TW201605451A - Prophylactic or therapeutic agent for age-related macular degeneration - Google Patents

Abstract

The present invention pertains to a prophylactic or therapeutic agent for age-related macular degeneration containing as an active ingredient a compound shown by formula (1), an enantiomer or diastereomer thereof, or a pharmacologically acceptable salt thereof (also referred to as "this compound" below).

Description

Prophylactic or therapeutic agent for age-related macular degeneration

The present invention relates to a prophylactic or therapeutic agent for senile macular degeneration comprising a 3-aminocyclopentanecarboxamide derivative, especially formula (1):

The compound shown, its enantiomer or diastereomer, or a pharmaceutically acceptable salt thereof (hereinafter also referred to as "the present compound") is used as an active ingredient.

Age-related macular degeneration (hereinafter also referred to as "AMD") is one of the main causes of blindness in today's advanced countries, mainly in the elderly over 50 years old. The age-related macular degeneration is caused by the aging of the macula. It can be roughly divided into exudative age-related macular degeneration, atrophic age-related macular degeneration, and early age-related macular degeneration. Among them, the exudative senile macular degeneration is a neovascularization from the choroid in the macular part of the elderly, bleeding or exudative lesions in the retinal pigment epithelium or subretinal, and finally scar tissue (cicatrical) Tissue) disease. On the other hand, atrophic senile macular degeneration is a disease accompanied by atrophy of the macula or accumulation of drusen.

The basic pathological condition of exudative age-related macular degeneration is choroidal neovascularization, which is based on the age-related changes of the retinal pigment epithelial cells, Bruch's membrane, and choroidal vessels of the macula. However, the cause of choroidal angiogenesis is still unclear, and it is still an area to be developed in the future. On the other hand, it is known that early age-related macular degeneration and atrophic age-related macular degeneration are not accompanied by choroidal neovascularization. Furthermore, in the atrophic type of senile macular degeneration, it is determined that the visual acuity is reduced due to degeneration (cell death) of the photoreceptor cells accompanying atrophy, so that photoreceptor cell protection is attracting attention as a new therapeutic system. Patent Document 1).

On the other hand, a 3-aminocyclopentanecarbamamine derivative which is a chemokine receptor regulator is disclosed, and a synthesis example of a plurality of such derivatives is described. Further, the antagonistic effect of the derivative on the chemokine receptor CCR2 and the renal protective effect in the diabetic nephropathy rat model were examined (Patent Document 1).

However, regarding 3-aminocyclopentanecarbamamine derivatives, especially formula (1):

There is no review report on the preventive or therapeutic effects of the indicated compounds, their enantiomers or non-image isomers, or their pharmaceutically acceptable salts (present compounds) on age-related macular degeneration. Furthermore, this compound pair Whether the age-related macular degeneration, atrophic age-related macular degeneration, or exudative age-related macular degeneration has any prophylactic or therapeutic effect, and there is no review report.

[Previous Technical Literature] [Patent Literature]

[Patent Document 1] International Publication No. 2010/061329

[Non-patent literature]

[Non-Patent Document 1] Expert Opin. Ther. Targets, 11(5), 625-639 (2007)

[Summary of the Invention]

An object of the present invention is to provide a prophylactic or therapeutic agent for senile macular degeneration comprising a 3-aminocyclopentanecarbamamine derivative as an active ingredient.

The present inventors discovered and focused on the prevention or treatment of a novel age-related macular degeneration containing a 3-aminocyclopentanecarbamamine derivative as an active ingredient, and found that the compound is in the eye called the retina and the choroid. In the tissue, it has excellent angiogenesis inhibition and vascular hyperpermeability inhibition, and it has been found that this compound has excellent preventive or therapeutic effects on age-related macular degeneration, especially exudative age-related macular degeneration. The present invention has been completed.

That is, the present invention relates to the following matters.

The present invention relates to a prophylactic or therapeutic agent for senile macular degeneration comprising formula (1):

[In the formula (1), R ¹ represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; R ² represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; and R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; R ⁴ represents a nitrogen-containing aromatic ring group of 6 members which is unsubstituted or substituted with R ⁵ ; R ⁵ represents a halogen atom, a lower alkyl group or A compound represented by a halogen atom-substituted lower alkyl group, a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient.

