(E)-3-(2-(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid derivatives. A novel class of glycine site antagonists

Article abstract of DOI:10.1021/jm970416w

The synthesis and preliminary biological evaluation of novel (E)-3-(2- (N-phenylcarbamoyl)-vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at the 4- and 5-positions of the pyrrole ring are reported. These compou

Full text of DOI:10.1021/jm970416w

808
J . Med. Chem. 1998, 41, 808-820
(E)-3-(2-(N-P h en ylca r ba m oyl)vin yl)p yr r ole-2-ca r boxylic Acid Der iva tives.
A Novel Cla ss of Glycin e Site An ta gon ists
Cesarino Balsamini, Annalida Bedini, Giuseppe Diamantini, Gilberto Spadoni, Andrea Tontini, and
Giorgio Tarzia*
Istituto di Chimica Farmaceutica e Tossicologica, Universita` degli Studi di Urbino, Piazza Rinascimento,
6-61029 Urbino, Italy
Romano Di Fabio, Aldo Feriani, Angelo Reggiani, Giovanna Tedesco, and Roberta Valigi
GlaxoWellcome S.p.A., Via Fleming, 4-37100 Verona, Italy
Received J une 24, 1997
The synthesis and preliminary biological evaluation of novel (E)-3-(2-(N-phenylcarbamoyl)-
vinyl)pyrrole-2-carboxylic acids bearing alkyl, acyl, alkoxy, phenyl, and halo substituents at
the 4- and 5-positions of the pyrrole ring are reported. These compounds were studied for
their in vitro affinity at the strychnine-insensitive glycine-binding site of the N-methyl-D-
aspartate (NMDA) receptor complex. In the [3H]glycine binding assay (E)-4,5-dibromo-3-(2-
(N-phenylcarbamoyl)vinyl)pyrrole-2-carboxylic acid 6w (pKi ) 7.95 ( 0.01) and the 4-bromo-
5-methyl 6j (pKi ) 7.24 ( 0.01) and 4,5-dimethyl 6g (pKi ) 6.70 ( 0.03) analogues were the
most active compounds of the series. Qualitative structure-activity analysis points to a
negative correlation between bulk of the C-4 and C-5 substituents and affinity which is enhanced
by halo-substituents. QSAR analysis by the Hansch descriptors F, R, π, and MR, on a subset
of compounds with pKi g 4, indicates that electron-withdrawing groups at C-4 and C-5 enhance
the affinity. Bulk and lipophilicity are also relevant for the substituents at these positions.
6g was found to be a full antagonist (R ) 0; enhancement of the [3H]TCP binding). The in
vivo potency of 6g, 6j, and 6w was evaluated by the inhibition of NMDA-induced convulsions
in mice by both the iv and po routes; 6w was the most active compound (ED50 ) 3 × 10-3
(0.8-10) g/kg, iv and 30 × 10-3 (4.5-61) g/kg, po). The results of this study indicate that the
3,4-disubstitutedpyrrole-2-carboxylate represents a novel template for the design of new glycine
antagonists.
In tr od u ction
1f15 and benzazepine-2,5-dione 1g16 are the most rep-
resentative glycine antagonists (Figure 1), and a num-
ber of highly potent and selective molecules have been
found within these series. These leads can be fitted by
a model pharmacophore,9a which features (a) a 1-NH
hydrogen-bond donor, (b) an acidic group alpha to the
NH, (c) a size-limited hydrophobic binding site occupied
by a halo-substituted benzo-fused ring, and (d) a hy-
drogen bond acceptor flanked by a lipophilic group.
The rather limited structural variation of the leads
from which the model was derived led us to the conclu-
sion that it had been insufficiently tested with regard
to the disubstituted benzo group as an essential require-
ment for binding. In fact whereas it is unquestionable
that the hydrophobic binding site is limited in size, it
is not quite clear whether smaller compounds devoid of
the substituted benzo ring cannot be equally effective
ligands. To test our hypothesis, we decided to synthe-
size a series of pyrrole-2-carboxylic acids substituted in
the 3-position with the same 2-(N-phenylcarbamoyl)-
vinyl side chain of GV150526 A (1h ),17,18 which was
taken as our reference compound. Figure 29f shows the
fitting of one of these compounds (6w ) to the accepted
model.
The ionotropic N-methyl-D-aspartate (NMDA) glutama-
tergic receptor plays a pivotal role in the neurotoxic
cascade following cerebral ischaemia and hypoxic events.
Overstimulation of postsynaptic NMDA receptors by
excessive release of endogenous L-glutamate can cause
abnormal influx of Ca2+ into the postsynaptic neurons,
provoking cell death.1 This overstimulation has been
associated with many ischaemia- and hypoxia-related
disorders such as stroke, hypoglycemia, and traumatic
head and spinal cord injuries2,3 and may be involved in
some neurodegenerative diseases of the CNS, including
Huntington’s chorea and Alzheimer’s dementia.4-7 Sev-
eral binding sites have been identified on NMDA
receptor complex, and among them the allosteric strych-
nine-insensitive glycine binding site is particularly
important for its coupling to the receptor activation.8
Therefore, during the past decade, glycine antagonists
have been actively sought for their therapeutic potential
in the treatment of CNS diseases such as stroke, head
injuries, epilepsy and schizophrenia.9 Structural ex-
amination of different series of glycine antagonists
revealed that benzo-fused heterocycles such as kynurenic
acid 1a ,10 2-carboxytetrahydroquinolines 1b11,12 and
1c,11 indole-2-carboxylic acid 1e,13 2-quinolones 1d 14 and
This work was already well under way when a paper
was published by the Merck group in which some
tetramic acids were reported to be glycine antagonists,19
lending independent support to our hypothesis.
* To whom correspondence should be addressed. Tel: +39-722-2545;
+39-722-328274.
chim.uniurb.it.
Fax:
+39-722-2737.
E-mail:
chimfarm@
S0022-2623(97)00416-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/14/1998

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 809
bromination with N-bromosuccinimide (NBS) of 5-phen-
yl-2-(carboxymethyl)pyrrole.28 C-4 Friedel-Crafts acyl-
ation of 5-methyl-2-(carboxymethyl)pyrrole with chlo-
roacetyl chloride/AlCl3 gave the 3-chloroacetyl derivative
which was converted to 2n and 2o by Baeyer-Villiger
oxidation (m-chloroperbenzoic acid, NaHPO4) followed
by O-alkylation in the presence of NaH, with iodoethane
or benzyl bromide, respectively. The N-methyl aldehyde
4u was prepared by N-methylation (K2CO3/CH3I) of 4g.
Aldehyde 4r was prepared by Vilsmeyer formylation of
3-cyano-5-methylpyrrole29 to give 3-cyano-2-formyl-5-
methylpyrrole 7, which was transformed to ester 3r via
oxidation (AgNO3/1N NaOH) to the corresponding acid
and treatment with CH2N2. Bromo aldehydes 4v,w
were prepared by bromination of 4q20 with 1 or 2 equiv
of NBS, respectively. Bromination with NBS of the
corresponding 4- or 5-unsubstituted pyrroles gave 4-bro-
mo-5-phenyl-2-(carboxymethyl)pyrrole and 5-bromo-4-
phenyl-2-(carboxyethyl)pyrrole, which were then C-3
formylated by the Vilsmeyer procedure. Aldehydes 4t
and 4s were prepared by reductive debromination (H2/
Pd-C 10%) of the corresponding 5- and 4-bromo alde-
hydes.
b. P h a r m a cology. Evaluation of the compounds
was performed by assessing (a) affinity for the glycine
site (all compounds), (b) selectivity for glutamate recep-
tors and in vitro functional antagonism for a restricted
number of compounds selected on the basis of their pKi
values, and (c) in vivo anticonvulsant activity for the
selective full antagonists emerging from b.
Affinity for the glycine binding site associated with
the NMDA receptor channel complex was measured by
inhibition of the binding of [3H]glycine to crude synaptic
membranes prepared from adult rat cerebral cortex
(Experimental Section and Table 1). The selectivity of
some selected test compounds toward the glutamate
binding site of the NMDA receptor channel complex,
AMPA, and kainate ionotropic glutamate receptors was
evaluated by the inhibition of the binding of [3H]CPP
([3-[(()-2-carboxypiperazin-4-yl]propyl]phosphonic acid),
[3H]AMPA ((S,R)-R-amino-3-hydroxy-5-methyl-4-isoxaz-
olepropionic acid), and [3H]kainic acid ([ (2S)-(2R,3â,4â)]-
2-carboxy-4-(1-methylethenyl)-3-pyrrolidineacetic acid)
to rat cortical membranes (Experimental Section and
Table 2).
F igu r e 1. A selected sample of glycine antagonists (IC50).
Resu lts
a . Ch em istr y. Gly antagonists 6a -z were synthe-
sized as outlined in Scheme 1. The key intermediate
aldehydes 4a -w were prepared by C-3 Vilsmeyer
formylation of 2a -p , by diisobutylaluminum hydride
(DIBAL-H) reduction of 3q,r , as described for 4q,20 or
by modification of the aldehydes 4g, 4p , and 4q. Wittig
olefination of 4a -w , using commercially available
triphenyl((N-phenylcarbamoyl)methyl)phosphonium bro-
mide or tri-tert-butyl((N-phenylcarbamoyl)methyl)phos-
phonium bromide, gave the carbamoylvinyl derivatives
5a -w . The iodinated pyrroles 5y and 5x were obtained
respectively by iodination of 5r and 5q with 1 or 2 equiv
of N-iodosuccinimide (NIS). Compound 5z was obtained
by Friedel-Crafts acylation (Ac2O/SnCl2‚2H2O) of 5r .
Hydrolysis (LiOH, aqueous methanol, reflux) of 5a -z
gave the acids 6a -z. Pyrroles 2a -d ,21,22 2h , 2i,23 4g,24
and 3q26 were prepared according to published proce-
dures. The positional isomers 2e and 2f were prepared
according to the literature method previously described
for the ethyl ester of 2e.25 Pyrroles 2j,k were prepared
by halogenation of 5-methyl-2-carbomethoxypyrrole27
with N-halosuccinimides. The 4-methyl-5-isopropyl 2l
and the 4-isopropyl-5-methyl 2m derivatives were pre-
pared by means of Friedel-Crafts alkylation (AlCl3/
iPrCl/CS2/50 °C) of the corresponding 4- or 5-methyl
intermediates. 4-Bromo derivative 2p was obtained by
Functional antagonism at the glycine binding site was
demonstrated by the ability of the test compounds to
antagonize the glycine-induced enhancement in the
binding of the channel blocking agent [3H]TCP30 (N-[1-
(2-thienyl)cyclohexyl]piperidine) (Experimental Section
and Table 2). Three compounds (i.e. 6g,j,w ), selected
on the basis of their pKi values, were evaluated in vivo,
both by iv and po, by assessing their anticonvulsant
effect in the NMDA-induced convulsions model (Experi-
mental Section and Table 2).
c. QSAR Stu d y of th e C-4 a n d C-5 Su bstitu en ts.
QSAR analysis was performed on a subset of compounds
with pKi g 4 (Table 1). Compounds were parameterized
based on their Principal Properties (PPs)31 (principal
properties approach) and by classical physicochemical
properties descriptors32 (Hansch approach, HA). Sta-
tistical analysis was carried out by partial least squares
projections to latent variables (PLS)33 using the GOLPE
software version 3.0.34 Two methods were examined,

810 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Balsamini et al.
F igu r e 2. Pharmacophore model9f of the antagonists acting at the glycine binding site: superposition of compounds 1a (gray),
1b (orange), 1c (cyan), and 1d (colored by atom type) and 6w (dark gray).
Sch em e 1a
a
Reagents: (i) DMF, POCl3, ClCH2-CH2Cl; (ii) DIBAL-H, CH2Cl2, -20 °C; (iii) (R)3PCH2CONHPh, DBU, toluene, reflux; (iv) CH3I,
K2CO3, DMSO; (v) NIS, THF or CH2Cl2; (vi) Ac2O, SnCl2‚2H2O; (vii) LiOH, MeOH-H2O, reflux; (viii) NBS, AcOH-dioxane; (ix) H2, 10%
Pd-C, NaHCO3, THF.
principal component analysis (PCA)33 and linear PLS.33
Both PCA and PLS with principal properties values did
not yield a meaningful analysis (data not shown).
However PLS with Hansch descriptors (Table 3) pro-
duced a two components model accounting for 74% of
the variance. The predictive power of the model is

