JP2018104412A - Therapeutic and/or preventive agent of eye disease - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide compounds showing a therapeutic and/or preventive effect to eye diseases.SOLUTION: The therapeutic and/or preventive agent of eye diseases contains 4-{[(1R,2s,3S,5s,7s)-5-hydroxy-2-adamantyl]amino}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide represented by the following formula or a salt thereof, the eye diseases being age-related macular degeneration, diabetic retinopathy, diabetes macular edema, proliferation diabetic retinopathy, retinopathy of prematurity, retinal venous occlusion, Corts disease, macular telangiectasia, uveitis, scleritis, retinitis, optic neuritis, and rejection at the time of a cell allotransplantation.SELECTED DRAWING: None

Description

  The present invention relates to 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof. The present invention relates to a therapeutic and / or prophylactic agent for ophthalmic diseases.

  Janus kinase (JAK) present in cells is deeply involved in the production of inflammatory cytokines, and it is known that JAK activation is involved in the development of various diseases. Therefore, a JAK inhibitor that inhibits intracellular signal transduction by JAK is useful as a pharmaceutical. For example, tofacitinib is used as a therapeutic agent for rheumatoid arthritis, and ruxolitinib is used as a therapeutic agent for myelofibrosis.

  In addition, many JAK inhibitors are in clinical development stage, for example, INCB18424, INCB28050, AC430, AZD1480, GLPG0634, GSK2586184, R348, VX509, CYT387, ABT-494, PRT062070, etc., cancer, leukemia, rheumatoid arthritis, clone Approved as a therapeutic agent for diseases, myelofibrosis, polycythemia vera, etc., or in clinical development. However, in the ophthalmology field, R348 has only been clinically developed as a treatment for dry eye in GVHD patients.

  JAK is classified into subtypes of JAK1, JAK2, JAK3, and TYK2 based on differences in functions and the like. 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide exhibits excellent JAK3 inhibitory activity. It is known that it is useful as an active ingredient of a therapeutic and / or preventive agent for immune diseases (Patent Document 1), and its hydrobromide is clinically developed as a therapeutic agent for rheumatoid arthritis. . Oral containing 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof A pharmaceutical composition for administration has been reported (Patent Document 2, Patent Document 3). However, clinical development as an agent for the treatment and / or prevention of eye diseases has never been made, and 4-{[(1R, 2s, 3S, 5s, 7s) useful for the treatment and / or prevention of eye diseases. There are no reports on the route of administration of -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or its salts. Also, VEGF inhibition of 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof There is no report about an effect.

International Publication WO2007 / 077949 Pamphlet International publication WO2013 / 147135 pamphlet International Publication WO2014 / 157603 Pamphlet

  An object of the present invention is to find a new compound effective for the treatment and / or prevention of an eye disease.

  In order to solve the above-mentioned problems, the present inventors have intensively studied the effect of various compounds on eye diseases, and as a result, although other JAK inhibitors did not show an effect, 4-{[(1R , 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof, which is used to treat ophthalmic diseases by intravitreal administration and The inventors have found that the present invention has a preventive effect and completed the present invention.

  That is, the present invention relates to the following.

(1) Contains 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof A therapeutic and / or preventive agent for eye diseases.

(2) Eye diseases are age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, choroidal neovascularization in pathological myopia, Corts The therapeutic and / or prophylactic agent according to (1) above, which is a disease, macular telangiectasia, uveitis, scleritis, retinitis, optic neuritis or rejection at the time of allogeneic cell transplantation.

(3) The therapeutic and / or prophylactic agent according to (2) above, wherein the uveitis is non-infectious uveitis.

(4) Non-infectious uveitis is sarcoidosis, Vogt-Koyanagi-Harada disease, Behcet's disease, acute anterior uveitis, iritis, ciliary inflammation, scleritis, episclerosis, Fuchs iris discoloration (3), which is uveitis associated with idiopathic iridocyclitis, ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease or Posner-Schlossmann syndrome Treatment and / or prevention agent.

(5) The therapeutic and / or prophylactic agent according to (1) above, wherein the ocular disease is a disease accompanied by increased vascular permeability.

(6) The therapeutic and / or prophylactic agent according to (1) above, wherein the ocular disease is a disease associated with retinal neovascularization or choroidal neovascularization.

(7) The therapeutic and / or prophylactic agent according to (1) above, wherein the eye disease is a VEGF-related disease.

(8) The therapeutic and / or prophylactic agent according to any one of (1) to (7), for local ocular administration.

(9) The therapeutic and / or prophylactic agent according to (8) above, which is an injection for intravitreal administration.

(10) 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof is changed to 0. The therapeutic and / or prophylactic agent according to any one of (1) to (9), comprising 0.01 to 15% (w / v).

(11) 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof and a medicine A pharmaceutical composition for treating and / or preventing ophthalmic diseases, which contains an additive acceptable as an active ingredient.

(12) 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2, for use in the treatment and / or prevention of eye diseases 3-b] Pyridine-5-carboxamide or a salt thereof.

(13) 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- for the manufacture of a medicament for the treatment and / or prevention of eye diseases Use of pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof.

(14) A method for treating and / or preventing ophthalmic diseases, wherein an effective amount of 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo A method comprising administering [2,3-b] pyridine-5-carboxamide or a salt thereof to a subject in need thereof.

