JPH10218766A - Lacrimation-accelerating and keratoconjunctive disorder-treating agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a lacrimation-accelerating and keratoconjunctive disorder- treating agent by allowing the therapeutic agent to contain 1,3-dialkylurea derivative. SOLUTION: This pharmaceutical agent contains, as an active ingredient, a compound of the formula (R<1> is carboxyl or its ester; R<2> is H, lower alkyl, hydroxy; R<3> is a lower alkyl; R<4> is carboxyl or its ester; R<5> is an aromatic group; A is a lower alkylene), typically (2S)-2-[3-(2S)-2-carboxy-2-hydroxyethyl-3- isobutylureide]-3-(2-naphthyl)-propionic acid or a salt thereof. This compound functions as a nerve agent directly acting on lachrymal glands to promote their fluid secretion and is useful for treatment of dry eye, corneal epithelium detachment, corneal ulcer and other corneal disorders. This compound is given as an ophthalmic agent once to several times a day in a concentration of 0.001-3w/v% or, as an oral preparation, in an amount of 1-1,000mg in portions once to several times.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for promoting lacrimal secretion and treating keratoconjunctival disorders, which comprises a 1,3-dialkylurea derivative as an active ingredient.

[0002]

2. Description of the Related Art Tear, which is one of the mechanisms for maintaining the wettability of a living body, covers the cornea and conjunctiva (corneal conjunctiva), keeps the wetness, and prevents drying. In addition, tears serve as a lubricant to protect the corneal conjunctiva from stimuli caused by blinks, and contribute to maintaining the smoothness of the corneal surface. Tear has a bacteriostatic action and protects against infection from bacteria, fungi, viruses, etc., and also supplies oxygen and various nutrients to the cornea and removes carbon dioxide and metabolites. In addition, when the corneal conjunctiva is damaged, the tear fluid plays a role in diluting and removing the impaired stimulus, and also removes humoral components such as epidermal growth factor and fibronectin involved in wound healing. It has an action of transporting to a lesion, and is involved not only in retention of keratoconjunctival epithelial cells but also in regulation of wound healing. It is known that such a small amount of tears regulates the physiological state of the corneal conjunctiva, thereby maintaining the transparency and homeostasis of the cornea (New Ophthalmology, 11 , 1179-1185 ( 199
Four)).

[0003] As a method of treating keratoconjunctival disorders such as dry eye (dry keratoconjunctivitis, etc.), a method of externally supplying a tear component with artificial tears, or a method of viscoelastically removing tears remaining on the surface of the keratoconjunctiva. There is known a method of holding by a substance and leading to treatment of the keratoconjunctiva. Since tears have the effect of healing keratoconjunctival disorders as described above, finding a compound that works directly on lacrimal gland function and promotes lacrimal secretion can be useful for finding dry eye and other keratoconjunctival epithelial disorders. It is expected to be useful for recognized corneal epithelial detachment and corneal ulcer.

On the other hand, JP-A-8-208589 and JP-A-8-231492 report 1,3-dialkylurea derivatives. The structural characteristics of these compounds are that the compounds have a carboxylic acid at both ends of the alkylene chain of 1,3-dialkylurea, and further have an aromatic group such as a naphthyl group or a biphenylyl group in the alkylene chain. In particular, these compounds have been shown to be useful as therapeutic agents for cardiovascular diseases. However, no report has been made on the effects of these compounds on keratoconjunctival disorders.

[0005]

There has been little research on the application of 1,3-dialkylurea derivatives to ocular diseases, and research on the effects of this compound on ophthalmology, particularly on the keratoconjunctiva, is of great interest. There is an issue.

[0006]

Means for Solving the Problems The present inventors have developed a 1,3-
As a result of diligent research to find new effects of dialkyl urea derivatives in the field of ophthalmology, 1,3-dialkyl urea derivatives function as neuroactive agents that directly act on lacrimal gland function and have lacrimal secretion promoting action I found something.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention relates to a lacrimal secretion promoting agent and a therapeutic agent for keratoconjunctival disorders, comprising a compound represented by the following general formula [I] or a salt thereof (hereinafter, referred to as the present compound) as an active ingredient.

[0008]

Embedded image

Wherein R ¹ represents a carboxy group or an ester thereof.

R ² represents a hydrogen atom, a lower alkyl group or a hydroxy group.

R ³ represents a lower alkyl group.

R ⁴ represents a carboxy group or an ester thereof.

R ⁵ represents an aromatic group.