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 811
Ta ble 1. Affinities at the Glycine Binding Site of Compounds
6a -z
have a moderate to good affinity (pKi g 6) for the
glycine-binding site associated with the NMDA receptor.
Moreover, some of these compounds show high receptor
selectivity for the glycine-binding site (pKi < 4 at the
NMDA, AMPA, and kainate binding site) and behave
as selective antagonists (6g,j,w ). This, in addition to
the po activity of 6w , makes this class of compounds a
good target for further study.
Qualitative SAR are readily discernible. In general,
double substitution at C-4 and C-5 is necessary; the
unsubstituted derivative 6q is inactive, and removal of
the substituent either from C-4 (6r , 6s) or C-5 (6t, 6v)
dramatically reduces binding affinity. The 4,5-dimethyl
derivative 6g (pKi ) 6.70) is approximately as potent
as 2-carboxy-4,6-dichloroindole-3-propionic acid (1e)13
and about 100 times less potent than 3-(2′-carbamoyl-
ethyl)-4,6-dichloroindole-2-carboxylic acid 1h ,17,18 point-
ing to 6g as a new lead. The decrease in affinity
associated with increasing in bulk of the alkyl substit-
uents, as shown by the trend methyl (6g) > ethyl (6e,
6f) > isopropyl (6l, 6m ) or with the cycloalkyl deriva-
tives (6h , 6i) agrees with the suggested existence of a
size-limited binding pocket. The pKi values of 6l and
6m reflect the greater tolerance for bulky substituents
at the 4-position. The introduction of a phenyl group
in both the 4- and 5-positions, or in 5-position only,
abolishes activity, thus confirming that the steric toler-
ance is limited (6a -d ,p ,s,t). The 1-N-methyl derivative
6u is inactive, confirming the importance of the N-H
hydrogen-bond donor for interaction at the glycine site.
Introduction of small polar hydrogen-bond acceptor
groups such as ethoxy (6n ) and acetyl (6z) causes loss
of activity, indicating that the “west-side” binding pocket
of the glycine/NMDA site model is essentially hydro-
phobic. The introduction of halo and in particular
bromine substituents at C-4 and C-5 results in a
substantial increase in affinity. Compounds 6j,y,x,w
(pKi 7.24, 7.37, 7.45, 7.95, respectively) are the most
potent glycine ligands identified in the in vitro affinity
binding assay within the series and their sub-micromo-
lar affinity proves that the disubstituted benzo-fused
ring of the indole glycine antagonists is not essential
for binding to the receptor and can be replaced by
suitable substituents. This finding is in agreement with
the results obtained for tetrahydroquinolones37 and
tetramic acids.19 The affinity values are the result of
both electronic and steric factors associated with the C-4
and C-5 pyrrole substituents (vide infra). Since the PLS
model previously described the loadings of F(R2) and
F(R3) as positive, the substituents at these positions
compd
R2
R3
R4
pKia
6a
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
Me
Ph
Me
Ph
Et
Ph
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
<4
<4
<4
<4
2,4-ClPh
Ph
Me
Et
Me
6.08 ( 0.04
6.11 ( 0.02
6.70 ( 0.03
5.94 ( 0.06
6.21 ( 0.02
7.24 ( 0.01
6.50 ( 0.03
6.40 ( 0.04
5.21 ( 0.01
5.17 ( 0.01
5.32 ( 0.01
Me
Me
-(CH2)3-
-(CH2)4-
Me
Me
Me
i-Pr
Me
Me
Ph
Br
Cl
i-Pr
Me
OEt
OBz
Br
H
<4
<4
4.2
H
Me
Ph
H
Me
H
Br
I
Me
Me
H
H
6s
6t
<4
<4
<4
Ph
Me
Br
Br
I
6u
6v
6w
6x
6y
6z
5.48 ( 0.03
7.95 ( 0.01
7.45 ( 0.02
7.37 ( 0.03
5.24 ( 0.01
I
Ac
a
Inhibition of binding of [3H]Gly (refs 42, 43).
35a
relatively good, with an R2
calculated with the leave
cv
one out procedure36 of 0.44. The PLS loading plot
reported in Figure 3 shows that the correlation among
the descriptors is low in this data set. The calculated
vs observed pKi values for this model are shown in
Figure 4. The first component, which is the most
relevant descriptor, explains 62% of the activity vari-
ance, and its loading values are reported in Table 4. The
most significant electronic variables, boldface in Table
4, are the inductive and resonance effects for R3 (F(R3),
R(R3)), and for R2 the inductive effect (F(R2)) only. PLS
/HA likely generates a good model due to the introduc-
tion of cumulative terms35b and to the amplitude of the
explored parametric space.
Discu ssion
It is apparent from the data presented in Tables 1
and 2 that several 4,5-substituted pyrrole-2-carboxylates
Ta ble 2. Summary of Receptor Binding Studiesa
NMDA receptor/glycine site
NMDA receptor/glutamite site
[3H]CPP (ref 44)
AMPA receptor
kainate receptor
[3H]Gly (refs 42, 43)
[3H]AMPA (ref 45)
[3H]kainic acid (ref 46)
displ at 100 µM [3H]TCP (ref 47)
displ at 100 µM
displ at 100 µM
displ at 100 µM
compd
pKi
(%SB)
Re
pKi
(%SB)
pIC50
(%SB)
pKi
(%SB)
6gb
6jc
6.70 ( 0.03
7.24 ( 0.01
100
100
100
100
0
<4
0
0
0
<4
<4
<4
0
11
10
<4
9
0
5
n.d.
n.d.
0
<4
<4
<4
<4
6w d 7.95 ( 0.01
1h
8.50 ( 0.01
5.0
5.1
5.4
a
b
Cl 95% ) 95% confidence limit; SB ) specific binding. NMDA-induced convulsions model (CD-1 mice): ED50(Cl 95%) ) 10 × 10-3
(4.2-14.5) g/kg iv; no effect at 10 × 10-3 g/kg po. The corresponding 2-carbomethoxy derivative was totally inactive. c NMDA induced
convulsions model (CD-1 mice) (ref 48): no effect up to 3 × 10-3 g/kg iv and 3 × 10-3 g/kg po. NMDA induced convulsions model (CD-1
d
mice) (ref 48): ED50(Cl 95%) ) 3 × 10-3 (0.8-10) g/kg iv; ED50(Cl 95%) ) 30 × 10-3 (4.5-61) g/kg, po. e Enhancement of binding relative
to that of glycine (full agonist). R ) 1 full agonist; 0 < R < 1 partial agonist; R ) 0 full antagonist.

812 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Ta ble 3. Parameters Utilized for PLSa
Balsamini et al.
compd
R2
R3
F(R2)
R(R2)
F(R3)
R(R3)
π2 + π3
MR2 + MR3
pKi
6g
6e
6f
6y
6w
6n
6z
6m
6j
6k
6l
6r
6x
6v
6h
6i
Me
Et
Me
I
Br
OEt
Ac
Me
Br
Cl
i-Pr
H
Me
Me
Et
Me
Br
Me
Me
i-Pr
Me
Me
Me
Me
I
-0.04
-0.05
-0.04
0.4
0.44
0.22
0.32
-0.04
0.44
-0.13
-0.10
-0.13
-0.19
-0.17
-0.44
0.20
-0.13
-0.17
-0.15
-0.10
0.00
-0.19
-0.17
-0.1b
-0.1b
-0.67b
-0.04
-0.04
-0.05
-0.04
0.44
-0.04
-0.04
-0.05
-0.04
-0.04
-0.04
-0.04
0.40
-0.13
-0.13
-0.10
-0.13
-0.17
-0.13
-0.13
-0.1
0.95
1.48
1.48
1.42
1.65
1.05
0.25
1.88
1.46
1.31
1.88
0.50
2.37
0.96
1.01
1.57
2.93
0.93
1.39
1.39
1.77
1.55
1.55
1.43
1.86
1.24
0.96
1.86
0.46
2.61
0.78
1.21
1.68
3.59
6.70
6.08
6.11
7.37
7.95
5.17
5.24
5.21
7.23
6.50
6.40
4.20
7.45
5.48
5.94
6.21
5.32
-0.13
-0.13
-0.13
-0.13
-0.19
0.00
0.41
-0.05
0.00
I
Br
0.40
H
0.44
0.00
-(CH3)3-
-(CH3)4-
OBz Me
-0.05b
-0.05b
0.28b
-0.05b
-0.05b
-0.04b
-0.10b
-0.10b
-0.13b
6o
a
Swain and Lupton F(R2) and R(R2)32 of substituent R2; F(R3), R(R3), Swain and Lupton F and R32 of substituent R3; π2 + π3, sum of
lipophilicity of substituents R2 and R3, calculated with the Daylight 4.4149 program; MR2 + MR3, sum of molar refractivities of substituents
b
R2 and R3, calculated with the Daylight 4.41program.49 Estimated parameters according to ref 50.
Ta ble 4. Loading Values for the First and Second Components
(HA)
loading
variable
F(R2)
R(R2)
F(R3)
component 1
component 2
0.320
-0.167
0.568
0.001
0.395
-0.035
0.176
-0.307
-0.585a
-0.583
-0.358a
R(R3)
-0.463
π2 + π3
0.481
(π2 + π3)2
MR2 + MR3
(MR2 + MR3)2
0.041a
0.352
-0.378a
a
The correlation between the variables and their squares was
reduced by scaling the variable with respect to the range.
2-carboxylic acid or to an increase in the electron density
at the oxygen atom of the carboxylate. In addition, the
loadings of the global lipophilicity and bulk (π2 + π3)
and (MR2 + MR3), along with their square terms, are
also relevant, clearly indicating a nonlinear model. The
model fails to predict the inactivity of compounds
carrying a phenyl group connected directly to the pyrrole
ring (6a ,b,p ,s,t) whereas the lack of activity of 6c,d is
well predicted, probably because the two compounds are
also very bulky and lipophilic. Probably there are
specific effects related to the direct attachment of the
phenyl to the pyrrole ring. These effects could not
however be investigated as all the compounds of this
type are inactive. These results further substantiate
the existence of a size-limited binding pocket in agree-
ment with the accepted literature model for the indole
derivatives.
F igu r e 3. PLS loading plot of the first vs the second
component.
Con clu sion s
Our results show that the compounds examined in
this study are potent and selective glycine site antago-
nists. The data support our initial hypothesis that the
benzo moiety is not absolutely necessary for binding and
it is in fact possible to replace it with halo or alkyl
groups while maintaining good affinity for the glycine-
binding site. The fact that the benzo moiety is not
strictly necessary for binding and selectivity is an
important structure-activity acquisition. Careful mod-
eling of the leads, by modification of other regions
known to favor affinity, was not performed. This may
F igu r e 4. Recalculated vs observed pKi values for the
component model (HA).
should be electron-withdrawing groups as they increase
through induction effects the hydrogen bond forming
capability of the pyrrole NH (6a -t,v-z). On the other
hand, the negative loading for R(R3) indicates that at
this position an electron-donor substituent would en-
hance affinity through resonance effects. This is prob-
ably related either to a decrease in the acidity of the

