Pharmaceutical composition for preventing, suppressing, or treating symptoms associated with allergic reaction

Abstract

To provide a pharmaceutical composition for preventing, suppressing, or treating a symptom associated with an allergic reaction.SOLUTION: The present invention relates to a pharmaceutical composition for preventing, suppressing, or treating a symptom associated with an allergic reaction, the pharmaceutical composition including a compound having a P2X4 receptor antagonizing action or a pharmaceutically acceptable salt thereof as an active ingredient.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a pharmaceutical composition comprising a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof as an active ingredient, for example, a pharmaceutical composition for preventing, suppressing or treating symptoms associated with allergic reactions. This application claims priority based on Japanese Patent Application No. 2020-131412, filed on August 3, 2020, the contents of which are incorporated herein by reference. [Background technology]

[0002] The increasing number of patients with allergic diseases, such as atopic dermatitis, asthma, and hay fever, is becoming a major problem, especially in developed countries. Allergies are thought to be caused by the body's abnormal immune response to substances that it should not normally react to, and various immune cells are thought to be involved. However, there are still many unknowns about the molecular mechanisms behind the onset and worsening of allergic diseases, and since the only treatment available is symptomatic treatment, there is a need to elucidate the pathology in order to find a fundamental treatment.

[0003] The Guidelines for the Treatment of Nasal Allergies (Non-Patent Document 1) describes examples of drug treatments to be selected according to the severity of allergic rhinitis, divided into perennial and seasonal allergic rhinitis. In perennial allergic rhinitis, for mild cases, regardless of the disease type, the first choice is one of the following: second-generation antihistamines, chemical mediator release inhibitors, or type 2 helper T cell (Th2) cytokine inhibitors. For moderate cases, for sneezing and rhinorrhea, one of the following is selected: (1) second-generation antihistamines, (2) chemical mediator release inhibitors, or (3) nasal spray steroids, and (1) or (2) is used in combination with (3) as necessary. For severe cases with particularly strong sneezing and rhinorrhea, a second-generation antihistamine is used in combination with a nasal spray steroid, and for patients with severe nasal congestion, an antileukotriene drug is used in combination with a nasal spray steroid. In the drug treatment of hay fever, early treatment is recommended for patients who show strong hay fever symptoms every year, and the drug to be used is selected based on the expected amount of pollen dispersion, the disease type at the time when the symptoms are strongest, and the severity of the disease. Therefore, for the sneezing / rhinorrhea type, second-generation antihistamines and chemical mediator release inhibitors are used, while for the nasal congestion type, anti-leukotriene drugs are used. If symptoms worsen with an increase in pollen dispersion, nasal steroid sprays are added early on, and the treatment is stepped up according to the type of disease.

[0004] What is required of anti-allergy drugs is that they can maintain normal social life and productive activities while being taken, and it is important that they do not cause drowsiness or cognitive impairment (impaired performance) that limits social activities due to taking them, and they are considered to be drugs in which safety takes priority over efficacy (Non-Patent Document 2). On the other hand, it has been reported that the highest needs of patients for antihistamines are "effectiveness," followed by "safety" and "number of times to take them" (Non-Patent Documents 3 and 4). Antihistamines are classified into first-generation and second-generation, and first-generation antihistamines are fast-acting and highly effective, but their effects are short-lived and they are highly transferred to the brain, which causes major problems with central nervous system depressant effects such as drowsiness. Therefore, they should be administered with caution to people who drive cars or perform dangerous work.

[0005] In addition, because of their anticholinergic effects, caution is required when using them in the case of glaucoma, prostatic hyperplasia, or acute attacks of bronchial asthma (Non-Patent Document 2). In contrast, second-generation antihistamines are slightly less rapid-acting than first-generation antihistamines, but they have a longer effect and less central depressant and anticholinergic effects. Furthermore, late-stage second-generation antihistamines developed in recent years include those that have a shorter time to reach maximum blood concentration and are rapid-acting, and those that have a longer half-life in blood concentration and are effective when administered once a day.

[0006] Taniuchi et al. (Non-Patent Document 5) evaluated the brain histamine H1 receptor occupancy of first- and second-generation antihistamines by positron emission tomography (PET), and considered the relationship with the brain histamine H1 occupancy using antihistamine-induced drowsiness and objective decline in work efficiency as indicators. They classified antihistamines into three types based on the brain histamine H1 occupancy (20% or less: non-sedative, 20% to 50%: mild sedative, 50% or more: sedative). The international conference [Consensus Group on New Generation Antihistamines (CONGA)] also adopted a classification based on the brain histamine H1 occupancy using PET as a method for evaluating sedative effects (Non-Patent Document 6), and it is also adopted in Japan in the Japanese Dermatological Association's Atopic Dermatitis Treatment Guidelines (Non-Patent Document 7). The international guideline Allergic Rhinitis and its Impact on Asthma (ARIA) (Non-Patent Document 8) also recommends the use of oral antihistamines that are non-sedating and do not affect cytochrome P450 (CYP), and the guideline for urticaria EAACI / GA2LEN / EDF / WAO16 also recommends non-sedating oral antihistamines as the first choice. Many non-sedating second-generation antihistamines meet the ideal antihistamine conditions described in the Nasal Allergy Treatment Guidelines [fast acting, sustained effect, few side effects (sleepiness, reduced work efficiency, etc.), long-term administration (safety), and good compliance with once or twice a day administration] (Non-Patent Document 1), but some are known to have issues with convenience, such as those that are affected by drug metabolizing enzymes because active metabolites are produced by drug metabolism, those that need to be administered carefully to patients with reduced liver or kidney function, and those that interact with drugs that enhance central depressant effects, such as alcohol, sleep-inducing drugs, and anti-anxiety drugs.

[0007] As mentioned above, anti-allergy drugs are used according to the severity of the patient's condition, the presence or absence of complications, occupation, age, and the presence or absence of concomitant medications, as well as the patient's lifestyle, preferences, and medical history. Therefore, there is a demand for anti-allergy drugs that meet all of the ideal conditions that conventional antihistamines have not been able to meet: "fast-acting, sustained effect, few side effects (drowsiness, reduced work efficiency, etc.), long-term administration (safety), and easy compliance with once or twice a day administration," and that have a good balance of efficacy and safety and are convenient and non-sedative, meeting the medical needs of patients and medical professionals.

[0008] In addition, in previous findings, mast cells (MCs) recognize antigens (Ag) via high affinity IgE receptors (FcεRI) and cause type I allergic reactions, but Yoshida et al. have reported that stimulation of the ion channel P2X4 receptor (P2X4R) enhances degranulation via FcεRI (Non-Patent Documents 9 and 10). Specifically, using bone marrow-derived MCs (BMMCs) prepared from wild-type and P2X4 receptor-deficient (P2rx4- / -) mice, the role of P2X4 receptors in MC degranulation induced by stimulating IgE-FcεRI complexes with Ag was investigated, and the results showed that ATP significantly increased Ag-induced degranulation in BMMCs prepared from wild-type mice, while it reduced Ag-induced degranulation in BMMCs prepared from P2rx4- / - mice. Furthermore, they reported that the enhancing effect of ATP was restored by expressing P2X4 receptors in P2rx4- / -BMMCs.

[0009] However, Non-Patent Document 9 also states that the mechanism of the effect of ATP is Ca due to ion channel activity. 2+ This suggests that mechanisms other than influx may be involved, and the P2X4 receptor channel inhibitor Cu 2+ They also reported that pretreatment with ATP did not impair the effect of ATP. Therefore, it is not clear how P2X4 receptors are involved in degranulation, and it does not indicate that inhibitors of P2X4 receptor channels have anti-allergic effects.

[0010] Patent Document 1 describes an inhibitor of the P2X4 receptor channel (hereinafter referred to as a P2X4 receptor antagonist). However, the compounds described in the examples of Patent Document 1 are selective serotonin reuptake inhibitors such as Paroxetine and Fluoxetine, and have a completely different structure from the compounds of the present application, which are benzodiazepine derivative compounds. In addition, only experimental results using a neuropathic pain pathological model with nerve injury (L5 spinal nerve injury model) are shown, and it is not known that P2X4 receptor antagonists have a therapeutic effect on allergies.

[0011] Patent Document 2 also describes a compound that exhibits P2X4 receptor antagonistic activity, but just as in Patent Document 1, it only shows its effect in a neuropathic pain model, and it is unclear whether it has any therapeutic effect on allergies.

[0012] In addition, the applicant of the present application has filed patent applications relating to P2X4 receptor antagonists as shown in Patent Documents 3 to 9, but it is unclear whether any of these applications have therapeutic effects against allergies. [Prior art documents] [Patent documents]

[0013] [Patent Document 1] International Publication No. 2008 / 020651 [Patent Document 2] International Publication No. 2010 / 093061 [Patent Document 3] International Publication No. 2008 / 023847 [Patent Document 4] International Publication No. 2012 / 008478 [Patent Document 5] International Publication No. 2012 / 014910 [Patent Document 6] International Publication No. 2012 / 017876 [Patent Document 7] International Publication No. 2013 / 105608 [Patent Document 8] International Publication No. 2015 / 005468 [Patent Document 9] International Publication No. 2015 / 005467 [Non-patent literature]

[0014] [Non-Patent Document 1] Committee for the Creation of Guidelines for the Treatment of Nasal Allergies. Guidelines for the Treatment of Nasal Allergies - Perennial Rhinitis and Hay Fever - 2013 Edition (Revised 7th Edition). Tokyo: Life Sciences; 2013. p34-63. (Section 5.4.3) [Non-Patent Document 2] Kubo, Nobuo. What is required of antihistamines?. Pharmacology Japan. 2005;125:279-284. (Section 5.4.9) [Non-Patent Document 3] Masahiro Takikawa, Akira Iwatsuki, Shinji Shimada, Araki Tokura, Fukumi Furukawa. What do patients with pruritic skin diseases want from antihistamines (antiallergic drugs)? - Results of a patient questionnaire survey. Prog. Med. 2006; 26: 2289-2295. (Section 5.4.10) [Non-Patent Document 4] Ogino, Bin. Patient satisfaction with second-generation antihistamines for the treatment of hay fever - Results of an internet survey of patients (first report). Prog. Med. 2009;29:2531-2537. (Section 5.4.11) [Non-Patent Document 5] Yanai K, Zhang D, Tashiro M, Yoshikawa T, Naganuma F, Harada R, et al. Positron emission tomography evaluation of sedative properties of antihistamines. Expert Opin Drug Saf. 2011;10:613-622. (Section 5.4.12) [Non-Patent Document 6] Holgate ST, Canonica GW, Simons FE, Taglialatela M, Tharp M, Timmerman H, et al. Consensus Group on New-Generation Antihistamines (CONGA): present status and recommendations. Clin Exp Allergy. 2003;33:1305-1324. (Section 5.4.13)

Non-Patent Document 7

Non-Patent Document 8

Non-Patent Document 9

Non-Patent Document 10

[0015] The object of the present invention is to provide a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with allergic reactions, further to provide a pharmaceutical composition useful for preventing, suppressing or treating allergic diseases, particularly to provide a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with type I allergic reactions, more particularly to provide a pharmaceutical composition useful for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, more particularly to provide a pharmaceutical composition useful for suppressing anaphylactic shock, to provide a pharmaceutical composition useful for preventing or treating hay fever, and to provide a pharmaceutical composition useful for preventing or treating urticaria or atopic dermatitis. [Means for solving the problem]

[0016] Therefore, the present inventors have conducted intensive research to solve the above problems, and have found that the compounds represented by general formulas (A) to (BII) or pharma- ceutically acceptable salts thereof having P2X4 receptor antagonistic activity are useful for preventing, suppressing or treating symptoms associated with allergic reactions, and further found to be useful for preventing, suppressing or treating allergic diseases, and particularly found to be useful for preventing, suppressing or treating symptoms associated with type I allergic reactions, and more particularly found to be useful for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, and more particularly found to be useful for suppressing anaphylactic shock, and more particularly found to be useful for preventing or treating hay fever, urticaria or atopic dermatitis, and have thus completed the present invention.

