HK1121461B

HK1121461B - Water-soluble benzoazepine compound and its pharmaceutical composition

Info

Publication number: HK1121461B
Application number: HK09101802.7A
Authority: HK
Inventors: 真小松; 文孝後藤; 康宏校条; 圭吾山田; 高邦松田; 雄介加藤
Original assignee: 大塚制药株式会社
Priority date: 2005-12-27
Filing date: 2006-12-22
Publication date: 2012-05-04

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., R1 represents 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

Water-soluble benzazepine compounds and pharmaceutical compositions thereof

Technical Field

The present invention relates to novel benzazepinesCompounds and pharmaceutical compositions thereof.

Background

Tolvaptan (Tolvaptan) represented by the following formula (2) is a known compound and has been disclosed, for example, in the specification of U.S. Pat. No. US 5,258,510 (example 1199).

Tolvaptan is known to have pro-drainage activity and is useful as vasopressin antagonist (Circulation, 107, pp.2690-2696 (2003)). However, due to its low water solubility, tolvaptan has problems in that its intestinal absorption is insufficient, the dosage form and administration route are limited, and the like. Although efforts have been made to solve these problems, for example, tolvaptan can be administered in the form of an amorphous solid preparation (Japanese unexamined patent publication No. 1999-21241), in this application, the dosage form and route of administration of tolvaptan are still limited.

Disclosure of Invention

The object of the present invention is to provide novel benzazepinesThe compound to improve the solubility of tolvaptan in water.

The inventors of the present invention have conducted extensive studies to solve the above problems and found that when tolvaptan is in the form of a phosphate compound, its water solubility can be significantly improved.

The present invention has been achieved based on this finding.

In particular, the present invention provides the following benzazepinesThe compound, and a composition comprising the compound, are described in items 1 to 13 below.

Item 1 Benzazepine represented by the general formula (1)Compound or salt thereof

Wherein R represents a hydrogen atom, a hydroxyl group optionally protected by a protecting group, a mercapto group optionally protected by a protecting group, or an amino group optionally protected by one or two protecting groups; r¹Represents a hydrogen atom or a hydroxyl-protecting group; x represents an oxygen atom or a sulfur atom.

Benzazepine according to item 2A compound or a salt thereof, wherein X is an oxygen atom.

Benzazepines according to item 1 or 2A compound or salt thereof, wherein R is hydroxy optionally protected by a protecting group.

Benzazepines according to item 1 or 2A compound or a salt thereof, wherein R is a hydrogen atom, a mercapto group optionally protected by a protecting group, or an amino group optionally protected by one or two protecting groups.

Item 5 benzazepine according to any one of items 1, 2, 3 and 4A compound or a salt thereof, wherein R¹Is a hydroxyl protecting group.

Item 6 benzazepine according to any one of items 1, 2, 3 and 4A compound or a salt thereof, wherein R¹Is a hydrogen atom.

Item 7 benzazepine according to item 1A compound or a salt thereof, wherein X is a sulfur atom.

Benzazepines according to item 8A compound wherein X is an oxygen atom, R is a hydroxyl group, R is a salt thereof¹Is a hydrogen atom.

Item 9A pharmaceutical composition comprising the benzazepine of item 1A compound or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable dilutionAn agent and/or a carrier.

The pharmaceutical composition according to item 9, which is used as a vasodilator, a hypotensive agent, a drainage promoting agent, PKD or a platelet aggregation inhibitor.

An aqueous solution composition comprising the benzazepine of item 1A compound or a pharmaceutically acceptable salt thereof.

The aqueous solution composition according to item 12 or 11, which comprises the benzazepine of item 1A compound or a pharmaceutically acceptable salt thereof, and a buffer, an isotonicity agent and a solvent for injection, which are in the form of an injection.

The aqueous solution composition according to item 12, which further comprises a pH adjusting agent.

As used herein, "lower" means C unless otherwise indicated_1-6。

Examples of the protecting group in "hydroxy optionally protected by a protecting group", "mercapto optionally protected by a protecting group" and "hydroxy protecting group" include lower alkyl, phenyl (lower) alkyl, cyano lower alkyl and lower alkoxycarbonyl lower alkyl.

Examples of the protecting group in "amino group optionally protected by one or two protecting groups" include lower alkyl groups optionally having hydroxyl group.

Examples of the lower alkyl group in phenyl (lower) alkyl, cyano lower alkyl, lower alkoxycarbonyl lower alkyl and lower alkyl optionally having hydroxyl group include C_1-6Straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl and the like。

Preferred phenyl (lower) alkyl groups are, for example, benzyl, phenethyl, 3-phenylpropyl, trityl and the like.

Preferred cyano lower alkyl is C substituted by one to three cyano groups_1-6Straight-chain or branched alkyl radicals, for example cyanomethyl, 2-cyanoethyl, 1-, 2-or 3-cyano-n-propyl, 1-, 2-or 3-cyanoisopropyl, 1-, 2-, 3-or 4-cyano-n-butyl, 1-, 2-, 3-or 4-cyanoisobutyl, 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-cyanoisopentyl, 1-, 2-, 3-, 4-or 5-cyanoneopentyl, 1-, 2-, 3-, 4-, 5-or 6-cyano-n-hexyl, 1-, 2-, 3-, 4-, 5-or 6-cyanoisohexyl, 1-, 2-, 3-, 4-, 5-or 6-cyano-3-methylpentyl and the like.

Preferred lower alkoxycarbonyl lower alkyl is one wherein the alkoxy moiety is C_1-6Straight or branched alkoxy and the alkyl moiety is C_1-6Alkoxycarbonylalkyl groups which are straight-chain or branched alkyl groups, such as methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, isopropoxycarbonylmethyl, n-butoxycarbonylmethyl, isobutoxycarbonylmethyl, n-pentyloxycarbonylmethyl, n-hexyloxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl and the like.

Preferred lower alkyl optionally bearing hydroxy is C optionally substituted by one to three hydroxy_1-6Straight-chain or branched alkyl radicals, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-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-hydroxyisopropyl, 1-, 2-, 3-or 4-hydroxy-n-butyl, 1-, 2-, 3-or 4-hydroxyisobutyl, 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-, I-, N-propyl, N-pentyl, isopentyl, neopentyl, 2-, 3-, 4-or5-hydroxyisopentyl, 1-, 2-, 3-, 4-or 5-hydroxypivalyl, 1-, 2-, 3-, 4-, 5-or 6-hydroxyn-hexyl, 1-, 2-, 3-, 4-, 5-or 6-hydroxyisohexyl, 1-, 2-, 3-, 4-, 5-or 6-hydroxy-3-methylpentyl and the like.

Preferred amino groups optionally substituted with one or two protecting groups are optionally bearing one or two C_1-6Amino of a linear or branched alkyl radical, said C_1-6The straight-chain or branched alkyl group optionally has one to three hydroxyl groups, for example, amino group, methylamino group, dimethylamino group, ethylamino group, diethylamino group, n-propylamino group, di-n-propylamino group, isopropylamino group, diisopropylamino group, n-butylamino group, di-n-butylamino group, isobutylamino group, diisobutylamino group, tert-butylamino group, di-tert-butylamino group, n-pentylamino group, di-n-pentylamino group, n-hexylamino group, di-n-hexylamino group, hydroxymethylamino group, 2-hydroxyethylamino group, diethylamino group, di- (2-hydroxyethyl) amino group, 3-hydroxypropylamino group, 4-hydroxybutylamino group and the like.

Benzazepine represented by the above general formula (1)Among the compounds, the following compounds and salts thereof are preferred:

when X is an oxygen atom, the compound is,

(1) r is hydroxy and R¹Is a compound of a hydrogen atom, and is,

(2) r is hydroxy and R¹Is a compound which is a protecting group for a hydroxyl group,

(3) r is mercapto and R¹A compound which is a hydroxy protecting group, and

(4) r is an amino group protected by one or two protecting groups and R¹A compound that is a hydroxy protecting group; and

when X is a sulfur atom, the sulfur atom,

(1) r is hydroxy and R¹Is a hydrogen atom or a hydroxyl protecting group.

