WO1998025602A1 - Remede contre le glaucome - Google Patents

Remede contre le glaucome Download PDF

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Publication number
WO1998025602A1
WO1998025602A1 PCT/JP1997/004539 JP9704539W WO9825602A1 WO 1998025602 A1 WO1998025602 A1 WO 1998025602A1 JP 9704539 W JP9704539 W JP 9704539W WO 9825602 A1 WO9825602 A1 WO 9825602A1
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WO
WIPO (PCT)
Prior art keywords
group
carboxy
compound
glaucoma
lower alkyl
Prior art date
Application number
PCT/JP1997/004539
Other languages
English (en)
Japanese (ja)
Inventor
Eiichi Shirasawa
Masaaki Kageyama
Original Assignee
Santen Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Santen Pharmaceutical Co., Ltd. filed Critical Santen Pharmaceutical Co., Ltd.
Publication of WO1998025602A1 publication Critical patent/WO1998025602A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics

Definitions

  • the present invention relates to a therapeutic agent for glaucoma, comprising a 1,3-dialkyl urea derivative as an active ingredient.
  • Glaucoma is an intractable eye disease that causes an increase in intraocular pressure due to various factors and may lead to blindness, and various drugs are being studied.
  • new publications of JP-A Nos. 8-20589 and 8-231492 report novel 1,3-dialkylurea derivatives.
  • the structural features of these compounds are that they have carboxylic acid at both ends of the alkylene chain of 1,3-dialkyl urea, and that the alkylene chain has an aromatic moiety such as a naphthyl group or a biphenyl group.
  • the compounds have been shown to be useful as therapeutic agents for cardiovascular diseases. However, no report has been made on the effects of these compounds on eye diseases, particularly on glaucoma.
  • the present inventors have developed ophthalmic components of 1,3-dialkylurea derivatives. Intensive research was conducted to find effects in the field, and found that 1,3-dialkylurea derivatives have excellent intraocular pressure lowering effects. That is, they have found that 1,3-dialkylurea derivatives are useful as therapeutic agents for glaucoma.
  • the present invention relates to a therapeutic agent for glaucoma, comprising a compound represented by the following general formula [I] or a salt thereof (hereinafter, referred to as the present compound) as an active ingredient.
  • R 1 represents a carboxy group or an ester thereof
  • R 2 represents a hydrogen atom, a lower alkyl group or a hydroxy group
  • R d represents a lower alkyl group.
  • R 4 represents a carboxy group or an ester thereof.
  • R 5 represents an aromatic group.
  • A represents a lower alkylene group.
  • Lower alkyl refers to straight-chain or branched lower alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, butyl, hexyl, and isobutyl
  • lower alkylene refers to methylene
  • It represents a linear or branched lower alkylene having 1 to 6 carbon atoms, such as ethylene, propylene, butylene, and hexmethylene.
  • Ester is low
  • These groups are commonly used as esters of carboxylic acids, such as lower alkyl esters and phenyl lower alkyl esters, and are easily hydrolyzed to carboxylic acids.
  • the aromatic group refers to a hydrocarbon-based aromatic such as phenyl, naphthyl and biphenyl, which may be substituted with a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom.
  • the lower alkoxy refers to a straight or branched lower alkoxy having 1 to 6 carbon atoms such as methoxy, ethoxy, propoxy, butoxy, hexoxy, etc.
  • the halogen atom refers to a fluorine atom. Indicates sulfur, chlorine, bromine or iodine.
  • Preferred examples of the compound include the following: • Compounds in which R 1 represents a carboxy group in the above general formula [I], and salts thereof.
  • R 5 represents a phenyl group, a naphthyl group or a biphenyl group, more preferably a naphthyl group or a biphenyl group, in the above general formula [I].
  • examples of the compound having a preferable combination of substituents include the following.
  • R 1 and R 4 are hydroxyl groups Is a compound thereof, wherein R 2 represents a hydroxy group, R 3 represents a lower alkyl group, R 5 represents a naphthyl group or a biphenyl group, and A represents a lower alkylene group, and salts thereof.
  • R 1 and R 4 are hydroxyl groups
  • R 2 is a hydroxy group
  • R " 3 is an isobutyl group
  • R 5 is a naphthyl group
  • A is a methyl group.
  • a specific example of a particularly preferred compound is represented by the following formula [ ⁇ ].
  • the above salts may be any salts that are pharmaceutically acceptable, such as hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, and the like. Examples include methansulfonate and paratoluenesulfonate.
  • diastereoisomers and optical isomers exist in the above compounds, all of which are included in the present invention.
  • the above compound may be in the form of a hydrate. This compound is a useful drug as a therapeutic agent for cardiovascular diseases, but its effect on the eyes was not known.
  • the present inventors have studied the application of the present compound to the field of ophthalmology, and as a result, the details will be explained in the section on pharmacological tests. Was observed. From this, it is expected that this compound is useful as a therapeutic agent for glaucoma.
  • the compounds can be administered orally or parenterally.
  • Dosage forms include eye drops, injections, tablets, capsules, granules, and the like, and these preparations can be prepared using commonly used techniques.
  • isotonic agents such as sodium chloride and concentrated glycerin
  • buffering agents such as sodium phosphate and sodium acetate
  • Surfactants such as oxyethylene sorbitan monophosphate, polyoxy stearate 40, polyoxyethylene hydrogenated castor oil, and stable sodium citrate and sodium edetate
  • preservatives such as preservatives, benzalkonium chloride and paraben, and the pH should be within the range acceptable for ophthalmic preparations. Range is preferred.
  • Oral preparations such as tablets, capsules and granules may be used, if necessary, with bulking agents such as lactose, starch, microcrystalline cellulose, vegetable oil, etc., lubricants such as magnesium stearate, talc, etc.
  • Binders such as hydroxypropyl cellulose, polyvinylpyrrolidone, etc., disintegrants such as sulphoxymethylcellulose, disintegrators such as scalcium, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and gelatin coating agents It can be formulated by using
  • the dose is appropriately selected depending on the symptoms, age, dosage form, etc., but for eye drops, 0.001 to 3% (w / V) should be used daily. It may be administered once or several times. In the case of an oral preparation, it is usually sufficient to administer 1 mg to 100 mg per day in one or several divided doses.
  • Table 1 shows the change over time of the intraocular pressure with respect to the initial intraocular pressure (the intraocular pressure immediately before the injection) when the test compound solution was injected into the anterior chamber of the cynomolgus monkey.
  • the numerical value is the average value of 6 cases and is shown using the unit of mmHg.
  • Table 1 in the group treated with 0.1 mM of Compound A, the intraocular pressure was reduced by 1.8 mmHg 2 hours after injection and 4 hours after injection. In addition, in the group to which I mM Compound A was administered, the intraocular pressure was reduced by 1.2 mmHg 2 hours after the injection and 2.8 mmHg 4 hours after the injection.
  • compound A (the above formula [ ⁇ ]) has an excellent intraocular pressure lowering effect. Based on the above, it was confirmed that 1,3-dialkyl perylene derivatives have an excellent intraocular pressure lowering effect and are useful as therapeutic agents for glaucoma.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Ophthalmology & Optometry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une nouvelle activité pharmacologique des dérivés de 1,3-dialkylurée dans le domaine ophthalmique. Un remède contre le glaucome comprenant comme ingrédient actif un composé représenté par la formule générale (I) ou un sel de celui-ci, formule dans laquelle R1 représente un carboxy ou un ester de celui-ci; R2 représente un hydrogène, un alkyle inférieur ou un hydroxy; R3 représente un alkyle inférieur; R4 représente un carboxy ou un ester de celui-ci; R5 représente un groupe aromatique; et A représente un alkylène inférieur. Le composé est de préférence plus particulièrement représenté par la formule (I) dans laquelle R?1, R2, R3, R4 et R5¿ représentent respectivement un carboxy, un hydroxy, un isobutyle, un carboxy et un naphthyle, et A représente un méthylène.
PCT/JP1997/004539 1996-12-11 1997-12-10 Remede contre le glaucome WO1998025602A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/330581 1996-12-11
JP8330581A JPH10167961A (ja) 1996-12-11 1996-12-11 緑内障治療剤

