JPH10330369A - Heterocyclic compounds - Google Patents

Abstract

(57) Abstract: An allergic disease, an autoimmune disease such as systemic lupus erythematosus, or an acquired immunodeficiency syndrome (AIDS) by suppressing the production of Th2-type cytokines such as IL-4 and IL-5. )). SOLUTION: Formula 1 (In the formula, -X- represents -O-, -NH- or -S-. Represents a benzene ring, a substituted benzene ring, a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms, or a 6-membered substituted heterocyclic ring containing 1 or 2 nitrogen atoms. Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. Or a pharmaceutically acceptable salt thereof as an active ingredient

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pharmaceutical composition containing a heterocyclic compound as an active ingredient. More specifically, the present invention relates to a novel aminophenol derivative that suppresses the immune response of type 2 helper T cells (hereinafter abbreviated as Th2). More specifically, it relates to a novel pharmaceutical composition containing a heterocyclic compound that suppresses the production of Th2 characteristic cytokines such as interleukin 4 (IL-4) and interleukin 5 (IL-5). The novel pharmaceutical composition containing the heterocyclic compound of the present invention is:
It is useful as a therapeutic agent for diseases in which the immune response of 2 is pathologically abnormally elevated, for example, allergic diseases, autoimmune diseases such as systemic lupus erythematosus, acquired immune deficiency syndrome (AIDS) and the like. The present invention also relates to novel heterocyclic derivatives.

[0002]

BACKGROUND OF THE INVENTION Mosmann et al. For the first time proposed that lymphocytes called helper T cells (hereinafter abbreviated as Th), which play a central role in the immune response, are classified into two different subsets. The helper T cells (Th) of the mouse were
h1 and Th2 (J. Immunol. (1986) 1
36: 2348-2357). As a cytokine characteristic for Th1 (Th1 type cytokine), interleukin 2 (IL-2), interferon γ (IFN-γ)
And cytokines characteristic of Th2 (Th2 type cytokines) include IL-4 and IL-5. Nowadays, the classification of Th2 of Th1 is not limited to the classification of a subset of helper T cells.
It came to be classified as a 2-sided immune response. Further, Th1 type cytokine is used for cell-mediated immunity, and Th2 type cytokine is used for humoral immunity.
It is known that type cytokines are involved.

[0003] The main components of the Th1 side immune response include IL-2 and I-2 produced upon activation of Th1.
Activation of macrophages and natural killer cells by Th1 type cytokines such as FN-γ, or conversely, IL-1 produced from activated macrophages
Mechanisms such as enhancement of Th1 activation by actions such as 2 have been confirmed. Specifically, it is known that an immune response on the Th1 side is involved in protection against infection with viruses, bacteria, and the like.

On the other hand, the immune response on the Th2 side includes Th2
Antibody production (including IgE class) from B cells by Th2-type cytokines such as IL-4 and IL-5 produced from 2. Since the Th2 side produces many cytokines involved in allergic reaction, it is regarded as important as a regulatory cell for allergic reaction. For example, IL-4 induces B cells to produce IgE antibodies, and also induces gene expression of VCAM-1, a key molecule that functions when eosinophils adhere to vascular endothelial cells and infiltrate tissues. I do. Recently, Th2 has been attracting attention as its own differentiation growth factor. Further, IL-5 induces the differentiation and proliferation of eosinophils, migration, and activation, and is considered to be a cause of allergic inflammatory reaction. Therefore, Th
No. 2 is a central cell that controls two allergic reactions: an immediate reaction involving IgE antibodies and mast cells, and a late reaction involving eosinophils. That is, it can be said that an allergic disease is a state in which Th2 is pathologically hyperactive. Actually, production of Th2 type cytokines such as IL-4 and IL-5, or the presence of Th2 is confirmed in the respiratory tract which is an allergic disease lesion and skin.
It is widely accepted that controlling Th2 activation is important for treating allergic diseases (Clinician (1994) 20: 40-46).

In autoimmune diseases in which antibody production or humoral immunity such as systemic lupus erythematosus is abnormally enhanced, it is also presumed that Th2 is pathologically hyperfunctional (Medical Immunology (1988) 15). : 40
1). In addition, a recent study has confirmed an abnormal imbalance state in which Th2 is superior to Th1 in the later stage of AIDS, and passage of this abnormal imbalance condition leads to the transition to the final immunodeficiency state. It is thought that this may be an important stage. This Th2 is Th1
If you can improve the abnormal state of balance, which is superior to
It has been pointed out that AIDS can be delayed and stopped (Immunology Today (1993) 14:
107-111).

Chemical Abstracts Vol. 59, 14141e (196
In 3), 2- (2-benzothiazolyl) amino-5-nitrophenol is described as a dye production intermediate. JP-A-64-79162 describes that a 2-phenylamino-benzothiazole derivative is useful as an anti-asthma drug or the like by inhibiting 5-lipoxygenase. British Patent No. 134552 describes that 2-phenylamino-benzothiazole derivatives are useful as antibacterial agents and the like.
Suppresses Th2 immune response, or IL-4, I
Heterocyclic derivatives that suppress the production of cytokines characteristic of type 2 helper T cells such as L-5 are not known.

[0007]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention
The present invention is to provide a compound that improves the condition in which Th2 is pathologically hyperfunctional by suppressing the immune response of No. 2. Specifically, it is to provide a compound that suppresses the production of Th2-type cytokines such as IL-4 and IL-5. More specifically, the present invention provides a therapeutic agent for allergic diseases, autoimmune diseases such as systemic lupus erythematosus, and acquired immune deficiency syndrome (AIDS).

[0008]

[Means for Solving the Problems] The inventors of the present invention have conducted extensive studies to solve the above problems, and found that the heterocyclic compound was Th
By suppressing the immune response of No. 2, Th2 was found to improve the pathologically hyperfunctional state, and the present invention was completed.

That is, the present invention relates to (a)

[Chemical 12] (In the formula, -X- represents -O-, -NH- or -S-.

Embedded image Represents a benzene ring, a substituted benzene ring, a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms, or a 6-membered substituted heterocyclic ring containing 1 or 2 nitrogen atoms.

Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. And a heterocyclic compound represented by the formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0010] Specifically, the present invention relates to the pharmaceutical composition according to (a), which is (b) a type 2 helper T cell immune response inhibitor.

Specifically, (c)

Embedded image Wherein the electron-withdrawing substituent is a halogen atom, a nitro group, a perhalogenoalkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylamide group, a perhalogenoalkylamide group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, An aroyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, a substituted arylsulfonyl group, an alkylsulfonamide group, a substituted alkylsulfonamide group, an arylsulfonamide group, or a substituted arylsulfonamide group (a) or ( b) The pharmaceutical composition according to the above.

Specifically, (d)

Embedded image A substituent of the benzene ring or the 6-membered heterocycle containing 1 or 2 nitrogen atoms is halogen atom, nitro group,
Perhalogenoalkyl group, cyano group, carboxyl group,
Alkoxycarbonyl group, alkylamide group, perhalogenoalkylamide group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, alkylsulfonyl group, substituted alkylsulfonyl group, arylsulfonyl group, substituted arylsulfonyl group, alkylsulfonamide group A substituted alkylsulfonamide group, an arylsulfonamide group, a substituted arylsulfonamide group, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, An aryloxy group,
(A), (b) or (c) which is a substituted aryloxy group, a heterocyclic group, a substituted heterocyclic group, an amino group, a substituted amino group, a carbamoyl group, a substituted carbamoyl group, an alkoxycarbonyl group, or a substituted alkoxycarbonyl group. The described pharmaceutical composition.

More specifically, (e)

Embedded image Wherein the electron-withdrawing substituent is a halogen atom, a nitro group, a perhalogenoalkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylamide group, a perhalogenoalkylamide group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, An aroyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, a substituted arylsulfonyl group, an alkylsulfonamide group, a substituted alkylsulfonamide group, an arylsulfonamide group, or a substituted arylsulfonamide group (a), ( It relates to the pharmaceutical composition according to b) or (c).

More specifically, (f) type 2 helper T
(A) a production inhibitor of a cell-produced cytokine,
(B) The pharmaceutical composition according to (c), (d) or (e) or (g) an autoimmune disease such as allergic disease, systemic lupus erythematosus, or acquired immunodeficiency syndrome (AI)
The pharmaceutical composition according to (f), which is a therapeutic agent for DS).

Further, the present invention provides a method of formula (2)

Embedded image (In the formula, -X- represents -O-, -NH- or -S-.

Embedded image Represents a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms or a 6-membered substituted heterocyclic ring containing 1 or 2 nitrogen atoms.

[Chemical 20] Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. And a pharmaceutically acceptable salt thereof.

Specifically, the present invention relates to (h) the heterocyclic compound or a pharmaceutically acceptable salt thereof according to (h), wherein -X- is -O- or -S-. Specifically, (j) the electron-withdrawing group is a halogen atom, a nitro group, a perhalogenoalkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylamide group, a perhalogenoalkylamide group, an alkanoyl group or a substituted alkanoyl group. , An aroyl group, a substituted aroyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, a substituted arylsulfonyl group, an alkylsulfonamide group, a substituted alkylsulfonamide group, an arylsulfonamide group, or a substituted arylsulfonamide group ( h) or the heterocyclic compound described in (i) or a pharmaceutically acceptable salt thereof.

More specifically, (k) the electron-withdrawing group is a fluorine atom, a chlorine atom, a nitro group, a trifluoromethyl group, a cyano group, a trifluoroacetamido group, a trifluoroacetyl group, p-chlorobenzoyl, methane. Sulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonamide,
(H), (i) or (j), which is trifluoromethanesulfonamide, benzenesulfonamide or p-toluenesulfonamide, or a pharmaceutically acceptable salt thereof.

Further, the present invention relates to (1) Formula (3)

Embedded image (In the formula, X ¹ represents —O— or —S—. R ¹ represents a hydrogen atom or an electron-withdrawing group. R ² represents a hydrogen atom,
Alternatively, it represents an electron-withdrawing group. R ^{3 ′} represents an electron-withdrawing group. R ⁴ represents a hydrogen atom or an electron-withdrawing group.

Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. ) Or a pharmaceutically acceptable salt thereof.

Specifically, (k) the electron-withdrawing group is a fluorine atom, a chlorine atom, a nitro group, a trifluoromethyl group, a cyano group, a trifluoroacetamido group, a trifluoroacetyl group, p-chlorobenzoyl, methanesulfonyl. , Trifluoromethanesulfonyl, benzenesulfonyl, p
(L) toluene-sulfonyl, methanesulfonamide, trifluoromethanesulfonamide, benzenesulfonamide or p-toluenesulfonamide;
Or a pharmaceutically acceptable salt thereof. Related.

The compound group represented by the formula (1) is, for example,
It includes a preferred compound group represented by the following formula.

Embedded image

[0021]

[Chemical formula 24]

[0022]

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[0023]

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[0024]

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[0025]

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[0026]

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[0027]

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[0028]

[Chemical 31]

[0029]

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[0030]

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[0031]

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[0032]

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[0033]

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[0034]

[Chemical 37]

[0035]

[Chemical 38]

[0036]

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[0037]

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[0038]

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[0039]

[Chemical 42]

[0040]

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[0041]

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[0042]

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[0043]

[Chemical formula 46]

[0044]

[Chemical 47]

[0045]

[Chemical 48]

[0046]

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[0047]

[Chemical 50]

[0048]

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[0049]

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[0050]

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[0051]

[Chemical 54] (In the formula, R ¹ represents a hydrogen atom or an electron-withdrawing group. R ² represents a hydrogen atom or an electron-withdrawing group. R
^{3 ′} represents an electron-withdrawing group. R ³ represents a hydrogen atom or an electron-withdrawing group. R ⁴ represents a hydrogen atom or an electron-withdrawing group. R ⁵ represents a hydrogen atom or an electron-withdrawing group. R ⁶ represents a hydrogen atom or an electron-withdrawing group. R ⁷ represents a hydrogen atom or an electron-withdrawing group. R ⁸
Represents a hydrogen atom or an electron-withdrawing group. )

The group of compounds represented by Formula 2 is, for example, a compound represented by Formula (1)
9) to a compound group represented by the formula (108) and the like. Equation 3
The compounds represented by are, for example, formulas (4), (5),
(7), (8), (10), (11), (13), (1)
4), (16) and (17).

The groups used in the formulas (1) to (120) and the following formulas will be specifically described below.

[0054]

Embedded image Or

[Chemical 56] Examples of the 6-membered heterocycle containing 1 or 2 nitrogen atoms include a pyridine ring, a pyrazine ring, a pyrimidine ring, and the like.

[0055]

Embedded image Examples of the 6-membered hetero ring containing one or two nitrogen atoms in the above include a pyridine ring, a pyrazine ring and a pyrimidine ring.

Examples of the electron-withdrawing group include an inert substituent exhibiting o and p orientation and an inert substituent exhibiting m orientation in an aromatic electrophilic substitution reaction. Specifically, for example, a halogen atom, a nitro group, a perhalogenoalkyl group, a cyano group, a carboxyl group, an alkoxycarbonyl group, an alkylamide group, a perhalogenoalkylamide group, an alkanoyl group, a substituted alkanoyl group, an aroyl group, and a substituted aroyl group , An alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, a substituted arylsulfonyl group, an alkylsulfonamide group, a substituted alkylsulfonamide group, an arylsulfonamide group, a substituted arylsulfonamide group, and the like. Preferred are, for example, a fluorine atom, a chlorine atom,
Nitro group, trifluoromethyl group, cyano group, trifluoroacetamide group, trifluoroacetyl group, p-chlorobenzoyl, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonamide, trifluoromethanesulfonamide, Examples thereof include benzenesulfonamide and p-toluenesulfonamide.

Examples of the halogen atom include a fluorine atom and a chlorine atom.

Examples of the perhalogenoalkyl group include a trifluoromethyl group, a trichloromethyl group, a pentafluoroethyl group and the like.

