WO2002014272A1 - (thio)urea derivatives, process for their production and medicines containing the derivatives - Google Patents

Abstract

(Thio)urea derivatives of the general formula (|) or salts thereof; and process for producing the derivatives or the salts: (|) [wherein each symbol is as defined in the description]. The derivatives or the salts are novel compounds exhibiting VLA-4 antagonism, and are useful in medicines as VLA-4 antagonists.

Description

 Specification

(Cheo) urea, method of producing mosquitoes and 7 (Cheo) urea

 The present invention relates to a novel (thio) urea derivative, a method for producing the same, a drug containing the (thio) urea derivative, and a therapeutic method for administering the (thio) perrea derivative. More specifically, the present invention relates to a novel (thio) peria derivative or a salt thereof exhibiting VLA-4 antagonistic action, a method for efficiently producing the same, and a method for effectively producing the (thio) peria derivative or a salt thereof. The present invention relates to a medicament useful as a VL A-4 amino gonist, which is contained as an ingredient, and a method for treating a disease through cell adhesion, which comprises administering the (thio) perrea derivative or a salt thereof. Background branch 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 a single heterodimeric structure and fall into one of three main groups: the subfamilies of / 1, β2 and / 53.

 11 integrin is also called VLA protein, one of which, integrin VL A-4 (ひ 4-1), is expressed on lymphocytes, eosinophils, basophils and monocytes, and — 1 and fibronectin are ligands. That is, VLA-4 plays an important role in VCAM-1 and fibronectin-mediated cell-cell and cell-extracellular matrix interactions.

 In order for leukocytes to function in inflamed tissue, circulating leukocytes must pass through endothelial cells and infiltrate the site of inflammation.

VLA-4 and VCAM-1 binding is most critical for strong adhesion between leukocytes and vascular endothelium. This is one of the key mechanisms. Inflammatory cells such as T lymphocytes, B lymphocytes, monocytes and eosinophils express VLA-4, and VLA-4 / VCAM-1 mechanism is strongly involved in the invasion of these cells into inflammatory foci. I have. The adhesion molecules also play an important role in cell activation through cell-cell interaction, and the VLA-4 / VCAM-1 mechanism activates eosinophils to cause degranulation. VLA-4 mediated signaling has also been shown to be involved in i) W-specific proliferation activation of lymphocytes.

 In order to elucidate the role of the VLA-4 / VCAM-1 mechanism in inflammation and the like, attempts have been made to inhibit the binding between these molecules by using a monoclonal antibody. For example, anti-VLA-4 monoclonal antibodies inhibit the attachment of VLA-4 expressing Ramos cells to human umbilical vein vascular endothelial cells (HUVEC) and VCAM-1 transgenic COS cells.

 In several animal models, antibodies have shown efficacy in both treatment and prevention. For example, rat adjuvant arthritis model (Barbadillo et al., Arthr Rheuma., 1993, 36, 95), contact hypersensitivity, delayed hypersensitivity model (Ferguson and Kupper, J. Immunol., 1993, 150, 1172) Chisholm et al., Eur. J. Immunol., 1993, 23, 682) showed a significant effect. Experimental autoimmune encephalomyelitis (Yednock, Nature, 1992, 356, 63), asthma model (Abraham et al., J. Clin. Invest 1993, 93, 776), inflammatory bowel disease (IBD) model (Podolsky et 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 an appropriate antagonist is effective for the treatment of the above-mentioned various diseases including inflammatory diseases.

VLA-4 A peptide compound or a peptide-like compound has been proposed as an antagonist, but all of these compounds have problems such as lack of bioavailability in oral administration and easy degradability in vivo. Dots are left. Therefore, a VLA-4 antagonist with desirable properties for therapeutic and prophylactic use was desired. Censoring the launch

 Under these circumstances, a first object of the present invention is to provide a novel compound exhibiting VLA-4 antagonistic action which is excellent in oral absorption and in vivo kinetics. The second object is to provide a method for efficiently producing this compound.

 Further, a third object is to provide a medicament useful as a VLA-4 antagonist containing the above compound as an active ingredient, and a fourth object is to provide a disease through cell adhesion to which the above compound is administered. It is to provide a method of treatment.

 Thus, the present inventors have conducted intensive studies to achieve the above object, and as a result, have found that a (thio) perrea derivative having a specific structure or a salt thereof has an excellent VLA-4 anion gonist action. Then, they found that they can be manufactured efficiently by a specific process, and based on this finding, completed the present invention.

 That is, the first object of the present invention is to provide a compound represented by the general formula (I):

[Wherein, R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group or a heterocyclic alkyl group, and X ¹ represents a single bond or a formula

(Wherein, R ² and R ^{3 each} independently represent the same meaning as described above, and A ¹ represents an oxygen atom, a sulfur atom or —NR ⁴ — (wherein, R ⁴ has the same meaning as R ¹ ) And A ² represents a carbonyl group, a thiocarbonyl group, a sulfonyl group, or — (CH ₂ ) p 1 (wherein, P represents an integer of 0 to 5). X ² represents a group represented by the formula:

