WO2011149012A1 - Prophylactic or therapeutic agent for retinal/choroidal denaturation diseases comprising isoquinolinesulfonyl derivative as active ingredient, prophylactic or therapeutic method for retinal/choroidal denaturation diseases, and isoquinolinesulfonyl derivative or pharmaceutically acceptable salt thereof and use thereof - Google Patents
Prophylactic or therapeutic agent for retinal/choroidal denaturation diseases comprising isoquinolinesulfonyl derivative as active ingredient, prophylactic or therapeutic method for retinal/choroidal denaturation diseases, and isoquinolinesulfonyl derivative or pharmaceutically acceptable salt thereof and use thereof Download PDFInfo
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- WO2011149012A1 WO2011149012A1 PCT/JP2011/062072 JP2011062072W WO2011149012A1 WO 2011149012 A1 WO2011149012 A1 WO 2011149012A1 JP 2011062072 W JP2011062072 W JP 2011062072W WO 2011149012 A1 WO2011149012 A1 WO 2011149012A1
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- choroidal
- retinal
- macular degeneration
- related macular
- disease
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- UNGSQNVCWUJGPM-UHFFFAOYSA-N O=S(C1CCNCCC1)(c1cccc2c1ccnc2)=O Chemical compound O=S(C1CCNCCC1)(c1cccc2c1ccnc2)=O UNGSQNVCWUJGPM-UHFFFAOYSA-N 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
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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
- C07D401/12—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 linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to a preventive or therapeutic agent for a retina choroidal degenerative disease substantially free of angiogenesis, which contains at least one of a specific isoquinoline sulfonyl 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 isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof.
- the present invention also relates to an isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of the retina choroidal degenerative disease.
- the present invention further relates to the use of such an isoquinoline sulfonyl derivative or a pharmaceutically acceptable 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.
- Treatments such as surgery, neovascularization, and foveal movement have been performed, but these treatments have limitations.
- Treatment with an angiogenesis inhibitor bevacizumab [bevacizumab, trade name: Avastin], ranibizumab [tradename: Lucentis] or the like has also been performed.
- bevacizumab an angiogenesis inhibitor bevacizumab [bevacizumab, trade name: Avastin]
- ranibizumab [tradename: Lucentis] or the like has also been performed.
- the compound represented by the following general formula (1) is generally called Fasudil and is known as an active ingredient of Eryel (trade name) intravenous infusion, which is a therapeutic agent for brain dysfunction. It has been.
- isoquinoline sulfonamide derivatives containing fasudil act on mammalian vascular smooth muscle, vasodilators, cerebral circulation improving agents, angina pectoris, cerebrovascular thrombosis and hypertension preventive or therapeutic agent Is useful as US Pat. No. 4,678,783 (Patent Document 1). Furthermore, the production method and vasodilating action of these derivatives are described in Chem. Pharm. Bull. , 40 (3) 770-773 (1992) (Non-patent Document 1), its Rho kinase inhibitory action is reported in Am. J. et al. Physiol. Cell Physiol.
- Non-patent Document 2 Non-patent Document 2
- its angiogenesis inhibitory action is described in Mol. Cancer Ther. , 6 (5) 1517-1525 (2007) (non-patent document 3)
- its use as a therapeutic agent for eye diseases such as glaucoma and retinopathy is described in WO 97/23222 (patent document 2).
- 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
- atrophic age-related macular degeneration such as atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa
- 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 those diseases
- Finding drugs that have preventive or therapeutic effects on disorders is a very interesting task.
- the present inventors have a retina choroidal degenerative disease substantially free of neovascularization, for example, atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy or those diseases
- atrophic age-related macular degeneration for example, atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy or those diseases
- isoquinoline sulfonyl derivatives or their salts were found to be effective against photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model.
- the inventors have found that they have a suppressing effect, and have reached the present invention. 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 compound of the present invention”.
- the present invention also provides a method for preventing or treating a choroidal degenerative disease substantially free of new blood vessels, comprising administering to a patient a pharmacologically effective amount of at least one of the compounds of the present invention.
- the present invention also provides the compound of the present invention for use in the prevention or treatment of a retina choroidal degenerative disease substantially free of neovascularization.
- the present invention further provides use of the compound of the present invention for producing a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of new blood vessels.
- 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 compound 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 associated with these diseases (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 atrophic type It is useful as a preventive or therapeutic agent for age-related macular degeneration and retina choroid disorder associated with the disease.
- a method for preventing or treating the choroidal degenerative disease using the compound of the present invention, a compound of the present invention for use in preventing or treating the choroidal degenerative disease, and a prophylactic or therapeutic agent for the choroidal degenerative disease Also provided is the use of a compound of the present invention to accomplish this.
- the present invention contains at least one of the isoquinoline sulfonyl derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof (the compound of the present invention) as an active ingredient, and is substantially free from angiogenesis. It is a preventive or therapeutic agent for choroidal degenerative diseases.
- the compound of the present invention has an inhibitory effect on photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model.
- Such a compound of the present invention is useful as a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of angiogenesis.
- a method for preventing or treating the choroidal degenerative disease using the compound of the present invention, the compound of the present invention for use in the prevention or treatment of the choroidal degenerative disease, and the choroidal degenerative disease is also provided. Also provided is the use of a compound of the invention for the manufacture of a prophylactic or therapeutic agent.
- the “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like.
- the hydrate and / or solvate is also included in the scope of the compound.
- the composition ratio of the free form of the compound of the present invention to the salt is 1: 1 or 1: when the salt is a monovalent inorganic acid or monovalent organic acid.
- the 2: 1 component ratio is when the salt is a trivalent inorganic acid or a trivalent organic acid, A composition ratio of 3: 1 is preferred.
- the composition ratio of the free form of the compound of the present invention, salt and water is as follows when the salt is a monovalent inorganic acid or monovalent organic acid:
- the composition ratio of 2: 1 or 1: 1: 3 is a divalent inorganic acid or divalent organic acid
- the composition ratio of 2: 1: 1 or 2: 1: 6 is Is a trivalent inorganic acid or a trivalent organic acid
- a composition ratio of 6: 2: 3 or 3: 1: 9 is preferred.
- 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 examples of the compound of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
- this invention compound can be manufactured in accordance with the normal method in the field
- 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 at least one selected from the group consisting of atrophic age-related macular degeneration
- 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, and polyacrylic acid, with the compound of the present invention, and compressing the powder. If necessary, excipients, binders, stabilizers, and pH adjusters can be used.
- a biodegradable polymer for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid
- 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 preventive or therapeutic agent of the present invention can be appropriately changed according to 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.
