WO2018056268A1 - Agent for treatment and/or prevention of inflammatory eye disorder - Google Patents

Abstract

Provided is an agent for the treatment and/or prevention of inflammatory eye disorder, containing (3S, 4R)-3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroethyl)pyrrolidine-1-carboxylic acid amide or a salt thereof.

Description

Treatment and / or prevention agent for inflammatory eye diseases

The present invention relates to (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2 -Trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof, which relates to a therapeutic and / or prophylactic agent for eye diseases, particularly inflammatory eye diseases.

The eye is a tissue in contact with the outside world, so it is easily exposed to pathogens such as bacteria and viruses, foreign substances such as particulate matter and chemicals, and external stresses such as ultraviolet rays and dryness. Is likely to occur.

Uveitis is an infectious or non-infectious intraocular inflammatory disease that causes symptoms such as foggy vision, flying mosquito disease, photophobia, vision loss, eye pain, and hyperemia. Anterior uveitis that occurs in the iris and ciliary body, intermediate uveitis that occurs in the ciliary flat part and vitreous body, vitreous body, choroid, retina, or optic nerve There is uveitis, as well as panuveitis that spans the front, middle and back. For treatment, steroid eye drops and systemic immunosuppressants for suppressing inflammation are used, but their use is accompanied by side effects caused by drugs with high probability. Therefore, development of a new therapeutic and / or preventive agent for uveitis with few side effects is desired.

Allergic conjunctivitis is a disease in which inflammation occurs in the conjunctiva due to an excessive biological defense reaction against foreign substances (allergen). Symptomatic treatment with antiallergic eyedrops and antihistamine eyedrops is common, but in the case of resistance to these treatments, steroids and immunosuppressive eye drops, and conjunctival papillectomy may be performed.

Dry eye is a disease of tears and keratoconjunctival epithelium due to various factors, accompanied by increased tear osmotic pressure and inflammation of the eye surface. In addition to frequent eye drops such as artificial tears and hyaluronic acid, steroids and immunosuppressants may be required.

When the cornea is damaged due to various diseases or trauma, visual function can be restored by corneal transplantation. Although it is the most successful operation among organ transplants, suppression of graft rejection is an important issue to be solved.

After the ophthalmic surgery, corneal and crystalline turbidity and refractive error may occur due to excessive inflammation. In addition, fibrotic scarring and tissue adhesion caused by inflammation eliminate the intraocular pressure lowering effect in glaucoma surgery. Therefore, suppression of inflammation after surgery is an indispensable technical element for improving treatment results of ophthalmic surgery.

Keratoconus is a disease in which the cornea is progressively thinned and protrudes into a cone. Surgical operations such as cross-linking of corneal parenchyma and corneal transplantation by riboflavin instillation and ultraviolet irradiation are necessary, and the development of effective drug therapy is awaited.

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 the clinical development stage, for example, INCB28050, INCB18424, AC430, AZD1480, GLPG0634, GSK2586184, R348, VX509, CYT387, ABT-494, PRT062070, etc., cancer, leukemia, rheumatoid arthritis, clone It is under clinical development as a therapeutic drug for diseases, myelofibrosis and polycythemia vera However, in the ophthalmology field, R348 has only been clinically developed as a treatment for dry eye in GVHD patients.

JAK is classified into JAK1, JAK2, JAK3, and TYK2 subtypes based on differences in functions and the like, and ABT-494 is known as a selective JAK1 inhibitor (Patent Document 1). ABT-494 has been clinically developed as a therapeutic agent for rheumatoid arthritis, but no clinical development has been made as a therapeutic agent for eye diseases.

International Publication WO2015 / 061665 Pamphlet

An object of the present invention is to find a new compound effective for the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases.

In order to solve the above-mentioned problems, the present inventors have conducted extensive studies on the effects of various compounds on eye diseases, particularly inflammatory eye diseases. As a result, (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof is administered by ophthalmic administration. It has been found that it has a therapeutic and / or prophylactic effect on inflammatory eye diseases, and has completed the present invention.

That is, the present invention relates to the following.

