Title of Invention

2-AMINOBICYCLO[3.1.0]HEXANE-2,6-DICARBOXYLIC ESTER DERIVATIVE

Abstract A drug effective for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related ailments thereof, depression, bipolar disorder and epilepsy. The drug antagonizes the action of group II metabotropic glutamate receptors and shows high activity in oral administraiton A 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic ester derivative represented by formula [I] [wherein R<SUP>1</SUP> and R<SUP>2</SUP> are identical or different, and each represents a hydrogen atom, a C<SUB>1-10</SUB>alkyl group or the like; X represents a hydrogen atom or a fluorine atom; Y represents -OCHR<SUP>3</SUP>R<SUP>4</SUP> or the like (wherein R<SUP>3</SUP> and R<SUP>4</SUP> are identical or different, and each represents a hydrogen atom, a C<SUB>1-10</SUB>alkyl group or the like; and n represents integer 1 or 2)], a pharmaceutically acceptable salt thereof or a hydrate thereof.
Full Text

DESCRIPTION
2-AMINO-BICYCLO [3.1.0] HEXANE-2,6-DICARBOXYLIC ESTER DERIVATIVE
FIELD OF THE INVENTION
The present invention relates to a parmaceutically effective 2-amino -bicyclo [3.1.0] hexane -2, 6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof, a hydrate thereof or a prodrug containing the above as an active ingredient. More specifically, the present invention relates to a prodrug of 2-amino- bicyclo [3.1.0] hexane -2,6-dicarboxylic acid derivative and so on that are a compound that acts as an antagonist of mGlu2/mGluR3 belonging to sub group II of metabolic (metabotropic) glutamate receptors (mGluR), which is effective for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related ailments thereof, depression, bipolar disorder and epilepsy; and also of neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy and head trauma.
Further, the present invention relates to the finding that a prodrug of a compound that acts as an antagonist of mGIuR2/mGluR3 shows high activity in oral administration and increases the amount of exposure in vivo of the parent compound.
BACKGROUND OF THE INVENTION
Metabotropic glutamate receptors are classified pharmacologically into three groups. Of these, group II (mGluR2/mGluR3) bind with adenylcyclase, and inhibit the accumulation of the Forskolin stimulation of cyclic adenosine monophosphate (cAMP) (see Trends Pharmacol. Sci., 14, 13,1993 (non-patent document 1 mentioned below)). Thus it is suggested that compounds that antagonize the action of group II metabotropic glutamate receptors are effective for the treatment and prevention of acute and chronic psychiatric disorders and neurological diseases. A 2-amino -bicyclo [3.1.0] hexane -2,6 -dicarboxylic acid derivative is a compound that has a strong antagonistic effect on group II metabotropic glutamate receptors.

LIST OF RELATED DOCUMENTS
Non-Patent Document 1
Trends Pharmacol. ScL, 14, 13,1993
It is an object of the present invention to provide a drug that is effective for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related ailments thereof, depression, bipolar disorder and epilepsy; and also effective for the treatment and prevention of neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia associated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy and head trauma; which is a drug that antagonizes the action of group II metabotropic glutamate receptors and shows high activity in oral administration.
DISCLOSURE OF THE INVENTION
The present inventors have conducted extensive examinations into 2-amino -bicyclo [3.1.0] hexane-2,6-dicarboxylic ester derivatives, and by conducting animal tests with a parent compound as the test drug, discovered that a prodrug of a 2-amino -bicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative that affects group II metabotropic glutamate receptors increases the amount of exposure in vivo of the parent compound, thereby completing the present invention.
The present invention provides a 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, (hereinafter may be referred to as 'the compound of the present invention'), a pharmaceutically acceptable salt thereof or a hydrate thereof, represented by formula
[i]


[wherein,
R' and Rz are identical or different, and each represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C]_ioalkoxyCi_ioalkyl group, a C1-10alkoxycarbonylCi_ioalkyl group, a farnesyl group, a4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaR (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group), a group represented by formula-CHRcOC(0)ZR (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a Ci_ioalkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii]; or,

in the case where either R or R represents a hydrogen atom, the other, represents a Ciooalkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a CMoalkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoCi_ioalkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyCj-ioalkyl

group, a C1-10alkoxycarbonylCi.ioalkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z, Rc and Rd are the same as described above), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii],

X represents a hydrogen atom or a fluorine atom. Y represents -OCHR R , -SR , -S(0)nR5, -SCHR3R4, -S(0)nCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3R4'), -NHCOR3
C T T' A Al
or -OCOR (wherein R , R , R and R are identical or different, and each represents a hydrogen atom, a C1-10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R5 represents a C1-10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy

group; and n represents integer 1 or 2)]
In an aspect of the present invention, it is preferred that in formula [I],
i ")
R1 and Rz are identical or different, and each represents a C1-10alkyl group, a
C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two
phenyl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an
azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group or a
C1-10alkoxycarbonylC1-10alkyl group; or,
1 ")
in the case where either R or R represents a hydrogen atom, the other represents a
C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group
substituted by one or two phenyl groups, a hydroxyC2-10alkyl group, a
halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a
C1-10alkoxyC1-10alkyl group or a C1-10alkoxycarbonylC1-10alkyl group.
In another aspect of the present invention, it is preferred that in formula [I], R and R are identical or different, and each represents a farnesyl group, a C1-10alkyl group substituted by one or two aryl groups, a Cj-ioalkoxycarbonylC1-10alkyl group, a 4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group), a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii]; or,


1 9
in the case where either R or R represents a hydrogen atom, the other represents a farnesyl group, a C1-10alkyl group substituted by one or two aryl groups, a CuioalkoxycarbonylC1-10alkyl group, a 4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z, Rc and Rd are the same as described above), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii];

In another aspect of the present invention, it is preferred that in formula [I], R represents a hydrogen atom.

In a further aspect of the present invetion, it is preferred that in formula [I], X represents a fluorine atom.
Further, in another aspect of the present invention, it is preferred that in formula [I], Y represnts -OCHR3R4, -SR3, -SCHR3R4, -S(0)nCHR3R4, -NHCHR3R4 or -N(CHR3R4)(CHR3R4') (wherein R3, R3', R4 and R4' are the same as described above).
In another aspect of the present invention, it is preferred that in formula [I], Y represents -SR3, -SCHR3R4, -S(0)nCHR3R4, -NHCHR3R4 or -N(CHR3R4)(CHR3R4') (wherein R3, RJ, R" and R* are the same as described above).
It is preferred that in formula [I], R3, R3, R4 and R4 used for describing Y each independently represents a hydrogen atom, a phenyl group, a naphthyl group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group. Of the above, it is more preferred that R3, R3, R4 and R4 each independently represents a hydrogen atom, a phenyl group, a naphthyl group or a phenyl group substituted by one to five halogen atoms.
1 0
In a further aspect of the present invention, it is preferred that in formula [I], R and R each independently represents a hydrogen atom, a C1-10alkyl group, a C2-6alkenyl group, a C2-6alkynyl group, a C1-ealkyi group substituted by one or two phenyl groups, a hydroxyC2-6alkyl group, a halogenoCjlyalkyl group, an azidoC1lyalkyl group, an aminoC2-6alkyl group, a C1lyalkoxyC1-ealkyl group or a C1lyalkoxycarbonylC1-6yalkyl group. Of the above, it is more preferred that R represents a hydrogen atom and R represents a straight-chain or branched chain C1-10alkyl group, C2-6alkenyl group, or Clyalkyl group substituted by one or two phenyl groups.
Further, in another aspect of the present invention, it is preferred that in formula [I], R and R each independently represents a hydrogen atom, a farnesyl group, a C1lyalkyl group substituted by one or two aryl groups, a C1_6alkoxycarbonylC1_6alkyl group, a 4-morpholinylC1_6alkyl group, a Cj.ioalkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z,RC and Rd are the same as described

above), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii].

Of the above, it is more preferred that R represents a hydrogen atom; and R represents a farnesyl group, a C1-ealkyi group substituted by one or two unsubstituted or substituted phenyl groups, a C i _6alkoxycarbonylC i lyalkyl group, a 4-morpholinylC1_6alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z,RC and Rd are the same as described above), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii].


1 ■* sIt is preferred that in formula [I], Ra and R used to describe R and R represent a hydrogen atom or a C1lyalkyl group. It is preferred that Rc represents a hydrogen atom, a C1_6alkyl group, a C2-6alkenyl group or an aryl group. And it is preferred that R represents a C1lyalkyl group, a C2-6alkenyl group or an aryl group. The terms used in the present invention are defined as follows. Cn-m means that the group following Cn.m has from n to m carbon atoms.
The C1-10alkyl group means a straight-chain alkyl group having one to ten carbon atoms, a branched chain alkyl group having three to ten carbon atoms or a cyclic alkyl group having three to ten carbon atoms. Examples of the straight-chain alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group and a decyl group. Examples of the branched chain alkyl group include an isopropyl group, an isobutyl group, a 1-methylpropyl group, a t-butyl group, a 1-methylbutyl group, a 2-methylbutyl group, a 3-methylbutyl group, a 1 -ethylpropyl group, a 1,1 -dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-methyIpenty 1 group, a 2-methylpentyl group, a 3-methylpentyl group, a 4-methylpentyl group, a 1-ethylbutyl group, a 2-ethylbutyl group, a 1,1-dimethylbutyl group, a 1,2-dimethylbutyl group, a 1,3-dimethylbutyl group, a 2,2-dimethylbutyl group, a 2,3-dimethylbutyl group, a 3,3-dimethylbutyl group, a 5-methylhexyl group, a 3-ethylpentyl group, a 1-propylbutyl group, a 1,4-dimethylpentyl group, a 3,4-dimethylpentyl group, a 1,2,3-trimethylbutyl group, a 1-isopropylbutyl group, a 4,4-dimethylpentyl group, a 5-methylheptyl group, a 6-methylheptyl group, a 4-ethylhexyl group, a 2-propylpentyl group, a 2,5-dimethylhexyl group, a 4,5-dimethylhexyl group, a 2-ethyl-3-methylpentyl group, a 1,2,4-trimethylpentyl group, a 2-methyl- 1-isopropylbutyl group, a 3-methyloctyl group, a 2,5-dimethylheptyl group, a 1 -(1 -methylpropyl)-2-methylbutyl group, a 1,4,5-trimethylhexyl group, a 1,2,3,4-tetramethylpentyl group, a 7-methyloctyl group, a 6-methylnonyl group, a 8-methylnonyl group, a 5-ethyl-2-methylheptyl group, a

2,3-dimethyl-l -(1 -methylpropyl)butyl group, a cyclopropylmethyl group, a 2-(cyclopropyl)ethyl group, a 3,7-dimethyloctyl group, a 3-(cyclobutyl)pentyl group, a cyclopentylmethyl group and a cyclohexylmethyl group. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group.
The C2-ioalkenyl group means a straight-chain alkenyl group having two to ten carbon atoms with at least one double bond, a branched chain alkenyl group having three to ten carbon atoms or a cyclic alkenyl group having five to ten carbon atoms, examples of which include a vinyl group, an allyl group, a 3-butenyl group, a 4-pentenyl group, a 5-hexenyl group, a 6-heptenyl group, a 7-octenyl group, a 8-noneyl group, a 9-decenyl group, a l-methyl-2-butenyl group, a 2-methyl-2-butenyl group, a 2-methyl-3-butenyl group, a 2-pentenyl group, a 2-methyl-2-hexenyl group and a 2-cyclopentenyl group.
The C2-ioalkynyl group means a straight-chain alkynyl group having two to ten carbon atoms with at least one triple bond or a branched chain alkynyl group having four to ten carbon atom, examples of which include a 2-propynyl group, a 3-butynyl group, a 4-pentynyl group, a 5-hexynyl group, a 6-heptynyl group, a 7-octynyl group, a 8-nonynyl group, a 9-deC1nyl group, a 3-pentynyl group and a 4-methyl-2-pentynyl group.
The C1-10alkyl group substituted by one or two aryl groups means, for example, a benzyl group, a diphenylmethyl group, a 2-phenyethyl group, a 2-phenylpropyl group, a 1-methyl-1-phenyethyl group, a l-methyl-2-phenylpentyl group, a 2-nitrobenzyl group, a 3-nitrobenzyl group, a 4-nitrobenzyl group, a 2,4-dinitrobenzyl group, a 2,4,6-trinitrobenzyl group, a 2-phenylbenzyl group, a 3-phenylbenzyl group, a 4-phenylbenzyl group, a 2-hydroxybenzyl group, a 3-hydroxybenzyl group, a 4-hydroxybenzyl group, a 2-chlorobenzyl group, a 3-chlorobenzyl group, a 4-chlorobenzyl group, a 2-fluorobenzyl group, a 3-fluorobenzyl group, a 4-fluorobenzyl group, a 2-beromobenzyl group, a 3-beromobenzyl group, a 4-beromobenzyl group, a 2-iodobenzyl group, a 2-iodobenzyl group, a 2,3-dichlorobenzyl group, a 2,4-dichlorobenzyl group, a 2,5-dichlorobenzyl group, a 2,6-dichlorobenzyl group, a 3,4-dichlorobenzyl group, a 3,5-dichlorobenzyl group, a 2-methylbenzyl group, a 3-methylbenzyl group, a 4-methylbenzyl group, a 2-ethylbenzyl group, a 3-ethylbenzyl group, a 4-ethylbenzyl group, a 2-isopropylbenzyl group, a 3-isopropylbenzyl group, a 4-isopropylbenzyl group, a 2-methoxybenzyl group, a 3-methoxybenzyl group, a

4-methoxybenzyl group, a 2,3-dimethoxybenzyl group, a 2,4-dimethoxybenzyl group, a 2,5-dimethoxybenzyl group, a 2,6-dimethoxybenzyl group, a 3,4-dimethoxybenzyl group, a 3,5-dimethoxybenzyl group, a 2-ethoxybenzyl group, a 3-ethoxybenzyl group, a 4-ethoxybenzyl group, a 2-isopropoxybenzyl group, a 3-isopropoxybenzyl group, a 4-isopropoxybenzyl group, a 2-methoxymethylbenzyl group, a 3-methoxymethylbenzyl group, a 4-methoxymethylbenzyl group, a 2-isopropyxymethylbenzyl group, a 3-isopropyxymethylbenzyl group, a 4-isopropyxymethylbenzyl group, a 2-trifluoromethyl group, a 3-trifluoromethyl group, a 4-trifluoromethyl group, a 2-hydroxycarbonylbenzyl group, a 3-hydroxycarbonylbenzyl group, a 4-hydroxycarbonylbenzyl group, a 2-aminobenzyl group, a 3-aminobenzyl group, a 4-aminobenzyl group, a 2-aminomethylbenzyl group, a 3-aminomethylbenzyl group, a 4-aminomethylbenzyl group, a 2-cyanobenzyl group, a 3-cyanobenzyl group, a 4-cyanobenzyl group, a 2-hydroxymethylbenzyl group, a 3-hydroxymethylbenzyl group, a 4-hydroxymethylbenzyl group, a 2-phenoxybenzyl group, a 3-phenoxybenzyl group and a 4-phenoxybenzyl group.
The aryl group means a phenyl group, a substituted phenyl group or a polycyclic aromatic group such as a 1-naphthyl group or a 2-naphthyl group.
The substituted phenyl group means a phenyl group substituted by one to three substituents selected from a group containing a halogen atom, a hydroxyl group, a phenyl group,a Cj-ioalkyl group, a C1-10alkoxy group, a C1-10alkoxyC1-10alkyl group, a trifluoromethyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group, a hydroxymethyl group, a aminomethyl group and a phenoxy group. Examples of the substituted phenyl group include a 2-nitrophenyl group, a 3-nitrophenyl group, a 4-nitrophenyl group, a 2, 4-dinitrophenyl group, a 2, 4, 6-trinitrophenyl group, a 2-phenylphenyl group, a 3-phenylphenyl group, a 4-phenylphenyl group, a 2-hydroxyphenyl group, a 3-hydroxyphenyl group, a 4-hydroxyphenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-beromophenyl group, a 3-beromophenyl group, a 4-beromophenyl group, a 2-iodophenyl group, a 2-iodophenyl group, a 2, 3-dichlorophenyl group, a 2, 4-dichlorophenyl group, a 2, 5-dichlorophenyl group, a 2, 6-dichlorophenyl group, a 3, 4-dichlorophenyl group, a 3, 5-dichlorophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-ethylphenyl group, a 3-ethylphenyl group, a 4-ethylphenyl group, a 2-isopropylphenyl group, a 3-isopropylphenyl group, a

4-isopropylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2, 3-dimethoxyphenyl group, a 2, 4-dimethoxyphenyl group, a 2, 5-dimethoxyphenyl group, a 2, 6-dimethoxyphenyl group, a 3, 4-dimethoxyphenyl group, a 3, 5-dimethoxyphenyl group, a 2-ethoxyphenyl group, a 3-ethoxyphenyl group, a 4-ethoxyphenyl group, a 2-isopropoxyphenyl group, a 3-isopropoxyphenyl group, a 4-isopropoxyphenyl group, a 2-methoxymethylphenyl group, a 3-methoxymethylphenyl group, a 4-methoxymethylphenyl group, a 2-isopropyxymethylphenyl group, a 3-isopropyxymethylphenyl group, a 4-isopropyxymethylphenyl group, a 2-trifluoromethyl group, a 3-trifluoromethyl group, a 4-trifluoromethyl group, a 2-hydroxycarbonylpheny 1 group, a 3 -hydroxycarbonylphenyl group, a 4-hydroxycarbonylphenyl group, a 2-aminophenyl group, a 3-aminophenyl group, a 4-aminophenyl group, a 2-aminomethylphenyl group, a 3-aminomethylphenyl group, a 4-aminomethylphenyl group, a 2-cyanophenyl group, a 3-cyanophenyl group, a 4-cyanophenyl group, a 2-hydroxymethylphenyl group, a 3-hydroxymethylphenyl group, a 4-hydroxymethylphenyl group, a 2-phenoxyphenyl group, a 3-phenoxyphenyl group and a 4-phenoxyphenyl group.
Of the above C1-10alkyl groups substituted by one or two aryl groups, the C1-10alkyl group sustituted by one or two phenyl groups is preferred.
The hydroxyC2-10alkyl group means a C2-10alkyl group substituted by at least one hydroxyl group, examples of which include a 2-hydroxyethyl group, a 3-hydroxypropyl group, a 4-hydroxybutyl group, a 5-hydroxypentyl group, a 6-hydroxyhexyl group, a 7-hydroxyheptyl group, a 8-hydroxyoctyl group, a 9-hydroxynonyl group, a 10-hydroxydecyl group, a 2-hydroxypropyl group, a 2,3-dihydroxypropyl group and a 2-hydroxy-3-methylbutyl group.
The halogenoC1-10alkyl group means a Cj.ioalkyl group substituted by at least one fluorine atom, chlorine atom, bromine atom or iodine atom, examples of which include a 2-chloroethyl group, a 2-bromoethyl group, a 2-iodoethyl group, a 3-chloropropyl group, a 3-bromopropyl group, a 3-iodopropyl group, a 4-chlorobutyl group, a 4-bromobutyl group, a 4-iodobutyl group, a 5-chloropentyl group, a 6-chlorohexyl group, a 7-chloroheptyl group, a 8-chlorooctyl group, a 9-chlorononyl group, a 10-chlorodecyl group, a 2-chloropropyl group, a 2-chlorobutyl group, a 2,4-dichlorobutyl group and a 2-chloro-3-methylbutyl group.

