Drug for prevention or treatment of irritable bowel syndrome or inflammatory bowel disease

Abstract

To provide a drug for prevention or treatment of irritable bowel syndrome or inflammatory bowel disease.SOLUTION: The present invention provides a drug for preventing or treating irritable bowel syndrome or inflammatory bowel disease, comprising as an active ingredient a compound having a P2X4 receptor antagonistic action or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a preventive or therapeutic agent for irritable bowel syndrome and inflammatory bowel disease. [Background technology]

[0002] Irritable Bowel Syndrome (IBS) is a representative functional gastrointestinal disorder, and its core symptoms are abdominal pain or discomfort and associated changes in bowel habits such as diarrhea and constipation. IBS symptoms can be aggravated by psychological factors and stress. According to the Rome III diagnostic criteria, the symptoms are classified into diarrhea type, constipation type, mixed type that has characteristics of both diarrhea type and constipation type, and unclassifiable type that does not meet any of the criteria. It has been proposed to subclassify IBS according to the stool shape (25% or more of the total).

[0003] In the drug treatment of irritable bowel syndrome, for example, tricyclic antidepressants are effective for diarrhea-predominant irritable bowel syndrome, but side effects such as drowsiness, constipation, and dry mouth are likely to occur. 5-HT3 antagonists are used overseas as drugs for constipation-predominant irritable bowel syndrome. In addition, 5-HT4 receptor agonists and drugs that act as 5-HT4 receptor agonists and 5-HT3 receptor agonists are effective overseas for abdominal pain and constipation. However, the use of 5-HT series drugs is limited due to side effects. Therefore, drug therapy for irritable bowel syndrome has been very limited to date (Non-Patent Document 1).

[0004] Inflammatory bowel disease (IBD) is a multifactorial immune disorder characterized by chronic and recurrent inflammation in the intestinal tract. Inflammatory bowel disease is broadly classified into Crohn's disease (CD) and ulcerative colitis (UC), and simple ulcers, nonspecific multiple small intestinal ulcers, etc. are sometimes referred to as inflammatory bowel disease in the narrow sense (Non-Patent Document 2). Although Crohn's disease and ulcerative colitis share similar clinical symptoms, such as diarrhea, bloody stools, and abdominal pain, the etiology of inflammatory bowel disease is currently unknown.

[0005] However, when certain environmental factors trigger a genetically susceptible host, it is believed that a disturbance in the immune system and / or an unbalanced interaction with microorganisms leads to the development of chronic intestinal inflammation.Th1 cells have been thought to play an important role in the pathogenesis associated with chronic inflammation of the intestine, especially in Crohn's disease, while Th2 cells are thought to play an important role in ulcerative colitis. In recent years, activation of Th17 cells and an imbalance between Th17 and regulatory T (Treg) cells have been recognized as important factors in the development of intestinal inflammation (Non-Patent Document 3). The high and increasing incidence of inflammatory bowel disease can be attributed in part to the poor efficacy and / or safety of conventional drugs (corticosteroids, immunosuppressants, and salicylates). Other treatment options include biotechnology drug treatments, which are somewhat effective but are also characterized by severe side effects.

[0006] As a result, no pharmacological treatment for IBD is satisfactory, and efforts are currently underway to find new drugs that offer a favorable benefit / risk profile (Non-Patent Document 4).

[0007] In such a situation, many evidences have been reported over the years that ATP plays an important role in the formation of immune / inflammatory responses. From these reports, it has become clear that P2X4 receptors are involved in mediating such ATP-regulated activities. In particular, P2X4 receptors sustain proinflammatory responses that sustain the release of proinflammatory cytokines such as IL-1β and IL-18. Furthermore, there is some evidence showing the involvement of P2X4 in multiple immune / inflammatory pathologies, such as postischemic inflammation, rheumatoid arthritis, asthmatic airway inflammation, neurodegenerative diseases, and even metabolic syndrome (Non-Patent Documents 5-7).

[0008] As described above, Non-Patent Documents 1 to 7 show that conventional drugs and treatments can be used as therapeutic agents for irritable bowel syndrome or inflammatory bowel disease, but they are known to be poorly effective or to cause some side effects, and are not effective as therapeutic agents for irritable bowel syndrome or inflammatory bowel disease.

[0009] Patent Document 1 describes a P2X4 receptor antagonist. However, the compounds described in the examples of Patent Document 1 are selective serotonin reuptake inhibitors such as Paroxetine and Fluoxetine, and have a completely different structure from the compound of the present application, which is a benzodiazepine derivative compound. In addition, only experimental results using a neuropathic pain pathological model with nerve injury (L5 spinal nerve injury model) are shown, and it is not known that P2X4 receptor antagonists have a therapeutic effect on irritable bowel syndrome or inflammatory bowel disease.

[0010] Patent Document 2 also describes a compound exhibiting P2X4 receptor antagonistic activity. However, as in Patent Document 1, only the effect in a neuropathic pain model is shown, and it is unclear whether the compound has a therapeutic effect on irritable bowel syndrome or inflammatory bowel disease.

[0011] In addition, the applicant of the present application has filed patent applications relating to P2X4 receptor antagonists as shown in Patent Documents 3 to 9, but it is unclear whether any of these applications have a therapeutic effect on irritable bowel syndrome or inflammatory bowel disease. [Prior art documents] [Patent documents]

[0012] [Patent Document 1] International Publication No. 2008 / 020651 [Patent Document 2] International Publication 2010 / 093061 [Patent Document 3] International Publication No. 2008 / 023847 [Patent Document 4] International Publication No. 2012 / 008478 [Patent Document 5] International Publication No. 2012 / 014910 [Patent Document 6] International Publication No. 2012 / 017876 [Patent Document 7] International Publication No. 2013 / 105608 [Patent Document 8] International Publication No. 2015 / 005468 [Patent Document 9] International Publication No. 2015 / 005467 [Non-Patent Document]

[0013] [Non-Patent Document 1] Japanese Society of Gastroenterology, Clinical Practice Guidelines for Functional Gastrointestinal Disorders 2014 - Irritable Bowel Syndrome (IBS) [Non-Patent Document 2] Journal of the Japanese Society of Internal Medicine 98(1), 5 - 11, January 10, 2009 [Non-Patent Document 3] Kim DH and Cheon JH (2017) Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. Immune network 17: 25 - 40. [Non-Patent Document 4] Katz S (2007) "Mind the Gap": an unmet need for new therapy in IBD. Journal of clinical gastroenterology 41: 799 - 809. [Non-Patent Document 5] Kawano A, Tsukimoto M, Mori D, Noguchi T, Harada H, Takenouchi T, Kitani H and Kojima S (2012) Regulation of P2X7-dependent inflammatory functions by P2X4 receptor in mouse macrophages. Biochemical and Biophysical Research Communications 420: 102-107.

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[0014] An object of the present invention is to provide a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease. [Means for solving the problem]

[0015] In order to solve the above problems, the present inventors have conducted intensive research and found that compounds represented by general formulas (A) to (BII) having P2X4 receptor antagonist activity are useful for the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease, and have completed the present invention.

[0016] That is, the present invention provides a medicine for preventing and / or treating irritable bowel syndrome or inflammatory bowel disease, which comprises a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof as an active ingredient.

[0017] As a compound having a P2X4 receptor antagonistic activity, for example, a compound represented by the following general formula (A) to (BII) can be used. More preferably, as a compound having a P2X4 receptor antagonistic activity, a compound represented by the following general formula (BI) or (BII) can be used.

