JPH1129475A - Inhibitor against activation of stat6 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject medicine which allows treatment and prevention of allergic diseases, autoallergic diseases, viral infectious diseases, bacterial infectious diseases, parasitic infectious diseases, and so on, by including an iminothiazole-derivative as an active ingredient. SOLUTION: This medicine is prepared by including a compound shown by formula I [X<1> to X<5> are each H, an alkyl, an aralky, an aryl, a halogen, cyano, an alkoxy, phenoxy, an alkanoyl, an aroyl, etc.; two adjacent groups selected from X<1> -X<5> can form a phenyl ring; R<1> is H, an alkyl, a cycloalkyl, an aralky, an aryl, etc.; R<2> is H, an alkyl, a cycloalkyl, an aralky, etc.; R<1> and R<2> can form a cycloalkenyl or phenyl ring; (n) is 1-4]. The compound shown by formula I is obtained, for example, by the reaction of a compound shown by formula II with a compound shown by formula III [Y is a leaving group such as I, Br, and Cl] in an inert solvent. The medicine is effective also to the treatment/prevention of carcinoma, HVG disease, AIDS, and so on.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to the transcription factor Stat6 (S)
TAT6). Specific examples of the activation inhibitor of the transcription factor Stat6 (STAT6) of the present invention include, for example, allergic diseases, parasitic infections, autoimmune diseases such as systemic lupus erythematosus, virus or bacterial infections, malignant tumors, HVG (Host-versus-Graft)
It is useful as an agent for treating or preventing diseases or acquired immunodeficiency syndrome (AIDS).

[0002]

2. Description of the Related Art Certain iminothiazole derivatives are conventionally known as glycosylation inhibitors (WO96).
22095).

For the first time, Mosmann et al. 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. They classified mouse helper T cells (Th) into two groups, Th1 and Th2, according to the pattern of cytokines produced (J. Immunol. (19).
86) 136: 2348-2357). This classification of Th1 and Th2 has made it possible to classify not only a subset of helper T cells but also various immune responses in a living body as a Th1 side immune response or a Th2 side immune response. In addition, cell-mediated immunity involves Th1 type cytokines,
Humoral immunity has become known to involve Th2-type cytokines.

[0004] The immune response on the Th2 side includes interleukin 4 (IL-4), interleukin 5 (IL-5), and interleukin 10 (IL) produced from Th2.
-10), T such as interleukin 13 (IL-13)
antibody production from B cells (including IgE class) by h2 type cytokines. Since Th2 produces many cytokines involved in allergic reactions, it has recently been regarded as important as a regulatory cell for allergic reactions. Interleukin 4 induces the production of IgE antibodies and also activates and proliferates mast cells. It also induces gene expression of VCAM-1, an important molecule that functions when eosinophils adhere to vascular endothelial cells and infiltrate tissues. Furthermore, interleukin 4 acts on naive T cells, which are precursor cells of helper T cells, induces functional differentiation into Th2, and also acts as a growth factor for T cells after differentiation and maturation. Interleukin 13 also has the same action as interleukin 4.

[0005] It can be said that Th2 is a central cell that causes not only an immediate allergic reaction involving IgE antibodies and mast cells but also a late allergic reaction involving eosinophils. In addition, interleukin 4 plays a major role as a Th2 differentiation / growth factor,
On the one hand, it is an important cytokine produced from Th2 and deeply involved in both immediate and delayed allergic reactions. However, in order for interleukin 4 to exhibit biological activity, after binding to a specific receptor on the target cell,
Information must be transmitted inside the cell. With the recent development of molecular biology, the mechanism of intracellular signal transduction from interleukin-4 receptor has been elucidated, and major intracellular molecules have been identified. Among them, Stat 6 was found as a particularly important molecule (Science 265: 1701-1706 (199
Four)).

[0006] Stat 6 is a unique molecule that transmits the information of interleukin 4 into cells, functions itself as a transcription factor, and induces gene expression.
Moreover, the stat 6 functions only when activated by the stimulation of the interleukin 4 or the interleukin 13. When interleukin 4 binds to the interleukin 4 receptor, tyrosine residues in the intracellular region of the receptor are phosphorylated. Then, the stat 6 which is always present in the cytoplasm can specifically bind thereto. Stat6 bound to the receptor has its tyrosine residue phosphorylated by JAK kinase. Stat6 in which tyrosine residues are phosphorylated forms a dimer, leaves the receptor, moves into the cell nucleus, and functions as a transcription factor.

[0007] Recently, Stat6 deficient mice have been produced using genetic engineering techniques, and their physiological roles have been investigated (Nature 380: 627-630, 630-633 (1996), Imm
unity 4: 313-319 (1996)). In these mice, it has been confirmed that information on interleukin 4 cannot be transmitted to cells, and as a result, no allergic reaction occurs. For example, differentiation of Th2, which is a central cell that causes not only an immediate allergic reaction but also a delayed allergic reaction, cannot be induced. Furthermore, the T cells of these mice cannot produce interleukins 4 and 5. Similarly, the B cells of these mice cannot produce IgE antibodies. In other words, it was directly proved that stat 6 was essential for inducing an allergic reaction. More importantly, the differentiation, activation and the like of Th1 responsible for infection protection are normal, and no abnormalities in individuals have been observed. This suggests that the Stat6 activation inhibitor has no risk of side effects.

[0008] Against this background, the development of a completely new type of drug that inhibits the activation of stat 6 in order to specifically suppress the function of interleukin 4 involved in the pathology of allergic diseases is expected. . Moreover, such a drug can suppress an immediate reaction and a delayed reaction in an allergic disease without causing side effects.

[0009]

An object of the present invention is to provide a stat 6 activation inhibitor.

[0010]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, the expression 1

Embedded image(Where X¹Is hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. X^TwoRepresents a hydrogen atom, an alkyl group,
Substituted alkyl group, cycloalkyl group, cycloalkyl group
Alkyl group, aralkyl group, substituted aralkyl group, aryl
Group, substituted aryl group, halogen atom, cyano group, trif
Fluoromethyl group, alkoxy group, phenoxy group, substituted
Phenoxy, alkanoyl, aroyl, substituted alloy
Group, alkoxycarbonyl group, carbamoyl group, nitro
Represents an alkyl group or an alkylamide group. X^ThreeIs a hydrogen atom,
Alkyl group, substituted alkyl group, cycloalkyl group, cycloalkyl
Loalkylalkyl, aralkyl, substituted aralkyl
Group, aryl group, substituted aryl group, halogen atom, shea
, Trifluoromethyl, alkoxy, phenoxy
Si group, substituted phenoxy group, alkanoyl group, aroyl
Group, substituted aroyl group, alkoxycarbonyl group, carba
Represents a moyl group, a nitro group or an alkylamide group. X
^FourRepresents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl group, aryl group, substituted aryl group, halo
Gen atom, cyano group, trifluoromethyl group, alkoxy
Si group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. X^FiveIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. Or X¹, X^Two, X^Three, X^Four,
And X^FiveWherein two adjacent groups are bonded to each other
A phenyl ring or a substituted phenyl ring may be formed.
R¹Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl
Group, substituted aralkyl group, aryl group or substituted aryl
Represents a group. R^TwoIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Represents an aralkyl group or a substituted aralkyl group. Or R
¹And R^TwoAre bonded to each other to form a cycloalkenyl ring,
It may form a nyl ring or a substituted phenyl ring. n is
Represents an integer selected from 1, 2, 3 and 4. )
Iminothiazole derivative or pharmaceutically acceptable
That salts that inhibit the activation of transcription factor Stat6
The inventors have completed the present invention. More specifically
Is given by Equation 1

