WO2011052519A1 - ベンズアゼピン化合物 - Google Patents
ベンズアゼピン化合物 Download PDFInfo
- Publication number
- WO2011052519A1 WO2011052519A1 PCT/JP2010/068807 JP2010068807W WO2011052519A1 WO 2011052519 A1 WO2011052519 A1 WO 2011052519A1 JP 2010068807 W JP2010068807 W JP 2010068807W WO 2011052519 A1 WO2011052519 A1 WO 2011052519A1
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- Prior art keywords
- group
- chloro
- benzo
- azepine
- salt
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- 0 *C(**1)(C1(*)N(C(C=O)c(c(*)c1*)c(*)c(*)c1NCc1c(*)c(*)c(*)c(*)c1*)c(c(*)c1*)c2c(*)c1Cl)C(*)(*)C2(*)O Chemical compound *C(**1)(C1(*)N(C(C=O)c(c(*)c1*)c(*)c(*)c1NCc1c(*)c(*)c(*)c(*)c1*)c(c(*)c1*)c2c(*)c1Cl)C(*)(*)C2(*)O 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a benzazepine compound.
- Patent Documents 1 to 3 and Non-patent Documents 1 and 2 have been developed (for example, Patent Documents 1 to 3 and Non-patent Documents 1 and 2), but the development of a compound having a more superior vasopressin antagonistic action. Is desired.
- Example 430 of Patent Document 3 a compound having an excellent vasopressin antagonistic action is disclosed, and tolvaptan represented by the following formula is also disclosed therein.
- a novel benzazepine compound that has a superior vasopressin antagonism compared with tolvaptan and creates other benefits, for example, a compound with high metabolic stability, and further extended the pharmacological effective period
- a novel benzazepine compound represented by the following general formula (1) has a superior vasopressin antagonistic action by converting tolvaptan into D-form. And found to have metabolic stability.
- the present invention has been completed based on such findings.
- R 1 is the same or different and represents H or D.
- R 2 is the same or different and represents H or D.
- R 3 represents a C1-C6 alkyl group, a C1-C6 deuteroalkyl group, or a C1-C6 perdeuteroalkyl group.
- R 4 represents a C1-C6 alkyl group, a C1-C6 deuteroalkyl group, or a C1-C6 perdeuteroalkyl group.
- R 5 is the same or different and represents H or D.
- Item 3. A pharmaceutical composition comprising the benzazepine compound or a salt thereof according to Item 1 or 2 as an active ingredient and a pharmacologically acceptable carrier.
- Item 4. Use of the benzazepine compound or a salt thereof according to Item 1 or 2 as a drug.
- Item 5 A vasopressin antagonist comprising the benzazepine compound or a salt thereof according to item 1 or 2 as an active ingredient.
- Item 6 Hypertension, edema, ascites, heart failure, renal dysfunction, vasopressin secretion syndrome (SIADH), cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, motion sickness, water metabolism disorder, renal failure, cerebral infarction, Item 4.
- PPD polycystic kidney disease
- Item 7. The pharmaceutical composition according to Item 3, which is used as a drug selected from the group consisting of a vasodilator, an antihypertensive, a diuretic, a platelet aggregation inhibitor, a urea excretion promoter, an antiheart failure agent, and an antirenal failure agent.
- Item 8 The benzazepine compound or a salt thereof according to Item 1 or 2, comprising administering to a human or animal, hypertension, edema, ascites, heart failure, renal dysfunction, vasopressin secretion syndrome (SIADH), cirrhosis, hyponatremia
- SIADH vasopressin secretion syndrome
- cirrhosis hyponatremia
- a disease selected from the group consisting of hypokalemia, diabetes, circulatory failure, motion sickness, water metabolism disorder, renal failure, cerebral infarction, myocardial infarction and polycystic kidney disease (PKD).
- the present invention provides a benzazepine compound represented by the general formula (1) or a salt thereof.
- C1-C6, preferably C1-C3 alkyl group defined in R 3 and R 4 in the general formula (1) include a methyl group, an ethyl group, an n-propyl group, an iso-propyl group. Groups and the like.
- the C1-C6, preferably C1-C3 deuteroalkyl group defined in R 3 and R 4 in the general formula (1) is a group in which at least one hydrogen atom constituting the alkyl group is substituted with a deuterium atom. (However, all the hydrogen atoms constituting the alkyl group are substituted with deuterium atoms.)
- n is an integer of 1 to 6, preferably 1 to 3, and m is an integer of 1 to 2n
- deuteromethyl group dideuteromethyl group, deuteroethyl group, dideuteroethyl group, trideuteroethyl group, tetradeuteroethyl group, deuteropropyl group, ditero Examples include deuteropropyl group, trideuteropropyl group, tetradeuteropropyl group, pentadeuteropropyl group and the like.
- the C1-C6, preferably C1-C3, perdeuteroalkyl groups defined in R 3 and R 4 in the general formula (1) include, specifically, a perdeuteromethyl group, a perdeutero group. Examples include teloethyl group, perdeutero-n-propyl group, and perdeutero-iso-propyl group.
- the benzazepine compound or a salt thereof of the present invention is produced, for example, according to the methods described in the following Reference Examples and Examples or according to these methods.
- the benzazepine compound of the present invention obtained by these methods can be separated from the reaction system by ordinary separation means and further purified.
