JP2012144442A - Baff binding inhibitor having 4-(2-benzylidene hydrazinyl)-2-phenylpyrimidine derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a drug which inhibits the BAFF binding to a BR3 receptor and has excellent preventing and treating effects on autoimmune diseases, acquired immunodeficiency syndrome, and non-Hodgkin lymphoma.SOLUTION: The BAFF binding inhibitor to a BR3 receptor includes a compound represented by formula (1) (wherein Ris a 1-10C alkyl group; and R, R, R, and Rmay be the same as or different from one another and are each hydrogen or a hydroxyl group), a salt thereof or a solvate thereof as an active ingredient.

Description

  The present invention relates to a binding inhibitor of BAFF for BR3 receptor comprising 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative as an active ingredient. More specifically, the present invention relates to a prophylactic and / or therapeutic agent for autoimmune disease comprising 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative as an active ingredient, prevention of acquired immune deficiency syndrome and The present invention relates to a therapeutic agent or a preventive and / or therapeutic agent for non-Hodgkin lymphoma.

  The immunity in the living body is originally a biological defense mechanism for recognizing and eliminating foreign antigenic proteins such as bacteria, viruses or tumors, and a specific reaction to a foreign antigen occurs to produce specific antibodies and cytotoxic T With cell activation. In these acquired immunity, B cells play a central role through humoral immunity, and produce specific antibodies against foreign antigens to eliminate foreign antigens (Non-patent Document 1). However, in an autoimmune disease, an excessive reaction to a self antigen occurs, which is accompanied by autoantibody production and T cell activation. In autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus Erythematosus (SLE) with autoimmune reaction in the background, production of autoreactive B cells and autoantibodies is enhanced. Therefore, many studies have been conducted on elucidation of mechanisms that control maturation and activation of B cells and antibody production.

  B cells are derived from bone marrow hematopoietic stem cells and are a group of cells that express immunoglobulin on the cell surface, occupy about 10 to 30% of peripheral blood lymphocytes, and are mediated by B cell receptors (BCR) in the spleen. In response to antigen stimulation or activation stimulation from T cells, the cells differentiate into immunoglobulin-producing cells (plasma cells). Activated B cells produce inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), and via costimulatory molecules such as CD40 expressed on the cell surface. To activate T cells. Thus, B cells are greatly involved not only as autoantibody-producing cells but also as functions of antigen-presenting cells, and pathogenesis of autoimmune diseases through crosstalk with cytokine-producing cells and T cells. It has been made clear. Furthermore, monoclonal antibodies against CD20, a CD antigen specific for B cells (Rituximab, Rituxan, rituximab, Non-Patent Document 2) are clinically confirmed to be effective in improving symptoms of B-cell non-Hodgkin lymphoma, RA or SLE. There is a great expectation for the treatment of autoimmune diseases targeting B cells.

  Recently, BAFF (B cell activating factor belonging to TNF superfamily) has been discovered as a B cell survival and maturation factor (Non-patent Document 3, Patent Document 1). BAFF is also known as BLyS, TALL-1, THANK, zTNF4, TNFSF13B, or Kay ligand (see Patent Document 1), and is positioned as a member of the superfamily of TNF-alpha, an inflammatory cytokine. BAFF exists as a precursor protein on the surface of monocytes, macrophages, and dendritic cells, and is stimulated by interferon-gamma (IFN-gamma), LPS (lipopolysaccharide) or interleukin-10 (IL-10). Its expression is enhanced (Non-Patent Document 4). BAFF undergoes processing by furin-type protease to become secreted, and this activated BAFF protein forms a homotrimer, and similarly binds to a receptor expressed on the surface of the B cell as a trimer (non-reactive). Patent Document 5). The main effect of BAFF on B cells is to induce Bcl-2, which acts antagonistically to apoptosis, and induces B cell activation such as prolonging survival of B cells and enhancing production of IgM, which is an immunoglobulin. Increases overproduction of autoantibodies (Non-patent Document 6). The intracellular signal is due to the transcription factor NF-kappaB2 / p100 being processed into p52 (Non-patent Document 7). BAFF transgenic mice have been confirmed to have enlarged lymph nodes or spleen, hyperplasia of B cells in the tissue, and a severe autoimmune disease-like phenotype (Non-patent document 8, Non-patent document 9). . On the other hand, almost no mature B cells were observed in BAFF knockout mice, and lack of humoral immune response has been reported (Non-patent Document 10).

