CN1812960A - 2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives - Google Patents

Abstract

The purpose of the present invention is to provide a drug having high oral activity and antagonistic activity against group II metabotropic glutamate receptorsThe medicine is effective in treating and preventing schizophrenia, anxiety and related diseases, depression, bipolar disorder, epilepsy and other psychomedical disorders. The above object is achieved by the formula [ I]2-amino-bicyclo [3.1.0] s shown]Hexane-2, 6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt thereof or hydrate thereof [ wherein R represents¹And R²The same or different represent a hydrogen atom, C_1－10Alkyl, etc., X represents a hydrogen atom or a fluorine atom, Y represents-OCHR³R⁴Etc. (wherein R is³And R⁴The same or different represent a hydrogen atom, C_1－10Alkyl, etc., n represents an integer of 1 or 2)]。

Description

2-Amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives

technical field

The present invention relates to 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives, their pharmaceutically acceptable salts, their hydrates, or using them as active ingredients prodrug. More specifically, the present invention relates to psychiatric disorders such as schizophrenia, anxiety and its related disorders, bipolar disorder, epilepsy, and drug dependence, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease As a metabolically active (metabotropic) glutamate receptor (mGluR) effective in the treatment and prevention of neurological diseases such as neurological diseases such as neuropathy, dyskinesia accompanied by muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders Prodrugs such as compounds 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives that act as antagonists of mGluR2/mGluR3 of subgroup II.

The present invention also relates to the fact that the prodrugs of the compounds acting as mGluR2/mGluR3 antagonists can increase the oral activity and increase the exposure of the parent compound in vivo.

Background technique

Metabotropic glutamate receptors are pharmacologically divided into 3 groups. Wherein group II (mGluR2/mGluR3) combines with adenylate cyclase, inhibits the forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (referring to Trends Pharmacol.Sci., 14,13, 1993 (following non- Patent Document 1)), therefore it can be considered that compounds that antagonize group II metabotropic glutamate receptors are effective in the treatment or prevention of acute and chronic psychiatric and neurological diseases, 2-amino-bicyclo[3.1.0] Hexane-2,6-dicarboxylic acid derivatives are compounds with strong antagonistic effects on group II metabotropic glutamate receptors.

Literature list

Non-Patent Document 1

Trends Pharmacol. Sci., 14 , 13, 1993

The object of the present invention is to provide drugs that antagonize group II metabotropic glutamate receptors, which are effective for psychiatric disorders such as schizophrenia, anxiety and related diseases, depression, bipolar affective disorders, epilepsy, and drugs Neurological diseases such as dependence, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorder with muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorder, and head disorder are effective in treatment and prevention Effect, high oral activity.

Contents of the invention

The present inventors conducted in-depth studies on 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives, and found that: for the 2 - Prodrugs of amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives, which can lead to exposure of the parent compound in vivo when the parent compound is used as the test drug in animal experiments The amount is improved, thereby completing the present invention.

The present invention is 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivatives (hereinafter referred to as "compounds of the present invention") shown in formula [I], which can be used pharmaceutically Accepted salts or their hydrates:

[wherein, R ¹ and R ² are the same or different, representing C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1-10 alkyl substituted by 1 or 2 aryl groups , hydroxy C _2-10 alkyl, halogenated C _{1-10 alkyl, azido C 1-10} alkyl, amino C _2-10 alkyl, _{C 1-10 alkoxy} C _1-10 alkyl, C _1-10 alkoxycarbonyl C _1-10 alkyl, farnesyl, 4-morpholinyl C _1-10 alkyl, by formula -C (O) NR ^a R ^b (wherein, R ^a and R ^b are the same or different, representing a hydrogen atom or a C _1-10 alkyl group substituted by a group represented by a C _1-10 alkyl group, the formula -CHR ^c OC(O) ZR ^d (in the formula, Z represents an oxygen atom, a nitrogen atom , sulfur atom or single bond, R ^c represents hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, aryl, R ^d represents C _1-10 alkyl, C _2-10 alkenyl, aryl) The group shown, the formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

the group shown, or

When any one of R ¹ and R ² is a hydrogen atom, the other represents C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C _1- substituted by 1 or 2 aryl groups ₁₀ alkyl, hydroxy C _2-10 alkyl, halogenated C _1-10 alkyl, azido C _1-10 alkyl, amino C _2-10 alkyl, C _1-10 alkoxy C _1-10 Alkyl, C _1-10 alkoxycarbonyl C _1-10 alkyl, farnesyl, 4-morpholinyl C _1-10 alkyl, by formula -C (O) NR ^a R ^b (in the formula, R ^a and R ^b have the same meaning as above) represented by C _1-10 alkyl substituted by the group represented by the formula -CHR ^c OC (O) ZR ^d (in the formula, Z, R ^c and R ^d have the same meaning as above) group, formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

the indicated group;

X represents a hydrogen atom or a fluorine atom; Y represents -OCHR ³ R ⁴ , -SR ³ , -S(O) _n R ⁵ , -SCHR ³ R ⁴ , -S(O) _n CHR ³ R ⁴ , -NHCHR ³ R ^4. -N(CHR ³ R ⁴ )(CHR ^3' R ^4' ), -NHCOR ³ or -OCOR ⁵ (wherein, R ³ , R ^3' , R ⁴ and R ^4' are the same or different, and represent a hydrogen atom , C _1-10 alkyl, C _1-10 alkenyl, phenyl, naphthyl, naphthyl substituted by 1-7 halogen atoms, heteroaryl, or substituted by 1-5 halogen atoms, phenyl , C _1-10 alkyl, C _1-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy substituent substituted phenyl, R ⁵ represents C _1-10 alkyl, C _1-10 alkenyl, phenyl, naphthyl, naphthyl, heteroaryl substituted by 1-7 halogen atoms, or substituted by 1-5 halogen atoms, phenyl, C _1-10 alkyl, C _1-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy substituent substituted phenyl, n represents 1 or 2 integer)].

In one embodiment of the present invention, in the above formula [I], preferably R ¹ and R ² are the same or different, representing C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, by 1 or C _1-10 alkyl substituted by 2 phenyl groups, hydroxy C _2-10 alkyl, halogenated C _1-10 alkyl, azido C _1-10 alkyl, amino C _2-10 alkyl, C _{1 -10} alkoxy C _1-10 alkyl, C _1-10 alkoxycarbonyl C _1-10 alkyl,

Or when any one of R ^{and R} is a hydrogen atom, the other represents C _1-10 alkyl, C _2-10 alkenyl, C _2-10 alkynyl, C ₁ substituted by 1 or 2 phenyl groups _-10 alkyl, hydroxy C _2-10 alkyl, halogenated C _1-10 alkyl, azido C _1-10 alkyl, amino C _2-10 alkyl, C _1-10 alkoxy C _{1- 10} alkyl, C _1-10 alkoxycarbonyl C _1-10 alkyl.

In another embodiment of the present invention, in the above formula [I], preferably R ¹ and R ² are the same or different, representing farnesyl, C _1-10 alkyl substituted by 1 or 2 aryl groups, C _{1- 10} alkoxycarbonyl C _1-10 alkyl, 4-morpholinyl C _1-10 alkyl, represented by the formula -C (O) NR ^a R ^b (wherein, R ^a and R ^b are the same or different, representing C _1-10 alkyl substituted by a group represented by hydrogen atom or C _1-10 alkyl), the formula -CHR ^c OC(O) ZR ^d (wherein, Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, R ^c represents a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl, aryl, R ^d represents a group represented by C _1-10 alkyl, C _2-10 alkenyl, aryl), Formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

the indicated group;

Or when any one of R ^{and R} is a hydrogen atom, the other preferably represents farnesyl, C _1-10 alkyl substituted by 1 or 2 aryl groups, C _1-10 alkoxycarbonyl C _{1- 10} ^{alkyl , 4} -morpholinyl ^C _1-10 alkyl, C _{1- 10} Alkyl groups, groups represented by the formula -CHR ^c OC(O) ZR ^d (wherein, Z, R ^c and R ^d have the same meaning as above), formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

group shown.

In another embodiment of the present invention, in the above formula [I], preferably R ² is a hydrogen atom.

In yet another embodiment of the present invention, in the above formula [I], preferably X is a fluorine atom.

In another embodiment of the present invention, in the above formula [I], Y is preferably -OCHR ³ R ⁴ , -SR ³ , -SCHR ³ R ⁴ , -S(O) _n CHR ³ R ⁴ , -NHCHR ³ R ⁴ or -N(CHR ³ R ⁴ )(CHR ^3' R ^4' ) (wherein, R ³ , R ^3' R ⁴ and R ^4' have the same meaning as above).

In yet another embodiment of the present invention, in the above formula [I], Y is preferably -SR ³ , -SCHR ³ R ⁴ , -S(O) _n CHR ³ R ⁴ , -NHCHR ³ R ⁴ or -N(CHR ³ R ⁴ )(CHR ^3' R ^4' ) (wherein, R ³ , R ^3' R ⁴ and R ^4' have the same meaning as above).

Here, in the above formula [I], R ³ , R ^3' R ⁴ and R ^4' used in the description of Y are preferably independently hydrogen atom, phenyl, naphthyl, or 1-5 selected from Phenyl substituted by substituents of halogen atom, phenyl, C _1-10 alkyl, C _1-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy . Among them, it is more preferable that R ³ , R ^3' R ⁴ and R ^4' are each independently a hydrogen atom, a phenyl group, a naphthyl group, or a phenyl group substituted by 1-5 halogen atoms.

In yet another embodiment of the present invention, in the above formula [I], preferably R ¹ and R ² are independently hydrogen atom, C _1-10 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _1-6 alkyl substituted by 1 or 2 phenyl groups, hydroxy C _2-6 alkyl, halogenated C _1-6 alkyl, azido C _1-6 alkyl, amino C _2-6 alkyl , C _1-6 alkoxy C _1-6 alkyl, or C _1-6 alkoxycarbonyl C _1-6 alkyl. Among them, preferably R ² represents a hydrogen atom, and R ¹ is a linear or branched C _1-10 alkyl group, a C _2-6 alkenyl group, or a C _1-6 alkyl group substituted by 1 or 2 phenyl groups .

In another embodiment of the present invention, in the above formula [I], preferably R ¹ and R ² are each independently a hydrogen atom, a farnesyl group, a C _1-6 alkyl group substituted by 1 or 2 aryl groups, C _1-6 alkoxycarbonyl C _1-6 alkyl, 4-morpholinyl C _1-6 alkyl, by formula -C (O) NR ^a R ^b (in the formula, R ^a and R ^b have the same meaning as above ) represented by a C _1-6 alkyl group substituted by a group represented by the formula -CHR ^c OC(O)ZR ^d (in the formula, Z, R ^c and R ^d have the same meanings as above), a group represented by the formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

group shown. Among them, preferably R ² is a hydrogen atom, R ¹ is farnesyl, C _1-6 alkyl substituted by 1 or 2 phenyl or substituted phenyl, C _1-6 alkoxycarbonyl C _1-6 alkyl , 4-morpholinyl C _1-6 alkyl, C _1-6 alkyl substituted by the group represented by the formula -C(O)NR ^a R ^b (in the formula, R ^a and R ^b have the same meaning as above) , the group represented by the formula -CHR ^c OC(O)ZR ^d (wherein, Z, R ^c and R ^d have the same meaning as above), the formula [i]

(In the formula, R ^d has the same meaning as above), or the group represented by the formula [ii]

group shown.

Here, in the above formula [I], R ^a and R ^b used in the description of R ¹ and R ² are preferably a hydrogen atom or a C _1-6 alkyl group. Preferably, R ^c is a hydrogen atom, a C _1-6 alkyl group, a C _2-6 alkenyl group or an aryl group. On the other hand, R ^d is preferably C _1-6 alkyl, C _2-6 alkenyl or aryl. The terms used in this specification are defined as follows. Here "C _nm " means that the following group has n to m carbon atoms.

The C _1-10 alkyl group represents a straight chain having 1 to 10 carbon atoms, a branched chain having 3 to 10 carbon atoms, or a cyclic alkyl having 3 to 10 carbon atoms. Examples of linear alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like. Branched chain alkyl such as isopropyl, isobutyl, 1-methylpropyl, tert-butyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl propyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3- Methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3- Dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 5-methylhexyl, 3-ethylpentyl, 1 -Propylbutyl, 1,4-dimethylpentyl, 3,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1-isopropylbutyl, 4,4- Dimethylpentyl, 5-methylheptyl, 6-methylheptyl, 4-ethylhexyl, 2-propylpentyl, 2,5-dimethylhexyl, 4,5-dimethylhexyl , 2-ethyl-3-methylpentyl, 1,2,4-trimethylpentyl, 2-methyl-1-isopropylbutyl, 3-methyloctyl, 2,5-di Methylheptyl, 1-(1-methylpropyl)-2-methylbutyl, 1,4,5-trimethylhexyl, 1,2,3,4-tetramethylpentyl, 7- Methyloctyl, 6-methylnonyl, 8-methylnonyl, 5-ethyl-2-methylheptyl, 2,3-dimethyl-1-(1-methylpropyl)butyl radical, cyclopropylmethyl, 2-(cyclopropyl)ethyl, 3,7-dimethyloctyl, 3-(cyclobutyl)pentyl, cyclopentylmethyl, cyclohexylmethyl, etc. Cyclic alkyl groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

C _2-10 alkenyl means having at least 1 double bond, straight chain with 2-10 carbon atoms, branched chain with 3-10 carbon atoms, or cyclic alkenes with 5-10 carbon atoms Base, such as vinyl, allyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 6-heptenyl, 7-octenyl, 8-nonenyl, 9-decenyl Alkenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 2-methyl-3-butenyl, 2-pentenyl, 2-methyl-2-hexyl Alkenyl, 2-cyclopentenyl, etc.

C _2-10 alkynyl means having at least 1 triple bond, a straight-chain alkynyl with 2-10 carbon atoms or a branched alkynyl with 4-10 carbon atoms, for example, 2-propynyl, 3 -Butynyl, 4-pentynyl, 5-hexynyl, 6-heptynyl, 7-octynyl, 8-nonynyl, 9-decynyl, 3-pentynyl, 4-methyl Base-2-pentynyl, etc.

C _1-10 alkyl substituted by 1 or 2 aryls, such as benzyl, diphenylmethyl, 2-phenylethyl, 2-phenylpropyl, 1-methyl-1-phenylethyl Base, 1-methyl-2-phenylpentyl, 2-nitrobenzyl, 3-nitrobenzyl, 4-nitrobenzyl, 2,4-dinitrobenzyl, 2,4,6 -Trinitrobenzyl, 2-phenylbenzyl, 3-phenylbenzyl, 4-phenylbenzyl, 2-hydroxybenzyl, 3-hydroxybenzyl, 4-hydroxybenzyl, 2-chlorobenzyl Base, 3-chlorobenzyl, 4-chlorobenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-bromobenzyl, 3-bromobenzyl, 4-bromobenzyl, 2-iodobenzyl, 2-iodobenzyl, 2,3-dichlorobenzyl, 2,4-dichlorobenzyl, 2,5-dichlorobenzyl, 2,6-dichlorobenzyl, 3, 4-dichlorobenzyl, 3,5-dichlorobenzyl, 2-methylbenzyl, 3-methylbenzyl, 4-methylbenzyl, 2-ethylbenzyl, 3-ethylbenzyl , 4-ethylbenzyl, 2-isopropylbenzyl, 3-isopropylbenzyl, 4-isopropylbenzyl, 2-methoxybenzyl, 3-methoxybenzyl, 4- Methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl, 2,5-dimethoxybenzyl, 2,6-dimethoxybenzyl, 3,4-dimethoxybenzyl, 3,5-dimethoxybenzyl, 2-ethoxybenzyl, 3-ethoxybenzyl, 4-ethoxybenzyl, 2-isopropyl Oxybenzyl, 3-isopropoxybenzyl, 4-isopropoxybenzyl, 2-methoxymethylbenzyl, 3-methoxymethylbenzyl, 4-methoxymethyl Benzyl, 2-isopropoxymethylbenzyl, 3-isopropoxymethylbenzyl, 4-isopropoxymethylbenzyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-hydroxycarbonylbenzyl, 3-hydroxycarbonylbenzyl, 4-hydroxycarbonylbenzyl, 2-aminobenzyl, 3-aminobenzyl, 4-aminobenzyl, 2-aminomethyl benzyl, 3-aminomethylbenzyl, 4-aminomethylbenzyl, 2-cyanobenzyl, 3-cyanobenzyl, 4-cyanobenzyl, 2-hydroxymethylbenzyl, 3 -Hydroxymethylbenzyl, 4-hydroxymethylbenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl, 4-phenoxybenzyl. Aryl represents polycyclic aromatic groups such as phenyl, substituted phenyl, or 1-naphthyl and 2-naphthyl.

