WO2007114315A1 - Agent therapeutique pour trouble corneen/conjonctival - Google Patents

Agent therapeutique pour trouble corneen/conjonctival Download PDF

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Publication number
WO2007114315A1
WO2007114315A1 PCT/JP2007/057032 JP2007057032W WO2007114315A1 WO 2007114315 A1 WO2007114315 A1 WO 2007114315A1 JP 2007057032 W JP2007057032 W JP 2007057032W WO 2007114315 A1 WO2007114315 A1 WO 2007114315A1
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WO
WIPO (PCT)
Prior art keywords
corneal
keratitis
eye
group
hydrogen atom
Prior art date
Application number
PCT/JP2007/057032
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English (en)
Japanese (ja)
Inventor
Shin-Ichiro Hirai
Keiichi Shibagaki
Masatsugu Nakamura
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 WO2007114315A1 publication Critical patent/WO2007114315A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0048—Eye, e.g. artificial tears
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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

Definitions

  • the present invention relates to dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry horn containing benzylcarboxyl compound or a salt thereof as an active ingredient.
  • the present invention relates to a therapeutic agent for keratoconjunctival disorders such as conjunctivitis, upper ring keratoconjunctivitis, and filiform keratitis.
  • the cornea is a transparent avascular tissue having a diameter of about 1 cm and a thickness of about 1 mm
  • the conjunctiva is a mucous membrane covering the surface of the eyeball behind the cornea edge and the back of the eyelid. It is known that when the cornea and conjunctiva are damaged, visual function is significantly affected. Corneal and conjunctival damage caused by various diseases such as corneal ulcer, keratitis, conjunctivitis, and dry eye adversely affects the normal reconstruction of the corneal epithelium and conjunctival epithelium, resulting in the structure and function of the corneal stroma and corneal endothelium. Can be harmed.
  • Non-patent document 1 Non-patent document 2
  • Patent Document 1 compounds such as (1) 2- (4-chlorophenol) 2- [3- (trifluoromethyl) phenoxy] acetic acid 2- (acetylamino) ethyl ester It is described that there is an effect of effectively reducing resterol and blood lipids.
  • Patent Document 1 Japanese Patent Publication No. 44-30087
  • Non-Patent Document 1 Eyesight, 46, 738-743 (1992)
  • Non-patent document 2 Ophthalmic surgery, 5, 719-727 (1992)
  • the inventors of the present invention conducted intensive research to search for a new medicinal use of benzylcarboxyl compound.
  • a corneal disorder healing efficacy test using a corneal disorder model (-) 2— (4-chlorophenyl) -2- [3 (trifluoromethyl) phenoxy] acetic acid 2- (acetylamino) ethyl ester and (1) 2- (4-chlorophenyl) -2- [3 (trifluoromethyl) phenoxy ] Acetic acid was found to exhibit an excellent improvement effect on corneal injury, leading to the present invention.
  • the present invention provides:
  • a therapeutic agent for keratoconjunctival disorder comprising a compound represented by the following general formula (1) or a salt thereof (hereinafter referred to as “the present compound” ⁇ ⁇ ) as an active ingredient;
  • R 1 represents a hydrogen atom, a lower alkyl group, an aryl group or A—NR 2 (R 3 ); R 2 and R 3 may be the same or different and each represents a hydrogen atom or a substituent. And A represents a lower alkylene group.
  • the keratoconjunctival disorder is, for example, dry eye, corneal ulcer, keratitis, conjunctivitis, punctate surface layer
  • the disease is keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis or filamentous keratitis.
  • the therapeutic agent for keratoconjunctival disorder according to the present invention is preferably an eye drop or an eye ointment.
  • the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 6 carbon atoms, and includes, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butanol Tert-butinole, n-pentinole, isopentinole, neopentinole, n-xinole, isohexyl group and the like.
  • aryl group refers to a monocyclic or bicyclic aromatic hydrocarbon having 6 to 10 carbon atoms, and examples thereof include phenyl and naphthyl groups.
  • the "acyl group” refers to a hydrocarbyl, an alkyl carbo yl or an allyl carbo ol.
  • the acyl group may have a substituent such as a halogen atom.
  • hydrocarbons include formylca
  • alkylcarbols include, for example, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivalol, monochloroacetyl, and trifluoroacetyl. Nzoyl, naphthoyl, toluoyl and the like.
