WO2016010130A1 - 後眼部疾患の予防または治療剤 - Google Patents
後眼部疾患の予防または治療剤 Download PDFInfo
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- WO2016010130A1 WO2016010130A1 PCT/JP2015/070477 JP2015070477W WO2016010130A1 WO 2016010130 A1 WO2016010130 A1 WO 2016010130A1 JP 2015070477 W JP2015070477 W JP 2015070477W WO 2016010130 A1 WO2016010130 A1 WO 2016010130A1
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- alkyl group
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- 0 CN(*)C(CCC1N(CCC2N(*)*)C2=O)CC1NC(*)=O Chemical compound CN(*)C(CCC1N(CCC2N(*)*)C2=O)CC1NC(*)=O 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
- A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
- A61K49/0008—Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
- A61K9/0051—Ocular inserts, ocular implants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
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- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
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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
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- A—HUMAN NECESSITIES
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- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
Definitions
- the present invention relates to 3-amino-2-oxopyrrolidine derivatives, in particular the formula (1): Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof (hereinafter also referred to as “the present compound”) as an active ingredient.
- Posterior ocular diseases generally refer to diseases in the vitreous, retina, choroid, sclera or optic nerve, and these diseases are deeply related to neovascularization.
- increased neovascularization is a major factor in pathogenesis and progression in posterior ocular diseases such as age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinal vein occlusion, and uveitis. It is known that inhibiting the activity is useful for the treatment of these diseases (Non-patent Documents 1 and 2).
- Formula (1b) Is described as having CCR-2 and CCR-5 receptor inhibitory activity, and the compound is used for the treatment of inflammatory diseases, allergic diseases, autoimmune diseases, cancer and / or cardiovascular diseases. It has been shown to be useful (Patent Document 1).
- An object of the present invention is to provide a preventive or therapeutic agent for posterior eye diseases containing a 3-amino-2-oxopyrrolidine derivative as an active ingredient.
- the inventors of the present invention conducted intensive studies to search for a preventive or therapeutic agent for posterior ocular diseases containing a 3-amino-2-oxopyrrolidine derivative as an active ingredient.
- the formula (1) And the enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof, has been found to have an excellent angiogenesis inhibitory effect and an inhibitory effect on vascular permeability enhancement in posterior eye tissues such as the retina and choroid.
- the present inventors have found that this compound has an excellent preventive or therapeutic effect on posterior ocular diseases, and have led to the present invention.
- the present invention relates to the following.
- R 1 and R 2 are the same or different and each represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom;
- R 3 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom;
- R 4 represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom;
- R 5 represents a nitrogen-containing bicyclic aromatic ring group which is unsubstituted or substituted with R 6 ;
- R 6 represents a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom.
- R 1 and R 2 are the same or different and each represents a hydrogen atom or a lower alkyl group;
- R 3 represents a hydrogen atom or a lower alkyl group;
- R 4 represents a hydrogen atom or a lower alkyl group;
- R 5 is represented by formula (2a), (2b) or (2c): Indicates;
- R 6 represents a lower alkyl group or a lower alkyl group substituted with a halogen,
- a prophylactic or therapeutic agent for posterior ocular diseases comprising a compound, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the formula (2a), (2b) or (2c) represents a point of attachment to the nitrogen atom to which R 5 is bonded.
- the compound represented by the formula (1) is Formula (1 ′): Indicated by A prophylactic or therapeutic agent for posterior ocular diseases comprising a compound, an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- R 1 represents a hydrogen atom
- R 2 represents tert-butyl
- R 3 represents methyl
- R 4 represents a hydrogen atom
- R 5 represents formula (2b): Indicates
- R 6 represents tert-butyl
- ⁇ in the formula (2b) represents a point of attachment to the nitrogen atom to which R 5 is bonded.
- an agent for preventing or treating the posterior ocular disease is a disease in the vitreous body, retina, choroid, sclera or optic nerve.