Substituted phenyl means 1-3 selected from halogen atom, hydroxyl, phenyl, C _1-10 alkyl, C _1-10 alkoxy, C _1-10 alkoxy C _1-10 alkyl, trifluoro Phenyl substituted by substituents of methyl, hydroxycarbonyl, amino, nitro, cyano, hydroxymethyl, aminomethyl and phenoxy. For example: 2-nitrophenyl, 3-nitrophenyl, 4-nitrophenyl, 2,4-dinitrophenyl, 2,4,6-trinitrophenyl, 2-phenyl Phenyl, 3-phenylphenyl, 4-phenylphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chloro Phenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 2-iodophenyl , 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5- Dichlorophenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-iso Propylphenyl, 3-isopropylphenyl, 4-isopropylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2,3-di Methoxyphenyl, 2,4-dimethoxyphenyl, 2,5-dimethoxyphenyl, 2,6-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2-ethoxyphenyl, 3-ethoxyphenyl, 4-ethoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxy Phenyl, 4-isopropoxyphenyl, 2-methoxymethylphenyl, 3-methoxymethylphenyl, 4-methoxymethylphenyl, 2-isopropoxymethyl Phenyl, 3-isopropoxymethylphenyl, 4-isopropoxymethylphenyl, 2-trifluoromethyl, 3-trifluoromethyl, 4-trifluoromethyl, 2-hydroxycarbonyl Phenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-aminomethylphenyl, 3-aminomethylphenyl , 4-aminomethylphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-hydroxymethylphenyl, 3-hydroxymethylphenyl, 4-hydroxymethyl phenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxyphenyl.

Among these C _1-10 alkyl groups substituted with 1 or 2 aryl groups, C _1-10 alkyl groups substituted with 1 or 2 phenyl groups are preferred.

Hydroxy C _2-10 alkyl means C _2-10 alkyl substituted by at least one hydroxyl group, such as 2-hydroxyethyl, 3-hydroxypropyl, 4-hydroxybutyl, 5-hydroxypentyl, 6- Hydroxyhexyl, 7-hydroxyheptyl, 8-hydroxyoctyl, 9-hydroxynonyl, 10-hydroxydecyl, 2-hydroxypropyl, 2, 3-dihydroxypropyl, 2-hydroxy-3-methyl Butyl, etc.

Halogenated C _1-10 alkyl means C _1-10 alkyl substituted by at least one or more fluorine atoms, chlorine atoms, bromine atoms and iodine atoms, such as 2-chloroethyl, 2-bromoethyl, 2-iodoethyl, 3-chloropropyl, 3-bromopropyl, 3-iodopropyl, 4-chlorobutyl, 4-bromobutyl, 4-iodobutyl, 5-chloropentyl, 6- Chlorohexyl, 7-chloroheptyl, 8-chlorooctyl, 9-chlorononyl, 10-chlorodecyl, 2-chloropropyl, 2-chlorobutyl, 2,4-dichlorobutyl, 2- Chloro-3-methylbutyl, etc.

Azido C _1-10 alkyl means C _1-10 alkyl substituted by at least one or more azido groups, such as 2-azidoethyl, 3-azidopropyl, 4-azido Azidobutyl, 5-azidopentyl, 6-azidohexyl, 7-azidoheptyl, 8-azidooctyl, 9-azidononyl, 10-azidodecyl group, 2-azidopropyl group, 2-azidobutyl group, 2-azido-3-methylbutyl group, etc.

Amino C _2-10 alkyl means C _2-10 alkyl substituted by at least one amino group, such as 2-aminoethyl, 3-aminopropyl, 6-aminohexyl, 7-aminoheptyl, 8-amino Octyl, 9-aminononyl, 10-aminodecyl, 4-aminobutyl, 2,4-diaminobutyl, etc.

C _1-10 alkoxy C _1-10 alkyl means straight chain with 1-10 carbon atoms, branched chain with 3-10 carbon atoms, or cyclic with 3-10 carbon atoms An alkyl group with 1-10 carbon atoms substituted by an alkoxy group, such as 2-methoxyethyl, 2-ethoxyethyl, 2-propoxyethyl, 2-isopropoxyethyl, 2-butoxyethyl, 2-isobutoxyethyl, 2-tert-butoxyethyl, 2-pentyloxyethyl, 2-hexyloxyethyl, 3-ethoxypropyl, 4-ethoxybutyl, 4-ethoxy-3-methoxybutyl, 4-ethoxy-3-methylpentyl and the like.

C _1-10 alkoxycarbonyl C _1-10 alkyl represents a straight chain having 1-10 carbon atoms, a branched chain having 3-10 carbon atoms, or a ring having 3-10 carbon atoms An alkyl group with 1-10 carbon atoms substituted by an alkoxycarbonyl group, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, isopropoxycarbonylmethyl, butoxy ylcarbonylmethyl, isobutoxycarbonylmethyl, tert-butoxycarbonylmethyl, pentyloxycarbonylmethyl, hexyloxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl, 3-(ethyl oxycarbonyl)propyl, 4-(ethoxycarbonyl)butyl, 4-(ethoxycarbonyl)pentyl, 4-(ethoxycarbonyl)-3-methylpentyl and the like.

Farnesyl means (2Z,6Z)-3,7,11-trimethyldodeca-2,6,10-trienyl.

4-morpholinyl C _1-10 alkyl represents an alkyl group with 1-10 carbon atoms substituted by 4-morpholinyl, such as 2-(4-morpholinyl) ethyl, 3-(4- Morpholinyl) propyl, 4-(4-morpholinyl) butyl, 5-(4-morpholinyl) pentyl, 6-(4-morpholinyl) hexyl, 7-(4-morpholinyl) ) heptyl, 8-(4-morpholinyl) octyl, 9-(4-morpholinyl) nonyl, 10-(4-morpholinyl) decyl, 2-(4-morpholinyl) pentyl base, 1-methyl-3-(4-morpholinyl)butyl.

By the formula C (O) NR ^a R ^b (wherein, R ^a and R ^b are the same or different, representing a hydrogen atom or a C _1-10 alkyl) substituted examples of C _1-10 alkyl include 2-(N, N-Dimethylaminocarbonyl) ethyl, 2-(N, N-diethylaminocarbonyl) ethyl, 3-(N, N-diethylaminocarbonyl) propyl, 2-(N-methyl Aminocarbonyl)ethyl, 2-(N-ethylaminocarbonyl)ethyl, 2-(N,N-methylethylaminocarbonyl)ethyl, 2-(N,N-ethylpropylaminocarbonyl) ethyl, 2-(N,N-diethylaminocarbonyl)-1-methylethyl.

Naphthyl substituted by 1-7 halogen atoms means naphthyl substituted by at least one fluorine atom, chlorine atom, bromine atom, or iodine atom, such as 1-fluoro-2-naphthyl, 2-fluoro-1-naphthalene Base, 1-chloro-2-naphthyl, 2-chloro-1-naphthyl, 1-bromo-2-naphthyl, 2-bromo-1-naphthyl, 1-iodo-2-naphthyl, 2-iodo -1-naphthyl, 1,3-difluoro-2-naphthyl, etc.

Heteroaryl means a monocyclic 5-membered or 6-membered aromatic ring containing at least one or more atoms of oxygen atom, nitrogen atom or sulfur atom, or benzene rings are fused on these single rings to form or fused to each other to form A bicyclic aromatic ring formed. For example, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, benzofuryl, indolyl Indolyl, benzothienyl, indazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, pyridyl, quinolinyl, isoquinolyl Linyl, pyridazinyl, pyrimidinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, etc.

C _1-10 alkoxy represents a straight-chain or branched alkoxy group with 1-10 carbon atoms, such as: methoxy, ethoxy, propoxy, isopropoxy, butoxy base, isobutoxy, tert-butoxy, pentyloxy, isopentyloxy, etc.

1-5 selected from halogen atoms, phenyl, C _1-10 alkyl, C _1-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy The phenyl substituted by the substituent means 1-5 selected from fluorine atom, chlorine atom, bromine atom, iodine atom, C _1-10 alkyl, cyclic C _3-10 alkyl, C _1-10 alkoxy , Cyclic C _3-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano or phenoxy substituent substituted phenyl. For example, phenyl substituted by 1 substituent includes: 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2 -Bromophenyl, 3-bromophenyl, 4-bromophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 2-methylphenyl, 3-methylphenyl, 4 -Methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 2-isopropylphenyl, 3-isopropylphenyl, 4-isopropylphenyl , 2-cyclopropylphenyl, 3-cyclopropylphenyl, 4-cyclopropylphenyl, 2-cyclohexylphenyl, 3-cyclohexylphenyl, 4-cyclohexylphenyl, 2-methoxy phenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-isopropoxyphenyl, 3-isopropoxyphenyl, 4-isopropoxyphenyl, 2-cyclo Butoxyphenyl, 3-cyclobutoxyphenyl, 4-cyclobutoxyphenyl, 2-cyclohexyloxyphenyl, 3-cyclohexyloxyphenyl, 4-cyclohexyloxyphenyl , 2-trifluoromethylphenyl, 3-fluoromethylphenyl, 4-trifluoromethylphenyl, 2-phenylphenyl, 3-phenylphenyl, 4-phenylphenyl, 2- Hydroxycarbonylphenyl, 3-hydroxycarbonylphenyl, 4-hydroxycarbonylphenyl, 2-aminophenyl, 3-aminophenyl, 4-aminophenyl, 2-nitrophenyl, 3-nitrophenyl , 4-nitrophenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-phenoxyphenyl, 3-phenoxyphenyl, 4-phenoxy Phenyl, etc. Examples of phenyl substituted by 2 substituents are: 2,3-difluorophenyl, 2,4-difluorophenyl, 2,5-difluorophenyl, 2,6-difluorophenyl, 3 , 4-difluorophenyl, 3,5-difluorophenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,6-dichloro Phenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2,5-dibromophenyl, 2, 6-dibromophenyl, 3,4-dibromophenyl, 3,5-dibromophenyl, 2,3-diiodophenyl, 2,4-diiodophenyl, 2,5-diiodophenyl Base, 2,6-diiodophenyl, 3,4-diiodophenyl, 3,5-diiodophenyl, 3-chloro-4-fluorophenyl, 4-chloro-3-fluorophenyl, 3 -Bromo-4-fluorophenyl, 4-bromo-3-fluorophenyl, 4-bromo-3-chlorophenyl, 3-bromo-4-chlorophenyl, 3-chloro-4-methylphenyl, 4-chloro-3-methylphenyl, 3-fluoro-4-methylphenyl, 4-fluoro-3-methylphenyl, 3-fluoro-4-methoxyphenyl, 4-fluoro-3 -Methoxyphenyl, 3-bromo-4-methoxyphenyl, 4-bromo-3-methoxyphenyl, 3-chloro-4-phenoxyphenyl, 4-chloro-3-benzene Oxyphenyl, 3-chloro-4-nitrophenyl, 4-chloro-3-nitrophenyl, 4-bromo-3-nitrophenyl, 3-bromo-4-nitrophenyl, 3 -amino-4-bromophenyl, 4-amino-3-bromophenyl, 3-bromo-4-hydroxycarbonyl, 4-bromo-3-hydroxycarbonylphenyl, 4-fluoro-3-hydroxycarbonyl, 3- Fluoro-4-hydroxycarbonylphenyl, 4-fluoro-3-hydroxycarbonyl, 3-cyano-4-fluorophenyl, 3-cyano-4-fluorophenyl, 4-cyano-3-methylbenzene group, 3-cyano-4-methylphenyl, 3-cyano-4-methoxyphenyl, 4-cyano-3-methoxyphenyl, etc. Examples of phenyl substituted by 3 substituents are: 2,3,4-trifluorophenyl, 3,4,5-trifluorophenyl, 3,4,5-trichlorophenyl, 3-chloro- 2,6-difluorophenyl, 3,5-dichloro-4-methoxyphenyl or 3,5-dibromo-4-methoxyphenyl and the like. Examples of the phenyl group substituted with four substituents include 2,5-dibromo-3,4-dimethoxyphenyl, 3,4-dibromo-2,4-dimethoxyphenyl and the like. Examples of phenyl substituted with 5 substituents include 2,3,4,5,6-pentafluorophenyl and the like.

In addition, the pharmaceutically acceptable salts in the present invention are, for example: salts formed with inorganic acids such as sulfuric acid, hydrochloric acid, and phosphoric acid; salts formed with acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, Salts with organic acids such as acid, salts with amines such as trimethylamine and methylamine, or salts with metal ions such as sodium ions, potassium ions, and calcium ions, etc.

The hydrate in the present invention is a pharmaceutically acceptable hydrate of the compound of the present invention or a salt thereof. The compound of the present invention and its salt may absorb water when exposed to the atmosphere or recrystallized, and may absorb water or become a hydrate. The hydrates in the present invention include the above-mentioned hydrates.

There are 5 asymmetric carbon atoms on the bicyclo[3.1.0]hexane ring of the compound represented by formula [I].

The preferred stereo configuration of the compound of the present invention is an optical isomer having an absolute configuration represented by formula [II], which may exist in the form of an isomer mixture such as an enantiomer or a racemate. That is, the compound of the present invention includes all enantiomeric mixtures and diastereomeric mixtures such as optical isomers and racemates of the compound represented by the following formula [II].

Neither formulas [I] nor [II] as compounds of the present invention have an effect on group II metabotropic glutamate receptors. However, they can be transformed into compounds represented by formulas [III] and [IV] that have strong antagonistic effects on group II metabotropic glutamate receptors by enzymatic hydrolysis or chemical hydrolysis in vivo. Therefore, the compounds of the present invention can exert pharmaceutical functions acting on group II metabotropic glutamate receptors.

[In the formula, X represents a hydrogen atom or a fluorine atom. Y represents -OCHR ³ R ⁴ , -SR ³ , -S(O) _n R ⁵ , -SCHR ³ R ⁴ , -S(O) _n CHR ³ R ⁴ , -NHCHR ³ R ⁴ , -N(CHR ³ R ⁴ ) (CHR ^3' R ^4' ), -NHCOR ³ or -OCOR ⁵ (in the formula, R ³ , R ^3' , R ⁴ and R ^4' are the same or different, representing a hydrogen atom, C _1-10 alkyl, C _1-10 alkenyl, phenyl, naphthyl, naphthyl substituted by 1-7 halogen atoms, heteroaryl or substituted by 1-5 halogen atoms, phenyl, C _1-10 alkyl, C _1-10 alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy substituent substituted phenyl. ^{R 5} represents C _1-10 alkyl, C _{1- 10} alkenyl, phenyl, naphthyl, naphthyl substituted by 1-7 halogen atoms, heteroaryl or 1-5 selected from halogen atoms, phenyl, C _1-10 alkyl, C _1-10 Phenyl substituted by substituents of alkoxy, trifluoromethyl, phenyl, hydroxycarbonyl, amino, nitro, cyano and phenoxy, n represents an integer 1 or 2). ] the 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylate derivative, its pharmaceutically acceptable salt or its hydrate.

The best way to practice the invention

The present invention relates to the compound of the present invention represented by formula [1] or formula [2], its pharmaceutically acceptable salt or its hydrate. The compounds of the present invention can be synthesized by known organic synthesis methods. For example, it can be produced by the method shown below.

First, synthetic intermediates necessary for the synthesis of compound [I] of the present invention—compounds (9), (16), (24), (27), (30) and (33) can be produced as follows. (In the following reaction formula, X, Y, Z, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ have the same meaning as above. ^{R 6} represents methylsulfonyl, benzenesulfonyl, tosyl, tri Aryl groups such as fluoromethanesulfonyl and alkylsulfonyl groups, benzoyl, 4-nitrobenzoyl. R ⁷ represents alkyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, etc. Oxycarbonyl, benzoyl, p-phenylbenzoyl, (pyridin-2-yl)carbonyl and other acyl groups, aryl, benzyl, p-methoxybenzyl, bis(p-methoxyphenyl)methyl Equal alkyl, 5,5-dimethyl-3-oxo-1-cyclohexenyl and other alkenyl, benzenesulfinyl, 2,4-dinitrosulfinyl and other sulfinyl, benzylsulfonyl A protecting group for amino groups such as acyl, diphenylphosphino or dialkyl phosphoryl. A ¹ represents formula R ³ or formula CHR ³ R ⁴ . ^{A 2} represents formula R ⁵ or formula CHR ³ R ⁴ . Q represents formula SR ³ , S(O) _n R ⁵ , the formula SCHR ³ R ⁴ or the formula S(O) _n CHR ³ R ⁴ ).

