Prophylactic and / or therapeutic agent for internal carotid artery stenosis

Abstract

The present disclosure addresses the problem of providing a prophylactic and / or therapeutic agent capable of effectively inhibiting progression of internal carotid artery stenosis.　This prophylactic and / or therapeutic agent for internal carotid artery stenosis includes an inhibitor of the P2X4 receptor as an active ingredient. The inhibitor of the P2X4 receptor is an antagonist against the P2X4 receptor. Examples of the antagonist against the P2X4 receptor include paroxetine, suramin, fluvoxamine, NP-1815-PX, NC-2600, NCP-916, BAY 2328065, 5-BDBD, BX430, and the like. The antagonist is preferably paroxetine.

Description

Preventive and / or therapeutic drug for internal carotid artery stenosis

[0001] The present disclosure relates to a drug for preventing and / or treating internal carotid artery stenosis. The present disclosure also relates to a method for preventing and / or treating internal carotid artery stenosis.

[0002] Internal carotid artery stenosis is a disease caused mostly by atherosclerotic lesions, in which the blood vessel narrows due to the accumulation of plaque (a mass of cholesterol) at the origin of the internal carotid artery. The arterial intima thickens, narrowing the arterial lumen, and if this progresses to severe stenosis or occlusion, it can lead to cerebral infarction (Non-Patent Documents 1 to 4).

[0003] In a cohort study of the general population aged 50 to 79, the prevalence of internal carotid artery stenosis was 7.9% in men and 1.3% in women with stenosis exceeding 50% as measured by the ECST method, and it was more common in men and tended to increase with age (Non-Patent Document 5).

[0004] Internal carotid artery stenosis is treated medically by treating underlying diseases such as diabetes, hypertension, and hyperlipidemia and administering antiplatelet drugs, or surgically by carotid endarterectomy (CEA), carotid artery stenting (CAS), and extracranial-intracranial artery bypass surgery (Non-Patent Documents 6 and 7).

[0005] However, no drugs are known that can effectively prevent and / or treat internal carotid artery stenosis.

[0006] Amarenco P, Bogousslavsky J, Callahan A 3rd, et al: Highdose atorvastatin after stroke or transient ischemic attack. N Engl J Med 355: 549-559, 2006Sabatine MS, Wiviott SD, Im K, et al: Efficacy and safety of further lowering of low-density lipoprotein cholesterol in patients starting with very low levels. JAMA Cardiol 3: 823-828, 2018Mihaylova B, Emberson J, Blackwell L, et al: The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 380: 581-590, 2012Hirt LS: Progression rate and ipsilateral neurological events in asymptomatic carotid stenosis. Stroke 45: 702-706, 2014Mannami T, Konishi M, Baba S, et al: Prevalence of asymptomatic carotid atherosclerotic lesions detected by high-resolution ultrasonography and its relation to cardiovascular risk factors in the general population of a Japanese city: the Suita study.Stroke 28: 518-525, 1997National Institute for Health and Care Excellence: Cardio vascular disease: risk assessment and reduction, including lipid modification, 2014. Available at: https: / / www.nice.org.uk / guidance / cg181 / chapter / 1-Recommendations#lifestyle-modifications-for-the-primary-and-secondary-prevention-of-cvd [Accessed: 10th February, 2018] Tsujita K, Sugiyama S, Sumida H, et al: Impact of dual lipid lowering strategy with ezetimibe and atorvastatin on coronary plaque regression in patients with percutaneous coronary intervention: the multicenter randomized controlled PRECISE-IVUS trial. J Am Coll Cardiol 66: 495-507, 2015.

[0007] The present disclosure aims to provide an effective drug for preventing and / or treating internal carotid artery stenosis.

[0008] The present inventors have conducted extensive research to solve the above problems and have found that inhibition of P2X4 receptors enables effective prevention and / or treatment of internal carotid artery stenosis. The present invention has been completed through further research based on this finding.

