WO1997000068A1 - Corneal clouding inhibitor - Google Patents

Corneal clouding inhibitor 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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Prior art keywords
hydrogen
group
corneal
compound
hydroxyl
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PCT/JP1996/001636
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French (fr)
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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Priority to JP7/150092 priority Critical
Priority to JP15009295 priority
Application filed by Senju Pharmaceutical Co., Ltd., Tsumura & Co. filed Critical Senju Pharmaceutical Co., Ltd.
Publication of WO1997000068A1 publication Critical patent/WO1997000068A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D207/00Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02Heterocyclic 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
    • C07D207/30Heterocyclic 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
    • C07D207/34Heterocyclic 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 heteroatoms 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

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

Specification corneal opacity inhibitor technology field

The present invention, corneal clouding inhibitor, more particularly, a traumatic injury to a useful corneal opacity inhibitor corneal opacity inhibitor after corneal injury caused by such ophthalmic procedures. BACKGROUND

Traumatic injury or surgery, turbid ophthalmic repair processes of corneal injury caused by procedures such as laser irradiation procedure is triggered.

In particular, in recent years, it has been studied for clinical application of excimer laser, therapeutic superficial keratectomy in the treatment of such corneal degeneration diseases and astigmatism eye, astigmatism correction surgery has been performed, among other things, for myopic and hyperopic eyes refractive surgery is expected. However, the turbidity of the reticular diffusely the cornea on subcutaneous occurs has become a problem in the irradiation area of ​​the corneal incision surgery by excimer laser. Therefore, usually, and instillation of steroid agent is used postoperative, it is to be effective in suppressing corneal opacities.

However, there is a report of the steroids agent to enhance the farsightedness of

[Yamaguchi, T. etc., Am. J. Ophthalmol., 9 7, 2 1 5- 2 2 0

(1 9 8 6), Hays, JC etc., J. Refractive Surg., 2, 1 3 9

(1 9 8 6)], also is a concern for side effects, such as hatred and steroid glaucoma of post-operative infections. Therefore, fewer side effects, it has been desired to develop corneal opacity inhibitor that can be safely used. In view of such circumstances, the present invention is for the purpose of development of corneal clouding inhibitor side effects can be used safely without respect corneal opacity after corneal injury caused by traumatic injury or ophthalmic procedures is there. Disclosure of the Invention

The present inventors have found that excellent was searched for various compounds in search of corneal clouding inhibitor was, 2, known as angiogenesis inhibitors, to have 5-Bisufue two Lefranc induction body excellent corneal opacification inhibitory effect found, further investigation result Hazuki groups on these findings, the present invention has been completed.

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

Wherein, 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 which may aromatic carbon ring optionally) primary alkyl group or a (heterocyclic ring which may be substituted) - alkyl group, and X represents oxygen or nitrogen. However, when X is oxygen, R 13 represents a lone pair of oxygen. There is provided a compound or corneal clouding inhibitor comprising a salt thereof represented by.

- in general formula (I), as R 2, R 3, R 4 , R 5, R 6, R 7, R 8, R 9 or hydroxy group which may be substituted represented by R 1 () is For example, a hydroxyl group, an alkoxy group, and optionally substituted alkylcarbonyl O alkoxy group.

As the alkoxy group include an alkoxy group of from 1 to 6 carbon, favored properly alkoxy group of from 1 to 4 carbon atoms, specifically, main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy, sec- butoxy , and the like tert Ryo butoxy. Of these, the main butoxy is preferred.

Is the alkyl group of the alkyl carbonyl O alkoxy group which may be the substituent, for example, an alkyl group of from 1 to 6 carbon, preferably § alkyl group of 1-4 carbon atoms, specifically, methyl, Echiru , propyl, isopropyl, Petit Le, isobutyl, sec- butyl, tert- butyl. Of this, preferably methyl. Examples of the optionally substituted alkyl optionally carbonylation Ruoki-substituted group group may also have, for example, an amino group, a hydroxyl group, a force Rupokishiru group, a thiol group, such as a force Rubamoiru group. The optionally substituted alkylcarbonyl O alkoxy group, preferably, Asechiruo alkoxy or aminoalkyl carbonyl O alkoxy group, a group formed in particular removal of hydrogen carboxyl group of the amino acid, specifically, , Gurishiruokishi (ie aminomethyl carbonyl O carboxylate), Araniruokishi, / 3-Araniru Okishi, Roishiruokishi, isoleucyl O carboxymethyl, Rijiruokishi, Seriruo alkoxy, Homoseriruokishi, one or / 3 § Spa rutile O carboxymethyl one hand the § Monteagle Tamil O carboxymethyl, § Supara Guinea Ruo xylene, etc. glutaminyl Ruo Kin, and the like. Among particular, Gurishiruokishi (i.e. aminomethyl carbonyl O alkoxy) are preferred. Ri R 2, R 3, R "R 5, R 6, R 7, R 8, R 9 and R 10, rather preferably are the same or different hydrogen, hydroxyl group, an alkoxy group (preferably main bets carboxymethyl) or optionally substituted alkylcarbonyl O alkoxy group (rather preferably has § Mino alkylcarbonyl O alkoxy group, more preferably Aminomechiru carbonyl O carboxymethyl) it is.

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 each identical.

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 Le, such as tert- butyl.

The R u or esterified carboxyl group which may be represented by 2, for example, a carboxyl group, and the like alkoxycarbonyl groups. The alkoxy group of the alkoxycarbonyl group include an alkoxy group having a carbon number of 1-6, to preferably an alkoxy group having 1 to 4 carbon atoms, concrete, main butoxy, ethoxy, Purobokishi, Isopurobokishi, butoxy, isobutoxy , sec- butoxy, tert- butoxy.

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.

The Kaoru incense carbocyclic ring represented by (optionally an aromatic carbon ring optionally substituted) primary alkyl group R 13, for example, benzene ring. Examples of the aromatic substituent which may be carbocyclic ring optionally having, 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, iodine) and the like. The number of the substituents is preferably 1 to 5, which may be a possible, not a Re position of the aromatic carbon ring. The (optionally an aromatic carbon ring optionally substituted) - Examples of the alkyl group Al kill groups, for example, an alkyl group having 1 to 6 carbon atoms, is preferred properly alkyl group having 1 to 4 carbon atoms, specifically, methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl, etc. tert- butyl. Among particularly preferably methyl.

The terrorist ring to (the optionally substituted heterocyclic) of primary alkyl group represented by R 1 3, containing terrorist atom as a ring-constituting atom of nitrogen, at least one of the selected from oxygen and sulfur the 5-7 membered ring, specifically to, a pyridine ring, an imidazole ring, pyrosulfate Ichiru ring, pyrazole ring, isothiazole ring, Isoo Kisazoru ring, pyrazine ring, pyrimidine ring, pyridazine ring Ru mentioned. Among them, a pyridine ring and an imidazole ring. The heterocyclic ring may be substituted at any possible position may be bonded to the alkyl group. 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, number is preferably 1-5 c the substituents and the like iodine), which may be in any possible position of the heterocycle. As, for example, an alkyl group having 1 to 6 carbon atoms, preferably an alkyl group having 1 to 4 carbon atoms, particularly an alkyl group having one alkyl group wherein (heterocyclic ring which may be substituted), methyl, Echiru, propyl, isopropyl, butyl, isobutyl, sec- butyl, tert- butyl. Of these, methyl is preferred. Specific preferred examples of the compound represented by formula (I) 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 hydrogen, RH is methyl, the compound wherein R 12 is methyl, and X is oxygen (compound a, GS- 01);

But hydrogen, R 2 is a hydroxyl group, R 3 is hydrogen, R 4 is hydroxyl, R 5 is hydrogen, R 6 is hydrogen, R 7 is a hydroxyl group, R 8 is hydrogen, R 9 is a hydroxyl group, R lfl hydrogen, Rn is hydrogen, compounds wherein 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-methyl, and X is an oxygen compound (compound No. 23, GS-B637

(Hydrochloride));

But hydrogen, R 2 turtles butoxy, R 3 is hydroxyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 turtles butoxy, R 8 is hydroxyl, R 9 is hydrogen, R 1 () is hydrogen, but hydrogen, R 12 is hydrogen, compounds wherein R 13 is hydrogen, and X is a nitrogen (compound number 14, GS-B624); and

But hydrogen, R 2 turtles butoxy, R 3 is hydroxyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 turtles butoxy, 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).

