2-substituted (2SR)-2-amino-2-((1SR,2SR)-2-carboxycycloprop-1- yl)glycines as potent and selective antagonists of group II metabotropic glutamate receptors. 2. Effects of aromatic substitution, pharmacological characterization, and bioavailability

Article abstract of DOI:10.1021/jm970498o

In this paper we describe the synthesis of a series of α-substituted analogues of the potent and selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1'S,2'S)-carboxycyclopropylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity realized for the α-phenylethyl analogue 3, in this paper we explored the effects of substitution on the aromatic ring as a strategy to increase the affinity of these compounds for group II mGluRs. Affinity for group II mGluRs was measured using [³H]glutamic acid (Glu) binding in rat forebrain membranes. Antagonist activity was confirmed for these compounds by measuring their ability to antagonize (1S,3R)-1- aminocyclopentane-1,3-dicarboxylic acid-induced inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2 and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-fold increases in affinity. Substitution with p-fluorine, as in 97 (IC₅₀ = 0.022 ± 0.002), was the exception. Here, a greater increase in affinity was realized than for either the ortho- or meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution of the aromatic. At best, only modest increases in affinity were realized for certain compounds bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and 104, were resolved into their four constituent isomers, and affinity and functional activity for group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1. With an IC₅₀ = 2.9 ± 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent compound from this SAR. Amino acid 168 demonstrated high plasma levels following intraperitoneal (ip) administration and readily penetrated into the brain. This compound, however, had only limited (~5%) oral bioavailability. Systemic administration of 168 protected mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with an ED₅₀ = 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study the role of group II mGluRs in disease.

Full text of DOI:10.1021/jm970498o

358
J . Med. Chem. 1998, 41, 358-378
2-Su bstitu ted (2SR)-2-Am in o-2-((1SR,2SR)-2-ca r boxycyclop r op -1-yl)glycin es a s
P oten t a n d Selective An ta gon ists of Gr ou p II Meta botr op ic Glu ta m a te
Recep tor s. 2. Effects of Ar om a tic Su bstitu tion , P h a r m a cologica l
Ch a r a cter iza tion , a n d Bioa va ila bility
Paul L. Ornstein,* Thomas J . Bleisch, M. Brian Arnold, J oseph H. Kennedy, Rebecca A. Wright,
Bryan G. J ohnson, J oseph P. Tizzano, David R. Helton, Mary J eanne Kallman, and Darryle D. Schoepp
Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285
Marc He´rin
Lilly Development Centre S.A., Parc Scientifique de Louvain-la-Neuve, Rue Granbonpre, 11, 1348 Mont Saint-Guibert, Belgium
Received J uly 30, 1997
In this paper we describe the synthesis of a series of R-substituted analogues of the potent and
selective group II metabotropic glutamate receptor (mGluR) agonist (1S,1′S,2′S)-carboxycyclo-
propylglycine (2, L-CCG 1). Incorporation of a substituent on the amino acid carbon converted
the agonist 2 into an antagonist. All of the compounds were prepared and tested as a series
of four isomers, i.e., two racemic diastereomers. On the basis of the improvement in affinity
realized for the R-phenylethyl analogue 3, in this paper we explored the effects of substitution
on the aromatic ring as a strategy to increase the affinity of these compounds for group II
mGluRs. Affinity for group II mGluRs was measured using [3H]glutamic acid (Glu) binding
in rat forebrain membranes. Antagonist activity was confirmed for these compounds by
measuring their ability to antagonize (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced
inhibition of forskolin stimulated cyclic-AMP in RGT cells transfected with human mGluR2
and mGluR3. Meta substitution on the aromatic ring of 3 with a variety of substituents, both
electron donating (e.g., methyl, hydroxy, amino, methoxy, phenyl, phenoxy) and electron
withdrawing (e.g., fluorine, chlorine, bromine, carboxy, trifluoromethyl) gave from 1.5- to 4.5-
fold increases in affinity. Substitution with p-fluorine, as in 97 (IC50 ) 0.022 ( 0.002), was
the exception. Here, a greater increase in affinity was realized than for either the ortho- or
meta-substituted analogues; 97 was the most potent compound resulting from monosubstitution
of the aromatic. At best, only modest increases in affinity were realized for certain compounds
bearing either two chlorines or two fluorines, and two methoxy groups gave no improvement
in affinity (all examined in a variety of substitution patterns). Three amino acids, 4, 5, and
104, were resolved into their four constituent isomers, and affinity and functional activity for
group II mGluRs was found to reside solely in the S,S,S-isomers of each, consistent with 1.
With an IC50 ) 2.9 ( 0.6 nM, the resolved xanthylmethyl compound 168 was the most potent
compound from this SAR. Amino acid 168 demonstrated high plasma levels following
intraperitoneal (ip) administration and readily penetrated into the brain. This compound,
however, had only limited (∼5%) oral bioavailability. Systemic administration of 168 protected
mice from limbic seizures produced by the mGluR agonist 3,5-dihydroxyphenylglycine, with
an ED50 ) 31 mg/kg (ip, 60 min preinjection). Thus, 168 represents a valuable tool to study
the role of group II mGluRs in disease.
Metabotropic glutamate receptors (mGluRs) are a
type of excitatory amino acid receptor that are coupled
through G-proteins to enzyme systems which liberate
second messengers to transduce signals.1 Three types
of mGluR receptors, group I (mGluR1 and mGluR5),
group II (mGluR2 and mGluR3), and group III (mGluR4,
mGluR6, mGluR7, and mGluR8) have been identified;
each is distinguished on the basis of on pharmacology
and sequence homology. We have vigorously pursued
the synthesis of compounds which function as antago-
nists of these receptors. The dearth of potent agonists
and antagonists for mGluRs has impeded our under-
standing of the physiological role these receptors play
in the central nervous system and their potential
utilities as therapeutic agents.2
In the preceding paper,3 we detailed the preparation
of a series of amino acids related to 1 (more commonly
referred to as L-CCG 1, CCG refers to carboxycyclopro-
pylglycine; Chart 1), a potent and somewhat selective
agonist for group II mGluRs.4 We determined affinity
of these compounds for group II mGluRs using [3H]-
glutamic acid binding in rat forebrain membranes,
which under the conditions employed was very selective
for binding to mGluRs (vis a´ vis ionotropic glutamate
* Address correspondence to: Paul L. Ornstein, Lilly Research
Laboratories, Lilly Corporate Center, DC 0510, Indianapolis, IN 46285.
Phone: 317-276-3226. Fax: 317-276-7600. E-mail: ornstein paul@
lilly.com.
S0022-2623(97)00498-6 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/14/1998

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 359
Sch em e 1a
a
(a) RI, Zn(Cu), PhH, N,N-dimethylacetamide, 60 °C; Pd(Ph3P)4, room temperature; (b) NaH, THF, ArCHO, room temperature to
reflux; (c) H2, 5% Pd/C, EtOH, room temperature, 15 psi; (d) NaOH, H2O, EtOH, 70 °C; add KCN and (NH4)2CO3, 55 °C; (e) see Table 1
for hydrolysis conditions used for each substrate; Dowex 50-X8, 10% pyridine/water.
Ch a r t 1
xanthyl compound 5 (IC50 ) 0.010 ( 0.001 µM), signifi-
cantly enhanced potency. In this paper, we examine the
effects of substitution on the aromatic ring of 3 with
either one or two substituents, the resolution of three
compounds into their constituent isomers to determine
in which isomer the mGluR antagonist activity resides,
some preliminary in vivo effects of these compounds,
and some data relating to the bioavailability of 5 in rats.
Ch em istr y
Syn th esis of Ra cem ic Am in o Acid s. As in the
preceding paper,3 we prepared keto-esters 8-50 (Table
1) either by coupling 6 with an organozincate (prepared
from the corresponding iodide with zinc-copper couple)
in the presence of palladium(0) (Scheme 1; 8, 10-21,
25-29, 38, 40, 42, 43, 45, 48, and 49) or by reaction of
the sodium salt of 7 with an aldehyde followed by
hydrogenation of the enone (Scheme 1; 9, 22-24, 30-
37, 39, 41, 44, 46, 47, and 50). We prepared the
requisite iodides as described before from the corre-
sponding substituted phenylethyl alcohol, which was
either commercially available or prepared by reduction
of the commercially available substituted phenylacetic
acid. For ketone 25, methyl 3-hydroxyphenylacetate
was converted to triflate 149, followed by Stille coupling
with phenyl tri-n-butylstannane to afford the ester 150,
which after reduction afforded the alcohol 151 (Scheme
2). For ketones 22 and 23, we prepared the aldehydes
needed for Horner-Emmons condensation by palladium-
mediated coupling of either cyclopropylmagnesium bro-
mide or cyclopentylmagnesium chloride with 142 to
afford 143 and 145, respectively, which upon hydrolysis
gave 144 and 146, respectively (Scheme 2).8 Hydroge-
receptors-iGluRs).5-7 We found that appending a
substituent such as ethyl (2) onto the amino acid carbon
converted an agonist to an antagonist, although with a
significant loss in potency. Affinity was increased
relative to 1 (IC50 ) 0.47 µM) and 2 (IC50 ) 2.2 µM)
when a phenyl ring was attached at the ethyl terminus,
leading to 3 (IC50 ) 0.32 µM). 2,2-Diphenylethyl
substitution (4; IC50 ) 0.24 ( 0.08 µM)) gave a further
increase in potency, and linking those two aromatic
rings with, for example, an oxygen atom as in the

360 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
Ta ble 1. Experimental Information for the Synthesis of Keto-Esters, Hydantoin Acids, and Amino Acidsa

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 361
Ta ble 1 (Continued)
a
b
See Experimental Section for full detail. “OH” indicates that the 2-arylethyl alcohol was commercially available. “CO2H” indicates
that the 2-aryl acetic acid was commercially available, and was reduced to the alcohol with borane methyl sulfide. Alcohols were
converted to the iodide with iodine, triphenylphosphine, and imidazole in dichloromethane. c “Zincate” refers to formation of the
ketone by palladium-mediated coupling of an organozincate (formed from the iodide and zinc/copper couple) with acid chloride 6.
“H-E” refers to Horner-Emmons condensation of the sodium salt of 7 with the corresponding aldehyde to form an enone, which is
d
then hydrogenated to give the ketone. All ketones are racemic. One isomer is shown for clarity. e For either method of hydantoin
formation, the keto-ester was hydrolyzed to the keto-acid prior to reaction, except where indicated. Method A: reaction in a sealed
tube at the temperature indicated in parentheses; 2.5 equiv of sodium cyanide and 4.5 equiv of ammonium carbonate; 1:1 ethanol/
water. Method B: reaction in an open system; 5 equiv of sodium cyanide and 9 equiv of ammonium carbonate; 1:1 ethanol/water;
55-60 °C. Method B (alt): the same as method A, except that the ester was hydrolyzed to the acid without isolation prior to the
addition of sodium cyanide and ammonium carbonate. f All hydantoins and amino acids are a mixture of two racemic diastereomers
(except for 76, 77, 123, and 124, which are single racemic diastereomers). One isomer of the cyclopropane is shown for clarity.
g
Method C: hydrolysis with 5 N sodium hydroxide in an open system at reflux. Method D: hydrolysis with 5 N sodium hydroxide in
a sealed tube at the temperature indicated in parentheses for 24 h. Method E: hydrolysis with 5 N sodium hydroxide in a stainless
steel high-pressure reactor at 250 °C overnight. Method F: hydrolysis with 1.5 N barium hydroxide in an open system at reflux.
Method G: hydrolysis with 1.5 N barium hydroxide in a stainless steel high-pressure reactor overnight at the temperature inidicated
in parentheses. Method H: hydrolysis with 1 N sodium hydroxide in a stainless steel high-pressure reactor at 200 °C overnight.
N-BOC: Refers to conversion of 61 to the bis-BOCed hydantion with di-tert-butyl dicarbonate, triethylamine, and DMAP in
acetonitrile, followed by attempted hydrolysis to 105 with 1 N aqueous NaOH in THF at reflux. When this failed, the material was
then hydrolyzed by method D. See text and Experimental Section for explicit conditions. 48% HBr: Refers to demethylation of the
h
corresponding O-methyl amino acid with refluxing 48% aqueous HBr. All amino acids were isolated by cation exchange
chromatography (see experimental) except for 109 and 130, which were isolated by isoelectric precipitation. Amino acids 102 and 132
i
j
were recrystallized from acetic acid following ion exchange chromatography. Not applicable. The elemental analysis for this
k
l
compound is actually for hydantoin 52. The elemental analysis for this compound is actually for hydantoin 58. 16. Anal. C: calcd,
73.82; found, 76.06. 36. Anal. C: calcd, 68.94; found, 69.88. 49. Anal. C: calcd, 66.65; found, 67.17. 108. Anal. N: calcd, 3.60; found,
3.15. 113. Anal. H: calcd, 6.40; found, 5.89. 117. Anal. H: calcd, 6.37; found, 5.87. 119. Anal. H: calcd, 6.37; found, 5.85. 137. Anal.
m
C: calcd, 50.62; found, 52.43. Anal. H: calcd, 4.55; found, 5.19. The functional group on ketones 34/35 and hydantoins 78/79 was a
nitrile, which was then hydrolyzed to the carboxylate in the final hydrolysis. The amino group of ketone 36 is protected as the
n
N-tert-butoxycarbonyl (N-BOC) group prior to hydantoin formation; it is then removed in the final hydrolysis. The elemental
analysis for this compound is actually for the enone, not the saturated ketone 46. The enone was recrystallized from ethylacetate/
hexane. o Hydantoin 90 was converted to the N-benzenesulfonimide (on the imide nitrogen of the hydantoin) prior to hydrolysis.