A represents a lower alkylene group. The groups defined above will be described in more detail. Lower alkyl is methyl, ethyl, propyl, butyl, hexyl,
A carbon atom such as isobutyl represents a linear or branched lower alkyl having 1 to 6 carbon atoms, and the lower alkylene is methylene,
It represents a linear or branched lower alkylene having 1 to 6 carbon atoms such as ethylene, propylene, butylene and hexamethylene. Ester refers to a group commonly used as esters of carboxylic acids such as lower alkyl esters and phenyl lower alkyl esters, which are easily hydrolyzed to carboxylic acids. The aromatic group indicates a hydrocarbon aromatic such as phenyl, naphthyl, biphenylyl, etc., which may be substituted with a lower alkyl group, a lower alkoxy group, a hydroxy group or a halogen atom. Also, lower alkoxy is
Methoxy, ethoxy, propoxy, butoxy, hexyloxy and the like represent a straight-chain or branched lower alkoxy having 1 to 6 carbon atoms, and a halogen atom means fluorine, chlorine,
Indicates bromine or iodine.

Preferred examples of the compound include the following.

Compounds of the formula [I] wherein R ¹ represents a carboxy group and salts thereof.

Compounds and salts thereof in which R ² represents a lower alkyl group or a hydroxy group, more preferably a hydroxy group, in the above formula [I].

Compounds and salts thereof in which R ³ represents a lower alkyl group, more preferably an isobutyl group in the general formula [I].

Compounds of the formula [I] wherein R ⁴ represents a carboxy group and salts thereof.

A compound and a salt thereof, in which R ⁵ in the general formula [I] represents a phenyl group, a naphthyl group or a biphenylyl group, more preferably a naphthyl group or a biphenylyl group.

Compounds and salts thereof in the above formula [I] wherein A represents a lower alkylene group, more preferably a methylene group.

Examples of the compound having a preferable combination of substituents in the above general formula [I] include the following.

In the above general formula [I], R ¹ and R ⁴ represent a carboxy group or an ester thereof, R ² represents a hydroxy group, R ³ represents a lower alkyl group, R ⁵ represents a naphthyl group or biphenylyl group, and A Is a lower alkylene group and salts thereof.

The compounds having a particularly preferred combination of substituents in the above general formula [I] include the following.

A compound in which R ¹ and R ⁴ in the above general formula [I] each represent a carboxy group, R ² represents a hydroxy group, R ³ represents an isobutyl group, R ⁵ represents a naphthyl group, and A represents a methylene group; Its salts.

Specific examples of particularly preferred compounds are represented by the following formula:
(II) -2- (3- (2S) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (hereinafter, referred to as [II])
Compound A) or a salt thereof.

[0027]

Embedded image

The above salts may be pharmaceutically acceptable salts, for example, hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate. , Paratoluenesulfonate and the like. The above compounds include diastereoisomers and optical isomers, all of which are included in the present invention. Further, the above compounds may be in the form of a hydrate.

This compound is a drug useful as a therapeutic agent for cardiovascular diseases, but its pharmacological action on keratoconjunctiva was not known. Therefore, the present inventors have studied the application of the present compound to the field of ophthalmology, and as described in detail in the section of pharmacological test, when the present compound was reacted with the isolated rabbit lacrimal gland, excellent tear fluid was obtained. They have found that they have a secretion promoting action. As described in detail in the section of the prior art, tears have an effect of curing disorders of the keratoconjunctiva, and it is expected that the present compound is useful as a therapeutic agent for keratoconjunctival disorders. Representative examples of keratoconjunctival disorders include dry eye, corneal epithelial detachment and corneal ulcer.

The present compound can be administered orally or parenterally. Examples of the dosage form include eye drops, injections, tablets, capsules, granules, and the like, and these preparations can be prepared using widely used techniques. For example, in the case of eye drops, isotonic agents such as sodium chloride and concentrated glycerin, buffering agents such as sodium phosphate and sodium acetate, polyoxyethylene sorbitan monooleate, polyoxystearate 40, polyoxyethylene hydrogenated castor oil Surfactants such as sodium citrate,
Stabilizers such as sodium edetate, benzalkonium chloride, parabens and the like can be formulated as necessary using preservatives and the like, and the pH may be within the range acceptable for ophthalmic preparations. A range of 8 is preferred. In addition, tablets, capsules, oral preparations such as granules, if necessary,
Bulking agents such as lactose, starch, crystalline cellulose, vegetable oils,
Using lubricants such as magnesium stearate and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as calcium carboxymethylcellulose, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and gelatin coating agents It can be formulated.