Compound X is oxygen among the compounds represented by formula (I) (hereinafter referred to as Compound (1 -1)), for example by a method according way or in described in JP WO 94Z15594 (especially, compound a or its salt is described in the Gazette), or according to scheme 1 below, by condensing butane 1, 4-dione of the diketone induction member (II), can be obtained directly or indirectly it can.

Scheme 1

[ヽ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' each Rh R 2, R 3, R 4, R 5, R 6, R 7 , R 8, R 9, R 10. Rn and groups defined R 12 (hydroxyl group of normal hydroxyl coercive Mamorumoto (eg, may be protected by benzyl)) the show]

The condensation reaction of the diketone derivative (II) is desirably carried out under acidic conditions, hydrochloric acid diketone derivative ([pi), mineral acids such as sulfuric acid, P- toluenesulfonic acid, organic acids such as tri Furuoro acid, such as aluminum chloride using a Lewis acid, dichloromethane as a reaction 応溶 medium, black hole Holm, toluene, benzene, either alone or mixed organic solvent such as methanol, preferably is accomplished by heating under reaction.

Further, a diketone derivative ([pi), phosphorus pentoxide, it is possible to obtain acetic anhydride, compound by heating in a suitable organic solvent with a dehydrating agent such as chloride Asechiru the (I one 1).

Compound obtained by the condensation reaction (I one 1) is optionally esters of de base Njiru of 2-position and 5-position substituent of the benzene ring, Asechiru of hydroxyl, the hydroxyl group and Amino Acid conversion may be performed substituents such as the formation or the like. Debenzylation, palladium one-carbon catalyst, palladium hydroxide on carbon catalyst, palladium chloride, palladium black, Raney nickel, a catalyst such as Nikkeruborai de, hydrogen gas, a suitable formate salt, such as Anmoniumu formic acid, the Kisaji E down like cyclohexane use L, Ru conventional reducing conditions, or be achieved by conventional methods due to the action of chloride Hou containing an organic solvent such as dichloromethane is possible.

Asechiru of hydroxyl groups, have use acetic anhydride, the Asechiru agent such as chloride Asechiru, pyridine, Toryechiruamin, 4, 4-dimethyl § Mino tertiary amines presence such as pyridine, never itself is Asechiru of It is accomplished by reacting at 0 ° Celsius to about room temperature in an organic solvent.

Ester formation between hydroxyl group and Amino acids, if commonly used method may be used any method, Amino group optionally amino tert such one Butokin force Ruponiru group Ya base Njiruokishi force Ruponiru group after introducing a suitable protecting group, it may be reacted.

Further, after ester formation by reacting an organic acid such as an inorganic acid or maleic acid such as hydrochloric acid, it can be converted into a salt.

Further, 3- and 4-position substituent of the furan ring is optionally hydrolysed, esterified, Ami de reduction may Gyotsu hydroxamic oxide or sodium chloride. In this case, hydrolysis is preferably conducted under basic conditions or acidic conditions. If under basic conditions, Al force Li hydroxides such as sodium hydroxide, a mixed solvent of an organic solvent and water, such as water or alcohol, can be achieved by reacting at room temperature for ~ 1 0 o ° c . If carried out in acidic conditions, using hydrochloric acid, mineral acids such as sulfuric, p- toluenesulfonic acid, an organic acid such as Torifuruoro acetate, can be achieved by reacting with 0~1 0 o ° c.

Conversion from the force Rupon acid to water-soluble and non-toxic salts are converted by a known method. Suitable salts include alkali metal salts (sodium, potassium etc.), alkaline earth metal salts (calcium, magnesium etc.), an organic amine salt and the like that may be pharmaceutically acceptable. Furthermore, esterification and amine de of the carboxylic acid derivative, after converting the carboxylic acid derivative more corresponding acid Kurori de derivative chloride Chioniru Ya chloride Okizariru like, corresponding with appropriate alcohol Ya § Min or non Dorokishiruamin, ester Ya § Mi Doaru physician or usual way of converting the hydroxamic acid derivatives, pyridine, preparative Riechiruamin, 4, 4 - dimethyl § Mino 3 KyuRyo Min presence such as pyridine, hexyl carbonitrile di imide dicyclohexyl, Jechirukuro port phosphate, after using suitably selected from condensing agent such as Jifuwe two ruri phosphate azide, can be achieved by a method in which reaction with alcohols Ya Amin.

In the conversion of the substituents explained above, if necessary, protection of hydroxyl groups of the compounds to be handled, can be deprotected. For example, introduction of a protecting group in a suitable solvent in the presence of a base such as carbonate Al force Li with benzyl agents such as benzyl payment de the corresponding compound containing a hydroxyl group in the case of benzyl group, cooling or heating it can be carried out by the lower reaction. The introduction of the silyl groups, Amin a compound containing a hydroxyl group with a silylating agent such Shiriruharai de, the presence of such carbonate al force Li, can achievement by cooling or heating in a suitable solvent. Removal of the base Njiru group which is a protecting group is as previously described. Further, removal of the silyl group, an acid such as hydrochloric acid, or potassium fluoride, ammonium © beam acids, can be carried out by reacting in a suitable solvent with the fluorine compound such as hydrofluoric acid .

As described above, the compounds of formula (I one 1) is condensed diketone derivative (II), by performing the conversion of the substituents, if necessary, be directly or obtained indirectly can. The combination of specific reactions and operations for obtaining the compound represented by formula (I one 1) will be described in Examples below. Furthermore, compounds wherein X is nitrogen among compounds represented by formula (I) (hereinafter referred to as Compound (1-2)) in accordance with Scheme 2 below, for example, wearer's own hair tons derivative (II) and primary the Amin, general acid (e.g., hydrochloric acid, acetic acid, p-.-toluenesulfonic acid) in the presence of, for example, toluene, benzene, dichloroethylene Rorometan, black hole Holm, organic solvent such as as tetrahydrofuran, Atsushi Muro - 100 ° C, preferably reacted with heating, further optionally by performing a transformation of the aforementioned substituents, leaving at can be obtained directly or indirectly.

Scheme 2

[In the formula, 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, R 9, R 1 (), group (hydroxyl group as defined in RH and R 1 2 are optionally protected by conventional hydroxyl coercive Mamorumoto (e.g., benzyl) show also may)]

Used as the starting material in the above reaction schemes 1 and 2, diketone derivative (II) may be obtained by any method as long as it is a known production method. For example, alpha - silyl O alkoxy styrene derivatives, copper chloride (11), lead tetraacetate, silver oxide (1), triflumizole Ruo b copper methanesulfonate (I :), manganese (II) oxide or Yodoso oxide such as benzene a method of reacting in the presence of agents, also - viii Roaseto Fuenon derivatives, bromide bis (triflate Uni Le phosphine) nickel (11), zinc, reductive in the presence of iodide and like tetra E chill ammonium Niu arm way is attached to, or, Asetofuwenon derivatives and - viii Roasetofuwenon derivatives, a method of reacting under basic conditions, or a Benzoiru 鲊酸 Arukirue ester, a method of reacting in the presence of such Peruokiso sulfate force Riumu copper sulfate it can be obtained by.