362 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
Sch em e 2a
a
(a) c-C3H5MgBr for 143, c-C5H9MgBr for 145, Pd(Ph3P)4, THF, reflux; (b) 4:1 CH3CN/1 N HCl, room temperature; (c) N-phenyltriflimide,
i-Pr2NEt, CH2Cl2, room temperature; (d) CH2dCHSn-n-Bu3, Pd(Ph3P)4, LiCl, dioxane, 100 °C; (e) 2.5% OsO4 in 2-propanol, dioxane,
water; NaIO4; (f) PhSn-n-Bu3, Pd(Ph3P)4, LiCl, toluene, reflux; (g) LAH, THF, room temperature; (h) n-BuLi, THF, -78 °C; MeSSMe,
warm to room temperature; (i) m-CPBA, CH2Cl2, -78 °C to room temperature.
nation of the enone leading to 22 was accompanied by
cleavage of the cyclopropane introduced into 144 on the
aromatic ring, leading to the n-propyl substituent. For
ketone 24, we prepared aldehyde 148 by conversion of
3-tert-butylphenol to the corresponding triflate 147,
followed by Stille coupling with vinyl tri-n-butylstan-
nane and then oxidative cleavage with osmium tetroxide
and sodium metaperiodate (Scheme 2). Metal-halogen
exchange of 142 with n-butyllithium followed by quench
with dimethyl disulfide afforded 152, and hydrolysis
then afforded 153, the aldehyde required for synthesis
of ketone 32 (Scheme 2). Alternatively, we oxidized 152
to the sulfone 154, which upon hydrolysis yielded 155,
the aldehyde required for synthesis of ketone 33 (Scheme
2). The substituent on the aromatic ring of ketones 34
and 35 is a nitrile, which is hydrolyzed in the last step
to yield a carboxylate. For ketone 36, the 3-amino
substituent is introduced through reaction of 3-ni-
trobenzaldehyde with the sodium salt of 7, which upon
reduction of the enone yields the corresponding 3-amino
compound; this is then protected as the N-BOC prior to
hydantoin formation and ultimately regenerated again
as an amine following the subsequent hydantoin hy-
drolysis.
As described in the previous paper,3 we prepared
hydantoins 51-94 by condensation of the keto-acids
derived from 8-50 (by hydrolysis prior to hydantoin
formation) with sodium cyanide and ammonium car-
bonate either in a sealed tube (Table 1, method A, 54-
56, 59-61, and 70-72) or an open system (Table 1,
method B, 51-53, 57, 58, 62-69, and 73-94). In
certain cases, the keto-ester was hydrolyzed to the
keto-acid in situ, and this is indicated as method B (alt)
in Table 1.9
Hydrolysis to the amino acids 95-141 was effected
by the method indicated in Table 1. These methods
were described in detail in the preceding paper.3 In
nearly all cases, the amino acid was isolated as the inner
salt following cation-exchange chromatography.3 In a
few instances, we were able to facilitate isolation and
obviate ion-exchange chromatography using isoelectric
precipitation (amino acids 109 and 130). We prepared
the hydroxy-substituted compounds 117, 118, and 119
by demethylation of the methoxy-substituted amino
acids 114, 115, and 116, respectively, with refluxing
48% aqueous hydrobromic acid.
Because of the difficulties encountered in the hydroly-
ses of these hydantoins, in a few cases we explored

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 363
Sch em e 3a
a
(a) (BOC)2O, Et3N, DMAP, CH3CN, room temperature; (b) 1 N NaOH, reflux; concentrated HCl, pressure tube, 150 °C; Dowex 50-X8,
10% pyridine/water; (c) NaN(SiMe3)2, THF, room temperature; PhSO2Cl; (d) 1.5 N Ba(OH)2, 200 °C (see method G, Table 1); Dowex
50-X8, 10% pyridine/water; (e) BnBr, KHCO3, DMF, 130 °C.
alternative methods that activated the hydantoin prior
to hydrolysis. For example, 61 was converted to the bis-
tert-butoxycarbonyl derivative 156 (Scheme 3). It was
reported by Rebek that this technique allows for hy-
dantoin hydrolysis under relatively mild conditions (1
N sodium hydroxide at room temperature).10 In our
hands, this technique did not work particularly well,
and we found that hydrolysis required reflux in 1 N
sodium hydroxide followed by heating with concentrated
hydrochloric acid at 150 °C to afford amino acid 105.
For hydantoin 90, we examined activation as the
N-benzenesulfonylimide (prepared from 90 with sodium
bis(trimethylsilyl)amide, diisopropyl-N-ethylamine and
benzenesulfonyl chloride); however, we found no sig-
nificant improvement in yield to amino acid 137 follow-
ing hydrolysis of the proposed product 157 with 1.5 N
barium hydroxide at 200 °C in a sealed system (Scheme
3).
LTMP and bromochloromethane.11 We thus required
a strategy to separate the hydantoin diastereomers.
Syn th esis of Non r a cem ic Am in o Acid s. We de-
cided to prepare the four constituent isomers of the
amino acids with (xanth-9-yl)methyl (5), (3-methylphe-
nyl)ethyl (104), and 2,2-diphenylethyl (4) side chains to
determine in which isomer or isomers the mGluR
antagonist activity resided. We believed this was a
representative sample of what was found to be active
in this SAR. We had ready access to both antipodes of
nonracemic cyclopropanedicarboxylate (S,S-158 and
R,R-159; the designators refer to the stereochemistry
of the cyclopropane carbons) using a known procedure
that prepared this compound by diastereoselective alky-
lation/cyclopropanation of dimenthyl succinate with
We found that it was very difficult to separate
hydantoin diastereomers by either normal or reverse
phase preparative chromatography, and the techniques
that worked modestly well were impractical for large-
scale synthesis. Hydantoins 76 and 77 were the only
ones which readily separated by fractional crystalliza-
tion. Thus we believed that our best strategy was to
introduce a group onto these compounds that would
modulate their polarity and enhance opportunities for
chromatographic separation. We hoped, for example,
that we could introduce a benzyl group onto the imide
nitrogen of the hydantoin (with concomitant esterifica-

364 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
F igu r e 1. Stereoview of SR,SR,SR-161 from the X-ray crystallograph.
tion), separate the diastereomers, and then remove the
benzyl group prior to hydrolysis. To this end, alkylation
of the racemic hydantoin-acid mixture 160 with benzyl
bromide and potassium bicarbonate in dimethylforma-
mide cleanly afforded the N,O-bisalkylated compound,
whose diastereomers 161a (first to elute on chromatog-
raphy) and 161b separated readily by flash chromatog-
raphy on silica gel (Scheme 3). That we obtained 161b
as an X-ray suitable crystal was a distinct advantage
of this exercise (Figure 1). It allowed us to unambigu-
ously assign the relative stereochemistry of the two
diastereomers: 161b is SR,SR,SR (by X-ray) and 161a
is SR,RS,RS (by default).
Since we were unable to remove the N-benzyl group
of 160 or 161 by either hydrogenation or strong acid
solvolysis, we switched to the p-methoxybenzyl group.
These compounds still separated quite easily, and the
group was removed using ceric ammonium nitrate
oxidation (vide infra).
Selective hydrolysis of either S,S-158 or R,R-159 to
the acid-ester with 1 equiv of sodium hydroxide in
aqueous 2-propanol, followed by acid chloride formation
with neat thionyl chloride, afforded S,S-162a or R,R-
162b, respectively, (Scheme 4 for 162a , Scheme 5 for
162b). We found it necessary to use 2-propanol as the
cosolvent instead of ethanol (which was used in the
preparation of 6) to suppress transesterification. Pal-
ladium-mediated coupling of S,S-162a with the orga-
nozincate from 9-xanthylmethyl iodide and zinc/copper
couple afforded the nonracemic ketone 163 (Scheme 4),
which was transformed to a mixture of hydantoin-acids
164 using method B (alt). We found that reaction of
this mixture with p-methoxybenzyl bromide and potas-
sium bicarbonate in dimethylformamide afforded N-
alkylation of the imide nitrogen along with esterification
of the cyclopropanecarboxylate. The two diastereomeric
products from this reaction were easily separable by
chromatography, affording 165 and 166.12 Our inten-
tion in using the p-methoxybenzyl group was that it
could be removed oxidatively prior to hydrolysis. How-
ever, we believed that the xanthyl group would not be
stable to ceric ammonium nitrate (a fact which we
verified experimentally), and so we decided to attempt
hydrolysis on the N-substituted hydantoin. We were
thus gratified to find that hydrolysis of 165 with barium
hydroxide in a sealed system (method G) or hydrolysis
of 166 with sodium hydroxide in a sealed system
(method H) gave the R,S,S-amino acid 167 and the
S,S,S-amino acid 168, respectively. Removal of the
benzyl group was unnecessary. Using the same se-
quence of reactions (Scheme 5), condensation of R,R-
162b with the above organozincate afforded 169, which
was converted to the mixture of hydantoin-acids 170
using the two-pot method B. N,O-Di-p-methoxybenzy-
lation afforded the readily separated 171 and 172, which
were each hydrolyzed with method G to afford the
S,R,R-amino acid 173 and the R,R,R-amino acid 174,
respectively.
Schemes 4 and 5 show the preparation of the (3-
methylphenyl)ethyl-substituted compounds. Condensa-
tion of either S,S-162a (Scheme 4) or R,R-162b (Scheme
5) with the organozincate from (3-methylphenyl)ethyl
iodide afforded the ketones 175 and 181, respectively.
N,O-Di-p-methoxybenzylation of each afforded two sepa-
rable diastereomers: 177 and 178 from 176 (Scheme
4); 183 and 184 from 182 (Scheme 5). Oxidative
cleavage with ceric ammonium nitrate on 177, 183, and
184, cleanly afforded the diastereomerically pure hy-
dantoins without the p-methoxybenzyl groups; each was
then hydrolyzed with barium hydroxide in a sealed
system to afford amino acids 179, 185, and 186,
respectively. As for the xanthyl compounds, we found
that the N,O-di-p-methoxybenzylated hydantoin 178
could be hydrolyzed to the amino acid 180 without
difficulty, using conditions that we found to be optimal
for these hydrolyses (1 N sodium hydroxide in a sealed
system at 200 °C, Scheme 4).
Schemes 4-6 show the preparation of the 2,2-diphe-
nylethyl-substituted compounds. Reaction of the orga-
nozincate from 2,2-diphenylethyl iodide with either S,S-
162a (Scheme 4) or R,R-162b (Scheme 5) gave ketones
187 and 193, respectively. Hydantoin formation with
187 afforded 188, which was converted to the N,O-bis-
(p-methoxybenzyl)hydantoins 189 and 190 (Scheme 4).