Step 1: In an inert solvent, in the presence of a base, compound (1) is mixed with a trifluoromethanesulfonylating agent such as trifluoromethanesulfonic anhydride, N-phenyl-bis(trifluoromethanesulfonimide), etc. reaction, compound (2) can be derived. Here, as the inert solvent, for example, hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, ethers such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane can be used. System solvents, acetonitrile, or their mixed solvents, etc. Bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine and other amines, potassium hydride, sodium hydride and other inorganic bases, lithium diisopropylamide, bis(trimethyl Metal amides such as potassium silyl)amide and lithium hexamethyldisilazane, and metal alcoholates such as sodium methoxide and potassium tert-butoxide. Reaction with N-phenyl-bis(trifluoromethanesulfonimide) preferably in tetrahydrofuran in the presence of lithium hexamethyldisilazane at -78°C to room temperature for 2 hours to 4 hours, Compound (2) can be derived.

Step 2: In an inert solvent, in the presence of a transition metal catalyst, in organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, or inorganic bases such as potassium carbonate and sodium bicarbonate Compound (3) can be derived by reacting compound (2) with carbon monoxide and R ² OH in the presence of species (see Tetrahedron Letters 26, 1109 (1985)). Here, the transition metal catalyst is, for example, a zero-valent palladium reagent. For example, divalent palladium such as palladium (II) and triphenylphosphine, 2,2'-bis(diphenylphosphino)-1,1-binaphthyl ( Ligands such as BINAP) are prepared in the reaction system. Alternatively, a zero-valent palladium reagent such as tetrakis(triphenylphosphine)palladium(0) may be used as it is. As an inert solvent, for example, hydrocarbon solvents such as benzene, toluene, and hexane, ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, acetonitrile, N,N-dimethylformamide, or their derivatives can be used. mixed solvents, etc. Reaction of compound (2) with carbon monoxide and ^R2OH , preferably in N,N-dimethylformamide, in the presence of diisopropylethylamine, palladium(II) acetate and triphenylphosphine at room temperature 2 hours to 7 hours, from which compound (3) can be derived.

Step 3: In an inert solvent, by using a conventional diolation reaction such as osmium tetroxide (refer to M. Hudlicky, "Oxidations in Organic Chemistry"), or a Sharpless asymmetric cis-dihydroxyl reaction using AD-mix as a reagent Compound (3) Oxidation to diols leads to compound (4). Here, the inert solvent can be, for example, alcohol solvents such as t-butanol, hydrocarbon solvents such as benzene, toluene, and hexane, ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, acetonitrile, acetone, N, N-dimethylformamide, water or their mixed solvents, etc. Preferably, compound (3) is reacted in a mixed solvent of acetonitrile and water using osmium tetroxide at room temperature for 30 minutes to 3 hours, oxidized to a diol, and compound (4) is derived.

Step 4: In hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , in inert solvents such as acetonitrile or their mixed solvents, in the presence of organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, or inorganic bases such as potassium carbonate and sodium bicarbonate, or In absence, compound (4) is reacted with thionyl chloride, and then in hydrocarbon solvents such as benzene, toluene, hexane, halogen solvents such as methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2-Dimethoxyethane and other ether solvents, acetonitrile, acetone, water or their mixed solvents and other inert solvents, through hydrogen peroxide, potassium persulfate preparation, ruthenium trichloride-metaperiodic acid Compound (5) can be derived by oxidation with conventional oxidizing agents such as sodium (see M. Hudlicky, "Oxidations in Organic Chemistry"). Preferably in dichloromethane, in the presence of triethylamine, under ice cooling, compound (4) is reacted with thionyl chloride for 30 minutes to 2 hours, and then in a mixed solvent of carbon tetrachloride, acetonitrile and water, Oxidation at 0°C to room temperature for 30 minutes to 2 hours. Compound (5) can be derived.

Step 5: react compound (5) with sodium azide in an inert solvent such as ether solvents such as tetrahydrofuran, ketones such as acetone, N, N-dimethylformamide, water or these mixed solvents, and then hydrolyze , Compound (6) can be derived from this (see J. Am. Chem. Soc. 110, 7538 (1988)). Preferably in a mixed solvent of N,N-dimethylformamide and water, at room temperature to 50°C, react compound (5) with sodium azide for 1 hour to 20 hours, and then react in a mixed solvent of diethyl ether and water Using 20% sulfuric acid in , hydrolyzed at room temperature for 1-2 days to derive compound (6).

In the formula [III], when Y is the formula OCHR ³ R ⁴ , the compound (9), the synthetic intermediate of the compound of the present invention, can be derived from the obtained compound (6) through the following steps 7, 8 and 9.

X=H, F, Y=OCHR ³ R ⁴

Step 7: For example, in hydrocarbon-based solvents such as benzene, toluene, hexane, and cyclohexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane In inert solvents such as ether solvents or their mixed solvents, in Bronsted acid catalysts such as trifluoromethanesulfonic acid, trifluoroacetic acid or hydrogen chloride, boron trifluoride diethyl ether complex, zinc chloride, chlorine In the presence of a Lewis acid catalyst such as tin chloride or trimethylsilyl-trifluoromethanesulfonate, the hydroxyl group and L of the compound (6) in which R ^{and R} are groups other than hydrogen atoms are ² , 2 , the reaction of the compound shown in the formula R ³ R ⁴ CHL ¹ of 2-trichloroiminoacetoxy can derive compound (7) (with reference to J.Chem.Soc.Perkin Trans.1, 2247 (1985), Synthesis, 568 (1987)). Here, ^L1 is a leaving group, such as a halogen atom, ethoxycarbonyloxy, phenoxycarbonyloxy and the like.

For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents, in sodium hydride, potassium hydride, potassium carbonate, sodium carbonate , sodium hydroxide, potassium hydroxide and other inorganic bases, bis(trimethylsilyl) lithium amide, diisopropyl lithium amide, sodium amide and other amidated metals, triethylamine, diisopropyl In the presence of organic bases such as ethylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, and potassium tert-butoxide, ^R1 and ^R2 are hydrogen atoms The hydroxyl group of the compound (6) other than the group and L ² is 2,2,2-trichloroiminoacetoxy groups other than the formula R ³ R ^{4 CHL} compound shown in the group reaction, can derive compound ( 7). Here, ^L2 is a leaving group, such as a halogen atom, tosylsulfonate, trifluoromethanesulfonate, toluenesulfonate, and the like. Preferably, in a mixed solvent of chloroform and cyclohexane, in the presence of trifluoromethanesulfonic acid, the hydroxyl group of compound (6) is reacted with the compound represented by formula R ³ R ⁴ CHL ¹ at room temperature for 1 hour to 3 hours, by This leads to compound (7).

Step 8: For example, in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , acetonitrile, acetone, water or their mixed solvents and other inert solvents, by the Staudinger (Staudinger) reaction carried out by triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. Bull.Chem.Soc.Fr., 815(1985)); and inert solvents such as alcohols such as ethanol and methanol, esters such as ethyl acetate, N,N-dimethylformamide, water or their mixed solvents Among them, hydrogenation in the presence of metal catalysts such as palladium carbon and palladium black; the reduction reaction of conventional azido groups represented by hydride reduction with lithium aminoborohydride, etc. (refer to A.F.Abdel-Magid, "Reductions in Organic Synthesis"), compound (8) can be derived from compound (7). The compound (8) can be derived by reacting the compound (7) at room temperature for 2 hours to 12 hours, preferably by the Stödinger reaction using trimethylphosphine in a mixed solvent of tetrahydrofuran and water.

Step 9: by conventional hydrolysis reaction (referring to TWGreene, PGM Wuts, "Protective Groups in Organic Synthesis"), R ¹ and R ² are represented by formula COOR ¹ and formula COOR ² in compound (8) of groups other than hydrogen atoms The part of is transformed into formic acid, which can lead to compound (9), the synthetic intermediate of the compound of the present invention. Preferably, compound (8) is hydrolyzed for 1 day to 7 days using lithium hydroxide in a mixed solvent of tetrahydrofuran and water at room temperature to 50° C., and compound (9), a synthetic intermediate of the compound of the present invention, can be derived.

In formula [III], for the case where Y is formula SR ³ , formula S(O) _n R ⁵ , formula SCHR ³ R ⁴ , formula S(O) _n CHR ³ R ⁴ , the following steps 10, 11, 12, 13, 14 and 15, compound (16), a synthetic intermediate of the compound of the present invention, is derived from compound (6).

X=H, F, Y=SR ³ , S(O) _n R ⁵ , SCHR ³ R ⁴ , S(O) _n CHR ³ R ⁴

Step 10: For example, in hydrocarbon solvents such as benzene, toluene, hexane, and cyclohexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane Ether solvents, N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents, in sodium hydride, potassium hydride, carbonic acid Potassium, sodium carbonate, sodium hydroxide, potassium hydroxide and other inorganic bases, bis(trimethylsilyl) lithium amide, diisopropyl lithium amide, sodium amide and other amide metals, triethylamine, In the presence of organic bases such as pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, and potassium tert-butoxide, R ¹ and R ² is the hydroxyl group of the compound (6) other than a hydrogen atom, and trifluoromethanesulfonylating agents such as trifluoromethanesulfonic anhydride, N-phenyl-bis(trifluoromethanesulfonimide), or methyl Compound (10) can be derived by reacting alkyl and aryl sulfonylating agents such as sulfonyl chloride, benzenesulfonyl chloride, and toluenesulfonyl chloride. Compound (10) can be derived by reacting the hydroxyl group of compound (6) with trifluoromethanesulfonic anhydride preferably in dichloromethane in the presence of pyridine at -78°C to ice-cooling for 30 minutes to 3 hours.

Step 11: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , dimethyl sulfoxide or N,N-dimethylformamide or their mixed solvents and other inert solvents, with metal alcoholates such as sodium ethoxide and potassium tert-butoxide, sodium, potassium, sodium hydride, potassium hydride Compound (11) can be derived from compound (10) by reacting with compounds represented by formula A ¹ SNa and formula A ¹ SK prepared from thiols ^represented by formula A 1 SH and thiophenols. Preferably in dimethyl sulfoxide, react with the compound shown in formula A ¹ SHNa prepared from sodium and the compound shown in formula A ¹ SH at room temperature for 10 minutes to 1 hour, thus compound (11) can be derived from compound (10) ).

Step 12: For example, in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, acetic acid, water or their mixed solvents and other inert solvents, by using sodium periodate or peracetic acid, etc. Compound (12) can be derived from compound (11) in which A ¹ is not a hydrogen atom by performing a conventional oxidation reaction from sulfide to sulfoxide (refer to M. Hudlicky, "Oxidations in Organic Chemistry").

Step 13: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water or their mixed solvents and other inert solvents, such as using 3-chloroperbenzoic acid or hydrogen peroxide, etc. to carry out conventional Compound (13) can be derived from compound (12) or compound (11) in which A ¹ is not a hydrogen atom by the oxidation reaction of sulfide or sulfoxide to sulfone (see M. Hudlicky, "Oxidations in Organic Chemistry"). Or, for example, in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, In inert solvents such as acetonitrile, acetone, dimethyl sulfoxide, N,N-dimethylformamide, water or their mixed solvents, use conventional oxidants such as 3-chloroperbenzoic acid or hydrogen peroxide (refer to M. Hudlicky, "Oxidations inOrganic Chemistry" reference), by controlling reaction conditions such as oxidant equivalent number, reaction time, reaction temperature or solvent, can obtain compound (12) and compound (13) by the compound (11) that ^A is not a hydrogen atom mixture. Compound (12) and compound (13) can be derived by reacting compound (11) with 3-chloroperbenzoic acid preferably in dichloromethane at -78°C to room temperature for 1 hour to 24 hours.

Step 14: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , acetonitrile, acetone, water or their mixed solvents and other inert solvents, by the Stödinger reaction (referring to Bull.Chem .Soc.Fr., 815(1985)); and in inert solvents such as alcohols such as ethanol and methanol, esters such as ethyl acetate, N,N-dimethylformamide, water or their mixed solvents, through Hydrogenation in the presence of metal catalysts such as palladium carbon, palladium black, etc.; conventional azide reduction reactions represented by hydride reduction with lithium aminoborohydride, etc. (refer to A.F. Abdel-Magid, "Reductions in Organic Synthesis" ), compound (15) can be derived from compound (14). Compound (15) can be derived by reacting compound (14) at room temperature for 1 to 2 hours, preferably in a mixed solvent of tetrahydrofuran and water, by the Stödinger reaction using trimethylphosphine.

Step 15: According to the same method as Step 9, at least one of R ¹ and R ² is a group other than a hydrogen atom, and the part represented by the formula COOR ¹ and the formula COOR ² in the compound (15) is hydrolyzed, and the present invention can be derived Synthetic intermediate of compound-compound (16). Preferably, in a mixed solvent of tetrahydrofuran and water, using lithium hydroxide, at room temperature to 40 ° C, the compound (15) is hydrolyzed for 5 days to 7 days, so that the synthetic intermediate of the compound of the present invention-compound (16) can be derived . Or preferably use 60% sulfuric acid at 100°C-150°C to hydrolyze compound (15) for 1-5 days, thereby deriving compound (16), a synthetic intermediate of the compound of the present invention.

In the formula [III], for the case where Y is the formula NHCHR ³ R ⁴ or the formula N(CHR ³ R ⁴ )(CHR ^3' R ^4' ), through the following steps 16, 17, 18, 19, 20, 21 and 22, the synthetic intermediates of the compounds of the present invention-compounds (24) and (27) can be derived from the synthetic intermediate (6).

X=H, F, Y=NHCHR ³ R ⁴

Step 16: Compounds (17) and (21) can be derived from compounds (6) and (20) by reducing the azide group in the same manner as in Step 14. Preferably, in a mixed solvent of tetrahydrofuran and water, compound (6) and compound (20) are reacted at room temperature for 1 hour to 12 hours by using the Stödinger reaction of trimethylphosphine to derive compound (17) respectively and compound (21).

Step 17: Amino compound (18) can be derived from the amino group of compound (17) by conventional amino protection reaction (refer to T.W. Greene, P.G.M. Wuts, "Protective Groups in Organic Synthesis"). Compound (18) can be derived by reacting compound (17) with di-tert-butyl dicarbonate preferably in tetrahydrofuran at room temperature in the presence of saturated aqueous sodium bicarbonate solution for 2 hours to 6 hours.

Step 18: In the same manner as in Step 10, compound (19) can be derived by alkylating and aryl sulfonylation of the hydroxyl group of compound (18) in which R ¹ and R ² are groups other than hydrogen atoms. Compound (19) can be derived by reacting the hydroxyl group of compound (18) with trifluoromethanesulfonic anhydride preferably in dichloromethane in the presence of pyridine at -78°C to ice cooling for 30 minutes to 2 hours.

Step 19: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , ethyl acetate, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water or their mixed solvents and other inert solvents can be reacted by making compound (19) and sodium azide Compound (20) was derived. Compound (20) can be derived by reacting compound (19) with sodium azide preferably in N,N-dimethylformamide at room temperature to 35°C for 1 to 2 days.

Step 20: For example, in hydrocarbon-based solvents such as benzene, toluene, hexane, and cyclohexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane Ether solvents, N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents, in sodium hydride, potassium hydride, carbonic acid Potassium, sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and other inorganic bases, bis(trimethylsilyl) lithium amide, diisopropyl lithium amide, sodium amide and other metal amides, In the presence of organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, potassium tert-butoxide or In the absence of compound (21) and (22) formula -NH ₂ and formula -R ³ R ⁴ CHNH shown in the amino group and formula R ³ R ⁴ CHL ² or formula R ^3' R ^4' CHL ² shown in the compound reaction , compounds (22) and (25) can be derived respectively. Here, ^L2 is a leaving group, such as a halogen atom, tosylsulfonate, trifluoromethanesulfonate, toluenesulfonate, and the like. And, for example, in hydrocarbon solvents such as benzene, toluene, hexane, and cyclohexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, etc. Ether solvents, N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide, ethanol, methanol, water or their mixed solvents and other inert solvents, in triacetyl In the presence of reducing ^agents such ^{as sodium} oxyborohydride or sodium cyanotriborohydride, the Borch ^reaction ( Referring to AFAbdel-Magid et al., Tetrahedron Lett., 31, 5595 (1990)), the compound (22) and (25) can be derived by subjecting it to a reductive amination reaction. Compound (22) can be derived by reacting compound (21) with the compound represented by the formula R ³ R ⁴ CHBr in chloroform preferably in the presence of pyridine at room temperature for 1-4 days. On the other hand, preferably in N,N-dimethylformamide, in the presence of potassium carbonate, the compound (22) is reacted with the compound represented by the formula R ^3' R ^4' CHI at room temperature for 1 day to 4 days, Compound (25) can be derived.

