JP2006193507A - Preventive and therapeutic agent for depression - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine that is effective for prevention and therapy of depression and is antagonistic to the group II metabotropic glutamic acid acceptor having high oral activity. <P>SOLUTION: The preventive and therapeutic agent includes, as an active ingredient, 2-amino-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid ester derivative represented by formula [I] [wherein R<SP>1</SP>and R<SP>2</SP>are identical or different and each H or a 1-10C alkyl and the like; X is H or F; Y is -OCHR<SP>3</SP>R<SP>4</SP>(wherein R<SP>3</SP>and R<SP>4</SP>are identical or different and each H, a 1-10C alkyl or the like; n is an integer of 1 or 2) or the like] or its pharmaceutically acceptable salts or their hydrates. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to prevention of depression, comprising 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof, and a hydrate thereof as an active ingredient. It relates to therapeutic drugs.

  Metabotropic glutamate receptors are pharmacologically classified into three groups. Among them, group II (mGluR2 / mGluR3) binds to adenyl cyclase and suppresses forskolin-stimulated accumulation of cyclic adenosine monophosphate (cAMP) (see Non-Patent Document 1). Compounds that antagonize the metabotropic glutamate receptor are believed to be effective in the treatment or prevention of acute and chronic psychiatric and neurological disorders, and 2-amino-bicyclo [3.1.0] hexane-2 The 6,6-dicarboxylic acid derivative is a compound having a strong antagonistic action on the group II metabotropic glutamate receptor.

Trends Pharmacol. Sci., 14, 13, 1993

  An object of the present invention is to provide a drug that is effective for the prevention and treatment of depression and antagonizes a group II metabotropic glutamate receptor having high oral activity.

  As a result of intensive studies on 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivatives, the present inventors have found that 2-amino-bicyclo affects group II metabotropic glutamate receptors. [3.1.0] With respect to prodrugs of hexane-2,6-dicarboxylic acid derivatives, animal experiments using the parent compound as a test drug are conducted, and this type of prodrug increases the exposure of the parent compound in vivo. The headline and the present invention were completed.

  The present invention provides a compound of the formula [I]

［式中、Ｒ¹及びＲ²は同一又は異なって、Ｃ_1-10アルキル基、Ｃ_2-10アルケニル基、Ｃ_2-10アルキニル基、１若しくは２個のアリール基で置換されたＣ_1-10アルキル基、ヒドロキシＣ_2-10アルキル基、ハロゲン化Ｃ_1-10アルキル基、アジドＣ_1-10アルキル基、アミノＣ_2-10アルキル基、Ｃ_1-10アルコキシＣ_1-10アルキル基、Ｃ_1-10アルコキシカルボニルＣ_1-10アルキル基、ファルネシル基、４−モルホリニルＣ_1-10アルキル基、式−Ｃ(Ｏ)ＮＲ^aＲ^b（式中、Ｒ^a及びＲ^bは同一又は異なって、水素原子又はＣ_1-10アルキル基を示す。）で表される基によって置換されたＣ_1-10アルキル基、式−ＣＨＲ^cＯＣ(Ｏ)ＺＲ^d（式中、Ｚは、酸素原子、窒素原子、硫黄原子若しくは単結合を示し、Ｒ^cは、水素原子、Ｃ_1-10アルキル基、Ｃ_2-10アルケニル基、アリール基を示し、Ｒ^dは、Ｃ_1-10アルキル基、Ｃ_2-10アルケニル基、アリール基を示す。）で表される基、式［i］

[Wherein, R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1- substituted with one or two aryl groups. ₁₀ alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different, hydrogen atom or a C _1-10 C _1-10 alkyl group substituted by a group represented by an alkyl group.), wherein ^{-CHR c OC (O) ZR d} ( wherein, Z is an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, R ^c is a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl group, Ali Indicates Le group, R ^d is, C _1-10 alkyl, C _2-10 alkenyl group, an aryl group.), A group represented by the formula [i]

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基を示し、或いは、
Ｒ¹及びＲ²の何れか一方が水素原子のとき、他方がＣ_1-10アルキル基、Ｃ_2-10アルケニル基、Ｃ_2-10アルキニル基、１若しくは２個のアリール基で置換されたＣ_1-10アルキル基、ヒドロキシＣ_2-10アルキル基、ハロゲン化Ｃ_1-10アルキル基、アジドＣ_1-10アルキル基、アミノＣ_2-10アルキル基、Ｃ_1-10アルコキシＣ_1-10アルキル基、Ｃ_1-10アルコキシカルボニルＣ_1-10アルキル基、ファルネシル基、４−モルホリニルＣ_1-10アルキル基、式−Ｃ(Ｏ)ＮＲ^aＲ^b（式中、Ｒ^a及びＲ^bは前記と同義である。）で表される基によって置換されたＣ_1-10アルキル基、式−ＣＨＲ^cＯＣ(Ｏ)ＺＲ^d（式中、Ｚ、Ｒ^c及びＲ^dは前記と同義である。）で表される基、式［i］

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C substituted with 1 or 2 aryl groups _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group , C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are as defined above) A C _1-10 alkyl group substituted by a group represented by the formula: —CHR ^c OC (O) ZR ^d , wherein Z, R ^c and R ^d are as defined above. The group represented by formula [i]

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基を示す。
Ｘは水素原子又はフッ素原子を示す。Ｙは、−ＯＣＨＲ³Ｒ⁴、−ＳＲ³、−Ｓ（Ｏ）_nＲ⁵、−ＳＣＨＲ³Ｒ⁴、−Ｓ（Ｏ）_nＣＨＲ³Ｒ⁴、−ＮＨＣＨＲ³Ｒ⁴、−Ｎ（ＣＨＲ³Ｒ⁴）（ＣＨＲ^3'Ｒ^4'）、−ＮＨＣＯＲ³、又は−ＯＣＯＲ⁵を示す（式中、Ｒ³、Ｒ^3'、 Ｒ⁴及びＲ^4'は同一又は異なって、水素原子、Ｃ_1-10アルキル基、Ｃ_1-10アルケニル基、フェニル基、ナフチル基、１〜７個のハロゲン原子で置換されたナフチル基、複素芳香族基、又は、ハロゲン原子、フェニル基、Ｃ_1-10アルキル基、Ｃ_1-10アルコキシ基、トリフルオロメチル基、フェニル基、ヒドロキシカルボニル基、アミノ基、ニトロ基、シアノ基及びフェノキシ基からなる群より選ばれる１〜５個の置換基で置換されたフェニル基を示す。Ｒ⁵は、Ｃ_1-10アルキル基、Ｃ_1-10アルケニル基、フェニル基、ナフチル基、１〜７個のハロゲン原子で置換されたナフチル基、複素芳香族基、又は、ハロゲン原子、フェニル基、Ｃ_1-10アルキル基、Ｃ_1-10アルコキシ基、トリフルオロメチル基、フェニル基、ヒドロキシカルボニル基、アミノ基、ニトロ基、シアノ基及びフェノキシ基からなる群より選ばれる１〜５個の置換基で置換されたフェニル基を示し、ｎは１又は２の整数を示す。）。］で表される２−アミノ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸エステル誘導体（以下、「本発明の化合物」ともいう。）、その医薬上許容される塩又はその水和物を有効成分として含有する、うつ病の予防又は治療薬である。

The group represented by these is shown.
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 group, C _1-10 alkenyl group, phenyl group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl Phenyl substituted with 1 to 5 substituents selected from the group consisting of a group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group R ⁵ represents a C _1-10 alkyl group, a C _1-10 alkenyl group, phenyl Group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group , Phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenyl group substituted with 1 to 5 substituents selected from the group consisting of phenoxy group, n represents an integer of 1 or 2 .) ] 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative (hereinafter also referred to as “the compound of the present invention”), a pharmaceutically acceptable salt thereof, or a salt thereof It is a prophylactic or therapeutic agent for depression containing a hydrate as an active ingredient.

In one embodiment of the present invention, in the formula [I], R ¹ and R ² are the same or different, and a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, 1 or 2 C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _{1 -10} alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, or when ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-10 alkyl group A C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 phenyl groups, a hydroxy C _2-10 alkyl group, a halogenated C _1-10 alkyl group, Azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl And a C _1-10 alkoxycarbonyl C _1-10 alkyl group.

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

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基を示し、或いは、
Ｒ¹及びＲ²の何れか一方が水素原子のとき、他方がファルネシル基、１若しくは２個のアリール基で置換されたＣ_1-10アルキル基、Ｃ_1-10アルコキシカルボニルＣ_1-10アルキル基、４−モルホリニルＣ_1-10アルキル基、式−Ｃ(Ｏ)ＮＲ^aＲ^b（式中、Ｒ^a及びＲ^bは前記と同義である。）で表される基によって置換されたＣ_1-10アルキル基、式−ＣＨＲ^cＯＣ(Ｏ)ＺＲ^d（式中、Ｚ、Ｒ^c及びＲ^dは前記と同義である。）で表される基、式［i］

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a farnesyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a C _1-10 alkoxycarbonyl C _1-10 alkyl group , 4-morpholinyl C _1-10 alkyl group, C _1- substituted by a group represented by the formula —C (O) NR ^a R ^b , wherein R ^a and R ^b are as defined above. ₁₀ an alkyl group, a group represented by the formula —CHR ^c OC (O) ZR ^d (wherein Z, R ^c and R ^d are as defined above), a formula [i]

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基を示すものであることが好ましい。

It is preferable to show a group represented by:

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

  Furthermore, in another aspect of the present invention, in the formula [I], X is preferably a fluorine atom.

Furthermore, in another aspect of the present invention, in the formula [I], Y is
^{-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 ′} are as defined above).

In another embodiment of the present invention, in the formula [I], Y represents —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 ′} are as defined above) is preferable.

Here, in the formula [I], R ³ , R ^{3 ′} R ⁴ and R ^{4 ′} used for explaining Y are each independently a hydrogen atom, a phenyl group, a naphthyl group, or a halogen atom, 1 to 5 selected from the group consisting of phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group It is preferable that it is the phenyl group substituted by the substituent of these. Among these, 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 with 1 to 5 halogen atoms. It is more preferable.

Furthermore, in another aspect of the present invention, in the formula [I], R ¹ and R ² each independently represent a hydrogen atom, a C _1-10 alkyl group, a C _2-6 alkenyl group, C _{2 -6} alkynyl group, C _1-6 alkyl group substituted by 1 or 2 phenyl groups, hydroxy C _2-6 alkyl group, halogenated C _1-6 alkyl group, azido C _1-6 alkyl group, amino C It is preferably a _2-6 alkyl group, a C _1-6 alkoxy C _1-6 alkyl group, or a C _1-6 alkoxycarbonyl C _1-6 alkyl group. Among these, R ² represents a hydrogen atom, and R ¹ is substituted with a linear or branched C _1-10 alkyl group, a C _2-6 alkenyl group, or 1 or 2 phenyl groups. C _1-6 alkyl group is preferred.

Furthermore, in another aspect of the present invention, in Formula [I], R ¹ and R ² are each independently C substituted with a hydrogen atom, a farnesyl group, or 1 or 2 aryl groups. _1-6 alkyl group, C _1-6 alkoxycarbonyl C _1-6 alkyl group, 4-morpholinyl C _1-6 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same as defined above) A C _1-6 alkyl group substituted by a group represented by the formula: —CHR ^c OC (O) ZR ^d (wherein Z, R ^c and R ^d are as defined above). ), A group represented by formula [i]

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基であることが好ましい。これらの中でも、Ｒ²が水素原子であり、Ｒ¹が、ファルネシル基、１若しくは２個のフェニル基若しくは置換フェニル基で置換されたＣ_1-6アルキル基、Ｃ_1-6アルコキシカルボニルＣ_1-6アルキル基、４−モルホリニルＣ_1-6アルキル基、式−Ｃ(Ｏ)ＮＲ^aＲ^b（式中、Ｒ^a及びＲ^bは前記と同義である。）で表される基によって置換されたＣ_1-6アルキル基、式−ＣＨＲ^cＯＣ(Ｏ)ＺＲ^d（式中、Ｚ、Ｒ^c及びＲ^dは前記と同義である。）で表される基、式［i］

It is preferable that it is group represented by these. Among these, R ² is a hydrogen atom, and R ¹ is a farnesyl group, a C _1-6 alkyl group substituted with one or two phenyl groups or a substituted phenyl group, C _1-6 alkoxycarbonyl C _{1- 6} alkyl group, 4-morpholinyl C _1-6 alkyl group, substituted by a group represented by the formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are as defined above). A group represented by a C _1-6 alkyl group, a formula —CHR ^c OC (O) ZR ^d (wherein Z, R ^c and R ^d are as defined above), a formula [i]

（式中、Ｒ^dは前記と同義である。）で表される基、又は式［ii］

Wherein R ^d is as defined above, or a group represented by formula [ii]

で表される基であることが好ましい。

It is preferable that it is group represented by these.

Here, in the formula [I], R ^a and R ^b used for explaining R ¹ and R ² are preferably a hydrogen atom or a C _1-6 alkyl group. R ^c is preferably 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 a C _1-6 alkyl group, a C _2-6 alkenyl group, or an aryl group.

  2-amino-3-alkoxy-6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid derivative, pharmaceutically acceptable salt or hydrate thereof, which is one embodiment of the present invention Is a potent antagonist of the metabotropic glutamate receptor. Accordingly, it has become possible to provide pharmaceuticals effective for the prevention and treatment of depression.

The terms used in this specification are as defined below. Here, “C _nm ” indicates that the subsequent group has n to m carbon atoms.

The C _1-10 alkyl group is a straight chain having 1 to 10 carbon atoms, a branched chain having 3 to 10 carbon atoms, or a cyclic alkyl group having 3 to 10 carbon atoms. Examples of the linear alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group, a pentyl group, a hexyl group, a heptyl group, an octyl group, a nonyl group, and a decyl group. Examples of the branched alkyl group include isopropyl group, isobutyl group, 1-methylpropyl group, t-butyl group, 1-methylbutyl group, 2-methylbutyl group, 3-methylbutyl group, 1-ethylpropyl group, 1, 1-dimethylpropyl group, 2,2-dimethylpropyl group, 1,2-dimethylpropyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 4-methylpentyl group, 1-ethylbutyl group 2-ethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,2-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3- Dimethylbutyl group, 5-methylhexyl group, 3-ethylpentyl group, 1-propylbutyl group, 1,4-dimethylpentyl group, 3,4-dimethylpentene Group, 1,2,3-trimethylbutyl group, 1-isopropylbutyl group, 4,4-dimethylpentyl group, 5-methylheptyl group, 6-methylheptyl group, 4-ethylhexyl group, 2-propylpentyl group, 2,5-dimethylhexyl group, 4,5-dimethylhexyl group, 2-ethyl-3-methylpentyl group, 1,2,4-trimethylpentyl group, 2-methyl-1-isopropylbutyl group, 3-methyloctyl Group, 2,5-dimethylheptyl group, 1- (1-methylpropyl) -2-methylbutyl group, 1,4,5-trimethylhexyl group, 1,2,3,4-tetramethylpentyl group, 7-methyl Octyl group, 6-methylnonyl group, 8-methylnonyl group, 5-ethyl-2-methylheptyl group, 2,3-dimethyl-1- (1-methylpropyl) butyl group Cyclopropylmethyl group, 2- (cyclopropyl) ethyl, 3,7-dimethyl octyl group, 3- (cyclobutyl) pentyl group, cyclopentylmethyl group, and a cyclohexylmethyl group. Examples of the cyclic alkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group.

The C _2-10 alkenyl group has at least one double bond, a straight chain having 2 to 10 carbon atoms, a branched chain having 3 to 10 carbon atoms, or 5 to 5 carbon atoms. 10 cyclic alkenyl groups, for example, vinyl, allyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 6-heptenyl, 7-octenyl, 8-nonenyl, 9-decenyl Group, 1-methyl-2-butenyl group, 2-methyl-2-butenyl group, 2-methyl-3-butenyl group, 2-pentenyl group, 2-methyl-2-hexenyl group, 2-cyclopentenyl group, etc. Can be mentioned.

The C _2-10 alkynyl group is a straight chain having 2 to 10 carbon atoms or a branched alkynyl group having 4 to 10 carbon atoms having at least one triple bond, such as 2-propynyl. Group, 3-butynyl group, 4-pentynyl group, 5-hexynyl group, 6-heptynyl group, 7-octynyl group, 8-nonayl group, 9-decynyl group, 3-pentynyl group, 4-methyl-2-pentynyl group Etc.

Examples of the C _1-10 alkyl group substituted with 1 or 2 aryl groups include benzyl, diphenylmethyl group, 2-phenylethyl group, 2-phenylpropyl group, 1-methyl-1-phenylethyl group, 1-methyl-2-phenylpentyl group, 2-nitrobenzyl group, 3-nitrobenzyl group, 4-nitrobenzyl group, 2,4-dinitrobenzyl group, 2,4,6-trinitrobenzyl group, 2-phenyl Benzyl group, 3-phenylbenzyl group, 4-phenylbenzyl group, 2-hydroxybenzyl, 3-hydroxybenzyl group, 4-hydroxybenzyl group, 2-chlorobenzyl group, 3-chlorobenzyl group, 4-chlorobenzyl group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-velomobenzyl group, 3-velomobe Gyl group, 4-velomobenzyl group, 2-iodobenzyl group, 2-iodobenzyl group, 2,3-dichlorobenzyl group, 2,4-dichlorobenzyl group, 2,5-dichlorobenzyl group, 2,6-dichlorobenzyl Group, 3,4-dichlorobenzyl group, 3,5-dichlorobenzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2-ethylbenzyl group, 3-ethylbenzyl group, 4- Ethylbenzyl group, 2-isopropylbenzyl group, 3-isopropylbenzyl group, 4-isopropylbenzyl group, 2-methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, 2,3-dimethoxybenzyl group, 2, 4-dimethoxybenzyl group, 2,5-dimethoxybenzyl group, 2,6-dimethoxybenzyl group, 3,4-dimethoxy Sibenzyl group, 3,5-dimethoxybenzyl group, 2-ethoxybenzyl group, 3-ethoxybenzyl group, 4-ethoxybenzyl group, 2-isopropoxybenzyl group, 3-isopropoxybenzyl group, 4-isopropoxybenzyl group, 2-methoxymethylbenzyl group, 3-methoxymethylbenzyl group, 4-methoxymethylbenzyl group, 2-isopropoxymethylbenzyl group, 3-isopropoxymethylbenzyl group, 4-isopropoxymethylbenzyl group, 2-trifluoromethyl Group, 3-trifluoromethyl group, 4-trifluoromethyl group, 2-hydroxycarbonylbenzyl group, 3-hydroxycarbonylbenzyl group, 4-hydroxycarbonylbenzyl group, 2-aminobenzyl group, 3-aminobenzyl group, 4 -Aminobenzyl group, 2-amino Tylbenzyl group, 3-aminomethylbenzyl group, 4-aminomethylbenzyl group, 2-cyanobenzyl group, 3-cyanobenzyl group, 4-cyanobenzyl group, 2-hydroxymethylbenzyl group, 3-hydroxymethylbenzyl group, 4 -Hydroxymethylbenzyl group, 2-phenoxybenzyl group, 3-phenoxybenzyl group, 4-phenoxybenzyl group can be mentioned.

  The aryl group represents a phenyl group, a substituted phenyl group, or a polycyclic aromatic group such as a 1-naphthyl group and a 2-naphthyl group.