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 365
Sch em e 4a
a
(a) 5 N NaOH, 2-propanol, 70 °C; SOCl2, room temperature; (b) RI, Zn(Cu), PhH, N,N-dimethylacetamide, 60 °C; Pd(Ph3P)4, room
temperature; (c) NaOH, H2O, EtOH, 55 °C; add KCN and (NH4)2CO3, 55 °C; (d) p-MeOPhCH2Br, KHCO3, DMF, 125 °C; flash
chromatography, 30% EtOAc/hexane; (e) for 177 and 189, prior to hydrolysis: ceric ammonium nitrate, CH3CN, H2O, room temperature;
see Table 1 for hydrolysis conditions; 167, 179, and 191, method G; 168, 180, and 192, method H.
The p-methoxybenzyl groups of 189 were removed with
ceric ammonium nitrate followed by exhaustive hy-
drolysis to afford 191. As for other amino acids, we
found that it was not necessary to remove the p-
methoxybenzyl groups prior to hydrolysis, and thus 190
afforded 192. To our surprise, conversion of 193 to the
hydantoin afforded a small amount of diastereomerically
pure compound 195, along with the typical mixture of
hydantoins 194 and 195 (Scheme 6). With this com-
pound, we wanted to explore if derivatization of the
hydantoin with the benzenesulfonyl group on the imide
nitrogen would allow for hydrolysis to the amino acid
under much milder conditions, while still providing ease
of diastereomer separation. To this end, reaction of the
mixture of hydantoins 194 and 195 with sodium bis-
(trimethylsilyl)amide followed by benzenesulfonyl chlo-
ride afforded a not so readily separable mixture of
compounds 196 and 197. Hydrolysis of 196 with barium
hydroxide at reflux in an open system gave the desired
amino acid 198, albeit in very low yield. The diaste-
reomerically pure hydantoin 195 was also converted to
the N-benzenesulfonyl compound 197, but in this case
hydrolysis was carried out with 1 N sodium hydroxide
at reflux. This yielded a small amount of amino acid
199, along with a product that was distinct from the
hydantoin but still appeared to contain an N-benzene-
sulfonyl group. This material was exhaustively hydro-
lyzed with 6 N hydrochloric acid to afford an additional
small quantity of 199. Our overall results with the
N-benzenesulfonyl group were disappointing, and it was
not used for any subsequent compound.
All of the nonracemic amino acids were evaluated for
optical purity using a chiral HPLC column, Chiracel-
OD. All of the amino acids (167, 168, 173, 174, 179,
180, 181, 185, 186, 191, 198, and 199) were found to
have enantiomeric excesses (ee’s) of greater than 98%,
except for 192, which was found to have an ee of 93%.13
The TLC and flash chromatography elution profiles
of the diastereomeric pairs of dibenzylated hydantoin-
acids were consistent across the different pairs, with the
R,S,S- or S,R,R-isomers eluting first and the S,S,S- or
R,R,R-isomers eluting second. This was true for all
three side chains ((3-methylphenyl)ethyl, 2,2-diphenyl-
ethyl, or xanthylmethyl), whether substituted with
benzyl or p-methoxybenzyl. As was mentioned above,
an X-ray crystallograph of 161b (which is racemic)
confirmed the relative stereochemistry of the first- and
second-eluting isomers. The absolute stereochemistry
of these compounds then follows because we know the
absolute stereochemistry of the dimenthyl cyclopro-
panedicarboxylates from which they are derived. 1H
NMR chemical shifts and coupling patterns were very
similar for the benzylic and cyclopropane protons of the
racemic N,O-dibenzyl hydantoins 161a and 161b and
the corresponding nonracemic N,O-bis(p-methoxyben-
zyl)hydantoins 189 and 190, respectively. Consistent
1
patterns were observed in the H NMR spectra of the
cyclopropane protons for each pair of derivatized hy-

366 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
Sch em e 5a
a
(a) 5 N NaOH, 2-propanol, 70 °C; SOCl2, room temperature; (b) RI, Zn(Cu), PhH, N,N-dimethylacetamide, 60 °C; Pd(Ph3P)4, room
temperature; (c) NaOH, H2O, EtOH, 55 °C; add KCN and (NH4)2CO3, 55 °C; (d) p-MeOPhCH2Br, KHCO3, DMF, 125 °C; flash
chromatography, 30% EtOAc/hexane; (e) for 183 and 184, prior to hydrolysis: ceric ammonium nitrate, CH3CN, H2O, room temperature;
173, 174, 185, and 186 hydrolyzed by method G (see Table 1).
Sch em e 6a
a
(a) NaOH, H2O, EtOH, 55 °C; KCN, (NH4)2CO3, H2O, EtOH, 55 °C; (b) NaN(SiMe3)2, THF, room temperature; PhSO2Cl, reflux; (c)
Ba(OH)2, H2O, reflux; isoelectric precipitation; (d) 1 N NaOH, reflux; Dowex 50-X8, 10% pyridine/water; forerun from ion exchange: 6 N
HCl, reflux.
dantoins, independent of the R-substituent.14 For ex-
ample, the relative spacing of the cyclopropane protons
for the first-eluted R,S,S- (165, 177, and 189) or S,R,R-
isomers (171 and 183) was very consistent, although the
absolute chemical shifts varied slightly. This was also
true for the second-eluted S,S,S- (166, 178, and 190) or
R,R,R- (172 and 184) isomers. The pattern of cyclopro-
pane protons for the first-eluted isomers was, however,
distinct from that of the second-eluted isomers. Con-
sistent patterns amongst these two sets of isomers were
also seen for the N- and O-benzylmethylenes.10 Thus
we feel confident in our absolute stereochemical assign-
ments for the various nonracemic amino acids prepared
herein.
Str u ctu r e-Activity Stu d ies: Su bstitu ted P h e-
n yleth yl Am in o Acid s. All of the amino acids pre-

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 367
pared in this study were evaluated for their ability to
inhibit binding of [3H]glutamic acid to rat forebrain
membranes,5-7 and these data are shown in Table 2
(data for the unsubstituted analogue 1 is provided for
comparison). Most of the novel compounds were evalu-
ated as a mixture of four stereoisomers; however, the
non racemic amino acids 167, 168, 173, 174, 179, 180,
185, 186, 191, 192, 198, and 199 were the exceptions.
than 104) or eliminated it entirely. The unusual
exception was the phenoxy analogue 121, which was
about 1.5-fold more potent than 3. Methoxy (115) was
a beneficial substitution, but the isosteric thiomethoxy
122 was less active than 3, and oxidation of 122 to the
sulfone (124) increased activity.
When selected analogues from this part of the SAR
were evaluated in functional assays, they were found
to be antagonists at both mGluR2 and mGluR3. In
general, compounds were not selective for either mGluR,
except for the carboxy (125) and amino (127) analogues,
which were 15-20-fold more potent at mGluR3. In-
creases in receptor affinity for 97, 99, 107, 115, 118,
and 124 led to increases in functional antagonist
potency relative to the unsubstituted compound 3.
Selected analogues in this series were also evaluated
for functional agonist or antagonist activity in nonneu-
ronal cell lines (RGT for rat glutamate transporter)
expressing either cloned human mGluR2 or mGluR3
(Table 2) receptors.15,16 No agonist activity was ob-
served with the compounds alone (data not shown).
Antagonist activity was assessed in these cell lines by
looking at the ability of these compounds to block 1S,3R-
ACPD-induced inhibition of forskolin-stimulated cyclic-
AMP.
In the next aspect of the SAR, we explored whether
an additional substituent on the aromatic ring might
further enhance affinity. We looked at two fluorines
(128-132), two chlorines (134-137), and two methoxys
(138-141). We also prepared the perfluorophenyl
compound 133, and this change gave a slight decrease
in affinity. An additional chlorine provided some ben-
efit, an additional fluorine was neither beneficial nor
deleterious, and an additional methoxy was deleterious
to affinity. In general, 3,5-disubstitution was best, as
in 132, 137, and 141. The difluoro analogue 132 was
equipotent to the 4-fluoro compound 97, and the dichloro
analogue 137 was about 3-fold more potent than the
3-chloro compound 99 and nearly as potent as 97. The
dimethoxy analogue 141 was slightly less potent than
the 3-methoxy compound 115. One might conclude from
these data that along with a steric component there may
also be an electronic component that in the right cases
leads to increased affinity.
On the basis of the significant improvement in affinity
realized with amino acid 3 (phenylethyl substitution),
we focused a significant portion of the SAR on exploring
the effects of substitution on the aromatic ring. We
looked at both mono- and disubstituted compounds. It
was our hope that minor structural changes, such as
substitution on the aromatic ring, would afford signifi-
cant increases in affinity and functional potency. In
fact, these goals were realized.
We explored a variety of substituents, both electron
donating and withdrawing, oriented ortho, meta, and
para on the aromatic ring. The results of these efforts
are shown in Table 2. In a comprehensive fashion, we
looked at halogens, such as fluorine (95, 96, and 97),
chlorine (98, 99, and 100) and bromine (101 and 102);
alkyls such as methyl (103, 104, and 105) and trifluo-
romethyl (106, 107, and 108); hydroxy (117, 118, and
119), methoxy (114, 115, and 116), and phenoxy (120
and 121); phenyl (112 and 113); and carboxy (125 and
126). We also looked at some other substituents, such
as thiomethyl (122), sulfonylmethyl (124), and amino
(127) only in the meta position. We found that meta
substitution of a variety of functional groups consis-
tently provided a significant increase in affinity for
mGluRs, ranging from 1.4- to 14-fold over the unsub-
stituted compound. Ortho substitution was either much
less effective or deleterious to affinity, while para
substitution was in general deleterious. Fluorine was
the only substituent that showed an increase in affinity
when substituted in the para position (97), and 97 was
more potent than its meta-substituted counterpart 96.
It is interesting to note that both electron-donating (e.g.,
hydroxy (118), amino (127), methoxy (115), and methyl
(104)) and electron-withdrawing (e.g., trifluoromethyl
(107), carboxy (125), and chloro (99)) substituents gave
increases in affinity. We also observed that both
positively (127) and negatively (125) charged substitu-
ents increased affinity, the latter better than the former.
On the basis of these observations, we suspected that
the increase in affinity for meta-substitution in large
part reflected the benefit of a small increase in steric
bulk. To explore the scope of this steric change, we
prepared larger alkyls such as n-propyl (109), cyclopen-
tyl (110), and tert-butyl (111), along with phenyl (112)
and phenoxy (121). Most of these substitutions either
decreased activity (109 and 112 were 6-fold less potent
St r u ct u r e-Act ivit y St u d ies: R esolved Am in o
Acid s. We chose three compounds, 104, 4, and 5, from
the SAR reported herein and in the previous paper, to
be resolved into their four constituent isomers. We felt
that this would represent the scope of structural changes
made (e.g., meta-substituted phenylethyl, diphenylethyl,
and constrained diphenylethyl) which offered significant
increases in affinity. Of the four diastereomers possible
for the CCGs, the greatest potency for mGluRs was seen
with CCG-1. Of that diastereomer, activity resided in
the S,S,S-isomer 1. The nature of our preparation of
these amino acids afforded us racemic mixtures of two
of the four CCG diastereomers, corresponding to CCG-1
and CCG-2. It was our hope that the same pattern of
stereoselectivity for CCGs vis-a´-vis agonist activity
would also be realized for the antagonists, i.e., one
isomer bearing the bulk of the activity.
We found that as for 1, affinity for group II mGluRs
resided in the S,S,S-isomers 168 (xanthyl), 180 ((3-
methylphenyl)ethyl), and 192 (diphenylethyl). These
compounds were also found to be potent functional
antagonists of both mGluR2 and -3, with no significant
differences in selectivity observed between those two
mGluRs. All of the other isomers were either margin-
ally active or inactive. The xanthylmethyl compound
168 (LY341495) binds with very high affinity to rat
brain mGluRs, with an IC50 of 2.9 ( 0.6 nM, and is a
very potent functional antagonist, with IC50s at human
mGluR2 and mGluR3 of 23 ( 4 and 10 ( 8 nM,
respectively. Thus, the addition of this substituent to

