JP2014005276A - Glaucoma therapeutic agent containing peptide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a search for an intraocular pressure-lowering agent having a new action mechanism.SOLUTION: A peptide derivative of the general formula (1) strongly and continuously lowers rabbit intraocular pressure by anterior chamber administration or eye drop, so is expected to be a new glaucoma therapeutic agent. (In the formula, Rrepresents a 2-naphthoylamino group or the like; X represents a carbon atom or the like; the dash line represents a double bond or the like; Y represents -CHCO- or the like; and Z represents a covalent bond or the like; Rrepresents a 2-methylbutyl group or the like.)

Description

  The present invention relates to a therapeutic agent for glaucoma containing a peptide derivative or a salt thereof.

  Glaucoma is a refractory eye disease that has a risk of leading to blindness due to increased intraocular pressure due to various etiologies and damage to internal tissues of the eyeball (retina, optic nerve, etc.). As a method for treating glaucoma, intraocular pressure lowering therapy is common, and pharmacotherapy, laser therapy, surgical treatment, etc. are known as typical ones, but it is necessary to continue to control intraocular pressure over a long period of time. In the treatment of glaucoma, drug therapy is particularly important.

  However, there are patients who cannot control intraocular pressure with existing drugs, and development of a powerful intraocular pressure-lowering agent having a new mechanism of action is awaited.

  In order to lower the intraocular pressure by a drug, it is necessary to deliver the drug into the anterior chamber. However, because of its high safety, it is usual to select eye drops as the administration route. However, since the drug is washed out by tears after instillation, and only a small part of the instilled drug moves into the anterior chamber because the cornea functions as a barrier, it realizes a route of administration other than instillation. Development of ophthalmic preparations for this purpose is also in progress.

  For example, Pharmaceutics, 4 (1), 197-211 (2012) (Non-patent Document 1) includes a continuous preparation administered subconjunctivally or subtenonally, and an intraocular pressure lowering agent in the form of a punctum plug. It is disclosed. Although it is not common to administer intraocular pressure-lowering agents to the posterior segment of the eye, such as non-patent document 1, it is also disclosed that intraocular pressure-lowering drugs having a neuroprotective action can be administered intravitreally. Has been.

Atrial natriuretic peptide (A trial N atriuretic P eptide: ANP) is a hormone consisting of 28 amino acids, also called Atrial Natriuretic Factor (ANF). Japanese Patent No. 2855143 (Patent Document 1) discloses peptide derivatives obtained by modifying partial peptides of this ANP, but there is no report examining the intraocular pressure lowering action of these peptide derivatives.

  By the way, in Neuropeptides, 12, 219-224 (1988) (Non-patent Document 2), when ANP (ANF) was administered to a rabbit in the anterior chamber, miosis was observed, but the intraocular pressure was affected. It has been described that there is a possibility that administration of ANP to the anterior segment of the eye does not reduce intraocular pressure. On the other hand, Invest. Ophthalmol. Vis. Sci. , 28 (8), 1357-1364 (1987) (Non-patent Document 3), it was described that when rANP (rat ANP) was administered into the vitreous body of rabbits, a drop in intraocular pressure was observed. At the same time, it has also been disclosed that the partial peptide of rANP was not confirmed to have decreased intraocular pressure even when it was administered into the vitreous body of rabbits.

  That is, Non-Patent Documents 2 and 3 suggest that even if ANP is administered to the anterior ocular segment, it is not possible to obtain an intraocular pressure lowering effect. Further, regarding the partial peptide, the posterior ocular segment (vitreous body) It is described that the intraocular pressure cannot be lowered even if administered to the patient.

Japanese Patent No. 2855143

Pharmaceutics, 4 (1), 197-211 (2012). Neuropeptides, 12, 219-224 (1988) Invest. Ophthalmol. Vis. Sci. , 28 (8), 1357-1364 (1987)

  It is an interesting task to search for an intraocular pressure-lowering agent having a new mechanism of action.

  As a result of intensive studies, the present inventor has found that when a peptide derivative modified with a partial peptide of ANP is administered to the anterior ocular segment, a strong and sustained decrease in intraocular pressure can be obtained, and the present invention is completed. It came.

