WO1999065874A1 - Derives de benzanilide et compositions medicinales - Google Patents

Derives de benzanilide et compositions medicinales Download PDF

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WO1999065874A1
WO1999065874A1 PCT/JP1999/003276 JP9903276W WO9965874A1 WO 1999065874 A1 WO1999065874 A1 WO 1999065874A1 JP 9903276 W JP9903276 W JP 9903276W WO 9965874 A1 WO9965874 A1 WO 9965874A1
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methyl
yield
amino
title compound
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PCT/JP1999/003276
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Japanese (ja)
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Yasuhiro Ohtake
Katsuhiro Kawano
Akira Naito
Kenji Naito
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Wakamoto Pharmaceutical Co., Ltd.
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Priority to AU41688/99A priority Critical patent/AU4168899A/en
Publication of WO1999065874A1 publication Critical patent/WO1999065874A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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 benzanilide derivative and a pharmaceutical composition.
  • the present invention relates to a novel benzanilide derivative and a pharmacologically acceptable salt thereof, and a pharmaceutical composition using the same, particularly as a vasopressin antagonist.
  • an in vivo active substance having a vasoconstrictive action binds to a receptor on the vascular smooth muscle cell membrane
  • opening of receptor-sensitive calcium channels causes the influx of calcium from outside the cell into the cell and the action of the intracellular stimulus transmission system.
  • the increase in calcium in the cell and the increase in calcium sensitivity due to the activation of the intracellular stimulus transmission system enhances the calcium-carbomodulin-dependent phosphorylation of myosin light chain, resulting in vasoconstriction.
  • Excessive vasoconstriction causes tissue damage due to a rapid rise in blood pressure and poor tissue microcirculation.
  • Known in vivo active substances having a vasoconstrictive action include nordrenaline, angiotensin, and vasopressin.
  • Vasopressin is a neuroendocrine hormone secreted from the posterior pituitary gland.In the periphery, it mainly exerts a potent vasoconstrictor action via the V1 receptor and a water reabsorption promoting action via the V2 receptor in the renal collecting duct. It plays a role in circulatory dynamics and maintaining body fluid homeostasis. Vasopressin also has a variety of other physiological actions such as the action of promoting glycogen degradation in the liver, the promotion of secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland, or the action of promoting platelet aggregation.
  • ACTH adrenocorticotropic hormone
  • vasopressin having such an effect can be caused by various pathological conditions, such as depressive heart failure (Pharmacological Review, 43, 73–108, 1991), cerebral edema (Stroke, 2_3_, 1767- 1773, 199 2), arginine vasopressin hypersecretion syndrome (Journal of Cardiov ascular Ph a rma cology, 8, S 36—S 43, 1 986), cirrhosis (Ann. International, Med., 96, 413-417,
  • vasopressin antagonist if a superior vasopressin antagonist is developed, these diseases caused by excess vasopressin, such as congestive heart failure, cerebral circulation disorder, edema such as cerebral edema, ascites, pulmonary edema, arginine vasopressin hypersecretion syndrome, kidney
  • insufficiency Tengitis, hypertension, cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, Meniere's syndrome, oxitocin-related diseases, etc. , 1991).
  • vasopressin antagonists have been developed for the purpose of preventing or treating vasopressin-related diseases.
  • non-peptide compounds can be administered orally, unlike peptide compounds, and can be expected to be clinically useful.
  • the present invention has been made in view of the above-mentioned circumstances, and aims to create a pharmaceutical composition having sharpness, extremely high safety and efficacy, and particularly a compound useful as a vasopressin antagonist.
  • a first aspect of the present invention is a benzanilide derivative represented by the following general formula (1).
  • R 1 represents a group represented by the following general formula (1A) or a group represented by the following general formula (1B), and R 2 represents hydrogen or a group having 1 to 6 carbon atoms.
  • R 3 represents hydrogen, alkyl having 1 to 4 carbon atoms, halogen, alkoxy having 1 to 4 carbon atoms, and trifluoromethyl
  • R 4 represents hydrogen, alkyl having 1 to 4 carbon atoms, halogen, and Trifluoromethyl, alkoxy having 1 to 4 carbon atoms, phenoxy, benzyloxy, hydroxy, alkylthio having 1 to 4 carbon atoms, nitro, amino, or a group represented by the following general formula (1C), and n is 0 to 4 Represents an integer.
  • R 5 represents hydrogen, alkyl having 1 to 4 carbons, phenyl, or hydroxy, and m represents an integer of 0 to 3.
  • A 0, or represents NR 7 (R 7 is hydrogen, alkyl of 1 to 6 carbon atoms, alkyl force Rubamoiru alkyl force Ruponiru, 1 carbon atoms 5 of one to several atoms 5, base And a group represented by the following general formula (1D) or a group represented by the following general formula (1E)).
  • R 6 is hydrogen, alkyl having 1 to 4 carbons, halogen, alkyl having 1 to 4 carbons.
  • Coxy represents alkylthio having 1 to 4 carbon atoms, benzyl, phenoxy, or benzyloxy, and q represents an integer of 0 to 4.
  • R 8 is halogen
  • — NR 9 R 1 () (R 9 and R 1 () may be the same or different, and each represents hydrogen or alkyl having 1 to 4 carbon atoms. Represents) or morpholino, and r represents an integer of 0 to 4.
  • One (IE) is IE
  • t represents an integer of 0 to 4
  • u represents an integer of 0 to 3.
  • the second present invention is a pharmaceutical composition comprising the benzanilide derivative of the first present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention is a benzanilide derivative represented by the general formula (1).
  • the compound of the present invention represented by the above general formula (1) has the following chemical structural characteristics.
  • a group represented by the following formula (1F) is bonded to the other nitrogen atom.
  • the alkyl having 1 to 4 carbon atoms is linear May be branched, and examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl and the like. Of these, methyl is preferred.
  • the alkyl having 1 to 6 carbon atoms may be linear or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, Pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, hexyl, isohexyl, 1_ (2-methyl) pentyl, 1— (3-methyl) pentyl , 1-ethylbutyl, 1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, and the like.
  • methyl, isoptyl, isopentyl and isohexyl are preferred.
  • the alkyl chain of the alkoxy having 1 to 4 carbon atoms may be linear or branched, and includes, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy and the like. be able to. Of these, methoxy is preferred.
  • the alkyl chain of alkylthio having 1 to 4 carbon atoms may be linear or branched, and includes, for example, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio and the like. be able to. Of these, methylthio is preferred.
  • the alkyl chain of the alkylcarbonyl having 1 to 5 carbon atoms may be linear or branched, for example, acetyl, propionyl, isopropionyl, butyryl, isobutyryl, Valeryl, Vivaloyl and the like can be mentioned. Of these, isopropionyl and bivaloyl are preferred.
  • the alkyl chain of the alkyl group having 1 to 5 carbon atoms may be linear or branched, for example, methyl carbamoyl, ethyl carbamoyl, propyl group.
  • Isopropyl carbamoyl, butylcarbamoyl, isobutylcarbamoyl, tert-butylcarbamoyl and the like can be mentioned. Of these, isopropyl rubamoyl and tert-butyl Tilcarbamoyl is preferred.
  • the halogen is not particularly limited, and examples thereof include chlorine, bromine, fluorine, and iodine. Of these, fluorine and chlorine are preferred.
  • R 9 and R 1G of one NR 9 R 1D may be the same or different and each represent hydrogen or an alkyl group having 1 to 4 carbon atoms
  • _NR 9 R 1Q examples thereof include an amino group, a monoalkylamino group substituted with an alkyl group having 1 to 4 carbon atoms, and a dialkylamino group.
  • the alkyl group is not particularly limited as long as it has 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, and butyl. Good. Of these, methyl is preferred.
  • R 2 represents hydrogen or an alkyl group having 1 to 6 carbon atoms.
  • the alkyl group having 1 to 6 carbon atoms is not particularly limited, and examples thereof include methyl, ethyl, propyl, butyl, isobutyl, pentyl, isopentyl, hexyl, and isohexyl. It may be linear or linear. Of these, methyl is preferred.