The alkoxycarbonyl group represents a carbonyl group substituted with an alkyl group, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, 2-propoxycarbonyl, butoxycarbonyl and the like.

Examples of the alkylamide group include acetamide, propionamide, butylamide, t-butylamide and the like.

The perhalogenoalkylamide group includes
Examples thereof include trifluoroacetamide and trichloroacetamide.

The alkanoyl group includes, for example, a straight-chain or branched alkanoyl group having 1 to 6 carbon atoms, and specifically, formyl, acetyl, propanoyl,
2-propanoyl, pivaloyl and the like.

Examples of the substituted alkanoyl group include alkanoyl having a halogen atom as a substituent.
Specifically, fluoroacetyl, difluoroacetyl,
Trifluoroacetyl, trichloroacetyl and the like.

The aroyl group represents a carbonyl group substituted with an aryl group. Specific examples include benzoyl, 1-naphthylcarbonyl, 2-naphthylcarbonyl and the like.

Examples of the substituted aroyl group include p-methoxybenzoyl, p-chlorobenzoyl, p-toluenecarbonyl, m-nitrobenzoyl and the like.

Examples of the alkylsulfonyl group include, for example,
Methanesulfonyl, ethanesulfonyl and the like can be mentioned.

Examples of the substituted alkylsulfonyl group include trifluoromethanesulfonyl, pentafluoroethanesulfonyl and the like.

Examples of the arylsulfonyl group include:
Examples thereof include benzenesulfonyl and naphthylsulfonyl.

Examples of the substituted arylsulfonyl group include p-toluenesulfonyl, o-toluenesulfonyl, m-toluenesulfonyl and the like.

Examples of the alkylsulfonamide group include methanesulfonamide and ethanesulfonamide.

The substituted alkylsulfonamide group includes
For example, trifluoromethanesulfonamide, pentafluoroethanesulfonamide and the like can be mentioned.

The arylsulfonamide group includes, for example, benzenesulfonamide, naphthylsulfonamide and the like.

As the substituted arylsulfonamide group,
For example, p-toluenesulfonamide, o-toluenesulfonamide, m-toluenesulfonamide and the like can be mentioned.

Examples of the acyl group include an optionally substituted alkanoyl group, an optionally substituted aroyl group, an optionally substituted alkylsulfonyl group, an optionally substituted arylsulfonyl group and the like.

Examples of the alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms, and specific examples thereof include methyl, ethyl, propyl, 2-propyl, butyl and 2-. Butyl, 3-methylpropyl, 1,
1-Dimethylethyl, pentyl, hexyl and the like can be mentioned.

The substituent in the substituted alkyl group includes:
Examples include a cycloalkyl group, an aryl group, a halogen atom and a heterocyclic group, and a plurality of the same or different groups may be independently substituted. Specific examples of the substituted alkyl group include trifluoromethyl, 3-cyclohexylpropyl, 2-phenylbutyl, benzyl, naphthylmethyl, 2-pyridylethyl and the like.

As the alkoxy group, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms can be mentioned.
Specific examples include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.

The substituted alkoxy group means a compound having a substituent in the alkyl group of the alkoxy group. Examples of the substituent include a cycloalkyl group, an aryl group, a halogen atom and a heterocyclic group.

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

Examples of the substituent in the substituted cycloalkyl group include a cycloalkyl group, an aryl group, a halogen atom and a heterocyclic group.

The aryl group has, for example, 6 to 6 carbon atoms.
There are 10 groups, and specific examples thereof include phenyl, 1-naphthyl, 2-naphthyl and the like.

The substituent in the substituted aryl group includes:
For example, alkyl group, alkoxy group, halogen atom, cyano group, halogen-substituted alkyl group, nitro group, hydroxyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group , A carboxyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an alkanoyl group, an alkanoylamino group and the like, and a plurality of the same or different ones may be independently substituted. Specific substituted aryl groups include 4-trifluoromethylolophenyl, 3-ethylphenyl, 4-cyanophenyl,
4- (N, N-dimethylcarbamoyl) phenyl, 2-
Chloro-4-bromophenyl, 3-methoxycarbonylphenyl, 4-carboxyphenyl, 4-methanesulfonylphenyl, 7-methoxy-1-naphthyl, 1-aminophenyl, 4-nitrophenyl and the like can be mentioned.

Examples of the aryloxy group include groups having 6 to 10 carbon atoms, and specific examples include phenoxy, 1-naphthoxy, 2-naphthoxy and the like.

The substituted aryloxy group refers to an aryloxy group having a substituent at the aryl group portion. Examples of the substituent include an alkyl group, an alkoxy group,
Halogen atom, cyano group, halogen-substituted alkyl group, nitro group, hydroxyl group, amino group, alkylamino group, dialkylamino group, carbamoyl group, N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, carboxyl group, alkoxycarbonyl group , An alkylsulfonyl group, an alkanoyl group, an alkanoylamino group, and the like, and the substituents may be the same or different and may independently be present.

Examples of the heterocyclic group include a monocyclic or bicyclic saturated or unsaturated heterocyclic group containing 1 to 3 nitrogen, oxygen and / or sulfur atoms. Specific examples of the saturated heterocyclic group include piperidyl, morpholyl, pyrrolidyl, pyrazolidyl,
Pyrazinyl, tetrahydrofuryl and the like. Specific examples of such an unsaturated heterocyclic group include pyridyl, piperazyl, pyrazyl, indolyl, isothiazolyl, isobenzofuranyl, chromenyl, pyrrolyl, furyl, thienyl, quinolyl and the like.

Examples of the substituent in the substituted heterocyclic group include an alkyl group, an alkoxy group, a halogen atom, a cyano group, a halogen-substituted alkyl group, a nitro group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, and a carbamoyl group. , N-alkylcarbamoyl group, N, N-dialkylcarbamoyl group, carboxyl group, alkoxycarbonyl group, alkylsulfonyl group, alkanoyl group, alkanoylamino group and the like, and the substituents are the same or different. May have

Examples of the substituent in the substituted amino group include an acyl group and an alkyl group. A plurality of the same or different ones may be independently substituted. Specific substituted amino groups include acetamido, propionamido, butylamido, 2-butylamido, methylamino,
2-methylpropylamino, diethylamino and the like can be mentioned.

Examples of the substituent in the substituted carbamoyl group include an alkyl group, an aryl group and a heterocyclic group, and a plurality of the same or different may be independently substituted. Specific substituted carbamoyl groups include N-ethylcarbamoyl, N, N-dimethylcarbamoyl, N
-Phenylcarbamoyl, N- (2-pyridyl) carbamoyl and the like.

The alkoxycarbonyl group represents a carbonyl group substituted with an alkyl group, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and 2-propoxycarbonyl.

The substituted alkoxycarbonyl group has a substituent in the alkyl group of the alkoxycarbonyl group. Examples of the substituent include a cycloalkyl group, an aryl group, a halogen atom and a heterocyclic group.

A halogen-substituted alkyl group or an alkyl group substituted with a halogen atom is shown. Specifically, for example, trifluoromethyl group, difluoromethyl group, fluoromethyl group, trichloromethyl group, dichloromethyl group, chloromethyl group, 2,2,2-trifluoroethyl group and the like can be mentioned.

Examples of the alkylamino group include an amino group substituted with a lower alkyl group having 1 to 6 carbon atoms, and specific examples include a methylamino group and an ethylamino group.

Examples of the dialkylamino group include an amino group substituted by the same or different lower alkyl groups having 1 to 6 carbon atoms, and specific examples include a dimethylamino group and a diethylamino group. Can be

Examples of the N-alkylaminocarbonyl group include an aminocarbonyl group substituted by a lower alkyl group having 1 to 6 carbon atoms, and specific examples thereof include a methylaminocarbonyl group and an ethylaminocarbonyl group. Groups and the like.

The N, N-alkylaminocarbonyl group includes, for example, an aminocarbonyl group substituted by the same or different lower alkyl groups having 1 to 6 carbon atoms, and specifically, for example, dimethylaminocarbonyl Group,
And a diethylaminocarbonyl group.

The alkanoylamino group represents an amino group substituted with an alkanoyl group, and specific examples thereof include a formylamino group, an acetylamino group and a propanoylamino group.

The heterocyclic compound which is the active ingredient of the medicine of the present invention can be made into a pharmaceutically acceptable salt. Examples of the pharmaceutically acceptable salt include an acid addition salt and a base addition salt. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, and organic acid salts such as citrate and oxalate.Examples of the base addition salt include sodium salt and calcium. Examples thereof include inorganic base salts such as salts, meglumine salts, and organic base salts such as trishydroxymethylaminomethane salts. The present invention also includes solvates such as hydrates of the heterocyclic compound or a pharmaceutically acceptable salt thereof.

[0098]

Embedded image (In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ⁸ have the same meanings as described above.) The heterocyclic compound represented by the formula (1) is a heterocyclic compound. May cause variability. For example, the heterocyclic compound represented by the above formula (4) may cause tautomerism and become an equilibrium mixture with the heterocyclic compound (201). The invention also includes its tautomers and mixtures thereof.

Examples of the compounds represented by the formulas (2) and (3) include the following. Table 1

[Table 1]

[Table 2]

[Table 3]

Table 2

[Table 4]

[Table 5]

[Table 6]

Table 3

[Table 7]

[Table 8]

[Table 9]

Table 4

[Table 10]

[Table 11]

[Table 12]

Table 5

[Table 13]

[Table 14]

[Table 15]

Table 6

[Table 16]

[Table 17]

[Table 18]

Table 7

[Table 19]

[Table 20]

[Table 21]

Table 8

[Table 22]

[Table 23]

[Table 24]

Table 9

[Table 25]

[Table 26]

[Table 27]

Table 10

[Table 28]

[Table 29]

[Table 30]

Table 11

[Table 31]

[Table 32]

[Table 33]

Table 12

[Table 34]

[Table 35]

[Table 36]

Table 13

[Table 37]

[Table 38]

[Table 39]

Table 14

[Table 40]

[Table 41]

[Table 42]

Table 15

[Table 43]

[Table 44]

[Table 45]

Table 16

[Table 46]

[Table 47]

[Table 48]

Table 17

[Table 49]

[Table 50]

[Table 51]

Table 18

[Table 52]

[Table 53]

[Table 54]

Table 19

[Table 55]

[Table 56]

[Table 57]

Table 20

[Table 58]

[Table 59]

[Table 60]

Table 21

[Table 61]

[Table 62]

[Table 63]

Table 22

[Table 64]

[Table 65]

[Table 66]

Table 23

[Table 67]

[Table 68]

[Table 69]

Table 24

[Table 70]

[Table 71]

[Table 72]

Table 25

[Table 73]

[Table 74]

[Table 75]

Table 26

[Table 76]

[Table 77]

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Table 27

[Table 79]

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Table 28

[Table 82]

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Table 29

[Table 85]

[Table 86]

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Table 30

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Table 31

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[Table 92]

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Table 32

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Table 33

[Table 97]

[Table 98]

[Table 99]

Table 34

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Table 35

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Table 36

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Table 37

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Table 38

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Table 39

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Table 40

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Table 41

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Table 42

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Table 43

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Table 44

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Table 45

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Table 46

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Table 47

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Table 48

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Table 49

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Table 50

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Table 51

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Table 52

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Table 53

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Table 54

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Table 55

[Table 162]

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Table 56

[Table 164]

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Table 57

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Table 58

[Table 168]

[Table 169]

Table 59

[Table 170]

[Table 171]

Table 60

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Table 61

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Table 62

[Table 176]

[Table 177]

Table 63

[Table 178]

[Table 179]

Table 64

[Table 180]

[Table 181]

Table 65

[Table 182]

[Table 183]

Table 66

[Table 184]

[Table 185]

[Table 186]

Table 67

[Table 187]

[Table 188]

[Table 189]

Table 68

[Table 190]

[Table 191]

[Table 192]

Table 69

[Table 193]

[Table 194]

Table 70

[Table 195]

[Table 196]

Table 71

[Table 197]

[Table 198]

Table 72

[Table 199]

[Table 200]

Table 73

[Table 201]

[Table 202]

Table 74

[Table 203]

[Table 204]

Table 75

[Table 205]

[Table 206]

Table 76

[Table 207]

[Table 208]

Table 77

[Table 209]

[Table 210]

Table 78

[Table 211]

[Table 212]

Table 79

[Table 213]

[Table 214]

Table 80

[Table 215]

[Table 216]

Table 81

[Table 217]

[Table 218]

[Table 219]

Table 82

[Table 220]

[Table 221]

[Table 222]

Table 83

[Table 223]

[Table 224]

Table 84

[Table 225]

[Table 226]

Table 85

[Table 227]

[Table 228]

Table 86

[Table 229]

[Table 230]

Table 87

[Table 231]

[Table 232]

Table 88

[Table 233]

[Table 234]

Table 89

[Table 235]

[Table 236]

Table 90

[Table 237]

[Table 238]

Table 91

[Table 239]

[Table 240]

[Table 241]

[Table 242]

[Table 243]

[Table 244]

Table 92

[Table 245]

[Table 246]

[Table 247]

[Table 248]

[Table 249]

[Table 250]

Table 93

[Table 251]

[Table 252]

[Table 253]

[Table 254]

[Table 255]

[Table 256]

Table 94

[Table 257]

[Table 258]

[Table 259]

[Table 260]

[Table 261]

[Table 262]

Table 95

[Table 263]

[Table 264]

[Table 265]

[Table 266]

[Table 267]

[Table 268]

Table 96

[Table 269]

[Table 270]

[Table 271]

[Table 272]

[Table 273]

[Table 274]

Table 97

[Table 275]

[Table 276]

[Table 277]

[Table 278]

[Table 279]

[Table 280]

Table 98

[Table 281]

[Table 282]

[Table 283]

[Table 284]

[Table 285]

[Table 286]

Table 99

[Table 287]

[Table 288]

[Table 289]

[Table 290]

[Table 291]

[Table 292]

Table 100

[Table 293]

[Table 294]

[Table 295]

[Table 296]

[Table 297]

[Table 298]

The aminophenol derivative of the present invention can be produced, for example, by the following two production methods. Manufacturing method 1

Embedded image (Where

Embedded image ,

Embedded image And X have the same meaning as described above. )

Compound (203) is an amine derivative (20)
It can be obtained by reacting 2) with an appropriate carbonylating agent in an inert organic solvent while controlling the reaction in the range of about room temperature to about the boiling point of the solvent. Specific examples of the carbonylating agent include, for example, carbonyldiimidazole,
Carbonates such as ethyl chlorocarbonate; phosgene; As the inert organic solvent, for example, benzene,
Toluene, hydrocarbon solvents such as hexane, dichloromethane, chloroform, halogenated hydrocarbon solvents such as dichloroethane, tetrahydrofuran, diethyl ether,
Examples include ether solvents such as dioxane, and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphorotriamide. This reaction is carried out using a base (for example, a tertiary amine such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine).
The reaction may be carried out in the presence of

Compound (205) is an amine derivative (20)
It can be obtained by reacting 2) with an appropriate thiocarbonylating agent in an inert organic solvent while controlling the reaction in the range of about room temperature to about the boiling point of the solvent. Specific examples of the thiocarbonylating agent include thiocarbonyldiimidazole and thiophosgene. Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene, and hexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane; ether solvents such as tetrahydrofuran, diethyl ether, and dioxane; dimethylformamide; and dimethyl. Aprotic polar solvents such as sulfoxide and hexamethylphosphorotriamide. This reaction may be carried out in the presence of a base (for example, a tertiary amine such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine).

