JP2016050174A - Prophylactic and/or therapeutic agent for keratoconjunctive diseases or presbyopia comprising catechin or catechin derivative as active ingredient - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a pharmaceutical composition for prophylaxis and/or therapy of keratoconjunctive diseases or presbyopia, comprising catechin or catechin derivatives as an active ingredient.SOLUTION: The present invention provides a pharmaceutical composition for prophylaxis and/or therapy of keratoconjunctive diseases or presbyopia, comprising catechin or a compound represented by formula (I), or a salt or a prodrug thereof, as an active ingredient (where m and n each represent an integer of 0 to 4, m+n≥1; and Rand Rare the same or different and represent a hydrogen atom or a C1-C17 hydrocarbon group).SELECTED DRAWING: None

Description

  The present invention relates to a pharmaceutical composition for preventing and / or treating keratoconjunctival disease or presbyopia containing catechin or a catechin derivative.

Catechin ((2R, 3S) -2- (3,4-dihydroxyphenyl) -3,4-dihydro-2H-chromene-3,5,7-triol) suppresses blood pressure elevation, regulates blood cholesterol, blood glucose Value adjustment, A flavonoid having various physiological activities such as an antioxidant action and an antibacterial action, and planar catechin obtained by cyclizing catechin is known to have a high radical scavenging activity (Non-patent Document 1).

J. Am. Chem. Soc. 2002, 124, 5952-5953

However, it has not been known that catechins or derivatives thereof are effective for the prevention and / or treatment of specific eye diseases.
An object of the present invention is to provide a pharmaceutical composition comprising catechin or a derivative thereof effective for preventing and / or treating keratoconjunctival disease or presbyopia.

In order to achieve the above object, the present inventors have an unexpected effect that catechin or a catechin derivative is effective in the prevention and / or treatment of keratoconjunctival diseases such as dry eye and presbyopia (presbyopia). As a result, the present invention has been completed.
That is, the present invention is as follows.
[1] A pharmaceutical composition for the prevention and / or treatment of keratoconjunctival disease or presbyopia containing catechin or a compound represented by formula (I), any salt or prodrug thereof as an active ingredient.

(In the formula, m and n are each an integer from 0 to 4, m + n ≧ 1, and R ₁ and R ₂ are the same or different, hydrogen or a hydrocarbon group having 1 to 17 carbon atoms.)
[2] The pharmaceutical composition according to item [1], wherein m and n are each an integer of 1 to 3.
[3] The pharmaceutical composition according to item [1], wherein m and n are each 2.
[4] The pharmaceutical composition according to item [1], wherein the compound represented by formula (I) is a compound represented by formula (III).

(In the formula, R ₁ and R ₂ are the same or different hydrocarbon groups having 1 to 17 carbon atoms.)
[5] The pharmaceutical composition according to any one of items [1] to [4], wherein R ₁ is a methyl group, and R ₂ is a hydrocarbon group having 1 to 17 carbon atoms.
[6] A preventive and / or therapeutic agent for keratoconjunctival disease or presbyopia containing catechin or a compound represented by the formula (I), any salt or prodrug thereof as an active ingredient.

(In the formula, m and n are each an integer from 0 to 4, m + n ≧ 1, and R ₁ and R ₂ are the same or different, hydrogen or a hydrocarbon group having 1 to 17 carbon atoms.)

  According to the present invention, the catechin or catechin derivative of the present invention, any salt thereof, or a prodrug thereof is useful for the prevention and / or treatment of keratoconjunctival disease or presbyopia.

The graph which shows the result of an electron spin resonance (ESR) measurement. (A), (B) Amount of tyrosine radical. Standard in the graph indicates samples that do not contain catechins or catechin derivatives. (A) The graph which shows the fluorescence-staining score at the time of administering various chemical | medical agents. (B) A table showing the number of corneas with scratches in each treatment. The graph which shows the elasticity modulus of the lens at the time of administering various chemical | medical agents.

In the present specification, “treatment” means cure or amelioration of a disease or symptom, or suppression of symptom, and includes “prevention”. “Prevention” means preventing the onset of a disease or symptom.
The compound of the present invention includes catechin or a compound represented by the following formula (I), any salt or prodrug thereof.

In the formula, m and n are each an integer from 0 to 4, m + n ≧ 1, and R ₁ and R ₂ are the same or different and are hydrogen or a hydrocarbon group having 1 to 17 carbon atoms. The “hydrocarbon group” includes straight-chain and branched-chain saturated and unsaturated hydrocarbon groups.

