PRODRUGS OF EXCITATORY AMINO ACIDS
This invention provides synthetic excitatory ami no acid prodrugs (compounds of
Formula 1) and processes for their preparation. The invention further relates to methods
of using, and pharmaceutical compositions comprising, the compounds of Formula 1 for
the treatment of neurological disorders and psychiatric disorders.
Background of the Invention
Treatment of neurological or psychiatric disorders, such as anxiety disorders, have
been Jinked to selective activation of metabotropic excitatory amino acid receptors. For
example, (+)-4-amino-2-sulfonylbicyclo[3.1.0]hexane-4,6-dicarboxylic acid is disclosed
as an active mGluR2 receptor agonist in U.S. Patent No. 5,688,826 (the '826 patent),
issued November 18, 1997. Additionally, (+)-2-amino-4-fluorobicyc]o[3.1.0]hexane-2,6-
dicarboxylic acid is disclosed as an active mGluR2 receptor agonist in U.S. Patent No.
5,958,960 (the '960 patent), issued September 28, 1999.
The present invention provides for prodrug forms of mGluR2 receptor agonist
compounds, which enhance the in vivo potency of the respective parent compound and
produce higher oral exposure of the parent compound. Compounds of the present
invention represent the best approach for maintaining the safety and efficacy of
previously disclosed mGluR2 receptor agonists with increased oral bioavailability.
Synthetic excitatory amino acid prodrugs and processes for their preparation are
disclosed in PCT Application Serial Nos. PCT/US01/45866 and PCT/US02/00488.

Summary of the Invention
The present invention provides a compound of Formula 1
wherein
A is H-(Q)p-;
Q is independency selected, each time taken, from the group amino acyl;
p is an integer from 1 to 10;
X is O, S, SO, SO2, or CR3R4;
R3 is fluovo, X'OR5, SO3H, tetrazol-5-yl, CN, PO3R62, hydroxy, or NO2, and
R4 is hydrogen; or R3 and R4 each represent fluoro; or R3 and R4 together represent =O,
=NOR7, or =CR8R9; Or one of R3 or R4 represents amino and the other represents
carboxyl; or R3 represents N3, (CH2)mCOOR5a, (CH2)mPO3R6a2, NHCONHR5b, or
NHSO2R5c, and R4 represents hydrogen; or R3 and R4 together represent =CHCOOR5b,
=CHPO3R6a2, or =CHCN;
X' represents a bond, CH2, or CO;
m is an integer from 1 to 3;
R5, R5a, R5b, R5c, R7, R8, and R9 are independently a hydrogen atom; an
optionally substituted (1-6C) alkyl group; an optionally substituted (2-6C) alkenyl group;
an optionally substituted (2-6C) alkynyl group; an optionally substituted aromatic group;
an optionally substituted heteroaromatic group; a non-aromatic carbocyclic group; a non-
aromatic heterocyclic group; a non-aromatic monocyclic carbocyclic group fused with
one or two monocyclic aromatic or heteroaromatic groups; or a non-aromatic monocyclic
heterocyclic group fused with one or two monocyclic aromatic or heteroaromatic groups;

R6 and R6a independently represent hydrogen or a (1-6C)alky) group;
R10 is hydrogen or fluoro; and
R11 is hydrogen, fluoro, or hydroxy;
or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound of Formula 1 wherein
substiutents are defined as above, provided that the compound is not one in which X is
CR3R4 wherein R3 is fluoro and R4 is hydrogen, p is 1, and Q is L-alany); or a
pharmaceutically acceptable salt thereof.
The present invention also provide a compound of Formula 1 wherein A is
H-(Q)p-; Q is independently selected, each time taken, from the group amino acyl; p is an
integer from 1 to 3; X is O, S, SO, SO2, or CR3R4; R3 is fluoro or hydroxy, and R4 is
hydrogen; or R3 and R4 together represent =O; R10 is hydrogen or fluoro; and R11 is
hydrogen, fluoro, or hydroxy; or a pharmaceutically acceptable salt thereof.
The present invention also provides a compound of Formula 1 wherein A is
H-(Q)p-; Q is L-alanyl; p is 1; X is CR3R4; R3 is fluoro and R4 is hydrogen; R10 is
hydrogen; and R11 is hydrogen: or a pharmaceutically acceptable salt thereof.
It will be appreciated that the compounds of Formula 1 contain at least four
asymmetric carbon atoms. The present invention includes all stereoisomeric forms of the
compounds of Formula 1, including each of the individual enantiomers and mixtures
thereof such as prodrug forms of compounds disclosed in the '826 patent such as, for
example, 1SR,4RS,5RS,6RS-4-amino-(2-su]fonylbicyclo[3.1.0]hexane)-4,6-dicarboxylic
acid.
A further aspect of the present invention provides for a pharmaceutical
formulation comprising in association with a pharmaceutically acceptable carrier,
dilutenl, or excipient, a compound of Formula 1, or a pharmaceutically acceptable salt
thereof.
A further aspect of the present invention provides for a method for affecting the
cAMP-linked metabotropic glutamate receptors in a patient, which comprises
administering to a patient requiring modulated excitatory amino acid neurotransmission a
pharmaceutically-effective amount of a compound of Formula 1. This invention also

provides for a use of a compound of Formula 1 for the manufacture of a medicament for
affecting the cAMP-linked metabotropic glutamate receptors in a patient.
A further aspect of the present invention provides for a method of administering
an effective amount of a compound of Formula 11 that comprises administering to a
patient requiring modulated excitatory amino acid neurotransmission a pharmaceutically
effective amount of a compound of Formula 1. This invention also provides for a use of a
compound of Formula 1 for the manufacture of a medicament for administering an
effective amount of a compound of Formula 11.
A further aspect of the present invention provides for a method for treating a
neurological disorder in a patient that comprises administering to the patient in need of
treatment thereof a pharmaceutically-effective amount of a compound of Formula I. This
invention also provides for a use of a compound of Formula 1 for the manufacture of a
medicament for treating a neurological disorder in a patient.
A further aspect of the present invention provides for a method for treating a
psychiatric disorder in a patient that comprises administering to the patient in need of
treatment thereof a pharmaceutically-effective amount of a compound of Formula 1. This
invention also provides for a use of a compound of Formula 1 for the manufacture of a
medicament for treating a psychiatric disorder in a patient.
Compounds of Formula 1 may be made by a process that is analogous to one
known in the chemical art for the production of structurally analogous heterocyclic
compounds or by a novel process described herein. Such processes and intermediates
useful for the manufacture of a compound of Formula 1 as defined above are illustrated by
the following procedures in which, unless otherwise specified, the meanings of the
generic radicals are as defined herein.

The present invention provides a process for preparing compounds of Formula 1
comprising acylating a compound of formula (ii):

with a corresponding amino acyl of Formula III

wherein PgN is a nitrogen-protecting group and A is as defined above;
whereafter, for any of the above procedures, when a functional group is protected
using a protecting group, removing the protecting group;
whereafter, for any of the above procedures: when a pharmaceutically acceptable
salt of a compound of Formula 1 is required, reacting the basic form of such a compound
of Formula 1 with an acid affording a pharmaceutically acceptable counterion; or for a
compound of Formula 1 which bears an acidic moiety, reacting the acidic form of such a
compound of Formula 1 with a base which affords a pharmaceutically acceptable cation;
or for a zwitterionic compound of Formula 1, neutralizing the acid-addition salt form or
base-addition salt form of such a compound of Formula 1; or by any other conventional
procedure.
The present invention also provides for compounds of Formula 1, wherein X is
CH2, R10 is fluoro, and the other variables are as defined above.

Detailed Description of the Invention
Compounds of the invention have been found to be useful prodrugs of compounds
that are selective agonists of metabotropic glutamate receptors, and are therefore useful in
the treatment of diseases of the central nervous system such as neurological diseases, for
example neurodegenerative diseases, and as antipsychotic, anxiolytic, drug-withdrawal,
antidepressam, anticonvulsant, analgesic and anti-emetic agents.
It will be appreciated that the compounds of Formula 1 contain at least four
asymmetric carbon atoms, three being in the cyclopropane ring and one being at the
a-carbon of the ammo acid group. Accordingly, the compounds of the invention may
exist in and be isolated in enantiomerically pure form, in racemic form, or in a
diastereoisomeric mixture.
The amino acid moiety preferably has the natural amino acid configuration, i.e.,
the L-configuration relative to D-glycerol aldehyde.
The present invention includes pharmaceutically acceptable salts of a compound
of Formula 1. These salts can exist in conjunction with the acidic or basic portion of the
molecule and can exist as acid addition, primary, secondary, tertiary, or quaternary
ammonium, alkali metal, or alkaline earth metal salts. Generally, the acid addition salts
may be prepared by the reaction of an acid with a compound of Formula 1. Alternatively,
acid addition salts may be prepared by reacting the penultimate compound (protected
which, in turn, may be reacted to produce a compound of Formula 1 or other salts . The
alkali metal and alkaline earth metal salts are generally prepared by the reaction of the
hydroxide form of the desired metal salt with a compound of Formula 1.
Some particular salts provide certain formulation advantages due to their
crystalline form. Non-crystalline amorphous forms of compounds may be hygroscopic.
Crystalline forms of pharmaceutical compounds are sometimes more desirable because
Acids commonly employed to form such salts include inorganic acids, for
example hydrochloric, hydrobromic, nitric, sulphuric or phoshoric acids, or with organic
acids, such as organic carboxylic acids, for example, glycollic, maleic, hydroxymaleic,
fumaric, malic, tartaric, citric, salicyclic, o-acetoxybenzoic, or organic sulphonic,