- Compound A ′ The pharmacological effect of Compound A dihydrochloride (hereinafter also referred to as “Compound A ′”) was evaluated using a mouse photopathy model.
- the mouse photopathy model is a model animal in which cell death of retinal photoreceptor cells and / or photoreceptors is induced by light irradiation, and is a retina choroidal degenerative disease substantially free of new blood vessels, for example, atrophic addition. It is widely used as a model animal for age-related macular degeneration, early 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: 1% (w / v) Compound A ′ solution suspended in an aqueous methylcellulose solution at a dose of 10 mg / kg, once 1 hour before light irradiation, Orally 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 of the present invention represented by Compound A ′ suppresses photoreceptor cell death and / or photoreceptor cell death. Therefore, the compound of the present invention has a prophylactic or therapeutic effect for a choroidal degenerative disease substantially free of neovascularization.
- 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.
- the compound 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, retinal center 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 those diseases (Preferably atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, and retina choroid disorder associated with these diseases, particularly preferably atrophy It is useful as a prevent
Abstract
A compound represented by general formula (1) or a salt thereof has an inhibitory effect on photoreceptor cell death and/or visual cell death in a light-induced damage mouse model, and is therefore useful as a prophylactic or therapeutic agent for retinal/choroidal denaturation diseases that do not substantially involve neovascularization (e.g., atrophic age-related macular degeneration, retinitis pigmentosa, gyrate atrophy of choroid and retina) and retinal and choroidal disorders associated with the aforementioned diseases.
Description
本発明は、特定のイソキノリンスルホニル誘導体またはその医薬的に許容される塩の少なくとも一つを有効成分として含有する、実質的に血管新生を伴わない網脈絡膜変性疾患の予防または治療剤に関する。また本発明は、このようなイソキノリンスルホニル誘導体またはその医薬的に許容される塩を用いた前記網脈絡膜変性疾患の予防または治療方法に関する。また、本発明は、前記網脈絡膜変性疾患の予防または治療に使用するためのイソキノリンスルホニル誘導体またはその医薬的に許容される塩に関する。さらに本発明は、このようなイソキノリンスルホニル誘導体またはその医薬的に許容される塩の、前記網脈絡膜変性疾患の予防または治療剤を製造するための使用にも関する。
The present invention relates to a preventive or therapeutic agent for a retina choroidal degenerative disease substantially free of angiogenesis, which contains at least one of a specific isoquinoline sulfonyl 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 isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof. The present invention also relates to an isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of the retina choroidal degenerative disease. The present invention further relates to the use of such an isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof for producing a prophylactic or therapeutic agent for the above-mentioned choroidal degenerative disease.
後眼部組織における網脈絡膜変性疾患には難治性のものが多く、失明の原因となる重篤な症状を示すものが少なくない。その代表的なものとして加齢黄斑変性、網膜色素変性症などが挙げられ、特に、加齢黄斑変性は、日本、米国、欧州などの先進国での、壮年から老年期における失明の主要原因となっている。
Many of the retinal choroidal degenerative diseases in the posterior segment of the eye are refractory, and many exhibit severe symptoms that cause blindness. Typical examples include age-related macular degeneration and retinitis pigmentosa.In particular, 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.
加齢黄斑変性は黄斑部の加齢に起因する疾患であり、高齢化社会となった現在、その患者数は増加の一途をたどっている。加齢黄斑変性は、脈絡膜からの新生血管を伴う滲出型（ｗｅｔ ｔｙｐｅ）と脈絡膜から発生する新生血管を伴わない萎縮型（ｄｒｙ ｔｙｐｅ）に大別され、前者の滲出型には、レーザー光凝固術、新生血管抜去術、中心窩移動術などによる治療が行われているが、それらの治療には限界がある。また、最近、血管新生阻害剤であるベバシズマブ［ｂｅｖａｃｉｚｕｍａｂ、商品名：Ａｖａｓｔｉｎ］、ラニビズマブ［ｒａｎｉｂｉｚｕｍａｂ、商品名：Ｌｕｃｅｎｔｉｓ］などによる治療もなされている。しかし、後者の萎縮型には、現在のところ有効な治療方法はなく、新たな薬剤の開発が望まれている。
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. Treatments such as surgery, neovascularization, and foveal movement have been performed, but these treatments have limitations. Recently, treatment with an angiogenesis inhibitor bevacizumab [bevacizumab, trade name: Avastin], ranibizumab [tradename: Lucentis] or the like has also been performed. However, there is currently no effective therapeutic method for the latter atrophic type, and the development of a new drug is desired.
一方、下記一般式（１）で表される化合物は、一般名でファスジル（Ｆａｓｕｄｉｌ）と呼ばれており、脳機能障害の治療剤であるエリル（商品名）点滴静注液の有効成分として知られている。
On the other hand, the compound represented by the following general formula (1) is generally called Fasudil and is known as an active ingredient of Eryel (trade name) intravenous infusion, which is a therapeutic agent for brain dysfunction. It has been.
また、ファスジルを含むイソキノリンスルホンアミド誘導体が、哺乳動物の血管平滑筋に作用する、血管拡張剤、脳循環改善剤、狭心症治療薬、脳血管系の血栓症および高血圧症の予防または治療薬として有用であることが、米国特許第４６７８７８３号明細書（特許文献１）に記載されている。さらに、それらの誘導体の製法および血管拡張作用がＣｈｅｍ．Ｐｈａｒｍ．Ｂｕｌｌ．，４０（３） ７７０－７７３（１９９２）（非特許文献１）に、そのＲｈｏキナーゼ阻害作用がＡｍ．Ｊ．Ｐｈｙｓｉｏｌ．Ｃｅｌｌ Ｐｈｙｓｉｏｌ．，２７８：Ｃ５７－Ｃ６５（２０００）（非特許文献２）に、その血管新生阻害作用がＭｏｌ．Ｃａｎｃｅｒ Ｔｈｅｒ．，６（５） １５１７－１５２５（２００７）（非特許文献３）に、その緑内障、網膜症などの眼疾患治療薬として用途が、国際公開第９７／２３２２２号（特許文献２）に記載されており、その他にも種々の薬理作用を示すことが知られている。
In addition, isoquinoline sulfonamide derivatives containing fasudil act on mammalian vascular smooth muscle, vasodilators, cerebral circulation improving agents, angina pectoris, cerebrovascular thrombosis and hypertension preventive or therapeutic agent Is useful as US Pat. No. 4,678,783 (Patent Document 1). Furthermore, the production method and vasodilating action of these derivatives are described in Chem. Pharm. Bull. , 40 (3) 770-773 (1992) (Non-patent Document 1), its Rho kinase inhibitory action is reported in Am. J. et al. Physiol. Cell Physiol. , 278: C57-C65 (2000) (Non-patent Document 2), its angiogenesis inhibitory action is described in Mol. Cancer Ther. , 6 (5) 1517-1525 (2007) (non-patent document 3), its use as a therapeutic agent for eye diseases such as glaucoma and retinopathy is described in WO 97/23222 (patent document 2). In addition, it is known to exhibit various other pharmacological actions.
