WO2021039791A1 - Medicinal composition for preventing or treating angiogenesis-related diseases - Google Patents

Medicinal composition for preventing or treating angiogenesis-related diseases Download PDF

Info

Publication number
WO2021039791A1
WO2021039791A1 PCT/JP2020/032037 JP2020032037W WO2021039791A1 WO 2021039791 A1 WO2021039791 A1 WO 2021039791A1 JP 2020032037 W JP2020032037 W JP 2020032037W WO 2021039791 A1 WO2021039791 A1 WO 2021039791A1
Authority
WO
WIPO (PCT)
Prior art keywords
angiogenesis
pharmaceutical composition
composition according
eye
bpu17
Prior art date
Application number
PCT/JP2020/032037
Other languages
French (fr)
Japanese (ja)
Inventor
木村和博
Original Assignee
国立大学法人山口大学
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 国立大学法人山口大学 filed Critical 国立大学法人山口大学
Priority to JP2021542934A priority Critical patent/JPWO2021039791A1/ja
Publication of WO2021039791A1 publication Critical patent/WO2021039791A1/en

Links

Images

Classifications

    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • 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
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to a pharmaceutical composition containing 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient.
  • retinal choroidal disorders such as diabetic retinopathy, retinal detachment, and age-related macular degeneration will continue to increase as a cause of blindness in Japan, which has entered an aging society.
  • biologics such as anti-VEGF intraocular injections that suppress neovascularization
  • the prognosis of these previously blinded diseases is improving.
  • the visual function prognosis of severe cases such as being left untreated or repeated for a long period of time is still poor.
  • an anti-VEGF intraocular injection preparation is used, the problem of recurrence and prolongation of intraocular neovascularization cannot be avoided.
  • Neovascularization is fragile and prone to rupture, and blood or its components in the blood can leak into surrounding tissues. Leakage of blood or components in the blood to such surrounding tissues may cause inflammation, scars associated with the inflammation may be formed, and cells of the surrounding tissues may be destroyed, causing various diseases.
  • retinal repositioning even if retinal repositioning is obtained by surgery, if the retinal cells are already irreversibly damaged, the photoreceptor cell function will decline.
  • the eye is an organ that makes no sense if visual function is lost, even if the wound is healed.
  • it is important to control the neovascular rupture of the retinal choroid or ocular inflammation with less damage, and to control the subsequent secondary reaction.
  • the present inventors are proceeding with research on an agent for suppressing retinochoroidal damage, for example, (E) -4-(2- ⁇ 3-[(1H-pyrazole-1-yl) methyl] -5, 5, 8,8-Tetramethyl-5,6,7,8-Tetrahydronaphthalene-2-yl ⁇ vinyl)
  • An inhibitor of retinochoroidal damage containing benzoic acid, an ester thereof or a salt thereof as an active ingredient is disclosed. (See Patent Document 1).
  • Non-Patent Document 1 a compound having an acylphenylurea structure as a basic skeleton inhibits the movement of melanoma.
  • Non-Patent Document 1 the relationship between compounds having an acylphenylurea structure as a basic skeleton and retinochoroidal disorders or EMT is unknown.
  • An object of the present invention is to provide a pharmaceutical composition effective for the prevention or treatment of angiogenesis-related diseases.
  • the above-mentioned 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea suppresses angiogenesis and suppresses the expression of fibrosis markers not only in retinal cells but also in lung and liver cells. I found out what to do and completed the present invention.
  • the present invention is as follows.
  • the pharmaceutical composition according to the above [1] which is used for the prevention or treatment of angiogenesis-related diseases.
  • the pharmaceutical composition according to the above [2] wherein the angiogenesis-related disease is an angiogenesis-related disease in the eye.
  • the pharmaceutical composition according to the above [3], wherein the angiogenesis-related disease in the eye is retinochoroidal disorder, keratoconjunctival disorder, or angiogenic glaucoma.
  • Retinopathy of prematurity is diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreous retinopathy, uveitis, eye infection, retinopathy of prematurity, neovascular macular degeneration, or retinopathy.
  • [6] The above-mentioned [3] that the angiogenesis-related disease in the eye is the formation or contraction of fibrous scar caused by any one selected from retinochoroidal disorder, keratoconjunctival disorder, and angiogenic glaucoma.
  • Angiogenesis-related disease is organ fibrosis.
  • Example 1 the result of adding 0.3% FBS-containing DMEM (control) or 0.3% FBS-containing DMEM + BPU17 (1,3, or 5 ⁇ M) and measuring the width of the wound on the culture bottom after culturing for 18 hours. It is a figure which shows. It is a figure which shows the photograph of the culture bottom after the treatment for 0 hour or 18 hours when DMEM (control) containing 0.3% FBS or BPU17 3 ⁇ M was added in Example 1. It is a figure which shows the result of having observed the cell with a fluorescence microscope in Example 2. It is a figure which shows the result of the immunoblot in Example 2. It is a figure which shows the result of having taken out the eyeball and observed with a microscope in Example 3. FIG.
  • Example 5 It is a figure which shows the measurement result of the fibrotic area of the removed eyeball in Example 3. This is the result of examining the uptake rate of BrdU in aortic vascular endothelial cells in Example 4.
  • Example 5 it is a figure which shows the photograph by the microscope observation ( ⁇ 40) 22 hours after inoculation of the HAoEC solution.
  • Example 5 it is a figure which shows the ratio (%) of branching points per cell number 22 hours after inoculation of HAoEC solution.
  • the pharmaceutical composition in the present specification is 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea (1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) represented by the following formula (I).
  • urea Particularly limited as long as it is a pharmaceutical composition containing the "Compound” or "BRU17”) or a pharmacologically acceptable salt thereof as an active ingredient (hereinafter, also referred to as "Pharmaceutical Composition”). However, it is preferably used for the prevention or treatment of angiogenesis-related diseases and for suppressing angiogenesis.
  • angiogenesis-related disease examples include angiogenesis-related disease in the eye or organ fibrosis.
  • examples of such "neovascularization-related diseases in the eye” include angiogenesis-related diseases in the retinal, choroidal membrane, cornea, conjunctiva, sclera, uvea, vitreous body or lens, and examples thereof include reticuloconjunctival disorder and keratoconjunctival disorder.
  • Neovascular glaucoma can be mentioned.
  • the retinochoroid means a tissue in which the retina and the choroid are combined.
  • the above-mentioned "retinal choroidal disorder” in the present specification means a state in which a tissue composed of photoreceptor cells, ganglion cells, retinal pigment epithelial cells and each of the above cells in the retina and / or the choroid is damaged, and finally. In some cases, cell death or tissue dysfunction occurs, and visual function such as visual acuity and visual acuity is abnormal.
  • diabetic retinopathy retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreous retinopathy, vaginitis, eye infection, premature infant retinopathy, neovascular macular degeneration, retinal choroiditis, retina and / or Examples include retinal and / or subretinal hemorrhage secondary to the formation of choroidal neovascularization, retina and / or choroidal neovascularization.
  • corneal conjunctival disorder in the present specification refers to a state in which the corneal epithelium, the stroma layer of the cornea, and the corneal endothelium are damaged.
  • corneal inflammation corneal trauma, corneal ulcer, corneal epithelial detachment, dry eye, corneal erosion, rejection after corneal transplantation, corneal erosion, protracted corneal disorder, punctate superficial keratopathy, corneal epithelial defect, corneal blood vessels
  • examples include neoplasia, conjunctival inflammation, conjunctival ulcer, conjunctival epithelial defect, and conjunctival angiogenesis.
  • the above-mentioned "fibrous scar” in the present specification is fibrous connective tissue generated at a damaged site of inflamed tissue as inflammation subsides or progresses due to bleeding, surgery, infection, or the like.
  • formation of fibrous scar means that fibrous connective tissue is formed at the injured site as the inflammation subsides or progresses
  • contraction of fibrous scar means formation.
  • the fibrous scar may be caused by any one selected from retinochoroidal disorder, keratoconjunctival disorder, and neovascular glaucoma.
  • the place where the fibrous scar is formed or contracted may be any of the eyes, and the fibrous scar on the retina, the intraretinal, and / or the subretinal, the fibrous scar on the cornea, and the fibrous on the conjunctiva.
  • Scars can be mentioned, and fibrous scars in the retinal pigment epithelial tissue under the retina can be preferably mentioned.
  • the "above the retina” means above the surface of the retina, and the "subretina” means between the retina and the choroid, intrachoroidally, and subchoroidally.
  • fibrous scar on the retina, intraretinal, and / or subretinal refers to fibrous connective tissue generated at an injured site on the retina, intraretinal, and / or subretinal as the ocular inflammation subsides or progresses. It is a tissue, preferably a fibrous connective tissue generated at an injured site under the retina, and is a tissue mainly composed of retinal pigment epithelial cells, fibroblasts, glial cells and the like and an extracellular matrix including collagen.
  • Such supretinal, intraretinal, and / or subretinal formation and contraction of fibrous scars occur in sequence, and by suppressing the formation and contraction of this fibrous scar, supretinal, intraretinal, and / or subretinal. It is possible to prevent the macular region of the fibrous scar and the surrounding tissue from being deformed and impairing the retinal choroidal function.
  • organ fibrosis in one process in wound healing of an injured organ, and is an excessive state (chronic inflammation) in which the balance between inflammation and production and decomposition of extracellular matrix is lost. )
  • organ fibrosis include pulmonary fibrosis, liver fibrosis, renal fibrosis, pancreatic fibrosis, myocardial fibrosis, gastrointestinal fibrosis, myelofibrosis, and postoperative scarring.
  • neovascularization in the above-mentioned “suppression of neovascularization” in the present specification is not particularly limited, but neovascularization in the eye, preferably neovascularization in the retina, intraretinal and / or subretinal, cornea, or conjunctiva is preferably mentioned. be able to.
  • suppression of angiogenesis means suppressing the formation or growth of new blood vessels from existing blood vessels.
  • the compound, which is the active ingredient of the pharmaceutical composition, or a salt thereof can be obtained by an organic synthesis method using a known organic chemical reaction, such as the method described in Non-Patent Document 1, or a commercially available product. You can also buy it.
  • the above-mentioned "pharmaceutically acceptable salt” includes (1) as an acid addition salt, an inorganic salt such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a phosphate; Acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluo Organic acid salts such as lomethane sulfonate, benzene sulfonate, p-toluene sulfonate, glutamate or asparagate, or (2) basic salts such as sodium salt, potassium salt, calcium salt or magnesium salt.
  • Metal salts; inorganic salts such as ammonium salts; or organic amine salts such as triethylamine salts or guanidine salts can be preferably mentioned.
  • the Pharmaceutical Composition can be mixed with an appropriate pharmacologically acceptable additive and administered by eye drops as an eye drop.
  • Formulation by a well-known method by appropriately blending an tonicity agent, a buffer, a pH adjuster, a solubilizer, a thickener, a stabilizer, a preservative (preservative), etc. as additives. Can be done.
  • a stable eye drop can be obtained by suspending the drug by adding a pH adjuster, a thickener, a dispersant, or the like.
  • tonicity agent examples include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
  • buffering agent examples include phosphoric acid, phosphate, citric acid, acetic acid, ⁇ -aminocaproic acid and the like.
  • pH adjusting agent examples include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate or hydrogen carbonate. Examples include sodium and the like.
  • solubilizer examples include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000 and the like.
  • thickener and dispersant examples include cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose; polyvinyl alcohol; or polyvinylpyrrolidone, and examples of stabilizers include edetic acid and edetic acid. Examples include sodium and the like.
  • preservative examples include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like, and these preservatives. Can also be used in combination.
  • the pH of the above eye drops may be within the range allowed for ophthalmic preparations, but it is desirable to set it to 4.0 to 8.5.
  • the Pharmaceutical Composition is an ointment (preferably an eye ointment), an injection, a tablet, a granule, which is produced by mixing with an appropriate pharmacologically acceptable additive in addition to the above-mentioned ointment type.
  • Oral or parenteral intravenous administration, intravenous administration, in the form of fine granules, powders, capsules, inhalants, syrups, pills, solutions, suspensions, emulsions, transdermal absorbents, suppositories, lotions, etc. It can also be administered by intramuscular administration, intraperitoneal administration, transdermal administration, transairway administration, intradermal administration or subcutaneous administration).
  • These formulations are prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents or diluents.
  • excipients examples include organic excipients and inorganic excipients.
  • Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, ⁇ -starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextrin; or pull run and the like.
  • examples of the inorganic excipient include light anhydrous silicic acid; and sulfates such as calcium sulfate.
  • the lubricants include, for example, stearic acid; metal stearic acid salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bead wax or gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; Glycols; fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above excipients.
  • binder examples include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, compounds shown by the above excipients, and the like.
  • the disintegrant is, for example, a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally cross-linked carboxymethyl cellulose calcium; cross-linked polyvinylpyrrolidone; or chemically modified such as carboxymethyl starch or sodium carboxymethyl starch.
  • a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally cross-linked carboxymethyl cellulose calcium; cross-linked polyvinylpyrrolidone; or chemically modified such as carboxymethyl starch or sodium carboxymethyl starch.
  • examples include starch and cellulose derivatives.
  • the emulsifiers are, for example, colloidal clays such as bentonite or beagum; anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride; or polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acids. Examples thereof include nonionic surfactants such as esters and sucrose fatty acid esters.
  • the stabilizers include, for example, parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalconium chloride; phenols such as phenol or cresol; timerosal; anhydrous. Acetic acid; or sorbic acid.
  • parahydroxybenzoic acid esters such as methylparaben or propylparaben
  • alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol
  • benzalconium chloride phenols such as phenol or cresol
  • timerosal anhydrous.
  • Acetic acid or sorbic acid.
  • sweeteners such as sodium saccharin or aspartame
  • acidulants such as citric acid, malic acid or tartaric acid
  • flavors such as menthol, lemon extract or orange extract.
  • the above-mentioned diluent is a compound usually used as a diluent, for example, lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol. , Starch, polyvinylpyrrolidone or a mixture thereof and the like.
  • ointment preferably eye ointment
  • a general-purpose base such as white petrolatum or liquid paraffin.
  • the dose of the pharmaceutical composition can be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, age, weight, judgment of a doctor, etc., but in the case of eye drops, 0.000001 to An active ingredient concentration of 10% (W / V), preferably 0.00001 to 3% (W / V), more preferably 0.0001 to 1% (W / V) once or several times a day.
  • W / V an active ingredient concentration of 10%
  • W / V preferably 0.00001 to 3%
  • W / V more preferably 0.0001 to 1%
  • oral preparations which can be administered, in general, 0.01 to 5000 mg, preferably 0.1 to 2500 mg, more preferably 0.5 to 1000 mg per day is divided into one or several times for adults. Can be administered.
  • eye ointment it is 0.00001 to 10% (W / W), preferably 0.0001 to 3% (W / W), and more preferably 0.001 to 1% (W / W).
  • the active ingredient concentration can be administered once or several times a day.
  • prevention means a means for suppressing or preventing the onset and recurrence of diseases related to cell, tissue, organ defect and dysfunction, and dysfunction.
  • treatment refers to the loss and dysfunction of cells, tissues and organs, the slowing or stopping of progression and exacerbation of diseases associated with dysfunction, and the loss and function of cells, tissues and organs. It means a means aimed at ameliorating, ameliorating, or curing a disease related to a disorder or dysfunction.
  • Example 1 In order to investigate the effect of BPU17 on the prevention or treatment of reticulochoroidal disorders, the following experiments were performed using human retinal pigment epithelial cell RPE-1.
  • the retinal pigmented cells are typical cell components that form fibrous scars in the retina.
  • Human retinal pigment epithelial cell RPE-1 was cultured in 10% FBS medium. The cultured cells were seeded in a 24-well dish and the culture was continued until confluent. Then, after culturing in Dulbecco's modified Eagle's medium (DMEM) free of serum (without FBS) for 24 hours, the bottom of the culture is injured with a single width, and DMEM (control) containing 0.3% FBS or DMEM + containing 0.3% FBS.
  • DMEM Dulbecco's modified Eagle's medium
  • BPU17 (1,3, or 5 ⁇ M) was added and cultured for 18 hours.
  • BPU17 used was provided by Professor Bunta Watanabe of Kyoto University.
  • the width of the wound on the bottom of the culture was measured to quantitatively evaluate the amount of cell migration.
  • the result of measuring the width of the wound of each culture bottom is shown in FIG.
  • DMEM (control) with 0.3% FBS is 0.3% FBS
  • DMEM + BPU17 (1,3, or 5 ⁇ M) with 0.3% FBS is 0.3% FBS
  • 0.3% FBS + BPU17 1 ⁇ M 0.3% FBS + BPU17 3 ⁇ M, respectively.
  • FIG. 2 shows a photograph of the culture bottom after 0-hour or 18-hour culture when DMEM (control) containing 0.3% FBS or 0.3% FBS + BPU17 3 ⁇ M was added.
  • DMEM control
  • FIGS. 1 and 2 the addition of BPU17 suppresses the migration of retinal pigment cells, which is one of the biological properties in epithelial to mesenchymal transition (EMT), in a concentration-dependent manner. It became clear that there was.
  • Example 2 In the same culture system as in Example 1, treatment with DMEM (None), 0.3% FBS, or 0.3% FBS + BPU17 3 ⁇ M was performed, and RPE-1 cells after 18 hours were formalin-fixed and alpha smooth muscle actin ( ⁇ ). -SMA) and nuclei were stained with anti- ⁇ -SMA antibody and DAPI, respectively. Subsequently, the cells are stimulated with DMEM (none), transforming growth factor- ⁇ 2 (TGF- ⁇ 2), which is a cytokine that promotes fibrosis, or TGF- ⁇ 2 + BPU17 3 ⁇ M, and then the cell extract is collected to counter immunoblot. This was done using ⁇ -SMA antibody. The result of observing the cells with a fluorescence microscope after collecting the cell extract is shown in FIG. 3, and the result of immunoblot is shown in FIG.
  • TGF- ⁇ 2 transforming growth factor- ⁇ 2
  • TGF- ⁇ 2 stimulation increased the expression of ⁇ -SMA that promotes fibrosis, but treatment with BPU17 suppressed the expression of ⁇ -SMA.
  • EMT epithelial-mesenchymal transition
  • Example 3 Based on the results of Example 2 above, it was examined whether BPU17 has an inhibitory effect on subretinal fibrous scar formation using a mouse subretinal scar formation model.
  • the subretinal scar model in mice was prepared by the method shown below according to the method of Kobayashi et al. (Investigative ophthalmology & visual science, Volume 60, Issue 2 (2019)). Specifically, the retina of an 8-week-old mouse (CL57BL / 6 female: SLC) was irradiated with a laser (200 mW, 75 ⁇ m, 0.1 second, 532 nm) to perform photocoagulation around the optic nerve, specifically around the Disc 2 About 4 places were constructed with a diameter of 3 papillae.
  • control without BPU17 (0.3% FBS) and 0.3% FBS + BPU17 (30, 100, 300 ⁇ M) were injected into the eye. Furthermore, after 7 days, a control without BPU17, 0.3% FBS + BPU17 (30, 100, 300 ⁇ M) was injected into the eye again.
  • type I collagen was stained with a primary collagen antibody and observed under a microscope, and the fibrotic area was measured. The observation result with a microscope is shown in FIG. 5, and the measurement result of the fibrotic area is shown in FIG. The vertical axis in FIG. 6 is the fibrotic area ( ⁇ m 2 ).
  • HAoEC Human aortic vascular endothelial cells
  • BrdU Bromodeoxyuridine
  • HAoEC was cultured in Matrigel, and tube-formation, which is an index of angiogenesis, was examined by the following method.
  • a 1.25 mL / 2 mL tube of Matrigel solution was prepared on a 24-well plate (stored at ⁇ 20 ° C. before use) coated with Matrigel (registered trademark: (Becton Dickinson)). Further, the following Matrigel solution (300 ⁇ L / well) was added to a 24-well plate (3 well / sample) and incubated at 37 ° C. for 1 hour.
  • FIG. 8 A photograph taken by microscopic observation ( ⁇ 40) 22 hours after inoculation is shown in FIG. 8, the ratio (%) of branching points per number of cells is shown in FIG. 9A, and the lumen length ( ⁇ m) is shown in FIG. 9B. ..
  • FIGS. 8 and 9A and 9B it was clarified that the addition of BPU17 inhibits lumen formation. Therefore, when examined together with the results of Example 4, it was shown that BPU17 can suppress angiogenesis.
  • Example 6 Based on the results of Example 5 above, it was examined whether BPU17 has an inhibitory effect on CNV formation using a mouse retinochoroidal neovascularization (CNV) model.
  • the CNV model in mice was prepared by the method shown below according to the method of Ishikawa et al. (Exp Eye Res. 2016; 142: 19-25). Specifically, the retina of an 8-week-old mouse (CL57BL / 6 female: SLC) was irradiated with a laser (200 mW, 75 ⁇ m, 0.1 second, 532 nm) to perform photocoagulation around the optic nerve, specifically around the Disc 2 About 4 places were constructed with a diameter of 3 papillae.
  • a laser 200 mW, 75 ⁇ m, 0.1 second, 532 nm
  • Example 7 the EMT inhibitory effect of BPU17 was examined using EMT markers.
  • Human alveolar epithelial-derived cell line A549 or human liver stellate cell line LI90 was cultured in the above-mentioned formation-free DMEM medium for 24 hours.
  • TGF ⁇ -2 1 ng / mL or TGF ⁇ -2 1 ng / mL and BPU17 3 ⁇ M were added, and the cells were further cultured for 18 hours.
  • RNA is extracted using Rneasy Mini Kit (Kiagen), cDNA is synthesized, and qPCR is performed by SYBR Green reagents and a StepOnePlus Real Time PCR System (Applied Biosystems) to obtain fibrosis-related molecules.
  • CTGF connective tissue growth factor
  • the expression level of a certain connective tissue growth factor (CTGF) mRNA was measured.
  • CTGF connective tissue growth factor
  • the human liver stellate cell line LI90 was cultured in the above-mentioned formation-free DMEM medium for 24 hours. Next, TGF ⁇ -2 1 ng / mL alone, without TGF ⁇ , or TGF ⁇ -2 1 ng / mL and BPU17 3 ⁇ M were added and cultured for an additional 18 hours.
  • RNA was extracted in the same manner as above, cDNA was synthesized, and qPCR was performed to measure the expression level of ⁇ -smooth muscle actin ( ⁇ SM-actin) mRNA, which is a fibrosis-related molecule. The results are shown in FIGS. 12 and 13.
  • ⁇ SM-actin ⁇ -smooth muscle actin
  • the pharmaceutical composition of the present invention can be used in the prevention or treatment of angiogenesis-related diseases.
  • diabetic retinopathy In particular, diabetic retinopathy, age-related macular degeneration, retinal detachment, and proliferative vitreous by strongly suppressing the formation of retinochoroidal neovascularization by vascular endothelial cells in the retinochoroid or the formation of fibrous scars in the retinal pigment epithelial tissue.
  • It can be used as a preventive or therapeutic agent for retinochoroidal disorders such as retinopathy, uveitis, eye infection, retinopathy of prematurity, neovascular macular degeneration, and retinochoroiditis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Ophthalmology & Optometry (AREA)
  • Epidemiology (AREA)
  • Pulmonology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

The present invention addresses the problem of providing a novel medicine that is effective for preventing or treating angiogenesis-related diseases.　As a means for solving the problem, produced is a medicinal composition that comprises, as an active ingredient, 1-(cyclobutylcarbonyl)-3-(4-chlorophenyl)urea or a pharmacologically acceptable salt thereof. Preferably, the medicinal composition is used for preventing or treating angiogenesis-related diseases. Preferably, the angiogenesis-related diseases are ophthalmic angiogenesis-related diseases. Preferably, the ophthalmic angiogenesis-related diseases concern to the formation or constriction of fibrous scars in epiretinal, intraretinal and/or subretinal tissues.

