WO2018056269A1 - Goutte ophtalmiques contenant un inhibiteur de jak - Google Patents

Goutte ophtalmiques contenant un inhibiteur de jak Download PDF

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Publication number
WO2018056269A1
WO2018056269A1 PCT/JP2017/033761 JP2017033761W WO2018056269A1 WO 2018056269 A1 WO2018056269 A1 WO 2018056269A1 JP 2017033761 W JP2017033761 W JP 2017033761W WO 2018056269 A1 WO2018056269 A1 WO 2018056269A1
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eye
salt
eye drop
acid
pyrrolo
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PCT/JP2017/033761
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English (en)
Japanese (ja)
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篤史 吉田
豊実 藤澤
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参天製薬株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications

Definitions

  • 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, and relates to an eye drop having a pH of 4.0 to 9.0.
  • JAK Janus kinase
  • a JAK inhibitor that inhibits intracellular signal transduction by JAK is useful as a pharmaceutical.
  • tofacitinib is used as a therapeutic agent for rheumatoid arthritis
  • ruxolitinib is used as a therapeutic agent for myelofibrosis.
  • 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 function, etc.
  • ABT-494 is known as a selective JAK1 inhibitor, and clinical development is proceeding as an oral rheumatoid arthritis drug.
  • Patent Document 1 specifically discloses an experiment in which ABT-494 was orally administered.
  • Patent Document 2 specifically discloses a preparation for transdermal administration of ABT-494.
  • An object of the present invention is to find a particularly useful preparation as a medicament containing ABT-494, which is a JAK inhibitor.
  • the present inventors have intensively studied a preparation of ABT-494 based on the effect on inflammatory eye diseases.
  • the ophthalmic solution of 0.0 was found to exhibit a particularly excellent therapeutic and / or preventive effect on inflammatory eye diseases, and the present invention was completed.
  • the present invention relates to the following.
  • a method for the treatment and / or prevention of eye diseases, particularly inflammatory eye diseases 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 salt thereof in a solution having a pH of 4.0 to 9.0 And administering to a subject in need thereof, particularly ophthalmic administration.
  • each of the configurations (1) to (13) can be arbitrarily selected and combined in two or more.
  • the eye drop of the present invention is less invasive and can be easily administered compared to other preparations such as injections, and exhibits excellent therapeutic and / or preventive effects on eye diseases.
  • 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 eye drop of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • 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.
  • 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.
  • L-tartrate is particularly preferable.
  • 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 eye drop of the present invention is not particularly limited.
  • the lower limit is preferably 0.0001% (w / v), and 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.
  • 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).
  • 0.1 to 1.5% (w / v) is particularly preferable, and 0.5 to 1% (w / v) is most preferable.
  • 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.
  • “% (w / v)” means the mass (g) of the target component (here, the present compound or a salt thereof) contained in 100 mL of eye drops.
  • the present compound 0.01% (w / v) means that the content of the present compound contained in 100 mL of eye drops is 0.01 g.
  • the target component is an additive such as a surfactant.
  • additives can be used as necessary.
  • additives for example, surfactants, buffers, tonicity agents, stabilizers, preservatives, antioxidants, thickening agents, pH adjusting agents and the like can be added.
  • a surfactant that can be used as a pharmaceutical additive can be appropriately blended.
  • 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.
  • 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.
  • 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.
  • polyoxyethylene sorbitan fatty acid ester examples 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.
  • polyoxyethylene fatty acid ester examples include polyoxyl 40 stearate.
  • 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.
  • sucrose fatty acid ester examples include sucrose stearate.
  • the content can be appropriately adjusted depending on the type of the surfactant and the like, 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.
  • 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, ⁇ -aminocaproic acid, trometamol, and the like.
  • 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.
  • a buffering agent When a buffering agent is blended in the eye drop 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.
  • an isotonic agent that can be used as a pharmaceutical additive can be appropriately blended.
  • 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
  • examples of the nonionic tonicity agent include glycerin, propylene glycol, sorbitol, mannitol, and the like.
  • an isotonic agent When an isotonic agent is added to the eye drop of the present invention, its content can be appropriately adjusted depending on the type of isotonic agent and the like, 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.
  • a stabilizer that can be used as a pharmaceutical additive can be appropriately blended.
  • the stabilizer examples 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.
  • the content thereof 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.
  • a preservative that can be used as a pharmaceutical additive can be appropriately blended.
  • preservatives examples include benzalkonium chloride, benzalkonium bromide, benzethonium chloride, sorbic acid, potassium sorbate, methyl parahydroxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like.
  • the content can be appropriately adjusted depending on the type of the 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.
  • an antioxidant that can be used as an additive for pharmaceuticals can be appropriately blended.
  • antioxidants examples include ascorbic acid, tocophenol, dibutylhydroxytoluene, butylhydroxyanisole, sodium erythorbate, propyl gallate, sodium sulfite and the like.
  • the content can be appropriately adjusted depending on the kind of the antioxidant and the like, 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.
  • a thickening agent that can be used as a pharmaceutical additive can be appropriately blended.
  • 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.
