MX2008008511A

MX2008008511A - Water-soluble benzoazepine compound and its pharmaceutical composition

Info

Publication number: MX2008008511A
Application number: MXMX/A/2008/008511A
Authority: MX
Inventors: Keigo Yamada; Fumitaka Goto; Takakuni Matsuda; Yasuhiro Menjo; Makoto Komatsu; Yusuke Kato
Original assignee: Fumitaka Goto; Yusuke Kato; Makoto Komatsu; Takakuni Matsuda; Yasuhiro Menjo; Otsuka Pharmaceutical Co Ltd; Keigo Yamada
Priority date: 2005-12-27
Filing date: 2008-06-26
Publication date: 2008-09-26

Abstract

The present invention provides a benzoazepine compound represented by following general formula (1):or a salt thereof, wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, etc., R1represents a hydrogen atom or hydroxy-protecting group, and X represents an oxygen atom or a sulfur atom. The benzoazepine compound of the present invention and salts thereof have high solubility in water, and can be suitably used for injections.

Description

COMPOUND BENZOAZEPINE SOLUBLE IN WATER AND ITS PHARMACEUTICAL COMPOSITION FIELD OF THE INVENTION The present invention relates to a novel benzoazepine compound and its pharmaceutical composition.

BACKGROUND OF THE INVENTION Tolvaptan represented by the following formula (2) is a known compound, and has been described in, for example, US Pat. No. 5,258,510 specification (example 1199).

It is known that tolvaptan is useful as a vasopressin antagonist having aquatic activity (Circulation, 107, pp. 2690-2696 (2003)). However, due to its low solubility in water, tolvaptan has problems as it is poorly absorbed by the intestinal canal, its dosage form and Administration route are limited, etc. Although attempts have been made to solve these problems so that, for example, tolvaptan can be administered in the form of an amorphous solid preparation composition (Japanese Unexamined Patent Publication No. 1999-21241), in the application of tolvaptan, its dosage form and route of administration remain limited.

BRIEF DESCRIPTION OF THE INVENTION The present invention seeks to provide a novel benzoazepine compound to improve the solubility of tolvaptan in water. The present inventors conducted extensive research to solve the above problem, and as a result found that when tolvaptan is in the form of a phosphate ester compound, the solubility in water thereof can be markedly improved. The present invention has been made based on this finding. Specifically, the present invention provides the following benzazepine compounds, and compositions comprising the same, as described in the items 1 to 13 below. Element 1. A benzoazepine compound represented by the general formula (1) or a salt thereof, wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, a mercapto group optionally protected with a protecting group, or an amino group optionally protected with one or two protecting groups, R1 represents a hydrogen atom or a hydroxy-protective group; and X represents an oxygen atom or sulfur atom. Element 2. A benzoazepine compound according to element 1 or a salt thereof, wherein X is an oxygen atom. Element 3. A benzoazepine compound according to element 1 or 2, or a salt thereof, wherein R is a hydroxy group optionally protected with a protecting group. Element 4. A benzoazepine compound according to element 1 or 2, or a salt thereof, wherein R is a hydrogen atom, a mercapto group optionally protected with a protecting group, or a amino group optionally protected with one or two protecting groups. Element 5. A benzoazepine compound according to any of elements 1, 2, 3 and 4, or a salt thereof, wherein R1 is a hydroxy-protective group. Element 6. A benzoazepine compound according to any of elements 1, 2, 3 and 4, or a salt thereof, wherein R 1 is a hydrogen atom. Element 7. A benzoazepine compound according to element 1 or a salt thereof, wherein X is a sulfur atom. Element 8. A benzoazepine compound according to element 1 or a salt thereof, wherein X is an oxygen atom, R is a hydroxy group, and R1 is a hydrogen atom. Element 9. A pharmaceutical composition comprising a benzoazepine compound of element 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and / or carrier. Element 10. A pharmaceutical composition according to item 9, for use as a vasodilator, hypotensor, aquaric agent, PKD, or platelet aggregation inhibitor. Element 11. An aqueous solution composition comprising a benzoazepine compound of element 1 or a pharmaceutically acceptable salt thereof. Element 12. A composition of aqueous solution according to Element 11, which comprises a benzoazepine compound of element 1 or a pharmaceutically acceptable salt thereof, together with a pH regulator, isotonization agent and injection solvent, and which is in the form of an injection. Element 13. An aqueous solution composition according to element 12, which additionally comprises a pH adjuster. "Inferior" as used here indicates C? -6 unless otherwise noted. Examples of protecting groups for a "hydroxy group optionally protected with a protecting group", "optionally protected mercapto group with a protecting group" and "hydroxy protecting group" include lower alkyl groups, phenyl-lower alkyl groups, cyano-alkyl groups lower and lower alkyloxycarbonyl-lower alkyl groups. Examples of protecting groups for an "amino group optionally protected with one or two protecting groups" include lower alkyl groups optionally bearing hydroxy group (s). Examples of lower alkyl groups and lower alkyl groups in phenyl-lower alkyl groups, cyano-lower alkyl groups, lower alkyloxycarbonyl-lower alkyl groups, and lower alkyl groups optionally bearing hydroxy group (s) include alkyl groups of C- | 6 straight or branched, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, sohexilo, 3- methylpentyl, and the like.

Preferred phenyl-lower alkyl groups are, for example, benzyl, phenethyl, 3-phenylpropyl, trityl, etc. Preferred cyano-lower alkyl groups are C? Alkyl groups 6 straight or branched substituted with one to three cyano groups, for example, cyanomethyl, 2-cyanoethyl, 1-, 2-, or 3-cyano-n-propyl, 1-, 2- or 3-cyano-isopropyl, 1- , 2-, 3-, or 4-cyano-n-butyl, 1-, 2-, 3-, or 4-cyano-isobutyl, 1 -, 2-, 3-, or 4-cyano-tert-butyl, 1-, 2-, 3-, or 4-cyano-sec-butyl, 1-, 2-, 3-, 4-, or 5-cyano-n-pentyl, 1-, 2-, 3-, 4- , or 5-cyano-isopentyl, 1-, 2-, 3-, 4-, or 5-cyano-neopentyl, 1-, 2-, 3-, 4-, 5- or 6-cyano-n-hexyl, 1-, 2-, 3-, 4-, 5- or 6-cyano-isohexyl, 1-, 2-, 3-, 4-, 5-, or 6-cyano-3-methylpentyl, and the like. Preferable lower alkyloxycarbonyl groups lower alkyl groups are alkyloxycarbonylalkyl wherein the alkyloxy moiety is a C1-6 alkyloxy group straight or branched and the alkyl moiety is an alkyl group of C? -6 straight or branched, for example methoxycarbonylmethyl, ethoxycarbonylmethyl, n -propoxicarbonilmetilo, isopropoxycarbonylmethyl, n-butoxycarbonylmethyl, isobutoxycarbonylmethyl, n-pentoxicarbonilmetilo, n-hexyloxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, 5-metoxicarbonilpentilo, 6-metoxicarbonilhexilo, and the like. Groups preferred lower alkyl optionally bearing group (s) hydroxy are alkyl groups of d-6 straight or branched optionally substituted with one to three hydroxy groups, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere -butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, hydroxymethyl, 2- hydroxyethyl, 1-, 2-, or 3-hydroxy-n-propyl, 1-, 2-, or 3-hydroxy-isopropyl, 1-, 2-, 3-, or 4-hydroxy-n-butyl, 1- , 2-, 3-, or 4-hydroxy-isobutyl, 1-, 2-, 3-, or 4-hydroxy-tert-butyl, 1-, 2-, 3-, or 4-hydroxy-sec-butyl, 1-, 2-, 3-, 4-, or 5-hydroxy-n-pentyl, 1-, 2-, 3-, 4-, or 5-hydroxy-isopentyl, 1-, 2-, 3-, 4 -, or 5-hydroxy-neopentyl, 1-, 2-, 3-, 4-, 5-, or 6-hydroxy-n-hexyl, 1-, 2-, 3-, 4-, 5-, or 6 -hydroxy-isohexyl, 1-, 2-, 3-, 4-, 5-, or 6-hydroxy-3-methylpentyl, and the like. Preferable amino groups optionally substituted with one or two protecting groups are amino groups optionally bearing one or two alkyl groups of C -6 straight or branched optionally bearing one to three hydroxy groups, for example, amino, methylamino, dimethylamino, ethylamino, I diethylamino , n-propylamino, di-n-propylamino, isopropylamino, di-iso-propylamino, n-butyl amino, di-n-butylamino, iso-butyl amino, di-iso-butylamino, tert-butyl amino, di-tert-butylamino, n-pentylamino, di-n-pentylamino , n-hexyl amino, di-n-hexylamino, hydroxymethylamino, 2-hydroxyethylamino, diethylamino, di- (2-hydroxyethyl) amino, 3-hydroxypropylamino, 4-hydroxybutyl amino, and the like. Among the benzoazepine compounds represented by the above general formula (1), the following compounds and their salts are preferable: when X is an oxygen atom, (1) compounds wherein R is a hydroxy group and R1 is a hydrogen atom, (2) compounds wherein R is a hydroxy group and R1 is a hydroxy protecting group, (3) compounds wherein R is a mercapto group and R1 is a hydroxy protecting group, and (4) compounds wherein R is an amino group protected with one or two protecting groups, and R1 is a hydroxy protecting group; and when X is a sulfur atom, (1) compounds wherein R is a hydroxy group and R1 is a hydrogen atom or hydroxy protecting group. Particularly preferable of these is the compound wherein X is an oxygen atom, R is a hydroxy group, and R1 is a hydrogen atom; or its salt. Benzoazepine compounds represented by the above general formula (1) can be produced by several methods, and an example thereof is a method as shown by the following reaction schemes 1 to 7: REACTION SCHEME 1 wherein R3 and R4 are independently a lower alkyl group or optionally substituted phenyl group, or R3 and R4 may instead be linked together through or with one or more additional heteroatoms form, together with the nitrogen atom to which they are attached , a saturated or unsaturated ring of 5 to 8 members; and R a and R 2a may be the same or different, and each represents a hydroxy protecting group. Examples of lower alkyl groups are as mentioned above, including straight or branched C-? 6 alkyl groups, by example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tere-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, and the like. Examples of substituents for optionally substituted phenyl groups include lower alkyl groups as above; straight or branched C-α-6 alkoxy groups, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, and the like; and halogen atoms, for example, fluorine, chlorine, bromine, iodine, and the like. Preferable examples of optionally substituted phenyl groups include phenyl; 2-, 3-, or 4-methylphenyl; 2-, 3-, or 4-chlorophenyl; 2-, 3-, or 4-methoxyphenyl; etc. Examples of saturated or unsaturated rings of 5 to 8 members formed by R3 and R4 that are bonded together, include morpholine ring, etc. The compound (4) can be produced by reacting the compound (2) with the compound (3) in a suitable solvent in the presence of acid. Examples of solvents include halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; etc. Examples of acids include mean acids, for example, 1 H-tetrazole, 5-methyltetrazole, pyridinium hydrobromide, and the like.