  Note that two or more of the configurations (1) to (14) can be arbitrarily selected and combined.

  The therapeutic and / or prophylactic agent of the present invention is useful as a therapeutic and / or prophylactic agent for ophthalmic diseases because it exhibits excellent therapeutic and / or prophylactic effects for ocular diseases. In particular, the therapeutic and / or prophylactic agent of the present invention is desirably administered intravitreally.

  Hereinafter, embodiments of the present invention will be described in detail. Hereinafter, unless otherwise specified, the “treatment and / or prevention agent” of the present invention is simply expressed as “therapeutic agent”.

で表される化合物であり（ＣＡＳ登録番号；９４４１１８−０１−８）、ＡＳＰ０１５Ｋ、ＰＥＦＩＣＩＴＩＮＩＢともいう。本化合物は、４−｛［（１Ｒ，２ｓ，３Ｓ，５ｓ，７ｓ）−５−ヒドロキシ−２−アダマンチル］アミノ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジン−５−カルボキサミドのエナンチオマー及び／又はジステレオマーを含んでもよく、好ましくは実質的に純粋な４−｛［（１Ｒ，２ｓ，３Ｓ，５ｓ，７ｓ）−５−ヒドロキシ−２−アダマンチル］アミノ｝−１Ｈ−ピロロ［２，３−ｂ］ピリジン−５−カルボキサミドである。本化合物は、国際公開ＷＯ２００７／０７７９４９号パンフレットに記載の方法、又は当該技術分野における通常の方法等に従って製造することができる。 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5 contained in the therapeutic agent of the present invention -Carboxamide or a salt thereof (hereinafter also referred to as the present compound) is represented by the following formula (1):

(CAS registration number; 944118-01-8), also referred to as ASP015K and PEFICITINIB. The compound comprises an enantiomer of 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide and / or Or may contain diastereomers, preferably substantially pure 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3 -B] Pyridine-5-carboxamide. This compound can be produced according to the method described in the pamphlet of International Publication No. WO2007 / 077949, or a normal method in the technical field.

  The salt of the present compound contained in the therapeutic agent of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt. For example, a salt with an inorganic acid, a salt with an organic acid, a quaternary ammonium salt, a salt with a halogen ion, a salt with an alkali metal, a salt with an alkaline earth metal, a metal salt, a salt with an organic amine, etc. It is done. Examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Salts with organic acids include acetic acid, oxalic acid, fumaric acid, maleic acid, succinic acid, malic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, alanine , Lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, gallic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p- Examples thereof include salts with toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid, sulfosalicylic acid and the like. Examples of quaternary ammonium salts include salts with methyl bromide, methyl iodide and the like. Salts with halogen ions include salts with chloride ions, bromide ions, iodide ions, etc. Salts with alkali metals include salts with lithium, sodium, potassium, etc., alkaline earths Examples of the salt with metal include salts with calcium, magnesium and the like, and examples of the metal salt include salts with iron, zinc and the like. Examples of salts with organic amines include triethylenediamine, 2-aminoethanol, 2,2-iminobis (ethanol), 1-deoxy-1- (methylamino) -2-D-sorbitol, 2-amino-2- (hydroxy And salts with methyl) -1,3-propanediol, procaine, N, N-bis (phenylmethyl) -1,2-ethanediamine and the like. As the salt of the present compound contained in the therapeutic agent of the present invention, a hydrobromide salt is particularly preferable.

  Moreover, this compound or its salt may take the form of the hydrate or the solvate.

  The content of the present compound or a salt thereof contained in the therapeutic agent for ophthalmic diseases of the present invention is not particularly limited. For example, in the case of injections (intravitreal administration, intraatrial administration and subconjunctival administration are preferred) The lower limit is preferably 0.01% (w / v), more preferably 0.1% (w / v), still more preferably 0.2% (w / v), and 0.5% (w / v). Is particularly preferable, 1% (w / v) is most preferable, and the upper limit is preferably 15% (w / v), more preferably 10% (w / v), still more preferably 7% (w / v), 6% (w / v) is particularly preferred and 5% (w / v) is most preferred. More specifically, the content is preferably 0.01 to 15% (w / v), more preferably 0.1 to 10% (w / v), further 0.2 to 7% (w / v). Preferably, 0.5 to 6% (w / v) is particularly preferable, and 1 to 5% (w / v) is most preferable. In the case of eye drops, the lower limit is preferably 0.001% (w / v), more preferably 0.01% (w / v), still more preferably 0.05% (w / v), 0.1% (W / v) is particularly preferable, 0.3% (w / v) is most preferable, and the upper limit is preferably 10% (w / v), more preferably 5% (w / v), and 3% (w / V) is more preferable, 2% (w / v) is particularly preferable, and 1% (w / v) is most preferable. More specifically, the content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), and even more preferably 0.05 to 3% (w / v). Preferably, 0.1 to 2% (w / v) is particularly preferable, and 0.3 to 1% (w / v) is most preferable.

