ZA200510124B

ZA200510124B - 2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative

Info

Publication number: ZA200510124B
Application number: ZA200510124A
Authority: ZA
Inventors: Yasuhara Akito; Sakagami Kazunari; Ohta Hiroshi; Nakazato Atsuro
Original assignee: Taisho Pharmaceutical Co Ltd
Priority date: 2003-06-26
Filing date: 2005-12-13
Publication date: 2006-11-29
Also published as: ES2355144T3; CN1812960A; CN100582087C

Description

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 mGluR2/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 (mGIluR2/mGIuR3) 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. Sci., 14, 13.1993

It 1s 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 discases 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 1

X ee

Y 2

H,N COOR [1]

@ [ wherein,

R' and R? are identical or different, and each represents a C).jalkyl group, a

Ca.10alkenyl group, a Ca.j0alkynyl group, a Cj jealkyl group substituted by one or two aryl groups, a hydroxyC;.jalkyl group, a halogenoCj. palkyl group, an azidoC,.jgalky] group. an aminoCs.jpalkyl group, a Ci.0alkoxyCy.jalkyl group, a

Cy.0alkoxycarbonylC.jgalkyl group. a famesyl group, a 4-morpholinylC_jgalkyl group, a Cy.joalkyl group substituted by a group represented by formula-C(O)NR?R® (wherein

R? and RP are identical or different, and each represents a hydrogen atom or a Cyypalkyl group), a group represented by formula-CHR‘OC(0)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a Cy. oalkyl group, a C,.jpalkenyl group or an aryl group; and RY represents a

Ci.0alkyl group, a Cs.jgalkenyl group or an aryl group), a group represented by formula (1] oi 0 =o

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

O

\

AY

FY

[ii] in the case where either R} or R? represents a hydrogen atom, the other represents a

Ci.oalkyl group, a Cj.jpalkenyl group, a C,.jpalkynyl group, a Ci.joalkyl group substituted by one or two aryl groups, a hydroxyC,.jpalkyl group, a halogenoC,_ alkyl group, an azidoCj.jpalkyl group, an aminoC,.jealkyl group, a Ci.10alkoxyC. alkyl group, a Cy jealkoxycarbonylCy.jpalkyl group, a famesyl group, a @ 4-morpholinylCj. alkyl group, a C,.jpalky! group substituted by a group represented by formula-C(O)NR®R® (wherein R® and R® are the same as described above), a group represented by formula-CHR‘OC(O)ZR? (wherein Z, R® and RY are the same as described above), a group represented by formula [i] -! O =o

RI“ TO [i] (wherein Ris the same as described above) or a group represented by formula [ii).

O

\

A

[ii]

X represents a hydrogen atom or a fluorine atom. Y represents -OCHR’R?, -SR?, -S(0)nR>, -SCHR’R?, -S(0),CHR’R*, -NHCHR’R?, -N(CHR?R*)(CHR>R*), -NHCOR? or -OCOR? (wherein R3, R?, R’and R* are identical or different, and each represents a hydrogen atom, a C,.jealkyl group, a Cy oalkenyl 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 C,.jealkyl group, a Ci.1palkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R’ represents a Cj_jpalkyl group, a

Cj.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 Cy.jpalkyl group, a C).jpalkoxy 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 [1],

R' and R? are identical or different, and each represents a C,palkyl group, a

Cs.0alkenyl group, a Cy.jpalkynyl group, a Ci.ioalkyl group substituted by one or two phenyl groups, a hydroxyCs.jpalkyl group, a halogenoCj.jpalky] group, an azidoCy.jpalkyl group, an aminoC.jpalky! group, a Cy.10alkoxyC).palky! group or a

Ci.0alkoxycarbonylC,_galkyl group; or, in the case where either R' or R? represents a hydrogen atom, the other represents a

Ci.ioalkyl group, a C,.palkenyl group, a Cj.joalkynyl group, a C;.jpalkyl group substituted by one or two phenyl groups, a hydroxyCs.jpalkyl group, a halogenoC,_jpalkyl group, an azidoC,.jpalkyl group, an aminoCj.jpalkyl group, a

Ci.10alkoxyCy.0alkyl group or a C).10alkoxycarbonylC_jpalkyl group.

In another aspect of the present invention, it is preferred that in formula (11,

R' and R? are identical or different, and each represents a famesyl group, a Cy. jpalkyl group substituted by one or two aryl groups, a Ci.joalkoxycarbonylC,. palkyl group, a 4-morpholinylC,.jealkyl group, a Cy.jealkyl group substituted by a group represented by formula-C(O)NRR® (wherein R? and R® are identical or different, and each represents a hydrogen atom or a C,_jpalkyl group), a group represented by formula-CHROC(0)ZR* (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond;

R® represents a hydrogen atom, a Cj.jgalkyl group, a Cy. jalkenyl group or an aryl group; and R? represents a Ci.10alkyl group, a Cy.jealkenyl group or an aryl group), a group represented by formula [i] i 0 !

RI” TO

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

O ry *\

FEY

[ii] in the case where either R' or R? represents a hydrogen atom, the other represents a farnesyl group, a Cj.jealkyl group substituted by one or two aryl groups, a

Ci.10alkoxycarbonylC,.jealkyl group, a 4-morpholinylC;.jpalkyl group, a C,.jalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R? and R® are the same as described above), a group represented by formula-CHR°OC(0)ZR* (wherein Z, R° and R%are the same as described above), a group represented by formula

[1] > O =o

RI” O [i] (wherein R?is the same as described above) or a group represented by formula [ii]; 0) a) *

FY

[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 [1], Y represnts -OCHR’RY, -SR’, -SCHR’R®, -S(0),CHRR’. -NHCHR’R' or -N(CHR’R*)(CHR*R*) (wherein rR’, RY, R*and R* are the same as described above).

In another aspect of the present invention, it is preferred that in formula [1]. Y represents -SR’, -SCHR’R?, -$(0),CHR’R", -NHCHRR’ or -N(CHR’R*)(CHR®* R*) (wherein R?,

R®, R*and R* are the same as described above).

It is preferred that in formula [I], R’, R*, R* and R* 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 C,_palkyl group, a Cj jpalkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbony! group, an amino group, a nitro group, a cyano group and a phenoxy group. Of the above, it is more preferred that

R?, R*, R*and R* each independently represents a hydrogen atom, a phenyl! group, a naphthyl group or a phenyl group substituted by one to five halogen atoms.

In a further aspect of the present invention, it is preferred that in formula [1], R' and R? each independently represents a hydrogen atom, a Cy.jpalkyl group, a C,.salkenyl group, a Cyealkynyl group, a Cjealkyl group substituted by one or two phenyl groups, a hydroxyC,.¢alkyl group, a halogenoC,alkyl group, an azidoC, alkyl group, an aminoC,alkyl group, a Cj¢alkoxyCi.ealkyl group or a CjealkoxycarbonylC, ¢alkyl group. Of the above, it is more preferred that R? represents a hydrogen atom and R' represents a straight-chain or branched chain Cj.jpalkyl group, C,.calkenyl group, or

Ci.salkyl group substituted by one or two phenyl groups.

