Medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease

Abstract

The present application relates to a medicine for preventing or treating irritable bowel syndrome or inflammatory bowel disease, the medicine comprising, as an active ingredient, a compound having P2X4 receptor antagonistic action or a pharmaceutically acceptable salt of the compound.

Description

TECHNICAL FIELD

[0001] The present application relates to a medicament for preventing or treating irritable bowel syndrome and inflammatory bowel disease. BACKGROUND

[0002] Irritable bowel syndrome (IBS) is a typical functional gastrointestinal disorder and is a chronic disorder whose core symptoms are accompanied by abdominal pain, abdominal discomfort, and defecation changes associated therewith, such as diarrhea and constipation. Psychological factors or stress can exacerbate the symptoms of irritable bowel syndrome. According to the ROME III diagnostic criteria, it is recommended that the symptoms be classified into diarrhea type, constipation type, mixed type which is a combination of features of both diarrhea type and constipation type, and undifferentiated type which does not satisfy any of these three types, and IBS is subdivided into these types according to the form of stool (25% or more of the whole stool).

[0003] As a pharmaceutical treatment for irritable bowel syndrome, for example, tricyclic antidepressants are effective for diarrhea type, however, can cause side effects such as drowsiness, constipation, or dry mouth. A 5-HT3 antagonist has been used as a drug for constipation-dominant irritable bowel syndrome in foreign countries. In addition, a drug having a 5-HT4 receptor stimulating action or a 5-HT4 receptor stimulating and 5-HT3 receptor stimulating action is effective for abdominal pain and constipation in foreign countries. However, 5-HT drugs are limited in use due to side effects. Therefore, the pharmaceutical treatment for irritable bowel syndrome has been extremely limited to date (non-patent literature 1).

[0004] Inflammatory bowel disease (IBD) is a multifactorial immune disorder that can lead to chronic, recurrent inflammation of the intestinal tract. Inflammatory bowel disease is roughly classified into Crohn's disease (CD) and ulcerative colitis (UC), and into simple ulcer of the small intestine and nonspecific multiple ulcers, etc. (non-patent literature 2) which are called inflammatory bowel disease in the narrow sense.

[0005] Crohn's disease and ulcerative colitis share common symptoms of diarrhea, bloody stool, abdominal pain, etc. in the clinic, however, the etiology of inflammatory bowel disease is currently unknown.

[0006] However, it is considered that the breakdown of the immune system and / or unbalanced interaction with microorganisms in the case where a host that can be genetically affected is induced by specific environmental factors is associated with the onset of chronic enteritis. To date, it has been considered that Th1 cells play an important role in the etiology associated with chronic inflammation in the intestine, particularly Crohn's disease, and that Th2 cells play an important role in ulcerative colitis.

[0007] In addition, activation of Thl7 cells and imbalance between Thl7 / regulatory T (Treg) cells have recently been considered as an important element in the development of inflammation in the intestine (Non-Patent Document 3).

[0008] Examples of the cause of the increase in the incidence of inflammatory bowel disease can mention insufficiency of effectiveness and / or safety of conventional drugs (corticosteroids, immunosuppressants, and salicylates). Examples of other treatment options can mention treatment using biotechnological drugs. However, even if the treatment exhibits a certain degree of effectiveness, the treatment is accompanied by serious side effects.

[0009] Accordingly, efforts are currently being made to find new drugs from which a positive benefit / risk profile is obtained, instead of being satisfied with the drug treatment of IBD (Non-Patent Document 4).

[0010] In such a case, for many years, a number of evidences have been reported that ATP plays an important role in the development of immune / inflammatory responses. From these reports, it has been shown that P2X4 receptors are involved in mediating such ATP-modulated activation. Specifically, P2X4 receptors maintain proinflammatory responses, which maintain the release of proinflammatory cytokines such as IL-1β and IL-18. In addition, there are several evidences that P2X4 is involved in various immune / inflammatory pathologies, such as post-ischemic inflammation, rheumatoid arthritis, respiratory inflammatory asthma, nervous system degenerative diseases, and metabolic syndrome (Non-Patent Documents 5 to 7).

[0011] As described above, conventional drugs or treatments in Non-Patent Documents 1 to 7 can also be used as drugs for treating irritable bowel syndrome or inflammatory bowel disease, however, it is known that the effects thereof are weak, or the drugs can cause certain side effects, and thus the drugs are not effective as drugs for treating irritable bowel syndrome or inflammatory bowel disease.

[0012] Patent Document 1 discloses P2X4 receptor antagonists.

[0013] However, the compounds described in the examples of Patent Document 1 are selective serotonin reuptake inhibitors such as Paroxetine, Fluoxetine, and the like, and have a structure completely different from the compounds of the present application, which are benzodiazepine derivative compounds. In addition, only the results of experiments using a neuropathic pain pathology model in which nerve injury was performed (L5 spinal nerve injury model) were shown, and it was not determined whether P2X4 receptor antagonists have a therapeutic effect in irritable bowel syndrome or inflammatory bowel disease.

[0014] In addition, Patent Literature 2 also discloses a compound exhibiting P2X4 receptor antagonistic action, but as in Patent Literature 1, only an effect exhibited by a neuropathic pain model is shown, and it is not clear whether the compound has a therapeutic effect in irritable bowel syndrome or inflammatory bowel disease.

[0015] In addition, the present applicant has also filed patent applications related to P2X4 receptor antagonists as in Patent Literatures 3 to 9, but it is not clear in all the applications whether the P2X4 receptor antagonists have a therapeutic effect in irritable bowel syndrome or inflammatory bowel disease.

[0016] Bibliographic List

[0017] Patent Literature

[0018] Patent Literature 1: WO2008 / 020651A

[0019] Patent Literature 2: WO2010 / 093061A

[0020] Patent Literature 3: WO2008 / 023847A

[0021] Patent Literature 4: WO2012 / 008478A

[0022] Patent Literature 5: WO2012 / 014910A

[0023] Patent Literature 6: WO2012 / 017876A

[0024] Patent Literature 7: WO2013 / 105608A

[0025] Patent Literature 8: WO2015 / 005468A

[0026] Patent Literature 9: WO2015 / 005467A

[0027] Non-Patent Literature

[0028] Non-Patent Literature 1: Japanese Society of Gastroenterology Clinical Practice Guidelines for Functional Dyspepsia 2014 Irritable Bowel Syndrome (IBS)

[0029] Non-Patent Literature 2: The Journal of the Japanese Society of Internal Medicine 98(1), 5-11, 2009-01-10

[0030] Non-patent literature 3: Kim DH and Cheon JH (2017) Pathogenesis of Inflammatory Bowel Disease and Recent Advances in Biologic Therapies. Immune network 17: 25-40.

[0031] Non-patent literature 4: Katz S (2007) "Mind the Gap": an unmet need for new therapy in IBD. Journal of clinical gastroenterology 41: 799-809.

[0032] Non-patent literature 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.

[0033] Non-patent literature 6: Sakaki H, Fujiwaki T, Tsukimoto M, Kawano A, Harada H and Kojima S (2013) P2X4 receptor regulates P2X7 receptor-dependent IL-1 beta and IL-18 release in mouse bone marrow-derived dendritic cells. Biochemical and biophysical research communications 432: 406-411.

[0034] Non-patent literature 7: Suurvali J, Boudinot P, Kanellopoulos J and Ruutel Boudinot S (2017) P2X4: A fast and sensitive purinergic receptor. Biomedical journal 40: 245-256.

[0035] Non-patent literature 8: Antonioli L, et al. Inhibition of Adenosine Deaminase Attenuates Inflammation in Experimental Colitis. J Pharmacol Exp Ther. 2007; 322(2): 435-42

[0036] Non-patent literature 9: Antonioli L, et al. The Blockade of Adenosine Deaminase Ameliorates Chronic Experimental Colitis through the Recruitment of Adenosine A2A and A3 Receptors. J Pharmacol Exp Ther. 2010; 335(2): 434-42

[0037] Non-patent literature 10: Pellegrini C, et al. Front Pharmacol. 2018; 9: 1405

[0038] Non-patent literature 11: JOHN L. Wallace and CATHERINE M. Keenan. An orally active inhibitor of leukotriene synthesis accelerates healing in a rat model of colitis. The American journal of physiology 1990; 258(4 Pt 1): G527-34.

[0039] Non-patent document 12: Fornai M et al. Differential Role of Cyclooxygenase 1 and 2 Isoforms in the Modulation of Colonic Neuromuscular Function in Experimental Inflammation. J Pharmacol Exp Ther. 2006; 317(3):938-45. SUMMARY

[0041] PROBLEMS TO BE SOLVED BY THE INVENTION

[0042] An object of the present application is to provide a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease.

[0043] SOLUTION TO THE PROBLEM

[0044] In order to solve the above problem, the present inventors conducted intensive studies, and as a result, the present inventors found that a compound represented by General Formulae (A) to (BII) having P2X4 receptor antagonistic action is useful for preventing or treating irritable bowel syndrome or inflammatory bowel disease, thereby completing the present application.

[0045] That is, the present application provides a medicament for preventing and / or treating irritable bowel syndrome or inflammatory bowel disease, the medicament comprising, as an active ingredient, a compound having P2X4 receptor antagonistic action or a pharmaceutically acceptable salt thereof.

[0046] A compound represented by, for example, the following General Formulae (A) to (BII) can be used as the compound having P2X4 receptor antagonistic action. More preferably, a compound represented by the following General Formula (BI) or (BII) can be used as the compound having P2X4 receptor antagonistic action.

[0047] The medicament of the present application can be used, for example, in the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease, and in particular, for the prevention or treatment of Crohn's disease in inflammatory bowel disease or the prevention or treatment of ulcerative colitis in inflammatory bowel disease. Furthermore, the medicament of the present application can be used, for example, in remission induction therapy or remission maintenance therapy of inflammatory bowel disease. Furthermore, the medicament of the present application can be used, for example, in remission induction therapy or remission maintenance therapy of Crohn's disease or ulcerative colitis.

[0048] Furthermore, the medicament of the present application can be used, for example, in the inhibition or reduction of adhesion or ulceration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Furthermore, the medicament of the present application can be used, for example, in the inhibition or reduction of transmural inflammatory areas in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0049] Further, the medicament of the present application can be used, for example, to inhibit or reduce histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Further, the medicament of the present application can be used, for example, to inhibit or reduce mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Further, the medicament of the present application can be used, for example, to inhibit or reduce cell infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Further, the medicament of the present application can be used, for example, to protect or maintain the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0050] From another viewpoint, the present application provides: the use of a compound having P2X4 receptor antagonistic action or a pharmaceutically acceptable salt thereof for the manufacture of a medicament; and a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease, particularly a method for preventing or treating Crohn's disease in inflammatory bowel disease, a method for preventing or treating ulcerative colitis in inflammatory bowel disease, remission induction therapy or remission maintenance therapy of inflammatory bowel disease, remission induction therapy or remission maintenance therapy in Crohn's disease or ulcerative colitis, a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for inhibiting or reducing adhesion or ulcer in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for inhibiting or reducing transmural inflammation area in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, a method for preventing or treating irritable bowel syndrome or inflammatory bowel disease for inhibiting or reducing cell infiltration in the 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 the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, the method comprising the step of administering a compound having P2X4 receptor antagonistic action or a pharmaceutically acceptable salt thereof to a mammal (including a human) in a dose effective for preventing or treating irritable bowel syndrome or inflammatory bowel disease.

[0051] Advantages of the Invention

[0052] The drug of the present application is used as a drug for preventing or treating irritable bowel syndrome or inflammatory bowel disease, particularly as a drug for preventing or treating Crohn's disease in inflammatory bowel disease or as a drug for preventing or treating ulcerative colitis in inflammatory bowel disease, in addition, as a drug for remission induction therapy or remission maintenance therapy of inflammatory bowel disease, or as a drug for remission induction therapy or remission maintenance therapy of Crohn's disease or ulcerative colitis, in addition, the drug is used as, for example, a drug for inhibiting or reducing adhesion or ulceration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or as a drug for inhibiting or reducing transmural inflammatory areas in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, and in addition, the drug is also used as, for example, a drug for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, as a drug for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, as a drug for inhibiting or reducing cell infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, or as a drug for protecting or maintaining the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease, each of which is predicted to be very effective. BRIEF DESCRIPTION OF DRAWINGS

[0053] Figure 1 is a graph showing the comparison of the increase or decrease in (A) body weight and (B) pancreas weight in control rats and DNBS-induced colitis models, and further comparison thereof in the model and orally administering Compound A to control rats, and in the model and orally administering Compound A or dexamethasone to the model.

[0054] Figure 2 is a graph of the macroscopic damage of the colon tissue in control rats and DNBS-induced colitis models, and further comparison thereof in the model and orally administering Compound A to control rats, and in the model and orally administering Compound A or dexamethasone to the model.

[0055] Figure 3 is a graph showing the comparison of the microscopic damage (histological damage) of the colon tissue in control rats and DNBS-induced colitis models, and further comparison thereof in the model and orally administering Compound A to control rats, and in the model and orally administering Compound A or dexamethasone to the model.

[0056] Figure 4 is a graph showing the comparison of the correlation with proinflammatory cytokines (A) TNF and (B) interleukin-1β in the colon tissue of control rats and the colon tissue of DNBS-induced colitis models subjected to colon damage, and further comparison thereof in the model and orally administering Compound A to control rats, and in the model and orally administering Compound A or dexamethasone to the model.

[0057] Figure 5 Figure 2 is a graph showing a comparison of the expression effect of the closure protein in the colon tissue of control rats and DNBS-induced colitis model subjected to colon injury and further comparison thereof in the model and in the case where Compound A is orally administered to the model.

[0058] Figure 6 Figure 3 is a graph showing a comparison of (A) caspase pro-1 expression effect and (B) caspase-1 expression effect in the colon tissue of control rats and DNBS-induced colitis model subjected to colon injury and further comparison thereof in the model and in the case where Compound A is orally administered to the model.

[0059] Figure 7 Figure 4 is a graph showing a comparison of (A) body weight and (B) increase or decrease in pancreas weight in control rats and DNBS-induced colitis model and further comparison thereof in the model and in the case where Compound B is orally administered to the control rats and in the case where Compound B or dexamethasone is orally administered to the model.

[0060] Figure 8 Figure 5 is a graph showing a comparison of macroscopic injury of colon tissue in control rats and DNBS-induced colitis model and further comparison thereof in the model and in the case where Compound B is orally administered to the control rats and in the case where Compound B or dexamethasone is orally administered to the model.

[0061] Figure 9 Figure 6 is a graph showing a further comparison of microscopic injury (histological injury) of colon tissue by histological examination of colon samples in control rats, DNBS-induced colitis model, and model to which Compound B or dexamethasone is orally administered.

[0062] Figure 10 Figure 7 is a graph showing a comparison of microscopic injury (histological injury) of colon tissue in control rats and DNBS-induced colitis model and further comparison thereof in the model and in the case where Compound B is orally administered to the control rats and in the case where Compound B or dexamethasone is orally administered to the model.

[0063] Figure 11 Figure 8 is a graph showing a comparison of the association with proinflammatory cytokines (A) TNF and (B) interleukin-1 beta in the colon tissue of control rats and DNBS-induced colitis model subjected to colon injury and further comparison thereof in the model and in the case where Compound B is orally administered to the control rats and in the case where Compound B or dexamethasone is orally administered to the model.

[0064] Figure 12is a graph showing a comparison of the expression effect of occludin in the colon tissue of control rats and DNBS-induced colitis model subjected to colon injury and further comparison thereof in the model and in the case where Compound B is orally administered to the model.

[0065] Figure 13 is a graph showing a comparison of the expression effect of (A) procaspase-1 and (B) caspase-1 in the colon tissue of control rats and DNBS-induced colitis model subjected to colon injury and further comparison thereof in the model and in the case where Compound B is orally administered to the model.

[0066] In this, Figures 1 to 8 and Figures 10 to 13 the symbol "*" indicates that there is a significant difference (P<0.05) in the comparison result with control rats, and the symbol "a" indicates that there is a significant difference (P<0.05) in the comparison result with DNBS-induced colitis model.

[0067] Description of Embodiments

[0068] The drug of the present application can be used as a drug for preventing or treating irritable bowel syndrome or inflammatory bowel disease, and also can be used as a drug for the following use.

[0069] The drug of the present application can be used as a drug for preventing or treating Crohn's disease or ulcerative colitis in inflammatory bowel disease.

[0070] The drug of the present application can be used as a drug for remission induction therapy or remission maintenance therapy of inflammatory bowel disease.

[0071] The drug of the present application can be used as a drug for remission induction therapy or remission maintenance therapy of Crohn's disease or ulcerative colitis.