(1) (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2- A therapeutic and / or prophylactic agent for eye diseases, particularly inflammatory eye diseases, comprising (trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof.

(2) The therapeutic and / or prophylactic agent according to item (1), wherein the inflammatory eye disease is uveitis, keratoconjunctive disorder, allergic conjunctivitis, rejection after corneal transplantation, postoperative inflammation or keratoconus .

(3) The therapeutic and / or prophylactic agent according to item (2), 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 Item (3), which is uveitis associated with idiopathic iriditis, ankylosing spondylitis, juvenile idiopathic arthritis, rheumatoid arthritis, psoriasis, ulcerative colitis, Crohn's disease or Posner-Schlossmann syndrome Treatment and / or prevention agent.

(5) The keratoconjunctive disorder is dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratoconjunctivitis, limbal keratoconjunctivitis, filiform keratoconjunctivitis, non-infectious keratitis Or the treatment and / or prevention agent of claim | item (2) which is non-infectious conjunctivitis.

(6) Dry eye decreased tear stability, tear reduction, dry eye, hypoxia, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, Graves' disease, lacrimal gland dysfunction, meibomian gland function The treatment and / or prevention agent according to Item (5), which is dry eye resulting from insufficiency, diabetes, graft-versus-host disease, VDT (Visual Display Terminal) work, surgery, drugs, trauma, or contact lens wearing.

(7) The therapeutic and / or prophylactic agent according to item (2), wherein the allergic conjunctivitis is seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis, or spring catarrh.

(8) The treatment and / or prevention according to item (2), wherein the postoperative inflammation is inflammation after cataract surgery, glaucoma surgery, vitreous surgery or retinal detachment surgery, or fibrotic scarring or tissue adhesion accompanying inflammation. Agent.

(9) The therapeutic and / or prophylactic agent according to any one of items (1) to (8), which is administered locally to the eye.

(10) The therapeutic and / or prophylactic agent according to item (9), which is an eye drop.

(11) (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2- The therapeutic and / or prophylactic agent according to any one of Items (1) to (10), comprising 0.0001 to 5% (w / v) of trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof. .

(12) The therapeutic and / or prophylactic agent according to any one of items (1) to (11), wherein the pH is 4.0 to 9.0.

(13) The therapeutic and / or prophylactic agent according to item (12), wherein the pH is 4.0 to 5.0.

(14) (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2- (Trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof and a pharmaceutically acceptable additive as an active ingredient, a pharmaceutical composition for the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases.

(15) (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,] for use in the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases. 3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof.

(16) (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] for the manufacture of a medicament for the treatment and / or prevention of eye diseases, in particular inflammatory eye diseases Use of pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof.

(17) A method for treating and / or preventing eye diseases, particularly inflammatory eye diseases, comprising an effective amount of (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo Administering [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof to a subject in need thereof. Including.

It should be noted that the configurations (1) to (17) can be arbitrarily selected and combined in two or more.

Since the therapeutic and / or prophylactic agent of the present invention exhibits an excellent therapeutic and / or prophylactic effect on eye diseases, particularly inflammatory eye diseases, it is useful as a therapeutic and / or prophylactic agent for inflammatory eye diseases. . In particular, the therapeutic and / or prophylactic agent of the present invention can be administered as an eye drop.

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”.

(3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N— contained in the therapeutic agent of the present invention (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide (hereinafter also referred to as this compound) is represented by the following formula (1):

(CAS number: 1310726-60-3), also referred to as ABT-494 and UPADACTINIB. This compound comprises (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2 -Trifluoroethyl) pyrrolidine-1-carboxylic acid amide enantiomers and / or diastereomers, preferably substantially pure (3S, 4R) -3-ethyl-4- (3H-imidazo [1 , 2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide. The present compound can be produced according to the method described in International Publication WO2011 / 068881 pamphlet, a usual method in the technical field, or the like.

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. 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, L-tartrate is particularly preferred.

In addition, the present compound or a salt thereof may take the form of a hydrate or a solvate, and the tetrahydrate is preferred as the hydrate.