    Each aromatic ring of the compound represented by formula (I) has a lower alkyl group having 1 to 6 carbon atoms (for example, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec-butyl, tert- Butyl, cyclopropyl, cyclobutyl, etc.), C1-C6 lower alkoxy groups (eg methoxy, ethoxy, propoxy, isopropoxy etc.), halogen atoms (eg fluorine, chlorine, bromine etc.) etc. Good.

  Certain compounds of the compounds of formula (I) may exist in stereoisomeric forms, but in this specification R- and S-enantiomers, diastereomers, (D) -isomers All such compounds are contemplated, including the (L) -isomer, racemic mixtures thereof, and other mixtures. In addition, asymmetric carbon atoms may be present in a substituent such as an alkyl group. All such isomers and mixtures thereof are encompassed herein.

  The position of the hydroxyl group on the aromatic ring may be any of the ortho-position, meta-position, and para-position, and the present inventor has an activity related to keratoconjunctival disease or presbyopia regardless of these positions. These studies have revealed this. The greater the number of hydroxyl groups on the aromatic ring, the greater the activity associated with keratoconjunctival disease or presbyopia, but the stability of the compound is impaired.

  In one embodiment, m and n are each an integer from 1 to 3. In another embodiment, m and n are each 2.

In one embodiment, R ₁ and R ₂ are the same or different hydrogen or a hydrocarbon group having 1 to 17 carbon atoms, and R ₁ and R ₂ are not both hydrogen atoms. In one embodiment, R ₁ and R ₂ are the same or different hydrocarbon groups having 1 to 17 carbon atoms. In another embodiment, _one of R ₁ and R ₂ is methyl and the other of R ₁ and R ₂ is a hydrocarbon group having 1 to 17 carbon atoms.

Examples of the hydrocarbon group R ₁ and R ₂ having 1 to 17 carbon atoms include a methyl group, 4-methyl-3-pentenyl group, 4,8-dimethylnona-3,7-dienyl group, 4,8,12, Examples include 16-tetramethylheptadeca-3,7,11,15-tetraenyl group.

In another embodiment, R ₁ and R ₂ are each independently a hydrogen atom or general formula (II) (wherein R 3 and R 4 are each independently a hydrogen atom or an alkyl group having 1 to 5 carbon atoms). Any one of the bonds (a) to (c) represented by a solid line with a wavy line is a double bond and the rest is a single bond, and n is an integer of 1 to 3. And R1 and R2 are not hydrogen atoms at the same time.

  In one embodiment, the specific compound of the compound represented by the formula (I) is a compound represented by the following formula (III).

In the formula, R ₁ and R ₂ are the same or different hydrocarbon groups having 1 to 17 carbon atoms. The compound of formula (III) is a catechin derivative in which a linear or branched saturated or unsaturated hydrocarbon group (usually C1 to C17) is introduced at the 5-position of the benzopyrano ring of catechin, and is also referred to as planar catechin. The For details on planar catechins, see JEOL News Vol. 41, 34-41 (2009).

  In one embodiment, the compound of the invention described above is catechin.

  In one embodiment, the above-mentioned compound of the present invention is a compound represented by the following formula (IV) which is an example of planar catechin.

  In one embodiment, the compound of the present invention is a compound represented by the following formula (V), which is another planar catechin.

  The compound represented by the formula (I) of the present invention may form a salt, such as an acid addition salt such as an inorganic acid salt (for example, hydrochloride, sulfate, hydrobromide, Phosphates, etc.), organic acid salts (eg acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, lactate, oxalate, Methanesulfonate, p-toluenesulfonate, etc.).

  Furthermore, the present invention also includes various hydrates and solvates of the compound represented by the formula (I) or a salt thereof and a polymorphic substance.

  The present invention may be a prodrug of the compound represented by formula (I). The prodrug of the compound represented by formula (I) refers to a compound that is converted into the compound represented by formula (I) by a reaction in vivo.

  Examples of the prodrug of the compound represented by the formula (I) include compounds in which the hydroxyl group of the compound represented by the formula (I) is acetylated, acylated, alkylated, phosphorylated, sulfated, or borated. It is done. These compounds can be produced by a method known per se.

  The prodrug of the compound represented by formula (I) may be itself or a pharmacologically acceptable salt. Examples of such salts include salts with inorganic bases, organic bases, and the like when the prodrug of the compound represented by formula (I) has an acidic group such as a carboxyl group, and is represented by formula (I). When the prodrug of the compound has a basic group such as an amino group, a salt with an inorganic acid or an organic acid can be mentioned. The prodrug of the compound represented by formula (I) may be either a hydrate or a non-hydrate.

