JP2005162735A - Remedy for keratoconjunctive disorder - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound capable of developing an excellent improving effect on a model of keratic disorder and useful as a remedy for keratoconjunctive disorder, such as dry eye, keratohelcosis, keratitis, conjunctivitis, superficial punctate keratitis, keratic epithelial defect, conjunctive epithelial defect, dry keratoconjunctivitis, superior limbic keratoconjunctivitis, and filamentous keratitis. <P>SOLUTION: This remedy for the keratoconjunctive disorder contains 5-[4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl]methoxy]phenylmethyl]thiazolidine-2,4-dione and N-[(4-methoxyphenoxy)carbonyl]-N-[[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]methyl]glycine or their salt as active ingredients. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to 5- [4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, N-[(4-methoxyphenoxy ) Carbonyl] -N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine or a salt thereof as an active ingredient, dry eye, corneal ulcer, keratitis The present invention relates to a therapeutic agent for keratoconjunctive disorders such as conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, and filiform keratitis.

  The cornea is a transparent avascular tissue with a diameter of about 1 cm and a thickness of about 1 mm. The conjunctiva is a mucous membrane covering the surface of the eyeball behind the corneal margin and the back of the eyelid. It is known to have a significant effect on visual function. Keratoconjunctival disorders caused by various diseases such as corneal ulcer, keratitis, conjunctivitis, dry eye, etc., if repair is delayed for some reason or prolonged without repair, the tissue where the cornea and conjunctiva are connected Therefore, the normal construction of the epithelium is adversely affected, and even the structure and function of the corneal stroma and the endothelium may be impaired. In recent years, with the development of cell biology, factors involved in cell division, migration, adhesion, extension, differentiation, etc. have been elucidated, and these factors play an important role in the repair of corneal disorders. (Non-Patent Document 1, Non-Patent Document 2).

  By the way, Patent Document 1 describes an invention relating to a heterocyclic compound, and includes 5- [4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2, Azolidinedione derivatives such as 4-dione and its sodium salt are effective as therapeutic agents for diseases caused by insulin resistance such as type II diabetes and dyslipidemia, cardiovascular disorders such as hypertension and coronary heart disease. It is disclosed that there is. Patent Document 2 describes an invention relating to a substituted acid derivative useful as an antidiabetic agent and an antiobesity agent. N-[(4-methoxyphenoxy) carbonyl] -N-[[4- [2- (5-methyl- Compounds such as 2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine are effective as therapeutic agents for diabetes (particularly type II diabetes), hyperglycemia, hyperinsulinemia, hyperlipidemia, obesity, etc. It is disclosed that. Patent Document 3 discloses an invention relating to a pharmaceutical composition in which a diuretic and an insulin resistance improver are combined, and the heart weight generally known as a side effect of the insulin resistance improver by using the diuretic in combination. The invention is characterized in that it suppresses the expression of cardiac hypertrophy, cardiac hypertrophy, edema, fluid retention, etc., and N-[(4-methoxyphenoxy) carbonyl] -N- [ [4- [2- (5-Methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine is disclosed.

However, there are no reports on the pharmacological effects of these compounds on eye diseases such as keratoconjunctival disorders.
JP-T-2002-515874 Special table 2003-509503 gazette JP 2000-255854 A Eyesight, 46, 738-743 (1992) Ophthalmic Surgery, 5, 719-727 (1992)

  5- [4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione and N-[(4-methoxyphenoxy) carbonyl]- Searching for new pharmaceutical uses for N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine is an interesting challenge.

  The inventors of the present invention conducted intensive studies to search for new pharmaceutical uses of the above compounds, and in a corneal disorder healing efficacy test using a corneal disorder model, these compounds were all excellent against corneal disorders. The inventors have found that the improvement effect is exhibited, and have reached the present invention.

  That is, the present invention relates to 5- [4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, N-[(4- Methoxyphenoxy) carbonyl] -N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine or a salt thereof (hereinafter referred to as “the present compound”) ) As an active ingredient, keratoconjunctive disorders such as dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, filiform keratitis It is a therapeutic agent.

  5- [4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione and N-[(4-methoxyphenoxy) carbonyl]- The salt of N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl] ethoxy] phenyl] methyl] glycine is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a sodium salt. , Potassium salt, lithium salt, calcium salt, magnesium salt, salt with inorganic acid such as hydrochloric acid, nitric acid, sulfuric acid, salt with organic acid such as acetic acid, fumaric acid, maleic acid, succinic acid, tartaric acid, etc. In addition, quaternary ammonium salts are also included in the salts in the present invention. Preferred salts are sodium and potassium salts. In addition, this compound may take the form of the hydrate and the solvate. Geometric isomers, optical isomers, tautomers, polymorphs and the like of the present compound are also included in the scope of the present invention.

  In the present invention, corneal and conjunctival disorders refer to those in which the cornea or conjunctiva is damaged due to various factors, such as dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect , Conjunctival epithelial defect, dry keratoconjunctivitis, upper ring keratoconjunctivitis, filiform keratitis, and the like.

  The therapeutic agent for keratoconjunctival disorder of the present invention can be administered orally or parenterally.

  Examples of the dosage form include eye drops, eye ointments, injections, tablets, capsules, granules, powders and the like, and eye drops are particularly preferable. These can be formulated using widely used techniques. For example, the eye drops are isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil A surfactant such as sodium citrate and sodium edetate, and a preservative such as benzalkonium chloride and paraben can be used as necessary. The pH may be in the range acceptable for ophthalmic preparations, but is preferably in the range of 4-8.

