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Water-soluble benzoazepine compound and its pharmaceutical composition

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Water-soluble benzoazepine compound and its pharmaceutical composition


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. or a salt thereof, The present invention provides a benzoazepine compound represented by following general formula (1):

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Inventors: Makoto Komatsu, Fumitaka Goto, Yasuhiro Menjo, Keigo Yamada, Takakuni Matsuda, Yusuke Kato
USPTO Applicaton #: #20120277189 - Class: 514 80 (USPTO) - 11/01/12 - Class 514 
Drug, Bio-affecting And Body Treating Compositions > Designated Organic Active Ingredient Containing (doai) >Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai >Nitrogen Containing Hetero Ring >Polycylo Ring System Having A Ring Nitrogen In The System



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The Patent Description & Claims data below is from USPTO Patent Application 20120277189, Water-soluble benzoazepine compound and its pharmaceutical composition.

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TECHNICAL FIELD

The present invention relates to a novel benzoazepine compound and its pharmaceutical composition.

BACKGROUND OF ART

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

It is known that tolvaptan is useful as a vasopressin antagonist having aquaretic activity (Circulation, 107, pp. 2690-2696 (2003)). However, because of its low water solubility, tolvaptan has problems in that 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 administration route still remain limited.

DISCLOSURE OF THE INVENTION

The present invention aims to provide a novel benzoazepine compound for improving 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 water solubility thereof can be remarkably improved.

The present invention has been accomplished based on this finding.

Specifically, the present invention provides the following benzoazepine compounds, and compositions comprising the same, as described in Item 1 to 13 below.

Item 1. A benzoazepine compound represented by 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-protecting group; and X represents an oxygen atom or a sulfur atom.

Item 2. A benzoazepine compound according to item 1 or a salt thereof, wherein X is an oxygen atom.

Item 3. A benzoazepine compound according to item 1 or 2, or a salt thereof, wherein R is a hydroxy group optionally protected with a protecting group.

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

Item 5. A benzoazepine compound according to any one of items 1, 2, 3 and 4, or a salt thereof, wherein R1 is a hydroxy-protecting group.

Item 6. A benzoazepine compound according to any one of items 1, 2, 3 and 4, or a salt thereof, wherein R1 is a hydrogen atom.

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

Item 8. A benzoazepine compound according to item 1 or a salt thereof, wherein X is an oxygen atom, R is a hydroxy group, and R1 is a hydrogen atom.

Item 9. A pharmaceutical composition comprising a benzoazepine compound of item 1 or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable diluent and/or carrier.

Item 10. A pharmaceutical composition according to item 9, for use as a vasodilator, hypotensor, aquaretic agent, PKD, or platelet aggregation inhibitor.

Item 11. An aqueous solution composition comprising a benzoazepine compound of item 1 or a pharmaceutically acceptable salt thereof.

Item 12. An aqueous solution composition according to item 11, comprising a benzoazepine compound of item 1 or a pharmaceutically acceptable salt thereof, together with a buffer, isotonizing agent and injection solvent, and which is in the form of an injection.

Item 13. An aqueous solution composition according to item 12, further comprising a pH adjuster.

“Lower” as used herein indicates C1-6 unless otherwise noted.

Examples of protecting groups for a “hydroxy group optionally protected with a protecting group”, “mercapto group optionally protected with a protecting group” and “hydroxy-protecting group” include lower alkyl groups, phenyl(lower)alkyl groups, cyano lower alkyl groups, 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 C1-6 straight or branched alkyl groups, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, and the like.

Preferable phenyl(lower)alkyl groups are, for example, benzyl, phenethyl, 3-phenylpropyl, trityl, etc.

Preferable cyano lower alkyl groups are C1-6 straight or branched alkyl groups 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 lower alkyl groups are alkyloxycarbonylalkyl groups wherein the alkyloxy moiety is a C1-6 straight or branched alkyloxy group and the alkyl moiety is a C1-6 straight or branched alkyl group, for example, methoxycarbonylmethyl, ethoxycarbonylmethyl, n-propoxycarbonylmethyl, isopropoxycarbonylmethyl, n-butoxycarbonylmethyl, isobutoxycarbonylmethyl, n-pentoxycarbonylmethyl, n-hexyloxycarbonylmethyl, 2-methoxycarbonylethyl, 3-methoxycarbonylpropyl, 4-methoxycarbonylbutyl, 5-methoxycarbonylpentyl, 6-methoxycarbonylhexyl, and the like.