  • the compounds of the present invention also include pharmacologically acceptable salts thereof.
  • the pharmacologically acceptable salt of the compound of the present invention is an acid addition salt with an inorganic acid or an organic acid, and is a pharmacologically acceptable salt.
  • salts include, for example, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid; formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, benzoic acid, p-toluenesulfonic acid, isethionic acid, glucuronic acid, dalconic acid, methanesulfonic acid, ethanesulfonic acid; acidic acids such as aspartic acid and glutamic acid And acid addition salts with amino acids.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid
  • formic acid acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric
  • the compound of the present invention represented by the above general formula (1) has a pharmacological effect that it does not exhibit a contraction inhibitory effect on vasoconstriction caused by noradrenaline, angiotensin and the like, but exhibits a contraction inhibitory effect only on vasoconstriction caused by vasopressin. Has features.
  • the compound of the present invention and a salt thereof can be synthesized by various methods. less than Illustrate a typical production method ⁇
  • R 3 and n are as described above, X represents halogen, R 11 is a group represented by the above general formula (1A), a group represented by the following general formula (1 G) the stands, R 1 2 denotes an alkyl having 1 to 4 carbon atoms, R 13 is hydrogen, alkyl of 1 to 4 carbon atoms, halogen, 1 to 4 carbon atoms alkoxy, phenoxy, 1 to 4 carbon atoms Represents alkylthio, benzyloxy, nitro, trifluoromethyl, or a group represented by the above general formula (1C).
  • a 1 is ⁇ or NR 14 (R 14 is alkyl having 1 to 4 carbons, alkyl rubonyl having 1 to 5 carbons, alkyl rubamoyl having 1 to 5 carbons, benzyl, or the above general formula (Representing a group represented by the formula (1E)).
  • the above-mentioned compound (2) can be converted into the above-mentioned amine compound (3) by a reduction reaction of a nitro group.
  • the reduction method include chemical reduction and catalytic reduction, and can be used according to a conventional method.
  • R 3 is halogen or R 1 is benzyl, chemical reduction is preferred.
  • Examples of the reducing agent used in the above chemical reduction include metals such as tin, zinc and iron; metal compounds such as nickel chloride, chromium chloride and chromium acetate; aluminum hydride, aluminum lithium hydride, and sodium aluminum hydride. And aluminum hydride compounds such as sodium borohydride, lithium borohydride, sodium cyanoborohydride, porane and dipolane.
  • the chemical reduction can be performed under acidic, neutral, or basic conditions. When the chemical reduction is performed under acidic conditions, an acid may be used. Examples of the acid include organic acids such as formic acid, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid; and inorganic acids such as hydrochloric acid and hydrobromic acid.
  • a base When the chemical reduction is performed under basic conditions, a base may be used.
  • the base include ammonia, ammonium chloride, sodium hydroxide and the like.
  • Examples of the catalyst used for the above-mentioned catalytic reduction include palladium catalysts such as palladium carbon, palladium oxide, spongy palladium, and palladium colloid; nickel catalysts such as Raney nickel, nickel oxide, and reduced nickel; platinum plates, platinum oxide, and sponge Platinum catalysts, such as platinum, can be mentioned.
  • palladium catalysts such as palladium carbon, palladium oxide, spongy palladium, and palladium colloid
  • nickel catalysts such as Raney nickel, nickel oxide, and reduced nickel
  • platinum plates, platinum oxide, and sponge Platinum catalysts, such as platinum, can be mentioned.
  • the above reduction reaction is usually performed in a solvent.
  • the solvent include alcohols such as methanol, ethanol, and propanol; ethers such as getyl ether, dioxane, tetrahydrofuran, and dimethoxyethane; a single solvent such as water, or a mixed solvent. Can be.
  • the reaction temperature is not particularly limited, and the reaction is preferably carried out under cooling or heating, if necessary.
  • the compound (4) can be produced by an amide bond-forming reaction between the amine compound (3) and 4,212 benzoic acid chloride.
  • the amide bond forming reaction can be easily performed using known amide bond forming reaction conditions.
  • Solvents used in the amide bond formation reaction include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, tetrahydrofuran, and dioxane. And ethers such as dimethoxyethane, etc .; esters such as ethyl acetate; single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, or mixtures thereof. Solvents and the like can be mentioned.
  • Examples of the above-mentioned organic base include N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazavicic mouth [4,3,0] nonene-5 (DBN), 1,8 —Diazabicyclo [5,4,0] indene—7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DAB CO).
  • Examples of the inorganic base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.
  • the reaction temperature of the amide bond forming reaction is usually preferably about 20 to 150 ° C, more preferably about -5 to 50.
  • the reaction time of the amide bond formation reaction is preferably about 5 minutes to 18 hours, and more preferably about 5 minutes to 2 hours.
  • the above-mentioned compound (4) can be converted into the above-mentioned compound (5) by known alkylation using an alkyl halide having 1 to 4 carbon atoms in an appropriate solvent in the presence of a base.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene and xylene; and ethers such as dimethyl ether, tetrahydrofuran, dioxane and dimethoxyethane. Ters; alcohols such as methanol, ethanol, and propanol; single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixed solvents thereof.
  • aromatic hydrocarbons such as benzene, toluene and xylene
  • ethers such as dimethyl ether, tetrahydrofuran, dioxane and dimethoxyethane.
  • Ters alcohols such as methanol, ethanol, and propanol
  • single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide
  • Examples of the base include N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonen-5 (DBN), 1,8-diazabicyclo [5 Organic bases such as, 4,0] pendene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (D ABC ⁇ ); alkali metals such as lithium, sodium and potassium; magnesium and calcium Alkaline earth metals such as hydrides, hydroxides, and inorganic bases such as carbonates.
  • DBU pendene-7
  • D ABC ⁇ 1,4-diazabicyclo [2,2,2] octane
  • alkali metals such as lithium, sodium and potassium
  • magnesium and calcium Alkaline earth metals such as hydrides, hydroxides, and inorganic bases such as carbonates.
  • alkyl halide having 1 to 4 carbon atoms examples include methyl iodide, chlorinated ethyl chloride, propyl chloride, isopropyl chloride, and isobutyl bromide.
  • the reaction temperature of the above-mentioned alkylation reaction is usually preferably from 0 ° C to about the boiling point of the solvent used, more preferably from 20 ° C to the boiling point of the solvent used.
  • the reaction time of the above alkylation reaction is preferably about 5 minutes to 18 hours, and more preferably about 5 minutes to 5 hours.
  • the above-mentioned compound (5) can be converted into the above-mentioned amine compound (6) by a reduction reaction of a nitro group.
  • the above reduction reaction can be easily achieved by a method similar to the reduction reaction used for the conversion of the above compound (2) into the above amine compound (3).
  • catalytic reduction is usually preferable, and when R 3 is halogen or R 14 is benzyl, chemical reduction is preferable.
  • the compound (la) of the present invention can be produced by an amide bond forming reaction between the amine compound (6) and the carboxylic acid (7).
  • the above-mentioned amide bond formation reaction can be easily carried out using known amide bond formation reaction conditions exemplified below.
  • Acid chloride method A carboxylic acid (7) is reacted with a halogenating agent to form an acid chloride, which is then reacted with an amine compound (6).
  • a halogenating agent include, for example, , Thionyl chloride, oxalyl chloride, phosphorus pentachloride and the like.
  • Carpoimide method Carboxylic acid (7) is reacted with amide (6) in the presence of a condensing agent.
  • the condensing agent include dicyclohexylcarbodiimide, N-ethyl-N '-(3-dimethylaminopropyl) carbodiimide, and carbonyldiimidazole.
  • Activated ester method A carboxylic acid (7) is used as an activated ester, and an amine (6) is reacted with the activated ester.
  • the activated ester include nitro- or halogen-substituted phenyl esters, aromatic thioesters, N-hydroxysuccinic esters, 1-hydroxybenzotriazole esters, enoesters, and the like. .