(Wherein B represents a heterocyclic ring, and R ⁵ and R ⁶ are each independently a hydrogen atom, a substituent having no organic group, a bond directly to a carbon atom of a heterocyclic ring, or an oxygen atom, A hydrocarbon group bonded via a sulfur atom, an oxycarbonyl group, a sulfonyl group or a sulfinyl group, one NR ¹⁵ R ¹⁶ , one NR ¹⁵ COR ¹⁶ or one NR ¹⁵ S0 ₂ R ¹⁶ (wherein R ¹⁵ and R ¹⁶ Represents independently a hydrogen atom, a hydrocarbon group, a hydrocarbon oxy group, a heterocyclic group or a heterocyclic alkyl group.) Represents a group represented by), and Y represents an oxygen atom or sulfur Z represents —NR ⁷ R ^S (where R ⁷ and R ⁸ are each independently a hydrogen atom, a hydrocarbon group, a heterocyclic group, a heterocyclic alkyl group, -CR ¹⁷ R ¹⁸ _{- (CH 2) q-CONR} 19 R 20 s - CR 17 R 18 - (CH 2) q-NR 19 CO 20, - CR 17 R 18 - (CH 2) q- NR 19 SO 2 R 20, - _{^{CR 17 R 18 - (CH 2}} ) q- 0 R 19, -CR 17 R 18 - (CH 2) qN 19 R 20, - CR 17 R 18 - (CH 2) q- SR 19, -CR 17 R 18 — (CH ₂ ) q— S0 ₂ R ¹⁹ or CH ¹⁷ R ¹⁸ — (CH ₂ ) q— NR ¹⁹ — V— NR ²⁰ R ²¹ (wherein R ¹⁷ and R ¹⁸ are each independently a hydrogen atom , An alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an arylalkyl group or a heterocyclic alkyl group, wherein R ¹⁹ , R ^2Q and R ²¹ each independently have the same meaning as R ¹⁵ V represents a carbonyl group or a thiocarbyl group, and q represents an integer of 0 to 5.)).

(式中、 R R R¹¹および R¹²はそれそれ独立して水素原子、 炭素数 1〜6 のアルキル基を表し、 ： rは 0〜 3の整数を表す。 ） または式

(Wherein, RRR ¹¹ and R ¹² represent the same it independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,:. R represents an integer of 0-3) or formula

(Wherein, R ¹³ and R ¹⁴ represent the same meaning as R ^1, and s and t each independently represent an integer of 0 to 3.) ]

This is achieved by a (chi) ゥ rare derivative or a salt thereof.

 A second object of the present invention is to provide a compound represented by the general formula (II)

(In the formula, X ¹ , X ² and R ¹ represent the same meaning as described above, and R represents an alkyl group having 1 to 6 carbon atoms.)

And a compound represented by Z—H (wherein Z has the same meaning as described above) and a carbonyl or thiocarbonyl group-introducing reagent are reacted with each other to obtain a compound represented by the general formula (1-1) )

(Wherein X ¹ , X ² , Y, Z, R ¹ and R have the same meanings as described above.) A compound represented by the general formula (I) )

(In the formula, X ¹ , X ² , Y, Z and R ¹ represent the same meaning as described above.)

This is achieved by a method for producing a (Cho) rare derivative represented by

 Further, a third object of the present invention is to provide a medicament containing the (thio) perrea derivative represented by the above general formula (I) or a salt thereof as an active ingredient, and a pharmaceutical composition comprising the (thio) urea derivative or a salt thereof. Achieved by the inclusion of VL A-4 as an ingredient.

 A fourth object of the present invention is to provide a cell adhesion comprising administering the (thio) urea derivative represented by the general formula (I) or a salt thereof, the drug or the VLA-4 antagonist. Is achieved by a method of treating a disease as described above.

 In the present invention, the (thio) peria derivative means both a perrea derivative and a thioperea derivative.の for transportation

 The (thio) perrea derivative of the present invention or a salt thereof is represented by the general formula (I):

 (I)

で表される化合物またはその塩である。

Or a salt thereof.

In the above general formula (I), R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group or a heterocyclic alkyl group. Specifically, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, and a 7 to 7 carbon atoms Represents an arylalkyl group of 13 or a heterocyclic alkyl group having 1 to 6 carbon atoms. X ¹ is a single bond or a formula

[Wherein, and R ³ independently represent the same meaning as H ¹ above, and Α ¹ represents an oxygen atom, a sulfur atom or one NR ⁴ _ (wherein, R ⁴ has the same meaning as R ¹ A ² represents a carbonyl group, a thiocarbonyl group, a sulfonyl group or 1 (CH ₂ ) p − (where p represents an integer of 0 to 5). ].

X ² is the formula

[Wherein B represents a hetero atom, and R ⁵ and R ^{6 each} independently represent a hydrogen atom, a substituent having no organic group, a bond directly to a carbon atom of a heterocycle, or an oxygen atom. , a sulfur atom, O alkoxycarbonyl group, a hydrocarbon group bonded through a sulfonyl group or a sulfinyl group, one ^{NR 15 R 16, - NR 15} COR 16 or a NR ¹⁵ S 0 ₂ R 16

(In the formula, R ¹⁵ and R ¹⁶ each independently represent a hydrogen atom, a hydrocarbon group, a hydrocarbyloxy group, a heterocyclic group or a heterocyclic alkyl group.) ] Represents the group represented by. Specifically, R ⁵ and R ⁶ are each independently a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, and a cycloalkyl having 3 to 7 carbon atoms. Group, alkoxy group having 1 to 6 carbon atoms, aryl group having 6 to 10 carbon atoms, arylalkyl group having 7 to 13 carbon atoms, aryl alkoxy group having 7 to 13 carbon atoms, carbon number 2-7 alkoxycarbonyl group, an alkylthio group having 1 to 4 carbon atoms, an alkylsulfonyl group having 1 to 4 carbon atoms, alkylsulfinyl group having 1-4 carbon atoms, one NR ¹⁵ R ^16, one NR ¹⁵ COR ¹⁶ or a NR ¹⁵ SO ₂ R ¹⁶ (wherein, R ¹⁵ and R ¹⁶ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkoxy group having 1 to 6 carbon atoms, and a cyclo group having 3 to 7 carbon atoms. Alkyl group, charcoal Prime number 6 ~ 10 aryl group, carbon number? ~ 13 arylalkyl groups, carbon number? Represents an arylalkoxy group, a heterocyclic group or a heterocyclic alkyl group having 1 to 6 carbon atoms. ).

 Y represents an oxygen atom or a sulfur atom.