The azidoC1-10alkyl group means a C1-10alkyl group substituted by at least one azide group, examples of which include a 2-azidoethyl group, a 3-azidopropyl group, a 4-azidobutyl group, a 5-azidopentyl group, a 6-azidohexyl group, a 7-azidoheptyl group, a 8-azidooctyl group, a 9-azidononyl group, a 10-azidodecyl group, a 2-azidopropyl group, a 2-azidobutyl group and a 2-azido-3-methylbutyl group.
The aminoC2-10alkyl group means aC2-10alkyl group substituted by at least one amino group, examples of which include a 2-aminoethyl group, a 3-aminopropyl group, a 6-aminohexyl group, a 7-aminoheptyl group, a 8-aminooctyl group, a 9-aminononyl group, a 10-aminodecyl group, a 4-aminobutyl group and a 2, 4-diaminobutyl group.
The C1-10alkoxyC1-10alkyl group means a alkyl group having one to ten carbons which is substituted by a straight-chain alkoxy group having one to ten carbons, a branched chain alkoxy group having three to ten carbon atoms or a cyclic alkoxy group having three to ten carbon atoms, examples of which include a 2-methoxyethyl group, a 2-ethoxyethyl group, a 2-propoxyethyl group, a 2-isopropoxyethyl group, a 2-butoxyethyl group, a 2-isobutoxyethyl group, a 2-t-butoxyethyl group, a 2-pentyloxyethyl group, a 2-hexenyloxyethyl group, a 3-ethoxypropyl group, a 4-ethoxybutyl group, a 4-ethoxy-3-methoxybutyl group and a 4-ethoxy-3-methylpentyl group.
methoxycarbonylmethyl
propyloxycarbonylmethyl
butyltoxycarbonylmethyl
t-butoxycarbonylmethyl
hexyloxycarbonylmethyl
3 -(ethoxy carbonyl)propy 1 group,
The C1-10alkoxycarbonylC1-10alkyl group means a alkyl group having one to ten carbons which is substituted by a straight-chain alkoxycarbonyl group having one to ten carbons, a branched chain alkoxycarbonyl group having three to ten carbon atoms or a cyclic alkoxycarbonylgroup having three to ten carbon atoms, examples of which include a
group, a
group, a
group, a
group, a
group, a
aroun. a
group, an
group, an
group, an
group, a
group, a
group. a
ethoxycarbonylmethyl isopropoxycarbonylmethyl isobutoxycarbonylmethyl pentyloxycarbonylmethyl 2-(ethoxy carbonyl)ethyl 4-(ethoxycarbonyl)butyl group,
4-(ethoxycarbonyl)pentyl group and a 4-(ethoxycarbonyl)-3-methylpentyl group.
The farnesyl group means a (2Z,6Z)-3,7,ll-trimethyldodeca-2,6,10-trienyl group.
The 4-morpholinylCj-ioalkyl means a alkyl group having one to ten carbons which is substituted by a 4-morpholinyl group, examples of which include a

2-(4-morpholinyl)ethyl group, a 3-(4-morpholinyl)propyl group, a
4-(4-morpholinyl)butyl group, a 5-(4-morpholinyl)pentyl group, a
6-(4-morpholinyl)hexyl group, a 7-(4-morpholinyl)heptyl group, a
8-(4-morpholinyl)octyl group, a 9-(4-morpholinyl)nonyl group, a
10-(4-morpholinyl)decyl group, a 2-(4-morpholinyl)pentyl group, and a
1 -methyl-3 -(4-morpholinyl)butyl group.
The C1-10alkyl group substituted by formula C(0)NRaRb (wherein Raand Rbare identical
or different, and each represents a hydrogen atom or a Cj.ioalkyl group) means, for
example, a 2-(N,N-dimethylaminocarbonyl)ethyl group, a
2-(N,N-diethylaminocarbonyl)ethyl group, a 3-(N,N-diethylaminocarbonyl)propyl
group, a 2-(N-methylaminocarbonyl)ethyl group, a 2-(N-ethylaminocarbonyl)ethyl
group, a 2-(N,N-methylethylaminocarbonyl)ethyl group, a
2-(N,N-ethylpropylaminocarbonyl)ethyl group or a
2-(N,N-diethylaminocarbonyl)-1 -methylethyl group.
The naphthyl group substituted by one to seven halogen atoms means a naphthyl group substituted by at least one fluorine atom, chloride atom, bromine atom or iodine atom, examples of which include a l-fluoro-2-naphthyl group, a 2-fluoro-l -naphthyl group, a l-chloro-2-naphthyl group, a 2-chloro-l-naphthyl group, a l-bromo-2-naphthyl group, a 2-bromo-l -naphthyl group, a l-iodo-2-naphthyl group, a 2-iodo-l-naphthyl group, and a l,3-difluoro-2-naphthyl group.
The heteroaromatic group means a monocyclic aromatic 5 membered or 6 membered ring containing at least one atom selected from an oxygen atom, a nitrogen atom or a sulfur atom; a monocyclic ring such as above which is fused with a benzene ring; or a hetrocyclic aromatic ring which is fused with one another. Examples of the hetero aromatic group include furyl, pyrrolyl, thiophenyl, oxazoyl, isoxazoyl, imidazoyl, pyrazoyl, thiazoyl, isothiazoyl, oxadiazoyl, thiadiazoyl, benzofuranyl, indolyl, benzothiophenyl, indazoyl, benzoisoxazoyl, benzoisothiazoyl, benzoimidazoyl, benzooxazoyl, benzothiazoyl, pyrizinyl, quinolinyl, isoquinolinyl, pyrodazinyl, pyrimizinyl, pyradinyl, C1nnolinyl, phthalazinyl, quinazolinyl and quinoxalinyl.
The C1-10alkoxy group means a straight-chain or branched chain alkoxy group having one to ten carbon atoms, examples of which include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a t-butoxy

group, a pentyloxy group and an isopentyloxy group.
The phenyl group substituted by one to five substituents selected from a group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group means a phenyl group substituted by one to five substituents selected from a fluorine atom, a chloride atom, a bromine atom, an iodine atom, a C1-10alkyl group, a cyclicC3_ioalkyl group, a Cj-ioalkoxy group, a cyclic C3_ioalkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group or a phenoxy group. Examples of the phenyl group substituted by one substituent include a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, a 2-bromophenyl group, a 3-bromophenyl group, a 4-bromophenyl group, a 2-iodophenyl group, a 3-iodophenyl group, a 4-iodophenyl group, a 2-methylphenyl group, a 3-methylphenyl group, a 4-methylphenyl group, a 2-ethylphenyl group, a 3-ethylphenyl group, a 4-ethylphenyl group, a 2-isopropylphenyl group, a 3-isopropylphenyl group, a 4-isopropylphenyl group, a 2-cyclopropylphenyl group, a 3-cyclopropylphenyl group, a 4-cyclopropylphenyl group, a 2-cyclohexylphenyl group, a 3-cyclohexylphenyl group, a 4-cyclohexylphenyl group, a 2-methoxyphenyl group, a 3-methoxyphenyl group, a 4-methoxyphenyl group, a 2-isopropoxyphenyl group, a 3-isopropoxyphenyl group, a 4-isopropoxyphenyl group, a 2-cyclobutyloxyphenyl group, a 3-cyclobutyloxyphenyl group, a 4-cyclobutyloxyphenyl group, a 2-cyclohexyloxyphenyl group, a 3 -cyclohexyloxy phenyl group, a 4-cyclohexyloxyphenyl group, a 2-trifluoromethylphenyl group, a 3-fluoromethylphenyl group, a 4-trifluoromethylphenyl group, a 2-phenylphenyl group, a 3-phenylphenyl group, a 4-phenylphenyl group, a 2-hydroxycarbonylphenyl group, a 3-hydroxycarbonylphenyl group, a 4-hydroxycarbonylphenyl group, a 2-aminophenyl group, a 3-aminophenyl group, a 4-aminophenyl group, a 2-nitrophenyl group, a 3-nitrophenyl group, a 4-nitrophenyl group, a 2-cyanophenyl group, a 3-cyanophenyl group, a 4-cyanophenyl group, a 2-phenoxyphenyl group, a 3-phenoxyphenyl group and a 4-phenoxyphenyl group. Examples of the phenyl group substituted by two substituents include a 2,3-difluorophenyl group, a 2,4-difluorophenyl group, a 2,5-difluorophenyl group, a 2,6-difluorophenyl group, a 3,4-difluorophenyl group, a 3,5-difluorophenyl group, 2,3-dichlorophenyl group, a 2,4-dichlorophenyl group, a 2,5-dichlorophenyl group, a 2,6-dichlorophenyl group, a 3,4-dichlorophenyl group, a 3,5-dichlorophenyl group, a

2,3-dibromophenyl group, a 2,4-dibromophenyl group, a 2,5-dibromophenyl group, a 2,6-dibromophenyl group, a 3,4-dibromophenyl group, a 3,5-dibromophenyl group, a 2,3-diiodophenyl group, a 2,4-diiodophenyl group, a 2,5-diiodophenyl group, a 2,6-diiodophenyl group, a 3,4-diiodophenyl group, a 3,5-diiodophenyl group, a 3-chloro-4-fluorophenyl group, a 4-chloro-3-fluorophenyl group, a 3 -bromo-4-fluorophenyl group, a 4-bromo-3 -fluorophenyl group, a 4-bromo-3-chlorophenyl group, a 3-bromo-4-chlorophenyl group, a 3-chloro-4-methylphenyl group, a 4-chloro-3-methylphenyl group, a 3-fluoro-4-methylphenyl group, a 4-fluoro-3-methylphenyl group, a 3-fluoro-4-methoxyphenyl group, a 4-fluoro-3-methoxyphenyl group, a 3-bromo-4-methoxyphenyl group, a 4-bromo-3-methoxyphenyl group, a 3-chloro-4-phenoxyphenyl group, a 4-chloro-3-phenoxyphenyl group, a 3-chloro-4-nitrophenyl group, a 4-chloro-3-nitrophenyl group, a 4-bromo-3-nitrophenyl group, a 3-bromo-4-nitrophenyl group, a 3-amino-4-bromophenyl group, a 4-amino-3 -bromophenyl group, a 3 -bromo-4-hydroxycarbonyl group, a 4-bromo-3-hydroxycarbonylphenyl group, a 4-fluoro-3-hydroxycarbonyl group, a 3-fluoro-4-hydroxycarbonylphenyl group, a 4-fluoro-3-hydroxycarbonyl group, a 3-cyano-4-fluorophenyl group, a 3-cyano-4-fluorophenyl group, a 4-cyano-3 -methylphenyl group, a 3 -cyano-4-methylphenyl group, a 3-cyano-4-methoxyphenyl group and a 4-cyano-3-methoxyphenyl group. Examples of the phenyl group substituted by three substituents include a 2,3, 4-trifluorophenyl group, a 3,4,5-trifluorophenyl group, a 3,4,5-trichlorophenyl group, a 3-chloro-2,6-difluorophenyl group, a 3,5-dichloro-4-methoxyphenyl group and a 3,5-dibromo-4-methoxyphenyl group. Examples of the phenyl group substituted by four substituents include a 2,5-dibromo-3,4-dimethoxyphenyl group and a 3,4-dibromo-2,4-dimethoxyphenyl group. Examples of the phenyl group substituted by five substituents include a 2,3,4,5,6-pentafluorophenyl group.
The pharmaceutically acceptable salt in the present invention means, for example, a salt with a mineral aC1d such as sulfuric aC1d, hydrochloric aC1d or phosphoric aC1d; a salt with organic aC1ds such as acetic aC1d, oxalic aC1d, lactic aC1d, tartaric aC1d, fumaric aC1d, maleic aC1d, methanesulfonic aC1d or benzenesulfonic aC1d; a salt with an amine such as trimethylamine or methylamine; or a salt with a metal ion such as sodium ion, potassium ion or calC1um ion.
The hydrate in the present invention means a pharmaceutically acceptable hydrate of the

compound of the present invention or of the salt thereof. The compound of the present invention or the salt thereof may absorb moisture and accumulate drops of water or become a hydrate by being exposed to the atmosphere or by recrystallization. The hydrate in the present invention includes such a hydrate.
In the compounds represented by formula [I], five assymetric carbon atoms are present in the bicyclo[3.1.0]hexane ring.
The preferred stereostructure of the compounds of the present invention are optically active bodies having the absolute structure represented by formula [II], but the compounds of the present invention may be present as enantiomers or enantiomer mixtures such as racemic bodies. Therefore, the compounds of the present invention include all of the optically active bodies, the enantiomer mixtures such as racemic bodies and the diastereomer mixtures of the compounds represented by formula [II] below.

The compounds of the present invention represented by formula [I] and formula [II] have no effect on group II metabotropic glutamate receptors. However, they can be hydrolyzed with oxygen or with chemicals in vivo, thereby yielding compounds represented by formula [III] and formula [V], respectively, which are compounds that have a strong antagonistic effect on group II metabotropic receptors. Therefore, the compounds of the present invention are effective as drugs that affect the action of group II metabotropic glutamate receptors. The compounds relates to 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof,


[wherein X represents a hydrogen atom or a fluorine atom. Y represents -OCHR3R45 -SR3?-S(0)nR5rSCHR3R4,-S(0)nCHR3R4rNHCHR3R4rN(CHR3R4)(CHR3R4,),-NHCO RJ or -OCORJ (wherein R°, RJ, RH and R* are identical or different, and each represents a hydrogen atom, a C1-10alkyl group, a Cj-ioalkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a Cj-ioalkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R5 represents a C1-10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; and n represents integer 1 or 2)].
BEST METHOD FOR CARRYING OUT THE INVENTION The present invention relates to a compound of the present invention represented by formula [I] or formula [II], a pharmaceutically acceptable salt thereof or a hydrate thereof. The compounds of the present invention may be synthesized using publicly known methods of organic synthesis. The compounds of the present invention may be prepared, for example, according to the following methods.
First, compounds (9), (16), (24), (27), (30) and (33) which are synthetic intermediates required for synthesizing the compounds of the present invention represented by formula [I] may be prepared as follows. (In the formulas below, X, Y, Z, n, R , R , R , R4 and R5 are the same as described above. R represents an aryl- or alkyl-sulfonyl group such as a methyl group, a phenylsulfonyl group, a tosyl group or a trifluoromethylsulfonyl group, a benzoyl group or a 4-nitrobenzoyl group. R represents

a protecting group for an amino group, examples of which include an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group, a t-butoxycorbonyl group or a benzyloxycarbonyl group; an acyl group such as a benzoyl group, a p-phenylbenzoyl group or a (pyridine2-yl) carbonyl group; an alkyl group such as an aryl group, a benzyl group, a p-methoxybenzyl group or a di(p-methoxyphenyl)methyl group; an alkenyl group such as a 5,5-dimethyl-3-oxo-l-cyclohexenyl group; a sulfenyl group such as a benzene sulfenyl group or a 2,4-dinitrosulfenyl group; a benzylsulfonyl group; a diphenylphosphinyl group; and a dialkylphosphoryl group. A1 represents formula R3 or formula CHR3R4. A2 represents formula R5 or formula CHR3R4. And Q represents formula SR3, formula S(0)nR5, formula SCHR3R4 or formula S(0)nCHR3R4).

Stepl: Compound (2) may be prepared, for example, by reacting compound (1) with a trifluoromethanesulfonylation agent such as trifluoromethane sulfonic aC1d anhydride or N-phenyl-bis(trifluoromethanesulfonimide), in an inert solvent, in the presence of a base. Examples of the inert solvent include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; or a mixture of these solvents. Examples of the base include amines such as triethylamine, N-methylmorpholine, diisopropylethylamine and

pyridine; inorganic bases such as potassium hydride and sodium hydride; metal amides such as lithium diisopropylamide, potassium bis(trimethylsilyl)amide and lithium hexamethyldisilazane; and metal alcoholates such as sodium methoxide and potassium t-butoxide. Preferably, compound (2) may be prepared by reacting compound (1) with N-phenyl-bis(trifluoromethanesulfonimide) for 2 to 4 hours at -78°C to room temperature, in tetrahydrofuran, in the presence of lithium hexamethyldisilazane.
Step 2: Compound (3) may be prepared, for example, by reacting compound (2) with carbon monoxide and R OH, in the presence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine and pyridine or inorganic bases such as potassium carbonate and sodium hydrogen carbonate, in an inert solvent, in the presence of a transition metal catalyst (see Tetrahedron Letters 26, 1109(1985)). Examples of the transition metal catalyst include a zero-valent palladium reagent which may be prepared in the reaction system, for example, from a divalent palladium such as palladium(II) acetate and a ligand such as triphenylphosphine or 2,2'-bis(diphenylphosphino)-l,l-binaphthyl (BINAP). It is also possible to directly use a zero-valent palladium reagent such as tetrakis (triphenylphosphine) palladium (0). Examples of the inert solvent include hydrocarbon type solvents such as benzene, toluene and hexane; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; N,N-dimethylformamide; or a mixture of these solvents. Preferably, compound (3) is prepared by reacting compound (2) with carbon monoxide and R OH for 2 to 7 hours at room temperature, in N,N-dimethylformamide, in the presence of diisopropylethylamine, palladium(II) acetate and triphenylphosphine.
Step 3: Compound (4) may be prepared, for example, by oxidizing compound (3) by means of a common diol-formation reaction with osmium tetraoxide (see M. Hudlicky, "Oxidations in Organic Chemistry" or a Sharpless asymmetric C1s-dihydroxylation reaction (Sharpless AD) with AD-mix as the reagent (see Tetrahedron Asymmetry 4, 133(1993), J. Org. Chem. 57, 2768(1992), J. Org. Chem. 61, 2582(1996)), in an inert solvent. Examples of the inert solvent include alcohol type solvents such as t-butylalcohol; hydrocarbon type solvents such as benzene, toluene and hexane; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; N,N-dimethylformamide; water; or a mixture of these solvents. Preferably, compound (4) may be prepared by oxidizing compound (3) into diol with osmium tetraoxide for 30 minutes to 3 hours at room temperature, in a mixture of acetonitrile and water.

Step 4: Compound (5) may be prepared, for example, by reacting compound (4) with thionyl chloride, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; or a mixture of these solvents, in the presence or absence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine and pyridine or inorganic bases such as potassium carbonate and sodium hydrogen carbonate, followed by oxidation with a common oxidizing agent such as hydrogen peroxide, OXONE® or ruthenium trichloride-sodium metaperiodate (see M. Hudlicky, "Oxidations in Organic Chemistry"), in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; water; or a mixture of these solvents. Preferably, compound (5) may be prepared by reacting compound (4) with thionyl chloride for 30 minutes to 2 hours at ice-cooling, in dichloromethane, in the presence of triethylamine, followed by oxidation for 30 minutes to 2 hours at 0°C to room temperature, in a mixture of carbon tetrachloride, acetonitrile and water.
Step 5: Compound (6) may be prepared, for example, by reacting compound (5) with sodium azide in an inert solvent, examples of which include ether type solvents such as tetrahydrofuran; ketones such as acetone; N,N-dimethylformamide; water; or a mixture of these solvents, followed by hydrolysis (see J. Am. Chem. Soc. 110, 7538(1988)). Preferably, compound (6) may be prepared by reacting compound (5) with sodium azide for 1 to 20 hours at room temperature, in a mixture of N,N-dimethylformamide and water, followed by hydrolysis with 20% sulfuric aC1d for 1 to 2 days at room temperature, in a mixture of diethyl ether and water.
Compound (9), which is a synthetic intermediate of the compound of the present invention, may be prepared from the obtained compound (6) according to Steps 7, 8 and 9 below in the case where in formula [III], Y represents formula OCHR3R4.


