Pharmaceutical composition for preventing, inhibiting or treating symptoms accompanying allergic reactions

Abstract

This invention relates to a pharmaceutical composition comprising a compound having P2X4 receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, for the prevention, inhibition or treatment of symptoms associated with an allergic reaction.

Description

Technical Field

[0001] This invention relates to pharmaceutical compositions comprising a compound having P2X4 receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient, such as pharmaceutical compositions for the prevention, suppression or treatment of symptoms associated with allergic reactions.

[0002] This application claims priority based on Japanese Patent Application No. 2020-131412, filed in Japan on August 3, 2020, the contents of which are incorporated herein by reference. Background Technology

[0003] Allergic diseases, such as atopic dermatitis, asthma, and hay fever, are becoming increasingly prevalent, particularly in developed countries, posing a serious problem. Allergies are thought to result from abnormal immune responses to substances that the body should not otherwise react to, with various immune cells involved. However, many aspects of the molecular mechanisms underlying the pathogenesis and exacerbation of allergic diseases remain unclear, leading to limited treatment options that are currently symptomatic. Therefore, elucidating the pathology is crucial for achieving a fundamental cure.

[0004] The guidelines for the treatment of nasal allergies (non-patent literature 1) classify cases of drug treatment as perennial and seasonal allergic rhinitis based on the severity of allergic rhinitis symptoms.

[0005] In perennial allergic rhinitis, for mild cases, regardless of the disease type, any one of the following should be the first choice: a second-generation antihistamine, a chemical mediator release inhibitor, or a type 2 helper T cell (Th2) cytokine inhibitor. For moderate cases, in the sneezing and runny nose type, any one of (1) a second-generation antihistamine, (2) a chemical mediator release inhibitor, or (3) a nasal spray steroid should be chosen, and (3) may be used in combination with (1) or (2) as needed. In severe cases, in cases of particularly severe sneezing and runny nose, a second-generation antihistamine may be used in combination with a nasal spray steroid, and in patients with severe nasal congestion, an anti-leukotriene drug may be used in combination with a nasal spray steroid. In the drug treatment of hay fever, initial therapy is recommended for patients who have a history of severe hay fever symptoms perennially, and the choice of medication should be based on the expected amount of pollen dispersal and the type and severity of symptoms during the period of most severe symptoms. Therefore, it is recommended to use second-generation antihistamines and chemical mediator release inhibitors for sneezing and runny nose, and anti-leukotriene drugs for nasal congestion. When symptoms worsen as pollen dispersal increases, nasal spray steroids should be added as early as possible, and the treatment should be upgraded according to the type of disease.

[0006] The requirement for antihistamines is that they should maintain normal social life and productive activities while being taken. Importantly, they should not cause drowsiness or impaired performance due to the medication, making safety a higher priority than efficacy (Non-Patent Literature 2). On the other hand, reports indicate that the highest demand from patients for antihistamines is "efficacy," followed by "safety" and "frequency of administration" (Non-Patent Literature 3 and 4). Antihistamines are classified into first-generation and second-generation drugs. First-generation antihistamines are fast-acting and have a strong effect, but the effect is short-lived and they transfer more to the brain, thus causing significant central nervous system depression such as drowsiness. Therefore, they should be used with caution by people who drive vehicles or perform hazardous work.

[0007] Furthermore, due to its anticholinergic effects, caution should be exercised when using it in cases of glaucoma, benign prostatic hyperplasia, or acute exacerbations of bronchial asthma (Non-Patent Literature 2). In contrast, while second-generation antihistamines have slightly less rapid-acting action compared to first-generation drugs, they offer longer-lasting effects and have less central nervous system depressant and anticholinergic effects. In addition, recent developments of later-generation second-generation antihistamines have resulted in formulations that reach peak plasma concentrations in a shorter time, exhibit superior rapid-acting action, and have longer plasma concentration half-lives, requiring only once-daily dosing for effectiveness.

[0008] Tani et al. (Non-Patent Literature 5) used positron emission tomography (PET) to evaluate the occupancy of histamine H1 receptors in the brain of first- and second-generation antihistamines. They examined the relationship between antihistamine-induced drowsiness and objectively reduced work efficiency and the occupancy of histamine H1 receptors in the brain. Based on the occupancy of histamine H1 receptors in the brain, they classified antihistamines into three types: less than 20%: non-sedative; 20%–50%: mildly sedative; and more than 50%: sedative. The international conference [Consensus Group on New Generation Antihistamines (CONGA)] also adopted a classification based on the occupancy of histamine H1 receptors in the brain using PET as a method for evaluating sedative effects (Non-Patent Literature 6), and it is also used in the Japanese Society of Dermatology's guidelines for the treatment of atopic dermatitis (Non-Patent Literature 7). The international guideline *Allergic Rhinitis and its Impact on Asthma* (Non-Patent Literature 8) recommends the use of non-sedating oral antihistamines that do not affect cytochrome P450 (CYP). The guidelines for urticaria, EAACI / GA2LEN / EDF / WAO16, also recommend non-sedating oral antihistamines as the first-line treatment. Most non-sedating second-generation antihistamines meet the criteria for ideal antihistamines as described in the guidelines for the treatment of nasal allergies: rapid onset, sustained effect, fewer side effects (drowsiness, decreased work efficiency, etc.), long-term administration (safety), dosing frequency of 1-2 times per day, and good adherence (Non-Patent Literature 1). However, they are also known to have issues regarding convenience, such as the influence of drug-metabolizing enzymes due to the production of active metabolites after drug metabolism; caution in patients with impaired liver and kidney function; and interactions with agents that enhance central nervous system depressant effects, such as alcohol, hypnotics, and anti-anxiety drugs.

[0009] As mentioned above, antihistamines are used considering not only the severity of the patient's symptoms, the presence or absence of comorbidities, occupation, age, and concurrent medications, but also lifestyle, patient preferences, and medical history. Therefore, the ideal antihistamine should meet all the conditions that conventional antihistamines have failed to address: "rapid onset, sustained effect, few side effects (drowsiness, decreased work efficiency, etc.), long-term administration (safety), dosing once or twice daily, good adherence," and excellent convenience and non-sedation properties to meet the medical needs of both patients and healthcare professionals, achieving a good balance between effectiveness and safety.

[0010] Furthermore, among the known insights, Yoshida et al. reported that mast cells (MCs) induce type I hypersensitivity reactions by recognizing antigens (Ag) via high-affinity IgE receptors (FcεRI), and that stimulation with the ion channel P2X4 receptor (P2X4R) enhances FcεRI-induced degranulation (Non-Patent Literature 9 and 10). Specifically, they reported investigating the role of the P2X4 receptor in IgE-FcεRI complex-induced MC degranulation using bone marrow-derived MCs (BMMCs) prepared from wild-type and P2X4 receptor-deficient (P2rx4- / -) mice. The results showed that ATP significantly increased Ag-induced degranulation in BMMCs prepared from wild-type mice, while decreasing it in BMMCs prepared from P2rx4- / - mice. Furthermore, the enhancing effect of ATP was restored by expressing the P2X4 receptor in P2rx4- / - BMMCs.

[0011] However, Non-Patent Literature 9 also suggests that the mechanism of the above-mentioned ATP effect exists in addition to Ca2+ based on ion channel activity. 2+ The possibility of involvement through mechanisms other than influx was also reported, along with the use of Cu, an inhibitor of the P2X4 receptor channel. 2 + The aforementioned ATP effect was not impaired during the pretreatment. Therefore, it is unclear how the P2X4 receptor participates in degranulation, and not all inhibitors of the P2X4 receptor channel have anti-allergic effects.

[0012] Patent document 1 describes an inhibitor of the P2X4 receptor channel (hereinafter referred to as a P2X4 receptor antagonist).

[0013] However, the compounds described in the embodiments of Patent Document 1 are, for example, selective serotonin reuptake inhibitors such as paroxetine and fluoxetine, which are related to benzodiazepines. The derivative compounds of this application have completely different structures. Furthermore, only experimental results obtained using a neurogenic pain symptom model with applied nerve injury (L5 spinal cord injury model) are shown; no evidence is presented that the P2X4 receptor antagonist has any therapeutic effect on allergies.

[0014] In addition, Patent Document 2 also describes a compound that exhibits P2X4 receptor antagonism, but like Patent Document 1, it only shows the effect based on a neurogenic pain model and it is unclear whether it has an allergic treatment effect.

[0015] In addition, the applicant of this application has filed other patent applications related to P2X4 receptor antagonists as described in Patent Documents 3 to 9, but none of these applications clearly demonstrate any effect on treating allergies.

[0016] Existing technical documents

[0017] Patent documents

[0018] Patent Document 1: International Publication No. 2008 / 020651

[0019] Patent Document 2: International Publication No. 2010 / 093061

[0020] Patent Document 3: International Publication No. 2008 / 023847

[0021] Patent Document 4: International Publication No. 2012 / 008478

[0022] Patent Document 5: International Publication No. 2012 / 014910

[0023] Patent Document 6: International Publication No. 2012 / 017876

[0024] Patent Document 7: International Publication No. 2013 / 105608

[0025] Patent Document 8: International Publication No. 2015 / 005468

[0026] Patent Document 9: International Publication No. 2015 / 005467

[0027] Non-patent literature

[0028] Non-Patent Literature 1: Nasal Allergy Treatment Guidelines Production Committee. Nasal Allergy Treatment Guidelines - Perennial Rhinitis and Hay Fever - 2013 Edition (Revised 7th Edition). Tokyo: Life Sciences; 2013. pp. 34-63. (Section 5.4.3)

[0029] Non-Patent Literature 2: Nobuo Kubo. Requirements for antihistamines. Japanese Journal of Pharmacology. 2005; 125:279-284. (Item 5.4.9)

[0030] Non-Patent Literature 3: Masahiro Tatsukawa, Hiroshi Iwatsuki, Maji Shimada, Shinki Tokura, Fukumi Furukawa. What are the requirements of patients with pruritic skin diseases for antihistamines (anti-allergy drugs)? - Results of a patient questionnaire survey - Prog. Med. 2006; 26:2289-2295. (Item 5.4.10)

[0031] Non-Patent Literature 4: Satoshi Ogino. Patient satisfaction with second-generation antihistamines in the treatment of hay fever – Results of an Internet-based patient survey (Case 1) – Prog. Med. 2009; 29: 2531-2537. (Item 5.4.11)

[0032] Non-patent literature 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. (Item 5.4.12)

[0033] Non-patent literature 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. (Item 5.4.13)

[0034] Non-patent literature 7: Japanese Dermatological Society Atopic Dermatitis Treatment Guidelines Production Committee. Atopic Dermatitis Treatment Guidelines. Journal of Japanese Dermatology. 2009; 119: 1515-1534. (Item 5.4.5)

[0035] Non-patent literature 8: Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010; 126:466-476. (Item 5.4.14)

[0036] Non-patent literature 9: Yoshida, K.; Ito, M.; Yamamoto, K.; Koizumi, S.; Tanaka, S.; Furuta, K.; Matsuoka, I. Extracellular ATP augments antigen-induced murine mastcell degranulation and allergic responses via P2X4 receptor activation. J. Immunol. 2019.

[0037] Non-patent document 10: Yoshida K, et al. Co-Stimulation of Purinergic P2X4 and Prostanoid EP3 Receptors Triggers Synergistic Degranulation in Murine MastCells. Int.J.Mol.Sci.2019, 20, 5157. Summary of the Invention

[0038] The objective of this invention is to provide pharmaceutical compositions useful for the prevention, suppression, or treatment of symptoms accompanying allergic reactions, and further to provide pharmaceutical compositions useful for the prevention, suppression, or treatment of allergic diseases, particularly pharmaceutical compositions useful for the prevention, suppression, or treatment of symptoms accompanying type I hypersensitivity reactions, more particularly pharmaceutical compositions useful for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma, or allergic dermatitis, more particularly pharmaceutical compositions useful for the suppression of anaphylactic shock, pharmaceutical compositions useful for the prevention or treatment of hay fever, and pharmaceutical compositions useful for the prevention or treatment of urticaria or atopic dermatitis.

[0039] Therefore, the inventors conducted in-depth research to solve the above-mentioned problems, and as a result, they found that compounds represented by general formulas (A) to (BII) or pharmaceutically acceptable salts thereof with P2X4 receptor antagonism are useful for the prevention, suppression or treatment of symptoms associated with allergic reactions, and further found to be useful 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 even more particularly for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, and even more particularly for the suppression of anaphylactic shock, and even more particularly for the prevention or treatment of hay fever, urticaria or atopic dermatitis, thus completing the present invention.

[0040] That is, according to the present invention, a pharmaceutical composition useful for the prevention, suppression or treatment of symptoms accompanying allergic reactions, and further useful for the prevention, suppression or treatment of allergic diseases, particularly useful for the prevention, suppression or treatment of symptoms accompanying type I allergic reactions, more particularly useful for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, useful for the suppression of anaphylactic shock or useful for the prevention or treatment of hay fever, urticaria or atopic dermatitis, and is a pharmaceutical composition comprising a compound having P2X4 receptor antagonistic activity or a pharmaceutically acceptable salt thereof as an active ingredient.

[0041] As compounds exhibiting P2X4 receptor antagonistic activity, compounds represented by the following general formulas (A) to (BII) can be used, for example. Compounds represented by the following general formulas (BI) or (BII) are more preferably used as compounds exhibiting P2X4 receptor antagonistic activity. Additionally, pharmaceutically acceptable salts of the above-mentioned compounds can be used.

[0042] The pharmaceutical compositions of the present invention can be used, for example, for the prevention, suppression or treatment of symptoms accompanying allergic reactions, and further for the prevention, suppression or treatment of allergic diseases, particularly for the prevention, suppression or treatment of symptoms accompanying type I allergic reactions, and more particularly for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, for the suppression of anaphylactic shock or for the prevention or treatment of hay fever, urticaria or atopic dermatitis.

[0043] From other perspectives, according to the present invention, the use of a compound having P2X4 receptor antagonistic activity or a pharmaceutically acceptable salt thereof in the manufacture of the above-mentioned pharmaceutical compositions is provided; as well as methods for the prevention, suppression, or treatment of symptoms associated with allergic reactions, and further methods for the prevention, suppression, or treatment of allergic diseases, particularly methods for the prevention, suppression, or treatment of symptoms associated with type I allergic reactions, and more particularly methods for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma, or allergic dermatitis, methods for the suppression of anaphylactic shock, or methods for the prevention or treatment of hay fever, urticaria, or atopic dermatitis, and the above methods include the step of administering to mammals, including humans, a preventive, suppressive, or therapeutically effective amount of a compound having P2X4 receptor antagonistic activity or a pharmaceutically acceptable salt thereof.

[0044] The pharmaceutical compositions of the present invention are useful as pharmaceutical compositions for the prevention, suppression or treatment of symptoms accompanying allergic reactions, and further useful as pharmaceutical compositions for the prevention, suppression or treatment of allergic diseases, particularly useful as pharmaceutical compositions for the prevention, suppression or treatment of symptoms accompanying type I allergic reactions, and even more particularly useful as pharmaceutical compositions for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma or allergic dermatitis, pharmaceutical compositions for the suppression of anaphylactic shock, or pharmaceutical compositions for the prevention or treatment of hay fever, urticaria or atopic dermatitis, with high efficacy expected in each case. Attached Figure Description

[0045] Figure 1 The graph shows the inhibitory effect of compound A on the degranulation reaction induced by co-stimulation of IgE-sensitized BMMCs with DNP-HSA and ATP.

[0046] Figure 2 The graph shows the inhibitory effect of compound B on the degranulation reaction induced by co-stimulation of IgE-sensitized BMMCs with DNP-HSA and ATP.

[0047] Figure 3 The graph shows the inhibitory effect of the above compounds on PCA by inducing passive cutaneous anaphylaxis (PCA) in mice that were previously sensitized with IgE and given either compound A or B or not.

[0048] Figure 4 The graph shows the inhibitory effect of the above compounds on PSA by inducing passive systemic anaphylaxis in mice sensitized with IgE beforehand, in groups that were given compound A and groups that were not given compound A.

[0049] Figure 5 The graph shows the inhibitory effect of the above compounds on PSA by inducing passive systemic anaphylaxis (PSA) in mice that were previously sensitized with IgE and given compound B and mice that were not given compound B.

[0050] Figure 6 The graph shows the inhibitory effect of compound A on the degranulation reaction induced by co-stimulation of IgE-sensitized BMMCs with PGE2 and ATP.

[0051] Figure 7 This is a graph showing the inhibitory effect of compound A on IL-6 release induced by stimulation of BMMC.

[0052] Figure 8This is a graph showing the inhibitory effect of compound A on the release of IL-13 induced by stimulation of BMMC.

[0053] Figure 9 This is a graph showing the inhibitory effect of compound A on TNF-α release induced by stimulation of BMMCs. Detailed Implementation

[0054] The pharmaceutical compositions of the present invention can be used as pharmaceutical compositions useful for the prevention, suppression or treatment of symptoms accompanying allergic reactions, and can also be used as pharmaceutical compositions for the purposes described below.

[0055] The pharmaceutical compositions of the present invention can be used as pharmaceutical compositions useful for the prevention, inhibition or treatment of allergic diseases.

[0056] The pharmaceutical compositions of the present invention can be used as pharmaceutical compositions useful for the prevention, suppression or treatment of symptoms accompanying type I hypersensitivity reactions.

[0057] The pharmaceutical composition of the present invention can be used as a useful pharmaceutical composition for the prevention or treatment of anaphylactic shock.

[0058] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of allergic rhinitis.

[0059] The pharmaceutical composition of the present invention can be used as a useful pharmaceutical composition for the prevention or treatment of bronchial asthma.

[0060] The pharmaceutical composition of the present invention can be used as a useful pharmaceutical composition for the prevention or treatment of allergic dermatitis.

[0061] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for suppressing anaphylactic shock.

[0062] The pharmaceutical composition of the present invention can be used as a useful pharmaceutical composition for the prevention or treatment of hay fever.

[0063] The pharmaceutical composition of the present invention can be used as a useful pharmaceutical composition for the prevention or treatment of urticaria.

[0064] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition useful for the prevention or treatment of atopic dermatitis.

[0065] In another respect, the pharmaceutical compositions of the present invention can also be used as pharmaceutical compositions for the purposes described below.