[0072] The drug of the present application can be used as a drug for inhibiting or reducing adhesion or ulcer in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0073] The drug of the present application can be used as a drug for inhibiting or reducing transmural inflammatory area in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0074] The drug of the present application can be used as a drug for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0075] The drug of the present application can be used as a drug for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0076] The drug of the present application can be used as a drug for inhibiting or reducing cell infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0077] The medicament of the present application can be used as a medicament for protecting or maintaining the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0078] As another aspect, the medicament of the present application can be used as a medicament for the following use.

[0079] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by adhesion or ulcer in the intestinal tissue.

[0080] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by development of transmural inflammatory area in the intestinal tissue.

[0081] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by histological damage in the intestinal tissue.

[0082] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by necrosis or damage of the mucosa in the intestinal tissue.

[0083] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by cellular infiltration in the intestinal tissue.

[0084] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by increase of proinflammatory cytokine.

[0085] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by increase of interleukin-1β.

[0086] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by colonic damage and increase of proinflammatory cytokine.

[0087] The medicament of the present application can be used as a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by colonic damage and increase of interleukin-1β.

[0088] In the present specification, the term "prevention" is a concept including prevention of onset before the outbreak of a "disease" or "abnormality" symptom, state or disease, and an action or method therefor.

[0089] In the present specification, the term "treatment" is a concept which includes elimination, complete cure, cure or alleviation of a "diseased" or "abnormal" symptom, state or disease and an act or method therefor, inhibition of aggravation of a "diseased" or "abnormal" symptom, state or disease and an act or method therefor, and improvement. Here, the term "improvement" is a concept which includes bringing a "diseased" or "abnormal" symptom, state or disease close to a "healthy" or "normal" state or an act or method therefor, and bringing a "diseased" or "abnormal" symptom, state or disease to a "healthy" or "normal" state or an act or method therefor. Thus, in one embodiment, the term "improvement" includes the concept that a value according to an index of a "diseased" or "abnormal" symptom or state becomes smaller or larger to approach a normal value or becomes a normal value. Furthermore, the term "inhibition" is a concept which includes halting or slowing down the aggravation or progression of a symptom, state or disease and thus improving the symptom, state or disease or an act or method therefor. Here, the term "improvement" has the above-mentioned meaning. The expression "aggravation or progression of a symptom, state or disease" includes aggravation or progression of a "diseased" or "abnormal" symptom, state or disease and aggravation or progression of a symptom, state or disease from a "healthy" or "normal" state to a "diseased" or "abnormal" state. In one embodiment, the term "inhibition" is halting or slowing down the aggravation or progression of a symptom, state or disease or an act or method therefor. In another embodiment, the term "inhibition" means halting or slowing down the aggravation or progression of a symptom, state or disease.

[0090] In one embodiment, the term "treatment" is elimination, complete cure, cure or alleviation of a "diseased" or "abnormal" symptom, state or disease and an act or method therefor. In another embodiment, the term "treatment" is elimination, complete cure, cure or alleviation of a "diseased" or "abnormal" symptom, state or disease. In the present specification, the term "relief-inducing treatment" means a treatment method performed for alleviation of a "diseased" or "abnormal" symptom, state or disease during the onset or aggravation of the symptom, state or disease, particularly during the acute phase of the aggravation. Furthermore, the term "relief-maintaining treatment" means a treatment method performed for maintaining the relieved state of a symptom, state or disease or for preventing the recurrence of a symptom, state or disease. In one embodiment, the "relief-inducing treatment" is a treatment method performed for alleviation of irritable bowel syndrome or inflammatory bowel disease or a symptom accompanying irritable bowel syndrome or inflammatory bowel disease, and the term "relief-maintaining treatment" means a treatment method performed for maintaining the relieved state of irritable bowel syndrome or inflammatory bowel disease or a symptom accompanying irritable bowel syndrome or inflammatory bowel disease, or a treatment method performed for preventing the recurrence of irritable bowel syndrome or inflammatory bowel disease or a symptom accompanying irritable bowel syndrome or inflammatory bowel disease.

[0091] In the present specification, the expression "protection of a mucous membrane" means maintenance or protection of the tissue or function of a normal mucous membrane, or inhibition of impairment or failure of the tissue or function of a mucous membrane. Here, the term "inhibition" has the above-mentioned meaning. The expression "maintenance of a mucous membrane" means protection of the tissue or function of a normal mucous membrane, or inhibition of deterioration of the tissue or function of a mucous membrane. Here, the term "inhibition" has the above-mentioned meaning.

[0092] In the present specification, a symptom, a state or a disease, a value used as an index for these, or a state or function of a mucous membrane tissue can be evaluated by comparison before and after administration of the medicament provided by the present application or by comparison between a group to which a placebo or a control not containing the medicament provided by the present application is administered and a group to which the medicament provided by the present application is administered.

[0093] In the present specification, the term "inhibition" can be used as a term meaning stoppage or slowing of an increase in the amount supplied in a living body.

[0094] In the present specification, "maintenance of the health of a large intestinal tissue" means maintenance or protection of a normal large intestinal tissue or its function, or inhibition of impairment or failure of the large intestinal tissue or its function. Here, the term "inhibition" has the above-mentioned meaning. The term "aiding" means exhibiting an ability to change a specific state or function to a desired state or function. The expression "aiding maintenance of the health of a large intestinal tissue" means, in one embodiment, exhibiting an ability to change a damaged state and its function to a normal state of a large intestinal tissue and its function due to some impairment of the large intestinal tissue.

[0095] A compound represented by the following general formulae (A) to (BII) or a pharmaceutically acceptable salt thereof can be used as an active ingredient of the medicament of the present application.

[0096] The symbols and the like used in the following table 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.

[0097] In the following table and the like, a substituent can be labeled together with a position number indicating a position of the substituent. In addition, in order to distinguish position numbers showing the same position from each other in a chemical formula, for the sake of convenience, one position number can be expressed with an apostrophe "'", but the apostrophe can not be used to express the position number as long as a definite structure of a compound name can be indicated.

[0098] (A-1) A compound (A) represented by the following general formula A or a pharmaceutically acceptable salt thereof:

[0099]

[0100] (In the formula, R 1Aa 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 and substituted with 1 to 3 halogen atoms, or an alkyl group having 1 to 3 carbon atoms and substituted with a phenyl group;

[0101] R 2A and R 3A may 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 and substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms and 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 and 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 (alkoxy moiety having 1 to 8 carbon atoms), a carbamoyl group, an alkylsulfanyl 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;

[0102] 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 and substituted with 1 to 3 halogen atoms, or an alkyl group having 1 to 3 carbon atoms and substituted with a phenyl group; and

[0103] W A represents a five- or six-membered heterocyclic ring containing 1 to 4 nitrogen atoms as a member of the ring, which can have a substituent.

[0104] In General Formula (A), examples of the alkyl group having 1 to 8 carbon atoms represented by R 1A , R 2A , R 3A , R 4A , and R 5A may include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, and the like.

[0105] Examples of the alkenyl group having 2 to 8 carbon atoms represented by R 1A may include an allyl group, and the like.

[0106] Examples of the aryl group represented by R1A R 2A R 3A R 4A and R 5A Or R 11A R 12A R 13A R 14A and R 15A Examples of alkyl groups having 1 to 8 carbon atoms and being substituted by 1 to 3 halogen atoms may include methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, tert-butyl groups, etc., substituted by 1 to 3 halogen atoms such as fluorine, chlorine and bromine atoms, and preferred examples may include trifluoromethyl groups, chloromethyl groups, 2-chloroethyl groups, 2-bromoethyl groups, 2-fluoroethyl groups, etc.

[0107] By R 1A R 4A and R 5A Examples of alkyl groups having 1 to 3 carbon atoms and being replaced by phenyl groups may include benzyl groups, etc.

[0108] By R 2A and R 3A Examples of alkoxy groups having 1 to 8 carbon atoms may include methoxy groups, ethoxy groups, propoxy groups, isopropoxy groups, butoxy groups, isobutoxy groups, tert-butoxy groups, pentoxy groups, hexoxy groups, etc.

[0109] By R 2A and R 3A Examples of alkoxy groups having 1 to 8 carbon atoms and being substituted by 1 to 3 halogen atoms may include methyl groups, ethyl groups, propyl groups, isopropyl groups, butyl groups, tert-butyl groups, etc., substituted by 1 to 3 halogen atoms such as fluorine, chlorine and bromine atoms, and preferred examples may include trifluoromethoxy groups, 2-chloroethoxy groups, 2-bromoethoxy groups, 2-fluoroethoxy groups, etc.

[0110] By R 2A and R 3A Examples of representative halogen atoms may include fluorine atoms, chlorine atoms, bromine atoms, etc.

[0111] By R 2A and R 3A Examples of alkylamino groups having 1 to 8 carbon atoms may include methylamino groups, ethylamino groups, etc.

[0112] By R 2A and R 3AExamples of dialkylamino groups having 1 to 8 carbon atoms may include dimethylamino groups, diethylamino groups, etc.

[0113] By R 2A and R 3A Examples of acylamino groups having 2 to 8 carbon atoms may include acetylamino groups.

[0114] By R 2A and R 3A Examples of acylamino groups having 2 to 8 carbon atoms and being substituted with 1 to 3 halogen atoms may include trifluoromethyl carbonylamino groups.

[0115] By R 2A and R 3A Examples of alkylsulfonylamino groups having 1 to 8 carbon atoms may include methylsulfonylamino groups.

[0116] By R 2A and R 3A Examples of acyl groups having 2 to 8 carbon atoms may include acetyl groups.

[0117] By R 2A and R 3A Examples of representative alkoxycarbonyl groups (the alkoxy moiety has 1 to 8 carbon atoms) may include methoxycarbonyl groups, ethoxycarbonyl groups, etc.

[0118] By R 2A and R 3A Examples of alkyl thio groups having 1 to 8 carbon atoms may include methyl thio groups.

[0119] By R 2A and R 3A Examples of alkyl sulfinyl groups having 1 to 8 carbon atoms may include methyl sulfinyl groups.

[0120] By R 2A and R 3A Examples of alkyl sulfonyl groups having 1 to 8 carbon atoms may include methyl sulfonyl groups.

[0121] By W A Examples of representative five- or six-membered heterocycles (which may have substituents) containing one to four nitrogen atoms as ring members can include tetrazolium, 1,2,4-triazole, 1,2,3-triazole, 1,2,4- diazole, pyrazole, imidazole azole, isotonic Azole, pyrrole, thiazole, pyridine, and pyrrolidine.

[0122] Included in WA Examples of substituents in a five- or six-membered heterocycle containing 1 to 4 nitrogen atoms as a member of the ring (which can have a substituent) represented by R

[0123] R in General Formula (A) 2A and R 3A may have 1 to 3 substituents which are the same or different in the benzene ring substituted by R 2A and R 3A may have 1 to 3 substituents which are the same or different in the benzene ring substituted by R

[0124] As the compound represented by General Formula (A), the following compounds are preferable.

[0125] (A-2) The compound according to (A-1), wherein W A represents tetrazole, 1,2,4-triazole, 1,2,3-triazole, 1,2,4- diazole, pyrazole, or imidazole, which can have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and substituted by 1 to 3 halogen atoms, a halogen atom, a cyano group, an oxo group, and a thio group.

[0126] (A-3) The compound according to (A-1) or (A-2), wherein W A represents tetrazole, 1,2,4-triazole, or 1,2,3-triazole, which can have a substituent selected from the group consisting of an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and substituted by 1 to 3 halogen atoms, a halogen atom, and a cyano group.

[0127] (A-4) The compound according to any one of (A-1) to (A-3), wherein W A represents 5-oxo-1,2,4- diazole, or 5-thioxo-1,2,4- diazole.

[0128] (A-5) The compound according to any one of (A-1) to (A-4), wherein W A represents tetrazole.

[0129] (A-6) The compound according to any one of (A-1) to (A-5), wherein R 1A represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.

[0130] (A-7) The compound according to any one of (A-1) to (A-6), wherein R 1A represents a hydrogen atom.

[0131] (A-8) The compound according to any one of (A-1) to (A-7), wherein R 4A represents a hydrogen atom, and R 5A represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.

[0132] (A-9) The compound according to any one of (A-1) to (A-8), wherein R 4A and R 5A both represent a hydrogen atom.

[0133] (A-10) The compound according to any one of (A-1) to (A-9), wherein R 2A represents 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 (alkoxy moiety having 1 to 8 carbon atoms).

[0134] (A-11) The compound according to any one of (A-1) to (A-10), wherein R 2A represents a hydrogen atom.

[0135] (A-12) The compound according to any one of (A-1) to (A-11), wherein R 3A represents 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 (alkoxy moiety having 1 to 8 carbon atoms).

[0136] (A-13) The compound according to any one of (A-1) to (A-12), wherein R 3A represents a hydrogen atom.

[0137] R 2A and R 3AIn the case where R represents an amino group or the like, examples of the pharmaceutically acceptable salt of the compound represented by General Formula (A) can include a hydrochloride and the like. In addition, in General Formula (A), R 2A and R 3A In the case where R represents a carboxyl group, examples of the pharmaceutically acceptable salt of the compound represented by General Formula (A) can include alkali metal salts such as sodium salts, potassium salts and lithium salts.

[0138] Typical compounds included in the compound represented by General Formula (A) are as follows.

[0139] <Typical Compound A-100>

[0140]

[0141] (the substituent positions of R 1A , R 4A , R 5A and W A and W A in the formula are shown in Tables 1 to 3)

[0142] In Tables 1 to 3, the substituent positions of W A indicate the substituent positions on the benzene ring. That is, positions 2, 3 and 4 in the table correspond to positions 2', 3' and 4', respectively, in the formula of Typical Compound A-100.

[0143] [Table 1]

[0144] [R 1A ]]> W A substitution position [WC A ]]> [R 4A / R 5A ]]> H 2- 1H-tetrazol-5-yl H / H H 3- 1H-tetrazol-5-yl H / H H 3- (1-methyl-lH-tetrazol)-5-yl H / H H 4- 1H-tetrazol-5-yl H / H Me 3- 1H-tetrazol-5-yl H / H Me 3- 1H-tetrazol-5-yl Me / H Bn 3- 1H-tetrazol-5-yl H / H H 3- 1H-tetrazol-1-yl H / H H 3- 1H-tetrazol-1-yl Me / Me H 3- (1,2,3-triazol)-5-yl H / H H 3- (1,2,4-triazol)-3-yl H / H H 4- (1,2,4-triazol)-3-yl H / H

[0145] [Table 2]

[0146]

[0147]

[0148] [Table 3]

[0149]

[0150] <Typical Compound A-200>

[0151]

[0152] (the substituent positions of R 1A , R 2A , R 4A , R 5A and W A and W A in the formula are shown in Tables 4 and 5)

[0153] In Tables 4 and 5, the substituent positions of W AThe substitution position of W and W indicates the substitution position on the phenyl ring. That is, positions 2, 3 and 4 in the table correspond to positions 2', 3' and 4' in the formula of Typical Compound A-200, respectively.

[0154] [Table 4]

[0155]

[0156] [Table 5]

[0157]

[0158]

[0159] <Typical Compound A-300>

[0160]

[0161] (R 1A , R 2A , R 3A , R 4A , R 5A and W A and W A in the formula are as defined above)

[0162] In Tables 6 and 7, the substitution position of W A indicates the substitution position on the phenyl ring. That is, positions 3 and 4 in the table correspond to positions 3' and 4' in the formula of Typical Compound A-300, respectively.

[0163] [Table 6]

[0164]

[0165]

[0166] [Table 7]

[0167]

[0168] (B-1) a compound represented by the following general formula (BI) or a pharmaceutically acceptable salt thereof:

[0169]

[0170] (in the formula, R 1B and R 2BThese can be the same or different, and represent hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms), substituted phenyl groups, substituted pyridyl groups, or aralkyl groups (aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 8 carbon atoms), or

[0171] R 1B and R 2B They can combine with the benzene rings they are attached to to form fused rings, said fused rings being selected from naphthalene rings, quinoline rings, isoquinoline rings, tetrahydronaphthalene rings, indenium rings, tetrahydroquinoline rings, and tetrahydroisoquinoline rings, and are composed of R 1B and R 2B The ring formed by their combination with R 1B and R 2B The combined carbon atoms may be substituted together by 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, cycloalkyl groups having 3 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms), and aralkyl groups (aryl moiety having 6 to 10 carbon atoms, and alkylene moiety having 1 to 8 carbon atoms).

[0172] R 3B and R 4BThese can be the same or different, and represent hydrogen atoms, alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms), or aralkyl groups (aryl moiety having 6 to 10 carbon atoms, and alkylene moiety having 1 to 8 carbon atoms).