Further, in another aspect of the present invention, it is preferred that in formula [1], R! and R? each independently represents a hydrogen atom, a famnesyl group, a Cgalkyl group substituted by one or two aryl groups, a C.calkoxycarbonylC, alkyl group, a 4-morpholinylCi.ealkyl group, a C).jealkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R* and R® are the same as described above), a group represented by formula-CHR°OC(0)ZR? (wherein Z,R and R% are the same as described above). a group represented by formula [1] ~! O )=o0

RY O

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

O

®)

A

[ii]

Of the above, it is more preferred that R? represents a hydrogen atom; and R' represents a farnesyl group, a Cjealkyl group substituted by one or two unsubstituted or : substituted phenyl groups, a Ci.salkoxycarbonylCj_¢alkyl group, a 4-morpholinylC, alkyl group, a C).jqalky! group substituted by a group represented by formula-C(O)NR®R® (wherein R? and R® are the same as described above), a group represented by formula-CHR‘OC(0)ZR® (wherein Z,R® and R? are the same as described above), a group represented by formula [i] -! O =o

RY O

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

PY O

Oo aN [ii]

It is preferred that in formula [1]. R® and R” used to describe R' and R2 represent a hydrogen atom or a C,_galky] group. It is preferred that R® represents a hydrogen atom, a

Ci.ealkyl group, a C,.alkenyl group or an aryl group. And it is preferred that R° represents a Cy.qalkyl group, a Cy salkenyl group or an aryl group. The terms used in the present invention are defined as follows. C,.m means that the group following C,., has from n to m carbon atoms.

The C).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 cychce alkyl group having three to ten carbon atoms. Examples of the straight-chain alky] 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 nony) 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 I-ethylpropyl group, a 1,1-dimethylpropyl group, a 2,2-dimethylpropyl group, a 1,2-dimethylpropyl group, a 1-methylpentyl 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-cthylpentyl group, a 1-propylbuty] group, a 1,4-dimethylpentyl group, a 3,4-dimethylpentyl group, a 1,2,3-trimethylbuty] group, a l-isopropylbutyl group, a 4,4-dimethylpentyl group, a 5S-methylheptyl group, a 6-methylheptyl group, a 4-ethylhexyl group, a 2-propylpentyl group, a 2,5-dimethylhexyl group, a 4,5-dimethylhexy! group, a 2-ethyl-3-methylpentyl group, a 1,2,4-trimethylpenty! group, a 2-methyl-1-isopropylbuty] group, a 3-methyloctyl group, a 2,5-dimethylheptyl group, a 1-(1-methylpropyl)-2-methylbuty] 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-1-(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 Cy.jpalkenyl 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 I-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 Cy.jpalkynyl 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 S-hexynyl group, a 6-heptynyl group, a 7-octynyl group, a 8-nonynyl group, a 9-decinyl group, a 3-pentynyl group and a 4-methyl-2-pentynyl group.

The C,.j0alkyl group substituted by one or two ary] 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 1-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-fluorobenzy! group, a 4-fluorobenzyl group, a 2-beromobenzy! 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-dichlorobenzy! 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-ethylbenzy] 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 4-1sopropoxybenzyl group, a 2-methoxymethylbenzy! group, a 3-methoxymethylbenzyl group, a 4-methoxymethylbenzyl group, a 2-isopropyxymethylbenzyl group, a 3-1sopropyxymethylbenzyl ~~ group, a 4-isopropyxymethylbenzyl ~~ group, a 2-rifluoromethyl group, a 3-trifluoromethyl group, a 4-trifluoromethyl group, a 2-hydroxycarbonylbenzyl group, a 3-hydroxycarbonylbenzy] 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 I-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 hydroxy! group, a phenyl group,a C.ioalkyl group, a C,.jpalkoxy group, a C.jpalkoxyC).jgalkyl 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-nitropheny! 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, S-dichlorophenyl group, a 2, 6-dichlorophenyl group, a 3, 4-dichlorophenyl group, a 3, S-dichlorophenyl group, a 2-methylphenyl group. a 3-methylphenyl group, a 4-methylphenyl group, a 2-ethylphenyl group, a 3-ethylpheny] 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-methoxypheny! group, a 2, 3-dimethoxyphenyl group, a 2, 4-dimethoxyphenyl group. a 2, 5-dimethoxypheny! group, a 2, 6-dimethoxyphenyl group, a 3. 4-dimethoxyphenyl group, a 3, S-dimethoxyphenyl group, a 2-ethoxypheny! group, a 3-ethoxyphenyl group. a 4-ethoxyphenyl group, a 2-isopropoxyphenyl group, a 3-isopropoxyphenyl group, a 4-1sopropoxypheny! 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-triflucromethyl group, a 2-hydroxycarbonylphenyl group, a 3-hydroxycarbonylphenyl group, a 4-hydroxycarbonylphenyl group, a 2-aminophenyl group, a 3-aminopheny! 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-hydroxymethylpheny! group, a 4-hydroxymethylphenyl group, a 2-phenoxyphenyl group, a 3-phenoxyphenyl group and a 4-phenoxyphenyl group.

Of the above Cj palkyl groups substituted by one or two aryl groups, the Cj.jalkyl group sustituted by one or two phenyl groups is preferred.

The hydroxyCj.jpalkyl group means a Cjpalkyl 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-hydroxypropy! group, a 2,3-dihydroxypropyl group and a 2-hydroxy-3-methylbutyl group.

The halogenoC;_jpalkyl group means a Cj. jpalkyl 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 S-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 azidoC,.jpalkyl group means a Ci.i0alkyl 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-azidopropy! group, a 2-azidobutyl group and a 2-azido-3-methylbutyl group.

The aminoC,. palkyl group means aC. 0alkyl 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 C;.j0alkoxyC,. alkyl 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-cthoxypropyl group, a 4-ethoxybutyl group, a 4-ethoxy-3-methoxybutyl group and a 4-ethoxy-3-methylpentyl group.

The C,.jpalkoxycarbonylIC.jealkyl group means a alkyl group having one to ten carbons which 1s 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 methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propyloxycarbonylmethyl group, an isopropoxycarbonylmethyl group, a butyltoxycarbonylmethyl ~~ group, an isobutoxycarbonylmethyl group, a t-butoxycarbonylmethyl group, a pentyloxycarbonylmethyl group, a hexyloxycarbonylmethyl group, a 2-(ethoxycarbonyl)ethyl group, a 3-(ethoxycarbonyl)propyl group, a 4-(ethoxycarbonyl)butyl group, a 4-(ethoxycarbonyl)pentyl group and a 4-(ethoxycarbonyl)-3-methylpentyl group.

The farnesyl group means a (22.62)-3,7.11-trimethyldodeca-2,6,10-trienyl group.

The 4-morpholinylC;.galkyl 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-morpholinylhbutyl 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)nony] group, a 10-(4-morpholinyl)decyl group, a 2-(4-morpholinyl)pentyl group, and a l-methyl-3-(4-morpholinyl)butyl group.

The Cy.y0alkyl group substituted by formula C(O)NR"R® (wherein R*and R® are identical or different, and each represents a hydrogen atom or a Cy.jpalkyl group) means, for example, a 2-(N.N-dimethylaminocarbonyl)ethyl group, a 2-(N,N-diethylaminocarbonyl)ethyl group, a 3-(N.N-diethylaminocarbonyl)propy! 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 1-fluoro-2-naphthyl group, a 2-fluoro-1-naphthyl group, a 1-chloro-2-naphthyl group, a 2-chloro-1-naphthyl group, a 1-bromo-2-naphthyl group, a 2-bromo-1-naphthyl group, a 1-iodo-2-naphthyl group, a 2-10do-1-naphthyl! group, and a 1,3-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, cinnolinyl, phthalaziny, quinazolinyl and quinoxalinyl.

