Compound, angiotensin-ii type 1 receptor antagonist, and pharmaceutical composition

Abstract

To provide a compound having AT1 receptor antagonistic effect or the like.SOLUTION: The present invention provides a compound represented by formula (1) or a pharmaceutically acceptable salt thereof [where R1 represents hydrogen, alkyl, alkoxy or alkoxyalkyl, R2 independently represent alkyl, n represents an integer of 0-2, and Ar represents an isoxazole derivative or a pyrazine derivative].SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to compounds, angiotensin II type 1 receptor antagonists and pharmaceutical compositions. [Background technology]

[0002] Receptors for angiotensin II include the angiotensin II type 1 receptor (AT1 receptor) and the angiotensin II type 2 receptor (AT2 receptor), and various diseases related to (mediated by) the AT1 receptor have been reported.

[0003] AT1 receptor-related diseases include, for example, hypertension (Patent Document 1), heart disease (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, diastolic dysfunction, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmia, tachycardia, and myocardial infarction) (Non-Patent Documents 1 and 2), progression of heart failure after myocardial infarction (Non-Patent Document 3), kidney disease (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, and organ damage including nephropathy due to radiation exposure) (Non-Patent Documents 4 and 5), vascular thickening, obstruction, and organ damage after intervention (e.g., percutaneous coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, and coronary thrombolytic therapy) (Non-Patent Document 6), Eye diseases (e.g., glaucoma and ocular hypertension) (Non-Patent Documents 7 and 8), neurodegenerative diseases (e.g., Alzheimer's disease) (Non-Patent Document 9), central nervous system disorders (e.g., disorders such as cerebral hemorrhage and cerebral infarction, and their sequelae and complications) (Non-Patent Document 10), dementia (e.g., cerebrovascular dementia) (Non-Patent Document 11), liver diseases (e.g., non-alcoholic fatty liver disease) (Non-Patent Documents 12 and 13), eosinophilic esophagitis (Non-Patent Document 14), bone diseases (e.g., osteoarthritis of the knee) (Non-Patent Document 15), skin diseases (e.g., epidermolysis bullosa) (Non-Patent Document 16), systemic diseases (e.g., Marfan syndrome) (Non-Patent Document 17), and cancer (Non-Patent Document 18) have been reported. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. WO 2005 / 80384 [Non-Patent Document]

[0005] [Non-Patent Document 1] Vascular Health and Risk Management 2008, 4, 67. [Non-Patent Document 2] Annals of Palliative Medicine 2021, 10, 8684. [Non-Patent Document 3] The Lancet 2002, 360, 752. [Non-Patent Document 4] The New England Journal of Medicine 2001, 345, 861. [Non-Patent Document 5] Blood Pressure 2019, 28, 358. [Non-Patent Document 6] BMC Cardiovascular Disorders 2017, 17, 278. [Non-Patent Document 7] Experimental Eye Research 2005, 80, 629. [Non-Patent Document 8] Journal of Cardiovascular Pharmacology 2000, 36, 169. [Non-Patent Document 9] Journal of Clinical Investigation 2007, 117, 3393. [Non-Patent Document 10] International Journal of Molecular Sciences 2012, 13, 7739. [Non-Patent Document 11] Hypertension Research 2009, 32, 738. [Non-Patent Document 12] Oncotarget 2018,9,24155. [Non-Patent Document 13] Physiological Reports 2016,4,e13016. [Non-Patent Document 14] Expert Review of Clinical Immunology 2020,16,421. [Non-Patent Document 15] Journal of Orthopedic Translation 2021,29,30. [Non-Patent Document 16] Dermatologic Therapy 2020,e14279. [Non-Patent Document 17] European Heart Journal 2020,41,4181. [Non-Patent Document 18] Biochemical Pharmacology 2018,151,96. Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide a compound having AT1 receptor antagonistic activity, or an AT1 receptor antagonist or pharmaceutical composition containing the compound. [Means for solving the problem]

[0007] As a result of extensive investigations, the present inventors have found that a compound having a specific structure has an AT1 receptor antagonistic effect, and have thus completed the present invention.