[0017] That is, the present invention provides a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with allergic reactions, further a pharmaceutical composition useful for preventing, suppressing or treating allergic diseases, particularly a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with type I allergic reactions, more particularly a pharmaceutical composition useful for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, a pharmaceutical composition useful for suppressing anaphylactic shock, or a pharmaceutical composition useful for preventing or treating hay fever, urticaria or atopic dermatitis, which comprises a compound having P2X4 receptor antagonistic activity or a pharma- ceutical composition that is pharma-ceutical composition useful for preventing or treating hay fever, urticaria or atopic dermatitis.

[0018] As a compound having a P2X4 receptor antagonistic activity, for example, a compound represented by the following general formula (A) to (BII) can be used. More preferably, as a compound having a P2X4 receptor antagonistic activity, a compound represented by the following general formula (BI) or (BII) can be used. In addition, a pharma- ceutically acceptable salt of the compound can be used.

[0019] The pharmaceutical composition of the present invention can be used, for example, for the prevention, suppression or treatment of symptoms associated with allergic reactions, and further for the prevention, suppression or treatment of allergic diseases, particularly for the prevention, suppression or treatment of symptoms associated with type I allergic reactions, and more particularly for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, the suppression of anaphylactic shock, or the prevention or treatment of hay fever, urticaria or atopic dermatitis.

[0020] From another point of view, the present invention provides the use of a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof for the manufacture of the above-mentioned pharmaceutical composition; and a method for preventing, suppressing or treating symptoms associated with allergic reactions, further a method for preventing, suppressing or treating allergic diseases, particularly a method for preventing, suppressing or treating symptoms associated with type I allergic reactions, more particularly a method for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, a method for suppressing anaphylactic shock, or a method for preventing or treating hay fever, urticaria or atopic dermatitis, comprising the step of administering an effective amount of a compound having P2X4 receptor antagonistic activity or a pharma-ceutical acceptable salt thereof to a mammalian animal, including a human, for preventing, suppressing or treating the same. Effect of the Invention

[0021] The pharmaceutical composition of the present invention is useful as a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with allergic reactions, and further as a pharmaceutical composition useful for preventing, suppressing or treating allergic diseases, particularly as a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with type I allergic reactions, and more particularly as a pharmaceutical composition useful for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, a pharmaceutical composition useful for suppressing anaphylactic shock, or a pharmaceutical composition useful for preventing or treating hay fever, urticaria or atopic dermatitis, each of which is expected to be highly effective. [Brief description of the drawings]

[0022] [Figure 1] FIG. 1 shows the inhibitory effect of compound A on the degranulation reaction induced by costimulation of IgE-sensitized BMMC with DNP-HSA and ATP. [Diagram 2] This is a graph showing the inhibitory effect of compound B on the degranulation reaction induced by costimulation of IgE-sensitized BMMC with DNP-HSA and ATP. [Diagram 3] Mice were pre-sensitized to IgE and administered either compound A or B, or not. Passive cutaneous anaphylaxis (PCA) was induced in each group of mice, and the inhibitory effect of the compounds on PCA was measured. [Figure 4] Mice were pre-sensitized to IgE and given two groups of compound A, one to which compound A was administered, and the other not. Passive systemic anaphylaxis (PSA) was induced in each group of mice, and the inhibitory effect of the compound on PSA was measured. [Diagram 5] Mice were pre-sensitized to IgE and given two groups of compound B, one to which compound B was administered, and the other not. Passive systemic anaphylaxis (PSA) was induced in each group of mice, and the inhibitory effect of the compound on PSA was measured. [Figure 6] This is a graph showing the inhibitory effect of compound A on the degranulation reaction induced by costimulation of IgE-sensitized BMMC with PGE2 and ATP. [Figure 7] FIG. 1 shows the inhibitory effect of compound A on IL-6 release caused by stimulation of BMMC. [Figure 8] FIG. 1 shows the inhibitory effect of compound A on IL-13 release caused by stimulation of BMMC. [Figure 9] FIG. 1 shows the inhibitory effect of compound A on TNF-α release caused by stimulation of BMMC. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for preventing, suppressing, or treating symptoms associated with allergic reactions, but can also be used as a pharmaceutical composition for the following applications. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for preventing, suppressing, or treating allergic diseases. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for preventing, suppressing, or treating symptoms associated with type I allergic reactions. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of anaphylactic shock. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of allergic rhinitis. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of bronchial asthma. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of allergic dermatitis. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for suppressing anaphylactic shock. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for preventing or treating hay fever. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for preventing or treating urticaria. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of atopic dermatitis.

[0024] In another aspect, the pharmaceutical composition of the present invention can be used as a pharmaceutical composition for the following applications. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition for preventing, suppressing, or treating symptoms associated with the allergic reaction, which is accompanied by inflammation. The pharmaceutical composition of the present invention can be used as a pharmaceutical composition for preventing, suppressing or treating symptoms associated with the allergic reaction, which involves the extracellular release of secretory granules in mast cells.

[0025] As used herein, "symptoms associated with allergic reactions" include allergic diseases (also referred to as allergic disorders). As used herein, "allergic disorders" refers to illnesses caused by allergies. As used herein, the term "prevention" is a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means for achieving this. In the present specification, "treatment" includes the disappearance, complete cure, cure or remission of "pathological" or "abnormal" symptoms, conditions or diseases, and the actions or means therefor, the suppression of the worsening of "pathological" or "abnormal" symptoms, conditions or diseases, and the actions or means therefor, and is also a concept including improvement. Here, "improvement" is a concept including the bringing of "pathological" or "abnormal" symptoms, conditions or diseases closer to a "healthy" or "normal" state, or the actions or means therefor, and the bringing of "healthy" or "normal" state, or the actions or means therefor. Thus, in one embodiment, "improvement" includes the fact that a numerical value that is an index of a "pathological" or "abnormal" symptom or condition becomes smaller or larger according to the "improvement", and approaches a normal value or becomes a normal value. In addition, "suppression" is a concept including the stopping or slowing down the worsening or progression of a symptom, condition or disease, and the actions or means therefor, and also includes the improvement of the symptom, condition or disease, or the actions or means therefor. Here, "improvement" has the above meaning. The "worsening or progression of a symptom, condition or disease" includes the worsening or progression of a "pathological" or "abnormal" symptom, condition or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition or disease. In one embodiment, "suppression" refers to stopping or slowing down the worsening or progression of a symptom, condition or disease, or an act or means therefor. In another embodiment, "suppression" refers to stopping or slowing down the worsening or progression of a symptom, condition or disease. In one embodiment, "treatment" refers to the disappearance, cure, treatment or amelioration of a "pathological" or "abnormal" symptom, condition or disease, and the act or means therefor. In another embodiment, "treatment" refers to the disappearance, cure, treatment or amelioration of a "pathological" or "abnormal" symptom, condition or disease. In this specification, the symptoms, conditions or diseases or numerical values ​​indicative thereof, or conditions or functions may be evaluated by comparing results before and after administration of a pharmaceutical provided by the present invention, or by comparing a group administered a pharmaceutical provided by the present invention with a group administered a placebo or a control not containing the pharmaceutical provided by the present invention.

[0026] As the active ingredient of the pharmaceutical composition of the present invention, a compound represented by the following general formulas (A) to (BII) or a pharma- ceutical acceptable salt thereof can be used. The abbreviations used in the tables below are as follows: Me: methyl group, Et: ethyl group, Pr: n-propyl group, iPr: isopropyl group, tBu: tert-butyl group, Ac: acetyl group, Ph: phenyl group. In the tables shown below, a substituent may be indicated together with the position number of the substitution position. In a chemical formula, a prime "'" may be added to one of the position numbers for convenience in order to distinguish between seemingly identical position numbers. In a compound name, the position number may be expressed without the prime as long as the structure can be uniquely identified.

[0027] (A-1) The following general formula (A): [ka] (In the formula, R 1A represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group, R 2A and R 3Amay be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkylsulfonylamino group having 1 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8), a carbamoyl group, an alkylthio group having 1 to 8 carbon atoms, an alkylsulfinyl group having 1 to 8 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms, or a sulfamoyl group; R 4A and R 5A may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkyl group having 1 to 3 carbon atoms substituted with a phenyl group, And W A represents a 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms as ring-constituting elements which may have a substituent.) or a pharma- ceutically acceptable salt thereof.

[0028] In the general formula (A), R 1A , R 2A , R 3A , R 4A and R 5A Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group. R 1A Examples of the alkenyl group having 2 to 8 carbon atoms include an allyl group. R 1A , R 2A , R 3A , R 4A and R 5A or R 11A , R 12A , R 13A , R14A and R 15A Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, etc. substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group, etc. R 1A , R 4A and R 5A Examples of the alkyl group having 1 to 3 carbon atoms substituted with a phenyl group include a benzyl group. R 2A and R 3A Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group.

[0029] R 2A and R 3A Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, etc. substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, etc. R 2A and R 3A The halogen atom includes a fluorine atom, a chlorine atom, a bromine atom, and the like. R 2A and R 3A Examples of the alkylamino group having 1 to 8 carbon atoms include a methylamino group and an ethylamino group. R 2A and R 3A Examples of the dialkylamino group having 1 to 8 carbon atoms include a dimethylamino group and a diethylamino group. R 2A and R 3AAn example of the acylamino group having 2 to 8 carbon atoms is an acetylamino group. R 2A and R 3A Examples of the acylamino group having 2 to 8 carbon atoms and substituted with 1 to 3 halogen atoms include a trifluoromethylcarbonylamino group.

[0030] R 2A and R 3A An example of the alkylsulfonylamino group having 1 to 8 carbon atoms is a methylsulfonylamino group. R 2A and R 3A An example of the acyl group having 2 to 8 carbon atoms is an acetyl group. R 2A and R 3A Examples of the alkoxycarbonyl group (alkoxy moiety having 1 to 8 carbon atoms) include a methoxycarbonyl group, an ethoxycarbonyl group, and the like. R 2A and R 3A An example of the alkylthio group having 1 to 8 carbon atoms is a methylthio group. R 2A and R 3A An example of the alkylsulfinyl group having 1 to 8 carbon atoms is a methylsulfinyl group. R 2A and R 3A An example of the alkylsulfonyl group having 1 to 8 carbon atoms is a methylsulfonyl group.

[0031] W A Examples of the 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms as ring-constituting elements which may have a substituent include tetrazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-oxadiazole, pyrazole, imidazole, oxazole, isoxazole, pyrrole, thiazole, pyridine, and pyrrolidine. W AExamples of the substituent that may be possessed by the 5- or 6-membered heterocycle containing 1 to 4 nitrogen atoms as a ring-constituting element that may have the substituent include an alkyl group having 1 to 8 carbon atoms such as a methyl group, an ethyl group, etc., an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms such as a trifluoromethyl group, a halogen atom such as a fluorine atom, a cyano group, an oxo group, a thioxo group, etc. R in general formula (A) 2A and R 3A is R 2A , R 3A The benzene ring substituted with may have 1 to 3 identical or different groups.

[0032] As the compound of general formula (A), the following compounds are preferred. (A-2)W A The compound according to (A-1), wherein the substituent is tetrazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-oxadiazole, pyrazole or imidazole, which may have as a substituent a substituent selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a cyano group, an oxo group and a thioxo group. (A-3)W A The compound according to (A-1) or (A-2), wherein the substituent is tetrazole, 1,2,4-triazole or 1,2,3-triazole, which may have as a substituent selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom and a cyano group. (A-4)W A The compound according to any one of (A-1) to (A-3), wherein (A-5)W A The compound according to any one of (A-1) to (A-4), wherein

[0033] (A-6)R 1A is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms (A-1) to (A-5). (A-7)R 1A The compound according to any one of (A-1) to (A-6), wherein (A-8)R 4A is a hydrogen atom, and R 5A is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms (A-1) to (A-7). (A-9)R 4A and R 5A and (A-1) or (A-2) are each a hydrogen atom. (A-10)R 2A is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, an acyl group having 2 to 8 carbon atoms, or an alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8). (A-11)R 2A The compound according to any one of (A-1) to (A-10), wherein (A-12)R 3A is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a carboxyl group, an acyl group having 2 to 8 carbon atoms, or an alkoxycarbonyl group (the number of carbon atoms in the alkoxy moiety is 1 to 8). (A-13)R 3A The compound according to any one of (A-1) to (A-12), wherein Examples of pharma- ceutically acceptable salts of the compound represented by general formula (A) include those represented by the formula (A) R 2A , R 3A When R is an amino group, etc., examples of the salt include hydrochloride, etc. 2A , R 3AWhen is a carboxyl group, examples of the salt include alkali metal salts such as sodium, potassium and lithium salts.