しかしながら、上記一般式（１）で表される化合物またはその塩における、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、さらにはそれらの疾患に伴う網脈絡膜障害の予防または治療効果については全く知られていない。
However, in the compound represented by the above general formula (1) or a salt thereof, 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 In addition, nothing is known about the preventive or therapeutic effects of cerebral rotational retinal choroidal atrophy, and retina choroidal disorders associated with those diseases.
実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、さらにはそれらの疾患に伴う網脈絡膜障害の予防または治療効果を有する薬剤を見出すことは非常に興味深い課題である。
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 those diseases Finding drugs that have preventive or therapeutic effects on disorders is a very interesting task.
本発明者らは、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症またはそれらの疾患に伴う網脈絡膜障害の予防または治療効果のある薬剤を見出す為に鋭意研究を行なった結果、イソキノリンスルホニル誘導体またはその塩が、マウス光障害モデルにおける、光受容体細胞死および／または視細胞死に対して抑制効果を有することを見出し、本発明に至った。すなわち、本発明は以下のとおりである。
The present inventors have a retina choroidal degenerative disease substantially free of neovascularization, for example, atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy or those diseases As a result of diligent research to find a drug that has an effect of preventing or treating choroidal disorders associated with phenotypes, isoquinoline sulfonyl derivatives or their salts were found to be effective against photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model. As a result, the inventors have found that they have a suppressing effect, and have reached the present invention. That is, the present invention is as follows.
本発明は、下記式（１）で表される化合物またはその医薬的に許容される塩の少なくとも一つを有効成分として含有する、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療剤である。以下、下記式（１）で表される化合物またはその塩を「本発明化合物」と呼称する。
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. Hereinafter, the compound represented by the following formula (1) or a salt thereof is referred to as “the compound of the present invention”.
本発明はまた、患者に、本発明化合物の少なくとも一つを薬理上有効な量投与することを含む、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療方法についても提供する。
The present invention also provides a method for preventing or treating a choroidal degenerative disease substantially free of new blood vessels, comprising administering to a patient a pharmacologically effective amount of at least one of the compounds of the present invention.
また本発明は、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療に使用するための、本発明化合物についても提供する。
The present invention also provides the compound of the present invention for use in the prevention or treatment of a retina choroidal degenerative disease substantially free of neovascularization.
本発明はさらに、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療剤を製造するための、本発明化合物の使用についても提供する。
The present invention further provides use of the compound of the present invention for producing a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of new blood vessels.
本発明における前記網脈絡膜変性疾患は、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種であることが好ましく、中でも、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種であることが特に好ましい。
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 Preferably, 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.
本発明化合物は、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）、さらにはそれらの疾患に伴う網脈絡膜障害など（好ましくは、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害、特に好ましくは、萎縮型加齢黄斑変性およびその疾患に伴う網脈絡膜障害）の予防または治療剤として有用である。また本発明化合物を用いた前記網脈絡膜変性疾患の予防または治療方法、前記網脈絡膜変性疾患の予防または治療に使用するための本発明化合物、ならびに、前記網脈絡膜変性疾患の予防または治療剤を製造するための本発明化合物の使用についても提供される。
The compound 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 associated with these diseases (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 atrophic type It is useful as a preventive or therapeutic agent for age-related macular degeneration and retina choroid disorder associated with the disease. In addition, a method for preventing or treating the choroidal degenerative disease using the compound of the present invention, a compound of the present invention for use in preventing or treating the choroidal degenerative disease, and a prophylactic or therapeutic agent for the choroidal degenerative disease Also provided is the use of a compound of the present invention to accomplish this.
本発明は、下記一般式（１）で表されるイソキノリンスルホニル誘導体またはその医薬的に許容される塩（本発明化合物）の少なくとも一つを有効成分として含有する、実質的に血管新生を伴わない網脈絡膜変性疾患の予防または治療剤である。
The present invention contains at least one of the isoquinoline sulfonyl derivative represented by the following general formula (1) or a pharmaceutically acceptable salt thereof (the compound of the present invention) as an active ingredient, and is substantially free from angiogenesis. It is a preventive or therapeutic agent for choroidal degenerative diseases.
その詳細については後述の［薬理試験］の項で説明するが、本発明化合物は、マウス光障害モデルにおける、光受容体細胞死および／または視細胞死の抑制効果を有する。このような本発明化合物は、実質的に血管新生を伴わない網脈絡膜変性疾患の予防または治療剤として有用である。また本発明によれば、本発明化合物を用いた前記網脈絡膜変性疾患の予防または治療方法、前記網脈絡膜変性疾患の予防または治療に使用するための本発明化合物、ならびに、前記網脈絡膜変性疾患の予防または治療剤を製造するための本発明化合物の使用についても提供される。
The details will be described in the section of [Pharmacological test] described later. The compound of the present invention has an inhibitory effect on photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model. Such a compound of the present invention is useful as a prophylactic or therapeutic agent for a retina choroidal degenerative disease substantially free of angiogenesis. Further, according to the present invention, there is provided a method for preventing or treating the choroidal degenerative disease using the compound of the present invention, the compound of the present invention for use in the prevention or treatment of the choroidal degenerative disease, and the choroidal degenerative disease. Also provided is the use of a compound of the invention for the manufacture of a prophylactic or therapeutic agent.
本発明化合物における「塩」とは、医薬的に許容される塩であれば特に制限はなく、塩酸、臭化水素酸、ヨウ化水素酸、硝酸、硫酸、リン酸などの無機酸との塩、酢酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸、アジピン酸、グルコン酸、グルコヘプト酸、グルクロン酸、テレフタル酸、メタンスルホン酸、乳酸、馬尿酸、１，２－エタンジスルホン酸、イセチオン酸、ラクトビオン酸、オレイン酸、パモ酸、ポリガラクツロン酸、ステアリン酸、タンニン酸、メタンスルホン酸、トリフルオロメタンスルホン酸、ベンゼンスルホン酸、ｐ－トルエンスルホン酸、硫酸ラウリルエステル、硫酸メチル、ナフタレンスルホン酸、スルホサリチル酸などの有機酸との塩などが挙げられ、好ましくは、塩酸、臭化水素、硝酸、硫酸、リン酸、フマル酸、マレイン酸、コハク酸、クエン酸、酒石酸（Ｄ体、Ｌ体、メソ体）、メタンスルホン酸との塩が好ましい。
The “salt” in the compound of the present invention is not particularly limited as long as it is a pharmaceutically acceptable salt, and is a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid or the like. , Acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1,2-ethanedisulfonic acid, isethion Acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalenesulfonic acid And salts with organic acids such as sulfosalicylic acid, preferably hydrochloric acid, hydrogen bromide, nitric acid, sulfuric acid, Phosphate, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid (D forms, L, meso), salt with methanesulfonic acid is preferred.