- posterior eye diseases comprising a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the posterior eye diseases are age-related macular degeneration, diabetic retinopathy, diabetic macular edema, retinitis pigmentosa, proliferative vitreoretinopathy, 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 choroiditis, neovascular macular disease, retinal artery A prophylactic or therapeutic agent that is at least one selected from the group consisting of aneurysm, retinal hemangiomas, optic neuropathy caused by
- the prevention or treatment of posterior ocular diseases comprising a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- a choroidal neovascularization inhibitor comprising as an active ingredient a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof.
- the prevention or treatment of posterior ocular diseases comprising a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient. It is a prophylactic or therapeutic agent, or an inhibitor, in which the dosage form is ophthalmic administration, intravitreal administration, subconjunctival administration, intraconjunctival sac administration, subtenon administration or oral administration.
- the prevention or treatment of posterior ocular diseases comprising a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
- the agent is a prophylactic or therapeutic agent, or an inhibitor whose dosage form is an eye drop, eye ointment, insertion agent, patch, injection, tablet, fine granule or capsule.
- the present invention also relates to the following.
- Another aspect of the present invention is a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of posterior ocular diseases.
- Another aspect of the present invention relates to a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or treatment of posterior ocular diseases. Is the use of.
- Another aspect of the present invention is the prevention of posterior ocular diseases comprising a therapeutically effective amount of a compound of formula (1) above, enantiomers or diastereomers thereof, or pharmaceutically acceptable salts and additives thereof. Or a pharmaceutical composition for treatment.
- Another aspect of the present invention is a method for the prevention or treatment of posterior ocular diseases, which is a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof. Administration of an effective amount of.
- a preventive or therapeutic agent for posterior ocular diseases comprising as an active ingredient a compound represented by the above formula (1), an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof. can do.
- Halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
- the “lower alkyl group” refers to a linear or branched alkyl group having 1 to 8 carbon atoms, preferably a linear or branched alkyl group having 1 to 6 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 and the like.
- lower alkyl group substituted with a halogen atom refers to a lower alkyl group substituted with one or more (eg, 2 or 3) halogen atoms, and the lower alkyl substituted with 3 halogen atoms Groups are preferred. Specific examples include trifluoromethyl and the like. When a plurality of halogen atoms are present, these halogen atoms may be the same or different.
- the “nitrogen-containing bicyclic aromatic ring group” refers to a bicyclic aromatic ring in which at least one of the ring atoms is a nitrogen atom, for example, 8, 9 or 10 ring atoms and An aromatic ring containing 1, 2, 3 or 4 nitrogen atoms as atoms is preferable.
- quinolinyl isoquinolinyl, cinnolinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, quinoxalinyl, quinazoline, benzotriazolyl, indolyl, indazolyl, pyrazolo [1,5-a ] [1,3,5] triazine, pyrimido [5,4-d] pyrimidine and the like.
- the compound contained in the preventive or therapeutic agent for posterior ocular diseases of the present invention can be produced according to a usual method in the field of synthetic organic chemistry. For example, it can manufacture according to the method described in the international publication 2011/046916 pamphlet.
- geometric isomers cis-trans isomers
- optical isomers enantiomers, diastereomers
- tautomers of the compound are isolated and purified by usual methods such as column chromatography and HPLC. You can also
- the compound contained in the preventive or therapeutic agent for posterior ocular diseases of the present invention has the formula (1): Or an enantiomer or diastereomer thereof, or a pharmaceutically acceptable salt thereof.
- R 1 and R 2 are the same or different and represent a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom.
- R 3 represents a hydrogen atom, a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom.
- R 4 represents a hydrogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom.
- R 5 represents a nitrogen-containing bicyclic aromatic ring group which is unsubstituted or substituted with R 6 .
- R 6 represents a halogen atom, a lower alkyl group, or a lower alkyl group substituted with a halogen atom.
- R 1 and R 2 are preferably the same or different and each is a hydrogen atom or a lower alkyl group, more preferably, R 1 is a hydrogen atom and R 2 is a lower alkyl group, Particularly preferably, R 1 is a hydrogen atom and R 2 is tert-butyl.
- R 3 is preferably a lower alkyl group, and particularly preferably methyl.
