JP6604470B2 - Allergy suppressor, antiallergic pharmaceutical composition, and Th2 cytokine inhibitor - Google Patents

Description

  The present invention relates to an allergy inhibitor, an antiallergic pharmaceutical composition, and a Th2 cytokine inhibitor.

  In recent years, the number of allergic patients in developed countries including Japan continues to increase. The main cause of allergies is reduced contact with microorganisms and parasites, but various other factors have been reported to be involved.

  Helper T cells that regulate immune responses include Th1 cells that control cellular immunity and Th2 cells that control humoral immunity. Allergies are caused by the balance between Th1 cells and Th2 cells, Th2 cells predominating, and excessive humoral immunity. It is known that interleukins (for example, IL-4, IL-5, IL-13, etc.) which are a kind of cytokine secreted by Th2 cells themselves promote differentiation from Th0 cells to Th2 cells, There is a great potential to fundamentally improve allergic reactions by suppressing the production of interleukins.

A splenosine derivative has been reported as a compound expected to have a cytokine inhibitory effect (see, for example, Non-Patent Document 1). This derivative group has a 9-membered ring dilactone structure and suppresses the production of IL-5. Antimycin A ₂ having a structure similar to that of the sprenosine derivative group is also expected to have a cytokine suppressing effect.

Furthermore, as a novel antifungal compound, a derivative of UK-2, which is a fermentation product of a microorganism belonging to Streptobacillus, has been reported (for example, see Patent Documents 1 and 2). UK-2 has Supurenoshin derivatives and antimycin A ₂ and structure are similar, having a 9-membered ring dilactone structure.

International Publication No. 99/40081 Japanese Patent No. 3526602

Potent Inhibitors of Pro-Inflammatory Cytokine Production Produced by a Marine-Derived Bacterium.Wendy K. Strangman, Hak Cheol Kwon, David Broide, Paul R. Jensen, and William Fenical; J. Med. Chem. 2009, 52,2317-2327 .

In Non-Patent Document 1, Supurenoshin derivatives and antimycin A ₂ is to have a cytokine-suppressing effect have been suggested, has a cytotoxic, it is difficult to use as a treatment for allergy.
Patent Documents 1 and 2 describe that UK-2 derivatives have strong antibacterial activity, but no other useful effects have been reported.

  The present invention has been made in view of the above circumstances, and an object thereof is to provide an effective allergy inhibitor having low cytotoxicity.

[1] An allergy suppressor comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[In the general formula (1), ^{R 1} represents a partial岐鎖chain alkyl group having a carbon number of 1-4. R ² represents a methyl group. R ³ represents a benzyl group.

R ⁴ represents a group represented by the following general formula (3).

[In general formula (3), * represents a bonding position. Y represents a carbonyl group, —C (═O) —O—, or —O—C (═O) —. Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ each independently represent a methine group or a nitrogen atom. R ⁶ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n2 represents the number of R ⁶ and is an integer of 0 to 5. ] ]

[2] The allergy inhibitor according to [1], wherein the allergy is a type I allergy.
[3] The compound represented by the general formula (1), or a pharmaceutically acceptable salt thereof, and antiallergic pharmaceutical composition which comprises a pharmaceutically acceptable carrier, and / or diluent .
[4] A Th2 cytokine inhibitor comprising the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
[5] The Th2 cytokine inhibitor according to [4], wherein the Th2 cytokine is IL-4.

  According to the present invention, an effective therapeutic agent for allergy with low cytotoxicity can be provided.

5 is a graph showing the evaluation results of cytotoxicity of UK-2A, splenosine B and antimycin A in Test Example 2. 6 is a graph showing evaluation results of Th2 cytokine gene transcription inhibitory activity of UK-2A, splenosine B and antimycin A in Test Example 3.

[Allergy suppressant]
The allergy inhibitor of the present invention contains a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[In General Formula (1), R ^{1 to} R ⁴ represent the same meaning as described above. ]

  The present inventor has revealed for the first time that the compound represented by the general formula (1) having no methyl group at the C-4 position has low cytotoxicity and exhibits a remarkable allergy-suppressing effect. The general formula (1A) with position numbers assigned below is shown.

[In General Formula (1A), R ^{1 to} R ⁴ represent the same meaning as described above. ]

  The allergy suppressing agent of the present invention is preferably effective against type I allergy. In the present specification, “type I allergy” is also referred to as an immediate allergic reaction or an anaphylactic reaction, and is an allergic reaction in which lesions appear in 15 to 20 minutes after reacting with an antigen. It is mainly IgE class antibodies (for example, reagin) that are involved in type I allergy, and bind to Fc receptors on the surface of mast cells and basophils at the Fc portion. When the antigen enters the body again, it reacts with the IgE class antibody on the cell surface and a cross-link is formed between the antibodies. This triggers degranulation of mast cells and basophils, and the chemical mediator contained in the granules is released out of the cell. Examples of chemical mediators include histamine, serotonin, SRS-A (Slow Reacting Substance of Anaphylaxis), ECF-A (Eosinopil chemical factor of anaphylaxis), PAF (Platelet gland). These chemical mediators exhibit pharmacological actions such as increased permeability of capillaries, smooth muscle contraction, and exocrine gland stimulation to form lesions. Thus, diseases that develop due to type I allergy include anaphylactic shock, bronchial asthma, allergic rhinitis, hives, atopic dermatitis, drug allergy, and the like.

In the general formula (1), R ¹ represents a linear or branched alkyl group having 1 to 4 carbon atoms which is unsubstituted or has a substituent.

In the present specification and claims, “unsubstituted” means only a group serving as a base. Further, when there is no description of “having a substituent” and only the name of the base group is described, it means “unsubstituted” unless otherwise specified.
In the present specification, “having a substituent” means that any hydrogen atom of a base group is substituted with a group having the same or different structure from the base. Accordingly, a “substituent” is another group bonded to a base group. The number of substituents may be one, or two or more. Two or more substituents may be the same or different.

  Examples of the “substituent” include a halogen atom, a nitro group, a cyano group, a hydroxy group, a carboxyl group, an aldehyde group, a sulfonic acid group, an alkylsulfonyl group, a halogenosulfonyl group, a thiol group, an alkylthio group, an isocyanate group, and a thioisocyanate. Group, alkyl group, alkenyl group, alkynyl group, alkoxy group, alkoxycarbonyl group, alkylamidocarbonyl group, alkylcarbonylamide group, acyl group, amino group, monoalkylamino group, dialkylamino group, silyl group, monoalkylsilyl group , A dialkylsilyl group, a trialkylsilyl group, a monoalkoxysilyl group, a dialkoxysilyl group, a trialkoxysilyl group, an aryl group, and a heteroaryl group. However, the substituents other than these substituents are not limited to these substituents because the cytotoxicity can be lowered by further introducing appropriate substituents.

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

  The alkyl group, alkenyl group, and alkynyl group may be linear, branched, or cyclic (aliphatic ring group). 1-8 are preferable and, as for carbon number of these groups, 1-6 are more preferable. Examples of the alkyl group include methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t-butyl group (tert-butyl group), pentyl group, isoamyl group, hexyl group, heptyl group, An octyl group etc. are mentioned. Examples of the alkenyl group include a vinyl group, an allyl group, a 1-propenyl group, an isopropenyl group, a 2-butenyl group, a 1,3-butadienyl group, a 2-pentenyl group, and a 2-hexenyl group. Examples of the alkynyl group include ethynyl group, 1-propynyl group, 2-propynyl group, isopropynyl group, 1-butynyl group, isobutynyl group and the like.