  The compound represented by the formula (I) is produced by cyclization of a flavonoid structure by an oxa-Pictet-Spengler reaction. For the oxa-Pictet-Spengler reaction, see Larghi, E. L. et al., Synthesis (2): 187-210.

  The catechin or catechin derivative of the present invention (hereinafter simply referred to as “the compound of the present invention”) is useful as a prophylactic and / or therapeutic agent for keratoconjunctival disease because it is excellent in preventing and / or treating keratoconjunctival disease. Thus, a pharmaceutical composition for preventing and / or treating a keratoconjunctival disease containing the compound of the present invention as an active ingredient is also included in the scope of the present invention. The keratoconjunctive disease includes dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion, corneal ulcer and the like.

  As used herein, “corneal conjunctiva” means the cornea and / or conjunctiva, and “keratoconjunctival disease” is a disease in the cornea and / or conjunctiva. Diseases such as dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion, or corneal ulcer in the present invention are generally diseases included in keratoconjunctival diseases, but are not necessarily caused by keratoconjunctival diseases. It doesn't have to be a thing. Accordingly, the dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion, corneal ulcer and the like in the present invention include those that do not depend on keratoconjunctival disease.

 In addition, since the compound of the present invention is excellent in the prevention and / or treatment effect of presbyopia, it is useful as an agent for the prevention and / or treatment of presbyopia, and presbyopia containing the compound of the present invention as an active ingredient. Pharmaceutical compositions for prevention and / or treatment are also within the scope of the present invention.

 Furthermore, since the compound of the present invention is excellent in antioxidant action, it is also useful as an antioxidant.

  The compound of the present invention can be used for mammals including humans (for example, humans, cows, horses, pigs, monkeys, dogs, cats, mice, rats, rabbits, goats, sheep, etc.), preferably humans Used.

  When the compound of the present invention is contained in a pharmaceutical composition, it can be combined with a pharmaceutically acceptable carrier as necessary, and various administration forms can be adopted depending on the purpose of prevention or treatment, and the form is particularly limited. Examples thereof include eye drops, oral preparations, injections, suppositories, ointments, patches, and the like, and eye drops are preferred. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art. The eye drops may be any of aqueous eye drops, non-aqueous eye drops, suspension eye drops, emulsion eye drops, eye ointments and the like. Such a preparation is prepared as a composition suitable for the dosage form, if necessary, as a pharmaceutically acceptable carrier, for example, an isotonic agent, a chelating agent, a stabilizer, a pH adjusting agent, a preservative, an antioxidant. , A solubilizing agent, a thickening agent, and the like, and can be produced by a method known to those skilled in the art.

  Isotonic agents include glucose, trehalose, lactose, fructose, mannitol, xylitol, sorbitol and other sugars, glycerin, polyethylene glycol, propylene glycol and other polyhydric alcohols, sodium chloride, potassium chloride, calcium chloride and other inorganic salts The blending amount is preferably 0 to 5% by weight with respect to the total amount of the composition.

  Examples of chelating agents include edetates such as disodium edetate, disodium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate Citric acid and the like, and the blending amount is preferably 0 to 0.2% by weight based on the total amount of the composition.

  Examples of the stabilizer include sodium bisulfite and the like, and the blending amount is preferably 0 to 1% by weight with respect to the total amount of the composition.

  Examples of the pH adjuster include acids such as hydrochloric acid, carbonic acid, acetic acid and citric acid, and further alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or hydrogen carbonates such as sodium carbonate, Examples include alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, bases such as trometamol, and the like, and the blending amount is preferably 0 to 20% by weight based on the total amount of the composition.

  As preservatives, sorbic acid, potassium sorbate, methyl paraoxybenzoate, ethyl paraoxybenzoate, paraoxybenzoic acid ester such as propyl paraoxybenzoate, butyl paraoxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, Examples include quaternary ammonium salts such as cetylpyridinium chloride, alkylpolyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, chlorhexidine, and the blending amount is 0 to 0.2% by weight based on the total amount of the composition. Is preferred.

  Examples of the antioxidant include sodium bisulfite, dry sodium sulfite, sodium pyrosulfite, concentrated mixed tocopherol, and the like, and the blending amount is preferably 0 to 0.4% by weight with respect to the total amount of the composition.