The amount of acid is usually at least about 1 mole, and preferably about 1 to about 10 moles, per mole of compound (2). The amount of compound (3) is usually 0.5 to 2 moles, and preferably 0.7 to 1.5 moles, per mole of compound (2). The reaction temperature is usually from -20 to 50 ° C, preferably from 0 to 50 ° C, and more preferably from 0 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours. The compound (1 a) can be produced by reacting the compound (4) with an oxidizing agent in a suitable solvent. Examples of solvents include halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; etc. Examples of oxidation agents include perdoses, for example, hydrogen peroxide, and metachloroperbenzoic acid, peracetic acid, permalic acid, and the like. The amount of the oxidizing agent is usually at least about 1 mole, and preferably about 1 to about 3 moles, per mole of compound (4).

The reaction temperature is usually from -100 to 50 ° C, preferably from -40 ° C to room temperature, and more preferably from -40 to 0 ° C. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 30 minutes to 2 hours. The compound (1b) can be obtained by deprotection of protected hydroxy groups of the compound (1a) by routine methods. When, for example, the hydroxy-protected groups are lower alkyl groups, the deprotection can be carried out under routine hydrolysis conditions. Said hydrolysis is preferably carried out in the presence of a base or acid (including Lewis acid). A wide range of known inorganic and organic bases can be used such as a base. Preferred inorganic bases are, for example, alkali metals (eg, sodium, potassium, etc.); alkaline earth metals (eg, magnesium, calcium, etc.); and its hydroxides, carbonates and acid carbonates. Preferred organic bases are, for example, trialkylamines (for example, trimethylamine, triethylamine, etc.), picoline, and 1,5-diazabicyclo [4.3.0] non-5-ene. A wide range of known organic and inorganic acids can be used such as an acid. Preferred organic acids are fatty acids, for example, formic acid, acetic acid, propionic acid, and the like; and trihaloacetic acids, for example, trichloroacetic acid, acid trifluoroacetic, and the like. Preferred inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc. Examples of Lewis acids include ether complex of boron thiouluoride, boron tribromide, aluminum chloride, ferric chloride, etc. When a trihaloacetic acid or Lewis acid is used, hydrolysis is preferably performed in the presence of a cationic scavenger (eg, anisole, phenol, etc.). The amount of base or acid is not limited as long as it meets the hydrolysis requirements. The reaction temperature is usually from -20 to 100 ° C, preferably from 0 to 50 ° C, and more preferably from 0 ° C to room temperature. The reaction time is usually from 5 minutes to 24 hours, preferably from 15 minutes to 6 hours, and more preferably from 15 minutes to 3 hours. When, for example, the hydroxy protecting groups are phenyl-lower alkyl groups, the deprotection can be carried out by a routine catalytic reduction. Suitable catalysts for said catalytic reduction are platinum catalysts (e.g., platinum plate, porous platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., porous palladium, palladium black, palladium oxide, palladium carbon, palladium / barium sulfate, palladium / carbonate barium, etc.), nickel catalysts (eg, nickel reduced, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., cobalt reduced, Raney cobalt, etc.), iron catalysts (e.g. , reduced iron, etc.), and the like. When a palladium carbon catalyst is used, the catalytic reduction is preferably carried out in the presence of zinc bromide. The amount of catalyst used for the catalytic reduction is not limited, and may be a routine amount. The reaction temperature is usually from 0 to 100 ° C, preferably from 0 to 50 ° C, and more preferably from room temperature to 50 ° C. The reaction time is usually from 5 minutes to 24 hours, preferably from 5 minutes to 3 hours, and more preferably from 5 minutes to 1 hour.

REACTION SCHEME 2 The compound (2) is reacted with phosphorus oxychloride, and then hydrolyzed to provide the compound (1b).

The amount of phosphorus oxychloride is usually from 1 mol to large excess, and preferably from 1 to 5 mol, per mol of compound (2). The above reaction is carried out in the presence of the basic compound in a suitable solvent. Examples of solvents for the reaction with phosphorus oxychloride include ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; etc. Examples of basic compounds include carbonates, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, and the like; alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide, and the like; hydroxides of alkaline earth metals, for example, calcium hydroxide and the like; phosphonates, for example potassium phosphate, sodium phosphate, and the like; organic bases, for example, pyridine, midazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2. 2] octane (DABCO), and the like; and its mixtures. The amount of basic compound is usually at least about 3 moles, and preferably from about 3 to about 10 moles, per mole of compound (2). The temperature of The reaction is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours. Hydrolysis can be achieved by the addition of water to the above reaction mixture or by the addition of the reaction mixture to water. Because this is normally accompanied by the decomposition of the excess reagent and thus heat is generated, preferably the hydrolysis is carried out with cooling. To complete the reaction, the heating is preferably carried out after the initial reaction has ended. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours.

REACTION SCHEME 3 wherein R1 is the same as above. The compound (2) is reacted with diphenyl phosphite, and then reacted with an alcohol (R1OH) to provide the compound (1c). The amount of diphenyl phosphite is usually from 1 mol to large excess, and preferably from 1 to 5 mol, per mol of compound (2). The amount of alcohol (R1OH) is usually from 1 mol to large excess, and preferably from 1 to 10 mol, per mol of compound (2). The above reaction is carried out in the presence of basic compound in a suitable solvent. Examples of solvents include ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate, and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; and acetonitrile. Examples of basic compounds include carbonates, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, and the like; alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide, and the like; alkaline earth metal hydroxides, for example, calcium hydroxide, and the like; phosphates, for example, potassium phosphate, sodium phosphate, and the like; organic bases, for example, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and the like; and its mixtures. The amount of basic compound is usually at least about 1 mole, and preferably about 1 to about 10 moles, per mole of compound (2). Organic solvents can also be used as a solvent. The reaction temperature is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours.

REACTION SCHEME 4 wherein R1 is the same as above. The oxidation of phosphite can be carried out using from about 1 to about 3 equivalents of phosphorous acid oxidizing agent, at a temperature in the range of about 0 ° C to about 50 ° C. Preferably, the reaction is carried out using from about 5 to about 15% phosphorous acid oxidation agent in excess of 0 ° C at room temperature. A phosphorous acid oxidation agent is a reagent that oxidizes a phosphite to a phosphate. Their examples include peroxides, for example, hydrogen peroxide; metachloroperbenzoic acid and the like; iodine in water; bromine; nitrogen tetroxide; etc. Iodine is preferable in water. The above reaction is carried out in a suitable solvent. Examples of solvents include ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; solvents halogenated hydrocarbon, for example, methylene chloride, chloroform, 1,2-dichloroethane, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; and pyridine. The reaction temperature is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 15 minutes to 6 hours, and more preferably 15 minutes to 3 hours.

REACTION SCHEME 5 wherein R1 is the same as above; and R11 and R12 may be the same or different, and each represents a hydrogen atom or a lower alkyl group optionally bearing hydroxy group (s). Amines (R11R12NH) and carbon tetrachloride are reacted with phosphorous acid diester (1c) to give phosphoramidite (1 e).