  • the "lower alkylene group” refers to a linear or branched alkylene group having 1 to 8 carbon atoms.
  • methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, otatamethylene, methylmethylene, ethylmethylene group and the like can be mentioned.
  • the salt in this compound is not particularly limited as long as it is a pharmaceutically acceptable salt, salt with inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid. And salts with organic acids such as quaternary ammonium salts are also included in the salts of the present invention.
  • this compound may take the form of a hydrate and a solvate. Further, racemates, optical isomers, polymorphs, tautomers and the like of the present compounds are also included in the scope of the present invention.
  • keratoconjunctival disorder means that the cornea or conjunctiva is damaged due to various factors. For example, dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, filiform keratitis, etc. It is done.
  • the therapeutic agent for keratoconjunctival disorder of the present invention can be administered either orally or parenterally.
  • Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops are particularly preferable. These can be formulated using widely used techniques.
  • eye drops include isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monolate, polyoxyl 40 stearate, polyoxyethylene It can be prepared using surfactants such as hydrogenated castor oil, stabilizers such as sodium quenate and sodium edetate, preservatives such as salt benzalcoum and paraben as necessary. . If the pH is within the acceptable range for ophthalmic preparations, the range of 4-8 is preferred.
  • the eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.
  • oral preparations such as tablets, capsules, granules, powders, etc. include lactose, crystal cellulose, starch, vegetable oil, etc., lubricants such as magnesium stearate, talc, hydroxypropylcellulose, polyvinylpyrrolidone
  • disintegrants such as carboxymethylcellulose calcium and low-substituted hydroxypropylmethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol, and silicone resin, and coating agents such as gelatin film as necessary.
  • the present invention also provides a method for treating keratoconjunctival disorder, comprising administering to a patient a pharmacologically effective amount of a compound represented by the above general formula (1) or a salt thereof.
  • the dosage may be appropriately selected according to symptoms, age, dosage form, etc.
  • % (w / v), preferably 0.001 to 3% (w / v), may be instilled once to several times a day.
  • it is usually 0.1 to 5000 mg per day, preferably 1 to: LOOOmg should be administered once or in several divided doses!
  • Corneal conjunctiva such as dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper ring keratoconjunctivitis, filiform keratitis Useful as a therapeutic agent for disorders.
  • a corneal injury model was prepared according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96—100 (2001)). After the corneal injury model was created, corneal injury was scored according to the method of Murakami et al. (New Ophthalmology 21 (1): 87-90 (2004)) to determine the improvement rate of corneal injury after instillation.
  • a physiological phosphate buffer solution of Compound A (0.02%) was instilled into both eyes 6 times a day for 14 days (4 eyes per group, 8 eyes).
  • a physiological phosphate buffer solution of Compound B (0.02%) was instilled into both eyes 6 times a day for 14 days (4 animals per group, 8 eyes).
  • the damaged part of the cornea was stained with fluorescein.
  • the degree of staining with fluorescein was scored according to the following criteria for each of the upper, middle, and lower parts of the cornea, and the average value of the total score in each of the above parts was calculated. For normal eyes, the average value of the total score in each part was determined.
  • the improvement rate of the compound A administration group calculated by the following formula using the average value of the total score of the control group (physiological phosphate buffer) as the standard (improvement rate: 0%) is shown in Table 1, and the compound B administration group The improvement rates are shown in Table 2.
  • the average score is the average of 8 cases.
  • Improvement rate (%) ⁇ (control) (compound A or B) ⁇ / failure degree X 100
  • the concentration is 0.001% (wZv), 0.01% (wZv), 0 l% (w / v), 0.3% (w / v), 1.0% (w / v), 3.0% (wZv) eye drops can be prepared.
  • an eye ointment with a concentration of 1% (w / w) or 3% (w / w) can be prepared.

