WO1997000068A1 - Inhibiteur de l'opacification corneenne - Google Patents

Inhibiteur de l'opacification corneenne Download PDF

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Publication number
WO1997000068A1
WO1997000068A1 PCT/JP1996/001636 JP9601636W WO9700068A1 WO 1997000068 A1 WO1997000068 A1 WO 1997000068A1 JP 9601636 W JP9601636 W JP 9601636W WO 9700068 A1 WO9700068 A1 WO 9700068A1
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WIPO (PCT)
Prior art keywords
hydrogen
group
hydroxyl
compound
corneal opacity
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PCT/JP1996/001636
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English (en)
Japanese (ja)
Inventor
Masakazu Takeda
Masaharu Kigawa
Noriko Watanabe
Yasuko Umegaki
Yasushi Okumura
Original Assignee
Senju Pharmaceutical Co., Ltd.
Tsumura & Co.
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Application filed by Senju Pharmaceutical Co., Ltd., Tsumura & Co. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO1997000068A1 publication Critical patent/WO1997000068A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
    • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms

Definitions

  • the present invention relates to a corneal opacity inhibitor, and more particularly to a corneal opacity inhibitor useful as a corneal opacity inhibitor after corneal damage caused by traumatic injury, ophthalmic treatment, or the like.
  • Opaques are induced during the repair of corneal damage caused by traumatic injury or ophthalmic procedures such as surgery or laser irradiation.
  • an object of the present invention is to develop a corneal opacity inhibitor that can be used safely without side effects on corneal opacity after corneal injury caused by traumatic injury or ophthalmic treatment. is there. Disclosure of the invention
  • the present inventors searched for various compounds in search of an excellent corneal opacity inhibitor, and found that a 2,5-bisphenylfuran derivative known as an angiogenesis inhibitor has an excellent corneal opacity inhibitory effect. As a result of further investigation based on these findings, they have completed the present invention.
  • the present invention provides a compound represented by the formula (I):
  • R u and R 12 are the same or different and each is hydrogen, an alkyl group or an esterified but it may also have a carboxyl group
  • R 13 is hydrogen, hydroxyl, (substituted An optionally substituted aromatic carbon ring) a monoalkyl group or a (optionally substituted heterocycle) -alkyl group
  • X represents oxygen or nitrogen. However, when X is oxygen, R 13 represents an lone pair of oxygen.
  • a salt thereof The present invention provides a corneal opacity inhibitor.
  • the optionally substituted hydroxyl group represented by R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 or R 1 is
  • a hydroxyl group, an alkoxy group, an optionally substituted alkylcarbonyloxy group and the like can be mentioned.
  • the alkoxy group includes, for example, an alkoxy group having 1 to 6 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms, specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy. Tert-butoxy and the like. Of these, methoxy is preferred.
  • alkyl group of the optionally substituted alkylcarbonyloxy group examples include an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, specifically, methyl and ethyl. , Propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Of these, methyl is preferred.
  • substituent which the optionally substituted alkylcarboxy group may have include an amino group, a hydroxyl group, a hydroxyl group, a thiol group, and a hydroxyl group.
  • the optionally substituted alkylcarbonyloxy group is preferably an acetyloxy or aminoalkylcarbonyloxy group, particularly a group formed by removing hydrogen of a carboxyl group of an amino acid, specifically, Glycyloxy (ie, aminomethylcarbonyloxy), aranyloxy, / 3-aralanoxy, leucyloxy, isoleucyloxy, lysyloxy, seryloxy, homoseryloxy, naichi or / 3-aspartyloxy, Examples include aglutamyloxy, asparaginyloxy, glutaminyloxy, and the like. Of these, glycyloxy (ie, aminomethylcarbonyloxy) is particularly preferred.
  • Ri R 2 , R 3 , R "R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are preferably the same or different and are hydrogen, hydroxyl, alkoxy (preferably methoxy) Or an optionally substituted alkylcarbonyloxy group (preferably an aminoalkylcarbonyloxy group, more preferably an aminomethylcarbonyloxy group).
  • Ri and R 6 , R 2 and R 7 , R 3 and R 8 , R 4 and R 9 , and R 5 and R 1 () are the same.
  • R 5 and R 10 are preferably hydrogen.
  • the alkyl group represented by Ru, or R 12 for example, an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, specifically, methylation, Echiru, propyl, isopropyl, butyl, Isobutyl, sec-butyl, tert-butyl and the like.
  • the R u or esterified carboxyl group which may be represented by 2, for example, a carboxyl group, and the like alkoxycarbonyl groups.
  • alkoxy group of the alkoxycarbonyl group include an alkoxy group having 1 to 6 carbon atoms, preferably an alkoxy group having 1 to 4 carbon atoms, and specifically, methoxy, ethoxy, propoxy, isopropoxy, butoxy, and isobutoxy. , Sec-butoxy, tert-butoxy and the like.
