isatin ana-
logue 20a and indolone analogue 21a were prepared.
Isatin 20a had fairly weak activity at NR1A/2B recep-
tors, while indolone 21a had similar potency to indazole
18a and benzotriazole 19a . However, in this case
the propynyl indolone analogue 21b was significantly
more potent with an IC50 value of 0.11 µM, equipotent
with the starting phenol analogue 9. This trend was
repeated with benzimidazolones 46a and 46b. Butynyl-
benzimidazolone 46a was a potent antagonist with an
NR1A/2B IC50 value of 0.089 µM, but propynylbenz-
imidazolone 46b was significantly more active, with an
IC50 value of 0.0053 µM. Both of these compounds
remained highly selective, with 46b being over 1000-
fold selective for NR1A/2B receptors. The thiobenz-
imidazolone analogues 47a and 47b were a little weaker
than their benzimidazolone counterparts, with the pro-
pynyl analogue 47b again being much more potent than
the butynyl analogue 47a .
The benzimidazolinone analogues 60a and 60b were
also potent NR1A/2B receptor antagonists (IC50 values
0.12 and 0.049 µM, respectively), although weaker than
the benzimidazolones. The benzoxazinone analogue 63
had reduced NR1A/2B potency (IC50 1.1 µM) compared
to the five-membered amide heterocycles, and the
corresponding propyne analogue was not made.
At this point we concentrated on the propyne benz-
imidazolone template. Methylation of the meta (to the
propyne) NH (compound 67) reduced NR1A/2B potency
nearly 20-fold compared to parent 46b. Methylation of
the para NH (compound 71) reduced NR1A/2B potency
drastically. This drop in potency reflects not only the
importance of the H-bond donor for high potency at
NR1A/2B receptors but also suggests that the methyl is
causing interference with binding at the receptor -
possibly via steric interactions. These results underscore
the importance of the para H-bond donor for high NR1A/
2B potency but also suggest other, more subtle roles for
the carbonyl and/or the meta NH moiety.
The propynylbenzimidazolone system in compound
46b seemed to be optimal, and we looked to modifica-
tions on the benzylpiperidine system for further opti-
mization of this series. Our previous studies had shown
that substitution on the aromatic ring of the benzyl
group or 4-hydroxylation of the piperidine ring did not

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18 3413
Ta ble 1. NMDA Receptor Activity for Analogues of 8 and 9
a
IC50 values for inhibition of NMDA responses at cloned NMDA receptors expressed in Xenopus oocytes. Number of determinations
(n) shown in parentheses. Data are presented as mean ( SEM. Less than 50% inhibition at 100 µM. c Not tested. Slight potentiation
of agonist-induced responses was observed. No attempt was made to investigate the mechanism of this observation.
b
d
improve NR1A/2B potency, but these changes did have
effects on selectivity - especially with respect to affinity
for R-1 adrenergic and D2 dopaminergic receptors. In
Table 2, the data for 46b includes the R-1 adrenergic
(0.5 µM) and dopamine D2 (2.6 µM) receptor IC50 values.
While there is a clear selectivity for NR1A/2B receptor
activity versus affinity for these receptors, the selectivity
versus R-1 adrenergic receptors in particular is lower
than desired. Substitution on the 4-position of the benzyl
group of 46b gave compounds 48-51. There was not a
clear preference for electron-withdrawing or -donating
substituents for potent NR1A/2B activity, although
increasing substituent size may have a minor negative
effect on potency. The 3-fluoro analogue 52 had similar
potency at NR1A/2B receptors compared to 4-fluoro
analogue 48 or unsubstituted parent 46b. Hence small
substituents on the aromatic ring of the benzyl group
of 46b were tolerated. No clear trends in selectivity
versus R-1 adrenergic and D2 dopaminergic receptor
affinities were seen across this series. However, this
tolerance to substitution may give us a means to slow
metabolism on the benzyl group, if necessary.
The incorporation of a hydroxyl group on the 4-posi-
tion of the piperidine moiety (compounds 53 and 54)
caused a 3-4-fold drop in NR1A/2B potency for both
compounds. However, there was a much larger drop in
R-1 adrenergic and dopamine D2 receptor affinities,
resulting in an improved overall selectivity profile for
both compounds. For example, compound 53 had >1000-
fold selectivity for NR1A/2B receptor IC50 versus R-1
adrenergic and dopamine D2 receptor affinities.
All of the compounds in Table 2, with the exception
of 53, were tested in the 6-hydroxydopamine-lesioned
(6-OHDA) rat model. Compounds 46b, 48, 49, and 50
were dosed at 30 mg/kg orally and showed significant
potentiation of the effects of L-DOPA in this model,

3414 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Ta ble 2. NMDA Receptor Activity for Analogues of
Wright et al.
40-mm i.d. × 350-mm (∼200 g of silica gel) or 51-mm i.d. ×
450-mm (∼400 g of silica gel) glass columns using 32-63 µm,
60 A pore silica gel. Alternatively, disposable Biotage 40- or
90-g of silica gel cartridges were used. HPLC was performed
on Beckman Ultrasphere 5-µm 4.6-mm × 25-cm C-18 columns
eluting with pH 3 buffer:acetonitrile mixtures (unless other-
wise noted) at 1.5 mL/min and compounds detected using UV
absorption at 214 nm. pH 3 buffer was prepared by adjusting
a 0.05 M solution of Et3N in water to pH 3 with phosphoric
acid. Ether refers to diethyl ether.
5-Iod o-1H -b en zot r ia zole (15). A mixture of 5-amino-
benzotriazole (2 g, 15 mmol) in 6 N HCl (5 mL) was treated
with NaNO2 (1.07 g, 15.5 mmol) in water (2.5 mL) at 0 °C with
stirring. The resulting bright red solution was treated with
KI (3 g, 18 mmol) in water (6 mL) and allowed to warm to
25 °C. The mixture was allowed to stir for 2 h at 25 °C.
Na2SO3 (250 mg, 2 mmol) was added followed by water (100
mL) and the mixture warmed over a steam bath. The resulting
suspension was filtered. The solids were suspended in EtOAc,
filtered and washed with excess EtOAc. The filtrate was
concentrated to give 15 as an orange solid (1.18 g, 32%): 1H
NMR (DMSO-d6) δ 8.41 (s, 1H), 7.81 (d, J ) 8.8 Hz, 1H), 7.76
(d, J ) 8.6 Hz, 1H).
5-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]-1H-in dole (16a).
A mixture of 4-benzyl-1-(3-butynyl)piperidine15 (10a ) (908 mg,
4 mmol), 5-bromo-1-(phenylsulfonyl)-1H-indole16 (11) (1.34 g,
4 mmol) and Pd(PPh3)4 (240 mg, 0.2 mmol) was stirred in
pyrrolidine (10 mL) and deoxygenated by bubbling N2 through
the mixture for 10 min. The mixture was stirred at 50 °C under
N2 overnight. The pyrrolidine was evaporated and the residue
purified by MPLC (200 g of silica gel) loading with CH2Cl2 and
eluting with 50% f 100% EtOAc/hexanes to give a pale yellow
oil (1.55 g, 80%): 1H NMR (CDCl3) δ 7.86 (d, J ) 8.8 Hz, 1H),
7.81 (d, J ) 7.3 Hz, 2H), 7.51 (m, 3H), 7.39 (t, J ) 7.8 Hz,
2H), 7.22-7.29 (m, 3H), 7.09-7.16 (m, 3H), 6.56 (d, J ) 3.7
Hz, 1H), 2.90 (d, J ) 11.7 Hz, 2H), 2.52-2.63 (m, 4H), 2.49 (d,
J ) 7.1 Hz, 2H), 1.96 (t, J ) 10.7 Hz, 2H), 1.58-1.62 (m, 2H),
1.49 (m, 1H), 1.29 (dq, J ) 3.2, 12.5 Hz, 2H). This oil (1.49 g)
was stirred in EtOH (200 mL) and 50% NaOH (1 mL) at room
temperature for 2 days. Most of the EtOH was evaporated and
the residue diluted with water (500 mL). The precipitate was
filtered off, washed copiously with water and dried on the filter.
