JP2002201168A - Cyclohexane derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new compound which exhibits a VLA-4 antagonist action in an excellent dynamic state in a living body or its salt, and to provide a medicine containing the compound as an active ingredient. SOLUTION: A cyclohexane derivative represented by the general formula (I) (R1 and R2 are each H, an alkyl, or the like; X is O, NH or the like; A is CO or SO2; R3 is a hydrocarbon group, a heterogeneous aryl group, a heterogeneous arylalkyl group, or the like; R4 is a hydrocarbon group, a heterogeneous aryl group, a heterogeneous arylalkyl group, a pyrrolidine ring-containing group, or the like) or its salt, and a medicine or VLA-4 antagonist containing the cyclohexane derivative or its salt as an active ingredient, are provided.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel cyclohexane derivative or a salt thereof, an intermediate for producing the same, a medicament containing them as an active ingredient, and VLA-
4 antagonists.

[0002]

2. Description of the Related Art The adhesion phenomenon is indispensable for complex life phenomena caused by cell-cell interactions such as cell activation, migration, proliferation and differentiation. Such cell-cell or cell-extracellular matrix interactions involve cell adhesion molecules classified as integrins, immunoglobulins, selectins, cadherins, and the like.
Integrins have an αβ-heterodimer structure and have 3
It is divided into subfamilies of major groups β1, β2 and β3 of species.

[0003] β1 integrin is also called VLA protein, one of which is VLA-4 (α4β1).
Expressed on lymphocytes, eosinophils, basophils, monocytes, VCAM
-1 and fibronectin are ligands. That is,
VLA-4 plays an important role in cell-cell and cell-extracellular matrix interactions via VCAM-1 and fibronectin. In order for leukocytes to function in inflamed tissue, leukocytes circulating in the blood must pass through vascular endothelial cells and infiltrate the site of inflammation.

[0004] The binding between VLA-4 and VCAM-1 is one of the most important mechanisms for strong adhesion between leukocytes and vascular endothelium. Inflammatory cells such as T lymphocytes, B lymphocytes, monocytes and eosinophils express VLA-4, and the VLA-4 / VCAM-1 mechanism is strongly involved in the invasion of these cells into inflammatory foci. I have. Adhesion molecules also play an important role in cell activation through cell-cell interaction, and VCAM-
It has been shown that the 1 / VLA-4 mechanism activates eosinophils and causes degranulation, and that signals mediated by VLA-4 are also involved in antigen-specific proliferation activation of lymphocytes. I have.

[0005] VCAM-1 / VLA- in inflammation and the like
In order to elucidate the roles of the four mechanisms, attempts have been made to inhibit the binding between these molecules by monoclonal antibodies. For example, anti-VLA-4 monoclonal antibodies inhibit adhesion of VLA-4 expressing Ramos cells to human umbilical vein vascular endothelial cells (HUVEC) and VCAM-1 transgenic COS cells.

[0006] Antibodies have been shown to be effective in both treatment and prevention in several animal models. For example, a rat adjuvant arthritis model (Barbadillo et al., Ar
thrRheuma., 1993, 36, 95), contact hypersensitivity, delayed hypersensitivity model (Ferguson and Kupper, J. Immunol., 1993,
150, 1172; Chisholm et al., Eur. J. Immunol., 199
3, 23, 682) showed a significant effect. Experimental autoimmune encephalomyelitis (Yednock, Nature, 1992, 356, 63), asthma model (Abraham et al., J. Clin. Invest., 1993, 9
3, 776), an inflammatory bowel disease (IBD) model (Podolsky et al.)
al., J. Clin. Invest., 1993, 92, 372) also evaluated the effect of the antibody.

In addition, cell adhesion by VLA-4 plays a role in rheumatoid arthritis, nephritis, diabetes, systemic lupus erythematosus, late-onset allergy, multiple sclerosis, arteriosclerosis, organ transplantation and various malignancies. It was shown to fulfill. Therefore, VLA-4 blockade by a suitable antagonist is effective for treating the above-mentioned various diseases including inflammatory diseases.

[0008] Peptides and peptide-like compounds have been proposed as VLA-4 antagonists, but all of these compounds have problems such as lack of bioavailability upon oral administration and easy degradability in vivo. Dots are left. Therefore, there is a need for a VLA-4 antagonist having a favorable profile for use in therapy and prophylaxis.

[0009]

DISCLOSURE OF THE INVENTION The present invention has been made in view of the treatment and prevention of such a disease mediated by VLA-4, and an object of the present invention is to improve the dynamics in vivo. It is an object of the present invention to provide a novel compound having a VLA-4 antagonistic activity or a salt thereof, and a medicament containing these as an active ingredient. Further another aspect of the present invention
One object is to provide useful intermediates for the production of compounds that exhibit VLA-4 antagonistic activity.

[0010]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve these problems, and as a result, have found that a cyclohexane derivative having a specific structure has an excellent VLA-4 antagonistic action. The present invention has been completed based on the findings.

That is, the present invention relates to (1) a compound represented by the general formula (I)

[0012]

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Wherein R ¹ and R ² each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
X represents an oxygen atom or —NR ⁵ — (where R ⁵ has the same meaning as R ¹ ), and A represents —CO.
— Or —SO ₂ —, wherein R ³ is a monovalent hydrocarbon group having 1 to 11 carbon atoms, a heteroaryl group having 6 to 10 carbon atoms, a heteroarylalkyl group having 7 to 11 carbon atoms, or —NR.
⁶ R ⁷ (wherein, R ⁶ and R ⁷ are each independently a hydrogen atom, a monovalent hydrocarbon group having 1 to 11 carbon atoms,
0 represents a heteroaryl group or a heteroarylalkyl group having 7 to 11 carbon atoms. Wherein R ⁴ has 1 to 1 carbon atoms.
11, a monovalent hydrocarbon group, a C6-10 heteroaryl group, a C7-11 heteroarylalkyl group or a general formula (a)

[0014]

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(Wherein E represents a carbonyl group, a sulfonyl group or a single bond, and G is a monovalent hydrocarbon group having 1 to 11 carbon atoms which may be bonded to E via one oxygen atom.) A heteroaryl group having 6 to 10 carbon atoms or 7 carbon atoms
Represents a heteroarylalkyl group of 1 to 11, R ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, D represents O,
S or -CH ₂ - represents, m and n are 1, respectively
Represents an integer of 3. ), And the dashed line represents saturated or unsaturated. Or a salt thereof (hereinafter referred to as cyclohexane derivative I), (2) a general formula (II)

[0016]

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(In the formula, Z represents a hydroxyl group or an amino group which may be protected, and R ⁹ and R ¹⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, 7 represents a cycloalkyl group, an arylalkyl group having 7 to 11 carbon atoms, or a protecting group, and a broken line represents saturation or unsaturation.) Or a salt thereof (hereinafter, referred to as cyclohexane derivative II). ,
(3) a medicament containing the cyclohexane derivative of (1) or a salt thereof as an active ingredient; and (4) a VLA-4 antagonist containing the cyclohexane derivative of (1) or a salt thereof as an active ingredient. It is.

[0018]

DETAILED DESCRIPTION OF THE INVENTION The cyclohexane derivative I of the present invention
Is represented by the general formula (I)

[0019]

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A cyclohexane derivative having a structure represented by the following formula or a salt thereof.

In the general formula (I), R ¹ and R ²
Are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, or 7 carbon atoms.
To 11 arylalkyl groups. X represents an oxygen atom or —NR ⁵ — (wherein R ⁵ has the same meaning as R ¹ above), and A represents —CO— or —SO ₂ —.

R ³ is a monovalent hydrocarbon group having 1 to 11 carbon atoms, a heteroaryl group having 6 to 10 carbon atoms,
1 heteroarylalkyl group or —NR ⁶ R ⁷ (wherein, R ⁶ and R ⁷ are each independently a hydrogen atom, a monovalent hydrocarbon group having 1 to 11 carbon atoms, a heteroatom having 6 to 10 carbon atoms) An aryl group or a heteroarylalkyl group having 7 to 11 carbon atoms). Here, the carbon number 1 to 1
Examples of the monovalent hydrocarbon group include an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a
Preferred are an aryl group having 0 and an arylalkyl group having 7 to 11 carbon atoms.

R ⁴ is a monovalent hydrocarbon group having 1 to 11 carbon atoms, a heteroaryl group having 6 to 10 carbon atoms, and 7 to 1 carbon atoms.
A heteroarylalkyl group of the general formula (a):

[0024]

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Wherein E represents a carbonyl group, a sulfonyl group or a single bond, and G represents a monovalent hydrocarbon group having 1 to 11 carbon atoms which may be bonded to E via one oxygen atom. A heteroaryl group having 6 to 10 carbon atoms or 7 carbon atoms
Represents a heteroarylalkyl group of 1 to 11, R ⁸ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, D represents O,
S or -CH ₂ - represents, m and n are 1, respectively
Represents an integer of 3. ) Represents a group represented by Here, examples of the monovalent hydrocarbon group having 1 to 11 carbon atoms include the same as those exemplified in the description of the monovalent hydrocarbon group having 1 to 11 carbon atoms in R ³ . In the group represented by the general formula (a), a monovalent hydrocarbon group having 1 to 11 carbon atoms and a heterocyclic group having 6 to 10 carbon atoms, which bond to E via one oxygen atom of G. Examples of the aryl group or the heteroarylalkyl group having 7 to 11 carbon atoms include an alkoxyl group having 1 to 6 carbon atoms, a cycloalkyloxy group having 3 to 7 carbon atoms, an aryloxy group having 6 to 10 carbon atoms, and a carbon number. 7 to 11 arylalkoxyl group, 6 to 10 carbon atoms heteroaryloxy group or 7 to 7 carbon atoms
And 11 heteroarylalkoxyl groups. Dashed lines represent saturation or unsaturation.