The content of the present compound or a salt thereof contained in the therapeutic agent of the present invention is not particularly limited, but in the case of eye drops, specifically, the lower limit is preferably 0.0001% (w / v), 0.001 % (W / v) is more preferred, 0.01% (w / v) is more preferred, 0.1% (w / v) is particularly preferred, and 0.5% (w / v) is most preferred. The upper limit is preferably 5% (w / v), more preferably 3% (w / v), still more preferably 2% (w / v), particularly preferably 1.5% (w / v)) 1% (W / v) is most preferred. More specifically, the content is preferably 0.0001 to 5% (w / v), more preferably 0.001 to 3% (w / v), and further preferably 0.01 to 2% (w / v). Preferably, 0.1 to 1.5% (w / v) is particularly preferable, and 0.5 to 1% (w / v) is most preferable. In addition, 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 ophthalmic solution. For example, 0.01% (w / v) of the present compound means that the content of the present compound contained in 100 mL of ophthalmic solution 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 castor oil is preferable.

More specifically, as the 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, preferably 20 to 50. More preferably, 30 to 40 is particularly preferable, and 35 is most preferable. Specific examples of the 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, and polyoxyl 35 castor oil is most preferable.

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, ~ 70 are 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. Ethylene hydrogenated castor oil 60 is most preferred.

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

Vitamin E TPGS is also called tocopherol polyethylene glycol 1000 succinate.

Examples of the polyoxyethylene fatty acid ester 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.

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 20% (w / v), 01 to 15% (w / v) is more preferable, 0.1 to 10% (w / v) is more preferable, 0.5 to 3% (w / v) is particularly preferable, and 0.8 to 2% ( w / v) is most preferred.

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

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

When an isotonic agent is added to the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of isotonic agent, etc., but is preferably 0.01 to 10% (w / v), 0.02 to 7% (w / v) is more preferable, 0.1 to 5% (w / v) is more preferable, 0.5 to 4% (w / v) is particularly preferable, and 0.8 to 3 % (W / v) is most preferred.

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

Examples of the stabilizer include edetic acid, monosodium edetate, disodium edetate, tetrasodium edetate, sodium citrate and the like, and disodium edetate is particularly preferable. The edetate sodium may be a hydrate.

When a stabilizer is added to the therapeutic agent of the present invention, the content can be adjusted as appropriate 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.

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

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 with the therapeutic agent of the present invention, the content can be appropriately adjusted depending on the type of preservative, etc., but is preferably 0.0001 to 1% (w / v), preferably 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.

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

Examples of the antioxidant 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 kind 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.

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

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, its content can be appropriately adjusted depending on the type of the thickening agent, etc., but is preferably 0.001 to 5% (w / v), 0.01 to 1% (w / v) is more preferable, and 0.1 to 0.5% (w / v) is most preferable.

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

Examples of pH adjusting agents 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, particularly 4.0 to 8.0, more particularly 4.0 to 7.5, and even more particularly 4.0 to 9.0. 7.0, preferably 4.0 to 6.5, more preferably 4.0 to 6.0, even more preferably 4.0 to 5.5, and most preferably 4. 0-5.0.

The therapeutic agent of the present invention can be administered either orally or parenterally. 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 preferred, and are minimally invasive and simple. Eye drops are most preferred because they can be administered and exhibit excellent therapeutic and / or prophylactic effects for various inflammatory eye diseases. 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, a container made of polyethylene or polypropylene can be used.

The therapeutic agent of the present invention contains one or more, preferably 1 to 3, more preferably 1 or 2, other therapeutic and / or prophylactic agents for inflammatory eye diseases other than the present compound. Or may be used in combination with other therapeutic and / or prophylactic agents for inflammatory eye diseases. 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.

The dosage of the present compound or a salt thereof contained in the therapeutic agent of the present invention is not particularly limited as long as it is a dosage sufficient for exhibiting a desired drug effect, disease symptoms, patient age and weight, pharmaceutical agent It can be appropriately selected according to the shape and the like. For example, in the case of topical ocular administration, the present compound is about 0.00001 to about 100 mg, preferably about 0.0001 to about 10 mg, more preferably about 0.001 to about 5 mg, particularly preferably about 0.001 per day. It is administered at 01 to about 1 mg, most preferably at about 0.1 to about 0.5 mg.