  Alkylsulfonyl group, alkylthio group, alkoxy group, alkoxycarbonyl group, alkylamidocarbonyl group, alkylcarbonylamide group, monoalkylamino group, dialkylamino group, monoalkylsilyl group, dialkylsilyl group, trialkylsilyl group, monoalkoxysilyl Examples of the alkyl group moiety in the group, dialkoxysilyl group, and trialkoxysilyl group include the same alkyl groups as those described above. For example, as alkoxy group, methoxy group, ethoxy group, propyloxy group, isopropyloxy group, n-butyloxy group, isobutyloxy group, t-butyloxy group, pentyloxy group, isoamyloxy group, hexyloxy group, heptyloxy group And octyloxy group. Further, for example, as monoalkylamino group, methylamino group, ethylamino group, propylamino group, isopropylamino group, butylamino group, isobutylamino group, t-butylamino group, pentylamino group, hexylamino group, etc. Examples of the dialkylamino group include dimethylamino group, diethylamino group, dipropylamino group, diisopropylamino group, dibutylamino group, diisobutylamino group, dipentylamino group, dihexylamino group, ethylmethylamino group, and methylpropyl group. Examples thereof include an amino group, a butylmethylamino group, an ethylpropylamino group, and a butylethylamino group.

Examples of the aryl group include a phenyl group, a naphthyl group, an indenyl group, and a biphenyl group.
Examples of the heteroaryl group include a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a thienyl group, a furanyl group, an oxazolyl group, an isoxazolyl group, a thiazolyl group, an isothiazolyl group, and a thiadiazole group; a pyridinyl group and a pyrazinyl group Groups, 6-membered heteroaryl groups such as pyrimidinyl group, pyridazinyl group; indolyl group, isoindolyl group, indazolyl group, quinolidinyl group, quinolinyl group, isoquinolinyl group, benzofuranyl group, isobenzofuranyl group, chromenyl group, benzoxazolyl And a condensed heteroaryl group such as a benzoisoxazolyl group, a benzothiazolyl group, and a benzoisothiazolyl group.

  The alkyl group, alkenyl group, alkynyl group, aryl group, and heteroaryl group may be an unsubstituted group, and one or more hydrogen atoms may be substituted with a substituent. Examples of the substituent include a halogen atom, alkyl group, alkoxy group, nitro group, cyano group, hydroxy group, amino group, thiol group, carboxyl group, aldehyde group, sulfonic acid group, isocyanate group, thioisocyanate group, and aryl group. And heteroaryl groups.

In the above R ¹ , examples of the “C1-C4 linear or branched alkyl group” include, for example, methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, isobutyl group, t- A butyl group (tert-butyl group) etc. are mentioned. Among these, an isopropyl group or an isobutyl group is preferable.

R ² represents an unsubstituted or substituted C1-C4 linear or branched alkyl group, and examples thereof include the same as R ¹ in the general formula (1). Among these, R ² is preferably a methyl group.

R ³ represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms or a group represented by the following general formula (2).

[In general formula (2), * represents a bonding position. R ⁵ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n1 represents the number of R ⁵ and is an integer from 0 to 5. ]

"Linear or branched alkyl group having 1 to 4 carbon atoms" in R ³ is the same as R ¹ in the general formula (1) can be mentioned. Among these, R ³ is preferably an n-butyl group.

<Group represented by general formula (2)>
In the general formula (2), n1 represents the number of R ⁵ . n1 is an integer of 0 to 5, and 0 is preferable. That is, an unsubstituted benzene ring is preferable.

Examples of the “C1-C4 linear or branched alkyl group” for R ⁵ include the same as those for R ¹ in the general formula (1).

Examples of the “carboxyl group having a substituent” in R ⁵ include a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, and a t-butoxycarbonyl. Group, alkoxycarbonyl group such as n-pentyloxycarbonyl group and n-hexyloxycarbonyl group; alkenyloxycarbonyl group such as vinyloxycarbonyl group and allyloxycarbonyl group; alkynyloxy such as ethynyloxycarbonyl group and propargyloxycarbonyl group And aryloxycarbonyl groups such as carbonyl group and phenoxycarbonyl group; aralkyloxycarbonyl groups such as benzyloxycarbonyl group and the like.

Examples of the “carbamoyl group having a substituent” in R ⁵ include alkylcarbamoyl groups such as methylcarbamoyl group, ethylcarbamoyl group, dimethylcarbamoyl group and diethylcarbamoyl group; arylcarbamoyl groups such as phenylcarbamoyl group and 4-methylphenylcarbamoyl group Etc.

Examples of the “hydroxy group having a substituent” in R ⁵ include a methoxy group, an ethoxy group, an n-propoxy group, an n-butoxy group, an n-pentyloxy group, an n-hexyloxy group, an i-propoxy group, and an i-butoxy group. Group, s-butoxy group, t-butoxy group, 1-ethylpropoxy group, i-hexyloxy group, 4-methylpentoxy group, 3-methylpentoxy group, 2-methylpentoxy group, 1-methylpentoxy Group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, Alkoxy groups such as 1-ethylbutoxy group and 2-ethylbutoxy group; cycloalkenyl groups such as cyclopropylmethyloxy group and 2-cyclopentylethyloxy group Kill alkoxy group; aralkyloxy group such as benzyloxy group; chloromethoxy group, dichloromethoxy group, trichloromethoxy group, trifluoromethoxy group, 1-fluoroethoxy group, 1,1-difluoroethoxy group, 2,2,2- Haloalkoxy groups such as trifluoroethoxy group and pentafluoroethoxy group; vinyloxy group, 1-propenyloxy group, allyloxy group, 1-butenyloxy group, 2-butenyloxy group, 3-butenyloxy group, 1-pentenyloxy group, 2- Pentenyloxy group, 3-pentenyloxy group, 4-pentenyloxy group, 1-hexenyloxy group, 2-hexenyloxy group, 3-hexenyloxy group, 4-hexenyloxy group, 5-hexenyloxy group, 1-methyl- 2-propenyloxy group, 2-methyl-2 Alkenyloxy groups such as propenyloxy group, 1-methyl-2-butenyloxy group, 2-methyl-2-butenyloxy group; ethynyloxy group, propynyloxy group, propargyloxy group, 1-butynyloxy group, 2-butynyloxy group, 3 -Butynyloxy group, 1-pentynyloxy group, 2-pentynyloxy group, 3-pentynyloxy group, 4-pentynyloxy group, 1-hexynyloxy group, 1-methyl-2-propynyloxy group, 2-methyl Alkynyloxy groups such as -3-butynyloxy group, 1-methyl-2-butynyloxy group, 2-methyl-3-pentynyloxy group, 1,1-dimethyl-2-butynyloxy group; cyclopropyloxy group, cyclobutyloxy Group, cyclopentyloxy group, cyclohexyloxy group, cycloheptyl Oxy group, cyclooctyloxy group, 2-methylcyclopropyloxy group, 2-ethylcyclopropyloxy group, 2,3,3-trimethylcyclobutyloxy group, 2-methylcyclopentyloxy group, 2-ethylcyclohexyloxy group, Cycloalkyloxy groups such as 2-ethylcyclooctyloxy group, 4,4,6,6-tetramethylcyclohexyloxy group, 1,3-dibutylcyclohexyloxy group; phenyloxy group, naphthyloxy group, azulenyloxy group, indenyl Aryloxy groups such as oxy group, indanyloxy group and tetralinyloxy group; arylalkyloxy groups such as benzyloxy group, phenethyloxy group and 2-naphthylmethyloxy group; acetyloxy group, propionyloxy group, n- Propylcarbonyloxy Group, i-propylcarbonyloxy group, n-butylcarbonyloxy group, i-butylcarbonyloxy group, pentanoyloxy group, pivaloyloxy group and other acyloxy groups; methoxycarbonylmethyloxy group, 1-methoxycarbonyl-1-methylethyl Examples thereof include alkoxycarbonylalkyloxy groups such as oxy groups; alkylsilyloxy groups such as trimethylsilyloxy groups and t-butyldimethylsilyloxy groups.