Incidentally, silyl O alkoxy styrene, corresponding Asetofuwenon derivative lithium dialkyl amino de presence of a base such as Toryechiruamin, using Shiriruha Lai Doya silyl sulfonates as silylating agent, tetrahydrofuran orchid, aprotic organic such as dichloromethane solvent at room temperature to one 8 0 ° C (Nozomu Mashiku is 0-1 8 0 ° C) is obtained by reacting at.

In the present invention, corneal opacity refers to those corneas damaged due traumatic injury or ophthalmic treatment occurs in the course of restoration, lamellar structure of the corneal real quality is disturbed by various factors, to pass through the cornea generated as a result of light has brought about the scattering is also of the. As a factor, for example the corneal wound, and the case of collecting 簇 keratocytes is a fibroblast-like cells, such as when the cytoplasm is swollen edematous. However, the corneal opacity of the present application, corneal opacity caused by traumatic injury or angiogenesis ophthalmic treatment after standing are eliminated. Trauma, for example gravel, flying into the solid foreign matters such as iron, etc. due to damage knives and nails, the ophthalmic Remedy, for example, a metal knife, keratotomy with a diamond knife, an incision of the cornea by excimer one The one irradiation or ablation, such as corneal transplantation, and the like. Corneal opacity inhibitor of the present invention, as an expression a compound represented by (I) (Compound (I)) or a salt thereof as an active ingredient, resulting et be by a variety of dosage forms of the formulation. The salt of compound (I), for example, sodium salts, potassium salts of any alkali metal salts, magnesium salts, alkaline earth metal salts such as calcium salts, generally less toxic tertiary amine salt, the acid addition salts ( examples include acceptable salt good UNA pharmaceutically hydrochloride). Compounds in corneal opacity inhibitor

(I) or the content of a salt thereof varies depending on the form of the preparation, usually, 0.0 1 of the total formulation:. L 0.0 wt%, preferably 0.0 5 to 2 0 double it is the amount%.

The form of the preparation, may be used any form, for example, aqueous solution, can be suspensions, gels, ointments, emulsions, is Rukoto used as such sustained or sustained release formulation. Further, powders, etc. and to granules or tablets, it may be in the form used by the like dissolved in such person standing in purified water for use. On its application, it is preferable that the dosage forms for eye drops.

To the preparation of corneal opacity inhibitor of the present invention can be used the preparation that is used in the manufacture generally ophthalmic agent. For example, the preparation of eye drops and eye ointments, twelfth Japanese Pharmacopoeia Reference, General Rules for Preparations [Japan official statement Association supervision, Hirokawa Shoten (Tokyo) publication, 1 9 9 1 year] and eye drops [this Seto Kenji al, MinamiyamaDo (Tokyo), prepared according to the process of 1 9 8 4 years] above. In the case of sustained-release formulation, For example, Bio-Pharmaceuticals, tick scan O blanking Okiyura one drag Deripa 're one (BIOPHARMACEUTICS OF OCULAR DRUG DELIVERY) [Peter Edma ed., CRC Press (USA), 1 9 9 3 years], etc. Ru is produced by the method described in.

To formulate corneal clouding inhibitor of the present invention for instillation, it is preferable to contain an additive for use in well-known ophthalmic agents generally.

The additives when formulated as an aqueous ophthalmic solution, for example, preservatives, isotonic agents, buffers, stabilizers, thickening agents, suspending agents, such as surfactants and p H adjusting agent used. Preservatives, parabens (Paraokishi repose Kosan methyl, etc. Paraokishi propyl benzoate), invert stone Gen compound (downy chloride Nzarukoniumu, downy chloride Nzetoniumu, to Darukon acid chlorine chlorhexidine, salts cetyl pyridinylbenzoyloxy © beam, etc.) , alcohol derivatives (chlorobutanol, Hue sulfonyl ethyl alcohol, benzyl alcohol), organic acids and salts thereof such (de arsenate mud 齚酸 sodium, sorbic acid and its salts), Fueno Le acids (Parakurorume Tokishifuwenoru, parachloromethacresol-cresol etc.) and organic mercurials (thimerosal, nitrate Fuweniru mercury, etc. Nitoromezoru) and the like. As the isotonic agent, sodium chloride, glycerin, mannitol and the like are used. As the buffer, (such as e © sand) boric acid and salts thereof, phosphates (disodium hydrogen phosphate, dihydrogen phosphate sodium, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, etc.), acetate (sodium acetate, acetic Anmoniumu) and amino acid salts (glutamic acid, epsilon - and aminocaproic acid) and the like. As the stabilizer, an antioxidant (sodium sulfite, sodium bisulfite, metabisulfite sodium, etc.), and chelating agents (sodium Edeto acids, salts Kuen acid and its) and the like. Examples of the thickener include polyhydric alcohols (glycerin, macrogol and the like), sugars (sorbitol, mannitol, and sucrose), celluloses (methyl cellulose, sodium carboxymethyl cellulose, such as hydroxycarboxylic cellulose) and synthetic high content child compound (polyvinyl alcohol, polyvinyl pyrrolidone, etc. Karubokishibi two Ruporima) and the like. Suspending agents, the cellulose scan such, like other surfactants of the synthetic polymer compound is used. As the surfactant, polysorbate, non I ON surfactants such as polyoxyethylene hydrogenated castor oil, cationic surfactants such as quaternary Anmoniumu salts, such as Al Kill sulfate anionic Ion surfactant and lecithin, etc. amphoteric surfactant is used. The p H adjusting agent hydrochloric acid, acetic acid, sodium hydroxide, etc.-phosphate is used.

The amount of these additives, active ingredients and varies by the amount used, it is desirable to approximate the physiological conditions of the normal eye (tear isotonic), for example, to normally 2 3 0 4 5 O mO sm , preferably used in adjustments to 2 6 0~3 2 O mO sm.

If corneal opacity inhibitor of the present invention are formulated into forms such as gels, the preservative, other water-soluble polymer is prepared by blending a sodium alginate. If corneal opacity inhibitor of the present invention is formulated in the form of a non-aqueous, such as ointments, in addition to the preservative, for example liquid paraffin, propylene glycol, 5-O click chilled octadecanol, petrolatum, plastibase, purified Ranori emissions are produced by blending the vegetable oils.

If corneal opacity inhibitor of the present invention is used as eye drop, eye drops to be advantageous to use adjusted to a p H range is normally used, typically, for example, hydrochloric acid, acetic acid, phosphoric acid, p H 3 to 8 with a suitable p H adjusting agent such as sodium hydroxide, are preferably used to adjust the p H 4 to 7.

Also, the corneal opacity inhibitor of the present invention, generally, the other pharmaceutical ingredients used in ophthalmic topical, for example, glaucoma, cataract agents, antimicrobial agents, vasoconstrictors, antiallergic agents and / or anti it may be compounded such as inflammation agent. The glaucoma therapeutic agents, pilocarpine, bromide distigmine, Jipibaru acid Epine flip down, timolol maleate, hydrochloride and the like bupranolol is used. The cataract therapeutics, pirenoxine, glutathione and the like. The antimicrobial agents, antibiotics (penicillin G potassium, chlorambucil Muhu We Niko Le, erythromycin, kanamycin sulfate, tetracycline hydrochloride, etc. Joseph Menokishimu), antifungal agents (pimaricin, amphotericin B, etc. Naisuta Chin) and the like. The vasoconstrictors, naphazoline nitrate, hydrochloric Okishimetazon, such as hydrochloric Fuwenirefurin is used. The antiallergic one agent., Antihistamines (hydrochloric Jifuwenhi Doramin, such as maleic thunk Rorufeniramin), sodium cromoglycate, etc. amlexanox is used. Anti-inflammatory agents, corticosteroids (cortisone, prednisolone, triamcinolone § Seto acetonide, dexamethasone, etc. Betame Tazon), non-steroid anti-inflammatory agents (indomethacin, Fururubipurofue emissions, such as pranoprofen) and the like.