  Examples of solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, macrogol, D-mannitol, and the blending amount thereof is based on the total amount of the composition. 0 to 3% by weight is preferred.

  Examples of the thickening agent include polyethylene glycol, methyl cellulose, ethyl cellulose, carmellose sodium, xanthan gum, sodium chondroitin sulfate, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinyl pyrrolidone, polyvinyl alcohol, and the like. 0 to 70% by weight is desirable based on the total amount of the composition.

 When preparing eye drops, for example, the desired components described above are dissolved or suspended in an aqueous solvent such as sterilized purified water or physiological saline, or a non-aqueous solvent such as vegetable oil such as cottonseed oil, soybean oil, sesame oil, or peanut oil. The osmotic pressure can be adjusted to a predetermined osmotic pressure and subjected to sterilization such as filtration sterilization.

  In addition, when preparing an eye ointment, an ointment base can be included in addition to the various components described above. The ointment base is not particularly limited, but is an oily base such as petrolatum, liquid paraffin, or polyethylene; an emulsion base obtained by emulsifying an oil phase and an aqueous phase with a surfactant; hydroxypropyl methylcellulose, carboxymethylcellulose A water-soluble base composed of polyethylene glycol or the like is preferred.

  In one embodiment, the preventive or therapeutic agent or pharmaceutical composition for keratoconjunctival disease and / or presbyopia of the present invention does not contain deep water.

When the preventive or therapeutic agent for keratoconjunctival disease and / or presbyopia of the present invention is administered, the dose varies depending on the patient's weight, age, sex, symptom, dosage form, number of administrations, etc. The compound of the present invention may be administered at a dose of 0.1 to 1000 μg, preferably 1 to 200 μg per day, or divided into several doses. In the case of liquid eye drops, 0.01 to 50 mg. / ML, preferably 0.1 to 10 mg / mL, may be instilled 1 to several drops at a time several times a day.
The disclosures of all patent applications and documents cited herein are hereby incorporated by reference in their entirety.

  Hereinafter, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

Example 1 Production of Compound of the Present Invention Natural catechin was obtained from Sigma-Aldrich. Planar catechin PC1 (compound represented by formula (IV)) is a natural catechin according to Larghi, EL et al., Synthesis (2): 187-210 and J. Am. Chem. Soc. 2002, 124-5952-5932. Was synthesized by adding BF ₃ / Et ₂ O in acetone and stirring. Planar catechin PC2 (compound represented by the formula (V)) was synthesized according to Example 1 of JP2013-043863.

Example 2 Electron Spin Resonance (ESR) Measurement Test The residual amount of tyrosine radicals when catechin, PC1 and PC2 as compounds of the present invention were added to tyrosine radicals as standard substances was examined. Using myoglobin as a tyrosine radical, a standard solution consisting of 50 mM NaPi buffer (pH 7.4), 10 mM DMPO, 1.6 mM myoglobin, and 1 mM H ₂ O ₂ was prepared. 0.02 mass%, 0.002 mass%, 0.0002 mass% C1 and 0.02 mass% PC2 are added to the standard solution, and electron spin resonance (ESR) is performed using ESR measuring device RX-1 (manufactured by JEOL Ltd.). The amount of tyrosine radical was measured against the change in absorption spectrum. The ESR settings were a microwave output of 10 mW, an adjustment frequency of 100 KHz, an adjustment magnetic field of 0.1 G, a receiver gain of 1000, and a time constant of 0.3 s. The results are shown in FIGS.
As a result, it was found that catechin and PC1 suppressed the generation of tyrosine radicals in a concentration-dependent manner, and catechin, PC1 and PC2 all had strong radical generation inhibitory activity.

Example 3 Curing efficacy test using smoking rats
As described in WO2012 / 161112, a model of keratoconjunctival epithelial disorder caused by dry eye was prepared by the following method, and the healing effect of catechin and planar catechin (PC1) on keratoconjunctival epithelial disorder was evaluated.
In this experiment, both eyes of each individual were used, the same drug solution was administered to both eyes, and comparison was made between groups.
(experimental method)
Male SD rats (6 weeks old) were treated with smoking to produce dry eye and presbyopia models.

  That is, mainstream smoke (300 mL) was added 6 times every 30 minutes into the chamber containing the rats, and treatment for 12 days caused keratoconjunctival epithelial disorder. As instillation conditions, 0.1% by mass of catechin or planar catechin (PC1) in PBS, 5 μL each, once before smoking treatment, 3 times after treatment, 4 times a day, 11 days daily did. The animals were 4 (8 eyes) in each group. After smoking treatment after 11 days, body weight, fluorescent staining score and lens hardness were measured.