The usage of the therapeutic agent of the present invention is not particularly limited as long as it is a usage sufficient for achieving a desired drug effect, and can be appropriately selected according to disease symptoms, patient age and weight, drug dosage form, and the like. For example, when the therapeutic agent of the present invention is an eye drop, a single dose of 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, The eye drops can be administered preferably 1 to 3 times a day, more preferably 1 to 2 times a day, particularly preferably once a day, every day to every week, preferably every day. 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 is a therapeutic and / or prophylactic agent for eye diseases, particularly inflammatory eye diseases, more particularly inflammatory eye diseases associated with TNFα. There are no particular restrictions on the type of inflammatory eye disease. Examples of inflammatory eye diseases include uveitis, keratoconjunctivitis, allergic conjunctivitis, rejection after corneal transplantation, postoperative inflammation and keratoconus, especially uveitis Is mentioned.

There is no particular limitation on the type of uveitis, but non-infectious uveitis is preferred. 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. In addition, any of front uveitis, intermediate uveitis, and rear uveitis is not particularly limited, but front uveitis is preferable.

There are no particular restrictions on the type of keratoconjunctive disorder, dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratoconjunctivitis, upper limbal keratoconjunctivitis, filiform keratoconjunctivitis, non-infected Keratitis and non-infectious conjunctivitis. There are no particular restrictions on the type of dry eye, decreased tear stability, decreased lacrimation, dry eye, hypoxia, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, Graves' disease, lacrimal gland dysfunction, Examples include meibomian gland dysfunction, diabetes, graft-versus-host disease, VDT (Visual Display Terminal) work, dry eye resulting from surgery, drugs, trauma or contact lens wear, tear abnormalities and keratoconjunctivitis.

There is no particular limitation on the type of allergic conjunctivitis, and seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis, and spring catarrh are listed.

There are no particular limitations on the type of post-operative inflammation, and examples include inflammation after cataract surgery, glaucoma surgery, vitreous surgery or retinal detachment surgery, as well as fibrotic scarring and tissue adhesion.

Examples of subjects (patients) in need of treatment and / or prevention of the above diseases include animals including or not including humans, particularly mammals including or not including humans.

The above detailed description of the therapeutic agent of the present invention is also applied to the following aspects of the present invention.

One embodiment of the present invention is directed to (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2, 2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof and a pharmaceutically acceptable additive, ophthalmic compositions, ophthalmic diseases, particularly inflammatory ocular diseases, more particularly associated with TNFα A pharmaceutical composition for the treatment and / or prevention of inflammatory eye diseases.

One aspect of the present invention provides (3S, 4R) -3-ethyl-4- for use in the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases, and more particularly inflammatory eye diseases associated with TNFα. (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof is there.

One aspect of the present invention provides (3S, 4R) -3- for the manufacture of a medicament for the treatment and / or prevention of eye diseases, in particular inflammatory eye diseases, more particularly inflammatory eye diseases associated with TNFα. Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide Or the use of a salt thereof.

One aspect of the present invention is a method for the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases, more particularly inflammatory eye diseases associated with TNFα, comprising an effective amount of (3S, 4R) -3-ethyl. -4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or A method comprising administering the salt 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.

1. 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]
Eye drops (in 100 mL)
This compound 0.2g
Polyoxyl 35 castor oil 2g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 2]
Eye drops (in 100 mL)
This compound 0.5g
Polyoxyl 35 castor oil 5g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

[Formulation Example 3]
1 g of this compound
Polyoxyl 35 castor oil 10g
Dilute hydrochloric acid Appropriate amount Sodium hydroxide Appropriate amount Purified water Appropriate amount

In Formulation Examples 1 to 3, a desired drug can be obtained by appropriately adjusting the type and / or blending amount of the present compound and / or additive.