  From the phenotypes of these BAFF transgenic mice and BAFF knockout mice, it can be considered that they are deeply involved in autoimmune diseases accompanied by B cell activation. The possibility of application to treatment of various autoimmune diseases is shown in the review by Matsushita et al., SLE, Sjogren's syndrome, RA, systemic sclerosis (SSc), multiple sclerosis (Multiple Sclerosis: MS), application to antitumor agents such as non-classifiable immunodeficiency (CVID) and non-Hodgkin's lymphoma (Non-Patent Document 11). In patients with acquired immune deficiency syndrome (AIDS), blood T cells decrease, B cells increase and immunoglobulin production increases, and expression of BAFF protein on the surface of B cells increases. This suggests that BAFF and its receptor are involved in the progression of AIDS pathology (Non-patent Document 12).

  Examples of receptors for BAFF include BCMA (B Cell Maturation Antigen, also known as TNFRSF17, Non-Patent Document 13), TACI (Transmembrane Activator and CAML-Interactor, also known as TNFRSF13B, Non-Patent Document 14), and BR3 (also known as TNFSFR13C, BAFF Receptor, BAFF). -R may be abbreviated as -R.3 types of transmembrane proteins of Non-Patent Document 15) have been reported, and these receptors are members of the TNF receptor superfamily as well as ligands. Among these, APRIL (A Proliferation Inducing Ligand), which is one of TNF family members, binds to BCMA and TACI as a ligand (Non-patent Document 16). Among these three receptors, it is suggested that the action of BAFF on B cells is mainly mediated by BR3 (Non-patent Document 15). As in the case of BAFF-deficient mice, BR3 knockout mice have phenotypes such as deletion of mature B cells and a decrease in immunoglobulin production ability (Non-patent Document 17). In WySnJ mice, the importance of BAFF and BR3 in the maturation process of B cells has been suggested, such as a marked decrease in the number of peripheral B cells (Non-patent Document 18).

  In recent years, for the treatment of autoimmune diseases including rheumatoid arthritis (RA), biopharmaceuticals such as a specific antibody of a target protein or a soluble receptor using a receptor of the target protein have been developed. Enbrel (Etanercept, Non-Patent Document 19), a soluble receptor protein preparation of TNF-alpha, which is an inflammatory cytokine, is used for RA treatment. Similarly, development of a specific antibody against BAFF or a soluble receptor protein using its receptor has been promoted, and it has been developed for the treatment of autoimmune diseases and other diseases associated with B cells. (Non-Patent Document 6). For example, belimumab (Lymphostat), an anti-human BAFF antibody, has been tested against SLE (Non-patent Document 20), and Atacicept, a TACI-Fc fusion protein, has also been tested in SLE patients for the purpose of inhibiting BAFF. (Non-patent document 21). In addition, the relationship between the survival rate of non-Hodgkin's lymphoma patients and the blood BAFF concentration has been suggested (Non-patent Document 22), and the development of a therapeutic method targeting BAFF is also expected in diseases other than autoimmune diseases. Furthermore, the development of BR3-Fc, which is a soluble receptor, has also been promoted for the purpose of controlling B cell activation (Non-patent Document 23).

  As mentioned above, targeting BAFF and its receptor, autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis, unclassifiable immunodeficiency, acquired immune deficiency Development of biologics such as anti-BAFF antibody and BR3-Fc protein is underway as a treatment for anti-tumor agents such as Syndrome and non-Hodgkin's lymphoma. There have been no reports on compounds, and only a partial peptide of BR3 protein has been reported (Non-patent Document 24, Patent Document 2). Further, as described above, at least three types of receptors to which BAFF binds are known. Of these, the BR3 receptor is the only BAFF-specific receptor and is thought to mainly transmit the BAFF signal.