[0008] The present invention includes the following embodiments. [1] The following formula (1): [ka] [In the formula, R 1is hydrogen, alkyl, alkoxy or alkoxyalkyl; R 2 are each independently alkyl; n is an integer from 0 to 2, Ar is represented by the following formula (Ar1) or (Ar2): [ka] (In the formula, R 3 and R 4 are each independently alkyl, haloalkyl, or halogen; R 5 are each independently alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy; m is an integer from 0 to 3. is] or a pharma- ceutically acceptable salt thereof. [2] R 1 or a pharma- ceutical acceptable salt thereof according to [1], wherein R is alkoxyalkyl. [3] The compound according to [1] or [2], wherein n is 0, or a pharma- ceutically acceptable salt thereof. [4] The compound according to any one of [1] to [3], wherein Ar is formula (Ar1), or a pharma- ceutically acceptable salt thereof. [5] R 3 and R 4 are each independently alkyl or halogen, or a pharma- ceutical acceptable salt thereof, according to any one of [1] to [4]. [6] The following compound: [ka] [ka] The compound according to [1], or a pharma- ceutical acceptable salt thereof, selected from the group consisting of: [7] An angiotensin II type 1 receptor antagonist comprising the compound according to any one of [1] to [6] or a pharma- ceutically acceptable salt thereof. [8] An angiotensin II type 1 receptor antagonist according to [7], which selectively inhibits angiotensin II type 1 receptor with respect to endothelin A receptor. [9] A pharmaceutical composition comprising the compound according to any one of [1] to [6] or a pharma- ceutical acceptable salt thereof.

[10] The pharmaceutical composition according to [9], for preventing or treating hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorders, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[11] The pharmaceutical composition according to [9] or

[10] , which is an injection, a patch or an eye drop.

[0009] The present invention also includes the following embodiments. [A1] A method for inhibiting angiotensin II type 1 receptor, comprising administering to a patient in need thereof an effective amount of a compound according to any one of [1] to [6] or a pharma- ceutical acceptable salt thereof. [A2] The method according to [A1], wherein the angiotensin II type 1 receptor is selectively inhibited with the endothelin A receptor as a control. [A3] A method for preventing or treating a disease, comprising administering to a patient in need thereof an effective amount of a compound according to any one of [1] to [6] or a pharma- ceutical acceptable salt thereof. [A4] The method according to [A3], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0010] [B1] The compound according to any one of [1] to [6] or a pharma- ceutically acceptable salt thereof for use in inhibiting angiotensin II type 1 receptor. [B2] The compound according to [B1] or a pharma- ceutically acceptable salt thereof, which selectively inhibits angiotensin II type 1 receptor with respect to endothelin A receptor. [B3] The compound according to any one of [1] to [6] or a pharma- ceutically acceptable salt thereof for use in the prophylaxis or treatment of a disease. [B4] The compound according to [B3] or a pharma- ceutical acceptable salt thereof, wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0011] [C1] Use of the compound according to any one of [1] to [6] or a pharma- ceutical acceptable salt thereof for inhibiting angiotensin II type 1 receptor. [C2] The use according to [C1], which selectively inhibits angiotensin II type 1 receptor with endothelin A receptor as a control. [C3] Use of the compound according to any one of [1] to [6] or a pharma- ceutically acceptable salt thereof for preventing or treating a disease. [C4] The use according to [C3], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

[0012] [D1] Use of the compound according to any one of [1] to [6] or a pharma- ceutical acceptable salt thereof in the manufacture of an angiotensin II type 1 receptor antagonist. [D2] The use described in [D1], wherein the angiotensin II type 1 receptor antagonist selectively inhibits the angiotensin II type 1 receptor with respect to the endothelin A receptor. [D3] Use of the compound according to any one of [1] to [6] or a pharma- ceutically acceptable salt thereof in the manufacture of a pharmaceutical composition for preventing or treating a disease. [D4] The use according to [D3], wherein the disease is hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorder, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer. Effect of the Invention

[0013] According to the present invention, it is possible to provide a compound having AT1 receptor antagonistic activity, or an AT1 receptor antagonist or pharmaceutical composition containing the compound. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] Hereinafter, the embodiments of the present invention will be described in detail, however, the present invention is not limited to these and various modifications are possible without departing from the gist of the present invention.

[0015] <Compound> One embodiment of the present invention is a compound represented by the following formula (1): [ka] [In the formula, R 1 is hydrogen, alkyl, alkoxy or alkoxyalkyl; R 2 are each independently alkyl; n is an integer from 0 to 2, Ar is represented by the following formula (Ar1) or (Ar2): [ka] (In the formula, R 3 and R 4 are each independently alkyl, haloalkyl, or halogen; R 5 are each independently alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy; m is an integer from 0 to 3. is] or a pharma- ceutically acceptable salt thereof.

[0016] In relation to formula (1), alkyl (including alkyl in alkoxyalkyl and haloalkyl) may be linear or branched. In relation to formula (1), the alkyl moiety contained in the alkoxy (including the alkoxy in alkoxyalkyl and haloalkoxy) may be linear or branched.

[0017] In formula (1), R 1 is hydrogen, alkyl, alkoxy or alkoxyalkyl, preferably alkoxyalkyl.