Particularly preferred among these compounds are those in which X is an oxygen atom, R is a hydroxyl group and R is¹A compound which is a hydrogen atom or a salt thereof.

Benzazepine represented by the above general formula (1)The compounds can be prepared by a variety of methods, examples of which are shown in the following reaction schemes 1 to 7:

reaction scheme-1

Wherein R is³And R⁴Independently is lower alkyl or optionally substituted phenyl, or R³And R⁴May also be linked together, with or without one or more other heteroatoms, to form a 5-to 8-membered saturated or unsaturated ring together with the nitrogen atom to which it is linked; and R is^1aAnd R^2aWhich may be the same or different, each represents a hydroxyl protecting group.

Examples of lower alkyl groups are as described above, including C_1-6Straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl and the like.

Examples of the substituent of the optionally substituted phenyl group include the above-mentioned lower alkyl groups; c_1-6A straight-chain or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy and the like; and halogen atoms such as fluorine, chlorine, bromine, iodine, etc.

Preferred examples of the optionally substituted phenyl group include phenyl groups; 2-, 3-or 4-methylphenyl; 2-, 3-or 4-chlorophenyl; 2-, 3-, or 4-methoxyphenyl, and the like.

From R³And R⁴The 5-to 8-membered saturated or unsaturated ring formed by the linkage includes a morpholine ring and the like.

Compound (4) can be prepared by reacting compound (2) with compound (3) in the presence of an acid in a suitable solvent.

Examples of the solvent include halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and the like; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; acetonitrile, and the like.

Examples of acids include weak acids such as 1H-tetrazole, 5-methyltetrazole, pyridine hydrobromide, and the like.

The amount of acid is generally at least about 1 mole of acid, preferably from about 1 to about 10 moles of acid per mole of compound (2).

The amount of the compound (3) is usually 0.5 to 2 moles, preferably 0.7 to 1.5 moles, of the compound (3) per mole of the compound (2).

The reaction temperature is usually from-20 ℃ to 50 ℃, preferably from 0 ℃ to 50 ℃, more preferably from 0 ℃ to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 1 to 3 hours.

Compound (1a) can be produced by reacting compound (4) with an oxidizing agent in a suitable solvent.

Examples of oxidizing agents include peracids, such as hydrogen peroxide, and m-chloroperbenzoic acid, peracetic acid, permaleic acid, and the like.

The amount of the oxidizing agent is usually at least about 1 mole, preferably about 1 to about 3 moles, per mole of the compound (4).

The reaction temperature is usually from-100 ℃ to 50 ℃, preferably from-40 ℃ to room temperature, more preferably from-40 ℃ to 0 ℃. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 30 minutes to 2 hours.

Compound (1b) can be obtained from compound (1a) by removing the hydroxyl protecting group by a conventional method.

For example, when the hydroxy protecting group is lower alkyl, deprotection can be carried out under conventional hydrolysis conditions.

Such hydrolysis is preferably carried out in the presence of a base or an acid (including lewis acids).

A large number of known inorganic and organic bases can be used as such bases. Preferred inorganic bases are, for example, alkali metals (e.g., sodium, potassium, etc.); alkaline earth metals (e.g., magnesium, calcium, etc.); and hydroxides, carbonates and bicarbonates thereof. Preferred organic bases are, for example, trialkylamines (e.g., trimethylamine, triethylamine, etc.), picoline and 1, 5-diazabicyclo [4, 3, 0] non-5-ene.

A large number of known organic and inorganic acids can be used as such acids. Preferred organic acids are fatty acids, for example, formic acid, acetic acid, propionic acid, and the like; and trihaloacetic acids such as trichloroacetic acid, trifluoroacetic acid and the like. Preferred inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, and the like. Examples of lewis acids include boron trifluoride ether complex, boron tribromide, aluminum chloride, ferric chloride, and the like.

When trihaloacetic acid or lewis acid is used, the hydrolysis is preferably carried out in the presence of a cation scavenger (e.g., anisole, phenol, etc.).

The amount of base or acid is not limited provided that the hydrolysis needs are met.

The reaction temperature is usually from-20 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃, more preferably from 0 ℃ to room temperature. The reaction time is usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours, more preferably 15 minutes to 3 hours.

For example, when the hydroxyl protecting group is phenyl (lower) alkyl, deprotection can be carried out by conventional catalytic reduction.

Suitable catalysts for this catalytic reduction are platinum catalysts (for example, platinum sheet, platinum sponge, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (for example, palladium sponge, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, palladium/barium carbonate, etc.), nickel catalysts (for example, reduced nickel, nickel oxide, raney nickel, etc.), cobalt catalysts (for example, reduced cobalt, raney cobalt, etc.), iron catalysts (for example, reduced iron, etc.), and the like. When a palladium on carbon catalyst is used, the catalytic reduction is preferably carried out in the presence of zinc bromide.

The amount of the catalyst used for the catalytic reduction is not limited and may be a conventional amount.

The reaction temperature is usually from-0 ℃ to 100 ℃, preferably from 0 ℃ to 50 ℃, more preferably from room temperature to 50 ℃. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 3 hours, more preferably 5 minutes to 1 hour.

Reaction scheme-2

The compound (2) is reacted with phosphorus oxychloride and then hydrolyzed to give a compound (1 b).

The amount of phosphorus oxychloride is usually from 1 mole to a large excess, preferably from 1 to 5 moles, per mole of compound (2).

The above reaction is carried out in a suitable solvent in the presence of a basic compound.

Examples of the solvent used for the phosphorus oxychloride reaction include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoethylene glycol dimethyl ether (monoglyme), diethylene glycol dimethyl ether and the like; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and the like; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; acetonitrile, and the like.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides such as calcium hydroxide and the like; phosphates such as potassium phosphate, sodium phosphate, etc.; organic bases such as 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), etc.; and mixtures thereof.

The amount of the basic compound is usually at least about 3 moles, preferably about 3 to about 10 moles, per mole of the compound (2). The reaction temperature is usually from-100 ℃ to 50 ℃, preferably from-50 ℃ to room temperature, more preferably from-30 ℃ to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 1 to 3 hours.

Hydrolysis may be accomplished by adding water to the reaction mixture described above or by adding the reaction mixture to water.

Since this reaction is usually accompanied by decomposition of excess reagents and thereby heat generation, the hydrolysis is preferably carried out under cooling. To complete the reaction, it is preferable to perform heating after the initial reaction is weakened.

The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 1 to 3 hours.

Reaction scheme-3

Wherein R is¹The same as above.

Reaction of Compound (2) with Diphenyl phosphiteShould then be reacted with alcohol (R)¹OH) to obtain a compound (1 c).

The amount of diphenyl phosphite is generally from 1 mole to a large excess, preferably from 1 to 5 moles, of diphenyl phosphite per mole of compound (2). Alcohol (R)¹OH) is generally used in a molar amount of from 1 to a large excess, preferably from 1 to 10 mol, of alcohol (R) per mole of compound (2)¹OH)。

Examples of the solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and the like; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; and (3) acetonitrile.

The amount of the basic compound is usually at least about 1 mole, preferably from about 1 to about 10 moles, per mole of the compound (2). Organic solvents may also be used as solvents.

The reaction temperature is usually from-100 ℃ to 50 ℃, preferably from-50 ℃ to room temperature, more preferably from-30 ℃ to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 30 minutes to 6 hours, more preferably 1 to 3 hours.

Reaction scheme-4

Wherein R is¹The same as above.

The oxidation of the phosphite can be carried out using from about 1 to about 3 equivalents of the phosphorous acid oxidizing agent and at a reaction temperature ranging from about 0 ℃ to about 50 ℃. Preferably, the reaction is carried out with a phosphorous acid oxidizing agent in an excess of about 5% to 15% at a temperature between 0 ℃ and room temperature.

Phosphorous acid oxidants are reagents that oxidize phosphites to phosphates. Examples include peroxides, such as hydrogen peroxide; m-chloroperbenzoic acid, etc.; iodine in the water; bromine; dinitrogen tetroxide, and the like. Iodine in water is preferred.