[0018] The pharmaceutical of the present invention can be used, for example, for the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease, particularly for the prevention or treatment of Crohn's disease in the inflammatory bowel disease, or for the prevention or treatment of ulcerative colitis in the inflammatory bowel disease.Furthermore, it can be used, for example, for remission induction therapy or remission maintenance therapy in inflammatory bowel disease.Furthermore, it can be used, for example, for remission induction therapy or remission maintenance therapy in Crohn's disease or ulcerative colitis. It can further be used to inhibit or reduce adhesions or ulcers in intestinal tissue, for example in irritable bowel syndrome or inflammatory bowel disease, and it can further be used to inhibit or reduce areas of transmural inflammation in intestinal tissue, for example in irritable bowel syndrome or inflammatory bowel disease. Furthermore, it can be used to suppress or reduce histological damage in intestinal tissue, for example, in irritable bowel syndrome or inflammatory bowel disease. It can also be used to suppress or reduce mucosal necrosis in intestinal tissue, for example, in irritable bowel syndrome or inflammatory bowel disease. It can also be used to suppress or reduce cell infiltration in intestinal tissue, for example, in irritable bowel syndrome or inflammatory bowel disease. It can also be used to protect or maintain the mucosa in intestinal tissue, for example, in irritable bowel syndrome or inflammatory bowel disease.

[0019] From another viewpoint, the present invention provides use of a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof for the manufacture of the above-mentioned medicine; and a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease, in particular a method for preventing or treating Crohn's disease in the inflammatory bowel disease, or a method for preventing or treating ulcerative colitis in the inflammatory bowel disease, or remission induction therapy or remission maintenance therapy in inflammatory bowel disease, or remission induction therapy or remission maintenance therapy in Crohn's disease or ulcerative colitis, or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for suppressing or reducing adhesions or ulcers in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for suppressing or reducing transmural inflammatory areas in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for suppressing or reducing histological damage in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for suppressing or reducing mucosal necrosis in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for suppressing or reducing cell infiltration in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for protecting or maintaining mucosa in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, the method comprising a step of administering a prophylactic or therapeutically effective amount of a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof to a mammalian animal including a human. Effect of the Invention

[0020] The medicament of the present invention is useful as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease, particularly as a medicament for preventing or treating Crohn's disease in the inflammatory bowel disease, or as a medicament for preventing or treating ulcerative colitis in the inflammatory bowel disease, and further, for example, as a medicament for remission induction therapy or remission maintenance therapy in inflammatory bowel disease, for example, as a medicament for remission induction therapy or remission maintenance therapy in Crohn's disease or ulcerative colitis, and further, for example, as a medicament for suppressing or reducing adhesions or ulcers in intestinal tissue in irritable bowel syndrome or inflammatory bowel disease. , and further, for example, are useful as a medicine for suppressing or reducing histological damage in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, are useful as a medicine for suppressing or reducing mucosal necrosis in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, are useful as a medicine for suppressing or reducing cellular infiltration in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, and are useful as a medicine for protecting or maintaining the mucosa in intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, and each is expected to be highly effective. [Brief description of the drawings]

[0021] [Figure 1] FIG. 1 shows a comparison of (A) body weight and (B) pancreas weight changes between control rats and a DNBS-induced colitis model, as well as a similar comparison between the model and the control rats orally administered Compound A, and between the model and the model orally administered Compound A or dexamethasone. [Diagram 2] FIG. 1 shows a comparison of macroscopic damage to colonic tissue in control rats and a DNBS-induced colitis model, as well as a similar comparison between the model and the control rats orally administered Compound A, and between the model and the model orally administered Compound A or dexamethasone. [Diagram 3]FIG. 1 shows a comparison of colonic tissue microscopic damage (histological damage) between control rats and a DNBS-induced colitis model, as well as a comparison between the model and the control rats orally administered Compound A, and between the model and the model orally administered Compound A or dexamethasone. [Figure 4] FIG. 1 shows a comparison of the association of inflammatory cytokines (A) TNF and (B) interleukin-1β in colon tissue during colon injury in a control rat and a DNBS-induced colitis model, as well as a comparison between the model and the control rats orally administered Compound A, and the model and the model orally administered Compound A or dexamethasone. [Diagram 5] FIG. 1 shows a comparison of the expression effect of occludin in colonic tissue of a control rat and in colonic tissue of a DNBS-induced colitis model upon colonic injury, and also shows a similar comparison between the model and the model orally administered with Compound A. [Figure 6] FIG. 1 shows a comparison of (A) the effect of expressing procaspase-1 and (B) the effect of expressing caspase-1 in colonic tissue of a control rat and a DNBS-induced colitis model upon colonic injury, as well as a comparison between the model and a model administered compound A orally. [Figure 7] FIG. 1 shows a comparison of (A) the increase or decrease in body weight and (B) the increase or decrease in pancreas weight in control rats and a DNBS-induced colitis model, as well as a similar comparison between the model and the control rats orally administered Compound B, and between the model and the model orally administered Compound B or dexamethasone. [Figure 8] FIG. 1 shows a comparison of macroscopic damage to colonic tissue in control rats and a DNBS-induced colitis model, as well as a similar comparison between the model and the control rats orally administered Compound B, and between the model and the model orally administered Compound B or dexamethasone. [Figure 9]FIG. 1 is a diagram comparing microscopic damage (histological damage) of colonic tissue in control rats, a DNBS-induced colitis model, and the above model administered with oral administration of Compound B or dexamethasone, as determined by histological examination of colon specimens. [Figure 10] FIG. 1 shows a comparison of colonic tissue microscopic damage (histological damage) between control rats and a DNBS-induced colitis model, as well as a comparison between the model and the control rats orally administered Compound B, and between the model and the model orally administered Compound B or dexamethasone. [Figure 11] FIG. 1 shows a comparison of the association of inflammatory cytokines (A) TNF and (B) interleukin-1β in colon tissue during colon injury in a control rat colon tissue and a DNBS-induced colitis model, as well as a comparison between the model and the control rats orally administered Compound B, and between the model and the model orally administered Compound B or dexamethasone. [Figure 12] FIG. 1 shows a comparison of the effect of occludin expression in colonic tissue of control rats and in a DNBS-induced colitis model upon colonic injury, as well as a comparison between the model and the model administered compound B orally. [Figure 13] This figure shows a comparison of (A) the expression effect of procaspase-1 and (B) the expression effect of caspase-1 in colon tissue of a control rat and colon tissue of a DNBS-induced colitis model at the time of colon injury, and also shows a similar comparison between the model and the model orally administered with compound B. In Figures 1 to 8 and Figures 10 to 13, "*" indicates that there is a significant difference (P<0.05) as compared with the control rat, and "a" indicates that there is a significant difference (P<0.05) as compared with the DNBS-induced colitis model. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for preventing or treating irritable bowel syndrome or inflammatory bowel disease, and can also be used for the following applications. The medicament of the present invention can be used as a medicament for preventing or treating the inflammatory bowel disease, Crohn's disease or ulcerative colitis. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for remission induction therapy or remission maintenance therapy for the inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for remission induction therapy or remission maintenance therapy for Crohn's disease or ulcerative colitis. The medicament of the present invention can be used as a medicament for inhibiting or reducing adhesions or ulcers in intestinal tissues in the irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing transmural inflammatory areas in intestinal tissues of the irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing histological damage in intestinal tissues due to the irritable bowel syndrome or the inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for inhibiting or reducing mucosal necrosis in intestinal tissues associated with the irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing cell infiltration in intestinal tissues of the irritable bowel syndrome or the inflammatory bowel disease. The medicament of the present invention can be used as a medicament for protecting or maintaining the mucosa in intestinal tissue in patients with irritable bowel syndrome or inflammatory bowel disease.