[0018] R 1 The alkyl is preferably an alkyl having 1 to 6 carbon atoms, and more preferably an alkyl having 1 to 3 carbon atoms. R 1 The alkoxy is preferably an alkoxy having 1 to 6 carbon atoms, more preferably an alkoxy having 1 to 3 carbon atoms, and even more preferably an alkoxy having 1 or 2 carbon atoms. R 1 The alkoxy in the alkoxyalkyl is preferably an alkoxy having 1 to 6 carbon atoms, more preferably an alkoxy having 1 to 3 carbon atoms, and even more preferably an alkoxy having 1 or 2 carbon atoms. R 1 The alkyl in the alkoxyalkyl is preferably an alkyl having 1 to 6 carbon atoms, more preferably an alkyl having 1 to 3 carbon atoms, still more preferably an alkyl having 1 or 2 carbon atoms, and particularly preferably methyl.

[0019] In formula (1), R 2 are each independently alkyl, preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl.

[0020] In formula (1), n ​​is an integer of 0 to 2, preferably 0 or 1, and more preferably 0.

[0021] In formula (1), Ar is formula (Ar1) or formula (Ar2), preferably formula (Ar1).

[0022] In formula (1), R 3 is alkyl, haloalkyl or halogen, preferably alkyl or halogen.

[0023] R 3 The alkyl (including the alkyl in haloalkyl) is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl. R 3The halogen in the above, and the halo in the haloalkyl, are preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.

[0024] In formula (1), R 4 is alkyl, haloalkyl or halogen, preferably alkyl or halogen, more preferably alkyl.

[0025] R 4 The alkyl (including the alkyl in haloalkyl) is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl. R 4 The halogen in the above, and the halo in the haloalkyl, are preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine.

[0026] In formula (1), R 5 are each independently alkyl, haloalkyl, halogen, alkoxy or haloalkoxy, preferably alkyl or alkoxy.

[0027] R 5 The alkyl (including the alkyl in haloalkyl) is preferably alkyl having 1 to 6 carbon atoms, more preferably alkyl having 1 to 3 carbon atoms, further preferably alkyl having 1 or 2 carbon atoms, and particularly preferably methyl. R 5 The halogen in the above, and the halo in the haloalkyl and haloalkoxy, are preferably fluorine, chlorine, bromine or iodine, and more preferably chlorine. R 5 The alkoxy (including the alkoxy in haloalkoxy) is preferably an alkoxy having 1 to 6 carbon atoms, more preferably an alkoxy having 1 to 3 carbon atoms, still more preferably an alkoxy having 1 or 2 carbon atoms, and particularly preferably methoxy.

[0028] In formula (1), m is an integer of 0 to 3, preferably 1 or 2, and more preferably 2.

[0029] The compound represented by formula (1) is not particularly limited, but is preferably the following compound. [ka] [ka]

[0030] The pharma- ceutically acceptable salt of the compound represented by formula (1) is not particularly limited as long as it is usable as a medicament, and examples thereof include inorganic acid salts such as hydrochloride, sulfate, nitrate, phosphate, hydrobromide, etc.; organic acid salts such as fumarate, maleate, malate, tartrate, succinate, citrate, methanesulfonate, p-toluenesulfonate, acetate, lactate, palmitate, etc.; inorganic base salts such as sodium salt, potassium salt, calcium salt, magnesium salt, aluminum salt, ammonium salt, etc.; and organic base salts such as diethylamine salt, diethanolamine salt, meglumine salt, N,N'-dibenzylethylenediamine salt, etc.

[0031] The compound represented by formula (1) or a pharma- ceutically acceptable salt thereof may form a solvate such as a hydrate. In this specification, the solvate is included in the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof.

[0032] When stereoisomers (e.g., enantiomers and diastereomers) exist in the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof, the individual stereoisomers and mixtures thereof (e.g., racemates) are intended to be encompassed by the compound represented by formula (1) or a pharma-ceutically acceptable salt thereof.

[0033] <Angiotensin II type 1 receptor antagonist> One embodiment of the present invention relates to an AT1 receptor antagonist comprising a compound represented by formula (1) or a pharma- ceutical acceptable salt thereof. The AT1 receptor antagonist of this embodiment can selectively inhibit the AT1 receptor, preferably with respect to the endothelin A receptor (ETA receptor). By selectively inhibiting the AT1 receptor, the risk of side effects (e.g., teratogenicity) caused by inhibition of the ETA receptor can be reduced.

[0034] Specifically, the ETA receptor inhibitory concentration (IC 50 ) / AT1 receptor inhibitory concentration (IC 50 ) is preferably 100 or more, more preferably 200 or more, even more preferably 500 or more, and particularly preferably 1,000 or more. 50 ) / AT1 receptor inhibitory concentration (IC 50 ) is not particularly limited, and may be, for example, 10,000, 8,000, 6,000, 4,000, etc. The ETA receptor inhibitory concentration and the AT1 receptor inhibitory concentration can be measured by the method described in the Examples.

[0035] The AT1 receptor inhibitory concentration (IC 50 ) is preferably 1.0 nM or less, more preferably 0.5 nM or less, even more preferably 0.2 nM or less, and particularly preferably 0.1 nM or less. The AT1 receptor inhibitory concentration (IC 50 The lower limit of is not particularly limited, but may be, for example, 0.0025 nM, 0.005 nM, 0.01 nM, 0.02 nM, etc.