Substituted phenyl group means halogen atom, hydroxyl group, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, C _1-10 alkoxy C _1-10 alkyl group, trifluoromethyl group, hydroxycarbonyl group, amino A phenyl group substituted with 1 to 3 substituents selected from the group consisting of a group, a nitro group, a cyano group, a hydroxymethyl group, an aminomethyl group, and a phenoxy group. For example, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2,4-dinitrophenyl group, 2,4,6-trinitrophenyl group, 2-phenylphenyl group, 3-phenylphenyl group 4-phenylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 4-hydroxyphenyl group, 2-chlorophenyl group, 3-chlorophenyl group, 4-chlorophenyl group, 2-fluorophenyl group, 3-fluorophenyl Group, 4-fluorophenyl group, 2-velophenyl group, 3-velophenyl group, 4-velophenyl group, 2-iodophenyl group, 2-iodophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2 , 5-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophen Group, 3,5-dichlorophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-isopropylphenyl Group, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2,3-dimethoxyphenyl group, 2,4-dimethoxyphenyl group, 2, 5-dimethoxyphenyl group, 2,6-dimethoxyphenyl group, 3,4-dimethoxyphenyl group, 3,5-dimethoxyphenyl group, 2-ethoxyphenyl group, 3-ethoxyphenyl group, 4-ethoxyphenyl group, 2- Isopropoxyphenyl group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group, -Methoxymethylphenyl group, 3-methoxymethylphenyl group, 4-methoxymethylphenyl group, 2-isopropoxymethylphenyl group, 3-isopropoxymethylphenyl group, 4-isopropoxymethylphenyl group, 2-trifluoromethyl group 3-trifluoromethyl group, 4-trifluoromethyl group, 2-hydroxycarbonylphenyl group, 3-hydroxycarbonylphenyl group, 4-hydroxycarbonylphenyl group, 2-aminophenyl group, 3-aminophenyl group, 4- Aminophenyl group, 2-aminomethylphenyl group, 3-aminomethylphenyl group, 4-aminomethylphenyl group, 2-cyanophenyl group, 3-cyanophenyl group, 4-cyanophenyl group, 2-hydroxymethylphenyl group, 3-hydroxymethylphenyl group, 4- Examples thereof include a hydroxymethylphenyl group, a 2-phenoxyphenyl group, a 3-phenoxyphenyl group, and a 4-phenoxyphenyl group.

Among C _1-10 alkyl groups substituted by these one or two aryl groups, C _1-10 alkyl groups substituted by one or two phenyl groups are preferred.

The hydroxy C _2-10 alkyl group refers to a C _2-10 alkyl group substituted by at least one hydroxyl group, such as 2-hydroxyethyl group, 3-hydroxypropyl group, 4-hydroxybutyl group, 5 -Hydroxypentyl group, 6-hydroxyhexyl group, 7-hydroxyheptyl group, 8-hydroxyoctyl group, 9-hydroxynonyl group, 10-hydroxydecyl group, 2-hydroxypropyl group, 2,3-dihydroxypropyl group, 2- Examples thereof include a hydroxy-3-methylbutyl group.

The halogenated C _1-10 alkyl group means a C _1-10 alkyl group substituted by at least one fluorine atom, chlorine atom, bromine atom and iodine atom, for example, 2-chloroethyl group, 2-bromoethyl group 2-iodoethyl group, 3-chloropropyl group, 3-bromopropyl group, 3-iodopropyl group, 4-chlorobutyl group, 4-bromobutyl group, 4-iodobutyl group, 5-chloropentyl group, 6-chlorohexyl group 7-chloroheptyl group, 8-chlorooctyl group, 9-chlorononyl group, 10-chlorodecyl group, 2-chloropropyl group, 2-chlorobutyl group, 2,4-dichlorobutyl group, 2-chloro-3-methylbutyl group Etc.

The azido C _1-10 alkyl group refers to a C _1-10 alkyl group substituted by at least one azide group, such as a 2-azidoethyl group, a 3-azidopropyl group, a 4-azidobutyl group, and a 5-azido. Pentyl group, 6-azidohexyl group, 7-azidoheptyl group, 8-azidooctyl group, 9-azidononyl group, 10-azidodecyl group, 2-azidopropyl group, 2-azidobutyl group, 2-azido-3-methylbutyl group, etc. Can be mentioned.

An amino C _2-10 alkyl group refers to a C _2-10 alkyl group substituted with at least one amino group, such as a 2-aminoethyl group, a 3-aminopropyl group, a 6-aminohexyl group, 7 -Aminoheptyl group, 8-aminooctyl group, 9-aminononyl group, 10-aminodecyl group, 4-aminobutyl group, 2,4-diaminobutyl group and the like can be mentioned.

The C _1-10 alkoxy C _1-10 alkyl group is a linear alkoxy group having 1 to 10 carbon atoms, a branched chain having 3 to 10 carbon atoms, or a cyclic alkoxy group having 3 to 10 carbon atoms. Represents an alkyl group having 1 to 10 carbon atoms substituted by, for example, 2-methoxyethyl group, 2-ethoxyethyl group, 2-propoxyethyl group, 2-isopropoxyethyl group, 2-butoxyethyl group, 2 -Isobutoxyethyl group, 2-t-butoxyethyl group, 2-pentyloxyethyl group, 2-hexenyloxyethyl group, 3-ethoxypropyl group, 4-ethoxybutyl group, 4-ethoxy-3-methoxybutyl group, Examples include 4-ethoxy-3-methylpentyl group.

The C _1-10 alkoxycarbonyl C _1-10 alkyl group is a linear alkoxy having 1 to 10 carbon atoms, a branched chain having 3 to 10 carbon atoms, or a cyclic alkoxy having 3 to 10 carbon atoms. An alkyl group having 1 to 10 carbon atoms substituted by a carbonyl group, for example, a methoxycarbonylmethyl group, an ethoxycarbonylmethyl group, a propyloxycarbonylmethyl group, an isopropoxycarbonylmethyl group, a butyloxycarbonylmethyl group, an isobutoxy Carbonylmethyl group, t-butoxycarbonylmethyl group, pentyloxycarbonylmethyl group, hexyloxycarbonylmethyl group, 2- (ethoxycarbonyl) ethyl group, 3- (ethoxycarbonyl) propyl group, 4- (ethoxycarbonyl) butyl group, 4- (ethoxycarbonyl) pentyl group, 4 -(Ethoxycarbonyl) -3-methylpentyl group etc. are mentioned.

  The farnesyl group represents a (2Z, 6Z) -3,7,11-trimethyldodeca-2,6,10-trienyl group.

The 4-morpholinyl C _1-10 alkyl represents an alkyl group having 1 to 10 carbon atoms substituted by a 4-morpholinyl group, and examples thereof include a 2- (4-morpholinylethyl) group, 3- (4- Morpholinyl) propyl group, 4- (4-morpholinyl) butyl group, 5- (4-morpholinyl) pentyl group, 6- (4-morpholinyl) hexyl group, 7- (4-morpholinyl) heptyl group, 8- (4- Morpholinyl) octyl, 9- (4-morpholinyl) nonyl, 10- (4-morpholinyl) decyl, 2- (4-morpholinyl) pentyl, 1-methyl-3- (4-morpholinyl) butyl It is done.

(Wherein, R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group.) Formula C (O) NR ^a R ^b The C _1-10 alkyl group substituted by, 2- (N, N-dimethylaminocarbonyl) ethyl group, 2- (N, N-diethylaminocarbonyl) ethyl group, 3- (N, N-diethylaminocarbonyl) propyl group, 2- (N-methylaminocarbonyl) ethyl Group, 2- (N-ethylaminocarbonyl) ethyl group, 2- (N, N-methylethylaminocarbonyl) ethyl, 2- (N, N-ethylpropylaminocarbonyl) ethyl group, 2- (N, N- A diethylaminocarbonyl) -1-methylethyl group.

  The naphthyl group substituted with 1 to 7 halogen atoms refers to a naphthyl group substituted with at least one fluorine atom, chlorine atom, bromine atom or iodine atom, for example, 1-fluoro-2-naphthyl group 2-fluoro-1-naphthyl group, 1-chloro-2-naphthyl group, 2-chloro-1-naphthyl group, 1-bromo-2-naphthyl group, 2-bromo-1-naphthyl group, 1-iodo- Examples include 2-naphthyl group, 2-iodo-1-naphthyl group, 1,3-difluoro-2-naphthyl group.

  The heteroaromatic group is a monocyclic 5-membered or 6-membered aromatic ring containing at least one atom among oxygen atom, nitrogen atom or sulfur atom, or these monocycles are condensed with a benzene ring. Or a bicyclic aromatic ring condensed with each other. For example, furyl, pyrrolyl, thiophenyl, oxazoyl, isoxazoyl, imidazoyl, pyrazoyl, thiazoyl, isothiazoyl, oxadiazoyl, thiadiazoyl, benzofuranyl, indolyl, benzothiophenyl, indazoyl, benzoisoxazoyl, benzoisothiazoyl, benzoimidazoyl, benzoxa Examples include zoyl, benzothiazoyl, pyridyl, quinolinyl, isoquinolinyl, pyrodazinyl, pyrimidinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl and the like.

The C _1-10 alkoxy group represents a linear or branched alkoxy group having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, and an isobutoxy group. , T-butoxy group, pentyloxy group, isopentyloxy group and the like.

1 selected from the group consisting of a halogen atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group A phenyl group substituted with up to 5 substituents is a fluorine atom, chlorine atom, bromine atom, iodine atom, C _1-10 alkyl group, cyclic C _3-10 alkyl group, C _1-10 alkoxy group, cyclic A phenyl group substituted with 1 to 5 substituents selected from a C _3-10 alkoxy group, a trifluoromethyl group, a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group, or a phenoxy group. For example, as a phenyl group substituted with one substituent, a 2-fluorophenyl group, a 3-fluorophenyl group, a 4-fluorophenyl group, a 2-chlorophenyl group, a 3-chlorophenyl group, a 4-chlorophenyl group, 2- Bromophenyl group, 3-bromophenyl group, 4-bromophenyl group, 2-iodophenyl group, 3-iodophenyl group, 4-iodophenyl group, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl Group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-isopropylphenyl group, 3-isopropylphenyl group, 4-isopropylphenyl group, 2-cyclopropylphenyl group, 3-cyclopropylphenyl Group, 4-cyclopropylphenyl group, 2-cyclohexylphenyl group, 3-cyclyl Hexylphenyl group, 4-cyclohexylphenyl group, 2-methoxyphenyl group, 3-methoxyphenyl group, 4-methoxyphenyl group, 2-isopropoxyphenyl group, 3-isopropoxyphenyl group, 4-isopropoxyphenyl group, 2 -Cyclobutyroxyphenyl group, 3-cyclobutyroxyphenyl group, 4-cyclobutyroxyphenyl group, 2-cyclohexyloxyphenyl group, 3-cyclohexyloxyphenyl group, 4-cyclohexyloxyphenyl group, 2-trifluoromethylphenyl Group, 3-fluoromethylphenyl group, 4-trifluoromethylphenyl group, 2-phenylphenyl group, 3-phenylphenyl group, 4-phenylphenyl group, 2-hydroxycarbonylphenyl group, 3-hydroxycarbonylphenyl group, 4 - Roxycarbonylphenyl group, 2-aminophenyl group, 3-aminophenyl group, 4-aminophenyl group, 2-nitrophenyl group, 3-nitrophenyl group, 4-nitrophenyl group, 2-cyanophenyl group, 3-cyano A phenyl group, 4-cyanophenyl group, 2-phenoxyphenyl group, 3-phenoxyphenyl group, 4-phenoxyphenyl group, etc. are mentioned. Examples of the phenyl group substituted with two substituents include 2,3-difluorophenyl group, 2,4-difluorophenyl group, 2,5-difluorophenyl group, 2,6-difluorophenyl group, 3,4 -Difluorophenyl group, 3,5-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenyl group, 2,6-dichlorophenyl group, 3,4-dichlorophenyl group, 3, 5-dichlorophenyl group, 2,3-dibromophenyl group, 2,4-dibromophenyl group, 2,5-dibromophenyl group, 2,6-dibromophenyl group, 3,4-dibromophenyl group, 3,5-dibromo Phenyl group, 2,3-diiodophenyl group, 2,4-diiodophenyl group, 2,5-diiodophenyl group, 2,6-diiodo Phenyl group, 3,4-diiodophenyl group, 3,5-diiodophenyl group, 3-chloro-4-fluorophenyl group, 4-chloro-3-fluorophenyl group, 3-bromo-4-fluorophenyl group 4-bromo-3-fluorophenyl group, 4-bromo-3-chlorophenyl group, 3-bromo-4-chlorophenyl group, 3-chloro-4-methylphenyl group, 4-chloro-3-methylphenyl group, 3- Fluoro-4-methylphenyl group, 4-fluoro-3-methylphenyl group, 3-fluoro-4-methoxyphenyl group, 4-fluoro-3-methoxyphenyl group, 3-bromo-4-methoxyphenyl group, 4- Bromo-3-methoxyphenyl group, 3-chloro-4-phenoxyphenyl group, 4-chloro-3-phenoxyphenyl group, 3-chloro-4-nitrate Phenyl group, 4-chloro-3-nitrophenyl group, 4-bromo-3-nitrophenyl group, 3-bromo-4-nitrophenyl group, 3-amino-4-bromophenyl group, 4-amino-3-bromo Phenyl group, 3-bromo-4-hydroxycarbonyl group, 4-bromo-3-hydroxycarbonylphenyl group, 4-fluoro-3-hydroxycarbonylphenyl group, 3-fluoro-4-hydroxycarbonylphenyl group, 4-fluoro- 3-hydroxycarbonylphenyl group, 3-cyano-4-fluorophenyl group, 3-cyano-4-fluorophenyl group, 4-cyano-3-methylphenyl group, 3-cyano-4-methylphenyl group, 3-cyano Examples include -4-methoxyphenyl group and 4-cyano-3-methoxyphenyl group. Examples of the phenyl group substituted with three substituents include 2,3,4-trifluorophenyl group, 3,4,5-trifluorophenyl group, 3,4,5-trichlorophenyl group, and 3-chloro. Examples include -2,6-difluorophenyl group, 3,5-dichloro-4-methoxyphenyl group, 3,5-dibromo-4-methoxyphenyl group, and the like. Examples of the phenyl group substituted with four substituents include 2,5-dibromo-3,4-dimethoxyphenyl group and 3,4-dibromo-2,4-dimethoxyphenyl group. Examples of the phenyl group substituted with five substituents include 2,3,4,5,6-pentafluorophenyl group.

  Examples of the pharmaceutically acceptable salt in the present invention include salts with mineral acids such as sulfuric acid, hydrochloric acid, and phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, and benzenesulfone. A salt with an organic acid such as an acid, a salt with an amine such as trimethylamine or methylamine, or a salt with a metal ion such as sodium ion, potassium ion or calcium ion.

  Moreover, the hydrate in this invention is a pharmaceutically acceptable hydrate of the compound of this invention, or its salt. The compound of the present invention and the salt thereof may absorb moisture or become adsorbed water or may be hydrated by exposure to the atmosphere or recrystallization. The hydrate in the present invention includes such a hydrate.

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

  A preferred steric structure of the compound of the present invention is an optically active substance having an absolute structure represented by the formula [II], but it may exist as a mixture of enantiomers such as enantiomers and racemates thereof. That is, the compound of the present invention includes all enantiomer mixtures and diastereomer mixtures of the optically active compound, racemate and the like of the compound represented by the following formula [II].

  The compounds [I] and [II] of the compounds of the present invention do not affect the group II metabotropic glutamate receptor. However, the compounds represented by the formulas [III] and [IV], which are hydrolyzed enzymatically or chemically in vivo and have a strong antagonistic action on group II metabotropic glutamate receptors, Each is converted. Therefore, the compound of the present invention exhibits a function as a drug acting on a group II metabotropic glutamate receptor.

［式中、Ｘは水素原子又はフッ素原子を示す。Ｙは、−ＯＣＨＲ³Ｒ⁴、−ＳＲ³、−Ｓ（Ｏ）_nＲ⁵、−ＳＣＨＲ³Ｒ⁴、−Ｓ（Ｏ）_nＣＨＲ³Ｒ⁴、−ＮＨＣＨＲ³Ｒ⁴、−Ｎ（ＣＨＲ³Ｒ⁴）（ＣＨＲ^3'Ｒ^4'）、−ＮＨＣＯＲ³、又は−ＯＣＯＲ⁵を示す（式中、Ｒ³、Ｒ^3'、 Ｒ⁴及びＲ^4'は同一又は異なって、水素原子、Ｃ_1-10アルキル基、Ｃ_1-10アルケニル基、フェニル基、ナフチル基、１〜７個のハロゲン原子で置換されたナフチル基、複素芳香族基、又は、ハロゲン原子、フェニル基、Ｃ_1-10アルキル基、Ｃ_1-10アルコキシ基、トリフルオロメチル基、フェニル基、ヒドロキシカルボニル基、アミノ基、ニトロ基、シアノ基及びフェノキシ基からなる群より選ばれる１〜５個の置換基で置換されたフェニル基を示す。Ｒ⁵は、Ｃ_1-10アルキル基、Ｃ_1-10アルケニル基、フェニル基、ナフチル基、１〜７個のハロゲン原子で置換されたナフチル基、複素芳香族基、又は、ハロゲン原子、フェニル基、Ｃ_1-10アルキル基、Ｃ_1-10アルコキシ基、トリフルオロメチル基、フェニル基、ヒドロキシカルボニル基、アミノ基、ニトロ基、シアノ基及びフェノキシ基からなる群より選ばれる１〜５個の置換基で置換されたフェニル基を示し、ｎは１又は２の整数を示す。）。］で表される２−アミノ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸エステル誘導体、その医薬上許容される塩又はその水和物である。

[Wherein, 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 group, C _1-10 alkenyl group, phenyl group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl Phenyl substituted with 1 to 5 substituents selected from the group consisting of a group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group R ⁵ represents a C _1-10 alkyl group, a C _1-10 alkenyl group, phenyl Group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group , Phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenyl group substituted with 1 to 5 substituents selected from the group consisting of phenoxy group, n represents an integer of 1 or 2 .) ] 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt, or its hydrate represented by these.

  The present invention relates to a compound of the present invention represented by the formula [1] or [2], a pharmaceutically acceptable salt thereof or a hydrate thereof. The compounds of the present invention can be synthesized using known organic synthesis techniques. For example, it can be produced by the following method.

First, compounds (9), (16), (24), (27), (30) and (33) which are also synthetic intermediates necessary for synthesizing the compound [I] of the present invention are as follows. Can be manufactured. (In the following reaction formulas, X, Y, Z, n, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above. R ⁶ represents a mesyl group, a phenylsulfonyl group, a tosyl group, aryl and alkyl sulfonyl group such as trifluoromethylsulfonyl group, a benzoyl group, is .R ⁷ showing a 4-nitrobenzoyl group, a methoxycarbonyl group, an ethoxycarbonyl group, t-butoxycarbonyl group, an alkoxycarbonyl, such as benzyloxycarbonyl group Group, benzoyl group, p-phenylbenzoyl group, acyl group such as (pyridin-2-yl) carbonyl group, alkyl group such as aryl group, benzyl group, p-methoxybenzyl group, di (p-methoxyphenyl) methyl group , An alkenyl group such as a 5,5-dimethyl-3-oxo-1-cyclohexenyl group, a benzenesulfenyl group, , 4-dinitrophenyl sulfone sulfenyl group such as a phenyl group, a benzyl sulfonyl group, .A ¹ showing the amino-protecting group such as diphenylphosphoryl sulfinyl group or a dialkyl phosphoryl Le group, wherein R ³ or formula CHR ³ R ⁴ .A ² showing the can, .Q showing the formula R ⁵ or formula CHR ³ R ⁴ has the formula _{^{SR 3, S (O) n}} R 5, wherein SCHR ³ R ^4, or formula S (O) _n CHR ³ R ⁴ is shown).

