Medicines for diabetic peripheral neuropathy

Abstract

To provide a medicine for preventing and / or treating diabetic peripheral neuropathy.SOLUTION: The present invention relates to a medicine for preventing or treating a pain caused by diabetic peripheral neuropathy, the medicine comprising, as an active ingredient, 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione or a pharmaceutically acceptable salt thereof.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to a preventive or therapeutic agent for diabetic peripheral neuropathy. This application claims priority based on Japanese Patent Application No. 2018-164392, filed on September 3, 2018, the contents of which are incorporated herein by reference. [Background technology]

[0002] Diabetic neuropathy is said to be one of the three major complications of diabetes, along with diabetic retinopathy and diabetic nephropathy. Of these, diabetic neuropathy in which the peripheral nerves have suffered some kind of damage is called diabetic peripheral neuropathy. Diabetic peripheral neuropathy is classified into polyneuropathy, which is characterized by symptoms such as numbness, pain, abnormal temperature sensation, and hypoesthesia in the limbs; autonomic neuropathy, which presents with abnormal sweating and bowel movements; and mononeuropathy, which manifests as cranial nerve abnormalities such as facial nerve paralysis and external ophthalmoplegia. Of these, polyneuropathy and autonomic neuropathy are caused by abnormalities in polyol metabolism and are collectively called diffuse symmetric neuropathy. Mononeuropathy is thought to be caused by vascular occlusion.

[0003] Among these, pain in the limbs in polyneuropathy, which is said to be the earliest to develop, is classified as neuropathic pain, which is thought to be caused by dysfunction or damage to the peripheral or central nervous system itself, and its main symptoms include allodynia and hyperalgesia, in which tactile stimuli are mistaken for pain. Polyneuropathy is the most common type of diabetic neuropathy, manifesting in multiple areas of the body. It is caused by damage to sensory and motor nerves. Sensory neuropathy can cause abnormal sensations (hyperalgesia, hypoesthesia, numbness (including tingling), cold sensations, burning sensations, crawling sensations, etc.) and pain (sciatica, trigeminal neuralgia, intercostal neuralgia, or neuralgia associated with pain in the limbs). The pain is accompanied by numbness and is described as a "tingling pain," often worsening at night. Symptoms begin with pain and numbness in the extremities of the hands and feet, specifically in areas covered by socks or gloves, and a numbness that feels like tissue paper is stuck to the soles of the feet (glove-and-sock pattern). Symptoms then spread from the toes to the knees, from the hands to the elbows, and toward the center of the body. The pain described above can also be neuropathic. Motor nerve damage occurs later than sensory damage and causes muscle weakness and atrophy. Specifically, muscle atrophy and weakness in the buttocks and thighs are accompanied by pain.

[0004] Pain stimuli are received by nociceptors present at the free terminals of cutaneous sensory nerves and transmitted to the dorsal horn of the spinal cord via peripheral primary afferent C fibers or Aδ fibers. Pain information is then transmitted to higher centers via second-order neurons, ultimately reaching the limbic system and cerebral cortex, where it is perceived as pain. Recently, the finding that microglia, a type of glial cell present in the dorsal horn of the spinal cord, play an important role in pain transmission has attracted attention. In a neuropathic pain model induced by spinal nerve injury, microglia are activated in the dorsal horn of the spinal cord, and the activated microglia show a significant upregulation of the ATP receptor, P2X4, suggesting its crucial role in the development of neuropathic pain. ATP receptors are broadly classified into ionotropic ATP receptors (P2X) and G protein-coupled ATP receptors (P2Y), each with seven subtypes (P2X1-7) and eight subtypes (P2Y1, 2, 4, 6, 11-14). So far, there has been no evidence that P2X4 receptors are involved in diabetic peripheral neuropathy.

[0005] (Therapeutic drug for neuropathic pain other than that mediated by P2X4 receptor) According to Non-Patent Document 1, the current first-line drugs for neuropathic pain are the calcium channel α2δ ligands pregabalin and gabapentin, the tricyclic antidepressants amitriptyline, nortriptyline, and imipramine, and the serotonin-noradrenaline reuptake inhibitor duloxetine.

[0006] However, the mechanisms of action of these existing drugs are different from those of P2X4 receptor antagonists, and they are known to cause side effects such as drowsiness and dizziness, necessitating careful administration.

[0007] Pregabalin inhibits the release of excitatory neurotransmitters by binding to the α2δ subunit of voltage-dependent calcium channels in the central nervous system. It has been shown to have a significant analgesic effect compared to placebo for postherpetic neuralgia, pain and numbness associated with diabetic neuropathy, and pain after spinal cord injury, and also improves sleep quality and pain-related depression and anxiety. However, pregabalin has side effects such as drowsiness, dizziness, and dizziness, so careful titration is required. Furthermore, the dosage must be reduced in patients with impaired renal function. The initial dose of pregabalin is recommended as 150 mg / day, administered twice a day after breakfast and dinner, but in elderly patients and to reduce side effects, it may be started with 25–75 mg / day, administered once before bedtime.

[0008] Furthermore, gabapentin, an α2δ ligand for calcium channels, has side effects such as drowsiness and dizziness, similar to pregabalin, and requires careful gradual increase in dosage.

[0009] Furthermore, Non-Patent Document 1 describes that tricyclic antidepressants have a significant analgesic effect compared to placebo on a wide variety of peripheral and central neuropathic pain. For example, amitriptyline's analgesic effect on neuropathic pain is similar to that of amitriptyline, which is used to treat various diseases and conditions such as postherpetic neuralgia, pain and numbness due to diabetic neuropathy, traumatic nerve injury, and stroke, and its analgesic effect on the pain and numbness is almost the same. However, tricyclic antidepressants have been reported to increase the incidence of falls and sudden cardiac death in elderly patients, and should be used with caution, starting at a low dose.

[0010] Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), which is safer and easier to use than tricyclic antidepressants and is considered a better option for patients with heart disease. Clinical trials have also shown its analgesic effects compared to placebo in the treatment of pain and numbness caused by diabetic neuropathy. However, Non-Patent Document 2 reports that duloxetine can cause suicidal thoughts and suicide attempts, and that discontinuing administration (especially suddenly) can cause side effects such as dizziness, headache, and nausea, so it must be administered with caution.

[0011] As described above, the therapeutic agents for neuropathic pain other than those involving the P2X4 receptor known from Non-Patent Documents 1 and 2 can also be used as therapeutic agents for diabetic neuropathy, but they are known to cause some side effects and require careful administration, which is a problem.

[0012] Patent Document 1 describes that a P2X4 receptor antagonist can be used for diabetic neuralgia. However, the compounds described in the examples of Patent Document 1 are selective serotonin reuptake inhibitors such as Paroxetine and Floxetine, which have a completely different structure from the compound of the present application, which is a benzodiazepine derivative compound. Furthermore, no experiments have been conducted using animal models of diabetic neuropathic pain, and only experimental results using a neuropathic pain pathology model with nerve injury (L5 spinal nerve injury model) have been shown, and it has not been found that P2X4 receptor antagonists have a therapeutic effect on diabetic neuropathy.

[0013] Patent Document 2 also describes that compounds exhibiting P2X4 receptor antagonistic activity are useful as agents for preventing or treating pain associated with diabetic neuropathy. However, as in Patent Document 1, only the effects in a neuropathic pain model have been demonstrated, and it was unclear whether the compounds have a therapeutic effect on diabetic neuropathy.

[0014] The applicant of the present application has also filed patent applications relating to P2X4 receptor antagonists as shown in Patent Documents 3 to 9, but it is unclear whether any of these applications have a therapeutic effect on diabetic neuropathy. On the other hand, Patent Document 7 discloses that substances that inhibit the action of P2X4 receptors are useful as preventive or therapeutic agents for nociceptive pain, inflammatory pain, and neuropathic pain. [Prior art documents] [Patent documents]

[0015] [Patent Document 1] International Publication No. 2008 / 020651 [Patent Document 2] International Publication No. 2010 / 093061 [Patent Document 3] International Publication No. 2008 / 023847 [Patent Document 4] International Publication No. 2012 / 008478 [Patent Document 5] International Publication No. 2012 / 014910 [Patent Document 6] International Publication No. 2012 / 017876 [Patent Document 7] International Publication No. 2013 / 105608 [Patent Document 8] International Publication No. 2015 / 005468 [Patent Document 9] International Publication No. 2015 / 005467 [Non-patent literature]

[0016] [Non-Patent Document 1] Guidelines for Pharmacotherapy of Neuropathic Pain, Revised 2nd Edition (June 30, 2016, 2nd Edition, 1st Printing) [Non-patent document 2] Duloxetine Hydrochloride Capsules Cymbalta Pharmaceutical Interview Form January 2017 Revised (Revised 11th Edition) Summary of the Invention [Problem to be solved by the invention]

[0017] An object of the present invention is to provide a pharmaceutical for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, which has few side effects caused by the central nervous system and can be prevented or treated without careful administration. More specifically, an object of the present invention is to provide a pharmaceutical for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, which has no effect on the ability to drive or operate machinery, has no effect on the ability to drive a car, does not require restrictions on administration to patients engaged in dangerous operation of machinery including driving a car, or can be administered to patients engaged in dangerous operation of machinery including driving a car. Another object of the present invention is to provide a medicament for preventing or treating pain, particularly pain in the limbs, caused by diabetic peripheral neuropathy. Another object of the present invention is to provide a medicine for preventing or treating pain caused by diabetic peripheral neuropathy, particularly pain in the limbs, by using a P2X4 receptor antagonist, which has few side effects caused by the central nervous system and can be prevented or treated without careful administration. That is, a further object of the present invention is to provide a medicine for preventing or treating pain caused by diabetic peripheral neuropathy, particularly pain in the limbs, which has no effect on the ability to drive or operate machinery, has no effect on the ability to drive a car, does not require any administration restrictions for patients engaged in operating dangerous machinery including driving a car, or can be administered to patients engaged in operating dangerous machinery including driving a car. [Means for solving the problem]

[0018]

[0009] Therefore, the present inventors have conducted extensive research to solve the above problems, and as a result have found that compounds represented by general formula (I) and / or (II) having P2X4 receptor antagonist activity have little effect on coordination ability. Furthermore, the present inventors have found that the compounds have no effect on driving or machine operation ability, no effect on car driving ability, do not require any administration restrictions for patients engaged in dangerous machine operation including car driving, or can be administered to patients engaged in dangerous machine operation including car driving, are useful for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, and are also useful for preventing or treating pain caused by diabetic peripheral neuropathy, particularly pain in the limbs, and have completed the present invention.

