JPH06256209A - Preventive and therapeutic agent against ulcer of eye ball and its peripheral tissue - Google Patents

Abstract

PURPOSE:To obtain a medicine excellently preventing and treating ulcers of eyeball and its peripheral tissue, especially various corneal damages regarded as an intractable diseases followed by accentuation of MMPs. CONSTITUTION:A preventive and a therapeutic agent comprises a peptidylhydroxamic acid of the formula [X<1> to X<4> are alpha-amino acid residue; X<1> is glycine or sarcosine (H in its amino group may be replaced with acetyl, benzoyl, benzyloxy, t-butoxycarbonyl, benzyloxycarbonyl, p-aminobenzoyl, p- aminobenzyl or p-hydroxybenzoyl); X<2> is D- or L-proline, hydroxyproline, thioproline or alanine; X<3> is glutamine, glutamic acid, D- or L-leucine, isoleucine or phenylalanine; X<4> is glycine, D- or L-alanine, valine, D- or L-leucine or sarcosine] such as benzoylglycyl-prolyl-D-leucylalanylhydroxamic acid.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive and / or therapeutic agent for ulcers of the eyeball and peripheral tissues containing a peptidylhydroxamic acid derivative as an active ingredient.

[0002]

BACKGROUND ART Ulcers of the eyeball and its peripheral tissues, particularly various corneal ulcers, are induced by, for example, infection with bacteria, fungi or viruses, or some external stimulus, and the degradation of collagen and mucopolysaccharide in the corneal stroma is caused. Is caused, and as a result, the cornea is irreversibly decomposed and melted. These diseases are collagenase,
Matrix metalloproteinases containing gelatinase and stromelysin (Matrix Metallop
Rotases, (hereinafter referred to as MMPs) FAS
EBJ. 5 : p2145 (1991)], which is a refractory disease caused by the enhancement of the activity of a series of tissue-disrupting enzymes. Bacteria at the time of slight detachment of the cornea during detachment and attachment of contact lenses, which have been widely used recently, or detachment,
Infection due to fungi, viruses, etc., or dry eye caused by an abnormal amount of lacrimal gland that does not produce an appropriate amount of tear fluid also causes corneal ulcers. Corneal ulcers are roughly classified into infectious corneal ulcers and non-infectious corneal ulcers.Infectious corneal ulcers include bacterial corneal ulcers, fungal corneal ulcers, viral corneal ulcers, and other non-infectious corneal ulcers. There are edematous corneal ulcer, limbal corneal ulcer, catarrhal corneal ulcer, vitamin deficient corneal ulcer, corneal ulcer after chemical corrosion, burn corneal ulcer, radiation corneal ulcer, neuroplegic corneal ulcer and the like. As a substance for treating corneal ulcer,
Conventionally, steroids, antibiotics, and vitamins have been known [Invest. Ophthalmo
l. , 16 : p21 (1977). Invest. Op
hthalmol. , 33 (12): p3325 (19
92). Invest. Ophthalmol. , 2
9 : p1110 (1988)], the effect of improving the medical condition by using them is extremely low. In addition, a compound having a functional group in the molecule, which has a function of capturing zinc, which is an activator of collagenase, which is a type of MMPs, such as EDT
A-2Na, L-cysteine (L-cystein)
e), N-acetyl cysteine (N-acetylcy)
Stein), glutathione
e), D-penicillamine (D-penicillami)
ne) and the like have been proposed, but [Invest. O
phthalmol. , 33 (12): p3325 (1
992). Invest. Ophthalmol. , 3
1 (1): p107 (1990)], EDTA-2Na
In the case of using, the compound having cytotoxicity is effective, and with respect to the compound having an SH group, since it is chemically unstable and has low water solubility, etc. Since the amount cannot be kept in the affected area, frequent administration is required, and care for that is complicated, which is also very inconvenient for the patient.
Thus, until now, no satisfactory preventive / therapeutic agent effective for corneal ulcer has been provided.

The present invention has been made in view of the above situation, and is an ulcer of the eyeball and its peripheral tissues, particularly MMP.
It is an object of the present invention to provide an excellent drug for the prevention and treatment of various corneal ulcers, which are associated with intractable diseases and are associated with increased s.