2-hydroxyethane sulphonic, toluene-p-sulphonic, methane-sulfonic, naphthalene-2-
sulphonic, benzene sulfonic, or ethane sulfonic acid.
In addition to pharmaceutically acceptable salts, other salts are included in the
invention. They may serve as intermediates in the purification of compounds or in the
preparation of other pharmaceutically acceptable acid addition salts, or are useful for
identification, characterization, or purification.
In the present invention, compounds of Formula 1 include solvates thereof.
Particularly, compounds of Formula 1 include hydrates thereof.
Furthermore, the present invention contemplates prodrugs of fluorinated
compounds as disclosed in International Application Nos. PCT/JP99/03984,
PCT/JP99/00324, and PCT/JP01/05550. See International Publication Nos.
WO/0012464, WO/9938S39, and WO/0200605, respectively. For example, the present
invention contemplates prodrugs of 1S,2R,5S,6S-2-amino-6-fluoro-4-
oxobicydo[3.1.0]hexane-2,6-dicarboxyIic acid; 1S,2R,4S,5S,6S-2-amino-6-fluoro-4-
hydroxybicyclo[3.1.0]hexane-2.6-dicarboxylic acid; 1S,2R,3R,5S,6S-2-amino-3-
fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid; and 15,2R,3S,5S,6S-2-amino-6-fluoro-
3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic acid.
A variety of physiological functions have been shown to be subject to influence
by excessive or inappropriate stimulation of excitatory amino acid transmission. The
Formula 1 compounds of the present invention are believed to have the ability to treat a
variety of neurological disorders in mammals associated with this condition, including
acute neurological disorder such as cerebral deficits subsequent to cardiac bypass surgery
and grafting, stroke, cerebral ischemia, spinal cord trauma, head trauma, perinatal
hypoxia, cardiac arrest, and hypoglycemic neuronal damage. The Formula 1 compounds
are believed to have the ability to treat a variety of chronic neurological disorders, such as
Alzheimer's disease, Huntington's Chorea, amyotrophic lateral sclerosis, AIDS-induced
dementia, ocular damage and retinopathy. cognitive disorders, and idiopathic and drug-
induced Parkinson's. The present invention also provides methods for treating these
disorders which comprises administering to a patient in need thereof an effective amount
of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

The Formula 1 compounds of the present invention treat a vanety of other
neurological disorders in patients that are associated with giutamate dysfunction,
including muscular spasms, convulsions, migraine headaches, urinary incontinence, pain,
. premenstrual dysphoric disorder (PDD), psychosis, (such as schizophrenia), drug
tolerance, withdrawal, cessation, and craving (such as nicotine, opiates, cocaine,
bcnzodia7epines, and ethanol), anxiety and related disorders, emesis, brain edema,
chronic pain, and tardive dyskinesia. The Formula 1 compounds are also useful as
antidepressant and analgesic agents. Therefore, the present invention also provides
methods for treating these disorders which comprise administering to a patient in need
thereof an effective amount of a compound of Formula 1, or a pharmaceutically
acceptable salt thereof.
The following definitions are to set forth the meaning and scope of the various
terms used herein. The general terms used herein have their usual meanings.
The term "affecting" refers to a Formula 1] compound acting as an agonist
at an excitatory amino acid receptor. The term "excitatory amino acid receptor"
refers to a metabotropic giutamate receptor, a receptor that is coupled to cellular
effectors via GTP-binding protein's. The term "cAMP-linked metabotropic
giutamate receptor" refers to a metabotropic receptor that is coupled to inhibition
of adenylate cyclase activity.
The term "neurological disorder" refers to both acute and chronic
neurodegenerative conditions, including cerebral deficits subsequent to cardiac
bypass surgery and grafting, cerebral ischemia (for example stroke resulting from
cardiac arrest), spinal cord trauma, head trauma, Alzheimer's Disease,
Huntington's Chorea, amyotrophic lateral sclerosis, AlDS-induced dementia,
perinatal hypoxia, hypoglycemic neuronal damage, ocular damage and
retinopathy, cognitive disorders, idiopathic and drug-induced Parkinson's Disease.
This term also includes other neurological conditions that are caused by glutamate
dysfunction, including muscular spasms, migraine headaches, urinary
incontinence, drug tolerance, withdrawal, cessation, and craving (i.e. opiates,
benzodiazepines, nicotine, cocaine, or ethanol), smoking cessation, emesis, brain
edema, chronic pain, sleep disorders, convulsions, Tourette's syndrome, attention
deficit disorder, and tardive dyskinesia.

The term "psychiatric disorder" refers to both acute and chronic
psychiatric conditions, including schizophrenia, anxiety and related disorders (e.g.
panic attack and stress-related cardiovascular disorders), depression, bipolar
disorders, psychosis, obsessive compulsive disorders, generalized anxiety
disorder, acute stress disorder, and panic disorder.
As used herein the term "effective amount" refers to the amount or dose of
the compound, upon single or multiple dose administration to the patient, which
provides the desired effect in the patient under diagnosis or treatment.
An effective amount can be readily determined by the attending
diagnostician, as one skilled in the art, by the use of known techniques and by
observing results obtained under analogous circumstances. In determining the
effective amount or dose of compound administered, a number of factors are
considered by the attending diagnostician, including, but not limited to: the
species of mammal; its size, age, and general health; the specific disease involved;
the degree of or involvement or the severity of the disease; the response of the
individual patient; the particular compound administered; the mode of
administration; the bioavailability characteristics of the preparation administered;
the dose regimen selected; the use of concomitant medication; and other relevant
circumstances. For example, a typical daily dose may contain from about 5 mg to
about 300 mg of the active ingredient. The compounds can be administered by a
variety of routes including oral, rectal, transdermal, subcutaneous, intravenous,
intramuscular, bucal, or intranasal routes. Alternatively, the compound may be
administered by continuous infusion.
As used herein the term "patient" refers to a mammal, such as a mouse,
guinea pig, rat, dog or human. It is understood that the preferred patient is a
human.
The term "treating" (or "treat") as used herein includes its generally accepted
meaning which encompasses prohibiting, preventing, restraining, and slowing, stopping,
or reversing progression of a resultant symptom. As such, the methods of this invention
encompass both therapeutic and prophylactic administration.

The genera] chemical terms used herein have their usual meanings. For example,
the term "(1-6C) alky!" means a straight or branched group. Examples of values for a (1-
6C) alkyl group include (1-4C) alkyl such as methyl, ethyl, propyl, isopropyl, butyl, and
isobutyl. The term "(2-6C) alkenyl" includes (2-4C) alkenyl, such as allyl. The term "(2-
6C) alkynyl" includes (2-4C) alkenyl, such as propynyl.
The term "optionally substituted," as used in the terms "optionally substituted (1-
6C) alkyl group." "optionally substituted (2-6C) alkenyl group," and "optionally
substituted (2-6C) alkynyl group," herein signifies that one or more substituents may be
present, preferably one to three, said substituents being selected from atoms and groups
which, when present in the compound of Formula 1, do not prevent the compound of
Formula 1 from modulating metabotropic glutamate receptor function.
Examples of atoms and groups which may be present in an optionally substituted
(1-6C) alkyl group, an optionally substituted (2-6C) alkenyl group, or an optionally
substituted (2-6C) alkynyl group are an optionally substituted aromatic group, an
optionally substituted heteroaromatic group, a non-aromatic carbocyclic group, a non-
aromatic heterocyclic group, a non-aromatic monocyclic carbocyclic group fused with
one or two monocyclic aromatic or heteroaromatic groups and a non-aromatic
monocyclic heterocyclic group fused with one or two monocyclic aromatic or
heteroaromatic groups.
The term "heteroaromatic group" includes an aromatic 5-6 membered ring
containing from one to four heteroatoms selected from oxygen, sulfur and nitrogen, and
an aromatic bicyclic group consisting of a 5-6 membered ring containing from one to four
heteroatoms selected from oxygen, sulfur and nitrogen fused with a benzene ring or a 5-6
membered ring containing from one to four heteroatoms selected from oxygen, sulfur and
nitrogen. Examples of heteroaromatic groups are furyl, thiophenyl, oxazolyl, isoxazolyl,
thiazoyl, isothiazolyl, imidazolyl, pyrimidyl, benzofuryl, benzothiophenyl,
benzimidazolyl. benzoxazolyl, benzothiazolyl and indolyl.
The term "aromatic group" includes phenyl and a polycyclic aromatic carbocyclic
ring such as naphthyl.
The term "optionally substituted," as used in the terms "optionally substituted
heteroaromatic group" and "optionally substituted aromatic group," herein signifies that
one or more substituents may be present, said substituents being selected from atoms and

groups which, when present in the compound of Formula 1, do not prevent the compound
of Formula J from modulating mctabotropic glutamate receptor function.
Examples of atoms and groups which may be present in an optionally substituted
heteroaromatic or an optionally substituted aromatic group are amino, hydroxy, nitro,
halogeno, (1-6C) alkyl, (1-6C) alkoxy, (1-6C)alkylthio, carboxy, (1-6C) alkoxycarbonyl,
carbamoyl, (1-6C) alkanoylamino, (1-6C)alkylsulphonyl, (1-6C) alkylsulphonylamino,
optionally substituted phenyl, phenoxy, phenylthio, phenylsulphonyl,
phenylsulphonylamino, toluenesulphonylamino, (1-6C)fluoroalkyl and (1-
6C)fluoroalkoxy. Examples of particular values are amino, hydroxy, fluoro, chloro,
bromo, iodo, methyl, methoxy, methylthio, carboxy, acetylamino, methanesulphonyl,
nitro, acetyl, phenoxy, phenylthio, phenylsulphonyl, methanesulphonylamino and
trifluoromethyl.
Examples of values for an optionally substituted aromatic group are 1-naphthyl, 2-
naphthyl, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-hydroxyphenyl, 3-
hydroxyphenyl, 4-hydroxyphenyl, 2-fluorophenyl, 3-fIuorophenyl, 4-fluorophenyl, 2,4-
difluorophenyl, 3,4-difluorophenyl, pentafluoropheny, 2-chlorophenyl, 3-chlorophenyl,
4-chlorophenyl, 2,4-dichlorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 3,5-
dichlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-methylphenyl, 3-
methylphenyl 4-methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,
2,3-dimethoxyphenyl, 2,5-dimethoxyphenyl, 3,4-dimethoxypheny), 3,5-dimethoxyphenyl,
2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 2-fluoro-3-
trifluoromethylphenyl, 3-trifluoromethyl-4-fluorophenyl, 3-trifluoromethyl-5-
fluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 3-
carboxyphenyl, and 4-carboxyphenyl.
The term "non-aromatic carbocyclic group" includes a monocyclic group, for
example a (3-10C)cycloalkyl group, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, cydooctyl, cyclononyl or cyclodecyl, and a fused polycyclic
group such as 1-adamantyl or 2-adamantyl, 1-decalyl, 2-decalyl, 4a-decalyl,
bicyclo[3,3,0]oct-1 -yl, -2-yl or -3-yl, bicyclo[4,3,0]non-]-yl, -2-yl, -3-yl or -7-yl,
bicyc]o[5,3,0]dec-1-yl, -2-yl -3-yl, -4-yl, -8-yl or -9-yl and bicyclo[3.3.1]non-1-yl,-2-yl,-
3-yl or 9-yl.

