JP2008273852A - Tricyclic pyrimidinone derivative and stat6 activation inhibitor containing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a STAT6 activation inhibitor which can precisely inhibit the activation of STAT6. <P>SOLUTION: The STAT6 activation inhibitor contains a tricyclic pyrimidinone derivative represented by general formula (1) [R<SP>1</SP>is H, a straight chain or branched chain 1-6C alkyl group or a halogen atom; R<SP>2</SP>is H, or a straight chain or branched 1-6C alkyl; X is a carbonyl group or a group represented by formula (2)] or a solvate thereof as an active ingredient. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a STAT6 activation inhibitor, and a prophylactic / therapeutic agent for diseases involving STAT6, in particular, respiratory diseases such as asthma, allergic diseases such as allergic rhinitis and allergic conjunctivitis, atopic asthma, atopy The present invention relates to a drug useful for prevention of onset / progress, amelioration, treatment, etc. of inflammatory diseases such as atopic dermatitis.

  The transcription factor STAT family (signal transducer and activator of transcription family) is a transcription factor that induces gene expression in response to a stimulus such as a cytokine, and subtypes from STAT1 to STAT6 are known. STAT is a protein composed of about 750 to 850 amino acids, and has a coiled coil domain, a DNA binding domain, a linker domain, and an SH2 domain. These all contain tyrosine that is phosphorylated in the vicinity of about 700th, activated by phosphorylation of the tyrosine, and dimerized by phosphorylated tyrosine and SH2 domain to form a stable complex.

  STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays an important role in interleukin-4 (IL-4) and interleukin-13 (IL-13) signaling. When IL-4 or IL-13 binds to IL-4 receptor or IL-13 receptor, protein kinases JAK1 and JAK3 associated with the receptor are activated in the cell and phosphorylate 641Tyr residue of STAT6 . Phosphorylated STAT6 forms a homodimer via its own SH2 domain, moves into the nucleus, and binds to specific DNA recognition sequences present in the promoter regions of various genes. The optimal base sequence of STAT6 is TTCNNNNGAA (N represents an arbitrary base). When this recognition sequence is present in series at an interval of about 10 base pairs, the dimer bound to each recognition sequence. Is said to bind with high affinity. Immunoglobulin-E (IgE) germline Cε transcript, CD23, eotaxin and the like that are known to be involved in allergic inflammation have been reported as genes having a STAT6 recognition sequence in the promoter region.

  Regarding abnormalities in IL-4 signal transduction and asthma development in humans, according to Mitsuyasu et al. (Non-patent Document 1), 1) Point mutation of the 50th amino acid in IL-4 receptor α chain in atopic asthma patients (Val50Ile) is observed at a higher rate than normal individuals, 2) this point mutation enhances T cell and B cell signaling, and 3) therefore, IL-4 in atopic asthma It has been suggested that abnormal signaling is a factor. Furthermore, when antigen sensitization and inhalation induction were performed using STAT6-deficient mice (mouse asthma model), (1) airway inflammation and airway hypersensitivity were suppressed as compared to wild-type mice, (2 ) It was directly proved that STAT6 is essential for the development of asthma because IgE production and infiltration of eosinophils into the respiratory tract were not observed (Non-patent Document 2). Moreover, the differentiation and activation of Th1 cells responsible for infection protection were normal, and no abnormality of the individual was observed.

  From these facts, STAT6 activation inhibitor can be expected as a completely new type of drug by inhibiting the activation of STAT6 involved in the pathology of allergic diseases, and the possibility of side effects based on this mechanism. Is considered to be extremely low, and research and development of drugs based on the STAT6 activation inhibitory action is underway. As activation inhibitors of STAT6, recently, heterocyclic compounds (Patent Document 1, Patent Document 2), tricyclic compounds (Non-Patent Document 3), quinoline compounds (Patent Document 3), aminoisoxazole derivatives (patents) 4), tetrahydrobenzisoxazole derivatives (see Patent Document 5), iminothiazole derivatives (see Patent Document 6), imidazo [2,1-b] thiazole derivatives (see Patent Document 7), dihydrothiadiazole derivatives (Patent Document) 8)) has been reported. In addition, a method using a STAT6 decoy (a portion having a base sequence to which a transcription factor binds or an oligonucleotide containing the same) has also been reported (see Patent Documents 9 and 10).

  It has been reported that allergic symptoms are improved by administering decoy nucleic acid to atopic dermatitis model mice or contact dermatitis model mice (Non-patent Documents 4 and 5). However, there are problems such as being easily decomposed and not being able to be administered orally.

Under such circumstances, an activation inhibitor of STAT6 having a new skeleton has been demanded, but an activation inhibitor of STAT6 having a tricyclic pyrimidinone derivative skeleton has not been known.
US2005227959 WO2002238107 brochure WO200279165 brochure JP-A-10-175964 Japanese Patent Laid-Open No. 10-175965 JP 11-29475 A JP-A-11-106340 JP 2000-229959 A JP 2005-306877 A JP 2005-523703 A H Mitsyusu et al. Immunol. (1999) 162 (3) 1227-1231 T Akimoto et al. Exp. Med. (1998) 187 (9) 1537-1542 J. et al. Antibiot. 56, no. 6,513-519 (2003) K Sumi et al., Gene Ther. (2004) 1763-1771 H Yokozeki et al. Gene Ther. (2004) 11 (4) 1753-1762

  Accordingly, an object of the present invention is to provide a STAT6 activation inhibitor that accurately inhibits STAT6 activation. In addition, for STAT6 related diseases, such as respiratory diseases such as asthma, allergic diseases such as allergic rhinitis and allergic conjunctivitis, inflammatory diseases such as atopic asthma and atopic dermatitis The object is to provide a medicament useful for prevention, improvement of disease state, treatment and the like. It is another object of the present invention to provide a STAT6 activation inhibitor and a novel compound that can be used as an active ingredient of a pharmaceutical useful for prevention, pathological improvement, treatment, etc. of diseases involving STAT6.