  • RH and R 12 Ah preferably are the same or different and each is hydrogen, an alkyl group (preferably methyl), a carboxyl group or an alkoxycarbonyl group (favorable Mashiku ethoxycarbonyl), more preferably, hydrogen or methyl.
  • Ru and R 12 are the same.
  • Examples of the aromatic carbon ring of the monoalkyl group (optionally substituted aromatic carbon ring) represented by R 13 include a benzene ring.
  • the aromatic carbon ring is Examples of the substituent that may have, for example, an alkyl group (e.g., C -! Good Mashiku is C 1 - 4 alkyl, particularly, methyl, Echiru, propyl, Petit Le), halogen (e.g., Fluorine, chlorine, bromine, and iodine).
  • the number of the substituents is preferably 1 to 5, and these may be located at any possible position on the aromatic carbon ring.
  • alkyl group of the (optionally substituted aromatic carbocycle) —alkyl group examples include an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, and specifically, Examples include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl. Of these, methyl is particularly preferred.
  • the heterocyclic ring of the alkyl group contains at least one heteroatom atom selected from nitrogen, oxygen and sulfur as a ring-constituting atom.
  • examples thereof include a pyridine ring, an imidazole ring, a pyrrol ring, a pyrazole ring, an isothiazole ring, an isooxazole ring, a pyrazine ring, a pyrimidine ring, and a pyridazine ring.
  • a pyridine ring and an imidazole ring are preferred.
  • the heterocycle may be linked to the alkyl group at any possible position.
  • substituents that may have the heterocycle is, for example, an alkyl group (e.g., d - preferably C -! 4 alkyl, particularly, methyl, Echiru, propyl, blanking chill), halogen (e.g. , Fluorine, chlorine, bromine, iodine) c
  • alkyl group e.g., d - preferably C -! 4 alkyl, particularly, methyl, Echiru, propyl, blanking chill
  • halogen e.g. , Fluorine, chlorine, bromine, iodine
  • alkyl group of the (optionally substituted hetero ring) monoalkyl group examples include an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, specifically, methyl, Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl and the like. Of these, methyl is preferred.
  • Preferred specific examples of the compound represented by the formula (I) are shown below.
  • R 2 is a hydroxyl group, R 3 turtles butoxy
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is a hydroxyl group
  • R 9 is hydrogen
  • R 1 () is A compound in which hydrogen, RH is methyl, R 12 is methyl, and X is oxygen (Compound A, GS-01);
  • R 2 is hydroxyl
  • R 3 is hydrogen
  • R 4 is hydroxyl
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is hydroxyl
  • R 8 is hydrogen
  • R 9 is hydroxyl
  • R lfl is hydrogen
  • Rn is A compound in which hydrogen, R 12 is hydrogen, and X is oxygen (Compound No. 4, GS—B5.58);
  • Ri is hydrogen
  • R 2 is ⁇ amino methylcarbonyl O alkoxy
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is ⁇ Mino methylcarbonyl O alkoxy
  • R 9 is hydrogen
  • R 10 is hydrogen
  • RH is methyl
  • 2 is methyl
  • X is oxygen
  • R 1 is A compound in which hydrogen, is hydrogen, R 12 is hydrogen, R 13 is hydrogen, and X is nitrogen (Compound No. 14, GS-B624);
  • R 2 is methoxy
  • R 3 is hydroxyl
  • R 4 is hydrogen
  • R 5 is hydrogen
  • R 6 is hydrogen
  • R 7 is methoxy
  • R 8 is hydroxyl
  • R 9 is hydrogen
  • R 10 is hydrogen
  • Rn is hydrogen
  • R 12 is hydrogen
  • R 13 is 4 one-methylbenzyl
  • X is a nitrogen of compound (compound No. 16, GS-B 620).
  • a compound in which X is oxygen (hereinafter, referred to as compound (1-1)) can be obtained by, for example, a method described in WO 94Z15594 or a method analogous thereto (particularly, Compound A or its salt Alternatively, according to the following scheme 1, the compound can be obtained directly or indirectly by condensing the butane 1,4-dione moiety of the diketone derivative (II).
  • Rn' and R 12 ′ are Rh R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10.
  • Rn and R 12 the hydroxyl group may be protected by a normal hydroxyl protecting group (eg, benzyl)
  • the condensation reaction of the diketone derivative (II) is desirably carried out under acidic conditions.
  • the diketone derivative (II) can be converted to a mineral acid such as hydrochloric acid or sulfuric acid, an organic acid such as P-toluenesulfonic acid or trifluoroacetic acid, or an aluminum chloride or the like.
  • the reaction can be achieved by using a Lewis acid in a single or mixed organic solvent such as dichloromethane, chloroform, toluene, benzene, and methanol as a reaction solvent, preferably under heating conditions.