Examples of the “amino group having a substituent” in R ⁵ include alkylamino groups such as a methylamino group, an ethylamino group, an n-propylamino group, an n-butylamino group, a dimethylamino group, and a diethylamino group; a phenylamino group, Monoarylamino groups such as 4-methylphenylamino group; diarylamino groups such as di1-naphthylamino group; aralkylamino groups such as benzylamino group; acylamino groups such as acetylamino group, trifluoroacetylamino group and benzoylamino group Group; alkoxycarbonylamino group such as methoxycarbonylamino group and t-butoxycarbonylamino group; formylamino group and the like.

Examples of the “mercapto group having a substituent” in R ⁵ include alkylthio groups such as methylthio group and ethylthio group; arylthio groups such as phenylthio group and 4-methylphenylthio group; acylthio groups such as acetylthio group and benzoylthio group Etc.

As the “sulfinyl group having a substituent” in R ⁵ , the methylsulfonyl group, ethylsulfonyl group, n-propylsulfonyl group, i-propylsulfonyl group, n-butylsulfonyl group, i-butylsulfonyl group, s-butyl Alkylsulfonyl groups such as sulfonyl group, t-butylsulfonyl group, n-pentylsulfonyl group, i-pentylsulfonyl group, neopentylsulfonyl group, 1-ethylpropylsulfonyl group, n-hexylsulfonyl group, i-hexylsulfonyl group; Haloalkylsulfonyl groups such as trifluoromethylsulfonyl group; arylsulfonyl groups such as phenylsulfonyl group and 4-methylphenylsulfonyl group; alkoxysulfonyl groups such as methoxysulfonyl group and ethoxysulfonyl group; N-methylsulfamoyl group; Monoaryl such as N-ethylsulfamoyl group, N, N-dimethylsulfamoyl group, sulfamoyl group such as N, N-diethylsulfamoyl group, phenylsulfamoyl group, 4-methylphenylsulfamoyl group Examples thereof include a sulfamoyl group.

Examples of the “halogen atom” in R ⁵ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

  Preferable specific examples of the group represented by the general formula (2) include a group (benzyl group) represented by the following formula (2-1).

R ⁴ represents a hydrogen atom, an alkoxycarbonyl group, a group represented by the following general formula (3), a group represented by the following general formula (4), or a group represented by the following general formula (5).

[In general formula (3), * represents a bonding position. Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —. Z ¹ , Z ² , Z ³ , Z ⁴ , and Z ⁵ each independently represent a methine group or a nitrogen atom. R ⁶ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n2 represents the number of R ⁶ and is an integer of 0 to 5. ]

[In General Formula (4), * represents a bonding position. Y represents the same meaning as in the general formula (3). Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , Z ¹⁰ , Z ¹¹ , and Z ¹² each independently represent a methine group or a nitrogen atom. R ⁷ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n3 represents the number of R ⁷ and is an integer of 0 to 7. ]

［一般式（５）中、★は結合位置を表す。Ｙは、上記一般式（３）と同じ意味を表す。Ｚ^１３、Ｚ^１４、Ｚ^１５、Ｚ^１６、Ｚ^１７、Ｚ^１８及びＺ^１９は、それぞれ独立して、メチン基又は窒素原子を表す。Ｒ^８は、それぞれ独立して、無置換の若しくは置換基を有する炭素数１〜４の直鎖状若しくは分岐鎖状のアルキル基、無置換の若しくは置換基を有するカルボキシル基、無置換の若しくは置換基を有するカルバモイル基、無置換の若しくは置換基を有するヒドロキシ基、無置換の若しくは置換基を有するアミノ基、無置換の若しくは置換基を有するメルカプト基、置換基を有するスルフィニル基、シアノ基、ニトロ基又はハロゲン原子を表す。ｎ４は、Ｒ^８の個数を表し、０〜７のいずれかの整数である。］

[In General Formula (5), * represents a bonding position. Y represents the same meaning as in the general formula (3). Z ¹³ , Z ¹⁴ , Z ¹⁵ , Z ¹⁶ , Z ¹⁷ , Z ¹⁸ and Z ¹⁹ each independently represent a methine group or a nitrogen atom. R ⁸ each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n4 represents the number of R ⁸ and is an integer of 0 to 7. ]

As the “alkoxycarbonyl group” in R ⁴ , a methoxycarbonyl group, an ethoxycarbonyl group, an n-propoxycarbonyl group, an i-propoxycarbonyl group, an n-butoxycarbonyl group, an i-butoxycarbonyl group, a t-butoxycarbonyl group, Examples include an n-pentyloxycarbonyl group and an n-hexyloxycarbonyl group. Among these, a methoxycarbonyl group and a t-butoxycarbonyl group are preferable.

<Group represented by general formula (3)>
In General Formula (3), Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —, and is preferably a carbonyl group.
Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ each independently represent a methine group or a nitrogen atom. That is, it constitutes a benzene ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, or a triazine ring. Among these, Z ⁴ or Z ⁵ is a nitrogen atom, the other is a pyridine ring which is a methine group, Z ² and Z ⁴ are nitrogen atoms, and the others are a pyrimidine ring which is a methine group, or Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ preferably constitute a benzene ring which is a methine group.

n2 represents the number of R ⁶ , is an integer of 0 to 5, and is preferably 2. When there are a plurality of R ^{6 s, they} may be the same or different, and are preferably different.

Examples of the “C1-C4 linear or branched alkyl group” for R ⁶ include the same as those for R ¹ in the general formula (1).

“Carboxyl group having a substituent”, “Carbamoyl group having a substituent”, “Hydroxy group having a substituent”, “Amino group having a substituent”, “Mercapto group having a substituent”, “Substitution” in R ⁶ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2).

Among these, R ⁶ is preferably a hydroxy group, a nitro group, an amino group, a dimethylamino group, a diethylamino group, a formylamino group, a halogen atom, a methoxy group, an ethoxy group, an acetyloxy group, or a propionyloxy group.

  Preferable specific examples of the group represented by the general formula (3) include groups represented by the following general formulas (3-1) to (3-4).

In general formula (3-1), * represents a bonding position. R ⁹ each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n5 represents the number of R ⁹ , is an integer of 0 to 5, and is preferably 2. When there are a plurality of R ^{9 s, they} may be the same or different, and are preferably different. The bonding position of R ⁹ is not particularly limited.

Examples of the “C1-C4 linear or branched alkyl group” for R ⁹ include the same as those for R ¹ in the general formula (1).

“Carboxyl group having a substituent”, “Carbamoyl group having a substituent”, “Hydroxy group having a substituent”, “Amino group having a substituent”, “Mercapto group having a substituent”, “Substitution” in R ⁹ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2). Among these, R ⁹ is preferably a hydroxy group, a nitro group, an amino group, a dimethylamino group, a diethylamino group, a formylamino group, a halogen atom, a methoxy group or an ethoxy group.

In general formula (3-2), * represents a bonding position. R ¹⁰ each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n6 represents the number of R ¹⁰ , is an integer of 0 to 4, and is preferably 2. When there are a plurality of R ^{10 s, they} may be the same or different, and are preferably different. The bonding position of R ¹⁰ is not particularly limited.

The "linear or branched alkyl group having 1 to 4 carbon atoms" of R ^10, those similar to R ¹ in the general formula (1) can be mentioned.

“Carboxyl group having substituent”, “Carbamoyl group having substituent”, “Hydroxy group having substituent”, “Amino group having substituent”, “Mercapto group having substituent”, “Substitution” in R ¹⁰ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2). Among these, R ¹⁰ is preferably a hydroxy group, a methoxy group, an ethoxy group, an acetyloxy group, or a propionyloxy group.