  On the other hand, 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivatives related to the present invention have, for example, an IL-12 production inhibitory action and are useful for rheumatoid arthritis and the like (Patent Document 3, Patent Document 4), compound having inhibitory action on mixed lymphocyte culture reaction, useful for suppressing rejection reaction during bone marrow transplantation and organ transplantation (Patent Document 5), compound useful as anticancer agent (Patent Document 6), β- A compound having a secretase inhibitory effect and useful as a therapeutic agent for Alzheimer's disease (Patent Document 7) is disclosed. However, the compounds disclosed in these documents differ from the compounds of the present invention in the manner of substitution on the pyrimidine ring. In addition, there is no description or suggestion regarding inhibition of binding of BAFF to BR3 receptor, autoimmune disease, acquired immune deficiency syndrome, or non-Hodgkin lymphoma in any document.

WO99 / 12964 pamphlet WO2005 / 005462 pamphlet WO2009 / 100406 pamphlet WO2003 / 047516 pamphlet JP-A-2005-14595 WO2007 / 065940 pamphlet WO2006 / 029850 pamphlet

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As described above, by inhibiting the binding of BAFF to the BR3 receptor, autoimmunity such as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, multiple sclerosis, unclassifiable immunodeficiency, etc. It is known that it is possible to provide a drug excellent in the preventive and therapeutic effects of diseases and the preventive and / or therapeutic effects of acquired immune deficiency syndrome or cancer.
An object of the present invention is to provide an agent that inhibits the binding of BAFF to the BR3 receptor and has an excellent prophylactic and / or therapeutic effect on autoimmune diseases, acquired immune deficiency syndrome or non-Hodgkin's lymphoma. In particular, the present invention provides a low-molecular compound that can inhibit the binding of BAFF to the BR3 receptor, and an inhibitor of the binding of BAFF to the BR3 receptor using the low-molecular compound.

  As described above, BAFF binding inhibitors are being developed in biologics such as anti-BAFF antibodies and BR3-Fc receptors, but there have been no reports of low molecular weight compounds. As described above, at least three types of receptors to which BAFF binds are known, and it is also suggested that the BR3 receptor is the most important. Therefore, we decided to conduct screening aiming to create a low molecular weight compound that inhibits this BAFF-BR3 binding, and constructed and screened a ligand-receptor binding assay system using BR3-expressing cells. As a result, it was found that the 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative of the present invention unexpectedly inhibits this BAFF-BR3 binding, and the present invention was completed.

That is, the present invention provides the following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, or a solvate thereof as an active ingredient, which is used as a binding inhibitor of BAFF to the BR3 receptor and a binding inhibitor of BAFF to the BR3 receptor A pharmaceutical composition is provided. The compound represented by the general formula (1) of the present invention is used as a binding inhibitor of BAFF to BR3 receptor, as rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic sclerosis, multiple sclerosis and non-classifiable type. It can be used as an agent for preventing and / or treating autoimmune diseases such as immunodeficiency. In addition, the compound represented by the general formula (1) of the present invention is similarly used as a BAFF binding inhibitor for the BR3 receptor, as a preventive and / or therapeutic agent for acquired immune deficiency syndrome, and prevention of non-Hodgkin lymphoma. And / or can be used as a therapeutic agent.

The present invention will be described in detail as follows.
[1] A binding inhibitor of BAFF for BR3 receptor comprising the compound represented by the general formula (1), a salt thereof, or a solvate thereof as an active ingredient.
[2] The binding inhibitor according to [1], wherein at least one of the two substituents of R ² and R ³ , R ⁴ and R ^{5 in} the general formula (1) is a hydroxyl group.
[3] The compound represented by the general formula (1) is the following compound:
(E) -4- {2- (2-hydroxybenzylidene) hydrazinyl} -2- (2-hydroxyphenyl) -6-methylpyrimidine, and
(E) -4- {2- (2,4-dihydroxybenzylidene) hydrazinyl} -2- (2-hydroxyphenyl) -6-methylpyrimidine is at least one compound selected from the group [1 ] Or the binding inhibitor according to [2].
[4] Inhibition of binding of BAFF to BR3 receptor comprising the compound according to any one of [1] to [3] above, or a salt thereof, or a solvate thereof, and a pharmaceutically acceptable carrier. A pharmaceutical composition for use as an agent.