  That is, the present invention refers to a glaucoma therapeutic agent (hereinafter simply referred to as “the present therapeutic agent”) containing a peptide derivative represented by the following general formula (1) (hereinafter also simply referred to as “the present peptide derivative”) or a salt thereof. ).

[Wherein, R ¹ represents 2- (2-naphthyl) ethylamino group, 2-naphthylacetyl group, 2-naphthylacetylamino group, 2-naphthylacetylaminomethyl group, 2-naphthoyl group, 2-naphthoylmethyl group 2-naphthoylmethylamino group, 2-naphthoylamino group, 2-naphthoylaminomethyl group, 2-naphthoxyacetyl group, 2-naphthoxyacetylamino group, 2-bromoacetylphenylamino group, 2-chloro -2-phenylacetylamino group or 2-bromo-2-phenylacetylamino group; X represents a carbon atom or a nitrogen atom; when X is a carbon atom, a broken line represents a single bond or a double bond; dashed line when X is a nitrogen atom represents a single bond; Y is _{-CH 2 -, - CH 2 NH} -, - CH 2 CH 2 NH -, - CH 2 CO- also It indicates -CO-; Z represents a Ile or a covalent bond; _{R 2} represents a hydrogen atom or a 2-methylbutyl group. ]
In the present peptide derivative, preferably, in the general formula (1), Z represents a covalent bond.

More preferably, in the general formula (1), R ¹ represents a 2-naphthylacetyl group, a 2-naphthoylamino group, a 2-naphthoxyacetyl group, or a 2-naphthoxyacetylamino group in the general formula (1); When X is a carbon atom, the broken line indicates a double bond, and when X is a nitrogen atom, the broken line indicates a single bond; Y indicates —CH ₂ NH—, —CH ₂ CO— or —CO—. Z represents a covalent bond; R ₂ represents a 2-methylbutyl group.

  The peptide derivative is more preferably a compound represented by the following formulas (2) to (25).

  The peptide derivative is particularly preferably a compound represented by the following formula (26) (hereinafter also simply referred to as “compound A”).

Moreover, one aspect of the present invention is the present therapeutic agent characterized by being administered to the anterior segment.
Another aspect of the present invention is the present therapeutic agent characterized by being administered to eye drops, intraanterior administration, subconjunctival administration, subtenon administration, or conjunctival sac or punctum.

  Another aspect of the present invention is the present therapeutic agent characterized in that the dosage form is an eye drop, an eye ointment, an injection, an intraocular implant preparation or an insertion agent.

  As is clear from the results of the intra-anterior administration test and the eye drop test described below, Compound A strongly and continuously lowered the intraocular pressure of the rabbit by intra-anterior administration or eye drop. Therefore, this peptide derivative is expected to be a new therapeutic agent for glaucoma.

It is a graph which shows a time-dependent change of the intraocular pressure value after administering the compound A into a normal intraocular pressure rabbit in an anterior chamber. It is a graph which shows the time-dependent change of the intraocular pressure value after administering the compound A into a normal intraocular pressure rabbit (automatic intraocular pressure measuring system) in the anterior chamber. It is a graph which shows the time-dependent change of the intraocular pressure value after instilling the compound A to a normal intraocular pressure rabbit.

  In the present invention, Arg, Ile or Asp in the general formula (1) represents L-type or D-type arginine, isoleucine or aspartic acid, respectively.

In the present invention, in the general formula (1), when Z in the general formula is Ile, the N-terminal of a peptide consisting of “(N-terminal side) Arg-Ile-Asp-Arg-Ile (C-terminal side)” A compound in which the hydrogen atom of the amino group of Arg on the side is substituted with the group of the following formula (a) and the OH of the carboxy group of Ile on the C-terminal side is substituted with the NHR ₂ group is shown.

In the present invention, the general formula (1) is an N-terminal side of a peptide consisting of “(N-terminal side) Arg-Ile-Asp-Arg (C-terminal side)” when Z in the general formula is a covalent bond. A compound in which the hydrogen atom of the amino group of Arg is substituted with the group of the formula (a) and the OH of the carboxy group of Arg on the C-terminal side is substituted with the NHR ₂ group.

  In the present invention, Arg, Ile or Asp in the general formula (1) is preferably all L-type.