Compound (203) is an amine derivative (20)
It can also be obtained by reacting 2) with carbon disulfide in a mixture of aqueous potassium hydroxide and methanol. The reaction temperature is selected from the range of about room temperature to about 100 ° C.

Compound (203) or compound (20)
5) can be reacted with phosphorus pentachloride in phosphorus oxychloride to give an intermediate of formula 7 (ES Lazer, et.
al., J. Med. Chem., 37, 913 (1994)). Reaction temperatures range from about room temperature to about 100 ° C.

Compound (208) is obtained by reacting compound (205) with methyl halide in an inert organic solvent in the presence of a base while controlling the reaction in the range of about -20 ° to the boiling point of the solvent. Can be As the base, for example,
Sodium hydride, potassium hydride, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide,
Examples include inorganic bases such as sodium hydroxide, and organic metal bases such as butyl lithium, methyl lithium, dimsyl anion, lithium diisopropylamide, and sodium bistrimethylsilylamide. Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene, and hexane; ether solvents such as tetrahydrofuran, diethyl ether and dioxane; and aprotic polar solvents such as dimethylformamide, dimethylsulfoxide, and hexamethylphosphorotriamide. And the like. Examples of the methyl halide include methyl chloride, methyl bromide, and methyl iodide.

Compound (204) or Compound (206)
And the amino alcohol derivative (207) in an inert organic solvent while controlling the reaction in the range of about room temperature to about the boiling point of the solvent to obtain the compound of the present invention represented by Formula 1. Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene, and hexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane; ether solvents such as tetrahydrofuran, diethyl ether, and dioxane; dimethylformamide; and dimethyl. Aprotic polar solvents such as sulfoxide and hexamethylphosphorotriamide; This reaction may be carried out in the presence of a base (for example, a tertiary amine such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine, diisopropylethylamine).

Production method 2

Embedded image (Where

[Chemical formula 63] ,

And X has the same meaning as described above. P represents a hydroxyl-protecting group. )

The isothiocyanate derivative (209) is
Amine derivative (20) in which the ortho-position hydroxyl group is protected by a suitable protecting group or obtained by a known method (20
It can be obtained by reacting 8) with a suitable thiocarbonylating agent in the presence of a base in an inert organic solvent while controlling the reaction in the range of about room temperature to about the boiling point of the solvent. Examples of the thiocarbonylating agent include thiocarbonyldiimidazole and thiophosgene. Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene and hexane, halogenated hydrocarbon solvents such as dichloromethane, chloroform and dichloroethane, ether solvents such as tetrahydrofuran, diethyl ether and dioxane, dimethylformamide and dimethyl. Examples include aprotic polar solvents such as sulfoxide and hexamethylphosphorotriamide. Examples of the base include tertiary amines such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaminopyridine and diisopropylethylamine.

Examples of the hydroxyl-protecting group include ethers (methyl, ethyl, methoxymethyl, methylthiomethyl, t-butoxymethyl, 2-methoxyethoxymethyl, tetrahydropyranyl, allyl, benzyl, p-methoxybenzyl, trimethylsilyl, t-butyldimethylsilyl,
t-butyldiphenylsilyl, etc.) and esters (acetate, chloroacetate, methoxyacetate, benzoate, etc.).

The compound (210) can be obtained by reacting the isothiocyanate derivative (209) and the amine derivative (202) in an inert organic solvent while controlling the reaction in a range from about room temperature to the boiling point of the solvent. . Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene, and hexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane; ether solvents such as tetrahydrofuran, diethyl ether, and dioxane; dimethylformamide; and dimethyl. Aprotic polar solvents such as sulfoxide and hexamethylphosphorotriamide; Further, a divalent mercury salt such as mercury oxide or mercury chloride may coexist in the reaction system. This reaction is described in detail in the literature (J. Heterocyclic Chem., 28 , 359 (1991)).

Compound (210) was dissolved in an inert organic solvent at about
While controlling the reaction in the range of -20 degrees to the boiling point of the solvent,
The compound (1), which is an active ingredient of the present invention, can be obtained by reacting with an acid, an alkali, a Lewis acid or the like to remove the protective group. Examples of the inert organic solvent include hydrocarbon solvents such as benzene, toluene, and hexane; halogenated hydrocarbon solvents such as dichloromethane, chloroform, and dichloroethane; ether solvents such as tetrahydrofuran, diethyl ether, and dioxane; dimethylformamide; and dimethyl. Aprotic polar solvents such as sulfoxide and hexamethylphosphorotriamide; Examples of the acid include inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, etc.) and organic acids (eg, methanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid,
Oxalic acid, acetic acid, trifluoroacetic acid, etc.), and as the alkali, potassium hydroxide, sodium hydroxide,
Examples include lithium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, and the like, and examples of Lewis acids include aluminum chloride, tin chloride, boron chloride, boron bromide, trimethylsilane chloride, trimethylsilane iodide, and the like.

Further, after producing compound (1) which is an active ingredient of the present invention,

Embedded image Or

Embedded image Further substituents can be introduced. In performing the above reaction, if necessary, techniques for protection and deprotection can be used. For protection and deprotection technologies,
(TW Greene and PGM Wuts, "Protecting Grou
ps in Organic Synthesis ", 1990).

The aminophenol derivative of the present invention can be administered orally or parenterally. When administered orally, it can be administered in commonly used dosage forms such as tablets, capsules, syrups, suspensions and the like. For parenteral administration, for example, liquid preparations such as solutions, emulsions and suspensions can be administered as injections, or rectally administered in the form of suppositories. Such a dosage form can be produced according to a general method by blending the active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added. The dose and the number of administrations vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 1000 mg, preferably about 10 to about 500 mg per day for an adult. The range can be administered once or in several divided doses. When administered as an injection, it can be administered to an adult usually in a range of about 0.1 to about 500 mg per day, preferably in a range of about 3 to about 100 mg once or several times. .

The aminophenol derivative of the present invention suppresses IL-4 production and IL-5 production from mouse lymph node cells by antigen-specific stimulation. The cytokine production regulating activity test is performed, for example, by the following method. Cytokine production regulatory activity test Keyhole Lympet Hemocyanin (hereinafter referred to as KLH) 0.2
mg of aluminum hydroxide Alu-Gel-S (Serva Feinbioch
emica GmbH & Co., Code No. 12261) or Freund's complete adjuvant (Difco Lab., Detroit, Michigan,
Inject subcutaneously into the mouse footpad with Code No. 3113-60-5) (0.1 ml). Eight to ten days later, the popliteal lymph nodes are removed,
Prepare cell suspension. Lymph node cell suspension (2.5-5 x
KLH (0.1 mg / ml) and drug were added to 10 ⁶ cells / ml) and cultured at 37 ° C in the presence of 5% CO ₂ for 4 days (Corning 25850,
After 0.15 ml / well), the cytokine produced in the supernatant is quantified by a specific ELISA method. Interleukin 4 (IL-4) or interleukin 5 (IL-5) is quantified as a typical Th2 type cytokine.

[0214]

【Example】

Example 1 2- (6-nitro-2-benzoxazolyl) amino-
Synthesis of 5-nitrophenol 1) 2-mercapto-6-nitrobenzoxazole 85% potassium hydroxide (944 mg, 1
4.3 mmol) in methanol (14 ml) -water (2.
9 ml) and carbon disulfide (860 μl, 14.3 μl).
mmol) and 2-amino-5-nitrophenol (2.00 g, 13.0 mmol), and the mixture was refluxed for 8 hours. Acetic acid (2.6 ml) was added to the reaction solution, the solvent was distilled off under reduced pressure by about half, and the precipitated solid was collected by filtration and dried to obtain the title compound (1.90 g, 74%). ¹ H-NMR (Acetone-d ₆ ) δ: 8.13 (dd, 1H, J = 2.1, 8.8
Hz), 8.06 (d, 1H, J = 2.1 Hz), 7.58 (d, 1H, J = 8.
8 Hz), one proton is not detected.

2) 2-Chloro-6-nitrobenzoki
Phosphorus oxychloride (14.2 ml, 154 mmol) was added to 2-mercapto-6-nitrobenzoxazole (3.05 g, 15.6 mmol) under a stream of sasol nitrogen to form a suspension, and phosphorus pentachloride (3.48 g, 16 (0.7 mmol) and stirred at room temperature for 18 hours. After phosphorus oxychloride was distilled off under reduced pressure, an ethyl acetate solution was obtained, which was filtered through a glass filter. Water was added to the filtrate, and extracted twice with ethyl acetate.
The organic layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 2/1) to give the title compound (540 mg, 21%). ¹ H-NMR (CDCl ₃ ) δ: 8.45 (d, 1H, J = 2.0 Hz), 8.35
(dd, 1H, J = 2.0, 8.6 Hz), 7.82 (d, 1H, J = 8.6 H
z)

3) 2- (6-Nitro-2-benzoki)
(Sazolyl) amino-5-nitrophenol Under a nitrogen stream, 2-amino-5-nitrophenol (352 mg, 2.29 mmol) was added to a solution of 2-chloro-6-nitrobenzoxazole (300 mg, 1.51 mmol) in acetonitrile (15 ml). ) And add 1 at room temperature.
After stirring for 6 hours, the mixture was further stirred at 50 ° C. for 4 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration. The obtained solid was washed with methanol, collected by filtration, and dried to give the title compound (479 mg,> 99%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.2 (br, 1H), 10.9 (br, 1H),
8.46 (d, 1H, J = 8.9 Hz), 8.44 (d, 1H, J = 2.2 H
z), 8.22 (dd, 1H, J = 2.2, 8.9 Hz), 7.86 (dd, 1H,
J = 2.6, 8.9 Hz), 7.72 (d, 1H, J = 2.6 Hz), 7.66
(d, 1H, J = 8.9Hz)

Embodiment 22- (6-Nitro-2-benzimidazolyl) amino-
Synthesis of 5-nitrophenol 1) 2-chlorobenzimidazole Under a nitrogen stream, 2-benzimidazolol (4.00 g,
29.8 mmol) with phosphorus oxychloride (13 ml)
In addition, the mixture was heated under reflux for 4 hours. Return the reaction solution to room temperature, and add ice water
And pH adjusted to 7-8 with aqueous sodium hydroxide
And extracted with ethyl acetate. Extract magnesium sulfate
Dried with water, filtered, and evaporated to remove the solvent.
(3.07 g, 68%) was obtained.¹ H-NMR (DMSO-d₆) δ: 7.48-7.53 (m, 2H), 7.19-7.25
(m, 2H), one protonis not detected.

2) 2-Chloro-6-nitrobenziimi
Under imidazole nitrogen stream, 85% nitronium tetrafluoroborate (656 mg, 3.93 mmol) in methylene chloride suspension (10 ml), 2-chloro-benzimidazole (600 mg, 3.93 mmol) in methylene chloride suspension (20ml ) Was added dropwise under ice cooling, and the mixture was stirred at room temperature for 7 hours. The reaction solution was adjusted to pH 7 with 1N aqueous sodium hydroxide
After adjusting to ８8, the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated.
The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (371).
mg, 48%). ¹ H-NMR (DMSO-d ₆ ) δ: 8.43 (d, 1H, J = 2.3 Hz), 8.1
5 (dd, 1H, J = 2.3,8.9 Hz), 7.71 (d, 1H, J = 8.9 H
z), one proton is not detected.