The Cj.i0alkoxy 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 Ci-10alky} group, a C;.jealkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbony! group, an amino group, a nitro group, a cyano group and a phenoxy group means a phenyl group substituted by one 10 five substituents selected from a fluorine atom, a chloride atom, a bromine atom. an iodine atom, a C,.jealkyl group, a cyclicCs.joalkyl group, a Cj jealkoxy group, a cyclic Cs.jpalkoxy 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-ethylpheny! 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-cyclohexyloxyphenyl group, a 4-cyclohexyloxyphenyl group, a 2-trifluoromethylphenyl group, a 3-fluoromethylphenyl group, a 4-trifluoromethylpheny! 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-cyanopheny] group, a 2-phenoxyphenyl group, a 3-phenoxyphenyl group and a 4-phenoxypheny] group. Examples of the phenyl group substituted by two substituents include a 2.3-difluorophenyl group, a 2,4-diflucropheny} 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-dibromopheny! 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-diiodopheny] group, a 2.4-diiodophenyl group, a 2.5-diodophenyl 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-fluoropheny] 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 acid such as sulfuric acid, hydrochloric acid or phosphoric acid; a salt with organic acids such as acetic acid. oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid or benzenesulfonic acid; a salt with an amine such as trimethylamine or methylamine; or a salt with a metal ion such as sodium ion, potassium ion or calcium 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 [1], 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 [I] below.

X H X

Lye 9h

NN “H

Y 9 Y PB 5

HoN COOR [1 HoN COOR [1]

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,

X H X

® [ooo Ole one

NS /

Y HN COOH [1] Y Ho COOH [IV] [wherein X represents a hydrogen atom or a fluorine atom. Y represents -OCHR’RY, -SR*-S(0),R*,-SCHR’R* -$(0),CHR’R*,-NHCHR R*,-N(CHR’R*)(CHR* R*),-NHCO

R’ or -OCOR’ (wherein R?, R*, R*and R* are identical or different, and each represents a hydrogen atom, a C,ealkyl group, a C,.jpalkenyl 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 C,.jalkyl group, a C.jpalkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R’ represents a C.jpalkyl group, a

Ci-i0alkenyl 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 {rom a group consisting of a halogen atom, a phenyl group. a Cj.jpalkyl group, a Cy.jpalkoxy 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 [IJ 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’,

R* and R’ are the same as described above. R° represents an aryl- or alkyl-sulfony] 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)methy! group; an alkenyl group such as a 5.5-dimethyl-3-oxo0-1-cyclohexenyl group; a sulfenyl group such as a benzenesulfenyl group or a 2,4-dinitrosulfenyl group; a benzylsulfonyl group; a diphenylphosphinyl group; and a dialkylphosphoryl group. A' represents formula R* or formula CHR’R®. A? represents formula R® or formula CHR’R®. And Q represents formula SR?, formula S(0).R?, formula SCHR’R? or formula S(0),CHR’RY).

X _coor! X_ coor! X_COOR!

Tq Step! off Step 2 qd

H (2) (3)

X_COOR! oi

Step 3 8 Step4 oO COOR?

No “) (5)

F_COOR!

Step 5 ol 5 non, COOR (6)

Stepl: Compound (2) may be prepared. for example, by reacting compound (1) with a trifluoromethanesulfonylation agent such as trifluoromethane sulfonic acid 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’0OH, 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 (sce 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(Il) acetate and a ligand such as triphenylphosphine or 2,2’-bis(diphenylphosphino)-1.1-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; acctonitrile; 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 cis-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: cther 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 lemperature, 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 acid 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 [111], Y represents formula OCHR3R?,

° X=H, F, Y = OCHR®R*

X _COOR! X _Coor'

X_coor! o o.

COOR? COOR? ol Step 7 be Ns Step 8 1 Ni;

HO Ns rR? R3 RA R3 (6) N (7 (8)

COOH

Step 9 oa. 0 NH

EN

(9)

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 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-acid catalyst such as trifluoromethanesulfonic acid, trifluoroacetic acid or hydrogen chloride, or a Lewis-acid 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, L' 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 R' and R? 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-dimethoxyecthane; 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 hydroxy] 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 acid.

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 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 (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 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 COOR' and formula COOR? of compound (8) into carboxylic acid 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 [111], Y represents formula SR®, formula

S(O)R”, formula SCHRR* and formula S(0),CHR’R?.

X=H, F, Y = SR? $(0),R® SCHR®R* S(0),CHR’R*

X X X _COOR!

COOR' COOR r —_— —_ 1

Kel Step 10 7, Step 11 A Ng | Nj 5

COOR? COOR? COOR (6) (10) (11)

X _COOR'’ X _COOR'

Step 12 e 7 N, Step 13 ge ,

Oo COOR? 0, COOR (12) (13)

X _COooR!' X_COOR’ X _cooH . Step 14 i. NH; Step15 . coor? COOR? coon (14) (15) (16)

Stepl0: 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 acid anhydride or N-phenyl-bis(trifluoromethanesulfonimide); or with an alkyl- or aryl-sulfonylation agent such as methanechloride sulfonic acid, benzenechloride sulfonic acid or toluenechloride sulfonic acid, 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 tricthylamine, 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 acid 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 A'SH, 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 A'SHNa, 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 A’ 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 acid 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 acid; water; or a mixture or these solvents.

Step 13: Compound (13) may be prepared from compound (12) or from compound (1 1) wherein A' 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 acid, 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 }.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 A' represents something other than a hydrogen atom. for example, by using a common oxidizing agent such as 3-chloroperbenzoic acid or hydrogen peroxide (sce 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 acid 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.

® Step15: 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 R! 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 acid 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 [111], Y represents formula NHCHR’R? or formula N(CHR’R*)(CHR? R*).

® X=H, F, Y = NHCHR®R*

X coor! X _COOR! X coor! X coor! fol Step16 A. Step? d. 7 Step18 ol 7

HO Nj , ep HO NH, ep HO HR RSO NHR

COOR COOR COOR COOR

(6) (7) (18) (19)

X 1

COOR X COOR X _COOR! —_ » —— —_ - R3

Step19 Ng —~ NHR? Step16 - NHR? Step20 WENN /_ NHR?

COOR 2% CooR? H COOR? (20) 3) (22)

Jeon X COOH

Rr? R3

Step21 RIN NHz ‘Step22 NEN —NH,

H COOR H COOH

(23) (24)

X =H, FY = N(CHR?R*)(CKRR?)

X 1

COOR

X COOR!

A A 7 - NHR 7 4

RN NAR sep20 RTONT pooRo

H COOR RAN pd (22) (25) *|_COOR' X COOH

R® rR? - — A .. PY .

RN 2 Step22 RA 2

Step21 I Coor? we REN Coon

RY ORY IAN

(26) (27)

Step 16: Compounds (17) and (21) may be prepared from compounds (6) and (20), respectively, by reducing 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 R' and R’ 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 Step10. Preferably. compound (19) may be prepared by reacting the hydroxyl group of compound (18) with trifluoromethane sulfonic acid anhydride for 30 minutes to 2 hours at -78°C to ice-cooling, in dichloromethane, in the presence of pyridine.