The solid was recrystallized from hot EtOH and dried at
50 °C under high vacuum overnight to give 16a as an off-white
solid (854 mg, 81%): mp 165-166 °C; IR 1469, 1343, 1116,
a
IC50 values for inhibition of NMDA responses at cloned NMDA
receptors expressed in Xenopus oocytes. Number of determinations
(n) shown in parentheses. Data are presented as mean ( SEM.
b
Compounds were evaluated at nine concentrations for the
displacement of [3H]prazosin from rat brain cortices and an IC50
calculated, n ) 1. c Compounds were evaluated at nine concentra-
tions for the displacement of [3H]raclopride from rat brain striata
d
and an IC50 calculated, n ) 1. Lowest oral dose that shows
significant potentiation of total contraversive rotations over 3 h
caused by L-DOPA (10 mg/kg sc) in 6-hydroxydopamine-lesioned
rats, n ) 8. e Less than 50% inhibition at 100 µM. f Slight
potentiation of agonist-induced responses was observed. No at-
tempt was made to investigate the mechanism of this observation.
g
Not tested.
while the remainder were inactive at 30 mg/kg. Com-
pound 46b showed significant activity at 10 mg/kg po.
However, 46b dosed orally or intraperitoneally (ip) has
similar potency in this test to phenol 9 dosed ip (all have
a minimum effective dose of 10 mg/kg) despite 46b being
20-fold more potent at NR1A/2B receptors. As 46b gave
similar results dosed ip or po, this suggests good oral
bioavailability. In contrast, phenol 9 was inactive at 30
mg/kg orally. These results suggest that 46b suffers
from lower brain penetration than 9.
1
883, 808, 728, 706 cm-1; H NMR (DMSO-d6) δ 11.16 (s, 1H),
7.51 (s, 1H), 7.31 (t, J ) 2.7 Hz, 1H), 7.27 (d, J ) 8.3 Hz, 1H),
7.21 (t, J ) 7.3 Hz, 2H), 7.09-7.13 (m, 3H), 7.00 (dd, J ) 1.3,
8.3 Hz, 1H), 6.34 (br s, 1H), 2.82 (d, J ) 11.5 Hz, 2H), 2.42-
2.47 (m, 6H), 1.85 (t, J ) 11.0 Hz, 2H), 1.47 (d, J ) 12.7 Hz,
2H), 1.41 (m, 1H), 1.12 (dq, J ) 3.2, 12.2 Hz, 2H); APCI MS
m/z 343.6 (MH+, 100); HPLC (60% pH 3 buffer:40% MeCN)
6.17 min (99.01%). Anal. (C24H26N2‚0.10H2O) C, H, N, water.
5-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]-1H-in dole (16b).
A procedure similar to that above for 16a using 4-benzyl-1-
(2-propynyl)piperidine15 (10b) gave 16b as a yellow oil (541
mg). This oil was stirred in MeCN (50 mL) and oxalic acid
dihydrate (208 mg) in EtOH (5 mL) added. A pale tan solid
precipitated on standing in the freezer overnight; it was
collected and recrystallized from hot EtOH to give the oxalate
salt of 16b as an off-white solid (348 mg, 52%): mp 185-188
°C; IR 2232, 1723, 1633, 1453, 700 cm-1; 1H NMR (DMSO-d6)
δ 11.32 (s, 1H), 7.67 (s, 1H), 7.33-7.37 (m, 2H), 7.24 (t, J )
7.4 Hz, 2H), 7.14 (m, 4H), 6.39 (t, J ) 1.6 Hz, 1H), 4.00 (br. s,
2H), 3.30 (d, J ) 11.2 Hz, 2H), 2.73 (t, J ) 11.1 Hz, 2H), 2.48
(d, J ) 6.3 Hz, 2H), 1.67-1.71 (m, 3H), 1.33-1.39 (m, 2H);
APCI MS m/z 329.3 (MH+, 100); HPLC (60% 0.1% TFA in
water:40% MeCN) 7.48 min (98.91%). Anal. (C23H24N2‚C2H2O4)
C, H, N, water.
In summary, we have discovered several bicyclic
heterocyclic systems containing a para H-bond donor
that are good replacements for a phenol moiety. In
particular, compound 46b is a very potent, selective
NR1A/2B receptor antagonist. This compound demon-
strated oral activity in a rodent model of Parkinson’s
disease at 10 and 30 mg/kg.
Exp er im en ta l Section
Melting points were determined on a Gallenkamp capillary
melting point apparatus and are uncorrected. 1H NMR spectra
were determined on Varian Unity 400 spectrometers. Mass
spectra were obtained on Finnigan 4500 or VG Analytical
7070E/HF mass spectrometers. IR spectra were recorded on a
Nicolet MX-1 FT spectrophotometer. Robertson Laboratories
performed elemental analyses. TLC was performed on 0.25-
mm silica gel F254 (E. Merck) glass plates. Medium-pressure
liquid chromatography (MPLC) was performed on self-packed
Michel-Miller 21-mm i.d. × 300-mm (∼80 g of silica gel),
6-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]-1H-in dole (17a).
A mixture of 4-benzyl-1-but-3-ynylpiperidine15 (10a ) (398
mg, 1.75 mmol), 6-bromoindole (12) (343 mg, 1.75 mmol) and
Pd(PPh3)4 (101 mg, 0.09 mmol) in pyrrolidine (10 mL) was
deoxygenated with N2 and stirred at 60 °C for 2 h. The

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18 3415
pyrrolidine was evaporated and the residue purified by MPLC
(90-g Biotage silica gel cartridge) eluting with 200:8:1 f
100:8:1 CH2Cl2:EtOH:30% aqueous ammonia to give a pale
yellow oil (472 mg). This oil was further purified by MPLC
(90-g Biotage silica gel cartridge) eluting with 50% f 100%
EtOAc/hexanes to give 17a as a white solid (75 mg, 13%): mp
under N2 overnight. The DMF was evaporated and residue
purified by MPLC (200 g of silica gel) eluting with 1:1:0.01
ethyl acetate: hexane: triethylamine to give a solid (238 mg).
The solid was recrystallized from 10% water/2-propanol to
yield 20a as orange crystals (152 mg, 26%): mp 140-141 °C;
IR 3026, 2923, 1743, 1621, 1482 and 699 cm-1 1H NMR
;
136-138 °C; IR 1494, 1452, 1321, 1111, 820, 705 cm-1
;
1H
(CDCl3) δ 7.49 (s, 1H), 7.40 (d, J ) 8.1 Hz, 1H), 7.21 (m, 2H),
7.13 (m, 3H), 6.73 (d, J ) 8.1 Hz, 1H), 2.97 (d, J ) 11.5 Hz,
2H), 2.61 (t, J ) 6.8 Hz, 2H), 2.55 (t, J ) 6.8 Hz, 2H), 2.50 (d,
J ) 7.1 Hz, 2H), 1.98 (t, J ) 11.7 Hz, 2H), 1.62 (d, J ) 13.2
Hz, 2H), 1.52 (m, 1H), 1.29 (m, 2H); APCI MS m/z 373 (MH+,
39). Anal. (C24H24N2O2‚1.51H2O) C, H, N, water.
NMR (DMSO-d6) δ 11.11 (s, 1H), 7.41 (d, J ) 8.1 Hz, 1H), 7.33
(m, 2H), 7.21 (t, J ) 7.3 Hz, 2H), 7.11 (m, 3H), 6.90 (dd, J )
1.5, 8.3 Hz, 1H), 6.36 (d, J ) 2.2 Hz, 1H), 2.82 (d, J ) 11.5 Hz,
2H), 2.43-2.48 (m, 6H), 1.85 (t, J ) 10.5 Hz, 2H), 1.47 (d, J )
12.7 Hz, 2H), 1.41 (m, 1H), 1.12 (dq, J ) 4.2, 12.9 Hz, 2H);
APCI MS m/z 343.1 (MH+, 100); HPLC (65% pH 3 buffer:35%
MeCN) 13.00 min (98.83%). Anal. (C24H26N2) C, H, N.
