JP2003306433A - Pyridine derivative or its salt and cytokine production inhibitor comprising the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a cytokine production inhibitor useful as a therapeutic agent and a prophylactic agent for diseases associated with immune hyperfunctions. <P>SOLUTION: The cytokine production inhibitor comprises a pyridine derivative represented by formula (I) [wherein, X<SP>1</SP>is hydrogen, a halogen, nitro, trifluoromethyl, an alkyl or cyano; X<SP>2</SP>is hydrogen, trifluoromethyl or an alkyl; X<SP>3</SP>is hydrogen, a halogen, trifluoromethyl, an alkyl, an alkoxycarbonyl, nitro, cyano or methylsulfonyl; X<SP>4</SP>is hydrogen, a halogen, trifluoromethyl, an alkyl or an alkoxy; T is O, S, SO, SO<SB>2</SB>or NH; Y is a halogen, a substitutable alkyl, a substitutable alkoxy, nitro, a hydroxy group, an alkylsulfonylamino, an alkyl- substitutable amino or the like; and n is an integer of 0-5] or it salt as an active ingredient. <P>COPYRIGHT: (C)2004,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a pyridine derivative or a salt thereof, and a cytokine production inhibitor containing them as an active ingredient. The cytokine production inhibitor of the present invention is useful as a preventive or therapeutic drug for diseases associated with abnormally enhanced immune function.

[0002]

2. Description of the Related Art In the immune reaction of a living body, cytokines produced by various immunocompetent cells control the direction of the immune response. Helper T cells play a central role in the regulation of this immune response, and are classified into a subset of Th1 and Th2 depending on the type of cytokine produced. Th1 type cells mainly consist of interleukin 2 (IL-2) and interferon γ (I
It is known to produce FN-γ) and the like and participate in cell-mediated immunity such as defense against infection against viruses and bacteria. Th2-type cells are mainly interleukin-4
(IL-4), interleukin 5 (IL-5), interleukin 6 (IL-6), interleukin 10
(IL-10), interleukin 13 (IL-13)
, Etc., and is involved in humoral immunity such as protection against infection by parasites and antibody production from B cells.
However, it has been clarified that when the control of these biological defense mechanisms is disabled or lowered for some reason, abnormal hyperactivity and imbalance of immune functions occur and various diseases are induced and exacerbated.

[0003] Th2-type immune responses are allergic inflammatory reactions such as immediate allergic reactions mainly involving IgE antibodies and mast cells and delayed allergic reactions mainly involving eosinophils due to their abnormally elevated levels. Is induced and activated and is deeply involved in the induction and exacerbation of various allergic diseases such as urticaria, food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis. ing. In addition, systemic autoimmune diseases in which the production of antibodies such as systemic lupus erythematosus or humoral immunity is abnormally enhanced are also associated with Th.
The abnormal enhancement of two types of immune responses is deeply involved. It is considered important to control the Th2-type immune response in order to prevent or treat these allergic diseases. On the other hand, the Th1-type immune response induces and activates a cell-mediated immune response due to its abnormal increase,
It is deeply involved in the induction and exacerbation of organ-specific autoimmune diseases such as rheumatoid arthritis, type I diabetes, Hashimoto thyroiditis, myasthenia gravis, and multiple sclerosis. In addition, the rejection reaction associated with organ transplantation is closely related to the Th1 type cell-mediated immune reaction. It is considered important to control the Th1 type immune response in order to prevent or treat these autoimmune diseases and rejection after transplantation.

Some of the compounds of formula (I) described below are disclosed in
4-55575, JP-A-55-69566, WO8
2/00400, EP published patent application No. 483, EP published patent application No. 273242, and the like. However, it is not known that the compounds described in these have a cytokine production inhibitory action.

[0005]

To date, it has been difficult to specifically control and treat Th1 or Th2 type immune responses in these severe immune / allergic diseases. In addition, immunosuppressive agents that strongly suppress both Th1 and Th2 type cytokine production, such as cyclosporine and FK506, are currently the main components of the therapeutic system for these diseases. However, with steroids, various side effects such as adrenocortical dysfunction, diabetes, peptic ulcer, glaucoma, etc.
Cyclosporine and FK506 cause serious side effects such as renal disorders and central nervous system disorders, and development of a new type of cytokine production inhibitor different from these is expected.

[0006]

Means for Solving the Problems The present inventors have found that a pyridine derivative having a chemical structure completely different from that of the active ingredient of the existing drug has a cytokine production inhibitory action, and have proposed the present invention. These suppress urticaria, food allergy, anaphylactic shock, eosinophilia syndrome, by suppressing Th2 type cytokine production.
Various allergic diseases such as asthma, allergic rhinitis, allergic conjunctivitis, atopic dermatitis; useful as prophylactic or therapeutic drug for systemic autoimmune diseases with abnormally enhanced antibody production or systemic lupus erythematosus Is. In addition, by suppressing Th1 type cytokine production, organ-specific autoimmune diseases such as rheumatoid arthritis, type I diabetes, Hashimoto's thyroiditis, myasthenia gravis, and multiple sclerosis; It is useful as a prophylactic or therapeutic drug.

The present inventors have completed the present invention as a result of various investigations in order to find a better cytokine production inhibitor. That is, the present invention provides formula (I):

[Chemical 11] [In the formula, X¹Is a hydrogen atom, halogen atom, nitro group,
A fluoromethyl group, an alkyl group or a cyano group
R; X²Is a hydrogen atom, a trifluoromethyl group or
Is a kill group; X³Is hydrogen atom, halogen atom, trif
Luoromethyl group, alkyl group, alkoxycarbonyl
A group, a nitro group, a cyano group or a methylsulfonyl group
R; X^FourIs hydrogen atom, halogen atom, trifluoromethy
Is an alkyl group, an alkyl group or an alkoxy group; T is O,
S, SO, SO₂Or NH; Y is a halogen source
Child, optionally substituted alkyl group, optionally substituted group
Lucoxy group, nitro group, hydroxyl group, alkylsulfonyl group
A mino group, an amino group which may be substituted with an alkyl group, an alkyl group
Killcarbonylamino group, cycloalkylcarbonyl group
Mino group, alkoxycarbonylamino group, alkoxyca
Rubonylalkylamino group, hydroxycarbonyl al
Kiramino group or OA-COZ group {A is CR¹R
²Group, CR¹R²CR³R^FourGroup or CR¹R²CR³R^FourCR^Five
R⁶Group (R¹, R², R³, R ^Four, R^FiveAnd R⁶Each is German
Vertically hydrogen atom, halogen atom, optionally substituted alkyl
Group, alkoxy group, optionally substituted phenyl group,
Optionally substituted naphthyl group, optionally substituted phenoxy
Si group, optionally substituted heterocyclic group, optionally substituted heterocyclic group
Elementary ring oxy group, alkoxycarbonyl group or carboxy
Is a silyl group; or R¹And R²To form a ring with
Z) is a hydroxyl group, an alkoxy group or an alkoxy group.
Cyalkoxy group, alkenyloxy group, cycloalkoxy
Si group, acyloxymethyl group, alkyl group, alkyl group
Group, benzyloxy group, optionally substituted aryl group
Xy group, optionally substituted arylthio group, NR⁷R⁸Basis
(R⁷And R⁸Are each independently a hydrogen atom,
Optionally alkyl group, optionally substituted alkylsulfoni
Group, optionally substituted cycloalkyl group, substituted
Optionally alkenyl group, optionally substituted cycloalkenyl
Group, optionally substituted aryl group, optionally substituted
Heterocyclic group, hydroxyl group, alkoxy group or may be substituted
Is an arylsulfonyl group; or R⁷And R⁸But
Together they form a ring with or without heteroatoms.
Or NHNR⁷R⁸Group (R⁷, R⁸Is the above
Or by forming a ring with Z and A
And n is an integer of 0 to 5]
Contains a pyridine derivative or its salt as an active ingredient
The present invention relates to a cytokine production inhibitor.

The salt of the pyridine derivative represented by the above formula (I) may be any pharmaceutically acceptable salt, and examples thereof include mineral salts such as hydrochloride, sulfate and nitrate; p-toluenesulfonic acid. Organic salts such as salts, propane sulfonates and methane sulfonates; alkali metal salts such as potassium salts and sodium salts; alkaline earth metal salts such as calcium salts; triethanolamine salts, tris (hydroxymethyl) ) Examples include organic amine salts such as aminomethane salts. Also, some of these salts have water of crystallization.

The alkyl group or alkyl moiety contained in the formula (I) has 1 to 18 carbon atoms, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl,
Examples include octyl, nonyl, decyl, nonadecyl, and the like, which include structural isomers of linear or branched fatty chains.

Examples of the alkenyl group or alkenyl moiety include those having 2 to 18 carbon atoms, such as vinyl, propenyl, butenyl, pentenyl, hexenyl, decenyl, nonadecenyl and the like, which are structural isomers of linear or branched fatty chains. Including things.

The cycloalkyl group or the cycloalkyl moiety has a carbon number of 3 to 10, for example, a monocyclic group such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cyclooctyl, as well as a condensed polycyclic group and a bridge. Type polycyclic groups and the like.

The cycloalkenyl group or cycloalkenyl moiety has 3 to 10 carbon atoms, for example, monocyclic groups such as cyclopentenyl, cyclohexenyl and cyclooctenyl, as well as fused polycyclic groups and bridged polycyclic groups. Groups and the like.

As the aryl group or the aryl moiety,
In addition to phenyl, there may be mentioned fused polycyclic groups such as naphthyl, indanyl and tetrahydronaphthyl.

Examples of the heterocyclic group or heterocyclic moiety include pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, dihydrofuranyl, tetrahydrofuranyl, thienyl, dihydrothienyl, tetrahydrothienyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, Oxazolinyl, oxazolidinyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl or 5-isoxazolyl), isoxazolinyl, isoxazolidinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, isothiazolinyl, isothiazolidinyl,
Oxadiazolyl, oxadiazolinyl, oxadiazolidinyl, thiadiazolyl, thiadiazolinyl, thiadiazolidinyl, triazolyl, triazolinyl, triazolidinyl, tetrazolyl, tetrazolinyl, tetrazolidinyl, dioxolyl, dioxolanyl, dithiolyl, dithiolanyl, pyridyl (2-pyridyl, 3-pyridyl Or 4-pyridyl), dihydropyridyl, tetrahydropyridyl, piperidinyl, pyrimidyl, dihydropyrimidyl, tetrahydropyrimidyl, hexahydropyrimidyl, pyridazinyl, dihydropyridazinyl, tetrahydropyridazinyl, hexahydropyrida Dinyl, pyrazinyl, dihydropyrazinyl, tetrahydropyrazinyl, piperazinyl, pyranyl, dihydropyranyl, tetrahydropyranyl, di Hexynyl, Jiokiseniru, dioxanyl, dithianyl, monocyclic heterocyclic groups such as morpholinyl; thienothienyl, dihydro cyclopentanol Tachi enyl, indolyl, tetrahydroindolyl, isoindolyl, tetrahydroisoquinoline indolyl, benzothienyl,
Tetrahydrobenzothienyl, benzofuranyl, tetrahydrobenzofuranyl, benzoxazolyl, tetrahydrobenzoxazolyl, benzisoxazolyl, tetrahydrobenzisoxazolyl, benzothiazolyl, tetrahydrobenzothiazolyl, benzisothiazolyl, tetrahydrobenzo Isothiazolyl, benzimidazolyl, tetrahydrobenzimidazolyl, benzodioxolyl, benzodithiolyl, benzodioxanyl,
Examples thereof include condensed polycyclic heterocyclic groups such as benzodithianyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl and purinyl; and bridged polycyclic heterocyclic groups such as quinuclidinyl.