- separation and purification means for example, distillation method, recrystallization method, column chromatography, ion exchange chromatography, gel chromatography, affinity chromatography, preparative thin layer chromatography, solvent extraction method and the like can be employed.
- the benzazepine compound of the present invention may form a suitable salt.
- Suitable salts thereof include suitable salts of the compound (1) exemplified below.
- Suitable salts of the compound (1) are pharmacologically acceptable salts such as alkali metal salts (for example, sodium salts and potassium salts), alkaline earth metal salts (for example, calcium salts and magnesium salts).
- Metal salts such as ammonium salts, alkali metal carbonates (for example, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrocarbon salts (for example, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.) Salts of inorganic bases such as alkali metal hydroxides (eg, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.); for example, tri (lower) alkylamines (eg, trimethylamine, triethylamine, N— Ethyldiisopropylamine), pyridine, quinoline, piperidine, imidazole, Phosphorus, dimethylaminopyridine, dimethylaniline, N- (
- a compound in a form in which a solvate eg, hydrate, ethanolate, etc.
- a solvate eg, hydrate, ethanolate, etc.
- Preferred solvates include hydrates.
- the compound represented by the general formula (1) of the present invention naturally includes isomers such as geometric isomers, stereoisomers, and optical isomers.
- the compound of the general formula (1) and a salt thereof are used in the form of a general pharmaceutical preparation.
- the preparation is prepared by using diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
- diluents or excipients such as fillers, extenders, binders, moisturizers, disintegrants, surfactants, lubricants and the like that are usually used.
- Various forms of this pharmaceutical preparation can be selected according to the purpose of treatment. Representative examples thereof include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquid, suspension, etc.).
- various carriers well known in the art can be widely used as carriers.
- carriers include lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients, water, ethanol, propanol, simple syrup, glucose solution, starch solution, Binders such as gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, lauryl sulfate Disintegrators such as sodium, stearic acid monoglyceride, starch, lactose, disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil, absorption accelerators such as quaternary ammonium base, sodium lauryl sulfate, glyce E
- a wide variety of carriers conventionally known in this field can be used.
- carriers include excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oil, kaolin and talc, binders such as gum arabic powder, tragacanth powder, gelatin, ethanol, and disintegrants such as laminaran and agar. Can be used.
- conventionally known carriers When molding into a suppository form, conventionally known carriers can be widely used. Examples thereof include polyethylene glycol, cocoa butter, higher alcohols, higher alcohol esters, gelatin, semi-synthetic glycerides and the like.
- Capsules are usually prepared by mixing the active ingredient compounds with the various carriers exemplified above and filling them into hard gelatin capsules, soft capsules and the like according to conventional methods.
- solutions, emulsions and suspensions are preferably sterilized and isotonic with blood, and are commonly used in this field as diluents when molded into these forms
- diluents when molded into these forms
- water, ethyl alcohol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used.
- a sufficient amount of sodium chloride, glucose or glycerin may be contained in the pharmaceutical preparation to prepare an isotonic solution, and a normal solubilizing agent, buffering agent, soothing agent, etc. may be added. May be. Further, if necessary, a colorant, a preservative, a flavoring agent, a sweetening agent, and other pharmaceuticals may be contained in the pharmaceutical preparation.
- the amount of the compound of the general formula (1) or a salt thereof to be contained in the pharmaceutical preparation of the present invention is not particularly limited and is appropriately selected from a wide range, but is usually about 0.1 to 70 in the pharmaceutical composition. % By weight, preferably about 0.1 to 30% by weight.
- the administration method of the pharmaceutical preparation of the present invention is not particularly limited, and it is administered by a method according to various preparation forms, patient age, sex and other conditions, the degree of disease, and the like.
- a method for example, in the case of tablets, pills, solutions, suspensions, emulsions, granules and capsules, they are administered orally.
- a normal replacement fluid such as glucose and amino acids
- it is administered intramuscularly, intradermally, subcutaneously or intraperitoneally as necessary.
- a suppository it is administered intrarectally.
- the dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, the age of the patient, sex and other conditions, the degree of disease, etc.
- the amount of the active ingredient compound is about 0.1 to 1 kg / kg body weight per day. It should be about 10 mg.
- the active ingredient compound is preferably contained in the dosage unit form in a range of about 1 to 200 mg.
- vasopressin antagonistic action More specific actions of vasopressin antagonistic action include, for example, vasodilatory action, blood pressure lowering action, hepatic glucose release inhibitory action, mesangial cell proliferation inhibitory action, water diuretic action, platelet aggregation inhibitory action, vomiting inhibitory action, urea excretion promoting action , Factor VIII secretion inhibitory action, cardiac function enhancing action, mesangial cell contraction inhibitory action, hepatic gluconeogenesis inhibitory action, aldosterone secretion inhibitory action, endothelin production inhibitory action, renin secretion regulating action, memory regulating action, body temperature regulating action, prostagland Such as gin production regulating action.
- the pharmaceutical composition containing the benzazepine compound of the present invention as an active ingredient includes, for example, a vasodilator, an antihypertensive agent, a diuretic, a platelet aggregation inhibitor, a urea excretion promoter, an antiheart failure agent, and an antirenal failure agent.
- SIADH vasopressin secretion syndrome
- the benzazepine compound of the present invention is characterized by few side effects and long duration of medicinal effect.
