JP3496111B2 - Promotes tear secretion and treats keratoconjunctival disorders - Google Patents

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Lacrimal fluid, which is one of the mechanisms for maintaining the wettability of a living body, covers the cornea and the conjunctiva (corneal conjunctiva) to maintain its wettability and prevent it from drying. In addition, tear fluid serves as a lubricant that protects the corneal conjunctiva from stimuli caused by blinking, and contributes to maintaining the smoothness of the corneal surface. Tear fluid has a bacteriostatic action and protects against infection from bacteria, fungi, viruses, etc., and also supplies oxygen and various nutrients to the cornea and also removes carbon dioxide and metabolites. In addition, when the keratoconjunctiva is damaged, the tear fluid plays a role of diluting and removing the impaired stimulus, and at the same time, humoral components such as epidermal growth factor involved in wound healing and blood cell components such as fibronectin are involved. It has a function of transporting to damaged areas and is involved not only in the maintenance of keratoconjunctival epithelial cells but also in the regulation of wound healing. Thus, it is known that the scarcity of tears maintains the corneal transparency and homeostasis by adjusting the physiological state of the corneal conjunctiva (New Ophthalmology, 11 , 1179-1185 ( 199
Four)).

As a method for treating keratoconjunctival disorders such as dry eye (keratoconjunctivitis sicca), artificial tears are used to replenish tear components from the outside, and tears remaining on the surface of the keratoconjunctiva are viscoelastic. A method is known in which the substance is held by a substance, which leads to treatment of the keratoconjunctiva. Since tears have the effect of healing the above-mentioned keratoconjunctival disorders, finding compounds that directly act on the lacrimal gland function and promote tear secretion suggests that dry eye and other keratoconjunctival epithelial disorders may occur. It is expected to be useful for the observed corneal epithelial detachment and corneal ulcer.

On the other hand, 1,3-dialkylurea derivatives are reported in JP-A-8-208589 and JP-A-8-231492. The structural characteristics of these compounds are that the compounds have carboxylic acids at both ends of the alkylene chain of 1,3-dialkylurea and further have aromatic groups such as naphthyl group and biphenylyl group in the alkylene chain. In particular, these compounds have been shown to be useful as therapeutic agents for cardiovascular diseases. However, the effects of these compounds on keratoconjunctival disorders have not been reported.

[0005]

There has been little research on the application of 1,3-dialkylurea derivatives to eye diseases, and research on the action of this compound on the ophthalmic field, particularly on the keratoconjunctiva is of great interest. It is an issue.

[0006]

The present inventors have found that 1,3-
As a result of intensive research to find out a new action of the dialkylurea derivative in the field of ophthalmology, the 1,3-dialkylurea derivative functions as a nerve agonist directly acting on the lacrimal gland function and has a lacrimal secretion promoting action. I found a thing.

[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, which comprises 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]

[Chemical 3]

[In the formula, 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 group defined above will be described in more detail. Lower alkyl is methyl, ethyl, propyl, butyl, hexyl,
A straight-chain or branched lower alkyl having 1 to 6 carbon atoms such as isobutyl is shown, and lower alkylene means methylene,
It represents a straight chain or branched lower alkylene having 1 to 6 carbon atoms such as ethylene, propylene, butylene and hexamethylene. The ester refers to a group which is widely used as an ester of a carboxylic acid such as a lower alkyl ester and a phenyl lower alkyl ester and is easily hydrolyzed to a carboxylic acid. The aromatic group represents 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. Further, lower alkoxy means
Methoxy, ethoxy, propoxy, butoxy, hexyloxy and the like represent a straight or branched lower alkoxy having 1 to 6 carbon atoms, and the halogen atom is fluorine, chlorine,
Indicates bromine or iodine.

Examples of preferable compounds of the present compound include the following.

Compounds of the above general formula [I] in which R ¹ represents a carboxy group and salts thereof.

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

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

Compounds of the above general formula [I] in which R ⁴ represents a carboxy group and salts thereof.

Compounds of the above general formula [I] in which R ⁵ represents a phenyl group, a naphthyl group or a biphenylyl group, more preferably a naphthyl group or a biphenylyl group, and salts thereof.

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

Examples of the compound having a preferable combination of substituents in the above general formula [I] are as follows.

In the above general formula [I], R ¹ and R ⁴ are a carboxy group or its ester, R ² is a hydroxy group, R ³ is a lower alkyl group, R ⁵ is a naphthyl group or a biphenylyl group, A And a salt thereof, wherein is a lower alkylene group.

Examples of the compound 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 are carboxy groups, R ² is a hydroxy group, R ³ is an isobutyl group, R ⁵ is a naphthyl group, and A is a methylene group in the above general formula [I]; Its salt.

The following formulas are shown as specific examples of particularly preferable compounds.
(2S) -2- [3- (2S) -2-carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid represented by [II] (hereinafter,
Compound A) or salts thereof may be mentioned.