  The content of the present compound or a salt thereof contained in the therapeutic agent for VEGF-related diseases of the present invention is not particularly limited. For example, in the case of an injection (intravitreal administration, intracameral administration, and subconjunctival administration are preferred) The lower limit is preferably 0.01% (w / v), more preferably 0.1% (w / v), still more preferably 0.2% (w / v), and 0.5% (w / v). ) Is particularly preferred, 1% (w / v) is most preferred, and the upper limit is preferably 15% (w / v), more preferably 10% (w / v), and even more preferably 7% (w / v). 6% (w / v) is particularly preferable, and 5% (w / v) is most preferable. More specifically, the content is preferably 0.01 to 15% (w / v), more preferably 0.1 to 10% (w / v), further 0.2 to 7% (w / v). Preferably, 0.5 to 6% (w / v) is particularly preferable, and 1 to 5% (w / v) is most preferable. In the case of eye drops, the lower limit is preferably 0.001% (w / v), more preferably 0.01% (w / v), still more preferably 0.05% (w / v), 0.1% (W / v) is particularly preferable, 0.3% (w / v) is most preferable, and the upper limit is preferably 10% (w / v), more preferably 5% (w / v), and 3% (w / V) is more preferable, 2% (w / v) is particularly preferable, and 1% (w / v) is most preferable. More specifically, the content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), and even more preferably 0.05 to 3% (w / v). Preferably, 0.1 to 2% (w / v) is particularly preferable, and 0.3 to 1% (w / v) is most preferable.

  The content of the present compound or a salt thereof contained in the therapeutic agent for uveitis of the present invention is not particularly limited. For example, in the case of an injection (intravitreal administration, intraatrial administration and subconjunctival administration are preferred) Specifically, the lower limit is preferably 0.01% (w / v), more preferably 0.1% (w / v), further preferably 0.2% (w / v), 0.5% ( w / v) is particularly preferred, and 1% (w / v) is most preferred. The upper limit is preferably 15% (w / v), more preferably 10% (w / v), still more preferably 5% (w / v), particularly preferably 4% (w / v)) and 3% (w / V) is most preferred. More specifically, the content is preferably 0.01 to 15% (w / v), more preferably 0.1 to 10% (w / v), and further preferably 0.2 to 5% (w / v). Preferably, 0.5 to 4% (w / v) is particularly preferable, and 1 to 3% (w / v) is most preferable. In the case of eye drops, the lower limit is preferably 0.001% (w / v), more preferably 0.01% (w / v), still more preferably 0.05% (w / v), 0.1% (W / v) is particularly preferable, 0.3% (w / v) is most preferable, and the upper limit is preferably 10% (w / v), more preferably 5% (w / v), and 3% (w / V) is more preferable, 2% (w / v) is particularly preferable, and 1% (w / v) is most preferable. More specifically, the content is preferably 0.001 to 10% (w / v), more preferably 0.01 to 5% (w / v), and even more preferably 0.05 to 3% (w / v). Preferably, 0.1 to 2% (w / v) is particularly preferable, and 0.3 to 1% (w / v) is most preferable.

  In this invention, the said content in the case of being the salt of this compound, or the hydrate or solvate of this compound or its salt is calculated based on the mass of this compound which is a free body. Here, “% (w / v)” means the mass (g) of the target component (here, the present compound or a salt thereof) contained in 100 mL of the therapeutic agent. For example, 0.01% (w / v) of the present compound means that the content of the present compound contained in 100 mL of the therapeutic agent is 0.01 g. The same applies when the target component is an additive such as a surfactant.

  In the therapeutic agent of the present invention, additives can be used as necessary. The additive is not particularly limited as long as it is an additive that can be used as a pharmaceutical product. For example, surfactants, buffers, tonicity agents, stabilizers, preservatives, antioxidants, thickening agents, A pH adjuster or the like can be added.

  In the therapeutic agent of the present invention, a surfactant that can be used as a pharmaceutical additive can be appropriately blended.

  Examples of surfactants include polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, vitamin E TPGS, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene glycol, sucrose fatty acid ester Polyoxyethylene sorbitan fatty acid ester is preferable, and polysorbate 80 is more preferable.

  More specifically, as polyoxyethylene castor oil, various polyoxyethylene castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 5 to 100, and preferably 20 to 50. More preferably, 30 to 40 is particularly preferable, and 35 is most preferable. Specific examples of polyoxyethylene castor oil include polyoxyl 5 castor oil, polyoxyl 9 castor oil, polyoxyl 15 castor oil, polyoxyl 35 castor oil, polyoxyl 40 castor oil, and the like.

  As the polyoxyethylene hydrogenated castor oil, various polyoxyethylene hydrogenated castor oils having different polymerization numbers of ethylene oxide can be used, and the polymerization number of ethylene oxide is preferably 10 to 100, more preferably 20 to 80, and 40 ~ 70 is particularly preferred and 60 is most preferred. Specific examples of the polyoxyethylene hydrogenated castor oil include polyoxyethylene hydrogenated castor oil 10, polyoxyethylene hydrogenated castor oil 40, polyoxyethylene hydrogenated castor oil 50, polyoxyethylene hydrogenated castor oil 60, and the like.

  Examples of the polyoxyethylene sorbitan fatty acid ester include polysorbate 80, polysorbate 65, polysorbate 60, polysorbate 40, polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan trioleate and the like, and polysorbate 80 is most preferable.

  Vitamin E TPGS is also referred to as tocopherol polyethylene glycol 1000 succinate.

  Examples of polyoxyethylene fatty acid esters include polyoxyl 40 stearate.

  As polyoxyethylene polyoxypropylene glycol, polyoxyethylene (160) polyoxypropylene (30) glycol, polyoxyethylene (42) polyoxypropylene (67) glycol, polyoxyethylene (54) polyoxypropylene (39) And glycol, polyoxyethylene (196) polyoxypropylene (67) glycol, polyoxyethylene (20) polyoxypropylene (20) glycol and the like.