Description

血管新生関連疾患の予防又は治療用医薬組成物Pharmaceutical composition for the prevention or treatment of angiogenesis-related diseases
　本発明は、１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩を有効成分として含有する医薬組成物に関する。 The present invention relates to a pharmaceutical composition containing 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient.
　糖尿病網膜症、網膜剥離、加齢黄斑変性等の網脈絡膜障害は、高齢化社会を迎えた我が国において、これからも失明原因としてその割合が上昇すると考えられている。硝子体手術の発展や新生血管を抑制する抗VEGF眼内注射製剤等の生物製剤の導入によって、以前は失明していたこれらの疾患の予後が改善されつつある。しかし、初期症例はともかく、長期間放置若しくは反復する等の重症例の視機能予後は未だ芳しくない。また、抗VEGF眼内注射製剤を用いても眼内新生血管の再発、遷延化の問題は避けては通れない。新生血管は脆弱であり破綻しやすく、血液又はその血液中の成分が周囲の組織に漏出することがある。かかる周囲の組織への血液又はその血液中の成分の漏出により炎症が生じることや、炎症に伴う瘢痕が形成されて、ひいては周辺組織の細胞が破壊されて様々な疾患を引き起こすことがある。 It is thought that the proportion of retinal choroidal disorders such as diabetic retinopathy, retinal detachment, and age-related macular degeneration will continue to increase as a cause of blindness in Japan, which has entered an aging society. With the development of vitrectomy and the introduction of biologics such as anti-VEGF intraocular injections that suppress neovascularization, the prognosis of these previously blinded diseases is improving. However, aside from the initial cases, the visual function prognosis of severe cases such as being left untreated or repeated for a long period of time is still poor. Moreover, even if an anti-VEGF intraocular injection preparation is used, the problem of recurrence and prolongation of intraocular neovascularization cannot be avoided. Neovascularization is fragile and prone to rupture, and blood or its components in the blood can leak into surrounding tissues. Leakage of blood or components in the blood to such surrounding tissues may cause inflammation, scars associated with the inflammation may be formed, and cells of the surrounding tissues may be destroyed, causing various diseases.
　また、手術によって網膜復位が得られても、網膜細胞がすでに不可逆的な二次的なダメージを受けていると視細胞機能が低下する。眼はたとえ傷が治っても、視機能が失われては全く意味をなさない臓器である。網膜機能を温存するためには、如何に少ないダメージで網脈絡膜の新生血管破綻若しくは眼炎症の抑制、それに引き続く二次的反応を制御できるかが重要である。 Also, even if retinal repositioning is obtained by surgery, if the retinal cells are already irreversibly damaged, the photoreceptor cell function will decline. The eye is an organ that makes no sense if visual function is lost, even if the wound is healed. In order to preserve retinal function, it is important to control the neovascular rupture of the retinal choroid or ocular inflammation with less damage, and to control the subsequent secondary reaction.
　網脈絡膜新生血管の形成若しくは破綻には、血管内皮細胞の増殖、管腔形成能亢進等が関与していることが報告されている。さらに網膜線維性瘢痕を構成する代表的な細胞成分として網膜色素上皮細胞の関与が報告されている。進行した網脈絡膜障害においては、網膜色素上皮細胞の上皮間葉系移行（EMT）が助長され、瘢痕形成及び収縮をきたして網膜機能障害が生じる。そこで網膜色素上皮細胞の上皮間葉系移行、血管内皮細胞の増殖、あるいは管腔形成亢進を抑制することは網脈絡膜障害等の疾患に対して有効であると考えられる。 It has been reported that proliferation of vascular endothelial cells, enhancement of lumen formation ability, etc. are involved in the formation or rupture of retinochoroidal neovascularization. Furthermore, the involvement of retinal pigment epithelial cells has been reported as a typical cellular component constituting retinal fibrous scar. In advanced reticulochoroidal damage, epithelial-mesenchymal transition (EMT) of retinal pigment epithelial cells is promoted, resulting in scar formation and contraction, resulting in retinal dysfunction. Therefore, suppressing epithelial-mesenchymal transition of retinal pigment epithelial cells, proliferation of vascular endothelial cells, or increased lumen formation is considered to be effective for diseases such as retinochoroidal disorders.
　本発明者らは、網脈絡膜障害の抑制剤の研究を進めており、たとえば、（Ｅ）－４－（２－｛３－［（１Ｈ－ピラゾール－１－イル）メチル］－５，５，８，８－テトラメチル－５，６，７，８－テトラヒドロナフタレン－２－イル｝ビニル）安息香酸、そのエステル又はそれらの塩を有効成分として含有する網脈絡膜障害の抑制剤が開示されている（特許文献１参照）。 The present inventors are proceeding with research on an agent for suppressing retinochoroidal damage, for example, (E) -4-(2-{3-[(1H-pyrazole-1-yl) methyl] -5, 5, 8,8-Tetramethyl-5,6,7,8-Tetrahydronaphthalene-2-yl} vinyl) An inhibitor of retinochoroidal damage containing benzoic acid, an ester thereof or a salt thereof as an active ingredient is disclosed. (See Patent Document 1).
　一方、近年、アシルフェニルウレア構造を基本骨格に持つ化合物がメラノーマの運動を阻害することが明らかにされている（非特許文献１参照）。しかしながら、アシルフェニルウレア構造を基本骨格に持つ化合物と網脈絡膜障害やEMTとの関係は知られていない。 On the other hand, in recent years, it has been clarified that a compound having an acylphenylurea structure as a basic skeleton inhibits the movement of melanoma (see Non-Patent Document 1). However, the relationship between compounds having an acylphenylurea structure as a basic skeleton and retinochoroidal disorders or EMT is unknown.
国際公開第２０１４／１８８７１６号パンフレットInternational Publication No. 2014/188716 Pamphlet
　本発明の課題は、血管新生関連疾患の予防又は治療に有効な医薬組成物を提供することにある。 An object of the present invention is to provide a pharmaceutical composition effective for the prevention or treatment of angiogenesis-related diseases.
　血管新生関連疾患、特に網脈絡膜障害に有効な薬物を探索することは、眼分野において重要且つ興味深い課題である。本発明者は、網脈絡膜障害に有効な新たな薬物を探索すべく鋭意研究を行ったところ、１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア（1-(cyclobutylcarbonyl)-3-(4-chlorophenyl)urea）、又はその薬理上許容される塩が、ヒト網膜色素上皮細胞を用いた薬理試験において、細胞移動及び上皮間葉系移行の抑制作用を示し、更にマウス網膜線維化モデルにて線維性瘢痕形成を抑制することを見出した。さらに、上記、１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレアが血管新生を抑制することや、網膜細胞だけでなく肺や肝臓の細胞に対しても線維化マーカーの発現を抑制することを見いだし、本発明を完成した。 Searching for effective drugs for angiogenesis-related diseases, especially retinochoroidal disorders, is an important and interesting task in the ocular field. The present inventor conducted diligent research to search for a new drug effective for retinal choroidal damage, and found that 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea (1- (cyclobutylcarbonyl) -3-. (4-chlorophenyl) urea), or a pharmacologically acceptable salt thereof, showed an inhibitory effect on cell migration and epithelial-mesenchymal transition in pharmacological tests using human retinal pigment epithelial cells, and further, a mouse retinal fibrosis model. It was found that it suppresses fibrous scar formation. Furthermore, the above-mentioned 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea suppresses angiogenesis and suppresses the expression of fibrosis markers not only in retinal cells but also in lung and liver cells. I found out what to do and completed the present invention.
　すなわち、本発明は、以下のとおりである。
〔１〕１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩を有効成分として含有する医薬組成物。
〔２〕血管新生関連疾患の予防又は治療に用いられることを特徴とする上記〔１〕記載の医薬組成物。
〔３〕血管新生関連疾患が眼における血管新生関連疾患であることを特徴とする上記〔２〕記載の医薬組成物。
〔４〕眼における血管新生関連疾患が、網脈絡膜障害、角結膜障害、又は血管新生緑内障であることを特徴とする、上記〔３〕記載の医薬組成物。
〔５〕網脈絡膜障害が、糖尿病網膜症、加齢黄斑変性症、網膜剥離、増殖硝子体網膜症、ぶどう膜炎、眼感染症、未熟児網膜症、新生血管黄斑症又は網脈絡膜炎であることを特徴とする上記〔４〕記載の医薬組成物。
〔６〕眼における血管新生関連疾患が、網脈絡膜障害、角結膜障害、血管新生緑内障から選択されるいずれか一種に起因する線維性瘢痕の形成又は収縮であることを特徴とする上記〔３〕記載の医薬組成物。
〔７〕線維性瘢痕が、網膜上、網膜内及び／又は網膜下における線維性瘢痕であることを特徴とする、上記〔６〕記載の医薬組成物。
〔８〕線維性瘢痕が、網膜下の網膜色素上皮組織における線維性瘢痕であることを特徴とする、上記〔７〕記載の医薬組成物
〔９〕血管新生関連疾患が臓器線維症であることを特徴とする、上記〔３〕記載の医薬組成物
〔１０〕臓器線維症が肺線維症又は肝臓線維症であることを特徴とする、上記〔９〕記載の医薬組成物。
〔１１〕血管新生の抑制に用いられることを特徴とする、上記〔１〕記載の医薬組成物。
〔１２〕血管新生が眼における血管新生であることを特徴とする、上記〔１１〕記載の医薬組成物。
〔１３〕血管新生が網膜上、網膜内及び／又は網膜下における血管新生であることを特徴とする、上記〔１２〕記載の医薬組成物。 That is, the present invention is as follows.
[1] A pharmaceutical composition containing 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient.
[2] The pharmaceutical composition according to the above [1], which is used for the prevention or treatment of angiogenesis-related diseases.
[3] The pharmaceutical composition according to the above [2], wherein the angiogenesis-related disease is an angiogenesis-related disease in the eye.
[4] The pharmaceutical composition according to the above [3], wherein the angiogenesis-related disease in the eye is retinochoroidal disorder, keratoconjunctival disorder, or angiogenic glaucoma.
[5] Retinopathy of prematurity is diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreous retinopathy, uveitis, eye infection, retinopathy of prematurity, neovascular macular degeneration, or retinopathy. The pharmaceutical composition according to the above [4].
[6] The above-mentioned [3] that the angiogenesis-related disease in the eye is the formation or contraction of fibrous scar caused by any one selected from retinochoroidal disorder, keratoconjunctival disorder, and angiogenic glaucoma. The pharmaceutical composition described.
[7] The pharmaceutical composition according to the above [6], wherein the fibrous scar is a fibrous scar on the retina, intraretinal and / or subretinal.
[8] The pharmaceutical composition according to the above [7], wherein the fibrotic scar is a fibrotic scar in the retinal pigment epithelial tissue under the retina. [9] Angiogenesis-related disease is organ fibrosis. The pharmaceutical composition according to the above [3], wherein the organ fibrosis is pulmonary fibrosis or liver fibrosis.
[11] The pharmaceutical composition according to the above [1], which is used for suppressing angiogenesis.
[12] The pharmaceutical composition according to the above [11], wherein the angiogenesis is angiogenesis in the eye.
[13] The pharmaceutical composition according to the above [12], wherein the angiogenesis is angiogenesis on the retina, intraretinal and / or subretinal.
　また、本発明の他の態様は、以下のとおりである。
（１）血管新生関連疾患の予防又は治療に用いるための１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩。
（２）１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩の有効量を、必要とする対象に投与することを特徴とする血管新生関連疾患の予防又は治療方法。
（３）１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩の、血管新生関連疾患の予防又は治療に用いるための医薬組成物を調整するための使用。
（４）血管新生の抑制に用いるための１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩。
（５）１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩の有効量を、必要とする対象に投与することを特徴とする血管新生の抑制方法。
（６）１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩の、血管新生の抑制に用いるための医薬組成物を調整するための使用。 In addition, other aspects of the present invention are as follows.
(1) 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea for use in the prevention or treatment of angiogenesis-related diseases, or a pharmacologically acceptable salt thereof.
