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WO2010058779A1 - Agent thérapeutique pour maladies dégénératives choriorétiniennes comprenant un dérivé de la pyridine-3-carbaldéhyde o-(pipéridine-1-yl-propyl)-oxime en tant qu'ingrédient actif - Google Patents

Agent thérapeutique pour maladies dégénératives choriorétiniennes comprenant un dérivé de la pyridine-3-carbaldéhyde o-(pipéridine-1-yl-propyl)-oxime en tant qu'ingrédient actif Download PDF

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Publication number
WO2010058779A1
WO2010058779A1 PCT/JP2009/069526 JP2009069526W WO2010058779A1 WO 2010058779 A1 WO2010058779 A1 WO 2010058779A1 JP 2009069526 W JP2009069526 W JP 2009069526W WO 2010058779 A1 WO2010058779 A1 WO 2010058779A1
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WO
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Prior art keywords
group
hydrogen atom
general formula
hydroxy
atom
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Ceased
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PCT/JP2009/069526
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English (en)
Japanese (ja)
Inventor
慎一郎 平井
篤史 吉田
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Santen Pharmaceutical Co Ltd
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Santen Pharmaceutical Co Ltd
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Priority to CA2743782A priority Critical patent/CA2743782A1/fr
Priority to EA201100805A priority patent/EA201100805A1/ru
Priority to BRPI0919867A priority patent/BRPI0919867A2/pt
Priority to CN2009801459746A priority patent/CN102215842A/zh
Priority to US13/129,569 priority patent/US20110224200A1/en
Priority to EP09827560A priority patent/EP2356988A4/fr
Publication of WO2010058779A1 publication Critical patent/WO2010058779A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • the present invention relates to a prophylactic or therapeutic agent for a choroidal degenerative disease containing at least one of pyridine-3-carbaldehyde O- (piperidin-1-yl-propyl) -oxime derivative or a salt thereof as an active ingredient.
  • the derivative has an inhibitory effect on photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model, and is useful as a preventive or therapeutic agent for reticulochoroidal degenerative diseases such as age-related macular degeneration and retinitis pigmentosa It is.
  • retinal choroidal degenerative diseases in the posterior segment of the eye are refractory, and many have severe symptoms that cause blindness.
  • Representative examples of retina choroidal degenerative diseases include age-related macular degeneration, retinitis pigmentosa, etc.
  • age-related macular degeneration has been observed in developed countries such as Japan, the United States, and Europe in the middle to old age. It has become one of the main causes.
  • This 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 divided into a dry type that does not involve neovascularization that occurs from the choroid (dry type) and a wet type that involves neovascularization from the choroid (wet) type).
  • dry type dry type
  • wet that involves neovascularization from the choroid
  • Patent Document 1 discloses N- (2-hydroxy-3- (1-piperidinyl) propoxy) -pyridine-1-oxide-3-carboximidoyl chloride, which is a compound represented by the general formula (1).
  • N-((2R) -2-hydroxy-3- (1-piperidinyl) propoxy) -pyridine-1-oxide-3-carboximidoyl chloride (Arimoclomol) is disclosed and has its insulin resistance reducing action and The use as a treatment for diabetic complications is described.
  • Patent Document 2 discloses N- (2-hydroxy-3- (1-piperidinyl) propoxy) -pyridine-3-carboximidoyl chloride (Bimoclomol), which is a compound represented by the general formula (1).
  • Patent Document 3 discloses ( ⁇ )-5- (piperidin-1-ylmethyl) -3- (pyridin-3-yl) -5,6-dihydro-2H— which is a compound represented by the general formula (1).
  • 1,2,4-Oxadiazine (Iroxanadine) is disclosed, and its use as a therapeutic agent for diseases related to vascular diseases and vascular abnormalities is described.
  • Patent Document 4 discloses an N- (2-hydroxy-3-piperidin-1-yl-propoxy) -nicotinamidine derivative, which is a compound represented by the general formula (1), and its use for treating diabetic vascular disorders Is described.
  • Patent Document 5 discloses N- (2-hydroxy-3- (1-piperidinyl) propoxy) -pyridine-1-oxide-3-carboximidoyl chloride, which is a compound represented by the general formula (1).
  • the inventors of the present invention conducted intensive studies to search for new pharmaceutical uses of pyridine-3-carbaldehyde O- (piperidin-1-yl-propyl) -oxime derivatives or salts thereof. As a result, the present inventors have found that the derivative or a salt thereof has an inhibitory effect on photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model, leading to the present invention.