Sodium hypochlorite can also be used instead of carbon tetrachloride. The amount of carbon tetrachloride is usually from 1 mol to large excess, and preferably from 1 to 5 mol, per mol of compound (1c). The amount of amine (R 11 R 12 NH) is usually from 1 mol to large excess, and preferably from 1 to 10 mol, per mol of compound (1c). The above reaction is carried out in the presence of the basic compound in a suitable solvent. Examples of solvents include ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; etc. Examples of basic compounds include carbonates, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, and the like; alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide, and the like; alkaline earth metal hydroxides, for example, calcium hydroxide and the like; phosphates, for example, potassium phosphate, sodium phosphate, and the like; organic bases, for example, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1, 5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and the like; and its mixtures. The amount of basic compound is usually at least about 1 mole, and preferably about 1 to 10 moles, per mole of compound (2). Organic solvents can also be used as a solvent. The reaction temperature is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually from 1 minute to 24 hours, preferably from 1 minute to 6 hours, and more preferably from 1 minute to 3 hours.

REACTION SCHEME 6 wherein R1 is the same as above. Diaster of the phosphorous acid (1c) is reacted with sulfur to provide diester of the phosphorothionic acid (1f). The amount of sulfur normally from 1 mol to large excess, and preferably from 1 to 5 moles, per mole of compound (1 c). The above reaction is carried out in the presence of basic compound in a suitable solvent. Examples of solvents include ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; acetonitrile; and pyridine. Examples of basic compounds include carbonates, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, and the like; alkali metal hydroxides, for example, sodium hydroxide, potassium hydroxide, and the like; alkaline earth metal hydroxides, for example, calcium hydroxide and the like; phosphates, for example, potassium phosphate, sodium phosphate, and the like; alkali metal hydrides, eg, sodium hydride, potassium hydride, and the like; alkali metals, for example, potassium, sodium, and the like; sodium amide; metal alcoholates, for example, sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, and the like; organic bases, for example, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and the similar; and its mixtures. The amount of basic compound is usually at least about 1 mole, and preferably about 1 to about 10 moles, per mole of compound (2). Organic solvents can also be used as a solvent. The reaction temperature is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours.

REACTION SCHEME 7 wherein R1 is a hydroxy protecting group. The compound protecting group (1g), which is a compound (1f) obtained by the reaction scheme 6 wherein R 1 is a hydroxy protecting group, is stirred to provide the compound (1 h). When R1 is a cyanoethyl group, the protecting group can be Remove when using a basic compound. The above reaction is carried out in the presence of the basic compound in a suitable solvent. Examples of solvents include water, alcohols, for example, methanol, ethanol, isopropyl alcohol, and the like; ethers, for example, diethyl ether, dioxane, tetrahydrofuran, monoglyme, diglyme, and the like; halogenated hydrocarbon solvents, for example, methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride, and the like; esters, for example, ethyl acetate and the like; aromatic hydrocarbons, for example, benzene, toluene, xylene, and the like; aprotic polar solvents, for example, dimethylformamide (DMF), dimethisulfoxide (DMSO), and the like; ketones, for example, acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; acetonitrile; and its mixtures. Examples of basic compounds include carbonates, for example, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, cesium carbonate, and the like; alkali metal hydroxides; for example, sodium hydroxide, potassium hydroxide, and the like; alkaline earth metal hydroxides, for example, calcium hydroxide and the like; phosphates, for example, potassium phosphate, sodium phosphate, and the like; alkali metal hydrides, eg, sodium hydride, potassium hydride, and the like; alkali metals, for example, potassium, sodium, and the like; sodium amide; metal alcoholates, for example, sodium methylate, sodium ethylate, sodium n-butoxide, sodium tert-butoxide, tert-butoxide potassium, and the like; organic bases, for example, pyridine, imidazole, N-ethyldiisopropylamine, dimethylaminopyridine, triethylamine, trimethylamine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2] octane (DABCO), and the like; and its mixtures. The amount of basic compound is usually at least about 1 mole, and preferably about 1 to about 10 moles, per mole of compound (2). Organic solvents can also be used as a solvent. The reaction temperature is usually from -100 to 50 ° C, preferably from -50 ° C to room temperature, and more preferably from -30 ° C to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, and more preferably 1 to 3 hours. Compounds (2), (3), (4), (1a), (1b), (1c), (1d), (1e), (1f), (1g) and (1h) in the schemes of the above reaction can be their suitable salts. Examples of such suitable salts include the same groups of salts as with the compound (1). Compounds obtained according to the above reaction schemes can be isolated and purified from the reaction mixture by conventional manners, for example, after cooling the reaction mixture, isolation of the crude reaction product by filtration, concentration, extraction or similar isolation procedures, and then purification of the resultant by column chromatography, recrystallization or similar routine purification procedures. Compounds represented by the general formula (I) of the present invention include stereoisomers, optical isomers, and solvates (hydrates, ethanolates, etc.) thereof. Examples of salts of compounds represented by the general formula (1) of the present invention include pharmaceutically acceptable salts for example, metal salts, for example, alkali metal salts (eg, sodium salts, potassium salts, etc.), alkaline earth metal salts (eg, calcium salts, magnesium salts, etc.) and the like; ammonium salts; basic organic salts (for example, trimethylamine salts, triethylamine salts, pyridine salts, picoline salts, dicyclohexylamine salts, ethylenediamine salts, N, N'-dibenzylethylenediamine salts, tris (hydroxymethyl) aminomethane salts, ethanolamine salts, etc. ); etc. Among these, alkali metal salts are preferable, and sodium salts are more preferable. Said salts can be formed easily by applying, to the compound of the present invention, the corresponding pharmaceutically acceptable basic compound. Examples of applicable basic compounds include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogen carbonate, etc. The compound of the present invention has, for example, vasopressin antagonism, vasodilation activity, hypotensive activity, activity to inhibit saccharin release in liver, inhibitory activity of mesangial cell growth, aquaric activity, and platelet aggregation inhibitory activity. The compound is useful as a vasodilator, hypotensor, aquaristic agent, and inhibitor of platelet aggregation, and is effective in the prevention and treatment of hypertension, edema (e.g., cardiac edema, hepatic edema, renal edema, cerebral edema), dropsia abdominal, cardiac deficiency (for example, severe cardiac deficiency), renal dysfunction, syndrome of inappropriate vasopressin secretion (SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory failure, polycystic kidney disease (PKD), cerebral infarction, infarction of myocardium, and the like. When administered to the human body as a medicine, the compound of the present invention can be used simultaneously or separately with other vasopressin antagonists, ACE inhibitors, β-blocking agents, aquaric agents, angiotensin II (ARB) antagonists, digoxin , and / or similar pharmaceutical drugs. The compound of the present invention is usually used in the form of a general pharmaceutical composition. Said pharmaceutical composition can be prepared by a conventional method using diluents and / or excipients that are commonly used, for example, filler, expanders, binders, humectants, disintegrators, surfactants, lubricants, etc. The form of the pharmaceutical composition containing the compound of the present invention can be appropriately selected depending on the purpose of the treatment. It can be in the form of, for example, a tablet, pill, powder, solution, suspension, emulsion, capsule, suppository, ointment or granules. An aqueous solution composition, for example, injection, instillation, and the like is particularly preferable. When, for example, the preparation of an injection using the compound of the present invention, such as injection is preferably formulated in a solution, emulsion, or suspension that has been sterilized, and is isotonic with blood. For the preparation of a solution, emulsion or suspension using the compound of the present invention, any of the diluents commonly used in this field can be used. Examples of such diluents include water, aqueous solutions of lactic acid, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol., and esters of polyoxyethylene fatty acid sorbitan. In addition, in this case, sodium chloride, glucose, mannitol, glycerol and similar isotonization agents in amounts sufficient to prepare an isotonic solution can be mixed in the pharmaceutical composition. Ordinary pH adjusters, solubilizers, pH regulators, sedative agents and the like can also be added. An injection containing the compound of the present invention can be prepared by a conventional method, using a compound represented by the general formula (1) or its pharmaceutically acceptable salt, together with a pH regulator, isotonization agent, solvent for injection, and, if necessary, pH adjuster.

Examples of pH regulators include carbonates, borates, phosphates, citrates, tris (hydroxymethyl) aminomethane, malate, and tartrates. It is also possible to use individually an acid or base which form a pH regulator. Examples of pH adjusters include basic compounds, for example, sodium hydroxide and the like; acids, for example, hydrochloric acid and the like. In addition, colorants, preservatives, fragrances, flavors, sweeteners, and the like, as well as other medicines, may also be mixed in the pharmaceutical composition, as necessary. The content of the compound represented by the general formula (1) of the present invention or its salt in the pharmaceutical composition are not limited, and can be suitably selected from a wide range. The content is usually from 0.01 to 70% by weight of the pharmaceutical composition. The method for the administration of a pharmaceutical composition is not limited, and can be administered by a suitable method depending on the form of the pharmaceutical composition; the age of the patient, gender, etc .; the degree of the patient's symptoms; and the similar. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. The injections may be administered by intravenous injection, alone or as a mixture with glucose, amino acid and / or similar ordinary dispensers. The injections they may also be provided alone by intramuscular, intracutaneous, subcutaneous or intraperitoneal administration, as necessary. The dose of the pharmaceutical composition of the present invention can be selected depending on the use, the age of the patient, gender, etc .; the degree of the disease; and the similar. The dose is usually such that the compound represented by the general formula (1), which is an effective ingredient, is administered in an amount of 0.001 to 100 mg, and preferably 0.001 to 50 mg, per 1 kg of body weight per day. in one or more administrations. The various doses with various conditions. A smaller dose than the previous interval may be sufficient, while a larger dose than the previous interval may be necessary. The patents, patent applications, and documents cited herein are incorporated for reference.