Step19: 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-NH, and formula-R*R*CHNH of compounds (21) and (22) with a compound of formula

R3R*CHL? or formula R*RYCHL?, 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, 1.2

Claims

® 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] X ye Y 2 H,N COOR [1 [wherein, R' and R? are identical or different, and each represents a Cj alkyl group, a

Ca.10alkenyl group, a Cy.jpalkynyl group, a C).jpalkyl group substituted by one or two aryl groups, a hydroxyC,.jpalkyl group, a halogenoC,_jealkyl group, an azidoCj.palkyl group. an aminoCpjalkyl group, a CjjoalkoxyCi.jpalkyl group, a Ci-10alkoxycarbonylC;.jgalkyl group, a farnesyl group, a 4-morpholinylC.jgalkyl group, a Cy.joalkyl group substituted by a group represented by formula-C(O)NR?R® (wherein R* and R" arc identical or different, and each represents a hydrogen atom or a Cj.jpalkyl group), a group represented by formula-CHR‘OC(O)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a Cy joalkyl group, a Cy.jpalkenyl group or an aryl group; and R represents a Ci-10alkyl group, a Cy.palkenyl group or an aryl group), a group represented by formula

[1] ~ O =O RI” TO

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

® O ro *\ FY [ii] in the case where either R' or R? represents a hydrogen atom, the other represents a Ciaoalkyl group, a Cj.jpalkenyl group. a Cy. jpalkynyl group, a Cj,palkyl group substituted by one or two aryl groups, a hydroxyC,.jgalkyl group, a halogenoC,.)galkyl group, an azidoC).jpalky] group, an aminoC,.galkyl group, a Cj.jpalkoxyCj.jpalkyl group, a Cj.jalkoxycarbonylCypalkyl group, a farnesyl group, a 4-morpholinylC, alkyl group, a C,.jpalkyl group substituted by a group represented by formula-C(O)NR°R" (wherein R* and R® are the same as described above), a group represented by formula-CHR®OC(O)ZR? (wherein Z, RS and RY are the same as described above), a group represented by formula [i] i ') =o Rd O

[1] (wherein R%is the same as described above) or a group represented by formula [ii]; O ron '\ RY [ii] X represents a hydrogen atom or a fluorine atom; and

® Y represents -OCHR’RY, -SR’. -S(O),R’, -SCHR’R', -S(0),CHR’R’, -NHCHR’R?, -N(CHR’R*)(CHR’R*)., -NHCOR® or -OCOR® (wherein R’, R, R and R* are identical or different, and each represents a hydrogen atom, a Ci. palkyl group, a Cj joalkenyl 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 Cy.jalkyl group, a C).jpalkoxy group. a trifluoromethyl! group. a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R* represents a Cy.jpalkyl group, a Cj.jpalkenyl 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 Cy jealkyl group, a

Ci.i0alkoxy 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 pharmaceutically acceptable salt thereof or a hydrate thereof, represented by formula [11] H X </ "'COOR’ wg HoN TOOR? [1] (wherein, R' and R? are identical or different, and each represents a Cj alkyl group, a

Cy.10alkenyl group, a Cj.jpalkynyl group, a Cy jpalkyl group substituted by one or two aryl groups, a hydroxyCs.jpalkyl group, a halogenoC,.jgalkyl group, an azidoC,.jpalkyl group, an aminoC,.jalkyl group, a CjalkoxyCy. alkyl group, a

Ci.0alkoxycarbonylC,.joalkyl group, a famesyl group. a 4-morpholinyiC,.galkyl group,

a C.jpalkyl group substituted by a group represented by formula-C(O)NRR® (wherein R? and RP are identical or different, and each represents a hydrogen atom or a Cj_jpalkyl group), a group represented by formula-CHR‘OC(0)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R represents a hydrogen atom, a Cy jealkyl group, a Cy jealkenyl group or an aryl group, and R* represents a

® C,.10alkyl group, a Cy. jgalkenyl group or an aryl group), a group represented by formula

~t O ! TX © RI” TO [i] (wherein R%is the same as described above) or a group represented by formula [11]; or, O Oo \ \ VERY [ii] in the case where cither R' or R? represents a hydrogen atom, the other represents a Cijealkyl group, a Cijpalkenyl group, a C,.jpalkynyl group, a Cj jpalkyl group substituted by one or two aryl groups, a hydroxyC,.jpalkyl group. a halogenoC,.;palkyl group, an azidoCj.jpalkyl group, an aminoCj.jpalkyl group, a C.jpalkoxyCi.jpalkyl group, a CjjoalkoxycarbonylC.jealkyl group, a farnesyl group, a 4-morpholinylC;.jpalkyl group, a Ci.jpalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R* and R® are the same as described above), a group represented by formula-CHR*OC(O)ZR? (wherein Z, R® and RY are the same as described above), a group represented by formula [1] ~! O =o RI" TO [i] (wherein Ris the samc as described above) or a group represented by formula [ii];

@ | . O \ AN [ii] X represents a hydrogen atom or a fluorine atom; and Y represents -OCHR’R!, -SR’, -S(O),R®, -SCHR’R!, -S(O),CHR’R’ -NHCHR’R®, -N(CHR’R*)(CHR*R"), -NHCOR® or -OCOR® (wherein R3, R®, R’ and R* are identical or different, and each represents a hydrogen atom, a C,_jpalkyl group, a Cj.jpalkenyl 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 C).jpalkyl group, a C,.jpalkoxy group, a trifluoromethy! group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group; R’ represents a Cy.joalkyl group, a C).jealkenyl 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 Ci.10alkyl group, a

Ci.i0alkoxy 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. 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 (11, R' and R’? are identical or different, and each represents a C,.jgalkyl group, a

C,.10alkenyl group, a Cy. jealkynyl group, a C).jalkyl group substituted by one or two phenyl groups, a hydroxyCs.joalkyl group, a halogenoCy.jealkyl group, an azidoCj.jpalkyl group. an aminoCy.jealkyl group, a C,.jpalkoxyC.jealkyl group or a

C.10alkoxycarbonylC,.jgalkyl group; or, in the case where either R' or R? represents a hydrogen atom, the other represents a Croalkyl group, a Ciyealkenyl group, a Cs.jalkynyl group, a C,.jalkyl group e substituted by one or two phenyl groups, a hydroxyCi.jpalkyl group, a halogenoC,.galkyl group, an azidoC).palkyl group, an aminoC,.palkyl group, a

Ci.10alkoxyCy jpalkyl group ora Cj jealkoxycarbonylC,.jpalkyl group.