368 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
Ta ble 2. Affinities of Novel Compounds for Group II Metabotropic Glutamate Receptors in Rat Forebrain Membranes and
Functional Antagonist Activity in Cloned (RGT) Cells Expressing Human Group II MGluRs

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 369
Ta ble 2 (Continued)

370 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ta ble 2 (Continued)
Ornstein et al.
a
All compounds are a mixture of four stereoisomers (S,S,S; R,S,S; S,R,R; R,R,R; the first letter denotes stereochemistry at the amino
b
acid carbon, and the next two letters denote stererochemistry at the cyclopropane carbons), unless otherwise noted. See refs 5 and 6. All
experiments are single-point determinations, except as noted. Numbers in parentheses refer to percent displacement of radioligand at 1
d
µM. c See refs 15 and 16. All experiments are single-point determinations, except as noted. Average of two determinations. e Average of
three determinations.
the amino acid carbon of 1 imparts a 162-fold increase
in receptor affinity.
for 168 at 15 min, the first time point at which
measurements were taken. By 4 h, 168 is nearly
cleared from plasma. The half-life by both routes is
nearly identical, about 45 min. Peak brain concentra-
tions are achieved somewhere between 15 and 30 min
after either iv or ip administration, indicating that the
compound rapidly crosses the blood-brain barrier in
rats. It appears that about 10% of the iv and ip dose
gets into the brain.
P h a r m a cok in etic Eva lu a tion of 168 follow in g
System ic Ad m in istr a tion in Ra ts. We evaluated 168
in rats following intravenous (iv), intraperitoneal (ip),
and oral (po) administration to determine its oral and
systemic bioavailability. We looked at both plasma and
brain concentrations, measured over time, following all
three routes of administration (Table 4). Isolation and
detection of the compound was made possible from
plasma and brain by first derivatization with ethyl
chloroformate and methanol, which yielded the monom-
ethyl ester/ethyl carbamate. This material was ex-
tracted from plasma and brain with toluene and then
alkylatively esterified with perfluorobenzyl bromide to
afford derivative 200 (eq 1), which could be detected
using GC/MS.
Oral administration of either a 10 or 100 mg/kg dose
of 168 gave peak plasma concentrations at 30 min for
the low dose and 60 min for the high dose; however,
oral plasma concentrations were significantly lower
than those observed by the parenteral routes of admin-
istration. Oral absorption was much more consistent
over time, indicating that the compound may be more
slowly absorbed by this route. Peak brain levels were
achieved at a much later time (4-6 h) than was
observed following parenteral administration. We found
that 168 was less than 5% bioavailable following oral
administration. Thus, while the bioavailability of 168
is excellent following parenteral administration, oral
bioavailability was low.
In Vivo An ta gon ist Effects of 168. Amino acid 201
(LY354740) is a very potent and highly selective group
II mGluR agonist which is active following parenteral
We found that, following either an iv or ip dose of 10
mg/kg, peak plasma concentrations (Cmax) were observed

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 371
Ta ble 3. Physical Chemical Data for Resolved Amino Acids and Intermediates: Optical Rotations and Elemental Analyses
a
The stereochemical designators for the ketone refer to the stereochemistry of the cyclopropane carbons. Although not shown, these
compounds are either the (1R,2S,5R)-menthyl (163, 175, 187) or the (1S,2R,5S)-menthyl (169, 181, 193) esters. The stereochemical
designators for the hydantoins and amino acids are given in an order where the first letter refers to C-5 of the hydantoin or the amino
b
acid carbon and the second and third letters refer to the stereochemistry of the cyclopropane carbons. All rotations on the ketones and
N,O-bis(p-methoxybenzyl)hydantoins were done at c ) 1 in dichloromethane, except for 187, which was c ) 1 in methanol. All rotations
on the amino acids were done in 1 N sodium hydroxide at the concentration indicated in parentheses. c 169. Anal. C: calcd, 78.00; found,
d
78.51. H: calcd, 7.67; found, 7.01. All of the amino acids, with the exception of 192, were found to have an optical purity (enatiomeric
excess) g98%, as determined by HPLC on a Chiracel OD-R column. See footnote 13 for conditions. e The optical rotation and elemental
analysis for 194 are for the parent hydantoin diastereomer, containing no p-methoxybenzyl groups. The elemental analysis for 197 is for
the N-(phenylsulfonyl)hydantoin, which also contains no p-methoxybenzyl groups. See Scheme 6 for structures.

372 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
Ta ble 4. Plasma and Brain Concentrations and
Pharmacokinetic Parameters of 168 following Intravenous (iv),
Intraperitoneal (ip), and Oral (po) Administration in Rats
In Vivo Activity of 168 in a Mou se Lim bic
Seizu r e Mod el. The lack of very potent and selective
antagonists for mGluRs has hampered our ability to
understand the therapeutic potential of these com-
pounds. We hope that these potent and systemically
active group II mGluR antagonists will be useful
research tools to define what value these compounds
may have as therapeutic agents.
It has been shown that intracerebral (ic) injection of
(1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ACPD
(1S,3R-ACPD) or (3,5-dihydroxyphenyl)glycine (3,5-
DHPG; 202) produces a characteristic limbic seizure in
CD-1 mice.17 The former compound is a nonselective
group I and II mGluR agonist,18 while the latter is a
selective group I mGluR agonist.19,20 Confident that 168
demonstrated very good bioavailability following par-
enteral administration, we evaluated this amino acid
for its ability to block limbic seizures induced by 202.
Given intraperitoneally 60 min prior to 400 nmol (ic) of
202, we saw a dose-dependent protection from limbic
seizures at doses ranging from 10 to 100 mg/kg, with
an ED50 of 31 mg/kg.
10 mg/kg
iv
10 mg/kg
ip
10 mg/kg
po
100 mg/kg
po
time (h)
Plasma Concentrations (ng/mL)
0.25
0.5
1
2
4
12020
14270
10690
4572
1121
39.9
5968
2436
845.2
35.9
64.1
48.3
50.0
28.3
17.5
197.2
475.3
419.6
95.5
6
102.2
Brain Concentrations (ng/g)
0.25
0.5
1
2
4
233.8
210.9
245.5
235.1
202.3
148.9
243.4
187.9
177.3
144.8
1.7
2.1
3.0
7.4
4.8
5.1
16.4
23.9
20.1
29.6
6
10 mg/kg 10 mg/kg 10 mg/kg 100 mg/kg
parametersa
iv
ip
po
po
Plasma Pharmacokinetic Parameters
t1/2 (h)
0.48
1.19
0.83
12020
0.25
8374
0.44
0.78
0.49
14270
0.25
2.64
1.94
Cl (p) (L/h/kg)
Vd (area) (L/kg)
Cmax (ng/mL)
Tmax (h)
AUC (4 or 6)
(ng/mL) h
64.1
0.5
217.4
475.3
1
1378
Con clu sion s
12727
In this and the preceding paper, we showed that by
appending a lipophilic group onto the amino acid carbon
of the potent and selective mGluR agonist 1, we
obtained a very potent series of group II mGluR
antagonists. Incorporation of a substituent onto the
aromatic ring of 3 provided in many cases a significant
increase in potency. Except for fluorine, activity was
optimized when the substituent was meta on the
aromatic ring. In many cases, activity was increased
regardless of whether the substituent was electron
donating or withdrawing, leading us to believe that the
improvement in activity was mostly a result of a
favorable steric interaction with the receptor protein.
When three amino acids were resolved into their
constituent isomers, activity for each was found to reside
in the S,S,S-isomer.
AUC (infinity)
(ng/mL) h
8399
12752
283.9
1663
2.0
% bioavailability
<Tr>
152
3.4
Brain Pharmacokinetic Parameters
t1/2 (h)
Cmax (ng/g)
Tmax (h)
5.43
243.4
0.5
4.75
245.5
0.5
NC
7.4
4
NC
30.0
6
AUC (4 or 6)
(ng/mL) h
AUC (infinity)
(ng/mL) h
701.4
773.5
26.5
120.4
1837
1794
NC
NC
a
t1/2, half-life; Cl, clearance rate; Vd, volume of distribution;
C
max, maximum concentration achieved in plasma or brain; Tmax
,
time of maximum concentration; AUC, area under the curve.
and oral administration in animals. For example, ip
administration of a 10 mg/kg dose of 201 (20 min prior
One compound, the S,S,S-xanthylmethyl compound
168 (the most potent analogue from this SAR), was
evaluated for oral and systemic bioavailability. We
found that while good plasma and brain levels were
achieved following iv and ip administration, oral bio-
availability for this compound was disappointingly low
(e5%). A low dose of amino acid 168 was able to block
anxiolytic effects of an mGluR agonist in the elevated
plus maze in mice, and higher doses were effective in
blocking agonist-induced limbic seizures in mice, both
following ip administration. Thus, these compounds
should serve as a useful systemically active tools to
explore the nature of group II mGluRs in CNS disorders,
possibly beginning to define the therapeutic potential
for this class of compounds.
to evaluation) significantly increased the time that male
NIH Swiss mice spent exploring the open zone of an
elevated plus maze (Figure 2), which indicated an
anxiolytic profile for this compound.12 We felt that the
use of 201 in this assay might allow us to demonstrate
in vivo group II mGluR antagonist activity with a
compound, from this SAR, e.g., 168. We looked at doses
of 0.03, 0.1, and 0.3 mg/kg of 168, administered ip 20
min prior to administration of 201 (Figure 2). We found
that the dose of 0.3 mg/kg was effective in antagonizing
the effects of 201, as indicated by a decrease in time
spent exploring the open zone of the elevated plus maze,
without altering closed arm performance or nose pokes.
Thus, we demonstrated that this in vivo pharmacologi-
cal effect of 201, a highly selective group II mGluR
agonist, can be blocked by in vivo administration of the
group II mGluR antagonist, 168.
Exp er im en ta l Section
Gen er a l. See the preceding paper.3
2-(3-Cyclop r op ylp h en yl)-1,3-d ioxola n e (143). A solution
of 5.0 g (21.8 mmol) of 2-(3-bromophenyl)-1,3-dioxolane (142),
0.64 g (0.55 mmol) of tetrakis(triphenylphosphine)palladium-
(0), and cyclopropylmagnesium bromide (prepared from 4.2 g
(34.9 mmol) of cyclopropyl bromide and 0.79 g (32.7 mmol) of
magnesium filings in 18 mL of THF) in 120 mL of THF was
heated to reflux for 5 h, then cooled, and treated with 50 mL