The secondary substituents of the alkyl group which may be substituted, the alkoxy group which may be substituted, the alkylsulfonyl group which may be substituted and the alkenyl group which may be substituted may be a halogen atom, a hydroxyl group or a mercapto group. , Substitutable alkoxy group, Substitutable alkylthio group, Substitutable alkenyloxy group, Substitutable alkenylthio group, Substitutable alkynyloxy group, Substitutable alkynylthio group, Substitutable cycloalkyl group, Substitutable cycloalkenyl group, Substitutable cyclo Alkoxy group, Substitutable cycloalkylthio group, Substitutable cycloalkenyloxy group, Substitutable cycloalkenylthio group, Substitutable alkoxycarbonyl group, Substitutable alkylcarbonyl group, Substitutable alkylcarbonyloxy group, Substitutable alkenyloxycarbonyl group, Substituted Alkenyl carbonyl group, position Yes alkenylcarbonyl group,
Substitutable alkynyloxycarbonyl group, replaceable alkynylcarbonyl group, replaceable alkynylcarbonyloxy group, replaceable cycloalkoxycarbonyl group, replaceable cycloalkylcarbonyl group, replaceable cycloalkylcarbonyloxy group, replaceable cycloalkenyloxycarbonyl group, Substitutable cycloalkenylcarbonyl group, replaceable cycloalkenylcarbonyloxy group, replaceable aryl group, replaceable aryloxy group, replaceable arylthio group,
Substitutable Aryloxycarbonyl group, Substitutable arylcarbonyl group, Substitutable arylcarbonyloxy group, Substitutable heterocyclic group, Substitutable heterocyclic oxy group, Substitutable heterocyclic thio group, Substitutable heterocyclic oxycarbonyl group, Substituteable Heterocyclic carbonyl group, replaceable heterocyclic carbonyloxy group, replaceable amino group, cyano group, nitro group, carboxyl group, replaceable aminocarbonyl group, replaceable alkylsulfonyl group,
Substitutable alkenylsulfonyl groups, substitutable alkynylsulfonyl groups, substitutable cycloalkylsulfonyl groups, substitutable cycloalkenylsulfonyl groups, substitutable arylsulfonyl groups, substitutable heterocyclic sulfonyl groups, substitutable aminosulfonyl groups, and the like. The number of the substituents may be 1 or 2 or more, and when the number of the substituents is 2 or more, those substituents may be the same or different.

Optionally substituted phenyl group, optionally substituted naphthyl group, optionally substituted phenoxy group, optionally substituted heterocyclic group, optionally substituted heterocyclic oxy group, optionally substituted Secondary of a good aryloxy group, an optionally substituted arylthio group, an optionally substituted cycloalkyl group, an optionally substituted cycloalkenyl group, an optionally substituted aryl group and an optionally substituted arylsulfonyl group As the substituent, a halogen atom, a hydroxyl group, a mercapto group, a replaceable alkyl group, a replaceable alkenyl group, a replaceable alkynyl group, a replaceable alkoxy group, a replaceable alkylthio group, a replaceable alkenyloxy group, a replaceable alkenylthio group, Substitutable alkynyloxy group, Substitutable alkynylthio group, Substitutable cycloalkyl group, Substitutable cycloalkenyl group Substitutable cycloalkoxy group, replaceable cycloalkylthio group, replaceable cycloalkenyloxy group, replaceable cycloalkenylthio group, replaceable alkoxycarbonyl group, replaceable alkylcarbonyl group, replaceable alkylcarbonyloxy group, replaceable alkenyloxycarbonyl Group, Substitutable alkenylcarbonyl group, Substitutable alkenylcarbonyloxy group, Substitutable alkynyloxycarbonyl group, Substitutable alkynylcarbonyl group, Substitutable alkynylcarbonyloxy group, Substitutable cycloalkoxycarbonyl group, Substitutable cycloalkylcarbonyl group,
Substitutable cycloalkylcarbonyloxy group, replaceable cycloalkenyloxycarbonyl group, replaceable cycloalkenylcarbonyl group, replaceable cycloalkenylcarbonyloxy group, replaceable aryl group, replaceable aryloxy group, replaceable arylthio group, replaceable aryl Oxycarbonyl group, Substitutable arylcarbonyl group, Substitutable arylcarbonyloxy group, Substitutable heterocyclic group, Substitutable heterocyclic oxy group, Substitutable heterocyclic thio group, Substitutable heterocyclic oxycarbonyl group, Substitutable heterocyclic carbonyl Group, substitutable heterocyclic carbonyloxy group, substitutable amino group, cyano group, nitro group, carboxyl group, substitutable aminocarbonyl group, substitutable alkylsulfonyl group, substitutable alkenylsulfonyl group, substitutable alkynylsulfonyl group, substitutable Cycloalkylsulfonyl group A substitutable cycloalkenyl sulfonyl group, a substitutable arylsulfonyl group, a substitutable heterocyclic sulfonyl group, such as a substitutable aminosulfonyl group and the like,
The number of the substituents may be 1 or 2 or more, and when the number of the substituents is 2 or more, the substituents may be the same or different.

Of the above secondary substituents, the tertiary substituents of each substitutable group are halogen atom, hydroxyl group, mercapto group, cyano group, nitro group, carboxyl group, amino group, alkyl group, alkenyl group, Alkynyl group, cycloalkyl group, cycloalkenyl group, aryl group, heterocyclic group, alkoxy group, alkenyloxy group, alkynyloxy group, cycloalkyloxy group, cycloalkenyloxy group, aryloxy group, heterocyclic oxy group, alkylthio group , Alkenylthio group, alkynylthio group, cycloalkylthio group, cycloalkenylthio group, arylthio group, heterocyclic thio group, alkylsulfonyl group, alkenylsulfonyl group, alkynylsulfonyl group, cycloalkylsulfonyl group, cycloalkenylsulfonyl group, arylsulfonyl , Heterocyclic sulfonyl group, alkylcarbonyl group, alkenylcarbonyl group, alkynylcarbonyl group, cycloalkylcarbonyl group, cycloalkenylcarbonyl group, arylcarbonyl group, heterocyclic carbonyl group, alkyloxycarbonyl group, alkenyloxycarbonyl group, alkynyloxycarbonyl Group, cycloalkyloxycarbonyl group, cycloalkenyloxycarbonyl group, aryloxycarbonyl group, heterocyclic oxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group,
Alkenylaminocarbonyl group, alkynylaminocarbonyl group, cycloalkylaminocarbonyl group, cycloalkenylaminocarbonyl group, arylaminocarbonyl group, heterocyclic aminocarbonyl group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, alkenylaminosulfonyl group Group, alkynylaminosulfonyl group, cycloalkylaminosulfonyl group, cycloalkenylaminosulfonyl group, arylaminosulfonyl group, heterocyclic aminosulfonyl group, alkylamino group, dialkylamino group, alkenylamino group, alkynylamino group, cycloalkylamino group , A cycloalkenylamino group, an arylamino group, a heterocyclic amino group, an alkylcarbonylamino group, an alkenylcarbonylamino group, Rukinylcarbonylamino group, cycloalkylcarbonylamino group, cycloalkenylcarbonylamino group, arylcarbonylamino group, heterocyclic carbonylamino group, alkylsulfonylamino group, alkenylsulfonylamino group, alkynylsulfonylamino group, cycloalkylsulfonylamino group, Examples thereof include a cycloalkenylsulfonylamino group, an arylsulfonylamino group and a heterocyclic sulfonylamino group, and the number of the tertiary substituents may be one or two or more, and in the case of two or more, those The substituents may be the same or different. Furthermore, when the secondary substituent is an amino group substituted by two tertiary substituents, the tertiary substituents may together form a ring with or without heteroatoms.

Also, the alkyl moiety of these tertiary substituents,
The alkenyl moiety, alkynyl moiety, cycloalkyl moiety, cycloalkenyl moiety, aryl moiety, and heterocyclic moiety are further halogen atom, hydroxyl group, mercapto group, cyano group, nitro group, carboxyl group, amino group, alkyl group, haloalkyl group, alkoxy group. Group, haloalkoxy group, alkylthio group, haloalkylthio group, alkoxycarbonyl group, aminocarbonyl group, alkylaminocarbonyl group, dialkylaminocarbonyl group, aminosulfonyl group, alkylaminosulfonyl group, dialkylaminosulfonyl group, alkylamino group, It may be substituted with a quaternary substituent such as a dialkylamino group, an alkylcarbonylamino group, an alkylsulfonylamino group, a cycloalkyl group, an aryl group and a heterocyclic group, and the number of these substituents is one. And it may be two or more than,
When the number of substituents is 2 or more, those substituents may be the same or different.

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION Next, some preferred embodiments of the present invention will be described, but the present invention is not limited thereto.

Among the above-mentioned pyridine derivatives of formula (I) or salts thereof, the following compounds are more excellent as the active ingredient of the cytokine production inhibitor. In particular, the compound described in (3) has excellent interleukin 5 selectivity.

(1) Formula (I '):

[Chemical 12] [Wherein X ¹ , X ² , X ³ and X ⁴ are as described above,
T is O, S, SO or SO ₂ ; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or an alkoxy group; R ¹ is a hydrogen atom, an alkyl group, a haloalkyl group, an optionally substituted phenyl group, A pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group; R ² is a hydrogen atom, a halogen atom,
It is an alkyl group, an alkoxycarbonyl group or a carboxyl group; or R ¹ and R ² may form a ring by an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkenyloxy group, a cycloalkoxy group, an acyloxy. A methyl group, an optionally substituted aryloxy group, an optionally substituted arylthio group,
NR ⁷ R ⁸ group (R ⁷ and R ⁸ are each independently a hydrogen atom,
Optionally substituted alkyl group, optionally substituted alkylsulfonyl group, optionally substituted cycloalkyl group,
Whether it is an optionally substituted aryl group, an optionally substituted heterocyclic group, a hydroxyl group, an alkoxy group or an optionally substituted arylsulfonyl group; or whether R ⁷ and R ⁸ together comprise a hetero atom Or a NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above); and n ′ is an integer of 0 to 2] Or its salt.