[0019] That is, the present invention provides a pharmaceutical for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, which has no effect on the ability to drive or operate machinery, or has no effect on the ability to drive a car, or which does not require any restrictions on administration to patients engaged in operating dangerous machinery including driving a car, or which can be administered to patients engaged in operating dangerous machinery including driving a car; or a pharmaceutical for preventing or treating pain, particularly pain in the limbs, caused by diabetic peripheral neuropathy, which comprises, as an active ingredient, a compound having P2X4 receptor antagonistic activity, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0020] As a compound having a P2X4 receptor antagonistic activity, for example, a compound represented by the following general formula (I) and / or (II) can be used.

[0021] The pharmaceutical agent of the present invention has little effect on coordination ability and can therefore be used for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain, has no effect on the ability to drive or operate machinery, has no effect on the ability to drive a car, can be used without restrictions on administration to patients engaged in operating dangerous machinery, including driving a car, or can be administered to patients engaged in operating dangerous machinery, including driving a car. Furthermore, the pharmaceutical agent of the present invention can be used, for example, for the prevention and / or treatment of pain caused by diabetic peripheral neuropathy, particularly for the prevention and / or treatment of pain caused by polyneuropathy in diabetic peripheral neuropathy, or pain caused by mononeuropathy in diabetic peripheral neuropathy, and more particularly for the prevention and / or treatment of pain associated with neuropathic pain and / or pain caused by sciatica, trigeminal neuralgia, intercostal neuralgia, or pain in the limbs, particularly pain in the limbs.

[0022] From another aspect, the present invention provides use of a compound having P2X4 receptor antagonistic activity, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for the manufacture of the above-mentioned medicament; and a method for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, which comprises administering a prophylactically or therapeutically effective amount of a compound having P2X4 receptor antagonistic activity, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a patient in need thereof, particularly a patient engaged in operating dangerous machinery including driving a car, and a method for preventing pain caused by diabetic peripheral neuropathy. and / or methods for treating pain caused by polyneuropathy in diabetic peripheral neuropathy, particularly methods for preventing and / or treating pain caused by mononeuropathy in diabetic peripheral neuropathy, and more particularly methods for preventing and / or treating pain associated with neuropathic pain and / or pain caused by sciatica, trigeminal neuralgia, intercostal neuralgia or pain in the limbs, particularly pain in the limbs, which comprise the step of administering a therapeutically effective amount of a compound having P2X4 receptor antagonistic activity, a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof to a mammal including a human. [Effects of the Invention]

[0023] The pharmaceutical of the present invention has little effect on coordination ability and can therefore be used for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain, and is useful as a pharmaceutical that has no evident effect on the ability to drive or operate machinery, has no evident effect on the ability to drive a car, can be used without administration restrictions by patients engaged in operating dangerous machinery, including driving a car, or can be administered to patients engaged in operating dangerous machinery, including driving a car. Furthermore, the medicament of the present invention is useful as a medicament for preventing and / or treating pain caused by diabetic peripheral neuropathy, particularly as a medicament for preventing and / or treating pain caused by polyneuropathy in diabetic peripheral neuropathy, or as a medicament for preventing and / or treating pain caused by mononeuropathy in diabetic peripheral neuropathy, and more particularly can exhibit high efficacy as a medicament for preventing and / or treating pain associated with neuropathic pain and / or pain caused by sciatica, trigeminal neuralgia, intercostal neuralgia or pain in the limbs, particularly pain in the limbs. Furthermore, it is possible to provide a medicine that has few side effects caused by the central nervous system when used and can be prevented or treated without careful administration. That is, it is possible to provide a medicine for preventing or treating pain caused by diabetic peripheral neuropathy, particularly pain in the limbs, that has no effect on the ability to drive or operate machinery, that has no effect on the ability to drive a car, that does not require restrictions on administration to patients engaged in operating dangerous machinery including driving a car, or that can be administered to patients engaged in operating dangerous machinery including driving a car. [Brief explanation of the drawings]

[0024] [Figure 1] FIG. 1 is a graph showing the calculation of 50% withdrawal response thresholds after oral administration of compound A to STZ-induced diabetic neuropathy model rats and stimulation by up-down stimulation method. DETAILED DESCRIPTION OF THE INVENTION

[0025] The active ingredient of the pharmaceutical of the present invention may be a compound represented by the following general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0026] In this specification, the term "machine" as used in "machine operation" or "hazardous machine operation" refers to any machine whose operation may be affected by a decrease in coordinated motor skills, and examples thereof include automobiles, bicycles, motorcycles, and various machine tools.

[0027] As used herein, "restricting administration" means restricting administration to patients in consideration of side effects other than the analgesic effect, which is the main effect of the medicament of the present invention, and examples thereof include restricting the administration time. More specifically, examples include prohibiting administration or reducing the dosage before engaging in dangerous machinery operations, including driving a car (e.g., prohibiting administration or reducing the dosage within 12 hours, 6 hours, 3 hours, or 1 hour before engaging in dangerous machinery operations, including driving a car), or prohibiting administration or reducing the dosage while engaging in dangerous machinery operations, including driving a car. As used herein, the term "administration" can be read as "taking the medicine."

[0028] As used herein, "no effect is observed" when describing "no effect on the ability to drive or operate machines" or "no effect on the ability to drive a car" means that no significant difference is observed when comparing subjects administered with a placebo or control and subjects administered with the medicament of the present invention. In another aspect, "no effect is observed" when describing "no effect on the ability to drive or operate machines" or "no effect on the ability to drive a car" means that when comparing subjects administered with the medicament of the present invention, the effect on driving or operating machines or the effect on the ability to drive a car is significantly smaller in subjects administered with the medicament of the present invention, when comparing subjects administered with a placebo or control, a sham drug or comparison drug that has the aforementioned effect.

[0029] In this specification, "prevention" of pain is a concept that includes preventing the onset of pain before it occurs and actions to achieve this. As used herein, "treatment" of pain refers to reducing, eliminating, curing, healing, or remission of pain, and the actions therefor. In another embodiment, the "treatment" refers to reducing, eliminating, curing, healing, or remission of pain. The reduction, elimination, cure, healing, or remission can be evaluated by comparing with the state before administration or when a placebo or control is administered, and can also be evaluated subjectively by the patient by comparing with the state before administration.

[0030] The abbreviations used in the tables below are as follows: Me: methyl group, Et: ethyl group, Pr: n-propyl group, iPr: isopropyl group, tBu: tert-butyl group, Ac: acetyl group, Ph: phenyl group.

[0031] (A-1) The following general formula (I): [ka] (In the formula, R 1 and R 2 may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), a phenyl group which may have a substituent, a pyridyl group which may have a substituent, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms); or R 1 and R 2may be taken together with the benzene ring to which they are attached to form a fused ring selected from a naphthalene ring, a quinoline ring, an isoquinoline ring, a tetrahydronaphthalene ring, an indane ring, a tetrahydroquinoline ring, or a tetrahydroisoquinoline ring, and R 1 and R 2 Together, R 1 and R 2 are bonded to a ring consisting of carbon atoms, and may be substituted with 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms); R 3 and R 4 may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy portion has 1 to 8 carbon atoms), or an aralkyl group (the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 8 carbon atoms), R 5represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), R 6 and R 7 may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, or an amino group; X represents C, CH or N; Y represents N, NH, or C(=O); However, when X is N, Y is not N or NH, Also, when X is C or CH, Y is not C(=O), A double line consisting of a solid line and a dashed line represents a single bond or a double bond. Z represents an oxygen atom or a sulfur atom; A represents a benzene ring, pyridine ring, thiophene ring, pyrimidine ring, naphthalene ring, quinoline ring, or indole ring which may have 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group, or represents a bond; B is N(R 8 )C(=O), NHCONH, CON(R 9 ), NHC(=S)NH, N(R 10 )SO2, SO2N(R 11 ) or OSO2, where R8 , R 9 , R 10 and R 11 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), D represents an alkylene chain having 1 to 6 carbon atoms, which may have 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkyl group or aralkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), and which may further have a double bond, or a bond; E is O, S, NR 12 , or a bond, where R 12 represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), G is a substituent 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, an alkylsulfonyl group having 1 to 6 carbon atoms, an aralkyl group (wherein the carbon atom in the aryl moiety is the number of carbon atoms in the alkylene moiety is 1 to 8), and represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, each of which may have 1 to 4 identical or different substituents selected from an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolyl group, an optionally substituted oxazolyl group, or an optionally substituted thiazolyl group; And, m represents an integer of 0 to 5. However, R 1 and R 2 do not combine with each other to form a ring, excluding the case where X is C, Y is N, the double line consisting of a solid line and a dashed line is a double bond, Z is an oxygen atom, A is a benzene ring, m is 0, B is C(=O)NH, E is a bond, and G is a phenyl group), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0032] (B-1) The following general formula (II): [ka] (In the formula, [ka] represents a naphthalene ring, a quinoline ring, an isoquinoline ring, a tetrahydronaphthalene ring, an indane ring, a tetrahydroquinoline ring, or a tetrahydroisoquinoline ring, These rings may be substituted with 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), R 3a and R 4b may be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy portion has 1 to 8 carbon atoms), or an aralkyl group (the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 8 carbon atoms), R 5a represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), R 6a and R 7amay be the same or different and represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, or an amino group; [ka] represents a benzene ring, a pyridine ring, a thiophene ring, a pyrimidine ring, a naphthalene ring, a quinoline ring, or an indole ring, which optionally has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group; B a is N(R 8a )C(=O),NHCONH,CON(R 9a ), NHC(=S)NH, N(R 10a )SO2, SO2N(R 11a ), or OSO2, where R 8a , R 9a , R 10a and R 11a represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), E a O, S, NR 12a or represents a bond, where R 12arepresents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), G a is substituted with an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, an alkylsulfonyl group having 1 to 6 carbon atoms, an aralkyl group (wherein the carbon atom in the aryl moiety is the number of carbon atoms in the alkylene moiety is 1 to 8), and represents piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine or pyrimidine, each of which may have 1 to 4 identical or different substituents selected from an optionally substituted phenyl group, an optionally substituted pyridyl group, an optionally substituted imidazolyl group, an optionally substituted oxazolyl group, or an optionally substituted thiazolyl group; and n represents an integer of 0 to 5.), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0033] The present invention will now be described in detail. In this specification, Examples of the alkyl group having 1 to 8 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an i-butyl group, a t-butyl group, a pentyl group, and a hexyl group. Examples of the cycloalkyl group having 3 to 8 carbon atoms include a cyclopropyl group and a cyclohexyl group. Examples of the alkenyl group having 2 to 8 carbon atoms include an allyl group. Examples of the alkoxy group having 1 to 8 carbon atoms include a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an i-butoxy group, a t-butoxy group, a pentyloxy group, and a hexyloxy group.

