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WO2011149010A1 - Nouveau dérivé d'indazole ou son sel, intermédiaire pour la production de celui-ci, agent prophylactique ou thérapeutique pour les maladies de dénaturation choriorétinienne et procédé thérapeutique pour maladies de dénaturation choriorétinienne utilisant celui-ci, et utilisation du dérivé d'indazole ou de son sel - Google Patents

Nouveau dérivé d'indazole ou son sel, intermédiaire pour la production de celui-ci, agent prophylactique ou thérapeutique pour les maladies de dénaturation choriorétinienne et procédé thérapeutique pour maladies de dénaturation choriorétinienne utilisant celui-ci, et utilisation du dérivé d'indazole ou de son sel Download PDF

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Publication number
WO2011149010A1
WO2011149010A1 PCT/JP2011/062070 JP2011062070W WO2011149010A1 WO 2011149010 A1 WO2011149010 A1 WO 2011149010A1 JP 2011062070 W JP2011062070 W JP 2011062070W WO 2011149010 A1 WO2011149010 A1 WO 2011149010A1
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WIPO (PCT)
Prior art keywords
choroidal
macular degeneration
related macular
retinal
compound
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP2011/062070
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English (en)
Japanese (ja)
Inventor
康司 大橋
慎一郎 平井
一貴 木戸
智和 藤本
雄 松木
昌彦 萩原
健一 小森
洋 西田
康則 津▲崎▼
昭 高間
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Santen Pharmaceutical Co Ltd
Ube Corp
Original Assignee
Santen Pharmaceutical Co Ltd
Ube Industries Ltd
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Publication of WO2011149010A1 publication Critical patent/WO2011149010A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the present invention relates to a novel indazole derivative or a salt thereof, and a production intermediate thereof.
  • the present invention also relates to a preventive or therapeutic agent for a choroidal degenerative disease substantially free of angiogenesis, comprising at least one of the indazole derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • the present invention also relates to a method for preventing or treating the choroidal degenerative disease using such an indazole derivative or a salt thereof.
  • the present invention further relates to the use of such an indazole derivative or a salt thereof for producing a prophylactic or therapeutic agent for the above-mentioned choroidal degenerative disease.
  • age-related macular degeneration is a major cause of blindness in middle to old age in developed countries such as Japan, the United States, and Europe. It has become.
  • Age-related macular degeneration is a disease caused by aging of the macular region, and the number of patients is steadily increasing at present as an aging society. Age-related macular degeneration is roughly classified into wet type with neovascularization from the choroid and dry type without neovascularization that occurs from the choroid.
  • the former exudative type is laser photocoagulation.
  • Patent Document 1 describes a compound group represented by a general formula including a compound represented by the following formula (1). Patent Document 1 discloses that these compound groups have Rho kinase inhibitory action and are useful as therapeutic agents for glaucoma and the like.
  • Patent Document 2 describes a retinal nerve cell protective agent containing a compound group represented by the general formula including a compound represented by the following formula (1) as an active ingredient. ing.
  • Patent Documents 1 and 2 do not disclose the compound itself represented by the above formula (1), and atrophic age-related macular degeneration and early age-related macular due to the compound represented by the above formula (1). Described specifically, also preventive or therapeutic effects on retina choroidal degenerative diseases that do not substantially involve new blood vessels, such as retinitis pigmentosa, brain retinal choroidal atrophy, and retina choroid disorders associated with those diseases, Not suggested.
  • Recurrent choroidal degenerative disease substantially free of new blood vessels, such as atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, and retina choroid associated with these diseases It is a very interesting problem to find a drug having a preventive or therapeutic effect on a disorder, and to create a novel compound or a salt thereof having an action effect thereof, and an intermediate for producing the novel compound.
  • the inventors of the present invention have a retina choroidal degenerative disease substantially free of new blood vessels, such as atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, and further As a result of earnest research to find a drug having a preventive or therapeutic effect on the choroidal disorder associated with other diseases, the inventors succeeded in creating a novel indazole derivative represented by the above formula (1) or a salt thereof. It has been found that the novel compound has an inhibitory effect on photoreceptor cell death in a mouse photodamage model and an inhibitory effect on spermidine-induced retinal pigment epithelial cell death. That is, the present invention is as follows.