Step 7: Compound (7) may be prepared from compound (6) wherein R and R represent something other than a hydrogen atom, for example, by reacting the hydroxyl group of
*1 A 1 1
compound (6) with a compound of formula R R CHL wherein L represents a 2, 2, 2-trichloroacetimidoyloxy group, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, hexane and cyclohexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; or a mixture of these solvents, in the presence of a Bronsted-aC1d catalyst such as trifluoromethanesulfonic aC1d, trifluoroacetic aC1d or hydrogen chloride, or a Lewis-aC1d catalyst such as boron trifluoride-diethyl ether complex, zinc chloride, tin chloride or trimethylsilyl-trifluoromethansulfonate (see J. Chem. Soc. Perkin Trans. 1, 2247(1985), Synthesis, 568 (1987)). In this caes, L1 represents a leaving group, for example, a halogen atom, an ethoxycarbonyloxy group or a phenoxycarbonyloxy group.
It is also possible to prepare compound (7) from compound (6) wherein R1 and R2 represent something other than a hydrogen atom, for example, by reacting the hydroxyl group of compound (6) with a compound of formula R R CHL wherein L represents something other than a 2,2,2-trichloroacetimidoyloxy group, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and

N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a mixture of these solvents, in the
presence of inorganic bases such as sodium hydride, potassium hydride, potassium
carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; metal amides
such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide and sodium amide;
organic bases such as triethylamine, diisopropylethylamine,
4-(N,N-dimethylamino)pyridine and 2,6-di-t-butylpyridine; or bases such as potassium t-butoxide. In this case, L represents a leaving group, for example, a halogen atom, a tosylsulfonate, a trifluoromethansulfonate or a tolylsulfonate. Preferably, compound (7) may be prepared by reacting compound (6) with the hydroxyl group of a compound of formula R R CHL for 1 to 3 hours at room temperature, in a mixture of chloroform and cyclohexane, in the presence of trifluoromethane sulfonic aC1d.
Step 8: Compound (8) may be prepared from compound (7), for example, by means of a common reduction reaction of an azide group, typical examples of which include: (a) Staudinger reaction with triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine or the like (see Bull. Chem. Soc. Fr., 815(1985)), in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofiiran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; water; or a mixture of these solvents; (b) hydrogenation in an inert solvent, examples of which include alcohols such as ethanol and methanol, esters such as ethyl acetate; N,N-dimethylformamide; water; or a mixture of these solvents, in the presence of a metal catalyst such as palladium/carbon or palladium black; and (c) hydride reduction with lithium aminoborohydride or the like (see A. F. Abdel-Magid, "Reductions in Organic Synthesis"). Preferably, compound (8) may be prepared by reacting compound (7) by means of a Staudinger reaction with trimethylphosphine for 2 to 12 hours at room temperature, in a mixture of tetrahydrofuran and water.
Step 9: Compound (9), which is a synthetic intermediate of the compound of the present
*i ")
invention, may be prepared from compound (8) wherein R and R represent something
other than a hydrogen atom, by converting the moieties represented by formula COOR1
and formula COOR of compound (8) into carboxylic aC1d by means of a common
hydrolysis reaction (see T. W. Greene, P. G. M. Wuts, "Protective Groups in Organic
Synthesis"). Preferably, compound (9), which is a synthetic intermediate of the
compound of the present invention, may be prepared by hydrolizing compound (8) with

lithium hydroxide for 1 to 7 days at room temperature to 50°C, in a mixture of tetrahydrofuran and water.
Compound (16), which is a synthetic intermediate of the compound of the present invention, may be prepared from compound (6) according to Steps 10, 11, 12, 13, 14 and 15 below in the caes where in formula [III], Y represents formula SR, formula S(0)nR5, formula SCHR3R4 and formula S(0)nCHR3R4.

i *?
SteplO: Compound (10) may be prepared from compound (6) wherein R and R
represent something other than a hydrogen atom, for example, by reacting the hydroxyl
group of compound (6) with a trifluoromethanesulfonylation agent such as
trifluoromethane sulfonic aC1d anhydride or N-phenyl-bis(trifluoromethanesulfonimide);
or with an alkyl- or aryl-sulfonylation agent such as methanechloride sulfonic aC1d,
benzenechloride sulfonic aC1d or toluenechloride sulfonic aC1d, in an inert solvent,
examples of which include hydrocarbon type solvents such as benzene, toluene, hexane
and cyclohexan; halogen type solvents such as dichloromethane, chloroform and carbon
tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and
1,2-dimethoxyethane, amides such as N,N-dimethylformamide and

N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a mixture of these solvents, in the presence of inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; metal amides such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide and sodium amide; organic bases such as triethylamine,pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine and di-t-butylpyridine; or bases such as potassium t-butoxide. Preferably, compound (10) may be prepared by reacting the hydroxyl group of compound (6) with trifluoromethane sulfonic aC1d anhydride for 30 minutes to 3 hours at -78°C to ice-cooling, in dichloromethane, in the presence of pyridine.
Step 11: Compound (11) may be prepared, for example, by reacting compound (10) with a compound of formula A*SNa, formula A*SK or the like, which is prepared from metal alcoholates such as sodium ethoxide and potassium t-butoxide; sodium; potassium; sodium hydride; potassium hydride; and mercaptans and thiophenols represented by formula AlSH, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; dimethylsulfoxide; N,N-dimethylformamide; or a mixture of these solvents. Preferably, compound (11) is prepared by reacting compound (10) with a compound of formula AlyHNa, which is prepared from sodium and from a compound of formula A!SH, for 10 minutes to 1 hour at room temperature, in dimethylsulfoxide.
Step 12: Compound (12) may be prepared from compound (11) wherein A1 represents
something other than a hydrogen atom, for example, by means of a common oxidation
reaction that coverts sufides into sulfoxides using sodium periodate, peracetic aC1d or
the like (see M. Hudlicky, "Oxidations in Organic Chemistry"), in an inert solvent,
examples of which include hydrocarbon type solvents such as benzene, toluene and
hexane; halogen type solvents such as dichloromethane, chloroform and carbon
tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and
1,2-dimethoxyethane; acetonitrile; acetone; dimethylsulfoxide;
N,N-dimethylformamide; methanol; ethanol; acetic aC1d; water; or a mixture or these solvents.
Step 13: Compound (13) may be prepared from compound (12) or from compound (11) wherein A1 represents something other than a hydrogen atom, for example, by means of

a common oxidation reaction that converts sulfides or sulfoxides into sulfines using 3-chloroperbenzoic aC1d, hydrogen peroxide or the like (see M. Hudlicky, "Oxidations in Organic Chemistry"), in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; dimethylsulfoxide; N,N-dimethylformamide; water; or a mixture of these solvents. It is also possible to prepare a mixture of compound (12) and compound (13) from compound (11) wherein A1 represents something other than a hydrogen atom, for example, by using a common oxidizing agent such as 3-chloroperbenzoic aC1d or hydrogen peroxide (see M. Hudlicky, "Oxidations in Organic Chemistry") and by controlling the reaction conditions such as the amount, reaction time, reaction temperature and solvent of the oxidizing agent, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; dimethylsulfoxide; N,N-dimethylformamide; water; or a mixture of these solvents. Preferably, compound (12) and compound (13) may be prepared by reacting compound (11) with 3-chloroperbenzoic aC1d for 1 to 24 hours at -78°C to room temperature, in dichloromethane.
Step 14: Compound (15) may be prepared from compound (14), for example, by means of a common reduction reaction of an azide group, typical examples of which include: (a) Staudinger reaction with triethyl phosphite, trimethylphosphine, tributylphosphine or triphenylphosphine (see Bull. Chem. Soc. Fr., 815(1985)) in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; water; or a mixture of these solvents; (b) hydrogenation in an inert solvent, examples of which include alcohols such as ethanol and methanol, esters such as ethyl acetate; N,N-dimethylformamide; water; or a mixture of these solvents, in the presence of a metal catalyst such as palladium/carbon or palladium black; and (c) hydride reduction with lithium aminoborohydride or the like (see A. F. Abdel-Magid, "Reductions in Organic Synthesis"). Preferably, compound (15) may be prepared by reacting compound (14) by means of a Staudinger reaction with trimethylphosphine for 1 to 2 hours at room temperature, in a mixture of tetrahydrofuran and water.

Step 15: Compound (16), which is a synthetic intermediate of the compound of the present invention, may be prepared from compound (15) wherein at least one of R1 and R represent something other than a hydrogen atom, by hydrolyzing the moieties represented by formula COOR and formula COOR of compound (15) by means of the same method as Step 9. Preferably, compound (16), which is a synthetic intermediate of the compound of the present invention, may be prepared by hydrolyzing compound (15) with lithium hydroxide for 5 to 7 days at room temperature to 40°C, in a mixture of tetrahydrofuran and water. Or preferably, compound (16) may be prepared by hydrolyzing compound (15) with 60% sulfuric aC1d for 1 to 5 days at 100°C to 150°C.
Compounds (24) and (27), which are synthetic intermediates of the compound of the present invention, may be prepared from synthestic intermediate (6) according to Steps 16, 17, 18, 19, 20, 21 and 22 below in the case where in formula [III], Y represents formula NHCHR3R4 or formula N(CHR3R4)(CHR3R4).


Step 16: Compounds (17) and (21) may be prepared from compounds (6) and (20), respectively, by reduC1ng the azide group by means of the same method as Step 14. Preferably, compound (17) and compound (21) may be prepared from compound (6) and compound (20), respectively, by means of a Staudinger reaction with trimethylphosphine for 1 to 12 hours at room temperature, in a mixture of tetrahydrofuran and water.
Step 17: Compound (18) may be prepared from compound (17) by protecting the amino

group of compound (17) by means of a common protection reaction of an amino group (see T. W. Greene, P. G M. Wuts, "Protective Groups in Organic Synthesis"). Preferably, compound (18) may be prepared by reacting compound (17) with di-t-butyldicarbonate for 2 to 6 hours at room temperature, in tetrahydrofuran, in the presence of a saturated aqueous solution of sodium hydrogen carbonate.
Step 18: Compound (19) may be prepared from compound (18) wherein R1 and R2 represent something other than a hydrogen atom, by alkyl- or aryl-sulfonylating the hydroxyl group of compound (18) by means of the same method as SteplO. Preferably, compound (19) may be prepared by reacting the hydroxyl group of compound (18) with trifluoromethane sulfonic aC1d anhydride for 30 minutes to 2 hours at -78°C to ice-cooling, in dichloromethane, in the presence of pyridine.
Stepl9: Compound (20) may be prepared, for example, by reacting compound (19) with sodium azide in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; ethyl acetate; acetonitrile; acetone; dimethylsulfoxide; N,N-dimethylformamide; water; or a mixture of these solvents. Preferably, compound (20) may be prepared by reacting compound (19) with sodium azide for 1 to 2 days at room temperature to 35°C, in N,N-dimethylformamide.
Step 20: Compounds (22) and (25) may be prepared from compounds (21) and (22), respectively, for example, by reacting the amino groups represented by formula-NH2
T A
and formula-R R CHNH of compounds (21) and (22) with a compound of formula R R CHL or formula R R CHL , in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, hexane and cyclohexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a mixture of these solvents, in the presence or absence of inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and potassium hydroxide; metal amides such as lithium bis(trimethylsilyl)amide, lithium diisopropylamide and sodium amide; organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine and 2,6-di-t-butylpyridine; or bases such as potassium t-butoxide. In this case, L

represents a leaving group, for example, a halogen atom, a tosylsulfonate, a trifluoromethansulfonate or a tolylsulfonate. It is also possible to prepare compounds (22) and (25), respectively, for example, by reductively aminating compounds (21) and (22) by means of a Borch reaction in which compounds (21) and (22) are reacted with compounds of formula R3COR4 or formula R3 COR4 (see A. F. Abdel-Magid et al., Tetrahedron Lett., 31, 5595 (1990)) in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, hexane and cyclohexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; ethanol; methanol; water; or a mixture of these solvents, in the presence of a reduC1ng agent such as sodium triacetoxyborohydride or sodium cyanotrihydroborate. Preferably, compound (22) may be prepared by reacting compound (21) with a compound of formula R R CHBr for 1 to 4 days at room temperature, in chloroform, in the presence of pyridine. And preferably, compound (25) may be prepared by reacting compound (22) with a compound of formula R R CHI for 1 to 4 days at room temperature, in N,N-dimethylformamide, in the presence of potassium carbonate.
Step 21: Compounds (23) and (26) may be prepared from compound (22) and compound (25), respectively, by deprotecting R , which is the protecting group for the amino group of compounds (22) and (25), by means of a common deprotection reaction (see T. W. Greene, R G. M. Wuts, "Protective Groups in Organic Synthesis") that converts R into an amino group. Preferably, compound (23) and compound (26) may be prepared by deprotecting compound (22) and compound (25) with 4N hydrogen chloride/ethyl acetate for 12 to 36 hours at ice-cooling to room temperature.
Step 22: Compounds (24) and (27), which are synthetic intermediates of the compound of the present invention, may be prepared from compounds (23) and (26) wherein at least one of R and R represent something other than a hydrogen atom, by hydrolyzing the moieties represented by formula COOR and COOR of compounds (23) and (26), by means of the same method as Step 9. Preferably, compound (24) and compound (27), which are synthetic intermediates of the compound of the present invention, may be prepared by hydrolyzing compound (23) and compound (26), respectively, with lithium hydroxide for 1 to 7 days, in a mixture of tetrahydrofuran and water.
Compound (30), which is a synthetic intermediate of the compound of the present

invention, may be prepared from compound (21) according to Steps 23, 24 and 25 below in the case where in formula [III], Y represents formula-NHCOR3.

Step 23: Compound (28) may be prepared from compound (21), for example, by
reacting the 3-position amino group of compound (21) with a compound of formula
L COR or formula R COOCOR in an inert solvent, examples of which include
hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents
such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such
as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; amides such as
N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a
mixture of these solvents, in the presence or absence of organic bases such as
triethylamine, pyridine, morpholine, diisopropylethylamine,
4-(N,N-dimethylamino)pyridine and 2,6-di-t-butylpyridine.
In this case, L1 represents a leaving group, for example, a halogen atom, an ethoxycarbonyloxy group or a phenoxycarbonyloxy group. It is also possible to prepare compound (28) by means of a common formylation reaction (see T. W. Greene, P. G M. Wuts,"Protective Groups in Organic Synthesis") in the case where R represents a hydrogen atom. Preferably, compound (28) may be prepared by reacting compound (21) with a compound of formula R3COCl for 1 to 4 hours at room temperature, in chloroform, in the presence of pyridine.
Step 24: Compound (29) may be prepared from compound (28) by means of the same

deprotection reaction of formula-NHR7 as Step 21. Preferably, compound (29) may be prepared by deprotecting compound (28) with 4N hydrogen chloride/ethyl acetate for 30 minutes to 2 hours at ice-cooling.
Step 25: Compound (30), which is an intermediate of the compound of the present invention, may be prepared from compound (29) wherein at least one of R1 and R2 represent something other than a hydrogen atom, by means of the same method of hydrolysis reaction of formula-COOR1 and formula-COOR2 as Step 9. Preferably, compound (30), which is a synthetic intermediate of the compound of the present invention may be prepared by hydrolyzing compound (29) with lithium hydroxide for 1 to 7 hours at room temperature, in a mixture of tetrahydrofuran and water. Compound (33), which is a synthetic intermediate of the compound of the present invention, may be prepared from synthetic intermediate (6) wherein R represents a benzyl group, according to Steps 26, 27 and 28 below in the case where in formula [III], Y represents formula-OCOR5.

Step 26: Compound (31) may be prepared from compound (6) wherein R1 represents something other than a hydrogen atom and R represents a benzyl group, for example, by reacting the hydroxyl group of compound (6) with a compound of formula LJCOR5 or formula R5COOCOR5 either in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such

as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethan; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a mixture of these solvents or in the absence of any solvent, in the presence or absence of organic bases such as triethylamine, pyridine, morpholine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine and 2, 6-di-t-butylpyridine. In this case, L1 represents a leaving group, for example, a halogen atom, an ethoxycarbonyloxy group or a phenoxycarbonyloxy group. Preferably, compound (31) may be prepared by reacting compound (6) with a compound of formula R5COCl for 12 to 36 hours at room temperature, in pyridine.
Step 27: compound (32) may be prepared from compound (31), for example, by yielding an amino body by means of a Staudinger reaction with triethyl phosphite, trimethylphosphine, tributylphosphine or triphenylphosphine, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; water; or a mixture of these solvents (see Bull. Chem. Soc. Fr., 815(1985)), and then, for example, by reductively deprotecting the benzyl group of the obtained amino body by means of a hydrogenation reaction, in an inert solvent, examples of which include alcohols such as ethanol and methanol; esters such as ethyl acetate; N,N-dimethylformamide; water; or a mixture of these solvents, in the presence of a metal catalyst such as palladium/carbon or palladium black. It is also possible to directly prepare compound (32) from compound (31), for example, by means of a hydrogenation reaction, in an inert solvent, examples of which include alcohols such as ethanol and methanol; esters such as ethyl acetate; N,N-dimethylformamide; water; or a mixture of these solvents, in the presence of a metal catalyst such as palladium/carbon or palladium black. Preferably, an amine body may be prepared by reacting compound (31) by means of a Staudinger reaction with trimethylphosphine for 30 minutes to 2 hours at room temperature, in a mixture of tetrahydrofuran and water. Compound (32) may then be prepared by reacting the amine body for 30 minutes to 2 hours at room temperature, in ethanol, in the presence of 5%palladium carbon, under a hydrogen atmosphere.
Step 28: Compound (33), which is a synthetic intermediate of the compound of the present invention, may be prepared from compound (32) wherein R1 represents something other than a hydrogen atom, by means of the same method as Step 9.

Preferably, compound (33), which is a synthetic intermediate of the compound of the present invention, may be prepared by hydrolyzing compound (32) with lithium hydroxide for 30 minutes to 2 hours at room temperature, in a mixture of tetrahydrofuran and water.
Compound [I] of the present invention may be prepared by means of monoesterification or diesterification of the two carboxylic aC1d moieties of the obtained synthetic intermediate [III].
Compound [I], which is the compound of the present invention, may be prepared by means of diesterification or monoesterification of the carboxylic aC1d moieties of compound [III] according to Step 29 below.