[0173] R 5B Representing 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 moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms),

[0174] R 6B and R 7B They can 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.

[0175] X B Represents C, CH, or N.

[0176] Y B Represents N, NH, or C (=O),

[0177] The premise is that when X B When Y is N, B Not N or NH, and

[0178] When X B When Y is C or CH B Not C (=O),

[0179] A double line consisting of solid and dashed lines represents a single or double bond.

[0180] Z B Represents oxygen or sulfur atoms.

[0181] AB represents a bond or represents a phenyl ring, a pyridyl ring, a thiophene ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, or an indole ring, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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, and a pyridyl group,

[0182] B B represents N(R 8B )C(=O), NHCONH, CON(R 9B ), NHC(=S)NH, N(R 10B )SO2, SO2N(R 11B ), or OSO2, wherein

[0183] R 8B , R 9B , R 10B , and R 11B 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, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms),

[0184] D B represents a bond or represents an alkylene chain having 1 to 6 carbon atoms, which can have 1 to 4 identical or different substituents, and can also have a double bond, the substituents being selected from the group consisting of, as substituents, 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, and an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms),

[0185] E B represents O, S, NR 12B , or a bond, wherein

[0186] 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 and substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms and substituted with a hydroxyl group, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms),

[0187] G B represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, indole, benzofuran, pyrrole, pyridine, or pyrimidine, which can have 1 to 4 identical 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 and substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms and 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 (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group which can be substituted, a pyridyl group which can be substituted, an imidazolyl group which can be substituted, a thiazolyl group which can be substituted, and

[0188] m B represents an integer of 0 to 5,

[0189] provided that when R 1B and R 2B are not bound together to form a ring, these compounds are excluded in which X B is C, Y B is N, the double line consisting of a solid line and a dotted line is a double bond, Z B is an oxygen atom, A B is a benzene ring, m B is 0, B B is C(=O)NH, E B is an atomic bond, and G B is a phenyl group).

[0190] (B-2) a compound represented by the following general formula (BII) or a pharmaceutically acceptable salt thereof:

[0191] (B-2) a compound represented by the following general formula (BII) or a pharmaceutically acceptable salt thereof:

[0192] (in the formulae

[0193]

[0194] represents a naphthalene ring, a quinoline ring, an isoquinoline ring, a tetrahydronaphthalene ring, an indane ring, a tetrahydroquinoline ring or a tetrahydroisoquinoline ring, and

[0195] These rings can be substituted by 1 to 4 identical or different substituents selected from the group consisting of alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms and substituted by 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms and substituted by 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms) and aralkyl groups (aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 8 carbon atoms),

[0196] R 3Ba and R 4Ba may be identical 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 and substituted by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms and substituted by 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 (alkoxy moiety having 1 to 8 carbon atoms) or an aralkyl group (aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 8 carbon atoms),

[0197] R 5Ba represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms and substituted by 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms and substituted by a hydroxyl group or an aralkyl group (aryl moiety having 6 to 10 carbon atoms and alkylene moiety having 1 to 8 carbon atoms),

[0198] R 6Baand 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,

[0199]

[0200] represents a benzene ring, a pyridine ring, a thiophene ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, or an indole ring, which can have 1 to 4 substituents which are the same or different, the substituents being selected from the group consisting of 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 having 6 to 10 carbon atoms, and the alkylene moiety having 1 to 8 carbon atoms), a phenyl group, and a pyridyl group as substituents,

[0201] B Ba represents N(R 8Ba )C(=O), NHCONH, CON(R 9Ba ), NHC(=S)NH, N(R 10Ba )SO2, SO2N(R 11Ba ), or OSO2, wherein

[0202] R 8Ba , R 9Ba , R 10Ba , and R 11Ba 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, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl moiety having 6 to 10 carbon atoms, and the alkylene moiety having 1 to 8 carbon atoms),

[0203] E Ba represents O, S, NR 12Ba , or an atomic bond, wherein

[0204] R 12Baan 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 and substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms and substituted with a hydroxyl group, or an aralkyl group (an aryl moiety has 6 to 10 carbon atoms, and an alkylene moiety has 1 to 8 carbon atoms),

[0205] G Ba represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, indole, benzofuran, pyrrole, pyridine, or pyrimidine, which can have 1 to 4 identical 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 and substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms and 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 (an aryl moiety has 6 to 10 carbon atoms, and an alkylene moiety has 1 to 8 carbon atoms), a substitutable phenyl group, a substitutable pyridyl group, a substitutable imidazolyl group, a substitutable thiazolyl group, and a substitutable thiazolyl group, and

[0206] n B represents an integer of 0 to 5).

[0207] Next, substituents in General Formulae (BI) and (BII) of the present specification are described.

[0208] Examples of the alkyl group having 1 to 8 carbon atoms can include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, and the like.

[0209] Examples of the cycloalkyl group having 3 to 8 carbon atoms can include a cyclopropyl group, a cyclohexyl group, and the like.

[0210] Examples of the alkenyl group having 2 to 8 carbon atoms can include an allyl group, and the like.

[0211] Examples of the alkoxy group having 1 to 8 carbon atoms can include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a tert-butoxy group, a pentoxy group, a hexyloxy group, and the like.

[0212] Examples of the alkyl group having 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms can include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, and the like, substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, and a bromine atom, and preferred examples thereof can include a trifluoromethyl group, a chloromethyl group, a 2-chloroethyl group, a 2-bromoethyl group, a 2-fluoroethyl group, and the like.

[0213] Examples of the alkoxy group having 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms can include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, and the like, substituted with 1 to 3 halogen atoms such as a fluorine atom, a chlorine atom, and a bromine atom, and preferred examples thereof can include a trifluoromethoxy group, a chloromethoxy group, a 2-chloroethoxy group, a 2-bromoethoxy group, a 2-fluoroethoxy group, and the like.

[0214] Examples of the halogen atom can include a fluorine atom, a chlorine atom, a bromine atom, and the like.

[0215] Examples of the alkylamino group having 1 to 8 carbon atoms can include a methylamino group, an ethylamino group, and the like.

[0216] Examples of the dialkylamino group having 2 to 8 carbon atoms can include a dimethylamino group, a diethylamino group, and the like.

[0217] Examples of the acylamino group having 2 to 8 carbon atoms can include an acetylamino group, and the like.

[0218] Examples of the acyl group having 2 to 8 carbon atoms can include an acetyl group, and the like.

[0219] Examples of the alkoxycarbonyl group (the alkoxy moiety having 1 to 8 carbon atoms) can include a methoxycarbonyl group, and the like.

[0220] Examples of the aralkyl group (the aryl moiety having 6 to 10 carbon atoms, and the alkylene moiety having 1 to 8 carbon atoms) can include a benzyl group, and the like.

[0221] Examples of the alkyl group having 1 to 8 carbon atoms and substituted with a hydroxyl group can include a 2-hydroxyethyl group, and the like.

[0222] Examples of the alkylsulfinyl group having 1 to 6 carbon atoms can include a methanesulfinyl group, and the like.

[0223] Examples of the alkylsulfinyl group having 1 to 6 carbon atoms can include a methylsulfinyl group, and the like.

[0224] Examples of the alkylsulfonyl group having 1 to 6 carbon atoms can include a methylsulfonyl group, and the like.

[0225] Examples of the substituents that can be included in the phenyl group that can be substituted, the pyridyl group that can be substituted, the imidazolyl group that can be substituted, the Examples of the substituents that can be included in the phenyl group that can be substituted, the pyridyl group that can be substituted, the imidazolyl group that can be substituted, the

[0226] As the compound represented by General Formula (BI), the following compounds are preferable.

[0227] (B-1-1)

[0228] The compound according to (B-1), wherein R 1B and R 2B 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 and substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms and 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 that can be substituted, a pyridyl group that can be substituted, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms).

[0229] (B-1-2)

[0230] The compound according to (B-1) or (B-1-1), wherein R 1B and R 2B are combined together to form a naphthalene ring or a tetrahydronaphthalene ring together with the benzene ring to which they are combined, and R 1B and R 2B are combined with each other, R 1B and R 2BThe benzene ring or cyclohexene ring formed by the bonded carbon atoms may be substituted by 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, cyano groups, amino groups, alkylamino groups having 1 to 8 carbon atoms, dialkylamino groups having 2 to 8 carbon atoms, acylamino groups having 2 to 8 carbon atoms, carboxyl groups, acyl groups having 2 to 8 carbon atoms, alkoxycarbonyl groups (alkoxy moiety having 1 to 8 carbon atoms), and aralkyl groups (aryl moiety having 6 to 10 carbon atoms, and alkylene moiety having 1 to 8 carbon atoms).

[0231] (B-1-3)

[0232] According to the compound described in (B-1) or (B-1-1), wherein R 1B and R 2B They combine together to form a naphthalene ring together with the benzene ring they are bonded to, and are formed by R 1B and R 2B Combined with R 1B and R 2B The benzene ring formed by the combined carbon atoms can be substituted by 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, and amino groups.

[0233] (B-1-4)

[0234] According to the compound described in (B-1) or (B-1-1), wherein R 1B and R 2B They combine together to form naphthalene rings or tetrahydronaphthalene rings together with the benzene rings they are bound to.

[0235] (B-1-5)

[0236] The compound according to any one of (B-1) and (B-1-1) to (B-1-4), wherein R 3B and R 4Bwhich can 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, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms).

[0237] (B-1-6)

[0238] The compound according to any one of (B-1) and (B-1-1) to (B-1-5), wherein R 5B which represents a hydrogen atom, an alkyl group having 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).

[0239] (B-1-7)

[0240] The compound according to any one of (B-1) and (B-1-1) to (B-1-6), wherein R 5B which represents a hydrogen atom.

[0241] (B-1-8)

[0242] The compound according to any one of (B-1) and (B-1-1) to (B-1-7), or a pharmaceutically acceptable salt thereof, wherein R 6B and R 7B which can be the same or different, and each 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, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

[0243] (B-1-9)

[0244] The compound according to any one of (B-1) and (B-1-1) to (B-1-8), wherein R 6B and R 7B both represent a hydrogen atom.

[0245] (B-1-10)

[0246] The compound according to any one of (B-1) and (B-1-1) to (B-1-9), wherein R 3B , R 4B , R 5B , R 6Band R 7B is a hydrogen atom.

[0247] (B-1-11)

[0248] The compound according to any one of (B-1) and (B-1-1) to (B-1-10), wherein X B represents N, Y B represents C(=O), and the double line composed of a solid line and a dotted line represents a single bond.

[0249] (B-1-12)

[0250] The compound according to any one of (B-1) and (B-1-1) to (B-1-11), wherein X B represents C, Y B represents N, and the double line composed of a solid line and a dotted line represents a double bond.

[0251] (B-1-13)

[0252] The compound according to any one of (B-1) and (B-1-1) to (B-1-12), wherein Z B represents an oxygen atom.

[0253] (B-1-14)

[0254] The compound according to any one of (B-1) and (B-1-1) to (B-1-13), wherein A B represents a phenyl group or a pyridyl group, which can have 1 to 4 substituents 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 (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, and a pyridyl group as a substituent.

[0255] (B-1-15)

[0256] The compound according to any one of (B-1) and (B-1-1) to (B-1-14), wherein A Ba phenyl group which can have 1 to 4 identical or different substituents selected from the group consisting of 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 by 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted by 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, and an amino group as the substituents.

[0257] (B-1-16)

[0258] The compound according to any one of (B-1) and (B-1-1) to (B-1-15), wherein A B represents a phenyl group or a pyridyl group.

[0259] (B-1-17)

[0260] The compound according to any one of (B-1) and (B-1-1) to (B-1-16), wherein A B represents an atomic bond.

[0261] (B-1-18)

[0262] The compound according to any one of (B-1) and (B-1-1) to (B-1-17), wherein B B represents NHC(=0), NHCONH, CONH, NHC(=S)NH, NHS02, S02NH, or OS02.

[0263] (B-1-19)

[0264] The compound according to any one of (B-1) and (B-1-1) to (B-1-18), wherein B B represents NHC(=0), NHCONH, or NHS02.

[0265] (B-1-20)

[0266] The compound according to any one of (B-1) and (B-1-1) to (B-1-19), wherein B B represents NHC(=0) or NHS02.

[0267] (B-1-21)

[0268] The compound according to any one of (B-1) and (B-1-1) to (B-1-20), wherein B B represents NHC(=0).

[0269] (B-1-22)

[0270] The compound according to any one of (B-1) and (B-1-1) to (B-1-21), wherein D B represents an alkylene chain having 1 to 6 carbon atoms, which can have 1 to 4 identical or different substituents, and which can also have a double bond, the substituents being selected from the group consisting of alkyl groups having 1 to 8 carbon atoms and alkyl groups having 1 to 8 carbon atoms which are substituted by 1 to 3 halogen atoms, as substituents.

[0271] (B-1-23)

[0272] The compound according to any one of (B-1) and (B-1-1) to (B-1-22), wherein D B represents an atomic bond.

[0273] (B-1-24)

[0274] The compound according to any one of (B-1) and (B-1-1) to (B-1-23), wherein D B having 1 to 4 identical or different substituents, the substituents being selected from the group consisting of alkyl groups having 1 to 8 carbon atoms and alkenyl groups having 2 to 8 carbon atoms, as substituents.

[0275] (B-1-25)

[0276] The compound according to any one of (B-1) and (B-1-1) to (B-1-24), wherein D B having 1 to 4 identical or different substituents, the substituents being selected from the group consisting of alkyl groups having 1 to 3 carbon atoms and alkenyl groups having 2 or 3 carbon atoms, as substituents.

[0277] (B-1-26)

[0278] The compound according to any one of (B-1) and (B-1-1) to (B-1-25), wherein E B represents an atomic bond.

[0279] (B-1-27)

[0280] The compound according to any one of (B-1) and (B-1-1) to (B-1-26), wherein G B represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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, and an alkylsulfonyl group having 1 to 6 carbon atoms.

[0281] (B-1-28)

[0282] The compound according to any one of (B-1) and (B-1-1) to (B-1-27), wherein G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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, and an alkylsulfonyl group having 1 to 6 carbon atoms.

[0283] (B-1-29)

[0284] The compound according to any one of (B-1) and (B-1-1) to (B-1-27), wherein G Brepresents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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 and 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.

[0285] (B-1-30)

[0286] The compound according to any one of (B-1) and (B-1-1) to (B-1-29), wherein G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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 and 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.

[0287] (B-1-31)

[0288] The compound according to any one of (B-1) and (B-1-1) to (B-1-30), wherein m B represents 0.

[0289] (B-1-32)

[0290] The compound according to any one of (B-1) and (B-1-1) to (B-1-31), wherein 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 an atomic bond, E B represents an atomic bond, and G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of, as substituents, 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 and 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.

[0291] (B-1-33)

[0292] The compound according to any one of (B-1) and (B-1-1) to (B-1-32), wherein A B represents a benzene ring, m B represents 0, B B represents NHC(=O), DB Represents an atomic bond, E B Represents an atomic bond, and G B Representing benzene, which may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms and hydroxy groups having 1 to 8 carbon atoms and being replaced by 1 to 3 halogen atoms.

[0293] (B-1-34)

[0294] The compound according to any one of (B-1) and (B-1-1) to (B-1-33), wherein R 1B and R 2B They combine together to form a naphthalene ring, R 3B R 4B R 5B R 6B and R 7B Represents a hydrogen atom, X B Representing N, Y B Representing C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B Represents oxygen atom, A B Represents the benzene ring, m B Representing 0, B B Represents NHC (=O) or NHSO2, D B E represents an alkyl group or atomic bond having 1 to 3 carbon atoms. B Represents an atomic bond, and G B Representing benzene, which may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups.

[0295] (B-1-35)

[0296] The compound according to any one of (B-1) and (B-1-1) to (B-1-34), wherein, in general formula (BI), R 1B and R 2B They combine together to form a naphthalene ring, R 3B R 4B R 5B R 6B and R 7B Represents a hydrogen atom, X B Representing N, Y B Representing C (=O), the double line consisting of solid and dashed lines represents a single bond, Z B Represents oxygen atom, A B Represents the benzene ring, mB Representing 0, B B Represents NHC (=O), D B Represents an atomic bond, E B Represents an atomic bond, and G B Representing benzene, which may have 1 to 4 identical or different substituents selected from alkyl groups, halogen atoms and hydroxy groups having 1 to 8 carbon atoms and being replaced by 1 to 3 halogen atoms.

[0297] The following compounds are preferred as compounds represented by the general formula (BII).