  In the present invention, the 2-methylbutyl group means either “(S) -2-methylbutyl group” or “(R) -2-methylbutyl group”, preferably “(S) -2-methylbutyl group”. Means.

  (A) This peptide derivative is a compound in which each group is a group shown below in the compound represented by the following general formula (1).

(A1) R ¹ is 2- (2-naphthyl) ethylamino group, 2-naphthylacetyl group, 2-naphthylacetylamino group, 2-naphthylacetylaminomethyl group, 2-naphthoyl group, 2-naphthoylmethyl group, 2-naphthoylmethylamino group, 2-naphthoylamino group, 2-naphthoylaminomethyl group, 2-naphthoxyacetylamino group, 2-naphthoxyacetylamino group, 2-bromoacetylphenylamino group, 2-chloro- Represents 2-phenylacetylamino group or 2-bromo-2-phenylacetylamino group;
(A2) X represents a carbon atom or a nitrogen atom;
(A3) When X is a carbon atom, the broken line represents a single bond or a double bond, and when X is a nitrogen atom, the broken line represents a single bond;
(A4) Y is _{-CH 2 -, - CH 2 NH} -, - CH 2 CH 2 NH -, - CH 2 CO- or -CO- indicates;
(A5) Z represents Ile or a covalent bond; and (A6) R ₂ represents a hydrogen atom or a 2-methylbutyl group.

  That is, this peptide derivative is a compound represented by the general formula (1), wherein each group listed in the above (A1), (A2), (A3), (A4), (A5) and (A6). Is a combination.

  (B) As a preferred example of the present peptide derivative, in the compound represented by Z in the general formula (1), that is, a compound represented by the following general formula (1-2), each group is a group represented by The compound which is is mentioned.

(B1) R ¹ is a 2- (2-naphthyl) ethylamino group, 2-naphthylacetyl group, 2-naphthylacetylamino group, 2-naphthylacetylaminomethyl group, 2-naphthoyl group, 2-naphthoylmethyl group, 2-naphthoylmethylamino group, 2-naphthoylamino group, 2-naphthoylaminomethyl group, 2-naphthoxyacetylamino group, 2-naphthoxyacetylamino group, 2-bromoacetylphenylamino group, 2-chloro- Represents 2-phenylacetylamino group or 2-bromo-2-phenylacetylamino group;
(B2) X represents a carbon atom or a nitrogen atom;
(B3) When X is a carbon atom, the broken line represents a single bond or a double bond, and when X is a nitrogen atom, the broken line represents a single bond;
(B4) Y is _{-CH 2 -, - CH 2 NH} -, - CH 2 CH 2 NH -, - CH 2 CO- or -CO- indicates; and (B5) _{R 2} is a hydrogen atom or a 2-methylbutyl group Indicates.

  That is, preferred examples of the present peptide derivative are the compounds represented by the general formula (1-2), and the compounds listed in the above (B1), (B2), (B3), (B4) and (B5). It is a combination of groups.

  (C) As a more preferable example of this peptide derivative, the compound whose each group is the group shown below in the said General formula (1-2) is mentioned.

(C1) R ¹ represents a 2-naphthylacetyl group, a 2-naphthoylamino group, a 2-naphthoxyacetyl group, or a 2-naphthoxyacetylamino group;
(C2) X represents a carbon atom or a nitrogen atom;
(C3) when X is a carbon atom, the broken line indicates a double bond, and when X is a nitrogen atom, the broken line indicates a single bond;
(C4) Y represents —CH ₂ NH—, —CH ₂ CO— or —CO—; and (C5) R ₂ represents a 2-methylbutyl group.

  That is, more preferable examples of the present peptide derivatives are listed in the above-mentioned (C1), (C2), (C3), (C4) and (C5) in the compound represented by the general formula (1-2). Each group is combined.

  (D) As a more preferable example of this peptide derivative, the compound whose each group is the group shown below in the said General formula (1-2) is mentioned.

(D1) R ¹ represents a 2-naphthoylamino group;
(D2) X represents a carbon atom;
(D3) the broken line indicates a double bond;
(D4) Y represents —CH ₂ CO—; and / or (D5) R ₂ represents a (S) -2-methylbutyl group.