  • the compound can also be prepared by heating the diketone derivative ( ⁇ ) together with a dehydrating agent such as phosphorus pentoxide, acetic anhydride, and acetyl chloride in a suitable organic solvent. It is possible to obtain (I-1).
  • a dehydrating agent such as phosphorus pentoxide, acetic anhydride, and acetyl chloride
  • the compound (I-11) obtained by this condensation reaction may be used, if necessary, to debenzylate the substituents at the 2- to 5-positions of the benzene ring, to acetylate the hydroxyl group, and to esterify the hydroxyl group with an amino acid. Conversion of substituents, such as formation, may be performed. Debenzylation is carried out by using a catalyst such as palladium monocarbon catalyst, palladium hydroxide carbon catalyst, palladium chloride, palladium black, Raney nickel, nickel boride, etc., hydrogen gas, suitable formate such as ammonium formate, cyclohexadiene, etc. It can be achieved by the usual method using L, ordinary reducing conditions, or by acting boron chloride in an organic solvent such as dichloromethane.
  • a catalyst such as palladium monocarbon catalyst, palladium hydroxide carbon catalyst, palladium chloride, palladium black, Raney nickel, nickel boride, etc.
  • suitable formate such as ammoni
  • the hydroxyl group is acetylated using an acetylating agent such as acetic anhydride or acetyl chloride, and is not itself acetylated in the presence of a tertiary amine such as pyridine, triethylamine or 4,4-dimethylaminopyridine. It is achieved by reacting at 0 ° C. to around room temperature in an organic solvent.
  • an acetylating agent such as acetic anhydride or acetyl chloride
  • the ester formation between the hydroxyl group and the amino acid may be carried out by any commonly used method. If necessary, the amino group of the amino acid may be replaced with a tert-butoxy- or benzyloxy-lponyl group. After introducing an appropriate protecting group, the reaction can be carried out.
  • ester after the ester is formed, it can be converted into a salt by reacting with an inorganic acid such as hydrochloric acid or an organic acid such as maleic acid.
  • the substituents at the 3- and 4-positions of the furan ring may be subjected to hydrolysis, esterification, amidation, hydroxam oxidation or sodium chloride, if necessary.
  • the hydrolysis reaction is desirably performed under basic conditions or acidic conditions.
  • an alkaline hydroxide such as sodium hydroxide is added to water or a mixed solvent of water and an organic solvent such as alcohol. It can be achieved by reacting at room temperature to 10 ° C.
  • the reaction can be achieved by using a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid at 0 to 10 ° C.
  • a mineral acid such as hydrochloric acid or sulfuric acid
  • an organic acid such as p-toluenesulfonic acid or trifluoroacetic acid at 0 to 10 ° C.
  • Suitable salts include alkali metal salts (such as sodium and potassium), alkaline earth metal salts (such as calcium and magnesium), and pharmaceutically acceptable organic amine salts.
  • Esterification or amidation of a carboxylic acid derivative is performed by converting the carboxylic acid derivative into a corresponding acid chloride derivative with thionyl chloride or oxalyl chloride and then using an appropriate alcoholamine or hydroxylamine.
  • a protecting group is introduced by cooling or heating a compound containing a hydroxyl group in a suitable solvent together with a corresponding benzylating agent such as benzyl halide in the presence of a base such as aluminum carbonate.
  • the reaction can be carried out by performing the following reaction.
  • the introduction of a silyl group can be achieved by cooling or heating a compound containing a hydroxyl group together with a silylating agent such as silyl halide in an appropriate solvent in the presence of amine, alkali carbonate or the like.
  • the removal of the benzyl group which is a protecting group is as described above.
  • the silyl group can be removed by reacting with an acid such as hydrochloric acid or a fluorine compound such as potassium fluoride, ammonium fluoride or hydrofluoric acid in a suitable solvent. It is possible to do.
  • the compound represented by the formula (I-11) can be obtained directly or indirectly by condensing a diketone derivative (II) and further performing substituent conversion as necessary. Can be. Specific combinations of reactions and operations for obtaining the compound represented by the formula (I-11) will be described in Examples below.
  • Compounds of the formula (I) in which X is nitrogen may be prepared according to the following scheme 2, for example, diketone derivative (II) and primary Amine in the presence of common acids (eg, hydrochloric acid, acetic acid, p-toluenesulfonic acid), for example, in an organic solvent such as toluene, benzene, dichloromethane, chloroform, tetrahydrofuran, at room temperature to The reaction can be carried out at 100 ° C., preferably while heating, and if necessary, the above-mentioned conversion of substituents can be carried out directly or indirectly.