Embedded image(Where X¹Is hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. X^TwoRepresents a hydrogen atom, an alkyl group,
Substituted alkyl group, cycloalkyl group, cycloalkyl group
Alkyl group, aralkyl group, substituted aralkyl group, aryl
Group, substituted aryl group, halogen atom, cyano group, trif
Fluoromethyl group, alkoxy group, phenoxy group, substituted
Phenoxy, alkanoyl, aroyl, substituted alloy
Group, alkoxycarbonyl group, carbamoyl group, nitro
Represents an alkyl group or an alkylamide group. X^ThreeIs a hydrogen atom,
Alkyl group, substituted alkyl group, cycloalkyl group, cycloalkyl
Loalkylalkyl, aralkyl, substituted aralkyl
Group, aryl group, substituted aryl group, halogen atom, shea
, Trifluoromethyl, alkoxy, phenoxy
Si group, substituted phenoxy group, alkanoyl group, aroyl
Group, substituted aroyl group, alkoxycarbonyl group, carba
Represents a moyl group, a nitro group or an alkylamide group. X
^FourRepresents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl group, aryl group, substituted aryl group, halo
Gen atom, cyano group, trifluoromethyl group, alkoxy
Si group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. X^FiveIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. Or X¹, X^Two, X^Three, X^Four,
And X^FiveWherein two adjacent groups are bonded to each other
A phenyl ring or a substituted phenyl ring may be formed.
R¹Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl
Group, substituted aralkyl group, aryl group or substituted aryl
Represents a group. R^TwoIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Represents an aralkyl group or a substituted aralkyl group. Or R
¹And R^TwoAre bonded to each other to form a cycloalkenyl ring,
It may form a nyl ring or a substituted phenyl ring. n is
Represents an integer selected from 1, 2, 3 and 4. )
Iminothiazole derivative or pharmaceutically acceptable
Allergic diseases and parasite infections containing active salts as active ingredients
Disease, autoimmune disease, viral or bacterial infection
Disease, malignancy, HVG (Host-versus-Graft) disease or acquired
A therapeutic or prophylactic agent for immunodeficiency syndrome (AIDS)
I do.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The compound represented by Formula 1 is, for example, the following Formula (2), Formula (3), Formula (4), Formula (5), Formula (6), Formula (7), or Formula (8) ), Equation (9), Equation (10),
Equations (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), It includes compounds represented by formula (21), formula (22), formula (23), formula (24), formula (25), and the like.

[0012]

Embedded image

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Embedded image

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ and X ⁵ represent the same meaning as described above. R ^{1 ′} represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group, a substituted aralkyl group, an aryl group or a substituted aryl group. R ^{2 ′} represents a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, a cycloalkylalkyl group, an aralkyl group or a substituted aralkyl group. Z
Represents a substituent. Examples of the substituent for Z include an alkyl group, a substituted alkyl group, an alkoxy group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a carbamoyl group, and an alkylamino group. Examples include a carbonyl group, a dialkylaminocarbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an alkanoyl group, and an alkylamide group. One or a plurality of the same or different substituents may be present.

In X ¹ , X ² , X ³ , X ⁴ and X ⁵ , when two adjacent arbitrary groups are bonded to form a phenyl ring or a substituted phenyl ring, specific examples include:
Expressions (26), (27), (28), (29), and the like, as shown below, can be given.

Embedded imageWhere R¹, R^TwoAnd n represent the same meaning as described above. X^{1 '}
Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Kill group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl, aryl, substituted aryl, halogen
Atom, cyano group, trifluoromethyl group, alkoxy
Group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. X^{2 '}Is hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. X^{3 '}Represents a hydrogen atom, an alkyl group,
Substituted alkyl group, cycloalkyl group, cycloalkyl group
Alkyl group, aralkyl group, substituted aralkyl group, aryl
Group, substituted aryl group, halogen atom, cyano group, trif
Fluoromethyl group, alkoxy group, phenoxy group, substituted
Phenoxy, alkanoyl, aroyl, substituted alloy
Group, alkoxycarbonyl group, carbamoyl group, nitro
Represents an alkyl group or an alkylamide group. X^Four'Is a hydrogen atom,
Alkyl group, substituted alkyl group, cycloalkyl group, cycloalkyl
Loalkylalkyl, aralkyl, substituted aralkyl
Group, aryl group, substituted aryl group, halogen atom, shea
, Trifluoromethyl, alkoxy, phenoxy
Si group, substituted phenoxy group, alkanoyl group, aroyl
Group, substituted aroyl group, alkoxycarbonyl group, carba
Represents a moyl group, a nitro group or an alkylamide group. X
^Five'Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl group, aryl group, substituted aryl group, halo
Gen atom, cyano group, trifluoromethyl group, alkoxy
Si group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. Z 'represents a substituent. A substituent at Z ′
For example, an alkyl group, a substituted alkyl group, an alkoxy group
Si group, halogen atom, cyano group, trifluoromethyl
Group, nitro group, hydroxyl group, amino group, alkylamino group,
Dialkylamino group, carbamoyl group, alkylamino
Carbonyl group, dialkylaminocarbonyl group, carbo
Xyl group, alkoxycarbonyl group, alkyl sulfo
And a benzyl group, an alkanoyl group and an alkylamide group.
It is. One or a plurality of the same or different substituents
There may be.

In the present invention, X ¹ , X ² , X ³ , X ⁴ ,
^{X 5, X 1 ', X} 2', X 3 ', X 4', X 5 ', R 1, R 2,
The groups in R ^{1 ′} , R ^{2 ′} , Z and Z ′ will be specifically described. Examples of the alkyl group include a linear or branched lower alkyl group having 1 to 6 carbon atoms. Specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 3-methylpropyl, 1,1
-Dimethylethyl, pentyl, hexyl and the like.

Examples of the substituent of the substituted alkyl group include a hydroxyl group, an amino group, an alkylamino group, a dialkylamino group, a carboxyl group and an alkoxy group.

Examples of the halogen atom include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

The alkoxy group includes, for example, a linear or branched lower alkoxy group having 1 to 6 carbon atoms. Specifically, for example, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, , 1-dimethylethoxy, pentoxy, hexoxy and the like.

The alkanoyl group includes, for example, a linear or branched lower alkanoyl group having 1 to 6 carbon atoms. Specifically, for example, formyl, acetyl,
And propanoyl, 2-propanoyl, pivaloyl and the like.

The alkoxycarbonyl group includes, for example, a linear or branched lower alkoxycarbonyl group having 2 to 6 carbon atoms. Specifically, for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, And propoxycarbonyl.