[0023] In another aspect, the pharmaceutical agent of the present invention can be used as a pharmaceutical agent for the following applications. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease accompanied by adhesions or ulcers in intestinal tissue. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by the appearance of transmural inflammatory areas in intestinal tissue. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by histological damage in intestinal tissue. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by necrosis or damage of the mucosa in intestinal tissue. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by cellular infiltration in intestinal tissue. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for preventing or treating the irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in inflammatory cytokines. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease accompanied by an increase in interleukin-1β. The medicament of the present invention can be used as a medicament for preventing or treating the irritable bowel syndrome or inflammatory bowel disease, which are accompanied by damage to the colon and an increase in inflammatory cytokines. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for preventing or treating the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by colon damage and an increase in interleukin-1β.

[0024] As used herein, the term "prevention" is a concept that includes preventing the onset of "pathological" or "abnormal" symptoms, conditions, or diseases, and actions or means for achieving this. In the present specification, "treatment" includes the disappearance, complete cure, cure or remission of "pathological" or "abnormal" symptoms, conditions or diseases, and the actions or means therefor, the suppression of the worsening of "pathological" or "abnormal" symptoms, conditions or diseases, and the actions or means therefor, and is also a concept including improvement. Here, "improvement" is a concept including the bringing of "pathological" or "abnormal" symptoms, conditions or diseases closer to a "healthy" or "normal" state, or the actions or means therefor, and the bringing of "healthy" or "normal" state, or the actions or means therefor. Thus, in one embodiment, "improvement" includes the fact that a numerical value that is an index of a "pathological" or "abnormal" symptom or condition becomes smaller or larger according to the "improvement", and approaches a normal value or becomes a normal value. In addition, "suppression" includes the stopping or slowing down the worsening or progression of a symptom, condition or disease, and the actions or means therefor, and is also a concept including the improvement of the symptom, condition or disease, or the actions or means therefor. Here, "improvement" has the above meaning. The "worsening or progression of a symptom, condition or disease" includes the worsening or progression of a "pathological" or "abnormal" symptom, condition or disease, and the worsening or progression from a "healthy" or "normal" state to a "pathological" or "abnormal" symptom, condition or disease. In one embodiment, "suppression" refers to stopping or slowing down the worsening or progression of a symptom, condition or disease, or an act or means therefor. In another embodiment, "suppression" refers to stopping or slowing down the worsening or progression of a symptom, condition or disease.

[0025] In one embodiment, "treatment" refers to the disappearance, complete cure, cure or remission of a "pathological" or "abnormal" symptom, condition or disease, and the action or means therefor. In another embodiment, "treatment" refers to the disappearance, complete cure, cure or remission of a "pathological" or "abnormal" symptom, condition or disease. As used herein, "remission induction therapy" refers to a treatment method carried out for the remission of a "pathological" or "abnormal" symptom, condition or disease, particularly in the acute phase of the onset or exacerbation of the symptom, condition or disease. In addition, "remission maintenance therapy" refers to a treatment method carried out for the purpose of maintaining the state of remission of the symptom, condition or disease, or for the purpose of preventing the recurrence of the symptom, condition or disease. In one embodiment, "remission induction therapy" refers to a therapeutic method performed for the remission of irritable bowel syndrome or inflammatory bowel disease, or symptoms associated therewith, and "remission maintenance therapy" refers to a therapeutic method performed for maintaining a state of remission of irritable bowel syndrome or inflammatory bowel disease, or symptoms associated therewith, or for preventing recurrence of irritable bowel syndrome or inflammatory bowel disease, or symptoms associated therewith. As used herein, "protection of mucosa" means maintaining or preserving normal mucosal tissue or function, or suppressing damage or impairment of mucosal tissue or function. Here, "suppression" has the meaning described above. "Maintenance of mucosa" means maintaining normal mucosal tissue or function, or suppressing deterioration of mucosal tissue or function. Here, "suppression" has the meaning described above. In this specification, the symptoms, conditions or diseases or numerical values ​​indicative thereof, or the condition or function of mucosal tissue may be evaluated by comparing results before and after administration of a pharmaceutical provided by the present invention, or by comparing a group administered a pharmaceutical provided by the present invention with a group administered a placebo or a control not containing the pharmaceutical provided by the present invention. As used herein, the term "inhibit" may mean to stop or slow down the increase in the amount of a substance in the body. As used herein, "maintaining the health of colonic tissue" means maintaining or preserving normal colonic tissue or its function, or inhibiting damage or impairment to colonic tissue or its function. Inhibit has the above-mentioned meaning. "Contribute" means exerting a force to change a certain state or function to a desired state or function. In one embodiment, "contributing to the function of maintaining the health of colonic tissue" means exerting a force to change a state or function of colonic tissue that has suffered some damage or been damaged, etc., to a normal state or function of colonic tissue.

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

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

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

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

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

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

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

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

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

[0035] [Table 1]

[0036] [Table 2]

[0037] [Table 3]

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

[0039] [Table 4]

[0040] [Table 5]

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

[0042] [Table 6]

[0043] [Table 7]

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0089] <Representative compound example B-100>

[0090] [ka]

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

[0092] [Table 8]

[0093] [Table 9]

[0094] [Table 10]

[0095] [Table 11]

[0096] [Table 12]

[0097] [Table 13]

[0098] [Table 14]

[0099] [Table 15]

[0100] [Table 16]

[0101] [Table 17]

[0102] <Representative compound example B-200>

[0103] [ka]

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

[0105] [Table 18]

[0106] [Table 19]

[0107] <Representative compound example B-300>

[0108] [ka]

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

[0110] [Table 20]

[0111] <Representative compound example B-400>

[0112] [ka]

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

[0114] [Table 21]

[0115] <Representative compound example B-500>

[0116] [ka]

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

[0118] [Table 22]

[0119] <Representative compound example B-600>

[0120] [ka]

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

[0122] [Table 23]

[0123] <Representative compound example B-700>

[0124] [ka]

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

[0126] [Table 24]

[0127] <Representative compound example B-800>

[0128] [ka]

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

[0130] [Table 25]

[0131] <Representative compound example B-900>

[0132] [ka]

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

[0134] [Table 26]

[0135] <Representative compound example B-1000>

[0136] [ka]

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

[0138] [Table 27]

[0139] <Representative compound example B-1100>

[0140] [ka]

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

[0142] [Table 28]

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

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

[0145] Moreover, the above-mentioned International Publication No. 2010 / 093061 and International Publication No. 2013 / 105608 state that the compounds represented by the above general formulae (A) to (BII) have a P2X4 receptor antagonistic activity.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0175] As the active ingredient of the medicament of the present invention, in addition to the compounds represented by the above general formulas (A) to (BII), any solvate of the above compounds in free form or in salt form may be used as the active ingredient of the medicament of the present invention. The above solvates include hydrates. In this specification, unless otherwise specified, the compounds represented by the above general formulas (A) to (BII) may include cis / trans isomers, optically active compounds, stereoisomers such as racemates, tautomers, any optical isomers based on an asymmetric carbon, racemates, diastereoisomers based on two or more asymmetric carbons, and mixtures thereof.

