WO2010058779A1 - ピリジン-3-カルバルデヒド o-(ピペリジン-1-イル-プロピル)-オキシム誘導体を有効成分として含有する網脈絡膜変性疾患の治療剤 - Google Patents
ピリジン-3-カルバルデヒド o-(ピペリジン-1-イル-プロピル)-オキシム誘導体を有効成分として含有する網脈絡膜変性疾患の治療剤 Download PDFInfo
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- 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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- 0 *C(*)(C*1(CCCCC1)O)CO*c1c*(O)ccc1 Chemical compound *C(*)(C*1(CCCCC1)O)CO*c1c*(O)ccc1 0.000 description 2
Classifications
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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
Description
R2は水素原子又は低級アルキル基を示し;
R3はハロゲン原子、水素原子、低級アルキル基又はヒドロキシ基若しくはそのエステルを示し;
R4はハロゲン原子、水素原子、ヒドロキシ基、低級アルコキシ基、アミノ基、低級アルキルアミノ基又は低級シクロアルキルアミノ基を示し;又は
R3とR4が、窒素原子を介して一緒になって、不飽和の[1,2,4]オキサジアジン環を形成してもよく;
R5は水素原子、低級アルキル基又は低級シクロアルキル基を示し;
mは0又は1を示し;
nは0又は1を示す。以下、同じ。]
本明細書中で使用される文言(原子、基等)の定義について以下に詳しく説明する。
また、具体的には、メチルカルボニルオキシ、ヘプタデカニルカルボニルオキシ、2-クロロフェニルカルボニルオキシ、4-メトキシフェニルカルボニルオキシ、3-トリフルオロメチルカルボニルオキシ、チエニルカルボニルオキシ、フリルカルボニルオキシ基、ピリジルカルボニルオキシ基等を示す。
(a3)R2は水素原子又は低級アルキル基を示し;および/又は
(a4)R3はハロゲン原子、水素原子、低級アルキル基又はヒドロキシ基若しくはそのエステルを示し;および/又は
(a5)R4はハロゲン原子、水素原子、ヒドロキシ基、低級アルコキシ基、アミノ基、低級アルキルアミノ基又は低級シクロアルキルアミノ基を示し;又は
(a6)R3とR4が、窒素原子を介して一緒になって、不飽和の[1,2,4]オキサジアジン環を形成してもよく;および/又は
(a7)R5は水素原子、低級アルキル基又は低級シクロアルキル基を示し;および/又は
(a8)mは0又は1を示し;および/又は
(a9)nは0又は1を示す。
(b3)R2は水素原子を示し;および/又は
(b4)R3はヒドロキシ基又はそのエステルを示し;および/又は
(b5)R4はハロゲン原子を示し;又は
(b6)R3とR4が、窒素原子を介して一緒になって、不飽和の[1,2,4]オキサジアジン環を形成してもよく;および/又は
(b7)mは0を示し;および/又は
(b8)nは0又は1を示す。
(c3)R2は水素原子を示し;および/又は
(c4)R3はヒドロキシ基を示し;および/又は
(c5)R4は塩素原子を示し;又は
(c6)R3とR4が、窒素原子を介して一緒になって、5,6-ジヒドロ-4H-[1,2,4]オキサジアジン環を形成してもよく;および/又は
(c7)mは0を示し;および/又は
(c8)nは0又は1を示す。
・N-((2R)-2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-1-オキシド-3-カルボキシイミドイルクロライド(以下、「化合物B」ともいう)、
・N-(2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-3-カルボキシイミドイルクロライド(以下、「化合物C」ともいう)、又は
・(-)-5-(ピペリジン-1-イルメチル)-3-(ピリジン-3-イル)-5,6-ジヒドロ-2H-1,2,4-オキサジアジン(以下、「化合物D」ともいう)。
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のマレイン酸塩(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/又は視細胞の細胞死を誘発させたモデル動物であり、主に網脈絡膜変性疾患、例えば、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)。
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、electroretinogram(ERG)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。なお、正常対照群は、光照射を行わず、暗室にて暗順応を20時間施したあと、ERGを測定した。[式3]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、4匹(8眼)である。
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:薬物投与群の振幅(μV)
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、光照射直前に1回、経口投与した。
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。
化合物A ’を使用した時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。