Step 29: Compound [I], which is the compound of the present invention, may be prepared by means of a common esterification reaction of the carboxylic aC1d moiety of compound [III] (see T. W. Greene, P. G. M. Wuts, "Protective Groups in Organic Synthesis")- Preferably, compound [I] of the present invention may be prepared by converting the carboxylic aC1d moiety of compound [III] to lithium salt using lithium hydroxide at room temperature in tetrahydrofuran, and then by reacting compound [III] with compounds of formula R Br and formula R Br for 4 to 12 hours at room temperature to 90°C, in N,N-dimethylformamide. It is also possible to selectively prepare compound [I], which is the compound of the present invention and wherein R represents a hydrogen atom, by reacting the carboxylic aC1d moiety on the 6-position carbon of compound [III] with alcohol represented by formula RlyH, for a short period of time or by controlling the reaction temperature, either in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; dimethylsulfoxide; N,N-dimethylformamide; or a mixture of these solvents or without

any solvent, in the presence or absence of mineral aC1ds such as sulfuric aicd, phosphoric aC1d and hydrochloric aC1d; organic aC1ds such as acetic aC1d, oxalic aC1d and methanesulfonic aC1d; or chloride aC1ds such as thionyl chloride and phosphoryl chloride. Preferably, compound [I] of the present invention wherein R2 represents a hydrogen atom may be prepared by reacting the carboxylic aC1d moiety on the 6-position carbon of compound [III] for 1 hour to 3 days at ice-cooling to 80°C, in the presence of alcohol represented by formula R*OH and of thionyl chloride.
It is also possible to selectively prepare compound [I] wherein R represents a hydrogen atom by protecting the amino aC1d moiety on the 2-position carbon by means of a protection method of a-amino aC1d using triethylboran, copper(II)complex or the like (see Internatiomal Journal of Peptide & Protein Research, 37, 210 (1991); Synthesis, 119 (1990); Helv. Chem. Acta, 44, 159 (1961)), and then esterifying the carboxylic aC1d moiety on the 6-position carbon by means of a commmon esterification reaction (see T. W. Greene, P. G M. Wuts,"Protective Groups in Organic Synthesis"), followed by a deprotection reaction of the a-amino aC1d moiety (see Internatiomal Journal of Peptide & Protein Research, 37, 210 (1991); Synthesis, 119 (1990); Helv. Chem. Acta, 44, 159 (1961)).
After compound [I] wherein R represents an hydrogen atom has been selectively
1 9
prepared, compound [I] of the present invention wherein R and R both represent something other than a hydrogen atom may be prepared by either protecting or not protecting the amino group on the 2-position carbon with a common protecting group for an amino group such as an allyloxycarbonyl group or a tert-butoxycarbonyl group (see T. W. Greene, P. G. M. Wuts, "Protective Groups in Organic Synthesis") and then esterifying the carboxylic aC1d moiety on the 2-position carbon by means of a common esterification reaction (see T. W. Greene, P. G M. Wuts, "Protective Groups in Organic Synthesis"), and in the case where the amino group has been protected, followed by a deprotection reaction of amino groups (see T. W. Greene, P. G M. Wuts, "Protective Groups in Organic Synthesis"). Preferably, Compound [I] of the present invention
1 0
wherein R and R both represent something other than a hydrogen atom may be prepared by protecting the amino group on the 2-position carbon with an allyloxycarbonyl group by reacting the amino group for 8 hours at room temperature, in the presence of allyl chloroformate and saturated sodium hydrogen carbonate; and then reacting the amino group with RX' (wherein R represents a halogen atom and X' preferably represents a bromine atom or a iodine atom) for 1 to 24 hours, in the

presence of potassium carbonate; followed by a deprotection reaction of an amino group in which the amino group is reacted with tetrakis(triphenylphosphine)palladium for 1 to 24 hours at room temperature to 80°C, in the presence of 1,3-dimethylbarbituric aC1d.
It is also possible to selectively prepare compound [I], which is the compound of the present invention wherein R1 represents a hydrogen atom, from compound [I] wherein R and R represent something other than a hydrogen atom, by converting the moiety represented by formula COOR1 of compound [I] into a carboxylic aC1d by means of a common hydrolysis reaction (see T. W. Greene, P. G M. Wuts, "Protective Groups in Organic Synthesis"), for a short period of time or at a low temperature. Preferably, compound [I] of the present invention wherein R1 represents a hydrogen atom may be prepared from compound [I] wherein R and R represent something other than a hydrogen atom, by hydrolyzing the moiety represented by formula COOR1 of compound [I] with lithium hydroxide for 30 minutes to 3 hours at 0°C to room temperature, in a mixture of tetrahydrofuran and water.
It is further possible to prepare compound [I] wherein at least one of R1 and Rz
represent an azidoC1-10alkyl group from a corresponding compound [I] wherein at least
1 *?
one of R and R represent a halogenoC1-10alkyl, for example, by reacting compound
[I] with sodium azide in an inert solvent, examples of which include hydrocarbon type
solvents such as benzene, toluene and hexane; halogen type solvents such as
dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as
tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; ethyl acetate; acetonitrile;
acetone; dimethylsulfoxide; N,N-dimethylformamide; water; or a mixture of these
solvents. Preferably, compound [I] wherein at least one of R and R represent an
azidoC1-10alkyl group may be prepared by reacting a compound [I] wherein at least one
of R1 and R2 represent a halogenoC1-10alkyl group with sodium azide for 6 to 18 hours
at room temperature to 60°C, in a mixture of N,N-dimethylformamide and water.
It is further possible to prepare compound [I] wherein at least one of R and R represent an aminoC2-10alkyl group from a correspoding compound [I] wherein at least one of R1 and R2 represent an azidoC1-10alkyl group, by hydrolyzing the azido moiety of compound [I] by means of a common reduction reaction of an azide group, typical examples of which include: (a) Staudinger reaction with triethyl phosphite, trimethylphosphine, tributylphosphine or triphenylphosphine (see Bull. Chem. Soc. Fr.5 815(1985)) in an inert solvent, examples of which include hydrocarbon type solvents

such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; acetonitrile; acetone; water; or a mixture of these solvents; (b) hydrogenation in an inert solvent, examples of which include alcohols such as ethanol and methanol, esters such as ethyl acetate; N,N-dimethylformamide; water; or a mixture of these solvents, in the presence of a metal catalyst such as palladium/carbon or palladium black; and (c) hydride reduction with lithium aminoborohydride or the like (see A. F. Abdel-Magid /'Reductions in Organic Synthesis"). Preferably, compound [I] wherein at least one of R and R represent a aminoC1-10alkyl group may be prepared by reacting compound [I] wherein at least one of R and R represent an azidoC1-10alkyl group by means of a Staudinger reaction with trimethylphosphine for 6 to 18 hours at room temperature, in a mixture of tetrahydrofuran and water.
Further, it is also possible to prepare compound [I] of the present invention wherein R1 represents something other than a hydrogen atom and R represents a hydrogen atom from the obtained compound [III] according to Steps 30, 31, 32 and 33 below.

Step 30: compound (34) may be prepared, for example, by reacting the amino group of compound [III] with allyl chloroformate in an inert solvent, examples of which include

hydrocarbon type solvents such as benzene, tolueneand hexane; halogen type solvents
such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such
as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and 1,4-dioxane; amides such as
N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; water; or a
mixture of these solvents, in the presence or absence of organic bases such as
triethylamine, pyridine, morpholine, diisopropylethylamine,
4-(N,N-dimethylamino)pyridine and 2,6-di-t-butylpyridine or inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. Preferably, compound (34) may be prepared by reacting compound [III] with allyl chloroformate for 6 to 18 hours at room temperature, in 1,4-dioxane, in the presence of a saturated aqueous solution of sodium hydrogen carbonate.
Step 31: Compound (35) may be prepared, for example, by reacting compound (34) with an appropriate catalyst such as p-toluenesulfonic aC1d or oxalic aC1d, and either with or without using a dehydration apparatus such as a Dean-Stark distillation trap, in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; or a mixture of these solvents, in the presence of an aldehyde such as paraformaldehyde. Preferably, compound (35) may be prepared by heat refluxing compound (34) with paraformaldehyde using a Dean-Stark distillation trap for 1 to 5 hours, in benzene, in the presence of paratoluenesulfonic aC1d.
Step 32: Compound (36) may be prepared from compound (35) by means of a common esterification reaction (see T. W. Greene , P. G. M. Wuts, "Protective Groups in Organic Synthesis"). It is also possible to prepare compound (36) by reacting the ester moieties of a compound of formula L CHRcOC(0)ZR (wherein L represents a leaving group, for example, a halogen atom, a tosylsulfonate, a trifluoromethansulfonate or a tolylsulfonate) and of compound (35), in an inert solvent, examples of which include hydrocarbon type solvents such as benzene, toluene, hexane and cyclohexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachloride; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane; amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidinone; dimethylsulfoxide; or a mixture of these solvents, in the presence of inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide and potassium hydroxide; metal amides such as lithium

bis(trimethylsilyl)amide, lithium diisopropylamide and sodium amide; organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine and 2,6-di-t-butylpyridine; or bases such as potassium t-butoxide, in the presence or absence of an appropriate activating agent such as sodium iodide. Preferably, compound
(36) may be prepared by reacting compound (35) with R!C1 for 2 to 24 hours at room
temperature to 75°C, in N,N-dimethylformamide, in the presence of sodium iodide.
Step 33: Compound (37), which is the compound of the present invention, may be prepared from compound (36) by deprotecting the a-amino aC1d moiety, in an inert solvent, examples of which iinclude hydrocarbon type solvents such as benzene, toluene and hexane; halogen type solvents such as dichloromethane, chloroform and carbon tetrachlorid; ether type solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethan; or a mixture of these solvents, in the presence of a zero-valent palladium catalysts such as tetrakis(triphenylphosphine)palladium(0) and a regeneration reagent of a metal catalyst such as 1,3-dimethylbarbituric aC1d. Preferably, compound
(37) of the present invention may be prepared by deprotecting compound (36) for 30
minutes to 3 hours at room temperature to 50°C, in chloroform, in the presence of
tetrakis(triphenylphosphine)palladium and 1,3-dimethylbarbituric aC1d.
The compounds of the present invention may be made into pharmaceutical formulations or pharmaceutical compositions by being combined with one or more pharmaceutically acceptable carriers, exC1pients or diluents. Examples of the carriers, exC1pients and diluents include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, arginate, calC1um silicate, calcuim phosphate, cellulose, water syrup, mathylcellulose, polyvinyl pyrrolidone, alkyl parahydroxybenzoate, talc, magnesuim stearate, stearic aC1d, glycerol and oils such as sesame oil, olive oil and soybean oil.
The compounds of the present invention may be formulated by means of common formulation procedures into drugs for oral or parenteral adminstration, in particular as group II metabotropic glutamate receptor antagonists, in the form of tablets, pills, capsules, granules, powders, liquids, emulsions, suspensions, ointments, injections and skin plasters, after being mixed with the said carriers, exC1pients or diluents and if necessary, with additives such as commonly employed fillers, binders, disintegrants, pH regulators and solubilizers.

The compounds of the present invention can be administered orally of parenterally to an adult patient in a quantity of 0.01 to 500 mg per day in a single dose or in several doses. Oral adimistration is preferable from the point of usability and mediC1nal benefits. The dosage can be increased or decreased as appropriate according to the type of the disease targeted for treatment and the age, weight and symptoms of the patient.
EXAMPLE
The following Reference Examples, Examples and Test Example illustrate the present invention in detail. It should be understood that the present invention is not limited to these examples.
REFERENCE EXAMPLE 1
Synthesis of (1R, 2R, 3R, 5R, 6R)-2-amino-3- (3,4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d
(1) 245 mL of a 2.66M n-butyl lithium hexane solution was added dropwise to 700 mL of a tetrahydrofuran solution containing 137 mL of hexamethyldisilazane, and the mixture was stirred for 1 hour while being maintained at -63°C to -54°C. 340 mL of a tetrahydrofuran solution containing 101 g of (1R, 5R, 6R) -6-fluoro-2-oxo-bicyclo [3.1.0] hexane-6-carboxylate ethyl ester was added dropwise thereto while being maintained at -63°C to -52°C. 700 mL of a tetrahydrofuran solution containing 213 g of N-phenyl-bis(trifluoromethanesulfonimide) was added an hour later at -63°C to -45 °C. The reaction solution was warmed naturally to room temperature and further stirred for 2.5 hours. The reaction solution was diluted with diethyl ether, washed three times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:l to 20:1 to 5:1). The obtained 175g of (1R, 5R, 6R) -6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo [3.1.0] hex-2-en-6-carboxylate ethyl ester was dissolved in 875 mL of N,N-dimethylformamide and 875 mL of ethanol, and after 95.1 mL of diisopropylethylamine, 8.65 g of triphenylphosphine and 3.70 g of palladium acetate were added, the mixture was stirred for 5.5 hours at room temperature

under a carbon monoxide atmosphere. IN hydrochloric aC1d was added thereto, and the reaction solution was extracted six times with diethyl ether. The organic layers were combined, washed four times with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=30:l to 20:1 to 10:1), thereby yielding 92.6 g of (lR,5R,6R)-6-fluorobicyclo[3.1.0]hex-2-en-2,6-dicarboxylic aC1d diethyl ester. 'H-NMR (200 MHz, CDC13, TMS); 1.31(t, J=7.03 Hz, 3H), 1.33(t, J=7.03 Hz, 3H), 2.37-2.51(m, 1H), 2.65-2.81(m, 1H), 2.88-3.04(m5 1H), 3.10 (dd, J=7.47, 2.64 Hz, 1H), 4.12-4.40(m, 4H), 6.77-6.79(m, 1H). MS(ESI)(Pos)m/z; 265 (M+Na)+ [a]D21 = +158.0° (CHC13, c=1.5)
(2) 160 mL of a 50% N-methylmorpholine N-oxide solution and 121 mL of a 5%
osmium (VIII) oxide solution was added to 92.4 g of (IR, 5R, 6R) -6-fluorobicyclo
[3.1.0] hexa-2-en-2, 6-dicarboxylic aC1d diethyl ester dissolved in 1.76 L of acetonitrile
and 680 mL of water, and the mixture was stirred for 1 hour at room temperature.
Sodium sulfite was added thereto at ice cooling, and the reaction solution was stirred for
30 minutes at room temperature and then filtered through celite. A saturated aqueous
solution of sodium chloride was added thereto, and the filtrate was extracted twice with
ethyl acetate. The organic layers were combined, washed with a saturated aqueous
solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the
desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the
residue was purified by column chromatography (silica gel: Wako gel C200, eluent:
hexane-ethyl acetate=4:l to 1:1), thereby yielding 95.6g of (IR, 2S, 3R, 5R, 6R)
-6-fluoro-2, 3-dihydroxybicyclo [3.1.0] hexane- 2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.31(t, J=7.25 Hz, 6H), 2.03-2.34(m, 3H),
2.40-2.55(m, 1H), 2.70(d, J=9.23 Hz, 1H), 4.09(s, 1H), 4.18-4.47(m, 5H).
MS(ESI)(Nega) m/z; 275 (M-H)~
[a]D27 = -69.1° (CHC13, c=1.4)
(3) 106 mL of triethylamine was added to 1.24 L of a dichloromethane solution
containing 95.4 g of (IR, 2S, 3R, 5R, 6R)-6-fluoro-2, 3-dihydroxybicyclo [3.1.0]
hexane-2, 6-dicarboxylic aC1d diethyl ester at ice-cooling, 37.6 mL of thionyl chloride

was added dropwise thereto, and the mixture was stirred for 30 minutes. The reaction solution was washed twice with water and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure. The residue was dissolved in 640 mL of carbon tetrachloride, 640 mL of acetonitrile and 760 mL of water. 96.0 g of sodium metaperiodate and 655 mg of ruthenium (III) chloride hydrate were added thereto, and the solution was stirred for 1 hour at room temperature. After the mixture was filtured through celite, the filtrate was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:l), thereby yielding 109 g of (1R, laR, lbS, 4aR, 5aR) -l-fluoro-3, 3-dioxotetrahydro-2, 4-dioxa-3 X 6-thiacyclopropa [a] pentalen-1, lb-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.33(t, J=7.03 Hz, 3H), 1.34(t, J=7.03 Hz, 3H), 2.52-2.94(m, 4H), 4.23-4.47(m, 4H), 5.40-5.53(m, 1H). MS(ESI)(Pos)m/z; 361 (M+Na)+ [a]D28 = +18.3° (CHC13, c=1.0)
(4) 37.7 g of sodium azide was added to 109 g of (1R, laR, lbS, 4aR, 5aR)-l-fluoro-3, 3-dioxotetrahydro-2, 4-dioxa-3 X 6-thiacyclopropa [a] pentalen-1, lb-dicarboxylic aC1d diethyl ester dissolved in 1.10 L of N,N-dimethylformamide and 110 mL of water, and the mixture was stirred for 14 hours at 50°C. The solvent was distilled under reduced pressure, and after the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V/V) sulfuric aC1d was added thereto, and the mixture was stirred for 34 hours at room temperature. After the reaction solution was separated, the organic layers were washed twice with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. After the desiccant was filtured off the, filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate~4:l), thereby yielding 88.5 g of (1R, 2R, 3R, 5R, 6R)-2-azide-6-fluoro-3-hydroxybicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.33 (t, J=7.03 Hz, 3H), 1.38 (t, J=7.03 Hz, 3H), 2.18-2.61 (m, 5H), 4.21-4.48 (m, 5H). MS(ESI)(Pos)m/z; 324 (M+Na)+