The term "non-aromatic heterocyclic group" includes a 4 to 7 membered ring
containing one or two heteroatoms selected from oxygen, sulphur and nitrogen, for
example azetidin-1-yl or -2-yl, pyrrolidin-1-yl, -2-yl or -3-yl, piperidin-1-yl, -2-yl, -3-yl
or -4-yl, hexahydroazepin-1-yl, -2-yl, -3-yl or -4-yl, oxetan-2-yl or -3-yl, tetrahydrofuran-
2-yl or -3-yl, tetrahydropyran-2-yl, -3-yl or -4-yl, hexahydrooxepin-2-yl, -3-yl or -4-yl,
thietan-2-yl or -3-yl, tetrahydrothiophen-2-yl or -3-yl, letrahydrothiopyran-2-yl, -3-yl or -
4-yl, hexahydrothiepin-2-yl, -3-yl or -4-yl, piperazin-1-yl or -2-yl, morpholin-1-yl, -2-yl
or -3-yl, thiomorpholin-1-yl, -2-yl or -3-yl, tetrabydropyrimidin-1-yl, -2-yl, -4-yl or -5-yl,
imidazolin-1 -yl, -2-yl or -4-yl, imidazolidin-1-yl, -2-yl or -4-yl, oxazolin-2-yl, -3-yl, -4-yl
or -5-yl, oxazolidin-2-y], -3-yl, -4-yl or -5-yl, thiazolin-2-yl, -3-yl, -4-yl or -5-yl, or
thiazolidin-2-yl, -3-yl, -4-yl or -5-yl.
The term "a non-aromatic monocyclic carbocyclic group fused with one or two
monocyclic aromatic or heteroaromatic groups" includes a (3-10C)cycloalkyl group fused
with a benzene ring or a an aromatic 5-6 membered ring containing from one to four
heteroatoms selected from oxygen, sulfur and nitrogen, such as indanyl, 1,2,3,4-
tetrahydronaphth-1 -yl or -2-yl, 5,6,7.S-tetrahydroquinolin-5-yl, -6-yl, -7-yl or 8-yl,
5,6,7,8-tetrahydroisoquinolin-5-yl, -6-yl. -7-yl or 8-yl, 4,5,6,7-tetrahydrobenzothiophen-
4-yl, -5-yl, -6-yl or -7-yl, dibenzo[2.3,6,7]cycloheptan-1-yl or -4-yl,
dibenzo[2,3,6,7]cyclohept-4-en-1-yl or -4-yl, or 9-fluorenyl.
The term "a non-aromatic monocyclic heterocyclic group fused with one or two
monocyclic aromatic or heteroaromatic groups" includes a 4 to 7 membered ring
containing one or two heteroatoms selected from oxygen, sulphur and nitrogen, fused
with a benzene ring or a an aromatic 5-6 membered ring containing from one to four
heteroatoms selected from oxygen, sulfur and nitrogen, such as 2,3-dihydrobenzopyran-2-
yl, -3-yl or -4-yl, xanthen-9-yl, 1,2,3,4-tetrahydroquinolin-1 -yl, -2-yl, -3-yl or -4-yl, 9,10-
dihydroacridin-9-yl or -10-yl, 2,3-dihydrobenzothiopyran-2-yl, -3-yl or -4-yl, or
dibenzothiopyran-4-yl.
The term "nitrogen-protecting group," as used herein and as represented by
"PgN," refers to those groups intended to protect or block the nitrogen group against
undesirable reactions during synthetic procedures. Choice of the suitable nitrogen-
protecting group used will depend upon the conditions that will be employed in
subsequent reaction steps wherein protection is required, as is well within the knowledge

of one of ordinary skill in the art. Commonly used nitrogen-protecting groups are
disclosed in T.W. Greene and P.G.M. Wuts, Protective Groups In Organic Synthesis, 3rd
Ed. (John Wiley & Sons, New York (1999)). A preferred nitrogen-protecting group is
tert-butoxycarbonyl.
The term "carboxy-protecting group," as used herein and as represented by
"PgC," refers to one of the ester derivatives of the carboxylic acid group commonly
employed to block or protect the carboxylic acid group while reactions are carried out on
other functional groups of the compound. Particular values include, for example, methyl,
ethyl, tert-butyl, benzyl, methoxymethyl, trimethylsilyl, and the like. Further examples of
such groups may be found in T.W. Greene and P.G.M. Wuts, Protecting Groups in
Organic Synthesis, 3rd Ed. (John Wiley & Sons, New York (1999)). Preferred carboxy-
protecting group are methyl and ethyl. The ester is decomposed by using a conventional
procedure which does not affect another portion of the molecule.
The term "hydroxyl protecting group" denotes a group understood by one skilled
in the organic chemical arts of the type described in Chapter 2 of Greene and Wuts.
Representative hydroxyl protecting groups include, for example, ether groups, substituted
ethyl ether groups, isopropyl ether groups, phenyl and substituted phenyl ether groups,
benzyl and substituted benzyl ether groups, alkylsilyl ether groups, ester protecting
groups, and the like. The species of hydroxyl protecting group employed is not critical so
long as the derivatized hydroxyl group is stable to the conditions of subsequent
reaction(s) on other positions of the intermediate molecule and can be selectively
removed at the appropriate point without disrupting the remainder of the molecule
including any other hydroxyl protecting group(s).
The term "amino acyl" means an amino acyl derived from an amino acid selected
from the group consisting of natural and unnatural amino acids as defined herein. The
natural amino acids may be neutral, positive or negative depending on the substituents in
the side chain. "Neutral amino acid" means an amino acid containing uncharged side
chain substituents. Exemplary neutral amino acids include alanine, valine, leucine,
isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine, threonine,
cysteine, glutamine, and asparagine. "Positive amino acid" means an amino acid in which
the side chain substituents are positively charged at physiological pH. Exemplary
positive amino acids include lysine. arginine and histidine. "Negative amino acid" means

an amino acid in which the side chain substituents bear a net negative charge al
physiological pH. Exemplary negative amino acids include aspartic acid and glutamic
acid. Preferred amino acids are oc-amino acids. The most preferred amino acids are α-
amino acids having L stereochemistry at the α-carbon. Exemplary natural α-amino acids
are valine, isoleucine, proline, phenylalanine, tryptophan, methionine, glycine, serine,
threonine, cysteine, tyrosine, asparagine, glutamine, lysine, arginine, histidine, aspartic
acid and glutamic acid.
"Unnatural amino acid" means an amino acid for which there is no nucleic acid
codon. Examples of unnatural amino acids include, for example, the D-isomers of the
natural a-amino acids as indicated above; Aib (aminobutyric acid), βAib (3-
aminoisobutyric acid),Nva (norvaline), β-Ala, Aad (2-aminoadipic acid), βAad (3-
aminoadipic acid), Abu (2-aminobutyric acid), Gaba (γ-aminobutyric acid), Acp(6-
aminocaproic acid). Dbu (2,4-diaminobutryic acid), α-aminopimelic acid, TMSA
(trimethylsilyl-Ala), alle (allo-isoleucine), Mle (norleucine), tert-Leu, Cit (citrulline), Om,
Dpm (2,2'-diaminopimelic acid), Dpr (2,3-diaminopropionic acid), α- or β-Nal, Cha
(cyclohexyl-Ala), hydroxyproline, Sar (sarcosine), O-methyl tyrosine, phenyl glycine and
the like; cyclic amino acids; Nα-alkylated amino acids where Nα-alkylated amino acid is
Nα-(1-10C)alkyl nmino acid such as MeGly (Nα-methylglycine), EtGly (Nα-ethylglycine)
and EtAsn (Nα-ethylasparagine) and amino acids in which the a-carbon bears two side-
chain substituents. Exemplary unnatural a-amino acids include D-alanine, D-leucine and
phenylglycine. The names of natural and unnatural amino acids and residues thereof used
herein follow the naming conventions suggested by the 1UPAC-1UB Joint Commission
on Biochemical Nomenclature (JCBN) as set out in "Nomenclature and Symbolism for
Amino Acids and Peptides (Recommendations, 1983)" European Journal of
Biochemistry, 138, 9-37 (1984). To the extent that the names and abbreviations of amino
acids and residues thereof employed in this specification and appended claims differ from
those noted, differing names and abbreviations will be made clear.