[0036] The AT1 receptor inhibitory concentration (IC 50 The ETA receptor inhibitory concentration (IC) is preferably 10 nM or more, more preferably 20 nM or more, even more preferably 50 nM or more, and particularly preferably 100 nM or more. 50 ) is not particularly limited, but may be, for example, 1,000 nM, 800 nM, 600 nM, 400 nM, etc.

[0037] By using the AT1 receptor antagonist of this embodiment, it is possible to treat and / or prevent diseases associated with (mediated by) the AT1 receptor, such as those described in the section "Pharmaceutical Compositions" below.

[0038] The subjects to which the AT1 receptor antagonist of this embodiment and the pharmaceutical composition described below are administered are preferably mammals, more preferably humans, monkeys, cats, pigs, horses, cows, mice, rats, guinea pigs, dogs, and rabbits, and even more preferably humans.

[0039] <Pharmaceutical Composition> One embodiment of the present invention relates to a pharmaceutical composition comprising a compound represented by formula (1) or a pharma- ceutically acceptable salt thereof.

[0040] Examples of diseases that can be prevented or treated by the pharmaceutical composition of this embodiment include the following. Hypertension; Cardiac disease (e.g., cardiac hypertrophy, acute heart failure, chronic heart failure including congestive heart failure, diastolic dysfunction, cardiomyopathy, angina pectoris, myocarditis, atrial fibrillation, arrhythmias, tachycardia, and myocardial infarction); Progression of heart failure after myocardial infarction; Renal disease (e.g., nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, complications of dialysis, and organ damage including radiation-induced nephropathy); Vascular thickening, obstruction, and organ damage following interventions (e.g., percutaneous coronary intervention, stent placement, coronary angioscopy, intravascular ultrasound, and intracoronary thrombolysis); Eye diseases (e.g., glaucoma and ocular hypertension); Neurodegenerative diseases (e.g., Alzheimer's disease); Central nervous system disorders (e.g., disorders such as cerebral hemorrhage and cerebral infarction, as well as their sequelae and complications); Dementia (e.g., vascular dementia); liver disease (e.g., nonalcoholic fatty liver disease); Eosinophilic esophagitis; Bone diseases (e.g., knee osteoarthritis); Skin disorders (e.g., epidermolysis bullosa); Systemic diseases (e.g., Marfan syndrome); cancer.

[0041] The pharmaceutical composition of this embodiment can be administered orally or parenterally. Examples of dosage forms for oral administration include tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions. Examples of dosage forms for parenteral administration include injections, infusions, drips, eye drops, patches, and suppositories. Although not particularly limited, the pharmaceutical composition of this embodiment is preferably an injection. By making it an injection, it can be suitably used for diseases requiring high urgency. Examples of diseases requiring high urgency include acute hypertension accompanied by organ damage such as cerebral hemorrhage and myocardial infarction.

[0042] When the pharmaceutical composition of the present embodiment is used as an injection, the injection may contain a second active ingredient in addition to the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof. Examples of the second active ingredient include compounds having AT1 receptor antagonistic activity other than the compound represented by formula (1) or a pharma- ceutical acceptable salt thereof, and specific examples thereof include losartan, valsartan, candesartan, telmisartan, olmesartan, irbesartan, azilsartan, etc.

[0043] The pharmaceutical composition of the present embodiment may contain excipients, binders, lubricants, disintegrants, sweeteners, surfactants, suspending agents, emulsifiers, colorants, preservatives, fragrances, flavorings, stabilizers, thickeners, etc., as necessary.

[0044] The dosage of the pharmaceutical composition of this embodiment varies depending on the condition and weight of the patient, the type of compound, the type of disease, the route of administration, etc., and an appropriate amount can be determined by a physician.

[0045] <Method of manufacturing compound> The compound represented by formula (1) or a pharma- ceutical acceptable salt thereof can be synthesized by appropriately utilizing a known method. As an example of the synthesis method, the following scheme A can be mentioned. [ka]

[0046] In Scheme A, R 1 ~R 4 and n are as defined above, and X 1 ~X 3 is a halogen and Pro is a protecting group.

[0047] In scheme A, compound (A1) is reacted with a reducing agent (e.g., dimethylsulfide borane) to obtain compound (A2) (step A1), compound (A2) is reacted with a halogenating agent (e.g., carbon tetrabromide) to obtain compound (A3) (step A2), compound (A4) is reacted with a metal hydride (e.g., sodium hydride) and then reacted with compound (A3) to obtain compound (A5) (step A3), and compound (A5) is reacted with bis(pinacolato)diboron to obtain compound (A6) (step A4).