The above reaction is carried out in a suitable solvent.

Examples of the solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, etc.; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; acetonitrile; and pyridine.

The reaction temperature is usually from-100 ℃ to 50 ℃, preferably from-50 ℃ to room temperature, more preferably from-30 ℃ to room temperature. The reaction time is usually 15 minutes to 24 hours, preferably 15 minutes to 6 hours, more preferably 15 minutes to 3 hours.

Reaction scheme-5

Wherein R is¹Same as above; and R is¹¹And R¹²May be the same or different, each independently represents a hydrogen atom or a lower group optionally having a hydroxyl groupAn alkyl group.

Amine (R)¹¹R¹²NH) and carbon tetrachloride with the phosphorous acid diester (1c) to give the phosphoric acid amide (1 e).

Sodium hypochlorite can also be used instead of carbon tetrachloride.

The amount of carbon tetrachloride is usually 1 mole to a large excess, preferably 1 to 5 moles, per mole of the compound (1 c). Amine (R)¹¹R¹²NH) is usually employed in an excess of from 1 to a large amount, preferably from 1 to 10 mol, of amine (R) per mole of compound (1c)¹¹R¹²NH)。

Examples of the solvent include ethers such as diethyl ether, dioxane, tetrahydrofuran, monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and the like; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; acetonitrile; and the like.

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides such as calcium hydroxide and the like; phosphates such as potassium phosphate, sodium phosphate, etc.; organic bases such as 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), etc.; and mixtures thereof. The amount of the basic compound is usually at least about 1 mole, preferably from about 1 to about 10 moles, per mole of the compound (2). Organic solvents may also be used as solvents.

The reaction temperature is usually from-100 ℃ to 50 ℃, preferably from-50 ℃ to room temperature, more preferably from-30 ℃ to room temperature. The reaction time is usually 1 minute to 24 hours, preferably 1 minute to 6 hours, more preferably 1 minute to 3 hours.

Reaction scheme-6

Wherein R is¹The same as above.

The phosphorous acid diester (1c) is reacted with sulfur to give a thiophosphoric acid diester (1 f).

The amount of sulfur is usually 1 mole to a large excess amount, preferably 1 to 5 moles, per mole of the compound (1 c).

Examples of the basic compound include carbonates such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, cesium carbonate and the like; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, etc.; alkaline earth metal hydroxides such as calcium hydroxide and the like; phosphates such as potassium phosphate, sodium phosphate, etc.; alkali metal hydrides such as sodium hydride, potassium hydride and the like; alkali metals such as potassium, sodium, etc.; sodium amide; metal alcoholates such as sodium methoxide, sodium ethoxide, sodium n-butoxide, sodium t-butoxide, potassium t-butoxide and the like; organic bases such as 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), etc.; and mixtures thereof. The amount of the basic compound is usually at least about 1 mole, preferably from about 1 to about 10 moles, per mole of the compound (2). Organic solvents may also be used as solvents.

Reaction scheme-7

Wherein R is¹Is a hydroxyl protecting group.

The protecting group of the Compound (1g) is a Compound (1f) obtained by reaction scheme 6, wherein R¹Is a hydroxyl-protecting group, and the protecting group of compound (1g) is removed to give compound (1 h).

When R is¹In the case of cyanoethyl, the protecting group can be removed by using a basic compound.

Examples of the solvent include water; alcohols such as methanol, ethanol, isopropanol, and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran, monoethylene glycol dimethyl ether, diethylene glycol dimethyl ether, and the like; halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1, 2-dichloroethane, carbon tetrachloride and the like; esters such as ethyl acetate and the like; aromatic hydrocarbons such as benzene, toluene, xylene, etc.; aprotic polar solvents such as Dimethylformamide (DMF), Dimethylsulfoxide (DMSO), and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, and the like; acetonitrile; and mixtures thereof.

The compounds (2), (3), (4), (1a), (1b), (1c), (1d), (1e), (1f), (1g) and (1h) in the above reaction scheme may be suitable salts thereof. Examples of such suitable salts include salts of the same kind as the compound (1).

The compound obtained according to the above reaction scheme can be isolated and purified from the reaction mixture by a conventional manner, for example, after the reaction mixture is cooled, the crude product is isolated by filtration, concentration, extraction or the like, and then the product is purified by column chromatography, recrystallization or the like conventional purification methods.

The compound represented by the general formula (1) of the present invention includes stereoisomers, optical isomers and solvates (hydrates, ethanolates, etc.) thereof.

Examples of the salt of the compound represented by the general formula (1) of the present invention include pharmaceutically acceptable salts such as metal salts, for example, alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, magnesium salt, etc.), etc.; an ammonium salt; organic base salts (e.g., trimethylamine salt, triethylamine salt, pyridine salt, picoline salt, dicyclohexylamine salt, ethylenediamine salt, N' -dibenzylethylenediamine salt, tris (hydroxymethyl) aminomethane salt, ethanolamine salt, etc.); and so on. Among these, alkali metal salts are preferred, and sodium salts are more preferred.

Such salts can be readily formed by reacting a compound of the present invention with a corresponding pharmaceutically acceptable basic compound. Examples of the applicable basic compound include sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium hydrogencarbonate and the like.

The compounds of the present invention have, for example, vasopressin antagonistic action, vasodilating activity, hypotensive activity, hepatic carbohydrate release inhibitory activity, mesangial cell growth inhibitory activity, aquaretic activity and platelet aggregation inhibitory activity. The compounds are useful as vasodilators, hypotensives, drainage promoting agents and platelet aggregation inhibitors, and are effective in the prevention and treatment of hypertension, edema (e.g., cardiac edema, hepatic edema, renal edema, cerebral edema), ascites disease, heart failure (e.g., severe heart failure), renal dysfunction, vasopressin secretion dysfunction Syndrome (SIADH), liver cirrhosis, hyponatremia, hypokalemia, diabetes, circulatory insufficiency, Polycystic Kidney Disease (PKD), cerebral infarction, myocardial infarction and the like.

When administered as a medicament to a human, the compounds of the present invention may be used simultaneously or separately with other vasopressin antagonists, ACE inhibitors, beta-blockers, aquaretic agents, angiotensin II Antagonists (ARBs), digoxin and/or the like.

The compounds of the present invention are generally used in the form of a general pharmaceutical composition. Such pharmaceutical compositions may be prepared by conventional methods using commonly used diluents and/or excipients such as fillers, bulking agents, binders, wetting agents, disintegrants, surfactants, lubricants and the like.

The form of the pharmaceutical composition comprising the compound of the present invention may be selected accordingly depending on the therapeutic purpose. It may be, for example, in the form of tablets, pills, powders, solutions, suspensions, emulsions, capsules, suppositories, ointments or granules. Particularly preferred are aqueous solution compositions such as injections, instillations and the like.

For example, when an injection is prepared using the compound of the present invention, such an injection is preferably formulated as a solution, emulsion or suspension that has been sterilized and is isotonic with blood. Any diluent commonly used in the art may be used to prepare such solutions, emulsions or suspensions using the compounds of the present invention. Examples of such diluents include water, aqueous lactic acid solution, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxyisostearyl alcohol and polyoxyethylene sorbitan fatty acid ester. In addition, in this case, sodium chloride, dextrose, mannitol, glycerol, and the like can be incorporated into the pharmaceutical composition in amounts sufficient to prepare an isotonic solution. Common pH regulator, solubilizer, buffer, soothing agent, etc. can also be added.

An injection comprising the compound of the present invention can be prepared by a conventional method using the compound represented by the general formula (1) or a pharmaceutically acceptable salt thereof, and a buffer, an isotonic agent, an injection solvent and, if necessary, a pH adjusting agent.

Examples of buffers include carbonate, borate, phosphate, citrate, tris (hydroxymethyl) aminomethane, malate, and tartrate buffers. The acid or base forming such a buffer may also be used alone.