3) 2- (6-Nitro-2-benziimi)
Dazolyl) amino-5-nitrophenol Under a nitrogen stream, 2-chloro-6-nitrobenzimidazole (122 mg, 0.617 mmol) was dissolved in dioxane (2.0 ml) and tetrahydrofuran (3.0 ml). 2-aminophenol (95.0
(mg, 0.616 mmol) was added and the mixture was heated under reflux for 23 hours. The reaction solution was returned to room temperature, and the precipitated solid was collected by filtration, washed with methanol, and dried to give the title compound (49.8 m
g, 26%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.3 (br, 1H), 10.0 (brs, 1
H), 8.70 (d, 1H, J = 8.9 Hz), 8.35 (d, 1H, J = 2.3
Hz), 8.05 (dd, 1H, J = 2.3, 8.9 Hz), 7.87 (dd, 1
H, J = 2.6, 8.9 Hz), 7.77 (d, 1H, J = 2.6 Hz), 7.5
9 (d, 1H, J = 8.9Hz)

Example 3 2- (6-nitro-2-benzthiazolyl) amino-5
Synthesis of -nitrophenol 1) 2-methoxy-4-nitrophenylisothiocyan
Under inert nitrogen gas stream, 2-methoxy-4-nitroaniline (1.
00g, 5.95mmol) in chloroform (28m
l) and saturated aqueous sodium hydrogen carbonate (12 ml), thiophosgene (710 µl, 9.31 mmol) was added, and the mixture was stirred at room temperature for 7 hours. Separate the reaction solution, remove the chloroform layer,
After drying over magnesium sulfate and filtration, the solvent of the filtrate was distilled off to obtain the title compound (1.25 g, quant.). ¹ H-NMR (CDCl ₃ ) δ: 7.83 (dd, 1H, J = 2.3, 8.6 Hz),
7.77 (d, 1H, J = 2.3 Hz), 7.19 (d, 1H, J = 8.6 H
z), 4.03 (s, 3H)

2) N- (2-benzthiazolyl) -2
-Methoxy-4-nitroaniline 2-methoxy-4-nitrophenyl isothiocyanate (563 mg, 2.67 mmol) in toluene (1
2-aminothiophenol (285 μl,
(2.66 mmol) was added and the mixture was heated under reflux for 2 hours. Mercury oxide (577 mg, 2.66 mmol) was added to the reaction solution, and the mixture was heated under reflux for 5 hours. Bring the reaction to room temperature,
After filtration, the solvent of the filtrate is distilled off, and the residue is subjected to silica gel column chromatography (hexane / ethyl acetate = 3/1).
The title compound (686 mg, 85%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 10.54 (brs, 1H), 8.97 (d, 1H,
J = 9.1 Hz), 8.03 (dd, 1H, J = 2.6, 9.1 Hz), 7.88
(d, 1H, J = 7.4 Hz), 7.83 (d, 1H, J = 2.6Hz), 7.7
1 (d, 1H, J = 7.4 Hz), 7.38 (dd, 1H, J = 7.4, 7.4
Hz), 7.23 (dd, 1H, J = 7.4, 7.4 Hz), 4.04 (s, 3H)

3) N- (6-Nitro-2-benzthia)
Zoriru) -2-methoxy-4-nitroaniline nitrogen stream, 85% nitronium tetrafluoroborate (223 mg, methylene chloride suspension 1.43mmol) (5ml), N- ( 2- benzthiazolyl) -2
-Methoxy-4-nitroaniline (319 mg, 1.0
6 mmol) in methylene chloride (10 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1.5 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The extract layer was washed with a saturated saline solution, dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 4/1 → 3/1 → 1 /
Purification by 1) afforded the title compound (19.1 mg, 5%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.96 (s, 1H), 8.93 (d, 1H, J
= 8.9 Hz), 8.93 (d, 1H, J = 2.4 Hz), 8.23 (dd, 1H,
J = 2.4, 9.0 Hz), 8.01 (dd, 1H, J = 2.6,8.9 Hz),
7.86 (d, 1H, J = 2.6 Hz), 7.81 (d, 1H, J = 9.0 H
z), 4.05 (s, 3H)

4) 2- (6-Nitro-2-benzthia
Zolyl) amino-5-nitrophenol N- (6-nitro-2-benzthiazolyl) -2-methoxy-4-nitroaniline (14.0 m) under a nitrogen stream.
g, 4.04 × 10 ^-2 mmol) to a methylene chloride suspension (1.8 ml), 0.5N boron tribromide methylene chloride solution (690 μl, 3.45 × 10 ^-1 mmol) was added, Stir at room temperature for 14 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the solvent of the filtrate was evaporated. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 3
/ 1 → 1/1) to give the title compound (4.1 mg, 3 mg).
1%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.25 (s, 1H), 10.91 (s, 1H),
8.91 (d, 1H, J = 2.6 Hz), 8.85 (d, 1H, J = 8.9 H
z), 8.22 (dd, 1H, J = 2.6, 8.9 Hz), 7.86 (dd, 1H,
J = 2.6, 8.9 Hz), 7.80 (d, 1H, J = 8.9 Hz), 7.73
(d, 1H, J = 2.6Hz)

Example 4 2- (6-Nitro-2-benzoxazolyl) amino-
4-nitrophenol and 2- (5-nitro-2-benz)
Equilibrium with oxazolyl) amino-5-nitrophenol
Under a nitrogen stream of the mixture , 2-chloro-6-nitro-benzoxazole (51.0 mg, 0.257 mmol) and 4-nitro-2-aminophenol (38.8 mg, 0.25 mmol) were used.
2 mmol) in dioxane (2.1 ml)
The mixture was refluxed for 0 hours. The reaction solution was returned to room temperature, a 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 → 1/1),
The title compound (18.8 mg, 24%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.06 (d, 1H, J = 2.7 Hz), 8.4
1 (d, 1H, J = 2.2 Hz), 8.21 (dd, 1H, J = 2.2, 8.7
Hz), 7.98 (dd, 1H, J = 2.7, 8.9 Hz), 7.65 (d, 1H, J
= 8.7 Hz), 7.07 (d, 1H, J = 8.9 Hz), 4.05 (s, 3H)

Embodiment 5 2- (5-chloro-2-benzoxazolyl) amino-
Synthesis of 4-nitrophenol 1) 2-chloro-5-nitrobenzoxazole 85% nitronium tetrafluorovolley under nitrogen flow
(1.38 g, 8.83 mmol) in methylene chloride
2-Chlorobenzoxazole was added to the suspension (25 ml).
(1.00 ml, 8.76 mmol) in methylene chloride
The suspension (15 ml) was added dropwise under ice cooling and stirred at the same temperature for 3 hours.
Stirred. Water was added to the reaction solution, and extracted with ethyl acetate.
Wash the extract with saturated saline and dry over magnesium sulfate
After filtration, the solvent of the filtrate was distilled off. Silica gel residue
Column chromatography (hexane / ethyl acetate = 2
0/1) to give the title compound (141 mg, 8.1
%) With 2-chloro-6-nitrobenzoxazole (3
(54 mg, 20%).¹ H-NMR (CDCl₃) δ: 8.60 (d, 1H, J = 2.3 Hz), 8.36
(dd, 1H, J = 2.3, 8.9 Hz), 7.66 (d, 1H, J = 8.9 H
z)

2) 2- (5-chloro-2-benzoxy)
(Sazolyl) amino-4-nitrophenol A mixture of 2-chloro-5-nitrobenzoxazole and 2-chloro-6-nitrobenzoxazole (112 mg, 0.565 mmol) under the same conditions as in Example 4.
And 4-chloro-2-aminophenol (80.3 mg,
0.559 mmol) from the title compound (5.3 mg, 1
1%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.78 (brs, 1H), 10.22 (s, 1
H), 9.13 (d, 1H, J = 2.6 Hz), 7.94 (dd, 1H, J = 2.
6, 8.9 Hz), 7.59 (d, 1H, J = 2.2 Hz), 7.53 (d, 1H,
J = 8.6 Hz), 7.19 (dd, 1H, J = 2.2, 8.6 Hz), 7.06
(d, 1H, J = 8.9 Hz)

Example 6 2- (6-nitro-2-benzoxazolyl) amino-
4-chlorophenol and 2- (5-chloro-2-benz)
Equilibrium with oxazolyl) amino-5-nitrophenol
In the same manner as in Synthesis Example 5 of the mixture , the title compound (33.2 mg,
27%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.4 (brs, 1H), 10.3 (brs, 1
H), 8.38 (d, 1H, J = 2.1 Hz), 8.19 (dd, 1H, J = 2.
1, 8.7 Hz), 8.07 (d, 1H, J = 2.6 Hz), 7.59 (d, 1H,
J = 8.7 Hz), 7.06 (dd, 1H, J = 2.6, 8.6 Hz), 6.92
(d, 1H, J = 8.6 Hz) δ: 11.15 (brs, 1H), 10.39 (brs, 1H), 8.50 (d, 1H,
J = 8.9 Hz), 7.86 (dd, 1H, J = 2.6, 8.97 Hz), 7.7
0 (d, 1H, J = 2.6 Hz), 7.60 (d, 1H, J = 2.2 Hz), 7.
56 (d, 1H, J = 8.5 Hz), 7.22 (dd, 1H, J = 2.2, 8.5
Hz)

Example 7 2- (4,6-dichloro-2-benzthiazolyl) amido
Synthesis of no-5-nitrophenol 1) N- (4,6-dichloro-2-benzthiazoly)
) -2-methoxy-4-nitroaniline nitrogen stream, N-(2-benzthiazolyl) -2-methoxy-4-nitroaniline (114mg, 0.378m
mol) in dimethylformamide (2.6 ml)
In addition, N-chlorosuccinimide (187 mg, 1.40)
mmol) and stirred at about 60 ° C. for 27 hours. Water was added and extracted with ethyl acetate-toluene. The extract was washed with water, dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 8/1) to give the title compound (23.1 mg, 17%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.81 (s, 1H), 8.99 (d, 1H, J
= 8.9 Hz), 8.03 (d, 1H, J = 2.0 Hz), 8.01 (dd, 1H,
J = 2.6, 8.9 Hz), 7.85 (d, 1H, J = 2.6 Hz), 7.59
(d, 1H, J = 2.0 Hz), 4.05 (s, 3H)

2) 2- (4,6-dichloro-2-ben)
N- (4,6-)-( thiazolyl) amino-5-nitrophenol N- (4,6-
Dichloro-2-benzthiazolyl) -2-methoxy-4
-Nitroaniline (17.5 mg, 0.0473 mmol
l) and 0.5N boron tribromide methylene chloride solution (20
0 μl, 0.100 mmol) from the title compound (0.8
mg, 5%). ¹ H-NMR (Acetone-d ₆ ) δ: 9.9 (br, 2H), 9.02 (d, 1H,
J = 9.0 Hz), 7.93 (dd, 1H, J = 2.5, 9.0 Hz), 7.89
(d, 1H, J = 2.1 Hz), 7.81 (d, 1H, J = 2.5 Hz), 7.5
1 (d, 1H, J = 2.1 Hz)

Example 8 2- (6-chloro-2-benzthiazolyl) amino-5
- Synthesis of Nitrophenol 1) N-(6- chloro-2-benzothiazolyl) -2
-Methoxy-4-nitroaniline Under the same conditions as in Example 7-1), N- (2-benzthiazolyl) -2-methoxy-4-nitroaniline (103
mg, 0.342 mmol) and N-chlorosuccinimide (56.3 mg, 0.421 mmol) to give the title compound (13.3 mg, 12%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.62 (s, 1H), 8.93 (d, 1H, J
= 9.1 Hz), 8.03 (d, 1H, J = 2.3 Hz), 8.00 (dd, 1H,
J = 2.3, 9.1 Hz), 7.84 (d, 1H, J = 2.3 Hz), 7.68
(d, 1H, J = 8.7 Hz), 7.39 (dd, 1H, J = 2.3, 8.7 H
z), 4.04 (s, 3H)

2) 2- (6-chloro-2-benzthia
Zolyl) amino-5-nitrophenol N- (6-chloro-2) under the same conditions as in Example 2-3).
-Benzthiazolyl) -2-methoxy-4-nitroaniline (12.1 mg, 0.0360 mmol) and 0.5
Normal boron tribromide methylene chloride solution (210 μl, 0.1 mL
105 mmol) of the title compound (7.8 mg, 67
%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.14 (s, 1H), 10.54 (s, 1H),
8.85 (d, 1H, J = 8.9 Hz), 8.01 (d, 1H, J = 2.1 H
z), 7.84 (dd, 1H, J = 2.6, 8.9 Hz), 7.70 (d, 1H, J
= 2.6 Hz), 7.67 (d, 1H, J = 8.7 Hz), 7.38 (dd, 1
(H, J = 2.1, 8.7Hz)

Example 92- (5-chloro-2-benzoxazolyl) amino-
Synthesis of 4-chlorophenol 1) 2-methoxy-5-chlorophenylisothiocyan
Nart  Under the same conditions as in Example 3-1), 2-methoxy-5-c
Loloaniline (558mg, 3.54mmol) and thio
Titled from phosgene (400 μl, 5.25 mmol)
A compound (777 mg, quant.) Was obtained.¹ H-NMR (CDCl_Three) δ: 7.18 (dd, 1H, J = 2.6, 8.9 Hz),
 7.08 (d, 1H, J = 2.6 Hz), 6.82 (d, 1H, J = 8.9 H
z), 3.90 (s, 3H)

2) N- (5-chloro-2-benzoxy)
Synthesis of Sazolyl) -2-methoxy-5-chloroaniline Under the same conditions as in Example 3-2), 2-methoxy-5-chlorophenylisothiocyanate (205 mg, 1.0 mg) was used.
3 mmol) and 2-amino-4-chlorophenol (1
44 mg, 1.00 mmol) and mercury oxide (22
4 mg, 1.03 mmol) from the title compound (30.3
mg, 10%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.09 (s, 1H), 8.30 (d, 1H),
7.58 (d, 1H, J = 2.0Hz), 7.51 (d, 1H, J = 8.6 Hz),
7.12-7.18 (m, 3H), 3.87 (s, 3H)

3) 2- (5-Chloro-2-benzoxy)
Sazolyl) amino-4-chlorophenol N- (5-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-5-chloroaniline (19.8 mg, 0.0640 mmol) and 0.1.
5 N boron tribromide methylene chloride solution (350 μl,
0.175 mmol) from the title compound (14.1 mg,
75%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.28 (s, 1H), 9.89 (s, 1H),
8.16 (d, 1H, J = 2.3 Hz), 7.54 (d, 1H, J = 2.3 Hz),
7.49 (d, 1H, J = 8.6 Hz), 7.14 (dd, 1H, J = 2.3,
8.6 Hz), 6.98 (dd, 1H, J = 2.3, 8.6 Hz), 6.89 (d,
(1H, J = 8.6 Hz)