5-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]-1H -in d a zole
(18a ). Coupling of 4-benzyl-1-but-3-ynylpiperidine15 (10a )
(454 mg, 2 mmol), 5-iodoindazole17 (14) (488 mg, 2 mmol)
as described for 16a followed by MPLC (200 g of silica gel)
eluting with 30% f 100% EtOAc/hexanes gave a white, waxy
solid (515 mg). This solid was recrystallized from hot 9:1
EtOH:water to give 18a as an off-white solid (444 mg, 65%):
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-1,3-d ih yd r oin -
d ol-2-on e (21a ). A solution of 20a (209 mg, 0.6 mmol) in
hydrazine hydrate (1.5 mL) was warmed to reflux with
stirring. The reaction was cooled after 35 min and quenched
with water. The mixture was extracted with EtOAc, dried
over MgSO4 and concentrated to give solid. The solid was
purified by MPLC (80 g of silica gel) eluting with 400:8:1
CH2Cl2:EtOH:30% aqueous ammonia to give a solid (126 mg).
This solid was dissolved in MeOH and oxalic acid dihydrate
(78 mg) in ether (2 mL) was added. A tan precipitate was
filtered off and dried under vacuum for 16 h to give 21a (80
mg, 18%): mp 164.5-165.4 °C; IR 3425, 3025, 2923, 1698,
1623, 1490, 701 cm-1; 1H NMR (DMSO-d6) δ 10.54 (s, 1H), 7.29
(t, J ) 7.2 Hz, 2H), 7.22 (m, 5H), 6.79 (d, J ) 8.4 Hz, 1H),
3.46 (s, 2H), 3.39 (d, J ) 10.4 Hz, 2H), 3.14 (m, 2H), 2.80 (m,
4H), 2.55 (m, 2H), 1.73 (d, J ) 11.8 Hz, 3H), 1.41 (br d, J )
11.1 Hz, 2H); APCI MS m/z 359.0 (MH+, 100). Anal. (C24H26N2O‚
1.03C2H4O4‚0.1H2O) C, H, N, water.
mp 143-146 °C; IR 1655, 1466, 1297, 953, 812, 749, 700 cm-1
;
1H NMR (CDCl3) δ 10.33 (br s, 1H), 7.99 (s, 1H), 7.76 (s, 1H),
7.37 (m, 2H), 7.22-7.26 (m, 2H), 7.09-7.17 (m, 3H), 2.93 (d,
J ) 11.7 Hz, 2H), 2.56-2.68 (m, 4H), 2.50 (d, J ) 7.1 Hz, 2H),
1.99 (dt, J ) 2.2, 11.7 Hz, 2H), 1.63 (d, J ) 13.2 Hz, 2H), 1.50
(m, 1H), 1.31 (dq, J ) 3.9, 12.7 Hz, 2H); APCI MS m/z 344.6
(MH+, 100); HPLC (70% pH 3 buffer:30% MeCN) 8.08 min
(97.71%). Anal. (C23H25N3‚0.25H2O) C, H, N, water.
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1H-in d a zole
(18b). A procedure similar to that above for 18a starting with
10b gave 18b which was isolated as the oxalate salt (268 mg,
32%): mp 214-216 °C; IR 2240, 1732, 1620, 1452, 939, 704
cm-1; 1H NMR (DMSO-d6) δ 8.05 (s, 1H), 7.92 (s, 1H), 7.51 (d,
J ) 8.5 Hz, 1H), 7.36 (dd, J ) 1.4, 8.5 Hz, 1H), 7.23 (m, 2H),
7.14 (m, 3H), 3.98 (s, 2H), 3.28 (d, J ) 11.7 Hz, 2H), 2.70 (t,
J ) 11.9 Hz, 2H), 2.48 (d, J ) 6.6 Hz, 2H), 1.66-1.70 (m, 3H),
1.32-1.38 (m, 2H); APCI MS m/z 330.2 (MH+, 100); HPLC
(60% 0.1% TFA in water:40% MeCN) 2.95 min (100%). Anal.
(C22H23N3‚C2H2O4‚0.1H2O) C, H, N, water.
5-[3-(4-Ben zylpiper idin -1-yl)pr op-1-yn yl]-1,3-dih ydr oin -
d ol-2-on e (21b). A procedure similar to that above for 20a /
21a starting with 10b gave 21b as yellow crystals: mp 164-
166 °C; IR 1704, 1488, 1294, 1229, 1108, 819, 699 cm-1 1H
;
NMR (DMSO-d6) δ 10.46 (s, 1H), 7.09-7.23 (m, 7H), 6.71 (d,
J ) 8.3 Hz, 1H), 3.37 (s, 2H), 3.27 (s, 2H), 2.75 (d, J ) 11.3
Hz, 2H), 2.44 (m, 2H), 2.04 (t, J ) 9.7 Hz, 2H), 1.50 (d, J )
12.2 Hz, 2H), 1.40 (m, 1H), 1.14 (dq, J ) 3.6, 12.2 Hz, 2H);
APCI MS m/z 345.2 (MH+, 100); HPLC (60% 0.1% TFA in
water:40% MeCN) 2.95 min (100%). Anal. (C23H24N2O‚0.07H2O)
C, H, N, water.
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-1H-ben zotr ia -
zole (19a ). A mixture of 4-benzyl-1-(3-butynyl)piperidine15
(10a ) (565 mg, 2.5 mmol), 5-iodo-1H-benzotriazole (15) (612
mg, 2.5 mmol) and Pd(PPh3)4 (144 mg, 0.125 mmol) was stirred
in pyrrolidine (5 mL) and deoxygenated by bubbling N2
through the mixture for 10 min. The mixture was stirred at
25 °C under N2 overnight. The pyrrolidine was evaporated and
the residue purified by MPLC (200 g of silica gel) eluting with
CH2Cl2 f 100:8:1 CH2Cl2:EtOH:30% aqueous ammonia to give
a semisolid. The semisolid was dissolved in ether and concen-
trated giving 19a as a foam (176 mg, 26%): IR 3428, 2930,
4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-2-n it r ob en -
zen ea m in e (30b). Coupling of 4-bromo-2-nitroaniline (29)
(Maybridge) (5.00 g, 23 mmol) and 4-benzyl-1-prop-2-ynylpi-
peridine15 (10b) (5.55 g, 26 mmol) as described for 16a followed
by chromatography on silica gel (400 g) eluting with EtOAc
1
gave 30b (7.33 g, 91%): mp 125-126 °C; H NMR (CDCl3) δ
8.17 (s, 1H), 7.32 (dd, J ) 2.2, 10.1 Hz, 1H), 7.22 (m, 2H), 7.15
(d, J ) 7.1 Hz, 1H), 7.10 (d, J ) 7.8 Hz, 2H), 6.68 (d, J ) 8.1
Hz, 1H), 6.15 (br s, 2H), 3.43 (s, 2H), 2.95 (d, J ) 12.2 Hz,
2H), 2.50 (d, J ) 6.8 Hz, 2H), 2.20 (m, 2H), 1.65 (d, J ) 12.2
Hz, 2H), 1.50 (m, 1H), 1.27 (m, 2H).
2847, 1451, 1207 and 701 cm-1 1H NMR (CDCl3) δ 8.24 (s,
;
1H), 7.64 (m, 3H), 7.19 (m, 1H), 7.09 (m, 3H), 3.16 (d, J )
11.5 Hz, 2H), 2.80 (t, J ) 7.3 Hz,2H), 2.68 (t, J ) 7.3 Hz, 2H),
2.50 (d, J ) 6.8 Hz, 2H), 2.12 (t, J ) 11.2 Hz, 2H), 1.71 (d,
J ) 12.7 Hz, 2H), 1.58 (m, 1H), 1.41 (m, 2H); APCI MS m/z
330.2 (MH+, 100). Anal. (C22H24N4‚0.31H2O) C, H, N, water.
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1H -b en zo-
tr ia zole (19b). A procedure similar to that above for 19a
starting with 10b gave 19b which was isolated as the oxalate
salt: mp 169-176 °C; IR 2240, 1729, 1617, 1453, 1208, 998,
700 cm-1; 1H NMR (DMSO-d6) δ 8.07 (s, 1H), 7.87 (d, J ) 8.3
Hz, 1H), 7.46 (d, J ) 8.6 Hz, 1H), 7.23 (m, 2H), 7.14 (m, 3H),
3.99 (s, 2H), 3.26 (d, J ) 11.8 Hz, 2H), 2.68 (t, J ) 12.0 Hz,
2H), 2.49 (d, J ) 6.6 Hz, 2H), 1.66-1.70 (m, 3H), 1.31-1.37
(m, 2H); APCI MS m/z 331.2 (MH+, 100); HPLC (60% 0.1%
TFA in water:40% MeCN) 3.22 min (98.76%). Anal. (C21H22N4‚
1.1C2H2O4‚0.3H2O) C, H, N, water.