[0176] As the active ingredient of the medicament of the present invention, in addition to the compounds represented by the above general formulas (A) to (BII), acid addition salts or base addition salts of these compounds may be used. Examples of the acid addition salts include, but are not limited to, mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, p-toluenesulfonate, oxalate, and malate. Examples of the base addition salts include, but are not limited to, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, ammonium salt, and organic amine salts such as triethylamine salt and ethanolamine salt. Of these salts, it is preferable to use a pharma- ceutically acceptable salt as the active ingredient of the medicament of the present invention.

[0177] The pharmaceutical agent of the present invention can be used for the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease. Preferably, the pharmaceutical agent can be used for the prevention or treatment of ulcerative colitis or Crohn's disease, which are inflammatory bowel diseases. More preferably, the pharmaceutical agent can be used for remission induction therapy or remission maintenance therapy for inflammatory bowel disease. Even more preferably, the pharmaceutical agent can be highly effective in remission induction therapy or remission maintenance therapy for Crohn's disease or ulcerative colitis. Furthermore, the medicament of the present invention can be used to inhibit or reduce adhesions or ulcers in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease, and can be used to inhibit or reduce transmural inflammatory areas in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. Furthermore, the pharmaceutical composition of the present invention can be used to suppress or reduce histological damage in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. Preferably, the pharmaceutical composition can be used to suppress or reduce mucosal necrosis in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. More preferably, the pharmaceutical composition can be used to suppress or reduce cell infiltration in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. Even more preferably, the pharmaceutical composition can be used to protect or maintain the mucosa in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease.

[0178] In another aspect, the medicament of the present invention can be used for the following purposes. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease accompanied by adhesions or ulcers in intestinal tissue. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by the appearance of transmural inflammatory areas in intestinal tissue. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by histological damage in intestinal tissue. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by necrosis or damage of the mucosa in intestinal tissue. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by cellular infiltration in intestinal tissue. The pharmaceutical agent of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease accompanied by an increase in inflammatory cytokines. The pharmaceutical agent of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by an increase in interleukin-1β. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by damage to the colon and an increase in inflammatory cytokines. The medicament of the present invention can be used for the prevention or treatment of the irritable bowel syndrome or the inflammatory bowel disease, which are accompanied by colon damage and increased interleukin-1β. All of these inflammatory bowel diseases are targets for application of the medicament of the present invention, although the targets for application of the medicament of the present invention are not limited to these.

[0179] The pharmaceutical agent of the present invention can be administered orally or parenterally. The pharmaceutical agent of the present invention can be prepared in an appropriate dosage form such as tablets, granules, powders, capsules, suspensions, inhalants, inhalation powders, inhalation liquids, inhalation aerosols, injections, suppositories, etc., according to a conventional method in the technical field of pharmaceutical preparations.

[0180] These preparations can be manufactured using common techniques, and for example, in the case of tablets, pharma- ceutically acceptable additives such as ordinary excipients, disintegrants, binders, lubricants, and dyes can be used. Examples of excipients include lactose, D-mannitol, crystalline cellulose, and glucose; examples of disintegrants include starch and carboxymethylcellulose calcium (CMC-Ca); examples of lubricants include magnesium stearate and talc; and examples of binders include hydroxypropylcellulose (HPC), gelatin, and polyvinylpyrrolidone (PVP).

[0181] Injections are prepared using pharma- ceutically acceptable additives such as solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. These pharma- ceutically acceptable additives and preparation methods for formulations can be appropriately selected by those skilled in the art. That is, the medicament of the present invention can be provided as a pharmaceutical composition containing the active ingredient and a pharma- ceutical acceptable additive.

[0182] Inhalants for parenteral administration include aerosols, powders for inhalation, liquids for inhalation (e.g., solutions for inhalation, suspensions for inhalation, etc.), or capsule-shaped inhalants, and the liquids for inhalation may be in a form that is dissolved or suspended in water or other suitable medium when used. These inhalants can be administered using a suitable inhalation container, and for example, a sprayer (atomizer, nebulizer) or the like can be used when administering liquids for inhalation, and a powder medicine inhaler or the like can be used when administering powders for inhalation.

[0183] These inhalants are produced according to known methods. For example, the compounds represented by the general formulae (A) to (BII) are powdered or liquid, mixed with an inhalation propellant or carrier, and filled into an appropriate inhalation container. When the compounds represented by the general formulae (A) to (BII) are powdered, they are powdered according to a conventional method. For example, they are finely powdered together with lactose, starch, magnesium stearate, etc., and mixed uniformly or granulated to prepare a powder. When the compounds represented by the general formulae (A) to (BII) are liquefied, for example, the compounds may be dissolved in a liquid carrier such as water, physiological saline, or an organic solvent. As the propellant, a conventionally known propellant, for example, a fluorocarbon alternative, a liquefied gas propellant (e.g., fluorocarbon, liquefied petroleum, diethyl ether, dimethyl ether, etc.), a compressed gas (e.g., a soluble gas (e.g., carbon dioxide, nitrous oxide, etc.), an insoluble gas (e.g., nitrogen gas, etc.), etc.) can be used.

[0184] The inhalant may further contain pharma- ceutically acceptable additives as necessary. Any commonly used additives may be used, and examples of such additives include solid excipients (e.g., sucrose, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid excipients (e.g., propylene glycol, etc.), binders (starch, dextrin, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, sucrose, etc.), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g., citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, etc.), preservatives (e.g., sodium benzoate, sulfur dioxide, etc.), and the like. In the case of inhalation liquid, for example, preservatives, colorants, buffers, isotonicity agents, thickeners, and absorption promoters are used. For example, in the case of inhalation liquid, preservatives, colorants, buffers, isotonicity agents, thickeners, and absorption promoters are appropriately selected as necessary. In the case of powders for inhalation, for example, lubricants, binders, excipients, colorants, preservatives, absorption enhancers (bile salts, chitosan, etc.), etc. are appropriately selected as necessary and prepared.

[0185] Furthermore, in order to make the compound represented by the general formula (A) to (BII) sustained-release, the inhalant may contain a biodegradable polymer. Examples of the biodegradable polymer include fatty acid ester polymers or copolymers thereof, polyacrylic acid esters, polyhydroxybutyric acids, polyalkylene oxalates, polyorthoesters, polycarbonates, and polyamino acids, and these may be used in a mixture of one or more. Phospholipids such as egg yolk lecithin, chitosan, etc. may also be used. Examples of the fatty acid ester polymers or copolymers thereof include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, and lactic acid-glycolic acid copolymers, and these may be used in a mixture of one or more. In addition, a mixture of one or more of polyα-cyanoacrylic acid esters, polyβ-hydroxybutyric acid, polytrimethylene oxalates, polyorthoesters, polyorthocarbonates, polyethylene carbonates, polyγ-benzyl-L-glutamic acid, and poly-L-alanine may also be used. Polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer is preferred, and lactic acid-glycolic acid copolymer is more preferred. Furthermore, microspheres or nanospheres containing a drug may be prepared using a biodegradable polymer such as lactic acid-glycolic acid copolymer.

[0186] The dosage of the medicament of the present invention is not particularly limited, but is generally about 100 mg / kg / day for an adult. Inhalants, powder inhalants, liquid inhalants, and aerosol inhalants are administered in an amount of about 0.01 μg to 100 mg, preferably 0.3 μg to 10 mg, per day as the active ingredient. The amount of active ingredient in the injection is about 0.01mg to 100mg per day. Oral administration: 0.01mg to 2000mg per day However, the dosage is not limited to the above amounts, and may be increased or decreased depending on age, symptoms, etc.