[0009] That is, one aspect of the present disclosure provides the following aspects of the invention. Item 1-1. A preventive and / or therapeutic agent for internal carotid artery stenosis, comprising a P2X4 receptor inhibitor as an active ingredient. Item 1-2. The preventive and / or therapeutic agent for internal carotid artery stenosis according to Item 1-1, wherein the P2X4 receptor inhibitor is paroxetine. Item 1-3. The preventive and / or therapeutic agent for internal carotid artery stenosis according to Item 1-1 or 1-2, wherein the internal carotid artery stenosis is characterized by a stenosis degree of 30% or more or an area stenosis rate of 50% or more as measured by the NASCET method. Item 1-4. The preventive and / or therapeutic agent for internal carotid artery stenosis according to any one of Items 1-1 to 1-3, which is administered in combination with an antiplatelet agent. Item 1-5. The preventive and / or therapeutic agent for internal carotid artery stenosis according to any one of Items 1-1 to 1-4, which is administered in combination with an HMG-CoA reductase inhibitor. Item 1-6. Item 2-1. A method for preventing and / or treating internal carotid artery stenosis, comprising administering a therapeutically effective amount of a P2X4 receptor inhibitor to a person in need of prevention or treatment of internal carotid artery stenosis. Item 2-2. A method for preventing and / or treating internal carotid artery stenosis, according to Item 2-1, wherein the P2X4 receptor inhibitor is paroxetine. Item 2-3. A method for preventing and / or treating internal carotid artery stenosis, according to Item 2-1 or 2-2, wherein the person in need of prevention or treatment of internal carotid artery stenosis has internal carotid artery stenosis with a stenosis degree of 30% or more by NASCET method or an area stenosis rate of 50% or more. Item 2-4. Item 2-5. The method for preventing and / or treating internal carotid artery stenosis according to any one of Items 2-1 to 2-3, wherein the P2X4 receptor inhibitor and an antiplatelet agent are administered in combination to a person in need of prevention or treatment of internal carotid artery stenosis. Item 2-6. The method for preventing and / or treating internal carotid artery stenosis according to any one of Items 2-1 to 2-4, wherein the P2X4 receptor inhibitor and an HMG-CoA reductase inhibitor are administered in combination to a person in need of prevention or treatment of internal carotid artery stenosis.Item 2-6. The method for preventing and / or treating internal carotid artery stenosis according to Item 2-5, wherein the HMG-CoA reductase inhibitor is a drug selected from the group consisting of mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin. Item 3-1. Use of a P2X4 receptor inhibitor for the manufacture of a drug for preventing and / or treating internal carotid artery stenosis. Item 3-2. The use according to Item 3-1, wherein the P2X4 receptor inhibitor is paroxetine. Item 3-3. The use according to Item 3-1 or 3-2, wherein the internal carotid artery stenosis is a stenosis degree of 30% or more or an area stenosis rate of 50% or more as determined by the NASCET method. Item 3-4. The use according to any one of Items 3-1 to 3-3, wherein the P2X4 receptor inhibitor is administered in combination with an antiplatelet drug. Item 3-5. Item 3-6. The use according to any one of Items 3-1 to 3-4, wherein the P2X4 receptor inhibitor is administered in combination with an HMG-CoA reductase inhibitor. Item 3-5. The use according to Item 3-6, wherein the HMG-CoA reductase inhibitor is a drug selected from the group consisting of mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin. Item 4-1. A P2X4 receptor inhibitor used for the prevention and / or treatment of internal carotid artery stenosis. Item 4-2. The P2X4 receptor inhibitor according to Item 4-1, wherein the P2X4 receptor inhibitor is paroxetine. Item 4-3. The preventive and / or therapeutic agent for internal carotid artery stenosis according to Item 4-1 or 4-2, wherein the internal carotid artery stenosis is a stenosis degree of 30% or more or an area stenosis rate of 50% or more as determined by the NASCET method. Item 4-4. Item 4-3. The P2X4 receptor inhibitor according to any one of Items 4-1 to 4-3, which is administered in combination with an antiplatelet drug. Item 4-5. The P2X4 receptor inhibitor according to any one of Items 4-1 to 4-4, which is administered in combination with an HMG-CoA reductase inhibitor. Item 4-6. The P2X4 receptor inhibitor according to Item 4-5, wherein the HMG-CoA reductase inhibitor is a drug selected from the group consisting of mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin.