The present inventors have previously provided a peptidylhydroxamic acid derivative which inhibits collagenase activity (Japanese Patent Laid-Open No. 160997/1989). As a result of further research,
It was found that these peptidyl hydroxamic acid derivatives also have enzyme inhibitory activity against stromelysin, which decomposes gelatinase and mucopolysaccharide which is one of the components of the cornea belonging to MMPs, and further, these peptidyl hydroxamic acid derivatives, We have found the fact that it is chemically stable and useful for alkali-induced corneal ulcer, which is a corneal ulcer model. The present invention has been made based on such findings.

[0005]

DISCLOSURE OF THE INVENTION The present invention is characterized by containing a peptidylhydroxamic acid derivative represented by the following general formula (I) or a pharmacologically acceptable salt thereof as an active ingredient, and an eyeball and its peripheral part. The present invention provides a preventive / therapeutic agent for tissue ulcers. X ¹ -X ² -X ³ -X ⁴ -NHOH (I) (In the formula, X ¹ , X ² , X ³ and X ⁴ are respectively residues of α-amino acid in a peptide bond as shown below. X ¹ is a residue of an α-amino acid selected from glycine and sarcosine, and the hydrogen atom in the amino group is acetyl group, benzoyl group, benzyloxy group, t-butoxycarbonyl group, benzyloxycarbonyl group. Optionally substituted by a functional group selected from a group, a paraaminobenzoyl group, a paraaminobenzyl group or a parahydroxybenzoyl group, X ² is an amino acid selected from D- or L-proline, hydroxyproline, thioproline and alanine. X ³ is a residue, glutamine, glutamic acid, D- or L-leucine, isoleucine and fe Is a residue of an amino acid selected from nylalanine, X ⁴ is a residue of an α-amino acid selected from glycine, D- or L-alanine, valine, D- or L-leucine and sarcosine, and X ⁴ is α-amino acid carboxyl group and X ² α-amino acid amino group, X ² α-amino acid carboxyl group and X ³ α-
The amino group of the amino acid, the carboxyl group of the α-amino acid of X ^{3 and} the amino group of the α-amino acid of X ⁴ and the carboxyl group of the α-amino acid of X ⁴ and -NHOH are respectively bonded by a peptide bond form. Indicates)

The present invention will be described in detail below.
Prevention against ulcer of the eyeball and its peripheral tissues of the present invention
The peptidylhydroxamic acid derivative which is an active ingredient of a therapeutic agent, in particular, a drug for preventing and treating various corneal ulcers has the above-mentioned general formula X ¹ -X ² -X ³ -X ⁴ 4-NHOH (I).
The compound represented by or a pharmacologically acceptable salt thereof is produced by a general method commonly used in peptide synthetic chemistry. These techniques are
Although described in detail in the known literature, for example,
The specific method is described in “Shiro Akahori, Takeo Kaneko, Kozo Narita, Protein Chemistry 1, Amino Acids / Peptides, Kyoritsu Shuppan, 1969”. The following two methods are shown as typical examples. The abbreviations of the substituents used in the description are usually conventional, and the definition is given in the following description.

A compound represented by the formula Boc-X ⁴ —NHOBzl is used as a starting material, and a peptide chain is extended on the Boc-N group side to form an X ³ —X ⁴ — group first, followed by X ² —X. ³ -X ⁴ - via a ^group, X 1 ^-X 2 ^{-X
A method} of forming a ^3- X ⁴ -group, and finally removing an O-benzyl group on the hydroxamic acid side to form a target compound, represented by the formula Boc-X ⁴ -OR (R: methyl group or ethyl group) Compound as a starting material, the peptide chain is extended on the Boc-N group side to form an X ³ -X ⁴ -group first, and then X ² -X ³ -X ⁴ -group, and then X ¹
After forming a —X ² —X ³ —X ⁴ — group and synthesizing the corresponding peptide derivative, X ¹ —X ² —X ³ —X ⁴ —OR, react this compound with hydroxylamine to form the target compound. How to blame.