Z is one NR ⁷ R ^{8 wherein} R ⁷ and R ⁸ are each independently a hydrogen atom, a hydrocarbon group, a heterocyclic group, a heterocyclic alkyl group, — CR ¹⁷ R ¹⁸ — (CH ₂ ) q— CONR ^ls R ²⁰ , — CR ¹⁷ R ¹⁸ — (CH ₂ ) q — NR ¹⁹ COR ² . ^{, - CR 17 R 18 - (} CH 2) q-NR 19 S 0 2 R 20, one _{^{CR 17 R 18 - (CH 2}} ) q- OR 19, - CR 17 R 18 - (CH 2) q- N 19 ^{R 20, - CR 17 R 18} - (CH 2) q- SR 19, -CR 17 R 18 - (CH 2) q- S 0 2 R 19 or a _{^{CR 17 R 18 - (CH 2}} ) q- NR 19 — V— NR ²⁰ R ²¹ (wherein R ¹⁷ and R ¹⁸ are each independently a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an arylalkyl group or a heterocyclic alkyl R ¹⁹ , R ^2fl and R ²¹ each independently represent the same meaning as R ¹⁵ , V represents a carbonyl group or a thiocarpoxyl group, and q represents an integer of 0 to 5.) Represent. ], Expression

(Wherein, R ⁹ , R ^1D , R ¹¹ and R ¹² each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, and r represents an integer of 0 to 3) or

(Wherein, R ¹³ and R ¹⁴ have the same meaning as R ^1, and s and t each independently represent an integer of 0 to 3.). R ⁷ and R ⁸ are each independently a hydrogen atom and a carbon number:! 6 to 6 alkyl groups, 3 to 7 carbon atoms, cycloalkyl group, 6 to 10 carbon atoms, aryl group, carbon number? ~ 13 aryl alkyl Group, a heterocyclic group, heterocyclic alkyl group to the 1 to 6 carbon ^{atoms, -CR l7 R 18 - (CH} 2) q- CONR 19 R 2. , — CR ¹⁷ R ¹⁸ — (CH ₂ ) q — NR ¹³ COR ² . ^{, - CR 17 R 18 - (} CH 2) q - NR 19 S0 2 H 2. CR ¹⁷ R ¹⁸ — (CH ₂ ) q — OR ¹⁹ , — CR ¹⁷ R ¹⁸ — (CH ₂ ) q-NR ¹⁹ R ² °, CR ¹⁷ R ¹⁸ — (CH ₂ ) q — SR ¹⁹ CR ¹⁷ R ¹⁸ — (CH ₂ ) q—S 0 ₂ R ¹⁹ or one CR ¹⁷ R ¹⁸ — (CH ₂ ) q—NR ¹⁹ — V—NR ² ° R ²¹ (where R ¹⁷ and R ¹⁸ are each Independently, a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an amino amino group having 1 to 5 carbon atoms, and 7 to 13 carbon atoms ^Represents an arylalkyl group or a heterocyclic alkyl group having 1 to 6 carbon atoms, R ¹⁹ , R ^2fl and R ^{21 each} independently represent the same meaning as R ^15, and V represents a carbonyl group or a thiocarboyl group. And q represents an integer of 0 to 5.).

 Each substituent in the general formula (I) will be described.

 Specific examples of the “halogen atom” include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

 Specific examples of the “alkyl group having 1 to 6 carbon atoms” include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, and a n-butyl group. Examples include a linear or branched alkyl group such as a 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. .

 Specific examples of “alkoxyl group having 1 to 6 carbon atoms” include methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, tert-butoxy group, sec-butoxy group, n Linear or branched alkoxyl groups such as —pentyloxy group, tert-amyloxy group, 3-methylbutoxy group, neopentyloxy group and n-hexyloxy group.

Specific examples of “hydroxyalkyl group having 1 to 5 carbon atoms” include hydroxymethyl And a 1-hydroxyethyl group, a 2-hydroxyethyl group and a hydroxypropyl group.

 Specific examples of the “aminoalkyl group having 1 to 5 carbon atoms” include an aminomethyl group, a 2-aminoethyl group, a 3-aminopropyl group, and a 4-aminobutyl group. The amino group may be substituted, and examples of the substituent include a methyl group, an ethyl group, a benzyl group, an acetyl group, a benzoyl group, a methoxycarbonyl group, a benzyloxycarbonyl group, and a tert-butoxycarbonyl group. And the like.

 The “aryl group having 6 to 10 carbon atoms” refers to a mono- or di-substituted aromatic hydrocarbon group having 6 to: L 0 unsubstituted or 1 to 3 substituted carbon atoms. Phenyl, 0-tolyl, 2-methoxyphenyl, 3-chlorophenyl, 11-naphthyl, 2-naphthyl 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, and an aryloxy group having 6 to 10 carbon atoms.

 The term "C7-C13 arylalkyl group" refers to an unsubstituted or 1-3-substituted monocyclic or bicyclic araliphatic hydrocarbon group having 7-13 carbon atoms. Examples thereof include a benzyl group, a phenethyl group, a 1 (S) -phenylethyl group, a 1 (R) -phenylethyl group, a 1-phenylpropyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group and the like. Further, the aromatic ring of the araliphatic hydrocarbon may combine with the aliphatic chain to form a ring, and specific examples thereof include an indanyl group, and a 1,2,3,4-tetrahydronaphthyl 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, and an aryloxy group having 6 to 10 carbon atoms.

The "arylalkoxy group having 7 to 13 carbon atoms" means an unsubstituted or 1 to 3 substituted carbon atom having 7 to: monocyclic or bicyclic aromatic hydrocarbon alkoxyl group having L3. Examples include benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 1-naphthylmethoxy, 2-naphthylmethoxy, 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, and a carbon atom having 6 to 10 carbon atoms. Aryloxy group and the like.

 The “aryloxy group having 6 to 10 carbon atoms” refers to an unsubstituted or 1 to 3 substituted monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. Examples include phenoxy, 2-methylphenoxy, 4-methoxyphenoxy, 3,5-dichlorophenoxy, 11-naphthyloxy, 2-naphthyloxy, 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, and a halogen atom.

 Specific examples of the “alkoxycarbonyl group having 2 to 7 carbon atoms” include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl, sec-butoxycarbonyl, tert- A linear or branched alkoxycarbonyl group such as a butoxycarbonyl group is exemplified.