  • the present invention relates to prevention or treatment of a retina choroidal degenerative disease substantially free of neovascularization, comprising at least one of the compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient. It is an agent.
  • the compound represented by the following formula (1) or a salt thereof is referred to as “the present compound (1)”.
  • the present invention also provides the present compound (1) itself.
  • the present invention is a compound represented by the above formula (1), which is for use in the prevention or treatment of a retina choroidal degenerative disease substantially free of neovascularization, among the compounds of the present invention (1) Also provided is a pharmaceutically acceptable salt thereof.
  • the present invention also involves a neovascularization substantially comprising administering to a patient a pharmacologically effective amount of at least one of the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof.
  • a method for preventing or treating a recurrent choroidal degenerative disease is also provided.
  • the present invention provides at least one compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof for producing a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of neovascularization. Also provides for the use of.
  • the retina choroidal degenerative disease in the present invention is atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, central retinal artery occlusion, central retinal vein occlusion, retinal pigment At least one selected from the group consisting of epithelial detachment, central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and recurrent choroidal disorders associated with those diseases
  • it is selected from the group consisting of atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy and reticulochoroidal disorders associated with those diseases
  • Particularly preferred is at least one.
  • the present invention further provides a compound represented by the following formula (2) or a salt thereof.
  • the compound represented by the following formula (2) which is a production intermediate of the compound (1) of the present invention or a salt thereof is referred to as “the compound (2) of the present invention”.
  • Inventive compound (2) is generically referred to as “present compound”.
  • Boc represents a tert-butoxycarbonyl group
  • THP represents a tetrahydropyranyl group.
  • the compound (1) of the present invention is a retina choroidal degenerative disease substantially free of new blood vessels, for example, atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retina choroidal atrophy, retina Central arterial occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and even those Recurrent choroidal disorders associated with diseases (preferably atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy and recurrent choroidal disorders associated with these diseases, particularly preferably It is useful as a preventive or therapeutic agent for atrophic age-related macular degeneration and retina choroidal disorders associated with the disease.
  • the present invention also provides
  • the compound (1) of the present invention is an indazole derivative represented by the following formula (1): 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethyl Propylamine and its salt, and the compound (2) of the present invention is a production intermediate of the compound (1) of the present invention represented by the following formula (2): 1- ⁇ 6- [4-cyclopropyl-1- ( Tetrahydropyran-2-yl) -1H-indazol-5-yl] pyridin-3-yl ⁇ -1-ethylpropylcarbamic acid tert-butyl ester and salts thereof.
  • the “salt” in the compound of the present invention is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid or phosphoric acid.
  • a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid (D-form, L-form, meso-form), methanesulfonic acid Preferably, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, fumaric acid, maleic acid, succinic acid, tartaric acid (L form), and methanesulfonic acid are used.
  • this invention compound (1) can form a salt of arbitrary ratios with an inorganic acid, an organic acid, an alkali metal, or an alkaline-earth metal etc., The each or those mixture is, Included in the present invention.
  • crystal polymorph group refers to various crystal forms depending on conditions and states (including the formulated state in this state) such as production, crystallization, and storage of these crystals. It means the crystal form and the whole process at each stage when changing.
  • Preferred specific examples of the compound of the present invention include the following compounds or salts thereof.
  • the compound (1) of the present invention can be produced by preparing the compound (2) of the present invention by deprotection and / or simultaneous and / or subsequent salting with the compound by a general method. it can.
  • the prophylactic or therapeutic agent of the present invention is a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of neovascularization, which is a compound represented by the above formula (1) (1- [6- (4-cyclo Propyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine) or a pharmaceutically acceptable salt thereof as an active ingredient. Details thereof will be described in the section of [Pharmacological test] described later.
  • the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is a photoreceptor cell death in a mouse photodamage model. Was suppressed. It also showed an inhibitory effect on spermidine-induced retinal pigment epithelial cell death.