  That is, a more preferable example of the present peptide derivative is that the compound represented by the general formula (1-2) satisfies the condition (B), and (D1), (D2), (D3), ( A combination of the groups listed in D4) and / or (D5).

  Specific examples of the peptide derivative include the compound (AP564) represented by the formula (2), the compound (AP568) represented by the formula (3), the formula (3), which is disclosed in Japanese Patent No. 2855143. 4) Compound (AP574), Compound (AP704) represented by Formula (5), Compound (AP790) represented by Formula (6), Compound (7) ( AP791), compound represented by formula (8) (AP792), compound represented by formula (9) (AP793), compound represented by formula (10) (AP794), formula (11) A compound represented by formula (AP795), a compound represented by formula (12) (AP796), a compound represented by formula (13) (AP816), a compound represented by formula (14) (AP817). , The above formula (1 ) Compound (AP818), the compound (AP819) represented by formula (16), the compound (AP538) represented by formula (17), the compound (AP539) represented by formula (18). ), The compound represented by formula (19) (AP560), the compound represented by formula (20) (AP562), the compound represented by formula (21) (AP557), and the formula (22). A compound represented by formula (AP810), a compound represented by formula (23) (AP811), a compound represented by formula (24) (AP812) and a compound represented by formula (25) (AP813). The compound represented by the formula (23) is particularly preferable.

  A particularly preferred example of this peptide derivative is the compound of formula (26) (compound A) in which each amino acid of the compound represented by formula (23) is L-type.

  This peptide derivative can also be produced according to the method described in Japanese Patent No. 2855143, and for Compound A, California Peptide Research, Inc. A commercially available product (AP-81 / NPR-C receptor ligand) can also be used.

  The salt of this peptide derivative is not particularly limited as long as it is a pharmaceutically acceptable salt. Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, acetic acid, Fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobion Organic acids such as acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid Quaternary ammonium salt with methyl bromide, methyl iodide, etc .; bromine ion, chloride ion Salts with halogen ions such as iodine ions; Salts with alkali metals such as lithium, sodium and potassium; Salts with alkaline earth metals such as calcium and magnesium; Metal salts with iron and zinc; Salts with ammonia; Triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxymethyl) -1,3-propane Examples thereof include salts with organic amines such as diol, procaine, and N, N-bis (phenylmethyl) -1,2-ethanediamine.

  In addition, the present peptide derivative or a salt thereof may take the form of a hydrate or a solvate.

  When geometric isomers or optical isomers are present in the peptide derivative or a salt thereof, the isomer or a salt thereof is also included in the scope of the present invention. Moreover, when proton tautomerism exists in this peptide derivative or its salt, the said tautomer or those salts are also contained in the scope of the present invention.

  When there are crystal polymorphs and crystal polymorph groups (crystal polymorph systems) in the peptide derivative or a salt thereof (including hydrates or solvates), those crystal polymorphs and crystal polymorph groups ( Crystal polymorph systems) are also within the scope of the present invention. Here, the crystal polymorphism group (crystal polymorphism system) means that the crystal form changes depending on the conditions and state of production, crystallization and storage of these crystals (including the formulated state in this state). Means the individual crystal forms at each stage and the whole process.

  In the present invention, glaucoma includes primary open-angle glaucoma, normal-tension glaucoma, aqueous humor production hyperglaucoma, ocular hypertension, acute closed-angle glaucoma, chronic closed-angle glaucoma, mixed glaucoma, steroid glaucoma, amyloid Examples include glaucoma, neovascular glaucoma, malignant glaucoma, capsular glaucoma of the lens, plateau iris syndrome and the like.

  In the present invention, the glaucoma therapeutic agent means a medicament for treating and / or preventing glaucoma. The glaucoma therapeutic agent of the present invention includes an intraocular pressure lowering agent.

  In the present invention, the peptide derivative can be administered to a patient orally or parenterally, but is preferably administered parenterally, more preferably administered locally to the eye, It is particularly preferred that it be administered.