  In order to develop a therapeutic / prophylactic agent that is effective against asthma and various allergic diseases and has few side effects, the present inventors have focused on STAT6 and have conducted intensive studies on a drug that can inhibit the activation of STAT6. The present inventors have found that the tricyclic pyrimidinone derivative represented by (1) or a solvate thereof has an action of inhibiting the activation of STAT6 and completed the present invention.

［式中、
Ｒ^１は水素原子、直鎖又は分岐鎖のＣ_１〜Ｃ_６アルキル基、又はハロゲン原子を示し、
Ｒ^２は水素原子、又は直鎖又は分岐鎖のＣ_１〜Ｃ_６アルキル基を示し、
Ｘはカルボニル基、又は次式（２）：

で表される基を示す。］
で表される３環性ピリミジノン誘導体又はその溶媒和物を有効成分とする、ＳＴＡＴ６活性化阻害剤に関する。 That is, the present invention provides the following general formula (1):

[Where:
R ¹ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, or a halogen atom,
R ² represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group,
X is a carbonyl group or the following formula (2):

The group represented by these is shown. ]
The STAT6 activation inhibitor which uses as an active ingredient the tricyclic pyrimidinone derivative represented by these, or its solvate.

  The present invention also relates to a pharmaceutical composition comprising a tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof and a pharmaceutically acceptable carrier, and more specifically, a STAT6 activation inhibitory action. It relates to a pharmaceutical composition having

  Furthermore, the present invention provides a preventive and / or therapeutic agent for respiratory diseases such as asthma, a preventive and / or therapeutic agent for allergic diseases, and a prophylactic and / or inflammatory disease comprising the aforementioned compound of the present invention. Or it relates to a therapeutic agent.

  The present invention also provides a STAT6 activation inhibitor, a preventive and / or therapeutic agent for respiratory diseases, a preventive and / or therapeutic agent for allergic diseases, and / or a prophylactic and / or therapeutic agent for inflammatory diseases. It relates to the use of a compound according to the invention for the manufacture of a formulation.

  The present invention also relates to a method for preventing and / or treating respiratory diseases, allergic diseases, and / or inflammatory diseases by administering an effective amount of a STAT6 activation inhibitor.

  Furthermore, the present invention relates to a tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof.

The present invention will be described more specifically as follows.
<1> A STAT6 activation inhibitor comprising a tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof as an active ingredient.
<2> The tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof is 4-isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione or 7-fluoro. The STAT6 activation inhibitor according to <1>, which is -4-isopropyl-2H-indeno [1,2-d] pyrimidine-2,5-dione, or a solvate thereof.
<3> The STAT6 activation inhibitor according to <1> or <2>, wherein the STAT6 activation inhibition is inhibition of STAT6 activation based on IL-4 stimulation.
<4> A pharmaceutical composition comprising, as an active ingredient, the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof.
<5> A prophylactic and / or therapeutic agent for respiratory diseases comprising, as an active ingredient, the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof.
<6> A prophylactic and / or therapeutic agent for allergic diseases comprising, as an active ingredient, the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof.
<7> A prophylactic and / or therapeutic agent for inflammatory diseases comprising, as an active ingredient, the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof.
<8> A method for inhibiting activation of STAT6, comprising a step of administering the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof to mammals including humans. (Method).
<9> Respiratory disease, allergic disease, comprising a step of administering the tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof to mammals including humans, and A method for the prevention and / or treatment of a disease selected from the group consisting of inflammatory diseases.
<10> Use of a tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof for producing a preparation for inhibiting the activation of STAT6 (use) .
<11> General formula (1) according to <1> above for producing a preparation for the prevention and / or treatment of a disease selected from the group consisting of respiratory diseases, allergic diseases, and inflammatory diseases. Use of represented tricyclic pyrimidinone derivatives or solvates thereof.
<12> A tricyclic pyrimidinone derivative represented by the general formula (1) according to <1> or a solvate thereof.
<13> 4-Isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione, or 7-fluoro-4-isopropyl-2H-indeno [1,2-d] pyrimidine-2,5- Dione or a solvate thereof.

  The STAT6 activation inhibitor containing the tricyclic pyrimidinone derivative of the present invention or a solvate thereof as an active ingredient has an excellent STAT6 activation inhibitory action. In addition, the medicament comprising the tricyclic pyrimidinone derivative of the present invention or a solvate thereof as an active ingredient is used for diseases involving STAT6 activation, for example, respiratory diseases such as asthma, allergic rhinitis, allergic conjunctivitis and the like. It is useful for prevention of onset / progression, pathological improvement, treatment, etc. for inflammatory diseases such as sexually transmitted diseases, atopic asthma, and atopic dermatitis.

In the general formula (1), R ¹ represents a hydrogen atom, a linear or branched C _{1 to} C ₆ alkyl group, or a halogen atom.

In the general formula (1), the linear or branched C ₁ -C ₆ alkyl group represented by R ¹ includes a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, Examples thereof include a sec-butyl group, a tert-butyl group, a pentyl group, and a hexyl group.