  Examples of the sucrose fatty acid ester include sucrose stearate ester.

  When a surfactant is added to the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of the surfactant, etc., but is preferably 0.001 to 10% (w / v). 01 to 5% (w / v) is more preferable, 0.05 to 3% (w / v) is more preferable, and 0.1 to 1% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with a buffering agent that can be used as a pharmaceutical additive.

  Examples of the buffer include phosphoric acid or a salt thereof, boric acid or a salt thereof, citric acid or a salt thereof, acetic acid or a salt thereof, carbonic acid or a salt thereof, tartaric acid or a salt thereof, ε-aminocaproic acid, trometamol, and the like. . More specifically, examples of the phosphate include sodium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium phosphate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, and boric acid. Examples of the salt include borax, sodium borate, and potassium borate. Examples of the citrate include sodium citrate, disodium citrate, and trisodium citrate. Examples of the acetate include sodium acetate. And potassium acetate. Examples of the carbonate include sodium carbonate and sodium bicarbonate. Examples of the tartrate include sodium tartrate and potassium tartrate.

  When a buffering agent is blended with the therapeutic agent of the present invention, its content can be appropriately adjusted depending on the type of buffering agent, etc., but is preferably 0.001 to 10% (w / v), 0.01 to 5% (w / v) is more preferable, 0.1 to 3% (w / v) is more preferable, and 0.2 to 2% (w / v) is most preferable.

  In the therapeutic agent of the present invention, an isotonic agent that can be used as a pharmaceutical additive can be appropriately blended.

Examples of isotonic agents include ionic and nonionic tonicity agents.
Examples of the ionic tonicity agent include sodium chloride, potassium chloride, calcium chloride, and magnesium chloride. Examples of the nonionic tonicity agent include glycerin, propylene glycol, sorbitol, mannitol, and the like. preferable.

  When a tonicity agent is blended with the therapeutic agent of the present invention, its content can be adjusted as appropriate depending on the type of tonicity agent, etc., but is preferably 0.01 to 10% (w / v), 0.1 to 7% (w / v) is more preferable, 0.5 to 5% (w / v) is more preferable, and 1 to 3% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with a stabilizer that can be used as an additive for pharmaceuticals.

  Examples of stabilizers include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, with disodium edetate being particularly preferred. The edetate sodium may be a hydrate.

  When a stabilizer is added to the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of the stabilizer, etc., but is preferably 0.001 to 1% (w / v), 005 to 0.5% (w / v) is more preferable, and 0.01 to 0.1% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with a preservative that can be used as an additive for pharmaceuticals.

  Examples of preservatives include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.

  When a preservative is blended in the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of the preservative, etc., but is preferably 0.0001 to 1% (w / v), 0.0005 to 0.1% (w / v) is more preferable, 0.001 to 0.05% (w / v) is further preferable, and 0.005 to 0.01% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with an antioxidant that can be used as a pharmaceutical additive.

  Examples of antioxidants include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.

  When an antioxidant is blended with the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of the antioxidant, etc., but is preferably 0.0001 to 1% (w / v). 0005 to 0.1% (w / v) is more preferable, and 0.001 to 0.05% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with a thickening agent that can be used as an additive for pharmaceuticals.

  Examples of thickening agents include methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, Examples thereof include carboxymethyl ethyl cellulose, cellulose acetate phthalate, polyvinyl pyrrolidone, polyvinyl alcohol, carboxy vinyl polymer, polyethylene glycol and the like.

  When a thickening agent is blended in the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of the thickening agent, etc., but 0.001 to 5% (w / v) is preferable, 0.01 to 1% (w / v) is more preferable, and 0.1 to 0.5% (w / v) is most preferable.

  The therapeutic agent of the present invention can be appropriately mixed with a pH adjuster that can be used as a pharmaceutical additive.

  Examples of the pH adjusting agent include hydrochloric acid, phosphoric acid, citric acid, acetic acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogen carbonate and the like.

  The pH of the therapeutic agent of the present invention is, for example, 4.0 to 9.0, preferably 4.5 to 7.5, and most preferably 5.0 to 7.0.

  The therapeutic agent of the present invention can be administered either orally or parenterally, and in the case of parenteral, it can be administered topically to the eye. These preparations do not require a special technique, and can be prepared using a widely used technique. Examples of the dosage form include eye drops, eye ointments, ophthalmic injections, tablets, capsules, granules, powders, etc. Eye drops, eye ointments, ophthalmic injections are preferable, and ophthalmic injections are more preferable. Preferably, an injection for intravitreal administration, intraanterior administration or subconjunctival administration is more preferred, and an injection for intravitreal administration is most preferred. When the therapeutic agent of the present invention is a liquid agent, it may be a suspension or emulsion in addition to a solution, and the solvent or dispersion medium is preferably water.

  The therapeutic agent of the present invention can be stored in containers made of various materials. For example, containers made of glass, polyethylene, polypropylene, or the like can be used.