[0010] According to the present disclosure, by using a P2X4 receptor inhibitor as an active ingredient, internal carotid artery stenosis can be effectively prevented and / or treated.

[0011] 2 is a diagram for explaining the definition of the stenosis rate by the NASCET method. Figure 3 shows images of the expression levels of MCP-1, COX-2, TNFα, IL-1β, iNOS, IL-6, and IL-18 measured by Western blotting in the carotid arteries of a control mouse (P2X4(+ / +) w / o coil) without a carotid artery constriction coil, a control mouse (P2X4(+ / +) w coil) with a carotid artery constriction coil, and a P2X4 gene-deficient mouse (P2X4(- / -) w coil) with a carotid artery constriction coil. Figure 3 shows the expression level of each gene shown in Figure 2 quantified based on the signal intensity of the band.

[0012] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings. However, these embodiments are intended to facilitate understanding of the principles of the present invention, and the scope of the present invention is not limited to the following embodiments. Other embodiments in which a person skilled in the art appropriately replaces the configuration of the following embodiments are also included in the scope of the present invention.

[0013] The preventive and / or therapeutic agent for internal carotid artery stenosis of the present disclosure contains a P2X4 receptor inhibitor as an active ingredient.

[0014] P2X receptors are nonselective cation channels, and their structure is formed by the assembly of two-pass transmembrane subunits (approximately 400-600 amino acid residues) to form an ion channel. P2X4 receptors have higher calcium permeability than other P2X receptors. In humans, P2X4 receptors are expressed in a wide range of organs, including the brain, spinal cord, heart, lungs, liver, and kidneys. Their intracellular distribution is characterized by their localization in lysosomes, but multiple sugar chains on the lysosomal lumen side of the P2X4 receptor prevent proteolysis. P2X4 receptors expressed in vascular endothelial cells are involved in vasodilatory responses and vascular remodeling induced by changes in blood flow.

[0015] The P2X4 receptor inhibitor is an antagonist to the P2X4 receptor. Examples of the antagonist to the P2X4 receptor include paroxetine, suramin, fluvoxamine, NP-1815-PX (CAS No. 1239578-79-0), NC-2600, NCP-916, BAY 2328065 (CAS No. 2147709-94-0), 5-BDBD (CAS No. 768404-03-1), BX430 (CAS No. 688309-70-8) and the like. In one embodiment of the present disclosure, paroxetine can be suitably used as the P2X4 receptor inhibitor.

[0016] Paroxetine has been used as an antidepressant under the trade name Paxil due to its other pharmacological action, namely, its serotonin reuptake inhibitory activity, and has been shown to have no significant side effects. Therefore, it is expected to be clinically applicable as a drug for the prevention and / or treatment of internal carotid artery stenosis.