The amount of the pharmaceutical ingredient, Compound (I) or against its salt 1 part by weight, normally 0.0 0 1 to 1 0 0 parts by weight, preferably 0.0 to 5 0 parts by hole .

For corneal opacity inhibitor of the present invention is that with the formulations of the sustained or sustained-release preparations, for example, a biodegradable polymer (hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose § cetearyl one Tosakushine Bok, etc.), acrylic acid resin (methacrylic acid Akuriru ester copolymer one, such as methacrylic acid-methacrylic acid ester copolymer) had better be added pressure and the like. The amount added, the compound (I) or against its salt 1 part by weight, normally, 0.. 1 to: L 0 0 parts by weight, preferably 0.5 to 5 0 parts by weight. Thus corneal opacity inhibitor of the present invention obtained by the traumatic injury or surgery, ophthalmic corneal damage caused by treatment repair turbidity induced by excessive extent, such as a laser irradiation procedure, and fibroblast-like and a suppression win excellent action of corneal opacity with cell proliferation. Thus, mammals (e.g., mouse, rat, hamster, Usagi, cat, I j, © Ma, © shea, Hijji, monkey, human, etc.) traumatic injury or surgery of ophthalmic such as laser irradiation procedure induced by repair processes of corneal damage caused by treatment turbidity, for example, therapeutic superficial keratectomy by E key island laser generated diffuse under the corneal epithelium in the irradiation area of ​​post refractive surgery and astigmatism correction surgery It can be safely used in the prevention or treatment of corneal opacity with the growth of beauty fibroblast-like cells Oyo turbidity reticular. Use of corneal opacity inhibitor of the present invention varies depending on the form, can be carried out according to the method used in the ophthalmic agent generally publicly known, for example, carried out by a method such as direct dropping and TenIri the conjunctival sac be able to.

Specifically, when using a corneal opacity inhibitor corneal opacity of excimer Mareza irradiation postoperative adult as an aqueous ophthalmic solution of the present invention, for example, age, body weight, symptoms, administration method and the like, compound (I) or the concentration of the salt 0.01~10.0w / v%, Yo Unishi preferably becomes 0.05~2.0Wv%, which 1 曰 3-6 times, a few drops to ophthalmic dosage once 1 good. Also, when used as an eye ointment, Compound (I) or the concentration of the salt 0.02-10.0 wt%, preferably made to be 0.05 to 2.0 wt%, which 1 曰 3-6 times, the point input it is preferable to TenIri to 1 times the amount of 30~10 Omg conjunctival sac with a stick. Example

Test Examples The following Examples and Reference Examples The present invention described in more detail Suruga, these are merely examples, but the scope of the present invention is not limited thereto.

Test Example 1

For corneal opacity suppressing operation in the corneal surface after resection by Excimer laser irradiation

(Test substance)

As the test substance, the compound A was used which was suspended in physiological saline so as to be LwZv%, which was used as a compound A eye drop. Saline and 0.1% Rinderon as a control drug (registered trademark; betamethasone sodium phosphate ophthalmic solution, manufactured by Shionogi & Co., Ltd.) was used.

(Excimer laser irradiation conditions)

Irradiation conditions of the excimer laser, the diameter: 2. 5 mm, frequency: 50H z, irradiation energy: 16 OM j ZCM 2, number of scans: 60, ablation rate were set to be a 0. 8 τ scan.

(Test method)

Brown Roh roux Wei the (Brown Norway) strain female rats (9 to 1 0 weeks old) Ketalar (registered trademark; ketamine hydrochloride, Sankyo Co., Ltd.) were anesthetized with, base Nokishiru ophthalmic solution (registered trademark; hydrochloric acid Okishibupuro force Inn, the Santen Pharmaceutical stock Company, Ltd.) was local anesthesia was dropped into the eye. Underwent; (PRK photorefractive keratectomy) corneal surface resection by irradiating excimer laser to both eyes cornea of ​​rats. Saline, compound A eyedrops or 0.1% Rinderon is the PRK treatment day, twice after PRK treatment, 4 times a day from the next day, was instilled once 5 ^ 1, further prevent infection Taribi' DOO eye drops for (registered trademark: ofloxacin, Santen Pharmaceutical Co., Ltd.) saline, compound a eyedrops or 0.5 was instilled 1% Rinderon instillation before. Scan rate cards to treatment 3 and 6 曰後 by observing the cornea, after 6 days, scored Te 従Tsu the scoring criteria shown below to calculate the inhibition rate against scoring value, physiological salt solution applied group of corneal opacity . In addition, the pathological tissue specimens were created made in accordance with a conventional method were enucleated eyeball after treatment 7 days. Perform central portion Matokinrin 'Eojin stained thin Setsugo to, ocular, under an optical microscope (X 4 0) histological observation and corneal subepithelial fibroblast-like fine 胞層 number and a predetermined length (3 3 6 // m) was measured the number of fibroblast-like cells per.

(Scoring criteria)

0: turbidity is not observed

1: whole turbid mild (iris Torumi is good)

2: partly cloudy moderate (iris Torumi somewhat bad)

3: turbidity of moderate to whole

4: partially cloudy altitude (iris Torumi difficult)

5: Advanced turbidity in the whole

(Slit Trump observations)

Observation of cornea with slits playing cards PRK 3 曰後, saline, Compound A eye drop or a normal reproduction Repairing least 0.1% Rinderon group instilled corneal epithelium was observed, drug corneal epithelial repair in each group the delay and the effect of promoting was not recognized, et al. The PRK 6 曰後 inhibition rate against scoring values ​​and physiological saline solution applied group corneal opacity by slit playing cards shown in Table 1. Example Number inhibition rate group corneal opacity Rating value

(Eye) (%) physiological saline solution applied 10 3.9 mechanic 0.4

It 匕合 compound A eye drops eye drops 18 2.8 Sat 0.9 ** 28.2

The 0.1% Rinderon eye 10 3. 3 ± 0. 5 * 15. 4 Dane' preparative (Dunnett) multiple comparison test method,

*: Significant difference is observed in the risk rate of 5% relative to saline instillation group.

**: significant difference is observed in 1% risk factor with respect to physiological saline solution applied group,

Although corneal opacity in each group were observed, the compound A eye drop instillation group, a significant inhibition as compared to corneal opacity with physiological saline solution applied group was observed. Also in 0.1% Rindero emissions applied group, compared to the physiological saline solution applied group, the degree but significant inhibition of corneal opacity was observed, was weaker than the compound A eye drop instillation group. Further, corneal perforation was observed in two cases of 0.1% Rinderon applied group. Note that during both the observation by Suritsu Trump, angiogenesis was not observed in each group.

(Histological observations)

Result of eye treatment 7 曰後 was observed histologically, cornea PRK treatment site, compared to the corneal thickness of the saline instillation group and compound A eye drop instillation group, a 0.1% Rinderon applied group, 10 thinning of the cornea was observed in 8 patients in the examples.

The proliferation of fibroblast-like cells were observed under the corneal epithelium in both each group. Number of cell layers fibroblast-like cells were observed under the corneal epithelium of each group, the inhibition rate against saline group instilled cell number and drug applied group shown in Table 2.

Table 2

Number of cases ■ fibroblast-like cell layer number

Group fibroblast-like cell number

(Eye) (% inhibition) (% inhibition) saline ophthalmic 8 7.3 Soil 5. 1 32. 7 ± 5. 8 Compound A eye drop instillation 16 4. 3 ± 3. 0 8. 2 ± 4 . 0 **

(41.1) (74.9)

0.1% Li, Ideron eye drops 7 6.0 Sat 3. 0 1 7. 8 ± 4. 0 *

The (17.8) (45.6) Dane' bets (Dunnett) multiple comparison test method,

*: Significant difference is observed in the risk rate of 5% relative to saline instillation group.