  • a method in which carboxylic acid (7) is converted into a sulfonic acid anhydride with a dehydrating agent such as acetic anhydride and reacted with an amine compound (6); an ester of carboxylic acid (7) with a lower alcohol A method of reacting an amine compound (6) under high pressure and high temperature; a method of reacting a carboxylic acid (7) with an amine compound (6) in the presence of a phosphorus compound condensing agent.
  • Examples of the condensing agent for the phosphorus compound include, for example, triphenylphosphine, diphenylphosphine chloride, phenyl-N-phenylphosphoramidochloridate, getylchlorophosphate, getyl cyanophosphate, diphenylphosphoric azide, bis (2-oxo_3 —Oxazolidinyl) phosphinic chloride and the like.
  • the compound of the present invention can be obtained simply and easily.
  • the solvent used for the amide bond forming reaction varies depending on the method selected, but includes, for example, halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; Ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; esters such as ethyl acetate; single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide Or a mixed solvent thereof.
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • Ethers such as getyl ether, tetrahydrofuran, dioxane, and dim
  • Examples of the above-mentioned organic base include N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5_diazavisic mouth [4,3,0] nonene-5 (DBN), 1,8 —Diazabicyclo [5,4,0] indene-17 (DBU), 1,4-diazabicyclo [2,2,2] octane (DABCO) and the like.
  • Examples of the inorganic base include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate and the like.
  • the reaction temperature of the amide bond formation reaction is usually preferably about 120 to 150 ° C, more preferably about 15 to 50 ° C.
  • the reaction time of the amide bond forming reaction is preferably about 5 minutes to 18 hours, and more preferably about 5 minutes to 2 hours.
  • the reduction reaction from the compound (4) to the amine compound (8) can be performed under the same reaction conditions as the reduction reaction from the compound (5) to the amine compound (6) in [Reaction formula 1].
  • the conversion of the amine (8) to the compound (lb) of the present invention can be carried out in the same manner as the reaction for producing the compound (la) of the present invention from the amine (6) of [Reaction formula 1]. It can be easily carried out depending on the reaction conditions (eg, solvent used, reaction temperature, etc.)
  • R 14 represents a group represented by the above general formula (1A) or a group represented by the following formula (1H).
  • Examples of the base include N-methylmorpholine, trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [ Organic bases such as 5,4,0] pendene-7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DABCO); inorganic bases such as potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydrogen carbonate Bases and the like can be mentioned.
  • the solvent examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
  • Ethers such as ethyl acetate; single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethyl sulfoxide, and hexamethylphosphoric triamide, or mixed solvents thereof, or Examples of the solvent include a mixed solvent with water.
  • the reaction temperature of the above condensation reaction is usually preferably from 0 ° C. to about the boiling point of the solvent used, and more preferably from 25 ° C. to about the boiling point of the solvent used.
  • the reaction time of the above condensation reaction is preferably about 5 minutes to 20 hours, and more preferably about 5 minutes to 10 hours.
  • R 3 and X are as described above, and R 15 represents an alkyl having 1 to 6 carbon atoms or a group represented by the above general formula (1E).
  • the condensation reaction from the compound (9) to the compound (11) can be performed under the same reaction conditions as the condensation reaction from the compound (9) to the compound (10) in the above [Reaction formula 3]. .
  • the above-mentioned compound (11) is converted into the above-mentioned compound (12) using the above-mentioned compound (11) and an alkyl halide having 1 to 6 carbon atoms or a compound represented by the following general formula (II).
  • the reaction can be carried out by a known alkylation reaction in a suitable solvent in the presence of a base.
  • X represents a halogen
  • t represents an integer of 0 to 4
  • u represents an integer of 0 to 3.
  • alkyl halides having 1 to 6 carbon atoms include, for example, methyl iodide, chlorinated tyl, propyl chloride, isoptyl bromide, pentyl bromide, isopentyl bromide, And isohexyl chloride.
  • Examples of the compound represented by the general formula (II) include cyclopentyl bromide, cyclohexyl bromide, cyclohexylmethyl bromide, 3- (cyclohexyl) propyl chloride and the like.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, and propanol; N, N-dimethyl
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as diethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane
  • alcohols such as methanol, ethanol, and propanol
  • N N-dimethyl
  • a single solvent such as an aprotic polar solvent such as formamide, dimethyl sulfoxide, and hexamethylphosphoric acid triamide, or a mixed solvent thereof can be used.
  • the base examples include alkali metals such as lithium, sodium, and potassium; alkaline earth metals such as magnesium and calcium; inorganic bases such as hydrides, hydroxides, and carbonates thereof; trimethylamine, triethylamine, and the like.
  • alkali metals such as lithium, sodium, and potassium
  • alkaline earth metals such as magnesium and calcium
  • inorganic bases such as hydrides, hydroxides, and carbonates thereof
  • trimethylamine, triethylamine, and the like trial of kiramine, picoline, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] pendecene-7 (DBU), 1,4 diazabicyclo [2 , 2,2] octane (DABCO) and other organic bases.
  • the reaction temperature of the above-mentioned alkylation reaction is usually preferably from 0 ° C to about the boiling point of the solvent used, more preferably from 20 ° C to the boiling point of the solvent used.
  • the reaction time of the above alkylation reaction is preferably about 5 minutes to 18 hours, and more preferably about 5 minutes to 10 hours.
  • R 3 and X are as described above, and R 16 represents an alkyl group having 1 to 5 carbon atoms.
  • the above-mentioned compound (11) can be converted to the above-mentioned compound (13) by an acylation reaction of the above-mentioned compound (11) with XR 16 or (R 16 ) 2 O.
  • the acylation can be carried out in a suitable solvent in the presence of a base, using an alkanol halide having 1 to 5 carbon atoms, an anhydride of an alkanoic acid having 2 to 5 carbon atoms, or the like.
  • the base examples include alkali metals such as lithium, sodium and potassium; alkaline earth metals such as magnesium and calcium; inorganic bases such as hydrides, hydroxides, carbonates and bicarbonates; N-methyl Morpholine, trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] ⁇ decene And organic bases such as 7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (D ABCO).
  • alkali metals such as lithium, sodium and potassium
  • alkaline earth metals such as magnesium and calcium
  • inorganic bases such as hydrides, hydroxides, carbonates and bicarbonates
  • N-methyl Morpholine trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonen
  • the solvent examples include halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane. Alcohols such as methanol, ethanol, and propanol; single solvents such as aprotic polar solvents such as N, N-dimethylformamide, dimethylsulfoxide, and hexamethylphosphoric triamide; and mixed solvents thereof. it can.
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as ethyl ether, tetrahydrofuran, dioxane, and dimethoxyethane.
  • alkanoyl halide having 1 to 5 carbon atoms examples include acetyl chloride, propionyl chloride, butyryl bromide, isobutyryl bromide, isovaleryl chloride, and pivaloyl chloride.
  • anhydride of the alkanoic acid having 2 to 5 carbon atoms examples include acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, hexanoic anhydride and the like.
  • the reaction temperature of the acylation reaction is usually from ⁇ 40 to about the boiling point of the solvent used, and more preferably from ⁇ 10 ° C. to about the boiling point of the solvent used.
  • the reaction time of the acylation reaction is preferably about 5 minutes to 20 hours, and more preferably about 5 minutes to 10 hours.
  • R 3 is as described above, and R 17 represents an alkyl rubamoyl having 15 carbon atoms.
  • Conversion of the compound (1 1) above compound to (14) may be carried out by ureido formation reaction of the compound (1 1) and OCNR 17.
  • the ureide formation reaction can be carried out in a suitable solvent using a C 15 alkyl isocyanate and a known peridode formation reaction.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; alcohols such as methanol, ethanol, and propanol; And halogenated hydrocarbons such as dichloroethane and chloroform; esters such as ethyl acetate; a single solvent such as acetone, or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane
  • alcohols such as methanol, ethanol, and propanol
  • halogenated hydrocarbons such as dichloroethane and chloroform
  • esters such as ethyl acetate
  • a single solvent such as acetone
  • Examples of the above alkyl isocyanate having 15 carbon atoms include methyl isocyanate, ethyl isocyanate, propyl isocyanate, isopropyl isocyanate, butyl isocyanate, isobutyl isocyanate, and tert-butyl isocyanate. And the like.