Effect of the invention The compound (1) of the present invention or its salt has remarkably excellent water solubility, excellent absorption capacity, etc. The compound (1 b) in particular or its salt has remarkably excellent water solubility, excellent absorption capacity, etc. When administered in a human body, the compound (1) of the present invention or its salt, the compound (1b) or its salt in particular, they allow the easy generation of tolvaptan from active ingredient. In addition, the compound (1) of the present invention or its salt can be easily crystallized and is excellent in operability. In addition, the compound (1) of the present invention or its salt has excellent chemical stability. The compound (1a) of the present invention can suitably be used as a starting material for the production of the compound (1b). The use of the compound (1) of the present invention or its salt allows the compositions to be provided in various forms that express drug efficacy equal to tolvaptan, which is an effective drug.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the change in serum concentration of tolvaptan in female rats after rapid administration to the tail vein of a solution of compound (1 b) in a dose such that 1 mg of tolvaptan is produced per kg of body weight. Figure 2 is a graph showing the change in serum concentration of tolvaptan in female rats after oral administration of a solution of compound (1 b) in a dose such that 1 mg of tolvaptan is produced per kg of body weight .

PREFERRED MODALITY OF THE INVENTION Examples, test examples and preparation examples are provided below to illustrate the present invention in further detail, but the scope of the invention is not limited to these examples.

EXAMPLE 1 An amount of 1.0 g of tolvaptan (compound (2)) and 460 mg of 1 H-tetrazole are dissolved in 30 ml of methylene chloride, and 1.2 g of dibenzyl diisopropylphosphoramidite is added dropwise to this solution at room temperature with agitation. The mixture is stirred for 2 hours at the same temperature.

The reaction mixture obtained is cooled to -40 ° C, and 6 ml of methylene chloride solution of 920 mg of metachloroperbenzoic acid are added dropwise thereto. The mixture is then stirred at the same temperature for 30 minutes, and at 0 ° C for 30 minutes. The reaction mixture is washed with an aqueous solution of sodium thiosulfate and saturated aqueous sodium bicarbonate, and then dried over anhydrous sodium sulfate. The obtained reaction mixture is filtered and concentrated, and the residue is purified by column chromatography on silica gel (eluent: n-hexane: ethyl acetate = 1: 1) to give 1.5 g of amorphous compound (1a-1). ) (yield 97.2%). NMR (DMSO-d6, 100 ° C) d ppm; 9.86 (1 H, br s), 7.56 (1 H, s), 7.50- 7.10 (17H, m), 7.00-6.80 (2H, m), 5.60-5.50 (1 H, m), 5.15-5.00 (4H , m), 5.00-2.75 (2H, m), 2.36 (3H, s), 2.34 (3H, s), 2.10-1.70 (4H, m).

EXAMPLE 2 An amount of 4.5 g of tolvaptan (compound (2)) and 2.2 g of 1 H-tetrazole is dissolved in 120 ml of methylene chloride, and a solution of 4.0 g of di-butyl diisopropylphosphoramidite dissolved in 10 ml of methylene chloride is added dropwise to this solution under ice-cooling and stirring. The mixture is then stirred at room temperature for 2 hours. The reaction mixture obtained is cooled to -40 ° C, and 20 ml of methylene chloride solution of 4.0 g of metachloroperbenzoic acid are added dropwise thereto. The mixture is then stirred at the same temperature for 30 minutes and at 0 ° C for 40 minutes. The reaction mixture is washed with an aqueous solution of sodium thiosulfate and bicarbonate of saturated aqueous sodium, and then dried over anhydrous sodium sulfate. The obtained reaction mixture is filtered and concentrated and the residue is purified by column chromatography on silica gel (eluent: hexane: ethyl acetate = 1: 1) to give 3.0 g of amorphous compound (1 a-2) ( 46.7% yield). NMR (DMSO-d6) d 10.50-10.20 (1 H, m), 8.00-6.50 (10H, m), 5.55- 5.20 (1 H, m), 4.90-4.50 (1 H, m), 2.85-2.60 ( 1 H, m), 2.40-2.20 (6H, m), 2.20-1.60 (4H, m), 1.60-1.30 (18H, m).

EXAMPLE 3 An amount of 5.3 g of compound (1 a-1) is dissolved in 100 ml of ethanol, and, using 2 g of 5% palladium-carbon as a catalyst, the solution is subjected to catalytic reduction at room temperature and atmospheric pressure. for 10 minutes. The catalyst is removed from the solution by filtration, and the filtrate obtained is concentrated (4.2 g). The residue obtained is crystallized from methanol / water. The crystals are collected by filtration and then dried under reduced pressure (pentoxide of diphosphorus) to provide 3.5 g of white powdery compound (1 b) (88.5% yield). Melting point: 150 to 152 ° C. NMR (DMSO-d6-D20, 100 ° C) d ppm; 7.50-6.70 (10H, m), 5.50-5.40 (1H, m), 5.00-2.50 (2H, m), 2.37 (6H, s), 2.40-1.50 (4H, m).

EXAMPLE 4 An amount of 3.0 g of compound (1a-2) is dissolved in 100 ml of methylene chloride, and a solution of 10 ml of trifluoroacetic acid is dissolved in 5 ml of methylene chloride is added dropwise to this solution with cooling with ice and agitation. The mixture is then stirred at the same temperature for 2 hours. The solvent is removed from the solution. The residue obtained is dissolved again in methylene chloride, and then concentrated. The residue obtained is crystallized from methanol / water. The crystals are collected by filtration and then dried under reduced pressure (diphosphorus pentoxide) to provide 1.9 g of white powdery compound (1 b) (yield 76.8%).

EXAMPLE 5 An amount of 240 ml of 1,2-dimethoxyethane (DME) and 84 ml of triethylamine (0.60 mol, 9 equivalents) are added to 30 g (66 mmol) of tolvaptan (compound (2)), and the mixture is cooled under a stream of nitrogen at -15 ° C. An amount of 19 ml (0.20 mol, 3 equivalents) of phosphorus oxychloride (POCI3) is added dropwise to the mixture obtained at an internal temperature of not more than -12 ° C, and the stirring is carried out at -12 ° C. C for 2 hours. An amount of 200 ml of 5N aqueous sodium hydroxide solution is added to 1 kg of crushed ice, and the above reaction mixture is added in small portions thereto with stirring. To the obtained mixture, 500 ml of toluene are added. The mixture is heated to 50 ° C and then separated into an aqueous layer and a layer of toluene. An amount of 500 ml of toluene is added again to the aqueous layer, stirring is carried out at 50 ° C, and the mixture is then separated into an aqueous layer and a layer of toluene. The aqueous layer is cooled to 10 ° C, 80 ml of 6N hydrochloric acid are added thereto, and the extraction is carried out with 500 ml of ethyl acetate two times. The extract is dried over sodium sulfate and filtered, and the filtrate is concentrated. The concentrate is dried under reduced pressure at room temperature to provide 34 g of the amorphous compound (1 b). Yield: 97%.

EXAMPLE 6 Production of calcium salt of compound (1b) (1) An amount of 2.6 g (5.0 mmol) of compound (1 b) is dissolved in 25 ml of isopropyl alcohol, and 2.2 ml of 5N aqueous sodium hydroxide solution is added thereto at room temperature. The obtained mixture is concentrated under reduced pressure. To the residue is added 30 ml of water to dissolve the solid content, and an aqueous solution of 0.61 g (5.5 mol) of calcium chloride is then added thereto. The precipitated solids are collected by filtration, washed with water, and dried with hot air at 60 ° C to provide 2.2 g of white powder calcium salt of compound (1 b).

Yield: 78% 1 H NMR (DMSO-d 6, 100 ° C) d ppm; 1.3-2.4 (10H, m), 2.8-4.5 (2H, m), 5.2-5.8 (1H, m), 6.4-8.1 (10H, m), 9.0-10.2 (1H, m). (2) An amount of 280 mg (0.53 mmol) of compound (1 b) is dissolved in a mixed solution of 2 ml of methanol and 1 ml of water, and 43 mg (0.58 mmol) of calcium hydroxide is then added to this. The mixture is stirred at room temperature for 1 hour. The precipitated solids are collected by filtration. The filtrate is suspended in methanol, stirred with heating, and then filtered hot. The filtrate is concentrated, and the residue is recrystallized from methanol to provide 75.4 mg of white powder calcium salt of the compound (1b). Yield: 25% Melting point: 263 to 265 ° C.