[0048] Compound (A7) is diazotized and then reacted with sulfur dioxide to obtain compound (A8) (Step A5). Compound (A8) is reacted with compound (A9) to obtain compound (A10) (Step A6), and the amino group of compound (A10) is protected with a protecting group (e.g., methoxymethyl group) to obtain compound (A11) (Step A7).

[0049] The compound (A6) is reacted with the compound (A11) to obtain the compound (A12) (Step A8), and the compound (A12) is deprotected to obtain the compound (A13) (Step A9).

[0050] The method for synthesizing the compound represented by formula (1) or a pharma- ceutically acceptable salt thereof is not limited to the above scheme A, and a person skilled in the art can appropriately determine an appropriate synthetic route and reaction conditions depending on the structure of the final compound. EXAMPLES

[0051] The present invention will be described in more detail below using examples, but the technical scope of the present invention is not limited to these examples.

[0052] [Production Example 1-1] Methyl 4-bromo-3-(methoxymethyl)benzoate [ka] Sodium methoxide (1.23 g, 22.8 mmol) was slowly added to a mixture of methyl 4-bromo-3-(bromomethyl)benzoate (3.50 g, 11.4 mmol), methanol (28 mL) and N,N-dimethylformamide (7 mL) at 0° C., and the mixture was stirred at room temperature for 16 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.50 g). ESI-MS: m / z 258.9 [M+1]+

[0053] [Production Example 1-2] 4-Bromo-3-(methoxymethyl)benzoic acid [ka] To a mixture of methyl 4-bromo-3-(methoxymethyl)benzoate (2.00 g, 7.75 mmol) and methanol (20.0 mL), 2 mol / L aqueous sodium hydroxide solution (5.00 mL, 10.0 mmol) was added at 0° C. and stirred at room temperature for 2 hours. The reaction mixture was evaporated under reduced pressure, and the residue was neutralized with 2 mol / L hydrochloric acid. The precipitate was collected by filtration to obtain the title compound (1.50 g). ESI-MS: m / z 242.89 [M-1]-

[0054] [Production Example 1-3] (4-Bromo-3-(methoxymethyl)phenyl)methanol [ka] Dimethylsulfide borane (0.58 mL, 9.22 mmol) was slowly added to a mixture of 4-bromo-3-(methoxymethyl)benzoic acid (1.50 g, 6.14 mmol) and THF (20 mL) at 0° C., and the reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was brought to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.30 g). 1H NMR (400 MHz, CDCl3) δ 7.52 (d, J = 8 Hz, 1H), 7.45 (s, 1H), 7.16 (d, J = 8 Hz, 1H), 4.74 (s, 2H), 4.62 (s, 2H), 3.47 (s, 3H).

[0055] [Production Example 1-4] 1-Bromo-4-(bromomethyl)-2-(methoxymethyl)benzene [ka] To a mixture of (4-bromo-3-(methoxymethyl)phenyl)methanol (1.30 g, 5.65 mmol), triphenylphosphine (2.96 g, 11.3 mmol) and dichloromethane (15 mL), carbon tetrabromide (1.87 g, 8.51 mmol) was slowly added at 0° C., and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.30 g). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.18 (d, J = 8 Hz, 1H), 4.50 (s, 2H), 4.45 (s, 2H), 3.49 (s, 3H).

[0056] [Production Example 1-5] 3-(4-Bromo-3-(methoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ka] To a mixture of 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (1.19 g, 6.12 mmol) and DMF (20 mL), 60% sodium hydride (544 mg, 11.3 mmol) was slowly added at 0°C and stirred at the same temperature for 30 minutes. 1-Bromo-4-(bromomethyl)-2-(methoxymethyl)benzene (1.2 g, 4.08 mmol) was slowly added to the reaction mixture and stirred at the same temperature for 2 hours. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.20 g). ESI-MS: m / z 407.30 [M+1]+

[0057] [Production Example 1-6] 2-Butyl-3-(3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one [ka] Under an argon atmosphere, 3-(4-bromo-3-(methoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (0.50 g, 1.23 mmol), bis(pinacolato)diboron (0.469 g, 1.84 mmol), potassium acetate (0.241 g, 2.46 mmol) and 1,4-dioxane (10.0 mL) were added with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (0.050 g, 0.061 mmol), and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.10 g). ESI-MS: m / z 455.43 [M+1]+