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 813
MHz) δ 10.27 (br s, 1H), 6.73 (d, 1H), 3.80 (s, 3H), 2.23 (s,
3H); IR (Nujol) 3298, 1689 cm-1; MS (EI) m/z 173 (M+), 141
(100).
leave room for improvement of the value of the pKi of
our best compounds (6x,w ). The 2-carboxypyrroles can
therefore be considered a new chemical lead in this field,
providing further insight into requirements for the
binding to the glycine antagonist-recognition site.
Meth yl 4-Isop r op yl-5-m eth yl- a n d 5-Isop r op yl-4-m eth -
ylp yr r ole-2-ca r boxyla te (2l,m ). AlCl3 (0.16 g, 1.2 mmol)
was added to a solution of methyl 4-methylpyrrole-2-carboxyl-
ate41 (or methyl 5-methylpyrrole-2-carboxylate27) (1 mmol) in
CS2 (4 mL); after 15 min a solution of isopropyl chloride (0.1
mL, 1 mmol) in CS2 (1 mL) was added dropwise, and the
resulting reaction mixture was refluxed under stirring over-
night. The reaction was quenched by pouring the mixture onto
ice, and the aqueous layer was separated, saturated with NaCl,
and extracted with CH2Cl2. The organic phase was washed
with water and dried (Na2SO4). The solvent was evaporated
under reduced pressure to give a crude material which was
purified by flash chromatography (silica gel; cyclohexane-
EtOAc, 8:2, as eluent) and crystallization.
Exp er im en ta l Section
Ch em istr y. Solvents and reagents were of the highest
available commercial grade and were used without additional
purification. Melting points were determined on a Bu¨chi SMP-
510 capillary melting point apparatus and are uncorrected.
1H NMR spectra were recorded with a Varian Unity 400,
Varian Unity plus 500, Varian VXRS 5000, or Varian EM 60
spectrometer using tetramethylsilane as internal standard;
chemical shifts are reported in ppm and given in δ units. EI-
MS spectra (70 eV) were taken on a Fisons-Trio 1000 (only
molecular ions M+ and base peaks are given); FAB-MS were
obtained on a VG-4 triple quadrupole on a 4-nitrobenzoic acid
matrix, and only (M + H)+ are given. Infrared spectra were
recorded on a Brucker IFS 48 spectrometer; absorbances are
reported in ν (cm-1). Elemental analyses were performed on
a Carlo Erba analyzer and, when reported (C, H, N), are within
(0.4% of the theoretical value.
Meth yl 5-(2,4-Dich lor op h en yl)-4-m eth ylp yr r ole-2-ca r -
boxyla te (2c). This compound was prepared according to the
literature procedure21 starting from (E)-3-(2,4-dichlorophenyl)-
2-methyl-2-propenal38 and methyl azidoacetate:39 yield 45%;
mp 136-39 °C (EtOAc-hexane); 1H NMR (DMSO) δ 11.88 (s,
1H), 7.72 (d, 1H), 7.47 (dd, 1H), 7.39 (d, 1H), 6.69 (d, 1H), 3.73
(s, 3H), 1.89 (s, 3H); IR (Nujol) 3325, 1678 cm-1; MS (FAB)
m/z 285 (M + H)+.
4-Isop r op yl-5-m eth ylp yr r ole-2-ca r boxyla te (2l): yield
0.096 g (53%): mp 101-3 °C (MeOH); 1H NMR (DMSO, 60
MHz) δ 9.2 (br s, 1H), 6.75 (d, 1H), 3.8 (s, 3H), 2.8 (m, 1H), 2.2
(s, 3H), 1.2 (d, 6H); IR (Nujol) 3280, 1670 cm-1; MS (EI) m/z
181 (M+), 134 (100).
5-Isop r op yl-4-m eth ylp yr r ole-2-ca r boxyla te (2m ): yield
1
0.125 g (69%): mp 94 °C (i-Pr2O); H NMR (DMSO) δ 11.21
(s, 1H), 6.49 (d, 1H), 3.68 (s, 3H), 2.96 (m, 1H), 1.94 (s, 3H),
1.17 (d, 6H); IR (Nujol) 3321, 1684 cm-1; MS (EI) m/z 181 (M+),
134 (100).
Meth yl 4-Eth oxy-5-m eth yl- a n d 4-(Ben zyloxy)-5-m eth -
ylp yr r ole-2-ca r boxyla tes (2n ,o). Chloroacetyl chloride (3.75
mL, 47 mmol) was added dropwise to an ice-cooled suspension
of AlCl3 (6 g, 45 mmol) in dry CH2Cl2 (40 mL), a solution of
5-methyl-2-carbomethoxypyrrole27 (1.39 g, 10 mmol) in dry
CH2Cl2 (13 mL) was added to the resulting mixture, and the
mixture was stirred for 2 h at room temperature. The reaction
was quenched by pouring the mixture into brine; after the
aqueous layer was extracted with EtOAc, the organic phase
was washed with water (2×), with saturated NaHCO3 solution
(2×), and with water (1×) and then dried (Na2SO4). The
solvent was evaporated under reduced pressure to give the
methyl 4-(chloroacetyl)-5-methylpyrrole-2-carboxylate as a
white solid which was purified by crystallization from MeOH:
yield 1.93 g (90%); mp 196 °C; 1H NMR (DMSO) δ 12.49 (br s,
1H), 7.31 (d, 1H), 4.81 (s, 2H), 3.77 (s, 3H), 2.44 (s, 3H); IR
(Nujol) 3258, 1691, 1676, 1564 cm-1; MS (EI) m/z 215 (M+),
134 (100). Na2HPO4 (5.34 g) and m-chloroperbenzoic acid 57-
86% (4.26 g) were added to a suspension of methyl 4-(chloro-
acetyl)-5-methylpyrrole-2-carboxylate (1.9 g, 9 mmol) in CH2Cl2
(27 mL). The mixture was stirred for 5 h at room temperature,
then washed with water (2×), with saturated NaHCO3 solution
(2×), and with water (1×), and dried (Na2SO4). The solvent
was evaporated under reduced pressure to give methyl 4-[(chlo-
roacetyl)oxy]-5-methylpyrrole-2-carboxylate as a crude mate-
rial which was purified by crystallization from MeOH. Mother
liquors from crystallization were purified by flash chromatog-
raphy (silica gel; CH2Cl2-EtOAc, 95:5, as eluent): yield 1.33
g (64%); mp 124 °C; 1H NMR (DMSO) δ 11.84 (br s, 1H), 6.59
(d, 1H), 4.63 (s, 2H), 3.72 (s, 3H), 2.06 (s, 3H); IR (Nujol) 3279,
1765, 1661 cm-1; MS (EI) m/z 231 (M+), 155 (100).
Meth yl 4,5-Dip h en ylp yr r ole-2-ca r boxyla te (2d ). This
compound was prepared according to the literature procedure21
starting from 2,3-diphenylpropenal40 and methyl azidoace-
tate:39 yield 35%; mp 170-1 °C (Et2O); 1H NMR (DMSO) δ
12.18 (s, 1H), 7.36-7.14 (m, 10H), 6.96 (d, 1H), 3.78 (s, 3H);
IR (Nujol) 3258, 1672 cm-1; MS (FAB) m/z 278 (M + H)+.
Met h yl 4-E t h yl-5-m et h ylp yr r ole-2-ca r b oxyla t e (2e).
This product was prepared according to a previously described
method for the corresponding ethyl ester derivative:25 yield
1
17%; mp 108 °C (EtOH); H NMR (CDCl3, 60 MHz) δ 8.9 (br
s, 1H), 6.7 (d, 1H), 3.85 (s, 3H), 2.4 (m, 2H), 2.25 (s, 3H), 1.2
(t, 3H); IR (neat) 3280, 1670 cm-1; MS (EI) m/z 167 (M+), 120
(100).
Meth yl 5-Eth yl-4-m eth ylpyr r ole-2-car boxylate (2f). This
product was prepared according to the method used for 2e:
yield 45%; mp 84 °C (MeOH); 1H NMR (CDCl3, 60 MHz) δ 9.1
(br s, 1H), 6.6 (d, 1H), 3.8 (s, 3H), 2.55 (q, 2H), 1.95 (s, 3H),
1.2 (t, 3H); IR (neat) 3280, 1670 cm-1; MS (EI) m/z 167 (M+),
152 (100).
Met h yl 4-Br om o-5-m et h ylp yr r ole-2-ca r b oxyla t e (2j).
NBS (1.96 g, 11 mmol) was added to an ice-cooled solution of
methyl 5-methylpyrrole-2-carboxylate27 (1.4 g, 10 mmol) in dry
CHCl3 (50 mL) and the mixture stirred for 30 min at 0 °C.
The mixture was poured onto an ice-cooled 2 N NaOH solution
(20 mL) and extracted with CHCl3, and the combined extracts
were washed twice with water (20 mL) and dried (Na2SO4).
Evaporation of the solvent gave a residue which was purified
by crystallization from MeOH: yield 1.96 g (90%); mp 149-
50 °C; 1H NMR (CDCl3, 60 MHz) δ 8.17 (br s, 1H), 6.82 (d,
1H), 3.83 (s, 3H), 2.27 (s, 3H); IR (Nujol) 3297, 1683 cm-1; MS
(EI) m/z 217, 219 (M+), 185, 187 (100).
Meth yl 4-Ch lor o-5-m eth ylp yr r ole-2-ca r boxyla te (2k ).
N-Chlorosuccinimide (NCS) (1.47 g, 11 mmol) was added to a
solution of methyl 5-methylpyrrole-2-carboxylate27 (1.39 g, 10
mmol) in dry CHCl3 (50 mL), and the mixture was stirred for
24 h at room temperature. The mixture was poured onto an
ice-cooled 2 N NaOH solution (20 mL) and extracted with
CHCl3, and the combined extracts were washed twice with
water (20 mL) and dried (Na2SO4). Evaporation of the solvent
gave a residue which was purified by crystallization from
MeOH: yield 1.38 g (80%); mp 143-4 °C; 1H NMR (CDCl3, 60
A solution of K2CO3 (0.828 g, 6 mmol) in water (8 mL) was
added to a solution of methyl 4-[(chloroacetyl)oxy]-5-meth-
ylpyrrole-2-carboxylate (0.931 g, 4 mmol) in MeOH (36 mL),
and the mixture was stirred at room temperature for 15 min.
After evaporation of the solvent in vacuo a crude material was
obtained; after the addition of water, it was acidified (2 N HCl
pH ) 5-6) and extracted with EtOAc (2×). The combined
organic phases were washed with water (2×) and dried (Na2-
SO4). The solvent was evaporated and the residue purified
by crystallization (Et2O-hexane) to give methyl 4-hydroxy-5-
methylpyrrole-2-carboxylate as pure compound. Yield 0.5 g
(80%); mp 144 °C; 1H NMR (acetone-d6, 60 MHz) δ 7.0 (s, 1H),
6.3 (d, 1H), 3.7 (s, 3H), 2.16 (s, 3H); IR (Nujol) 3283, 1678 cm-1
;
MS (EI) m/z 155 (M+), 123 (100).
Ethyl iodide (2.73 mmol) (or benzyl bromide for 2o) and NaH
(2.56 mmol) were added to a -20 °C cooled suspension of