(2) Formula (I ″):

[Chemical 13] [Wherein X ¹ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group; X ² is a hydrogen atom, a trifluoromethyl group or an alkyl group; X ³ is a hydrogen atom, a halogen atom, trifluoro A methyl group, an alkoxycarbonyl group, a nitro group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or An alkoxy group; R ¹ is an alkyl group, a haloalkyl group,
An optionally substituted phenyl group, a pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group; R ² is a hydrogen atom, a halogen atom, an alkoxycarbonyl group or a carboxyl group; or R ¹ and R ² may form a ring with an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxymethyl group, an optionally substituted aryloxy group, and an NR ⁷ R ⁸ group (R ⁷ and R ⁸ are respectively Independently hydrogen atom, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocyclic group, hydroxyl group, alkoxy group or optionally substituted aryl A sulfonyl group;
Or R ⁷ and R ⁸ together may form a ring with or without heteroatoms) or a NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above); n'is 0
Is an integer of 2] or a salt thereof.

(3) X ² is a hydrogen atom or a trifluoromethyl group; X ³ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkoxycarbonyl group or a nitro group; X ⁴ is a hydrogen atom or a halogen atom. Or a trifluoromethyl group; R ¹ is an alkyl group, a haloalkyl group, an optionally substituted phenyl group, a pyridyl group or a naphthyl group; R ² is a hydrogen atom, a halogen atom or a carboxyl group; or R ¹ And R ² may form a ring by an alkylene chain; Z is a hydroxyl group,
Alkoxy group, optionally substituted aryloxy group, N
R ⁷ R ⁸ group (R ⁷ and R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a hydroxyl group, an alkoxy group or a substituted group. May be an arylsulfonyl group)
Alternatively, the compound or salt thereof according to the above (2), which is an NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above).

(4) X ¹ is a halogen atom; X ² is a hydrogen atom; X ³ is a trifluoromethyl group;
X ⁴ is a hydrogen atom; Y ′ is a halogen atom;
The compound or salt thereof according to (2), wherein n ′ is 1 or 2.

(5) X ¹ is a halogen atom; X ² is a hydrogen atom; X ³ is a trifluoromethyl group;
X ⁴ is a hydrogen atom; Y ′ is a halogen atom;
n ′ is 1 or 2; R ¹ is an alkyl group; R ²
Is a hydrogen atom; Z is a hydroxyl group, or a compound or salt thereof according to (2) above.

Of the compounds described in (2) above,
The following compounds have hitherto not been known. (I) Formula (I ''-a):

[Chemical 14] A pyridine derivative represented by the formula: wherein X ¹ , X ² , X ³ , X ⁴ , Y ′, R ¹ , Z and n ′ are as defined in the above formula (I ″) or Its salt.

(Ii) Formula (I ″):

[Chemical 15] Wherein, X ¹ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group,; X ² represents a hydrogen atom, a trifluoromethyl group or an alkyl group; X ³ is a hydrogen atom, a halogen atom, tri A fluoromethyl group, an alkoxycarbonyl group, a nitro group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group;
Is a halogen atom, a haloalkyl group, an alkyl group or an alkoxy group; R ¹ is an alkyl group, a haloalkyl group, an optionally substituted phenyl group, a pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group. R ² is a hydrogen atom, a halogen atom,
An alkoxycarbonyl group or a carboxyl group;
Alternatively, R ¹ and R ² may form a ring with an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxymethyl group, an optionally substituted aryloxy group, an NR ⁷ R ⁸ group (R ⁷ And R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a hydroxyl group, an alkoxy group or a substituted group. Or an arylsulfonyl group which may be substituted; or R ⁷ and R ⁸ together may form a ring with or without a heteroatom) or NHNR ⁷ R ⁸
Is a group (R ⁷ and R ⁸ are as described above); n ′ is an integer of 0 to 2 (provided that X ² and X ⁴ are hydrogen atoms, R ¹ is a methyl group, R ² is a hydrogen atom,
n ′ is 0, Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an amino group which may be substituted with an alkyl group, a 2-pyridylamino group, an NR—Ar group (Ar is naphthyl which may be substituted with a halogen atom) Group; halogen atom, alkyl, alkylthio, alkoxy, hydroxy, monoalkylamino, dialkylamino, amino,
A benzyl group optionally substituted with trifluoromethyl, thioamide or nitro; or optionally substituted with a halogen atom, alkyl, alkylthio, alkoxy, hydroxy, monoalkylamino, dialkylamino, amino, trifluoromethyl, thioamide or nitro A phenyl group, R is a hydrogen atom or a C _1-3 alkyl group) or a NR'R "group (R 'is a hydrogen atom, C
_1-4 alkyl group or C _2-3 hydroxyalkyl group; R ″ is hydrogen atom, C _1-4 alkyl group, C _2-3 hydroxyalkyl group or methoxy group),
(1) X ¹ is a hydrogen atom; and X ³ is a halogen atom or a trifluoromethyl group, and (2) X
¹ is a halogen atom or a trifluoromethyl group;
And a case where X ³ is a hydrogen atom, a halogen atom or a trifluoromethyl group}], or a salt thereof.

The compound represented by the above formula (I) is a compound useful as an active ingredient of a cytokine production inhibitor, and is useful, for example, as a prophylactic or therapeutic drug for diseases associated with abnormally enhanced immune function listed below. is there. (1) At least one allergic disease selected from urticaria, food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis and atopic dermatitis. (2) At least one allergic disease selected from eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis and atopic dermatitis. (3) Eosinophilia syndrome or asthma. (4) A systemic autoimmune disease in a condition in which antibody production or humoral immunity is abnormally enhanced. (5) Rheumatoid arthritis, type I diabetes, Hashimoto thyroiditis,
At least one organ-specific autoimmune disease selected from myasthenia gravis and multiple sclerosis. (6) Diseases associated with abnormally high immune function are caused by transplantation (organ,
Tissue, bone marrow, blood transfusion) rejection.

The compound of formula (I) or a salt thereof can be produced by the following production methods [1] to [3].

Manufacturing method [1] Formula (II):

[Chemical 16] (In the formula, X ¹ , X ² , X ³ and X ⁴ are as described above,
Hal is a halogen atom) and a compound represented by the formula (III):

[Chemical 17]

(Wherein Y and n are as described above,
T ′ is O, S, or NH) to react with a compound represented by the formula (I-1):

[Chemical 18] (Wherein X ¹ , X ² , X ³ , X ⁴ , Y, T ′ and n are as described above).

The reaction of the production method [1] can be carried out in the presence of a suitable solvent. Specific solvents used include alcohols such as methanol, ethanol, propanol and butanol; ketones such as acetone, methyl ethyl ketone, dimethyl ketone, diethyl ketone and methyl isobutyl ketone; aromatic carbonization such as benzene, toluene and xylene. Hydrogens; Aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; Ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile and propionitrile Acids such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphoric acid such as hexamethylphosphoramide Bromide such; chloroform, dichloromethane, carbon tetrachloride, 1,
Mention may be made of halogenated hydrocarbons such as 2-dichloroethane and mixed solvents thereof.

In the production method [1], in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene and N, N-dimethylaniline; lithium, sodium. , Alkali metal such as potassium; hydroxide of alkali metal such as sodium hydroxide and potassium hydroxide; carbonate of alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal hydrogen carbonates such as; hydrides of alkali metals such as lithium hydride, sodium hydride, potassium hydride; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like. . The reaction of the manufacturing method [1] is
It is generally carried out at a reaction temperature of 0 to 150 ° C, preferably 0 to 100 ° C. The reaction time is generally 0.5 to 24 hours. In the reaction of the production process [1], the compound of the formula (III) is used in a proportion of 0.8 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to 1 mol of the compound of the formula (II). it can.

The reaction conditions in the production method [1] can be appropriately combined with each other. Further, among these various reaction conditions, there are those having a reaction range in a normal range and a reaction range in a desirable range, and these can be appropriately selected and combined with each other.

Further, the formula (I-2):

[Chemical 19] (In the formula, X ¹ , X ² , X ³ , X ⁴ , Y and n are as described above, and T ″ is SO or SO ₂ ), and the compound represented by the above formula (I-1 In the above, it can be produced by subjecting a compound in which T ′ is S to an ordinary oxidation reaction.

Manufacturing method [2] Formula (I-3):

[Chemical 20] (Wherein X ¹ , X ² , X ³ , X ⁴ , Y and n are as described above, and T ′ ″ is S or O), and a compound represented by the formula (V): Hal -A-COZ (in the formula, Hal, A
And Z are as described above) to react with a compound represented by the formula (I-4):

[Chemical 21] (Wherein X ¹ , X ² , X ³ , X ⁴ , A, Z, T ′ ″, Y and n are as described above).

The compound represented by the above formula (I-3) can be produced by the method described in the production method [1]. That is, the compound of the formula (II) and the compound of the formula (III-1):

[0038]

[Chemical formula 22] It can be produced by reacting with a compound represented by the formula (wherein T ″ ′, Y and n are as described above).

The reaction of the production method [2] can be carried out in the presence of a suitable solvent. Specific solvents used include alcohols such as methanol, ethanol, propanol and butanol; ketones such as acetone, methyl ethyl ketone, dimethyl ketone, diethyl ketone and methyl isobutyl ketone; aromatic carbonization such as benzene, toluene and xylene. Hydrogens; Aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; Ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; Nitriles such as acetonitrile and propionitrile Acids such as dimethylformamide and dimethylacetamide; sulfoxides such as dimethylsulfoxide; sulfones such as sulfolane; phosphoric acid such as hexamethylphosphoramide Bromide such; chloroform, dichloromethane, carbon tetrachloride, 1,
Mention may be made of halogenated hydrocarbons such as 2-dichloroethane and mixed solvents thereof.

In the production method [2], in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene and N, N-dimethylaniline; lithium, sodium. , Alkali metal such as potassium; hydroxide of alkali metal such as sodium hydroxide and potassium hydroxide; carbonate of alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal hydrogen carbonates such as; hydrides of alkali metals such as lithium hydride, sodium hydride, potassium hydride; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like. .

The reaction of the production method [2] is generally 0 to 150.
C., preferably at a reaction temperature of 0-100.degree. The reaction time is generally 0.5 to 48 hours.