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 373
F igu r e 2. Effects of a group II mGluR antagonist (168) on a group II mGluR agonist (201)-induced increases on the elevated
plus maze in male NIH Swiss mice. Amino acid 168 was administered 20 min prior to administration of 201, which was
administered 20 min before evaluation in the maze.
of water. The mixture was extracted three times with 100 mL
each of ether, and then the combined organic extracts were
dried (MgSO4), filtered, and concentrated in vacuo. Chroma-
tography (250 g silica gel, 10% ethyl acetate/hexane) afforded
2.3 g (56%) of 143.
3-Cyclop r op ylben za ld eh yd e (144). A solution of 2.3 g
(12.1 mmol) of 143 in 70 mL of acetonitrile and 18 mL of 1 N
hydrochloric acid were stirred overnight at room temperature
and then concentrated in vacuo to remove most of the aceto-
nitrile. The mixture was diluted with 25 mL of water and
extracted three times with 25 mL each of ether. The combined
organic extracts were washed once with 25 mL of saturated
aqueous sodium bicarbonate, then dried (MgSO4), filtered, and
concentrated in vacuo to afford 1.6 g (91%) of 144.
50 mL of water. The organic extract was dried (MgSO4),
filtered, and concentrated in vacuo. The residue (3-tert-butyl-
1-vinylbenzene) was dissolved in 200 mL of dioxane and 65
mL of water and then treated with 7.2 mL of a 2.5% solution
of osmium tetroxide in 2-propanol (0.57 mmol). After 10 min
at room temperature, 18.6 g (87.0 mmol) of sodium metape-
riodate was added and the mixture stirred for 1 h at room
temperature. Water (200 mL) and 100 mL of ether were
added, the organic layer was separated, and the aqueous layer
was extracted twice with 100 mL each of ether. The combined
organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo. Chromatography (400 g silica gel, 5% ethyl acetate/
hexane) afforded 3.2 g (45%, three steps) of 148.
Met h yl
3-(((Tr iflu or om et h yl)su lfon yl)oxy)p h en yl-
2-(3-Cyclop en tylp h en yl)-1,3-d ioxola n e (145). As for
143, 5.0 g (21.8 mmol) of 142, 0.64 g (0.55 mmol) of tetrakis-
(triphenylphosphine)palladium(0), and 27.2 mL (54.5 mmol)
of cyclopentylmagnesium chloride in 120 mL of THF afforded
2.2 g (47%) of 145.
a ceta te (149). As for 147, 24.2 g (146 mmol) of methyl
3-hydroxyphenylacetate, 65 g (182 mmol) of N-phenyltriflim-
ide, and 18.8 g (146 mmol) of diisopropyl-N-ethylamine in 500
mL of dichloromethane gave 43.5 g (100%) of 149.
Meth yl 3-Bip h en yla ceta te (150). A solution of 15.3 g
(51.2 mmol) of 149, 18.8 g (51.2 mmol) of phenyltri-n-
butylstannane, and 6.4 g (153.6 mmol) of lithium chloride in
173 mL of toluene was degassed by evacuating with a vacuum
and then purging with nitrogen (three times), the 2.3 g (2.0
mmol) of tetrakis(triphenylphosphine)palladium(0) was added,
and the mixture was heated to reflux for 6 h, then cooled,
diluted with 170 mL of ether and filtered, through diatoma-
ceous earth. This solution was washed three times with 100
mL each of saturated aqueous potassium fluoride, then dried
(MgSO4), filtered, and concentrated in vacuo. Chromatography
(500 g of silica gel, 10% ethyl acetate/hexane) afforded 3.9 g
(33%) of 150.
3-Cyclop en tylben za ld eh yd e (146). As for 144, 2.2 g (10.2
mmol) of 145 afforded 1.6 g (91%) of 146.
3-t er t -Bu t yl-1-(((t r iflu or om e t h yl)su lfon yl)oxy)b e n -
zen e (147). A room-temperature solution of 7.4 g (46.6 mmol)
of 3-tert-butylphenol, 20.8 g (58.3 mmol) of N-phenyltriflimide,
and 6.0 g (46.6 mmol) of diisopropyl-N-ethylamine in 130 mL
of dichloromethane was stirred overnight and then concen-
trated in vacuo. The residue was partitioned between 200 mL
of ethyl acetate and 50 mL of water, the organic layer was
separated, then dried (MgSO4), filtered, and concentrated in
vacuo. Chromatography (600 g of silica gel, 25% ethyl acetate/
hexane) afforded 12.3 g (93%) of 147.
3-ter t-Bu tylben za ld eh yd e (148). A solution of 12.3 g
(43.5 mmol) of 147, 14.2 g (44.8 mmol) of vinyl tri-n-butyl-
stannane, 5.5 g (131 mmol) of lithium chloride, and 2.5 g (2.2
mmol) of tetrakis(triphenylphosphine)palladium(0) in 170 mL
of dioxane was heated to 100 °C for 3 h, then cooled, diluted
with 200 mL of ether, filtered through diatomaceous earth and
concentrated in vacuo. The residue was dissolved in 150 mL
of hexane and washed once with 100 mL of water and once
with 100 mL of saturated aqueous potassium fluoride. Ether
(150 mL) was added to break the emulsion, the aqueous layer
was separated, and the organic layer was washed once with
2-(3-Bip h en ylyl)eth a n ol (151). A solution of 3.8 g (16.8
mmol) of 150 in 10 mL of THF was added slowly to a room
temperature suspension of 0.2 g (5.0 mmol) of lithium alumi-
num hydride in 50 mL of THF. An additional 0.2 g (5.0 mmol)
of lithium aluminum hydride was added and the mixture
stirred for 1 h more, wherein another 0.2 g (5.0 mmol) of
lithium aluminum hydride was added. After an additional 1
h, the reaction was quenched slowly with 50 mL of saturated
aqueous sodium bicarbonate. The organic layer was separated
and the aqueous layer extracted four times with 20 mL each

374 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
of ether. The combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo to afford 3.7 g (100%) of
151.
(2SR)- a n d (2RS)-2-Am in o-2-((1SR,2SR)-2-ca r boxycy-
clop r op -1-yl)-4-(3,5-d ich lor op h en yl)bu ta n oic Acid (137).
A 5 mL (5.0 mmol) portion of 1 N sodium bis(trimethylsilyl)-
amide was added to a solution containing 0.9 g (2.5 mmol) of
90 and 0.7 g (5.0 mmol) of N,N-diisopropylethylamine in 8 mL
of tetrahydrofuran. The mixture was stirred 20 min, then 1.0
g (5.0 mmol) of p-toluenesulfonyl chloride was added, and
stirring was continued overnight. The mixture was added to
10 mL of 10% aqueous sodium bisulfate and then extracted
three times with 5 mL each of ethyl acetate. The combined
organics were dried (MgSO4), filtered, and concentrated in
vacuo. The residue and 4.0 g (12.5 mmol) of barium hydroxide
in 20 mL of water was heated to 200 °C for 24 h in a stainless
steel high-pressure reactor. The mixture was cooled and
acidified to pH 7 with 0.7 mL (12.5 mmol) of concentrated
sulfuric acid. The resulting solid was filtered and washed
three times with 10 mL each of 0.25 N sodium hydroxide.
Cation-exchange chromatography of the filtrate afforded a
solid that was suspended in water, filtered, washed with water,
acetone, and ether, and dried in vacuo at 60 °C to afford 0.11
g (14%) of 137.
Non r a cem ic Am in o Acid s. (1S,2S)-2-((1R,2S,5R)-Ca r -
bom en th yloxy)cyclop r op a n e-1-ca r bon yl Ch lor id e (162a ).
A solution of 35 g (86.1 mmol) of di-(1R,2S,5R)-menthyl
(1S,2S)-cyclopropane-1,2-dicarboxylate (158)9 and 18.9 mL
(94.7 mmol) of 5 N aqueous sodium hydroxide in 260 mL of
isopropyl alcohol was stirred overnight at 70 °C and then
concentrated in vacuo. The residue was dissolved in 300 mL
of water and washed two times with 100 mL each of ether,
and then the aqueous layer was acidified to pH 1 by the
addition of 1 N hydrochloric acid. This solution was extracted
four times with 100 mL each of ethyl acetate, and then the
combined organic extracts were dried (MgSO4), filtered, and
concentrated in vacuo to afford 19.7 g (86%) of the acid-ester.
This residue was dissolved in 70 mL (114.0 g, 0.96 mol) of
thionyl chloride, stirred overnight at room temperature, and
then concentrated in vacuo to afford 20.1 g (82% overall) of
162a .
(1R,2R)-2-((1S,2R,5S)-Car bom en th yloxy)cyclopr opan e-
1-ca r bon yl Ch lor id e (162b). As for 162a , 18 g (44.3 mmol)
of di-(1S,2R,5S)-menthyl (1R,2R)-cyclopropane-1,2-dicarboxy-
late (159)9 and 9.8 mL (48.7 mmol) of 5 N aqueous sodium
hydroxide in 135 mL of isopropyl alcohol afforded the acid-
ester, which with 36 mL (58.7 g, 0.49 mol) of thionyl chloride
gave 10.1 g (80%) of 162b.
(1S,2S )-2-((1R ,2S ,5R )-Ca r b om e n t h yloxy)cyclop r op -
1-yl (9-Xa n th yl)m eth yl Keton e (163). A solution of 11.3 g
(35 mmol) of (9-xanthyl)methyl iodide and 5.5 g (84 mmol) of
zinc/copper couple in 115 mL of benzene and 16 mL of N,N-
dimethylacetamide was stirred for 3 h at 60 °C, then treated
with 1.6 g (1.4 mmol) of tetrakis(triphenylphosphine)palladium-
(0), and heated for 5 min more. The heating bath was
removed, 10 g (35 mmol) of 162a was added, and the mixture
was stirred at room temperature for 1 h. The mixture was
diluted with 115 mL of ethyl acetate and filtered through
diatomaceous earth. The filtrate was washed with 200 mL of
10% aqueous sodium bisulfate, 200 mL of saturated aqueous
sodium bicarbonate, and 200 mL of saturated aqueous sodium
chloride. The organic layer was dried (MgSO4), filtered, and
concentrated in vacuo. Chromatography (500 g of silica gel,
10% ethyl acetate/hexane) of the residue afforded 9.6 g (61%)
of 163.
2-(3-(Meth ylth io)p h en yl)-1,3-d ioxola n e (152). To a -78
°C solution of 60.0 g (201 mmoL) of 142 in 450 mL of THF
was added 132 mL (211 mmoL; 1.6 M in hexane) of n-
butyllithium, and the mixture was stirred for 10 min at -78
°C. Then 18.9 g (201 mmol) of dimethyl disulfide was added,
and the mixture was stirred for 1 h and then warmed to room
temperature over 1 h. The mixture was quenched with 300
mL of water and extracted three times with 200 mL each of
ether. The combined organic extracts were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (750 g
of silica gel, 5% EtOAc/toluene) afforded 31.8 g (81%) of 152.
3-(Meth ylth io)ben za ld eh yd e (153). As for 144, 2.3 g
(11.8 mmol) of 152 afforded 1.4 g (77%) of 153.
2-(3-(Meth ylsu lfon yl)p h en yl)-1,3-d ioxola n e (154). To a
-78 °C solution of 31.8 g (162 mmoL) of 152 in 500 mL of
dichloromethane was added a slurry of 102 g (324 mmol) of
55% m-CPBA in 200 mL of dichloromethane. The mixture was
stirred for 30 min at -78 °C and for 1 h while warming to
room temperature. Then 250 mL of 1 N sodium thiosulfate
was added, and the mixture was stirred for 15 min. Then 500
mL of saturated aqueous sodium bicarbonate was added, the
organic layer was separated, and the aqueous layer was
extracted twice with 250 mL each of ether. The combined
organic extracts were dried (MgSO4), filtered, and concentrated
in vacuo to afford 36 g (99%) of 154.
3-(Meth ylsu lfon yl)ben za ld eh yd e (155). A solution of 36
g (159 mmol) of 154 in 750 mL of acetonitrile and 200 mL of
1 N hydrochloric acid was stirred overnight at room temper-
ature, then concentrated in vacuo to about 400 mL. 500 mL
of ether and 100 mL of brine were added, the organic layer
separated and the aqueous layer extracted twice with 150 mL
of ether. The combined organic extracts were washed once
with 250 mL of saturated aqueous sodium bicarbonate, then
dried (MgSO4), filtered and concentrated in vacuo to afford 25
g (84%) of 155.
(2SR)- a n d (2RS)-2-Am in o-2-((1SR,2SR)-2-ca r boxycy-
clop r op -1-yl)-4-(4-h yd r oxyp h en yl)bu ta n oic Acid (119). A
solution of 0.36 g (1.2 mmol) of 116 in 5 mL of 48% aqueous
hydrobromic acid was heated to 110 °C for 24 h, then cooled,
and concentrated in vacuo. The residue was dissolved in 5
mL of water and concentrated in vacuo, and this procedure
was then repeated. Cation-exchange chromatography of the
residue gave a solid that was suspended in water, filtered,
washed with water, acetone, and ether, and dried in vacuo at
60 °C to afford 0.17 g (52%) of 119.
(5SR)- a n d (5RS)-2,4-Bis-(ter t-b u t oxyca r b on yl)-5-
((1SR,2SR)-2-ca r boxycyclop r op -1-yl)-5-(2-(4-m eth ylp h e-
n yl)eth yl)im id a zolid in e-2,4-d ion e (156). A solution of 0.8
g (2.6 mmol) of 61, 0.5 g (5.2 mmol) of triethylamine, 1.7 g
(7.7 mmol) of di-tert-butyl dicarbonate, and 0.025 g (0.2 mmol)
of 4-(N,N-dimethylamino)pyridine in 10 mL of acetonitrile was
stirred at room temperature for 3 h. The mixture was washed
with 20 mL of 10% aqueous sodium bisulfate, the organic layer
was separated, and the aqueous layer was extracted three
times with 25 mL of ether. The combined organics were dried
(MgSO4), filtered, and concentrated in vacuo to afford 1.2 g
(100%) of 156.
(2SR)- a n d (2RS)-2-Am in o-2-((1SR,2SR)-2-ca r boxycy-
clop r op -1-yl)-4-(4-m eth ylp h en yl)bu ta n oic Acid (105). A
solution of 1.2 g (2.6 mmol) of 156 in 25 mL of 1 N sodium
hydroxide was heated to reflux for 24 h, then cooled, and
dissolved in 25 mL of concentrated hydrochloric acid. The
resulting solution was placed in a 3.5 × 20 cm pressure tube,
sealed with a no. 15 Teflon screw plug, and heated to 150 °C
for 8 h. The solution was cooled, extracted once with 50 mL
of ether, and then concentrated in vacuo. Cation-exchange
chromatography of the residue afforded a solid that was
suspended in water, filtered, washed with water, acetone, and
ether, and dried in vacuo at 60 °C to afford 0.23 g (32%) of
105.
(5SR)-5-((1SR,2SR)-2-Car boxycyclopr op-1-yl)-5-((9-xan -
th yl)m eth yl)im id a zolid in e-2,4-d ion e (164). A solution of
26.6 g (59.6 mmol) of 163 in 135 mL of ethanol and 65.5 mL
of 1 N sodium hydroxide was stirred 24 h at 55 °C. Then 19.4
g (298.0 mmol) of potassium cyanide, 41.8 g (536 mmol) of
ammonium carbonate, and 65 mL of water were added; then
this mixture was heated to 55 °C for 48 h. The mixture was
cooled, extracted once with 100 mL of ether then added to 300
mL of 5 N hydrochloric acid. The resulting mixture was
allowed to stand at room temperature, then the solid was
filtered, and recrystallization from acetone and water afforded
11.5 g (51%) of 164.