  Step 1: By reacting compound (1) with a trifluoromethanesulfonylating agent such as trifluoromethanesulfonic anhydride, N-phenyl-bis (trifluoromethanesulfonimide) in the presence of a base in an inert solvent, To compound (2). Here, examples of the inert solvent include hydrocarbon solvents such as benzene, toluene, and hexane, halogen solvents such as dichloromethane, chloroform, and carbon tetrachloride, ethers such as tetrahydrofuran, diethyl ether, and 1,2-dimethoxyethane. A system solvent, acetonitrile, or a mixed solvent thereof can be used. Examples of the base include amines such as triethylamine, N-methylmorpholine, diisopropylethylamine and pyridine, inorganic bases such as potassium hydride and sodium hydride, lithium diisopropylamide, potassium bis (trimethylsilyl) amide, lithium hexamethyldi Metal amides such as silazane, metal alcoholates such as sodium methoxide and potassium t-butoxide can be used. Preferably, it is reacted with N-phenyl-bis (trifluoromethanesulfonimide) in tetrahydrofuran in the presence of lithium hexamethyldisilazane at −78 ° C. to room temperature for 2 to 4 hours to give compound (2). Can lead.

Step 2: Compound (2) in an inert solvent in the presence of a transition metal catalyst, for example, organic bases such as triethylamine, N-methylmorpholine, diisopropylethylamine and pyridine, or inorganic bases such as potassium carbonate and sodium bicarbonate In the presence of, it can lead to compound (3) by reacting with carbon monoxide and R ² OH (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) acetate and triphenylphosphine, 2,2′-bis (diphenylphosphino) -1,1- It can be prepared in the reaction system using a ligand such as binaphthyl (BINAP). A zero-valent palladium reagent such as tetrakistriphenylphosphine palladium (0) can also be used directly. Examples of the inert solvent include hydrocarbon solvents such as benzene, toluene, hexane, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, acetonitrile, N, N-dimethylformamide, or a mixture thereof. A solvent or the like can be used. Preferably, compound (2) is reacted with carbon monoxide and R ² OH in N, N-dimethylformamide in the presence of diisopropylethylamine, palladium (II) acetate and triphenylphosphine at room temperature for 2 to 7 hours. This can lead to compound (3).

Step 3: A general diolation reaction using compound (3) in an inert solvent such as osmium tetroxide (see M. Hudlicky, “Oxidations in Organic Chemistry”) and Sharpless's reagent using AD-mix as a reagent. Asymmetric cis-dihydroxylation (Sharpless AD) (see Tetrahedron Asymmetry 4 , 133 (1993), J. Org. Chem. 57 , 2768 (1992), J. Org. Chem. 61 , 2582 (1996)) Can be oxidized to a diol, leading to compound (4). Here, the inert solvent is, for example, an alcohol solvent such as t-butyl alcohol, a hydrocarbon solvent such as benzene, toluene or hexane, an ether solvent such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, acetonitrile. , Acetone, N, N-dimethylformamide, water, or a mixed solvent thereof can be used. Preferably, the compound (3) can be oxidized to a diol by using osmium tetroxide in a mixed solvent of acetonitrile and water at room temperature for 30 minutes to 3 hours to lead to the compound (4).

  Step 4: Compound (4) is a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. In the presence of an organic base such as triethylamine, N-methylmorpholine, diisopropylethylamine, pyridine, or an inorganic base such as potassium carbonate or sodium hydrogencarbonate in an inert solvent such as a solvent, acetonitrile, or a mixed solvent thereof, or not. In the presence, after reaction with thionyl chloride, hydrocarbon solvents such as benzene, toluene, hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane , General oxidizing agents such as hydrogen peroxide, oxone (trade name), ruthenium trichloride-sodium metaperiodate in an inert solvent such as cetonitrile, acetone, water, or a mixed solvent thereof (M. Hudlicky, “ Oxidations in Organic Chemistry ”)) and can be led to compound (5). Preferably, the compound (4) is reacted with thionyl chloride in dichloromethane in the presence of triethylamine in the presence of triethylamine for 30 minutes to 2 hours, and then in a mixed solvent of carbon tetrachloride, acetonitrile and water at 0 ° C. to room temperature for 30 minutes. Can be oxidized for 2 hours to lead to compound (5).

Step 5: Compound (5) was reacted with sodium azide in an inert solvent such as an ether solvent such as tetrahydrofuran, ketones such as acetone, N, N-dimethylformamide, water, or a mixed solvent thereof. Thereafter, hydrolysis can lead to compound (6) (see J. Am. Chem. Soc. 110 , 7538 (1988)). Preferably, the compound (5) is reacted with sodium azide in a mixed solvent of N, N-dimethylformamide and water at room temperature to 50 ° C. for 1 to 20 hours, and then 20% in a mixed solvent of diethyl ether and water. Hydrolysis using sulfuric acid at room temperature for 1 to 2 days can lead to compound (6).

The obtained compound (6) is converted into the compound (9) which is a synthetic intermediate of the compound of the present invention by the following steps 7, 8 and 9 when Y is the formula OCHR ³ R ^{4 in} the formula [III]. Can lead.

Step 7: The hydroxyl group of the compound (6) in which R ¹ and R ² are other than a hydrogen atom is a hydrocarbon solvent such as benzene, toluene, hexane or cyclohexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, Bronsted acid catalyst such as trifluoromethanesulfonic acid, trifluoroacetic acid, or hydrogen chloride in an ethereal solvent such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, or an inert solvent such as a mixed solvent thereof. Formula R ³ R wherein L ¹ is a 2,2,2-trichloroacetimidoyloxy group in the presence of a Lewis acid catalyst such as boron bromide / diethyl ether complex, zinc chloride, tin chloride, or trimethylsilyl-trifluoromethanesulfonate ⁴ by reaction with a compound represented by the CHL ^1, compound (7) Can be derived (J. Chem. Soc. Perkin Trans. 1, 2247 (1985), see Synthesis, 568 (1987)). Here, L ¹ is a leaving group, such as a halogen atom, an ethoxycarbonyloxy group, a phenoxycarbonyloxy group, or the like.

Further, the hydroxyl group of the compound (6) in which R ¹ and R ² are other than a hydrogen atom is exemplified by hydrocarbon solvents such as benzene, toluene and hexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran and diethyl. Hydrogenation in an inert solvent such as ether, ether solvent such as 1,2-dimethoxyethane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof. Inorganic bases such as sodium, potassium hydride, potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide, metal amides such as lithium bis (trimethylsilyl) amide, lithium diisopropylamide and sodium amide, triethylamine, diisopropylethylamine, 4 -(N , N-dimethylamino) pyridine, organic bases such as 2,6-di-t-butylpyridine, and L ² is 2,2,2-trichloroacetimidoyloxy in the presence of a base such as potassium t-butoxide. By reacting with a compound represented by the formula R ³ R ⁴ CHL ² other than the group, the compound (7) can also be led. Here, L ² is a leaving group such as a halogen atom, tosyl sulfonate, trifluoromethane sulfonate, tolyl sulfonate, and the like. Preferably, the hydroxyl group of compound (6) is reacted with a compound represented by the formula R ³ R ⁴ CHL ¹ in a mixed solvent of chloroform and cyclohexane in the presence of trifluoromethanesulfonic acid at room temperature for 1 to 3 hours. This can lead to compound (7).

  Step 8: Compound (7) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether system such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Staudinger reaction (Bull. Chem. Soc. Fr.) with triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. in an inert solvent such as a solvent, acetonitrile, acetone, water, or a mixed solvent thereof. 815 (1985)), palladium / carbon in an inert solvent such as alcohols such as ethanol and methanol, esters such as ethyl acetate, N, N-dimethylformamide, water, or a mixed solvent thereof, palladium black Hydrogenation in the presence of metal catalysts such as It can lead to reduction of the general azide group typified by hydride reduction, such as with lithium amino borohydride such as (A. F. Abdel-Magid, "Reductions in Organic Synthesis" referenced) by the compound (8). Preferably, compound (7) can be led to compound (8) by reacting at room temperature for 2 to 12 hours using a Staudinger reaction using trimethylphosphine in a mixed solvent of tetrahydrofuran and water. .

Step 9: General hydrolysis reaction a moiety of the formula COOR ¹ and formula COOR ² of compound R ¹ and R ² is other than hydrogen atoms (8) (TW Greene, PGM Wuts, "Protective Groups in Organic Synthesis The compound can be converted into a carboxylic acid by “see” to lead to a compound (9) which is a synthetic intermediate of the compound of the present invention. Preferably, the compound (8) is a synthetic intermediate of the compound of the present invention by hydrolyzing the compound (8) in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at room temperature to 50 ° C. for 1 to 7 days. It can lead to a compound (9).

Compound (6) is represented by the following formula (III) when Y is formula SR ³ , formula S (O) _n R ⁵ , formula SCHR ³ R ⁴ , formula S (O) _n CHR ³ R ⁴ Steps 10, 11, 12, 13, 14 and 15 shown can lead to compound (16) which is a synthetic intermediate of the compound of the present invention.

Step 10: A hydroxyl group of the compound (6) in which R ¹ and R ² are other than a hydrogen atom, for example, a hydrocarbon solvent such as benzene, toluene, hexane, cyclohexane, a halogen solvent such as dichloromethane, chloroform, carbon tetrachloride, In an inert solvent such as tetrahydrofuran, diethyl ether, ether solvents such as 1,2-dimethoxyethane, amides such as N, N-dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof. , Inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, metal amides such as lithium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium amide, triethylamine, pyridine , Diisop In the presence of organic bases such as propylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butylpyridine, and bases such as potassium t-butoxide, anhydrous trifluoromethanesulfonic acid, N To compound (10) by reacting with a trifluoromethanesulfonylating agent such as -phenyl-bis (trifluoromethanesulfonimide) or alkyl and arylsulfonylating agents such as chloromethanesulfonic acid, chlorobenzenesulfonic acid, and toluenesulfonic acid chloride Can lead to. Preferably, the hydroxyl group of compound (6) is led to compound (10) by reacting with trifluoromethanesulfonic anhydride in dichloromethane in the presence of pyridine in a temperature range of −78 ° C. under ice cooling for 30 minutes to 3 hours. be able to.

Step 11: Compound (10) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. In an inert solvent such as a system solvent, dimethyl sulfoxide, N, N-dimethylformamide, or a mixed solvent thereof, metal alcoholates such as sodium ethoxide, potassium t-butoxide, sodium, potassium, sodium hydride, potassium hydride and the formula By reacting with a compound represented by the formula A ¹ SNa, formula A ¹ SK or the like prepared from a mercaptan represented by A ¹ SH and a thiophenol, the compound (11) can be derived. Preferably, compound (10) is reacted with a compound of formula A ¹ SHNa prepared from sodium and a compound of formula A ¹ SH in dimethyl sulfoxide at room temperature for 10 minutes to 1 hour. As a result, it can be led to the compound (11).

Step 12: Compound (11) in which A ¹ is not a hydrogen atom includes, for example, hydrocarbon solvents such as benzene, toluene and hexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2 -In an inert solvent such as ether solvent such as dimethoxyethane, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, methanol, ethanol, acetic acid, water or a mixed solvent thereof, such as sodium periodate or peracetic acid And the like (see M. Hudlicky, “Oxidations in Organic Chemistry”) can be used to lead to the compound (12).

Step 13: Compound (12) or Compound (11) in which A ¹ is not a hydrogen atom includes, for example, hydrocarbon solvents such as benzene, toluene, hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, In an inert solvent such as diethyl ether, 1,2-dimethoxyethane or the like, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water or a mixed solvent thereof, for example, 3-chloroperbenzoic acid, A general sulfide (eg, M. Hudlicky, “Oxidations in Organic Chemistry”) using sulfide or sulfoxide using hydrogen peroxide or the like can be used to lead to the compound (13). Alternatively, from the compound (11) in which A ¹ is not a hydrogen atom, for example, hydrocarbon solvents such as benzene, toluene, hexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, diethyl ether, 1, 2 -General solvents such as 3-chloroperbenzoic acid and hydrogen peroxide in an inert solvent such as ether solvents such as dimethoxyethane, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water or a mixed solvent thereof. Compound (12) and compound by controlling reaction conditions such as equivalent number of oxidant, reaction time, reaction temperature and solvent using a suitable oxidant (see M. Hudlicky, “Oxidations in Organic Chemistry”) It is also possible to obtain a mixture of (13). Preferably, compound (11) can be led to compound (12) and compound (13) by reacting with 3-chloroperbenzoic acid in dichloromethane at −78 ° C. to room temperature for 1 to 24 hours. .

  Step 14: Compound (14) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether system such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Staudinger reaction (Bull. Chem. Soc. Fr.) with triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. in an inert solvent such as a solvent, acetonitrile, acetone, water, or a mixed solvent thereof. 815 (1985)), palladium / carbon in an inert solvent such as alcohols such as ethanol and methanol, esters such as ethyl acetate, N, N-dimethylformamide, water, or a mixed solvent thereof, palladium black Hydrogen in the presence of metal catalysts such as Pressure can lead to reduction of the general azide group typified by hydride reduction, such as with lithium amino borohydride such as (A. F. Abdel-Magid, "Reductions in Organic Synthesis" referenced) by compound (15). Preferably, compound (14) can be led to compound (15) by reacting at room temperature for 1 to 2 hours using Staudinger reaction using trimethylphosphine in a mixed solvent of tetrahydrofuran and water. .

Step 15: By hydrolyzing the portion represented by the formula COOR ¹ and the formula COOR ² of the compound (15) in which at least one of R ¹ and R ² is other than a hydrogen atom in the same manner as in Step 9, It can lead to the compound (16) which is a synthetic intermediate of the compound. Preferably, compound (15) is hydrolyzed in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at room temperature to 40 ° C. for 5 to 7 days to give a synthetic intermediate of the compound of the present invention. It can lead to a certain compound (16). Alternatively, preferably, the compound (15) is a synthetic intermediate of the compound of the present invention by hydrolyzing the compound (15) with 60% sulfuric acid at 100 to 150 ° C. for 1 to 5 days. Can lead to.
In the formula [III], when Y is the formula NHCHR ³ R ⁴ or the formula N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ), from the synthetic intermediate (6), the following steps 16, 17, 18, 19, 20, 21 and 22 can lead to compounds (24) and (27) which are synthetic intermediates of the compounds of the present invention.

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

  Step 17: The amino group of compound (17) can be converted to compound (18) by a general amino group protection reaction (see T. W. Greene, P. G. M. Wuts, “Protective Groups in Organic Synthesis”). Preferably, compound (17) is led to compound (18) by reacting with di-t-butyl dicarbonate in tetrahydrofuran in the presence of a saturated aqueous sodium hydrogen carbonate solution at room temperature for 2 to 6 hours. Can do.

Step 18: Alkyl and arylsulfonylation of the hydroxyl group of the compound (18) in which R ¹ and R ² are other than a hydrogen atom can be led to the compound (19) by the same method as in Step 10. Preferably, the hydroxyl group of compound (18) is converted to compound (19) by reacting with trifluoromethanesulfonic anhydride in dichloromethane in the presence of pyridine in a temperature range of −78 ° C. under ice cooling for 30 minutes to 2 hours. be able to.

  Step 19: Compound (19) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Derived to compound (20) by reacting with sodium azide in an inert solvent such as a system solvent, ethyl acetate, acetonitrile, acetone, dimethyl sulfoxide, N, N-dimethylformamide, water, or a mixed solvent thereof. it can. Preferably, compound (19) can be led to compound (20) by reacting with sodium azide in N, N-dimethylformamide at room temperature to 35 degrees for 1 to 2 days.

Step 20: The amino groups represented by the formulas —NH ₂ and —R ³ R ⁴ CHNH of the compounds (21) and (22) are converted into hydrocarbon solvents such as benzene, toluene, hexane, cyclohexane, dichloromethane, chloroform, for example. , Halogen solvents such as carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or Inert solvents such as mixed solvents, inorganic bases such as sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide, lithium bis (trimethylsilyl) amide, lithium Diisopropylamide, sodium amide, etc. In the presence of metal amides, organic bases such as triethylamine, pyridine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butylpyridine, bases such as potassium t-butoxide or In the absence, reaction with a compound represented by the formula R ³ R ⁴ CHL ² or R ^{3 ′} R ^{4 ′} CHL ² can lead to compounds (22) and (25), respectively. Here, L ² is a leaving group such as a halogen atom, tosyl sulfonate, trifluoromethane sulfonate, tolyl sulfonate and the like. Further, the compounds (21) and (22) are, for example, hydrocarbon solvents such as benzene, toluene, hexane and cyclohexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2- Triacetoxy hydrogen in an inert solvent such as ether solvents such as dimethoxyethane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, ethanol, methanol, water or a mixed solvent thereof. Borch reaction (AF Abdel-Magid et al., Tetrahedron) in which the compound is reacted with a compound represented by the formula R ³ COR ⁴ or the formula R ^{3 ′} COR ^{4 ′} in the presence of a reducing agent such as sodium borohydride or sodium cyanotrihydroboron. Lett., 31, 5595 (1990)). Compound (22) and can be guided to (25). Preferably, compound (21) can be converted to compound (22) by reacting with a compound represented by the formula R ³ R ⁴ CHBr in chloroform in the presence of pyridine at room temperature for 1 to 4 days. . On the other hand, the compound (22) is preferably reacted with a compound represented by the formula R ^{3 ′} R ^{4 ′} CHI at room temperature for 1 to 4 days in the presence of potassium carbonate in N, N-dimethylformamide. To compound (25).

Step 21: Deprotecting amino group protecting group R ⁷ of compound (22) and compound (25) by a general deprotection reaction (see TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”) Can be converted to compounds (23) and (26), respectively. Preferably, the compound (23) and the compound (25) are deprotected using 4N hydrogen chloride / ethyl acetate from ice-cooled to room temperature for 12 to 36 hours. 26).

Step 22: By hydrolyzing the portion represented by the formulas COOR ¹ and COOR ² of the compounds (23) and (26) in which at least one of R ¹ and R ² is other than a hydrogen atom, in the same manner as in Step 9, It can lead to compounds (24) and (27) which are synthetic intermediates of the compounds of the present invention. Preferably, the compound (23) and the compound (26) are hydrolyzed in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at room temperature for 1 to 7 days, thereby synthesizing the compound of the present invention. To the compound (24) and the compound (27) as the body.

In the formula [III], when Y is the formula —NHCOR ³ , the compound (21) is led to the compound (30) which is a synthetic intermediate of the compound of the present invention by the following steps 23, 24 and 25. Can do.

Step 23: The amino group at the 3-position of the compound (21) is converted into a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, tetrahydrofuran, diethyl ether, 1,2- Triethylamine, pyridine, morpholine, diisopropylethylamine in an inert solvent such as ether solvents such as dimethoxyethane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or mixed solvents thereof , 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butylpyridine and the like, in the presence or absence of organic bases, represented by the formula L ¹ COR ³ or R ³ COOCOR ³ Can be led to compound (28).

Here, L ¹ is a leaving group, such as a halogen atom, an ethoxycarbonyloxy group, a phenoxycarbonyloxy group, or the like. Alternatively, when R ³ is a hydrogen atom, it can be led to the compound (28) by a general formylation reaction (see TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”). Preferably, compound (21) can be led to compound (28) by reacting with a compound represented by the formula R ³ COCl in chloroform in the presence of pyridine at room temperature for 1 to 4 hours. Step 24: Compound (28) can be led to compound (29) by deprotection of formula —NHR ⁷ by the same method as in Step 21. Preferably, compound (28) can be led to compound (29) by deprotection using 4N hydrogen chloride / ethyl acetate under ice-cooling for 30 minutes to 2 hours.