After the instillation, the damaged part of the corneal epithelium was stained with the fluorescent dye fluorescein. The degree of corneal epithelial damage was determined by dividing the entire cornea into nine parts, upper, middle, lower, and left middle right, and scoring the damage for each part according to the following criteria, and obtaining the total value. Thereafter, the score values were compared between groups. In the statistical analysis, the significant difference of each group with respect to the smoking treatment group was tested using the Dunnett method. In order to make a fair evaluation, from the start of instillation to scoring of corneal epithelial disorder, the contents of the drug solution administered to each group were blinded and collated after scoring.
(Criteria for fluorescein staining score of corneal epithelium)
0: Not stained (no point fluorescence)
1: Slight point-like fluorescence is observed 2: Remarkably many point-like fluorescence is observed 3: Point-like fluorescence is observed densely The lens hardness was measured by combining an electronic balance and a height gauge. Place the lens whose minor axis length has been measured in advance on the electronic balance and adjust the weight to zero. Operate the handle of the height gauge from above the lens so that the tip is in contact with the lens. Further, operate the handle to lower the tip about 5-10% of the short axis length and apply pressure to the lens. The change in weight at this time was measured with an electronic balance, and the weight was divided by the moving distance indicated by the height gauge as the hardness. It shows that it is so hard that a value is large.

Statistical analysis of lens hardness was performed using Dunnett's method to test the significance of each group compared to the smoking treatment group.
(result)
There was no significant difference in body weight between the non-smoking group and the smoking group (data not shown).

  The fluorescence staining score increased in the smoking treatment group (fluorescence score average value: 5.1 ± 1.1) compared to the non-smoking treatment group (fluorescence score average value: 1.1 ± 1.0), but decreased due to drug administration (catechin) Group (fluorescence score average value: 2.0 ± 1.8), p <0.005 for smoking treatment group; PC1 group (fluorescence score average value: 2.3 ± 1.7), p <0.005 for smoking treatment group, ophthalmic solution of the present invention The improvement of the corneal state was recognized by (FIG. 2 (A), (B)).

  As is apparent from the results of the fluorescent staining score, or from the results of the fluorescent staining score, the agent of the present invention prevents corneal and conjunctival diseases such as dry eye, dry keratoconjunctivitis, punctate superficial keratopathy, corneal erosion, or corneal ulcer. And / or useful as a therapeutic agent.

  Lens elasticity is an index of presbyopia because the lens hardens with aging, but increased in the smoking treatment group (elastic modulus: 1.24 ± 0.11) compared to the non-smoking group (elastic modulus: 0.84 ± 0.07). , Significantly decreased due to drug administration (catechin group (elasticity: 1.11 ± 0.10), p <0.05 for smoking treatment group; PC1 group (elasticity: 0.84 ± 0.05), p <0.05 for smoking treatment group) Lens hardening was observed, and the lens hardening could be suppressed by instillation of the drug of the present invention (FIG. 3).

 As is apparent from the lens elasticity test results, the agent of the present invention is also useful as a preventive and / or therapeutic agent for presbyopia.

Claims (6)

A pharmaceutical composition for preventing and / or treating keratoconjunctival disease or presbyopia comprising catechin or a compound represented by formula (I), any salt or prodrug thereof as an active ingredient.
(In the formula, m and n are each an integer from 0 to 4, m + n ≧ 1, and R ₁ and R ₂ are the same or different, hydrogen or a hydrocarbon group having 1 to 17 carbon atoms.)   The pharmaceutical composition according to claim 1, wherein m and n are each an integer of 1 to 3.   The pharmaceutical composition according to claim 1, wherein m and n are each 2. The pharmaceutical composition according to claim 1, wherein the compound represented by the formula (I) is a compound represented by the formula (III).
(In the formula, R ₁ and R ₂ are the same or different hydrocarbon groups having 1 to 17 carbon atoms.) R ₁ is a methyl group, a pharmaceutical composition according to any one of claims 1 to 4 R ₂ is a hydrocarbon group of 1 to 17 carbon atoms. A preventive and / or therapeutic agent for keratoconjunctival disease or presbyopia containing catechin or a compound represented by formula (I), any salt or prodrug thereof as an active ingredient.
(In the formula, m and n are each an integer from 0 to 4, m + n ≧ 1, and R ₁ and R ₂ are the same or different, hydrogen or a hydrocarbon group having 1 to 17 carbon atoms.)