[0034] Examples of the alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methyl group, ethyl group, propyl group, isopropyl group, butyl group, or t-butyl group substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethyl group, chloromethyl group, 2-chloroethyl group, 2-bromoethyl group, or 2-fluoroethyl group. Examples of the alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms include a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, or t-butoxy group substituted with 1 to 3 halogen atoms such as fluorine atoms, chlorine atoms, or bromine atoms, and preferred examples include a trifluoromethoxy group, chloromethoxy group, 2-chloroethoxy group, 2-bromoethoxy group, or 2-fluoroethoxy group. Examples of the halogen atom include a fluorine atom, a chlorine atom, and a bromine atom.

[0035] Examples of the alkylamino group having 1 to 8 carbon atoms include a methylamino group and an ethylamino group. Examples of the dialkylamino group having 2 to 8 carbon atoms include a dimethylamino group and a diethylamino group. An example of the acylamino group having 2 to 8 carbon atoms is an acetylamino group. Examples of the acyl group having 2 to 8 carbon atoms include an acetyl group.

[0036] Examples of the alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms) include a methoxycarbonyl group. Examples of the aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms) include a benzyl group. Examples of the alkyl group having 1 to 8 carbon atoms substituted with a hydroxyl group include a 2-hydroxyethyl group.

[0037] Examples of the alkylsulfinyl group having 1 to 6 carbon atoms include a methanesulfinyl group. Examples of the alkylthio group having 1 to 6 carbon atoms include a methylthio group. Examples of the alkylsulfonyl group having 1 to 6 carbon atoms include a methanesulfonyl group.

[0038] Examples of the substituent that the optionally substituted phenyl group, optionally substituted pyridyl group, optionally substituted imidazolyl group, optionally substituted oxazolyl group and optionally substituted thiazolyl group may have include a halogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms.

[0039] As the compound of the present invention represented by the above general formula (I), the following compounds are preferred. (A-2) R 1 and R 2 wherein R, R, and R may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, a phenyl group which may have a substituent, a pyridyl group which may have a substituent, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0040] (A-3) R 1 and R 2 together with the benzene ring to which they are attached form a naphthalene ring or a tetrahydronaphthalene ring, and R 1 and R 2 Together, R 1 and R 2 and a tautomer or stereoisomer of the compound (A-1), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-4) R 1 and R 2 together form a naphthalene ring together with the benzene ring to which they are attached, and R 1 and R 2 Together, R 1 and R 2and the like are bonded to a benzene ring which is optionally substituted with 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, and an amino group; a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-5) R 1 and R 2 and (A-1) above, wherein, together with the benzene ring to which they are attached, form a naphthalene ring or a tetrahydronaphthalene ring, or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0041] (A-6) R 3 and R 4 may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), or a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-7) R 5 is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-8) R 5 is a hydrogen atom, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0042] (A-9) R 6 and R 7 may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-10) R 6 and R 7 are both hydrogen atoms, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof, according to any one of the above (A-1) to (A-9).

[0043] (A-11) R 3 , R 4 , R 5 , R 6 and R 7 is a hydrogen atom, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0044] (A-12) The compound according to any one of the above (A-1) to (A-11), wherein X is N, Y is C(=O), and the double line consisting of a solid line and a dashed line is a single bond, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-13) The compound according to any one of the above (A-1) to (A-12), wherein X is C, Y is N, and the double line consisting of a solid line and a dashed line is a double bond, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-14) The compound according to any one of the above (A-1) to (A-13), wherein Z is an oxygen atom, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0045] (A-15) The compound according to any one of the above (A-1) to (A-14), wherein A is a phenyl group or a pyridyl group even if it has 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group, as substituents, or a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-16) The compound according to any one of the above (A-1) to (A-15), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein A is a phenyl group even if having 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, or an amino group as substituents.

[0046] (A-17) The compound according to any one of the above (A-1) to (A-16), wherein A is a phenyl group or a pyridyl group, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (A-18) The compound according to any one of the above (A-1) to (A-17), wherein A is a bond, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0047] (A-19) The compound according to any one of (A-1) to (A-18) above, wherein B is NHC(=O), NHCONH, CONH, NHC(=S)NH, NHSO2, SO2NH, or OSO2, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-20) The compound according to any one of the above (A-1) to (A-19), wherein B is NHC(=O), NHCONH, or NHSO2, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0048] (A-21) A compound according to any one of the above (A-1) to (A-20), wherein B is NHC(=O) or NHSO2, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (A-22) The compound according to any one of the above (A-1) to (A-21), wherein B is NHC(=O), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0049] (A-23) The compound according to any one of the above (A-1) to (A-22), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein D is an alkylene chain having 1 to 6 carbon atoms, which may have 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, or an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, and which may further have a double bond. (A-24) The compound according to any one of the above (A-1) to (A-23), wherein D is a bond, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0050] (A-25) The compound according to any one of the above (A-1) to (A-24), wherein D has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms and an alkenyl group having 2 to 8 carbon atoms, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-26) The compound according to any one of the above (A-1) to (A-25), wherein D has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 3 carbon atoms and an alkenyl group having 2 to 3 carbon atoms, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-27) The compound according to any one of the above (A-1) to (A-26), wherein E is a bond, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0051] (A-28) G is a substituent 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 a The compound according to any one of the above (A-1) to (A-27), which is piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine, or pyrimidine, each of which may have 1 to 4 of the same or different substituents selected from alkylsulfonyl groups having 1 to 6 substituents; a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (A-29) The compound according to any one of the above (A-1) to (A-28), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein G is benzene optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms, as substituents.

[0052] (A-30) The compound according to any one of the above (A-1) to (A-29), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, wherein G is benzene or pyridine optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, an amino group, a dialkylamino group having 2 to 8 carbon atoms, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms as substituents.

[0053] (A-31) The compound according to any one of the above (A-1) to (A-30), wherein G is benzene which may have 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group, as substituents, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0054] (A-32) The compound according to any one of the above (A-1) to (A-31), wherein m is 0, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0055] (A-33) The compound according to any one of the above (A-1) to (A-32), wherein A is a benzene ring, m is 0, B is NHC(=O) or NHSO2, D is an alkyl group having 1 to 3 carbon atoms or a bond, E is a bond, and G is benzene optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group, or a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (A-34) The compound according to any one of the above (A-1) to (A-33), wherein A is a benzene ring, m is 0, B is NHC(═O), D is a bond, E is a bond, and G is benzene optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0056] (A-35) R 1 and R 2 together form a naphthalene ring together with the benzene ring to which they are attached, and R 3 , R 4 , R 5 , R 6 and R 7 represents a hydrogen atom, X is N, Y is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, Z represents an oxygen atom, A represents a benzene ring, m represents 0, B represents NHC(=O) or NHSO2, D represents an alkyl group having 1 to 3 carbon atoms or a bond, E represents a bond, and G is benzene optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as substituents, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (A-36) In the above general formula (I), R 1 and R 2 together form a naphthalene ring together with the benzene ring to which they are attached, and R 3 , R 4 , R 5 , R 6 and R 7represents a hydrogen atom, X is N, Y is C(═O), the double line consisting of a solid line and a dashed line represents a single bond, Z represents an oxygen atom, A represents a benzene ring, m represents 0, B represents NHC(═O), D represents a bond, E represents a bond, and G is benzene which may have, as substituents, 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group, or a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, according to any one of the above (A-1) to (A-35).