In general formula (3-3), * represents a bonding position. R ¹¹ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n7 represents the number of R ¹¹ , is an integer of 0 to 4, and is preferably 2. When there are a plurality of R ^{11 s, they} may be the same or different and are preferably different. The bonding position of R ¹¹ is not particularly limited.

Examples of the “C1-C4 linear or branched alkyl group” for R ¹¹ include the same as those for R ¹ in the general formula (1).

“Carboxyl group having substituent”, “Carbamoyl group having substituent”, “Hydroxy group having substituent”, “Amino group having substituent”, “Mercapto group having substituent”, “Substitution” in R ¹¹ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2). Among these, R ¹¹ is preferably a hydroxy group.

In general formula (3-4), * represents a bonding position. R ¹² each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n8 represents the number of R ¹² , is an integer of 0 to 3, and is preferably 2. When there are a plurality of R ^{12 s, they} may be the same or different, and are preferably different. The bonding position of R ¹² is not particularly limited.

Examples of the “C1-C4 linear or branched alkyl group” for R ¹² include the same groups as those for R ¹ in the general formula (1).

"Carboxyl group having a substituent" in R ^12, "carbamoyl group having a substituent", "hydroxy group which may have a substituent", "amino group having a substituent", "mercapto group having a substituent", "substituent Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2). Among these, R ¹² is preferably a hydroxy group.

  Preferable specific examples of the groups represented by the general formulas (3-1) to (3-4) include the following formulas (3-1-1), (3-1-2), (3-2-1) , (3-2-2), (3-3-1), and a group represented by (3-4-1).

<Group represented by general formula (4)>
In General Formula (4), Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —, and is preferably a carbonyl group.
In General Formula (4), Z ⁶ , Z ⁷ , Z ⁸ , Z ⁹ , Z ¹⁰ , Z ¹¹ , and Z ¹² each independently represent a methine group or a nitrogen atom. That is, it forms a naphthalene ring, a quinoline ring, an isoquinoline ring, a quinoxaline ring, a cinnoline ring, or a pteridine ring. Among these, it is preferable to constitute a quinoline ring in which Z ⁸ is a nitrogen atom.

n3 represents the number of R ⁷ , is an integer of 0 to 7, and is preferably 2.

Examples of the “C1-C4 linear or branched alkyl group” for R ⁷ include the same as those for R ¹ in the general formula (1).

“Carboxyl group having substituent”, “Carbamoyl group having substituent”, “Hydroxy group having substituent”, “Amino group having substituent”, “Mercapto group having substituent”, “Substitution” in R ⁷ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2).

  Preferable specific examples of the group represented by the general formula (4) include a group represented by the following general formula (4-1).

In general formula (4-1), * represents a bonding position. R ¹³ each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted. Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n9 represents the number of R ¹³ , is an integer of 0 to 6, and is preferably 2. When there are a plurality of R ^{13 s, they} may be the same or different, and are preferably different. The bonding position of R ¹³ is not particularly limited.

Examples of the “C1-C4 linear or branched alkyl group” for R ¹³ include those similar to R ¹ in the general formula (1).

“Carboxyl group having substituent”, “Carbamoyl group having substituent”, “Hydroxy group having substituent”, “Amino group having substituent”, “Mercapto group having substituent”, “Substitution” in R ¹³ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2).
R ¹³ is preferably a hydroxy group, a methyl group or an ethyl group.

  Preferable specific examples of the group represented by the general formula (4-1) include a group represented by the following formula (4-1-1).

<Group represented by general formula (5)>
In General Formula (5), Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —, and is preferably a carbonyl group.
In General Formula (5), Z ¹³ , Z ¹⁴ , Z ¹⁵ , Z ¹⁶ , Z ¹⁷ , Z ¹⁸ and Z ¹⁹ each independently represent a methine group or a nitrogen atom. That is, it forms a naphthalene ring, a quinoline ring, an isoquinoline ring, a quinoxaline ring, a cinnoline ring, or a pteridine ring. Among these, it is preferable to constitute a quinoxaline ring in which Z ¹⁴ and Z ¹⁹ are nitrogen atoms.

n4 represents the number of R ⁸ , is an integer from 0 to 7, and is preferably 1.

Examples of the “C1-C4 linear or branched alkyl group” for R ⁸ include the same as those for R ¹ in the general formula (1).

"Carboxyl group having a substituent" in R ^8, "carbamoyl group having a substituent", "hydroxy group which may have a substituent", "amino group having a substituent", "mercapto group having a substituent", "substituent Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2).

  Preferable examples of the group represented by the general formula (5) include a group represented by the following general formula (5-1).

In general formula (5-1), * represents a bonding position. R ¹⁴ each independently represents an unsubstituted or substituted linear or branched alkyl group having 1 to 4 carbon atoms, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom.

n10 represents the number of R ¹⁴ , is an integer of 0 to 5, and is preferably 1. When there are a plurality of R ^{14 s, they} may be the same or different, and are preferably different. The bonding position of R ¹⁴ is not particularly limited.

Examples of the “C1-C4 linear or branched alkyl group” for R ¹⁴ include the same as those for R ¹ in the general formula (1).

“Carboxyl group having substituent”, “Carbamoyl group having substituent”, “Hydroxy group having substituent”, “Amino group having substituent”, “Mercapto group having substituent”, “Substitution” in R ¹⁴ Examples of the “sulfinyl group having a group” and “halogen atom” are the same as those for R ⁵ in the general formula (2).
R ¹⁴ is preferably a hydroxy group.

  Preferable specific examples of the group represented by the general formula (5-1) include a group represented by the following formula (5-1-1).

<Specific Example of Compound Represented by General Formula (1)>
Preferable specific examples of the compound represented by the general formula (1) include a compound represented by the following general formula (1-1).

In general formula (1-1), R ¹ , R ³ , R ⁶ , n 2, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ represent the same meaning as described above. From the viewpoint of low cytotoxicity, R ¹ is preferably an isopropyl group or an isobutyl group, R ³ is preferably an n-butyl group or a benzyl group, and R ⁶ is preferably a hydroxy group, a methoxy group or a formylamino group, and n 2 Is preferably 2, Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ are pyridine rings in which Z ⁵ is a nitrogen atom and the other is a methine group, or Z ¹ , Z ² , Z ³ , Z It is preferable that ⁴ and Z ⁵ constitute a benzene ring in which all are methine groups.
A preferable relative configuration of the compound represented by the general formula (1-1) is represented by the following general formula (1-1-0).
Shown in

  Furthermore, preferred specific examples of the compound represented by the general formula (1-1) include a formula (1-1-1), a formula (1-1-2), a formula (1-1-3), or a formula ( The compound represented by 1-1-4) is mentioned.

The allergy suppressing agent of the present invention may contain a pharmaceutically acceptable salt.
In the present invention, the term “pharmaceutically acceptable” generally means an extent that causes no side effects when properly administered to a subject animal.
The salt is preferably a pharmaceutically acceptable acid addition salt or basic salt.
Acid addition salts include salts with inorganic acids such as hydrochloric acid, phosphoric acid, hydrobromic acid, sulfuric acid; acetic acid, formic acid, propionic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, citric acid, malic acid, benzoic acid Examples thereof include salts with acids, organic acids such as methanesulfonic acid and benzenesulfonic acid.
Examples of the basic salt include salts with inorganic bases such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and magnesium hydroxide; salts with organic bases such as caffeine, piperidine, trimethylamine and pyridine.

  The allergy inhibitor of the present invention may contain additives such as a buffer solution such as PBS and Tris-HCl, sodium azide, and glycerol as other components.

In the present invention, a method for treating allergy can be provided by using the allergy inhibitor of the present invention.
The subject of treatment is not limited, and examples thereof include humans and mammals other than humans, and humans are preferred.