The formula (I-4) obtained by the production method [2]
The compound of can also be converted to another compound represented by the formula (I-4) by a conventional method. For example, formula (A):

[Chemical formula 23] (Wherein X ¹ , X ² , X ³ , X ⁴ , T ′ ″, A, Y and n
Is as described above), and a compound represented by the above formula (I
In (4), it can be produced by subjecting a compound in which Z is an alkoxy group to an ordinary hydrolysis reaction. Also, the formula (B):

[Chemical formula 24] (In the formula, X ¹ , X ² , X ³ , X ⁴ , T ′ ″, A, R ⁷ ,
R ⁸ , Y and n are as described above, and the compound represented by the formula (A) is represented by HNR ⁷ R ⁸ by converting the compound of the formula (A) into an acid chloride derivative with a chlorinating agent such as thionyl chloride or phosgene. Compound (in the formula, R ⁷ and R ⁸ are as described above).

The reaction conditions in the production method [2] can be appropriately combined with each other. Further, among these various reaction conditions, there are those having a reaction range in a normal range and a reaction range in a desirable range, and these can be appropriately selected and combined with each other.

Manufacturing method [3] Formula (C):

[Chemical 25] (Wherein X ¹ , X ² , X ³ , X ⁴ , T ′ ″, Z, Y and n
Is as described above), and the compound represented by the formula (D):

[Chemical formula 26] (Wherein X ¹ , X ² , X ³ , X ⁴ , T ′ ″, Z, Y and n
Is as described above), and then R ¹ ′ H (wherein R ¹ ′ is an optionally substituted phenoxy group or an optionally substituted heterocyclic oxy group). )
The compound represented by the formula (E)

[Chemical 27] (Wherein X ¹ , X ² , X ³ , X ⁴ , T ′ ″, R ¹ ′, Z, Y and n are as described above).

The reaction of the production process [3] can be carried out in the presence of a suitable solvent. Specific solvents used include alcohols such as methanol, ethanol, propanol and butanol; ketones such as acetone, methyl ethyl ketone, dimethyl ketone, diethyl ketone and methyl isobutyl ketone; aromatics such as benzene, toluene and xylene. Hydrocarbons; aliphatic hydrocarbons such as pentane, hexane, heptane, petroleum ether, ligroin, petroleum benzine; ethers such as diethyl ether, dipropyl ether, dibutyl ether, tetrahydrofuran, dioxane; acetonitrile, propionitrile, etc. Nitriles; Acid amides such as dimethylformamide and dimethylacetamide; Sulfoxides such as dimethylsulfoxide; Sulfones such as sulfolane; Phosphorus such as hexamethylphosphoramide Amides; chloroform, dichloromethane, carbon tetrachloride, 1,
Mention may be made of halogenated hydrocarbons such as 2-dichloroethane and mixed solvents thereof.

In the production method [3], in order to carry out the reaction efficiently, it is desirable to carry out the reaction in the presence of a base. Specific examples of the base used include organic bases such as triethylamine, pyridine, N-methylmorpholine, 1,8-diazabicyclo [5.4.0] -7-undecene and N, N-dimethylaniline; lithium, sodium. , Alkali metal such as potassium; hydroxide of alkali metal such as sodium hydroxide and potassium hydroxide; carbonate of alkali metal such as lithium carbonate, sodium carbonate and potassium carbonate; lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate Alkali metal hydrogen carbonates such as; hydrides of alkali metals such as lithium hydride, sodium hydride, potassium hydride; alkoxides such as sodium methoxide, sodium ethoxide, potassium t-butoxide, and the like. .

The reaction of the production method [3] is generally 0 to 150.
C., preferably at a reaction temperature of 0-100.degree. The reaction time is generally 0.5 to 48 hours.

The reaction conditions in the production process [3] can be appropriately combined with each other. Further, among these various reaction conditions, there are those having a reaction range in a normal range and a reaction range in a desirable range, and these can be appropriately selected and combined with each other.

The compound of the above formula (I) obtained by the above-mentioned production processes [1] to [3] and the processes associated therewith can be prepared by known means such as concentration, concentration under reduced pressure, distillation, fractional distillation, phase transfer,
It can be isolated and purified by solvent extraction, crystallization, recrystallization, chromatography and the like.

When the compound of formula (I) is obtained in a free form, a salt can be formed by a usual method. In addition, the compound of the formula (I), a salt thereof, or a stereoisomer thereof exhibits a cytokine production inhibitory action either alone or in the form of a mixture. In particular, the stereoisomer (S) form has a stronger cytokine production inhibitory action than the stereoisomer (R) form.

Of the compounds of the formula (I) or salts thereof, the compounds of the formula (I ″) or salts thereof can be prepared by the following [A] or [B] according to the above-mentioned production methods [1] to [3]. It can be produced by the production method described.

[A] Formula (II):

[Chemical 28] [Wherein X ¹ , X ² , X ³ and X ⁴ are as defined in the above formula (I ″) and Hal is a halogen atom], and a compound represented by the formula (III ′ ):

[Chemical 29] [Wherein Y ′, n ′, Z, R ¹ and R ² are as defined in the above formula (I ″)] and reacted with a compound represented by the formula (I ″) A method for producing the compound or the salt thereof. The production method [A] is based on the production method [1], and the reaction conditions of the production method [1] can be applied.

[B] (1) The compound of the above formula (II) and the compound of the formula (III'-1):

[Chemical 30] [Wherein Y ′ and n ′ are as defined in the above formula (I ″)] to react with a compound of the formula (I′-3):

[Chemical 31] [Wherein X ¹ , X ² , X ³ and X ⁴ are as defined in the above formula (I ″) and Y ′ and n ′ are as described above] First step of manufacturing and
(2) The compound of the formula (I′-3) obtained in the first step and the compound of the formula (V ′): Hal-OCR ¹ R ² —COZ (in the formula, Hal
Is a halogen atom, and R ¹ , R ² and Z are as defined in the above formula (I ″)) to give a compound of the above formula (I ″) A method for producing the compound or a salt thereof, which comprises the second step of obtaining The first step of the manufacturing method [B] is
This is based on the above-mentioned production method [1], and the reaction conditions of the production method [1] can be applied. The second step of the production method [B] is in accordance with the production method [2], and the reaction conditions of the production method [2] can be applied.

The compound of formula (I) is usually used in the form of a general pharmaceutical preparation (for example, the method defined in the 12th revision Japanese Pharmacopoeia). This pharmaceutical preparation contains commonly used fillers, fillers, binders, moisturizers, disintegrants, surface-active agents,
It is prepared using a diluent such as a lubricant or an excipient.
Various forms of the pharmaceutical preparation can be selected according to the therapeutic purpose, and tablets, pills, powders, powders, granules, capsules, suppositories, solutions, suspensions, emulsions, injections (solutions, suspensions) etc),
Spray, aerosol, cream, ointment, lotion,
Examples include transdermal agents (patches, matrix agents, tapes) and the like.

In the case of molding into tablets, those known in the art can be widely used as carriers, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and the like. Excipient, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose,
Binders such as potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, etc. Disintegrants, sucrose, stearin, cocoa butter, disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, glycerin, moisturizers such as starch, starch, lactose, kaolin,
Examples thereof include adsorbents such as bentonite and colloidal silicic acid, refined talc, stearates, boric acid powders, and lubricants such as polyethylene glycol. Further, the tablet may be a tablet coated with a usual coating, if necessary, such as a sugar-coated tablet, a gelatin-coated tablet, an enteric-coated tablet, a film-coated tablet, a double tablet, or a multi-layer tablet.

In the case of molding in the form of pills, those conventionally known in this field can be widely used as carriers, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like, Arabic. Examples thereof include rubber powder, tragacanth powder, a binder such as gelatin and ethanol, a disintegrating agent such as laminaranthantene, and the like.

In the case of molding in the form of suppositories, conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, and semisynthetic glycerides. it can.

When prepared as an injection, a liquid preparation,
Emulsions and suspensions are preferably sterilized and isotonic with blood, and when molding these solutions, emulsions and suspensions, all diluents commonly used in this field are used. Examples thereof include water, aqueous lactic acid solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin for preparing an isotonic solution may be contained in the pharmaceutical preparation, and a usual solubilizing agent, buffer, soothing agent, etc. may be added. May be. If necessary, coloring agents, preservatives, fragrances, flavors,
A sweetener and other pharmaceuticals may be included in the pharmaceutical preparation.

The amount of the compound of formula (I) is not particularly limited and can be appropriately selected within a wide range, but it is usually 1 to 70% by weight, preferably 5 to 50% by weight in the whole composition.

The method of administration of the compound of formula (I) is not particularly limited, and various dosage forms, patient's age, sex and other conditions,
It is administered orally or parenterally by a method depending on the degree of disease and the like. For example, tablets when administered orally,
Pills, liquids, suspensions, emulsions, granules, capsules and the like are mentioned as desirable embodiments. Parenterally, it can be administered in the form of topical administration, injection, transdermal agent, nasal agent, pulmonary agent, suppository, eye drop and the like. In the case of an injection, it is intravenously administered alone or mixed with a normal replacement fluid such as glucose and amino acid, and further intramuscularly alone if necessary,
It is preferably administered intradermally, subcutaneously or intraperitoneally. In the case of a suppository, it is desirable that it be administered rectally.

The dose of the compound of the formula (I) is appropriately selected depending on the usage, the age of the patient, the sex and other conditions, the degree of the disease, etc., but is usually about 0.05 per 1 kg of body weight per day.
The dose is preferably about 50 mg and can be administered once or in several divided doses. Further, it is desirable that the dosage unit form contain 1 to 1000 mg of the active ingredient.

[0062]

EXAMPLES Examples according to the present invention will be described below, but the present invention is not limited thereto.

<Synthesis Example 1> α- [4- (6-chloro-4-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid n-butyl ester (compound
No.32) (1) 0.5 mol / 4 in 28 ml of ethanol solution of potassium hydroxide
-Mercaptophenol 1.75 g was added at room temperature. The mixture was heated to 50-60 ° C and stirred for 20 minutes before 2,6-dichloro-4
-3.0 g of trifluoromethylpyridine was added. Then 4
After heating under reflux for 5 minutes, cool to room temperature, and cool the reaction solution to 200
The separated oil was extracted with 100 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 4: 1 distillation) to give 4- (6-chloro-4-trifluoromethyl-2-pyridylthio) phenol having a melting point of 173-174 ° C (compound No.288) 3.55g
Got

(2) 4- (6-chloro-4-trifluoromethyl-2-pyridylthio) phenol obtained in the above (1) (compound N
o.288) 2.00 g, α-bromopropionic acid n-butyl ester 1.51 g, anhydrous potassium carbonate 0.99 g and methyl ethyl ketone 20 ml were mixed and reacted under heating and reflux for 7 hours. After the reaction was completed, after cooling, it was poured into 100 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate,
The solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 distillation), and α- [4- (6-chloro-4-trifluoromethyl-2-pyridylthio) was obtained as an objective oily substance. ) Phenoxy] propionic acid n-butyl ester (Compound No. 32) 1.76
got g.

