WO1997000068A1

WO1997000068A1 - Corneal clouding inhibitor

Info

Publication number: WO1997000068A1
Application number: PCT/JP1996/001636
Authority: WO
Inventors: Masakazu Takeda; Masaharu Kigawa; Noriko Watanabe; Yasuko Umegaki; Yasushi Okumura
Original assignee: Senju Pharmaceutical Co., Ltd.; Tsumura & Co.
Priority date: 1995-06-16
Filing date: 1996-06-14
Publication date: 1997-01-03

Abstract

A corneal clouding inhibitor which comprises a compound represented by general formula (I) or a salt thereof, wherein R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 are the same or different and each represents hydrogen or optionally substituted hydroxy; R11 and R12 are the same or different and each represents hydrogen, alkyl or optionally esterified carboxy; R13 represents hydrogen, hydroxy, (optionally substituted aromatic carbon ring)-alkyl or (optionally substituted heterocycle)-alkyl; and X represents oxygen or nitrogen, provided that R13 represents an unshared electron pair, when X is oxygen.

Description

Description Corneal opacity inhibitor Technical field

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. Background art

Opaques are induced during the repair of corneal damage caused by traumatic injury or ophthalmic procedures such as surgery or laser irradiation.

In particular, in recent years, clinical application of excimer lasers has been studied, and therapeutic superficial keratotomy and astigmatic correction have been performed for the treatment of corneal dysplasia and astigmatism, especially for myopic and hyperopic eyes. Refractive surgery is expected. However, diffuse reticular opacification in the epidermis and subcutaneous area of the cornea occurs after irradiation with excimer laser. For this reason, ophthalmic administration of steroids is usually used after surgery, which is said to be effective in suppressing corneal opacity.

However, steroids have been reported to enhance hyperopia.

[Yamaguchi, T. et al., Am. J. Ophthalmol., 97, 2 15—2 20

(1989), Hays, J. C., et al., J. Refractive Surg., 2, 1339.

(1966)], and there are concerns about adverse effects such as hatred of postoperative infectious diseases and steroid glaucoma. Therefore, the development of a safe corneal opacity inhibitor with few side effects is desired. In view of such circumstances, 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.

That is, the present invention provides a compound represented by the formula (I):

Where Rh R ₂ , R ₃ , R ₄ , R ₅ , R _e , R ₇ , R ₈ , R ₉ and. The same or different and each is hydrogen or an optionally substituted hydroxyl group, 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, and X represents oxygen or nitrogen. However, when X is oxygen, R ₁₃ represents an lone pair of oxygen. ] Or a salt thereof The present invention provides a corneal opacity inhibitor.

—In the general formula (I), 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 For example, 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.

Examples of the alkyl group of the optionally substituted alkylcarbonyloxy group 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. Examples of the 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).

Preferably, 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. Examples of the 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.

Preferably, 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. Examples of the alkyl group of the (optionally substituted aromatic carbocycle) —alkyl group 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.

(Hetero ring which may be substituted) represented by R _{13 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. Of these, a pyridine ring and an imidazole ring are preferred. The heterocycle may be linked to the alkyl group at any possible position. Examples of the substituent 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 The number of the substituents is preferably 1 to 5, and these may be located at any possible position of the heterocycle. Examples of the alkyl group of the (optionally substituted hetero ring) monoalkyl group 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.

But hydrogen, 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 ₈ turtles butoxy, 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);

Is hydrogen, 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 ₃ turtles butoxy, R ₄ is hydrogen, R ₅ is hydrogen, R ₆ is hydrogen, R ₇ is § Mino methylcarbonyl O alkoxy, R ₈ turtles butoxy , R ₉ is hydrogen, R ₁₀ is hydrogen, RH is methyl, ₂ is methyl, and X is oxygen (Compound No. 23, GS-B637

(Hydrochloride));

Is hydrogen, 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, and 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); and

Is hydrogen, 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, and X is a nitrogen of compound (compound No. 16, GS-B 620).

Among the compounds represented by the formula (I), 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).

Scheme 1

[Wherein Ri ヽ R 2 * s R 3 'R 4, 5, R 6 ゝ R7 ヽ Rs' ヽ R 9 ', Rio, Rn' and R ₁₂ ′ are Rh R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ , R _10. Groups defined by Rn and R ₁₂ (the hydroxyl group may be protected by a normal hydroxyl protecting group (eg, benzyl)) Shows]

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 (Π) 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).

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.

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.

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.

Further, 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.

Further, 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. In this case, the hydrolysis reaction is desirably performed under basic conditions or acidic conditions. Under basic 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. When the reaction is carried out under acidic conditions, 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.