  The eye ointment can be prepared using a widely used base such as white petrolatum or liquid paraffin. Oral preparations such as tablets, capsules, granules, powders, etc., bulking agents such as lactose, crystalline cellulose, starch, vegetable oil, lubricants such as magnesium stearate, talc, hydroxypropyl cellulose, polyvinylpyrrolidone, etc. Binders, carboxymethyl cellulose, disintegrating agents such as low-substituted hydroxypropyl methylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol, silicone resin, and coating agents such as gelatin film Etc. can be added as needed.

  The dose can be appropriately selected depending on the symptoms, age, dosage form, etc. The eye drop is 0.0001 to 5% (w / v), preferably 0.001 to 3% (w / v). It may be instilled once to several times a day. Oral preparations may be administered usually in an amount of 0.1 to 5000 mg, preferably 1-1000 mg per day, in one or several divided doses.

  As will be described later, when a corneal disorder healing efficacy test was conducted, all of these compounds exhibited an excellent improvement effect in a corneal disorder model, so dry eye, corneal ulcer, keratitis, conjunctivitis, punctate surface cornea It is useful as a therapeutic agent for keratoconjunctive disorders such as keratosis, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper ring keratoconjunctivitis, and filiform keratitis.

  The results of pharmacological tests and formulation examples using the present compound are shown below, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.

[Pharmacological test]
Test for Curing Efficacy of Corneal Disorder A model of corneal injury was prepared using male SD rats according to the method of Fujihara et al. (Invest. Ophthalmol. Vis. Sci 42 (1): 96-100 (2001)). After the corneal injury model was created, the improvement rate of corneal injury was determined by the method of Murakami et al. (New Ophthalmology 21 (1): 87-90 (2004)).

(experimental method)
Male SD rats were used to administer Nembutal and general anesthesia, and then the extraorbital lacrimal gland was removed to induce corneal injury over 2 months.

  Next, 5- [4-[[3-methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione (Compound A) and N-[(4 -Methoxyphenoxy) carbonyl] -N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine (Compound B) was administered as follows.

Compound A ophthalmic group:
A physiological saline solution of Compound A (0.02%) was instilled into both eyes 6 times a day for 7 days (4 eyes per group, 8 eyes).

Compound B ophthalmic group:
A physiological saline solution of Compound B (0.02%) was applied to both eyes 6 times a day for 7 days (4 eyes per group, 8 eyes).

  In the control group, physiological saline was instilled into both eyes 6 times a day for 7 days (4 eyes per group, 8 eyes).

  Seven days after the start of instillation, the damaged part of the cornea was stained with fluorescein. The degree of staining with fluorescein for each of the upper part, middle part and lower part of the cornea was scored according to the following criteria, and the average value of the total score of each part was calculated.

  Furthermore, the average value of the total score was also obtained for normal eyes.

(Criteria)
0: Not dyed 1: Stain is sparse and each dot-like dyed part is separated 2: Dyeing is moderate, and part of the dot-like dyed part is adjacent 3: Dyeing Dense and each dot-like stained part is adjacent

(result)
Table 1 shows the respective improvement rates of the Compound A eyedrop group and the Compound B eyedrop group, which were calculated by the following formula using the average value of the total score of the control group (saline) as a standard (improvement rate: 0%). And in Table 2. In addition, the average value of a score is an average of 8 cases each.

Improvement rate (%) = {(control)-(present compound)} / degree of failure × 100
Disability level = {(control) − (normal eye)}

(Discussion)
As is clear from the results of the above pharmacological tests using rats (Tables 1 and 2), both Compound A and Compound B significantly improve corneal damage.

[Formulation example]
The typical formulation example using the compound A and the compound B is shown below.

Formulation Example 1
Compound A 10mg in 100ml
Sodium chloride 900mg
Sterilized purified water

  By changing the amount of compound A added, the concentration was 0.001% (w / v), 0.03% (w / v), 0.1% (w / v), 0.3% (w / v) 1.0% (w / v), 3.0% (w / v) eye drops can be prepared.

Formulation Example 2
Compound B 100mg in 100ml
Sodium chloride 800mg
Disodium hydrogen phosphate 100mg
Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount

  By changing the amount of compound B added, concentrations of 0.01% (w / v), 0.3% (w / v), 0.5% (w / v), 1.5% (w / v) 3% (w / v) eye drops can be prepared.

Formulation Example 3
Compound A 0.3g in 100g
Liquid paraffin 10.0g
White petrolatum

  By changing the amount of Compound A added, eye ointments having a concentration of 1% (w / w) and 3% (w / w) can be prepared.

Formulation Example 4
Compound 100g in 100g
Liquid paraffin 10.0g
White petrolatum

By changing the amount of Compound B added, eye ointments having a concentration of 1% (w / w) and 3% (w / w) can be prepared.

Claims (3)

5- [4-[[3-Methyl-4-oxo-3,4-dihydro-2-quinazolinyl] methoxy] phenylmethyl] thiazolidine-2,4-dione, N-[(4-methoxyphenoxy) carbonyl]- A therapeutic agent for keratoconjunctival disorder comprising N-[[4- [2- (5-methyl-2-phenyl-4-oxazolyl) ethoxy] phenyl] methyl] glycine or a salt thereof as an active ingredient. 2. The keratoconjunctive disorder is dry eye, corneal ulcer, keratitis, conjunctivitis, punctate superficial keratopathy, corneal epithelial defect, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis or filiform keratitis Therapeutic agent. The therapeutic agent according to claim 1, wherein the dosage form is an eye drop or an eye ointment.