  In the present invention, “administered to the anterior segment” means local administration of the eye for transferring the drug into the anterior chamber, and does not include drug administration to the posterior segment of the eye such as vitreous body or retinal injection. (1) Formulating the peptide derivative into an ophthalmic solution or eye ointment and instilling (including instillation); (2) Formulating the peptide derivative into an injection or intraocular implant formulation (3) The peptide derivative is formulated into an injection or intraocular implant and administered subconjunctivally; (4) The peptide derivative is formulated into an injection or intraocular implant. (5) The peptide derivative is formulated into an intercalating agent and administered to the conjunctival sac (cul-de-sac), or (6) The peptide derivative is administered into an intraocular implant (punctum) It is intended to include the administration of the punctum formulated to lag).

  In the present invention, the present peptide derivative is formulated into a dosage form suitable for administration together with a pharmaceutically acceptable additive as necessary. Examples of dosage forms suitable for oral administration include capsules, subtle granules, granules, powders, pills, tablets, and the like. It is done. Examples of dosage forms suitable for parenteral administration include eye drops, eye ointments, injections, intraocular implant preparations (including punctal plugs), inserts, patches, gels, and the like. In addition, these can be prepared using the normal technique currently used widely in the said field | area. Furthermore, this peptide derivative can also be made into the formulation converted into DDS (drug delivery system) such as microspheres.

  As described above, since this peptide derivative is preferably administered to the anterior segment, preferred dosage forms of this peptide derivative include eye drops, eye ointments, injections, intraocular implant preparations (a punctum plug). Or an intercalating agent.

  The peptide derivatives include, for example, excipients such as crystalline cellulose, lactose, glucose, D-mannitol, calcium hydrogen anhydride, starch, sucrose; carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, crospovidone , Starch, partially pregelatinized starch, low substituted hydroxypropylcellulose and other disintegrants; hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol and other binders Lubricants such as magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, hydrogenated oil; Coating agents (coating agents) such as sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, and polyvinylpyrrolidone; flavoring agents such as citric acid, aspartame, ascorbic acid, and menthol are appropriately selected and added. Thus, it can be prepared as a capsule, fine granule, granule, powder, pill or tablet.

  In the present invention, the eye drops are isotonic agents such as sodium chloride, potassium chloride and concentrated glycerin; buffering agents such as sodium phosphate, sodium acetate and epsilon-aminocaproic acid; polyoxyethylene sorbitan monooleate, polyoxyl stearate 40, surfactants such as polyoxyethylene hydrogenated castor oil; stabilizers such as sodium citrate and sodium edetate; preservatives such as benzalkonium chloride and paraben, etc. can do. The pH of the ophthalmic solution may be within the range acceptable for ophthalmic preparations, but is usually preferably within the range of 4-8.

  In the present invention, the eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.

  In the present invention, the injection is prepared from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose as necessary. It can be selected and used.

  In the present invention, a preparation for an intraocular implant can be prepared using a biodegradable polymer, for example, a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose. . The punctal plug can be manufactured by the method disclosed in Japanese Translation of PCT International Publication No. 2011-525388.

  In the present invention, the intercalating agent is obtained by crushing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid and the like together with the present compound, and compressing the powder. Can be used, and if necessary, excipients, binders, stabilizers, pH adjusters and the like can be used.

  In the present invention, the dosage of the peptide derivative can be appropriately changed according to the dosage form, the severity of the symptoms of the patient to be administered, age, weight, doctor's judgment, etc. 0.000001 to 1000 mg per day can be administered once or divided into several times.

  When this peptide derivative is administered as an eye drop to the anterior segment, it is generally 0.01 to 10% (w / v), preferably 0.1 to 10 (w / v), more preferably 1 for adults. An active ingredient concentration of ˜5 (w / v) can be administered once or several times a day. In addition, when the peptide derivative is instilled into the anterior ocular segment as an eye ointment, it is generally 0.01 to 10% (w / w), preferably 0.1 to 10 (w / w) for an adult. ), More preferably those having an active ingredient concentration of 1 to 5 (w / w) can be administered once or several times a day.

  When the peptide derivative is administered as an injection to the anterior segment of the eye, generally 0.000001 to 1000 mg, preferably 0.00001 to 100 mg, more preferably 0.0001 to 10 mg once a day or It can be administered in several divided doses.

  When this peptide derivative is administered as an intraocular implant preparation (including a punctal plug) to the anterior ocular segment, an intraocular implant preparation (including a punctal plug) containing 0.000001 to 1000 mg of active ingredient for adults ) Can be implanted.