Although all of the compounds of Formula 1 are useful active mGluR2 receptor
agonists, certain compounds are preferred. The following paragraphs define preferred
classes.
A) Q is glycyl, alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tyrosyl,
tryptophyl, methionyl, lysyl, or serinyl.
B) Q is alanyl.
C) Q is methionyl.
D) p is 1.
E) p is 2.
F) X is SO2.
G) X is CR3R4.
H) R3 is fluoro and R4 is hydrogen.
I) R3 is hydroxy and R4 is hydrogen.
J) R3 and R4 together represent =0.
K) R10 is hydrogen.
L) R10 is fluoro.
M) R11 is hydrogen.
N) The compound is a free base.
O) The compound is a salt.
P) The compound is the hydrochloride salt.
Q) The compound is the mesylate salt.
R) The compound is the esylate salt.
S) The compound is the tosylate salt.
The preceding paragraphs may be combined to define additional preferred classes
of compounds.
The compounds of Formula 1 are useful for the treatment of disorders of
mammals, and the preferred mammal is a human.
The compounds of the present invention can be prepared by a variety of
procedures, some of which are illustrated in the schemes below. The particular order of
steps required to produce the compounds of Formula 1 is dependent upon the particular
compound being synthesized, the starting compound, and the relative lability of the

substituted moieties. Some substituents may have been eliminated in the following
schemes for the sake of clarity, and are not intended to limit the teaching of the schemes
in any way. As one of ordinary skill in the art will appreciate, substituents R15 and R16
represent the appropriate side chain to form the desired amino acyl.
If not commercially available, the necessary starting materials for the following
schemes may be made by procedures which are selected from standard techniques of
organic and heterocyclic chemistry, techniques which analogous to the syntheses of
known, structurally similar compounds, and the procedures described in the preparations
and examples, including novel procedures.

Compounds of Formula I are converted via enzymatic or hydrolytic process in
vivo to form compounds of Formula II, as shown in Scheme 1 above. In particular, a
crystalline form of a compound of Formula I may be prepared according to the route
outlined in Scheme 2 below.


The hydrolysis of the di-ester protected peptidyl compound of formula (iii) with a
suitable base such as lithium hydroxide or sodium hydroxide in a suitable solvent, such as
THF or THF/water. affords the di-acid protected peptidyl compound of formula (iv). A
compound of formula (iv) may be deprotected with a suitable acid in a suitable solvent.
Such conditions may produce the corresponding acid salt of the di-acid peptidyl
compound, depicted in Formula 1 salt, us an amorphous solid or, directly, a crystalline
solid, wherein X" represents the corresponding anion. In the case of an amorphous solid,
subsequent crystallization may occur from suitable solvents. Carboxylate salts may be
formed by the introduction of a cationic species by a reagent such as sodium acetate.

Finally, the zwitterionic compound may be afforded by treatment of the crystalline salt
compound with an appropriate base.
For example, a di-acid protected peptidyl compound of formula (iv) when treated
hydrogen chloride gas in suitable solvent provides the deprotected hydrochloride salt as
an amorphous solid. The amorphous hydrochloride compound may then be crystallized
from acetone and water to afford the crystalline hydrochloride salt compound. In the case
of a crystalline solid which is formed directly, filtration of the reaction mixture may
afford the crystalline salt. The zwitterionic compound is afforded by treatment of the
crystalline hydrochloride salt compound with sodium hydroxide: alternatively, treatment
of the mesylate salt compound or the tosylate salt compound with sodium hydroxide will
also afford the zwitterionic compound. It will be appreciated by one of ordinary skill in
the art that a compound of Formula I may be prepared in one procedure where the
indicated intermediates are not isolated.

The di-ester of formula (ii) is acylated with a compound of Formula III using a
suitable coupling agent to afford a di-ester protected peptidyl compound of formula (iii).
Alternatively, this transformation could be achieved using the acid chloride of a
compound of Formula III.
Suitable peptide coupling reagents include dicyclohexylcarbodiimide (DCC), 1-
(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), isobutyl chloroformate, diphenyl
chlorophosphate, 2-ch)oro-4,6-dimethoxy-1,3,5-triazine (CDMT), bis(2-oxo-3-
oxazolidinyl)phosphinic chloride, and benzolriazol-1-
y]oxytris(dimethylamino)phosphonium hexafluorophosphate.


In Scheme 4 above, a compound of Formula II, a di-acid, is treated with a suitable
carboxy-protecting agent, such as catalytic hydrochloric acid or thionyl chloride and
methanol or ethanol, affording the corresponding di-ester of formula (ii). Alternatively, a
compound of Formula II first may be treated with a nitrogen-protecting agent such as
BOC2O to afford a nitrogen-protected compound of formula (i). Next, a compound of
formula (i) may be treated with a carboxy-protecting agent such as methyl iodide in the
presence of a base such as potassium carbonate, followed then by an nitrogen
deprotecting agent such as hydrochloric acid or trifluoroacetic acid to afford a compound
of formula (ii).
Additionally, one of ordinary skill in the art would recognize that depending on X,
an appropriate protecting agent may be necessary. For example, if X represents CR3R4,
R3 represents hydroxy, and R4 represents hydrogen, then one of ordinary skill in the art
would appreciate that a suitable hydroxyl protecting group may be necessary before
proceeding with any of the above schemes.

Compounds of Formula I] are known in the an. For example, preparations of
these compounds may be found in U.S. Patent Nos. 5,688,826 (the '826 patent) and
5,958,960 (the '960 patent).
Various improvements upon the synthetic route to compounds of Formula II have
been made over the processes previously disclosed. The improvements involve sulfur
and alcohol oxidation, as well as optical resolution of various intermediates as described
below.
The first improvement relates to the conversion described in the '826 patent at
column 8, lines 22-34, and column 7, beginning at column 33 (Formula V), involving
oxidation of a compound of Formula VII of the '826 patent

to form a compound of Formula V of the '826 patent

It has been discovered that the sulfur trioxide-pyridine complex or trifluoroacetic
anhydride in conjunction with DMSO are preferred of the many oxidation methods
known in the art.

Second, with respect to the resolution of a compound of Formula III of the '826
patent

in which R2 represents a carboxyl group, referred to in column S, at lines 3-7, and column
6, beginning at line 1 (Formula III), it has been discovered that (R)-α-methy)benzylamine
and quinine are preferred. (R)-α-rnethy]benzylamine is particularly preferred.
Further, it has been discovered that when oxidizing the sulfide of a compound of
Formula III of the '826 patent where X is sulfur to form a compound of Formula III of the
'826 patent where X is sulfonyl, as referred to in the '826 patent at column 8, lines 39-53,
that a basic aqueous system and hydrogen peroxide used in combination with a catalyst
are preferred.
The following Examples further illustrate the compounds of the present invention
and the methods for their synthesis. The Examples are not intended to be limiting to the
scope of the invention in any respect, and should not be so construed. All experiments
are run under a positive pressure of dry nitrogen or argon. All solvents and reagents are
purchased from commercial sources and used as received, unless otherwise indicated.
Dry tetrahydrofuran (THF) may be obtained by distillation from sodium or sodium
benzophenone ketyl prior to use. Proton nuclear magnetic resonance (1H NMR) spectra
are obtained on a Bruker Avance II bay-500 at 500 MHz, a Bruker Avance 1 bay-200 at
200MHz, or a Varian Inova/Varian 300/Varian 400 at 500 MHz. Electrospray mass
spectroscopy (ESI) is performed on a Agilent MSD/B intrument using
acetonitrile/aqueous ammonium acetate as the mobile phase. Free atom bombardment
mass spectroscopy (FABMS) is performed on a VG ZAB-2SE instrument. Field
desorption mass spectroscopy (FDMS) is performed using either a VG 70SE or a Varian
MAT 731 instrument. Optical rotations are measured with a Perkin-Elmer 241
polarimeter. Chromatographic separation on a Waters Prep 500 LC is generally carried

out using a linear gradient of the solvents indicated in the text. The reactions are
generally monitored for completion using thin layer chromatography (TLC). Thin layer
chromatography is performed using E. Merck Kieselgel 60 F254 plates, 5 cm X 10 cm,
0.25 mm thickness. Spots are detected using a combination of UV and chemical
detection (plates dipped in a cerie ammonium imolybdate solution [75 g of ammonium
molybdate and 4 g of cerium (IV) sulfate in 500 mL of 10% aqueous sulfuric acid] and
then healed on a hot plate). Flash chromatography is performed as described by Still, et
al. Still, Kahn, and Mitra, J. Org. Chem., 43, 2923 (1978). Elemental analyses for
carbon, hydrogen, and nitrogen are determined on a Control Equipment Corporation 440
Elemental Analyzer or are performed by the Universidad Complutense Analytical Centre
(Facultad de Farmacia, Madrid, Spain). Melting points are determined in open glass
capillaries on a Gallenkamp hot air bath melting point apparatus or a Buchi melting point
apparatus, and are unconnected.
The abbreviations, symbols and terms used in the examples have the following
meanings.
Ac = acetyl
Anal. = elemental analysis
ATR = attenuated total internal reflection
Bn or Bz) - benzyl
Bu = butyl
BOC = t-butoxycarbonyl
calcd = calculated
D?O = deuterium oxide
DCC = dicyclohexylcarbodiimide
DCM = 1,2-dichloromethane
D1BAL-H = diisobutyl aluminum hydride
DMAP - 4-dimethylaminopyridine
DMF = dimethylformamide
DMSO = dimethylsulfoxide
DSC = differentia] scanning calorimetry
EDC = N-ethyl-N'N"-dimethylaminopropyl carbodiimide hydrochloride
ES = Electrospray