814 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Balsamini et al.
methyl 4-hydroxy-5-methylpyrrole-2-carboxylate (0.397 g, 2.56
mmol) in dry DMF (1 mL) under dry N2. The mixture was
stirred at -20 °C for 15 min (plus 1 h at room temperature
for 2o). The mixture was poured onto brine and extracted with
EtOAc; the organic phases were combined and dried (Na2SO4).
The solvent was evaporated and the residue purified by flash
chromatography (silica gel; cyclohexanes-EtOAc, 1:1, as elu-
ent). The collected fractions were further purified by crystal-
lization from Et2O-hexane.
Meth yl 5-eth yl-3-for m yl-4-m eth ylp yr r ole-2-ca r boxyl-
a te (4f): yield 57%; mp 175 °C (EtOH); H NMR (CDCl3) δ
1
10.53 (s, 1H), 9.1 (br s, 1H), 3.92 (s, 3H), 2.61 (q, 2H), 2.25 (s,
3H), 1.22 (t, 3H); IR (Nujol) 3198, 1713, 1647 cm-1; MS (EI)
m/z 195 (M+), 162 (100).
Eth yl 3-for m ylcyclopen ta[b]pyr r ole-2-car boxylate (4h ):
yield 14%; mp 174-5 °C (Et2O); 1H NMR (DMSO) δ 12.24 (br
s, 1H), 10.32 (s, 1H), 4.29 (q, 2H), 2.64 (m, 4H), 2.35 (m, 2H),
1.30 (t, 3H); IR (Nujol) 3128, 3053, 1701, 1645 cm-1; MS (FAB)
m/z 208 (M + H)+.
Meth yl 4-eth oxy-5-m eth ylp yr r ole-2-ca r boxyla te (2n ):
1
yield 0.28 g (60%): mp 124 °C; H NMR (DMSO) δ 11.41 (br
Eth yl 3-for m ylcycloh exa [b]p yr r ole-2-ca r boxyla te (4i):
yield 66%; mp 159 °C (i-Pr2O); 1H NMR (DMSO) δ 12.14 (br s,
1H), 10.39 (s, 1H), 4.29 (q, 2H), 2.62 (t, 2H), 2.52 (t, 2H), 1.65
s, 1H), 6.42 (d, 1H), 3.85 (q, 2H), 3.68 (s, 3H), 2.05 (s, 3H),
1.21 (t, 3H); IR (Nujol) 3292, 1661, 1591 cm-1; MS (EI) m/z
183 (M+), 53 (100).
(m, 4H), 1.30 (t, 3H); IR (Nujol) 3180, 3138, 1693, 1647 cm-1
;
MS (FAB) m/z 222 (M + H)+.
Meth yl 4-(ben zyloxy)-5-m eth ylp yr r ole-2-ca r boxyla te
(2o): yield 0.31 g (50%): mp 105 °C; 1H NMR (DMSO) δ 11.43
(br s, 1H), 7.35 (m, 5H), 6.47 (d, 1H), 4.91 (s, 2H), 3.68 (s, 3H),
2.05 (s, 3H); IR (Nujol) 3281, 1668, 1593 cm-1; MS (EI) m/z
245 (M+), 154 (100).
Meth yl 4-br om o-3-for m yl-5-m eth ylp yr r ole-2-ca r boxyl-
a te (4j): yield 7%; mp 225-7 °C (EtOAc); 1H NMR (DMSO) δ
12.86 (br s, 1H), 10.32 (s, 1H), 3.85 (s, 3H), 2.17 (s, 3H); IR
(Nujol) 3267, 1666 cm-1; MS (EI) m/z 245, 247 (M+), 214, 212
(100).
Meth yl 4-Br om o-5-p h en ylp yr r ole-2-ca r boxyla te (2p ).
NBS (11 mmol, 1.96 g) was added portionwise over 1 h to an
ice-cooled solution of methyl 5-phenylpyrrole-2-carboxylate28
(10 mmol, 2.01 g) in dry CHCl3 (50 mL), and the mixture was
stirred for 12 h at room temperature. The mixture was poured
onto an ice-cooled 2 N NaOH solution (20 mL) and extracted
with CHCl3, and the combined extracts were washed twice
with water (20 mL) and dried (Na2SO4). Evaporation of the
solvent gave a residue which was purified by crystallization
from i-Pr2O: yield 2.1 g (75%): mp 146-7 °C; 1H NMR (CDCl3)
δ 9.31 (s, 1H), 7.68 (m, 2H), 7.48-7.36 (m, 3H), 6.98 (d, 1H),
3.86 (s, 3H); IR (CDCl3) 3437, 1703 cm-1; MS (EI) m/z 279,
281 (M+), 140 (100).
Gen er a l P r oced u r e for t h e p r ep a r a t ion of Alk yl
3-F or m ylp yr r ole-2-ca r boxyla tes (4a -p ). A solution of
POCl3 (0.46 mL, 4.93 mmol) in dry 1,2-dichloroethane (1.5 mL)
was added dropwise (carefully, exothermic reaction) under
stirring to a solution of dry DMF (or N-methylformanilide for
4p and for ethyl 5-bromo-3-formyl-4-phenylpyrrole-2-carboxy-
late) (5.55 mmol) in dry 1,2-dichloroethane (1 mL). The
mixture was stirred at room temperature for 15 min, after
which a solution of the opportune pyrrole (1 mmol) in the
minimal amount of dry 1,2-dichloroethane (1-5 mL) was
added. The mixture was refluxed until the starting material
disappeared (TLC analysis), cooled to 0 °C, and poured onto a
cooled solution of CH3COONa‚3H2O (2.75 g) in water (5 mL).
The stirring was continued for 1 h at room temperature, and
then the layers were separated and the water-phase was
extracted (2 × 5 mL) with CH2Cl2; the organic phases were
collected, washed (1 × 5 mL) with water, and dried (Na2SO4).
The solvent was evaporated under reduced pressure, and the
crude material was purified by flash chromatography on silica
gel using cyclohexane-EtOAc, 6:4, as eluent.
Meth yl 4-ch lor o-3-for m yl-5-m eth ylp yr r ole-2-ca r boxyl-
a te (4k ): yield 10%; mp 224-5 °C (EtOAc); 1H NMR (DMSO)
δ 12.79 (br s, 1H), 10.34 (s, 1H), 3.85 (s, 3H), 2.16 (s, 3H); IR
(Nujol) 3177, 1717, 1655 cm-1; MS (FAB) m/z 202 (M + H)+.
Met h yl 3-for m yl-4-isop r op yl-5-m et h ylp yr r ole-2-ca r -
boxyla te (4l): yield 25%: mp 148 °C (EtOH); 1H NMR
(DMSO) δ 12.15 (br s, 1H), 10.43 (s, 1H), 3.82 (s, 3H), 3.37 (m,
1H), 2.21 (s, 3H), 1.15 (d, 6H); IR (Nujol) 3267, 1666 cm-1
;
MS (EI) m/z 209 (M+), 162 (100).
Met h yl 3-for m yl-5-isop r op yl-4-m et h ylp yr r ole-2-ca r -
1
boxyla te (4m ): yield 71%; mp 110-112 °C (EtOH); H NMR
(DMSO) δ 12.0 (br s, 1H), 10.41 (s, 1H), 3.83 (s, 3H), 3.04 (m,
1H), 2.16 (s, 3H), 1.19 (d, 6H); IR (Nujol) 3244, 1707, 1649
cm-1; MS (EI) m/z 209 (M+), 162 (100).
Meth yl 4-eth oxy-3-for m yl-5-m eth ylp yr r ole-2-ca r boxyl-
a te (4n ): yield 50%; mp 137 °C (CH2Cl2-hexane); 1H NMR
(CDCl3) δ 10.42 (s, 1H), 8.95 (br s, 1H), 4.04 (q, 2H), 3.92 (s,
3H), 2.22 (s, 3H), 1.32 (t, 3H); IR (Nujol) 3285, 1713, 1680 cm-1
;
MS (EI) m/z 211 (M+, 100).
Meth yl 4-(ben zyloxy)-3-for m yl-5-m eth ylp yr r ole-2-ca r -
boxyla te (4o): yield 78%; mp 128 °C (CH2Cl2-hexane); 1H
NMR (DMSO) δ 12.24 (br s, 1H), 10.35 (s, 1H), 7.35 (m, 5H),
4.89 (s, 2H), 3.83 (s, 3H), 1.90 (s, 3H); IR (Nujol) 3194, 3155,
1711, 1654, 1589 cm-1; MS (EI) m/z 273 (M+).
Meth yl 4-br om o-3-for m yl-5-p h en ylp yr r ole-2-ca r boxyl-
a t e (4p ): yield 20%; mp 193 °C (EtOAc-hexane); 1H NMR
(CDCl3) δ 10.52 (s, 1H), 9.73 (br s, 1H), 7.69-7.44 (m, 5H),
3.95 (s, 3H); IR (CDCl3) 3418, 1707, 1682 cm-1; MS (FAB) m/z
307, 309 (M + H)+.
3-Cya n o-2-for m yl-5-m eth ylp yr r ole (7). 7 was prepared
by means of Vilsmeyer-Haack formylation (following the above-
described general procedure) starting from 3-cyano-5-methyl-
pyrrole:29 yield 54%; mp 154 °C (CH2Cl2-hexane); 1H NMR
(DMSO) δ 12.87 (br s, 1H), 9.54 (s, 1H), 6.54 (s, 1H), 2.24 (s, 3H);
IR (Nujol) 3252, 2228, 1645 cm-1; MS (EI) m/z 134 (M+, 100).
Meth yl 3-Cya n o-5-m eth ylp yr r ole-2-ca r boxyla te (3r ). A
solution of AgNO3 (0.13 g, 0.76 mmol) in water (10 mL) was
added to a solution of 7 (0.070 g, 0.52 mmol) protected from
light in 1 N NaOH (20 mL), and the mixture was stirred for 1
h at room temperature. It was then acidified using 65% HNO3
and filtered on Celite, and the filtrate was extracted with
EtOAc; the organic phases were combined, washed with water,
and dried (Na2SO4). The solvent was evaporated under
reduced pressure to give a solid residue which was dissolved
in THF and treated with CH2N2 at 0 °C. After evaporation of
the solvent, the crude residue of the title compound was
purified by crystallization from MeOH: yield 0.65 g (77%); mp
Meth yl 3-for m yl-4-m eth yl-5-p h en ylp yr r ole-2-ca r boxyl-
a te (4a ): yield 88%; mp 157-8 °C (Et2O); IR (Nujol) 3435,
3302, 1718, 1664, 1649 cm-1; MS (FAB) m/z 244 (M + H)+.
Meth yl 3-for m yl-5-m eth yl-4-p h en ylp yr r ole-2-ca r boxyl-
a te (4b): yield 88%; mp 157-8 °C (Et2O); 1H NMR (CDCl3, 60
MHz) δ 10.4 (s, 1H), 9.2 (br s, 1H), 7.3 (m, 5H), 3.95 (s, 3H),
2.2 (s, 3H); IR (Nujol) 3220, 1720, 1700, 1650 cm-1; MS (EI)
m/z 243 (M+), 210 (100).
Meth yl 5-(2,4-d ich lor op h en yl)-3-for m yl-4-m eth ylp yr -
r ole-2-ca r boxyla te (4c): yield 76%: mp 219-220 °C (CH2-
1
Cl2-hexane); H NMR (DMSO) δ 12.7 (s, 1H), 10.49 (s, 1H),
7.77 (d, 1H), 7.52 (dd, 1H), 7.48 (d, 1H), 3.85 (s, 3H), 2.06 (s,
3H); IR (Nujol) 3155, 3136, 1726, 1651 cm-1; MS (FAB) m/z
312 (M + H)+.
Met h yl 3-for m yl-4,5-d ip h en ylp yr r ole-2-ca r b oxyla t e
(4d ): yield 69%: mp 134-6 °C (EtOAc-hexane); MS (FAB)
m/z 306 (M + H)+.
1
190 °C; H NMR (CDCl3, 60 MHz) δ 6.3 (s, 1H), 4.0 (s, 3H),
2.3 (s, 3H); IR (Nujol) 3273, 2232, 1684 cm-1; MS (EI) m/z 164
(M+), 52 (100).
Meth yl 4-eth yl-3-for m yl-5-m eth ylp yr r ole-2-ca r boxyl-
1
a te (4e): yield 13%: mp 161-2 °C (EtOH); H NMR (CDCl3,
Meth yl 3-F or m yl-5-m eth ylp yr r ole-2-ca r boxyla te (4r ).
A suspension of 3r (0.6 g, 3.7 mmol) in dry CH2Cl2 (19 mL)
was added carefully under nitrogen to a stirred and -20 °C
cooled 1 M solution of DIBAL-H in hexane (8.1 mL). The mix-
60 MHz) δ 10.5 (s, 1H), 9.6 (br s, 1H), 3.9 (s, 3H), 2.7 (q, 2H),
1.05 (t, 3H); IR (Nujol) 3188, 3140, 1718, 1709 cm-1; MS (EI)
m/z 195 (M+, 100).