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 375
(5R)-5-(1S,2S-2-(((4-Met h oxyb en zyl)oxy)ca r b on yl)cy-
clop r op -1-yl)-5-((9-xa n th yl)m eth yl)-3-(4-m eth oxyben zyl)-
im id a zolid in e-2,4-d ion e (165) a n d (5S)-5-((1S,2S)-2-(((4-
Me t h o x y b e n zy l)o x y )c a r b o n y l)c y c lo p r o p -1-y l)-5-((9-
xa n th yl)m eth yl)-3-(4-m eth oxyben zyl)im id a zolid in e-2,4-
d ion e (166). A solution of 3.8 g (10 mmol) of 164 and 2.8 g
(28 mmol) of potassium bicarbonate in 30 mL of DMF was
treated with 3.6 g (23 mmol) of 4-methoxybenzyl chloride and
heated to 125 °C for 2 h. The mixture was diluted with 30
mL of ether and 60 mL of water. The organic layer was
removed, the aqueous layer was extracted three times with
20 mL each of ether, of then the combined organics were dried
(MgSO4), filtered, and concentrated in vacuo. Chromatography
(600 g of silica gel, 30% ethyl acetate/hexane) of the residue
afforded 2.3 g (38%) of 165 (higher Rf material) and 2.2 g (36%)
of 166 (lower Rf material).
(2R)-2 Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-3-(9-
xa n th yl)p r op a n oic Acid (167). A solution of 2.3 g (3.7
mmol) of 165 and 5.9 g (18.6 mmol) of barium hydroxide in 25
mL of water was heated to 200 °C for 24 h in a stainless steel
high-pressure reactor. The mixture was cooled and acidified
to pH 7 with 1.0 mL (18.6 mmol) of concentrated sulfuric acid.
The resulting solution was heated at 100 °C for 1 h, and then
the solid was filtered and washed three times with 10 mL each
of water. Cation-exchange chromatography of the filtrate
afforded a solid that was suspended in water, filtered, washed
with water, acetone, and ether, and dried in vacuo at 60 °C to
afford 0.15 g (11%) of 167.
(2S)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-3-(9-
xa n th yl)p r op a n oic Acid (168). A solution of 5.2 g (8.4
mmol) of 166 in 100 mL of 1 N sodium hydroxide was heated
to 200 °C for 24 h in a stainless steel high-pressure reactor.
The mixture was cooled, extracted three times with 30 mL each
of ether, and then acidified to pH 7 with concentrated hydro-
chloric acid. Cation-exchange chromatography of this solution
afforded a solid that was suspended in water, filtered, washed
with water, acetone, and ether, and dried in vacuo at 60 °C to
afford 1.5 g (52%) of 168.
(1R,2R)-2-((1S,2R,5S)-Ca r b om e n t h yloxy)cyclop r op -
1-yl (9-Xa n th yl)m eth yl Keton e (169). As for 163, 6.7 g (20.7
mmol) of (9-xanthyl)methyl iodide, 2.6 g (39.6 mmol) of zinc/
copper couple, and then 0.4 g (0.34 mmol) of tetrakis(triph-
enylphosphine)palladium(0) and 4.9 g (17.2 mmol) of 162b in
60 mL of benzene and 6 mL of N,N-dimethylacetamide
afforded 5.0 g (65%) of 169.
(1R,2R)-2-Car boxycyclopr op-1-yl (9-Xan th yl)m eth yl Ke-
t on e. A solution of 4.7 g (10.5 mmol) of 169 in 30 mL of
ethanol and 11.5 mL of 1 N sodium hydroxide was stirred 7 h
at 65 °C, then 5.2 mL (5.2 mmol) more 1 N sodium hydroxide
was added. The reaction mixture was stirred for an additional
16 h at 60 °C. The mixture was concentrated in vacuo, and
the residue was dissolved in 50 mL of water, extracted three
times with 50 mL each of ether, and then brought to pH 1
with 10% aqueous sodium bisulfate. The resulting solution
was extracted three times with 50 mL each of ethyl acetate,
and the combined organics were dried (MgSO4), filtered, and
concentrated in vacuo to afford 3.1 g (95%) of (1R,2R)-2-
carboxycycloprop-1-yl (9-xanthyl)methyl ketone.
(5SR)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-((9-xa n th -
yl)m eth yl)im id a zolid in e-2,4-d ion e (170). A solution of 7.1
g (23.1 mmol) of (1R,2R)-2-carboxycycloprop-1-yl (9-xanthyl)-
methyl ketone in 40 mL of ethanol was added to a solution of
7.5 g (115.5 mmol) of potassium cyanide and 20.0 g (207.4
mmol) of ammonium carbonate in 40 mL of water, and then
this mixture was heated to 55 °C for 120 h. The mixture was
cooled and added to 400 mL of 10% aqueous sodium bisulfate.
The resulting mixture was allowed to stand at room temper-
ature, the solid was filtered, and recrystallization from acetone
and water afforded 6.8 g (78%) of 170.
d ion e (172). As for 165/166, 5.8 g (15.3 mmol) of 170, 4.3 g
(42.8 mmol) of potassium bicarbonate, and 5.5 g (35.2 mmol)
of 4-methoxybenzyl chloride in 60 mL of DMF afforded 4.0 g
(43%) of 171 (higher Rf material) and 4.2 g (44%) of 172 (lower
Rf material).
(2S)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-3-(9-
xa n th yl)p r op a n oic Acid (173). A mixture of 3.7 g (6.1
mmol) of 171 and 9.5 g (30.3 mmol) of barium hydroxide in 40
mL of water was heated to 200 °C for 24 h in a stainless steel
high-pressure reactor. The mixture was cooled and acidified
to pH 2 with 4 N sulfuric acid. The resulting solution was
heated at 100 °C for 1 h, and then the solid was filtered and
washed three times with 50 mL each of 0.2 N sodium
hydroxide. Cation-exchange chromatography of the filtrate
afforded 80 mg of a solid that was soluble in acetone. The
filter cake from filtration after acidification was washed two
times with 0.25 N sodium hydroxide and once with 30 mL of
water. After the pH was adjusted 2 with 5 N hydrochloric
acid, cation-exchange chromatography afforded a solid which
was suspended in acetone, filtered, rinsed with acetone and
ether, and then dried in vacuo at 60 °C to afford 41 mg (2%)
of 173.
(2R)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-3-(9-
xa n th yl)p r op a n oic Acid (174). A solution of 4.0 g (6.5
mmol) of 172 and 10.2 g (32.3 mmol) of barium hydroxide in
40 mL of water was heated to 200 °C for 24 h in a stainless
steel high-pressure reactor. The mixture was cooled and
acidified to pH 2 with 4 N sulfuric acid. The resulting solution
was filtered through diatomaceous earth and washed two
times with 25 mL each of 0.25 N sodium hydroxide. Cation-
exchange chromatography of the filtrate afforded a solid that
was suspended in water, filtered, washed with water, acetone,
and ether, and dried in vacuo at 60 °C to afford 1.0 g (43%) of
174.
(1S ,2S )-2-((1R ,2S ,5R )-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2-(3-Meth ylp h en yl)eth yl Keton e (175). As for 163, 5.4
g (22 mmol) of 1-iodo-2-(3-methylphenyl)ethane and 3.4 g (52
mmol) of zinc/copper couple, then 0.9 g (0.8 mmol) of tetrakis-
(triphenylphosphine)palladium(0) and 5.7 g (20 mmol) of 162a
in 66 mL of benzene and 8 mL of N,N-dimethylacetamide,
afforded 4.6 g (61%) of 175.
(5SR)-5-((1S,2S)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m e-
th ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e (176). As for
164, 25.5 g (69.0 mmol) of 175 and 76 mL of 1 N sodium
hydroxide in 150 mL of ethanol and then 22.4 g (344.0 mmol)
of potassium cyanide, 48.3 g (619.0 mmol) of ammonium
carbonate, and 75 mL of water afforded 18.1 g (90%) of 176.
(5R)-5-((1S,2S)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-3-(4-m eth oxyben zyl)-5-(2-(3-m eth ylp h en yl)-
eth yl)im id a zolid in e-2,4-d ion e (177) a n d (5S)-5-(1S,2S)-2-
(((4-Met h oxyb en zyl)oxy)ca r b on yl)cyclop r op -1-yl)-3-(4-
m et h oxyb en zyl)-5-(2-(3-m et h ylp h en yl)et h yl)im id a zoli-
d in e-2,4-d ion e (178). As for 165/166, 2.6 g (8.9 mmol) of 176,
2.5 g (25.1 mmol) of potassium bicarbonate, and 3.2 g (20.6
mmol) of 4-methoxybenzyl chloride in 30 mL of DMF afforded
1.6 g (33%) of 177 (higher Rf material) and 1.6 g (33%) of 178
(lower Rf material).
(5R)-5-((1S,2S)-Ca r b oxycyclop r op -1-yl)-5-(2-(3-m et h -
ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e. A solution of 1.5
g (2.8 mmol) of 177 in 90 mL of acetonitrile was added to a
solution of 12.3 g (22.4 mmol) of ceric ammonium nitrate in
30 mL of water, and then this mixture was stirred at room
temperature for 2.5 h. The mixture was diluted with 90 mL
of brine, the organic layer was separated, the aqueous layer
extracted four times with 30 mL each of ethyl acetate, and
then the combined organics were dried (MgSO4), filtered, and
concentrated in vacuo. Chromatography (150 g of silica gel,
2% glacial acetic acid/50% ethyl acetate/48%hexane) of the
residue afforded 0.49 g (60%) of (5R)-5-((1S,2S)-2-carboxycy-
cloprop-1-yl)-5-(2-(3-methylphenyl)ethyl)imidazolidine-2,4-di-
one.
(5S)-5-((1R,2R)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-5-((9-xa n th yl)m eth yl)-3-(4-m eth oxyben zyl)-
im id a zolid in e-2,4-d ion e (171) a n d (5R)-5-((1R,2R)-2-(((4-
Me t h o x y b e n zy l)o x y )c a r b o n y l)c y c lo p r o p -1-y l)-5-((9-
xa n th yl)m eth yl)-3-(4-m eth oxyben zyl)im id a zolid in e-2,4-
(2R)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (179). A solution of 0.49 g
(1.7 mmol) of (5R)-5-((1S,2S)-2-carboxycycloprop-1-yl)-5-(2-(3-