[0017] Other examples of antagonists to P2X4 receptors include the compounds shown in the following (1) to (125) and pharmaceutically acceptable salts thereof. Examples of pharmaceutically acceptable salts of the compounds shown in (1) to (125) include inorganic acid salts such as hydrochlorides; alkali metal salts such as sodium salts and potassium salts; and the like. (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; (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; (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; (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; (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; (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;(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; (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; (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; (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-trifluoromethylbenzoyl)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; (91) 5-[4-(2-tert-butylbenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepine-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-hydroxyamino)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; (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; (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;(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; (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; (135) 5-[4-(2-chloro-6-methoxybenzoylamino)phenyl]-1,3-dihydronaphtho[1,2-e]-1,4-diazepine-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-diazepine-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; (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; (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-5-yl)phenyl]-3-pyridinesulfonamide; (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; (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-bromobenzenesulfonate; (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; (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; (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; (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; (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; (206) 5-[4-[2-[(pyridin-3-yl)oxy]acetylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;(207) 5-[4-[(pyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (208) 5-[4-[(2-methylpyridin-3-yl)carbonylamino]phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione; (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; (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; (215) 5-[3-(1H-tetrazol-5-yl)phenyl]-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione;

[0018] The prophylactic and / or therapeutic agent of the present disclosure may use one type of P2X4 receptor inhibitor alone, or may use two or more types of P2X4 receptor inhibitors in combination.

[0019] In the present disclosure, a P2X4 receptor inhibitor is used for preventing and / or treating internal carotid artery stenosis. In the present disclosure, when a P2X4 receptor inhibitor is used for the purpose of preventing internal carotid artery stenosis, the subject may be any person for whom prevention of internal carotid artery stenosis is desired. Examples of people for whom prevention of internal carotid artery stenosis is desired include people with arteriosclerosis and people who have been treated for internal carotid artery stenosis and are required to prevent its recurrence. In the present disclosure, when a P2X4 receptor inhibitor is used for the purpose of treating internal carotid artery stenosis, the subject may be any person for whom internal carotid artery stenosis has developed. In the present disclosure, "treatment" includes halting the progression of stenosis in internal carotid artery stenosis and slowing the rate of progression of stenosis in internal carotid artery stenosis. On the other hand, "prevention" includes suppressing the onset of internal carotid artery stenosis and delaying its onset.

[0020] The degree of stenosis in cases of internal carotid artery stenosis to which the preventive and / or therapeutic agents of the present disclosure are applicable is not particularly limited. One example is a stenosis degree of 30% or more as determined by the NASCET method. In one embodiment of the preventive and / or therapeutic agents of the present disclosure, the target patients are those with internal carotid artery stenosis with a stenosis degree of 50% or more, preferably 50 to 99%, and more preferably 50 to 90% as determined by the NASCET method. As shown in Figure 1 , the NASCET method is a method for determining the stenosis rate by dividing the normal blood vessel diameter by the patent blood vessel diameter as the numerator and the normal blood vessel diameter as the denominator. A high stenosis rate indicates a narrower patent blood vessel lumen. The internal carotid artery is one of the arteries branching from the left and right common carotid arteries, which branch from the ascending aorta, a cardiac blood vessel, and is one of the major blood vessels in the head and neck.

[0021] Another example of the degree of stenosis in cases of internal carotid artery stenosis to which the preventive and / or therapeutic agents of the present disclosure are applicable is an area stenosis rate of 50% or more. In one embodiment of the preventive and / or therapeutic agents of the present disclosure, the target of application is individuals suffering from internal carotid artery stenosis with an area stenosis rate of 50 to 99%, preferably 50 to 99%, and more preferably 50 to 90%. The area stenosis rate is a value calculated using an angiogram captured by carotid artery echocardiography according to the formula: {(original cross-sectional area of ​​the blood vessel - cross-sectional area of ​​the stenotic portion) / original cross-sectional area of ​​the blood vessel} × 100.

[0022] The subject animal to which the preventive and / or therapeutic agent of the present disclosure is administered is not particularly limited, and may be, for example, a mammal such as a human, mouse, rat, hamster, guinea pig, rabbit, cat, dog, goat, sheep, pig, cow, or monkey, but is preferably a human.

[0023] The prophylactic and / or therapeutic agent of the present disclosure may contain additives generally used in pharmaceuticals in addition to containing a P2X4 receptor inhibitor as an active ingredient.

