WO1999055329A1 - Medicament contre la cataracte - Google Patents

Medicament contre la cataracte Download PDF

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Publication number
WO1999055329A1
WO1999055329A1 PCT/JP1999/002239 JP9902239W WO9955329A1 WO 1999055329 A1 WO1999055329 A1 WO 1999055329A1 JP 9902239 W JP9902239 W JP 9902239W WO 9955329 A1 WO9955329 A1 WO 9955329A1
Authority
WO
WIPO (PCT)
Prior art keywords
cataract
present
compound
therapeutic agent
dce
Prior art date
Application number
PCT/JP1999/002239
Other languages
English (en)
Japanese (ja)
Inventor
Kazumi Ogata
Takahiro Sakaue
Yutaka Inoue
Original Assignee
Senju 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 Senju Pharmaceutical Co., Ltd. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO1999055329A1 publication Critical patent/WO1999055329A1/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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/223—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of alpha-aminoacids

Definitions

  • the present invention relates to a useful cataract treatment agent. More specifically, the present invention relates to a useful cataract treatment agent comprising a triester derivative of S- (1,2-dicarboxyethyl) glucanthione or a pharmacologically acceptable salt thereof.
  • Cataract is a disease in which the lens becomes opaque for various reasons. For example, senile cataract and cataract caused by drugs such as steroids are known.
  • the present inventors have conducted intensive studies in search of a compound having a further excellent cataract treatment agent.
  • the carboxyl group of the glycine residue of S- (1,2-dicarboxyethyl) daryuthione and the succinic acid moiety It has been found that a triester derivative in which all of the carboxyl groups are esterified has an extremely powerful cataract treatment effect, and the present invention has been completed based on these new findings.
  • the present invention provides a therapeutic agent for cataract containing a triester of S- (1,2-dicarboxyethyl) glucanthione.
  • R 2 and R 3 are the same or different and C, -C,. Represents a lower alkyl group. Or a pharmacologically acceptable salt thereof (hereinafter referred to as “the present compound”) as an active ingredient;
  • the present invention relates to the cataract treatment agent according to [1] or [2] above, wherein the dosage form is for topical administration to the eye.
  • the present compound contained in the therapeutic agent for cataract of the present invention contains a carboxy group of a glycine residue of S— (1,2-dicarboxyethyl) glucanthione and succinic acid. It is a triester in which all carboxyl groups are esterified.
  • the lower alkyl groups of R 2 and R 3 may be the same or different, and preferably have 1 to 10 carbon atoms.
  • the carbon chain in the alkyl group may be linear, branched or cyclic, and may further include a cyclic portion. That is, alkyl groups include methyl, ethyl, n-propyl, i-propyl, cyclopropyl, n-butyl, t-butyl, sec-butyl, n-pentyl, and 1-ethylpropyl And an i-pentyl group, among which an ethyl group and an i-propyl group are particularly preferred.
  • the compound is a free acid or a pharmacologically acceptable salt, for example, an alkali metal salt such as a sodium salt or a potassium salt, It can be used as alkaline earth metal salts such as calcium salts and magnesium salts.
  • alkali metal salt such as a sodium salt or a potassium salt
  • alkaline earth metal salts such as calcium salts and magnesium salts.
  • the acid salt of the present compound include inorganic salts such as hydrochloric acid, sulfuric acid and nitric acid, and organic salts such as acetic acid and citrate-tartaric acid, but are not limited to these as long as they are pharmacologically acceptable salts.
  • the free form of the DCE-GS triester which is the active ingredient of the therapeutic agent for cataract of the present invention, that is, S— (1,2-dicarboxyethyl) glucanthione, is obtained from DH Cal am and SG Waley ( Biochem. J. 86 226 (1963) is a biological substance found in the bovine lens, but the inventors have previously found that the carboxyl group of the succinic acid portion of DCE-GS and DCE-GS was mono (or di- It has been found that esterified compounds have an anticoagulant effect, a platelet aggregation inhibitory effect, an anti-inflammatory and antiallergic effect, an antitumor effect, a liver damage inhibitory effect, etc. (Japanese Patent Publication No. 5-86931, 2-255624, JP-A-3-48626, JP-A-3-112933, JP-A-3-118334).
  • the present inventors have reported that the DCE-GS triester of the present compound has an anti-inflammatory effect, an anti-allergic and hepatic disorder-suppressing effect (International Publication No .: WO91 / 12262), and an effect of improving lipid metabolism. (Japanese Unexamined Patent Publication No. 6-80582).
  • the DCE-GS triester which is an active ingredient of the therapeutic agent for cataract of the present invention, has better corneal permeability than the above-mentioned DCE-GS and DCE-GS diesters. A therapeutic effect can be expected.
  • the triester of the present compound has a high absorbability from the gastrointestinal tract, and as a result, has an excellent rate of reaching the affected ocular local area. It can be used to advantage.
  • the therapeutic agent for cataract of the present invention may contain one or more of the present compounds as appropriate, if necessary.
  • the present compound used as an active ingredient of the therapeutic agent for cataract of the present invention namely DCE-GS