[0057] As the compound of the present invention represented by the above general formula (II), the following compounds are preferred. (B-2) [ka] is a naphthalene ring or a tetrahydronaphthalene ring optionally substituted by 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acylamino group having 2 to 8 carbon atoms, a carboxyl group, an acyl group having 2 to 8 carbon atoms, an alkoxycarbonyl group (the alkoxy moiety has 1 to 8 carbon atoms), or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), as well as a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (B-3) [ka] is a naphthalene ring optionally substituted with 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, and an amino group, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof, according to (B-1) or (B-2).

[0058] (B-4) R 3a and R 4a may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, or an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), or a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (B-5) R 5a is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an aralkyl group (the aryl portion has 6 to 10 carbon atoms, and the alkylene portion has 1 to 8 carbon atoms), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (B-6) R 5a is a hydrogen atom, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0059] (B-7) R 6a and R7a may be the same or different and are a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, or an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (B-8) R 6a and R 7a are both hydrogen atoms, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof, according to any one of the above (B-1) to (B-7).

[0060] (B-9) [ka] wherein R is a phenyl group or a pyridyl group even if it has 1 to 4 substituents which may be the same or different and are selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an aralkyl group (the aryl moiety has 6 to 10 carbon atoms, and the alkylene moiety has 1 to 8 carbon atoms), a phenyl group, or a pyridyl group, as substituents; a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. (B-10) [ka] is a phenyl group even though it has 1 to 4 substituents, which may be the same or different, selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, or an amino group, as substituents, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, according to any one of the above (B-1) to (B-9). (B-11) [ka] is a bond, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0061] (B-12) B a The compound according to any one of the above (B-1) to (B-11), wherein is NHC(=O), NHCONH, CONH, NHC(=S)NH, NHSO2, SO2NH, or OSO2, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (B-13) B a The compound according to any one of the above (B-1) to (B-12), wherein is NHC(=O), NHCONH, or NHSO2, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (B-14) E a is a bond, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0062] (B-15) G aand the substituent is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or a The compound according to any one of the above (B-1) to (B-14), which is piperazine, piperidine, morpholine, cyclohexane, benzene, naphthalene, quinoline, quinoxaline, benzimidazole, thiophene, imidazole, thiazole, oxazole, indole, benzofuran, pyrrole, pyridine, or pyrimidine, each optionally having 1 to 4 of the same or different substituents selected from 1 to 6 alkylsulfonyl groups, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof. (B-16) G a is benzene optionally having 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, an alkoxy group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, a cyano group, an amino group, an alkylamino group having 1 to 8 carbon atoms, a dialkylamino group having 2 to 8 carbon atoms, an acyl group having 2 to 8 carbon atoms, a methylenedioxy group, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, or an alkylsulfonyl group having 1 to 6 carbon atoms, as substituents, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[0063] (B-17) The compound according to any one of the above (B-1) to (B-16), wherein n is 0, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a hydrate or solvate thereof.

[0064] The pharmaceutical of the present invention, which can use the compounds represented by general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, can be used as an active ingredient of a pharmaceutical for the prevention and / or treatment of pain caused by diabetic peripheral neuropathy, and can also be used as a pharmaceutical for the following uses.

[0065] (C-1) The medicine according to any one of (A-1) to (A-36) and (B-1) to (B-17), wherein the neuropathic pain is caused by diabetic peripheral neuropathy.

[0066] (C-2) The pharmaceutical composition according to any one of (A-1) to (A-36), (B-1) to (B-17) and (C-1), wherein the diabetic peripheral neuropathy is polyneuropathy. (C-3) The pharmaceutical composition according to any one of (A-1) to (A-36), (B-1) to (B-17) and (C-1), wherein the diabetic peripheral neuropathy is a mononeuropathy.

[0067] (C-4) The medicine according to any one of (A-1) to (A-36), (B-1) to (B-17), and (C-1) to (C-3), wherein the pain is sciatica, trigeminal neuralgia, intercostal neuralgia, or pain in the limbs. (C-5) The medicine according to any one of (A-1) to (A-36), (B-1) to (B-17), and (C-1) to (C-3), wherein the pain is pain in the limbs.

[0068] Representative compounds encompassed by general formula (I) and / or (II) are shown below.

[0069] (Representative compound example 1)

[0070] [ka]

[0071] (In the formula, Ba (substitution position), n, Ea, and Ga are as shown in Tables 1 to 10.)

[0072] [Table 1]

[0073] [Table 2]

[0074] [Table 3]

[0075] [Table 4]

[0076] [Table 5]

[0077] [Table 6]

[0078] [Table 7]

[0079] [Table 8]

[0080] [Table 9]

[0081]

Table 10

[0082] (Representative Compound Example 2)

[0083]

Chem.

[0084] (wherein Ba(substitution position), n, Ea and Ga are as described in Tables 11 and 12)

[0085]

Table 11

[0086] ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​

[0093] (In the formula, Ba (substitution position), n, Ea, and Ga are as shown in Table 14.)

[0094] [Table 14]

[0095] (Representative compound example 5)

[0096] [ka]

[0097] (In the formula, Ba (substitution position), n, Ea, and Ga are as shown in Table 15.)

[0098] [Table 15]

[0099] (Representative compound example 6)

[0100] [ka]

[0101] (wherein B (substitution position), D, E and G are as shown in Table 16)

[0102] [Table 16]

[0103] (Representative compound example 7)

[0104] [ka]

[0105] (wherein m (substitution position), B, D, E and G are as shown in Table 17)

[0106] [Table 17]

[0107] (Representative compound example 8)

[0108] [ka]

[0109] (In the formula, Xa, Ya, Ba (substitution position), n, Ea, and Ga are as shown in Table 18.)

[0110] [Table 18]

[0111] (Representative compound example 9)

[0112] [ka]

[0113] (In the formula, I=II-III=IV, Ba (substitution position), n, Ea, and Ga are as shown in Table 19.)

[0114] [Table 19]

[0115] (Representative compound example 10)

[0116] [ka]

[0117] (In the formula, I-II-III-IV, Ba (substitution position), n, Ea, and Ga are as described in Table 20.)

[0118] [Table 20]

[0119] (Representative compound example 11)

[0120] [ka]

[0121] (In the formula, R 5a , Ba (substitution position), n, Ea and Ga are as shown in Table 21)

[0122] [Table 21]

[0123] The compounds represented by the above general formula (I) and / or (II) are disclosed in International Publication WO2013 / 105608, and any of these compounds can be easily obtained by referring to these international publications. The disclosures of these international publications are incorporated herein by reference in their entirety.

[0124] Furthermore, the above-mentioned International Publication WO2013 / 105608 describes that the compounds represented by the above-mentioned general formula (I) and / or (II) have a P2X4 receptor antagonistic activity.

[0125] Specific examples of suitable compounds encompassed by the above general formula (I) and / or (II) or pharmaceutically acceptable salts thereof are shown below, but the compounds usable as active ingredients of the medicament of the present invention or pharmaceutically acceptable salts thereof are not limited to these. (1) 5-(4-benzoylaminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (2) 5-[4-[(2-trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (3) 5-[4-(3-bromobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (4) 5-[4-[4-(trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (5) 5-[4-(2-methylbenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (6) 5-[4-(2,6-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (7) 5-[4-(2,6-dichlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (8) 5-[4-(3-chlorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (9) 5[4-(2-phenylacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (10) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylthiourea;

[0126] (11) 5-[4-(2,3-dimethoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (12) 5-[4-(2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (13) 5-[4-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (14) 5-[4-(2,3-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (15) 5-[4-(2,5-dimethylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (16) 5-[4-(5-bromo-2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (17) 5-[4-(2,4-dichlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (18) 5-[4-(2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (19) 5-[4-(2,3-dihydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (20) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-phenylurea;

[0127] (21) 5-[4-[(2,6-dichlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (22) 5-[4-[(2-methoxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (23) 5-[4-[(2-hydroxyphenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (24) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]thiourea; (25) 5-[4-[3-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (26) 5-[4-[2-[(2-trifluoromethyl)phenyl]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (27) 1-(2-chlorophenyl)-3-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]urea; (28) 5-[4-[(2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (29) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (30) 5-[4-(3-phenylpropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0128] (31) 5-[4-[(1H-indole-3-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (32) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (33) 5-[4-[(2-methyl-2-phenylpropionyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (34) 5-[4-(2-phenoxyacetylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (35) 5-[4-[2-(2-chloro-4-methoxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (36) 5-[4-[(1-methyl-1H-imidazole-2-carbonyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (37) 5-[4-[2-(2,4-dichlorophenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (38) 5-[4-[2-(2-chloro-4-hydroxyphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (39) 5-[4-(3-phenylpropenylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (40) 5-[4-[(3-pyridylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride;

[0129] (41) 5-[4-(1H-benzimidazole-2-carbonylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (42) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-methoxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (43) 5-[4-[(benzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (44) 5-[4-[(2-chlorobenzoylamino)methyl]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (45) 1-[4-(2,3-dimethylbenzoylamino)phenyl]-7-hydroxy-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (46) 5-[4-(2-chlorobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (47) 5-[4-(2-bromobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (48) 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (49) 5-[4-(2,3-dimethylbenzoylamino)-3-fluorophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (50) 5-[4-[2-(2-methylphenyl)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0130] (51) 5-[4-[(quinoxalin-2yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (52) 5-[4-[(5-methylthiophen-2yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (53) 5-[3-[(2-chlorophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (54) 5-[4-[(2,4,6-trimethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (55) 5-[4-(cyclohexylcarbonylamino)phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (56) 1-[4-(2,3-dimethylbenzoyl)aminophenyl]-6-methyl-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (57) 5-[4-[(2-ethylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (58) 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; (59) 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; (60) 1-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-(2-methylphenyl)thiourea;