Example 10 2- (6-chloro-2-benzoxazolyl) amino-
5-nitrophenol and 2- (6-nitro-2-benz)
Equilibrium with oxazolyl) amino-5-chlorophenol
Synthesis of mixture 1) 5-chloro-2-nitrophenol m-chlorophenol (5 ml) was added to a methylene chloride suspension (50 ml) of 85% nitronium tetrafluoroborate (7.67 g, 49.1 mmol) under a nitrogen stream. .10
ml, 49.1 mmol) in methylene chloride (10 mL).
0 ml) was added dropwise under ice cooling, and the mixture was stirred at the same temperature for 1 hour.
Water was added to the reaction solution, and extracted with methylene chloride. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to obtain the title compound (3.62 g, 43%). ¹ H-NMR (CDCl ₃ ) δ: 10.66 (s, 1H), 8.07 (d, 1H, J =
9.0 Hz), 7.19 (d, 1H, J = 2.2 Hz), 6.98 (dd, 1H,
(J = 2.2, 9.0 Hz)

2) 2-Amino-5-chlorophenol 5-chloro-2-nitrophenol (60
3 mg, 3.47 mmol) in methanol (10 ml)
, And 10% palladium-carbon (120 mg) was added, followed by hydrogen replacement and hydrogenation for 1.5 hours. The reaction solution was filtered through celite, the solvent of the filtrate was distilled off, and silica gel column chromatography (hexane / ethyl acetate = 3/1)
The title compound (334 mg, 67%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.43 (brs, 1H), 6.65-6.68 (m,
3H), 4.62 (brs, 2H)

3) N- (6-Chloro-2-benzoxy)
Sazolyl) -2-methoxy-4-nitroaniline Under the same conditions as in Example 3-2), 2-methoxy-5-nitrophenylisothiocyanate ( 149 mg , 0.7
09 mmol), 2-amino-5-chlorophenol (100 mg, 0.697 mmol) and mercury oxide (155 mg, 0.716 mmol) to give the title compound (14.8 mg, 7%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.57 (s, 1H), 8.61 (d, 1H, J
= 9.0 Hz), 8.02 (dd, 1H, J = 2.5, 9.0 Hz), 7.84
(d, 1H, J = 2.5 Hz), 7.76 (d, 1H, J = 1.9 Hz), 7.5
4 (d, 1H, J = 8.5 Hz), 7.33 (dd, 1H, J = 1.9, 8.5
Hz), 4.01 (s, 3H)

4) 2- (6-Chloro-2-benzoxy)
Sazolyl) amino-5-nitrophenol and 2- (6
-Nitro-2-benzoxazolyl) amino-5-chloro
Equilibrium mixture with rophenol N- (6-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-4-nitroaniline (11.6 mg, 0.0363 mmol) and 0.1.
5N boron tribromide methylene chloride solution (300 μl,
0.155 mmol) from the title compound (9.1 mg, 8
2%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.5 (br, 2H), 8.52 (d, 1H, J
= 8.9 Hz), 7.86 (dd, 1H, J = 2.6, 8.9Hz), 7.73 (d,
1H, J = 2.0 Hz), 7.70 (d, 1H, J = 2.6 Hz), 7.51
(d, 1H, J = 8.6 Hz), 7.31 (dd, 1H, J = 2.0, 8.6 Hz) δ: 10.5 (br, 2H), 8.36 (d, 1H, J = 2.3 Hz), 8.17
(dd, 1H, J = 2.3, 8.9Hz), 7.89 (d, 1H, J = 9.6H
z), 7.52 (d, 1H, J = 8.9 Hz), 6.94 (d, 1H, J = 2.3
Hz), 6.94 (dd, 1H, J = 2.3, 9.6 Hz)

Example 11 2- (6-chloro-2-benzoxazolyl) amino-
Synthesis of 5-chlorophenol 1) 5-chloro-2-nitrophenyl methyl ether Under a nitrogen stream, 5-chloro-2-nitrophenol (1.
00g, 5.76 mmol) in acetone (10 m
l), potassium carbonate (797 mg, 5.67 mmo
l), methyl iodide (1.70 ml, 27.3 mmo)
l) was added, and the mixture was heated under reflux for 5 hours. Add water to the reaction mixture,
Extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
10/1) and the title compound (964 mg, 89
%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.94 (d, 1H, J = 8.7 Hz), 7.4
9 (d, 1H, J = 2.1 Hz), 7.20 (dd, 1H, J = 2.1, 8.7
Hz), 3.95 (s, 3H)

2) 4-Chloro-2-methoxyaniline 5-chloro-2-nitrophenol (53
0 mg, 2.83 mmol) in ethanol (15 ml)
And stannous chloride (2.00 g, 8.86 mmol)
l) was added, and the mixture was heated under reflux for 1.5 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated.
The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (262)
mg, 59%). ¹ H-NMR (CDCl ₃ ) δ: 6.74-6.78 (m, 2H), 6.61 (d, 1H,
J = 8.9 Hz), 3.84 (s, 3H), 3.76 (brs, 2H)

3) 4-chloro-2-methoxyphenyl
Under the same conditions as isothiocyanate Example 3-1), 2-methoxy-4-chloroaniline (252 mg, 1.60 mmol) and thiophosgene (200 [mu] l, 2.62 mmol) were reacted to silica gel column chromatography (hexane /
Purification with ethyl acetate = 50/1) gave the title compound (315).
mg, 99%). ¹ H-NMR (CDCl ₃ ) δ: 7.02 (dd, 1H, J = 1.0, 7.6 Hz),
6.89 (d, 1H, J = 1.0 Hz), 6.87 (d, 1H, J = 7.6 H
z), 3.91 (s, 3H)

4) N- (6-chloro-2-benzoki
Sazolyl) -4-chloro-2-methoxyaniline 4-chloro-2-methoxyphenylisothiocyanate (118 mg, 0.591 mmol) and 2
-Amino-5-chlorophenol (81.4 mg, 0.
(567 mmol) was heated at reflux for 18 hours in toluene. The solvent of the reaction solution is distilled off, and the residue is subjected to silica gel column chromatography (hexane / ethyl acetate = 10/1).
The title compound (29.2 mg, 17%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 9.94 (s, 1H), 8.16 (d, 1H, J
= 8.7 Hz), 7.66 (d, 1H, J = 2.0 Hz), 7.41 (d, 1H, J
= 8.4 Hz), 7.25 (dd, 1H, J = 2.0, 8.4 Hz), 7.16
(d, 1H, J = 2.2 Hz), 7.07 (dd, 1H, J = 2.2, 8.7 H
z), 3.88 (s, 3H)

5) 2- (6-Chloro-2-benzoxy)
Sazolyl) amino-5-chlorophenol N- (6-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-4-chloroaniline (20.5 mg, 0.0663 mmol) and 0.1.
5 N boron tribromide methylene chloride solution (400 μl,
0.200 mmol) from the title compound (14.1 mg,
72%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.46 (s, 1H), 9.77 (s, 1H),
8.02 (d, 1H, J = 8.0Hz), 7.64 (d, 1H, J = 2.0 Hz),
7.39 (d, 1H, J = 8.6 Hz), 7.24 (dd, 1H, J = 2.0,
8.6 Hz), 6.92 (dd, 1H, J = 2.1, 8.0 Hz), 6.90 (d,
(1H, J = 2.1 Hz)

Embodiment 122- (6-chloro-2-benzoxazolyl) amino-
Synthesis of 4-nitrophenol 1) 2-methoxy-5-nitrophenylisothiocyan
Nart Under the same conditions as in Example 3-1), 2-methoxy-5-ni
Troaniline (1.00 g, 5.95 mmol) and thio
Titled from phosgene (700 μl, 9.18 mmol)
Compound (1.27 mg, quant.) Was obtained.¹ H-NMR (CDCl₃) δ: 8.16 (dd, 1H, J = 2.8, 9.0 Hz),
 7.98 (d, 1H, J = 2.8 Hz), 6.98 (d, 1H, J = 9.0 H
z), 4.05 (s, 3H)

2) N- (6-Chloro-2-benzoxy)
Sazolyl) -2-methoxy-5-nitroaniline Under the same conditions as in Example 11-4), 2-methoxy-5
Nitrophenyl isothiocyanate (107 mg, 0.1 mg).
509 mmol) and 2-amino-5-chlorophenol (72.5 mg, 0.505 mmol) to give the title compound (9.7 mg, 6%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.39 (s, 1H), 9.26 (d, 1H, J
= 2.9 Hz), 8.04 (dd, 1H, J = 2.9, 9.1 Hz), 7.73
(d, 1H, J = 2.0 Hz), 7.54 (d, 1H, J = 8.6 Hz), 7.2
8-7.32 (m, 2H), 4.02 (s, 3H)

3) 2- (6-chloro-2-benzoki)
Sazolyl) amino-4-nitrophenol N- (6-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-5-nitroaniline (6.2 mg, 0.0194 mmol) and 0.5
Normal methylene chloride solution of boron tribromide (250 μl, 0.
125 mmol) from the title compound (2.0 mg, 34
%). ¹ H-NMR (Acetone-d ₆ ) δ: 9.42 (d, 1H, J = 2.6 Hz),
7.94 (dd, 1H, J = 2.6, 8.9 Hz), 7.54 (d, 1H, J =
8.3 Hz), 7.55 (d, 1H, J = 2.0 Hz), 7.32 (dd, 1H, J
= 2.0, 8.3 Hz), 7.16 (d, 1H, J = 8.9 Hz), two pro
ton is not detected.

Example 13 2- (4-chloro-2-benzoxazolyl) amino-
Synthesis of 4-nitrophenol 1) 3-Chloro-2-nitrophenol m-chlorophenol (5.00 g, 3
To 8.9 mmol), 61% nitric acid was added dropwise under ice cooling, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract is dried over magnesium sulfate, filtered,
The solvent of the filtrate was distilled off. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 6/1 → 3 /
Purification in 1) gave the title compound as a mixture with isomers (3.40 g). ¹ H-NMR (CDCl ₃ ) δ: 7.40 (dd, 1H, J = 7.8, 7.8 Hz),
7.07-7.12 (m, 2H)

[0248]2) 2-amino-3-chlorophenol  Under the same conditions as in Example 11-2), 3-chloro-2-ni
Mixture of trophenol and isomer (3.35 g, 19.
3 mmol) and stannous chloride (13.6 g, 57.9 m)
mol), the title compound (473 mg, 8.6%, 2
(steps).¹ H-NMR (DMSO-d₆) δ: 9.57 (brs, 1H), 6.68 (dd, 1H,
 J = 1.5, 8.1 Hz), 6.62 (dd, 1H, J = 1.5, 8.1 Hz),
 6.41 (dd, 1H, J = 8.1, 8.1 Hz), 4.57 (brs, 2H)

3) N- (4-Chloro-2-benzoxy)
Sazolyl) -2-methoxy-5-nitroaniline Under the same conditions as in Example 11-4), 2-methoxy-5
Nitrophenyl isothiocyanate (112 mg, 0.1 mg).
533 mmol) and 2-amino-3-chlorophenol (75.9 mg, 0.529 mmol) to give the title compound (75.7 mg, 45%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.47 (s, 1H), 9.31 (d, 1H, J
= 2.9 Hz), 8.06 (dd, 1H, J = 2.9, 9.1 Hz), 7.52
(dd, 1H, J = 0.9, 7.9 Hz), 7.34 (dd, 1H, J = 0.9,
7.9 Hz), 7.31 (d, 1H, J = 9.1 Hz), 7.18 (dd, 1H, J
= 7.9, 7.9 Hz), 4.02 (s, 3H)

4) 2- (4-Chloro-2-benzoxy)
Sazolyl) amino-4-nitrophenol N- (4-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-5-nitroaniline (37.0 mg, 0.116 mmol) and 1.0
Normal methylene chloride solution of boron tribromide (250 μl, 0.
250 mmol) from the title compound (25.7 mg, 7
2%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.74 (brs, 1H), 10.29 (s, 1
H), 9.20 (d, 1H, J = 2.6 Hz), 7.95 (dd, 1H, J = 2.
6, 8.9 Hz), 7.51 (d, 1H, J = 7.6 Hz), 7.33 (d, 1H,
J = 7.6 Hz), 7.16 (dd, 1H, J = 7.6, 7.6 Hz), 7.07
(d, 1H, J = 8.9 Hz)

Embodiment 142- (7-chloro-2-benzoxazolyl) amino-
Synthesis of 4-nitrophenol 1) 6-chloro-2-nitrophenol Under the same conditions as in Example 10-1), 85% nitronium was used.
Tetrafluoroborate (8.80 g, 56.3 mmo
l) and 2-chlorophenol (5.80 ml, 56.0)
mmol) from the title compound as a mixture with the raw materials
(4.23 g) was obtained.¹ H-NMR (CDCl₃) δ: 11.04 (s, 1H), 8.07 (dd, 1H, J
= 1.7, 8.6 Hz), 7.71 (dd, 1H, J = 1.7, 7.9 Hz), 7.0
0 (dd, 1H, J = 7.9, 8.6 Hz)

2) 2-Amino-6-chlorophenol Under the same conditions as in Example 11-2), a mixture of 6-chloro-2-nitrophenol and 2-chlorophenol (3.
90g) and stannous chloride (10.2g, 43.4mmo)
1), the title compound (375 mg, 5.0%, 2st
eps). ¹ H-NMR (CDCl ₃ ) δ: 6.73 (dd, 1H, J = 2.4, 7.9 Hz),
6.69 (dd, 1H, J = 7.1, 7.9 Hz), 6.62 (dd, 1H, J =
2.4, 7.1 Hz), 5.43 (brs, 1H), 3.84 (brs, 2H)