- R 4 is preferably a hydrogen atom.
- R 5 is preferably the formula (2a), (2b) or (2c): And particularly preferably the formula (2b): It is.
- the formula (2a), (2b) or (2c) represents a point of attachment to the nitrogen atom to which R 5 is bonded.
- R 6 is preferably a lower alkyl group or a lower alkyl group substituted with a halogen atom, more preferably tert-butyl or trifluoromethyl, and most preferably tert-butyl.
- the above formula (1) is preferably the formula (1 ′): It is.
- Specific examples of the compound represented by the above formula (1) or formula (1 ′) include the formula (1a): N-((1R, 2S, 5R) -2-((S) -3-((6- (tert-butyl) pyrimido [5,4-d] pyrimidin-4-yl) amino)- 2-oxopyrrolidin-1-yl) -5- (tert-butylamino) cyclohexyl) acetamide (hereinafter also referred to as “compound 1a”), its enantiomers and diastereomers, and mixtures thereof (eg, racemic mixtures, Stereo mixture etc.).
- Specific examples of the compound represented by the formula (1) or the formula (1 ′) include a formula (1b): N-((1R, 2S, 5R) -5- (tert-butylamino) -2-((S) -3- (7-tert-butylpyrazolo [1,5-a] [1,3 , 5] triazin-4-ylamino) -2-oxopyrrolidin-1-yl) cyclohexyl) acetamide (hereinafter also referred to as “compound 1b”), its enantiomers and diastereomers, and mixtures thereof (eg, racemic mixtures, A diastereomer mixture).
- Specific examples of the compound represented by the above formula (1) or formula (1 ′) include formula (1c): N-((1R, 2S, 5R) -5- (tert-butylamino) -2-((S) -2-oxo-3-((6- (trifluoromethyl) quinazoline-4- Yl) amino) pyrrolidin-1-yl) cyclohexyl) acetamide (hereinafter also referred to as “compound 1c”), its enantiomers and diastereomers, and mixtures thereof (eg, racemic mixtures, diastereo mixtures, etc.).
- the “pharmaceutically acceptable salt” of the compound represented by the above formula (1), (1 ′), (1a), (1b) or (1c) is, for example, a salt with an inorganic acid or an organic acid.
- the salt examples include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
- organic acids include acetic acid, fumaric acid, maleic acid, succinic acid, citric acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, methanesulfonic acid, lactic acid, hippuric acid, 1, 2 -Ethanedisulfonic acid, isethionic acid, lactobionic acid, oleic acid, pamoic acid, polygalacturonic acid, stearic acid, tannic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, lauryl sulfate, methyl sulfate, naphthalene Examples include sulfonic acid and sulfosalicylic acid.
- the compound represented by the above formula (1), (1 '), (1a), (1b) or (1c) may be in the form of a hydrate or a solvate.
- 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.
- the posterior segment disease is a disease in the vitreous body, retina, choroid, sclera or optic nerve.
- the posterior eye diseases include age-related macular degeneration (wet age-related macular degeneration, atrophic age-related macular degeneration, early age-related macular degeneration), diabetic retinopathy, diabetic macular edema, retinitis pigmentosa, proliferative vitreous Retinopathy, retinal artery occlusion, retinal vein occlusion, uveitis, label disease, retinopathy of prematurity, retinal detachment, retinal pigment epithelial detachment, central serous chorioretinopathy, central exudative chorioretinopathy, polyp Choroidal vasculopathy, multiple choroiditis, neovascular macular disease, retinal aneurysm, retinal hemangiomatous proliferation, optic neuropathy caused by these diseases, optic neuropathy caused by glau
- this compound When this compound is used for the treatment of posterior ocular diseases, it can be administered to patients orally or parenterally.
- oral administration topical administration to the eye (eye drops, conjunctiva)
- Intracapsular administration Intravitreal administration, subconjunctival administration, subtenon administration, etc.), intravenous administration, transdermal administration, and the like.
- an eye drop or an eye ointment is used, or an injection, particularly a subconjunctival agent, a tenon sac administration agent or an intravitreal administration agent is used. Used.