  The dosage of the therapeutic agent for ophthalmic diseases of the present invention is not particularly limited as long as it is a dosage sufficient for achieving a desired drug effect, depending on the symptom of the disease, the age and weight of the patient, the dosage form of the drug, etc. It can be selected as appropriate. For example, in the case of an injection for intravitreal or anterior chamber administration, 1 to 100 μL is preferable, 1 to 70 μL is more preferable, 1.5 to 60 μL is further preferable, and 2 to 50 μL is most preferable. In the case of an injection for subconjunctival administration, 10 to 1000 μL is preferable, 20 to 800 μL is more preferable, 50 to 700 μL is more preferable, and 100 to 500 μL is most preferable. The dose of this compound is preferably 0.0001 to 30 mg / eye, more preferably 0.0005 to 10 mg / eye, further preferably 0.001 to 5 mg / eye, and most preferably 0.005 to 3 mg / eye. In the case of eye drops, the dose is 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop 1 to 4 times a day, preferably 1 to 3 drops a day. Daily, preferably once or twice a day, more preferably once or twice a day, and once a day. It is preferable to administer 1 to 2 drops per day, 1 to 2 drops per day, more preferably 1 to 2 drops per day. Here, one drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, and more preferably about 0.02 to about 0.05 mL. Yes, particularly preferably about 0.03 mL.

  The dosage of the therapeutic agent for VEGF-related diseases of the present invention is not particularly limited as long as it is a dosage sufficient for achieving a desired drug effect, and depends on the disease symptoms, patient age and weight, drug dosage form, and the like. Can be selected as appropriate. For example, in the case of an injection for intravitreal or anterior chamber administration, 1 to 100 μL is preferable, 1 to 70 μL is more preferable, 1.5 to 60 μL is further preferable, and 2 to 50 μL is most preferable. In the case of an injection for subconjunctival administration, 10 to 1000 μL is preferable, 20 to 800 μL is more preferable, 50 to 700 μL is more preferable, and 100 to 500 μL is most preferable. The dose of this compound is preferably 0.0001 to 30 mg / eye, more preferably 0.0005 to 10 mg / eye, further preferably 0.001 to 5 mg / eye, and most preferably 0.005 to 3 mg / eye. In the case of eye drops, the dose is 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop 1 to 4 times a day, preferably 1 to 3 drops a day. Daily, preferably once or twice a day, more preferably once or twice a day, and once a day. It is preferable to administer 1 to 2 drops per day, 1 to 2 drops per day, more preferably 1 to 2 drops per day. Here, one drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, and more preferably about 0.02 to about 0.05 mL. Yes, particularly preferably about 0.03 mL.

  The dosage of the therapeutic agent for uveitis of the present invention is not particularly limited as long as it is a dosage sufficient for achieving the desired drug effect, and depends on the symptom of the disease, the age and weight of the patient, the dosage form of the drug, etc. Can be selected as appropriate. For example, in the case of an injection for intravitreal administration or intraanterior administration, 1 to 100 μL is preferable, 2 to 70 μL is more preferable, 3 to 60 μL is more preferable, and 4 to 50 μL is most preferable. In the case of an injection for subconjunctival administration, 10 to 1000 μL is preferable, 20 to 800 μL is more preferable, 50 to 700 μL is more preferable, and 100 to 500 μL is most preferable. The dose of this compound is preferably 0.001 to 30 mg / eye, more preferably 0.005 to 10 mg / eye, still more preferably 0.01 to 5 mg / eye, and most preferably 0.05 to 3 mg / eye. In the case of eye drops, the dose is 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop 1 to 4 times a day, preferably 1 to 3 drops a day. Daily, preferably once or twice a day, more preferably once or twice a day, and once a day. It is preferable to administer 1 to 2 drops per day, 1 to 2 drops per day, more preferably 1 to 2 drops per day. Here, one drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, and more preferably about 0.02 to about 0.05 mL. Yes, particularly preferably about 0.03 mL.

  When the therapeutic agent of the present invention is administered continuously in the vitreous, in the anterior chamber or under the conjunctiva, the administration interval is not particularly limited as long as it is sufficient to achieve a desired drug effect, but once to 3 times a week. Preferably once a year, once a week, once every two weeks, once a month, once every two months, once every three months, once every four months, More preferably, once every 5 months, once every 6 months, once a year, once every 2 years or once every 3 years, once every 2 months, and once every 3 months Most preferably, it is administered once, every 4 months, once every 5 months, or once every 6 months. In addition, the administration interval can be appropriately changed.

  When the therapeutic agent of the present invention is an eye drop, the therapeutic agent of the present invention is, for example, 1 to 5 drops, preferably 1 to 3 drops, more preferably 1 to 2 drops, particularly preferably 1 drop. 1 to 4 times a day, preferably 1 to 3 times a day, more preferably 1 to 2 times a day, particularly preferably once a day, daily to weekly, preferably daily. . It is preferable to administer one drop once a day daily. Here, one drop is usually about 0.01 to about 0.1 mL, preferably about 0.015 to about 0.07 mL, and more preferably about 0.02 to about 0.05 mL. Yes, particularly preferably about 0.03 mL.