本発明化合物に水和物および／または溶媒和物が存在する場合は、それらの水和物および／または溶媒和物も本化合物の範囲に含まれる。
When a hydrate and / or solvate is present in the compound of the present invention, the hydrate and / or solvate is also included in the scope of the compound.
なお、本発明化合物が塩の形態をとる場合、本発明化合物のフリー体と塩の構成比は、該塩が１価の無機酸または１価の有機酸である場合、１：１または１：２の構成比が、該塩が２価の無機酸または２価の有機酸である場合、２：１の構成比が、該塩が３価の無機酸または３価の有機酸である場合、３：１の構成比が好ましい。また、本発明化合物が水和物の形態をとる場合、本発明化合物のフリー体と塩と水の構成比は、該塩が１価の無機酸または１価の有機酸である場合、２：２：１または１：１：３の構成比が、該塩が２価の無機酸または２価の有機酸である場合、２：１：１または２：１：６の構成比が、該塩が３価の無機酸または３価の有機酸である場合、６：２：３または３：１：９の構成比が好ましい。
When the compound of the present invention takes the form of a salt, the composition ratio of the free form of the compound of the present invention to the salt is 1: 1 or 1: when the salt is a monovalent inorganic acid or monovalent organic acid. When the salt is a divalent inorganic acid or a divalent organic acid, the 2: 1 component ratio is when the salt is a trivalent inorganic acid or a trivalent organic acid, A composition ratio of 3: 1 is preferred. Further, when the compound of the present invention takes the form of a hydrate, the composition ratio of the free form of the compound of the present invention, salt and water is as follows when the salt is a monovalent inorganic acid or monovalent organic acid: When the composition ratio of 2: 1 or 1: 1: 3 is a divalent inorganic acid or divalent organic acid, the composition ratio of 2: 1: 1 or 2: 1: 6 is Is a trivalent inorganic acid or a trivalent organic acid, a composition ratio of 6: 2: 3 or 3: 1: 9 is preferred.
本発明化合物に結晶多形および結晶多形群（結晶多形システム）が存在する場合には、それらの結晶多形体および結晶多形群（結晶多形システム）も本発明化合物の範囲に含まれる。ここで、結晶多形群（結晶多形システム）とは、それら結晶の製造、晶出、保存などの条件および状態（なお、本状態には製剤化した状態も含む）により、結晶形が種々変化する場合の各段階における結晶形およびその過程全体を意味する。
When a crystalline polymorph and a crystalline polymorph group (crystalline polymorphic system) exist in the compound of the present invention, those crystalline polymorphs and crystalline polymorphic group (crystalline polymorphic system) are also included in the scope of the compound of the present invention. . Here, the crystal polymorph group (crystal polymorph system) 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.
本発明化合物における好ましい具体例として、以下の化合物またはその医薬的に許容される塩を挙げることができる。
Preferred examples of the compound of the present invention include the following compounds or pharmaceutically acceptable salts thereof.
・ヘキサヒドロ－１－（５－イソキノリンスルホニル）－１Ｈ－１，４－ジアゼピン（以下、「化合物Ａ」ともいう）。
Hexahydro-1- (5-isoquinolinesulfonyl) -1H-1,4-diazepine (hereinafter also referred to as “Compound A”).
なお、本発明化合物は、有機合成化学の分野における通常の方法に従って製造できる。たとえば、米国４６７８７８３号特許明細書、Ｃｈｅｍ．Ｐｈａｒｍ． Ｂｕｌｌ．，４０（３） ７７０－７７３（１９９２）などに記載された方法に準じて製造することができる。
In addition, this invention compound can be manufactured in accordance with the normal method in the field | area of synthetic organic chemistry. For example, US Pat. No. 4,678,783, Chem. Pharm. Bull. , 40 (3) 770-773 (1992), and the like.
本発明における「実質的に新生血管を伴わない網脈絡膜変性疾患」とは、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害などからなる群から選ばれる少なくとも１種が挙げられ、好ましくは、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群から選ばれる少なくとも１種であり、特に好ましくは、萎縮型加齢黄斑変性およびその疾患に伴う網脈絡膜障害からなる群から選ばれる少なくとも１種である。
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 at least one selected from the group consisting of atrophic age-related macular degeneration and reticulochoroidal disorders associated with the disease A.
また、本発明の予防または治療剤は、必要に応じて、医薬的に許容される他の活性成分および／または添加剤を加えて、単独製剤および／または配合製剤として、汎用される技術を用いて製剤化することができる。
In addition, the 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.
本発明の予防または治療剤は、患者に対して経口的または非経口的に投与することができ、投与形態としては、経口投与、眼への局所投与（点眼投与、結膜嚢内投与、硝子体内投与、結膜下投与、テノン嚢下投与など）、静脈内投与、経皮投与などが挙げられ、必要に応じて、医薬的に許容され得る添加剤と共に、投与に適した剤型に製剤化される。経口投与に適した剤型としては、たとえば、錠剤、カプセル剤、顆粒剤、細粒剤、散剤などが挙げられ、非経口投与に適した剤型としては、たとえば、注射剤、点眼剤、眼軟膏、貼布剤、ゲル剤、挿入剤などが挙げられる。これらは当該分野で汎用されている通常の技術を用いて調製することができる。また、本発明の予防または治療剤は、これらの製剤の他に眼内インプラント用製剤やマイクロスフェアーなどのＤＤＳ（ドラッグデリバリーシステム）化された製剤にすることもできる。
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. . Examples of dosage forms suitable for oral administration include tablets, capsules, granules, fine granules, powders, etc. Examples of 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. In addition to these preparations, 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.