  • the reaction temperature of the above-mentioned urea forming reaction is usually preferably from 120 ° C. to about the boiling point of the solvent used, more preferably from 0 ° C. to the boiling point of the solvent used.
  • the reaction time of the ureide formation reaction is preferably about 5 minutes to 24 hours, and more preferably about 5 minutes to 10 hours.
  • R 2 , R 3 and X are as described above, and R 18 represents a group represented by the following general formula (1J).
  • R 19 represents alkyl having 1 to 4 carbon atoms, phenyl, pyridyl, V is an integer of 0-3.
  • R 18 is, for example, a phenylalkoxycarbonyl such as benzyloxycarbonyl; an alkoxycarbonyl such as tert-butoxycarbonyl; a protecting group for an amino group such as pyridylalkoxycarbonyl such as 2- (4-pyridyl) ethoxycarponyl.
  • the reaction from the above compound (15) to the above compound (18) is similar to the reaction from the compound (2) to the compound (5) in the above [Reaction formula 1] under the same reaction and reaction conditions ( For example, the reaction can be easily performed by using a solvent used, a reaction temperature and the like.
  • the deprotection reaction from the above compound (18) to the above compound (19) can be performed by a usual deprotection reaction.
  • the introduction of the protecting group to the amino group of the above compound (11) and the deprotection reaction of the above compound (18) are described in, for example, “Groene (Greene)” and “Wots”, “Protective Grousin. Organic Synthesis (2nd edition) ".
  • the alkylation reaction from compound (19) to compound (20) is similar to the reaction and reaction conditions for the reaction from compound (11) to compound (12) in [Reaction formula 4] (for example, the solvent used). , Reaction temperature, etc.).
  • R 2 , R 3 , R 16 and X are as described above.
  • R 2 , R 3 and R 17 are as described above.
  • the above-mentioned compound (19) is converted into the above-mentioned compound (22) by the same reaction and reaction conditions as the ureide formation reaction from the above-mentioned compound (11) to the compound (14) in [Reaction formula 6] (for example, the solvent used) , Reaction temperature, etc.).
  • R 2 , R 3 , R 13 , R 18 and n are as described above.
  • reaction from the above-mentioned compound (18) to the above-mentioned compound (24) is performed under the same reaction and reaction conditions as those for the above-mentioned [reaction formula 1] from the compound (5) to the compound (la) (for example, Depending on the solvent used, the reaction temperature, etc.)
  • reaction from the compound (24) to the compound of the present invention (lc) is similar to the reaction from the compound (18) to the compound (19) in the above [Reaction formula 7] under the same reaction conditions and reaction conditions (for example, the solvent used). , Reaction temperature, etc.).
  • R 2 , R 3 , R 13 , X and y are as described above, and R 2 represents NR 9 R 10 (R 9 and R lfl are as described above) and morpholino.
  • the conversion of the compound (Ic) of the present invention to the compound (Id) of the present invention can be carried out by an acylation reaction between the compound (Ic) of the present invention and the above compound (25).
  • the acylation reaction can be carried out using a known acylation reaction in an appropriate solvent in the presence of a base.
  • Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; single solvents such as ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and mixed solvents thereof.
  • Examples of the base include alkali gold such as lithium, sodium, and potassium.
  • alkaline earth metals such as magnesium and calcium
  • inorganic bases such as hydroxides, carbonates and bicarbonates
  • N-methylmorpholine trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1 , 5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] decene-1 7 (DBU), 1,4-diazabicyclo [2,2,2]
  • Organic bases such as octane (DA BCO) can be mentioned.
  • the reaction temperature of the above acylation reaction is generally preferably from 120 ° C. to about the boiling point of the solvent used, more preferably from 0 ° C. to the boiling point of the solvent used.
  • the reaction time of the acylation reaction is preferably about 5 minutes to 20 hours, and more preferably about 5 minutes to 10 hours.
  • the conversion of the compound of the present invention (Id) to the compound of the present invention (le) is carried out by condensing the compound of the present invention (Id) and an amine compound (HR 2G ) in a suitable solvent in the presence of a base. be able to.
  • the solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane; and halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform. Or a mixed solvent thereof.
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxyethane
  • halogenated hydrocarbons such as dichloromethane, dichloroethane, and chloroform. Or a mixed solvent thereof.
  • the base examples include: alkali metals such as lithium, sodium and potassium; alkaline earth metals such as magnesium and calcium; inorganic bases such as hydroxides, carbonates and bicarbonates; N-methylmorpholine; Trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DBN), 1,8-diazabicyclo [5,4,0] pandecene-1 Organic bases such as 7 (DBU) and 1,4-diazabicyclo [2,2,2] octane (DA BCO) can be mentioned.
  • alkali metals such as lithium, sodium and potassium
  • alkaline earth metals such as magnesium and calcium
  • inorganic bases such as hydroxides, carbonates and bicarbonates
  • N-methylmorpholine Trimethylamine, triethylamine, N, N-dimethylamine, pyridine, 1,5-diazabicyclo [4,3,0] nonene-5 (DB
  • Examples of the amine compound (HR 2 °) include dimethylamine, ethylamine, getylamine, propylamine, diisopropylamine, dibutylamine, tert-butylamine, and morpholine.
  • the reaction temperature of the above conversion is preferably from ⁇ 20 ° C. to about the boiling point of the solvent used, and more preferably from 10 ° C. to the boiling point of the solvent used.
  • the time is preferably about 5 minutes to 20 hours, more preferably about 5 minutes to 10 hours.
  • the conversion of the compound of the present invention (1) into the compound of the present invention (lg) can be carried out under the same reaction conditions as the reduction reaction from the compound (2) to the compound (3) in the above [Reaction formula 1]. it can.
  • the above conversion is usually preferably performed by catalytic reduction, and when R 3 is a halogen, it is preferably performed by chemical reduction.
  • RR 2 , R 3 and n are as described above.
  • the compound (1i) of the present invention can be produced by subjecting the compound (lh) of the present invention to debenzylation.
  • the debenzylation can be easily carried out by a conventional method, for example, by the reaction conditions described in [Greene] and [Wuts], [Protective Global Organic Synthesis (2nd edition)]. It can be carried out.
  • the reaction product obtained by each of the above production methods is isolated and purified as a free compound, a salt, a hydrate or various solvates.
  • the above salts are produced by the usual salt formation reaction.
  • isolation and purification operations include chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • the compound of the present invention When the compound of the present invention is administered as a medicament, the compound of the present invention is administered to animals including humans as it is or as a pharmaceutical composition carried in a pharmaceutically acceptable nontoxic and inert carrier.
  • the content of the compound of the present invention is preferably 0.1 to 99.5%, more preferably 0.5 to 90% in the above pharmaceutical composition.
  • the second present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the benzanilide derivative of the first present invention or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the carrier of the pharmaceutical composition of the present invention include solid, semi-solid, or liquid diluents, fillers, and other prescription auxiliaries. These may be used alone or in combination of two or more.
  • the pharmaceutical compositions are administered in dosage unit form.
  • the administration method of the pharmaceutical composition of the present invention include oral administration, intravenous administration, local administration such as intranasal administration, nasal administration and ophthalmic administration, and rectal administration. Of these, oral administration is preferred.
  • a dosage form suitable for each administration method is selected.
  • the dose of the compound of the present invention represented by the above general formula (1) or a salt thereof contained in the pharmaceutical composition of the present invention depends on the patient's condition such as age, body weight, etc., administration route, disease symptoms and severity, etc. Is preferably set in consideration of the following.
  • the dose of the compound of the present invention for an adult is preferably 5 to 150 Omg human Z days, more preferably 10 to 30 Omg Z human days for oral administration, when administered orally.