Step 25: The compound (29) in which at least one of R ¹ and R ² is not a hydrogen atom is obtained by subjecting the compound of the present invention to the hydrolysis of the formula —COOR ¹ and the formula —COOR ² by the same method as in Step 9. It can lead to compound (30) which is an intermediate.
Preferably, compound (29) is hydrolyzed in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at room temperature for 1 to 7 hours to give compound (29) which is a synthetic intermediate of the compound of the present invention ( 30). In the formula [III], when Y is the formula —OCOR ⁵ , the synthetic intermediate of the compound of the present invention is synthesized from the synthetic intermediate (6) in which R ² is a benzyl group by the following steps 26, 27 and 28. It can lead to (33).

Step 26: A hydroxyl group of the compound (6) in which R ¹ is not a hydrogen atom and R ² is a benzyl group, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen such as dichloromethane, chloroform or carbon tetrachloride. Solvent, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof. In an active solvent or in a useless medium, in the presence or absence of organic bases such as triethylamine, pyridine, morpholine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butylpyridine at, the compounds of the formula L ¹ COR ⁵ or formula R ⁵ COOCOR ⁵ anti It can be converted into the compound (31) and is. Here, L ¹ is a leaving group, such as a halogen atom, an ethoxycarbonyloxy group, a phenoxycarbonyloxy group, or the like. Preferably, compound (6) can be led to compound (31) by reacting with a compound represented by the formula R ⁵ COCl in pyridine at room temperature for 12 to 36 hours.

  Step 27: Compound (31) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Staudinger reaction (Bull. Chem. Soc. Fr) with triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. in an inert solvent such as a system solvent, acetonitrile, acetone, water, or a mixed solvent thereof , 815 (1985)), and further, for example, alcohols such as ethanol and methanol, esters such as ethyl acetate, N, N-dimethylformamide, water, or a mixed solvent thereof. Palladium / carbon, inert gas in inert solvent It can be derived reductively benzyl deprotected compounds by hydrogenation reaction in the presence of a metal catalyst such as ethidium black to (32). Compound (31) is, for example, an alcohol such as ethanol and methanol, an ester such as ethyl acetate, N / N-dimethylformamide, water, palladium / carbon in an inert solvent such as a mixed solvent thereof, It can also be directly led to the compound (32) by a hydrogenation reaction in the presence of a metal catalyst such as palladium black. Preferably, the compound (31) can be led to an amine compound by reacting at 30 ° C. for 2 hours at room temperature using a Staudinger reaction using trimethylphosphine in a mixed solvent of tetrahydrofuran and water. Then, the amine compound can be led to the compound (32) by reacting in ethanol in the presence of 5% palladium carbon in a hydrogen atmosphere at room temperature for 30 minutes to 2 hours.

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

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

  The carboxylic acid part of compound [III] can be led to compound [I] which is the compound of the present invention by diesterification or monoesterification by the step 29 shown below.

Step 29: The carboxylic acid part of compound [III] is led to compound [I] which is the compound of the present invention by a general esterification reaction (see TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”). be able to. Preferably, the carboxylic acid portion of the compound [III], in tetrahydrofuran, was a lithium salt using lithium hydroxide at room temperature, N, N- dimethylformamide, wherein R ¹ Br and wherein at 90 ° C. from room temperature By reacting with a compound represented by R ² Br for 4 to 12 hours, it can be led to the compound [I] of the present invention. In addition, the carboxylic acid moiety on the 6-position carbon of the compound [III] is substituted with a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, tetrahydrofuran, diethyl ether, 1, 2 or the like. -Mineral acids such as sulfuric acid, phosphoric acid, hydrochloric acid, acetic acid, oxalic acid, methanesulfonic acid in ether solvents such as dimethoxyethane, dimethyl sulfoxide, N, N-dimethylformamide, or mixed solvents thereof or without solvent organic acids such as, thionyl chloride, the presence or absence of an acid chloride such as phosphoryl chloride, by controlling the alcohol and the short or the reaction temperature of the formula R ¹ OH reaction, selectively R ² Is a compound of the present invention in which is a hydrogen atom. Preferably, the carboxylic acid moiety on the 6-position carbon of compound [III] is reacted in the presence of an alcohol represented by the formula R ¹ OH and thionyl chloride under ice cooling at 80 ° C. for 1 hour to 3 days. , R ² can be led to the compound [I] of the present invention.
In addition, after protecting the α-amino acid moiety on the 2-position carbon by the protection method of α-amino acid using triethylborane or copper (II) complex (Internatiomal Journal of Peptide & Protein Research, 37, 210 (1991); Synthesis, 119 (1990); Helv. Chem. Acta, 44, 159 (1961)), general esterification of carboxylic acids on the 6-position carbon (TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”) And then deprotecting the α-amino acid moiety (Internatiomal Journal of Peptide & Protein Research, 37, 210 (1991); Synthesis, 119 (1990); Helv. Chem. Acta, 44, 159 (1961) It is also possible to lead to compound [I] wherein R ² is a hydrogen atom.

Further, after selectively leading to a compound [I] in which R ² is a hydrogen atom, the amino group on the 2-position carbon is protected with a general amino group such as an allyloxycarbonyl group or a tert-butoxycarbonyl group. The carboxylic acid moiety on the 2-position carbon is protected by a general esterification reaction (TW Greene, PGM Wuts, see “Protective Groups in Organic Synthesis”) or without protection (TW Greene, PGM Wuts , “Protective Groups in Organic Synthesis”) and when the amino group is further protected, the amino group is deprotected (see TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”) R ¹ and R ² can be led to the compound [I] of the present invention which is other than a hydrogen atom. Preferably, the amino group on the 2-position carbon is protected with an allyloxycarbonyl group by reacting for 8 hours at room temperature in the presence of allyl chloroformate and saturated sodium bicarbonate, and R ² X ′ (X 'Is a halogen atom, and X' is preferably a bromine atom or an iodine atom) for 1 to 24 hours, and in the presence of 1,3-dimethylbarbituric acid, tetrakistriphenylphosphine palladium, By deprotecting the amino group by reacting at room temperature to 80 ° C. for 1 to 24 hours, R ¹ and R ² can be led to the compound [I] of the present invention other than a hydrogen atom.

In addition, a moiety represented by the formula COOR ¹ of the compound [I] in which R ¹ and R ² are other than a hydrogen atom is subjected to a general hydrolysis reaction (TW Greene, PGM Wuts, “Protective Groups in Organic” in a short time or at a low temperature. The compound [I], which is a compound of the present invention, in which R ¹ is a hydrogen atom can be selectively converted by conversion into a carboxylic acid in Synthesis ”(see Synthesis). Preferably, the moiety represented by the formula COOR ¹ of the compound [I] wherein R ¹ and R ² are other than a hydrogen atom is used in a mixed solvent of tetrahydrofuran and water using lithium hydroxide at 0 ° C. to room temperature for 30 minutes. The compound can be led to the compound [I] of the present invention in which R ¹ is a hydrogen atom by hydrolysis for 3 hours.

Further, the compound [I] in which at least one of R ¹ and R ² is an azido C _1-10 alkyl group is obtained by changing the corresponding compound [I], which is a halogenated C _1-10 alkyl, for example, benzene, toluene, hexane. Hydrocarbon solvents such as dichloromethane, chloroform, carbon tetrachloride and other halogen solvents, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane and other ether solvents, ethyl acetate, acetonitrile, acetone, dimethyl sulfoxide, N, N -It can also guide | lead by making it react with sodium azide in inert solvents, such as a dimethylformamide, water, or these mixed solvents. Preferably, compound [I] wherein at least one of R ¹ and R ² is a halogenated C _1-10 alkyl group is mixed with sodium azide in a mixed solvent of N, N-dimethylformamide and water at room temperature to 60 ° C. By reacting for 6 to 18 hours, the compound [I] in which at least one of R ¹ and R ² is an azido C _1-10 alkyl group can be led.

Further, the compound [I] in which at least one of R ¹ and R ² is an amino C _2-10 alkyl group is obtained by reacting the corresponding azide moiety of the compound [I] which is an azido C _1-10 alkyl group with, for example, benzene, Hydrocarbon solvents such as toluene and hexane, halogen solvents such as dichloromethane, chloroform and carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, acetonitrile, acetone, water, or a mixture thereof Staudinger reaction with triethyl phosphite, trimethylphosphine, tributylphosphine, triphenylphosphine, etc. in inert solvents such as solvents (see Bull. Chem. Soc. Fr., 815 (1985)), ethanol, methanol, etc. Alcohols, esters such as ethyl acetate, N, N-dimethylformamide, General azide reduction represented by hydrogenation in the presence of a metal catalyst such as palladium / carbon or palladium black in water or an inert solvent such as a mixed solvent thereof, hydride reduction by lithium aminoborohydride, etc. It can also be induced by reduction by reaction (see AF Abdel-Magid, “Reductions in Organic Synthesis”). Preferably, the compound [I] in which at least one of R ¹ and R ² is an azido C _1-10 alkyl group is subjected to a Staudinger reaction using trimethylphosphine in a tetrahydrofuran / water mixed solvent at room temperature for 6 hours. The compound [I] in which at least one of R ¹ and R ² is an amino C _1-10 alkyl group can be led by reacting for 18 hours.

Furthermore, the obtained compound [III] is led to the compound [I] of the present invention in which R ¹ is other than a hydrogen atom and R ² is a hydrogen atom by the steps 30, 31, 32 and 33 shown below. You can also.

  Step 30: The amino group of compound [III] is converted into a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Triethylamine in an inert solvent such as ether solvents such as 1,4-dioxane, amides such as N, N-dimethylformamide, N-methyl-2-pyrrolidinone, dimethyl sulfoxide, water, or a mixed solvent thereof. Organic bases such as pyridine, morpholine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butylpyridine, or inorganic salts such as potassium carbonate, sodium carbonate, sodium bicarbonate In the presence or absence of allyl chloroformate By response can lead to the compound (34). Preferably, compound [III] can be led to compound (34) by reacting with allyl chloroformate in 1,4-dioxane in the presence of a saturated aqueous sodium hydrogen carbonate solution at room temperature for 6 to 18 hours. .

  Step 31: Compound (34) is, for example, a hydrocarbon solvent such as benzene, toluene or hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane. Dehydration such as Dean-Stark moisture separator using an appropriate solvent such as p-toluenesulfonic acid and oxalic acid in the presence of an aldehyde such as paraformaldehyde in an inert solvent such as a system solvent or a mixed solvent thereof. Carrying out the reaction with or without equipment can lead to compound (35). Preferably, the compound (34) can be led to the compound (35) by heating and refluxing in benzene with paraformaldehyde and a Dean-Stark water separator in the presence of paratoluenesulfonic acid for 1 to 5 hours. .

Step 32: Compound (35) can be converted to compound (36) by a general esterification reaction (see TW Greene, PGM Wuts, “Protective Groups in Organic Synthesis”). An ester of the formula L ² CHR ^c OC (O) ZR ^d (wherein L ² is a leaving group, for example, a halogen atom, tosyl sulfonate, trifluoromethane sulfonate, tolyl sulfonate) and the compound (35) For example, hydrocarbon solvents such as benzene, toluene, hexane, cyclohexane, halogen solvents such as dichloromethane, chloroform, carbon tetrachloride, ether solvents such as tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, N, In an inert solvent such as amides such as N-dimethylformamide and N-methyl-2-pyrrolidinone, dimethyl sulfoxide, or a mixed solvent thereof, sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, Inorganic salts such as sodium hydroxide and potassium hydroxide Groups, metal amides such as lithium bis (trimethylsilyl) amide, lithium diisopropylamide, sodium amide, triethylamine, pyridine, diisopropylethylamine, 4- (N, N-dimethylamino) pyridine, 2,6-di-t-butyl The compound (36) can also be obtained by reacting in the presence or absence of a suitable activator such as sodium iodide in the presence of an organic base such as pyridine or a base such as potassium t-butoxide. Preferably, compound (35) is led to compound (36) by reacting with R ¹ Cl at room temperature to 75 ° C. for 2 to 24 hours in the presence of sodium iodide in N, N-dimethylformamide. be able to.

  Step 33: Compound (36) is prepared in the presence of a zero-valent palladium catalyst such as tetrakistriphenylphosphine palladium (0) and a metal catalyst regeneration reagent such as 1,3-dimethylbarbituric acid, for example, benzene, toluene, In an inert solvent such as a hydrocarbon solvent such as hexane, a halogen solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether solvent such as tetrahydrofuran, diethyl ether or 1,2-dimethoxyethane, or a mixed solvent thereof. Deprotection of the amino acid moiety can lead to compound (37) which is a compound of the present invention. Preferably, the compound (36) is deprotected in chloroform at room temperature to 50 ° C. for 30 minutes to 3 hours in the presence of tetrakistriphenylphosphine palladium and 1,3-dimethylbarbituric acid. To compound (37).

  The compound of the present invention can be combined with any one or more of one or more pharmaceutically acceptable carriers, excipients and diluents to form a pharmaceutical formulation or pharmaceutical composition. Examples of the carrier, excipient, and diluent include water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, and cellulose. And various oils such as water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil and the like.

  The compound of the present invention is mixed with these carriers, excipients or diluents, and additives such as extenders, binders, disintegrants, pH adjusters, and solubilizers that are generally used as necessary. Above, oral or parenteral drugs such as tablets, pills, capsules, granules, powders, solutions, emulsions, suspensions, ointments, injections, skin patches, etc., especially Group II Prepared as a metabotropic glutamate receptor antagonist.

  The compound of the present invention can be orally or parenterally administered to an adult patient in an amount of 0.01 to 500 mg once or several times a day. However, from the viewpoint of ease of use and efficacy. Oral administration is preferred. This dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.

  EXAMPLES The present invention will be specifically described below with reference to examples and test examples, but the present invention is not limited to these.

(Reference Example 1)
Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) While maintaining at −63 to −54 ° C., 245 mL of a 2.66M n-butyllithium hexane solution was added dropwise to a solution of 137 mL of hexamethyldisilazane in 700 mL of tetrahydrofuran, followed by stirring for 1 hour. In this solution, a solution of (1R, 5R, 6R) -6-fluoro-2-oxo-bicyclo [3.1.0] hexane-6-carboxylic acid ethyl ester (101 g) in tetrahydrofuran (340 mL) was kept at -63 ° C to -52 ° C. While dripping. After 1 hour, a solution of 213 g of N-phenyl-bis (trifluoromethanesulfonimide) in 700 mL of tetrahydrofuran was added at −63 to −45 ° C. The reaction solution was naturally warmed to room temperature and further stirred for 2.5 hours. The reaction solution was diluted with diethyl ether, washed 3 times with a saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, 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 to 20: 1 to 5: 1). ). 175 g of the obtained (1R, 5R, 6R) -6-fluoro-2-trifluoromethanesulfonyloxy-bicyclo [3.1.0] hex-2-ene-6-carboxylic acid ethyl ester was converted into N, N-dimethylformamide. After dissolving in 875 mL and 875 mL of ethanol, diisopropylethylamine 95.1 mL, triphenylphosphine 8.65 g, and palladium acetate 3.70 g were added, followed by stirring in a carbon monoxide atmosphere at room temperature for 5.5 hours. 1N hydrochloric acid was added to the reaction solution, and the mixture was extracted 6 times with diethyl ether. The organic layers were combined, washed four times with a saturated aqueous sodium hydrogen carbonate solution and with saturated brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, 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 to 20: 1 to 10: 1). ) To obtain 92.6 g of (1R, 5R, 6R) -6-fluoro-bicyclo [3.1.0] hex-2-ene-2,6-dicarboxylic acid diethyl ester.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.31 (t, J = 7.03 Hz, 3H), 1.33 (t, J = 7.03 Hz, 3H), 2.37-2.51 (m, 1H), 2.65-2.81 (m, 1H), 2.88-3.04 (m, 1H), 3.10 (dd, J = 7.47, 2.64 Hz, 1H), 4.12-4.40 (m, 4H), 6.77-6.79 (m, 1H).
MS (ESI) (Pos) m / z; 265 (M + Na) ⁺
[α] _D ²¹ = + 158.0 ° (CHCl ₃ , c = 1.5)

(2) (1R, 5R, 6R) -6-fluoro-bicyclo [3.1.0] hex-2-ene-2,6-dicarboxylic acid diethyl ester dissolved in 1.76 L of acetonitrile and 680 mL of water 92. To 4 g, 160 mL of 50% N-methylmorpholine N-oxide aqueous solution and 121 mL of 5% osmium (VIII) aqueous solution were added and stirred at room temperature for 1 hour. Sodium sulfite was added to the reaction solution under ice-cooling, and the mixture was stirred at room temperature for 30 minutes, and then filtered through celite. Saturated brine was added to the filtrate, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 4: 1 to 1: 1), and (1R, 2S , 3R, 5R, 6R) -6-fluoro-2,3-dihydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester 95.6 g was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.31 (t, J = 7.25 Hz, 6H), 2.03-2.34 (m, 3H), 2.40-2.55 (m, 1H), 2.70 (d, J = 9.23 Hz, 1H), 4.09 (s, 1H), 4.18-4.47 (m, 5H).
MS (ESI) (Nega) m / z; 275 (MH) ^-
[α] _D ²⁷ = -69.1 ° (CHCl ₃ , c = 1.4)

(3) Under ice cooling, 95.4 g of (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 a 1.24 L solution of dichloromethane, and 37.6 mL of thionyl chloride was added dropwise, followed by stirring for 30 minutes. The reaction solution was washed twice with water and saturated brine, and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was dissolved in 640 mL of carbon tetrachloride, 640 mL of acetonitrile and 760 mL of water. To this solution, 96.0 g of sodium metaperiodate and 655 mg of ruthenium trichloride hydrate were added and stirred at room temperature for 1 hour. After performing Celite filtration, 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 the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 4: 1), and (1R, 1aR, 1bS, 4aR). , 5aR) -1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ ⁶ -thiacyclopropa [a] pentalene-1,1b-dicarboxylic acid diethyl ester 109 g was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.33 (t, J = 7.03 Hz, 3H), 1.34 (t, J = 7.03 Hz, 3H), 2.52-2.94 (m, 4H), 4.23-4.47 (m, 4H), 5.40-5.53 (m, 1H).
MS (ESI) (Pos) m / z; 361 (M + Na) ⁺
[α] _D ²⁸ = + 18.3 ° (CHCl ₃ , c = 1.0)

(4) (1R, 1aR, 1bS, 4aR, 5aR) -1-fluoro-3,3-dioxotetrahydro-2,4-dioxa-3λ ⁶ dissolved in 1.10 L of N, N-dimethylformamide and 110 mL of water -Thiacyclopropa [a] pentalene-1,1b-dicarboxylic acid To 109 g of diethyl ester, 37.7 g of sodium azide was added and stirred at 50 ° C. for 14 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in 6.48 L of diethyl ether and 177 mL of water, 516 mL of 20% (V / V) sulfuric acid was added, and the mixture was stirred at room temperature for 34 hours. After separating the reaction solution, the organic layer was washed twice with saturated brine and then dried over anhydrous magnesium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 4: 1), and (1R, 2R, 3R, 5R). , 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester 88.5 g.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.33 (t, J = 7.03 Hz, 3H), 1.38 (t, J = 7.03 Hz, 3H), 2.18-2.61 (m, 5H), 4.21-4.48 (m, 5H).
MS (ESI) (Pos) m / z; 324 (M + Na) ⁺
[α] _D ²² = -48.7 ° (CHCl ₃ , c = 1.0)