たとえば、錠剤は、乳糖、ブドウ糖、Ｄ－マンニトール、無水リン酸水素カルシウム、デンプン、ショ糖などの賦形剤；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、クロスカルメロースナトリウム、クロスポピドン、デンプン、部分アルファー化デンプン、低置換度ヒドロキシプロピルセルロースなどの崩壊剤；ヒドロキシプロピルセルロース、エチルセルロース、アラビアゴム、デンプン、部分アルファー化デンプン、ポリビニルピロリドン、ポリビニルアルコールなどの結合剤；ステアリン酸マグネシウム、ステアリン酸カルシウム、タルク、含水二酸化ケイ素、硬化油などの滑沢剤；精製白糖、ヒドロキシプロピルメチルセルロース、ヒドロキシプロピルセルロース、メチルセルロース、ピロリドンなどのコーティング剤；クエン酸、アスパルテーム、アスコルビン酸、メントールなどの矯味剤などを適宜選択して用い、調製することができる。
For example, 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.
注射剤は、塩化ナトリウムなどの等張化剤；リン酸ナトリウムなどの緩衝化剤；ポリオキシエチレンソルビタンモノオレートなどの界面活性剤；メチルセルロースなどの増粘剤などから必要に応じて選択して用い、調製することができる。
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. Can be prepared.
点眼剤は、塩化ナトリウム、濃グリセリンなどの等張化剤；リン酸ナトリウム、酢酸ナトリウムなどの緩衝化剤；ポリオキシエチレンソルビタンモノオレート、ステアリン酸ポリオキシル４０、ポリオキシエチレン硬化ヒマシ油などの界面活性剤；クエン酸ナトリウム、エデト酸ナトリウムなどの安定化剤；塩化ベンザルコニウム、パラベンなどの防腐剤などから必要に応じて選択して用い、調製することができ、ｐＨは眼科製剤に許容される範囲内にあればよいが、通常４～８の範囲内が好ましい。また、眼軟膏は、白色ワセリン、流動パラフィンなどの汎用される基剤を用い、調製することができる。
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.
挿入剤は、生体分解性ポリマー、たと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、カルボキシビニルポリマー、ポリアクリル酸などの生体分解性ポリマーを本発明化合物とともに粉砕混合し、この粉末を圧縮成型することにより、調製することができ、必要に応じて、賦形剤、結合剤、安定化剤、ｐＨ調整剤を用いることができる。
The intercalating agent is prepared by crushing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, with the compound of the present invention, and compressing the powder. If necessary, excipients, binders, stabilizers, and pH adjusters can be used.
眼内インプラント用製剤は、生体分解性ポリマー、たとえばポリ乳酸、ポリグリコール酸、乳酸・グリコール酸共重合体、ヒドロキシプロピルセルロースなどの生体分解性ポリマーを用い、調製することができる。
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.
本発明の予防または治療剤の投与量は、剤型、投与すべき患者の症状の軽重、年令、体重、医師の判断などに応じて適宜変えることができるが、経口投与の場合、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回または数回に分けて投与することができ、注射剤の場合、一般には、成人に対し０．０００１～２０００ｍｇを１回または数回に分けて投与することができる。また、点眼剤または挿入剤の場合には、０．０００００１～１０％（ｗ／ｖ）、好ましくは０．００００１～１％（ｗ／ｖ）、より好ましくは０．０００１～０．１％（ｗ／ｖ）の有効成分濃度のものを１日１回または数回投与することができる。さらに、貼布剤の場合は、成人に対し０．０００１～２０００ｍｇを含有する貼布剤を貼布することができ、眼内インプラント用製剤の場合は、成人に対し０．０００１～２０００ｍｇ含有する眼内インプラント用製剤を眼内にインプラントすることができる。
The dose of the preventive or therapeutic agent of the present invention can be appropriately changed according to the dosage form, the severity of the patient's symptoms to be administered, age, weight, doctor's judgment, etc. In general, 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. Can be administered 0.0001-2000 mg to adults in one or several divided doses. In the case of eye drops or intercalating agents, 0.000001 to 10% (w / v), preferably 0.00001 to 1% (w / v), more preferably 0.0001 to 0.1% ( The active ingredient concentration of w / v) can be administered once or several times a day. Furthermore, in the case of a patch, a patch containing 0.0001 to 2000 mg can be applied to an adult. In the case of an intraocular implant preparation, 0.0001 to 2000 mg is included for an adult. An intraocular implant formulation can be implanted in the eye.
以下に、薬理試験例および製剤例を示すが、これらの例は本発明をよりよく理解するためのものであり、本発明の範囲を限定するものではない。
Hereinafter, examples of pharmacological tests and formulation examples are shown, but these examples are for better understanding of the present invention and do not limit the scope of the present invention.
［薬理試験例］
１．マウス光障害モデルを用いた試験
マウス光障害モデルを用いて、化合物Ａの二塩酸塩（以下、「化合物Ａ’」ともいう）の薬理効果を評価した。なお、マウス光障害モデルは光照射により、網膜光受容細胞および／または視細胞の細胞死を誘発させたモデル動物であり、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症などのモデル動物として汎用されている（Ｉｎｖｅｓｔ． Ｏｐｈｔｈａｌｍｏｌ． Ｖｉｓ． Ｓｃｉ．， ２００５； ４６： ９７９－９８７）。 [Pharmacological test example]
1. Test Using Mouse Photopathy Model The pharmacological effect of Compound A dihydrochloride (hereinafter also referred to as “Compound A ′”) was evaluated using a mouse photopathy model. The mouse photopathy model is a model animal in which cell death of retinal photoreceptor cells and / or photoreceptors is induced by light irradiation, and is a retina choroidal degenerative disease substantially free of new blood vessels, for example, atrophic addition. It is widely used as a model animal for age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, etc. (Invest. Ophthalmol. Vis. Sci., 2005; 46: 979-987).
１．マウス光障害モデルを用いた試験
マウス光障害モデルを用いて、化合物Ａの二塩酸塩（以下、「化合物Ａ’」ともいう）の薬理効果を評価した。なお、マウス光障害モデルは光照射により、網膜光受容細胞および／または視細胞の細胞死を誘発させたモデル動物であり、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症などのモデル動物として汎用されている（Ｉｎｖｅｓｔ． Ｏｐｈｔｈａｌｍｏｌ． Ｖｉｓ． Ｓｃｉ．， ２００５； ４６： ９７９－９８７）。 [Pharmacological test example]
1. Test Using Mouse Photopathy Model The pharmacological effect of Compound A dihydrochloride (hereinafter also referred to as “Compound A ′”) was evaluated using a mouse photopathy model. The mouse photopathy model is a model animal in which cell death of retinal photoreceptor cells and / or photoreceptors is induced by light irradiation, and is a retina choroidal degenerative disease substantially free of new blood vessels, for example, atrophic addition. It is widely used as a model animal for age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, etc. (Invest. Ophthalmol. Vis. Sci., 2005; 46: 979-987).