<Synthesis Example 2> Synthesis of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenylacetic acid methyl ester (Compound No. 10) (1) 4- 17.1 g mercaptophenol, 15.3 g sodium methylate (28% methanol solution) and 100 m methanol solution
After mixing L and stirring for 2 hours, 10.0 g of 2,3-dichloro-5-trifluoromethylpyridine was added. After stirring for 45 minutes at room temperature, the reaction solution was poured into 400 ml of water, the separated oil was extracted with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a melting point of 123-124.
20.5 g of 4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenol (Compound No. 278) at 0 ° C was obtained.

(2) 4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenol obtained in (1) above (compound N
o.278) 1.00 g, α-bromophenylacetic acid methyl ester
0.90 g, anhydrous potassium carbonate 0.55 g and methyl isobutyl ketone 10 ml were mixed, and the mixture was reacted for 2 hours at 100 ° C. under heating. After completion of the reaction, the reaction mixture was cooled and then poured into 50 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 9).
5: 5 distillate), and the target product α- with a melting point of 73-74 ° C
[4- (3-chloro-5-trifluoromethyl-2-pyridylthio)
Phenoxy] -α-phenylacetic acid methyl ester (compound
No. 10) 0.91 g was obtained.

<Synthesis Example 3> Synthesis of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenylacetic acid (Compound No. 11) α- [4- (3 After mixing 0.40 g of -chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenylacetic acid methyl ester (Compound No. 10) and 6 ml of 1,4 dioxane, 1N-N
4 ml of aqueous aOH solution was added. After stirring for 90 minutes at room temperature, the reaction mixture was poured into 400 ml of water, acidified with 6N-hydrochloric acid, and extracted with 50 ml of ethyl acetate. After drying the solution over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure to give a melting point.
Α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenylacetic acid at 91-93 ℃ (Compound No.
11) 0.27 g was obtained.

<Synthesis Example 4> Synthesis of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenoxyacetic acid ethyl ester (Compound No. 19) (1) 4- (3-Chloro-5-trifluoromethyl-2-pyridylthio) phenol (Compound No. 278) 10.0 g, α-bromoacetic acid ethyl ester 6.6 g, anhydrous potassium carbonate 5.5 g and methyl isobutyl ketone 100 ml are mixed and mixed for 3 hours. The reaction was carried out under heating at 100 ° C. After the reaction is complete, cool the
It was poured into 0 ml, extracted with 200 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (hexane:
Ethyl acetate = 95: 5 distillate), α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-acetic acid ethyl ester (compound No.1
5) 6.6g was obtained.

(2) α- [4- (3-chloro-5-obtained in the above (1)
Trifluoromethyl-2-pyridylthio) phenoxy] acetic acid ethyl ester (Compound No. 15) 1.0 g, bromine 0.4 g, AI
0.01 g of BN and 20 ml of carbon tetrachloride were mixed and heated under reflux for 2 hours while irradiating with light. After completion of the reaction, after cooling, it was poured into 100 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an oily α- [4- (3-chloro- 5-trifluoromethyl-2-
0.88 g of a crude product of pyridylthio) phenoxy] -α-bromoacetic acid ethyl ester was obtained.

(3) α- [4- (3-chloro-5-, obtained in (4) above.
Trifluoromethyl-2-pyridylthio) phenoxy] -α-
0.20 g of crude bromoacetic acid ethyl ester, phenol
0.04 g, 0.06 g of anhydrous potassium carbonate and 5 ml of methyl isobutyl ketone were mixed and allowed to react for 4 hours under heating at 100 ° C. After completion of the reaction, the reaction mixture was cooled and then poured into 50 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
9: 1 distillation) to obtain the desired product, oily α- [4- (3-
Chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenoxyacetic acid ethyl ester (Compound No. 1
9) 0.09 g was obtained.

<Synthesis Example 5> Synthesis of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenoxyacetic acid (Compound No. 20) α- [4- (3 After mixing 0.07 g of -chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenoxyacetic acid ethyl ester (Compound No. 19) and 1 ml of 1,4 dioxane, 1N
-1 ml of aqueous NaOH solution was added. After stirring for 90 minutes at room temperature, the reaction solution was poured into 50 ml of water, acidified with 6N-hydrochloric acid, and then extracted with 50 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -α-phenoxy having a melting point of 103 ° C. Acetic acid (Compound N
o.20) 0.07 g was obtained.

<Synthesis Example 6> Synthesis of N-4-chlorophenyl-α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid amide (Compound No. 54) (1) 4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenol (Compound No. 278) 6.4 g, α-bromopropionic acid ethyl ester 4.6 g, anhydrous potassium carbonate 3.5 g and methyl isobutyl ketone 70 ml are mixed. The mixture was reacted for 5 hours at 100 ° C. under heating. After completion of the reaction, the reaction mixture was cooled, poured into 300 ml of cold water, extracted with 150 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7 distillate) to give the desired product, oily α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio). 6.3 g of phenoxy] propionic acid ethyl ester (Compound No. 21) was obtained.

(2) 6.0 g and 1 of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 21) obtained in (1) After mixing 30 ml of 4,4 dioxane, 30 ml of 1N-NaOH aqueous solution was added. After stirring for 100 minutes at room temperature, 400 ml of water was added to the reaction mixture.
The mixture was poured into a flask, adjusted to be acidic with 6N-hydrochloric acid, and then extracted with 100 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give α- [4
5.0 g of-(3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 41) was obtained.

(3) 3.0 g of α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 41) obtained in (2) and 8.0 g of thionyl chloride After stirring for 2 hours at room temperature, unreacted thionyl chloride was distilled off under reduced pressure to give oily crude α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid chloride. 3.2 g of the product was obtained.

(4) After mixing 0.16 g of 4-chloroaniline and 20 ml of tetrahydrofuran, α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid obtained in (3) Chloride 0.50 g was added dropwise, and the mixture was stirred at room temperature for 2 hours. Pour the reaction mixture into 50 ml of water and add 50 ml of ethyl acetate.
It was extracted with. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the concentrated residue (hexane: ethyl acetate = 1: 1)
The desired product, N-4-chlorophenyl-α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid amide (compound N
o.54) 0.31 g was obtained.

<Synthesis Example 7> Synthesis of (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 120) (1) 4 -(3-Chloro-5-trifluoromethyl-2-pyridylthio) phenol (Compound No. 278) 2.8 g, (R)-(+)-α-bromopropionic acid ethyl ester 1.7 g, anhydrous potassium carbonate
1.9 g and 30 ml of methyl isobutyl ketone were mixed and reacted at 100 ° C. for 5 hours under heating. After completion of the reaction, the reaction mixture was cooled, poured into 200 ml of cold water, extracted with 100 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue is purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7 distillation),
As a result, 1.6 g of an oily (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 120) was obtained.

<Synthesis Example 8> Synthesis of (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 121) Obtained in Synthesis Example 7. (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 120) (1.0 g) and 1,4 dioxane (10 ml) were mixed together, and then mixed with 1N. -Add 5 ml of NaOH aqueous solution. After stirring for 4 hours at room temperature, the reaction mixture was poured into 100 ml of water, acidified with 6N-hydrochloric acid, and extracted with 50 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give (S) -α- [4- (3- (3-
0.57 g of chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 121) was obtained.

<Synthesis Example 9> Synthesis of (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 118) (1) 4 2.8 g of-(3-chloro-5-trifluoromethyl-2-pyridylthio) phenol (Compound No. 278), 1.7 g of (S)-(-)-α-bromopropionic acid ethyl ester, 1.9 g of anhydrous potassium carbonate and Mix 30 ml of methyl isobutyl ketone,
The reaction was performed under heating at 100 ° C for a time. After completion of the reaction, the reaction mixture was cooled, poured into 200 ml of cold water, extracted with 100 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 93: 7 distillation), and the desired product, oily (R) -α- [4- (3-chloro-5-trifluoromethyl-), was obtained. 2-pyridylthio) phenoxy] propionic acid ethyl ester (Compound No. 118) (1.9 g) was obtained.

<Synthesis Example 10> Synthesis of (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 119) Obtained in Synthesis Example 9. After mixing 1.2 g of (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid ethyl compound (Compound No. 118) and 10 ml of 1,4 dioxane, 1N -Add 5 ml of NaOH aqueous solution. After stirring for 4 hours at room temperature, the reaction mixture was poured into 100 ml of water, acidified with 6N-hydrochloric acid, and extracted with 50 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give (R) -α- [4- (3- (3-
0.92 g of chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 119) was obtained.

<Synthesis Example 11> of N-3-isoxazoyl- (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid amide (Compound No. 125) Synthesis (1) 0.38 g of (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 121) obtained in Synthesis Example 8 and thionyl chloride After mixing 3 g and stirring at room temperature for 2 hours, unreacted thionyl chloride was distilled off under reduced pressure to obtain oily (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy]. 0.37 g of crude propionyl chloride was obtained.

(2) Obtained in (1) after mixing 0.09 g of 3-aminoisoxazole and 10 ml of tetrahydrofuran.
2 ml of a tetrahydrofuran solution containing 0.37 g of (S) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionyl chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 65: 35 distillation) and the desired product, N-3-isoxazoyl- (S) -α- [4- ( 3-chloro-5-trifluoromethyl-
0.31 g of 2-pyridylthio) phenoxy] propionic acid amide (Compound No. 125) was obtained.

<Synthesis Example 12> N-3-isoxazoyl- (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid amide (Compound No. 124) Synthesis (1) 0.38 g of (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionic acid (Compound No. 119) obtained in Synthesis Example 10 and thionyl chloride After mixing 3 g and stirring at room temperature for 2 hours, unreacted thionyl chloride was distilled off under reduced pressure to obtain oily (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy]. 0.39 g of a crude product of propionic acid chloride was obtained.

(2) Obtained in (1) after mixing 0.09 g of 3-aminoisoxazole and 10 ml of tetrahydrofuran.
2 ml of a tetrahydrofuran solution containing 0.39 g of (R) -α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] propionyl chloride was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was poured into 50 ml of water and extracted with 50 ml of ethyl acetate. The solution was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 65: 35 distillate), and the desired product, N-3-isoxazoyl- (R) -α- [4- ( 3-chloro-5-trifluoromethyl-
0.29 g of 2-pyridylthio) phenoxy] propionic acid amide (Compound No. 124) was obtained.