In the case of condensing each of the above amino acids, for example, dicyclohexylcarbodiimide (DC
C), N, N-dimethylaminopropylethylcarbodiimide, mixed acid anhydride method, azide method, active ester method, redox method, DCC-additive (1-hydroxybenzotriazole, N-hydroxy) Succinimide, N-hydroxy-5-norbornene-
2,3-dicarboximide, etc.) can be used. When a solvent is used in these reactions, as the solvent, N, N-dimethylformamide, tetrahydrofuran, methylene chloride, dioxane,
Acetic acid ethyl ester or mixtures thereof can be used. The protecting group for each amino acid described above includes
For example, as a protecting group for an amino group or an imino group, benzyloxycarbonyl, t-butoxycarbonyl (B
oc), benzoyl (Bz), acetyl, formyl, paramethoxybenzyloxycarbonyl, trifluoroacetyl and the like, and examples of the protective group for the carboxyl group include methyl, ethyl, butyl, benzyl, nitrobenzyl and the like. , Acetyl as a hydroxyl protecting group,
Examples include benzyl, benzyloxycarbonyl, t-butyl and the like. The symbols in parentheses in the description indicating the above-mentioned compounds or groups are abbreviations for indicating these compounds or groups, and these abbreviations are used in the text of the present specification.

In the process of each reaction, as a method for removing the above-mentioned protecting group, for example, a method by catalytic reduction, trifluoroacetic acid, hydrogen fluoride, hydrogen bromide, hydrogen chloride, sodium hydroxide, hydroxylation is used. A method using potassium or the like is used.

The pharmacologically acceptable salt of the compound represented by the above general formula (I) is an N-addition salt, for example,
Examples thereof include hydrobromide, sulfate, phosphate, formate, acetate, propionate, malonate, succinate, lactate, oxalate and tartrate. Further, as the salt when the amino group is protected, for example, sodium salt, potassium salt, magnesium salt, calcium salt, aluminum salt, piperidine salt, morpholine salt, dimethylamine salt,
Examples thereof include diethylamine salt and the like.

The above-mentioned peptidylhydroxamic acid derivative, which is an active ingredient of the prophylactic / therapeutic agent according to the present invention, has a strong inhibitory action on collagenase, gelatinase and stromelysin derived from vertebrates. This active ingredient substance is extremely safe, including in vivo metabolites, because the constituent components in its structure are naturally occurring highly safe amino acids or their derivatives.

The preventive / therapeutic agent according to the present invention can be prepared, for example, as follows. The manufacture of eye drops is
It is carried out in accordance with the usual method for preparing eye drops, but an appropriate amount of the above-mentioned peptidylhydroxamic acid derivative or a pharmacologically acceptable salt thereof is dissolved in an aqueous solvent, for example, sterilized purified water, and pharmacologically acceptable. It can be prepared by adding a stabilizer, a pH adjusting agent, a preservative, an isotonicity agent, a solubilizing agent, a thickening agent or other appropriate additive as required. Examples of stabilizers include, for example, aminoacetic acid,
Sodium bisulfite, sodium edetate, potassium chloride, sodium acetate, diethanolamine, dried sodium sulfite, sodium citrate, sodium hydrogen carbonate, sodium carbonate, sodium thiosulfate, lactose, sodium pyrosulfite, butylhydroxyanisole, glucose, propylene glycol, Examples thereof include water-soluble substances such as D-mannitol and sodium sulfate.

Examples of pH adjusters include aminoacetic acid, calcium chloride, acetic acid, hydrochloric acid, citric acid, sodium citrate, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, boric acid, macrogol 400, macrogol. 4000, macrogol 6000, sodium dihydrogen phosphate, sodium hydrogen phosphate, sodium phosphate and the like. Examples of preservatives include sodium benzoate, chlorobutanol, sorbic acid, potassium sorbate, sodium dehydroacetate, paraoxybenzoic acid esters, phenylethyl alcohol, benzyl alcohol, boric acid, borax and the like. Examples of the tonicity agent include, for example, potassium chloride, calcium chloride, sodium chloride, sodium acetate, glucose,
Examples thereof include benzyl alcohol and D-mannitol. Examples of the solubilizing agent include hydrochloric acid, acetic acid, sodium acetate, diethanolamine, sodium hydroxide, sodium hydrogen carbonate, sodium carbonate, propylene glycol, benzyl alcohol, polyvinylpyrrolidone and the like. Examples of the thickener include polyvinyl alcohol, polyvinylpyrrolidone, methyl cellulose and the like. In the above eye drop, the concentration of the peptidylhydroxamic acid derivative is 0.01 to
900 mg / ml, preferably 0.1-500 mg / m
can be prepared and used in