(2) Angiogenesis-related diseases characterized in that an effective amount of 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof is administered to a subject in need. Prevention or treatment method.
(3) To prepare a pharmaceutical composition of 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea, or a pharmacologically acceptable salt thereof, for use in the prevention or treatment of angiogenesis-related diseases. use.
(4) 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea for use in suppressing angiogenesis, or a pharmacologically acceptable salt thereof.
(5) A method for suppressing angiogenesis, which comprises administering an effective amount of 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof to a subject in need. ..
(6) Use of 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea, or a pharmacologically acceptable salt thereof, for preparing a pharmaceutical composition for use in suppressing angiogenesis.
　本発明により、血管新生関連疾患の予防又は治療や、血管新生の抑制に対して優れた効果を発揮する医薬組成物を提供できる。 INDUSTRIAL APPLICABILITY According to the present invention, it is possible to provide a pharmaceutical composition that exerts an excellent effect on the prevention or treatment of angiogenesis-related diseases and the suppression of angiogenesis.
実施例1において、0.3% FBS入りDMEM（コントロール）、又は0.3% FBS入りDMEM+BPU17(1,3,or 5μM)それぞれを添加して１８時間培養後における培養底の傷の幅を測定した結果を示す図である。In Example 1, the result of adding 0.3% FBS-containing DMEM (control) or 0.3% FBS-containing DMEM + BPU17 (1,3, or 5 μM) and measuring the width of the wound on the culture bottom after culturing for 18 hours. It is a figure which shows. 実施例１において、0.3% FBS入りDMEM（コントロール）又はBPU17 3μMを添加した場合の処理０時間又は１８時間培養後における培養底の写真を示す図である。It is a figure which shows the photograph of the culture bottom after the treatment for 0 hour or 18 hours when DMEM (control) containing 0.3% FBS or BPU17 3 μM was added in Example 1. 実施例２において、細胞を蛍光顕微鏡で観察した結果を示す図である。It is a figure which shows the result of having observed the cell with a fluorescence microscope in Example 2. 実施例２において、イムノブロットの結果を示す図である。It is a figure which shows the result of the immunoblot in Example 2. 実施例３において、眼球を摘出して顕微鏡で観察した結果を示す図である。It is a figure which shows the result of having taken out the eyeball and observed with a microscope in Example 3. FIG. 実施例３において、摘出した眼球の線維化面積の測定結果を示す図である。It is a figure which shows the measurement result of the fibrotic area of the removed eyeball in Example 3. 実施例４において、大動脈血管内皮細胞におけるBrdUの取り込み率を調べた結果である。This is the result of examining the uptake rate of BrdU in aortic vascular endothelial cells in Example 4. 実施例５において、HAoEC溶液の接種から２２時間後の顕微鏡観察（×40）による写真を示す図である。In Example 5, it is a figure which shows the photograph by the microscope observation (× 40) 22 hours after inoculation of the HAoEC solution. 実施例５において、HAoEC溶液の接種から２２時間後の細胞数あたりの分岐点（branching points）の割合（%）を示す図である。In Example 5, it is a figure which shows the ratio (%) of branching points per cell number 22 hours after inoculation of HAoEC solution. 実施例５において、HAoEC溶液の接種から２２時間後のチューブ長（μm）を示す図である。It is a figure which shows the tube length (μm) 22 hours after inoculation of the HAoEC solution in Example 5. 実施例６において、眼球を摘出して顕微鏡で観察した結果を示す図である。It is a figure which shows the result of having taken out the eyeball and observed with a microscope in Example 6. 実施例６において、摘出した眼球の網脈絡膜新生血管（CNV）面積の測定結果を示す図である。It is a figure which shows the measurement result of the reticulochoroidal neovascularization (CNV) area of the excised eyeball in Example 6. 実施例７において、CTGF mRNA発現量を測定した結果を示す図である。It is a figure which shows the result of having measured the CTGF mRNA expression level in Example 7. 実施例７において、αSM-actin mRNA発現量を測定した結果を示す図である。It is a figure which shows the result of having measured the αSM-actin mRNA expression level in Example 7.
　本明細書における医薬組成物としては、以下の式（I）で表される１－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア（1-(cyclobutylcarbonyl)-3-(4-chlorophenyl)urea：以下、「本件化合物」又は「BRU17」ともいう）、又はその薬理上許容される塩を有効成分として含有する医薬組成物（以下、「本件医薬組成物」ともいう）であれば特に制限されないが、血管新生関連疾患の予防又は治療に用いられることや、血管新生の抑制に用いられることが好ましい。 The pharmaceutical composition in the present specification is 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea (1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) represented by the following formula (I). urea: Particularly limited as long as it is a pharmaceutical composition containing the "Compound" or "BRU17") or a pharmacologically acceptable salt thereof as an active ingredient (hereinafter, also referred to as "Pharmaceutical Composition"). However, it is preferably used for the prevention or treatment of angiogenesis-related diseases and for suppressing angiogenesis.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　本明細書における上記「血管新生関連疾患」としては、眼における血管新生関連疾患、又は臓器線維症を挙げることができる。かかる「眼における血管新生関連疾患」としては、網膜、脈絡膜、角膜、結膜、強膜、ぶどう膜、硝子体又は水晶体における血管新生関連疾患を挙げることができ、例えば、網脈絡膜障害、角結膜障害、血管新生緑内障を挙げることができる。なお、網脈絡膜とは網膜と脈絡膜を合わせた組織を意味する。 Examples of the above-mentioned "angiogenesis-related disease" in the present specification include angiogenesis-related disease in the eye or organ fibrosis. Examples of such "neovascularization-related diseases in the eye" include angiogenesis-related diseases in the retinal, choroidal membrane, cornea, conjunctiva, sclera, uvea, vitreous body or lens, and examples thereof include reticuloconjunctival disorder and keratoconjunctival disorder. , Neovascular glaucoma can be mentioned. The retinochoroid means a tissue in which the retina and the choroid are combined.
　本明細書における上記「網脈絡膜障害」とは、網膜及び／又は脈絡膜における視細胞、神経節細胞、網膜色素上皮細胞及び上記各細胞から構成された組織に損傷が生じた状態を意味し、最終的には細胞死や組織機能障害をきたし、視力や視野などの視機能に異常をきたした状態にあることもある。具体的には、糖尿病網膜症、加齢黄斑変性症、網膜剥離、増殖硝子体網膜症、ぶどう膜炎、眼感染症、未熟児網膜症、新生血管黄斑症、網脈絡膜炎、網膜及び／又は脈絡膜血管新生、網膜及び／又は脈絡膜血管新生の形成に続発する網膜及び／又は網膜下出血を挙げることができる。 The above-mentioned "retinal choroidal disorder" in the present specification means a state in which a tissue composed of photoreceptor cells, ganglion cells, retinal pigment epithelial cells and each of the above cells in the retina and / or the choroid is damaged, and finally. In some cases, cell death or tissue dysfunction occurs, and visual function such as visual acuity and visual acuity is abnormal. Specifically, diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreous retinopathy, vaginitis, eye infection, premature infant retinopathy, neovascular macular degeneration, retinal choroiditis, retina and / or Examples include retinal and / or subretinal hemorrhage secondary to the formation of choroidal neovascularization, retina and / or choroidal neovascularization.
　本明細書における上記「角結膜障害」とは、角膜上皮、角膜実質層、角膜内皮に損傷が生じた状態にあるものをいう。具体的には、角膜炎、角膜外傷、角膜潰瘍、角膜上皮剥離、ドライアイ、角膜びらん、角膜移植後拒絶反応、角膜糜爛、遷延性角膜障害、点状表層角膜症、角膜上皮欠損、角膜血管新生、結膜炎、結膜潰瘍、結膜上皮欠損、結膜血管新生を挙げることができる。 The above-mentioned "corneal conjunctival disorder" in the present specification refers to a state in which the corneal epithelium, the stroma layer of the cornea, and the corneal endothelium are damaged. Specifically, corneal inflammation, corneal trauma, corneal ulcer, corneal epithelial detachment, dry eye, corneal erosion, rejection after corneal transplantation, corneal erosion, protracted corneal disorder, punctate superficial keratopathy, corneal epithelial defect, corneal blood vessels Examples include neoplasia, conjunctival inflammation, conjunctival ulcer, conjunctival epithelial defect, and conjunctival angiogenesis.
　本明細書における上記「線維性瘢痕」とは、出血、手術、感染等による炎症の沈静化あるいは進行に伴い、炎症組織の損傷部位で生じた線維性結合組織である。また、上記「線維性瘢痕の形成」とは、上記炎症の沈静化あるいは進行に伴い、損傷部位で線維性結合組織が形成されることをいい、上記「線維性瘢痕の収縮」とは、形成された線維性瘢痕が治癒する際に、線維性瘢痕の周辺の組織を引きつけて収縮することをいう。線維性瘢痕の形成及び収縮は一連に生じ、この線維性瘢痕の形成及び収縮を抑制することにより、線維性瘢痕の周辺の組織の変形が生じて眼組織の機能に障害が生じることを防ぐことができる。 The above-mentioned "fibrous scar" in the present specification is fibrous connective tissue generated at a damaged site of inflamed tissue as inflammation subsides or progresses due to bleeding, surgery, infection, or the like. Further, the above-mentioned "formation of fibrous scar" means that fibrous connective tissue is formed at the injured site as the inflammation subsides or progresses, and the above-mentioned "contraction of fibrous scar" means formation. When the fibrous scar is healed, it attracts and contracts the tissue around the fibrous scar. The formation and contraction of fibrous scars occur in a series, and by suppressing the formation and contraction of this fibrous scar, it is possible to prevent the tissue around the fibrous scar from being deformed and impairing the function of eye tissue. Can be done.
　線維性瘢痕は網脈絡膜障害、角結膜障害、血管新生緑内障から選択されるいずれか一種に起因するものであればよい。また線維性瘢痕が形成又は収縮される場所としては眼のいずれであってもよく、網膜上、網膜内、及び／又は網膜下における線維性瘢痕や、角膜における線維性瘢痕や、結膜における線維性瘢痕を挙げることができ、網膜下の網膜色素上皮組織における線維性瘢痕を好適に挙げることができる。上記「網膜上」とは網膜面の上をいい、上記「網膜下」とは、網膜と脈絡膜との間、脈絡膜内及び脈絡膜下をいう。 The fibrous scar may be caused by any one selected from retinochoroidal disorder, keratoconjunctival disorder, and neovascular glaucoma. The place where the fibrous scar is formed or contracted may be any of the eyes, and the fibrous scar on the retina, the intraretinal, and / or the subretinal, the fibrous scar on the cornea, and the fibrous on the conjunctiva. Scars can be mentioned, and fibrous scars in the retinal pigment epithelial tissue under the retina can be preferably mentioned. The "above the retina" means above the surface of the retina, and the "subretina" means between the retina and the choroid, intrachoroidally, and subchoroidally.
　上記「網膜上、網膜内、及び／又は網膜下における線維性瘢痕」とは、眼炎症の沈静化あるいは進行に伴い、網膜上、網膜内及び／又は網膜下の損傷部位で生じた線維性結合組織、好ましくは網膜下の損傷部位で生じた線維性結合組織であり、主に網膜色素上皮細胞、線維芽細胞、グリア細胞等とコラーゲンを始めとする細胞外マトリックスから構成された組織である。かかる網膜上、網膜内、及び／又は網膜下における線維性瘢痕の形成及び収縮は一連に生じ、この線維性瘢痕の形成及び収縮を抑制することにより、網膜上、網膜内、及び／又は網膜下における線維性瘢痕の黄斑部並びに周辺の組織の変形が生じて網脈絡膜機能に障害が生じることを防ぐことができる。 The above-mentioned "fibrous scar on the retina, intraretinal, and / or subretinal" refers to fibrous connective tissue generated at an injured site on the retina, intraretinal, and / or subretinal as the ocular inflammation subsides or progresses. It is a tissue, preferably a fibrous connective tissue generated at an injured site under the retina, and is a tissue mainly composed of retinal pigment epithelial cells, fibroblasts, glial cells and the like and an extracellular matrix including collagen. Such supretinal, intraretinal, and / or subretinal formation and contraction of fibrous scars occur in sequence, and by suppressing the formation and contraction of this fibrous scar, supretinal, intraretinal, and / or subretinal. It is possible to prevent the macular region of the fibrous scar and the surrounding tissue from being deformed and impairing the retinal choroidal function.