[0024] Examples of additives include excipients, binders, lubricants, disintegrants, colorants, flavorings, emulsifiers, surfactants, solubilizers, suspending agents, isotonicity agents, buffers, preservatives, antioxidants, stabilizers, and absorption enhancers, and these can also be used in appropriate combinations as desired.

[0025] Specific examples of the excipient include lactose, sucrose, glucose, corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, light anhydrous silicic acid, aluminum silicate, calcium silicate, magnesium aluminometasilicate, and calcium hydrogen phosphate. Examples of the binder include polyvinyl alcohol, methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, and macrogol. Examples of the lubricant include magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol, and colloidal silica. Examples of the disintegrant include crystalline cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, low-substituted hydroxypropylcellulose, carboxymethylcellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethylstarch, and sodium carboxymethylstarch. Examples of the coloring agents include those permitted for use in pharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide, carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodium phosphate, and yellow aluminum lake. Examples of the flavoring agents include cocoa powder, peppermint, aromatic powder, peppermint oil, menthol, borneol, and cinnamon powder. Examples of the emulsifiers or surfactants include stearyl triethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, glycerin monostearate, sucrose fatty acid esters, and glycerin fatty acid esters. Examples of the solubilizing agents include polyethylene glycol, propylene glycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodium carbonate, sodium citrate, polysorbate 80, and nicotinamide.Examples of the suspending agent include, in addition to the surfactants, hydrophilic polymers such as polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylcellulose. Examples of the isotonic agent include glucose, sodium chloride, mannitol, and sorbitol. Examples of the buffer include buffer solutions such as phosphates, acetates, carbonates, and citrates. Examples of the preservative include methylparaben, propylparaben, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, and sorbic acid. Examples of the antioxidant include sulfites, ascorbic acid, and α-tocopherol. Examples of the stabilizer include ascorbic acid, sodium edetate, erythorbic acid, and tocopherol. Examples of the absorption enhancer include isopropyl myristate, tocopherol, and calciferol.

[0026] The method of administering the preventive and / or therapeutic agent of the present disclosure is not particularly limited, and examples thereof include oral administration, intravascular (intra-arterial or intravenous) injection, continuous infusion, subcutaneous administration, intramuscular administration, enteral administration, intraperitoneal administration, topical administration, pulmonary administration (inhalation), etc. Among these administration methods, oral administration is a preferred example.

[0027] The dosage of the preventive and / or therapeutic agent of the present disclosure can be appropriately set to a therapeutically effective amount within a range in which the P2X4 receptor inhibitor as the active ingredient is not toxic to the recipient. For example, the optimal amount can be appropriately determined depending on the recipient's physique, age, sex, etc., as well as the degree of stenosis. The same applies to the administration interval and number of times. Although not particularly limited, the dosage can be, for example, 0.01 to 1,000 mg per adult per day. Specifically, the dosage can be 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250, or 500 mg. Preferably, the dosage is 10 to 40 mg per day.

[0028] The frequency of administration of the prophylactic and / or therapeutic agent of the present disclosure is not particularly limited, and may be, for example, once or twice a day. The administration period of the prophylactic and / or therapeutic agent of the present disclosure may be appropriately determined taking into consideration the severity of symptoms of internal carotid artery stenosis, the progress of treatment, etc., and is preferably continued until the stenosis is improved.

[0029] The preventive and / or therapeutic drug of the present disclosure can also be administered in combination with an antiplatelet drug. In internal carotid artery stenosis, microthrombi generated by plaque rupture or erosion formation tend to become emboli and cause embolism at distal sites, so the platelet aggregation inhibitory effect of the antiplatelet drug is effective.

[0030] Furthermore, the prophylactic and / or therapeutic agent of the present disclosure can be administered in combination with an HMG-CoA reductase inhibitor. HMG-CoA reductase inhibitors contribute to plaque stabilization, thereby suppressing local acute occlusion due to thrombus formation following plaque rupture and occlusion due to thrombus / plaque embolism from the rupture site. The HMG-CoA reductase inhibitor is not particularly limited, and examples include mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin, and lovastatin.