  • the present invention relates to a prophylactic or therapeutic agent for a retina choroidal degenerative disease containing at least one of a compound represented by the following general formula (1) or a salt thereof (hereinafter also referred to as “the present compound”) as an active ingredient,
  • a compound represented by the following general formula (1) or a salt thereof hereinafter also referred to as “the present compound”
  • the present compound is a preventive or therapeutic agent for age-related macular degeneration, retinitis pigmentosa and the like.
  • A represents the following general formula (p1), (p2) or (p3);
  • R 1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a hydroxy group or an ester thereof
  • R 2 represents a hydrogen atom or a lower alkyl group
  • R 3 represents a halogen atom, a hydrogen atom, a lower alkyl group, a hydroxy group or an ester thereof
  • R 4 represents a halogen atom, a hydrogen atom, a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group or a lower cycloalkylamino group; or R 3 and R 4 are combined through a nitrogen atom, May form an unsaturated [1,2,4] oxadiazine ring
  • R 5 represents a hydrogen atom, a lower alkyl group or a lower cycloalkyl group
  • m represents 0 or 1
  • n represents 0 or 1. same as below. ] Definitions of terms (atoms, groups, etc.) used in this specification
  • Halogen atom means a fluorine, chlorine, bromine or iodine atom.
  • the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8, preferably 1 to 6, and particularly preferably 1 to 4 carbon atoms. Specific examples include methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl group and the like. .
  • the “lower cycloalkyl group” refers to a cycloalkyl group having 3 to 8 carbon atoms, preferably 3 to 6 carbon atoms. Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl groups.
  • aryl group is a residue obtained by removing one hydrogen atom from a monocyclic aromatic hydrocarbon having 6 to 14 carbon atoms or a bicyclic or tricyclic condensed polycyclic aromatic hydrocarbon. Show. Specific examples include phenyl, naphthyl, anthryl, phenanthryl group and the like.
  • “Lower alkoxy group” refers to a group in which a hydrogen atom of a hydroxy group is substituted with a lower alkyl group. Specific examples include methoxy, ethoxy, n-propoxy, n-butoxy, n-pentoxy, n-hexyloxy, n-heptyloxy, n-octyloxy, isopropoxy, isobutoxy, sec-butoxy, tert-butoxy, isopentoxy group Etc.
  • an “aralkyl group” is substituted with an aryl group in which one or more hydrogen atoms of a lower alkyl group may have a substituent (wherein the substituent means one or more halogen atoms) Represents a group formed.
  • substituent means one or more halogen atoms
  • Specific examples include benzyl, phenethyl, naphthylmethyl groups and the like.
  • lower alkylamino group refers to a group in which one or both hydrogen atoms of the amino group are substituted with a lower alkyl group. Specific examples include methylamino, ethylamino, propylamino, dimethylamino, diethylamino, and ethyl (methyl) amino groups.
  • lower cycloalkylamino group refers to a group in which one or both hydrogen atoms of an amino group are substituted with a lower cycloalkyl group.
  • Specific examples include cyclopropylamino, cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino, cyclooctylamino, dicyclopropylamino group, cyclopropyl (methyl) amino group, and the like.
  • “Ester of hydroxy group” means a group represented by the following general formula (2).
  • R is an alkyl group having 1 to 15 carbon atoms, and an aryl group which may have a substituent (wherein the substituent is selected from a halogen atom, a lower alkoxy group or a trifluoromethyl group) 1 or a plurality of groups.), Thienyl group, furyl group or pyridyl group.
  • a substituent selected from a halogen atom, a lower alkoxy group or a trifluoromethyl group 1 or a plurality of groups.
  • Thienyl group e.g., methylcarbonyloxy, heptadecanylcarbonyloxy, 2-chlorophenylcarbonyloxy, 4-methoxyphenylcarbonyloxy, 3-trifluoromethylcarbonyloxy, thienylcarbonyloxy, furylcarbonyloxy group, pyridylcarbonyloxy Group etc. are shown.
  • Unsaturated [1,2,4] oxadiazine refers to a group represented by the following formula (3), (4), (5), (6), (7) or (8).
  • R 4 is an amino group, a lower alkylamino group or a lower cycloalkylamino group, and these amino groups have one or more hydrogen atoms
  • the following tautomers are assumed, and these These tautomers are also included in the scope of the present compounds.
  • N ⁇ O in the general formula (1) of the present compound can also be expressed as “N + —O ⁇ ”.