**: significant difference is observed in 1% risk factor with respect to physiological saline solution applied group,

Both Compound A eye drop instillation group and 0.1% Rinderon applied group, the comparison with the physiological saline salt solution applied group significant fibroblast-like cell layer and cell growth inhibition was Me certified. Compound A eye drop instillation group, inhibitory effect as compared to 0.1% Rinderon applied group was great.

The above results, Compound A eye drop did not show side effects such as 菲 thin and corneal perforation of the cornea, such as steroid eye drops, fibers found in corneal opacities and under the corneal epithelium that occurs excimer laser irradiation after surgery it is a has decreased clearly show excellent inhibitory effect on fibroblast-like cells proliferation.

Test Example 2

Corneal stroma cytostatic action

(Test method)

Buraun'noruu you (Brown Norway) male rats (9~: L 0-week-old) were sacrificed, after peeling off the corneal epithelium with a scalpel, were removed eyeball. After the cut out of the cornea from the eye, the corneal endothelial peeled off and removed to obtain a corneal stroma. The resulting stroma was minced, 10v / v% © Shi fetal serum (FBS, Gibco) were suspended in containing Eagle's MEM medium (Nissui Pharmaceutical Co., Ltd.), 37 ° C, 5% CO 2, They were cultured under 20% O 2. Cells are subcultured when cell growth reached saturation point, the 7 and 10 subculture cells were used in the following test. The test was sowing on a 24-well plate (manufactured by Becton Dickinson) so that the cells to be 10% Konfuru Ento. After the cells cultured for 24 hours, was added 3曰間culture so that the test drug and 10_ 5 M. Half of the culture medium was replaced with a test drug added to the culture medium to test drug added 2 曰後. Cell numbers, prior to the addition test drug, the test drug added 3 曰後 measure to have use a hemocytometer were calculated keratocytes proliferation inhibition rate.

Test drug dissolved in dimethyl sulfoxide (DMSO), and diluted prepared to a concentration of interest in 10v / v% FB S-containing Eagle MEM culture locations to a final concentration of 0. lv / v% of DMSO.

(Test results)

The keratocytes proliferation inhibition rate of each test drug is shown in Table 3. Each test drug inhibited the growth of keratocytes in 10- 5 M. Table 3

殖抑 system rate compound 澳度 (M) corneal stromal cells increase

(%)

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, the present compounds it is possible to suppress the proliferation of keratocytes fibroblast-like cells, it is possible to suppress the corneal opacity that occurs after corneal injury due to traumatic injury or ophthalmic procedures.

Example 1

(Eye drops)

Compound A 1.0 g

Mannitol 5.0 g

Hydroxycarboxylic methyl cellulose 0.1 g

-Phosphate sodium dihydrogen 0.1 g

Benzarukoniumu chloride 0.005 g

Sodium hydroxide qs Sterile purified water total amount 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 pH was adjusted to 7.0 with sodium hydroxide, to make a total volume 100ml further added sterile purified water to a 1.0 wZv% Compound A ophthalmic suspension. Osmotic pressure of the resulting eye drop is 300 mO sm der

Example 2

(Eye drops)

Compound A 0.01 g

Sodium chloride 0.9 g

Polyvinylpyrrolidone 0.1 g

Sodium dihydrogen phosphate 0.1 g

Benzarukoniumu chloride 0.005 g

Sodium hydroxide qs

Sterile purified water total volume of 100ml

Sodium chloride at about 8 Om 1 sterilized purified water, polyvinylpyrrolidone was dissolved sodium dihydrogen phosphate and chloride Benzarukoniumu. Compound A was dispersed into the solution. Then pH was adjusted to 7.0 with sodium hydroxide, to make a total volume 100ml further added sterile purified water to a 1. OwZv% Compound A ophthalmic suspension. Osmotic pressure of the resulting eye drop was 30 omo sm. Example 3

(Eye drops)

Compound A 0.0 g

Concentrated glycerin 2.6 g Polysorbate 80 0.1 g

Acetic acid Na door potassium 0.1 g

Paraokishi benzoate 0.026 g

Paraokishi propyl benzoate 0.014 g

Sodium hydroxide qs

Sterile purified water total volume of 100ml

About 80 m 1 sterilized purified water heated to about 80 ° C, were dissolved Paraokishi methyl benzoate and Paraokishi propyl benzoate. Cold 却後 The solution to room temperature, concentrated glycerin, dissolving the Polysorbate 80 and 詐酸 sodium was dispersed Compound A. Then it was adjusted to pH 5.0 with sodium hydroxide, to make a total volume of 100 m 1 was further added sterile purified water to a 1. OwZv% Compound A ophthalmic suspension. Osmotic pressure of the resulting eye drop was 305mO sm. Example 4

(Eye drops)

Compound A 0.1

Man'nitonore 5.0 g

Poly O · The shell Ji Ren hydrogenated castor oil 60 0.1 g

Boric acid 2.0 g

Borax appropriate amount

Benzarukoniumu chloride 0.005 g

Sterile purified water total amount of 10 Oml

About 8 Om 1 sterile purified water heated to about 80 ° C, were dissolved boric acid and Poriokishe styrene hydrogenated castor oil 60. The solution was cooled to room temperature and dissolved man two tall and chloride Benzarukoniumu. Compound A was dispersed into the solution. The pH was then adjusted to 7.0 with borax, and total volume of 100ml was added further to sterile purified water, the osmotic pressure of which was 1.0WZv% Compound A ophthalmic suspension (resulting eye drop was 30 omo sm.

Example 5

(Eye ointment)

Compound A 1.0 g

White Waserin 10.0 g

Liquid paraffin 89.0 g

Paraokishi benzoate 0.02 g

Paraokishi propyl benzoate 0.014 g

Miscible white Waserin and liquid paraffin. The mixture was heated, by means of an emulsifying tester (Nikko Chemicals ET- 1 A type) was stirred at l OO rpm. When the whole is liquefied, it was added and dissolved Paraokishi benzoate and para Okishi propyl benzoate. After cooling to 80 ° C, Compound A was added, and stirred at emulsification tester, papermaking Compound A eye ointments.

Example 6

(Gels)

Compound A 1.0 g

Karubokishibi two Ruporima 0.4 g

Benzarukoniumu chloride 0.005 g

Sodium hydroxide qs

Sterile purified water total amount of 100 m 1

Karubokishibi two Ruporima was dispersed in about 8 Om 1 sterile purified water, the pH was adjusted to 7.0 with sodium hydroxide, and the total volume added to sterile purified water and 100 ml. Stirred at 200 r pm using this emulsion tester (Nikko Chemicals ET- 1 A type). To made by stirring with Compound A and emulsion tester chloride was added Benzaruko two © beam in the gel base.

Example 7

(Eye drops)

GS-B 624 0.5 g

Concentrated glycerin 2.6 g

Dipotassium hydrogen phosphate 0.1 g

Chlorhexidine 0.04 g to gluconic Sankuguchiru

Black hole butanol one Norre 0.3 g

Hydrochloric acid appropriate amount

Sterile purified water total volume of 100ml

Sterile purified water to about 80ml to GS- B 624, concentrated glycerin, dipotassium hydrogen phosphate, was dissolved chlorhexidine and Kurorobutano Ichiru to gluconic acid chlorine, pH was adjusted to 7.2 with hydrochloric acid, the total amount added further sterilized purified water was a 100 ml, was 0.5wZv% GS- B624 ophthalmic solution.