EXAMPLE 7 Production of Magnesium Salt of Compound (1b) (1) An amount of 1.0 g (1.9 mmol) of compound (1 b) is dissolved in 15 ml of methanol, and 0.76 ml of aqueous solution of 5N solid hydroxide are added thereto. The mixture is concentrated under reduced pressure. The residue is dissolved in 10 ml of methanol, and 3 ml of methanol solution of 0.18 g of magnesium chloride are added to the solution obtained at room temperature. The precipitated insoluble matter (NaCl) is removed by filtration, and the filtrate is concentrated. To the residue, 10 ml of water are added, and the stirring is carried out with heating. The mixture after stirring is allowed to cool to room temperature. The insoluble matter is then collected by filtration, washed with water, dried under reduced pressure at 60 ° C to provide 400 mg of white powder magnesium salt of compound (1b). Yield: 38% 1 H NMR (DMSO-de, 100 ° C) d 1.4-2.4 (10H, m), 2.8-4.5 (2H, m), . 3-5.5 (1 H, m), 6.4-7.8 (10H, m), 9.7 (1 H, br). (2) An amount of 282 mg (0.53 mmol) of compound (1 b) is dissolved in 2 ml of methanol, and 41 mg (0.70 mmol) of magnesium ethoxide is added thereto under cooling with ice. To the obtained mixture is further added 2 ml of ethanol and an aqueous suspension (0.5 ml) of 36 mg (0.58 mmol) of magnesium hydroxide, and the stirring is carried out at room temperature for 1 hour. The insoluble matter is removed by filtration, and the filtrate is allowed to stand overnight. The precipitated solids are collected by filtration and then dried under reduced pressure to provide 24.9 mg of white powder magnesium salt of compound (1 b). Yield: 11% Melting point: 250 to 252 ° C.

EXAMPLE 8 Production of monosodium salt of the compound (1 b) An amount of 0.5 ml of aqueous solution of sodium hydroxide 1N and 1 ml of water are added to a methanol solution (2 ml) of 266 mg (0.5 mmol) of compound (1 b) with ice cooling, and the obtained solution is stirred at room temperature for 1 hour. The reaction mixture is concentrated under reduced pressure, and the residue is recrystallized from methanol-water to provide 45.2 mg of white compound powder monosodium salt (1 b). Yield: 16% Melting point: 235 to 238 ° C.

EXAMPLE 9 Production of disodium salt of a compound (1b) An amount of 1.0 ml of aqueous sodium hydroxide solution is added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of compound (1 b) with ice cooling, and the mixture obtained is stirred for 5 minutes. . The reaction mixture is concentrated under reduced pressure, and the residue is recrystallized from acetone-water to provide 221 mg of white powdery disodium salt of the compound (1 b). Yield: 73% Melting point: 250 to 252 ° C.

EXAMPLE 10 Production of diammonium salt of compound (1b) An amount of 1.0 ml of 25% aqueous ammonia solution is added to methanol solution (2 ml) of 271 mg (0.51 mmol) of the compound (1 b) with ice cooling, and the mixture obtained is stirred for 10 minutes. . The reaction mixture is concentrated under reduced pressure, and the residue is recrystallized from methanol-water to provide 104 mg of white powder diammonium salt of the compound (1 b). Performance: 36%. Melting point: 195 to 198 ° C.

EXAMPLE 11 Production of monopotassium salt of compound (1b) You can see a can. The aqueous solution of 1N potassium hydroxide was added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of the compound (1b) under ice-cooling, and the mixture obtained was stirred for 10 minutes. The reaction mixture is concentrated under reduced pressure, and the residue is recrystallized from isopropyl alcohol to give 110.6 mg of monopotassium salt in white powder of compound (1b). Yield: 37% Melting point: 200 to 203 ° C.

EXAMPLE 12 Production of dipotassium salt of compound (1b) An amount of 1.0 ml of 1 N potassium hydroxide aqueous solution is added to a methanol solution (2 ml) of 276 mg (0.52 mmol) of the compound (1 b) with ice cooling, and the mixture obtained is stirred for 5 minutes. The reaction mixture is concentrated under reduced pressure, and diethyl ether is added to the residue. The insoluble matter is collected by filtration and then dried to give 273.9 mg of white powdered dipotassium salt of the compound (1 b). Yield: 86% Melting point: 255 to 265 ° C (decomposition).

EXAMPLE 13 Production of the zinc salt of the compound (1 b) An amount of 1.0 ml (1.9 mmol) of the compound is dissolved (1 b) in 15 ml of methanol, and 0.76 ml of aqueous sodium hydroxide solution 5N are added to this solution. The mixture is concentrated under reduced pressure.

The residue obtained is dissolved in 10 ml of methanol, and 3 ml of methanol solution of 259 mg of zinc chloride are added thereto at room temperature. The precipitated insoluble matter (NaCl) is removed by filtration, and the filtrate is concentrated. To the obtained residue, 10 ml of water are added, and the stirring is carried out with heating. The mixture is then allowed to cool to room temperature. The insoluble matter is collected by filtration, washed with water, and dried under reduced pressure at 60 ° C to provide 900 mg of powdered white zinc salt of the compound (1 b). Yield: 80% Melting point: 235 to 239 ° C (decomposition) 1 H-NMR (DMSO-de, 100 ° C) d ppm: 1.3-2.4 (10H, m), 2.8-4.5 (2H, m), 5.3-5.7 (1 H, m), 6.6-7.7 (10H, m), 9.7 (1 H, br).

EXAMPLE 14 Production of ethylenediamine salt of the compound (1 b) An amount of 0.074 ml (1.1 mmol) of ethylenediamine is added to a solution of ethanol (10 ml) of 600 mg (1.1 mmol) of compound (1 b). The obtained reaction mixture is concentrated under reduced pressure, and the residue is recrystallized from isopropyl alcohol to give 250 mg of white powder ethylenediamine salt of the compound (1 b). 1 H-NMR (DMSO-d 6, 100 ° C) d ppm: 1.5-2.0 (3H, m), 2.1-2.4 (7H, m), 2.77 (4H, s), 2.8-4.3 (2H, m), 5.3 -5.5 (1 H, m), 6.6-6.9 (1 H, m), 6.9-7.2 (2H, m), 7.2-7.5 (5H, m), 7.58 (2H, d, J = 7.6 Hz), 9.80 (1 H, br).

EXAMPLE 15 Production of diethanolamine salt of compound (1b) An amount of 0.14 ml (2.3 mmol) of ethanolamine is added to a solution of isopropyl alcohol (6 ml) of 600 mg (1.1 mmol) of compound (1 b). An amount of 6 ml of isopropyl alcohol is added to the obtained mixture, dissolution is carried out with heating, and recrystallization from isopropyl alcohol gives 280 mg of white powder diethanolamine salt of compound (1 b). H-NMR (DMSO-d6, 100 ° C) d ppm: 1.4-2.0 (3H, m), 2.2-2.5 (7H, m), 2.75 (4H, t, J = 5.5 Hz), 3.52 (4H, t , J = 5.5 Hz), 2.8-4.3 (2H, m), 5.3-5.5 (1 H, m), 6.7-6.9 (1 H, m), 6.9-7.2 (2H, m), 7.2-7.4 (4H , m), 7.42 (1 H, d, J = 7.7 Hz), 7.57 (2 H, d, J = 6.5 Hz), 7.58 (2 H, d, J = 7.6 Hz), 9.80 (1 H, br).

EXAMPLE 16 An amount of 1.3 ml (6.6 mmol) of diphenyl phosphite is added to a solution of pyridine (10 ml) of 1.0 g (2.2 mmol) of tolvaptan (compound (2)) with cooling with ice. The obtained mixture is stirred at 0 ° C for 30 minutes, and then at room temperature for 30 minutes. To the reaction mixture 0.58 ml of ethanol are added, and stirring is carried out at room temperature for 30 minutes. To this mixture is added 1 N hydrochloric acid, and the extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with a saturated aqueous sodium acid carbonate solution, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The residue obtained is purified by silica gel column chromatography (n-hexane: ethyl acetate = 27: 73 → 0: 100). The purified product is concentrated under reduced pressure, and the residue is dissolved in a mixed solvent of 10 ml of acetonitrile and 10 ml of water and then freeze dried to give 450 mg of white amorphous solid target compound.

Yield: 38% 1 H-NMR (toluene-da, 100 ° C) d ppm: 1.0-1.1 (3H, m), 1.4-1.9 (4H, m), 2.31 (3H, s), 2.42 (3H, s) , 2.0-4.0 (2H, m), 3.7-4.1 (2H, m), 5.5 (0.5H, d, J = 4.8 Hz), 6.4-7.5 (10H, m), 7.8 (0.5H, d, J = 8.6 Hz).

EXAMPLE 17 A solution of pyridine (50 ml) of 10.0 g (22 mmol) of tolvaptan (compound (2)) is added under cooling with ice, and 13 ml (66 mmol) of diphenyl phosphite is slowly added thereto under an atmosphere of nitrogen. The obtained mixture is stirred at room temperature for 30 minutes. To this mixture is added 4.5 ml of methanol, and the stirring is carried out at room temperature for 30 minutes. The reaction mixture obtained is added with cooling with ice to 325 ml of 2N hydrochloric acid, and the extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is purified by chromatography silica gel column (ethyl acetate: methanol = 100: 0 -> 93: 7). The purified product is concentrated under reduced pressure to provide 10.5 g of white amorphous solid target compound. Yield: 91% 1 H-NMR (toluene-d 8, 100 ° C) d ppm: 1.5-2.0 (4H, m), 2.41 (3H, m), 2.49 (3H, s), 3.0-4.2 (2H, m) , 5.5 (0.5H, d, J = 4.8 Hz), 5.5-5.8 (1 H, m), 6.6 (1 H, d, J = 8.3 Hz), 6.7-6.9 (1 H, m), 6.9-7.2 (6H, m) 7.3-7.5 (2H, m), 7.81, 7.84 (0.5H, d, J = 8.1 Hz).