The conversion of capuluronic acid into a water-soluble and non-toxic salt is carried out by a known method. 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. The usual method of conversion to an esteramide or hydroxamic acid derivative, or dicyclohexylcarbodiimide, in the presence of a tertiary amine such as pyridine, triethylamine, 4,4-dimethylaminopyridine, etc. After appropriately selecting and using a condensing agent such as getylclophosphoric acid and difluorophosphoric acid azide, it can be achieved by a method of reacting with alcoholamine.

In the above-described conversion of the substituent, protection and deprotection of the hydroxyl group of the compound to be handled can be performed, if necessary. For example, in the case of a benzyl group, 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.

As described above, 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 (hereinafter referred to as compound (1-2)) 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.

Scheme 2

[Where,

_{_{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)]

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. For example, an α-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. Method of reacting acetophenone derivative and -octaloacetophenone derivative under basic conditions, or method of reacting alkyl benzoyl ester in the presence of potassium peroxosulfate-copper sulfate etc. Can be obtained by

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).

In the present invention, 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. However, 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). Compounds in corneal opacity inhibitors

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. %.

As the form of the 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.

As the method for producing the corneal opacity inhibitor of the present invention, a production method generally used for producing ophthalmic agents can be used. For example, 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]. In the case of sustained-release preparations, for example, BIOPHARMACEUTICS OF OCULAR DRUG DELIVERY (Peter Edma, CRC Press (USA), 1993) Manufactured by the method described in You.

In order to formulate 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. As 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). As the 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, ε-aminocaproic acid, etc.). As the stabilizer, an antioxidant (such as sodium sulfite, sodium bisulfite, sodium metabisulfite, etc.) and a chelating agent (such as sodium edetate, citric acid and salts thereof) are used. Examples of the thickener 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. Examples of 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. 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.

When 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. When 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.

When the corneal opacity inhibitor of the present invention is 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.

In addition, 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. Midori As the therapeutic agent for disorders, pilocarpine, distigmine bromide, epinephrine dipivalate, timolol maleate, bupranolol hydrochloride and the like are used. As 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.). As vasoconstrictors, naphazoline nitrate, oxymethasone hydrochloride, phenylephrine hydrochloride and the like are used. Examples of 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. 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. 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.

Specifically, when the corneal opacity inhibitor of the present invention is 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. When used as an ophthalmic ointment, 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. Example

Hereinafter, the present invention will be described in more detail with reference to Test Examples, Examples, and Reference Examples. However, these are merely examples, and the scope of the present invention is not limited thereto.

Test example 1

Excimer laser irradiation suppresses corneal opacity after corneal surface resection

(Test substance)

As a test substance, 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.) were used as control drugs.

(Excimer laser irradiation conditions)

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 τ scan.

(Test method)

Brown Norway female rats (9-10 weeks old) were anesthetized with Ketalal (registered trademark; ketamine hydrochloride, manufactured by Sankyo Co., Ltd.), and venoxil ophthalmic solution (registered trademark; oxybupro hydrochloride) (Manufactured by Santen Pharmaceutical Co., Ltd.) was dropped on the eyeball for local anesthesia. An excimer laser was applied to the cornea of both eyes of the rat, and a photorefractive keratectomy (PRK) was performed. 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) Mark: Ofloxacin, Santen Pharmaceutical Co., Ltd.) was instilled before physiological saline, Compound A ophthalmic solution or 0.1% Rinderone. 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. . Seven days after the treatment, 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.

(Scoring criteria)

0: No turbidity is observed

1: Mild opacity overall (good iris see-through)

2: Partial cloudiness is moderate (Iris see-through is somewhat poor)

3: Moderate turbidity overall

4: Partial cloudiness is high (it is difficult to see through the iris)

5: High turbidity throughout

(Slit lamp observation result)

When the cornea was observed with a slit lamp after PRK3, normal regeneration of the corneal epithelium was restored in both the physiological saline, Compound A ophthalmic solution and 0.1% Rinderon ophthalmic group, and the corneal epithelium repair was observed for the drugs in each group. No delay or promotion effect was observed. 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

(Eye) (%) Instillation of physiological saline solution 10 3. 9 0.4

匕合合 A A 液 A 2. 2. 2. 2. 2.

0.1% Rinderon ophthalmic solution 10 3.3 ± 0.5 * 15.4 According to Dunnett's multiple comparison test,

*: There is a significant difference at a risk rate of 5% compared to the saline instillation group.

**: Significant difference is recognized at 1% risk compared to saline instillation group,

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.

(Histological observation results)

As a result of histological observation of the eyeballs after the treatment 7, 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.

In each group, proliferation of fibroblast-like cells was observed subepithelial of the cornea. 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.