<Synthesis Example 13> Synthesis of 2- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -propionitrile (Compound No. 301) 4- (3-chloro-5 2.3 g of -trifluoromethyl-2-pyridylthio) phenol (Compound No. 278), 1.0 g of 2-bromopropionitrile, 1.6 g of anhydrous potassium carbonate and 20 ml of methyl isobutyl ketone are mixed and heated at 100 ° C for 3 hours. It was made to react with. After completion of the reaction, the reaction mixture was cooled, poured into 100 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 92: 8 distillation), and 2- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) having a melting point of 79-80 ° C. 1.6 g of phenoxy] -propionitrile (Compound No. 301) was obtained.

<Synthesis Example 14> 5- (1- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxyethyl])-1H-tetrazole (Compound No.
302) Synthesis of 2- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) phenoxy] -propionitrile (Compound No. 301) obtained in Synthesis Example 13 (0.6 g), sodium azide 0.11 g, ammonium chloride 0.09 g and dimethylformamide 10 ml
Were mixed and reacted at 120 ° C. for one day under heating. After completion of the reaction, the reaction mixture was cooled and then poured into 50 ml of cold water, extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 5 distillation), and 5- (1- [4- (3-chloro-5-trifluoromethyl-2) having a melting point of 171-174 ° C was purified. -Pyridylthio) phenoxyethyl])-1
0.26 g of H-tetrazole (Compound No. 302) was obtained.

<Synthesis Example 15> α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) -3,5-difluorophenoxy] propionic acid (Compound N
O.207) (1) 3,5-difluoro-4-mercaptophenol (melting point 57-5 in 0.55 mol / potassium hydroxide ethanol solution 6.15 ml)
(8 ° C) 499 mg was added at room temperature. The mixture was heated to 50-60 ° C. and after stirring for 20 minutes, 665 mg of 2,3-dichloro-5-trifluoromethylpyridine was added. After heating and refluxing for 100 minutes, cool to room temperature, pour the reaction solution into 30 ml of cold water,
The precipitated crystals are collected by filtration, washed with water, dried, and have a melting point of 139 to 142 ° C.
4- (3-chloro-5-trifluoromethyl-2-pyridylthio)
951 mg of -3,5-difluorophenol (Compound No. 327) was obtained.

(2) 0.90 g of 4- (3-chloro-5-trifluoromethyl-2-pyridylthio) -3,5-difluorophenol (Compound No.327) obtained in (1) above, α-bromo 0.48 g of propionic acid ethyl ester, 0.36 g of anhydrous potassium carbonate and 10 ml of methyl ethyl ketone were mixed and reacted under heating reflux for 8 hours. After completion of the reaction, the mixture was cooled, poured into 30 ml of cold water, extracted with 100 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 distillation) to give an oily substance α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) -3, 5-Difluorophenoxy] propionic acid ethyl ester (Compound N
o.203) 0.86 g was obtained.

(3) α- [4- (3-chloro-5-obtained in (2) above]
Trifluoromethyl-2-pyridylthio) -3,5-difluorophenoxy] propionic acid ethyl ester (Compound No. 20
3) To a mixed solution of 482 mg and 1,4-dioxane 5 ml, 8N-Na
A mixture of 348 mg of OH aqueous solution and 4 ml of water was added. Then, after stirring at room temperature for 5 hours, the reaction solution was poured into 40 ml of water, and 1.5N-
The mixture was adjusted to acidic with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to obtain the desired product, α- [4- (3-chloro-5
462 mg of -trifluoromethyl-2-pyridylthio) -3,5-difluorophenoxy] propionic acid (Compound No. 207) was obtained.

<Synthesis Example 16> α- [4- (3-chloro-5-trifluoromethyl-2-pyridylthio) -2,3-difluorophenoxy] propionic acid (Compound N
o.206) (1) 0.5mol / 8.5ml of ethanol solution of potassium hydroxide
2,3-difluoro-4-mercaptophenol (melting point 39-41
(.Degree. C.) 0.694 g was added at room temperature. The mixture was heated to 50-60 ° C. and stirred for 20 minutes, after which 0.924 g of 2,3-dichloro-5-trifluoromethylpyridine was added. After that, the mixture was heated under reflux for 90 minutes, cooled to room temperature, poured into 40 ml of cold water,
The precipitated crystals are collected by filtration, washed with water, dried, and have a melting point of 125-128 ° C.
4- (3-chloro-5-trifluoromethyl-2-pyridylthio)
1.232 g of -2,3-difluorophenol (Compound No. 328) was obtained.

(2) 0.60 g of 4- (3-chloro-5-trifluoromethyl-2-pyridylthio) -2,3-difluorophenol (Compound No. 328) obtained in the above (1), α-bromo 0.32 g of propionic acid ethyl ester, 0.24 g of anhydrous potassium carbonate and 6 ml of methyl ethyl ketone were mixed and reacted under heating and reflux for 8 hours. After completion of the reaction, the mixture was cooled, poured into 30 ml of cold water, extracted with 100 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was purified by silica gel column chromatography (hexane: ethyl acetate = 9: 1 distillate) to give α- [4- (3-chloro) as an oily substance.
-5-Trifluoromethyl-2-pyridylthio) -2,3-difluorophenoxy] propionic acid ethyl ester (Compound No.
204) 0.59 g was obtained.

(3) α- [4- (3-chloro-5-, obtained in (2) above.
Trifluoromethyl-2-pyridylthio) -2,3-difluorophenoxy] propionic acid ethyl ester (Compound No. 20
4) 8N-Na was added to a mixed solution of 330 mg and 1,4-dioxane 4 ml.
A mixed solution of 238 mg of an OH aqueous solution and 3 ml of water was added. Then, after stirring at room temperature for 5 hours, the reaction solution was poured into 40 ml of water, and 1.5N-
After adjusting to acidity with hydrochloric acid, the separated oil was extracted with 50 ml of ethyl acetate, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The concentrated residue was crystallized with hexane and dichloromethane, and the crystals were collected by filtration, washed with hexane and dried to give the desired product, α- [4- (3-chloro-5-
217 mg of trifluoromethyl-2-pyridylthio) -2,3-difluorophenoxy] propionic acid (Compound No. 206) was obtained.

Synthesis Examples 1 to 16 and the above-mentioned production method [1]
~ Compounds of formula (I) produced by a method according to [3] are shown in Tables 1 to 19.

[0093]

[Table 1]

[0094]

[Table 2]

[0095]

[Table 3]

[0096]

[Table 4]

[0097]

[Table 5]

[0098]

[Table 6]

[0099]

[Table 7]

[0100]

[Table 8]

[0101]

[Table 9]

[0102]

[Table 10]

[0103]

[Table 11]

[0104]

[Table 12]

[0105]

[Table 13]

[0106]

[Table 14]

[0107]

[Table 15]

[0108]

[Table 16]

[0109]

[Table 17]

[0110]

[Table 18]

[0111]

[Table 19]

Test Example 1 (Evaluation Test of Cytokine Production Inhibitory Action) Mouse spleen cells were treated with anti-mouse CD3 antibody and IL-2 to induce cytokine production. A test compound was added to this cytokine production system and its inhibitory effect was evaluated. That is, anti-mouse CD3 antibody prepared at 10 to 20 μg / ml with borate buffered saline solution (pH 8.5) was dispensed into a 96-well cell culture plate at 50 μl / well,
It was left at 4 ° C. for 18 hours. After removing the unreacted solution and washing once with Hanks' buffer, IL-2 prepared at 10 ng / ml with RPMI solution containing 10% fetal calf serum (FCS) was added to 50.
μl / well was dispensed. In the negative control group, only the solution was treated except for anti-CD3 antibody and IL-2. Subsequently, a test compound diluent (concentration 100 ppm unless otherwise specified) was dispensed at 50 μl / well, and 1 × 10 1 was prepared from the spleen of Balb / c mice (female, 7 to 10 weeks old). ⁷ /
ml cell suspension was dispensed at 100 μl / well. Culture in an incubator (37 ° C, 5% carbon dioxide) 40
After 48 hours, the culture supernatant was collected and the amount of cytokine produced was measured by the ELISA method.

Interleukin 5 (IL-5) was measured as a typical Th2 type cytokine, and interferon γ (IFN-γ) was measured as a typical Th1 type cytokine by the following methods. That is, the quantification of IL-5 was performed by the following ELISA method. First, rat anti-mouse IL-5 antibody (Endogen, Code No. MM-550C) was used as a primary antibody in a carbonate buffer solution (p
H9.5) to 1 μg / ml and 50 μl / well 9
6-well plate (IWAKI, Code No. 386
0-096) and coated overnight (16-24 hours) at 4 ° C. Thereafter, the plate was blocked with phosphate buffered saline (pH 7.2) containing 10% FCS (blocking buffer) at 37 ° C. for 2 hours (250 μl).
/hole). The plate is PBS containing 0.05% Tween 20 (Nacalai Tesque, Code No. 281-51).
The cells were washed 4 times with (washing buffer), 50 μl / well of culture supernatant diluted solution was seeded, and incubated at room temperature for 1 hour. Recombinant mouse I for preparing calibration curve
L-5 (R & D Systems, Code No. 405-M
L) was used. Plate 4 with wash buffer
After washing twice, a biotin-labeled rat anti-mouse IL-5 antibody (Pharmingen, Code No. 18) was used as a secondary antibody.
(062D) was diluted with blocking buffer containing 0.05% Tween 20 to 0.5 μg / ml (50 μl / well), and incubated at room temperature for 1 hour.
After washing the plate 4 times with a washing buffer, streptavidin-labeled peroxidase (prozyme, CodeN
o. CJ30H001) diluted 800-fold with 0.05% Tween20-containing blocking buffer was added (50 μl / well), and the mixture was reacted at room temperature for 15 minutes. The plate was washed 4 times with a washing buffer, 100 μl / well of TNB substrate solution (Sigma, Code No. T-8665) was added, and color was developed for 10 to 20 minutes. 1M sulfuric acid solution 10
After stopping the reaction by adding 0 μl / well, the absorbance was measured using a microplate reader (Spectramax, Wako Pure Chemical Industries, Ltd.) (wavelength 450 nm). For quantification of IFN-γ, rat anti-mouse IFN-γ antibody (Pharmingen, Code No. 18181D) was used as the primary antibody, and biotin-labeled rat anti-mouse IFN-γ antibody (Pharmingen, Code No. 18112D) was used as the secondary antibody. ) Was used in the same manner as the IL-5 measurement. Recombinant mouse IFN-γ (Genzyme, Co
deNo. 3485) was used. The experiment was performed in duplicate, and the average value of cytokine production was determined. The inhibition ratio (%) was calculated from the average value by the following formula, and the results are shown in Tables 20 to 31. In addition, No. in the table represents the compound No., and in the case where the inhibition rate when the test compound concentration was not 100 ppm was described, the test compound concentration is shown in parentheses after the inhibition rate. Inhibition rate (%) = {1- (TN) / (PN)} × 100 where T: average value of test compound treated group, N: average value of negative control group, P: positive control It represents the average value of the group.