[5] Prevention and / or treatment of autoimmune disease, comprising as an active ingredient the compound according to any one of [1] to [3] above, or a salt thereof, or a solvate thereof. Agent.
[6] The autoimmune disease according to [5], wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis, or unclassifiable immunodeficiency Disease prevention and / or treatment agent.
[7] Prevention of acquired immune deficiency syndrome and / or comprising the compound according to any one of [1] to [3] above, or a salt thereof, or a solvate thereof as an active ingredient Therapeutic agent.
[8] A preventive and / or therapeutic agent for non-Hodgkin's lymphoma comprising the compound according to any one of [1] to [3] above, or a salt thereof, or a solvate thereof as an active ingredient .
[9] The non-Hodgkin lymphoma is a precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, precursor cell leukemia, small lymphocytic lymphoma, lymphoplasma cell lymphoma, immunocytoma, mantle cell lymphoma, Prevention and / or prevention of non-Hodgkin lymphoma according to [8] above, which is follicular lymphoma, marginal lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell lymphoma or Burkitt lymphoma It relates to a therapeutic agent.

The present invention also provides:
[10] The following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
A method for preventing and / or treating autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin's lymphoma, which comprises administering an effective amount of the compound represented by: or a salt thereof, or a solvate thereof,
[11] The following general formula (1) for producing a preventive and / or therapeutic agent for autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin lymphoma:

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
And a salt thereof, or a solvate thereof, and [12] the following, for use in the prevention and / or treatment of autoimmune disease, acquired immune deficiency syndrome or non-Hodgkin lymphoma General formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, or a solvate thereof.

  Furthermore, the present invention inhibits the binding of BAFF to the BR3 receptor by contacting the compound represented by the general formula (1), or a salt thereof, or a solvate thereof with a cell having a BR3 receptor. On how to do.

  The compound represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof has a BAFF binding inhibitory action on the BR3 receptor and is a low-molecular compound, and the BAFF receptor Can be administered orally, unlike soluble proteins, etc., as a preventive and / or therapeutic agent for autoimmune diseases, as a preventive and / or therapeutic agent for acquired immune deficiency syndrome, or as a preventive and / or therapeutic agent for non-Hodgkin lymphoma Useful as an agent.

Hereinafter, the present invention will be described in detail.
The definitions of terms in the present invention are as follows.

  As used herein, non-Hodgkin lymphoma is a malignant lymphoma other than Hodgkin lymphoma, such as a Revised European American Lymphoma (REAL) classification. (For example, Harris et al., Blood, 84 (5), 1361-1392 (1994), Mizoguchi et al., History of Medicine, Hematology Ver.2, Biomedical Publishing, 303-307 (1998)) reference). Examples of the non-Hodgkin lymphoma of the present invention include B cell lymphoma (precursor B-lymphoblastic leukemia), chronic B lymphocytic leukemia, progenitor leukemia. (B-cell prolymphocytic leukemia), B-cell small lymphocytic lymphoma, lymphoplasmacytoid lymphoma, immunocytoma, Mantle cell lymphoma, follicular Lymphoma (follicle center lymphoma), marginal zone B-cell lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell Lymphoma (Diffuse Large B-cell lymphoma), Burkitt's lymphoma, etc.), T-cell lymphoma, or NK-cell lymphoma (T-cell chronic lymphocytic leukerni) a), T-cell prolymphocytic leukemia, T-cell Large granular lymphocyte leukemia, NK-cell Large granular lymphocyte leukemia, bacteria Mycosis fungoides, Sezary syndrome, Peripheral T-cell lymphomas, Angioimmunoblastic T-cell lymphoma, Angiocentric lymphoma ), Intestinal T-cell lymphoma, adult T-cell lymphoma, anaplastic large cell lymphoma, and the like.

As used herein, the “C _1-10 alkyl group” means a linear or cyclic saturated group having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms. An unsaturated hydrocarbon group. Although it does not specifically limit as " _C1-10 alkyl group", For example, a methyl group, an ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group etc. Is mentioned.

In general formula (1), R ¹ is preferably a “methyl group or an ethyl group”, and more preferably a methyl group.

In general formula (1), R ² is preferably a hydroxyl group. Moreover, it is preferable that the coupling | bonding position is ortho position with respect to the coupling | bonding position with a pyrimidine ring.

In general formula (1), R ³ is preferably a hydrogen atom.

In general formula (1), R ⁴ is preferably a hydroxyl group. Moreover, it is preferable that the bond position is an ortho position with respect to the bond position with methylene.