4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]ben zen e-1,2-
d ia m in e (38b). Five drops of concentrated HCl were added
to a refluxing mixture of 30b (1.0 g, 2.87 mmol) and Fe powder
(1 g) in 20% aqueous EtOH (50 mL). After stirring at reflux
for 30 min, the mixture was filtered through Celite to remove
Fe and some tar and the filtrate was concentrated to a foam.
Purification by column chromatography (80 g of silica gel)
eluting with 15% 1 N methanolic NH3 in CHCl3 provided 38b
(0.8 g, 87%): mp 96-97 °C; 1H NMR (DMSO-d6) δ 7.22 (m,
2H), 7.15 (m, 3H), 7.05 (m, 2H), 6.50 (s, 1H), 6.40 (dd, J ) 1.7,
7.8 Hz, 1H), 6.36 (d, J ) 7.8 Hz, 1H), 4.72 (s, 2H), 4.49 (s,
2H), 3.30 (s, 2H), 2.73 (d, J ) 11.2 Hz, 2H), 2.49 (m, DMSO+
2H), 2.01 (t, J ) 11.0 Hz, 2H), 1.50 (d, J ) 11.7 Hz, 2H), 1.40
(m, 1H), 1.18 (dq, J ) 3.7, 12.2 Hz, 2H); APCI MS m/z 320.2
(MH+, 100). Anal. (C21H25N3) C, H, N.
5-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]-1,3-dih ydr oben -
zoim id a zol-2-on e (46a ). 4-[4-(4-Benzylpiperidin-1-yl)but-
1-ynyl]benzene-1,2-diamine15 (38a ) (333 mg, 1 mmol) and
carbonyl diimidazole (CDI) (162 mg, 1 mmol) in THF (5 mL)
were stirred at room temperature for 1 h. More CDI (100 mg)
was added and stirring continued for 1 h. The mixture was
diluted with ether (10 mL), the precipitate filtered off and
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-1H-in d ole-2,3-
d ion e (20a ). A mixture of 4-benzyl-1-(3-butynyl)piperidine15
(10a ) (904 mg, 4 mmol), Pd(PPh3)2Cl2 (41 mg, 0.1 mmol) and
CuI (76 mg, 0.4 mmol) was stirred in Et3N (4 mL) and DMF
(10 mL) and stirred at 25 °C for 30 min. 5-Iodoisatin (13) (546
mg, 2 mmol) was added and the mixture was stirred at 25 °C

3416 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Wright et al.
washed with ether to leave 46a as a white powder (233 mg,
65%): mp 221-223 °C; IR 1757, 1704, 1497, 699 cm-1; 1H NMR
(DMSO-d6) δ 10.68 (s, 1H), 10.60 (s, 1H), 7.21 (t, J ) 7.4 Hz,
2H), 7.08-7.13 (m, 3H), 6.88 (dd, J ) 1.2, 8.0 Hz, 1H), 6.79
(dd, J ) 4.2, 5.6 Hz, 2H), 2.79 (d, J ) 11.5 Hz, 2H), 2.44 (m,
6H), 1.84 (t, J ) 10.6 Hz, 2H), 1.46 (d, J ) 12.7 Hz, 2H), 1.40
(m, 1H), 1.11 (dq, J ) 3.4, 12.0 Hz, 2H); APCI MS m/z 360.6
(MH+, 100); HPLC (70% pH 3 buffer:30% MeCN) 4.35 min
(100%). Anal. (C23H25N3O‚0.10H2O) C, H, N, water.
1.40 (m, 1H), 1.15 (dq, J ) 4.0, 12.0 Hz, 2H); APCI MS m/z
377.2 (MH+, 100). Anal. (C23H25N3O2) C, H, N.
5-{3-[4-(3-F lu or ob en zyl)p ip er id in -1-yl]p r op -1-yn yl}-
1,3-d ih yd r oben zoim id a zol-2-on e (52): mp 210-212 °C; 1H
NMR (DMSO-d6) δ 10.72 (s, 1H), 10.62 (s, 1H), 7.25 (m, 1H),
6.95 (m, 4H), 6.80 (m, 2H), 3.38 (s, 2H), 2.87 (d, J ) 11.7 Hz,
2H), 2.55 (m, 2H), 2.07 (t, J ) 11.7 Hz, 2H), 1.52 (d, J ) 12.9
Hz, 2H), 1.45 (m, 1H), 1.15 (dq, J ) 4.0, 12.0 Hz, 2H); APCI
MS m/z 362.0 (MH+, 100). Anal. (C22H22N3FO) C, H, N, F.
5-[3-(4-Ben zyl-4-h yd r oxyp ip er id in -1-yl)p r op -1-yn yl]-
1,3-d ih yd r oben zoim id a zol-2-on e (53): mp 237-239 °C; IR
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1,3-d ih yd r o-
ben zoim id a zol-2-on e (46b). A mixture of 38b (0.80 g, 2.5
mmol) and CDI (1.0 g, 6 mmol) in THF (60 mL) was stirred at
room temperature for 3 days. After the solvent was removed
in vacuo, the residue was purified by column chromatography
(80 g of silica gel) eluting with 15% 1 N methanolic NH3
1
1715, 1497, 1472, 702 cm-1; H NMR (DMSO-d6) δ 10.72 (s,
1H), 10.63 (s, 1H), 7.10-7.21 (m, 5H), 6.94 (dd, J ) 1.5, 8.1
Hz, 1H), 6.83 (m, 2H), 4.10 (s, 1H), 3.34 (s, 2H), 2.60 (s, 2H),
2.40-2.46 (m, 4H), 1.45 (dt, J ) 4.6, 11.8 Hz, 2H), 1.33 (d,
J ) 12.7 Hz, 2H); APCI MS m/z 362.1 (MH+, 100); HPLC (75%
pH 3 buffer:25% MeCN) 2.48 min (100%). Anal. (C22H23N3O2)
C, H, N, water.
1
in CHCl3 to provide 46b (0.52 g, 61%): mp 212-213 °C; H
NMR (CDCl3) δ 10.05 (br s, 1H), 9.95 (br s, 1H), 7.24 (m, 2H),
7.05-7.15 (m, 5H), 6.83 (d, J ) 7.0 Hz, 1H), 3.43 (s, 2H), 3.05
(d, J ) 11.7 Hz, 2H), 2.50 (d, J ) 6.8 Hz, 2H), 2.05 (t, J ) 11.7
Hz, 2H), 1.65 (d, J ) 12.9 Hz, 2H), 1.45 (m, 1H), 1.11 (dq, J )
4.0, 12.0 Hz, 2H); APCI MS m/z 346.1 (MH+, 100). Anal.
(C22H23N3O) C, H, N.
5-{3-[4-(4-Flu or oben zyl)-4-h ydr oxypip er idin -1-yl]p r op -
1-yn yl}-1,3-d ih yd r oben zoim id a zol-2-on e (54): mp 230-
232 °C; 1H NMR (DMSO-d6) δ 10.72 (s, 1H), 10.60 (s, 1H), 7.15
(m, 2H), 7.05 (t, J ) 8.1 Hz, 2H), 6.95 (d, J ) 8.1 Hz, 1H),
6.81 (m, 2H), 4.10 (s, 1H), 3.38 (s, 2H), 2.60 (s, 2H), 2.42 (m,
4H), 1.45 (t, J ) 11.7 Hz, 2H), 1.30 (d, J ) 12.9 Hz, 2H); APCI
MS m/z 380.0 (MH+, 100). Anal. (C22H22N3FO2‚0.2H2O) C, H,
N, F.
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-2-n itr op h en ol
(56). A mixture of 4-benzyl-1-(3-butynyl)piperidine15 (10a )
(10.63 g, 47 mmol), 5-bromo-2-nitrophenol19 (55) (9.32 g, 43
mmol), Pd(PPh3)2Cl2 (600 mg, 0.85 mmol) and CuI (93 mg,
0.85 mmol) was stirred in Et3N (18 mL) and dichloroethane
(100 mL) and deoxygenated by bubbling N2 through the
mixture for 30 min. The mixture was stirred at reflux for
16 h. The reaction was cooled, concentrated and purified
by MPLC (200 g of silica gel) eluting with CH2Cl2 f 400:8:1
CH2Cl2:EtOH:30% aqueous ammonia to give 56 as a semisolid
(5.85 g): 1H NMR (CDCl3) δ 7.98 (d, J ) 8.8 Hz, 1H), 7.24
(m, 2H), 7.09 (m, 4H), 6.89 (dd, J ) 1.7, 8.8 Hz, 1H), 2.87 (br
d, J ) 11.5 Hz, 2H), 2.61 (m, 4H), 2.49 (d, J ) 7.1 Hz, 2H),
1.96 (dt, J ) 2.4, 11.7 Hz, 2H), 1.64 (d, J ) 12.9 Hz, 2H), 1.49
(m, 1H), 1.29 (dt, J ) 3.7, 12.4 Hz, 2H).