[0114]

[Table 20]

[0115]

[Table 21]

[0116]

[Table 22]

[0117]

[Table 23]

[0118]

[Table 24]

[0119]

[Table 25]

[0120]

[Table 26]

[0121]

[Table 27]

[0122]

[Table 28]

[0123]

[Table 29]

[0124]

[Table 30]

[0125]

[Table 31]

Test Example 2 (Drug efficacy evaluation test in antigen (OVA) -induced IL-5 production in mouse) BALB / c mouse (purchased from Japan SLC, male,
Alum adjuvant (aluminum potassium sulfate, No. 017 manufactured by Nacalai Tesque, Inc.) under the skin of 5 to 8 weeks old
27) Ovalbumin (OVA) prepared with 2 mg
(SIGMA No. A-5503) 0.2 mg / animal was immunized. Two weeks later, 0.2 μl of 5 μg / ml OVA physiological saline was intraperitoneally administered to the mouse to induce interleukin-5 (IL-5) production. After 6 hours, the mouse was euthanized with carbon dioxide, 2 ml of 0.01 M phosphate buffered saline (PBS) having a pH of 7.2 was intraperitoneally injected, and the abdomen was well rubbed, and then the intraperitoneal fluid was collected. did. Cool the collected liquid, small centrifuge 10,000 rpm, 4
After centrifugation at ℃ for 10 minutes, the supernatant is collected and measured at -80 ℃
It was frozen and stored in. The amount of IL-5 produced is the same as the above E
It was measured by the LISA method. The test compound was subcutaneously or orally administered 1 hour before the intraperitoneal administration of OVA. The efficacy evaluation was represented by the inhibition rate (%) compared with the solvent control. The results are shown in Table 32. In addition, No. in the table. Represents the compound number.

[0127]

[Table 32]

Test Example 3 (Drug efficacy evaluation test for antigen (OVA) -induced eosinophil infiltration in mice) BALB / c mouse (purchased from Japan SLC, male,
Alum adjuvant (aluminum hydroxide gel, LSL No. LG-6000) 2 m under the skin of 5-8 weeks old)
Ovalbumin (OVA) (SIGM
A company No. A-5503) 10 μg / animal was immunized.
Two weeks after that, OVA was subcutaneously immunized again in the same manner. Twelve days after the second immunization, 0.2 ml of 5 μg / ml OVA physiological saline was intraperitoneally administered to the mice to induce eosinophil infiltration. After a further 24 hours, the mouse was euthanized with carbon dioxide gas, and 0.01 M phosphate buffered saline (pH 7.2) (P
(BS) 2 ml is injected into the abdominal cavity and the abdomen is rubbed well,
The intraperitoneal fluid was collected. The collected solution was stained with Hinkelman's solution, and the number of eosinophils was counted under a microscope. The test compound was 300 mg / kg 1 hour before intraperitoneal administration of OVA.
It was administered subcutaneously. The efficacy evaluation was expressed by the inhibition rate (%) compared with the solvent control. Table 33 shows the drug efficacy evaluation results.

[0129]

[Table 33]

Test Example 4 (Antigen (OV in sensitized guinea pig)
A) Drug efficacy evaluation test in induced airway hyperresponsiveness) Hartley guinea pig (purchased from Kudo Co., Ltd., male,
After acclimation for 5 weeks (according to 5 weeks old), 0.5 ml of physiological saline containing 10 μg of OVA and 10 mg of aluminum hydroxide gel was intraperitoneally administered for sensitization. Further, 14 days later, the same antigen preparation was performed and booster administration was performed, and on the 14th to 21st days after the final sensitization, a drug efficacy evaluation test against hyperreactivity of the respiratory tract was performed. Treatment with pyrilamine (10 mg / kg, ip) 30 minutes before induction of OVA inhalation, using an ultrasonic nebulizer (NE-U12 manufactured by OMRON), 10 mg /
ml of OVA solution was exposed by inhalation for 10 minutes. Measurement of airway resistance under awakening is performed by the comprehensive respiratory function analysis system (MIPS
Pulmos-I) manufactured by the same company was used to measure the airway resistance (sRaw) of 100 breaths each before induction of OVA inhalation and once after 4 hours. The airway reactivity was measured by measuring the airway resistance and then measuring the animals with pentobarbital (50 mg / k).
g, ip), anesthesia was performed, and trachea and common jugular vein were cannulated. The tracheal cannula was connected to a quantitative ventilation system and artificial respiration was performed. Airway reactivity of acetylcholine (ACh) (2, 5, 10 and 20 μg / kg, iv at 5 minute intervals) 5 hours after OVA inhalation induction was measured as airway contraction. Airway constriction is achieved by a differential pressure transducer (Validyne, Gou) connected to the collateral passage of the tracheal cannula.
It was measured as a change in aeration pressure according to Id). Compound N
o. 63 was subcutaneously administered 300 mg / kg 1 hour before inhalation of OVA. The evaluation results of airway resistance and airway responsiveness are shown in Tables 34 and 35.

[0131]

[Table 34] **: Significantly different from pre at p <0.01 (pai
red t-test)

[0132]

[Table 35] **: p <0.01, significant difference from negative control group (S
student t-test) ##: p <0.01, significant difference from positive control group (D
unnett's multiple test)

Test Example 5 (Antigen in sensitized mouse (OVA)
Drug efficacy evaluation test in induced airway hypersensitivity reaction) BALB / c mouse (purchased from Japan SLC, male,
Alum adjuvant (aluminum potassium sulfate, No. 017 manufactured by Nacalai Tesque, Inc.) under the skin of 5 to 8 weeks old
27) Ovalbumin (OVA) prepared with 2 mg
(SIGMA No. A-5503) 0.2 mg / animal was immunized. After 14 days, the same antigen preparation was carried out and
1 mg / mouse booster was administered. Ultrasonic wave nebulizer (OM-NE1 NE-U1 for 3 days from the 14th day of final sensitization)
2), and a 20 mg / ml OVA solution 2 times once a day
Inhalation exposure was performed for 0 minutes. The measurement of airway responsiveness under awakening was performed by the respiratory function analysis system (BOXCO) in an unrestrained chamber.
WBP-SYSTEM) manufactured by the company, and 24 hours after the final OVA inhalation induction, methacholine (MCh) (3 at 8 minute intervals,
Respiratory responsiveness of 6, 12, 25 and 50 mg / ml) was evaluated by Enhanced Pause (Penh) (Am JR
espir Crit Care Med, Volume 156, 7
66-775, 1997b, Hamelmann E.
Etc. as a reference). Compound No. 207 is OV
300 mg / kg was orally administered every 1 hour before A inhalation. Table 36 shows the evaluation results of airway reactivity.

[0134]

[Table 36] Note) ***: p <0.001 is significantly different from negative control group (Studentt-test) #: p <0.05 is significantly different from positive control group (St)
unique t-test)

[0135]

INDUSTRIAL APPLICABILITY The present invention provides a cytokine production inhibitor useful as a therapeutic and / or preventive agent for diseases associated with abnormally enhanced immune function.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/4545 A61K 31/4545 31/496 31/496 31/497 31/497 A61P 7/00 A61P 7 / 00 11/02 11/02 11/06 11/06 17/06 00/00 27/14 27/14 37/06 37/06 37/08 37/08 43/00 111 43/00 111 C07D 213/64 C07D 213/64 213/70 213/70 213/75 213/75 213/80 213/80 213/85 213/85 401/12 401/12 405/12 405/12 413/12 413/12 417/12 417 / 12 // C07D 213/71 213/71 213/74 213/74 (72) Inventor Kiyoshi Tamai 2-3-1, Nishi-Shibukawa, Kusatsu City, Shiga Ishihara Sangyo Co., Ltd. Central Research Laboratory (72) Inventor Mitsuo Sano Shiga 2-3-1 Nishi-Shibukawa, Kusatsu-shi, Ishikawa In the Central Research Institute of Ishihara Sangyo Co., Ltd. (72) Inventor: Sae Pumieda 2-3-1, Nishi-Shibukawa, Kusatsu-shi, Shiga Ishihara Industrial Co., Ltd. Central Research Laboratory F-term (reference) 4C055 AA01 BA02 BA42 BA47 BA52 BB08 CA02 CA03 CA39 CA57 CA59 CB02 DA01 FA13 4C063 AA01 BB07 CC34 CC51 CC61 DD12 EE01 4C086 AA01 AA02 AA03 AA04 BC17 BC48 BC50 BC79 GA33 MA04 NA14 MA14 GA14 GA14 GA14 MA14 ZA59 ZA89 ZB08 ZB13 ZC02

Claims (17)