[0298] (B-2-1)

[0299]

[0300] According to the compound described in (B-2), wherein the above-mentioned portion represents a naphthalene ring or a tetrahydronaphthalene ring, which may have 1 to 4 identical or different substituents selected as substituents of 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 portion has 1 to 8 carbon atoms), and an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms).

[0301] (B-2-2)

[0302]

[0303] According to the compound described in (B-2) or (B-2-1), wherein the above-mentioned portion represents a naphthalene ring, which may have 1 to 4 identical or different substituents selected from alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, alkoxy groups having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, and amino groups.

[0304] (B-2-3)

[0305] The compound according to any one of (B-2), (B-2-1), and (B-2-2), wherein 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, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms).

[0306] (B-2-4)

[0307] The compound according to any one of (B-2) and (B-2-1) to (B-2-3), wherein R 5Ba represents a hydrogen atom, an alkyl group having 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).

[0308] (B-2-5)

[0309] The compound according to any one of (B-2) and (B-2-1) to (B-2-4), wherein R 5Ba represents a hydrogen atom.

[0310] (B-2-6)

[0311] The compound according to any one of (B-2) and (B-2-1) to (B-2-5), wherein 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 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.

[0312] (B-2-7)

[0313] The compound according to any one of (B-2) and (B-2-1) to (B-2-6), wherein R 6Ba and R 7Ba both represent a hydrogen atom.

[0314] (B-2-8)

[0315]

[0316] The compound according to any one of (B-2) and (B-2-1) to (B-2-7), wherein the above moiety represents a phenyl group or a pyridyl group, which can have 1 to 4 identical 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 aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, and a pyridyl group as the substituents.

[0317] (B-2-9)

[0318]

[0319] The compound according to any one of (B-2) and (B-2-1) to (B-2-8), wherein the above moiety represents a phenyl group, which can have 1 to 4 identical 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, and an amino group.

[0320] (B-2-10)

[0321]

[0322] The compound according to any one of (B-2) and (B-2-1) to (B-2-9), wherein the above moiety represents an atomic bond.

[0323] (B-2-11)

[0324] The compound according to any one of (B-2) and (B-2-1) to (B-2-10), wherein B Ba represents NHC(=O), NHCONH, CONH, NHC(=S)NH, NHSO2, SO2NH, or OSO2.

[0325] (B-2-12)

[0326] The compound according to any one of (B-2) and (B-2-1) to (B-2-11), wherein B Ba represents NHC(=0), NHCONH or NHSO2.

[0327] (B-2-13)

[0328] The compound according to any one of (B-2) and (B-2-1) to (B-2-12), wherein E Ba represents an atomic bond.

[0329] (B-2-14)

[0330] The compound according to any one of (B-2) and (B-2-1) to (B-2-13), wherein G Ba represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, which can have 1 to 4 identical or different substituents selected from the group consisting of 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 and an alkylsulfonyl group having 1 to 6 carbon atoms, as a substituent.

[0331] (B-2-15)

[0332] The compound according to any one of (B-2) and (B-2-1) to (B-2-14), wherein G Barepresent a benzene ring, which can have 1 to 4 identical or different substituents selected from the group consisting of 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, and an alkylsulfonyl group having 1 to 6 carbon atoms.

[0333] (B-2-16)

[0334] The compound according to any one of (B-2) and (B-2-1) to (B-2-15), wherein n B represents 0.

[0335] In General Formula (BI), preferably R B1 and R B2 are combined together to form a fused ring selected from a naphthalene ring or a tetrahydronaphthalene ring together with the benzene ring to which they are combined, and particularly preferably R B1 and R B2 are combined together to form a naphthalene ring together with the benzene ring to which they are combined.

[0336] In General Formula (BI), preferably R B3 , R B4 , R B5 , R B6 and R B7 represent a hydrogen atom.

[0337] In General Formula (BI), preferably X B represents N, Y B represents C(=O), and the double line composed of a solid line and a dotted line represents a single bond.

[0338] In General Formula (BI), preferably Z B represents an oxygen atom.

[0339] In General Formula (BI), preferably A B represents a benzene ring or a pyridine ring, and particularly preferably A B represents a benzene ring.

[0340] In General Formula (BI), preferably m B represents 0 to 4, and particularly preferably m B represents 0.

[0341] In general formula (BI), preferably B B represents N(R 8B )C(=O) or N(R 10B )SO2, and in this case, more preferably R 8B and R 10B represent a hydrogen atom. Furthermore, in general formula (BI), particularly preferably B B represents NHC(=O).

[0342] In general formula (BI), preferably D B represents an atomic bond or represents an alkylene chain having 1 to 4 identical or different substituents selected from the group consisting of alkyl groups having 1 to 8 carbon atoms and alkenyl groups having 2 to 8 carbon atoms as substituents, more preferably D B represents an atomic bond or represents an alkylene chain having 1 to 4 identical or different substituents selected from the group consisting of alkyl groups having 1 to 3 carbon atoms and alkenyl groups having 2 or 3 carbon atoms as substituents, and particularly preferably D B represents an atomic bond.

[0343] In general formula (BI), preferably E B represents O or an atomic bond, and particularly preferably E B represents an atomic bond.

[0344] In general formula (BI), preferably G B represents benzene or pyridine, which can have 1 to 4 identical or different substituents selected from the group consisting of alkyl groups having 1 to 8 carbon atoms, alkenyl groups having 2 to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms, alkyl groups having 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, halogen atoms, hydroxyl groups, nitro groups, amino groups, dialkylamino groups having 2 to 8 carbon atoms, carboxyl groups, alkylsulfinyl groups having 1 to 6 carbon atoms, alkylthio groups having 1 to 6 carbon atoms, and alkylsulfonyl groups having 1 to 6 carbon atoms as substituents, and particularly preferably G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of alkyl groups having 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, halogen atoms, and hydroxyl groups as substituents.

[0345] In general formula (BI), particularly preferably 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 an atomic bond, E Brepresents a bond, and G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of alkyl radicals having 1 to 8 carbon atoms, alkyl radicals having 1 to 8 carbon atoms which are substituted by 1 to 3 halogen atoms, halogen atoms and hydroxyl radicals as substituents.

[0346] In general formula (BI), A B represents a benzene ring, m B represents 0, B B represents NHC(=0), D B represents a bond, E B represents a bond, and G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of alkyl radicals having 1 to 8 carbon atoms, alkyl radicals having 1 to 8 carbon atoms which are substituted by 1 to 3 halogen atoms, halogen atoms and hydroxyl radicals as substituents.

[0347] In general formula (BI), R B1 and R B2 are bound together to form, together with the benzene ring to which they are bound, a naphthalene ring, R B3 , R B4 , R B5 , R B6 and R B7 represent a hydrogen atom, X B represents N, Y B represents C(=0), the double line consisting of a solid line and a dashed line represents a single bond, Z B represents an oxygen atom, A B represents a benzene ring, m B represents 0, B B represents NHC(=0) or NHSO2, D B represents an alkyl radical having 1 to 3 carbon atoms or a bond, E B represents a bond, and G B represents benzene, which can have 1 to 4 identical or different substituents selected from the group consisting of alkyl radicals having 1 to 8 carbon atoms, alkyl radicals having 1 to 8 carbon atoms which are substituted by 1 to 3 halogen atoms, halogen atoms and hydroxyl radicals as substituents.

[0348] In general formula (BI), R B1 and R B2 are bound together to form, together with the benzene ring to which they are bound, a naphthalene ring, R B3 , R B4 , R B5 , R B6 and R B7 represent a hydrogen atom, X B represents N, YB represents C(=O), a double line composed of a solid line and a dotted line represents a single bond, Z B represents an oxygen atom, A B represents a benzene ring, m B represents 0, B B represents NHC(=O), D B represents an atomic bond, E B represents an atomic bond, and G B represents benzene, which can have 1 to 4 substituents the same or different, selected from the group consisting of an alkyl group having 1 to 8 carbon atoms and substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as a substituent.

[0349] Typical compounds included in the compounds represented by General Formula (BI) and / or (BII) are as follows.

[0350] <Typical Compound Example B-100>

[0351]

[0352] (B Ba (substitution position), n B , E Ba , and G Ba shown in Tables 8 to 17)

[0353] [Table 8]

[0354]

[0355]

[0356] [Table 9]

[0357] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> NHCO(4) 0 atom bond (2,4-Cl)phenyl NHCO(4) 0 atom bond (2-OH)phenyl NHCO(4) 0 atom bond (2,3-OH)phenyl NHC(=O)NH(4) 0 atom bond phenyl NHCO(4) 1 atom bond (2,6-Cl)phenyl NHCO(4) 1 atom bond (2-OMe)phenyl NHCO(4) 1 atom bond (2-OH)phenyl NHC(=S)NH(4) 0 atom bond (2-Cl)phenyl NHCO(4) 0 atom bond (3-CF3)phenyl NHCO(4) 1 atom bond (2-CF3)phenyl NHC(=O)NH(4) 0 atom bond (2-Cl)phenyl NHCO(4) 0 atom bond (2-Cl,3-OMe)phenyl NHCO(4) 2 atom bond phenyl NHCO(4) 0 atom bond 3-indole NHCO(4) 0 atom bond (2-Cl,3-OH)phenyl NHCO(4) 1 O phenyl

[0358] [Table 10]

[0359]

[0360]

[0361] [Table 11]

[0362]

[0363]

[0364] [Table 12]

[0365]

[0366]

[0367] [Table 13]

[0368] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> CONH(4) 0 atom bond (2-Cl)phenyl NHCO(4) 0 atom bond (5-Br,2,3-methylenedioxy)phenyl NHCO(4) 0 atom bond (2-OMe,6-Br)phenyl NHCO(4) 0 atom bond (2-OH,6-Br)phenyl NHCO(4) 0 atom bond (2-OMe,6-Cl)phenyl NHCO(4) 0 atom bond (2-OH,6-Cl)phenyl NHCO(4) 0 atom bond (2-OH,6-OMe)phenyl NHCO(4) 0 atom bond (2-OMe, 6-CF3)phenyl NHCO(4) 0 atom bond (2-OH, 6-CF3)phenyl NHCO(4) 0 atom bond (2-Cl,5-SMe)phenyl NHCO(4) 0 atom bond (2-SMe)phenyl NHCO(4) 0 atom bond (3-SMe)phenyl NHCO(4) 0 atom bond (2-OMe,6-Et)phenyl NHCO(4) 0 atom bond (3-S02Me)phenyl NHCO(4) 0 atom bond (2-OH,6-Et)phenyl NHCO(4) 0 atom bond (3-S(=O)Me)phenyl

[0369] [Table 14]

[0370]

[0371]

[0372] [Table 15]

[0373]

[0374]

[0375] [Table 16]

[0376] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> [NHSO2(4)] 1 atom bond (2-NO2)phenyl [NHSO2(4)] 2 atom bond phenyl [NHSO2(4)] 1 atom bond (4-Cl)phenyl [CAT] (4) 1 atom bond (2-CF3)phenyl [CAT] (4) 1 atom bond (2-Et)phenyl [CAT] (4) 1 atom bond (2,3-Me)phenyl [CAT] (4) 2 atom bond (2-Cl)phenyl [CAT] (4) 1 atom bond (2-NO2)phenyl [Me2NCH2]2 1 atom bond (2-NH2)phenyl [Me2NCH2]2 1 atom bond (2-NMe2)phenyl

[0377] [Table 17]

[0378]

[0379]

[0380] [Typical Compound Examples B-200]

[0381]

[0382] (R in the formula Ba (substituted position), n B , E Ba and G Ba are shown in Tables 18 and 19)

[0383] [Table 18]

[0384]

[0385]

[0386] [Table 19]

[0387] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> [NHSO2(4)] 0 atom bond (2-NO2)phenyl [CAT] (4) 0 atom bond (2-NO2)phenyl SO2NH(4) 0 atom bond phenyl OSO2(4) 0 atom bond (3-Br)phenyl [NHSO2(4)] 1 atom bond (2-Cl)phenyl [NHSO2(4)] 0 atom bond (3-Br)phenyl [NHSO2(4)] 0 atom bond (3-OMe)phenyl [NHSO2(4)] 1 atom bond (2,3-Cl)phenyl [NHSO2(4)] 1 atom bond (2,6-Cl)phenyl [NHSO2(4)] 1 atom bond (2-I)phenyl [CAT] (4) 1 atom bond (2-Cl)phenyl

[0388] [Typical Compound Examples B-300]

[0389]

[0390] (R in the formula 1B , B Ba (substituted position), n B , EBa and G Ba shown in Table 20)

[0391] [Table 20]

[0392]

[0393]

[0394] <Exemplified Compound Examples B-400>

[0395]

[0396] (B in the formula is Ba (substitution position), n B , E Ba and G Ba shown in Table 21)

[0397] [Table 21]

[0398] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> NHCO 0 atom bond (2-Cl, 3-OMe)phenyl NHCO 0 atomic bond (2-I)phenyl [NHSO2] 1 atomic bond (2-Cl)phenyl [NHSO2] 1 atomic bond (2-Cl)phenyl

[0399] <Exemplified Compound Examples B-500>

[0400]

[0401] (B in the formula is Ba (substitution position), n B , E Ba and G Ba shown in Table 22)

[0402] [Table 22]

[0403] B Ba (substitution position) n B ]]> E Ba ]]> G Ba ]]> NHCO(4) 0 atomic bond (2-Cl, 3-OMe)phenyl NHCO(4) 0 atomic bond (2-Cl, 3-OH)phenyl NHCO(4) 0 atomic bond (2-tBu)phenyl NHCO(4) 0 atomic bond (2-Cl, 6-OMe)phenyl NHCO(4) 0 atomic bond (2-Cl, 6-OH)phenyl NHSO2(3) 0 atomic bond phenyl NHSO2(4) 0 atomic bond (2-Cl)phenyl

[0404] <Exemplified Compound Examples B-600>

[0405]

[0406] (B in the formula is B (substitution position), D B , E B and G B shown in Table 23)

[0407] [Table 23]

[0408] B B (substitution position) D B ]]> E B ]]> G B ]]> NHCO(4) C(Me)H atomic bond phenyl NHCO(4) [C(Me)2] atomic bond phenyl NHCO(4) CH=CH atomic bond phenyl NHCO(4) C(Me)H O phenyl NHCO(4) [C(Me)2] O phenyl NHCO(4) CH=CH atomic bond (2-Me)phenyl NHCO(4) CH=CH atomic bond (2-Cl)phenyl

[0409] <Exemplified Compound Examples B-700>

[0410]

[0411] (m in the formula) B (replacement position), B B D B E B and G B (As shown in Table 24)

[0412] [Table 24]

[0413]

[0414] <Example of Typical Compounds B-800>

[0415]

[0416] (X in the formula) Ba Y Ba B Ba (replaces position), n B E Ba and G Ba (As shown in Table 25)

[0417] [Table 25]

[0418]

[0419]

[0420] <Example of Typical Compounds B-900>

[0421]

[0422] (In the formula, I = II - III = IV, B) Ba (replaces position), n B E Ba and G Ba (As shown in Table 26)

[0423] [Table 26]

[0424]

[0425]

[0426] <Examples of Typical Compounds B-1000>

[0427]

[0428] (in the formula, I-II-III-IV, B) Ba (replaces position), n B E Ba and G Ba (As shown in Table 27)

[0429] [Table 27]

[0430]

[0431]

[0432] [Typical compound examples B-1100]

[0433]

[0434] (R in the formulae 5Ba , B Ba (substitution position), n B , E Ba , and G Ba are shown in Table 28)

[0435] [Table 28]

[0436] [R 5Ba ]]> B Ba (Positions of Substitutions) n B ]]> E Ba ]]> G Ba ]]> Bn NBnSO2(4) 0 atomic bond (2-NO2)phenyl Me NBnSO2(4) 0 atomic bond (2-NO2)phenyl<!-- 43 --> Et NBnSO2(4) 0 atomic bond (2-NO2)phenyl

[0437] Since the compounds represented by General Formula (A) are disclosed in WO 2010 / 093061 A, all the compounds can be easily obtained by referring to this international publication. The disclosure of this international publication is incorporated herein by reference in its entirety.

[0438] Since the compounds represented by General Formulae (BI) and (BII) are disclosed in WO 2013 / 105608 A, all the compounds can be easily obtained by referring to this international publication. The disclosure of this international publication is incorporated herein by reference in its entirety.

[0439] Further, WO 2010 / 093061 A and WO 2013 / 105608 A disclose that the compounds represented by General Formulae (A) to (BII) have P2X4 receptor antagonistic action.

[0440] Specific examples of the preferred compounds included in the compounds represented by General Formulae (A) to (BII) or pharmaceutically acceptable salts thereof are shown below, however, the compounds or pharmaceutically acceptable salts thereof useful as active ingredients of the medicaments of the present application are not limited thereto.