Examples of the pH adjuster include basic compounds such as sodium hydroxide and the like; acids such as hydrochloric acid and the like.

In addition, coloring agents, preservatives, aromatic agents, flavoring agents, sweetening agents, and the like, and other drugs may be mixed in the pharmaceutical composition as necessary.

The content of the compound represented by the general formula (1) or a salt thereof in the pharmaceutical composition of the present invention is not limited and may be suitably selected from a wide range. It is usually present in an amount of 0.01 to 70 wt% of the pharmaceutical composition.

The administration form of such a pharmaceutical composition is not limited, and an appropriate administration form may be adopted depending on the form of the pharmaceutical composition, the age, sex, etc. of the patient, the degree of symptoms of the patient, etc. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules can be administered orally. The injection can be administered intravenously alone or as a mixture with glucose, amino acids and/or similar common supplements. The injection can also be singly administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally as required.

The dosage of the pharmaceutical composition of the present invention can be selected according to the use, age, sex, etc. of the patient, the degree of the disease, etc. The dose is usually such that the compound represented by the general formula (1) as an active ingredient is administered in an amount of 0.001 to 100mg, preferably 0.001 to 50mg, per kg of body weight per day in one or more administrations.

The dosage varies with different conditions. Doses less than the above range may be sufficient, while doses greater than the above range may also be necessary.

The patents, patent applications, and literature cited herein are incorporated herein by reference.

Effects of the invention

The compound (1) or a salt thereof of the present invention has excellent water solubility, excellent absorbability and the like.

In particular, the compound (1b) or a salt thereof has excellent water solubility, excellent absorbability and the like.

When administered to a human body, the compound (1) or a salt thereof, particularly the compound (1b) or a salt thereof, of the present invention makes it easy to produce tolvaptan as an active ingredient.

Further, the compound (1) or a salt thereof of the present invention is easily crystallized and has excellent operability. In addition, the compound (1) of the present invention or a salt thereof has excellent chemical stability.

The compound (1a) of the present invention is suitably used as a starting material for the preparation of the compound (1 b).

The use of the compound (1) of the present invention or a salt thereof provides a composition in various forms of a drug having a potency equivalent to that of the effective drug tolvaptan.

Brief description of the drawings

FIG. 1 shows the change in serum concentration of tolvaptan after rapid administration of a compound (1b) solution to female rats via the tail vein at a dose yielding 1mg of tolvaptan per kg body weight.

FIG. 2 shows the change in serum concentration of tolvaptan after oral administration of a compound (1b) solution at a dose yielding 1mg of tolvaptan per kg body weight to female rats.

Best mode for carrying out the invention

Examples, test examples and preparation examples are given below to illustrate the present invention in further detail, but the scope of the present invention is not limited to these examples.

Example 1

1.0g of tolvaptan (compound (2)) and 460mg of 1H-tetrazole were dissolved in 30ml of dichloromethane, and 1.2g of diisopropylphosphoramidite dibenzyl ester was added dropwise to the solution at room temperature with stirring. The mixture was then stirred at the same temperature for 2 hours.

The resulting reaction mixture was cooled to-40 ℃ and 6ml of a solution of 920mg of m-chloroperbenzoic acid in dichloromethane were added dropwise thereto. The mixture was stirred at the same temperature for 30 minutes and at 0 ℃ for 30 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The resulting reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate: 1) to obtain 1.5g of amorphous compound (1a-1) (yield 97.2%).

NMR(DMSO-d₆，100℃)δppm；9.86(1H，brs)，7.56(1H，s)，7.50-7.10(17H，m)，7.00-6.80(2H，m)，5.60-5.50(1H，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

4.5g of tolvaptan (compound (2)) and 2.2g of 1H-tetrazole were dissolved in 120ml of dichloromethane, and a solution of 4.0g of di-tert-butyl diisopropylphosphoramidite in 10ml of dichloromethane was added dropwise to the solution under ice cooling and stirring. The mixture was then stirred at room temperature for 2 hours.

The resulting reaction mixture was cooled to-40 ℃ and 20ml of a solution of 4.0g of m-chloroperbenzoic acid in methylene chloride was added dropwise thereto. The mixture was then stirred at the same temperature for 30 minutes and at 0 ℃ for 40 minutes. The reaction mixture was washed with an aqueous sodium thiosulfate solution and a saturated aqueous sodium bicarbonate solution, and then dried over anhydrous sodium sulfate. The resulting reaction mixture was filtered and concentrated, and the residue was purified by silica gel column chromatography (eluent: n-hexane: ethyl acetate: 1) to obtain 3.0g of amorphous compound (1a-2) (yield 46.7%).

NMR(DMSO-d₆)δppm；10.50-10.20(1H，m)，8.00-6.50(10H，m)，5.55-5.20(1H，m)，4.90-4.50(1H，m)，2.85-2.60(1H，m)，2.40-2.20(6H，m)，2.20-1.60(4H，m)，1.60-1.30(18H，m)

Example 3

5.3g of the compound (1a-1) was dissolved in 100ml of ethanol, and the solution was subjected to catalytic reduction reaction at room temperature and atmospheric pressure for 10 minutes using 2g of 5% palladium on carbon as a catalyst. The catalyst in the solution was removed by filtration, and the resulting filtrate (4.2g) was concentrated. The resulting residue was crystallized from methanol/water. The crystals were collected by filtration and then dried under reduced pressure (phosphorus pentoxide), to give 3.5g of compound (1b) as a white powder (yield 88.5%).

Melting point: 150 to 152 DEG C

NMR(DMSO-d₆-D₂O，100℃)δppm；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

3.0g of the compound (1a-2) was dissolved in 100ml of dichloromethane, and a solution of 10ml of trifluoroacetic acid in 5ml of dichloromethane was added dropwise to the solution under ice cooling and stirring. The mixture was then stirred at the same temperature for 2 hours. The solvent is removed from the solution. The residue was redissolved in dichloromethane and then concentrated. The resulting residue was crystallized from methanol/water. The crystals were collected by filtration and then dried under reduced pressure (phosphorus pentoxide), to give 1.9g of compound (1b) as a white powder (yield 76.8%).

Example 5

To 30g (66mmol) of tolvaptan (compound (2)) were added 240ml of 1, 2-Dimethoxyethane (DME) and 84ml of triethylamine (0.60mol, 9 equivalents), and the mixture was cooled to-15 ℃ under a nitrogen stream. 19ml (0.20mol, 3 equivalents) of phosphorus oxychloride were added dropwise to the obtained mixture at an internal temperature of not more than-12 ℃ and stirred at-12 ℃ for 2 hours. 200ml of a 5N aqueous sodium hydroxide solution was added to 1kg of crushed ice, and the above reaction mixture was added thereto in small portions with stirring. To the resulting mixture was added 500ml of toluene. The mixture was heated to 50 ℃ and then separated into an aqueous layer and a toluene layer. 500ml of toluene was again added to the aqueous layer, and the mixture was stirred at 50 ℃ to separate the mixture into an aqueous layer and a toluene layer. The aqueous layer was allowed to cool to 10 ℃, 80ml of 6N hydrochloric acid was added thereto, and extraction was performed twice with 500ml of ethyl acetate. The extract was dried over sodium sulfate and filtered, and the filtrate was concentrated. The concentrated solution was dried under reduced pressure at room temperature to obtain 34g of amorphous compound (1 b).

Yield: 97 percent

Example 6

Preparation of calcium salt of Compound (1b)

(1) 2.6g (5.0mmol) of the compound (1b) was dissolved in 25ml of isopropanol, and 2.2ml of a 5N aqueous sodium hydroxide solution was added at room temperature. The resulting mixture was concentrated under reduced pressure. To the residue was added 30ml of water to dissolve the solid, followed by addition of 0.61g (5.5mmol) of an aqueous solution of calcium chloride. The precipitated solid was collected by filtration, washed with water, and dried with hot air at 60 ℃ to obtain 2.2g of a calcium salt of the compound (1b) as a white powder.