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

Abstract

La présente invention concerne un composé représenté par la formule générale (1) ou un sel de celui-ci, qui présente une excellente activité d'amélioration dans un modèle de trouble cornéen et est donc utile en tant qu'agent thérapeutique pour un trouble cornéen/conjonctival tel que l'œil sec, l'ulcère cornéen, la kératite, la conjonctivite, la kératopathie ponctuée superficielle, un défaut épithélial cornéen, un défaut épithélial conjonctival, la kératoconjonctivite sèche, la kératoconjonctivite limbique supérieure et la kératite filamenteuse. [Formule chimique] (1) où R1 représente un atome d'hydrogène, un groupe alkyle inférieur, un groupe aryle ou A-NR2(R3) ; R2 et R3 représentent indépendamment un atome d'hydrogène ou un groupe acyle ; et A représente un groupe alkylène inférieur.
PCT/JP2007/057032 2006-03-30 2007-03-30 Agent therapeutique pour trouble corneen/conjonctival WO2007114315A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2006094167 2006-03-30
JP2006-094167 2006-03-30

Publications (1)

Publication Number Publication Date
WO2007114315A1 true WO2007114315A1 (fr) 2007-10-11

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PCT/JP2007/057032 WO2007114315A1 (fr) 2006-03-30 2007-03-30 Agent therapeutique pour trouble corneen/conjonctival

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TW (1) TW200806285A (fr)
WO (1) WO2007114315A1 (fr)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074666A2 (fr) * 1999-06-04 2000-12-14 Metabolex, Inc. Utilisation de derives d'acide acetique (-) (3-trihalomethylphenoxy) (4-halophenyl) permettant de traiter la resistance insulinique, les diabetes de type 2, l'hyperlipidemie et l'hyperuricemie
WO2002044133A1 (fr) * 2000-11-28 2002-06-06 Pfizer Products Inc. Preparation d'inhibiteurs de type 1 d'echangeur de sodium-hydrogene
US20030220399A1 (en) * 1999-06-04 2003-11-27 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia
JP2005008570A (ja) * 2003-06-19 2005-01-13 Santen Pharmaceut Co Ltd 角膜疾患治療剤
WO2006030753A1 (fr) * 2004-09-13 2006-03-23 Santen Pharmaceutical Co., Ltd. Agent thérapeutique pour un trouble de type kératoconjonctivite
WO2007026630A1 (fr) * 2005-08-29 2007-03-08 Kissei Pharmaceutical Co., Ltd. Agent préventif ou thérapeutique pour une maladie causée par une baisse du liquide lacrymal
WO2007061094A1 (fr) * 2005-11-28 2007-05-31 Senju Pharmaceutical Co., Ltd. Médicament qui comprend un agoniste ppar

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000074666A2 (fr) * 1999-06-04 2000-12-14 Metabolex, Inc. Utilisation de derives d'acide acetique (-) (3-trihalomethylphenoxy) (4-halophenyl) permettant de traiter la resistance insulinique, les diabetes de type 2, l'hyperlipidemie et l'hyperuricemie
US20030220399A1 (en) * 1999-06-04 2003-11-27 Metabolex, Inc. Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia
WO2002044133A1 (fr) * 2000-11-28 2002-06-06 Pfizer Products Inc. Preparation d'inhibiteurs de type 1 d'echangeur de sodium-hydrogene
JP2005008570A (ja) * 2003-06-19 2005-01-13 Santen Pharmaceut Co Ltd 角膜疾患治療剤
WO2006030753A1 (fr) * 2004-09-13 2006-03-23 Santen Pharmaceutical Co., Ltd. Agent thérapeutique pour un trouble de type kératoconjonctivite
WO2007026630A1 (fr) * 2005-08-29 2007-03-08 Kissei Pharmaceutical Co., Ltd. Agent préventif ou thérapeutique pour une maladie causée par une baisse du liquide lacrymal
WO2007061094A1 (fr) * 2005-11-28 2007-05-31 Senju Pharmaceutical Co., Ltd. Médicament qui comprend un agoniste ppar

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BONAZZI A. ET AL.: "Regulation of Cyclooxygenase-2 by Hypoxia and Peroxisome Proliferators in the Corneal Epithelium", J. BIOL. CHEM., vol. 275, no. 4, 2000, pages 2837 - 2844, XP002378239 *

Also Published As

Publication number Publication date
TW200806285A (en) 2008-02-01

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