5-[4-(4-Ben zylpiper idin -1-yl)bu t-1-yn yl]-1,3-dih ydr oben -
zoim id a zole-2-th ion e (47a ). A procedure similar to that
above for 46a employing 38a and thiocarbonyldiimidazole gave
47a : mp 245-246 °C; 1H NMR (DMSO-d6) δ 12.50 (br s, 1H),
7.10 (m, 2H), 7.05 (m, 3H), 7.00 (m, 3H), 3.46 (s, 2H), 2.80 (d,
J ) 11.7 Hz, 2H), 2.45 (m, 6H), 1.85 (t, J ) 11.7 Hz, 2H), 1.50
(d, J ) 12.9 Hz, 2H), 1.40 (m, 1H), 1.10 (dq, J ) 4.0, 12.0 Hz,
2H); APCI MS m/z 376.0 (MH+, 100). Anal. (C23H25N3S‚0.4H2O)
C, H, N, S.
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1,3-d ih yd r o-
ben zoim id a zole-2-th ion e (47b). A procedure similar to that
above for 46b employing 38b and thiocarbonyldiimidazole gave
47b: mp 224-225 °C; 1H NMR (DMSO-d6) δ 12.65 (br s, 1H),
12.50 (br s, 1H), 7.25 (m, 2H), 7.15 (m, 3H), 7.05 (m, 3H), 3.40
(s, 2H), 2.85 (d, J ) 11.7 Hz, 2H), 2.45 (m, 2H), 2.05 (t, J )
11.7 Hz, 2H), 1.55 (d, J ) 12.9 Hz, 2H), 1.40 (m, 1H), 1.15 (dq,
J ) 4.0, 12.0 Hz, 2H); APCI MS m/z 360.0 (MH+, 100). Anal.
(C22H23N3S‚0.2H2O) C, H, N, S.
Compounds 48-54 were made using the procedure de-
scribed above for 46b.
5-Br om o-2-n itr op h en yl Eth yl Ca r bon a te (57). A mix-
ture of 5-bromo-2-nitrophenol19 (55) (1.78 g, 8.18 mmol), ethyl
chloroformate (939 µL, 9.82 mmol) and K2CO3 (1.70 g, 12.3
mmol) in MeCN (150 mL) was stirred at room temperature
overnight. The mixture was filtered and evaporated to leave
57 as a yellow solid (2.38 g, 100%): 1H NMR (CDCl3) δ 7.98
(d, J ) 8.8 Hz, 1H), 7.53 (dd, J ) 2.0, 8.8 Hz, 1H), 7.48 (d,
J ) 1.7 Hz, 1H), 4.34 (d, J ) 7.2 Hz, 2H), 1.38 (t, J ) 7.2 Hz,
3H).
5-{3-[4-(4-F lu or ob en zyl)p ip er id in -1-yl]p r op -1-yn yl}-
1,3-d ih yd r oben zoim id a zol-2-on e (48): mp 206-207 °C; 1H
NMR (DMSO-d6) δ 10.72 (s, 1H), 10.62 (s, 1H), 7.25 (m, 2H),
7.15 (t, J ) 8.1 Hz, 2H), 6.95 (dd, J ) 2.2, 8.1 Hz,1H), 6.81
(m, 2H), 3.38 (s, 2H), 2.87 (d, J ) 11.7 Hz, 2H), 2.45 (m, 2H),
2.07 (t, J ) 11.7 Hz, 2H), 1.52 (d, J ) 12.9 Hz, 2H), 1.40 (m,
1H), 1.15 (dq, J ) 4.0, 12.0 Hz, 2H); APCI MS m/z 362.0 (MH+,
100). Anal. (C22H22N3FO‚0.2H2O) C, H, N, F.
5-{3-[4-(4-Ch lor ob en zyl)p ip er id in -1-yl]p r op -1-yn yl}-
1,3-d ih yd r oben zoim id a zol-2-on e (49): mp 225-227 °C; 1H
NMR (DMSO-d6) δ 10.75 (s, 1H), 10.62 (s, 1H), 7.27 (d, J )
8.1 Hz, 2H), 7.13 (d, J ) 8.1 Hz, 2H), 6.93 (dd, J ) 2.2, 7.5 Hz,
1H), 6.83 (m, 2H), 3.38 (s, 2H), 2.87 (d, J ) 11.7 Hz, 2H), 2.45
(m, 2H), 2.05 (t, J ) 11.7 Hz, 2H), 1.52 (d, J ) 12.9 Hz, 2H),
1.40 (m, 1H), 1.15 (dq, J ) 4.0, 12.0 Hz, 2H); APCI MS m/z
378.1 (MH+, 100). Anal. (C22H22ClN3O‚0.4H2O) C, H, N, Cl.
5-{3-[4-(4-Met h ylb en zyl)p ip er id in -1-yl]p r op -1-yn yl}-
1,3-d ih yd r oben zoim id a zol-2-on e (50): mp 234-235 °C; 1H
NMR (DMSO-d6) δ 10.72 (s, 1H), 10.60 (s, 1H), 7.05 (d, J )
8.1 Hz, 2H), 7.00 (d, J ) 8.1 Hz, 2H), 6.93 (dd, J ) 2.2, 7.5 Hz,
1H), 6.83 (m, 2H), 3.38 (s, 2H), 2.77 (d, J ) 11.7 Hz, 2H), 2.40
(d, J ) 7.0 Hz, 2H), 2.20 (s, 3H), 2.05 (t, J ) 11.7 Hz, 2H),
1.52 (d, J ) 12.9 Hz, 2H), 1.40 (m, 1H), 1.15 (dq, J ) 4.0, 12.0
Hz, 2H); APCI MS m/z 358.2 (MH+, 100). Anal. (C23H25N3O‚
0.15H2O) C, H, N.
5-{3-[4-(4-Meth oxyben zyl)p ip er id in -1-yl]p r op -1-yn yl}-
1,3-d ih yd r oben zoim id a zol-2-on e (51): mp 227-229 °C; 1H
NMR (DMSO-d6) δ 10.77 (s, 1H), 10.62 (s, 1H), 7.05 (d, J )
8.1 Hz, 2H), 7.00 (d, J ) 8.1 Hz, 2H), 6.95 (d, J ) 7.5, 1H),
6.83 (m, 2H), 6.72 (d, J ) 8.1 Hz, 2H), 3.65 (s, 3H) 3.38 (s,
2H), 2.77 (d, J ) 11.7 Hz, 2H), 2.40 (d, J ) 7.0 Hz, 2H), 2.20
(s, 3H), 2.05 (t, J ) 11.7 Hz, 2H), 1.52 (d, J ) 12.9 Hz, 2H),
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-2-n itr op h en yl
Eth yl Ca r bon a te (58a ). A mixture of 56 (547 mg, 1.5 mmol),
ethyl chloroformate (0.22 mL, 1.8 mmol) and K2CO3 (228 mg,
1.65 mmol) was stirred at 25 °C in MeCN (100 mL) for 1.5 h.
The reaction was quenched with water (100 mL) and concen-
trated to ∼100 mL. The aqueous was extracted with EtOAc
to give crude solid (768 mg). This solid was purified by MPLC
(90-g silica gel cartridge) loading in toluene and eluting with
25% EtOAc:hexanes to give 58a as a yellow solid (305 mg,
47%): 1H NMR (CDCl3) δ 8.02 (d, J ) 8.6 Hz, 1H), 7.33 (d,
J ) 8.5 Hz, 1H), 7.25 (m, 3H), 7.16-7.09 (m, 3H), 4.33 (q, J )
7.1 Hz, 2H) 2.89 (br d, J ) 11.5 Hz, 2H), 2.60 (m, 3H), 2.51 (d,
J ) 7.1 Hz, 2H), 1.96 (t, J ) 11.7 Hz, 2H), 1.63 (br d, J ) 13.7
Hz, 2H) 1.52 (m, 3H), 1.37 (t, J ) 7.1 Hz, 2H), 1.29 (dq, J )
3.2, 12.0 Hz, 2H).