In the general formula (1), examples of the halogen atom represented by R ¹ include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, and a fluorine atom is particularly preferable.

In general formula (1), R ¹ is preferably a hydrogen atom or a halogen atom.

In general formula (1), R ² represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group.

In the general formula (1), examples of the linear or branched C ₁ -C ₆ alkyl group represented by R ² include the same groups as described above, C ₂ -C ₆ alkyl groups are preferable, and isopropyl group is particularly preferable. preferable.

In general formula (1), R ² is preferably a linear or branched C ₁ -C ₆ alkyl group.

In general formula (1), as a suitable combination of X, R ¹ and R ² ,
When X represents a carbonyl group, R ¹ preferably represents a halogen atom, and R ² preferably represents a linear or branched C ₁ -C ₆ alkyl group,
In the case where X represents a group represented by the above formula (2), it is preferable that R ¹ represents a hydrogen atom and R ² represents a linear or branched C ₁ -C ₆ alkyl group.

  Preferred examples of the tricyclic pyrimidinone derivative of the present invention include 4-isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione, 7-fluoro-4-isopropyl-2H-indeno [1, 2-d] pyrimidine-2,5-dione.

  Examples of the solvate of the tricyclic pyrimidinone derivative of the present invention include hydrates.

1) Method for Producing Tricyclic Pyrimidinone Derivative of the Present Invention wherein X is a Carbonyl Group in General Formula (1) The tricyclic pyrimidinone derivative of the present invention wherein X is a carbonyl group is produced as follows: However, it is not limited to this. That is, compound (VI) can be produced by subjecting urea (IV), aldehyde derivative (III) and betaketocarboxylic acid ester (V) to a dehydration condensation reaction in the presence of an acid. Reactions are described in, for example, Strategic applications of named reactions in organic synthesis, Academic Pr. , 2005, 58-59, etc. can be applied.

  Compound (I ′) can be produced by reacting compound (VI) with an equimolar amount or an excess amount of acid. The acid is not particularly limited, but for example, mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, zinc chloride, aluminum trichloride, lanthanoid triflate Lewis acids such as can be used. The solvent is not particularly limited, and for example, methylene chloride, chloroform, dichloroethane, diethyl ether, dioxane, benzene, toluene, nitrobenzene, dichlorobenzene and the like can be used alone or in combination. The reaction temperature is −100 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is 1 hour to 10 days, preferably 1 day to 4 days, and the desired product (I ′) is obtained.

〔式中、Ｒ^１及びＲ^２は前記一般式（１）におけるものと同じ置換基を示し、Ｒ^１１はＣ_１〜Ｃ_６アルキル基を示す〕

[Wherein, R ¹ and R ² represent the same substituents as those in the general formula (1), and R ¹¹ represents a C ₁ -C ₆ alkyl group]

2) Method for producing a tricyclic pyrimidinone derivative of the present invention, wherein X is a group represented by the above formula (2) in the above general formula (1), wherein X is a group represented by the above formula (2) The tricyclic pyrimidinone derivative of the invention can be produced as follows, but is not limited thereto. That is, by reacting cyanamide (VII) with alcohols such as methanol, ethanol, isopropanol, and n-propanol under acidic conditions, an isourea derivative represented by general formula (VIII) can be produced. In the reaction, cyanamide and an equimolar or excess amount of alcohol are reacted in the presence of an acid. The acid is not particularly limited, but mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and nitric acid or organic acids such as acetic acid, trifluoroacetic acid and methanesulfonic acid, zinc chloride, aluminum trichloride, lanthanoid triflate, etc. The Lewis acid can be used. The solvent is not particularly limited, and for example, methylene chloride, chloroform, dichloroethane, diethyl ether, dioxane, benzene, toluene, nitrobenzene, dichlorobenzene and the like can be used alone or in combination. The reaction temperature is −100 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is 1 hour to 10 days, preferably 1 day to 4 days, and the desired product (VIII) is obtained. Commercially available products can be used for cyanamide (VII) and alcohols.

  Compound (IX) can be produced by subjecting aldehyde (III ′) and betaketocarboxylic acid ester (V) to a dehydration condensation reaction in the presence of an acid or a base. For the reaction, for example, the method described in the Chemical Society of Japan “New Experimental Chemistry Course Vol. 14, Synthesis and Reaction of Organic Compounds I” (Maruzen Co., Ltd., 1977, p221) can be applied. Aldehyde (III ′) may be a commercially available product, but alcohol (III is a general method for protecting hydroxyl groups described in Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc., etc.). “) Can be protected to produce aldehyde (III ′). The protective group for the alcohol group is not particularly limited, but preferably includes a benzyl group and a 4-methoxybenzyl group.

〔式中、Ｒ^１は前記一般式（１）におけるものと同じ置換基を示し、Ｒ^３はアルコール保護基を示す〕

[Wherein R ¹ represents the same substituent as in the general formula (1), and R ³ represents an alcohol protecting group]

  A cyclization reaction of compound (IX) and isourea derivative (VIII) in the presence of a base produces a mixture (X) of 1,4-dihydropyrimidine compound and 3,4-dihydropyrimidine compound that cannot be separated. it can. In the reaction, compound (IX) is reacted with an equimolar or excess amount of isourea derivative (VIII) in the presence of a base. Although the base is not particularly limited, for example, alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride, alkali hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, lithium carbonate, Alkali carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, alkali metals bicarbonate such as sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium t-butoxide Further, metal salts of alcohols such as potassium t-butoxide can be used. The solvent is not particularly limited. For example, alcohols such as methanol, ethanol, isopropanol, and n-propanol, tetrahydrofuran, toluene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, propionitrile, acetone, and methyl ethyl ketone Water or the like can be used alone or in combination. The reaction temperature is −40 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is 1 hour to 2 days, more preferably 1 to 24 hours to obtain the desired product.