  When administering this peptide derivative to an anterior ocular segment as an intercalating agent, an intercalating agent containing 0.000001 to 1000 mg of an active ingredient can be inserted into an adult.

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

[Anterior chamber administration test-1]
The effect of intraocular administration of Compound A on the intraocular pressure of rabbits with normal intraocular pressure was examined.

(Sample preparation)
^10-3 M Compound A solution: 1 mg of Compound A was dissolved in 5 μL of dimethyl sulfoxide (DMSO), and 1.04 mL of physiological saline was added to prepare. For compound A, California Peptide Research, Inc. What was purchased from the company was used (hereinafter the same in the examples).

· ^{10 -4} M Compound A solution: ^{10 -3} M compound A solution was prepared by diluting 10-fold with 0.5% DMSO-containing physiological saline.

Base: 0.5% DMSO-containing physiological saline was used.
(Experimental animal)
Acclimatized Japanese white rabbits with normal intraocular pressure (strain: JW, sex: male) were used (6 per group).

(Drug administration method and test method)
・ 10 ⁻³ M Compound A solution administration group Immediately before drug administration, 0.4% oxybuprocaine hydrochloride (trade name: Benoxeal ^{(registered trademark)} ophthalmic solution 0.4%) was ^{added to} both eyes of the experimental animals (6 animals). Instillation was performed, and intraocular pressure was measured using an applanation type intraocular pressure measuring device, and this was used as initial intraocular pressure. Thereafter, 20 μL of a 10 ⁻³ M compound A solution was administered into the anterior chamber of each experimental animal using a microsyringe (the contralateral eye was untreated). Intraocular pressure was measured in the same manner as described above 2, 4, or 6 hours after intra-anterior administration. The intraocular pressure was measured three times, and the average value was taken as the intraocular pressure value at the measurement time.

^-10-4M compound A solution administration group It is the same as that of the ^10-3M compound A solution administration group except that the administered drug was changed to a ^10-4M compound A solution.

Base administration group Same as the 10 ⁻³ M Compound A solution administration group except that the administration drug was used as a base.

(Test results)
The test results are shown in FIG. The vertical axis represents the intraocular pressure change value (mmHg) from the initial intraocular pressure, and the horizontal axis represents the elapsed time (hr) after administration. The initial intraocular pressures of the base administration group, the 10 ⁻⁴ M compound A solution administration group, and the 10 ⁻³ M compound A solution administration group were 17.3 mmHg, 17.0 mmHg, and 16.8 mmHg, respectively. Moreover, data show the average value of 6 animals per group.

  In FIG. 1, ** P <0.01, *** P <0.001 vs base (Dunnett's multiple comparison test).

As is clear from FIG. 1, a concentration-dependent decrease in intraocular pressure was confirmed in the 10 ⁻⁴ M compound A solution administration group and the 10 ⁻³ M compound A solution administration group. In particular, in the 10 ⁻³ M compound A solution administration group, a statistically significant decrease in intraocular pressure was observed even 6 hours after administration.

(Discussion)
Administration of Compound A into the anterior chamber continuously lowers intraocular pressure, suggesting the possibility that continuous reduction in intraocular pressure can be obtained by delivering this peptide derivative into the anterior chamber by some method. .

[Anterior chamber administration test-2]
Using an automatic intraocular pressure measurement system, the effect of intraocular administration of Compound A on the intraocular pressure of rabbits with normal intraocular pressure was examined.

(Sample preparation)
The same as in the anterior chamber administration test-1.