 Specific examples of the "alkylthio group having 1 to 4 carbon atoms" include straight-chain such as methylthio group, ethylthio group, n-propylthio group, isopropylthio group, n-butylthio group, sec-butylthio group and tert-butylthio group. Or a branched alkylthio 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, A straight-chain or branched alkylsulfonyl group such as a tert-butylsulfonyl group is exemplified.

 Specific examples of the “alkylsulfinyl group having 1 to 4 carbon atoms” include a methanesulfinyl group, an ether sulfinyl group, an η-propylsulfinyl group, an isopropylsulfinyl group, an η-butylsulfinyl group, a sec-butylsulfinyl group, Examples thereof include a linear or branched alkylsulfinyl group such as a tert-butylsulfinyl group.

“Hetero group” refers to a 5- to 7-membered monocyclic heterocyclic group containing 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom or a sulfur atom in a ring. , Furyl, chenyl, imidazolyl, thiazolyl, oxazolyl, Examples include a pyridyl group, a bilazinyl group, a vilolidinyl group, a piperidinyl group, a piperazinyl group, a homopiperazinyl group, a morpholinyl group, and a dioxanyl group. Or a bicyclic or tricyclic fused heterocyclic group in which the monocyclic heterocyclic ring and a benzene ring or the monocyclic heterocyclic ring are fused, and specific examples thereof include a benzofuranyl group, a benzothenyl group, an indolyl group, and a benzimidazolyl group. Group, chromanyl group, piperonyl group, quinolyl group, 1,2,3,4-tetrahydroquinolyl group, 5,6,7,8-tetrahydropyrido [4,3-d] pyrimidyl group . These may be substituted, and 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, an aryloxy group having 6 to 10 carbon atoms, a hydroxyl group, And an amino group. The same applies to "heterocycle".

 The “heterocyclic alkyl group having 1 to 6 carbon atoms” refers to an alkyl group having 1 to 6 carbon atoms substituted with the above “heterocyclic group”, and specific examples thereof include imidazolylmethyl group and indolyl Examples include a methyl group, a benzothiazolylmethinole group, a pyridinolemethyl group, a 1-pyridylethyl group, a 2-pyridylethyl group, a 3-phenylphenyl group, and a 2-pyridinoethyl group.

 When an asymmetric carbon atom is present in the compound of the present invention represented by the general formula (I), any of its racemate, diastereoisomer and individual optically active compound is included in the present invention. Yes, and when geometric isomers are present, the (E) -form, the (Z) -form and mixtures thereof are all included in the present invention.

The salt of the compound of the present invention represented by the general formula (I) is not particularly limited as long as it is a pharmacologically acceptable salt. For example, a salt with an inorganic base, a salt with an organic base, an organic acid And salts with inorganic acids and salts with amino acids. Examples of the salt with an inorganic base include an alkali metal salt such as a sodium salt, a potassium salt, and a calcium salt, and an ammonium 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, and the like. Examples of salts with organic acids include formate, acetate, tartrate, maleate, succinate, and methanesulfonate. No. Examples of salts with inorganic acids include hydrochlorides, hydrobromides, nitrates and the like. Examples of the salt with an amino acid include glycine salt, alanine salt, arginine salt, glutamate, and aspartate.

 The thio (uree) derivative of the present invention represented by the general formula (I) can be efficiently produced by the method of the present invention described below. That is, according to the method of the present invention, general formula (II)

(I I)

(In the formula, X ¹ , X ² and R ¹ represent the same meaning as described above, and R represents an alkyl group having 1 to 6 carbon atoms.)

And a compound represented by Z—H (wherein Z represents the same meaning as described above), and a reagent for introducing a carbonyl group or a thiocarbonyl group, and the compound represented by the general formula (I-a)

(l-a)

(Wherein X ¹ , X ² , Y, Z, R ¹ and R have the same meanings as described above). After obtaining a compound represented by the formula, the compound represented by the general formula (I)

(式中、 X¹、 X²、 Y、 Ζおよび R¹は前記と同じ意味を表す。 ） で表される （チォ） ゥレア誘導体を製造することができる。

(Wherein X ¹ , X ² , Y, Ζ, and R ¹ have the same meanings as described above.).

 Specifically, the (thio) urea derivative of the present invention can be obtained by the following production method 1 and production method 2.

 [Production method 1]

 (1-1 -a)

Process 2

 (1-1)

(Wherein, X ¹ , X ² , ¹ , R and Z represent the same meaning as described above.)

 Compound (1-1) can be produced by the reaction of the following steps 1 and 2.

 (Step 1) In this step, compound (Ι-1-a) can be produced by reacting compound (Π), compound (III) and a reagent for introducing a thiocarbonyl group. Examples of the reagent for introducing a thiocarbonyl group include thiocarbonyldiimidazole and thiophosgene. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but dichloromethane, dichloroethane, tetrahydrofuran 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 3 to 72 hours.

(Step 2) In this step, the compound (Ι-1-a) obtained in Step 1 is treated under alkaline conditions. The compound (1-1) can be produced by the following hydrolysis reaction. A known reaction may be used for the hydrolysis reaction under alkaline conditions, and examples of the aqueous solution include lithium hydroxide, sodium hydroxide, potassium hydroxide and the like. 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 the like. The reaction temperature is not particularly limited, and is usually 0 to: L 0 ° C, and the reaction time is preferably 30 minutes to 3 hours. '

 [Production method 2]

(1-2) (wherein, X ¹ , X ² , Y, Z, R ¹ and R have the same meanings as described above.) Compound (1-2) is produced by the reaction of the following steps 1 and 2. can do.

(Step 1) In this step, compound (1-2-a) can be produced by reacting compound (II), compound (III) and a reagent for introducing a carbonyl group. Examples of the reagent for introducing a carbonyl group include carbonyldiimidazole, triphosgene and phosgene. This reaction is usually performed in the presence of a base. Suitable bases include pyridine, triethylamine, N, N-diisopro Pyruetylamine, N-methylmorpholine and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, and preferred are dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dioxane and the like. 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 24 hours.

 (Step 2) In this step, compound (1-2) can be produced from compound (I-2-a) obtained in step 1 by the same reaction as in step 2 of production method 1.