[0066] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition for the prevention, suppression or treatment of symptoms accompanying the above-mentioned allergic reactions accompanied by inflammation.

[0067] The pharmaceutical composition of the present invention can be used as a pharmaceutical composition for the prevention, suppression or treatment of symptoms associated with the above-mentioned allergic reactions, which are accompanied by the extracellular release of secretory granules from mast cells.

[0068] The phrase "symptoms accompanying an allergic reaction" in this instruction manual includes allergic diseases (or allergic illnesses). In this instruction manual, "allergic disease" refers to a condition caused by an allergy.

[0069] In this specification, "prevention" means the concept of avoiding the onset of "pathological" or "abnormal" symptoms, states, or diseases, as well as the actions or means used to achieve that purpose.

[0070] In this specification, "treatment" refers to the concept of eliminating, curing, resolving, or alleviating "pathological" or "abnormal" symptoms, states, or diseases, as well as the actions or means used to achieve this purpose. It also includes the concept of suppressing the worsening of "pathological" or "abnormal" symptoms, states, or diseases, as well as the actions or means used to achieve this purpose, and further includes the concept of improvement. Here, "improvement" refers to the concept of bringing "pathological" or "abnormal" symptoms, states, or diseases closer to a "healthy" or "normal" state, or the actions or means used to achieve this purpose, as well as the concept of changing "pathological" or "abnormal" symptoms, states, or diseases to a "healthy" or "normal" state, or the actions or means used to achieve this purpose. Therefore, in one embodiment, "improvement" means that the value of an indicator of a "pathological" or "abnormal" symptom or state decreases or increases and approaches or becomes normal as a result of the aforementioned "improvement." Furthermore, "suppression" refers to the concept of stopping or slowing down the worsening or progression of symptoms, states, or diseases, as well as the actions or means used to achieve this purpose, and further includes the concept of improving the aforementioned symptoms, states, or diseases, or the actions or means used to achieve this purpose. Here, "improvement" has the aforementioned meaning. The aforementioned "worsening or progression of symptoms, conditions, or diseases" includes the worsening or progression of "pathological" or "abnormal" symptoms, conditions, or diseases, as well as the deterioration or progression from a "healthy" or "normal" state to "pathological" or "abnormal" symptoms, conditions, or diseases. In one embodiment, "inhibition" refers to stopping or slowing down the worsening or progression of symptoms, conditions, or diseases, or to actions or means used to achieve that purpose. In another embodiment, "inhibition" refers to stopping or slowing down the worsening or progression of symptoms, conditions, or diseases.

[0071] In one embodiment, "treatment" means the disappearance, cure, healing, or relief of "pathological" or "abnormal" symptoms, states, or diseases, as well as the actions or means used to achieve that purpose. In another embodiment, "treatment" means the disappearance, cure, healing, or relief of "pathological" or "abnormal" symptoms, states, or diseases.

[0072] In this specification, the above-mentioned symptoms, conditions or diseases, or numerical values ​​as indicators thereof, or states or functions, can be evaluated by comparing the pharmaceutical products provided by this invention before and after administration, or by comparing the administration groups of placebo or control products not containing the pharmaceutical products provided by this invention with the administration groups of the pharmaceutical products provided by this invention.

[0073] As an active ingredient in the pharmaceutical composition of the present invention, a compound represented by the general formulas (A) to (BII) shown below, or a pharmaceutically acceptable salt thereof, may be used.

[0074] The abbreviations used in the tables shown below are as follows: Me: methyl, Et: ethyl, Pr: n-propyl, iPr: isopropyl, tBu: tert-butyl, Ac: acetyl, Ph: phenyl.

[0075] In the tables shown below, the position numbers of substituents and their substitution positions are sometimes recorded together. Additionally, in chemical formulas, to distinguish seemingly identical position numbers, an apostrophe "'" is sometimes used to indicate a position number. However, in compound names, if the structure can be fundamentally determined, the position number is sometimes recorded without using the aforementioned apostrophe.

[0076] (A-1): The compound represented by the following general formula (A) or a pharmaceutically acceptable salt thereof.

[0077]

[0078] (where R is in the formula) 1A The terms "hydrogen atom", "alkyl group with 1 to 8 carbon atoms", "alkenyl group with 2 to 8 carbon atoms", "alkyl group with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms", or "alkyl group with 1 to 3 carbon atoms substituted with phenyl" represent hydrogen atoms.

[0079] R 2A and R 3A These can be the same or different and represent hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups with 1 to 8 carbon atoms, dialkylamino groups with 2 to 8 carbon atoms, acylamino groups with 2 to 8 carbon atoms, acylamino groups with 2 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkylsulfonylamino groups with 1 to 8 carbon atoms, carboxyl groups, acyl groups with 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety has 1 to 8 carbon atoms), carbamoyl groups, alkylthio groups with 1 to 8 carbon atoms, alkylsulfinyl groups with 1 to 8 carbon atoms, alkylsulfonyl groups with 1 to 8 carbon atoms, or aminosulfonyl groups.

[0080] R 4A and R 5A They can be the same or different, representing hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or alkyl groups with 1 to 3 carbon atoms substituted with phenyl groups.

[0081] Moreover, W A This refers to a heterocycle, which may have substituents and contains 1 to 4 nitrogen atoms as ring-forming elements, consisting of five or six-membered rings.

[0082] In general formula (A), R is used as 1A R 2A R 3A R 4A and R 5A Alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

[0083] As R 1A Alkenes with 2 to 8 carbon atoms, such as allyl, can be cited as examples.

[0084] As R 1A R 2A R 3A R 4A and R 5A or R 11A R 12A R 13A R 14A and R 15A Alkyl groups having 1 to 8 carbon atoms that are replaced by 1 to 3 halogen atoms, such as methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, which are replaced by 1 to 3 halogen atoms such as fluorine, chlorine, or bromine. Preferred examples include trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-fluoroethyl.

[0085] As R 1A R 4A and R 5A Alkyl groups with 1 to 3 carbon atoms that are replaced by phenyl groups, such as benzyl groups.

[0086] As R 2A and R 3A Alkoxy groups with 1 to 8 carbon atoms can be exemplified by methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, or hexoxy.

[0087] As R 2A and R 3AThe alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms can be exemplified by methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl groups substituted by 1 to 3 halogen atoms such as fluorine, chlorine, or bromine. Trifluoromethoxy, 2-chloroethoxy, 2-bromoethoxy, or 2-fluoroethoxy are preferred examples.

[0088] As R 2A and R 3A Halogen atoms can be fluorine, chlorine, or bromine atoms, among others.

[0089] As R 2A and R 3A Alkylamino groups with 1 to 8 carbon atoms include methylamino and ethylamino.

[0090] As R 2A and R 3A Dialkylamino groups with 1 to 8 carbon atoms include dimethylamino and diethylamino.

[0091] As R 2A and R 3A Acylamino groups with 2 to 8 carbon atoms can be exemplified by acetylamino.

[0092] As R 2A and R 3A Acylamino groups with 2 to 8 carbon atoms that are replaced by 1 to 3 halogen atoms, such as trifluoromethylcarbonylamino.

[0093] As R 2A and R 3A Alkylsulfonylamino groups with 1 to 8 carbon atoms, such as methylsulfonylamino.

[0094] As R 2A and R 3A Acyl groups with 2 to 8 carbon atoms, such as the acetyl group.

[0095] As R 2A and R 3A Alkoxycarbonyl groups (alkoxy moiety has 1 to 8 carbon atoms) can be exemplified by methoxycarbonyl and ethoxycarbonyl.

[0096] As R 2A and R 3A Alkyl thio groups with 1 to 8 carbon atoms, such as methyl thio groups.

[0097] As R 2A and R 3A Alkyl sulfinyl groups with 1 to 8 carbon atoms, such as methyl sulfinyl groups.

[0098] As R 2A and R3A Alkyl sulfonyl groups with 1 to 8 carbon atoms, such as methyl sulfonyl groups.

[0099] As W A Heterocyclic rings containing 1 to 4 nitrogen atoms as ring constituent elements, which may have substituents, are five- or six-membered rings. Examples include tetrazolium, 1,2,4-triazole, 1,2,3-triazole, and 1,2,4-triazole. diazole, pyrazole, imidazole azole, isotonic Azole, pyrrole, thiazole, pyridine, pyrrolidine.

[0100] As W A Heterocyclic rings containing 1 to 4 nitrogen atoms as ring constituent elements, which may have substituents, include alkyl groups with 1 to 8 carbon atoms such as methyl and ethyl, alkyl groups with 1 to 8 carbon atoms such as trifluoromethyl with 1 to 3 halogen atoms, halogen atoms such as fluorine atoms, cyano, oxo, thio, etc.

[0101] R in general formula (A) 2A and R 3A In replacing R 2A R 3A One to three identical or different groups may exist on the benzene ring.

[0102] As compounds of general formula (A), the compounds shown below are preferred.

[0103] (A-2): The compound described in (A-1), wherein W A Tetraazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4-triazole can have groups selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, cyano groups, oxo groups, and thio groups as substituents. Diazole, pyrazole, or imidazole.

[0104] (A-3): The compound described in (A-1) or (A-2), wherein W A It can be a tetrazolium, 1,2,4-triazole or 1,2,3-triazole having a substituent selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, or cyano groups.

[0105] (A-4): The compound of any one of (A-1) to (A-3), wherein W A 5-Oxo-1,2,4- diazole or 5-thio-1,2,4- diazole.

[0106] (A-5): A compound according to any one of (A-1) to (A-4), wherein W A It is a tetrazolium.

[0107] (A-6): The compound of any one of (A-1) to (A-5), wherein R 1A It is an alkyl group having 1 to 8 hydrogen atoms or carbon atoms.

[0108] (A-7): A compound according to any one of (A-1) to (A-6), wherein R 1A It is a hydrogen atom.

[0109] (A-8): A compound of any one of (A-1) to (A-7), wherein R 4A It is a hydrogen atom and R 5A It is an alkyl group having 1 to 8 hydrogen atoms or carbon atoms.

[0110] (A-9): A compound according to any one of (A-1) to (A-8), wherein R 4A and R 5A Both are hydrogen atoms.

[0111] (A-10): The compound of any one of (A-1) to (A-9), wherein R 2A It can be a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an alkoxy group with 1 to 8 carbon atoms, an alkyl group with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group with 1 to 8 carbon atoms substituted by 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 with 2 to 8 carbon atoms, or an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms).

[0112] (A-11): The compound of any one of (A-1) to (A-10), wherein R 2A It is a hydrogen atom.

[0113] (A-12): The compound of any one of (A-1) to (A-11), wherein R 3A It can be a hydrogen atom, an alkyl group with 1 to 8 carbon atoms, an alkoxy group with 1 to 8 carbon atoms, an alkyl group with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, an alkoxy group with 1 to 8 carbon atoms substituted by 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 with 2 to 8 carbon atoms, or an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms).

[0114] (A-13): The compound of any one of (A-1) to (A-12), wherein R 3A It is a hydrogen atom.

[0115] As a pharmaceutically acceptable salt of a compound represented by general formula (A), for example, R of general formula (A). 2A R 3A When the form is an amino group, examples include hydrochlorides. Additionally, R in general formula (A) 2A R 3A When the group is carboxyl, examples include alkali metal salts such as sodium, potassium, and lithium.

[0116] The following shows representative compounds contained in general formula (A).

[0117] <Representative compound A-100>

[0118]

[0119] (where R is in the formula) 1A R 4A R 5A and W A and W A The substitution positions are shown in Tables 1-3. (In Tables 1-3, W...) A The substitution positions indicate the substitution positions on the benzene ring. That is, positions 2, 3, and 4 in the table correspond to positions 2', 3', and 4' in the formula representing compound A-100, respectively.

[0120] [Table 1]

[0121] <![CDATA[R 1A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 4A / R 5A ]]> H 2- 1H-Tetrazol-5-yl H / H H 3- 1H-Tetrazol-5-yl H / H H 3- (1-Methyl-1H-tetrazole)-5-yl H / H H 4- 1H-Tetrazol-5-yl H / H <![CDATA[CH3]]> 3- 1H-Tetrazol-5-yl H / H <![CDATA[CH3]]> 3- 1H-Tetrazol-5-yl <![CDATA[CH3 / H]]> Phenyl 3- 1H-Tetrazol-5-yl H / H H 3- 1H-Tetrazol-1-yl H / H H 3- 1H-Tetrazol-1-yl <![CDATA[CH3 / CH3 <!-- 9 -->]]> H 3- (1,2,3-triazol)-5-yl H / H H 3- (1,2,4-triazol)-3-yl H / H H 4- (1,2,4-triazol)-3-yl H / H

[0122] [Table 2]

[0123] <![CDATA[R 1A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 4A / R 5A ]]> H 2- (1,2,4-triazol)-1-yl H / H H 3- (1,2,4-triazol)-1-yl H / H H 3- [5-(trifluoromethyl)-1,2,4-triazol]-3-yl H / H H 3- [5-(trifluoromethyl)-1,2,4-triazol]-3-yl Ethyl / H H 3- [5-Fluoro-1,2,3-triazole]-4-yl H / H H 3- [5-Fluoro-1,2,3-triazole]-4-yl <![CDATA[CH3 / CH3]]> H 3- [5-Cyano-1,2,3-triazole]-4-yl H / H H 4- 1H-imidazol-1-yl H / H H 4- 1H-imidazol-1-yl Pr / H H 3- 1H-Imidazol-2-yl H / H H 3- 1H-imidazol-4-yl H / H H 3- Imidazoline-2-yl H / H

[0124] [Table 3]

[0125]

[0126] <Representative compound A-200>

[0127]

[0128] (where R is in the formula) 1A R 2A R 4A R 5A and W A and W A The replacement positions are shown in Tables 4 and 5.

[0129] In Tables 4 and 5, W A The substitution positions indicate the substitution positions on the benzene ring. That is, positions 2, 3, and 4 in the table correspond to positions 2', 3', and 4' in the formula representing compound A-200, respectively.

[0130] [Table 4]

[0131] <![CDATA[R 1A ]]> <![CDATA[R 2A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 4A / R 5A ]]> H 4-OH 3- 1H-Tetrazol-5-yl H / H H <![CDATA[4-OCH3]]> 3- 1H-Tetrazol-5-yl H / H <![CDATA[CH3]]> 2-Cl 3- 1H-Tetrazol-5-yl H / H H 2，6-Cl 3- 1H-Tetrazol-5-yl H / H H 4-F 3- 1H-Tetrazol-5-yl H / H H 4-Br 3- 1H-Tetrazol-5-yl Ethyl / H H <![CDATA[3-OCH3]]> 4- (1-Methyl-1H-tetrazole)-5-yl H / H H <![CDATA[4-CH3]]> 3- 1H-Tetrazol-5-yl H / H

[0132] [Table 5]

[0133] <![CDATA[R 1A ]]> <![CDATA[R 2A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 4A / R 5A ]]> H 4-Cl 3- (1,2,3-triazol)-5-yl <![CDATA[CH3 / H]]> H <![CDATA[4-CF3]]> 3- (1,2,3-triazol)-5-yl H / H H <![CDATA[3-SCH3]]> 4- (1,2,4-triazol)-1-yl H / H H <![CDATA[3-SO2CH3]]> 4- 1H-imidazol-1-yl H / H H <![CDATA[3-NHSO2CH3]]> 4- 1H-imidazol-1-yl H / H H <![CDATA[4-OCH3]]> 3- 1H-imidazol-4-yl H / H H 4-F 2- Pyrazole-3-yl H / H

[0134] <Representative compound A-300>

[0135]

[0136] (where R is in the formula) 1A R 2A R 3A R 4A R 5A and W A and W A The replacement positions are shown in Tables 6 and 7.

[0137] In Tables 6 and 7, W A The substitution positions indicate the substitution positions on the benzene ring. That is, positions 3 and 4 in the table correspond to positions 3' and 4' in the formula representing compound A-300, respectively.

[0138] [Table 6]

[0139] <![CDATA[R 1A ]]> <![CDATA[R 2A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 3A ]]> <![CDATA[R 4A / R 5A ]]> H H 3- 1H-Tetrazol-5-yl 9-Br H / H H <![CDATA[4-OCH3]]> 3- 1H-Tetrazol-5-yl 9-Cl H / H H 4-OH 3- 1H-Tetrazol-5-yl <![CDATA[10-OCH3]]> H / H H 2-Cl 3- 1H-Tetrazol-5-yl 9-Br H / H H 2，6-Cl 3- 1H-Tetrazol-5-yl <![CDATA[9-CH3]]> H / H H H 3- 1H-Tetrazol-5-yl 10-Cl <![CDATA[CH3 / H]]> H <![CDATA[3-OCH3]]> 4- (1-Methyl-1H-tetrazole)-5-yl <![CDATA[9-CF a ]]> H / H

[0140] [Table 7]

[0141] <![CDATA[R 1A ]]> <![CDATA[R 2A ]]> <![CDATA[W A Replacement position]]> <![CDATA[W A ]]> <![CDATA[R 3A ]]> <![CDATA[R 4A / R 5A ]]> H <![CDATA[4-CH3]]> 3- 1H-Tetrazole-1-yl 9-CN Pr / H <![CDATA[CH3]]> H 3- (1,2,3-triazol)-5-yl 9-OH H / H Ethyl H 3- (1,2,3-triazol)-5-yl 10-F H / H H 3-Br 4- (1,2,4-triazol)-1-yl <![CDATA[9-SCH3]]> H / H Allyl H 4- 1H-imidazol-1-yl <![CDATA[8-OCH3]]> H / H H H 3- 1H-imidazol-1-yl <![CDATA[10-OCH3]]> <![CDATA[CH3 / CH3]]>

[0142] (B-1): The following general formula (BI) represents a compound or a pharmaceutically acceptable salt thereof.