　本明細書における上記「臓器線維症」とは、傷害の加わった臓器の創傷治癒における一過程における線維症であり、炎症と細胞外基質の産生と分解のバランスが崩れて過剰な状態（慢性炎症）が続き、臓器の硬化性変化を引き起こした状態を意味し、かかる臓器線維症においては臓器機能障害ひいては臓器不全につながる。上記臓器線維症としては、肺線維症、肝臓線維症、腎線維症、膵線維症、心筋線維症、消化管線維症、骨髄線維症、術後瘢痕を挙げることができる。 The above-mentioned "organ fibrosis" in the present specification is fibrosis in one process in wound healing of an injured organ, and is an excessive state (chronic inflammation) in which the balance between inflammation and production and decomposition of extracellular matrix is lost. ) Continues, meaning a state that has caused sclerosing changes in the organ, leading to organ dysfunction and eventually organ failure in such organ fibrosis. Examples of the organ fibrosis include pulmonary fibrosis, liver fibrosis, renal fibrosis, pancreatic fibrosis, myocardial fibrosis, gastrointestinal fibrosis, myelofibrosis, and postoperative scarring.
　本明細書における上記「血管新生の抑制」における血管新生としては特に制限されないが、眼における血管新生、好ましくは網膜上、網膜内及び／又は網膜下、角膜、又は結膜における血管新生を好適に挙げることができる。また、血管新生の抑制とは、既存の血管からの新しい血管の形成又は成長を抑制することを意味する。 The neovascularization in the above-mentioned "suppression of neovascularization" in the present specification is not particularly limited, but neovascularization in the eye, preferably neovascularization in the retina, intraretinal and / or subretinal, cornea, or conjunctiva is preferably mentioned. be able to. In addition, suppression of angiogenesis means suppressing the formation or growth of new blood vessels from existing blood vessels.
　本件医薬組成物の有効成分である本件化合物、又はその塩は、たとえば上記非特許文献１に記載された方法等、公知の有機化学反応を用いる有機合成手法によって得ることもできるほか、市販品を購入することもできる。 The compound, which is the active ingredient of the pharmaceutical composition, or a salt thereof can be obtained by an organic synthesis method using a known organic chemical reaction, such as the method described in Non-Patent Document 1, or a commercially available product. You can also buy it.
　上記「薬理上許容される塩」としては、（１）酸付加塩として、塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硝酸塩、硫酸塩若しくはリン酸塩等の無機酸塩；又は酢酸塩、トリフルオロ酢酸塩、安息香酸塩、シュウ酸塩、マロン酸塩、コハク酸塩、マレイン酸塩、フマル酸塩、酒石酸塩、クエン酸塩、メタンスルホン酸塩、エタンスルホン酸塩、トリフルオロメタンスルホン酸塩、ベンゼンスルホン酸塩、ｐ－トルエンスルホン酸塩、グルタミン酸塩若しくはアスパラギン酸塩等の有機酸塩、或いは（２）塩基性塩として、ナトリウム塩、カリウム塩、カルシウム塩若しくはマグネシウム塩等の金属塩；アンモニウム塩等の無機塩；又はトリエチルアミン塩若しくはグアニジン塩等の有機アミン塩等を好適に挙げることができる。 The above-mentioned "pharmaceutically acceptable salt" includes (1) as an acid addition salt, an inorganic salt such as a hydrochloride, a hydrobromide, a hydroiodide, a nitrate, a sulfate or a phosphate; Acetate, trifluoroacetate, benzoate, oxalate, malonate, succinate, maleate, fumarate, tartrate, citrate, methanesulfonate, ethanesulfonate, trifluo Organic acid salts such as lomethane sulfonate, benzene sulfonate, p-toluene sulfonate, glutamate or asparagate, or (2) basic salts such as sodium salt, potassium salt, calcium salt or magnesium salt. Metal salts; inorganic salts such as ammonium salts; or organic amine salts such as triethylamine salts or guanidine salts can be preferably mentioned.
　本件医薬組成物は、適宜の薬理上許容される添加剤と混合して、点眼剤として点眼投与することができる。添加剤として、等張化剤、緩衝剤、ｐＨ調節剤、可溶化剤、増粘剤、安定化剤、保存剤（防腐剤）等を適宜配合することにより、周知の方法で製剤化することができる。また、ｐＨ調節剤、増粘剤、分散剤等を添加し、薬物を懸濁化させることによって、安定な点眼剤を得ることもできる。 The Pharmaceutical Composition can be mixed with an appropriate pharmacologically acceptable additive and administered by eye drops as an eye drop. Formulation by a well-known method by appropriately blending an tonicity agent, a buffer, a pH adjuster, a solubilizer, a thickener, a stabilizer, a preservative (preservative), etc. as additives. Can be done. In addition, a stable eye drop can be obtained by suspending the drug by adding a pH adjuster, a thickener, a dispersant, or the like.
　上記等張化剤としては、例えば、グリセリン、プロピレングリコール、塩化ナトリウム、塩化カリウム、ソルビトール若しくはマンニトール等を挙げることができる。 Examples of the tonicity agent include glycerin, propylene glycol, sodium chloride, potassium chloride, sorbitol, mannitol and the like.
　上記緩衝剤としては、例えば、リン酸、リン酸塩、クエン酸、酢酸若しくはε-アミノカプロン酸等を挙げることができる。 Examples of the buffering agent include phosphoric acid, phosphate, citric acid, acetic acid, ε-aminocaproic acid and the like.
　上記ｐＨ調節剤としては、例えば、塩酸、クエン酸、リン酸、酢酸、水酸化ナトリウム、水酸化カリウム、ホウ酸、ホウ砂、リン酸水素二ナトリウム、リン酸二水素ナトリウム、炭酸ナトリウム若しくは炭酸水素ナトリウム等を挙げることができる。 Examples of the pH adjusting agent include hydrochloric acid, citric acid, phosphoric acid, acetic acid, sodium hydroxide, potassium hydroxide, boric acid, borax, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium carbonate or hydrogen carbonate. Examples include sodium and the like.
　上記可溶化剤としては、例えば、ポリソルベート８０、ポリオキシエチレン硬化ヒマシ油６０、マクロゴール４０００等を挙げることができる。 Examples of the solubilizer include polysorbate 80, polyoxyethylene hydrogenated castor oil 60, macrogol 4000 and the like.
　上記増粘剤及び分散剤としては、例えば、ヒドロキシプロピルメチルセルロース若しくはヒドロキシプロピルセルロース等のセルロース系高分子；ポリビニルアルコール；又はポリビニルピロリドン等を、また、安定化剤としては、例えば、エデト酸若しくはエデト酸ナトリウム等を挙げることができる。 Examples of the thickener and dispersant include cellulosic polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose; polyvinyl alcohol; or polyvinylpyrrolidone, and examples of stabilizers include edetic acid and edetic acid. Examples include sodium and the like.
　上記保存剤（防腐剤）としては、例えば、汎用のソルビン酸、ソルビン酸カリウム、塩化ベンザルコニウム、塩化ベンゼトニウム、パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル若しくはクロロブタノール等が挙げられ、これらの保存剤を組み合わせて使用することもできる。 Examples of the preservative (preservative) include general-purpose sorbic acid, potassium sorbate, benzalkonium chloride, benzethonium chloride, methyl paraoxybenzoate, propyl paraoxybenzoate, chlorobutanol and the like, and these preservatives. Can also be used in combination.
　上記点眼剤のｐＨは眼科製剤に許容される範囲内にあればよいが、４．０～８．５に設定することが望ましい。 The pH of the above eye drops may be within the range allowed for ophthalmic preparations, but it is desirable to set it to 4.0 to 8.5.
　本件医薬組成物は、上記の点眼剤型に加えて、適宜の薬理上許容される添加剤と混合して製造される、軟膏剤（好ましくは、眼軟膏）、注射剤、錠剤、顆粒剤、細粒剤、散剤、カプセル剤、吸入剤、シロップ剤、丸剤、液剤、懸濁剤、乳剤、経皮吸収剤、坐剤、ローション等の形態で、経口、又は非経口（静脈内投与、筋肉内投与、腹腔内投与、経皮投与、経気道投与、皮内投与又は皮下投与）で投与することもできる。これらの製剤は、賦形剤、滑沢剤、結合剤、崩壊剤、乳化剤、安定剤、矯味矯臭剤又は希釈剤等の添加剤を使用して、周知の方法で製造される。 The Pharmaceutical Composition is an ointment (preferably an eye ointment), an injection, a tablet, a granule, which is produced by mixing with an appropriate pharmacologically acceptable additive in addition to the above-mentioned ointment type. Oral or parenteral (intravenous administration, intravenous administration, in the form of fine granules, powders, capsules, inhalants, syrups, pills, solutions, suspensions, emulsions, transdermal absorbents, suppositories, lotions, etc. It can also be administered by intramuscular administration, intraperitoneal administration, transdermal administration, transairway administration, intradermal administration or subcutaneous administration). These formulations are prepared by well-known methods using additives such as excipients, lubricants, binders, disintegrants, emulsifiers, stabilizers, flavoring agents or diluents.
　上記賦形剤は、例えば、有機系賦形剤又は無機系賦形剤が挙げられる。有機系賦形剤は、例えば、乳糖、ショ糖、ブドウ糖、マンニトール若しくはソルビトール等の糖誘導体；トウモロコシデンプン、馬鈴薯デンプン、α－デンプン若しくはデキストリン等のデンプン誘導体；結晶セルロース等のセルロース誘導体；アラビアゴム；デキストラン；又はプルラン等が挙げられる。無機系賦形剤は、例えば、軽質無水珪酸；又は硫酸カルシウム等の硫酸塩等が挙げられる。 Examples of the above-mentioned excipient include organic excipients and inorganic excipients. Organic excipients include, for example, sugar derivatives such as lactose, sucrose, glucose, mannitol or sorbitol; starch derivatives such as corn starch, potato starch, α-starch or dextrin; cellulose derivatives such as crystalline cellulose; gum arabic; Dextrin; or pull run and the like. Examples of the inorganic excipient include light anhydrous silicic acid; and sulfates such as calcium sulfate.
　上記滑沢剤は、例えば、ステアリン酸；ステアリン酸カルシウム若しくはステアリン酸マグネシウム等のステアリン酸金属塩；タルク；コロイドシリカ；ビーズワックス若しくはゲイロウ等のワックス類；硼酸；アジピン酸；硫酸ナトリウム等の硫酸塩；グリコール；フマル酸；安息香酸ナトリウム；Ｄ，Ｌ－ロイシン；ラウリル硫酸ナトリウム；無水珪酸若しくは珪酸水和物等の珪酸類；又は上記の賦形剤におけるデンプン誘導体等が挙げられる。 The lubricants include, for example, stearic acid; metal stearic acid salts such as calcium stearate or magnesium stearate; talc; colloidal silica; waxes such as bead wax or gay wax; boric acid; adipic acid; sulfates such as sodium sulfate; Glycols; fumaric acid; sodium benzoate; D, L-leucine; sodium lauryl sulfate; silicic acids such as anhydrous silicic acid or silicic acid hydrate; or starch derivatives in the above excipients.
　上記結合剤は、例えば、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロース、ポリビニルピロリドン、マクロゴール又は上記の賦形剤で示された化合物等が挙げられる。 Examples of the binder include hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinylpyrrolidone, macrogol, compounds shown by the above excipients, and the like.
　上記崩壊剤は、例えば、低置換度ヒドロキシプロピルセルロース、カルボキシメチルセルロース、カルボキシメチルセルロースカルシウム若しくは内部架橋カルボキシメチルセルロースカルシウム等のセルロース誘導体；架橋ポリビニルピロリドン；又はカルボキシメチルスターチ若しくはカルボキシメチルスターチナトリウム等の化学修飾されたデンプン若しくはセルロース誘導体等が挙げられる。 The disintegrant is, for example, a cellulose derivative such as low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethyl cellulose calcium or internally cross-linked carboxymethyl cellulose calcium; cross-linked polyvinylpyrrolidone; or chemically modified such as carboxymethyl starch or sodium carboxymethyl starch. Examples include starch and cellulose derivatives.
　上記乳化剤は、例えば、ベントナイト若しくはビーガム等のコロイド性粘土；ラウリル硫酸ナトリウム等の陰イオン界面活性剤；塩化ベンザルコニウム等の陽イオン界面活性剤；又はポリオキシエチレンアルキルエーテル、ポリオキシエチレンソルビタン脂肪酸エステル若しくはショ糖脂肪酸エステル等の非イオン界面活性剤等が挙げられる。 The emulsifiers are, for example, colloidal clays such as bentonite or beagum; anionic surfactants such as sodium lauryl sulfate; cationic surfactants such as benzalkonium chloride; or polyoxyethylene alkyl ethers, polyoxyethylene sorbitan fatty acids. Examples thereof include nonionic surfactants such as esters and sucrose fatty acid esters.