  • the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof is useful as a prophylactic or therapeutic agent for a choroidal degenerative disease substantially free of neovascularization.
  • the prevention or treatment method for the recurrent choroidal degenerative disease using the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof there is also provided use of a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent.
  • the “retina choroidal degenerative disease substantially free of new blood vessels” in the present invention means atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, central retinal artery occlusion , Central retinal vein occlusion, retinal pigment epithelial detachment, central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and the choroid associated with these diseases And at least one selected from the group consisting of disorders, preferably atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, and networks associated with these diseases At least one selected from the group consisting of choroidal disorders, particularly preferably selected from the group consisting of early age-related macular degeneration, atrophic age
  • preventive or therapeutic agent of the present invention uses a widely used technique as a single preparation and / or combination preparation by adding other pharmaceutically acceptable active ingredients and / or additives as necessary. Can be formulated.
  • the prophylactic or therapeutic agent of the present invention can be administered to a patient orally or parenterally.
  • the administration form includes oral administration, topical administration to the eye (instillation administration, intraconjunctival sac administration, intravitreal administration). , Subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, etc., and if necessary, formulated with a pharmaceutically acceptable additive into a dosage form suitable for administration.
  • dosage forms suitable for oral administration include tablets, capsules, granules, fine granules, powders, etc.
  • dosage forms suitable for parenteral administration include injections, eye drops, and eyes.
  • An ointment, a patch, a gel, an insertion agent, etc. are mentioned. These can be prepared using conventional techniques widely used in the field.
  • the preventive or therapeutic agent of the present invention can also be made into preparations for DDS (drug delivery system) such as preparations for intraocular implants and microspheres.
  • DDS drug delivery
  • tablets are made of excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch ,
  • Disintegrating agents such as low-substituted hydroxypropylcellulose; binders such as hydroxypropylcellulose, ethylcellulose, gum arabic, starch, partially pregelatinized starch, polyvinylpyrrolidone, polyvinyl alcohol; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide ,
  • Lubricants such as hydrogenated oil; refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, pyrrolidone, etc.
  • Coating agents citric acid, aspartame, ascorbic acid, using appropriately selected and flavoring agents such as menthol, can be prepared.
  • the injection is selected as necessary from an isotonic agent such as sodium chloride; a buffering agent such as sodium phosphate; a surfactant such as polyoxyethylene sorbitan monooleate; a thickener such as methylcellulose.
  • an isotonic agent such as sodium chloride
  • a buffering agent such as sodium phosphate
  • a surfactant such as polyoxyethylene sorbitan monooleate
  • a thickener such as methylcellulose.
  • Eye drops include isotonic agents such as sodium chloride and concentrated glycerin; buffering agents such as sodium phosphate and sodium acetate; surface activity such as polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil Agents; Stabilizers such as sodium citrate and sodium edetate; Preservatives such as benzalkonium chloride and paraben can be selected and used as necessary, and pH is acceptable for ophthalmic preparations Although it may be within the range, it is usually preferably within the range of 4-8.
  • the eye ointment can be prepared using a commonly used base such as white petrolatum or liquid paraffin.
  • the intercalating agent is prepared by crushing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, and the like together with the active ingredient, and compressing the powder. If necessary, an excipient, a binder, a stabilizer, and a pH adjuster can be used.
  • a biodegradable polymer for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid, and the like.
  • an excipient, a binder, a stabilizer, and a pH adjuster can be used.
  • the preparation for an intraocular implant can be prepared using a biodegradable polymer, for example, a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • a biodegradable polymer such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • the dose of the prophylactic or therapeutic agent of the present invention can be appropriately changed depending on the dosage form, the severity of the patient's symptoms to be administered, age, weight, doctor's judgment, etc.
  • 0.01 to 5000 mg, preferably 0.1 to 2500 mg, more preferably 0.5 to 1000 mg per day can be administered to adults in one or several divided doses.
  • the active ingredient concentration of w / v) can be administered once or several times a day.