Table 2

No. of blast cells

Group Number of fibroblast-like cells

(Eye) (Inhibition rate%) (Inhibition rate%) Physiological saline ophthalmic solution 87.3 Sat 5.1 32.7 ± 5.8 Compound A ophthalmic solution ophthalmic solution 164.3 ± 3.0 0.28.2 ± 4 . 0 **

(41.1) (74.9)

0.1% Li, idelon instillation 76.0 Sat 3.0 1 7.8 ± 4.0 *

(17.8) (45.6) Dunnett's multiple comparison test

In both the Compound A ophthalmic solution ophthalmic solution ophthalmic solution ophthalmic solution and the 0.1% Rinderone ophthalmic ophthalmic solution group, significant suppression of fibroblast-like cell layer and cell proliferation was observed as compared with the physiological saline ophthalmic solution ophthalmic solution ophthalmic solution. The inhibitory effect of the compound A ophthalmic solution ophthalmic group was greater than that of the 0.1% rindelone ophthalmic group.

Based on the above results, 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 example 2

Corneal stromal cell growth inhibitory action

(Test method)

Male Brown Norway rats (9-: L0 weeks old) were sacrificed, the corneal epithelium was detached with a scalpel, and the eyes were enucleated. After the cornea was cut out from the eyeball, the corneal endothelium was peeled off and removed to obtain a corneal stroma. The obtained corneal stroma was minced and suspended in Eagle's MEM medium (manufactured by Nissui Pharmaceutical Co., Ltd.) containing 10% v / v% fetal serum (FBS, Gibco), 37 ° C, 5% CO ₂ , The cells were cultured under 20% O ₂ . Cells were passaged when cell growth reached saturation point, and cells at passages 7 and 10 were used in the following tests. In the 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曰間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.

The 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%.

(Test results)

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 (M) Increased corneal stromal cells

(%)

Compound A 1 ο · ⁵ 73. 1

^{GS-B 558 1 ο · 5} 59. 4

^{GS-B637 1 ο · 5 62.} 1

Compound A 10 ^s 66.6

^{GS-B620 1 ο · 5 68.} 5

G SB 624 10 · ⁵ 55. 9

From the above, since 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.

Example 1

(Eye drops)

Compound A 1.0 g

5.0 g mannitol

Hydroxypropyl methylcellulose 0.1 g

Sodium dihydrogen phosphate 0.1 g

Benzalkonium chloride 0.005 g

Sodium hydroxide appropriate amount Sterile purified water Total volume 100 m 1

Mannitol to about 80 m 1 sterilized purified water, hydroxycarboxylic propyl methyl cellulose, Compound A was dispersed in _c its dissolution ¾ dissolving the dihydrogen phosphate, sodium and chloride Benzarukoniumu. Then, the pH was adjusted to 7.0 with sodium hydroxide, and sterile purified water was further added to adjust the total volume to 100 ml, whereby 1.0 wZv% Compound A suspension ophthalmic solution was obtained. The osmotic pressure of the obtained eye drops is 300 mO sm.

Example 2

(Eye drops)

Compound A 0.01 g

Sodium chloride 0.9 g

Polyvinylpyrrolidone 0.1 g

Sodium dihydrogen phosphate 0.1 g

Benzalkonium chloride 0.005 g

Sodium hydroxide suitable amount

100 ml of sterilized purified water

Sodium chloride, polyvinylpyrrolidone, sodium dihydrogen phosphate and benzalkonium chloride were dissolved in about 8 Om1 of sterile purified water. Compound A was dispersed in the solution. Then, the pH was adjusted to 7.0 with sodium hydroxide, and sterile purified water was added to make a total volume of 100 ml. 1. OwZv% Compound A suspension ophthalmic solution was prepared. The osmotic pressure of the obtained eye drops was 30 OmO sm. Example 3

(Eye drops)

Compound A 0.0 g

2.6 g concentrated glycerin Polysorbate 80 0.1 g

Sodium acetate 0.1 g

Methyl paraoxybenzoate 0.026 g

Propyl paraoxybenzoate 0.014 g

Sodium hydroxide suitable amount

100 ml of sterilized purified water

About 80 ml of sterilized purified water was heated to about 80 ° C. to dissolve methyl paraoxybenzoate and propyl paraoxybenzoate. After cooling the solution to room temperature, concentrated glycerin, polysorbate 80 and sodium formate were dissolved, and Compound A was dispersed. Then, the pH was adjusted to 5.0 with sodium hydroxide, and sterile purified water was further added to adjust the total amount to 100 ml. 1. OwZv% Compound A suspension ophthalmic solution was prepared. The osmotic pressure of the obtained eye drops was 305 mO sm. Example 4

(Eye drops)