Example 8

(Eye 軟奢)

GS-B620 2.0 g

Paraokishi benzoate 0.026 g

Paraokishi propyl benzoate 0.014 g

White Waserin total amount of 100 g

White Waserin about 10 g to GS- B 620, added Paraokishi benzoate Contact and Paraokishi propyl benzoate, homogeneously mixed, the total weight was 100 g added with further stirring white Wa serine, 2.0 w / w % GS- was B 620 ophthalmic ointment. Reference Example 1

Argon gas atmosphere, 0 ° C under a 8.8 ml (hexane solution 1.6M) n-butyllithium, adding as tetrahydrofuran and Jie isopropyl § Min 7.9ml

And the mixture was stirred for 10 minutes. To this solution - 78 ° C cooling under stirring, 4'Benjiruokin - 3 '- (.. J. Org Chem, 57, 7248 (1992)) main Toki Xia Seto full We non tetra arsenide Dorofuran solution 2.56g was dropped , and the mixture was stirred for 30 minutes. Then trimethylsilyl chloride 2.2ml added, and after stirring for 10 minutes, followed by stirring at room temperature for 1.5 hours. After concentrating the reaction mixture under reduced pressure, it was added 10% aqueous sodium hydrogen carbonate, and extracted with ether. The organic layer was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, like a yellow oil, 4'Benjiruokishi 3'main butoxy - - give the trimethylsilyl O xylene styrene emission (3.27 g, 99.6% yield) . Physicochemical properties of the resulting 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)

Masusu Bae-vector

m / z: 328 (+)

Previously obtained 4 '- Benjiruokishi -3' - main butoxy - - dissolving Bok trimethyl silyl O carboxymethyl styrene 328mg of dichloromethane, under an argon gas atmosphere and cooled to -78 ° C. Added lead tetraacetate 246mg and tetrahydrofuran was stirred for 1.5 hours and stirred at room temperature for 1 hour. Water was added, extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue dichloride port methane - was recrystallized from hexane, colorless needles 1, to give 2- bis (4-Benzyl Okishi 3 main Tokishibenzoiru) Etan (196 mg, 76.9% yield). Physicochemical properties of the resulting 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)

Masusu Bae-vector

m / z: 510 (M +)

Previously obtained 1, it was dissolved 2- bis (4-Benjiruokishi 3 main Tokishibenzoiru) Etan 2.70g in black port Holm, a mixed solution of chloride Asechiru 360 il and methanol, and the mixture was refluxed for 3 hours. The reaction solution was cooled, concentrated under reduced pressure, than was purified by silica force gel strength column chromatography hexane fraction into dichloromethane primary, 2 colorless needles, 5- bis (4-Benjiruokishi 3 main Tokishifue sulfonyl ) was obtained furan (1.23 g, yield 47.4¾).

Reference Example 2

Argon gas atmosphere, 0 ° C under a 16 ml (hexane solution 1.6M) n-butyllithium, and stirred for 10 min by addition of tetrahydrofuran and diisopropylamine 3.6 ml. To this solution - 78 ° C cooling under stirring, 2'Benjiruokishi - 4'main butoxy Asetofuwenon (Hua Hsueh, 41, 61 (1983)) was added dropwise tetrahydrofuran solvent solution of 5.76 g. After stirring for 15 min, dimethylformamidine de solution of copper chloride (11) 3.37 g was added and after stirring for 30 minutes, followed by stirring at room temperature for 1.5 hours. Of 2N aqueous hydrochloric acid was added, followed by extraction with acetic acid Echiru, the organic layer was washed 2N aqueous hydrochloric acid, water and saturated brine. After the insoluble matter was dissolved by adding dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in black port Holm 60 ml, a mixed solution of chloride § cetyl 0.9ml of methanol was added and refluxed for 2 hours. The reaction solution was cooled, a saturated aqueous sodium hydrogen carbonate was added, the organic layer was washed with water extracted with dichloromethane, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and recrystallization of the solid obtained from hexane-fraction in dichloromethane one to dichloromethane one methanol, colorless needles 2, 5-bis (2 - Benjiruokishi - 4 - Main Tokishifuweniru ) furan (2. 57 g, to obtain a yield 46. 4¾.

Reference Example 3

Obtained in Reference Example 1, 2, 5-bis - dissolving (4 Benjiruokishi 3 main Tokishifuweniru) full run 246mg in dichloromethane, 10% Parajiumu carbon catalyst 10mg addition, under a hydrogen gas atmosphere, stirred at room temperature for 8 hours did. The insoluble matter is collected by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was recrystallized from hexane to dichloromethane and foremost, 2 pale blue needles, 5- bis (4 - hydroxy - 3 main Tokishifue sulfonyl) furan (Compound shown in Table 4 1, GS-B285) It was obtained (102 mg, yield: 65.6) to. Rika biological properties of the compound are shown in Table 6.

The same manner, 2, 5- bis (2-hydroxy-4-menu Tokishifuweniru) furans (compound shown in Table 4 2. GS-B 603), 2, 5- bis (2-arsenate Dorokishifueniru) full run (Table 4 shows compounds 3, GS-B 607), 2, 5-bis (3, 5-dihydrazide Dorokishifuwe yl) furan (compound shown in Table 4 4. GS-b558), 2, 5- bis (3-arsenide Dorokishi - 4 - main Tokishifue yl) furan (Table 4 shows compounds 5, GS-B560), 2, 5- bis (3 - was prepared hydroxyphenyl sulfonyl) furan (compound shown in Table 4 6. GS-B535). These physicochemical properties are shown in Table 6.

Reference Example 4

2 obtained in Reference Example 2, 5- bis (2, 4-dibenzyl O carboxymethyl off We yl) furan 644mg dichloromethane - methanol: water (2 1), added 10¾ Parajiumu carbon catalyst 70 mg, hydrogen gas atmosphere and stirred for 1 hour at room temperature. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in dichloromethane, acetic anhydride was added lml pyridine 1. 1 ml, and stirred at room temperature for 2 hours. 2N aqueous hydrochloric acid was added, and the mixture was extracted with dichloromethane, the organic layer was washed with saturated aqueous sodium hydrogen carbonate, and washed with water. After drying over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue was re-force gel strength column chromatography to afford obtained from hexane fraction to acetic acid Echiru solid was recrystallized from hexane to acetic Echiru, colorless needles 2 crystals, 5- bis (2, 4-Jiasetokishifu sulfonyl) furan (compound Ί shown in Table 3, GS- B588) (165mg, physicochemical properties was obtained yield 36. 5¾. this compound in Table 6 It is shown.

Reference Example 5

Known 2, 5- bis (4-Benjiruokishi 3 main Tokishibenzoiru) butane-1, 4-dicarboxylic acid Jechiru (J. Chem. Soc., Perkin Trans. I, 183 (1982)) 2. 6g in toluene dissolved, added Benjiruamin 22ml acetic acid 11. 6 ml, was refluxed for 24 hours. After cooling, it added 醉酸 Echiru the reaction solution, and washed with water. After drying over anhydrous sulfate Ma Guneshiumu, and concentrated under reduced pressure, the residue was purified by silica gel column black Matogurafi one, the § motor Rufasu obtained from hexane fraction to ether one, pale recrystallized from dichloromethane one methanol of yellow plate crystal N- benzyl - 2, 5-bis (4-Benjiruokishi 3 main Tokishifue two Le) pyrrole - 3, 4-di force Rupon acid Jechiru (1. 24 g, yield 43. 2¾I) a Obtained.