(5) 1.36 g of 60% sodium hydride (oil) was washed twice with hexane, suspended in 46 mL of tetrahydrofuran, and 60.1 g of 3,4-dichlorobenzyl alcohol dissolved in 68 mL of tetrahydrofuran was added dropwise. After stirring at room temperature for 30 minutes, 34 mL of trichloroacetonitrile was added dropwise while cooling with salt-ice. The mixture was stirred at this temperature for 30 minutes, under ice-cooling for 30 minutes, in a water bath for 30 minutes, and further 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 the mixture was vigorously stirred at room temperature for 30 minutes. After the inorganic salt was filtered off, the filtrate was concentrated under reduced pressure to obtain 106.8 g of crude 3,4-dichlorobenzyl-2,2,2-trichloroacetimidate.
2.03 g of crude 3,4-dichlorobenzyl-2,2,2-trichloroacetimidate and (1R, 2R, 3R, 5R, 6R) -2-azido-3-hydroxy-6-fluoro-bicyclo [3 .1.0] Hexane-2,6-dicarboxylic acid diethyl ester (1.27 g) was dissolved in chloroform (5.4 mL) and cyclohexane (10.8 mL). After cooling in an ice bath, 187 μL of trifluoromethanesulfonic acid was added. After stirring at 30 ° C. for 1.5 hours, 93 μL of trifluoromethanesulfonic acid was further added and stirred for 1 hour. The inorganic salt was filtered off, and saturated aqueous sodium hydrogen carbonate solution was added under ice cooling. After extracting twice with chloroform, the organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 15: 1), and (1R, 2R, 3R, 5R). , 6R) -2-azido-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester (771 mg) was obtained.
¹ H-NMR (200 MHz, 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 = 11.9 Hz, 1H), 4.64 (d, J = 11.9 Hz, 4H), 7.05-7.14 (m, 1H), 7.36-7.43 (m, 2H).
MS (ESI) (Pos) m / z; 482 (M + Na) ⁺
[Α] _D ²⁴ = -14.5 ° (CHCl ₃ , c = 0.94)

(6) (1R, 2R, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1 dissolved in 825 mL of tetrahydrofuran and 82.5 mL of water 0.0] Hexane-2,6-dicarboxylic acid 25.7 g of 1M trimethylphosphine / tetrahydrofuran solution was added to 27.5 g and stirred at room temperature for 4 hours. The mixture was diluted with 825 mL of diethyl ether, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 4: 1-3: 2), and (1R, 2R , 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester (23.1 g). Obtained.
¹ H-NMR (200 MHz, 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 = 12.5 Hz), 4.53 (1H, d, J = 12.5 Hz), 7.10-7.19 (1H, m), 7.36-7.45 (2H, m) .
MS (ESI) (Pos) m / z; 456 (M + Na) ⁺
[Α] _D ²² = + 11.6 ° (CHCl ₃ , c = 0.50%)

(7) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] dissolved in 480 mL of tetrahydrofuran and 240 mL of water. ] 5.53 g of lithium hydroxide hydrate was added to 22.9 g of hexane-2,6-dicarboxylic acid diethyl ester, and the mixture was stirred at room temperature for 3 days. Further, 443 mg of lithium hydroxide hydrate was added, and the mixture was stirred at room temperature for 1 day. Under ice cooling, 169 mL of 1N hydrochloric acid was added dropwise, and the mixture was stirred at room temperature for 14 hours. The precipitated solid was collected by filtration, washed with 200 mL of tetrahydrofuran and 100 mL of water, and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro. -12.3 g of bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, D ₂ O, TMSP); 2.28-2.45 (3H, m), 2.50 (1H, dd, J = 7.6, 13.4 Hz), 4.05-4.11 (1H, m), 4.52 (1H , d, J = 12.1 Hz), 4.60 (1H, d, J = 12.1 Hz), 7.26-7.58 (3H, m).
MS (ESI) (Nega) m / z; 376 (MH) ^-
[α] _D ²⁷ = -10.0 ° (1N NaOH, c = 1.02)

(Reference Example 2)
Synthesis of (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dissolved in 20 mL of dichloromethane under nitrogen atmosphere To 120 mg of dicarboxylic acid diethyl ester, 48 μL of pyridine and 78 μL of trifluoromethanesulfonic anhydride dissolved in 0.4 mL of dichloromethane were added dropwise at −75 ° C., followed by stirring for 1.5 hours under ice cooling. At −75 ° C., 24 μL of pyridine and 39 μL of trifluoromethanesulfonic anhydride dissolved in 0.2 mL of dichloromethane were added dropwise, followed by stirring for 25 minutes under ice cooling. After adding 10 mL of ether and filtering off the solid, 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), and (1R, 2R). , 3R, 5R, 6R) -2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester 166 mg was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.35 (t, J = 7.0 Hz, 3H), 1.38 (t, J = 7.0 Hz, 3H), 2.35-2.50 (m, 2H), 2.62-2.86 (m, 2H), 4.31 (q, J = 7.0 Hz, 2H), 4.27-4.55 (m, 2H), 4.94-5.10 (m, 1H).
MS (FAB) (Pos) m / z; 434 (M + H) ⁺
[α] _D ²⁶ = -31.2 ° (CHCl ₃ , c = 0.4)

(2) (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3.1.0] dissolved in 6.9 mL of N, N-dimethylformamide After adding 688 mg of potassium nitrite and 428 mg of 18-crown-6 ether to 701 mg of hexane-2,6-dicarboxylic acid diethyl ester, the mixture was stirred at room temperature for 1.5 days in a nitrogen atmosphere, and further 3.5 ° C. at 45 ° C. Stirred for a day. After adding water, the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 5: 1) and (1R, 2R, 3S, 5R). , 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2,6-diethyl ester 388 mg was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.34 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H), 2.16 (dd, J = 2.9 Hz, 14.9 Hz, 1 H), 2.17-2.30 (m, 1H), 2.44 (dd, J = 3.1 Hz, 8.1 Hz, 1H), 2.61 (dd, J = 12.3 Hz, 16.0 Hz, 1H), 2.80-2.99 (m, 1H ), 4.29 (q, J = 7.0 Hz, 2H), 4.34 (q, J = 7.0 Hz, 2H), 4.48-4.64 (m, 1H).
MS (ESI) (Pos) m / z; 324 (M + Na) ⁺
[α] _D ²⁵ = + 6.4 ° (CHCl ₃ , c = 1.0)

(3) (1R, 2R, 3S, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2 dissolved in 6.1 mL of dichloromethane under nitrogen atmosphere To 364 mg of 6-dicarboxylic acid diethyl ester and 0.21 mL of pyridine, 0.36 mL of trifluoromethanesulfonic anhydride dissolved in 1.2 mL of dichloromethane at −77 ° C. to −69 ° C. was added dropwise. After stirring at -77 ° C for 30 minutes, the mixture was stirred for 30 minutes under ice cooling. 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: Wako gel C200, developing solvent: hexane-ethyl acetate = 5: 1), and (1R, 2R, 3S, 5R, 6R) -2-azido-6-fluoro-3- 487 mg of trifluoromethanesulfonyloxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.36 (t, J = 7.03 Hz, 3H), 1.39 (t, J = 7.47 Hz, 3H), 2.26-2.63 (m, 3H), 2.91-3.10 (m, 1H), 4.25-4.45 (m, 4H), 5.57 (dd, J = 9.01, 2.86 Hz, 1H).
MS (ESI) (Pos) m / z; 456 (M + Na) ⁺
[α] _D ²⁶ = -41.4 ° (CHCl ₃ , c = 1.1)

(4) Under a nitrogen atmosphere, 2.59 g of 3,4-dichlorobenzyl mercaptan was added to 308 mg of sodium dissolved in 18 mL of ethanol at room temperature, and the mixture was stirred for 5 minutes and then concentrated under reduced pressure. To the residue was added 64 mL of dimethyl sulfoxide and dissolved in 6.4 mL of dimethyl sulfoxide at room temperature (1R, 2R, 3S, 5R, 6R) -2-azido-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3. 1.0] 3.23 g of hexane-2,6-dicarboxylic acid diethyl ester was added and stirred for 10 minutes. Diethyl ether (250 mL) was added, and the upper layer and the lower layer were separated. The lower layer was extracted twice with diethyl ether. The organic layers were combined, washed with cooled 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 10: 1 to 5: 1), and (1R, 2S, 3R, 5R, 6R) -2-azido-3- 3.35 g of (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.34 (t, J = 7.03 Hz, 3H), 1.38 (t, J = 7.03 Hz, 3H), 2.20-2.49 (m, 4H) 2.99-3.13 ( m, 1H), 3.68 (d, J = 13.62 Hz, 1H), 3.84 (d, J = 13.62 Hz, 1H), 4.22-4.51 (m, 4H), 7.16 (dd, J = 8.13, 1.98 Hz, 1H ), 7.34-7.46 (m, 2H).
MS (ESI) (Pos) m / z; 498 (M + Na) ⁺
[α] _D ²⁴ = + 129.9 ° (CHCl ₃ , c = 0.5)

(5) (1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [3.1. Dissolved in 100 mL of tetrahydrofuran and 10 mL of water. 0] Hexane-2,6-dicarboxylic acid diethyl ester (3.35 g) was added with 1M trimethylphosphine / tetrahydrofuran solution (7.7 mL) and stirred at room temperature for 1 hour. After diluting with 200 mL of diethyl ether and adding 50 mL of saturated aqueous sodium hydrogen carbonate solution, the mixture was stirred at room temperature for 1.5 hours. After separation, the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was diluted with chloroform, and silica gel [Wakogel C200] was added. After concentration under reduced pressure and allowing to stand at room temperature for 18 hours, purification was performed by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 2: 1), (1R, 2S, 3R, 5R, 6R). There was obtained 2.78 g of 2-amino-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester.
¹ H-NMR (300 MHz, CDCl ₃ , TMS); 1.31 (t, J = 7.2 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 2.08-2.15 (m, 1H), 2.24-2.40 (m, 3H), 2.86-2.93 (m, 1H), 3.73 (d, J = 13.4 Hz, 1H), 3.88 (d, J = 13.4 Hz, 1H), 4.21-4.37 (m, 4H), 7.15 ( dd, J = 8.2, 2.2 Hz, 1H), 7.36 (d, J = 8.2 Hz, 1H), 7.42 (d, J = 2.2 Hz, 1H).
MS (ESI) (Pos) m / z; 472 (M + Na) ⁺
[α] _D ²⁶ = + 94.4 ° (CHCl ₃ , c = 0.25)

(6) (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [1R dissolved in 0.8 mL of tetrahydrofuran and 0.4 mL of water 3.1.0] Hexane-2,6-dicarboxylic acid diethyl ester (41 mg) was added with lithium hydroxide hydrate (12 mg) and stirred at room temperature for 5.5 days. The pH was adjusted to 3 using 1N hydrochloric acid in an ice bath. After adding 30 mL of water and stirring at room temperature for 1 hour, it was purified by ion exchange resin (AG 50W-X8 Resin (H type), developing solvent: water, 40% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution). The solid was further washed with tetrahydrofuran and (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo [3.1.0] hexane. 26 mg of -2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, D ₂ O, TMSP); 2.17-2.48 (m, 4H), 3.04-3.13 (m, 1H), 3.80 (d, J = 14.9 Hz, 1H), 3.85 (d, J = 14.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H).
MS (ESI) (Nega) m / z; 392 (MH) ^-
[α] _D ³⁰ = + 47.5 ° (1N NaOH, c = 0.41)

(Reference Example 3)
Synthesis of (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) (1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfanyl) -6-fluoro-bicyclo dissolved in 1.46 mL of dichloromethane in a dry ice-acetone bath [3.1.0] Hexane-2,6-dicarboxylic acid diethyl ester (73 mg) was added with 3-chloroperbenzoic acid (32 mg) and stirred for 1 hour. The mixture was stirred in an ice bath for 3.5 hours and then stirred at room temperature for 11 hours. In a dry ice-acetone bath, 15 mg of 3-chloroperbenzoic acid was further added and stirred for 1 hour, followed by stirring in an ice bath for 4 hours. The reaction solution was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 4: 1 to 2: 1), and (1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester 63 mg, and (1R, 2S, 3R, 5R, 6R) -2-azide 12 mg of -3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
(1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester :
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.36 (t, J = 7.03 Hz, 3H), 1.38 (t, J = 7.03 Hz, 3H), 2.33 (dd, J = 14.06, 8.35 Hz, 1H ), 2.43-2.61 (m, 2H), 2.80-2.97 (m, 1H), 3.11-3.24 (m, 1H), 3.79 (d, J = 13.19 Hz, 1H), 4.09 (d, J = 13.19 Hz, 1H), 4.25-4.43 (m, 4H), 7.17 (dd, J = 8.35, 2.20 Hz, 1H), 7.40-7.50 (m, 2H).
MS (ESI) (Pos) m / z; 514 (M + Na) ⁺
[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-dicarboxylic acid diethyl ester :
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.36 (t, J = 7.03 Hz, 3H), 1.39 (t, J = 7.03 Hz, 3H), 2.33-2.58 (m, 3H), 2.86-3.05 (m, 1H), 3.53 (dd, J = 11.21, 8.13 Hz, 1H), 4.24-4.46 (m, 6H), 7.28 (dd, J = 8.35, 2.20 Hz, 1H), 7.44-7.56 (m, 2H ).
MS (ESI) (Pos) m / z; 530 (M + Na) ⁺
[α] _D ²⁹ = + 7.9 ° (CHCl ₃ , c = 0.7)

(2) (1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro-bicyclo [3] in the same manner as in Reference Example 2 (5) .1.0] Hexane-2,6-dicarboxylic acid From 61 mg of diethyl ester, (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro- Bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester 41 mg was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.34 (t, J = 7.0 Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H), 2.30-2.43 (m, 3H), 2.78-3.12 (m, 2H), 3.80 (d, J = 13.2 Hz, 1H), 4.19-4.36 (m, 5H), 7.17 (dd, J = 8.4, 2.2 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H).
MS (ESI) (Pos) m / z; 488 (M + Na) ⁺
[α] _D ²⁹ = + 59.1 ° (CHCl ₃ , c = 0.32)

(3) (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro-bicyclo [3] .1.0] Hexane-2,6-dicarboxylic acid From 38 mg of diethyl ester, (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfinyl) -6-fluoro- 17 mg of bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, 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 = 13.1 Hz, 1H), 4.26 (d, J = 13.1 Hz, 1H), 7.29 (d, J = 8.5 Hz, 1H), 7.56 (s, 1H), 7.60 (d, J = 8.5 Hz, 1H).
MS (ESI) (Nega) m / z; 408 (MH) ^-
[α] _D ²⁵ = + 79.7 ° (1N NaOH, c = 0.30)

(Reference Example 4)
Synthesis of (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1R, 2S, 3R, 5R, 6R) -2-azido-3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3.1. 0] Hexane-2,6-dicarboxylic acid from 190 mg of diethyl ester from (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3. 1.0] 169 mg of hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.34 (t, J = 7.0 Hz, 3H), 1.36 (t, J = 7.0 Hz, 3H), 2.28-2.42 (m, 3H), 2.83-3.01 (m, 1H), 3.41-3.53 (m, 1H), 4.23-4.37 (m, 6H), 7.28 (dd, J = 8.4, 1.8 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 7.55 (d, J = 1.8 Hz, 1H).
MS (ESI) (Pos) m / z; 482 (M + H) ⁺
[α] _D ²⁹ = + 24.0 ° (CHCl ₃ , c = 0.86)

(2) (1R, 2S, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic 108 mg of acid diethyl ester was stirred at 130 ° C. for 3 days in 1.08 mL of 60% sulfuric acid (W / V%). The reaction solution was ice-cooled and neutralized with 5N aqueous sodium hydroxide solution. After stirring at room temperature for 1 hour, it was purified with ion exchange resin (AG 50W-X8 Resin (H type), developing solvent: water, 30% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution), and (1R, 2S, 3R, 76 mg of 5R, 6R) -2-amino-3- (3,4-dichlorobenzylsulfonyl) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, D ₂ O, TMSP); 2.33-2.45 (m, 3H), 2.82-2.94 (m, 1H), 3.98 (dd, J = 10.1, 9.48 Hz, 1H), 4.55 (d , J = 15.2 Hz, 1H), 4.60 (d, J = 15.3 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.64 (s, 1H ).
MS (ESI) (Nega) m / z; 424 (MH) ^-
[α] _D ²⁸ = -5.1 ° (1N NaOH, c = 0.72)

(Reference Example 5)
Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylamino) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) (1R, 2R, 3S, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane- dissolved in 7.0 mL of tetrahydrofuran and 0.7 mL of water To 245 mg of 2,6-dicarboxylic acid diethyl ester, 0.89 mL of 1M trimethylphosphine / tetrahydrofuran solution was added and stirred at room temperature for 12 hours. The mixture was diluted with 14 mL of diethyl ether, added with a saturated aqueous sodium hydrogen carbonate solution, and stirred at room temperature for 1 hour. After 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 the desiccant was filtered off, 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), and (1R, 2R, 3S, 5R, 6R) -2-amino-6-fluoro-3-hydroxy -163 mg of bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.32 (t, J = 7.25 Hz, 6H), 2.07-2.23 (m, 2H), 2.41 (dd, J = 8.13, 3.30 Hz, 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) (1R, 2R, 3S, 5R, 6R) -2-amino-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid dissolved in 0.8 mL of tetrahydrofuran To 160 mg of diethyl ester, 0.8 mL of a saturated aqueous sodium hydrogen carbonate solution and 152 mg of di-t-butyl dicarbonate were added, 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 the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 2: 1), and (1R, 2R, 3S, 5R, 6R) -2-t-butoxycarbonylamino-6- 214 mg of fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.29 (t, J = 7.03 Hz, 3H), 1.30 (t, J = 7.03 Hz, 3H), 1.44 (s, 9H), 2.20-2.48 (m , 3H), 2.77-2.98 (m, 2H), 4.07-4.48 (m, 4H), 5.57 (s, 1H).
MS (ESI) (Pos) m / z; 398 (M + Na) ⁺
[α] _D ²² = -14.0 ° (CHCl ₃ , c = 0.9)

(3) (1R, 2R, 3S, 5R, 6R) -2-t-Butoxycarbonylamino-6-fluoro-3-hydroxy-bicyclo [3.1.0] in the same manner as in Reference Example 2 (1) From 1.47 g of hexane-2,6-dicarboxylic acid diethyl ester, (1R, 2R, 3S, 5R, 6R) -2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3. 1.0] 1.65 g of hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, 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 = 8.35 Hz, 1H).
MS (ESI) (Nega) m / z; 506 (MH) ^-
[α] _D ²⁸ = + 79.8 ° (CHCl ₃ , c = 0.5)

(4) (1R, 2R, 3S, 5R, 6R) -2-t-butoxycarbonylamino-6-fluoro-3-trifluoromethanesulfonyloxy-bicyclo [3. Dissolved in 16.3 mL of N, N-dimethylformamide. 1.0] Hexane-2,6-dicarboxylic acid 1.63 g of sodium azide was added to 1.63 g, and the mixture was stirred at room temperature for 1 hour and at 35 ° C for 20 hours. Furthermore, after adding 104 mg of sodium azide, the mixture was stirred at 35 ° C. for 18 hours. After dilution with 50 mL of diethyl ether, the mixture was washed twice with water and with saturated brine. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, 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), and (1R, 2R, 3R, 5R, 6R) -3-azido-2-t-butoxycarbonyl. 775 mg of amino-6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.29 (t, J = 7.03 Hz, 3H), 1.33 (t, J = 7.03 Hz, 3H), 1.45 (s, 9H), 2.21-2.56 (m , 3H), 2.92 (dd, J = 7.69, 2.42 Hz, 1H), 3.78-3.88 (m, 1H), 4.17-4.41 (m, 4H), 5.01 (s, 1H).
MS (ESI) (Pos) m / z; 423 (M + Na)
[α] _D ²⁶ = + 0.79 ° (CHCl ₃ , c = 1.4)