Step 21: by conventional deprotection reaction (referring to TWGreene, PGMWuts, "Protective Groups in Organic Synthesis" reference), the protecting group ^R of the amino group of compound (22) and compound (25) is deprotected and transformed into amino group, From this, compounds (23) and (26) can be derived respectively. Preferably use 4 equivalents of hydrogen chloride/ethyl acetate, under ice-cooling to room temperature, carry out deprotection to compound (22) and compound (25) for 12 hours-36 hours, thus can derive compound (23) and compound (26) .

Step 22: According to the same method as Step 9, at least one of R ¹ and R ² is a group other than a hydrogen atom, and the moieties represented by the formulas COOR ¹ and COOR ² in compounds (23) and (26) are hydrolyzed, by This leads to the synthesis intermediates of the compounds of the present invention - compounds (24) and (27). Preferably in a mixed solvent of tetrahydrofuran and water, use lithium hydroxide to hydrolyze compound (23) and compound (26) at room temperature for 1 day to 7 days, thereby deriving the synthetic intermediate of the compound of the present invention-compound ( 24) and compound (27).

In the formula [III], when Y is the formula -NHCOR ³ , the compound (30), the synthetic intermediate of the compound of the present invention, can be derived from the compound (21) through the following steps 23, 24 and 25.

Y = NHCOR ³

Step 23: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents, in triethylamine, pyridine, morpholine, diiso In the presence or absence of organic bases such as propylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, the amino group at the 3-position in the compound (21) and Compound (28) can be derived by reacting the compound represented by formula L ¹ COR ³ or formula R ³ COOCOR ³ .

Here, L ¹ is a leaving group, such as a halogen atom, ethoxycarbonyloxy, phenoxycarbonyloxy and the like. Or when R ³ is a hydrogen atom, the compound (28) can be derived by a conventional formylation reaction (refer to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis"). Compound (28) can be derived by reacting compound (21) with the compound represented by the formula R ³ COCl at room temperature, preferably in chloroform in the presence of pyridine, for 1 hour to 4 hours.

Step 24: According to the same method as Step 21, compound (29) can be derived by deprotecting compound (28) with formula -NHR ⁷ . Compound (29) can be derived by deprotecting compound (28) under ice-cooling, preferably using 4 equivalents of hydrogen chloride/ethyl acetate for 30 minutes to 2 hours.

Step 25: According to the same method as Step 9, at least one of R ¹ and R ² is a compound (29) in which the formula -COOR ¹ and the formula -COOR ² in the group other than a hydrogen atom are subjected to a hydrolysis reaction, by This leads to compound (30), an intermediate of the compound of the present invention. Preferably, compound (29) is hydrolyzed in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at room temperature for 1 hour to 7 hours to derive compound (30), a synthetic intermediate of the compound of the present invention. In formula [III], for the situation that Y is formula-OCOR ⁵ , can pass through following steps 26,27 and 28, by ^R Be the synthetic intermediate (6) of benzyl and derive the synthetic intermediate (33) of compound of the present invention ).

Y=OCOR ⁵ , R ² =Bn

Step 26: For example, in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents or solvent-free, in triethylamine, pyridine, morphine In the presence or absence of organic bases such as phylloline, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, ^R is not a hydrogen atom The compound (31) can be derived by reacting the hydroxyl group of the compound (6) in which R ² is benzyl with the compound represented by the formula L ¹ COR ⁵ or the formula R ⁵ COOCOR ⁵ . Here, ^L1 is a leaving group, for example, a halogen atom, ethoxycarbonyloxy, phenoxycarbonyloxy or the like. Compound (31) can be derived by reacting compound (6) with a compound represented by formula R ⁵ COCl preferably in pyridine at room temperature for 12 hours to 36 hours.

Step 27: For example, in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane , acetonitrile, acetone, water or their mixed solvents and other inert solvents, by the Staudinger (Staudinger) reaction carried out by triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. Bull.Chem.Soc.Fr., 815(1985)), obtain amides from compound (31), and then in alcohols such as ethanol and methanol, esters such as ethyl acetate, N,N-dimethylformamide , in an inert solvent such as water or a mixed solvent thereof, in the presence of a metal catalyst such as palladium carbon or palladium black, the deprotection of the benzyl group is reductively carried out by a hydrogenation reaction, thereby deriving the compound (32). For example, in alcohols such as ethanol, methanol, esters such as ethyl acetate, N, N-dimethylformamide, water or their mixed solvents and other inert solvents, in the presence of metal catalysts such as palladium carbon and palladium black, Compound (32) can also be directly derived from compound (31) by hydrogenation reaction. An aminated compound can be derived by reacting the compound (31) at room temperature for 30 minutes to 2 hours, preferably in a mixed solvent of tetrahydrofuran and water, by the Stödinger reaction using trimethylphosphine. Then, compound (32) can be derived by reacting the aminated compound at room temperature for 30 minutes to 2 hours in ethanol in the presence of 5% palladium-on-carbon under hydrogen atmosphere.

Step 28: By the same method as Step 9, compound (33), a synthetic intermediate of the compound of the present invention, can be derived from compound (32) in which R ¹ is a group other than a hydrogen atom. Compound (33), a synthetic intermediate of the compound of the present invention, can be derived by hydrolyzing compound (32) at room temperature for 30 minutes to 2 hours using lithium hydroxide, preferably in a mixed solvent of tetrahydrofuran and water.

The compound [I] of the present invention can be produced by monoesterification or diesterification of two formic acid moieties of the obtained synthetic intermediate [III].

The compound [I], which is the compound of the present invention, can be derived by di-esterifying or mono-esterifying the formic acid moiety of the compound [III] in Step 29 shown below.

Step 29: Compound [I], the compound of the present invention, can be derived by subjecting the formic acid moiety of compound [III] to a conventional esterification reaction (refer to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis"). Preferably in tetrahydrofuran at room temperature, the formic acid moiety of compound [III] is prepared as a lithium salt using lithium hydroxide, and then in N,N-dimethylformamide at room temperature to 90°C, with the formula R ¹ Br React with the compound represented by the formula R ² Br for 4 hours to 12 hours, thereby deriving the compound [I] of the present invention. It can also be used in hydrocarbon-based solvents such as benzene, toluene, and hexane, halogen-based solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether-based solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane. Methyl sulfoxide, N,N-dimethylformamide or their mixed solvents or in solvent-free, inorganic acids such as sulfuric acid, phosphoric acid, hydrochloric acid, organic acids such as acetic acid, oxalic acid, methanesulfonic acid, thionyl In the presence or absence of acid chlorides such as dichloride and phosphorus oxychloride, the formic acid moiety on the 6-carbon of compound [III] is reacted with the alcohol represented by formula R ^1OH for a short time or controlled reaction temperature, optionally The compound [I] of the present invention in which R ² is a hydrogen atom is derived. Preferably in the presence of the alcohol represented by the formula R ¹ OH and thionyl chloride, under ice cooling to 80 ° C, the formic acid moiety on the 6-carbon of compound [III] is reacted for 1 hour to 3 days, from which R can be derived Compound [I] of the present invention in which ² is a hydrogen atom.

In addition, after protecting the α-amino acid moiety at the 2-carbon by using an α-amino acid protection method using triethylborane or a copper (II) complex (refer to International Journal of Peptide & Protein Research, 37, 210 (1991 ); Synthesis, 119(1990); Helv.Chem.Acta, 44,159(1961)), by conventional esterification (referring to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis") on the 6-carbon formic acid Esterification, and then by the deprotection reaction of α amino acid part (referring to International Journal of Peptide & Protein Research, 37,210 (1991); Synthesis, 119 (1990); Helv.Chem.Acta, 44,159 (1961)), can Selectively derive compound [I] in which R ² is a hydrogen atom.

After selectively deriving ^R as a compound [I] of a hydrogen atom, use conventional amino protecting groups such as allyloxycarbonyl or tert-butoxycarbonyl (referring to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis") The amino group on the 2-position carbon is protected, or without protection, through a conventional esterification reaction (referring to TWGreene, PGMWuts, "Protective Groups in Organic Synthesis"), the formic acid part on the 2-position carbon is esterified, and then the amino group is protected. In this case, the compound [I] of the present invention in which both R ¹ and R ² are groups other than hydrogen atoms can be derived by deprotecting the amino group (see TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis"). Preferably, in the presence of allyl chloroformate and saturated sodium bicarbonate, react the amino group on the 2-carbon at room temperature for 8 hours, protect it with an allyloxycarbonyl group, and then, in the presence of potassium carbonate, react with R ² X'( X' is a halogen atom, X' is preferably a bromine atom or an iodine atom) for 1 hour to 24 hours, and then in the presence of 1,3-dimethylbarbituric acid, through tetrakis (triphenylphosphine) palladium, in React at room temperature to 80°C for 1 hour to 24 hours to carry out the deprotection reaction of the amino group, thereby deriving the compound [I] of the present invention in which both R ¹ and R ² are groups other than hydrogen atoms.

It is also possible to convert R ¹ and R ² into the compound [I] of the formula COOR of groups other than hydrogen atoms by conventional hydrolysis reaction (refer to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis") in a short time or at low temperature The part shown in ¹ is converted into formic acid, thereby selectively deriving the compound [I], the compound of the present invention in which R ¹ is a hydrogen atom. Preferably, in a mixed solvent of tetrahydrofuran and water ^{, lithium hydroxide is used to hydrolyze the part represented by the formula COOR 1 in} the compound [I] in which R ^and R are groups other than hydrogen atoms at 0°C to room temperature for 30 minutes to 3 hours, thus deriving the compound [I] of the present invention in which R ¹ is a hydrogen atom.

At least one of R ^{and R} is an azido C _1-10 alkyl compound [I] can be derived as follows: for example, in hydrocarbon solvents such as benzene, toluene, hexane, dichloromethane, chloroform, carbon tetrachloride Halogen solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and other ether solvents, ethyl acetate, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water or their mixed solvents and other inert solvents, the corresponding halogenated C _1-10 alkyl compound [I] is reacted with sodium azide. Preferably, in a mixed solvent of N,N-dimethylformamide and water, at room temperature to 60°C, the compound [I] in which at least one of R ^{and R} is a halogenated C _1-10 alkyl group and an alkene Sodium nitride was reacted for 6 hours-18 hours, and at least one of R ^{and R} could be derived from the compound [I] in which at least one was an azido C _1-10 alkyl group.

Compound [I] in which at least one of R ^{and R} is amino C _2-10 alkyl can be derived as follows: For example, in hydrocarbon solvents such as benzene, toluene, hexane, etc. solvents, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and other ether solvents, acetonitrile, acetone, water or their mixed solvents and other inert solvents, by triethyl phosphite, trimethylphosphine , tributylphosphine, triphenylphosphine, etc. (refer to Bull.Chem.Soc.Fr., 815 (1985)); for example, alcohols such as ethanol, methanol, ethyl acetate, etc. In an inert solvent such as esters, N, N-dimethylformamide, water or their mixed solvents, through the hydrogenation reaction in the presence of metal catalysts such as palladium carbon and palladium black; Conventional azido group reduction reaction represented by hydride reduction etc. (referring to AFAbdel-Magid, "Reductions in Organic Synthesis"), the azido moiety of the corresponding azido C _1-10 alkyl compound [I] reduction. Preferably, in tetrahydrofuran and water mixed solvent, using the Stordinger reaction using trimethylphosphine, the compound [I] in which at least one of R ^{and R} is an azido C _1-10 alkyl group is reacted at room temperature 6 hours-18 hours, thus can derive R ¹ and R ² at least one is the compound [I] of amino C _1-10 alkyl.

The obtained compound [III] can also be converted into the compound [I] of the present invention in which R ¹ is a group other than a hydrogen atom and R ² is a hydrogen atom by the following steps 30, 31, 32 and 33.

Step 30: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, 1,4 -in ether solvents such as dioxane, amides such as N,N-dimethylformamide and N-methyl-2-pyrrolidone, inert solvents such as dimethyl sulfoxide, water or their mixed solvents, in three Ethylamine, pyridine, morpholine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine and other organic bases or potassium carbonate, sodium carbonate, carbonic acid Compound (34) can be derived by reacting the amino group of compound [III] with allyl chloroformate in the presence or absence of inorganic salts such as sodium hydrogen. Compound (34) can be derived by reacting compound [III] with allyl chloroformate at room temperature, preferably in 1,4-dioxane, in the presence of saturated aqueous sodium bicarbonate solution for 6 hours to 18 hours.

Step 31: For example, in hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, and ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane Or in inert solvents such as their mixed solvents, in the presence of aldehydes such as paraformaldehyde, use suitable catalysts such as p-toluenesulfonic acid, oxalic acid, use or do not use dehydration devices such as Dean-Stark moisture separator, make compound (34 ) to react, the compound (35) can be derived. Compound (35) can be derived by heating compound (34) to reflux, preferably in benzene, in the presence of p-toluenesulfonic acid, using paraformaldehyde and a Dean-Stark moisture separator for 1 hour to 5 hours.

Step 32: Compound (36) can be derived from compound (35) by a conventional esterification reaction (refer to TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis"). For example, it can also be used in hydrocarbon solvents such as benzene, toluene, hexane, and cyclohexane, halogen solvents such as methylene chloride, chloroform, and carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, etc. Ether solvents, N, N-dimethylformamide, N-methyl-2-pyrrolidone and other amides, dimethyl sulfoxide or their mixed solvents and other inert solvents, in sodium hydride, potassium hydride, potassium carbonate , sodium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide and other inorganic bases, bis(trimethylsilyl) lithium amide, diisopropyl lithium amide, sodium amide and other metal amides, In the presence of organic bases such as triethylamine, pyridine, diisopropylethylamine, 4-(N,N-dimethylamino)pyridine, 2,6-di-tert-butylpyridine, and potassium tert-butoxide, In the presence or absence of a suitable activator such as sodium iodide, the formula L ² CHR ^c OC(O)ZR ^d (wherein L ² is a leaving group, such as a halogen atom, tosylsulfonate, Compound (36) can be derived by reacting the ester moiety of compound (35) with trifluoromethanesulfonate, tosylate). Compound (36) is derived by reacting compound (35) with R ¹ Cl preferably in N,N-dimethylformamide in the presence of sodium iodide at room temperature to 75°C for 2 hours to 24 hours .

Step 33: In the presence of a regeneration agent for metal catalysts such as 0-valent palladium catalysts such as tetrakis(triphenylphosphine)palladium(0) and metal catalysts such as 1,3-dimethylbarbituric acid, for example, in benzene, toluene, hexane, etc. Inert solvents such as hydrocarbon solvents, halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane, or their mixed solvents, the compound (36) Deprotection of the α-amino acid moiety is carried out, whereby the compound (37), which is the compound of the present invention, can be derived. Compound (36) is preferably deprotected in chloroform in the presence of tetrakis(triphenylphosphine)palladium and 1,3-dimethylbarbituric acid at room temperature to 50° C. for 30 minutes to 3 hours , and thus the compound (37) of the present invention can be derived.

The compounds of the present invention can be combined with one or more pharmaceutically acceptable carriers, excipients and diluents to prepare pharmaceutical preparations or pharmaceutical compositions. Examples of the above-mentioned carriers, excipients and diluents are: water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gelatin, alginate, Calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkylparabens, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, large Various oils such as soybean oil.

The compounds of the present invention can be mixed with the above-mentioned carriers, excipients or diluents, and on the basis of mixing commonly used additives such as bulking agents, binders, disintegrants, pH regulators, dissolving agents, etc., through commonly used Preparation technology, making oral or parenteral drugs such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches, etc. II metabotropic glutamate receptor antagonists.

The compound of the present invention can be administered to adult patients at 0.01-500 mg once or more times a day, orally or parenterally, and oral administration is preferred from the viewpoints of ease of use and efficacy. The dose can be appropriately increased or decreased according to the type of disease to be treated, the patient's age, body weight, symptoms, and the like.