Compound A 0.1

Mannitonore 5.0 g

Polyoxetylene hardened castor oil 60 0.1 g

2.0 g boric acid

Borax suitable amount

Benzalkonium chloride 0.005 g

Sterilized purified water Total 10 Oml

About 8 Om 1 of sterilized purified water was heated to about 80 ° C. to dissolve boric acid and polyoxyethylene hydrogenated castor oil 60. The solution was cooled to room temperature to dissolve mannitol and benzalkonium chloride. Compound A was dispersed in the solution. Then adjust the pH to 7.0 with borax, and add sterile purified water. In addition, the total volume was adjusted to 100 ml to give a 1.0 wZv% compound A suspension ophthalmic solution ₍ the osmotic pressure of the obtained ophthalmic solution was 30 OmO sm.

Example 5

(Eye ointment)

Compound A 1.0 g

White Pserin 10.0 g

Liquid paraffin 89.0 g

Methyl paraoxybenzoate 0.02 g

Propyl paraoxybenzoate 0.014 g

Mix white deserin and liquid paraffin. This mixture was heated and stirred at 100 rpm using an emulsification tester (Nikko Chemicals ET-1A type). When the whole liquid was liquefied, methyl paraoxybenzoate and propyl paraoxybenzoate were added and dissolved. After cooling to 80 ° C., Compound A was added, and the mixture was stirred with an emulsification tester to produce Compound A eye ointment.

Example 6

(Gel)

Compound A 1.0 g

Carboxyvinyl polymer 0.4 g

Benzalkonium chloride 0.005 g

Sodium hydroxide suitable amount

Sterile purified water Total volume 100 m 1

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.

Example 7

(Eye drops)

GS-B 624 0.5 g

2.6 g concentrated glycerin

Dipotassium hydrogen phosphate 0.1 g

Kuhexyl gluconate 0.04 g

Black mouth butanore 0.3 g

Hydrochloric acid

100 ml of sterilized purified water

Dissolve GS-B624, concentrated glycerin, dipotassium hydrogen phosphate, chlorhexidine gluconate and chlorobutanol in about 80 ml of sterilized purified water, adjust the pH to 7.2 with hydrochloric acid, and add sterilized purified water to the total volume. Was adjusted to 100 ml to obtain 0.5 wZv% GS-B624 ophthalmic solution.

Example 8

(Eye softness)

GS-B620 2.0 g

Methyl paraoxybenzoate 0.026 g

Propyl paraoxybenzoate 0.014 g

White gserine 100 g

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

Under argon gas atmosphere, add 7.9 ml of tetrahydrofuran and diisopropylamine to 8.8 ml of n-butyllithium (1.6 M hexane solution) at 0 ° C.

Stirred for 10 minutes. To this solution was added dropwise a solution of 2.56 g of 4'-benzyloquin-3'-methoxyacetophenone (J. Org. Chem., 57, 7248 (1992)) in tetrahydrofuran under cooling and stirring at -78 ° C. Stirred for 30 minutes. Next, 2.2 ml of trimethylsilyl chloride was added, and the mixture was stirred for 10 minutes and then at room temperature for 1.5 hours. The reaction solution was concentrated under reduced pressure, 10% aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ether. 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.

^-MRC ^ pm in CDC1 _S ):

0.26 (9H, s), 3.90 (3H, s), 4.35 (lH, d, J = 2Hz), 5.16 (2H, s), 6.82 (1H, d, J = 8Hz), 7.08-7.15 (2H, m ), 7.28-7.45 (5H.m)

Mass vector

m / z: 328 (+)

328 mg of the 4'-benzyloxy-3'-methoxy-trimethylsilyloxystyrene obtained above was dissolved in dichloromethane and cooled to -78 ° C under an argon gas atmosphere. 246 mg of lead tetraacetate and tetrahydrofuran were added, and the mixture was stirred for 1.5 hours and then at room temperature for 1 hour. Water was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The obtained residue was recrystallized from dichloromethane-methane-hexane to give colorless needle crystals of 1,2-bis (4-benzyloxy-3-methoxybenzoyl) ethane (196 mg, yield 76.9%). The physicochemical properties of the obtained compound are as follows. 'HN RCippm in CDC1 ₃ ):

3.38 (4H, s), 3.93 (6H, s), 5.24 (4H, s), 6.92 (2H, d, J = 8Hz), 7.31-7.46 (bottle m), 7.57-7.65 (4H.m)

Mass vector

m / z: 510 (M +)

2.70 g of 1,2-bis (4-benzyloxy-3-methoxybenzoyl) ethane obtained above was dissolved in chloroform, a mixed solution of 360 il of acetyl chloride and methanol was added, and the mixture was refluxed for 3 hours. After cooling the reaction solution, it is concentrated under reduced pressure, purified by silica gel gel column chromatography, and colorless needle crystals of 2,5-bis (4-benzyloxy-3-methoxyphenyl) are obtained from a dichloromethane-hexane fraction. ) Furan (1.23 g, yield 47.4¾) was obtained.