  • the 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.
  • a pH adjuster that can be used as a pharmaceutical additive can be appropriately blended.
  • pH adjusting agents examples 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 eye drop of the present invention is 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 7. 0.0, 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 eye drop of the present invention may be a suspension or emulsion in addition to a solution, and the solvent or dispersion medium is preferably water. No special technique is required for the preparation of the eye drop of the present invention, and it can be formulated using a widely used technique.
  • the eye drop of the present invention can be stored in containers made of various materials.
  • a container made of polyethylene or polypropylene can be used.
  • the eye drop 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, TNF ⁇ inhibitors and the like can be mentioned.
  • steroid agents include dexamethasone, prednisolone, fluorometholone, betamethasone, triamcinolone, difluprednate, and the like
  • immunosuppressants include cyclosporine, tacrolimus, sirolimus, azathioprine, mycophenolate mofetil, methotrexate. And cyclophosphamide.
  • NSAIDs include bromfenac, diclofenac, pranoprofen, indomethacin and the like.
  • TNF ⁇ 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 ophthalmic solution 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.
  • 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 ophthalmic solution of the present invention is not particularly limited as long as it is sufficient to produce a desired medicinal effect, and can be appropriately selected according to disease symptoms, patient age and weight, drug dosage form, and the like.
  • 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 eye drop of the present invention is useful as a therapeutic and / or prophylactic agent for eye diseases, particularly inflammatory eye diseases, more particularly inflammatory eye diseases associated with TNF ⁇ , and there is no particular limitation on the type of inflammatory eye diseases, Examples of inflammatory eye diseases include uveitis, keratoconjunctival disorders, allergic conjunctivitis, rejection after corneal transplantation, postoperative inflammation and keratoconus, especially uveitis.
  • 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.
  • meningitis examples include sarcoidosis, Vogt-Koyanagi-Harada disease, Behcet's disease, acute anterior uveitis, ulceris, 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.
  • any of front uveitis, intermediate uveitis, and rear uveitis is not particularly limited, but front uveitis is preferable.
  • 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.
  • 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.
  • 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, and has a pH of 4.0 to 9.0, particularly ophthalmic disease
  • One embodiment of the present invention provides (3S, 4R) for the manufacture of a medicament or eye drop for treating and / or preventing an eye disease, particularly an inflammatory eye disease, having a pH of 4.0 to 9.0. ) -3-Ethyl-4- (3H-imidazo [1,2-a] pyrrolo [2,3-e] pyrazin-8-yl) -N- (2,2,2-trifluoroethyl) pyrrolidine-1
  • carboxylic acid amides or their salts are used.
  • One aspect of the present invention is a method for the treatment and / or prevention of eye diseases, in particular inflammatory eye diseases, 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 salt thereof having a pH of 4.0 to 9 0.0 solution and administration to a subject in need thereof, particularly eye drop administration.
  • eye diseases in particular inflammatory eye diseases
  • Formulation Example A typical formulation example in the eye drop of the present invention is shown below.
  • the compounding quantity of each component in the following formulation example is a content in 100 mL of eye drops.
  • a desired drug can be obtained by appropriately adjusting the type and / or blending amount of the present compound and / or additive.
  • TNF ⁇ is considered to be a major pathogenic factor in uveitis
  • TNF ⁇ inhibitors infliximab and adalimumab
  • TNF ⁇ 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 TNF ⁇ , suggesting that when allergic conjunctivitis patients are exposed to allergen, TNF ⁇ is released into tears (Ann). Allergy Asthma Immunol. 2000; 84: 505-508).
  • TNF ⁇ in tears is increased by instilling allergens in patients with atopic conjunctivitis and that the concentration of TNF ⁇ 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).
  • TNF ⁇ 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.
  • TNF ⁇ 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 TNF ⁇ gene haplotype is associated with rejection. From the above, it is suggested that TNF ⁇ is associated with rejection (J Interferon Cytokine Res. 1999; 19 (6): 661-669, Transplant Proc. 2014; 46 (5): 1540-1547). In fact, inhibition of TNF ⁇ 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.
  • TNF ⁇ in the aqueous humor rises after cataract surgery, and that TNF ⁇ is a causative substance of the main inflammatory reaction (Chin Med Sci J. 1999 Mar; 14 (1): 64-66).
  • Instilliximab a TNF ⁇ antibody after glaucoma filtration surgery, reduces the number of fibroblasts and mononuclear cells and the expression of TGF ⁇ , FGF ⁇ 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.
  • TNF ⁇ When TNF ⁇ is allowed to act on keratocytes from a keratoconus patient, the expression of matrix metalloprotease is increased through IL6 production, suggesting that TNF ⁇ 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.
  • 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).
  • Test method (1) The prepared test solution, base, or betamethasone phosphate solution was administered to each eye by 5 ⁇ L at 1 hour intervals from 1 hour before and 7 hours after TNF ⁇ was administered into the anterior chamber. (2) After 24 hours from the administration of TNF ⁇ , 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.
  • 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 )
  • Table 1 shows the average value of the ocular inflammation suppression rate of each administration group.
  • 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.
  • 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.
  • 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.
  • AC430 of Comparative Example 3 is (S)-(4-fluorophenyl) ⁇ 4-[(5-methyl-1H-pyrazol-3-yl) amino] -2-quinazolinyl ⁇ methanol.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 TNF ⁇ 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). From the above, it was found that the eye drop containing the present compound is effective for the treatment and / or prevention of inflammatory eye diseases, and particularly exhibits an excellent effect when the pH is around 4.5.