[0058] [Production Example 1-7] 2-Bromothiophene-3-amine hydrochloride [ka] To a mixture of tert-butyl (2-bromothiophen-3-yl)carbamate (5.10 g, 18.3 mmol) and dichloromethane (60.0 mL), 4.0 mol / L hydrogen chloride·1,4-dioxane solution (10.0 mL) was added at 0° C., and the reaction mixture was stirred at room temperature for 3 hours. The solvent in the reaction mixture was distilled off under reduced pressure, and the residue was washed with diethyl ether to obtain the title compound (3.50 g) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0059] [Production Example 1-8] 2-Bromothiophene-3-sulfonyl chloride [ka] Sodium nitrite (0.64 g, 9.38 mmol) dissolved in a small amount of water was slowly added to a mixture of crude 2-bromothiophene-3-amine hydrochloride (2.00 g, 9.38 mmol), tetrahydrofuran, and concentrated hydrochloric acid (3 mL) at -10°C, and the mixture was stirred at the same temperature for 5 minutes. The reaction mixture was added to a mixture of copper(I) chloride (0.27 g, 2.81 mmol), acetic acid (2.30 mL), and water (10.0 mL) charged with sulfur dioxide at 0°C, and the mixture was stirred for 30 minutes. The reaction mixture was diluted with ethyl acetate, and washed with 1 mol / L hydrochloric acid, water, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride. The organic phase was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.70 g). 1H NMR (400 MHz, DMSO-d6) δ 7.39 (d, 1H, J = 5.6 Hz), 7.04 (d, 1H, J = 5.6 Hz).

[0060] [Production Example 1-9] 2-Bromo-N-(4,5-dimethylisoxazol-3-yl)thiophene-3-sulfonamide [ka] 4-Dimethylaminopyridine (14 mg, 0.11 mmol) and 2-bromothiophene-3-sulfonyl chloride (0.3 g, 1.15 mmol) were slowly added to a mixture of 4,5-dimethylisoxazol-3-amine (0.194 g, 1.73 mmol) and pyridine (5.0 mL) at 0° C., and the reaction mixture was stirred at 55° C. for 16 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound as a crude product. The obtained crude product was used in the next reaction without further purification. ESI-MS: m / z 338.89 [M+3]+

[0061] [Production Example 1-10] 2-Bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide [ka] To a mixture of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)thiophene-3-sulfonamide (0.27 g, 0.80 mmol) and DMF (5.0 mL), 60% sodium hydride (80 mg, 8.90 mmol) was slowly added at 0°C and stirred at the same temperature for 30 minutes. Chloromethyl methyl ether (0.12 mL, 1.60 mmol) was slowly added to the reaction mixture and stirred at room temperature for 3 hours. Ice-cold water was added to the reaction mixture, and it was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.17 g). ESI-MS: m / z 382.94 [M+3]+

[0062] [Production Example 1-11] 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(methoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide [ka] Under an argon atmosphere, 2-bromo-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide (100 mg, 0.26 mmol), 2-butyl-3-(3-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one (119 mg, 0.26 mmol), and N,N-dimethylformamide (2.0 mL) were added. To a mixture of 1,3-dichlorophenylphosphine (1,3-dichlorophenyl)-2,4-di ... ESI-MS: m / z 629.34 [M+1]+

[0063] [Example 1] 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(methoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)thiophene-3-sulfonamide [ka] 6 mol / L hydrochloric acid (0.50 mL) was added to a mixture of 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(methoxymethyl)phenyl)-N-(4,5-dimethylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide (80 mg, 0.12 mmol) and methanol (1.00 mL) at room temperature, and the reaction mixture was stirred at 70° C. for 16 hours. The reaction mixture was brought to room temperature, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue, washed with water, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by high-performance liquid chromatography (Sunfire C18 (19×250) 10 μm, 0.1% trifluoroacetic acid aqueous solution / acetonitrile) to obtain the title compound (12 mg). ESI-MS: m / z 585.25 [M+1]+

[0064] [Production Example 2-1] 4-Bromo-3-(ethoxymethyl)benzoic acid [ka] Sodium ethoxide (446 mg, 6.55 mmol) was slowly added to a mixture of methyl 4-bromo-3-(bromomethyl)benzoate (1.0 g, 3.27 mmol), ethanol (8 mL) and N,N-dimethylformamide (2 mL) at 0° C., and the mixture was stirred at room temperature for 4 hours. Ice-cold water and 1 mol / L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.30 g). 1H NMR (400 MHz, DMSO-d6) δ 13.18 (bs, 1H), 8.01 (s, 1H), 7.75-7.73 (m, 2H), 4.52 (s, 2H), 3.60 (q, J = 7.2 Hz, 2H), 1.20 (t, J = 7.2 Hz, 3H)

[0065] [Production Example 2-2] (4-Bromo-3-(ethoxymethyl)phenyl)methanol [ka] Dimethylsulfide borane (0.22 mL, 2.32 mmol) was slowly added to a mixture of 4-bromo-3-(ethoxymethyl)benzoic acid (0.30 g, 1.16 mmol) and THF (5 mL) at 0° C., and the reaction mixture was stirred at 80° C. for 6 hours. The reaction mixture was brought to room temperature, methanol was added, and the solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.25 g). 1H NMR (400 MHz, CDCl3) δ 7.52-7.46 (m, 2H), 7.15 (d, J = 8 Hz, 1H), 4.66 (s, 2H), 4.55 (s, 2H), 3.66-3.61 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H).