[0143]

[0144] (where R is in the formula) 1B and R 2BThese can be the same or different and can represent hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, cycloalkyl groups with 3 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups with 1 to 8 carbon atoms, dialkylamino groups with 2 to 8 carbon atoms, acylamino groups with 2 to 8 carbon atoms, carboxyl groups, acyl groups with 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety with 1 to 8 carbon atoms), phenyl groups that may have substituents, pyridyl groups that may have substituents, or aralkyl groups (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms), or

[0145] R 1B and R 2B They can together with the benzene rings they are bonded to form fused rings selected from naphthalene rings, quinoline rings, isoquinoline rings, tetrahydronaphthalene rings, indenium rings, tetrahydroquinoline rings, or tetrahydroisoquinoline rings, and are composed of R 1B and R 2B Together and R 1B and R 2B The ring formed by the separately bonded carbon atoms can be substituted by 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, cycloalkyl with 3 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acylamino with 2 to 8 carbon atoms, carboxyl, acyl with 2 to 8 carbon atoms, alkoxycarbonyl (alkoxy moiety with 1 to 8 carbon atoms), or aralkyl (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms).

[0146] R 3B and R 4B These can be the same or different and can represent hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups with 1 to 8 carbon atoms, dialkylamino groups with 2 to 8 carbon atoms, acylamino groups with 2 to 8 carbon atoms, carboxyl groups, acyl groups with 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety with 1 to 8 carbon atoms), or aralkyl groups (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms).

[0147] R 5B This refers to hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups with 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0148] R 6B and R 7B They can be the same or different, representing hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, or amino groups.

[0149] X B Indicates C, CH or N,

[0150] Y B It represents N, NH or C (=O),

[0151] Among them, X B When Y is N, B Not N, NH

[0152] Additionally, X B When Y is C or CH B Not C (=O),

[0153] A double line consisting of a solid line and a dashed line represents a single bond or a double bond.

[0154] Z B Represents oxygen or sulfur atoms.

[0155] A B This indicates that the ring may have 1 to 4 substituents selected from alkyl (1 to 8 carbon atoms), alkenyl (2 to 8 carbon atoms), alkoxy (1 to 8 carbon atoms), alkyl (1 to 8 carbon atoms) substituted with 1 to 3 halogen atoms, alkoxy (1 to 8 carbon atoms) substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl, nitro, cyano, amino, alkylamino (1 to 8 carbon atoms), dialkylamino (2 to 8 carbon atoms), aralkyl (6 to 10 carbon atoms in the aryl moiety and 1 to 8 carbon atoms in the alkylene moiety), phenyl, or pyridyl, which may be the same or different substituents, or it may indicate a bonding site.

[0156] B B N(R) 8B C(=O), NHCONH, CON(R) 9B ), NHC(=S)NH, N(R)10B SO2, SO2N(R) 11B ) or OSO2,

[0157] Here, R 8B R 9B R 10B and R 11B This refers to hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups with 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0158] D B This indicates that it may have 1 to 4 substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups having 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), which may be the same or different, and may have an alkylene chain having 1 to 6 carbon atoms with a double bond, or a bonding site.

[0159] E B Indicates O, S, NR 12B Or bonding site,

[0160] Here, R 12B The terms "hydrogen atom", "alkyl group with 1 to 8 carbon atoms", "alkenyl group with 2 to 8 carbon atoms", "alkyl group with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms", "alkyl group with 1 to 8 carbon atoms substituted by hydroxyl groups", or "aralkyl group (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms)" represent the following:

[0161] G B This indicates that it may have a group selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), phenyl with substituents, pyridyl with substituents, imidazolyl with substituents, and others with substituents. Piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, etc., containing 1 to 4 identical or different substituents in the azole group or the thiazole group that may have substituents. azoles, indole, benzofurans, pyrroles, pyridines, or pyrimidines

[0162] Moreover, m B Represents integers from 0 to 5.

[0163] Among them, R 1B and R 2B When they do not form a cycle together, X is not included. B For C and Y B N, the double line consisting of solid and dashed lines represents a double bond, Z B For oxygen atoms, A B It is a benzene ring, m B 0, B B For C(=O)NH, E B For bonding sites and G B (Including the case of phenyl.)

[0164] (B-2): The compound represented by the following general formula (BII) or a pharmaceutically acceptable salt thereof.

[0165]

[0166] (in the formula,

[0167] This indicates a naphthalene ring, quinoline ring, isoquinoline ring, tetrahydronaphthalene ring, indane ring, tetrahydroquinoline ring, or tetrahydroisoquinoline ring.

[0168] Furthermore, these rings can be substituted by 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms), or aralkyl groups (aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 8 carbon atoms).

[0169] R 3Ba and R 4BaThese can be the same or different and can represent hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups with 1 to 8 carbon atoms, dialkylamino groups with 2 to 8 carbon atoms, acylamino groups with 2 to 8 carbon atoms, carboxyl groups, acyl groups with 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety with 1 to 8 carbon atoms), or aralkyl groups (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms).

[0170] R 5Ba This refers to hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups with 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0171] R 6Ba and R 7Ba They can be the same or different, representing hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, or amino groups.

[0172] This indicates that it may have 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), phenyl, or pyridyl, which may be the same or different substituents, in benzene ring, pyridine ring, thiophene ring, pyrimidine ring, naphthyl ring, quinoline ring, or indole ring.

[0173] B Ba N(R) 8Ba C(=O), NHCONH, CON(R) 9Ba ), NHC(=S)NH, N(R) 10Ba SO2, SO2N(R) 11Ba ), or OSO2,

[0174] Here, R 8Ba R 9BaR 10Ba and R 11Ba This refers to hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups with 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0175] E Ba Indicates O, S, NR 12Ba Or bonding site,

[0176] Here, R 12Ba This refers to hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkyl groups with 1 to 8 carbon atoms substituted with hydroxyl groups, or aralkyl groups (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0177] G Ba This indicates that it may have a group selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, alkylsulfonyl with 1 to 6 carbon atoms, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), phenyl with substituents, pyridyl with substituents, imidazolyl with substituents, and others with substituents. Piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, etc., containing 1 to 4 identical or different substituents in the azole group or the thiazole group that may have substituents. azoles, indole, benzofurans, pyrroles, pyridines, or pyrimidines

[0178] Moreover, n B Represents integers from 0 to 5.

[0179] Next, the substituents in the general formulas (BI) and (BII) of this specification will be explained.

[0180] Examples of alkyl groups having 1 to 8 carbon atoms include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

[0181] Examples of cycloalkyl groups with 3 to 8 carbon atoms include cyclopropyl and cyclohexyl.

[0182] Examples of alkenyl groups with 2 to 8 carbon atoms include allyl.

[0183] Examples of alkoxy groups with 1 to 8 carbon atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentoxy, or hexoxy.

[0184] Examples of alkyl groups with 1 to 8 carbon atoms that are substituted with 1 to 3 halogen atoms include methyl, ethyl, propyl, isopropyl, butyl, or tert-butyl, which are substituted with 1 to 3 halogen atoms such as fluorine, chlorine, or bromine. Trifluoromethyl, chloromethyl, 2-chloroethyl, 2-bromoethyl, or 2-fluoroethyl are preferred examples.

[0185] Examples of alkoxy groups with 1 to 8 carbon atoms that are substituted with 1 to 3 halogen atoms include methoxy, ethoxy, propoxy, isopropoxy, butoxy, or tert-butoxy, which are substituted with 1 to 3 halogen atoms such as fluorine, chlorine, or bromine. Preferred examples include trifluoromethoxy, chloromethoxy, 2-chloroethoxy, 2-bromoethoxy, or 2-fluoroethoxy.

[0186] Examples of halogen atoms include fluorine, chlorine, and bromine atoms.

[0187] Examples of alkylamino groups with 1 to 8 carbon atoms include methylamino and ethylamino.

[0188] Examples of dialkylamino groups with 2 to 8 carbon atoms include dimethylamino and diethylamino.

[0189] Acetylamino is an example of an acylamino group with 2 to 8 carbon atoms.

[0190] Examples of acyl groups with 2 to 8 carbon atoms include the acetyl group.

[0191] Examples of alkoxycarbonyl groups (where the number of carbon atoms in the alkoxy moiety is 1 to 8) include methoxycarbonyl.

[0192] Examples of aralkyl groups (where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms) include benzyl groups.

[0193] Examples of alkyl groups with 1 to 8 carbon atoms that are substituted with hydroxyl groups include 2-hydroxyethyl.

[0194] Examples of alkyl sulfinyl groups with 1 to 6 carbon atoms include methane sulfinyl groups.

[0195] Examples of alkyl thio groups with 1 to 6 carbon atoms include methyl thio groups.

[0196] Examples of alkyl sulfonyl groups with 1 to 6 carbon atoms include methanesulfonyl groups.

[0197] As a phenyl group that can have substituents, a pyridyl group that can have substituents, an imidazole group that can have substituents, or any other group that can have substituents. The substituents that the azole group and the thiazolyl group, which may have substituents, can include halogen atoms, alkyl groups with 1 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms that are replaced by 1 to 3 halogen atoms, and alkoxy groups with 1 to 8 carbon atoms that are replaced by 1 to 3 halogen atoms.

[0198] As compounds of the above general formula (BI), the compounds shown below are preferred.

[0199] (B-1-1)

[0200] The compound described in (B-1) above, wherein R 1B and R 2B The following can be the same or different and are hydrogen atoms, alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl, nitro, cyano, amino, phenyl with substituents, pyridyl or aralkyl with substituents (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms).

[0201] (B-1-2)

[0202] The compounds described in (B-1) or (B-1-1) above, wherein R 1B and R 2B Together with the benzene rings they are bonded to, they form naphthalene rings or tetrahydronaphthalene rings, and are composed of R... 1B and R 2B Together and R 1B and R 2BThe benzene ring or cyclohexene ring formed by the separately bonded carbon atoms can be substituted by 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acylamino with 2 to 8 carbon atoms, carboxyl, acyl with 2 to 8 carbon atoms, alkoxycarbonyl (alkoxy moiety with 1 to 8 carbon atoms), or aralkyl (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms).

[0203] (B-1-3)

[0204] The compounds described in (B-1) or (B-1-1) above, wherein R 1B and R 2B Together with the benzene ring they are bonded to, they form a naphthalene ring, and R... 1B and R 2B Together and R 1B and R 2B The benzene ring formed by the separately bonded carbon atoms can be substituted by 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, and amino groups, which can be the same or different substituents.

[0205] (B-1-4)

[0206] The compounds described in (B-1) or (B-1-1) above, wherein R 1B and R 2B Together with the benzene rings they are bonded to, they form naphthalene rings or tetrahydronaphthalene rings.

[0207] (B-1-5)

[0208] The compound described in any one of (B-1) or (B-1-1) to (B-1-4) above, wherein R 3B and R 4B They may be the same or different and are hydrogen atoms, alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, halogen atoms, hydroxyl, nitro, cyano, amino, or aralkyl (the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 8 carbon atoms).

[0209] (B-1-6)

[0210] The compound of any one of (B-1) or (B-1-1) to (B-1-5), wherein R 5B It is an alkyl or aralkyl group with 1 to 8 carbon atoms (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0211] (B-1-7)

[0212] The compound described in any one of (B-1) or (B-1-1) to (B-1-6) above, wherein R 5B It is a hydrogen atom.

[0213] (B-1-8)

[0214] The compound or a pharmaceutically acceptable salt thereof described in any one of (B-1) or (B-1-1) to (B-1-7) above, wherein R 6B and R 7B They may be the same or different and are hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

[0215] (B-1-9)

[0216] The compound of any one of (B-1) or (B-1-1) to (B-1-8) above, wherein R 6B and R 7B Both are hydrogen atoms.

[0217] (B-1-10)

[0218] The compound of any one of (B-1) or (B-1-1) to (B-1-9) above, wherein R 3B R 4B R 5B R 6B and R 7B It is a hydrogen atom.

[0219] (B-1-11)

[0220] The compound described in any one of (B-1) or (B-1-1) to (B-1-10) above, wherein X B For N and Y B The double line consisting of solid and dashed lines represents a single bond (C = O).

[0221] (B-1-12)

[0222] The compound described in any one of (B-1) or (B-1-1) to (B-1-11) above, wherein X B For C and Y B The double line consisting of N, solid and dashed lines, represents a double bond.

[0223] (B-1-13)

[0224] The compound described in any one of (B-1) or (B-1-1) to (B-1-12) above, wherein Z B It is an oxygen atom.

[0225] (B-1-14)

[0226] The compound described in any one of (B-1) or (B-1-1) to (B-1-13) above, wherein A B It can be a phenyl or pyridyl group having 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), phenyl or pyridyl.

[0227] (B-1-15)

[0228] The compound described in any one of (B-1) or (B-1-1) to (B-1-14) above, wherein A B It is a phenyl group that may have 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, or amino, which may be the same or different substituents.

[0229] (B-1-16)

[0230] The compound described in any one of (B-1) or (B-1-1) to (B-1-15) above, wherein A B It is phenyl or pyridyl.

[0231] (B-1-17)

[0232] The compound described in any one of (B-1) or (B-1-1) to (B-1-16) above, wherein A B These are bonding sites.

[0233] (B-1-18)

[0234] The compound described in any one of (B-1) or (B-1-1) to (B-1-17) above, wherein B B It can be NHC (=O), NHCONH, CONH, NHC (=S)NH, NHSO2, SO2NH or OSO2.

[0235] (B-1-19)

[0236] The compound described in any one of (B-1) or (B-1-1) to (B-1-18) above, wherein B B It can be NHC (=O), NHCONH, or NHSO2.

[0237] (B-1-20)

[0238] The compound described in any one of (B-1) or (B-1-1) to (B-1-19) above, wherein B B It is NHC (=O) or NHSO2.

[0239] (B-1-21)

[0240] The compound described in any one of (B-1) or (B-1-1) to (B-1-20) above, wherein B B It is NHC (=O).

[0241] (B-1-22)

[0242] The compound described in any one of (B-1) or (B-1-1) to (B-1-21) above, wherein D B It may have 1 to 4 substituents selected from alkyl groups having 1 to 8 carbon atoms or alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, which may be the same or different, and may further have a double bond of alkylene chain having 1 to 6 carbon atoms.

[0243] (B-1-23)

[0244] The compound described in any one of (B-1) or (B-1-1) to (B-1-22) above, wherein D B These are bonding sites.

[0245] (B-1-24)

[0246] The compound described in any one of (B-1) or (B-1-1) to (B-1-23) above, wherein D BIt has 1 to 4 substituents selected from alkyl groups having 1 to 8 carbon atoms and alkenyl groups having 2 to 8 carbon atoms, which may be the same or different.

[0247] (B-1-25)

[0248] The compound described in any one of (B-1) or (B-1-1) to (B-1-24) above, wherein D B It has 1 to 4 substituents selected from alkyl groups having 1 to 3 carbon atoms and alkenyl groups having 2 to 3 carbon atoms, which may be the same or different.

[0249] (B-1-26)

[0250] The compound described in any one of (B-1) or (B-1-1) to (B-1-25) above, wherein E B These are bonding sites.

[0251] (B-1-27)

[0252] The compound described in any one of (B-1) or (B-1-1) to (B-1-26) above, wherein G B Piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, and hydroxyl, nitro, cyano, amino, alkylamino, dialkylamino, acyl, methylenedioxy, carboxyl, alkylsulfinyl, alkylthio, or alkylsulfonyl, having 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, or alkylsulfonyl with 1 to 6 carbon atoms as substituents. Azole, indole, benzofuran, pyrrole, pyridine, or pyrimidine.

[0253] (B-1-28)

[0254] The compound described in any one of (B-1) or (B-1-1) to (B-1-27) above, wherein G BThe benzene may have 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, or alkylsulfonyl with 1 to 6 carbon atoms as substituents.

[0255] (B-1-29)

[0256] The compound described in any one of (B-1) or (B-1-1) to (B-1-28) above, wherein G B The benzene or pyridine may have 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl, nitro, amino, dialkylamino with 2 to 8 carbon atoms, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, and alkylsulfonyl with 1 to 6 carbon atoms as substituents.

[0257] (B-1-30)

[0258] The compound described in any one of (B-1) or (B-1-1) to (B-1-29) above, wherein G B The benzene may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups that are substituted with 1 to 3 halogen atoms and have 1 to 8 carbon atoms.

[0259] (B-1-31)

[0260] The compound described in any one of (B-1) or (B-1-1) to (B-1-30) above, wherein m B It is 0.

[0261] (B-1-32)

[0262] The compound described in any one of (B-1) or (B-1-1) to (B-1-31) above, wherein A B It is a benzene ring, m B B is 0. B For NHC (=O) or NHSO2, D B E is an alkyl group or bonding site with 1 to 3 carbon atoms. B For bonding sites, GB The benzene may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups as substituents.

[0263] (B-1-33)

[0264] The compound described in any one of (B-1) or (B-1-1) to (B-1-32) above, wherein A B It is a benzene ring, m B B is 0. B For NHC (=O), D B For bonding sites, E B For bonding sites, G B The benzene may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups that are substituted with 1 to 3 halogen atoms and have 1 to 8 carbon atoms.

[0265] (B-1-34)

[0266] The compound described in any one of (B-1) or (B-1-1) to (B-1-33) above, wherein R 1B and R 2B Together with the benzene ring they are bonded to, they form a naphthalene ring, R 3B R 4B R 5B R 6B and R 7B X represents a hydrogen atom. B For N, Y B For C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B A represents an oxygen atom. B Indicates a benzene ring, m B Represents 0, B B Indicates NHC (=O) or NHSO2, D B E represents an alkyl group or bonding site with 1 to 3 carbon atoms. B Indicates the bonding site, G B The benzene may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups as substituents.

[0267] (B-1-35)

[0268] The compound of any one of (B-1) or (B-1-1) to (B-1-34), wherein, in the above general formula (BI), R 1B and R 2BTogether with the benzene ring they are bonded to, they form a naphthalene ring, R 3B R 4B R 5B R 6B and R 7B X represents a hydrogen atom. B For N, Y B For C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B A represents an oxygen atom. B Indicates a benzene ring, m B Represents 0, B B Represents NHC (=O), D B Indicates the bonding site, E B Indicates the bonding site, G B The benzene may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups that are substituted with 1 to 3 halogen atoms and have 1 to 8 carbon atoms.

[0269] As compounds of the above general formula (BII), the compounds shown below are preferred.

[0270] (B-2-1)

[0271] The compound described above (B-2), wherein,

[0272] It is a naphthalene ring or tetrahydronaphthalene ring that can be substituted by 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acylamino with 2 to 8 carbon atoms, carboxyl, acyl with 2 to 8 carbon atoms, alkoxycarbonyl (alkoxy moiety with 1 to 8 carbon atoms), or aralkyl (aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 8 carbon atoms), which may be the same or different substituents.