Reference example 2

Under an argon gas atmosphere, tetrahydrofuran and 3.6 ml of diisopropylamine were added to 16 ml of n-butyllithium (1.6 M hexane solution) at 0 ° C., followed by stirring for 10 minutes. A solution of 5.76 g of 2'-benzyloxy-4'-methoxyacetophenone (Hua Hsueh, 41, 61 (1983)) in tetrahydrofuran was added dropwise to the solution under cooling and stirring at -78 ° C. After stirring for 15 minutes, a solution of 3.37 g of copper chloride (11) in dimethylformamide was added, and the mixture was stirred for 30 minutes and then at room temperature for 1.5 hours. 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 2N hydrochloric acid, water and saturated saline. The insolubles were dissolved by adding dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in 60 ml of chloroform, a mixed solution of 0.9 ml of acetyl chloride and methanol was added, and the mixture was refluxed for 2 hours. After cooling the reaction solution, saturated aqueous sodium bicarbonate was added, and the organic layer extracted with dichloromethane was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, The solid obtained from the 1-hexane fraction was recrystallized from dichloromethane-methanol to give colorless needle crystals of 2,5-bis (2-benzyloxy-4-methoxyphenyl) furan (2.57 g, yield 46.4.). I got

Reference example 3

246 mg of 2,5-bis (4-benzyloxy-3-methoxyphenyl) furan obtained in Reference Example 1 is dissolved in dichloromethane, 10 mg of a 10% palladium carbon catalyst is added, and the mixture is stirred at room temperature under a hydrogen gas atmosphere for 8 hours. did. The insolubles were collected by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from dichloromethane-hexane to give light blue needle-like crystals of 2,5-bis (4-hydroxy-3-methoxyphenyl) furan (compound 1, GS-B285 shown in Table 4). (102 mg, yield 65.6) was obtained. The physicochemical properties of this compound are as shown in Table 6.

In a similar manner, 2,5-bis (2-hydroxy-4-methoxyphenyl) furan (compound 2. GS-B603 shown in Table 4), 2,5-bis (2-hydroxyphenyl) furan (table 4, 3,5-bis (3,5-dihydroxyphenyl) furan (compound 4. GS-B558 shown in Table 4), 2,5-bis (3-hydroxy- 4-Methoxyphenyl) furan (compound 5, GS-B560 shown in Table 4) and 2,5-bis (3-hydroxyphenyl) furan (compound 6, GS-B535 shown in Table 4) were produced. Their physicochemical properties are shown in Table 6.

Reference example 4

644 mg of 2,5-bis (2,4-dibenzyloxyphenyl) furan obtained in Reference Example 2 was dissolved in dichloromethane-methanol (2: 1), 70 mg of 10-palladium carbon catalyst was added, and hydrogen gas was added. The mixture was stirred at room temperature for 1 hour under an atmosphere. After filtering off insolubles, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane, lml of acetic anhydride and 1.1ml of pyridine were added, and the mixture was stirred at room temperature for 2 hours. Add 2N aqueous hydrochloric acid, extract with dichloromethane, and wash the organic layer with saturated aqueous sodium hydrogen carbonate and water. And washed. After drying over anhydrous magnesium sulfate, the mixture was concentrated under reduced pressure, the residue was purified by silica gel gel column chromatography, and the solid obtained from the ethyl acetate-hexane fraction was recrystallized from ethyl acetate-hexane to give a colorless needle. Crystalline 2,5-bis (2,4-diacetoxyphenyl) furan (compound に, GS-B588 shown in Table 3) (165 mg, yield 36.5¾) was obtained.The physicochemical properties of this compound are shown in Table 6. It is shown.

Reference example 5

2.6 g of known 2,5-bis (4-benzyloxy-3-methoxybenzoyl) butane-1,4-dicarboxylate getyl (J. Chem. Soc., Perkin Trans. I, 183 (1982)) in toluene After dissolution, 22 ml of benzylamine and 11.6 ml of acetic acid were added, and the mixture was refluxed for 24 hours. After cooling, ethyl acetate was added to the reaction solution, which was washed with water. After drying over anhydrous magnesium sulfate, the mixture is concentrated under reduced pressure, and the residue is purified by silica gel column chromatography. N-benzyl-2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrrole-3,4-diethylruponate (1.24 g, yield 43.2¾i) as yellow plate crystals Obtained.