[Method for producing compound represented by general formula (1)]
Below, an example of the manufacturing method of the compound represented by the said General formula (1) is demonstrated in detail. Reaction conditions such as temperature, catalyst, and solvent are not limited to those described below.
First, a compound represented by the general formula (6) is obtained from p-methoxybenzyl alcohol and trichloroacetonitrile (see reaction formula (A-1)). Further, the compound represented by the general formula (6) is converted into a compound represented by the general formula (8) in which the hydroxyl group is MPM protected under acidic conditions. Subsequently, the compound is reduced to a compound represented by the general formula (9) which is an aldehyde with DIBAL (diisobutylaluminum hydride) (see reaction formula (A-2)).

  Next, the compound represented by the general formula (10) and the compound represented by the formula (11) are reacted to synthesize the compound represented by the general formula (12) (reaction formula (B-1)). reference).

  Next, an asymmetric Evans aldol reaction is performed using the compound represented by the general formula (9) and the compound represented by the general formula (12) to obtain the compound represented by the general formula (13). . Hydrolysis is performed using lithium hydroxide and aqueous hydrogen peroxide to remove the asymmetric auxiliary group (see reaction formula (C-1)).

By protecting the hydroxyl group of the compound represented by the general formula (14), which is the hydroxycarboxylic acid obtained by the reaction formula (C-1), with TBS (tert-butyldimethylsilyl group, tert-butyldimethylsilyl group), It converts into the compound represented with General formula (15) which is carboxylic acid. Subsequently, the carboxyl group of the compound represented by the general formula (15) is benzyl-protected using benzyl alcohol, diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh ₃ ). Further, the MPM group is oxidatively deprotected using 2,3-dichloro-5,6-p-benzoquinone (DDQ) to obtain a compound represented by the general formula (17) which is an alcohol (reaction). (Refer Formula (D-1)).

A coupling reaction is performed using a compound represented by the general formula (17) which is an alcohol and a compound represented by the general formula (18) which is a carboxylic acid derived from L-serine. By using 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCI.HCl) and 4-dimethylaminopyridine (DMAP) as a condensing agent, it is represented by the general formula (19). A compound is obtained. Subsequently, debenzylation is performed by hydrogenation at normal pressure using Pd (OH) ₂ as a catalyst, and a compound represented by the general formula (20) as a cyclization precursor is obtained (reaction formula) (See (E-1)).

  The compound represented by the general formula (20), which is a cyclization precursor, can be closed by a lactonization reaction via an ethoxyvinyl ester. First, a compound represented by the general formula (21), which is an ethoxyvinyl ester, using a compound represented by the general formula (20), which is a cyclization precursor, using dichloro (p-cymene) ruthenium dimer and ethoxyacetylene. Convert to Subsequently, to a dichloroethane solution containing a catalytic amount of (±) -camphorsulfonic acid, a solution containing a compound represented by the general formula (21) which is an ethoxyvinyl ester is slowly added under reflux over 7 to 12 hours. The compound represented by General Formula (22), which is a 9-membered ring dilactone, can be obtained (see Reaction Formula (F-1)).

  Hydrogen fluoride-pyridine complex, pyridine, THF (tetrahydrofuran, tetrahydrofuran) is added to the compound represented by the general formula (22), which is the 9-membered dilactone obtained in the reaction formula (F-1), at 5: 3: 8. The TBS group is selectively deprotected by adding the solution mixed at the ratio of 8 to 12 hours, and the compound represented by the general formula (23) that is an alcohol can be obtained. Further, by reacting the compound represented by the general formula (24) in the presence of pyridine, the C-3 position at the base of the amino group is epimerized, and the carbonyl group is added to the hydroxy group. The compounds represented can be obtained (see reaction formulas (G-1) and (G-2)).

In addition, in order to obtain a compound represented by the general formula (1) "without epimerization, the condensing agent 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride is present in the presence of dichloromethane. (EDCl · HCl) and 4-dimethylaminopyridine (DMAP) can be used for synthesis by adding a carboxylic acid having an R ¹ group to be introduced (see Reaction Formula (G-3)).

The salt of the compound according to the present invention is obtained by bringing an inorganic acid compound, an organic acid compound, an alkali metal compound, an alkaline earth metal compound, a transition metal compound, an ammonium compound, or the like into contact with the compound represented by the general formula (1). Can be prepared.
In any reaction, after completion of the reaction, the target product can be efficiently isolated by applying a conventional post-treatment operation in organic synthetic chemistry and, if necessary, conventionally known separation and purification means.
The structure of the target product can be identified and confirmed by measurement of ¹ H-NMR spectrum, IR spectrum, mass spectrum, elemental analysis, or the like.

[Antiallergic pharmaceutical composition]
The antiallergic pharmaceutical composition of the present invention comprises the compound represented by the general formula (1), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier and / or diluent.
Acceptable carriers and diluents include excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, thickeners, flavoring agents, dissolution agents. An adjuvant, an additive, etc. are mentioned. By using one or more of these carriers and diluents, pharmaceutical compositions in the form of injections, solutions, capsules, suspensions, emulsions, syrups and the like can be prepared.

Administration of the antiallergic pharmaceutical composition of the present invention to a test animal (human or non-human mammal, preferably human) is, for example, intraarterial injection, intravenous injection, subcutaneous injection, etc. Can be carried out by methods known to those skilled in the art, such as mechanical, transbronchial, intramuscular, percutaneous, or oral.
The dosage varies depending on the body weight and age of the subject animal, the administration method, etc., but those skilled in the art can appropriately select an appropriate dosage.
The dose of the antiallergic pharmaceutical composition of the present invention varies depending on symptoms, but in the case of oral administration, generally for adults (weight 60 kg), about 0.1 to 100 mg per day, preferably It is believed that it is about 1.0 to 50 mg, more preferably about 1.0 to 20 mg.
When administered parenterally, the single dose varies depending on the symptom and administration method. For example, in the form of an injection, it is usually about 0.01 to about 0.01 per day for an adult (with a body weight of 60 kg). It may be convenient to administer 30 mg, preferably about 0.1 to 20 mg, more preferably about 0.1 to 10 mg by intravenous injection.
As the frequency of administration, it is preferable to administer once to several times per day on average.
Injections can also be prepared as non-aqueous diluents (eg, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, etc.), suspensions, or emulsions. Such sterilization of an injection can be performed by blending a filter sterilization with a filter, a bactericide, or the like. Injectables can be manufactured in the form of business preparation. That is, it can be used as a sterile solid composition by lyophilization or the like, dissolved in distilled water for injection or other solvent before use.
The antiallergic pharmaceutical composition of the present invention may be administered prophylactically to a test animal, or may be administered when allergic symptoms appear in the test animal.

Another aspect of the present invention provides a compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof for the treatment of allergy.
Another aspect of the present invention provides use of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof for producing an allergy suppressing agent.
Another aspect of the present invention is the administration of a therapeutically effective amount of the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof to a patient in need of treatment. A method of treatment is provided.
In the present invention, “suppression” of allergy refers to the release of chemical mediators released from cells triggered by an antibody-antigen (allergen) reaction that inhibits the reaction between an antigen (allergen) and an antibody. It means to alleviate diseases caused by pharmacological action such as inhibition of capillary permeability, smooth muscle contraction, exocrine gland stimulation, etc., which are inhibited or induced by the release of chemical mediators. Examples of diseases caused by allergic reactions include anaphylactic shock, bronchial asthma, allergic rhinitis, hives, atopic dermatitis, drug allergy, and the like.
In the present invention, “treatment” of allergy means that an allergy inhibitor is administered to an allergic patient to inhibit the allergic reaction and suppress the above-mentioned diseases caused by the allergic reaction. Preferably, such treatment inhibits allergic reactions and can alleviate the above mentioned diseases caused by allergic reactions. More preferably, such treatment can radically improve the allergic reaction.