(5) (1R, 2R, 3R, 5R, 6R) -3-Azido-2-t-butoxycarbonylamino-6-fluoro-bicyclo [3.1.0] in the same manner as (1) in Reference Example 5. From 725 mg of hexane-2,6-dicarboxylic acid diethyl ester, (1R, 2R, 3R, 5R, 6R) -3-amino-2-tert-butoxycarbonylamino-6-fluoro-bicyclo [3.1.0] hexane 553 mg of -2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl _3, TMS); 1.30 (t, J = 7.03 Hz, 3H), 1.32 (t, J = 7.03 Hz, 3H), 1.44 (s, 9H), 2.06-2.27 (m , 2H), 2.40-2.55 (m, 1H), 2.61-2.72 (m, 1H), 3.28-3.47 (m, 1H), 4.17-4.41 (m, 4H), 5.05 (s, 1H).
MS (ESI) (Pos) m / z; 397 (M + Na) ⁺
[α] _D ²⁷ = -14.2 ° (CHCl ₃ , c = 1.4)

(6) (1R, 2R, 3R, 5R, 6R) -3-amino-2-tert-butoxycarbonylamino-6-fluoro-bicyclo [3.1.0] dissolved in 0.88 mL of chloroform under ice cooling After adding 42 μL of pyridine and 123 mg of 3,4-dichlorobenzyl bromide to 175 mg of hexane-2,6-dicarboxylic acid diethyl ester, the mixture was stirred at room temperature for 3 days. Saturated saline was added, and the mixture was extracted 5 times with chloroform. The organic layers were combined and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: chloroform-ethanol = 100: 1 to 50: 1, then hexane-ethyl acetate = 5: 1), and (1R, 2R, 3R, 5R). , 6R) -2-t-butoxycarbonylamino-3- (3,4-dichlorobenzylamino) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester (98 mg) was obtained. .
¹ H-NMR (200 MHz, 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, 7.25 Hz, 1H), 2.83-2.93 (m, 1H), 3.02-3.15 (m, 1H), 3.71 (d, J = 13.19 Hz, 1H), 3.80 (d, J = 13.19 Hz, 1H), 4.12-4.39 (m , 4H), 4.82 (s, 1H), 7.11 (dd, J = 8.13, 1.98 Hz, 1H), 7.33-7.45 (m, 2H).
MS (ESI) (Nega) m / z; 531 (MH) ^-
[α] _D ²⁷ = -15.1 ° (CHCl ₃ , c = 0.5)

(7) Under ice-cooling, (1R, 2R, 3R, 5R, 6R) -2-t-butoxycarbonylamino-3- (3,4-dichlorobenzylamino) -6-fluoro-bicyclo [3.1.0] ] 2.8 mL of 4N hydrogen chloride / ethyl acetate solution was added to 28 mg of hexane-2,6-dicarboxylic acid diethyl ester, and the mixture was stirred for 6 hours and then stirred at room temperature for 18 hours. The reaction solution was ice-cooled, neutralized with a saturated aqueous sodium hydrogen carbonate solution, and then separated. The aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylamino) -6-fluoro-bicyclo [3. 1.0] 21 mg of hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.31 (t, J = 7.0 Hz, 3H), 1.34 (t, J = 6.2 Hz, 3H), 2.03-2.28 (m, 3H), 2.35-2.51 (m, 1H), 2.94-3.08 (m, 1H), 3.77 (s, 2H), 4.16-4.40 (m, 4H), 7.12 (d, J = 7.9 Hz, 1H), 7.35 (d, J = 7.9 Hz, 1H), 7.40 (s, 1H).
MS (ESI) (Pos) m / z, 433 (M + H) ⁺
[α] _D ²⁴ = -8.4 ° (CHCl ₃ , c = 0.56)

(8) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylamino) -6-fluoro-bicyclo [3] .1.0] Hexane-2,6-dicarboxylic acid From 28 mg of diethyl ester, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzylamino) -6-fluoro- 17 mg of bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, D ₂ O, TMSP); 2.31-2.77 (m, 4H), 3.59-3.74 (m, 1H), 4.06 (d, J = 13.5 Hz, 1H), 4.15 (m, J = 13.5 Hz, 1H), 7.35 (d, J = 7.77 Hz, 1H), 7.58-7.64 (m, 2H).
MS (ESI) (Nega) 375 (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-2 Synthesis of 1,6-dicarboxylic acid (1) (1R, 2R, 3R, 5R, 6R) -2-t-butoxycarbonylamino-3- (3,4-dichloro) dissolved in 1.36 mL of N, N-dimethylformamide 71 mg of potassium carbonate and 64 μL of methyl iodide were added to 136 mg of benzylamino) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester, and the mixture was stirred at room temperature for 3 days. A saturated aqueous sodium thiosulfate solution was added, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200 (manufactured by Wako Pure Chemical Industries, Ltd.), developing solvent: hexane-ethyl acetate = 5: 1), and (1R, 2R, 3R, 5R, 6R) -2-t- 126 mg of butoxycarbonylamino-3- [N, N- (3,4-dichlorobenzyl) methylamino] -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.28 (t, J = 7.03 Hz, 3H), 1.29 (t, J = 7.03 Hz, 3H), 1.43 (s, 9H), 2.11 (s, 3H ), 2.16-2.58 (m, 3H), 2.80-3.07 (m, 2H), 3.29 (d, J = 13.62 Hz, 1H), 3.78 (d, J = 13.62 Hz, 1H), 4.05-4.43 (m, 4H), 4.86 (s, 1H), 7.08 (dd, J = 8.35, 1.76 Hz, 1H), 7.31-7.41 (m, 2H).
MS (ESI) (Pos) m / z; 547 (M + H) ⁺
[α] _D ²⁵ = -51.9 ° (CHCl ₃ , c = 0.5)

(2) (1R, 2R, 3R, 5R, 6R) -2-t-butoxycarbonylamino-3- [N, N- (3,4-dichlorobenzyl) in the same manner as in Reference Example 5 (7) From 124 mg of methylamino] -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester, (1R, 2R, 3R, 5R, 6R) -2-amino-3- [N, 96 mg of N- (3,4-dichlorobenzyl) methylamino] -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , TMS); 1.33 (t, J = 7.0 Hz, 3H), 1.35 (t, J = 7.0 Hz, 3H), 2.06 (s, 3H), 2.03-2.21 (m , 1H), 2.23-2.60 (m, 3H), 2.68-2.84 (m, 1H), 3.22 (d, J = 14.1 Hz, 1H), 3.97 (d, J = 14.1 Hz, 1H), 4.18-4.32 ( m, 4H), 7.07 (dd, J = 8.1, 2.0 Hz, 1H), 7.30-7.39 (m, 2H).
MS (ESI) (Pos) m / z; 447 (M + H) ⁺
[α] _D ²³ = -24.9 ° (CHCl ₃ , c = 0.84)

(3) (1R, 2R, 3R, 5R, 6R) -2-amino-3-[(3,4-dichlorobenzyl) -methyl-amino] -6 From 94 mg of fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester, (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 62 mg was obtained.
¹ H-NMR (300 MHz, 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 = 13.4 Hz, 1H), 4.27 (d, J = 13.4 Hz, 1H), 7.35-7.41 (m, 1H), 7.61-7.69 (m, 2H).
MS (ESI) (Nega) m / z; 389 (MH) ^-
[α] _D ²⁴ = -35.2 ° (1N NaOH, c = 0.51)

(Reference Example 7)
Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoylamino) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) (1R, 2R, 3R, 5R, 6R) -3-amino-2-t-butoxycarbonylamino-6-fluoro-bicyclo [3.1.0] hexane-2 dissolved in 0.17 mL of chloroform, To 17 mg of 6-dicarboxylic acid diethyl ester, 7.3 μL of pyridine and 14 mg of 3,4-dichlorobenzoyl chloride were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: chloroform-ethanol = 100: 1), and (1R, 2R, 3R, 5R, 6R) -2-t-butoxycarbonylamino-3- ( 21 mg of 3,4-dichlorobenzoylamino) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.19 (t, J = 7.03 Hz, 3H), 1.31 (t, J = 7.25 Hz, 3H), 1.41 (s, 9H), 2.21-2.64 (m , 3H), 2.82-2.91 (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) (1R, 2R, 3R, 5R, 6R) -2-t-Butoxycarbonylamino-3- (3,4-dichlorobenzoylamino) -6-fluoro-, as in (7) of Reference Example 5 Bicyclo [3.1.0] hexane-2,6-dicarboxylic acid From 107 mg of diethyl ester, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoylamino) -6 85 mg of fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.30 (t, J = 6.8 Hz, 3H), 1.33 (t, J = 7.0 Hz, 3H), 2.09-2.43 (m, 3H), 2.53-2.38 (m, 1H), 4.19-4.38 (m, 4H), 4.52-4.71 (m, 1H), 7.48-7.55 (m, 2H), 7.75-7.84 (m, 1H).
MS (ESI) (Pos) m / z; 469 (M + Na) ⁺
[α] _D ²⁷ = + 8.3 ° (CHCl ₃ , c = 0.93)

(3) Similar to (6) of Reference Example 2, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoylamino) -6-fluoro-bicyclo [3. 1.0] Hexane-2,6-dicarboxylic acid From 48 mg of diethyl ester, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoylamino) -6-fluoro-bicyclo [3.1.0] 24 mg of hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, D ₂ O, TMSP); 2.33-2.42 (m, 2 H), 2.57-2.67 (m, 2 H), 4.46-4.55 (m, 1H), 7.58-7.68 (m, 2H), 7.87-7.90 (m, 1H).
MS (ESI) (Nega) m / z; 389 (MH) ^-
[α] _D ²⁸ = + 6.0 ° (CHCl ₃ , c = 0.34)

(Reference Example 8)
Synthesis of (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1) (1R, 2R, 3R, 5R, 6R) -2-azido-6-fluoro-3-hydroxy-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid dissolved in 3.7 mL of pyridine 2-Benzyl ester 234 mg of 3,4-dichlorobenzoyl chloride was added to 202 mg of 6-ethyl ester, and the mixture was stirred at room temperature for 28 hours under a nitrogen atmosphere. 100 mL of ethyl acetate was added to the reaction solution, and this ethyl acetate solution was washed with a saturated aqueous solution of copper sulfate and water and then dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Wako gel C200, developing solvent: hexane-ethyl acetate = 10: 1), and (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 ester 298 mg. Obtained.
¹ H-NMR (200 MHz, CDCl ₃ ); 1.35 (t, J = 7.3 Hz, 3H), 2.35-2.55 (m, 3H), 2.77-2.87 (m, 1H), 4.31 (q, J = 7.3 Hz , 2H), 5.24-5.46 (m, 3H), 7.28-7.60 (m, 6H), 7.90-8.20 (m, 2H).
MS (ESI) (Pos) m / z; 558 (M + Na) ⁺

(2) Similar to (5) of Reference Example 2, (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 From 6-ethyl ester 298 mg, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoyloxy)- 218 mg of 6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester was obtained.
¹ H-NMR (200 MHz, CDCl ₃ , TMS); 1.33 (t, J = 7.3 Hz, 3H), 2.25-2.80 (m, 4H), 4.28 (q, J = 7.3 Hz, 2H), 5.05-5.13 (m, 1H), 5.16 (d, J = 12.3 Hz, 1H), 5.31 (d, J = 12.3 Hz, 1H), 7.24-7.36 (m, 5H), 7.44 (d, J = 8.4 Hz, 1H) , 7.57 (dd, J = 8.4, 2.20 Hz, 1H), 7.90 (d, J = 2.2 Hz, 1H).
MS (ESI) (Pos) m / z; 532 (M + Na) ⁺
[α] _D ²² = + 31.8 ° (CHCl ₃ , c = 0.55)

(3) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoyloxy) -6-fluoro-bicyclo [3.1.0] hexane-dissolved in 10 mL of ethanol To 218 mg of 2,6-dicarboxylic acid 2-benzyl ester 6-diethyl ester, 15 mg of 5% palladium carbon was added and stirred at room temperature for 50 minutes in a hydrogen atmosphere. The palladium carbon was filtered off using Celite, the filtrate was concentrated under reduced pressure, and the resulting solid was dissolved in a mixed solvent of 2 mL of tetrahydrofuran and 1 mL of water. To this solution, 10 mg of lithium hydroxide monohydrate was added under ice cooling and stirred for 30 minutes. Under ice-cooling, 0.5 mL of 1N hydrochloric acid was added, diluted to 50 mL with water, and then ion exchange resin (AG 50W-X8 Resin (H type), developing solvent: water, 40% tetrahydrofuran aqueous solution, 10% pyridine aqueous solution) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzoyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6 -25 mg of dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, 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 = 8.5 Hz , 1H), 7.89 (d, J = 8.5 Hz, 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 (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1] suspended in 8 mL of methanol. 0.0] 0.65 mL of thionyl chloride was added to 800 mg of hexane-2,6-dicarboxylic acid under ice cooling, followed by stirring at 50 ° C. for 4 hours. After stirring at room temperature for 3 hours, methanol was distilled off under reduced pressure. After adding 20 mL of hexane to the residue and stirring for 2 hours, the solid was collected by filtration. This solid was washed with diisopropyl ether and hexane to give (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0]. Hexane-2,6-dicarboxylic acid 6-methyl ester hydrochloride 820 mg was obtained.

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

(Example 3)
(1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethoxy Synthesis of carbonyl methyl ester.
(1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [suspended in a mixed solvent of 0.8 mL of tetrahydrofuran and 0.4 mL of water 3.1.0] To 36 mg of hexane-2,6-dicarboxylic acid, 4.4 mg of lithium hydroxide hydrate was added at room temperature and stirred 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 the mixture was 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, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography (silica gel 60F ₂₅₄ (manufactured by Merck), developing solvent: hexane-ethyl acetate = 1: 1), and (1R, 2R, 3R, 5R, 6R) -2-amino-3- 12 mg of (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid diethoxycarbonylmethyl ester was obtained.

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 (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4) dissolved in a mixed solvent of 0.2 mL of N, N-dimethylformamide and 0.02 mL of water -Dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (2-iodoethyl) ester (18 mg) was added with sodium azide (6 mg) at room temperature. And stirred for 12 hours. After allowing to cool, the solvent was distilled off under reduced pressure, and the residue was purified by reverse-phase column chromatography (Wakogel 50C18: developing solvent water to 70% acetonitrile aqueous solution), and (1R, 2R, 3R, 5R, 6R) -2-amino 7 mg of -3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (2-azidoethyl) ester was obtained.

(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 (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) dissolved in a mixed solvent of 0.15 mL of tetrahydrofuran and 0.02 mL of water ) To 6 mg of 6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (2-azidoethyl) ester, 20 μL of a 1M trimethylphosphine / tetrahydrofuran solution was added at room temperature and stirred for 13 hours. . The solvent was distilled off under reduced pressure, and the solid obtained by purification by reverse-phase column chromatography (Wakogel 50C18 (Wako Pure Chemical Industries): developing solvent water to 50% acetonitrile aqueous solution) was further washed with tetrahydrofuran (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (2- 2 mg of aminoethyl) ester were obtained.

  The structures and physical property data of the compounds described in Examples 1, 2, 3, 4 and 5 and the compounds obtained in the same manner are shown in the following table.

(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 (1)

ジオキサン２．６ｍＬに懸濁した（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アミノ−３−（３，４−ジクロロベンジル）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸７４０ｍｇに、飽和炭酸水素ナトリウム６．７ｍＬを加え、室温で１０分間攪拌した。この溶液に、クロロギ酸アリル０．４１ｍＬを滴下し、室温で１２時間攪拌した。この反応溶液に水２．６ｍＬを加え、この水層を酢酸エチルで洗浄した後、氷浴中、１規定塩酸で酸性とし、酢酸エチルで２回抽出した。合わせた酢酸エチル層を無水硫酸ナトリウムで乾燥後、減圧下濃縮し、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アリルオキシカルボニルアミノ−３−（３，４−ジクロロベンジルオキシ）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸９３０ｍｇを得た。
¹H-NMR (300 MHz, CD₃OD, TMS); 2.15-2.53 (m, 3 H) 2.89-3.01 (m, 1 H) 4.06-4.19 (m, 1 H) 4.46 (d, J=11.7 Hz, 1 H) 4.55 (d, J=4.8 Hz, 1 H) 4.71 (d, J=11.7 Hz, 1 H) 5.16-5.20 (m, 1 H) 5.29-5.36 (m, 1 H) 5.89-5.99 (m, 1 H) 7.22 (dd, J=8.2, 2.0 Hz, 1 H) 7.44 (d, J=8.2 Hz, 1 H) 7.48 (d, J=2.0 Hz, 1 H)
MS(ESI)(Nega)m/z; 460 (M-H)^-
（２）

(1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyl) -6-fluoro-bicyclo [3.1.0] hexane-2 suspended in 2.6 mL of dioxane , 6-Dicarboxylic acid (740 mg) was added with saturated sodium bicarbonate (6.7 mL) and stirred at room temperature for 10 minutes. To this solution, 0.41 mL of allyl chloroformate was added dropwise and stirred 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 1N hydrochloric acid in an ice bath, and extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (1R, 2R, 3R, 5R, 6R) -2-allyloxycarbonylamino-3- (3,4-dichlorobenzyloxy) -6. -930 mg of fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was obtained.
¹ H-NMR (300 MHz, CD ₃ OD, TMS); 2.15-2.53 (m, 3 H) 2.89-3.01 (m, 1 H) 4.06-4.19 (m, 1 H) 4.46 (d, J = 11.7 Hz , 1 H) 4.55 (d, J = 4.8 Hz, 1 H) 4.71 (d, J = 11.7 Hz, 1 H) 5.16-5.20 (m, 1 H) 5.29-5.36 (m, 1 H) 5.89-5.99 ( m, 1 H) 7.22 (dd, J = 8.2, 2.0 Hz, 1 H) 7.44 (d, J = 8.2 Hz, 1 H) 7.48 (d, J = 2.0 Hz, 1 H)
MS (ESI) (Nega) m / z; 460 (MH) ^-
(2)

ベンゼン１０ｍLに溶解した（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アリルオキシカルボニルアミノ−３−（３，４−ジクロロベンジルオキシ）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸３８０ｍｇ、パラホルムアルデヒド１０９ｍｇ、パラトルエンスルホン酸１水和物８ｍｇの混合物をＤｅａｎ−Ｓｔａｒｋ水分分離器を付け３．５時間、加熱還流した。放冷後、酢酸エチルで希釈し、この酢酸エチル溶液を水洗した。酢酸エチル層を無水硫酸ナトリウムで乾燥した後、減圧下濃縮し、（１’Ｒ，２’Ｒ，３’Ｒ，５’Ｒ，６’Ｒ）−３’−（３，４−ジクロロベンジルオキシ）−６’−フルオロ−３−アリルオキシカルボニル−５−オキソ−オキサゾリジノン−４−スピロ−２’−ビシクロ［３．１．０］ヘキサン−６’−カルボン酸３７０mgを得た。
¹H-NMR (300 MHz, CDCl₃, TMS); 2.07-2.54 (m, 4 H) 4.17-4.24 (m, 1 H) 4.39 (d, J=12.3 Hz, 1 H) 4.52 (d, J=12.3 Hz, 1 H) 4.63 (d, J=6.2 Hz, 2 H) 5.23 (d, J=4.4 Hz, 1 H) 5.28-5.54 (m, 2 H) 5.53 (d, J=4.5 Hz, 1 H) 5.85-5.98 (m, 1 H) 7.07 (dd, J=8.2, 1.9 Hz, 1 H) 7.32 (d, J=1.9 Hz, 1 H) 7.41 (d, J=8.2 Hz, 1 H).
MS(ESI)(Nega)m/z; 472 (M-H)^-
（３）