[0131] (61) 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; (62) 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; (63) 5-[4-(2,3-dimethylbenzoylamino)-3-hydroxyphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (64) 5-[4-(2-chloro-3-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (65) 5-[4-[(4-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (66) 5-[4-[2-(2,4-dichlorophenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (67) 5-[4-[2-(2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (68) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)butyl]-2-chloro-3-methoxybenzamide; (69) 5-[4-(2-chloro-3-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (70) 5-[4-(2-acetylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0132] (71) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (72) 5-[2-(2-iodobenzoyl)aminoethyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (73) 5-[3-[(2-iodobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (74) 6,7-dimethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (75) 5-[4-[(1-methylpiperidin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (76) 5[4-[(benzofuran-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (77) 5-[4-[(1-methyl-1H-indol-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (78) 5-[4-(2-propenylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (79) 5-[4-(2-propylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (80) 5-[3-fluoro-4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0133] (81) 5-[4-(2-hydroxy-3-methylbenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (82) 5-[4-[(2-isopropoxybenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (83) 5-[4-[(3-methylthiophen-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (84) 5-[4-(2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (85) 5-[4-[2-(4-chloro-2-methylphenoxy)acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (86) 5-[4-[(4-fluoro-2-trifluoromethyl)benzoyl]aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (87) 5-[4-(4-fluoro-2-methoxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (88) 5-[4-(4-fluoro-2-hydroxybenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (89) 5-[3-[(2-iodophenylacetyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (90) 5-[4-(2-methyl-2-phenoxypropionylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0134] (91) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (92) 5-[4-[(3-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (93) 5-[4-(4-iodo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (94) 5-[4-(6-fluoro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (95) 5-[4-(2-hydroxy-4-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (96) 5-[4-(6-fluoro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (97) 5-[4-(2-fluorobenzoyl)aminophenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (98) 5-[4-[(2-dimethylaminobenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (99) 5-[4-(2-methoxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (100) 5-[4-(2-hydroxy-6-methylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0135] (101) 5-[4-[3-(2-methylphenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (102) 5-(4-phenylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (103) 5-(4-benzylcarbamoylphenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (104) 5-[4-[3-(2-methylphenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (105) 5-[4-[3-(2-chlorophenyl)propionylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (106) 5-[4-(2-iodobenzoyl)aminophenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (107) 5-[4-[(1-methyl-1H-pyrrol-2-ylacetyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (108) 5-[4-(2-chlorobenzyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (109) 5-[4-[3-(2-chlorophenyl)propenoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (110) 5-[4-(2-chlorophenyl)carbamoylphenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0136] (111) 5-[4-(6-bromo-2,3-methylenedioxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (112) 5-[4-(6-bromo-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (113) 5-[4-[(2-tert-butylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (114) 5-[2-(2-iodobenzoyl)aminopyridin-5-yl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (115) 5-[4-(6-bromo-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (116) 5-[4-(6-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (117) 5-[4-(2-iodobenzoylamino)phenyl]-1H-[1,4]diazepino[2,3-h]quinoline-2,4(3H,5H)-dione; (118) 5-[4-(6-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (119) 5-[4-(2-hydroxy-6-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (120) 5-[4-[2-methoxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0137] (121) 5-[4-[2-hydroxy-6-(trifluoromethyl)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (122) 5-[4-[(2-isopropenylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (123) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (124) 5-[4-[2-chloro-5-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (125) 5-[4-[2-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (126) 5-[4-[3-(methylthio)benzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (127) 5-[4-[2-ethyl-6-methoxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (128) 5-[4-(3-methanesulfonylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (129) 6-Ethyl-1-[4-(2-iodobenzoyl)aminophenyl]-1H-1,5-benzodiazepine-2,4(3H,5H)-dione; (130) 5-[4-[2-ethyl-6-hydroxybenzoylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0138] (131) 5-[4-(3-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (132) 5-[4-(2-chloro-5-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (133) 5-[4-(2-methanesulfinylbenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (134) 5-[4-[[2-(4-morpholinyl)acetyl]amino]phenyl]-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (135) 5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepin-2-one; (136) 5-[4-[[(3-chloropyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (137) 5-[4-(2-chloro-6-hydroxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2- e ]-1,4-diazepin-2-one; (138) 5-[4-(3-chloro-2-methoxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (139) 5-[4-[(3-methylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (140) 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;

[0139] (141) 5-[4-(3-chloro-2-hydroxybenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (142) 5-[4-[[(3-hydroxypyridin-2-yl)carbonyl]amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (143) 5-[4-[(3-vinylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (144) 5-[4-[(3-ethylpyridin-2-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (145) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide; (146) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (147) 3-Bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (148) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide; (149) N-[3-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (150) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-nitrobenzenesulfonamide;

[0140] (151) 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; (152) 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; (153) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (154) 4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)-N-phenylbenzenesulfonamide; (155) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diazepin-5-yl)phenyl]-2-naphthalenesulfonamide; (156) N-[3-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b]-[1,4]diazepin-5-yl)phenyl]-1-naphthalenesulfonamide; (157) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]cyclohexanesulfonamide; (158) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-3-pyridinesulfonamide hydrochloride; (159) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-4-isopropylbenzenesulfonamide; (160) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenylmethanesulfonamide;

[0141] (161) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-3-pyridinesulfonamide; (162) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-naphthalenesulfonamide; (163) 4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho-[1,2-b][1,4]diazepin-5-yl)phenyl 3-bromobenzene-sulfonate; (164) N-benzyl-N-[4-(1-benzyl-2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-nitrobenzenesulfonamide; (165) N-benzyl-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5yl)phenyl]-2-nitrobenzenesulfonamide; (166) 3-Bromo-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylbenzenesulfonamide; (167) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-methyl-2-nitrobenzenesulfonamide; (168) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-N-(2-hydroxyethyl)-2-nitrobenzenesulfonamide; (169) N-[4-(7-chloro-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (170) N-[4-(7-bromo-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide;

[0142] (171) N-[4-[(2,4-dioxo-7-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)]phenyl]benzenesulfonamide; (172) N-[4-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (173) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (174) 1-(3-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (175) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho-[1,2-b][1,4]-diazepin-5-yl)phenyl]-2-trifluoromethylbenzenesulfonamide; (176) N-[4-(7-bromo-6-methyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-1-yl)phenyl]benzenesulfonamide; (177) 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; (178) 3-Bromo-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]benzenesulfonamide; (179) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-3-methoxybenzenesulfonamide; (180) 1-(2-bromophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide;

[0143] (181) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-methylphenyl)methanesulfonamide; (182) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-nitrophenyl)methanesulfonamide; (183) N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-2-phenylethanesulfonamide; (184) 1-(2,3-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (185) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-methoxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (186) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-7-hydroxy-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (187) 1-(4-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (188) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)benzyl]methanesulfonamide; (189) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-methoxyphenyl]methanesulfonamide; (190) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)-2-hydroxyphenyl]methanesulfonamide;

[0144] (191) 1-(2,6-dichlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (192) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-6-methyl-1H-benzo[1,2-b][1,4]diazepin-1-yl)phenyl]methanesulfonamide; (193) 1-(2-chlorophenyl)-N-[4-(2,4-dioxy-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)propyl]methanesulfonamide; (194) 1-(2-chlorophenyl)-N-[2-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)ethyl]methanesulfonamide; (195) N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-1-(2-iodophenyl)methanesulfonamide; (196) 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4,8,9,10,11-octahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]-N-methylmethanesulfonamide; (197) 1-(2-chlorophenyl)-N-[4-(2-oxo-2,3-dihydro-1H-naphtho[1,2-e][1,4]diazepin-5-yl)phenyl]methanesulfonamide; (198) 1-[(2-trifluoromethyl)phenyl]-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (199) 1-(2-ethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (200) 1-(2,3-dimethylphenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide;

[0145] (201) 2-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylethanesulfonamide; (202) 1-(2-nitrophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (203) 1-(2-aminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (204) 1-(2-dimethylaminophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]phenyl-N-methylmethanesulfonamide; (205) 5-[4-[(pyridin-4-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (206) 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (207) 5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (208) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione hydrochloride; (209) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (210) 5-[4-[2-[(pyridin-2-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0146] (211) 5-[4-[[4-(trifluoromethyl)pyridin-3-yl]carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (212) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione; (213) 5-[4-[(2-chloropyridin-3-yl)carbonylamino]phenyl]-8,9,10,11-tetrahydro-1H-[1,4]diazepino[2,3-f]isoquinoline-2,4(3H,5H)-dione; (214) 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione.

[0147] In the above general formula (I), R 1 and R 2 are preferably taken together with the benzene ring to which they are attached to form a fused ring selected from a naphthalene ring or a tetrahydronaphthalene ring, and more preferably form a naphthalene ring.

[0148] In the above general formula (I), R 3 , R 4 , R 5 , R 6 and R 7 preferably represents a hydrogen atom.

[0149] In the above general formula (I), it is preferred that X is N, Y is C(=O), and the double line consisting of a solid line and a broken line is a single bond.

[0150] In the above general formula (I), Z is preferably an oxygen atom.

[0151] In the above general formula (I), A preferably represents a benzene ring or a pyridine ring, and more preferably represents a benzene ring.

[0152] In the above general formula (I), m preferably represents 0 to 4, and more preferably represents 0.

[0153] In the above general formula (I), B is N(R 8 )C(=O) or N(R 10 )SO2, where R 8 and R 10 More preferably, represents a hydrogen atom. In the above general formula (I), B preferably represents NHC(=O).

[0154] In the above general formula (I), D preferably has 1 to 4 substituents, which may be the same or different, selected from alkyl groups having 1 to 8 carbon atoms and alkenyl groups having 2 to 8 carbon atoms, or represents a bond, more preferably has 1 to 4 substituents, which may be the same or different, selected from alkyl groups having 1 to 3 carbon atoms and alkenyl groups having 2 to 3 carbon atoms, or represents a bond, and more preferably represents a bond.