- the dissociation constant (K d ) and the number of receptors (B max ) were calculated by Scatchard plot analysis of the results of [ 3 H] AVP binding saturation experiment.
- the binding rate of [ 3 H] AVP in the presence of the compound was calculated by the following formula.
- Bond rate (%) (B-NSB) / (TB-NSB) x 100 (B: amount of [ 3 H] AVP bound in the presence of each compound, NSB: amount of [ 3 H] AVP bound in the presence of 1 ⁇ M unlabeled AVP, TB: in the absence of 1 ⁇ M unlabeled AVP [ 3 H] AVP binding amount)
- K i IC 50 / (1 + [L] / K d ) Kd: [ 3 H] AVP dissociation constant, [L]: [ 3 H] AVP concentration used in the test. As a result, it was confirmed that the compound had excellent vasopressin antagonism.
- reaction conditions The reaction system without coenzyme was preincubated at 37 ° C for 5 minutes, and then coenzyme was added to start the reaction. After addition of the coenzyme, incubation was carried out for 0, 5, 10, 20, 30 and 60 minutes. A part of the reaction solution was withdrawn every predetermined time and added to an acetonitrile solution containing an internal standard substance to stop the reaction.
- ESI electrospray ionization
- MRM selective reaction detection
- the residual ratio of the data analysis evaluation compound was calculated by the following formula.
- Residual rate (peak area of evaluation compound at reaction time t minutes / peak area of internal standard substance) / (peak area of evaluation compound at reaction time 0 minute / peak area of internal standard substance)
- Example 4 Metabolic stability in human liver microsomes was evaluated for tolvaptan and its deuterium substitute (Example 4).
- the metabolic stability was significantly improved as compared with tolvaptan.
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Abstract
Description
R2は、同一又は異なって、H又はDを示す。
R3は、C1~C6のアルキル基、C1~C6のジューテロアルキル基又はC1~C6のペルジューテロアルキル基を示す。
R4は、C1~C6のアルキル基、C1~C6のジューテロアルキル基又はC1~C6のペルジューテロアルキル基を示す。
R5は、同一又は異なって、H又はDを示す。]
で表されるベンズアゼピン化合物又はその塩。
(2) N-(4-(7-クロロ-2,3-ジヒドロ-5-ヒドロキシ-4,4,5-トリジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド、
(3) N-(4-(7-クロロ-5-ヒドロキシ-2,2-ジジューテロ-3,4,5-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド、
(4) N-(4-(7-クロロ-5-ヒドロキシ-2,2,4,4,5-ペンタジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド及び
(5) N-{4-(7-クロロ-5-ヒドロキシ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル}-3,4,5,6-テトラジューテロ-2-トリジューテロメチルベンズアミド
からなる群から選ばれたベンズアゼピン化合物又はその塩。
-CnD2n+1-mHm
(式中nは1~6、好ましくは1~3の整数であり、mは1~2nの整数である)
で表され、より具体的には、ジューテロメチル基、ジジューテロメチル基、ジューテロエチル基、ジジューテロエチル基、トリジューテロエチル基、テトラジューテロエチル基、ジューテロプロピル基、ジジューテロプロピル基、トリジューテロプロピル基、テトラジューテロプロピル基、ペンタジューテロプロピル基等が挙げられる。
N-(4-(7-クロロ-5-オキソ-2,3,4-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミドの製造
N-(4-(7-クロロ-5-ヒドロキシ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド(2g)のジクロロメタン(40ml)懸濁液に、二酸化マンガン(2g)を加え、7時間還流した。反応混合物を冷却した後、セライト濾過し、ジクロロメタンを用いて洗浄後、シリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=10:1→3:1)にて精製し、0.94gの標題化合物を得た。