Examples of the alkylamide group include a linear or branched lower alkylamide group having 2 to 6 carbon atoms, and specific examples thereof include, for example, acetamide, propionamide, butylamide, 2-butylamide and the like. Is mentioned.

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

Examples of the cycloalkylalkyl group include lower cycloalkylalkyl groups having 4 to 13 carbon atoms, such as cyclopropylmethyl, cyclopentylethyl, cyclohexylmethyl and cyclohexylpropyl. Can be

Examples of the aralkyl group include, for example, those having 7 carbon atoms.
To 15 groups, specifically, for example, benzyl, phenylethyl, naphthylmethyl, naphthylpropyl and the like.

Examples of the aroyl group include, for example, those having 7 to 7 carbon atoms.
Examples include 11 groups, and specific examples include benzoyl, 1-naphthoyl, 2-naphthoyl, and the like.

The aryl group includes, for example, those having 6 to 6 carbon atoms.
Ten groups are mentioned, and specific examples include phenyl, naphthyl and the like.

Examples of the cycloalkenyl ring formed by combining R ¹ and R ² with each other include a 5- to 7-membered cycloalkenyl ring, and specific examples include cyclopentenyl, cyclohexenyl, cycloheptenyl and the like. .

Examples of the substituent for the aralkyl group, phenoxy group, aroyl group, aryl group and phenyl ring include, for example, an alkyl group, an alkoxy group, a halogen atom, a cyano group, a trifluoromethyl group, a nitro group, a hydroxyl group, an amino group, Examples include an alkylamino group, a dialkylamino group, a carbamoyl group, an alkylaminocarbonyl group, a dialkylaminocarbonyl group, a carboxyl group, an alkoxycarbonyl group, an alkylsulfonyl group, an alkanoyl group, and an alkylamide group. One or a plurality of the same or different substituents may be present.

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. Specific examples include a dimethylamino group and a diethylamino group. No.

Examples of the alkylaminocarbonyl group include, for example, an aminocarbonyl group substituted with a lower alkyl group having 1 to 6 carbon atoms.
Examples thereof include a methylaminocarbonyl group and an ethylaminocarbonyl group.

As the dialkylaminocarbonyl group,
For example, an aminocarbonyl group substituted with the same or different lower alkyl group having 1 to 6 carbon atoms and the like can be mentioned, and specific examples include a dimethylaminocarbonyl group and a diethylaminocarbonyl group.

Examples of the alkylsulfonyl group include a sulfonyl group substituted by a lower alkyl group having 6 or less carbon atoms, and specific examples include a methylsulfonyl group and an ethylsulfonyl group.

Since the compound of the present invention has a basic substituent, it can form a salt with an acid. Examples of the salt-forming acid include salts with inorganic acids such as hydrochloric acid, sulfuric acid, and hydrobromic acid, and organic acids such as acetic acid, oxalic acid, citric acid, malic acid, tartaric acid, fumaric acid, and maleic acid. And the like.

The compounds specifically included in the present invention include, for example, the following compounds.

The compound of the present invention can be synthesized by the following method.

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ , R ¹ , R ² and n have the same meaning as described above. Y represents a leaving group such as an iodine atom, a bromine atom or a chlorine atom. Compound (30) and compound (31) are reacted in an inert solvent to obtain compound (1). Examples of the inert solvent include ether solvents such as tetrahydrofuran (hereinafter abbreviated as THF), 1,4-dioxane, and diglyme; aprotic solvents such as dimethylformamide (hereinafter abbreviated as DMF) and acetonitrile; Methanol, ethanol, 2-propanol, alcohol solvents such as t-butyl alcohol, benzene, aromatic hydrocarbon solvents such as toluene, acetone,
Examples thereof include ketone solvents such as methyl ethyl ketone and methyl isobutyl ketone. The reaction temperature is selected, for example, from the range of about room temperature to the boiling point of the solvent. The amount of compound (30) is preferably about equimolar to compound (31).

[0036]

Embedded image In the formula, R ¹ and R ² represent the same meaning as described above. Compound (30) is obtained by converting compound (32) and compound (33)
₂ , in the presence of a halogenating agent such as Br ₂ or I ₂ in an inert solvent such as benzene at a temperature ranging from about room temperature to the boiling point of the solvent. The amount of compound (33) is selected from the range of about 1.5-fold mole to about 2.5-fold mole based on compound (32). The amount of the halogenating reagent is preferably about equimolar to compound (32). Compound (3
0) is a method for converting compound (32) and compound (33) into a compound such as benzene in the presence of a halogenating reagent such as N-bromosuccinimide (hereinafter abbreviated as NBS) and a small amount of a catalyst such as benzoyl peroxide. The reaction can also be carried out by reacting the solvent in an inert solvent at a temperature ranging from about room temperature to the boiling point. Compound (33)
Is preferably about 1-fold the molar amount of the compound (32). The amount of the halogenating reagent is preferably about equimolar to compound (32).

[0037]

Embedded image In the formula, R ¹ and R ² represent the same meaning as described above. X represents a halogen atom. Compound (30) can react compound (34) with compound (33) in an inert solvent. Examples of the inert solvent include alcohol solvents such as methanol and ethanol, aprotic solvents such as DMF and dimethyl sulfoxide (hereinafter abbreviated as DMSO), ether solvents such as THF and dioxane, and the like. The reaction temperature is selected from the range of about 60 ° C. to the boiling point of the solvent. The amount of compound (33) is preferably about 2 moles per mole of compound (34). Compound (34)
Can react compound (32) with a halogenating reagent such as Cl ₂ , Br ₂ or I _{2 in} a solvent such as water in the presence of a base such as an alkali metal such as sodium hydroxide. The amount of the halogenating agent is selected from the range of about 2 moles to about 4 moles relative to the compound (32). The amount of the base is selected from the range of about 5 moles to about 10 moles relative to compound (32). The reaction temperature is preferably about room temperature.

Compound (34) is obtained by combining compound (32) with C
l ₂ , Br ₂ , I _2, etc., with halogenated reagents such as acetic acid, carbon disulfide, carbon tetrachloride, chloroform, methylene chloride, etc., ether solvents such as diethyl ether, alcohols such as methanol In a solvent such as a system solvent or the like, an alkali metal acetate such as sodium acetate or the like can be reacted with a trace amount of a catalyst such as hydrogen bromide. The amount of the halogenating agent is preferably in the range of about 1: 1 mole to about 1.5 times mole based on Compound (32). The reaction temperature is preferably in the range of about 0 ° C. to about room temperature.

The compound in which R ² is a hydrogen atom in compound (1) can be produced from compound (35) by the method described above.

Embedded image In the formula, R ¹ and X represent the same meaning as described above. Compound (35) can be obtained by reacting compound (36) with compound (33) in an inert solvent. Examples of the inert solvent include THF, 1,4-dioxane,
Ether solvents such as diglyme; aprotic solvents such as DMF, DMSO and acetonitrile; alcohol solvents such as methanol, ethanol, 2-propanol and t-butyl alcohol; and aromatic hydrocarbon solvents such as benzene and toluene. No. The reaction temperature is selected, for example, from the range of room temperature to the boiling point of the solvent. The amount of the compound (33) is about 1-fold molar to about 2 times the amount of the compound (36).
It is selected from a molar range.