[Claims] 1. Formula (I): [Chemical 1] [In the formula, X¹Is a hydrogen atom, halogen atom, nitro group,
A fluoromethyl group, an alkyl group or a cyano group
R; X²Is a hydrogen atom, a trifluoromethyl group or
Is a kill group; X³Is hydrogen atom, halogen atom, trif
Luoromethyl group, alkyl group, alkoxycarbonyl
A group, a nitro group, a cyano group or a methylsulfonyl group
R; X^FourIs hydrogen atom, halogen atom, trifluoromethy
Is an alkyl group, an alkyl group or an alkoxy group; T is O,
S, SO, SO₂Or NH; Y is a halogen source
Child, optionally substituted alkyl group, optionally substituted group
Lucoxy group, nitro group, hydroxyl group, alkylsulfonyl group
A mino group, an amino group which may be substituted with an alkyl group, an alkyl group
Killcarbonylamino group, cycloalkylcarbonyl group
Mino group, alkoxycarbonylamino group, alkoxyca
Rubonylalkylamino group, hydroxycarbonyl al
Kiramino group or OA-COZ group {A is CR¹R
²Group, CR¹R²CR³R^FourGroup or CR¹R²CR³R^FourCR^Five
R⁶Group (R¹, R², R³, R ^Four, R^FiveAnd R⁶Each is German
Vertically hydrogen atom, halogen atom, optionally substituted alkyl
Group, alkoxy group, optionally substituted phenyl group,
Optionally substituted naphthyl group, optionally substituted phenoxy
Si group, optionally substituted heterocyclic group, optionally substituted heterocyclic group
Elementary ring oxy group, alkoxycarbonyl group or carboxy
Is a silyl group; or R¹And R²To form a ring with
Z) is a hydroxyl group, an alkoxy group or an alkoxy group.
Cyalkoxy group, alkenyloxy group, cycloalkoxy
Si group, acyloxymethyl group, alkyl group, alkyl group
Group, benzyloxy group, optionally substituted aryl group
Xy group, optionally substituted arylthio group, NR⁷R⁸Basis
(R⁷And R⁸Are each independently a hydrogen atom,
Optionally alkyl group, optionally substituted alkylsulfoni
Group, optionally substituted cycloalkyl group, substituted
Optionally alkenyl group, optionally substituted cycloalkenyl
Group, optionally substituted aryl group, optionally substituted
Heterocyclic group, hydroxyl group, alkoxy group or may be substituted
Is an arylsulfonyl group; or R⁷And R⁸But
Together they form a ring with or without heteroatoms.
Or NHNR⁷R⁸Group (R⁷, R⁸Is the above
Or by forming a ring with Z and A
And n is an integer of 0 to 5]
Contains a pyridine derivative or its salt as an active ingredient
Cytokine production inhibitor. 2. Formula (I ′): [In the formula, X ¹ is a hydrogen atom, a halogen atom, a nitro group, a trifluoromethyl group, an alkyl group or a cyano group; X ² is a hydrogen atom, a trifluoromethyl group or an alkyl group; and X ³ is a hydrogen atom. A halogen atom, a trifluoromethyl group, an alkyl group, an alkoxycarbonyl group, a nitro group, a cyano group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group; T is O,
S, SO or SO ₂ ; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or an alkoxy group;
R ¹ is hydrogen atom, alkyl group, haloalkyl group, optionally substituted phenyl group, pyridyl group, naphthyl group, alkoxyalkyl group, phenoxy group or pyridyloxy group; R ² is hydrogen atom, halogen atom, alkyl group , An alkoxycarbonyl group or a carboxyl group; or R ¹ and R ² may form a ring by an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an alkenyloxy group, a cycloalkoxy group, an acyloxymethyl group. , An optionally substituted aryloxy group, an optionally substituted arylthio group, NR ⁷ R ⁸
Groups (R ⁷ and R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkylsulfonyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, a substituted Optionally a heterocyclic group, a hydroxyl group, an alkoxy group or an optionally substituted arylsulfonyl group; or R ⁷ and R ⁸ together form a ring containing or not containing a hetero atom. Good) or NHNR ⁷ R ⁸ groups (R ⁷ and R ⁸ are as described above)
And n ′ is an integer of 0 to 2] or a cytokine production inhibitor containing the salt thereof as an active ingredient. 3. Formula (I ″): embedded image [Wherein X ¹ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group; X ² is a hydrogen atom, a trifluoromethyl group or an alkyl group; X ³ is a hydrogen atom, a halogen atom, trifluoro A methyl group, an alkoxycarbonyl group, a nitro group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or An alkoxy group; R ¹ is an alkyl group, a haloalkyl group,
An optionally substituted phenyl group, a pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group; R ² is a hydrogen atom, a halogen atom, an alkoxycarbonyl group or a carboxyl group; or R ¹ and R ² may form a ring with an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxymethyl group, an optionally substituted aryloxy group, and an NR ⁷ R ⁸ group (R ⁷ and R ⁸ are respectively Independently hydrogen atom, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocyclic group, hydroxyl group, alkoxy group or optionally substituted aryl A sulfonyl group;
Or R ⁷ and R ⁸ together may form a ring with or without heteroatoms) or a NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above); n'is 0
An integer of 2] or a salt thereof as an active ingredient. 4. X ² is a hydrogen atom or a trifluoromethyl group; X ³ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkoxycarbonyl group or a nitro group; X ⁴ is a hydrogen atom, a halogen atom or A trifluoromethyl group; R ¹ is an alkyl group, a haloalkyl group, an optionally substituted phenyl group, a pyridyl group or a naphthyl group; R ² is a hydrogen atom, a halogen atom or a carboxyl group; or R ¹ and R ² may form a ring with an alkylene chain; Z is a hydroxyl group, an alkoxy group, an optionally substituted aryloxy group, NR ⁷ R ⁸
Group (R ⁷ and R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted aryl group, an optionally substituted heterocyclic group, a hydroxyl group, an alkoxy group or an optionally substituted aryl group. The cytokine production inhibitor according to claim 3, which is a sulfonyl group) or an NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above). 5. The cytokine production inhibitor according to claim 1, wherein the cytokine is a Th1 type cytokine. 6. The cytokine production inhibitor according to claim 1, wherein the cytokine is interferon γ. 7. The cytokine production inhibitor according to claim 1, wherein the cytokine is a Th2 type cytokine. 8. The cytokine production inhibitor according to claim 1, wherein the cytokine is interleukin 5. 9. A preventive or therapeutic agent for a disease associated with abnormally enhanced immune function, which comprises the compound according to claim 1 or a salt thereof. 10. The disease associated with abnormally enhanced immune function is at least one selected from urticaria, food allergy, anaphylactic shock, eosinophilia syndrome, asthma, allergic rhinitis, allergic conjunctivitis and atopic dermatitis. The preventive or therapeutic drug according to claim 9, which is an allergic disease. 11. The preventive or therapeutic drug according to claim 9, wherein the disease associated with abnormally enhanced immune function is eosinophilia syndrome or asthma. 12. Formula (I ″ -a): embedded image [Wherein X ¹ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group; X ² is a hydrogen atom, a trifluoromethyl group or an alkyl group; X ³ is a hydrogen atom, a halogen atom, trifluoro A methyl group, an alkoxycarbonyl group, a nitro group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or An alkoxy group; R ¹ is an alkyl group, a haloalkyl group,
A phenyl group, a pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group which may be substituted; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxymethyl group or an optionally substituted aryloxy group. , NR ⁷ R ⁸ group (R ⁷ and R ⁸ are each independently a hydrogen atom, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group, or an optionally substituted hetero group. Ring group, hydroxyl group,
An alkoxy group or an optionally substituted arylsulfonyl group; or R ⁷ and R ⁸ together may form a ring with or without a heteroatom) or NH
NR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above; n ′ is an integer of 0 to 2) or a salt thereof. 13. Formula (I ″): embedded image [Wherein X ¹ is a hydrogen atom, a halogen atom, a nitro group or a trifluoromethyl group; X ² is a hydrogen atom, a trifluoromethyl group or an alkyl group; X ³ is a hydrogen atom, a halogen atom, trifluoro A methyl group, an alkoxycarbonyl group, a nitro group or a methylsulfonyl group; X ⁴ is a hydrogen atom, a halogen atom, a trifluoromethyl group, an alkyl group or an alkoxy group; Y ′ is a halogen atom, a haloalkyl group, an alkyl group or An alkoxy group; R ¹ is an alkyl group, a haloalkyl group,
An optionally substituted phenyl group, a pyridyl group, a naphthyl group, an alkoxyalkyl group, a phenoxy group or a pyridyloxy group; R ² is a hydrogen atom, a halogen atom, an alkoxycarbonyl group or a carboxyl group; or R ¹ and R ² may form a ring with an alkylene chain; Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an acyloxymethyl group, an optionally substituted aryloxy group, and an NR ⁷ R ⁸ group (R ⁷ and R ⁸ are respectively Independently hydrogen atom, optionally substituted alkyl group, optionally substituted cycloalkyl group, optionally substituted aryl group, optionally substituted heterocyclic group, hydroxyl group, alkoxy group or optionally substituted aryl A sulfonyl group;
Or R ⁷ and R ⁸ together may form a ring with or without heteroatoms) or a NHNR ⁷ R ⁸ group (R ⁷ and R ⁸ are as described above); n'is 0
Is an integer of 2 to 2 (provided that X ² and X ⁴ are hydrogen atoms, R ¹ is a methyl group, R ² is a hydrogen atom, and n ′.
Is 0, Z is a hydroxyl group, an alkoxy group, an alkoxyalkoxy group, an amino group which may be substituted with an alkyl group,
2-pyridylamino group, NR-Ar group (Ar is a naphthyl group which may be substituted with a halogen atom; halogen atom, alkyl, alkylthio, alkoxy, hydroxy, monoalkylamino, dialkylamino, amino, trifluoromethyl, thioamide or nitro A benzyl group which may be substituted with; or a halogen atom, alkyl, alkylthio, alkoxy, hydroxy, monoalkylamino, dialkylamino, amino, trifluoromethyl,
Phenyl group optionally substituted with thioamide or nitro, R is a hydrogen atom or a C _1-3 alkyl group) or NR′R ″ group (R ′ is a hydrogen atom, C _1-4 alkyl group or C _{2 -3 is a} hydroxyalkyl group; R "
Is a hydrogen atom, a C _1-4 alkyl group, a C _2-3 hydroxyalkyl group or a methoxy group), (1) X ¹
Is a hydrogen atom; and X ³ is a halogen atom or a trifluoromethyl group; and (2) X ¹ is a halogen atom or a trifluoromethyl group; and X ³
Is a hydrogen atom, a halogen atom or a trifluoromethyl group}]. 14. X ¹ is a halogen atom; X ² is a hydrogen atom; X ³ is a trifluoromethyl group; X ⁴ is a hydrogen atom; Y ′ is a halogen atom; n ′ is 1
The pyridine derivative or a salt thereof according to claim 13, which is or 2. 15. X ¹ is a halogen atom; X ² is a hydrogen atom; X ³ is a trifluoromethyl group; X ⁴ is a hydrogen atom; Y ′ is a halogen atom; n ′ is 1
Or 2; R ¹ is an alkyl group; R ² is a hydrogen atom; Z is a hydroxyl group. 16. The formula (I ″) according to claim 13.
A method for producing a compound of the formula (I) or a salt thereof, comprising the formula (II): (Wherein X ¹ , X ² , X ³ and X ⁴ are as defined in claim 13 and Hal is a halogen atom) and a compound of formula (III ′): 7] (Wherein Y ′, n ′, Z, R ¹ and R ² are the same as those defined in the above 1).
(As defined in 3)), and a method for producing the above compound or a salt thereof. 17. The formula (I ″) according to claim 13.
And a salt thereof, which comprises the formula (1):
I): (Wherein X ¹ , X ² , X ³ and X ⁴ are as defined in claim 13 and Hal is a halogen atom), and a compound represented by the formula (III′-1): [Chemical 9] By reacting with a compound represented by the formula (wherein Y ′ and n ′ are as defined in claim 13): (Wherein X ¹ , X ² , X ³ , X ⁴ , Y ′ and n ′ are as described above), the compound obtained by the first step and (2) the first step A compound of formula (I′-3),
Formula (V ′): Hal—OCR ¹ R ² —COZ [in the formula, Ha
1 is a halogen atom, and R ¹ , R ² and Z are as defined in the above item 13], and a compound of the formula (I ″) is obtained. A method for producing the above compound or a salt thereof, which comprises two steps.