　上記安定剤は、例えば、メチルパラベン若しくはプロピルパラベン等のパラヒドロキシ安息香酸エステル類；クロロブタノール、ベンジルアルコール若しくはフェニルエチルアルコール等のアルコール類；塩化ベンザルコニウム；フェノール若しくはクレゾール等のフェノール類；チメロサール；無水酢酸；又はソルビン酸が挙げられる。 The stabilizers include, for example, parahydroxybenzoic acid esters such as methylparaben or propylparaben; alcohols such as chlorobutanol, benzyl alcohol or phenylethyl alcohol; benzalconium chloride; phenols such as phenol or cresol; timerosal; anhydrous. Acetic acid; or sorbic acid.
　上記矯味矯臭剤は、例えば、サッカリンナトリウム若しくはアスパルテーム等の甘味料；クエン酸、リンゴ酸若しくは酒石酸等の酸味料；又はメントール、レモンエキス若しくはオレンジエキス等の香料等が挙げられる。 Examples of the flavoring and odorant include sweeteners such as sodium saccharin or aspartame; acidulants such as citric acid, malic acid or tartaric acid; or flavors such as menthol, lemon extract or orange extract.
　上記希釈剤は、通常希釈剤として使用される化合物であり、例えば、乳糖、マンニトール、ブドウ糖、ショ糖、硫酸カルシウム、ヒドロキシプロピルセルロース、微結晶性セルロース、水、エタノール、ポリエチレングリコール、プロピレングリコール、グリセロール、デンプン、ポリビニルピロリドン又はこれらの混合物等が挙げられる。 The above-mentioned diluent is a compound usually used as a diluent, for example, lactose, mannitol, glucose, sucrose, calcium sulfate, hydroxypropyl cellulose, microcrystalline cellulose, water, ethanol, polyethylene glycol, propylene glycol, glycerol. , Starch, polyvinylpyrrolidone or a mixture thereof and the like.
　上記軟膏剤（好ましくは、眼軟膏）の場合は、白色ワセリン若しくは流動パラフィン等の汎用される基剤を用いて調製することができる。 In the case of the above ointment (preferably eye ointment), it can be prepared using a general-purpose base such as white petrolatum or liquid paraffin.
　本件医薬組成物の投与量は、剤型、投与すべき患者の症状の軽重、年齢、体重、医師の判断等に応じて適宜変えることができるが、点眼剤の場合には、０．０００００１～１０％（Ｗ／Ｖ）、好ましくは０．００００１～３％（Ｗ／Ｖ）、より好ましくは０．０００１～１％（Ｗ／Ｖ）の有効成分濃度のものを１日１回又は数回投与することができ、経口剤の場合、一般には、成人に対し１日あたり０．０１～５０００ｍｇ、好ましくは０．１～２５００ｍｇ、より好ましくは０．５～１０００ｍｇを１回又は数回に分けて投与することができる。また、眼軟膏の場合には、０．００００１～１０％（Ｗ／Ｗ）、好ましくは０．０００１～３％（Ｗ／Ｗ）、より好ましくは０．００１～１％（Ｗ／Ｗ）の有効成分濃度のものを１日１回又は数回投与することができる。 The dose of the pharmaceutical composition can be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, age, weight, judgment of a doctor, etc., but in the case of eye drops, 0.000001 to An active ingredient concentration of 10% (W / V), preferably 0.00001 to 3% (W / V), more preferably 0.0001 to 1% (W / V) once or several times a day. In the case of oral preparations, which can be administered, in general, 0.01 to 5000 mg, preferably 0.1 to 2500 mg, more preferably 0.5 to 1000 mg per day is divided into one or several times for adults. Can be administered. In the case of eye ointment, it is 0.00001 to 10% (W / W), preferably 0.0001 to 3% (W / W), and more preferably 0.001 to 1% (W / W). The active ingredient concentration can be administered once or several times a day.
　本明細書中において、「予防」とは、細胞、組織、臓器の欠損及び機能障害、機能不全に関連する疾患の発症及び再発を抑制、防止することを目的とする手段を意味する。 In the present specification, "prevention" means a means for suppressing or preventing the onset and recurrence of diseases related to cell, tissue, organ defect and dysfunction, and dysfunction.
　本明細書中において、「治療」とは、細胞、組織、臓器の欠損及び機能障害、機能不全に関連する疾患の進行、増悪を減速又は停止すること、及び細胞、組織、臓器の欠損及び機能障害、機能不全に関連する疾患を軽快、改善、治癒することを目的とする手段を意味する。 As used herein, "treatment" refers to the loss and dysfunction of cells, tissues and organs, the slowing or stopping of progression and exacerbation of diseases associated with dysfunction, and the loss and function of cells, tissues and organs. It means a means aimed at ameliorating, ameliorating, or curing a disease related to a disorder or dysfunction.
　以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to Examples, but the technical scope of the present invention is not limited to these examples.
［実施例１］
　網脈絡膜障害の予防又は治療に対するBPU17の効果を調べるため、ヒト網膜色素上皮細胞RPE-１を用いて以下の実験を行った。なお、網膜色素上細胞は網膜における線維性瘢痕を形成する代表的な細胞成分である。ヒト網膜色素上皮細胞RPE-１を10% FBS培地で培養した。培養した細胞を２４ウェルディッシュに播種し、コンフルエントまで培養を続けた。その後、血清フリー(FBSなし)のダルベッコ改変イーグル培地（DMEM）で２４時間培養後、培養底に単一の幅の傷をつけ、0.3% FBS入りDMEM（コントロール）、又は0.3% FBS入りDMEM+BPU17(1,3,or 5μM)を添加して１８時間培養した。BPU17は国立大学法人京都大学の渡辺文太先生より提供いただいたものを用いた。１８時間後に培養底の傷の幅を測定して、細胞移動量の定量評価を行った。それぞれの培養底の傷の幅を測定した結果を図１に示す。図中、0.3% FBS入りDMEM（コントロール）を0.3% FBS、0.3% FBS入りDMEM+BPU17(1,3,or 5μM)をそれぞれ0.3% FBS 、0.3% FBS+BPU17 1μM、0.3% FBS+BPU17 3μM、0.3% FBS+BPU17 5μMで表し、縦軸は培養底の傷の幅（μm）である。また、0.3% FBS入りDMEM（コントロール）又は0.3% FBS+BPU17 3μMを添加した場合の０時間又は１８時間培養後におけるにおける培養底の写真を図２に示す。図１、２に示すように、BPU17を加えることで、濃度依存的に上皮間葉転換（Epithelial to mesenchymal transition; EMT）における生物的特性の一つである網膜色素上細胞の移動を抑制していることが明らかとなった。 [Example 1]
In order to investigate the effect of BPU17 on the prevention or treatment of reticulochoroidal disorders, the following experiments were performed using human retinal pigment epithelial cell RPE-1. The retinal pigmented cells are typical cell components that form fibrous scars in the retina. Human retinal pigment epithelial cell RPE-1 was cultured in 10% FBS medium. The cultured cells were seeded in a 24-well dish and the culture was continued until confluent. Then, after culturing in Dulbecco's modified Eagle's medium (DMEM) free of serum (without FBS) for 24 hours, the bottom of the culture is injured with a single width, and DMEM (control) containing 0.3% FBS or DMEM + containing 0.3% FBS. BPU17 (1,3, or 5 μM) was added and cultured for 18 hours. BPU17 used was provided by Professor Bunta Watanabe of Kyoto University. After 18 hours, the width of the wound on the bottom of the culture was measured to quantitatively evaluate the amount of cell migration. The result of measuring the width of the wound of each culture bottom is shown in FIG. In the figure, DMEM (control) with 0.3% FBS is 0.3% FBS, DMEM + BPU17 (1,3, or 5 μM) with 0.3% FBS is 0.3% FBS, 0.3% FBS + BPU17 1 μM, 0.3% FBS + BPU17 3 μM, respectively. , 0.3% FBS + BPU17 5 μM, vertical axis is the width of the wound on the culture bottom (μm). In addition, FIG. 2 shows a photograph of the culture bottom after 0-hour or 18-hour culture when DMEM (control) containing 0.3% FBS or 0.3% FBS + BPU17 3 μM was added. As shown in FIGS. 1 and 2, the addition of BPU17 suppresses the migration of retinal pigment cells, which is one of the biological properties in epithelial to mesenchymal transition (EMT), in a concentration-dependent manner. It became clear that there was.
［実施例２］
　実施例１と同様の培養系にて、DMEM(None)、0.3% FBS、又は0.3% FBS+BPU17 3μMで処理し、１８時間後のRPE-1細胞をホルマリン固定し、alpha smooth muscle actin（α-SMA）、核をそれぞれ抗α-SMA抗体、DAPIにて細胞染色を行った。続いて、DMEM(none)、線維化を促進するサイトカインであるトランスフォーミング増殖因子-β2（TGF-β2）、若しくはTGF-β2+ BPU17 3μMで刺激し、その後細胞抽出液を回収し、イムノブロットを抗α-SMA抗体を用いて行った。細胞抽出液を回収した後の細胞を蛍光顕微鏡で観察した結果を図３に、イムノブロットの結果を図４に示す。 [Example 2]
In the same culture system as in Example 1, treatment with DMEM (None), 0.3% FBS, or 0.3% FBS + BPU17 3 μM was performed, and RPE-1 cells after 18 hours were formalin-fixed and alpha smooth muscle actin (α). -SMA) and nuclei were stained with anti-α-SMA antibody and DAPI, respectively. Subsequently, the cells are stimulated with DMEM (none), transforming growth factor-β2 (TGF-β2), which is a cytokine that promotes fibrosis, or TGF-β2 + BPU17 3 μM, and then the cell extract is collected to counter immunoblot. This was done using α-SMA antibody. The result of observing the cells with a fluorescence microscope after collecting the cell extract is shown in FIG. 3, and the result of immunoblot is shown in FIG.
　図３、４に示すように、BPU17なしではTGF-β2の刺激によって、線維化を亢進させるα-SMAの発現が増加しているが、BPU17で処理することによってα-SMAの発現が抑制されていた。したがって、上記実施例１の結果と併せて検討すると、BPU17で処理することによって網膜色素上細胞の上皮間葉転換（EMT）が抑制されて、網膜における線維性瘢痕形成の抑制につながると考えられる。 As shown in FIGS. 3 and 4, without BPU17, TGF-β2 stimulation increased the expression of α-SMA that promotes fibrosis, but treatment with BPU17 suppressed the expression of α-SMA. Was there. Therefore, when examined in combination with the results of Example 1, it is considered that treatment with BPU17 suppresses epithelial-mesenchymal transition (EMT) of retinal pigmented cells, leading to suppression of fibrous scar formation in the retina. ..
［実施例３］
　上記実施例２の結果を踏まえて、マウス網膜下瘢痕形成モデルを用いて、BPU17が網膜下線維性瘢痕形成の抑制作用を有するかどうかを検討した。マウスにおける網膜下瘢痕モデルは、Kobayashiらの方法（Investigative ophthalmology & visual science, Volume 60, Issue 2(2019)）に準じて以下に示す方法で作製した。具体的には、８週齢のマウス（CL57BL/6 雌：SLC社）の網膜にレーザー（200mW, 75μm, 0.1秒，532nm）を照射し、光凝固を視神経周囲、具体的にはDisc周辺２～３乳頭径に４箇所ほど施工した。同時にBPU17なしのコントロール（0.3% FBS ）、0.3% FBS+BPU17(30, 100, 300μM)を眼内に打ち込んだ。さらに、７日後に再度BPU17なしのコントロール、0.3% FBS+BPU17 (30, 100, 300μM)を眼内に打ち込んだ。２１日目に、眼球を摘出して固定後、コラーゲン一次抗体にてＩ型コラーゲンを染色して顕微鏡で観察すると共に線維化面積を測定した。顕微鏡での観察結果を図５に、線維化面積の測定結果を図６に示す。図６における縦軸は線維化面積（μｍ２）である。 [Example 3]
Based on the results of Example 2 above, it was examined whether BPU17 has an inhibitory effect on subretinal fibrous scar formation using a mouse subretinal scar formation model. The subretinal scar model in mice was prepared by the method shown below according to the method of Kobayashi et al. (Investigative ophthalmology & visual science, Volume 60, Issue 2 (2019)). Specifically, the retina of an 8-week-old mouse (CL57BL / 6 female: SLC) was irradiated with a laser (200 mW, 75 μm, 0.1 second, 532 nm) to perform photocoagulation around the optic nerve, specifically around the Disc 2 About 4 places were constructed with a diameter of 3 papillae. At the same time, control without BPU17 (0.3% FBS) and 0.3% FBS + BPU17 (30, 100, 300 μM) were injected into the eye. Furthermore, after 7 days, a control without BPU17, 0.3% FBS + BPU17 (30, 100, 300 μM) was injected into the eye again. On the 21st day, after the eyeball was removed and fixed, type I collagen was stained with a primary collagen antibody and observed under a microscope, and the fibrotic area was measured. The observation result with a microscope is shown in FIG. 5, and the measurement result of the fibrotic area is shown in FIG. The vertical axis in FIG. 6 is the fibrotic area (μm 2 ).
　図５、図６に示すようにBPU17を投与すると、濃度依存的にＩ型コラーゲンによる線維化が抑制されていた。したがって、インビボによる試験によってもBPU17が網膜における線維化を抑制することが確認された。 When BPU17 was administered as shown in FIGS. 5 and 6, fibrosis due to type I collagen was suppressed in a concentration-dependent manner. Therefore, in vivo tests also confirmed that BPU17 suppressed fibrosis in the retina.
［実施例４］