On the other hand, the cyclohexane derivative II of the present invention
Is the general formula (II)

[0027]

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A cyclohexane derivative having a structure represented by the following formula or a salt thereof.

In the general formula (II), Z represents a hydroxyl group or an amino group which may be protected. R ⁹ and R ¹⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, or a protecting group. Dashed lines represent saturation or unsaturation.

Next, the general formula (I) and the general formula (I
Each substituent in I) will be described. "C1-C1
Specific examples of the “alkyl group 6” include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group,
Examples thereof include a linear or branched alkyl group such as an isobutyl group, a tert-butyl group, a sec-butyl group, an n-pentyl group, a tert-amyl group, a 3-methylbutyl group, a neopentyl group, and an n-hexyl group.

Specific examples of the "cycloalkyl group having 3 to 7 carbon atoms" include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group.

The "aryl group having 6 to 10 carbon atoms" refers to an unsubstituted or 1 to 4 substituted monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Phenyl, p-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 1-naphthyl, 2-naphthyl, 2,6-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dimethoxyphenyl And a 5-methoxybenzo [1,3] dioxoloryl group.

Examples of the substituent include an alkyl group having 1 to 6 carbon atoms.
Kill group, alkoxyl group having 1 to 6 carbon atoms, halogen source
Child, nitro group, cyano group, hydroxyl group, trifluoromethyl
Group, aryloxy group having 6 to 10 carbon atoms, 1 to 4 carbon atoms
Alkylsulfonyl group, aryls having 6 to 10 carbon atoms
Rufonyl group, -NR¹¹R¹², -CONR¹¹R¹², -SO
_Two NR¹¹R¹²(Where R¹¹, R¹²Are each independently
Hydrogen atom, alkyl group having 1 to 6 carbon atoms, 3 to 7 carbon atoms
Cycloalkyl group, aryl group having 6 to 10 carbon atoms, carbon
A heteroaryl group having 6 to 10 carbon atoms, an ant having 7 to 11 carbon atoms
Alkyl group, heteroarylalkyl having 7 to 11 carbon atoms
Represents a kill group. ) Or two adjacent substituents are
Together form a 3- to 7-membered carbocyclic or heterocyclic ring,
The heterocyclic ring is one or two selected from N, O or S
Containing a hetero atom.

The “C 6-10 aryloxy group” refers to an unsubstituted or 1-3-substituted C 6-10 aryloxy group.
Represents a monocyclic or bicyclic aromatic hydrocarbonoxy group of
Specific examples include a phenoxy group, an o-tolyloxy group,
2-methoxyphenoxy group, 3-chlorophenoxy group,
Examples thereof include a 2,6-dichlorophenoxy group, a 3,5-dichlorophenoxy group, a 1-naphthyloxy group, and a 2-naphthyloxy group. Examples of the substituent include those having 1 to 1 carbon atoms.
Examples thereof include an alkyl group having 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms.

"Arylalkyl group having 7 to 11 carbon atoms"
Is an unsubstituted or 1 to 3 substituted carbon number of 7 to 1
Represents one monocyclic or bicyclic araliphatic hydrocarbon group,
Specific examples include a benzyl group, a phenethyl group, a 3-hydroxyphenylmethyl group, a 1-phenylethyl group,
Phenylpropyl group, 3-phenylpropyl group, 2,6
-Dichlorophenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group, 1- (1-naphthyl) ethyl group and the like. Examples of the substituent include those having 1 carbon atom.
And alkyl groups having 6 to 6 carbon atoms, alkoxyl groups having 1 to 6 carbon atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, trifluoromethyl groups, and aryloxy groups having 6 to 10 carbon atoms.

The "arylalkoxy group having 7 to 11 carbon atoms" refers to an unsubstituted or 1 to 3 substituted arylalkoxy group.
To 11 monocyclic or bicyclic aromatic hydrocarbon alkoxyl groups, specific examples of which include a benzyloxy group, a phenethyloxy group, a 1-phenylethoxy group, a 1-phenylpropoxy group, a 3-phenylpropoxy group, 2,6-
Examples thereof include a dichlorophenylpropoxy group, a 1-naphthylmethoxy group, and a 2-naphthylmethoxy group. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms and 1 to 6 carbon atoms.
6, an alkoxyl group, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms.

The "heteroaryl group having 6 to 10 carbon atoms" refers to 1 to 3 carbon atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in an unsubstituted or 1 to 4 substituted ring.
Represents a 5- to 7-membered heterocyclic aromatic group containing two heteroatoms, and specific examples thereof include a furyl group, a pyrrolyl group, a thienyl group, an imidazolyl group, a thiazolyl group, an oxazolyl group,
Isoxazolyl group, pyridinyl group, pyrazinyl group, pyrimidinyl group, 1,3,5-triazinyl group, 3-methylthienyl group, 4-methoxypyridinyl group, 2-chloropyridin-3-yl group, 6-chloropyridine- 4-yl group, 6-chloropyrimidin-4-yl group, 2,6-dichloro-4-pyridyl group, 3,5-dichloro-4-pyridyl group, 2,4-dichloro-3-pyridyl group, 4,6- Dimethoxy-1,3,5-triazinyl group, 4-methoxy-6
-Propylamino-1,3,5-triazinyl group, 4,6
-Dipropyloxy-1,3,5-triazinyl group, 6-
Propylthiopyrimidin-4-yl group, 6-propylsulfonylpyrimidin-4-yl group, 6-propylsulfinylpyrimidin-4-yl group, 6-methoxy-2-methylsulfonylpyrimidin-4-yl group, 4-acetyl
-1,2,5-trimethyl-3-pyrrolyl group, 4-acetyl-3,5-dimethyl-2-pyrrolyl group, 4-acetyl-
2,5-dimethyl-3-pyrrolyl group, 1-methyl-2-
Indolyl group, 2- (4-chlorophenyl) -3- (trifluoromethyl) -4-pyrazolyl group, 2-phenyl-4-thiazolyl group, 2-phenoxy-3-pyridyl group, 2-acetyl-3-thienyl group , 4-quinolinyl group, and the like. Examples of the substituent include those having 1 carbon atom.
-C6 alkyl group, C1-C6 alkoxyl group, halogen atom, nitro group, cyano group, hydroxyl group, acetyl group, trifluoromethyl group, C6-C10 aryloxy group, C1-C4 Alkylthio group, having 1 to 1 carbon atoms
4, an alkylsulfonyl group having 4 to 4 carbon atoms, an arylsulfonyl group having 6 to 10 carbon atoms, an arylalkylthio group having 7 to 11 carbon atoms, a heteroarylalkylthio group having 7 to 11 carbon atoms, -NR ¹¹ R
¹² , -CONR ¹¹ R ¹² , -SO ₂ NR ¹¹ R ¹² (wherein R
¹¹ and R ¹² each independently represent a hydrogen atom, a carbon number of 1 to 6;
An alkyl group, a cycloalkyl group having 3 to 7 carbon atoms, an aryl group having 6 to 10 carbon atoms, a heteroaryl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 11 carbon atoms, and a heteroalkyl having 7 to 11 carbon atoms Represents an arylalkyl group. Or two adjacent substituents together form a 3- to 7-membered carbocyclic or heterocyclic ring, wherein the heterocyclic ring has 1 to 2 heteroatoms selected from N, O or S. Groups to be contained.

The term "heteroarylalkyl group having 7 to 11 carbon atoms" refers to a group in which 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom are present in an unsubstituted or 1 to 3 substituted ring. A 5- to 7-membered heterocyclic araliphatic group including, for example, a pyridinylmethyl group, 3
-Thienylpropyl group, 2-imidazolylethyl group and the like. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms. And the like.

The "heteroarylalkoxy group having 7 to 11 carbon atoms" means one or three hetero atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in an unsubstituted or 1 to 3 substituted ring. Represents a functional group to which a 5- to 7-membered heterocyclic araliphatic group is bonded via one oxygen atom, and specific examples thereof include a pyridinylmethoxy group, a 3-thienylpropyloxy group, and a 2-imidazolylethoxy group. And the like. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms. And the like.

The "heteroarylalkylthio group having 7 to 11 carbon atoms" is a group in which 1 to 3 hetero atoms selected from a nitrogen atom, an oxygen atom or a sulfur atom are present in an unsubstituted or 1 to 3 substituted ring. And a 5- to 7-membered heterocyclic araliphatic group represents a functional group bonded through one sulfur atom, and specific examples thereof include a 3-pyridinylmethylthio group,
-Thienylmethylthio group, 2-imidazolylethylthio group, 4-chloro-2-pyridylmethylthio group and the like. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms. And the like.

The term "carbocycle" refers to a saturated, partially unsaturated or aromatic stable 3- to 7-membered monocyclic or bicyclic ring. Specific examples thereof include a cyclopentene ring, a cyclohexene ring and a benzene ring. Examples include, but are not limited to, rings.