（マウス光障害モデルの作製方法および評価方法）
化合物Ａ’投与群および基剤投与群として、８週齢のＢＡＬＢ／ｃ雄性マウスを、暗室にて暗順応を２０時間施した後、白色蛍光灯で５０００ｌｕｘ、２時間光照射を実施して、光障害を誘発した。その後、暗室にて暗順応を２０時間施し、網膜電図（ｅｌｅｃｔｒｏｒｅｔｉｎｏｇｒａｍ、以下、「ＥＲＧ」ともいう）を測定した。得られた波形からａ波およびｂ波の振幅（μＶ）を算出した。また、暗室にて暗順応を２０時間施した後、光照射を行なわずにＥＲＧを測定した群を正常対照群とした。下記式１に従い、ａ波およびｂ波のそれぞれについて、振幅減弱抑制率（％）を算出した。なお、各群の例数は、２匹（４眼）である。 (Method for producing and evaluating mouse light damage model)
As a compound A ′ administration group and a base administration group, 8-week-old BALB / c male mice were subjected to dark adaptation in a dark room for 20 hours, and then subjected to 5000 lux for 2 hours with white fluorescent light, Induced light damage. Thereafter, dark adaptation was performed in a dark room for 20 hours, and an electroretinogram (hereinafter also referred to as “ERG”) was measured. The amplitude (μV) of the a wave and the b wave was calculated from the obtained waveform. In addition, a group in which ERG was measured without performing light irradiation after dark adaptation in a dark room for 20 hours was defined as a normal control group. According to the following formula 1, the amplitude attenuation suppression rate (%) was calculated for each of the a wave and the b wave. In addition, the number of examples in each group is 2 (4 eyes).
化合物Ａ’投与群および基剤投与群として、８週齢のＢＡＬＢ／ｃ雄性マウスを、暗室にて暗順応を２０時間施した後、白色蛍光灯で５０００ｌｕｘ、２時間光照射を実施して、光障害を誘発した。その後、暗室にて暗順応を２０時間施し、網膜電図（ｅｌｅｃｔｒｏｒｅｔｉｎｏｇｒａｍ、以下、「ＥＲＧ」ともいう）を測定した。得られた波形からａ波およびｂ波の振幅（μＶ）を算出した。また、暗室にて暗順応を２０時間施した後、光照射を行なわずにＥＲＧを測定した群を正常対照群とした。下記式１に従い、ａ波およびｂ波のそれぞれについて、振幅減弱抑制率（％）を算出した。なお、各群の例数は、２匹（４眼）である。 (Method for producing and evaluating mouse light damage model)
As a compound A ′ administration group and a base administration group, 8-week-old BALB / c male mice were subjected to dark adaptation in a dark room for 20 hours, and then subjected to 5000 lux for 2 hours with white fluorescent light, Induced light damage. Thereafter, dark adaptation was performed in a dark room for 20 hours, and an electroretinogram (hereinafter also referred to as “ERG”) was measured. The amplitude (μV) of the a wave and the b wave was calculated from the obtained waveform. In addition, a group in which ERG was measured without performing light irradiation after dark adaptation in a dark room for 20 hours was defined as a normal control group. According to the following formula 1, the amplitude attenuation suppression rate (%) was calculated for each of the a wave and the b wave. In addition, the number of examples in each group is 2 (4 eyes).
［式１］
振幅減弱抑制率（％）＝（（Ｖx－Ｖ0）／（Ｖn－Ｖ0））×１００
Ｖ0：基剤投与群の振幅（μＶ）
Ｖn：正常対照群の振幅（μＶ）
Ｖx：化合物Ａ’投与群の振幅（μＶ）
（投与方法）
１）光照射前の単回投与時
・化合物Ａ投与群：１％（ｗ／ｖ）メチルセルロース水溶液に懸濁した化合物Ａ’溶液を１０ｍｇ／ｋｇの用量で、光照射１時間前に１回、経口投与した。 [Formula 1]
Amplitude attenuation suppression rate (%) = ((V x −V 0 ) / (V n −V 0 )) × 100
V 0 : Amplitude of base administration group (μV)
V n : amplitude of normal control group (μV)
V x : Amplitude of compound A ′ administration group (μV)
(Method of administration)
1) Single administration before light irradiation Compound A administration group: 1% (w / v) Compound A ′ solution suspended in an aqueous methylcellulose solution at a dose of 10 mg / kg, once 1 hour before light irradiation, Orally administered.
振幅減弱抑制率（％）＝（（Ｖx－Ｖ0）／（Ｖn－Ｖ0））×１００
Ｖ0：基剤投与群の振幅（μＶ）
Ｖn：正常対照群の振幅（μＶ）
Ｖx：化合物Ａ’投与群の振幅（μＶ）
（投与方法）
１）光照射前の単回投与時
・化合物Ａ投与群：１％（ｗ／ｖ）メチルセルロース水溶液に懸濁した化合物Ａ’溶液を１０ｍｇ／ｋｇの用量で、光照射１時間前に１回、経口投与した。 [Formula 1]
Amplitude attenuation suppression rate (%) = ((V x −V 0 ) / (V n −V 0 )) × 100
V 0 : Amplitude of base administration group (μV)
V n : amplitude of normal control group (μV)
V x : Amplitude of compound A ′ administration group (μV)
(Method of administration)
1) Single administration before light irradiation Compound A administration group: 1% (w / v) Compound A ′ solution suspended in an aqueous methylcellulose solution at a dose of 10 mg / kg, once 1 hour before light irradiation, Orally administered.
・正常対照群および基剤投与群：１％（ｗ／ｖ）メチルセルロース水溶液を、光照射１時間前に１回、経口投与した。
Normal control group and base administration group: A 1% (w / v) methylcellulose aqueous solution was orally administered 1 hour before light irradiation.
（結果）
化合物Ａ’を使用した場合の試験結果を以下の表１に示す。表１から明らかなように化合物Ａ’は光照射によるＥＲＧのａ波およびｂ波の減弱に対して、顕著な抑制作用を示した。 (result)
The test results when Compound A ′ is used are shown in Table 1 below. As is clear from Table 1, Compound A ′ exhibited a remarkable inhibitory action against the attenuation of ERG a wave and b wave by light irradiation.
化合物Ａ’を使用した場合の試験結果を以下の表１に示す。表１から明らかなように化合物Ａ’は光照射によるＥＲＧのａ波およびｂ波の減弱に対して、顕著な抑制作用を示した。 (result)
The test results when Compound A ′ is used are shown in Table 1 below. As is clear from Table 1, Compound A ′ exhibited a remarkable inhibitory action against the attenuation of ERG a wave and b wave by light irradiation.