Further, in formula (I), Z is - if it is NHR ^7, for example can be the production of (Chio) Urea derivatives of the present invention by the production method 3 below.

 [Production method 3]

 (11-1) (I-3)

(Wherein, X ¹ , XY, R ¹ and R ⁷ represent the same meaning as described above.)

 Compound (1-3) or a salt thereof can be produced by reacting compound (II-1) or a salt thereof with compound (IV). This reaction is usually performed in the presence of an inorganic or organic base. Suitable inorganic bases include sodium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, and the like. Preferred organic bases include triethylamine, N, N-diisopropylethylamine, —Methylmorpholine, pyridine and the like. The reaction solvent is not particularly limited as long as it does not significantly inhibit the reaction, but the reaction is carried out in water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixed solvent thereof. 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 10 hours.

The (thio) perrea derivative of the present invention produced by the above-mentioned production method is a free compound, It is isolated and purified as various solvates such as salts, hydrates or ethanol solvates, or crystalline polymorphs. The pharmacologically acceptable salt of the (thio) perylene derivative 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 (Cho) perrea derivative of the present invention or a salt thereof exhibits excellent VLA-4 antagonistic action, and is a disease caused by leukocyte adhesion and infiltration or a disease in which a VLA-4 dependent adhesion process plays a role. It is useful as a medicament for the treatment or prophylaxis of, for example, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, Scheigren's syndrome, and various organ inflammations, asthma, and atby associated therewith. Allergic diseases such as atopic dermatitis, nasal congestion, rhinitis, inflammatory bowel diseases including Crohn's disease, nephritis, hepatitis, inflammatory diseases of the central nervous system, cardiovascular diseases, arteriosclerosis, diabetes, various Malignant tumors, prevention of transplanted organ damage, prevention of tumor growth or metastasis, etc.

 The (thio) perrea derivative or a salt thereof of the present invention is administered systemically or locally by a method such as oral, intravenous injection, subcutaneous injection, or rectal administration, with oral administration being preferred. The dosage form can be conveniently selected according to the route of administration, for example, tablets, troches, sublingual tablets, dragees, capsules, pills, powders, granules, solutions, emulsions, syrups, inhalants Preparations, eye drops, nasal drops, injections, suppositories and the like. These preparations can be produced by mixing excipients, preservatives, wetting agents, emulsifiers, stabilizers, dissolution aids and the like. -The dose of the (thio) perrea derivative or a salt thereof of the present invention may be appropriately determined depending on conditions such as the administration subject, administration route and symptoms. For example, when administered orally to an adult patient, it is effective. The compound of the present invention is usually administered in a single dose of about 0.1 to 10 Omg / kg, preferably 1 to 3 OmgZkg, and it is preferable to administer 1 to 3 times. .

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited thereto. is not. The proton nuclear magnetic resonance (H-NMR) spectrum was measured with a JNM-EX270 type spectrometer (270 MHz, manufactured by JEOL Ltd.) using tetramethylsilane (TMS) as an internal standard. Indicated. In the following structural formulas and tables, Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, Bu represents a butyl group, and Ph represents a phenyl group.

 [Example 1] 3- [4-[(3,5-dichloropyridine-1-4-carbonyl) amino] phenyl] -2 (S)-[3-isobutyl-1-3- [1 (S) -phenylethyl] [Reid] Propionic acid

(Step 1) To a solution of triphosgene (53 mg, 0.18 mmol 1) in dichloromethane (2 ml) at 0 ° C. was added 4-[(3,5-dichloropyridine-1-4-carbonyl) amino] 1-L-phenylalanine A dichloromethane solution (2 ml) of methyl ester (200 mg, 0.54 mmol) and N, N-diisopropylethylamine (0.12 ml, 0.70 mmol) was added dropwise over 20 minutes. After 10 minutes, dichloromethane of N-isobutyl-1 (S) -phenylethylamine (124 mg, 0.7 Ommo 1) and N, N-diisopropylethylamine (0.12 ml, 0.70 mmo 1) The solution (2 ml) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction, the solvent was concentrated under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water, saturated aqueous sodium hydrogen carbonate and brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 11: 1) to give 3- [4-[(3,5-dichloropyridine-1-4-carbonyl) amino]. [Phenyl] -1 2 (S) 1 [3-Isoptyl-3 -[1 (S) -Phenylethyl] perido] Propionic acid methyl ester (223 mg, 72%) was obtained as a colorless powder. The physical properties are shown below.

_{-NMR (CDCl 3) 5: 8.58} (s, 2H), 7.69 (s, 1H), 7.48 (d, J = 8.3Hz 3 2H), 7.37- 7.29 (m, 5H), 6.98 (d 5 J = 8.3 Hz, 2H), 5.Z3 (q, J = 7.3Hz, 1H), 4.86-4.69 (m, 2H), 3.72 (s, 3H) ₅ 3.52-2.91 (m, 3H), 2.81 (dd, J = 7.3, 14.8Hz, 1H), 1.79- 1.69 (m, 1H), 1.57 (d 3 J = 7.3Hz, 3H), 0.83 (d, J = 6.6Hz, 3H), 0.76 (d, J = 6 z, 3H).

 (Step 2) 3- [4 — [(3,5-dichloropyridine-14-carbonyl) amino] phenyl] 1-2 (S) — [3-isobutyl-3— [1 (S) — obtained in Step 1 [Phenylethyl] perido] Propionic acid methyl ester (217 mg, 0.38 mmo 1) is dissolved in methanol (4 ml) and tetrahydrofuran (1 ml), and a 2 mol / l aqueous lithium hydroxide solution (1.34 ml, 2.63 mmo 1) is dissolved. Was added and stirred at room temperature for 1 hour. After the reaction, the pH was adjusted to 3 by adding 2 mol ZL hydrochloric acid at 0 ° C, and the solvent was concentrated under reduced pressure. Water was added to the residue and the mixture was collected by filtration to give the title compound (206 mg, 97%) as a colorless powder. The physical properties are shown below.