[Th2 cytokine inhibitor]
The Th2 cytokine inhibitor of the present invention contains the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof. In the present specification, the “Th2 cytokine inhibitor” refers to suppressing production of IL (interleukin) -4, IL (interleukin) -5, etc., which are cytokines secreted by Th2 cells that govern humoral immunity, Means to reduce IgE antibodies and eosinophils. In the present invention, the Th2 cytokine inhibitor is preferably one that suppresses IL-4 production.
While the pharmaceutical composition of the present invention is suitably used for test animals (human or non-human mammals, preferably humans), the Th2 cytokine inhibitor of the present invention is suitably used for cultured cells.
The concentration of the Th2 cytokine inhibitor of the present invention in the medium is preferably 10 nM to 10 μM, more preferably 10 nM to 1 μM, and particularly preferably 10 nM to 0.1 μM.
A method for inducing the production of Th2 cytokines in the cells is appropriately set, and examples thereof include a method of adding IgE antibody to a dish medium in which cells are cultured.
According to the Th2 cytokine inhibitor of the present invention, production of IL-4 secreted by Th2 cells can be suppressed at a concentration in the medium of the order of μmol / L.

  EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to a following example.

[Example 1] Production of compound (UK-2A) represented by formula (1-1-1) First, a compound represented by formula (6) was obtained from p-methoxybenzyl alcohol and trichloroacetonitrile (reaction). Formula (A-1) reference). Subsequently, using the compound represented by Formula (6), it converted into the compound represented by Formula (25) which protected the hydroxyl group of L-ethyl lactate with MPM under acidic conditions. Then, it reduced to the compound represented by Formula (26) which is an aldehyde with DIBAL (diisobutylaluminum hydride, diisobutylaluminum hydride) (refer Reaction Formula (H-1)).

  Next, (R) -4-isopropyloxazolidine-2-one (compound represented by formula (11)) and acid chloride were reacted to synthesize a compound represented by formula (27) (reaction formula ( I-1)).

  Next, an asymmetric Evans aldol reaction was performed using the compound represented by the formula (26) and the compound represented by the formula (27) to obtain a compound represented by the formula (28). Furthermore, it hydrolyzed using lithium hydroxide and hydrogen peroxide water, and the asymmetric auxiliary group was removed (refer reaction formula (J-1)).

By protecting the hydroxyl group of the compound represented by the formula (29) which is the hydroxycarboxylic acid obtained by the reaction formula (J-1) with TBS (tert-butyldimethylsilyl group, tert-butyldimethylsilyl group), It converted into the compound represented by Formula (30) which is an acid. Subsequently, the carboxyl group of the compound represented by the formula (30) was benzyl-protected using benzyl alcohol, diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh ₃ ). Further, the MPM group was oxidatively deprotected using 2,3-dichloro-5,6-p-benzoquinone (DDQ) to obtain a compound represented by the formula (32) which is an alcohol (reaction formula) (See (K-1)).

A coupling reaction was performed using a compound represented by the formula (32) which is an alcohol and a compound represented by the formula (33) which is a carboxylic acid derived from L-serine. A compound represented by the formula (34) by using 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCI.HCl) and 4-dimethylaminopyridine (DMAP) as a condensing agent Got. Subsequently, debenzylation was performed by hydrogenation at normal pressure using Pd (OH) ₂ as a catalyst, and a compound represented by Formula (35) as a cyclization precursor was obtained (Reaction Formula ( L-1)).

  The compound represented by the formula (35), which is a cyclization precursor, was closed by a lactonization reaction via an ethoxyvinyl ester. First, the compound represented by Formula (35), which is a cyclization precursor, is converted into a compound represented by Formula (36), which is an ethoxy vinyl ester, using dichloro (p-cymene) ruthenium dimer and ethoxyacetylene. did. Next, a solution containing a compound represented by the formula (36), which is an ethoxyvinyl ester, is slowly added to a dichloroethane solution containing a catalytic amount of (±) -camphorsulfonic acid kept at 80 ° C. over 7 hours under reflux. In addition, a compound represented by the formula (37) which is a 9-membered ring dilactone was obtained (see reaction formula (M-1)).

  Hydrogen fluoride-pyridine complex, pyridine, THF (tetrahydrofuran, tetrahydrofuran) was added to the compound represented by the formula (37) which is a 9-membered ring dilactone obtained by the reaction formula (M-1) at a ratio of 5: 3: 8. The solution mixed at a ratio was added and stirred for 8 hours, whereby the TBS group was selectively deprotected to obtain a compound represented by the formula (38) which is an alcohol. Then, in the presence of dichloromethane, isobutyric acid is added using the condensing agents 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCl · HCl) and 4-dimethylaminopyridine (DMAP), A compound represented by the formula (39) was obtained. Furthermore, in the presence of dichloromethane, trifluoroacetic acid (TFA) was added to convert the compound to the compound represented by formula (40) from which the Boc group was eliminated (reaction formulas (N-1) and (N-2)). reference).

Next, a picolinic acid derivative was synthesized by the following steps. Using 3-hydroxypyridine as a starting material, the compound was converted to a compound represented by the formula (41), which is a methoxymethyl ether form, with potassium tert-butoxide and methoxymethyl chloride. Furthermore, the 4-position of the compound represented by the formula (41) is regioselectively lithiated with tert-butyllithium and treated with 1,2-dibromo-1,1,2,2-tetrafluoroethane. , Converted to a compound represented by formula (42) which is a 4-bromo form. Next, by treatment with sodium methoxide, a substitution reaction occurred at the 4-position, and a compound represented by the formula (43) which was a 4-methoxy form was obtained (see reaction formula (O-1)). Further, tert-butyllithium is added to a solution containing THF represented by the formula (43) as a solvent, CO ₂ gas is blown to introduce a carboxyl group, and treatment with 1M hydrochloric acid is performed. The compound represented by Formula (45) which is an acid derivative was obtained (refer Reaction formula (O-2)).

The compound represented by the formula (45) which is the obtained picolinic acid derivative and the compound represented by the formula (40) which is a 9-membered ring dilactone are subjected to a coupling reaction, whereby a formula (UK-2A) ( The compound represented by 1-1-1) was obtained (see reaction formula (P-1)).
The identification result of the compound represented by Formula (1-1-1) obtained by the above synthesis is shown below.
¹ H-NMR (CDCl ₃ , δ ppm) 11.90 (1H, s), 8.73 (1H, d, J = 6.2 Hz), 7.99 (1H, d, J = 4.8 Hz), 7 .26 (2H, t, J = 7.3 Hz), 7.19 (1H, t, J = 7.3 Hz), 7.12 (2H, d, J = 7.3 Hz), 6.87 (1H, d, J = 4.8 Hz), 5.33 (1H, br), 5.20 (1H, dd, J = 9.5, 9.5 Hz), 5.15 (1H, br q, J = 5. 5 Hz), 4.99 (1H, dq, J = 9.5, 6.2 Hz), 3.95 (3H, s), 3.68 (1H, br), 2.97 (1H, td, J = 9.5 Hz), 2.96 (1 H, dd, J = 11.7, 9.5 Hz), 2.72 (1 H, br d, J = 11.7 Hz), 2.60 (1 H, septet, J = 7 0Hz), 1.32 (3H, J = 6.2Hz), 1.23 (6H, d, J = 7.0Hz)

Reference Example 1 Production of Compound Represented by Formula (1-1-2) In the same manner as in Example 1, a compound represented by Formula (26) was obtained (Reaction Formula (A-1) and (See (H-1)). Next, the compound represented by Formula (46) and the compound represented by Formula (11) were reacted to synthesize the compound represented by Formula (47) (see Reaction Formula (I-2)). .