  The therapeutic agent of the present invention can be used as a therapeutic and / or prophylactic agent for eye diseases. There are no particular limitations on the type of ocular disease, but diseases involving increased vascular permeability, diseases involving angiogenesis (particularly diseases involving retinal neovascularization or choroidal neovascularization), VEGF-related diseases, etc. Macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, choroidal neovascularization in pathological myopia, Corts disease, macular telangiectasia, Uveitis (eg non-infectious uveitis, especially sarcoidosis, forked-Koyanagi-Harada disease, Behcet's disease, acute anterior uveitis, iritis, ciliary inflammation, scleritis, episclitis, Fuchs Uveitis with iris iridid iriditis, ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, Posner-Schlossmann syndrome, etc. , Scleritis, retinitis, optic neuritis, and a rejection or the like at the time allogeneic cell transplantation. In addition, the eye disease is not particularly limited in the onset site, and examples thereof include an external eye disease, an internal eye disease, an anterior eye disease, and a posterior eye disease.

  The therapeutic agent of the present invention can be used as a therapeutic and / or prophylactic agent for VEGF-related diseases. A VEGF-related disease is a disease in which VEGF is related to the cause or progression of a disease state, and there is no particular limitation on the type thereof, but cancer (for example, colorectal cancer, non-small cell lung cancer, breast cancer), rheumatoid arthritis, and autologous psoriasis. , Atherosclerosis, age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, choroidal neovascularization in pathological myopia, Corts Disease, macular telangiectasia, etc., age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, pathological myopia In particular, choroidal neovascularization, Corts disease, and macular telangiectasia are preferred.

  The therapeutic agent of the present invention can be used as a therapeutic and / or prophylactic agent for uveitis. Although there is no restriction | limiting in particular in the kind of uveitis, Non-infectious uveitis is preferable. Non-infectious uveitis is uveitis excluding infectious uveitis that is suspected of being infected with bacteria, fungi, parasites, viruses, etc. in the local area of the eye. Examples of meningitis include sarcoidosis, Vogt-Koyanagi-Harada disease, Behcet's disease, acute anterior uveitis, iritis, ciliary inflammation, scleritis, suprasclerosis, Fuchs iris iridescent Examples include uveitis associated with somatitis, ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease, Posner-Schlossmann syndrome and the like. Uveitis is not particularly limited by any of anterior uveitis, intermediate uveitis, posterior uveitis, panuveitis, but intermediate uveitis, posterior uveitis, panvine Membranitis is preferred.

  The therapeutic agent for eye diseases of the present invention contains one or more, preferably 1 to 3, more preferably 1 or 2, other therapeutic and / or preventive agents for eye diseases other than the present compound. It may be used in combination. The therapeutic and / or prophylactic agent for the other eye diseases is not particularly limited, but specifically, therapeutic and / or prophylactic agents for commercially available or developing eye diseases are preferable, and commercially available flaming eye diseases A therapeutic and / or prophylactic agent is more preferred, and a commercially available therapeutic and / or prophylactic agent or the like for a commercially available eye disease having a different mechanism of action from the present compound is particularly preferred.

  The therapeutic agent for VEGF-related diseases of the present invention comprises one or more, preferably 1 to 3, more preferably 1 or 2, therapeutic and / or prophylactic agents for VEGF-related diseases other than the present compound. It may contain and may be used together. The therapeutic and / or prophylactic agent for the other VEGF-related diseases is not particularly limited, but specifically, a therapeutic and / or prophylactic agent for a VEGF-related disease that is commercially available or under development is preferred, and a commercially available VEGF-related disease is preferred. A therapeutic and / or prophylactic agent for diseases is more preferred, and a therapeutic and / or prophylactic agent for commercially available VEGF-related diseases having a different mechanism of action from the present compound is particularly preferred. More specifically, examples include ranibizumab, bevacizumab, and aflibercept.

  The therapeutic agent for uveitis of the present invention, together with the present compound, is a therapeutic and / or prophylactic agent for one or more, preferably 1 to 3, more preferably 1 or 2, other inflammatory eye diseases. Or may be used in combination. The therapeutic and / or prophylactic agent for the other inflammatory eye diseases is not particularly limited, and specifically, a therapeutic and / or prophylactic agent for inflammatory eye diseases that are commercially available or under development is preferable. A therapeutic and / or prophylactic agent for inflammatory eye diseases is more preferable, and a commercially available therapeutic and / or prophylactic agent for inflammatory eye diseases and the like having a different mechanism of action from the present compound is particularly preferable. More specifically, steroid agents, immunosuppressants, NSAIDs, TNFα inhibitors and the like can be mentioned.

  Specific examples of steroid agents include dexamethasone, prednisolone, fluorometholone, betamethasone, triamcinolone, difluprednate, and the like, and specific examples of immunosuppressants include cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil, methotrexate. And cyclophosphamide. Specific examples of NSAIDs include bromfenac, diclofenac, pranoprofen, indomethacin and the like. Specific examples of TNFα inhibitors include infliximab, adalimumab, etanercept, golimumab, and certolizumab. Pegor and the like.

  Patients in need of prevention and / or treatment of the above diseases include animals that include or do not include humans, particularly mammals that include or do not include humans.

  The above detailed description of the therapeutic agent of the present invention also applies to the following embodiments of the present invention.

  One embodiment of the present invention includes 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or A pharmaceutical composition for the treatment and / or prevention of ophthalmic diseases comprising the salt and pharmaceutically acceptable additives as active ingredients.

  One aspect of the present invention provides 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H- for use in the treatment and / or prevention of eye diseases. It is pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof.

  One aspect of the present invention is a 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino for the manufacture of a medicament for the treatment and / or prevention of eye diseases. } -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof.