2. Pharmacological tests (About pharmacological test models)
In order to evaluate the effect of this compound on inflammatory eye diseases, examination was performed using a TNFα-induced eye inflammation model. TNFα is considered to be a major pathogenic factor in uveitis, and TNFα inhibitors, infliximab and adalimumab, have been shown to significantly suppress uveitis and are clinically effective ( Arch Ophthalmol. 2012; 130 (5): 592-598, Ocul Immunol Inflamm. 2016; 24 (3): 319-26). That is, it is thought that the compound which shows effectiveness with respect to this model can be used for the treatment of uveitis.

TNFα is known to be involved in the pathogenesis of various eye diseases besides uveitis.

Mast cells play an important role in allergic conjunctivitis, and allergen binding to antigen-specific IgE present on the cell surface causes allergic symptoms such as itching and hyperemia through the release of chemical mediators. Stimulation of mast cells extracted from the conjunctiva with IgE antibody secretes TNFα, suggesting that when allergic conjunctivitis patients are exposed to allergen, TNFα is released into tears (Ann). Allergy Asthma Immunol. 2000; 84: 505-508). In fact, it has been reported that TNFα in tears is increased by instilling allergens in patients with atopic conjunctivitis and that the concentration of TNFα is increased in the conjunctival tissue of patients with spring catarrh (Clin Exp Allergy) 1999; 29 (4): 537-542, Journal of the Japanese Ophthalmological Society 2002; 106 (7): 392-397). TNFα is thought to increase the expression of inflammatory cytokines such as IL-1, IL-6 and IL-8, and cell adhesion factors such as ICAM-1 and VCAM-1, and to be involved in the enhancement of the inflammatory response (Ann Allergy Immunol). 2001; 87: 424-429, Cornea 2003; 22: 557-561), compounds that show efficacy against this model are considered to be therapeutic agents for allergic conjunctivitis.

In dry eye patients, as a result of decreased tear production and increased evaporation, tear osmotic pressure increases and TNFα production from corneal epithelial cells increases (Exp Eye Res. 2006; 82 (4): 588-596. ). In fact, the concentration of TNFα in the tears and conjunctival tissues of patients with dry eye caused by Sjogren's syndrome, meibomian gland dysfunction, diabetes, and graft-versus-host disease, as well as patients with general dry eye abnormalities (Journal of the Japanese Ophthalmological Society, 2004; 108 (5): 297-301, Am J Ophthalmol. 2009; 147 (2): 198-205, Cornea. 2009; 28 (9) : 1023-1027, Mol Vis. 2011; 17: 2605-2611, BMJ Open. 2016; 6 (8): e01010979). Since inhibitors of TNFα improve dry eye symptoms (Invest Ophthalmol Vis Sci. 2013; 54 (12): 7557-7666), compounds that show efficacy against this model are considered to be dry eye therapeutics. .

TNFα increased in expression after corneal transplantation disappears rapidly in the case of syngeneic transplantation, while it continuously increases in the case of allogeneic transplantation, and the TNFα gene haplotype is associated with rejection. From the above, it is suggested that TNFα is associated with rejection (J Interferon Cytokine Res. 1999; 19 (6): 661-669, Transplant Proc. 2014; 46 (5): 1540-1547). In fact, inhibition of TNFα prolongs the survival of corneal grafts (Clin Exp Immunol. 2000; 122 (1): 109-116), and compounds showing efficacy against this model are corneal transplants. It is considered that it can be used to suppress the rejection reaction.

It has been suggested that TNFα in the aqueous humor rises after cataract surgery, and that TNFα is a causative substance of the main inflammatory reaction (Chin Med Sci J. 1999 Mar; 14 (1): 64-66). Instilliximab, a TNFα antibody after glaucoma filtration surgery, reduces the number of fibroblasts and mononuclear cells and the expression of TGFβ, FGFβ and PDGF (Drug Des Devel Ther. 2014; 8: 421-429) It is considered that a compound showing effectiveness against this model suppresses post-operative inflammation and contributes to suppression of fibrosis and improvement of surgical results.