  • common acids eg, hydrochloric acid, acetic acid, p-toluenesulfonic acid
  • organic solvent such as toluene, benzene, dichloromethane, chloroform, tetrahydrofuran
  • R 2 ', R 3', R 4 ', R 5', R e ', R, R 8', R 9 ', Rio' R u ' and R 12' are each R !, R 2, R 3, R 5, R 6, R 7 , R 8, Represents a group defined by R 9 , R 1 () , RH and R 12 (the hydroxyl group may be protected with a normal hydroxyl protecting group (eg, benzyl)]
  • a normal hydroxyl protecting group eg, benzyl
  • the diketone derivative (II) used as a raw material in the reactions of the above schemes 1 and 2 may be obtained by any known production method.
  • an ⁇ -silyloxystyrene derivative is converted to an oxide such as copper chloride (11), lead tetraacetate, silver oxide (1), copper trifluoromethanesulfonate (I :), manganese oxide (II) or odosobenzene.
  • the reaction is carried out in the presence of an agent, or -octaloacetophenone derivative is reduced in the presence of bis (trifuunylphosphine) nickel bromide (11), zinc, tetraethylammonium iodide, etc.
  • Silyloxystyrene is obtained by using a corresponding acetofenone derivative in the presence of a base such as lithium dialkyl amide or triethylamine, using a silyl halide or silyl sulfonate as a silylating agent, and using an aprotic organic compound such as tetrahydrofuran or dichloromethane. It is obtained by reacting in a solvent at room temperature to 180 ° C (preferably 0 to 180 ° C).
  • corneal opacity refers to corneal opacity that occurs in the process of repair of a cornea damaged by traumatic injury or ophthalmic treatment, etc. It is the result of light scattering.
  • the factors include, for example, a case where corneal stromal cells are aggregated into fibroblast-like cells in a corneal wound, and a case where the cytoplasm swells like an edema.
  • the corneal opacity of the present application excludes corneal opacity due to traumatic injury or neovascularization after ophthalmic treatment.
  • Trauma includes, for example, gravel, Ophthalmological procedures, such as the penetration of solid foreign objects such as iron pieces and damage by blades and nails, include corneal incision with a metal scalpel or diamond scalpel, incision or resection of the cornea by excimer laser irradiation, corneal transplantation, etc. Included.
  • the corneal opacity inhibitor of the present invention can be obtained by preparing a preparation in various dosage forms using the compound represented by the formula (I) (compound (I)) or a salt thereof as an active ingredient.
  • Examples of the salt of compound (I) include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, tertiary amine salts generally having low toxicity, and acid addition salts (for example, pharmaceutically acceptable salts such as hydrochloride).
  • alkali metal salts such as sodium salt and potassium salt
  • alkaline earth metal salts such as magnesium salt and calcium salt
  • tertiary amine salts generally having low toxicity
  • acid addition salts for example, pharmaceutically acceptable salts such as hydrochloride.
  • the content of (I) or a salt thereof varies depending on the form of the preparation, but is usually from 0.01 to: L 0.0% by weight, preferably from 0.05 to 2.0 weight% based on the whole preparation. %.
  • any form can be used, and for example, it can be used as an aqueous solution, suspension, gel, ointment, emulsion, sustained-release or sustained-release preparation. Further, it may be in the form of a powder, granule, tablet or the like, which is dissolved in purified water or the like before use. For its application, it is preferable to use a dosage form for eye drops.
  • a production method generally used for producing ophthalmic agents can be used.
  • the manufacturing methods of eye drops and eye ointments are described in the 12th revised edition of the Japanese Pharmacopoeia, General Rules for Preparations [edited by the Japanese Official Standards Association, published by Hirokawa Shoten (Tokyo), 1991], and eye drops [Honse Kenji, Nanzan-do (Tokyo), 1984].
  • sustained-release preparations for example, BIOPHARMACEUTICS OF OCULAR DRUG DELIVERY (Peter Edma, CRC Press (USA), 1993) Manufactured by the method described in You.
  • the corneal opacity inhibitor of the present invention for ophthalmic use, it is preferable to add known additives commonly used for ophthalmic preparations.
  • Additives when formulated as an aqueous eye drop include, for example, preservatives, tonicity agents, buffers, stabilizers, thickeners, suspending agents, surfactants and pH adjusters Used.
  • preservatives parabens (methyl paraoxybenzoate, propyl paraoxybenzoate, etc.), inverting stones (benzalkonium chloride, benzethonium chloride, chlorhexidine dalconate, cetylpyridinium chloride, etc.) , Alcohol derivatives (chlorobutanol, phenylethyl alcohol, benzyl alcohol, etc.), organic acids and their salts (sodium dehydrophosphate, sorbic acid and its salts, etc.), phenols (parachloromethoxyphenol, parachloromethcresol) And organic mercury agents (such as thimerosal, phenylmercuric nitrate, and nitromezole).
  • tonicity agent sodium chloride, glycerin, mannitol and the like are used.