Et = ethyl
EtOH = ethanol
FAB = Fast Atom Bombardment (Mass Spectrascopy)
FDMS = field desorption mass spectrum
FTIR = Fourier transform infrared spectrometry
HOAt = 1-hydroxy-7-azabenzotriazole
HOBt = 1-hydroxybenzotriazole
HPLC = High Performance Liquid Chromatography
HRMS = high resolution mass spectrum
i-PrOH = isopropanol
1R = Infrared Spectrum
L = liter
Me = methyl
MeOH = methanol
MPLC = Medium Pressure Liquid Chromatography
Mp = melting point
MTBE = t-butyl methyl ether
NBS = N-bromosuccinimide
NMR = Nuclear Magnetic Resonance
PC-TLC = preparative centrifugal thin layer chromatography
Ph = phenyl
p.o. = oral administration
i-Pr = isopropyl
Rochelle's Salt = potassium sodium tartrate
rt - room temperature
SM = starting material
TBS = tert-butyldimethylsilyl
TEA = triethylamine
Temp. = temperature
TFA = trifluoroacetic acid
THF = tetrahydrofuran
TLC = thin layer chromatography

t-BOC = tert-bmoxycarbonyl
General Procedure A
EDC coupling between amines and N-BOC-(L)aminoacids
Suspend the starting amino dialkyl ester (a compound of formula ii, Scheme 3)
(1.0 equiv.) in dry dichloromethane under nitrogen. Sequentially add the corresponding
N-Boc-(L)-aminoacid (1.5-2.0 equiv), EDC (1.5-2.0 equiv), HOBt (1.5-2.0 equiv), and
dimethylaminopyridine (DMAP, 0.1-0.2 equiv). Stir the reaction mixture at room
temperature until judged complete by TLC unless otherwise noted. Dilute the reaction
mixture with ethyl acetate and wash sequentially with saturated aqueous NaHCO3 and/or
aqueous NaHSO4. and brine. After drying over sodium sulfate and evaporation in vacuo
purify the crude residue (a compound of formula iii) by silica gel chromatography using
the appropriate eluent (typically ethyl acetate/hexanes).
General Procedure B
Anhydride coupling between amine and M-BOC-(L)-aminoacid isobutyl anhydrides
To a solution of the corresponding N-Boc-(L)-aminoacid (1.5 equiv) in dry
dichloromethane (10 mL) at -20°C under nitrogen add N-methyl morpholine (NMM, 1.5
equiv, in 1 mL CH2Cl2) followed by dropwise addition of iso-butyl chloroformate (IBCF,
1.5 equiv, in 5 mL CH2Cl2) at a rate so the internal reaction temperature does not exceed
-15°C. Stir the resulting reaction mixture at -20°C for 30 minutes then add a -20°C
solution of (1S,2S,4S,5R,6R)-2-(2'-amino-propionylamino)-4-hydroxy-
bicyc]o[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester hydrochloride (1.0 equiv) in
dichloromethane (10 mL) at a rate so the internal reaction temperature does not exceed
-15°C. Upon complete addition, remove the cooling bath and stir the reaction mixture at
room temperature until judged complete by TLC. Dilute the reaction mixture with ethyl
acetate and sequentially wash with saturated aqueous NaHCO3, aqueous NaHSO4, and
brine. After drying over magnesium sulfate and evaporation in vacuo purify the crude
residue by silica gel chromatography using the appropriate eluent (typically hexanes/ethyl
acetate).

General Procedure C
Sequential N-Boc and ester protecting group removal
Stir the corresponding N-Boc dicster peptide derivative (a compound of formula
iii, Scheme 2) (1.0 equiv) in a 1:1 mixture of THF/2.5 N LiOH (10-20 equiv) at room
temperature for up to 4 hours. Dilute the reaction with H2O and wash with ethyl acetate.
Discard the organic layer. Adjust the aqueous phase to pH 2 with 1 N HCl (NaCl added
to aqueous phase to enhance extractability as needed) and exhaustively extract the N-boc
dicarboxylic acid product (a compound of formula iv) with ethyl acetate. Combine all
organics, wash with brine, dry over MgSO4, and concentrate to dryness in vacuo to afford
the desired carboxylate product as a foamy solid. Dissolve in ethyl acetate and chill to
0°C. Purge the reaction mixture with anhydrous HCl gas until saturated with HCl. Stir
the resulting reaction mixture at 0°C for up to 4 hours. Isolate the fully deprotected
peptide derivative (a compound of Formula 1) as its hydrochloride salt by filtration under
N2 or by concentration of the reaction mixture to dryness followed by trituration with
ethyl acetate or Et2O and concentration to a white powder. Optionally, to remove residual
solvent and excess HCl, reconstitution of the products in H2O, freezing, and subsequent
lyophilization afford the desired hydrochloride products.
Preparation 1
(1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid
diethyl ester

To a slurry of (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-
4,6-dicarboxylic acid (10 g, 42.5 mmol, U.S. Patent No. 5,688,826) in 100mL of 2B
ethanol at room temperature is added thionyl chloride (15.5 mL, 212.6 mmol) dropwise
over 20 minutes followed by rinsing with 40 mL of ethanol. Heat the slurry to reflux and
stir overnight. Analysis via 500 MHz 1H NMR (CD3OD) of a concentrated aliquot
reveals complete consumption of starting material and intermediate monoester. Allow the

resultant solution to cool to room temperature, then concentrate to a gelatinous residue.
Add EtOAc (50 mL) to the gelatin that was farther concentrated to a solid, then dilute
with another 94 mL of EtOAc. Add 15% aqueous sodium carbonate (70 mL) slowly to
the mixture with swirling by hand to gradually affoTd dissolution, giving a final pH of
7.95. Filter the resulting sodium carbonate precipitation before extracting the layers.
Back extract the aqueous layer with ElOAc (2 x 100 mL). Wash the combined organic
extracts with brine (1 x 100 mL), dry (MgSO4), filter, and concentrate in vacuo to
provide a faint yellow oil that solidified to give the title compound as an off-white solid
(11.71 g, 95% yield).
Recrystallization
A mixture of the title compound (200 mg) in EtOAc (800 µL) is heated to 56 °C at
which time dissolution occurs. After stirring for 15 minutes at 56 °C, heptane (1 mL) is
added dropwise to the solution. The heat is turned off. Allow the solution to cool to 52
°C at which time precipitation occurs. Upon cooling and further dilution with heptane
(600 µL), the slurry forms. Stir the resultant slurry at room temperature for 1 hour before
filtering, washing with heptane (2 x 500 µL), and drying at 45 °C overnight to give 145
mg (73% recovery) of the title compound as a white solid.
mp 80-83 °C.
[α]25D -57.7° (c 1.04,CH3OH).
500 MHz 1H NMR (CD3Cl3) δ 4.31 (q, 2H, J = 7.0 Hz), 4.20 (m, 2H), 3.78 (d, 1H, J =
15.0 Hz), 3.36 (dd, 1H,J = 4.0, 7.0 Hz), 2.93 (dd, 1H, J =4.0, 7.0 Hz), 2.8) (d, 1H, J =
15.0 Hz), 2.46 (t, 1H, J = 4.0), 1.34 (t, 3H, J = 7.0), 1.30 (t, 3H, J = 7.0).
13C NMR(125Mllz,CD3Cl3)δ 171.68, 168.57,63.26,62.42,59.96,56.06,43.78,
32.25,22.49, 14.31, 14.25.
FTIR (ATR) 3364.15 (s), 1725.95 (s), 1304.91 (s), 1259.24 (s), 1200.84 (s), 1104.91 (s),
1022.99 (s), 896.45 (s), 851.21 (s)cm-l.
Anal. Cald for C11H17NO6S:C, 45.35; H, 5.88; N, 4.81. Found: C, 45.02; H, 5.75; N,
4.82.

Preparation 2
(1R,4S,5S,6S)-4-(2'S-tert-butoxycarbonylamino-propionylamino)-2,2-dioxo-2λ6-thia-
bicyc]o[3.1.0]hexane-4,6-dicarboxylic acid diethyl ester

To a solution of N-Boc-L-alanine (43.52 g, 230 mmol) and N-methyl morpholine
(25.5 mL, 232 mmol) in 457 mL of methylene chloride at -30 °C under nitrogen add iso-
butyl chloroformate (30.4 mL, 234 mmol) dropwise over 10 minutes. Stir the resultant
thin slurry at -25 to -30 °C for 30 min at which time a solution of (1R,4S,5S,6S)-4-amino-
2,2-dioxo-2λ6-thia-bicyclo[3.1.0]bexane-4,6-dicarboxylic acid diethyl ester (63.90 g, 219
mmol, Preparation 1) in 213 mL of methylene chloride is added over 25 minutes such that
the reaction temperature does not exceed -25 °C. Upon completion of the addition,
remove the cooling bath and allow to stir at ambient temperature for 60 minutes at which
time the reaction temperature reached 19 °C and the color became faint orange. Treat the
reaction with 350 mL of 1 N HCl and separate the layers. Wash the organic layer with
saturated aqueous NaHCO3, (1 x 350 mL) and brine (1 x 350 mL), dry (Na2SO4), filter,
and concentrate in vacuo to a white foam (105.2 g, 104%).
1H NMR (300 MHz, CDCl3) δ: 7.62 (brs, 1H), 4.90 (brd, 1H, J = 7.1 Hz), 4.34-4.10 (m,
6H), 3.39 (ddd, 1H, J = 7.2, 3.9, 1.0 Hz), 3.00 (dd, 1H, J = 7.1, 3.9 Hz), 2.90 (brd, 1H, J =
14.9 Hz), 2.43 (t, 1H, J = 4.1 Hz), 1.46 (s, 9H), 1.31 (m, 9H).
13C NMR (75 MHz, CDCl3) δ: 173.0, 168.6, 167.6, 80.9, 76.5, 63.3, 62.3, 59.9, 55.7,
42.8, 31.5, 28.2, 22.7, 16.6, 14.0, 13.9.MS (ES) m/z 461.0 [M-H]-.

Preparation 3
(1R,4S,5S,6S)-4-(2'S-tert-buloxycarbonylamino-propionylamino)-2.2-dioxo-2λ6-thia-
bicyclo[3.1.0]hexane-4.6-dicarboxylic acid

To a solution of (1R,4S,5S,6S)-4-(2'S-tert-butoxycarbony]amino-
propiony]amino)-2,2-dioxo-2λ6-thia-bicyc]o[3.1.0]hexane-4,6-dicarboxylic acid diethyl
ester (181.4 g, 392 mmol theoretical, Preparation 2) in 292 mL of THF at room
temperature add 490 mL (980 mmol) of 2N sodium hydroxide. Allow the biphasic
mixture to stir vigorously at room temperature for 1.25 hours at which time the reaction is
homogeneous. Dilute the mixture with 490 mL of ethyl acetate and separate the layers.
Dilute the aqueous layer with 490 mL of ethyl acetate, and lower the pH of the mixture to
1.5 with concentrated HCl. Separate the layers and back-extract the aqueous layer with
245 mL of ethyl acetate. Dry the combined organic layers (Na2SO4), filter, and
concentrate to provide 167.9 g (105%) of the title compound as a white foam. This
material was used without characterization in Examples 1 and 2.