  Compound (XI) can be produced by reacting mixture (X) with an oxidizing agent. As the oxidizing agent, 1,4-dichloro-5,6-dicyanobenzoquinone or the like can be applied, and it reacts with the mixture (X) in an equimolar or excess amount of oxidizing agent. The solvent is not particularly limited. For example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, dichlorobenzene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, propionitrile, acetone, methyl ethyl ketone, etc. They can be used alone or in combination. The reaction temperature is −40 to 150 ° C., preferably 0 to 100 ° C., and the reaction time is 1 minute to 1 day, more preferably 30 minutes to 4 hours.

〔式中、Ｒ^１及びＲ^２は前記一般式（１）におけるものと同じ置換基を示し、Ｒ^３はアルコール保護基を示し、Ｒ^１０及びＲ^１１はＣ_１〜Ｃ_６アルキル基を示す〕

[Wherein, R ¹ and R ² represent the same substituents as those in the general formula (1), R ³ represents an alcohol protecting group, and R ¹⁰ and R ¹¹ represent a C _{1 to} C ₆ alkyl group]

  Compound (I ") can be produced by reacting compound (XI) with an acid or an oxidizing agent. The acid is not particularly limited, but a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid or the like Organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, etc. can be used, and the oxidizing agent is not particularly limited, but 2,3-dichloro-5,6-dicyanobenzoquinone, etc. can be used. Is not particularly limited, for example, methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, toluene, dichlorobenzene, dioxane, N, N-dimethylformamide, N-methylpyrrolidone, acetonitrile, propionitrile, acetone, methyl ethyl ketone, etc. The reaction temperature is −80 to 150 ° C., preferably 0 to 100 ° C., during the reaction. 1 hour to 10 days, preferably, the target compound (I ") is obtained by reacting 1 hour to 4 days.

〔式中、Ｒ^１及びＲ^２は前記一般式（１）におけるものと同じ置換基を示し、Ｒ^３は前記と同じアルコール保護基を示し、Ｒ^１０及びＲ^１１はＣ_１〜Ｃ_６アルキル基を示す〕

[Wherein, R ¹ and R ² represent the same substituents as those in the general formula (1), R ³ represents the same alcohol protecting group as described above, and R ¹⁰ and R ¹¹ represent C ₁ -C ₆ alkyl groups. Indicates

  The tricyclic pyrimidinone derivative of the present invention or a solvate thereof can be purified using a conventional purification means such as a recrystallization method or column chromatography, if necessary. If necessary, the desired solvate can be obtained by a conventional method.

  In the present invention, “STAT6 activation inhibition” is not particularly limited as long as it can inhibit the activation of STAT6 as a transcription factor, and particularly can inhibit activation based on IL-4 stimulation. More specifically, it inhibits activation in a signal transduction system involving STAT6, for example, inhibition of phosphorylation, inhibition of activation by dimerization, inhibition of transcription reaction by STAT6, etc. Also good. In addition, examples of the signal transduction system involving STAT6 include those based on IL-4 stimulation.

  Since the tricyclic pyrimidinone derivative of the present invention or a solvate thereof has a STAT6 activation inhibitory action as shown in the following test examples, it is a STAT6 activation inhibitor and diseases involving STAT6 such as asthma Useful for prevention, progression, treatment, etc. of allergic diseases such as respiratory diseases, allergic rhinitis, allergic conjunctivitis, etc., and inflammatory diseases such as atopic asthma, atopic dermatitis Useful as.

  The medicament of the present invention comprises the tricyclic pyrimidinone derivative of the present invention or a solvate thereof as an active ingredient, and the dosage form is not particularly limited and can be appropriately selected depending on the therapeutic purpose. Solid preparations, oral liquid preparations, injections, suppositories, external preparations, eye drops, inhalants, aerosols, patches may be used, and these dosage forms are formulated with a pharmaceutically acceptable carrier. It can be produced by conventional formulation methods known to those skilled in the art. In addition, the solvate in the present invention is a compound for facilitating the handling in the preparation when a free compound is formulated as an active ingredient, and it does not become effective until it becomes a solvate. Absent.

  When preparing an oral solid preparation, the tricyclic pyrimidinone derivative of the present invention or a solvate thereof is used as an excipient, and if necessary, a binder, a disintegrant, a lubricant, a coloring agent, a corrigent, and a flavoring agent. Etc., tablets, granules, powders, capsules and the like can be produced by conventional methods. Such additives may be those commonly used in the art. For example, as excipients, lactose, sodium chloride, glucose, starch, microcrystalline cellulose, silicic acid and the like are used as binders. Water, ethanol, propanol, simple syrup, gelatin solution, hydroxypropylcellulose, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc., as disintegrant, agar powder, sodium bicarbonate, sodium lauryl sulfate, stearic acid monoglyceride, etc. As a lubricant, refined talc, stearate, borax, polyethylene glycol, etc., as a coloring agent, β-carotene, yellow ferric oxide, carmela, etc., as a corrigent, white sugar, orange peel, etc. It can be illustrated.