By the same method, 2, 5- bis (4-Benjiruokishi 3 main Tokishibenzoiru) butane - 1, 4-dicarboxylic acid Jechiru than 2, 5- bis (4-Benjiruokishi 3 main Tokishibenzoiru) pyro Ichiru -3 , 4-dicarboxylic acid Jechiru, N-(4 black port base Njiru) -2, 5- bis (4-Benjiruokishi 3 main Tokishifuweniru) pyro Ichiru -3, 4-dicarboxylic acid Jechiru, N-(4- methylbenzyl) -2, 5- bis (4-Benjiruoki sheet 3 main Tokishifue sulfonyl) pyrrole - 3, 4-dicarboxylic acid Jechiru, N- hydro carboxymethyl-2,5-bis (4-Benjiruokishi 3- menu Tokishifueniru) pyrrole - 3, 4-dicarboxylic acid Jechiru, N- benzyl-2,5-bis (4-Benjiruokishi 3 main Toki Shifuweniru) pyrrole - 3, 4-di force carboxylic acid Jechiru, 2, 5-bis (4-benzyl Okishi 3 main Tokishifu x sulfonyl) pyro Ichiru, N-(4 black port benzyl) -2, 5-bi (4 Benjiruokishi 3 main Tokishifuweniru) pyrrole, N-(4-methylbenzyl) -2, 5- bis (4-Benjiruokishi 3 main Tokishifueniru) pyrrole, 3-, 5- bi scan (4- Benjiruokishi - 3 main Tokishifeniru) - 1-pyrrolylmethyl} pyridine, 1- [3- is 5- bis (4-Benjiruokishi 3 main Tokishifeniru) -1-pyrrolyl} flop port propyl] was prepared Imiguzoru.

Reference Example 6

N- benzyl-2 obtained in Reference Example 5, 5- bis (4-Benjiruokishi 3 main Tokishifue sulfonyl :) pyrrole - 3, 4-dicarboxylic acid Jechiru 290 mg, tetrahydrofuran one methanol (1: 1) to dissolve was added 10¾ palladium-carbon catalyst 10 mg, under a hydrogen gas atmosphere and stirred at room temperature for 6 hours. After filtering off the insoluble matter, N- benzyl-2 by concentrating the filtrate under reduced pressure, 5- bis (4-hydroxy-3-menu Tokishifue sulfonyl) pyrrole - 3, 4-dicarboxylic acid Jechiru (Table 5 compound 8, GS-B106) 252mg shown was obtained in quantitative yield. Physicochemical properties of the compounds Asked Ride that shown in Table 7.

The same manner, performed debenzylation of Reference Example 5 A compound according, 2, 5- bis (4-hydroxy - 3 main Tokishifueniru) pyrrole - 3, 4-dicarboxylic acid GETS chill (compound shown in Table 4 9 , GS-B63), N-(4-chlorobenzyl) -2, 5- bis (4-arsenide Dorokin - 3 main Tokishifuweniru) pyrrole -. 3, compounds shown in 4-dicarboxylic acid Jechiru (Table 5 1 O GS . -B72) NU- methylbenzyl) -2, 5- bis (4-hydro carboxymethyl-3 main Tokishifuweniru) pyrrole - 3, 4-di force carboxylic acid Jechiru (shown in Table 5 to compound 1 1, GS-B 114 ), N- human Dorokishi-2,5-bis (4-hydroxy-3-menu Toki Shifuweniru) pyrrole - 3, 4-dicarboxylic acid Jechiru (compound shown in Table 5 1 2, GS - B169), N- benzyl - 2, 5-bis (4-hydroxy-3-menu Tokishifue yl) pyro Lumpur (compound shown in Table 5 1 3, GS-B613), 2, 5- bis (4-hydroxy - 3 main Toki Shifuweni ) Pyrrole (Compound 1 4 shown in Table 5, GS- B624), N- (4- black port benzyl) -2, 5- bis (4-arsenide Dorokishi - 3 main Tokishifuweniru) pyrrole (compound shown in Table 5 1 5, GS-B617), N- (4- methylbenzyl) -2, 5- bis (4-arsenide Dorokishi 3 main Tokishifuyu sulfonyl) pyrrole (compound shown in Table 5 1 6, GS-B620), 3- {2, 5-bi scan (4-hydroxy-3 - main Tokishifuweniru) -1-pyrrolylmethyl}. pyridine, (. compounds shown in Table 5 1 7 GS-B625) 1- [3-, 5- bis ( 4 - Hidorokin - 3 main Toki Shifuwe sulfonyl) - 1-pyrrolyl} propyl] was prepared Imidazoru (compound shown in Table 5 1 8, GS-B630). Physicochemical properties of this compound are shown in Table 7.

Reference Example 7

In addition Reference Example 1 1 according 2- bis (4-Benjiruokishi 3 main Tokishibenzoiru) E Tan 510 mg, 4 aminomethyl Kei cinnamate methyl 573mg and 1 drop of acetic acid in toluene was refluxed for 68 hours. The reaction solution was cooled, dichloromethane was added and washed with 2N salt acid solution, with water. After drying over anhydrous magnesium sulfate, and concentrated under reduced pressure, the residue pale green needles by Rukoto to recrystallization of the amorphous obtained from Jikurorome Tan fraction was purified by silica gel column chromatography from hexane acetate Echiru of 4 {2, 5-bis (4-Benjiruokishi - 3 main DOO Kishifuweniru) -1-pyrrolylmethyl} was obtained Gay cinnamic acid methyl (380 mg, yield 57. 2¾0.

Then the 4- {2, 5-bis (4-Benjiruokishi 3 main Tokishifeniru) -1-pin port Rirumechiru} Gay cinnamic acid methyl 266mg was dissolved in Jikuroroetan, under argon gas scan atmosphere, to -30 ° C It cooled. Boron trichloride (1. 0M in dichloromethane) was added dropwise 1. 6 ml, followed by stirring for 2 hours. The addition of methanol, after stirring for 30 minutes, water was added and extracted with dichloromethane. The organic layer was dried over anhydrous sulfate magnesium © beam, and concentrated under reduced pressure, the residue was recrystallized from hexane to ether one, 4-, 5- bis (4-arsenide Dorokishi 3 main Tokishifue) -1- pyrrolylmethyl} Gay cinnamate methyl (compound shown in Table 5 1 9, GS-B615) (144mg, yield: 74. 4¾ί) was obtained. Physicochemical properties of this compound are shown in Table 7.

Reference Example 8

Obtained in Reference Example 6, Nyu- benzyl-2, 5 - bis (4-arsenide Dorokishi 3 main Tokishifue sulfonyl) pyrrole - 3, were dissolved 4-dicarboxylic acid Jechiru 800mg ethanol, 10% hydroxide Natoriumu 3 . 5 ml and the mixture was refluxed for 24 hours. The reaction solution was cooled, concentrated in vacuo, and dissolved by adding water to the residue. And acidified with 2N aqueous hydrochloric acid, the resulting precipitate was filtered and washed with water. The solid was dissolved in 1N aqueous sodium hydroxide and extracted with dichloromethane.

To the aqueous layer was acidified with 2N aqueous hydrochloric acid, the resulting precipitate was filtered, washed with water, a pale brown powder by drying N- benzyl-2,5-bis (4-hydroxy - 3 main Tokishifuweniru ) pyrrole - 3, compounds shown in 4-di force Rupon acid (Table 5 2 0, GS -B110) (yield 541 mg, yield 75.3%). Physicochemical properties of this compound are shown in Table 7.