  Next, an asymmetric Evans aldol reaction was performed using the compound represented by Formula (26) and the compound represented by Formula (47) to obtain a compound represented by Formula (48). Furthermore, it hydrolyzed using lithium hydroxide and hydrogen peroxide water, and the asymmetric auxiliary group was removed (refer reaction formula (J-2)).

By protecting the hydroxyl group of the compound represented by the formula (49) which is the hydroxycarboxylic acid obtained by the reaction formula (J-2) with TBS (tert-butyldimethylsilyl group, tert-butyldimethylsilyl group), It converted into the compound represented by Formula (50) which is an acid. Subsequently, the carboxyl group of the compound represented by the formula (50) was benzyl-protected using benzyl alcohol, diethyl azodicarboxylate (DEAD) and triphenylphosphine (PPh ₃ ). Furthermore, the MPM group was oxidatively deprotected using 2,3-dichloro-5,6-p-benzoquinone (DDQ) to obtain a compound represented by the formula (52) which is an alcohol (reaction formula (See (K-2)).

A coupling reaction was performed using the compound represented by the formula (52) which is an alcohol and the compound represented by the formula (33) which is a carboxylic acid derived from L-serine as in Example 1. A compound represented by the formula (53) by using 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCI.HCl) and 4-dimethylaminopyridine (DMAP) as a condensing agent Got. Subsequently, debenzylation was performed by hydrogenating at normal pressure using Pd (OH) ₂ as a catalyst, and a compound represented by Formula (54) as a cyclization precursor was obtained (Reaction Formula (L -2)).

  The compound represented by the formula (54), which is a cyclization precursor, was closed by a lactonization reaction via an ethoxyvinyl ester. First, the compound represented by Formula (54), which is a cyclization precursor, is converted into a compound represented by Formula (55), which is an ethoxy vinyl ester, using dichloro (p-cymene) ruthenium dimer and ethoxyacetylene. did. Next, a solution containing a compound represented by the formula (55), which is an ethoxyvinyl ester, is slowly added to a dichloroethane solution containing a catalytic amount (±) -camphorsulfonic acid kept at 80 ° C. over 7 hours under reflux. In addition, a compound represented by the formula (56) which is a 9-membered ring dilactone was obtained (see reaction formula (M-2)).

  Hydrogen fluoride-pyridine complex, pyridine, THF (tetrahydrofuran, tetrahydrofuran) was added to the compound represented by the formula (56) which is the 9-membered ring dilactone obtained by the reaction formula (M-2) at a ratio of 5: 3: 8. The TBS group was selectively deprotected by adding a solution mixed at a ratio and stirring for 8 hours, to obtain a compound represented by the formula (57) which is an alcohol. Subsequently, isobutyric acid chloride was added in the presence of pyridine to obtain a compound represented by the formula (58) in which the C-3 position at the base of the amino group was epimerized. Furthermore, in the presence of dichloromethane, trifluoroacetic acid (TFA) was added to convert the compound to the compound represented by the formula (59) from which the Boc group was eliminated (reaction formulas (N-3) and (N-4)). reference).

A picolinic acid derivative was prepared in the same manner as in Example 1 (see reaction formulas (O-1) and (O-2)). A compound represented by the formula (45) which is a picolinic acid derivative and a compound represented by the formula (59) which is a 9-membered ring dilactone are subjected to a coupling reaction, thereby being represented by the formula (1-1-2). Was obtained (see Reaction Formula (P-2)).
The identification result of the compound represented by Formula (1-1-2) obtained by the above synthesis is shown below.
¹ H-NMR (CDCl ₃ , δ ppm) 12.42 (1H, s), 8.84 (1H, br d, J = 7.8 Hz), 7.72 (1H, d, J = 5.1 Hz), 6.06 (1H, d, J = 5.1 Hz), 5.29 (1H, t, J = 9.8 Hz), 5.43-5.27 (1H, m), 5.15-5.07 (1H, m), 4.95 (1H, dq, J = 9.8, 6.3 Hz), 3.06 (3H, s), 2.53-2.46 (1H, m), 2.26 (1H, septet, J = 6.9 Hz), 1.95-1.86 (2H, m), 1.38-1.10 (4H, m), 1.08 (3H, d, J = 6. 3 Hz), 0.99 (3 H, d, J = 7.1 Hz), 0.97 (3 H, d, J = 7.1 Hz), 0.75 (3 H, t, J = 7.1 Hz)

[Example 3] Production of compound represented by formula (1-1-3) In the same manner as in Example 1, a compound represented by formula (38) as an alcohol was obtained (reaction formula (A- 1), (H-1), (I-1), (J-1), (K-1), (L-1), (M-1) and (N-1) reference). Subsequently, isovaleric acid was added using the condensing agents 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (EDCl · HCl) and 4-dimethylaminopyridine (DMAP) in the presence of dichloromethane. Thus, a compound represented by the formula (60) was obtained. Furthermore, in the presence of dichloromethane, trifluoroacetic acid (TFA) was added to convert the compound to the compound represented by Formula (61) from which the Boc group was eliminated (see Reaction Formula (N-5)).

A picolinic acid derivative was prepared in the same manner as in Example 1 (see reaction formulas (O-1) and (O-2)). A compound represented by formula (45) which is a picolinic acid derivative and a compound represented by formula (61) which is a 9-membered ring dilactone are subjected to a coupling reaction, thereby being represented by formula (1-1-3). Was obtained (see reaction formula (P-3)).
The identification result of the compound represented by Formula (1-1-3) obtained by the above synthesis is shown below.
¹ H-NMR (CDCl ₃ , δ ppm) 12.37 (1H, s), 8.75 (1H, br d, J = 7.3 Hz), 7.67 (1H, d, J = 5.1 Hz), 7.12-7.07 (4H, m), 7.02-6.98 (1H, m), 6.03 (1H, d, J = 5.2 Hz), 5.41 (1H, t, J = 10.0 Hz), 5.16 (1 H, m), 5.03-4.96 (2 H, m), 3.14 (1 H, dd, J = 11.7, 13.4 Hz), 3.09 (3H, s), 2.93 (1H, dt, J = 3.0, 9.9 Hz), 2.78 (1H, dd, J = 3.2, 13.4 Hz), 2.01 (1H, septet, J = 6.6 Hz), 1.92-1.86 (2H, m), 1.12 (3H, d, J = 6.3 Hz), 0.797 (3H, d, J = 6.6 Hz) ), .795 (3H, d, J = 6.6Hz)

Example 4 Production of Compound Represented by Formula (1-1-4) A compound represented by Formula (40) was obtained in the same manner as in Example 1 (Reaction Formula (A-1), (See (H-1), (I-1), (J-1), (K-1), (L-1), (M-1), (N-1) and (N-2))). Subsequently, a salicylic acid derivative was synthesized by the following steps. Using 3-aminosalicylic acid as a starting material, the amino group of 3-aminosalicylic acid was formylated by stirring with N-formylsaccharin in a THF solvent. Since the hydroxyl group of the compound represented by the formula (62), which is the obtained hydroxycarboxylic acid, hinders subsequent amidation, the carboxyl group was converted to a methyl ester, and then the hydroxyl group was protected with benzyl. Furthermore, it converted into the compound represented by Formula (65) which is a salicylic acid derivative by hydrolysis using lithium hydroxide (see Reaction Formulas (O-3) and (O-4)).