[a]Dz/ = -48.7°(CHCl3,c=1.0)
(5) 1.36 g of 60% sodium hydride (oily) was washed twice with hexane and suspended
in 46 mL of tetrahydrofiiran, and then 60. lg of 3,4-dichlorobenzyl alcohol dissolved in
68 mL of tetrahydrofiiran was added dropwise thereto. The mixture was stirred for 30
minutes at room temperature, and 34 mL of trichloroacetonitrile was added dropwise
thereto while being cooled with salt-ice. The solution was stirred for 30 minutes at this
temperature, 30 minutes at ice-cooling, 30 minutes in a water bath, and a futher 2 hours
at room temperature. The reaction solution was concentrated under reduced pressure,
and after 45 mL of pentane and 1.1 mL of methanol was added thereto, the residue was
stirred vigorously for 30 minutes at room temperature. After the inorganic salt was
filtured off, the filtrate was concentrated under reduced pressure, thereby yielding 106.8
g of crude 3, 4-dichlorobenzyl-2, 2, 2-trichloroacetimidate.
2.03 g of the crude 3,4-dichlorobenzyl-2, 2, 2-trichloroacetimidate and 1.27 g of (IR, 2R, 3R, 5R, 6R)-2-azide-3-hydroxy-6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester were dissolved in 5.4 mL of chloroform and 10.8 mL of cyclohexane. After being cooled in an ice bath, 187 JJL of trifluoromethane sulfonic aC1d was added thereto. After the mixture was stirred for 1.5 hours at 30°C, 93 lyL of trifluoromethane sulfonic aC1d was further added thereto, and the mixture was stirred for 1 hour. The inorganic salt was filtured off, and a saturated aqueous solution of sodium hydrogen carbonate was added thereto at ice-cooling. After the solution was extracted twice with chloroform, the organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=15:l), thereby yielding 771 mg of (IR, 2R, 3R, 5R, 6R) -2-azide-3- (3, 4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester.
]H-NMR (200 MHz, CDC13, TMS); 1.26-1.39 (m, 6H), 2.24-2.51 (m, 4H), 3.91-4.05 (m, 1H), 4.18-4.35 (m, 4H), 4.42 (d, J=11.9 Hz, 1H), 4.64 (d, J=11.9 Hz, 4H), 7.05-7.14 (m, 1H), 7.36-7.43 (m,2H). MS(ESI)(Pos)m/z; 482 (M+Na)+ [a] D24 = -14.5°(CHCl3,c-0.94)
(6) 65.7 mL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 27.5 g

oi LYIK, ZK, JK, :>K, OK) -2-azide-3- (3, 4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diester dissolved in 825 mL of tetrahydrofuran and 82.5 mL of water, and the mixture was stirred for 4 hours at room temperature. The mixture was diluted with 825 mL of diethyl ether, washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:l to 3:2), thereby yielding 23.1 g of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3, 4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester.
JH-NMR (200 MHz, CDC13, TMS); 1.24-1.40 (6H, m), 2.02-2.28 (2H, m), 2.51-2.80 (2H, m), 3.98-4.08 (1H, m), 4.18-4.34 (4H, m), 4.43 (1H, d, J=12.5 Hz), 4.53 (1H, d, J=12.5 Hz), 7.10-7.19 (1H, m), 7.36-7.45 (2H, m). MS(ESI)(Pos)m/z; 456 (M+Na)+ W D22 = +11.6°(CHCl3,c=0.50%)
(7) 5.53 g of lithium hydroxide hydrate was added to 22.9 g of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3, 4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester dissolved in 480 mL of tetrahydrofuran and 240 mL of water, and the mixture was stirred for three days at room temperature. 443 mg of lithium hydroxide hydrate was further added thereto, and the mixture was stirred for 1 day at room temperature. 169 mL of IN hydrochloric aC1d was added dropwise thererto at ice-cooling, and the mixture was stirred for 14 hours at room temperature. The preC1pitated solids were filtured, and then washed with 200 mL of tetrahydrofuran and 100 mL of water, thereby yielding 12.3 g of (1R, 2R, 3R, 5R, 6R)-2-amino-3- (3, 4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d. 'H-NMR (300 MHz, D20, TMSP); 2.28-2.45 (3H, m), 2.50 (1H, dd, J=7.6, 13.4 Hz), 4.05-4.11 (1H, m), 4.52 (1H, d, J=12.1 Hz), 4.60 (1H, d, J=12.1 Hz), 7.26-7.58 (3H, m). MS (ESI)(Nega)m/z; 376 (M-H)" [a]D27= -10.0° (INNaOH, c=1.02)
REFERNCE EXAMPLE 2
Synthesis of (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3, 4-dichlorobenzylsulfanyl) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d

(1) 48 |iL of pyridine, and 78 l μL of trifluoromethane sulfonic aC1d anhydride dissolved
in 0.4 mL of dichloromethane was added dropwise to 120 mg of (1R, 2R, 3R, 5R, 6R)
-2-azide-6-fluoro-3-hydroxybicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester
dissolved in 20 mL of dichloromethane at -75°C under a nitrogen atmosphere, and the
mixture was stirred for 1.5 hours at ice-cooling. 39 μL of trifluoromethane sulfonic aC1d
anhydride dissolved in 24 lμL of pyridine and 0.2 mL of dichloromethane was added
dropwise thereto at -75°C, and the mixture was stirred for 25 minutes at ice-cooling. 10
mL of ether was added thereto, and after the solids were filtured off, the filtrate was
concentrated under reduced pressure, and the residue was purified by column
chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:l), thereby
yielding 166 mg of (1R, 2R, 3R, 5R, 6R) -2-azide-6-fluoro-3-
trifluoromethanesulfonyloxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.35 (t, J=7.0 Hz, 3H), 1.38 (t, J-7.0 Hz, 3H),
2.35-2.50 (m, 2H), 2.62-2.86 (m, 2H), 4.31 (q, J=7.0 Hz, 2H), 4.27-4.55 (m, 2H),
4.94-5.10 (m, 1H).
MS(FAB)(Pos)m/z; 434 (M+H)+ [a]D26 = -31.2° (CHC13, c=0.4)
(2) 688 mg of potassium nitrite and 428 mg of 18-crown -6 ether was added to 701 mg
of (1R,2R,3R,5R,6R) -2-azide-6-fluoro- 3-trifluoromethanesulfonyloxy-bicyclo [3.1.0]
hexane -2,6 -dicarboxylic aC1d diethyl ester dissolved in 6.9 mL of
N,N-dimethylformamide, and the mixture was stirred for 1.5 days at room temperature
under a nitrogen atmosphere, and further stirred for 3.5 days at 45°C. Water was added
thereto, and the mixture was extracted twice with ethyl acetate. The organic layers were
combined, washed with a saturated aqueous solution of sodium chloride, and then dried
over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was
concentrated under reduced pressure, and the residue was purified by column
chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:l), thereby
yielding 388 mg of (1R, 2R, 3S, 5R, 6R) -2-azide-6-fluoro-3-hydroxybicyclo [3.1.0]
hexane-2, 6-dicarboxylic aC1d-2,6-diethyl ester.
ly-NMR (200 MHz, CDC13, TMS); 1.34 (t, J=7.0 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H), 2.16 (dd, J=2.9Hz, 14.9 Hz, 1 H), 2.17-2.30 (m, 1H), 2.44 (dd, J=3.1 Hz, 8.1 Hz, 1H), 2.61 (dd, J=12.3 Hz, 16.0 Hz, 1H), 2.80-2.99 (m, 1H), 4.29 (q, J=7.0 Hz, 2H), 4.34 (q, J-7.0 Hz, 2H), 4.48-4.64 (m, 1H). MS(ESI)(Pos)m/z; 324 (M+Na)+

[a]D/D = +6.4°(CHCl3?c-1.0)
(3)Under a nitrogen atmosphere, 0.36 mL of trifluoromethane sulfonic aC1d anhydride dissolved in 1.2 mL of dichloromethane was added dropwise to 364 mg of (1R, 2R, 3S, 5R, 6R) -2-azide-6-fluoro-3-hydroxybicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester dissolved in 6.1 mL of dichloromethane and 0.21 mL of pyridine at -77°C to-69°C. The solution was stirred for 30 minutes at -77°C, and further stirred for 30 minutes at ice-cooling. 30 mL of diethyl ether was added thereto, and after the solids were filtured off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=5:l)5 thereby yielding 487 mg of (1R, 2R, 3S, 5R, 6R) -2-azide-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester. ]H-NMR (200 MHz, CDC13, TMS); 1.36 (t, J=7.03 Hz, 3H), 1.39 (t, J=7.47 Hz, 3H), 2.26-2.63 (m, 3H), 2.91-3.10 (m, 1H), 4.25-4.45 (m, 4H), 5.57 (dd, J=9.01, 2.86 Hz, 1H).
MS(ESI)(Pos)m/z; 456 (M+Na)+ [a]D26=-41.4°(CHCl3, c=l,l)
(4) 2.59 g of 3,4-dichlorobenzylmercaptan was added to 308 mg of sodium dissolved inl8 mL of ethanol at room temperature under a nitrogen atmosphere, and the mixture was stirred for 5 minutes and then concentrated under reduced pressure. 64 mL of dimethylsulfoxide was added to the filturate, and after 3.23 g of (1R, 2R, 3S, 5R, 6R) -2-azide-6-fluoro-3- trifluoromethanesulfonyloxy-bicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d diethyl ester dissolved in 6.4 mL of dimethylsulfoxide was added thereto at room temperature, the mixture was stirred for ten minutes. 250 mL of diethyl ether was added thereto, and then the upper and lower layers were separated .The lower layer was extracted twice with diethyl ether. The organic layers were combined, washed with a cooled IN hydrochloric aC1d and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=10:l to 5:1), thereby yielding 3.35 g of (1R, 2S, 3R, 5R, 6R) -2-azide-3-(3, 4-dichlorobenzylsulfanyl) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.34 (t, J=7.03 Hz, 3H), 1.38 (t, J=7.03 Hz, 3H), 2.20-2.49 (m, 4H) 2.99-3.13 (m, 1H), 3.68 (d, J=13.62 Hz, 1H), 3.84 (d, J-13.62 Hz,

1H), 4.22-4.51 (m, 4H), 7.16 (dd, J=8.13, 1.98 Hz, 1H), 7.34-7.46 (m, 2H). MS(ESI)(Pos)m/z; 498 (M+Na)+ [a]D24 = +129.9° (CHCl3,'c=0.5)
(5) 7.7 mL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 3.35 g of
(lR,2S,3R,5R,6R)-2-azide-3-(3?4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester dissolved in 100 mL of tetrahydrofuran and 10 mL
of water, and the mixture was stirred for 1 hour at room temperature. After the solution
was diluted with 200 mL of diethyl ether, 50 mL of a saturated aqueous solution of
sodium hydrogen carbonate was added thereto, and the mixture was stirred for 1.5 hours
at room temperature. After separation, the organic layers were washed with a saturated
aqueous solution of sodium chloride and then dried over anhydrous sodium sulfate.
After the desiccant was filtured off, the filtrate was concentrated under reduced pressure.
The residue was diluted with chloroform, and silica gel [Wako gel C200] was added
thereto. After being concentrated under reduced pressure and then left to stand for 18
hours at room temperature, the residue was purified by column chromatography (silica
gel: Wako gel C200, eluent: hexane-ethyl acetate=2:l), thereby yielding 2.78 g of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester
!H-NMR (300 MHz, CDC13? TMS); 1.31 (t, J=7.2 Hz, 3H), 1.35 (t, J=7.2 Hz, 3H), 2.08-2.15 (m, 1H), 2.24-2.40 (m, 3H), 2.86-2.93 (m, 1H), 3.73 (d, J=13.4 Hz, 1H), 3.88 (d, J=13.4 Hz, 1H), 4.21-4.37 (m, 4H), 7.15 (dd, J=8.2, 2.2 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 7.42 (d, J=2.2 Hz, 1H). MS(ESI)(Pos)m/z; 472 (M+Na)+ [a]D26 = +94.4° (CHC13, c=0.25)
(6) 12 mg of lithium hydroxide hydrate was added to 41 mg of
(lR,2S,3R?5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester dissolved in 0.8 mL of tetrahydrofuran and 0.4 mL
of water, and the mixture was stirred for 5.5 days at room temperature. The mixture was
adjusted to pH-3 with IN hydrochloric aC1d in an ice bath. 30 mL of water was added
thereto, and after the mixture was stirred for 1 hour at room temperature and then
purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent: water, a 40%
aqueous solution of tetrahydrofuran and a 10% aqueous solution of pyridine), the
obtained solids were further washed with tetrahydrofuran, thereby yielding 26 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluorobicyclo[3.1.0]hexan

e-2,6-dicarboxylic aC1d.
'H-NMR (300 MHz, D20, TMSP); 2.17-2.48 (m, 4H), 3.04-3.13 (m, 1H), 3.80 (d,
J=14.9 Hz, 1H), 3.85 (d, J=14.9 Hz, 1H), 7.31 (d, J=8.1 Hz, 1H), 7.53 (d, J=8.1 Hz, 1H),
7.59 (s,lH).
MS(ESI)(Nega)m/z; 392 (M-H)'
[a]D30 = +47.5° (IN NaOH, c=0.41)
REFERENCE EXAMPLE 3
Synthesis of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfinyl)-6-fluorobicyclo[3.1.0]hexan e-2,6-dicarboxylic aC1d
(1) 32 mg of 3-chloroperbenzoic aC1d was added to 73 mg of (1R, 2S, 3R, 5R, 6R) -2-azide -3-(3, 4-dichlorobenzylsulfanyl) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d diethyl ester dissolved in 1.46 mL of dichloromethane in a dry ice-acetone bath, and the mixture was stirred for 1 hour. The mixture was further stirred for 3.5 hours in an ice bath, and then for 11 hours at room temperature. After 15 mg of 3-chloroperbenzoic aC1d was further added in a dry ice-acetone bath, the mixture was stirred for 1 hour, and further stirred for 4 hours in an ice bath. The reaction solution was washed with a saturated aqueous solution of sodium hydrogen carbonate and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=4:l to 2:1), thereby yielding 63 mg of (1R, 2S, 3R, 5R, 6R) -2-azide-3- (3,4-dichlorobenzylsulfinyl) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester and 12 mg of (1R, 2S, 3R, 5R, 6R) -2-azide-3-(3,4-dichlorobenzylsulfonyl) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d diethyl ester.
(1R, 2S, 3R, 5R, 6R) -2-azide-3- (3,4-dichlorobenzylsulfinyl) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester:
*H-NMR (200 MHz, CDC13, TMS); 1.36 (t, J=7.03 Hz, 3H), 1.38 (t, J=7.03 Hz, 3H), 2.33 (dd, J=14.06, 8.35 Hz, 1H), 2.43-2.61 (m, 2H), 2.80-2.97 (m, 1H), 3.11-3.24 (m, 1H), 3.79 (d, J-13.19 Hz, 1H), 4.09 (d, J=13.19 Hz, 1H), 4.25-4.43 (m, 4H), 7.17 (dd, J=8.35, 2.20 Hz, 1H), 7.40-7.50 (m, 2H). MS(ESI)(Pos) m/z; 514 (M+Na)+

[CX]D = +36.0° (CHC13, c=0.5)
(lR,2S,3R,5R,6R)-2-azide-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester:
1 H-NMR (200 MHz, CDC13, TMS); 1.36 (t, J=7.03 Hz, 3H), 1.39 (t, J=7.03 Hz, 3H),
2.33-2.58 (m, 3H), 2.86-3.05 (m, 1H), 3.53 (dd, J=11.21, 8.13 Hz, 1H), 4.24-4.46 (m,
6H), 7.28 (dd, J=8.35, 2.20 Hz, 1H), 7.44-7.56 (m, 2H).
MS(ESI)(Pos)m/z; 530 (M+Na)+
[a]D29 = +7.9° (CHC13, c=0.7)
(2) By means of the same method as Reference Example 2(5), 41 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfinyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester was yielded from 61 mg of
(lR,2S,3R,5R,6R)-2-azide-3-(3,4-dichlorobenzylsulfinyl)-6-fluorobicyclo[3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.34 (t, J=7.0 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H), 2.30-2.43 (m, 3H), 2.78-3.12 (m, 2H), 3.80 (d, J=13.2 Hz, 1H), 4.19-4.36 (m, 5H), 7.17 (dd, J=8.4, 2.2 Hz, 1H), 7.44 (d, J=8.4 Hz, 1H), 7.44 (d, J=2.2 Hz, 1H). MS(ESI)(Pos)m/z; 488 (M+Na)+ [a]D29 = +59.1° (CHCb, c=0.32)
(3) By means of the same method as Reference Example 2(6), 17 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfinyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d was yielded from 38 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfinyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (300 MHz, D20, TMSP); 2.16-2.29 (m, 2H), 2.44-2.49 (m, 1H), 2.77-2.88 (m, 1H), 3.44-3.53 (m, 1H), 4.05 (d, J=13.1 Hz, 1H), 4.26 (d, J=13.1 Hz, 1H), 7.29 (d, J=8.5 Hz, 1H), 7.56 (s, 1H), 7.60 (d, J=8.5 Hz, 1H). MS(ESI)(Nega)m/z; 408 (M-H)' [a]D25 = +79.7° (IN NaOH, c=0.30)
REFERENCE EXAMPLE 4
Synthesis of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexan e-2,6-dicarboxylic aC1d

(1) By means of the same method as Reference Example 2(5), 169 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester was yielded from 190 mg of
(lR,2S,3R,5R,6R)-2-azide-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester.
JH-NMR (200 MHz, CDC135 TMS); 1.34 (t, J=7.0 Hz, 3H), 1.36 (t, J=7.0 Hz, 3H), 2.28-2.42 (m, 3H), 2.83-3.01 (m, 1H), 3.41-3.53 (m, 1H), 4.23-4.37 (m, 6H), 7.28 (dd, J=8.4, 1.8 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.55 (d, J=1.8 Hz, 1H). MS(ESI)(Pos)m/z; 482 (M+H)+ [a]D29 = +24.0° (CHC13, c=0.86)
(2) 108 mg of (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfonyl)
-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester was stirred in 1.08
mL of 60% sulfuric aC1d (W/V%) for 3 days at 130°C. The reaction solution was
ice-cooled, and neutralized with an aqueous solution of 5N sodium hydroxide. The
mixture was stirred for 1 hour at room temperature, and then purified by ion exchange
resin (AG 50W-X8 Resin (H form), eluent: water, a 30% aqueous solution of
tetrahydrofuran, and a 10% aqueous solution of pyridine), thereby yielding 76 mg of
(lR,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d.
'H-NMR (300 MHz, D20, TMSP); 2.33-2.45 (m, 3H), 2.82-2.94 (m, 1H), 3.98 (dd, J=10.1, 9.48 Hz, 1H), 4.55 (d, J=15.2 Hz, 1H), 4.60 (d, J=15.3 Hz, 1H), 7.37 (d, J=8.4 Hz, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.64 (s, 1H). MS(ESI)(Nega)m/z; 424 (M-H)" [ REFERENCE EXAMPLE 5
Synthesis of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane -2,6-dicarboxylic aC1d
(1) 0.89 mL of a 1M trimethylphosphine/tetrahydrofuran solution was added to 245 mg of (lR,2R,3S,5R,6R)-2-azide-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d diethyl ester dissolved in 7.0 mL of tetrahydrofuran and 0.7 mL of water, and the

mixture was stirred for 12 hours at room temperature. The mixture was diluted with 14 mL of diethyl ether, and after a saturated aqueous solution of sodium hydrogen carbonate was added thereto, the mixture was stirred for 1 hour at room temperature. After separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gehWako gel C200, eluent: chloroform-ethanol=50:l), thereby yielding 163 mg of (1R,2R,3S,5R,6R) -2-amino-6-fluoro -3-hydroxybicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d diethyl ester.
*H-NMR (200 MHz, CDC13, TMS); 1.32 (t, J-7.25 Hz, 6H), 2.07-2.23 (m, 2H), 2.41 (dd, J=8.13,3.30Hz, 1H), 2.71-2.91 (m, 1H), 4.10-4.41 (m, 5H). MS(ESI)(Pos) m/z; 276 (M+H)+ [a]D25 = +2.8°(CHCl3, c=1.5)
(2) 0.8 mL of a saturated aqueous solution of sodium hydrogen carbonate and 152 mg of
di-t-butyldicarbonate were added to 160 mg of (1R, 2R, 3S, 5R, 6R) -2-amino
-6-fluoro-3 -hydroxybicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester dissolved
in 0.8 mL of tetrahydrofuran, and the mixture was stirred for 4 hours at room
temperature. The reaction solution was extracted twice with ethyl acetate. The organic
layers were combined, washed with a saturated aqueous solution of sodium chloride,
and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the
filtrate was concentrated under reduced pressure. The residue was purified by column
chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate-2:l), thereby
yielding 214 mg of (1R, 2R, 3S, 5R, 6R) -2-t-butoxycarbonylamino-
6-fluoro-3-hydroxybicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.29 (t, J=7.03 Hz, 3H), 1.30 (t, J=7.03 Hz, 3H),
1.44 (s, 9H), 2.20-2.48 (m, 3H), 2.77-2.98 (m, 2H), 4.07-4.48 (m, 4H), 5.57 (s, 1H).
MS(ESI)(Pos)m/z; 398 (M+Na)+
[a]D22 = -14.0o(CHCl3,c=0.9)
(3) By means of the same method as Reference Example 2(1), 1.65 g of
(lR,2R,3S,5R,6R)-2-/-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bi
cyclo[3.1.0]hexane-2,6-dicarboxylic aC1d diethyl ester was yielded from 1.47 g of
(lR,2R,3S,5R,6R)-2-t-butoxycarbonylamino-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2
,6-dicarboxylic aC1d diethyl ester.