  • the dose is preferably 0.1 to 100 Omg / human day, more preferably 1 to 60 Omg / human day.
  • the concentration of the compound of the present invention is preferably 0.001 to 10% (V / W), more preferably 0.01 to 2% (V / W). W).
  • the dose required in each individual case is different, and a dose lower than the above may be sufficient, or a dose higher than the above may be required.Adjust the dose accordingly. May be.
  • composition of the present invention may be divided and administered 2 to 4 times a day.
  • its dosage form includes, for example, powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets And other solid or liquid dosage units.
  • the above powder can be produced by comminuting the compound of the present invention to an appropriate fineness and then mixing the same with a pharmaceutical carrier such as edible carbohydrates such as starch and mannitol, and other additives. it can.
  • a pharmaceutical carrier such as edible carbohydrates such as starch and mannitol, and other additives. it can.
  • the tablet can be manufactured by preparing a powder mixture of the pharmaceutical composition of the present invention, granulating or slugging, adding a disintegrant or a lubricant, and tableting.
  • the above-mentioned powder mixture is obtained by mixing the appropriately pulverized compound of the present invention with the above-mentioned diluents and bases. Agents may be used in combination.
  • the powder mixture can be granulated by first moistening with a binder and then forcibly passing through a sieve. Further, the powder mixture may be granulated by crushing the imperfect slag obtained after the tablet mixture is applied to a tableting machine.
  • the granules thus produced can be prevented from adhering to each other by adding a lubricant.
  • the lubricated mixture may then be tableted, and the resulting uncoated tablet may be coated with a film or coated with sugar.
  • the pharmaceutical composition of the present invention may be directly tableted after being mixed with a fluid inert carrier without going through the above-mentioned steps of granulating and slugging.
  • a transparent or translucent protective coating composed of a shellac hermetic coating, a coating of sugar or a polymer material, or a polishing coating composed of wax may be used.
  • the capsule can be produced by first filling a powdered powder or a granulated powder into a capsule shell such as a gelatin capsule.
  • a lubricant or a fluidizing agent may be mixed with the granulated product, and then a filling operation may be performed.
  • a disintegrant or a solubilizing agent is added, the effectiveness of the capsule as a medicament when ingested can be improved.
  • the fine powder of the compound of the present invention may be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, or a surfactant, and wrapped with a gelatin sheet to form a soft capsule.
  • the above-mentioned suspensions can be formulated by dispersing the compound of the present invention in a non-toxic carrier.
  • the pharmaceutical composition of the present invention can be formulated in a dosage unit form so that a certain amount thereof contains a certain amount of the compound of the present invention in other oral administration forms such as a liquid, a syrup, and an elixir. it can.
  • the syrup can be produced by dissolving the compound in an appropriate aqueous flavor solution, and the elixir can be produced by using a non-toxic alcoholic carrier.
  • the dosage unit formulation for oral administration of the pharmaceutical composition of the present invention may be microencapsulated, if necessary. According to the above formulation, the action time can be extended and sustained release can be achieved by coating the compound of the present invention or embedding it in a polymer or wax.
  • the pharmaceutical composition of the present invention can be administered to tissues by using a liquid dosage unit form such as a solution or suspension for subcutaneous / muscular or intravenous injection.
  • a predetermined amount of the compound of the present invention is suspended or suspended in a non-toxic liquid carrier such as an aqueous or oily medium suitable for injection.
  • a non-toxic liquid carrier such as an aqueous or oily medium suitable for injection.
  • the resulting suspension or solution may be sterilized, or a certain amount of the compound of the present invention may be placed in a vial, and then the vial and its contents may be sterilized and sealed.
  • preliminary vials and carriers may be prepared in addition to the powdered or lyophilized compound of the present invention.
  • non-toxic salts or salt solutions may be added to make the injection solution isotonic.
  • eye drops To administer the pharmaceutical composition of the present invention to the eye, forms such as eye drops, eye ointments and the like can be used.
  • the above eye drops may be formulated using isotonic agents, buffering agents, nonionic surfactants, stabilizers, preservatives, etc., and the pH of the eye drops is within the range acceptable for ophthalmic preparations. It is good if it is within, but the range of 4-8 is preferred.
  • a suppository can be prepared by mixing the compound of the present invention with a low-melting water-soluble or insoluble solid.
  • tonicity agent examples include sodium chloride, concentrated glycerin and the like.
  • buffering agent examples include sodium phosphate and sodium acetate.
  • nonionic surfactant examples include polyoxyethylene sorbin monolate, polyoxyl stearate 40, and polyoxyethylene hydrogenated castor oil.
  • Examples of the above stabilizer include sodium citrate and sodium edetate.
  • preservative examples include benzalkonium chloride and paraben.
  • Examples of the above lubricants and fluidizers include colloidal silica, talc, stearic acid, magnesium stearate, stearic acid salts such as calcium stearate, solid polyethylene glycol, and mineral oil.
  • Examples of the disintegrant and solubilizer include carboxymethylcellulose, carboxymethylcellulose calcium, low-substituted hydroxypropylcellulose, croscarmellose sodium, sodium carboxystarch, calcium carbonate, sodium carbonate and the like.
  • binder examples include sodium carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose, gelatin, polyvinylpyrrolidone, and polyvinyl alcohol.
  • dissolution retarder examples include paraffin, wax, and hydrogenated castor oil.
  • adsorbent examples include bentonite, kaolin, dicalcium phosphate and the like.
  • binder examples include syrup, starch paste, gum arabic, cellulose solution, polymer solution and the like.
  • Examples of the solid that is soluble or insoluble in the low-melting water include higher esters such as polyethylene glycol, cocoa butter, myristyl palmitate, and mixtures thereof.
  • a flavoring agent if necessary, a flavoring agent, a dispersing agent, a coloring agent Fragrances, solubilizers and emulsifiers, preservatives, flavor enhancers, stabilizers and other additives may be used.
  • solubilizer and emulsifier examples include ethoxylated isostearyl alcohols and polyoxyethylene sorbitol esters.
  • examples of the flavor imparting agent include pamint oil and saccharin.
  • the benzanilide derivative of the present invention has a vasopressin antagonistic action. Therefore, the pharmaceutical composition of the present invention containing the benzanilide derivative of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient can be used as a vasopressin antagonist.
  • the benzanilide derivative of the present invention has an inhibitory effect on vasoconstriction. Therefore, the pharmaceutical composition of the present invention has a vasorelaxant effect and can be used as a vasorelaxant.
  • the benzanilide derivative of the present invention has an inhibitory effect on vasoconstriction. Therefore, the pharmaceutical composition of the present invention has a therapeutic effect on congestive heart failure, high blood pressure, and cerebral circulatory disorder caused by vasoconstriction, and is used as a therapeutic agent for congestive heart failure, high blood pressure, and cerebral circulatory disorder. be able to.
  • the benzanilide derivative of the present invention has an inhibitory effect on vasoconstriction. Therefore, the pharmaceutical composition of the present invention has a preventive effect on congestive heart failure, hypertension, and cerebral circulatory disorder caused by vasoconstriction, and is used as a preventive agent for congestive heart failure, hypertension, and cerebral circulatory disorder. be able to.
  • the benzanilide derivative and the pharmaceutical composition according to the present invention have extremely low toxicity and can be safely administered to animals including humans.
  • a method of applying the pharmaceutical composition of the present invention to animals including humans for the purpose of prevention and treatment or treatment and treating is also an aspect of the present invention.
  • the use of the benzanilide derivative according to the present invention for industrial production (Manufacturng) of the pharmaceutical composition of the present invention is also one of the present invention.
  • the vasopressin antagonist, the vasorelaxant, the therapeutic or prophylactic agent for depressive heart failure, hypertension, and cerebral circulatory disorder of the present invention each use the benzanilide derivative according to the present invention.
