JP2000086657A - 5-aminoisoxazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having excellent inhibitory effect on P38 MAP kinase especially activating a certain kind of transcription factor, and useful as a treatment agent for tumor necrosis factor(TNF)-α-related diseases, interleukin-1-related diseases, cyclooxigenaseII-related diseases, or the like based on the above inhibitory activity. SOLUTION: This new compound (or a salt thereof) is represented by formula I (X is H or a halogen; R1 is H or a lower alkyl; R2 is H, an organic sulfonyl or the like; wherein, when X is H, R1 and R2 are each not H at the same time), e.g. 3-(4-fluorophenyl)-5-methylamino-4-(4-pyridyl) isoxazole. The compound of formula I where R1 and R2 are each H is obtained by treating an aldehyde compound of formula II with hydroxylamine (salt) to form an oxime compound, which is then halogenated, and the resulting halide of formula III is then reacted with acetonitrile. A dose of the compound of formula I is pref. 0.1-2 mg/kg.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel 5-aminoisoxazole derivative or a salt thereof. The compound of the present invention has a P38 MAP kinase (CSBP kinase) inhibitory activity and a tumor necrosis factor-α (hereinafter referred to as “TNF
-Α ”), interleukin-1 (hereinafter“ IL-
1)), interleukin-6 (hereinafter "IL-
6 ") or cyclooxygenase II (hereinafter referred to as" C
OX-II ").
It is useful as a therapeutic agent for TNF-α-related diseases, IL-1-related diseases, IL-6-related diseases or COX-II-related diseases.

[0002]

2. Description of the Related Art TNF-α, IL-1, IL-6 and C
OX-II is a protein mainly produced from immunocompetent cells such as macrophages and neutrophils, and is one of important factors involved in, for example, immunoregulatory functions and inflammatory symptoms.
Further, TNF-α and the like are known as factors involved in many biological reactions in the hematopoietic system, endocrine system, nervous system and the like. Therefore, production of TNF-α or the like in a living body in an excessive or uncontrolled manner is considered to be closely related to the occurrence or deterioration of related diseases such as TNF-α.

On the other hand, P present in various cells in a living body
38 MAP kinase is known to specifically activate certain transcription factors. That is, NF-κB, AP-
1, transcription factors such as CREB are TNF-α, IL-1,
DNA of a certain sequence common to IL-6, COX-II, etc.
And promotes transcription, but these transcription factors are activated by the action of P38 MAP kinase in the cell nucleus, and as a result, proteins such as TNF-α are synthesized from the transcribed mRNA. In addition, mRNA that has exited the nucleus in the presence of calcium ions becomes inactive by binding to a protein having a specific sequence, and is rapidly degraded. However, P38 MAP kinase activated by phosphorylation becomes inactive. When present, mRNA is dissociated from the protein and becomes activated, and as a result, TNF-α,
It is thought that the synthesis of proteins such as IL-1, IL-6, and COX-II is promoted.

Therefore, by inhibiting this P38 MAP kinase, TNF-α, IL-1, IL-6, CO
It is considered that the production of X-II and the like is inhibited. Based on this idea, a compound having a P38 MAP kinase inhibitory activity and a compound having a TNF-α, IL-1, IL-6, COX-II or other production inhibitory activity based on the inhibitory activity is considered. Several proposals have been made (eg, Bioorganic & Medicinal Chemistry, Vol. 5,
No. 1, pp. 49-64, 1997 and JP-A-7-503017).

[0005] These TNF-α production inhibitors, IL-1
A production inhibitor, an IL-6 production inhibitor or a COX-II production inhibitor is a TNF-α-related disease, an IL-1-related disease,
L-6 related disease or COX-II related disease such as rheumatoid arthritis, cachexia, acute infection, acute inflammation, chronic inflammation, malignancy, autoimmune disease, diabetes, psoriasis, Crohn's disease, AIDS, ischemic Heart disease, cerebrovascular disorder, meningitis,
Tuberculosis, multiple cerebral sclerosis, sepsis, DIC, multiple myeloma, Castleman disease, mesangial proliferative nephritis,
It is expected to be effective in treating or preventing diseases such as colon polyps and colon cancer.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a group of 5-aminoisoxazole derivatives or salts thereof which exhibit excellent P38 MAP kinase inhibitory activity.

[0007] Another object of the present invention is to provide an excellent P38MAP.
TNF-α-related diseases based on kinase inhibitory action, IL-
An object of the present invention is to provide a therapeutic agent for 1-related disease, IL-6-related disease or COX-II-related disease.

[0008]

Means for Solving the Problems The present inventors have found that in a 5-aminoisoxazole derivative, the 3-position of the isoxazole ring is substituted with a phenyl group which may be substituted with halogen, and The compound substituted at the 4-position with a 4-pyridyl group has an excellent P38 MAP kinase inhibitory activity, and TNF-α, IL-1, IL
-6 and COX-II.

According to the present invention, the compound represented by the general formula (I)

[0010]

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[0011] In the formula, X represents a hydrogen or halogen atom, R ¹ represents a hydrogen atom or a lower alkyl group, R ²
Is a hydrogen atom, a lower alkyl group, an aralkyl group, an organic sulfonyl group or

[0012]

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Wherein R ³ represents a hydrogen atom or an organic residue, Y represents an oxygen or sulfur atom, W represents a direct bond, an oxygen atom or —NH—, provided that X is a hydrogen atom. In some cases, the present invention provides a 5-aminoisoxazole derivative represented by the formula: wherein R ¹ and R ² do not simultaneously represent a hydrogen atom, or a salt thereof.

In the present specification, the term "lower" means that the group or compound to which this term is attached has 6 or less carbon atoms,
It means that the number is preferably 4 or less.

Thus, as the "lower alkyl group",
For example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-
Examples thereof include butyl, n-pentyl, and n-hexyl groups.

An "aralkyl group" is an alkyl group substituted with an aryl group, preferably an aryl-substituted lower alkyl group such as benzyl, 1-phenylethyl, 2-
Phenylethyl, 1-phenylpropyl, 3-phenylpropyl, 4-phenylbutyl, 1-naphthylmethyl,
Examples thereof include 2-naphthylmethyl and diphenylmethyl groups.

The "organic sulfonyl group" is a residue obtained by removing a hydroxy group from an organic sulfonic acid.
Examples include methanesulfonyl, ethanesulfonyl, benzenesulfonyl, and p-toluenesulfonyl groups. On the other hand, the “halogen atom” includes fluorine, chlorine, bromine and iodine atoms.

The “organic residue” represented by the symbol R ³ is not particularly limited as long as it is a residue composed of an organic compound. In this specification, generally, the term “substituted or unsubstituted” refers to a saturated or unsaturated substituted or unsubstituted. It means a linear, branched or cyclic hydrocarbon group, a substituted or unsubstituted heterocyclic group or a substituted carbonyl group.

Here, "a substituted or unsubstituted, saturated or unsaturated, linear, branched or cyclic hydrocarbon group"
Preferably, substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, bridged cycloalkyl or spiroalkyl group, more preferably, substituted or unsubstituted alkyl, cycloalkyl or Aryl groups are mentioned, among which particularly preferred are substituted or unsubstituted lower alkyl, cycloalkyl having 5 to 7 carbon atoms or aryl group having 6 to 10 carbon atoms.

In the present specification, the “alkyl group” generally includes an alkyl group having 1 to 20 carbon atoms,
For example, in addition to the lower alkyl group, 5-methylhexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl, n-octadecyl group and the like are mentioned, and the `` alkenyl group '' generally has a number of carbon atoms. It includes 2 to 20 alkenyl groups, e.g. vinyl, allyl, 1-propenyl, isopropenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 1,4-hexadienyl, 9
An alkynyl group generally includes an alkynyl group having 2 to 20 carbon atoms, such as an ethynyl, 2-propynyl, and 4-pentynyl group. Further, the “cycloalkyl group” generally includes a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. The "group" generally includes a cycloalkenyl group having 4 to 10 carbon atoms, for example, 2-cyclobutenyl, 2-cyclopentenyl, 2-cyclohexenyl group and the like, and the "aryl group" generally includes a carbon atom. The aryl group includes 6 to 20 aryl groups, such as phenyl, 1-indenyl, 1-naphthyl, 2-naphthyl, 1-azulenyl, 2-anthryl, 2-phenanthryl, and 1-acenaphthenyl. Further, the “bridged cycloalkyl group” generally includes a bridged cycloalkyl group having 4 to 20 carbon atoms, for example, bicyclo [2.2.1] hept-2-yl, bicyclo [3.2.1]. Oct-2-yl, bicyclo [4.3.2] undec-2-yl, an adamantyl group and the like, and the “spiroalkyl group” generally includes a spiroalkyl group having 7 to 20 carbon atoms. For example, spiro [4.5] dec-2-yl, spiro [5.5]
And a deca-3-yl group.

The heterocyclic group in the “substituted or unsubstituted heterocyclic group” used in the present specification is
Preferably, a heteroatom selected from N, O and S is 1
May be a monocyclic or polycyclic saturated or unsaturated heterocyclic ring containing from 4 to 4 and one ring is a 4- to 8-membered ring, wherein the heterocyclic ring has a cyclic hydrocarbon group and a condensed ring. It may be formed. More preferred among such heterocyclic groups are monocyclic or bicyclic rings containing one or two heteroatoms selected from N, O and S and one ring being a 5- or 6-membered ring. Examples include a saturated or unsaturated heterocyclic group of the formula, which may be optionally condensed with a phenyl group.

Thus, these "heterocyclic groups" include, for example, pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyranyl, pyrimidinyl, pyridazinyl, pyrazinyl, Azepinyl, azocinyl, purinyl,
Naphtidinyl, pteridinyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl, morpholinyl, benzothienyl, benzofuranyl, indolyl, isoindolyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinolyl, isoquinolyl, cloquinyl, clomenyl Carbazolyl, phenanthridinyl, acridinyl, dibenzazepinyl, indolinyl, isoindolinyl, 1,2,3,4
-Tetrahydroisoquinolyl, chromanyl, isochromanyl groups and the like.

Further, the term "substituted carbonyl group" used in the above definition of "organic residue" means a substituted carbonyl group, preferably a substituted or unsubstituted alkyloxycarbonyl, alkylcarbonyl or aryl. A carbonyl group is exemplified, and more preferable examples thereof include a substituted or unsubstituted lower alkyloxycarbonyl or phenylcarbonyl group.