The ophthalmic ointment can be prepared according to a conventional method for preparing an ophthalmic ointment, but it is pharmacologically acceptable with the above-mentioned peptidylhydroxamic acid derivative or a pharmacologically acceptable salt thereof. Ointment base such as white petrolatum, liquid paraffin, purified lanolin, polyoxyl stearate 40, macrogol 300, macrogol 40
0, cetanol, glyceryl monostearate, gelene 50W (JELENE 50W), plastibase or plastibase 50W, poloid and the like are mixed with a base appropriately selected to be prepared aseptically. At that time, a pharmacologically acceptable stabilizer, preservative or other appropriate additive can be added as necessary. Examples of the stabilizer include propylene glycol and the like. Examples of preservatives include paraoxybenzoic acid ester, chlorobutanol and the like.

The concentration of the peptidyl hydroxamic acid derivative in the eye ointment is 0.01 to 900 mg /
g, and preferably 0.1 to 500 mg / g. The preparation of the present invention is a human corneal ulcer, for example, as an infectious corneal ulcer, a bacterial corneal ulcer, a fungal corneal ulcer or a viral corneal ulcer, etc. It is effective for the prevention and treatment of limbal corneal ulcer, catarrhal corneal ulcer, vitamin deficient corneal ulcer, corneal ulcer after chemical corrosion, burn corneal ulcer, radiation corneal ulcer, nerve paralyzing corneal ulcer, etc.

Next, the present invention will be specifically described with reference to examples and experimental examples, but the present invention is not limited to these examples. The peptidylhydroxamic acid derivative and its pharmacologically acceptable salt used in the preparation of the present invention should be prepared and obtained by the method described in JP-A-1-160997. You can

[Example 1] 2 g of benzoylglycyl-prolyl-D-leucyl-D-alanyl-hydroxamic acid (note: reference) and 0.33 g of sodium chloride were dissolved in sterile purified water to make 100 ml in total. Note: JP-A-1-160997, Example 35

Example 2 Benzoylglycyl-prolyl-leucyl-alanyl-hydroxamic acid (Note: reference)
1 g, anhydrous sodium dihydrogen phosphate 0.56 g, anhydrous sodium monohydrogen phosphate. 28 g, sodium chloride 0.2
6 g was dissolved in a 0.002% benzalkonium chloride solution solution to make the total amount 100 ml. Note: JP-A-1-160997, Example 34

Example 3 0.5 g of t-butoxycarbonylglycyl-prolyl-phenylalanyl-glycyl-hydroxamic acid (Note: reference), sodium chloride 0.3
3 g and 0.10 g of anhydrous sodium sulfite were dissolved in sterile purified water to make the total amount 100 ml. Note: JP-A-1-160997, Example 3

Example 4 Paraaminobenzoylglycyl-prolyl-D-leucyl-D-alanyl-hydroxamic acid acetate (note: reference) 1 g, sodium chloride 0.
33 g was dissolved in sterile purified water to make the total amount 100 ml. Note: JP-A-1-160997, Example 6

Example 5 1 g of an acetic acid salt of paraaminobenzoylglycyl-prolyl-leucyl-alanyl-hydroxamic acid (Note: reference) and 0.30 g of zinc sulfate were dissolved in sterile purified water to make a total volume of 100 ml. Note: JP-A-1-160997, Example 41

Example 6 White petrolatum (95 g), liquid paraffin (5 g) and paraaminobenzoylglycyl-prolyl-D-leucyl-D-alanyl-hydroxamic acid acetate salt (Note: reference) were uniformly mixed. Kaihei 1-160997, Example 6

Example 7 White petrolatum 95 g, purified lanolin 5 g and parahydroxybenzoylglycyl-
0.5 g of prolyl-D-leucyl-D-alanyl-hydroxamic acid (Note: reference) was mixed uniformly. Note: JP-A-1-160997, Example 7