Preferable lower alkyl groups optionally bearing hydroxy group(s) are C1-6 straight or branched alkyl groups optionally substituted with one to three hydroxy groups, 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-hydroxy-isopropyl, 1-, 2-, 3-, or 4-hydroxy-n-butyl, 1-, 2-, 3-, or 4-hydroxy-isobutyl, 1-, 2-, 3-, or 4-hydroxy-test-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 group(s) are amino groups optionally bearing one or two C1-6 straight or branched alkyl groups optionally bearing one to three hydroxy groups, for example, amino, methylamino, dimethylamino, ethylamino, diethylamino, n-propylamino, di-n-propylamino, iso-propylamino, di-iso-propylamino, n-butyl amino, di-n-butylamino, iso-butyl amino, di-iso-butylamino, tert-butyl amino, di-tert-butylamino, n-pentyl amino, 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 benzoazepine compounds represented by the above general formula (1), the following compounds and salts thereof 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 an 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 a salt thereof.

Benzoazepine compounds represented by the above general formula (1) can be produced by various methods, and an example thereof is a method as shown by the following reaction schemes 1 to 7:

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 without one or more additional heteroatoms to form, together with the nitrogen atom to which they are bound, a 5- to 8-membered saturated or unsaturated ring; and R1a and R2a may be the same or different, and each represents a hydroxy-protecting group.

Examples of lower alkyl groups are as mentioned above, including C1-6 straight or branched alkyl groups, for example, 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 substituents for optionally-substituted phenyl groups include lower alkyl groups as above; C1-6 straight or branched 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 5- to 8-membered saturated or unsaturated rings formed by R3 and R4 being linked together include morpholine ring, etc.

Compound (4) can be produced by reacting compound (2) with 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 mild acids, for example, 1H-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 mol of compound (2).

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

The reaction temperature is usually −20 to 50° C., preferably 0 to 50° C., and more preferably 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.

Compound (1a) can be produced by reacting 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 oxidizing agents include peracids, for example, hydrogen peroxide, and metachloroperbenzoic acid, peracetic acid, permaleic acid, and the like.

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

The reaction temperature is usually −100 to 50° C., preferably −40° C. to room temperature, and more preferably −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.

Compound (1b) can be obtained by deprotecting the protected hydroxy groups of compound (1a) by routine methods.

When, for example, the hydroxy-protecting groups are lower alkyl groups, deprotection can be performed under routine hydrolysis conditions.

Such hydrolysis is preferably performed in the presence of base or acid (including Lewis acid).

A wide range of known inorganic and organic bases can be used as such a base. Preferable inorganic bases are, for example, alkali metals (e.g., sodium, potassium, etc.); alkaline earth metals (e.g., magnesium, calcium, etc.); and their hydroxides, carbonates and hydrogencarbonates. Preferable organic bases are, for example, trialkylamines (e.g., 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 as such an acid. Preferable organic acids are fatty acids, for example, formic acid, acetic acid, propionic acid, and the like; and trihaloacetic acids, for example, trichloroacetic acid, trifluoroacetic acid, and the like. Preferable inorganic acids are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen chloride, hydrogen bromide, etc. Examples of Lewis acids include boron trifluoride ether complex, boron tribromide, aluminium chloride, ferric chloride, etc.

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

The amount of base or acid is not limited so long as it satisfies hydrolysis requirements.

The reaction temperature is usually −20 to 100° C., preferably 0 to 50° C., and more preferably 0° C. to room temperature. The reaction time is usually 5 minutes to 24 hours, preferably 15 minutes to 6 hours, and more preferably 15 minutes to 3 hours.

When, for example, the hydroxy-protecting groups are phenyl(lower)alkyl groups, deprotection can be preformed by a routine catalytic reduction.

Catalysts suitable for such catalytic reduction are platinum catalysts (e.g., platinum plate, spongy platinum, platinum black, colloidal platinum, platinum oxide, platinum wire, etc.), palladium catalysts (e.g., spongy palladium, palladium black, palladium oxide, palladium carbon, palladium/barium sulfate, palladium/barium carbonate, etc.), nickel catalysts (e.g., reduced nickel, nickel oxide, Raney nickel, etc.), cobalt catalysts (e.g., reduced cobalt, 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 performed 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 0 to 100° C., preferably 0 to 50° C., and more preferably room temperature to 50° C. The reaction time is usually 5 minutes to 24 hours, preferably 5 minutes to 3 hours, and more preferably 5 minutes to 1 hour.

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

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

The above reaction is carried out in the presence of 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.



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stats Patent Info
Application #
US 20120277189 A1
Publish Date
11/01/2012
Document #
13461665
File Date
05/01/2012
USPTO Class
514 80
Other USPTO Classes
540542
International Class
/
Drawings
2


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Drug, Bio-affecting And Body Treating Compositions   Designated Organic Active Ingredient Containing (doai)   Phosphorus Containing Other Than Solely As Part Of An Inorganic Ion In An Addition Salt Doai   Nitrogen Containing Hetero Ring   Polycylo Ring System Having A Ring Nitrogen In The System