The dose is appropriately selected depending on the symptoms, age, dosage form, etc., but in the case of eye drops, 0.001 to 3% (w /
v) may be instilled once to several times a day. In the case of an oral preparation, 1 mg to 1000 mg per day may be usually administered once or several times.

Hereinafter, a pharmacological test will be described as an example.

[0033]

【Example】

(Pharmacological test) Since it is difficult to directly determine the increase in the amount of tear secretion, there is known a method of measuring the total amount of protein contained in tear to convert it into the amount of tear secretion. (Adv. Exp. Med. Biol., 350 , 141-146 (1994)).
Thus, in the present invention, rabbit isolated lacrimal glands were used, and when a 1,3-dialkylurea derivative was added thereto, the increase in protein was measured, and the pharmacological effect of the compound on the increase in tear secretion was examined. .

1. Preparation of test compound solution a) Sodium chloride (83.00 g), potassium chloride (3.38 g), calcium chloride dihydrate (3.70 g)
g), magnesium chloride hexahydrate (2.435 g) and HEPES (47.60 g), and sterilized purified water were added thereto.
The total volume was 500 ml. After diluting the solution (50 ml) 20 times with sterile purified water, 2.0 g of glucose was dissolved in the diluted solution, and the solution was adjusted to pH = 7.4 with a 1N sodium hydroxide solution. This is used as a culture solution.

B) A culture solution was added to and dissolved in the test compound to make the total volume 1000 ml. This is used as a test compound solution.

2. Preparation of section preparation A male Japanese white rabbit was exsanguinated and killed under anesthesia, and the lacrimal gland tissue was excised and cut into approximately 50 mg. 0.5 ml of the culture solution was added to the lacrimal gland tissue section, and incubated at 37 ° C. for 60 minutes to obtain a steady state section specimen.

3. Experimental method a) 0.5 ml of the culture solution was added to the section preparation, and the mixture was added at 37 ° C. for 2 hours.
Incubated for 0 minutes. After removing the section preparation from the solution, a bio-Rad protein test staining reagent was added to the culture solution, and the amount of protein was measured. In addition, the protein secretion rate at this time was set to 100%, and the secretion rate before the test compound treatment was set.

B) 0.5 ml of the test compound solution was added to the section preparation after the incubation in a),
For 20 minutes. After removing the section preparation from the solution, a bio-Rad protein test staining reagent was added to the test compound solution, and the amount of protein was measured. The protein secretion rate at this time was defined as the secretion rate after treatment with the test compound.

3. Results As an example of the experimental results, (2S) -2 was used as the test compound.
Protein secretion in isolated rabbit lacrimal gland when using [-(3- (2S) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (10 ^-4 mol) The rates are shown in Table 1.

[0040]

[Table 1]

As can be seen from Table 1, the protein secretion rate after the test compound treatment was 14% as compared to that before the test compound treatment.
Improved. That is, it was clarified that the test compound had an excellent protein secretion promoting action and promoted tear secretion.

[0042]

As described above, the 1,3-dialkylurea derivative has a lacrimal secretion promoting action in the lacrimal gland,
It was found to be useful as an agent for promoting lacrimal secretion and treating keratoconjunctival disorders.

Claims (5)

[Claims] 1. A lacrimation promoter composition comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein, R ¹ represents a carboxy group or an ester thereof. R ² represents a hydrogen atom, a lower alkyl group or a hydroxy group. R ³ represents a lower alkyl group. R ⁴ represents a carboxy group or an ester thereof. R ⁵ represents an aromatic group. A represents a lower alkylene group. ] 2. A therapeutic agent for a keratoconjunctival disorder, comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. Embedded image [Wherein, R ¹ represents a carboxy group or an ester thereof. R ² represents a hydrogen atom, a lower alkyl group or a hydroxy group. R ³ represents a lower alkyl group. R ⁴ represents a carboxy group or an ester thereof. R ⁵ represents an aromatic group. A represents a lower alkylene group. ] 3. An active ingredient comprising (2S) -2- [3- (2S) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof. Lacrimation promoter. 4. An active ingredient comprising (2S) -2- [3- (2S) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof. A therapeutic agent for keratoconjunctival disorders. 5. The therapeutic agent for corneal conjunctival disorder according to claim 2, wherein the corneal conjunctival disorder is dry eye, corneal epithelial detachment and / or corneal ulcer.