[0031] The present invention will be specifically described below with reference to examples, but the present invention is not limited to these examples.

[0032] (1) Verification of the effectiveness of P2X4 receptor inhibitors. Carotid artery constriction coils were placed in the left carotid artery of 7-week-old P2X4 gene-deficient mice and control mice fed a high-cholesterol diet. After 4 weeks, the carotid arteries were excised and the carotid artery occlusion rates were compared. P2X4 gene-deficient mice were generated according to the method of Yamamoto et al. (Flow-dependent impairment of vascular tone and remodeling in P2X4-deficient mice, Nature Medicine volume 12, pages 133-137 (2006)).

[0033] As shown in Table 1 below, 9 out of 13 control mice were occluded, whereas 5 out of 16 P2X4 gene-deficient mice were occluded, showing a significantly lower carotid artery occlusion rate (p = 0.039).

[0034]

[0035] This example showed that P2X4 gene-deficient mice could suppress the progression of carotid artery stenosis compared with control mice, revealing that stimulation of P2X4 receptors is related to the progression of carotid artery stenosis and that P2X4 receptor inhibitors can suppress the progression of carotid artery stenosis.

[0036] Since P2X4 gene-deficient mice are identical to control mice in other genes, the effects of P2X4 deficiency can be observed. Therefore, the fact that the progression of carotid artery stenosis was suppressed in P2X4 gene-deficient mice compared to control mice indicates that this effect was achieved by P2X4 inhibition. This indicates that all P2X4 inhibitors, including paroxetine, are effective in suppressing the progression of carotid artery stenosis.

[0037] (2) Confirmatory Verification of the Effectiveness of Paroxetine, a P2X4 Receptor Inhibitor: To confirm the experimental results using P2X4 gene-deficient mice in a different experimental system, we also performed experiments using a P2X4 receptor inhibitor. Paroxetine has a pronounced P2X4 antagonistic effect. Therefore, we placed a carotid artery constriction coil in 7-week-old mice fed a high-cholesterol diet and simultaneously implanted a capsule (ALZET Pump Model No. 2004) subcutaneously in the abdomen to continuously administer 0.025 mg / kg paroxetine per hour (paroxetine-treated mice group). Four weeks after capsule implantation, the carotid arteries were excised and the carotid artery occlusion rate was observed. Meanwhile, we placed a carotid artery constriction coil in 7-week-old mice fed a high-cholesterol diet but did not administer paroxetine (control mice group). Four weeks after placement of the carotid artery constriction coil, the carotid arteries were excised and the carotid artery occlusion rate was observed. In the paroxetine-treated group, all four of four mice had patent carotid arteries, whereas in the control group, only four of 13 mice had patent carotid arteries and nine of 13 mice had occluded carotid arteries (Fischer's exact test, p=0.0294).

[0038] This confirmed that paroxetine, an example of a P2X4 receptor inhibitor, has the effect of suppressing the progression of carotid artery stenosis. Combined with the results of experiments using P2X4 gene-deficient mice, it can be concluded that inhibition of P2X4 has the effect of suppressing the progression of carotid artery stenosis. Therefore, it is clear that all P2X4 receptor antagonists, including suramin, fluvoxamine, NP-1815-PX, NC-2600, NCP-916, BAY 2328065, 5-BDBD, BX430, etc., also have the effect of suppressing the progression of carotid artery stenosis.