[0155] In the above general formula (I), E preferably represents O or a bond, and more preferably represents a bond.

[0156] In the above general formula (I), G preferably represents benzene or pyridine which may have, as substituents, 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, a hydroxyl group, a nitro group, an amino group, a dialkylamino group having 2 to 8 carbon atoms, a carboxyl group, an alkylsulfinyl group having 1 to 6 carbon atoms, an alkylthio group having 1 to 6 carbon atoms, and an alkylsulfonyl group having 1 to 6 carbon atoms; and G preferably represents benzene which may have, as substituents, 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group.

[0157] In the above general formula (I), it is more preferable that A represents a benzene ring, m represents 0, B represents NHC(=O) or NHSO2, D represents an alkyl group having 1 to 3 carbon atoms or a bond, E represents a bond, and G represents benzene which may have 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as a substituent.

[0158] In the above general formula (I), it is more preferable that A represents a benzene ring, m represents 0, B represents NHC(═O), D represents a bond, E represents a bond, and G represents benzene which may have 1 to 4 identical or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as substituents.

[0159] In the above general formula (I), R 1 and R 2 together form a naphthalene ring together with the benzene ring to which they are attached, and R 3 , R 4 , R 5 , R 6 and R 7represents a hydrogen atom, X is N, Y is C(=O), the double line consisting of a solid line and a dashed line represents a single bond, Z represents an oxygen atom, A represents a benzene ring, m represents 0, B represents NHC(=O) or NHSO2, D represents an alkyl group having 1 to 3 carbon atoms or a bond, E represents a bond, and G represents benzene which may have 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms, an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as a substituent.

[0160] In the above general formula (I), R 1 and R 2 together form a naphthalene ring together with the benzene ring to which they are attached, and R 3 , R 4 , R 5 , R 6 and R 7 represents a hydrogen atom, X is N, Y is C(═O), the double line consisting of a solid line and a dashed line represents a single bond, Z represents an oxygen atom, A represents a benzene ring, m represents 0, B represents NHC(═O), D represents a bond, E represents a bond, and G represents benzene which may have 1 to 4 of the same or different substituents selected from an alkyl group having 1 to 8 carbon atoms substituted with 1 to 3 halogen atoms, a halogen atom, and a hydroxyl group as substituents.

[0161] Compounds more suitable as the active ingredient of the medicament of the present invention include those encompassed by general formula (I) and / or (II): 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; 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; phenyl]-1H-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; 1-(2-chlorophenyl)-N-[4-(2,4-dioxo-1,2,3,4-tetrahydronaphtho[1,2-b][1,4]diazepin-5-yl)phenyl]methanesulfonamide; and 5-[4-[(2-isopropylbenzoyl)amino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione. However, the active ingredient of the medicament of the present invention is not limited to the above-mentioned specific compounds.

[0162] The compounds represented by the above general formulas (AI) to (HI) may exist as stereoisomers such as cis-trans isomers, optically active compounds, and racemates, and all of these are included in the present invention.

[0163] Furthermore, the compounds represented by the above general formula (I) and / or (II) may have one or more asymmetric carbon atoms depending on the type of substituent, and any optical isomer based on these asymmetric carbon atoms, any mixture of optical isomers, racemates, diastereoisomers based on two or more asymmetric carbon atoms, any mixture of diastereoisomers, etc. may be used as the active ingredient of the medicament of the present invention. When the compounds represented by the above general formula (I) and / or (II) contain a double bond or a cyclic structure, geometric isomers may exist, and in addition to pure geometric isomers, mixtures of these isomers in any ratio may be used as the active ingredient of the medicament of the present invention.

[0164] In addition to the compounds represented by the general formula (I) and / or (II) above, acid addition salts or base addition salts of these compounds may also be used as the active ingredient of the medicament of the present invention. Examples of acid addition salts that can be used include, but are not limited to, mineral acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as methanesulfonate, p-toluenesulfonate, oxalate, and malate. Examples of base addition salts that can be used include, but are not limited to, metal salts such as lithium salt, sodium salt, potassium salt, magnesium salt, and calcium salt, ammonium salt, and organic amine salts such as triethylamine salt and ethanolamine salt. Among these salts, it is preferable to use a pharmaceutically acceptable salt as the active ingredient of the medicament of the present invention. Furthermore, any hydrate or solvate of the compound in free form or in salt form may also be used as the active ingredient of the medicament of the present invention.

[0165] Next, the pharmacological effects of the present invention will be described.

[0166] The compounds of the present invention were examined for their P2X4 receptor antagonistic activity by the following method.

[0167] In one embodiment, the study was performed by introducing ATP receptor (human P2X4) into 1321N1 cells and using a stable P2X4 receptor expression system. P2X4 receptor-expressing cells were seeded into a 96-well plate and cultured at 37°C and 5% CO2 for 24 hours before use in calcium measurements. The calcium fluorescent indicator Fura-2AM was dissolved in extracellular solution for calcium imaging, and the seeded cells were then incubated at room temperature for 45 minutes to allow intracellular uptake of Fura-2AM. Measurements were performed using a microplate reader, EnVision (PerkinElmer). Light emitted from a xenon lamp was passed through 340 nm and 380 nm filters, respectively, and the 510 nm fluorescence F340 and F380 emitted upon irradiation of the cells were observed. Changes in the ratio F340 / F380 were used as an index of intracellular calcium changes. ATP was added to each well to a final concentration of 1 μM, and the ATP-induced intracellular calcium response was observed over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and calculated by comparing with the activity in the absence of the test substance.

[0168] As is clear from Example 1, the compounds of the present invention exhibited excellent P2X4 receptor antagonistic activity (Table 22).

[0169] Next, we investigated whether it has an inhibitory effect on diabetic peripheral neuropathy (diabetic neuropathy). In one embodiment, the study was carried out by administering the compound of the present invention to STZ-induced diabetic neuropathy model rats, then applying stimulation by up-down stimulation method, and calculating the 50% withdrawal response threshold.

[0170] As is clear from Example 2, the compound of the present invention exhibited excellent analgesic activity in diabetic peripheral neuropathy.

[0171] Therefore, it is considered that the diazepine derivative compounds represented by the above general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof have a P2X4 receptor antagonistic activity and are useful as active ingredients of agents for preventing or treating pain caused by diabetic peripheral neuropathy.

[0172] Furthermore, the compounds of the present invention have less side effects caused by the central nervous system, such as less effect on coordination. As is clear from Example 3, the compounds of the present invention had no effect on coordinated movement ability.

[0173] Therefore, in one embodiment, the diazepine derivative compounds represented by the above general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, have P2X4 receptor antagonistic activity and are useful as active ingredients in preventive or therapeutic agents for nociceptive pain, inflammatory pain, or neuropathic pain, which have no effect on driving or machine operation ability, no effect on automobile driving ability, do not require administration restrictions for patients engaged in dangerous machine operation including automobile driving, or can be administered to patients engaged in dangerous machine operation including automobile driving. In another embodiment, the diazepine derivative compounds represented by the above general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, have P2X4 receptor antagonistic activity and are useful as active ingredients in preventive or therapeutic agents for pain caused by diabetic peripheral neuropathy, particularly pain in the limbs. Furthermore, side effects caused by the central nervous system, such as, in one embodiment, minimal effects on coordination, can be prevented or treated without careful administration. That is, in one embodiment, by using a diazepine derivative compound represented by the above general formula (I) and / or (II), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof as an active ingredient, it is possible to provide a pharmaceutical for preventing or treating pain caused by diabetic peripheral neuropathy, particularly pain in the limbs, which has no effect on the ability to drive or operate machinery, has no effect on the ability to drive a car, does not require administration restrictions for patients engaged in dangerous operation of machinery including driving a car, or can be administered to patients engaged in dangerous operation of machinery including driving a car.

[0174] In one embodiment, the diazepine derivative compound represented by the above general formula (I) and / or (II), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof has a P2X4 receptor antagonistic activity and is useful as an active ingredient of a preventive or therapeutic agent for pain caused by diabetic peripheral neuropathy, particularly a preventive or therapeutic agent for pain caused by polyneuropathy in diabetic peripheral neuropathy, or a preventive or therapeutic agent for pain caused by mononeuropathy in diabetic peripheral neuropathy, more particularly a preventive or therapeutic agent for pain associated with neuropathic pain and / or pain caused by sciatica, trigeminal neuralgia, intercostal neuralgia, or pain in the limbs, particularly pain in the limbs.

[0175] Furthermore, the preventive or therapeutic agent (sometimes referred to as a medicine) of the present invention may be used in combination with other drugs as needed, for example, in combination with opioid analgesics (morphine, fentanyl), sodium channel blockers (novocaine, lidocaine), NSAIDs (aspirin, ibuprofen), etc.

[0176] In one embodiment, the medicament of the present invention can be used for the prevention and / or treatment of pain caused by diabetic peripheral neuropathy. Preferably, it can be used for the prevention and / or treatment of pain caused by polyneuropathy in diabetic peripheral neuropathy. Alternatively, it can be used for the prevention and / or treatment of pain caused by mononeuropathy in diabetic peripheral neuropathy. More preferably, it can be used for the prevention and / or treatment of pain associated with neuropathic pain and / or pain caused by sciatica, trigeminal neuralgia, intercostal neuralgia, or pain in the limbs, particularly pain in the limbs. In either case, high efficacy can be demonstrated. All of these diabetic peripheral neuropathies are targets for the medicament of the present invention. However, the targets for the medicament of the present invention are not limited to these.