3) N- (7-Chloro-2-benzoxy)
Sazolyl) -2-methoxy-5-nitroaniline Under the same conditions as in Example 11-4), 2-methoxy-5
Nitrophenyl isothiocyanate (102 mg, 0.
485 mmol) and 2-amino-6-chlorophenol (70.0 mg, 0.488 mmol) to give the title compound (29.6 mg, 19%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.55 (s, 1H), 9.27 (d, 1H, J
= 2.8 Hz), 8.05 (dd, 1H, J = 2.8, 8.9 Hz), 7.52
(dd, 1H, J = 3.3, 5.6 Hz), 7.26-7.31 (m, 3H), 4.02
(s, 3H)

4) 2- (7-Chloro-2-benzoxy)
Sazolyl) amino-4-nitrophenol N- (7-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-methoxy-5-nitroaniline (19.7 mg, 0.0616 mmol) and 1.
0N Boron tribromide methylene chloride solution (350 μl,
0.350 mmol) from the title compound (7.3 mg,
39%). ¹ H-NMR (DMSO-d ₆ ) δ: 11.74 (brs, 1H), 10.32 (s, 1
H), 9.16 (d, 1H, J = 3.0 Hz), 7.94 (dd, 1H, J = 3.
0, 8.9 Hz), 7.49 (dd, 1H, J = 2.8, 5.8 Hz), 7.23-7.
30 (m, 2H), 7.04 (d, 1H, J = 8.9 Hz)

Example 15 2- (7-Chloro-2-benzoxazolyl) amino-
Synthesis of 6-chlorophenol 1) 7-chloro-2-mercaptobenzoxazole 85% potassium hydroxide (82.0 mg,
1.24 mmol) was dissolved in methanol (1.8 ml) -water (280 μl) and carbon disulfide (75 μl, 1.
25 mmol) and 2-amino-6-chlorophenol (150 mg, 1.04 mmol) were added, and the mixture was heated under reflux for 3.5 hours. A 5% aqueous solution of potassium hydrogen sulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / hexane).
Purification with ethyl acetate = 2/1) gave the title compound (124 m
g, 64%). ¹ H-NMR (DMSO-d ₆ ) δ: 7.35 (dd, 1H, J = 1.7, 7.8 H
z), 7.30 (dd, 1H, J = 7.8, 7.8 Hz), 7.20 (dd, 1H, J
= 1.7, 7.8 Hz), 5.86 (brs, 1H)

2) 2,7-Dichlorobenzoxazo
Under Le nitrogen stream, the 7-chloro-2-mercaptobenzoxazole (73.8 mg, 0.398 mmol), phosphorus oxychloride (1.30 ml, 14.2 mmol) and phosphorus pentachloride (94.0 mg, 0.451 mmol) Was added, and the mixture was stirred at room temperature for 8 hours. The solvent of the reaction solution was distilled off under reduced pressure, and water and a 5% aqueous potassium carbonate solution were added.
And extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 10/1) to give the title compound (31.8 mg, 42%). ¹ H-NMR (CDCl ₃ ) δ: 7.58 (dd, 1H, J = 1.3, 7.8 Hz),
7.36 (dd, 1H, J = 1.3, 7.8 Hz), 7.30 (dd, 1H, J =
(7.8, 7.8 Hz)

3) 2- (7-Chloro-2-benzoxy)
Sazolyl) amino-6-chlorophenol 2,7-dichlorobenzoxazole (2
1.1 mg, 0.112 mmol) in dioxane (1.
0 ml), 2-amino-6-chlorophenol (16.1 mg, 0.112 mmol) and triethylamine (20 μl, 0.143 mmol) were added, and the mixture was heated under reflux for 4 hours. The reaction solution was returned to room temperature, a 5% aqueous potassium hydrogen sulfate solution was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 6/1) and subsequently (hexane / chloroform = 1/1) to give the title compound (0.
6 mg, 2%). ¹ H-NMR (Acetone-d ₆ ) δ: 9.3 (br), 8.11 (dd, 1H, J
= 1.5, 8.1 Hz), 7.41 (dd, 1H, J = 1.3, 7.9 Hz), 7.2
6 (dd, 1H, J = 7.9, 7.9 Hz), 7.19 (dd, 1H, J = 1.
3, 7.9 Hz), 7.18 (dd, 1H, J = 1.5, 8.1 Hz), 6.99
(d, 1H, J = 8.1, 8.1 Hz)

Example 162- (4-chloro-2-benzoxazolyl) amino-
Synthesis of 3-chlorophenol 1) 2-chloro-6-methoxyaniline  Under a nitrogen stream, 2-methoxyaniline (1.00 ml,
8.87 mmol) dimethylformamide solution (30
ml), N-chlorosuccinimide (1.30 g,
9.74 mmol) at room temperature for 1 hour and then 60
Stir at 1 ° C for 1 hour. Saturated aqueous sodium bicarbonate and 5% charcoal
Potassium hydroxide aqueous solution, and extracted with ethyl acetate-toluene.
I put it out. The extract is dried over magnesium sulfate, filtered,
The solvent of the filtrate was distilled off. The residue is purified by silica gel column chromatography.
Purified by chromatography (hexane / ethyl acetate = 8/1)
The title compound was obtained as a mixture with the dichloro compound (295
mg).

2) 2-chloro-6-methoxyphenyl
Under the same conditions as isothiocyanate Example 3-1), 2-chloro-6-methoxy aniline (140mg, 0.888mmol) and from thiophosgene (250 [mu] l, 3.28 mmol), the title compound (107 mg, 13%, 2 steps ) Got. ¹ H-NMR (CDCl ₃ ) δ: 7.13 (dd, 1H, J = 8.3, 8.3 Hz),
6.98 (dd, 1H, J = 1.2, 8.3 Hz), 6.81 (dd, 1H, J =
1.2, 8.3 Hz), 3.92 (s, 3H)

3) N- (4-Chloro-2-benzoxy)
Sazolyl) -2-chloro-6-methoxyaniline Under the same conditions as in Example 11-4), 2-chloro-6-methoxyphenylisothiocyanate (83.5 mg,
0.418 mmol) and 2-amino-3-chlorophenol (60.0 mg, 0.418 mmol) to give the title compound (21.0 mg, 16%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.03 (s, 1H), 7.34-7.40 (m,
2H), 7.14-7.23 (m, 3H), 7.03 (dd, 1H, J = 8.1, 8.1
Hz), 3.80 (s, 3H)

4) 2- (4-Chloro-2-benzoxy)
Sazolyl) amino-3-chlorophenol N- (4-chloro-2) under the same conditions as in Example 3-4).
-Benzoxazolyl) -2-chloro-6-methoxyaniline (17.3 mg, 0.0560 mmol) and 1.
0 N boron tribromide methylene chloride solution (200 μl,
0.200 mmol) from the title compound (5.8 mg,
35%). ¹ H-NMR (Acetone-d ₆ ) δ: 9.10 (s, 1H), 8.98 (brs, 1
H), 7.34 (dd, 1H, J = 1.0, 8.0 Hz), 7.25 (dd, 1H, J
= 8.2, 8.2 Hz), 7.23 (dd, 1H, J = 1.0, 8.0 Hz),
7.08 (dd, 1H, J = 8.0, 8.0 Hz), 7.08 (dd, 1H, J =
1.4, 8.2 Hz), 7.01 (dd, 1H, J = 1.4, 8.2 Hz)

Example 17 2- (4,6-dichloro-2-benzoxazolyl) a
Synthesis of Mino-3,5-dichlorophenol 1) 3,5-Dichloro-2-nitrophenol 85% nitronium tetrafluoroborate (1.58 g, 10.1 mmol) under the same conditions as in Example 10-1).
l) and 3,5-dichlorophenol (1.63 g, 1
0.0 mmol) to give the title compound (2.04 g, 97
%). ¹ H-NMR (CDCl ₃ ) δ: 9.5-10.3 (br, 1H), 7.11 (s, 2H)

2) 3,5-dichloro-2-nitrophen
A solution of 3,5-dichloro-2-nitrophenol (1.21 g, 5.83 mmol) in acetone (1
0 ml) and potassium carbonate (982 mg, 7.10 mmol)
l), methyl iodide (475 μl, 7.62 mmol)
Was added and stirred at room temperature for 1.5 hours. The reaction solution was added to water and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel (hexane / ethyl acetate =
10/1) to give the title compound (921 mg, 71
%). ¹ H-NMR (CDCl ₃ ) δ: 7.09 (d, 1H, J = 2.0 Hz), 6.95
(d, 1H, J = 2.0 Hz), 3.92 (s, 3 H)

3) 2,4-Dichloro-6-methoxya
Niline Under the same conditions as in Example 11-2), 3,5-dichloro-
2-nitrophenyl methyl ether (408 mg, 1.
84 mmol) and stannous chloride (1.58 g, 7.00).
mmol) to give the title compound (217 mg, 61%). ¹ H-NMR (CDCl ₃ ) δ: 6.91 (d, 1H, J = 2.3 Hz), 6.68
(d, 1H, J = 2.3 Hz), 4.12 (br, 2H), 3.85 (s, 3H)

4) 2,4-Dichloro-6-methoxyp
Enyl isothiocyanate Under the same conditions as in Example 3-1), 2,4-dichloro-6
-Methoxyaniline (217 mg, 1.13 mmol)
And thiophosgene (240 μl, 3.15 mmol) to give the title compound (243 mg, 92%). ¹ H-NMR (CDCl ₃ ) δ: 7.01 (d, 1H, J = 2,0 Hz), 6.80
(d, 1H, J = 2.0 Hz), 3.91 (s, 3H)

5) 3,5-Dichloro-2-aminophen
Under the same conditions as in Example 11-2), 3,5-dichloro-
2-nitrophenol (412 mg, 1.98 mmol
l) and stannous chloride (1.58 g, 6.98 mmol)
Thus, the title compound (276 mg, 78%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 6.91 (d, 1H, J = 2.3 Hz), 6.67
(d, 1H, J = 2.3 Hz), 5.36 (br, 1H), 3.97 (br, 2H)

6) N- (4,6-dichloro-2-ben
Zoxazolyl) -2,4-dichloro-6-methoxya
Niline Under the same conditions as in Example 11-4), 2,4-dichloro-
6-methoxyphenyl isothiocyanate (70.1 m
g, 0.299 mmol) and 3,5-dichloro-2-aminophenol (54.3 mg, 0.305 mmol)
As a result, a mixture (71.0 mg) containing the title compound was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 10.28 (s, 1H), 7.65 (d, 1H, J
= 2.0 Hz), 7.38 (d, 1H, J = 2.0 Hz), 7.36 (d, 1H,
J = 2.3 Hz), 7.29 (d, 1H, J = 2.3 Hz), 3.83 (s, 3
H)

7) 2- (4,6-dichloro-2-ben
[Duoxazolyl) amino-3,5-dichlorophenol N- (4,6-dichloro-2-benzoxazolyl) -2,4-dichloro-6 under the same conditions as in Example 3-4).
-Methoxyaniline-containing mixture (71.0 mg) and 0.5N boron tribromide in methylene chloride solution (1.00 m
1, 0.500 mmol) to give a mixture (8.2 mg) containing the title compound. ¹ H-NMR (CD ₃ OD) δ: 7.42 (d, J = 1.7 Hz, 1H), 7.29
(d, J = 1.7 Hz, 1H), 7.09 (d, J = 2.3 Hz, 1H), 6.96
(d, J = 2.3 Hz, 1H)

Example 18 2- (5,7-Dichloro-2-benzoxazolyl) a
Synthesis of mino-4,6-dichlorophenol 1) 2,4-dichloro-6-nitrophenylmethoxy
Under conditions similar to those of methyl ether Example 10-1), 85% nitronium tetrafluoroborate (1.63 g, 10.4 mmo)
l) and 2,4-dichlorophenol (1.63 g, 1
0.0mmol) to give 2,4-dichloro-6-nitrophenol (1.84 g, 89%). 2,4-dichloro-6-nitrophenol (203
mg, 0.976 mmol) in a dimethylformamide solution and potassium carbonate (168 mg, 1.21 mmol) and chloromethyl methyl ether (169 mg, 2.10 m2).
mol), and the mixture was stirred at room temperature for 30 minutes. The reaction solution was added to water and extracted with ethyl acetate-toluene. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 10/1) to give the title compound (234 mg, 95%). ¹ H-NMR (CDCl ₃ ) δ: 7.70 (d, 1H, J = 2.6 Hz), 7.64
(d, 1H, J = 2.6 Hz), 5.15 (s, 2H), 3.56 (s, 3H)

2) 3,5-dichloro-2-methoxymeth
Tokishianirin nitrogen stream, 2,4-dichloro-6-nitrophenyl methoxymethyl ether (234mg, 0.926mmo
10% palladium-carbon (38 mg) was added to an ethyl acetate solution (5.0 ml) of 1), and the mixture was replaced with hydrogen and hydrogenated for 1 hour. The reaction solution was filtered through celite, and the solvent of the filtrate was distilled off. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to give the title compound (98.4 mg, 48%). ¹ H-NMR (CDCl ₃ ) δ: 6.74 (d, 1H, J = 2.6 Hz), 6.63
(d, 1H, J = 2.6 Hz), 5.07 (s, 2H), 4.13 (br, 2H),
3.62 (s, 3H)

3) 2-Amino-4,6-dichlorofe
Under the same conditions as in Example 17-2), 2,4-dichloro-
6-nitrophenol (407 mg, 1.96 mmol
From 1), the title compound (255 mg, 73%) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 6.72 (d, 1H, J = 2.3 Hz), 6.61
(d, 1H, J = 2.3 Hz), 5.36 (br, 1H), 3.92 (br, 2H)