(Experimental animal)
Biol. Pharm. Bull. , 31 (5), 970-975 (2008), the measured pressure value (intraocular pressure value) is automatically received and input on the computer by the transmitter embedded in the eye. A system was built. That is, after anesthesia with indomethacin 10 mg / kg intraperitoneally and dicroad ^{(registered trademark)} ophthalmic solution ophthalmic administration, ketamine 40 mg / kg intramuscular administration and xylazine 4 mg / kg intramuscular administration gave general anesthesia, and then a telemetry transmitter ( TA11PA-C40 Implant) was inserted subcutaneously into the right cheek and fixed by suturing. Then, the catheter connected to the telemetry transmitter is passed subcutaneously to the eyelid conjunctiva. The conjunctiva is incised and passed under the superior rectus muscle. Using a 18-20G needle, a hole is made in the sclera about 5 mm away from the corneal limbus and superior rectus muscle, and the catheter is inserted into the vitreous. Thereafter, the catheter was fixed by suturing the sclera, and the conjunctiva was sutured. After the operation, 0.3% ofloxacin (trade name: Talivid ^{(registered trademark)} ophthalmic solution 0.3%) and 0.1% diclofenac sodium (trade name: dicrode ^{(registered trademark)} ophthalmic solution 0. 3 days after surgery ⁾ . 1%) was treated up to 7 days after surgery. Before conducting the test, it was confirmed that data was received and input from the telemetry transmitter to the PC normally.

(Drug administration method and test method)
^{-10 <-3>} M compound A solution administration group 20 [mu] L of 10 ^<-3> M compound A solution was administered into one eye of the above experimental animals (six animals) (the contralateral eye was untreated). Intraocular pressure values before and after drug administration were calculated by analyzing data measured by an automatic intraocular pressure measurement system. That is, in the automatic intraocular pressure measurement system, the intraocular pressure is measured every 2.5 minutes, but the measured intraocular pressure value is averaged every hour to obtain the intraocular pressure value for the measurement time. The intraocular pressure value immediately before administration was taken as the initial intraocular pressure.

Base administration group Same as the 10 ⁻³ M Compound A solution administration group except that the administration drug was used as a base.

(Test results)
The test results are shown in FIG. The vertical axis represents the intraocular pressure change value (mmHg) from the initial intraocular pressure, and the horizontal axis represents the elapsed time (hr) after administration. In addition, data show the average value of 6 animals per group.

As is clear from FIG. 2, a continuous decrease in intraocular pressure for 24 hours or more was confirmed in the 10 ⁻³ M compound A solution administration group.

(Discussion)
From the above test results, it was shown that the present peptide derivative can be formulated into an injection or an intraocular implant preparation and administered into the anterior chamber to obtain a continuous decrease in intraocular pressure. Furthermore, the peptide derivative is formulated into an injection or intraocular implant preparation and administered subconjunctivally or subtenonally, and is formulated into an intercalator and administered to a cul-de-sac. It is expected that a continuous intraocular pressure lowering effect can be obtained also by delivering into the anterior chamber by formulating into an internal implant preparation (punctal plug) and administering it to the punctum.

[Instillation test]
The effect of instillation of Compound A on the intraocular pressure of rabbits with normal intraocular pressure was examined.

(Sample preparation)
4% Compound A solution: Prepared by dissolving 20 mg of Compound A in 12.5 μL of DMSO and adding 0.488 mL of MilliQ-water.

Base: MilliQ-water containing 2.5% DMSO was used.
(Experimental animal)
Acclimatized Japanese white rabbits with normal intraocular pressure (strain: JW, sex: male) were used (6 per group).

(Drug administration method and test method)
-4% Compound A solution ophthalmic group Immediately before instillation, instilling 0.4% oxybuprocaine hydrochloride (trade name: Benokiseal ^{(registered trademark)} ophthalmic solution 0.4%) to both eyes of the experimental animals (6 animals) Intraocular pressure was measured using an applanation type intraocular pressure measuring device, and this was used as the initial intraocular pressure. Thereafter, 50 μL of 4% Compound A solution was instilled into one eye of each experimental animal (the contralateral eye was untreated). After 2, 4 or 6 hours of instillation, the intraocular pressure was measured in the same manner as described above. The intraocular pressure was measured three times, and the average value was taken as the intraocular pressure value at the measurement time.

-Base administration group Same as the 4% Compound A solution ophthalmic group except that the ophthalmic drug was used as the base.

(Test results)
The test results are shown in FIG. The vertical axis represents the intraocular pressure change value (mmHg) from the initial intraocular pressure, and the horizontal axis represents the elapsed time (hr) after administration. The initial intraocular pressures of the base administration group and the 4% Compound A solution administration group were 16.3 mmHg and 16.1 mmHg, respectively. Moreover, data show the average value of 6 animals per group.