[0273] (B-2-2)

[0274] The compounds described in (B-2) or (B-2-1) above, wherein,

[0275] It is a naphthalene ring that can be substituted by 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, and amino groups, which may be the same or different substituents.

[0276] (B-2-3)

[0277] The compound of any one of (B-2) or (B-2-1) to (B-2-2) above, wherein R 3Ba and R 4Ba They can be the same or different, and can be hydrogen atoms, alkyl groups with 1 to 8 carbon atoms, alkenyl groups with 2 to 8 carbon atoms, alkoxy groups with 1 to 8 carbon atoms, alkyl groups with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy groups with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, or aralkyl groups (the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 8 carbon atoms).

[0278] (B-2-4)

[0279] The compound described in any one of (B-2) or (B-2-1) to (B-2-3) above, wherein R 5Ba It is an alkyl or aralkyl group with 1 to 8 carbon atoms (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms).

[0280] (B-2-5)

[0281] The compound described in any one of (B-2) or (B-2-1) to (B-2-4) above, wherein R 5Ba It is a hydrogen atom.

[0282] (B-2-6)

[0283] The compound described in any one of (B-2) or (B-2-1) to (B-2-5) above, wherein R 6Ba and R 7Ba They can be the same or different, and can be hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

[0284] (B-2-7)

[0285] The compound described in any one of (B-2) or (B-2-1) to (B-2-6) above, wherein R 6Ba and R7Ba Both are hydrogen atoms.

[0286] (B-2-8)

[0287] The compound described in any one of (B-2) or (B-2-1) to (B-2-7) above, wherein,

[0288] It can be a phenyl or pyridyl group having 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, aralkyl (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), phenyl or pyridyl.

[0289] (B-2-9)

[0290] The compound described in any one of (B-2) or (B-2-1) to (B-2-8) above, wherein,

[0291] It is a phenyl group that may have 1 to 4 substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, or amino, which may be the same or different substituents.

[0292] (B-2-10)

[0293] The compound described in any one of (B-2) or (B-2-1) to (B-2-9) above, wherein,

[0294] These are bonding sites.

[0295] (B-2-11)

[0296] The compound described in any one of (B-2) or (B-2-1) to (B-2-10) above, wherein B Ba It can be NHC (=O), NHCONH, CONH, NHC (=S)NH, NHSO2, SO2NH or OSO2.

[0297] (B-2-12)

[0298] The compound described in any one of (B-2) or (B-2-1) to (B-2-11) above, wherein B Ba It can be NHC (=O), NHCONH, or NHSO2.

[0299] (B-2-13)

[0300] The compound described in any one of (B-2) or (B-2-1) to (B-2-12) above, wherein E Ba These are bonding sites.

[0301] (B-2-14)

[0302] The compound described in any one of (B-2) or (B-2-1) to (B-2-13) above, wherein G Ba Piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, and hydroxyl, nitro, cyano, amino, alkylamino, dialkylamino, acyl, methylenedioxy, carboxyl, alkylsulfinyl, alkylthio, or alkylsulfonyl, having 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, or alkylsulfonyl with 1 to 6 carbon atoms as substituents. Azole, indole, benzofuran, pyrrole, pyridine, or pyrimidine.

[0303] (B-2-15)

[0304] The compound described in any one of (B-2) or (B-2-1) to (B-2-14) above, wherein G Ba The benzene may have 1 to 4 identical or different substituents selected from alkyl with 1 to 8 carbon atoms, alkenyl with 2 to 8 carbon atoms, alkoxy with 1 to 8 carbon atoms, alkyl with 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy with 1 to 3 halogen atoms substituted with 1 to 3 halogen atoms, halogen atom, hydroxyl, nitro, cyano, amino, alkylamino with 1 to 8 carbon atoms, dialkylamino with 2 to 8 carbon atoms, acyl with 2 to 8 carbon atoms, methylenedioxy, carboxyl, alkylsulfinyl with 1 to 6 carbon atoms, alkylthio with 1 to 6 carbon atoms, or alkylsulfonyl with 1 to 6 carbon atoms as substituents.

[0305] (B-2-16)

[0306] The compound described in any one of (B-2) or (B-2-1) to (B-2-15) above, wherein n B It is 0.

[0307] In the above general formula (BI), R is preferred. B1 and R B2 Together with the benzene rings they are bonded to, they form fused rings selected from naphthalene rings or tetrahydronaphthalene rings, with naphthalene rings being particularly preferred.

[0308] In the above general formula (BI), R is preferred. B3 R B4 R B5 R B6 and R B7 It represents a hydrogen atom.

[0309] In the above general formula (BI), X is preferred. B For N, Y B For C (=O), the double line consisting of solid and dashed lines represents a single bond.

[0310] In the above general formula (BI), Z is preferred. B It is an oxygen atom.

[0311] In the above general formula (BI), A B Preferably, it represents a benzene ring or a pyridine ring, and particularly preferably, it represents a benzene ring.

[0312] In the above general formula (BI), m B Preferred is represented by 0 to 4, and particularly preferred is represented by 0.

[0313] In the above general formula (BI), B B Preferred representation of N(R) 8B C(=O) or N(R) 10B SO2, at this point, R is preferred. 8B and R 10B This represents a hydrogen atom. Furthermore, in the above general formula (BI), B is particularly preferred. B It represents NHC (=O).

[0314] In the above general formula (BI), D B Preferably, it is represented as a chain or bonding site having 1 to 4 alkylene chains or carbon atoms having the same or different substituents selected from alkyl groups having 1 to 8 carbon atoms and alkenyl groups having 2 to 8 carbon atoms. More preferably, it is represented as a chain or bonding site having 1 to 4 alkylene chains or carbon atoms having the same or different substituents selected from alkyl groups having 1 to 3 carbon atoms and alkenyl groups having 2 to 3 carbon atoms. Particularly preferred is a bonding site.

[0315] In the above general formula (BI), EB Preferably, it represents O or a bonding site, and more preferably, it represents a bonding site.

[0316] In the above general formula (BI), G B Preferably, it refers to benzene or pyridine having 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 3 halogen atoms substituted, halogen atoms, hydroxyl groups, nitro groups, amino groups, dialkylamino groups having 2 to 8 carbon atoms, carboxyl groups, alkylsulfinyl groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, and alkylsulfonyl groups having 1 to 6 carbon atoms as substituents. B Particularly preferred means benzene having 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups with 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms.

[0317] In the above general formula (BI), A is particularly preferred. B Indicates a benzene ring, m B Represents 0, B B Indicates NHC (=O) or NHSO2, D B E represents an alkyl group or bonding site with 1 to 3 carbon atoms. B Indicates the bonding site, G B This refers to benzene that may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups.

[0318] In the above general formula (BI), A is particularly preferred. B Indicates a benzene ring, m B Represents 0, B B Represents NHC (=O), D B Indicates the bonding site, E B Indicates the bonding site, G B This refers to benzene that may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups that are substituted with 1 to 3 halogen atoms and have 1 to 8 carbon atoms.

[0319] In the above general formula (BI), R is further preferred. B1 and R B2 Together with the benzene ring they are bonded to, they form a naphthalene ring, R B3 R B4 R B5 R B6 and R B7 X represents a hydrogen atom. B For N, Y BFor C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B A represents an oxygen atom. B Indicates a benzene ring, m B Represents 0, B B Indicates NHC (=O) or NHSO2, D B E represents an alkyl group or bonding site with 1 to 3 carbon atoms. B Indicates the bonding site, G B This refers to benzene that may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups.

[0320] In the above general formula (BI), R is particularly preferred. B1 and R B2 Together with the benzene ring they are bonded to, they form a naphthalene ring, R B3 R B4 R B5 R B6 and R B7 X represents a hydrogen atom. B For N, Y B For C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B A represents an oxygen atom. B Indicates a benzene ring, m B Represents 0, B B Represents NHC (=O), D B Indicates the bonding site, E B Indicates the bonding site, G B This refers to benzene that may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms, and hydroxyl groups that are substituted with 1 to 3 halogen atoms and have 1 to 8 carbon atoms.

[0321] The following shows representative compounds contained in general formula (BI) and / or (BII).

[0322] <Representative compound example B-100>

[0323]

[0324] (where B is in the formula) Ba (replaces position), n B E Ba and G Ba (As recorded in Tables 8-17)

[0325] [Table 8]

[0326] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site Phenyl NHCO(4) 0 bonding site <![CDATA[(2-CF3)phenyl]]> NHCO(4) 0 bonding site (3-Br)phenyl NHCO(4) 0 bonding site <![CDATA[(4-CF3)phenyl]]> NHCO(4) 0 bonding site (2-Me)phenyl NHCO(4) 0 bonding site (2,6-Me)phenyl NHCO(4) 0 bonding site (2,6-Cl)phenyl NHCO(4) 0 bonding site (3-Cl)phenyl NHCO(4) 1 bonding site Phenyl NHC(=S)NH(4) 0 bonding site Phenyl NHCO(4) 0 bonding site (2,3-OMe)phenyl NHCO(4) 0 bonding site (2-OMe)phenyl NHCO(4) 1 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site (2,3-Me)phenyl NHCO(4) 0 bonding site (2,5-Me)phenyl NHCO(4) 0 bonding site (2-Cl,5-Br)phenyl

[0327] [Table 9]

[0328] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site (2,4-Cl)phenyl NHCO(4) 0 bonding site (2-OH)phenyl NHCO(4) 0 bonding site (2,3-OH)phenyl NHC(=O)NH(4) 0 bonding site Phenyl NHCO(4) 1 bonding site (2,6-Cl)phenyl NHCO(4) 1 bonding site (2-OMe)phenyl NHCO(4) 1 bonding site (2-OH)phenyl NHC(=S)NH(4) 0 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site <![CDATA[(3-CF3)phenyl]]> NHCO(4) 1 bonding site <![CDATA[(2-CF3)phenyl]]> NHC(=O)NH(4) 0 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site (2-Cl,3-OMe)phenyl NHCO(4) 2 bonding site Phenyl NHCO(4) 0 bonding site 3-Indolyl NHCO(4) 0 bonding site (2-Cl,3-OH)phenyl NHCO(4) 1 O Phenyl

[0329] [Table 10]

[0330] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 1 bonding site (2-Cl,4-OMe)phenyl NHCO(4) 0 bonding site (1-Me)imidazol-2-yl NHCO(4) 1 bonding site (2,4-Cl)phenyl NHCO(4) 1 bonding site (2-Cl,4-OH)phenyl NHCO(4) 1 bonding site Pyridin-3-yl NHCO(4) 0 bonding site Benzimidazole-2-yl NHCO(4) 0 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site (2-Br)phenyl NHCO(4) 0 bonding site (2-I)phenyl NHCO(4) 1 bonding site (2-Me)phenyl NHCO(4) 0 bonding site Quinoxalo-2-yl NHCO(4) 0 bonding site (5-Me)thiophen-2-yl NHCO(3) 1 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site (2,4,6-Me)phenyl NHCO(4) 0 bonding site (2-Et)phenyl NHC(=S)NH(4) 0 bonding site (2-Me)phenyl

[0331] [Table 11]

[0332] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site <![CDATA[(4-NMe2)phenyl]]> NHCO(4) 1 O (2,4-Cl)phenyl NHCO(4) 1 O (2-Me)phenyl NHCO(4) 0 bonding site (2-Ac)phenyl NHCO(4) 0 bonding site (2-tBu)phenyl NHCO(3) 0 bonding site (2-I)phenyl NHCO(4) 0 bonding site (1-Me)piperidin-4-yl NHCO(4) 0 bonding site Benzofuran-2-yl NHCO(4) 0 bonding site (1-Me)indol-3-yl NHCo(4) 0 bonding site (2-Allyl)phenyl NHCO(4) 0 bonding site (2-nPr)phenyl NHCO(4) 0 bonding site (2-iPro)phenyl NHCO(4) 0 bonding site 3-Me-thiophene-2-yl NHCO(4) 1 O (2-Me,3-Cl)phenyl NHCO(4) 0 bonding site <![CDATA[(2-CF3, 4-F)phenyl]]> NHCO(4) 0 bonding site (2-OMe, 4-F)phenyl

[0333] [Table 12]

[0334] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site (2-OH,4-F)phenyl NHCO(3) 1 bonding site (2-I)phenyl NHCO(4) 0 bonding site <![CDATA[(3-NMe2)phenyl]]> NHCO(4) 0 bonding site (2-OMe, 4-I)phenyl NHCO(4) 0 bonding site (2-OMe, 6-F)phenyl NHCO(4) 0 bonding site (2-OH,4-I)phenyl NHCO(4) 0 bonding site (2-OH, 6-F)phenyl NHCO(4) 0 bonding site (2-F)phenyl NHCO(4) 0 bonding site <![CDATA[(2-NMe2)phenyl]]> NHCO(4) 0 bonding site (2-OMe, 6-Me)phenyl NHCO(4) 0 bonding site (2-OH,6-Me)phenyl NHCO(4) 2 bonding site (2-Me)phenyl CONH(4) 0 bonding site Phenyl CONH(4) 1 bonding site Phenyl NHCO(4) 2 bonding site (2-Cl)phenyl CONH(4) 1 bonding site (2-Cl)phenyl

[0335] [Table 13]

[0336] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> CONH(4) 0 bonding site (2-Cl)phenyl NHCO(4) 0 bonding site (5-Br-2,3-methylenedioxy)phenyl NHCO(4) 0 bonding site (2-OMe, 6-Br)phenyl NHCO(4) 0 bonding site (2-OH,6-Br)phenyl NHCO(4) 0 bonding site (2-OMe, 6-Cl)phenyl NHCO(4) 0 bonding site (2-OH, 6-Cl)phenyl NHCO(4) 0 bonding site (2-OH, 6-OMe)phenyl NHCO(4) 0 bonding site <![CDATA[(2-OMe, 6-CF3)phenyl]]> NHCO(4) 0 bonding site <![CDATA[(2-OH, 6-CF3)phenyl]]> NHCO(4) 0 bonding site (2-Cl, 5-SMe)phenyl NHCO(4) 0 bonding site (2-SMe)phenyl NHCO(4) 0 bonding site (3-SMe)phenyl NHCO(4) 0 bonding site (2-OMe, 6-Et)phenyl NHCO(4) 0 bonding site <![CDATA[(3-SO2Me)phenyl]]> NHCO(4) 0 bonding site (2-OH, 6-Et)phenyl NHCO(4) 0 bonding site (3-S(=O)Me)phenyl

[0337] [Table 14]

[0338] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site (2-Cl, 5-S(=O)Me)phenyl NHCO(4) 0 bonding site (2-S(=O)Me)phenyl NHCO(4) 0 bonding site (3-Cl)pyridin-2-yl NHCO(4) 0 bonding site (2-OMe, 3-Cl)phenyl NHCO(4) 0 bonding site (3.Me)pyridin-2-yl NHCO(4) 0 bonding site (2-OH,3-Cl)phenyl NHCO(4) 0 bonding site (3-OH)pyridin-2-yl NHC0(4) 0 bonding site (3-vinyl)pyridin-2-yl NHCO(4) 0 bonding site (2-Et)pyridin-2-yl <![CDATA[NHSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NHSO2(4)]]> 0 bonding site Phenyl <![CDATA[NHSO2(4)]]> 0 bonding site (3-Br)phenyl <![CDATA[NHSO2(4)]]> 0 bonding site (3-OMe)phenyl <![CDATA[NHSO2(3)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NMeSO2(3)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NHSO2(3)]]> 0 bonding site Naphthyl-2-yl

[0339] [Table 15]

[0340] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> <![CDATA[NHSO2(3)]]> 0 bonding site Naphth-1-yl <![CDATA[NHSO2(4)]]> 0 bonding site Cyclohexyl <![CDATA[NHSO2(4)]]> 0 bonding site Pyridin-3-yl <![CDATA[NHSO2(4)]]> 0 bonding site (4-iPr)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site Phenyl <![CDATA[NHSO2(4)]]> 0 bonding site Thiophene-2-yl <![CDATA[NHSO2(4)]]> 0 bonding site Naphthyl-2-yl <![CDATA[NBnSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NMeSO2(4)]]> 0 bonding site (3-Br)phenyl <![CDATA[NMeSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[N(CH2CH2OH)SO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (3-Br)phenyl <![CDATA[NHSO2(4)]]> 0 bonding site <![CDATA[(2-CF3)phenyl <!-- 27 -->]]> <![CDATA[NHSO2(4)]]> 1 bonding site (2-Br)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (2-Me)phenyl

[0341] [Table 16]

[0342] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> <![CDATA[NHSO2(4)]]> 1 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NHSO2(4)]]> 2 bonding site Phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (4-Cl)phenyl <![CDATA[NMeSO2(4)]]> 1 bonding site <![CDATA[(2-CF3)phenyl]]> <![CDATA[NMeSO2(4)]]> 1 bonding site (2-Et)phenyl <![CDATA[NMeSO2(4)]]> 1 bonding site (2,3-Me)phenyl <![CDATA[NMeSO2(4)]]> 2 bonding site (2-Cl)phenyl <![CDATA[NMeSO2(4)]]> 1 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NMeSO2(4)]]> 1 bonding site <![CDATA[(2-NH2)phenyl]]> <![CDATA[NMeSO2(4)]]> 1 bonding site <![CDATA[(2-NMe2)phenyl]]>

[0343] [Table 17]

[0344] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site Pyridin-4-yl NHCO(4) 1 O Pyridin-3-yl NHCO(4) 0 bonding site Pyridin-3-yl NHCO(4) 0 bonding site (2-Me)pyridin-3-yl NHCO(4) 0 bonding site (2-Cl)pyridin-3-yl NHCO(4) 1 O Pyridin-2-yl NHCO(4) 0 bonding site <![CDATA[(4-CF3)pyridin-3-yl]]> NHCO(4) 0 bonding site (2-iPr)phenyl

[0345] <Representative compound example B-200>

[0346]

[0347] (where B is in the formula) Ba (replaces position), n B E Ba and G Ba (As shown in Tables 18 and 19)

[0348] [Table 18]