（考察）
以上の結果から、化合物Ａ’に代表される本発明化合物は、光受容体細胞死および／または視細胞死を抑制することが分かった。よって、本発明化合物は実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療効果を有する。 (Discussion)
From the above results, it was found that the compound of the present invention represented by Compound A ′ suppresses photoreceptor cell death and / or photoreceptor cell death. Therefore, the compound of the present invention has a prophylactic or therapeutic effect for a choroidal degenerative disease substantially free of neovascularization.
以上の結果から、化合物Ａ’に代表される本発明化合物は、光受容体細胞死および／または視細胞死を抑制することが分かった。よって、本発明化合物は実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療効果を有する。 (Discussion)
From the above results, it was found that the compound of the present invention represented by Compound A ′ suppresses photoreceptor cell death and / or photoreceptor cell death. Therefore, the compound of the present invention has a prophylactic or therapeutic effect for a choroidal degenerative disease substantially free of neovascularization.
［製剤例］
製剤例を挙げて本発明の薬剤をさらに具体的に説明するが、本発明はこれらの製剤例にのみ限定されるものではない。 [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.
製剤例を挙げて本発明の薬剤をさらに具体的に説明するが、本発明はこれらの製剤例にのみ限定されるものではない。 [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.
（処方例１：錠剤）
１００ｍｇ中
化合物Ａ’ １ｍｇ
乳糖 ６６．４ｍｇ
トウモロコシデンプン ２０ｍｇ
カルボキシメチルセルロースカルシウム ６ｍｇ
ヒドロキシプロピルセルロース ６ｍｇ
ステアリン酸マグネシウム ０．６ｍｇ
化合物Ａ’、乳糖を混合機中で混合し、その混合物にカルボキシメチルセルロースカルシウムおよびヒドロキシプロピルセルロースを加えて造粒し、得られた顆粒を乾燥後整粒し、その整粒顆粒にステアリン酸マグネシウムを加えて混合し、打錠機で打錠する。また、化合物Ａ’の添加量を変えることにより、１００ｍｇ中の含有量が０．１ｍｇ、１０ｍｇまたは５０ｍｇの錠剤を調製できる。 (Prescription Example 1: Tablet)
Compound A '1mg in 100mg
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 6mg
Magnesium stearate 0.6mg
Compound A ′ and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. In addition, mix and tablet with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, or 50 mg can be prepared by changing the addition amount of compound A ′.
１００ｍｇ中
化合物Ａ’ １ｍｇ
乳糖 ６６．４ｍｇ
トウモロコシデンプン ２０ｍｇ
カルボキシメチルセルロースカルシウム ６ｍｇ
ヒドロキシプロピルセルロース ６ｍｇ
ステアリン酸マグネシウム ０．６ｍｇ
化合物Ａ’、乳糖を混合機中で混合し、その混合物にカルボキシメチルセルロースカルシウムおよびヒドロキシプロピルセルロースを加えて造粒し、得られた顆粒を乾燥後整粒し、その整粒顆粒にステアリン酸マグネシウムを加えて混合し、打錠機で打錠する。また、化合物Ａ’の添加量を変えることにより、１００ｍｇ中の含有量が０．１ｍｇ、１０ｍｇまたは５０ｍｇの錠剤を調製できる。 (Prescription Example 1: Tablet)
Compound A '1mg in 100mg
Lactose 66.4mg
Corn starch 20mg
Carboxymethylcellulose calcium 6mg
Hydroxypropylcellulose 6mg
Magnesium stearate 0.6mg
Compound A ′ and lactose are mixed in a blender, carboxymethylcellulose calcium and hydroxypropylcellulose are added to the mixture and granulated. The resulting granules are dried and sized, and magnesium stearate is added to the sized granules. In addition, mix and tablet with a tableting machine. Moreover, the tablet whose content in 100 mg is 0.1 mg, 10 mg, or 50 mg can be prepared by changing the addition amount of compound A ′.
（処方例２：眼軟膏）
１００ｇ中
化合物Ａ’ ０．３ｇ
流動パラフィン １０．０ｇ
白色ワセリン 適量
均一に溶融した白色ワセリンおよび流動パラフィンに、化合物Ａ’を加え、これらを十分に混合して後に徐々に冷却することで眼軟膏を調製する。化合物Ａ’の添加量を変えることにより、濃度が０．０５％（ｗ／ｗ）、０．１％（ｗ／ｗ）、０．５％（ｗ／ｗ）または１％（ｗ／ｗ）の眼軟膏を調製できる。 (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 becomes 0.05% (w / w), 0.1% (w / w), 0.5% (w / w) or 1% (w / w) Eye ointments can be prepared.
１００ｇ中
化合物Ａ’ ０．３ｇ
流動パラフィン １０．０ｇ
白色ワセリン 適量
均一に溶融した白色ワセリンおよび流動パラフィンに、化合物Ａ’を加え、これらを十分に混合して後に徐々に冷却することで眼軟膏を調製する。化合物Ａ’の添加量を変えることにより、濃度が０．０５％（ｗ／ｗ）、０．１％（ｗ／ｗ）、０．５％（ｗ／ｗ）または１％（ｗ／ｗ）の眼軟膏を調製できる。 (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 becomes 0.05% (w / w), 0.1% (w / w), 0.5% (w / w) or 1% (w / w) Eye ointments can be prepared.
（処方例３：注射剤）
１０ｍｌ中
化合物Ａ’ １０ｍｇ
塩化ナトリウム ９０ｍｇ
ポリソルベート８０ 適量
滅菌精製水 適量
化合物Ａ’および塩化ナトリウムを滅菌精製水に加えて注射剤を調製する。化合物Ａ’の添加量を変えることにより、１０ｍｌ中の含有量が０．１ｍｇ、１０ｍｇまたは５０ｍｇの注射剤を調製できる。 (Prescription Example 3: Injection)
Compound A '10mg in 10ml
Sodium chloride 90mg
Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound A ′ and sodium chloride are added to sterile purified water to prepare an injection. By changing the amount of Compound A ′ added, an injection with a content of 0.1 mg, 10 mg or 50 mg in 10 ml can be prepared.
１０ｍｌ中
化合物Ａ’ １０ｍｇ
塩化ナトリウム ９０ｍｇ
ポリソルベート８０ 適量
滅菌精製水 適量
化合物Ａ’および塩化ナトリウムを滅菌精製水に加えて注射剤を調製する。化合物Ａ’の添加量を変えることにより、１０ｍｌ中の含有量が０．１ｍｇ、１０ｍｇまたは５０ｍｇの注射剤を調製できる。 (Prescription Example 3: Injection)
Compound A '10mg in 10ml
Sodium chloride 90mg
Polysorbate 80 Appropriate amount Sterilized purified water Appropriate amount Compound A ′ and sodium chloride are added to sterile purified water to prepare an injection. By changing the amount of Compound A ′ added, an injection with a content of 0.1 mg, 10 mg or 50 mg in 10 ml can be prepared.