[0187] The medicament of the present invention can be used in combination with other drugs useful for the treatment or prevention of various irritable bowel syndromes or inflammatory bowel diseases. The individual components of such combinations can be administered in separate or single preparations at different times or simultaneously during the treatment or prevention period. Therefore, the present invention should be interpreted as including all simultaneous or different time administrations, and the administration in the present invention should be interpreted accordingly. The scope of the combination of the medicament of the present invention with other drugs useful for the treatment or prevention of various irritable bowel syndromes or inflammatory bowel diseases as described above includes, in principle, combinations with any pharmaceutical preparations useful for the treatment or prevention of various irritable bowel syndromes or inflammatory bowel diseases as described above.

[0188] Each preparation in the combination preparation according to the present invention may be in various forms and may be prepared in the same manner as the above-mentioned preparations. In addition, a combination preparation containing the medicament of the present invention and other various therapeutic or prophylactic drugs for irritable bowel syndrome or inflammatory bowel disease may be easily prepared by a person skilled in the art according to a conventional method or conventional technology. The above combinations include combinations of the medicament of the present invention with not only one other active substance, but also two or more other active substances. There are many examples of combinations of the medicament of the present invention with one, two or more active substances selected from the above-mentioned various therapeutic or prophylactic drugs for irritable bowel syndrome or inflammatory bowel disease.

[0189] The present invention has the following aspects. <1a> A method for preventing or treating irritable bowel syndrome or inflammatory bowel disease, comprising administering to a subject in need thereof (e.g., a mammal including a human) a therapeutically effective amount of a compound having a P2X4 receptor antagonistic activity (e.g., a compound represented by any one of general formulas (A) to (BII)) or a pharma- ceutically acceptable salt thereof; <2a> the method according to <1a>, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis; <3a> the method according to <1a>, wherein the method for preventing or treating inflammatory bowel disease is remission induction therapy or remission maintenance therapy for the inflammatory bowel disease; <4a> the method according to <1a>, wherein the method for preventing or treating inflammatory bowel disease is remission induction therapy or remission maintenance therapy for Crohn's disease or ulcerative colitis; <5a> the method according to any one of <1a> to <4a>, further comprising inhibiting or reducing adhesion or ulcer in intestinal tissue; <6a> the method according to any one of <1a> to <5a>, further comprising suppressing or reducing transmural inflammatory areas in intestinal tissue; <7a> the method according to any one of <1a> to <6a>, further comprising suppressing or reducing histological damage in intestinal tissue; <8a> the method according to any one of <1a> to <7a>, further comprising suppressing or reducing mucosal necrosis in intestinal tissue; <9a> the method according to any one of <1a> to <8a>, further comprising suppressing or reducing cell infiltration in intestinal tissue; <10a> the method according to any one of <1a> to <9a>, further comprising protecting or maintaining the mucosa in intestinal tissue; <11a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by adhesions or ulcers in intestinal tissue; <12a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by the appearance of transmural inflammatory areas in intestinal tissue; <13a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by histological damage in intestinal tissue; <14a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by necrosis or damage of the mucosa in intestinal tissue; <15a> the method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by cellular infiltration in intestinal tissue; <16a> the method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in inflammatory cytokines; <17a> the method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in interleukin-1β; <18a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and an increase in inflammatory cytokines; and <19a> The method according to <1a>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and an increase in interleukin-1β.

[0190] The present invention has the following other aspects. <1b> A compound having P2X4 receptor antagonistic activity (e.g., a compound represented by general formula (A) to (BII)) or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease; <2b> the compound for use according to <1b> or a pharma- ceutical acceptable salt thereof, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis; <3b> the compound according to <1b> or a pharma- ceutical acceptable salt thereof for use in remission induction therapy or remission maintenance therapy for inflammatory bowel disease; <4b> the compound according to <2b> or a pharma- ceutical acceptable salt thereof for use in remission induction therapy or remission maintenance therapy for Crohn's disease or ulcerative colitis; <5b> a compound or a pharma- ceutical acceptable salt thereof according to any one of <1b> to <4b> for use in inhibiting or reducing adhesion or ulcer in intestinal tissue in the irritable bowel syndrome or inflammatory bowel disease; <6b> a compound or a pharma- ceutical acceptable salt thereof according to any one of <1b> to <5b> for use in inhibiting or reducing transmural inflammatory areas in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease; <7b> a compound according to any one of <1b> to <6b> or a pharma- ceutically acceptable salt thereof for use in inhibiting or reducing histological damage in intestinal tissue in the irritable bowel syndrome or inflammatory bowel disease; <8b> a compound according to any one of <1b> to <7b> or a pharma- ceutically acceptable salt thereof for use in inhibiting or reducing mucosal necrosis in intestinal tissues associated with irritable bowel syndrome or inflammatory bowel disease; <9b> a compound according to any one of <1b> to <8b> or a pharma- ceutical acceptable salt thereof for use in inhibiting or reducing cellular infiltration in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease; <10b> further comprising the compound according to any one of <1b> to <9b> or a pharma- ceutical acceptable salt thereof for use in protecting or maintaining the mucosa in intestinal tissue in the irritable bowel syndrome or inflammatory bowel disease; <11b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by adhesions or ulcers in intestinal tissue; <12b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by the appearance of transmural inflammatory areas in intestinal tissue; <13b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by histological damage in intestinal tissue; <14b> the compound or pharma- ceutically acceptable salt thereof for use according to <1b>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by necrosis or damage of the mucosa in intestinal tissue; <15b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by cellular infiltration in intestinal tissue; <16b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in inflammatory cytokines; <17b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in interleukin-1β; <18b> the compound for use according to <1b> or a pharma- ceutically acceptable salt thereof, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and an increase in inflammatory cytokines; and <19b> The compound or pharma- ceutical acceptable salt thereof for use according to <1b>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and an increase in interleukin-1β.

[0191] The present invention has the following further aspect. <1c> use of a compound having P2X4 receptor antagonistic activity (e.g., a compound represented by general formula (A) to (BII)) or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease; <2c> the use according to <1c>, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis; <3c> the use according to <1c> for producing a medicament for remission induction therapy or remission maintenance therapy for the inflammatory bowel disease; <4c> the use according to <2c> for producing a medicament for remission induction therapy or remission maintenance therapy for the Crohn's disease or the ulcerative colitis; <5c> the use according to any one of <1c> to <4c>, further for the manufacture of a medicine for inhibiting or reducing adhesion or ulcer in intestinal tissues of the irritable bowel syndrome or the inflammatory bowel disease; <6c> the use according to any one of <1c> to <5c>, further for the manufacture of a medicament for suppressing or reducing transmural inflammatory areas in intestinal tissues of the irritable bowel syndrome or the inflammatory bowel disease; <7c> the use according to any one of <1c> to <6c>, further for the manufacture of a medicine for inhibiting or reducing histological damage in intestinal tissues due to the irritable bowel syndrome or the inflammatory bowel disease; <8c> the use according to any one of <1c> to <7c>, further for the manufacture of a medicine for inhibiting or reducing mucosal necrosis in intestinal tissues associated with the irritable bowel syndrome or the inflammatory bowel disease; <9c> the use according to any one of <1c> to <8c>, further for the manufacture of a medicament for inhibiting or reducing cellular infiltration in intestinal tissues of the irritable bowel syndrome or the inflammatory bowel disease; <10c> the use according to any one of <1c> to <9c>, further for producing a medicine for protecting or maintaining a mucosa in intestinal tissue in the irritable bowel syndrome or the inflammatory bowel disease; <11c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by adhesions or ulcers in intestinal tissue; <12c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by the appearance of transmural inflammatory areas in intestinal tissue; <13c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by histological damage in intestinal tissue; <14c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by necrosis or damage of the mucosa in the intestinal tissue; <15c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by cellular infiltration in intestinal tissue; <16c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in inflammatory cytokines; <17c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in interleukin-1β; <18c> the use according to <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and an increase in inflammatory cytokines; and <19c> The use described in <1c>, wherein the irritable bowel syndrome or the inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by damage to the colon and increased interleukin-1β. EXAMPLES