[0040]

Embedded image In the formula, R ¹ and X represent the same meaning as described above. Compound (36) can be prepared by reacting compound (37) with a halogenating agent such as Cl ₂ , Br ₂ or I ₂ in an inert solvent such as benzene to a concentration of about 0.
It is obtained by reacting at a temperature in the range of ℃ to about room temperature.
The amount of the halogenating agent is preferably about equimolar to compound (37). The amount of the halogenating reagent is the same as that of the compound (37).
The molar ratio is preferably about 1: 1. Compound (36) is
It can be obtained by reacting compound (37) with a halogenating reagent such as Cl ₂ , Br ₂ , I _2, etc. in an inert solvent while irradiating light with a tungsten lamp or the like. Examples of the inert solvent include halogenated hydrocarbon solvents such as carbon tetrachloride, chloroform and methylene chloride, and carbon disulfide. The reaction temperature is selected from the range of about -20 ° C to about room temperature.

[0041]

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and Y have the same meaning as described above. In the compound (1), an intermediate compound (38) corresponding to the case where n is 1 can be produced by the following method. Compound (38) is obtained by combining compound (39) with Cl ₂ , Br ₂ ,
A halogenating reagent such as I ₂ can be reacted in a solvent such as water in the presence of a base such as an alkali metal such as sodium hydroxide. As the amount of the halogenating agent, the compound (3
It is selected from the range of about 2 times mole to about 4 times mole of 9). The amount of the base is selected from the range of about 5 moles to about 10 moles relative to compound (39). The reaction temperature is preferably about room temperature.

Compound (38) is obtained by combining compound (39) with C
l ₂ , Br ₂ , I _2, etc., with halogenated reagents such as acetic acid, carbon disulfide, carbon tetrachloride, chloroform, methylene chloride, etc., ether solvents such as diethyl ether, alcohols such as methanol In a solvent such as a solvent, an alkali metal acetate such as sodium acetate or the like can be reacted with a trace amount of a catalyst such as hydrogen bromide. The amount of the halogenating reagent is preferably in the range of about 1-fold mole to about 1.5-fold mole based on Compound (39). The reaction temperature is preferably in the range of about 0 ° C. to about room temperature.

[0043]

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and Y have the same meaning as described above. Y ′ represents chlorine, bromine or iodine.
n ′ represents an integer of 2, 3 or 4. In the compound (31), a compound (4) wherein n is an integer of 2, 3 or 4
0) can be obtained by the following Friedel-Crafts reaction. Compound (42) and compound (41) are reacted in an inert solvent in the presence of a Lewis acid such as aluminum chloride or aluminum bromide in an inert solvent at about room temperature to about 50 ° C.
The compound (40) is obtained by reacting in the range described above. Examples of the inert solvent include carbon disulfide, carbon tetrachloride, nitrobenzene, and the like.

[0044]

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ and X ⁵ represent the same meaning as described above. In the compound (31), the compound (43) wherein n is 2 can be produced from the compound (46) by the following method.
Compound (45) can be obtained by reacting compound (46) with trimethylsilyl chloride in the presence of a base such as triethylamine or lithium diisopropylamide in a solvent such as DMF or THF at a temperature in the range of about -78 ° C to about room temperature.

Compound (44) is prepared by adding compound (45) to methane diiodide and a reagent such as diethyl zinc or Zn-CuCl in an ether solvent such as diethyl ether or THF in an amount of about 0.
It is obtained by reacting in the range of from ° C to the boiling point of the solvent. During the reaction, a catalyst such as iodine may be added.

Compound (43) can be obtained by reacting compound (44) with bromine in a solvent such as methylene chloride in the range of about -70 to about room temperature.

[0047]

Embedded image In the formula, X ¹ , X ² , X ³ , X ⁴ , X ⁵ and Y have the same meaning as described above. R ¹⁰ represents, for example, lower alkyl such as methyl, ethyl and propyl. In the compound (31), n
Is (3) can be produced from compound (49) by the above route. Compound (48) is obtained by converting compound (49) and compound (50) into an alkali metal alkoxide such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, or an alkaline earth metal such as magnesium methoxide or magnesium ethoxide. In the presence of a base such as an alkali metal hydride such as alkoxide, sodium hydride and potassium hydride, diethyl ether, T
It is obtained by reacting in an ether solvent such as HF, dioxane, dimethoxyethane and the like, and an aromatic solvent such as benzene, toluene and xylene in a range of about 0 ° C. to the boiling point of the solvent.

Compound (47) is compound (48) and hydrochloric acid,
It can be obtained by reacting hydrobromic acid or the like with water, an ether solvent such as diethyl ether, or an aromatic solvent such as benzene or toluene in a range from about room temperature to the boiling point of the solvent.

Compound (1) or an intermediate for producing it can be purified by a conventional method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, and ketone solvents such as acetone. Examples thereof include a solvent, a hydrocarbon solvent such as hexane, an aprotic solvent such as acetonitrile, and a mixed solvent thereof.

In carrying out the above reaction, if necessary, techniques for protection and deprotection can be used. protection,
For deprotection technology, see (TW Greene and PG
M. Wuts, "Protecting Groups in Organic Synthesis",
1990).

When the compound (1) has a substituent having an asymmetric carbon, optical isomers exist, and a mixture of these optical isomers and an isolated optical isomer are included in the compound (1). As a method for obtaining such an optical isomer purely,
For example, there is optical division.

As the optical resolution method, for example, compound (1) is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, an ester solvent such as ethyl acetate, toluene). Aromatic solvents such as acetonitrile, etc.), optically active acids (e.g., monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid), dicarboxylic acids such as tartaric acid, o-diisopropylidene tartaric acid and malic acid Acid, camphorsulfonic acid, sulfonic acid such as bromocamphorsulfonic acid) or an optically active amine (eg, α-phenethylamine, quinine,
A salt with an organic amine such as quinidine, cinchonidine, cinchonine, strychnine, etc.) to form a salt.

The temperature at which the salt is formed may be in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield. The amount of the optically active acid or amine used is about 0.5 to about 2.0 with respect to the substrate.
A range of equivalents, preferably a range of about 1 equivalent is appropriate. If necessary, the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; Recrystallization with acetonitrile) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with a base by a usual method to obtain a free form.

The STAT6 activation inhibitor 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 frequency of administration vary depending on the disease to be treated, symptoms of the patient, age, body weight, etc., and dosage form, but when administered orally, the active ingredient is usually about 1 to about 1000 mg per adult per day. A range, preferably from about 10 to about 500 mg, can be administered in one or several divided doses. When administered as an injection, the active ingredient can be administered in a range of about 0.1 to about 500 mg, preferably in a range of about 3 to about 100 mg, in one or several divided doses.