Examples of the substituent in the “substituted or unsubstituted alkyl group” used in the definition of the organic residue include a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an arylcarbonyloxy group, an aryloxy group. Group, mercapto group, lower alkylthio group, lower alkanoylthio group, arylcarbonylthio group, arylthio group, amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, arylcarbonylamino group, aralkyloxycarbonylamino Group, lower alkoxycarbonylamino group, N-lower alkyl-N-lower alkoxycarbonylamino group, guanidino group, carboxy group, lower alkoxycarbonyl group, aralkyloxycarbonyl group, carbamoyl group, Lower alkylcarbonyl group, arylcarbonyl group, cycloalkyl group, aryl group (this aryl group may be halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group, lower alkylenedioxy group, hydroxy group, lower alkanoyl Substituted with one to three substituents selected from an oxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, an aralkyloxycarbonylamino group, a lower alkoxycarbonylamino group and a nitro group. Or a monocyclic or bicyclic ring containing one or two heteroatoms selected from N, S and O, wherein one ring is a 5- or 6-membered ring and may be condensed with a benzene ring A saturated or unsaturated heterocyclic group (this heterocyclic group may be a halogen atom , Lower alkyl group, and a lower alkoxy group and a nitro group 1
Or may be substituted with two substituents), and the alkyl group can be substituted with one to three substituents selected from these. Among them, particularly preferred are a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an aryloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, an aralkyloxycarbonylamino group, and a lower alkoxycarbonylamino group. , N-lower alkyl-N-lower alkoxycarbonylamino group, carboxy group, lower alkoxycarbonyl group, cycloalkyl group, aryl group (this aryl group is optionally halogen atom, lower alkyl group, halogenated lower alkyl group, lower alkoxy group) Group, a hydroxy group, a lower alkanoyloxy group, an amino group, a lower alkoxycarbonylamino group and a nitro group, which may be substituted with one or two substituents) and a hetero atom selected from N and S Containing A monocyclic or bicyclic unsaturated heterocyclic group in which one ring is a 5-membered ring and may be condensed with a benzene ring (this heterocyclic group may be optionally substituted by a lower alkyl group; Or a lower alkyl group which may be substituted with one or two substituents selected from the following.

The substituent in the "substituted or unsubstituted cycloalkyl group" used in the definition of the organic residue includes, for example, a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, a carboxy group, a lower alkoxy group. A carbonyl group and an oxo group, and the cycloalkyl group is one or two selected from these;
May be substituted with at least one substituent. Among them, particularly preferable ones are unsubstituted and having 5 to 7 carbon atoms.
Cycloalkyl groups.

Examples of the substituent in the "substituted or unsubstituted aryl group" used in the definition of the organic residue include a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylenedioxy group, a hydroxy group,
A lower alkanoyloxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, a nitro group, and the like.The aryl group is substituted with one to three substituents selected from these. Can be. Among them, particularly preferred are unsubstituted aryl groups having 6 to 10 carbon atoms.

The substituent in the "substituted or unsubstituted heterocyclic group" used in the definition of the organic residue includes, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylenedioxy group, a hydroxy Group, lower alkanoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, aralkyloxycarbonyl group, lower alkoxycarbonyl group, nitro group, and the like. May be substituted with 1 to 3 substituents selected from Among them, particularly preferable ones may be optionally substituted by one aralkyloxycarbonyl group or lower alkoxycarbonyl group, contain one or two heteroatoms selected from N and O, and form one ring. Is a 5- or 6-membered ring, and may be a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may be condensed with a benzene ring.

The “substituted or unsubstituted lower alkyloxycarbonyl group” used in the definition of the substituted carbonyl group includes, for example, a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group and an aryl group (optionally). These groups may be optionally substituted with a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a hydroxy group, a lower alkanoyloxy group, an amino group, a lower alkoxycarbonylamino group or a nitro group. 1 selected from
Or a lower alkyloxycarbonyl group which may be substituted with two substituents. Among them, a particularly preferable example is an unsubstituted lower alkyloxycarbonyl group.

The "substituted or unsubstituted phenylcarbonyl group" used in the definition of the substituted carbonyl group may be, for example, a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, an amino group, a lower alkoxycarbonyl group. Examples include a phenylcarbonyl group which may be substituted with 1 to 3 substituents selected from an amino group and a nitro group. Among them, a particularly preferable example is an unsubstituted phenylcarbonyl group.

Further, in the present specification, a "lower alkoxy group" is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning, for example, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy. ,
and a t-butoxy group.

The "lower alkanoyloxy group" is a lower alkylcarbonyloxy group in which the lower alkyl moiety has the above-mentioned meaning, and includes, for example, acetoxy, propionyloxy, butyryloxy, valeryloxy and the like.

The "arylcarbonyloxy group" includes, for example, benzoyloxy, 4-nitrobenzoyloxy, 2-naphthoyloxy group and the like.

As the "aryloxy group", for example, phenoxy, 4-methylphenoxy, 1-naphthoxy group and the like can be mentioned.

As the "lower alkylthio group", for example, a methylthio, ethylthio, isopropylthio group and the like can be mentioned.

As the "lower alkanoylthio group", for example, acetylthio, propionylthio group and the like can be mentioned.

As the “arylcarbonylthio group”,
For example, a benzoylthio, 1-naltoylthio group and the like can be mentioned.

As the "arylthio group", for example, phenylthio, 2-naphthylthio group and the like can be mentioned.

The "lower alkylamino group" includes, for example, methylamino, ethylamino, n-propylamino and the like.

The "di-lower alkylamino group" includes, for example, dimethylamino, diethylamino, di-n-propylamino group and the like.

As the "lower alkanoylamino group",
For example, acetylamino, propionylamino group and the like can be mentioned.

The "arylcarbonylamino group" includes, for example, a benzoylamino group.

"Aralkyloxycarbonylamino group"
As, for example, benzyloxycarbonylamino,
4-bromobenzyloxycarbonylamino, 4-methoxybenzyloxycarbonylamino, 4-nitrobenzyloxycarbonylamino and the like.

The "lower alkoxycarbonylamino group" includes, for example, a t-butoxycarbonylamino group.

The "N-lower alkyl-N-lower alkoxycarbonylamino group" includes, for example, N-methyl-
Nt-butoxycarbonylamino, N-ethyl-N-
and a t-butoxycarbonylamino group.

As the "lower alkoxycarbonyl group", for example, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl group and the like can be mentioned.

As the "aralkyloxycarbonyl group", for example, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl group and the like can be mentioned.

As the “lower alkylcarbonyl group”,
For example, acetyl, propionyl group and the like can be mentioned.

The "arylcarbonyl group" includes, for example, a benzoyl group.

As the “halogenated lower alkyl group”,
For example, trifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like can be mentioned.

As the “lower alkylenedioxy group”,
For example, a methylenedioxy, ethylenedioxy, propylenedioxy group and the like can be mentioned.

A preferred group of compounds in the present invention is
A compound of the formula (I) wherein X represents a hydrogen atom, a 4-fluoro group or a 3-chloro group.

Another group of compounds which are preferred according to the invention are those of the formula (I) in which X represents a 4-fluoro or 3-chloro group and R ¹ and R ² both represent a hydrogen atom.
Is a compound of

Another group of compounds which are preferred according to the invention are the compounds of the formula (I) in which R ¹ represents a hydrogen atom.

Another group of compounds preferred in the present invention are those wherein R ² is

[0055]

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Is a compound of formula (I) wherein

A further group of compounds which are preferred according to the invention are those of the formula (I) in which Y represents an oxygen atom and W represents a direct bond.

Representative examples of the compounds of the formula (I) provided by the present invention include the following in addition to those listed in the following Examples.

3- (4-fluorophenyl) -5-methylamino-4- (4-pyridyl) isoxazole, 5-
Isobutylamino-3- (4-fluorophenyl) -4
-(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5-n-pentylamino-4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl)
-5-ethylamino-4- (4-pyridyl) isoxazole, 5-ethylamino-3-phenyl-4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (3-phenylpropylamino ) -4- (4
-Pyridyl) isoxazole, 3- (4-fluorophenyl) -5- [2- (1-naphthyl) ethylamino]-
4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl) -5- (2-phenylethylamino) -4
-(4-pyridyl) isoxazole, 3-phenyl-5
-(2-phenylethylamino) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl)-
5-methanesulfonylamino-4- (4-pyridyl) isoxazole, 5-ethanesulfonylamino-3- (4
-Fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl) -5- (4-methylbenzenesulfonylamino) -4- (4-pyridyl)
Isoxazole, 5-benzenesulfonylamino-3-
Phenyl-4- (4-pyridyl) isoxazole, 5-
n-heptanoylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4
-Fluorophenyl) -4- (4-pyridyl) -5-trifluoroacetylaminoisoxazole, 5- (3-
(Chloropropionylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 3-
(4-fluorophenyl) -5- (3-hydroxypropionylamino) -4- (4-pyridyl) isoxazole, 5-ethoxyacetylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5
-(3-acetoxypropionylamino) -3- (4-
(Fluorophenyl) -4- (4-pyridyl) isoxazole, 5-benzoyloxyacetylamino-3- (4
-Fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (3-phenoxypropionylamino) -4- (4-pyridyl)
Isoxazole, 3- (4-fluorophenyl) -5
Mercaptoacetylamino-4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5-methylthioacetylamino-4- (4-pyridyl) isoxazole, 5-acetylthioacetylamino-3- (4-
Fluorophenyl) -4- (4-pyridyl) isoxazole, 5-benzoylthioacetylamino-3- (4-
Fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5-phenylthioacetylamino-4- (4-pyridyl) isoxazole, 5-aminoacetylamino-3- (4-fluoro Phenyl) -4- (4-pyridyl) isoxazole, 3-
(4-fluorophenyl) -5- (L-leucylamino) -4- (4-pyridyl) isoxazole, 3- (4
-Fluorophenyl) -5-methylaminoacetylamino-4- (4-pyridyl) isoxazole, 5-diethylaminoacetylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5-acetylaminoacetyl Amino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5-
(N'-p-methoxycarbobenzoxy-L-alanylamino) -3- (4-fluorophenyl) -4- (4-
Pyridyl) isoxazole, 5- (N'-carbo-t-
Butoxy-glycylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5-arginylamino-3- (4-fluorophenyl) -4-
(4-pyridyl) isoxazole, 5-carboxyacetylamino-3- (4-fluorophenyl) -4- (4
-Pyridyl) isoxazole, 5- (4-carboxybutyrylamino) -3- (4-fluorophenyl) -4-
(4-pyridyl) isoxazole, 5- (3-t-butoxycarbonylpropionylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5- (3-benzyloxycarbonylpropionylamino)- 3- (4-fluorophenyl) -4- (4-
Pyridyl) isoxazole, 5- (3-carbamoylpropionylamino) -3- (4-fluorophenyl)-
4- (4-pyridyl) isoxazole, 5- (3-acetylpropionylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5- (3
-Benzoylpropionylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole,
5-cyclopentylacetylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole,
3- (4-fluorophenyl) -5- (5-phenyl)
Pentanoylamino-4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (2-fluorophenylacetylamino) -4- (4-pyridyl)
Isoxazole, 3- (4-fluorophenyl) -5
(4-isopropylphenylacetylamino) -4-
(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (2-methoxyphenylacetylamino) -4- (4-pyridyl) isoxazole, 3- (4
-Fluorophenyl) -5- (2,3-dimethoxyphenylacetylamino) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (2,3
-Methylenedioxyphenylacetylamino) -4-
(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (2-hydroxyphenylacetylamino) -4- (4-pyridyl) isoxazole, 3-
(4-fluorophenyl) -5- (4-methylaminophenylacetylamino) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (4-
Dimethylaminophenylacetylamino) -4- (4-
Pyridyl) isoxazole, 5- (4-acetylaminophenylacetylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 5- (4
-Carbobenzoxyaminophenylacetylamino)-
3- (4-fluorophenyl) -4- (4-pyridyl)
Isoxazole, 3- (4-fluorophenyl) -4-
(4-pyridyl) -5- (L-tyrosylamino) isoxazole, 3- (4-fluorophenyl) -4- (4-
Pyridyl) -5- (2-pyridylacetylamino) isoxazole, 3- (4-fluorophenyl) -4- (4
-Pyridyl) -5- (2-quinolylacetylamino) isoxazole, 3- (4-fluorophenyl) -5-
(3-piperidinopropionylamino) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -4- (4-pyridyl) -5- (L-tryptofilamino) isoxazole, 5- Cyclopentylcarbonylamino-3- (4-fluorophenyl) -4- (4
-Pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (4-methylcyclohexylcarbonylamino) -4- (4-pyridyl) isoxazole, 3-
(4-Fluorophenyl) -5- (4-hydroxycyclohexylcarbonylamino) -4- (4-pyridyl)
Isoxazole, 5- (2-chlorobenzoylamino)
-3- (4-Fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl)-
5- (4-hydroxybenzoylamino) -4- (4-
Pyridyl) isoxazole, 5- (4-acetylaminobenzoylamino) -3- (4-fluorophenyl)-
4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -4- (4-pyridyl) -5- (3-pyrrolylcarbonylamino) isoxazole, 3- (4-
Fluorophenyl) -5- (3-furoylamino) -4
-(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -4- (4-pyridyl) -5- (2-thenoylamino) isoxazole, 3- (4-fluorophenyl) -5- (3-indolyl Carbonylamino) -4
-(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (3-isoquinolylcarbonylamino) -4- (4-pyridyl) isoxazole, 3- (4
-Fluorophenyl) -5- (4-methylpiperazinylcarbonylamino) -4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl) -5- (4-chlorophenylacetylamino) -4- (4- Pyridyl) isoxazole, 3- (3-chlorophenyl) -5- (4-
Methylphenylacetylamino) -4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl) -5
-(4-hydroxyphenylacetylamino) -4-
(4-pyridyl) isoxazole, 5- (4-aminophenylacetylamino) -3- (3-chlorophenyl)
-4- (4-pyridyl) isoxazole, 3- (3-chlorophenyl) -4- (4-pyridyl) -5- (3-thienylacetylamino) isoxazole, 5- (L-alanylamino) -3- (3- Chlorophenyl) -4-
(4-pyridyl) isoxazole, 3- (3-chlorophenyl) -4- (4-pyridyl) -5- (4-quinolylcarbonylamino) isoxazole, 5-ethoxalylamino-3- (4-fluorophenyl)- 4- (4-pyridyl) isoxazole, 5-benzyloxyoxalylamino-3- (4-fluorophenyl) -4- (4-
Pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (2-methoxyethoxyoxalylamino)
-4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (4-methoxyphenyloxalylamino) -4- (4-pyridyl) isoxazole,
3- (4-fluorophenyl) -5- (4-nitrophenyloxalylamino) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5-methoxycarbonylamino-4- (4-pyridyl ) Isoxazole, 5-isopropoxycarbonylamino-3- (4
-Fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (4-methoxybenzyloxycarbonylamino) -4- (4-
Pyridyl) isoxazole, 5- (4-chlorobenzyloxycarbonylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 3- (4
-Fluorophenyl) -5- (3-furylmethoxycarbonylamino) -4- (4-pyridyl) isoxazole, 5- (N'-ethylureido) -3- (4-fluorophenyl) -4- (4-pyridyl ) Isoxazole,
5- (N'-benzylureido) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole, 3
-(4-Fluorophenyl) -5- [N '-(p-methylbenzyl) ureido] -4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- [phenyl (thioacetylamino) ] -4- (4-pyridyl)
Isoxazole, 3- (4-fluorophenyl) -5
Dimethylamino-4- (4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- [N- (4-
Methoxyphenylacetyl) -N-methylamino] -4
-(4-pyridyl) isoxazole, 3- (4-fluorophenyl) -5- (N-ethyl-N-phenylacetylamino) -4- (4-pyridyl) isoxazole and the like.