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Abstract

Ces gouttes ophtalmiques contiennent un amide d'acide (3S,4R)-3-éthyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine-8-yl)-N-(2,2,2-trifluoroéthyl)pyrrolidine-1-carboxylique ou un sel de celui-ci, et ont un pH de 4,0 à 9,0.
PCT/JP2017/033761 2016-09-20 2017-09-19 Goutte ophtalmiques contenant un inhibiteur de jak WO2018056269A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020115213A1 (fr) * 2018-12-07 2020-06-11 Lek Pharmaceuticals D.D. Solvate d'un inhibiteur sélectif de jak1
WO2021244323A1 (fr) * 2020-06-05 2021-12-09 苏州科睿思制药有限公司 Forme cristalline d'upadacitinib, son procédé de préparation et son utilisation

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WO2018056268A1 (fr) * 2016-09-20 2018-03-29 参天製薬株式会社 Agent pour le traitement et/ou la prévention d'un trouble oculaire inflammatoire

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012504639A (ja) * 2008-10-02 2012-02-23 インサイト・コーポレイション ドライアイおよび他の目に関連する疾患を治療するためのヤヌスキナーゼ阻害剤
US20150118229A1 (en) * 2013-10-24 2015-04-30 Abbvie Inc. Jak1 selective inhibitor and uses thereof
WO2016033308A1 (fr) * 2014-08-27 2016-03-03 Abbvie Inc. Formulation topique

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WO2018056268A1 (fr) * 2016-09-20 2018-03-29 参天製薬株式会社 Agent pour le traitement et/ou la prévention d'un trouble oculaire inflammatoire

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012504639A (ja) * 2008-10-02 2012-02-23 インサイト・コーポレイション ドライアイおよび他の目に関連する疾患を治療するためのヤヌスキナーゼ阻害剤
US20150118229A1 (en) * 2013-10-24 2015-04-30 Abbvie Inc. Jak1 selective inhibitor and uses thereof
WO2016033308A1 (fr) * 2014-08-27 2016-03-03 Abbvie Inc. Formulation topique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020115213A1 (fr) * 2018-12-07 2020-06-11 Lek Pharmaceuticals D.D. Solvate d'un inhibiteur sélectif de jak1
WO2021244323A1 (fr) * 2020-06-05 2021-12-09 苏州科睿思制药有限公司 Forme cristalline d'upadacitinib, son procédé de préparation et son utilisation

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