[0034] Representative compounds encompassed by general formula (A) are shown below. <Representative compound A-100> [ka] (In the formula, R 1A , R 4A , R 5A and W A And W A The substitution positions are as shown in Tables 1 to 3. In Tables 1 to 3, W A The substitution positions of indicate the substitution positions on the benzene ring. That is, the 2nd, 3rd, and 4th positions in the table correspond to the 2'-, 3'-, and 4'-positions in the formula of Representative Compound A-100, respectively.

[0035] [Table 1]

[0036] [Table 2]

[0037] [Table 3]

[0038] <Representative compound A-200> [ka] (In the formula, R 1A , R 2A , R 4A , R 5A and W A And W A The substitution positions are as shown in Tables 4 and 5. In Tables 4 and 5, W AThe substitution positions of indicate the substitution positions on the benzene ring. That is, the 2nd, 3rd, and 4th positions in the table correspond to the 2'-, 3'-, and 4'-positions in the formula of the representative compound A-200, respectively.

[0039] [Table 4]

[0040] [Table 5]

[0041] <Representative compound A-300> [ka] (In the formula, R 1A , R 2A , R 3A , R 4A , R 5A and W A And W A The substitution positions are as shown in Tables 6 and 7. In Tables 6 and 7, W A The substitution positions of indicate the substitution positions on the benzene ring. That is, the 3rd and 4th positions in the table correspond to the 3' and 4' positions in the formula of the representative compound A-300, respectively.

[0042] [Table 6]

[0043] [Table 7]

[0044] (B-1) The following general formula (BI): [ka] (In the formula, R 1B and R 2Bmay be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), a phenyl group which may have a substituent, a pyridyl group which may have a substituent, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms); R 1B and R 2B may be taken together with the benzene ring to which they are attached to form a fused ring selected from a naphthalene ring, a quinoline ring, an isoquinoline ring, a tetrahydronaphthalene ring, an indane ring, a tetrahydroquinoline ring, or a tetrahydroisoquinoline ring, and R 1B and R 2B Together, R 1B and R 2B is bonded to a ring consisting of carbon atoms, which may be substituted with 1 to 4 substituents selected from an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms); R 3B and R 4Bmay be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms); R 5B represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), R 6B and R 7B may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, or an amino group, X B represents C, CH or N, Y B represents N, NH or C(=O), However, X B When N, Y B is not N or NH, Also, X B When is C,CH, Y B is not C(=O), A double line consisting of a solid line and a dashed line represents a single bond or a double bond. Z B represents an oxygen atom or a sulfur atom, A Brepresents a benzene ring, a pyridine ring, a thiophene ring, a pyrimidine ring, a naphthalene ring, a quinoline ring or an indole ring which may have 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group or a pyridyl group, or represents a bond; B B is N(R 8B )C(=O), NHCONH, CON(R 9B ), NHC(=S)NH, N(R 10B )SO2, SO2N(R 11B ) or OSO2, Here, R 8B , R 9B , R 10B and R 11B represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), D B represents an alkylene chain having 1 to 6 carbon atoms which may have 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group or aralkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), and which may further have a double bond, or a bond; E B are O, S, and NR 12B , or a bond, Here, R 12Brepresents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), G B may have as a substituent an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aralkyl group (wherein the carbon atom of the aryl moiety is the number of carbon atoms in the alkylene moiety is 1 to 8), and represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine which may have 1 to 4 identical or different substituents selected from an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolyl group, an optionally substituted oxazolyl group, or an optionally substituted thiazolyl group; And m B represents an integer from 0 to 5. However, R 1B and R 2B do not form a ring together, and X B C, Y B is N, the double line consisting of a solid line and a dashed line is a double bond, and Z B is an oxygen atom, and A B is a benzene ring, m B is 0, B B is C(=O)NH, and E B is a bond and G B(Except when R is a phenyl group) or a pharma- ceutically acceptable salt thereof.

[0045] (B-2) The following general formula (BII): [ka] (In the formula, [ka] represents a naphthalene ring, a quinoline ring, an isoquinoline ring, a tetrahydronaphthalene ring, an indane ring, a tetrahydroquinoline ring, or a tetrahydroisoquinoline ring, These rings may be substituted with 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms); R 3Ba and R 4Ba may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms); R 5Ba represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), R 6Ba and R 7Ba may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, or an amino group, [ka] represents a benzene ring, a pyridine ring, a thiophene ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, or an indole ring which may have 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (wherein the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group; B Ba is N(R 8Ba )C(=O), NHCONH,CON(R 9Ba ), NHC(=S)NH, N(R 10Ba )SO2, SO2N(R 11Ba ), or OSO2, Here, R 8Ba , R 9Ba , R 10Ba and R 11Barepresents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), E Ba are O, S, and NR 12Ba or represents a bond, Here, R 12Ba represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), G Ba may have as a substituent an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aralkyl group (wherein the carbon atom of the aryl moiety is the number of carbon atoms in the alkylene moiety is 1 to 8), and represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine which may have 1 to 4 identical or different substituents selected from an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolyl group, an optionally substituted oxazolyl group, or an optionally substituted thiazolyl group; And n B represents an integer of 0 to 5.) or a pharma- ceutically acceptable salt thereof.

[0046] Next, the substituents in the general formulae (BI) and (BII) of this specification will be described. Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group and a cyclohexyl group. Examples of the alkenyl group having 2 to 8 carbon atoms include an allyl group. Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group.

[0047] Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, t-butyl group, etc. substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group, etc. Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, t-butoxy group, and the like, each of which is substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, and the like. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.

[0048] Examples of the alkylamino group having 1 to 8 carbon atoms include a methylamino group and an ethylamino group. Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group and a diethylamino group. An example of the acylamino group having 2 to 8 carbon atoms is an acetylamino group. Examples of the acyl group having 2 to 8 carbon atoms include an acetyl group.

[0049] Examples of the alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms) include a methoxycarbonyl group. Examples of the aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms) include a benzyl group. Examples of the alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group include a 2-hydroxyethyl group.

[0050] Examples of the alkylsulfinyl group having 1 to 6 carbon atoms include a methanesulfinyl group. Examples of the alkylthio group having 1 to 6 carbon atoms include a methylthio group. Examples of the alkylsulfonyl group having 1 to 6 carbon atoms include a methanesulfonyl group.

[0051] Examples of the substituent that the optionally substituted phenyl group, the optionally substituted pyridyl group, the optionally substituted imidazolyl group, the optionally substituted oxazolyl group and the optionally substituted thiazolyl group may have include a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and the like.

[0052] As the compound of the above general formula (BI), the following compounds are preferred. (B-1-1) R 1B and R 2Bmay be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a phenyl group which may have a substituent, a pyridyl group which may have a substituent or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0053] (B-1-2) R 1B and R 2B together form a naphthalene ring or a tetrahydronaphthalene ring together with the benzene ring to which they are attached, and R 1B and R 2B Together, R 1B and R 2B and the like are bonded to a benzene ring or a cyclohexene ring, each of which may be substituted with 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms). (B-1-3) R 1B and R 2B together form a naphthalene ring together with the benzene ring to which they are attached, and R 1B and R 2B Together, R 1B and R 2Bare bonded to a benzene ring which is optionally substituted with 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, and an amino group. (B-1-4) R 1B and R 2B The compound according to the above (B-1) or (B-1-1), in which, together with the benzene ring to which they are attached, form a naphthalene ring or a tetrahydronaphthalene ring.

[0054] (B-1-5) R 3B and R 4B may be the same or different, and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms). (B-1-6) R 5B is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms). (B-1-7) R 5B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-6), wherein (B-1-8) R 6B and R 7Bmay be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or a compound or a pharma- ceutically acceptable salt thereof according to any one of the above (B-1) or (B-1-1) to (B-1-7). (B-1-9) R 6B and R 7B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-8), wherein both are hydrogen atoms.

[0055] (B-1-10) R 3B , R 4B , R 5B , R 6B and R 7B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-9), wherein

[0056] (B-1-11) X B is N and Y B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-10), wherein is C(=O) and the double line consisting of a solid line and a dashed line is a single bond. (B-1-12) X B is C and Y B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-11), wherein is N and the double line consisting of a solid line and a dashed line is a double bond. (B-1-13) Z B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-12), wherein

[0057] (B-1-14) A BThe compound according to any one of the above (B-1) or (B-1-1) to (B-1-13), wherein, as a substituent, the phenyl group or pyridyl group optionally has 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group. (B-1-15) A B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-14), wherein is a phenyl group optionally having 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, or an amino group.

[0058] (B-1-16) A B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-15), wherein is a phenyl group or a pyridyl group. (B-1-17) A B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-16), wherein

[0059] (B-1-18) B B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-17), wherein (B-1-19) B B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-18), wherein

[0060] (B-1-20) B B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-19), wherein (B-1-21) B B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-20), wherein (B-1-22) D B is an alkylene chain having 1 to 6 carbon atoms and optionally having a double bond, and which may have 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, as a substituent. (B-1-23) D B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-22), wherein

[0061] (B-1-24) D B has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms and an alkenyl group having 2 to 8 carbon atoms, as substituents. (B-1-25) D B has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 3 carbon atoms and an alkenyl group having 2 to 3 carbon atoms, as substituents. (B-1-26) EB The compound according to any one of the above (B-1) or (B-1-1) to (B-1-25), wherein

[0062] (B-1-27) G B and the substituents are an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, a carbon atom, a The compound according to any one of the above (B-1) or (B-1-1) to (B-1-26), which is piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, each of which may have 1 to 4 identical or different substituents selected from an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms. (B-1-28) G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-27), wherein the alkyl group is a benzene group which may have 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms.

[0063] (B-1-29) G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-28), wherein the substituent is benzene or pyridine which may have 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, an amino group, a dialkylamino group having 2 to 8 carbon atoms, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms.

[0064] (B-1-30) G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-29), wherein R is a benzene group which may have, as substituents, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0065] (B-1-31) m B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-30), wherein is 0.

[0066] (B-1-32) A B is a benzene ring, and m B is 0, and B B is NHC(=O) or NHSO2, and D B is an alkyl group having 1 to 3 carbon atoms or a bond, and E B is a bond, and G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-31), wherein R is a benzene group which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0067] (B-1-33) A B is a benzene ring, and m B is 0, and B B is NHC(=O) and D B is a bond, and E B is a bond, and G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-32), wherein R is a benzene group which may have, as substituents, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group. (B-1-34) R 1B and R 2B together form a naphthalene ring together with the benzene ring to which they are attached, and R 3B , R 4B , R 5B , R 6B and R 7B represents a hydrogen atom, and X B is N and Y B is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, and Z B represents an oxygen atom, and A B represents a benzene ring, m B represents 0, B B represents NHC(=O) or NHSO2, D B represents an alkyl group having 1 to 3 carbon atoms or a bond, E B represents a bond, and G B The compound according to any one of the above (B-1) or (B-1-1) to (B-1-33), which is benzene optionally having 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group. (B-1-35) In the above general formula (BI), R 1B and R 2B together form a naphthalene ring together with the benzene ring to which they are attached, and R 3B , R 4B , R 5B, R 6B and R 7B represents a hydrogen atom, and X B is N and Y B is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, and Z B represents an oxygen atom, and A B represents a benzene ring, m B represents 0, B B represents NHC(=O), and D B represents a bond, and E B represents a bond, and G B The compound according to any one of (B-1) or (B-1-1) to (B-1-34), wherein R is a benzene group which may have, as a substituent, 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0068] As the compound of the above general formula (BII), the following compounds are preferred. (B-2-1) [ka] is a naphthalene ring or tetrahydronaphthalene ring optionally substituted by 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms). (B-2-2) [ka] is a naphthalene ring optionally substituted with 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, and an amino group.