  • it is a pharmaceutical composition containing as an active ingredient, as long as the benzoanilide derivative according to the present invention is contained as an active ingredient as described above, it falls within the scope of the present invention regardless of whether or not it contains other components. Things. BEST MODE FOR CARRYING OUT THE INVENTION
  • Test Example 1 Inhibitory effect on vasopressin contraction in rat aorta
  • vasopressin (3 nM, final concentration) was applied, and the first contraction height was measured from the contraction reaction extracted on the recorder. Thereafter, washout is repeated 3 to 4 times approximately every 15 minutes, 10 minutes after the last washout, the solvent or test compound solution is applied, and 30 minutes later, vasopressin is applied again for the first time.
  • the second contraction height was measured in the same manner as in the above, and the inhibition rate at 10 to 17 M was calculated by the following formula. The results are shown in Table 1-1.
  • the test compound was prepared by dissolving in water for injection or dimethyl sulfoxide, and then diluting and dissolving with water for injection.
  • a ' Shrinkage height by application of vasopressin after treatment with test compound Similarly, the inhibition rate at each concentration was determined, and a concentration-response curve was prepared. IC5 () (50% of the test compound inhibiting contraction by vasopressin by 50% ) Concentration). As a comparison, similarly IC 5 with certain OPC- 2 1 2 6 8 known material. Values were calculated. The results are shown in Tables 1-2.
  • Tables 11 and 12 indicate that the compounds of the present invention strongly inhibit vasopressin contraction to rat aorta.
  • the compounds of the present invention not described in Tables 1-1 and 1-2 also exhibited excellent vasopressin contraction inhibitory effects.
  • Test example 2 Acute toxicity test
  • Reference Example 27 The same procedure as in Reference Example 50 was carried out using 1_ (2-aminophenyl) pyrrolidine and 4-nitrobenzoyl sulfide to obtain the title compound. The yield is 70.2%.
  • Reference Example 52
  • Reference Example 50 The same procedure as in Reference Example 50 was carried out using 11- (2-amino-4-fluorophenyl) piperidine obtained in Reference Example 36 and 4-nitrobenzoyl chloride to obtain the title compound. The yield was 95.5%.
  • Reference example 6 1 2 ′ — (4_Benzylpiperazinyl) 1-412-trobenzanilide Using 1- (2-aminophenyl) -4-benzylpiperazine obtained in Reference Example 37 and 4-12-trobenzoyl chloride, The title compound was obtained in the same manner as in Reference Example 50. The yield was 84.4%.
  • Reference Example 62 The same procedure as in Reference Example 50 was carried out using 11- (2-amino-4-fluorophenyl) piperidine obtained in Reference Example 36 and 4-nitrobenzoyl chloride to obtain the title compound. The yield was 95.5%.
  • Reference example 6 1 2 ′ — (4_Benzylpiperazinyl) 1-412-trobenzanilide Using 1- (2
  • N-Methyl-4-nitro-2 '-(4_propylpiperazinyl) benzanilide Sodium hydride 0.13 g in DMF 5 OmL solution was added to the N-methyl-4-nitro- A solution of 1.08 g of 2'-piperazinyl benzanilide in 15 mL of DMF was gradually added dropwise at room temperature. After completion of the dropwise addition, the mixture was stirred at 55 ° C for 30 minutes. The reaction solution was returned to room temperature, and a solution of 0.47 g of propyl bromide in 1 mL of DMF was gradually added dropwise. After the addition was completed, the mixture was again stirred at 55 ° C for 2 hours.
  • Reference Example 76 The title compound was obtained in the same manner as in Reference Example 105, using the obtained N-methyl-4-12-trough 2 '-(1-pyrrolidinyl) benzylanilide. The yield was 85.0%.
  • Reference Example 109 The title compound was obtained in the same manner as in Reference Example 105, using the obtained N-methyl-4-12-trough 2 '-(1-pyrrolidinyl) benzylanilide. The yield was 85.0%.
  • Reference Example 109 The title compound was obtained in the same manner as in Reference Example 105, using the obtained N-methyl-4-12-trough 2 '-(1-pyrrolidinyl) benzylanilide. The yield was 85.0%.
  • Reference Example 109 The title compound was obtained in the same manner as in Reference Example 105, using the obtained N-methyl-4-12-trough 2 '-(1-pyrrolidinyl) benzylanilide. The yield was 85.0%.
  • N_Methyl_2' (1-pyrrolidinyl) —4— [[2- (p-tolyl) benzoyl] amino] benzanilide
  • Example 2 The same operation as in Example 1 was carried out using benzanilide and 2_ (p-tolyl) benzoic acid, and recrystallized from ethyl acetate-hexane to obtain the title compound. The yield was 78.6%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-5'-clo-mouth N-methyl-2 '-(1-pyrrolidinyl) benzanilide obtained in 16 and 2-phenylbenzoic acid. The residue was recrystallized from ethyl acetate-hexane to give the title compound. The yield was 72.2%.
  • Example 108 Using 4-amino-N-methyl-2 '_ (1-pyrrolidinyl) benzanilide and tolylacetic acid obtained in Reference Example 108, the same operation as in Example 1 was performed, and recrystallization from ethyl acetate-hexane was performed. The title compound was obtained as an amorphous powder. The yield was 65.4%.
  • Example 2 4- (benzoylamino) 1 N-methyl-1 2'-piperidinobenzanilide
  • Reference Example 11 4-amino-N-methyl-2'-piperidinobenzanilide obtained in 10
  • the same operation as in Example 2 was carried out and recrystallized from ethyl acetate / hexane to obtain the title compound as an amorphous powder. Yield was 78.2%.
  • Example 11 The same operation as in Example 2 was performed using 4-amino-N-methyl-2'-piperidinobenzalide and toluoyl chloride obtained in 10 to obtain a mixture of ethyl acetate and hexane. Recrystallization afforded the title compound. The yield was 72.5%. m. p .: 190-191 ° C
  • Example 23
  • Example 11 The same operation as in Example 2 was performed using 4-amino-N-methyl-2'-piperidinobenzanilide and 2-fluorobenzoyl chloride obtained in 110. The residue was recrystallized from ethyl acetate-hexane to give the title compound. The yield was 69.1%.
  • Example 1 The same operation as in Example 2 was carried out using 4-amino-N-methyl-2'-piperidinobenzalilide obtained in 10 and 2- (trifluoromethyl) benzoyl oxalate. This was recrystallized from ethyl acetate-hexane to give the title compound. The yield was 85.8%.
  • Example 1 The same operation as in Example 2 was performed using 4-amino-N-methyl_2'-piperidinobenzanilide and 2-methoxybenzoyl chloride obtained in 10 to obtain ethyl acetate-hexane. Further recrystallization gave the title compound as amorphous powder. The yield was 80.6%.
  • Example 28 0.45 g of 4-[(2-benzyloxybenzoyl) amino] -N-methyl-1,2-piperidinobenzanilide obtained in Example 28 was added to 10% palladium hydroxide in 20 mL of methanol. The catalytic reduction was carried out at room temperature in the presence of 0.1 g of a carbon catalyst. After the completion of the reaction, the catalyst was removed and concentrated to dryness. The concentrated residue was recrystallized from ethyl acetate-hexane to obtain 0.38 g (yield: 60.6%) of the title compound.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-N-methyl-2'-piperidinobenzalide and 2- (methylthio) benzoic acid obtained in 10 to obtain ethyl acetate. Recrystallization from hexane gave the title compound. The yield was 79.6%.
  • Example 1 The same operation as in Example 1 was performed using 4-amino-N-methyl-2'-piperidinobenzalidide obtained in 10 and 4_phenylbutyric acid to obtain ethyl acetate-hexane. Recrystallization afforded the title compound. The yield was 68.0%.
  • Example 36 The same operation as in Example 1 was carried out using 2-lide and 5-phenylvaleric acid, and recrystallized from ethyl hexane acetate to obtain the title compound. The yield was 70.0%. m.p .: 144-145 ° C Example 36
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-N-methyl-2'-piperidinobenzalidide obtained in 10 and 2-phenylbenzoic acid to obtain ethyl acetate. Recrystallization from hexane gave the title compound. The yield was 83.5%. m.p .: 208—209
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-N-methyl_2'-piperidinobenzallide obtained in 10 and 2- (4-ethylphenyl) benzoic acid, The crystals were recrystallized from ethyl acetate-hexane to give the title compound as amorphous powder. The yield was 80.8%.