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-2-n itr op h en -
yl Eth yl Ca r bon a te (58b). A mixture of 57 (1.28 g, 4.4 mmol),
4-benzyl-1-(2-propynyl)piperidine15 (10b) (852 mg, 4 mmol),
CuI (15.2 mg, 0.08 mmol) and Et3N (1.7 mL, 12 mmol) in
CH2Cl2 (25 mL) was deoxygenated by bubbling N2 though
for 15 min. Pd(PPh3)2Cl2 (56 mg, 0.08 mmol) was added and
the mixture stirred at reflux under N2 overnight. The sol-
vents were evaporated and the residue purified by MPLC
(90-g silica gel cartridge) eluting with CH2Cl2 f 100:8:1

Subtype-Selective NMDA Receptor Antagonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18 3417
1
CH2Cl2:EtOH:30% aqueous ammonia to give 58b as a brown
oil (1.44 g, 85%): 1H NMR (CDCl3) δ 8.03 (d, J ) 8.5 Hz, 1H),
7.37 (dd, J ) 1.7, 8.5 Hz, 1H), 7.30 (d, J ) 1.7 Hz, 1H), 7.22-
7.27 (m, 2H), 7.09-7.19 (m, 3H), 4.33 (d, J ) 7.2 Hz, 2H), 3.50
(s, 2H), 2.91 (d, J ) 11.5 Hz, 2H), 2.51 (d, J ) 7.1 Hz, 2H),
2.17 (t, J ) 10.7 Hz, 2H), 1.67 (d J ) 12.0 Hz, 2H), 1.51 (m,
1H), 1.33-1.39 (m, 5H including 1.37 (t, J ) 7.1 Hz, 3H)).
5-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-2-a m in op h en -
yl Eth yl Ca r bon a te (59a ). Reduction of 58a (300 mg, 0.7
mmol) as described for 38b followed by MPLC (80 g of silica
gel) eluting with CH2Cl2 f 400:8:1 CH2Cl2:EtOH:30% aqueous
ammonia to give 59a as an off-white solid (152 mg, 53%): 1H
NMR (CDCl3) δ 7.43 (d, J ) 8.1 Hz, 1H), 7.25 (m, 1H), 7.18-
7.09 (m, 3H), 6.97 (s, 1H), 6.86 (dd, J ) 1.7, 8.3 Hz, 1H), 6.80
(s, 1H), 4.22 (q, J ) 7.3 Hz, 2H), 3.69 (q, J ) 6.8 Hz, 1H), 2.98
(br d, J ) 12.0 Hz, 2H), 2.67 (t, J ) 7.6 Hz, 3H), 2.55 (t, J )
7.3 Hz, 2H), 2.50 (d, J ) 7.1 Hz, 2H), 2.01 (t, J ) 11.9 Hz,
2H), 1.62 (br d, J ) 13.7 Hz, 2H) 1.50 (m, 3H), 1.32 (m, 2H),
1.20 (t, J ) 7.1 Hz, 2H).
6-[4-(4-Ben zylp ip er id in -1-yl)b u t -1-yn yl]-3H -b en zoox-
a zol-2-on e (60a ). A mixture of 59a (135 mg, 0.3 mmol) and
K2CO3 (135 mg, 1.0 mmol) in MeCN (100 mL) was stirred at
reflux. After 3 h, the reaction was cooled and filtered. The
filtrate was concentrated and purified by MPLC (40-g silica
gel cartridge) eluting with CH2Cl2 f 400:8:1 CH2Cl2:EtOH:30%
aqueous ammonia to give 60a as an off-white solid (98 mg,
90%): mp 135.1-135.5 °C; IR 2924, 2847, 1771, 1498, 1261,
702 cm-1; 1H NMR (CDCl3) δ 7.24 (m, 2H), 7.15-7.07 (m, 4H),
7.01 (d, J ) 8.1 Hz, 1H), 6.79 (d, J ) 8.1 Hz, 1H), 3.00 (d, J )
11.7 Hz, 2H), 2.63 (t, J ) 6.8 Hz, 2H), 2.55 (t, J ) 6.6 Hz, 2H),
2.50 (d, J ) 7.1 Hz, 2H), 1.97 (t, J ) 12.4 Hz, 2H), 1.66 (broad
d, J ) 12.7 Hz, 2H) 1.52 (m, 1H), 1.31 (dt, J ) 3.1, 12.7 Hz,
2H); APCI MS m/z 361.0 (MH+, 100). Anal. (C23H24N2O2‚
0.15H2O) C, H, N, water.
cm-1; H NMR (CDCl3) δ 8.00 (s, 1H), 7.25 (m, 2H), 7.14 (m,
3H) 6.93 (d, J ) 6.6 Hz, 2H), 6.65 (d, J ) 8.6 Hz, 1H), 4.56 (s,
2H), 2.90 (d, J ) 11.5 Hz, 2H), 2.62-2.48 (m, 6H), 1.95 (t, J )
11.8 Hz, 2H), 1.62 (br d, J ) 12.7 Hz, 2H), 1.48 (m, 1H), 1.28
(dq, J ) 2.9, 12.2 Hz, 2H); APCI MS m/z 375.2 (MH+, 100).
Anal. (C24H26N2O2) C, H, N.
5-Br om o-N-m eth yl-2-n itr oa n ilin e (64). A solution of 1,3-
dibromo-4-nitrobenzene (1.5 g, 5.34 mmol) and 40% aqueous
MeNH2 (40 mL) in EtOH (40 mL) was heated to reflux for
2 h. The reaction mixture was allowed to sit 18 h and the
resulting shiny yellow plates were collected by filtration to
give 64 (0.93 g, 75%): mp 115-116 °C; 1H NMR (CDCl3) δ
8.05 (s, 1H), 8.0 (d, J ) 7.5 Hz, 1H), 6.95 (s, 1H), 6.7 (dd, J )
2.2, 7.5 Hz, 1H) 3.0 (d, J ) 2.2 Hz, 3H); APCI MS m/z 231.0
(MH+, 100).
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-N-m eth yl-2-
n itr oa n ilin e (65). A mixture of 64 (0.93 g, 4.03 mmol),
4-benzyl-1-(2-propynyl)piperidine15 (10b) (0.87 g, 4.1 mmol),
CuI (0.154 g, 0.81 mmol), Pd(PPh3)2Cl2 (0.082 g, 0.12 mmol),
Et3N (5 g, 5 mmol) and DMF (15 mL) was stirred under N2
for 18 h at 50 °C. The solvents were removed in vacuo and the
residue was purified by MPLC (80 g of silica gel) eluting with
EtOAc to provide 65 as dark red crystals (0.85 g, 58%): mp
102-105 °C; 1H NMR (CDCl3) δ 8.05 (d, J ) 7.5 Hz, 1H), 7.92
(s, 1H), 7.22 (m, 2H), 7.10 (m, 1H), 7.05 (m, 2H), 6.82 (s, 1H),
6.58 (d, J ) 7.5 Hz, 1H), 3.42 (s, 2H), 2.95 (d, J ) 2.2 Hz, 3H),
2.9 (d, J ) 11.7 Hz, 2H), 2.5 (d, J ) 7.5 Hz, 2H), 2.12 (t, J )
12.9 Hz, 2H), 1.65 (d, J ) 12.9 Hz, 2H), 2.12 (t, J ) 12.0 Hz,
2H), 1.62 (d, J ) 12.0 Hz, 2H), 1.45 (m, 1H), 1.30 (dq, J ) 2.2,
12.0 Hz, 2H).
6-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1-m eth ylben -
zen e-1,2-d ia m in e (66). Compound 65 (0.8 g, 2.2 mmol) was
reduced as described for 38b followed by MPLC (80 g of silica
gel) eluting with 10:1 CHCl3:1 N NH3/MeOH and the homo-
geneous fractions concentrated to provide 66 (0.4 g, 50%),
which was used immediately without any characterization due
to its instability.