- a preparation containing the present compound as an active ingredient is formulated into a dosage form suitable for administration together with a pharmaceutically acceptable additive, if necessary.
- dosage forms suitable for oral administration include tablets, capsules, granules, powders, and the like.
- dosage forms suitable for parenteral administration include injections, eye drops, eye ointments, and patches.
- Agents, gels, intercalating agents and the like can be prepared using conventional techniques widely used in the field.
- it may be a DDS preparation such as an intraocular implant preparation or a microsphere.
- a tablet can be prepared by appropriately selecting an excipient, a disintegrant, a binder, a lubricant, a coating agent, a corrigent and the like.
- the excipient include lactose, glucose, D-mannitol, anhydrous calcium hydrogen phosphate, starch, and sucrose.
- the disintegrant include carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellose sodium, crospovidone, starch, partially pregelatinized starch, and low-substituted hydroxypropylcellulose.
- binder examples include hydroxypropyl cellulose, ethyl cellulose, gum arabic, starch, partially pregelatinized starch, polyvinyl pyrrolidone, and polyvinyl alcohol.
- lubricant examples include magnesium stearate, calcium stearate, talc, hydrous silicon dioxide, and hardened oil.
- coating agent examples include purified sucrose, hydroxypropylmethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, polyvinylpyrrolidone and the like.
- corrigent examples include citric acid, aspartame, ascorbic acid, menthol and the like.
- injections can be prepared by selecting and using isotonic agents, buffering agents, surfactants, thickeners and the like as necessary.
- isotonizing agent sodium chloride etc. are mentioned, for example.
- buffering agent include sodium phosphate.
- surfactant include polyoxyethylene sorbitan monooleate.
- thickener include methyl cellulose.
- the eye drops can be selected and used as necessary from isotonic agents, buffering agents, surfactants, stabilizers, preservatives, etc., and the pH is acceptable for ophthalmic preparations.
- isotonic agent include sodium chloride and concentrated glycerin.
- buffering agent include sodium phosphate and sodium acetate.
- surfactant include polyoxyethylene sorbitan monooleate, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil, and the like.
- stabilizer include sodium citrate and sodium edetate.
- the preservative include benzalkonium chloride and paraben.
- the eye ointment can be prepared using a commonly used base such as white petrolatum, liquid paraffin and the like.
- the intercalating agent is prepared by crushing and mixing a biodegradable polymer, for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid and the like, and compressing the powder. And an excipient, a binder, a stabilizer, and a pH adjuster can be used as necessary.
- a biodegradable polymer for example, a biodegradable polymer such as hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxyvinyl polymer, polyacrylic acid and the like.
- an excipient, a binder, a stabilizer, and a pH adjuster can be used as necessary.
- an intraocular implant preparation 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 this compound can be appropriately changed according to the dosage form, the severity of the patient's symptoms, age, weight, eye volume, doctor's judgment, etc. 0.01 to 10000 mg per day, preferably 0.1 to 5000 mg, more preferably 0.5 to 2500 mg can be administered in one or several divided doses. For adults, 0.0001 to 2000 mg can be administered once or in 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.
- 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.
- Rats were anesthetized by intramuscular administration of 1 mL / kg of a mixed solution (7: 1) of 5% (W / V) ketamine hydrochloride injection and 2% xylazine hydrochloride injection, and 0.5% (W / V) Tropicamide-0.5% phenylephrine hydrochloride ophthalmic solution was instilled to make mydriasis, and then photocoagulated with a krypton laser photocoagulator.
- Photocoagulation was performed in the posterior region of the fundus, avoiding thick retinal blood vessels, and focusing on the deep retina at 8 spots per eye (coagulation conditions: spot size 100 ⁇ m, output 100 mW, coagulation time 0.1 seconds). . After photocoagulation, fundus photography was performed to confirm the laser irradiation site.