[0066] [Production Example 2-3] 1-Bromo-4-(bromomethyl)-2-(ethoxymethyl)benzene [ka] To a mixture of (4-bromo-3-(ethoxymethyl)phenyl)methanol (0.20 g, 0.81 mmol), triphenylphosphine (425 mg, 1.62 mmol) and dichloromethane (4 mL), carbon tetrabromide (538 mg, 1.62 mmol) was slowly added at 0° C., and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (160 mg). 1H NMR (400 MHz, CDCl3) δ 7.51-7.49 (m, 2H), 7.18 (d, J = 8 Hz, 1H), 4.53 (s, 2H), 4.45 (s, 2H), 3.66-3.61 (m, 2H), 1.30-1.25 (t, J = 7.2Hz, 3H).

[0067] [Production Example 2-4] 3-(4-Bromo-3-(ethoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one [ka] To a mixture of 2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (152 mg, 0.783 mmol) and DMF (3 mL), 60% sodium hydride (38 mg, 0.783 mmol) was slowly added at 0°C, and the mixture was stirred at the same temperature for 30 minutes. To the reaction mixture, a mixture of 1-bromo-4-(bromomethyl)-2-(ethoxymethyl)benzene (160 mg, 0.52 mmol) and DMF (2 mL) was slowly added, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture, ice-cold water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.1 g). ESI-MS: m / z 423.13 [M+3]+

[0068] [Production Example 2-5] 2-Butyl-3-(3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one [ka] Under an argon atmosphere, 3-(4-bromo-3-(ethoxymethyl)benzyl)-2-butyl-1,3-diazaspiro[4.4]non-1-en-4-one (0.26 g, 0.62 mmol), bis(pinacolato)diboron (236 mg, 0.93 mmol), potassium acetate (122 mg, 1.24 mmol) and 1,4-dioxane (5 mL) were added with [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (25 mg, 0.03 mmol), and the reaction mixture was stirred at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (120 mg). ESI-MS: m / z 469.42 [M+1]+

[0069] [Production Example 2-6] 2-Bromo-N-(4-chloro-5-methylisoxazol-3-yl)thiophene-3-sulfonamide [ka] 4-Dimethylaminopyridine (75 mg, 0.60 mmol) and 2-bromothiophene-3-sulfonyl chloride (0.52 g, 2.0 mmol) were slowly added to a mixture of 4-chloro-5-methylisoxazol-3-amine (0.64 g, 1.73 mmol) and pyridine (8.0 mL) at 0° C., and the reaction mixture was stirred at 55° C. for 16 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2 mol / L hydrochloric acid and saturated saline, and dried over sodium sulfate. The solvent was distilled off under reduced pressure to obtain the title compound (0.50 g). ESI-MS: m / z 358.97 [M+3]+

[0070] [Production Example 2-7] 2-Bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide [ka] To a mixture of 2-bromo-N-(4,5-dimethylisoxazol-3-yl)thiophene-3-sulfonamide (0.50 g, 1.40 mmol) and DMF (5.0 mL), 60% sodium hydride (168 mg, 3.51 mmol) was slowly added at 0° C. and stirred at the same temperature for 30 minutes. Chloromethyl methyl ether (0.21 mL, 2.81 mmol) was slowly added to the reaction mixture and stirred at room temperature for 3 hours. Ice-cold water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.30 g) as a crude product. The obtained crude product was used in the next reaction without further purification.

[0071] [Example 2] 2-(4-((2-butyl-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl)methyl)-2-(ethoxymethyl)phenyl)-N-(4-chloro-5-methylisoxazol-3-yl)thiophene-3-sulfonamide [ka] Under an argon atmosphere, bis(triphenylphosphine)palladium(II) dichloride (20 mg, 0.028 mmol) was added to a mixture of crude 2-bromo-N-(4-chloro-5-methylisoxazol-3-yl)-N-(methoxymethyl)thiophene-3-sulfonamide (250 mg, 0.62 mmol), 2-butyl-3-(3-(ethoxymethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)-1,3-diazaspiro[4.4]non-1-en-4-one (250 mg, 0.53 mmol), N,N-dimethylformamide (5 mL) and potassium carbonate (0.150 g, 1.06 mmol), and the reaction mixture was stirred at 100° C. for 6 hours. The reaction mixture was brought to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) and high performance liquid chromatography (Sunfire C18 (19×250) 10 μm, 0.1% trifluoroacetic acid aqueous solution / acetonitrile) to obtain the title compound (27 mg). ESI-MS: m / z 619.26 [M+1]+