  When preparing an oral liquid preparation, a liquid preparation, syrup, elixir, etc. are added by conventional methods by adding a corrigent, buffer, stabilizer, preservative, etc. to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof. An agent etc. can be manufactured. Such additives may be those commonly used in the field, such as sucrose as a flavoring agent, sodium citrate as a buffer, tragacanth as a stabilizer, Examples of the preservative include paraoxybenzoic acid esters.

  When preparing an injection, a pH regulator, a stabilizer, an isotonic agent and the like are added to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof, and subcutaneous, intramuscular and intravenous injections are prepared by a conventional method. Can be manufactured. Such additives may be those commonly used in the field. For example, sodium phosphate or the like is used as a pH adjuster, sodium pyrosulfite or the like is used as a stabilizer, and isotonic agents. Examples thereof include sodium chloride.

  When preparing a suppository, it can be produced by a conventional method by adding a carrier and a surfactant to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof. As such an additive, what is generally used in the said field | area may be used, For example, a polyethyleneglycol, a hard fat, etc. are illustrated as a support | carrier, Polysorbate 80 etc. are illustrated as surfactant.

  When preparing an external preparation, a base, a water-soluble polymer, a solvent, a surfactant, a preservative, etc. are added to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof, and then a liquid or cream is prepared by a conventional method. , Gels, ointments and the like can be produced. Such additives may be those commonly used in the field, for example, liquid paraffin, white petrolatum, purified lanolin, etc. as bases, carboxyvinyl polymer, etc. as water-soluble polymers. However, examples of the solvent include glycerin and water, examples of the surfactant include polyoxyethylene fatty acid esters, and examples of the preservative include paraoxybenzoate esters.

  When an eye drop is prepared, it can be produced by a conventional method by adding a pH adjuster, stabilizer, isotonic agent, preservative, etc. to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof. Such additives may be those commonly used in the art, such as sodium phosphate as a pH adjuster, sodium pyrosulfite, EDTA, etc. as stabilizers, Examples of isotonic agents include sodium chloride, and examples of preservatives include chlorobutanol.

  For use as an inhalant or aerosol, the tricyclic pyrimidinone derivative of the present invention or a solvate thereof in the form of a solution, suspension or fine powder, with a gas or liquid propellant, and optionally a wetting agent Or what is necessary is just to fill an aerosol container with normal adjuvants, such as a dispersing agent.

  When preparing a patch, a water-containing patch, plaster patch, etc. are added by a conventional method by adding an adhesive, a solvent, a crosslinking agent, a surfactant, etc. to the tricyclic pyrimidinone derivative of the present invention or a solvate thereof. Can be manufactured. Such additives may be those commonly used in the art. For example, the pressure-sensitive adhesive may be a partially neutralized polyacrylic acid, sodium polyacrylate, 2-ethylhexyl polyacrylate, styrene- Isoprene-styrene block copolymer, etc., glycerin, water, etc. as solvent, dihydroxyaluminum aminoacetate, dry aluminum hydroxide gel etc. as crosslinking agent, polyoxyethylene fatty acid ester etc. as surfactant It can be illustrated.

  The dosage and administration method of the pharmaceutical agent of the present invention vary depending on the patient's age, weight, symptom, dosage form and number of administrations. It is preferable to administer mg orally or parenterally in 1 or several divided doses.

  Hereinafter, the present invention will be described with reference to production examples, test examples, and examples, but the present invention is not limited thereto.

シアナミド（５０．０ ｇ）を２−プロパノール（１５０ ｍＬ）に溶かし、氷水冷却下、メタンスルホン酸（１１４ ｇ）の２−プロパノール（１００ ｍＬ）溶液を約３０分間かけて滴下し、室温で６３時間攪拌した。２−プロパノールを留去し、表題化合物（２３０ ｇ、９８％）を無色固体として得た。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ６）δ：１．２９（６Ｈ，ｄ、Ｊ＝６．１ Ｈｚ），２．３７（３Ｈ，ｓ），４．８０−４．９２（１Ｈ，ｍ），８．４２（４Ｈ，ｂｒｓ）． [Production Example 1]
Production of o-isopropylisourea methanesulfonate

Cyanamide (50.0 g) was dissolved in 2-propanol (150 mL), and a solution of methanesulfonic acid (114 g) in 2-propanol (100 mL) was added dropwise over about 30 minutes while cooling with ice water. Stir for hours. 2-Propanol was distilled off to give the title compound (230 g, 98%) as a colorless solid.
¹ H-NMR (DMSO-d6) δ: 1.29 (6H, d, J = 6.1 Hz), 2.37 (3H, s), 4.80-4.92 (1H, m), 8 .42 (4H, brs).

サリチルアルデヒド（６１１ ｍｇ）をＮ，Ｎ−ジメチルホルムアミド（２．０ ｍＬ）に溶かし、氷水冷却下、炭酸カリウム（１．０３ ｇ）及び４−メトキシベンジルクロリド（８６１ ｍｇ）を加え、７０℃で１時間撹拌した。反応液を室温まで冷却後、不溶物をろ過し減圧下溶媒を留去した。残渣に水を加えクロロホルムで抽出後、得られた有機層を順次飽和食塩水、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣（１．５２ ｇ）をクロロホルム−ヘキサンより再結晶し、表題化合物（７０６ ｍｇ、５８．３％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：３．８２（３Ｈ，ｓ），５．１２（２Ｈ，ｓ），６．９３（２Ｈ，ｄ，Ｊ＝８．８ Ｈｚ），７．０２−７．０８（２Ｈ，ｍ），７．３６（２Ｈ，ｄ，Ｊ＝８．８ Ｈｚ），７．５４（１Ｈ，ｄ，Ｊ＝７．３， ７．８ Ｈｚ），７．８５（１Ｈ，ｄ，Ｊ＝７．８ Ｈｚ），１０．５２（１Ｈ，ｓ）． [Production Example 2]
Production of 2- (4-methoxybenzyloxy) benzaldehyde