Preparation 4
(1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid
dimethyl ester

Add thionyl chloride (6.2 mL, 85.0 mmol) dropwise to a rapidly stirred
suspension of (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-
dicarboxylic acid (10.0 g, 42.5 mmol, U.S. Patent No. 5,688,826) in MeOH (170 mL, 5
°C). Upon complete addition, allow the reaction mixture to warm slowly to room
temperature, then warm under reflux for 48 h. Remove the volatiles under reduced
pressure, and partition the residue between a saturated solution of NaHCO3 (200 mL) and
ethyl acetate (400 mL). Separate the layers and extract the aqueous one with ethyl acetate
(2 x 400 mL each time). Dry the combined organic layers over K2CO3, and concentrate
under reduced pressure to afford 8.10 g (30.8 mmol) of the title compound in 72% yield.

Anal Calcd for C9H13NO6S: C, 41.06; H, 4.98; N, 5.32. Found: C, 40.94; H, 4.93; N,
5.30.
MS (ES) m/z 264.0 [M+H]+.

Preparation 5
(1R,4S,5S,6S)-4-(2'S-tert-Butoxycarbonylamino-3'-phenyl-propionylamino)-2,2-dioxo-
2λ6-thia-bicyclo[3.1.0]hexane-4.6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC-
(L)-Phenylalanine and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1 .0]hexane-
4,6-dicarboxylic acid dimethyl ester (Preparation 4). Reflux reaction mixture overnight.
Purify by PC-TLC, 4 mm SiO2 rotor, (10 % ethyl acetate/hexanes to 100% ethyl acetate).
Yield 0.85 g (88 %, 1.67 mmol) of a white foam.

1H NMR (300 MHz, CDCl3) δ 1.43 (9H, s), 2.38-2.40 (1H, m), 2.86 (1H, d, J = 15.0 Hz),
2.91 (1H, dd, J = 4.4, 7.3 Hz), 3.04 (2H, d, J = 7.3 Hz), 3.35-3.39 (1H, m), 3.77 (3H, s),
3.84 (3H, s), 4.11 (1H, d, J = 14.3), 4.30 (1H, app. q, J = 7.3), 4.96 (1H, bd, J = 6.6 Hz),
6.96 (1H, bs), 7.22-7.36 (5H, m).
Anal Calcd for C23H30N2O9S.0.1H20: C, 53.92; H, 5.94; N, 5.47. Found: C, 53.62; H,
5.90; N, 5.28.
MS (ES) m/z 509.16 [M - H]-; 411.2 [M - Boc]+.

Preparation 6
(1R,4S,5S,6S)-4-(2'S-tert-Butoxycarbonylamino-3'S-methyl-pentanoylamino)-2,2-dioxo-
2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC-
(L)-lsoleucine and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-
dicarboxylic acid dimethyl ester (Preparation 4). Reflux reaction mixture overnight.
Purify by PC-TLC, 4 mm SiO2 rotor, (10 % ethyl acetate/hexanes to 100% ethyl acetate).
Yield 0.75 g (83 %, 1.57 mmol) of a white foam.

1H NMR (300 MHz, CDCl3) δ 0.91 (3H, t, J = 7.3 Hz), 0.93 (3H, d, J = 6.6 Hz), 1.10-1.18
(lH,m), 1.46(9H,s), 1.42-1.52 (1H, m), 1.81-1.86 (14H, bm), 2.51 (1H, t, J = 4.0 Hz),
2.95 (1H, d, J = 15.0 Hz), 3.06 (1H, dd, J = 4.4, 7.3 Hz), 3.43 (3H, dd, J = 3.7, 7.0 Hz),
3.78 (3H, s), 3.85 (3H, s), 3.82-3.90 (1H, m), 4.20 (1H, d, J = 14.7 Hz), 4.94 (1H, d, J =
8.4Hz),7.19(lH,bs).
Anal Calcd for C20H32M2O9S: C, 50.41 :H, 6.77; N, 5.88. Found: C, 50.32; H, 6.92; N
5.76.
MS(ES)m/z 475.1 [M - H]-

Preparation 7
(1R,4S,5S,6S)-4-(2'S-tert-Butoxycarbonylamino-3'-methyl-butyrylamino)-2,2-dioxo-
2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC-
(L)-Valine and (lR,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-
dicarboxylic acid dimethyl ester (Preparation 4). Reflux reaction mixture overnight.
Purify by PC-TLC, 4 mm SiO2 rotor, (10 % ethyl acetate/hexanes to 100% ethyl acetate).
Yield 0.41 g (47 %, 0.89 mmol) of a white foam.

1H NMR (300 MHz. CDCl3) δ 0.93 (3H, d, J = 7.0 Hz), 0.96 (3H, d, J = 6.6 Hz), 1.46
(9H, s), 2.06-2.13 (1H, m), 2.50 (1H, t, J = 4.0 Hz), 2.94 (1H, d, J = 15.0 Hz), 3.04 (1H,
dd, J = 4.4, 7.3 Hz), 3.43 (1H, dd, J = 3.3, 6.6), 3.78 (3H, s), 3.80-3.86 (1H, m), 3.86 (3H,
s), 4.24 (1H, d, J = 15.0 Hz), 4.94 (1H, d, J = 8.1 Hz), 7.15 (1H, bs).
Anal Calcd for C19H30N2O9S: C, 49.34; H, 6.54; N, 6.06. Found: C, 49.33; H, 6.44; N,
6.05.
MS (ES) m/z 461.2 [M-H]-

Preparation 8
(1R,4S,5S,6S)-4-(2'S-tert-Butoxycarbonylamino-4'-methyl-pentanoylamino)-2,2-dioxo-
2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC-
(L)-Leucine monohydrate and (lR,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-
bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester (Preparation 4). Reflux the
reaction mixture overnight. Purify by PC-TLC, 4 mm SiO2 rotor, (10 % ethyl
acetate/hexanes to 100% ethyl acetate). Yield 0.85 g (94 %, 1.78 mmol) of a white foam.

1H NMR (300 MHz, CDCl3) δ 0.92 (3H, d, J = 6.2 Hz), 0.95 (3H, d, J = 6.6 Hz), 1.47
(9H, s), 1.42-1.47 (1H, m), 1.63-1.67 (1H, m), 2.46 (1H, t, J = 3.7 Hz), 2.87 (1H, d, J =
15.0 Hz), 3.04 (1H, dd, J = 4.4, 7.3 Hz), 3.41 (1H, dd, J = 3.7, 7.0), 3.78 (3H, s), 3.86
(3H, s), 4.00-4.05 (1H, m), 4.20 (1H, d, J = 15.0 Hz), 4.75 (1H, d, J = 6.6 Hz), 7.43 (1H,
bs).
Anal Calcd for C20H32N2O9S: C, 50.41; H, 6.77; N, 5.88. Found; C, 50.30; H, 6.82; N,
5.75.
MS (ES) m/z 475.2 [M - H]-.

Preparation 9
(lR,4S,5S,6S)-4-(2'S,6'-bis-tert-butoxycarbonylamino-hexanoylamino)-2,2-dioxo-2λ6-
thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC- .
Lys(BOC)-OH and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyc]o[3.1.0]hexane-4,6-
dicarboxylic acid dimethyl ester (Preparation 4). Reflux the reaction mixture overnight.
Purify by PC-TLC, 4 mm SiO2 rotor, (10% ethyl acetate/hexanes to 100% ethyl acetate).
Yield 1.04 g (93 %, 1.76 mmol) of a white foam.

1H NMR (300MHz,CDCl3)δ 1.44 (9H, s), 1.46 (9H, s), 1.39-1.53 (3H, m), 1.56-1.65
(1H, m), 1.77-1.84 (2H, m), 2.50 (1H, t, J = 4.4 Hz), 2.98-3.20 (4H, m), 3.42 (1H, dd, J =
3.7, 7.0 Hz), 3.76 (3H, s), 3.86 (3H, s), 4.01 (1H, dd, J = 7.7, 13.2 Hz), 4.09-4.19 (1H,
m), 4.71 (1H, t, J = 7.3 Hz), 5.13 (1H, bs), 7.59 (1H, bs).
Anal Calcd for C25H41N3O11S: C, 50.75; H, 6.98; N, 7.10. Found: C, 50.36; H, 6.99; N,
6.87.
MS (ES) m/z 590.2 [M - H]-

Preparation 10
(1R,4S,5S,6S)-4-[2'S-tert-Butoxycarbonylamino-4'-(trityl-carbamoyl)-butyrylamino]-
2,2-dioxo-2λ6 -thia-bicyclo[3.1 .0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available N-BOC-
(L)-Glutamine (Trt)-OH and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-
bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester (Preparation 4). Reflux the
reaction mixture overnight. Purify by PC-TLC, 4 mm SiO2 rotor, (10 % ethyl
acetate/hexanes to 100% ethyl acetate). Yield 0.53 g (48 %, 0.72 mmol) of a white foam.

1H NMR (300 MHz, CDCl3) δ 1.42 (9H, s), 1.83-1.88 (1H, m), 2.03-2.18 (1H, m), 2.16
(1H, t, J = 4.0 Hz), 2.57-2.64 (1H, m), 2.60 (1H, d, J = 15.0 Hz), 2.64-2.80 (1H, m), 2.88
(1H, dd, J = 4.4, 7.3 Hz), 3.26 (1H, dd, J = 4.0, 7.0 Hz), 3.47 (3H, s), 3.76-3.90 (1H, m),
3.81 (3H, s), 4.05 (111, d, .1 = 15.0 Hz ), 5.47 (1H, bs), 7.02 (1H, bs), 7.20-7.35 (15H, m),
08.6S(1H,bs).
Anal Calcd for C38H43N3O10S: C, 62.20; H, 5.91; N, 5.73. Found: C, 61.83; H, 6.09; N,
5.57.
MS (ES)m/z 731.9 [M - H]-:
HRMS calcd for C38H43N3O10S [M + Na]', 756.2567. Found, 756.2585.