  • Buffers include boric acid and its salts (such as borax), phosphates (such as disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate and potassium dihydrogen phosphate), and acetate salts (Sodium acetate, ammonium acetate, etc.) and amino acid salts (glutamic acid, ⁇ -aminocaproic acid, etc.).
  • an antioxidant such as sodium sulfite, sodium bisulfite, sodium metabisulfite, etc.
  • a chelating agent such as sodium edetate, citric acid and salts thereof
  • the thickener examples include polyhydric alcohols (glycerin, macrogol, etc.), sugars (sorbitol, mannitol, sucrose, etc.), celluloses (methylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, etc.) and synthetic polymers. Child compounds (polyvinyl alcohol, polyvinyl pyrrolidone, carboxyvinyl polymer, etc.) are used. As the suspending agent, surfactants and the like are used in addition to the above-mentioned celluloses and synthetic polymer compounds.
  • surfactants include nonionic surfactants such as polysorbate and polyoxyethylene hydrogenated castor oil, cationic surfactants such as quaternary ammonium salts, anionic surfactants such as alkyl sulfates, and lecithin.
  • nonionic surfactants such as polysorbate and polyoxyethylene hydrogenated castor oil
  • cationic surfactants such as quaternary ammonium salts
  • anionic surfactants such as alkyl sulfates
  • lecithin lecithin.
  • the amphoteric surfactant is used. Hydrochloric acid, acetic acid, sodium hydroxide, phosphoric acid and the like are used as pH adjusters.
  • the amount of these additives used depends on the active ingredient and the amount used, but it is usually desirable to approximate the physiological condition of the eye (isotonic with tears). For example, usually 230 to 45 OmO sm It is preferably adjusted to 260 to 32 O mO sm before use.
  • the corneal opacity inhibitor of the present invention is formulated in the form of a gel or the like
  • the corneal opacity inhibitor is prepared by mixing sodium alginate and the like in addition to the preservative and the water-soluble polymer.
  • the corneal opacity inhibitor of the present invention is formulated in a non-aqueous form such as an ointment, in addition to the above preservatives, for example, liquid paraffin, propylene glycol, 5-octyldodecanol, petrolatum, plastibase, purified lanoli And vegetable oils.
  • the corneal opacity inhibitor of the present invention When used for eye drops, it is advantageous to use the corneal opacity inhibitor adjusted to a pH range usually used for eye drops. Usually, for example, hydrochloric acid, acetic acid, phosphoric acid, The pH is adjusted to 3 to 8, preferably 4 to 7 using a suitable pH adjuster such as sodium hydroxide.
  • the corneal opacity inhibitor of the present invention generally includes other pharmaceutical ingredients used locally in the eye, for example, glaucoma treatment agent, cataract treatment agent, antibacterial agent, vasoconstrictor, antiallergic agent and / or antiallergic agent.
  • An inflammatory agent or the like may be added.
  • glaucoma treatment agent for example, pilocarpine, distigmine bromide, epinephrine dipivalate, timolol maleate, bupranolol hydrochloride and the like are used.
  • cataract treatment agents pyrenoxine, glutathione and the like are used.
  • Antibacterial agents include antibiotics (potassium penicillin G, chloramphenicol, erythromycin, kanamycin sulfate, tetracycline hydrochloride, cefmenoxime, etc.), and antifungal agents (pimaricin, amphotericin B, nystatin, etc.).
  • antibiotics potassium penicillin G, chloramphenicol, erythromycin, kanamycin sulfate, tetracycline hydrochloride, cefmenoxime, etc.
  • antifungal agents primaricin, amphotericin B, nystatin, etc.
  • vasoconstrictors naphazoline nitrate, oxymethasone hydrochloride, phenylephrine hydrochloride and the like are used.
  • antiallergic agents include antihistamines (diphenhydramine hydrochloride, chlorpheniramine maleate, etc.), sodium cromoglycate, amlexanox and the like.
  • Anti-inflammatory agents include corticosteroids (cortisone, prednisolone, triamcinolone acetonide, dexamethasone, betamethasone, etc.) and non-steroid anti-inflammatory agents (indomethacin, flurbiprofen, pranoprofen, etc.).
  • the amount of these pharmaceutical ingredients to be used is generally 0.01 to 100 parts by weight, preferably 0.01 to 50 parts by weight, per 1 part by weight of compound (I) or a salt thereof. .
  • the corneal opacity inhibitor of the present invention can be formulated into a sustained or sustained-release preparation by, for example, a biodegradable polymer (such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate) or acrylic. It is preferable to add an acid-based resin (methacrylic acid / acrylic acid ester copolymer, methacrylic acid / methacrylic acid ester copolymer, etc.). The addition amount is usually 0.1 to 0.5 parts by weight, preferably 0.5 to 50 parts by weight, based on 1 part by weight of compound (I) or a salt thereof.