The STAT6 activation inhibitor of the present invention is specifically exemplified by, for example, allergic diseases, parasitic infections, autoimmune diseases such as systemic lupus erythematosus, virus or bacterial infections, malignant tumors, HVG (Host- versus-Gr
aft) It can be used as a therapeutic or prophylactic agent for diseases or acquired immunodeficiency syndrome (AIDS). The administration method includes an oral or parenteral administration method. 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 the disease to be treated, the condition of the patient, age, weight, etc., and the administration form. However, when administered orally, the active ingredient is usually from about 1 to about 1000 per adult per day.
The dose may be in the range of mg, preferably in the range of about 10 to about 500 mg, in one or several doses. When administered as an injection, the active ingredient can be administered in a range of about 0.1 to about 500 mg, preferably in a range of about 3 to about 100 mg, in one or several divided doses.

[0056]

[Example] Example 1

Embedded image 1- (4-phenylphenyl) -2- (2-imino-3
(2H) -thiazolyl) ethanone hydrobromide 1.00 g of 2-aminothiazole and 2.75 g of 4-phenylphenacyl bromide are added to 40 ml of acetonitrile, and the mixture is heated under reflux for 2 hours. After completion of the reaction, the reaction solution was cooled, and the precipitated crystals were collected by filtration and washed with acetonitrile.
Dry to give the title 1- (4-phenylphenyl) -2-
3.42 g of (2-imino-3 (2H) -thiazolyl) ethanone hydrobromide were obtained. (Yield 91%) ¹ H NMR (TMS / DMSO-d ₆ ) δ 5.87 (2H, s), 7.08 (1H,
d, J = 4.6 Hz), 7.38 (1H, d, J = 4.6 Hz), 7.43-
7.56 (3H, m), 7.78 (2H, m), 7.93 (2H, d, J = 8.4 H
z), 8.12 (2H, d, J = 8.4 Hz), 9.55 (2H, brs)

Embodiment 2

Embedded image 1- (4-methylphenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 585 mg (9
3%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.44 (3H, s), 5.79 (2H,
s), 7.06 (1H, d, J = 4.4 Hz), 7.35 (1H, d, J = 4.6
Hz), 7.43 (2H, d, J = 8.2 Hz), 7.92 (2H, d, J = 8.
3 Hz), 9.50 (2H, brs)

Embodiment 3

Embedded image 1- (2-naphthyl) -2- (2-imino-3 (2H)
-Thiazolyl) ethanone hydrobromide According to the method of Example 1, 671 mg of the title compound (9
6%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 5.96 (2H, s), 7.09 (1H,
d, J = 4.4 Hz), 7.39 (1H, d, J = 4.6 Hz), 7.65-
7.76 (2H, m), 8.00-8.20 (4H, m), 8.76 (1H, s), 9.
54 (2H, brs)

Embodiment 4

Embedded image 1- (4-fluorophenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 603 mg (9
5%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 5.81 (2H, s), 7.07 (1H,
d, J = 4.4 Hz), 7.34 (1H, d, J = 4.4 Hz), 7.45 (2
H, m), 8.12 (2H, m), 9.52 (2H, brs)

Embodiment 5

Embedded image 1- (4-chlorophenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 593 mg (8
9%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 5.81 (2H, s), 7.07 (1H,
d, J = 4.4 Hz), 7.33 (1H, d, J = 4.4 Hz), 7.71 (2
H, d, J = 8.6 Hz), 8.04 (2H, d, J = 8.6 Hz), 9.52
(2H, brs)

Embodiment 6

Embedded image 1- (4-bromophenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide 692 mg (9%) of the title compound was prepared according to the method of Example 1.
2%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 5.80 (2H, s), 7.06 (1H,
d, J = 4.4 Hz), 7.33 (1H, d, J = 4.4 Hz), 7.85 (2
H, d, J = 8.6 Hz), 7.96 (2H, d, J = 8.6 Hz), 9.51
(2H, brs)

Embodiment 7

Embedded image 1- (2-methoxyphenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 583 mg (8
9%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 4.02 (3H, s), 5.56 (2H,
s), 7.03 (1H, d, J = 4.4 Hz), 7.13 (1H, t, J = 7.4
Hz), 7.31 (1H, d, J = 8.3 Hz), 7.35 (2H, d, J = 4.
4 Hz), 7.71 (1H, m), 7.91 (1H, dd, J = 7.7 Hz, 1.8
Hz), 9.44 (2H, brs)

Embodiment 8

Embedded image 1- (3-methoxyphenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 571 mg (8
7%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 3.86 (3H, s), 5.81 (2H,
s), 7.06 (1H, d, J = 4.4 Hz), 7.30-7.35 (2H, m),
7.50-7.64 (3H, m), 9.51 (2H, brs)

Embodiment 9

Embedded image 1- (4-methoxyphenyl) -2- (2-imino-3
(2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 626 mg (8
3%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 3.89 (3H, s), 5.76 (2H,
s), 7.06 (1H, d, J = 4.4 Hz), 7.14 (2H, d, J = 8.8
Hz), 7.35 (1H, d, J = 4.4 Hz), 8.00 (2H, d, J = 8.
8 Hz), 9.50 (2H, brs)

Embodiment 10

Embedded image 1- (2,5-Dimethoxyphenyl) -2- (2-imino-3 (2H) -thiazolyl) ethanone hydrobromide 455 mg (6%) of the title compound according to the method of Example 1.
3%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 3.77 (3H, s), 3.97 (3H,
s), 5.55 (2H, s), 7.03 (1H, d, J = 4.6 Hz), 7.24-
7.39 (4H, m), 9.45 (2H, brs)

Embodiment 11

Embedded image 1- (4-methylphenyl) -2- (2-imino-3
(2H) -Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 348 mg (4
8%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.46 (3H, s), 6.06 (2H,
s), 7.40-7.54 (4H, m), 7.67 (1H, d, J = 7.5 Hz),
8.02 (3H, m), 10.22 (2H, br)

Embodiment 12

Embedded image 1- (4-phenylphenyl) -2- (2-imino-3
(2H) -Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 377 mg (4%) of the title compound was obtained.
4%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 6.15 (2H, s), 7.41-7.5
7 (5H, m), 7.73 (1H, d, J = 7.9 Hz), 7.80 (2H, d,
J = 8.4 Hz), 7.96 (2H, d, J = 8.4 Hz), 8.04 (1H, d
d, J = 7.7 Hz, 1.0Hz), 8.20 (2H, d, J = 8.6 Hz), 1
0.29 (2H, br)

Embodiment 13

Embedded image 1- (2-naphthyl) -2- (2-imino-3 (2H)
-Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 606 mg (7
6%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 6.24 (2H, s), 7.41-7.5
4 (2H, m), 7.67-7.78 (3H, m), 8.03-8.22 (5H,
m), 8.88 (1H, s), 10.28 (2H, br)

Embodiment 14

Embedded image 1- (4-fluorophenyl) -2- (2-imino-3
(2H) -Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 451 mg (6%) of the title compound was obtained.
1%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 6.09 (2H, s), 7.40-7.5
3 (4H, m), 7.71 (1H, d, J = 7.5 Hz), 8.03 (1H, dd,
J = 7.7 Hz, 1.1 Hz), 8.19 (2H, m), 10.22 (2H, br)