[0349] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site Cyclohexyl NHCO(4) 0 bonding site (6-Me)pyridin-2-yl NHCO(4) 0 bonding site (2-Me)pyridin-3-yl NHCO(4) 0 bonding site (2-OMe,3-Me)phenyl NHCO(4) 0 bonding site (2,3-Cl)phenyl NHCO(4) 0 bonding site (2-OH,3-Me)phenyl NHCO(4) 0 bonding site (2-I)phenyl NHCO(4) 1 bonding site (1-Me)pyrrolo-2-yl NHCO(4) 1 bonding site (2-tBu)phenyl NHCO(4) 0 bonding site (2-Isopropenyl)phenyl NHCO(4) 0 bonding site (2-iPr)phenyl NHCO(4) 1 bonding site Morpholin-2-yl NHCO(4) 0 bonding site (2-Cl)pyridin-2-yl

[0350] [Table 19]

[0351] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> <![CDATA[NHSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[NMeSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> <![CDATA[SO2NH(4)]]> 0 bonding site Phenyl <![CDATA[OSO2(4)]]> 0 Bonding points (3-Br)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl <![CDATA[NHSO2(4)]]> 0 bonding site (3-Br)phenyl <![CDATA[NHSO2(4)]]> 0 bonding site (3-OMe)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (2,3-Cl)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (2,6-Cl)phenyl <![CDATA[NHSO2(4)]]> 1 bonding site (2-I)phenyl <![CDATA[NMeSO2(4)]]> 1 bonding site (2-Cl)phenyl

[0352] <Representative compound example B-300>

[0353]

[0354] (where R is in the formula) 1B B Ba (replaces position), n B E Ba and G Ba As shown in Table 20)

[0355] [Table 20]

[0356] <![CDATA[R 1B ]]> <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> 7-OMe NHCO(4) 0 bonding site (2,3-Me)phenyl 7-OH NHCO(4) 0 Bonding points (2,3-Me)phenyl 6-Me NHCO(4) 0 bonding site (2,3-Me)phenyl 6,7-Me NHCO(4) 0 bonding site (2-I)phenyl 6-Et NHCO(4) 0 bonding site (2-I)phenyl 7-Ph NHCO(4) 0 bonding site (2-Isopropyl)phenyl 7-(pyridin-3-yl) NHCO(4) 0 bonding site (2-Isopropyl)phenyl 7-(pyridin-2-yl) NHCO(4) 0 bonding site (2-Isopropyl)phenyl 7-Cl <![CDATA[NHSO2(4)]]> 0 bonding site (2-Isopropyl)phenyl 7-Br <![CDATA[NHSO2(4)]]> 0 bonding site (2-Isopropyl)phenyl <![CDATA[7-CF3]]> <![CDATA[NHSO2(4)]]> 0 bonding site (2-Isopropyl)phenyl H <![CDATA[NHSO2(4)]]> 0 bonding site (2-Isopropyl)phenyl 6-Me, 7-Br <![CDATA[NHSO2(4)]]> 0 bonding site (2-Isopropyl)phenyl 7-OMe <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl 7-OH <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl 6-Me <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl

[0357] <Representative compound example B-400>

[0358]

[0359] (where B is in the formula) Ba (replaces position), n B E Ba and G Ba As shown in Table 21)

[0360] [Table 21]

[0361] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO 0 bonding site (2-Cl,3-OMe)phenyl NHCO 0 bonding site (2-I)phenyl <![CDATA[NHSO2]]> 1 bonding site (2-Cl)phenyl <![CDATA[NHSO2]]> 1 bonding site (2-Cl)phenyl

[0362] <Representative compound example B-500>

[0363]

[0364] (where B is in the formula) Ba (replaces position), n B E Ba and G Ba As shown in Table 22)

[0365] [Table 22]

[0366] <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> NHCO(4) 0 bonding site (2-Cl,3-OMe)phenyl NHCO(4) 0 bonding site (2-Cl,3-OH)phenyl NHCO(4) 0 bonding site (2-tBu)phenyl NHCO(4) 0 bonding site (2-Cl, 6-OMe)phenyl NHCO(4) 0 bonding site (2-Cl, 6-OH)phenyl NHSO2(3) 0 bonding site Phenyl NHSO2(4) 0 bonding site (2-Cl)phenyl

[0367] <Representative compound example B-600>

[0368]

[0369] (where B is in the formula) B (replaces position), D B E B and G B As shown in Table 23)

[0370] [Table 23]

[0371] <![CDATA[B B (Replaces position)]]> <![CDATA[D B ]]> <![CDATA[E B ]]> <![CDATA[G B ]]> NHCO(4) C(Me)H bonding site Phenyl NHCO(4) <![CDATA[C(Me)2]]> bonding site Phenyl NHCO(4) CH=CH bonding site Phenyl NHCO(4) C(Me)H O Phenyl NHCO(4) <![CDATA[C(Me)2]]> O Phenyl NHCO(4) CH=CH bonding site (2-Me)phenyl NHCO(4) CH=CH Bonding points (2-Cl)phenyl

[0372] <Representative compound example B-700>

[0373]

[0374] (where m) B (replacement position), B B D B E B and G B As shown in Table 24)

[0375] [Table 24]

[0376] <![CDATA[m B (Replaces position)]]> <![CDATA[B B ]]> <![CDATA[D B ]]> <![CDATA[E B ]]> <![CDATA[G B ]]> 1(4) NHCO bonding site bonding site Phenyl 1(4) NHCO bonding site bonding site (2-Cl)phenyl 1(4) <![CDATA[NHSO2]]> <![CDATA[CH2]]> bonding site (2-Cl)phenyl

[0377] <Representative compound example B-800>

[0378]

[0379] (where X) Ba Y Ba B Ba (replaces position), n B E Ba and G Ba As shown in Table 25)

[0380] [Table 25]

[0381] <![CDATA[X Ba ]]> <![CDATA[Y Ba ]]> <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> CH CF NHCO(4) 0 bonding site (2,3-Me)phenyl CH C-OH NHCO(4) 0 bonding site (2,3-Me)phenyl CH CF NHCO(4) 0 bonding site (2-I)phenyl CH N NHCO(4) 0 bonding site (2-I)phenyl CH N NHCO(4) 0 bonding site Phenyl N CH NHCO(4) 0 bonding site (2-I)phenyl CH N NHCO(4) 0 bonding site (2-Cl)phenyl CH N NHCO(4) 0 bonding site (2-OH)phenyl CH N NHC(=0)NH(4) 0 bonding site (2-OH)phenyl CH N NHCO(4) 0 bonding site (2-OH,6-Me)phenyl CH N NHCO(4) 0 bonding site (2-OH, 6-Cl)phenyl CH N NHCO(3) 0 bonding site (2-OH, 6-Cl)phenyl CH N NHCO(4) 0 bonding site (2-Cl)pyridin-2-yl CH N NHCO(4) 1 bonding site (2-Cl)pyridin-2-yl CH N NHCO(4) 0 bonding site (2-Me)pyridin-2-yl CH C-OMe <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl CH C-OH <![CDATA[NHSO2(4)]]> 1 bonding site (2-Cl)phenyl

[0382] <Representative compound example B-900>

[0383]

[0384] (In the formula, I = II - III = IV, B) Ba (replaces position), n B E Ba and G Ba As shown in Table 26)

[0385] [Table 26]

[0386] I = II - III = IV <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> N=CH-CH=CH NHCO(4) 0 bonding site (2-I)phenyl CH=N-CH=CH NHCO(4) 0 bonding site (2-I)phenyl CH=CH-N=CH NHCO(4) 0 bonding site (2-I)phenyl CH=CH-CH=N NHCO(4) 0 bonding site (2-I)phenyl N=CH-CH=CH NHCO(4) 1 O Phenyl N=CH-CH=CH NHCO(3) 0 bonding site (2-I)phenyl N=CH-CH=CH NHCO(4) 0 bonding site (2-Cl)phenyl N=CH-CH=CH NHCO(4) 0 bonding site (2-OH)phenyl N=CH-CH=CH NHC(=O)NH(4) 0 bonding site (2-OH)phenyl N=CH-CH=CH NHCO(4) 1 O (2-OH,6-Me)phenyl N=CH-CH=CH NHCO(4) 0 bonding site (2-OH, 6-Cl)phenyl N=CH-CH=CH NHCO(3) 0 bonding site (2-OH, 6-Cl)phenyl N=CH-CH=CH NHCO(4) 0 bonding site (2-Cl)pyridin-2-yl N=CH-CH=CH NHCO(4) 1 bonding site (2-Cl)pyridin-2-yl N=CH-CH=CH NHCO(4) 0 bonding site (2-Me)pyridin-2-yl CH=CH-N=CH NHCO(4) 0 bonding site (2-Cl)pyridin-3-yl

[0387] <Representative compound example B-1000>

[0388]

[0389] (where I-II-III-IV, B) Ba (replaces position), n B E Ba and G Ba As shown in Table 27)

[0390] [Table 27]

[0391] I-II-III-IV <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> <![CDATA[NH-CH2-CH2-CH2]]> NHCO(4) 0 bonding site (2-I)phenyl <![CDATA[CH2-NH-CH2-CH2]]> NHCO(4) 0 bonding site (2-I)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-I)phenyl <![CDATA[CH2-CH2-CH2-NH]]> NHCO(4) 0 bonding site (2-I)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 1 O Phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(3) 0 bonding site (2-I)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-Cl)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-Cl)pyridin-3-yl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-OH)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHC(=O)NH(4) 0 bonding site (2-OH)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 1 O (2-OH,6-Me)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-OH, 6-Cl)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(3) 0 bonding site (2-OH, 6-Cl)phenyl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-Cl)pyridin-2-yl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 1 bonding site (2-Cl)pyridin-2-yl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-Me)pyridin-2-yl <![CDATA[CH2-CH2-NH-CH2]]> NHCO(4) 0 bonding site (2-Cl)pyridin-3-yl

[0392] <Representative compound example B-1100>

[0393]

[0394] (where R is in the formula) 5Ba B Ba (replaces position), n B E Ba and G Ba As shown in Table 28)

[0395] [Table 28]

[0396] <![CDATA[R 5Ba ]]> <![CDATA[B Ba (Replaces position)]]> <![CDATA[n B ]]> <![CDATA[E Ba ]]> <![CDATA[G Ba ]]> Bn <![CDATA[NBnSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> Me <![CDATA[NBnSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]> Et <![CDATA[NBnSO2(4)]]> 0 bonding site <![CDATA[(2-NO2)phenyl]]>

[0397] The compounds represented by the above general formula (A) are disclosed in International Publication 2010 / 093061, and any of these compounds can be readily obtained by referring to these international publications. The entire contents of these international publications are incorporated herein by reference.

[0398] The compounds represented by the above general formulas (BI) and (BII) are disclosed in International Publication 2013 / 105608, and any of these compounds can be readily obtained by referring to these international publications. The entire contents of these international publications are incorporated herein by reference.

[0399] In addition, the compounds represented by the above general formulas (A) to (BII) are described in the aforementioned international publications 2010 / 093061, 2013 / 105608 and 2015 / 005467 as having P2X4 receptor antagonistic effects.

[0400] It should be noted that the following examples show suitable compounds or pharmaceutically acceptable salts thereof contained in the compounds represented by the above general formulas (A) to (BII), but the compounds or pharmaceutically acceptable salts thereof that can be used as active ingredients in the pharmaceutical compositions of the present invention are not limited thereto.

[0401] (Compound A1) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0402] (Compound A2) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0403] (Compound A3) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone potassium salt;

[0404] (Compound A4) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0405] (Compound A5) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0406] (Compound A6) 1-Methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0407] (Compound A7) 1,3-Dimethyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0408] (Compound A8) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0409] (Compound A9) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0410] (Compound A10) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0411] (Compound A11) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0412] (Compound A12) 5-[2-bromo-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0413] (Compound A13) 5-[3-(2-methyl-2H-tetrazole-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0414] (Compound A14) 5-[3-(1-methyl-1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0415] (Compound A15)5-[3-(5-oxo-4H-[1,2,4-] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0416] (Compound A16)5-[3-(5-thio-4H-[1,2,4-]) [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0417] (Compound A17)5-[3-(5-thio-4H―[1,2,4)-] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0418] (Compound A18)5-[3-( [Azolium-2-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0419] (Compound A19) 5-[3-(1H-pyrazol-4-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0420] (Compound A20) 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0421] (Compound A21) 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt;

[0422] (Compound B1) 5-(4-benzoylaminophenyl)-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0423] (Compound B2)5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0424] (Compound B3)5-[4-(3-bromobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0425] (Compound B4)5-[4-[4-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0426] (Compound B5) 5-[4-(2-methylbenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0427] (Compound B6)5-[4-(2,6-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0428] (Compound B7) 5-[4-(2,6-dichlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0429] (Compound B8) 5-[4-(3-chlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0430] (Compound B9) 5-[4-(2-phenylacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0431] (Compound B10)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-phenylthiourea;

[0432] (Compound B11)5-[4-(2,3-dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0433] (Compound B12)5-[4-(2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0434] (Compound B13)5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0435] (Compound B14)5-[4-(2,3-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0436] (Compound B15) 5-[4-(2,5-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0437] (Compound B16)5-[4-(5-bromo-2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0438] (Compound B17)5-[4-(2,4-dichlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0439] (Compound B18) 5-[4-(2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0440] (Compound B19) 5-[4-(2,3-dihydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0441] (Compound B20)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-phenylurea;

[0442] (Compound B21)5-[4-[(2,6-dichlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0443] (Compound B22)5-[4-[(2-methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0444] (Compound B23)5-[4-[(2-hydroxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0445] (Compound B24) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]thiourea;

[0446] (Compound B25) 5-[4-[3-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0447] (Compound B26)5-[4-[2-[2-(trifluoromethyl)phenyl]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0448] (Compound B27) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]urea;

[0449] (Compound B28)5-[4-[(2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0450] (Compound B29) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0451] (Compound B30)5-[4-(3-phenylpropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0452] (Compound B31) 5-[4-[(1H-indole-3-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0453] (Compound B32)5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0454] (Compound B33)5-[4-[(2-methyl-2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0455] (Compound B34) 5-[4-(2-phenoxyacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0456] (Compound B35) 5-[4-[2-(2-chloro-4-methoxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0457] (Compound B36) 5-[4-[(1-methyl-1H-imidazol-2-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0458] (Compound B37) 5-[4-[2-(2,4-dichlorophenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0459] (Compound B38) 5-[4-[2-(2-chloro-4-hydroxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0460] (Compound B39) 5-[4-(3-phenylpropenylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0461] (Compound B40) 5-[4-[(3-pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0462] (Compound B41) 5-[4-(1H-benzimidazole-2-carbonylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0463] (Compound B42) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0464] (Compound B43)5-[4-[(benzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0465] (Compound B44)5-[4-[(2-chlorobenzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0466] (Compound B45) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-hydroxy-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0467] (Compound B46) 5-[4-(2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0468] (Compound B47) 5-[4-(2-bromobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0469] (Compound B48) 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0470] (Compound B49) 5-[4-(2,3-dimethylbenzoylamino)-3-fluorophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0471] (Compound B50) 5-[4-[2-(2-methylphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0472] (Compound B51) 5-[4-[(quinoxolin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0473] (Compound B52)5-[4-[(5-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0474] (Compound B53) 5-[3-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0475] (Compound B54) 5-[4-[(2,4,6-trimethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0476] (Compound B55) 5-[4-(cyclohexylcarbonylamino)phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0477] (Compound B56) 1-[4-(2,3-dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0478] (Compound B57) 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0479] (Compound B58) 5-[4-[(6-methylpyridin-2-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0480] (Compound B59) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0481] (Compound B60)1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-(2-methylphenyl)thiourea;

[0482] (Compound B61) 5-[4-(2-methoxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0483] (Compound B62)5-[4-(2,3-dichlorobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0484] (Compound B63)5-[4-(2,3-dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0485] (Compound B64) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diaza -2-keto;

[0486] (Compound B65) 5-[4-[(4-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0487] (Compound B66) 5-[4-[2-(2,4-dichlorophenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0488] (Compound B67) 5-[4-[2-(2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0489] (Compound B68)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)butyl]-2-chloro-3-methoxybenzamide;

[0490] (Compound B69) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diaza -2-keto;

[0491] (Compound B70) 5-[4-(2-acetylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0492] (Compound B71)5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0493] (Compound B72)5-[2-(2-iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0494] (Compound B73)5-[3-[(2-iodobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0495] (Compound B74) 6,7-Dimethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0496] (Compound B75) 5-[4-[(1-methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0497] (Compound B76) 5-[4-[(benzofuran-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0498] (Compound B77) 5-[4-[(1-methyl-1H-indol-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0499] (Compound B78) 5-[4-(2-propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0500] (Compound B79) 5-[4-(2-propylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0501] (Compound B80) 5-[3-fluoro-4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0502] (Compound B81)5-[4-(2-hydroxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0503] (Compound B82)5-[4-[(2-isopropoxybenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0504] (Compound B83)5-[4-[(3-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0505] (Compound B84) 5-[4-(2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0506] (Compound B85) 5-[4-[2-(4-chloro-2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0507] (Compound B86)5-[4-[(4-fluoro-2-trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0508] (Compound B87) 5-[4-(4-fluoro-2-methoxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0509] (Compound B88) 5-[4-(4-fluoro-2-hydroxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0510] (Compound B89) 5-[3-[(2-iodophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0511] (Compound B90) 5-[4-(2-methyl-2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0512] (Compound B91) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diaza -2-keto;