In general formula (1), R ⁵ may be either a hydrogen atom or a hydroxyl group, but the bonding position is preferably para to the bonding position with methylene.

  Preferable specific examples of the 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention include the following compounds.

  The 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention, or a salt thereof, or a solvate thereof is the 4- (2-benzylidene) of the present invention. Hydrazinyl) -2-phenylpyrimidine derivatives, pharmaceutically acceptable salts thereof, various hydrates and solvates thereof, substances having crystalline polymorphs, and prodrugs of these substances Is included.

  As a salt acceptable as a 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention, specifically, when treating a compound as a basic compound, , Acids with inorganic acids (eg hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid etc.) and organic acids (eg methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid etc.) Addition salts etc. are mentioned, and when a compound is handled as an acidic compound, inorganic salts (for example, sodium salt, potassium salt, lithium salt, barium salt, calcium salt, magnesium salt, etc.) and the like can be mentioned.

  Solvates of 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivatives represented by the general formula (1) of the present invention and pharmaceutically acceptable salts thereof include hydrates and various solvents. Solvates (for example, solvates with alcohols such as ethanol).

  The 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention can be produced by a known method. For example, although it can manufacture by the method shown to the following reaction process drawing, or the method according to this, it is not limited to this. Moreover, you may perform each reaction, protecting a functional group as needed. The protection and deprotection conditions can be carried out with reference to commonly used methods (Protective Groups in Organic Synthesis Third Edition, John Wiley & Sons, Inc.).

[Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ have the same meanings as defined above, R ⁶ represents a lower alkyl group, and X represents a halogen atom. ]

[Step A] The pyrimidine derivative (4) can be produced by reacting the amidine derivative (2) and the ketoester derivative (3) in a solvent in the presence of a base. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran Ethers such as dioxane and ethylene glycol dimethyl ether; alcohols such as methanol, ethanol, isopropanol, t-butanol and ethylene glycol; sulfoxides such as dimethyl sulfoxide and sulfolane; and dichloromethane and 1,2-dichloroethane. And halogenated hydrocarbons. Examples of the base include alkali metal alkoxides such as sodium methoxide, sodium ethoxide, potassium tert-butoxide. The reaction temperature in this step varies depending on the raw materials and the solvent to be used, but is usually room temperature to 120 ° C, preferably 80 ° C to 110 ° C. The reaction time in this step varies depending on the raw materials used, the solvent, and the reaction temperature, but is usually 1 to 7 days, preferably 1 to 3 days.

[Step B] Compound (5) can be produced by reacting pyrimidine derivative (4) with a halogenating agent in a solvent or without solvent. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether; dichloromethane, 1,2-dichloroethane And halogenated hydrocarbons such as benzene, toluene and xylene. Examples of the halogenating agent include phosphorus oxyhalides such as phosphorus oxychloride and phosphorus oxybromide; phosphorus halides such as phosphorus tribromide, phosphorus pentachloride and phosphorus pentabromide. The reaction temperature in this step is usually room temperature to 120 ° C, preferably 80 ° C to 100 ° C. The reaction time in this step varies depending on the raw materials used, the solvent, and the reaction temperature, but is usually 30 minutes to 24 hours, preferably 4 to 8 hours.

[Step C] 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine represented by the general formula (1) of the present invention by reacting compound (5) with hydrazine derivative (6) in a solvent. Derivatives can be produced. The solvent used in this step is not particularly limited as long as it does not inhibit the reaction. For example, amides such as N, N-dimethylformamide and N, N-dimethylacetamide; diethyl ether, diisopropyl ether, tetrahydrofuran And ethers such as dioxane and ethylene glycol dimethyl ether; sulfoxides such as dimethyl sulfoxide and sulfolane; halogenated hydrocarbons such as dichloromethane and 1,2-dichloroethane. The reaction temperature in this step is usually 0 to 150 ° C, preferably 60 to 100 ° C. The reaction time in this step varies depending on the raw materials used, the solvent, and the reaction temperature, but is usually 30 minutes to 48 hours, preferably 24 to 48 hours.

  Intermediates and target products obtained in the above reactions are necessary for purification methods commonly used in organic synthetic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization, various chromatography, etc. Can be isolated and purified. In addition, the intermediate can be subjected to the next reaction without any particular purification.