[0441] (compound A1) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0442] (compound A2) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone sodium salt;

[0443] (Compound A3) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone potassium salt;

[0444] (Compound A4) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone;

[0445] (Compound A5) 5-[4-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone sodium salt;

[0446] (Compound A6) 1-methyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone;

[0447] (Compound A7) 1,3-dimethyl-5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone;

[0448] (Compound A8) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone;

[0449] (Compound A9) 5-[2-chloro-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone sodium salt;

[0450] (Compound A10) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone;

[0451] (Compound A11) 5-[2-methyl-5-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine - 2,4(3H,5H)-diketone sodium salt;

[0452] (Compound A12) 5-[2-bromo-5-(1 H-tetrazol-5-yl)phenyl]-1 H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0453] (Compound A13) 5-[3-(2-methyl-2H-tetrazol-5-yl)phenyl]-1 H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0454] (Compound A14) 5-[3-(1 -methyl-1 H-tetrazol-5-yl)phenyl]-1 H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0455] (Compound A15) 5-[3-(5-oxo-4H-[1,2,4] triazol-3-yl)phenyl]-1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0456] (Compound A16) 5-[3-(5-thioxo-4H-[1,2,4] triazol-3-yl)phenyl]-1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0457] (Compound A17) 5-[3-(5-thioxo-4H-[1,2,4] triazol-3-yl)phenyl]-1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione sodium salt;

[0458] (Compound A18) 5-[3- oxazol-2-yl)phenyl]-1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0459] (Compound A19) 5-[3-(1 H-pyrazol-4-yl)phenyl]-1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0460] (Compound A20) 5-[4-fluoro-3-(1 H-tetrazol-5-yl)phenyl]-1 H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0461] (Compound A21) 5-[4-fluoro-3-(lH-tetrazol-5-yl)phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-diketone sodium salt;

[0462] (Compound B1) 5-(4-benzoylamino phenyl)-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0463] (Compound B2) 5-[4-[2-(trifluoromethyl)benzoyl]amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0464] (Compound B3) 5-[4-(3-bromobenzoyl)amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0465] (Compound B4) 5-[4-[4-(trifluoromethyl)benzoyl]amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0466] (Compound B5) 5-[4-(2-methylbenzoyl)amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0467] (Compound B6) 5-[4-(2,6-dimethylbenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0468] (Compound B7) 5-[4-(2,6-dichlorobenzoyl)amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0469] (Compound B8) 5-[4-(3-chlorobenzoyl)amino phenyl]-lH-naphtho[l,2-b][l,4]diazepine -2,4(3H,5H)-dione;

[0470] (Compound B9) 5-[4-(2-phenylacetyl amino) phenyl]-lH-naphtho[l,2-b][l,4]diazepine - 2,4(3H,5H)-dione;

[0471] (Cpd. B10) 1 -[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2-b][ 1,4]diazepin- -5-yl)phenyl]-3-phenylthiourea;

[0472] (Cpd. B11) 5-[4-(2,3-dimethoxybenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0473] (Cpd. B12) 5-[4-(2-methoxybenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0474] (Cpd. B13) 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0475] (Cpd. B14) 5-[4-(2,3-dimethylbenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0476] (Cpd. B15) 5-[4-(2,5-dimethylbenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0477] (Cpd. B16) 5-[4-(5-bromo-2-chlorobenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0478] (Cpd. B17) 5-[4-(2,4-dichlorobenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0479] (Cpd. B18) 5-[4-(2-hydroxybenzoylamino)phenyl]-lH-naphtho[l,2-b][l,4]diazepin- -2,4(3H,5H)-dione;

[0480] (Compound B19) 5-[4-(2,3-dihydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0481] (Compound B20) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea; -2,4(3H,5H)-dione;

[0482] (Compound B21) 5-[4-[(2,6-dichlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0483] (Compound B22) 5-[4-[(2-methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0484] (Compound B23) 5-[4-[(2-hydroxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0485] (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; -2,4(3H,5H)-dione;

[0486] (Compound B25) 5-[4-[3-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0487] (Compound B26) 5-[4-[2-[(2-trifluoromethyl)phenyl]acetylaminolphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0488] (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; -2,4(3H,5H)-dione;

[0489] (Compound B28) 5-[4-[(2-phenylpropanoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0490] (Compound B29) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0491] (Compound B30) 5-[4-(3-phenylpropanoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0492] (Compound B31) 5-[4-[(1H-indole-3-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0493] (Compound B32) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0494] (Compound B33) 5-[4-[(2-methyl-2-phenylpropanoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0495] (Compound B34) 5-[4-(2-phenoxyacetylaminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0496] (Compound B35) 5-[4-[2-(2-chloro-4-methoxyphenyl)acetylaminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0497] (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;

[0498] (Compound B37) 5-[4-[2-(2,4-dichlorophenyl)acetylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0499] (Compound B38) 5-[4-[2-(2-chloro-4-hydroxyphenyl)acetylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0500] (Compound B39) 5-[4-(3-phenylpropenylamino)phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0501] (Compound B40) 5-[4-[(3-pyridinylacetyl)amino]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride;

[0502] (Compound B41) 5-[4-(1H-benzimidazole-2-carbonylamino)phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0503] (Compound B42) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5- benzodiazepine -2,4(3H,5H)-dione;

[0504] (Compound B43) 5-[4-[(benzoylamino)methyl]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0505] (Compound B44) 5-[4-[(2-chlorobenzoylamino)methyl]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0506] (Compound B45) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-hydroxy-1H-1,5- benzodiazepine -2,4(3H,5H)-dione;

[0507] (Compound B46) 5-[4-(2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0508] (Compound B47) 5-[4-(2-bromobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0509] (Compound B48) 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0510] (Compound B49) 5-[4-(2,3-dimethylbenzoylamino)-3-fluorophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0511] (Compound B50) 5-[4-[2-(2-methylphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0512] (Compound B51) 5-[4-[(quinoxaline-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0513] (Compound B52) 5-[4-[(5-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0514] (Compound B53) 5-[3-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0515] (Compound B54) 5-[4-[(2,4,6-trimethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0516] (Compound B55) 5-[4-(cyclohexylcarbonylamino)phenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0517] (Compound B56) 1-[4-(2,3-dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5- benzodiazepine -2,4(3H,5H)-dione;

[0518] (Compound B57) 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0519] (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;

[0520] (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;

[0521] (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 -2,4(3H,5H)-dione;

[0522] (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;

[0523] (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;

[0524] (Compound B63) 5-[4-(2,3-dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2- b][1,4]diazepine - 2,4(3H,5H)-dione;

[0525] (Cpd. B64) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1,3- dihydro naphtho[1,2-e]-1,4-diazepin-2-one; - 2-ketone;

[0526] (Cpd. B65) 5-[4-[(4-dimethylaminobenzoyl)amino]phenyl]-1H- naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0527] (Cpd. B66) 5-[4-[2-(2,4-dichlorophenoxy)acetylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0528] (Cpd. B67) 5-[4-[2-(2-methylphenoxy)acetylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0529] (Cpd. B68) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5- yl)butyl]-2-chloro-3-methoxybenzamide; - 2,4(3H,5H)-dione;

[0530] (Cpd. B69) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1,3- dihydronaphtho[1,2-e]-1,4-diazepin-2-ketone; - 2-ketone;

[0531] (Cpd. B70) 5-[4-(2-acetylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4] diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0532] (Cpd. B71) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4] diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0533] (Cpd. B72) 5-[2-(2-iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4] diazepin-2,4(3H,5H)-dione; - 2,4(3H,5H)-dione;

[0534] (Compound B73) 5-[3-[(2-iodobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0535] (Compound B74) 6,7-dimethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5- benzodiazepine -2,4(3H,5H)-dione;

[0536] (Compound B75) 5-[4-[(1-methylpiperidin-4-yl)carbonylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride;

[0537] (Compound B76) 5-[4-[(benzofuran-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0538] (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;

[0539] (Compound B78) 5-[4-(2-propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4] diazepine -2,4(3H,5H)-dione;

[0540] (Compound B79) 5-[4-(2-propylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4] diazepine -2,4(3H,5H)-dione;

[0541] (Compound B80) 5-[3-fluoro-4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0542] (Compound B81) 5-[4-(2-hydroxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0543] (Compound B82) 5-[4-[(2-isopropoxybenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0544] (Compound B83) 5-[4-[(3-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0545] (Compound B84) 5-[4-(2-phenoxypropanoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0546] (Compound B85) 5-[4-[2-(4-chloro-2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0547] (Compound B86) 5-[4-[(4-fluoro-2-trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0548] (Compound B87) 5-[4-(4-fluoro-2-methoxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0549] (Compound B88) 5-[4-(4-fluoro-2-hydroxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0550] (Compound B89) 5-[3-[(2-iodophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0551] (Compound B90) 5-[4-(2-methyl-2-phenoxypropanoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0552] (Compound B91) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepine -2-ketone;

[0553] (Compound B92) 5-[4-[(3-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0554] (Compound B93) 5-[4-(4-iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0555] (Compound B94) 5-[4-(6-fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0556] (Compound B95) 5-[4-(2-hydroxy-4-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0557] (Compound B96) 5-[4-(6-fluoro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0558] (Compound B97) 5-[4-(2-fluorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0559] (Compound B98) 5-[4-[(2-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0560] (Compound B99) 5-[4-(2-methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0561] (Compound B100) 5-[4-(2-hydroxy-6-methylbenzoyl- amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0562] (Compound B101) 5-[4-[3-(2-methylphenyl)propionylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0563] (Compound B102) 5-(4-phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0564] (Compound B103) 5-(4-benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0565] (Compound B104) 5-[4-[3-(2-methylphenyl)propenoylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0566] (Compound B105) 5-[4-[3-(2-chlorophenyl)propionylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0567] (Compound B106) 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0568] (Compound B107) 5-[4-[(1-methyl-1H-pyrrol-2-ylacetyl)amino]phenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0569] (Compound B108) 5-[4-(2-chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0570] (Compound B109) 5-[4-[3-(2-chlorophenyl)propenoyl- amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0571] (Compound B110) 5-[4-(2-chlorophenyl)carbamoylphenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0572] (Compound B111) 5-[4-(6-bromo-2,3-methylenedioxybenzoyl- amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0573] (Compound B112) 5-[4-(6-bromo-2-methoxybenzoyl- amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0574] (Compound B113) 5-[4-[(2-tert-butylbenzoyl)amino]phenyl]- 1,2,3,4,8,9,10,11-octahydro-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0575] (Compound B114) 5-[2-(2-iodobenzoyl)aminopyridin-5-yl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0576] (Compound B115) 5-[4-(6-bromo-2-hydroxybenzoyl- amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0577] (Compound B116) 5-[4-(6-chloro-2-methoxybenzoyl- amino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0578] (Compound B117) 5-[4-(2-iodobenzoyl- amino)phenyl]-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione; -2,4(3H,5H)-dione;

[0579] (Compound B118) 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0580] (Compound B119) 5-[4-(2-hydroxy-6-methoxybenzoylamino)phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0581] (Compound B120) 5-[4-[2-methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0582] (Compound B121) 5-[4-[2-hydroxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0583] (Compound B122) 5-[4-[(2-isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine 2,4(3H,5H)-dione;

[0584] (Compound B123) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11- octahydro naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0585] (Compound B124) 5-[4-[2-chloro-5-(methylthio)benzoylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0586] (Compound B125) 5-[4-[2-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0587] (Compound B126) 5-[4-[3-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -2,4(3H,5H)-dione;

[0588] (Cpd. B127) 5-[4-[2-ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0589] (Cpd. B128) 5-[4-(3-methanesulfonylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0590] (Cpd. B129) 6-ethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine -2,4(3H,5H)-dione;

[0591] (Cpd. B130) 5-[4-[2-ethyl-6-hydroxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0592] (Cpd. B131) 5-[4-(3-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0593] (Cpd. B132) 5-[4-(2-chloro-5-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0594] (Cpd. B133) 5-[4-(2-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione;

[0595] (Cpd. B134) 5-[4-[[2-(4-morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydro- naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride;

[0596] (Cpd. B135) 5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepine -2-ketone;

[0597] (Compound B136) 5-[4-[[(3-chloropyridin-2-yl)carbonyl]amino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0598] (Compound B137) 5-[4-(2-chloro-6-hydroxybenzoylamino)phenyl]-1,3- dihydronaphtho[1,2-e]-1,4-diazepine-2-ketone -2-ketone;

[0599] (Compound B138) 5-[4-(3-chloro-2-methoxybenzoylamino)phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0600] (Compound B139) 5-[4-[(3-methylpyridin-2-yl)carbonylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0601] (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 -2,4(3H,5H)-dione;

[0602] (Compound B141) 5-[4-(3-chloro-2-hydroxybenzoylamino)phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0603] (Compound B142) 5-[4-[[(3-hydroxypyridin-2-yl)carbonyl]amino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0604] (Compound B143) 5-[4-[(3-vinylpyridin-2-yl)carbonylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0605] (Compound B144) 5-[4-[(3-ethylpyridin-2-yl)carbonylamino]phenyl]-1H- naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione -2,4(3H,5H)-dione;

[0606] (Compound B145) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B146) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]benzenesulfonamide;

[0607] (Compound B147) 3-bromo-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B148) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide;

[0608] (Compound B149) N-[3-(2-oxo-2,3-dihydro- 1 H-naphtho[ 1,2-e][ 1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (Compound B150) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0609] (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;

[0610] (Compound B153) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (Compound B154) N-[3-(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;

[0611] (Compound B155) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B156) N-[3-(2,4-dioxo- 1,2,3,4,8,9, 10, 11 -octahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0612] (Compound B157) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B158) N-[3-(2,4-dioxo- 1,2,3,4,8,9, 10, 11 -octahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0613] (Compound B159) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B160) N-[3-(2,4-dioxo- 1,2,3,4,8,9, 10, 11 -octahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0614] (Compound B161) N-[3-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (Compound B162) N-[3-(2,4-dioxo- 1,2,3,4,8,9, 10, 11 -octahydro- naphtho-[ 1,2-b][ 1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0615] (Compound B154) 4-(2,4-dioxo-l,2,3,4,8,9,10,11-octahydronaphtho[l,2-b][l,4]diazepin-5-yl)-N- phenylbenzenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0616] (Compound B155) N-[3-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b]- [l,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0617] (Compound B156) N-[3-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b]- [l,4]diazepin-5-yl)phenyl]-l-naphthalenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0618] (Compound B157) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]cyclohexanesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0619] (Compound B158) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]-3-pyridinesulfonamide hydrochloride; -5-yl)-N-phenylbenzenesulfonamide;

[0620] (Compound B159) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]-4-isopropylbenzenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0621] (Compound B160) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]phenylmethanesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0622] (Compound B161) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]-2-thiophenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0623] (Compound B162) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho[l,2-b][l,4]diazepin-5- yl)phenyl]-2-naphthalenesulfonamide; -5-yl)-N-phenylbenzenesulfonamide;

[0624] (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-bromobenzenesulfonate; -5-yl)phenyl 3-bromobenzenesulfonate;

[0625] (Compound B164) N-benzyl-N-[4-(l-benzyl-2,4-dioxo-l,2,3,4-tetrahydronaphtho- [1,2-b][1,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; -5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0626] (Compound B165) N-benzyl-N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho-[l,2- b][l,4]diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; -5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0627] (Compound B166) 3-bromo-N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho-[l,2- b][l,4]diazepin-5-yl)phenyl]-N-methylbenzenesulfonamide; -5-yl)phenyl]-N-methylbenzenesulfonamide;

[0628] (Compound B167) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho-[l,2-b][l,4]- diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; -5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide;

[0629] (Compound B168) N-[4-(2,4-dioxo-l,2,3,4-tetrahydronaphtho-[l,2-b][l,4]- diazepin-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide; -5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide;

[0630] (Compound B169) N-[4-(7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-l-yl)phenyl]benzenesulfonamide; -1-yl)phenyl]benzenesulfonamide;

[0631] (Compound B170) N-[4-(7-bromo-2,4-dioxo-2,3,4,5-tetrahydro-lH- benzo[b][l,4]diazepin-l-yl)phenyl]benzenesulfonamide; -1-yl)phenyl]benzenesulfonamide;

[0632] (Compound B171) N-[4-[(2,4-dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro- lH-benzo[b][l,4]diazepin-l-yl)]phenyl]benzenesulfonamide; -1-yl)]phenyl]benzenesulfonamide;

[0633] (Compound B172)N-[4-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza] -1-yl)phenyl]benzenesulfonamide;