The term "heterocycle" refers to a saturated, partially unsaturated or aromatic stable 3- to 7-membered monocyclic or bicyclic ring, which independently represents N, O and S
Consisting of 1-3 heteroatoms selected from the group consisting of: wherein the nitrogen and sulfur heteroatoms are optionally oxidized;
Nitrogen is optionally quaternized. As a specific example,
Dioxolol ring, oxathiol ring, dihydrooxathiin ring, dihydrodioxin ring, dihydrofuran ring,
Examples include, but are not limited to, dihydrothiophene rings, dihydropyrrole rings, furan rings, thiophene rings, pyrrole rings, oxazole rings, thiazole rings, pyridine rings, and the like.

Specific examples of the "halogen atom" include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
Specific examples of "alkoxyl group having 1 to 6 carbon atoms" include:
Methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert
Linear or branched alkoxyl groups such as -butoxy group, sec-butoxy group, n-pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group and n-hexyloxy group.

The “arylsulfonyl group having 6 to 10 carbon atoms” refers to an unsubstituted or 1 to 3 substituted arylsulfonyl group.
Represents a functional group in which 10 to 10 monocyclic or bicyclic aromatic hydrocarbon groups are bonded via one sulfonyl, and specific examples include a phenylsulfonyl group, an o-toluenesulfonyl group, and a 2-methoxyphenylsulfonyl group , 3-chlorophenylsulfonyl, 2,6-dichlorophenylsulfonyl, 3,5-dichlorophenylsulfonyl, 1-
Examples include a naphthylsulfonyl group and a 2-naphthylsulfonyl group. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms. And the like.

Specific examples of the "alkylthio group having 1 to 4 carbon atoms" include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, s
Examples thereof include linear or branched alkylthio groups such as an ec-butylthio group and a tert-butylthio group. Specific examples of the "alkylsulfonyl group having 1 to 4 carbon atoms" include:
Methanesulfonyl group, ethanesulfonyl group, n-propylsulfonyl group, isopropylsulfonyl group, n-butylsulfonyl group, sec-butylsulfonyl group, ter
Examples thereof include a linear or branched alkylsulfonyl group such as a t-butylsulfonyl group.

Specific examples of "alkylsulfinyl group having 1 to 4 carbon atoms" include methanesulfinyl group, ethanesulfinyl group, n-propylsulfinyl group, isopropylsulfinyl group, n-butylsulfinyl group, s
Examples thereof include linear or branched alkylsulfinyl groups such as an ec-butylsulfinyl group and a tert-butylsulfinyl group.

The "C7-C11 arylalkylthio group" is an unsubstituted or 1-3-substituted C7-C7 arylalkylthio group.
1 to 11 monocyclic or bicyclic araliphatic hydrocarbon groups are 1
Represents a functional group bonded through two sulfur atoms, and specific examples thereof include a benzylthio group, a 4-methylbenzylthio group,
-Chlorobenzylthio, phenethylthio, 1-phenylpropylthio, 2,6-dichlorophenylpropylthio, 1-naphthylmethylthio, 2-naphthylmethylthio, and the like. Examples of the substituent include an alkyl group having 1 to 6 carbon atoms, an alkoxyl group having 1 to 6 carbon atoms, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a trifluoromethyl group, and an aryloxy group having 6 to 10 carbon atoms. And the like.

Specific examples of the “protecting group” include tert-
Butoxycarbonyl group, benzyloxycarbonyl group,
o-methylbenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, o-chlorobenzyloxycarbonyl group, 2,4-dichlorobenzyloxycarbonyl group, p
-Bromobenzyloxycarbonyl group, allyloxycarbonyl group and the like.

In the compounds of the present invention represented by the general formulas (I) and (II), when an asymmetric carbon is present, any of racemic, diastereoisomeric and individual optically active isomers may be used. Are included in the present invention, and when a geometric isomer exists, any of the (E) -form, the (Z) -form and a mixture thereof are also included in the present invention.

The salts of the compounds of the present invention represented by the general formulas (I) and (II) are not particularly limited as long as they are pharmacologically acceptable salts. ,
Salts with organic bases, salts with organic acids, salts with inorganic acids, salts with amino acids and the like are included. Examples of the salt with an inorganic base include an alkali metal salt such as a lithium salt, a sodium salt, a potassium salt, a calcium salt, and a magnesium salt, and an alkaline earth metal salt. Examples of the salt with an organic base include a triethylamine salt, a pyridine salt, an ethanolamine salt, a cyclohexylamine salt, a dicyclohexylamine salt, a dibenzylethanolamine salt and the like. Examples of salts with organic acids include formate, acetate, tartrate, maleate, succinate, lactate, malate, ascorbate, oxalate, glycolate, phenylacetate, Methane sulfonate and the like can be mentioned. Examples of salts with inorganic acids include hydrochloride, hydrobromide, phosphate, sulfamate, nitrate and the like. Examples of salts with amino acids include glycine salts, alanine salts, arginine salts, glutamates, aspartates and the like.

The compounds of the present invention represented by the general formula (I) may be in the form of a prodrug. By "prodrug" is meant a covalent compound that releases the active parent drug of general formula (I) in vivo when the prodrug is administered to a mammalian patient. Prodrugs of the compounds of general formula (I) are prepared by modifying the present compounds in a manner such that the modifying group becomes the parent compound in routine operation or in vivo. Prodrugs are modified by any group in which the carboxyl group, amino group or hydroxyl group of the compound of general formula (I) is decomposed in vivo to give a free carboxyl group, amino group or hydroxyl group when administered. Including the compounds described above. Examples of prodrugs include methyl ester, ethyl ester, aminoalkyl ester derivatives of carboxyl groups of compounds of general formula (I), acetate, formate and benzoate derivatives of alcohol and amine functions of compounds of general formula (I) And the like, but are not limited thereto.

Examples of the cyclohexane derivative represented by the general formula (I) of the present invention include, but are not limited to, compounds shown in Tables 1 to 11.

[0053]

[Table 1]

[0054]

[Table 2]

[0055]

[Table 3]

[0056]

[Table 4]

[0057]

[Table 5]

[0058]

[Table 6]

[0059]

[Table 7]

[0060]

[Table 8]

[0061]

[Table 9]

[0062]

[Table 10]

[0063]

[Table 11]

Next, the compound represented by the general formula (I) which is the cyclohexane derivative I of the present invention and the compound represented by the general formula (II) which is the cyclohexane derivative II of the present invention are represented by the following three types. Can be efficiently manufactured by the manufacturing method of

Production Method 1 In this production method 1, the compound represented by the general formula (Ib) can be produced by the reaction in the following steps 1 and 2.

[0066]

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(Wherein, R ³ , R ⁴ , X and A have the same meaning as described above, and R ¹³ is an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, 11 represents an arylalkyl group or a protecting group, and J represents a halogen atom or a hydroxyl group.)

<Step 1> In step 1, compound (II)
The compound represented by the general formula (Ia) is produced by condensing the compound (IV) with Ia) or a salt thereof. In the condensation reaction, when J of the compound (IV) is an acid halide having a halogen atom, the reaction is carried out in the presence of an organic base such as triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, collidine or lutidine. . The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane and the like are preferable. The reaction temperature is not particularly limited, and is usually 0 to 10
The reaction is performed at 0 ° C., and the reaction time is preferably 2 to 24 hours.

When J of compound (IV) is a hydroxyl group,
This is accomplished using any of a number of methods for forming amide bonds known to those skilled in the art of organic synthesis. Standard coupling methods such as the azide method, the mixed carboxylic anhydride (isobutyl chloroformate) method, the carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide or water-soluble carbodiimide) method,
Active ester (p-nitrophenyl ester, N-hydroxysuccinimide ester) methods, carbonyl diimidazole method, use of phosphorus reagents such as, but not limited to, BOP-Cl. Some of these methods (particularly the carbodiimide method) are facilitated by adding 1-hydroxybenzotriazole and / or 4-dimethylaminopyridine. As the reaction solvent,
Although it is not particularly limited as long as it does not significantly inhibit the reaction, chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane, dimethylformamide, dimethylsulfoxide and the like are preferable. The reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C., and the reaction time is 2 to
24 hours is preferred.

<Step 2> In step 2, the compound (Ia) obtained in step 1 is hydrolyzed under alkaline conditions to produce a compound represented by the general formula (Ib). A known method may be used for the hydrolysis treatment under the alkaline condition, and examples of the aqueous alkaline solution include lithium hydroxide, sodium hydroxide, and potassium hydroxide. The reaction solvent is not particularly limited as long as it is an organic solvent miscible with water, but is preferably methanol, ethanol, tetrahydrofuran, dimethoxyethane, or a mixed solvent thereof. The reaction temperature is usually from 0 to 70 ° C, and the reaction time is preferably from 1 to 24 hours. The compound (IIIa) can be produced by the steps a and b as shown below.

[0071]

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(Wherein, R ³ , R ¹³ and X have the same meaning as described above, R ¹⁴ represents a protecting group, Z ¹ represents a hydroxyl group or an amino group, and J ¹ represents a halogen atom.)

<Step a> In step a, compound (IIIb) is produced by reacting compound (V) with compound (IIa) or a salt thereof. This reaction is usually performed in the presence of an organic base. Suitable organic bases include triethylamine, diisopropylethylamine, N-methylmorpholine, 4-dimethylaminopyridine, collidine, lutidine and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane, pyridine and the like are preferable. The reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C, and the reaction time is preferably 2 to 24 hours.

<Step b> In the step b, the compound (IIIb) obtained in the step a is subjected to deprotection of an amino group under acidic conditions to produce a compound (IIIa). The deprotection under this acidic condition may be performed by a known method. Examples of the acid include trifluoroacetic acid, hydrochloric acid, hydrogen bromide, trimethylsilyl iodide and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction,
Chloroform, methylene chloride, tetrahydrofuran,
Preferred is 1,4-dioxane, ethyl acetate, acetic acid, or a mixed solvent thereof.