Further, another aspect of the present invention is a prophylactic or therapeutic agent for senile macular dementia, which comprises a compound of the above formula (1), each of which has the following image, a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient, R ¹ represents a lower alkyl group or a lower alkyl group substituted by a halogen atom; R ² represents a hydrogen atom or a lower alkyl group; and R ³ represents a lower alkyl group or is substituted by a halogen atom. Lower alkyl; R ⁴ represents formula (2a) or (2b): R ⁵ represents a lower alkyl group substituted with the halogen atom or a lower alkyl group,

Wherein ‧ in the formula (2a) or (2b) represents a bond point with a nitrogen atom to which R ⁴ is bonded.

Further, another aspect of the present invention is a prophylactic or therapeutic agent for senile macular dementia, which comprises the compound represented by the above formula (1): (1'):

The compound shown or a pharmaceutically acceptable salt thereof is used as an active ingredient.

Further, another aspect of the present invention is a prophylactic or therapeutic agent for senile macular dementia, which comprises a compound of the above formula (1) or formula (1'), each of which has the following composition, a mirror image isomer or a non- a mirror image isomer, or a pharmaceutically acceptable salt thereof, as an active ingredient, R ¹ represents a methyl group; R ² represents a hydrogen atom; R ³ represents an isopropyl group; and R ⁴ represents a formula (2b): R ⁵ represents a trifluoromethyl group; wherein in the formula (2b) ‧ node represents a bond and R ⁴ are bonded to the nitrogen atom.

Further, another aspect of the present invention is a preventive or therapeutic agent which comprises as an effective a compound represented by the above formula (1), a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof A prophylactic or therapeutic agent for senile macular degeneration, wherein the senile macular degeneration is exudative senile macular degeneration.

Further, another aspect of the present invention is a choroidal angiogenesis inhibitor comprising the compound represented by the above formula (1), a mirror image isomer or a non-image thereof, or a pharmaceutically acceptable salt thereof, as Active ingredients.

Further, another aspect of the present invention is a prophylactic or therapeutic agent, or an inhibitor, which comprises a compound represented by the above formula (1), a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable substance thereof The salt is used as an active ingredient for the prevention or treatment of senile macular degeneration. The administration forms are eye-dropping, intravitreal administration, subconjunctival administration, intraconjunctival intracapsular administration, and Tenon capsule. Under the investment or oral investment.

Further, another aspect of the present invention is a prophylactic or therapeutic agent, or an inhibitor, which comprises a compound represented by the above formula (1), a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable substance thereof The salt is used as an active ingredient for the prevention or treatment of senile macular degeneration, and the dosage form is an eye drop, an ophthalmic ointment, an insert, a patch, an injection, a tablet, a fine granule or a capsule.

Furthermore, the present invention also relates to the following matters.

Another aspect of the invention is for senile macular degeneration A compound represented by the above formula (1), a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof, for use in the prevention or treatment.

Further, another aspect of the present invention is the use of a compound represented by the above formula (1), a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof, for use in senile macular degeneration Manufacture of medicine for prevention or treatment.

Further, another aspect of the present invention is a pharmaceutical composition for the prevention or treatment of senile macular dementia, which comprises a therapeutically effective amount of a compound represented by the above formula (1), a mirror image isomer or a non-mirror A construct, or a pharmaceutically acceptable salt thereof and an additive thereof.

Further, another aspect of the present invention is a method for preventing or treating senile macular degeneration comprising administering a compound represented by the above formula (1), a mirror image isomer or a non-mirror thereof. An effective amount of the isomer, or a pharmaceutically acceptable salt thereof.

According to the present invention, there can be provided a prophylactic or therapeutic agent for senile macular degeneration, particularly exudative senile macular degeneration, which comprises a compound represented by the above formula (1), a mirror image isomer or a non-image isomerism thereof. Or a pharmaceutically acceptable salt thereof as an active ingredient.

[Formation of the Invention]

Hereinafter, the present invention will be described in detail.

The "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

"Lower alkyl" means a straight chain of 1 to 8 carbon atoms. Or a branched alkyl group in which a linear or branched alkyl group having 1 to 6 carbon atoms is preferred. Specific examples thereof include methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, n-heptyl group, n-octyl group, isopropyl group, isobutyl group, and secondary butyl group. , tertiary butyl, isopentyl and the like.