[0634] (Compound B173) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0635] (Compound B174) 1-(3-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0636] (Compound B175)N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diaza] [-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide;

[0637] (Compound B176)N-[4-(7-bromo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diaza] -1-yl)phenyl]benzenesulfonamide;

[0638] (Compound B177) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0639] (Compound B178) 3-Bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]benzenesulfonamide;

[0640] (Compound B179)N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza] [-5-yl)phenyl]-3-methoxybenzenesulfonamide;

[0641] (Compound B180) 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]methanesulfonamide;

[0642] (Compound B181) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)phenyl]- 1 -(2-methylphenyl)methanesulfonamide;

[0643] (Compound B182) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)phenyl]- 1 -(2-nitrophenyl)methanesulfonamide;

[0644] (Compound B183) N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)phenyl]-2-phenylethananesulfonamide;

[0645] (Compound B184) 1 -(2,3-dichlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4,8,9,10,11 - octahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)phenyl]methanesulfonamide;

[0646] (Compound B185) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy- 1 H- benzo[ 1,2-b] [ 1,4]diazepin- -1 -yl)phenyl]methanesulfonamide;

[0647] (Compound B186) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy- 1 H- benzo[ 1,2-b] [ 1,4]diazepin- -1 -yl)phenyl]methanesulfonamide;

[0648] (Compound B187) 1 -(4-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)phenyl]methanesulfonamide;

[0649] (Compound B188) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydro- naphtho[ 1,2-b] [ 1,4]diazepin- -5-yl)benzyl]methanesulfonamide;

[0650] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0651] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0652] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0653] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0654] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0655] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0656] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0657] (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide; (Compound B189) 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4-tetrahydronaphtho[ 1,2- b][l,4]diazepin-5-yl)-2-methoxyphenyl]methane sulfonamide;

[0658] (Compound B197) 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diaza] [-5-yl)phenyl]methanesulfonamide;

[0659] (Compound B198) 1-[(2-trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0660] (Compound B199) 1-(2-ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0661] (Compound B200) 1-(2,3-dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0662] (Compound B201)2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylethanesulfonamide;

[0663] (Compound B202) 1-(2-nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0664] (Compound B203) 1-(2-aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0665] (Compound B204) 1-(2-dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0666] (Compound B205) 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione hydrochloride;

[0667] (Compound B206) 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione hydrochloride;

[0668] (Compound B207) 5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione hydrochloride;

[0669] (Compound B208) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione hydrochloride;

[0670] (Compound B209) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0671] (Compound B210) 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0672] (Compound B211) 5-[4-[[4-(trifluoromethyl)pyridin-3-yl]carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione;

[0673] (Compound B212)5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diaza [2,3-f]isoquinoline-2,4(3H,5H)-dione;

[0674] (Compound B213) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-8,9,10,11-tetrahydro-1H-[1,4]diaza [2,3-f]isoquinoline-2,4(3H,5H)-dione; and

[0675] (Compound B214) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione.

[0676] More preferable compounds or pharmaceutically acceptable salts thereof as the active ingredient of the medicament of the present application include those represented by the general formulae (A) to (BII) or pharmaceutically acceptable salts thereof. Specific examples of the more preferable compounds or pharmaceutically acceptable salts thereof can include 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] diazepin-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione; 5-[3-(5-thioxo-4H-[1,2,4] diazepin-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-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1H-tetrazole -5-yl)phenyl]-3-phenylurea; 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione; 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- octahydro naphtho[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]diazepine -5-yl)phenyl]benzenesulfonamide; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4- tetrahydronaphtho[1,2-b][1,4]diazepine -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]diazepine -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]diazepine -5-yl)phenyl]methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepine -5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide; N-[4-(2,4-dioxo-1,2,3,4- tetrahydronaphtho[1,2-b][1,4]diazepine -5-yl)phenyl]-2-phenylethanedisulfonamide; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11- octahydronaphtho[1,2-b][1,4]diazepine -5-yl)phenyl]-N-methylmethanesulfonamide; 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H- naphtho[1,2-e][1,4]diazepine -2,4(3H,5H)-dione; 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2- b][1,4]diazepine -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. Note that the active ingredient of the medicament of the present application is not limited to the above specific compounds or pharmaceutically acceptable salts thereof.

[0677] Even more preferred compounds or pharmaceutically acceptable salts thereof as the effective ingredient of the medicament of the present application are included in the compounds represented by General Formulae (A) to (BII) or pharmaceutically acceptable salts thereof. Specific examples of the even more preferred compounds or pharmaceutically acceptable salts thereof can include 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-(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; 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-[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 and 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4] diazepine - 2,4(3H,5H)-dione. Note that the active ingredient of the medicament of the present application is not limited to the above specific compounds or pharmaceutically acceptable salts thereof.

[0678] Stereoisomers of the compounds represented by General Formulae (A) to (BII), such as cis-trans isomers, optically active forms, or racemic forms thereof, can also exist, all of which are encompassed in the present application.

[0679] Tautomers of the compounds represented by General Formulae (A) to (BII) can also exist, and the tautomers exhibit the same activity as the compounds and are encompassed in the present application.

[0680] Further, the compounds represented by General Formulae (A) to (BII) can have one or two or more asymmetric carbons depending on the type of substituents, and any optically active isomer or any mixture or racemic form of the optically active isomers based on the asymmetric carbons, or diastereomers or any mixture of the diastereomers based on two or more asymmetric carbons, can also be used as the active ingredient of the medicament of the present application. In the case where the compounds represented by General Formulae (A) to (BII) have a double bond or a cyclic structure, geometric isomers can exist, and in addition to pure forms of the geometric isomers, mixtures of the geometric isomers (the geometric isomers are contained in the mixture at an arbitrary ratio) can also be used as the active ingredient of the medicament of the present application.

[0681] In addition to the compounds represented by General Formulae (A) to (BII), any solvates of the salt forms of the compounds or the free forms of the compounds can also be used as the active ingredient of the medicament of the present application. The solvates also include hydrates.

[0682] In the present specification, the compounds represented by General Formulae (A) to (BII) are not particularly limited, and the compounds represented by General Formulae (A) to (BII) can include stereo isomers of the compounds, such as cis-trans isomers, optically active forms, or racemates thereof; tautomers of the compounds; any optically active isomer or racemic form of the compounds based on asymmetric carbons; and diastereomers of the compounds based on two or more asymmetric carbons and mixtures thereof.

[0683] In addition to the compounds represented by General Form (A) to (BII), acid addition salts or base addition salts of these compounds can be used as the active ingredient of the medicament of the present application. As the acid addition salts, for example, inorganic acid salts (e.g., hydrochloride, sulfate, and nitrate), organic acid salts (e.g., methanesulfonate, p-toluenesulfonate, oxalate, malate), and the like can be used, however, the acid addition salts are not limited thereto. Examples of the base addition salts can include metal salts (e.g., lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt), ammonium salts, organic amine salts (e.g., triethylamine salt and ethanolamine salt), and the like; however, the base addition salts are not limited thereto. Among these salts, pharmaceutically acceptable salts are preferably used as the active ingredient of the medicament of the present application.

[0684] The medicament of the present application can be used for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease. Preferably, the medicament of the present application can be used for the prophylaxis or treatment of ulcerative colitis or Crohn's disease as inflammatory bowel disease. More preferably, the medicament of the present application can be used for remission induction therapy or remission maintenance therapy of inflammatory bowel disease. Even more preferably, the medicament of the present application can exhibit high effectiveness in remission induction therapy or remission maintenance therapy of Crohn's disease or ulcerative colitis.

[0685] Further, the medicament of the present application can be used for inhibiting or reducing adhesion or ulceration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Further, the medicament of the present application can be used for inhibiting or reducing transmural inflammatory areas in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0686] Further, the medicament of the present application can be used for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Preferably, the medicament of the present application can be used for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. More preferably, the medicament of the present application can be used for inhibiting or reducing cellular infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease. Even more preferably, the medicament of the present application can be used for protecting or maintaining the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0687] As another aspect, the medicament of the present application can be used for the following use.

[0688] The medicament of the present application can be used for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease accompanied by adhesion or ulceration in the intestinal tissue.

[0689] The medicament of the present application can be used for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease accompanied by development of transmural inflammatory areas in the intestinal tissue.

[0690] The medicament of the present application can be used for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease accompanied by histological damage in the intestinal tissue.

[0691] The medicament of the present application can be used for the prophylaxis or treatment of irritable bowel syndrome or inflammatory bowel disease accompanied by necrosis or damage of the mucosa in the intestinal tissue.

[0692] The medicament of the present application can be used for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by cell infiltration in intestinal tissue.

[0693] The medicament of the present application can be used for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by increase of proinflammatory cytokine.

[0694] The medicament of the present application can be used for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by increase of interleukin-1β.

[0695] The medicament of the present application can be used for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and increase of proinflammatory cytokine.

[0696] The medicament of the present application can be used for preventing or treating irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and increase of interleukin-1β.

[0697] All of these inflammatory bowel diseases are the application targets of the medicament of the present application. Note that the application target of the medicament of the present application is not limited to this.

[0698] The medicament of the present application can be administered by oral administration or parenteral administration. The medicament of the present application can be manufactured in a suitable dosage form, such as tablets, granules, powders, capsules, suspensions, inhalants, dry powder inhalers, inhalation liquids, aerosol inhalers, injections, and suppositories, according to a general method in the technical field of pharmaceutical preparations.

[0699] These pharmaceutical preparations can be manufactured using general techniques. For example, in the case of tablets, general pharmaceutically acceptable additives such as diluents, disintegrants, binders, lubricants, and coloring agents can be used. Examples of the diluents can include lactose, D-mannitol, microcrystalline cellulose, glucose, and the like. Examples of the disintegrants can include starch, carboxymethylcellulose calcium (CMC-Ca), and the like. Examples of the lubricants can include magnesium stearate, talc, and the like. Examples of the binders can include hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), and the like.

[0700] Pharmaceutically acceptable additives such as solvents, stabilizers, solubilizers, suspending agents, emulsifiers, analgesics, buffers, and antiseptics are used for adjusting injections. A person skilled in the art can appropriately select pharmaceutically acceptable additives and methods of preparing pharmaceutical preparations.

[0701] In other words, the medicament of the present application can be provided as a pharmaceutical composition containing an active ingredient and pharmaceutically acceptable additives.

[0702] The type of inhalant for parenteral administration includes an aerosol, a dry powder for inhalation, a liquid agent for inhalation (e.g., a solution for inhalation, a suspension for inhalation, etc.), and a capsule for inhalation, and the liquid agent for inhalation can be in a form that is used by being dissolved or suspended in water or other suitable medium at the time of use. A suitable inhalation container is used to administer the inhalant. For example, when the liquid agent for inhalation is administered, a nebulizer (atomizer or sprayer), etc. can be used, and when the dry powder for inhalation is administered, an inhaler for dry powder medicine, etc. can be used.

[0703] The inhalant can be manufactured according to known methods. For example, the inhalant is manufactured by obtaining a dry powder or a liquid agent of the compound represented by General Formulae (A) to (BII), blending the dry powder or the liquid agent of the compound into an inhalation propellant or a carrier, and filling a suitable inhalation container with the blended product. In the case where the compound represented by General Formulae (A) to (BII) is powdered, the powdering is performed according to a general method. For example, the dry powder is prepared by obtaining a compound and fine powders of lactose, starch, magnesium stearate, etc., thereby obtaining a homogeneous mixture; or granulating the compound. In addition, in the case where the compound represented by General Formulae (A) to (BII) is liquefied, for example, the compound can be dissolved in a liquid carrier such as water, physiological saline, and an organic solvent. As the propellant, a conventionally known propellant is used, such as an alternative chlorofluorocarbon, a liquefied gas propellant (e.g., a fluorinated hydrocarbon, a liquefied petroleum, diethyl ether, dimethyl ether, etc.), a compressed gas (e.g., a soluble gas (e.g., carbon dioxide gas, nitrous oxide gas, etc.), an insoluble gas (e.g., nitrogen, etc.)), etc.

[0704] The pharmaceutically acceptable additive can be suitably blended into the inhalant as needed. The additive can be any additive generally used. For example, solid diluents (e.g., sucrose, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid diluents (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, ammonium glycyrrhizinate, glycine, orange powder, etc.), preservatives (e.g., sodium benzoate, sodium bisulfite, methyl paraben, propyl paraben, etc.), stabilizers (e.g., citric acid, sodium citrate, etc.), suspending or emulsifying agents (e.g., methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, lecithin, sorbitan trioleate, etc.), dispersing agents (e.g., surfactants, etc.), solvents (e.g., water, etc.), tonicity agents (e.g., sodium chloride, concentrated glycerol, etc.), pH adjusters (e.g., hydrochloric acid, sulfuric acid, etc.), solubilizers (e.g., ethanol, etc.), preservatives (benzalkonium chloride, p-hydroxybenzoate, etc.), coloring agents, buffering agents (sodium phosphate, sodium acetate, etc.), thickening agents (carboxyvinyl polymers, etc.), absorption enhancers, etc. can be used. The liquid agent for inhalation is prepared by, for example, suitably selecting a preservative, a coloring agent, a buffering agent, a tonicity agent, a thickening agent, an absorption enhancer, etc. as needed. In addition, the dry powder agent for inhalation is prepared by, for example, suitably selecting a lubricant, a binder, a diluent, a coloring agent, a preservative, an absorption enhancer (bile salts, chitosan, etc.), etc. as needed.

[0705] In addition, in order to prepare the compound represented by General Formulas (A) to (BII) into a sustained release form, the inhalant can include a biodegradable polymer. Examples of the biodegradable polymer can include a fatty acid ester polymer or a copolymer thereof, a polyacrylate, a polyhydroxybutyric acid, a polyoxalate alkylene ester, a polyortho ester, a polycarbonate, and a polyamino acid, and one polymer can be used alone, or two or more kinds thereof can be used in combination. In addition, a phospholipid such as egg yolk lecithin, chitosan, etc. can also be used. Examples of the fatty acid ester polymer or the copolymer thereof can include polylactic acid, polyglycolic acid, polylactic acid, polymalic acid, and lactic acid-glycolic acid copolymer, and one polymer or copolymer can be used alone, or two or more kinds thereof can be used in combination. In addition, one of poly-α-cyanoacrylate, poly-β-hydroxybutyric acid, polytrimethylene oxide, polyortho ester, polyorthocarbonate, polyethylene carbonate, poly-γ-benzyl-L-glutamic acid, and poly-L-alanine can be used alone, or two or more kinds thereof can be used in combination. The fatty acid ester polymer or the copolymer thereof is preferably polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer, and more preferably lactic acid-glycolic acid copolymer. In addition, microspheres or nanospheres can be prepared by encapsulating a drug using a biodegradable polymer such as lactic acid-glycolic acid copolymer.

[0706] The dose of the medicament of the present application is not particularly limited, and is generally not particularly limited for an adult.

[0707] In the case of administration by inhalant, dry powder inhaler, liquid inhalant, and aerosol inhaler, about 0.01 μg to 100 mg, and preferably 0.3 μg to 10 mg, can be administered per day as the active ingredient amount,

[0708] In the case of administration by injection, about 0.01 mg to 100 mg can be administered per day as the active ingredient amount, and

[0709] In the case of oral administration, about 0.01 mg to 2,000 mg can be administered per day. Note that the dose is not limited to the above-mentioned dose, and the dose can be increased or decreased depending on the age or symptoms.

[0710] The medicament of the present application can be used in combination with other medicaments useful for the treatment or prevention of various irritable bowel syndrome or inflammatory bowel disease. During the treatment or prevention, the individual components in such a combination can be administered separately in separate pharmaceutical preparations or in a single pharmaceutical preparation at different times or simultaneously. Thus, it should be understood that the present application encompasses both simultaneous administration and administration at different times, and administration in the present application should be interpreted in such a manner. The range of combinations of the medicament of the present application with other medicaments useful for the treatment or prevention of various irritable bowel syndrome or inflammatory bowel disease includes in principle combinations with certain pharmaceutical preparations useful for the treatment or prevention of various irritable bowel syndrome or inflammatory bowel disease.

[0711] Each of the pharmaceutical preparations in the combination pharmaceutical preparation according to the present application can be selected in various forms, and can be manufactured simultaneously with the above-mentioned pharmaceutical preparations. Furthermore, a pharmaceutical combination comprising the medicament of the present application and other medicaments useful for the treatment or prevention of various irritable bowel syndrome or inflammatory bowel disease can also be easily manufactured by a person skilled in the art according to conventional methods or conventional techniques.