Example

Examples and test examples are given below to describe the present invention in detail, but the present invention is not limited thereto.

(reference example 1)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid synthesis

(1) While maintaining the temperature at -63°C to -54°C, 245mL of a 2.66M n-butyllithium hexane solution was added dropwise to a solution of 137mL of hexamethyldisilazane in 700mL of tetrahydrofuran, and stirred for 1 hour. While keeping -63°C to -52°C, 101 g of (1R,5R,6R)-6-fluoro-2-oxo-bicyclo[3.1.0]hexane-6-ethyl carboxylate was added dropwise to the solution. 340mL tetrahydrofuran solution. After 1 hour, a solution of 213 g of N-phenyl-bis(trifluoromethanesulfonimide) in 700 mL of tetrahydrofuran was added at -63°C to -45°C. The reaction solution was naturally warmed to room temperature, and stirred for another 2.5 hours. The reaction solution was diluted with diethyl ether, washed three times with saturated aqueous sodium bicarbonate solution, washed with saturated brine, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: Wako Gel C200 (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-ethyl acetate=30:1-20:1-5:1 )purification. 175 g of the obtained ethyl (1R, 5R, 6R)-6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hex-2-ene-6-carboxylate was dissolved in 875 mL of N,N-di To methylformamide and 875 mL of ethanol, 95.1 mL of diisopropylethylamine, 8.65 g of triphenylphosphine and 3.70 g of palladium acetate were added, followed by stirring at room temperature for 5.5 hours under a carbon monoxide atmosphere. 1N hydrochloric acid was added to the reaction solution, followed by extraction with diethyl ether 6 times. The organic layers were combined, washed 4 times with saturated aqueous sodium bicarbonate solution, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel: Wako Gel C200 (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-ethyl acetate=30:1-20:1-10:1 ) purification to obtain 92.6 g of diethyl (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.31(t, J=7.03Hz, 3H), 1.33(t, J=7.03Hz, 3H), 2.37-2.51(m, 1H), 2.65-2.81( m, 1H), 2.88-3.04(m, 1H), 3.10(dd, J=7.47, 2.64Hz, 1H), 4.12-4.40(m, 4H), 6.77-6.79(m, 1H).

MS(ESI)(Pos)m/z; 265(M+Na) ⁺

[α] _D ²¹ =+158.0° (CHCl ₃ , c=1.5)

(2) To 92.4g (1R,5R,6R)-6-fluoro-bicyclo[3.1.0]hex-2-ene-2,6-dicarboxylate dissolved in 1.76L acetonitrile and 680mL water, add 160mL 50% N-methylmorpholine N-oxide aqueous solution and 121mL 5% osmium(VIII) oxide aqueous solution were stirred at room temperature for 1 hour. Sodium sulfite was added to the reaction solution under ice-cooling, stirred at room temperature for 30 minutes, and then filtered with celite. Saturated brine was added to the filtrate, and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate=4:1-1:1) to obtain 95.6 g (1R, 2S ,3R,5R,6R)-6-Fluoro-2,3-dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.31(t, J=7.25Hz, 6H), 2.03-2.34(m, 3H), 2.40-2.55(m, 1H), 2.70(d, J=9.23 Hz, 1H), 4.09(s, 1H), 4.18-4.47(m, 5H).

MS(ESI)(Nega)m/z; 275(MH) ^-

[α] _D ²⁷ = -69.1° (CHCl ₃ , c = 1.4)

(3) Under ice cooling, add 95.4g (1R, 2S, 3R, 5R, 6R)-6-fluoro-2,3-dihydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester 106 mL of triethylamine was added to 1.24 L of dichloromethane solution, and 37.6 mL of thionyl chloride was added dropwise, followed by stirring for 30 minutes. The reaction solution was washed twice with water, washed with saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was dissolved in 640 mL of carbon tetrachloride, 640 mL of acetonitrile and 760 mL of water. To this solution were added 96.0 g of sodium metaperiodate and 655 mg of ruthenium trichloride hydrate, and stirred at room temperature for 1 hour. After filtering with celite, the filtrate was separated, and the aqueous layer was extracted with diethyl ether. The organic layers were combined, washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 4:1) to obtain 109 g of (1R, 1aR, 1bS, 4aR, 5aR)-1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ6-thiacyclopropeno[a]pentalene-1,1b-dicarboxylate .

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.33(t, J=7.03Hz, 3H), 1.34(t, J=7.03Hz, 3H), 2.52-2.94(m, 4H), 4.23-4.47( m, 4H), 5.40-5.53 (m, 1H).

MS(ESI)(Pos)m/z; 361(M+Na) ⁺

[α] _D ²⁸ =+18.3° (CHCl ₃ , c=1.0)

(4) To 109 g (1R, 1aR, 1bS, 4aR, 5aR)-1-fluoro-3,3-dioxotetrahydro-2,4 dissolved in 1.10L N,N-dimethylformamide and 110 mL of water 37.7 g of sodium azide was added to diethyl -dioxa-3λ ⁶ -thieno[a]pentadiene-1,1b-dicarboxylate, and stirred at 50°C for 14 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, then 516 mL of 20% (V/V) sulfuric acid was added, and the mixture was stirred at room temperature for 34 hours. After the reaction liquid was separated, the organic layer was washed twice with saturated brine, and then dried over anhydrous magnesium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: ワコウゲル C200, developing solvent: hexane-ethyl acetate = 4:1) to obtain 88.5 g (1R, 2R, 3R, 5R ,6R)-diethyl 2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.33(t, J=7.03Hz, 3H), 1.38(t, J=7.03Hz, 3H), 2.18-2.61(m, 5H), 4.21-4.48( m, 5H).

MS(ESI)(Pos)m/z; 324(M+Na) ⁺

[α] _D ²² = -48.7° (CHCl ₃ , c = 1.0)

(5) 1.36g of 60% sodium hydride (oily) was washed twice with hexane, then suspended in 46mL of tetrahydrofuran, and 60.1g of 3,4-dichlorobenzyl alcohol dissolved in 68mL of tetrahydrofuran was added dropwise. Stir at room temperature for 30 minutes, then cool with salt-ice, and add 34 mL of trichloroacetonitrile dropwise. The mixture was stirred at this temperature for 30 minutes, under ice-cooling for 30 minutes, under a water bath for 30 minutes, and at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 45 mL of pentane and 1.1 mL of methanol were added to the residue, and vigorously stirred at room temperature for 30 minutes. After filtering off inorganic salts, the filtrate was concentrated under reduced pressure to obtain 106.8 g of crude 3,4-dichlorobenzyl-2,2,2-trichloroiminoacetate.

2.03 g of crude 3,4-dichlorobenzyl-2,2,2-trichloroiminoacetate and 1.27 g (1R, 2R, 3R, 5R, 6R)-2-azido-3- Diethyl hydroxy-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate was dissolved in 5.4 mL of chloroform and 10.8 mL of cyclohexane. After cooling in an ice bath, 187 μL of trifluoromethanesulfonic acid was added. Stir at 30°C for 1.5 hours, then add 93 μL of trifluoromethanesulfonic acid, and stir for 1 hour. Inorganic salts were filtered off, and saturated aqueous sodium bicarbonate solution was added under ice cooling. After extraction with chloroform twice, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 15:1) to obtain 771 mg (1R, 2R, 3R, 5R, 6R)-diethyl 2-azido-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.26-1.39(m, 6H), 2.24-2.51(m, 4H), 3.91-4.05(m, 1H), 4.18-4.35(m, 4H), 4.42 (d, J=11.9Hz, 1H), 4.64(d, J=11.9Hz, 4H), 7.05-7.14(m, 1H), 7.36-7.43(m, 2H).

MS (ESI) (Pos) m/z; 482 (M+Na) ⁺

[α] _D ²⁴ = -14.5° (CHCl ₃ , c = 0.94)

(6) 27.5 g (1R, 2R, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzyloxy)-6-fluoro -Add 65.7mL of 1M trimethylphosphine/tetrahydrofuran solution to bicyclo[3.1.0]hexane-2,6-dicarboxylate diester, and stir at room temperature for 4 hours. Diluted with 825 mL of diethyl ether, washed with saturated aqueous sodium bicarbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate=4:1-3:2) to obtain 23.1 g (1R, 2R ,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.24-1.40 (6H, m), 2.02-2.28 (2H, m), 2.51-2.80 (2H, m), 3.98-4.08 (1H, m), 4.18 -4.34(4H, m), 4.43(1H, d, J=12.5Hz), 4.53(1H, d, J=12.5Hz), 7.10-7.19(1H, m), 7.36-7.45(2H, m).

MS(ESI)(Pos)m/z; 456(M+Na) ⁺

[α] _D ²² = +11.6° (CHCl ₃ , c = 0.50%)

(7) To 22.9 g (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[ 3.1.0] Add 5.53 g of lithium hydroxide hydrate to diethyl hexane-2,6-dicarboxylate, and stir at room temperature for 3 days. Further, 443 mg of lithium hydroxide hydrate was added, followed by stirring at room temperature for 1 day. Under ice-cooling, 169 mL of 1N hydrochloric acid was added dropwise, and stirred at room temperature for 14 hours. The precipitated solid was collected by filtration, and the solid was washed with 200 mL of tetrahydrofuran and 100 mL of water to obtain 12.3 g of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6 -Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.28-2.45 (3H, m), 2.50 (1H, dd, J=7.6, 13.4Hz), 4.05-4.11 (1H, m), 4.52 (1H, d, J=12.1Hz), 4.60(1H, d, J=12.1Hz), 7.26-7.58(3H, m).

MS(ESI)(Nega)m/z; 376(MH) ^-

[α] _D ²⁷ = -10.0° (1N NaOH, c = 1.02)

(reference example 2)

(1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl (sulfanil))-6-fluoro-bicyclo[3.1.0]hexane-2, Synthesis of 6-dicarboxylic acid

(1) In a nitrogen atmosphere at -75°C, dissolve 120 mg of (1R, 2R, 3R, 5R, 6R)-2-azido-6-fluoro-3-hydroxyl-bicyclo[3.1 in 20 mL of dichloromethane .0] 78 μL of trifluoromethanesulfonic anhydride dissolved in 48 μL of pyridine and 0.4 mL of dichloromethane was added dropwise to diethyl hexane-2,6-dicarboxylate, followed by stirring under ice cooling for 1.5 hours. At -75°C, 39 µL of trifluoromethanesulfonic anhydride dissolved in 24 µL of pyridine and 0.2 mL of dichloromethane was added dropwise, followed by stirring under ice-cooling for 25 minutes. Add 10 mL of diethyl ether, filter off the solid, and concentrate the filtrate under reduced pressure. The residue is purified by column chromatography (silica gel: Wakowgel C200, developing solvent: hexane-ethyl acetate=5:1) to obtain 166 mg (1R, 2R, 3R ,5R,6R)-2-Azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.35(t, J=7.0Hz, 3H), 1.38(t, J=7.0Hz, 3H), 2.35-2.50(m, 2H), 2.62-2.86( m, 2H), 4.31(q, J=7.0Hz, 2H), 4.27-4.55(m, 2H), 4.94-5.10(m, 1H).

MS(FAB)(Pos)m/z; 434(M+H) ⁺

[α] _D ²⁶ = -31.2° (CHCl ₃ , c = 0.4)

(2) To 701 mg (1R, 2R, 3R, 5R, 6R)-2-azido-6-fluoro-3-trifluoromethanesulfonyloxygen dissolved in 6.9 mL of N,N-dimethylformamide Add 688mg potassium nitrite, 428mg 18-crown-6 ether to diethyl-bicyclo[3.1.0]hexane-2,6-dicarboxylate, then stir at room temperature under nitrogen atmosphere for 1.5 days, and then Stirring was carried out at 45°C for 3.5 days. After adding water, it was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 5:1) to obtain 388 mg (1R, 2R, 3S, 5R, 6R)-2,6-diethyl 2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.34(t, J=7.0Hz, 3H), 1.36(t, J=7.0Hz, 3H), 2.16(dd, J=2.9Hz, 14.9Hz, 1H ), 2.17-2.30(m, 1H), 2.44(dd, J=3.1Hz, 8.1Hz, 1H), 2.61(dd, J=12.3Hz, 16.0Hz, 1H), 2.80-2.99(m, 1H), 4.29(q, J=7.0Hz, 2H), 4.34(q, J=7.0Hz, 2H), 4.48-4.64(m, 1H).

MS(ESI)(Pos)m/z; 324(M+Na) ⁺

[α] _D ²⁵ =+6.4° (CHCl ₃ , c=1.0)

(3) Under a nitrogen atmosphere, at -77°C to -69°C, to 364 mg (1R, 2R, 3S, 5R, 6R)-2-azido-6-fluoro- 0.36 mL of trifluoromethanesulfonic anhydride dissolved in 1.2 mL of dichloromethane was added dropwise to 3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate diethyl ester and 0.21 mL of pyridine. Stirring was carried out at -77°C for 30 minutes, and then under ice cooling for 30 minutes. 30 mL of diethyl ether was added, the solid was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 5:1) to obtain 487 mg of (1R, 2R, 3S, 5R, 6R)-2-azido-6 -Diethyl fluoro-3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.36(t, J=7.03Hz, 3H), 1.39(t, J=7.47Hz, 3H), 2.26-2.63(m, 3H), 2.91-3.10( m, 1H), 4.25-4.45 (m, 4H), 5.57 (dd, J=9.01, 2.86Hz, 1H).

MS(ESI)(Pos)m/z; 456(M+Na) ⁺

[α] _D ²⁶ = -41.4° (CHCl ₃ , c = 1.1)

(4) Under a nitrogen atmosphere, at room temperature, 2.59 g of 3,4-dichlorobenzyl mercaptan was added to 308 mg of sodium dissolved in 18 mL of ethanol, stirred for 5 minutes and then concentrated under reduced pressure. To the residue was added 64 mL of dimethyl sulfoxide and 3.23 g of (1R,2R,3S,5R,6R)-2-azido-6-fluoro dissolved in 6.4 mL of dimethyl sulfoxide was added at room temperature -Diethyl 3-trifluoromethanesulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate, stirred for 10 minutes. 250 mL of diethyl ether was added to separate the upper and lower layers. The lower layer was extracted twice with diethyl ether. The organic layers were combined, washed with cooled 1 N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako Ugel C200, developing solvent: hexane-ethyl acetate=10:1-5:1) to obtain 3.35 g of (1R, 2S, 3R, 5R, 6R)-2- Diethyl azido-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.34(t, J=7.03Hz, 3H), 1.38(t, J=7.03Hz, 3H), 2.20-2.49(m, 4H) 2.99-3.13(m , 1H), 3.68(d, J=13.62Hz, 1H), 3.84(d, J=13.62Hz, 1H), 4.22-4.51(m, 4H), 7.16(dd, J=8.13, 1.98Hz, 1H) , 7.34-7.46(m, 2H).

MS (ESI) (Pos) m/z; 498 (M+Na) ⁺

[α] _D ²⁴ =+129.9° (CHCl ₃ , c=0.5)

(5) To 3.35 g (1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfanyl)-6- Add 7.7 mL of 1M trimethylphosphine/tetrahydrofuran solution to diethyl fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate, and stir at room temperature for 1 hour. Dilute with 200 mL of diethyl ether, add 50 mL of saturated aqueous sodium bicarbonate solution, and stir at room temperature for 1.5 hours. After separation, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was diluted with chloroform, and silica gel [ワコウゲル C200] was added. Concentrate under reduced pressure, leave at room temperature for 18 hours, and then purify by column chromatography (silica gel: Wakowgel C200, developing solvent: hexane-ethyl acetate = 2:1) to obtain 2.78 g of (1R, 2S, 3R, 5R, 6R)-diethyl 2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (300MHz, CDCl ₃ , TMS); 1.31(t, J=7.2Hz, 3H), 1.35(t, J=7.2Hz, 3H), 2.08-2.15(m, 1H), 2.24-2.40( m, 3H), 2.86-2.93(m, 1H), 3.73(d, J=13.4Hz, 1H), 3.88(d, J=13.4Hz, 1H), 4.21-4.37(m, 4H), 7.15(dd , J=8.2, 2.2Hz, 1H), 7.36(d, J=8.2Hz, 1H), 7.42(d, J=2.2Hz, 1H).