[0069] (B-2-3) R 3Ba and R 4Ba may be the same or different, and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms). (B-2-4) R 5Ba is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), (B-2-5) R 5Ba The compound according to any one of the above (B-2) or (B-2-1) to (B-2-4), wherein (B-2-6) R 6Ba and R 7Ba may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms. (B-2-7) R 6Ba and R 7Ba The compound according to any one of the above (B-2) or (B-2-1) to (B-2-6), wherein both are hydrogen atoms.

[0070] (B-2-8) [ka] The compound according to any one of the above (B-2) or (B-2-1) to (B-2-7), wherein, as a substituent, the phenyl group or pyridyl group optionally has 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group. (B-2-9) [ka] The compound according to any one of the above (B-2) or (B-2-1) to (B-2-8), wherein is a phenyl group optionally having 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, or an amino group. (B-2-10) [ka] The compound according to any one of the above (B-2) or (B-2-1) to (B-2-9), wherein

[0071] (B-2-11) B Ba The compound according to any one of the above (B-2) or (B-2-1) to (B-2-10), wherein (B-2-12) B Ba The compound according to any one of the above (B-2) or (B-2-1) to (B-2-11), wherein (B-2-13) E Ba The compound according to any one of the above (B-2) or (B-2-1) to (B-2-12), wherein

[0072] (B-2-14) G Ba which may be substituted with an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, or an alkylsulfinyl group having 1 to 6 carbon atoms, The compound according to any one of the above (B-2) or (B-2-1) to (B-2-13), which is piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, which may have 1 to 4 identical or different substituents selected from an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms. (B-2-15) G BaThe compound according to any one of the above (B-2) or (B-2-1) to (B-2-14), wherein the alkyl group is a benzene group which may have 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms.

[0073] (B-2-16) n B The compound according to any one of the above (B-2) or (B-2-1) to (B-2-15), wherein is 0.

[0074] In the above general formula (BI), R B1 and R B2 preferably combine with the benzene ring to which they are attached to form a condensed ring selected from a naphthalene ring or a tetrahydronaphthalene ring, and particularly preferably form a naphthalene ring.

[0075] In the above general formula (BI), R B3 , R B4 , R B5 , R B6 and R B7 Preferably, represents a hydrogen atom.

[0076] In the above general formula (BI), X B is N and Y B is C(=O) and the double line consisting of a solid line and a dashed line is preferably a single bond.

[0077] In the above general formula (BI), Z B is preferably an oxygen atom.

[0078] In the above general formula (BI), A B preferably represents a benzene ring or a pyridine ring, and particularly preferably represents a benzene ring.

[0079] In the above general formula (BI), m B Preferably, represents 0 to 4, and particularly preferably represents 0.

[0080] In the above general formula (BI), B B is N(R 8B )C(=O) or N(R 10B )SO2, where R 8B and R 10B More preferably, B represents a hydrogen atom. B It is particularly preferred that represents NHC(=O).

[0081] In the above general formula (BI), D B preferably represents an alkylene chain having 1 to 6 carbon atoms having 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms and an alkenyl group having 2 to 8 carbon atoms, or a bond, more preferably represents an alkylene chain having 1 to 6 carbon atoms having 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 3 carbon atoms and an alkenyl group having 2 to 3 carbon atoms, or a bond, and particularly preferably represents a bond.

[0082] In the above general formula (BI), E B preferably represents O or a bond, and particularly preferably represents a bond.

[0083] In the above general formula (BI), G Bpreferably represents benzene or pyridine which may have, as a substituent, 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, an amino group, a dialkylamino group having 2 to 8 carbon atoms, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms; B It is particularly preferable that represents benzene which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0084] In the above general formula (BI), A B represents a benzene ring, m B represents 0, B B represents NHC(=O) or NHSO2, D B represents an alkyl group having 1 to 3 carbon atoms or a bond, E B represents a bond, and G B It is particularly preferable that represents a benzene group which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0085] In the above general formula (BI), A B represents a benzene ring, m B represents 0, B B represents NHC(=O), and D B represents a bond, and E B represents a bond, and G B It is particularly preferable that represents benzene which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0086] In the above general formula (BI), R B1 and R B2 together form a naphthalene ring together with the benzene ring to which they are attached, and R B3 , R B4 , R B5 , R B6 and R B7 represents a hydrogen atom, and X B is N and Y B is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, and Z B represents an oxygen atom, and A B represents a benzene ring, m B represents 0, B B represents NHC(=O) or NHSO2, D B represents an alkyl group having 1 to 3 carbon atoms or a bond, E B represents a bond, and G B It is more preferable that represents benzene which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0087] In the above general formula (BI), R B1 and R B2 together form a naphthalene ring together with the benzene ring to which they are attached, and R B3 , R B4 , R B5 , R B6 and R B7 represents a hydrogen atom, and X B is N and Y B is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, and Z B represents an oxygen atom, and A B represents a benzene ring, m B represents 0, B B represents NHC(=O), and D B represents a bond, and E B represents a bond, and G BIt is particularly preferable that represents benzene which may have, as a substituent, 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0088] Representative compounds encompassed by general formula (BI) and / or (BII) are shown below.

[0089] <Representative compound example B-100>

[0090] [ka]

[0091] (In the formula, B Ba (replacement position), n B , E Ba and G Ba (as shown in Tables 8 to 17)

[0092] [Table 8]

[0093] [Table 9]

[0094] [Table 10]

[0095] [Table 11]

[0096] [Table 12]

[0097] [Table 13]

[0098] [Table 14]

[0099] [Table 15]

[0100] [Table 16]

[0101] [Table 17]

[0102] <Representative compound example B-200>

[0103] [ka]

[0104] (In the formula, B Ba (replacement position), n B , E Ba and G Ba as shown in Tables 18 and 19)

[0105] [Table 18]

[0106] [Table 19]

[0107] <Representative compound example B-300>

[0108] [ka]

[0109] (In the formula, R 1B , B Ba (replacement position), n B , E Ba and G Ba as shown in Table 20)

[0110] [Table 20]

[0111] <Representative compound example B-400>

[0112] [ka]

[0113] (In the formula, B Ba (replacement position), n B , E Ba and G Ba as shown in Table 21)

[0114] [Table 21]

[0115] <Representative compound example B-500>

[0116] [ka]

[0117] (In the formula, B Ba (replacement position), n B , E Ba and G Ba as shown in Table 22)

[0118] [Table 22]

[0119] <Representative compound example B-600>

[0120] [ka]

[0121] (In the formula, B B (substitution position), D B , E B and G B as shown in Table 23)

[0122] [Table 23]

[0123] <Representative compound example B-700>

[0124] [ka]

[0125] (In the formula, m B (substitution position), B B , D B , E B and G B as shown in Table 24)

[0126] [Table 24]

[0127] <Representative compound example B-800>

[0128] [ka]

[0129] (In the formula, X Ba , Y Ba , B Ba (replacement position), n B , E Ba and GBa as shown in Table 25)

[0130] [Table 25]

[0131] <Representative compound example B-900>

[0132] [ka]

[0133] (In the formula, I=II-III=IV, B Ba (replacement position), n B , E Ba and G Ba as shown in Table 26)

[0134] [Table 26]

[0135] <Representative compound example B-1000>

[0136] [ka]

[0137] (In the formula, I-II-III-IV, B Ba (replacement position), n B , E Ba and G Ba (See Table 27)

[0138] [Table 27]

[0139] <Representative compound example B-1100>

[0140] [ka]

[0141] (In the formula, R 5Ba , B Ba (replacement position), n B , E Ba and G Ba as shown in Table 28)

[0142] [Table 28]

[0143] The compounds represented by the above general formula (A) are disclosed in International Publication No. 2010 / 093061, and therefore any of these compounds can be easily obtained by referring to these International Publications. The disclosures of these International Publications are incorporated herein by reference in their entirety.

[0144] The compounds represented by the above general formulas (BI) and (BII) are disclosed in International Publication No. 2013 / 105608, and therefore any of these compounds can be easily obtained by referring to these International Publications. The disclosures of these International Publications are incorporated herein by reference in their entirety.

[0145] Moreover, the above-mentioned International Publication Nos. 2010 / 093061, 2013 / 105608, and 2015 / 005467 disclose that the compounds represented by the above general formulae (A) to (BII) have a P2X4 receptor antagonistic effect.

[0146] Specific examples of suitable compounds included in the compounds represented by the above general formulas (A) to (BII) or pharma- ceutically acceptable salts thereof are shown below, but the compounds usable as active ingredients in the pharmaceutical composition of the present invention or pharma- ceutically acceptable salts thereof are not limited to these. (Compound A1) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A2) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; (Compound A3) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione potassium salt; (Compound A4) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A5) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; (Compound A6) 1-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A7) 1,3-dimethyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A8) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A9) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; (Compound A10) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0147] (Compound A11) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; (Compound A12) 5-[2-bromo-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A13) 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A14) 5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A15) 5-[3-(5-oxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A16) 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A17) 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; (Compound A18) 5-[3-(oxazol-2-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A19) 5-[3-(1H-pyrazol-4-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A20) 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound A21) 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt;

[0148] (Compound B1) 5-(4-benzoylaminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B2) 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B3) 5-[4-(3-bromobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B4) 5-[4-[4-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B5) 5-[4-(2-methylbenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B6) 5-[4-(2,6-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B7) 5-[4-(2,6-dichlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B8) 5-[4-(3-chlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B9) 5-[4-(2-phenylacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B10) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylthiourea;

[0149] (Compound B11) 5-[4-(2,3-dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B12) 5-[4-(2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B13) 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B14) 5-[4-(2,3-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B15) 5-[4-(2,5-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B16) 5-[4-(5-bromo-2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B17) 5-[4-(2,4-dichlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B18) 5-[4-(2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B19) 5-[4-(2,3-dihydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B20) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea;

[0150] (Compound B21) 5-[4-[(2,6-dichlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B22) 5-[4-[(2-methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B23) 5-[4-[(2-hydroxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B24) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]thiourea; (Compound B25) 5-[4-[3-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B26) 5-[4-[2-[2-(trifluoromethyl)phenyl]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B27) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]urea; (Compound B28) 5-[4-[(2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B29) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B30) 5-[4-(3-phenylpropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0151] (Compound B31) 5-[4-[(1H-indole-3-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B32) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B33) 5-[4-[(2-methyl-2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B34) 5-[4-(2-phenoxyacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B35) 5-[4-[2-(2-chloro-4-methoxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B36) 5-[4-[(1-methyl-1H-imidazole-2-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B37) 5-[4-[2-(2,4-dichlorophenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B38) 5-[4-[2-(2-chloro-4-hydroxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B39) 5-[4-(3-phenylpropenylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B40) 5-[4-[(3-pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride;

[0152] (Compound B41) 5-[4-(1H-benzimidazole-2-carbonylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B42) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (Compound B43) 5-[4-[(benzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B44) 5-[4-[(2-chlorobenzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B45) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-hydroxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (Compound B46) 5-[4-(2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B47) 5-[4-(2-bromobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B48) 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B49) 5-[4-(2,3-dimethylbenzoylamino)-3-fluorophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B50) 5-[4-[2-(2-methylphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0153] (Compound B51) 5-[4-[(quinoxalin-2yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B52) 5-[4-[(5-methylthiophen-2yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B53) 5-[3-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B54) 5-[4-[(2,4,6-trimethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B55) 5-[4-(cyclohexylcarbonylamino)phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B56) 1-[4-(2,3-dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (Compound B57) 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B58) 5-[4-[(6-methylpyridin-2-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B59) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B60) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-(2-methylphenyl)thiourea;