  • a biodegradable polymer such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate
  • acrylic an acid-based resin
  • the addition amount is usually 0.1 to 0.5 parts by weight, preferably 0.5 to 50 parts by weight, based on 1 part by weight of compound (I) or a salt thereof.
  • the corneal opacity inhibitor of the present invention thus obtained can be used for opacity induced during the repair of corneal damage caused by traumatic injury or ophthalmic treatment such as surgery or laser irradiation, and fibroblast-like It has an excellent effect of suppressing corneal opacity accompanying cell proliferation. Therefore, traumatic injuries to mammals (eg, mice, rats, hamsters, egrets, cats, cats, dogs, dogs, dogs, horses, hedges, monkeys, humans, etc.) or ophthalmological procedures such as laser surgery.
  • mammals eg, mice, rats, hamsters, egrets, cats, cats, dogs, dogs, dogs, horses, hedges, monkeys, humans, etc.
  • ophthalmological procedures such as laser surgery.
  • Opaques induced during the repair of corneal damage caused by the procedure e.g., diffuse epidermal subepithelial epithelium in the irradiated area after therapeutic laser keratotomy, refractive and astigmatic correction with excimer laser It can be used safely for prevention or treatment of retinal opacity and corneal opacity accompanied by proliferation of fibroblast-like cells.
  • the use of the corneal opacity inhibitor of the present invention varies depending on the form, but can be carried out according to a known method generally used for ophthalmic preparations. be able to.
  • the corneal opacity inhibitor of the present invention when used as an aqueous ophthalmic solution for corneal opacity after excimer laser irradiation in adults, the compound may vary depending on, for example, age, body weight, symptoms, administration method, etc.
  • the concentration of (I) or its salt should be 0.01 to 10.0 w / v%, preferably 0.05 to 2.0 wv%, and this should be administered 3 to 6 times, 1 to several drops in drops. Is good.
  • the concentration of compound (I) or a salt thereof is adjusted to 0.02-10.0% by weight, preferably 0.05 to 2.0% by weight. It is recommended to use a stick to inject a dose of 30-10 Omg into the conjunctival sac.
  • a suspension of Compound A in physiological saline so as to be lwZv% was used, and this was used as Compound A ophthalmic solution.
  • Physiological saline and 0.1% Rinderone registered trademark; betamethasone sodium phosphate ophthalmic solution, Shionogi & Co., Ltd.
  • Rinderone registered trademark; betamethasone sodium phosphate ophthalmic solution, Shionogi & Co., Ltd.
  • the irradiation conditions of the excimer laser were set so that the diameter was 2.5 mm, the frequency was 50 Hz, the irradiation energy was 16 OmJ Zcm 2 , the number of scans was 60, and the excision rate was 0.8 ⁇ scan.
  • Ketalal registered trademark; ketamine hydrochloride, manufactured by Sankyo Co., Ltd.
  • venoxil ophthalmic solution registered trademark; oxybupro hydrochloride
  • PRK photorefractive keratectomy
  • Physiological saline, Compound A ophthalmic solution or 0.1% Rinderone are applied twice a day after PRK treatment on the day of PRK treatment, 4 times a day from the next day, 5 ⁇ 1 each time, and prevent infection
  • Taribit ophthalmic solution registered trademark: Ofloxacin, Santen Pharmaceutical Co., Ltd.
  • the cornea was observed with a slit lamp after treatment 3 and 6, and after 6 days, the cornea was scored according to the following scoring criteria, and the corneal opacity score and the suppression rate for the saline eye drop group were calculated. .
  • the eyeball was enucleated and a histopathological specimen was prepared according to a standard method. After slicing the central part of the eyeball, hematinlin 'eosin staining was performed, histological observation was performed under a light microscope (X40), and the number and fixed length of the subepithelial fibroblast-like cell layer (330) The number of fibroblast-like cells per // m) was counted.
  • Table 1 shows the score of corneal opacity by the slit lamp after PRK 6 and the suppression rate for the saline instillation group. Number of cases Suppression rate group Corneal opacity scoring value
  • Corneal opacity was observed in each group, but significant suppression of corneal opacity was observed in the compound A ophthalmic solution ophthalmic solution group as compared with the physiological saline ophthalmic solution ophthalmic solution group. Also in the 0.1% Rinderone ophthalmic group, significant suppression of corneal opacity was observed as compared with the physiological saline ophthalmic group, but the extent was less than that of the Compound A ophthalmic solution ophthalmic group. In addition, corneal perforation was observed in two cases in the 0.1% Rinderon ophthalmic group. No angiogenesis was observed in any of the groups at any time by slit lamp observation.
  • the cornea at the PRK treatment site was 10% less in the 0.1% Rinderon ophthalmic group than in the saline solution group and the compound A ophthalmic solution group. Eight of the cases had corneal thinning Was.