(1R, 2R, 3R, 5R, 6R) -2-allyloxycarbonylamino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane- dissolved in 10 mL of benzene A mixture of 380 mg of 2,6-dicarboxylic acid, 109 mg of paraformaldehyde and 8 mg of paratoluenesulfonic acid monohydrate was attached to a Dean-Stark water separator and heated to reflux for 3.5 hours. After allowing to cool, it was diluted with ethyl acetate, and this ethyl acetate solution was washed with water. The ethyl acetate layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and (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'-carboxylic acid 370 mg was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , TMS); 2.07-2.54 (m, 4 H) 4.17-4.24 (m, 1 H) 4.39 (d, J = 12.3 Hz, 1 H) 4.52 (d, J = 12.3 Hz, 1 H) 4.63 (d, J = 6.2 Hz, 2 H) 5.23 (d, J = 4.4 Hz, 1 H) 5.28-5.54 (m, 2 H) 5.53 (d, J = 4.5 Hz, 1 H ) 5.85-5.98 (m, 1 H) 7.07 (dd, J = 8.2, 1.9 Hz, 1 H) 7.32 (d, J = 1.9 Hz, 1 H) 7.41 (d, J = 8.2 Hz, 1 H).
MS (ESI) (Nega) m / z; 472 (MH) ^-
(3)

Ｎ，Ｎ−ジメチルホルムアミド２ｍＬに溶解した（１’Ｒ，２’Ｒ，３’Ｒ，５’Ｒ，６’Ｒ）−３’−（３，４−ジクロロベンジルオキシ）−６’−フルオロ−３−アリルオキシカルボニル−５−オキソ−オキサゾリジノン−４−スピロ−２’−ビシクロ［３．１．０］ヘキサン−６’−カルボン酸５８ｍｇに、炭酸カリウム３７ｍｇ及びＮ，Ｎ−ジエチルクロロアセトアミド３７μＬを加え、室温で１５時間攪拌した。酢酸エチルで希釈し、水および飽和食塩水で酢酸エチル層を洗浄し後、酢酸エチル層を無水硫酸ナトリウムで乾燥した。乾燥剤を濾別後、濾液を減圧下濃縮し、残渣をカラムクロマトグラフィー（シリカゲル：シキカゲル６０Ｎ（関東化学）、展開溶媒：ヘキサン−酢酸エチル＝１：２）にて精製し、（１’Ｒ，２’Ｒ，３’Ｒ，５’Ｒ，６’Ｒ）−３’−（３，４−ジクロロベンジルオキシ）−６’−フルオロ−３−アリルオキシカルボニル−５−オキソ−オキサゾリジノン−４−スピロ−２’−ビシクロ［３．１．０］ヘキサン−６’−カルボン酸 ６−（Ｎ，Ｎ−ジエチルアミノカルボニルメチル）エステル６０ｍｇを得た。
¹H-NMR (300 MHz, CDCl₃, TMS); 1.12 (t, J=7.23Hz, 3 H) 1.23 (t, J=7.2 Hz, 3 H) 2.21-2.60 (m, 4 H) 3.23 (q, J=7.2 Hz, 2 H) 3.38 (q, J=7.2 Hz, 2 H) 4.19-4.27 (m, 1 H) 4.38 (d, J=12.3 Hz, 1 H) 4.52 (d, J=12.3 Hz, 1 H) 4.63-4.65 (m, 2 H) 4.74 (d, J=14.1 Hz, 1 H) 4.85 (m, J=14.1 Hz, 1 H) 5.23 (d, J=4.3 Hz, 1 H) 5.24-5.33 (m, 2 H) 5.51 (d, J=4.3 Hz, 1 H) 5.87-6.00 (m, 1 H) 7.07 (dd, J=8.2, 2.0 Hz, 1 H) 7.31 (d, J=2.0 Hz, 1 H) 7.40 (d, J=8.2 Hz, 1 H).
MS(ESI)(Pos)m/z; 609 (M+Na)⁺
（４）

(1′R, 2′R, 3′R, 5′R, 6′R) -3 ′-(3,4-dichlorobenzyloxy) -6′-fluoro-dissolved in 2 mL of N, N-dimethylformamide To 58 mg of 3-allyloxycarbonyl-5-oxo-oxazolidinone-4-spiro-2′-bicyclo [3.1.0] hexane-6′-carboxylic acid, 37 mg of potassium carbonate and 37 μL of N, N-diethylchloroacetamide were added. The mixture was further stirred at room temperature for 15 hours. After diluting with ethyl acetate and washing the ethyl acetate layer with water and saturated brine, the ethyl acetate layer was dried over anhydrous sodium sulfate. After the desiccant was filtered off, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel: Shikika Gel 60N (Kanto Chemical), developing solvent: hexane-ethyl acetate = 1: 2) (1′R , 2′R, 3′R, 5′R, 6′R) -3 ′-(3,4-dichlorobenzyloxy) -6′-fluoro-3-allyloxycarbonyl-5-oxo-oxazolidinone-4- 60 mg of spiro-2′-bicyclo [3.1.0] hexane-6′-carboxylic acid 6- (N, N-diethylaminocarbonylmethyl) ester was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , TMS); 1.12 (t, J = 7.23Hz, 3 H) 1.23 (t, J = 7.2 Hz, 3 H) 2.21-2.60 (m, 4 H) 3.23 (q , J = 7.2 Hz, 2 H) 3.38 (q, J = 7.2 Hz, 2 H) 4.19-4.27 (m, 1 H) 4.38 (d, J = 12.3 Hz, 1 H) 4.52 (d, J = 12.3 Hz , 1 H) 4.63-4.65 (m, 2 H) 4.74 (d, J = 14.1 Hz, 1 H) 4.85 (m, J = 14.1 Hz, 1 H) 5.23 (d, J = 4.3 Hz, 1 H) 5.24 -5.33 (m, 2 H) 5.51 (d, J = 4.3 Hz, 1 H) 5.87-6.00 (m, 1 H) 7.07 (dd, J = 8.2, 2.0 Hz, 1 H) 7.31 (d, J = 2.0 (Hz, 1 H) 7.40 (d, J = 8.2 Hz, 1 H).
MS (ESI) (Pos) m / z; 609 (M + Na) ⁺
(4)

クロロホルムに溶解した（１’Ｒ，２’Ｒ，３’Ｒ，５’Ｒ，６’Ｒ）−３’−（３，４−ジクロロベンジルオキシ）−６’−フルオロ−３−アリルオキシカルボニル−５−オキソ−オキサゾリジノン−４−スピロ−２’−ビシクロ［３．１．０］ヘキサン−６’−カルボン酸 ６−（Ｎ，Ｎ−ジエチルアミノカルボニルメチル）エステル５８ｍｇに、窒素雰囲気下、１，３−ジメチルバルビツール酸４６ｍｇ、テトラキストリフェニルホスフィンパラジウム４ｍｇを加え、４０℃で１．５時間攪拌した。反応液を減圧下濃縮後、残渣に酢酸エチル加え、室温で１時間攪拌した。析出した固体をろ別後、ろ液を減圧下濃縮し得られた残渣を逆相クロマトグラフィー（ワコーゲル５０Ｃ１８（和光純薬）：展開溶媒 水 〜 ５０％アセトニトリル水溶液）にて精製し、得られた固体をさらに酢酸エチルで洗浄し、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アミノ−３−（３，４−ジクロロベンジルオキシ）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２，６−カルボン酸 ６−（Ｎ，Ｎ−ジエチルアミノカルボニルメチル）エステル５ｍｇを得た。

(1′R, 2′R, 3′R, 5′R, 6′R) -3 ′-(3,4-dichlorobenzyloxy) -6′-fluoro-3-allyloxycarbonyl- dissolved in chloroform 5-oxo-oxazolidinone-4-spiro-2′-bicyclo [3.1.0] hexane-6′-carboxylic acid 6- (N, N-diethylaminocarbonylmethyl) ester was added to 58 mg under nitrogen atmosphere and 1,3 -46 mg of dimethyl barbituric acid and 4 mg of tetrakistriphenylphosphine palladium were added, and it stirred at 40 degreeC for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate was added to the residue, and the mixture was stirred at room temperature for 1 hr. After the precipitated solid was filtered off, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by reverse phase chromatography (Wakogel 50C18 (Wako Pure Chemical Industries): developing solvent water to 50% acetonitrile aqueous solution). The solid was further washed with ethyl acetate and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane. 5 mg of -2,6-carboxylic acid 6- (N, N-diethylaminocarbonylmethyl) ester was obtained.

(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

４−フルオロベンジルアルコール０.３ｍLに懸濁させた（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アミノ−３−（３，４−ジクロロベンジルオキシ）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２,６−ジカルボン酸３０ｍｇに、室温で、塩化チオニル２３μLを加えた後、６０℃で３日間攪拌した。放冷後、反応溶液を逆相クロマトグラフィー（ワコーゲル５０Ｃ１８（和光純薬）：展開溶媒 水〜７０％アセトニトリル水溶液）にて精製し、（１Ｒ，２Ｒ，３Ｒ，５Ｒ，６Ｒ）−２−アミノ−３−（３，４−ジクロロベンジルオキシ）−６−フルオロ−ビシクロ［３．１．０］ヘキサン−２，６−ジカルボン酸 ６−（４−フルオロベンジル）エステル５ｍｇを得た。

(1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1] suspended in 0.3 mL of 4-fluorobenzyl alcohol. 0.0] Thionyl chloride (23 μL) was added to 30 mg of hexane-2,6-dicarboxylic acid at room temperature, followed by stirring at 60 ° C. for 3 days. After allowing to cool, the reaction solution was purified by reverse phase chromatography (Wakogel 50C18 (Wako Pure Chemical Industries): developing solvent water to 70% acetonitrile aqueous solution), and (1R, 2R, 3R, 5R, 6R) -2-amino- 5 mg of 3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6- (4-fluorobenzyl) ester was obtained.

  The structures and physical property data of the compounds described in Examples 6 and 7 and the compounds obtained in the same manner are shown in the following table.

(Example 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 (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro suspended in 20 mL of 3-methylbutanol -1.0 mL of thionyl chloride was added to 1.50 g of bicyclo [3.1.0] hexane-2,6-dicarboxylic acid under ice cooling, and then the mixture was stirred at 70 ° C for 3 hours. After allowing to cool, 3-methylbutanol was distilled off under reduced pressure. Ethanol (15 mL) and propylene oxide (15 mL) were added to the residue, and the mixture was heated to reflux for 1 hour. After allowing to cool, it was diluted with diethyl ether, and the precipitated solid was collected by filtration. This solid was washed with water, diisopropyl ether, hexane, and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1. 0.0] 1.01 g of hexane-2,6-dicarboxylic acid 6- (3-methyl) -n-butyl ester was obtained.

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 (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy)-suspended in 10 mL of 6-methyl-1-heptanol To 1.00 g of 6-fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid was added 0.4 mL of thionyl chloride under ice cooling, and the mixture was stirred at 80 ° C. for 6 hours. After allowing to cool, the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by reverse phase column chromatography (Wakogel 50C18 (Wako Pure Chemical Industries): developing solvent water to 70% acetonitrile aqueous solution). The obtained solid was recrystallized from ethanol: water to give (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1. 0.0] hexane-2,6-dicarboxylic acid 6- (6-methyl) heptyl ester 557 mg was obtained.

  The structures and physical property data of the compounds described in Examples 8 and 9 and the compounds obtained in the same manner are shown in the following table.

(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 ester 6-ethyl ester and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluoro-bicyclo [3.1.0] hexane-2 , 6-Dicarboxylic acid 2-butyl ester synthesis (1) In the same manner as in Example 1, (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6 From 4.00 g of fluoro-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy)- 6-Fluorobicyclo [3.1.0] Hexane-2,6-dicarboxylic acid 6-ethyl ester 2.96 g of hydrochloride was obtained.

(2) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6-Ethyl ester hydrochloride (400 mg) was added to a mixed solution of ethanol (5 mL) and propylene oxide (5 mL), and the mixture was heated to reflux for 2.5 hours. After allowing to cool, the precipitated solid was collected by filtration, washed with diethyl ether, recrystallized from water: ethanol, and (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4) -Dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 6-ethyl ester 230 mg was obtained.

(3) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-suspended in 1 mL of dioxane To 200 mg of 2,6-dicarboxylic acid 6-ethyl ester was added 2 mL of saturated sodium hydrogen carbonate, and the mixture was stirred at room temperature for 10 minutes. To this solution, 0.18 mL of allyl chloroformate was added and stirred at room temperature for 8 hours. The reaction solution was acidified by adding 1 mL of 1N hydrochloric acid, 10 mL of water was added, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was dissolved in 20 mL of N, N-dimethylformamide. To this solution, 141 mg of 1-iodobutane and 106 mg of potassium carbonate were added and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The combined ethyl acetate layers were dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel: Kanto Chemical Silica Gel 60 (spherical), developing solvent: hexane-ethyl acetate = 5: 1). (1R, 2R, 3R, 5R, 6R) -2-allyloxycarbonylamino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6- 159 mg of dicarboxylic acid 2-butyl ester 6-ethyl ester was obtained.
¹ H-NMR (300 MHz, CDCl ₃ , TMS) 0.89 (3 H, t, J = 7.4 Hz), 1.24-1.43 (5 H, m), 1.56-1.66 (2 H, m), 2.22-2.51 ( 3 H, m), 2.93-3.00 (1 H, m), 3.81-3.89 (1 H, m), 4.08-4.65 (8 H, m), 5.16-5.37 (3 H, m), 5.84 5.98 (1 H, m), 7.09 (1 H, dd, J = 8.2, 2.0 Hz), 7.37 (1 H, d, J = 2.0 Hz), 7.40 (1 H, d, J = 8.2 Hz)

(4) (1R, 2R, 3R, 5R, 6R) -2-allyloxycarbonylamino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane dissolved in chloroform -2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester To 190 mg, under a nitrogen atmosphere, 81 mg of 1,3-dimethylbarbituric acid and 12 mg of tetrakistriphenylphosphine palladium were added and stirred at 50 ° C for 1 hour. The residue obtained by concentrating the reaction solution under reduced pressure is purified by column chromatography (silica gel: Kanto Chemical Silica Gel 60 (spherical), developing solvent: hexane-ethyl acetate = 5: 1), and (1R, 2R, 3R, 5R). , 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester 180 mg is obtained. It was.

(5) (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] dissolved in 2 mL of tetrahydrofuran and 1 mL of water 15 mg of lithium hydroxide monohydrate was added to 131 mg of hexane-2,6-dicarboxylic acid 2-butyl ester 6-ethyl ester, and the mixture was stirred at room temperature for 1.5 hours. 2 mL of 1N hydrochloric acid was added to the reaction solution, and the residue obtained after concentration under reduced pressure was purified by reverse phase chromatography (Wakogel 50C18 (Wako Pure Chemical Industries): developing solvent water to 40% acetonitrile solution), (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6-dicarboxylic acid 2-butyl ester 37 mg Obtained.

  The structure and physical property data of the compound described in Example 10 and the compound obtained in the same manner are shown in the following table.

(Test Example 1) Evaluation of antidepressant action by rat forced swimming test
(1) Male SD rats (body weight 220-240 g Nippon Charles River) were used as experimental animals.

(2) The following compounds were used as test drugs.
LY341495 (Journal of Medicinal Chemistry 1998, 41, 358-378): (2S) -2-amino-2-((1S, 2S) -2-carboxycycloprop-1-yl) -3- (9-xanthyl) Propionic acid ((2S) -2-Amino-2-((1S, 2S) -2-carboxycycloprop-1-yl) -3- (9-xanthyl) propanoic acid)
Parent compounds of compounds 1, 4 and 10 of the present invention: (1R, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1. 0] Hexane-2,6-dicarboxylic acid ((1S, 2R, 3R, 5R, 6R) -2-amino-3- (3,4-dichlorobenzyloxy) -6-fluorobicyclo [3.1.0] hexane-2,6 -dicarboxylic acid)

(3) The forced swimming test was carried out with a slight modification to the method reported by Porsolt et al. (European Journal of Pharmacology 1978, 47, 379-391). That is, a rat was placed in a cylinder containing water at a depth of 30 cm, and a forced swimming for 15 minutes was first performed, followed by a forced swimming test (main test) for 5 minutes after 24 hours. And the immobilization time in this test was measured, and the antidepressant action of the test drug was evaluated.

  In the administration group, each test drug of LY341495 and the parent compounds of compounds 1, 4 and 10 was dissolved in 1/15 M phosphate buffer, and the ratio was 0.3 mg / kg, 1 mg / kg, 3 mg / kg. Thus, it was intraperitoneally administered twice 24 hours before and 1 hour before this test. Further, only 1 / 15M phosphate buffer was intraperitoneally administered to the solvent group in the same manner.

(4) Symbols * and ** in FIGS. 1 and 2 are 1/15 M phosphate buffer at P <0.05 and P <0.01, respectively, when significant difference test is performed by Dunnett's test. It shows that there is a significant difference compared to the solvent group. Therefore, as shown in FIGS. 1 and 2, the immobilization time was significantly decreased in a dose-dependent manner in the group in which the test compound LY341495 and the parent compounds of compounds 1, 4 and 10 were intraperitoneally administered as compared with the solvent group. As a result, it has become clear that it has an excellent antidepressant effect. This indicates that a compound having a group II metabotropic glutamate receptor antagonistic action is useful as an antidepressant.

(Test Example 2) Measurement of in vivo exposure based on rat plasma concentration In vivo exposure, for example, in the compounds 1, 4 and 10 of the present invention, and in formula [IV], X is a fluorine atom and Y is 3 The plasma concentration of the parent compound of the compound 1 of the present invention after oral administration in rats of the parent compounds of the compounds 1, 4 and 10 of the present invention, which is a 1,4-dichlorobenzyloxy group, was measured and compared as follows: investigated. Further, in the same manner, the plasma concentrations of the parent compound of the compound 44 of the present invention after oral administration in rats of the compound 44 of the present invention and its parent compound were measured, compared, and examined.

  Seven-week-old rats (240-280 g, male, strain CD (SD) IGS) obtained from Charles River, Japan were used after acclimatization for 2 days or more. The compound of the present invention was dissolved in 0.03N hydrochloric acid containing 10% HP-β-CD to give 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 a decision tube (with EDTA) and immediately centrifuged (10000 × g, 4 ° C., 10 minutes) to collect plasma to obtain a plasma sample. Plasma samples were stored frozen at -80 ° C or lower. Add a methanol solution of the internal standard substance to a plasma sample thawed under ice-cooling conditions, deproteinize, centrifuge (10000 × g, 4 ° C., 10 minutes), and determine the concentration of the parent compound of the compound of the present invention in the supernatant. Measured by LC / MS / MS.

  As shown in the table below, administration of the compound of the present invention dramatically increased the plasma concentration of the parent compound of the present compound and increased the amount of in vivo exposure.

  According to the present invention, development of an excellent antidepressant is expected.