  • crystal polymorph group refers to various crystal forms depending on the conditions and states of production, crystallization, storage, etc. of these crystals (including the formulated state in this state). It means the crystal form and the whole process at each stage when changing.
  • (A1) A represents the following general formula (p1), (p2) or (p3); and / or
  • R 1 represents a hydrogen atom, a lower alkyl group, an aralkyl group, a hydroxy group or an ester thereof; and / or (a3) R 2 represents a hydrogen atom or a lower alkyl group; and / or (a4) R 3 Represents a halogen atom, a hydrogen atom, a lower alkyl group or a hydroxy group or an ester thereof; and / or (a5) R 4 represents a halogen atom, a hydrogen atom, a hydroxy group, a lower alkoxy group, an amino group, a lower alkylamino group or a lower group.
  • R 3 and R 4 may combine together through a nitrogen atom to form an unsaturated [1,2,4] oxadiazine ring; and / or (A7)
  • R 5 represents a hydrogen atom, a lower alkyl group or a lower cycloalkyl group; and / or (a8) m represents 0 or 1; and / or (a9) n Represents 0 or 1.
  • (B1) A represents the following general formula (p1); and / or
  • R 1 represents a hydrogen atom; and / or (b3) R 2 represents a hydrogen atom; and / or (b4) R 3 represents a hydroxy group or an ester thereof; and / or (b5) R 4 Represents a halogen atom; or (b6) R 3 and R 4 may be joined together through a nitrogen atom to form an unsaturated [1,2,4] oxadiazine ring; and / or ( b7) m represents 0; and / or (b8) n represents 0 or 1.
  • (C1) A represents the following general formula (p1); and / or
  • R 1 represents a hydrogen atom; and / or (c3) R 2 represents a hydrogen atom; and / or (c4) R 3 represents a hydroxy group; and / or (c5) R 4 represents a chlorine atom Or (c6) R 3 and R 4 may combine together through a nitrogen atom to form a 5,6-dihydro-4H- [1,2,4] oxadiazine ring; and / Or (c7) m represents 0; and / or (c8) n represents 0 or 1.
  • A is (p2):
  • A is (p3):
  • This compound can be produced according to a usual method in the field of organic synthetic chemistry. For example, it can be produced according to the methods described in International Publication No. 00/50403 pamphlet, International Publication No. 90/04584 pamphlet, International Publication No. 00/35914 pamphlet, US Pat. No. 4,187,220.
  • the “salt” in the present compound is not particularly limited as long as it is a pharmaceutically acceptable salt.
  • Salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid, 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, isethionic acid, Organics such as lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl s
  • the retina choroidal degenerative disease in the present invention is age-related macular degeneration (drusen formation in early age-related macular degeneration, atrophic age-related macular degeneration, wet age-related macular degeneration), retinitis pigmentosa, retinal artery occlusion, retina Venous occlusion, uveitis, label disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative chorioretinopathy, polypoidal choroidal vasculopathy, polychoidal inflammation , Neovascular macular disease, retinal aneurysm and optic neuropathy associated with these diseases, preferably age-related macular degeneration or retinal pigment degeneration, in particular, this compound is drusen in early age-related macular degeneration It is useful as a preventive or therapeutic agent for formation or atrophic age-related macular degeneration.
  • the present compound can be formulated by using a technique widely used as a single preparation or a combined preparation by adding a pharmaceutically acceptable additive as necessary.
  • this compound When this compound is used for the prevention or treatment of the aforementioned eye diseases, it can be administered to patients orally or parenterally.
  • oral administration topical administration to the eye (instillation administration)
  • Intraconjunctival sac administration Intravitreal administration, subconjunctival administration, subtenon administration, etc.
  • intravenous administration transdermal administration, etc.
  • pharmaceutically acceptable additives Formulated into a suitable dosage form.
  • 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 ordinary techniques widely used in the field. In addition to these preparations, this compound can also be made into preparations for DDS (drug delivery system) such as preparations for intraocular implants and microspheres.
  • DDS drug delivery system