  • Table 2 shows the number of cell layers and the number of fibroblast-like cells observed under the epithelium of the cornea in each group, and the inhibitory rate of the drug instillation group to the saline instillation group.
  • Compound A ophthalmic solution does not show side effects such as corneal thinning and corneal perforation like steroid ophthalmic solution, and corneal opacity and subcutaneous epithelium observed after excimer laser irradiation. For blast-like cell proliferation It has been found that they exhibit an excellent inhibitory action.
  • test cells were seeded on a 24-well plate (manufactured by Becton Dickinson) so that the cells became 10% confluent. After the cells cultured for 24 hours, it was added 3 ⁇ culture so that the test drug and 10_ 5 M. After the test drug addition 2, half of the culture solution was replaced with the test drug-added culture solution. The number of cells was measured using a hemocytometer before and after adding the test drug, and the corneal stromal cell growth inhibition rate was calculated.
  • test drug was dissolved in dimethylsulfoxide (DMSO) and diluted to the desired concentration in an Eagle MEM medium containing 10 v / v% FBS so that the final DMSO concentration was 0.1 lv / v%.
  • DMSO dimethylsulfoxide
  • Table 3 shows the corneal stromal cell growth inhibition rate of each test drug. Each test drug inhibited the growth of keratocytes in 10- 5 M. Table 3
  • Anti-proliferation rate Compound Oo Increased corneal stromal cells
  • the compound of the present invention can suppress the proliferation of corneal stromal fibroblast-like cells, it can suppress corneal opacity that occurs after corneal injury due to traumatic injury or ophthalmic treatment.
  • the carboxyvinyl polymer was dispersed in about 8 Om1 of sterile purified water, the pH was adjusted to 7.0 with sodium hydroxide, and sterile purified water was added to make a total volume of 100 ml. This is stirred at 200 rpm using an emulsification tester (Nikko Chemicals ET-1A type). Compound A and benzalco chloride are added to this gel base. Add dimethyl and stir with an emulsification tester to produce.
  • GS-B620 methyl paraoxybenzoate and propyl paraoxybenzoate are added to about 10 g of white perserin, mixed evenly, and further mixed with white perserin with stirring to make the total amount 100 g, 2.0 w / w % GS-B 620 eye ointment.
  • Reference example 1 methyl paraoxybenzoate and propyl paraoxybenzoate are added to about 10 g of white perserin, mixed evenly, and further mixed with white perserin with stirring to make the total amount 100 g, 2.0 w / w % GS-B 620 eye ointment.
  • the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 4'-benzyloxy-3'-methoxy-trimethylsilyloxystyrene (3.27 g, yield 99.6%) as a yellow oil. .
  • the physicochemical properties of the obtained compound are as follows.
  • NU-Methylbenzyl) -2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-diethyl rubonate (Compound 11 shown in Table 5, GS-B114 ), N-Hydroxy-2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole-Jetyl 3,4-dicarboxylate (Compound 12 shown in Table 5, GS-B169), N-benzyl- 2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrol (compound 13 shown in Table 5, GS-B613), 2,5-bis (4-hydroxy-3-methoxy) Cifenyl) pyrrole (compound 14 shown in Table 5, GS-B624), N- (4-chlorobenzyl) -2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole (shown in Table 5) Compound 15, GS-B617), N- (4-methylbenzyl) -2,5
  • ester hydrolysis is performed to give NU-clo- mouth benzyl) from 2,4-bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-dicarboxylate getyl.
  • -2,5-Bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-dipyruroponic acid (compound 21, GS-B81 shown in Table 5) was converted to N- (4-methylbenzyl).
  • Et i-tyl group
  • Bn benzyl group
  • 4-MeBn 4-methylbenzyl group
  • 3-PyMe 3-pyridylmethyl group
  • 1-lmPr 3 (1-imidazolyl) propyl group
  • 4-MeCi 4-methyl methyl cinnamate -98-
  • the corneal opacity inhibitor of the present invention is low-toxic and corneal opacity generated in the process of repairing corneal damage caused by traumatic injury or ophthalmic treatment such as surgical operation or laser irradiation. It has an excellent inhibitory effect on corneal opacity, and is useful for the prevention and treatment of corneal opacity.
  • the corneal opacity inhibitor of the present invention exhibits an inhibitory effect on fibroblast-like cells proliferating by traumatic injury or ophthalmic treatment such as surgical operation, laser irradiation, etc. It is useful for the prevention and treatment of breeding.

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  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Un inhibiteur de l'opacification cornéenne comprend un composé représenté par la formule générale (I) ou un sel de celui-ci. Dans cette formule, R1, R2, R3, R4, R5, R6, R7, R8, R9 et R10 sont les mêmes ou différents et chacun représente hydrogène ou hydroxy éventuellement substitué; R11 et R12 sont les mêmes ou différents et chacun représente un hydrogène, un alkyle, ou une carboxy, éventuellement estérifié; R13 représente un hydrogène, un hydroxy, un (cycle carboné aromatique éventuellement substitué)-alkyle ou un (hétérocycle éventuellement substitué)-alkyle; et X représente un oxygène ou un azote, à condition que R13 représente une paire d'électrons non partagés quand X est un oxygène.