MS (ESI) (Pos) m/z; 472 (M+Na) ⁺

[α] _D ²⁶ =+94.4° (CHCl ₃ , c=0.25)

(6) To 41 mg (1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro - Add 12 mg of lithium hydroxide hydrate to diethyl bicyclo[3.1.0]hexane-2,6-dicarboxylate, and stir at room temperature for 5.5 days. In an ice bath, adjust to pH=3 using 1N hydrochloric acid. Add 30mL of water, stir at room temperature for 1 hour, then use ion exchange resin (AG 50W-X8 resin (H type), developing solvent: water, 40% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution) to purify, and then use tetrahydrofuran to obtain the solid Washing gave 26 mg of (1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2 , 6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.17-2.48(m, 4H), 3.04-3.13(m, 1H), 3.80(d, J=14.9Hz, 1H), 3.85(d, J= 14.9Hz, 1H), 7.31(d, J=8.1Hz, 1H), 7.53(d, J=8.1Hz, 1H), 7.59(s, 1H).

MS(ESI)(Nega)m/z; 392(MH) ^-

[α] _D ³⁰ = +47.5° (1N NaOH, c = 0.41)

(reference example 3)

(1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfanyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-di Synthesis of formic acid

(1) In a dry ice-acetone bath, add 73 mg (1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfide dissolved in 1.46 mL of dichloromethane Add 32 mg of 3-chloroperbenzoic acid to diethyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate, and stir for 1 hour. Stir in ice bath for 3.5 hours, then at room temperature for 11 hours. Then add 15 mg of 3-chloroperbenzoic acid in a dry ice-acetone bath, stir for 1 hour, then stir in an ice bath for 4 hours. The reaction solution was washed with saturated aqueous sodium bicarbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakoyugel C200, developing solvent: hexane-ethyl acetate = 4:1-2:1) to obtain 63 mg of (1R, 2S, 3R, 5R, 6R)-2- alkene Nitro-3-(3,4-dichlorobenzylsulfinyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate and 12 mg (1R, 2S, 3R, 5R,6R)-2-Azido-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.

(1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfinyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6 - Diethyl dicarboxylate:

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.36(t, J=7.03Hz, 3H), 1.38(t, J=7.03Hz, 3H), 2.33(dd, J=14.06, 8.35Hz, 1H) , 2.43-2.61(m, 2H), 2.80-2.97(m, 1H), 3.11-3.24(m, 1H), 3.79(d, J=13.19Hz, 1H), 4.09(d, J=13.19Hz, 1H ), 4.25-4.43(m, 4H), 7.17(dd, J=8.35, 2.20Hz, 1H), 7.40-7.50(m, 2H).

MS(ESI)(Pos)m/z; 514(M+Na) ⁺

[α] _D ²⁸ =+36.0° (CHCl ₃ , c=0.5)

(1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6- Diethyl dicarboxylate:

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.36(t, J=7.03Hz, 3H), 1.39(t, J=7.03Hz, 3H), 2.33-2.58(m, 3H), 2.86-3.05( m, 1H), 3.53(dd, J=11.21, 8.13Hz, 1H), 4.24-4.46(m, 6H), 7.28(dd, J=8.35, 2.20Hz, 1H), 7.44-7.56(m, 2H) .

MS(ESI)(Pos)m/z; 530(M+Na) ⁺

[α] _D ²⁹ =+7.9° (CHCl ₃ , c=0.7)

(2) As in (5) of Reference Example 2, 61 mg of (1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfinyl)-6 -Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylated diethyl ester gave 41mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyl Sulfinyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.34(t, J=7.0Hz, 3H), 1.35(t, J=7.0Hz, 3H), 2.30-2.43(m, 3H), 2.78-3.12( m, 2H), 3.80(d, J=13.2Hz, 1H), 4.19-4.36(m, 5H), 7.17(dd, J=8.4, 2.2Hz, 1H), 7.44(d, J=8.4Hz, 1H ), 7.44 (d, J=2.2Hz, 1H).

MS(ESI)(Pos)m/z; 488(M+Na) ⁺

[α] _D ²⁹ =+59.1° (CHCl ₃ , c=0.32)

(3) As in (6) of Reference Example 2, 38 mg of (1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfinyl)-6-fluoro -Diethyl bicyclo[3.1.0]hexane-2,6-dicarboxylate to give 17 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfin Acyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.16-2.29(m, 2H), 2.44-2.49(m, 1H), 2.77-2.88(m, 1H), 3.44-3.53(m, 1H), 4.05(d, J=13.1Hz, 1H), 4.26(d, J=13.1Hz, 1H), 7.29(d, J=8.5Hz, 1H), 7.56(s, 1H), 7.60(d, J=8.5 Hz, 1H).

MS(ESI)(Nega)m/z; 408(MH) ^-

[α] _D ²⁵ = +79.7° (1N NaOH, c = 0.30)

(reference example 4)

(1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Synthesis

(1) Same as (5) of Reference Example 2, from 190 mg (1R, 2S, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzylsulfonyl)-6- Diethyl fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate gave 169 mg of (1R,2S,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzylsulfonate Acyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.34(t, J=7.0Hz, 3H), 1.36(t, J=7.0Hz, 3H), 2.28-2.42(m, 3H), 2.83-3.01( m, 1H), 3.41-3.53(m, 1H), 4.23-4.37(m, 6H), 7.28(dd, J=8.4, 1.8Hz, 1H), 7.46(d, J=8.4Hz, 1H), 7.55 (d, J=1.8Hz, 1H).

MS(ESI)(Pos)m/z; 482(M+H) ⁺

[α] _D ²⁹ =+24.0° (CHCl ₃ , c=0.86)

(2) 108 mg (1R, 2S, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2 , Diethyl 6-dicarboxylate was stirred in 1.08 mL of 60% sulfuric acid (W/V%) at 130°C for 3 days. The reaction solution was ice-cooled, and neutralized with 5N aqueous sodium hydroxide solution. Stir at room temperature for 1 hour, then purify with ion exchange resin (AG 50W-X8 resin (H type), developing solvent: water, 30% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution) to obtain 76 mg (1R, 2S, 3R, 5R ,6R)-2-amino-3-(3,4-dichlorobenzylsulfonyl)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.33-2.45(m, 3H), 2.82-2.94(m, 1H), 3.98(dd, J=10.1, 9.48Hz, 1H), 4.55(d, J=15.2Hz, 1H), 4.60(d, J=15.3Hz, 1H), 7.37(d, J=8.4Hz, 1H), 7.63(d, J=8.8Hz, 1H), 7.64(s, 1H) .

MS(ESI)(Nega)m/z; 424(MH) ^-

[α] _D ²⁸ = -5.1° (1N NaOH, c = 0.72)

(reference example 5)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid synthesis

(1) To 245 mg (1R, 2R, 3S, 5R, 6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane dissolved in 7.0 mL tetrahydrofuran and 0.7 mL water- Add 0.89 mL of 1M trimethylphosphine/tetrahydrofuran solution to diethyl 2,6-dicarboxylate, and stir at room temperature for 12 hours. Diluted with 14 mL of diethyl ether, added saturated aqueous sodium bicarbonate solution, and stirred at room temperature for 1 hour. After liquid separation, the aqueous layer was extracted twice with chloroform. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako Gel C200, developing solvent: chloroform-ethanol = 50:1) to obtain 163 mg of (1R, 2R, 3S, 5R, 6R)-2-amino-6-fluoro-3- Diethyl hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.32(t, J=7.25Hz, 6H), 2.07-2.23(m, 2H), 2.41(dd, J=8.13, 3.30Hz, 1H), 2.71- 2.91(m, 1H), 4.10-4.41(m, 5H).

MS(ESI)(Pos)m/z; 276(M+H) ⁺

[α] _D ²⁵ =+2.8° (CHCl ₃ , c=1.5)

(2) To 160mg (1R, 2R, 3S, 5R, 6R)-2-amino-6-fluoro-3-hydroxyl-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid dissolved in 0.8mL tetrahydrofuran 0.8 mL of saturated aqueous sodium bicarbonate solution and 152 mg of di-tert-butyl dicarbonate were added to diethyl ester, followed by stirring at room temperature for 4 hours. The reaction solution was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 2:1) to obtain 214 mg of (1R, 2R, 3S, 5R, 6R)-2-tert-butoxycarbonyl Diethyl amino-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.29(t, J=7.03Hz, 3H), 1.30(t, J=7.03Hz, 3H), 1.44(s, 9H), 2.20-2.48(m, 3H), 2.77-2.98(m, 2H), 4.07-4.48(m, 4H), 5.57(s, 1H).

MS (ESI) (Pos) m/z; 398 (M+Na) ⁺

[α] _D ²² = -14.0° (CHCl ₃ , c = 0.9)

(3) Same as (1) of Reference Example 2, from 1.47g (1R, 2R, 3S, 5R, 6R)-2-tert-butoxycarbonylamino-6-fluoro-3-hydroxyl-bicyclo[3.1.0 ] hexane-2,6-dicarboxylate to give 1.65 g of (1R,2R,3S,5R,6R)-2-tert-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy - Diethyl bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.25-1.41 (m, 6H), 1.44 (s, 9H), 2.13-2.26 (m, 1H), 2.40-2.57 (m, 2H), 2.97-3.20 ( m, 1H), 4.14-4.47(m, 4H), 5.32(s, 1H), 5.99(d, J=8.35Hz, 1H).

MS(ESI)(Nega)m/z; 506(MH) ^-

[α] _D ²⁸ = +79.8° (CHCl ₃ , c = 0.5)

(4) To 1.63g (1R, 2R, 3S, 5R, 6R)-2-tert-butoxycarbonylamino-6-fluoro-3-trifluoromethane dissolved in 16.3mL N,N-dimethylformamide 313 mg of sodium azide was added to diethylsulfonyloxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate, followed by stirring at room temperature for 1 hour and at 35°C for 20 hours. Then 104 mg of sodium azide was added, and stirred at 35° C. for 18 hours. Dilute with 50 mL of diethyl ether, then wash with water twice and with saturated brine. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako Gel C200, developing solvent: hexane-ethyl acetate = 5:1) to obtain 775 mg of (1R, 2R, 3R, 5R, 6R)-3-azido-2 -Diethyl tert-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.29(t, J=7.03Hz, 3H), 1.33(t, J=7.03Hz, 3H), 1.45(s, 9H), 2.21-2.56(m, 3H), 2.92(dd, J=7.69, 2.42Hz, 1H), 3.78-3.88(m, 1H), 4.17-4.41(m, 4H), 5.01(s, 1H).

MS(ESI)(Pos)m/z; 423(M+Na)

[α] _D ²⁶ =+0.79° (CHCl ₃ , c=1.4)

(5) Same as (1) of Reference Example 5, from 725 mg (1R, 2R, 3R, 5R, 6R)-3-azido-2-tert-butoxycarbonylamino-6-fluoro-bicyclo[3.1. 0] Diethyl hexane-2,6-dicarboxylate yielded 553 mg of (1R, 2R, 3R, 5R, 6R)-3-amino-2-tert-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0 ] Diethyl hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.30(t, J=7.03Hz, 3H), 1.32(t, J=7.03Hz, 3H), 1.44(s, 9H), 2.06-2.27(m, 2H), 2.40-2.55(m, 1H), 2.61-2.72(m, 1H), 3.28-3.47(m, 1H), 4.17-4.41(m, 4H), 5.05(s, 1H).

MS (ESI) (Pos) m/z; 397 (M+Na) ⁺

[α] _D ²⁷ = -14.2° (CHCl ₃ , c = 1.4)

(6) Under ice cooling, to 175 mg (1R, 2R, 3R, 5R, 6R)-3-amino-2-tert-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane dissolved in 0.88 mL chloroform Add 42 μL of pyridine and 123 mg of 3,4-dichlorobenzyl bromide to diethyl alkane-2,6-dicarboxylate, and then stir at room temperature for 3 days. Saturated brine was added, and extracted 5 times with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakoyugel C200, developing solvent: chloroform-ethanol = 100:1-50:1, followed by hexane-ethyl acetate = 5:1) to obtain 98 mg (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid di ethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.23-1.34(m, 6H), 1.44(s, 9H), 2.03-2.26(m, 2H), 2.43(dd, J=12.97, 7.25Hz, 1H ), 2.83-2.93(m, 1H), 3.02-3.15(m, 1H), 3.71(d, J=13.19Hz, 1H), 3.80(d, J=13.19Hz, 1H), 4.12-4.39(m, 4H), 4.82(s, 1H), 7.11(dd, J=8.13, 1.98Hz, 1H), 7.33-7.45(m, 2H).

MS(ESI)(Nega)m/z; 531(MH) ^-

[α] _D ²⁷ = -15.1° (CHCl ₃ , c = 0.5)

(7) Under ice cooling, add 28 mg of (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1 .0] 2.8 mL of 4N hydrogen chloride/ethyl acetate solution was added to hexane-2,6-dicarboxylate, stirred for 6 hours, and then stirred at room temperature for 18 hours. The reaction solution was ice-cooled, neutralized with saturated aqueous sodium bicarbonate solution, and then subjected to liquid separation. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure to obtain 21 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclo[3.1. 0] Diethyl hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.31(t, J=7.0Hz, 3H), 1.34(t, J=6.2Hz, 3H), 2.03-2.28(m, 3H), 2.35-2.51( m, 1H), 2.94-3.08(m, 1H), 3.77(s, 2H), 4.16-4.40(m, 4H), 7.12(d, J=7.9Hz, 1H), 7.35(d, J=7.9Hz , 1H), 7.40(s, 1H).

MS(ESI)(Pos)m/z, 433(M+H) ⁺

[α] _D ²⁴ = -8.4° (CHCl ₃ , c = 0.56)

(8) Same as (6) of Reference Example 2, from 28 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylamino)-6-fluoro-bicyclic [3.1.0] Diethyl hexane-2,6-dicarboxylate yielded 17 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzylamino)-6 -Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.31-2.77(m, 4H), 3.59-3.74(m, 1H), 4.06(d, J=13.5Hz, 1H), 4.15(m, J= 13.5Hz, 1H), 7.35(d, J=7.77Hz, 1H), 7.58-7.64(m, 2H).

MS(ESI)(Nega)375(MH) ^-

[α] _D ²⁷ = -14.6° (1N NaOH, c = 0.29)

(reference example 6)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-[N,N-(3,4-dichlorobenzyl)methylamino]-6-fluoro-bicyclo[3.1.0]hexane -Synthesis of 2,6-dicarboxylic acid

(1) To 136mg (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorobenzyl) dissolved in 1.36mL N,N-dimethylformamide Add 71 mg of potassium carbonate and 64 μL of methyl iodide to diethyl 6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate, and stir at room temperature for 3 days. Saturated aqueous sodium thiosulfate solution was added, and extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako Ugel C200 (manufactured by Wako Pure Chemical Industries), developing solvent: hexane-ethyl acetate=5:1) to obtain 126 mg of (1R, 2R, 3R, 5R, 6R)-2 -tert-butoxycarbonylamino-3-[N,N-(3,4-dichlorobenzyl)methylamino]-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid di ethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.28(t, J=7.03Hz, 3H), 1.29(t, J=7.03Hz, 3H), 1.43(s, 9H), 2.11(s, 3H) , 2.16-2.58(m, 3H), 2.80-3.07(m, 2H), 3.29(d, J=13.62Hz, 1H), 3.78(d, J=13.62Hz, 1H), 4.05-4.43(m, 4H ), 4.86(s, 1H), 7.08(dd, J=8.35, 1.76Hz, 1H), 7.31-7.41(m, 2H).

MS(ESI)(Pos)m/z; 547(M+H) ⁺

[α] _D ²⁵ = -51.9° (CHCl ₃ , c = 0.5)

(2) Same as (7) of Reference Example 5, from 124 mg (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3-[N,N-(3,4-dichloro Benzyl)methylamino]-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate to obtain 96 mg of (1R,2R,3R,5R,6R)-2-amino-3- Diethyl [N,N-(3,4-dichlorobenzyl)methylamino]-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (300MHz, CDCl ₃ , TMS); 1.33(t, J=7.0Hz, 3H), 1.35(t, J=7.0Hz, 3H), 2.06(s, 3H), 2.03-2.21(m, 1H), 2.23-2.60(m, 3H), 2.68-2.84(m, 1H), 3.22(d, J=14.1Hz, 1H), 3.97(d, J=14.1Hz, 1H), 4.18-4.32(m , 4H), 7.07(dd, J=8.1, 2.0Hz, 1H), 7.30-7.39(m, 2H).