[0072] [Test Example 1: Angiotensin II type 1 receptor inhibitory effect] The inhibitory effect of angiotensin II type 1 receptor was examined by the following method. CHO-K1-mt aequorin-Gα16 cells expressing human Angiotensin II type 1 receptor (Accession Number NP_000676.1) were cultured in antibiotic-free medium for 18 hours, then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 minutes, 405×g, room temperature), and suspended in assay buffer (DMEM / HAM's F12 with HEPES+0.1% BSA protease free). 1×10 6The cells (cells / mL) were incubated at room temperature for 4 hours or more in the presence of Coelenterazin h (Molecular Probes) at a final concentration of 5 μM, and the agonist response by Angiotensin II was confirmed, and the concentration of Angiotensin II corresponding to EC80 was determined. Next, 50μL of cell suspension treated with Coelenterazin h (10,000 cells / well) and 50μL of assay buffer containing the test substance (final concentration 0.5% DMSO) were added to a 96-well plate, and 100μL of Angiotensin II solution was added after 15 minutes so that the final concentration was the EC80 concentration, and receptor activity was measured by luminescence using FDSS6000 (Hamamatsu Photonics). IC50 values ​​were calculated using XLfit (IDBS).

[0073] The IC50 value was 1.0 nM or less, or 50% or more of the inhibitory effect was observed at 1.0 nM, and was classified as "A." The IC50 value was 100 nM or more, or 50% or less of the inhibitory effect was observed at 100 nM, and was classified as "C." The values ​​between "A" and "C" were classified as "B." The results are shown in Table 1. [Table 1]

[0074] [Test Example 2: Endothelin A receptor inhibitory effect] The inhibitory effect of endothelin A receptor was examined by the following method. CHO-K1-mt aequorin cells expressing human Endothelin A receptor (Accession Number NP_001948.1) were cultured in antibiotic-free medium for 18 hours, then treated with PBS-EDTA (5 mM EDTA), centrifuged (2 minutes, 405 × g, room temperature), and suspended in assay buffer (DMEM / HAM's F12 with HEPES + 0.1% BSA protease free). 1×10 6The cells (cells / mL) were incubated in the presence of Coelenterazin h (Molecular Probes) at a final concentration of 5 μM for 4 hours at room temperature, and the agonist response by endothelin was confirmed, and the endothelin concentration corresponding to EC80 was determined. Next, 50μL of cell suspension treated with Coelenterazin h (10,000 cells / well) and 50μL of assay buffer containing the test substance (final concentration 0.5% DMSO) were added to a 96-well plate, and endothelin was added after 15 minutes to a final concentration of EC80, and receptor activity was measured by luminescence using FDSS6000 (Hamamatsu Photonics). IC50 values ​​were calculated using XLfit (IDBS).

[0075] The IC50 value was 1.0 nM or less, or 50% or more of the inhibitory effect was observed at 1.0 nM, and was classified as "A." The IC50 value was 100 nM or more, or 50% or less of the inhibitory effect was observed at 100 nM, and was classified as "C." The values ​​between "A" and "C" were classified as "B." The results are shown in Table 2. [Table 2]

Claims

1. The following formula (1): 【Chemistry 1】 [In the formula, R 1 is hydrogen, alkyl, alkoxy or alkoxyalkyl; R 2 are each independently alkyl; n is an integer from 0 to 2, Ar is represented by the following formula (Ar1) or (Ar2): 【Chemistry 2】 (In the formula, R 3 and R 4 are each independently alkyl, haloalkyl, or halogen; R 5 are each independently alkyl, haloalkyl, halogen, alkoxy, or haloalkoxy; m is an integer from 0 to 3. is] or a pharma- ceutically acceptable salt thereof.

2. R 1 or a pharma- ceutically acceptable salt thereof, of claim 1, wherein: is alkoxyalkyl.

3. 3. The compound according to claim 1 or 2, wherein n is 0, or a pharma- ceutically acceptable salt thereof.

4. The compound according to any one of claims 1 to 3, wherein Ar is of formula (Ar1), or a pharma- ceutically acceptable salt thereof.

5. R 3 and R 4 The compound according to any one of claims 1 to 4, wherein each is independently alkyl or halogen, or a pharma- ceutically acceptable salt thereof.

6. The following compound: 【Chemistry 3-1】 【Chemistry 3-2】 2. The compound of claim 1, selected from the group consisting of:

7. An angiotensin II type 1 receptor antagonist comprising the compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

8. The angiotensin II type 1 receptor antagonist according to claim 7, which selectively inhibits the angiotensin II type 1 receptor with respect to the endothelin A receptor.

9. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharma- ceutically acceptable salt thereof.

10. The pharmaceutical composition according to claim 9 for preventing or treating hypertension, heart disease, progression of heart failure after myocardial infarction, renal disease, vascular thickening after intervention, obstruction after intervention, organ damage after intervention, glaucoma, ocular hypertension, Alzheimer's disease, central nervous system disorders, dementia, liver disease, eosinophilic esophagitis, osteoarthritis of the knee, epidermolysis bullosa, Marfan syndrome, or cancer.

11. The pharmaceutical composition according to claim 9 or 10, which is an injection, a patch, or an eye drop.

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