6-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-3H-ben zoox-
a zol-2-on e (60b). Compound 58b (1.44 g, 3.4 mmol) was re-
duced as described for 38b and purified by MPLC (90-g silica
gel cartridge) eluting with CH2Cl2 f 100:8:1 CH2Cl2:EtOH:30%
aqueous ammonia to give a mixture of 59b, 60b and amino-
phenol as a beige solid (853 mg). This solid was stirred in
MeCN (200 mL) with K2CO3 (1 g) at reflux for 1 h. The mixture
was filtered and carbonyl diimidazole (1 g) added. After
stirring at room temperature for 1 h, the solvent was evapo-
rated. The residue was triturated with EtOH/ether to give a
beige solid (565 mg). The solid was dissolved in EtOH (50 mL)
and oxalic acid‚2H2O (206 mg) in EtOH (2 mL) added. The
oxalate salt precipitated on standing in the freezer; it was
collected, washed with EtOH and dried at 50 °C under high
vacuum to give 60b as a beige powder (507 mg, 27% from
58b): mp 191-192 °C; IR 1768, 1604, 1497, 1451, 1280, 923,
6-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1-m eth yl-1,3-
d ih yd r oben zoim id a zol-2-on e (67). A mixture of 66 (0.2 g,
0.58 mmol) and carbonyldiimidazole (0.4 g, 2.47 mmol) was
stirred at room temperature in THF (50 mL) for 18 h. The
concentrated reaction mixture was purified MPLC (80 g of
silica gel) eluting with 25:1 CHCl3:2 N NH3/MeOH. After the
homogeneous fractions were combined and concentrated, the
resulting residue was triturated with ether to provide 67 (0.1
g, 48%): mp 196-198 °C; 1H NMR (CDCl3) δ 8.60 (s, 1H), 7.25
(m, 2H), 7.15 (m, 4H), 6.98 (s, 1H), 6.92 (d, J ) 7.5 Hz, 1H),
3.45 (s, 2H), 3.38 (s, 3H), 2.92 (d, J ) 11.7 Hz, 2H), 2.52 (d,
J ) 7 Hz, 2H), 2.15 (t, J ) 11.7 Hz, 2H), 1.65 (d, J ) 12.9 Hz,
2H), 1.50 (m, 1H), 1.15 (dq, J ) 4.0, 12.0 Hz, 2H); APCI MS
m/z 360.2 (MH+, 100). Anal. (C23H25N3O‚0.3H2O) C, H, N.
1
756, 701 cm-1; H NMR (DMSO-d6) δ 7.34 (s, 1H), 7.18-7.24
(m, 3H), 7.11-7.14 (m, 3H), 7.03 (d, J ) 8.1 Hz, 1H), 3.68 (s,
2H), 3.01 (d, J ) 11.0 Hz, 2H), 2.46 (m, 2H), 2.37 (t, J ) 11.2
Hz, 2H), 1.59 (d, J ) 12.7 Hz, 2H), 1.53 (m, 1H), 1.25 (q, J )
12.0 Hz, 2H); APCI MS m/z 347.2 (MH+, 100); HPLC (60%
0.1% aq TFA:40% MeCN) 3.53 min (96.66%). Anal. (C22H22N2O2‚
2.25C2H2O4‚0.25H2O) C, H, N, water.
N-(4-Br om o-2-n itr op h en yl)-N-m eth yl Meth yl Ca r ba m -
a te (68). To a solution of 4-bromo-2-nitroaniline (3 g, 13.8
mmol) and methyl chloroformate (6.48 g, 69 mmol) in THF
(100 mL) was added sodium hydride (60%, 0.69 g, 17.27 mmol)
and the mixture was heated to reflux for 18 h. The cooled
reaction mixture was poured over cold saturated NH4Cl (100
mL) and extracted with EtOAc (300 mL). A TLC of the organic
layer indicated 2:1 of product:starting material. The organic
layer was concentrated and the residue purified by MPLC (200
g of silica gel) eluting with 3:1 hexanes:EtOAc and trituration
with ether provided the carbamate (1.8 g, 47%): mp 105-107
7-Tr iflu or om eth ylsu lfon yloxy-4H-ben zo[1,4]oxa zin -3-
on e (62). A mixture of 6-hydroxy-2H-1,4-benzoxazin-3(4H)-
one20 (61) (500 mg, 3.3 mmol), N-phenyltrifluoromethane
sulfonimide (2.59 g, 7.26 mmol) and Et3N (0.45 mL, 7.26 mmol)
was stirred at 25 °C in THF (10 mL) for 16 h. The reaction
was concentrated and crude mixture purified by MPLC (200
g of silica gel) eluting with 1% MeOH:CH2Cl2 to give 62 as an
off-white solid (581 mg, 60%): 1H NMR (CDCl3) δ 9.16 (br s,
1H), 7.22 (s, 1H), 6.88 (m, 2H), 4.63 (s, 2H).
7-[4-(4-Ben zylp ip er id in -1-yl)bu t-1-yn yl]-4H-ben zo[1,4]-
oxa zin -3-on e (63). Coupling of 4-benzyl-1-(3-butynyl)piperi-
dine15 (10a ) (678 mg, 3 mmol) and triflate 62 (446 mg, 1.5
mmol) as described for 16a followed by MPLC (80 g of silica
gel) eluting with CH2Cl2 f 400:8:1 CH2Cl2:EtOH:30% aqueous
ammonia gave an off-white solid (186 mg). This solid was
recrystallized from MeCN to give 63 as white needles (125 mg,
20%): mp 201-202 °C; IR 3170, 3027, 2913, 1693, 1521, 696
1
°C; H NMR (CDCl3) δ 9.75 (s, 1H), 8.45 (d, J ) 7.5 Hz, 1H),
8.25 (d, J ) 2.2 Hz, 1H), 7.65 (dd, J ) 2.2, 7.5 Hz, 1H) 3.90 (s,
3H). A solution of the carbamate (1.7 g, 6.2 mmol) in DMF
(20 mL) was treated with MeI (1.93 mL, 31 mmol) followed by
NaH (0.37 g, 60%, 9.25 mmol) and stirred at RT for 18 h. The
mixture was cooled to 0 °C and treated with saturated NH4Cl
(20 mL) and ether (200 mL). The organic layer was back-
washed with saturated aq. NaCl, dried over MgSO4 and
concentrated to an oil. Trituration with hexane provided 68
(1.53 g, 85%): 1H NMR (CDCl3) δ 8.06 (d, J ) 2.2 Hz, 1H),

3418 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 18
Wright et al.
7.65 (dd, J ) 2.2, 7.5 Hz, 1H), 7.20 (d, J ) 7.5 Hz, 1H), 3.55
and 3.75 (2s, rotamers, 3H), 3.23 (s, 3H); APCI MS m/z 289.0
(MH+, 100).
aliquots (1% DMSO final) to 96-well, 1.0-mL volume assay
plates and incubated in a total volume of 500 µL for 60 min at
room temperature as described below. Assays were terminated
by filtration through GF/B filter plates (Packard, Meriden, CT)
and the filter plates were rinsed three times with ∼0.8 mL of
assay buffer/well. Microscint-20 scintillation cocktail (50 µL/
well; Packard) was added to the dried filter plates, which were
then counted on a TopCount (Packard) scintillation counter
for 8 min/well. IC50 values were determined by fitting the
data to the sigmoidal equation using Prism (GraphPad, San
Diego, CA).
N-{4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-2-n it r o-
p h en yl}-N-m eth yl Meth yl Ca r ba m a te (69). Coupling of 68
(1.53 g, 5.29 mmol) and 4-benzyl-1-(2-propynyl)piperidine15
(10b) (1.28 g, 6 mmol) as described for 16a followed by MPLC
(200 g of silica gel) eluting with 5% 1 N NH3/MeOH in CHCl3
gave 1.2 g of material that was a 50:50 mixture of the desired
69 and the deformylated methylamine. A small amount of the
mixture was purified to give pure 69: 1H NMR (CDCl3) δ 7.91
(d, J ) 2.2 Hz, 1H), 7.55 (dd, J ) 2.2, 7.5 Hz, 1H), 7.20 (m,
3H), 7.12 (d, J ) 7.5 Hz, 1H), 7.07 (d, J ) 7.5 Hz, 2H), 3.57
and 3.72 (2s, rotamers, 3H), 3.23 (s, 3H), 2.86 (d, J ) 11.7 Hz,
2H), 2.46 (d, J ) 7.0 Hz, 2H), 2.12 (t, J ) 11.7 Hz, 2H), 1.65
(d, J ) 12.9 Hz, 2H), 1.47 (m, 1H), 1.25 (dq, J ) 2.0, 12.0 Hz,
2H).