MS(ESI)(Pos)m/z; 447(M+H) ⁺

[α] _D ²³ = -24.9° (CHCl ₃ , c = 0.84)

(3) Same as (6) of Reference Example 2, from 94 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-[(3,4-dichlorobenzyl)-methyl-amino] -6-Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester to obtain 62 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-[N,N-(3 ,4-dichlorobenzyl)methylamino]-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.31-2.41(m, 1H), 2.45-2.53(m, 1H), 2.64(s, 3H), 2.73-2.82(m, 2H), 3.72- 3.82(m, 1H), 4.01(d, J=13.4Hz, 1H), 4.27(d, J=13.4Hz, 1H), 7.35-7.41(m, 1H), 7.61-7.69(m, 2H).

MS(ESI)(Nega)m/z; 389(MH) ^-

[α] _D ²⁴ = -35.2° (1N NaOH, c = 0.51)

(reference example 7)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid Synthesis

(1) To 17 mg (1R, 2R, 3R, 5R, 6R)-3-amino-2-tert-butoxycarbonylamino-6-fluoro-bicyclo[3.1.0]hexane-2 dissolved in 0.17 mL chloroform , 7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added to diethyl 6-dicarboxylate, and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: chloroform-ethanol = 100:1) to obtain 21 mg of (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3 -(3,4-Dichlorobenzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid diethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.19(t, J=7.03Hz, 3H), 1.31(t, J=7.25Hz, 3H), 1.41(s, 9H), 2.21-2.64(m, 3H), 2.82-2.91(m, 1H), 4.07-4.37(m, 4H), 4.58-4.75(m, 1H), 6.20(s, 1H), 6.39-6.50(m, 1H), 7.46-7.57( m, 2H), 7.80-7.85 (m, 1H).

MS(ESI)(Nega)m/z; 545(MH) ^-

[α] _D ²³ =+12.1° (CHCl ₃ , c=0.9)

(2) Same as (7) of Reference Example 5, from 107 mg (1R, 2R, 3R, 5R, 6R)-2-tert-butoxycarbonylamino-3-(3,4-dichlorobenzoylamino) -Diethyl 6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate to obtain 85 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichloro Diethyl benzoylamino)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.30(t, J=6.8Hz, 3H), 1.33(t, J=7.0Hz, 3H), 2.09-2.43(m, 3H), 2.53-2.38( m, 1H), 4.19-4.38(m, 4H), 4.52-4.71(m, 1H), 7.48-7.55(m, 2H), 7.75-7.84(m, 1H).

MS (ESI) (Pos) m/z; 469 (M+Na) ⁺

[α] _D ²⁷ = +8.3° (CHCl ₃ , c = 0.93)

(3) As in (6) of Reference Example 2, 48 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzoylamino)-6-fluoro- Diethyl bicyclo[3.1.0]hexane-2,6-dicarboxylate gave 24 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzoylamino) -6-Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.33-2.42(m, 2H), 2.57-2.67(m, 2H), 4.46-4.55(m, 1H), 7.58-7.68(m, 2H), 7.87-7.90(m, 1H).

MS(ESI)(Nega)m/z; 389(MH) ^-

[α] _D ²⁸ =+6.0° (CHCl ₃ , c=0.34)

(reference example 8)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-di Synthesis of formic acid

(1) To 202 mg (1R, 2R, 3R, 5R, 6R)-2-azido-6-fluoro-3-hydroxy-bicyclo[3.1.0]hexane-2,6- 234 mg of 3,4-dichlorobenzoyl chloride was added to 2-benzyl 6-ethyl dicarboxylate, and stirred at room temperature for 28 hours under a nitrogen atmosphere. 100 mL of ethyl acetate was added to the reaction solution, and the ethyl acetate solution was washed with a saturated aqueous copper sulfate solution and water, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wakogel C200, developing solvent: hexane-ethyl acetate = 10:1) to obtain 298 mg (1R, 2R, 3R, 5R, 6R)-2-Azido-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-benzyl ester 6 - Ethyl esters.

¹ H-NMR (200MHz, CDCl ₃ ); 1.35(t, J=7.3Hz, 3H), 2.35-2.55(m, 3H), 2.77-2.87(m, 1H), 4.31(q, J=7.3Hz, 2H), 5.24-5.46(m, 3H), 7.28-7.60(m, 6H), 7.90-8.20(m, 2H).

MS (ESI) (Pos) m/z; 558 (M+Na) ⁺

(2) Same as (5) of Reference Example 2, from 298 mg (1R, 2R, 3R, 5R, 6R)-2-azido-3-(3,4-dichlorobenzoyloxy)-6 -Fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate 2-benzyl ester 6-ethyl ester gave 218 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3 , 2-benzyl 4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate 6-ethyl ester.

¹ H-NMR (200MHz, CDCl ₃ , TMS); 1.33(t, J=7.3Hz, 3H), 2.25-2.80(m, 4H), 4.28(q, J=7.3Hz, 2H), 5.05-5.13( m, 1H), 5.16(d, J=12.3Hz, 1H), 5.31(d, J=12.3Hz, 1H), 7.24-7.36(m, 5H), 7.44(d, J=8.4Hz, 1H), 7.57(dd, J=8.4, 2.20Hz, 1H), 7.90(d, J=2.2Hz, 1H).

MS (ESI) (Pos) m/z; 532 (M+Na) ⁺

[α] _D ²² =+31.8° (CHCl ₃ , c=0.55)

(3) To 218 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1. 0] Add 15 mg of 5% palladium on carbon to 2-benzyl 6-diethyl hexane-2,6-dicarboxylate, and stir at room temperature for 50 minutes under a hydrogen atmosphere. Palladium carbon was filtered through celite, the filtrate was concentrated under reduced pressure, and the obtained solid was dissolved in a mixed solvent of 2 mL of tetrahydrofuran and 1 mL of water. To this solution was added 10 mg of lithium hydroxide monohydrate under ice-cooling, followed by stirring for 30 minutes. Add 0.5mL1 equivalent hydrochloric acid under ice cooling, dilute with water to 50mL, then use ion exchange resin (AG 50W-X8 resin (H type), developing solvent: water, 40% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution) to obtain 25mg (1R ,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzoyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, D ₂ O, TMSP); 2.40-2.45(m, 2H), 2.71-2.77(m, 2H), 5.28-5.36(m, 1H), 7.68(d, J=8.5Hz, 1H), 7.89(d, J=8.5Hz, 1H), 8.16(s, 1H).

MS(ESI)(Nega)m/z; 390(MH) ^-

[α] _D ²⁸ =+9.2° (MeOH, c=0.23)

(Example 1)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 -Synthesis of methyl ester hydrochloride

Under ice-cooling, to 800 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1. 0] Add 0.65 mL of thionyl chloride to hexane-2,6-dicarboxylic acid, then stir at 50°C for 4 hours. After stirring at room temperature for 3 hours, methanol was distilled off under reduced pressure. 20 mL of hexane was added to the residue, stirred for 2 hours, and the solid was collected by filtration. The solid was washed with diisopropyl ether and hexane to give 820 mg of (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[ 3.1.0] 6-methyl hexane-2,6-dicarboxylate hydrochloride.

(Example 2)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 -Synthesis of pentyl esters

Under ice-cooling, add 300 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1. 0] Add 225 μL of thionyl chloride to hexane-2,6-dicarboxylic acid, and then stir at 50° C. for 3 hours. After cooling, the reaction solution was concentrated under reduced pressure to about 1 mL, 200 mL of hexane was added, and the mixture was stirred for 12 hours. The precipitated solid was filtered off, and purified by reverse-phase column chromatography (Wako-gel 50C18 (Wako Pure Chemical Industries): developing solvent water-50% acetonitrile aqueous solution) to obtain 188 mg of (1R, 2R, 3R, 5R, 6R)-2- 6-pentyl amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

(Example 3)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid di Synthesis of Ethoxycarbonyl Methyl Ester.

At room temperature, to 36 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)- Add 4.4 mg of lithium hydroxide hydrate to 6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and stir for 10 minutes. After concentration under reduced pressure, 0.36 mL of N,N-dimethylformamide and 21 μL of ethyl bromoacetate were added to the residue, and stirred at room temperature for 2 hours, at 50°C for 2 hours, and at 90°C for 4 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure. The residue was purified by thin-layer chromatography (silica gel 60F254 (manufactured by Merck), developing solvent: hexane-ethyl acetate = 1:1) to obtain 12 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3 -diethoxycarbonylmethyl (3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

(Example 4)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 Synthesis of -(2-azidoethyl)ester

At room temperature, 18 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4 -Dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-iodoethyl) ester was added with 6 mg of sodium azide, stirred at 60°C for 12 Hour. After cooling down, the solvent was distilled off under reduced pressure, and purified by reverse phase column chromatography (Wako-gel 50C18: developing solvent water-70% acetonitrile aqueous solution) to obtain 7 mg of (1R, 2R, 3R, 5R, 6R)-2-amino- 6-(2-azidoethyl) 3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

(Example 5)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 Synthesis of -(2-aminoethyl)ester

At room temperature, to 6 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)- Add 20 μL of 1M trimethylphosphine/tetrahydrofuran solution to 6-(2-azidoethyl) 6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate, and stir for 13 hours. The solvent was distilled off under reduced pressure, purified by reverse phase column chromatography (Wako-gel 50C18 (Wako Pure Chemical Industries), developing solvent: water-50% acetonitrile aqueous solution), and the obtained solid was washed with tetrahydrofuran to obtain 2 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6-(2-amino ethyl) ester.

Table 1 shows the structures and physical property data of the compounds described in Examples 1, 2, 3, 4 and 5, and compounds obtained in the same manner.

^* 1 hydrochloride

(Example 6)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-carboxylic acid 6- Synthesis of Diethylcarbamoyl Methyl Ester

To 740 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyl)-6-fluoro-bicyclo[3.1.0]hexane suspended in 2.6 mL of dioxane Add 6.7 mL of saturated sodium bicarbonate to alkane-2,6-dicarboxylic acid, and stir at room temperature for 10 minutes. To this solution was added dropwise 0.41 mL of allyl chloroformate, followed by stirring at room temperature for 12 hours. 2.6 mL of water was added to the reaction solution, and the aqueous layer was washed with ethyl acetate, acidified with 1 N hydrochloric acid in an ice bath, and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 930 mg of (1R, 2R, 3R, 5R, 6R)-2-allyloxycarbonylamino-3-(3,4-di Chlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid.

¹ H-NMR (300MHz, CD ₃ OD, TMS); 2.15-2.53 (m, 3H) 2.89-3.01 (m, 1H) 4.06-4.19 (m, 1H) 4.46 (d, J = 11.7Hz, 1H) 4.55 (d, J = 4.8Hz, 1H) 4.71 (d, J = 11.7Hz, 1H) 5.16-5.20 (m, 1H) 5.29-5.36 (m, 1H) 5.89-5.99 (m, 1H) 7.22 (dd, J =8.2, 2.0Hz, 1H) 7.44 (d, J = 8.2Hz, 1H) 7.48 (d, J = 2.0Hz, 1H)

MS(ESI)(Nega)m/z; 460(MH) ^-

(2)

380 mg (1R, 2R, 3R, 5R, 6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1 .0] A mixture of hexane-2,6-dicarboxylic acid, 109 mg paraformaldehyde, and 8 mg p-toluenesulfonic acid monohydrate was charged into a Dean-Stark water separator, and heated to reflux for 3.5 hours. After standing to cool, it was diluted with ethyl acetate, and the ethyl acetate solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 370 mg (1'R, 2'R, 3'R, 5'R, 6'R)-3'-(3,4-di Chlorobenzyloxy)-6'-fluoro-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2'-bicyclo[3.1.0]hexane-6'-carboxylic acid.

¹ H-NMR (300MHz, CDCl ₃ , TMS); 2.07-2.54(m, 4H) 4.17-4.24(m, 1H) 4.39(d, J=12.3Hz, 1H) 4.52(d, J=12.3Hz, 1H) ) 4.63 (d, J=6.2Hz, 2H) 5.23 (d, J=4.4Hz, 1H) 5.28-5.54 (m, 2H) 5.53 (d, J=4.5Hz, 1H) 5.85-5.98 (m, 1H) 7.07(dd, J=8.2, 1.9Hz, 1H) 7.32(d, J=1.9Hz, 1H) 7.41(d, J=8.2Hz, 1H).

MS(ESI)(Nega)m/z; 472(MH) ^-

(3)

To 58mg (1'R, 2'R, 3'R, 5'R, 6'R)-3'-(3,4-dichlorobenzyloxy) dissolved in 2mL N,N-dimethylformamide )-6'-fluoro-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2'-bicyclo[3.1.0]hexane-6'-carboxylic acid, add 37mg potassium carbonate and 37 μL N,N-diethylchloroacetamide, stirred at room temperature for 15 hours. It was diluted with ethyl acetate, the ethyl acetate layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. After filtering off the desiccant, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Shiki Kagel 60N (Kanto Chemical), developing solvent: hexane-ethyl acetate = 1:2) to obtain 60 mg of (1'R, 2'R, 3'R, 5'R, 6'R)-3'-(3,4-dichlorobenzyloxy)-6'-fluoro-3-allyloxycarbonyl-5-oxo- Oxazolidinone-4-spiro-2'-bicyclo[3.1.0]hexane-6'-carboxylate 6-(N,N-diethylaminocarbonylmethyl)ester.

¹ H-NMR (300MHz, CDCl ₃ , TMS); 1.12(t, J=7.23Hz, 3H) 1.23(t, J=7.2Hz, 3H) 2.21-2.60(m, 4H) 3.23(q, J=7.2 Hz, 2H) 3.38 (q, J = 7.2Hz, 2H) 4.19-4.27 (m, 1H) 4.38 (d, J = 12.3Hz, 1H) 4.52 (d, J = 12.3Hz, 1H) 4.63-4.65 (m , 2H) 4.74 (d, J = 14.1Hz, 1H) 4.85 (m, J = 14.1Hz, 1H) 5.23 (d, J = 4.3Hz, 1H) 5.24-5.33 (m, 2H) 5.51 (d, J = 4.3Hz, 1H) 5.87-6.00 (m, 1H) 7.07 (dd, J = 8.2, 2.0Hz, 1H) 7.31 (d, J = 2.0Hz, 1H) 7.40 (d, J = 8.2Hz, 1H).

MS (ESI) (Pos) m/z; 609 (M+Na) ⁺

(4)

Under nitrogen atmosphere, to 58 mg (1'R, 2'R, 3'R, 5'R, 6'R)-3'-(3,4-dichlorobenzyloxy)-6' dissolved in chloroform -Fluoro-3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2'-bicyclo[3.1.0]hexane-6'-carboxylic acid 6-(N,N-diethyl 46 mg of 1,3-dimethylbarbituric acid and 4 mg of tetrakis(triphenylphosphine)palladium were added to (aminocarbonylmethyl) ester, and stirred at 40°C for 1.5 hours. The reaction solution was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was stirred at room temperature for 1 hour. The precipitated solid was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography (Wako-gel 50C18 (Wako Pure Chemical Industries): the developing solvent was water-50% acetonitrile aqueous solution), and the resulting solid was purified with acetic acid Ethyl ester was washed to obtain 5 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2 , 6-(N,N-diethylaminocarbonylmethyl) 6-carboxylate.

(Example 7)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 Synthesis of -(4-fluorobenzyl)ester

At room temperature, to 30 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo [3.1.0] Add 23 µL of thionyl chloride to hexane-2,6-dicarboxylic acid, and then stir at 60°C for 3 days. After standing to cool, the reaction solution was purified by reverse phase chromatography (Wako-gel 50C18 (Wako Pure Chemical Industries): the developing solvent was water-70% acetonitrile aqueous solution) to obtain 5 mg of (1R, 2R, 3R, 5R, 6R)-2 - 6-(4-fluorobenzyl)amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylate.

The structures and physical property data of the compounds described in Examples 6 and 7 and the similarly obtained compounds are shown in Table 2 below.

(Embodiment 8)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 Synthesis of -(3-methyl)butyl Ester

Under ice cooling, to 1.50 g (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro - Add 1.0 mL of thionyl chloride to bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, and then stir at 70° C. for 3 hours. After standing to cool, 3-methylbutanol was distilled off under reduced pressure. 15 mL of ethanol and 15 mL of propylene oxide were added to the residue, and heated to reflux for 1 hour. After standing to cool, it was diluted with diethyl ether, and the precipitated solid was collected by filtration. The solid was washed with water, diisopropyl ether, hexane to give 1.01 g of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro - 6-(3-methyl)-n-butyl bicyclo[3.1.0]hexane-2,6-dicarboxylate.