  • a patch containing 0.0001 to 2000 mg can be applied to an adult.
  • a patch containing 0.0001 to 2000 mg can be applied to an adult.
  • an intraocular implant preparation 0.0001 to 2000 mg is included for an adult.
  • An intraocular implant formulation can be implanted in the eye.
  • Example 1 1- ⁇ 6- [4-Cyclopropyl-1- (tetrahydropyran-2-yl) -1H-indazol-5-yl] pyridin-3-yl ⁇ -1-ethylpropylcarbamic acid tert- Synthesis of butyl ester> 4-Cyclopropyl-1- (tetrahydropyran-2-yl) -5- (4,4,5,5-tetramethyl [1,3,2] dioxaborolanyl) -1H-indazole (130 g, 353 mmol , International Publication No.
  • Example Compound 1 (104 g) was obtained as a white powder (yield 66%).
  • Example 2 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine hydrochloride 1- ⁇ 6- [4-Cyclopropyl-1- (tetrahydropyran-2-yl) -1H-indazol-5-yl] pyridin-3-yl ⁇ -1-ethylpropylcarbamic acid tert-butyl ester (Examples) To Compound 1, 100 g (198 mmol), ethanol (250 ml), water (11 ml) and 38 wt% hydrogen chloride / ethanol solution (179 ml) were added, and the mixture was stirred at 30 ° C. to 43 ° C. for 5 hours under an argon stream.
  • the reaction solution was cooled to 12 ° C. and stirred at the same temperature for 0.3 hours.
  • the precipitated solid was collected by filtration and washed with ethanol (100 ml).
  • Ethanol (270 ml) was added to the obtained solid (90 g) and heated to 75 ° C.
  • water (35 ml) was added and stirred with heating for 0.5 hour.
  • the produced solid was collected by filtration, washed with ethanol (200 ml), and dried at 40 ° C. for 10 hours to obtain a white solid (71 g).
  • Example 3 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine hydrobromide 1- ⁇ 6- [4-Cyclopropyl-1- (tetrahydropyran-2-yl) -1H-indazol-5-yl] pyridin-3-yl ⁇ -1-ethylpropylcarbamic acid tert-butyl ester (Examples) To compound 1, 2.1 g, 4.2 mmol), ethanol (20 ml) and 48 wt% hydrogen bromide solution (10 ml) were added, and the mixture was stirred with heating at 40 ° C. for 4 hours.
  • Example 4 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine
  • 1- [6- (4-Cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine hydrochloride (Example Compound 2, 30.0 g, 76.3 mmol) was added to n -Butanol (300 ml) and 4M aqueous sodium hydroxide solution (370 ml) were added, and the mixture was stirred at room temperature for 1.5 hours. The organic layer was separated and washed with water (150 ml), and then the organic layer was concentrated to obtain a solid (22.6 g).
  • Example 5 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine L-tartrate To a solution of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine (Example Compound 4, 4.0 g, 12 mmol) in ethanol (160 ml). A solution of L-tartaric acid (2.8 g, 19 mmol) in ethanol (85 ml) was added dropwise at room temperature over 0.5 hours and stirred at the same temperature for 0.67 hours.
  • Example 6 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine maleate To a solution of maleic acid (11 mg, 0.095 mmol) in tetrahydrofuran (110 ⁇ l) was added 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine.
  • Example Compound 4, 10 mg, 0.031 mmol) in tetrahydrofuran (800 ⁇ l) was added, and the mixture was allowed to stand at room temperature for 6 days.
  • Example compound 6 (11 mg) was obtained as a white solid (yield 71%). Melting point: 174-178 ° C.
  • Example 7 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine fumarate 1- [6- (4-Cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine was added to a solution of fumaric acid (11 mg, 0.095 mmol) in tetrahydrofuran (275 ⁇ l).
  • Example Compound 4, 10 mg, 0.031 mmol) in tetrahydrofuran (667 ⁇ l) was added, and the mixture was allowed to stand at room temperature for 3 days.
  • Example compound 7 (8.8 mg) was obtained as a white solid (yield 75%). Melting point: 257 ° C.