The compounds of the formula (I) of the present invention can also form salts. Examples of the salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. And salts with organic acids such as acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid and p-toluenesulfonic acid. Among them, pharmaceutically acceptable salts are preferable.

According to the present invention, in formula (I), R
The compound of formula (I) wherein ¹ and R ² both represent a hydrogen atom has the formula

[0062]

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Wherein X is as defined above, wherein the aldehyde compound is treated with hydroxylamine or a salt thereof;
The following formula obtained

[0064]

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In the formula, X has the above-mentioned meaning, and is obtained by halogenating an oxime compound represented by the following formula:

[0066]

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In the formula, X ¹ represents a halogen atom, and X has the above-mentioned meaning, and can be produced by reacting a halide compound with 4-pyridylacetonitrile.

The compound of formula (I) thus obtained when R ¹ and R ² both represent a hydrogen atom, ie

[0069]

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Wherein X has the above-mentioned meaning, and in the case where X represents a halogen atom, the compound of the formula (V) is a novel compound which has not been described in a conventional literature. Which is one of the compounds

The compound of the above formula (V) is an important starting material for producing the compound of the formula (I) of the present invention when R ¹ and / or R ² in the above formula (I) represent other than a hydrogen atom. Can be used as raw material.

In the above formula (I), R¹ And / or R^Two 
Is a compound of the formula (I) according to the present invention wherein
Things are R¹ And R^Two Depends on the type of substituent represented by
For example, one of the following (a) to (f)
It can be manufactured by the method. Method (a) : In the above formula (I), R¹ Represents a hydrogen atom
I, R^Two But

[0073]

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Where Y is an oxygen atom and W
Compounds of formula (I) when but representing a direct bond or an oxygen atom, a compound of formula R ³ -W in ¹ -COOH (VI) formula of the formula (V), W ¹ represents a direct bond or an oxygen atom , R ³ can be produced by reacting with a carboxylic acid having the above-mentioned meaning or a reactive derivative thereof.

Method (b) : In the above formula (I), R ¹ represents a hydrogen atom and R ² represents

[0076]

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Where Y is an oxygen atom and W
There are compounds of formula (I) in which an oxygen atom or -NH-, treating a compound of formula (V) with an alcohol or the formula R ³ -NH ₂ amine phenyl chloroformate and wherein R ³ -OH It can be manufactured by the following.

Method (c) : In the above formula (I), R ¹ represents a hydrogen atom, and R ² represents

[0079]

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A compound of the formula (I) wherein Y represents a sulfur atom can be produced by treating a compound of the formula (I) wherein Y represents an oxygen atom with a Lawesson reagent. it can.

Method (d) : In the above formula (I), when R ¹ represents a hydrogen atom and R ² represents a lower alkyl group or an aralkyl group, the compound of the formula (I) comprises (i) R ² is lower It can be produced by reducing the compound of the formula (I) in the case of representing an alkylcarbonyl group or an aralkylcarbonyl group, or (ii) treating the compound of the formula (V) with a lower alkyl halide or an aralkyl halide. it can.

Process (e) : In the above formula (I), when R ¹ represents a hydrogen atom and R ² represents an organic sulfonyl group, the compound of the formula (I) is obtained by converting the compound of the above formula (V) to an organic sulfone. It can be produced by treating with an acid or a reactive derivative thereof.

Method (f) : When R ¹ in the above formula (I) represents a lower alkyl group, the compound of the formula (I)
It can be produced by treating a compound of the formula (I) wherein ¹ represents a hydrogen atom with a lower alkyl halide.

The reaction of the aldehyde compound of the formula (II) with hydroxylamine or a salt thereof is generally carried out in an inert solvent such as water; alcohols such as methanol and ethanol; organic carboxylic acids such as acetic acid and propionic acid. Can be done in The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from room temperature to 50 ° C.

The use ratio of hydroxylamine or a salt thereof to the aldehyde compound of the formula (II) is generally at least 1 mol, preferably 1.05 to 2 mol, of the hydroxylamine or the salt thereof per mol of the compound of the formula (II).
Mole, more preferably in the range of 1.1 to 1.5 mole. When a hydroxylamine salt is used in this reaction, the reaction is preferably performed in the presence of an alkali such as sodium hydroxide, potassium hydroxide, and sodium acetate.

The halogenation reaction of the resulting oxime compound of the formula (III) is generally carried out in an inert organic solvent, for example, amides such as dimethylformamide and dimethylacetamide; halogenated hydrocarbons such as chloroform and carbon tetrachloride. And the like, it can be carried out by treating with a halogenating reagent such as N-chlorosuccinimide, N-bromosuccinimide, sulfuryl chloride, chlorine and bromine. The reaction temperature is usually from 0 ° C. to 50 ° C., preferably from ice-cooled to about room temperature.

The use ratio of the halogenating reagent to the oxime compound of the formula (III) is generally at least 1 mol, preferably 1 to 1.5 mol, more preferably 1 mol, per mol of the compound of the formula (III). Is 1.
It can be in the range of from 01 to 1.2 mol.

The reaction between the thus obtained halide compound of the formula (IV) and 4-pyridylacetonitrile is generally carried out in an inert organic solvent, for example, alcohols such as methanol and ethanol; ethers such as dioxane, tetrahydrofuran and dimethoxyethane. And the like, sodium ethoxide, sodium methoxide, potassium-t
-In the presence of a base such as butoxide. The reaction temperature is usually from 0 ° C. to 50 ° C., preferably under ice cooling to about room temperature.

The proportion of 4-pyridylacetonitrile used per mole of compound of formula (IV) is generally at least 1 mole, preferably 1 to 1.5 mole, of 4-pyridylacetonitrile per mole of compound of formula (IV). Preferably it can be in the range of 1 to 1.05 mol.

Thus, the compound of the above formula (V) can be obtained in high yield, and as described above, the compound of the formula (I) of the present invention has a structure in which R ¹ and / or R ² is hydrogen. It can be used as an important starting material in the production of a compound when it represents other than an atom.

In the above method (a), the compound of the formula (V) and the carboxylic acid of the formula (VI) or a reactive derivative thereof (for example, acid chloride, acid anhydride, mixed acid anhydride, active amide, active ester, etc.) ) Is generally carried out in an inert organic solvent, for example, ethers such as dioxane, tetrahydrofuran and dimethoxyethane; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as dichloromethane and chloroform; Amides such as dimethylformamide and dimethylacetamide; among dimethylsulfoxide and the like, if necessary, a base such as 1,8
-Diazabicyclo [5.4.0] undec-7-ene (DBU), triethylamine, diisopropylethylamine, dimethylaminopyridine, pyridine, N-methylmorpholine and the like. The reaction temperature varies depending on the type of the carboxylic acid of the formula (VI) or its reactive derivative to be used, but it is usually 0 ° C. to the reflux temperature of the reaction mixture, preferably a temperature in the range of under ice-cooling to 50 ° C. ing.

In the method (a), when a free carboxylic acid is used as the carboxylic acid of the formula (VI), the carboxylic acid may be, for example, 1,1-carbonyldiimidazole,
It is preferable to convert to a reactive derivative such as imidazolide by treating with 1,1-thionyldiimidazole or the like.