[0192] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples. In the following examples, 5-[3-(5-thioxo-4H-[1,2,4]oxadiazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt (WO2010 / 093061, compound of Example 14: hereinafter referred to as "Compound A") and 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (WO2013 / 105608, compound of Example 48: hereinafter referred to as "Compound B") were used as P2X4 receptor antagonists, as well as other compounds shown below: 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione sodium salt;5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepine-5-yl)phenyl]-3- Phenylurea;5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2- b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide;N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide;1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11- Octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide;1-(2-Chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide;5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione Hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione. ; In the examples of the present application, significant differences are indicated by "*" and "a" in Figures 1 to 8 and 10 to 13, and each indicates that P<0.05. In Figures 1 to 8 and 10 to 13, "*" indicates that there is a significant difference as compared to the control rats, and "a" indicates that there is a significant difference as compared to the DNBS-induced colitis model. In the present examples, the number of specimens was 8 to 10.

[0193] Example 1 Measurement of P2X4 receptor antagonistic activity of the compound which is the active ingredient of the present invention (Test Method) The P2X4 receptor antagonistic activity of the compound, which is an active ingredient of the present invention, was measured. ATP receptor (human P2X4) was introduced into 1321N1 cells and used as a P2X4 receptor stable expression system. P2X4 receptor expressing cells were seeded on a 96-well plate, cultured under 37°C and 5% CO2 conditions for 24 hours, and used for calcium measurement. Fura-2AM, a calcium fluorescent indicator, was dissolved in extracellular solution for calcium imaging, treated with the seeded cells, and allowed to stand at room temperature for 45 minutes to allow Fura-2AM to be taken up into the cells. EnVision (PerkinElmer), a microplate reader, was used for the measurement. Light irradiated from a xenon lamp was passed through 340nm and 380nm filters, respectively, and the 510nm fluorescence F340 and F380 emitted when irradiated to the cells were observed, and the change in the ratio value F340 / F380 was used as an index of intracellular calcium change. The measurement was performed by adding ATP to each well so that the final concentration was 1 μM, and observing the ATP-induced intracellular calcium response over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and calculated by comparing with the case in the absence of the test substance. The results are shown in Table 29 below.

[0194] (Test Results) [Table 29]

[0195] Example 2 (Preparation of model animals used) The model animals used were male albino Sprague-Dawley rats (body weight 200-225g). The model animals were housed three per cage in a temperature-controlled environment at 22-24°C, 50-60% humidity, and a 12-hour light cycle, and were given standard laboratory chow and tap water ad libitum. They were not used for at least one week after being brought into the laboratory. The care and handling of the model animals was in accordance with the provisions of the European Communities Council Directive 210 / 63 / UE approved and adopted by the Italian Government. The experiments were approved by the Animal Experiments Ethics Committee of the University of Pisa and the Italian Ministry of Health (approval number 674 / 2016-PR).

[0196] (Establishment of DNBS-induced colitis model) A colitis model was prepared in which colitis was induced with 2,4-dinitrobenzenesulfonic acid (hereinafter referred to as DNBS, manufactured by Sigma-Aldrich) (referred to herein as "DNBS-induced colitis model").

[0197] (Induction of colitis) Colitis was induced according to the method of Antonioli et al. (Non-Patent Document 8). During brief anesthesia with isoflurane (Abbott Laboratories), 15 mg of 2,4-dinitrobenzenesulfonic acid (DNBS) in 0.25 ml of 50% ethanol was administered intrarectally via a polyethylene PE-60 catheter inserted 8 cm proximal to the anus. Control rats received 0.25 ml of 50% ethanol.

[0198] (Control rats) As a control group, male albino Sprague-Dawley rats (body weight 200-225 g) that were not treated with DNBS were used (referred to as "control rats" in this specification). Note that in the drawings, the control rats are referred to as "Control."

[0199] The anti-inflammatory effect of Compound A on the DNBS model was confirmed in Examples 3 to 8. The test compounds used, the administration method, the observation of the model during the test, and the preparation of specimens were performed as follows.

[0200] (Test compound, administration method, etc.) Immediately after delivery of DNBS, rats were orally administered Compound A (3, 10, 30 mg / kg) or dexamethasone (1 mg / kg). Therefore, the effect of Compound A as a remission maintenance therapy can be confirmed in this experiment. Separately from the above groups, compound A (30 mg / kg) was orally administered to control rats. In addition, in Examples 3 to 8, the groups simply referred to as "group administered with compound A" or "group administered with dexamethasone" refer to the groups administered with compound A or dexamethasone immediately after delivery of DNBS.

[0201] (Observation of DNBS-induced colitis model during testing) Food intake was monitored daily from the start of drug treatment. Additionally, rats were weighed every morning throughout the duration of the experiment and examined for evidence of diarrhea and blood in the stool or rectal bleeding. Normal was defined as formed pellet feces, soft feces as pasty and semi-formed feces not sticking to the anus, and diarrhea as the presence of feces stuck to the fur or around the tail, and rectal bleeding was defined as the presence of visible blood around the rectal area of ​​the animal.

[0202] (Preparation of specimen) DNBS-induced colitis model and control rats were euthanized in a CO2 chamber. After death, a midline abdominal incision was made, and the colon was removed, opened longitudinally (towards the longitudinal muscle), rinsed with sterile saline, and divided longitudinally into two parts.

[0203] Example 3 (Changes in body and spleen weight) A significant weight loss was recorded in the DNBS-induced colitis model: 6 days after DNBS administration, the rats lost an average of −15 ± 5 g (−37.6 ± 4.4%) of body weight, whereas the control rats showed a weight gain (+37.5 ± 8.7 g, (+23.5 ± 3.8%)) (Figure 1A). Body weight was also decreased in the group administered with dexamethasone (1 mg / kg), whereas an increase in body weight was observed in the groups administered with compound A (3, 10, and 30 mg / kg) (FIG. 1A). Here, spleen weight is assumed to be an index of systemic inflammation. In the DNBS-induced colitis model, a significant increase in spleen weight (+42%) was observed (FIG. 1B). On the other hand, in the group administered with compound A and dexamethasone, the spleen weight was significantly reduced as compared to the DNBS-induced colitis model (FIG. 1B). As a result, it was confirmed that administration of compound A significantly improved the weight loss and spleen weight increase in the DNBS-induced colitis model.

[0204] Example 4 (Macroscopic Damage) The macroscopic damage was evaluated by the following method. (evaluation) Macroscopic damage was assessed by scoring the specimens, which were prepared by excising colon tissue and rinsing with saline, as described above. Scoring was performed according to a slightly modified standard (Non-Patent Document 12) reported in Non-Patent Document 11. The macroscopic scoring criteria for colonic damage were as follows (1) to (4) (Non-Patent Documents 8 to 10), and the total score of (1) to (4) was calculated. (1) Presence of ulcers: None: 0 points, No ulcers but congested: 1 point, Ulcers present without congested or thickened bowel wall: 2 points, One ulcer with inflammation: 3 points, Two or more ulcers with inflammation: 4 points, Extensive damage >1 cm along the length of the colon: 5 points, Extensive damage >2 cm along the length of the colon: 6 points. (2) Presence of adhesions between colonic tissue and other organs: no adhesions: 0 points, adhesions to only one adjacent organ: 1 point, adhesions to multiple adjacent organs: 2 points. (3) Regarding the hardness of the stool: 0 points for stool that is partially formed, 1 point for loose stool, 2 points for liquid stool (4) Thickness of colonic tissue (colon wall) (mm): 1 mm was scored as 1 point.