Embodiment 15

Embedded image 1- (4-chlorophenyl) -2- (2-imino-3
(2H) -Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 458 mg (6
0%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 6.07 (2H, s), 7.40-7.5
3 (2H, m), 7.73 (3H, m), 8.03 (1H, d, J = 7.9 Hz),
8.11 (2H, d, J = 8.8 Hz), 10.21 (2H, br)

Embodiment 16

Embedded image 1- (4-bromophenyl) -2- (2-imino-3
(2H) -Benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 548 mg (6%) of the title compound was obtained.
4%). ¹ H NMR (TMS / CDCl ₃ ) δ 6.07 (2H, s), 7.40-7.54
(2H, m), 7.73 (1H, d, J = 7.5 Hz), 7.88 (2H, d, J =
8.6 Hz), 8.02 (3H, m), 10.21 (2H, br)

Embodiment 17

Embedded image 1- (4-methoxyphenyl) -2- (2-imino-3
(2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 525 mg (6
9%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 3.91 (3H, s), 6.07 (2H,
s), 7.17 (2H, d, J = 8.8 Hz), 7.40-7.53 (2H, m),
7.66 (1H, d, J = 7.7 Hz), 7.99-8.11 (3H, m), 10.
26 (2H, br)

Embodiment 18

Embedded image 1- (4-methylphenyl) -2- (4,5,6,7-
Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 183 mg of the title compound (2
5%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.76 (4H, brs), 2.34 (2
H, brs), 2.44 (3H, s), 2.56 (2H, brs), 5.71 (2H,
s), 7.42 (2H, d, J = 8.0 Hz), 7.96 (2H, d, J = 8.0 Hz)
Hz), 9.51 (2H, brs)

Embodiment 19

Embedded image 1- (4-phenylphenyl) -2- (4,5,6,7
-Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 499 mg (5%) of the title compound is obtained.
8%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.78 (4H, brs), 2.37 (2
H, brs), 2.58 (2H, brs), 5.78 (2H, s), 7.43-7.56
(3H, m), 7.77 (2H, d, J = 8.0 Hz), 7.92 (2H, d, J
= 8.4 Hz), 8.15 (2H, d, J = 8.4 Hz), 9.52 (2H, br
s)

Embodiment 20

Embedded image 1- (2-naphthyl) -2- (4,5,6,7-tetrahydro-2-imino-3 (2H) -benzothiazolyl)
Etanone hydrobromide 514 mg (6 mg) of the title compound according to the method of Example 1.
4%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.76 (4H, brs), 2.38 (2
H, brs), 2.58 (2H, brs), 5.87 (2H, s), 7.66-7.77
(2H, m), 8.00-8.31 (4H, m), 8.80 (1H, s), 9.52
(2H, brs)

Embodiment 21

Embedded image 1- (4-fluorophenyl) -2- (4,5,6,7
-Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 284 mg of the title compound (3
8%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.75 (4H, brs), 2.34 (2
H, brs), 2.56 (2H, brs), 5.72 (2H, s), 7.47 (2H,
t, J = 8.8 Hz), 8.11-8.17 (2H, m), 9.48 (2H, brs)

Embodiment 22

Embedded image 1- (4-chlorophenyl) -2- (4,5,6,7-
Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 341 mg of the title compound (4
4%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.76 (4H, brs), 2.34 (2
H, brs), 2.56 (2H, brs), 5.72 (2H, s), 7.70 (2H,
d, J = 8.6 Hz), 8.07 (2H, d, J = 8.6 Hz), 9.49 (2H,
brs)

Embodiment 23

Embedded image 1- (4-bromophenyl) -2- (4,5,6,7-
Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 294 mg of the title compound (3
4%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.76 (4H, brs), 2.34 (2
H, brs), 2.56 (2H, brs), 5.70 (2H, s), 7.85 (2H,
d, J = 8.6 Hz), 7.98 (2H, d, J = 8.6 Hz), 9.48 (2H,
brs)

Embodiment 24

Embedded image 1- (4-methoxyphenyl) -2- (4,5,6,7
-Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 474 mg (6%) of the title compound is obtained.
2%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.75 (4H, brs), 2.32 (2
H, brs), 2.56 (2H, brs), 3.89 (3H, s), 5.67 (2H,
s), 7.14 (2H, d, J = 9.0 Hz), 8.03 (2H, d, J = 9.0
Hz), 9.47 (2H, brs)

Embodiment 25

Embedded image 1- (2,5-dimethoxyphenyl) -2- (4,5
6,7-Tetrahydro-2-imino-3 (2H) -benzothiazolyl) ethanone hydrobromide According to the method of Example 1, 386 mg of the title compound (4
7%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 1.76 (4H, brs), 2.32 (2
H, brs), 2.56 (2H, brs), 3.77 (3H, s), 3.97 (3H,
s), 5.41 (2H, s), 7.23-7.35 (3H, m), 9.46 (2H,
brs)

Embodiment 26

Embedded image 1- (4-methylphenyl) -2- (2-imino-4-
Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 368 mg (5
6%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.11 (3H, d, J = 1.1 H
z), 2.44 (3H, s), 5.75 (2H, s), 6.77 (1H, d, J =
1.1 Hz), 7.44 (2H, d, J = 8.1 Hz), 7.97 (2H, d, J =
8.2 Hz), 9.50 (2H, brs)

Embodiment 27

Embedded image1- (4-phenylphenyl) -2- (2-imino-4
-Methyl-3 (2H) -thiazolyl) ethanone Bromide
According to the method of Example 1, 483 mg (6%) of the title compound was obtained.
2%). ¹ H NMR (TMS / DMSO-d₆) δ 2.15 (3H, d, J = 1.2 H
z), 5.83 (2H, s), 6.78 (1H, d, J = 1.0 Hz), 7.43-
 7.57 (3H, m), 7.78 (2H, d, J = 8.6 Hz), 7.94 (2H,
d, J = 8.6 Hz), 8.16 (2H, d, J = 8.4 Hz), 9.53 (2
H, brs)

Embodiment 28

Embedded image1- (2-naphthyl) -2- (2-imino-4-methyl
-3 (2H) -Thiazolyl) ethanone hydrobromide According to the method of Example 1, 477 mg (6
6%). ¹ H NMR (TMS / DMSO-d₆) δ 2.17 (3H, s), 5.94 (2H,
s), 6.80 (1H, s), 7.66- 7.76 (2H, m), 8.02-8.18
(4H, m), 8.82 (1H, s), 9.55 (2H, brs)

Embodiment 29

Embedded image1- (4-chlorophenyl) -2- (2-imino-4-
Methyl-3 (2H) -thiazolyl) ethanone hydrogen bromide
According to the method of Example 1, 529 mg (7
6%). ¹ H NMR (TMS / DMSO-d₆) δ 2.13 (3H, d, J = 1.2 H
z), 5.77 (2H, s), 6.77 (1H, d, J = 1.2 Hz), 7.72
(2H, d, J = 8.6 Hz), 8.08 (2H, d, J = 8.6 Hz), 9.52
 (2H, brs)