EXAMPLE 18 An amount of 0.1 ml of water and 254 mg (1.0 mmol) of iodine is added to a solution of pyridine (5 ml) of 500 mg (0.95 mmol) of the compound of example 17, and the mixture obtained is stirred at room temperature during 30 minutes. To this mixture is added 2 ml of triethylamine, and concentrated under reduced pressure. An amount of 20 ml of toluene is added to the residue, and a concentration is carried out under reduced pressure. Water is added to the residue, and a wash is carried out with a mixed solvent of ethyl acetate and diethyl ether. 1 N hydrochloric acid is added to the aqueous layer, and the extraction is carried out with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and then filtered, and the filtrate is concentrated. The residue obtained is purified by silica gel column chromatography (dichloromethane: methanol = 90: 10-50: 50). The purified product is concentrated under reduced pressure, and the residue is dissolved in 30 ml of water. The obtained solution is filtered through celite, and the filtrate is dried by freezing to give 140 mg of white amorphous solid target compound. 1 H-NMR (toluene-de, 100 ° C) d ppm: 1.4-2.0 (4H, m), 2.33 (3H, m), 2.34 (3H, s), 2.5-4.5 (5H, m), 5.4-5.7 (2H, m), 6.5 (2H, d, J = 7.9 Hz), 6.7 (2H, d, J = 7.9 Hz), 6.8-7.2 (5H, m), 7.2-7.4 (2H, m), 7.55 ( 1 H, s).

EXAMPLE 19 An amount of 64 mg (1.0 mg) of sulfur is added to a solution of pyridine (5 ml) of 500 mg (0.9 mmol) of the compound of the example 17, and the obtained mixture is stirred at room temperature for 2 hours. To this mixture is added 1 ml of triethylamine, and a concentration is carried out under reduced pressure. An amount of 10 ml of toluene is added to the obtained residue, and a concentration is carried out under reduced pressure. Water is added to the residue for dissolution, and filtration is performed using celite. 1 N hydrochloric acid is added to the filtrate, and extraction is carried out with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and then filtered, and the filtrate is concentrated. Water is added to the obtained residue, and the insoluble matter is collected by filtration and then dried to give 300 mg of white amorphous solid target compound. 1 H-NMR (toluene-d 8, 100 ° C) d ppm: 1.1-2.0 (4H, m), 2.2-2.5 (6H, m), 3.5 (3H, dd, J = 13.9, 14.9 Hz), 2.5-5.0 (2H, m), 3.5-5.7 (1 H, m), 6.4-7.5 (10H, m).

EXAMPLE 20 An amount of 0.5 ml of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.072 ml (1.2 mmol) of ethanolamine are added to a solution of acetonitrile (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture is stirred at room temperature for 10 minutes. Water is added to this mixture, and the extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The residue obtained is purified by silica gel column chromatography (ethyl acetate: methanol = 100: 0 -> 80: 20). The purified product is concentrated under reduced pressure to provide 540 mg of white amorphous solid target compound. 1 H-NMR (DMSO-dβ, 100 ° C) d ppm: 1.6-2.3 (4H, m), 2.36 (6H, s), 2. 7-3.1 (2H, m), 2.5-4.5 (2H, m), 3.3-3.5 (2H, m), 3.65 (3H, dd, J = 9.6, 11.2 Hz), 4.0-4.3 (1 H, m), 4.4-4.8 (1 H, m), 5.3-5.7 (1 H, m), 6.7-7.1 (2H, m), 7.1-7.5 (5H, m), 7.57 (1 H, s), 9.76 (1 H, s).

EXAMPLE 21 An amount of 0.5 ml of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.119 ml (1.2 mmol) of methylamine (40% methanol solution) are added to a solution of acetonitrile (5 ml) of 500 mg (0.95 mmol) of the compound of Example 17, and the obtained mixture is stirred at room temperature for 10 minutes. Water is added to this mixture, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The residue obtained is purified by silica gel column chromatography (ethyl acetate: methanol = 94: 6 → 85: 15). The purified product is concentrated under reduced pressure to provide 250 mg of white amorphous solid target compound. 1 H-NMR (DMSO-d 6, 100 ° C) d ppm: 1.7-2.3 (4H, m), 2.37 (6H, s), 2.4-2.6 (3H, m), 2.8-4.3 (2H, m), 3.63 (3H, t, J = 10.7 Hz), 4.4-4.8 (1 H, m), 5.3-5.6 (1 H, m), 6.6-7.1 (2H, m), 7.1-7.5 (5H, m), 7.58 (1 H, s), 9.81 (1 H, s).

EXAMPLE 22 An amount of 0.5 ml of water, 0.5 ml of carbon tetrachloride, 0.5 ml of triethylamine, and 0.115 ml (1.2 mmol) of diethanolamine are added to a solution of acetonitrile (5 ml) of 500 mg (0.95 mmol) of the compound of the Example 17, and the obtained mixture is stirred at room temperature for 10 minutes. Water is added to this mixture, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is purified by silica gel column chromatography (ethyl acetate: methanol = 88: 12 → 70: 30).

The purified product is concentrated under reduced pressure, and the residue is recrystallized from methanol containing water to provide 250 mg of target compound in white powder. 1 H-NMR (DMSO-d 6, 100 ° C) d ppm: 1.6-2.2 (4H, m), 2.37 (6H, s), 3.0-3.2 (4H, m), 3.5-3.7 (7H, m), 2.8 -4.3 (2H, m), 4.1-4.4 (1H, m), 5.3-5.7 (1H, m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.5-7.7 ( 1 H, m), 9.80 (1 H, br).

EXAMPLE 23 An amount of 3.8 mg (20 mmol) of diphenyl phosphite is added to a solution of pyridine (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound (2)), and the obtained mixture is stirred at room temperature during 1 hour. To this mixture 2 ml of water are added, and stirring is carried out at room temperature for 30 minutes. The reaction mixture obtained is concentrated under reduced pressure, 1N hydrochloric acid is added to the residue, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated saline twice, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is purified by means of silica gel column chromatography (ethyl acetate: methanol = 100: 0 → 50:50). The purified product is concentrated under pressure. The residue is dissolved in water, and the insoluble matter which precipitates on adding 1N hydrochloric acid is collected by filtration and then dried to give 0.83 g of target compound in white powder. Yield: 24% 1 H-NMR (DMSO-de, 100 ° C) d ppm: 1.7-2.2 (4H, m), 2.35 (3H, s), .36 (3H, s), 2.8-4.3 (2H, m), 5.4-5.6 (1 H, m), 5.8 (0.5 H, br), 6.7-7.4 (8H, m), .47 (1 H, d, J = 2.3 Hz), 7.55 (1 H, s), 9.79 (1 H, br).

EXAMPLE 24 An amount of 2.9 ml of phosphorous trichloride is added under a stream of nitrogen to tetrahydrofuran (THF) (29 ml). The mixture obtained is cooled with ice, and 6.1 ml (44 mmol) of triethylamine are added thereto. This mixture is cooled in an ice-methanol bath. A THF solution (120 ml) of 10.0 g (22 mmol) of tolvaptan (compound (2)) is then added dropwise thereto at an internal temperature of not more than -10 ° C, and stirring is carried out at the same temperature for 2 hours. An amount of 130 ml of 1 N aqueous sodium hydroxide solution is added dropwise to the reaction mixture obtained at an internal temperature of not more than 0 ° C, 200 ml of water is added to this additionally, and an Wash with toluene twice. The aqueous solution obtained is cooled in an ice-methanol bath, 1 N HCl is added dropwise thereto at an internal temperature of not more than 0 ° C, and extraction is carried out with ethyl acetate. The ethyl acetate layer is dry over sodium sulfate and then filter, and the filtrate is concentrated to give 6.8 g of white amorphous solid target compound. Yield: 60%.

EXAMPLE 25 An amount of 3.8 ml (20 mmol) of diphenyl phosphite is added to a solution of pyridine (10 ml) of 3.0 g (6.7 mmol) of tolvaptan (compound (2)), and the obtained mixture is stirred at room temperature during 1 hour. To this mixture is added 5.2 ml (66.6 mmol) of methyl glycolate, and stirring is carried out at room temperature for 12 hours. To the reaction mixture 50 ml of water are added, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with 1 N hydrochloric acid twice, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is purified by means of silica gel column chromatography (n-hexane: ethyl acetate = 50: 50 → 0: 100). The purified product is concentrated under reduced pressure to give 0.79 g of white amorphous solid target compound.