4. 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

[11]. R' and R? are identical or different, and each represents a Cy.jgalkyl group, a Cy_¢alkenyl group. a Cy.ealkynyl group, a Cj alkyl group substituted by one or two phenyl groups, a hydroxyCs.¢alkyl group, a halogenoC, alkyl group, an azidoC,.ealkyl group, an aminoCs.alkyl group, a CalkoxyC.ealkyl group or a Ci.¢alkoxycarbonylC, alkyl group; or, in the casc where either R' or R? represents a hydrogen atom. the other represents a

C\.salkyl group, a C,.4alkenyl group, a Cyealkynyl group, a C,.¢alkyl group substituted by one or two phenyl groups, a hydroxyC,._galkyl group. a halogenoC, alkyl group, an azidoCy.¢alkyl group, an aminoCj.alkyl group, a Ci.ealkoxyCj.¢alkyl group or a

Ci.salkoxycarbonylC, alkyl 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

[11], R' and R? are identical or different, and each represents a farnesyl group, a Cj. galkyl group substituted by one or two aryl groups, a C).jpalkoxycarbonylC.jcalkyl group, a 4-morpholinylC.1ealkyl group, a C).jalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R?and RP are identical or different, and each represents a hydrogen atom or a C;_jpalkyl group), a group represented by formula-CHR‘OC(0)ZR* (wherein Z represents an oxygen ator, a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a Cj. jpalkyl group, a Cy.jealkenyl group or an aryl group; and R¢ represents a Cj.joalkyl group, a Cy.jpalkenyl group or an aryl group), a group represented by formula [i] i 0 go Rd O [i]

(wherein R%is the same as described above) or a group represented by formula [ii]; or, Oo ro *\ PERN [ii] in the case where either R' or R? represents a hydrogen atom, the other represents a farnesyl group, a Cj.jpalkyl group substituted by one or two aryl groups, a

Ci.joalkoxycarbonylCj_jpalkyl group, a 4-morpholinylC,.jpalkyl group, a Cj alkyl group substituted by a group represented by formula-C(O)NR*R” (wherein R? and R® are the same as described above), a group represented by formula-CHR‘OC(O)ZR® (wherein Z, R® and R? are the same as described above), a group represented by formula

[1] Zi 0 ! )=0 Rd Oo

[1] (wherein RY is the same as described above) or a group represented by formula [ii]. O O \ \ FE [ii]

® 6. 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 [11], R' and R? are identical or different, and each represents a farnesyl group. a C,.galkyl group substituted by one or two aryl groups, a Cj.salkoxycarbonylCi.¢alkyl group. a 4-morpholinylC,_ealkyl group, a C;.¢alkyl group substituted by a group represented by formula-C(O)NR"R” (wherein R?and R® are identical or different, and each represents a hydrogen atom or a Cy.alkyl group), a group represented by formula-CHR‘OC(0O)ZR* (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R represents a hydrogen atom, a C, alkyl group, a Cj.4alkenyl group or an aryl group; and R° represents a Cjealkyl group, a Cj.ealkenyl group or an aryl group), a group represented by formula [i] i 0 i RO

[1] (wherein R% is the same as described above) or a group represented by formula [ii]; or, O rn '\ FE [ii] in the case where either R' or R? represents a hydrogen atom, the other represents a farnesyl group. a Cjgalkyl group substituted by one or two aryl groups, a

C,.¢alkoxycarbonylC, ¢alkyl group, a 4-morpholinylC, ¢alkyl group, a Cy_jealkyl group substituted by a group represented by formula-C(O)NR?R® (wherein R? and RP are the same as described above), a group represented by formula-CHR*OC(O)ZR (wherein ZR and RY arc the same as described above), a group represented by formula [i]

-! O RTO

[1] (wherein R? is the same as described above) or a group represented by formula [ii]. O rn IN FE [ii]

7. A 2-amino-bicyclo[3.1.0Jhexane-2.6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thercof according to claim 2, wherein in the formula [II], R? represents a hydrogen atom.

8. A 2-amino-bicyclo[3.1.0]hexanc-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thercof or a hydrate thereof according to claim 2, wherein in the formula [11], 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 [11], 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 -OCHR’R* (wherein R* and R* 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 [I], R’ represents a hydrogen atom; X represents a fluorine atom; and Y represents -SCHR’R* (wherein R® and R* 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 -SR? (wherein R? 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 [11], R? represents a hydrogen atom; X represents a fluorine atom; and Y represents -S(0),CHR’R* (wherein R>, R* 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 -NHCHR?R* (wherein R? and R? 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, wherein in the formula [II], R? represents a hydrogen atom; X represents a fluorine atom; and Y represents -N(CHR’R*)(CHR*R*) (wherein R>. R*’, R* and R* are the same as described above).

16. A 2-amino-bicyclo[3.1.0Jhexane-2,6-dicarboxylic ~~ ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [11], 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[3.1.0Jhexane-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 -SCHR’R* (wherein R” and R* are the same as described above).

18. A 2-amino-bicyclo[3.1.0Jhexane-2.6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [11], 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),CHR’R* (wherein R3, R* 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 -NHCHR’R" (wherein R* and R* arc 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 thercof according to claim 2, wherein in the formula [II], R? represents a hydrogen atom; X represents a hydrogen atom; and Y represents -N(CHR’R*)(CHR*R*) (wherein R?, R*, R* and R* are the same as described above).

22. A 2-amino-bicyclo{3.1.0}Jhexane-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* and R* are the same as described above); and R! represents a Cy.joalkyl group, a Cy. jpalkenyl group, a Cs.jpalkynyl group, a Ci.i0alkyl group substituted by one or two aryl groups, a hydroxyC.jpalkyl group, a halogenoCj.jpalkyl group, an azidoC,.palkyl group, an aminoCj. alkyl group, a

Ci.10alkoxyC.joalkyl group, a C,.jpalkoxycarbonylC_jalkyl group, a farnesyl group, a 4-morpholinylC, palkyl group or a Cj. jpalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a C_jpalkyl group).

23. 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 [lI]. R’ represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR’R’ (wherein R* and R* are the same as described above); and R' represents a group represented by formula-CHROC(0)ZR® (wherein Z represents an oxygen atom. a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a C).jpalkyl group, a C,.jpalkenyl group or an aryl group; and R® represents a

Cy.10alkyl group, a C,.jeatkenyl group or an aryl group), a group represented by formula

[1] - O )=0 Rd O

[1] (wherein R %is the same as described above) or a group represented by formula [ii]. Oo rn ' EY [il]

24. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative pharmaceutically acceptable salt thercof or a hydrate thereof according to claim 2, wherein in the formula [11), R? represents a hydrogen atom; X represents a fluorine atom; Y represents -SCHR’R? (wherein R*and Rare the same as described above); and R! represents a C.jpalkyl group. a Cy jpalkenyl group, a Cy.jpalkynyl group, a C;_jpalkyl group substituted by one or two aryl groups, a hydroxyCa.jealkyl group, a halogenoCj.jpalkyl group, an azidoC,.jpalkyl group, an aminoC,.jealkyl group, a

Ci.i0alkoxyCy_jpalkyl group, a C,.jpalkoxycarbonylC).jpalkyl group, a famesyl group, a

® 4-morpholinylC,.jgalkyl group or a C).jpalkyl group substituted by a group represented by formula-C(O)NRR® (wherein R* and R" are identical or different, and each represents a hydrogen atom or a Cy. jpalkyl 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 [11], 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-CHR‘OC(O)ZR® (wherein Z represents an oxygen atom, a nitrogen atom. a sulfur atom or a single bond; R® represents a hydrogen atom, a C,.jalkyl group, a C.jpalkenyl group or an aryl group: and R® represents a Ci-i0alkyl group, a Cy.jealkenyl group or an aryl group), a group represented by formula