Example 8 100 g of white petrolatum and 1 g of t-butoxycarbonylglycyl-prolyl-D-leucyl-glycyl-hydroxamic acid (Note: reference) were uniformly mixed. Note: JP-A-1-160997, Example 21

Experimental Example 1 Human fibroblast-derived collagenase inhibitory activity measurement test The inhibitory activity (IC ₅₀ ) of the peptidylhydroxamic acid derivative against human fibroblast-derived collagenase was
Nagai et al. (Inflammation, 4 (2), p123 (198)
4)). The results are shown in Table-1.

[Experimental Example 2] Human Granulocyte-Derived Gelatinase Inhibitory Activity Measurement Test The inhibitory activity (IC ₅₀ ) of the peptidylhydroxamic acid derivative against human granulocyte-derived gelatinase was determined as Ma
sui et al. (Biochem. Med., 17 , p.
215 (1977)). The results are shown in Table-1
Shown in.

[Experimental Example 3] Assay for inhibiting human fibroblast-derived stromelysin inhibitory activity The inhibitory activity (IC ₅₀ ) of the above-mentioned peptidylhydroxamic acid derivative against human fibroblast-derived stromelysin
The Twining method (Anal. Bioche
m. , 143 , p30 (1984)). The results are shown in Table-1.

[0028]

[Table 1]

[Experimental Example 4] Acute toxicity test using mouse An acute toxicity test (LD ₅₀ ) using mouse was carried out on the peptidylhydroxamic acid derivative and a pharmacologically acceptable salt thereof. The results are shown in Table-2.

[0030]

[Table 2]

[Experimental Example 5] Ocular mucosa irritation test (eye drops) The eye drops prepared in Example 4 were continuously administered to one eye of a rabbit (New Zealand white, 7 birds) three times a day for 17 days. did. After continuous administration, clinical examination (congestion, presence of cloudiness),
As a result of histological analysis (leukocyte migration, presence or absence of corneal damage in a pathological tissue sample) and comparison with the case where no drug was administered, no abnormality was observed.

[Experimental Example 6] Ocular mucosa irritation test (eye ointment) The eye ointment prepared in Example 6 was tested in the same manner as in Experimental Example 5 and evaluated in the same manner. I was not able to admit.

Experimental Example 7 Effectiveness Confirmation Test (Eye Ointment) Invest. Ophthalmol. , 31 (1):
According to the method described in p107 (1990), both eyes of a rabbit (New Zealand white, male, 9 birds) were subjected to alkaline treatment, and then washed with physiological saline. The ointment preparation prepared in Example 6 was administered to one eye, and this was used as a drug administration group and the other eye was used as a control group, and only the base was administered. The administration was to be performed 3 times a day for 14 consecutive days. As a result of clinical confirmation of the occurrence of corneal ulcers, the number of corneal ulcers was found to be 5 out of 9 in the control group. On the other hand, in the drug administration group, no corneal ulcer was observed in 1 of 9 cases.

[Procedure amendment]

[Submission date] March 25, 1994

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0002

[Correction method] Change

[Correction content]

[0002]