　ヒト大動脈血管内皮細胞（HAoEC）を培養し、Bromodeoxyuridine(BrdU)の取り込みによって細胞増殖性を評価した。HAoECを12ウェルプレートディッシュ（COLI-film 14 mm coverslip:1mL HEC-C1培地/well）に播種し、その後０．５時間後にウェル毎に培地（1mL HEC-C1）を置換した。翌日、ウェル毎に（１）HEC-C1培地のみ、（２）HEC-C1培地＋BPU17 1μM、（３）HEC-C1培地＋BPU17 3μM、（４）HEC-C1培地＋BPU17 10μMのいずれかで培地を置換した。その後４．５時間後にBrdU(再終濃度100μM:BruU 25mM 4μl/well)を加えた。 [Example 4]
Human aortic vascular endothelial cells (HAoEC) were cultured and cell proliferation was evaluated by uptake of Bromodeoxyuridine (BrdU). HAoEC was seeded on a 12-well plate dish (COLI-film 14 mm coverslip: 1 mL HEC-C1 medium / well), and 0.5 hours later, the medium (1 mL HEC-C1) was replaced for each well. The next day, replace the medium with one of (1) HEC-C1 medium only, (2) HEC-C1 medium + BPU17 1 μM, (3) HEC-C1 medium + BPU17 3 μM, and (4) HEC-C1 medium + BPU17 10 μM for each well. did. Then, 4.5 hours later, BrdU (refinal concentration 100 μM: BruU 25 mM 4 μl / well) was added.
　さらにその翌日に、４％パラホルムアルデヒド(PFA)＋４％ Sucrose in ×1 PBS(-)で固定化した（20h BrdUインキュベーション）。その後、以下を行った。
・×1 PBS(-)で4回洗浄
・PBS(-)+0.1% Triton X-100 室温で15分インキュベート
・×1 PBS(-)で4回洗浄
・1N HCl 氷上で10分インキュベート
・2N HCl 室温で10分インキュベート
・×1 PBS(-)で4回洗浄
・0.1 M ホウ酸 pH8.5 室温で5分インキュベートを2回
・×1 PBS(-)で4回洗浄
・37℃で45分ブロッキング
・BrdU-Ab(Dako社 M0744)　1/100希釈　37℃で1.5時間
・×1 PBS(-)で4回洗浄
・Alexa（登録商標）568標識マウス抗体　1/500希釈　37℃で1時間
・×1 PBS(-)で4回洗浄
・Hoechst(登録商標)2μg/ml 室温で5分
・×100で顕微鏡観察 The next day, it was immobilized with 4% paraformaldehyde (PFA) + 4% Sucrose in × 1 PBS (-) (20h BrdU incubation). Then, the following was done.
・ Wash 4 times with × 1 PBS (-) ・ PBS (-) + 0.1% Triton X-100 Incubate for 15 minutes at room temperature ・ Wash 4 times with × 1 PBS (-) ・ Incubate for 10 minutes on 1N HCl ice ・ 2N HCl Incubate for 10 minutes at room temperature ・ Wash 4 times with × 1 PBS (-) ・ 0.1 M borate pH8.5 Incubate for 5 minutes at room temperature twice ・ Wash 4 times with × 1 PBS (-) ・ Blocking at 37 ° C for 45 minutes・ BrdU-Ab (Dako M0744) 1/100 diluted 37 ℃ for 1.5 hours ・ × 1 Washed 4 times with PBS (-) ・ Alexa® 568 labeled mouse antibody 1/500 diluted 1 hour at 37 ℃ ・ × 1 Wash 4 times with PBS (-) ・ Hoechst® 2 μg / ml 5 minutes at room temperature ・ Microscopic observation at × 100
　結果を図７に示す。図７から明らかなように、BPU17は濃度依存的に大動脈血管内皮細胞におけるBrdUの取り込みを抑制することが明らかとなった。すなわち、BPU17によって血管内皮細胞の増殖を抑制することができるといえる。 The results are shown in Fig. 7. As is clear from FIG. 7, it was revealed that BPU17 suppresses the uptake of BrdU in aortic vascular endothelial cells in a concentration-dependent manner. That is, it can be said that BPU17 can suppress the proliferation of vascular endothelial cells.
［実施例５］
　HAoECをマトリゲル内で培養して、血管新生の指標となる管腔形成（tube-formation）を以下の手法で検討した。まず、Matrigel（登録商標：(Becton Dickinson)）をコートした２４ウェルプレート（使用前まで－２０℃で保存）にMatrigel溶液1.25 mL/2mL tubeを用意した。さらに以下のMatrigel溶液（300μL/well）を２４ウェルプレートに加えて（3 well/sample）３７℃で１時間インキュベートした。
（１）コントロール（ジメチルスルホキシド:DMSO）
（２）DMSO+BPU17  1μM( 1 mM 1.25μL)
（３）DMSO+BPU17  3μM(10 mM 0.375μL)
（４）DMSO+BPU17 10μM(10 mM 1.25μL) [Example 5]
HAoEC was cultured in Matrigel, and tube-formation, which is an index of angiogenesis, was examined by the following method. First, a 1.25 mL / 2 mL tube of Matrigel solution was prepared on a 24-well plate (stored at −20 ° C. before use) coated with Matrigel (registered trademark: (Becton Dickinson)). Further, the following Matrigel solution (300 μL / well) was added to a 24-well plate (3 well / sample) and incubated at 37 ° C. for 1 hour.
(1) Control (dimethyl sulfoxide: DMSO)
(2) DMSO + BPU17 1 μM (1 mM 1.25 μL)
(3) DMSO + BPU17 3 μM (10 mM 0.375 μL)
(4) DMSO + BPU17 10 μM (10 mM 1.25 μL)
　次にHAoEC（第７継代:P7）懸濁液（2×104 cells/1 mL HEC-C1）と共に以下の（５）～（８）のいずれかを1 ml/ wellほどマトリゲルに接種した。
（５）コントロール（DMSO） 3 mL HEC-C1
（６）DMSO+BPU17  1μM( 1 mM 3 μL/3 mL HEC-C1)
（７）DMSO+BPU17  3μM(10 mM 0.9 μL/3 mL HEC-C1)
（８）DMSO+BPU17 10μM(10 mM 3 μL/3 mL HEC-C1) Next, 1 ml / well of any of the following (5) to (8) was inoculated into Matrigel together with a HAoEC (7th passage: P7) suspension (2 × 10 4 cells / 1 mL HEC-C1). ..
(5) Control (DMSO) 3 mL HEC-C1
(6) DMSO + BPU17 1 μM (1 mM 3 μL / 3 mL HEC-C1)
(7) DMSO + BPU17 3 μM (10 mM 0.9 μL / 3 mL HEC-C1)
(8) DMSO + BPU17 10 μM (10 mM 3 μL / 3 mL HEC-C1)
　接種から２２時間後の顕微鏡観察（×40）による写真を図８に、細胞数あたりの分岐点（branching points）の割合（%）を図９Ａに、管腔長（μm）を図９Ｂに示す。図８、図９Ａ、Ｂから明らかなように、BPU17を加えることで管腔形成を阻害していることが明らかとなった。したがって、実施例４の結果と併せて検討すると、BPU17によって血管新生を抑制することが可能であることが示された。 A photograph taken by microscopic observation (× 40) 22 hours after inoculation is shown in FIG. 8, the ratio (%) of branching points per number of cells is shown in FIG. 9A, and the lumen length (μm) is shown in FIG. 9B. .. As is clear from FIGS. 8 and 9A and 9B, it was clarified that the addition of BPU17 inhibits lumen formation. Therefore, when examined together with the results of Example 4, it was shown that BPU17 can suppress angiogenesis.
［実施例６］
　上記実施例５の結果を踏まえて、マウス網脈絡膜新生血管（CNV）モデルを用いて、BPU17がCNV形成の抑制作用を有するかどうかを検討した。マウスにおけるCNVモデルは、Ishikawaらの方法（Exp Eye Res. 2016; 142:19-25）に準じて以下に示す方法で作製した。具体的には、８週齢のマウス（CL57BL/6 雌：SLC社）の網膜にレーザー（200mW, 75μm, 0.1秒，532nm）を照射し、光凝固を視神経周囲、具体的にはDisc周辺２～３乳頭径に４箇所ほど施工した。同時に0.3% FBS+BPU17 (30, 100μM)を眼内に打ち込んだ。７日目に、眼球を摘出して固定後、Alexa Fluor 488結合イソレクチン(Isolectin)GS-IB4と共に24時間インキュベートし、PBS中で1:100に希釈した。調製物を最後にPBSで洗浄し、PBS中50%グリセロールでマウントし、BZ-X710蛍光顕微鏡(Keyence社)で検査した。NIH ImageJソフトウェアを使用して、CNVの面積を測定した。なお、BPU17なしのコントロールとして、PBSを０日に眼内に打ち込んだ。顕微鏡での観察結果を図１０に、CNV面積の測定結果を図１１に示す。図１０における縦軸は線維化面積（μｍ２）である。 [Example 6]
Based on the results of Example 5 above, it was examined whether BPU17 has an inhibitory effect on CNV formation using a mouse retinochoroidal neovascularization (CNV) model. The CNV model in mice was prepared by the method shown below according to the method of Ishikawa et al. (Exp Eye Res. 2016; 142: 19-25). Specifically, the retina of an 8-week-old mouse (CL57BL / 6 female: SLC) was irradiated with a laser (200 mW, 75 μm, 0.1 second, 532 nm) to perform photocoagulation around the optic nerve, specifically around the Disc 2 About 4 places were constructed with a diameter of 3 papillae. At the same time, 0.3% FBS + BPU17 (30, 100 μM) was injected into the eye. On day 7, the eyeballs were removed and fixed, then incubated with Alexa Fluor 488-binding Isolectin GS-IB4 for 24 hours and diluted 1: 100 in PBS. The preparation was finally washed with PBS, mounted with 50% glycerol in PBS and tested under a BZ-X710 fluorescence microscope (Keyence). The area of the CNV was measured using NIH ImageJ software. As a control without BPU17, PBS was injected into the eye on the 0th day. The observation result with a microscope is shown in FIG. 10, and the measurement result of the CNV area is shown in FIG. The vertical axis in FIG. 10 is the fibrotic area (μm 2 ).
　図１０、図１１に示すようにBPU17を投与すると、濃度依存的にCMVが抑制されていた。したがって、インビボによる試験によってもBPU17が網脈絡膜における血管新生を抑制することが確認された。 When BPU17 was administered as shown in FIGS. 10 and 11, CMV was suppressed in a concentration-dependent manner. Therefore, in vivo tests also confirmed that BPU17 suppressed angiogenesis in the retinochoroid.
［実施例７］
　次に、BPU17によるEMT阻害効果を、EMTマーカーによって調べた。
　ヒト肺胞上皮由来細胞株A549又はヒト肝臓星細胞株LI90を上記結成フリーのDMEM培地で２４時間培養した。次にTGFβ-2 1ng/mLのみ、又はTGFβ-2 1ng/mL及びBPU17 3μMを加えてさらに１８時間培養した。その後細胞を回収し、Rneasy Mini Kit（キアゲン社）を用いてtotalRNAを抽出し、cDNAを合成後にSYBR Green reagents and a StepOnePlus Real Time PCR System(Applied Biosystems社)によりqPCRを行い、線維化関連分子であるconnective tissue growth factor（CTGF） mRNA発現量を測定した。同様にヒト肝臓星細胞株LI90を上記結成フリーのDMEM培地で２４時間培養した。次にTGFβ-2 1ng/mLのみ、TGFβなし、又はTGFβ-2 1ng/mL及びBPU17 3μMを加えてさらに１８時間培養した。その後細胞を回収し、上記と同様にtotalRNAを抽出し、cDNAを合成後にqPCRを行い、線維化関連分子であるα-smooth muscle actin (αSM-actin) mRNA発現量を測定した。結果を図１２、１３に示す。 [Example 7]
Next, the EMT inhibitory effect of BPU17 was examined using EMT markers.
Human alveolar epithelial-derived cell line A549 or human liver stellate cell line LI90 was cultured in the above-mentioned formation-free DMEM medium for 24 hours. Next, only TGFβ-2 1 ng / mL or TGFβ-2 1 ng / mL and BPU17 3 μM were added, and the cells were further cultured for 18 hours. After that, the cells are collected, total RNA is extracted using Rneasy Mini Kit (Kiagen), cDNA is synthesized, and qPCR is performed by SYBR Green reagents and a StepOnePlus Real Time PCR System (Applied Biosystems) to obtain fibrosis-related molecules. The expression level of a certain connective tissue growth factor (CTGF) mRNA was measured. Similarly, the human liver stellate cell line LI90 was cultured in the above-mentioned formation-free DMEM medium for 24 hours. Next, TGFβ-2 1 ng / mL alone, without TGFβ, or TGFβ-2 1 ng / mL and BPU17 3 μM were added and cultured for an additional 18 hours. After that, cells were collected, total RNA was extracted in the same manner as above, cDNA was synthesized, and qPCR was performed to measure the expression level of α-smooth muscle actin (αSM-actin) mRNA, which is a fibrosis-related molecule. The results are shown in FIGS. 12 and 13.
　図１２、１３から明らかなように、肺胞上皮由来の細胞におけるCTGFや肝臓星細胞におけるαSM-actinの発現を抑制することが明らかとなった。したがってBPU17は網膜だけでなく肺や肝臓においても線維化抑制効果を有する可能性があることが確認された。 As is clear from FIGS. 12 and 13, it was revealed that the expression of CTGF in cells derived from alveolar epithelium and αSM-actin in hepatic stellate cells was suppressed. Therefore, it was confirmed that BPU17 may have an inhibitory effect on fibrosis not only in the retina but also in the lung and liver.
　本発明の医薬組成物は血管新生関連疾患の予防又は治療において利用可能である。特に、網脈絡膜における血管内皮細胞による網脈絡膜新生血管形成、又は網膜色素上皮組織における線維性瘢痕の形成を強力に抑制することにより、糖尿病網膜症，加齢黄斑変性症，網膜剥離，増殖硝子体網膜症，ぶどう膜炎，眼感染症，未熟児網膜症，新生血管黄斑症，網脈絡膜炎等の網脈絡膜障害の予防又は治療剤に利用できる。 The pharmaceutical composition of the present invention can be used in the prevention or treatment of angiogenesis-related diseases. In particular, diabetic retinopathy, age-related macular degeneration, retinal detachment, and proliferative vitreous by strongly suppressing the formation of retinochoroidal neovascularization by vascular endothelial cells in the retinochoroid or the formation of fibrous scars in the retinal pigment epithelial tissue. It can be used as a preventive or therapeutic agent for retinochoroidal disorders such as retinopathy, uveitis, eye infection, retinopathy of prematurity, neovascular macular degeneration, and retinochoroiditis.