4) 3,5-Dichloro-2-methoxymeth
Butoxy phenyl isothiocyanate under nitrogen stream, 3,5-dichloro-2-methoxy-methoxyaniline (750 mg, 3.38 mmol) in chloroform solution (10ml) of triethylamine (1.70
ml, 12.2 mmol), thiophosgene (400 μm
1,5.25 mmol) and stirred at room temperature for 2.5 hours. The reaction solution was added to water and extracted with chloroform. The extract layer was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 20/1) to give the title compound (392 mg, 44%). ¹ H-NMR (CDCl ₃ ) δ: 7.30 (d, 1H, J = 2.6 Hz), 7.13
(d, 1H, J = 2.6 Hz), 5.19 (s, 2H), 3.68 (s, 3H)

5) N- (5,7-dichloro-2-ben
Duxazolyl) -3,5-dichloro-2-methoxymeth
Under the same conditions as Tokishianirin Example 3-2), 3,5-dichloro-2
-Methoxymethoxyphenyl isothiocyanate (7
0.5 mg, 0.301 mmol) and 2-amino-4,
6-dichlorophenol (53.8 mg, 0.302 m
mol) and mercury oxide (61.5 mg, 0.284
mmol), the title compound (28.2 mg, 23%)
I got ¹ H-NMR (DMSO-d ₆ ) δ: 10.78 (s, 1H), 8.28 (d, 1H, J
= 2.5 Hz), 7.63 (d, 1H, J = 1.8 Hz), 7.44 (d, 1H,
J = 2.5 Hz), 7.41 (d, 1H, J = 1.8 Hz), 5.12 (s, 2
H), 3.51 (s, 3H)

6) 2- (5,7-dichloro-2-ben)
[Duoxazolyl) amino-4,6-dichlorophenol N- (5,7-dichloro-2-benzoxazolyl)-
3,5-dichloro-2-methoxymethoxyaniline (2
7.5 mg, 0.0674 mmol) of methanol (1
ml) -tetrahydrofuran (8 ml) solution, 4N hydrochloric acid dioxane solution (2.0 ml) was added,
Stir for hours. Saturated sodium hydrogen carbonate solution was added to the reaction solution to adjust the pH to 7
, Water was added, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, the solvent of the filtrate was distilled off, and the residue was purified by silica gel chromatography (toluene / ethyl acetate = 10/1) to give the title compound (2.5 mg,
10%). ¹ H-NMR (DMSO-d ₆ ) δ: 10.50 (s, 1H), 10.19 (s, 1H),
8.02 (d, 1H, J = 2.6 Hz), 7.57 (d, 1H, J = 1.8 H
z), 7.37 (d, 1H, J = 2.6 Hz), 7.37 (d, 1H, J = 1.8
Hz)

Example 19 2- (5,6-Dichloro-2-benzoxazolyl) a
Synthesis of Mino-4,5-dichlorophenol 1) 4,5-Dichloro-2-nitrophenol 85% nitronium tetrafluoroborate (1.69 g, 10.8 mmol) under the same conditions as in Example 10-1).
l) and 3,4-dichlorophenol (1.63 g, 1
0.0 mmol) to give the title compound (2.09 g,> 9
9%). ¹ H-NMR (CDCl ₃ ) δ: 10.47 (s, 1H), 8.
23 (s, 1H), 7.33 (s, 1H)

2) 4,5-Dichloro-2-nitrophen
Nyl methyl ether Under a nitrogen stream, potassium carbonate (973 mg, 973 mg) was added to a solution of 4,5-dichloro-2-nitrophenol (1.28 g, 6.16 mmol) in dimethylformamide (10 ml).
7.04 mmol), methyl iodide (440 μl, 7.
07 mmol) and stirred at 50 ° C. for 1 hour. The reaction solution was added to water and extracted with ethyl acetate / toluene.
The extract was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off to obtain the title compound (1.28 g, 96%). ¹ H-NMR (CDCl ₃ ) δ: 8.01 (s, 1H), 7.20 (s, 1H), 3.9
8 (s, 3H)

3) 4,5-dichloro-2-methoxya
4,5-Dichloro-2-nitrophenyl methyl ether (1.28) under the same conditions as in the synthesis of nilin Example 11-2).
g, 5.77 mmol) and stannous chloride (4.70 g,
20.8 mmol) to give the title compound (801 mg, 72
%). ¹ H-NMR (CDCl ₃ ) δ: 6.80 (s, 1H), 6.75 (s, 1H), 3.8
3 (br, 5H)

4) 4,5-Dichloro-2-methoxyp
4,5-Dichloro-2-methoxyaniline (801 mg, 4.17 m) under the same conditions as in the synthesis of phenyl isothiocyanate Example 18-4).
mol), thiophosgene (460 μl, 6.03 mmol)
l), triethylamine (1.67 ml, 12.0 mm)
ol) to give the title compound (836 mg, 86%). ¹ H-NMR (CDCl ₃ ) δ: 7.17 (s, 1H), 6.97 (s, 1H), 3.9
1 (s, 3H)

5) 2-Amino-4,5-dichlorofe
Under the same conditions as in the synthesis of Example 18-2), 4,5-dichloro-2-nitrophenol (413 mg, 1.99 m
mol) to give the title compound (295 mg, 83%). ¹ H-NMR (CDCl ₃ ) δ: 6.82 (s, 1H), 6.81 (s, 1H), 5.1
(br, 1H), 3.7 (br, 2H)

6) N- (5,6-dichloro-2-ben
Duxazolyl) -4,5-dichloro-2-methoxya
Under the same conditions as in the synthesis of nilin Example 11-4), 4,5-dichloro-2-methoxyphenylisothiocyanate (7
3.8 mg, 0.315 mmol) and 2-amino-4,
5-dichlorophenol (54.5 mg, 0.302 m
mol), a 1: 1 mixture (17.2 mg) of the title compound and 4,5-dichloro-2-methoxyaniline was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 10.42 (s, 1H), 8.43 (s, 1H),
7.94 (s, 1H), 7.81 (s, 1H), 7.37 (s, 1H), 3.90 (s, 1H)
3H)

7) 2- (5,6-Dichloro-2-ben)
N- (5,6 -dioxazolyl) amino-4,5-dichlorophenol under the same conditions as in the synthesis of Example 3-4).
1: 1 mixture of dichloro-2-benzoxazolyl) -4,5-dichloro-2-methoxyaniline and 4,5-dichloro-2-methoxyaniline (17.2 mg) and 0.5N tribromide Boron in methylene chloride (1.00
ml, 0.500 mmol) from the mixture of the title compound and 2-amino-4,6-dichlorophenol (13.0).
mg). ¹ H-NMR (CD ₃ OD) δ: 8.42 (s, 1H), 7.63 (s, 1H), 7.6
1 (s, 1H), 7.02 (s, 1H)

Example 20 2- (5-methyl-2-benzoxazolyl) amino-
5-nitrophenol and 2- (6-nitro-2-benz)
Equilibrium with oxazolyl) amino-4-methylphenol
Under a nitrogen stream of the mixture, a solution of 2-chloro-6-nitrobenzoxazole (58.7 mg) in acetonitrile (3.0 m) was used.
2-Amino-p-cresol (37.8 mg) was added to l), and the mixture was stirred at room temperature for 21 hours. Add water to the reaction solution,
Extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the filtrate was evaporated. The residue was subjected to silica gel chromatography (chloroform / methanol = 1).
/ 0 → 20/1) to give the title compound (54.3m
g) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ: 11.13 (br, 1H), 10.2 (br, 1
H), 8.56 (d, 1H, J = 9.2 Hz), 7.86 (dd, 1H, J = 9.
2, 2.6 Hz), 7.69 (d, 1H, J = 2.6 Hz), 7.51 (d, 1H,
J = 8.9 Hz), 7.36-7.34 (m, 1H), 6.89-6.84 (m, 1
H), 2.39 (s, 3H) δ: 10.2 (br, 1H), 9.68 (br, 1H), 8.34 (d, 1H, J =
2.3 Hz), 8.17 (dd, 1H, J = 8.4, 2.3 Hz), 7.61-7.5
8 (m, 1H), 7.40 (d, 1H, J = 8.4 Hz), 7.03-6.98 (m,
1H), 6.81 (d, 1H, J = 8.3 Hz), 2.24 (s, 3H)

Example 21 2- (6-methyl-2-benzoxazolyl) amino-
5-nitrophenol and 2- (6-nitro-2-benz)
Equilibrium with oxazolyl) amino-5-methylphenol
Synthesis of a mixture Under the same conditions as in Example 20, 2-chloro-6-nitrobenzoxazole (58.6 mg) and 6-amino-m-
From cresol (36.2 mg), the title compound (50.
3 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 10.17 (br, 1H), 9.80 (br, 1H),
8.56 (d, 1H, J = 9.2 Hz), 7.87 (dd, 1H, J = 9.2,
2.6 Hz), 7.68 (d, 1H, J = 2.6 Hz), 7.41 (d, 1H, J
= 7.9 Hz), 7.37 (m, 1H), 7.09 (m, 1H), 2.40 (s, 3H) δ: 11.12 (br, 1H), 10.14 (br, 1H), 8.32 (d, 1H, J
= 2.3 Hz), 8.15 (dd, 1H, J = 8.4, 2.3 Hz), 7.59
(d, 1H, J = 8.4 Hz), 7.46 (d, 1H, J = 8.7 Hz), 6.7
4 (m, 1H), 6.68 (m, 1H), 2.24 (s, 3H)

Embodiment 225-nitro-2- (oxazolo [4,5-b] pyridine
-2-yl) aminophenol  1)2-methoxy-4-nitro-N- (oxazolo
[4,5-b] pyridin-2-yl) aniline Under a nitrogen stream, 2-methoxy-4-nitrophenylisothi
Toluene solution of cyanate (132 mg) (3.5 m
l), 2-amino-3-hydroxypyridine (68.
0 mg) was added and the mixture was heated under reflux for 9 hours. Furthermore, oxidation
Mercury (100 mg) was added, and the mixture was heated under reflux for 7 hours. Anti
The reaction mixture was returned to room temperature, filtered, and the solvent in the filtrate was distilled off under reduced pressure.
did. The residue was subjected to silica gel column chromatography (f.
Purify with xane: ethyl acetate = 2: 1 → 1: 1) to give the title
A compound (59.6 mg) was obtained. ¹ H-NMR (DMSO-d₆) δ: 10.75 (s, 1H), 8.63 (d, 1H, J
 = 9.1 Hz), 8.31 (dd, 1H, J = 1.4, 4.9Hz), 8.04 (d
d, 1H, J = 2.4, 9.1Hz), 7.94 (dd, 1H, 1.4, 7.9Hz),
 7.86 (d, 1H, J = 2.4 Hz), 7.21 (dd, 1H, J = 4.9,
7.9 Hz), 4.03 (s, 3H)

2) 5-Nitro-2- (oxazolo [4,
5-b] pyridin-2-yl) aminophenol Chloride of 5-nitro-2- (oxazolo [4,5-b] pyridin-2-yl) aminophenol (35.7 mg) under a nitrogen stream. To the methylene suspension (2 ml)
0.5N boron tribromide methylene chloride solution (400μ
l) was added and stirred at room temperature for 15 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, the solvent of the filtrate was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform:
Purification with methanol = 20: 1) gave the title compound (8.6).
mg). ¹ H-NMR (DMSO-d ₆ ) δ: 11.19 (s, 1H), 10.57 (s, 1H),
8.54 (d, 1H, J = 8.9Hz), 8.30 (d, 1H, J = 5.0Hz),
7.92 (d, 1H, 7.9Hz), 7.88 (dd, 1H, J = 2.6, 8.9 H
z), 7.72 (d, 1H, J = 2.6Hz), 7.19 (dd, 1H, J = 5.
(0, 7.9 Hz)

Example 23 2- (oxazolo [4,5-b] pyridin-2-yl)
Amino-3-pyridinol 1) 3-Methoxy-2-nitropyridine Diisopropylethylamine (1.3 m) was added to a solution of 3-hydroxy-2-nitropyridine (1.00 g) in tetrahydrofuran (20 ml) under a nitrogen stream under ice-cooling.
l) and methyl triflate (850 μl) were added, and the mixture was stirred at room temperature for 6 hours. Aqueous ammonia was added to the reaction solution, and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 2) to obtain the title compound (540 mg). ¹ H-NMR (CDCl ₃ ) δ: 8.10 (dd, 1H, J = 2.0, 4.0 Hz),
7.51-7.58 (m, 2H), 3.99 (s, 3H)

2) 2-Amino-3-methoxypyridine Under a nitrogen stream, 3-methoxy-2-nitropyridine (350 mg) obtained above was dissolved in ethyl acetate (9.0 ml), and 10% Pd-C ( 89.8 mg), and the mixture was purged with hydrogen and hydrogenated at normal pressure for 2.5 hours. The catalyst was filtered through celite, and the solvent in the filtrate was evaporated under reduced pressure to give the title compound (274 m
g) was obtained. ¹ H-NMR (CDCl ₃ ) δ: 7.66 (dd, 1H, J = 1.3, 5.0 Hz),
6.91 (dd, 1H, J = 1.3,7.8Hz), 6.62 (dd, 1H, J = 5.
0, 7.8Hz), 4.63 (bs, 2H), 3.84 (s, 3H)

3) 2- (3-methoxypyridyl) isothi
Thiosphosgene (1) was added to a mixture of 2-amino-3-methoxypyridine (200 mg), chloroform (7.5 ml) and saturated aqueous sodium bicarbonate (3.0 ml) obtained above under a stream of ocyanate nitrogen.
75 μl) and stirred at room temperature for 7 hours. The chloroform layer was separated, dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give the title compound (135 mg). ¹ H-NMR (CDCl ₃ ) δ: 7.98 (dd, 1H, J = 1.8, 4.5 Hz),
7.15-7.24 (m, 2H), 3.94 (s, 3H)