Preparation 11
(1R,4S,5S,6S)-4-[2'S-tert-Butoxycarbonyl-pyrrolidine-2'S-carbonyl)-amino]-2,2-dioxo-
2λ6-thia-bicyclo[3.1.0.]hexane-4.6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available Boc-(L)-
proline (0.61 g, 2.9 mmol) and (]R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-
bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester (0.5 g, 1.9 mmol, Preparation
4). Purify using PC-TLC (ethyl acetate/hexanes) to yield 0.S7 gram (99.2%) of the title
compound.

1H NMR (300 MHz, CDCl3) δ 1.51 (9H, s), 1.75-1.98 (311, m), 2.35-2.5 (2H, m), 2.84
(1H, d, J=14.7 Hz), 2.9-3.03 (1H, m), 3.25-3.4 (1H, m), 3.3-4.1 (2H, m), 3.76 (3H, s),
3.86 (3H, s), 4.14-4.31 (2H, m), 8.66 (1H, s).
MS (ES) m/z 459.2 [M-1]-.

Preparation 12
(1R,4S,5S,6S)-4-(2'S-tert-Butoxycarbonylamino-4-methylsulfanyl-butyrylamino)-2,2-
dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using commercially available Boc-(L)-
Methionine (0.71 g, 2.9 mmol) and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2-thia-
bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester (0.5 g, 1.9 mmol, Preparation
4). Purify using PC-TLC (ethyl acetate/hexanes) to yield 0.85 gram (90.5%) of the title
compound.

1HNMR(300 MHz,CDCl3)δ 1.46 (9H, s), 1.69 (1H.s), 1.8-2.05 (2H, m), 1.9-2.0 (1H,
m), 1.95-2.3 (3H, bs), 2.0-2.2 (1H, m), 2.4-2.8 (2H, m), 2.48 (1H, t, J = 4.0 Hz), 2.5S (1H,
bs), 2.92 (1H, d, J = 14.7 Hz), 3.01 (1H, dd, J = 4.4, 7.0 Hz), 3.42 (1H, dd,, J = 3.7, 7.3 Hz),
3.78 (3H, s), 3.87 (3H, s), 4.22-4.24 (2H, m). 5.06 (1H, d, J = 7.7 Hz), 7.27 (1H, s).
MS (ES) m/z 493.1[M-1]-.

Preparation 13
(lR,4S,5S,6S)-4-[2'S-tert-Butoxycarbonylamino-3'-(1-tert-butoxycarbonyl-1H-indol-3-
yl)-propionylamino]-2,2-dioxo-2λ6'-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid
dimethyl ester

Prepare according to General Procedure A using commercially available Boc-(L)-
Tryptophan(Boc) (1.1 g, 2.8 mmol) and (1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-
bicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester (0.5 g, 1.9 mmol, Preparation
4). Purify using PC-TLC (ethyl acetate/hexanes) to yield 0.7 g (56.7%) of the title
compound.
1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 1.67 (9H, s), 2.37 (1H, bs), 2.86 (1H, d,
J=15.0 Hz), 2.88 (1H, t, J=4.4 Hz), 3.15 (2H, d, J=6.6 Hz), 3.39 (1H, dd, J=3.7, 7.0 Hz),
3.73 (3H, s), 3.83 (3H, s), 4.18 (1H, d, J=14.7 Hz), 4.37-4.44 (]H, m), 5.01 (1H, bd, J=8.1
Hz), 7.11 (1H, bs), 7.25-7.59 (4H, m), 8.14 (1H, bd, J=8.4 Hz).

Anal. Calcd. For C30H39N3O11S 1.0 C4H8O2: C, 55.35; H, 6.42; N, 5.70. Found: C, 54.98;
H, 6.09; N, 6.07.
HRMS calcd for C30H39N3O11Na1S 672.2203. Found, 672.2180.

Preparation 14
(1R,4S,5S,6S)-4-[2'S-tert-Butoxycarbonylamino-3'-(4-tert-butoxycarbonyloxy-phenyl)-
propionylamino]-2,2-dioxo-2λ6-thia-bicyclo[3.1.0.]hexane-4,6-dicarboxylic acid dimethyl
ester

Prepare according to General Procedure A using commercially available 2S-tert-
butoxycarbonylamino-3-(4-tert-butoxycarbonyloxy-phenyl)-propionic acid (1.1 g, 2.9
mmol) and (1 R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-
dicarboxylic acid dimethyl ester (0.5 g, 1.9 mmol, Preparation 4). Purify using PC-TLC
(ethyl acetate/hexanes) to yield 0.94 g (79.0%) of the title compound.

1H NMR (300 MHz, CDCl3) δ 1.44 (9H, s), 1.56 (9H, s), 2.44 (1H, t, J=4.0 Hz), 2.88 (1H,
d, J=14.7 Hz), 2.98 (1H, dd, J=4.4, 7.3 Hz), 3.04 (2H, d, J=7.3 Hz), 3.38 (1H, dd, J=4.0,
7.3 Hz), 3.77 (3H; S), 3.83 (3H, s), 4.11 (1H, d, J=14.3 Hz), 4.22-4.29 (1H, app q, J=7.3
Hz), 4.92 (1H, bd, J=7.7 Hz), 7.07 (1H, bs), 7.1-7.26 (4H, m).
HRMS calcd for C28H38N2O12SNa, 649.2043. Found, 649.2001.

Preparation 1 5
(lR,4S,5S,6S)-4-(3'-Acetoxv-2'S-tert-butoxycarbonylamino-propionyl)amino-2.2-dioxo-
2λ6-thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid dimethyl ester

Prepare according to General Procedure A using 3-acetoxy-2S-(tert-
butoxycarbonylamino)propionic acid (0.25 g, 1.0 mmol, Preparation 44) and
(1R,4S,5S,6S)-4-Amino-2,2-dioxo-2λ6-thia-bicyclo[3.1.0]hexane-4,6-dicarboxylic acid
dimethyl ester (0.2 g, 0.8 mmol, Preparation 4) with the exception that DMAP is not used.
Purify using PC-TLC (ethyl acetate/hexanes) to yield 0.19 g (48.2%) of the title
compound.

1H NMR (300 MHz, CDCl3) δ 1.47 (9H, s), 2.10 (3H, s), 2.51 (1H, t, J=4.4 Hz), 2.99-
3.07(2H, m), 3.43 (1H, dd, J=4.0, 7.3 Hz), 3.77(3H, s), 3.86 (3H, s), 4.14-4.40 (4H, m),
5.29 (1H, bd, J=7.3 Hz), 7.64 (1H, bs).
HRMS calcd for C19H28N2O11SNa, 515.1312. Found, 515.1305.

Preparation 16
(1R,2S,4R,5R,6R)-2-Amino-4-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl
ester

To a slurry of (1R,2S,4R,5R,6R)-2-amino-4-fluorobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid (14.45 g, 71.12 mmol, U.S. Patent No. 5,958,960) in 202 mL of
absolute ethanol at room temperature add thionyl chloride (26 mL, 356 mmol) dropwise
over 20 minutes. Heat the slurry to reflux and allow to stir for 3 hours. Allow to cool to
room temperature and stir overnight. Concentrate the resultant solution in vacuo to a
residue then dilute with 136 mL of ethyl acetate and treat with 306 mL of 10% aqueous
sodium carbonate over 15 minutes with swirling by hand such that the final pH is 10.
Separate the layers and wash the aqueous layer with ethyl acetate (1 x 136 mL). Wash
the combined organic extracts with brine (1 x 136 mL), dry (MgSO4), filter, and
concentrate in vacuo to provide 17.07 g (93%) of the title compound as white solid.

m.p. = 64-66 °C.
1H NMR (400 MHz, CDCl3) δ 1.28 (3H, t, J = 7.3 Hz), 1.31 (3H, t, J = 6.8 Hz), 1.34-1.45
(1H, m), 1.85 (2H, bs), 2.17-2.21 (2H, m), 2.32-2.34 (1H, m), 2.49 (1H, dd, J = 7.8, 14.1
Hz), 4.24 (2H, dq, J = 1.5, 7.3 Hz), 5.33-5.52 (1H, m).Anal. calcd. for C12H18FNO4: C,
55.59; H, 7.00; N, 5.40. Found: C, 55.29; H, 6.75; N, 5.45.
MS (ES) m/z found 260.3 [M+H]+.

Preparation 17
(1R,2S,4R,5R,6R)-2-[2'S-(tert-butoxycarbonylamino)propionyl]amino-4-
flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester

To a solution of N-Boc-L-alanine (38.62 g, 204 mmol) in 396 mL of methylene
chloride at -22 °C under nitrogen add N-methyl morpholine (22.44 mL, 204 mmol)
followed by iso-butyl chloroformate (26.48 mL, 204 mmol) dropwise over 15 min such
that the reaction temperature does not exceed -18°C. Allow the resultant thin slurry to stir
at -20°C for 30 minutes at which time a solution of (1R,2S,4R,5R,6R)-2-amino-4-
fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (49.46 g, 191 mmol,
Preparation 16) in 247 mL of methylene chloride is added over 40 min such that the
reaction temperature does not exceed -16°C. Upon completion of the addition, remove
the reaction from the cooling bath and allow to stir at ambient temperature for 70 minutes
at which time the reaction temperature reached 15 °C and the color became faint orange.
Treat the reaction with 408 mL of 1 N HCl and stir for 5 minutes then separate the layers.
Wash the organic layer with saturated aqueous sodium bicarbonate (1 x 408 mL), dry
(Na2SO4), filter, and concentrate in vacuo to a white foam (88.16 g).
Anal, calcd. For C20H31FN2O7.0.1 CH2Cl2: C, 55.00; H, 7.16; N, 6.38. Found: C, 55.18;
H, 7.18; N, 6.49.
MS (ES) m/z 431.3 [M+H]+, 331.2 [M+H-Boc]+.