  In addition, it is * P <0.05 vs base (Aspin-Welch t test method) in FIG.

  As is clear from FIG. 3, a significant drop in intraocular pressure was confirmed in the 4% Compound A solution ophthalmic group.

(Discussion)
From the above test results, the possibility that an excellent intraocular pressure lowering effect can be obtained by formulating the peptide derivative into an ophthalmic solution and instilling it was shown. Furthermore, it is expected that an excellent intraocular pressure lowering effect can be obtained by formulating the peptide derivative into an eye ointment and putting it into the eye ointment.

[Formulation example]
The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.

(Prescription Example 1)
Eye drops (4% (w / v)) Compound A 4g in 100ml
Sodium chloride 0.9g
Sodium hydrogen phosphate hydrate Appropriate amount Sterilized purified water Appropriate amount Add the compound A and other components to sterilized purified water and mix them thoroughly to prepare eye drops. By changing the compounding amount of Compound A, an ophthalmic solution having a concentration of Compound A of 0.1% (w / v), 0.5% (w / v) or 1% (w / v) can be prepared.

(Prescription example 2)
Eye ointment (4% (w / w)) Compound A 4g in 100g
Liquid paraffin Appropriate amount White petrolatum Appropriate amount An ointment is prepared by adding compound A to uniformly melted white petrolatum and liquid paraffin, and thoroughly cooling them after being mixed well. By changing the compounding amount of Compound A, an ophthalmic solution having a concentration of Compound A of 0.1% (w / w), 0.5% (w / v) or 1% (w / v) can be prepared.

  This peptide derivative is expected to be a new treatment for glaucoma because it strongly and continuously lowers the intraocular pressure of rabbits by intra-anterior administration or instillation.

Claims (9)

A therapeutic agent for glaucoma containing a peptide derivative represented by the following general formula (1) or a salt thereof.

[Wherein, R ¹ represents 2- (2-naphthyl) ethylamino group, 2-naphthylacetyl group, 2-naphthylacetylamino group, 2-naphthylacetylaminomethyl group, 2-naphthoyl group, 2-naphthoylmethyl group 2-naphthoylmethylamino group, 2-naphthoylamino group, 2-naphthoylaminomethyl group, 2-naphthoxyacetyl group, 2-naphthoxyacetylamino group, 2-bromoacetylphenylamino group, 2-chloro Represents 2-phenylacetylamino group or 2-bromo-2-phenylacetylamino group;
X represents a carbon atom or a nitrogen atom;
When X is a carbon atom, the broken line indicates a single bond or a double bond; when X is a nitrogen atom, the broken line indicates a single bond;
Y _-CH 2 is _{-, - CH 2 NH -,} - CH 2 CH 2 NH -, - CH 2 CO- or -CO- indicates;
Z represents Ile or covalent bond;
R ₂ represents a hydrogen atom or a 2-methylbutyl group. ]   The therapeutic agent according to claim 1, wherein, in the general formula (1), Z represents a covalent bond. In the general formula (1),
R ¹ represents a 2-naphthylacetyl group, a 2-naphthoylamino group, a 2-naphthoxyacetyl group, or a 2-naphthoxyacetylamino group;
When X is a carbon atom, the broken line indicates a double bond; when X is a nitrogen atom, the broken line indicates a single bond;
Y is _{-CH 2 NH -, - CH 2} CO- or -CO- indicates;
Z represents a covalent bond;
The therapeutic agent according to claim 1, wherein R ₂ represents a 2-methylbutyl group. The therapeutic agent according to claim 1, wherein the peptide derivative is represented by the following formulas (2) to (25).

The therapeutic agent according to claim 1, wherein the peptide derivative is represented by the following formula (26).

  The therapeutic agent according to claim 1, wherein the therapeutic agent is administered to the anterior segment.   The therapeutic agent according to claim 6, wherein the therapeutic agent is administered by instillation, intraatrial administration, subconjunctival administration, subtenon administration, or conjunctival sac or punctum.   The therapeutic agent according to claim 6, wherein the dosage form is an eye drop, an eye ointment, an injection, an intraocular implant preparation or an insertion agent.   The therapeutic agent according to claim 5, wherein the therapeutic agent is administered to the anterior segment.

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