  One aspect of the present invention is a method for the treatment and / or prevention of eye diseases comprising an effective amount of 4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino}. A method comprising administering -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof to a subject in need thereof.

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

Formulation Examples Typical formulation examples of the therapeutic agent of the present invention are shown below. In the following formulation examples, the amount of each component is the content in 100 mL of the formulation.

[Formulation Example 1]
Injection for intravitreal administration (in 100 mL)
2g of this compound
Polysorbate 80 0.5g
Glycerin 2.6g
Purified water

[Formulation Example 2]
Injection for intravitreal administration (in 100 mL)
1 g of this compound
Polysorbate 80 0.5g
Glycerin 2.6g
Purified water

  In addition, in the said formulation examples 1-2, a desired chemical | medical agent can be obtained by adjusting the kind and / or compounding quantity of this compound and / or an additive suitably.

  Example

[Pharmacological test 1]
Using the rat VEGF-induced retinal vascular permeability model, the ability of this compound to inhibit VEGF function was evaluated.

(Preparation of test solution)
The final concentration is 2.6% (w / v) glycerin, 0.4% (w / v) Tween 80, and this compound is 4 mg / mL and 40 mg / mL. (Example test solution). In the same manner, while the comparative compound was pulverized in a mortar, CP690550 would be 1.2 mg / mL and 12 mg / ml, GLPG0634, GSK2586184, PRT062070 and R333 would be 40 mg / mL, INCB18424, INCB28050 and AZD1480 would be 4 mg / mL and 40 mg / mL. (Test solutions of Comparative Examples 1 to 8).

(Test method)
(1) Brown Norway rats (Nippon Charles River) were mixed with 5% (w / v) ketamine hydrochloride injection solution and 2% (w / v) xylazine hydrochloride injection solution (7: 1) at 1 mL / kg intramuscularly. After administration and general anesthesia, 5 μL of a 1: 1 mixture of rat VEGF ₁₆₄ (80 μg / mL, R & D Systems) and test solution or base dissolved in PBS was administered into the vitreous body of a rat using a 32G needle. The normal control group was administered with 5 μL of a 1: 1 mixture of PBS and administration liquid base. Each group was administered to 4 eyes and 8 eyes, and cases with abnormalities such as bleeding and turbidity of the lens were excluded.
(2) After 24 hours from the administration, the rats were exsanguinated and the vitreous humor was collected.
(3) The protein concentration in the vitreous humor was quantified using Bradford Protein Assay (Bio-Rad), and used as an indicator of vascular permeability.
(4) According to Equation 1, the increase in the protein concentration of the base administration group relative to the normal control group was taken as 100%, and the inhibition rate of increased vascular permeability of each test solution was calculated.
{(Protein concentration in base administration group) − (Protein concentration in test solution administration group)} / {(Protein concentration in base administration group) − (Protein concentration in normal control group)} × 100 (Formula 1)

(Results and discussion)
Table 1 shows the average value of the inhibition rate for VEGF-induced retinal vascular permeability enhancement in each administration group.

で表される化合物である。 In Table 1, CP690550 of Comparative Example 1 is 3-[(3R, 4R) -4-methyl-3- [methyl (7H-pyrrolo [2,3-d] pyrimidin-4-yl) amino] piperidine-1 -Yl] -3-oxopropanenitrile having the following formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, INCB18424 of Comparative Example 2 is (3R) -3-cyclopentyl-3- (4- {7H-pyrrolo [2,3-d] pyrimidin-4-yl} -1H-pyrazol-1-yl) Propanenitrile, the following formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, INCB28050 of Comparative Example 3 is 2- [1-ethylsulfonyl-3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl]. Azetidin-3-yl] acetonitrile with the following formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, AZD1480 of Comparative Example 4 is 5-chloro-N2-[(1S) -1- (5-fluoro-2-pyrimidinyl) ethyl] -N4- (5-methyl-1H-pyrazol-3-yl ) -2,4-pyrimidinediamine, which has the following formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, GLPG0634 of Comparative Example 5 is N- (5- {4-[(1,1-dioxide-4-thiomorpholinyl) methyl] phenyl} [1,2,4] triazolo [1,5-a]. Pyridin-2-yl) cyclopropanecarboxamide having the formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, R333 of Comparative Example 6 is N- (3-aminosulfonylphenyl-4-methyl) -5-fluoro-N ′-[4- (prop-2-ynyloxy) phenyl] -2,4-pyrimidine. Diamine, the following formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, GSK2586184 of Comparative Example 7 is N- (5- {4-[(3,3-dimethylazetidin-1-yl) carbonyl] phenyl} [1,2,4] triazolo [1,5- a] pyridin-2-yl) cyclopropanecarboxamide having the formula:

It is a compound represented by these.

で表される化合物である。 In Table 1, PRT062070 of Comparative Example 8 is 4- (cyclopropylamino) -2-({4- [4- (ethylsulfonyl) piperazin-1-yl] phenyl} amino) pyrimidine-5-carboxamide. The following formula:

It is a compound represented by these.

  It has been clarified that the present compound exerts a remarkable effect on a VEGF-induced retinal vascular permeability enhancement model by intravitreal administration. On the other hand, the comparative compound not only exerted little effect on this model, but there was a compound that greatly deteriorated. Based on the above results, the present compounds show that VEGF-related diseases, particularly diseases associated with excessive production of VEGF, such as eye diseases (especially age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity) , Retinal vein occlusion, polypoidal choroidal angiopathy, choroidal neovascularization in pathological myopia, etc.) has been found to be useful for the treatment and / or prevention. It was also found that this compound can be used as a topical ophthalmic preparation.