性状:無色無定形粉末
1H-NMR(CDCl3)δppm
1.91-1.31(2H,m),2.43(3H,s),2.49(3H,s),2.89(2H,t,J=6.3Hz),3.30-4.60(2H,m),6.48-7.00(2H,m),7.01-7.70(8H,m),7.78(1H,s)。
N-(4-(7-クロロ-5-ヒドロキシ-2,3,4-トリヒドロ-5-ジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミドの製造
N-(4-(7-クロロ-5-オキソ-2,3,4-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド(0.4g)の重メタノール(10ml)溶液に、重水素化ホウ素ナトリウム(0.045g)を0℃にて加え、同温にて2時間攪拌した。得られる反応混合物に重水(2ml)を加え、10分攪拌後、水を加え、酢酸エチルにて抽出した。得られる水層を再度酢酸エチルにて抽出した。得られる酢酸エチル層を合わせ、これを無水硫酸マグネシウムにて乾燥した後、溶媒を留去し、残渣をアセトン-ジエチルエーテルから再結晶して、0.35gの標題化合物を得た。
収率:87%
性状:白色粉末
1H-NMR(DMSO-d6、80℃) δppm
1.40-2.19(4H,m), 2.36(3H,s), 2.38(3H,s), 3.35-4.94(2H,br), 5.35(1H,s),6.56-7.70(10H,m),9.93(1H,brs)
MS:(M+,449)
融点:227.8℃。
N-(4-(7-クロロ-5-オキソ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド(300mg)の重メタノール(10ml)溶液に、0.05M水酸化ナトリウム重メタノール溶液(13μl)を加え、アルゴン雰囲気下、室温にて攪拌した。16時間攪拌後、1H-NMRにて4位プロトンの消失を確認し、反応液に重水素化ホウ素ナトリウム(0.037g)を0℃にて加え、同温にて2時間攪拌した。得られる反応混合物に重水(2ml)を加え、10分攪拌後、水を加え、酢酸エチルにて抽出した。得られる水層を再度酢酸エチルにて抽出した。得られる酢酸エチル層を合わせ、これを無水硫酸マグネシウムにて乾燥した後、溶媒を留去し、残渣をアセトン-ジエチルエーテルから再結晶し、0.22gの標題化合物を得た。
収率:73%
性状:白色粉末
1H-NMR(DMSO-d6、80℃) δppm
1.51-2.06(2H,m),2.36(3H,s),2.38(3H,s)3.36-5.02(2H,br),5.34(1H,s),6.58-7.70(10H,m),9.94(1H,brs)
MS:(M+,451)
融点:225.1℃。
臭化亜鉛(1.21g)を減圧下、15分間加熱乾燥後、これに5-クロロ-2-ニトロベンズアルデヒド(5.0g)及びジクロロメタン(70ml)を加えた。得られる混合物に[(1-エトキシシクロプロピル)オキシ]トリメチルシラン(6.50ml)を0℃にて滴下した後、室温にて6時間攪拌した。反応液を減圧濃縮した後、残渣を塩基性シリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=20:1→10:1)にて精製し、4.76gの標題化合物を得た。
収率:49%
性状:黄色油状物
1H-NMR(CDCl3) δppm
0.05(9H,s),1.26(3H,t,J=7.1Hz),1.80-2.00(1H,m),2.01-2.20(1H,m),2.45(2H,t,J=7.5Hz),4.13(2H,q,J=7.1Hz),5.29-5.45(1H,m),7.37(1H,dd,J=2.4Hz,8.7Hz),7.80(1H,d,J=2.4Hz),7.91(1H,d,J=8.7Hz)。
エチル 4-(5-クロロ-2-ニトロフェニル)-4-(トリメチルシリルオキシ)ブタノエート(4.76g)のエタノール(25ml)-水(5ml)溶液に、クエン酸(0.51g)を加え、室温にて1.5時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、酢酸エチル層を飽和食塩水にて洗浄し、次いで無水硫酸マグネシウムにて乾燥した後、溶媒を留去し、残渣をシリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=20:1→10:1)にて精製し、3.8gの標題化合物を得た。
性状:淡黄色油状物
1H-NMR(CDCl3) δppm
1.29(3H,t,J=7.1Hz),1.91-2.09(1H,m),2.10-2.25(1H,m),2.51-2.72(2H,m),3.50(1H,d,J=3.9Hz),4.18(2H,q,J=7.1Hz),5.31-5.43(1H,m),7.39(1H,dd,J=2.3Hz,8.7Hz),7.90(1H,d,J=2.3Hz),7.95(1H,d,J=8.7Hz)。
エチル 4-(5-クロロ-2-ニトロフェニル)-4-ヒドロキシブタノエート(3.8g)の無水ジメチルホルムアミド(25ml)溶液に、イミダゾール(5.4g)及びtert-ブチルジメチルシリルクロライド(3.98g)を加え、室温にて16時間攪拌した。反応液に水を加え、酢酸エチルにて抽出し、酢酸エチル層を水にて3回洗浄し、次いで無水硫酸マグネシウムにて乾燥した後、溶媒を留去し、残渣を塩基性シリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=20:1→10:1)にて精製し、5.3gの標題化合物を定量的収率で得た。
性状:黄色油状物
1H-NMR(DMSO-d6) δppm
-0.19(3H,s),0.03(3H,s),0.84(9H,s),1.17(3H,t,J=7.1Hz),1.81-2.11(3H,m),2.33-2.45(1H,m),4.02(2H,q,J=7.1Hz),5.17-5.29(1H,m),7.64(1H,dd,J=2.4Hz,8.7Hz),7.74(1H,d,J=2.4Hz),8.01(1H,d,J=8.7Hz)。