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 815
ture was stirred under nitrogen for 1 h at -20°, after which it
was carefully poured onto 30 mL of a stirred 10% aqueous solu-
tion of citric acid; stirring was continued for 1 h before the
layers were separated, the aqueous phase was extracted with
CH2Cl2, and the collected organic phases were dried (Na2SO4)
and evaporated to dryness to give a crude solid from which
pure 4r was obtained by flash chromatography (silica gel; CH2-
Cl2-EtOAc, 95:5, as eluent): yield 0.41 g (66%); mp 153-4
°C (EtOAc-petroleum ether); 1H NMR (DMSO) δ 12.36 (br s,
1H), 10.31 (s, 1H), 6.34 (s, 1H), 3.87 (s, 3H), 3.23 (s, 3H); IR
(Nujol) 3192, 3144, 1709, 1651 cm-1; MS (EI) m/z 167 (M+),
134 (100).
Meth yl 3-F or m yl-5-p h en ylp yr r ole-2-ca r boxyla te (4s).
(The debromination of 4p using H2/ Pd-C 10% gave a mixture
of 4s and of the corresponding 3-hydroxymethyl derivative: the
latter converted into the desired title compound 4s by PCC
oxidation.)
mL) and K2CO3 (0.61 g, 4.4 mmol) was added portionwise to a
solution of 4g (0.181 g, 1 mmol) in DMSO (4.5 mL) and the
mixture was stirred for 1 h at room temperature; CH2Cl2 and
water were added, the water phase was extracted twice with
CH2Cl2, and the combined organic phases were washed once
with water and dried (Na2SO4). The solvent was evaporated
under reduced pressure to give a crude product which was
purified by crystallization from Et2O-hexane: yield 0.175 g
(90%); mp 91 °C; 1H NMR (CDCl3, 60 MHz) δ 10.4 (s, 1H), 3.9
(s, 3H), 3.8 (s, 3H), 2.2 (s, 3H), 2.1 (s, 3H); IR (Nujol) 1695,
1674 cm-1; MS (EI) m/z 195 (M+), 180 (100).
Eth yl 4-Br om o-3-for m ylpyr r ole-2-car boxylate (4v). NBS
(0.18 g, 1 mmol) was added to an ice-cooled solution of ethyl
3-formylpyrrole-2-carboxylate20 (0.170 g, 1 mmol) in AcOH-
dioxane, 2:1 (3 mL), and the mixture was stirred at 0 °C for
1.5 h and then at room temperature for 0.5 h. The solvent
was evaporated under reduced pressure, the residue was
dissolved in CH2Cl2, and the resulting solution was then
washed with saturated aqueous NaHCO3 (2×) and with water
(2×). The organic phase was dried (Na2SO4) and evaporated
under reduced pressure to give a crude residue containing
(TLC and GC-MS analysis) ethyl 4-bromo-3-formylpyrrole-
2-carboxylate together with unreacted starting material and
minor amounts of a structurally undetermined monobromo
derivative and of ethyl 4,5-dibromo-3-formylpyrrole-2-carboxy-
late. The crude material was purified by flash column chro-
matography (CH2Cl2-EtOAc, 95:5, as eluent) to give after
crystallization from EtOAc-hexane the desired compound
4v: yield 0.08 g (33%): mp 148-9 °C; 1H NMR (CDCl3) δ 10.52
(s, 1H), 7.02 (d, 1H), 4.45 (q, 2H), 1.42 (t, 3H); IR (Nujol) 3148,
1723, 1662 cm-1; MS (EI) m/z 245-247 (M+), 216-218 (100).
A suspension of methyl 3-formyl-4-bromo-5-phenylpyrrole-
2-carboxylate (0.31 g, 1 mmol) and NaHCO3 (0.085 g, 1 mmol)
in THF (20 mL) was hydrogenated in a closed vessel over 10%
Pd-C (0.045 g) at 4.5 atm of H2 for 20 h at 90 °C; the catalyst
was filtered on Celite, the filtrate was evaporated in vacuo,
the residue was dissolved in EtOAc, and the organic phase
obtained was washed with water, dried (Na2SO4), and evapo-
rated to give a crude mixture (TLC) of methyl 3-formyl-5-
phenylpyrrole-2-carboxylate and the 3-hydroxymethyl deriva-
tive which were separated by flash chromatography on silica
gel using cyclohexanes-EtOAc, 7:3, as eluent. The alcohol was
then converted into the formyl derivative as described below.
A solution of methyl 3-(hydroxymethyl)-5-phenyl-2-pyrrole-
carboxylate (0.2 g, 0.65 mmol) in dry CH2Cl2 (4 mL) was added
to a suspension of pyridinium chlorochromate (PCC) (0.21 g,
0.98 mmol) in dry CH2Cl2 (2 mL). The mixture was stirred at
room temperature for 3.5 h, Et2O (10 mL) was added, and the
solution was separated from the dark gummy residue, which
was further washed with Et2O (3 × 5 mL). The organic phases
were collected, concentrated in vacuo, filtered on Florisil,
and finally evaporated to dryness to give pure methyl
3-formyl-5-phenylpyrrole-2-carboxylate: overall yield 70%; mp
Eth yl 4,5-Dibr om o-3-for m ylpyr r ole-2-car boxylate (4w).
NBS (0.392 g, 2.2 mmol) was added to an ice-cooled solution
of ethyl 3-formylpyrrole-2-carboxylate20 (0.17 g, 1 mmol) in
AcOH-dioxane 2:1 (3 mL) and the mixture was stirred at 0
°C for 1 h, then at room temperature for 3 h. The mixture
was cooled and poured carefully onto an ice-cooled mixture of
30% aqueous NaOH, and the aqueous phase was extracted
with EtOAc (3×). The organic phases were collected, washed
with brine, dried (Na2SO4), and evaporated under reduced
pressure to give a solid residue which was purified by crystal-
lization from acetone-hexane: yield 0.25 g (77%): mp 231-2
°C; 1H NMR (acetone-d6) δ 12.2 (br s, 1H), 10.42 (s, 1H), 4.40
1
188-9 °C (CHCl3-hexane); H NMR (CDCl3) δ 10.49 (s, 1H),
9.58 (br s, 1H), 7.46-7.57 (m, 5H), 7.06 (d, 1H), 4.01 (s, 3H);
IR (Nujol) 3240, 1709, 1655 cm-1
.
E t h yl 3-F or m yl-4-p h en ylp yr r ole-2-ca r b oxyla t e (4t ).
NBS (1 mmol, 0.178 g) was added to a solution of ethyl
4-phenylpyrrole-2-carboxylate22 (1 mmol, 0.215 g) in dry CHCl3
(6 mL), and the mixture was stirred under N2 for 1 h at room
temperature. The mixture was washed once with a 2 N NaOH
solution (2 mL) and then once with H2O and dried (Na2SO4).
Evaporation of the solvent gave ethyl 5-bromo-4-phenylpyrrole-
2-carboxylate which was purified by crystallization from
(q, 2H), 1.36 (t, 3H); IR (Nujol) 3220, 1679, 1676, 1610 cm-1
;
MS (EI) m/z 325 (M+), 296 (100).
Gen er a l P r oced u r e for th e P r ep a r a tion of Alk yl (E)-
3-[2-(N-P h en ylca r b a m oyl)vin yl]p yr r ole-2-ca r b oxyla t es
(5a -w ). A suspension of the suitable 3-formylpyrroles 4a -w
(1 mmol), triphenyl(N-phenylcarbamoyl)methyl)-phosphonium
bromide (1.5 mmol) [or tri-tert-butyl(N-phenylcarbamoyl)-
methyl)-phosphonium bromide], and DBU (0.22 mL) was
refluxed in toluene (16 mL). The disappearance of the starting
formylpyrrole was monitored by TLC (cyclohexane-EtOAc,
1:1, as eluent). The solvent was evaporated under reduced
pressure and the residue dissolved in CH2Cl2, washed with
water, dried (Na2SO4), and evaporated in vacuo to give a crude
product that was purified by flash chromatography on silica
gel (cyclohexane-EtOAc, 1:1, or CH2Cl2-EtOAc, 9:1). 5d was
obtained together with 21% (NMR) of its (Z)-isomer; this
mixture was refluxed for 24 h in toluene with 5% of dry
p-toluenesulfonic acid. The solution was cooled, washed with
sodium bicarbonate and then with water, dried, and evapo-
rated in vacuo to give pure (NMR) 5d as a white solid (mp
220-3 °C).
Meth yl (E)-4-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
5-p h en ylp yr r ole-2-ca r boxyla te (5a ): yield 85%; mp 262-3
°C (cyclohexanes-EtOAc); 1H NMR (DMSO) δ 12.10 (br s, 1H),
10.13 (br s, 1H), 8.28 (d, J ) 16.2 Hz, 1H), 7.69 (d, 2H), 7.48
(m, 4H), 7.37 (tt, 1H), 7.31 (t, 2H), 7.04 (tt, 1H), 6.68 (d, 1H J
) 16.2 Hz), 3.82 (s, 3H), 2.28 (s, 3H); IR (Nujol) 3325, 1678,
1620 cm-1; MS (FAB) m/z 361 (M + H)+.
Meth yl (E)-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
4-p h en ylp yr r ole-2-ca r boxyla te (5b): yield 80%; mp 251-3
°C (i-Pr2O); 1H NMR (CDCl3) δ 9.00 (br s, 1H), 7.39 (br s, 1H),
1
CHCl3: yield 0.264 g (90%): mp 142-3 °C; H NMR (CDCl3)
δ 9.16 (br s, 1H), 7.58 (m, 2H), 7.41 (m, 2H), 7.30 (m, 1H),
7.05 (m, 1H), 4.35 (q, 2H), 1.38 (t, 3H); IR (Nujol) 3256, 1680
cm-1; MS (EI) m/z 293, 295 (M+).
Ethyl 5-bromo-3-formyl-4-phenylpyrrole-2-carboxylate was
obtained by the general procedure reported above starting from
ethyl 5-bromo-4-phenylpyrrole-2-carboxylate: yield 12%; mp
213-14 °C (EtOAc); 1H NMR (CDCl3) δ 10.49 (s, 1H), 9.50 (br
s, 1H), 7.44-7.32 (m, 5H), 4.46 (q, 2H), 1.43 (t, 3H); IR (Nujol)
3134-3000, 1717, 1663 cm-1; MS (EI) m/z 321, 323 (M+).
A suspension of ethyl 5-bromo-3-formyl-4-phenylpyrrole-2-
carboxylate (0.32 g, 1 mmol) and NaHCO3 (0.085 g, 1 mmol)
in THF (20 mL) was hydrogenated in a closed vessel over 10%
Pd-C (0.045 g) at 4.5 atm of H2 for 8 h at 80 °C. The catalyst
was filtered on Celite, the filtrate was evaporated in vacuo,
the residue was dissolved in EtOAc, and the organic phase
obtained was washed with water, dried (Na2SO4), and evapo-
rated to give a crude product which was purified by crystal-
lization from CHCl3: yield 0.18 g (75%): mp 192 °C; 1H NMR
(CDCl3) δ 10.64 (s, 1H), 9.45 (br s, 1H), 7.49-7.29 (m, 5H),
6.97 (d, 1H), 4.45 (q, 2H), 1.42 (t, 3H); IR (Nujol) 3179, 1713,
1699, 1657 cm-1; MS (FAB) m/z 244 (M + H)+.
Meth yl 3-For m yl-N,4,5-tr im eth ylp yr r ole-2-ca r boxyla te
(4u ). A solution of CH3I (0.07 mL, 1.1 mmol) in DMSO (0.7