Salicylaldehyde (611 mg) was dissolved in N, N-dimethylformamide (2.0 mL), and potassium carbonate (1.03 g) and 4-methoxybenzyl chloride (861 mg) were added with cooling with ice water at 70 ° C. Stir for 1 hour. After cooling the reaction solution to room temperature, insolubles were filtered and the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The obtained organic layer was successively dried over saturated brine and anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (1.52 g) was recrystallized from chloroform-hexane to give the title compound (706 mg, 58.3%).
¹ H-NMR (CDCl ₃ ) δ: 3.82 (3H, s), 5.12 (2H, s), 6.93 (2H, d, J = 8.8 Hz), 7.02-7. 08 (2H, m), 7.36 (2H, d, J = 8.8 Hz), 7.54 (1H, d, J = 7.3, 7.8 Hz), 7.85 (1H, d , J = 7.8 Hz), 10.52 (1H, s).

〔式中、ＭＰＭは４−メトキシベンジル基を示す。〕
２−（４−メトキシベンジルオキシ）ベンズアルデヒド（３００ ｍｇ）、エチル イソブチリルアセテート（２１５ ｍｇ）及びｏ−イソプロピルイソウレア メタンスルホン酸塩（４９０ ｍｇ）をＮ，Ｎ−ジメチルホルムアミド（２．０ ｍＬ）に溶解し、重曹（４１６ ｍｇ）を加え、５０℃で１日撹拌した。反応液を室温まで冷却後、減圧下溶媒を留去した。残渣に水を加えクロロホルムで抽出後、得られた有機層を順次飽和食塩水、無水硫酸ナトリウムで乾燥後、減圧下溶媒を留去した。得られた残渣（６７９ ｍｇ）を塩化メチレン（２．０ ｍＬ）に溶解し、２，３−ジクロロ−５，６−ジシアノ−１，４−ベンゾキノン（２８１ ｍｇ）を加え、室温で３０分撹拌した。反応液に水を加え、３０分撹拌後、不溶物をろ過し減圧下溶媒を留去した。シリカゲルカラムクロマトグラフィーで精製し、表題化合物（１２６ ｍｇ、２ ｓｔｅｐｓ、２１．８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：０．８６（３Ｈ，ｔ，Ｊ＝７．１ Ｈｚ），１．３０（６Ｈ，ｄ，Ｊ＝６．８ Ｈｚ），１．４０（６Ｈ，ｄ，Ｊ＝６．１ Ｈｚ），３．３８−３．４５（１Ｈ，ｍ），３．７８（３Ｈ，ｓ），３．９８（２Ｈ，ｑ，Ｊ＝７．３ Ｈｚ），４．９６（２Ｈ，ｓ），５．３３−５．４０（１Ｈ，ｍ），６．８１（２Ｈ，ｄ，Ｊ＝８．５ Ｈｚ），６．９３（１Ｈ，ｄ，Ｊ＝８．０ Ｈｚ），７．０３（１Ｈ，ｄｄ，Ｊ＝７．６， ８．０ Ｈｚ），７．２１（２Ｈ，ｄ，Ｊ＝８．５ Ｈｚ），７．３４（１Ｈ，ｄｄ，Ｊ＝７．６， ８．０ Ｈｚ），７．４１（１Ｈ，ｄ，Ｊ＝７．６ Ｈｚ）． [Production Example 3]
Preparation of 4- [2- (4-methoxybenzyloxy) phenyl] -5-ethyloxycarbonyl-6-isopropyl-2-isopropyloxypyrimidine

[Wherein, MPM represents a 4-methoxybenzyl group. ]
2- (4-methoxybenzyloxy) benzaldehyde (300 mg), ethyl isobutyryl acetate (215 mg) and o-isopropylisourea methanesulfonate (490 mg) were added to N, N-dimethylformamide (2.0 mL). ), Sodium bicarbonate (416 mg) was added, and the mixture was stirred at 50 ° C. for 1 day. After cooling the reaction solution to room temperature, the solvent was distilled off under reduced pressure. Water was added to the residue and the mixture was extracted with chloroform. The obtained organic layer was successively dried over saturated brine and anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue (679 mg) was dissolved in methylene chloride (2.0 mL), 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (281 mg) was added, and the mixture was stirred at room temperature for 30 minutes. did. Water was added to the reaction mixture, and the mixture was stirred for 30 minutes. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. Purification by silica gel column chromatography gave the title compound (126 mg, 2 steps, 21.8%).
¹ H-NMR (CDCl ₃ ) δ: 0.86 (3H, t, J = 7.1 Hz), 1.30 (6H, d, J = 6.8 Hz), 1.40 (6H, d, J = 6.1 Hz), 3.38-3.45 (1H, m), 3.78 (3H, s), 3.98 (2H, q, J = 7.3 Hz), 4.96 ( 2H, s), 5.33-5.40 (1H, m), 6.81 (2H, d, J = 8.5 Hz), 6.93 (1H, d, J = 8.0 Hz), 7.03 (1H, dd, J = 7.6, 8.0 Hz), 7.21 (2H, d, J = 8.5 Hz), 7.34 (1H, dd, J = 7.6) 8.0 Hz), 7.41 (1H, d, J = 7.6 Hz).