"Lower alkyl substituted by halogen atom" means 1 or more A plurality of (e.g., 2 or 3) lower alkyl groups in which a halogen atom is substituted, wherein a lower alkyl group substituted with 3 halogen atoms is preferred. Specific examples include a trifluoromethyl group and the like. Further, in the case where a plurality of halogen atoms are present, the halogen atoms may be the same or different.

"6-membered nitrogen-containing aromatic ring group" means a monocyclic or polycyclic aromatic ring having 6 ring atoms and at least one ring atom of which is a nitrogen atom, wherein one or two nitrogen atoms are used as a ring atom. An aromatic ring is preferred. Specific examples include pyridyl and pyridyl Base, pyrimidinyl, oxime Base.

Prophylactic or therapeutic agent for senile macular degeneration of the present invention The compound to be contained can be produced by a usual method in the field of organic synthetic chemistry. For example, it can be manufactured according to the method described in International Publication No. 2010/061329. Further, the geometric isomer (cis-trans isomer), optical isomer (mirroromer, non-image isomer) or tautomer of the compound can be subjected to column chromatography, The usual method such as HPLC is carried out by separation and purification.

The compound contained in the prophylactic or therapeutic agent for senile macular degeneration of the present invention is of the formula (1):

A compound, a mirror image or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof.

The presence of a geometric isomer (cis-trans isomer), an optical isomer (mirroromer, a non-image isomer) or a tautomer in the compound represented by the above formula (1) These are also included in the range of the compound represented by the formula (1). Further, the compound represented by the formula (1) may be selected from the group consisting of geometric isomers (cis-trans isomers), optical isomers (mirroromers, non-image isomers), and tautomers. A mixture of one or more isomeric species in a group of constructs.

In the above formula (1), R ¹ represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by a halogen atom.

In the above formula (1), R ² represents a hydrogen atom, a lower alkyl group or a lower alkyl group substituted by a halogen atom.

In the above formula (1), R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkyl group substituted by a halogen atom.

In the above formula (1), R ⁴ represents a nitrogen-containing aromatic ring group of 6 members which is unsubstituted or substituted with R ⁵ .

In the above formula (1), R ⁵ represents a halogen atom, a lower alkyl group or a lower alkyl group substituted by a halogen atom.

Preferred examples of each substituent are as follows.

In the above formula (1), R ^{1 is} preferably a lower alkyl group or a lower alkyl group substituted by a halogen atom, particularly preferably a lower alkyl group, and most preferably a methyl group.

In the above formula (1), R ^{2 is} preferably a hydrogen atom or a lower alkyl group, and particularly preferably a hydrogen atom.

In the above formula (1), R ^{3 is} preferably a lower alkyl group or a lower alkyl group substituted by a halogen atom, particularly preferably a lower alkyl group, and most preferably an isopropyl group.

In the above formula (1), R ^{4 is} preferably a formula (2a) or (2b), and particularly preferably a formula (2b).

In the above formula (1), R ^{5 is} preferably a lower alkyl group or a lower alkyl group substituted by a halogen atom, particularly preferably a lower alkyl group substituted by a halogen atom, and most preferably a trifluoromethyl group.

The above formula (1) is preferably the formula (1'):

Specific examples of the compound represented by the above formula (1) or formula (1') include the formula (1a):

1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-isopropyl-3-({(1S,4S)-5-[5-(three) Fluoromethyl) 3-yl]-2,5-diazabicyclo[2,2,1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D-erythro-penta Pentaol (hereinafter also referred to as "Compound 1a"), its mirror image isomers and non-mironomers, and mixtures thereof (for example, racemic mixtures, non-mirrored mixtures, etc.).

Further, specific examples of the compound represented by the above formula (1) or formula (1') include the formula (1b):

1,5-anhydro-2,3-dideoxy-3-{[(1R,3S)-3-isopropyl-3-({(1S,4S)-5-[6-(three) Fluoromethyl)pyrimidin-4-yl]-2,5-diazabicyclo[2,2,1]hept-2-yl}carbonyl)cyclopentyl]amino}-4-O-methyl-D - erythro-pentapentaol (hereinafter also referred to as "compound 1b"), its mirror image isomers and non-image isomers, and mixtures thereof (for example, racemic mixtures, non-mirrored mixtures, etc.).

a compound represented by the above formula (1), (1'), (1a) or (1b) The "pharmaceutically acceptable salt" may, for example, be a salt with an inorganic acid or a salt with an organic acid. Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, and the like. Examples of the organic acid include acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, grape heptanoic acid, glucuronic acid, and terephthalic acid. Methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, Trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfonic acid salicylic acid, and the like.