Embodiment 30

Embedded image 1- (3-methoxyphenyl) -2- (2-imino-4
-Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 377 mg (5%) of the title compound was obtained.
5%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.13 (3H, d, J = 1.2 H
z), 3.87 (3H, s), 5.79 (2H, s), 6.78 (1H, d, J =
1.2 Hz), 7.32-7.36 (1H, m), 7.53-7.56 (2H, m),
7.67 (1H, d, J = 7.9 Hz), 9.52 (2H, brs)

Embodiment 31

Embedded image 1- (4-methoxyphenyl) -2- (2-imino-4
-Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 585 mg (8
5%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.11 (3H, d, J = 1.0 H
z), 3.89 (3H, s), 5.72 (2H, s), 6.77 (1H, d, J =
1.0 Hz), 7.15 (2H, d, J = 9.0 Hz), 8.04 (2H, d, J =
9.0 Hz), 9.49 (2H, brs)

Embodiment 32

Embedded image 1- (4-methylphenyl) -2- (2-imino-5-
Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 605 mg (9
2%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.27 (3H, d, J = 1.1 H
z), 2.51 (3H, s), 5.73 (2H, s), 7.08 (1H, d, J =
1.5 Hz), 7.42 (2H, d, J = 8.4 Hz), 7.92 (2H, d, J =
8.0 Hz), 9.45 (2H, brs)

Embodiment 33

Embedded image 1- (4-phenylphenyl) -2- (2-imino-5
-Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 727 mg (9
3%). ¹ H NMR (TMS / DMSO-d ₆ ) δ 2.29 (3H, d, J = 1.4 H
z), 5.79 (2H, s), 7.10 (1H, d, J = 1.4 Hz), 7.43-
7.57 (3H, m), 7.79 (2H, d, J = 8.6 Hz), 7.93 (2H,
d, J = 8.6 Hz), 8.10 (2H, d, J = 8.6 Hz), 9.46 (2
H, brs)

Embodiment 34

Embedded image 1- (2-Naphthyl) -2- (2-imino-5-methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 662 mg (9
1%). ¹ H NMR (TMS / DMSO-d ₆ ) d 2.30 (3H, d, J = 1.3 Hz),
5.90 (2H, s), 7.13 (1H, d, J = 1.5 Hz), 7.65-7.
76 (2H, m), 7.99-8.20 (4H, m), 8.75 (1H, s), 9.4
9 (2H, brs)

Embodiment 35

Embedded image 1- (4-chlorophenyl) -2- (2-imino-5
Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 616 mg (8
9%). ¹ H NMR (TMS / DMSO-d ₆ ) d 2.27 (3H, d, J = 1.5 Hz),
5.76 (2H, s), 7.08 (1H, d, J = 1.5 Hz), 7.70 (2H, s)
d, J = 8.8 Hz), 8.03 (2H, d, J = 8.8 Hz), 9.49 (2
H, brs)

Embodiment 36

Embedded image 1- (3-methoxyphenyl) -2- (2-imino-5
-Methyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 578 mg (8
4%). ¹ H NMR (TMS / DMSO-d ₆ ) d 2.27 (3H, d, J = 1.3 Hz),
3.86 (3H, s), 5.77 (2H, s), 7.09 (1H, d, J = 1.5
Hz), 7.30-7.34 (1H, m), 7.50-7.63 (3H, m), 9.4
9 (2H, brs)

Embodiment 37

Embedded image 1- (2-Naphthyl) -2- (2-imino-4,5-dimethyl-3 (2H) -thiazolyl) ethanone hydrobromide According to the method of Example 1, 568 mg of the title compound (7
5%). ¹ H NMR (TMS / DMSO-d ₆ ) d 2.09 (3H, s), 2.26 (3H,
s), 5.91 (2H, s), 7.66- 7.77 (2H, m), 8.01-8.19
(4H, m), 8.82 (1H, s), 9.49 (2H, brs)

Example 38 (Inhibition of Stat-6 activation) 1) Cells Mouse fibroblast L929 was obtained from Dainippon Pharmaceuticals (Osaka). 2) Medium RPMI 1640 medium “Digo” (Nippon Pharmaceutical, Tokyo) Code N
o. Fetal bovine serum (Fetal Bovine Serum, Defined, Code No. A-1111) inactivated at 56 degrees and 30 minutes at 394-00735).
-L, HyClone Lab., Logan, Utah), 10%, 2-mercaptoethanol (Sigma, St Louis, MO, Code No. M-6)
250) was added to 50 μM for use. 3) Drug The test drug was dissolved in dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 134-45) to a concentration of 8 mg / ml and diluted with a medium to a final concentration of 10 μg / ml.

4) Construction of STAT6 reporter gene The IL-4 response region (including the STAT6 binding region) on the mouse immunoglobulin germline ε gene promoter was
The ligated oligonucleotide of SEQ ID NO: 1 and its complementary strand were purchased from Japan Bio Services (Saitama). The oligonucleotide of SEQ ID NO: 1 and its complementary strand were mixed, and after heat denaturation and annealing, the 5 and 3 ends were restricted with the restriction enzyme SacI
(Takara Shuzo (Otsu) Code No. 1078A) and BglII (Takara Shuzo (Otsu) Code No. 1021A).
Promoter Vector (Promega Corporation, Madison, W
I, Code No. E1761) was cloned into the SacI / BglII site. 5) Gene Transfer and Preparation of Stable Expression Cell Line 5 × 10 ⁵ L929 cells were used in a 6-well plate for Falcon tissue culture (Becton Dickinson Labware, Bedford, Mass., USA).
Code No. 3046), and the cells were washed with a medium containing no fetal calf serum. 4 μg of the prepared STAT6 reporter gene, pSV2neo (GIBCOB
RL, Gaithersburg, MD) 0.5 μg and Lipofectamine (GIBCO BRL, Gaithersburg, MD, Code No. 1832)
4-012) 20 μl of 0.4 ml of medium without fetal calf serum
And left to stand at room temperature for 30 minutes. Thereafter, 1.6 ml of a medium containing no fetal calf serum was further added to the washed cells, and the cells were cultured for 5 hours. 2 ml of a medium containing fetal calf serum was added, and the cells were further cultured for 19 hours. After changing the medium and further culturing for 24 hours, G418 (GIBCO BRL, Ga
ithersburg, MD, Code No. 10131-019) 0.2 mg
/ Ml to continue the culture and select drug-resistant cells. The obtained drug-resistant cells are suspended in a medium containing G418, and a Falcon microplate (Becton Dickinson Labware, Bedfor
d, MA, Code No. 3072), and a clone expressing luciferase in response to IL-4 was obtained.