  • Example 8 Synthesis of 1- [6- (4-cyclopropyl-1H-indazol-5-yl) pyridin-3-yl] -1-ethylpropylamine succinate
  • succinic acid 11 mg, 0.093 mmol
  • Example Compound 4 10 mg, 0.031 mmol) in tetrahydrofuran (667 ⁇ l) was added, and the mixture was allowed to stand at room temperature for 6 days.
  • mouse photopathy model is a model animal in which cell death of retinal photoreceptor cells is induced by light irradiation, and is a choroidal degenerative disease substantially free of new blood vessels, such as atrophic age-related macular degeneration, early stage It is widely used as a model animal for age-related macular degeneration, retinitis pigmentosa, etc. (Invest. Ophthalmol. Vis. Sci., 2005; 46: 979-987).
  • Amplitude attenuation suppression rate (%) ((V x ⁇ V 0 ) / (V n ⁇ V 0 )) ⁇ 100
  • V 0 Amplitude of base administration group ( ⁇ V)
  • V n amplitude of normal control group ( ⁇ V)
  • V x Amplitude of compound A administration group ( ⁇ V) (Method of administration) 1)
  • Single administration before light irradiation Compound A administration group: Compound A solution suspended in 1% (w / v) methylcellulose aqueous solution at a dose of 10 mg / kg, once orally 1 hour before light irradiation Administered.
  • Normal control group and base administration group A 1% (w / v) methylcellulose aqueous solution was orally administered 1 hour before light irradiation.
  • the compound represented by the above formula (1) represented by the compound A or a pharmaceutically acceptable salt thereof suppresses photoreceptor cell death. Therefore, the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof has an effect of preventing or treating a choroidal degenerative disease substantially free of neovascularization.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS Ham's F-12 Medium containing 10% fetal bovine serum
  • DPBS Dulbecco's phosphate buffer
  • the medium was exchanged with 100 ⁇ L of spermidine (250 ⁇ M) containing Compound A (1 ⁇ M) or Y-39983 (1 ⁇ M).
  • a group treated with a medium containing 100 ⁇ L of spermidine (250 ⁇ M) except that compound A and Y-39983 were not contained was designated as a solvent treatment group.
  • the group was cultured overnight at 37 ° C. and 5% CO 2 /95% Air, and then replaced with 100 ⁇ L of 10% FBS-containing DMEM / Ham's F-12 medium containing 1% DPBS. A normal control group was used.
  • the viable cell count was evaluated by the MTS method (Cancer Commun., 1991; 3 (7): 207-212, J. Immunol. Methods., 1983; 65, 55-63). That is, 20 ⁇ L of MTS reagent was added to the medium, and after 2 hours, the absorbance at 490 nm (Abs490) (reference wavelength was 655 nm) was used as an index of the number of living cells. According to the following formula 2, the cell death inhibition rate (%) was calculated. Note that the number of examples in each group is four.
  • the compound represented by the above formula (1) represented by compound A or a pharmaceutically acceptable salt thereof suppresses spermidine-induced retinal pigment epithelial cell death. Therefore, the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof prevents recurrent choroidal degenerative diseases such as atrophic age-related macular degeneration, brain atrophy, and the like, which are substantially free of new blood vessels. Or has a therapeutic effect.
  • formulation example The pharmaceutical agent of the present invention will be described more specifically with formulation examples, but the present invention is not limited to these formulation examples.
  • (Formulation example 2: eye ointment) Compound A 0.3g in 100g Liquid paraffin 10.0g White petrolatum appropriate amount An ointment is prepared by adding compound A to uniformly melted white petrolatum and liquid paraffin, mixing them well, and then gradually cooling. By changing the amount of compound A added, the concentration is 0.05% (w / w), 0.1% (w / w), 0.5% (w / w) or 1% (w / w). An eye ointment can be prepared.