Production Method 2 In this production method 2, the compound represented by the general formula (IIb) and the compound represented by the general formula (IIc) can be produced by the reactions in the following steps 1 to 6. it can.

[0076]

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[Wherein, R ⁹ and R ¹⁰ have the same meaning as described above, and Me represents a methyl group (the same applies hereinafter)].

<Step 1> In step 1, compound (V
Reduction of I) gives compound (VII). This reduction reaction is generally called birch reduction, and is performed with an alkali metal or an alkaline earth metal in liquid ammonia in the presence or absence of an alcohol. When the raw material is hardly soluble, an auxiliary solvent may be added. Suitable alkali metals include lithium, sodium, potassium and the like, and alkaline earth metals include beryllium,
Magnesium, calcium and the like. Alcohols that can be used include ethanol, isopropanol, tert-butanol and the like. The auxiliary solvent is not particularly limited as long as it does not significantly inhibit the reaction, but is preferably tetrahydrofuran. The reaction temperature is not particularly limited, and the reaction is usually performed at -78 to -34 ° C, and the reaction time is preferably 1 to 6 hours.

<Step 2> In step 2, compound (VIII) is produced by hydrolyzing the enol ether portion of compound (VII) obtained in step 1. The hydrolysis reaction is not particularly limited as long as it can hydrolyze general enol ether moieties, but suitable conditions include use of an aqueous acetic acid solution. When the raw material is hardly soluble, an auxiliary solvent may be added. The auxiliary solvent is not particularly limited as long as it does not significantly inhibit the reaction, but tetrahydrofuran, 1,4-dioxane, dimethoxyethane, dimethylsulfoxide and the like are preferable. The reaction temperature is not particularly limited, and the reaction is usually performed at 0 to 100 ° C., and the reaction time is preferably 30 minutes to 6 hours.

<Step 3> In step 3, the carbonyl moiety of compound (VIII) obtained in step 2 is reduced with a reducing reagent to produce a compound represented by general formula (IIb). Examples of the reducing reagent include sodium borohydride, lithium borohydride, and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction,
Preference is given to methanol, ethanol, isopropanol and the like. The reaction temperature is not particularly limited, and is usually -10 to 30.
C., and the reaction time is preferably 30 minutes to 6 hours. When the raw material is hardly soluble, an auxiliary solvent may be added. The auxiliary solvent is not particularly limited as long as it does not significantly inhibit the reaction, and tetrahydrofuran,
Preferred are 1,4-dioxane, dimethoxyethane, chloroform, methylene chloride and the like.

<Step 4> In step 4, the double bond part of compound (IIb) obtained in step 3 is reduced to produce a compound represented by general formula (IIc). This reaction is performed in a hydrogen atmosphere in the presence of a catalyst. As a catalyst,
Examples include palladium reagents such as palladium-carbon, palladium hydroxide, palladium black, and palladium-barium sulfate; platinum reagents such as platinum oxide and platinum black; and nickel reagents such as Raney nickel.
The hydrogen pressure is not particularly limited, but is usually from normal pressure to 0.
The reaction is performed at 5 MPa, and the reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran and the like are preferable. The reaction temperature is not particularly limited, and the reaction is usually performed at 10 to 50 ° C., and the reaction time is preferably 30 minutes to 12 hours.

<Step 5> In step 5, the double bond of compound (VIII) is reduced in the same manner as in step 4.
Compound (IX) is produced.

<Step 6> In step 6, the carbonyl moiety of compound (IX) is reduced in the same manner as in step 3.
A compound represented by the general formula (IIc) is produced.

Production method 3 In this production method 3, the compounds represented by the general formula (IIe) and the general formula (IIf) are converted into the following steps 1 to 5:
Can be produced by the reaction in

[0085]

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(In the formula, R ⁹ , R ¹⁰ and J ¹ have the same meanings as described above, and R represents a methyl group, a phenyl group or a p-tolyl group.)

<Step 1> In step 1, compound (II)
b) is reacted with compound (X) to produce compound (IId). This reaction is usually performed in the presence of an organic base. Suitable organic bases include triethylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4-dimethylaminopyridine, collidine, lutidine and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but chloroform, methylene chloride, tetrahydrofuran, 1,4-dioxane, pyridine and the like are preferable. The reaction temperature is not particularly limited and is usually performed at 0 to 100 ° C., and the reaction time is 2
~ 24 hours are preferred.

<Step 2> In step 2, compound (XI) is produced by reacting compound (IId) obtained in step 1 with an azidating reagent. Examples of the azide reagent include lithium azide, sodium azide, potassium azide and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but dimethylformamide, dimethylsulfoxide, methanol,
Preference is given to ethanol, dimethoxyethane, diethylene glycol dimethyl ether, acetone, water or a mixture thereof. The reaction temperature is not particularly limited.
The reaction is performed at 25 to 120 ° C., and the reaction time is preferably 2 to 96 hours.

<Step 3> In step 3, the azide moiety of compound (XI) obtained in step 2 is reduced with a reducing reagent,
A compound represented by the general formula (IIe) is produced. Examples of the reducing reagent include triphenylphosphine-water, tributylphosphine-water, hydrogen-Lindler catalyst, hydrogen-palladium / barium sulfate / quinoline, and hydrogen-palladium /
Calcium carbonate / quinoline and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but includes methanol, ethanol, isopropanol, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, 1,4-dioxane, water or a mixed solvent thereof. preferable. The reaction temperature is not particularly limited and is usually performed at 10 to 80 ° C, and the reaction time is 30 minutes to
48 hours is preferred. In the reaction carried out under a hydrogen stream, the hydrogen pressure is not particularly limited, but is usually from normal pressure to 0.5 MPa.

<Step 4> In step 4, the compound represented by formula (IIf) is produced by subjecting compound (XI) obtained in step 2 to a usual catalytic reduction reaction. That is, in the presence of a catalyst, carried out in a hydrogen atmosphere, as a catalyst, palladium-carbon, palladium hydroxide, palladium black, palladium reagent such as palladium-barium sulfate, or platinum oxide, platinum reagent such as platinum black,
Alternatively, a nickel reagent such as Raney nickel is used. The hydrogen pressure is not particularly limited, but is usually from normal pressure to 0.5 MPa. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and may be methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran. Are preferred. The reaction temperature is not particularly limited, and the reaction is usually performed at 10 to 50 ° C, and the reaction time is 30.
Minutes to 12 hours are preferred.

<Step 5> In step 5, the double bond of compound (IIe) is reduced in the same manner as in step 4 to produce a compound represented by formula (IIf). The compound of the present invention produced by the above-mentioned method is isolated and purified as a free compound, a salt thereof, a hydrate thereof or various solvates such as ethanolate or a polymorphic substance. The pharmacologically acceptable salt of the compound of the present invention can be produced by a conventional salt formation reaction. Isolation and purification are performed by applying chemical operations such as extraction fractionation, crystallization, and various types of fractional chromatography. The optical isomer can be obtained as a stereochemically pure isomer by selecting an appropriate starting compound or by optical resolution of a racemic compound.

The cyclohexane derivative I of the present invention exhibits excellent VLA-4 antagonistic activity and is useful for the treatment or prevention of diseases caused by leukocyte adhesion and infiltration or diseases in which VLA-4 dependent adhesion process plays a role. It is useful as a medicine, for example, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, autoimmune diseases such as Sjogren's syndrome, and various organ inflammations associated therewith, asthma, atopic dermatitis, nasal congestion, rhinitis and the like. Allergic diseases, inflammatory bowel diseases including Crohn's disease, nephritis, hepatitis, inflammatory diseases of the central nervous system, cardiovascular diseases,
Examples include arteriosclerosis, diabetes, various malignant tumors, prevention of damage to transplanted organs, inhibition of tumor growth or metastasis, and the like.

The cyclohexane derivative I of the present invention can be used systemically or locally for oral, nasal, respiratory, pulmonary, ophthalmic,
It is administered by intravenous injection, subcutaneous injection, rectal administration and the like. The dosage form can be appropriately selected according to the administration route, for example, tablets, troches, sublingual tablets, dragees, capsules, pills, powders, granules, solutions, emulsions, syrups, eye drops, Nasal drops, inhalants, injections and the like. These formulations also include excipients, preservatives, wetting agents,
It can be produced by blending an emulsifier, a stabilizer, a solubilizing agent and the like.

The dose of the cyclohexane derivative I of the present invention may be appropriately determined depending on conditions such as the administration subject, administration route and symptoms. For example, when orally administered to an adult patient, the compound of the present invention as an active ingredient Is usually 0.1 to 100 mg / kg, preferably 1 to 30 mg / kg.
The dose may be in the range of mg / kg, and preferably 1 to 3 times a day.

[0095]

The present invention will be described below by way of specific examples.
The present invention is not limited to these. In addition, ¹ H
-NMR spectrum is tetramethylsilane (TMS)
Was measured using a JNM-EX270 type spectrum meter (270 MHz, manufactured by JEOL Ltd.)
The values are shown in ppm.