[1] i 0 )=0

RE. 0

[1] (wherein R “is the same as described above) or a group represented by formula [ii] O Oo A [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], R? represents a hydrogen atom; X represents a fluorine atom; Y represents-SR® (wherein R® is the same as described above); and R' represents a C;.jgalkyl group, a Ca.10alkenyl group. a C,.jpalkynyl group, a Ci.i0alkyl

® group substituted by one or two aryl groups, a hydroxyCj.jpalkyl group, a halogenoC,_galkyl group, an azidoC).jpalkyl group, an aminoCy.ealkyl group, a

Ci.i0alkoxyC). alkyl group, a Cy.jpalkoxycarbonylC;.jpalkyl group, a farnesyl group, a 4-morpholinylC;_ alkyl group or a C,_jgalkyl group substituted by a group represented by formula-C(O)NRR® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a C,_jpalkyl group). 27 A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxvlic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [11], R? represents a hydrogen atom; X represents a fluorine atom; Y represents -SR? (wherein R% is the same as described above); and R' represents a group represented by formula-CHR‘OC(0)ZR® (wherein Z represents an oxygen atom. a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a C,.jpalkyl group, a Cy. jpalkenyl group or an aryl group; and R® represents a

Ci.i0alkyl group, a Cy.jpalkenyl group or an aryl group). a group represented by formula

[1] t - O =o RI“ TO [i] (wherein R%is the same as described above) or a group represented by formula [ii] @) @) \ \ FE [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,

Lod - 20 05 / 1 0 ® wherein in the formula [II], R? represents a hydrogen atom; X represents a fluorine atom; Y represents -S(0),CHR’R? (wherein R*, R* and n are the same as described above); and R' represents a Cy.jalkyl group, a Cy.jealkenyl group, a Ca.jpalkynyl group, a C;.jalkyl group substituted by one or two aryl groups, a hydroxyCs.jpalky! group, a halogenoC). palkyl group, an azidoCjy.jealkyl group, an aminoCs. alkyl group. a

Ci.i0alkoxyC,. alkyl group, a Ci.0alkoxycarbonylCy.jalkyl group, a farnesyl group, a 4-morpholinylC,. alkyl group or a C, jealkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a Cy. palkyl group).

29. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thercof according to claim 2, wherein in the formula [lI], R? represents a hydrogen atom; X represents a fluorine atom; Y represents -S(0),CHR*R* (wherein R’.R* and n are the same as described above); and R' represents a group represented by formula-CHR*QC(Q)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢represents a hydrogen atom, a Cy.jalkyl group, a Cs.jpalkenyl group or an aryl group; and R® represents a Ci-i0alkyl group, a Cy.palkenyl group or an aryl group), a group represented by formula

[1] i 0 Di - Rd O

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

® 0 @) \ A [i1]

30. A 2-amino-bicyclo[3.1.0]Jhexane-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 -NHCHR’R* (wherein Rand R” are the same as described above); and R' represents a Cj.jpalkyl group, a Cy.jpalkenyl group, a C,.jpalkynyl group, a C,_jpalkyl group substituted by one or two aryl groups, a hydroxyCj.jealkyl group, a halogenoCi.jpalkyl group, an azidoC,.palkyl group, an aminoCy.ealkyl group, a

Ci.i0alkoxyCi.j0alkyl group. a C.jpalkoxycarbonylC,.jpalkyl group, a farnesyl group, a 4-morpholinylC,.iealkyl group or a C,.jealkyl group substituted by a group represented by formula-C(O)NRR® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a Cj. alkyl group).

31. A 2-amino-bicyclo[3.1.0]hexanc-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thercof 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 -NHCHR’R? (wherein R* and R* are the same as described above); and R! represents a group represented by formula-CHR°OC(0)ZR? (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a Cy. palkyl group, a Cy. palkenyl group or an aryl group; and RY represents a

Ci.10alkyl group, a Cy. 0alkenyl group or an aryl group), a group represented by formula

@® o 0 RY O [i] (wherein R%is the same as described above) or a group represented by formula [ii]. O ry '\ FRY [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(CHR’R*)(CHR*R*) (wherein R®, R*, R* and R” are the same as described above); and R! represents a Cy.jpalkyl group, a C,.jpalkenyl group, a Cs.10alkynyl group, a Cy. jpalkyl group substituted by one or two aryl groups, a hydroxyCy alkyl group, a halogenoCi.jpalkyl group, an azidoC,.jpalkyl group, an aminoCs.jgalkyl group, a

Ci.0alkoxyCy.jpalkyl group, a C;_jpalkoxycarbonylC). palkyl group, a farnesyl group, a 4-morpholinylC,. alkyl group or a Cy. alkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R? and R® are identical or different, and each represents a hydrogen atom or a Cj_jpalkyl group).

33. A 2-amino-bicyclo[3.1.0Jhexane-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(CHR’R*}(CHR*R") (wherein R, R*, R*and R* are the same as described above); and R' represents a group represented by formula-CHR*OC(0)ZR® (wherein Z represents an

® OXygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a Cj_jpalkyl group, a Cs. jpalkenyl group or an aryl group; and RY represents a

Ci.i0alkyl group, a C,.jpalkenyl group or an aryl group), a group represented by formula

[1] i i 0) oT © RO [i] (wherein RYis the same as described above) or a group represented by formula [ii]. O O ~ \ PRY [ii]

34. A 2-amino-bicyclof3.1.0}hexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [ll], 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 Rr represents a Cy.jpalkyl group, a Cy. jpalkenyl group, a Cy.jpalkynyl group, a Cy_jpalkyl group substituted by one or two aryl groups, a hydroxyCs.jalkyl group, a halogenoC,.jpalkyl group. an azidoCj.palkyl group, an aminoCs.jalkyl group, a

Ci.10alkoxyCy.jealkyl group, a Cy. jpalkoxycarbonylC,.jealkyl group, a farnesyl group, a 4-morpholinylCy.joalkyl group or a Cy jalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a Cy_jpalkyl 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 [11], 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 R' represents a group represented by formula-CHROC(0)ZR® (wherein Z represents an OXygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a C,.jpalkyl group. a Cyealkeny! group or an aryl group; and RY represents a

Ci.i0alkyl group. a Ca.jealkenyl group or an aryl group). a group represented by formula

[1] i 0 =o Rd oO [i] (wherein Ris the same as described above) or a group represented by formula [ii]. O Toy *\ FRY [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 [11], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -SCHR’R® (wherein R? and R* are the same as described above); and R' represents a C).jpalkyl group, a C,.jpalkenyl] group, a Ca.10alkynyl group, a Ci.palkyl group substituted by onc or two aryl groups, a hydroxyC,.jpalky] group, a halogenoC,.jpalkyl group, an azidoC,.jpalkyl group, an aminoCj.jpalkyl group, a Ci-0alkoxyCy.joalkyl group or a Cy. jpalkoxycarbonylC,.ealkyl group, a farmesyl group, a 4-morpholinylC,.jealkyl group. a C.jpalkyl group substituted by a group represented by formula-C(O)NR®R® (wherein R* and R® are identical or different, and each represents a hydrogen atom or a Cj_jpalkyl group).