376 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3
Ornstein et al.
methylphenyl)ethyl)imidazolidine-2,4-dione and 2.7 g (8.5
mmol) of barium hydroxide in 10 mL of water was heated to
200 °C for 24 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 7 with 0.5 mL (8.5
mmol) of concentrated sulfuric acid. The resulting solution
was heated at 100 °C for 1 h, and then the solid was filtered
and washed three times with 10 mL each of water. Cation-
exchange chromatography of the filtrate afforded a solid that
was suspended in water and filtered, washed, water, acetone,
and ether, and dried in vacuo at 60 °C to afford 0.21 g (44%)
of 179.
(2S)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (180). A solution of 7.3 g
(13.4 mmol) of 178 in 100 mL of 1 N sodium hydroxide was
heated to 200 °C for 24 h in a stainless steel high-pressure
reactor. The mixture was cooled, washed three times with 30
mL each of ether, and then acidified to pH 7 with concentrated
hydrochloric acid. Cation-exchange chromatography of this
solution afforded a solid that was suspended in water, filtered,
washed with water, acetone, and ether, and dried in vacuo at
60 °C to afford 1.9 g (50%) of 180.
(1R,2R)-2-((1S,2R,5S)-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2-(3-Meth ylp h en yl)eth yl Keton e (181). As for 163, 5.7
g (23.0 mmol) of 1-iodo-2-(3-methylphenyl)ethane and 2.9 g
(44.2 mmol) of zinc/copper couple then with 0.44 g (0.38 mmol)
of tetrakis(triphenylphosphine)palladium(0) and 5.5 g (19.2
mmol) of 162b in 65 mL of benzene and 6.5 mL of N,N-
dimethylacetamide afforded 4.7 g (65%) of 181.
(1R,2R)-2-(Ca r boxycyclop r op -1-yl) 2-(3-Meth ylp h en yl)-
eth yl Keton e. A solution of 4.4 g (11.8 mmol) of 181 in 35
mL of ethanol and 14.3 mL of 1 N sodium hydroxide was
stirred 18 h at 65 °C and then concentrated in vacuo. The
residue was dissolved in 30 mL of water, extracted three times
with 10 mL each of ether, and then brought to pH 2 with 10%
aqueous sodium bisulfate. The resulting solution was ex-
tracted four times with 15 mL each of ethyl acetate, and then
the combined organics were dried (MgSO4), filtered, and
concentrated in vacuo at 60 °C to afford 2.3 g (95%) of (1R,2R)-
2-carboxycycloprop-1-yl 2-(3-methylphenyl)ethyl ketone.
(5SR)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m e-
th ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e (182). A solu-
tion of 2.4 g (10.3 mmol) of (1R,2R)-2-carboxycycloprop-1-yl
2-(3-methylphenyl)ethyl ketone in 16 mL of ethanol was added
to a solution of 3.4 g (51.7 mmol) of potassium cyanide and
8.9 g (93.0 mmol) of ammonium carbonate in 16 mL of water,
and then this mixture was heated to 55 °C for 24 h. The
mixture was cooled and added to 200 mL of 10% aqueous
sodium bisulfate. The resulting mixture was allowed to stand
at room temperature, the solid thus obtained was filtered, and
recrystallization from acetone and water afforded 2.0 g (63%)
of 182.
(5S)-5-((1R,2R)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-3-(4-m eth oxyben zyl)-5-(2-(3-m eth ylp h en yl)-
eth yl)im id a zolid in e-2,4-d ion e (183) a n d (5R)-5-((1R,2R)-
2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cyclop r op -1-yl)-3-(4-
m et h oxyb en zyl)-5-(2-(3-m et h ylp h en yl)et h yl)im id a zoli-
d in e-2,4-d ion e (184). As for 165/166, 2.0 g (6.5 mmol) of 182,
1.8 g (18.3 mmol) of potassium bicarbonate, and 2.4 g (15.0
mmol) of 4-methoxybenzyl chloride in 25 mL of DMF afforded
1.7 g (48%) of 183 (higher Rf material) and 1.2 g (34%) of 184
(lower Rf material).
(5S)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m eth -
ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e. A solution of 1.6
g (2.9 mmol) of 183 in 90 mL of acetonitrile was added to a
solution of 12.5 g (22.9 mmol) of ceric ammonium nitrate in
30 mL of water, and then this mixture was stirred at room
temperature for 2.5 h. The mixture was diluted with 60 mL
of brine and extracted four times with 40 mL each of ethyl
acetate, and then the combined organics were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (200 g
of silica gel, 2% glacial acetic acid/50% ethyl acetate/48%
hexane) of the residue afforded a solid which was recrystallized
from water/acetone. The crystals were filtered, rinsed with
water, and dried in vacuo at 60 °C to afford 0.44 g (50%) of
(5S)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-methylphenyl)-
ethyl)imidazolidine-2,4-dione.
(2S)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (185). A solution of 0.44 g
(1.4 mmol) of (5S)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-
methylphenyl)ethyl)imidazolidine-2,4-dione and 2.3 g (7.2
mmol) of barium hydroxide in 12 mL of water was heated to
250 °C for 16 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 2 with concentrated
sulfuric acid. The resulting solution was heated at 90 °C for
1 h, and then the solid was filtered and washed three times
with 10 mL each of water. The filtrate was concentrated in
vacuo to a volume of 10 mL. Cation-exchange chromatography
of the filtrate afforded a solid that was dissolved in water and
concentrated in vacuo. The resulting solid was suspended in
acetone, filtered, washed with acetone and ether, and then
dried in vacuo at 60 °C to afford 21 mg (5%) of 185.
(5R)-5-((1R,2R)-2-Ca r boxycyclop r op -1-yl)-5-(2-(3-m eth -
ylp h en yl)eth yl)im id a zolid in e-2,4-d ion e. A solution of 1.0
g (1.9 mmol) of 184 in 60 mL of acetonitrile was added to a
solution of 8.3 g (15.2 mmol) of ceric ammonium nitrate in 20
mL of water, and then this mixture was stirred at room
temperature for 2.5 h. The mixture was diluted with 60 mL
of brine and extracted four times with 20 mL each of ethyl
acetate, and then the combined organics were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (50 g of
silica gel, 2% glacial acetic acid/50% ethyl acetate/48% hexane)
of the residue afforded a solid which was recrystallized from
water/acetone. The crystals were filtered, rinsed with water,
and dried in vacuo at 60 °C to afford 0.25 g (42%) of (5R)-5-
((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-(3-methylphenyl)ethyl)-
imidazolidine-2,4-dione.
(2R)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4-(3-
m eth ylp h en yl)bu ta n oic Acid (186). A solution of 0.53 g
(1.75 mmol) of (5R)-5-((1R,2R)-2-carboxycycloprop-1-yl)-5-(2-
(3-methylphenyl)ethyl)imidazolidine-2,4-dione and 2.8 g (8.8
mmol) of barium hydroxide in 15 mL of water was heated to
250 °C for 16 h in a stainless steel high-pressure reactor. The
mixture was cooled and acidified to pH 2 with concentrated
sulfuric acid. The resulting solution was heated at 90 °C for
1 h, and then the solid was filtered through Celite, washed
three times with 10 mL each of water and three times with
10 mL each of 0.33 N sodium hydroxide, and concentrated in
vacuo to about 10 mL. Cation-exchange chromatography of
the filtrate afforded a solid that was suspended in water,
filtered, washed with water, acetone, and ether, and dried in
vacuo at 60 °C to afford 0.09 g (19%) of 186.
(1S ,2S )-2-((1R ,2S ,5R )-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2,2-Dip h en yleth yl Keton e (187). As for 163, 5.5 g (18
mmol) of 2,2-diphenyl-1-iodoethane and 2.8 g (42.9 mmol) of
zinc/copper couple and then 0.8 g (0.7 mmol) of tetrakis-
(triphenylphosphine)palladium(0) and 4.7 g (16.4 mmol) of
162a in 60 mL of benzene and 8 mL of N,N-dimethylacetamide
afforded 5.2 g (73%) of 187.
(5SR)-5-((1S,2S)-2-Car boxycyclopr op-1-yl)-5-(2,2-diph e-
n yleth yl)im id a zolid in e-2,4-d ion e (188). As for 164, 9.4 g
(21.7 mmol) of 187 and 24 mL of 1 N sodium hydroxide in 50
mL of ethanol and then 7.7 g (119.0 mmol) of potassium
cyanide, 19.5 g (195.0 mmol) of ammonium carbonate, and 24
mL of water afforded 4.0 g (50%) of 188.
(5R)-5-((1S,2S)-2-(((4-Meth oxyben zyl)oxy)ca r bon yl)cy-
clop r op -1-yl)-5-(2,2-d ip h en yleth yl)-3-(4-m eth oxyben zyl)-
im id a zolid in e-2,4-d ion e (189) a n d (5S)-5-((1S,2S)-2-((4-
Meth oxy)ben zyloxy)cyclopr op-1-yl)-5-(2,2-diph en yleth yl)-
3-(4-m eth oxyben zyl)im id a zolid in e-2,4-d ion e (190). As for
165/166, 4.0 g (11.0 mmol) of 187, 3.1 g (30.7 mmol) of
potassium bicarbonate, and 3.9 g (25.2 mmol) of 4-methoxy-
benzyl chloride in 40 mL of DMF afforded 2.0 g (30%) of 189
(higher Rf material) and 2.7 g (41%) of 190 (lower Rf material).
(5R)-5-((1S,2S)-2-Ca r boxycyclop r op -1-yl)-5-(2,2-d ip h e-
n yleth yl)im id a zolid in e-2,4-d ion e. A solution of 1.0 g (1.6
mmol) of 189 in 50 mL of acetonitrile was added to a solution
of 7.2 g (13.2 mmol) of ceric ammonium nitrate in 15 mL of
water, and then this mixture was stirred at room temperature