  Furthermore, various isomers can be isolated by applying a conventional method using the difference in physicochemical properties between the isomers. For example, a racemic mixture is obtained by a general racemic resolution method such as a method of optically resolving a diastereomeric salt with a general optically active acid such as tartaric acid or a method using optically active column chromatography. Can lead to optically pure isomers. Further, the diastereomeric mixture can be divided by, for example, fractional crystallization or various chromatography. An optically active compound can also be produced by using an appropriate optically active raw material.

  The inhibitor of binding of BAFF to the BR3 receptor of the present invention or an agent for preventing and / or treating autoimmune diseases or the like is represented by 4- (2-benzylidenehydrazinyl) -2- represented by the general formula (1). It contains a phenylpyrimidine derivative, a salt thereof, or a solvate thereof as an active ingredient, and can be used as a pharmaceutical composition. In that case, the compound of the present invention may be used alone, but it is usually used in combination with a pharmaceutically acceptable carrier and / or diluent.

  The administration route is not particularly limited, but can be appropriately selected depending on the purpose of treatment. For example, any of oral preparations, injections, suppositories, inhalants and the like may be used. Pharmaceutical compositions suitable for these dosage forms can be produced by utilizing known preparation methods.

  When preparing an oral solid preparation, the compound represented by the general formula (1) is a pharmaceutically acceptable excipient, and further, if necessary, a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent. After adding a flavoring agent, tablets, coated tablets, granules, powders, capsules and the like can be produced using conventional methods. The additive may be one commonly used in the art. Examples of excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid and the like. Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, and polyvinylpyrrolidone. Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol. Examples of the corrigent include sucrose, orange peel, citric acid, tartaric acid and the like.

  When preparing a liquid preparation for oral administration, a liquid medicine, syrup, elixir is added to the compound represented by the general formula (1) by adding a corrigent, a buffer, a stabilizer, a corrigent and the like using conventional methods. An agent etc. can be manufactured. As the corrigent, those listed above may be used. Examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.

  When preparing an injection, a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, etc. are added to the compound represented by the general formula (1), and subcutaneously using a conventional method. Intramuscular and intravenous injections can be manufactured. Examples of the pH adjuster and buffer include sodium citrate, sodium acetate, sodium phosphate and the like. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.

  When preparing a suppository, a known suppository carrier such as polyethylene glycol, lanolin, cacao butter, fatty acid triglyceride, etc., and a surfactant (for example, , Tween (registered trademark)) and the like can be added and then manufactured using a conventional method.

  In addition to the above, it is possible to appropriately prepare a preferable preparation using a conventional method.

  The dose of the 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention varies depending on age, body weight, symptom, dosage form, number of administrations, etc. 0.1 mg to 1000 mg, preferably 1 mg to 1000 mg, more preferably 1 mg to 500 mg per day as a compound represented by the general formula (1) for adults in a single dose or in several doses orally or parenterally It is preferable to do this.

  The present invention will be described more specifically with reference to the following examples. However, the present invention is not limited to these examples.

[Example 1] Binding inhibition test of BAFF and BR3 receptor 1) Establishment of BR3-expressing cells Raji cell-derived RNA, which is a human B cell culture strain with reference to the sequence described in GenBank Accession No. AF373846 The full length was obtained from the obtained product by RT-PCR and subcloned into a cloning vector pBlueScript II vector (Stratagen). Subsequently, the same gene was inserted into a pEAK10 vector (EdgeBio), which is a vector for mammalian cell expression, and E. coli strain DH5α (TOYOBO) was transformed to obtain a clone. CHO-K1 cells, an epithelial cell line, were transfected. CHO-K1 cells were subcultured using Nutrient Mixture Ham's F-12 medium (Sigma) containing 10% fetal bovine serum, penicillin, and streptomycin. After obtaining a puromycin drug-resistant cell clone, expression of BR3 protein was confirmed by flow cytometry using a mouse anti-human BR3 antibody (Abcam) and a FITC-labeled anti-mouse IgG antibody (Prozyme).