6) STAT6 activation inhibition test The transfected L929 cells were 1 × 10 ⁴ cells / 0.1
microplate (costar)
3610, Corning Costar Corporation, Cambridge, M
A) and cultured overnight. Next day, test drug and IL
-4 10 U / ml (PharMingen, San Diego, CA, Cod
e No. PM-19231V) was added to make 0.2 ml / well, and the cells were cultured for 6 hours. After the culture, the supernatant was removed by suction, and the attached cells were lysed by adding 0.025 ml / well of a solubilizer. 0.1 ml of a luciferase substrate solution is added to each well, and the luciferase activity is measured using a luminometer (Micr
oLumatLB96P, EG & G BERTHOLD, Bad Wildbad, German
y). The experiment was performed by triplicate, and the average value was obtained. The solubilizer and substrate solution are commercially available Luciferase A
ssay System (Promega Corporation, Madison, WI, Co
de No. E1500) was used. The STAT6 activation inhibitory effect of the test compound was expressed as an inhibition rate (%) of luciferase activity induced by IL-4 stimulation. Inhibition rate (%)
Was calculated by the following equation. Inhibition rate (%) = 100− (E−B) / (C−B) × 10
0 Experimental Activity (E): I in the presence of the test compound
Luciferase activity induced by L-4 stimulation Control Activity (C): IL in the absence of test compound
-4-Luciferase activity induced by stimulation Background Activity (B): Luciferase activity induced without stimulation in the absence of the test compound The results are shown in Table 1.

[Table 1] In the table, + represents an inhibition rate of 10% or more and less than 50%, ++ represents an inhibition rate of 50% or more and less than 90%, and +++ represents an inhibition rate of 90% or more.

[Sequence list]

SEQ ID NO: 1 Sequence length: 97 Sequence type: Number of nucleic acid strands: Single strand Topology: Linear Sequence type: Synthetic DNA sequence CGGAGCTCTG CCTTAGTCAA CTTCCCCCAAGA ACAGATGCCT TAGTCAACTT CCCAAGAACA 60 GATGCCTTAG TCAACTTCCC AAGAACAGAA GATCTCG 97

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/425 ADZ A61K 31/425 ADZ AEC AEC AED AED // C07D 277/40 C07D 277/40 (72) Inventor Shigeyuki Nishinaka Mitsuo Aoki, 3-1-198, Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor, Sumitomo Pharmaceutical Co., Ltd. 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Hajime Kawakami 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd.

Claims (3)

[Claims] (1) Formula 1(Where X¹Is hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. X^TwoRepresents a hydrogen atom, an alkyl group,
Substituted alkyl group, cycloalkyl group, cycloalkyl group
Alkyl group, aralkyl group, substituted aralkyl group, aryl
Group, substituted aryl group, halogen atom, cyano group, trif
Fluoromethyl group, alkoxy group, phenoxy group, substituted
Phenoxy, alkanoyl, aroyl, substituted alloy
Group, alkoxycarbonyl group, carbamoyl group, nitro
Represents an alkyl group or an alkylamide group. X^ThreeIs a hydrogen atom,
Alkyl group, substituted alkyl group, cycloalkyl group, cycloalkyl
Loalkylalkyl, aralkyl, substituted aralkyl
Group, aryl group, substituted aryl group, halogen atom, shea
, Trifluoromethyl, alkoxy, phenoxy
Si group, substituted phenoxy group, alkanoyl group, aroyl
Group, substituted aroyl group, alkoxycarbonyl group, carba
Represents a moyl group, a nitro group or an alkylamide group. X
^FourRepresents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl group, aryl group, substituted aryl group, halo
Gen atom, cyano group, trifluoromethyl group, alkoxy
Si group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. X^FiveIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. Or X¹, X^Two, X^Three, X^Four,
And X^FiveWherein two adjacent groups are bonded to each other
A phenyl ring or a substituted phenyl ring may be formed.
R¹Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl
Group, substituted aralkyl group, aryl group or substituted aryl
Represents a group. R^TwoIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Represents an aralkyl group or a substituted aralkyl group. Or R
¹And R^TwoAre bonded to each other to form a cycloalkenyl ring,
It may form a nyl ring or a substituted phenyl ring. n is
Represents an integer selected from 1, 2, 3 and 4. )
Iminothiazole derivative or pharmaceutically acceptable
STAT6 activation inhibitor comprising a salt as an active ingredient. (2) Formula 1(Where X¹Is hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. X^TwoRepresents a hydrogen atom, an alkyl group,
Substituted alkyl group, cycloalkyl group, cycloalkyl group
Alkyl group, aralkyl group, substituted aralkyl group, aryl
Group, substituted aryl group, halogen atom, cyano group, trif
Fluoromethyl group, alkoxy group, phenoxy group, substituted
Phenoxy, alkanoyl, aroyl, substituted alloy
Group, alkoxycarbonyl group, carbamoyl group, nitro
Represents an alkyl group or an alkylamide group. X^ThreeIs a hydrogen atom,
Alkyl group, substituted alkyl group, cycloalkyl group, cycloalkyl
Loalkylalkyl, aralkyl, substituted aralkyl
Group, aryl group, substituted aryl group, halogen atom, shea
, Trifluoromethyl, alkoxy, phenoxy
Si group, substituted phenoxy group, alkanoyl group, aroyl
Group, substituted aroyl group, alkoxycarbonyl group, carba
Represents a moyl group, a nitro group or an alkylamide group. X
^FourRepresents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl group,
Substituted aralkyl group, aryl group, substituted aryl group, halo
Gen atom, cyano group, trifluoromethyl group, alkoxy
Si group, phenoxy group, substituted phenoxy group, alkanoyl
Group, aroyl group, substituted aroyl group, alkoxycarbonyl
Group, carbamoyl group, nitro group or alkylamide
Represents a group. X^FiveIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Aralkyl group, substituted aralkyl group, aryl group, substituted ant
Group, halogen atom, cyano group, trifluoromethyl
Group, alkoxy group, phenoxy group, substituted phenoxy group,
Alkanoyl group, aroyl group, substituted aroyl group, alcohol
Xycarbonyl, carbamoyl, nitro or amino groups
Represents a rukylamido group. Or X¹, X^Two, X^Three, X^Four,
And X^FiveWherein two adjacent groups are bonded to each other
A phenyl ring or a substituted phenyl ring may be formed.
R¹Represents a hydrogen atom, an alkyl group, a substituted alkyl group,
Alkyl group, cycloalkylalkyl group, aralkyl
Group, substituted aralkyl group, aryl group or substituted aryl
Represents a group. R^TwoIs hydrogen atom, alkyl group, substituted alkyl
Group, cycloalkyl group, cycloalkylalkyl group,
Represents an aralkyl group or a substituted aralkyl group. Or R
¹And R^TwoAre bonded to each other to form a cycloalkenyl ring,
It may form a nyl ring or a substituted phenyl ring. n is
Represents an integer selected from 1, 2, 3 and 4. )
Iminothiazole derivative or pharmaceutically acceptable
Allergic diseases and parasite infections containing active salts as active ingredients
Disease, autoimmune disease, viral or bacterial infection
Disease, malignancy, HVG (Host-versus-Graft) disease or acquired
A therapeutic or prophylactic agent for immunodeficiency syndrome (AIDS). 3. The agent according to claim 1, comprising a compound of the formula (1) wherein n is 2 as an active ingredient.