以上の結果から、化合物A’に代表される本化合物は、光受容体細胞死および/又は視細胞死を抑制する。よって、本化合物は網脈絡膜変性疾患に対して予防又は改善効果を有することが示された。
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。
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及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Cの添加量を変えることにより、100mg中の含有量が0.1mg、10mg又は50mgである錠剤を調製することができる。
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及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B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)又は1%(w/w)である眼軟膏を調製することができる。
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又は50mgである注射剤を調製することができる。
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)又は1%(w/v)である点眼剤を調製することができる。
Claims (12)
- 下記一般式(1)で表される化合物又はその塩の少なくとも一つを有効成分として含有する網脈絡膜変性疾患の予防又は治療剤。
R2は水素原子又は低級アルキル基を示し;
R3はハロゲン原子、水素原子、低級アルキル基又はヒドロキシ基若しくはそのエステルを示し;
R4はハロゲン原子、水素原子、ヒドロキシ基、低級アルコキシ基、アミノ基、低級アルキルアミノ基又は低級シクロアルキルアミノ基を示し;又は
R3とR4が、窒素原子を介して一緒になって、不飽和の[1,2,4]オキサジアジン環を形成してもよく;
R5は水素原子、低級アルキル基又は低級シクロアルキル基を示し;
mは0又は1を示し;
nは0又は1を示す。] - 一般式(1)で表される化合物が、
・N-(2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-1-オキシド-3-カルボキシイミドイルクロライド、
・N-((2R)-2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-1-オキシド-3-カルボキシイミドイルクロライド、
・N-(2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-3-カルボキシイミドイルクロライド、又は
・(-)-5-(ピペリジン-1-イルメチル)-3-(ピリジン-3-イル)-5,6-ジヒドロ-2H-1,2,4-オキサジアジン
である請求項1記載の予防又は治療剤。 - 網脈絡膜変性疾患が、加齢黄斑変性、網膜色素変性症、網膜動脈閉塞症、網膜静脈閉塞症、ぶどう膜炎、レーベル病、未熟児網膜症、網膜剥離、網膜色素上皮剥離、中心性漿液性脈絡網膜症、中心性滲出性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、新生血管黄斑症、網膜動脈瘤およびこれらの疾患に伴う視神経障害である、請求項1~4のいずれか1記載の予防又は治療剤。
- 網脈絡膜変性疾患が、加齢黄斑変性又は網膜色素変性症である請求項1~4のいずれか1記載の予防又は治療剤。
- 患者に、下記一般式(1)で表される化合物又はその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、網脈絡膜変性疾患の予防又は治療方法。
R2は水素原子又は低級アルキル基を示し;
R3はハロゲン原子、水素原子、低級アルキル基又はヒドロキシ基若しくはそのエステルを示し;
R4はハロゲン原子、水素原子、ヒドロキシ基、低級アルコキシ基、アミノ基、低級アルキルアミノ基又は低級シクロアルキルアミノ基を示し;又は
R3とR4が、窒素原子を介して一緒になって、不飽和の[1,2,4]オキサジアジン環を形成してもよく;
R5は水素原子、低級アルキル基又は低級シクロアルキル基を示し;
mは0又は1を示し;
nは0又は1を示す。] - 一般式(1)で表される化合物が、
・N-(2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-1-オキシド-3-カルボキシイミドイルクロライド、
・N-((2R)-2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-1-オキシド-3-カルボキシイミドイルクロライド、
・N-(2-ヒドロキシ-3-(1-ピペリジニル)プロポキシ)-ピリジン-3-カルボキシイミドイルクロライド、又は
・(-)-5-(ピペリジン-1-イルメチル)-3-(ピリジン-3-イル)-5,6-ジヒドロ-2H-1,2,4-オキサジアジン
である請求項7記載の予防又は治療方法。 - 網脈絡膜変性疾患が、加齢黄斑変性、網膜色素変性症、網膜動脈閉塞症、網膜静脈閉塞症、ぶどう膜炎、レーベル病、未熟児網膜症、網膜剥離、網膜色素上皮剥離、中心性漿液性脈絡網膜症、中心性滲出性脈絡網膜症、ポリープ状脈絡膜血管症、多発性脈絡膜炎、新生血管黄斑症、網膜動脈瘤およびこれらの疾患に伴う視神経障害である、請求項7~10のいずれか1記載の予防又は治療方法。
- 網脈絡膜変性疾患が、加齢黄斑変性又は網膜色素変性症である請求項7~10のいずれか1記載の予防又は治療方法。
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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 |