[0513] (Compound B92)5-[4-[(3-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0514] (Compound B93)5-[4-(4-iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0515] (Compound B94) 5-[4-(6-fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0516] (Compound B95) 5-[4-(2-hydroxy-4-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0517] (Compound B96) 5-[4-(6-fluoro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0518] (Compound B97) 5-[4-(2-fluorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0519] (Compound B98) 5-[4-[(2-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0520] (Compound B99) 5-[4-(2-methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0521] (Compound B100)5-[4-(2-hydroxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0522] (Compound B101)5-[4-[3-(2-methylphenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0523] (Compound B102)5-(4-phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0524] (Compound B103)5-(4-benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0525] (Compound B104)5-[4-[3-(2-methylphenyl)acryloylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0526] (Compound B105) 5-[4-[3-(2-chlorophenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0527] (Compound B106) 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0528] (Compound B107) 5-[4-[(1-methyl-1H-pyrrolo-2-ylacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0529] (Compound B108) 5-[4-(2-chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0530] (Compound B109)5-[4-[3-(2-chlorophenyl)acryloylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0531] (Compound B110)5-[4-(2-chlorophenyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0532] (Compound B111)5-[4-(6-bromo-2,3-methylenedioxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0533] (Compound B112)5-[4-(6-bromo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0534] (Compound B113)5-[4-[(2-tert-butylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0535] (Compound B114) 5-[2-(2-iodobenzoyl)aminopyridin-5-yl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0536] (Compound B115) 5-[4-(6-bromo-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0537] (Compound B116)5-[4-(6-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0538] (Compound B117)5-[4-(2-iodobenzoylamino)phenyl]-1H-[1,4]diaza [2,3-h]quinoline-2,4(3H,5H)-dione;

[0539] (Compound B118)5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0540] (Compound B119) 5-[4-(2-hydroxy-6-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0541] (Compound B120)5-[4-[2-methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0542] (Compound B121)5-[4-[2-hydroxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0543] (Compound B122)5-[4-[(2-isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0544] (Compound B123)5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0545] (Compound B124)5-[4-[2-chloro-5-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0546] (Compound B125) 5-[4-[2-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0547] (Compound B126) 5-[4-[3-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0548] (Compound B127) 5-[4-[2-ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0549] (Compound B128)5-[4-(3-methanesulfonylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0550] (Compound B129) 6-Ethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0551] (Compound B130) 5-[4-[2-ethyl-6-hydroxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0552] (Compound B131)5-[4-(3-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0553] (Compound B132)5-[4-(2-chloro-5-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0554] (Compound B133)5-[4-(2-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0555] (Compound B134)5-[4-[[2-(4-morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0556] (Compound B135) 5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diaza -2-keto;

[0557] (Compound B136)5-[4-[[(3-chloropyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0558] (Compound B137) 5-[4-(2-chloro-6-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diaza -2-keto;

[0559] (Compound B138) 5-[4-(3-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0560] (Compound B139) 5-[4-[(3-methylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0561] (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]diaza -2,4(3H,5H)-dione;

[0562] (Compound B141)5-[4-(3-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0563] (Compound B142)5-[4-[[(3-hydroxypyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0564] (Compound B143)5-[4-[(3-vinylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0565] (Compound B144) 5-[4-[(3-ethylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0566] (Compound B145)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza) [-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0567] (Compound B146)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]benzenesulfonamide;

[0568] (Compound B147) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]benzenesulfonamide;

[0569] (Compound B148)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-methoxybenzenesulfonamide;

[0570] (Compound B149)N-[3-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diaza] [-5-yl)phenyl]benzenesulfonamide;

[0571] (Compound B150)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza [-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0572] (Compound B151)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]-diaza) [-5-yl)phenyl]-2-nitro-benzenesulfonamide;

[0573] (Compound B152)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]-diaza] [-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;

[0574] (Compound B153)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza] [-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;

[0575] (Compound B154)4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza) -5-yl)-N-phenylbenzenesulfonamide;

[0576] (Compound B155)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diaza [-5-yl)phenyl]-2-naphthalenesulfonamide;

[0577] (Compound B156)N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diaza [-5-yl)phenyl]-1-naphthalenesulfonamide;

[0578] (Compound B157)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]cyclohexanesulfonamide;

[0579] (Compound B158)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-pyridinesulfonamide hydrochloride;

[0580] (Compound B159)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-4-isopropylbenzenesulfonamide;

[0581] (Compound B160)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenylmethanesulfonamide;

[0582] (Compound B161)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-2-thiophene-sulfonamide;

[0583] (Compound B162)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-2-naphthalenesulfonamide;

[0584] (Compound B163)4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho-[1,2-b][1,4]diaza) (-5-yl)phenyl-3-bromobenzene-sulfonate;

[0585] (Compound B164) N-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0586] (Compound B165) N-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0587] (Compound B166) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-N-methylbenzenesulfonamide;

[0588] (Compound B167)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza) [-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;

[0589] (Compound B168)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza) [-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide;

[0590] (Compound B169)N-[4-(7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza] [-1-yl)phenyl]benzenesulfonamide;

[0591] (Compound B170)N-[4-(7-bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza] [-1-yl)phenyl]benzenesulfonamide;

[0592] (Compound B171)N-[4-[(2,4-dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza] -1-yl)]phenyl]benzenesulfonamide;

[0593] (Compound B172)N-[4-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza) [-1-yl)phenyl]benzenesulfonamide;

[0594] (Compound B173) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0595] (Compound B174) 1-(3-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0596] (Compound B175)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza) [-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide;

[0597] (Compound B176)N-[4-(7-bromo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazaphen-1-yl)phenyl]benzenesulfonamide;

[0598] (Compound B177) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0599] (Compound B178) 3-bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]benzenesulfonamide;

[0600] (Compound B179)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-methoxybenzenesulfonamide;

[0601] (Compound B180) 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0602] (Compound B181)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide;

[0603] (Compound B182)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-1-(2-nitrophenyl)methanesulfonamide;

[0604] (Compound B183)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-2-phenylethanesulfonamide;

[0605] (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]diaza] [-5-yl)phenyl]methanesulfonamide;

[0606] (Compound B185) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diaza] -1-yl)phenyl]methanesulfonamide;

[0607] (Compound B186) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy-1H-benzo[1,2-b][1,4]diaza] -1-yl)phenyl]methanesulfonamide;

[0608] (Compound B187) 1-(4-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0609] (Compound B188) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)benzyl]methanesulfonamide;

[0610] (Compound B189) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)-2-methoxyphenyl]methanesulfonamide;

[0611] (Compound B190) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)-2-hydroxyphenyl]methanesulfonamide;

[0612] (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]diaza] [-5-yl)phenyl]methanesulfonamide;

[0613] (Compound B192) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-6-methyl-1H-benzo[1,2-b][1,4]diaza] -1-yl)phenyl]methanesulfonamide;

[0614] (Compound B193) 1-(2-chlorophenyl)-N-[3-(2,4-dioxy-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)propyl]methanesulfonamide;

[0615] (Compound B194) 1-(2-chlorophenyl)-N-[2-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)ethyl]methanesulfonamide;

[0616] (Compound B195)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza [-5-yl)phenyl]-1-(2-iodophenyl)methanesulfonamide;

[0617] (Compound B196) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-N-methylmethanesulfonamide;

[0618] (Compound B197) 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0619] (Compound B198) 1-[2-(trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0620] (Compound B199) 1-(2-ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0621] (Compound B200) 1-(2,3-dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0622] (Compound B201)2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylethanesulfonamide;

[0623] (Compound B202)1-(2-nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0624] (Compound B203)1-(2-aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0625] (Compound B204)1-(2-dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0626] (Compound B205) 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0627] (Compound B206)5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0628] (Compound B207)5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0629] (Compound B208)5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride;

[0630] (Compound B209)5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0631] (Compound B210)5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0632] (Compound B211)5-[4-[[4-(trifluoromethyl)pyridin-3-yl]carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0633] (Compound B212)5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diaza [2,3-f]isoquinoline-2,4(3H,5H)-dione;

[0634] (Compound B213)5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-8,9,10,11-tetrahydro-1H-[1,4]diaza [2,3-f]isoquinoline-2,4(3H,5H)-dione; and

[0635] (Compound B214)5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione.

[0636] More preferably, the compound or a pharmaceutically acceptable salt thereof that is an active ingredient in the pharmaceutical composition of the present invention comprises a compound or a pharmaceutically acceptable salt thereof represented by general formulas (A) to (BII). More specifically, 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone potassium salt; 5-[3-(5-thio-4H-[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[3-(5-thio-4H-[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-fluoro-3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-phenylurea; 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]benzenesulfonamide; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -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]diaza] -5-yl)phenyl]methanesulfonamide; 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-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]diaza] [-5-yl)phenyl]-N-methylmethanesulfonamide; 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diaza] 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione. However, the active ingredient of the pharmaceutical compositions of the present invention is not limited to the specific compounds described above or their pharmaceutically acceptable salts.

[0637] Further preferred are compounds or pharmaceutically acceptable salts thereof that are active ingredients in the pharmaceutical compositions of the present invention and are contained in compounds or pharmaceutically acceptable salts represented by general formulas (A) to (BII). More specifically, 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[3-(5-thio-4H-[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[3-(5-thio-4H-[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione and 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione. However, the active ingredient of the pharmaceutical compositions of the present invention is not limited to the specific compounds described above or their pharmaceutically acceptable salts.

[0638] The compounds represented by the above general formulas (A) to (BII) may also sometimes exist as stereoisomers such as cis-trans isomers, optically active isomers, and racemic isomers, all of which are included in this invention.

[0639] The compounds represented by the above general formulas (A) to (BII) sometimes also have tautomers, which exhibit the same activity as the above compounds and are included in the present invention.

[0640] Furthermore, the compounds represented by the above general formulas (A) to (BII) sometimes have one or more chiral carbons depending on the type of substituents. Any optical isomers based on these chiral carbons, any mixtures of optical isomers, racemates, diastereomers based on two or more chiral carbons, and any mixtures of diastereomers can also be used as active ingredients in the pharmaceutical compositions of the present invention. When the compounds represented by the above general formulas (AI) to (BII) contain double bonds or cyclic structures, geometric isomers sometimes exist. In addition to purely geometric isomers, mixtures of them in any proportion can also be used as active ingredients in the pharmaceutical compositions of the present invention.

[0641] In addition to the compounds represented by the general formulas (A) to (BII) described above, any solvate of the free form or salt form of the above-described compounds may also be used as an active ingredient in the pharmaceutical composition of the present invention. The solvates also include hydrates.

[0642] In this specification, unless otherwise specified, the compounds represented by the general formulas (A) to (BII) above may include cis-trans isomers, optically active isomers, racemic isomers, tautomers, any optical isomers based on chiral carbons, racemic isomers, diastereomers based on two or more chiral carbons, and mixtures thereof.

[0643] In addition to the compounds represented by the general formulas (A) to (BII) described above, acid addition salts or base addition salts of these compounds may also be used as active ingredients in the pharmaceutical compositions of the present invention. Examples of acid addition salts include inorganic acid salts such as hydrochlorides, sulfates, and nitrates, as well as organic acid salts such as methanesulfonates, p-toluenesulfonates, oxalates, and malates, but these are not limited to these. Examples of base addition salts include metal salts such as lithium salts, sodium salts, potassium salts, magnesium salts, or calcium salts, as well as ammonium salts, or organic amine salts such as triethylamine salts or ethanolamine salts, but these are not limited to these. Among these salts, pharmaceutically acceptable salts are preferred as active ingredients in the pharmaceutical compositions of the present invention.

[0644] The pharmaceutical compositions of the present invention can be used for the prevention, suppression, or treatment of symptoms accompanying allergic reactions. Furthermore, they can be used for the prevention, suppression, or treatment of allergic diseases. Preferably, they can be used for the prevention, suppression, or treatment of symptoms accompanying type I hypersensitivity reactions. More preferably, they can be used for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma, or allergic dermatitis. Further, they can be used for the suppression of anaphylactic shock or the prevention or treatment of hay fever, urticaria, or atopic dermatitis.

[0645] Furthermore, the pharmaceutical compositions of the present invention can be used to prevent, suppress, or reduce inflammation in symptoms accompanying allergic reactions. Additionally, the pharmaceutical compositions of the present invention can be used to inhibit the extracellular release of secretory granules from mast cells in symptoms accompanying allergic reactions.

[0646] In another respect, the pharmaceutical compositions of the present invention can also be used for the following purposes.

[0647] The pharmaceutical compositions of the present invention can be used for the prevention, suppression, or treatment of symptoms accompanying the above-mentioned allergic reactions accompanied by inflammation.

[0648] The pharmaceutical composition of the present invention can be used for the prevention, suppression or treatment of symptoms associated with the above-mentioned allergic reactions, which are accompanied by the extracellular release of secretory granules from mast cells.

[0649] These symptoms accompanying allergic reactions are all applicable to the pharmaceutical compositions of the present invention. However, the application of the pharmaceutical compositions of the present invention is not limited to this.

[0650] The pharmaceutical compositions of the present invention can be administered orally or non-orally. The pharmaceutical compositions of the present invention can be manufactured into suitable dosage forms such as tablets, granules, powders, capsules, suspensions, inhalers, inhaled powders, inhaled liquids, inhaled aerosols, ointments, gels, creams, wet dressings, patches, liniments, plasters, poultices, injections, and suppositories, according to conventional methods in the field of pharmaceutical formulation. In one embodiment, the "pharmaceutical composition" comprises the above-described active ingredients and pharmaceutically acceptable additives.

[0651] These formulations can be manufactured using common techniques. For example, in the case of tablets, pharmaceutically acceptable additives such as common excipients, disintegrants, binders, lubricants, and colorants can be used. Examples of excipients include lactose, D-mannitol, crystalline cellulose, and glucose; examples of disintegrants include starch and calcium carboxymethyl cellulose (CMC-Ca); examples of lubricants include magnesium stearate and talc; and examples of binders include hydroxypropyl cellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).

[0652] Injectable formulations may use pharmaceutically acceptable additives such as solvents, stabilizers, solubilizers, suspending agents, emulsifiers, analgesics, buffers, and preservatives. Those skilled in the art can appropriately select these pharmaceutically acceptable additives and the formulation preparation methods.

[0653] That is, the pharmaceutical composition of the present invention can be provided as a pharmaceutical composition comprising the above-mentioned active ingredients and pharmaceutically acceptable additives.

[0654] Inhalants for non-oral administration include aerosols, inhaled powders, inhaled liquids (e.g., inhalation solutions, inhalation suspensions, etc.), or capsule inhalants. The aforementioned inhaled liquids may be in a form that is dissolved or suspended in water or other suitable media for use. These inhalants can be applied using appropriate inhalation containers; for example, when administering inhaled liquids, a nebulizer (nebulizer, inhaler) may be used, and when administering inhaled powders, a powder inhaler may be used.

[0655] These inhalers are manufactured using known methods. For example, they are manufactured by preparing compounds represented by general formulas (A) to (BII) into powder or liquid, combining them with an inhalation propellant or carrier, and filling them into a suitable inhalation container. When pulverizing compounds represented by general formulas (A) to (BII), pulverization is performed using conventional methods. For example, micro-powders are prepared together with lactose, starch, magnesium stearate, etc., to form a homogeneous mixture, or granulation is performed to prepare a powder. When liquefying compounds represented by general formulas (A) to (BII), for example, the compounds are simply dissolved in a liquid carrier such as water, saline solution, or an organic solvent. As propellants, conventionally known propellants include, for example, Freon substitutes, liquefied gas propellants (e.g., fluorinated hydrocarbons, liquefied petroleum gas, diethyl ether, dimethyl ether, etc.), compressed gases (e.g., soluble gases (e.g., carbon dioxide gas, nitrous oxide gas, etc.), insoluble gases (e.g., nitrogen gas, etc.)).

[0656] Inhalers may be further formulated with pharmaceutically acceptable additives as needed. Any commonly used additive may be used, for example, solid excipients (e.g., white sugar, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid excipients (e.g., propylene glycol, etc.), binders (starch, dextrin, methylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, polyethylene glycol, white sugar, etc.), lubricants (e.g., magnesium stearate, light anhydrous silicate, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g., citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, etc.), and preservatives (e.g., sodium benzoate, sodium bisulfite, p-hydroxypropyl esters, etc.). Examples of active ingredients include: methyl benzoate, propylparaben, stabilizers (e.g., citric acid, sodium citrate), suspending agents or emulsifiers (e.g., methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, lecithin, sorbitan trioleate, etc.), dispersants (e.g., surfactants), solvents (e.g., water), isotonic agents (e.g., sodium chloride, concentrated glycerol, etc.), pH adjusters (e.g., hydrochloric acid, sulfuric acid, etc.), solubilizers (e.g., ethanol, etc.), preservatives (benzalkonium chloride, parabens, etc.), colorants, buffers (sodium phosphate, sodium acetate, etc.), thickeners (carboxyethylene polymers, etc.), and absorption promoters. For example, in the case of inhalation liquids, preservatives, colorants, buffers, isotonic agents, thickeners, and absorption promoters are appropriately selected as needed. Similarly, in the case of inhalation powders, lubricants, binders, excipients, colorants, preservatives, and absorption promoters (bile salts, chitosan, etc.) are appropriately selected as needed.

[0657] Furthermore, to enable sustained-release properties of compounds represented by general formulas (A) to (BII), biodegradable polymers may be included in the inhaler. Examples of biodegradable polymers include fatty acid ester polymers or copolymers thereof, polyacrylates, polyhydroxybutyrates, polyalkylene oxalates, polyorthoesters, polycarbonates, and polyamino acids; one or more of these may be used. Additionally, phospholipids such as egg yolk lecithin and chitosan may also be used. Examples of fatty acid ester polymers or copolymers thereof include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, and lactic acid-glycolic acid copolymers; one or more of these may be used. Furthermore, one or more of poly(α-cyanoacrylate), poly(β-hydroxybutyrate), polypropylene oxalate, polyorthoesters, polyorthocarbonates, polyethylene carbonate, poly(γ-benzyl-L-glutamic acid), and poly(L-alanine) may be used. Polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymers are preferred, and lactic acid-glycolic acid copolymers are more preferred. Alternatively, microspheres and nanospheres can be prepared by encapsulating drugs in biodegradable polymers such as lactic acid-glycolic acid copolymers.

[0658] Ointments are manufactured according to known or commonly used formulations. For example, they are prepared by mixing or melting one or more active ingredients with a base. The ointment base is selected from known or commonly used bases. For example, one of the following can be used alone or in combination with two or more: higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate ester, myristic acid ester, palmitic acid ester, stearate ester, oleate ester, etc.), waxes (beeswax, cetearine, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphates, etc.), higher alcohols (cetyl alcohol, stearyl alcohol, cetearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), hydrocarbons (hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), diols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, PEG, etc.), vegetable oils (castor oil, olive oil, sesame oil, turpentine, etc.), animal oils (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and rash preventers. It may also further include moisturizers, preservatives, stabilizers, antioxidants, fragrances, etc.