The compound represented by the above formula (1), (1'), (1a) or (1b) may also be in the form of a hydrate or a solvate.

a compound represented by the above formula (1), (1'), (1a) or (1b) There are cases in which crystalline polymorphisms and crystalline polymorphic groups (crystalline polymorphic systems) exist, and such crystalline polymorphs and crystalline polymorphic groups (crystalline polymorphic systems) are also included in the scope of the compounds of the present invention. Here, the crystalline polymorphic group (crystalline polymorphic system) means various conditions and states of production, crystallization, storage, and the like by this isocrystallization (further, the state of formulation is also included in this state), and various crystal forms occur. In the case of changes, the crystal form in each stage and its entire process.

In the present invention, senile macular lesions are expressed as described above Exudative age-related macular degeneration, atrophic age-related macular degeneration, and early senile macular degeneration of such pre-excited lesions.

The use of this compound in the prevention of age-related macular degeneration Or the treatment may be administered to the patient by oral or non-oral means. In terms of administration form, oral administration, local administration to the eye (point-eye administration, conjunctival sac) may be mentioned. Administration, intravitreal administration, subconjunctival administration, subcapsular injection, etc., intravenous administration, percutaneous administration, etc. For the preferred dosage form for the topical administration of the present compound to the eye, an eye drop or ophthalmic ointment, or an injection may be used, in particular, a subconjunctival administration agent, a sclerotherapy agent or an intravitreal agent may be used. Dosing agent. The preparation containing the present compound as an active ingredient can be formulated into a dosage form suitable for co-administration with a pharmaceutically acceptable additive, as needed. Examples of the dosage form suitable for oral administration include a tablet, a capsule, a granule, a powder, and the like. For a dosage form suitable for parenteral administration, for example, an injection, an eye drop, and an eye are mentioned. Use ointments, patches, gels, inserts, etc. These can be modulated by conventional techniques widely used in the art. Furthermore, in order to more effectively produce the sustained effect of the therapeutic effect of the present invention, it is also possible to make an eye A DDS-formed preparation such as a preparation or microspheres is implanted.

For example, lozenges can be selected and used excipients, disintegration The agent, the binder, the lubricant, the coating agent, the flavoring agent, and the like are prepared. Examples of the excipient include lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose, and the like. Examples of the disintegrator include carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crosslinked polyvinylpyrrolidone, starch, partially gelatinized starch, and low Degree of substitution hydroxypropyl cellulose and the like. Examples of the binder include hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially gelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol, and the like. Examples of the lubricant include magnesium stearate, calcium stearate, talc, aqueous cerium oxide, hardened oil, and the like. Examples of the coating agent include refined white sugar, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, and polyvinylpyrrolidone. Examples of the flavoring agent include citric acid, aspartame, ascorbic acid, menthol, and the like.

For example, an injection can be selected and used as an isotonic agent. It is prepared by an isotonicity agent, a buffering agent, a surfactant, a tackifier, and the like. Examples of the isotonic agent include sodium chloride and the like. Examples of the buffering agent include sodium phosphate and the like. Examples of the surfactant include polyoxyethylene sorbitan monooleate. Examples of the tackifier include methyl cellulose and the like.

For example, eye drops, can be used as needed, buffer The preparation is prepared by a chemical, a surfactant, a stabilizer, a preservative, etc., and the pH is preferably within a range acceptable for the ophthalmic preparation, but it is usually in the range of 4 to 8. For the isotonic agent, for example, Sodium chloride, concentrated glycerin, etc. Examples of the buffering agent include sodium phosphate, sodium acetate, and the like. Examples of the surfactant include polyoxyethylene ethyl sorbitan monooleate, polyoxyl stearate 40, polyoxyethylene hardened castor oil, and the like. Examples of the stabilizers include sodium citrate and sodium edetate. Examples of the preservative include, for example, benzalkonium chloride, paraben, and the like.

For example, ophthalmic ointments can be prepared using a wide base such as white petrolatum or flowing paraffin.