[0177] In one embodiment, a compound suitable as an active ingredient of the medicament of the present invention exhibits a dose-dependent and potent analgesic effect against pain caused by diabetic peripheral neuropathy. In one embodiment, when the compound was orally administered at 3 mg / mL to STZ-induced diabetic neuropathy model rats, the 50% withdrawal response threshold was significantly increased 2 hours and 4 hours after administration compared to the STZ control group. Furthermore, when the compound was administered at 10 mg / mL and 30 mg / mL, the 50% withdrawal response threshold was significantly increased in both cases from 1 hour to 4 hours after administration compared to the STZ control group. Furthermore, the compound exhibits efficacy both when administered intravenously and orally.

[0178] The medicament of the present invention can be administered orally or parenterally. The medicament of the present invention may be administered orally in the form of tablets, pills, granules, powders, capsules, suspensions, liquids, etc., or in the form of injections such as intrathecal, intraarticular, intravenous, or intramuscular, or in the form of parenteral administration such as suppositories, eye drops, eye ointments, transdermal liquids, ointments, creams, gels, poultices, patches, liniments, tapes, poultices, transdermal patches, transmucosal liquids, transmucosal patches, inhalants, inhalant powders, inhalant solutions, inhalant aerosols, etc., according to a conventional method in the technical field of formulations, and can be prepared as a medicament in an appropriate dosage form.

[0179] These preparations can be manufactured using common techniques, and for example, in the case of tablets, they can be provided as pharmaceutical compositions using ordinary excipients, disintegrants, binders, lubricants, pigments, etc. Examples of excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc.; disintegrants include starch, carboxymethylcellulose calcium (CMC-Ca), etc.; lubricants include magnesium stearate, talc, etc.; and binders include hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), etc.

[0180] Injectable preparations are prepared using solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. These pharmaceutical additives and preparation methods can be appropriately selected by those skilled in the art.

[0181] Inhalants for parenteral administration include aerosols, powders for inhalation, liquids for inhalation (e.g., solutions for inhalation, suspensions for inhalation, etc.), and capsule-shaped inhalants, and the liquids for inhalation may be in a form that is dissolved or suspended in water or other suitable medium before use. These inhalants can be administered using an appropriate inhalation container; for example, a sprayer (atomizer, nebulizer) or the like can be used when administering liquids for inhalation, and a powder inhaler or the like can be used when administering powders for inhalation.

[0182] These inhalants are produced according to known methods. For example, the compounds represented by general formula (I) and / or (II) are powdered or liquid, blended with an inhalation propellant and / or carrier, and filled into an appropriate inhalation container. When powdering the compounds represented by general formula (I) and / or (II), they are powdered according to conventional methods. For example, they are finely powdered with lactose, starch, magnesium stearate, etc., and then homogeneously mixed or granulated to prepare powders. When liquefying the compounds represented by general formula (I) and / or (II), for example, the compounds may be dissolved in a liquid carrier such as water, physiological saline, or an organic solvent. Examples of propellants that can be used include known propellants, such as alternatives to chlorofluorocarbons, liquefied gas propellants (e.g., fluorocarbons, liquefied petroleum, diethyl ether, dimethyl ether, etc.), compressed gases (e.g., soluble gases (e.g., carbon dioxide, nitrous oxide, etc.), and insoluble gases (e.g., nitrogen gas, etc.)).

[0183] The inhalant may further contain additives as needed. Any commonly used additives may be used, for example, solid excipients (e.g., sucrose, lactose, glucose, mannitol, sorbitol, maltose, cellulose, etc.), liquid excipients (e.g., propylene glycol, etc.), binders (starch, dextrin, methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone, polyethylene glycol, sucrose, etc.), lubricants (e.g., magnesium stearate, light anhydrous silicic acid, talc, sodium lauryl sulfate, etc.), flavoring agents (e.g., citric acid, menthol, glycyrrhizin ammonium salt, glycine, orange powder, etc.), preservatives (e.g., sodium benzoate, sulfite, etc.), and the like. Examples of suitable additives include sodium hydrogen carbonate, methylparaben, propylparaben, 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.), isotonicity agents (e.g., sodium chloride, concentrated glycerin, etc.), pH adjusters (e.g., hydrochloric acid, sulfuric acid, etc.), solubilizers (e.g., ethanol, etc.), preservatives (benzalkonium chloride, parabens, etc.), colorants, buffers (sodium phosphate, sodium acetate, etc.), thickeners (carboxyvinyl polymer, etc.), and absorption enhancers. For example, in the case of inhalation solutions, preservatives, colorants, buffers, isotonicity agents, thickeners, absorption enhancers, etc. are appropriately selected and prepared as needed. In the case of powders for inhalation, for example, lubricants, binders, excipients, colorants, preservatives, absorption enhancers (bile salts, chitosan, etc.), etc. are appropriately selected as needed and prepared.

[0184] Furthermore, inhalants may contain biodegradable polymers to sustain the release of the compounds represented by general formula (I) and / or (II). Examples of biodegradable polymers include fatty acid ester polymers or copolymers thereof, polyacrylic acid esters, polyhydroxybutyric acids, polyalkylene oxalates, polyorthoesters, polycarbonates, and polyamino acids. These may be used alone or in combination. Phospholipids such as egg yolk lecithin, chitosan, etc. may also be used. Examples of fatty acid ester polymers or copolymers thereof include polylactic acid, polyglycolic acid, polycitric acid, polymalic acid, and lactic acid-glycolic acid copolymers. These may be used alone or in combination. Other examples include polyα-cyanoacrylates, polyβ-hydroxybutyric acid, polytrimethylene oxalates, polyorthoesters, polyorthocarbonates, polyethylene carbonates, polyγ-benzyl-L-glutamic acid, and poly-L-alanine. Preferably, polylactic acid, polyglycolic acid, or lactic acid-glycolic acid copolymer is used, and more preferably, lactic acid-glycolic acid copolymer. Furthermore, microspheres or nanospheres encapsulating a drug may be prepared using biodegradable polymers such as lactic acid-glycolic acid copolymer.

[0185] Ointments are prepared by known or commonly used methods. For example, they are prepared by triturating or dissolving one or more active substances in a base. The ointment base is selected from known or commonly used bases. For example, higher fatty acids or higher fatty acid esters (adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipate esters, myristate esters, palmitate esters, stearate esters, oleate esters, etc.), waxes (beeswax, spermaceti, ceresin, etc.), surfactants (polyoxyethylene alkyl ether phosphate esters, etc.), higher alcohols (cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (dimethylpolysiloxane, etc.), hydrocarbons (hydrophilic petrolatum, white petrolatum, purified lanolin, liquid paraffin, etc.), glycols (ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents may be used alone or in combination of two or more. Furthermore, it may contain moisturizing agents, preservatives, stabilizers, antioxidants, flavoring agents, etc.

[0186] Gels are manufactured using known or commonly used methods. For example, they are manufactured and prepared by dissolving one or more active substances in a base. The gel base is selected from known or commonly used materials. For example, a single or a mixture of two or more of the following may be used: lower alcohols (ethanol, isopropyl alcohol, etc.), gelling agents (carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, ethylcellulose, etc.), neutralizing agents (triethanolamine, diisopropanolamine, etc.), surfactants (polyethylene glycol monostearate, etc.), gums, water, absorption enhancers, and anti-rash agents. Furthermore, preservatives, antioxidants, flavoring agents, etc. may also be included.

[0187] Creams are manufactured using known or commonly used formulations. For example, they are manufactured or prepared by dissolving or emulsifying one or more active substances in a base. The cream base is selected from known or commonly used bases. For example, higher fatty acid esters, lower alcohols, hydrocarbons, polyhydric alcohols (propylene glycol, 1,3-butylene glycol, etc.), higher alcohols (2-hexyldecanol, cetanol, etc.), emulsifiers (polyoxyethylene alkyl ethers, fatty acid esters, etc.), water, absorption enhancers, and anti-rash agents can be used alone or in combination of two or more. They may also contain preservatives, antioxidants, flavoring agents, etc.

[0188] Poultices are prepared using known or commonly used formulations. For example, they are prepared by dissolving one or more active substances in a base, kneading the mixture, and spreading it on a support. The poultice base is selected from known or commonly used bases. For example, thickeners (polyacrylic acid, polyvinylpyrrolidone, gum arabic, starch, gelatin, methylcellulose, etc.), humectants (urea, glycerin, propylene glycol, etc.), fillers (kaolin, zinc oxide, talc, calcium, magnesium, etc.), water, solubilizers, tackifiers, and anti-rash agents can be used alone or in combination of two or more. They may also contain preservatives, antioxidants, flavoring agents, etc.

[0189] Patches are manufactured using known or commonly used formulations. For example, they are manufactured by dissolving one or more active substances in a base and spreading the resulting mixture on a support. The base for patch is selected from known or commonly used bases. For example, a polymer base, oil or fat, higher fatty acid, tackifier, or anti-rash agent may be used alone or in combination of two or more. Furthermore, preservatives, antioxidants, flavoring agents, etc. may also be included.

[0190] Liniments are manufactured using known or commonly used formulations. For example, they are manufactured or prepared by dissolving, suspending, or emulsifying one or more active ingredients in one or more of water, alcohol (ethanol, polyethylene glycol, etc.), higher fatty acids, glycerin, soap, emulsifiers, suspending agents, etc. They may further contain preservatives, antioxidants, flavoring agents, etc.

[0191] The dosage of the pharmaceutical of the present invention is not particularly limited, but generally, for an adult, oral administration will give 0.01 mg to 2000 mg per day, injection will give about 0.01 mg to 100 mg of the active ingredient per day, inhalants, inhalable powders, inhalable liquids, and inhalable aerosols will give about 0.01 μg to 100 mg, preferably 0.3 μg to 10 mg, of the active ingredient per day, and ointments, creams, gels, poultices, patches, liniments, tapes, and poultices will give about 0.01 mg to 1000 mg of the active ingredient per day. However, the dosage is not limited to the above and can be increased or decreased depending on age, symptoms, etc.