816 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Balsamini et al.
7.24 (m, 7H), 7.07 (m, 3H), 6.94 (d, 1H), 6.03 (d, 1H), 3.84 (s,
3H), 2.29 (s, 3H); IR (CDCl3) 3441, 1690, 1650 cm-1; MS (FAB)
m/z 361 (M + H)+.
Met h yl (E)-5-(2,4-d ich lor op h en yl)-4-m et h yl-3-[2-(N-
p h en ylca r ba m oyl)vin yl]p yr r ole-2-ca r boxyla te (5c): yield
86%; mp 256-8 °C (cyclohexane-EtOAc); 1H NMR (CDCl3) δ
9.16 (br s, 1H), 8.30 (d, J ) 15.8 Hz, 1H), 7.59 (m, 3H), 7.32
(m, 5H), 7.12 (m, 1H), 6.65 (d, J ) 15.8 Hz, 1H), 3.94 (s, 3H),
2.18 (s, 3H); IR (CDCl3) 3433, 1709, 1699, 1626 cm-1; MS (FAB)
m/z 429 (M + H)+.
Meth yl (E)-3-[2-(N-ph en ylcar bam oyl)vin yl]-4,5-diph en -
ylp yr r ole-2-ca r boxyla te (5d ): yield 93%: mp 220-3 °C; 1H
NMR (CDCl3) δ 9.45 (br s, 1H), 8.19 (d, J ) 16 Hz, 1H), 7.51-
7.02 (m, 10H), 6.02 (d, J ) 16 Hz, 1H), 3.96 (s, 3H); IR (Nujol)
3447, 3331, 1721, 1668, 1623, 1599 cm-1; MS (EI) m/z 422 (M+),
119 (100).
210 °C (MeOH); 1H NMR (DMSO) δ 11.47 (s, 1H), 10.05 (s,
1H), 8.22 (d, J ) 16 Hz, 1H), 7.67 (d, 2H), 7.30 (t, 2H), 7.02 (t,
1H), 6.59 (d, J ) 16 Hz, 1H), 3.79 (s, 3H), 3.08 (heptet, 1H),
2.15 (s, 3H), 1.21 (d, 6H); IR (Nujol) 3358, 3290, 1688, 1657
cm-1; MS (EI) m/z 326 (M+), 234 (100).
Meth yl (E)-4-eth oxy-5-m eth yl-3-[2-(N-p h en ylca r ba m -
oyl)vin yl]p yr r ole-2-ca r boxyla te (5n ): yield 55%; mp 214-5
1
°C (MeOH); H NMR (acetone-d6) δ 10.66 (br s, 1H), 9.33 (s,
1H), 8.30 (d, J ) 16 Hz, 1H), 7.78 (dd, 2H), 7.31 (td, 2H), 7.04
(m, 2H), 3.91 (q, 2H), 3.82 (s, 3H), 2.25 (s, 3H), 1.33 (t, 3H); IR
(Nujol) 3292, 1672, 1657, 1622 cm-1; MS (EI) m/z 328 (M+),
176 (100).
Meth yl (E)-4-(ben zyloxy)-5-m eth yl-3-[2-(N-p h en ylca r -
ba m oyl)vin yl]p yr r ole-2-ca r boxyla te (5o): yield 83%: mp
1
213 °C dec (MeOH); H NMR (DMSO) δ 11.67 (s, 1H), 10.12
(s, 1H), 8.08 (d, J ) 15.6 Hz, 1H), 7.69 (d, 2H), 7.4-7.28 (m,
7H), 7.03 (m, 1H), 6.99 (d, J ) 15.6 Hz, 1H), 4.84 (s, 2H), 3.79
(s, 3H), 1.86 (s 3H); IR (Nujol) 3306, 3265, 1678, 1655, 1624
cm-1; MS (EI) m/z 390 (M+), 91(100).
Eth yl (E)-4-eth yl-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)-
vin yl]p yr r ole-2-ca r boxyla te (5e): yield 36%; mp 231 °C
1
(MeOH); H NMR (DMSO) δ 11.72 (s, 1H), 10.06 (br s, 1H),
8.17 (d, J ) 16 Hz, 1H), 7.68 (d, 2H), 7.30 (t, 2H), 7.03 (t, 1H),
6.59 (d, J ) 16 Hz, 1H), 3.77 (s, 3H), 2.56 (q, 2H), 2.16 (s, 3H),
1.08 (t, 3H); IR (Nujol) 3304, 1674, 1659, 1620 cm-1; MS (FAB)
m/z 313 (M + H)+.
Meth yl (E)-5-eth yl-4-m eth yl-3-[2-(N-ph en ylcar bam oyl)-
vin yl]p yr r ole-2-ca r boxyla te (5f): yield 58%; mp 243 °C
(MeOH); 1H NMR (DMSO) δ 11.70 (s, 1H), 10.06 (s, 1H), 8.22
(d, J ) 16.4 Hz, 1H), 7.67 (d, 2H), 7.30 (t, 2H), 7.02 (t, 1H),
6.61 (d, J ) 16.4 Hz, 1H), 3.78 (s, 3H), 2.55 (q, 2H), 2.14 (s,
3H), 1.09 (t, 3H); IR (Nujol) 3306, 1682, 1657, 1620 cm-1; MS
(FAB) m/z 313 (M + H)+.
Meth yl (E)-4-br om o-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
5-p h en ylp yr r ole-2-ca r boxyla te (5p ): yield 70%; mp 254-5
°C (CHCl3); 1H NMR (CDCl3) δ 9.38 (br s, 1H), 8.25 (d, J ) 16
Hz, 1H), 7.67-7.13 (m, 10H), 7.24 (d, J ) 16 Hz, 1H), 3.97 (s,
3H); IR (Nujol) 3310, 1680, 1657 cm-1; MS (FAB) m/z 425, 427
(M + H)+.
E t h yl (E)-3-[2-(N-p h en ylca r b a m oyl)vin yl]p yr r ole-2-
ca r boxyla te (5q): yield 70%; mp 202-3 °C dec (THF-hexane);
1H NMR (DMSO) δ 12.02 (br s, 1H), 10.06 (br s, 1H), 8.14 (d,
J ) 16 Hz, 1H), 7.69-7.03 (m, 4H), 7.04 (m, 2H), 6.60 (d, J )
16 Hz, 1H), 6.50 (br s, 1H), 4.29 (q, 2H), 1.32 (t, 3H); IR (Nujol)
3296, 1678, 1659, 1622 cm-1; MS (EI) m/z 284 (M+), 164 (100).
Meth yl (E)-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r b oxyla t e (5r ): yield 65%; mp 291-3 °C dec
Meth yl (E)-4,5-d im eth yl-3-[2-(N-p h en ylca r ba m oyl)vi-
n yl]p yr r ole-2-ca r boxyla te (5 g): yield 50%; mp 243 °C
1
(MeOH); H NMR (acetone-d6) δ 10.75 (br s, 1H), 9.35 (br s,
1
1H), 8.43 (d, J ) 16 Hz, 1H), 7.77 (d, 2H), 7.30 (t, 2H), 7.04
(tt, 1H), 6.69 (d, J ) 16 Hz, 1H), 3.80 (s, 3H), 2.25 (s, 3H),
2.15 (s, 3H); IR (Nujol) 3290, 1672, 1655 cm-1; MS (FAB) m/z
299 (M + H)+.
(EtOAc); H NMR (CDCl3) δ 8.90 (br s, 1H), 8.23 (d, J ) 15.6
Hz, 1H), 7.63-7.12 (m, 6H), 6.39 (d, J ) 15.6 Hz, 1H), 3.92 (s,
3H), 2.30 (s, 3H); MS (FAB) m/z 285 (M + H)+.
Meth yl (E)-3-[2-(N-p h en ylca r ba m oyl)vin yl]-5-p h en yl-
pyr r ole-2-car boxylate (5s): yield 77%; mp 234-5 °C (CHCl3);
1H NMR (DMSO) δ 10.17 (s, 1H), 8.14 (d, J ) 15.7 Hz, 1H),
7.90-7.04 (m, 10H), 6.94 (s, 1H), 6.70 (d, J ) 15.7 Hz, 1H),
3.87 (s, 3H); IR (Nujol) 3319, 1689, 1653, 1617 cm-1; MS (EI)
m/z 346 (M+), 254 (100).
Eth yl (E)-3-[2-(N-p h en ylca r ba m oyl)vin yl]cyclop en ta -
[b]pyr r ole-2-car boxylate (5h ): yield 78%; mp 258 °C (EtOAc);
1H NMR (DMSO) δ 11.70 (br s, 1H), 10.05 (br s, 1H), 8.18 (d,
J ) 16 Hz, 1H), 7.69 (d, 2H), 7.30 (t, 2H), 7.03 (t, 1H), 6.49 (d,
J ) 16 Hz, 1H), 4.25 (q, 2H), 2.78-2.40 (m, 6H), 1.29 (t, 3H);
IR (Nujol) 3279, 1672, 1653, 1616 cm-1; MS (FAB) m/z 325 (M
+ H)+.
Eth yl (E)-3-[2-(N-p h en ylca r ba m oyl)vin yl]cycloh exa [b]-
pyr r ole-2-car boxylate (5i): yield 50%; mp 309-11 °C (EtOAc);
1H NMR (DMSO) δ 11.64 (s, 1H), 10.04 (s, 1H), 8.27 (d, J )
16 Hz, 1H), 7.67 (d, 2H), 7.30 (t, 2H), 7.02 (t, 1H), 6.53 (d, J )
16 Hz, 1H), 4.25 (q, 2H), 2.63 (m, 2H), 2.54 (m, 2H), 1.74 (m,
4H), 1.30 (t, 3H); IR (Nujol) 3290, 1670, 1653, 1618 cm-1; MS
(FAB) m/z 339 (M + H)+.
Meth yl (E)-4-br om o-5-m eth yl-3-[2-(N-p h en ylca r ba m -
oyl)vin yl]p yr r ole-2-ca r boxyla te (5j): yield 82%; mp 240 °C
dec (MeOH-Et2O-petroleum ether); 1H NMR (DMSO) δ 12.42
(br s, 1H), 10.21 (s, 1H), 8.09 (d, J ) 16 Hz, 1H), 7.20 (d, J )
16 Hz, 2H), 7.69-7.03 (m, 5H), 3.81 (s, 3H), 2.20 (s, 3H); IR
(Nujol) 3287, 1672, 1597 cm-1; MS (EI) m/z 362, 364 (M+), 283
(100).
Meth yl (E)-4-ch lor o-5-m eth yl-3-[2-(N-p h en ylca r ba m -
oyl)vin yl]p yr r ole-2-ca r boxyla te (5k ): yield 80%; mp 231-2
°C (THF-hexane); 1H NMR (DMSO) δ 12.35 (br s, 1H), 10.20
(s, 1H), 8.13 (d, J ) 15.9 Hz, 1H), 7.69 (d, 2H), 7.30 (t, 2H),
7.15 (d, J ) 15.9 Hz, 1H), 7.03 (t, 1H), 3.82 (s, 3H), 2.20 (s,
3H); IR (Nujol) 3288, 1674, 1626 cm-1; MS (FAB) m/z 319 (M
+ H)+.
Eth yl (E)-3-[2-(N-ph en ylcar bam oyl)vin yl]-4-ph en ylpyr -
r ole-2-ca r boxyla te (5t): yield 62%; mp 188-89 °C (i-Pr2O);
1H NMR (CDCl3) δ 9.29 (s, 1H), 8.23 (d, J ) 15.7 Hz, 1H),
7.54-7.26 (m, 9H), 7.08 (m, 1H), 7.00 (br s, 1H), 6.94 (m, 1H),
6.34 (d, J ) 15.7 Hz, 1H), 4.42 (q, 2H), 1.44 (t, 3H); IR (Nujol)
3292, 1672-1622 cm-1; MS (FAB) m/z 361 (M + H)+.
Meth yl (E)-N,4,5-tr im eth yl-3-[2-(N-p h en ylca r ba m oyl)-
vin yl]p yr r ole-2-ca r boxyla te (5u ): yield 51%; mp 205 °C
(MeOH); 1H NMR (DMSO) δ 10.05 (br s, 1H), 8.10 (d, J ) 16.2
Hz, 1H), 7.67 (dd, 2H), 7.30 (t, 2H), 7.02 (tt, 1H), 6.50 (d, J )
16.2 Hz, 1H), 3.78 (s, 3H), 3.72 (s, 3H), 2.18 (s, 3H), 2.14 (s,
3H); IR (Nujol) 3261, 1693, 1657 cm-1; MS (EI) m/z 312 (M+).
Eth yl (E)-4-Br om o-3-[2-(N-ph en ylcar bam oyl)vin yl]pyr -
r ole-2-ca r boxyla te (5v): yield 70%; mp 207-8 °C (EtOAc-
1
hexane); H NMR (acetone-d6) δ 11.55 (br s, 1H), 9.56 (br s,
1H), 8.35 (d, J ) 16 Hz, 1H), 7.29 (d, J ) 16 Hz, 1H), 7.82-
7.06 (m, 6H), 4.32 (q, 2H), 1.38 (t, 3H); IR (Nujol) 3275, 1675,
1653, 1623 cm-1; MS (FAB) m/z 363, 365 (M + H)+.
Eth yl (E)-4,5-d ibr om o-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
pyr r ole-2-car boxylate (5w): yield 77%; mp 256-7 °C (EtOAc-
1
hexane); H NMR (acetone-d6) δ 12.30 (br s, 1H), 9.59 (br s,
1H), 8.32 (d, J ) 16 Hz, 1H), 7.82-7.07 (m, 5H), 7.30 (d, J )
16 Hz, 1H), 4.33 (q, 2H), 1.35 (t, 3H); IR (Nujol) 3286, 3232,
1683, 1661, 1626 cm-1; MS (FAB) m/z 443 (M + H)+.
Met h yl (E)-4-isop r op yl-5-m et h yl-3-[2-(N-p h en ylca r -
ba m oyl)vin yl]p yr r ole-2-ca r boxyla te (5l): yield 68%; mp
199 °C (MeOH-Et2O); 1H NMR (DMSO) δ 11.66 (s, 1H), 10.07
(s, 1H), 8.01 (d, J ) 16 Hz, 1H), 7.68 (d, 2H), 7.30 (t, 2H), 7.03
(t, 1H), 6.52 (d, J ) 16 Hz, 1H), 3.75 (s, 3H), 3.14 (heptet, 1H),
Eth yl (E)-4,5-Diiod o-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r boxyla te (5x). NIS (0.25 g, 1.11 mmol) was
added to a solution of 5q (0.142 g, 0.5 mmol) in THF (4 mL)
and CH2Cl2 (20 mL), and the mixture was stirred at room
temperature for 16 h; the mixture was then cooled, washed
with 2 N NaOH and with water, dried (Na2SO4), and evapo-
rated to give a crude material from which 5x was obtained by
flash chromatography (silica gel; CH2Cl2/EtOAc, 95:5, as
2.26 (s, 3H), 1.24 (d, 6H); IR (Nujol) 3288, 1672, 1620 cm-1
;
MS (EI) m/z 326 (M+), 234 (100).
Met h yl (E)-5-isop r op yl-4-m et h yl-3-[2-(N-p h en ylca r -
ba m oyl)vin yl]p yr r ole-2-ca r boxyla te (5m ): yield 98%; mp