[0039] (3) Verification of Factors Associated with Internal Carotid Artery Stenosis. Multiple inflammatory factors are associated with inflammatory diseases, but the expression patterns of inflammatory factors vary depending on the disease. Multiple inflammatory factors are also associated with internal carotid artery stenosis, and carotid artery stenosis has a unique expression pattern. Therefore, a carotid artery constriction coil was placed in the left carotid artery of 7-week-old P2X4 gene-deficient mice and control mice fed a high-cholesterol diet. After 4 weeks, the carotid arteries were excised and the expression levels of MCP-1, COX-2, TNFα, IL-1β, iNOS, IL-6, and IL-18 in the carotid artery were measured by Western blotting. Additionally, 7-week-old control mice (P2X4(+ / +)) fed a high-cholesterol diet were maintained for 4 weeks without the carotid artery constriction coil placed, after which the carotid arteries were excised and the expression levels of the above genes in the carotid artery were measured by Western blotting. The expression levels of each gene were normalized with GAPDH (loading control). The results are shown in Table 2 and Figures 2 and 3. The expression levels (band signal intensity) of COX-2 and MCP-1 were significantly lower in the carotid arteries of P2X4 gene-deficient mice (P2X4(- / -) w coil) with a carotid artery constriction coil implanted compared with the carotid arteries of control mice (P2X4(+ / +) w coil) with a carotid artery constriction coil implanted. Furthermore, the expression levels of TNFα, IL-1β, iNOS, IL-6, and IL-18 were also significantly lower in the carotid arteries of P2X4 gene-deficient mice (P2X4(- / -) w coil) with a carotid artery constriction coil implanted compared with the carotid artery constriction coil implanted in control mice (P2X4(+ / +) w coil). In internal carotid artery stenosis, the difference in COX-2 expression was greater than the difference in MCP-1 expression between control and P2X4 gene-deficient mice. In cerebral aneurysms, the difference in MCP-1 expression was greater than the difference in COX-2 expression between control and P2X4 gene-deficient mice, in contrast to carotid artery stenosis.

[0040]

[0041] Since the expression of inflammatory factors differs depending on the disease, the fact that P2X4 receptor inhibitors are effective in other inflammatory diseases does not necessarily mean that they will be effective in internal carotid artery stenosis. As shown in this example, the effectiveness of P2X4 receptor inhibitors in internal carotid artery stenosis can only be determined by comparing the carotid artery occlusion rate between P2X4 gene-deficient mice with a carotid artery constriction coil placed and a high-cholesterol diet fed control mice.

[0042] According to the present disclosure, inhibitors of P2X4 receptors can be used to prevent and / or treat internal carotid artery stenosis.

Claims

1. A preventive and / or therapeutic drug for internal carotid artery stenosis, which contains a P2X4 receptor inhibitor as an active ingredient.

2. The drug for preventing and / or treating internal carotid artery stenosis according to claim 1, wherein the P2X4 receptor inhibitor is paroxetine.

3. A preventive and / or therapeutic drug for internal carotid artery stenosis according to claim 1, wherein the internal carotid artery stenosis is characterized by a degree of stenosis of 30% or more by the NASCET method or an area stenosis rate of 50% or more.

4. The preventive and / or therapeutic drug for internal carotid artery stenosis according to claim 1, administered in combination with an antiplatelet drug.

5. A drug for preventing and / or treating internal carotid artery stenosis according to claim 1, administered in combination with an HMG-CoA reductase inhibitor.

6. The drug for preventing and / or treating internal carotid artery stenosis according to claim 5, wherein the HMG-CoA reductase inhibitor is a drug selected from the group consisting of mevastatin, atorvastatin, pravastatin, rosuvastatin, fluvastatin and lovastatin.

7. A method for preventing and / or treating internal carotid artery stenosis, comprising the step of administering a therapeutically effective amount of a P2X4 receptor inhibitor to a person in need of prevention or treatment of internal carotid artery stenosis.

8. Use of a P2X4 receptor inhibitor for the manufacture of a drug for the prevention and / or treatment of internal carotid artery stenosis.

9. P2X4 receptor inhibitors used for the prophylactic and / or therapeutic treatment of internal carotid artery stenosis.

Images