WO2021039791A1 - Composition médicinale pour la prévention ou le traitement de maladies associées à l'angiogenèse - Google Patents

Composition médicinale pour la prévention ou le traitement de maladies associées à l'angiogenèse Download PDF

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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
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angiogenesis
pharmaceutical composition
composition according
eye
bpu17
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PCT/JP2020/032037
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Japanese (ja)
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木村和博
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国立大学法人山口大学
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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
    • A61K31/16—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.

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Abstract

Le problème à la base de la présente invention concerne un nouveau médicament qui est efficace pour prévenir ou traiter des maladies associées à l'angiogenèse.　En tant que moyen pour résoudre le problème, l'invention porte sur une composition médicinale qui comprend, en tant que principe actif, du 1-(cyclobutylcarbonyl)-3-(4-chlorophényl)urée ou un sel pharmacologiquement acceptable correspondant. De préférence, la composition médicinale est utilisée pour prévenir ou traiter des maladies associées à l'angiogenèse. De préférence, les maladies associées à l'angiogenèse sont des maladies ophtalmiques associées à l'angiogenèse. De préférence, les maladies ophtalmiques associées à l'angiogenèse concernent la formation ou la constriction de cicatrices fibreuses dans des tissus épirétiniens, intrarétiniens et/ou sous-rétiniens.
PCT/JP2020/032037 2019-08-25 2020-08-25 Composition médicinale pour la prévention ou le traitement de maladies associées à l'angiogenèse WO2021039791A1 (fr)

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