Claims (13)

  1. １－（シクロブチルカルボニル）－３－（４－クロロフェニル）ウレア、又はその薬理上許容される塩を有効成分として含有する医薬組成物。 A pharmaceutical composition containing 1- (cyclobutylcarbonyl) -3- (4-chlorophenyl) urea or a pharmacologically acceptable salt thereof as an active ingredient.
  2. 血管新生関連疾患の予防又は治療に用いられることを特徴とする請求項１記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is used for the prevention or treatment of angiogenesis-related diseases.
  3. 血管新生関連疾患が眼における血管新生関連疾患であることを特徴とする請求項２記載の医薬組成物。 The pharmaceutical composition according to claim 2, wherein the angiogenesis-related disease is an angiogenesis-related disease in the eye.
  4. 眼における血管新生関連疾患が、網脈絡膜障害、角結膜障害、又は血管新生緑内障であることを特徴とする、請求項３記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the angiogenesis-related disease in the eye is retinochoroidal disorder, keratoconjunctival disorder, or angiogenic glaucoma.
  5. 網脈絡膜障害が、糖尿病網膜症、加齢黄斑変性症、網膜剥離、増殖硝子体網膜症、ぶどう膜炎、眼感染症、未熟児網膜症、新生血管黄斑症又は網脈絡膜炎であることを特徴とする請求項４記載の医薬組成物。 The retinochoroidal disorder is characterized by diabetic retinopathy, age-related macular degeneration, retinal detachment, proliferative vitreous retinopathy, uveitis, eye infection, retinopathy of prematurity, neovascular macular degeneration or retinochoroiditis. The pharmaceutical composition according to claim 4.
  6. 眼における血管新生関連疾患が、網脈絡膜障害、角結膜障害、血管新生緑内障から選択されるいずれか一種に起因する線維性瘢痕の形成又は収縮であることを特徴とする請求項３載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the angiogenesis-related disease in the eye is the formation or contraction of fibrous scars caused by any one selected from retinochoroidal disorders, keratoconjunctival disorders, and angiogenic glaucoma. Stuff.
  7. 線維性瘢痕が、網膜上、網膜内及び／又は網膜下における線維性瘢痕であることを特徴とする、請求項６記載の医薬組成物。 The pharmaceutical composition according to claim 6, wherein the fibrous scar is a fibrous scar on the retina, intraretinal and / or subretinal.
  8. 線維性瘢痕が、網膜下の網膜色素上皮組織における線維性瘢痕であることを特徴とする、請求項７記載の医薬組成物 The pharmaceutical composition according to claim 7, wherein the fibrous scar is a fibrous scar in the retinal pigment epithelial tissue under the retina.
  9. 血管新生関連疾患が臓器線維症であることを特徴とする、請求項３記載の医薬組成物 The pharmaceutical composition according to claim 3, wherein the angiogenesis-related disease is organ fibrosis.
  10. 臓器線維症が肺線維症又は肝臓線維症であることを特徴とする、請求項９記載の医薬組成物。 The pharmaceutical composition according to claim 9, wherein the organ fibrosis is pulmonary fibrosis or liver fibrosis.
  11. 血管新生の抑制に用いられることを特徴とする、請求項１記載の医薬組成物。 The pharmaceutical composition according to claim 1, which is used for suppressing angiogenesis.
  12. 血管新生が眼における血管新生であることを特徴とする、請求項１１記載の医薬組成物。 The pharmaceutical composition according to claim 11, wherein the angiogenesis is angiogenesis in the eye.
  13. 血管新生が網膜上、網膜内及び／又は網膜下における血管新生であることを特徴とする、請求項１２記載の医薬組成物。
          The pharmaceutical composition according to claim 12, wherein the angiogenesis is supraclavicular, intraretinal and / or subretinal angiogenesis.
PCT/JP2020/032037 2019-08-25 2020-08-25 Medicinal composition for preventing or treating angiogenesis-related diseases WO2021039791A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2021542934A JPWO2021039791A1 (en) 2019-08-25 2020-08-25