_{¾-NM (DMS0-d 6} ) δ: 12.50 (brs, 1H) 3 10.83 (s, 1H), 8.78 (s, 2H), 7.56 (d 3 J = 8.3Hz 5 2H) 3 7.32-7.18 (m 3 7H) ₃ 6.14 (d ₃ J = 7.9Hz, 1H), 5.31 (q ₃ J = 6.9Hz, 1H), 4.45-4.37 (m ₅ 1H), 3.07 (dd, J = 5.0, 13.5Hz, 1H), 2.97 (dd, J = 9.2, 13.5Hz, 1H), 2.77 (dd, J = 7.6, 14.2Hz, 1H), 2.60 (dd, J = 1.6, 14.5Hz, 1H), 1.61-1.48 (m, 1H) , 1.42 (d, J = 6.9Hz, 3H), 0.67 (d, J = 6.6Hz, 3H), 0.57 (d, J = 6.6Hz, 3H).

 The compounds shown in Examples 2 to 7 and 15 to 31 were produced in the same manner as in Example 1. The physical property values of the compounds are shown in Tables 1, 2, 3, and 4 below.

[Example 8] 3- [4-I-[(3,5-dichropyridine-14-carbonyl) amino] phenyl] 1-2 (S) -1- [3-isobutyl-1-3- [1 (S) -phenylethyl [Cho perido] Propionic acid

 (Step 1) 4-[(3,5-Dichloromouth pyridine 4-carbonyl) amino] 1 L 1-Fenylalanine methyl ester (98 mg, 0.27 mmol) in tetrahydrofuran (1.5 ml) ), Add thiocarbonyldiimidazole (52 mg, 0.29 mmo 1), stir at room temperature for 2 hours, and add N-isobutyl-1 (S) -phenylethylamine (57 mg, 0.32 mmo 1) Was added and the mixture was stirred for 48 hours. After the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 3: 1 → 2: 1) to give 3- [4-[(3,5- Dichloropyridine—4-monocarbonyl) amino] phenyl] —2 (S)-[3-isobutyryl-3- [1 (S) -phenylethyl] thioperido] Methyl propionate (1 45 mg, 93%) as a pale yellow oil Obtained. The physical properties are shown below.

_{¾- M (CDCl 3) δ:} 8.47 (s, 2H), 8.33 (s 5 1H), 7.47 (d, J = 8.3Hz, 2H), 7.37- 7.28 (m 3 5H), 6.99 (d, J = 8.3Hz, 2H) ₃ 6.66- 6.38 (m, 1H), 5.93 (d, J = 6.9Hz, 1H) ₅ 5.51-5.45 (m, 1H) ₃ 3.75 (s, 3H), 3.38 (dd, J = 6.3 , 14.2Hz, 1H), 3.16 (dd ₅ J = 4.6, 14.2Hz, 1H), 3.12-2.84 (m ₃ -2H), 1.83-1.78 (m ₅ 1H), 1.59 (d, J = 7.3Hz, 3H ), 0.80 (d, J = 6.6Hz, 3H), 0.64 (d, J = 6.6Hz 5 3H).

(Step 2) 3- [4-[(3,5-Dichloropyridine-4-carbonyl) amino] phenyl] obtained in Step 1 1 2 (S) 1 [3-Isoptyl-3- [1 (S)- [Phenylethyl] thioperido] Propionic acid methyl ester (145 mg, 0.25 mmo 1) was dissolved in methanol (4 ml), and a 2 mol / l lithium hydroxide aqueous solution (0.62 ml, 1.23 mmo 1) was added. Time stirring did. After the reaction, pH was adjusted to 3 by adding 2 mol ZL hydrochloric acid at 0 C, and the solvent was concentrated under reduced pressure. Water was added to the residue, and the mixture was collected by filtration to give the title compound (11 mg, 78%) as a pale-yellow powder. The physical properties are shown below.

Ή- flame _{(DMS0-d 6) 5:} 12.71 (brs 3 IH), 10.84 (s, 1H), 8.78 (s, 2H>, 7.55 (d, J = 8.3Hz, 2H), 7.35-7.20 (m 5 7H) ₃ 7.00 (d, J = 7.9Hz, IH), 6.70-6.53 (m, IH), 5.44-5.36 (m, 1H), 3.24 (dd ₅ J = 5.0, 13.9Hz ₅ IH), 3.12 (dd , J = 8.9 ₃ 13.9Hz, 1H), 3.01 (dd, J = 7.9, 14.9Hz, IH), 2.85 (dd, J = 7.6, 14.9Hz, 1H), 1.75-1.67 (m, 1H), 1.45 ( d ₃ J = 6.9Hz, 3H) ₅ 0.64 (d, J = 6.6Hz, 3H) ₃ 0.40 (d, J = 6.6Hz, 3H).

In the same manner as in Example 8, the compounds shown in Examples 9 to: I4 and 32 to 39 were produced. The physical properties of the compound are shown in Tables 1, 2 and 5.

 T-I T 挲

/ TOdf / X3d ZLZn / ZO OAV Table 1-2

S 12.65 (brs, IH), 10.83 (s, IH), 8.78 (s, 2H), 7.55 (d,

 Me J = 8.3Hz, 2H), 7.33-7.18 (m, 8H), 6.66-6.45 (m,

 IH), 5,27-5.16 (m,

 Ph person IH), 3.25-3.12 (m, 4H),

 1.65-1.50 (m, IH), L44 (d, J = 7.3Hz, 3H), 0.54 (d, J = 6.6Hz, 3H), 0.50 (d, J = 6.6Hz, 3H).