エチル 4-(tert-ブチルジメチルシリルオキシ)-4-(5-クロロ-2-ニトロフェニル)ブタノエート(4.6g)のテトラヒドロフラン:エタノール(1:1)(40ml)溶液に、5M-水酸化ナトリウム水溶液(3.43ml,17.2mmol)を加えた後、30℃にて1時間攪拌した。反応混合物に10%クエン酸水溶液を加え、酢酸エチルにて抽出した。酢酸エチル層を飽和食塩水にて洗浄し、次いで無水硫酸マグネシウムにて乾燥した後、溶媒を留去した。残渣に酢酸エチル(40ml)を加え、窒素雰囲気下にて 酸化白金(0.26g)を加えた後、1気圧水素雰囲気下、3時間攪拌した。酸化白金をセライト濾過し、酢酸エチルにて洗浄した。濾液を濃縮し、無水DMF(60ml)溶液に、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩(2.63g)、1-ヒドロキシベンゾトリアゾール水和物(2.1g)、トリエチルアミン(1.91ml)を加え、室温にて3日間攪拌した。反応混合物に水を加え、酢酸エチルにて抽出し、得られる水層を再度酢酸エチルにて抽出した。得られる酢酸エチル層を合わせ、これを水で3回洗浄し、無水硫酸マグネシウムにて乾燥した後、溶媒を留去した。残渣を塩基性シリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=20:1→8:1)にて精製し、0.55gの標題化合物を得た。
収率:15%
性状:無色無定形粉末
1H-NMR(CDCl3) δppm
0.01(3H,s),0.08(3H,s),0.93(9H,s),1.89-2.06(2H,m),2.20-2.36(2H,m),2.43-2.67(1H,m),4.96(1H,dd,J=7.1Hz,10.1Hz),6.87(1H,d,J=8.4Hz),7.16(1H,brs),7.23(1H,dd,J=2.1Hz,8.4Hz),7.58(1H,d,J=2.1Hz)。
5-(tert-ブチルジメチルシリルオキシ)-7-クロロ-3,4,5-トリヒドロ-1H-ベンゾ[b]アゼピン-2(3H)-オン(550mg)の無水THF(30ml)溶液に、重水素化ホウ素ナトリウム(424mg)を0℃にて加え、同温度にて三フッ化ホウ素ジエチルエーテル錯体(0.855ml)を滴下した。得られる混合物を0℃にて1時間攪拌後、重水素化ホウ素ナトリウム(210mg)を追加した。室温にて2時間攪拌後、重水(4ml)を0℃にて滴下し、同温度にて15分攪拌した。次いで、反応混合物にメタノール(10ml)を加え、室温にて20分攪拌した。反応混合物に水を加え、酢酸エチルにて抽出し、得られる水層を再度酢酸エチルにて抽出した。得られる酢酸エチル層を合わせ、これを無水硫酸マグネシウムにて乾燥した後、溶媒を留去した。残渣を塩基性シリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=20:1→10:1)にて精製し、470mgの標題化合物を得た。
性状:無色無定形粉末
1H-NMR(CDCl3) δppm
0.07(3H,s),0.09(3H,s),0.95(9H,s),1.70-1.90(2H,m),1.94-2.12(1H,m),3.58-3.80(1H,m),4.61-4.79(1H,m),6.63(1H,d,J=8.3Hz),7.00(1H,dd,J=2.5Hz,8.3Hz),7.48(1H,dd,J=0.9Hz,2.5Hz)。
2-メチル-4-(2-メチルベンズアミド)安息香酸(450mg)のジクロロメタン(30ml)懸濁液に、塩化チオニル(0.14ml)及びジメチルホルムアミド(1.2μl)を加え、3時間還流した。反応液を減圧濃縮後、トルエンにて2回共沸した。
性状:白色粉末
1H-NMR(DMSO-d6、80℃) δppm
1.41-2.06(2H,m),2.36(3H,s),2.38(3H,s),4.78-4.96(1H,m),5.37(1H,d,J=4.3Hz),6.61-7.69(10H,m),9.94(1H,brs)
MS:(M+,450)
融点:223.7℃。
N-(4-(7-クロロ-5-ヒドロキシ-2,2-ジジューテロ-3,4,5-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド(0.25g)のジクロロメタン(50ml)懸濁液に、二酸化マンガン(482mg)を加え、8時間還流した。反応混合物を冷却後、セライト濾過した。濾物をジクロロメタンで洗浄し、濾液濃縮後の残渣をシリカゲルによるカラムクロマトグラフィー(n-ヘキサン:酢酸エチル=10:1→3:1)にて精製し、0.24gの標題化合物を得た。
性状:無色無定形粉末
1H-NMR(CD3OD,50℃) δppm
1.98-2.18(2H,m),2.38(3H,s),2.41(3H,s),2.73-2.91(2H,m),6.73-7.78(10H,m)。
N-(4-(7-クロロ-5-オキソ-2,2-ジジューテロ-3,4-ジヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド(250mg)の重メタノール(10ml)溶液に、0.05M-水酸化ナトリウム重メタノール溶液(11μl)を加え、アルゴン雰囲気下、室温にて攪拌した。18時間攪拌後、1H-NMRにて4位プロトンの消失を確認した。反応液を濃縮後、重メタノール(10ml)懸濁液とし、重水素化ホウ素ナトリウム(0.030g)を0℃にて加え、同温にて2時間攪拌した。得られる反応混合物に重水(2ml)を加え、20分攪拌後、水を加え、酢酸エチルにて抽出した。得られる水層を再度酢酸エチルにて抽出した。得られる酢酸エチル層を合わせ、これを無水硫酸マグネシウムにて乾燥した後、溶媒を留去し、残渣をアセトン-ジエチルエーテルから再結晶し、0.17gの標題化合物を得た。
性状:白色粉末
1H-NMR(DMSO-d6、80℃) δppm
1.60-2.00(2H,m),2.36(3H,m),2.38(3H,s),5.34(1H,s),6.51-7.70(10H,m),9.93(1H,brs)
MS:(M+,453)
融点:224.7℃。
1H-NMR(CD3OD,50℃) δppm
1.94-2.19(2H,m),2.38(3H,s),2.41(3H,s),6.76-7.78(10H,m)。
N-{4-(7-クロロ-5-オキソ-2,3,4-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル}-3,4,5,6-テトラジューテロ-2-トリジューテロメチルベンズアミドの製造
1-(4-アミノ-2-メチルベンゾイル)-7-クロロ-2,3,4-トリヒドロ-1H-ベンゾ[b]アゼピン-5(2H)-オン(2.39g)、3,4,5,6-テトラジューテロ-2-トリジューテロメチル安息香酸(1.04g)及びトリエチルアミン(1.4ml,10mmol)のジメチルホルムアミド(24ml)溶液に、ヘキサフルオロリン酸2-(7-アザ-1H-ベンゾトリアゾール-1-イル)-1,1,3,3-テトラメチルウロニウム(3.04g)を加え、窒素雰囲気下、65℃にて4時間撹拌した。反応液を濃縮した後に、0.1N塩酸(100ml)を加え、酢酸エチル(100ml)にて抽出した。有機層を飽和重曹水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムにて乾燥した後、溶媒を留去した。得られた残渣を中圧シリカゲルカラムクロマトグラフィー(ジクロロメタン→ジクロロメタン/酢酸エチル=3/1)にて精製して、黄褐色アモルファス状固体の標題化合物(3.1g)を得た。