Example 1 4- [2 (S) -carboxy-2- (2,6-dichlorobenzoylamino) ethyl] 2,6-dichlorobenzoate
Of cyclohex-3-enyl ester (I-1)

[0097]

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(1) 2 (S) -tert-butoxycarbonylamino-3-
(4-Hydroxycyclohex-1-enyl) -propionic acid methyl ester (II-1) 2 (S) -tert-butoxycarbonylamino-3-
5.0 g of (4-methoxyphenyl) -propionic acid (1
6.9 mmol) in tert-butanol and tetrahydrofuran suspension (32 ml + 25 ml)
Ammonia gas (about 200 ml as a liquid) was blown in at. To this vigorously stirred mixture at -78 ° C was added a small portion of 540 mg (90 mmol) of lithium metal in several portions. After the addition of the metallic lithium, the mixture was further stirred for 30 minutes. Ammonium chloride was added to the deep blue reaction mixture until it became colorless, and ammonia was distilled off at room temperature and normal pressure. The remaining solvent is concentrated under reduced pressure, and the residue is
And weakly acidified with a 30% by weight aqueous solution of sodium dihydrogen phosphate, followed by extraction with chloroform three times. The extracts were combined, dried over magnesium sulfate and concentrated under reduced pressure.
The residue was treated with 60 ml of an 80% by weight aqueous acetic acid solution for 1 hour, and then concentrated under reduced pressure. The residue was diluted with 30 ml of xylene and concentrated under reduced pressure. This operation was repeated until the residue no longer had an acetic acid odor. The obtained residue was dissolved in 50 ml of ethanol, and 13.5 ml of a 2 mol / l hexane solution of trimethylsilyldiazomethane was added thereto.
7.0 mmol) were added dropwise. After stirring at room temperature for 1 hour, 1 ml of acetic acid was added and the mixture was further stirred for 30 minutes. After cooling this to 0 ° C., 640 mg of sodium borohydride (16.9)
mmol) and stirred for 30 minutes. After adding 20 ml of a saturated aqueous solution of ammonium chloride, the mixture was concentrated under reduced pressure until the volume became 1/3. The mixture was diluted with water, extracted with ethyl acetate, washed sequentially with water and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 5: 3 by weight) and 2 (S) -tert
4.1 g (81.0% yield) of -butoxycarbonylamino-3- (4-hydroxycyclohex-1-enyl) -propionic acid methyl ester (II-1) were obtained (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.426 (4.5 H, s), 1.
433 (4.5H, s), 1.50-2.52 (8H, m), 3.73 (1.5H, s), 3.75
(1.5H, s), 3.92 (1H, m), 4.40 (1H, m), 4.92 (0.5H,
m), 5.09 (0.5H, m), 5.39 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 300;

(2) 2,6-dichlorobenzoic acid 4- [2 (S) -tert-
Butoxycarbonylamino-2-methoxycarbonylethyl] -cyclohex-3-enyl ester (III-
1) 2 (S) -tert-butoxycarbonylamino-3- (4-hydroxycyclohex-1-) obtained in the above (1)
(Enyl) -propionic acid methyl ester (II-1) 7
55 mg (2.52 mmol) of anhydrous pyridine 2.0 m
The solution is added at 25 ° C. with 2,6-dichlorobenzoyl chloride 9
50 mg (4.55 mmol) was added, and the mixture was stirred at 90 ° C. for 90 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with a 1% by weight aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel developing solvent: ethyl acetate-chloroform-hexane = weight ratio 1: 2: 4).
-Dichlorobenzoic acid 4- [2 (S) -tert-butoxycarbonylamino-2-methoxycarbonylethyl]
-Cyclohex-3-enyl ester (III-1)
11 g (93.3 yield%) were obtained (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (DCl ₃ ) δ value: 1.42 (4.5 H, s), 1.44
(4.5H, s), 1.80-2.65 (8H, m), 3.66 (1.5H, s), 3.73
(1.5H, s), 4.40 (1H, m), 4.95 (1H, m), 5.35 (2H, m),
7.28 (3H, m). FAB-MS: Calculated M ⁺⁺ 1 474, 472; Found 474, 472.

(3) 2,6-dichlorobenzoic acid 4- [2 (S) -amino-2
-Methoxycarbonylethyl] -cyclohex-3-enyl ester trifluoroacetate (III-2) 4- [2,2-dichlorobenzoic acid obtained in the above (2)
(S) -tert-Butoxycarbonylamino-2-methoxycarbonylethyl] -cyclohex-3-enyl ester (III-1) in 0.degree. Acetic acid (1.2 ml) was added and the mixture was stirred for 90 minutes. After the reaction, the solvent was concentrated under reduced pressure, the residue was diluted with 6 ml of xylene, and then concentrated under reduced pressure. This operation was repeated until the odor of trifluoroacetic acid disappeared from the residue, and 2,6-dichlorobenzoic acid 4-
[2 (S) -amino-2-methoxycarbonylethyl]-
320 mg (100%) of cyclohex-3-enyl ester trifluoroacetate (III-2) were obtained. The physical properties are shown below. FAB-MS: Calculated M ⁺⁺ 1 374, 372; Found 374, 372.

(4) 4- [2 (S) -carboxy-2- (2,6-dichlorobenzoylamino) ethyl] 2,6-dichlorobenzoate
-Cyclohex-3-enyl ester (I-1) (Step 1) 4- [2 (S) -amino-2-methoxycarbonylethyl] -cyclohexyl 2,6-dichlorobenzoate prepared in (3) above. -3-enyl ester trifluoroacetate (III-2) 110 mg (0.2 mmol
l) in a solution of 2.0 ml of anhydrous methylene chloride at 25 ° C at 72 mg (0.71 mmol) of triethylamine and 68 mg (0.33 mm) of 2,6-dichlorobenzoyl chloride.
ol). After stirring at room temperature for 4 hours, 5 ml of a 1% by weight aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 1 hour to decompose excess acid chloride. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and a saturated saline solution,
After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = weight ratio 2: 3).
2,6-dichlorobenzoic acid 4- [2 (S)-(2,6-
Dichlorobenzoylamino) -2-methoxycarbonylethyl] -cyclohex-3-enyl ester 112
mg (100% yield) was obtained (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.80-2.72 (8H, m),
3.70 (1.5H, s), 3.77 (1.5H, s), 4.90 (1H, m), 5.35 (1
H, m), 5.47 (1H, bs), 6.25 (1H, m), 7.30 (6H, m). FAB-MS: Calculated M ⁺⁺ 1 548, 546, 544; Observed 548, 546,
544.

(Step 2) 2,6-dichlorobenzoic acid 4-
[2 (S)-(2,6-dichlorobenzoylamino)-
2-methoxycarbonylethyl] -cyclohex-3-
To 1.4 ml of a tetrahydrofuran solution of 78 mg (0.143 mmol) of the enyl ester was added 1 ml of a 1 mol / liter aqueous lithium hydroxide solution, and the mixture was stirred for 1 hour. After concentrating the reaction mixture, the mixture was diluted with 15 ml of water, and 1 mol / liter hydrochloric acid was added until the pH reached 2 with stirring. The resulting white solid was collected by filtration, washed with water, and dried in vacuo in the presence of phosphorus pentoxide to give the title compound, 44m
g (57.9% yield) (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.70-2.70 (8H,
m), 4.73 (1H, m), 5.23 (1H, m), 5.49 (1H, bs), 7.30 (6
H, m), 8.47 (1H, m), 12.40 (1H, m). FAB-MS: Calculated M ⁺⁺ 1 534, 532, 530; Found 534, 532,
530.

Example 2 2,6-Dichlorobenzoic acid 4- (2 (S) -carboxy-2-{[1- (3,5-dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino ｝
-Ethyl) -cyclohex-3-enyl ester (I-
2) Manufacturing

[0108]

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(Step 1) The compound prepared in Example 1 (3)
6-Dichlorobenzoic acid 4- [2 (S) -amino-2-methoxycarbonylethyl] -cyclohex-3-enyl ester trifluoroacetate (III-2) 110 mg
(0.2 mmol) of anhydrous dimethylformamide (DM
F) 100 mg (0.3 mmol) of 1- (3,5-dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carboxylic acid, 42 mg (0.3 mmol) of 1-hydroxybenzotriazole in a 2.0 ml solution at 0 ° C. , N-methylmorpholine 60 mg (0.59 mmol) and water-soluble carbodiimide 48 mg (0.3 mmol) were added. After stirring at room temperature for 14 hours, the reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed successively with 0.5 mol / liter hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is subjected to silica gel column chromatography (developing solvent: ethyl acetate-hexane = weight ratio 1: 1).
Purification by 2,4-dichlorobenzoic acid 4- (2
(S)-{[1- (3,5-dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino}
-2-methoxycarbonylethyl) -cyclohex-3
127 mg (91% yield) of the -enyl ester were obtained (diastereomeric ratio: about 1: 1) .The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.45-2.70 (12H, m),
3.13 (1H, m), 3.50 (1H, m), 3.73 (1.5H, s), 3.77 (1.5
H, s), 4.12 (1H, m), 4.66 (1H, m), 5.32 (1H, m), 5.44
(1H, bs), 7.11 (1H, m), 7.27 (3H, m), 7.61 (1H, d, J =
1.7), 7.74 (1H, d, J = 1.4). FAB-MS: Calculated M ⁺⁺ 1 681, 679, 677; Observed 681, 679,
677.