The onset mechanism of keratoconus has not yet been clarified, and until recently it has been considered to be a non-inflammatory corneal degeneration. However, it has been reported that expression of TNFα, IL6 and matrix metalloprotease is increased in tears of keratoconus patients, and as a result of chronic inflammation, thinning and degeneration of the cornea progresses through degradation of collagen fibers. (Ophthalmology. 2005; 112 (4): 654-659, BR J Ophthalmol. 2009; 93 (6): 820-824). When TNFα is allowed to act on keratocytes from a keratoconus patient, the expression of matrix metalloprotease is increased through IL6 production, suggesting that TNFα is a pathogenic factor for this disease (Exp Biol Med (Maywood) .2016 May 19, DOI: 10.1177 / 15353702216650940). Therefore, it is considered that a compound showing effectiveness against this model is effective as a therapeutic or preventive agent for keratoconus.

(Preparation of test solution)
To a base adjusted to a final concentration of 10% polyoxyl 35 castor oil, 0.24% sodium dihydrogen phosphate, 1.6% concentrated glycerin, 0.31 or 3% (w / v), and the pH was adjusted to 4.5 or 7.0 with sodium hydroxide and hydrochloric acid to prepare test solutions (formulations) of Examples 1 to 4. Similarly, to a base adjusted to a final concentration of 10% polyoxyl 35 castor oil, 0.24% sodium dihydrogen phosphate, 1.6% concentrated glycerin, the comparative compound was 1% (w / v). Then, the pH was adjusted to 4.5 or 8.0 with sodium hydroxide and hydrochloric acid, and test solutions (formulations) for Comparative Examples 1 to 7 were prepared. Moreover, the solution of only the base which does not contain a compound was prepared. Further, a betamethasone phosphate solution (formulation) was prepared by dissolving betamethasone phosphate in physiological saline so as to have a concentration of 0.1%.

(Creation of experimental animals)
The rats were given a 1% / kg intramuscular mixture of 5% (w / v) ketamine hydrochloride injection and 2% (w / v) xylazine hydrochloride injection (7: 1) intramuscularly and then subjected to general anesthesia. Eye inflammation was developed by injecting 10 μL of TNFα (R & D Systems, 10 μg / mL) into the anterior chamber of female Lewis rats. Treatment was performed on 8 eyes of 4 animals in each group.

(Test method)
(1) The prepared test solution, base, or betamethasone phosphate solution was administered to each eye by 5 μL at 1 hour intervals from 1 hour before and 7 hours after TNFα was administered into the anterior chamber.
(2) After 24 hours from the administration of TNFα, the rats were exsanguinated and the anterior aqueous humor was collected. Cases with only abnormalities such as bleeding and opacity of the lens were excluded.
(3) Leukocytes present in the anterior aqueous humor were stained with Turk's solution, and the number thereof was measured using a hemocytometer, which was used as an index of the severity of ocular inflammation.
(4) According to Equation 1, the inhibition rate of each test solution was calculated with the ocular inflammation inhibition rate of the betamethasone phosphate solution being 100%.
{(Number of leukocytes in the group administered with the base) − (number of leukocytes in the group administered with the test solution)} / {(number of leukocytes in the group administered with the base) − (number of leukocytes in the group administered with betamethasone phosphate)} × 100 (Formula 1 )

(Results and discussion)
Table 1 shows the average value of the ocular inflammation suppression rate of each administration group.

* In Table 1, “negative sign (−)” means that, for example, in the case of −4.1, the severity of ocular inflammation worsened as compared to the group administered with the base.

In Table 1, INCB28050 of Comparative Example 1 is {1- (ethylsulfonyl) -3- [4- (7H-pyrrolo [2,3-d] pyrimidin-4-yl) -1H-pyrazol-1-yl] -3-azetidinyl} acetonitrile with the following formula:

It is a compound represented by these.

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.

In Table 1, AC430 of Comparative Example 3 is (S)-(4-fluorophenyl) {4-[(5-methyl-1H-pyrazol-3-yl) amino] -2-quinazolinyl} methanol. Formula:

It is a compound represented by these.

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.

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.

In Table 1, GSK2586184 of Comparative Example 6 is N- [5- [4-[(3,3-dimethyl-1-azetidinyl) carbonyl] phenyl] [1,2,4] triazolo [1,5-a]. Pyridin-2-yl] -cyclopropanecarboxamide having the formula:

It is a compound represented by these.