  • Example 1 4-amino-N-methyl-2'- obtained in 10
  • the same operation as in Example 1 was carried out using dilide and 2- (4-fluorophenyl) benzoic acid, and recrystallized from ethyl acetate-hexane to obtain the title compound as an amorphous powder.
  • the yield was 70.4%.
  • Example 11 The same operation as in Example 2 was carried out using 4-Tamino-N, 3'-dimethyl-2'-piperidino benzanilide and toluoyl chloride obtained in 19, and re-formed from ethyl acetate-hexane. Crystallization gave the title compound as an amorphous powder. The yield was 76.9%.
  • Example 44 The same operation as in Example 2 was carried out using 4-amino-N-methyl-2'-piperidinobenzallide obtained in 10 and P-tolylacetic chloride to obtain ethyl acetate. Recrystallization from hexane gave the title compound. The yield was 81.8%. m.p .: 179.5—181 ° C Example 44
  • Example 1 The same operation as in Example 1 was performed using 4-amino-N-methyl-2'-piperidinobenzalide obtained in 10 and 2_ (trifluoromethyl) phenylacetic acid. Recrystallization from ethyl acetate-hexane gave the title compound. The yield was 74.7%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-N-methyl_2'-piperidinobenzarylide obtained in 10 and 41- (thiomethyl) phenylacetic acid. Recrystallization from hexane gave the title compound. The yield was 74.3%.
  • Example 49 The same operation as in Example 1 was performed using 4_amino-N-methyl-2′-piperidinobenzalide and 2-nitrophenylacetic acid obtained in 10 to obtain ethyl acetate-hexane. Recrystallization afforded the title compound. The yield was 80.3%. m.p .: 250-251 ° C Example 49
  • Example 2 The same operation as in Example 1 was carried out using 2-lide and 2-biphenylacetic acid, and recrystallized from ethyl hexane acetate to obtain the title compound. The yield was 84.7%.
  • Example 11 N-Pentyl-2'-piberidino 41- (toluoylamino) benzanilide Reference Example 11 The same operation as in Example 2 was carried out using 4-amino-N-pentyl-2'-piperidinobenzanilide obtained in 1-11 and toluoyl chloride. The residue was recrystallized from ethyl acetate-hexane to give the title compound as amorphous powder. The yield was 96.4%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino_N_methyl-2 '-(4-methylbiperidino) benzanilide obtained in 35 and 2_phenylbenzoic acid, and the reaction was repeated with ethyl acetate-hexane. After crystallization, the title compound was obtained as an amorphous powder. The yield was 57.3%.
  • Example 2 The same operation as in Example 2 was performed using 4-amino-dimethyl-2 -'- (4-phenylpyridino) benzanilide and toluoyl chloride obtained in Reference Example 136, and the reaction was carried out with ethyl acetate-hexane. Recrystallization afforded the title compound. The yield was 59.3%.
  • Example 2 The same operation as in Example 1 was carried out using N-methylbenzanilide and 2- (p-tolyl) benzoic acid, and recrystallized from ethyl acetate-hexane to obtain the title compound as an amorphous powder. The yield was 48.0%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-2'-hexamethyleneimino-N-methylpentenzanilide and 2-phenylbenzoic acid obtained in 12 to obtain ethyl acetate-hexane. Further recrystallization afforded the title compound. The yield was 74.0%.
  • Example 2 The same operation as in Example 2 was carried out using 4-amino-1 2'-heptamethyleneimino N-methylpenzuanilide obtained in Reference Example 13 and tolylacetic chloride, and recrystallized from ethyl acetate-hexane. The compound was obtained. The yield was 77.9%.
  • Example 11 The same operation as in Example 1 was carried out using 4-amino-2'-heptamethyleneimino_N-methylpentenzanilide obtained in 13 and 2-phenylbenzoic acid, and the reaction was carried out with ethyl acetate-hexane. Recrystallization afforded the title compound. The yield was 81.8%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-N-methyl-2'-morpholinobenzone dilide obtained in 14 and 2_ (p_tolyl) benzoic acid to obtain ethyl acetate-hexane. Further recrystallization gave the title compound as amorphous powder. The yield was 68.8%.
  • Example 1 The same operation as in Example 1 was performed using 4-amino-N_methyl_2'-morpholinobenzone dilide and 2- (4-methoxyphenyl) benzoic acid obtained in 14; Recrystallization from ethyl acetate-hexane gave the title compound as amorphous powder. The yield was 58.5%.
  • Example 2 The same operation as in Example 1 was carried out using 4-amino-2 '-[4- (tert-butoxycarbonyl) piperazinyl] —N-methylbenzanilide and 2_phenylbenzoic acid obtained in Reference Example 129. The residue was recrystallized from ethyl acetate-hexane to give the title compound. The yield was 78.3%.
  • N_Methyl _4 [(2-Phenylbenzoyl) amino] — 2,1- (4-propylbiperazinyl) benzanilide hydrochloride
  • N-methyl-41 [(2-phenylphenol) amino] _2 '-(4-propylpiperazinyl) benzanilide was hydrochlorinated in the same manner as in Example 73 to give the title compound N-methyl-41- [ (2_Fenzylpenzyl) amino] — 2 '— (4_propylpiperazinyl) benzanilide hydrochloride (60.0% yield) mp: 232-233 ° C
  • Example 1 The same operation as in Example 1 was performed using 4-amino-2 '-(4-isopentylpiperazinyl) -N-methylbenzanilide and 2-phenylbenzoic acid obtained in 23. 2 '_ (4 ⁇ sopentylpiperazinyl) — N-methyl—4— [(2_Fenylpenzyl) amino] Benzanilide was obtained as an amorphous powder. The yield was 89.1%.
  • Example 2 The same operation as in Example 1 was performed using the 4-amino-2 '_ (4-isopentylpiperazinyl) _N-methylbenzanilide obtained in Reference Example 123 and 2- (p-tolyl) benzoic acid. 2 '_ (4-Isopentylpiperazinyl) _N-methyl -4- [[2— (p_tolyl) benzoyl] amino] Benzanilide was obtained as amorphous powder. The yield was 81.8%.
  • Example 1 2 '-(4-Acetylpiperazinyl) _N-Methyl- 4 — [(2-phenylpenezyl) amino] benzanilide Reference Example 1 The same operation as in Example 1 was carried out using 2 '-(4-acetylpiperazinyl) -4-amino-N-methylbenzanilide and 2-phenylbenzoic acid obtained in 26. After recrystallization from ethyl acetate-hexane, the title compound was obtained as amorphous powder. The yield was 85.2%.
  • Example 1 The same operation as in Example 1 was carried out using 4-amino-2 '-(4-isopropionylbiperazinyl) -N-methylbenzanilide and 2-phenylbenzoic acid obtained in 27. The residue was recrystallized from ethyl acetate-hexane to give the title compound. The yield was 90.1%.
  • Example 1 The same operation as in Example 1 was performed using 4-amino-N-methyl-2 '_ (4-pivaloylpiperazinyl) benzanilide and 2-phenylbenzoic acid obtained in 28 to obtain ethyl acetate-hexane. Further recrystallization afforded the title compound. The yield was 79.7%.