For example, the intercalating agent can be combined with the present compound by a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid or the like. The mixture is pulverized and mixed, and the powder is compression-molded to prepare an excipient, a binder, a stabilizer, and a pH adjuster.

For example, the preparation for intraocular implantation can be prepared by using a biodegradable polymer such as a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid ‧ glycolic acid copolymer or hydroxypropyl cellulose.

The dosage of the compound may be appropriately changed depending on the dosage form, the severity of the symptoms of the patient to be administered, the age, the body weight, the volume of the eyeball, the judgment of the physician, etc., but in the case of oral administration, in general, For adults, 0.01 to 10000 mg, preferably 0.1 to 5000 mg, more preferably 0.5 to 2500 mg, once or divided into several doses per day; in the case of injections, in general, for adults, 0.0001 to 2000 mg 1 Or divided into several times. Further, in the case of an eye drop or an insertion agent, the active ingredient concentration may be 0.000001 to 10% (w/v), preferably 0.00001~. 1% (w/v), preferably 0.0001 to 0.1% (w/v), is administered once a day or in divided doses. Furthermore, in the case of a patching agent, for adults, a patch containing 0.0001 to 2000 mg may be applied; in the case of an intraocular implant preparation, for an adult, an intraocular implant containing 0.0001 to 2000 mg may be contained. The preparation is implanted into the eye.

[Examples]

The results of the pharmacological test and the formulation examples are shown below, but these examples are only intended to make the present invention easier to understand and not to limit the scope of the present invention.

[Pharmacological test 1]

The usefulness of the present compounds was evaluated using a laser-induced choroidal angiogenesis model in rats (Invest. Ophthalmol. Vis. Sci., 40(2), 459-466 (1999)).

(氪Lao-induced choroidal angiogenesis model in rats)

5% (w/v) ketamine hydrochloride injection and 2% toluene hydrochloride A mixture of (xylazine hydrochloride) injection (7:1) was intramuscularly administered to the rats in an amount of 1 mL/kg, and general anesthesia was performed with 0.5% (w/v) tropicamide- After 0.5% phenylephrine hydrochloride eye drops were dilated, the photocoagulation was carried out by a krypton laser photocoagulation apparatus. The photocoagulation system is partially behind the fundus, avoiding the thick retinal blood vessels, focusing on the deep layer of the retina, and performing it in a dispersed manner at 8 points per eye (coagulation conditions: spot size 100 μm, output 100 mW, solidification time 0.1 second) . After the photocoagulation, fundus photography is performed to confirm the laser irradiation site.

(test compound)

In the present pharmacological test, the above compound 1b synthesized according to the synthesis method described in International Publication No. 2010/061329 is used for the present compound.

(drug administration method)

The compound 1b is mixed with a 1% (w/v) methylcellulose solution (prepared by dissolving methylcellulose in purified water) at a ratio of 0.2 and 2 mg/mL, and a solution containing the compound 1b is contained. In the amount of 1 and 10 mg/kg, oral administration was carried out twice a day for 7 days from the day of the surgery including the photocoagulation surgery day. Further, the base administration group administered 1% (w/v) methylcellulose solution in the same manner.

(evaluation method)

On the 7th day after photocoagulation, 5% (w/v) ketamine hydrochloride injection and 2% toluene hydrochloride The mixture of injections (7:1) was intramuscularly administered to the rats at 1 mL/kg, and general anesthesia was performed with 0.5% (w/v) tropamide-0.5% phenylephrine hydrochloride eye drops. After the eye was dilated, 0.1 mL of a 10% luciferin solution was injected from the penile vein to perform fundus fundus angiography. By fluorescence fundus angiography, the spot where no fluorescence leaked was judged to be negative (no angiogenesis), and the spot where the luminescence leaked was judged to be positive. Further, a part of the light-solidified portion where the fluorescent light leaked out appeared, and when it was present at two places, it was judged to be positive (with angiogenesis). Then, according to Formula 1, the incidence rate (%) of choroidal angiogenesis is calculated from the number of positive spots of the light spot at 8 points of the laser irradiation, and the inhibition rate (%) of the evaluation drug is calculated according to Formula 2. The results of the compound 1b are shown in Table 1. Furthermore, the number of cases for each of the voting groups is 6 to 8.