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2019153316 2019-08-25
JP2019-153316 2019-08-25

Publications (1)

Publication Number Publication Date
WO2021039791A1 true WO2021039791A1 (en) 2021-03-04

Family

ID=74683310

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2020/032037 WO2021039791A1 (en) 2019-08-25 2020-08-25 Medicinal composition for preventing or treating angiogenesis-related diseases

Country Status (2)

Country Link
JP (1) JPWO2021039791A1 (en)
WO (1) WO2021039791A1 (en)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001323180A (en) * 2000-05-12 2001-11-20 Fuji Photo Film Co Ltd Methine compound and silver halide photosensitive material for photography containing the compound
JP2010506948A (en) * 2006-10-20 2010-03-04 アイアールエム・リミテッド・ライアビリティ・カンパニー Compositions and methods for modulating C-KIT and PDGFR receptors

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001323180A (en) * 2000-05-12 2001-11-20 Fuji Photo Film Co Ltd Methine compound and silver halide photosensitive material for photography containing the compound
JP2010506948A (en) * 2006-10-20 2010-03-04 アイアールエム・リミテッド・ライアビリティ・カンパニー Compositions and methods for modulating C-KIT and PDGFR receptors

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KOBAYASHI, MASAAKI ET AL.: "Inhibition of fibroproliferative by retinal pigment epithelial cells using MRTF inhibitors", JOURNAL OF JAPANESE OPHTHALMOLOGICAL SOCIETY, vol. 122, 2018, pages 262 *
KOBAYASHI, MASAAKI ET AL.: "Role of MRTF-A in epithelial-mesenchymal transition of retinal pigment epithelium cell", JOURNAL OF JAPANESE OPHTHALMOLOGICAL SOCIETY, vol. 123, 18 April 2019 (2019-04-18), pages 263 *
WATANABE, BUNTA: "Elucidation of action mechanism of a novel low molecular compound that inhibits cell movement and application to cancer treatment", REPORT OF GRANT, 2018, pages 1 - 6 *
ZIRVI, KARIMULLAH A, DAR M S, FAKOUHI T: "Biochemorphology of Cyclobutanecarbonylureas", JOURNAL OF PHARMACEUTICAL SCIENCES, vol. 64, no. 4, 1975, pages 649 - 651, XP055797061 *

Also Published As

Publication number Publication date
JPWO2021039791A1 (en) 2021-03-04

Similar Documents

Publication Publication Date Title
JP7234283B2 (en) Compositions and methods for treating pterygium
US9994560B2 (en) HPTP-β inhibitors
MX2013000664A (en) Bifunctional rho kinase inhibitor compounds, composition and use.
JP2013545792A (en) Methods for treating and preventing eye diseases
CN105050600A (en) Therapeutic agent for eyeground disease
JP2019069992A (en) Therapeutic agent for corneal conjunctival disorders
KR102303316B1 (en) Inhibitor for retinochoroidal disorders
WO2021039791A1 (en) Medicinal composition for preventing or treating angiogenesis-related diseases
JP2012006918A (en) Preventive or therapeutic agent of retinochoroidal degeneration disorder containing isoquinolinesulfonyl derivative as effective ingredient
JP2022530657A (en) Tie-2 activator targeting Schlemm&#39;s canal
US10537563B2 (en) Methods for treating ocular disease using inhibitors of CSF-1R
US20210061800A1 (en) Compounds for treating eye diseases and methods thereof
Bleau et al. Managing intraocular pressure: Innovation in glaucoma management
US20240043396A1 (en) Methods of treating ocular fibrotic pathologies
Toris et al. Aqueous humor dynamics II: clinical studies
JP7429500B2 (en) Corneal epithelial disorder therapeutic agent
WO2023201312A2 (en) Methods of treating ocular fibrotic pathologies
JP2014193854A (en) Posterior eye segment disease preventive or therapeutic agent containing tetrahydropyranyl amino cyclopentylcarbonyl tetrahydropyridopyridine derivative as active ingredient
JP2003221325A (en) Preventive or therapeutic drug for eye disease
NZ715245B2 (en) Inhibitor for retinochoroidal disorders

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20856465

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2021542934

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 20856465

Country of ref document: EP

Kind code of ref document: A1