(Step 2) 2,6-dichlorobenzoic acid 4-
120 mg of (2 (S)-{[1- (3,5-dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino} -2-methoxycarbonylethyl) -cyclohex-3-enyl ester .177mmo
l) tetrahydrofuran solution At 0 ° C., 1.2 ml of a 1 mol / liter aqueous solution of lithium hydroxide was added to the resulting mixture, followed by stirring for 1 hour and 30 minutes. After concentrating the reaction mixture, the mixture was diluted with 15 ml of water, and 1 mol / liter hydrochloric acid was added until the pH reached 2 with stirring. The generated white solid was collected by filtration, washed with water, and dried under vacuum in the presence of phosphorus pentoxide to obtain 90 mg (76.5% yield) of the title compound (diastereomer ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-2.50 (12H,
m), 3.27 (2H, m), 4.30 (2H, m), 5.20 (1H, m), 5.42 (1
H, bs), 7.52 (3H, m), 7.84 (2H, m), 7.98 (1H, m), 8.1
2 (1H, m), 12.70 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 667, 665, 663; Found 667, 665,
663.

Example 3 2,6-Dichlorobenzoic acid 4- {2 (S) -carboxy-2-[(5-methoxybenzo [1,3] dioxolol-4-carbonyl) -amino] -ethyl} -cyclohexyl Production of Su-3-enyl Ester (I-3)

[0114]

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The title compound was synthesized in the same manner as in Example 1 (4). The physical properties are shown below. Diastereomer A: ¹ H-NMR (DMSO-d ₆ ) δ value: 1.70-
2.60 (8H, m), 3.67 (3H, s), 4.46 (1H, m), 5.20 (1H,
m), 5.44 (1H, bs), 5.98 (2H, s), 6.40 (1H, d, J = 8.6),
6.87 (1H, d, J = 8.6), 7.52 (3H, m), 8.28 (1H, d, J = 7.
6), 12.61 (1H, bs). FAB-MS: Calculated value M ⁺⁺ 1 538, 536; Actual value 538, 536.

Diastereomer B: ¹ H-NMR (DMSO-d ₆ )
δ value: 1.70-2.60 (8H, m), 3.77 (3H, s), 4.60 (1H, m),
5.28 (1H, m), 5.49 (1H, bs), 6.05 (2H, d, J = 3.3), 6.5
1 (1H, d, J = 8.6), 6.95 (1H, d, J = 8.6), 7.64 (3H, m),
8.34 (1H, d, J = 7.9), 12.70 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 538, 536; Found 538, 536.

Example 4 (2 (S) -2,6-dichlorobenzoylamino) -3
Production of-[4- (2,6-dichlorobenzoylamino) -cyclohex-1-enyl proionic acid (I-4)

[0118]

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(1) 3- (4-aminocyclohex-1-enyl) -2
(S) -tert-butoxycarbonylaminopropionic acid methyl ester (II-2) 2 (S) -tert-butoxycarbonylamino-3- (4-hydroxycyclohexyl) obtained in Example 1 (1)
1-enyl) -propionic acid methyl ester (II-
1) To a solution of 721 mg (2.41 mmol) in 6.0 ml of anhydrous methylene chloride at 25 ° C was added 419 mg of pyridine.
(5.30 mmol) and methanesulfonyl chloride 419m
g (3.61 mmol) was added and stirred for 12 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, a 1% by weight aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 2 (S)
-Tert-Butoxycarbonylamino-3- (4-methanesulfonyloxycyclohex-1-enyl) -propionic acid methyl ester was obtained. This was dissolved in 10 ml of dimethylformamide, and sodium azide 4
70 mg (7.23 mmol) was added, and the mixture was stirred at 65 ° C for 30 hours. The reaction mixture was diluted with ethyl acetate, washed successively with water, a 1% by weight aqueous sodium hydrogen carbonate solution and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, 3- (4-azidocyclohex-1-enyl)-
2 (S) -tert-butoxycarbonylaminopropionic acid methyl ester was obtained. After dissolving this in 10 ml of tetrahydrofuran, 1.04 g (4.00 mmol) of triphenylphosphine and 72 mg (4.0) of water were added.
0 mmol) and stirred at 25 ° C. for 12 hours. Next, 2 ml of aqueous ammonia was added, and the mixture was stirred at 25 ° C. for 1 hour and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (developing solvent: chloroform-methanol = weight ratio 10:
1 → 3: 1) to give 3- (4-aminocyclohex-1-enyl) -2 (S) -tert-butoxycarbonylaminopropionic acid methyl ester (II
-2) 434 mg (60.3% yield) were obtained. The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.43 (9H, s), 1.75-
2.56 (10H, m), 2.98 (1H, m), 3.73 (3H, s), 4.40 (1H,
m), 4.93 (1H, m), 5.40 (1H, bs).

(2) 2 (S) -amino-3- [4- (2,6-dichlorobenzoylamino) -cyclohex-1-enyl] -propionic acid methyl ester trifluoroacetate (III-
3) 3- (4-Aminocyclohex-1-yl) obtained in the above (1)
Enyl) -2 (S) -tert-butoxycarbonylaminopropionic acid methyl ester (II-2) 215 mg
(0.72 mmol) in a solution of 3.0 ml of anhydrous methylene chloride at 25 ° C at 162 mg of triethylamine (1.6 m
mol) and 2,6-dichlorobenzoyl chloride 241
mg (1.15 mmol) was added. After stirring at 25 ° C. for 3 hours, 5 ml of a 1% by weight aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 1 hour to decompose excess acid chloride. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline and dried over anhydrous magnesium sulfate.
After concentration under reduced pressure, methyl 2 (S) -tert-butoxycarbonylamino-3- [4- (2,6-dichlorobenzoylamino) -cyclohex-1-enyl] -propionate was obtained (physical properties). FAB-MS: calc M ⁺⁺ 1 473, 471; found 473, 471).

After dissolving this in 2.6 ml of chloroform,
At ℃, 1.8 ml of trifluoroacetic acid was added,
Stirred for minutes. After the reaction, the solvent was concentrated under reduced pressure, the residue was diluted with 6 ml of xylene, and then concentrated under reduced pressure. This operation is repeated until the odor of trifluoroacetic acid disappears from the residue, and 2 (S) -amino-3- [4- (2,6-dichlorobenzoylamino) -cyclohex-1-enyl] -propionic acid methyl ester is obtained. Trifluoroacetic acid salt (II
I-3) 240 mg (100%) were obtained. The physical properties are shown below. FAB-MS: calc M ⁺⁺ 1 373, 371; found 373, 371.

(3) 2 (S)-(2,6-dichlorobenzoylamino) -3
-[4- (2,6-Dichlorobenzoylamino) -cyclohex-1-enyl] -propionic acid (I-4) Using the compound (III-3) obtained in the above (2), Example 1 was carried out.
The title compound was synthesized in the same manner as in (4) (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-2.56 (8H,
m), 3.94 (1H, m), 4.58 (1H, m), 5.45 (1H, bs), 7.45 (6
H, m), 8.55 (1H, m), 8.90 (1H, m), 12.40 (1H, m). FAB-MS: Calculated M ⁺⁺ 1 533, 531, 531, 529;
529.

Example 5 2 (S)-{[1- (3,5-Dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino} -3- [4- (2,6-dichlorobenzoyl) Amino) -cyclohex-1-enyl] -propionic acid (I-
5) Manufacturing

[0126]

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Using the compound (III-3) obtained in Example 4 (2), the title compound was synthesized in the same manner as in Example 2. The physical properties are shown below. Diastereomer A: ¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-2.
60 (12H, m), 3.30 (2H, m), 3.95 (1H, m), 4.28 (1H, m),
4.35 (1H, m), 5.45 (1H, bs), 7.40 (3H, m), 7.83 (1H, m
d, J = 1.7), 8.00 (1H, t, J = 1.7), 8.14 (1H, d, J = 7.9),
8.49 (1H, d, J = 7.9), 12.68 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 666, 664, 662; Found 666, 664,
662.

Diastereomer B: ¹ H-NMR (DMSO-d ₆ ) δ
Value: 1.40-2.60 (12H, m), 3.30 (2H, m), 3.90 (1H, m),
4.30 (1H, t, J = 4.3), 4.38 (1H, m), 5.44 (1H, bs), 7.4
2 (3H, m), 7.84 (1H, d, J = 1.7), 8.00 (1H, t, J = 1.7),
8.10 (1H, d, J = 8.3), 8.50 (1H, d, J = 7.9), 12.62 (1H,
bs). FAB-MS: Calculated M ⁺⁺ 1 666, 664, 662; Found 666, 664,
662.

Example 6 2 (S)-(2,6-Dichlorobenzenesulfonylamino) -3- [4- (2,6-dichlorobenzoylamino) -cyclohex-1-enyl] -propionic acid (I-
6) Manufacturing

[0130]

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Using the compound (III-3) obtained in Example 4 (2), the title compound was synthesized in the same manner as in Example 1 (4). The physical properties are shown below. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-2.60 (8H, m), 3.92 (1H,
m), 4.60 (1H, m), 5.45 (1H, bs), 7.50 (6H, m), 8.55 (1
H, m), 8.90 (1H, m), 12.61 (1H, m). FAB-MS: Calculated M ⁺⁺ 1 567, 565; Found 567, 565.