By the same method, performed ester hydrolysis, N-- black port benzyl) - 2, 5-bis (4-hydroxy-3-menu Tokishifuweniru) pyrrole - 3, from 4-dicarboxylic acid Jechiru, NU black port benzyl ) -2, 5- bis (4-hydroxy-3-menu Toki Shifuweniru) pyrrole - 3, 4-di force Rupon acid (compound shown in Table 5 2 1, GS-B81), N- (4- methylbenzyl ) -2, 5- bis (4-arsenide Dorokishi 3 main Tokishifuweniru) pyro Ichiru -3, from 4-dicarboxylic acid Jechiru, N-(4-methylbenzyl) -2, 5-bi scan (4-hydroxy 3 main Tokishifuweniru) pyrrole -. 3, 4-dicarboxylic acid (Table 5 shows compounds 2 2 GS-B 122) were prepared, respectively. Rika biological properties of these compounds are shown in Table 7. Compound A (GS-01)

Me = methyl group, Ac = 7 cetyl group

Compound No. 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

HH

(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 butyl group, Bn = benzyl group, 4-C Old n-4-black port base Njiru group, 4-MeBn = 4- methylbenzyl group, 3-PyMe = 3- pyridylmethyl group, 1-lmPr = 3 (1 Imidazoiru) propyl group, 4-MeCi = 4- Gay cinnamic acid methyl -98 -

9 拏

(ZS99-S9) εζ½ · No. ^^

0 / 96df / I3d 89000 / arm 6 OM

1

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

Argon gas atmosphere to dissolve the N-(t-but-kin carbonyl) glycine 1. 16g of dichloromethane. This 1, 3-dicyclohexyl added dichloromethane Kishirukarupoji imide 1.36g to, and the mixture was stirred under ice cooling for 30 minutes. 2 next to the reaction mixture, 5- bis (3-arsenide Dorokishi one 4-menu Tokishifue sulfonyl) -3, 4-dimethyl-furan 1.02 g of dichloromethane was added dropwise over 40 minutes, 18 hours at room temperature It stirred. The insoluble material was filtered off, the filtrate was concentrated. The residue was recrystallized from hexane over dichloromethane f a, white needles 2, 5-bi scan {3- [N- (t- butoxycarbonyl) § amino methylcarbonyl O carboxymethyl] one 4-menu Tokishifuwe sulfonyl} - 3 to give the 4 one dimethylfuran 1.63 g (83% yield). This compound has the following physicochemical properties shown below.

! H-NMRC ^ ppm in CDC1 3):

1.48 (Rat 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)

Mp: 153.5 to 155.5 ° C

2 obtained above, 5-bis {3- [N- (t one butoxide deer Lupo sulfonyl) Amino methylcarbonyl O carboxymethyl] one 4-menu Tokishifue sulfonyl} - 3, 4-Jimechirufu run 654 mg in ether one dichloromethane dissolved was bubbled under ice cooling hydrochloric acid gas into the solution for 10 minutes. It was further stirred for 3 hours at room temperature. After filtering off the precipitated solid, peach white powder 2 was recrystallized from methanol one ether, 5-bi scan [3- (aminomethyl carbonyl O carboxylate) one 4-menu Tokishifue sulfonyl] one 3, 4-dimethyl-furan- dihydrochloride (446 mg, 85% yield). This compound has the following physicochemical properties shown below.

^ -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)

Mp:. 181~182 5 ° C

As described above, corneal clouding inhibitor of the present invention, low toxicity, and traumatic damage or surgical operation, corneal opacity occurring in the repair process of the corneal damage caused by ophthalmic procedures, such as laser irradiation procedure to demonstrate the excellent inhibitory effect on, useful in the prevention and treatment of corneal opacities. Further, corneal opacity inhibitor of the present invention, traumatic injury or surgery, to show an inhibitory effect of fibroblast-like cells that proliferate Ri by the ophthalmic procedure such as laser irradiation procedure, fibroblast-like cells increase useful in the prevention and treatment of ingrowth.

Claims

The scope of the claims
. Formula (I)
Wherein, Rh R 2, R 3, R 4, R 5, R 6, R 7, R 8, R 9 and. The same is
Or different and represent a hydrogen or an optionally substituted hydroxyl group, isometric ^ Oyobi! ^^ 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, ( good aromatic carbon substituted
Ring) primary alkyl group or a (heterocyclic ring which may be substituted) primary alkyl group, and X represents oxygen or nitrogen. However, when X is oxygen, R 13 represents a lone pair of oxygen. Containing a compound or a salt thereof]
Consisting of 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
Or different hydrogen, hydroxyl, corneal clouding inhibitor according to claim 1 is an alkoxy group or an optionally substituted alkylcarbonyl O alkoxy group.
3. Ri, R 2, R 3 > R 5 Re, R 7> R 8, R 9 and Ri. But the same
Or different hydrogen, hydroxyl, corneal clouding inhibitor according to claim 1 is an alkoxy group or an amino alkyl carboxy Niruokishi group.
4. R "R 2, R 3 , R 4, R 5, R 6, R 7, R 8, R 9 and R 1 () is the same or different and each is hydrogen, hydroxyl, main butoxy or aminomethylcarbonyl O 'carboxylate corneal opacity inhibitor according to claim 1 is.
V 5. RH and R 12 are the same or different and each is hydrogen, an alkyl group, corneal clouding inhibitor according to claim 1 is a carboxyl group or an alkoxycarbonyl group.
6. and R 12 are the same or different and each is hydrogen, an alkyl group, corneal clouding inhibitor according to claim 1, wherein the carboxyl group or E butoxycarbonyl.
7. and R 12 are the same or different and each is hydrogen, methyl, corneal clouding inhibitor according to claim 1, wherein the carboxyl group or Etokin force Ruponiru.
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. it 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. substituents of optionally substituted aromatic carbocyclic ring one also be alkyl groups and substituted heterocyclic one even to good optionally alkyl groups represented by R 13 is an alkyl
* Corneal opacity inhibitor according to claim 1, wherein a group or a halogen.
.
The compound represented by 13. Formula (I) is
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 hydrogen, Rn is methyl, the compound wherein R 12 is methyl, and X is oxygen (compound a);
Ri is hydrogen, R 2 is a hydroxyl group, R 3 is hydrogen, R 4 is hydroxyl, R 5 is hydrogen, R 6 is hydrogen, R 7 is a hydroxyl group, R 8 is hydrogen, R 9 is a hydroxyl group, R 1D is hydrogen, but hydrogen, compounds wherein 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, R 9 is hydrogen, R 10 is hydrogen, but methyl, 2-methyl, and X is an oxygen compound (GS- B 637);
But hydrogen, R 2 turtles butoxy, R 3 is hydroxyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 turtles butoxy, 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
But hydrogen, R 2 turtles butoxy, R 3 is hydroxyl, R 4 is hydrogen, R 5 is hydrogen, R 6 is hydrogen, R 7 turtles butoxy, R 8 is hydroxyl, R 9 is hydrogen, 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. corneal opacity inhibitor according to claim 1, which is used for ophthalmic.
15. Compounds represented by formula (I) or corneal opacification suppression method comprising administering an effective amount of a salt to a subject in need of corneal opacification suppression.
16. in the manufacture of a corneal opacity inhibitor, used as an active ingredient of a compound or a salt thereof represented by the formula (I).
PCT/JP1996/001636 1995-06-16 1996-06-14 Corneal clouding inhibitor WO1997000068A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP7/150092 1995-06-16
JP15009295 1995-06-16

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018095A1 (en) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Aryl furan derivatives as pde iv inhibitors
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

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JPH02240058A (en) * 1989-02-10 1990-09-25 Basf Ag Diaryl-substituted heterocyclic compound

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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 (en) * 1989-02-10 1990-09-25 Basf Ag Diaryl-substituted heterocyclic compound

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999018095A1 (en) * 1997-10-03 1999-04-15 Merck Frosst Canada & Co. Aryl furan derivatives as pde iv inhibitors
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
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
US9755874B2 (en) 1999-08-09 2017-09-05 Kamilo Feher Digital mobile communication
US8849313B2 (en) 2005-08-03 2014-09-30 Kamilo Feher Cable connected mobile video, cellular and Wi-Fi communications
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)
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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