Yield: 78 percent of

¹H-NMR(DMSO-d₆，100℃)δppm：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) 280mg (0.53mmol) of the compound (1b) was dissolved in a mixed solution of 2ml of methanol and 1ml of water, and 43mg (0.58mmol) of calcium hydroxide was then added. The mixture was stirred at room temperature for 1 hour. The precipitated solid was collected by filtration. The filtered material was suspended in methanol, stirred with heating and then filtered hot. The filtrate was concentrated, and the residue was recrystallized from methanol to obtain 75.4mg of a white powdery calcium salt of compound (1 b).

Yield: 25 percent of

Melting point: 263 to 265 deg.C

Example 7

Preparation of magnesium salt of Compound (1b)

(1) 1.0g (1.9mmol) of compound (1b) was dissolved in 15ml of methanol, and 0.76ml of a 5N aqueous sodium hydroxide solution was added. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 10ml of methanol, and 3ml of a 0.18g methanol solution of magnesium chloride was added to the obtained solution at room temperature. Insoluble precipitate (NaCl) was removed by filtration, and the filtrate was concentrated. To the residue was added 10ml of water, followed by heating and stirring. The stirred mixture was allowed to cool to room temperature. Then, the insoluble matter was collected by filtration, washed with water, and dried under reduced pressure at 60 ℃ to obtain 400mg of a magnesium salt of the compound (1b) as a white powder.

Yield: 38 percent of

¹H-NMR(DMSO-d₆，100℃)δppm：1.4-2.4(10H，m)，2.8-4.5(2H，m)，5.3-5.5(1H，m)，6.4-7.8(10H，m)，9.7(1H，br)

(2) 282mg (0.53mmol) of the compound (1b) was dissolved in 2ml of methanol, and 41mg (0.70mmol) of magnesium ethoxide was added under ice-cooling. To the obtained mixture were further added 2ml of ethanol and an aqueous suspension (0.5ml) of 36mg (0.58mmol) of magnesium hydroxide, and the mixture was stirred at room temperature for 1 hour. Insoluble material was removed by filtration and the filtrate was allowed to stand overnight. The precipitated solid was collected by filtration and then dried under reduced pressure to obtain 24.9mg of a magnesium salt of compound (1b) as a white powder.

Yield: 11 percent of

Melting point: 250 to 252 DEG C

Example 8

Preparation of the monosodium salt of Compound (1b)

0.5ml of a 1N aqueous sodium hydroxide solution and 1ml of water were added to a 266mg (0.5mmol) of a methanol solution (2ml) of the compound (1b) under ice-cooling, and the resulting solution was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-water to give 45.2mg of a monosodium salt of compound (1b) as a white powder.

Yield: 16 percent of

Melting point: 235 to 238 DEG C

Example 9

Preparation of disodium salt of Compound (1b)

1.0ml of a 1N aqueous solution of sodium hydroxide was added to a solution of 276mg (0.52mmol) of the compound (1b) in methanol (2ml) under ice-cooling, and the resulting mixture was stirred at room temperature for 5 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from acetone-water to give 221mg of the disodium salt of compound (1b) as a white powder.

Yield: 73 percent

Melting point: 250 to 252 DEG C

Example 10

Preparation of the diammonium salt of Compound (1b)

1.0ml of a 25% aqueous ammonia solution was added to a solution of 271mg (0.51mmol) of the compound (1b) in methanol (2ml) under ice-cooling, and the resulting mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methanol-water to give 104mg of the diammonium salt of compound (1b) as a white powder.

Yield: 36 percent

Melting point: 195 to 198 deg.C

Example 11

Preparation of Monosylvite salt of Compound (1b)

0.5ml of a 1N aqueous potassium hydroxide solution was added to a solution of 276mg (0.52mmol) of the compound (1b) in methanol (2ml) under ice-cooling, and the resulting mixture was stirred for 10 minutes. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from isopropanol to give 110.6mg of a monopotassium salt of compound (1b) as a white powder.

Yield: 37 percent of

Melting point: 200 to 203 DEG C

Example 12

Preparation of dipotassium salt of Compound (1b)

1.0ml of a 1N aqueous potassium hydroxide solution was added to a solution of 276mg (0.52mmol) of the compound (1b) in methanol (2ml) under ice-cooling, and the resulting mixture was stirred for 5 minutes. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. The insoluble matter was collected by filtration and dried to obtain 273.9mg of the dipotassium salt of compound (1b) as a white powder.

Yield: 86 percent of the total weight

Melting point: 255 to 265 deg.C (decomposition)

Example 13

Preparation of Zinc salt of Compound (1b)

1.0g (1.9mmol) of the compound (1b) was dissolved in 15ml of methanol, and 0.76ml of a 5N aqueous sodium hydroxide solution was added to the solution. The mixture was concentrated under reduced pressure. The residue obtained is dissolved in 10ml of methanol and 3ml of a solution of 259mg of zinc chloride in methanol are added at room temperature. Insoluble precipitate (NaCl) was removed by filtration, and the filtrate was concentrated. To the obtained residue was added 10ml of water, followed by heating and stirring. The mixture was then allowed to cool to room temperature. The insoluble matter was collected by filtration, washed with water, and dried under reduced pressure at 60 ℃ to obtain 900mg of the zinc salt of the compound (1b) as a white powder.

Yield: 80 percent of

Melting point: 235 to 239 deg.C (decomposition)

¹H-NMR(DMSO-d₆，100℃)δppm：1.3-2.4(10H，m)，2.8-4.5(2H，m)，5.3-5.7(1H，m)，6.6-7.7(10H，m)，9.7(1H，br)

Example 14

Preparation of ethylenediamine salt of Compound (1b)

0.074ml (1.1mmol) of ethylenediamine was added to a solution of 600mg (1.1mmol) of the compound (1b) in ethanol (10 ml). The resulting reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from isopropanol to give 250mg of ethylenediamine salt of compound (1b) as a white powder.

¹H-NMR(DMSO-d₆，100℃)δppm：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(1H，m)，6.6-6.9(1H，m)，6.9-7.2(2H，m)，7.2-7.5(5H，m)，7.58(2H，d，J＝7.6Hz)，9.80(1H，br)

Example 15

Preparation of Diethanolamine salt of Compound (1b)

0.14ml (2.3mmol) of ethanolamine was added to a solution (6ml) of 600mg (1.1mmol) of the compound (1b) in isopropanol. To the resulting mixture was added 6ml of isopropyl alcohol, dissolved by heating, and recrystallized from isopropyl alcohol to obtain 280mg of a diethanolamine salt of the compound (1b) as a white powder.

¹H-NMR(DMSO-d₆，100℃)δppm：1.4-2.0(3H，m)，2.2-2.5(7H，m)，2.75(4H，t，J＝5.5Hz)，3.52(4H，t，J＝5.5Hz)，2.8-4.3(2H，m)，5.3-5.5(1H，m)，6.7-6.9(1H，m)，6.9-7.2(2H，m)，7.2-7.4(4H，m)，7.42(1H，d，J＝7.7Hz)，7.57(2H，d，J＝6.5Hz)，7.58(2H，d，J＝7.6Hz)，9.80(1H，br)

Example 16

1.3ml (6.6mmol) of diphenyl phosphite was added to a pyridine solution (10ml) of 1.0g (2.2mmol) of tolvaptan (compound (2)) under ice-cooling. The resulting mixture was stirred at 0 ℃ for 30 minutes and then at room temperature for 30 minutes. To the reaction mixture was added 0.58ml of ethanol, and the mixture was stirred at room temperature for 30 minutes. To the mixture was added 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate, then filtered, and the filtrate was concentrated. The obtained residue was purified by silica gel column chromatography (n-hexane: ethyl acetate ═ 27: 73 → 0: 100). The purified product was concentrated under reduced pressure, and the residue was dissolved in a mixed solvent of 10ml of acetonitrile and 10ml of water, followed by freeze-drying to obtain 450mg of the objective compound as a white amorphous solid.