In the same manner, 2,5-bis (4-benzyloxy-3-methoxybenzoyl) butane-1,2-dicarboxylate is converted to 2,5-bis (4-benzyloxy-3-methoxybenzoyl) pyrrolyl-3 by getyl. Dimethyl, 4-dicarboxylate, N- (4-chlorobenzyl) -2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrroyl-3,4-diethyl carboxylate, N- (4- Methylbenzyl) -2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrrole-3,4-dicarboxylate getyl, N-hydroxy-2,5-bis (4-benzyloxy-3-methyl) Toxylphenyl) pyrrole-3,4-dicarboxylate getyl, N-benzyl-2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrrole-3,4-diethyl carboxylate, 2,5-bis (4-benzyl N- (4-methylbenzyl) pyrrol, N- (4-chlorobenzyl) -2,5-bis (4-benzyloxy-3-methoxyphenyl) pyrrole, N- (4-methylbenzyl) -2 1,5-bis (4-benzyloxy-3-methoxyphenyl) pyrrole, 3-, 5-bis (4-benzyloxy-3-methoxyphenyl) -1-pyrrolylmethyl} pyridine, 1- [3- is 5- Bis (4-benzyloxy-3-methoxyphenyl) -1-pyrrolyl} pyrpyrimigimisol was prepared.

Reference example 6

290 mg of N-benzyl-2,5-bis (4-benzyloxy-3-methoxyphenyl:) pyrrole-3,4-dicarboxylate getyl obtained in Reference Example 5 was dissolved in tetrahydrofuran-methanol (1: 1). Then, 10 mg of 10% palladium carbon catalyst was added, and the mixture was stirred at room temperature for 6 hours under a hydrogen gas atmosphere. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain N-benzyl-2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-diethyl carboxylate (see Table 5). 252 mg of the indicated compound 8, GS-B106) was obtained in a quantitative yield. Table 7 shows the physicochemical properties of this compound.

In a similar manner, the compound described in Reference Example 5 was debenzylated to give dimethyl 2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-dicarboxylate (compound 9 shown in Table 4). , GS-B63), N- (4-chlorobenzyl) -2,5-bis (4-hydroxyquin-3-methoxyphenyl) pyrrole-3,4-diethyl carboxylate (Compound 1 O.GS shown in Table 5) -B72). 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-bis (4-hydroxy-3-methoxyfuryl) pyrrole (Compound 16, GS-B620 shown in Table 5) , 3- {2,5-bis (4-hydroxy-3-methoxypropyl) -1-pyrrolylmethyl} pyridine, (compound 17. GS-B625 shown in Table 5). 1- [3-, 5-bis (4-Hydroquin-3-methoxydiphenyl) -1-pyrrolyl} propyl] imidazole (Compound 18, GS-B630 shown in Table 5) was produced. The physicochemical properties of this compound are as shown in Table 7.

Reference Example 7

510 mg of 1,2-bis (4-benzyloxy-3-methoxybenzoyl) ethane described in Reference Example 1, 573 mg of methyl 4-aminomethylcarboxylate and 1 drop of acetic acid were added to toluene, and the mixture was refluxed for 68 hours. After cooling the reaction solution, dichloromethane was added, and the mixture was washed with 2N aqueous hydrochloric acid and water. After drying over anhydrous magnesium sulfate, the mixture is concentrated under reduced pressure, the residue is purified by silica gel column chromatography, and the amorphous obtained from the dichloromethane fraction is recrystallized from ethyl acetate-hexane to give pale yellow-green needle-like crystals. Methyl 4- {2,5-bis (4-benzyloxy-3-methoxyphenyl) -1-pyrrolylmethyl} gaylate (380 mg, yield 57.2¾0) was obtained.

Next, 266 mg of this 4- {2,5-bis (4-benzyloxy-3-methoxyphenyl) -1-pyrylmethyl} methyl methyl cinnamate was dissolved in dichloroethane, and the solution was heated to -30 ° C under an argon gas atmosphere. Cool. 1.6 ml of boron trichloride (1.0 M dichloromethane solution) was added dropwise and stirred for 2 hours. After adding methanol and stirring for 30 minutes, water was added and the mixture was extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized from ether-hexane to give 4-, 5-bis (4-hydroxy-3-methoxyphenyl) -1- Pyrrolylmethyl} gay Methyl cinnamate (Compound 19 shown in Table 5, GS-B615) (144 mg, yield 74.4 74) was obtained. The physicochemical properties of this compound are as shown in Table 7.