CA2743782A CA2743782A1 (en) | 2008-11-18 | 2009-11-18 | Therapeutic agent for chorioretinal degenerative disease containing pyridine-3-carbaldehyde o-(piperidin-1-yl-propyl)-oxime derivative as active ingredient |
EP09827560A EP2356988A4 (en) | 2008-11-18 | 2009-11-18 | THERAPEUTIC FOR CHORIORETINAL DEGENERATION WITH PYRIDINE-3-CARBALDEHYDE O- (PIPERIDIN-1-YL-PROPYL) OXIM DERIVATIVE AS ACTIVE SUBSTANCE |
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 |
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 |
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US (1) | US20110224200A1 (ja) |
EP (1) | EP2356988A4 (ja) |
JP (1) | JP2010150243A (ja) |
KR (1) | KR20110084514A (ja) |
CN (1) | CN102215842A (ja) |
BR (1) | BRPI0919867A2 (ja) |
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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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-
2009
- 2009-11-18 EP EP09827560A patent/EP2356988A4/en not_active Withdrawn
- 2009-11-18 JP JP2009262416A patent/JP2010150243A/ja not_active Abandoned
- 2009-11-18 CN CN2009801459746A patent/CN102215842A/zh active Pending
- 2009-11-18 US US13/129,569 patent/US20110224200A1/en not_active Abandoned
- 2009-11-18 CA CA2743782A patent/CA2743782A1/en not_active Abandoned
- 2009-11-18 KR KR1020117010960A patent/KR20110084514A/ko not_active Application Discontinuation
- 2009-11-18 BR BRPI0919867A patent/BRPI0919867A2/pt not_active IP Right Cessation
- 2009-11-18 WO PCT/JP2009/069526 patent/WO2010058779A1/ja active Application Filing
- 2009-11-18 EA EA201100805A patent/EA201100805A1/ru unknown
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US4187220A (en) | 1977-08-30 | 1980-02-05 | Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara R.T. | New O-(3-amino-2-hydroxy-propyl)-amidoxime derivatives, process for the preparation thereof and pharmaceutical compositions containing same |
WO1990004584A1 (en) | 1988-10-20 | 1990-05-03 | Biorex Kutató Fejleszto^' Kft. | Novel o-(3-amino-2-hydroxypropyl)-hydroximic acid halides and process for preparing the same |
WO2000035914A1 (en) | 1998-12-14 | 2000-06-22 | Biorex Kutató és Fejleszto Rt. | Optically active pyridyl-4h-1,2,4-oxadiazine derivative and its use in the treatment of vascular diseases |
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BRPI0919867A2 (pt) | 2015-12-15 |
EP2356988A4 (en) | 2012-05-09 |
US20110224200A1 (en) | 2011-09-15 |
CA2743782A1 (en) | 2010-05-27 |
EA201100805A1 (ru) | 2011-10-31 |
JP2010150243A (ja) | 2010-07-08 |
EP2356988A1 (en) | 2011-08-17 |
KR20110084514A (ko) | 2011-07-25 |
CN102215842A (zh) | 2011-10-12 |
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