  • the compound (1) of the present invention inhibited retinal photoreceptor cell death and spermidine-induced retinal pigment epithelial cell death. Therefore, the compound (1) of the present invention is a retina choroidal degenerative disease substantially free of new blood vessels, such as atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, Central retinal artery occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease), and more (Preferably atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy, and retina choroidal disorders associated with these diseases, particularly Preferably, it is useful as a preventive or therapeutic
  • the prevention or treatment method for the recurrent choroidal degenerative disease using the compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof there is also provided use of a compound represented by the above formula (1) or a pharmaceutically acceptable salt thereof for producing a therapeutic agent.

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  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un composé représenté par la formule (1) ou son sel pharmaceutiquement acceptable, qui présente un effet inhibiteur sur la mort des photorécepteurs dans un modèle de souris à sensibilité induite par la lumière et qui peut donc servir comme agent prophylactique ou thérapeutique pour les maladies de dénaturation choriorétinienne qui ne sont pas sensiblement accompagnées de néovascularisation (par ex. dégénérescence maculaire liée à l'âge de forme atrophique, rétinite pigmentaire, atrophie gyrée de la choroïde et de la rétine) et des troubles choriorétiniens associés aux maladies susmentionnées ; et un procédé permettant de prévenir ou de traiter les maladies de dénaturation choriorétinienne en utilisant un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci ; un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci destiné à être utilisé dans la prévention ou le traitement des maladies de dénaturation choriorétinienne et un intermédiaire pour la production du composé ou de son sel pharmaceutiquement acceptable ; et l'utilisation d'un composé représenté par la formule (1) ou un sel pharmaceutiquement acceptable de celui-ci pour la production d'un agent prophylactique ou thérapeutique pour les maladies de dénaturation choriorétinienne.
PCT/JP2011/062070 2010-05-27 2011-05-26 Nouveau dérivé d'indazole ou son sel, intermédiaire pour la production de celui-ci, agent prophylactique ou thérapeutique pour les maladies de dénaturation choriorétinienne et procédé thérapeutique pour maladies de dénaturation choriorétinienne utilisant celui-ci, et utilisation du dérivé d'indazole ou de son sel Ceased WO2011149010A1 (fr)

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JP2010121821 2010-05-27

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AR (1) AR081769A1 (fr)
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015002061A1 (fr) * 2013-07-04 2015-01-08 日本曹達株式会社 Dérivé de phénylimidazole, et médicament thérapeutique ou médicament préventif d'une maladie inflammatoire, etc.
JP2015523546A (ja) * 2012-05-01 2015-08-13 トランスレイタム メディカス インコーポレイテッド 失明性疾患を処置および診断するための方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005035506A1 (fr) * 2003-10-15 2005-04-21 Ube Industries, Ltd. Nouveau derive d'indazole
WO2006112313A1 (fr) * 2005-04-13 2006-10-26 Ube Industries, Ltd. Agent protecteur pour une cellule neuronale retinienne comprenant un derive d’indazole comme ingredient actif
JP2008247923A (ja) * 2001-04-11 2008-10-16 Senju Pharmaceut Co Ltd 視覚機能障害改善剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008247923A (ja) * 2001-04-11 2008-10-16 Senju Pharmaceut Co Ltd 視覚機能障害改善剤
WO2005035506A1 (fr) * 2003-10-15 2005-04-21 Ube Industries, Ltd. Nouveau derive d'indazole
WO2006112313A1 (fr) * 2005-04-13 2006-10-26 Ube Industries, Ltd. Agent protecteur pour une cellule neuronale retinienne comprenant un derive d’indazole comme ingredient actif

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015523546A (ja) * 2012-05-01 2015-08-13 トランスレイタム メディカス インコーポレイテッド 失明性疾患を処置および診断するための方法
WO2015002061A1 (fr) * 2013-07-04 2015-01-08 日本曹達株式会社 Dérivé de phénylimidazole, et médicament thérapeutique ou médicament préventif d'une maladie inflammatoire, etc.
CN105324366A (zh) * 2013-07-04 2016-02-10 日本曹达株式会社 苯基咪唑衍生物以及炎症性疾病等的治疗药或预防药

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AR081769A1 (es) 2012-10-17
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