Preparation 18
(1R.2S,4R.5R,6R)-2-[2'S-(tert-butoxycarbonylamino)propionyl]amino-4-
fluorobicyclo[3.1.0]hexane-2.6-dicarboxy]ic acid

To a solution of (lR,2S,4R,5R,6R)-2-[2'S-(tert-butoxycarbonylamino)propionyl]-
amino-4-flurobicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (88.16 g, 191
mmol, Preparation 17) in 238 mL of THF at room temperature add 238 mL (477 mmol)
of 2N sodium hydroxide. Allow the biphasic mixture to stir vigorously at room
temperature for 2.5 hours at which time the reaction is homogeneous. Dilute the mixture
with 238 mL t-butyl methyl ether followed by mixing and separation of the layers.
Further dilute the aqueous layer with 238 mL of water and filter to remove paniculate
matter. Treat the solution with concentrated HCl (42.9 mL, 515 mmol) over 30 minutes
optionally followed by seeding with the title compound and stirring for 1 hour. Filter the
resultant slurry, wash with water (2 x 100 mL), and vacuum dry at 45 °C for 40 hours to
provide 72.2 g of the title compound as a white solid. Stir a portion of the solid (69.5 g)
with 490 mL of acetone for 1 hour to produce a hazy solution; filter and wash with
acetone (2 x 100 mL). Concentrate the filtrate in vacuo to a white foam which is further
dried in vauo at 45 °C for 16 hours to provide 61.8 g (86%, corrected for 12% wt/wt
acetone) of the title compound. This material was used in Examples 14-18 without
characterization.

Preparation 19
(1S,2S,4S,5R,6R)-4-Acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo[3.1.0]hexane-2,6-
dicarboxylic acid diethyl ester

To a solution of (1S,2S,4S,5R,6R)-2-(tert-butoxycarbonyl)amino-4-
hydroxybicyclo[3.1.0]hexane-2,6-dicarboxy!lic acid diethyl ester (1.50 g, 4.20 mmol, US
5958960), pyridine (0.365 mL, 4.62 mmol) and DMAP (0.513 g, 4.20 mmol) in
dichloromethane (40 mL) under nitrogen add acetic anhydride (0.514 mL, 5.0 mmol).
Stir at room temperature for 16 hours, dilute with dichloromethane, and pour into 10 %
aqueous citric acid solution (50 mL). Wash the organic layer with water (50 mL) and
brine (50 mL). Dry over MgSO4, filter and concentrate in vacuo, to produce the title
compound as a white solid (1.295 g, 75 %) .
LCMS: m/z 400 [M + H]+ and m/z 300 [M + H - CO21Bu]+ @ RT 1.39 min.
Preparation 20
(1S,2S,4S,5R,6R)-4-Acetyloxy-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylicacid
diethyl ester

Dissolve (1S,2S,4S,5R,6R)-4-acetyloxy-2-(tert-butoxycarbonyl)aminobicyclo-
[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester (1.25 g, 3.13 mmol, Preparation 19) in a
solution of 95 % TFA in dichloromethane (60 mL) and stir under nitrogen at room
temperature for 5 minutes. After this time remove the TFA/ dichloromethane in vacuo.
Dissolve the crude product in a suspension of NaHCO3 (1.00 g) in dichloromethane (50
mL) and stir for 30 minutes. Filter the suspension, wash with dichloromethane (3 x 25
mL), and concentrate in vacuo to afford 916 mg (98 %) of the product as a yellow oil.

CLAIMS
1. A compound of Formula 1

wherein:
A is H-(Q)p-;
Q is independently selected, each time taken, from the group amino acyl derived
from an amino acid selected from the group consisting of natural amino acids and
unnatural amino acids selected from the D-isomers of the natural a-amino acids; Aib
(aminobutyric acid), βAib (3-aminoisobutyric acid), Nva (norvaline), β-Ala. Aad (2-
aminoadipic acid), βAad (3-aminoadipic acid), Abu (2-aminobutyric acid), Gaba (γ-
aminobutyric acid), Acp (6-aminocaproic acid), Dbu (2,4-diaminobutryic acid), α-
aminopimelic acid, TMSA (trimethylsilyl-Ala), alle (allo-isoleucine), Nle (norleucine).
tert-Leu, Cit (citrulline). Orn, Dpm (2.2'-diaminopimelic acid). Dpr (2,3-
diaminopropionic acid), α- or β-Nal. Cha (cyclohexyl-Ala). hydroxyproline. Sar
(sarcosine), O-melhyl tyrosine, phenyl glycine; cyclic amino acids; Nα-alkylated amino
acids where Nα-alkylated amino acid is Nα-( 1 -10C)alkyI amino acid such as McGly (Nα-
methylglycine), EtGly (Nα-ethylglycine) and EtAsn (Nα-ethylasparaginc) and amino acids
in which the α-carbon bears two side-chain substituents;
p is an integer from 1 to 10;
X is SO2;
R10 is hydrogen or fluoro; and
R11 is hydrogen, fluoro, or hydroxy;
or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein p is an integer from 1 to 3.

3. The compound according to claim 1 wherein p is 1.
4. The compound according to any one of claims 1 to 3 wherein Q is an amino
acyl derived from a natural amino acid.
5. A compound of Formula I

wherein:
A is H-(Q)p-;
Q is glycyl. alanyl, valyl, leucyl, isoleucyl, prolyl, phenylalanyl, tyrosyl,
tryptophyl, methionyl, lysyl, or serinyl;
p is an integer from 1 to 10;
X is SO2;
R10 is hydrogen or fluoro; and
R11is hydrogen, fluoro, or hydroxy;
or a pharmaceutically acceptable salt thereof.
6. The compound according to claim 5 wherein p is an integer from 1 to 3.
7. The compound according to claim 5 wherein p is 1.
8. The compound according to any one of claims 1 to 7 wherein Q is methionyl.
9. The compound according to any one of claims 1 to 8 wherein R10 is hydrogen.

10. The compound according to any one of claims 1 to 9 wherein R11 is hydrogen.
11. A pharmaceutically acceptable salt according to claim 1 or 5 that is an acid-
addition salt made with an acid which provides a pharmaceutically acceptable anion: a
base-addition salt made with a base which provides a pharmaceutically acceptable anion
for a compound which contains an acidic moiety; or a zwitterionic compound which
contains oppositely charged groups.
12. The compound according to claim 1 or 5 wherein
A is H-(Q)p-;
Q is L-alanyl;
p is 1;
X is SO2 ;
R10 is hydrogen; and
R11 is hydrogen:
or the hydrochloride salt, tosylate salt, mesylate salt, esylate salt, besylate salt, or
monosodium salt thereof.
13. The compound according to claim 12 which is (1R, 4S, 5S,6S)-4-(2'S-
Aminopropionyl)amino]-2,2-dioxo-2λ6-thia-bicyclo[3.1.0.]hexane-4,6-dicarboxylic acid
hydrochloride or (1R,4S,5S,6S)-4-(2'S-2'-Aminopropionyl)amino-2,2-dioxo-2λ6-thia-
bicyclo[3.1.0.]hexane-4,6-dicarboxylic acid tosylate.
14. A process for preparing a compound of Formula 1, or a pharmaceutically
acceptable salt thereof, as claimed in any one of claims 1 to 13 comprising acylating a
compound of formula (ii)

(ii)
with a corresponding amino acyl of Formula III
PgN-A-(III)
wherein PgN is a nitrogen-protecting group;
whereafter, for any of the above procedures, when a functional group is protected
using a protecting group, removing the protecting group;
whereafter, for any of the above procedures: when a pharmaceutically acceptable
salt of a compound of Formula 1 is required, reaching the basic form of such a compound
of Formula I with an acid affording a pharmaceutically acceptable countrrion; or for a
compound of Formula 1 which bears an acidic moiety, reacting the acidic form of such a
compound of Formula I with a base which affords a pharmaceutically acceptable cation:
or for a zwitterionic compound of Formula 1, neutralizing the acid-addition salt form or
base-addition salt form of such a compound of Formula 1; or by any other conventional
procedure.
15. A compound according to any one of claims 1 to 13 for use in therapy.
16. Use of a compound of according to any one of claims 1 to 13 for the
manufacture of a medicament for administering an effective amount of a compound of
Formula (II).

wherein X, R10 and R11 are defined as in claim 1.
17. A compound according to any one of claims 1 to 13 for use in the treatment of
a neurological disorder in a patient.

18. The compound according to claim 17 wherein said neurological disorder is
cerebral deficits subsequent to cardiac bypass and grafting; cerebral ischemia; spinal cord
trauma; head trauma; Alzheimer's Disease; Huntington's Chorea; amyotrophic lateral
sclerosis; AIDS-induced dementia; perinatal hypoxia; hypoglycemic neuronal damage;
ocular damage and retinopathy; cognitive disorders; idiopathic and drug-induced
Parkinson's Disease; muscular spasms; migraine headaches; urinary incontinence; drug
tolerance, withdrawal, cessation, and craving; smoking cessation; emesis; brain edema;
chronic pain; sleep disorders; convulsions; Tourette's syndrome; attention deficit
disorder; or tardive dyskinesia.
19. The compound according to claim 18 wherein said neurological disorder is
drug tolerance, withdrawal, cessation, and craving; or smoking cessation.
20. A compound according to any one of claims 1 to 1 3 for use in the treatment of
a psychiatric disorder in a patient.
21. The compound according to claim 20 wherein said psychiatric disorder is
schizophrenia, anxiety and related disorders, depression, bipolar disorders, psychosis, or
obsessive compulsive disorders.
22. The compound according to claim 21 wherein said psychiatric disorder is
anxiety and related disorders.
23. The compound according to claim 21 wherein said psychiatric disorder is
schizophrenia.
24. A pharmaceutical formulation comprising in association with a
pharmaceutically acceptable carrier, diluent or excipient a compound according to any
one of claims 1 to 13.
25. A compound of Formula I and/or a pharmaceutically acceptable salt and/or a
process for preparing and/or use of a compound and/or substantially as herein
described with reference to the foregoing examples.
Dated this 7th day of July, 2008.

This invention relates to synthetic excitatory amino acid prodrugs and processes for their preparation. The invention further relates to methods of using, and pharmaceutical composition comprising, the compounds for treatment of
neurological disorders and psychiatric disorders.