# US 7,612,066 B2 · Composition containing benzamidine derivative and method for stabilizing benzamidine derivative

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- Number: US 7,612,066 B2
- Document ID: US7612066B2
- Status: Granted
- Kind: B2
- Application number: 10/590,976
- Filed: 2005-03-04
- Published: 2007-09-06
- Granted: 2009-11-03
- Earliest claimed: 2004-03-04
- Assignees: Eisai R&D Management Co., Ltd.
- Inventors: Yasuyuki Suzuki; Satoshi Fujioka
- Web page: https://patentgrep.com/patent/US7612066B2

## CPC

- A61K 47/02: Inorganic compounds
- A61K 9/1611: {Inorganic compounds}
- A61K 9/19: lyophilised {, i.e. freeze-dried, solutions or dispersions (lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00)}
- A61K 9/2077: {Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets}
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61K 33/00: Medicinal preparations containing inorganic active ingredients
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 11/06: Antiasthmatics
- A61P 13/12: of the kidneys
- A61P 19/10: for osteoporosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/44: Iso-indoles; Hydrogenated iso-indoles
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention provides a composition containing a benzamidine derivative that does not decompose even when placed under humidification conditions and a method for stabilizing a benzamidine derivative. According to the present invention, decomposition reaction of a benzamidine derivative can be suppressed by adding to a benzamidine derivative represented by general formula (I) or a pharmacologically acceptable salt thereof, at least one type of electrolyte selected from the group consisting of halide salts of alkaline metal or alkaline earth metal and alkaline metal salts or alkaline earth metal salts of perchloric acid.

## Claims

### Claim 1

A solid composition comprising:
a benzamidine derivative represented by the following formula (I) or a pharmacologically acceptable salt thereof; and
at least one type of electrolyte selected from the group consisting of halide salts of alkaline metal or alkaline earth metal and alkaline metal salts or alkaline earth metal salts of perchloric acid:
wherein R1 and R2 are the same as or different from each other and each represents a hydrogen atom, a methoxy group or an ethoxy group, X represents a hydrogen atom or a halogen atom, and Ar represents a phenyl group that may be substituted with one or not less than two substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (XX),
wherein W represents CH or a nitrogen atom, A represents CH2 or a single bond, R3 represents a hydrogen atom or OR5, X represents CH2, an oxygen atom, a single bond or a carbonyl group, Y represents a single bond or a C1-4 alkyl group, R4 represents a hydrogen atom, OR6, a cyano group or COOR7, and R5, R6 and R7 represent a hydrogen atom or a C1-4 alkyl group.

### Claim 2 (depends on 1)

The solid composition according to claim 1, wherein the R1 and R2 represent an ethoxy group, and the X represents a fluorine atom.

### Claim 3

A solid composition comprising:
a benzamidine derivative represented by any one of the chemical formulae (II) to (VIII) or a pharmacologically acceptable salt thereof; and
at least one type of electrolyte selected from the group consisting of halide salts of alkaline metal or alkaline earth metal and alkaline metal salts or alkaline earth metal salts of perchloric acid:

### Claim 4 (depends on 1, 2, 3)

The solid composition according to any one of claims 1 to 3, wherein an amount of the electrolyte based on one part by weight of the benzamidine derivative or the pharmacologically acceptable salt thereof is from 0.5 parts by weight to 30 parts by weight.

### Claim 5 (depends on 3)

The solid composition according to claim 3, wherein the benzamidine derivative or the pharmacologically acceptable salt thereof is a hydrobromic acid salt of the benzamidine derivative represented by the following chemical formula (II):

### Claim 6

A method for stabilizing a benzamidine derivative, comprising the step of:
adding to a benzamidine derivative represented by the chemical formula (I) or a pharmacologically acceptable salt thereof, at least one type of electrolyte selected from the group consisting of halide salts of alkaline metal or alkaline earth metal and alkaline metal salts or alkaline earth metal salts of perchloric acid
wherein R1 and R2 are the same as or different from each other and each represents a hydrogen atom, a methoxy group or an ethoxy group, X represents a hydrogen atom or a halogen atom, and Ar represents a phenyl group that may be substituted with one or not less than two substituents selected from the group consisting of a methyl group, an ethyl group, a methoxy group, an ethoxy group, a t-butyl group, a morpholinyl group, or a substituent represented by the following formula (XX),
wherein, W represents CH or a nitrogen atom, A represents CH2 or a single bond, R3 represents a hydrogen atom or OR5, X represents CH2, an oxygen atom, a single bond or a carbonyl group, Y represents a single bond or a C1-4 alkyl group, R4 represents a hydrogen atom, OR6, a cyano group or COOR7, R5, R6 and R7 represent hydrogen atoms or C1-4 alkyl groups.

### Claim 7

A method for stabilizing a benzamidine derivative, comprising the step of:
adding to a benzamidine derivative represented by any one of the chemical formula (II) to (VIII) or a pharmacologically acceptable salt thereof at least one type of electrolyte selected from the group consisting of halide salts of alkali metal or alkaline earth metal and alkali metal salts or alkaline earth metal salts of perchloric acid:

### Claim 8 (depends on 6, 7)

The method according to claim 6 or 7, wherein an amount of the electrolyte based on one part by weight of the benzamidine derivative is from 0.5 parts by weight to 30 parts by weight.