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 817
eluent) and crystallization (acetone-hexane): yield 0.107 g
(40%); mp 246-50 °C; 1H NMR (acetone-d6) δ 9.89 (br s, 1H),
8.33 (d, J ) 15.8 Hz, 1H), 7.85-6.95 (m, 5H), 7.18 (d, J ) 15.8
Hz, 1H), 4.22 (q, 2H), 1.33 (s, 3H); IR (Nujol) 3258, 1682, 1660
cm-1; MS (EI) m/z 536 (M+), 207 (100).
(E)-4,5-Dip h en yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]p yr -
r ole-2-ca r boxylic a cid (6d ): yield 56%; mp 250-60 °C dec
(EtOH-H2O, 10%); 1H NMR (DMSO) δ 9.64 (s, 1H), 8.22 (d, J
) 15.9 Hz, 1H), 7.64 (m, 2H), 7.42-7.06 (m, 12H), 6.96 (m,
1H), 6.37 (d, J ) 15.9 Hz, 1H); IR (Nujol) 3402, 1616, 1599
cm-1; MS (FAB) m/z 409 (M + H)+. Anal. (C26H20N2O3‚2.5H2O)
C, H, N.
Meth yl (E)-4-Iod o-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)-
vin yl]p yr r ole-2-ca r boxyla te (5y). NIS (0.1 g, 0.45 mmol)
was added to a suspension of 5r (0.11 g, 0.38 mmol) in dry
CH2Cl2 (8 mL), and the mixture was stirred at room temper-
ature until the starting material was found to have disap-
peared by TLC analysis (about 4 h were necessary); then it
was washed once with 2 N NaOH and twice with water. The
organic phase was dried (Na2SO4) and the solvent evaporated
to give a residue that was purified by crystallization from
(E)-4-Eth yl-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6e): yield 60%; mp 180 °C dec
1
(MeOH); H NMR (DMSO) δ 10.91 (s, 1H), 9.91 (s, 1H), 8.71
(d, J ) 16.2 Hz, 1H), 7.68 (d, 2H), 7.27 (t, 2H), 6.98 (t, 1H),
6.40 (d, J ) 16.2 Hz, 1H), 2.53 (q, 2H), 2.11 (s, 3H), 1.07 (t,
3H); IR (Nujol) 3292, 1649, 1589 cm-1; MS (FAB) m/z 299 (M
+ H)+. Anal. (C17H18N2O3‚H2O) C, H, N.
1
MeOH-i-Pr2O: quantitative yield; mp 234 °C dec; H NMR
(E)-5-Eth yl-4-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6f): yield 79%; mp 196 °C dec
(acetone-d6, 60 MHz) δ 9.4 (br, 1H), 8.3 (d, J ) 16 Hz, 1H),
7.8-7.2 (m, 6H), 3.8 (s, 3H), 2.3 (s, 3H); IR (Nujol) 3280, 1675,
1623, 1595 cm-1; MS (EI) m/z 410 (M+), 191(100).
1
(MeOH); H NMR (DMSO) δ 12.51 (br s, 1H), 11.56 (s, 1H),
10.03 (s, 1H), 8.29 (d, J ) 16.2 Hz, 1H), 7.67 (d, 2H), 7.30 (t,
2H), 7.02 (t, 1H), 6.56 (d, J ) 16.2 Hz, 1H), 2.54 (q, 2H), 2.14
(s, 3H), 1.08 (t, 3H); IR (Nujol) 3121, 1676, 1610 cm-1; MS
(FAB) m/z 299 (M + H)+. Anal. (C17H18N2O3) C, H, N.
(E)-4,5-Dim eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]p yr -
r ole-2-ca r boxylic a cid (6 g): yield 88%; mp 197 °C. (EtOAc);
1H NMR (acetone-d6) δ 12.48 (br s, 1H), 11.59 (s, 1H), 10.03
(s, 1H), 8.30 (d, J ) 16.2 Hz, 1H), 7.68 (m, 2H), 7.31 (m, 1H),
7.03 (m, 1H), 6.58 (d, J ) 16.2 Hz, 1H), 2.16 (s, 3H), 2.14 (s,
3H); IR (Nujol) 3300-3000, 1670 cm-1; MS (FAB) m/z 285 (M
+ H)+. Anal. (C16H16N2O3‚MeOH) C, H, N.
Meth yl (E)-4-Acetyl-5-m eth yl-3-[2-(N-p h en ylca r ba m -
oyl)vin yl]p yr r ole-2-ca r boxyla te (5z). SnCl2‚2H2O (0.09 g,
0.4 mmol) was added in five portions (over 20 min) to a stirred
suspension of 5r (0.09 g, 0.31 mmol) in acetic anhydride (1.2
mL) at 55 °C, and the mixture was heated for 1 h at 55 °C.
After evaporation of the solvent under reduced pressure, the
crude material obtained was purified by flash chromatography
on silica gel, using cyclohexanes-EtOAc, 1:1, as eluent,
furnishing the desired product which was further purified by
crystallization from MeOH-i-Pr2O: yield 0.083 g (82%); mp
235-6 °C; 1H NMR (DMSO) δ 12.32 (s, 1H), 10.12 (s, 1H), 8.03
(d, J ) 16 Hz, 1H), 7.67 (dd, 2H), 7.30 (td, 2H), 7.03 (tt, 1H),
6.50 (d, J ) 16 Hz, 1H), 3.80 (s, 3H), 2.37 (s, 3H), 2.35 (s, 3H);
IR (Nujol) 3290, 1678, 1661, 1628 cm-1; MS (EI) m/z 326 (M+),
192 (100).
(E)-3-[2-(N-p h en ylca r ba m oyl)vin yl]cyclop en ta [b]p yr -
r ole-2-car boxylic acid (6h ): yield 78%; mp 214-6 °C (EtOH-
H2O 10%); 1H NMR (DMSO) δ 12.46 (br s, 1H), 11.59 (s, 1H),
10.03 (s, 1H), 8.21 (d, J ) 15.6 Hz, 1H), 7.65 (m, 2H), 7.30 (m,
2H), 7.02 (m, 1H), 6.45 (d, J ) 15.6 Hz, 1H), 2.77-2.38 (m,
6H); IR (Nujol) 3300-2500, 3207, 2500, 1668, 1610 cm-1; MS
(FAB) m/z 297 (M + H)+. Anal. (C17H16N2O3) C, H, N.
(E)-3-[2-(N-ph en ylcar bam oyl)vin yl]cycloh exa[b]pyr r ole-
2-ca r boxylic a cid (6i): yield 92%; mp 198 °C (EtOH-H2O,
10%); 1H NMR (DMSO) δ 12.5 (br s, 1H), 11.54 (s, 1H), 10.01
(s, 1H), 8.28 (d, J ) 16 Hz, 1H), 7.66 (d, 2H), 7.29 (t, 2H), 7.01
(t, 1H), 6.47 (d, J ) 16 Hz, 1H), 2.62-2.47 (m, 4H), 1.73 (m,
4H); IR (Nujol) 3315, 3192, 1645, 1601 cm-1; MS (FAB) m/z
311 (M + H)+. Anal. (C18H18N2O3 ‚ H2O) C, H, N.
Gen er a l P r oced u r e for th e p r ep a r a tion of (E)-3-[2-(N-
p h en ylca r ba m oyl)vin yl]p yr r ole-2-ca r boxylic Acid s (6a -
z). A suspension of the suitable esters 10a -z (1 mmol) and
LiOH‚H2O (4 mmol) was refluxed (60 h at room temperature
for 6z) in a mixture of methanol or ethanol (8 mL) and water
(2 mL). The disappearance of the starting esters was moni-
tored by TLC (cyclohexanes-EtOAc, 1:1, as eluent). After
evaporation of the solvent in vacuo, the residue was dissolved
in water (5 mL), acidified (2 N HCl), and extracted (2×) with
EtOAc, and then the combined organic extracts were washed
with water (4x) and dried (Na2SO4). The solvent was evapo-
rated in vacuo, and the residues were purified by crystalliza-
tion (6c was purified by flash chromatography on silica gel
using cyclohexanes-EtOAc, 3:7, as eluent). The hydrolysis
of 6y was stopped after 4 h to avoid dehalogenation. Some of
these carboxylic acids crystallized with variable quantities of
the crystallization solvents that were found to be very difficult
to eliminate. The presence of these solvents, whenever
(E)-4-Br om o-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6j): yield 70%; mp 200 °C dec
1
(MeOH-Et2O-hexane); H NMR (DMSO) δ 12.99 (br s, 1H),
12.27 (s, 1H), 10.19 (s, 1H), 8.17 (d, J ) 16 Hz, 1H), 7.69 (d,
2H), 7.30 (t, 2H), 7.17 (d, J ) 16 Hz, 1H), 7.03 (t, 1H), 2.19 (s,
3H); IR (Nujol) 3294, 1666, 1605 cm-1; MS (FAB) m/z 348, 350
(M + H)+. Anal. (C15H13BrN2O3‚H2O) C, H, N.
(E)-4-Ch lor o-5-m eth yl-3-[2-(N-ph en ylcar bam oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6k ): yield 82%; mp 230 °C dec
1
1
substantiated by H NMR, was taken into account in calculat-
(EtOAc-hexane); H NMR (DMSO) δ 12.98 (br s, 1H), 12.21
ing the microanalytical results.
(s, 1H), 10.19 (s, 1H), 8.21 (d, J ) 16 Hz, 1H), 7.71 (d, 2H),
7.33 (t, 2H), 7.14 (d, J ) 16 Hz, 1H), 7.06 (t, 1H), 2.21 (s, 3H);
IR (Nujol) 3207, 1678, 1610 cm-1; MS (FAB) m/z 305 (M +
H)+. Anal. (C15H13ClN2O3‚0.5H2O) C, H, N.
(E)-3-[2-(N-P h en ylcar bam oyl)vin yl]-4-m eth yl-5-ph en yl-
p yr r ole-2-ca r boxylic a cid (6a ): yield 38%; amorphous solid;
1H NMR (acetone-d6) δ 12-10 (br, 1H), 10.94 (s, 1H), 9.39 (s,
1H), 8.56 (d, J ) 15.6 Hz, 1H), 7.78 (m, 2H), 7.58 (m, 2H),
7.48 (m, 2H), 7.35 (m, 3H), 7.05 (m, 1H), 6.77 (d, J ) 15.6 Hz,
1H), 2.34 (s, 3H); IR (Nujol) 3500, 3300, 1659, 1622 cm-1; MS
(FAB) m/z 347 (M + H)+. Anal. (C21H18N2O3‚2H2O) C, H, N.
(E)-5-Meth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-4-p h en -
ylp yr r ole-2-ca r boxylic a cid (6b): yield 35%; mp >300 °C
(EtOH-H2O, 10%); 1H NMR (DMSO) δ 11.18 (s, 1H), 9.55 (s,
1H), 8.50 (d, J ) 16.4 Hz, 1H), 7.58 (d, 2H), 7.38 (m, 2H), 7.27-
7.18 (m, 5H), 6.94 (t, 1H), 5.98 (d, J ) 16.4 Hz, 1H), 2.06 (s,
3H); IR (Nujol) 3612, 3192, 1653, 1601 cm-1; MS (FAB) m/z
347 (M + H)+. Anal. (C21H18N2O3‚2.5H2O) C, H, N.
(E)-5-(2,4-Dich lor op h en yl)-4-m eth yl-3-[2-(N-p h en ylca r -
ba m oyl)vin yl]p yr r ole-2-ca r boxylic a cid (6c): yield 54%;
amorphous solid; 1H NMR (DMSO) δ 11.17 (br s, 1H), 9.91 (br
s, 1H), 8.73 (d, J ) 15.9 Hz, 1H), 7.67 (d, 3H), 7.40 (m, 2H),
7.28 (t, 2H), 6.99 (t, 1H), 6.49 (d, J ) 15.9 Hz, 1H), 2.1 (s, 3H);
IR (Nujol) 3412, 3184, 1655, 1599 cm-1; MS (FAB) m/z 415 (M
+ H)+. Anal. (C21H16Cl2N2O3‚1.5H2O) C, H, N.
(E)-4-Isop r op yl-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vi-
n yl]p yr r ole-2-ca r boxylic a cid (6l): yield 71%; mp 180 °C
dec (i-Pr2O); 1H NMR (DMSO) δ 12.38 (br s, 1H), 11.51 (s, 1H),
10.04 (s, 1H), 8.10 (d, J ) 16 Hz, 1H), 7.67 (d, 2H), 7.30 (t,
2H), 7.02 (t, 1H), 6.46 (d, J ) 16 Hz, 1H), 3.16 (heptet, 1H),
2.25 (s, 3H), 1.24 (d, 6H); IR (Nujol) 3304, 3267, 1657, 1620
cm-1; MS (FAB) m/z 313 (M + H)+. Anal. (C18H21N2O3‚0.5H2O)
C, H, N.
(E)-5-Isop r op yl-4-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vi-
n yl]p yr r ole-2-ca r boxylic a cid (6m ): yield 76%: mp 190 °C
dec (MeOH-i-Pr2O); 1H NMR (DMSO) δ 12.53 (br s, 1H), 11.35
(s, 1H), 10.02 (s, 1H), 8.28 (d, J ) 16 Hz, 1H), 7.67 (d, 2H),
7.29 (t, 2H), 7.02 (t, 1H), 6.55 (d, J ) 16 Hz, 1H), 3.06 (m,
1H), 2.15 (s, 3H), 1.20 (d, 6H); IR (Nujol) 3450-3261, 1649,
1628 cm-1; MS (FAB) m/z 313 (M + H)+. Anal. (C18H20N2O3)
C, H, N.
(E)-4-Eth oxy-5-m eth yl-3-[2-(N-ph en ylcar bam oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6n ): yield 60%; mp 168 °C dec