® 37. A 2-amino-bicyclo[3.1 .OJhexane-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 -SCHR*R* (wherein R® and R* are the same as described above); and R' represents a group represented by formula-CHR‘OC(O)ZR® (wherein Z represents an Oxygen atom, a nitrogen atom, a sulfur atom or a single bond, R “represents a hydrogen atom,C,.jpalkyl group, a Cj.jpalkenyl group or an aryl group; and R° represents a

Ci.10alkyl group, a Cy.1palkenyl group or an aryl group), a group represented by formula

[1] -! O =o Rd O [i] (wherein R%is the same as described above) or a group represented by formula [ii]. O ro '\ FEY [ii]

38. 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 [lI], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -SR> (wherein R? is the same as described above); and R’ represents a Cy.joalkyl group, a Cy.jpalkenyl group, a Cy. jpalkynyl group, a Ci-oalkyl group substituted by one or two aryl groups, a hydroxyC,.jpalkyl group, a halogenoC,.jpalkyl group, an azidoC,.palkyl group. an aminoCy.jpalkyl group, a Cy-10alkoxyCy.joalkyl group, a Cy.jpalkoxycarbonylC. alkyl group, a farnesyl group, a

@ 4-morpholinylC;. palkyl group, or a Cj. palkyl group substituted by a group represented by formula-C(O)NR®R® (wherein R? and R® are identical or different, and each represents a hydrogen atom or a Cy. jpalkyl 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 [11], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents-SR’ (wherein R? is the same as described above); and R' represents a group represented by formula-CHR*OC(O)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R represents a hydrogen atom, a Cy. alkyl group, a C,. alkenyl group or an aryl group: and R* represents a

Ci.10alkyl group, a C,. palkeny! group or an aryl group), a group represented by formula

[1] i 0 =o RY Oo

[1] (wherein R%is the same as described above) or a group represented by formula [11]. O rn '\ FRY [ii]

40. A 2-amino-bicyclo[3.1.0]Jhexane-2,6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [lI], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -S(O),CHR’R* (wherein R?, R* and n are the same as described above); and

® R' represents a C.jalkyl group, a Cy.jgalkenyl group, a Cs. jgalkynyl group, a Cy jpalkyl group substituted by one or two aryl groups. a hydroxyCs.jpalkyl group. a halogenoC, jqalkyl group. an azidoCj.jpalkyl group. an aminoCs.joalkyl group. a Cy-10alkoxyCi. alkyl group, a Ci.i0alkoxycarbonylCy alkyl group, a farnesyl group, a 4-morpholinylC,_ealkyl group or a C,_jalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R* and R® are identical or different. and each represents a hydrogen atom or a Cy. palkyl group).

41. A 2-amino-bicyclo[3.1.0Jhexane-2,6-dicarboxylic ester deri vative, 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),CHR’R? (wherein R3 R* and n are the same as described above); and R' represents a group represented by formula-CHR“OC(0)ZR? (wherein Z represents an OXygen atom, a nitrogen atom, a sulfur atom or a single bond; R “represents a hydrogen atom,C).joalkyl group, a Caealkenyl group or an aryl group; and R ‘represents a

Ci.0alkyl group, a Cy.jpalkenyl group or an aryl group), a group represented by formula [i] -! O RI“ TO [i] (wherein Ris the same as described above) or a group represented by formula [ii]. O rn \ FE [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 -NHCHR’R* (wherein R’ and R* are the same as described above); and R! represents a Cy jpalkyl group, a Ca.jpalkenyl group, a Cy.joalkynyl group, a Cy. palkyl group substituted by one or two aryl groups, a hydroxyCs. alkyl group, a halogenoC,.jpalkyl group, an azidoCj alkyl group, an aminoCy. palkyl group, a

Ci.10alkoxyC;.jgalkyl group, a Cj. galkoxycarbonylC. alkyl group, a farnesyl group, a 4-morpholinylC;.jpalkyl group or a Cy. palky! group substituted by a group represented by formula-C(O)NR’R" (wherein R? and R® are identical or different, and each represents a hydrogen atom or a Cy.jpalky] 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 -NHCHR’R* (wherein R® and R* are the same as described above); and R' represents a group represented by formula-CHROC(Q)XR? (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a Cj alkyl group, a Cy jpalkenyl group or an aryl group; and R* represents a

Ci.1alkyl group, a Cy.jalkenyl group or an aryl group), a group represented by formula

[1] i 0 J RY O

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

® 0 O \ A [ii]

44. A 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic ester derivative, a ~ pharmaceutically acceptable salt thereof or a hydrate thercof according to claim 2, wherein in the formula [lI], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -N(CHR’R*)(CHR*R*) (wherein R®, R*, R* and R* are the same as described above); and R' represents a Cy.jpalkyl group, a Cy.jpalkenyl group, a C,.j0alkynyl group, a C,_palkyl group substituted by one or two aryl groups, a hydroxyC,. alkyl group, a halogenoC,.jpalkyl group, an azidoC,.palkyl group, an aminoCy.jpalkyl group, a

Ci.i0alkoxyCj.joalkyl group, a Cj-10alkoxycarbonylCj.galkyl group, a farnesyl group, a 4-morpholinylC;.jealky] group or a C).jpalkyl group substituted by a group represented by formula-C(O)NR?R® (wherein R?* and R® are identical or different, and each represents a hydrogen atom or a Cy. palkyl 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 [11], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -N(CHR’R*}(CHR*R*") (wherein R?, R¥, R* and R* are the same as described above); and R' represents a group represented by formula-CHR ‘OC(0)ZR? (wherein Z represents an oXygen atom, a nitrogen atom, a sulfur atom or a single bond; R “represents a hydrogen atom,C_joalkyl group, a Cs.jpalkenyl group or an aryl group; and R ¢ represents a

Ci.10alkyl group, a C,.jealkenyl group or an aryl group), a group represented by formula

® 0 ] RY Oo [i] (wherein R%is the same as described above) or a group represented by formula [ii]. O rn '\ FY [ii]

46. A 2-amino-bicyclo[3.1.0Thexane-2,6-dicarboxylic ester derivativea pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula

[1], 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 C,.palkyl group, a Ci.iealkoxy 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 Ci.ioalkyl group, a C,.j0alkenyl group, a Cs.joalkynyl group, a C.jpalkyl group substituted by one or two aryl groups, a hydroxyC,.jalkyl group, a halogenoC,.jpalkyl group, an azidoC,.jealkyl group, an aminoC,. alkyl group, a

Ci.ipalkoxyCy.jealkyl group, a Ci.10alkoxycarbonylC, jalkyl group, a farmesyl group, a 4-morpholinylC).jealkyl group or a Cy.jpalkyl group substituted by a group represented by formula-C(O)NR®R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a C_jpalkyl 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 [1], 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 substutuents selected from a group containing a halogen atom, a phenyl group, a Cy. palkyl group, a C).jpalkoxy 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 group represented by formula-CHR‘OC(O)ZR® (wherein Z represents an Oxygen atom, a nitrogen atom, a sulfur atom or a single bond: RCrepresents a hydrogen atom, a C,.jpalkyl group, a Cy. palkenyl group or an aryl group; and RY represents a

Ci.10alkyl group, a Cs. jpalkenyl group or an aryl group), a group represented by formula {1] i 0 RY Oo

[1] (wherein R%is the same as described above) or a group represented by formula [11]. O 0) \ \ FER [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 -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 R! represents a C).jpalkyl group. a Cy. jpalkenyl group, a Ca.jpalkynyl group, a Ci.0alkyl group substituted by one or two aryl groups, a hydroxyCj.jpalkyl group, a

@® halogenoC;.galkyl group, an azidoC.palky] group, an aminoCy.jpalkyl group. a

Ci.i0alkoxyC.jpalkyl group, a C.jpalkoxycarbonylC,_jealkyl group, a farnesyl group, a 4-morpholinylC_jpalkyl group or a Ci.10alkyl group substituted by a group represented by formula-C(O)NRR® (wherein R* and R® are identical or different, and each represents a hydrogen atom or a Cy.jalkyl group).