!H-NMR (200 MHz, CDC13, TMS); 1.25-1.41 (m, 6H), 1.44 (s, 9H) 2.13-2.26 (m, 1H),
2.40-2.57 (m, 2H), 2.97-3.20 (m, 1H), 4.14-4.47 (m, 4H), 5.32 (s, 1H), 5.99 (d, J=8.35
Hz, 1H).
MS(ESI)(Nega)m/z; 506 (M-H)"
[a]D28 - +79.8° (CHC13, c=0.5)
(4) 313 mg of sodium azide was added to 1.63 g of (IR, 2R, 3S, 5R, 6R)
-2-r-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3.1.0]
hexane-2,6-dicarboxylic aC1d diethyl ester dissolved in 16.3 mL of N,N-
dimethylformamide, and the mixture was stirred for 1 hour at room temperature, and
then for 20 hours at 35°C. 104 mg of sodium azide was further added thereto, and the
mixture was stirred for 18 hours at 35°C. After being diluted with 50 mL of diethyl ether,
the mixture was washed twice with water and then with a saturated aqueous solution of
sodium chloride. The organic layers were dried over anhydrous sodium sulfate. After
the desiccant was filtured off, the filtrate was concentrated under reduced pressure. The
residue was purified by column chromatography (silica gel: Wako gel C200, eluent:
hexane-ethyl acetate=5:l), thereby yielding 775 mg of (IR, 2R, 3R, 5R, 6R)
-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d
diethyl ester.
*H-NMR (200 MHz, CDC13, TMS); 1.29 (t, J-7.03 Hz, 3H), 1.33 (t, J=7.03 Hz, 3H), 1.45 (s, 9H), 2.21-2.56 (m, 3H), 2.92 (dd, J=7.69, 2.42 Hz, 1H), 3.78-3.88 (m, 1H), 4.17-4.41 (m,4H), 5.01 (s, 1H). MS(ESI)(Pos) m/z; 423(M+Na) [a]D26 = +0.79° (CHC13, c=1.4)
(5) By means of the same method as Reference Example 5(1), 553 mg of (IR, 2R, 3R,
5R, 6R) -3-amino-2-t-butoxycarbonylamino-6-fluorobicyclo [3.1.0] hexane
-2,6-dicarboxylic aC1d diethyl ester was yielded from 725 mg of (IR, 2R, 3R, 5R, 6R)
-3-azido-2-t-butoxycarbonylamino-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d
diethyl ester.
*H-NMR (200 MHz, CDC13, TMS); 1.30 (t, J=7.03 Hz, 3H), 1.32 (t, J=7.03 Hz, 3H), 1.44 (s, 9H), 2.06-2.27 (m, 2H), 2.40-2.55 (m, 1H), 2.61-2.72 (m, 1H), 3.28-3.47 (m, 1H), 4.17-4.41 (m, 4H), 5.05 (s, 1H). MS(ESI)(Pos) m/z; 397 (M+Na)+ [a]D27 = -14.20(CHCl3,c=1.4)

(6) 42 μL of pyridine and 123 mg of 3,4-dichlorobenzylbromide were added to 175 mg
of (1R,2R,3R,5R,6R) -3-amino-2-t-butoxycarbonylamino -6-fluorobicyclo[3.1 .OJhexane
-2,6-dicarboxylic aC1d diethyl ester dissolved in 0.88 mL of chloroform at ice-cooling,
and the mixture was stirred for 3 days at room temperature. A saturated aqueous
solution of sodium chloride was added thereto, and the mixture was extracted five times
with chloroform. The organic layers were combined and then dried over anhydrous
sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under
reduced pressure. The residue was purified by column chromatography (silica gel:Wako
gel C200, eluent:chloroform-ethanol=100:l to 50:1, followed by hexane-ethyl
acetate=5:l), thereby yielding 98 mg of (1R, 2R, 3R, 5R, 6R)
-2-t-butoxycarbonylamino3- (3,4-dichlorobenzylamino)-6-fluorobicyclo [3.1.0]
hexane-2,6-dicarboxylic aC1d diethyl ester.
!H-NMR (200 MHz, CDC13, TMS); 1.23-1.34 (m, 6H), 1.44 (s, 9H), 2.03-2.26 (m, 2H), 2.43 (dd, J-12.97, 7.25 Hz, 1H), 2.83-2.93 (m, 1H), 3.02-3.15(m, 1H), 3.71 (d, J=13.19 Hz, lH),3.80(d, J=13.19Hz, 1H), 4.12-4.39 (m, 4H), 4.82 (s, 1H), 7.11 (dd, J=8.13, 1.98 Hz, 1H), 7.33-7.45 (m, 2H). MS(ESI)(Nega)m/z; 531 (M-H)' [a]D27 = -15.1°(CHCl3,c=0.5)
(7) 2.8 mL of a 4N hydrogen chloride/ethyl acetate solution was added to 28 mg of
(lR,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluorobicy
clo[3.1.0]hexane-2,6-dicarboxylic aC1d diethyl ester, and the mixture was stirred for 6
hours at ice-cooling, and further stirred for 18 hours at room temperature. The reaction
solution was ice-cooled, and then neutralized with a saturated aqueous solution of
sodium hydrogen carbonate, followed by separation. The aqueous layer was extracted
with ethyl acetate. The organic layers were combined, washed with saturated aqueous
solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the
desiccant was filtured off, the filtrate was concentrated under reduced pressure, thereby
yielding 21 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.31 (t, J=7.0 Hz, 3H), 1.34 (t, J=6.2 Hz, 3H), 2.03-2.28 (m, 3H), 2.35-2.51 (m, 1H), 2.94-3.08 (m, 1H), 3.77 (s, 2H), 4.16-4.40 (m, 4H), 7.12 (d, J=7.9 Hz, 1H), 7.35 (d, J=7.9 Hz, 1H), 7.40 (s, 1H). MS(ESI)(Pos)m/z, 433 (M+H)+ [a]D24=-8.4°(CHCl3,c=0.56)

(8) By means of the same method as Reference Example 2(6), 17 mg of (lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo[3.1.0]hexane -2,6-dicarboxylic aC1d was yielded from 28 mg of (1R, 2R, 3R, 5R, 6R) -2-amino-3-(3,4-dichlorobenzylamino)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester.
JH-NMR (300 MHz, D20, TMSP); 2.31-2.77 (m, 4H), 3.59-3.74 (m, 1H), 4.06 (d, J=13.5 Hz, 1H), 4.15 (m, J=13.5 Hz, 1H), 7.35 (d, J=7.77 Hz, 1H), 7.58-7.64 (m, 2H). MS(ESI)(Nega) 375 (M-H)-[a]D27= -14.6° (INNaOH, c=0.29)
REFERENCE EXAMPLE 6
Synthesis of (1R,2R,3R,5R,6R) -2-amino-3 -[N,N-(3,4-dichlorobenzyl)methylamino] -6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d
(1) 71 mg of potassium carbonate and 64 JIL of methyl iodide were added to 136 mg of
(lR,2R,3R,5R,6R)-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluorobicy
clo[3.1.0]hexane-2,6-dicarboxylic aC1d diethyl ester dissolved in 1.36 mL of
N,N-dimethylformamide, and the mixture was stirred for 3 days at room temperature. A
saturated aqueous solution of sodium thiosulfate was added thereto, and the mixture was
extracted twice with ethyl acetate. The organic layers were combined, washed with a
saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium
sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced
pressure. The residue was purified by column chromatography (silica gel: Wako gel
C200 (made by Wako Pure Chemical Industries Ltd.), eluent: hexane-ethyl acetate=5:l),
thereby yielding 126 mg of (1R,2R,3R,5R,6R) -2-t-butoxycarbonylamino
-3-[N,N-(3,4-dichlorobenzyl)methylamino] -6-fluorobicyclo [3.1.0]hexane
-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (200 MHz, CDC13, TMS); 1.28 (t, J=7.03 Hz, 3H), 1.29 (t, J=7.03 Hz, 3H), 1.43 (s, 9H), 2.11 (s, 3H), 2.16-2.58 (m, 3H), 2.80-3.07 (m, 2H), 3.29 (d, J-13.62 Hz, 1H), 3.78 (d, J=13.62 Hz, 1H), 4.05-4.43 (m, 4H), 4.86 (s, 1H), 7.08 (dd, J-8.35, 1.76 Hz, 1H), 7.31-7.41 (m,2H). MS(ESI)(Pos)m/z; 547 (M+H)+ [a]D25=-51.90(CHCl3, c=0.5)

(2) By means of the same method as Reference Example 5(7), 96 mg of
(lR,2R,3R,5R?6R)-2-amino-3-[N9N-(3,4-dichlorobenzyl)methylamino]-6-fluorobicyclo
[3.1.0]hexane-2,6-dicarboxylic aC1d diethyl ester was yielded from 124 mg of
(lR,2R,3R,5R,6R)-24-butoxycarbonylamino-3-|TS[9N-(3,4-dichlorobenzyl)methylamino
]-6-fluorobicyclo[3.1.0]hexane-2,6 JH-NMR (300 MHz, CDC13, TMS); 1.33 (t, J=7.0 Hz, 3H), 1.35 (t, J=7.0 Hz, 3H), 2.06
(s, 3H), 2.03-2.21 (m, 1H), 2.23-2.60 (m, 3H), 2.68-2.84 (m, 1H), 3.22 (d, J=14.1 Hz,
1H), 3.97 (d, J=14.1 Hz, 1H), 4.18-4.32 (m, 4H), 7.07 (dd, J=8.1, 2.0 Hz, 1H), 7.30-7.39
(m, 2H).
MS(ESI)(Pos)m/z; 447 (M+H)+
[a]D23 = -24.9° (CHC13, c=0.84)
(3) By means of the same method as Reference Example 2(6), 62 mg of
(lR,2R,3R,5R,6R)-2-amino-3-[N,N-(3,4-dichlorobenzyl)methylamino]-6-fluorobicyclo
[3.1.0]hexane-2,6-dicarboxylic aC1d was yielded from 94 mg of
(lR,2R,3R,5R,6R)-2-amino-3-[(3,4-dichlorobenzyl)methylamino]-6-fluorobicyclo[3.1.0
]hexane-2,6-dicarboxylic aC1d diethyl ester.
!H-NMR (300 MHz, D20, TMSP); 2.31-2.41 (m, 1H), 2.45-2.53 (m, 1H), 2.64 (s, 3H), 2.73-2.82 (m, 2H), 3.72-3.82(m, 1H), 4.01 (d, J=13.4 Hz, 1H), 4.27 (d, J=13.4 Hz, 1H), 7.35-7.41 (m, 1H), 7.61-7.69 (m, 2H). MS(ESI)(Nega)m/z; 389 (M-H)" [a]D24 = -35.2° (INNaOH, c=0.51)
REFERNCE EXAMPLE 7
Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoylamino) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d
(1) 7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to 17 mg of (1R, 2R, 3R, 5R, 6R) -3-amino-2-t-butoxycarbonylamino-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethyl ester dissolved in 0.17 mL of chloroform, and the mixture was stirred for 3 hours at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, eluent: chloroform-ethanol= 100:1), thereby yielding 21 mg of (1R, 2R, 3R, 5R, 6R) -2-t-butoxycarbonylamino -3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d

diethyl ester
*H-NMR (200 MHz, CDC13, TMS); 1.19 (t, J=7.03 Hz, 3H), 1.31 (t, J=7.25 Hz, 3H), 1.41 (s, 9H), 2.21-2.64 (m, 3H), 2.82-2.91 (m5 1H), 4.07-4.37 (m, 4H), 4.58-4.75 (m, 1H), 6.20 (s, 1H), 6.39-6.50 (m, 1H), 7.46-7.57 (m, 2H), 7.80-7.85 (m, 1H). MS(ESI)(Nega)m/z; 545 (M-H)~
[a]D23= +12.1° (CHC13, c=0.9)
(2) By means of the same method as Reference Example 5(7), 85 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester was yielded from 107 mg of (1R,2R,3R,5R,6R)
-2-t-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo[3.1.0]hexane-
2,6-dicarboxylic aC1d diethyl ester.
*H-NMR (200 MHz, CDC13, TMS); 1.30 (t, J-6.8 Hz, 3H), 1.33 (t, J=7.0 Hz, 3H), 2.09-2.43 (m, 3H), 2.53-2.38 (m, 1H), 4.19-4.38 (m, 4H), 4.52-4.71 (m, 1H), 7.48-7.55 (m,2H), 7.75-7.84 (m,lH). MS(ESI)(Pos)m/z; 469 (M+Na)+ [a]D27 = +8.3° (CHC13, c=0.93)
(3) By means of the same method as Reference Example 2(6), 24 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d was yielded from 48 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzoylamino)-6-fluorobicyclo[3.1.0]hexan
e-2,6-dicarboxylic aC1d diethyl ester.
'H-NMR (300 MHz, D20, TMSP); 2.33-2.42 (m, 2 H), 2.57-2.67 (m, 2 H), 4.46-4.55 (m, 1H), 7.58-7.68 (m, 2H), 7.87-7.90 (m, 1H). MS(ESI)(Nega)m/z; 389 (M-H)" [a]D28 = +6.0° (CHC13, c=0.34)
REFERENCE EXAMPLE 8
Synthesis of (1R,2R;3R,5R,6R)- 2-amino-3-(3,4-dichlorobenzoyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d
(1) 234 mg of 3,4-dichlorobenzoyl chloride was added to 202 mg of (lR,2R,3R,5R56R)-2-azide-6-fluoro-3-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 2-benzyl ester 6-ethyl ester dissolved in 3.7 mL of pyridine, and the mixture was

stirred for 28 hours at room temperature under a nitrogen atmosphere. 100 mL of ethyl acetate was added to the reaction solution, and the ethyl acetate solution was washed with a saturated aqueous solution of copper sulfate and with water, and then dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, eluent: hexane-ethyl acetate=10:l), thereby yielding 298 mg of (1R,2R,3R,5R,6R) -2-azide -3-(3,4-dichlorobenzoyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 2-benzyl ester 6-ethyl ester. *H-NMR (200 MHz, CDC13); 1.35 (t, J=7.3 Hz, 3H), 2.35-2.55 (m, 3H), 2.77-2.87 (m, 1H), 4.31 (q, J=7.3 Hz, 2H), 5.24-5.46 (m, 3H), 7.28-7.60 (m, 6H), 7.90-8.20 (m, 2H). MS(ESI)(Pos)m/z; 558 (M+Na)+
(2) By means of the same method as Reference Example 2(5), 218 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzoyloxy)-6-fluorobicyclo[3.1.0]hexane-
2,6-dicarboxylic aC1d 2-benzyl ester 6-ethyl ester was yielded from 298 mg of
(lR,2R,3R,5R,6R)-2-azide-3-(3,4-dichlorobenzoyloxy)-6-fluorobicyclo[3.1.0]hexane-2,
6-dicarboxylic aC1d 2-benzyl ester 6-ethyl ester.
]H-NMR (200 MHz, CDC13, TMS); 1.33 (t, J=7.3 Hz, 3H), 2.25-2.80 (m, 4H), 4.28 (q,
J=7.3 Hz, 2H), 5.05-5.13 (m, 1H), 5.16 (d, J=12.3 Hz, 1H), 5.31 (d, J=12.3 Hz, 1H),
7.24-7.36 (m, 5H), 7.44 (d, J=8.4 Hz, 1H), 7.57 (dd, J=8.4, 2.20 Hz, 1H), 7.90 (d, J=2.2
Hz, 1H).
MS(ESI)(Pos)m/z; 532 (M+Na)+
[a]D22= +31.8° (CHC13, c=0.55)
(3) 15 mg of 5% palladium carbon was added to 218 mg of (1R,2R,3R,5R,6R)
-2-amino-3-(3,4-dichlorobenzoyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic
aC1d 2-benzyl ester 6-diethyl ester dissolved in 10 mL of ethanol, and the mixture was
stirred for 50 minutes at room temperature under a hydrogen atmosphere. After the
palladium carbon was filtured off through celite, the filtrate was concentrated under
reduced pressure, and the obtained solids were dissolved in a mixture of 2 mL of
tetrahydrofuran and 1 mL of water. 10 mg of lithium hydroxide monohydrate was added
thereto at ice-cooling, and the mixture was stirred for 30 minutes. 0.5 mL of IN
hydrochloric aC1d was further added thereto, and after being diluted to 50mL with water,
the mixture was purified by ion exchange resin (AG 50W-X8 Resin (H form), eluent:
water, a 40% aqueous solution of tetrahydrofuran and a 10% aqueous solution of
pyridine), thereby yielding 25 mg of (1R, 2R, 3R, 5R, 6R) -2-amino

-3-(3,4-dichlorobenzoyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylicaC1d. *H-NMR (300 MHz, D20, TMSP); 2.40-2.45 (m? 2H), 2.71-2.77 (m5 2H), 5.28-5.36 (m, 1H)5 7.68 (d, J=8.5 Hz, 1H), 7.89 (d, J=8.5 Hz, 1H), 8.16 (s, 1H). MS(ESI)(Nega)m/z; 390 (M-H)-[a]D28 = +9.2° (MeOH, c=0.23)
EXAMPLE 1
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2, 6-dicarboxylic aC1d 6-methyl ester hydrochloride.
0.65 mL of thionyl chloride was added to 800 mg of (1R,2R,3R,5R,6R) -2-amino-3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d suspended in 8 mL of methanol at ice-cooling, and the mixture was stirred for 4 hours at 50°C. The mixture was further stirred for 3 hours at room temperature, and methanol was distilled under reduced pressure. After 20 mL of hexane was added to the residue, the mixture was stirred for 2 hours, and then the solids were filtured. The solids were washed with diisopropyl ether and hexane, thereby yielding 820 mg of (lR,2R,3R55R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic aC1d 6-methyl ester hydrochloride.
EXAMPLE 2
Synthesis of (1R,2R.3R,5R,6R) -2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-pentyl ester
225 \iL of thionyl chloride was added to 300 mg of (1R,2R,3R,5R,6R) -2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d suspended in 4 mL of pentanol at ice-cooling, and the mixture was stirred for 3 hours at 50°C. After standing to cool, the reaction solution was concentrated to about 1 mL under reduced pressure, 200 mL of hexane was added thereto, and the mixture was stirred for 12 hours. After the preC1pitated solids were filtured, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), thereby yielding 188 mg of (lR,2R,3R,5R,6R)-2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo[3.1.0] hexane-2,6-dicarboxylic aC1d 6-pentyl ester.