Publications (1)

Publication Number Publication Date
WO1998025602A1 true WO1998025602A1 (fr) 1998-06-18

Family

ID=18234257

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/004539 WO1998025602A1 (fr) 1996-12-11 1997-12-10 Remede contre le glaucome

Country Status (2)

Country Link
JP (1) JPH10167961A (fr)
WO (1) WO1998025602A1 (fr)

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57197255A (en) * 1981-03-23 1982-12-03 Merck & Co Inc Urea compound as antihypertensive
JPH05262709A (ja) * 1991-06-28 1993-10-12 Fujisawa Pharmaceut Co Ltd プロピオンアミド誘導体
JPH06184086A (ja) * 1992-12-22 1994-07-05 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
WO1995021609A1 (fr) * 1994-02-08 1995-08-17 Ciba-Geigy Ag Antagonistes de l'angiotensine ii destines au traitement du glaucome normotensif
JPH08208589A (ja) * 1994-11-04 1996-08-13 Santen Pharmaceut Co Ltd ヒドロキシ基を含有する新規１，３−ジアルキルウレア誘導体
JPH08231492A (ja) * 1994-12-14 1996-09-10 Santen Pharmaceut Co Ltd 新規１，３−ジアルキルウレア誘導体

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57197255A (en) * 1981-03-23 1982-12-03 Merck & Co Inc Urea compound as antihypertensive
JPH05262709A (ja) * 1991-06-28 1993-10-12 Fujisawa Pharmaceut Co Ltd プロピオンアミド誘導体
JPH06184086A (ja) * 1992-12-22 1994-07-05 Ono Pharmaceut Co Ltd （チオ）ウレア誘導体
WO1995021609A1 (fr) * 1994-02-08 1995-08-17 Ciba-Geigy Ag Antagonistes de l'angiotensine ii destines au traitement du glaucome normotensif
JPH08208589A (ja) * 1994-11-04 1996-08-13 Santen Pharmaceut Co Ltd ヒドロキシ基を含有する新規１，３−ジアルキルウレア誘導体
JPH08231492A (ja) * 1994-12-14 1996-09-10 Santen Pharmaceut Co Ltd 新規１，３−ジアルキルウレア誘導体

Also Published As

Publication number Publication date
JPH10167961A (ja) 1998-06-23

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