[0712] The combination includes not only a combination of the medicament of the present application with one other active substance, but also a combination of the medicament of the present application with two or more other active substances. There are various examples of combinations of the medicament of the present application with one, two or more activators selected from medicaments useful for the treatment or prevention of various irritable bowel syndrome or inflammatory bowel disease.

[0713] The present application has the following aspects.

[0714] <1a> A method of preventing or treating irritable bowel syndrome or inflammatory bowel disease, the method comprising administering to a subject (e.g., a mammal, including a human) in need thereof a therapeutically effective amount of a compound having P2X4 receptor antagonistic action (e.g., a compound represented by General Formula (A) to (BII)) or a pharmaceutically acceptable salt thereof;

[0715] <2a> The method of <1a>, wherein the inflammatory bowel disease is Crohn’s disease or ulcerative colitis;

[0716] <3a> The method of <1a>, wherein the method of preventing or treating inflammatory bowel disease is remission induction therapy or remission maintenance therapy for inflammatory bowel disease;

[0717] <4a> The method of <1a>, wherein the method of preventing or treating inflammatory bowel disease is remission induction therapy or remission maintenance therapy for Crohn’s disease or ulcerative colitis;

[0718] <5a> The method of any one of <1a> to <4a>, further comprising inhibiting or reducing adhesions or ulcers in the intestinal tissue;

[0719] <6a> The method of any one of <1a> to <5a>, further comprising inhibiting or reducing transmural inflammation zones in the intestinal tissue;

[0720] <7a> The method of any one of <1a> to <6a>, further comprising inhibiting or reducing histological damage in the intestinal tissue;

[0721] <8a> The method of any one of <1a> to <7a>, further comprising inhibiting or reducing mucosal necrosis in the intestinal tissue;

[0722] <9a> The method of any one of <1a> to <8a>, further comprising inhibiting or reducing cellular infiltration in the intestinal tissue;

[0723] <10a> The method of any one of <1a> to <9a>, further comprising protecting or maintaining the mucosa in the intestinal tissue;

[0724] <11a> The method of <1a>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with adhesions or ulcers in the intestinal tissue;

[0725] <12a> The method of <1a>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with development of transmural inflammation zones in the intestinal tissue;

[0726] <13a> The method of <1a>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with histological damage in the intestinal tissue;

[0727] <14a> The method of <1a>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with necrosis or damage to the mucosa in the intestinal tissue;

[0728] <15a> The method according to <la>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by cellular infiltration in the intestinal tissue;

[0729] <16a> The method according to <la>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in proinflammatory cytokines;

[0730] <17a> The method according to <la>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by an increase in interleukin-1 beta;

[0731] <18a> The method according to <la>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and an increase in proinflammatory cytokines; and

[0732] <19a> The method according to <la>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and an increase in interleukin-1 beta.

[0733] The present application has the following other aspects.

[0734] <1b> A compound having a P2X4 receptor antagonistic effect (e.g., a compound represented by General Formula (A) to (BII)) or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease;

[0735] <2b> The compound or a pharmaceutically acceptable salt thereof for use according to <1b>, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis;

[0736] <3b> The compound or a pharmaceutically acceptable salt thereof according to <1b> for use in remission-inducing treatment or remission-maintaining treatment of inflammatory bowel disease;

[0737] <4b> The compound or a pharmaceutically acceptable salt thereof according to <2b> for use in remission-inducing treatment or remission-maintaining treatment of Crohn's disease or ulcerative colitis;

[0738] <5b> The compound or a pharmaceutically acceptable salt thereof according to any one of <1b> to <4b>, which is further used for inhibiting or reducing adhesion or ulcer in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0739] <6b> The compound or a pharmaceutically acceptable salt thereof according to any one of <1b> to <5b>, which is further used for inhibiting or reducing a transmural inflammation area in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0740] <7b> The compound or pharmaceutically acceptable salt thereof according to any one of <1b> to <6b>, further for use in inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0741] <8b> The compound or pharmaceutically acceptable salt thereof according to any one of <1b> to <7b>, further for use in inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0742] <9b> The compound or pharmaceutically acceptable salt thereof according to any one of <1b> to <8b>, further for use in inhibiting or reducing cellular infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0743] <10b> The compound or pharmaceutically acceptable salt thereof according to any one of <1b> to <9b>, further for use in protecting or maintaining the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0744] <11b> The compound or pharmaceutically 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 with adhesions or ulcers in the intestinal tissue;

[0745] <12b> The compound or pharmaceutically 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 with development of transmural inflammatory zones in the intestinal tissue;

[0746] <13b> The compound or pharmaceutically 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 with histological damage in the intestinal tissue;

[0747] <14b> The compound or pharmaceutically 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 with necrosis or damage of the mucosa in the intestinal tissue;

[0748] <15b> The compound or pharmaceutically 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 with cellular infiltration in the intestinal tissue.

[0749] <16b> The compound or pharmaceutically 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 with an increase in proinflammatory cytokines;

[0750] <17b> The compound or pharmaceutically 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 with an increase in interleukin-1 beta;

[0751] <18b> The compound or pharmaceutically acceptable salt thereof for use according to <1 b>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and increase in proinflammatory cytokines; and

[0752] <19b> The compound or pharmaceutically acceptable salt thereof for use according to <1 b>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease accompanied by colonic injury and increase in interleukin-1 beta.

[0753] The present application also has the following other aspects.

[0754] <1c> Use of a compound having P2X4 receptor antagonistic action (e.g., a compound represented by General Formula (A) to (BII) or a pharmaceutically acceptable salt thereof) for manufacturing a medicament for preventing or treating irritable bowel syndrome or inflammatory bowel disease;

[0755] <2c> The use according to <1c>, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

[0756] <3c> The use according to <1c> for manufacturing a medicament for remission induction therapy or remission maintenance therapy for inflammatory bowel disease;

[0757] <4c> The use according to <2c> for manufacturing a medicament for remission induction therapy or remission maintenance therapy for Crohn's disease or ulcerative colitis;

[0758] <5c> The use according to any one of <1c> to <4c>, wherein the medicament is further for inhibiting or reducing adhesion or ulceration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0759] <6c> The use according to any one of <1c> to <5c>, wherein the medicament is further for inhibiting or reducing a transmural inflammation area in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0760] <7c> The use according to any one of <1c> to <6c>, wherein the medicament is further for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0761] <8c> The use according to any one of <1c> to <7c>, wherein the medicament is further for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0762] <9c> The use according to any one of <1c> to <8c>, wherein the medicament is further for inhibiting or reducing cell infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0763] <10c> The use according to any one of <1c> to <9c>, the medicament further for protecting or maintaining the mucosa in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease;

[0764] <11c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with adhesions or ulcers in the intestinal tissue;

[0765] <12c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with development of transmural inflammation zones in the intestinal tissue;

[0766] <13c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with histological lesions in the intestinal tissue;

[0767] <14c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with necrosis or lesions of the mucosa in the intestinal tissue;

[0768] <15c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with cellular infiltration in the intestinal tissue;

[0769] <16c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with an increase in proinflammatory cytokines;

[0770] <17c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with an increase in interleukin-1 beta;

[0771] <18c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with colon lesions and an increase in proinflammatory cytokines; and

[0772] <19c> The use according to <1c>, wherein the irritable bowel syndrome or inflammatory bowel disease is irritable bowel syndrome or inflammatory bowel disease with colon lesions and an increase in interleukin-1 beta. EXAMPLE

[0773] Hereinafter, the present application is described more specifically with examples, but the scope of the present application is not limited to the following examples.

[0774] In the following examples, 5-[3-(5-thioxo-4H-[1,2,4] thiazolin-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-diketone sodium salt (the compound in Example 14 of WO 2010 / 093061 A: hereinafter referred to as "Compound A"), 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione (the compound in Example 48 of WO 2013 / 105608 A: hereinafter referred to as "Compound B") and other compounds shown below as P2X4 receptor antagonists:

[0775] 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; 5-[4-[2-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]-3-phenylurea; 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione; N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]benzenesulfonamide; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diaza] -5-yl)phenyl]methanesulfonamide; 1 -(2-chlorophenyl)-N-[4-(2,4-dioxo- 1,2,3,4,8,9,10,11 - octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide -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 -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 -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 -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 -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 -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 -2,4(3H,5H)-dione hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]- 1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]- 1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]- 1 H-naphtho[1,2-b][1,4]diazepine -2,4(3H,5H)-dione hydrochloride; 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]- 1 H-naphtho[1,2-b][1,4]diazepine

[0776] Note that in the examples of the present application, significant differences are indicated by the symbols "*" and "a" in Figures 1 to 8 and Figures 10 to 13 , where each of these indicates P<0.05. Furthermore, in Figures 1 to 8 and Figures 10 to 13 , the symbol "*" indicates a significant difference in comparison with the results for control rats, and the symbol "a" indicates a significant difference in comparison with the results for the DNBS-induced colitis model.

[0777] In addition, the number of samples in the embodiments of the present application is 8 to 10.

[0778] Example 1: Measurement of P2X4 receptor antagonism of the compound as an active ingredient of the present application

[0779] (Test method)

[0780] P2X4 receptor antagonism of the compound as an effective ingredient of the present application was measured. 1321N1 cells into which ATP receptors (human P2X4) were introduced were used as a P2X4 receptor stably expressing system. Cells expressing P2X4 receptors were seeded into a 96-well plate and cultured at 37°C and 5% CO2 for 24 hours for calcium measurement. A calcium fluorescent indicator Fura-2AM was dissolved in an extracellular fluid for calcium imaging, and the seeded cells were treated therewith and left to stand at room temperature for 45 minutes, thereby incorporating Fura-2AM into the cells. An enzyme marker EnVision (PerkinElmer) was used for measurement. It was observed that when the cells were irradiated with light radiated from a xenon lamp, 510 nm fluorescence F340 and F380 were emitted and passed through 340 nm and 380 nm filters, respectively, and the change in the F340 / F380 ratio was observed as an index of intracellular calcium change. Measurement was performed by adding ATP to each well so that the final concentration of ATP became 1 µM and observing the ATP-induced intracellular calcium response over time. The inhibitory activity of the test substance was measured by pre-treating the test substance for 15 minutes by adding ATP, and the inhibitory activity was calculated by comparison with the case where the test substance was not present. This result is shown in Table 29 below.

[0781] (Test results)

[0782] [Table 29]

[0783] test compound IC 50 (μM) compound A2 0.53 compound A17 (compound A) 0.27 compound B2 0.75 compound B13 0.54 compound B20 1.2 compound B48 (compound B) 0.30 compound B57 0.72 compound B71 0.4 compound B106 1.8 compound B118 1.10 compound B146 0.67 compound B173 0.064 compound B177 0.056 compound B180 0.05 compound B181 0.068 compound B183 0.42 compound B196 0.97 compound B197 0.44 compound B208 1.3 compound B209 0.94 compound B210 1.4 compound B214 0.62

[0784] Example 2 (Preparation of model animals to be used)

[0785] Sprague-Dawley rats as female albino rats (body weight 200 to 225 g) were used as model animals. Three model animals were housed in one cage, and the controlled temperature of the environment was 22 to 24°C, the humidity was 50% to 60%, the light cycle was 12 hours, and the standard laboratory feed and tap water were freely taken, and at least one week was not used after being brought into the laboratory.

[0786] Model animals were housed and treated in accordance with the provisions of the Directive 210 / 63 / UE of the European Commission approved and adopted by the Italian Government. The experiment was approved by the Animal Experiment Ethics Committee of the University of Pisa and the Italian Ministry of Health (authorization no. 674 / 2016-PR).

[0787] (Preparation of DNBS-induced colitis model)

[0788] A model of colitis induced by 2,4-dinitrobenzenesulfonic acid (hereinafter, referred to as DNBS, manufactured by Sigma-Aldrich, Inc.) (referred to as “DNBS-induced colitis model” in the present specification) was prepared.

[0789] (Induction of colitis)

[0790] The induction of colitis was performed according to the method of Antonioli L et al. (Non-patent literature 8). Under a short period of anesthesia by isoflurane (manufactured by Abbott Laboratories), 0.25 ml of 15 mg 2,4-dinitrobenzenesulfonic acid (DNBS) in 50% ethanol was rectally administered by inserting a polyethylene PE-60 tube at 8 cm from the anus. To control rats, 0.25 ml of 50% ethanol was administered.

[0791] (Control rats)

[0792] Sprague-Dawley rats (body weight 200 to 225 g) as male albino rats (model animals not treated with DNBS) were used as a control group (referred to as “control rats” in the present specification). Note that in the accompanying drawings, control rats are indicated as “control”.

[0793] The anti-inflammatory effect of Compound A on the DNBS model was confirmed in Examples 3 to 8.

[0794] The test compound used, the administration method, model observation during the test, and sample preparation were performed by the following methods.

[0795] (Test compound, administration method, etc.)

[0796] Compound A (3, 10, and 30 mg / kg) or dexamethasone (1 mg / kg) was orally administered to rats immediately after the delivery of DNBS.

[0797] Therefore, in the present experiment, it was possible to confirm the remission maintenance therapeutic effect of Compound A.

[0798] In addition, unlike the above-described groups, Compound A (30 mg / kg) was orally administered to control rats.

[0799] Note that in Examples 3 to 8, the simple expression "group administered with Compound A" or "group administered with dexamethasone" means a group in which Compound A or dexamethasone was administered immediately after the delivery of DNBS.

[0800] (Observation of DNBS-induced colitis model during the test)

[0801] Food intake was monitored every day since the start of drug treatment. In addition, the body weight of the rats was measured every morning, and diarrhea and evidence of rectal bleeding in the feces were checked during the experiment.

[0802] Shaped granular feces was defined as normal, paste-like and semi-shaped feces that did not stick to the anus was defined as loose stool, and the case where feces adhered to the fur around the tail was defined as diarrhea. In addition, the case where visible blood was present around the rectal area of the animal was defined as rectal bleeding.

[0803] (Preparation of samples)

[0804] The DNBS-induced colitis model and control rats were euthanized in a CO2chamber. After death, a mid-abdominal incision was made, and the colon was cut and then opened in the longitudinal direction (longitudinal muscle direction), washed with sterile saline, and bisected longitudinally.

[0805] Example 3 (Changes in body weight and spleen weight)

[0806] It was recorded that the body weight of the DNBS-induced colitis model decreased significantly. Specifically, 6 days after the administration of DNBS, the body weight decreased by -15 ± 5 g (-37.6% ± 4.4%). On the other hand, the control rats showed an increase in body weight (+37.5 ± 8.7 g, (+23.5% ± 3.8%)) Figure 1 A).

[0807] The body weight also decreased in the group administered with dexamethasone (1 mg / kg), while an increase in body weight was observed in the groups administered with Compound A (3, 10, and 30 mg / kg) Figure 1 A).

[0808] Here, the spleen weight was assumed to be an index of systemic inflammation. A significant increase in spleen weight (+42%) was observed in the DNBS-induced colitis model Figure 1 B).

[0809] On the other hand, compared to the DNBS-induced colitis model, the spleen weight was significantly reduced in the groups administered with Compound A and dexamethasone Figure 1 B).

[0810] As a result, it was confirmed that in the DNBS-induced colitis model, significant improvements in terms of body weight reduction and spleen weight increase were caused by the administration of Compound A.

[0811] Example 4 (macroscopic injury)

[0812] The macroscopic injury was evaluated by the following method.

[0813] (Evaluation)

[0814] The evaluation was performed by scoring the macroscopic injury of the sample. As described above, the colon tissue that had been excised and washed with physiological saline was used as the sample.

[0815] The scoring was performed according to the criteria determined by making slight modifications to the criteria reported in Non-patent Literature 11 (Non-patent Literature 12). The criteria for the macroscopic scoring of the colon injury are shown below (1) to (4) (Non-patent Literatures 8 to 10), and the total score in (1) to (4) was used as the score.

[0816] (1) Regarding the presence of ulcer: no ulcer: 0 points, hyperemia but no ulcer: 1 point, ulcer but no hyperemia or thickening of the intestinal wall: 2 points, ulcer and inflammation at one site: 3 points, ulcer and inflammation at two or more sites: 4 points, extensive injury site extending over 1 cm along the length of the colon: 5 points, and extensive injury site extending over 2 cm along the length of the colon: 6 points;

[0817] (2) Regarding the presence of adhesion between the colon tissue and other organs: no adhesion: 0 points, adhesion to only one adjacent organ: 1 point, adhesion to multiple adjacent organs: 2 points;

[0818] (3) Regarding the hardness of stool: formed stool: 0 points, loose stool: 1 point, and liquid stool: 2 points;

[0819] (4) The thickness (mm) of the colon tissue (colon wall): 1 mm was scored 1 point.