Yield: 38 percent of

¹H-NMR (toluene-d)₈，100℃)δppm：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＝4.8Hz)，6.4-7.5(10H，m)，7.8(0.5H，d，J＝8.6Hz)

Example 17

To a pyridine solution (50ml) of 10.0g (22mmol) of tolvaptan (compound (2)) was slowly added 13ml (66mmol) of diphenyl phosphite under a nitrogen atmosphere with ice cooling. The resulting mixture was stirred at room temperature for 30 minutes, and 4.5ml of methanol was added to the mixture, followed by stirring at room temperature for 30 minutes. The resulting reaction mixture was added to 325ml of 2N hydrochloric acid under ice-cooling, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 93: 7). The purified product was concentrated under reduced pressure to obtain 10.5g of the objective compound as a white amorphous solid.

Yield: 91 percent

¹H-NMR (toluene-d)₈，100℃)δppm：1.5-2.0(4H，m)，2.41(3H，s)，2.49(3H，s)，3.0-4.2(2H，m)，5.5(0.5H，d，J＝4.8Hz)，5.5-5.8(1H，m)，6.6(1H，d，J＝8.3Hz)，6.7-6.9(1H，m)，6.9-7.2(6H，m)，7.3-7.5(2H，m)，7.81，7.84(0.5H，d，J＝8.1Hz)

Example 18

0.1ml of water and 254mg (1.0mmol) of iodine were added to 500mg (0.95mmol) of a pyridine solution (5ml) of the compound of example 17, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture was added 2ml triethylamine and concentrated under reduced pressure. To the residue was added 20ml of toluene, and concentrated under reduced pressure. Water was added to the residue, and the residue was washed with a mixed solvent of ethyl acetate and diethyl ether. To the aqueous layer was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (dichloromethane: methanol 90: 10 → 60: 50). The purified product was concentrated under reduced pressure and the residue was dissolved in 30ml of water. The resulting solution was filtered through celite (celite), and the filtrate was lyophilized to give 140mg of the title compound as a white amorphous solid.

¹H-NMR (toluene-d)₈，100℃)δppm：1.4-2.0(4H，m)，2.33(3H，s)，2.34(3H，s)，2.5-4.5(5H，m)，5.4-5.7(2H，m)，6.5(2H，d，J＝7.9Hz)，6.7(2H，d，J＝7.9Hz)，6.8-7.2(5H，m)，7.2-7.4(2H，m)，7.55(1H，s)

Example 19

64mg (1.0mmol) of sulfur was added to a solution of 500mg (0.9mmol) of the compound of example 17 in pyridine (5ml), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 1ml of triethylamine and concentrated under reduced pressure. To the resulting residue was added 10ml of toluene, and concentrated under reduced pressure. The residue was dissolved in water and filtered through celite (celite). To the filtrate was added 1N hydrochloric acid, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and filtered, and the filtrate was concentrated. To the resulting residue was added water, and insoluble matter was collected by filtration and then dried to obtain 300mg of the objective compound as a white powder.

¹H-NMR (toluene-d)₈，100℃)δppm：1.1-2.0(4H，m)，2.2-2.5(6H，m)，3.5(3H，dd，J＝13.9，14.9Hz)，2.5-5.0(2H，m)，3.5-5.7(1H，m)，6.4-7.5(10H，m)

Example 20

0.5ml of water, 0.5ml of carbon tetrachloride, 0.5ml of triethylamine and 0.072ml (1.2mmol) of ethanolamine are added to a solution (5ml) of 500mg (0.95mmol) of the compound of example 17 in acetonitrile and the resulting mixture is stirred at room temperature for 10 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 80: 20). The purified product was concentrated under reduced pressure to give 540mg of the desired product as a white amorphous solid.

¹H-NMR(DMSO-d₆，100℃)δppm：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＝9.6，11.2Hz)，4.0-4.3(1H，m)，4.4-4.8(1H，m)，5.3-5.7(1H，m)，6.7-7.1(2H，m)，7.1-7.5(5H，m)，7.57(1H，s)，9.76(1H，s)

Example 21

0.5ml of water, 0.5ml of carbon tetrachloride, 0.5ml of triethylamine and 0.119ml (1.2mmol) of methylamine (40% solution in methanol) were added to 500mg (0.95mmol) of a solution of the compound of example 17 in acetonitrile (5ml), and the resulting mixture was stirred at room temperature for 10 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol: 94: 6 → 85: 15). The purified product was concentrated under reduced pressure to give 250mg of the desired product as a white amorphous solid.

¹H-NMR(DMSO-d₆，100℃)δppm：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＝10.7Hz)，4.4-4.8(1H，m)，5.3-5.6(1H，m)，6.6-7.1(2H，m)，7.1-7.5(5H，m)，7.58(1H，s)，9.81(1H，s)

Example 22

0.5ml of water, 0.5ml of carbon tetrachloride, 0.5ml of triethylamine and 0.115ml (1.2mmol) of diethanolamine are added to a solution (5ml) of 500mg (0.95mmol) of the compound of example 17 in acetonitrile, and the resulting mixture is stirred at room temperature for 10 minutes. To the mixture was added water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 88: 12 → 70: 30). The purified product was concentrated under reduced pressure to give 250mg of the desired product as a white powder.

¹H-NMR(DMSO-d₆，100℃)δppm：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(1H，m)，9.80(1H，br)

Example 23

3.8g (20mmol) of diphenyl phosphite was added to a pyridine solution (10ml) of 3.0g (6.7mmol) of tolvaptan (compound (2)), and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added 2ml of water, and stirred at room temperature for 30 minutes. The obtained reaction mixture was concentrated under reduced pressure, and 1N hydrochloric acid was added to the residue to conduct extraction with ethyl acetate. The ethyl acetate layer was washed twice with saturated brine, dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 50: 50). The purified product was concentrated under reduced pressure. The residue was dissolved in water, and 1N hydrochloric acid was added to precipitate an insoluble matter and collected by filtration, followed by drying to obtain 0.83g of the objective compound as a white powder.

Yield: 24 percent of

¹H-NMR(DMSO-d₆，100℃)δppm：1.7-2.2(4H，m)，2.35(3H，s)，2.36(3H，s)，2.8-4.3(2H，m)，5.4-5.6(1H，m)，5.8(0.5H，br)，6.7-7.4(8H，m)，7.47(1H，d，J＝2.3Hz)，7.55(1H，s)，9.79(1H，br)

Example 24

2.9ml of phosphorus trichloride was added to Tetrahydrofuran (THF) (29ml) under a stream of nitrogen. The obtained mixture was cooled with ice, and 6.1ml (44mmol) of triethylamine was added thereto. The mixture was cooled in an ice-methanol bath. Then, a THF solution (120ml) of 10.0g (22mmol) of tolvaptan (compound (2)) was added dropwise at an internal temperature of not higher than-10 ℃ and stirred at the same temperature for 2 hours. To the resulting reaction mixture was added dropwise 130ml of a 1N aqueous solution of sodium hydroxide at an internal temperature of not higher than 0 ℃ and then 200ml of water was added, followed by washing twice with toluene. The resulting aqueous solution was cooled in an ice-methanol bath, 1N HCl was added dropwise at an internal temperature of not higher than-0 ℃, and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, then filtered, and the filtrate was concentrated to obtain 6.8g of the title compound as a white amorphous solid.

Yield: 60 percent of

Example 25

3.8g (20mmol) of diphenyl phosphite was added to a pyridine solution (10ml) of 3.0g (6.7mmol) of tolvaptan (compound (2)), and the resulting mixture was stirred at room temperature for 1 hour. To the mixture was added 5.2ml (66.6mmol) of methyl glycolate and stirred at room temperature for 12 hours. 50ml of water was added to the reaction mixture, followed by extraction with ethyl acetate. The ethyl acetate layer was washed twice with 1N hydrochloric acid, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (n-hexane: ethyl acetate 50: 50 → 0: 100). The purified product was concentrated under reduced pressure to obtain 0.79g of the objective compound as a white amorphous solid.