S 12.72 (brs, IH), 10.86 and 10.83 (s, IH), 8.79 and

 8.78 (s, 2Η), 7.59-7.53 (m, 2H), 7.26-6.86 (m, 7H),

6 ^X 6.75-6.55 and 6.55-6.25 (m, IH), 5.62-5.40 and

 5.30-5.13 (m, IH), 3.58-2.28 (m, 6H),

 2.22-1.55 (m, 5H), 0.95-0.48 (m, 6H).

s i-Bu 12.55 (brs, IH), 10.81 (s, IH), 8.77 (s, 2H), 7.54 (d,

J-8.2HZ, 2H), 7.24 (d, J = 8.2iiz, 2H), 7.00 (d, J = 7.9Hz ₅ IH), 5.20-5.18 (m, IH), 3.64 (dd, J = 6.9, 13.9 Hz, 2H), 3.23-3.04 (m, 4H), 1.91-1.86 (m, 2H), 0.75 (d, J = 6.3Hz, 6H), 0.73 (d, J = 6.3Hz, 6H.s Ph 12.84 ( brs, IH), 10.84 (s, IH), 8.79 (s, 2H), 7.49 (d,

J = 8.3Hz, 2H), 7.44-7.34 (m, 3H), 7.14 {d, J = 7.3Hz, 2H), 6.96 (d, J = 8.3Hz, 2H, 5.95 (d ₅ J = 7.6Hz, IH ), 5.10 (td, J = 5.6, 7.6Hz, IH), 4.04-3.96 (m, 2H), 3.17 (dd, J = 5.6, 13.7Hz, IH), 3.00 (dd, J = 5.6, 13.7Hz, IH), 1.75-1.65 (m, IH), 0.85 (d, J = 6.6Hz, 3H), 0.84 {d, J = 6.6Hz, 3H).

n

s拏

halla

/ T0df / I3d ZLZn / ZO OAV Table 3

表 4

Table 4

表 4一 2

Table 4-1 2

表 5—

Table 5—

表 5— 2

Table 5-2

[Test Example] V L A-4 NO V CAM-1 Adhesion Inhibition Test

 The inhibitory activity of the compounds of the present invention on the adhesion between Chinese hamster ovary cells (CH0 cells) transfected with human VCAM-1 gene and human promyelocytic cell line HL-60 cells expressing VLA-4 is shown below. Was evaluated using the method described above.

Add 7 x 10 ³ cells per well of the above VCAM-1 expressing CH0 cells to a 96-well culture plate, and add 10% by weight of Ham's F-1 medium containing 10% fetal serum (FCS) until confluent. And culture for 3 days.

The HL-60 cells were resuspended in 0.4% by weight of serum albumin (BSA) -containing phenol-containing solution, and 5M of 2 ', 7'-bis (, carboxyethyl) -5 (6) -carboxyfluorescein penta acetoxymethyl Label with the addition of ester (BCECF-AM). Pretreatment of BCECF-labeled HL-60 cell suspension resuspended at 4 × 10 ⁶ cells / ml in FCI-free RPMI1640 medium at 37 ° C for 15 minutes by adding 20 zl of test substance solutions at various concentrations I do. Then, before the the HL- 60 cells treated, VCAM - 1 expression CH0 cells and 2 chi [pi) ⁵ or layer per well in 96-well plates were cultured, adhere for 5 minutes at 37 ° C. Then weigh the plate 0.4 weight. /. Fill with BSA Hank's solution, cover with plates, invert the plate, and incubate for another 15 minutes. After washing, the cells are destroyed by adding PBS containing 1% by weight of NP-40, and the fluorescence intensity of the obtained supernatant is measured using a cytoFluor OO fluorescence measurement system (Millipore).

1 ° / as blank.蛍 光 -40 Fluorescent intensity of PBS containing Light-labeled HL- ⁶⁰ suspension was weighed to give 2 × 10 ⁵ , 10 ⁵ , 2 × 10 ⁴ _N / ml. Add to / oNP-40-containing PBS, disrupt cells, and measure the fluorescence intensity of the resulting supernatant.

 The test results were obtained by measuring the number of cells adhering to VCAM-1 expressing CH0 cells by adding a control substance and a test substance using a calibration curve created from the measurement of the standard. calculate.

 Cell adhesion inhibition rate (%) = 100 X [1-1 (Number of adherent cells in the test substance added group)

 Table 6 shows the 50% inhibitory concentration of the compound of the present invention obtained in this test. Table 6 Example 50% inhibitory concentration (nM)

 1 1. 1

 2 2.7

 3.2.1

 4 4. 7

 5 86

 6 52

 7 20

 8 3. 7

 9 15

 10 1.1

 11 8. 3

 12 78

 13 89

 14 15

 15 0.014

 16 2.0

 17 1.1

 18 99

 192.0

 20 0.55

 21 3. 7

 25 47

 26 25

34 47 の 禾 iiffl r small

 The (thio) perrea derivative of the present invention or a salt thereof exhibits an excellent VLA-4 antagonistic action, and plays a role in diseases caused by leukocyte adhesion and infiltration or in a VLA-4 dependent adhesion process. It is useful as a medicament for treating or preventing a disease mediated by VLA-4, such as a disease.

Claims

Claim formula (I)

[Wherein, R ¹ represents a hydrogen atom, an alkyl group, a cycloalkyl group, an arylalkyl group or a heterocyclic alkyl group, and X ¹ represents a single bond or a formula

(Wherein, H ² and R ³ independently represent the same meaning as R ¹ above, and Α ¹ represents an oxygen atom, a sulfur atom or — — (wherein represents the same meaning as R ¹ . Α ² represents a carbonyl group, a thiocarbonyl group, a sulfonyl group, or 1 (CH ₂ ) p — (where p represents an integer of 0 to 5). And X ² is an expression