When an acid chloride is used as the reactive derivative, the acid chloride can be treated with, for example, imidazole and DBU before converting to another reactive derivative such as imidazolide.

When the method (a) is carried out using an acid chloride as the reactive derivative, a carboxylic acid residue is introduced not only at the 5-position amino group of the isoxazole ring but also at the nitrogen atom constituting the isoxazole ring. Compounds may also be formed, which can be converted to the compounds of formula (I) of the present invention by subsequent treatment with an alkali such as sodium hydroxide, potassium hydroxide and the like.

In the method (a), the ratio of the carboxylic acid of the formula (VI) or the reactive derivative thereof to the compound of the formula (V) is generally based on the carboxylic acid of the formula (VI) per mole of the compound of the formula (V). The acid or its reactive derivative can be in the range of at least 1 mole, preferably 1.5 to 10 moles, more preferably 2 to 5 moles. The amount of the base used can be generally at least 1 mol, preferably 1 to 2 mol, per 1 mol of the carboxylic acid of formula (VI) or its reactive derivative.

In the above method (b), the treatment of the compound of formula (V) with phenyl chloroformate and an alcohol of formula R ³ —OH or an amine of formula R ³ —NH ₂ is generally carried out in an inert organic solvent, for example, Ethers such as dioxane, tetrahydrofuran and dimethoxyethane; halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride; amides such as dimethylformamide and dimethylacetamide; DB among dimethyl sulfoxide and the like;
U, triethylamine, diisopropylethylamine,
It can be carried out in the presence of a base such as dimethylaminopyridine, pyridine, N-methylmorpholine and the like. The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, and preferably from ice-cooled to 50 ° C.

In the method (b), a compound in which the amino group at the 5-position is phenoxycarbonylated once is produced as an intermediate, and the compound is subsequently reacted with the compound represented by the formula R ³ present in the reaction solution. -OH alcohol or formula R ³
By reaction with an amine of -NH _2, the compound of formula (I) of the present invention.

In the method (b), the proportion of phenyl chloroformate used relative to the compound of the formula (V) is generally at least 1 mol, preferably 1.5 to 10 mol of phenyl chloroformate per mol of the compound of the formula (V). Mole, more preferably in the range of 2-5 moles. Also, an alcohol of the formula R ³ —OH or a formula R ³ —NH ₂
It is usually preferable to use a large excess of the amine.
Further, the base can be used generally in a proportion within the range of 1 to 5 mol, preferably 1 to 2 mol, per 1 mol of phenyl chloroformate.

In the above method (c), when Y represents an oxygen atom, the treatment of the compound of the formula (I) with a Lawesson reagent is generally carried out in an inert organic solvent, for example, in the presence of an aromatic hydrocarbon such as benzene, toluene or xylene. It can be performed in hydrogen or the like. The reaction temperature is usually from 50 ° C. to the reflux temperature of the reaction mixture, preferably from 80 ° C. to the reflux temperature of the reaction mixture.

The Lawesson reagent used in the method (C) is 2,4-bis (4-methoxyphenyl) -1,
3-Dithia-2,4-diphosphetane-2,4-disulfide, which Lawson reagent is generally Y
Represents at least 1 mol, preferably 1.0 mol, of Lawesson's reagent per mol of the compound of formula (I)
It can be used in a ratio within the range of 5 to 1.5 mol.

In the above methods (d) and (i), when R ² represents a lower alkylcarbonyl group or an aralkylcarbonyl group, the reduction of the compound of the formula (I) is generally carried out in an inert organic solvent such as dioxane, tetrahydrofuran. , Dimethoxyethane and the like, and treatment with a borane-tetrahydrofuran complex, allane or the like. The reaction temperature is usually from room temperature to the reflux temperature of the reaction mixture, preferably from 50 ° C. to the reflux temperature of the reaction mixture.

The treatment of the compound of formula (V) in the above methods (d) and (ii) with a lower alkyl halide or an aralkyl halide is generally carried out in an inert organic solvent, for example, ethers such as dioxane, tetrahydrofuran and dimethoxyethane; Among amides such as dimethylformamide and dimethylacetamide; and aromatic hydrocarbons such as benzene and toluene, the reaction can be carried out in the presence of a base such as sodium hydride, sodium amide and potassium-t-butoxide. Examples of the lower alkyl halide or aralkyl halide that can be used in the above treatment include benzyl bromide, phenethyl bromide, methyl iodide, ethyl iodide, and isopropyl iodide. The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from ice-cooling to about room temperature.

The proportion of the lower alkyl halide or aralkyl halide to the compound of the formula (V) is generally
The halide can be at least 1 mol, preferably 1.1 to 2 mol, more preferably 1.1 to 1.5 mol, per 1 mol of the compound of the formula (V).

In the above method (e), the treatment with an organic sulfonic acid or a reactive derivative thereof (eg, acid chloride) is generally carried out in an inert organic solvent, for example, ethers such as dioxane, tetrahydrofuran and dimethoxyethane; benzene, toluene, and the like. The reaction can be carried out in aromatic hydrocarbons such as xylene; halogenated hydrocarbons such as dichloromethane and chloroform; amides such as dimethylformamide and dimethylacetamide; and dimethyl sulfoxide.
The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from ice-cooling to about room temperature.

It is preferred that the compound of formula (V) is previously treated with a base such as sodium hydride, sodium amide, potassium-t-butoxide and the like to activate its amino group.

In the method (e), the ratio of the organic sulfonic acid or the reactive derivative thereof to the compound of the formula (V) is generally at least one mole of the organic sulfonic acid or the reactive derivative thereof per mole of the compound of the formula (V). It can be in the range of 1 mol, preferably 1-2 mol, more preferably 1.05-1.5 mol.

In the above method (f), when R ¹ represents a hydrogen atom, the treatment of the compound of the formula (I) with a lower alkyl halide is generally carried out in an inert organic solvent, for example, an ether such as dioxane, tetrahydrofuran or dimethoxyethane. Amides such as dimethylformamide and dimethylacetamide; among aromatic hydrocarbons such as benzene and toluene, sodium hydride, sodium amide,
It can be carried out in the presence of a base such as potassium-t-butoxide. Lower alkyl halides that can be used in this treatment include, for example, methyl iodide,
Examples thereof include ethyl iodide and isopropyl iodide. The reaction temperature is usually from 0 ° C. to the reflux temperature of the reaction mixture, preferably from ice-cooling to about room temperature.

When R ¹ represents a hydrogen atom, the proportion of the lower alkyl halide to the compound of the formula (I) is generally at least 1 mole, preferably 1 mole, of the lower alkyl halide per mole of the compound of the formula (I). .1 to 1.5
It can be in the molar range.

In the present lower alkylation reaction, in addition to the conversion of the hydrogen atom of R ¹ in the compound of the formula (I) to a lower alkyl group, depending on the type of the group represented by R ² , May also introduce a lower alkyl group.

In the reaction described in the present specification, the group represented by R ² is an amino group, a hydroxy group,
When the compound contains a group which may participate in the reaction such as a carboxy group, the group may be a suitable protecting group, for example, a benzyloxycarbonyl group or a t-butoxycarbonyl group for an amino group, or an acetoxy group for a hydroxy group. Group,
It is advantageous that a methoxymethyl group or the like; a carboxyl group is appropriately protected with a methyl ester, an ethyl ester or the like, and the protective group is eliminated after the completion of the reaction.

The compound of formula (I) or a salt thereof produced as described above can be prepared by a method known per se, for example, a method such as recrystallization, distillation, column chromatography, thin layer chromatography and the like. It can be isolated and purified from the reaction mixture.

[0112]

The 5-aminoisoxazole derivative represented by the formula (I) or the salt thereof according to the present invention described above,
It has an excellent P38 MAP kinase inhibitory action and an inhibitory action on the production of TNF-α, IL-1, IL-6, COX-II, etc. based thereon.
It is useful as a therapeutic agent for -1 related diseases, IL-6 related diseases, COX-II related diseases and the like.

The compound of the formula (I) of the present invention or a salt thereof has a P
The 38 MAP kinase (P38 MAPK) inhibitory action can be measured as follows.

(1) Measurement of P38 MAPK binding inhibitory activity The P38 MAPK binding inhibitory activity was measured using the cytosol fraction of THP-1 cells, a human monocyte-derived cultured cell. That is, THP-1 cells were treated with a cell rice buffer (20 mM Tris-HCl buffer (pH 7.4), 1
The suspension was suspended in mM magnesium chloride, 1 mM PMSF (phenylmethylsulfonyl fluoride), 1 mM pepstatin A, 1 mM leupeptin, 10 mg / ml aprotinin, and then sonicated in water. Thereafter, the mixture was ultracentrifuged at 100,000 Xg for 1 hour, and the protein concentration of the resulting supernatant (cytosol fraction) was measured. The cell concentration of the cytosol fraction was adjusted to 1 mg / ml with a cell rice buffer. After dilution, it was aliquoted and stored at -80 ° C until use.

The binding inhibitory activity was determined by measuring the cytosol fraction of THP-1 cells (100 μg protein) and the test compound at 15 ° C.
After incubation for 30 minutes at ³ H-SB202190 (925 GBq / mmol,
(Amersham, UK)
The reaction was carried out at 3 ° C. for 3 hours. Non-specific binding was achieved with 20 μM S
B203580 was added and measured. To separate free and bound radioligand, charcoal solution (1%
After adding charcoal and 0.1% dextran T-70), the mixture was ice-cooled for 15 minutes and centrifuged (3,000 rpm, 1
0 min, 4 ° C). The radioactivity in the obtained supernatant was measured by adding a liquid scintillator and using a liquid scintillation counter.

The ³ H-
SB202190 is 4- (4-fluorophenyl)-
2- (4-hydroxy-3,5-di - ³ H- phenyl)
SB203580, which is -5- (4-pyridyl) imidazole and added for non-specific binding measurement,
(4-Fluorophenyl) -2- (4-methanesulfonylphenyl) -5- (4-pyridyl) imidazole.

The measurement results of the compound of the present invention are shown below.

Compound IC ₅₀ (nM) Example 2 0.241 Example 18 0.27 Example 20 0.020 Example 28 0.44 Example 58 7.05 Example 61 8.1 Example 78 4.7 As described above, the compound of the formula (I) or a salt thereof according to the present invention has excellent P38 MAPK binding inhibitory activity, and is used as a P38 MAP kinase inhibitor in the treatment and treatment of humans and other mammals. Thus, oral or parenteral administration (for example, intramuscular injection, intravenous injection, rectal administration, transdermal administration, etc.) can be performed.

When the compound of the present invention is used as a drug, it may be in a solid form (eg, tablet, hard capsule, soft capsule, granule, powder, fine granule, pill, troche, etc.) depending on the use. ), Semi-solid forms (eg, suppositories, ointments, etc.) or liquid forms (injections, emulsions, suspensions, lotions, sprays, etc.). Thus, non-toxic additives that can be used in the above formulations include, for example, starch, gelatin,
Glucose, lactose, fructose, maltose, magnesium carbonate, talc, magnesium stearate, methylcellulose, carboxymethylcellulose or salts thereof, gum arabic, polyethylene glycol, alkyl p-hydroxybenzoate, syrup, ethanol, propylene glycol, petrolatum, carbowax Glycerin, sodium chloride, sodium sulfite, sodium phosphate, citric acid and the like. The agent can also contain other therapeutically useful agents.