2) Binding test The ligand-receptor binding test was performed as follows. For fluorescently labeled BAFF, recombinant human BAFF (PeproTech) labeled with FMAT Blue labeling kit (Applied Biosystems) was used. BR3-expressing CHO-K1 cells were seeded at 1.0 × 10 ⁴ in a 96 well black clear microtiter plate and cultured overnight in a CO ₂ incubator. After removing the medium, 20 mM Hepes buffer (pH 7.4), Hank's Balanced Salt Solution (Sigma) (containing 0.1% BSA, 0.1% NaN ₃ , 0.08% CHAPS) was used as a reaction solution. After adding the test compound and labeled BAFF in this order, the affinity between the fluorescently labeled BAFF and the BR3 receptor of the expressed cells after standing for 6 hours at 25 ° C. in the dark using a fluorescence detector FMAT8200CDS (Applied Biosystems) Detected. The 50% inhibition concentration (IC ₅₀ value) of each test compound was measured with the maximum reaction of only the fluorescently labeled BAFF as 100%. Compounds 1 and 2 are available from Asinex, and those purchased from the company were used as they were in this test. EC ₅₀ values were calculated using a statistical analysis program, SAS preclinical package Ver 5.0 (SAS institute Japan Co., Tokyo).

3) Results Compound 1 showed an IC ₅₀ value of 0.7 μM and compound 2 showed a 2.6 μM IC ₅₀ value. From the above, it was confirmed that the compound of the present invention has a strong BAFF-BR3 receptor binding inhibitory action. Therefore, the 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) of the present invention or a salt thereof, or a solvate thereof inhibits binding between BAFF and BR3 receptor. Based on the action, it was confirmed to be effective as a preventive and / or therapeutic agent for autoimmune diseases, acquired immune deficiency syndrome or non-Hodgkin lymphoma.

  In the present invention, the 4- (2-benzylidenehydrazinyl) -2-phenylpyrimidine derivative represented by the general formula (1) or a salt thereof, or a solvate thereof is excellent in binding of BAFF and BR3 receptor. The present invention has been found for the first time to have an inhibitory action, and provides a preventive and / or therapeutic agent for low molecular weight autoimmune diseases, acquired immune deficiency syndrome and non-Hodgkin lymphoma that can be administered orally. The present invention provides a preventive and / or therapeutic agent for a new low molecular weight autoimmune disease, acquired immunodeficiency syndrome or non-Hodgkin lymphoma, which is useful in the pharmaceutical industry and has industrial applicability. is doing.

Claims (7)

The following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, or a solvate thereof, as an active ingredient, a binding inhibitor of BAFF to BR3 receptor. The compound represented by the general formula (1) is the following compound:
(E) -4- {2- (2-hydroxybenzylidene) hydrazinyl} -2- (2-hydroxyphenyl) -6-methylpyrimidine, and
(E) -4- {2- (2,4-dihydroxybenzylidene) hydrazinyl} -2- (2-hydroxyphenyl) -6-methylpyrimidine is at least one compound selected from the group consisting of A binding inhibitor of BAFF described in 1. The following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, or a solvate thereof as an active ingredient, a prophylactic and / or therapeutic agent for autoimmune diseases.   The prevention of autoimmune disease according to claim 3, wherein the autoimmune disease is rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, systemic scleroderma, multiple sclerosis or unclassifiable immunodeficiency. / Or therapeutic agent. The following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
Or a salt thereof, or a solvate thereof as an active ingredient, a preventive and / or therapeutic agent for acquired immune deficiency syndrome. The following general formula (1):

[Wherein, R ¹ represents a C _1-10 alkyl group, and R ² , R ³ , R ⁴ , and R ⁵ may be the same as or different from each other, and represent a hydrogen atom or a hydroxyl group. ]
A prophylactic and / or therapeutic agent for non-Hodgkin's lymphoma, comprising a compound represented by the formula: or a salt thereof, or a solvate thereof as an active ingredient.   The non-Hodgkin lymphoma is a precursor B cell lymphoblastic lymphoma, chronic B lymphocytic leukemia, progenitor leukemia, small lymphocytic lymphoma, lymphoplasma cell lymphoma, immunocytoma, mantle cell lymphoma, follicular lymphoma The prophylactic and / or therapeutic agent for non-Hodgkin lymphoma according to claim 6, which is limbic lymphoma, hairy cell leukemia, plasmacytoma, plasma cell myeloma, diffuse large cell lymphoma or Burkitt lymphoma.