In order to evaluate the antidepressant action, the immobilization time when a rat administered with a known group II metabotropic glutamate receptor antagonist LY341495 (Journal of Medicinal Chemistry 1998, 41, 358-378) was forced to swim was calculated. It is the measured graph. It is the graph which measured the immobilization time when the rat which administered the parent compound of this invention compound 1,4 and 10 was made to perform forced swimming.

Claims (57)

Formula [I]

[Wherein, R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1- substituted with one or two aryl groups. ₁₀ alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different, hydrogen atom or a C _1-10 C _1-10 alkyl group substituted by a group represented by an alkyl group.), wherein ^{-CHR c OC (O) ZR d} ( wherein, Z is an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, R ^c is a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl group, Ali Indicates Le group, R ^d is, C _1-10 alkyl, C _2-10 alkenyl group, an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C substituted with 1 or 2 aryl groups _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group , C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are as defined above) A C _1-10 alkyl group substituted by a group represented by the formula: —CHR ^c OC (O) ZR ^d , wherein Z, R ^c and R ^d are as defined above. The group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

Represents a group represented by
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 group, C _1-10 alkenyl group, phenyl group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl Phenyl substituted with 1 to 5 substituents selected from the group consisting of a group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group represents a group, R ⁵ is, C _1-10 alkyl, C _1-10 alkenyl group, a phenyl , Naphthyl group, one to seven naphthyl group substituted with a halogen atom, a heteroaromatic group or a halogen atom, a phenyl group, C _1-10 alkyl, C _1-10 alkoxy group, a trifluoromethyl group, A phenyl group substituted with 1 to 5 substituents selected from the group consisting of a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group, and n represents an integer of 1 or 2. ). ]
2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative represented by the above, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient to prevent depression or Remedy. Formula [II]

[Wherein, R ¹ and R ² are the same or different and each represents a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1- substituted with one or two aryl groups. ₁₀ alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different, hydrogen atom or a C _1-10 C _1-10 alkyl group substituted by a group represented by an alkyl group.), wherein ^{-CHR c OC (O) ZR d} ( wherein, Z is an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, R ^c is a hydrogen atom, C _1-10 alkyl, C _2-10 alkenyl group, Ali Indicates Le group, R ^d is, C _1-10 alkyl, C _2-10 alkenyl group, an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C substituted with 1 or 2 aryl groups _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group , C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are as defined above) A C _1-10 alkyl group substituted by a group represented by the formula: —CHR ^c OC (O) ZR ^d , wherein Z, R ^c and R ^d are as defined above. The group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

Represents a group represented by
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 group, C _1-10 alkenyl group, phenyl group, naphthyl group, naphthyl group substituted with 1 to 7 halogen atoms, heteroaromatic group, or halogen atom, phenyl group, C _1-10 alkyl Phenyl substituted with 1 to 5 substituents selected from the group consisting of a group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group represents a group, R ⁵ is, C _1-10 alkyl, C _1-10 alkenyl group, a phenyl , Naphthyl group, one to seven naphthyl group substituted with a halogen atom, a heteroaromatic group or a halogen atom, a phenyl group, C _1-10 alkyl, C _1-10 alkoxy group, a trifluoromethyl group, A phenyl group substituted with 1 to 5 substituents selected from the group consisting of a phenyl group, a hydroxycarbonyl group, an amino group, a nitro group, a cyano group and a phenoxy group, and n represents an integer of 1 or 2. ). ]
2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof represented by the formula: Drugs for preventing or treating depression. In the formula [II], R ¹ and R ² are the same or different and substituted with a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or 1 or 2 phenyl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl A group, a C _1-10 alkoxycarbonyl C _1-10 alkyl group, or when ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-10 alkyl group, a C _2-10 alkenyl group, A C _2-10 alkynyl group, a C _1-10 alkyl group substituted with one or two phenyl groups, a hydroxy C _2-10 alkyl group, a halogenated C _1-10 alkyl group, an azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 Arukokishikaru Indicates a nil C _1-10 alkyl group, as claimed in claim 2 wherein 2-amino - bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, salt or hydrate thereof their pharmaceutically acceptable A prophylactic or therapeutic agent for depression, comprising In the formula [II], R ¹ and R ² are the same or different and substituted with a C _1-10 alkyl group, a C _2-6 alkenyl group, a C _2-6 alkynyl group, or 1 or 2 phenyl groups. C _1-6 alkyl group, hydroxy C _2-6 alkyl group, halogenated C _1-6 alkyl group, azido C _1-6 alkyl group, amino C _2-6 alkyl group, C _1-6 alkoxy C _1-6 alkyl A group, a C _1-6 alkoxycarbonyl C _1-6 alkyl group, or when ^one of R ¹ and R ² is a hydrogen atom, the other is a C _1-6 alkyl group, a C _2-6 alkenyl group, A C _2-6 alkynyl group, a C _1-6 alkyl group substituted with one or two phenyl groups, a hydroxy C _2-6 alkyl group, a halogenated C _1-6 alkyl group, an azido C _1-6 alkyl group, amino C _2-6 alkyl group, C _1-6 alkoxy C _1-6 alkyl group, C _1-6 alkoxycarbonyl C _1-6 Al The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt thereof or hydrate thereof according to claim 2, which represents To prevent or treat depression. In the formula [II],
R ¹ and R ² are the same or different and are a farnesyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a C _1-10 alkoxycarbonyl C _1-10 alkyl group, 4-morpholinyl C _{1. -10} alkyl group, substituted by a group represented by the formula -C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-10 alkyl group). A C _1-10 alkyl group having 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 represents} an alkyl group, a C _2-10 alkenyl group, or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, or an aryl group.

Wherein R ^d is as defined above, or a group represented by formula [ii]

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a farnesyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a C _1-10 alkoxycarbonyl C _1-10 alkyl group , 4-morpholinyl C _1-10 alkyl group, C _1- substituted by a group represented by the formula —C (O) NR ^a R ^b , wherein R ^a and R ^b are as defined above. ₁₀ an alkyl group, a group represented by the formula —CHR ^c OC (O) ZR ^d (wherein Z, R ^c and R ^d are as defined above), a formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ¹ and R ² are the same or different and are a farnesyl group, a C _1-6 alkyl group substituted with one or two aryl groups, a C _1-6 alkoxycarbonyl C _1-6 alkyl. Group, 4-morpholinyl C _1-6 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-6 alkyl group). A C _1-6 alkyl group substituted by a group represented by 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, a C _1-6 alkyl group, a C _2-6 alkenyl group, and an aryl group, and R ^d represents a C _1-6 alkyl group, a C _2-6 alkenyl group, and an aryl group. Group, formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

Or a group represented by
When ^one of R ¹ and R ² is a hydrogen atom, the other is a farnesyl group, a C _1-6 alkyl group substituted with one or two aryl groups, a C _1-6 alkoxycarbonyl C _1-6 alkyl group , 4-morpholinyl C _1-6 alkyl group, C _1- substituted by a group represented by the formula —C (O) NR ^a R ^b , wherein R ^a and R ^b are as defined above. ₁₀ an alkyl group, a group represented by the formula —CHR ^c OC (O) ZR ^d (wherein Z, R ^c and R ^d are as defined above), a formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim ² , wherein R ² is a hydrogen atom in the formula [II], a pharmaceutically acceptable salt thereof, or A prophylactic or therapeutic agent for depression comprising the hydrate as an active ingredient. The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, wherein R ² is a hydrogen atom and X is a fluorine atom in the formula [II]. A prophylactic or therapeutic agent for depression comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, wherein R ² in the formula [II] is a hydrogen atom and X is a hydrogen atom. A prophylactic or therapeutic agent for depression comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. The formula [II], wherein R ² is a hydrogen atom, X is a fluorine atom, and Y is —SR ³ (wherein R ³ has the same meaning as defined above). A prophylactic or therapeutic agent for depression comprising an amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2 as an active ingredient. Drugs for preventing or treating depression. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} And R ⁴ and R ^{4 ′} have the same meanings as described above.) The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2 and a pharmaceutically acceptable product thereof. A prophylactic or therapeutic agent for depression comprising a salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. The formula [II], wherein R ² is a hydrogen atom, X is a hydrogen atom, and Y is —SR ³ (wherein R ³ has the same meaning as defined above). A prophylactic or therapeutic agent for depression comprising an amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2 as an active ingredient. Drugs for preventing or treating depression. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above). 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} And R ⁴ and R ^{4 ′} have the same meanings as described above.) The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2 and a pharmaceutically acceptable product thereof. A prophylactic or therapeutic agent for depression comprising a salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above),
R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with one or two aryl groups, a hydroxy C _2-10 alkyl group Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group , Farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group) 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, and a medicament thereof, which is a C _1-10 alkyl group substituted by a group represented by: A prophylactic or therapeutic agent for depression comprising the above acceptable salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a hydroxy C _2-10 alkyl group, Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, A farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). The 2-amino-bicyclo [3. is a C _1-10 alkyl group substituted by a group represented by 1.0] A prophylactic or therapeutic agent for depression comprising a hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —SR ³ (wherein R ³ is as defined above), and R ¹ is C _{1. -10} alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 alkyl group substituted with 1 or 2 aryl groups, hydroxy C _2-10 alkyl group, halogenated C _{1- 10} alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4- A morpholinyl C _1-10 alkyl group, represented by the formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). is a C _1-10 alkyl group substituted by a group, according to claim 2 wherein 2-amino - bicyclo [3.1.0] hex 2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or an active ingredient hydrate thereof, prophylactic or therapeutic agent for depression. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —SR ³ (wherein R ³ is as defined above), and R ¹ is a formula — CHR ^c OC (O) ZR ^d (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, and R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group, Represents an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, or an aryl group.), A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with one or two aryl groups, a hydroxy group C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl A C _1-10 alkyl group, a farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b , wherein R ^a and R ^b are the same or different and are a hydrogen atom or C ₁ . _{to -10} a C _1-10 alkyl group substituted by a group represented by an alkyl group), according to claim 2 wherein 2-amino - Cyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or an active ingredient hydrate thereof, prophylactic or therapeutic agent for depression. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). And R ¹ has the formula —CHR ^c OC (O) ZR ^d (wherein Z represents an oxygen atom, nitrogen atom, sulfur atom or single bond, R ^c represents a hydrogen atom, C _{1 A -10} alkyl group, a C _2-10 alkenyl group, and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, and an aryl group. ]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a hydroxy C _2-10 alkyl group, Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, A farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). The 2-amino-bicyclo [3] is C _1-10 alkyl group substituted by a group represented by .1.0] A prophylactic or therapeutic drug for depression comprising hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} And R ⁴ and R ^{4 ′} have the same meanings as described above), and R ¹ represents a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or one or two aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (where R ^a and R ^b are the same or different, C _1-10 alkyl group substituted by a group represented by a hydrogen atom or a C _1-10 alkyl group.), wherein 2. Prevention or treatment of depression comprising the 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, its pharmaceutically acceptable salt or its hydrate as described in 2. medicine. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} , R ⁴ and R ^{4 ′} are as defined above, and R ¹ is represented by the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a hydroxy C _2-10 alkyl group, Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, A farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). The 2-amino-bicyclo [3.1] is a C _1-10 alkyl group substituted by a group represented by: 0.0] A prophylactic or therapeutic agent for depression comprising hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a hydroxy C _2-10 alkyl group, Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, A farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). The 2-amino-bicyclo [3.1] is a C _1-10 alkyl group substituted by a group represented by: 0.0] A prophylactic or therapeutic agent for depression comprising hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —SCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —SR ³ (wherein R ³ is as defined above), and R ¹ is C _{1. -10} alkyl group, C _2-10 alkenyl group, C _2-10 alkynyl group, C _1-10 alkyl group substituted with 1 or 2 aryl groups, hydroxy C _2-10 alkyl group, halogenated C _{1- 10} alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4- A morpholinyl C _1-10 alkyl group, represented by the formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). is a C _1-10 alkyl group substituted by a group, according to claim 2 wherein 2-amino - bicyclo [3.1.0] hexane 2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or an active ingredient hydrate thereof, prophylactic or therapeutic agent for depression. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —SR ³ (wherein R ³ has the same meaning as described above), and R ¹ is represented by the formula — CHR ^c OC (O) ZR ^d (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, and R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group, Represents an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, or an aryl group.), A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with one or two aryl groups, a hydroxy group C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl A C _1-10 alkyl group, a farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b , wherein R ^a and R ^b are the same or different and are a hydrogen atom or C ₁ is a C _1-10 alkyl group substituted by a group represented by) shows _-10 alkyl group, as claimed in claim 2 wherein 2-amino -. bi Black [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or an active ingredient hydrate thereof, prophylactic or therapeutic agent for depression. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —S (O) _n CHR ³ R ⁴ (wherein R ³ , R ⁴ and n are as defined above). And R ¹ has the formula —CHR ^c OC (O) ZR ^d (wherein Z represents an oxygen atom, nitrogen atom, sulfur atom or single bond, R ^c represents a hydrogen atom, C _{1 A -10} alkyl group, a C _2-10 alkenyl group, and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, and an aryl group. ]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, a C _1-10 alkyl group substituted with 1 or 2 aryl groups, a hydroxy C _2-10 alkyl group, Halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, A farnesyl group, a 4-morpholinyl C _1-10 alkyl group, a formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and represent a hydrogen atom or a C _1-10 alkyl group). The 2-amino-bicyclo [3. is a C _1-10 alkyl group substituted by a group represented by 1.0] A prophylactic or therapeutic agent for depression comprising a hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —NHCHR ³ R ⁴ (wherein R ³ and R ⁴ are as defined above), and R ¹ represents a 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, a C _1-10 alkyl group, C _{2; A -10} alkenyl group and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group and an aryl group.), A group represented by the formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} And R ⁴ and R ^{4 ′} have the same meanings as described above), and R ¹ represents a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or one or two aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (where R ^a and R ^b are the same or different, C _1-10 alkyl group substituted by a group represented by a hydrogen atom or a C _1-10 alkyl group.), claims A prophylactic or therapeutic agent for depression comprising the described 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient . In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —N (CHR ³ R ⁴ ) (CHR ^{3 ′} R ^{4 ′} ) (wherein R ³ , R ^{3 ′} , R ⁴ and R ^{4 ′} are as defined above, and R ¹ is represented by the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or 1 or 2 aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 A Kill group, a farnesyl group, 4-morpholinyl C _1-10 alkyl group, wherein ^{-C (O) NR a R b} ( wherein, R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-10 alkyl group 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, which is a C _1-10 alkyl group substituted by a group represented by: A prophylactic or therapeutic agent for depression comprising the pharmaceutically acceptable salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group A phenyl group substituted with 5 substituents), and R ¹ is of the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the above formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a naphthyl group, heteroaromatic) Or a naphthyl group substituted with 1 to 7 halogen atoms, and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, 1 or C _1-10 alkyl group substituted with two aryl groups, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein , R ^a and R ^b are identical or different, a group represented by a hydrogen atom or a C _1-10 alkyl group.) A substituted C _1-10 alkyl group I, according to claim 2 wherein 2-amino - bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivatives, salts their pharmaceutically acceptable or A prophylactic or therapeutic agent for depression comprising the hydrate as an active ingredient. In the above formula [II], R ² is a hydrogen atom, X is a fluorine atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a naphthyl group, heteroaromatic) Or a naphthyl group substituted with 1 to 7 halogen atoms), and R ¹ is represented by the formula —CHR ^c OC (O) ZR ^d (wherein Z is an oxygen atom, a nitrogen atom, Represents a sulfur atom or a single bond; R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group, or an aryl group; R ^d represents a C _1-10 alkyl group, C _2-10 alkenyl; Group represents an aryl group), a group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the above formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and represent a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or 1 or 2 aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _{1-1 0} alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein R ^a and R ^b are the same or different and are a hydrogen atom or C _1-10 alkyl The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, which is a C _1-10 alkyl group substituted by a group represented by: A prophylactic or therapeutic agent for depression, comprising a pharmaceutically acceptable salt or hydrate thereof as an active ingredient. In the above formula [II], R ² is a hydrogen atom, X is a fluorine atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and represent a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group A phenyl group substituted with 5 substituents), and R ¹ is of the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or 1 or 2 aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 Al Group, a farnesyl group, 4-morpholinyl C _1-10 alkyl group, wherein ^{-C (O) NR a R b} ( wherein, R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-10 alkyl group 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, which is a C _1-10 alkyl group substituted by a group represented by: A prophylactic or therapeutic agent for depression comprising the pharmaceutically acceptable salt or hydrate thereof as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group A phenyl group substituted with 5 substituents), and R ¹ is of the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the above formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a hydrogen atom, R ⁴ is a naphthyl group, heteroaromatic) Or a naphthyl group substituted with 1 to 7 halogen atoms, and R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, 1 or C _1-10 alkyl group substituted with two aryl groups, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 alkyl group, farnesyl group, 4-morpholinyl C _1-10 alkyl group, formula —C (O) NR ^a R ^b (wherein , R ^a and R ^b are identical or different, a group represented by a hydrogen atom or a C _1-10 alkyl group.) Is a C _1-10 alkyl group substituted Te, 2-amino of claim 2, wherein - bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivatives, salts their pharmaceutically acceptable or A prophylactic or therapeutic agent for depression comprising hydrate as an active ingredient. In the formula [II], R ² is a hydrogen atom, X is a hydrogen atom, Y is —OCHR ³ R ⁴ (wherein R ³ is a C _1-10 alkyl group, and R ⁴ is a naphthyl group. And R ¹ is represented by the formula —CHR ^c OC (O) ZR ^d (wherein Z represents an oxygen atom, a nitrogen atom, a sulfur atom or a single bond, and R ^c represents a hydrogen atom, C _{A 1-10} alkyl group, a C _2-10 alkenyl group, and an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group, and an aryl group. i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component. In the above formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and represent a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group And R ¹ is a C _1-10 alkyl group, a C _2-10 alkenyl group, a C _2-10 alkynyl group, or 1 or 2 aryl groups. C _1-10 alkyl group, hydroxy C _2-10 alkyl group, halogenated C _1-10 alkyl group, azido C _1-10 alkyl group, amino C _2-10 alkyl group, C _1-10 alkoxy C substituted with _1-10 alkyl group, C _1-10 alkoxycarbonyl C _1-10 Alkyl group, a farnesyl group, 4-morpholinyl C _1-10 alkyl group, wherein ^{-C (O) NR a R b} ( wherein, R ^a and R ^b are the same or different and each represents a hydrogen atom or a C _1-10 alkyl group 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative according to claim 2, which is a C _1-10 alkyl group substituted by a group represented by: A prophylactic or therapeutic agent for depression comprising the pharmaceutically acceptable salt or hydrate thereof as an active ingredient. In the above formula [II], R ² is a hydrogen atom, X is a hydrogen atom, and Y is —OCHR ³ R ⁴ (wherein R ³ and R ⁴ are the same or different and represent a phenyl group or a halogen atom) 1 to 5 selected from the group consisting of an atom, phenyl group, C _1-10 alkyl group, C _1-10 alkoxy group, trifluoromethyl group, phenyl group, hydroxycarbonyl group, amino group, nitro group, cyano group and phenoxy group A phenyl group substituted with 5 substituents), and R ¹ is of the formula —CHR ^c OC (O) ZR ^d , wherein Z is an oxygen atom, nitrogen atom, sulfur atom or single bond R ^c represents a hydrogen atom, a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group, and R ^d represents a C _1-10 alkyl group, a C _2-10 alkenyl group or an aryl group. A group represented by formula [i]

Wherein R ^d is as defined above, or a group represented by formula [ii]

The 2-amino-bicyclo [3.1.0] hexane-2,6-dicarboxylic acid ester derivative, pharmaceutically acceptable salt or hydrate thereof according to claim 2, which is a group represented by the formula: A preventive or therapeutic agent for depression as a component.

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