The content of the compound of the present invention in the medicament varies depending on its dosage form, but it is generally at a concentration of 0.1 to 50% by weight in solid and semi-solid forms, and in liquid form. In such a case, it is desirable to contain it at a concentration of 0.05 to 10% by weight.

The dose of the compound of the present invention can be varied widely depending on the kind of the target human or other warm-blooded animals, the administration route, the severity of the symptoms, the diagnosis by a doctor, and the like.
Generally, it can be 0.02 to 10 mg / kg, preferably 0.1 to 2 mg / kg per day. However, it is, of course, possible to administer an amount smaller than the lower limit or larger than the upper limit of the above range, depending on the severity of the patient's symptoms and the diagnosis of the doctor. The above dose can be administered once or several times a day.

[0122]

The present invention will be described more specifically with reference to the following examples.

Example 1 (a) Synthesis of 4-fluorobenzaldehyde oxime 47 ml of ethanol and 137 ml of ice water were added to 25 g of 4-fluorobenzaldehyde and 15.4 g of hydroxylamine hydrochloride. After dropping 42.8 ml of a 50% aqueous sodium hydroxide solution at an internal temperature of 25 to 30 ° C, the mixture was stirred at room temperature for 1 hour. After washing the reaction solution with ether,
The mixture was neutralized with concentrated hydrochloric acid under ice cooling, and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue obtained is n-
Recrystallization from hexane-ether gave 24.3 g (yield: 87%) of the title compound as colorless crystals.

Melting point: 86.6-88.0 ° C. (n-hexane-ether) ¹ H-NMR (CDCl ₃ ) δ: 8.11 (s, 1H),
7.75 (s, 1H), 7.70 to 7.40 (m, 2
H), 7.23-6.90 (m, 2H) Mass, m / e: 139 (M ⁺ , base) (b) Synthesis of N-hydroxy-4-fluorobenzenecarboximidyl chloride 4-fluorobenzaldehyde oxime After dissolving 19.4 g in 140 ml of dimethylformamide, the internal temperature was lowered to 4 ml.
While maintaining the temperature at 0 ° C or lower, N-chlorosuccinimide 1
8.9 g were gradually added. After stirring at room temperature for 1.5 hours, the reaction solution was poured into ice water and extracted with ether. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from n-hexane-ether to give 23.41 g of the title compound as colorless crystals (9.
7%).

Melting point: 67.4-70.1 ° C. (n-hexane-ether) ¹ H-NMR (CDCl ₃ ) δ: 8.08 (s, 1H),
7.87 (dd, J = 2.2 Hz, 6.8 Hz, 1
H), 7.81 (dd, J = 2.2 Hz, 6.8 Hz,
1H), 7.14 (dd, J = 2.2 Hz, 6.8H
z, 1H), 7.04 (dd, J = 2.2 Hz, 6.8)
Hz, 1H) Mass, m / e: 175 (M ⁺⁺ 2), 173
(M ⁺ ), 95 (base) (c) 5-amino-3- (4-fluorophenyl) -4
Synthesis of-(4-pyridyl) isoxazole After dissolving 2.92 g of sodium in 200 ml of anhydrous ethanol, 200 ml of a tetrahydrofuran solution of 15 g of 4-pyridylacetonitrile was added dropwise. Then, 200 ml of an ethanol solution of 22.06 g of N-hydroxy-4-fluorobenzenecarboximidoyl chloride was added dropwise under ice cooling (internal temperature 5 to 10 ° C.), and the mixture was stirred at room temperature for 2 hours. After the reaction solution was distilled off under reduced pressure, water was added, and the crystals were collected by filtration. By washing with ether, 31.86 g (yield: 98%) of the title compound as pale yellow crystals was obtained.

Melting point: 192.5 to 194.5 ° C. (ethanol-water) ¹ H-NMR (CDCl ₃ ) δ: 8.55 (dd, J =
(1.8 Hz, 4.4 Hz, 2H), 7.50 to 6.90.
(M, 4H), 7.05 (dd, J = 1.8 Hz, 4.
4Hz, 2H), 4.83 (bs, 2H) IR (KBr) νmax: 3460, 1644, 160
6 cm ^-1 Mass, m / e: 255 (M ⁺ , base) Example 2 Synthesis of 3- (4-fluorophenyl) -5-phenylacetylamino-4- (4-pyridyl) isoxazole 1.36 g and 1 of imidazole 3.04 g of, 8-diazabicyclo [5.4.0] undec-7-ene (hereinafter abbreviated as DBU) was dissolved in 50 ml of tetrahydrofuran, and 3.09 g of phenylacetyl chloride was stirred under ice-cooling and stirring.
Was added dropwise, and the mixture was stirred at room temperature for 30 minutes. Then, 5-amino-3- (4-
After 2.55 g of (fluorophenyl) -4- (4-pyridyl) isoxazole and 20 ml of a tetrahydrofuran solution of 3.04 g of DBU were added dropwise, the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution, and extracted with ethyl acetate.
After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (350 g, elution solvent, chloroform: methanol = 40: 1) to obtain 3.06 g (yield: 82%) of the title compound as colorless crystals.

Melting point: 164.5-165.5 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 8.48 (dd, J =
1.7 Hz, 4.5 Hz, 2H), 7.69 (bs, 1
H), 7.50-6.97 (m, 9H), 6.89 (d
d, J = 1.7 Hz, 4.5 Hz, 2H), 3.75
(S, 2H) IR (KBr) νmax: 1712, 1630, 160
2,1436 cm ^-1 Mass, m / e: 373 (M ⁺ ), 91 (base) Examples 3 to 6 The corresponding acid chloride was used and treated in the same manner as in Example 2.
The compounds in Table 1 were obtained.

[0128]

[Table 1]

Example 7 Synthesis of 3- (4-fluorophenyl) -5-hydroxyacetylamino-4- (4-pyridyl) isoxazole 5-acetoxyacetylamino-3- (4-fluorophenyl) -4- (4 -Pyridyl) isoxazole 71 m
g was dissolved in 3 ml of ethanol, and 0.40 ml of a 1N aqueous sodium hydroxide solution was added dropwise with stirring at room temperature.
Stirred for hours. After concentrating under reduced pressure, adding 15 ml of water,
Neutralized with 0.40 ml of 1N hydrochloric acid. Chloroform 20m
The mixture was extracted three times with l, the organic layers were combined, washed with 10 ml of a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography 22 g (elution solvent, ethyl acetate: methanol =
9: 1), 56 mg of the title compound as a white powder
(Yield: 100%) was obtained. Melting point: 160.0-16
3.0 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.87 to 8.97 (b
r, 1H), 8.49 (dd, J = 1.6, 4.5H
z, 2H), 7.47-6.94 (m, 6H), 4.3
0 (s, 2H), 1.46 to 2.29 (br, 1H) IR (KBr) νmax: 3300, 1704, 163
8 cm ^-1 Mass, m / e: 313 (M ⁺ ), 255 (bas
e) Example 8 5- (3-carboxylpropionylamino) -3-
Synthesis of (4-fluorophenyl) -4- (4-pyridyl) isoxazole 5- (3-ethoxycarbonylpropionylamino)-
3- (4-fluorophenyl) -4- (4-pyridyl)
Isoxazole (58 mg) was dissolved in a mixture of ethanol (15 ml) and tetrahydrofuran (5 ml), and stirred at room temperature for 1N.
After dropwise adding 0.30 ml of an aqueous sodium hydroxide solution, 2
Stir for 1 hour. After concentrating under reduced pressure, adding 30 ml of water, washing twice with 10 ml of ether, and adding 0.30 of 1N hydrochloric acid.
Neutralized with ml. Extract three times with 30 ml of chloroform,
The organic layers were combined, washed with 5 ml of saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was recrystallized from chloroform-methanol to obtain 24 mg (yield: 45%) of the title compound as a white powder.

Melting point: 172.0-174.0 ° C. (chloroform-methanol) ¹ H-NMR (CD ₃ OD) δ: 8.49 (br, 2
H), 7.84-7.04 (m, 6H), 2.64.
(S, 4H) IR (KBr) νmax: 3244, 1696, 161
0 cm ^-1 Mass, m / e: 355 (M ⁺ ), 55 (base) Example 9 3- (4-Fluorophenyl) -5- (4-methylphenylacetylamino) -4- (4-pyridyl) isoxazole Synthesis of 4-methylphenylacetic acid (265 mg) and 1,1′-carbonyldiimidazole (286 mg) in tetrahydrofuran (1)
It was dissolved in 0 ml and stirred at room temperature for 1 hour. 5-amino-
3- (4-fluorophenyl) -4- (4-pyridyl)
A solution of 150 mg of isoxazole and 268 mg of DBU in 2 ml of anhydrous tetrahydrofuran were added sequentially,
Stir for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography 80 g (eluent, chloroform: methanol = 40: 1) to obtain 118 mg (yield: 52%) of the title compound.

Melting point: 191.3-192.0 ° C. (n-hexane-ethyl alcohol) ¹ H-NMR (CDCl ₃ ) δ: 8.49 (dd, J =
1.5 Hz, 4.6 Hz, 2H), 7.49 (bs, 1
H), 7.44-6.96 (m, 8H), 6.90 (d
d, J = 1.5 Hz, 4.6 Hz, 2H), 3.71
(S, 2H), 2.37 (s, 3H) IR (KBr) νmax: 3236, 1694, 163
2,1600, 1496 cm ^-1 Mass, m / e: 387 (M ⁺ ), 225, 105 (b
case) Examples 10-46 Treated in the same manner as in Example 9, using the corresponding carboxylic acid,
The compounds in Tables 2, 3, 4, 5, 6, and 7 were obtained.

[0132]

[Table 2]

[0133]

[Table 3]

[0134]

[Table 4]

[0135]

[Table 5]

[0136]

[Table 6]

[0137]

[Table 7]

Example 47 Synthesis of 5- (L-alanylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole hydrochloride 5- (N′-carbo-t-butoxy-L-alanylamino ) -3- (4-Fluorophenyl) -4- (4-pyridyl) isoxazole was dissolved in 10 ml of ethyl acetate,
6 ml of a 15% hydrogen chloride methanol solution or 10 ml of a 3N hydrogen chloride-dioxane solution was added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, the obtained residue was suspended in ethyl acetate, and the precipitated powder was collected by filtration to obtain 42 mg (yield 59%) of the title compound as a white powder.

Melting point: 174.5 to 177.6 ° C. ¹ H-NMR (CD ₃ OD) δ: 8.74 (d, J = 5.
7 Hz, 2H), 7.86 (d, J = 6.6 Hz, 2
H), 7.56-7.11 (m, 4H), 4.22.
(Q, J = 7.3 Hz, 1H), 1.68 (d, J =
7.0 Hz, 3H) IR (KBr) νmax: 3600 to 2700, 172
4,1630,1520,1434 cm ^-1 Mass, m / e: 326 (M ⁺ ) Examples 48 to 50 The corresponding raw materials were treated in the same manner as in Example 47 to obtain the compounds in Table 8.