４−［２−（４−メトキシベンジルオキシ）フェニル］−５−エチルオキシカルボニル−６−イソプロピル−２−イソプロピルオキシピリミジン（８８．４ ｍｇ）を塩化メチレン（１．０ ｍＬ）に溶解し、トリフルオロ酢酸（４３．８ μＬ）を加え、室温で１日撹拌した。減圧下溶媒を留去し、シリカゲルカラムクロマトグラフィーで精製し、表題化合物（３６ ｍｇ、７４．１％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．４５−１．５４（６Ｈ，ｍ），４．６０−４．７４（１Ｈ，ｍ），７．３３−７．５２（２Ｈ，ｍ），７．６８−７．７４（１Ｈ，ｍ），８．５８（１Ｈ，ｄ，Ｊ＝７．３ Ｈｚ）． [Example 1]
Preparation of 4-isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione

4- [2- (4-Methoxybenzyloxy) phenyl] -5-ethyloxycarbonyl-6-isopropyl-2-isopropyloxypyrimidine (88.4 mg) was dissolved in methylene chloride (1.0 mL), Fluoroacetic acid (43.8 μL) was added, and the mixture was stirred at room temperature for 1 day. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography to obtain the title compound (36 mg, 74.1%).
¹ H-NMR (CDCl ₃ ) δ: 1.45-1.54 (6H, m), 4.60-4.74 (1H, m), 7.33-7.52 (2H, m), 7 68-7.74 (1H, m), 8.58 (1H, d, J = 7.3 Hz).

４−フルオロベンズアルデヒド（４５１ ｍｇ）、エチルイソブチリルアセテート（５７５ ｍｇ）、ランタンクロリド・７水和物（６７５ ｍｇ）、尿素（３２８ ｍｇ）をエタノール（１０ ｍＬ）に溶解し、１００℃で１日加熱還流した。室温まで冷却後、反応液に水を加え、クロロホルムで抽出し、得られた有機層を順次飽和食塩水、硫化ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣（１．１０ ｇ）をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（４７７ ｍｇ、４２．８％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．１５（３Ｈ，ｔ，Ｊ＝７．１ Ｈｚ），１．１８−１．２１（６Ｈ，ｍ），４．０６（２Ｈ，ｑ，Ｊ＝７．１ Ｈｚ），４．１３−４．２１（１Ｈ，ｍ），５．３７（１Ｈ，ｄ，Ｊ＝２．９ Ｈｚ），５．９７（１Ｈ，ｓ），６．９７（１Ｈ，ｄ，Ｊ＝８．７ Ｈｚ），６．９９（１Ｈ，ｄ，Ｊ＝９．７ Ｈｚ），７．２３−７．２８（３Ｈ，ｍ）． [Production Example 4]
Preparation of 5-ethyloxycarbonyl-6- (4-fluorophenyl) -4-isopropyl-1,3H-tetrahydropyrimidin-2-one

4-Fluorobenzaldehyde (451 mg), ethylisobutyryl acetate (575 mg), lanthanum chloride 7 hydrate (675 mg), urea (328 mg) were dissolved in ethanol (10 mL), and 1 at 100 ° C. The mixture was heated to reflux for a day. After cooling to room temperature, water was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was dried successively with saturated brine and sodium sulfide, and the solvent was evaporated under reduced pressure. The obtained residue (1.10 g) was purified by silica gel column chromatography to obtain the title compound (477 mg, 42.8%).
¹ H-NMR (CDCl ₃ ) δ: 1.15 (3H, t, J = 7.1 Hz), 1.18-1.21 (6H, m), 4.06 (2H, q, J = 7) .1 Hz), 4.13-4.21 (1 H, m), 5.37 (1 H, d, J = 2.9 Hz), 5.97 (1 H, s), 6.97 (1 H, d) , J = 8.7 Hz), 6.99 (1H, d, J = 9.7 Hz), 7.23-7.28 (3H, m).

５−エチルオキシカルボニル−６−（４−フルオロフェニル）−４−イソプロピル−１、３Ｈ−テトラヒドロピリミジン−２−オン（４１２ ｍｇ）をニトロベンゼン（５．０ ｍＬ）に溶解し、氷冷下アルミニウムクロリド（１．０８ ｇ）、アセチルクロリド（５８０ ｍｇ）を加え、９０℃で１日撹拌した。室温まで冷却後、反応液に１Ｎ塩酸を加え、クロロホルムで抽出し、得られた有機層を順次飽和食塩水、硫化ナトリウムで乾燥し、減圧下溶媒を留去した。得られた残渣をシリカゲルカラムクロマトグラフィーで精製し、表題化合物（６２ ｍｇ、１７．７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ：１．２９（６Ｈ，ｄ，Ｊ＝７．１ Ｈｚ），３．６７−３．７５（１Ｈ，ｍ），７．５２−７．６３（２Ｈ，ｍ），７．９６（１Ｈ，ｄｄ，Ｊ＝５．４， ８．０ Ｈｚ），１２．１３（１Ｈ，ｂｒｓ）． [Example 2]
Preparation of 7-fluoro-4-isopropyl-2H-indeno [1,2-d] pyrimidine-2,5-dione

5-ethyloxycarbonyl-6- (4-fluorophenyl) -4-isopropyl-1,3H-tetrahydropyrimidin-2-one (412 mg) was dissolved in nitrobenzene (5.0 mL), and the aluminum chloride was cooled with ice. (1.08 g) and acetyl chloride (580 mg) were added, and the mixture was stirred at 90 ° C. for 1 day. After cooling to room temperature, 1N hydrochloric acid was added to the reaction mixture, and the mixture was extracted with chloroform. The obtained organic layer was successively dried over saturated brine and sodium sulfide, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain the title compound (62 mg, 17.7%).
¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, d, J = 7.1 Hz), 3.67-3.75 (1H, m), 7.52-7.63 (2H, m ), 7.96 (1H, dd, J = 5.4, 8.0 Hz), 12.13 (1H, brs).