  • tablets are made of excipients such as lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, sucrose; carboxymethylcellulose, sodium carboxymethylcellulose croscarmellose, crospovidone, starch, partially pregelatinized starch, low Degrading agents such as hydroxypropyl cellulose; hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinyl pyrrolidone, polyvinyl alcohol, etc .; magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, cured Lubricants such as oil; Coating agents such as refined sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, pyrrolidone; , Using aspartame, ascorbic acid, by appropriately selecting and flavoring agents such as menthol, it can be prepared.
  • excipients such as lactose, glucose, D-
  • 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; and 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; can be selected and used as needed from preservatives such as benzalkonium chloride and paraben, 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 pulverizing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, and polyacrylic acid, together with the compound, 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, and polyacrylic acid
  • Preparations for intraocular implants can be prepared using biodegradable polymers, for example, biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • biodegradable polymers such as polylactic acid, polyglycolic acid, lactic acid / glycolic acid copolymer, and hydroxypropylcellulose.
  • the dose of this compound can be appropriately changed depending on the dosage form, the severity of the patient's symptoms, age, weight, doctor's judgment, etc. 0.01-5000 mg per day, preferably 0.1-2500 mg, more preferably 0.5-1000 mg can be administered in one or several divided doses.
  • 0.0001 to 2000 mg can be administered once or divided into several times.
  • 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.
  • a patch a patch containing 0.0001 to 2000 mg can be applied to an adult.
  • 0.0001 to 2000 mg is included for an adult.
  • An intraocular implant formulation can be implanted in the eye.
  • this compound suppressed photoreceptor cell death and / or photoreceptor cell death in a mouse photodamage model. That is, this compound is a retina choroidal degenerative disease such as age-related macular degeneration (drusen formation in early age-related macular degeneration, atrophic age-related macular degeneration, wet age-related macular degeneration), retinitis pigmentosa, retinal artery occlusion , Retinal vein occlusion, uveitis, label disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative chorioretinopathy, polypoidal choroidal vasculopathy, multiple occurrences Drusen formation or atrophic form of preferably age-related macular degeneration or retinitis pigmentosa, especially in early age-related macular degeneration,
  • age-related macular degeneration drusen formation in
  • 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 mainly a choroidal degenerative disease such as age-related macular degeneration, retinal pigment degeneration. (Invest. Ophthalmol. Vis. Sci., 2005; 46: 979-987).
  • Amplitude attenuation suppression rate (%) (V x ⁇ V 0 ) / (V n ⁇ V 0 ) ⁇ 100
  • V 0 amplitude ( ⁇ V) of the base administration group
  • V n amplitude of normal control group ( ⁇ V)
  • V X amplitude of drug administration group ( ⁇ V)
  • Normal control group and base administration group A 1% (W / V) methylcellulose aqueous solution was orally administered 1 hour before light irradiation.
  • 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 1 Compound A ′ 1 mg in 100 mg tablet 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 the compound C.
  • Formulation Example 2 Eye Ointment 100g Compound A '0.3g Liquid paraffin 10.0g An appropriate amount of white petrolatum An ointment is prepared by adding compound A ′ to white petrolatum and liquid paraffin uniformly melted, thoroughly mixing them, and then gradually cooling them. By changing the amount of compound B 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.
  • Formulation Example 3 Compound A ′ 10 mg in 10 ml of injection
  • Sodium chloride 90mg Polysorbate 80 appropriate amount sterile purified water appropriate amount Compound A ′ and sodium chloride are added to sterile purified water to prepare an injection.
  • amount of Compound A added it is possible to prepare an injection whose content in 10 ml is 0.1 mg, 10 mg or 50 mg.
  • Formulation Example 4 Eyedrops Compound A ′ 10 mg in 100 ml 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 the above-mentioned 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). Certain eye drops can be prepared.
  • Compound A ' which is an active ingredient of the present invention suppressed photoreceptor cell death and / or photoreceptor cell death. Therefore, the active ingredient of the present invention is useful as a preventive or therapeutic agent for retina choroidal degenerative diseases, particularly as a prophylactic or therapeutic agent for age-related macular degeneration, retinitis pigmentosa and the like.