[0140]

[Table 8]

Example 51 Synthesis of 3- (4-fluorophenyl) -5-isobutyrylamino-4- (4-pyridyl) isoxazole 5-amino-3- (4-fluorophenyl) -4- (4
255 mg of-(pyridyl) isoxazole was dissolved in 20 ml of chloroform, 330 mg of isobutyryl chloride and 0.44 ml of triethylamine were added under ice-cooling and stirring, and the mixture was stirred at room temperature for 90 minutes. Water was added to the reaction solution, and extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was dissolved in 10 ml of methanol at room temperature, 1 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred for 30 minutes. The solvent was distilled off under reduced pressure, and the obtained residue was dissolved in 10 ml of water, neutralized with 2N hydrochloric acid, and the precipitated solid was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 30 g of the obtained residue was subjected to silica gel column chromatography (elution solvent, chloroform: methanol = 3).
0: 1) to give 250 mg of the title compound as colorless crystals
(Yield: 77%) was obtained.

Melting point: 213.5-215.8 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 8.57 (dd, J =
1.8 Hz, 4.6 Hz, 2H), 7.76 (bs, 1
H), 7.47-6.95 (m, 6H), 2.61.
(M, 1H), 1.22 (d, J = 7.0 Hz, 6H) IR (KBr) νmax: 1692, 1634, 159
6,1436 cm ^-1 Mass, m / e: 325 (M ⁺ ), 255 (bas
e) Examples 52-62 The corresponding compounds were treated as in Example 51 using the corresponding acid chloride to give the compounds of Tables 9 and 10.

[0143]

[Table 9]

[0144]

[Table 10]

Example 63 Synthesis of 5-benzyloxycarbonylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole 5-amino-3- (4-fluorophenyl) -4- (4
-Pyridyl) isoxazole 100 mg and triethylamine 119 mg, DBU 179 mg to chloroform solution 10 ml to carbobenzoxycyclolide 200 mg,
10 mg of dimethylaminopyridine was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by 40 g of silica gel column chromatography (elution solvent, chloroform: methanol = 50: 1) to obtain 63 mg (yield: 41%) of the title compound as a white powder. .

Melting point: 183.5-184.1 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.50 (m, 2H),
7.45 to 6.96 (m, 9H), 5.11 (s, 2
H) IR (KBr) νmax: 1746, 1630, 160
Example 2 Synthesis of 5-ethoxycarbonylamino-3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole 5-cm ^-1 Mass, m / e: 389 (M ⁺ ), 91 (base) -3- (4-Fluorophenyl) -4- (4
-Pyridyl) isoxazole 150 mg, triethylamine 178 mg, DBU 268 mg ethanol to chloroform solution 10 ml to phenyl chloroformate 2
76 mg and 10 mg of dimethylaminopyridine were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by 40 g of silica gel column chromatography (eluent, chloroform: methanol = 100: 1) to give 106 mg of the title compound as a white powder (yield: 55%).
I got

Melting point: 172.1 to 172.6 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.58 (dd, J =
1.54 Hz, J = 4.4 Hz, 2H), 7.47-
6.95 (m, 6H), 4.14 (q, J = 7.0H)
z, 2H), 1.22 (t, J = 7.0 Hz, 3H) IR (KBr) νmax: 2988, 1742, 163
8, 1606, 1520, 1442 cm ^-1 Mass, m / e: 327 (M ⁺ ) Example 65 5- (n-butoxycarbonylamino) -3- (4-fluorophenyl) -4- (4-pyridyl) isoxazole Synthesis of 5-amino-3- (4-fluorophenyl) -4- (4
-Pyridyl) isoxazole 150 mg, triethylamine 178 mg and n-butanol 131 mg were dissolved in tetrahydrofuran, and phenyl chloroformate 276 m
After stirring for 10 minutes, 268 mg of DBU and 10 mg of dimethylaminopyridine were added, and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (40 g, elution solvent, chloroform: methanol = 100: 1) to obtain 103 mg (yield: 49%) of the title compound as a white powder. .

Melting point: 134.0-136.7 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.61 (dd, J =
1.5 Hz, J = 4.4 Hz, 2H), 7.48-6.
96 (m, 4H), 7.14 (dd, J = 1.5 Hz,
J = 4.4 Hz, 2H), 4.14 (t, J = 6.6H)
z, 2H), 1.68-1.14 (m, 4H), 0.9
2 (t, J = 5.7 Hz, 3H) IR (KBr) νmax: 3076, 2964, 174
0, 1640, 1606, 1442 cm ^-1 Mass, m / e: 355 (M ⁺ ), 57 (base) Examples 66 to 69 Using the corresponding alcohol or amine, Example 6
The same treatment as in Example 5 gave the compounds in Table 11.

[0149]

[Table 11]

Example 70 3- (4-Fluorophenyl) -5- [N-methyl-N
-(2-phenylpropionyl) amino] -4- (4-
Synthesis of pyridyl) isoxazole and 3- (4-fluorophenyl) -5- (N-methyl-N-phenylacetylamino) -4- (4-pyridyl) isoxazole 5 ml of a suspension of 48 mg of 60% sodium hydride in dimethylformamide 3- (4-fluorophenyl) -5
-Phenylacetylamino-4- (4-pyridyl) isoxazole 255 mg in dimethylformamide solution 5 m
After the dropwise addition of l, the mixture was stirred at room temperature for 30 minutes. Then, 2 ml of a dimethylformamide solution containing 170 mg of methyl iodide
After dropwise addition, the mixture was stirred at room temperature for 1 hour. Dimethylformamide was distilled off under reduced pressure, and after extraction with chloroform, the organic layer was washed with water and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, silica gel column chromatography 30 g (elution solvent, n-hexane-ethyl acetate = 1: 1)
Purified in 1), and 80 mg of 3- (4-fluorophenyl) -5- [N-methyl-N- (2-phenylpropionyl) amino] -4- (4-pyridyl) isoxazole was used as the first eluate. Colorless oil, yield: 29%), as the second eluate, 3- (4-fluorophenyl) -5-
(N-methyl-N-phenylacetylamino) -4-
60 mg (colorless oil, yield: 23%) of (4-pyridyl) isoxazole was obtained.

First eluate ¹ H-NMR (CDCl ₃ ) δ: 8.42 (dd, J =
1.5Hz, 4.4Hz, 2H), 7.50-6.93
(M, 9H), 6.50 (dd, J = 1.5 Hz, 4.
4 Hz, 2H), 3.93 (q, J = 6.8 Hz, 1
H), 3.05 (s, 3H), 1.45 (d, J = 6.
8 Hz, 3H) IR (KBr) νmax: 1690, 1630 cm ^-1 Mass, m / e: 401 (M ⁺ ), 105 (bas)
e) Second eluate ¹ H-NMR (CDCl ₃ ) δ: 8.50 (dd, J =
(1.8 Hz, 4.4 Hz, 2H), 7.50 to 6.93.
(M, 9H), 6.69 (dd, J = 1.8 Hz, 4.
4 Hz, 2H), 3.72 (s, 1H), 3.11
(S, 3H) IR (NaCl) νmax: 1690, 1630 cm ^-1 Mass, m / e: 387 (M ⁺ ), 91 (base) Example 71 3- (4-Fluorophenyl) -5- (3-phenylpropyl arylamino) -4- (4-pyridyl) synthesis of isoxazole 1.0MBH ₃ - added a tetrahydrofuran solution 1ml of tetrahydrofuran 10 ml, with stirring under ice-cooling, 3- (4
-Fluorophenyl) -5- (3-phenylpropionylamino) -4- (4-pyridyl) isoxazole 13
After adding 1.0 mg, the mixture was stirred under reflux for 30 minutes. After returning the reaction solution to room temperature, 2 ml of 2N hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure. The pH was adjusted to 10 by adding a 4N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (20 g, elution solvent, chloroform-chloroform: methanol = 40: 1) to obtain 29.7 mg (yield: 24%) of the title compound as pale yellow crystals.

Melting point: 147.1 to 149.3 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.32 (d, J = 6.
6Hz, 2H), 7.43 to 6.99 (m, 9H),
6.90 (d, J = 6.6 Hz, 2H), 4.94 (b
t, J = 5.1 Hz, 1H), 3.66 to 3.44
(M, 2H), 2.77 (t, J = 7.0 Hz, 2
H), 2.22 to 1.99 (m, 2H) IR (Kbr) νmax: 1634, 1604, 152
8,1168 cm ^-1 Mass, m / e: 373 (M ⁺ ), 91 (base) Example 72 5-Ethylamino-3- (4-fluorophenyl) -4
Synthesis of-(4-pyridyl) isoxazole 2.1 mL of a 1.0 MBH ₃ -tetrahydrofuran solution was added to 20 ml of tetrahydrofuran, and the mixture was stirred under ice-cooling with stirring.
Acetylamino-3- (4-fluorophenyl) -4-
After 301.1 mg of (4-pyridyl) isoxazole was added, the mixture was stirred under heating and reflux for 30 minutes. After returning the reaction solution to room temperature, 7 ml of 2N hydrochloric acid was added dropwise, and the solvent was distilled off under reduced pressure. The pH was adjusted to 10 by adding a 4N aqueous sodium hydroxide solution, and the mixture was extracted with chloroform. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography (45 g) (elution solvent, chloroform-chloroform: methanol = 2).
0: 1) to give the title compound as pale yellow crystals.
6 mg (yield: 43%) was obtained.

Melting point: 155.4 to 157.7 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.51 (dd, J =
(1.6 Hz, 4.5 Hz, 2H), 7.49 to 6.95
(M, 6H), 4.88 (bt, J = 5.7 Hz, 1
H), 3.66-3.35 (m, 2H), 1.31.
(T, J = 7.1 Hz, 3H) IR (Kbr) νmax: 1624, 1600, 151
4,1438, 1230 cm ^-1 Mass, m / e: 283 (M ⁺ ), 63 (base) Example 73 5-benzylamino-3- (4-fluorophenyl)-
Synthesis of 4- (4-pyridyl) isoxazole 84.5 mg of sodium hydride was added to tetrahydrofuran 2
0-ml, and stirred under ice-cooling with 5-amino-3- (4-
530.6 mg of (fluorophenyl) -4- (4-pyridyl) isoxazole was added and stirred for 40 minutes. Then, 431.4 mg of benzyl bromide was added dropwise, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and extracted with chloroform. After drying the organic layer over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (45 g, elution solvent, chloroform) to give the title compound as orange crystals (102.0 mg).
(Yield: 14%) was obtained.