Yield: 20% 1 H-NMR (toluene-d 8, 100 ° C) d ppm: 1.6-2.2 (4H, m), 2.51 (3H, s), 2.60 (3H, s), 3.2-4.4 (2H, m) , 3.53 (3H, s), 4.43 (1 H, s), 4.47 (1 H, s), 5.87 (0.5H, s), 5.9-6.1 (1 H, m), 6.6-6.8 (1 H, m ), 6.8-7.0 (2H, m) 7.0-7.4 (5H, m), 7.48 (1 H, s), 7.63 (1 H, s), 8.27 (0.5H, s).

EXAMPLE 26 An amount of 0.8 ml of water is added to a solution of pyridine (7.9 ml) of 0.79 g (1.35 mmol) of the compound of example 25. To the obtained mixture 0.34 g (2.7 mmol) of iodine are added with cooling using ice, and it is stirred at room temperature for 1 hour. 1 N hydrochloric acid is added to the reaction mixture, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is dissolved in water and then freeze-dried to yield 80 mg of amorphous solid target compound White. Yield: 9.9% 1 H-NMR (DMSO-d 6, 100 ° C) d ppm: 1.7-2.3 (4H, m), 2.35 (3H, s), 2.36 (3H, s), 2.8-4.3 (2H, m) , 4.49 (2H, dd, J = 1.7, 10.1 Hz), 5.4-5.6 (1 H, m), 6.7-7.1 (2H, m), 7.1-7.5 (7H, m), 7.54 (1 H, s) 9.79 (1 H, br).

EXAMPLE 27 An amount of 3.0 g (6.7 mmol) of tolvaptan (compound (2)) is added in small portions to a pyridine solution (15 ml) of 3.8 ml (20 mmol) of diphenyl phosphite, and the mixture obtained is stirred at room temperature. environment for 0.5 hours. To this mixture is added 2.8 ml (40 mmol) of 3-hydroxypropionitrile, and stirring is carried out at room temperature for 0.5 hours. To the obtained reaction mixture 1 N hydrochloric acid is added, and extraction is carried out with ethyl acetate. The ethyl acetate layer is washed with water, dried over sodium sulfate, and then filtered, and the filtrate is concentrated. The obtained residue is purified by chromatography of column on silica gel (ethyl acetate: methanol = 100: 0-10: 1). The purified product is concentrated under reduced pressure to yield 2.8 g of white amorphous solid target compound. Yield: 75% 1 H-NMR (Toluene-dß, 100 ° C) d ppm: 1.4-2.0 (6H, m), 2.33 (3H, s), 2.40 (3H, s), 3.1 -3.8 (4H, m) , 5.40 (0.5H, d, J = 3.1 Hz), 5.3-5.4 (1 H, m), 6.5-6.7 (1 H, m), 6.7-6.9 (1 H, m), 6.9-7.2 (6H, m), 7.2-7.5 (2H, m), 7.76 (0.5H, d, J = 8.5 Hz).

EXAMPLE 28 An amount of 0.115 g (3.6 mmol) of sulfur is added to a pyridine solution (10 ml) of 1.0 g (1.8 mmol) of the compound of example 27, and the obtained mixture is stirred at room temperature for 2 hours. To this mixture is added 1N hydrochloric acid, and extraction is carried out with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and then filtered, and the filtrate is concentrated. The obtained residue is purified by column chromatography on silica gel (ethyl acetate: methanol = 0 -> 85: 15). The purified product is concentrated under reduced pressure to yield 0.91 g of white amorphous solid target compound. Yield: 85% 1 H-NMR (DMSO-d 6> 100 ° C) d ppm: 1.6-1.9 (3H, m), 2.0-2.3 (1 H, m), 2.10 (3H, m), 2.36 (6H, s), 2.3-4.2 (2H, m), 2.7-2.8 (2H, m), 3.9-4.2 (2H, m), 5.5-5.8 (1H, m), 6.7-6.9 (1H, m), 7.0 -7.4 (7H, m), 7.4-7.5 (1H, m), 7.56 (1H, s), 7.7-7.8 (0.3H, m), 8.5-8.6 (m, 0.7H), 9.76 (1H , br).

EXAMPLE 29 An amount of 300 mg (0.5 mmol) of the compound of Example 28 is added to 5 mL of 28% aqueous ammonia, and the obtained mixture is stirred at room temperature for three days. To this mixture is added 1N hydrochloric acid. The precipitated solids are collected by filtration and then dried to give 100 mg of white powder target compound.

Yield: 37% 1 H-NMR (pyridine-d 5 -D 20, 90 ° C) d ppm: 1.6-2.4 (4H, m), 2.43 (3H, s), 2.53 (3H, s), 2.8-4.3 (2H, m), 5.1-5.4 (1 H, m), 6.8-7.3 (6H, m), 7.4-7.7 (2H, m), 7.7-8.1 (2H, m).

EXAMPLE 30 An amount of 0.62 ml (6.6 mmol) of phosphorous oxychloride and 0.92 ml (6.6 mmol) of triethylamine is added under a stream of nitrogen to tetrahydrofuran (THF) (5 ml). The mixture obtained is cooled in an ice-methanol bath. A THF solution (10 ml) of 1.0 g (2.2 mmol) of tolvaptan (compound (2)) is then added dropwise, and stirred at the same temperature for 30 minutes. To this mixture is added 2.8 ml (20 mmol) of triethylamine and 1.1 ml (26.4 mmol) of methanol, and stirred for 30 minutes. Water is added to the obtained reaction mixture, and extraction is carried out with ethyl acetate. The ethyl acetate layer is dried over sodium sulfate and then filtered, and the filtrate is concentrated. The residue obtained is purified by column chromatography on silica gel (ethyl acetate: methanol = 100: 0 → 80: 20). The purified product is concentrated under reduced pressure, and the residue is recrystallized from methanol containing water to yield 400 mg of white powder target compound. Yield: 33% 1 H-NMR (DMSO-d 6l 100 ° C) d ppm: 1.7-2.2 (4H, m), 2.36 (6H, s), 2.8-4.3 (2H, m), 3.71 (6H, dd, J = 10.2, 11.1 Hz), 5.5-5.6 (1 H, m), 6.8-7.1 (2H, m), 7.1-7.5 (7H, m), 7.58 (1 H, s), 9.80 (1 H, br) .

EXAMPLE OF TEST 1 Solubility of the compound (1b) The compound (1b) as obtained in example 3 or 4 is added in excess to 0.1 N sodium phosphate pH regulator (pH 5, pH 6, pH 7, pH 8, pH 9 or pH 10), Tris pH-regulator / HCI 0.1 N (pH 8 or pH 9), 0.1 N sodium acid carbonate / pH regulator 0.1 N HCl (pH 8) or 0.1 N sodium citrate pH regulator (pH 8), and then it is stirred at room temperature for 16 days. If the test compound is dissolved even after about 6 to about 8% w / v has been added thereto, no further test compound is added. Each solution is filtered through a 0.45 μm filter, and then, under the following HPLC conditions, the solubility of the compound (1 b) is determined by absolute calibration.

HPLC conditions Detection: ultraviolet absorption photometer (wavelength measurement: 254 nm) Column: YMC (ODS) AM-302 (4.6 x 150 mm) Column temperature: constant temperature of approximately 25 ° C Eluate: acetonitrile / water / phosphoric acid = 450/550/1 Flow rate: 1 ml / minute Injection volume: 10 μl.

TABLE 1 Solubility of the compound (1b) in pH buffer (room temperature) * It shows that it has a high solubility so that the crystals can not be added in excess.

EXAMPLE OF TEST 2 Solubility of salt of the compound (1) A suitable amount of the test compound is added to a test tube, and 2.5 ml of water is added thereto. After stirring at 37 ° C for 30 minutes, the mixture is filtered through a 0.45 μm membrane filter, and 0.5 ml of the filtrate is weighed accurately. The mobile phase is added to this to obtain exactly 50 ml, preparing a test solution (dilution ratio: 100 times). They are roughly weighed Exact way 5 mg of authentic sample of free form, and acetonitrile is added to this to obtain exactly 50 ml. Exactly 2 ml of this liquid are weighed, and mobile phase is added thereto to obtain exactly 20 ml, preparing a standard solution (equivalent to 10 μg / ml). Using liquid chromatography under the following conditions, 20 μl of test solution and standard solution are analyzed to obtain the peak areas At and As of the standard solution and test solution. Concentration μg / ml) = Ws / 5 x 10 x At / As x 100 = Ws x At As x 200 Ws: true quantity of authentic sample (mg) Test conditions Detection: ultraviolet absorption photometer (wavelength measurement: 254 nm) Column: TOSOH TSKgel ODS-80Ts (0.46 cm x 15 cm) Column temperature: constant temperature of approximately 40 ° C Mobile phase: water / acetonitrile / trifluoroacetic acid = 500/500/1 Flow rate: 1 ml / minute.

TABLE 2 EXAMPLE OF TEST 3 Solubility of tolvaptan Excess Tolvaptan is added to Britton-Robinson pH buffer (pH 2, pH 7, or pH 12) or purified water, and then stirred at 25 ° C ± 1 ° C for 4 hours. Each solution is filtered through a filter, and then, using HPLC, the solubility of tolvaptan is quantified by absolute calibration.