Reference Example 8

800 mg of benzyl-benzyl-2,5-bis (4-hydroxy-3-methoxyphenyl) pyrrole-3,4-dicarboxylate obtained in Reference Example 6 was dissolved in ethanol, and 10% sodium hydroxide was dissolved in ethanol. .5 ml was added and refluxed for 24 hours. After the reaction solution was cooled and concentrated under reduced pressure, water was added to the residue to dissolve it. The mixture was acidified with 2N hydrochloric acid, and the resulting precipitate was filtered and washed with water. The solid was dissolved in a 1N aqueous solution of sodium hydroxide and extracted with dichloromethane.

The aqueous layer was acidified with 2N aqueous hydrochloric acid, and the resulting precipitate was filtered, washed with water and dried to give a light brown powder of N-benzyl-2,5-bis (4-hydroxy-3-methoxyphenyl). ) Pyrrole-3,4-dicarboxylic acid (compound 20, GS-B110 shown in Table 5) (541 mg, yield 75.3%) was obtained. The physicochemical properties of this compound are as shown in Table 7.

In a similar manner, 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). ) -2,5-Bis (4-hydroxy-3-methoxyphenyl) pyrrol-3,4-dicarboxylate from N- (4-methylbenzyl) -2,5-bis (4-hydroxy -3-Methoxyphenyl) pyrrole-3,4-dicarboxylic acid (compound 22. GS-B122 shown in Table 5) was produced. The physicochemical properties of these compounds are shown in Table 7. Compound A (GS-01)

Me = methyl group, Ac = 7 cetyl group

Compound number I ι »ι ^ Hi I o Q

8 COOEt Bn g COOEt H

10 COOEt 4-CIBn

11 COOEt 4-MeBn

12 COOEt OH

13 H Bn

14

H H

(GS-B624)

15 H 4-CIBn

16

H 4-MeBn

(GS-B620)

17 H 3-PyMe

18 H 1-lmPr

19 H 4-MeCi

20 COOH Bn

21 COOH 4-CIBn

22 COOH 4-MeBn

Et = i-tyl group, Bn = benzyl group, 4-C old n-4-chlorobenzyl 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-

9 Halla

(ZS99-S9) εζ½

0 / 96df / I3d 89,000 / m 6 OM

1

9e9I0 / 96df / XDd 89000/6 ΟΛ \ Reference Example 9

Under an argon gas atmosphere, 1.16 g of N- (t-butynecarbonyl) glycine was dissolved in dichloromethane. To this was added a dichloromethane solution of 1.36 g of 1,3-dicyclohexylcarposimide, and the mixture was stirred under ice cooling for 30 minutes. Next, a dichloromethane solution of 1.02 g of 2,5-bis (3-hydroxy-14-methoxyphenyl) -3,4-dimethylfuran was added dropwise to the reaction mixture over 40 minutes, and the mixture was added at room temperature for 18 hours. Stirred. After filtering off the insoluble matter, the filtrate was concentrated. The residue was recrystallized from hexane-dichloromethane to obtain white needle crystals 2,5-bis {3- [N- (t-butoxycarbonyl) aminoaminocarbonyloxy] -14-methoxyphenyl} -3 1.63 g (83% yield) of 4-dimethylfuran was obtained. This compound has the following physicochemical properties.

! H-NMRC ^ ppm in CDC1 3):

1.48 (mouse s), 2.18 (6H, s), 3.86 (6H, s), 4.25 (4H, d, J = 5Hz), 5.10 (2H, br s), 7.02 (2H, d, J = 9Hz), 7.38 (2H, d, J = 2Hz), 7.52 (2H, dd, J = 2, 9Hz)

Melting point: 153.5-155.5 ° C

654 mg of the 2,5-bis {3- [N- (t-butoxycarbonyl) aminomethylcarbonyloxy] -14-methoxyphenyl} —3,4-dimethylfuran obtained above was added to ether-dichloromethane. The solution was dissolved, and hydrochloric acid gas was blown into the solution under ice cooling for 10 minutes. The mixture was further stirred at room temperature for 3 hours. The precipitated solid was filtered off and recrystallized from methanol-ether to give a pinkish white powder 2,5-bis [3- (aminomethylcarbonyloxy) -14-methoxyphenyl] -1,3,4-dimethylfuran. The dihydrochloride (446 mg, yield 85%) was obtained. This compound has the following physicochemical properties.

^ -NMRC ^ ppm in DMS0-d6):

2.18 (6H, s), 3.85 (6H, s) .4.16 (4H, s), 7.29 (2H, d, J = 9Hz), 7.51 (2H, d, J = 2Hz), 7.59 (2H, dd, J = 2, 9Hz), 8.67 (4H, br s)

Melting point: 181-28.5 ° C

As described above, 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. In addition, 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.