- Compound 1b was mixed with 1% (W / V) methylcellulose solution (prepared by dissolving methylcellulose in purified water) to 20 mg / mL, and the compound 1b-containing administration solution was administered at a dose of 100 mg / kg on the day of photocoagulation surgery. Orally administered twice a day for 7 days including the day of surgery. A 1% (W / V) methylcellulose solution was similarly administered to the base administration group.
- 1% (W / V) methylcellulose solution prepared by dissolving methylcellulose in purified water
- Inhibition rate (%) ⁇ (A 0 ⁇ A X ) / A 0 ⁇ ⁇ 100
- a 0 incidence rate of choroidal neovascularization in base administration group
- a X incidence rate of choroidal neovascularization in drug administration group
- 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.
- eye drops having a concentration of 0.05% (w / v) to 1% (w / v) can be prepared.
- An eye ointment is prepared by adding this compound to uniformly melted white petrolatum and liquid paraffin, mixing them well, and gradually cooling. By changing the amount of this compound added, an eye ointment having a concentration of 0.05% (w / v) to 1% (w / w) can be prepared.
- Formulation Example 3 1 mg of this compound in 100 mg of tablets Lactose 66.4mg Corn starch 20mg Carboxymethylcellulose calcium 6mg Hydroxypropylcellulose 6mg Magnesium stearate 0.6mg
- This compound 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. Mix and compress with a tableting machine. In addition, tablets with a content of the present compound in 100 mg of 0.1 mg to 50 mg can be prepared by appropriately changing the addition amount of the present compound, carboxymethylcellulose calcium and hydroxypropylcellulose.
- an injection with a content of the present compound in 10 ml of 2 mg to 200 mg can be prepared.
- the injection prepared as described above can be administered as an injection for intraocular administration, for example, an intravitreal administration.
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Abstract
Description
で示される化合物がCCR-2およびCCR-5受容体阻害活性を有することが記載されており、当該化合物が炎症性疾患、アレルギー性疾患、自己免疫疾患、癌および/または循環器疾患の治療に有用であることが示されている(特許文献1)。
で示される化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩が、網膜や脈絡膜といった後眼部組織において優れた血管新生阻害作用および血管透過性亢進抑制作用を有することを見出し、本化合物が後眼部疾患に対して優れた予防または治療効果を有することを見出し、本発明に至った。
[式(1)中、
R1およびR2は、同一または異なって、水素原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R3は、水素原子、ハロゲン原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R4は、水素原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R5は、非置換またはR6で置換されている、含窒素二環式芳香環基を示し;
R6は、ハロゲン原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示す]
で示される化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する後眼部疾患の予防または治療剤である。
上記式(1)中、
R1およびR2が、同一または異なって、水素原子または低級アルキル基を示し;
R3が、水素原子または低級アルキル基を示し;
R4が、水素原子または低級アルキル基を示し;
R5が、式(2a)、(2b)または(2c):