[0027]

[Chemical 4]

The above-mentioned salts may be any pharmaceutically acceptable salts, for example, hydrochloride, sulfate, phosphate, lactate, maleate, fumarate, oxalate, methanesulfonate. , Paratoluene sulfonate, and the like. Further, the above compound has diastereoisomers and optical isomers, all of which are included in the present invention. Further, the above compound 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 the keratoconjunctiva has not been known. Therefore, the present inventors, as a result of examining the application of the present compound in the field of ophthalmology, the details will be explained in the section of the pharmacological test, but when the present compound was reacted with the rabbit lacrimal gland, excellent tear fluid was obtained. They have found that they have a secretagogue action. As described in detail in the section of the prior art, lacrimal fluid has an effect of healing a disorder of the keratoconjunctiva, and it is expected that the present compound is useful as a therapeutic agent for a keratoconjunctival disorder. Representative examples of keratoconjunctival disorders include dry eye, corneal epithelial detachment and corneal ulcer.

The compound can be administered orally or parenterally. Dosage forms include eye drops, injections, tablets, capsules, granules, and the like, and their formulations can be prepared using commonly 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, polyoxy 40 stearate, 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 such as preservatives, and the pH may be in the range acceptable for ophthalmic preparations, but 4 to A range of 8 is preferred. In addition, oral preparations such as tablets, capsules and granules may be taken as needed.
Extenders such as lactose, starch, crystalline cellulose, vegetable oil,
Using lubricants such as magnesium stearate and talc, binders such as hydroxypropylcellulose and polyvinylpyrrolidone, disintegrants such as carboxymethylcellulose calcium, coating agents such as hydroxypropylmethylcellulose, macrogol and silicone resin, and gelatin film agents. It can be formulated.

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

A pharmacological test will be shown below as an example.

[0033]

【Example】

(Pharmacological test) Since it is difficult to directly quantify the increase in tear production, it is known to measure the total amount of proteins contained in tear to convert it into tear production. (Adv.Exp.Med.Biol., 350 , 141-146 (1994)).
Therefore, in the present invention, an isolated rabbit lacrimal gland was used, and an increase in protein when the 1,3-dialkylurea derivative was added thereto was measured, and the pharmacological effect of the same compound on the increase in lacrimal 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), magnesium chloride hexahydrate (2.435 g) and HEPES (47.60 g) with sterile purified water,
The total volume was 500 ml. This solution (50 ml) was diluted 20 times with sterile purified water, 2.0 g of glucose was dissolved in this diluted solution, and this solution was adjusted to pH = 7.4 with 1N-sodium hydroxide solution. This is a culture solution.

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

2. Preparation of Section Specimen A male Japanese white rabbit was exsanguinated to death under anesthesia, and lacrimal gland tissue was excised and cut into about 50 mg pieces. 0.5 ml of a culture solution was added to the lacrimal tissue section and incubated at 37 ° C. for 60 minutes to prepare a steady-state section preparation.

3. Experimental method a) Add 0.5 ml of culture solution to the section preparation, and
Incubated for 0 minutes. After removing the section preparation from the solution, the bio-Rad protein test staining reagent was added to the culture solution to measure the amount of protein. The protein secretion rate at this time was defined as 100%, and the secretion rate before treatment with the test compound was used.

B) 0.5 ml of the test compound solution was added to the section preparation after the incubation in a), and the mixture was incubated at 37 ° C.
And incubated for 20 minutes. After taking out the section preparation from the solution, a bio-Rad protein test staining reagent was added to the test compound solution to measure the amount of protein. 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, the test compound was (2S) -2.
-[3- (2S) -2-Carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid (10 ^-4 mol) protein secretion in the isolated lacrimal gland of rabbits when used 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% compared to before the test compound treatment.
Improved. That is, it was revealed that the test compound has an excellent protein secretion promoting action and promotes tear secretion.

[0042]

From the 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 tear secretion and treating keratoconjunctival disorders.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-8-231492 (JP, A) JP-A-8-208589 (JP, A) JP-A-58-55451 (JP, A) (58) Field (Int.Cl. ⁷ , DB name) A61K 31/00-31/80 A61P 27/00-27/16 CAPLUS (STN) MEDLINE (STN) BIOSIS / MEDLINE / WPID S (STN) REGISTRY (STN) JISST file (JOIS)

Claims (5)

(57) [Claims] 1. A tear stimulating agent comprising a compound represented by the following general formula [I] or a salt thereof as an active ingredient. [Chemical 1] [In the formula, 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 keratoconjunctival disorders, which comprises a compound represented by the following general formula [I] or a salt thereof as an active ingredient. [Chemical 2] [In the formula, 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. (2S) -2- [3- (2S) -2-Carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof as an active ingredient. Tear secretagogue. 4. (2S) -2- [3- (2S) -2-Carboxy-2-hydroxyethyl) -3-isobutylureido] -3- (2-naphthyl) propionic acid or a salt thereof as an active ingredient. A therapeutic agent for keratoconjunctival disorders. 5. The therapeutic agent for keratoconjunctival disorders according to claim 2, wherein the keratoconjunctival disorders are dry eye, corneal epithelial detachment and / or corneal ulcer.