(Wherein B represents a hetero atom, and R ⁵ and R ⁵ independently represent a hydrogen atom, a substituent having no organic group, a bond directly to a carbon atom of a heterocyclic ring, or an oxygen atom, sulfur A hydrocarbon group bonded via an atom, an oxycarbonyl group, a sulfonyl group or a sulfinyl group, one NR ¹⁵ R ¹⁶ , one NR ¹⁵ COR ¹⁶ or one NR ¹⁵ S 0 ₂ R ¹⁶ (Wherein, R ¹⁵ and R ^{16 each} independently represent a hydrogen atom, a hydrocarbon group, a hydrocarbon oxy group, a heterocyclic group or a heterocyclic alkyl group.) ) Represents a group represented by Y, Y represents an oxygen atom or a sulfur atom, and Z represents —NR ⁷ R ⁸ (wherein R ⁷ and Each micro R ⁸ is independently a hydrogen atom, a hydrocarbon group, a heterocyclic group, a heterocyclic alkyl le ^{group, -CR 17 R 18 - (CH} 2) q-CONR I9 20, - CR 17 R 18 - (CH 2 ) q-NR ¹⁹ C OR ² . , — CR ¹⁷ R ¹⁸ — (CH ₂ ) q — NR ¹⁹ S0 ₂ R ² . ^{, - CR 17 R 18 - (} CH 2) q- 0 R 19, one _{^{CR 17 R 18 - (CH 2}} ) q- NR 19 R 20, one _{^{CR 17 R 18 - (CH 2}} ) q- SR 19, - CR ¹⁷ R ¹⁸ — (CH ₂ ) q— S0 ₂ R ¹⁹ or — CR ¹⁷ R ¹⁸ — (CH ₂ ) q— NR ¹⁹ -V— NR ²⁰ R ²¹ (where R ¹⁷ and R ¹⁸ are each independent Represents a hydrogen atom, an alkyl group, a cycloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an arylalkyl group or a heterocyclic alkyl group, and R ¹⁹ , R ^2D and R ²¹ each independently represent R Represents the same meaning as ¹⁵ , V represents a carbonyl group or a thiocarbonyl group, and q represents an integer of 0 to 5). ), Expression

( ^Wherein , R ⁹ , R ^lfl , R ¹¹ and R ^{12 each} independently represent a hydrogen atom or an alkyl group having carbon atoms, and r represents an integer of 0 to 3).

(Wherein, R ¹³ and R ¹⁴ have the same meaning as R ^1, and s and t each independently represent an integer of 0 to 3.) ø] (Cho) ゥ a rare derivative or a salt thereof. 2. In the general formula (I), R 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 13 carbon atoms, or a heteroalkyl group having 1 to 6 carbon atoms. R ⁵ and R ⁶ each independently represent a hydrogen atom, a halogen atom, a nitro group, a cyano group, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkyl group having 3 to 7 carbon atoms, Cycloalkyl group, alkoxy with 1 to 6 carbon atoms Si group, carbon number 6 or more: L 0 aryl group, carbon number? ~ 13 arylalkyl groups, carbon number? Aryloxy group having 13 to 13 carbon atoms, alkoxycarbonyl group having 2 to 7 carbon atoms, alkylthio group having 1 to 4 carbon atoms, alkylsulfonyl group having 1 to 4 carbon atoms, alkylsulfinyl group having 1 to 4 carbon atoms, one NR ¹⁵ R ¹⁶ , — NR ¹⁵ COR ¹⁶ or N ¹⁵ S0 ₂ R ¹⁶ (wherein R ⁱ⁵ and R ¹⁶ are each independently a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, Alkoxy group, cycloalkyl group having 3 to 7 carbon atoms, carbon number 6 to: aryl group having L0, arylalkyl group having 7 to 13 carbon atoms, arylalkyl group having 7 to 13 carbon atoms, heterocyclic group or R ⁷ and R ⁸ each independently represent a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, which represents a heterocyclic alkyl group having 1 to 6 carbon atoms. An aryl group having 6 to 10 carbon atoms, an arylalkyl group having 7 to 13 carbon atoms, Heterocyclic group, hetero璟alkyl group to 1-6 C ^{atoms, - CR 17 R 18 - (} CH 2) q- CONR 19 R 20, -CR 17 R 18 - (CH 2) q-NR 19 COR 20, — CR ¹⁷ R ¹⁸ — (CH ₂ ) q— NR ¹⁹ S 0 ₂ R ² . ^{, - CR 17 R 18 - (} CH 2) q- OR 19, -CR 17 R 18 - (CH 2) q-NR 19 R Z0, - CR 17 R 18 - (CH 2) q - SR 19, one CR _{^{17 R 18 - (CH 2)}} q- S 0 2 R 19 or a _{^{CR 17 R 18 - (CH 2}} ) q-NR 19 - V- NR M R 21 ( wherein, R ¹⁷ and R ¹⁸ that it independently A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a hydroxyalkyl group having 1 to 5 carbon atoms, an aminoalkyl group having 1 to 5 carbon atoms, a carbon number of 1 to 13 Represents an arylalkyl group or a heterocyclic alkyl group having 1 to 6 carbon atoms, R ¹⁹ , R ^2D and R ²¹ each independently represent the same meaning as R ^15, and V represents a carbonyl group or a thiocarbonyl group. And q represents an integer of 0 to 5. The (thio) ゥ rare derivative or a salt thereof according to claim 1, wherein  3. General formula (II) (I I)

(In the formula, X ¹ , X ² and R ¹ represent the same meaning as described above, and R represents an alkyl group having 1 to 6 carbon atoms.) And a compound represented by Z—H (wherein Z has the same meaning as described above) and a carbonyl or thiocarbonyl group-introducing reagent are reacted to obtain a compound represented by the general formula (I-a ) (l-a)

(Wherein X ¹ , Υ \ Υ, τ R ¹ and R have the same meanings as described above.) A compound represented by the general formula (I): (I)

(Wherein, X ¹ , X ² , Y, Ζ, and R ¹ represent the same meaning as described above.) A method for producing a (chi) rare derivative represented by the formula:  4. A medicament comprising the (thio) perrea derivative according to claim 1 or 2 or a salt thereof as an active ingredient.  5. A VLA-4 amino gonist containing the (thio) pera derivative according to claim 1 or 2 or a salt thereof as an active ingredient.  6. A method for treating a disease mediated by cell adhesion, which comprises administering the (thio) diarea derivative or a salt thereof according to claim 1 or 2.  7. A method for treating a disease mediated by cell adhesion, which comprises administering the medicament according to claim 4. 8. A cell comprising administering the VLA-4 antagonist of claim 5. A method for treating a disease through adhesion.  9. The therapeutic method according to claim 6, 7, or 8, which inhibits cell adhesion via VLA-4.