EXAMPLE 3
Synthesis of (1R,2R,3R,5R,6R) -2-amino-3- (3,4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethoxycarbonylmethyl ester.
4.4 mg of lithium hydroxide hydrate was added to 36 mg of (1R,2R,3R,5R,6R) -2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.L0]hexane-2?6-dicarboxylic aC1d suspended in a mixture of 0.8 mL of tetrahydrofuran and 0.4 mL of water at room temperature, and the mixture was stirred for 10 minutes. After the mixture was concentrated under reduced pressure, 0.36 mL of N,N-dimethylformamide and 21 μL of ethyl bromoacetate were added to the residue, and then the mixture was stirred for 2 hours at room temperature, 2 hours at 50°C and 4 hours at 90°C. Water was added thereto, and the reaction solution was extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. After the desiccant was filtured off, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (silica gel: 60 F 254 (made by Merck & Co.Jnc), eluent: hexane-ethyl acetate=l:l), thereby yielding 12 mg of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fiuorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d diethoxycarbonylmethyl ester.
EXAMPLE 4
Synthesis of (1R,2R,3R,5R,6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-(2-azidoethyl) ester
6 mg of sodium azide was added to 18 mg of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d 6-(2-iodoethyl) ester dissolved in a mixture of 0.2 mL of N,N-dimethylformamide and 0.02 mL of water at room temperature, and the mixture was stirred for 12 hours at 60°C. After standing to cool, the solvent was distilled under reduced pressure, and the residue was purified by reverse phase column chromatography (Wako gel 50C18, eluent: water to a 70% aqueous solution of acetonitrile), thereby yielding 7 mg of (1R,2R,3R,5R,6R) -2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 6-(2-azidoethyl) ester

EXAMPLE 5
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-(2-aminoethyl) ester
20 ΜL of a IM trimethylphosphine/tetrahydrofuran solution was added to 6 mg of (lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic aC1d 6-(2-azidoethyl) ester dissolved in a mixture of 0.15 mL of tetrahydrofuran and 0.02 mL of water at room temperature, and the mixture was stirred for 13 hours. After the solvent was distilled under reduced pressure, the residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.), eluent: water to a 50% aqueous solution of acetonitrile), and the obtained solids were further washed with tetrahydrofuran, thereby yielding 2 mg of
(lR52R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic aC1d 6-(2-aminoethyl) ester.
The structure and pysical data of the compounds described in Examples 1, 2, 3, 4 and 5, as well as those of compounds yielded by means of the same methods are shown in table 1 below.





















EXAMPLE 6
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-carboxylate 6-diethylcarbamoylmethyl ester

6.7 mL of saturated sodium hydrogen carbonate was added to 740 mg of (lR52R53R,5R,6R)-2-amino-3-(354-dichlorobenzyl)-6-fluorobicyclo[3.1.0]hexane-2,6-di carboxylic aC1d suspended in 2.6 mL of dioxane, and the mixture was stirred for 10 minutes at room temperature. 0.41 mL of allyl chloroformate was added dropwise thereto, and the solution was stirred for 12 hours at room temperature. After 2.6 mL of water was added to the reaction solution, the aqueous layer was washed with ethyl acetate, aC1dified with IN hydrochloric aC1d in an ice bath, and then extracted twice with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, thereby yielding 930 mg of
(lR,2R,3R,5R,6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo [3.1.0]hexane-2,6-dicarboxylic aC1d.
]H-NMR (300 MHz, CD3OD, TMS); 2.15-2.53 (m, 3 H) 2.89-3.01 (m, 1 H) 4.06-4.19 (m, 1 H) 4.46 (d, J=11.7 Hz, 1 H) 4.55 (d, J=4.8 Hz, 1 H) 4.71 (d, J=11.7 Hz, 1 H) 5.16-5.20 (m, 1 H) 5.29-5.36 (m, 1 H) 5.89-5.99 (m, 1 H) 7.22 (dd, J=8.2, 2.0 Hz, 1 H) 7.44 (d, 7=8.2 Hz, 1 H) 7.48 (d, .7=2.0 Hz, 1 H) MS(ESI)(Nega)m/z; 460 (M~H)"
(2)


A mixture of 380 mg of (1R,2R,3R,5R,6R) -2-allyloxycarbonylamino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d, 109 mg of paraformaldehyde and 8 mg of paratoluenesulfonic aC1d monohydrate dissolved in 10 mL of benzene was heated to reflux for 3.5 hours using a Dean-Stark distillation trap. After standing to cool, the mixture was diluted with ethyl acetate, and the ethyl acetate solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure, thereby yielding 370 mg of (rR,2'R,3'R,5'R,6'R) -3'-(3,4-dichlorobenzyloxy) -6'-fluoro -3-allyloxycarbonyl -5-oxo-oxazolidinone -4-spiro-2'-bicyclo [3.1.0] hexane -6'-carboxylate.
!H-NMR (300 MHz, CDC13, TMS); 2.07-2.54 (m, 4 H) 4.17-4.24 (m, 1 H) 4.39 (d, 7=12.3 Hz, 1 H) 4.52 (d, .7=12.3 Hz, 1 H) 4.63 (d, 7=6.2 Hz, 2 H) 5.23 (d, 7=4.4 Hz, 1 H) 5.28-5.54 (m, 2 H) 5.53 (d, 7=4.5 Hz, 1 H) 5.85-5.98 (m, 1 H) 7.07 (dd, 7=8.2, 1.9 Hz, 1 H) 7.32 (d, 7=1.9 Hz, 1 H) 7.41 (d, 7=8.2 Hz, 1 H). MS(ESI)(Nega)m/z; 472 (M-H)"

37 mg of potassium carbonate and 37 lyL of N,N-diethylchloroacetoamide were added
to 58 mg of (l'Rly'Rly'Rly'Rly'R) -3'-(3,4-dichlorobenzyloxy) -6'-fluoro
-3-allyloxycarbonyl -5-oxo-oxazolidinone -4-spiro-2'-bicyclo [3.1.0]
hexane-6'-carboxylate dissolved in 2 mL of N,N-dimethylformamide, and the mixture

was stirred for 15 hours at room temperature. After the mixture was diluted with ethyl
acetate, the ethyl acetate layer was washed with water and with a saturated aqueous
solution of sodium chloride, and then dried over anhydrous sodium sulfate. After the
drying agent was filtured off, the filtrate was concentrated under reduced pressure, and
the residue was purified by column chromatography (silica gel: silica gel 60N (Kanto
Chemical Co., Inc), eluent: hexane-ethyl acetate=l:2), thereby yielding 60 mg of
(l'R,2'R,3'R,5'R,6'R) -3'-(3,4-dichlorobenzyloxy) -6'-fluoro -3-allyloxycarbonyl
-5-oxo-oxazolidinone -4-spiro-2'-bicyclo [3.1.0] hexane-6'-carboxylate
6-(N,N-diethylaminocarbonylmethyl) ester.
]H-NMR (300 MHz, CDC13, TMS); 1.12 (t, 7=7.23Hz, 3 H) 1.23 (t, 7=7.2 Hz, 3 H) 2.21-2.60 (m, 4 H) 3.23 (q, 7=7.2 Hz, 2 H) 3.38 (q, 7=7.2 Hz, 2 H) 4.19-4.27 (m, 1 H) 4.38 (d, 7=12.3 Hz, 1 H) 4.52 (d, 7=12.3 Hz, 1 H) 4.63-4.65 (m, 2 H) 4.74 (d, 7=14.1 Hz, 1 H) 4.85 (m, 7=14.1 Hz, 1 H) 5.23 (d, 7=4.3 Hz, 1 H) 5.24-5.33 (m, 2 H) 5.51 (d, 7=4.3 Hz, 1 H) 5.87-6.00 (m, 1 H) 7.07 (dd, 7=8.2, 2.0 Hz, 1 H) 7.31 (d, 7=2.0 Hz, 1 H) 7.40 (d, 7=8.2 Hz, 1H). MS(ESI)(Pos)m/z; 609 (M+Na)+
(4)

46 mg of 1,3-dimethylbarbituric aC1d and 4 mg of tetrakis (triphenylphosphine) palladium were added to 58 mg of (rR,2'R,3'R,5'R,6'R) -3'-(3,4-dichlorobenzyloxy) -6'-fluoro -3-allyloxycarbonyl -5-oxo-oxazolidinone -4-spiro-2'-bicyclo [3.1.0]hexane -6' -carboxylate-6 -(N,N-diethylaminocarbonylmethyl)ester dissolved in chloroform under a nitrogen atmosphere, and the mixture was stirred for 1.5 hours at 40°C. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was stirred for 1 hour at room temperature. After the preC1pitated solids were filtured off, the filtrate was concentrated under reduced pressure and the obtained residue was purified by reverse phase chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent: water to a 50% aqueous

solution of acetonitrile), and then the obtained solids were further washed with ethyl acetate, thereby yielding 5 mg of (1R,2R,3R,5R,6R) -2-amino-3 -(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-carboxylic aC1d -6-(N,N-diethylaminocarbonylmethyl) ester.
EXAMPLE 7
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-(4-fluorobenzyl)ester

23 (J.L of thionyl chloride was added to 30 mg of
(lR52R,3R?5R56R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,
6-dicarboxylic aC1d suspended in 0.3 mL of 4-fluorobenzyl alcohol at room temperature,
and the mixture was stirred for 3 days at 60°C. After standing to cool, the reaction
solution was purified by reverse phase chromatography (Wako gel 50C18 (made by
Wako Pure Chemical Industries Ltd.) eluent: water, a 70% aqueous solution of
acetonitrile), thereby yielding 5 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic aC1d 6-(4-fluorobenzyl)ester.
The structure and physical data of the compounds described in Examples 6 and 7, as well as those of compounds yielded by means of the same methods are shown in table 2 below.














EXAMPLE 8
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)
-6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d 6-(3-methyl) butyl ester
1.0 mL of thionyl chloride was added to 1.50 g of (1R, 2R, 3R ,5R, 6R) -2-amino -3-(3, 4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d suspended in 20 mL of 3-methylbutanol at ice-cooling, and the mixture was stirred for 3 hours at 70°C. After standing to cool, 3-methylbutanol was distilled under reduced pressure. 15 mL of ethanol and 15 mL of propyleneoxide were added to the residue, and the mixture was heated to redux for 1 hour. After standing to cool, the mixture was diluted with diethyl ether, and the preC1pitated solids were filtured. The solids were washed with water, diisopropyl ether and hexane, thereby yielding 1.01 g of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-(3-methyl)-n-butyl ester.

EXAMPLE 9
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)
-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-(6-methyl) heptyl ester
0.4 mL of thionyl chloride was added to 1.00 g of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d suspended in 10 mL of 6-methyl-l-heptanol at ice-cooling, and the mixture was stirred for 6 hours at 80°C. After standing to cool, the insoluble matter was filtured off, and the filturate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.) eluent: water to a 70% aqueous solution of acetonitrile). The obtained solids were recrystalized from ethanol:water, thereby yielding 557 mg of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d 6-(6-methyl) heptyl ester.
The structure and physical data of the compounds described in Examples 8 and 9, as well as those of compounds yielded by means of the same methods are shown in table 3 below.
Table 3 The structure and physical data of the compounds described in Examples 8 and 9






EXAMPLE 10
Synthesis of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)
-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 2-butyl ester 6-ethyl ester and (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d 2-butyl ester
(1) By means of the same method as Example 1, 2.96 g of (lR,2R,3R?5R56R)-2-amino-3-(3?4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-23 6-dicarboxylic aC1d 6-ethyl ester hydrochloride was yielded from 4.00 g of (lR,2R,3R?5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2, 6-dicarboxylic aC1d.
(2) 400 mg of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-ethyl ester hydrochloride was added to a mixture of 5 mL of ethanol and 5 mL of propyleneoxide, and the mixture was heated to redux for 2.5 hours. After standing to cool, the preC1pitated solids were filtured, and the solids were washed with diethyl ether and then recrystallized from water: ethanol, thereby yielding 230 g of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane -2,6-dicarboxylic aC1d 6-ethyl ester.
(3) 2 mL of saturated sodium hydrogen carbonate was added to 200 mg of
(1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0]
hexane -2,6-dicarboxylic aC1d 6-ethyl ester suspended in 1 mL of dioxane, and the
mixture was stirred for 10 minutes at room temperature. 0.18 mL of allyl chloroformate
was added thereto, and the solution was stirred for 8 hours at room temperature. After
the reaction solution was aC1dified with 1 mL of IN hydrochloric aC1d, 10 mL of water
was added thereto, and the mixture was extracted twice with ethyl acetate. The ethyl
acetate layers were combined, dried over anhydrous sodium sulfate and concentrated
under reduced pressure, and the obtained residue was dissolved in 20 mL of
N,N-dimethylformamide. 141 mg of 1-iodobutane and 106 mg of potassium carbonate
were added to the solution, and the mixture was stirred for 16 hours at room
temperature. Water was added thereto, and the reaction solution was extracted twice
with ethyl acetate. After the ethyl acetate layers were combined and dried over

anhydrous sodium sulfate, the solvent was distilled under reduced pressure and purified by column chromatography (silica gel: Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:l), thereby yielding 159 mg of (1R,2R,3R,5R,6R) -2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 2-butyl ester 6-ethyl ester.
]H-NMR (300 MHz, CDC13? TMS) 0.89 (3 H, t, 7-7.4 Hz), 1.24 - 1.43 (5 H, m), 1.56 -1.66 (2 H, m), 2.22 - 2.51 (3 H, m), 2.93 - 3.00 (1 H, m), 3.81 - 3.89 (1 H, m), 4.08 -4.65 (8 H, m), 5.16 - 5.37 (3 H, m), 5.84 - 5.98 (1 H, m), 7.09 (1 H, dd, 7-8.2, 2.0 Hz), 7.37 (1 H, d, J=2.0 Hz), 7.40 (1 H, d, J=8.2 Hz)
(4) 81 mg of 1,3-dimethylbarbituric aC1d and 12 mg of tetrakis (triphenylphosphine)
palladium were added to 190 mg of (1R,2R,3R,5R,6R) -2-allyloxycarbonylamino
-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 2-butyl
ester 6-ethyl ester dissolved in chloroform under a nitrogen atmosphere, and the mixture
was stirred for 1 hour at 50°C. The reaction solution was concentrated under reduced
pressure, and the obtained residue was purified by column chromatography (silica gel:
Kanto Chemical silica gel 60 (spherical), eluent: hexane-ethyl acetate=5:l), thereby
yielding 180 mg of (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)
-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 2-butyl ester 6-ethyl ester.
(5) 15 mg of lithium hydroxide monohydrate was added to 131 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,
6-dicarboxylic aC1d 2-butyl ester 6-ethyl ester dissolved in 2 mL of tetrahydrofuran and 1
mL of water, and the mixture was stirred for 1.5 hours at room temperature. After 2 mL
of IN hydrochloric aC1d was added thereto, the reaction solution was concentrated under
reduced pressure, and the obtained residue was purified by reverse phase
chromatography (Wako gel 50C18 (made by Wako Pure Chemical Industries Ltd.)
eluent: water to a 40% acetonitrile solution), thereby yielding 37 mg of
(lR,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,
6-dicarboxylic aC1d 2-butyl ester.
The structure and physical data of the compound described in Example 10, as well as those of compounds yielded by means of the same method are shown in table 4 below.


TEST EXAMPLE 1
Measurement of the amount of exposure in vivo from the plasma concentration in rat
The amount of exposure in vivo was measured, for example, according to the following methods. Compounds 1, 4 and 10 of the present invention and the parent compounds of compounds 1, 4 and 10 of the present invention where in formula [IV], X represents a fluorine atom and Y represents a 3,4-dichlorobenzyloxy group, were orally administered to rat, and then the plasma concentration of the parent compound of the present invention was measured, compared and investigated as shown below. Also, by means of the same method, compound 44 of the present invention and the parent compound of compound 44 were orally admistered to rat, and then the plasma concentration of the parent compound of compound 44 of the present invention was measured, compared

and examined.
7-week-old rat (240-280g, male, strain CD(SD)IGS) obtained from Charles River Japan, Inc. habituated for more than 2 days was used as the test subject. The compound of the present invention was dissolved in 0.03N hydrochloric aC1d containing 10% HP-p -CD, adjusted to a concentration of 2 mg/mL, and then 10 mg/kg of the mixture was orally administered to rat. 1 hour and 2 hours later, blood was collected from the caudal vein with a blood collecting tube (with EDTA) and immediately centrifuged (lOOOOxg, 4°C, 10 minutes), thereby extracting the plasma for the plasma sample. The plasma sample was frozen and stored at -80°C and below. While still being cooled on ice, the plasma sample was melted, methanol solution was added thereto as an internal standard substance, and after the sample was deproteinized and then centrifuged (lOOOOxg, 4°C, 10 minutes), the concentration of the parent compound of the compound of the present invention in the supernatant was measured by LC/MS/MS.
As shown in the table below, the administration of the compound of the present invention resulted in a significantly higher plasma concentration of the parent compound of the compound of the present invention, and the amount of exposure in vivo was increased.
i ■ ■ ■
* Compound A (the parent compound of compound 1, 4 and 10 of the present
invention): (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)
-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d
* 2Compound 1 of the present invention: (1R,2R,3R,5R,6R) -2-amino

-3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic aC1d 6-methyl ester
* 3Compound 4 of the present invention: (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 6-n-butyl ester
* 4Compound 10 of the present invention: (1R,2R,3R,5R,6R) -2-amino -3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic aC1d 6-benzyl ester
*5Compound B (the parent compound of compound 44 of the present invention): (1S,2R,3R,5R,6S) -2-amino -3-(3,4-dichlorobenzyloxy) -bicyclo[3.1.0]hexane -2,6-dicarboxylic aC1d
* 6Compound 44 of the present invention: (1R,2R,3R,5R,6R) -2-amino
-3-(3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic
aC1d 6-(l-(cyclohexyloxycarbonyloxy)ethyl)ester
INDUSTRIAL APPLICABILITY
The compound of the present invention, a pharmaceutically acceptable salt thereof or a hydrate thereof may be employed as a prodrug of a metabotropic glutamate receptor antagonist, and thus can significantly increase the amount of exposure in vivo of the parent compound.
Therefore, the present invention makes it possible to provide a drug which is effective for the treatment and prevention of psychiatric disorders such as schizophrenia, anxiety and related ailments thereof, bipolar disorder and epilepsy; for the treatment and prevention of neurological diseases such as drug dependence, cognitive disorders, Alzheimer's disease, Huntington's chorea, Parkinson's disease, dyskinesia assoC1ated with muscular rigidity, cerebral ischemia, cerebral failure, myelopathy and head trauma; and for relieving convulsions, pain and nausea. The drug shows high activity in oral administration, which is preferable from the point of usability and mediC1nal benefits.