を示し;
R6が、低級アルキル基またはハロゲンで置換された低級アルキル基を示す、
化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する後眼部疾患の予防または治療剤である。ここで、式(2a)、(2b)または(2c)中の・は、R5が結合する窒素原子との結合点を示す。
式(1’):
で示される、
化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する後眼部疾患の予防または治療剤である。
上記式(1)または式(1’)中、
R1が、水素原子を示し;
R2が、tert-ブチルを示し;
R3が、メチルを示し;
R4が、水素原子を示し;
R5が、式(2b):
を示し;
R6が、tert-ブチルを示す、
化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する後眼部疾患の予防または治療剤である。ここで、式(2b)中の・は、R5が結合する窒素原子との結合点を示す。
であり、特に好ましくは、式(2b):
である。ここで、式(2a)、(2b)または(2c)中の・は、R5が結合する窒素原子との結合点を示す。
で示される、N-((1R,2S,5R)-2-((S)-3-((6-(tert-ブチル)ピリミド[5,4-d]ピリミジン-4-イル)アミノ)-2-オキソピロリジン-1-イル)-5-(tert-ブチルアミノ)シクロヘキシル)アセトアミド(以下、「化合物1a」ともいう)、そのエナンチオマー及びジアステレオマー、並びにそれらの混合物(例えば、ラセミ混合物、ジアステレオ混合物など)が挙げられる。
で示される、N-((1R,2S,5R)-5-(tert-ブチルアミノ)-2-((S)-3-(7-tert-ブチルピラゾロ[1,5-a][1,3,5]トリアジン-4-イルアミノ)-2-オキソピロリジン-1-イル)シクロヘキシル)アセトアミド(以下、「化合物1b」ともいう)、そのエナンチオマー及びジアステレオマー、並びにそれらの混合物(例えば、ラセミ混合物、ジアステレオ混合物など)が挙げられる。
で示される、N-((1R,2S,5R)-5-(tert-ブチルアミノ)-2-((S)-2-オキソ-3-((6-(トリフルオロメチル)キナゾリン-4-イル)アミノ)ピロリジン-1-イル)シクロヘキシル)アセトアミド(以下、「化合物1c」ともいう)、そのエナンチオマー及びジアステレオマー、並びにそれらの混合物(例えば、ラセミ混合物、ジアステレオ混合物など)が挙げられる。
レーザー誘発ラット脈絡膜血管新生モデル(Invest. Ophthalmol. Vis. Sci., 40(2), 459-466 (1999))を用いて、本化合物の有用性を評価した。
ラットに5%(W/V)塩酸ケタミン注射液および2%塩酸キシラジン注射液の混合液(7:1)1mL/kgを筋肉内投与して全身麻酔し、0.5%(W/V)トロピカミド-0.5%塩酸フェニレフリン点眼液を点眼して散瞳させた後、クリプトンレーザー光凝固装置により光凝固を行った。光凝固は、眼底後局部において、太い網膜血管を避け、焦点を網膜深層に合わせて1眼につき8ヶ所散在状に実施した(凝固条件:スポットサイズ100μm、出力100mW、凝固時間0.1秒)。光凝固後、眼底撮影を行い、レーザー照射部位を確認した。
本薬理試験では、本化合物として、国際公開2011/046916号パンフレットに記載の合成方法に準じて合成した上記化合物1bを使用した。
化合物1bを1%(W/V)メチルセルロース液(メチルセルロースを精製水に溶解させて調製)に20mg/mLになるように混合し、100mg/kgの用量で化合物1b含有投与液を光凝固手術日より手術日を含めて7日間1日2回経口投与した。なお、基剤投与群には1%(W/V)メチルセルロース液を同様に投与した。
光凝固後7日目、ラットに5%(W/V)塩酸ケタミン注射液および2%塩酸キシラジン注射液の混合液(7:1)1mL/kgを筋肉内投与して全身麻酔し、0.5%(W/V)トロピカミド-0.5%塩酸フェニレフリン点眼液を点眼して散瞳させた後、10%フルオレセイン溶液0.1mLを陰茎静脈から注入して、蛍光眼底造影を行った。蛍光眼底造影で、蛍光漏出が認められなかったスポットを陰性(血管新生なし)、蛍光漏出が認められたスポットを陽性と判断した。また、若干の蛍光漏出が認められる光凝固部位は、それが2箇所存在した時に陽性(血管新生あり)と判定した。その後、式1に従い、レーザー照射8ヶ所のスポットに対する陽性スポット数から脈絡膜血管新生発生率(%)を算出し、式2に従い、評価薬物の抑制率(%)を算出した。化合物1bの結果を表1に示す。なお、各投与群の例数は7または8である。
脈絡膜血管新生発生率(%)=(陽性スポット数/全光凝固部位数)×100
抑制率(%)={(A0-AX)/A0}×100
A0:基剤投与群の脈絡膜血管新生発生率
AX:薬物投与群の脈絡膜血管新生発生率
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。
100mL中
本化合物 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
100g中
本化合物 0.3g
流動パラフィン 10.0g
白色ワセリン 適量
100mg中
本化合物 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
10mL中
本化合物 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
Claims (10)
- 式(1):
[式(1)中、
R1およびR2は、同一または異なって、水素原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R3は、水素原子、ハロゲン原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R4は、水素原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示し;
R5は、非置換またはR6で置換されている、含窒素二環式芳香環基を示し;
R6は、ハロゲン原子、低級アルキル基、またはハロゲン原子で置換された低級アルキル基を示す]