性状:黄褐色無定形粉末
1H‐NMR(300MHz,CDCl3) δppm
1.86‐2.31(2H,m),2.40(3H,s),2.87(2H,t,J=6.3Hz),3.16‐5.04(2H,br),6.42‐7.41(4H,m),7.45‐7.70(2H,m),7.76(1H,br.s)。
N-{4-(7-クロロ-5-ヒドロキシ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル}-3,4,5,6-テトラジューテロ-2-トリジューテロメチルベンズアミドの製造
N-{4-(7-クロロ-5-オキソ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル}-3,4,5,6-テトラジューテロ-2-トリジューテロメチルベンズアミド(3.0g)のメタノール(30ml)懸濁液に、0℃にて水素化ホウ素ナトリウム(300mg)を加え、その後室温にて30分撹拌した。反応液に1N塩酸(40ml)及び水(100ml)を加え、酢酸エチル(150ml)にて抽出した。有機層を飽和重曹水、飽和食塩水の順に洗浄し、無水硫酸ナトリウムにて乾燥した後、溶媒を留去した。得られた残渣を中圧シリカゲルカラムクロマトグラフィー(ジクロロメタン/酢酸エチル=3/1~1/1)にて精製した後に、含水メタノールから再結晶して、白色粉末状の標題化合物(2.36g)を得た。
性状:白色粉末
融点:225‐228℃(メタノール‐水)。
試験方法およびデータ解析方法
12wellプレートで培養したヒトV1a受容体発現HeLa細胞(V1a-HeLa)あるいは,24wellプレートで培養したヒトV2受容体発現HeLa細胞(V2-HeLa)をD-PBSにて2回洗浄した。
[3H]AVP結合飽和実験では,AVP(1 μM)存在下および非存在下,反応液(DMEM-0.3%BSA)中で種々の濃度の[3H]AVP(V1a-HeLa; 0.4 nM - 7 nM,V2-HeLa; 0.3 nM - 6 nM)をウェルに添加し反応させた。一方,[3H]AVP結合阻害実験では,種々の濃度の各化合物(V1a-HeLa; 1 nM - 100 nM,V2-HeLa; 0.1 nM - 10 nM)存在下,反応液中で[3H]AVP(V1a-HeLa; 3.3 nM - 3.7 nM,V2-HeLa; 1.4 nM - 1.7 nM)をウェルに添加し反応させた。
(B:各化合物存在下での[3H]AVPの結合量,NSB:非標識AVP 1 μM存在下での[3H]AVPの結合量,TB:非標識AVP 1 μM非存在下での[3H]AVPの結合量)
Kd:[3H]AVPの解離定数,[L]:試験に用いた[3H]AVPの濃度
その結果、優れたバソプレシン拮抗作用を有しているのを確認した。
代謝安定性試験
反応系及びインキュベーション
Obach及びJonesらの方法(ref. 1,2)を参考に,下記に記す反応系を調製し,代謝安定性について評価した。なお,ヒト肝臓ミクロソームはBD GENTESTから購入し,使用した。評価化合物は10 mMになるようにDMSOに溶解し,さらにアセトニトリルで希釈して100 μMに調製し,使用した。
評価化合物 1 μM
肝臓ミクロソーム 0.2 mg/mL
補酵素(NADPH/NADH) 1 mM
塩化マグネシウム5 mM
100 mM Phosphate buffer (pH 7.4)
例数:n = 4
補酵素非添加の反応系を37℃で 5分間プレインキュベート後,補酵素を添加し反応を開始した。補酵素添加後,0,5,10,20,30及び60分インキュベートし,所定時間毎に一部反応溶液を抜き取り,内部標準物質を含むアセトニトリル溶液に添加し,反応を停止した。
反応停止後,遠心分離し,上清を液体クロマトグラフ-タンデム型質量分析装置(LC-MS/MS) に注入して反応系に残存する未変化体を測定した。イオン化はエレクトロスプレーイオン化(ESI)法を陽イオン化検出法で行い,設定したプリカーサーイオン及びプロダクトイオンを用いた選択反応検出(MRM)法を使用した。
評価化合物の残存率は下記の式で算出した。
Clint (μL/min/mg)=(0.693/t1/2)÷0.2 (mg/mL)×1000
トルバプタン及びその重水素置換体(実施例 4)についてヒト肝臓ミクロソームにおける代謝安定性を評価した。代謝安定性の指標である肝固有クリアランス(Clint)はそれぞれ
トルバプタン:214 ± 4.3 (μL/min/mg)
実施例 4 :166± 5.3* (μL/min/mg)
(two-tailed Dunnett’s test,*: p<0.001)
であった。実施例 4 についてはトルバプタンに比べて有意に代謝安定性が改善された。
1. R.S. Obach. Drug Metab. Dispos. 1999(27):1350-1359
2. H. Jones and J.B. Houston, Drug Metab Dispos, 2004 (32): 973-982
Claims (8)
- (1) N-(4-(7-クロロ-5-ヒドロキシ-2,3,4-トリヒドロ-5-ジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド、
(2) N-(4-(7-クロロ-2,3-ジヒドロ-5-ヒドロキシ-4,4,5-トリジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド、
(3) N-(4-(7-クロロ-5-ヒドロキシ-2,2-ジジューテロ-3,4,5-トリヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド、
(4) N-(4-(7-クロロ-5-ヒドロキシ-2,2,4,4,5-ペンタジューテロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル)-2-メチルベンズアミド及び
(5) N-{4-(7-クロロ-5-ヒドロキシ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b]アゼピン-1-カルボニル)-3-メチルフェニル}-3,4,5,6-テトラジューテロ-2-トリジューテロメチルベンズアミド
からなる群から選ばれたベンズアゼピン化合物又はその塩。 - 有効成分として請求項1又は2に記載のベンズアゼピン化合物又はその塩及び薬理学的に許容される担体を含む医薬組成物。