[0205] (Confirmation of the anti-inflammatory effect of compound A) In the DNBS-induced colitis model, 6 days after DNBS administration, the distal colon appeared thickened and ulcerated, with obvious areas of transmural inflammation, adhesions were frequently seen, the intestine was occasionally dilated, and the macroscopic damage score was 7.8 ± 1.4. On the other hand, the groups administered with compound A at doses of 10 and 30 mg / kg showed a significant decrease in macroscopic damage score compared to the DNBS-induced colitis model (Figure 2). The group administered with dexamethasone showed a significant decrease in macroscopic damage score compared to the DNBS-induced colitis model (Figure 2). As a result, it was confirmed that administration of Compound A significantly improved tissue parameters (macroscopic scores).

[0206] Example 5 (Microscopic Damage) The evaluation of microscopic damage was carried out by the following method. (evaluation) Hematoxylin / eosin stained tissue sections from whole intestine specimens were examined by light microscopy for microscopic damage and inflammation. The severity of colitis was assessed by scoring the microscopic damage (histologic damage) of specimens prepared by excision of colonic tissue and rinsing with saline, as previously described. Scoring was performed according to a slightly modified standard (Non-Patent Document 12) reported in Non-Patent Document 11. The criteria for microscopic scoring (histologic damage scoring) of colon damage were as follows (1) to (5) (Non-Patent Documents 8 to 10), and the total score of (1) to (5) was used as the score. Histological criteria: (1) Loss of mucosal structure (no loss of mucosal structure: 0 points, mild to severe loss of mucosal structure: 1 to 3 points) (2) Cell infiltration (no cell infiltration: 0 points, mild to severe cell infiltration: 1 to 3 points) (3) Muscle hypertrophy (no muscle hypertrophy: 0 points, mild to severe muscle hypertrophy: 1 to 3 points) (4) Crypt abscess (absent: 0 points, present: 1 point) (5) Goblet cell reduction (absent: 0 points, present: 1 point)

[0207] (Confirmation of the anti-inflammatory effect of compound A) Histological examination of colonic specimens from the DNBS-induced colitis model showed clear colitis, complete destruction of the glandular structure, and associated with large areas of mucosal necrosis. The submucosal tissue was thickened with a marked infiltration of inflammatory cells associated with edema and vasodilation. At times, these changes also involved the muscular layer, which also appeared to be thickened. The mucosa and submucosal tissue surrounding the necrotic areas showed inflammation associated with a marked cellular infiltration, compared with tissue obtained from control rats (Figure 3). Colon sections from inflamed rats (DNBS-induced colitis model) showed severe damage 6 days after DNBS administration (Figure 3). The colon tissue obtained from the group administered Compound A did not affect histological damage compared to the colon tissue of the DNBS-induced colitis model (Figure 3), whereas the colon tissue obtained from the group administered 1 mg / kg dexamethasone showed a significant improvement in microscopic score compared to the colon tissue of the DNBS-induced colitis model (Figure 3).

[0208] Example 6 (TNF and IL-1β Assays) Inflammatory cytokines (tumor necrosis factor (TNF) and interleukin-1β (IL-1β)) in colonic tissue at the time of colonic injury in a DNBS-induced colitis model, and the inflammatory cytokines when Compound A was administered were evaluated. (Sample preparation) Tissue samples stored at -80°C were weighed, thawed, homogenized at 4°C with 0.3 ml PBS (pH 7.2) per 100 mg, and centrifuged at 13,400 g and 10,894 rpm for 20 min, after which an aliquot (100 μl) of the supernatant was used for the assay. (Assessment of tissue proinflammatory indicators) Tissue levels of the proinflammatory cytokines TNF and IL-1β were measured with enzyme-linked immunosorbent assay (ELISA) kits (BioSource International, Camarillo, CA). (Confirmation of the anti-inflammatory effect of compound A) Colonic injury in the DNBS-induced colitis model was associated with a significant increase in both TNF (increased from 2.2 ± 0.3 to 12.4 ± 0.8 pg / mg) (Figure 4A) and IL-1β (increased from 9.3 ± 0.4 to 32.5 ± 1.4 pg / mg) (Figure 4B). Compound A did not affect these inflammatory indices (FIGS. 4A and 4B), whereas dexamethasone completely prevented them (FIGS. 4A and 4B).

[0209] Example 7 (Expression of Occludin in Colon Tissue) The effect of occludin (an integral membrane protein located in tight junctions) expression in colonic tissues upon colonic injury in a DNBS-induced colitis model and the effect of administration of Compound A on said expression were observed by Western blot. (Sample preparation) Colon tissue was weighed (30 μg protein) and the tissue was homogenized in lysis buffer. (Test Method) Proteins were quantified by the Bradford method. The proteins were separated on pre-cast 4-20% polyacrylamide gels (Biorad, Mini-PROTEAN® TGX gels) and then transferred to PVDF membranes (Biorad, Trans-Blot® Turbo™ PVDF Transfer packs). The membranes were blocked with 3% BSA diluted in Tris-buffered saline (TBS, 20 mM Tris-HCl, pH 7.5, 150 mM NaCl) containing 0.1% Tween 20. The antibody used was occludin antibody (ab167161, Abcam, diluted 1:5000). Protein bands were detected with ECL reagent (Clarity® Western ECL Blotting Substrate, Biorad). Densitometry was performed using ImageJ software.

[0210] (Observation of occludin expression) It was shown that occludin was significantly decreased in the colonic mucosa of the DNBS-induced colitis model compared with control rats (Fig. 5 ). In the groups administered compound A (10 mg / kg) (FIG. 5) or dexamethasone (1 mg / kg, not shown), the expression of occludin in the inflamed tissue was increased as compared to the DNBS-induced colitis model. These results indicate that Compound A counteracts the decrease in tight junction occludin observed in the DNBS-induced colitis model, and therefore contributes to maintaining the integrity of colonic tissue.

[0211] Example 8 (Expression of procaspase-1 and caspase-1 in colonic tissue) The expression effects of procaspase-1 and caspase-1 in colonic tissues at the time of colonic injury in a DNBS-induced colitis model and the expression effects when Compound A was administered were observed by Western blot. Sample preparation and test method were the same as in Example 7. (Sample preparation and test methods) Samples were prepared and tested in the same manner as in Example 7, except that procaspase-1 antibody and caspase antibody (both ad1872, Abcam, diluted 1:1000) were used instead of occludin antibody.

[0212] (Observation of procaspase-1 and caspase-1 expression) By Western blot, we observed increased expression of procaspase-1 in the DNBS-induced colitis model (Figure 6A). In parallel, the induction of colitis in the DNBS-induced colitis model was associated with increased caspase-1 expression at the colonic level (Figure 6B). Compound A (10 mg / kg) administration failed to reduce caspase-1 expression in the inflamed colon (FIG. 6B).

[0213] The anti-inflammatory effect of Compound B on the DNBS model was confirmed in Examples 9 to 14. The test compounds used and the administration methods were as follows.