Melting point: 154.3 to 156.8 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.49 (d, J = 5.
9Hz, 2H), 7.49 to 6.96 (m, 11H),
5.185 (bt, J = 5.9 Hz, 1H), 4.62
(D, J = 8.35 Hz, 2H) IR (Kbr) νmax: 1612, 1600, 151
0,1442,1222 cm ^-1 Mass, m / e: 345 (M ⁺ ), 91 (base) Example 74 3- (4-Fluorophenyl) -5-phenethylamino-4- (4-pyridyl) isoxazole 5-amino-3- (4-fluorophenyl)-was added to a suspension of 96 mg of sodium hydride (60% in oil) in 5 ml of anhydrous dimethylformamide (DMF) under ice-cooling.
DM of 4- (4-pyridyl) isoxazole 600 mg
20 ml of F solution was added and stirred for 10 minutes. Then, 10 ml of a DMF solution of 0.66 ml of 2-phenethyl bromide
Was added dropwise at the same temperature, followed by stirring for 30 minutes. After the reaction solution was distilled off, the residue was dissolved in chloroform (40 ml), washed with water (20 ml) and triethylamine (1 ml). Further, the organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. After the obtained residue was purified by silica gel column chromatography-30 g (elution solvent, ethyl acetate), the crystalline residue was recrystallized from ethyl acetate-hexane to give the title compound 19 as colorless crystals.
5 mg (yield: 23%) was obtained.

Melting point: 148.3 to 151.2 ° C. (ethyl acetate-hexane) ¹ H-NMR (CDCl ₃ ) δ: 8.45 (dd, J =
2.9 Hz, 6.2 Hz, 2H), 7.52 to 6.95.
(M, 9H), 6.87 (dd, J = 2.4 Hz, 6.
2.90 Hz (2 Hz, 2H) 4.90 (t-like, 1H);
71 (q, J = 6.8 Hz, 6.4 Hz, 2H);
98 (t, J = 6.8 Hz, 2H) IR (KBr) νmax: 1624, 1602, 144
6,1224 cm ^-1 Mass, m / e: 359 (M ⁺ ), 239 (bas
e) Example 75 5- (4-aminophenylacetylamino) -3- (4
Synthesis of -fluorophenyl) -4- (4-pyridyl) isoxazole 5- (t-butoxycarbonylaminophenylacetoxyamino) -3- (4-fluorophenyl) -4- (4
-Pyridyl) isoxazole (100 mg) was dispersed in 4 ml of ethyl alcohol, and 2 ml of 8N hydrogen chloride was added under cooling with water.
The dioxane solution was added dropwise. After stirring at room temperature for 4 hours,
The solvent was distilled off under reduced pressure, saturated aqueous sodium hydrogen carbonate was added to the residue, and the mixture was extracted with ethyl acetate. After the organic solvent layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. Residue crystals were n-hexane-
Recrystallize from ethyl acetate to give 44 mg of the title compound (yield:
55%).

Melting point: 198.5-206.8 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 8.52 (dd, J =
1.8 Hz, 4.4 Hz, 2H), 7.46 (bs, 1
H), 7.40 (t, J = 8.6 Hz, 2H), 7.3
7 (dd, J = 8.6 Hz, 5.3 Hz, 2H);
02 (d, J = 8.6 Hz, 2H), 6.90 (dd,
J = 1.8 Hz, 4.4 Hz, 2H), 6.67 (d,
J = 8.6 Hz, 2H), 3.76 (bs, 2H),
3.62 (s, 2H) IR (KBr) νmax: 1712, 1632, 160
4,1510,1224 cm ^-1 Mass, m / e: 388 (M ⁺ ), 255,133,1
06 (base) Example 76 Synthesis of 3- (4-fluorophenyl) -5- (4-hydroxyphenylacetylamino) -4- (4-pyridyl) isoxazole 5- (4-acetoxyphenylacetylamino)- 3-
63 mg of (4-fluorophenyl) -4- (4-pyridyl) isoxazole is dissolved in 30 ml of methanol,
1 ml of a 2N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was concentrated under reduced pressure, made weakly acidic with 2N hydrochloric acid, added with a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography-25 g (elution solvent, chloroform: methanol = 3).
0: 1) to give 45 mg of the title compound.

Melting point: 221.6-234.7 ° C. ¹ H-NMR (DMSO-d ₆ ) δ: 10.91 (bs,
1H), 9.27 (s, 1H), 8.45 (dd, J =
1.8Hz, 4.6Hz, 2H), 7.5-7.1
(M, 4H), 7.04 (d, J = 8.6 Hz, 2
H), 7.02 (dd, J = 1.8 Hz, 4.6 Hz,
2H), 6.69 (d, J = 8.6 Hz, 2H), 3.
52 (s, 2H) IR (KBr) νmax: 1700, 1680, 162
8, 1614, 1512 cm ^-1 Mass, m / e: 389 (M ⁺ ), 372, 255, 1
34,107 (base) Example 77 3- (4-Fluorophenyl) -4- (4-pyridyl)
Synthesis of -5-thioisobutyrylaminoisoxazole 3- (4-fluorophenyl) -5-isobutyrylamino-4- (4-pyridyl) isoxazole 162 mg and 2,4-bis (4-methoxyphenyl) -1,3-dithia-2,4-diphosphetane-2,4-disulfide 2
A mixture of 20 mg in 10 ml of toluene was heated at reflux for 100 minutes. The mixture was cooled and the solvent was distilled off under reduced pressure.
The obtained residue is subjected to silica gel column chromatography 5
0 g (elution solvent, chloroform: methanol = 50:
Purified in 1), 127 mg of the title compound as pale yellow crystals
(Yield: 74%) was obtained.

Melting point: 177.6-179.6 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 8.92 (bs, 1
H), 8.56 (dd, J = 1.5 Hz, 4.4 Hz,
2H), 7.52-6.98 (m, 4H), 7.10.
(Dd, J = 1.5 Hz, 4.4 Hz, 2H), 3.0
6 (m, 1H), 1.31 (d, J = 6.8 Hz, 6
H) IR (KBr) νmax: 1632, 1606, 143
6 cm ^-1 Mass, m / e: 341 (M ⁺ ), 220 (bas)
e) Example 78 Synthesis of 3- (4-fluorophenyl) -5-phenylthioacetylamino-4- (4-pyridyl) isoxazole The same operation as in Example 76 was performed to obtain the title compound.

Melting point: 151.6-154.5 ° C. (n-hexane-ethyl acetate) ¹ H-NMR (CDCl ₃ ) δ: 8.46 (dd, J =
1.5 Hz, 4.4 Hz, 2H), 7.45 to 6.92
(M, 9H), 6.84 (dd, J = 1.3 Hz, 4.
6Hz, 2H), 4.26 (s, 2H) IR (KBr) νmax: 1642, 1600, 141
0 cm ^-1 Mass, m / e: 389 (M ⁺ ), 268 (bas
e) Example 79 Synthesis of 3- (4-fluorophenyl) -5-phenylsulfonylamino-4- (4-pyridyl) isoxazole Under a stream of argon gas, 31 mg of 60% NaH was suspended in 5 ml of tetrahydrofuran, and 5-amino-3 was added. 5 ml of a tetrahydrofuran solution of 150 mg of-(4-fluorophenyl) -4- (4-pyridyl) isoxazole was added dropwise. After stirring at room temperature for 30 minutes, 114 mg of phenylsulfonyl chloride was added dropwise, and the mixture was stirred at room temperature for 6 hours. The reaction mixture was concentrated under reduced pressure, suspended in chloroform, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (20 g, elution solvent, chloroform: methanol = 100: 1) to obtain 3 mg (yield: 1.3%) of the title compound as a brown powder.

Melting point: 153.1 to 155.7 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.69 (d, J = 3.
5Hz, 2H), 8.10 (m, 2H), 7.60
(D, J = 7.5 Hz, 2H), 7.50-6.98
(M, 7H) IR (KBr) νmax: 1642, 1518, 142
8,1368,1154 cm ^-1 Mass, m / e: 395 (M ⁺ ) Example 80 Synthesis of 3- (4-fluorophenyl) -5- (p-toluenesulfonylamino) -4- (4-pyridyl) isoxazole The same operation as in Example 79 was performed to obtain the title compound.

Melting point: 165.2-168.0 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.73 (dd, J =
1.5 Hz, J = 4.4 Hz, 2H), 8.04 (d,
J = 8.6 Hz, 2H), 7.65 to 6.98 (m, 9
H), 2.39 (s, 3H) IR (KBr) νmax: 3080, 1640, 151
2,1424,1370,1154cm ^-1 Mass, m / e: 409 (M ⁺ ), 91 (base) Example 81 (a) Synthesis of 3-chlorobenzaldehyde oxime The same operation as in step (a) of Example 1 To give the title compound.

¹ H-NMR (CDCl ₃ ) δ: 8.09
(S, 1H), 7.60 to 7.25 (m, 5H) Mass, m / e: 155 (M ⁺ , base) (b) Synthesis of N-hydroxy-3-chlorobenzenecarboximidyl chloride Example 1 The same operation as in step (b) was performed to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 7.92
(S, 1H) 7.87 to 7.61 (m, 2H), 7.4
9 to 7.23 (m, 2H) Mass, m / e: 189 (M ⁺ ), 111 (bas)
e) (c) 5-amino-3- (3-chlorophenyl) -4-
Synthesis of (4-pyridyl) isoxazole The same operation as in step (c) of Example 1 was performed to obtain the title compound.

¹ H-NMR (CDCl ₃ ) δ: 8.54
(Dd, J = 1.5, 4.4 Hz, 2H), 7.52-
7.19 (m, 4H), 7.05 (dd, J = 1.5,
4.4 Hz, 2H), 4.94 (brs, 2H) Mass, m / e: 271 (M ⁺ ), 63 (base) Example 82 3- (3-chlorophenyl) -5-phenylacetylamino-4- Synthesis of (4-pyridyl) isoxazole The same operation as in Example 2 was performed to obtain the title compound.

Melting point: 150.5 to 152.0 ° C. ¹ H-NMR (CDCl ₃ ) δ: 8.49 (dd, J =
1.6, 4.5 Hz, 2H), 7.65 (brs, 1
H), 7.47 to 7.08 (m, 9H), 6.90 (d
d, J = 1.6, 4.5 Hz, 2H), 3.76 (s,
2H) IR (KBr) νmax: 1712, 1638 cm ^-1 Mass, m / e: 389 (M ⁺ ), 91 (base) Example 83 3-phenyl-5-phenylacetylamino-4- (4
Synthesis of -pyridyl) isoxazole The same operation as in Example 2 was performed to obtain the title compound in a yield of 87%.