Claims

The scope of the claims

Formula (I)

罾

[Wherein Rh R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and. Are the same

Or different hydrogen or a hydroxyl group which may be substituted, shaku ^ ぉ obi! ^^ are the same or different hydrogen, an alkyl group or a carboxyl group which may be esterified, R ₁₃ is hydrogen, a hydroxyl group, ( Optionally substituted aromatic charcoal

A prime ring) a monoalkyl group or a (optionally substituted heterocycle) monoalkyl group, and X represents oxygen or nitrogen. However, when X is oxygen, R ₁₃ represents an lone pair of oxygen. ] Or a salt thereof

Corneal opacity inhibitor.

_{_{2. R !, R 2, R 3}} , R 5, R 6, R 7, R 8, R 9 and R _{1 ()} is the same

2. The corneal opacity inhibitor according to claim 1, which is different from hydrogen, a hydroxyl group, an alkoxy group, or an optionally substituted alkylcarbonyloxy group.

_{_{3. Ri, R 2, R 3}} > R 5 Re, R 7> R 8, R 9 and Ri. Are the same

2. The corneal opacity inhibitor according to claim 1, wherein the corneal opacity inhibitor is hydrogen, a hydroxyl group, an alkoxy group, or an aminoalkylcarbonyloxy group.

4. R "R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ , R ₉ and R _{1 ()} are the same or different and each is hydrogen, hydroxyl, methoxy or aminomethylcarbonyloxy. 2. The corneal opacity inhibitor according to claim 1, which is

2. The corneal opacity inhibitor according to claim 1, wherein _V 5. RH and R ₁₂ are the same or different and are hydrogen, an alkyl group, a carboxyl group or an alkoxycarbonyl group.

6. The corneal opacity inhibitor according to claim 1, wherein R ₁₂ and R ₁₂ are the same or different and each is hydrogen, an alkyl group, a carboxyl group or ethoxycarbonyl.

7. The corneal opacity inhibitor according to claim 1, wherein R and R ₁₂ are the same or different and each is hydrogen, methyl, carboxyl group, or ethoxyquin ruponyl.

8. corneal opacity inhibitor according to claim 1 which is RH and R ₁₂ are the same or different and each is hydrogen or methyl.

9. I may be substituted represented by R _13, corneal clouding inhibitor according to claim 1 the aromatic carbon ring is a benzene ring of the aromatic carbocyclic one Arukiru group.

10. corneal opacity inhibitor according to claim 1, wherein heterocycle is a pyridine ring or Imidazoru ring to which may optionally be substituted into the heterocyclic primary alkyl group represented by R _13.

11. alkyl group optionally substituted aromatic carbocyclic ring one also be an alkyl group and the optionally substituted heterocyclic primary alkyl group represented by R ₁₃ is, corneal opacity inhibition of claim 1 wherein the methylation Agent.

12. The substituent of the optionally substituted aromatic carbocyclic monoalkyl group and the optionally substituted heterocyclic monoalkyl group represented by R ₁₃ is alkyl

2. The corneal opacity inhibitor according to claim 1, which is a * group or a halogen.

.

13. A compound represented by the formula (I)

Is hydrogen, R ₂ is hydroxyl, R _{3 is} methoxy, R ₄ is hydrogen, R ₅ is hydrogen, R ₆ Is hydrogen, R ₇ is hydroxyl, R _{8 is} methoxy, R ₉ is hydrogen, R _{1 ()} is hydrogen, Rn is methyl, R ₁₂ is methyl, and X is oxygen (compound A);

Ri is hydrogen, 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 _1D is hydrogen, A compound in which hydrogen, R ₁₂ is hydrogen, and X is oxygen (GS—B 558);

But hydrogen, R ₂ is § amino methylcarbonyl O alkoxy, R ₃ turtles butoxy, R ₄ is hydrogen, R ₅ is hydrogen, R ₆ is hydrogen, R ₇ is § Mino methylcarbonyl O alkoxy, R ₈ turtles butoxy, A compound wherein R ₉ is hydrogen, R ₁₀ is hydrogen, is methyl, ₂ is methyl, and X is oxygen (GS—B 637);

Is hydrogen, 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, compounds wherein R ₁₂ is hydrogen, R ₁₃ is hydrogen, and X is nitrogen (GS- B 624); or

Is hydrogen, 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, and R _{1 ()} is hydrogen, R _u is hydrogen, R ₁₂ is hydrogen, R ₁₃ is 4 one-methylbenzyl, and X is a nitrogen of compound (GS- B620) corneal opacity inhibitor according to claim 1 is.

14. The corneal opacity inhibitor according to claim 1, which is for eye drops.

15. A method for suppressing corneal opacity, which comprises administering an effective amount of the compound represented by the formula (I) or a salt thereof to a subject requiring corneal opacity suppression.

16. Use of a compound represented by the formula (I) or a salt thereof as an active ingredient in the manufacture of a corneal opacity inhibitor.