Example 7 2 (S)-(2,6-dichlorobenzoylamino) -3
-{4-[(5-methoxybenzo [1,3] dioxolol-4-carbonyl) -amino] -cyclohex-1
Preparation of -enyl} -propionic acid (I-7)

[0133]

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(1) 2 (S) -tert-butoxycarbonylamino-3-
{4-[(5-methoxybenzo [1,3] dioxolol-4-carbonyl) -amino] -cyclohex-1-
Methyl enyl 塩 化 -propionate (III-4) A solution of 260 mg (1.33 mmol) of 5-methoxybenzo [1,3] dioxolol-4-carboxylic acid in 3.0 ml of anhydrous methylene chloride at 25 ° C. was treated with oxalyl chloride at 25 ° C.
2 mg (2.06 mmol) and dimethylformamide (1 drop) were added. After stirring at 25 ° C for 3 hours, under reduced pressure,
The reaction mixture was concentrated to dryness. The residue was dissolved in anhydrous methylene chloride (2.0 ml) and stirred. To this, Example 4 (1)
3- (4-aminocyclohex-1-enyl)-obtained in
220 mg (0.74) of 2 (S) -tert-butoxycarbonylaminopropionic acid methyl ester (II-2)
mmol) and 186 mg of triethylamine (1.8).
4 mmol) of a mixed anhydrous methylene chloride solution (1.0 ml) was added. After stirring at 25 ° C. for 13 hours, 5 ml of a 1% by weight aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 1 hour to decompose excess acid chloride. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel developing solvent: ethyl acetate-hexane = weight ratio 1: 1) to give 2 (S) -tert-butoxycarbonylamino-3- {4-[(5-methoxybenzo [ 1,3] Dioxolol-4-carbonyl) -amino] -cyclohex-1-enyl} -propionic acid methyl ester (II
I-4) 303 mg (86.2% yield) was obtained (diastereomeric ratio: about 1: 1). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.34 (4.5 H, s), 1.3
7 (4.5H, s), 1.40-2.35 (6H, m), 3.59 (1.5H, s), 3.60
(1.5H, s), 3.68 (3H, s), 3.85 (1H, m), 4.12 (1H, m),
5.35 (1H, bs), 6.40 (1H, m), 6.82 (1H, m), 7.12 (1H,
m), 8.03 (1H, m). FAB-MS: calc. M ⁺⁺ 1 477; found 477. Melting point: 90-93 # C.

(2) Methyl 2 (S) -amino-3- {4-[(5-methoxybenzo [1,3] dioxolol-4-carbonyl) -amino] -cyclohex-1-enyl} -propionate Ester trifluoroacetate (III-5) 2 (S) -tert-butoxycarbonylamino-3- {4-[(5-methoxybenzo [1,
3] To a 2.4 ml chloroform solution of 234 mg (0.49 mmol) of dioxolol-4-carbonyl) -amino] -cyclohex-1-enyl} -propionic acid methyl ester (III-4) was added trifluoroacetic acid 1 at 0 ° C. And then stirred for 1 hour. After the reaction, the solvent was concentrated under reduced pressure, the residue was diluted with 6 ml of xylene, and then concentrated under reduced pressure. This operation was repeated until the odor of trifluoroacetic acid disappeared from the residue, and 2 (S) -amino-3- {4-
[(5-methoxybenzo [1,3] dioxolol-4
-Carbonyl) -amino] -cyclohex-1-enyl} -propionic acid methyl ester trifluoroacetate (III-5) (252 mg, 100%) was obtained. The physical properties are shown below. FAB-MS: Calculated M ⁺⁺ 1 377; Found 377.

(3) 2 (S)-(2,6-dichlorobenzoylamino) -3
-{4-[(5-methoxybenzo [1,3] dioxolol-4-carbonyl) -amino] -cyclohex-1
-Enyl} -propionic acid (I-7) Example 1 was prepared using the compound (III-5) obtained in the above (2).
The title compound was synthesized in the same manner as in (4). The physical properties are shown below.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.47 (1H, m), 1.7
0-2.52 (7H, m), 3.69 (3H, s), 3.88 (1H, m), 4.57 (1H,
m), 5.43 (1H, bs), 5.97 (2H, s), 6.41 (1H, d, J = 8.6),
6.84 (1H, m), 7.46 (3H, m), 8.07 (1H, m), 8.90 (1H, m
m), 12.61 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 537, 535, 533; Found 537, 5
35,.

Example 8 2 (S)-{[1- (3,5-Dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino} -3- {4-[(5-methoxybenzo [ Production of 1,3] dioxolol-4-carbonyl) -amino] -cyclohex-1-enyl} -propionic acid (I-8)

[0140]

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Using the compound (III-5) obtained in Example 7 (2), the title compound was synthesized in the same manner as in Example 2. The physical properties are shown below. ¹ H-NMR (DMSO-d ₆ ) δ value: 1.40-2.50 (12H, m), 3.15-3.45
(2H, m), 3.676 (1.5H, s), 3.681 (1.5H, s), 3.84 (1H,
m), 4.32 (2H, m), 5.42 (1H, bs), 5.96 (2H, s), 6.40 (1
H, m), 6.82 (1H, d, J = 8.6), 7.84 (2H, m), 8.03 (3H,
m), 12.65 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 670, 668, 666; Found 670, 668,
666.

Example 9 Preparation of 4- [2 (S) -carboxy- (2,6-dichlorobenzoylamino) ethyl] -cyclohexyl ester (I-9) 2,6-dichlorobenzoic acid

[0143]

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(1) 2 (S) -tert-butoxycarbonylamino-3-
(4-Hydroxycyclohexyl) -propionic acid methyl ester (II-3) 2 (S) -tert-butoxycarbonylamino-3- (4-hydroxycyclohexyl) obtained in Example 1 (1)
1-enyl) -propionic acid methyl ester (II-
1) 0.3 MPa of hydrogen was added to 420 mg (1.40 mmol) and 12 ml of methanol containing 80 mg of 5% by weight palladium-carbon, and the mixture was stirred for 20 hours. After the mixture was diluted with 200 ml of ethyl acetate, the catalyst was filtered through celite, and the resulting filtrate was concentrated. The residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate-hexane =
Purification at a weight ratio of 2: 1) gave 2 (S) -tert
-Butoxycarbonylamino-3- (4-hydroxycyclohexyl) -propionic acid methyl ester (II-
3) 420 mg (100% yield) were obtained (diastereomeric ratio: about 3: 2). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 0.87-2.10 (20H, m),
3.52 (0.6H, m), 1.45 (3H, s), 3.96 (0.4H, m), 4.32 (1
H, m), 4.90 (1H, m). FAB-MS: calc M ⁺⁺ 1 302; found 302.

(2) 2,6-dichlorobenzoic acid 4- [2 (S) -tert-
Butoxycarbonylamino-2-methoxycarbonylethyl] -cyclohexyl ester (III-6) 2 (S) -tert-butoxycarbonylamino-3- (4-hydroxycyclohexyl)-obtained in (1) above.
179 mg of methyl propionate (II-3)
(0.594 mmol) in a solution of 0.4 ml of anhydrous pyridine at 25 ° C. in 2,6-dichlorobenzoyl chloride (187 m).
g (0.891 mmol) and stirred at 90 ° C. for 90 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with a 1% by weight aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (silica gel developing solvent: ethyl acetate-chloroform-hexane = weight ratio 1: 3: 2) to give 2,6-dichlorobenzoic acid 4- [2 (S) -tert-butoxycarbonyl. 257 mg of amino-2-methoxycarbonylethyl] -cyclohexyl ester (III-6) (91.
(2% yield) was obtained (diastereomeric ratio: about 3:
2). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.00-2.27 (20H, m),
3.72 (1.2H, s), 3.74 (1.8H, s), 4.32 (1H, m), 4.95
(1.6H, m), 5.36 (0.4H, m), 7.28 (3H, m). FAB-MS: Calculated M ⁺⁺ 1 476, 474; Found 476, 474.

(3) 2,6-dichlorobenzoic acid 4- [2 (S) -amino-2
-Methoxycarbonylethyl] -cyclohexyl ester trifluoroacetate (III-7) 4- [2,2-dichlorobenzoic acid obtained in the above (2)
(S) -tert-Butoxycarbonylamino-2-methoxycarbonylethyl] -cyclohexyl ester (III-6) was added to 1.8 ml of a chloroform solution of 250 mg (0.527 mmol) at 0 ° C at 0 ° C.
5 ml was added and the mixture was stirred for 40 minutes. After the reaction, the solvent was concentrated under reduced pressure, the residue was diluted with 6 ml of xylene, and then concentrated under reduced pressure. This operation was repeated until the odor of trifluoroacetic acid disappeared from the residue, and 2,6-dichlorobenzoic acid 4-
[2 (S) -amino-2-methoxycarbonylethyl]-
Cyclohexyl ester trifluoroacetate (III-
7) 260 mg (100%) were obtained. The physical properties are shown below. FAB-MS: Calculated M ⁺ +1 376, 374; Found 376, 374.

(4) 4- [2 (S) -carboxy-2- (2,6-dichlorobenzoylamino) ethyl] 2,6-dichlorobenzoate
-Cyclohexyl ester (I-9) (Step 1) 2,6-dichlorobenzoic acid 4- [2 (S) -amino-2-methoxycarbonylethyl] -cyclohexyl ester trifluoroacetate produced in (3) above ( III-7) To a solution of 260 mg (0.527 mmol) in 5.0 ml of anhydrous methylene chloride at 25 ° C., 212 mg (2.10 mmol) of triethylamine and 2,2 chloride were added.
220 mg of 6-dichlorobenzoyl (1.05 mmol
l) was added. After stirring at room temperature for 1 hour, 5 ml of a 1% by weight aqueous sodium hydrogen carbonate solution was added, and the mixture was stirred for 1 hour to decompose excess acid chloride. The reaction mixture was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = weight ratio 2: 3).
2,6-dichlorobenzoic acid 4- [2 (S)-(2,6-
Dichlorobenzoylamino) -2-methoxycarbonylethyl] -cyclohexyl ester 250 mg (8
(6.8% yield) was obtained (diastereomer ratio: about 3: 2). The physical properties are shown below.