[0659] The gelling agent is manufactured according to a known or commonly used formulation. For example, it is prepared by melting one or more active substances with a base agent. The gelling base agent is selected from known or commonly used base agents. For example, one or more of the following may be used alone or in combination: lower alcohols (ethanol, isopropanol, etc.), gelling agents (carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.), colloids, water, absorption enhancers, and rash preventers. It may further include preservatives, antioxidants, fragrances, etc.

[0660] Creams are manufactured according to known or commonly used formulations. For example, they are prepared by melting or emulsifying one or more active ingredients with a base. The cream base is selected from known or commonly used bases. For example, one or more of the following may be used alone or in combination: higher fatty acid esters, lower alcohols, hydrocarbons, polyols (propylene glycol, 1,3-butanediol, etc.), higher alcohols (2-hexyldecyl alcohol, cetyl alcohol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption enhancers, and rash preventers. Preservatives, antioxidants, fragrances, etc., may also be included.

[0661] The wet dressing is manufactured according to a known or commonly used formulation. For example, it is manufactured by melting one or more active ingredients with a base agent to form a compound, which is then spread and coated onto a support. The wet dressing base agent is selected from known or commonly used base agents. For example, one or more of the following are used alone or in combination: 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, dissolving agents, adhesives, and rash preventants. It may further include preservatives, antioxidants, fragrances, etc.

[0662] The patch is manufactured according to a known or commonly used formulation. For example, it is manufactured by melting one or more active substances with a base and spreading them onto a support. The base for the patch is selected from known or commonly used bases. For example, one or more selected from polymeric bases, oils, higher fatty acids, adhesives, and rash preventants may be used alone or in combination. It may further include preservatives, antioxidants, fragrances, etc.

[0663] The liniment is manufactured according to a known or commonly used formula. For example, it is prepared by dissolving, suspending, or emulsifying one or more active ingredients in one or more of a single ingredient selected from water, alcohols (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifiers, suspending agents, etc. It may further include preservatives, antioxidants, fragrances, etc.

[0664] The dosage of the pharmaceutical composition of the present invention is not particularly limited. Generally, for adults, the dosage can be approximately 0.01 μg to 100 mg, preferably 0.3 μg to 10 mg, per day based on the amount of active ingredient, via inhaler, inhaled powder, inhaled liquid, or inhaled aerosol; approximately 0.01 mg to 1000 mg per day based on the amount of active ingredient, via ointment, gel, cream, wet compress, patch, liniment, plaster, or poultice; approximately 0.01 mg to 100 mg per day based on the amount of active ingredient, via injection; and approximately 0.01 mg to 2000 mg per day via oral administration. However, the dosage is not limited to the above-mentioned dosages and can be appropriately determined according to the method of administration, the age, weight, sex, symptoms, and sensitivity to the drug. The dosage can be adjusted according to the improvement of symptoms and can be increased or decreased according to age and symptoms.

[0665] The pharmaceutical compositions of the present invention can be used in combination with other pharmaceutical agents useful for the treatment or prevention of symptoms accompanying various allergic reactions. The individual components of such a combination can be administered separately at different times or simultaneously during treatment or prevention, in fractional or single formulations. Therefore, the present invention should be interpreted as encompassing all simultaneous or separate administration, and administration in the present invention should be interpreted in this way. The scope of the combination of the pharmaceutical compositions of the present invention with other pharmaceutical agents useful for the treatment or prevention of the aforementioned symptoms accompanying various allergic reactions also includes, in principle, combinations with any pharmaceutical preparation useful for the treatment or prevention of the aforementioned symptoms accompanying various allergic reactions.

[0666] The formulations in the combination formulations of the present invention can be selected in various forms and can be manufactured in the same manner as the formulations described above. Furthermore, in the case of a combination containing the pharmaceutical composition of the present invention and other therapeutic or preventative medications for symptoms associated with various allergic reactions, those skilled in the art can easily manufacture it using conventional methods or conventional techniques.

[0667] The above combinations include not only combinations of one other active substance in the pharmaceutical compositions of the present invention, but also combinations of two or more other active substances. There are many examples of combinations of the pharmaceutical compositions of the present invention with one, two, or more active substances selected from the above-mentioned therapeutic or preventative agents for various allergic reactions.

[0668] Examples of pharmaceutical agents that can be combined with the pharmaceutical compositions of the present invention include, for example, steroids, β2 agonists, muscarinic receptor antagonists, antihistamines, antihistamines, bronchodilators, leukotriene synthesis inhibitors, prostaglandins, leukotriene receptor antagonists, antipruritics, other antitussives, and expectorants, among which combinations with antihistamines and antihistamines are preferred. Furthermore, the pharmaceutical compositions of the present invention can be combined with Kampo medicines.

[0669] Examples of the aforementioned steroids include, for instance, clobetasol propionate, diflubenzuron acetate, fluocinolone acetonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate, betamethasone valerate, difluprednisolone, pradelineide, diflucorone valerate, ancinonide, halcinonide, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, diprednisolone propionate, prednisolone valerate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone neovalerate, aclomethasone propionate, clobetasol butyrate, prednisolone, beclomethasone propionate, and flumethasone hydrochloride; and topical medications such as cortisone acetate, hydrocortisone, hydrocortisone phosphate sodium, and hydrocortisone. Oral or injectable medications such as sodium succinate, fludrocortisone acetate, prednisolone, prednisolone acetate, prednisolone sodium succinate, butyl prednisolone acetate, prednisolone sodium phosphate, prednisolone haloacetate, methylprednisolone acetate, methylprednisolone acetate, methylprednisolone sodium succinate, triamcinolone, triamcinolone acetate, triamcinolone acetonide, dexamethasone, dexamethasone acetate, dexamethasone sodium phosphate, dexamethasone palmitate, peramisone acetate, and betamethasone; as well as inhalers such as beclomethasone propionate, fluticasone propionate, budesonide, flunisolone, triamcinolone, ST-126P, cicsolone, dexamethasone palmitate, mometasone furoate, prastorone sulfate, dexamethasone dipropionate, sulfonylurea, methylprednisolone sodium succinate, and methylprednisolone sodium succinate.

[0670] Examples of β2 agonists include formoterol, salmeterol, carmoterol, indaterol, vilanterol, aformoterol, bambuterol, isoprene, mivitol, clenbuterol, olodaterol, fenoterol, salbutamol, levosalbutamol, procaterol, terbutaline, pirbuterol, procaterol, metoprolol, bitoterol, ritodrine, and salbutamol.

[0671] Examples of muscarinic receptor antagonists include tiotropium, ipratropium, flutropium, oxytropium bromide, adecium bromide, darobromide, glycopyrronium bromide, and fudecium bromide.

[0672] Examples of antihistamines include diphenhydramine, benzopyrene hydrochloride, benzopyrene theochloride, chlormastine fumarate, diphenhydramine, dl-chlorpheniramine maleate, d-chlorpheniramine maleate, triprolidine hydrochloride, promethazine hydrochloride, alimazine tartrate, isoxepantar, perchlorcycline hydrochloride, hydroxyzine, cyproheptadine hydrochloride, levocabastine hydrochloride, astemizole, betosine, desloratadine, TAK-427, ZCR-2060, NIP-530, mometasone furoate, mizolastine, BP-294, anddoxalate, auranofen, and avastin.

[0673] Examples of anti-allergy medications include, for instance, free inhibitors of chemical transport substances such as sodium semolinate, tranilast, amiloride, repixilast, isobenzide, bemiscilast potassium, tazarotene, nedolomem, cromoglycate, and irapapan; histamine antagonists such as ketotifen fumarate, azelastine hydrochloride, oxamide, mequinatazine, terfenadine, emesitine fumarate, epinastine hydrochloride, ebastine, cetirizine hydrochloride, olopatadine hydrochloride, loratadine, and fexofenadine; thromboxane synthase inhibitors such as ozagrelor hydrochloride and mitralastine sodium; thromboxane antagonists such as cetralastine, ramatroban, domitroban calcium hydrate, and KT-2-962; and Th2 cytokine inhibitors such as supralastine tosylate.

[0674] Examples of bronchodilators include, for instance, xanthine derivatives such as aminophylline, theophylline, doxophylline, cipanthenine, dihydroxytheophylline, hydroxypropyltheophylline, and theocholine; adrenaline, ephedrine hydrochloride, dl-methylephedrine hydrochloride, methoxyphenamine hydrochloride, isoproterenol sulfate, isoproterenol hydrochloride, orsinarline sulfate, chlorpromazine hydrochloride, tratoquiquinol hydrochloride, salbutamol sulfate, terbutaline sulfate, hesonaline sulfate, tolometrol hydrochloride, procaterol hydrochloride, fenoterosterol hydrobromide, formoterol fumarate, and salts. Sympathetic nerve stimulants include clenbuterol, mabuterol hydrochloride, salmeterol tartrate, R,R-formoterol, tuloterol, pibuterol hydrochloride, ritodrine hydrochloride, bambuterol, dopexamine hydrochloride, merulone tartrate, AR-C68397, dextromethorphan, KUR-1246, KUL-7211, AR-C89855, and S-1319; and parasympathetic nerve blocking drugs such as ipratropium bromide, flutropium bromide, oxotrin bromide, cetirizine bromide, tilmivelin, tiotropium bromide, and revastatin.

[0675] Examples of leukotriene synthesis inhibitors include aurinophene, prgotrometrazine 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, and aminozanol E-6700.

[0676] Examples of prostaglandins include, for instance, agonists or antagonists of PGE2EP1, PGE2EP2, PGE2EP3, or PGE2EP4 receptors; agonists or antagonists of PGD2 or CRTH2 receptors; agonists or antagonists of PGFFP receptors; agonists or antagonists of PGIIP receptors; and agonists or antagonists of TX receptors.

[0677] Examples of leukotriene receptor antagonists include prunust hydrate, montelukast, zafirlukast, cetrakast, 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.

[0678] Other antitussives include codeine phosphate, dihydrocodeine phosphate, Oxymetebanol, dextromethorphan hydrobromide, pentoxyverine citrate, dimethionine phosphate, volopyridamole citrate, clopidogrel, phenylpropanol phosphate, chlorpheniramine hydrochloride, forminobenzene hydrochloride, noscapine, tepedidine hydroxybenzoylbenzene, ipredione hydrochloride, and plantain extract.

[0679] Examples of expectorants include ammoniacal anise extract, sodium bicarbonate, potassium iodide, bromhexine hydrochloride, cherry bark extract, carboxymethyl cysteine, ferdosteine, ambroxol hydrochloride, ambroxol hydrochloride sustained-release formulation, methylcysteine ​​hydrochloride, acetylcysteine, L-ethylcysteine ​​hydrochloride, and tyloxacillin.

[0680] Examples of antipruritic agents include diphenhydramine hydrochloride, clomiphene, and lidocaine.

[0681] The present invention has the following aspects.

[0682] <1a> A method for the prevention, suppression or treatment of symptoms associated with an allergic reaction, the method comprising the steps of administering to a subject (e.g., a mammal including a human) a preventive, suppressive or therapeutically effective amount of a compound having P2X4 receptor antagonistic activity (e.g., a compound represented by general formulas (A) to (BII)) or a pharmaceutically acceptable salt thereof.

[0683] <2a> According to the method described in <1a>, the above-mentioned symptoms accompanying allergic reactions are allergic diseases;

[0684] <3a> According to the method described in <1a> or <2a>, wherein the above-mentioned symptoms accompanying allergic reactions are symptoms accompanying type I allergic reactions;

[0685] <4a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying the allergic reaction are anaphylactic shock;

[0686] <5a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying allergic reaction are allergic rhinitis;

[0687] <6a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying the allergic reaction are bronchial asthma;

[0688] <7a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying the allergic reaction are allergic dermatitis;

[0689] <8a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying allergic reaction are hay fever;

[0690] <9a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanying the allergic reaction are urticaria;

[0691] <10a> The method according to any one of <1a> to <3a>, wherein the above-mentioned symptoms accompanied by allergic reaction are atopic dermatitis;

[0692] <11a> According to the method described in <1a>, wherein the above-mentioned allergic reaction is an allergic reaction accompanied by inflammation; and

[0693] <12a> According to the method described in <1a>, the above-mentioned allergic reaction is an allergic reaction accompanied by the extracellular release of secretory granules from mast cells.

[0694] The present invention has the following other aspects.

[0695] <1b> Compounds with P2X4 receptor antagonism (e.g., compounds represented by general formulas (A) to (BII)) or pharmaceutically acceptable salts thereof used for the prevention, suppression or treatment of symptoms accompanied by allergic reactions;

[0696] <2b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms associated with an allergic reaction as described in <1b>, wherein the symptoms associated with an allergic reaction are allergic diseases.

[0697] <3b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms associated with an allergic reaction as described in <1b> or <2b>, wherein the symptoms associated with an allergic reaction are symptoms associated with a type I allergic reaction.

[0698] <4b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are anaphylactic shock;

[0699] <5b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are allergic rhinitis;

[0700] <6b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are bronchial asthma.

[0701] <7b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are allergic dermatitis;

[0702] <8b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are hay fever;

[0703] <9b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are urticaria;

[0704] <10b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction according to any one of <1b> to <3b>, wherein the symptoms accompanied by an allergic reaction are atopic dermatitis;

[0705] <11b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms associated with an allergic reaction as described in <1b>, wherein the allergic reaction is an allergic reaction accompanied by inflammation; and

[0706] <12b> A compound or a pharmaceutically acceptable salt thereof for the prevention, suppression or treatment of symptoms accompanied by an allergic reaction as described in <1b>, wherein the allergic reaction is an allergic reaction accompanied by the extracellular release of secretory granules from mast cells.

[0707] The present invention has the following additional aspects.

[0708] <1c> The use of compounds having P2X4 receptor antagonistic activity (e.g., compounds represented by general formulas (A) to (BII)) or pharmaceutically acceptable salts thereof in the manufacture of pharmaceutical compositions for the prevention, inhibition or treatment of symptoms accompanied by allergic reactions;

[0709] <2c> According to the use described in <1c>, the above-mentioned symptoms accompanied by allergic reactions are allergic diseases;

[0710] <3c> Use according to <1c> or <2c>, wherein the above-mentioned symptoms accompanying allergic reaction are symptoms accompanying type I allergic reaction;

[0711] <4c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying an allergic reaction are anaphylactic shock;

[0712] <5c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanied by allergic reaction are allergic rhinitis;

[0713] <6c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying allergic reaction are bronchial asthma;

[0714] <7c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying an allergic reaction are allergic dermatitis;

[0715] <8c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying an allergic reaction are hay fever;

[0716] <9c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying an allergic reaction are urticaria;

[0717] <10c> Use according to any one of <1c> to <3c>, wherein the above-mentioned symptoms accompanying allergic reactions are atopic dermatitis;

[0718] <11c> According to the use described in <1c>, wherein the aforementioned allergic reaction is an allergic reaction accompanied by inflammation; and

[0719] <12c> According to the use described in <1c>, the above-mentioned allergic reaction is an allergic reaction accompanied by the extracellular release of secretory granules from mast cells.

[0720] Example

[0721] The present invention will now be described in more detail with reference to embodiments, but the scope of the present invention is not limited to the embodiments described below.

[0722] In the following examples, 5-[3-(5-thio-4H-[1,2,4]] is used as a P2X4 receptor antagonist. [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone 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]diaza -2,4(3H,5H)-dione (WO2013 / 105608, compound of Example 48: hereinafter referred to as "Compound B"), and other compounds shown below, namely,

[0723] 5-[3-(1H-tetrazole-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-phenylurea; 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]benzenesulfonamide; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -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]diaza] -5-yl)phenyl]methanesulfonamide; 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-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]diaza] [-5-yl)phenyl]-N-methylmethanesulfonamide; 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diaza] 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione.

[0724] Example 1: Determination of the P2X4 receptor antagonistic effect of the compound, which is the active ingredient of the present invention.

[0725] (Experimental Methods)

[0726] The antagonistic effect of the compound, which is the active ingredient of this invention, on the P2X4 receptor was determined. The ATP receptor (human P2X4) was introduced into 1321N1 cells as a stable expression system for the P2X4 receptor. P2X4 receptor-expressing cells were seeded in 96-well plates and cultured at 37°C and 5% CO2 for 24 hours for calcium assay. Fura-2AM, a calcium fluorescence indicator, was dissolved in extracellular fluid for calcium imaging. The seeded cells were treated and incubated at room temperature for 45 minutes to allow Fura-2AM to enter the cells. The assay was performed using an EnVision (PerkinElmer) microplate reader. The fluorescence at 510 nm (F340 and F380) was observed when xenon lamp light passed through 340 nm and 380 nm filters, respectively, and the change in the ratio F340 / F380 was used as an indicator of intracellular calcium changes. The assay was performed by adding ATP to each well to a final concentration of 1 μM and observing the ATP-induced intracellular calcium response over time. The inhibitory activity of the test substance was determined by treating the test substance 15 minutes before ATP addition and comparing it with the case where the test substance was not present. The results are shown in Table 29 below.

[0727] (Experimental Results)

[0728] [Table 29]

[0729] Test substance <![CDATA[IC 50 (μM)]]> Compound A2 0.53 Compound A17 (Compound A) 0.27 Compound B2 0.75 Compound B13 0.54 Compound B20 1.2 Compound B48 (Compound B) 0.30 Compound B57 0.72 Compound B71 0.4 Compound B106 1.8 Compound B118 1.10 Compound B146 0.67 Compound B173 0.064 Compound B177 0.056 Compound B180 0.05 Compound B181 0.068 Compound B183 0.42 Compound B196 0.97 Compound B197 0.44 Compound B208 1.3 Compound B209 0.94 Compound B210 1.4 Compound B214 0.62

[0730] Example 2 shows the effect of the degranulation reaction on BMMC.

[0731] The inhibitory effect of compounds A or B, which have P2X4 receptor antagonism, on the degranulation reaction induced by co-stimulation of IgE-sensitized bone marrow-derived mast cells (BMMCs) with dinitrophenyl-bonded human serum albumin (DNP-HSA) (10 ng / mL) and ATP (0.1 mM) was observed. It should be noted that the degranulation rate was determined by the release rate of β-aminohexosidase. The β-aminohexosidase release rate was measured as follows (degranulation experiment).