818 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6
Balsamini et al.
1
(MeOH-i-Pr2O); H NMR (DMSO) δ 12.58 (s, 1H), 11.54 (s,
16 Hz, 1H), 7.03 (t, 1H); IR (Nujol) 3441, 1659 cm-1; MS (FAB)
m/z 509 (M + H)+. We were unable to obtain an analytically
pure sample of this compound due to the presence of small
amounts of the monoiodo derivative.
1H), 10.06 (s, 1H), 8.14 (d, J ) 16 Hz, 1H), 7.68 (d, 2H), 7.29
(t, 2H), 7.02 (t, 1H), 6.88 (d, J ) 16 Hz, 1H), 3.84 (q, 2H), 2.12
(s, 3H), 1.31 (t, 3H); IR (Nujol) 3275, 1661, 1620 cm-1; MS
(FAB) m/z 315 (M + H)+. Anal. (C17H18N2O4‚i-Pr2O) C, H, N.
(E)-4-(Ben zyloxy)-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)-
vin yl]p yr r ole-2-ca r boxylic a cid (6o): yield 90%: mp 163
°C dec (EtOH-Et2O-hexane); 1H NMR (DMSO) δ 12.63 (s,
1H), 11.52 (s, 1H), 10.10 (s, 1H), 8.18 (d, J ) 16 Hz, 1H), 7.72
(m, 2H), 7.44-7.30 (m, 7H), 7.05 (m, 1H), 6.96 (d, J ) 16 Hz,
1H), 4.86 (s, 2H), 1.89 (s 3H); IR (Nujol) 3281, 3100-2500,
1659, 1626 cm-1; MS (FAB) m/z 377 (M + H)+. Anal.
(C20H20N2O4‚H2O) C, H, N.
(E)-4-Br om o-3-[2-(N-p h en ylca r b a m oyl)vin yl]-5-p h en -
ylp yr r ole-2-ca r boxylic a cid (6p ): yield 75%; mp 257-60 °C
(acetone-hexane); H NMR (DMSO) δ 10.04 (br s, 1H), 8.63
(d, J ) 16.2 Hz, 1H), 7.70 (d, 2H), 7.65 (d, 2H), 7.41 (t, 2H),
7.32 (t, 1H), 7.28 (t, 2H), 7.17 (d, J ) 16.2 Hz, 1H), 7.00 (t,
1H); IR (Nujol) 3196, 1657, 1600 cm-1; MS (FAB) m/z 411, 413
(M + H)+. Anal. (C20H15BrN2O3‚2H2O) C, H, N.
(E)-4-Iod o-5-m et h yl-3-[2-(N-p h en ylca r b a m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6y): yield 34%; mp >300 °C
1
(MeOH); H NMR (acetone-d6) δ 11.3 (br s, 1H), 11.25 (br s,
1H), 9.5 (s, 1H), 8.32 (d, J ) 16 Hz, 1H), 7.79 (d, 2H), 7.34 (d,
J ) 16 Hz, 1H), 7.31 (t, 1H), 7.05 (tt, 1H), 2.35 (s, 3H); IR
(Nujol) 3292, 3192, 1661, 1624 cm-1; MS (FAB) m/z 397 (M +
H)+. Anal. (C15H13IN2O3‚H2O) C, H, N.
(E)-4-Acetyl-5-m eth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6z): yield 58%; mp 213 °C
1
(MeOH-i-Pr2O); H NMR (acetone-d6) δ 11.2 (br s, 1H), 9.4
(br s, 1H), 8.33 (d, J ) 15.6 Hz, 1H), 7.79 (d, 2H), 7.30 (t, 2H),
7.05 (tt, 1H), 6.58 (d, J ) 15.6 Hz, 1H), 2.48 (s, 3H), 2.40 (s,
3H); IR (Nujol) 3285, 1668, 1638, 1618 cm-1; MS (FAB) m/z
313 (M + H)+. Anal. (C17H16N2O4) C, H, N.
1
P h a r m a cology. Bin d in g Assa ys. The test compounds
were dissolved at a concentration of 5 mM in 100% DMSO and
tested at seven concentrations (0.1 nM to 100 µM) in duplicate
in the [3H]glycine displacement experiments and, in duplicate,
at five concentrations (10 nM to 100 µM) in the other binding
assays. A reference compound was always included as a
control.
(E)-3-[2-(N-P h en ylca r ba m oyl)vin yl]p yr r ole-2-ca r box-
ylic a cid (6q): yield 81%; mp 233-37 °C dec (acetone-
hexane); 1H NMR (DMSO) δ 12.83 (s, 1H), 11.90 (s, 1H), 10.04
(s, 1H), 8.16 (d, J ) 15.6 Hz, 1H), 7.66 (m, 2H), 7.30 (m, 2H),
7.02 (m, 1H), 6.98 (t, 1H), 6.55 (d, J ) 15.6 Hz, 1H), 6.46 (t,
1H); IR (Nujol) 3369, 3304, 1680, 1657, 1626 cm-1; MS (FAB)
m/z 257 (M + H)+. Anal. (C14H12N2O3‚0.2H2O) C, H, N.
(E)-5-Meth yl-3-[2-(N-p h en ylca r ba m oyl)vin yl]p yr r ole-
2-ca r boxylic a cid (6r ): yield 98%; mp 245-252 °C dec
Affinity for the glycine-binding site was measured by
inhibition of the binding of [3H]glycine to crude synaptic
membranes prepared from adult rat cerebral cortex, as
described by Kishimoto et al.42 Incubation (20 min 4 °C) was
carried out in 50 mM Tris/citrate (pH 7.10) using 20 nM [3H]-
glycine. Data from displacement experiments, performed to
determine the inhibition constants (Ki) of displacer ligands,
were analyzed using the nonlinear curve-fitting software
program LIGAND.43 Ki values were measured from at least
six-point inhibition curves and are the geometric mean of at
least three different experiments. Inhibition of binding in [3H]-
CPP, [3H]AMPA, and [3H]kainic acid experiments was per-
formed in this case according to the methods by van Amster-
dam et al.,44 Giberti et al.,45 and Honore´ et al.46
1
(MeOH); H NMR (DMSO) δ 12.60 (br s, 1H), 11.65 (s, 1H),
10.01 (s, 1H), 8.13 (d, J ) 16 Hz, 1H), 7.66 (d, 2H), 7.29 (t,
2H), 7.02 (t, 1H), 6.48 (d, J ) 16 Hz, 1H), 6.17 (d, 1H), 2.19 (s,
3H); IR (Nujol) 3142, 1655 cm-1; MS (FAB) m/z 271 (M + H)+.
Anal. (C15H14N2O3‚MeOH) C, H, N.
(E)-3-[2-(N-P h en ylca r ba m oyl)vin yl]-5-p h en ylp yr r ole-
2-ca r boxylic a cid (6s): yield 84%; mp 219-21 °C (MeOH-
EtOAc); 1H NMR (DMSO) δ 12.08 (br s, 1H), 10.9 (s, 1H), 8.21
(d, J ) 15.9 Hz, 1H), 7.86 (d, 2H), 7.68 (d, 2H), 7.40 (t, 2H),
7.33-7.27 (m, 3H), 7.03 (t, 1H), 6.89 (s, 1H), 6.64 (d, J ) 15.9
Hz, 1H); IR (Nujol) 3396, 3310, 1661, 1595 cm-1; MS (FAB)
m/z 333 (M + H)+. Anal. (C20H16N2O3) C, H, N.
(E)-3-[2-(N-P h en ylca r ba m oyl)vin yl]-4-p h en ylp yr r ole-
2-ca r boxylic a cid (6t): yield 70%; mp 132-6 °C (EtOAc-
hexane); H NMR (CDCl3) δ 9.92 (s, 1H), 8.27 (d, J ) 16 Hz,
1H), 7.7 (s, 1H), 7.52 (m, 2H), 7.27-7.2 (m, 7H), 7.04 (m, 1H),
6.80 (d, 1H), 6.28 (d, J ) 16 Hz, 1H); IR (Nujol) 3321-3140,
1715, 1688 cm-1; MS (FAB) m/z 333 (M + H)+. Anal.
(C20H16N2O3‚EtOAc) C, H, N.
(E)-N,4,5-Tr im et h yl-3-[2-(N-p h en ylca r b a m oyl)vin yl]-
p yr r ole-2-ca r boxylic a cid (6u ): yield 77%; mp 174 °C dec
Enhancement of the binding of the channel blocking agent
[3H]TCP30 was expressed as the degree (R) of agonism (R ) 1
full agonist; 0 < a <1; partial agonist; R ) 0 full antagonist)
of the test compound as compared to glycine which was taken
as a full agonist (Table 2) in an extensively washed glycine-
sensitive rat cortical preparation.47 The R ratio measures the
relative ability of the compound to open the NMDA receptor-
associated ion channel allowing more [3H]TCP to bind to its
site inside the channel. Binding of [3H]TCP was carried out
(2 h, 30 °C) in Tris/5mM HCl (pH 7.7) and in the presence of
1 µM glutamic acid. Nonspecific binding was determined by
using 30 µM of (+)-MK801. In the presence of increasing
concentrations of the test compound, parallel rightward shifts
of the glycine concentration-response curves could be ob-
served, with no depression of the maximum response.
1
1
(MeOH); H NMR (DMSO) δ 12.64 (br s, 1H), 10.04 (s, 1H),
8.26 (d, J ) 16 Hz, 1H), 7.68 (d, 2H), 7.32 (t, 2H), 7.05 (t, 1H),
6.51 (d, J ) 16 Hz, 1H), 3.76 (s, 3H), 2.20 (s, 3H), 2.17 (s, 3H);
IR (Nujol) 3285, 1657, 1626 cm-1; MS (FAB) m/z 299 (M +
H)+. Anal. (C17H18N2O3) C, H, N.
An ticon vu lsa n t Effect.48 The selected compounds were
evaluated in vivo by assessing their anticonvulsant effects.
Convulsions were induced in male CD-1 mice (18-29 g) by
icv injection of NMDA (1 nmol/mouse) 1 min and 1 h after the
iv or the po administration of the test compound, respectively.
Animals were observed for the occurrence of generalized
seizures during the first 30 min after NMDA treatment and
were considered to be protected if convulsions did not occur
within this time. The percentage of animals showing convul-
sions in each treatment group was recorded and ED50 values,
i.e., the protecting dose of the compound giving 50% anticon-
vulsant effect, were estimated along with their 95% confidence
limits (Cl 95).
(E)-4-Br om o-3-[2-(N-p h en ylca r b a m oyl)vin yl]p yr r ole-
2-ca r boxylic a cid (6v): yield 80%; mp 190 °C dec (MeOH-
Et2O-petroleum ether); 1H NMR (DMSO) δ 13.15 (s, 1H),
12.39 (s, 1H), 10.20 (s, 1H), 8.16 (d, J ) 16 Hz, 1H), 7.69 (d,
2H), 7.30 (m, 2H), 7.21 (d, 1H), 7.16 (d, J ) 16 Hz, 1H), 7.03
(m, 1H); IR (Nujol) 3400-2400, 1659, 1601 cm-1; MS (FAB)
m/z 334-336 (M + H)+. Anal. (C14H11BrN2O3‚0.5H2O) C, H,
N.
(E)-4,5-Dib r om o-3-[2-(N-p h en ylca r b a m oyl)vin yl]p yr -
r ole-2-ca r boxylic a cid (6w ): yield 80%; mp 256-7 °C
(MeOH-Et2O-petroleum ether); 1H NMR (DMSO) δ 13.30 (br
d, 2H), 10.24 (s, 1H), 8.14 (d, J ) 16 Hz, 1H), 7.68 (d, 2H),
7.30 (t, 2H), 7.16 (d, J ) 16 Hz, 1H), 7.04 (m, 1H); IR (Nujol)
3410, 3275, 1674, 1612 cm-1; MS (FAB) m/z 415 (M + H)+.
Anal. (C14H10Br2N2O3‚0.5H2O) C, H, N.
Ack n ow led gm en t. The authors of the University
of Urbino gratefully acknowledge financial support from
GlaxoWellcome; they also thank Mr. Francesco Palazzi
for technical assistance.
(E)-4,5-Diiod o-3-[2-(N-p h en ylca r ba m oyl)vin yl]p yr r ole-
2-ca r boxylic a cid (6x): yield 50%; mp >310 °C (acetone-
1
hexane); H NMR (DMSO) δ 13.14 (br s, 1H), 10.23 (s, 1H),
8.06 (d, J ) 16 Hz, 1H), 7.70 (d, 2H), 7.30 (t, 2H), 7.14 (d, J )

A Novel Class of Glycine Site Antagonists
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 6 819
G. R.; Saywell, K. L.; Tricklebank, M. D. 3′-(Arylmethyl)- and
3′-(Aryloxy)-3-phenyl-4-hydroxyquinolin-2(1H)-ones: Orally Ac-
tive Antagonists of the Glycine Site on the NMDA Receptor. J .
Med. Chem. 1994, 37, 1402-1405.
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