  • Example 8 DMF of 2 '-[4- (chloroacetyl) piperazinyl] -N-methyl-41-((2-phenylbenzoyl) amino] benzanilide obtained in 8 and 0.74 g of potassium carbonate in 0.48 g of potassium carbonate To a 15 mL solution was added a 2 MN, N-dimethylamine-THF2.65 mL solution at room temperature. After stirring for 1 hour, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Example 8 Using 2 '_ [4- (chloroacetyl) piperazinyl] 1 N-methyl-4-[(2-phenylpenezyl) amino] benzanilide obtained in 8 and N, N-getylamine 8 Perform the same operation as in 9 to obtain the title compound, 2 '-[4- (N, N-getylaminoacetyl) piperazinyl] -1-N-methyl-4-[(2-phenylphenol) ylamino] benzanilide hydrochloride was obtained as an amorphous powder. The yield was 76.3%. I. R. (KB r) v cm " 1 : 3420, 3260, 2950, 1640, 1630, 1595, 1520, 1495, 1445
  • Example 88 Using 2 '-[4- (chloroacetyl) piperazinyl] -1-N-methyl-4-[(2-phenylbenzoyl) amino] benzanilide and morpholin obtained in Example 88, the same operation as in Example 89 was carried out. To obtain N-methyl_2 '-[4- (morpholinoacetyl) piperazinyl] -14 _ [(2-phenylbenzoyl) amino] benzanilide as an amorphous powder. The yield was 95.1%.
  • the present invention has the above-mentioned novel chemical structure, and is a novel compound.
  • the second present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the present invention as an active ingredient, has a reliable and excellent inhibitory action on aortic contraction by vasopressin, and has a vasopressin antagonist It is also expected to be used as a therapeutic or prophylactic agent for treating congestive heart failure, hypertension, cerebral circulatory disorders, arginine vasopressin hypersecretion syndrome, renal insufficiency, cirrhosis or cirrhosis, and for other pharmaceutical uses. .

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Abstract

Cette invention concerne des composés utilisés dans des compositions médicinales d'une grande sûreté et d'une grande efficacité et, plus précisément, des antagonistes de vasopressine. Ces composés consistent en des dérivés de benzanilide et se caractérisent en ce qu'ils correspondent à la formule générale (1).
PCT/JP1999/003276 1998-06-19 1999-06-18 Derives de benzanilide et compositions medicinales WO1999065874A1 (fr)

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JP18807198A JP2002179651A (ja) 1998-06-19 1998-06-19 ベンズアニリド誘導体及び医薬組成物

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Cited By (13)

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WO2003045393A1 (fr) * 2001-11-30 2003-06-05 F. Hoffmann-La Roche Ag Derives piperazines a utiliser comme antagonistes du recepteur ccr-3 pour le traitement de l'asthme
US7166738B2 (en) 2004-04-23 2007-01-23 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
WO2006133242A3 (fr) * 2005-06-07 2007-02-15 Pharmacopeia Drug Discovery Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress
US7388111B2 (en) 2005-10-19 2008-06-17 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
EP2100891A1 (fr) 2002-07-05 2009-09-16 Novartis AG Inhibiteurs de kinases de tyrosine
US7625949B2 (en) 2004-04-23 2009-12-01 Roche Palo Alto Llc Methods for treating retroviral infections
JP2012501344A (ja) * 2008-08-29 2012-01-19 トレヴェンティス コーポレイション アミロイド症を治療する組成物及び方法
WO2013070657A1 (fr) * 2011-11-08 2013-05-16 Arena Pharmaceuticals, Inc. Modulateurs pour le récepteur mas couplé à la protéine g et traitement des troubles qui y sont apparentés
EP2666481A3 (fr) * 2003-12-26 2014-01-01 HAGIWARA, Masatoshi Procédé de régulation de la phosphorylation de la protéine SR et agents antiviraux comprenant un régulateur de l'activité de la protéine SR comme principe actif
WO2014182673A1 (fr) * 2013-05-07 2014-11-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur mas couplé à la protéine g et traitement de troubles apparentés
NO20161397A1 (no) * 2004-04-23 2016-09-02 Hoffmann La Roche Ikke-nukleosidbaserte revers-transkriptase-inhibitorer
CN108026039A (zh) * 2015-08-28 2018-05-11 格兰马克药品股份有限公司 作为RORγ调节剂的新型碳环化合物
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels

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US7429603B2 (en) * 2003-04-25 2008-09-30 3-Dimensional Pharmaceuticals, Inc. C-fms kinase inhibitors

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JPH09512528A (ja) * 1994-04-25 1997-12-16 藤沢薬品工業株式会社 バソプレッシン拮抗物質としてのベンズアミド誘導体
WO1998024771A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives de benzamide presentant une activite antagoniste de la vasopressine

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JPH09512528A (ja) * 1994-04-25 1997-12-16 藤沢薬品工業株式会社 バソプレッシン拮抗物質としてのベンズアミド誘導体
WO1998024771A1 (fr) * 1996-12-02 1998-06-11 Fujisawa Pharmaceutical Co., Ltd. Derives de benzamide presentant une activite antagoniste de la vasopressine

Cited By (22)

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Publication number Priority date Publication date Assignee Title
US6906073B2 (en) 2001-11-30 2005-06-14 Roche Palo Alto Llc Piperazine CCR-3 receptor antagonists
WO2003045393A1 (fr) * 2001-11-30 2003-06-05 F. Hoffmann-La Roche Ag Derives piperazines a utiliser comme antagonistes du recepteur ccr-3 pour le traitement de l'asthme
CN1321115C (zh) * 2001-11-30 2007-06-13 霍夫曼-拉罗奇有限公司 作为哮喘治疗中的ccr－3受体拮抗剂的哌嗪衍生物
EP2100891A1 (fr) 2002-07-05 2009-09-16 Novartis AG Inhibiteurs de kinases de tyrosine
EP2368889A1 (fr) 2002-07-05 2011-09-28 Novartis AG Inhibiteurs de kinases de tyrosine
EP2357182A1 (fr) 2002-07-05 2011-08-17 Novartis AG Inhibiteurs de kinases de tyrosine
EP2666481A3 (fr) * 2003-12-26 2014-01-01 HAGIWARA, Masatoshi Procédé de régulation de la phosphorylation de la protéine SR et agents antiviraux comprenant un régulateur de l'activité de la protéine SR comme principe actif
US8816089B2 (en) 2003-12-26 2014-08-26 Masatoshi Hagiwara Methods for controlling SR protein phosphorylation, and antiviral agents whose active ingredients comprise agents that control SR protein activity
US8329755B2 (en) 2004-04-23 2012-12-11 Roche Palo Alto Llc Methods for treating retroviral infections
US7625949B2 (en) 2004-04-23 2009-12-01 Roche Palo Alto Llc Methods for treating retroviral infections
NO20161397A1 (no) * 2004-04-23 2016-09-02 Hoffmann La Roche Ikke-nukleosidbaserte revers-transkriptase-inhibitorer
US7166738B2 (en) 2004-04-23 2007-01-23 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
WO2006133242A3 (fr) * 2005-06-07 2007-02-15 Pharmacopeia Drug Discovery Inhibiteurs d'azinone et de diazinone v3 utilises dans les troubles lies a la depression et au stress
US8350043B2 (en) 2005-06-07 2013-01-08 Pharmacopeia, Inc. Azinone and diazinone V3 inhibitors for depression and stress disorders
JP2008542444A (ja) * 2005-06-07 2008-11-27 フアーマコペイア・インコーポレイテツド うつ病およびストレス疾患のためのアジノンおよびジアジノンｖ３阻害剤
US7388111B2 (en) 2005-10-19 2008-06-17 Roche Palo Alto Llc Non-nucleoside reverse transcriptase inhibitors
JP2012501344A (ja) * 2008-08-29 2012-01-19 トレヴェンティス コーポレイション アミロイド症を治療する組成物及び方法
WO2013070657A1 (fr) * 2011-11-08 2013-05-16 Arena Pharmaceuticals, Inc. Modulateurs pour le récepteur mas couplé à la protéine g et traitement des troubles qui y sont apparentés
WO2014182673A1 (fr) * 2013-05-07 2014-11-13 Arena Pharmaceuticals, Inc. Modulateurs du récepteur mas couplé à la protéine g et traitement de troubles apparentés
CN108026039A (zh) * 2015-08-28 2018-05-11 格兰马克药品股份有限公司 作为RORγ调节剂的新型碳环化合物
US10647661B2 (en) 2017-07-11 2020-05-12 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels
US11603351B2 (en) 2017-07-11 2023-03-14 Vertex Pharmaceuticals Incorporated Carboxamides as modulators of sodium channels

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