[0154] (Compound B61) 5-[4-(2-methoxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B62) 5-[4-(2,3-dichlorobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B63) 5-[4-(2,3-dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B64) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (Compound B65) 5-[4-[(4-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B66) 5-[4-[2-(2,4-dichlorophenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B67) 5-[4-[2-(2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B68) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)butyl]-2-chloro-3-methoxybenzamide; (Compound B69) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (Compound B70) 5-[4-(2-acetylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0155] (Compound B71) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B72) 5-[2-(2-iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B73) 5-[3-[(2-iodobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B74) 6,7-dimethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (Compound B75) 5-[4-[(1-methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B76) 5-[4-[(benzofuran-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B77) 5-[4-[(1-methyl-1H-indol-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B78) 5-[4-(2-propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B79) 5-[4-(2-propylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B80) 5-[3-fluoro-4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0156] (Compound B81) 5-[4-(2-hydroxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B82) 5-[4-[(2-isopropoxybenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B83) 5-[4-[(3-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B84) 5-[4-(2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B85) 5-[4-[2-(4-chloro-2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B86) 5-[4-[(4-fluoro-2-trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B87) 5-[4-(4-fluoro-2-methoxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B88) 5-[4-(4-fluoro-2-hydroxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B89) 5-[3-[(2-iodophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B90) 5-[4-(2-methyl-2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0157] (Compound B91) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (Compound B92) 5-[4-[(3-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B93) 5-[4-(4-iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B94) 5-[4-(6-fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B95) 5-[4-(2-hydroxy-4-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B96) 5-[4-(6-fluoro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B97) 5-[4-(2-fluorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B98) 5-[4-[(2-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B99) 5-[4-(2-methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B100) 5-[4-(2-hydroxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0158] (Compound B101) 5-[4-[3-(2-methylphenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B102) 5-(4-phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B103) 5-(4-benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B104) 5-[4-[3-(2-methylphenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B105) 5-[4-[3-(2-chlorophenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B106) 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B107) 5-[4-[(1-methyl-1H-pyrrol-2-ylacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B108) 5-[4-(2-chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B109) 5-[4-[3-(2-chlorophenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B110) 5-[4-(2-chlorophenyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0159] (Compound B111) 5-[4-(6-bromo-2,3-methylenedioxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B112) 5-[4-(6-bromo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B113) 5-[4-[(2-tert-butylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B114) 5-[2-(2-iodobenzoyl)aminopyridin-5-yl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B115) 5-[4-(6-bromo-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B116) 5-[4-(6-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B117) 5-[4-(2-iodobenzoylamino)phenyl]-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione; (Compound B118) 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B119) 5-[4-(2-hydroxy-6-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B120) 5-[4-[2-methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0160] (Compound B121) 5-[4-[2-hydroxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B122) 5-[4-[(2-isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B123) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B124) 5-[4-[2-chloro-5-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B125) 5-[4-[2-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B126) 5-[4-[3-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B127) 5-[4-[2-ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B128) 5-[4-(3-methanesulfonylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B129) 6-ethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (Compound B130) 5-[4-[2-ethyl-6-hydroxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0161] (Compound B131) 5-[4-(3-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B132) 5-[4-(2-chloro-5-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B133) 5-[4-(2-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B134) 5-[4-[[2-(4-morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B135) 5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (Compound B136) 5-[4-[[(3-chloropyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B137) 5-[4-(2-chloro-6-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (Compound B138) 5-[4-(3-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B139) 5-[4-[(3-methylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B140) 5-[4-[[(3-chloropyridin-2-yl)carbonyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0162] (Compound B141) 5-[4-(3-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B142) 5-[4-[[(3-hydroxypyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B143) 5-[4-[(3-vinylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B144) 5-[4-[(3-ethylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B145) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B146) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B147) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B148) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide; (Compound B149) N-[3-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B150) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0163] (Compound B151) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-nitro-benzenesulfonamide; (Compound B152) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (Compound B153) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (Compound B154) 4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)-N-phenylbenzenesulfonamide; (Compound B155) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide; (Compound B156) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diazepin-5-yl)phenyl]-1-naphthalenesulfonamide; (Compound B157) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]cyclohexanesulfonamide; (Compound B158) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-3-pyridine sulfonamide hydrochloride; (Compound B159) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-4-isopropylbenzenesulfonamide; (Compound B160) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenylmethanesulfonamide;

[0164] (Compound B161) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-thiophene-sulfonamide; (Compound B162) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-naphthalenesulfonamide; (Compound B163) 4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho-[1,2-b][1,4]diazepin-5-yl)phenyl 3-bromobenzene-sulfonate; (Compound B164) N-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B165) N-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B166) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylbenzenesulfonamide; (Compound B167) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (Compound B168) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide; (Compound B169) N-[4-(7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (Compound B170) N-[4-(7-bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide;

[0165] (Compound B171) N-[4-[(2,4-dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)]phenyl]benzenesulfonamide; (Compound B172) N-[4-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (Compound B173) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B174) 1-(3-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B175) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide; (Compound B176) N-[4-(7-bromo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (Compound B177) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B178) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B179) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide; (Compound B180) 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;

[0166] (Compound B181) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide; (Compound B182) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-nitrophenyl)methanesulfonamide; (Compound B183) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide; (Compound B184) 1-(2,3-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B185) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (Compound B186) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (Compound B187) 1-(4-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B188) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)benzyl]methanesulfonamide; (Compound B189) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-methoxyphenyl]methanesulfonamide; (Compound B190) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-hydroxyphenyl]methanesulfonamide;

[0167] (Compound B191) 1-(2,6-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B192) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-6-methyl-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (Compound B193) 1-(2-chlorophenyl)-N-[3-(2,4-dioxy-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)propyl]methanesulfonamide; (Compound B194) 1-(2-chlorophenyl)-N-[2-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)ethyl]methanesulfonamide; (Compound B195) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-iodophenyl)methanesulfonamide; (Compound B196) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide; (Compound B197) 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (Compound B198) 1-[2-(trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (Compound B199) 1-(2-ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (Compound B200) 1-(2,3-dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0168] (Compound B201) 2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylethanesulfonamide; (Compound B202) 1-(2-nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (Compound B203) 1-(2-aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (Compound B204) 1-(2-dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (Compound B205) 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B206) 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B207) 5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B208) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (Compound B209) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B210) 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0169] (Compound B211) 5-[4-[[4-(trifluoromethyl)pyridin-3-yl]carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (Compound B212) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione; (Compound B213) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-8,9,10,11-tetrahydro-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione; and (Compound B214) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione.

[0170] Compounds or pharma- ceutical acceptable salts thereof that are more suitable as an active ingredient of the pharmaceutical composition of the present invention are included in the compounds represented by the general formulas (A) to (BII) or pharma- ceutical acceptable salts thereof. More specifically, 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione Potassium salt;5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione ... Sodium salt;5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione Sodium salt;5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;1-[4-(2,4-dioxo-1,2,3,4-tetrafluoroethylene)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione Hydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea;5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione;5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione;5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;N-[4-(2,4-dioxo-1, 2,3,4-Tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;1-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-Chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-Bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide )-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide;1-(2-chlorophenoxy) 1-(2-Chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide;5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione hydrochloride;Examples include 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione. However, the active ingredient of the pharmaceutical composition of the present invention is not limited to the above specific compounds or their pharma- ceutical acceptable salts.

[0171] Compounds or pharma- ceutical acceptable salts thereof further suitable as an active ingredient of the pharmaceutical composition of the present invention are included in the compounds represented by the general formulas (A) to (BII) or pharma- ceutical acceptable salts thereof. More specifically, 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt Examples include sodium salts; 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione and 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione. However, the active ingredient of the pharmaceutical composition of the present invention is not limited to the above specific compounds or their pharma- ceutical acceptable salts.

[0172] The compounds represented by the above general formulas (A) to (BII) may exist as stereoisomers such as cis-trans isomers, optically active substances, and racemates, and all of these are included in the present invention.

[0173] The compounds represented by the above general formulae (A) to (BII) may have tautomers, which have the same activity as the above compounds and are included in the present invention.

[0174] In addition, the compounds represented by the above general formulae (A) to (BII) may have one or more asymmetric carbons depending on the type of the substituent, and any optical isomer based on these asymmetric carbons, any mixture of optical isomers, racemates, diastereoisomers based on two or more asymmetric carbons, any mixture of diastereoisomers, etc. may be used as the active ingredient of the pharmaceutical composition of the present invention. When the compounds represented by the above general formulae (AI) to (BII) contain a double bond or a cyclic structure, geometric isomers may exist, and in addition to the pure geometric isomers, mixtures of these isomers in any ratio may be used as the active ingredient of the pharmaceutical composition of the present invention.

[0175] As the active ingredient of the pharmaceutical composition of the present invention, in addition to the compounds represented by the above general formulas (A) to (BII), any solvate of the above compounds in free form or in salt form may be used as the active ingredient of the pharmaceutical composition of the present invention. The above solvates include hydrates.

[0176] In this specification, unless otherwise specified, the compounds represented by the above general formulas (A) to (BII) may include cis / trans isomers, optically active compounds, stereoisomers such as racemates, tautomers, any optical isomers based on an asymmetric carbon, racemates, diastereoisomers based on two or more asymmetric carbons, and mixtures thereof.

[0177] As the active ingredient of the pharmaceutical composition of the present invention, in addition to the compounds represented by the above general formulas (A) to (BII), acid addition salts or base addition salts of these compounds may be used. Examples of the acid addition salts include, but are not limited to, mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, p-toluenesulfonate, oxalate, and malate. Examples of the base addition salts include, but are not limited to, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, ammonium salt, and organic amine salts such as triethylamine salt and ethanolamine salt. Of these salts, it is preferable to use a pharma- ceutically acceptable salt as the active ingredient of the pharmaceutical composition of the present invention.

[0178] The pharmaceutical composition of the present invention can be used for the prevention, suppression, or treatment of symptoms associated with allergic reactions. It can also be used for the prevention, suppression, or treatment of allergic diseases. It can be preferably used for the prevention, suppression, or treatment of symptoms associated with type I allergic reactions. It can more preferably be used for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma, or allergic dermatitis, and can further be used for the suppression of anaphylactic shock or the prevention or treatment of hay fever, urticaria, or atopic dermatitis. Furthermore, the pharmaceutical composition of the present invention can be used to prevent, suppress, or reduce inflammation in symptoms associated with allergic reactions, and can also be used to suppress extracellular release of secretory granules in mast cells in symptoms associated with allergic reactions.

[0179] In another aspect, the pharmaceutical composition of the present invention can be used for the following applications. The pharmaceutical composition of the present invention can be used for preventing, suppressing, or treating symptoms associated with the allergic reaction, which is accompanied by inflammation. The pharmaceutical composition of the present invention can be used for preventing, suppressing or treating symptoms associated with the allergic reaction, which is accompanied by the extracellular release of secretory granules in mast cells. The pharmaceutical composition of the present invention can be used to treat any of these symptoms associated with allergic reactions, although the application of the pharmaceutical composition of the present invention is not limited to these.

[0180] The pharmaceutical composition of the present invention can be administered orally or parenterally.The pharmaceutical composition of the present invention can be prepared according to a conventional method in the technical field of formulations into a suitable dosage form such as tablets, granules, powders, capsules, suspensions, inhalants, inhalation powders, inhalation liquids, inhalation aerosols, ointments, gels, creams, poultices, patches, liniments, tapes, poultices, injections, suppositories, etc. In one embodiment, the "pharmaceutical composition" comprises the active ingredient and a pharmaceutically acceptable additive.

[0181] These preparations can be manufactured using common techniques, and for example, in the case of tablets, pharma- ceutically acceptable additives such as ordinary excipients, disintegrants, binders, lubricants, and dyes can be used. Examples of excipients include lactose, D-mannitol, crystalline cellulose, and glucose; examples of disintegrants include starch and carboxymethylcellulose calcium (CMC-Ca); examples of lubricants include magnesium stearate and talc; and examples of binders include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).

[0182] Pharmaceutically acceptable additives such as solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. can be used to prepare injections. Those skilled in the art can appropriately select these pharma- ceutically acceptable additives and preparation methods for formulations. That is, the pharmaceutical composition of the present invention can be provided as a pharmaceutical composition containing the active ingredient and a pharma- ceutical acceptable additive.