A compound represented by the formula (65) which is a salicylic acid derivative and a compound represented by the formula (40) which is a 9-membered ring dilactone in 1-ethyl-3- (3-dimethylaminopropyl) in a DMF solvent. -Condensation using carbodiimide hydrochloride (EDCl.HCl), 1-hydroxybenzothiazole (HOBt), and N-methylmorpholine (NMM) to synthesize a compound represented by formula (66). Furthermore, the compound represented by Formula (1-1-4) was obtained by adding hydrogen in the presence of Pd (OH) ₂ (see Reaction Formulas (P-4) and (P-5)).
The identification result of the compound represented by Formula (1-1-4) obtained by the above synthesis is shown below.
¹ H-NMR (CDCl ₃ , δ ppm) 12.59 (1H, s), 8.51 (1H, d, J = 8.1 Hz), 8.49 (1H, s), 8.06 (1H, br s), 7.34-7.11 (6H, m), 6.86 (1H, t, J = 8.1 Hz), 5.45 (1H, m), 5.33-5.15 (2H, m), 5.07-4.93 (1H, m), 3.63 (1H, brs), 3.10-2.90 (2H, m), 2.73 (1H, d, J = 11) .0Hz), 2.63 (1H, septet, J = 6.8 Hz), 1.33 (3H, d, J = 6.1 Hz), 1.25 (6H, d, J = 6.8 Hz)

[Test Example 1] Evaluation of cytotoxicity (1)
Antimycin A Comparative Example 1 and the compound prepared in Examples 1-4 were evaluated cytotoxicity of (Sigma-Aldrich Corp., mixture of antimycin _{A 1,} A _2, A 3, _{A 4).} The evaluation method is as follows.
A medium containing each compound was added to cultured LLC-PK1 cells derived from porcine liver cells and cultured for 1 hour. As a blank control, a compound to which no compound was added was also prepared. The colony formation rate in cells containing each compound was calculated with the number of colonies formed in the blank control as 100%, and the concentration at which colony formation was inhibited by 50% (IC50 value) was determined. The results are shown in Table 1.

  From Table 1, antimycin A showed strong cytotoxicity, but the compounds prepared in Examples 1 to 4 did not show cytotoxicity.

[Test Example 2] Evaluation of cytotoxicity (2)
Next, using the compound (UK-2A) prepared in Example 1, antimycin A (manufactured by Sigma-Aldrich) as Comparative Example 1, and splenosine B synthesized as Comparative Example 2, Cytotoxicity was evaluated by the evaluation method. The structures of antimycin A and sprenosine B are as follows. The antimycins A _1a , A _1b , A _2a , A _2b , A _3a , A _3b , A _4a , and A _4b are respectively the type of side chain at the C-7 position and the side chain fatty acid at the C-8 position. The side chain types and substitution patterns were different and mixtures of these were used.

  Details of the evaluation method will be described. Each compound was added to the suspension of cultured RBL-2H3 cells (rat basophilic leukemia cells) and cultured for 24 hours. As a control, a sample to which no compound was added was also prepared. After removing the supernatant, Cell Counting Kit-8 (manufactured by Dojindo Laboratories) and a medium were added, and the cells were cultured in an incubator for 1 hour for measurement. The measured value is calculated by comparing the cell growth rate with the control. The results are shown in FIG.

  From FIG. 1, the compounds of Comparative Examples 1 and 2 showed strong cytotoxicity at 40 nM. On the other hand, UK-2A, which is the compound of Example 1, showed no cytotoxicity even at high concentrations.

  From the results of Test Example 1 and Test Example 2, it was suggested that the presence or absence of the 4-position methyl group may have a great influence on the cytotoxicity.

[Test Example 3] Evaluation of Th2 cytokine production inhibitory activity Furthermore, the compound (UK-2A) prepared in Example 1, antimycin A (manufactured by Sigma-Aldrich) as Comparative Example 1, and splenosine synthesized as Comparative Example 2 B was used to evaluate Th2 cytokine production inhibitory activity. The evaluation method is as follows.
RBL-2H3 cells were seeded at 2.5 × 10 ⁵ cells / well in a 24-well microplate. After overnight culture, 500 μL of an anti-DNP-IgE antibody (manufactured by Sigma) adjusted to 50 ng / mL in DMEM medium containing 10% FBS was added and cultured for 2 hours. 125 μL of the extract diluted with the medium was added and heated at 37 ° C. for 10 minutes. Then, 125 μL of 100 ng / mL DNP-labeled human serum albumin (Sigma) was added and reacted at 37 ° C. for 30 minutes. A medium containing no extract was added and reacted in the same manner as a control. Moreover, it culture | cultivated by the subculture medium which does not contain an anti- DNP-IgE antibody, the culture medium which does not contain an extract was added, and what was made to react similarly was made into the blank. Total RNA was extracted from the cells after the reaction using RNeasy kit (Qiagen). CDNA was synthesized using Random Primer (TaKaRa) and PrimeScript Reverse Transscriptase (TaKaRa). Quantification of mRNA expression level by real-time PCR after adding Fast SYBR Green Master Mix (Applied Biosystems) and target gene (IL-4, β-actin) specific primer (TaKaRa) using the obtained cDNA as a template Went. The ratio of the target gene expression to β-actin used as the internal standard was calculated, and the expression level change relative to the control was calculated. The results are shown in FIG.

  From FIG. 2, in the compounds of Example 1, Comparative Example 1 and Comparative Example 2, concentration-dependent suppression of expression was observed, but no difference between the compounds was observed. Therefore, it is clear that the compounds of Example 1, Comparative Example 1 and Comparative Example 2 have Th2 cytokine production inhibitory activity.

  From Test Examples 1 to 3, antimycin A and splenosine B have cytotoxicity at high concentrations, and therefore, UK-2A and its derivatives that do not have a methyl group at the C-4 position are useful as allergy inhibitors. Was confirmed.

  From the above results, it is apparent that the present invention can provide an effective therapeutic agent for allergy with low cytotoxicity.

Claims (5)

An allergy suppressing agent comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[In General Formula (1), R ¹ represents a branched alkyl group having 1 to 4 carbon atoms. R ² represents a methyl group. R ³ represents a benzyl group. R ⁴ represents a group represented by the following general formula (3).

[In general formula (3), * represents a bonding position. Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —. Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ each independently represent a methine group or a nitrogen atom. R ⁶ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n2 represents the number of R ⁶ and is an integer of 0 to 5.
]]   The allergy suppressant according to claim 1, wherein the allergy is a type I allergy. Compounds represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, and / or anti-allergic pharmaceutical composition comprising a diluent.

[In General Formula (1), R ¹ represents a branched alkyl group having 1 to 4 carbon atoms. R ² represents a methyl group. R ³ represents a benzyl group. R ⁴ represents a group represented by the following general formula (3).

[In general formula (3), * represents a bonding position. Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —. Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ each independently represent a methine group or a nitrogen atom. R ⁶ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n2 represents the number of R ⁶ and is an integer of 0 to 5.
]] A Th2 cytokine inhibitor comprising a compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

[In General Formula (1), R ¹ represents a branched alkyl group having 1 to 4 carbon atoms. R ² represents a methyl group. R ³ represents a benzyl group. R ⁴ represents a group represented by the following general formula (3).

[In general formula (3), * represents a bonding position. Y represents a carbonyl group, —C (═O) —O— or —O—C (═O) —. Z ¹ , Z ² , Z ³ , Z ⁴ and Z ⁵ each independently represent a methine group or a nitrogen atom. R ⁶ is each independently an unsubstituted or substituted C 1-4 linear or branched alkyl group, an unsubstituted or substituted carboxyl group, unsubstituted or substituted Carbamoyl group having a group, unsubstituted or substituted hydroxy group, unsubstituted or substituted amino group, unsubstituted or substituted mercapto group, substituted sulfinyl group, cyano group, nitro group Represents a group or a halogen atom. n2 represents the number of R ⁶ and is an integer of 0 to 5.
]]   The Th2 cytokine inhibitor according to claim 4, wherein the Th2 cytokine is IL-4.

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