[Test example]
The STAT6 activation inhibitory action of the compound of the present invention was measured by the following method.
(1) Measurement method (STAT6 activation inhibition test)
The following sequence 1 containing a sequence in which four STAT6 binding motifs are repeated
Sequence 1: 5′-TCGAC ([AGTCCACTTCCCCAAGAACAGA] × 4) GGATC-3 ′ (Sequence 1)
A stable transformed cell line derived from human lung cancer epithelial cell A549 (Dainippon Pharmaceutical Co., Ltd.) in which a luciferase vector containing an oligonucleotide having the nucleotide sequence shown in FIG. Cells were seeded in a 96-well microplate (manufactured by Nuku) at 5 × 10 ⁴ cells / 0.1 ml / well and cultured overnight. On the next day, 0.01 ml of a test compound (0.25 mg / ml) dissolved in dimethyl sulfoxide and diluted with a medium was added, and 30 minutes later on COS-7 cell culture containing human recombinant IL-4 0.01 ml of the clear solution was added and cultured for 4 hours. After culturing, 0.08 ml / well of Bright-Glo Luciferase Assay System reaction solution (Promega) was added, and luciferase activity was measured with a luminometer (Wallac 1420 ARVOsx, manufactured by PerkinElmer). The STAT6 activation inhibitory action of the test compound was calculated by the following formula 1 as an inhibition rate (%) with respect to luciferase activity induced by IL-4 stimulation, and the results are summarized in Table 1. In addition, as a test compound, the compound manufactured in the said Example 1, 2 was used.

Inhibition rate (%) = 100− (A−B) / (C−B) × 100 (Formula 1)
In the formula, A: luciferase activity induced by IL-4 stimulation in the presence of a test compound B: luciferase activity induced by no stimulation in the absence of the test compound C: in the absence of the test compound The luciferase activity induced by IL-4 stimulation is shown.

(2) Table 1 shows the test results of each test compound.

  From the above pharmacological test results, the compound of Example 1 and the compound of Example 2 have STAT6 activation inhibitory action, and the tricyclic pyrimidinone derivative of the present invention or a solvate thereof is an excellent STAT6 activation inhibitor. It became clear that there was. In particular, the compound of Example 1 has a STAT6 activation inhibitory action of 60% or more, and it was revealed that it has a particularly excellent STAT6 activation inhibitory action.

  Based on the above results, the medicament comprising the tricyclic pyrimidinone derivative of the present invention or a solvate thereof as an active ingredient is used for diseases involving activation of STAT6, for example, respiratory diseases such as asthma, allergic rhinitis, allergic conjunctivitis It is found that it is useful for prevention of onset / progression, improvement of disease state, treatment, etc. for inflammatory diseases such as atopic asthma and atopic dermatitis.

  The STAT6 activation inhibitor containing the tricyclic pyrimidinone derivative of the present invention or a solvate thereof as an active ingredient has an excellent STAT6 activation inhibitory action and is associated with diseases involving activation of STAT6, for example, respiration such as asthma Used as a medicine for the prevention, progression, treatment, etc. of allergic diseases such as organ diseases, allergic rhinitis, allergic conjunctivitis, and inflammatory diseases such as atopic asthma, atopic dermatitis For example, in the pharmaceutical industry.

  Sequence number 1: The sequence which repeated STAT6 binding motif 4 times

Claims (8)

The following general formula (1):

[Where:
R ¹ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, or a halogen atom,
R ² represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group,
X is a carbonyl group or the following formula (2):

The group represented by these is shown. ]
The STAT6 activation inhibitor which uses as an active ingredient the tricyclic pyrimidinone derivative represented by these, or its solvate.   The tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof is 4-isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione or 7-fluoro-4- The STAT6 activation inhibitor according to claim 1, which is isopropyl-2H-indeno [1,2-d] pyrimidine-2,5-dione, or a solvate thereof.   A pharmaceutical composition comprising the tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof according to claim 1 or 2 as an active ingredient.   A prophylactic and / or therapeutic agent for respiratory diseases comprising the tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof according to claim 1 or 2 as an active ingredient.   A prophylactic and / or therapeutic agent for allergic diseases comprising the tricyclic pyrimidinone derivative represented by formula (1) or a solvate thereof as an active ingredient according to claim 1 or 2.   A prophylactic and / or therapeutic agent for inflammatory diseases comprising the tricyclic pyrimidinone derivative represented by the general formula (1) or a solvate thereof according to claim 1 or 2 as an active ingredient. The following general formula (1):

[Where:
R ¹ represents a hydrogen atom, a linear or branched C ₁ -C ₆ alkyl group, or a halogen atom,
R ² represents a hydrogen atom or a linear or branched C ₁ -C ₆ alkyl group,
X is a carbonyl group or the following formula (2):

The group represented by these is shown. ]
A tricyclic pyrimidinone derivative represented by the formula:   4-isopropyl-3H-chromeno [4,3-d] pyrimidine-2,5-dione, or 7-fluoro-4-isopropyl-2H-indeno [1,2-d] pyrimidine-2,5-dione, or Their solvates.