N-{4-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-2-n it r o-
p h en yl}-N-m eth yl Meth yl Ca r ba m a te (70). Crude 69 was
reduced as described for 38b followed by MPLC (200 g of silica
gel) eluting with 5% 2 N NH3/MeOH in CHCl3 to give 70 as a
gum (0.75 g): 1H NMR (CDCl3) δ 7.22 (m, 2H), 7.15 (d, J )
7.5 Hz, 1H), 7.08 (m, 2H), 6.90 (d, J ) 7.5 Hz, 1H), 6.75 (m,
2H), 3.60 (br s, 2H), 3.43 (s, 3H), 3.12 (s, 3H), 2.86 (d, J )
11.7 Hz, 2H), 2.50 (d, J ) 7.0 Hz, 2H), 2.15 (t, J ) 11.7 Hz,
2H), 1.65 (d, J ) 12.9 Hz, 2H), 1.47 (m, 1H), 1.30 (dq, J ) 2.0,
12.0 Hz, 2H); APCI MS m/z 392.2 (MH+, 100).
3. r-1 Ad r en er gic Recep tor Bin d in g. The [3H]prazosin
binding assay was modified from previously described meth-
ods.23 Frozen Sprague-Dawley rat cortices obtained from ABS
(Wilmington, DE) were thawed, homogenized in 10 volumes
of ice-cold 0.25 M sucrose/10 mM Tris-HCl, pH 7.4 buffer, and
centrifuged at 1000g for 10 min at 4 °C. The supernatant was
centrifuged at 40000g for 30 min, the pellet was resuspended
in 10 volumes of ice-cold 140 mM NaCl/5 mM MgCl2/50 mM
Tris-HCl, pH 7.4 buffer (prazosin binding buffer), and centri-
fuged at 40000g for 30 min. The pellet was resuspended in
prazosin binding buffer, centrifuged twice more for a total of
three wash steps, and the final pellet was stored at -80 °C.
On the day of the binding assay, the membrane pellets were
thawed, resuspended in prazosin binding buffer, and 200 µg
of membrane protein was incubated with 0.8 nM [3H]prazosin
(∼ 80 Ci/mmol; NEN, Boston, MA). Nonspecific binding was
determined in the presence of 10 µM phentolamine.
5-[3-(4-Ben zylp ip er id in -1-yl)p r op -1-yn yl]-1-m eth yl-1,3-
d ih yd r oben zoim id a zol-2-on e (71). A mixture of 70 (0.6 g,
1.5 mmol) and NaH (0.2 g, 5 mmol) in THF (50 mL) was heated
under reflux for 18 h, cooled, quenched with saturated NH4Cl
(20 mL) and partitioned between water and EtOAc. The dried
(K2CO3) layer was concentrated to an oil and purified by MPLC
(80 g of silica gel) eluting with 3% 2 N NH3/MeOH. The
homogeneous fractions were combined, concentrated, and the
resulting solid triturated with ether to provide 71 (0.15 g,
4. D2 Dop a m in er gic R ecep t or Bin d in g. The [3H]-
raclopride binding assay was modified from previously de-
scribed methods.24 Frozen Sprague-Dawley rat striata ob-
tained from ABS (Wilmington, DE) were thawed, homogenized
in ice-cold 50 mM Tris-HCl, pH 7.4 buffer (8-9 pairs of striata/
10 mL), and centrifuged at 20000g for 10 min at 4 °C. The
pellet was resuspended in 10 mL of ice-cold 50 mM Tris-HCl,
pH 7.4 buffer, and centrifuged at 20000g for 10 min. The pellet
was resuspended in 120 mM NaCl/5 mM KCl/50 mM Tris-
HCl, pH 7.4 buffer (raclopride binding buffer) (1 mL/pair of
striata) and was stored at -80 °C. On the day of the binding
assay, the membrane suspensions were thawed, diluted in
raclopride binding buffer, and 200 µg of membrane protein was
incubated with 3 nM [3H]raclopride (∼ 80 Ci/mmol; NEN).
Nonspecific binding was determined in the presence of 300 µM
sulpiride.
1
28%): mp 154-156 °C; H NMR (CDCl3) δ 9.35 (s, 1H), 7.22
(m, 3H), 7.18 (m, 4H), 6.85 (d, J ) 7.5 Hz, 1H), 3.35 (s, 3H),
2.95 (d, J ) 11.7 Hz, 2H), 2.50 (d, J ) 7.0 Hz, 2H), 2.15 (t, J )
11.7 Hz, 2H), 1.65 (d, J ) 12.9 Hz, 2H), 1.47 (m, 1H), 1.30 (dq,
J ) 2.0, 12.0 Hz, 2H); APCI MS m/z 360.2 (MH+, 100). Anal.
(C23H25N3O‚0.2H2O) C, H, N.
P h a r m a cologica l Meth od s. 1. Electr op h ysiology. Oo-
cytes were obtained from mature female Xenopus laevis and
were prepared and maintained as described previously.26
Individual oocytes were microinjected with a mixture of NMDA
receptor-encoding cRNAs, provided by Dr. P. H. Seeburg
(Heidelberg University, Heidelberg, Germany).27 NR1A and
NR2A were injected at a 1:4 ratio; all other binary subunit
combinations were injected 1:1 (1-10 ng of each subunit).
Oocytes were stored in Barth’s medium containing (in mM):
NaCl, 88; KCl, 1; CaCl2, 0.41; Ca(NO3)2, 0.33; MgSO4, 0.82;
NaHCO3, 2.4; HEPES 5; pH 7.4, with 0.1 mg/mL gentamycin
sulfate. Standard two electrode voltage-clamp recordings were
made at -70 mV in nominally Ca2+-free Ringer (in mM):
NaCl, 115; KCl, 2; BaCl2, 1.8; Hepes, 5; pH 7.4.22 All drugs
were diluted in Ringer, and applied via bath perfusion (7-10
mL/min) in a conventional flow-through chamber (volume ∼0.2
mL). Test drugs were initially dissolved in DMSO, and diluted
into Ringer just prior to application (final [DMSO] ) 0.1-1%).
IC50 values were obtained by fitting partial (3-5 point)
concentration-inhibition curves to the following equation
using Origin (Microcal):
5. 6-H yd r oxyd op a m in e-Lesion ed R a t .25 Adult male
Sprague-Dawley rats were anesthetized with chloral hydrate,
and unilateral lesions of the nigrostriatal dopamine system
were accomplished by infusion of 8 µg of 6-hydroxydopamine
HBr (6-OHDA) into the right medial forebrain bundle. Rats
were pretreated 30 min before surgery with desipramine HCl
25 mg/kg ip to protect noradrenergic neurons and pargyline
25 mg/kg ip to potentiate the effects of 6-OHDA. A minimum
of 3 weeks after surgery, the rotational behavior induced by
apomorphine HCl 50 µg/kg sc was assessed. Only rats dem-
onstrating more than 100 contraversive turns/h to apomor-
phine were used for the present experiments. Rotational
behavior was measured using an automated rotometer system
(Rotorat Rotational Activity System, MED Associates, Georgia,
VT). Anti-parkinsonian activity was assessed as the ability of
the compound to potentiate the contraversive rotation induced
by L-DOPA methyl ester, 10 mg/kg sc, over a 3-h period.
Experiments were conducted using a crossover paradigm
where each rat received either a vehicle plus L-DOPA or the
test compound plus L-DOPA, in randomized order. Rats were
tested at 7-day intervals. In experiments in which the com-
pound was tested orally, rats were food-deprived for 16 h.
Statistical analysis between treatment groups was performed
using a paired t-test.
I/Icontrol ) {(1 - min)/{1 + ([antagonist]/IC50)n}} + min
where Icontrol is the current in the absence of antagonist, min
(minimum) is the residual fractional response at saturating
concentration of antagonist, and IC50 is the concentration of
drug that causes one-half this level of inhibition. To fit the
curves for NR1A/2B, ′min′ was fixed at 0.15.28 Data in the text
are mean ( standard error (SE).
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