で示される化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する、後眼部疾患の予防または治療剤。 - 後眼部疾患が、硝子体、網膜、脈絡膜、強膜または視神経における疾患である、請求項1~4のいずれか1項記載の予防または治療剤。
- 後眼部疾患が、加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫、網膜色素変性症、増殖性硝子体網膜症、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、網膜血管腫状増殖、これらの疾患に起因する視神経障害、緑内障に起因する視神経障害および虚血性視神経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1~4のいずれか1項記載の予防または治療剤。
- 後眼部疾患が、加齢黄斑変性、糖尿病網膜症、糖尿病黄斑浮腫、網膜静脈閉塞症およびぶどう膜炎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6記載の予防または治療剤。
- 上記式(1)で示される化合物、そのエナンチオマーもしくはジアステレオマー、またはその薬学的に許容される塩を有効成分として含有する、脈絡膜血管新生阻害剤。
- 投与形態が、点眼投与、硝子体内投与、結膜下投与、結膜嚢内投与、テノン嚢下投与または経口投与である、請求項1~8のいずれか1項記載の予防もしくは治療剤、または阻害剤。
- 剤型が、点眼剤、眼軟膏、挿入剤、貼布剤、注射剤、錠剤、細粒剤またはカプセル剤である、請求項1~9のいずれか1項記載の予防もしくは治療剤、または阻害剤。
Priority Applications (10)
Application Number | Priority Date | Filing Date | Title |
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SG11201700331RA SG11201700331RA (en) | 2014-07-17 | 2015-07-17 | Prophylactic or therapeutic agent for a posterior ocular disease |
US15/326,728 US20170202845A1 (en) | 2014-07-17 | 2015-07-17 | Prophylactic or therapeutic agent for a posterior ocular disease |
BR112017000991A BR112017000991A2 (pt) | 2014-07-17 | 2015-07-17 | agente profilático ou terapêutico para uma doença ocular posterior |
EA201790231A EA201790231A1 (ru) | 2014-07-17 | 2015-07-17 | Профилактическое или терапевтическое средство для лечения болезней заднего сегмента глаза |
EP15821760.4A EP3170500A4 (en) | 2014-07-17 | 2015-07-17 | Prophylactic or therapeutic agent for diseases of posterior segment of eye |
KR1020177001365A KR20170029513A (ko) | 2014-07-17 | 2015-07-17 | 후안부 질환의 예방 또는 치료제 |
CA2955862A CA2955862A1 (en) | 2014-07-17 | 2015-07-17 | Prophylactic or therapeutic agent for a posterior ocular disease |
CN201580033445.2A CN106456641A (zh) | 2014-07-17 | 2015-07-17 | 眼后段疾病的预防或治疗剂 |
MX2017000580A MX2017000580A (es) | 2014-07-17 | 2015-07-17 | Agente profilactico o terapeutico para enfermedades del segmento posterior del ojo. |
PH12017500106A PH12017500106A1 (en) | 2014-07-17 | 2017-01-17 | Prophylactic or therapeutic agent for a posterior ocular disease |
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EP (1) | EP3170500A4 (ja) |
JP (1) | JP2016029037A (ja) |
KR (1) | KR20170029513A (ja) |
CN (1) | CN106456641A (ja) |
BR (1) | BR112017000991A2 (ja) |
CA (1) | CA2955862A1 (ja) |
EA (1) | EA201790231A1 (ja) |
MA (1) | MA40320A (ja) |
MX (1) | MX2017000580A (ja) |
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- 2015-07-17 TW TW104123160A patent/TW201625255A/zh unknown
- 2015-07-17 EA EA201790231A patent/EA201790231A1/ru unknown
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- 2015-07-17 US US15/326,728 patent/US20170202845A1/en not_active Abandoned
- 2015-07-17 KR KR1020177001365A patent/KR20170029513A/ko unknown
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