BACKGROUND ART Ulcers of the eyeball and its peripheral tissues, particularly various corneal ulcers, are induced by, for example, infection with bacteria, fungi or viruses, or some external stimulus, and the degradation of collagen and mucopolysaccharide in the corneal stroma is caused. Is caused, and as a result, the cornea is irreversibly decomposed and melted. These diseases are collagenase,
Matrix metalloprotease containing gelatinase and stromelysin [Matrix Metallop
Rotases, (hereinafter referred to as MMPs) FAS
EBJ. 5 : p2145 (1991)] is a refractory disease caused by a series of activities of tissue-disrupting enzymes. These MMPs are
It is considered to have the following roles. That is, stromelysin activates collagenase that decomposes collagen in the cornea secreted as a precursor [A
rch. Biochem. Biophys. , 267 ,
p211 (1988)], causing degradation and denaturation of collagen in the cornea. Then denatured collagen (gelatin)
Degradation gelatinase and stromelysin, which decomposes mucopolysaccharide, which is one of the components of the cornea, act to promote corneal damage and lead to irreparable corneal ulcer. Dryness that occurs due to the inability to secrete an appropriate amount of tear fluid due to slight corneal damage at the time of detachment of contact lenses that has been widely used recently, infection with bacteria, fungi, viruses, etc. at the time of detachment, or abnormality of the lacrimal gland. Eyes also cause corneal ulcers. Corneal ulcers are roughly classified into infectious corneal ulcers and non-infectious corneal ulcers.Infectious corneal ulcers include bacterial corneal ulcers, fungal corneal ulcers, viral corneal ulcers, and other non-infectious corneal ulcers. Corneal ulcer, limbal corneal ulcer, catarrhal corneal ulcer, vitamin deficient corneal ulcer, corneal ulcer after chemical corrosion, burn corneal ulcer,
There are radiation corneal ulcers, neuroplegic corneal ulcers, etc. As therapeutic substances for corneal ulcers, steroids, antibiotics, and vitamins have been conventionally known [Inves
t. Ophthalmol. , 16 : p21 (197)
7). Invest. Ophthalmol. , 33
(12): p3325 (1992). Invest. O
phthalmol. , 29 : p1110 (198
8)], the effect of improving the medical condition by using these is extremely low. In addition, a compound having a functional group having a function of capturing zinc, which is an activator of collagenase, which is a type of MMPs, in the molecule, for example, EDTA-2Na, L-cysteine, N-acetylcysteine ( N-acetylcysteine, glutathione, D-penicillamine (D
-Penicillamine) and the like have been proposed, but [Invest. Ophthalmol. , 33
(12): p3325 (1992). Invest. O
phthalmol. , 31 (1): p107 (199
0)], when EDTA-2Na is used, cytotoxicity is exhibited, and compounds having an SH group are locally unstable because they are chemically unstable and have low water solubility. Since the retention property is inferior, an effective amount cannot be retained in the affected area, and thus frequent administration is required, and care for that is complicated, which is also very inconvenient for the patient. Thus, so far,
There is no satisfactory preventive / therapeutic agent effective for corneal ulcer.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0003

[Correction method] Change

[Correction content]

The present invention has been made in view of the above situation, and is an ulcer of the eyeball and its peripheral tissues, especially MMPs.
It is an object of the present invention to provide an excellent drug for the prevention and treatment of various corneal ulcers which are associated with intractable diseases and which are associated with the increase in erythema. That is, in the process from corneal injury to corneal ulcer formation, MMPs, namely collagenase,
Enzymes such as gelatinase and stromelysin are involved in a complicated manner. Therefore, regarding prevention and treatment of corneal ulcers,
A compound having an inhibitory action against any of the actions of collagenase, gelatinase and stromelysin is effective.

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0004

[Correction method] Change

[Correction content]

The present inventors have previously provided a peptidylhydroxamic acid derivative which inhibits collagenase activity (see Japanese Patent Laid-Open No. 160997/1989). As a result of further research on the action of these peptidylhydroxamic acid derivatives, it was found that the derivatives have enzyme inhibitory activity not only on collagenase but also on other MMPs, namely gelatinase and stromelysin, and corneal ulcer It has been found that it has an excellent effect on the treatment of a model alkali-induced corneal ulcer. These peptidyl hydroxamic acid derivatives are chemically stable compounds, which have enzyme inhibitory activity against gelatinase and stromelysin, and are useful as prophylactic / therapeutic agents for corneal ulcers, So far unknown.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shinjiro Otake, 530 Chokeiji Temple, Takaoka City, Toyama Prefecture, Fuji Labs. Ltd. (72) Eiko Suda, 530 Chokeiji Temple, Takaoka City, Toyama Prefecture, Fuji Pharma Co., Ltd. In-house (72) Inventor Shimizu Atsushi 530 Chokeiji Temple, Takaoka City, Toyama Prefecture, Fuji Labs. Ltd. (72) Inventor, Kazuaki Nakahashi 530 Chokeiji Temple, Takaoka City, Toyama Prefecture (72) Inventor, Fuji Pharma Co., Ltd. Researcher Tadanori Morikawa 530 Chokei-ji Temple, Takaoka City, Toyama Prefecture Fuji Pharmaceutical Co., Ltd.