- 請求項1又は2に記載のベンズアゼピン化合物又はその塩の、薬剤としての使用。
- 有効成分として請求項1又は2に記載のベンズアゼピン化合物又はその塩を含有するバソプレシン拮抗剤。
- 高血圧、浮腫、腹水、心不全、腎機能障害、バソプレシン分泌異常症候群(SIADH)、肝硬変、低ナトリウム血症、低カリウム血症、糖尿病、循環不全、動揺病、水代謝障害、腎不全、脳梗塞、心筋梗塞及び多発性嚢胞腎(PKD)からなる群より選ばれる疾患を予防又は治療するための請求項3に記載の医薬組成物。
- 血管拡張剤、降圧剤、水利尿剤、血小板凝集抑制剤、尿素排泄促進剤、抗心不全剤、及び抗腎不全剤からなる群より選ばれる薬剤として用いられる請求項3に記載の医薬組成物。
- 請求項1又は2に記載のベンズアゼピン化合物又はその塩を、人又は動物に投与することを含む、高血圧、浮腫、腹水、心不全、腎機能障害、バソプレシン分泌異常症候群(SIADH)、肝硬変、低ナトリウム血症、低カリウム血症、糖尿病、循環不全、動揺病、水代謝障害、腎不全、脳梗塞、心筋梗塞及び多発性嚢胞腎(PKD)からなる群より選ばれる疾患を予防又は治療する方法。
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2011538404A JP5717645B2 (ja) | 2009-10-26 | 2010-10-25 | ベンズアゼピン化合物 |
EP10826651A EP2495236A4 (en) | 2009-10-26 | 2010-10-25 | BENZAZEPINE COMPOUND |
CN201080048410.3A CN102753530B (zh) | 2009-10-26 | 2010-10-25 | 苯并氮杂*化合物 |
IN3343DEN2012 IN2012DN03343A (ja) | 2009-10-26 | 2010-10-25 | |
US13/504,101 US8940727B2 (en) | 2009-10-26 | 2010-10-25 | Benzazepine compound |
BR112012009784A BR112012009784A2 (pt) | 2009-10-26 | 2010-10-25 | composto benzazepínico |
AU2010312651A AU2010312651A1 (en) | 2009-10-26 | 2010-10-25 | Benzazepine compound |
CA2778756A CA2778756A1 (en) | 2009-10-26 | 2010-10-25 | Benzazepine compound |
EA201290228A EA022253B1 (ru) | 2009-10-26 | 2010-10-25 | Соединение бензазепина и его применения |
ZA2012/02640A ZA201202640B (en) | 2009-10-26 | 2012-04-12 | Benzazepine compound |
IL219132A IL219132A0 (en) | 2009-10-26 | 2012-04-15 | Benzazepine compound |
Applications Claiming Priority (2)
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JP2009245434 | 2009-10-26 | ||
JP2009-245434 | 2009-10-26 |
Publications (1)
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WO2011052519A1 true WO2011052519A1 (ja) | 2011-05-05 |
Family
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Family Applications (1)
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PCT/JP2010/068807 WO2011052519A1 (ja) | 2009-10-26 | 2010-10-25 | ベンズアゼピン化合物 |
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Country | Link |
---|---|
US (1) | US8940727B2 (ja) |
EP (1) | EP2495236A4 (ja) |
JP (1) | JP5717645B2 (ja) |
KR (1) | KR20120092139A (ja) |
CN (3) | CN104829531A (ja) |
AU (1) | AU2010312651A1 (ja) |
BR (1) | BR112012009784A2 (ja) |
CA (1) | CA2778756A1 (ja) |
CO (1) | CO6481003A2 (ja) |
EA (1) | EA022253B1 (ja) |
IL (1) | IL219132A0 (ja) |
IN (1) | IN2012DN03343A (ja) |
MX (1) | MX2012004843A (ja) |
SG (1) | SG10201406839VA (ja) |
WO (1) | WO2011052519A1 (ja) |
ZA (1) | ZA201202640B (ja) |
Cited By (4)
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WO2019003433A1 (ja) * | 2017-06-30 | 2019-01-03 | 大塚製薬株式会社 | ベンゾアゼピン誘導体 |
WO2019116324A1 (en) | 2017-12-15 | 2019-06-20 | Richter Gedeon Nyrt. | Triazolobenzazepines as vasopressin v1a receptor antagonists |
WO2019116325A1 (en) | 2017-12-15 | 2019-06-20 | Richter Gedeon Nyrt. | Tricyclic compounds as vasopressin v1a receptor antagonists |