[0192] Examples of other embodiments of the present invention include the following. a) A method for preventing or treating nociceptive pain, inflammatory pain, or neuropathic pain, comprising administering to a patient in need thereof a prophylactically or therapeutically effective amount of a compound represented by the general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof; b) The method for preventing or treating the disease described in a) above, wherein the patient is a patient engaged in operating dangerous machinery, including driving a car; c) the method of prevention or treatment according to b), wherein the administration is carried out before (e.g., within 12 hours, within 6 hours, within 3 hours, or within 1 hour before) the patient engages in operating hazardous machinery, including driving a motor vehicle, or while the patient is engaged in operating hazardous machinery, including driving a motor vehicle; d) the method for preventing or treating any one of a) to c), wherein the pain is pain in the limbs caused by diabetic peripheral neuropathy;

[0193] aa) a compound represented by the general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for use in the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain; bb) A compound represented by general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof for use in aa), wherein the pain is pain in the limbs caused by diabetic peripheral neuropathy; cc) A compound represented by general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for use in the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain, wherein the use is for use without restriction on administration to patients engaged in hazardous machinery operation, including driving a car, or for use in patients engaged in hazardous machinery operation, including driving a car; dd) the compounds represented by general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, for use in cc), wherein the use is before (e.g., within 12 hours, within 6 hours, within 3 hours, or within 1 hour before) engaging in hazardous machinery operation, including driving a motor vehicle, or while engaging in hazardous machinery operation, including driving a motor vehicle; ee) A compound represented by general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for use in cc) or dd), wherein the pain is pain in the limbs caused by diabetic peripheral neuropathy;

[0194] aaa) use of a compound represented by general formula (I) and / or (II), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, for the manufacture of a medicament for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain; bbb) The use of aaa) above, wherein the pain is pain in the extremities caused by diabetic peripheral neuropathy; ccc) Use of the compounds represented by general formula (I) and / or (II), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof, for the manufacture of a medicament for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain, wherein the medicament has no effect on the ability to drive or operate machinery, has no effect on the ability to drive a car, does not require any restriction on administration to patients engaged in operating dangerous machinery including driving a car, or can be administered to patients engaged in operating dangerous machinery including driving a car; ddd) the use of ccc) above, wherein the medication is administered to a patient before (e.g., within 12 hours, within 6 hours, within 3 hours, or within 1 hour before) engaging in hazardous machinery operation, including driving a motor vehicle, or while engaging in hazardous machinery operation, including driving a motor vehicle; or eee) The use of ccc) or ddd) above, wherein the pain is pain in the extremities caused by diabetic peripheral neuropathy. [Example]

[0195] The present invention will be described in more detail below with reference to examples, but the scope of the present invention is not limited to the following examples. In the following examples, 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (the compound of Example 48 in WO2013 / 105608: hereinafter referred to as "Compound A") was used as a P2X4 antagonist.

[0196] Example 1 (P2X4 receptor antagonism)

[0197] The P2X4 receptor antagonistic activity of the compounds of the present invention was measured. (Test Method) ATP receptor (human P2X4) was transfected into 1321N1 cells and used as a stable P2X4 receptor expression system. P2X4 receptor-expressing cells were seeded into 96-well plates and cultured at 37°C and 5% CO2 for 24 hours before calcium measurements. The calcium fluorescent indicator Fura-2AM was dissolved in calcium imaging extracellular solution and applied to the seeded cells. The cells were then incubated at room temperature for 45 minutes to allow for intracellular uptake of Fura-2AM. Measurements were performed using an EnVision microplate reader (PerkinElmer). Light emitted from a xenon lamp was filtered through 340 nm and 380 nm filters, respectively, and the resulting 510 nm fluorescence F340 and F380 were monitored. Changes in the F340 / F380 ratio were used as an index of intracellular calcium changes. ATP was added to each well to a final concentration of 1 μM, and the ATP-induced intracellular calcium response was monitored over time. The inhibitory activity of the test substance was measured by pretreating the test substance with ATP for 15 minutes, and calculated by comparing with the activity in the absence of the test substance. The results are shown in Table 22 below.

[0198] (Test results) [Table 22]

[0199] Example 2 (Suppressive effect of Compound A on diabetic neuropathy)

[0200] (Establishment of a streptozotocin (STZ)-induced diabetic neuropathy model) A model was created by intravenously administering STZ to rats as a diabetogen. The animals used in the study developed diabetic neuropathy 35 days after STZ administration.

[0201] (Blood glucose measurement) On the day before STZ administration and the day before test substance administration, approximately 100 μL of blood was collected from the tail vein using a winged injection needle equipped with a heparinized capillary. The collected blood was centrifuged in a centrifuge (centrifugation conditions: 4°C, 3,000 rpm (× 2,150 g), 15 min) to obtain plasma. Blood glucose levels were measured using an automated biochemical analyzer using the hexokinase-G-6-PDH method. Because the amount of plasma obtained was very small, measurements were performed after diluting the plasma five-fold with saline. Animals with blood glucose levels below 300 mg / dL on the day before administration of the test substance were considered not to have developed diabetes and were not used in the study.

[0202] (Grouping) The 50% withdrawal threshold was measured before administration 35 days after STZ administration, and the animals were divided into groups of two so that the average withdrawal threshold and body weight were equal in each group (50% withdrawal threshold severity: 8; body weight severity: 2). The grouping was performed using a computer program (EXSUS version 8.0 (CAC Exicare)). Among the STZ-induced diabetes model animals, animals with blood glucose levels of 300 mg / dL or less on the day before administration of the test substance were determined not to have developed diabetes and were not used in the study.

[0203] (Pain assessment) Pain evaluation was performed before administration of the test substance and 1, 2, 4, and 6 hours after administration during the preliminary breeding period and 35 days after STZ administration. A von Frey filament (applied pressure: 1, 2, 4, 6, 8, or 15 g, North Coast Medical Inc.) was applied vertically to the center of the left hind paw for 6 seconds until the filament bent. The withdrawal response was observed using the up-down stimulation method (starting with a 2 g filament. If the withdrawal response was negative, the next stronger filament was applied, and if the withdrawal response was positive, the next weaker filament was applied). The 50% withdrawal threshold was calculated from the results using the following formula (rounded to two decimal places).

[0204] (Calculation method for 50% escape response threshold) From the first time when the presence or absence of a response changed (when the escape response changed from positive to negative, or from negative to positive), stimulation was performed four more times using the up-down stimulation method. For animals that showed no reaction up to 15 g of filament, animals that reached 15 g during the fourth stimulation, or animals whose calculated value was 15 g or more, the 50% withdrawal response threshold was set to 15.00 g. 50% escape threshold = (10(Xf+k×δ)) / 10,000 Xf: The evaluated size of the last von Frey filament used K: Escape response pattern δ: average difference between the filaments used (in this test, it was set to 0.224)

[0205] (Administration method) Compound A and water for injection (Japanese Pharmacopoeia Water for Injection, trade name: Otsuka Distilled Water, manufactured by Otsuka Pharmaceutical Co., Ltd.) were orally administered to STZ-induced diabetic model rats.

[0206] (Test results) The results obtained are shown in FIG. In the STZ control group administered with water for injection, there was no change in the 50% withdrawal response threshold from before administration to 6 hours after administration. In the 3 mg / mL compound A group, the 50% withdrawal threshold was significantly elevated at 2 and 4 hours after administration compared to the STZ control group. In the 10 mg / mL and 30 mg / mL groups, the 50% withdrawal threshold was significantly elevated at 1 to 4 hours after administration compared to the STZ control group.

[0207] Example 3 (Evaluation of the effect of Compound A on coordinated motor function) (the purpose) The effects on motor coordination were examined using the Rota-rod test as an index for examining the central depressant and muscle relaxant effects.

[0208] (method) Injectable water, Compound A (60 mg / kg), and pregabalin (60 mg / kg) were orally administered in a single dose to rats (SD, male). The number of specimens for each was 8. Before the test, the rotation speed of the Rota-rod (47700, UGO BASILE SRL) was set to 10 rpm using the mark on the rotating wheel, and the rat was gently placed on the rotating rod. After confirming that the rat was stable on the rod, the time (seconds) until the rat fell off the rod was recorded. The cut-off value was set at 120 seconds. Trials were conducted before and 3 hours after administration of the test substance, with up to three trials per measurement point. If the cut-off value was reached, the walking duration was recorded as 120 seconds. If the cut-off value was not reached in all three trials, the average of the three values ​​was recorded as the walking duration at that point.

[0209] (result) Compound A reached the cut-off value of 120 seconds and showed no effect on coordination. On the other hand, the walking duration in the pregabalin group was 22±5 seconds, which was significantly lower than that in the vehicle-administered group. [Industrial Applicability]

[0210] The pharmaceutical of the present invention has little effect on coordination ability, for example, and therefore can be used for the prevention or treatment of nociceptive pain, inflammatory pain, or neuropathic pain, has no evident effect on the ability to drive or operate machinery, has no evident effect on the ability to drive a car, can be used without administration restrictions in patients engaged in operating dangerous machinery, including driving a car, or is useful as a pharmaceutical that can be administered to patients engaged in operating dangerous machinery, including driving a car.

Claims

[Claim 1] A pharmaceutical for preventing or treating pain caused by diabetic peripheral neuropathy, comprising 5-[4-(2-iodobenzoylamino)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione or a pharmaceutically acceptable salt thereof as an active ingredient.

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