[0214] (Test compound, administration method, etc.) Immediately after delivery of DNBS, rats were orally administered Compound B (3, 10, 30 mg / kg) or dexamethasone (1 mg / kg). Therefore, the effect of compound B as a remission maintenance therapy can be confirmed in this experiment. Separately from the above groups, compound B (30 mg / kg) was orally administered to control rats. In Examples 9 to 14, the groups simply referred to as "group administered with compound B" or "group administered with dexamethasone" refer to the groups administered with compound B or dexamethasone immediately after delivery of DNBS.

[0215] Observation of the model and preparation of specimens during the test were performed in the same manner as described above for Compound A.

[0216] Example 9 (Changes in body and spleen weight) In the DNBS-induced colitis model, significant weight loss was recorded: 6 days after DNBS administration, the rats lost an average of −15 ± 5 g (−37.6 ± 4.4%) of body weight, whereas the control rats showed a weight gain (+37.5 ± 8.7 g, (+23.5 ± 3.8%)) (Figure 7A). Body weight was also decreased in the group administered with dexamethasone (1 mg / kg), whereas an increase in body weight was observed in the groups administered with compound B (3, 10, and 30 mg / kg) (FIG. 7A). Here, spleen weight is assumed to be an index of systemic inflammation. In the DNBS-induced colitis model, a significant increase in spleen weight (+42%) was observed (FIG. 7B). On the other hand, in the group administered with compound B and dexamethasone, the spleen weight was significantly reduced as compared with the DNBS-induced colitis model (FIG. 7B). As a result, it was confirmed that administration of compound B significantly improved the weight loss and spleen weight increase in the DNBS-induced colitis model.

[0217] Example 10 (Macroscopic Damage) The evaluation of macroscopic damage was carried out in the same manner as in Example 4. (Confirmation of the anti-inflammatory effect of compound B) In the DNBS-induced colitis model, 6 days after DNBS administration, the distal colon appeared thickened and ulcerated, with obvious areas of transmural inflammation, adhesions were frequently seen, the intestine was occasionally dilated, and macroscopic damage accounted for 7.8 ± 1.4 mm. On the other hand, the groups administered with compound B at doses of 3, 10 and 30 mg / kg showed a significant decrease in macroscopic damage score compared to the DNBS-induced colitis model (FIG. 8). The group administered with dexamethasone showed a significant decrease in macroscopic damage score compared to the DNBS-induced colitis model (FIG. 8). As a result, it was confirmed that administration of Compound B significantly improved tissue parameters (macroscopic scores).

[0218] Example 11 (Microscopic Damage) The microscopic damage was evaluated in the same manner as in Example 5. (Confirmation of the anti-inflammatory effect of compound B) Histological examination of colonic specimens from the DNBS-induced colitis model showed clear colitis, complete destruction of the glandular structure, and associated with large areas of mucosal necrosis. The submucosal tissue was thickened with a marked infiltration of inflammatory cells associated with edema and vasodilation. At times, these changes also involved the muscular layer, which also appeared to be thickened. The mucosa and submucosal tissue surrounding the necrotic areas showed inflammation associated with a marked cellular infiltration (Figure 9B) compared to tissue obtained from control rats (Figure 9A). Colon sections from inflamed rats (DNBS-induced colitis model) showed severe damage 6 days after DNBS administration (Figure 9B, Figure 10). Colon tissues from the group administered Compound B showed a dose-dependent reduction in histological damage compared to the colon tissues from the DNBS-induced colitis model (Figure 9C-E, Figure 10). Groups administered Compound B at doses of 10 and 30 mg / kg showed a significant improvement in microscopic scores compared to the colon tissues from the DNBS-induced colitis model (Figure 10). Colon tissues from the group administered dexamethasone 1 mg / kg showed a significant improvement in microscopic scores compared to the colon tissues from the DNBS-induced colitis model (Figure 9F, Figure 10).

[0219] Example 12 (TNF and IL-1β Assays) Inflammatory cytokines (TNF and IL-1β) in colonic tissue during colonic injury in a DNBS-induced colitis model and when Compound B was administered were evaluated. Preparation of samples for the evaluation and evaluation of tissue proinflammatory indicators (TNF, IL-1β) were performed in the same manner as in Example 6. (Confirmation of the anti-inflammatory effect of compound B) Colonic damage in the DNBS-induced colitis model was associated with a significant increase in TNF (from 4.5±0.4 to 12.1±1.7 pg / mg). Compound B did not affect this inflammatory index (FIG. 11A). In contrast, dexamethasone 1 mg / kg was completely prevented (FIG. 11A). The DNBS-induced colitis model was also associated with a significant increase in IL-1β (from 9.5±5.4 to 32.7±1.8 pg / mg) (FIG. 11B). Compound B (3, 10, and 30 mg / kg) and dexamethasone (1 mg / kg) treatment groups significantly reduced tissue IL-1β compared to the DNBS-induced colitis model (FIG. 11B). This indicates that compound B has the effect of reducing IL-1β, an inflammatory cytokine.

[0220] Example 13 (Expression of Occludin in Colon Tissue) Western blot was used to observe the expression effect of occludin (an integral membrane protein located in tight junctions) in colonic tissues during colonic injury in a DNBS-induced colitis model, and the expression effect when Compound B was administered. Sample preparation and test method were the same as in Example 7.

[0221] (Observation of occludin expression) It was shown that occludin was significantly decreased in the colonic mucosa of the DNBS-induced colitis model compared with control rats (Figure 12). In the groups administered with compound B (10 mg / kg) (FIG. 12) or dexamethasone (1 mg / kg, not shown), the expression of occludin in the inflamed tissue was increased as compared to the DNBS-induced colitis model. These results indicate that compound B counteracts the decrease in tight junction occludin observed in the DNBS-induced colitis model, and therefore contributes to maintaining the integrity of colonic tissue.

[0222] Example 14 (Expression of procaspase-1 and caspase-1 in colonic tissue) The expression effects of procaspase-1 and caspase-1 in colonic tissues at the time of colonic injury in the DNBS-induced colitis model and the expression effects when compound B was administered were observed by Western blot. Sample preparation and test method were the same as in Example 8.

[0223] (Observation of procaspase-1 and caspase-1 expression) By Western blot, we observed increased expression of procaspase-1 in the DNBS-induced colitis model (Figure 13A). In parallel, induction of colitis in the DNBS-induced colitis model was associated with increased caspase-1 expression at the colonic level (Figure 13B). In the group administered compound B (10 mg / kg), the expression of caspase-1 in the inflamed colon was shown to be reduced compared to the DNBS-induced colitis model (FIG. 13B). [Industrial Applicability]

[0224] The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for remission induction therapy or remission maintenance therapy for the above-mentioned inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for remission induction therapy or remission maintenance therapy for Crohn's disease or the ulcerative colitis. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for inhibiting or reducing adhesions or ulcers in intestinal tissues associated with irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing transmural inflammatory areas in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing histological damage in intestinal tissues caused by the irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for inhibiting or reducing mucosal necrosis in intestinal tissues associated with irritable bowel syndrome or inflammatory bowel disease. The pharmaceutical agent of the present invention can be used as a pharmaceutical agent for suppressing or reducing cell infiltration in intestinal tissues of irritable bowel syndrome or inflammatory bowel disease. The medicament of the present invention can be used as a medicament for protecting or maintaining the mucosa in intestinal tissues in patients with irritable bowel syndrome or inflammatory bowel disease.

Claims

[Claim 1] A pharmaceutical for preventing or treating irritable bowel syndrome or inflammatory bowel disease, comprising as an active ingredient a compound having P2X4 receptor antagonistic activity or a pharma- ceutical acceptable salt thereof.

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