[Pharmacological test 2]
In order to evaluate the effect of this compound on uveitis, it was examined using an experimental autoimmune uveitis model.

(Preparation of test solution)
20 mg of this compound and a comparative compound were pulverized in a mortar to an administration solution base of an aqueous solution prepared so that the final concentration was 2.6% (w / v) glycerin and 0.4% (w / v) Tween 80. It was dispersed so as to be / mL.

(Production of experimental animals)
R14 peptide derived from bovine photoreceptor retinoid binding protein (Curr Eye Res 1988; 7: 727-735) is dissolved in physiological saline at a concentration of 10 μg / mL, and contains 5 mg / mL Mycobacterium tuberculosis H37Ra (Difco) It was mixed and emulsified 1: 1 with complete Freund's adjuvant (Difco) to obtain a sensitizing solution. A 7-week-old female Lewis rat (Japan SLC) was sensitized by inoculating 100 μL of the sensitizing solution subcutaneously into the footpad.

(Test method)
(1) Six days after the sensitization, a mixed solution (7: 1) of 5% (w / v) ketamine hydrochloride injection and 2% (w / v) xylazine hydrochloride injection was intramuscularly administered to the rat at 1 mL / kg. After general anesthesia, the test solution or base was administered intravitreally in 5 μL using a 32G needle. In addition, the animal which administered the administration liquid base intravitreally to the animal which has not been sensitized was made into the normal control group. Each group was administered to 4 eyes and 8 eyes, and cases with abnormalities such as bleeding and turbidity of the lens were excluded.
(2) 14 days after the sensitization, the rats were exsanguinated and the vitreous humor was collected.
(3) The protein concentration in the vitreous humor was quantified using Bradford Protein Assay (Bio-Rad), and used as an index of the severity of uveitis.
(4) According to Formula 1, the inhibition rate of each test solution was calculated with the increase in the protein concentration of the base administration group relative to the normal control group as 100%.
{(Protein concentration in base administration group) − (Protein concentration in test solution administration group)} / {(Protein concentration in base administration group) − (Protein concentration in normal control group)} × 100 (Formula 1)

(Results and discussion)
The average value of the uveitis suppression rate of each administration group is shown in Table 1.

  In Table 2, CP690550, INCB18424, and AZD1480 are the compounds described above.

で表される化合物である。 In Table 2, VX509 of Comparative Example 11 is (2R) -2-methyl-2-[[2- (1H-pyrrolo [2,3-b] pyridin-3-yl) -4-pyrimidinyl] amino]- N- (2,2,2-trifluoroethyl) -butanamide having the following formula:

It is a compound represented by these.

  It has been clarified that this compound exerts a remarkable effect on ocular inflammation in an experimental autoimmune uveitis model by intravitreal administration. On the other hand, the comparative compound did not exhibit an effect on this model, and there was a compound that greatly deteriorated. In particular, it has been disclosed that CP690550 and VX509 can be used for uveitis (US Pat. No. 8,541,426 and International Publication No. WO2014 / 162300). From these experimental results, it was clarified that topical ocular administration had no effect on uveitis. From the above results, it was found that this compound is useful for the treatment and / or prevention of eye diseases such as uveitis. It was also found that this compound can be used as a topical ophthalmic preparation.

Claims (10)

  4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof Treatment and / or prevention agent.   Eye diseases include age-related macular degeneration, diabetic retinopathy, diabetic macular edema, proliferative diabetic retinopathy, retinopathy of prematurity, retinal vein occlusion, polypoidal choroidal vasculopathy, choroidal neovascularization in pathological myopia, Corts disease, macular The therapeutic and / or prophylactic agent according to claim 1, which is rejection at the time of partial telangiectasia, uveitis, scleritis, retinitis, optic neuritis or allogeneic cell transplantation.   The therapeutic and / or prophylactic agent according to claim 2, wherein the uveitis is non-infectious uveitis.   Non-infectious uveitis is sarcoidosis, Vogt-Koyanagi-Harada disease, Behcet's disease, acute anterior uveitis, iritis, ciliary inflammation, scleritis, episclerosis, Fuchs iris iridescent iris hair 4. The treatment according to claim 3 and / or uveitis associated with rhizitis, ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease or Posner-Schlossmann syndrome Or a preventive agent.   The therapeutic and / or prophylactic agent according to claim 1, wherein the eye disease is a disease associated with increased vascular permeability.   The therapeutic and / or prophylactic agent according to claim 1, wherein the ocular disease is a disease accompanied by retinal neovascularization or choroidal neovascularization.   The therapeutic and / or prophylactic agent according to claim 1, wherein the eye disease is a VEGF-related disease.   The therapeutic and / or prophylactic agent according to any one of claims 1 to 7, for topical administration to the eye.   The therapeutic and / or prophylactic agent according to claim 8, which is an injection for intravitreal administration.   4-{[(1R, 2s, 3S, 5s, 7s) -5-hydroxy-2-adamantyl] amino} -1H-pyrrolo [2,3-b] pyridine-5-carboxamide or a salt thereof from 0.01 to The therapeutic and / or prophylactic agent according to any one of claims 1 to 9, comprising 15% (w / v).