Melting point: 184.2-186.4 ° C. (n-hexane-ethyl alcohol) ¹ H-NMR (CDCl ₃ ) δ: 8.46 (dd, J =
1.5 Hz, 4.6 Hz, 2H), 7.61 (bs, 1
H), 7.50-7.10 (m, 10H), 6.89.
(Dd, J = 1.5 Hz, 4.6 Hz, 2H), 3.7
6 (s, 2H) IR (KBr) νmax: 1726, 1630, 160
2,1432, 1120 cm ^-1 Mass, m / e: 355 (M ⁺ ), 237, 118, 9
1 (base)

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/44 ABN A61K 31/44 ABN ACD ACD ACJ ACJ ACV ACV ADA ADA ADP ADP ADU ADU ADY ADY ADY ADZ ADZ ADZ AED AGZ AGZ (72) Inventor Norio Yamamoto 1-20-1 Nakanoshima, Tama-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Katsuyuki Keino 2-20-14-301, Kodai, Miyamae-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Matsui Lighting 2-13-36 Imperial Organ Dormitory, Sambaba, Tama-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Arihiro Kaneda 5-14-6-26, Kamikodanaka, Nakahara-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Shuji Ota Kanagawa Prefecture 1-21-2-12-301 Shimoodanaka, Nakahara-ku, Kawasaki-shi (72) Inventor Norihisa Saito Kanagawa, Japan 5-14-6-28 Kamiodanaka, Nakahara-ku, Kawasaki City (72) Inventor Shuichiro Sato 1-22-12-12-312, Shimoodanaka, Nakahara-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Akira Asahara, Nakahara-ku, Kawasaki City, Kanagawa Prefecture 1-22-12-412 Odanaka (72) Inventor Satoshi Doi 1-2-22-12-207 Shimoodanaka Nakahara-ku, Kawasaki-shi, Kanagawa Prefecture (72) Inventor Motohiro Kobayashi 458-2, Takatsu-ku, Kawasaki-shi, Kanagawa 458-2 (72) Inventor Jun Sato 5-10-2 Minami Ikuta, Tama-ku, Kawasaki City, Kanagawa Prefecture (72) Inventor Sou Asano 2-13-36, Sugambaba, Tama-ku, Kawasaki City, Kanagawa Prefecture Imperial Organ Dormitory F-term (reference) 4C063 AA01 AA03 BB01 BB09 CC51 DD04 DD12 EE01 4C086 AA01 AA02 AA03 BC67 GA08 GA09 MA01 MA04 NA14 ZA02 ZA36 ZA59 ZA66 ZA81 ZA89 ZB07 ZB11 ZB15 ZB26 ZB35 ZC20 ZC35 ZC54 ZC55

Claims (21)

[Claims] (1) Formula (1) In the formula, X represents a hydrogen atom or a halogen atom, R ¹ represents a hydrogen atom or a lower alkyl group, and R ² represents a hydrogen atom, a lower alkyl group, an aralkyl group, an organic sulfonyl group or Wherein R ³ represents a hydrogen atom or an organic residue, Y represents an oxygen or sulfur atom, W represents a direct bond, an oxygen atom or -NH-, provided that when X is a hydrogen atom, A 5-aminoisoxazole derivative or a salt thereof, wherein R ¹ and R ² do not simultaneously represent a hydrogen atom. 2. X is a hydrogen atom, a 4-fluoro group or 3-
The 5-aminoisoxazole derivative or a salt thereof according to claim 1, which represents a chloro group. 3. The 5-aminoisoxazole derivative or a salt thereof according to claim 1, wherein X represents a 4-fluoro group or a 3-chloro group, and R ¹ and R ² both represent a hydrogen atom. 4. The 5-aminoisoxazole derivative or a salt thereof according to claim 1, wherein R ¹ represents a hydrogen atom. (5) R ² is The 5-aminoisoxazole derivative according to claim 1 or a salt thereof. 6. The organic residue represented by R ³ is a substituted or unsubstituted, saturated or unsaturated, linear, branched or cyclic hydrocarbon group, a substituted or unsubstituted heterocyclic group or a substituted. The 5-aminoisoxazole derivative or a salt thereof according to claim 5, which represents a carbonyl group. 7. A substituted or unsubstituted, saturated or unsaturated, linear, branched or cyclic hydrocarbon group is substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, bridged. The 5-aminoisoxazole derivative or a salt thereof according to claim 6, which is a cycloalkyl or spiroalkyl group. 8. The heterocyclic group in the substituted or unsubstituted heterocyclic group contains 1 to 4 heteroatoms selected from N, O and S, and one ring is a 4- to 8-membered ring. A monocyclic or polycyclic saturated or unsaturated heterocyclic ring,
The 5-aminoisoxazole derivative or a salt thereof according to claim 6, wherein the heterocyclic ring may be condensed with a cyclic hydrocarbon group. 9. The 5-aminoisoxazole derivative or a salt thereof according to claim 6, wherein the substituted carbonyl group is a substituted or unsubstituted alkyloxycarbonyl, alkylcarbonyl or arylcarbonyl group. 10. The organic residue represented by R ³ is a substituted or unsubstituted alkyl, cycloalkyl or aryl group; a substituted or unsubstituted heterocyclic group, wherein the heterocyclic group is N, O And S is a monocyclic or bicyclic saturated or unsaturated heterocyclic group containing one or two heteroatoms selected from S and one ring being a 5- or 6-membered ring, wherein the heterocyclic ring is phenyl. The 5-aminoisoxazole derivative or a salt thereof according to claim 6, which is a heterocyclic group optionally condensed with a group, or a substituted or unsubstituted lower alkyloxycarbonyl or phenylcarbonyl group. 11. The substituted or unsubstituted alkyl, cycloalkyl or aryl group may be a halogen atom, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, an arylcarbonyloxy group, an aryloxy group, a mercapto group, a lower alkylthio group. Group, lower alkanoylthio group, arylcarbonylthio group, arylthio group, amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, arylcarbonylamino group, aralkyloxycarbonylamino group, lower alkoxycarbonylamino group , N-lower alkyl-N-lower alkoxycarbonylamino group, guanidino group, carboxy group, lower alkoxycarbonyl group,
Aralkyloxycarbonyl group, carbamoyl group, lower alkylcarbonyl group, arylcarbonyl group, cycloalkyl group, aryl group (this aryl group may be a halogen atom, a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a lower An oxy group,
Hydroxy group, lower alkanoyloxy group, amino group,
And optionally substituted with 1 to 3 substituents selected from a lower alkylamino group, a di-lower alkylamino group, a lower alkanoylamino group, an aralkyloxycarbonylamino group, a lower alkoxycarbonylamino group and a nitro group) and N A monocyclic or bicyclic saturated or unsaturated heterocycle containing one or two heteroatoms selected from, S and O, wherein one ring is a 5- or 6-membered ring and may be condensed with a benzene ring 1 to 3 selected from a cyclic group (this heterocyclic group may be optionally substituted with one or two substituents selected from a halogen atom, a lower alkyl group, a lower alkoxy group and a nitro group) An alkyl group which may be substituted with a substituent; optionally a lower alkyl group, a hydroxy group, a lower alkoxy group, a lower alkanoyloxy group, A cycloalkyl group optionally substituted with one or two substituents selected from a ruboxy group, a lower alkoxycarbonyl group and an oxo group; or, optionally, a halogen atom, a lower alkyl group, a lower alkoxy group, a lower alkylenedioxy Group, hydroxy group, lower alkanoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group and aryl group optionally substituted with 1 to 3 substituents selected from nitro group The 5-aminoisoxazole derivative or a salt thereof according to claim 10, which represents: 12. A substituted or unsubstituted alkyl group is
Optionally, a hydroxy group, lower alkoxy group, lower alkanoyloxy group, aryloxy group, amino group, lower alkylamino group, di-lower alkylamino group, aralkyloxycarbonylamino group, lower alkoxycarbonylamino group, N-lower alkyl-N A lower alkoxycarbonylamino group, a carboxy group, a lower alkoxycarbonyl group, a lower cycloalkyl group, an aryl group (this aryl group may be a halogen atom, a lower alkyl group,
Optionally substituted with one or two substituents selected from halogenated lower alkyl groups, lower alkoxy groups, hydroxy groups, lower alkanoyloxy groups, amino groups, lower alkoxycarbonylamino groups and nitro groups) and N and A monocyclic or bicyclic unsaturated heterocyclic group containing one heteroatom selected from S and one ring being a 5-membered ring and optionally condensed with a benzene ring (this heterocyclic The formula group according to claim 11, wherein the formula group is a lower alkyl group optionally substituted with one or two substituents selected from a lower alkyl group.
An aminoisoxazole derivative or a salt thereof. 13. The substituted or unsubstituted cycloalkyl or aryl group represents an unsubstituted cycloalkyl group having 5 to 7 carbon atoms or an unsubstituted aryl group having 6 to 10 carbon atoms. Item 11. A 5-aminoisoxazole derivative or a salt thereof according to Item 11. 14. A substituted or unsubstituted heterocyclic group is
Occasionally halogen atom, lower alkyl group, lower alkoxy group, lower alkylenedioxy group, hydroxy group, lower alkanoyloxy group, amino group, lower alkylamino group, di-lower alkylamino group, lower alkanoylamino group, aralkyloxycarbonyl group The 5-aminoisoxazole derivative or a salt thereof according to claim 6, which is a heterocyclic group which may be substituted with 1 to 3 substituents selected from a lower alkoxycarbonyl group and a nitro group. 15. A substituted or unsubstituted heterocyclic group is
It may be substituted with one aralkyloxycarbonyl group or a lower alkoxycarbonyl group, contains one or two heteroatoms selected from N and O, and one ring is a 5- or 6-membered ring; The 5-aminoisoxazole derivative or a salt thereof according to claim 14, which is a monocyclic or bicyclic saturated or unsaturated heterocyclic group which may be condensed with a ring. 16. A substituted or unsubstituted lower alkyloxycarbonyl or phenylcarbonyl group is optionally a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group or an aryl group (this aryl group is optionally a halogen atom, Substituted with a substituent selected from a lower alkyl group, a halogenated lower alkyl group, a lower alkoxy group, a hydroxy group, a lower alkanoyloxy group, an amino group, a lower alkoxycarbonylamino group and a nitro group). Or a phenylcarbonyl group optionally substituted by a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, an amino group, a lower alkoxycarbonylamino group or a nitro group. Item 10 Or a salt thereof. 17. The 5-amino compound according to claim 16, wherein the substituted or unsubstituted lower alkyloxycarbonyl group or the substituted or unsubstituted phenylcarbonyl group represents an unsubstituted lower alkoxycarbonyl group or an unsubstituted phenylcarbonyl group, respectively. Isoxazole derivatives or salts thereof. 18. The 5-aminoisoxazole derivative or a salt thereof according to claim 1, wherein Y represents an oxygen atom and W represents a direct bond. 19. A P38 MAP kinase inhibitor comprising the 5-aminoisoxazole derivative of the formula (I) according to claim 1 or a salt thereof as an active ingredient. 20. A tumor necrosis factor-α-related disease, an interleukin-1-related disease, comprising the 5-aminoisoxazole derivative of the formula (I) or a salt thereof according to claim 1 as an active ingredient. , A therapeutic agent for an interleukin-6-related disease or a cyclooxygenase II-related disease. 21. A tumor necrosis factor-α-related disease, an interleukin-1-related disease, an interleukin-6-related disease or a cyclooxygenase II-related disease, wherein the disease is rheumatoid arthritis, cachexia, acute infection, acute inflammation, or chronic inflammation. , Malignant tumor, autoimmune disease, diabetes, psoriasis, Crohn's disease, A
IDS, ischemic heart disease, cerebrovascular disease, meningitis, tuberculosis, multiple cerebral sclerosis, sepsis, DIC, multiple myeloma, Castleman's disease, mesangial cell proliferative nephritis, colon polyp or colon cancer Item 21. The therapeutic agent according to Item 20,