TABLE 3 Solubility of tolvaptan in Britton-Robinson pH regulator and purified water TEST EXAMPLE 4 Concentration in serum of tolvaptan in female rats after administration in the tail vein of a solution of the compound (1b) Method of the experiment A solution of the compound (1 b) (equivalent to 1 mg of tolvaptan per ml of solution) is prepared.

TABLE 4 Formulation (in 1 ml) Amount equivalent to 1.0 mg of tolvaptan per ml of solution Preparation method An amount of 79 mg of dihydrated sodium dihydrogen phosphate and 5 g of mannitol are dissolved in approximately 90 ml of water for injection. A solution of sodium hydroxide is added to this, and a solution of pH 7 is prepared. The compound (1 b) equivalent to 100 mg of tolvaptan is dissolved in this solution. A solution of sodium hydroxide is added to this, and the pH is adjusted to 7. Injection solvent is added to the solution obtained to obtain 100 ml, and sterile filtration is carried out with a 0.2 μm filter to prepare a solution of compound (1 b) (equivalent to 1 mg of tolvaptan per ml of solution). This solution is rapidly administered to female rats via the tail vein at a dose such that 1 mg of tolvaptan is produced per kg of body weight. From time to time, jugular vein blood is collected under light with ethyl ether anesthesia, and serum concentration of tolvaptan is determined by high performance liquid chromatography (HPLC). The results are shown in Figure 1. Tolvaptan is initially detected five minutes after the intravenous administration of a solution of the compound (1b) to female rats. This indicates that the compound (1b) is rapidly hydrolysed in tolvaptan in rats.

TEST EXAMPLE 5 Serum concentration of tolvaptan in female rats after oral administration of a solution of compound (1b) Method of the experiment A solution of the compound (1 b) (equivalent to 0.4 mg of tolvaptan per ml of solution) is prepared.

TABLE 5 Formulation (in 1 ml) * Amount equivalent to 1.0 mg of tolvaptan per ml of solution Preparation method An amount of 1 g of sodium acid carbonate is dissolved in about 400 ml of water for injection. A solution of sodium hydroxide is added thereto to adjust the pH to 9.0, and water for injection is added thereto, by preparing 500 ml of 0.2% sodium acid carbonate solution. An amount of 89 μl of 1 N sodium hydroxide solution and compound (1 b) equivalent to 20 mg of tolvaptan are added to about 40 ml of this 0.2% sodium hydrogen carbonate solution and dissolved. A 0.2% sodium hydrogen carbonate solution is additionally added thereto to obtain 50 ml, thereby preparing a solution of compound (1b) (equivalent to 0.4 mg of tolvaptan per ml of solution). The pH of this solution is 9.1. This solution is called "solution A". A spray-dried tolvaptan powder equivalent to 60 mg of tolvaptan, which is prepared in a similar manner to Example 3 of JP1999- 21241 -. 21241 -A, is suspended in 50 ml of water for injection in a porcelain mortar. This suspension is diluted three times with water for injection, preparing a suspension of spray-dried powder equivalent to 0.4 mg of tolvaptan per ml of suspension. This suspension is called "suspension B". The following tests are performed in order to examine the oral absorption characteristics of solution A and suspension B. Wistar female rats (body weight of approximately 160 g) that have been fasting for approximately 18 hours are used as test animals. Solution A and suspension B are each administered by forced oral administration using a probe for oral administration in a dose of 2.5 ml / kg of body weight, yielding 1 mg of tolvaptan per kg of body weight. Blood samples are collected from the jugular vein under light with ethyl ether anesthesia periodically after dosing, and serum concentrations of tolvaptan are determined when using UPLC-MS / MS (Waters). The results obtained are shown in Figure 2 and Table 6. Figure 2 shows the serum-time concentration profiles of tolvaptran after oral administration of solution A and suspension B (n = 4). Table 6 shows the average of the pharmacokinetic parameter values (n = 4). The parameters in table 6 have the following meanings. AUC8horaS: area under the curve in serum-time concentration for up to 8 hours after administration (ng hr / ml).

AUC8: area under the curve in serum-time concentration for up to an infinite time after administration (ng hr / ml). Cmax: maximum concentration in serum (ng / ml). Tmax time to reach the maximum serum concentration (hour). As a result, it is confirmed that the solution of the compound (1b) (solution A) takes a shorter time to reach the maximum serum concentration than the suspension of spray-dried tolvaptan (suspension B), and also leads to serum concentration much higher maximum (Cmax) and larger areas under the concentration curve in serum-time (AUC8hours, AUC8).

TABLE 6 AUCßhoras Cmax I max AUC8 (ng hr / ml) (ng hr / ml) (ng hr / ml) (ng-hr / ml) Solution A 217.5 61.0 1 .3 230.1 Suspension B 73.2 26.4 1 .5 76.1 These results reveal that when administered in vivo, the compound of the present invention, the compound (1 b) in particular, increases the absorption even more than the improved conventional absorption by depreciation, and consequently improves the bioavailability of tolvaptan.

EXAMPLE OF PREPARATION 1 An amount of 79 mg of dihydrated sodium dihydrogen phosphate and 5 g of mannitol are dissolved in approximately 90 ml of injection solvent. A solution of sodium hydroxide is added thereto, preparing a solution of pH 7. The compound (1 b) equivalent to 100 mg of tolvaptan is added to this solution. A solution of sodium hydroxide is added thereto, adjusting the pH to 7. Injection solvent is added to the obtained solution to obtain 100 ml, and sterile filtration is performed using a 0.2 μm filter to produce an injection of the present invention that contains compound (1 b) (equivalent to 1 mg of tolvaptan per ml of injection).

EXAMPLE OF PREPARATION 2 An amount of 79 mg of dihydrated sodium dihydrate phosphate and g of mannitol are dissolved in approximately 90 ml of injection solvent. A solution of sodium hydroxide is added to this, preparing a solution of pH 7.5. The compound (1 b) equivalent to 10 mg of tolvaptan is dissolved in the solution. Injection solvent is added to the obtained solution to obtain 100 ml, and sterile filtration is performed using a 0.2 μm filter to prepare an injection of the present invention containing compound (1 b) (equivalent to 0.1 mg tolvaptan per ml injection) ).

EXAMPLE OF PREPARATION 3 An amount of 380 mg of trisodium phosphate dodecahydrate and 4 g of mannitol are dissolved in approximately 90 ml of injection solvent. The compound (1 b) equivalent to 100 mg, 300 mg or 1000 mg of tolvaptan is dissolved in the obtained solution. When the compound (1 b) equivalent to 1000 mg of tolvaptan is dissolved, a solution of sodium hydroxide is added to improve the solubility. The pH of each solution obtained is adjusted from 8 to 9 with sodium hydroxide or hydrochloric acid, and an injection solvent is added thereto to obtain 100 ml. The obtained solution is filtered sterile through a 0.2 μm filter, preparing injections of the present invention containing compound (1 b) (equivalent to 1 mg, 3 mg or 10 mg of tolvaptan per ml of injection).

Claims

NOVELTY OF THE INVENTION CLAIMS

1. - A benzoazepine compound represented by the general formula (1) or a salt thereof, wherein R represents a hydrogen atom, a hydroxy group optionally protected with a protecting group, a mercapto group optionally protected with a protecting group, or an amino group optionally protected with one or two protecting groups, R1 represents a hydrogen atom or a hydroxy-protective group; and X represents an oxygen atom or sulfur atom.

2. The benzoazepine compound according to claim 1 or a salt thereof, further characterized in that X is an oxygen atom.

3. The benzoazepine compound in accordance with the claim 1 or 2, or a salt thereof, further characterized in that R is a hydroxy group optionally protected with a protecting group.

4. The benzoazepine compound according to claim 1 or 2, or a salt thereof, further characterized in that R is a hydrogen atom, a mercapto group optionally protected with a protecting group, or an amino group optionally protected with one or two protective groups.

5. The benzoazepine compound according to any of claims 1, 2, 3 and 4, or a salt thereof, further characterized in that R1 is a hydroxy-protective group.

6. The benzoazepine compound according to any of claims 1, 2, 3 and 4, or a salt thereof, further characterized in that R1 is a hydrogen atom.

7. The benzoazepine compound according to claim 1 or a salt thereof, further characterized in that X is a sulfur atom.

8. The benzoazepine compound according to claim 1 or a salt thereof, further characterized in that X is an oxygen atom, R is a hydroxy group, and R1 is a hydrogen atom.

9. A pharmaceutical composition comprising a benzoazepine compound according to claim 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and / or carrier.

10. - The pharmaceutical composition according to claim 9, for use as a vasodilator, hypotensor, aquaric agent, PKD, or platelet aggregation inhibitor.

11. An aqueous solution composition comprising a benzoazepine compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. The aqueous solution composition according to claim 11, further characterized in that it comprises a benzoazepine compound according to claim 1 or a pharmaceutically acceptable salt thereof, together with a pH regulator, isotonization agent and injection solvent. , and that is in the form of an injection.

13. The aqueous solution composition according to claim 12, further characterized in that it additionally comprises a pH adjuster.