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Abstract

L'invention porte sur un nouvel agent prophylactique ou thérapeutique destiné aux maladies dégénératives choriorétiniennes. Un composé représenté par la formule générale (1) ou un sel de celui-ci a un effet inhibiteur sur la mort des cellules photoréceptrices et/ou la mort des cellules visuelles dans un modèle expérimental de blessure causée par la lumière chez la souris. Il en résulte que le composé ou son sel est utile en tant qu'agent prophylactique ou thérapeutique pour les maladies dégénératives choriorétiniennes telles que la dégénérescence maculaire liée à l'âge et la rétinite pigmentaire. Dans la formule, A représente un groupe représenté par la formule générale (p1), (p2) ou (p3) ; R1 représente un atome d'hydrogène, un groupe alkyle inférieur, un groupe aralkyle, un groupe hydroxy ou un ester d'un élément quelconque choisi parmi l'atome et les groupes ; R2 représente un atome d'hydrogène, ou un groupe alkyle inférieur ; R3 représente un atome d'halogène, un atome d'hydrogène, un groupe alkyle inférieur, un groupe hydroxy ou un ester d'un élément quelconque choisi parmi les atomes et les groupes, et R4 représente un atome d'halogène, un atome d'hydrogène, un groupe hydroxy, un groupe alcoxy inférieur, un groupe amino, un groupe alkylamino inférieur ou un groupe cycloalkylamino inférieur, à la condition que R3, R4 et un atome d'azote puissent ensemble former un anneau [1,2,4]oxadiazine insaturé ; R5 représente un atome d'hydrogène, un groupe alkyle inférieur ou un groupe cycloalkyle inférieur ; m représente un nombre de 0 ou 1 ; et n représente un nombre de valeur 0 ou 1.
PCT/JP2009/069526 2008-11-18 2009-11-18 Agent thérapeutique pour maladies dégénératives choriorétiniennes comprenant un dérivé de la pyridine-3-carbaldéhyde o-(pipéridine-1-yl-propyl)-oxime en tant qu'ingrédient actif Ceased WO2010058779A1 (fr)

Priority Applications (6)

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CA2743782A CA2743782A1 (fr) 2008-11-18 2009-11-18 Agent therapeutique pour maladies degeneratives chorioretiniennes comprenant un derive de la pyridine-3-carbaldehyde o-(piperidine-1-yl-propyl)-oxime en tant qu'ingredient actif
EA201100805A EA201100805A1 (ru) 2008-11-18 2009-11-18 Терапевтический агент при хориоретинальном дегенеративном заболевании, содержащий в качестве активного ингредиента производное пиридин-3-карбальдегид-o-(пиперидин-1-илпропил)оксима
BRPI0919867A BRPI0919867A2 (pt) 2008-11-18 2009-11-18 agente terapeutico ou profilatico para uma doenca degenerativa coriorretiniana, e metodo profilatico ou terapeutico para uma doenca degenerativa coriorrentiniana
CN2009801459746A CN102215842A (zh) 2008-11-18 2009-11-18 含有吡啶-3-甲醛o-(哌啶-1-基-丙基)-肟衍生物作为有效成分的脉络膜视网膜变性疾病的治疗剂
US13/129,569 US20110224200A1 (en) 2008-11-18 2009-11-18 Therapeutic agent for chorioretinal degenerative disease containing pyridine-3-carbaldehyde 0-(piperidin-1-yl-propyl)-oxime derivative as active ingredient
EP09827560A EP2356988A4 (fr) 2008-11-18 2009-11-18 Agent thérapeutique pour maladies dégénératives choriorétiniennes comprenant un dérivé de la pyridine-3-carbaldéhyde o-(pipéridine-1-yl-propyl)-oxime en tant qu'ingrédient actif