[0732] (Adjustments to BMMC)

[0733] Bone marrow was recovered from the femur of male C57BL / 6J mice (7–8 weeks old, manufactured by SLC Corporation, Japan). Hemolyzed erythrocytes were cultured for 14 days in a medium containing 10% FBS (fetal bovine serum), penicillin (100 units / ml), streptomycin (100 μg / ml), and recombinant mouse IL-3 (10 ng / ml, manufactured by Peprotech). From day 15, stem cell factor (SCF) (10 ng / ml) was added to the medium, and the cells were cultured for 35–42 days for experiments. The expression levels of c-KIT and FcεRI were used to confirm whether the cells differentiated into mast cells. It should be noted that this confirmation was performed using FACSCant II (manufactured by BDBiosciences).

[0734] (De-particle experiment)

[0735] Anti-DNP-IgE antibody (clone: ​​SPE-7, Sigma-Aldrich) was added to the culture medium of BMMCs to achieve an overnight sensitization concentration of 50 ng / ml. The BMMCs were then washed with PBS (-) and resuspended 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) to achieve a concentration of 1 × 10⁻⁶. 6 cell / ml is used for experiments.

[0736] Next, 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 were added to the IgE-sensitized BMMC and pre-incubated at room temperature for 10 minutes.

[0737] Then, adjust the above BMMCs into the following 4 groups respectively.

[0738] (1) The group in the above BMMC that has nothing added

[0739] (2) The group in which only ATP was added to the above BMMC,

[0740] (3) The group in which only DNP-HSA (10 ng / ml) was added as the antigen in the above BMMC.

[0741] (4) The group in which a mixture of ATP and DNP-HSA (10 ng / ml) was simultaneously added to the above BMMC.

[0742] The four groups were stimulated at 37°C for 5 minutes, rapidly cooled on ice, and then centrifuged to stop the reaction. After recovering the supernatant, the precipitated cells were lysed with 0.1% Triton X-100. The supernatant and cell lysate (50 μL) were mixed with 10 mM 4-nitrophenyl-N-acetyl-β-D-aminoglycoside (Sigma-Aldrich) / 50 mM citrate buffer (pH 4.5, 50 μL) as the substrate for β-aminohexosidase 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 (TECAN) microplate reader. The release rate of β-aminohexosidase was calculated using the following formula.

[0743] β-Aminohexosidase release rate = (Supernatant absorbance / (Supernatant absorbance + Cell lysate absorbance)) × 100

[0744] It should be noted that the number of subjects in this embodiment was n=3, and significant differences in this embodiment were expressed using [missing information]. Figure 1 and Figure 2 In the attached figures, "*" or "**" indicate that P < 0.05 and P < 0.01, respectively. Additionally, Figure 1 and Figure 2 The "*" or "**" in the attached figures indicate that there are significant differences between the results in the same group and the control group.

[0745] (Experimental Results)

[0746] Compound A

[0747] For groups (1)–(3) without co-stimulation with ATP and DNP-HSA (10 ng / ml), the release rate of β-aminohexosidase in BMMCs treated with compound A and control BMMCs was less than 10%. Figure 1 (1) to (3)). In contrast, the release rate of β-aminohexosidase in the control BMMCs of (4) group, which was co-stimulated with ATP and DNP-HSA (10 ng / ml), was about 25%. Figure 1 (4)). However, compared with the control BMMCs, the release rate of β-aminohexosidase in the same group after pre-incubation with compound A was reduced in a manner dependent on the amount of compound A used, and the release rate was significantly reduced at any concentration of 1 μM, 3 μM and 10 μM. Figure 1 (4) in the middle.

[0748] Compound B

[0749] For groups (1) to (3) that did not receive co-stimulation with ATP and DNP-HSA (10 ng / ml), the release rate of β-aminohexosidase in BMMCs treated with compound B and control BMMCs was approximately 10% to 15%. Figure 2 (1) to (3)). In contrast, in group (4), the release rate of β-aminohexosidase in the control BMMCs of the group subjected to co-stimulation with ATP and DNP-HSA (10 ng / ml) exceeded 30%. Figure 2 (4)). However, in the same group, the release rate of β-aminohexosidase in BMMCs pre-incubated with compound B was reduced compared with the control BMMCs, depending on the amount of compound B used. The release rate was significantly reduced in BMMCs pre-incubated with 3 μM and 10 μM compound B. Figure 2 (4) in the middle.

[0750] Example 3: Effect on passive cutaneous anaphylaxis

[0751] IgE-sensitized mice were given a group that received either compound A or B, which has P2X4 receptor antagonism, and a group that did not receive such treatment. Passive cutaneous anaphylaxis (PCA) was induced in each group of mice, and the inhibitory effect on PCA was then determined.

[0752] (Preparation of IgE-sensitized mice)

[0753] Mice under anesthesia were sensitized by subcutaneous administration of 100 ng / 20 μL IgE to the right ear. The left ear was treated with only physiological saline.

[0754] It should be noted that the mice used were male C57BL / 6J mice (10-11 weeks old, manufactured by SLC Corporation, Japan).

[0755] (Drug administration)

[0756] Compound A (10 mg / kg) in physiological saline was administered intraperitoneally to the IgE-sensitized mice 30 minutes prior to DNP-HSA administration. It should be noted that DNP-HSA administration was performed via tail vein, adjusted to 24 hours after the initiation of the IgE-sensitization.

[0757] In addition, other IgE-sensitized mice were administered compound B (10 mg / kg) intraperitoneally one hour before DNP-HSA administration, containing a solvent prepared in a 1:1:8 ratio of DMSO:65% KolliphorEL (manufactured by BASF SE):water for injection (hereinafter referred to as Solvent B). It should be noted that the 65% KolliphorEL concentration was prepared using ethanol and a small amount of water for injection (or water). Furthermore, DNP-HSA administration was adjusted to 24 hours after the initiation of the IgE-sensitization in the mice.

[0758] In addition, other IgE-sensitized mice were prepared to be given a group (solvent group) of physiological saline as a control of compound A and a group (solvent group) of solvent B as a control of compound B.

[0759] (Creation of PCA model mice)

[0760] Twenty-four hours after the creation of the IgE-sensitized mice, DNP-HSA containing 100 ng / 200 μL (physiological saline) of 0.5% Evans blue was administered via the tail vein to induce an allergic reaction and create PCA model mice.

[0761] (Determination of inhibitory effect)

[0762] In the PCA model mice, edema causes fluid containing Evans blue to shift from the blood vessels to the auricle. Therefore, the change in the amount of Evans blue in the auricle when DNP-HSA is administered via the tail vein was measured, thereby determining the effect of compound A or B on PCA.

[0763] The PCA model mice were euthanized 30 minutes after DNP-HSA administration, and their auricles were recovered and weighed. The recovered auricles were chopped and heated overnight (65°C) in formamide (1 mL) to extract Evans blue. The absorbance of the extracted Evans blue and the standard curve was measured (620 nm) using a Sunrise (TECAN) microplate reader, and the concentration was calculated.

[0764] It should be noted that the number of subjects in this embodiment was n=5, and significant differences in this embodiment were expressed using [missing information]. Figure 3 The asterisk (*) in the attached figure indicates that p < 0.05. Additionally, Figure 3 The asterisks in the attached figures indicate a comparison between the groups given each compound and the groups not given the compound (solvent groups), and the results show significant differences.

[0765] (Experimental Results)

[0766] Pretreatment with compound B (10 mg / kg) followed by intravenous administration of DNP-HSA significantly inhibited the increase of Evans blue per unit weight of auricle.

[0767] In addition, pretreatment with compound B (10 mg / kg) significantly inhibited the increase in Evans blue per unit weight of auricle, even when administered orally, as significantly as when administered intraperitoneally (not illustrated).

[0768] Example 4: Effect on passive systemic anaphylactic reaction

[0769] Prepare groups of IgE-sensitized mice by administering either compound A or B, which has P2X4 receptor antagonistic activity, or by administering the above procedure to mice, and by administering the above procedure to mice in each group to induce a passive systemic anaphylaxis (PSA in this specification), thereby determining the inhibitory effect on PSA.

[0770] (Preparation of IgE-sensitized mice)

[0771] Anesthetized mice were sensitized by administering 10 μg / 200 μL (physiological saline) of IgE via the tail vein.

[0772] It should be noted that the mice used were male C57BL / 6J mice (7-8 weeks old or 10-11 weeks old, manufactured by SLC Corporation, Japan).

[0773] (Administration of medication)

[0774] The IgE-sensitized mice were administered compound A (10 mg / kg) in physiological saline intraperitoneally 30 minutes before DNP-HSA administration. It should be noted that DNP-HSA administration was adjusted to 24 hours after the initiation of the IgE-sensitization process.

[0775] In addition, other IgE-sensitized mice were administered compound B (10 mg / kg) in solvent B intraperitoneally 1 hour before DNP-HSA administration. It should be noted that DNP-HSA administration was adjusted to 24 hours after the initiation of the IgE-sensitized mice.

[0776] In addition, for other IgE-sensitized mice mentioned above, groups were prepared to be given physiological saline as a control of compound A (solvent group) and groups were given solvent B as a control of compound B (solvent group).

[0777] (Creation of PSA model mice)

[0778] Twenty-four hours after the creation of the IgE-sensitized mice, 100 ng / 200 μL (physiological saline) of DNP-HSA was administered into the tail vein of unanesthetized mice to create PSA model mice and induce allergic reactions.

[0779] (Determination of inhibitory effect)

[0780] The aforementioned PSA model mice exhibit a sharp drop in body temperature by inducing a passive systemic anaphylactic response. Therefore, the effects of compounds A or B on passive systemic anaphylactic response were determined by measuring changes in body temperature upon administration of DNP-HSA via the tail vein.

[0781] For the measurement of the above-mentioned body temperature changes, the DNP-HSA administration time was set to 0 minutes, and rectal body temperature was measured every 5 minutes from 0 minutes to 60 minutes after administration using a BAT-7001H Thermometer (PHYSITEMP INSTRUMENTS INS).

[0782] It should be noted that in this embodiment, the number of test subjects was n=7 in the compound A group, n=8 in the compound A control group, and n=9 in the compound B group and its control group. Significant differences in this embodiment are represented by... Figure 4 and Figure 5 The asterisk (*) in the attached figure indicates that p < 0.05. Additionally, Figure 4 and Figure 5 The asterisks in the attached figures indicate that there are significant differences between the groups given each compound and the control groups (solvent groups).

[0783] (Experimental Results)

[0784] In the IgE-sensitized mice, pretreatment with compounds A or B followed by intravenous administration of DNP-HSA resulted in significant inhibition of hypothermia. Furthermore, the hypothermia-inhibiting effect of compound A was significantly different at least within the 35-minute timeframe and persisted even after 60 minutes.

[0785] Example 5 shows the effect of the degranulation reaction on BMMC.

[0786] The inhibitory effects of compound A on degranulation induced by co-stimulation of IgE-sensitized BMMCs with DNP-HSA (10 ng / mL) and ATP (0.1 mM) were observed, as well as on degranulation induced by co-stimulation of IgE-sensitized BMMCs with prostaglandin E2 (PGE2 in this specification) (1 μg / mL) and ATP (0.1 mM).

[0787] It should be noted that the above degranulation reaction was conducted to determine the degranulation rate based on the release rate of β-aminohexosidase. The determination of the release rate of β-aminohexosidase was carried out as follows (degranulation experiment).

[0788] (Preparation of BMMC)

[0789] The procedure is performed according to the method described in Example 2.

[0790] (De-particle experiment)

[0791] Anti-DNP-IgE antibody (clone: ​​SPE-7, Sigma-Aldrich) was added to the culture medium of BMMCs to achieve an overnight sensitization concentration of 50 ng / ml. The BMMCs were then washed with PBS (-) and resuspended 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) to achieve a concentration of 1 × 10⁻⁶. 6 cell / ml is used for experiments.

[0792] Next, compound A (1 μM, 3 μM, or 10 μM) or 0.1% DMSO as a control was added to the IgE-sensitized BMMC and pre-incubated at room temperature for 10 minutes.

[0793] Then, adjust the above BMMCs to the following 6 groups respectively. It should be noted that the numbers in parentheses below are not the same as... Figure 6 The numbers in parentheses are consistent.

[0794] (1) Groups that have not been added to the above BMMC

[0795] (2) The group in which only ATP was added to the above BMMC,

[0796] (3) Groups in which only PGE2 (1 μM) was added to the above BMMC

[0797] (4) The group in which a mixture of ATP and PGE2 (1 μM) was added simultaneously to the above BMMC

[0798] (5) The group in which only DNP-HSA (10 ng / ml) as an antigen was added to the above BMMC, and

[0799] (6) The group in which a mixture of ATP and DNP-HSA (10 ng / ml) was added to the above BMMC.

[0800] The above six groups were stimulated at 37°C for 5 minutes, rapidly cooled on ice, and then centrifuged to stop the reaction. After recovering the supernatant, the precipitated cells were dissolved in 0.1% Triton X-100. The supernatant and cell lysate (50 μL) were mixed with 10 mM 4-nitrophenyl-N-acetyl-β-D-aminoglycoside (Sigma-Aldrich) / 50 mM citrate buffer (pH 4.5, 50 μL) as the substrate for β-aminohexosidase 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 (TECAN) microplate reader. The release rate of β-aminohexosidase was calculated using the following formula.

[0801] β-Aminohexosidase release rate = (Supernatant absorbance / (Supernatant absorbance + Cell lysate absorbance)) × 100

[0802] (Experimental Results)

[0803] For groups (1)–(3) that did not receive co-stimulation with ATP (0.1 mM) and PGE2 (1 μM), the release rate of β-aminohexosidase in BMMCs treated with compound A and control BMMCs was less than 5%. Figure 6 (1) to (3)). In contrast, the release rate of β-aminohexosidase in the control BMMC of the group (4) that was co-stimulated with ATP (0.1 mM) and PGE2 (1 μM) was about 15%. Figure 6 (4)). However, compared with the control BMMCs, the release rate of β-aminohexosidase in the same group that were pre-incubated with compound A was reduced in a manner dependent on the amount of compound A used, and the release rate was significantly reduced at any concentration of 1 μM, 3 μM and 10 μM. Figure 6 (4)).

[0804] It should be noted that the number of subjects in this embodiment was n=3. The significant differences in this embodiment are due to... Figure 6 In the attached figures, "*" or "**" indicate P < 0.05 and P < 0.01 (Dunnett), respectively. Additionally, Figure 6 The "*" or "**" in the attached figures indicate that the results are significantly different from those of the control group in the same group.

[0805] Example 6: Effects of P2X4 receptor inhibitors on the release of IL-6, IL-13, and TNF-α from BMMCs

[0806] (Experimental Methods)

[0807] BMMCs were washed with fresh culture medium and reacted for 3 hours in the presence and without the stimulants (100 μM ATP, 1 μM PGE2, 100 μM ATP + 1 μM PGE2).

[0808] The groups are shown below, with Figures 7-9 The numbers in parentheses in the description are consistent.

[0809] (1) Groups that have not been added to the above BMMC

[0810] (2) The group in which only ATP was added to the above BMMC,

[0811] (3) Groups that only include PGE2 in the above BMMCs,

[0812] (4) The group in which a mixture of ATP and PGE2 was added to the above BMMC.

[0813] The effects of compound A were observed after pretreatment at a concentration of 10 μM for 5 minutes. Cytokines (interleukin (IL)-6, IL-13, and TNF-α) released into the reaction solution were measured using ELISA kits (Invitrogen).

[0814] It should be noted that the number of subjects in this embodiment was n=3, and significant differences in this embodiment were expressed using [missing information]. Figures 7-9 In the attached figures, "**" indicates a p-value < 0.01. Furthermore, the above significant differences indicate... Figures 7-9 The accompanying figure shows the results compared to the non-drug group of compound A.

[0815] (Experimental Results)

[0816] The results are shown in Figures 7-9 .

[0817] This indicates that the increased release of IL-6, IL-13, and TNF-α induced by ATP was inhibited by compound A. Based on this result, it is suggested that the compound of this application is effective against allergic dermatitis, allergic bronchial asthma, etc.

[0818] Industrial availability

[0819] The pharmaceutical compositions of the present invention are useful as pharmaceutical compositions for the prevention, suppression, or treatment of symptoms accompanying allergic reactions, and further useful as pharmaceutical compositions for the prevention, suppression, or treatment of allergic diseases, particularly useful as pharmaceutical compositions for the prevention, suppression, or treatment of symptoms accompanying type I allergic reactions, and even more particularly useful as pharmaceutical compositions for the prevention or treatment of anaphylactic shock, allergic rhinitis, bronchial asthma, or allergic dermatitis, as pharmaceutical compositions for the suppression of anaphylactic shock, or as pharmaceutical compositions for the prevention or treatment of hay fever, urticaria, or atopic dermatitis, with high efficacy expected in each case.

Claims

1. Selected from (A17)5-[3-(5-thio-4H―[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt and (B48)5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza The use of compounds in -2,4(3H,5H)-diones or pharmaceutically acceptable salts thereof in the manufacture of pharmaceutical compositions for the prevention, inhibition or treatment of symptoms associated with allergic reactions. The symptoms accompanying the allergic reaction are selected from those of anaphylactic shock, allergic rhinitis, allergic dermatitis, hay fever, urticaria, and atopic dermatitis.

2. The use of claim 1, wherein, The symptoms accompanying the allergic reaction are anaphylactic shock.

3. The use according to claim 1, wherein, The symptoms accompanying the allergic reaction are allergic rhinitis.

4. The use of claim 1, wherein, The symptoms accompanying the allergic reaction are allergic dermatitis.

5. The use of claim 1, wherein, The symptoms accompanying the allergic reaction are hay fever.

6. The use of claim 1, wherein, The symptoms accompanying the allergic reaction are urticaria (hives).

7. The use of claim 1, wherein, The symptoms accompanying the allergic reaction are atopic dermatitis.

8. The use according to any one of claims 1 to 7, wherein The compound or its pharmaceutically acceptable salt is (A17)5-[3-(5-thio-4H-[1,2,4]]. [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt.

9. The use according to any one of claims 1 to 7, wherein The compound or its pharmaceutically acceptable salt is (B48)5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione.

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