[0183] Inhalants for parenteral administration include aerosols, powders for inhalation, liquids for inhalation (e.g., solutions for inhalation, suspensions for inhalation, etc.), or capsule-shaped inhalants, and the liquids for inhalation may be in a form that is dissolved or suspended in water or other suitable medium when used. These inhalants can be administered using a suitable inhalation container, and for example, a sprayer (atomizer, nebulizer) or the like can be used when administering liquids for inhalation, and a powder medicine inhaler or the like can be used when administering powders for inhalation.

[0184] These inhalants are produced according to known methods. For example, the compounds represented by the general formulas (A) to (BII) are powdered or liquid, mixed with an inhalation propellant or carrier, and filled into a suitable inhalation container. When the compounds represented by the general formulas (A) to (BII) are powdered, they are powdered according to a conventional method. For example, they are finely powdered together with lactose, starch, magnesium stearate, etc., and mixed uniformly or granulated to prepare a powder. When the compounds represented by the general formulas (A) to (BII) are liquefied, for example, the compounds may be dissolved in a liquid carrier such as water, physiological saline, or an organic solvent. As the propellant, a conventionally known propellant, for example, a fluorocarbon substitute, a liquefied gas propellant (for example, fluorocarbon, liquefied petroleum, diethyl ether, dimethyl ether, etc.), a compressed gas (for example, a soluble gas (for example, carbon dioxide, nitrous oxide, etc.), an insoluble gas (for example, nitrogen gas, etc.)), etc., may be used.

[0185] The inhalant may further contain pharma- ceutically acceptable additives as necessary. Any commonly used additives may be used, and examples of such additives include solid excipients (e.g., sucrose, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid excipients (e.g., propylene glycol, etc.), binders (starch, dextrin, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, sucrose, etc.), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g., citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, etc.), preservatives (e.g., sodium benzoate, sulfur dioxide, etc.), and the like. In the case of inhalation liquid, for example, preservatives, colorants, buffers, isotonicity agents, thickeners, carboxyvinyl polymers, etc., are used. For example, in the case of inhalation liquid, preservatives, colorants, buffers, isotonicity agents, thickeners, absorption promoters, etc. are appropriately selected as necessary to prepare the liquid. In the case of powders for inhalation, for example, lubricants, binders, excipients, colorants, preservatives, absorption enhancers (bile salts, chitosan, etc.), etc. are appropriately selected as necessary and prepared.

[0186] Furthermore, in order to make the compound represented by the general formula (A) to (BII) sustained-release, the inhalant may contain a biodegradable polymer. Examples of the biodegradable polymer include fatty acid ester polymers or copolymers thereof, polyacrylic acid esters, polyhydroxybutyric acids, polyalkylene oxalates, polyorthoesters, polycarbonates, and polyamino acids, and these may be used in a mixture of one or more. Phospholipids such as egg yolk lecithin, chitosan, etc. may also be used. Examples of the fatty acid ester polymers or copolymers thereof include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, and lactic acid-glycolic acid copolymers, and these may be used in a mixture of one or more. In addition, a mixture of one or more of polyα-cyanoacrylic acid esters, polyβ-hydroxybutyric acid, polytrimethylene oxalates, polyorthoesters, polyorthocarbonates, polyethylene carbonates, polyγ-benzyl-L-glutamic acid, and poly-L-alanine may also be used. Polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer is preferred, and lactic acid-glycolic acid copolymer is more preferred. Furthermore, microspheres or nanospheres containing a drug may be prepared using a biodegradable polymer such as lactic acid-glycolic acid copolymer.

[0187] Ointments are prepared by known or commonly used methods. For example, they are prepared by triturating or dissolving one or more active substances in a base. The ointment base is selected from known or commonly used bases. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid esters, myristic acid esters, palmitic acid esters, stearic acid esters, oleic acid esters, etc.), waxes (beeswax, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), hydrocarbons (hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents may be used alone or in combination of two or more. Furthermore, the composition may contain moisturizing agents, preservatives, stabilizers, antioxidants, flavoring agents, etc.

[0188] Gels are manufactured by known or commonly used recipes. For example, they are manufactured and prepared by dissolving one or more active substances in a base. The gel base is selected from known or commonly used ones. For example, the gel base may be selected from lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and rash prevention agents, either alone or in combination of two or more. In addition, the gel may contain preservatives, antioxidants, flavoring agents, etc.

[0189] Creams are manufactured by known or commonly used formulations. For example, they are manufactured or prepared by melting or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used ones. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption enhancers, and rash prevention agents are used alone or in combination of two or more. In addition, preservatives, antioxidants, fragrances, etc. may be included.

[0190] The poultice is manufactured by a known or commonly used recipe. For example, one or more active substances are dissolved in a base, kneaded, and spread on a support to produce the poultice. The poultice base is selected from known or commonly used bases. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), humectants (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, solubilizers, tackifiers, and rash prevention agents are used alone or in combination of two or more. In addition, preservatives, antioxidants, flavoring agents, etc. may be included.

[0191] The patch is manufactured by a known or commonly used formulation. For example, it is manufactured by dissolving one or more active substances in a base and spreading and coating the base on a support. The base for the patch is selected from known or commonly used ones. For example, polymer bases, oils and fats, higher fatty acids, tackifiers, and rash prevention agents are used alone or in combination of two or more. In addition, preservatives, antioxidants, flavoring agents, etc. may be contained.

[0192] Liniments are manufactured by known or commonly used methods. For example, they are manufactured or prepared by dissolving, suspending or emulsifying one or more active ingredients in one or more of water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acid, glycerin, soap, emulsifier, suspending agent, etc. Furthermore, they may contain preservatives, antioxidants, flavoring agents, etc.

[0193] The dosage of the pharmaceutical composition of the present invention is not particularly limited, but generally, for adults, the amount of active ingredient is about 0.01μg to 100mg, preferably 0.3μg to 10mg, per day for inhalants, inhalable powders, inhalable liquids, and inhalable aerosols, about 0.01mg to 1000mg, per day for ointments, gels, creams, poultices, patches, liniments, tapes, and poultices, about 0.01mg to 100mg, per day for injections, and about 0.01mg to 2000mg per day for oral administration. However, the dosage is not limited to the above dosage and is appropriately determined depending on the administration method, age, weight, sex, symptoms, sensitivity to drugs, etc. of the subject, but the dosage may be adjusted depending on the improvement of symptoms, and may be increased or decreased depending on age, symptoms, etc.

[0194] The pharmaceutical composition of the present invention can be used in combination with other drugs useful for treating or preventing symptoms associated with various allergic reactions. The individual components of such combinations can be administered in separate or single preparations at different times during the treatment or prevention period, or simultaneously. Therefore, the present invention should be interpreted as including all simultaneous or different time administrations, and administration in the present invention should be interpreted accordingly. The scope of the combination of the pharmaceutical composition of the present invention with other drugs useful for treating or preventing symptoms associated with the above-mentioned various allergic reactions includes, in principle, combinations with any pharmaceutical preparations useful for treating or preventing symptoms associated with the above-mentioned various allergic reactions.

[0195] Each preparation in the combination preparation of the present invention may be in various forms and may be prepared in the same manner as the above-mentioned preparations. In addition, a combination preparation containing the pharmaceutical composition of the present invention and a therapeutic or prophylactic drug for symptoms associated with various allergic reactions may be easily prepared by a person skilled in the art according to a conventional method or conventional technology. The above combinations include combinations of the pharmaceutical composition of the present invention with one other active substance, as well as two or more other active substances. There are many examples of combinations of the pharmaceutical composition of the present invention with one, two or more active substances selected from the drugs for treating or preventing symptoms associated with the various allergic reactions mentioned above.

[0196] The drugs that can be combined with the pharmaceutical composition of the present invention include, for example, steroids, β2 agonists, muscarinic receptor antagonists, antihistamines, antiallergic drugs, bronchodilators, leukotriene synthesis inhibitors, prostaglandins, leukotriene receptor antagonists, antipruritic drugs, other antitussives, and expectorants, and among these, combination with antihistamines and antiallergic drugs is preferred.The pharmaceutical composition of the present invention can also be combined with Chinese herbal medicine.

[0197] Examples of the steroids include clobetasol propionate, diflorasone acetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide, diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, and butyrate. Topical medications such as hydrocortisone propionate, deprodone propionate, prednisolone acetate valerate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclometasone propionate, clobetasone butyrate, prednisolone, peclomethasone propionate, and fludroxycortide; cortisone acetate, hydrocortisone, hydrocortisone sodium phosphate, hydrocortisone sodium succinate, etc. , fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, prednisolone butylacetate, prednisolone sodium phosphate, halopredone acetate, methylprednisolone, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate Oral or injectable medications such as samethasone, paramethasone acetate, and betamethasone; and inhalants such as beclomethasone propionate, fluticasone propionate, budesonide, flunisolide, triamcinolone, ST-126P, ciclesonide, dexamethasone paromycinate, mometasone furanocarbonate, prasterone sulfonate, deflazacort, methylprednisolone suleptanate, and methylprednisolone sodium succinate.

[0198] Examples of β2 agonists include formoterol, salmeterol, carmoterol, indacaterol, vilanterol, arformoterol, bambuterol, isoproterenol, mirveterol, clenbuterol, olodaterol, fenoterol, salbutamol, levalbuterol, procaterol, terbutaline, pirbuterol, procaterol, metaproterenol, bitolterol, ritodrine, and albuterol.

[0199] Examples of muscarinic receptor antagonists include tiotropium, ipratropium, flutropium, oxitropium, aclidinium, darotropium, glycopyrrolate, and umeclidinium.

[0200] Examples of antihistamines include diphenhydramine, diphenylpyraline hydrochloride, diphenylpyraline teoclate, clemastine fumarate, dimenhydrinate, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, triprolidine hydrochloride, promethazine hydrochloride, alimemazine tartrate, isothipendyl hydrochloride, homochlorcyclizine hydrochloride, hydroxyzine, cyproheptadine hydrochloride, levocabastine hydrochloride, astemizole, bepotastine, desloratadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, andolast, auranofin, acrivastine, and the like.

[0201] Examples of antiallergic agents include chemical mediator release inhibitors such as sodium cromoglycate, tranilast, amlexanox, repirinast, ibudilast, pemirolast potassium, dazanolast, nedocromil, cromoglycate, and israpafant; histamine antagonists such as ketotifen fumarate, azelastine hydrochloride, oxatomide, mequitazine, terfenadine, emedastine fumarate, epinastine hydrochloride, ebastine, cetirizine hydrochloride, olopatadine hydrochloride, loratadine, and fexofenadine; thromboxane synthase inhibitors such as ozagrel hydrochloride and imitrodast sodium; thromboxane antagonists such as seratrodast, ramatroban, domitroban calcium hydrate, and KT-2-962; and Th2 cytokine inhibitors such as suplatast tosilate.

[0202] Examples of bronchodilators include xanthine derivatives such as aminophylline, theophylline, doxofylline, cipamphylline, diprophylline, proxyphylline, and choline theophylline; epinephrine, ephedrine hydrochloride, dl-methylephedrine hydrochloride, methoxyphenamine hydrochloride, isoproterenol sulfate, isoproterenol hydrochloride, orciprenaline sulfate, chlorprenaline hydrochloride, trimetoquinol hydrochloride, salbutamol sulfate, terbutaline sulfate, hexoprenaline sulfate, tulobuterol hydrochloride, procaterol hydrochloride, fenoterol hydrobromide, formotene fumarate, and the like. sympathomimetics such as serotonin, clenbuterol hydrochloride, mabuterol hydrochloride, salmeterol xinafoate, R,R-formoterol, tulobuterol, pirbuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, meladoline tartrate, AR-C68397, levosalbutamol, KUR-1246, KUL-7211, AR-C89855, and S-1319; and parasympatholytic agents such as ipratropium bromide, flutropium bromide, oxitropium bromide, cimetropium bromide, temiverine, tiotropium bromide, and revatropate.