[0820] (Confirmation of anti-inflammatory effect of Compound A)

[0821] Six days after the administration of DNBS, in the DNBS-induced colitis model, the distal colon showed thickening and ulcer with a clear transmural inflammatory area. Adhesion was often observed, intestinal distension occasionally occurred, and the macroscopic injury score was 7.8 ± 1.4.

[0822] On the other hand, compared to the DNBS-induced colitis model, the group administered with Compound A at a dose of 10 and 30 mg / kg showed a significantly reduced macroscopic injury score ( Figure 2 ). Compared to the DNBS-induced colitis model, the group administered with dexamethasone showed a significantly reduced macroscopic injury score ( Figure 2 ).

[0823] As a result, it was confirmed that the histological parameters (macroscopic scores) were significantly improved by administration of Compound A.

[0824] Example 5 (microscopic damage)

[0825] Evaluation of microscopic damage was performed by the following method.

[0826] (Evaluation)

[0827] Evaluation of microscopic damage and inflammation was performed using tissue sections obtained from the entire intestinal sample and stained with hematoxylin / eosin using an optical microscope. Evaluation of the severity of intestinal inflammation was performed by scoring the microscopic damage (histological damage) of the sample. As described above, the colon tissue that had been excised and washed with physiological saline was used as the sample.

[0828] Scoring was performed according to the criteria determined by making slight modifications to the criteria reported in Non-patent Literature 11 (Non-patent Literature 12). The criteria for microscopic scoring of colon damage (scoring of histological damage) are shown below (1) to (5) (Non-patent Literatures 8 to 10), and the total score in (1) to (5) was used as the score.

[0829] Histological criteria:

[0830] (1) Loss of mucosal structure (no loss of mucosal structure: 0 points, and mild to severe loss of mucosal structure: 1 to 3 points);

[0831] (2) Cell infiltration (no cell infiltration: 0 points, and mild to severe cell infiltration: 1 to 3 points);

[0832] (3) Muscle thickening (no muscle thickening: 0 points, and mild to severe muscle thickening: 1 to 3 points);

[0833] (4) Crypt abscess (none: 0 points, and presence: 1 point);

[0834] (5) Reduction in goblet cells (no reduction: 0 points, and reduction: 1 point).

[0835] (Confirmation of anti-inflammatory effect of Compound A)

[0836] In the histological examination of the colon sample of the DNBS-induced colitis model, colitis was clearly identified, the glandular structure was completely destroyed, and showed an association with large areas of mucosal necrosis. The submucosal tissue was thickened by infiltration of labeled inflammatory cells associated with edema and vasodilation. These changes were occasionally associated with the muscle layer, and the muscle layer showed thickening as well. The mucosa and submucosal tissue around the necrotic area showed inflammation associated with infiltration of labeled cells compared to the tissue obtained from control rats. Figure 3

[0837] ​Severe damage was shown in the colon sections of rats with induced inflammation (DNBS-induced colitis model) 6 days after the administration of DNBS Figure 3 ).

[0838] In contrast to the colon tissue of the DNBS-induced colitis model, the histological damage was not affected in the colon tissue obtained from the group administered with Compound A Figure 3 ). On the other hand, in contrast to the colon tissue of the DNBS-induced colitis model, the colon tissue obtained from the group administered with 1 mg / kg of dexamethasone showed a significant increase in the microscopic score Figure 3 ).

[0839] Example 6 (TNF and IL-1 β assays)

[0840] The pro-inflammatory cytokines (tumor necrosis factor (referred to in this specification as TNF) and interleukin-1 β (referred to in this specification as IL-1 β)) in the colon tissue of the DNBS-induced colitis model subjected to intestinal damage and, in the case of the administration of Compound A, were evaluated.

[0841] (Sample preparation)

[0842] The tissue samples stored at -80°C were weighed and thawed. The tissue was homogenized with 0.3 ml of PBS (pH 7.2) per 100 mg of tissue at 4°C and centrifuged at 13,400 g and a speed of 10,894 rpm for 20 minutes. Then, an aliquot (100 μl) of the supernatant was used for the assays.

[0843] (Evaluation of the index of inducibility of inflammation in the tissue)

[0844] The levels of the pro-inflammatory cytokines TNF and IL-1 β in the tissue were measured with an enzyme-linked immunosorbent assay (ELISA) kit (BioSource International, Camarillo, CA).

[0845] (Confirmation of the anti-inflammatory effect of Compound A)

[0846] The colon damage in the DNBS-induced colitis model was associated with a significant increase in both TNF (from 2.2 ± 0.3 to 12.4 ± 0.8 pg / mg) Figure 4 A) and IL-1 β (from 9.3 ± 0.4 to 32.5 ± 1.4 pg / mg) Figure 4 B).

[0847] In the group administered with Compound A, these indicators of inflammation were not affected Figure 4 A and 4B). In contrast, the group administered with dexamethasone completely prevented inflammationFigure 4 (A and 4B).

[0848] Example 7 (Expression of closure protein in colon tissue)

[0849] Western blot analysis was conducted to observe the expression of closure protein (an integral plasma membrane protein located at tight junctions) in colon tissue of a DNBS-induced colitis model subjected to colonic injury, as well as its expression effect under the administration of compound A.

[0850] (Sample preparation)

[0851] The weight of colon tissue (30 μg protein) was measured and the tissue was homogenized in lysis buffer.

[0852] (Testing Method)

[0853] Protein quantification was performed using the Bradford method. Pre-prepared 4% to 20% polyacrylamide gels (manufactured by Bio-Rad Laboratories, Inc.) were used. Proteins are separated using a gel and then transferred to a PVDF membrane (manufactured by Bio-Rad Laboratories, Inc.). The membrane was blocked with 3% BSA diluted with Tris-buffered saline (TBS, 20 mM Tris-HCl, pH 7.5, 150 mM NaCl) containing 0.1% Tween 20. An anti-blocking protein antibody (ab167161, manufactured by Abcam plc., diluted 1:5,000) was used as the antibody. ECL reagent was used. Protein bands were detected using Western ECL Blotting Substrate (Bio-Rad Laboratories, Inc.). Concentrations were measured using ImageJ software.

[0854] (Observation of closure protein expression)

[0855] Compared with control rats, the colonic mucosa of the DNBS-induced colitis model showed a significant reduction in closure proteins. Figure 5 ).

[0856] Compared with the DNBS-induced colitis model, administration of compound A (10 mg / kg) ( Figure 5 The expression of closure protein was increased in the inflamed tissues of the group receiving either 1 mg / kg or dexamethasone (not shown in the figure).

[0857] From this result, it should be understood that Compound A counteracts the decrease in occludin observed in the DNBS-induced colitis model. Therefore, it should be understood that Compound A contributes to maintaining the health of the large intestinal tissue.

[0858] Example 8 (Expression of procaspase-1 and caspase-1 in the colon tissue)

[0859] The expression effects of procaspase-1 and caspase-1 in the colon tissue of the DNBS-induced colitis model subjected to colon injury and in the case of administration of Compound A were observed by western blotting. The sample preparation and test method were performed by the same method as in Example 7.

[0860] (Sample preparation and test method)

[0861] The sample was prepared and tested in the same manner as in Example 7, except that an anti-procaspase-1 antibody and an anti-caspase antibody (both ad1872, manufactured by Abeam pic., dilution 1:1,000) were used instead of an anti-occludin antibody as the antibody.

[0862] (Observation of procaspase-1 and caspase-1 expression)

[0863] An increase in procaspase-1 expression was observed in the DNBS-induced colitis model by western blotting Figure 6 A). In a similar manner, the induction of colitis in the DNBS-induced colitis model was associated with an increase in the expression of caspase-1 at the colon level Figure 6 B).

[0864] The group administered with Compound A (10 mg / kg) showed no decrease in caspase-1 expression in the colon induced to be inflamed Figure 6 B).

[0865] Examples 9 to 14 demonstrate the anti-inflammatory effect of Compound B on the DNBS model.

[0866] The test compound used and the administration method were performed by the following method.

[0867] (Test compound, administration method, etc.)

[0868] Compound B (3, 10, and 30 mg / kg) or dexamethasone (1 mg / kg) was orally administered to the rats immediately after the delivery of DNBS.

[0869] Therefore, it can be confirmed in this experiment that Compound B has a remission maintenance therapeutic effect.

[0870] In addition, compound B (30 mg / kg) was administered orally to control rats, unlike the groups described above.

[0871] Note that in examples 9 to 14, the groups simply expressed as "group administered with compound B" or "group administered with dexamethasone" refer to groups in which compound B or dexamethasone was administered immediately after the delivery of DNBS.

[0872] Sample preparation and observation of the model during the test were performed by the same method as the one described above for the test of compound A.

[0873] Example 9 (changes in body weight and spleen weight)

[0874] A significant decrease in body weight was recorded in the DNBS-induced colitis model. Specifically, 6 days after the administration of DNBS, the body weight decreased by -15 ± 5 g (-37.6% ± 4.4%). On the other hand, control rats showed an increase in body weight (+37.5 ± 8.7 g, (+23.5% ± 3.8%)) (p < 0.001) (Figure 1). Figure 7 A).

[0875] The body weight also decreased in the group administered with dexamethasone (1 mg / kg), while an increase in body weight was observed in the groups administered with compound B (3, 10 and 30 mg / kg) (p < 0.05) (Figure 1). Figure 7 A).

[0876] Here, the spleen weight was assumed to be an indicator of systemic inflammation. A significant increase in spleen weight (+42%) was observed in the DNBS-induced colitis model. Figure 7 B).

[0877] On the other hand, compared to the DNBS-induced colitis model, the spleen weight significantly decreased in the groups administered with compound B and dexamethasone (p < 0.05) (Figure 2). Figure 7 B).

[0878] As a result, it was confirmed that there was a significant improvement in the decrease in body weight and the increase in spleen weight in the DNBS-induced colitis model by the administration of compound B.

[0879] Example 10 (macroscopic lesions)

[0880] The evaluation of macroscopic lesions was performed by the same method as in example 4.

[0881] (Confirmation of the anti-inflammatory effect of compound B)

[0882] 6 days after the administration of DNBS, the distal colon showed thickening and ulcers with clear transmural inflammatory areas in the DNBS-induced colitis model. Adhesions were frequently observed, occasionally intestinal dilatation, and the macroscopic lesion score was 7.8 ± 1.4.

[0883] 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 ( Figure 8 ). The groups administered with dexamethasone showed a significant decrease in macroscopic damage score compared to the DNBS-induced colitis model ( Figure 8 ).

[0884] As a result, it was confirmed that the histological parameters (macroscopic score) were significantly improved by the administration of Compound B.

[0885] Example 11 (Microscopic damage)

[0886] The evaluation of microscopic damage was performed by the same method as in Example 5.

[0887] (Confirmation of anti-inflammatory effect of Compound B)

[0888] In the histological examination of the colon samples of the DNBS-induced colitis model, colitis was clearly identified, the glandular structure was completely destroyed, and showed an extensive mucosal necrosis associated. The submucosal tissue was thickened by the infiltration of labeled inflammatory cells associated with edema and vasodilation. These changes were occasionally associated with the muscular layer, and the muscular layer showed thickening as well. In comparison with the tissue obtained from control rats ( Figure 9 A), the mucosa and submucosal tissue around the necrotic area showed inflammation associated with the infiltration of labeled cells ( Figure 9 B).

[0889] At 6 days after the administration of DNBS, severe damage was shown in the colon sections of rats in which inflammation was induced (DNBS-induced colitis model) ( Figure 9 B and Figure 10 ). In comparison with the colon tissue of the DNBS-induced colitis model, the histological damage was reduced in a dose-dependent manner in the colon tissue obtained from the groups administered with Compound B ( Figure 9 C to E and Figure 10 ). In comparison with the colon tissue of the DNBS-induced colitis model, the groups administered with Compound B at doses of 10 and 30 mg / kg showed a significant improvement in microscopic score ( Figure 10 ). In comparison with the colon tissue of the DNBS-induced colitis model, the colon tissue obtained from the group administered with 1 mg / kg of dexamethasone showed a significant improvement in microscopic score ( Figure 9 F and Figure 10 ).

[0890] Example 12 (TNF and IL-1β assays)

[0891] The pro-inflammatory cytokines (TNF and IL-1 β) in the colon tissue of the DNBS-induced colitis model subjected to colon injury and the pro-inflammatory cytokines in the case of administration of Compound B were evaluated.

[0892] The sample preparation evaluation and the evaluation of the inflammation inducible indexes (TNF and IL-1 β) in the tissue were performed by the same method as in Example 6.

[0893] (Confirmation of the anti-inflammatory effect of Compound B)

[0894] The colon injury 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). In the group administered with Compound B, this inflammation index was not affected ( Figure 11 A). On the contrary, in the group administered with 1 mg / kg of dexamethasone, the inflammation was completely prevented ( Figure 11 A).

[0895] In addition, the DNBS-induced colitis model was associated with a significant increase in IL-1 β (from 9.5 ± 5.4 to 32.7 ± 1.8 pg / mg) Figure 11 B). In comparison with the DNBS-induced colitis model, the tissue IL-1 β was significantly reduced in the group administered with Compound B (3, 10 and 30 mg / kg) and in the group administered with dexamethasone (1 mg / kg) Figure 11 B).

[0896] Therefore, it should be understood that Compound B has an effect of reducing the pro-inflammatory cytokine IL-1 β.

[0897] Example 13 (Expression of occludin in colon tissue)

[0898] The effect of expression of occludin (integral plasma membrane protein located at the tight junctions) in the colon tissue of the DNBS-induced colitis model subjected to colon injury and in the case of administration of Compound B was observed by western blot. The sample preparation and the test method were performed by the same method as in Example 7.

[0899] (Observation of occludin expression)

[0900] The colon mucosa of the DNBS-induced colitis model showed a significant decrease in occludin in comparison with the control rats Figure 12 ).

[0901] In comparison with the DNBS-induced colitis model, the occludin expression was increased in the inflamed tissue of the group administered with Compound B (10 mg / kg) Figure 12 ) or dexamethasone (1 mg / kg, not shown in the figure).

[0902] From this result, it should be understood that Compound B counteracts the decrease in the occludin protein of tight junction observed in the DNBS-induced colitis model. Therefore, it should be understood that Compound B contributes to maintaining the health of the large intestinal tissue.

[0903] Example 14 (Expression of procaspase-1 and caspase-1 in the colon tissue)

[0904] The expression effect of procaspase-1 and caspase-1 in the colon tissue of the DNBS-induced colitis model subjected to colon injury and the expression effect in the case of administration of Compound B were observed by western blotting. The sample preparation and test method were performed by the same method as in Example 8.

[0905] (Observation of procaspase-1 and caspase-1 expression)

[0906] An increase in the expression of procaspase-1 in the DNBS-induced colitis model was observed by western blotting Figure 13 A). In a similar manner, the induction of colitis in the DNBS-induced colitis model was associated with the expression of caspase-1 at the level of the colon Figure 13 B).

[0907] The group administered with Compound B (10 mg / kg) showed a decrease in the expression of caspase-1 in the colon induced with inflammation compared to the DNBS-induced colitis model Figure 13 B).

[0908] Industrial applicability

[0909] The drug of the present application can be used as a drug for remission induction treatment or remission maintenance treatment of inflammatory bowel disease.

[0910] The drug of the present application can be used as a drug for remission induction treatment or remission maintenance treatment of Crohn's disease or ulcerative colitis.

[0911] The drug of the present application can be used as a drug for inhibiting or reducing adhesion or ulcer in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0912] The drug of the present application can be used as a drug for inhibiting or reducing transmural inflammatory area in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0913] The drug of the present application can be used as a drug for inhibiting or reducing histological damage in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0914] The drug of the present application can be used as a drug for inhibiting or reducing mucosal necrosis in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0915] The medicament of the present application can be used as a medicament for inhibiting or reducing cell infiltration in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

[0916] The medicament of the present application can be used as a medicament for protecting or maintaining the mucous membrane in the intestinal tissue of irritable bowel syndrome or inflammatory bowel disease.

Claims

1. Use of a compound having P2X4 receptor antagonistic activity, or a pharmaceutically acceptable salt thereof, as an active ingredient, in the preparation of a medicament for the prevention or treatment of irritable bowel syndrome or inflammatory bowel disease, wherein said compound or pharmaceutically acceptable salt thereof is selected from: A17: 5-[3-(5-thio-4H-[1,2,4]] [diazol-3-yl)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-diketone sodium salt; and B48: 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diaza -2,4(3H,5H)-dione.

2. The use according to claim 1, wherein the inflammatory bowel disease is Crohn's disease or ulcerative colitis.

3. The use according to claim 1, wherein prevention or treatment of inflammatory bowel disease is remission induction therapy or remission maintenance therapy for inflammatory bowel disease.

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