49. A 2-amino-bicyclo]3.1 .OJhexane-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 R' represents a group represented by formula-CHR‘OC(O)XR? (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a Cy.jpalkyl group, a Cy. jpalkenyl group or an aryl group; and RY represents a

Cy.0alkyl group, a Cy.joalkenyl group or an aryl group), a group represented by formula

[1] -! O =O RO [i] (wherein R%is the same as described above) or a group represented by formula [ii]. O O \ AN FER [ii]

50. A 2-amino-bicyclo[3.1 .O]hexane-2.6-dicarboxylic ester derivative, ga

@® pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2. wherein in the formula [11], R? represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR’R* (wherein R* and R* 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 Cj. jpalkyl group, a

Ci.10atkoxy group. a trifluoromethyl group, a phenyl group, a hydroxycarbony! group, an amino group, a nitro group, a cyano group and a phenoxy group); and R' represents a Cy.jpalkyl group, a Cj.jealkenyl group. a C,. alkynyl group, a C).joalky} group substituted by one or two aryl groups, a hydroxyCa. alkyl group, a halogenoC,.jpalkyl group, an azidoC.jjalkyl group, an aminoC,.jpalkyl group, a

Ci.10alkoxyC). palky! group, a Cj.10alkoxycarbonylCj.jpalkyl group, a farnesyl group, a 4-morpholinylC,.jpalkyl group or a C,.jpalkyl group substituted by a group represented by formula-C(O)NR®R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a C,.jpalkyl 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 [lI], R? represents a hydrogen atom; X represents a fluorine atom; Y represents -OCHR’R? (wherein R® and R* 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 C;. alkyl group, a

Ci.ioalkoxy 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 group represented by formula-CHR°OC(O)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R represents a hydrogen atom, a C,.joalkyl group, a Cj.jpalkenyl group or an aryl group; and R® represents a

Ci.joalkyl group. a Cy.jpalkenyl group or an aryl group), a group represented by formula

[1] I~ 0 Di - Rd O [i] (wherein Ris the same as described above) or a group represented by formula [ii].

® O Oo A [i1]

52. A 2-amino-bicyclo[3.1 .O]hexane-2.6-dicarboxylic ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thercof 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’ 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 Ci.0alkyl group, a C.jealkoxy 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 Ci.0alkyl group, a Cs.jpalkenyl group, a Cz.10alkynyl group, a Cy_jealkyl group substituted by one or two aryl groups, a hydroxyCj.ipalkyl group, a halogenoC,_jealkyl group, an azidoCj.jpalkyl group, an aminoCs.jpalkyl group, a

Ci.10alkoxyCi. galkyl group, a Ci.i0alkoxycarbonylCy.jpalkyl group, a farnesyl group, a 4-morpholinylC,.jpalkyl group or a Cy.jpalkyl group substituted by a group represented by formula-C(O)NRR® (wherein R® and R" are identical or different, and each represents a hydrogen atom or a Cy. palkyl 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 [I], R? represents a hydrogen atom; X represents a hydrogen 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 substutuents selected from a group containing a halogen atom, a phenyl group, a Ciaoalkyl group, a C) jpalkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and phenoxy group); and R' represents a group represented by formula-CHR°OC(O)ZR (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen

119 - 20 05/ C atom, a Cy. jealkyl group, a Cy.jpalkenyl group or an aryl group; and R¢ represents a

Ci.10alkyl group, a C,. alkenyl group or an aryl group), a group represented by formula

[1] ~ O RY O [i] (wherein R %is the same as described above) or a group represented by formula [ii] O O '\ FEY ) [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 [lI], R? represents a hydrogen atom; X represents a hydrogen 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 R' represents a C,.jalkyl group, a C;.jalkenyl group, a Cy. jgalkynyl group, a C;_jealkyl group substituted by one or two aryl groups, a hydroxyC,.salkyl group, a halogenoC,.jpalkyl group, an azidoC;.jalkyl group, an aminoCjpalkyl group, a

Ci.10alkoxyCy.jealkyl group, a Cj. palkoxycarbonylC).jpalkyl group, a farnesyl group, a 4-morpholinylC,. alkyl group or a C,.jalkyl group substituted by a group represented by formula-C(O)NR°R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a Cj. )galky! 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 -OCHR’R* (wherein R’ represents a Cj.jpalkyl group; and R’ represents a naphthyl group); and R' represents a group represented by formula-CHROC(0)ZR® (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R¢ represents a hydrogen atom, a Cy oalkyl group, a Cy. j0alkenyl group or an aryl group; and R¢ represents a

Cr.ialkyl group, a Cj.jpalkenyl group or an aryl group), a group represented by formula

[1] 1 O Bi © RI” TO [i] (wherein R%is the same as described above) or a group represented by formula [ii]. O O \ \ FR [ii]

56. A 2-amino-bicyclo[3.1.0lhexane-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 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 Cy.jpalkyl group, a

C.joalkoxy 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 Ci.jpalkyl group, a Cs.jpalkenyl group. a Cy.10alkynyl group, a Cy_jgalky]

® group substituted by one or two aryl groups, a hydroxyCy.jpalkyl group, a halogenoC)_galky} group, an azidoC,.palkyl group, an aminoC,.jpalkyl group, a

Ci.0alkoxyC).jgalkyl group, a Cy.jpalkoxycarbonylC)_jpalkyl group, a farnesyl group, a 4-morpholinylC,. alkyl group or a C,.jpalkyl group substituted by a group represented by formula-C(O)NR’R® (wherein R® and R® are identical or different, and each represents a hydrogen atom or a Cy. jgalkyl group).

57. A 2-amino-bicyclo|3.1 .O]hexane-2,6-dicarboxylic ester derivative. a pharmaceutically acceptable salt thereof or a hydrate thereof according to claim 2, wherein in the formula [lI], R? represents a hydrogen atom; X represents a hydrogen atom; Y represents -OCHR’R? (wherein R? and R? 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 C).jpalkyl group, a Cy-jealkoxy 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 group represented by formula-CHR ‘OC(0)ZR? (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond; R® represents a hydrogen atom, a Cj.jpalkyl group, a C.jealkenyl group or an aryl group; and RY represents a Ci-10alkyl group, a Cs.jpalkenyl group or an aryl group), a group represented by formula

[1] py @) I I © RY” TO [i] (wherein R?is the same as described above) or a group represented by formula [ii]. O O \ \ FERN [ii]

58. A drug comprising the 2-amino-bicyclo [3.1.0] hexane -2.6-dicarboxylic ester derivative, the pharmaceutically acceptable salt thereof or the hydrate thereof according 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.