JP2020109086A (ja) * | 2018-12-28 | 2020-07-16 | 大塚製薬株式会社 | 医薬組成物 |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JO3711B1 (ar) | 2015-07-13 | 2021-01-31 | H Lundbeck As | أجسام مضادة محددة لبروتين تاو وطرق استعمالها |
CN112851583B (zh) * | 2021-01-19 | 2023-09-08 | 徐州医科大学 | 新型苯并氮杂䓬类化合物、组合物及其用途 |
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- 2010-10-25 WO PCT/JP2010/068807 patent/WO2011052519A1/ja active Application Filing
- 2010-10-25 JP JP2011538404A patent/JP5717645B2/ja not_active Expired - Fee Related
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- 2010-10-25 AU AU2010312651A patent/AU2010312651A1/en not_active Abandoned
- 2010-10-25 US US13/504,101 patent/US8940727B2/en not_active Expired - Fee Related
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- 2010-10-25 BR BR112012009784A patent/BR112012009784A2/pt not_active IP Right Cessation
- 2010-10-25 CN CN201080048410.3A patent/CN102753530B/zh not_active Expired - Fee Related
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WO2019003433A1 (ja) * | 2017-06-30 | 2019-01-03 | 大塚製薬株式会社 | ベンゾアゼピン誘導体 |
WO2019004421A1 (en) | 2017-06-30 | 2019-01-03 | Otsuka Pharmaceutical Co., Ltd. | BENZAZEPINE DERIVATIVES |
JP2020503346A (ja) * | 2017-06-30 | 2020-01-30 | 大塚製薬株式会社 | ベンゾアゼピン誘導体 |
JP2020117525A (ja) * | 2017-06-30 | 2020-08-06 | 大塚製薬株式会社 | ベンゾアゼピン誘導体 |
US10889570B2 (en) | 2017-06-30 | 2021-01-12 | Otsuka Pharmaceutical Co., Ltd. | Benzazepine derivatives |
JP7055160B2 (ja) | 2017-06-30 | 2022-04-15 | 大塚製薬株式会社 | ベンゾアゼピン誘導体 |
US11673878B2 (en) | 2017-06-30 | 2023-06-13 | Otsuka Pharmaceutical Co., Ltd. | Benzazepine derivatives |
WO2019116324A1 (en) | 2017-12-15 | 2019-06-20 | Richter Gedeon Nyrt. | Triazolobenzazepines as vasopressin v1a receptor antagonists |
WO2019116325A1 (en) | 2017-12-15 | 2019-06-20 | Richter Gedeon Nyrt. | Tricyclic compounds as vasopressin v1a receptor antagonists |
US11298363B2 (en) | 2017-12-15 | 2022-04-12 | Richter Gedeon Nyrt. | Triazolobenzazepines as vasopressin V1a receptor antagonists |
JP2020109086A (ja) * | 2018-12-28 | 2020-07-16 | 大塚製薬株式会社 | 医薬組成物 |
JP7462589B2 (ja) | 2018-12-28 | 2024-04-05 | 大塚製薬株式会社 | 医薬組成物 |
Also Published As
Publication number | Publication date |
---|---|
EP2495236A4 (en) | 2013-03-27 |
BR112012009784A2 (pt) | 2016-05-17 |
IL219132A0 (en) | 2012-06-28 |
EA022253B1 (ru) | 2015-11-30 |
JP5717645B2 (ja) | 2015-05-13 |
JPWO2011052519A1 (ja) | 2013-03-21 |
ZA201202640B (en) | 2013-06-26 |
EP2495236A1 (en) | 2012-09-05 |
CO6481003A2 (es) | 2012-07-16 |
AU2010312651A1 (en) | 2012-05-03 |
EA201290228A1 (ru) | 2012-12-28 |
CA2778756A1 (en) | 2011-05-05 |
CN102753530A (zh) | 2012-10-24 |
IN2012DN03343A (ja) | 2015-10-23 |
US20130131045A1 (en) | 2013-05-23 |
US8940727B2 (en) | 2015-01-27 |
SG10201406839VA (en) | 2014-12-30 |
KR20120092139A (ko) | 2012-08-20 |
CN104829531A (zh) | 2015-08-12 |
CN102753530B (zh) | 2015-06-17 |
CN104447555A (zh) | 2015-03-25 |
MX2012004843A (es) | 2012-05-29 |
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