Yield: 20 percent of

¹H-NMR (toluene-d)₈，100℃)δppm：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(1H，s)，4.47(1H，s)，5.87(0.5H，s)，5.9-6.1(1H，m)，6.6-6.8(1H，m)，6.8-7.0(2H，m)，7.0-7.4(5H，m)，7.48(1H，s)，7.63(1H，s)，8.27(0.5H，s)。

Example 26

0.8ml of water was added to a solution of 0.79g (1.35mmol) of the compound of example 25 in pyridine (7.9 ml). To the resulting mixture was added ice-cooled 0.34g (2.7mmol) of iodine, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The resulting residue was dissolved in water and then lyophilized to give 80mg of the title compound as a white amorphous solid.

Yield: 9.9 percent

¹H-NMR(DMSO-d₆，100℃)δppm：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＝1.7，10.1Hz)，5.4-5.6(1H，m)，6.7-7.1(2H，m)，7.1-7.5(7H，m)，7.54(1H，s)，9.79(1H，br)

Example 27

3.0g (6.7mmol) of tolvaptan (compound (2)) was added in small portions to 3.8ml (20mmol) of a pyridine solution of diphenyl phosphite (15ml), and the resulting mixture was stirred at room temperature for 0.5 hours. To the mixture was added 2.8ml (40mmol) of 3-hydroxypropionitrile, and the mixture was stirred at room temperature for 0.5 hour. To the resulting reaction mixture was added 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was then washed with water, dried over sodium sulfate, and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 10: 1). The purified product was concentrated under reduced pressure to obtain 2.8g of the objective compound as a white amorphous solid.

Yield: 75 percent of

¹H-NMR (toluene-d)₈，100℃)δppm：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＝3.1Hz)，5.3-5.4(1H，m)，6.5-6.7(1H，m)，6.7-6.9(1H，m)，6.9-7.2(6H，m)，7.2-7.5(2H，m)，7.76(0.5H，d，J＝8.5Hz)

Example 28

0.115g (3.6mmol) of sulfur was added to 1.0g (1.8mmol) of a pyridine solution of the compound of example 27 (10ml), and the resulting mixture was stirred at room temperature for 2 hours. To the mixture was added 1N hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 85: 15). The purified product was concentrated under reduced pressure to obtain 0.91g of the objective compound as a white amorphous solid.

Yield: 85 percent of

¹H-NMR(DMSO-d₆，100℃)δppm：1.6-1.9(3H，m)，2.0-2.3(1H，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

300mg (0.5mmol) of the compound of example 28 are added to 5ml of 28% aqueous ammonia and the mixture is stirred at room temperature for 3 days. To this mixture was added 1N hydrochloric acid. The precipitated solid was collected by filtration and then dried to obtain 100mg of the objective compound as a white powder.

Yield: 37 percent of

¹H-NMR (pyridine-d)₅-D₂O，90℃)δppm：1.6-2.4(4H，m)，2.43(3H，s)，2.53(3H，s)，2.8-4.3(2H，m)，5.1-5.4(1H，m)，6.8-7.3(6H，m)，7.4-7.7(2H，m)，7.7-8.1(2H，m)

Example 30

0.62ml (6.6mmol) of phosphorus oxychloride and 0.92ml (6.6mmol) of triethylamine were added to Tetrahydrofuran (THF) (5ml) under a nitrogen stream. The resulting mixture was cooled in an ice-methanol bath. Then, a THF solution (10ml) of 1.0g (2.2mmol) of tolvaptan (compound (2)) was added dropwise thereto, and stirred at the same temperature for 30 minutes. To the mixture were added 2.8ml (20mmol) of triethylamine and 1.1ml (26.4mmol) of methanol, and the mixture was stirred for 30 minutes. To the resulting reaction mixture was added water, followed by extraction with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate: methanol 100: 0 → 80: 20). The purified product was concentrated under reduced pressure, and the residue was recrystallized from aqueous methanol to give 400mg of the objective compound as a white powder.

Yield: 33 percent

¹H-NMR(DMSO-d₆，100℃)δppm：1.7-2.2(4H，m)，2.36(6H，s)，2.8-4.3(2H，m)，3.71(6H，dd，J＝10.2，11.1Hz)，5.5-5.6(1H，m)，6.8-7.1(2H，m)，7.1-7.5(7H，m)，7.58(1H，s)，9.80(1H，br)

Test example 1

Solubility of Compound (1b)

The compound (1b) obtained in example 3 or 4 was added in excess to 0.1N sodium phosphate buffer (pH5, pH6, pH7, pH8, pH9 or pH10), 0.1N Tris/HCl buffer (pH8 or pH9), 0.1N sodium bicarbonate/HCl buffer (pH8) or 0.1N sodium citrate buffer (pH8) and shaken at room temperature for 16 days. If the test compound dissolves after addition of an amount of about 6 to about 8 w/v%, no more test compound is added.

Each solution was filtered through a 0.45 μm filter, and then the solubility of compound (1b) was determined by absolute calibration under the following HPLC conditions.

HPLC conditions

And (3) detection: ultraviolet absorption photometer

(measurement wavelength: 254nm)

Column: YMC (ODS) AM-302 (4.6X 150mm)

Column temperature: constant temperature of about 25 ℃

Eluent: acetonitrile/water/phosphoric acid 450/550/1

Flow rate: 1 ml/min

Injection volume: 10 μ l

TABLE 1

Solubility of Compound (1b) in buffer solution (room temperature)

^*The solubility of the sample was as high as the extent that no excess crystals could be added

Test example 2

Solubility of salt of Compound (1)

An appropriate amount of test compound was added to the tube, to which was added 2.5ml of water. After shaking at 37 ℃ for 30 minutes, the mixture is filtered through a 0.45 μm filter and 0.5ml of the filtrate is accurately weighed. The mobile phase was added to an accuracy of 50ml as a test solution (dilution ratio: 100 times). About 5mg of a free form reference sample was accurately weighed and acetonitrile was added thereto to an accuracy of 50 ml. 2ml of this liquid was accurately weighed and the mobile phase was added to an amount of 20ml as a standard solution (equivalent to 10 mg/ml). The 20. mu.l of the test solution and the standard solution were tested by liquid chromatography under the following conditions to obtain peak areas At and As of the test solution and the standard solution.

Concentration (. mu.g/ml): Ws/5X 10 XAt/As X100 ═ Ws X At/As X200

Ws: weight of reference sample (mg)

Test conditions

And (3) detection: ultraviolet absorption photometer

(measurement wavelength: 254nm)

Column: TOSOH TSKgel ODS-80Ts (0.46 cm. times.15 cm)

Column temperature: constant temperature of about 40 ℃

Mobile phase: water/acetonitrile/trifluoroacetic acid 500/500/1

Flow rate: 1 ml/min

TABLE 2

Test Compound (example No.)	Solubility (w/v%)
		5	＞0.1
7	＞0.1
		8	＞0.1
11	＞0.1
		16	＞0.1
17	＞0.1
		20	＞0.1
31	＞0.1

Test example 3

Solubility of tolvaptan

Excess tolvaptan was added to Britton-Robinson buffer (pH2, pH7 or pH12) or purified water and shaken at 25 ℃. + -. 1 ℃ for 4 hours. Each solution was filtered through a filter and then the solubility of tolvaptan was quantified by absolute calibration using HPLC.

TABLE 3

Solubility of tolvaptan in Britton-Robinson buffer and purified water

Solvent(s)	Solubility of tolvaptan (w/v%)
		Water (W)	0.00002
pH 2	0.00002
		pH 7	0.00003
pH 12	0.00002

Test example 4

Tolvaptan serum in female rats after caudal vein administration of compound (1b) solution Concentration of

Test method

Preparation of a solution of Compound (1b) (equivalent to 1mg of tolvaptan per ml solution)

TABLE 4

Formulation (in 1 ml)

	Amount (mg)
		Compound (1b)	1.0^*
Sodium dihydrogen phosphate dihydrate	0.79
		Mannitol	50
Sodium hydroxide	Adjusting the pH value to 7.0
		Water for injection	Proper amount of

^*Corresponding to an amount of 1mg of tolvaptan per ml of solution

Preparation method

79mg of sodium dihydrogen phosphate dihydrate and 5g of mannitol were dissolved in approximately 90ml of water for injection. To this was added sodium hydroxide solution to prepare a solution of pH7. The compound (1b) corresponding to 100mg of tolvaptan was dissolved in the solution. Sodium hydroxide was added to adjust the pH to 7. To the resulting solution was added an injection solvent to 100ml, and sterile-filtered with a 0.2 μm filter to obtain a solution of compound (1b) (equivalent to 1mg of tolvaptan per ml of solution).