(Example 9)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 6 Synthesis of -(6-methyl)heptyl ester

Under ice cooling, to 1.00 g (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)- 0.4 mL of thionyl chloride was added to 6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid, followed by stirring at 80°C for 6 hours. After cooling, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse-phase column chromatography (Wako-gel 50C18 (Wako Pure Chemical Industries): developing solvent: water-70% acetonitrile aqueous solution). The resulting solid was recrystallized from ethanol:water to give 557 mg of (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1. 0] 6-(6-methyl)heptyl hexane-2,6-dicarboxylate.

The structures and physical property data of the compounds described in Examples 8 and 9 and the similarly obtained compounds are shown in Table 3 below.

(Example 10)

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2 -Butyl 6-ethyl ester and (1R,2R,3R,5R,6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane -Synthesis of 2,6-dicarboxylic acid 2-butyl ester

(1) Same as Example 1, by 4.00g (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1. 0] hexane-2,6-dicarboxylic acid to obtain 2.96g (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1 .0] 6-ethyl hexane-2,6-dicarboxylate hydrochloride.

(2) 400mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6 - Add 6-ethyl dicarboxylate hydrochloride to a mixed solution of 5 mL ethanol and 5 mL propylene oxide, and heat to reflux for 2.5 hours. After cooling, the precipitated solid was collected by filtration, washed with diethyl ether, and then recrystallized with water: ethanol to obtain 230 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-di 6-ethyl chlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate.

(3) To 200 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1. 0] Add 2 mL of saturated sodium bicarbonate to 6-ethyl hexane-2,6-dicarboxylate, and stir at room temperature for 10 minutes. To this solution was added 0.18 mL of allyl chloroformate, and stirred at room temperature for 8 hours. 1 mL of 1 N hydrochloric acid was added to the reaction solution to make it acidic, then 10 mL of water was added, and extraction was performed twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, then concentrated under reduced pressure, and the resulting residue was dissolved in 20 mL of N,N-dimethylformamide. To this solution were added 141 mg of 1-iodobutane and 106 mg of potassium carbonate, and stirred at room temperature for 16 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate twice. The combined ethyl acetate layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure, followed by column chromatography (silica gel: Kanto Kagaku silica gel 60 (spherical), developing solvent: hexane-ethyl acetate=5:1) Purification afforded 159 mg of (1R, 2R, 3R, 5R, 6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane - 2-butyl 6-ethyl 2,6-dicarboxylate.

¹ H-NMR (300MHz, CDCl ₃ , TMS) 0.89 (3H, t, J=7.4Hz), 1.24-1.43 (5H, m), 1.56-1.66 (2H, m), 2.22-2.51 (3H, m) , 2.93-3.00(1H, m), 3.81-3.89(1H, m), 4.08-4.65(8H, m), 5.16-5.37(3H, m), 5.84-5.98(1H, m), 7.09(1H, dd, J=8.2, 2.0Hz), 7.37 (1H, d, J=2.0Hz), 7.40 (1H, d, J=8.2Hz)

(4) Under a nitrogen atmosphere, to 190 mg (1R, 2R, 3R, 5R, 6R)-2-allyloxycarbonylamino-3-(3,4-dichlorobenzyloxy)-6 dissolved in chloroform -Fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester, add 81mg 1,3-dimethylbarbituric acid, 12mg tetrakis(triphenylphosphine) palladium, Stir at 50°C for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: Kanto Kagaku Silica Gel 60 (spherical), developing solvent: hexane-ethyl acetate=5:1) to obtain 180 mg (1R, 2R, 3R, 5R,6R)-2-Butyl 6-ethyl 2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylate.

(5) To 131 mg (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1. 0] Add 15 mg of lithium hydroxide monohydrate to 2-butyl 6-ethyl hexane-2,6-dicarboxylate, and stir at room temperature for 1.5 hours. 2 mL of 1 N hydrochloric acid was added to the reaction solution, concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography (ワコ-ゲル 50C18 (Wako Pure Chemical Industries): the developing solvent was water-40% acetonitrile solution) to obtain 37 mg (1R , 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid 2-butyl ester .

The structures and physical property data of the compounds described in Example 10 and the compounds obtained in the same manner are shown in Table 4 below.

(Test Example 1) The in vivo exposure was measured by the plasma concentration in rats

The amount of exposure in vivo is, for example, compound 1, 4 and 10 of the present invention and the parent compound of compound 1, 4 and 10 of the present invention in which X is a fluorine atom and Y is 3,4-dichlorobenzyloxy in the formula [IV] After oral administration to rats, the plasma concentration of the parent compound of Compound 1 of the present invention was measured, compared and studied as follows. The plasma concentration of the parent compound of the compound 44 of the present invention after oral administration of the compound 44 of the present invention and its parent compound to rats was also measured, compared and studied in the same manner.

Seven-week-old rats (240-280 g, male, system CD (SD) IGS) purchased from Japan's Cha-lus Riba-Co., Ltd. were used after being acclimatized for more than 2 days. The compound of the present invention was dissolved in 0.03 N hydrochloric acid containing 10% HP-β-CD to a concentration of 2 mg/mL, and 10 mg/kg was orally administered. After 1 hour and 2 hours, blood was collected from the tail vein using blood collection tubes (with EDTA added), and immediately centrifuged (10000xg, 4°C, 10 minutes) to collect plasma as samples. Plasma samples were stored frozen below -80°C. Under the condition of ice-cooling, add the methanol solution of internal standard substance to the plasma sample after fusion, carry out centrifugation (10000xg, 4 ℃, 10 minutes) after removing protein, measure the present invention in the supernatant by LC/MS/MS The concentration of the compound's parent compound.

As shown in the table below, administration of the compound of the present invention significantly increases the plasma concentration of the parent compound of the compound of the present invention, and increases the exposure in vivo.

Comparison of Concentrations in Plasma of Compounds of the Invention and Parent Compounds of the Compounds of the Invention Compound (10mg/kg orally) The concentration of the parent compound of the compound of the present invention in plasma (ng/mL) 1 hour later 2 hours later Compound A ^*1 123 178 Compound of the present invention 1 ^*2 11332 8162 Compound of the present invention 4 ^*3 6863 7057 Compound 10 ^*4 of the present invention 5956 5754 Compound B ^*5 73 125 Compound 44 ^*6 of the present invention 235 610

^*1 Compound A (parent compound of compounds 1, 4 and 10 of the present invention):

(1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid

^*2 Compound 1 of the present invention: (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane- 6-methyl 2,6-dicarboxylate

^*3 Compound 4 of the present invention: (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane- 6-n-Butyl 2,6-dicarboxylate

^*4 Compound 10 of the present invention: (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane- 6-Benzyl 2,6-dicarboxylate

^*5 Compound B (parent compound of compound 44 of the present invention): (1S, 2R, 3R, 5R, 6S)-2-amino-3-(3,4-dichlorobenzyloxy)-bicyclo[3.1.0] Hexane-2,6-dicarboxylic acid

^*6 Compound 44 of the present invention: (1R, 2R, 3R, 5R, 6R)-2-amino-3-(3,4-dichlorobenzyloxy)-6-fluoro-bicyclo[3.1.0]hexane- 6-(1-(cyclohexyloxycarbonyloxy)ethyl) 2,6-dicarboxylate

Industrial applicability

The compound of the present invention, its pharmaceutically acceptable salt or its hydrate can be used as a prodrug of a metabotropic glutamate receptor antagonist, which can significantly increase the exposure of the parent compound in vivo.

Therefore, from the consideration of ease of use and drug efficacy, it is preferable to provide effective drugs for the prevention and treatment of psychiatric disorders such as schizophrenia, anxiety and related diseases, depression, bipolar affective disorder, and epilepsy in the form of oral administration. , and treatment of neurological diseases such as drug dependence, cognitive impairment, Alzheimer's disease, Huntington's disease, Parkinson's disease, movement disorders accompanied by muscle rigidity, cerebral ischemia, cerebral insufficiency, spinal cord disorders, and head disorders And preventive effective, antispasmodic, analgesic, antiemetic effective drugs.

Claims (59)

1. the hexane-2 of 2-amino-dicyclo [3.1.0] shown in the formula [I], 6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate:

In the formula, R ¹And R ²Identical or different, expression C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i]

In the formula, R ^dGroup shown in or the formula [ii] identical with aforementioned implication,

Perhaps

Work as R ¹And R ²In any one when being hydrogen atom, another represents C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical with aforementioned implication) shown in the C that replaces of group _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z, R ^cAnd R ^dIdentical with aforementioned implication) shown in group shown in the group, formula [i]

In the formula, R ^dIdentical with aforementioned implication,

Or group shown in the formula [ii];

X represents hydrogen atom or fluorine atom;

Y represents-OCHR ³R ⁴,-SR ³,-S (O) _nR ⁵,-SCHR ³R ⁴,-S (O) _nCHR ³R ⁴,-NHCHR ³R ⁴,-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) ,-NHCOR ³Or-OCOR ⁵(in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical or different, expression hydrogen atom, C _1-10Alkyl, C _1-10Thiazolinyl, phenyl, naphthyl, the naphthyl that is replaced by 1-7 halogen atom, heteroaryl or be selected from halogen atom, phenyl, C by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces, R ⁵Expression C _1-10Alkyl, C _1-10Thiazolinyl, phenyl, naphthyl, the naphthyl that is replaced by 1-7 halogen atom, heteroaryl or be selected from halogen atom, phenyl, C by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces; N represents integer 1 or 2.

2. the hexane-2 of 2-amino-dicyclo [3.1.0] shown in the formula [II], 6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate:

In the formula, R ¹And R ²Identical or different, expression C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i]

In the formula, R ^dIdentical with aforementioned implication,

Or group shown in the formula [ii],

Perhaps

Work as R ¹And R ²In any one when being hydrogen atom, another represents C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical with aforementioned implication) shown in the C that replaces of group _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z, R ^cAnd R ^dIdentical with aforementioned implication) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii];

X represents hydrogen atom or fluorine atom;

Y represents-OCHR ³R ⁴,-SR ³,-S (O) _nR ⁵,-SCHR ³R ⁴,-S (O) _nCHR ³R ⁴,-NHCHR ³R ⁴,-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) ,-NHCOR ³Or-OCOR ⁵(in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical or different, expression hydrogen atom, C _1-10Alkyl, C _1-10Thiazolinyl, phenyl, naphthyl, the naphthyl that is replaced by 1-7 halogen atom, heteroaryl or be selected from halogen atom, phenyl, C by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces, R ⁵Expression C _1-10Alkyl, C _1-10Thiazolinyl, phenyl, naphthyl, the naphthyl that is replaced by 1-7 halogen atom, heteroaryl or be selected from halogen atom, phenyl, C by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces; N represents integer 1 or 2.

3. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ¹And R ²Identical or different, expression C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 phenyl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl is perhaps worked as R ¹And R ²In any one when being hydrogen atom, another represents C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 phenyl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl.

4. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ¹And R ²Identical or different, expression C _1-10Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, the C that is replaced by 1 or 2 phenyl _1-10Alkyl, hydroxyl C _2-6Alkyl, halo C _1-6Alkyl, azido-C _1-6Alkyl, amino C _2-6Alkyl, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy carbonyl C _1-6Alkyl is perhaps worked as R ¹And R ²In any one when being hydrogen atom, another represents C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, the C that is replaced by 1 or 2 phenyl _1-6Alkyl, hydroxyl C _2-6Alkyl, halo C _1-6Alkyl, azido-C _1-6Alkyl, amino C _2-6Alkyl, C _1-6Alkoxy C _1-6Alkyl, C _1-6Alkoxy carbonyl C _1-6Alkyl.

5. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ¹And R ²Identical or different, expression farnesyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii],

Perhaps work as R ¹And R ²In any one when being hydrogen atom, another expression farnesyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical with aforementioned implication) shown in the C that replaces of group _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z, R ^cAnd R ^dIdentical with aforementioned implication) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

6. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ¹And R ²Identical or different, expression farnesyl, the C that is replaced by 1 or 2 aryl _1-6Alkyl, C _1-6Alkoxy carbonyl C _1-6Alkyl, 4-morpholinyl C _1-6Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-6Alkyl) C that group shown in replaces _1-6Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-6Alkyl, C _2-6Thiazolinyl, aryl, R ^dExpression C _1-6Alkyl, C _2-6Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii];

Perhaps work as R ¹And R ²In any one when being hydrogen atom, another expression farnesyl, the C that is replaced by 1 or 2 aryl _1-6Alkyl, C _1-6Alkoxy carbonyl C _1-6Alkyl, 4-morpholinyl C _1-6Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical with aforementioned implication) shown in the C that replaces of group _1-10Alkyl, formula-CHR ^cOC (O) ZR ^d(in the formula, Z, R ^cAnd R ^dIdentical with aforementioned implication) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

7. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom.

8. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom.

9. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom.

10. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication).

11. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication).

12. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication).

13. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n) with aforementioned implication.

14. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-NHCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n) with aforementioned implication.

15. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication).

16. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication).

17. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication).

18. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication).

19. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n) with aforementioned implication.

20. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-NHCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication).

21. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication).

22. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

23. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

24. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

25. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

26. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

27. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

28. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

29. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

30. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-NHCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

31. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-NHCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

32. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

33. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

34. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

35. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

36. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

37. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

38. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

39. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-SR ³(in the formula, R ³Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

40. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

41. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-S (O) _nCHR ³R ⁴(in the formula, R ³, R ⁴Identical with n with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

42. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-NHCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

43. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-NHCHR ³R ⁴(in the formula, R ³And R ⁴Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

44. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

45. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-N (CHR ³R ⁴) (CHR ^{3 '}R ^{4 '}) (in the formula, R ³, R ^{3 '}, R ⁴And R ^{4 '}Identical with aforementioned implication), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

46. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

47. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

48. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be naphthyl, heteroaryl or the naphthyl that replaced by 1-7 halogen atom), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C2-10 alkynyl, the C that is replaced by 1 or 2 aryl _1-1Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

49. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be naphthyl, heteroaryl or the naphthyl that replaced by 1-7 halogen atom), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

50. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical or different, be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

51. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a fluorine atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical or different, be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

52. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

53. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

54. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be hydrogen atom, R ⁴Be naphthyl, heteroaryl or the naphthyl that replaced by 1-7 halogen atom), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-1Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

55. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³Be C _1-10Alkyl, R ⁴Be naphthyl), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

56. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical or different, be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be C _1-10Alkyl, C _2-10Thiazolinyl, C _2-10Alkynyl, the C that is replaced by 1 or 2 aryl _1-10Alkyl, hydroxyl C _2-10Alkyl, halo C _1-10Alkyl, azido-C _1-10Alkyl, amino C _2-10Alkyl, C _1-10Alkoxy C _1-10Alkyl, C _1-10Alkoxy carbonyl C _1-10Alkyl, farnesyl, 4-morpholinyl C _1-10Alkyl, by formula-C (O) NR ^aR ^b(in the formula, R ^aAnd R ^bIdentical or different, expression hydrogen atom or C _1-10Alkyl) C that group shown in replaces _1-10Alkyl.

57. 2-amino-dicyclo [3.1.0] hexane-2 of claim 2,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate, in the wherein above-mentioned formula [II], R ²Be hydrogen atom, X is a hydrogen atom, and Y is-OCHR ³R ⁴(in the formula, R ³And R ⁴Identical or different, be selected from halogen atom, phenyl, C for phenyl or by 1-5 _1-10Alkyl, C _1-10The phenyl that the substituting group of alkoxyl group, trifluoromethyl, phenyl, hydroxycarbonyl group, amino, nitro, cyano group and phenoxy group replaces), R ¹Be formula-CHR ^cOC (O) ZR ^d(in the formula, Z represents Sauerstoffatom, nitrogen-atoms, sulphur atom or singly-bound, R ^cExpression hydrogen atom, C _1-10Alkyl, C _2-10Thiazolinyl, aryl, R ^dExpression C _1-10Alkyl, C _2-10Thiazolinyl, aryl) shown in group shown in the group, formula [i],

In the formula, R ^dIdentical with aforementioned implication

Or group shown in the formula [ii]

58. a medicine, its effective constituent are each 2-amino-dicyclo [3.1.0] hexane-2 among the claim 1-57,6-dicarboxylic ester derivative, its pharmacy acceptable salt or its hydrate.

59. the medicine of claim 58, this medicine is group II metabotropic glutamate receptor antagonists.