4) 3-Methoxy-2- (oxazolo
[4,5-b] pyridin-2-yl) aminopyridine 2- (3-methoxypyridyl) obtained above under a nitrogen stream.
Toluene (3.0 ml) was added to isothiocyanate (68.7 mg) and 3-hydroxy-2-aminopyridine (46.9 mg), and the mixture was heated under reflux for 3 hours. further,
Mercuric oxide (88.8 mg) was added, and the mixture was heated under reflux for 1.5 hours. The reaction mixture was returned to room temperature, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain the title compound (58.6 mg). ¹ H-NMR (CDCl ₃ ) δ: 8.30 (bs, 1H), 7.59 (d, 1H, J =
7.3Hz), 7.42 (bs, 1H), 7.05-7.09 (m, 2H), 6.73 (b
s, 1H), 3.98 (s, 3H)

5) 2- (oxazolo [4,5-b] pyri
Gin-2-yl) amino-3-pyridinol Methylene chloride of 3-methoxy-2- (oxazolo [4,5-b] pyridin-2-yl) aminopyridine (30.0 mg) obtained above under a nitrogen stream. In the suspension (2 ml)
0.5N boron tribromide methylene chloride solution (500μ
l) was added and stirred for 13 hours. Water was added and extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol = 40:
Purification in 1) afforded the title compound (11.7 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 8.21 (dd, 1H, J = 1.4, 5.3H
z), 7.85 (d, 1H, J = 5.9Hz), 7.80 (d, 1H, 7.9Hz),
7.27 (dd, 1H, J = 1.4, 7.8 Hz), 7.07-7.12 (m, 2H)

Example 24 3- (6-Nitro-2-benzoxazolyl) amino-
2-Pyridinol 1) 3-Amino-2-hydroxypyridine 2-nitro-3-nitropyridine (6
00 mg), methanol (10 ml), tetrahydrofuran (5 ml) and water (1.5 ml) were added and dissolved.
0% Pd-C (150 mg) was added to replace with hydrogen, and hydrogenated at normal pressure for 3 hours. The catalyst was filtered through celite, and the filtrate was evaporated under reduced pressure to give the title compound (444 mg). ¹ H-NMR (CDCl ₃ ) δ: 12.16 (bs, 1H), 6.81 (dd, 1H, J
= 1.7, 6.6Hz), 6.65 (dd, 1H, 1.7, 7.1Hz), 6.16 (d
d, 1H, J = 6.6, 7.1 Hz), 4.15 (bs, 2H)

2) 3- (6-nitro-2-benzoxa)
Zolyl) amino-2-methoxypyridine Under a nitrogen stream, 3-amino-2-hydroxypyridine (69.5 mg) and 2-methoxy-4-nitrophenylisothiocyanate (135 mg) obtained above were added to toluene (4.0 ml). And was heated to reflux for 3.5 hours. Further, add mercury oxide (136 mg), and
Heated to reflux. The reaction mixture was returned to room temperature, filtered, and the solvent of the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 2: 1 → 1:
Purification in 1) gave the title compound (67.9 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 10.68 (s, 1H), 8.63 (d, 1H, J
= 8.9 Hz), 8.10 (d, 1H, J = 5.1Hz), 8.02 (dd, 1H,
J = 8.9, 2.5Hz), 7.94 (d, 1H, 7.7Hz), 7.85 (d, 1H,
J = 2.5Hz), 7.35 (dd, 1H, J = 5.1, 7.7 Hz), 4.02
(s, 3H)

3) 3- (6-Nitro-2-benzoki)
Sazolyl) amino-2-pyridinol 3- (6-nitro-2-benzoxazolyl) amino-2-methoxypyridine (31.
To a suspension of methylene chloride (8 mg) in methylene chloride (2 ml) was added a 0.5 N boron tribromide methylene chloride solution (1.05 ml), and the mixture was stirred for 86 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over magnesium sulfate, filtered, and the solvent in the filtrate was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (chloroform: methanol =
20: 1) to give the title compound (9.2 mg). ¹ H-NMR (DMSO-d ₆ ) δ: 12.06 (bs, 1H), 10.42 (s, 1H),
8.38 (d, 1H, J = 2.3 Hz), 8.32 (dd, 1H, J = 1.8, 6.9
Hz), 8.20 (dd, 1H, 2.3, 8.7Hz), 7.61 (d, 1H, J = 8.7
Hz), 7.18 (dd, 1H, J = 1.8, 6.9Hz), 6.34 (dd, 1H, J
= 6.9, 6.9Hz)

Embodiment 25An example of cytokine production from mouse lymph node cells
Action of compounds of Examples 1 to 23  <Experimental method> 1.Animals BALB / c mice are purchased from Charles River Japan (Yokohama)
And 8-week-old females were used. 2. Medium RPMI1640 medium “Daigo” (Nippon Pharmaceutical, Tokyo) contains 56
Fetal bovine serum (Fetal Bovine Seru
m, Characterized, Code No.A-1115-L, HyClone Lab.,
Logan, Utah) added to 10% 2-mercapto
Ethanol (Sigma, St Louis, MO, Code No. M-6250)
Was added to be 50 μM before use.

3. Drug The test compound was dissolved in dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J) to a concentration of 100 mM, and diluted with the medium to a final concentration. 4. Sensitization and preparation of lymph node cells 0.2 mg of KLH was added to Freund's complete adjuvant (Difco La
b., Detroit, Michigan, Code No. 3113-60-5) and subcutaneously injected into the footpad of a mouse (0.1 ml). Eight days later, popliteal lymph nodes were removed to prepare a cell suspension. 5. Cytokine production by antigen stimulation Lymph node cell suspension (2.5 x 10 ⁶ cells / ml) contained KLH (0.1 m
g / ml) and drugs, and cultured at 37 ° C in the presence of 5% CO ₂ for 4 days (Corning 25850, 0.15 ml / well), then quantitate the cytokines produced in the supernatant by a specific ELISA method. did. Interleukin 4 (IL-4) and interleukin 5 (IL-5) were quantified as typical Th2 type cytokines.

6. ELISA Method The quantification of IL-4 was performed by the following ELISA method. As a primary antibody, a rat anti-mouse IL-4 antibody (Pharmingen, San Di
ego, CA, Code No. 18031D, 0.5 mg / ml) was diluted 250-fold with a carbonate buffer, and 50 μl / well was added to a 96-well plate (Falcon 3912, Becton Dickinson and company,
Franklin Lakes, NJ) and coated overnight at 4 ° C. Thereafter, the plate was blocked with PBS (−) containing 3% BSA (200 μl / well). Rinse the plate,
After drying, it was stored at -20 ° C until use. The culture supernatant was sown at 50 μl / well and incubated at room temperature for 4 hours. Recombinant mouse IL-4 (P
harmingen, Code No. 19231W). After rinsing the plate, a biotin-labeled rat anti-mouse IL-4 antibody (Pharmingen, Code No. 18042D, 0.5 mg /
ml) was diluted 500-fold with PBS (-) containing 0.1% BSA (100 ml / well), and incubated at room temperature for 1 hour. The bound secondary antibody was streptavidin alkaline phosphatase (Kirkegaard & Perry Lab.,
Gaithersburg, MD, Code No. 15-30-00) (0.25mg / ml,
100 μl / well). After incubating at 37 ° C for 1 hour, the plate was rinsed, and the PNPP substrate (p-nitrophenyl phosphate disodium, Nacalai Tesque) (1m
g / ml, 100 μl / well) for color development. For measurement, use a microplate reader (MTP-120 Microplatereade
r, Corona Electric) (wavelength 415 nm).

<Results> The results are shown in Table 101.

[Table 299] Table 101

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[Chemical 64]

[Table 299]

[Table 299]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/44 ADY A61K 31/44 ADY C07D 235/30 C07D 235/30 A 277/82 277/82 401/12 235 401/12 235 413/12 213 413/12 213 417/12 213 417/12 213 471/04 107 471/04 107A 473/00 473/00 473/40 473/40 498/04 105 498/04 105 513/04 343 513 / 04 343 (72) Ryu Nagata 3-1,98 Kasugade, Konohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor, Hiroshi Ochi 3-98, Kasugade, Konohana-ku, Osaka Tomo Pharmaceutical Co., Ltd. (72) Inventor Takamasa Watanabe 3-1,98 Kasuga, Konohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Chito Nakatani 3-chome, Kasugade, Konohana-ku, Osaka No. 98 Sumitomo Pharmaceutical Co., Ltd.

Claims (13)

[Claims] (1) Formula 1 (In the formula, -X- represents -O-, -NH- or -S-. Represents a benzene ring, a substituted benzene ring, a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms, or a 6-membered substituted heterocyclic ring containing 1 or 2 nitrogen atoms. Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The pharmaceutical composition according to claim 1, which is a type 2 helper T cell immune response inhibitor. 3. The method according to claim 1, wherein the electron-withdrawing substituent in the formula is a halogen atom,
Nitro group, perhalogenoalkyl group, cyano group, carboxyl group, alkoxycarbonyl group, alkylamide group, perhalogenoalkylamide group, alkanoyl group,
Substituted alkanoyl group, aroyl group, substituted aroyl group, alkylsulfonyl group, substituted alkylsulfonyl group, arylsulfonyl group, substituted arylsulfonyl group, alkylsulfonamide group, substituted alkylsulfonamide group,
3. The pharmaceutical composition according to claim 1, which is an arylsulfonamide group or a substituted arylsulfonamide group. 4. A compound represented by the formula: A substituent of the benzene ring or the 6-membered heterocycle containing 1 or 2 nitrogen atoms is halogen atom, nitro group,
Perhalogenoalkyl group, cyano group, carboxyl group,
Alkoxycarbonyl group, alkylamide group, perhalogenoalkylamide group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, alkylsulfonyl group, substituted alkylsulfonyl group, arylsulfonyl group, substituted arylsulfonyl group, alkylsulfonamide group A substituted alkylsulfonamide group, an arylsulfonamide group, a substituted arylsulfonamide group, a hydroxyl group, an alkyl group, a substituted alkyl group, an alkoxy group, a substituted alkoxy group, a cycloalkyl group, a substituted cycloalkyl group, an aryl group, a substituted aryl group, An aryloxy group,
The pharmaceutical composition according to claim 1, which is a substituted aryloxy group, a heterocyclic group, a substituted heterocyclic group, an amino group, a substituted amino group, a carbamoyl group, a substituted carbamoyl group, an alkoxycarbonyl group, or a substituted alkoxycarbonyl group. Stuff. (5) Wherein the substituent of the benzene ring or the 6-membered heterocyclic ring containing one or two nitrogen atoms is a halogen atom, a nitro group,
Perhalogenoalkyl group, cyano group, carboxyl group,
Alkoxycarbonyl group, alkylamide group, perhalogenoalkylamide group, alkanoyl group, substituted alkanoyl group, aroyl group, substituted aroyl group, alkylsulfonyl group, substituted alkylsulfonyl group, arylsulfonyl group, substituted arylsulfonyl group, alkylsulfonamide group 4. The pharmaceutical composition according to claim 1, which is a substituted alkylsulfonamide group, an arylsulfonamide group, or a substituted arylsulfonamide group. 6. The pharmaceutical composition according to claim 1, which is a type 2 helper T cell-producing cytokine production inhibitor. 7. An autoimmune disease such as allergic disease, systemic lupus erythematosus or acquired immunodeficiency syndrome (A).
The pharmaceutical composition according to claim 6, which is a therapeutic agent for IDS). 8. The formula (2) (Wherein, -X- represents -O-, -NH-, or -S-. Represents a 6-membered heterocyclic ring containing 1 or 2 nitrogen atoms or a 6-membered substituted heterocyclic ring containing 1 or 2 nitrogen atoms. Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. Or a pharmaceutically acceptable salt thereof. 9. The heterocyclic compound according to claim 8, wherein -X- is -O- or -S-, or a pharmaceutically acceptable salt thereof. 10. The electron-withdrawing group is a halogen atom, nitro group, perhalogenoalkyl group, cyano group, carboxyl group, alkoxycarbonyl group, alkylamide group, perhalogenoalkylamide group, alkanoyl group, substituted alkanoyl group, aroyl. A group, a substituted aroyl group, an alkylsulfonyl group, a substituted alkylsulfonyl group, an arylsulfonyl group, a substituted arylsulfonyl group, an alkylsulfonamide group, a substituted alkylsulfonamide group, an arylsulfonamide group, or a substituted arylsulfonamide group. 10. The heterocyclic compound according to 8 or 9, or a pharmaceutically acceptable salt thereof. 11. The method according to claim 11, wherein the electron-withdrawing group is a fluorine atom, a chlorine atom, a nitro group, a trifluoromethyl group, a cyano group, a trifluoroacetamide group, a trifluoroacetyl group or a p-acetyl group.
The heterocyclic compound according to claim 8, 9 or 10, which is chlorobenzoyl, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonamide, trifluoromethanesulfonamide, benzenesulfonamide or p-toluenesulfonamide. Or a pharmaceutically acceptable salt thereof. 12. The formula (3) (In the formula, X ¹ represents —O— or —S—. R ¹ represents a hydrogen atom or an electron-withdrawing group. R ² represents a hydrogen atom,
Alternatively, it represents an electron-withdrawing group. R ^{3 ′} represents an electron-withdrawing group. R ⁴ represents a hydrogen atom or an electron-withdrawing group. Embedded image Represents a benzene ring, a benzene ring substituted with an electron-withdrawing group, a pyridine ring, or a pyridine ring substituted with an electron-withdrawing group. And a pharmaceutically acceptable salt thereof. 13. An electron-withdrawing group comprising a fluorine atom, a chlorine atom, a nitro group, a trifluoromethyl group, a cyano group, a trifluoroacetamide group, a trifluoroacetyl group,
The heterocyclic compound according to claim 12, which is chlorobenzoyl, methanesulfonyl, trifluoromethanesulfonyl, benzenesulfonyl, p-toluenesulfonyl, methanesulfonamide, trifluoromethanesulfonamide, benzenesulfonamide or p-toluenesulfonamide, or a pharmaceutically acceptable salt thereof. Acceptable salt.