[0203] Examples of leukotriene synthesis inhibitors include auranofin, proglumetacin maleate, L-674636, A-81834, UPA-780, A-93178, MK-886, REV-5901A, SCH-40120, MK-591, Bay-x-1005, Bay-y-1015, DTI-0026, amlexanox, and E-6700.

[0204] Examples of prostaglandins include agonists or antagonists of the PGE2EP1 receptor, PGE2EP2 receptor, PGE2EP3 receptor, or PGE2EP4 receptor; agonists or antagonists of the PGD2 receptor or CRTH2 receptor; agonists or antagonists of the PGFFP receptor; agonists or antagonists of the PGIIP receptor; and agonists or antagonists of the TX receptor.

[0205] Examples of leukotriene receptor antagonists include pranlukast hydrate, montelukast, zafirlukast, seratrodast, MCC-847, KCA-757, CS-615, YM-158, L-740515, CP-195494, LM-1484, RS-635, A-93178, S-36496, BIIL-284, and ONO-4057.

[0206] Other antitussives include, for example, codeine phosphate, dihydrocodeine phosphate, oxymethobanol, dextromethorphan hydrobromide, pentoxyverine citrate, dimemorfan phosphate, oxeladin citrate, cloperastine, benproperine phosphate, clofedanol hydrochloride, fominoben hydrochloride, noscapine, tipemidine hibenzate, eprazinone hydrochloride, and scutellaria baicalensis extract.

[0207] Examples of expectorants include ammoniated fennel extract, sodium bicarbonate, potassium iodide, bromhexine hydrochloride, cherry bark extract, carbocysteine, fudosteine, ambroxol hydrochloride, ambroxol hydrochloride sustained-release preparation, methylcysteine ​​hydrochloride, acetylcysteine, L-ethylcysteine ​​hydrochloride, and tyloxapol.

[0208] Antipruritic agents include, for example, diphenhydramine hydrochloride, crotamiton, and lidocaine.

[0209] The present invention has the following aspects. <1a> A method for preventing, suppressing, or treating a symptom associated with an allergic reaction, comprising administering to a subject in need thereof (e.g., a mammalian animal including a human) an effective amount for preventing, suppressing, or treating a compound having a P2X4 receptor antagonistic activity (e.g., a compound represented by any one of general formulas (A) to (BII)) or a pharma- ceutically acceptable salt thereof; <2a> the method according to <1a>, wherein the symptom associated with the allergic reaction is an allergic disease; <3a> the method according to <1a> or <2a>, wherein the symptoms associated with an allergic reaction are symptoms associated with a type I allergic reaction; <4a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is anaphylactic shock; <5a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is allergic rhinitis; <6a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is bronchial asthma; <7a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is allergic dermatitis; <8a> The method according to any one of <1a> to <3a>, wherein the symptom associated with an allergic reaction is hay fever; <9a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is urticaria; <10a> The method according to any one of <1a> to <3a>, wherein the symptom associated with the allergic reaction is atopic dermatitis; <11a> The method according to <1a>, wherein the allergic reaction is an allergic reaction accompanied by inflammation; and <12a> The method according to <1a>, wherein the allergic reaction is an allergic reaction accompanied by extracellular release of secretory granules in mast cells.

[0210] The present invention has the following other aspects. <1b> A compound having P2X4 receptor antagonistic activity (e.g., a compound represented by general formula (A) to (BII)) or a pharma- ceutically acceptable salt thereof for use in the prevention, suppression, or treatment of symptoms associated with allergic reactions; <2b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is an allergic disease; <3b> the compound for use according to <1b> or <2b> or a pharma- ceutically acceptable salt thereof, wherein the symptoms associated with an allergic reaction are symptoms associated with a type I allergic reaction; <4b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is anaphylactic shock; <5b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is allergic rhinitis; <6b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is bronchial asthma; <7b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is allergic dermatitis; <8b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with an allergic reaction is hay fever; <9b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with the allergic reaction is urticaria; <10b> the compound for use according to any one of <1b> to <3b> or a pharma- ceutically acceptable salt thereof, wherein the symptom associated with an allergic reaction is atopic dermatitis; <11b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the allergic reaction is an allergic reaction accompanied by inflammation; and <12b> The compound or a pharma- ceutically acceptable salt thereof for use according to <1b>, wherein the allergic reaction is an allergic reaction accompanied by extracellular release of secretory granules in mast cells.

[0211] The present invention has the following further aspect. <1c> Use of a compound having P2X4 receptor antagonistic activity (e.g., a compound represented by general formula (A) to (BII)) or a pharma- ceutical acceptable salt thereof for the manufacture of a pharmaceutical composition for preventing, suppressing, or treating symptoms associated with an allergic reaction; <2c> the use according to <1c>, wherein the symptom associated with the allergic reaction is an allergic disease; <3c> the use according to <1c> or <2c>, wherein the symptoms associated with the allergic reaction are symptoms associated with a type I allergic reaction; <4c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is anaphylactic shock; <5c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is allergic rhinitis; <6c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is bronchial asthma; <7c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is allergic dermatitis; <8c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is hay fever; <9c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is urticaria; <10c> the use according to any one of <1c> to <3c>, wherein the symptom associated with the allergic reaction is atopic dermatitis; <11c> the use according to <1c>, wherein the allergic reaction is an allergic reaction accompanied by inflammation; and <12c> The use described in <1c>, wherein the allergic reaction is an allergic reaction accompanied by extracellular release of secretory granules in mast cells. EXAMPLES

[0212] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples. In the following examples, the P2X4 receptor antagonist is 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt (WO2010 / 093061, salt of Example 14: hereinafter referred to as "Compound A" for convenience), and 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (WO2013 / 105608, compound of Example 48: hereinafter referred to as "Compound B"), as well as the following other compounds, were used: 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt;5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepine-5-yl)phenyl]-3- Phenylurea;5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2- b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11- Octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide;1-(2-Chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide;5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione Hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione. ;

[0213] Example 1 Measurement of P2X4 receptor antagonistic activity of the compound which is the active ingredient of the present invention (Test Method) The P2X4 receptor antagonistic activity of the compound, which is an active ingredient of the present invention, was measured. ATP receptor (human P2X4) was introduced into 1321N1 cells and used as a P2X4 receptor stable expression system. P2X4 receptor expressing cells were seeded on a 96-well plate, cultured under 37°C and 5% CO2 conditions for 24 hours, and used for calcium measurement. Fura-2 AM, a calcium fluorescent indicator, was dissolved in extracellular solution for calcium imaging, treated with the seeded cells, and allowed to stand at room temperature for 45 minutes to allow Fura-2AM to be taken up into the cells. EnVision (PerkinElmer), a microplate reader, was used for the measurement. Light irradiated from a xenon lamp was passed through 340nm and 380nm filters, respectively, and the 510nm fluorescence F340 and F380 emitted when the light was irradiated to the cells were observed, and the change in the ratio value F340 / F380 was used as an index of intracellular calcium change. The measurement was performed by adding ATP to each well so that the final concentration was 1 μM, and observing the ATP-induced intracellular calcium response over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and calculated by comparing with the case in the absence of the test substance. The results are shown in Table 29 below.

[0214] (Test Results) [Table 29]

[0215] Example 2 Effect of BMMC on degranulation The inhibitory effect of P2X4 receptor antagonistic compound A or B on the degranulation reaction caused by co-stimulation of IgE-sensitized bone marrow-derived mast cells (BMMC) with dinitrophenyl-conjugated human serum albumin (DNP-HSA) (10 ng / mL) and ATP (0.1 mM) was observed. The degranulation reaction was performed by calculating the degranulation rate using the release rate of β-hexosaminidase as an index. The release rate of β-hexosaminidase was measured as follows (degranulation experiment).

[0216] (BMMC adjustment) Bone marrow was collected from the femur of male C57BL / 6J mice (7-8 weeks old, manufactured by Japan SLC Co., Ltd.). Red blood cells were lysed and the mice were cultured for 14 days in a medium containing 10% FBS (fetal bovine serum), penicillin (100 unit / ml), streptomycin (100 μg / ml), and recombinant mouse IL-3 (10 ng / ml, manufactured by Peprotech). From the 15th day, stem cell factor (SCF) (10 ng / ml) was added to the medium, and the mice were cultured for 35-42 days before use in the experiment. The degree of expression of c-KIT and FcεRI was used to confirm whether the cells had differentiated into mast cells. This confirmation was performed using a FACSCant II (manufactured by BD Biosciences).

[0217] (Degranulation experiment) Anti-DNP-IgE antibody (clone: ​​SPE-7, Sigma Aldrich) was added to the BMMC culture medium at a concentration of 50 ng / ml and sensitized overnight. The BMMC were washed with PBS(-) and then diluted with 1 × 10 IgG in Krebs Ringer-HEPES Buffer (NaCl 130 mM, KCl 4.7 mM, NaHCO3 4.0 mM, KH2P4 1.2 mM, Glucose 11.5 mM, HEPES 10 mM, CaCl2·H2O 1.8 mM). 6 The cells were suspended at cell / ml and used in the experiment. Next, the BMMCs sensitized with IgE were preincubated at room temperature for 10 minutes with compound A (1 μM, 3 μM, or 10 μM), compound B (1 μM, 3 μM, or 10 μM), or 0.1% DMSO as a control. Thereafter, each of the BMMCs was adjusted into the following four groups. (1) A group in which nothing is added to the BMMCs, (2) A group in which only ATP was added to the BMMCs (3) A group in which only DNP-HSA (10 ng / ml) was added to the BMMC as an antigen; (4) A group in which a mixture of ATP and DNP-HSA (10 ng / ml) was added simultaneously to the BMMCs. The above four groups were stimulated at 37°C for 5 minutes, rapidly cooled on ice, and centrifuged to stop the reaction. The supernatant was collected, and the precipitated cells were dissolved with 0.1% Triton X-100. The supernatant and cell lysate (50 μL) were mixed with 10 mM 4-Nitrophenyl N-acetyl-β-D-glucosaminide (Sigma Aldrich) / 50 mM citrate buffer (pH 4.5, 50 μL), which is a substrate for β-hexosaminidase, and incubated at 37°C for 30 minutes. The reaction was stopped by adding 50 mM carbonate buffer (pH 10.0, 100 μL), and the absorbance at 405 / 655 was measured using a Sunrise absorbance microplate reader (TECAN). The release rate of β-hexosaminidase was calculated using the following formula: β-hexosaminidase release rate = supernatant absorbance / (supernatant absorbance + cell lysis station absorbance) × 100 In this example, the number of specimens was 3 for each group, and significant differences in this example are indicated by "*" or "**" in Figures 1 and 2, which indicate P<0.05 and P<0.01, respectively. Also, "*" or "**" in Figures 1 and 2 indicate that there is a significant difference as a result of comparing with the control in the same group.

[0218] (Test Results) Regarding compound A In the groups (1) to (3) where no costimulation with ATP and DNP-HSA (10 ng / ml) was added, the release rate of β-hexosaminidase was less than 10% in both the BMMCs administered with compound A and the control BMMCs (Figures 1(1) to (3)). In contrast, the release rate of β-hexosaminidase in the control BMMCs in the group (4) where costimulation with ATP and DNP-HSA (10 ng / ml) was added was about 25% (Figure 1(4)). However, in the same group, the release rate of β-hexosaminidase in the BMMCs preincubated with compound A was reduced in a dose-dependent manner compared to the control BMMCs, and the release rate was significantly reduced at all concentrations of 1 μM, 3 μM, and 10 μM (Figure 1(4)).

[0219] Regarding compound B In the groups (1) to (3) where no costimulation with ATP and DNP-HSA (10 ng / ml) was added, the release rate of β-hexosaminidase was about 10% to 15% in both BMMCs administered with compound B and control BMMCs (Figures 2(1) to (3)). In contrast, the release rate of β-hexosaminidase in the control BMMCs in the group (4) where costimulation with ATP and DNP-HSA (10 ng / ml) was added exceeded 30% (Figure 2(4)). However, in the same group, the release rate of β-hexosaminidase in BMMCs preincubated with compound B was decreased in a dose-dependent manner compared to the control BMMCs, and the release rate was significantly decreased in BMMCs preincubated with 3 μM and 10 μM compound B (Figure 2(4)).