  • the triester can be obtained by a known method, for example, as follows (International Publication No .: WO91 / 12262).
  • the desired compound is obtained by using glucan thione ester as a raw material compound and leaving an equimolar mixture of this and maleic diester in an aqueous solution or alcoholic aqueous solution for 1 to 2 days under heating or at room temperature.
  • a triester derivative of S— (1,2-dicarboxyethyl) dalhythion is obtained.
  • an alkali metal salt, an alkaline earth metal salt or an acid salt can be appropriately prepared by a known method.
  • the DCE-GS triester used as an active ingredient of the therapeutic agent for cataract of the present invention is an ester derivative of a biological substance (DCE-GS), so it has low toxicity, excellent safety, and various administration forms. It can be advantageously used for various cataract treatment agents.
  • the therapeutic agent for cataract of the present invention is appropriately used orally or parenterally for the prevention and treatment of cataract due to various causes such as senile cataract and diabetic cataract. As mentioned above, it is particularly preferred to administer orally or topically to the eye.
  • a form of the preparation any form such as a solid preparation such as tablets, granules, powders and capsules or a liquid preparation such as eye drops and injections can be appropriately prepared by a known method.
  • binders for these preparations, commonly used binders, disintegrants, thickeners, dispersants, resorption promoters, flavoring agents, buffers, surfactants, solubilizers, preservatives, emulsifiers, isotonic agents
  • binders such as a stabilizing agent and a pH adjuster may be appropriately used.
  • the dosage of the compound used for the treatment of cataract varies depending on the type of the compound, the age of the patient, the body weight, the dosage form, the indication, etc.For example, in the case of an injection, an adult is about 0 once a day.
  • the dose is about 1 to 100 mg, preferably about 1 to 50 mg, and in the case of oral administration, the dose is about 5 to 1000 mg, preferably about 10 to 500 mg once a day for an adult several times a day.
  • a concentration of about 0.1 to ⁇ , preferably about 0.5 to 3% is preferably applied several times a day.
  • the therapeutic agent for cataract of the present invention may appropriately contain other therapeutic agents for cataract and Z or a component having another kind of medicinal effect, as long as the object of the present invention is not violated.
  • GSH Daryuthion
  • r-GCS r-glutamylcysteine synthetase
  • the group consisted of 8 to 12 animals per group.
  • Control group (2) Isopropyl S— (1,2-diethoxycarbonylethyl) dal thione (in the above formula, represents an isopropyl group, and R 2 and R 3 represent an ethyl group.
  • DCE-Et-GS iPr. 0.5 brain o 1 / kg administration group 3
  • DCE_Et-GS iPr 1.0 bandol ol / kg administration group and 3 normal group were set.
  • Cataract was induced by subcutaneous administration of 8303 mmol / kg for 2 days at 18:00 ⁇ 1 ⁇ 4:00.
  • Cataracts were observed using a slit lamp microscope after BS0 administration and after the newborn rat opened its eyes (day 19).
  • test substance was administered intraperitoneally 4 hours after BS0 administration, ie, at 12:00 PM and 20:00 PM, for 2 days.
  • the lens of the rat was observed on the 19th day of cataract induction using a slit lamp microscope.
  • the degree of cataract was scored based on the following grades.
  • V Lens with opacity up to the center
  • the above are mixed and sterile filtered.
  • the filtrate is aseptically filled into glass ampoules, 2 ml each, and sealed to prepare an injection.
  • the above is used as an eye drop according to a conventional method.
  • the DCE-GS triester which is the active ingredient of the therapeutic agent for cataract of the present invention, is more excellent in corneal permeability and oral localization rate by oral administration than the DCE-GS ester, and is therefore particularly suitable for topical ocular or intraocular administration.
  • a strong cataract treatment effect can be expected by oral administration. Therefore, the therapeutic agent for cataract of the present invention can be advantageously used for prevention and treatment of cataract based on various causes such as senile cataract and diabetic cataract.

Landscapes

  • Health & Medical Sciences (AREA)
  • Emergency Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

Ce médicament contre la cataracte est caractérisé en ce qu'il contient en tant que principe actif, soit un composé représenté par la formule (I), (dans laquelle R1, R2 et R3 sont semblables ou différents et représentent chacun alkyle C1-10), soit un sel de ce composé, acceptable sur le plan pharmacologique.
PCT/JP1999/002239 1998-04-27 1999-04-26 Medicament contre la cataracte WO1999055329A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/116974 1998-04-27
JP11697498 1998-04-27

Publications (1)

Publication Number Publication Date
WO1999055329A1 true WO1999055329A1 (fr) 1999-11-04

Family

ID=14700374

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1999/002239 WO1999055329A1 (fr) 1998-04-27 1999-04-26 Medicament contre la cataracte

Country Status (1)

Country Link
WO (1) WO1999055329A1 (fr)

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501354A1 (fr) * 1991-02-27 1992-09-02 Senju Pharmaceutical Co., Ltd. Composition anticataracte

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0501354A1 (fr) * 1991-02-27 1992-09-02 Senju Pharmaceutical Co., Ltd. Composition anticataracte

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