CLAIMS
1. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof, represented by formula [I]

[wherein,
R' and Rz are identical or different, and each represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1.10alkyl group, a C1-10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1_10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaR (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group), a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii]; or,


1 ")
in the case where either R or R represents a hydrogen atom, the other represents a C1_10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1_10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC1_10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z, Rc and Rd are the same as described above), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii];

X represents a hydrogen atom or a fluorine atom; and

Y represents -OCHR3R4, -SR3, -S(0)nR5, -SCHR3R4, -S(0)nCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3R4'), -NHCOR3 or -OCOR5 (wherein R3, R3, R4 and R are identical or different, and each represents a hydrogen atom, a C1-10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R5 represents a C1-10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; and n represents integer 1 or 2)]
2. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutical^ acceptable salt thereof or a hydrate thereof, represented by formula [II]

[wherein,
R1 and R2 are identical or different, and each represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a C1.10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group, a C1_10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rbare identical or different, and each represents a hydrogen atom or a C1-10alkyl group), a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group, and Rd represents a

C1-10 oalkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula [i]

(wherein R is the same as described above) or a group represented by formula [ii]; or,

in the case where either R or R represents a hydrogen atom, the other represents a C1-10alkyl group, a C2-10aIkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-i oalkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10 oalkyl group, a C1-10alkoxyC1-10 oalkyl group, a C1-10 oalkoxycarbonyl oalkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group, a C1-10 oalkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z, Rc and Rd are the same as described above), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii];


X represents a hydrogen atom or a fluorine atom; and
Y represents -OCHR3R4, -SR3, -S(0)nR5, -SCHR3R4, -S(0)nCHR3R4, -NHCHR3R4, -N(CHR3R4)(CHR3R4'), -NHCOR3 or -OCOR5 (wherein R3, R3', R4 and R are identical or different, and each represents a hydrogen atom, a C1.10alkyl group, a C1-10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substituted by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1.10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R5 represents a C1-10alkyl group, a C1_10alkenyl group, a phenyl group, a naphthyl group, a naphthyl group substitute by one to seven halogen atoms, a heteroaromatic group or a phenyl group substituted by one to five substituents selected from a group consisting of a halogen atom, a phenyl group, a C1_10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; and n represents integer 1 or 2)]
3. A2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula
[ii],
i •>
R' and Rz are identical or different, and each represents a C1-10alkyl group, a
C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two phenyl groups, a hydroxyC2-10alkyl group, a halogenoC1-10oalkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group or a Q.10alkoxycarbonylC1-10alkyl group; or,
in the case where either R1 or R2 represents a hydrogen atom, the other represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group

substituted by one or two phenyl groups, a hydroxyC2-10alkyl group, a halogenoC1-10Oalkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1-10alkyl group or a C1-10OalkoxycarbonylC1-10alkyl group.
4. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutical^
acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula
[ii],
R and R are identical or different, and each represents a C1.10alkyl group, a C2-6alkenyl group, a C2_6alkynyl group, a C1-6alkyl group substituted by one or two phenyl groups, a hydroxyC2-6alkyl group, a halogenoC1-6alkyl group, an azidoC1-6alkyl group, an aminoC2-6alkyl group, a C1-6alkoxyC1-ealkyl group or a C1-6alkoxycarbonylC1-ealkyl group; or,
in the case where either R or R represents a hydrogen atom, the other represents a C1-ealkyl group, a C2-6alkenyl group, a C2-6alkynyl group, a C1-6alkyl group substituted by one or two phenyl groups, a hydroxyC2-6alkyl group, a halogenoC1-6alkyl group, an azidoC1-6alkyl group, an aminoC2-6alkyl group, a C1-6alkoxyC1-6alkyl group or a C i _6alkoxycarbonylC i -ealkyi group
5. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically
acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula
[II],
R and R are identical or different, and each represents a farnesyl group, a C1-10alkyl
group substituted by one or two aryl groups, a C1-10alkoxycarbonylC1-10alkyl group, a
4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by
formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a
hydrogen atom or a C1-10alkyl group), a group represented by formula-CHRcOC(0)ZR
(wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond;
Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl
group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a
group represented by formula [i]


(wherein R is the same as described above) or a group represented by formula [ii]; or,

in the case where either R or R represents a hydrogen atom, the other represents a farnesyl group, a C1.10alkyl group substituted by one or two aryl groups, a C1_10alkoxycarbonylC1_10alkyl group, a 4-morpholinylC1-10alkyl group, a C1.10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rbare the same as described above), a group represented by formula-CHRcOC(0)ZRd (wherein Z, Rc and Rd are the same as described above), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].


6. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II],
R and R are identical or different, and each represents a farnesyl group, a C1-6alkyl group substituted by one or two aryl groups, a C1-6alkoxycarbonylC].6alkyl group, a 4-morpholinylC1-6alkyl group, a C1_6alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Raand Rb are identical or different, and each represents a hydrogen atom or a C1-6alkyl group), a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-ealkyl group, a C2-6alkenyl group or an aryl group; and Rd represents a C1-6alkyl group, a C2-6alkenyl group or an aryl group), a group represented by formula [i]

(wherein Rd is the same as described above) or a group represented by formula [ii]; or,

in the case where either R1 or R2 represents a hydrogen atom, the other represents a farnesyl group, a C -ealkyl group substituted by one or two aryl groups, a C1-6alkoxycarbonylC1.6alkyl group, a 4-morpholinylC1.6alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are the same as described above), a group represented by formula-CHRcOC(0)ZR (wherein Z,RC and Rd are the same as described above), a group represented by formula [i]


(wherein Rd is the same as described above) or a group represented by formula [ii].

7. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom.
8. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; and X represents a fluorine atom.
9. A 2-amino-bicyclo[3,1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], wherein R represents a hydrogen atom; and X represents a hydrogen atom.
10. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; and Y represents -OCHR3R4 (wherein R3 and R4 are the same as described above).

11. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R2 represents a hydrogen atom; X represents a fluorine atom; and Y represents -SCHR3R4 (wherein R3 and R4 are the same as described above).
12. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; and Y represents -SR3 (wherein R3 is the same as described above).
13. A 2-amino-bicyclo[3.1.0]hexane-2?6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; and Y represents -S(0)nCHR3R4 (wherein R3, R4 and n are the same as described above).
14. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; and Y represents -NHCHR3R4 (wherein R3 and R4 are the same as described above).
15. A 2-amino-bicyclo[3.1.0]hexane~2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
I*. wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; and Y represents -N(CHR3R4)(CHR3R4') (wherein R3, R3', R4 and R4' are the
same as described above).
16. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], represents a hydrogen atom; X represents a hydrogen atom; and Y represents -OCHR R (wherein R and R are the same as described above).
17. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], represents a hydrogen atom; X represents a hydrogen atom;

and Y represents -SCHR3R4 (wherein R3 and R4 are the same as described above).
18. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], represents a hydrogen atom; X represents a hydrogen atom; and Y represents -SR (wherein R is the same as described above).
19. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; and Y represents -S(0)nCHR3R4 (wherein R3, R4 and n are the same as described above).
20. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], wherein R represents a hydrogen atom; X represents a hydrogen atom; and Y represents -NHCHR3R4 (wherein R and R4 are the same as described above).
21. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; and Y represents -N(CHR3R4)(CHR3R4) (wherein R3, R3', R4 and R4' are the same as described above).
22. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R2 represents a hydrogen atom; X represents a fluorine
1 A 1 A
atom; Y represents -OCHR R (wherein R and R are the same as described above); and R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1.10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1.10alkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1.10alkyl group, a C1.10alkoxycarbonylC1.]0alkyl group, a farnesyl group, a 4-morpholinylC1_10alkyl group or a C1.10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1.10alkyl group).

23. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -OCHR3R4 (wherein R3 and R4 are the same as described above); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an
oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen
atom, a C1.joalkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a
C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rdis the same as described above) or a group represented by formula [ii].

24. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative pharmaceutical^
acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula
[II], R2 represents a hydrogen atom; X represents a fluorine atom; Y represents
-SCHR3R4 (wherein R3and R4are the same as described above); and
R1 represents a C1-10alkyl group, a C2_]0alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10Oalkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1-10alkyl group, a C1-10OalkoxycarbonylC1-i0alkyl group, a farnesyl group, a

4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10Oalkyl group).
25. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -SCHR R (wherein R and R are the same as described above); and
R represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an
oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen
atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a
C]_10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rdis the same as described above) or a group represented by formula [ii]

26. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R2 represents a hydrogen atom; X represents a fluorine
atom; Y represents-SR3 (wherein R3 is the same as described above); and
R1 represents a C1-10Oalkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10Oalkyl

group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10Oalkyl group, an aminoC2-i0alkyl group, a C1-i0alkoxyC1-10Oalkyl group, a C1-10alkoxycarbonylC1-i0alkyl group, a farnesyl group, a 4-morpholinylC1-100alkyl group or a C1-10Oalkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-i0alkyl group).
27 A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -SR (wherein R is the same as described above); and R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1_10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1_10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii]

28. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,

■J
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -S(0)nCHR3R4 (wherein R3, R4 and n are the same as described above); and
R1 represents a C1.10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1_10alkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1_10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
29. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -S(0)nCHR3R4 (wherein R3,R4 and n are the same as described above); and
R1 represents a group represented by formula-CHRcOC(0)ZR (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].


30. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
1 A 1 A
atom; Y represents -NHCHR R (wherein R and R are the same as described above); and
R represents a C1.10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1_10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1_10alkyl group, an azidoC1.10alkyl group, an aminoC2-10alkyl group, a C1_10alkoxyC1-10alkyl group, a C1-10alkoxycarbonylC1_10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
31. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -NHCHR3R4 (wherein R3 and R4 are the same as described above);
and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1_10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1_10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]


(wherein R is the same as described above) or a group represented by formula [ii].

32. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -N(CHR3R4)(CHR3R4) (wherein R3, R3', R4and R4are the same as
described above); and
R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1_10alkyl group, a C1_10alkoxycarbonylC1_10alkyl group, a farnesyl group, a 4-morpholinylC1.10alkyl group or a C1_10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1_10alkyl group).
33. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -N(CHR3R4)(CHR3R4) (wherein R3; R3', R4and R4are the same as
described above); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an

oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein R is the same as described above) or a group represented by formula [ii].

34. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents-OCHR R (wherein R and R are the same as described above); and R1 represents a C1.10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1_10alkyl group, a C1-10alkoxycarbonylC1.10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
35. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,

wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents-OCHR3R4 (wherein R3 and R4 are the same as described above); and R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].

36. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents -SCHR3R4 (wherein R3 and R4 are the same as described above); and R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1.10alkyl group, an aminoC2-10^lkyl group, a C1-10alkoxyC1-10alkyl group or a C1_10alkoxycarbonylC]_10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group, a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1.10alkyl group).

37. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -SCHR3R4 (wherein R3 and R4 are the same as described above); and
R represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an
oxygen atom, a nitrogen atom, a sulfur atom or a single bond, Rc represents a hydrogen
atom,C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a
C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii],

38. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -SR (wherein R is the same as described above); and
R1 represents a C1-10Oalkyl group, a C2-10alkenyl group, a C2_i0alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10Oalkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10Oalkyl group, a C1-10OalkoxycarbonylC1-10oalkyl group, a farnesyl group, a

4-morpholinylC1-10alkyl group, or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
39. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents-SR (wherein R is the same as described above); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1.10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1_10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii].

40. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -S(0)nCHR3R4 (wherein R3, R4 and n are the same as described
above); and

R represents a C1-10Oalkyl group, a C2-10alkenyl group, a C2_10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1.10alkoxyC1-10alkyl group, a C1-10alkoxycarbonylC1-10oalkyl group, a farnesyl group, a 4-morpholinylC1.10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1.10alkyl group).
41. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutical^ acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
T A *"1 A
atom; Y represents -S(0)nCHR R (wherein R , R and n are the same as described above); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom,C1_10alkyl group, a C2-10alkenyl group or an aryl group; and Rdrepresents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].


42. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -NHCHR3R4 (wherein R3 and R4 are the same as described above);
and
R represents a C1-10alkyl group, a C2-10alkenyl group, a C2_10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1.10alkyl group, an azidoC1-10alkyl group, an aminoC2_10alkyl group, a C1.10alkoxyC1-10alkyl group, a C1-10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1_10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
43. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -NHCHR3R4 (wherein R3 and R4 are the same as described above);
and
R1 represents a group represented by formula-CHRcOC(0)XRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii].


44. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Yrepresents -N(CHR3R4)(CHR3R4') (wherein R3, R3', R4and R4are the same as
described above); and
R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC1_10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
45. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Yrepresents -N(CHR3R4)(CHR3R4') (wherein R3, R3', R4and R4'are the same as
described above); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom,C1_10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1_10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]


(wherein Rd is the same as described above) or a group represented by formula [ii].

46. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivativea pharmaceutically
acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula
[II], R represents a hydrogen atom; X represents a fluorine atom; Y represents
-OCHR R (wherein R represents a hydrogen atom; R represents a phenyl group or a
phenyl group substituted by one to five substituents selected from a group coonsisting
of a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a
trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a
nitro group, a cyano group and a phenoxy group); and
R1 represents a C1-10alkyl group, a d-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1_10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
47. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], represents a hydrogen atom; X represents a fluorine atom; Y

*J A 1 A
represents -OCHR R (wherein R represents a hydrogen atom; R represents a phenyl group or a phenyl group substituted by one to five substutuents selected from a group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1.joalkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1.10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].

48. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR3R4 (wherein R3 represents a hydrogen atom; R4 represents a naphthyl group, a heteroaromatic group or a naphtyl group substituted by one to seven halogen atoms); and
R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a

halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1.joalkoxyC1-10alkyl group, a C1-10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1.joalkyl group or a C1_10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1.10alkyl group).
49. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine
atom; Y represents -OCHR R (wherein R represents a hydrogen atom, R represents a
naphthyl group, a heteroaromatic group or a naphtyl group substituted by one to seven
halogen atoms); and
R1 represents a group represented by formula-CHRcOC(0)XRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii].

50. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a

pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR3R4 (wherein R3 and R4 are identical or different, and each represents a phenyl group or a phenyl group substituted by one to five substutuents selected from a group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1.10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group); and R represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a d-10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
51. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR3R4 (wherein R3 and R4 are identical or different, and each represents a phenyl group or a phenyl group substituted by one to five substutuents selected from a group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group); and R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].


52. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -OCHR R4 (wherein R3 represents a hydrogen atom; R4 represents a
phenyl group or a phenyl group substituted by one to five substutuents selected from a
group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy
group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino
group, a nitro group, a cyano group and a phenoxy group); and
R1 represents a C1-10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1_10alkyl group substituted by one or two aryl groups, a hydroxyC2-10a!kyl group, a halogenoC1.10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1_10alkoxyC]-10alkyl group, a C1-10alkoxycarbonylC1-10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
53. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -OCHR3R4 (wherein R3 represents a hydrogen atom; R4 represents a
phenyl group or a phenyl group substituted by one to five substutuents selected from a
group containing a halogen atom, a phenyl group, a C1_10alkyl group, a C1-10alkoxy
group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino
group, a nitro group, a cyano group and phenoxy group); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen

atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula [i]
(wherein Rdis the same as described above) or a group represented by formula [ii]

54. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a
pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2,
wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen
atom; Y represents -OCHR3R4 (wherein R3 represents a hydrogen atom; R4 represents a
naphthyl group, a heteroaromatic group or a naphtyl group substituted by one to seven
halogen atoms); and
R1 represents a C1_10alkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1.10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC]_10alkyl group, a farnesyl group, a 4-morpholinylC1.10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
55. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a

pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents -OCHR3R4 (wherein R3 represents a C1-10alkyl group; and R4 represents a naphthyl group); and
R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10oalkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]

(wherein Rd is the same as described above) or a group represented by formula [ii].

56. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents -OCHR3R4 (wherein R3 and R4 are identical or different, and each represents a phenyl group or a phenyl group substituted by one to five substutuents selected from a group containing a halogen atom, a phenyl group, a C1-10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group); and R1 represents a C1-10Oalkyl group, a C2-10alkenyl group, a C2-10alkynyl group, a C1-10alkyl

group substituted by one or two aryl groups, a hydroxyC2-10alkyl group, a halogenoC1-10alkyl group, an azidoC1-10alkyl group, an aminoC2-10alkyl group, a C1-10alkoxyC1-10alkyl group, a C1_10alkoxycarbonylC1_10alkyl group, a farnesyl group, a 4-morpholinylC1-10alkyl group or a C1-10alkyl group substituted by a group represented by formula-C(0)NRaRb (wherein Ra and Rb are identical or different, and each represents a hydrogen atom or a C1-10alkyl group).
57. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [II], R represents a hydrogen atom; X represents a hydrogen atom; Y represents -OCHR3R4 (wherein R3 and R4 are identical or different, and each represents a phenyl group or a phenyl group substituted by one to five substutuents selected from a group containing a halogen atom, a phenyl group, a C1_10alkyl group, a C1-10alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group); and R1 represents a group represented by formula-CHRcOC(0)ZRd (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; Rc represents a hydrogen atom, a C1-10alkyl group, a C2-10alkenyl group or an aryl group; and Rd represents a C1-10alkyl group, a C2-10alkenyl group or an aryl group), a group represented by formula
[i]
(wherein Rd is the same as described above) or a group represented by formula [ii].


58. A drug comprising the 2-amino-bicyclo [3.1.0] hexane -2,6-dicarboxylic ester
derivative, the pharmaceutical^ acceptable salt thereof or the hydrate thereof according
to any one of claim 1 to 57 as an active ingredient.
59. A drug according to claim 58, wherein the drag is a group II metabotropic glutamate
receptor antagonist.


Documents:

3529-CHENP-2005 CORRESPONDENCE OTHERS.pdf

3529-CHENP-2005 CORRESPONDENCE PO.pdf

3529-CHENP-2005 FORM-13.pdf

3529-CHENP-2005 FORM-3.pdf

3529-CHENP-2005 PETITIONS.pdf

3529-CHENP-2005 POWER OF ATTORNEY.pdf

3529-chenp-2005 abstract duplicate.pdf

3529-chenp-2005 claims duplicate.pdf

3529-chenp-2005 description (compelet) duplicate.pdf

3529-chenp-2005-abstract.pdf

3529-chenp-2005-claims.pdf

3529-chenp-2005-correspondnece-others.pdf

3529-chenp-2005-description(complete).pdf

3529-chenp-2005-form 1.pdf

3529-chenp-2005-form 18.pdf

3529-chenp-2005-form 3.pdf

3529-chenp-2005-form 5.pdf

3529-chenp-2005-pct.pdf

abs-3529-chenp-2005.jpg

abs-3529.jpg


Patent Number 229603
Indian Patent Application Number 3529/CHENP/2005
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 18-Feb-2009
Date of Filing 26-Dec-2005
Name of Patentee TAISHO PHARMACEUTICAL CO., LTD
Applicant Address 24-1, Takada 3-chome, Toshima-ku, Tokyo 170-8633,
Inventors:
# Inventor's Name Inventor's Address
1 YASUHARA, Akito c/o Taisho Pharmaceutical Co., Ltd., 24-1, Takada 3-chome, Toshima-ku, Tokyo 170-8633,
2 SAKAGAMI, Kazunari c/o Taisho Pharmaceutical Co., Ltd., 24-1, Takada 3-chome, Toshima-ku, Tokyo 170-8633,
3 OHTA, Hiroshi c/o Taisho Pharmaceutical Co., Ltd., 24-1, Takada 3-chome, Toshima-ku, Tokyo 170-8633,
4 NAKAZATO, Atsuro c/o Taisho Pharmaceutical Co., Ltd., 24-1, Takada 3-chome, Toshima-ku, Tokyo 170-8633,
PCT International Classification Number C07C229/50
PCT International Application Number PCT/JP04/09398
PCT International Filing date 2004-06-25
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 2003-181930 2003-06-26 Japan
2 2003-373511 2003-10-31 Japan
3 2004-128663 2004-04-23 Japan