In Table 1, R348 of Comparative Example 7 is 5-fluoro-N- (4-methyl-3-propionylaminosulfonylphenyl) -N ′-[4- (prop-2-inyloxy) phenyl] -2,4- A choline salt of pyrimidinediamine, having the following formula:

It is a compound represented by these.

Note that the compounds of Comparative Examples 1 to 7 are JAK inhibitors.

This compound was found to exhibit the same effect as betamethasone phosphate, which is a steroid, from a low concentration of 0.3% (w / v) to ocular inflammation induced by TNFα when administered by eye drops. Moreover, it turned out that the direction of pH4.5 exhibits an effect more strongly than pH7.0. On the other hand, other JAK inhibitors had little effect on this model despite high concentrations of 1% (w / v) or 3% (w / v). Based on the above, it was suggested that this compound is effective for the treatment and / or prevention of inflammatory eye diseases.

Claims (17)

1. (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl ) A therapeutic and / or prophylactic agent for inflammatory eye diseases containing pyrrolidine-1-carboxylic acid amide or a salt thereof.
2. The therapeutic and / or prophylactic agent according to claim 1, wherein the inflammatory eye disease is uveitis, keratoconjunctival disorder, allergic conjunctivitis, rejection after corneal transplantation, postoperative inflammation or keratoconus.
3. The therapeutic and / or prophylactic agent according to claim 2, 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 body 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.
5. Keratoconjunctivopathy is dry eye, punctate superficial keratopathy, corneal epithelial defect, corneal erosion, corneal ulcer, conjunctival epithelial defect, dry keratoconjunctivitis, upper keratoconjunctivitis, filiform keratoconjunctivitis, non-infectious keratitis or non-infected The therapeutic and / or prophylactic agent according to claim 2, which is conjunctivitis.
6. Dry eye, decreased tear stability, lacrimation, dry eye, hypoxia, Sjogren's syndrome, dry keratoconjunctivitis, Stevens-Johnson syndrome, Graves' disease, lacrimal gland dysfunction, meibomian gland dysfunction, diabetes The treatment and / or prevention agent according to claim 5, which is dry eye resulting from graft-versus-host disease, VDT (Visual Display Terminal) work, surgery, medicine, trauma, or contact lens wearing.
7. The therapeutic and / or prophylactic agent according to claim 2, wherein the allergic conjunctivitis is seasonal allergic conjunctivitis, perennial allergic conjunctivitis, atopic keratoconjunctivitis, or spring catarrh.
8. The therapeutic and / or prophylactic agent according to claim 2, wherein the postoperative inflammation is inflammation after cataract surgery, glaucoma surgery, vitreous surgery or retinal detachment surgery, or fibrotic scarring or tissue adhesion associated with inflammation.
9. The therapeutic and / or prophylactic agent according to any one of claims 1 to 8, which is administered locally to the eye.
10. The therapeutic and / or prophylactic agent according to claim 9, which is an eye drop.
11. (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl The therapeutic and / or prophylactic agent according to any one of claims 1 to 10, comprising 0.0001 to 5% (w / v) of pyrrolidine-1-carboxylic acid amide or a salt thereof.
12. The therapeutic and / or prophylactic agent according to any one of claims 1 to 11, having a pH of 4.0 to 9.0.
13. The therapeutic and / or prophylactic agent according to claim 12, wherein the pH is 4.0 to 5.0.
14. (3S, 4R) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl ) A pharmaceutical composition for treating and / or preventing inflammatory eye diseases, comprising pyrrolidine-1-carboxylic acid amide or a salt thereof and a pharmaceutically acceptable additive as active ingredients.
15. (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazine-8 for use in the treatment and / or prevention of inflammatory eye diseases -Yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof.
16. (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] for the manufacture of a medicament for the treatment and / or prevention of inflammatory eye diseases ] Use of pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or a salt thereof.
17. A method for treating and / or preventing inflammatory eye diseases comprising an effective amount of (3S, 4R) -3-ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] Administering a pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1-carboxylic acid amide or salt thereof to a subject in need thereof.