¹ H-NMR (CDCl ₃ ) δ value: 1.00-2.30 (11H, m),
3.72 (1.2H, s), 3.80 (1.8H, s), 5.00 (1.6H, m), 5.37
(0.4H, m), 6.22 (1H, bd, J = 8.6), 7.30 (6H, m). FAB-MS: Calculated M ⁺⁺ 1 550, 548, 546;
546.

(Step 2) 2,6-dichlorobenzoic acid 4-
[2 (S)-(2,6-dichlorobenzoylamino)-
To a solution of 116 mg (0.212 mmol) of 2-methoxycarbonylethyl] -cyclohexyl ester in 1.5 ml of tetrahydrofuran was added 1.5 ml of a 1 mol / liter aqueous lithium hydroxide solution, and the mixture was stirred for 1 hour.
After concentrating the reaction mixture, the mixture was diluted with 15 ml of water, and 1 mol / liter hydrochloric acid was added until the pH reached 2 with stirring. The resulting white solid was collected by filtration, washed with water, and dried under vacuum in the presence of phosphorus pentoxide to give the title compound (95 mg)
(84.0% yield) was obtained (diastereomeric ratio: about 3: 2). The physical properties are shown below.

¹ H-NMR (DMSO-d ₆ ) δ value: 1.00-2.18 (11H,
m), 4.45 (1H, m), 4.91 (0.6H, m), 5.23 (0.4H, bs), 7.
30-7.68 (6H, m), 8.97 (1H, d, J = 8.3), 12.57 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 536, 534, 532; Observed 536, 534,
532.

Example 10 2,6-Dichlorobenzoic acid 4- (2 (S) -carboxy-2-{[1- (3,5-dichlorobenzenesulfonyl) -pyrrolidine-2 (S) -carbonyl] -amino ｝
-Ethyl) -cyclohexyl ester (I-10)

[0154]

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Using the compound (III-7) obtained in Example 9 (3), the title compound was synthesized in the same manner as in Example 2 (diastereomeric ratio: about 3: 2). The physical properties are shown below. ¹ H-NMR (DMSO-d ₆ ) δ value: 0.95-2.10 (18H, m), 3.10-3.50
(2H, m), 4.27 (2H, m), 4.87 (0.6H, m), 5.22 (0.4H,
m), 7.54 (3H, m), 7.83 (2H, m), 7.98 (1H, m), 8.31 (1
H, m), 12.62 (1H, bs). FAB-MS: Calculated M ⁺⁺ 1 667, 665, 663; Found 667, 665,
663.

Test Example 1 VLA-4 / VCAM-1 Adhesion Inhibition Test Chinese hamster ovary cells (CHO cells) transfected with the human VCAM-1 gene and VLA-
The inhibitory activity of the cyclohexane derivative I of the present invention on the adhesion between the human promyelocytic cell line HL-60 cells expressing the No. 4 was evaluated using the following method.

The above VCAM-1-expressing CHO cells were cultured for 96 hours.
Add 7 × 10 ³ cells per well to a well culture plate, and add 10% by weight fetal bovine serum (F
CS) Culture in Ham's F-12 containing medium for 3 days. HL-
60 cells were 0.4% by weight bovine serum albumin (BSA)
The suspension was resuspended in a Hanks-containing solution, and 5 µM of 2 ', 7'-bis (carboxyethyl) -5 (6) -carboxyfluorescein pentaacetoxymethyl ester (BCECF-
AM) and label. RPM116 without FCS
BCECF resuspended at 4 × 10 ⁶ cells / ml in 40 media
To 180 μl of the labeled HL-60 cell suspension, 20 μl of various concentrations of the test substance solutions are added and pretreated at 37 ° C. for 15 minutes.

The pretreated HL-60 cells were
CAM-1 expressing CHO cells are layered on a cultured 96-well plate at 2 × 10 ⁵ cells per well and adhered at 37 ° C. for 5 minutes. The plate is then filled with 0.4% by weight BSA Hanks solution, covered with a plate sealer and the plate is inverted and incubated for another 15 minutes. 1% by weight after washing
The cells are destroyed by adding NP-40-containing PBS, and the fluorescence intensity of the obtained supernatant is measured using a cytoFluor 2300 fluorescence measurement system (manufactured by Millipore).

As a blank, 1% by weight of NP-40 was used.
The fluorescence intensity of the PBS containing PBS, and as a standard, the fluorescence-labeled HL-60 suspension was added to 2 × 10 ⁵ , 10 ⁵ , 1 × 10 ⁴ ,
1 wt% NP-40 containing PBS so as to be 10 cells / ml
And the cells are disrupted, and the fluorescence intensity of the resulting supernatant is measured.

The test results were obtained by measuring the number of cells adhering to VCAM-1-expressing CHO cells by the addition of a control substance and a test substance using a calibration curve prepared from the measurement of standards, and determining the cell adhesion inhibition rate (%) by the following equation. calculate. Cell adhesion inhibition rate (%) = 100 × [1- (the number of adherent cells in the test substance-added group / the number of adherent cells in the control group)] The cyclohexane derivative I of the present invention obtained by this test
Are shown in Table 12.

[0161]

[Table 12]

[0162]

Industrial Applicability The cyclohexane derivative I of the present invention exhibits excellent VLA-4 antagonistic activity, and is used for VLA such as a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4-dependent adhesion process plays a role. -4
It is useful as a medicament for the treatment or prevention of a disease mediated by.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (Reference) A61K 31/4025 A61K 31/4025 4C086 31/426 31/426 4C206 31/4409 31/4409 4H006 31/4439 31/4439 4H045 38/00 A61P 29/00 A61P 29/00 43/00 43/00 C07C 229/14 C07C 229/14 271/22 271/22 311/19 311/19 C07D 207/16 C07D 207/16 213/79 213 / 79 277/06 277/06 317/68 317/68 401/12 401/12 405/12 405/12 417/12 417/12 C07K 5/06 C07K 5/06 A61K 37/02 (72) Inventor Tatsuhiro Harada 14 Kashin Pharmaceutical Co., Ltd., Shinomiya Minami-Kawaramachi, Yamashina-ku, Kyoto, Kyoto (72) Inventor Toshiaki Okuda Toshiaki Okuda 14 Kyoto Minato Kawaramachi, Shinomiya, Yamashina-ku, Kyoto, Japan 14F, Shinkangu Minami-Kawaramachi, Yamashina-ku, Kyoto, Kyoto Prefecture F-term in Kaken Pharmaceutical Co., Ltd. 4C033 AB04 AB06 AB17 AB20 4C055 AA01 BA01 CA0 3 CA39 DB11 4C063 AA01 BB07 BB09 CC12 CC62 CC81 DD03 DD12 EE01 4C069 AA18 AA23 BC18 BD06 4C084 AA02 AA03 AA06 BA01 BA14 NA14 ZB112 ZC412 4C086 AA01 AA02 AA03 BA13 BC07 BC17 ZA18 ZA14 Z14A14 Z14A14 AA03 GA37 MA01 MA04 NA14 ZB11 ZC41 4H006 AA01 AA03 AB22 AB23 BJ20 BJ50 BM30 BM72 BS10 BT12 BT32 4H045 AA10 AA30 BA11 EA20 FA40 HA02

Claims (4)

[Claims] 1. A compound of the general formula (I) Wherein R ¹ and R ² are each independently a hydrogen atom,
Alkyl group having 1 to 6 carbon atoms, a cycloalkyl group or an arylalkyl group having a carbon number of 7 to 11 3 to 7 carbon atoms, X is an oxygen atom or -NR ⁵ - (In the formula, R ⁵ is as R ¹ A represents -CO- or -SO
₂ - represents, R ³ is a monovalent hydrocarbon group of 1 to 11 carbon atoms,
A heteroaryl group having 6 to 10 carbon atoms, a heteroarylalkyl group having 7 to 11 carbon atoms, or -NR ⁶ R ⁷ (wherein R
⁶ and R ⁷ each independently represent a hydrogen atom,
11 represents a monovalent hydrocarbon group, a C6 to C10 heteroaryl group or a C7 to C11 heteroarylalkyl group. Wherein R ⁴ is a monovalent hydrocarbon group having 1 to 11 carbon atoms, a heteroaryl group having 6 to 10 carbon atoms, a heteroarylalkyl group having 7 to 11 carbon atoms, or a compound represented by the general formula (a): (Wherein E represents a carbonyl group, a sulfonyl group or a single bond, G is a monovalent hydrocarbon group having 1 to 11 carbon atoms, which may be bonded to E via one oxygen atom, 6
Represents a heteroaryl group having from 10 to 10 or a heteroarylalkyl group having from 7 to 11 carbon atoms, R ⁸ represents a hydrogen atom or an alkyl group having from 1 to 6 carbon atoms, and D represents O, S or -C
H ₂ —, m and n each represent an integer of 1 to 3; ), And the dashed line represents saturated or unsaturated. Or a salt thereof. 2. A compound of the general formula (II) (In the formula, Z represents a hydroxyl group or an amino group which may be protected, and R ⁹ and R ¹⁰ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cyclo group having 3 to 7 carbon atoms. Represents an alkyl group, an arylalkyl group having 7 to 11 carbon atoms or a protecting group, and a broken line represents saturated or unsaturated.)
Or a salt thereof. 3. A medicament comprising the cyclohexane derivative according to claim 1 or a salt thereof as an active ingredient. 4. A VLA-4 antagonist comprising the cyclohexane derivative according to claim 1 or a salt thereof as an active ingredient.