The solution was administered rapidly to female rats via the tail vein at a dose that yielded 1mg of tolvaptan per kilogram of body weight. Jugular venous blood was collected occasionally under mild ether anesthesia and serum concentrations of tolvaptan were measured by High Performance Liquid Chromatography (HPLC).

The results are shown in FIG. 1.

Tolvaptan was measured starting 5 minutes after intravenous administration of the compound (1b) solution to female rats. This indicates that compound (1b) is rapidly hydrolyzed to tolvaptan in rats in vivo.

Test example 5

Tolvaptan serum concentrate in female rats after oral administration of Compound (1b) solution Degree of rotation

Test method

Preparation of a solution of Compound (1b) (equivalent to 0.4mg of tolvaptan per ml of solution)

TABLE 5

Formulation (in 1 ml)

	Amount (mg)
		Compound (1b)	0.4^*
Sodium bicarbonate	2
		Sodium hydroxide	Amount (pH 9.1)
Water for injection	Proper amount of

^*Corresponding to an amount of 0.4mg of tolvaptan per ml of solution

Preparation method

1g of sodium bicarbonate was dissolved in about 400ml of water for injection. Sodium hydroxide solution was added to adjust the pH to 9.0 and water for injection was added to make 500ml of 0.2% sodium bicarbonate solution. 89. mu.l of a 1N sodium hydroxide solution and the compound (1b) corresponding to 20mg of tolvaptan were added to about 40ml of this 0.2% sodium bicarbonate solution and dissolved. A further 0.2% sodium bicarbonate solution was added to make 50ml, thereby preparing a solution of compound (1b) (equivalent to 0.4mg of tolvaptan per ml of solution). The pH of the solution was 9.1. Hereinafter, this solution will be referred to as "solution A".

A spray-dried tolvaptan powder equivalent to 60mg of tolvaptan, prepared by a method similar to example 3 of JP1999-21241-A, was suspended in 50ml of water for injection in a porcelain mortar. The suspension was diluted 3-fold with water for injection to give a spray-dried powder suspension corresponding to 0.4mg of tolvaptan per ml of suspension. This suspension is hereinafter referred to as "suspension B".

The following tests were used to determine the oral absorption properties of solution a and suspension B. Wistar female rats (body weight approximately 160g) fasted for approximately 18 hours were used as test animals. Solution A and suspension B were each administered by oral bougie, forcefully orally, at a dose of 2.5ml/kg body weight, so that 1mg of tolvaptan per kg body weight was administered. Jugular vein blood samples were taken periodically after dosing under mild ether anesthesia and serum concentrations of tolvaptan were determined using UPLC-MS/MS (waters).

The results are shown in FIG. 2 and Table 6. Figure 2 shows a serum concentration-time plot of tolvaptan after oral administration of solution a and suspension B (n-4). Table 6 shows the mean values of the pharmacokinetic parameter values (n-4). The parameters in table 6 have the following meanings.

AUC_8hr: area under serum concentration-time curve (ng hr/ml) after 8 hours of administration

AUC_∞: area under serum concentration-time curve (ng hr/ml) after infinite time of administration

C_max: maximum serum concentration (ng/ml)

T_max: time to maximum serum concentration (hr)

The results confirm that the compound (1B) solution (solution A) reached the maximum serum concentration in a shorter time and reached a higher maximum serum concentration (C) than the spray-dried tolvaptan suspension (suspension B)_max) And a larger area under the serum concentration-time curve (AUC)_8hr，AUC_∞)。

TABLE 6

These results reveal that the compound of the present invention, especially compound (1b), when administered in vivo, has improved absorption compared to conventional means of increasing absorption by amorphization, thereby improving the bioavailability of tolvaptan.

Formulation example 1

79mg of sodium dihydrogen phosphate dihydrate and 5g of mannitol were dissolved in about 90ml of a solvent for injection. To this was added sodium hydroxide solution to prepare a solution of pH7. To this solution, the compound (1b) equivalent to 100mg of tolvaptan was added. Sodium hydroxide solution was added to adjust the pH to 7. To the resulting solution was added an injection solvent to 100ml, and sterile filtration was performed using a 0.2 μm filter to obtain an injection solution of the present invention containing the compound (1b) (equivalent to 1mg of tolvaptan per ml of injection solution).

Formulation example 2

79mg of sodium dihydrogen phosphate dihydrate and 5g of mannitol were dissolved in about 90ml of a solvent for injection. A solution of pH7.5 was prepared by adding sodium hydroxide solution. The compound (1b) corresponding to 10mg of tolvaptan was dissolved in the solution. To the resulting solution was added an injection solvent to 100ml, and sterile-filtered using a 0.2 μm filter to obtain an injection of the present invention containing the compound (1b) (equivalent to 0.1mg of tolvaptan per ml of injection).

Formulation example 3

380mg of trisodium phosphate dodecahydrate and 4g of mannitol are dissolved in approximately 90ml of solvent for injection. The compound (1b) corresponding to 100mg, 300mg or 1000mg of tolvaptan was dissolved in the resulting solution. When the compound (1b) corresponding to 1000mg of tolvaptan was dissolved, a sodium hydroxide solution was added to improve the solubility. The pH of each solution obtained was adjusted to 8 to 9 with sodium hydroxide or hydrochloric acid, and a solvent for injection was added to make it 100 ml. The obtained solution was subjected to sterile filtration through a 0.2 μm filter to prepare an injection of the present invention containing the compound (1b) (corresponding to 1mg, 3mg or 10mg of tolvaptan per ml of injection).

Claims

1. Benzazepine represented by the general formula (1)Compound or salt thereof

Wherein R represents a hydrogen atom, a hydroxyl group optionally protected by a protecting group, a mercapto group optionally protected by a protecting groupOr an amino group optionally protected by one or two protecting groups; r¹Represents a hydrogen atom or a hydroxyl-protecting group; x represents an oxygen atom or a sulfur atom.

2. Benzazepines according to claim 1A compound or a salt thereof, wherein X is an oxygen atom.

3. Benzazepine according to claim 1 or 2A compound or salt thereof, wherein R is hydroxy optionally protected by a protecting group.

4. Benzazepine according to claim 1 or 2A compound or a salt thereof, wherein R is a hydrogen atom, a mercapto group optionally protected by a protecting group, or an amino group optionally protected by one or two protecting groups.

5. Benzazepines according to any of claims 1, 2, 3 or 4A compound or a salt thereof, wherein R¹Is a hydroxyl protecting group.

6. Benzazepines according to any of claims 1, 2, 3 or 4A compound or a salt thereof, wherein R¹Is a hydrogen atom.

7. Benzazepines according to claim 1A compound or a salt thereof, wherein X is a sulfur atom.

8. Benzazepines according to claim 1A compound or a salt thereof, wherein X is an oxygen atom, R is a hydroxyl group, and R is¹Is a hydrogen atom.

9. A pharmaceutical composition comprising the benzazepine of claim 1A compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent and/or carrier.

10. The pharmaceutical composition according to claim 9 for use as a vasodilator, a hypotensive agent, a drainage promoting agent, PKD or a platelet aggregation inhibitor.

11. An aqueous solution composition comprising the benzazepine of claim 1A compound or a pharmaceutically acceptable salt thereof.

12. An aqueous solution composition according to claim 11 comprising the benzazepine of claim 1Compound or its pharmaceutically acceptable salt and buffer, isotonic agent and injectionA solvent for injection, which is in the form of an injection.

13. The aqueous solution composition according to claim 12, further comprising a pH adjusting agent.