PCT/JP1996/001636 1995-06-16 1996-06-14 Inhibiteur de l'opacification corneenne WO1997000068A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018095A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylfurane utilises comme inhibiteurs de phosphodiesterase iv (pde iv)
US7280810B2 (en) 2005-08-03 2007-10-09 Kamilo Feher Multimode communication system
US7356343B2 (en) 2005-08-03 2008-04-08 Kamilo Feher Emergency location transceivers (ELT)
US7376180B2 (en) 1998-08-10 2008-05-20 Kamilo Feher Adaptive receivers for bit rate agile (BRA) and modulation demodulation (modem) format selectable (MFS) signals
US9319212B2 (en) 1999-08-09 2016-04-19 Kamilo Feher Fingerprint authenticated touchsceeen contolled cascaded 3G-OFDM mobile systems
US9373251B2 (en) 1999-08-09 2016-06-21 Kamilo Feher Base station devices and automobile wireless communication systems
US10009956B1 (en) 2017-09-02 2018-06-26 Kamilo Feher OFDM, 3G and 4G cellular multimode systems and wireless mobile networks

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4595693A (en) * 1984-06-04 1986-06-17 Merck & Co., Inc. Method of use of 2,5-diaryl tetrahydrofurans and analogs thereof as PAF-antagonists
JPH02240058A (ja) * 1989-02-10 1990-09-25 Basf Ag ジアリール置換複素環式化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4595693A (en) * 1984-06-04 1986-06-17 Merck & Co., Inc. Method of use of 2,5-diaryl tetrahydrofurans and analogs thereof as PAF-antagonists
JPH02240058A (ja) * 1989-02-10 1990-09-25 Basf Ag ジアリール置換複素環式化合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
"Nanzando's Medical Dictionary", NANZANDO CO., LTD., Feb. 1st, 1990, 7th Edit., Section, "Corneal Apacity". *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018095A1 (fr) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Derives d'arylfurane utilises comme inhibiteurs de phosphodiesterase iv (pde iv)
US7376180B2 (en) 1998-08-10 2008-05-20 Kamilo Feher Adaptive receivers for bit rate agile (BRA) and modulation demodulation (modem) format selectable (MFS) signals
US9397724B1 (en) 1999-08-09 2016-07-19 Kamilo Feher Transceivers digital mobile communications
US9755874B2 (en) 1999-08-09 2017-09-05 Kamilo Feher Digital mobile communication
US9742605B2 (en) 1999-08-09 2017-08-22 Kamilo Feher OFDM mobile networks
US9319212B2 (en) 1999-08-09 2016-04-19 Kamilo Feher Fingerprint authenticated touchsceeen contolled cascaded 3G-OFDM mobile systems
US9373251B2 (en) 1999-08-09 2016-06-21 Kamilo Feher Base station devices and automobile wireless communication systems
US8849313B2 (en) 2005-08-03 2014-09-30 Kamilo Feher Cable connected mobile video, cellular and Wi-Fi communications
US7356343B2 (en) 2005-08-03 2008-04-08 Kamilo Feher Emergency location transceivers (ELT)
US7280810B2 (en) 2005-08-03 2007-10-09 Kamilo Feher Multimode communication system
US10588174B2 (en) 2005-08-03 2020-03-10 Kamilo Feher Digital communications cellular multimode systems and wireless networks
US10616014B2 (en) 2005-08-03 2020-04-07 Kamilo Feher Pacemaker heart diagnostics implantable cardiac stimulation
US10659262B2 (en) 2005-08-03 2020-05-19 Kamilo Feher Automobile mobile communication networks and remote controlled devices
US11063796B2 (en) 2005-08-03 2021-07-13 Kamilo Feher Data communications, processing of camera, sensor and other digital signals, in 5G, 4G, 3G and 2G wireless and wired systems-networks
US11070408B2 (en) 2005-08-03 2021-07-20 Kamilo Feher Air based unmanned vehicle communications and control
US11146431B2 (en) 2005-08-03 2021-10-12 Kamilo Feher Computer 5G, 4G, 3G and 2G cellular and wi-fi communications
US11233682B2 (en) 2005-08-03 2022-01-25 Kamilo Feher Digital automobile multimedia, Wi-Fi, cellular communication, photo and video camera, remote control, navigation, GPS location
US10009956B1 (en) 2017-09-02 2018-06-26 Kamilo Feher OFDM, 3G and 4G cellular multimode systems and wireless mobile networks

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