Novel Metabotropic Glutamate Receptor Antagonists. 2
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 3 377
for 5 h. The mixture was diluted with 50 mL of brine. The
organic layer was separated, the aqueous layer was extracted
four times with 50 mL each of ethyl acetate, and then the
combined organics were dried (MgSO4), filtered, and concen-
trated in vacuo. Chromatography (150 g of silica gel, 2%
glacial acetic acid/50% ethyl acetate/48% hexane) of the residue
afforded 0.37 g (63%) of (5R)-5-((1S,2S)-2-carboxycycloprop-1-
yl)-5-(2,2-diphenylethyl)imidazolidine-2,4-dione.
mmol) of 196 and 1.3 g (4.0 mmol) of barium hydroxide in 10
mL of water was heated to reflux for 18 h. The mixture was
cooled and acidified to pH 3 with 4 N sulfuric acid and heated
to reflux for 1 h. While hot, the mixture was filtered through
Celite, and the filtrate was concentrated in vacuo. The
resulting solid was suspended in 0.5 mL of water, and 10 drops
of 1 N sodium hydroxide were added. The mixture was then
filtered, and the filtrate was acidified to pH 2 with 1 N
hydrochloric acid, whereupon
a precipitate formed. The
(2R)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-4,4-
d ip h en ylbu t a n oic Acid (191). A solution of 0.37 g (1.0
mmol) of (5R)-5-((1S,2S)-2-carboxycycloprop-1-yl)-5-(2,2-diphe-
nylethyl)imidazolidine-2,4-dione and 1.6 g (5 mmol) of barium
hydroxide in 10 mL of water was heated to 200 °C for 24 h in
a stainless steel high-pressure reactor. The mixture was
cooled and acidified to pH 7 with 0.27 mL (5 mmol) of
concentrated sulfuric acid. The resulting solid was filtered and
washed three times with 10 mL each of water. Cation-
exchange chromatography of the filtrate afforded a solid that
was suspended in water, filtered, washed with water, acetone,
and ether, and dried in vacuo at 60 °C to afford 0.028 g (8%)
of 191.
(2S)-2-Am in o-2-((1S,2S)-2-ca r boxycyclop r op -1-yl)-4,4-
d ip h en ylbu ta n oic Acid (192). A solution of 2.7 g (4.5 mmol)
of 190 in 100 mL of 1 N sodium hydroxide was heated to 200
°C for 24 h in a stainless steel high-pressure reactor. The
mixture was cooled, washed three times with 30 mL each of
ether, and then acidified to pH 7 with concentrated hydro-
chloric acid. This solution was concentrated to half its volume,
and then cation-exchange chromatography afforded a solid that
was suspended in water, filtered, washed with water, acetone,
and ether, and dried in vacuo at 60 °C to afford 0.91 g (59%)
of 192.
precipitate was filtered, washed with water, acetone, and
ether, and then dried in vacuo at 60 °C to afford 0.02 g (7%) of
198.
(5R)-5-((1R,2R)-2-((1S,2R,5S)-Ca r bom en th yloxy)cyclo-
p r op -1-yl)-3-(p h en ylsu lfon yl)-5-(2,2-d ip h en ylet h yl)im i-
d a zolid in e-2,4-d ion e (197). A solution of 0.51 g (1.0 mmol)
of 195 in 12 mL THF was treated with 1.1 mL (1.1 mmol) of
a 1 M THF solution of sodium bis(trimethylsilyl)amide. The
mixture was stirred at room temperature for 30 min, 0.19 g
(1.1 mmol) of benzenesulfonyl chloride was added, and the
mixture was heated to reflux for 16 h. The mixture was cooled,
diluted with 15 mL of water, and then extracted three times
with ether. The combined organics were dried (MgSO4),
filtered, and concentrated in vacuo. Chromatography (75 g of
silica gel, 30% ethyl acetate/hexane) of the residue afforded
0.41 g (63%) of 197.
(2R)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4,4-
d ip h en ylbu ta n oic Acid (199). A solution of 0.41 g (0.64
mmol) of 197 in 25 mL of 1 N aqueous sodium hydroxide was
heated to reflux for 18 h. The mixture was cooled and
extracted twice with 20 mL each of ether. The aqueous portion
was acidified to pH 2 with 5 N hydrochloric acid, and the
resulting precipitate was filtered, washed two times with 5
mL each of water, and then with acetone, whereupon the solid
dissolved. Cation-exchange chromatography of the filtrate
afforded a solid which was dissolved in acetone and concen-
trated in vacuo. The solid was suspended in ether, filtered,
and dried in vacuo at 60 °C to afford 7 mg (3%) of 199. The
forerun from the cation-exchange column was concentrated in
vacuo and heated to reflux for 18 h in 6 N aqueous hydrochloric
acid. The mixture was cooled and concentrated in vacuo.
Water was added, and the mixture was concentrated in vacuo
again. The resulting solid was suspended in 10 mL of water,
filtered, rinsed once with water, twice with acetone, and twice
with ether, and then dried in vacuo at 60 °C to afford another
24 mg (10%) of 199.
(1R,2R)-2-((1S,2R,5S)-Ca r b om e n t h yloxy)cyclop r op -
1-yl 2,2-Dip h en yleth yl Keton e (193). As for 163, 7.1 g (23.0
mmol) of 2,2-diphenyl-1-iodoethane and 2.9 g (44.2 mmol) of
zinc/copper couple and then 0.44 g (0.38 mmol) of tetrakis-
(triphenylphosphine)palladium(0) and 5.5 g (19.2 mmol) of
162b in 65 mL of benzene and 6.5 mL of N,N-dimethylaceta-
mide afforded 4.5 g (54%) of 193.
(5S)-5-((1R,2R)-2-((1S,2R,5S)-Ca r bom en th yloxy)cyclo-
p r op -1-yl)-5-(2,2-d ip h en yleth yl)im id a zolid in e-2,4-d ion e
(194) an d (5R)-5-((1R,2R)-2-((1S,2R,5S)-Car bom en th yloxy)-
cyclop r op -1-yl)-5-(2,2-d ip h en ylet h yl)im id a zolid in e-2,4-
d ion e (195). A solution of 6.3 g (14.5 mmol) of 193 in 35 mL
of ethanol was added to a solution of 4.7 g (72.3 mmol) of
potassium cyanide and 12.5 g (130.1 mmol) of ammonium
carbonate in 20 mL of water, and then this mixture was heated
to 55 °C for 24 h. The mixture was cooled, and 25 mL of water
was added. The mixture was extracted four times with 30 mL
each of ethyl acetate, and then the combined organics were
dried (MgSO4), filtered, and concentrated in vacuo. Chroma-
tography (400 g of silica gel, 25% ethyl acetate/hexane) of the
residue afforded 4.3 g of 193 and 2.3 g of a mixture of 194 and
195. Trituration with ethyl acetate afforded 0.54 g (7%) of
195 (two crops). The mother liquors were concentrated in
vacuo to afford 1.2 g (16%) of a mixture of 194 and 195
(undetermined ratio).
P h a r m a cok in etic Stu d ies w ith 168. Meth od s. 168 was
administered to male Fischer 344 rats either intravenously
(iv) at a dose of 10 mg/kg, intraperitoneally (ip) at a dose of
10 mg/kg, or orally (po) at a dose of 10 or 100 mg/kg. Five
rats were used per route and dose level. Blood and brain were
taken from one rat at 0.25, 0.5, 1, 2, and 4 h following iv or ip
administration, and at 0.5, 1, 2, 4, and 6 h following po
administration. Plasma and brain tissue homogenates were
prepared and analyzed by GCMS, using negative ion chemical
ionization, following derivatization and extraction as described
hereunder (LOQ 100 pg/mL plasma or 1 ng/g brain tissue).
Ack n ow led gm en t. The authors thank the Physical
Chemistry Department of Lilly Research Laboratories
for spectral data and elemental analyses. The authors
also especially thank J ack Campbell for the liberal use
of his high pressure hydrogenation equipment and J oe
Kennedy for the chiral HPLC analysis.
(5S)-5-((1R,2R)-2-((1S,2R,5S)-Ca r bom en th yloxy)cyclo-
p r op -1-yl)-3-(p h en ylsu lfon yl)-5-(2,2-d ip h en ylet h yl)im i-
d a zolid in e-2,4-d ion e (196). A solution of 1.1 g (2.1 mmol)
of the mixture of 194 and 195 in 15 mL of THF was treated
with 2.3 mL (2.3 mmol) of sodium bis(trimethylsilyl)amide (1
M in THF) and stirred at room temperature for 20 min. To
the mixture was added 0.4 g (2.2 mmol) of benzenesulfonyl
chloride, and the reaction mixture was refluxed for 2 h. The
reaction mixture was cooled, diluted with 15 mL of water, and
extracted three times with 20 mL each of ethyl acetate. The
combined organics were dried (MgSO4), filtered, and concen-
trated in vacuo. Chromatography (150 g of silica gel, 25%
ethyl acetate/hexane) of the residue afforded 0.55 g (43%) of
196, 0.21 g (16%) of a mixture of 196 and 197, and 0.05 g (4%)
of 197.
Su p p or tin g In for m a tion Ava ila ble: A list of all of the
1
names of the amino acids prepared in this paper and H NMR
spectra for compounds 165, 166, 177, 178, 189, and 190 (11
pages). Ordering information is given on any current mast-
head page.
Refer en ces
(2S)-2-Am in o-2-((1R,2R)-2-ca r boxycyclop r op -1-yl)-4,4-
d ip h en ylbu ta n oic Acid (198). A mixture of 0.51 g (0.8
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HPLC column, using UV detection at 210 nm, and at a column
temperature of 35 °C. Amino acids 167 (tR ) 5.71 min) and 168
(tR ) 4.47 min) were eluted with 20% acetonitrile/80% water with
0.1% trifluroacetic acid at a flow rate of 1.5 mL/min; amino acids
173 (tR ) 9.89 min) and 174 (tR ) 10.41 min) were eluted with
15% acetonitrile/85% water with 0.1% trifluroacetic acid at a
flow rate of 1.5 mL/min; amino acids 179 (tR ) 8.97 min), 180
(tR ) 7.47 min), 185 (tR ) 6.48 min), and 186 (tR ) 6.29 min)
were eluted with 10% acetonitrile/90% water with 0.1% tri-
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(tR ) 11.15 min), 192 (tR ) 8.70 min), 198 (tR ) 10.50 min), and
199 (tR ) 7.53 min) were eluted with 20% acetonitrile/80% water
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J M970498O