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JP2008294022 2008-11-18
JP2008-294022 2008-11-18

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WO2010058779A1 true WO2010058779A1 (fr) 2010-05-27

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US (1) US20110224200A1 (fr)
EP (1) EP2356988A4 (fr)
JP (1) JP2010150243A (fr)
KR (1) KR20110084514A (fr)
CN (1) CN102215842A (fr)
BR (1) BRPI0919867A2 (fr)
CA (1) CA2743782A1 (fr)
EA (1) EA201100805A1 (fr)
WO (1) WO2010058779A1 (fr)

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CN103391957B (zh) 2011-02-22 2016-01-20 东丽株式会社 二醇组合物及聚酯
CN103804309B (zh) * 2012-11-09 2019-08-02 广州喜鹊医药有限公司 一种氯肟类化合物及其制备方法和在制药中的应用

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WO1990004584A1 (fr) 1988-10-20 1990-05-03 Biorex Kutató Fejleszto^' Kft. Nouveaux halogenures d'acide o-(3-amino-2-hydroxy-propyle)-hydroximique et leur procede de preparation
WO2000035914A1 (fr) 1998-12-14 2000-06-22 Biorex Kutató és Fejleszto Rt. Derive de pyridyl-4h-1,2,4-oxadiazine optiquement actif et son utilisation dans le traitement des maladies vasculaires
WO2000050403A1 (fr) 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2005041965A1 (fr) 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
WO2008070010A2 (fr) * 2006-12-01 2008-06-12 Cytrx Corporation Rétablissement après une attaque
WO2008137149A1 (fr) * 2007-05-04 2008-11-13 Cytrx Corporation Guérison des plaies diabétiques

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WO1990004584A1 (fr) 1988-10-20 1990-05-03 Biorex Kutató Fejleszto^' Kft. Nouveaux halogenures d'acide o-(3-amino-2-hydroxy-propyle)-hydroximique et leur procede de preparation
WO2000035914A1 (fr) 1998-12-14 2000-06-22 Biorex Kutató és Fejleszto Rt. Derive de pyridyl-4h-1,2,4-oxadiazine optiquement actif et son utilisation dans le traitement des maladies vasculaires
WO2000050403A1 (fr) 1999-02-26 2000-08-31 BIOREX Kutató és Fejlesztő Rt. Chlorure de n-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxyde-3-carboximidoyl et ses utilisations dans le traitement de la resistance a l'insuline
WO2005041965A1 (fr) 2003-10-30 2005-05-12 Cytrx Corporation Utilisation d'un derive d'un halogenure d'acide hydroximique pour traiter des maladies neurodegeneratives
WO2008070010A2 (fr) * 2006-12-01 2008-06-12 Cytrx Corporation Rétablissement après une attaque
WO2008137149A1 (fr) * 2007-05-04 2008-11-13 Cytrx Corporation Guérison des plaies diabétiques

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See also references of EP2356988A4

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US20110224200A1 (en) 2011-09-15
CN102215842A (zh) 2011-10-12
CA2743782A1 (fr) 2010-05-27
KR20110084514A (ko) 2011-07-25
JP2010150243A (ja) 2010-07-08
BRPI0919867A2 (pt) 2015-12-15
EP2356988A1 (fr) 2011-08-17
EP2356988A4 (fr) 2012-05-09
EA201100805A1 (ru) 2011-10-31

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