Claims (10)

[Claims] 1. A compound represented by the general formula: X ¹ -X ² -X ³ -X ⁴ -NH
OH (I) (wherein X ¹ , X ² , X ³ and X ⁴ are respectively residues of α-amino acid in a peptide bond as shown below, and X ¹ is selected from glycine and sarcosine. A residue of an α-amino acid, the hydrogen atom of the amino group of which is an acetyl group, a benzoyl group,
It may be substituted with a functional group selected from a benzyloxy group, a t-butoxycarbonyl group, a benzyloxycarbonyl group, a paraaminobenzoyl group, a paraaminobenzyl group or a parahydroxybenzoyl group, X ²
Is a residue of an amino acid selected from D- or L-proline, hydroxyproline, thioproline and alanine, and X ³ is a residue of an amino acid selected from glutamine, glutamic acid, D- or L-leucine, isoleucine and phenylalanine. X ⁴ is a residue of an α-amino acid selected from glycine, D- or L-alanine, valine, D- or L-leucine and sarcosine, and X ¹
Α-amino acid carboxyl group and X ² α-amino acid amino group, X ² α-amino acid carboxyl group and X
³ α- amino acid amino group, ^{X 3} of α- amino acid amino group and ^{X 4} of the α- amino acid of the carboxyl group and ^{X 4} of the
The carboxyl group of α-amino acid and -NHOH are bound to each other by a peptide bond format)) or a pharmacologically acceptable salt thereof as an active ingredient. A prophylactic / therapeutic agent for ulcers of the eye and surrounding tissues. 2. The α-amino acid represented by X ¹ in the general formula (I) is glycine, and the hydrogen atom in the amino group of the α-amino acid has an acetyl group, a benzoyl group, a benzyloxy group, or t-butoxycarbonyl. It may be substituted with a functional group selected from a group, a benzyloxycarbonyl group, a paraaminobenzoyl group, a paraaminobenzyl group or a parahydroxybenzoyl group, wherein the α-amino acid of X ² is proline and the α-amino acid of X ³ is glutamine. , Glutamic acid, D- or L-leucine, isoleucine and phenylalanine, and the α-amino acid of X ⁴ is selected from glycine, D- or L-alanine and D- or L-leucine. Therapeutic agent. 3. The preventive / therapeutic agent according to claim 2, wherein the α-amino acid of X ³ in the general formula (I) is D-leucine, and the α-amino acid of X ⁴ is glycine. 4. The preventive / therapeutic agent according to claim 2, wherein the α-amino acid of X ³ in the general formula (I) is D-leucine, and the α-amino acid of X ⁴ is D-alanine. 5. The preventive / therapeutic agent according to claim 2, wherein the α-amino acid of X ³ in the general formula (I) is leucine, and the α-amino acid of X ⁴ is alanine. 6. The α-amino acid of X ¹ in the general formula (I) is para-aminobenzoylglycine, the α-amino acid of X ² is proline, the α-amino acid of X ³ is D-leucine, and the α-amino acid of X ⁴ is It is D-alanine.
The preventive / therapeutic agent described. 7. The α-amino acid of X ¹ in the general formula (I) is parahydroxybenzoylglycine, and the α of X ² is α.
The preventive / therapeutic agent according to claim 1, wherein the amino acid is proline, the α-amino acid of X ³ is D-leucine, and the α-amino acid of X ⁴ is D-alanine. 8. The α-amino acid of X ¹ in the general formula (I) is benzoylglycine, the α-amino acid of X ² is proline, the α-amino acid of X ³ is D-leucine, and the α of X ⁴ is α.
-Prevention according to claim 1, wherein the amino acid is D-alanine
Therapeutic agent. 9. The preventive preparation according to claim 1, which is an ophthalmic preparation containing 0.01 to 900 mg / ml of the peptidylhydroxamic acid derivative represented by the general formula (I) or a pharmacologically acceptable salt thereof. -Therapeutic agent. 10. The prevention according to claim 1, which is an ophthalmic ointment preparation containing 0.01 to 900 mg / g of a peptidylhydroxamic acid derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof. -Therapeutic agent.