（処方例４：点眼剤）
１００ｍｌ中
化合物Ａ’ １０ｍｇ
塩化ナトリウム ９００ｍｇ
ポリソルベート８０ 適量
リン酸水素二ナトリウム 適量
リン酸二水素ナトリウム 適量
滅菌精製水 適量
滅菌精製水に化合物Ａ’およびそれ以外の上記成分を加え、これらを十分に混合して点眼液を調製する。化合物Ａの添加量を変えることにより、濃度が０．０５％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．５％（ｗ／ｖ）または１％（ｗ／ｖ）の点眼剤を調製できる。 (Prescription Example 4: Eye drops)
Compound A '10mg in 100ml
Sodium chloride 900mg
Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Compound A ′ and other components are added to sterile purified water, and these are mixed well to prepare an ophthalmic solution. By changing the amount of compound A added, the concentration is 0.05% (w / v), 0.1% (w / v), 0.5% (w / v) or 1% (w / v). Eye drops can be prepared.
１００ｍｌ中
化合物Ａ’ １０ｍｇ
塩化ナトリウム ９００ｍｇ
ポリソルベート８０ 適量
リン酸水素二ナトリウム 適量
リン酸二水素ナトリウム 適量
滅菌精製水 適量
滅菌精製水に化合物Ａ’およびそれ以外の上記成分を加え、これらを十分に混合して点眼液を調製する。化合物Ａの添加量を変えることにより、濃度が０．０５％（ｗ／ｖ）、０．１％（ｗ／ｖ）、０．５％（ｗ／ｖ）または１％（ｗ／ｖ）の点眼剤を調製できる。 (Prescription Example 4: Eye drops)
Compound A '10mg in 100ml
Sodium chloride 900mg
Polysorbate 80 Appropriate amount Disodium hydrogen phosphate Appropriate amount Sodium dihydrogen phosphate Appropriate amount Sterilized purified water Appropriate amount Compound A ′ and other components are added to sterile purified water, and these are mixed well to prepare an ophthalmic solution. By changing the amount of compound A added, the concentration is 0.05% (w / v), 0.1% (w / v), 0.5% (w / v) or 1% (w / v). Eye drops can be prepared.
本発明の有効成分である化合物Ａ’は網膜光受容体細胞死および／または視細胞死を抑制した。よって、本発明化合物は、実質的に新生血管を伴わない網脈絡膜変性疾患、たとえば、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）、さらにはそれらの疾患に伴う網脈絡膜障害など（好ましくは、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害、特に好ましくは、萎縮型加齢黄斑変性およびその疾患に伴う網脈絡膜障害）の予防または治療剤として有用である。
Compound A 'which is an active ingredient of the present invention suppressed retinal photoreceptor cell death and / or photoreceptor cell death. Therefore, the compound 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, retinal center 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 those diseases (Preferably atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, cerebral rotational retinal choroidal atrophy, and retina choroid disorder associated with these diseases, particularly preferably atrophy It is useful as a preventive or therapeutic agent for type age-related macular degeneration and retina choroidal disorder associated with the disease.
Claims (12)
- 下記一般式（１）で表される化合物またはその医薬的に許容される塩の少なくとも一つを有効成分として含有する、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療剤。
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項１に記載の予防または治療剤。 The retina choroidal degenerative disease is atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy, central retinal artery occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, It is at least one selected from the group consisting of central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and recurrent choroidal disorders associated with those diseases The preventive or therapeutic agent according to claim 1.
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項１記載の予防または治療剤。 The retina choroidal degenerative disease is at least one 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 these diseases The prophylactic or therapeutic agent according to claim 1, which is a species.
- 患者に、下記一般式（１）で表される化合物またはその医薬的に許容される塩の少なくとも一つを薬理上有効な量投与することを含む、実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療方法。
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項４に記載の予防または治療方法。 The retina choroidal degenerative disease is atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy, central retinal artery occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, It is at least one selected from the group consisting of central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and recurrent choroidal disorders associated with those diseases The prevention or treatment method according to claim 4.
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項４記載の予防または治療方法。 The retina choroidal degenerative disease is at least one 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 these diseases The prevention or treatment method according to claim 4, which is a species.
- 実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療に使用するための、下記一般式（１）で表されるイソキノリンスルホニル誘導体またはその医薬的に許容される塩。
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項７に記載のイソキノリンスルホニル誘導体またはその医薬的に許容される塩。 The retina choroidal degenerative disease is atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy, central retinal artery occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, It is at least one selected from the group consisting of central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and recurrent choroidal disorders associated with those diseases The isoquinoline sulfonyl derivative according to claim 7, or a pharmaceutically acceptable salt thereof.
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項７に記載のイソキノリンスルホニル誘導体またはその医薬的に許容される塩。 The retina choroidal degenerative disease is at least one 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 these diseases The isoquinoline sulfonyl derivative or a pharmaceutically acceptable salt thereof according to claim 7, which is a seed.
- 実質的に新生血管を伴わない網脈絡膜変性疾患の予防または治療剤を製造するための、下記一般式（１）で表されるイソキノリンスルホニル誘導体またはその医薬的に許容される塩の使用。
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症、網膜中心動脈閉塞症、網膜中心静脈閉塞症、網膜色素上皮剥離、中心性漿液性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、ぶどう膜炎（ベーチェット病、原田病）およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項１０に記載の使用。 The retina choroidal degenerative disease is atrophic age-related macular degeneration, early age-related macular degeneration, retinitis pigmentosa, brain retinal choroidal atrophy, central retinal artery occlusion, central retinal vein occlusion, retinal pigment epithelial detachment, It is at least one selected from the group consisting of central serous chorioretinopathy, polypoidal choroidal vasculopathy, multiple choroiditis, uveitis (Behcet's disease, Harada disease) and recurrent choroidal disorders associated with those diseases 11. Use according to claim 10.
- 前記網脈絡膜変性疾患が、萎縮型加齢黄斑変性、初期加齢黄斑変性、網膜色素変性症、脳回転状網膜脈絡膜萎縮症およびそれらの疾患に伴う網脈絡膜障害からなる群より選択される少なくとも１種である、請求項１０に記載の使用。 The retina choroidal degenerative disease is at least one 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 these diseases Use according to claim 10, which is a seed.
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| JP2015523546A (en) * | 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 | Methods for treating and diagnosing blindness diseases |
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