[0220] Example 3: Effect on passive cutaneous anaphylaxis Mice were pre-sensitized to IgE, and were divided into two groups: one administered with compound A or B having P2X4 receptor antagonistic activity, and the other not administered. Passive cutaneous anaphylaxis (PCA) was induced in the mice of each group, and the inhibitory effect against PCA was measured.

[0221] (Creation of IgE-sensitized mice) Anesthetized mice were sensitized by subcutaneous injection of 100 ng / 20 μL IgE into the right ear, whereas the left ear received saline alone. The mice used were male C57BL / 6J mice (10 to 11 weeks old, manufactured by Japan SLC Co., Ltd.).

[0222] (Administration of drugs) Compound A (10 mg / kg) contained in physiological saline was intraperitoneally administered to the IgE-sensitized mice 30 minutes before the administration of DNP-HSA. Note that DNP-HSA was administered via tail vein, and was adjusted so that it was 24 hours after the preparation of the IgE-sensitized mice. In addition, compound B (10 mg / kg) contained in a solvent (hereinafter referred to as solvent B) prepared by mixing DMSO: 65% KolliphorEL (manufactured by BASF SE): water for injection at a ratio of 1:1:8 was intraperitoneally administered to another IgE-sensitized mouse one hour before the administration of DNP-HSA. The concentration of 65% KolliphorEL was adjusted using ethanol and a small amount of water for injection (or water). The administration of DNP-HSA was adjusted so that it would be 24 hours after the preparation of the IgE-sensitized mouse. Further, another group of the IgE-sensitized mice was prepared, which was administered physiological saline as a control for compound A (vehicle group), and which was administered solvent B as a control for compound B (vehicle group).

[0223] (Creation of PCA model mice) 24 hours after the preparation of the IgE-sensitized mice, anaphylaxis was induced by administering 100 ng / 200 μL (physiological saline) of DNP-HSA containing 0.5% Evans blue to the tail vein to prepare PCA model mice.

[0224] (Measurement of inhibitory effect) In the PCA model mice, edema causes body fluids containing Evans Blue to move from the blood vessels to the ears, so the effect of compound A or B against PCA was measured by measuring the change in the amount of Evans Blue in the ears when DNP-HSA was administered via the tail vein. The PCA model mice were euthanized 30 minutes after administration of DNP-HSA, and the ears were collected and weighed. The collected ears were finely chopped and heated overnight (65°C) in formamide (1 mL) to extract Evans blue. The absorbance (620 nm) of the extracted Evans blue and the standard curve were measured using an absorbance microplate reader Sunrise (TECAN), and the concentration was calculated. In this example, the number of samples was n=5, and the significant difference in this example is indicated by "*" in Figure 3, which indicates that P<0.05. Also, in Figure 3, "*" indicates that there was a significant difference between the group administered with each compound and the group not administered with the compound (vehicle group).

[0225] (Test Results) When DNP-HSA was administered via the tail vein after pretreatment with Compound B (10 mg / kg), the increase in Evans Blue per ear weight was significantly suppressed. Furthermore, pretreatment with compound B (10 mg / kg) significantly inhibited the increase in Evans Blue per ear weight even when the compound was administered orally, similarly to when the compound was administered intraperitoneally (not shown).

[0226] Example 4 Effect on passive systemic anaphylaxis Mice were pre-sensitized with IgE, and one group was administered with compound A or B, which has P2X4 receptor antagonistic activity, and the other group was administered with compound B. Passive systemic anaphylaxis (PSA) was induced in the mice of each group, and the inhibitory effect against PSA was measured.

[0227] (Creation of IgE-sensitized mice) Mice under anesthesia were sensitized by administering IgE (10 μg / 200 μL (physiological saline)) via the tail vein. The mice used were male C57BL / 6J mice (7 to 8 weeks old or 10 to 11 weeks old, manufactured by Japan SLC Co., Ltd.).

[0228] (Administration of drugs) Compound A (10 mg / kg) contained in physiological saline was intraperitoneally administered to the IgE-sensitized mice 30 minutes before the administration of DNP-HSA. Note that the administration of DNP-HSA was adjusted so that it would occur 24 hours after the preparation of the IgE-sensitized mice. Compound B (10 mg / kg) contained in solvent B was intraperitoneally administered to another IgE-sensitized mouse 1 hour before the administration of DNP-HSA. Note that the administration of DNP-HSA was adjusted so as to occur 24 hours after the preparation of the IgE-sensitized mouse. In addition, another group of the IgE-sensitized mice was prepared, which was administered physiological saline as a control for Compound A (vehicle group), and which was administered solvent B as a control for Compound B (vehicle group).

[0229] (Creation of PSA model mice) 24 hours after the preparation of the IgE-sensitized mice, 100 ng / 200 μL (physiological saline) of DNP-HSA was administered to the tail vein of the non-anesthetized mice to prepare PSA model mice and induce anaphylaxis.

[0230] (Measurement of inhibitory effect) In the PSA model mice, systemic anaphylaxis is induced, which causes a rapid drop in body temperature. Therefore, the effect of Compound A or B on passive systemic anaphylaxis was measured by measuring the change in body temperature when DNP-HSA was administered via the tail vein. The change in body temperature was measured by setting the time of administration of DNP-HSA as 0 min, and measuring rectal body temperature every 5 min from 0 min to 60 min after administration using a BAT-7001H Thermometer (Physitemp Instruments Ins). In this example, the number of specimens was n=7 for the compound A group, n=8 for the compound A control group, and n=9 for the compound B group and its control group, and the significant differences in this example are indicated by "*" in Figures 4 and 5, which indicates P<0.05. Also, "*" in Figures 4 and 5 indicates that there was a significant difference between the groups administered with each compound and the respective control groups (vehicle groups).

[0231] (Test Results) When the IgE-sensitized mice were pretreated with compound A or B, and then DNP-HSA was administered via the tail vein, a significant inhibitory effect on hypothermia was observed in both cases. Furthermore, the inhibitory effect of compound A on hypothermia was significant for at least 35 minutes, and the effect continued even after 60 minutes had passed.

[0232] Example 5 Effect of BMMC on degranulation The inhibitory effect of compound A on the degranulation reaction induced by costimulation of IgE-sensitized BMMC with DNP-HSA (10 ng / mL) and ATP (0.1 mM) and on the degranulation reaction induced by costimulation of prostaglandin E2 (referred to as PGE2 in this specification) (1 μg / mL) and ATP (0.1 mM) was observed. The degranulation reaction was carried out by determining the degranulation rate using the release rate of β-hexosaminidase as an index. The release rate of β-hexosaminidase was measured as follows (degranulation experiment). (BMMC adjustment) The method was carried out in accordance with that described in Example 2. (Degranulation experiment) Anti-DNP-IgE antibody (clone: ​​SPE-7, Sigma Aldrich) was added to the BMMC culture medium at a concentration of 50 ng / ml and sensitized overnight. The BMMC were washed with PBS(-) and then diluted with 1 × 10 IgG in Krebs Ringer-HEPES Buffer (NaCl 130 mM, KCl 4.7 mM, NaHCO3 4.0 mM, KH2P4 1.2 mM, Glucose 11.5 mM, HEPES 10 mM, CaCl2·H2O 1.8 mM). 6 The cells were suspended at cell / ml and used in the experiment. Next, compound A (1 μM, 3 μM, or 10 μM) or 0.1% DMSO as a control was added to the IgE-sensitized BMMCs and pre-incubated at room temperature for 10 minutes. Thereafter, each of the BMMCs was adjusted into the following six groups. Note that the numbers in parentheses below correspond to the numbers in parentheses in Figure 6. (1) A group in which nothing is added to the BMMCs, (2) A group in which only ATP was added to the BMMCs (3) A group in which only PGE2 (1 μM) was added to the BMMCs (4) A group in which a mixture of ATP and PGE2 (1 μM) was added to the BMMCs. (5) A group in which only DNP-HSA (10 ng / ml) was added to the BMMC as an antigen; (6) A group in which a mixture of ATP and DNP-HSA (10 ng / ml) was added simultaneously to the BMMCs. The six groups were stimulated at 37°C for 5 minutes, rapidly cooled on ice, and then centrifuged to stop the reaction. The supernatant was collected, and the precipitated cells were dissolved with 0.1% Triton X-100. The supernatant and cell lysate (50 μL) were mixed with 10 mM 4-Nitrophenyl N-acetyl-β-D-glucosaminide (Sigma Aldrich) / 50 mM citrate buffer (pH 4.5, 50 μL), which is a substrate for β-hexosaminidase, and incubated at 37°C for 30 minutes. The reaction was stopped by adding 50 mM carbonate buffer (pH 10.0, 100 μL), and the absorbance at 405 / 655 was measured using a Sunrise absorbance microplate reader (TECAN). The release rate of β-hexosaminidase was calculated using the following formula: β-hexosaminidase release rate = supernatant absorbance / (supernatant absorbance + cell lysis station absorbance) × 100

[0233] (Test Results) In the groups (1) to (3) where no costimulation with ATP (0.1 mM) and PGE2 (1 μM) was added, the release rate of β-hexosaminidase was less than 5% in both the BMMCs administered with compound A and the control BMMCs (Figures 6(1) to (3)). In contrast, in the group (4) where costimulation with ATP (0.1 mM) and PGE2 (1 μM) was added, the release rate of β-hexosaminidase in the control BMMCs was about 15% (Figure 6(4)). However, in the same group, the release rate of β-hexosaminidase in the BMMCs preincubated with compound A was reduced in a dose-dependent manner compared to the control BMMCs, and the release rate was significantly reduced at all concentrations of 1 μM, 3 μM, and 10 μM (Figure 6(4)). In this example, the number of specimens was 3 for each group, and the significant differences in this example are indicated by "*" or "**" in Fig. 6, which indicate that P<0.05 and P<0.01 (Dunnett), respectively. Also, "*" or "**" in Fig. 6 indicate that there is a significant difference as a result of comparing with the control in the same group.

[0234] Example 6 Effects of P2X4 receptor inhibitors on BMMC IL-6, IL-13 and TNF-α release (Test Method) BMMCs were washed with fresh medium and incubated for 3 h in the presence or absence of stimuli (100 μM ATP, 1 μM PGE2, 100 μM ATP + 1 μM PGE2). The grouping is as shown below, and corresponds to the numbers in parentheses in the notation of Figures 7 to 9. (1) A group in which nothing is added to the BMMCs, (2) A group in which only ATP was added to the BMMCs (3) A group in which only PGE2 was added to the BMMCs, (4) A group in which a mixture of ATP and PGE2 was added simultaneously to the BMMCs. The effect of compound A was observed after pretreatment for 5 minutes at a concentration of 10 μM. Cytokines (interleukin (IL)-6, IL-13 and TNF-α) released into the reaction solution were measured using ELISA kits (Invitrogen). In this example, the number of specimens was n=3, and the significant difference in this example is indicated by "**" in Figures 7 to 9, which indicates that P<0.01. The significant difference in Figures 7 to 9 indicates the result compared with the group not administered compound A.

[0235] (Test Results) The results are shown in Figures 7 to 9. It was shown that the ATP-induced increase in release of IL-6, IL-13 and TNF-α was suppressed by compound A. This result suggests that the compound of the present application is effective against allergic dermatitis, allergic bronchial asthma, and the like. [Industrial Applicability]

[0236] The pharmaceutical composition of the present invention is useful as a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with allergic reactions, and further as a pharmaceutical composition useful for preventing, suppressing or treating allergic diseases, particularly as a pharmaceutical composition useful for preventing, suppressing or treating symptoms associated with type I allergic reactions, and more particularly as a pharmaceutical composition useful for preventing or treating anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, a pharmaceutical composition useful for suppressing anaphylactic shock, or a pharmaceutical composition useful for preventing or treating hay fever, urticaria or atopic dermatitis, each of which is expected to be highly effective.

Claims

[Claim 1] A pharmaceutical composition for preventing, suppressing or treating a symptom associated with an allergic reaction, comprising a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof as an active ingredient.

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