[Formula 1]: incidence of choroidal angiogenesis (%) = (number of positive spots / number of all-photocoagulation sites) × 100

[Formula 2]: Inhibition rate (%) = {(A ₀ - Ax) / A ₀ } × 100

A ₀ : incidence of choroidal angiogenesis in the base administration group

Ax: incidence of choroidal angiogenesis in the drug-administered group

As shown in Table 1, Compound 1b inhibited choroidal neovascularization in a laser-induced choroidal angiogenesis model in rats. From the above results, it was revealed that the present compound has an excellent angiogenesis inhibitory effect in the choroid, and has an excellent preventive or therapeutic effect on senile macular lesions, particularly exudative senile macular degeneration.

[Formulation Example]

The formulation examples are listed to more specifically describe the agent of the present invention, but the present invention is not limited only to such formulation examples.

Prescription Example 1 Eye Drops

100mL

Adding this compound to sterile water The components are thoroughly mixed and prepared into an eye drop. An eye drop having a concentration of 0.05% (w/v) to 1% (w/v) can be prepared by changing the amount of the compound added.

Prescription Example 2 Ophthalmic Ointment

100g

In uniformly melted white petrolatum and mobile paraffin, This compound was added, and these were sufficiently mixed, and then slowly cooled to prepare an ophthalmic ointment. An ophthalmic ointment having a concentration of 0.05% (w/v) to 1% (w/w) can be prepared by changing the amount of the compound added.

Prescription Example 3 Lozenges

100mg

Mixing the compound and lactose in a mixer and mixing them in the mixture The carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated, and the obtained granules are dried and granulated, and magnesium stearate is added to the granules and mixed, and then the tableting machine is used. Make ingots. Further, by appropriately changing the amount of the compound, carboxymethylcellulose calcium and hydroxypropylcellulose added, it is possible to prepare a tablet having a content of the present compound in an amount of from 0.1 mg to 50 mg in 100 mg.

Formulation Example 4 Injection or intravitreal administration agent

In 10mL

Adding this compound to sterile water The ingredients are thoroughly mixed and dissolved or suspended to prepare an injection. An injection of 10 mg of the present compound in an amount of 2 mg to 200 mg can be prepared by appropriately changing the addition amount of the present compound and the above-mentioned components. The injection prepared in this manner can be administered as an injection for intraocular administration, for example, an intravitreal administration.

Claims (8)

A prophylactic or therapeutic agent for senile macular degeneration comprising formula (1): [In the formula (1), R ¹ represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; R ² represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; and R ³ represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom; R ⁴ represents a nitrogen-containing aromatic ring group of 6 members which is unsubstituted or substituted with R ⁵ ; and R ⁵ represents a halogen atom, a lower alkyl group or A compound represented by a halogen atom-substituted lower alkyl group, a mirror image isomer or a non-image isomer thereof, or a pharmaceutically acceptable salt thereof is used as an active ingredient. The prophylactic or therapeutic agent according to claim 1, wherein, in the formula (1), R1 represents a lower alkyl group or a lower alkyl group substituted with a halogen atom; R2 represents a hydrogen atom or a lower alkyl group; and R3 represents a lower alkyl group or a halogen atom. Substituted lower alkyl; R4 represents formula (2a) or (2b): R5 represents a lower alkyl group or a lower alkyl group substituted with a halogen atom. A prophylactic or therapeutic agent according to claim 1 or 2, wherein formula (1) represents formula (1'): The requested item 1-3 prophylactic or therapeutic agent of any one of, wherein in Formula (1) or Formula ⁽¹ '), R 1 represents a methyl group; R ² represents a hydrogen atom; R ³ represents an isopropyl group; R ⁴ Expression (2b): R ⁵ represents a trifluoromethyl group. The prophylactic or therapeutic agent according to any one of claims 1 to 4, wherein the senile macular lesion is exudative senile macular degeneration. A choroidal angiogenesis inhibitor comprising the compound represented by the above formula (1), a mirror image isomer or a non-image thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. The prophylactic or therapeutic agent, or inhibitor, according to any one of claims 1 to 6, which is administered in the form of eyedrop administration, intravitreal administration, subconjunctival administration, intraconjunctival administration, and sac ( Tenon capsule) is administered or administered orally. A prophylactic or therapeutic agent, or an inhibitor, according to any one of claims 1 to 7, which is in the form of an eye drop, an ophthalmic ointment, an insert, a patch, an injection, a troche, a fine granule or a capsule.